WO2006135479A2 - Anti-scarring agents, therapeutic compositions, and use thereof - Google Patents

Anti-scarring agents, therapeutic compositions, and use thereof Download PDF

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Publication number
WO2006135479A2
WO2006135479A2 PCT/US2006/013030 US2006013030W WO2006135479A2 WO 2006135479 A2 WO2006135479 A2 WO 2006135479A2 US 2006013030 W US2006013030 W US 2006013030W WO 2006135479 A2 WO2006135479 A2 WO 2006135479A2
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WO
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inhibitor
device
agent
item
anti
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PCT/US2006/013030
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French (fr)
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WO2006135479A3 (en )
Inventor
William L. Hunter
Philip M. Toleikis
David M. Gravett
Arpita Maiti
Richard T. Liggins
Aniko Takacs-Cox
Rui Avelar
Pierre E. Signore
Troy A. E. Loss
Anne Hutchinson
Gaye Mcdonald-Jones
Fara Lakhani
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Angiotech International Ag
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action

Abstract

The present invention provides devices or implants that comprise anti-scarring agents, methods or making such devices or implants, and methods of inhibiting fibrosis between the devices or implants and tissue surrounding the devices or implants. The present invention also provides compositions that comprise anti-fibrotic agents, and their uses in various medical applications including the prevention of surgical adhesions, treatment of inflammatory arthritis, treatment of scars and keloids, the treatment of vascular disease, and the prevention of cartilage loss.

Description

ANTI-SCARRING AGENTS, THERAPEUTIC COMPOSITIONS, AND USE

THEREOF

BACKGROUND OF THE INVENTION

Field of the Invention

This invention relates generally to devices and compositions that include a therapeutic agent (e.g., a fibrosis-inhibiting agent or an anti- infective agent), and to methods of making and using such compositions.

Description of the Related Art

The clinical function of numerous medical implants and devices is dependent upon the device being able to effectively maintain an anatomical, or surgically created, space or passageway. Unfortunately, many devices implanted in the body are subject to a "foreign body" response from the surrounding host tissues. In particular, injury to tubular _ anatomical structures (such as blood vessels, the gastrointestinal tract, the male and female reproductive tract, the urinary tract, sinuses, spinal nerve root canals, lacrimal ducts, Eustachian tubes, the auditory canal, and the respiratory tract) from surgery and/or injury created by the implantation of medical devices can lead to a well known clinical problem called "stenosis" (or narrowing). Stenosis occurs in response to trauma to the epithelial lining or the entire body tube during the procedure, including virtually any manipulation which attempts to relieve obstruction of the passageway, and is a major factor limiting the effectiveness of invasive treatments for a variety of diseases to be described later.

Stenosis (or "restenosis" if the problem recurs after an initially successful attempt to open a blocked passageway) is a form of response to injury leading to wall thickening, narrowing of the lumen, and loss of function in the tissue supplied by the particular passageway. Physical injury during an interventional procedure results in damage to epithelial lining of the tube and the smooth muscle cells (SMCs) that make up the wall. The damaged cells, particularly SMCs, release cytokines, which recruit inflammatory cells such as macrophages, lymphocytes and neutrophils (i.e., which are some of the known white blood cells) into the area. The white blood cells in turn release a variety of additional cytokines, growth factors, and tissue degrading enzymes that influence the behavior of the constituent cells of the wall (primarily epithelial cells and SMCs). Stimulation of the SMCs induces them to migrate into the inner aspect of the body passageway (often called the "intima"), proliferate and secrete an extracellar matrix - effectively filling all or parts of the lumen with reactive, fibrous scar tissue. Collectively, this creates a thickening of the intimal layer (known in some tissues as "neointimal hyperplasia") that narrows the lumen of the passageway and can be significant enough to obstruct its lumen.

Polymeric compositions, particularly those that include synthetic polymers or a combination of synthetic and naturally occurring polymers, have been used in a variety of medical applications, such as the prevention of surgical adhesions, tissue engineering, and as bioadhesive materials. U.S. Patent No. 5,162,430 describes the use of collagen- synthetic polymer conjugates prepared by covalently binding collagen to synthetic hydrophilic polymers such as various derivatives of polyethylene glycol. In a related patent, U.S. Patent No. 5,328,955, various activated forms of polyethylene glycol and various linkages are described, which can be used to produce collagen-synthetic polymer conjugates having a range of physical and chemical properties. U.S. Patent No. 5,324,775 also describes synthetic hydrophilic polyethylene glycol conjugates, but the conjugates involve naturally occurring polymers such as polysaccharides. EP 0732 109 A1 discloses a crosslinked biomaterial composition that is prepared using a hydrophobic crosslinking agent, or a mixture of hydrophilic and hydrophobic crosslinking agents. U.S. Patent No. 5,614,587 describes bioadhesives that comprise collagen that is crosslinked using a multifunctionally activated synthetic hydrophilic polymer. U.S. application Ser. No. 08/403,360, filed Mar. 14, 1995, discloses a composition useful in the prevention of surgical adhesions comprising a substrate material and an anti-adhesion binding agent, where the substrate material may comprise collagen and the binding agent may comprise at least one tissue-reactive functional group and at least one substrate-reactive functiona) group. U.S. application Ser. No. 08/476,825, filed Jun. 7, 1995, discloses bioadhesive compositions comprising collagen crosslinked using a multifunctionally activated synthetic hydrophilic polymer, as well as methods of using such compositions to effect adhesion between a first surface and a second surface, wherein at least one of the first and second surfaces may be a native tissue surface. U.S. Patent No. 5,874,500 describes a crosslinked polymer composition that comprises one component having multiple nucleophilic groups and another component having multiple electrophilic groups. Covalently bonding of the nucleophilic and electrophilic groups forms a three dimensional matrix that has a variety of medical uses including tissue adhesion, surface coatings for synthetic implants,, and drug delivery. More recent developments include the addition of a third component having either nucleophilic or electrophilic groups, as is described in U.S. Patent No. 6,458,889 to Trollsas et af. US 5,874,500, US 6,051,648 and US 6,312,725 disclose the in situ crosslinking or crosslinked polymers, in particular poly(ethylene glycol) based polymers, to produce a crosslinked composition. West and Hubbell, Biomaterials (1995) 16:1153-1156, disclose the prevention of post-operative adhesions using a photopolymerized polyethylene glycol-co-lactic acid diacrylate hydrogel and a physically crosslinked polyethylene glycol-co-polypropylene glycol hydrogel, POLOXAMER 407 (BASF Corporation, Mount Olive, NJ). Polymerizable cyanoacrylates have also been described for use as tissue adhesives (Ellis, et al., J. Otolaryngol. 19:68-72 (1990)). Two-part synthetic polymer compositions have been described that, when mixed together, form covalent bonds with one another, as well as with exposed tissue surfaces (PCTWO 97/22371 , which corresponds to U.S. application Ser. No. 08/769,806 U.S. Pat. No. 5,874,500).

BRIEF SUMMARY OF THE INVENTION

Briefly stated, in one aspect, the present invention provides compositions for delivery of selected therapeutic agents via medical implants or implantable medical devices, as well as methods for making and using these implants and devices. Within one aspect of the invention, drug- coated or drug-impregnated implants and medical devices are provided which reduce fibrosis in the tissue surrounding the device or implant, or inhibit scar development on the device/implant surface, thus enhancing the efficacy the procedure. Within various embodiments, fibrosis is inhibited by local or systemic release of specific pharmacological agents that become localized to the adjacent tissue.

The repair of tissues following a mechanical or surgical intervention involves two distinct processes: (1) regeneration (the replacement of injured cells by cells of the same type and (2) fibrosis (the replacement of injured cells by connective tissue). There are four general components to the process of fibrosis (or scarring) including: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells),- deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue). Within one embodiment of the invention, an implant or device is adapted to release an agent that inhibits fibrosis or regeneration through one or more of the mechanisms sited herein.

Within yet other aspects of the present invention, methods are provided for manufacturing a medical device or implant, comprising the step of coating (e.g., spraying, dipping, wrapping, or administering drug through) a medical device or implant. Additionally, the implant or medical device can be constructed so that the device itself is comprised of materials which inhibit fibrosis in or around the implant. A wide variety of medical devices and implants may be utilized within the context of the present invention, depending on the site and nature of treatment desired.

Within related aspects of the present invention, intravascular devices, gastrointestinal stents, tracheal and bronchial stents, genital urinary stents, ear and nose stents, ear ventilation tubes, intraocular implants, devices for treating hypertropic scar or keloid, vascular grafts, hemodialysis access devices, devices comprinsing a film or a mesh, glaucoma drainage devices, prosthetic heart valves or components thereof, penile implants, endotracheal or tracheostomy tubes, peritoneal dialysis catheters, central nervous system shunts or pressure monitor devices, inferior vena cava filters, gastrointestinal devices, central venous catheters, ventricular assist devices, spinal implants, implants that provide surgical adhesion barriers, and the like are provided comprising an implant or device, wherein the implant or device is in combination with an agent which inhibits fibrosis in vivo.

Within various embodiments of the invention, the implant or device is further coated with a composition or compound, which delays the onset of activity of the fibrosis-inhibiting agent for a period of time after implantation. Representative examples of such agents include heparin, PLGA/MePEG, PLA, and polyethylene glycol. Within further embodiments the fibrosis-inhibiting implant or device is activated before, during, or after deployment (e.g., an inactive agent on the device is first activated to one that reduces or inhibits an in vivo fibrotic reaction).

Within various embodiments of the invention, a device or implant is coated on one aspect, portion or surface with a composition which inhibits fibrosis, as well as being coated with a composition or compound which promotes scarring on another aspect, portion or surface of the device. Representative examples of agents that promote fibrosis and scarring include silk, wool, silica, bleomycin, neomycin, talcum powder, metallic beryllium, and copper as well as analogues and derivatives thereof. Also provided by the present invention are methods for treating patients undergoing surgical, endoscopic or minimally invasive therapies where a medical device or implant is placed as part of the procedure. As utilized herein, it should be understood that "inhibits fibrosis or stenosis" refers to a statistically significant decrease in the amount of scar tissue in or around the device or an improvement in the luminal area of the device/implant, which may or may not result in a permanent prohibition of any complications or failures of the device/implant.

The pharmaceutical agents and compositions are utilized to create novel drug-coated implants and medical devices that reduce the foreign body response to implantation and limit the growth of reactive tissue on the surface of, or around in the tissue surrounding the device, such that performance is enhanced. In many instances, the devices are used to maintain body lumens or passageways such as blood vessels, the gastrointestinal tract, the male and female reproductive tract, the urinary tract, bony foramena (e.g., sinuses, spinal nerve root canals, lacrimal ducts, Eustachian tubes, the auditory canal), and the respiratory tract, where obstruction of the device by scar tissue in the post-procedural period leads to the adverse clinical sequela or failure of the intervention. Medical devices and implants coated with selected pharmaceutical agents designed to prevent scar tissue overgrowth and preserve patency can offer significant clinical advantages over uncoated devices.

For example, in one aspect the present invention is directed to devices that comprise a medical implant and at least one of (i) an anti- scarring agent and (ii) a composition that comprises an anti-scarring agent. The agent is present so as to inhibit scarring that can otherwise occur when the implant is placed within an animal. In another aspect the present invention is directed to methods wherein both an implant and at least one of (i) an anti-scarring agent and (ii) a composition that comprises an anti- scarring agent, are placed into an animal, and the agent inhibits scarring that can otherwise occur. These and other aspects of the invention are summarized below.

Thus, in various independent aspects, the present invention provides the following: a device, comprising a medical device and an anti- scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising an intravascular device and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a a gastrointestinal stent and an anti-scarring agent or a composition comprising an anti- scarring agent, wherein the agent inhibits scarring; a device, comprising a tracheal and bronchial stent and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a genital urinary stent and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising an ear and nose stent and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising an ear ventilation tube and an anti- scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising an intraocular implant and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a medical device for treating hypertropic scar or keloid and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; device, comprising a vascular graft and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a hemodialysis access device and an anti- scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a device comprising a film or a mesh and an anti-scarring agent or a composition comprising an anti- scarring agent, wherein the agent inhibits scarring; a device, comprising glaucoma drainage device and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising prosthetic heart valve or component thereof and an anti- scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a penile implant and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising an endotracheal or tracheostomy tube and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a peritoneal dialysis catheter and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a central nervous system shunt or pressure monitor device and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising inferior vena cava filter and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a gastrointestinal device and an anti-scarring agentor a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a central venous catheter and an anti- scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a ventricular assist device and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring; a device, comprising a spinal implant and an anti-scarring agent or a composition comprising an anti- scarring agent, wherein the agent inhibits scarring; a device, comprising an implant that provides a surgical adhesion barrier and an anti-scarring agent or a composition comprising an anti-scarring agent, wherein the agent inhibits scarring. These and other devices are described in more detail herein.

In additional aspects, for each of the aforementioned devices combined with each of the anti-fibrotic agents disclosed herein, it is, for each combination, independently disclosed that the anti-fibrotic agent may be present in a composition along with a polymer. In one embodiment of this aspect, the polymer is biodegradable. In another embodiment of this aspect, the polymer is non-biodegradable. Other features and characteristics of the polymer, which may serve to describe the present invention for every combination of device and agent described above, are set forth in greater detail herein.

In addition to devices, the present invention also provides methods. For example, in additional aspects of the present invention, for each of the aforementioned devices, and for each of the aforementioned combinations of the devices with the anti-scarring agents, the present invention provides methods whereby a specified device is implanted into an animal, and a specified agent associated with the device inhibits scarring that can otherwise occur. Each of the devices identified herein may be a "specified device", and each of the anti-scarring agents identified herein may be an "anti-scarring agent", where the present invention provides, in independent embodiments, for each possible combination of the device and the agent.

The agent may be associated with the device prior to the device being placed within the animal. For example, the agent (or composition comprising the agent) may be coated onto an implant, and the resulting device then placed within the animal. In addition, or alternatively, the agent may be independently placed within the animal in the vicinity of where the device is to be, or is being, placed within the animal. For example, the agent may be sprayed or otherwise placed onto the tissue that will be contacting the medical implant or may otherwise undergo scarring. To this end, the present invention provides, in independent aspects: a method for inhibiting scarring comprising placing a medical device and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing an intravascular device and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a gastrointestinal stent and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a tracheal and bronchial stent and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a genital urinary stent and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing an ear and nose stent and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing an ear ventilation tube.and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing an intraocular implant and an anti- - scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a medical device for treating hypertropic scar or keloid and an anti-scarring agent or a composition comprising an anti- scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a vascular graft and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a hemodialysis access device and an anti- scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a medical device comprising a film or a mesh and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a glaucoma drainage device and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing prosthetic heart valve or component thereof and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a penile implant and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing an endotracheal or tracheostomy tube and an anti- scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a peritoneal dialysis catheter and an anti- scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a central nervous system shunt or pressure monitor device and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing inferioOr vena cava filter and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a gastrointestinal device and an anti- scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a central venous catheter and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a ventricular assist device and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing a spinal implant and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring; a method for inhibiting scarring comprising placing an implant that provides surgical barrier and an anti-scarring agent or a composition comprising an anti-scarring agent into an animal host, wherein the agent inhibits scarring.

In additional aspects, for each of the aforementioned methods used in combination with each of the aforementioned agents, it is, for each combination, independently disclosed that the agent may be present in a composition along with a polymer. In one embodiment of this aspect, the polymer is biodegradable. In another embodiment of this aspect, the polymer is non-biodegradable. Other features and characteristics of the polymer, which may serve to describe the present invention for every combination of device and agent described above, are set forth in greater detail herein.

In other aspects, the present invention provides compositions that contain both an anti-fibrotic agent and either a polymer or a pre- polymer, i.e., a compound that forms a polymer. In one embodiment, these compositions are formed in-situ when precursors thereof are delivered to a site in the body, or a site on an implant. For example, the compositions of the invention include the crosslinked reaction product that forms when two compounds (a multifunctional polynucleophilic compound and a multifunctional polyelectrophilic compound) are delivered to a site in a host (in other words, a patient) in the presence of an anti-fibrotic agent. However, the compositions of the invention also include a mixture of anti-fibrotic agent and a polymer, where the composition can be delivered to a site in a patient's body to achieve beneficial affects, e.g., the beneficial affects described herein.

In some instances, the polymers themselves are useful in various methods, including the prevention of surgical adhesions.

In another aspect, the present invention provides methods for treating and/or preventing surgical adhesions. The surgical adhesions can be the result of, for example, spinal or neurosurgical procedures, of gynecological procedures, of abdominal procedures, of cardiac procedures, of orthopedic procedures, of reconstructive procedures, and cosmetic procedures.

In another aspect, the present invention provides methods for treating or preventing inflammatory arthritis, such as osteoarthritis and rheumatoid arthritis. The method includes delivering to patient in need thereof an anti-fibrotic agent, optionally with a polymer.

In another aspect, the present invention provides for the prevention of cartilage loss as can occur, for example after a joint injury. The method includes delivering to the joint of the patient in need therof an anti-fibrotic agent, optionally with a polymer.

In another aspect, the present invention provides for treating hypertrophic scars and keloids. The method includes delivering to the scar or keloid of the patient in need thereof an anti-fibrotic agent, optionally with a polymer.

In another aspect, the present invention provides a method for the treatment of vascular disease, e.g., stenosis, restenosis or atherosclerosis. The method includes the perivascular delivery of an anti- fibrotic agent.

In one aspect, the present invention provides a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with i) an anti- fibrotic agent, ii) an anti-infective agent, iii) a polymer; iv) a composition comprising an anti-fibrotic agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-fibrotic agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

Optionally, in separate aspects, the invention provides: a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-fibrotic agent, and (b) implanting the medical device into the host; a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with an anti-infective agent, and (b) implanting the medical device into the host; a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a polymer; and (b) implanting the medical device into the host; a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-fibrotic agent and a polymer, and (b) implanting the medical device into the host; a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an anti-infective agent and a polymer, and (b) implanting the medical device into the host; and a method for implanting a medical device comprising: (a) infiltrating a tissue of a host where the medical device is to be, or has been, implanted with a composition comprising an.anti-fibrotic .. agent, an anti-infective agent and a polymer, and (b) implanting the medical device into the host.

In each of the aforementioned devices, compositions, methods of making the aforementioned devices or compositions, and methods of using the aforementioned devices or compostions, the present invention provides that the anti-fibrotic agent may be one or more of the following: 1) an anti-fibrotic agent that inhibits cell regeneration, 2) an anti-fibrotic agent that inhibits angiogenesis, 3) an anti-fibrotic agent that inhibits fibroblast migration, 4) an anti-fibrotic agent that inhibits fibroblast proliferation, 5) an anti-fibrotic agent that inhibits deposition of extracellular matrix, 6) an anti- fibrotic agent inhibits tissue remodeling, 7) an adensosine A2A receptor antagonist, 8) an AKT inhibitor, 9) an alpha 2 integrin antagonist, wherein the alpha 2 integrin antagonist is Pharmaprojects No. 5754 (Merck KgaA), 10) an alpha 4 integrin antagonist, 11) an alpha 7 nicotinic receptor agonist, 12) an angiogenesis inhibitor selected from the group consisting of AG- 12,958 (Pfizer), ATN-161 (Attenuon LLC), neovastat, an angiogenesis inhibitor from Jerina AG (Germany), NM-3 (Mercian), VGA-1155 (Taisho), FCE-26644 (Pfizer), FCE-26950 (Pfizer), FPMA (Meiji Daries), FR-111142 (Fujisawa), GGTI-298, GM-1306 (Ligand), GPA-1734 (Novartis), NNC-47- 0011 (Novo Nordisk), herbamycin (Nippon Kayaku), lenalidomide (Celegene), IP-10 (NIH), ABT-828 (Abbott), KIN-841 (Tokushima University, Japan), SF-1126 (Semafore Pharmaceuticals), laminin technology (NIH), CHIR-258 (Chiron), NVP-AEW541 (Novartis), NVP-AEW541 (Novartis), Vt16907 (Alchemia), OXI-8007 (Oxigene), EG-3306 (Ark Therapeutics), Maspin (Arriva), ABT-567 (Abbott), PPI-2458 (Praecis Pharmaceuticals), CC-5079, CC-4089 (Celgene), HIF-1 alpha inhibitors (Xenova), S-247 (Pfizer), AP-23573 (Ariad), AZD-9935 (Astra Zeneca), mebendazole (Introgen Therapeutics), MetAP-2 inhibitors (GlaxoSmithKline), AG-615 (Angiogene Pharmaceuticals), Tie-2 antagonists (Hybrigenics), NC-381 , CYC-381, NC-169, NC-219, NC-383, NC-384, NC-407 (Lorus Therapeutics), ATN-224 (Attenuon), ON-01370 (Onconova), Vitronectin antagonists (Amgen), SDX-103 (Salmedix), Vitronectin antagonists (Shire), CHP (Riemser), TEK (Amgen), Anecortave acetate (Alcon), T46.2 (Matrix Therapeutics), HG-2 (Heptagen), TEM antagonists (Genzyme), Oxi-4500 (Oxigene), ATN-161 (Attenuon), WX-293 (Wilex), M-2025 (Metris Therapeutics), Alphastatin (BioActa), YH-16 (Yantai Rongchang), BIBF- 1120 (Boehringer Ingelheim), BAY-57-9352 (Bayer), AS-1404 (Cancer Research Technology), SC-77964 (Pfizer), glycomimetics (BioTie Therapies), TIE-2 Inhibitors (Ontogen), DIMI, Octamer (Octamer), ABR- 215050 (Active Biotech), ABT-518 (Abbott), KDR inhibitors (Abbott), BSF- 466895 (Abbott), SCH-221153 (Schering-Plough), DAC:antiangiogenic (ConjuChem), TFPI (EntreMed), AZD-2171 (Astra-Zenaca), CDC-394 (Celgene), LY290293 (EIi Lilly), IDN-5390 (Indena), Kdr Kinase Inhibitors (Merck), CT-113020, CT-116433, CT-116563, CT-31890, CT-32228) (Cell Therapeutics), A-299620 (Abbott), TWEAK Inhibitor (Amgen), VEGF modulators (Johnson and Johnson), Tum-N53, tumstatin (Genzyme), Thios- 1 , Thios-2 (Thios Pharmaceuticals), MV-6401 (Miravant Medical Technologies), Spisulosine (PharmaMar), CEP-7055 (Cephalon), AUV-201 (Auvation), LM-609 (EIi Lilly), SKF-106615 (AnorMED), Oglufanide disodium (Cytran), BW-114 (Pharminox), Calreticulin (NIH), WX-678 (Wilex), SD-7784 (Pfizer), WX-UK1 (Wilex), SH-268 (Schering AG), 2-Me-PGA (Celgene), S- 137 (Pfizer), ZD-6126 (Angiogene Pharmaceuticals), SG-292 (SignalGen), Benefin (Lane Labs), A6, A36 (Angstrom), SB-2723005 (GlaxoSmithKline), SC-7 (Cell Therapeutics), ZEN-014 (AEterna Zentaris), 2-methoxyestradiol (EntreMed), NK-130119 (Nippon Kayaku), CC-10004 (Celgene), AVE- 8062A (Ajinomoto), Tacedinaline (Pfizer), Actinonin (Tokyo Metropolitan Institute of Medical Science), Lenalidomide (Celgene), VGA-1155, BTO-956 (SRI International), ER-68203-00 (Eisai), CT-6685 (UCB), JKC-362 (Phoenix Pharmaceuticals), DMI-3798 (DMI Biosciences, Angiomate (Ipsen), ZD-6474 (AstraZeneca), CEP-5214 (Cephalon), Canstatin (Genzyme), NM-3 (Mercian), Oridigm (MediQuest Therapeutics), Exherin (Adherex), BLS-0597 (Boston Life Sciences), PTC-299 (PTC Therapeutics), NPI-2358 (Nereus Pharmaceuticals), CGP-79787 (Novartis), AEE-788 (Novartis), CKD-732 (Chong Kun Dang), CP-564959 (OSI Pharmaceuticals), CM-101 (CarboMed), CT-2584, CT3501 (Cell Therapeutics), combretastatin and analogues and derivatives thereof (Oxigene), Rebimastat (Bristol-Meyers Squibb), Dextrin 2-sulfate (ML Laboratories), Cilengitide (Merk KGaA), NSC-706704 (Pharminox), KRN- 951 (Kirin Brewery), Ukrain, NSC-631570 (Nowicky Pharma), Tecogalan sodium (Daiichi Pharmaceutical), Tz-93 (Tsumura), TBC-1635 (Encysive Pharmaceuticals), TAN-1120 (Takeda), Semaxanib (Pfizer), BDI-7800 (Biopharmacopae), SD-186, SD-983 (Bristol-Meyers Squibb), SB-223245 (GlaxoSmithKline), SC-236 (Pfizer), RWJ-590973 (Johnson and Johnson), ILX-1850 (Genzyme), SC-68488, S-836 (Pfizer), CG-55069-11 (CuraGen), Ki-23057 (Kirin Brewery), CCX-700 (Chemoentryx), Pegaptanib octasodium (Giled Sciences), ANGIOCOL (available from Biostratum Inc.), or an analogue or derivative thereof, 13) an apoptosis antagonist, 14) an apoptosis activator, 15) a beta 1 integrin antagonist, 16) a beta tubulin inhibitor, 17) a blocker of enzyme production in Hepatitis C, 18) a Bruton's tyrosine kinase inhibitor, 19) a calcineurin inhibitor, 20) a caspase 3 inhibitor, 21) a CC chemokine receptor antagonist, 22) a cell cycle inhibitor selected from the group consisting of SNS-595 (Sunesis), synthadotin, KRX- 0403, homoharringtonine, and an analogue or derivative thereof, 23) a cathepsin B inhibitor, 24) a cathepsin K inhibitor, wherein the cathepsin K inhibitor is 462795 (GlaxoSmithKline), INPL-022-D6 (Amura Therapeutics), or an analogue or derivative thereof, 25) a cathepsin L inhibitor, 26) a CD40 antagonist, 27) a chemokine receptor agonist, 28) a chymase inhibitor, 29) a collagenase antagonist, 30) a CXCR antagonist, 31) a cyclin dependent kinase inhibitor selected from the group consisting of a CDK-1 inhibitor, a CDK-2 inhibitor, a CDK- 4 inhibitor, a CDK-6 inhibitor, a CAK1 inhibitor from GPC Biotech and Bristol-Myers Squibb, RGB-286199 (GPC Biotech), an anticancer agent from Astex Technology, a CAK1 inhibitor from GPC Biotech, a CDK inhibitor from Sanofi-Aventis, a CDK1/CDK2 inhibitor from Amgen, a CDK2 inhibitor from SUGEN-2 (Pfizer), a hearing loss therapy agent (Sound Pharmaceuticals), PD-0332991 (Pfizer), RGB-286199 (GPC Biotech), Ro-0505124 (Hoffmann-La Roche), a Ser/Thr kinase inhibitor from Lilly (EIi Lilly), CVT-2584 (CAS No. 199986-75-9) (CV Therapeutics), CGP 74514A, bohemine, olomoucine (CAS No. 101622-51-9), indole-3-carbinol (CAS No. 700-06-1), and an analogue or derivative thereof, 32) a cyclooxygenase 1 inhibitor, 33) a DHFR inhibitor, 34) a dual integrin inhibitor, 35) an elastase inhibitor, 36) an elongation factor-1 alpha inhibitor, 37) an endothelial growth factor antagonist, 38) an endothelial growth factor receptor kinase inhibitor selected from the group consisting of sorafenib tosylate (Bayer), AAL-993 (Novartis), ABP-309 (Novartis), BAY-57-9352 (Bayer), BIBF-1120 (Boehringer Ingelheim), E-7080 (Eisai), EG-3306 (Ark Therapeutics), EXEL-2880 (Exelixis), GW-654652 (GlaxoSmithKline), lavendustin A (CAS No. 125697-92-9), a KDR inhibitor from LG Life Sciences, CT-6685 and CT-6729 (UCB), KRN-633 and KRN-951 (Kirin Brewery), OSI-930 (OSI Pharmaceuticals), SP-5.2 (Supratek Pharma), SU- 11657 (Pfizer), a Tie-2 antagonist (Hybrigenics), SU 1498 (a VEGF-R inhibitor), a VEGFR-2 kinase inhibitor (Bristol-Myers Squibb), XL-647 (Exelixis), a KDR inhibitor from Abbott Laboratories, sorafenib tosylate, and an analogue or derivative thereof, 39) an endotoxin antagonist, 40) an epothilone and tubulin binder, 41) an estrogen receptor antagonist, 42) an FGF inhibitor, 43) a famexyl transferase inhibitor, 44) a farnesyltransferase inhibitor selected from the group of A-197574 (Abbott), a farnesyltransferase inhibitor from Servier, FPTIII (Strathclyde Institute for Drug R), LB-42908 (LG Life Sciences), Pharmaprojects No. 5063 (Genzyme), Pharmaprojects No. 5597 (Ipsen), Yissum Project No. B-1055 (Yissum), and an analogue or derivative thereof, 45) an FLT-3 kinase inhibitor, 46a) an FGF receptor kinase inhibitor, 47) a fibrinogen antagonist selected from the group consisting of AUV-201 (Auvation), MG-13926 (Sanofi-Aventis), plasminogen activator (CAS No. 105913-11-9) (from Sanofi-Aventis or UCB), plasminogen activator-2 (tPA-2) (Sanofi-Aventis), pro-urokinase (CAS Np. 82657-92-9) (Sanofi-Aventis), mevastatin, and an analogue or derivative thereof, 48) a heat shock protein 90 antagonist selected from the group consisting of SRN-005 (Sirenade), geldanamycin, NSC-33050 (17- allylaminogeldanamycin; 17-AAG), 17-dimethylaminoethylamino~17- demethoxy-geldanamycin (17-DMAG), rifabutin (rifamycin XIV, 1',4- didehydro-1-deoxy-1 ,4-dihydro-5'-(2-methylpropyl)-1-oxo-), radicicol from Humicola fuscoatra (CAS No. 12772-57-5), and an analogue or derivative thereof, 49) a histone deacetylase inhibitor, 50) an HMGCoA reductase inhibitor selected from the group consisting of an atherosclerosis therapeutic from Lipid Sciences, ATI-16000 (ARYx Therapeutics), KS-01-019 (Kos Pharmaceuticals), Pharmaprojects No. 2197 (Sanofi-Aventi), RP 61969 (Sanofi-Aventis), cerivastatin Na (CAS No. 143201-11-0), and an analogue or derivative thereof, 51) an ICAM inhibitor, 52) an IL, ICE and IRAK antagonist, wherein the antagonist is a CJ-14877, CP-424174 (Pfizer), NF- 61 (Negma-Lerads), and an analogue or derivative thereof, 53) an IL-2 inhibitor, 54) an immunosuppressant selected from the group consisting of teriflunomide (Sanofi Aventis), chlorsulfaquinoxalone (NSC-339004), chlorsulfaquinoxalone sulfate, CS-712 (Sankyo), ismomultin alfa (CAS No. 457913-93-8) (Akzo Nobel), antiallergics from GenPat77, antiinflammatories or AT-005 (Androclus Therapeutics), autoimmune disease therapeutics from EpiVax, BN-007 (Bone), budesonide (CAS No. 51333-22- 3) (MAP Pharmaceuticals), CO-14 (Genzyme), edratide (CAS No. 433922- 67-9) (Teva), EP-314 (Enanta), eprovafen (CAS No. 101335-99-3) (Sanofi- Aventis), HWA-131 (CAS No. 118788-41-3) (Sanofi-Aventis), immunomodulators from MerLion Pharmaceuticals, immunosuppressives from Alchemia, IPL-12 (Inflazyme), MDL-9563 (CAS No. 27086-86-8) (Sanofi-Aventis), Pharmaprojects No. 2330 (Sanofi-Aventis), Pharmaprojects No. 6426 (Abgenix), PXS-25 (Pharmaxis), rosmarinic acid (CAS No. 20283-92-5) (Sanofi-Aventis), RP 42927 or RP 54745 (CAS No. 135330-08-4) (Sanofi-Aventis), SGN-35 (Seattle Genetics), ST-1959 (Sigma-Tau), type I diabetes therapy from SYNX Pharma, U NIL-88 (Debiopharm), VP-025 (Vasogen), VR-694 (Vectura), PRTX-001 (Protalex), and an analogue or derivative thereof, 55) an IMPDH (inosine monophosphate), 56) an integrin antagonist, 57) an interleukin antagonist, 58) an inhibitor of type III receptor tyrosine kinase, 59) an irreversible inhibitor of enzyme methionine aminopeptidase type 2, 60) an isozyme selective delta protein kinase C inhibitor, 61) a JAK3 enzyme inhibitor, 62) a JNK inhibitor, 63) a kinase inhibitor, 64) a kinesin antagonist, 65) a leukotriene inhibitor and antagonist selected from the group consisting of ambicromil (CAS No. 58805-38-2) (Sanofi-Aventis), amelubant (CAS No. 346735-24-8) (Boehringer Ingelheim), DW-1141 (Dong Wha), ebselen (Daiichi Pharmaceutical), ibudilast (Kyorin), leucotriene inhibitors from Sanofi-Aventis, lymphotoxin-beta receptor (LT-β) from Biogen Idee, Pharmaprojects No. 1535 and 2728 (CAS No. 119340-33-9) (Sanofi- Aventis), R-112 (Rigel), Rev-5367 (CAS No. 92532-05-3) (Sanofi-Aventis), RG-14893 (CAS No. 141835-49-6) (Sanofi-Aventis), RG-5901-A (CAS No. 101910-24-1), 92532-23-5, RP 66153 (CAS No. 142422-79-5), RP 66364 (CAS No.186912-92-5), RP 69698 (CAS No. 141748-00-7) (Sanofi-Aventis), SC-411930 (Pfizer), SC-41930 (CAS No. 120072-59-5) (Pfizer), SC-50605 (CAS No. 138828-39-4) (Pfizer), SC-51146 (CAS No. 141059-52-1), SC- 53228 (CAS No. 153633-01-3) (Pfizer), spaglumic acid (ZY-15106) (CAS No.3106-85-2), 80619-64-3 (Novartis), tipredane (CAS No. 85197-77-9) (Bristol-Myers Squibb), U-75302 (CAS No. 119477-85-9) (Pfizer), and analogue or derivative thereof, 66) a MAP kinase inhibitor, 67) a matrix metalloproteinase inhibitor, 68) an MCP-CCR2 inhibitor, 69) an mTOR inhibitor, 70) an mTOR kinase inhibitor,71) a microtubule inhibitor selected from the group consisting of antibody-maytansinoid conjugates from Biogen Idee, colchicines (MantiCore Pharmaceuticals), anticancer immunoconjugates from Johnson & Johnson, DIME from Octamer, gni-1f (GNI), huC242-DM4, huMy9-6-DM1 (ImmunoGen), IDN-5404 (Indena), IMO-098, IMOderm (Imotep), mebendazole (Introgen Therapeutics), microtubule poisons from Cambridge Enterprise, paclitaxel such as LOTAX from Aphios (CAS No. 33069-62-4), Genexol-PM from Samyang, Pharmaprojects No. 6383 (Tapestry Pharmaceuticals), RPR-112378 (Sanofi-Aventis), SGN-75 (Seattle Genetics), SPL-7435 (Starpharma), SSR- 250411 (Sanofi-Aventis), trastuzumab-DM1 (Genentech), vinorelbine, dolastatin 15 (CAS No. 123884-00-4), vincamine, and an analogue or derivative thereof, 72) an MIF inhibitor, 73) an MMP inhibitor, 74) a neurokinin (NK) antagonist selected from the group consisting of anthrotainin (CAS No. 148084-40-6) (Sanofi-Aventis), an IBS thereapeutic from ArQuIe, MDL-105212A (CAS No. 167261-60-1) (Ssanofi-Aventis), Pharmaprojects No. 2744, 3258 (CAS No. 139167-47-8) 4006, 4201, or 5986 (Sanofi-Aventis), RP 67580 (CAS No. 135911-02-3), SR-144190 (CAS No. 201152-86-5), SSR-240600, SSR-241586 (Sanofi-Aventis), TKA-457 (Novartis), vestipitant mesylate (CAS No. 334476-64-1) (GlaxoSmithKline), Win-64821 (Sanofi-Aventis), PRX-96026 (Predix Pharmaceuticals), and an analogue or derivative thereof, 75) an NF kappa B inhibitor selected from the group consisting of emodin (CAS No. 518-82-1), AVE-0545 or AVE- 0547 (Sanofi-Aventis), bortezomib (CAS No. 179324-69-7) (Millennium Pharmaceuticals), dexanabinol (CAS No. 112924-45-5) (Pharmos), dexlipotam (Viatris), Pharmaprojects No. 6283 (INDRA) (OXiGENE), IPL- 576092 (CAS No. 137571-30-3) (\nf\azyme), NFKB decoy (Corgentech), NFKB decoy oligo (AnGes MG), NFKB's from Ariad, osteoporosis treatments or S5 (F005) from Fulcrum Pharmaceuticals, P61 (Phytopharm), R-flurbiprofen (CAS No. 5104-49-4) (Encore Pharmaceuticals), Bay 11- 7085, and an analogue or derivative thereof, 76) a nitric oxide agonist, 77) an ornithine decarboxylase inhibitor, 78) a p38 MAP kinase inhibitor selected from the group consisting of AZD-6703 (AstraZeneca), JX-401 (Jexys Pharmaceuticals), BMS-2 (Bristol-Myers Squibb), a p38 MAP kinase inhibitor from Novartis, a p38-alpha MAP kinase inhibitor from Amphora, Pharmaprojects No. 5704 (Pharmacopeia), SKF86002 (CAS No. 72873-74- 6), RPR-200765A (Sanofi-Aventis), SD-282 (Johnson & Johnson), TAK-715 (Takeda), and an analogue or derivative thereof, 79) a palmitoyl-protein thioesterase inhibitor, 80) a PDGF receptor kinase inhibitor selected from the group consisting of AAL-993, AMN-107, or ABP-309 (Novartis), AMG- 706 (Amgen), BAY-57-9352 (Bayer), CDP-860 (UCB), E-7080 (Eisai), imatinib (CAS No. 152459-95-5) (Novartis), OSI-930 (OSI Pharmaceuticals), RPR-127963E (Sanofi-Aventis), RWJ-540973 (Johnson & Johnson), sorafenib tosylate (Bayer), SlM 1657 (Pfizer), tandutinib (CAS No. 387867- 13-2) (Millennium Pharmaceuticals), vatalanib (Novartis), ZK-CDK (Schering AG), and an analogue or derivative thereof, 81) a peroxisome proliferators- activated receptor agonist selected from the group consisting of (-)- halofenate (Metabolex), AMG-131 (Amgen), antidiabetics from Japan Tobacco, AZD-4619, AZD-8450, AZD-8677 (AstraZeneca), DRF-10945, balaglitazone (Dr Reddy's), CS-00088, CS-00098 (Chipscreen Biosciences), E-3030 (Eisai), etalocib (CAS No. 161172-51-6) (EIi Lilly), GSK-641597 (Ligand), GSK-677954 (GlaxoSmithKline), GW-409544 (Ligand), GW- 590735 (GlaxoSmithKline), K-111 (Hoffmann-La Roche), LY-518674 (EIi Lilly), LY-674 (Ligand), LY-929 (Ligand), MC-3001 , MC-3002 (MaxoCore Pharmaceuticals), metformin HCI + pioglitazone (CAS No. 1115-70-4 and 112529-15-4), ACTOPLUS MET from Andrx), muraglitazar (CAS No. 331741-94-7) (Bristol-Myers Squibb), naveglitazar (Ligand), oleoylethanolamide (Kadmus Pharmaceuticals), ONO-5129, pioglitazone hydrochloride (CAS No. 111025-46-8 and 112529-15-4) (Takeda), PLX-204 (Plexxikon), PPAR agonists from Genfit, PPAR delta agonists from EIi Lilly, PPAR-alpha agonists from CrystalGenomics, PPAR-gamma modulators and PPAR-β modulators from CareX, rosiglitazone maleate (CAS No. 122320- 73-4 or 155141-29-0) (GlaxoSmithKline), rosiglitazone maleate/glimepir (CAS No. 155141-29-0 and 93479-97-1), AVANDARYL, rosiglitazone maleate/metformin extend (CAS No. 155141-29-0 and 657-24-9), AVANDAMET, rosiglitazone maleate+metformin, AVANDAMET (GlaxoSmithKline), tesaglitazar (AstraZeneca), LBM642, WY-14,643 (CAS No. 50892-23-4), GW7647, fenofibric acid (CAS No. 42017-89-0), MCC-555 (CAS No. 161600-01-7), GW9662, GW1929, GW501516, L-165,041 (CAS No. 79558-09-1), and an analogue or derivative thereof, 82) a phosphatase inhibitor, 83) a phosphodiesterase (PDE) inhibitor selected from the group consisting of avanafil (Tanabe Seiyaku), dasantafil (CAS No. 569351-91-3) (Schering-Plough), A-906119 (CAS No. 134072-58-5), DL-850 (Sanofi- Aventis), GRC-3015, GRC-3566, GRC-3886 (Glenmark), HWA-153 (CAS No. 56395-66-5) (Sanofi-Aventis), hydroxypumafentrine (Altana), IBFB- 130011 , IBFB-14-016, IBFB-140301 , IBFB-150007, IBFB-211913 (IBFB Pharma), L-826141 (Merck & Co), medorinone (CAS No. 88296-61-1) (Sanofi-Aventis), MEM-1917 (Memory Pharmaceuticals), ND-1251 (Neuro3d), PDE inhibitors from ICOS, PDE IV inhibitors from Memory Pharmaceuticals and CrystalGenomics, Pharmaprojects No. 2742 and 6141 (Sanofi-Aventis), QAD-171 (Novartis), RHC-2963 (CAS No. 76993-12-9 and 76993-14-1), RPR-117658, RPR-122818 derivatives, SR-24870 , and RPR- 132294 (Sanofi-Aventis), SK-350 (ln2Gen), stroke therapy agents from deCODE Genetics, TAS-203 (Taiho), tofimilast (CAS No. 185954-27-2) (Pfizer), UK-371800 (Pfizer), WIN-65579 (CAS No. 158020-82-7) (Sanofi- Aventis), IBFB-130020 (IBFB Pharma), OPC-6535 (CAS No. 145739-56-6) (Otsuka), theobromine (CAS No. 83-67-0), papverine hydrochloride (CAS No. 61-25-6), quercetin dehydrate (CAS No. 6151-25-3), YM 976 (CAS No. 191219-80-4), irsogladine (CAS No. 57381-26-7), a phosphodiesterase 111 inhibitor, enoximone, a phosphodiesterase IV inhibitor, fosfosal, Atopik (Barrier Therapeutics), triflusal, a phosphodiesterase V inhibitor, and an analogue or derivative thereof, 84) a PKC inhibitor, 85) a platelet activating factor antagonist, 86) a platelet-derived growth factor receptor kinase inhibitor, 87) a prolyl hydroxylase inhibitor, 88) a polymorphonuclear neutrophil inhibitor, 89) a protein kinase B inhibitor, 90) a protein kinase C stimulant, 91) a purine nucleoside analogue, 92) a purinoreceptor P2X antagonist, 93) a Raf kinase inhibitor, 94) a reversible inhibitor of ErbB1 and ErbB2, 95) a ribonucleoside triphosphate reductase inhibitor, 96) an SDF-1 antagonist, 97) a sheddase inhibitor, 98) an SRC inhibitor, 99) a stromelysin inhibitor, 100) an Syk kinase inhibitor, 101) a telomerase inhibitor, 102) a TGF beta inhibitor selected from the group consisting of pirfenidone (CAS No. 53179-13-8) (MARNAC), tranilast (CAS No. 53902-12-8) (Kissei), IN- 1130 (ln2Gen), mannose-6-phosphate (BTG), TGF-β antagonists from Inflazyme (Pharmaprojects No. 6075), TGF-β antagonists from Sydney, non-industrial source), TGF-β I receptor kinase inhibitors from EIi Lilly, TGF- β receptor inhibitors from Johnson & Johnson, and an analogue or derivative thereof, 103) a TNFα antagonist or TACE inhibitor selected from the group consisting of adalimumab (CAS No. 331731-18-1) (Cambridge Antibody Technology), AGIX-4207 (AtheroGenics), AGT-1 (Advanced Biotherapy), an anti-inflammatory from Borean Pharma, Cellzome, or Paradigm Therapeutics, anti-inflammatory vaccine (TNF-alpha kinoid) from Neovacs, humanized anti-TNF antibody or an anti-TNF MAb (CB0006) Celltech (UCB)1 apratastat (CAS No. 287405-51-0) (Wyeth), BMS-561392 (Bristol-Myers Squibb), BN-006 (Bone), certolizumab pegol (CAS No. 428863-50-7 or CH-138 (UCB), cilomilast (CAS No. 153259-65-5) (GlaxoSmithKline), CR-1 (Nuada Pharmaceuticals), CRx-119 (CombinatoRx), D-5410 (UCB), dacopafant (CAS No. 125372-33-0) (Sanofi- Aventis), dersalazine (CAS No. 188913-57-7/188913-58-8) (Uriach), etanercept (CAS No. 185243-69-0) (Amgen), ethyl pyruvate (Critical (Critical Therapeutics), golimumab (CAS No. 476181-74-5) (Johnson & Johnson), hormono-immunotherapy from Ipsen, CDP571 {e.g., Humicade from UCB), IC-485 (ICOS), infliximab (CAS No. 170277-31-3) (Johnson & Johnson), IP- 751 (Manhattan Pharmaceuticals), ISIS-104838 (CAS No. 250755-32-9) (ISIS Pharmaceuticals), lenalidomide (CAS No. 191732-72-6) (Celgene), lentinan (CAS No. 37339-90-5) (Ajinomoto), MDL-201112 (CAS No. 142130-73-2) (Sanofi-Aventis), medroxyprogesterone (CAS No. 520-85-4) (InKine Pharmaceutical), N-acetylcysteine (CAS No. 616-91-1) (Zambon), NBE-P2 (DIREVO Biotech), nerelimomab (CAS No. 162774-06-3) (Chiron), OM-294DP (OM PHARMA), onercept (CAS No. 199685-57-9) (Yeda), PASSTNF-alpha (Verigen), pentoxifylline or oxypentifylline (Sanofi-Aventis), Pharmaprojects No. 4091 , 4241 , 4295, or 4488 (Sanofi-Aventis), Pharmaprojects No. 5480 (Amgen), Pharmaprojects No. 6749 (Cengent), pirfenidone (CAS No. 53179-13-8) (MARNAC), RPR-132294 (Sanofi- Aventis), S5 (F002) (Fulcrum Pharmaceuticals), simvastatin (CAS No. 79902-63-9) (Merck & Co), STA-6292 (Synta Pharmaceuticals), tacrolimus (CAS No. 104987-11-3) (Fujisawa LifeCycle Pharma), talactoferrin alfa (CAS No. 308240-58-6) (Agennix), thalidomide (CAS No. 50-35-1) (Celgene), TNF antagonists form ProStrakan, and Synergen, TNF inhibitors (Amgen), TNF-alpha antagonists from Dynavax Technologies and Jerina AG (Germany), TNF-alpha inhibitors from IBFB Pharma and Xencor (Xencor), torbafylline (CAS No. 105102-21-4) (Sanofi-Aventis), UR-1505 (Uriach), VT-346 (Viron Therapeutics), YSIL6 (Y's Therapeutics), YSTH2 (Y's Therapeutics), NPI-1302a-3 (Nereus Pharmaceuticals, a TNF antagonist from Jerina AG (Germany), dersalazine, and an analogue or derivative thereof, 104) a tumor necrosis factor antagonist, 105) a Toll receptor inhibitor, 106) a tubulin antagonist, 107) a tyrosine kinase inhibitor selected from the group consisting of SU-011248, SUTENT from Pfizer Inc. (New York, NY), BMS-354825, PN-355 (Paracelsian Pharmaceuticals), AGN-199659 (Allergan), AAL-993 or ABP-309 (Novartis), adaphostin (NIH), AEE-788 (Novartis), AG-013736 (OSI Pharmaceuticals), AG-13736 (Pfizer), ALT-110 (Alteris Therapeutics), AMG-706 (Amgen), anticancer MAbs from Xencor, anti-EGFrvlll MAbs from Abgenix, anti-HER2 MAb from Abiogen, AZD-2171 or AZD-9935 (AstraZeneca), BAY-57-9352 (Bayer), BIBF-1120 (Boehringer Ingelheim), CEP-5214 (Cephalon), CEP-7055 (Cephalon), cetuximab (ImClone Systems), CHIR-200131 and CHIR-258 (Chiron), CP- 547632 (OSI Pharmaceuticals), CP-724714 (Pfizer), CT-301 (Creabilis Therapeutics), D-69491 (Baxter International), E-7080 (Eisai), EG-3306 (Ark Therapeutics), EGFR/ErbB2 inhibitors from Array BioPharma, erlotinib (CAS No. 183319-69-9) (OSI Pharmaceuticals), EXEL-2880 (Exelixis), FK-778 (Sanofi-Aventis) , gefitinib (CAS No. 184475-35-2) (AstraZeneca), GW-2286 or GW-654652 (GlaxoSmithKline), her2/neu antigen from AlphaVax, HER- 2/neu inhibitor from Generex, Herzyme (Medipad) (Sirna Therapeutics), HKI-272 (Wyeth), HuMax-EGFr (Genmab), idronoxil (CAS No. 81267-65-4) (Novogen), IGF-1 inhibitors from Ontogen, IMC-11F8 (ImClone Systems), kahalalide F (CAS No. 149204-42-2) (PharmaMar), KDR inhibitor from LG Life Sciences, KDR inhibitors from Abbott Laboratories, KDR kinase inhibitors (UCB), Kdr kinase inhibitors from Merck & Co, KRN-633 and KRN- 951 (Kirin Brewery), KSB-102 (Xenova), lapatinib ditosylate (CAS No. 388082-78-8) (GlaxoSmithKline), matuzumab (Merck KGaA), MDX-214 (Medarex), ME-103 (Pharmexa), MED-A300 (Gerolymatos), MNAC-13 (Lay Line Genomics), nimotuzumab (Center of Molecular Immunology), NSC- 330507 or NSC-707545 (NIH), NV-50 (Novogen), OSI-930 (OSI Pharmaceuticals), panitumumab (Abgenix), pelitinib (CAS No. 287933-82-7) (Wyeth), pertuzumab (CAS No. 380610-27-5) (Genentech), Pharmaprojects No. 3985 (Sanofi-Aventis), prostate cancer therapeutics from Sequenom (SQPC35, SQPC36, SQPC90), removab and remoxab (Trion Pharma), RG- 13022 (CAS No. 136831-48-6), RG-13291 (CAS No. 138989-50-1), or RG- 14620 (CAS No. 136831-49-7) (Sanofi-Aventis), RM-6427 (Romark), RNAi breast cancer therapy from Benitec, RP 53801 (CAS No. 125882-88-4) (Sanofi-Aventis), sorafenib tosylate (Bayer), SU-11657 (Pfizer), Tie-2 antagonists from Semaia (Hybrigenics), Tie-2 inhibitors from Ontogen, trastuzumab (CAS No. 180288-69-1) (Genentech), tyrosine kinase inhibitors from Sanofi-Aventis, U3-1287, U3-1565, U3-1784, U3-1800 (U3 Pharma), vatalanib (Novartis), VEGFR-2 kinase inhibitor from Bristol-Myers Squibb, XL-647 (Exelixis), ZD-6474 (AstraZeneca), ZK-CDK (Schering AG), an EGFR tyrosine kinase inhibitor, EKB-569 (Wyeth), herbimycin A, and an analogue or derivative thereof, 108) a VEGF inhibitor, 109) a vitamin D receptor agonist, 110) ZD-6474 (an angiogenesis inhibitor), 111) AP-23573 (an mTOR inhibitor), 112) synthadotin (a tubulin antagonist), 113) S-0885 (a collagenase inhibitor), 114) aplidine (an elongation factor-1 alpha inhibitor), 115) ixabepilone (an epithilone), 116) IDN-5390 (an angiogenesis inhibitor and an FGF inhibitor), 117) SB-2723005 (an angiogenesis inhibitor), 118) ABT-518 (an angiogenesis inhibitor), 119) combretastatin (an angiogenesis inhibitor), 120) anecortave acetate (an angiogenesis inhibitor), 121) SB- 715992 (a kinesin antagonist), 122) temsirolimus (an mTOR inhibitor), and 123) adalimumab (a TNFα antagonist), 124) erucylphosphocholine (an ATK inhibitor), 125) alphastatin (an angiogenesis inhibitor), 126) bortezomib (an NF Kappa B inhibitor), 127) etanercept (a TNFα antagonist and TACE inhibitor), 128) humicade (a TNFα inhibitor), and 129) gefitinib (a tyrosine kinase inhibitor), 130) a histamine receptor antagonist selected from the group consisting of phenothiazines (e.g., promethazine), alkylamines (e.g., chlorpheniramine (CAS No. 7054-11-7), brompheniramine (CAS No. 980- 71-2), fexofenadine hydrochloride, promethazine hydrochloride, loratadine, ketotifen fumarate salt, and acrivastine), methylxanthines (e.g., theophylline, theobromine, and caffeine), cimetidine (available under the tradename TAGAMET from SmithKline Beecham Phamaceutical Co., Wilmington, DE), ranitidine (available under the tradename ZANTAC from Warner Lambert Company, Morris Plains, NJ), famotidine (available under the tradename PEPCID from Merck & Co., Whitehouse Station, NJ), nizatidine (available under the tradename AXID from Reliant Pharmaceuticals, Inc., Liberty Corner, NJ), nizatidine, and roxatidine acetate (CAS No. 78628-28-1), H3 receptor antagonists {e.g., thioperamide and thioperamide maleate salt), and antihistamines (e.g., tricyclic dibenozoxepins, ethanolamines, ethylenediamines, piperizines, piperidines, and pthalazinones), 131) an alpha adrenergic receptor antagonist, 132) an anti-psychotic compound, 133) a CaM kinase Il inhibitor, 134) a G protein agonist, 135) an antibiotic selected from the group consisting of apigenin (Cas No. 520-36-5), ampicillin sodium salt (CAS No. 69-52-3), puromycin, and an analogue or derivative thereof, 136) an anti-microbial agent, 137) a DNA topoisomerase inhibitor selected from the group consisting of β-lapachone (CAS No. 4707- 32-8), (-)-arctigenin (CAS No. 7770-78-7), aurintricarboxylic acid, and an analogue or derivative thereof, 138) a thromboxane A2 receptor inhibitor selected from the group consisting of BM-531 (CAS No. 284464-46-6), ozagrel hydrochloride (CAS No. 78712-43-3), and an analogue or derivative thereof, 139) a D2 dopamine receptor antagonist, 140) a Peptidyl-Prolyl Cis/Trans lsomerase Inhibitor, 141) a dopamine antagonist, an anesthetic compound, 142) a clotting factor, 143) a lysyl hydrolase inhibitor, 144) a muscarinic receptor inhibitor, 145) a superoxide anion generator, 146) a steroid, 147) an antiproliferative agent selected from the group consisting of silibinin (CAS No. 22888-70-6), silymarin (CAS No. 65666-07-1), 1,2- hexanediol, dioctyl phthalate (CAS No. 117-81-7), zirconium (IV) oxide, glycyrrhizic acid, spermidine trihydrochloride, tetrahydrochloride, CGP 74514, spermine tetrahydrochloride, NG-methyl-L-arginine acetate salt, galardin, and an analogue or derivative thereof, 148) a diuretic, 149) an anticoagulant, 150) a cyclic GMP agonist, 151) an adenylate cyclase agonist, 152) an antioxidant, 153) a nitric oxide synthase inhibitor, 154) an antineoplastic agent selected from tirapazamine (CAS No. 27314-97-2), fludarabine (CAS No. 21679-14-1), cladribine, imatinib mesilate, and an analogue or derivative thereof, 155) a DNA synthesis inhibitor, 156) a DNA alkylating agent selected from dacarbazine (CAS No. 4342-03-4), temozolomide, procarbazine HCI, and an analogue or derivative thereof, 157) a DNA methylation inhibitor, 158) a NSAID agent, 159) a peptidylglycine alpha-hydroxylating monooxygenase inhibitor, 160) an MEK1/MEK 2 inhibitor, 161) a NO synthase inhibitor, 162) a retinoic acid receptor antagonist selected from isotretinoin (CAS No. 4759-48-2) and an analogue or derivative thereof, 163) an ACE inhibitor, 164) a glycosylation inhibitor, 165) an intracellular calcium influx inhibitor, 166) an anti-emetic agent, 167) an acetylcholinesterase inhibitor, 168) an ALK-5 receptor antagonist, 169) a RAR/RXT antagonist, 170) an elF-2a inhibitor, 171) an S- adenosyl-L-homocysteine hydrolase inhibitor, 172) an estrogen agonist, 173) a serotonin receptor inhibitor, 174) an antithrombotic agent, 175) a tryptase inhibitor, 176) a pesticide, 177) a bone mineralization promoter, 178) a bisphosphonate compound selected from risedronate and an analogue or derivative thereof, 179) an anti-inflammatory compound, 180) a DNA methylation promoter, 181) an anti-spasmodic agent, .182) a protein synthesis inhibitor, 183) an α-glucosidase inhibitor, 184) a calcium channel blocker, 185) a pyruvate dehydrogenase activator, 186) a prostaglandin inhibitor, 187) a sodium channel inhibitor, 188) a serine protease inhibitor, 189) an intracellular calcium flux inhibitor, 190) a JAK2 inhibitor; 191) an androgen inhibitor, 192) an aromatase inhibitor, 193) an anti-viral agent, 194) a 5-HT inhibitor, 195) an FXR antagonist, 196) an actin polymerization and stabilization promoter, 197) an AXOR12 agonist, 198) an angiotensin Il receptor agonist, 199) a platelet aggregation inhibitor, 200) a CB1/CB2 receptor agonist, 201) a norepinephrine reuptake inhibitor, 202) a selective serotonin reuptake inhibitor, 203) a reducing agent, 204) Isotretinoin, 205) radicicol, 206) clobetasol propionate, 207) homoharringtonine, 208) trichostatin A, 209) brefeldin A, 210) thapsigargin, 211) dolastatin 15, 212) cerivastatin, 213) jasplakinolide, 214) herbimycin A, 215) pirfenidone, 216) vinorelbine, 217) 17-DMAG, 218) tacrolimus, 219) loteprednol etabonate, 220) juglone, 221) prednisolone, 222) puromycin, 223) 3-BAABE, 224) cladribine, 225) mannose-6-phosphate, 226) 5-azacytidine, 227) Ly333531 (ruboxistaurin), 228) simvastatin, and 229) an immuno-modulator selected from Bay 11-7085, (-)-arctigenin, idazoxan hydrochloride, and an analogue or derivative thereof. These and other agents are described in more detail herein.

These and other aspects of the present invention will become evident upon reference to the following detailed description and attached drawings. In addition, various references are set forth herein which describe in more detail certain procedures and/or compositions, and are therefore incorporated by reference in the entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 schematically depicts the transcriptional regulation of matrix metalloproteinases.

Figure 2 is a blot which demonstrates that IL-1 stimulates AP-1 transcriptional activity. _ . . . . . . . . . .. . -

Figure 3 is a graph which shows that IL-1 induced binding activity decreased in lysates from chondrocytes which were pretreated with paclitaxel.

Figure 4 is a blot which shows that IL-1 induction increases collagenase and stromelysin in RNA levels in chondrocytes, and that this induction can be inhibited by pretreatment with paclitaxel.

Figures 5A-H are blots that show the effect of various anti- microtubule agents in inhibiting collagenase expression.

Figure 6 is a graph showing the results of a screening assay for assessing the effect of paclitaxel on smooth muscle cell migration.

Figure 7 is a graph showing the average rank of joint scores of Hartley guinea pig knees with ACL damage treated with paclitaxel. A reduction in score indicates an improvement in cartilage score. The dose response trend is statistically significant (p < 0.02). Figures 8A-C are examples of cross sections of Hartley guinea pig knees of control and paclitaxel treated animals. Figure 8A. Control speciment showing erosion of cartilage to the bone. Figure 8B. Paclitaxel dose 1 (low dose) showing fraying of cartilage. Figure 8C. Paclitaxel dose 2 (medium dose) showing minor defects to cartilage.

Figures 9A-F are safranin-O stained histological slides of representative synovial tissues from naive (healthy) knees (Figures 9A and 9D) and knees with arthritis induced by administration of albumin in Freund's complete adjuvant (Figures 9B and 9C) or carrageenan (Figures 9E and 9F). Arthritic knees received either control (Figures 9B and 9E) or 20% paclitaxel-loaded microspheres (Figures 9C and 9F). The data illustrate decreased proteoglycan red staining in arthritic knees treated with control microspheres and the proteoglycan protection properties of the paclitaxel- loaded formulation.

DETAILED DESCRIPTION OF THE INVENTION - -

Definitions

Prior to setting forth the invention, it may be helpful to an understanding thereof to first set forth definitions of certain terms that are used herein.

"Fibrosis," or "scarring," or "fibrotic response" refers to the formation of fibrous (scar) tissue in response to injury or medical intervention. Therapeutic agents which inhibit fibrosis or scarring are referred to herein as "fibrosis-inhibiting agents", "fibrosis-inhibitors", "anti- scarring agents", and the like, where these agents inhibit fibrosis through one or more mechanisms including: inhibiting inflammation or the acute inflammatory response, inhibiting migration or proliferation of connective tissue cells (such as fibroblasts, smooth muscle cells, vascular smooth muscle cells), inhibiting angiogenesis, reducing extracellular matrix (ECM) production or promoting ECM breakdown, and/or inhibiting tissue remodeling. When scarring occurs in a confined space (e.g., within a lumen) following surgery or instrumentation (including implantation of a medical device or implant), such that a body passageway (e.g., a blood vessel, the gastrointestinal tract, the respiratory tract, the urinary tract, the female or male reproductive tract, the eustacian tube etc.) is partially or completely obstructed by scar tissue, this is referred to as "stenosis" (narrowing). When scarring subsequently occurs to re-occlude a body passageway after it was initially successfully opened by a surgical intervention (such as placement of a medical device or implant), this is referred to as "restenosis."

"Host", "person", "subject", "patient" and the like are used synonymously to refer to the living being into which a device or implant of the present invention is implanted.

"Implanted" refers to having completely or partially placed a device or implant within a host. A device is partially implanted when some of the device reaches, or extends to the outside of, a host.

"Inhibit fibrosis", "reduce fibrosis", "Inhibits scarring" and the like are used synonymously to refer to the action of agents or compositions which result in a statistically significant decrease in the formation of fibrous tissue that can be expected to occur in the absence of the agent or composition.

"Anti-infective agent" refers to an agent or composition which prevents microrganisms from growing and/or slows the growth rate of microorganisms and/or is directly toxic to microorganisms at or near the site of the agent. These processes would be expected to occur at a statistically significant level at or near the site of the agent or composition relative to the effect in the absence of the agent or composition.

"Inhibit infection" refers to the ability of an agent or composition to prevent microorganisms from accumulating and/or proliferating near or at the site of the agent. These processes would be expected to occur at a statistically significant level at or near the site of the agent or composition relative to the effect in the absence of the agent or composition.

"Inhibitor" refers to an agent which prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process. The process may be a general one such as scarring or refer to a specific biological action such as, for example, a molecular process resulting in release of a cytokine.

"Antagonist" refers to an agent which prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process. While the process may be a general one, typically this refers to a drug mechanism where the drug competes with a molecule for an active molecular site or prevents a molecule from interacting with the molecular site. In these situations, the effect is that the molecular process is inhibited.

"Agonist" refers to an agent which stimulates a biological process or rate or degree of occurrence of a biological process. The process may be a general one such as scarring or refer to a specific biological action such as, for example, a molecular process resulting in release of a cytokine.

"Anti-microtubule agents" should be understood to include any protein, peptide, chemical, or other molecule which impairs the function of microtubules, for example, through the prevention or stabilization of polymerization. Compounds that stabilize polymerization of microtubules are referred to herein as "microtubule stabilizing agents." A wide variety of methods may be utilized to determine the anti-microtubule activity of a particular compound, including for example, assays described by Smith et al. {Cancer Lett 79(2):213-219, 1994) and Mooberry et al., (Cancer Lett. 96(2):261-266, 1995).

"Medical device", "implant", ""device", medical device", "medical implant", "implant/device" and the like are used synonymously to refer to any object that is designed to be placed partially or wholly within a patient's body for one or more therapeutic or prophylactic purposes such as for restoring physiological function, alleviating symptoms associated with disease, delivering therapeutic agents, and/or repairing, replacing, or augmenting etc. damaged or diseased organs and tissues. While normally composed of biologically compatible synthetic materials (e.g., medical-grade stainless steel, titanium and other metals; polymers such as polyurethane, silicon, PLA, PLGA and other materials) that are exogenous, some medical devices and implants include materials derived from animals (e.g., "xenografts" such as whole animal organs; animal tissues such as heart valves; naturally occurring or chemically-modified molecules such as collagen, hyaluronic acid, proteins, carbohydrates and others), human donors (e.g., "allografts" such as whole organs; tissues such as bone grafts, skin grafts and others), or from the patients themselves (e.g., "autografts" such as saphenous vein grafts, skin grafts, tendon/ligament/muscle transplants). Representative examples of medical devices that are of particular utility in the present invention include,,but are not restricted to, vascular stents, gastrointestinal stents, tracheal/bronchial stents, genital- urinary stents, ENT stents, intra-articular implants, intraocular lenses, implants for hypertrophic scars and keloids, vascular grafts, anastomotic connector devices, implantable sensors, implantable pumps, soft tissue implants (e.g., cosmetic implants and implants for reconstructive surgery), implantable electrical devices, such as implantable neurostimulators and implantable electrical leads, surgical adhesion barriers, glaucoma drainage devices, surgical films and meshes, prosthetic heart valves, tympanostomy tubes, penile implants, endotracheal and tracheostomy tubes, peritoneal dialysis catheters, intracranial pressure monitors, vena cava filters, central venous catheters (CVCs), ventricular assist devices (e.g., LVAD), spinal prostheses, urinary (Foley) catheters, prosthetic bladder sphincters, orthopedic implants, and gastrointestinal drainage tubes. "Chondroprotection" refers to the prevention of cartilage loss. Cartilage is formed from chondrocytes, and chondroprotection is the protection of the chondrocytes so that they do not die.

"Release of an agent" refers to a statistically significant presence of the agent, or a subcomponent thereof, which has disassociated from the implant/device and/or remains active on the surface of (or within) the device/implant.

"Biodegradable" refers to materials for which the degradation process is at least partially mediated by, and/or performed in, a biological system. "Degradation" refers to a chain scission process by which a polymer chain is cleaved into oligomers and monomers. Chain scission may occur through various mechanisms, including, for example, by chemical reaction (e.g., hydrolysis) or by a thermal or photolytic process. Polymer degradation may be characterized, for example, using gel permeation chromatography (GPC), which monitors the polymer molecular mass changes during erosion and drug release. Biodegradable also refers to materials may be degraded by an erosion process mediated by, and/or performed in, a biological system. "Erosion" refers to a process in which material is lost from the bulk. In the case of a polymeric system, the material may be a monomer, an oligomer, a part of a polymer backbone, or a part of the polymer bulk. Erosion includes (i) surface erosion, in which erosion affects only the surface and not the inner parts of a matrix; and (ii) bulk erosion, in which the entire system is rapidly hydrated and polymer chains are cleaved throughout the matrix. Depending on the type of polymer, erosion generally occurs by one of three basic mechanisms (see, e.g., Heller, J., CRC Critical Review in Therapeutic Drug Carrier Systems (1984), 1(1), 39-90); Siepmann, J. et al., Adv. Drug Del. Rev. (2001), 48, 229-247): (1) water-soluble polymers that have been insolubilized by covalent cross-links and that solubilize as the cross-links or the backbone undergo a hydrolytic cleavage; (2) polymers that are initially water insoluble are solubilized by hydrolysis, ionization, or pronation of a pendant group; and (3) hydrophobic polymers are converted to small water-soluble molecules by backbone cleavage. Techniques for characterizing erosion include thermal analysis (e.g., DSC), X-ray diffraction, scanning electron microscopy (SEM), electron paramagnetic resonance spectroscopy (EPR), NMR imaging, and recording mass loss during an erosion experiment. For microspheres, photon correlation spectroscopy (PCS) and other particles size measurement techniques may be applied to monitor the size evolution of erodible devices versus time.

As used herein, "analogue" refers to a chemical compound that is structurally similar to a parent compound, but differs slightly in composition (e.g., one atom or functional group is different, added, or removed). The analogue may or may not have different chemical or physical properties than the original compound and may or may not have improved biological and/or chemical activity. For example, the analogue may be more hydrophilic or it may have altered reactivity as compared to the parent compound. The analogue may mimic the chemical and/or- biologically activity of the parent compound (i.e., it may have similar or identical activity), or, in some cases, may have increased or decreased activity. The analogue may be a naturally or non-naturally occurring (e.g., recombinant) variant of the original compound. An example of an analogue is a mutein (i.e., a protein analogue in which at least one amino acid is deleted, added, or substituted with another amino acid). Other types of analogues include isomers (enantiomers, diasteromers, and the like) and other types of chiral variants of a compound, as well as structural isomers. The analogue may be a branched or cyclic variant of a linear compound. For example, a linear compound may have an analogue that is branched or otherwise substituted to impart certain desirable properties (e.g., improve hydrophilicity or bioavailability).

As used herein, "derivative" refers to a chemically or biologically modified version of a chemical compound that is structurally similar to a parent compound and (actually or theoretically) derivable from that parent compound. A "derivative" differs from an "analogue" in that a parent compound may be the starting material to generate a "derivative," whereas the parent compound may not necessarily be used as the starting material to generate an "analogue." A derivative may or may not have different chemical or physical properties of the parent compound. For example, the derivative may be more hydrophilic or it may have altered reactivity as compared to the parent compound. Derivatization (Ae., modification) may involve substitution of one or more moieties within the molecule (e.g., a change in functional group). For example, a hydrogen may be substituted with a halogen, such as fluorine or chlorine, or a hydroxyl group (-OH) may be replaced with a carboxylic acid moiety (- COOH). The term "derivative" also includes conjugates, and prodrugs of a parent compound (i.e., chemically modified derivatives which can be converted into the original compound under physiological conditions). For example, the prodrug may be an inactive form of an active agent. Under physiological conditions, the prodrug may be converted into the active form of the compound. Prodrugs may be formed, for example, by replacing one or two hydrogen atoms on nitrogen atoms by an acyl group (acyl prodrugs) or a carbamate group (carbamate prodrugs). More detailed information relating to prodrugs is found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; or H. Bundgaard, Drugs of the Future 16 (1991) 443. The term "derivative" is also used to describe all solvates, for example hydrates or adducts (e.g., adducts with alcohols), active metabolites, and salts of the parent compound. The type of salt that may be prepared depends on the nature of the moieties within the compound. For example, acidic groups, for example carboxylic acid groups, can form, for example, alkali metal salts or alkaline earth metal salts (e.g., sodium salts, potassium salts, magnesium salts and calcium salts, and also salts with physiologically tolerable quaternary ammonium ions and acid addition salts with ammonia and physiologically tolerable organic amines such as, for example, triethylamine, ethanolamine or tris-(2-hydroxyethyl)amine). Basic groups can form acid addition salts, for example with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. Compounds which simultaneously contain a basic group and an acidic group, for example a carboxyl group in addition to basic nitrogen atoms, can be present as zwitterions. Salts can be obtained by customary methods known to those skilled in the art, for example by combining a compound with an inorganic or organic acid or base in a solvent or diluent, or from other salts by cation exchange or anion exchange.

"Hyaluronic acid" or "HA" as used herein refers to all forms of hyaluronic acid that are described or referenced herein, including those that have been processed or chemically or physically modified, as well as hyaluronic acid that has been crosslinked (for example, covalently, ionically, thermally or physically). HA is a glycosaminoglycan composed of a linear chain of about 2500 repeating disaccharide units. Each disaccharide unit is composed of an N-acetylglucosamine residue linked to a glucuronic acid. Hyaluronic acid is a natural substance that is found in the extracellular matrix of many tissues including synovial joint fluid, the vitreous humor of the eye, cartilage, blood vessels, skin and the umbilical cord. Commercial forms of hyaluronic acid having a molecular weight of approximately 1.2 to 1.5 million Daltons (Da) are extracted from rooster combs and other animal sources. Other sources of HA include HA that is isolated from cell culture / fermentation processes. Lower molecular weight HA formulations are also available from a variety of commercial sources. The molecule can be of variable lengths (i.e., different numbers of repeating disaccharide units and different chain branching patterns) and can be modified at several sites (through the addition or subtraction of different functional groups) without deviating from the scope of the present invention. The term "inter-react" refers to the formulation of covalent bonds, noncovalent bonds, or both. The term thus includes crosslinking, which involves both intermolecular crosslinks and optionally intramolecular crosslinks as well, arising from the formation of covalent bonds. Covalent bonding between two reactive groups may be direct, in which case an atom in reactive group is directly bound to an atom in the other reactive group, or it may be indirect, through a linking group. Noncovalent bonds include ionic (electrostatic) bonds, hydrogen bonds, or the association of hydrophobic molecular segments, which may be the same or different. A crosslinked matrix may, in addition to covalent bonds, also include such intermolecular and/or intramolecular noncovalent bonds.

When referring to polymers, the terms "hydrophilic" and "hydrophobic" are generally defined in terms of an HLB value, i.e., a hydrophilic lipophilic balance. A high HLB value indicates a hydrophilic compound, while a low HLB value characterizes a hydrophobic compound. HLB values are well known in the art, and generally range from 1 to 18. Preferred multifunctional compound cores are hydrophilic, although as long as the multifunctional compound as a whole contains at least one hydrophilic component, crosslinkable hydrophobic components may also be present.

The term "synthetic" is used to refer to polymers, compounds and other such materials that are "chemically synthesized." For example, a synthetic material in the present compositions may have a molecular structure that is identical to a naturally occurring material, but the material perse, as incorporated in the compositions of the invention, has been chemically synthesized in the laboratory or industrially. "Synthetic" materials also include semi-synthetic materials, i.e., naturally occurring materials, obtained from a natural source, that have been chemically modified in some way. Generally, however, the synthetic materials herein are purely synthetic, i.e., they are neither semi-synthetic nor have a structure that is identical to that of a naturally occurring material. The term "effective amount" refers to the amount of composition required in order to obtain the effect desired. For example, a "tissue growth-promoting amount" of a composition refers to the amount needed in order to stimulate tissue growth to a detectable degree. Tissue, in this context, includes connective tissue, bone, cartilage, epidermis and dermis, blood, and other tissues. The actual amount that is determined to be an effective amount will vary depending on factors such as the size, condition, sex and age of the patient and can be more readily determined by the caregiver.

The term "in situ" as used herein means at the site of administration. Thus, compositions of the invention can be injected or otherwise applied to a specific site within a patient's body, e.g., a site in need of augmentation, and allowed to crosslink at the site of injection. Suitable sites will generally be intradermal or subcutaneous regions for augmenting dermal support, at a bone fracture site for bone repair, within sphincter tissue for sphincter augmentation (e.g., for restoration of continence), within a wound or suture, to promote tissue regrowth; and within or adjacent to vessel anastomoses, to promote vessel regrowth.

The term "aqueous medium" includes solutions, suspensions, dispersions, colloids, and the like containing water. The term "aqueous environment" means an environment containing an aqueous medium. Similarly, the term "dry environment" means an environment that does not contain an aqueous medium.

With regard to nomenclature pertinent to molecular structures, the following definitions apply:

The term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, /7-propyl, isopropyl, π-butyl, isobutyl, f-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. Generally, although again not necessarily, alkyl groups herein contain 1 to about 12 carbon atoms. The term "lower alkyl" intends an alkyl group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted alkyl" refers to alkyl substituted with one or more substituent groups. "Alkylene," "lower alkylene" and "substituted alkylene" refer to divalent alkyl, lower alkyl, and substituted alkyl groups, respectively.

The term "aryl" as used herein, and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring (monocyclic) or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety. The common linking group may also be a carbonyl as in benzophenone, an oxygen atom as in diphenylether, or a nitrogen atom as in diphenylamine. Preferred aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like. "Substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to aryl in which at least one carbon atom is replaced with a heteroatom. The terms "arylene" and "substituted arylene" refer to divalent aryl and substituted aryl groups as just defined.

The term "heteroatom-containing" as in a "heteroatom- containing hydrocarbyl group" refers to a molecule or molecular fragment in which one or more carbon atoms is replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon.

"Hydrocarbyl" refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. The term "lower hydrocarbyl" intends a hydrocarbyl group of one to six carbon atoms, preferably one to four carbon atoms. The term "hydrocarbylene" intends a divalent hydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, including branched or unbranched, saturated or unsaturated species, or the like. The term "lower hydrocarbylene" intends a hydrocarbylene group of one to six carbon atoms, preferably one to four carbon atoms. "Substituted hydrocarbyl" refers to hydrocarbyl substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbyl" and "heterohydrocarbyl" refer to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Similarly, "substituted hydrocarbylene" refers to hydrocarbylene substituted with one or more substituent groups, and the terms "heteroatom-containing hydrocarbylene" and "heterohydrocarbylene" refer to hydrocarbylene in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, "hydrocarbyl" indicates both unsubstituted and substituted hydrocarbyls, "heteroatom-containing hydrocarbyl" indicates both unsubstituted and substituted heteroatom- containing hydrocarbyls and so forth.

By "substituted" as in "substituted hydrocarbyl," "substituted alkyl," and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, or other moiety, at least one hydrogen atom bound to a carbon atom is replaced with one or more substituents that are functional groups such as alkoxy, hydroxy, halo, nitro, and the like. Unless otherwise indicated, it is to be understood that specified molecular segments can be substituted with one or more substituents that do not compromise a compound's utility. For example, "succinimidyl" is intended to include unsubstituted succinimidyl as well as sulfosuccinimidyl and other succinimidyl groups substituted on a ring carbon atom, e.g., with alkoxy substituents, polyether substituents, or the like.

Any concentration ranges, percentage range, or ratio range recited herein are to be understood to include concentrations, percentages or ratios of any integer within that range and fractions thereof, such as one tenth and one hundredth of an integer, unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the term "about" refers to ± 15% of any indicated structure, value, or range.

"A" and "an" refer to one or more of the indicated items. For example, "a" polymer refers to both one polymer or a mixture comprising two or more polymers; "a multifunctional compound " refers not only to a single multifunctional compound but also to a combination of two or more of the same or different multifunctional compounds; "a reactive group" refers to a combination of reactive groups as well as to a single reactive group, and the like.

As discussed above, the present invention provides polymeric compositions which greatly increase the ability to inhibit the formation of reactive scar tissue on, or around, the surface of a device or implant or at a treatment site. Numerous polymeric compositions and therapeutic agents are described herein.

The present invention provides for the combination of compositions (e.g., polymers) which include one or more therapeutic agents, described below. Also described in more detail below are methods for making and methods for utilizing such compositions.

Therapeutic Agents

Therapeutic agents useful in the present invention includes various anti-fibrosis agents, anti-infective agents, and polymers.

Anti-fibrosis Agents

In one aspect, the present invention discloses pharmaceutical agents which inhibit one or more aspects of the production of excessive fibrous (scar) tissue. Such agents may be readily determined based upon the in vitro and in vivo (animal) models such as those provided in Examples 16-20, 21-28, 29, 38, 39, 42, 43, and 81. Agents which inhibit fibrosis may be identified through in vivo models including inhibition of intimal hyperplasia development in the rat balloon carotid artery model (Examples 21 and 29). The assays set forth in Examples 20 and 28 may be used to determine whether an agent is able to inhibit cell proliferation in fibroblasts and/or smooth muscle cells. In one aspect of the invention, the agent has an IC50 for inhibition of cell proliferation within a range of about 10"6 to about 10"10 M. In certain embodiments, the agent may have an IC50 for inhibition of cell proliferation of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM. The assay set forth in Example 24 may be used to determine whether an agent may inhibit migration of fibroblasts and/or smooth muscle cells. In one aspect of the invention, the agent has an IC50 for inhibition of cell migration within a range of about 10"6 to about 10"9M. In certain embodiments, the agent may have an IC50 for inhibition of fibroblast or smooth muscle cell migration of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM. Assays set forth herein may be used to determine whether an agent is able to inhibit inflammatory processes, including nitric oxide production in macrophages (Example 16), and/or TNF-alpha production by macrophages (Example 17), and/or IL-1 beta production by macrophages (Example 25), and/or IL-8 production by macrophages (Example 26), and/or inhibition of MCP-1 by macrophages (Example 27). In one aspect of the invention, the agent has an IC50 for inhibition of any one of these inflammatory processes within a range of about 10"6 to about 10"10M. In certain embodiments, the agent may have an IC50 for any one of these inflammatory processes of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM. The assay set forth in Example 22 may be used to determine whether an agent is able to inhibit MMP production. In one aspect of the invention, the agent has an IC50 for inhibition of MMP production within a range of about 10"4 to about 10"8M. In certain embodiments, the agent may have an IC50 for inhibition of MMP production of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM. The assay set forth in Example 23 (also known as the CAM assay) may be used to determine whether an agent is able to inhibit angiogenesis. In one aspect of the invention, the agent has an IC50 for inhibition of angiogenesis within a range of about 10"6 to about 10"10M. In certain embodiments, the agent may have an IC50 for inhibition of angiogenesis of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM. The assay set forth in Example 81 may be used to determine whether an agent is able to inhibit MMP-1. In one aspect of the invention, the agent has an IC50 for inhibition of MMP-1 within a range of about 10"6 to about 10"10M. In certain embodiments, the agent may have an IC50 for inhibition of MMP-1 of less than about 10,000 nM; or less than about 1000 nM; or less than about 100 nM. Agents which reduce the formation of surgical adhesions may be identified through in vivo models including the rabbit surgical adhesions model (Examples 19, 39, 42, and 43) and the rat caecal sidewall model (Example 18). These pharmacologically active agents (described below) can then be delivered at appropriate dosages into to the tissue either alone, or via carriers (described herein), to treat the clinical problems described herein. . . _ _ . .

Numerous therapeutic compounds capable of inhibiting fibrosis may be identified as useful in the invention including:

1) Adensosine A2A receptor antagonist

In another embodiment, the fibrosis-inhibiting compound is an adensosine A2A receptor antagonist (e.g., Sch-63390 (Schering-Plough) or an A2A receptor antagonists from Almirall-Prodesfarma, SCH-58261 (CAS No. 160098-96-4), or an analogue or derivative thereof).

2) AKT inhibitor

In another embodiment, the fibrosis-inhibiting compound is an AKT inhibitor (e.g., PKB inhibitors from DeveloGen, AKT inhibitors from Array BioPharma, Celgene, Merck & Co, Amphora, NeoGenesis Pharmaceuticals, A-443654 (Abbott Laboratories), erucylphosphocholine (AEterna Zentaris), KRX-401 (Keryx), protein kinase B inhibitors from Astex Technology, PX-316 (ProlX), or an analogue or derivative thereof).

3) Alpha 2 Inteqrin Antagonist

In another embodiment, the fibrosis-inhibiting compound is an alpha 2 integrin antagonist (e.g., Pharmaprojects No. 5754 (Merck KGaA), or an analogue or derivative thereof).

4) Alpha 4 Integrin Antagonist

In another embodiment, the fibrosis-inhibiting compound is an alpha 4 integrin antagonist (e.g., T-0047 (Tanabe Seiyaku), VLA-4 antagonists from Sanofi-Aventis, Merck & Co., Biogen Idee, Uriach, and Molecumetics, alpha 4 integrin antagonists from Genentech), BIO-2421 (Biogen Idee), cell adhesion inhibitors from Kaken Pharmaceuticals, CT-737 (Wyeth), CT-767 (Elan), CY-9652 (Epimmune), CY-9701 (Epimmune), fibronectin antagonists from Uriach, integrin alpha4β7 antagonists frin Wilex, Pharmaprojects No. 5972 (UCB), Pharmaprojects No. 6603 (Wyeth), TBC- 3342, TBC-772, and TBC-3486 (Encysive Pharmaceuticals), TBC-4746 (Schering-Plough), or a VLA4/VCAM inhibitor (Elan Pharmaceuticals), ZD- 7349 (AstraZeneca), or an analogue or derivative thereof).

5) Alpha 7 Nicotinic Receptor Agonist

In another embodiment, the fibrosis-inhibiting compound is an alpha 7 nicotinic receptor agonist (e.g., AZD-0328 (AstraZeneca), galantamine (CAS No. 357-70-0) (Synaptec), MEM-3454 or nicotinic alpha-7 agonist (Memory Pharmaceuticals and Critical Therapeutics), Pharmaprojects No. 4779 (AstraZeneca), PNU-282987 (Pfizer), SSR- 180711 (Sanofi-Aventis), TC-1698 or TC-5280 (Targacept), or an analogue or derivative thereof). 6) Angiogenesis Inhibitors

In one embodiment, the fibrosis-inhibjting compound is an angiogenesis inhibitor (e.g., AG-") 2, 958 (Pfizer), ATN-161 (Attention LLC), neovastat, an angiogenesis inhibitor from Jerina AG (Germany), NM-3 (Mercian), VGA-1155 (Taisho), FCE-26644 (Pfizer), FCE-26950 (Pfizer), FPMA (Meiji Daries), FR-111142 (Fujisawa), GGTI-298, GM-1306 (Ligand), GPA-1734 (Novartis), NNC-47-0011 (Novo Nordisk), herbamycin (Nippon Kayaku), lenalidomide (Celegene), IP-10 (N(H)1 ABT-828 (Abbott), KIN-841 (Tokushima University, Japan), SF-1126 (Semafore Pharmaceuticals), laminin technology (NIH), CHIR-258 (Chiron), NVP-AEW541 (Novartis), NVP-AEW541 (Novartis), Vt16907 (Alchemia), OXI-8007 (Oxigene), EG- 3306 (Ark Therapeutics), Maspin (Arriva), ABT-567 (Abbott), PPI-2458 (Praecis Pharmaceuticals), CC-5079, CC-4089 (Celgene), HIF-1 alpha inhibitors (Xenova), S-247 (Pfizer), AP-23573 (Ariad), AZD-9935 (Astra Zeneca), mebendazole (Introgen Therapeutics), MetAP-2 inhibitors (GlaxoSmithKline), AG-615 (Angiogene Pharmaceuticals), Tie-2 antagonists (Hybrigenics), NC-381, CYC-381, NC-169, NC-219, NC-383, NC-384, NC- 407 (Lorus Therapeutics), ATN-224 (Attenuon), ON-01370 (Onconova), Vitronectin antagonists (Amgen), SDX-103 (Salmedix), Vitronectin antagonists (Shire), CHP (Riemser), TEK (Amgen), Anecortave acetate (Alcon), T46.2 (Matrix Therapeutics), HG-2 (Heptagen), TEM antagonists (Genzyme), Oxi-4500 (Oxigene), ATN-161 (Attenuon), WX-293 (Wilex), M- 2025 (Metris Therapeutics), Alphastatin (BioActa), YH-16 (Yantai Rongchang), BIBF-1120 (Boehringer Ingelheim), BAY-57-9352 (Bayer), AS- 1404 (Cancer Research Technology), SC-77964 (Pfizer), glycomimetics (BioTie Therapies), TIE-2 Inhibitors (Ontogen), DIMI, Octamer (Octamer), ABR-215050 (Active Biotech), ABT-518 (Abbott), KDR inhibitors (Abbott), BSF-466895 (Abbott), SCH-221153 (Schering-Plough), DAC:antiangiogenic (ConjuChem), TFPI (EntreMed), AZD-2171 (Astra-Zenaca), CDC-394 (Celgene), LY290293 (EIi Lilly), IDN-5390 (Indena), Kdr Kinase Inhibitors (Merck), CT-113020, CT-116433, CT-116563, CT-31890, CT-32228) (Cell Therapeutics), A-299620 (Abbott), TWEAK Inhibitor (Amgen), VEGF modulators (Johnson and Johnson), Tum-N53, tumstatin (Genzyme), Thios- 1, Thios-2 (Thios Pharmaceuticals), MV-6401 (Miravant Medical Technologies), Spisulosine (PharmaMar), CEP-7055 (Cephalon), AUV-201 (Auvation), LM-609 (EIi Lilly), SKF-106615 (AnorMED), Oglufanide disodium (Cytran), BW-114 (Pharminox), Calreticulin (NIH), WX-678 (Wilex), SD-7784 (Pfizer), WX-UK1 (Wilex), SH-268 (Schering AG), 2-Me-PGA (Celgene), S- 137 (Pfizer), ZD-6126 (Angiogene Pharmaceuticals), SG-292 (SignalGen), Benefin (Lane Labs), A6, A36 (Angstrom), SB-2723005 (GlaxoSmithKline), SC-7 (Cell Therapeutics), ZEN-014 (AEterna Zentaris), 2-methoxyestradiol (EntreMed), NK-130119 (Nippon Kayaku), CC-10004 (Celgene), AVE- 8062A (Ajinomoto), Tacedinaline (Pfizer), Actinonin (Tokyo Metropolitan Institute of Medical Science), Lenalidomide (Celgene), VGA-1155, BTO-956 (SRI International), ER-68203-00 (Eisai), CT-6685 (UCB), JKC-362 (Phoenix Pharmaceuticals), DMI-3798 (DMI Biosciences, Angfomate (Ipsen), ZD-6474 (AstraZeneca), CEP-5214 (Cephalon), Canstatin (Genzyme), NM-3 (Mercian), Oridigm (MediQuest Therapeutics), Exherin (Adherex), BLS-0597 (Boston Life Sciences), PTC-299 (PTC Therapeutics), NPI-2358 (Nereus Pharmaceuticals), CGP-79787 (Novartis), AEE-788 (Novartis), CKD-732 (Chong Kun Dang), CP-564959 (OSI Pharmaceuticals), CM-101 (CarboMed), CT-2584, CT3501 (Cell Therapeutics), combretastatin and analogues and derivatives thereof (such as combretastatin A-1, A-2, A-3, A-4, A-5, A-6, B-1, B-2, B-3, B-4, D-1 , D-2, and combretastatin A-4 phosphate (Oxigene)), Rebimastat (Bristol-Meyers Squibb), Dextrin 2-sulfate (ML Laboratories), Cilengitide (Merk KGaA), NSC- 706704 (Pharminox), KRN-951 (Kirin Brewery), Ukrain, NSC-631570 (Nowicky Pharma), Tecogalan sodium (Daiichi Pharmaceutical), Tz-93 (Tsumura), TBC-1635 (Encysive Pharmaceuticals), TAN-1120 (Takeda), Semaxanib (Pfizer), BDI-7800 (Biopharmacopae), SD-186, SD-983 (Bristol- Meyers Squibb), SB-223245 (GlaxoSmithKline), SC-236 (Pfizer), RWJ- 590973 (Johnson and Johnson), ILX-1850 (Genzyme), SC-68488, S-836 (Pfizer), CG-55069-11 (CuraGen), Ki-23057 (Kirin Brewery), CCX-700 (Chemoentryx), Pegaptanib octasodium (Giled Sciences), or an analogue or derivative thereof). In other embodiments, the angiogenesis inhibitor may be a recombinant anti-angiogenic compound such as ANGIOCOL (available from Biostratum Inc., Durham, NC).

7) Apoptosis Antagonists

In another embodiment, the fibrosis-inhibiting compound is an apoptosis antagonist (e.g., didemnin B, RGB-286199 (GPC Biotech), 5F- DF-203 (Cancer Research Technology), aplidine, bongkrekic acid, triammonium salt, [6]-gingerol (CAS No. 23513-14-6), or an analogue or derivative thereof).

8) Apoptosis Activators

In another embodiment, the fibrosis-inhibiting compound is an apoptosis activator (e.g., aplidine (CAS No. 137219-37-5) (PharmaMar), canfosfamide hydrochloride (CAS No. 58382-37-74 and 39943-59-6) (Telik), idronoxil (CAS No. 81267-65-4) (Novogen), OSI-461 (OSI Pharmaceuticals), DE-098 (Santen), ARQ-550RP (ArQuIe), ABJ-879 (Novartis), adaphostin (NIH), anticancer agents from Apogenix Biotechnology and Momenta Pharmaceuticals, anti-PARP-1 or anti-PARP-2 (Octamer), BA-1037 (BioAxone), CP-248 (CAS No. 200803-37-8) (OSI Pharmaceuticals), EM- 1421 (Erimos), lPI-504 (Infinity Pharmaceuticals), KP-372-1 (QLT), MPC- 6827 (Maxim), MT-103 (Medisyn Technologies), MX-116407 or MX-126374 (Maxim), NPI-0052 (Nereus Pharmaceuticals), NVP-AEW541 (Novartis), PARP inhibitor from Agouron (Pfizer), R-306465 (Johnson & Johnson), TG- 100-33 (TargeGen), a XIAP inhibitor from AEgera, ZEN-011 (AEterna Zentaris), canertinib dihydrochloride (CAS No. 289499-45-2) (Pfizer), BH31- 1, 3-BAABE, or an analogue or derivative thereof). 9) Beta 1 Inteqrin Antagonist

In another embodiment, the fibrosis-inhibiting compound is a beta 1 integrin antagonist (e.g., β-1 integrin antagonists, Berkeley Lab, or an analogue or derivative thereof).

10) Beta Tubulin Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a beta tubulin inhibitor (e.g., ZEN-017 (AEterna Zentaris), laulimalide (Kosan Biosciences), or an analogue or derivative thereof).

11) Blockers of Enzyme Production in Hepatitis C

In another embodiment, the fibrosis-inhibiting compound is an agent that blocks enzyme production in hepatitis C (e.g., merimepodib (Vertex Pharmaceuticals), or an analogue or derivative thereof).

12) Bruton's Tyrosine Kinase Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a Bruton's tyrosine kinase inhibitor (e.g., a Btk inhibitor from Cellular Genomics, or an analogue or derivative thereof).

13) Calcineurin Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a calcineurin inhibitor (e.g., tacrolimus (LifeCycle Pharma), or an analogue or derivative thereof).

14) Caspase 3 Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a caspase 3 inhibitor (e.g., NM-3 (Mercian), or an analogue or derivative thereof). 15) CC Chemokine Receptor Antagonists

In another embodiment, the fibrosis-inhibiting compound is a CC chemokine receptor antagonist {e.g., a chemokine receptor 3 antagonist, a chemokine receptor 6 antagonist, and a chemokine receptor 7 antagonist). Representative examples of CC chemokine receptor antagonists include chemokine antagonists such as the CCR7 antagonists from Neurocrine Biosciences.

In a related embodiment, the fibrosis-inhibiting compound is a CC chemokine receptor antagonist (CCR) 1 , 3, & 5 (e.g., peptide T (Advanced lmmuni T), a CCR3 antagonist from GlaxoSmithKline, a chemokine antagonist (Pharmaprojects No. 6322) from Neurocrine Biosciences or Merck & Co., an HIV therapy agent from ReceptoPharm (Nutra Pharma), Pharmaprojects No. 6129 (Sangamo BioSciences), or an analogue or derivative thereof).

In certain embodiments, the CCCR antagonist is a CCR2b chemokine receptor antagonist such as RS 102895 (CAS No. 300815-41-2).

16) Cell Cycle Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a cell cycle inhibitor (e.g., SNS-595 (Sunesis), homoharringtonine, or an analogue or derivative thereof).

In certain embodiments, the cell cycle inhibitor is an anti- microtubule agent (e.g., synthadotin, or an analogue or derivative thereof).

In certain embodiments, cell cycle inhibitor is a microtubule stimulant (e.g., KRX-0403, or an analogue or derivative thereof).

17) Cathepsin B Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a cathepsin B inhibitor (e,g., AM-4299A (Asahi Kasei Pharma), BDI-7800 (Biopharmacopae), a cathepsin B inhibitor from Axys (Celera Genomics), MDL-104903 (CAS No. 180799-56-8) (Sanofi-Aventis), NC-700 (Nippon Chemiphar), Pharmaprojects No. 2332 (Hoffmann-La Roche), Pharmaprojects No. 4884 (Takeda), Pharmaprojects No. 5134 (Nippon Chemiphar), or an analogue or derivative thereof).

18) Cathepsin K Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a cathepsin K inhibitor (e.g., 462795 (GlaxoSmithKline), INPL-022-D6 (Amura Therapeutics), or an analogue or derivative thereof).

19) Cathepsin L Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a cathepsin L Inhibitor (e.g., a cathepsin L inhibitor from Takeda, INPL-022- E10 (Amura Therapeutics), Pharmaprojects No. 5447 (Taiho), or an analogue or derivative thereof).

20) CD40 Antagonists . .. . .

In another embodiment, the fibrosis-inhibiting compound is a CD40 antagonists (e.g., 5D12 (Chiron), ABI-793 (Novartis), an anticancer antibody from Chiron, anti-CD40 MAb-2 (Kirin Brewery), anti-CD40 (Eli Lilly), anti-CD40L antibody (UCB), a CD40 inhibitor from Apoxis, CD40 ligand inhibitor from Millennium Pharmaceuticals, a CD40/CAP inhibitor from Snow Brand, CGEN-40 (Compugen), CHIR-12.12 (Chiron), Pharmaprojects No. 5163 (Nippon Kayaku), ruplizumab (Biogen Idee), SGN-40 (Seattle Genetics), TNX-100 (Akzo Nobel), toralizumab (CAS No. 252662-47-8) (Biogen Idee), or an analogue or derivative thereof).

21) Chemokine Receptor Agonists

In another embodiment, the fibrosis-inhibiting compound is a chemokine receptor agonist (e.g., a chemokine agonist from NeuroTarget, or an analogue or derivative thereof). 22) Chymase inhibitors

In another embodiment, the fibrosis-inhibiting compound is a chymase inhibitor {e.g., BL-3875 (Dainippon), LEX-043 (SuperGen), NK- 3201 (CAS No. 204460-24-2) (Nippon Kayaku), or an analogue or derivative thereof).

23) Collaαenase (Interstitial) Antagonists

In another embodiment, the fibrosis-inhibiting compound is a collagenase (interstitial) antagonist (e.g., IBFB-212543 (IBFB Pharma), Pharmaprojects No. 3762 (Sanofi-Aventis), S-0885 (CAS No. 117517-22-3) (Sanofi-Aventis), SC-40827 (CAS No. 101470-42-2) (Pfizer), or an analogue or derivative thereof).

24) CXCR (2. 4) Antagonists

In another embodiment, the fibrosis-inhibiting compound is a CXCR (2, 4) antagonist (e.g., SB-656933 (GlaxoSmithKline), AMD3100 octahydrochloride (CAS No. 155148-31-5), or an analogue or derivative thereof).

25) Cvclin Dependent Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a cyclin dependent kinase (CDK) inhibitor. In certain embodiments, the cyclin dependent kinase inhibitor is a CDK-1 inhibitor. In certain embodiments, the cyclin dependent kinase inhibitor is a CDK-2 inhibitor. In certain embodiments, the cyclin dependent kinase inhibitor is a CDK- 4 inhibitor. In certain embodiments, the cyclin dependent kinase inhibitor is a CDK-6 inhibitor. Representative examples of cyclin dependent kinase inhibitors include CAK1 inhibitors from GPC Biotech and Bristol-Myers Squibb, RGB- 286199 (GPC Biotech), or an analogue or derivative thereof.

Additional exemplary cyclin dependent protein kinase inhibitors include an anticancer agent from Astex Technology, a CAK1 inhibitor from GPC Biotech, a CDK inhibitor from Sanofi-Aventis, a CDK1/CDK2 inhibitor from Amgen, a CDK2 inhibitor from SUGEN-2 (Pfizer), a hearing loss therapy agent (Sound Pharmaceuticals), PD-0332991 (Pfizer), RGB-286199 (GPC Biotech), Ro-0505124 (Hoffmann-La Roche), a Ser/Thr kinase inhibitor from Lilly (EIi Lilly), CVT-2584 (CAS No. 199986-75- 9) (CV Therapeutics), CGP 74514A, bohemine, olomoucine (CAS No. 101622-51-9), indole-3-carbinol (CAS No. 700-06-1), and an analogue or derivative thereof.

26) Cvclooxyqenase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a cyclooxygenase inhibitor (e.g., NS-398 (CAS No. 123653-11-2), ketoprofen, or an analogue or derivative thereof). In some embodiments, the cyclooxygenase inhibitor is a COX-1 inhibitor such as triflusal, or an analogue or derivative thereof).

27) Dihydroorotate Dehydrogenase Inhibitor (PHFR) Inhibitors In another embodiment, the fibrosis-inhibiting compound is a

DHFR inhibitor (e.g., PDX (Allos Therapeutics), SC12267, sulfamerazine (CAS No. 127-79-7), or an analogue or derivative thereof).

28) Dual lntegrin Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a dual integrin inhibitor (e.g., R411 (Roche Pharmaceuticals), or an analogue or derivative thereof).

29) Elastase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an elastase inhibitor (e.g., orazipone, depelestat (CAS No. 506433-25-6) (Dyax), AE-3763 (Dainippon), or an analogue or derivative thereof). 30) Elongation Factor-1 Alpha Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an elongation factor-1 alpha inhibitor (e.g., aplidine, or an analogue or derivative thereof).

31) Endothelial Growth Factor Antagonists

In another embodiment, the fibrosis-inhibiting compound is an endothelial growth factor (EGF) antagonist (e.g., neovastat, NM-3 (Mercian), or an analogue or derivative thereof).

32) Endothelial Growth Factor Receptor Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an endothelial growth factor receptor (EGF-R) kinase inhibitor (e.g., sorafenib tosylate (Bayer), AAL-993 (Novartis), ABP-309 (Novartis), BAY-57-9352 (Bayer), BIBF-1120 (Boehringer Ingelheim), E-7080 (Eisai), EG-3306 (Ark Therapeutics), EXEL-2880 (Exelixis), GW-654652 (GlaxoSmithKline), lavendustin A (CAS No. 125697-92-9), a KDR inhibitor from LG Life Sciences, CT-6685 or CT-6729 (UCB)1 KRN-633 or KRN-951 (Kirin Brewery), OSI-930 (OSI Pharmaceuticals), SP-5.2 (Supratek Pharma), SU- 11657 (Pfizer), a Tie-2 antagonist (Hybrigenics), a VEGF-R inhibitor such as SU 1498, a VEGFR-2 kinase inhibitor (Bristol-Myers Squibb), XL-647 (Exelixis), a KDR inhibitor from Abbott Laboratories, or an analogue or derivative thereof).

In another embodiment, the fibrosis-inhibiting compound is an endothelial growth factor receptor 2 kinase inhibitor (e.g., sorafenib tosylate, or an analogue or derivative thereof).

33) Endotoxin Antagonists

In another embodiment, the fibrosis-inhibiting compound is an endotoxin antagonist (e.g., E5564 (Eisai Pharmaceuticals), or an analogue or derivative thereof). 34) Epothilone and Tubulin Binders

In another embodiment, the fibrosis-inhibiting compound is an epothilone or tubulin binder (e.g., ixabepilone (BMS), or an analogue or derivative thereof).

35) Estrogen Receptor Antagonists

In another embodiment, the fibrosis-inhibiting compound is an estrogen receptor antagonist (e.g., ERB-041 (Wyeth), or an analogue or derivative thereof).

36) FGF Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a FGF inhibitor (e.g., IDN-5390 (Indena), or an analogue or derivative thereof).

37) Farnexy) Transferase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an inhibitor of farnexyl transferase (FTI). In certain embodiments, the FTI inhibits the RAS oncogene family. Examples of FTI's include SARASAR (from Schering Corporation, Kenilworth, NJ), or an analogue or derivative thereof.

38) Famesyltransferase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a famesyltransferase inhibitor (e.g., A-197574 (Abbott), a famesyltransferase inhibitor from Servier, FPTIII (Strathclyde Institute for Drug R), LB-42908 (LG Life Sciences), Pharmaprojects No. 5063 (Genzyme), Pharmaprojects No. 5597 (Ipsen), Yissum Project No. B-1055 (Yissum), or an analogue or derivative thereof). 39) FLT-3 Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a FLT-3 kinase inhibitor (e.g., Amphora, or an analogue or derivative thereof).

40) FGF Receptor Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a FGF receptor kinase inhibitor (e.g., MED-A300 (Gerolymatos), SSR-128129 (Sanofi-Aventis), TBC-2250 (Encysive Pharmaceuticals), XL-999 (Exelixis), or a FGF receptor kinase inhibitor from Paradigm Therapeutics, or an analogue or derivative thereof).

41) Fibrinogen Antagonists

In another embodiment, the fibrosis-inhibiting compound is a fibrinogen antagonist (e.g., AUV-201 (Auvation), MG-13926 (Sanofi- Aventis), plasminogen activator (CAS No. 105913-11-9) (from Sanofi- Aventis or UCB), plasminogen activator-2 (tPA-2) (Sanofi-Aventis), pro- urokinase (CAS No. 82657-92-9) (Sanofi-Aventis), mevastatin, or an analogue or derivative thereof).

42) Heat Shock Protein 90 Antagonists

In another embodiment, the fibrosis-inhibiting compound is a heat shock protein 90 antagonist (e.g., SRN-005 (Sirenade), geldanamycin or a derivative thereof, such as NSC-33050 (17-allylaminogeldanamycin; 17-AAG) or 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17- DMAG), rifabutin (rifamycin XIV, 1\4-didehydro-1-deoxy-1 ,4-dihydro-5'-(2- methylpropyl)-1-oxo-), radicicol, Humicola fuscoatra (CAS No. 12772-57-5), or an analogue or derivative thereof).

43) Histone Deacetylase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a histone deacetylase inhibitor (e.g., FK228 (Gloucester), trichostatin A from Streptomyces sp. (CAS No. 58880-19-6), or an analogue or derivative thereof).

44) HMGCoA Reductase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an HMGCoA reductase inhibitor (e.g., an atherosclerosis therapeutic from Lipid Sciences, ATΪ-16000 (ARYx Therapeutics), KS-01-019 (Kos Pharmaceuticals), Pharmaprojects No. 2197 (Sanofi-Aventi), RP 61969 (Sanofi-Aventis), cerivastatin Na )CAS No. 143201-11-0), or an analogue or derivative thereof).

45) ICAM Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an ICAM inhibitor (e.g., alicaforsen (CAS No. 185229-68-9) (ISIS Pharmaceuticals), an ICAM-5 modulator (such as ICAM-4 from ICOS), or an analogue or derivative thereof). .. . ~

46) IL-1 , ICE & IRAK Antagonists

In another embodiment, the fibrosis-inhibiting compound is an IL-1 , ICE & IRAK antagonist (e.g., CJ-14877 or CP-424174 (Pfizer), NF-61 (Negma-Lerads), or an analogue or derivative thereof).

47) IL-2 Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an IL-2 inhibitor (e.g., AVE 8062 (Sanofi-Aventis), or an analogue or derivative thereof).

48) Immunosuppressants

Jn another embodiment, the fibrosis-inhibiting compound is an immunosuppressant (e.g., teriflunomide (Sanofi Aventis), chlorsulfaquinoxalone (NSC-339004), chlorsulfaquinoxalone sulfate, CS-712 (Sankyo), ismomυltin alfa (CAS No. 457913-93-8) (Akzo Nobel), antiallergics from GenPat77, antiinflammatories or AT-005 (Androclus Therapeutics), autoimmune disease therapeutics from EpiVax, BN-007 (Bone), budesonide (CAS No. 51333-22-3) (MAP Pharmaceuticals), CO-14 (Genzyme), edratide (CAS No. 433922-67-9) (Teva), EP-314 (Enanta), eprovafen (CAS No. 101335-99-3) (Sanofi-Aventis), HWA-131 (CAS No. 118788-41-3) (Sanofi-Aventis), immunomodulators from MerLion Pharmaceuticals, immunosuppressives from Alchemia, IPL-12 (Inflazyme), MDL-9563 (CAS No. 27086-86-8) (Sanofi-Aventis), Pharmaprojects No. 2330 (Sanofi-Aventis), Pharmaprojects No. 6426 (Abgenix), PXS-25 (Pharmaxis), rosmarinic acid (CAS No. 20283-92-5) (Sanofi-Aventis), RP 42927 or RP 54745 (CAS No. 135330-08-4) (Sanofi-Aventis), SGN-35 (Seattle Genetics), ST-1959 (Sigma-Tau), type I diabetes therapy from SYNX Pharma, UNIL-88 (Debiopharm), VP-025 (Vasogen), VR-694 (Vectura), PRTX-001 (Protalex), or an analogue or derivative thereof).

49) IMPDH (inosine monophosphate)

In another embodiment, the fibrosis-inhibiting compound is IMPDH (inosine monophosphate) (e.g., ribavirin (Hoffmann-La Roche) or an analogue or derivative thereof).

50) Inteqrin Antagonists

In another embodiment, the fibrosis-inhibiting compound is an integrin antagonist (e.g., 683699 from Glaxo Smith Kline, integrin antagonists from Jerina AG (Germany), or an analogue or derivative thereof).

51) lnterleukin Antagonists

In another embodiment, the fibrosis-inhibiting compound is an interleukin antagonist (e.g., dersalazine, or an analogue or derivative thereof). In another embodiment, the fibrosis-inhibiting compound is an interleukin 1 antagonist (e.g., NPI-1302a-3, or an analogue or derivative thereof).

52) Inhibitors of Type III Receptor Tyrosine Kinases

In another embodiment, the fibrosis-inhibiting compound is an inhibitor of type III receptor tyrosine kinase such as FLT3, PDGRF and c-KIT (e.g., MLN518 (Millenium Pharmaceuticals), or an analogue or derivative thereof).

53) Irreversible Inhibitors of Enzyme Methionine Aminopeptidase Type 2

In another embodiment, the fibrosis-inhibiting compound is an irreversible inhibitor of enzyme methionine aminopeptidase type 2 (e.g., PPI-2458 (Praecis Pharmaceuticals), or analogue or derivative thereof).

54) Isozvme-Selective Delta Protein Kinase C Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an isozyme-selective delta protein kinase C inhibitor (e.g., KAI-9803 (Kai Pharmaceuticals), or an analogue or derivative thereof).

55) JAK3 Enzyme Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a JAK3 enzyme inhibitor (e.g., CP-690,550 (Pfizer), or an analogue or derivative thereof).

56) JNK Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a JNK inhibitor (e.g., BF-67192 (BioFocus), XG-101 or XG-102 (Xigen), or an analogue or derivative thereof). 57) Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a kinase inhibitor (e.g., a kinase inhibitors from EVOTEC, or an analogue or derivative thereof).

58) Kinesin Antagonist

In another embodiment, the fibrosis-inhibiting compound is a kinesin antagonist (e.g., SB-715992 and an antifungal from Optokinetics, or an analogue or derivative thereof).

59) Leukotriene Inhibitors and Antagonists

In another embodiment, the fibrosis-inhibiting compound is a leukotriene inhibitor or antagonist (e.g., ambicromil (CAS No. 58805-38-2) (Sanofi-Aventis), amelubant (CAS No. 346735-24-8) (Boehringer Ingelheim), DW-1141 (Dong Wha), ebselen (Daiichi Pharmaceutical), ibudilast (Kyorin), leucotriene inhibitors from Sanofi-Aventis, lymphotoxin - beta receptor (LT-β) from Biogen Idee, Pharmaprojects No. 1535 or 2728 (CAS No. 119340-33-9) (Sanofi-Aventis), R-112 (Rigel), Rev-5367 (CAS No. 92532-05-3) (Sanofi-Aventis), RG-14893 (CAS No. 141835-49-6) (Sanofi- Aventis), RG-5901-A (CAS No. 101910-24-1), 92532-23-5, RP 66153 (CAS No. 142422-79-5), RP 66364 (CAS No.186912-92-5), or RP 69698 (CAS No. 141748-00-7) (Sanofi-Aventis), SC-411930 (Pfizer), SC-41930 (CAS No. 120072-59-5) (Pfizer), SC-50605 (CAS No. 138828-39-4) (Pfizer), SC- 51146 (CAS No. 141059-52-1) or SC-53228 (CAS No. 153633-01-3) (Pfizer), spaglumic acid (ZY-15106) (CAS No.3106-85-2) or 80619-64-3 (Novartis), tipredane (CAS No. 85197-77-9) (Bristol-Myers Squibb), U- 75302 (CAS No. 119477-85-9) (Pfizer), or analogue or derivative thereof).

60) MAP Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a MAP kinase inhibitor (e.g., SRN-003-556 (Sirenade), AEG-3482 (AEgera), ARRY-142886 (Array BioPharma), CDP-146 (UCB), or analogue or derivative thereof).

61) Matrix Metalloproteinase Inhibitors (MMPI)

In another embodiment, the fibrosis-inhibiting compound is a matrix metalloproteinase inhibitor. A variety of MMPI's may be used in the practice of the invention. In one embodiment, the MMPI is a MMP-1 inhibitor. In another embodiment, the MMPI is a MMP-2 inhibitor. In other embodiments, the MMPI is a MMP-4, MMP-5, MMP-6, MMP-7, or MMP-8 inhibitor. Representative examples of MMPI's include glucosamine sulfate, neovastat, GM1489 (CAS No. 170905-75-6), XL784 (EXEL-01370784), TNF-a Protease lnhibitor-1 or 2 (TAPM or TAPI-2), galardin, or an analogue or derivative thereof.

62) MCP- CCR2 Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a MCP-CCR2 inhibitor (e.g., MLN 1202 (Millennium Pharmaceuticals), or an analogue or derivative thereof).

63) mTOR Inhibitor

In another embodiment, the fibrosis-inhibiting compound is an mTOR inhibitor {e.g., temsirolimus (CAS No. 162635-04-3) (Wyeth), or an analogue or derivative thereof).

64) mTOR Kinase Inhibitor

In another embodiment, the fibrosis-inhibiting compound is an mTOR kinase inhibitor (e.g., ABT-578 (Abbott), temsirolimus (Wyeth), AP- 23573 (Ariad), or an analogue or derivative thereof). 65) Microtubule Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a microtubule inhibitor {e.g., antibody-maytansinoid conjugates from Biogen Idee, colchicines (MantiCore Pharmaceuticals), anticancer immunoconjugates from Johnson & Johnson, DIME from Octamer, gni-1f (GNI), huC242-DM4 or huMy9-6-DM1 (ImmunoGen), IDN-5404 (Indena), IMO-098 or IMOderm (Imotep), mebendazole (Introgen Therapeutics), microtubule poisons from Cambridge Enterprise, paclitaxel such as LOTAX from Aphios (CAS No. 33069-62-4), Genexol-PM from Samyang, Pharmaprojects No. 6383 (Tapestry Pharmaceuticals), RPR-112378 (Sanofi-Aventis), SGN-75 (Seattle Genetics), SPL-7435 (Starpharma), SSR- 250411 (Sanofi-Aventis), trastuzumab-DM1 (Genentech), vinorelbine, dolastatin 15 (CAS No. 123884-00-4) or an analogue or derivative thereof).

In certain embodiments, the microtubule inhibitor is a microtubule polymerization inhibitor such as vincamine, or an analogue or derivative thereof).

66) MIF Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a MIF inhibitor (e.g., AVP-13546 (Avanir), an MIF inhibitor from Genzyme, migration stimulation factor D, or an analogue or derivative thereof).

67) MMP (Stromolvsin) Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a MMP (stromolysin) inhibitor (e.g., anticancer tetracycline from Tetragenex, rhostatin (BioAxone), TIMP's from Sanofi-Aventis (CAS No. 86102-31-0), and MMP inhibitors form Cognosci and Tetragenex, or an analogue or derivative thereof). 68) Neurokinin (NK) Antagonist

In another embodiment, the fibrosis-inhibiting compound is a neurokinin (NK) antagonist (e.g., anthrotainin (CAS No. 148084-40-6) (Sanofi-Aventis), an IBS thereapeutic such as SLV-332 from ArQuIe, MDL- 105212A (CAS No. 167261-60-1) (Ssanofi-Aventis), Pharmaprojects No. 2744, 3258 (CAS No. 139167-47-8) 4006, 4201 , or 5986 (Sanofi-Aventis), RP 67580 (CAS No. 135911-02-3), SR-144190 (CAS No. 201152-86-5), SSR-240600 or SSR-241586 (Sanofi-Aventis), TKA-457 (Novartis), vestipitant mesylate (CAS No. 334476-64-1) (GlaxoSmithKline), Win-64821 (Sanofi-Aventis), PRX-96026 (Predix Pharmaceuticals), or an analogue or derivative thereof).

69) NF kappa B Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a NF kappa B (NFKB) inhibitor (e.g., emodin (CAS No. 518-82-1), AVE-0545 or AVE-0547 (Sanofi-Aventis), bortezomib (CAS No. 179324-69-7) (Millennium Pharmaceuticals), dexanabinol (CAS No. 112924-45-5) (Pharmos), dexlipotam (Viatris), Pharmaprojects No. 6283 (INDRA) (OXiGENE), IPL-576092 (CAS No. 137571-30-3) (Inflazyme), NFKB decoy (Corgentech), NFKB decoy oligo (AnGes MG), NFKB's from Ariad, osteoporosis treatments or S5 (F005) from Fulcrum Pharmaceuticals, P61 (Phytopharm), R-flurbiprofen (CAS No. 5104-49-4) (Encore Pharmaceuticals), Bay 11-7085, or an analogue or derivative thereof).

70) Nitric Oxide Agonists

In another embodiment, the fibrosis-inhibiting compound is a nitric oxide agonist (e.g., Acclaim, Angx-1039 or Angx-3227 (Angiogenix), CAS-1609 (CAS No. 158590-73-9) (Sanofi-Aventis), GCI-503 (Spear Therapeutics), HCT-3012 (CAS No. 163133-43-5) (NicOx), hydralazine + ISDN (NitroMed), isosorbide dinitrate, Diffutab (CAS No. 87-33-2) (Eurand), isosorbide mononitrate (CAS No. 16051-77-7) from AstraZeneca, Schering AGor Schwarz Pharma, LA-419 (Lacer), molsidomine (CAS No. 25717-80- 0) (from Takeda and Therabel), NCX-1000, NCX-2057, or NCX-4040 (NicOx), nitric oxide (ProStrakan), nitroglycerin in the form of a nitroglycerin patch, such as DERMATRANS from (Rottapharm), nitroglycerin (CAS No. 55-63-0) (from Cellegy Pharmaceuticals, Forest Laboratories, NovaDel, Schwarz Pharma, and Watson), NO-releasing prodrugs (Inotek), OM-294DP (OM PHARMA), oxdralazine (CAS No. 27464-23-9) (Sanofi-Aventis), pirsidomine (CAS No. 132722-74-8) (Sanofi-Aventis), prostaglandin and NO donor (Cellegy Pharmaceuticals), upidosin derivatives (Recordati), or an analogue or derivative thereof).

71) Ornithine Decarboxylase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an ornithine decarboxylase inhibitor {e.g., aplidine, or an analogue or derivative thereof).

72) p38 MAP Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a p38 MAP kinase inhibitor (e.g., AZD-6703 (AstraZeneca), JX-401 (Jexys Pharmaceuticals), BMS-2 (Bristol-Myers Squibb), a p38 MAP kinase inhibitor from Novartis, a p38-alpha MAP kinase inhibitor from Amphora, Pharmaprojects No. 5704 (Pharmacopeia), SKF86002 (CAS No. 72873-74- 6), RPR-200765A (Sanofi-Aventis), SD-282 (Johnson & Johnson), TAK-715 (Takeda), or an analogue or derivative thereof).

73) Palmitoyl-Protein Thioesterase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a palmitoyl-protein thioesterase inhibitor (e.g., aplidine, or an analogue or derivative thereof). 74) PDGF Receptor Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a PDGF receptor kinase inhibitors (e.g., AAL-993, AMN-107, or ABP-309 (Novartis), AMG-706 (Amgen), BAY-57-9352 (Bayer), CDP-860 (UCB), E- 7080 (Eisai), imatinib (CAS No. 152459-95-5) (Novartis), OSI-930 (OSI Pharmaceuticals), RPR-127963E (Sanofi-Aventis), RWJ-540973 (Johnson & Johnson), sorafenib tosylate (Bayer), SU-11657 (Pfizer), tandutinib (CAS No. 387867-13-2) (Millennium Pharmaceuticals), vatalanib (Novartis), ZK- CDK (Schering AG), or an analogue or derivative thereof).

75) Peroxisome Proliferator-Activated Receptor Agonists

In another embodiment, the fibrosis-inhibiting compound is a peroxisome proliferator-activated receptor (PPAR) agonists (e.g., (-)- halofenate (Metabolex), AMG-131 (Amgen), antidiabetics from Japan Tobacco, AZD-4619, AZD-8450, or AZD-8677 (AstraZeneca), DRF-10945 or balaglitazone (Dr Reddy's), CS-00088 or CS-00098 (Chipscreen Biosciences), E-3030 (Eisai), etalocib (CAS No. 161172-51-6) (EIi Lilly), GSK-641597 (Ligand), GSK-677954 (GlaxoSmithKline), GW-409544 (Ligand), GW-590735 (GlaxoSmithKline), K-111 (Hoffmann-La Roche), LY- 518674 (EIi Lilly), LY-674 (Ligand), LY-929 (Ligand), MC-3001 or MC-3002 (MaxoCore Pharmaceuticals), metformin HCI + pioglitazone (CAS No. 1115- 70-4 and 112529-15-4) (such as ACTOPLUS MET from Andrx), muraglitazar (CAS No. 331741-94-7) (Bristol-Myers Squibb), naveglitazar (Ligand), oleoylethanolamide (Kadmus Pharmaceuticals), ONO-5129, pioglitazone hydrochloride (CAS No. 111025-46-8 and 112529-15-4) (Takeda), PLX-204 (Plexxikon), PPAR agonists from Genfit, PPAR delta agonists from EIi Lilly, PPAR-alpha agonists from CrystalGenomics, PPAR- gamma modulators and PPAR-β modulators from CareX, rosiglitazone maleate (CAS No. 122320-73-4 or 155141-29-0) (GlaxoSmithKline), rosiglitazone maleate/glimepir (CAS No. 155141-29-0 and 93479-97-1), such as AVANDARYL or rosiglitazone maleate/metformin extend (CAS No. 155141-29-0 and 657-24-9) such as AVANDAMET, or rosiglitazone maleate+metformin, such as AVANDAMET (GlaxoSmithKline), tesaglitazar (AstraZeneca), LBM642, WY-14,643 (CAS No. 50892-23-4), or an analogue or derivative thereof).

In certain embodiments, the PPAR Agonist is a PPARα agonist such as GW7647 or fenofibric acid (CAS No. 42017-89-0), a PPAR γ agonist such as MCC-555 (CAS No. 161600-01-7), GW9662 or GW1929, a PPAERδ agonist such as GW501516, a PPARβ and PPARδ agonist such L- 165,041 (CAS No. 79558-09-1), or an analogue or derivative thereof.

76) Phosphatase Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a phosphatase inhibitor (e.g., diabetes thereapy such as SQMO3, SQDM38, SQDM60 from Sequenom, Pharmaprojects No. 4191 (Sanofi-Aventis), PRL- 3 inhibitors from Genzyme, WIP1 inhibitors from Amgen, or an analogue or derivative thereof).

77) Phosphodiesterase (PDE) Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a phosphodiesterase (PDE) inhibitor (e.g., avanafil (Tanabe Seiyaku), dasantafil (CAS No. 569351-91-3) (Schering-Plough), A-906119 (CAS No. 134072-58-5) or DL-850 (Sanofi-Aventis), GRC-3015, GRC-3566, or GRC- 3886 (Glenmark), HWA-153 (CAS No. 56395-66-5) (Sanofi-Aventis), hydroxypumafentrine (Altana), IBFB-130011, IBFB-14-016, IBFB-140301 , IBFB-150007, or IBFB-211913 (IBFB Pharma), L-826141 (Merck & Co), medorinone (CAS No. 88296-61-1) (Sanofi-Aventis), MEM-1917 (Memory Pharmaceuticals), ND-1251 (Neuro3d), PDE inhibitors from ICOS, PDE IV inhibitors from Memory Pharmaceuticals and CrystalGenomics, Pharmaprojects No. 2742 and 6141 (Sanofi-Aventis), QAD-171 (Novartis), RHC-2963 (CAS No. 76993-12-9 and 76993-14-1), RPR-117658, RPR- 122818 derivatives, SR-24870 , and RPR-132294 (Sanofi-Aventis), SK-350 (ln2Gen), stroke therapy agents from deCODE Genetics, TAS-203 (Taiho), tofimilast (CAS No. 185954-27-2) (Pfizer), UK-371800 (Pfizer), WIN-65579 (CAS No. 158020-82-7) (Sanofi-Aventis), IBFB-130020 (IBFB Pharma), OPC-6535 (CAS No. 145739-56-6) (Otsuka), theobromine (CAS No. 83-67- 0), papverine hydrochloride (CAS No. 61-25-6), quercetin dehydrate (CAS No. 6151-25-3), YM 976 (CAS No. 191219-80-4), irsogladine (CAS No. 57381-26-7), or an analogue or derivative thereof).

In one embodiment, the phosphodiesterase inhibitor is a phosphodiesterase III inhibitor (e.g., enoximone, or an analogue or derivative thereof). In other embodiments, the phosphodiesterase inhibitor is a phosphodiesterase IV inhibitor (e.g., fosfosal, Atopik (Barrier Therapeutics), triflusal, or an analogue or derivative thereof). In other embodiments, the phosphodiesterase inhibitor is a phosphodiesterase V inhibitor.

78) PKC Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a PKC inhibitor (e.g., HMR-105509 or P-10050 (Sanofi-Aventis), JNJ- 10164830 (Johnson & Johnson), Ro-31-8425 (CAS No. 131848-97-0), NPC- 15437 dihydrochloride (CAS No. 136449-85-9), or an analogue or derivative thereof).

In one embodiment, the PKC inhibitor is an inhibitor of PKC beta (e.g., ruboxistaurin (EIi Lilly), or an analogue or derivative thereof).

79) Platelet Activating Factor Antagonists

In another embodiment, the fibrosis-inhibiting compound is a platelet activating factor antagonist (e.g., dersalazine, or an analogue or derivative thereof). 80) Platelet-Derived Growth Factor Receptor Kinase Inhibitors In another embodiment, the fibrosis-inhibiting compound is a platelet-derived growth factor receptor kinase inhibitor (e.g., sorafenib tosylate, Raf or Ras inhibitors such as sorafenib tosylate from Bayer and Onyx Pharmaceuticals, or an analogue or derivative thereof).

81) Prolyl Hydroxylase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a prolyl hydroxylase inhibitor (e.g., FG-2216 (CAS No. 11096-26-7) or HIF agonists from FibroGen, or an analogue or derivative thereof).

82) Polymorphonuclear Neutrophil Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a polymorphonuclear neutrophil inhibitor (e.g., orazipone, or an analogue or derivative thereof).

83) Protein Kinase B Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a protein kinase B inhibitor (e.g., Akt-1 inhibitors from Amphora, or an analogue or derivative thereof).

84) Protein Kinase C Stimulants

In another embodiment, the fibrosis-inhibiting compound is a protein kinase C stimulant (e.g., bryostatin-1 , or analogue or derivative thereof).

85) Purine Nucleoside Analogues

In another embodiment, the fibrosis-inhibiting compound is a purine nucleoside analogue (e.g., cladrinbine and formulations thereof, such as MYLINAX from Serone SA and IVAX Research Inc. (Miami, FL), or an analogue or derivative thereof). 86) Purinoreceptor P2X Antagonist

In another embodiment, the fibrosis-inhibiting compound is a purinoreceptor P2X antagonist (e.g., AZD-9056 (AstraZeneca), R-1554 (Hoffmann-La Roche), AR-C118925XX (AstraZeneca), suramin (CAS No. 129-46-4), P2Y4 receptor from Euroscreen, or an analogue or derivative thereof).

87) Raf Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a Raf kinase inhibitor (e.g., sorafenib tosylate, or an analogue or derivative thereof).

88) Reversible Inhibitors of ErbB1 and ERbB2

In another embodiment, the fibrosis-inhibiting compound is a reversible inhibitor (e.g., lapatinib (GSK), or an analogue or derivative thereof).

89) Ribonucleoside Triphosphate Reductase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a cytoplasmic tyrosine kinase inhibitor such as a SRC inhibitor (e.g., SRN-004 (Sirenade), gallium maltolate (Titan Pharmaceutcals), or an analogue or derivative thereof), or an analogue or derivative thereof).

90) SDF-1 Antagonists

In another embodiment, the fibrosis-inhibiting compound is a SDF-1 antagonist (e.g., CTCE-9908 (Chemokine Therapeutics), or an analogue or derivative thereof).

91) Sheddase Inhibitor In another embodiment, the fibrosis-inhibiting compound is a sheddase inhibitor (e.g., INCB-7839 (Incyte Corporation), or an analogue or derivative thereof).

92) SRC Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a SRC inhibitor (e.g., SRN-004 (Sirenade), or an analogue or derivative thereof).

In certain embodiments, the SRC inhibitor is a SRC kinase inhibitor (e.g., AZD0530 (AstraZeneca), or an analogue or derivative thereof).

93) Stromelvsin Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a stromelysin inhibitor (e.g., glucosamine sulfate, or an analogue or derivative thereof).

94) Syk Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a syk kinase inhibitor (e.g., R406 (Rigel), or an analogue or derivative thereof).

95) Telomerase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a telomerase inhibitor (e.g., AS-1410 (Antisoma), or an analogue or derivative thereof).

96) TGF Beta Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a TGF beta inhibitor (e.g., pirfenidone (CAS No. 53179-13-8) (MARNAC), tranilast (CAS No. 53902-12-8) (Kissei), IN-1130 (ln2Gen), mannose-6- phosphate (BTG), TGF-β antagonists from Inflazyme (Pharmaprojects No. 6075), TGF-β antagonists (e.g., 1090 and 1091 from Sydney; non-industrial source), TGF-β I receptor kinase inhibitors from EIi Lilly, TGF-β receptor inhibitors from Johnson & Johnson, or an analogue or derivative thereof).

97) TNFα Antagonists and TACE Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a TNFα antagonist or TACE inhibitors (e.g., adalimumab (CAS No. 331731- 18-1) (Cambridge Antibody Technology), AGIX-4207 (AtheroGenics), AGT-1 (Advanced Biotherapy), an anti-inflammatory from Borean Pharma, Cellzome, or Paradigm Therapeutics, anti-inflammatory vaccine (TNF-alpha kinoid) from Neovacs, humanized anti-TNF antibody or an anti-TNF MAb (CB0006) Celltech (UCB), apratastat (CAS No. 287405-51-0) (Wyeth), BMS-561392 (Bristol-Myers Squibb), BN-006 (Bone), certolizumab pegol (CAS No. 428863-50-7 or CH-138 (UCB), cilomilast (CAS No. 153259-65-5) (GlaxoSmithKline), CFM (Nuada Pharmaceuticals), CRx- 11.9 (CombinatoRx), D-5410 (UCB), dacopafant (CAS No. 125372-33-0) (Sanofi- Aventis), dersalazine (CAS No. 188913-57-7/188913-58-8) (Uriach), etanercept (CAS No. 185243-69-0) (Amgen), ethyl pyruvate (Critical (Critical Therapeutics), golimumab (CAS No. 476181-74-5) (Johnson & Johnson), hormono-immunotherapy from Ipsen, CDP571 (e.g., humicade from UCB), IC-485 (ICOS), infliximab (CAS No. 170277-31-3) (Johnson & Johnson), IP- 751 (Manhattan Pharmaceuticals), ISIS-104838 (CAS No. 250755-32-9) (ISIS Pharmaceuticals), lenalidomide (CAS No. 191732-72-6) (Celgene), lentinan (CAS No. 37339-90-5) (Ajinomoto), MDL-201112 (CAS No. 142130-73-2) (Sanofi-Aventis), medroxyprogesterone (CAS No. 520-85-4) (InKine Pharmaceutical), N-acetylcysteine (CAS No. 616-91-1) (Zambon), NBE-P2 (DIREVO Biotech), nerelimomab (CAS No. 162774-06-3) (Chiron), OM-294DP (OM PHARMA), onercept (CAS No. 199685-57-9) (Yeda), PASSTNF-alpha (Verigen), pentoxifylline or oxypentifylline (Sanofi-Aventis), Pharmaprojects No. 4091, 4241, 4295, or 4488 (Sanofi-Aventis), Pharmaprojects No. 5480 (Amgen), Pharmaprojects No. 6749 (Cengent), pirfenidone (CAS No. 53179-13-8) (MARNAC), RPR-132294 (Sanofi- Aventis), S5 (F002) (Fulcrum Pharmaceuticals), simvastatin (CAS No. 79902-63-9) (Merck & Co), STA-6292 (Synta Pharmaceuticals), tacrolimus (CAS No. 104987-11-3) (from Fujisawa LifeCycle Pharma), talactoferrin alfa (CAS No. 308240-58-6) (Agennix), thalidomide (CAS No. 50-35-1) (Celgene), TNF antagonists form ProStrakan, and Synergen, TNF inhibitors (Amgen), TNF-alpha antagonists from Dynavax Technologies and Jerina AG (Germany), TNF-alpha inhibitors from IBFB Pharma and Xencor (Xencor), torbafylline (CAS No. 105102-21-4) (Sanofi-Aventis), UR-1505 (Uriach), VT-346 (Viron Therapeutics), YSIL6 (Y's Therapeutics), YSTH2 (Y's Therapeutics), NPI-1302a-3 (Nereus Pharmaceuticals, a TNF antagonist from Jerina AG (Germany), dersalazine, or an analogue or derivative thereof).

98) Tumor Necrosis Factor Antagonists

In another embodiment, the fibrosis-inhibiting compound is a tumor necrosis factor (TNF) antagonist (e.g., anti-inflammatory compounds from Biota Inc., or an analogue or derivative thereof).

99) Toll Receptor Antagonists

In another embodiment, the fibrosis-inhibiting compound is a Toll receptor antagonist (e.g., E5564 (Eisai Pharmaceuticals), or an analogue or derivative thereof).

100) Tubulin Antagonist

In another embodiment, the fibrosis-inhibiting compound is a tubulin antagonist (e.g., synthadotin, KRX-0403 (Keryx Biopharmaceuticals), or an analogue or derivative thereof). 101) Tyrosine Kinase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a tyrosine kinase inhibitor (e.g., SU-011248 (e.g., SUTENT from Pfizer Inc. (New York, NY), BMS-354825, PN-355 (Paracelsian Pharmaceuticals), AGN-199659 (Allergan), (e.g., AAL-993 or ABP-309 (Novartis), adaphostin (NIH), AEE-788 (Novartis), AG-013736 (OSI Pharmaceuticals), AG-13736 (Pfizer), ALT-110 (Alteris Therapeutics), AMG-706 (Amgen), anticancer MAbs from Xencor, anti-EGFrvlll MAbs from Abgenix, anti-HER2 MAb from Abiogen, AZD-2171 or AZD-9935 (AstraZeneca), BAY-57-9352 (Bayer), BIBF-1120 (Boehringer Ingelheim), CEP-5214 (Cephalon), CEP-7055 (Cephalon), cetuximab (ImCIone Systems), CHIR-200131 and CHIR-258 (Chiron), CP-547632 (OSI Pharmaceuticals), CP-724714 (Pfizer), CT-301 (Creabilis Therapeutics), D-69491 (Baxter International), E-7080 (Eisai), EG-3306 (Ark Therapeutics), EGFR/ErbB2 inhibitors from Array BioPharma, erlotinib (CAS No. 183319-69-9) (OSI Pharmaceuticals), EXEL-2880 (Exelixis), FK-778 (Sanofi-Aventis) , gefitinib (CAS No. 184475-35-2) (AstraZeneca), GW-2286 or GW-654652 (GlaxoSmithKline), her2/neu antigen from AlphaVax, HER-2/neu inhibitor from Generex, Herzyme (Medipad) (Sima Therapeutics), HKI-272 (Wyeth), HuMax-EGFr (Genmab), idronoxil (CAS No. 81267-65-4) (Novogen), IGF-1 inhibitors from Ontogen, IMC-11F8 (ImCIone Systems), kahalalide F (CAS No. 149204-42-2) (PharmaMar), KDR inhibitor from LG Life Sciences, KDR inhibitors from Abbott Laboratories, KDR kinase inhibitors (UCB), Kdr kinase inhibitors from Merck & Co, KRN-633 and KRN-951 (Kirin Brewery), KSB-102 (Xenova), lapatinib ditosylate (CAS No. 388082-78-8) (GlaxoSmithKline), matuzumab (Merck KGaA), MDX-214 (Medarex), ME-103 (Pharmexa), MED-A300 (Gerolymatos), MNAC-13 (Lay Line Genomics), nimotuzumab (Center of Molecular Immunology), NSC-330507 or NSC-707545 (NIH), NV-50 (Novogen), OSI-930 (OSI Pharmaceuticals), panitumumab (Abgenix), pelitinib (CAS No. 287933-82-7) (Wyeth), pertuzumab (CAS No. 380610-27- 5) (Genentech), Pharmaprojects No. 3985 (Sanofi-Aventis), prostate cancer therapeutics from Sequenom (SQPC35, SQPC36, SQPC90), removab and remoxab (Trion Pharma), RG-13022 (CAS No. 136831-48-6), RG-13291 (CAS No. 138989-50-1), or RG-14620 (CAS No. 136831-49-7) (Sanofi- Aventis), RM-6427 (Romark), RNAi breast cancer therapy from Benitec, RP 53801 (CAS No. 125882-88-4) (Sanofi-Aventis), sorafenib tosylate (Bayer), SlM 1657 (Pfizer), Tie-2 antagonists from Semaia (Hybrigenics), Tie-2 inhibitors from Ontogen, trastuzumab (CAS No. 180288-69-1) (Genentech), tyrosine kinase inhibitors from Sanofi-Aventis, U3-1287, U3-1565, U3-1784, or U3-1800 (U3 Pharma), vatalanib (Novartis), VEGFR-2 kinase inhibitor from Bristol-Myers Squibb, XL-647 (Exeiixis), ZD-6474 (AstraZeneca), ZK- CDK (Schering AG), herbimycin A, or an analogue or derivative thereof).

In certain embodiments, the tyrosine kinase inhibitor is an EGFR tyrosine kinase inhibitor such as EKB-569 (Wyeth), or an analogue or derivative thereof).

102) VEGF Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a VEGF Inhibitor (e.g., AZD2171 (AstraZeneca), or an analogue or derivative thereof).

103) Vitamin D Receptor Agonists

In another embodiment, the fibrosis-inhibiting compound is a vitamin D receptor agonist (e.g., BXL-628, BXL-922 (BioXell), or an analogue or derivative thereof).

104) Histamine Receptor Antagonists

In another embodiment, the fibrosis-inhibiting compound is an histamine receptor antagonist. Certain embodiments, the histamine receptor antagonists, such as H1 , H2, and H3 histamine receptor antagonists, block the production of pro-inflammatory cytokines such as TNFa and IL-1 (e.g., IL-1β). In certain embodiments, the histamine receptor antagonist inhibit NFkB activation. Representative examples of H1 histamine receptor antagonists include phenothiazines, such as promethazine, and alkylamines, such as chlorpheniramine (CAS No. 7054- 11-7), brompheniramine (CAS No. 980-71-2), fexofenadine hydrochloride, promethazine hydrochloride, loratadine, ketotifen fumarate salt, and acrivastine. Other examples of histamine receptor antagonists include broad spectrum histamine receptor antagonists such as methylxanthines (e.g., theophylline, theobromine, and caffeine). Representative examples of H2 receptor antagonists include those with a histamine-like structure including cimetidine (available under the tradename TAGAMET from SmithKline Beecham Phamaceutical Co., Wilmington, DE), ranitidine (available under the tradename ZANTAC from Warner Lambert Company, Morris Plains, NJ), famotidine (available under the tradename PEPCID from Merck & Co., Whitehouse Station, NJ), nizatidine (available under the tradename AXID from Reliant Pharmaceuticals, Inc., Liberty Corner, NJ), nizatidine, and roxatidine acetate (CAS No. 78628-28-1). Additional examples include H3 receptor antagonists (e.g., thioperamide and thioperamide maleate salt) and anti-histamines such as tricyclic dibenozoxepins, ethanolamines, ethylenediamines, piperizines, piperidines, and pthalazinones.

105) Alpha Adrenergic Receptor Antagonists

In another embodiment, the fibrosis-inhibiting compound is an alpha adrenergic receptor antagonist. Alpha adrenergic receptor antagonists may inhibit the production of pro-inflammatory cytokines such as TNFa. The alpha adrenergic receptor antagonist may be an alpha-1 and/or an alpha-2 adrenergic receptor antagonist. Representative examples of aipha-1 /alpha-2 antagonists include phenoxybenzamine. In certain embodiments, the alpha adrenergic receptor antagonist is a haloalkylamine compound or a catecholamine uptake inhibitor. Representative examples of alpha-1 adrenergic receptor antagonists include phenoxybenzamine hydrochloride and prazosin, a piperizinyl quinazoline. Representative examples of alpha-2 adrenergic receptor antagonists include imadazole based compounds such as idazoxan (CAS No. 79944-56-2), idazoxan hydrochloride, and loxapine succinate salt (CAS No. 27833-64-3). Additional examples of alpha adrenergic receptor antagonists include prazosin hydrochloride.

106) Anti-Psychotic Compounds

In another embodiment, the fibrosis-inhibiting compound is an anti-psychotic compound, such as a phenothiazine compound or an analogue or derivative thereof. In some embodiments, the fibrosis-inhibiting compound is a phenothiazine derivative capable of suppressing the production of pro-inflammatory cytokines such as TNFa and/or IL-1. Representative examples of phenothiazine compounds include chlorpromazine, fluphenazine, trifluorphenazine, mesoridazine, thioridazine, and perphenazine. Other examples of anti-psychotic compounds include thioxanthines such as chlorprothixene and thiothixene, clozapine, loxapine succinate, and olanzapine.

107) CaM Kinase Il Inhibitor

In another embodiment, the fibrosis-inhibiting compound is CaM kinase Il inhibitor, such as a lavendustin C, or an analogue or derivative thereof.

108) CaM Kinase Il Inhibitor

In another embodiment, the fibrosis-inhibiting compound is CaM kinase Il inhibitor, such as a lavendustin C, or an analogue or derivative thereof. 109) G Protein Agonist

In another embodiment, the fibrosis-inhibiting compound is G protein agonist, such as aluminum fluoride, or an analogue or derivative thereof.

110) Antibiotics and Anti-Microbials

In another embodiment, the fibrosis-inhibiting compound is an antibiotic, such as apigenin (Cas No. 520-36-5), ampicillin sodium salt (CAS No. 69-52-3), puromycin, or an analogue or derivative thereof.

In another embodiment, the fibrosis-inhibiting compound is an anti-microbial agent, such as brefeldin A (CAS No. 20350-15-6), terbinafine, benzoyl peroxide, pentamidine, ornidazole, imidazole, ketocanazole, sulconazole nitrate salt, or an analogue or derivative thereof.

111) PNA Topoisomerase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is DNA topoisomerase I inhibitor, such as β-lapachone (CAS No. 4707-32-8), or an analogue or derivative thereof.

In another embodiment, the fibrosis-inhibiting compound is DNA topoisomerase Il inhibitor, such as (-)-arctigenin (CAS No. 7770-78-7), aurintricarboxylic acid, or an analogue or derivative thereof.

112) Thromboxane A2 Receptor Inhibitor

In another embodiment, the fibrosis-inhibiting compound is thromboxane A2 receptor inhibitor, such as BM-531 (CAS No. 284464-46- 6), ozagrel hydrochloride (CAS No. 78712-43-3), or an analogue or derivative thereof. 113) D2-Dopamine Receptor Antagonist

In another embodiment, the fibrosis-inhibiting compound is a D2 dopamine receptor antagonist, such as clozapine (CAS No. 5786-21-0), mesoridazine benzenesulfonate, or an analogue or derivative thereof.

114) Peptidyl-Prolyl Cis/Trans lsomerase Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a Peptidyl-Prolyl Cis/Trans lsomerase Inhibitor, such as juglone (CAS No. 481-39-0), or an analogue or derivative thereof.

115) Dopamine Antagonists

In another embodiment, the fibrosis-inhibiting compound is a dopamine antagonist, such as thiothixene, thioridazine hydrochloride, or an analogue or derivative thereof.

116) Anesthetics

In another embodiment, the fibrosis-inhibiting compound is an anesthetic compound, such as lidocaine (CAS No. 137-58-6), or an analogue or derivative thereof.

117) Clotting Factors

In another embodiment, the fibrosis-inhibiting compound is a clotting factor, such as menadione (CAS No. 58-27-5), or an analogue or derivative thereof.

118) Lysyl Hydrolase Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a lysyl hydrolase inhibitor, such as minoxidil (CAS No. 38304-91-5), or an analogue or derivative thereof. 119) Muscarinic Receptor Inhibitor

In another embodiment, the fibrosis-inhibiting compound is a muscarinic receptor inhibitor, such as perphenazine (CAS No. 58-39-9), or an analogue or derivative thereof.

120) Superoxide Anion Generator

In another embodiment, the fibrosis-inhibiting compound is a superoxide anion generator, such as plumbagin (CAS No. 481-42-5), or an analogue or derivative thereof.

121) Steroids

In another embodiment, the fibrosis-inhibiting compound is a steroid, such as prednisolone, prednisolone 21-acetate (CAS No. 52-21-1), loteprednol etabonate, (CAS No. 82034-46-6), clobetasol propionate, or an analogue or derivative thereof.

122) Anti-Proliferative Agents

In another embodiment, the fibrosis-inhibiting compound is an antiproliferative agent, such as silibinin (CAS No. 22888-70-6), silymarin (CAS No. 65666-07-1), 1 ,2-hexanediol, dioctyl phthalate (CAS No. 117-81- 7), zirconium (IV) oxide, glycyrrhizic acid, spermidine trihydrochloride or tetrahydrochloride, CGP 74514A, spermine tetrahydrochloride, NG-methyl- L-arginine acetate salt, galardin, halofuginone hydrobromide (HBr), fascaplysin, or an analogue or derivative thereof.

123) Diuretics

In another embodiment, the fibrosis-inhibiting compound is a diuretic, such as spironolactone (CAS No. 52-01-7), or an analogue or derivative thereof. 124) Anti-Coagulants

In another embodiment, the fibrosis-inhibiting compound is an anti-coagulant, such as fucoidan from Fucus vesiculosus (CAS No. 9072- 19-9), or an analogue or derivative thereof.

125) Cyclic GMP Agonists

In another embodiment, the fibrosis-inhibiting compound is a cyclic GMP agonist, such as sinitrodil (CAS No. 143248-63-9), or an analogue or derivative thereof.

126) Adenylate Cyclase Agonist

In another embodiment, the fibrosis-inhibiting compound is an adenylate cyclase agonist, such as histamine (CAS No. 51-45-6), or an analogue or derivative thereof.

127) Antioxidants

In another embodiment, the fibrosis-inhibiting compound is an antioxidant, such as morpholine, phytic acid dipotassium salt, (-)- epigallocatechin or (-)-epigallocatechin gallate from green tea (CAS Nos. 970-74-1 and 1257-08-5, respectively), (-)-epigallocatechin gallate (CAS No. 989-51-5), nobiletin (CAS No. 478-01-3), probucol (CAS No. 23288-49-5), phosphorous acid, hesperetin, L-ascorbyl-2-phosphate, magnesium salt (CAS No. 84309-23-9), catechin, (±)-naringenin (CAS No. 67604-48-2), (-)- epicatechin, (-)-epicatechin gallate, 3-hydroxyflavone, (-)-arctigenin, or an analogue or derivative thereof.

128) Nitric Oxide Synthase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a nitric oxide synthase inhibitor, such as ammonium pyrrolidinedithiocarbamate (CAS No. 5108-96-3), or an analogue or derivative thereof. In another embodiment, the fibrosis-inhibiting compound is a reversible nitric oxide synthase inhibitor, such as NB-methyl-L-arginine acetate salt (L-NMMA) (CAS No. 53308-83-1), or an analogue or derivative thereof.

129) Anti-Neoplastic Agents

In another embodiment, the fibrosis-inhibiting compound is an antineoplastic agent, such as tirapazamine (CAS No. 27314-97-2), fludarabine (CAS No. 21679-14-1), cladribine, imatinib mesilate, or an analogue or derivative thereof.

130) DNA Synthesis Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a DNA synthesis inhibitor, such as S-(2-hydroxy-5-nitrobenyl)-6-thioguanosine or uracilfludarabine phosphate (CAS No. 75607-67-9), 6,11-dihydroxy-5,12- naphthacenedione, or an analogue or derivative thereof.

131) DNA Alkylating Agents

In another embodiment, the fibrosis-inhibiting compound is a DNA alkylating agent, such as dacarbazine (CAS No. 4342-03-4), temozolomide, procarbazine HCI, or an analogue or derivative thereof.

132) DNA Methylation Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a DNA methylation inhibitor, such as decitabine (CAS No. 2353-33-5), or an analogue or derivative thereof.

133) NSAID Agents

In another embodiment, the fibrosis-inhibiting compound is a NSAID agent, such as nabumetone, benzydamine hydrochloride, or an analogue or derivative thereof. 134) Peptidylglycine Alpha-Hydroxylatinq Monooxygenase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a peptidylglycine alpha-hydroxylating monooxygenase inhibitor, such as trans- styrylacetic acid, or an analogue or derivative thereof.

135) MEK1/MEK2 Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a MEK1/MEK 2 inhibitor, such as U0126 (CAS No. 109511-58-2), or an analogue or derivative thereof.

136) NO Synthase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an NO synthase inhibitor, such as L-NAME (CAS No. 53308-83-1), NG-Methyl- L-arginine acetate salt, or an analogue or derivative thereof.

137) Retinoic Acid Receptor Antagonists

In another embodiment, the fibrosis-inhibiting compound is retinoic acid receptor antagonist, such as isotretinoin (CAS No. 4759-48-2), or an analogue or derivative thereof.

138) ACE Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an ACE inhibitor, such as quinapril hydrochloride (CAS No. 85441-61-8), enalapril, or an analogue or derivative thereof.

139) Glvcosylation Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a glycosylation inhibitor, such as aminoguanidine hydrochloride, castanospermine, or an analogue or derivative thereof. 140) Intracellular Calcium Influx Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an intracellular calcium influx inhibitor, such as TAS-301 (CAS No. 193620-69- 8), or an analogue or derivative thereof.

141) Anti-Emetic Agents

In another embodiment, the fibrosis-inhibiting compound is an anti-emetic agent, such as amifostine (CAS No. 20537-88-6), or an analogue or derivative thereof.

142) Acetylcholinesterase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an acetylcholinesterase inhibitor, such as (-)-huperzine A (CAS No. 102518-79- 6), or an analogue or derivative thereof.

143) ALK-5 Receptor Antagonists . . _ . _ . . .

In another embodiment, the fibrosis-inhibiting compound is an ALK-5 receptor antagonist, such as SB 431542 (CAS No. 301836-41-9), or an analogue or derivative thereof.

144) RAR/RXR Antagonists

In another embodiment, the fibrosis-inhibiting compound is a RAR/RXT antagonist, such as 9-cis-retinoic acid, or an analogue or derivative thereof.

145) EIF-2a Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a elF-2a inhibitor, such as salubrinal, or an analogue or derivative thereof. 146) S-Adenosyl-L-Homocysteine Hydrolase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a S-adenosyl-L-homocysteine hydrolase inhibitor, such as 3-deazaadenosine, or an analogue or derivative thereof.

147) Estrogen Agonists

In another embodiment, the fibrosis-inhibiting compound is an estrogen agonist, such as coumestrol, bisphenol A, 1-linoleoyl-rac-glycerol (CAS No. 2277-28-3), daidzein (4,7-dihydroxy-iso-flavone), dihexyl phthalate, kaempferol, formononetin, , or an analogue or derivative thereof.

148) Serotonin Receptor Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a serotonin receptor inhibitor, such as amitriptyline hydrochloride, or an analogue or derivative thereof.

149) Anti-Thrombotic Agents

In another embodiment, the fibrosis-inhibiting compound is an anti-thrombotic agent, such as geniposidic acid, geniposide, or an analogue or derivative thereof.

150) Tryptase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a tryptase inhibitors, such as 2-azetidinone, or an analogue or derivative thereof.

151) Pesticides

In another embodiment, the fibrosis-inhibiting compound is a pesticide, such as allyl disulfide, or an analogue or derivative thereof. 152) Bone Mineralization Promotor

In another embodiment, the fibrosis-inhibiting compound is a bone mineralization promotor, such as glycerol 2-phosphate disodium salt hydrate, or an analogue or derivative thereof.

153) Bisphosphonate Compounds

In another embodiment, the fibrosis-inhibiting compound is a bisphosphonate compound, such as risedronate, or an analogue or derivative thereof.

154) Anti-Inflammatory Compounds

In another embodiment, the fibrosis-inhibiting compound is an anti-inflammatory compound, such as aucubin, cepharanthine, or an analogue or derivative thereof.

155) DNA Methylation Promotors

In another embodiment, the fibrosis-inhibiting compound is a DNA methylation promotor, such as 5-azacytidine, or an analogue or derivative thereof.

156) Anti-Spasmodic Agents

In another embodiment, the fibrosis-inhibiting compound is an anti-spasmodic agent, such as 2-hydroxy-4,6-dimethoxyacetophenone, or an analogue or derivative thereof.

157) Protein Synthesis Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a protein synthesis inhibitor, such as oxytetracycline hydrochloride, or an analogue or derivative thereof. 158) α-Glucosidase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a α-glucosidase inhibitor, such as myricetin (CAS No. 529-44-2), or an analogue or derivative thereof.

159) Calcium Channel Blockers

In another embodiment, the fibrosis-inhibiting compound is a calcium channel blocker, such as verapamil, nitrendipine, or an analogue or derivative thereof.

In another embodiment, the fibrosis-inhibiting compound is a L-type calcium channel blocker, such as nifedipine (CAS No. 21829-25-4), (+)-cis-diltiazem hydrochloride, or an analogue or derivative thereof.

In another embodiment, the fibrosis-inhibiting compound is a T-type calcium channel blocker, such as penfluridol (CAS No. 26864-56-2), or an analogue or derivative thereof.

160) Pyruvate Dehydrogenase Activators

In another embodiment, the fibrosis-inhibiting compound is a pyruvate dehydrogenase activator, such as dichloroacetic acid, or an analogue or derivative thereof.

161) Prostaglandin Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a prostaglandin inhibitor, such as betulinic acid, or an analogue or derivative thereof.

162) Sodium Channel Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a sodium channel inhibitor, such as amiloride hydrochloride hydrate, or an analogue or derivative thereof. 163) Serine Protease Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a serine protease inhibitor, such as gabexate mesylate, or an analogue or derivative thereof.

164) Intracellular Calcium Flux Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an intracellular calcium flux inhibitor, such as thapsigargin, or an analogue or derivative thereof.

165) JAK2 Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a JAK2 inhibitor (e.g., AG-490 (CAS No. 134036-52-5), or an analogue or derivative thereof).

166) Androgen Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an androgen inhibitor (e.g., tibolone (CAS No. 5630-53-5), or an analogue or derivative thereof).

167) Aromatase Inhibitors

In another embodiment, the fibrosis-inhibiting compound is an aromatase inhibitor (e.g., letrozole, or an analogue or derivative thereof).

168) Anti-Viral Agents

In another embodiment, the fibrosis-inhibiting compound is an anti-viral agent, such as imiquimod, or an analogue or derivative thereof. 169) 5-HT Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a 5-HT inhibitor, such as ketanserin tartrate, amoxapine, or an analogue or derivative thereof.

170) FXR Antagonists

In another embodiment, the fibrosis-inhibiting compound is a FXR antagonist, such as guggulsterone (CAS No. 95975-55-6), or an analogue or derivative thereof.

171) Actin Polymerization and Stabilization Promotors

In another embodiment, the fibrosis-inhibiting compound is an actin polymerization and stabilization promotor, such as jasplakinolide, or an analogue or derivative thereof.

172) AXOR 12 Agonists

In another embodiment, the fibrosis-inhibiting compound is an AXOR12 agonist, such as metastin (KiSS-1 (112-121), or an analogue or derivative thereof.

173) Angiotensin Il Receptor Antagonists

In another embodiment, the fibrosis-inhibiting compound is an angiotensin Il receptor agonist, such as losartan potassium, or an analogue or derivative thereof.

174) Platelet Aggregation Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a platelet aggregation inhibitor, such as clopidogrel, or an analogue or derivative thereof. 175) CB1/CB2 Receptor Agonists

In another embodiment, the fibrosis-inhibiting compound is a CB1/CB2 receptor agonist, such as HU-210 (CAS No. 112830-95-2), or an analogue or derivative thereof.

176) Norepinephrine Reuptake Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a norepinephrine reuptake inhibitor, such as nortriptyline hydrochloride, or an analogue or derivative thereof.

177) Selective Serotonin Reuptake Inhibitors

In another embodiment, the fibrosis-inhibiting compound is a selective serotonin reuptake inhibitor, such as paroxetine maleate, or an analogue or derivative thereof.

178) Reducing Agents

In another embodiment, the fibrosis-inhibiting compound is a reducing agent such as VVW-85 (Inotek), or an analogue or derivative thereof.

179) Immuno-modulators

In another embodiment, the fibrosis-inhibiting compound is an immunomodulators such as Bay 11-7085, (-)-arctigenin, idazoxan hydrochloride, or an analogue or derivative thereof .Anti-Infective Agents

The therapeutic agents useful in the present invention also include anti-infective agents. Such agents may reduce the likelihood of infection upon implantation of the composition or a medical implant and may be used in combination of an anti-fibrosis agent and/or a polymer. Infection is a common complication of the implantation of foreign bodies such as, for example, medical devices and implants. Foreign materials provide an ideal site for micro- organisms to attach and colonize. It is also hypothesized that there is an impairment of host defenses to infection in the microenvironment surrounding a foreign material. These factors make medical implants particularly susceptible to infection and make eradication of such an infection difficult, if not impossible, in most cases. In many cases, an infected implant or device must be surgically removed from the body in order to eradicate the infection.

The present invention provides agents (e.g., chemotherapeutic agents) that can be released from a composition, and which have potent antimicrobial activity at extremely low doses. A wide variety of anti-infective agents can be utilized in combination with the present compositions. Suitable anti-infective agents may be readily determined based upon the assays provided in Example 30). Discussed in more detail below are several representative examples of agents that can be, used as anti-infective agents, such as: (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin).

1) Anthracvclines

In one aspect, the therapeutic anti-infective agent is an anthracycline. Anthracyclines have the following general structure, where the R groups may be a variety of organic groups:

Figure imgf000092_0001
According to U.S. Patent 5,594,158, suitable R groups are as follows: Ri is CH3 or CH2OH; R2 is daunosamine or H; R3 and R4 are independently one of OH, NO2, NH2, F, Cl, Br, I, CN1 H or groups derived from these; R5 is hydrogen, ydroxyl, or methoxy; and R6-8 are aii hydrogen. Alternatively, R5 and Re are hydrogen and R7 and R8 are alkyl or halogen, or vice versa.

According to U.S. Patent 5,843,903, Ri may be a conjugated peptide. According to U.S. Patent 4,296,105, R5 may be an ether linked aikyl group. According to U.S. Patent 4,215,062, R5 may be OH or an ether linked alkyl group. R1 may also be linked to the anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having the C(O) linking moiety at its end, such as -CH2CH(CH2-X)C(O)-R1, wherein X is H or an alkyl group (see, e.g., U.S. Patent 4,215,062). R2 may alternately be a group linked by the functional group =N-NHC(O)-Y, where Y is a group such as a phenyl or substituted phenyl ring. Alternately R3 may have the following structure:

Figure imgf000093_0001

in which R9 is OH either in or out of the plane of the ring, or is a second sugar moiety such as R3. R10 may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903). Alternately, R1O may be derived from an amino acid, having the structure -C(O)CH(NHR11)(R12), in which R11 is H, or forms a C3-4 membered alkylene with R12. R12 may be H, alkyl, aminoalkyl, amino, hydroxyl, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105). Exemplary anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicjn, pirarubicin, zorubicin, and carubicin. Suitable compounds have the structures:

Figure imgf000094_0001

Ri K2 Rs doxorubicin: OCH3 C(O)CH2OH OH out of ring plane epirubicin:

(4' epimer of OCH3 C(O)CH2OH OH in ring plane doxorubicin) daunorubicin: OCH3 C(O)CH3 OH out of ring plane idarubicin: H C(O)CH3 OH out of ring plane pirarubicin: OCH3 C(O)CH2OH

Figure imgf000094_0002
zorubicin: OCH3 C(CH3X=N)NHC(O)C6H5 OH carubicin: OH C(O)CH3 OH out of ring plane

Other suitable anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A3, and plicamycin having the structures: R1 R2 R,

Menogaril H OCH3 H

Nogalarrycin σsugar H COOCH3

Figure imgf000095_0001

Mitoxanlrone

Figure imgf000095_0003

Olivomycin A COCH(CH3J2 CH3 COCH3 H

ChroiTDmycin Aa COCH3 CH3 COCH3 CH3

Plicarrycin H H H CH3

Figure imgf000095_0002

Other representative antbracyclinesjnclude, FCE 23762 doxorubicin derivative (Quaglia ef a/., J. Uq. Chromatogr. 17(18):3911-3923, 1994), annamycin (Zou et al., J. Pharm. Sci. 82(11): 1151 -1154, 1993), rυboxyl (Rapoport et al., J. Controlled Release 5S(2):153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi et al., CHn. Cancer Res. 4(11):2833-2839, 1998), N-(trifluoroacetyl)doxorubicin and 4'-O~acetyl- N-(trifluoroacetyl)doxorubicin (Berube & Lepage, Synth. Commun. 28(6): 1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy et a/., Proc. Nat'l Acad. Sci. U.S.A. 95(4): 1794-1799, 1998), disaccharide doxorubicin analogues (Arcamone et al., J. Nat'l Cancer Inst 89(16):1217-1223, 1997), 4-demethoxy-7-O-(2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-α-L-lyxo- hexopyranosy[)-α-L-lyxo-hexopyranosyi)adriamicinone doxorubicin disaccharide analogue (Monteagudo et al., Carbohydr. Res. 300(1):11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat'l Acad. Sci. U. S. A. 94(2):652-656, 1997), morpholinyl doxorubicin analogues (Duran etal., Cancer Chemother. Pharmacol. 38(3):210-216, 1996), enamϊnomalonyl-β- alanine doxorubicin derivatives (Seitz et al., Tetrahedron Lett. 36(9):1413- 16, 1995), cephalosporin doxorubicin derivatives (Vrudhula et al., J. Med. Cherri. 38(8):1380-5, 1995), hydroxyrubicin (Solary et al., Int. J. Cancer 58(1):85-94, 1994), methoxymorpholino doxorubicin derivative (Kuhl et al., Cancer Chemother. Pharmacol. 33(1):10-16, 1993), (6- maleimidocaproyl)hydrazone doxorubicin derivative (Willner et al., Bioconjugate Chem. 4(6):521-7, 1993), N-(5,5-diacetoxypent-1-yl) doxorubicin (Cherif & Farquhar, J. Med. Chem. 35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ripamonti etal., Br. J. Cancer 65(5):703-7 , 1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant et al., Biochim. Biophys. Acta 1118(1): 83-90, 1991), polydeoxynucleotide doxorubicin derivatives (Ruggiero et al., Biochim. Biophys. Acta 1129(3):294-302, 1991), morpholinyl doxorubicin derivatives (EPA 434960), mitoxantrone doxorubicin analogue (Krapcho et al., J. Med. Chem. 34(8):2373~80. 1991), AD198 doxorubicin analogue (Traganos et al., Cancer Res. 57(14):3682-9, 1991), 4-demethoxy-3'-N- trifluoroacetyldoxorubicin (Horton et al., Drug Des. Delivery 6(2): 123-9, 1990), 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm. 40(2):159-65, 1988; Weenen et al., Eur. J. Cancer Clin. Oncol. 20(7):919- 26, 1984), alkylating cyanomorpholino doxorubicin derivative (Scudder et al., J. Nat'l Cancer Inst. S0(16):1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya et al., Vestn. Mosk. Univ., 16(Biol. 1):21-7, 1988), 4'-deoxydoxorubicin (Schoelzel et al., Leuk. Res. 70(12):1455-9, 1986), 4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. Chemother. 16:285-70-285-77, 1983), 3'-deamino-3'- hydroxydoxorubicin (Horton et al., J. Antibiot. 37(8):853-8, 1984), 4- demethyoxy doxorubicin analogues (Barbieri et al., Drugs Exp. Clin. Res. 10(2):85-90, 1984), N-L-leucyl doxorubicin derivatives (Trouet et al., Anthracyclines (Proc. Int. Symp. Tumor Pharmacother.), 179-81, 1983), 3'- deamino-3'-(4-methoxy-1-piperidinyl) doxorubicin derivatives (U.S. 4,314,054), 3'-deamino-3'-(4-mortholinyl) doxorubicin derivatives (U.S. 4,301 ,277), 4'-deoxydoxorubicin and 4'-o-methyldoxorubicin (Giuliani et ai, Int. J. Cancer 27(1):5-13, 1981), aglycone doxorubicin derivatives (Chan & Watson, J. Pharm. Sci. 67(12):1748-52, 1978), SM 5887 {Pharma Japan 1468:20, 1995), MX-2 (Pharma Japan 1420:19, 1994), 4'-deoxy-13(S)- dihydro-4'-iododoxorubicin (EP 275966), morpholinyl doxorubicin derivatives (EPA 434960), 3'-deamino-3'-(4-methoxy-1~piperidinyl) doxorubicin derivatives (U.S. 4,314,054), doxorubicin-14-valerate, morpholinodoxorubicin (U.S. 5,004,606), 3'-deamino-3'-(3"-cyano-4"- morpholinyl doxorubicin; 3'~deamino-3'-(3"-cyano-4"-morpholinyl)-13- dihydoxorubicin; (3'-deamino-3'-(3"-cyano-4"-morpholiny() daunorubicin; 3'- deamino-3'-(3"-cyano-4"-morpholinyl)-3-dihydrodaunorubicin; and 3'- deamino-3'-(4"-morpholinyl-5-iminodoxorubicin and derivatives (U.S. 4,585,859), 3'-deamino-3'-(4-methoxy-1~piperidinyl) doxorubicin derivatives (U.S. 4,314,054) and 3-deamino-3-(4-morpholinyl) doxorubicin derivatives (U.S. 4,301 ,277).

2) Fluoropyrimidine analogues

In another aspect, the ant-infective therapeutic agent is a fluoropyrimidine analog, such as 5-fluorouracil, or an analogue or derivative thereof, including carmofur, doxifluridine, emitefur, tegafur, and floxuridine. Exemplary compounds have the structures:

Figure imgf000097_0001
Figure imgf000098_0001

5-fluoroυracil H H carmofur C(O)NH(CH2)5CH3 H doxifluridine Ai H floxuridine A2 H emitefur CH2OCH2CH3 B tegafur C H

Figure imgf000098_0002

Other suitable fluoropyrimidine analogues include 5-FudR (5- fluoro-deoxyuridine), or an analogue or derivative thereof, including 5- iododeoxyuridine (5-ludR), 5-bromodeoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP), and fluorodeoxyuridine monophosphate (5-dFUMP). Exemplary compounds have the structures:

Figure imgf000098_0003

5-fluoro-2'-deoxyuridine: R = F 5-bromo-2'-deoxyuridine: R = Br 5-iodo~2'-deoxyuridine: R = I Other representative examples of fluoropyrimidine analogues include N3-alkylated analogues of 5-fluorouracil (Kozai et a/., J. Chem. Soc, Perkin Trans. 7(19):3145-3146, 1998), 5-fluorouracil derivatives with 1 ,4- oxaheteroepane moieties (Gomez et a/., Tetrahedron 54(43):13295-13312, 1998), 5-fluorouraciJ and nucleoside analogues (Li, Anticancer Res. 77(1A):21-27, 1997), cis- and trans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van der Wilt et a/., Br. J. Cancer 68(4) :702-7, 1993), cyclopentane 5-fluorouracil analogues (Hronowski & Szarek, Can. J. Chem. 70(4): 1162-9, 1992), A-OT- fluorouracil (Zhang et al., Zongguo Yiyao Gongye Zazhi 20(11):513-15, 1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-5- fluorouridine (Miwa et al., Chem. Pharm. Bull. 38(4):998-1003, 1990), 1- hexylcarbamoyl-5-fluorouracil (Hoshi et al., J. Pharmacobio-Dun. 3(9):478- 81 , 1980; Maehara et al., Chemotherapy (Basel) 34(6):484-9, 1988), B-3839 (Prajda et al., In Vivo 2(2):151-4, 1988), uracil-1-(2-tetrahydrofuryl)-5- fluorouracil (Anai et al., Oncology 45(3): 144-7, 1988), 1 -(2'-deoxy-2'-fluoro- β-D-arabinofuranosyi)-5-fiuorouracii (Suzuko et a/., MoI. Pharmacol. 37(3):301-6, 1987), doxifluridine (Matuura et al., Oyo Yakuri 29(5):803-31, 1985), 5'-deoxy-5-fluorouridine (Bollag & Hartmann, Eur. J. Cancer 76(4):427-32, 1980), i-acetyl-S-O-toluyl-δ-fluorouracil (Okada, Hiroshima J. Med. Sci. 2S(1):49-66, 1979), 5-fluorouracil-m-formylbenzene-sulfonate (JP 55059173), N'-(2-furanidyl)~5-fluorouracil (JP 53149985) and 1-(2- tetrahydrofuryl)-5-fluorouracil (JP 52089680).

These compounds are believed to function as therapeutic agents by serving as antimetabolites of pyrimidine.

3) Folic acid antagonists

In another aspect, the anti-infective therapeutic agent is a folic acid antagonist, such as methotrexate or derivatives or analogues thereof, including edatrexate, trimetrexate, raltitrexed, piritrexim, denopterin, tomudex, and pteropterin. Methotrexate analogues have the following general structure:

Figure imgf000100_0001

The identity of the R group may be selected from organic groups, particularly those groups set forth in U.S. Patent Nos. 5,166,149 and 5,382,582. For example, R1 may be N, R2 may be N or C(CH3), R3 and R3' may H or alkyl, e.g., CH3, R4 may be a single bond or NR, where R is H or alkyl group. Rδ(6,8 nriay be H, OCH3, or alternately they can be halogens or hydro groups. R7 is a side chain of the general structure:

Figure imgf000100_0002

wherein n = 1 for methotrexate, n = 3 for pteropterin. The carboxyl groups in the side chain may be esterified or form a salt such as a Zn2+ salt. Rg and Rio can be NH2 or may be alkyl substituted.

Exemplary folic acid antagonist compounds have the structures:

Figure imgf000100_0003
Figure imgf000101_0001
methotrexate NH2 N N H N(CH3) H H A (n=1) H edatrexate NH2 N N H CH(CH2CH3) H H A (n=1) H trimetrexate NH2 CH C(CH3) H NH H OCH3 OCH3 OCH3 pteropterin OH N N H NH H H A (n=3) H denopterin OH N N CH3 N(CH3) H H A (n-1) H peritrexim NH2 N C(CH3) H single bond OCH3 H H OCH3

Figure imgf000101_0002

Figure imgf000101_0003

Other representative examples include 6-S aminoacyloxymethyl mercaptopurine derivatives (Harada et al., Chem. Pharm. Bull. 43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol. Pharm. Bull. 78(11): 1492-7, 1995), 7,8-po)ymethyleneimidazo-1 ,3,2- diazaphosphorines (Nilov et a/., Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al., J. Inorg. Biochem. 56(4):249-64, 1994), methyl-D-glucopyranoside mercaptopurine derivatives (Da Silva et al., Eur. J. Med. Chem. 29(2): 149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino et al., Khim.-Farm. Zh. 75(8):65-7, 1981); indoline ring and a modified ornithine or glutamic acid-bearing methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull. 45(7): 1146-1150, 1997), alkyl- substituted benzene ring C bearing methotrexate derivatives (Matsuoka et al, Chem. Pharm. Bull. 44(12):2287-2293, 1996), benzoxazine or benzothiazine moiety-bearing methotrexate derivatives (Matsuoka et al., J. Med. Chem. 40(1): 105-111, 1997), 10-deazaaminopterin analogues (DeGraw e/ a/., J. Med. Chem. 40(3): 370-376, 1997), 5-deazaaminopterin and 5,10-dideazaaminopterin methotrexate analogues (Piper ef al., J. Med. Chem. 40(3):377-384, 1997), indoline moiety-bearing methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull. 44(J)-A 332-1337, 1996), lipophilic amide methotrexate derivatives (Pignatello et al., World Meet. Pharm., Biopharm. Pharm. Techno!., 563-4, 1995), L-threo-(2S,4S)-4- fluoroglutamic acid and DL-3,3-difluoroglutamic acid-containing methotrexate analogues (Hart ef al., J. Med. Chem. 39(1):56-65, 1996), methotrexate tetrahydroquinazoline analogue (Gangjee, et al., J. Heterocycl. Chem. 32(1):243-8, 1995), N-(α-aminoacyl) methotrexate derivatives (Cheung et al., Pteridines 3(1 -2): 101 -2, 1992), biotin methotrexate derivatives (Fan et al., Pteridines 3(1-2):131-2, 1992), D-glutamic acid or D- erythrou, threo-4-fluoroglutamic acid methotrexate analogues (McGuire et al., Biochem. Pharmacol. 42(12):2400-3, 1991), β,γ-methano methotrexate analogues (Rosowsky et al., Pteridines 2(3):133-9, 1991), 10- deazaaminopterin (10-EDAM) analogue (Braakhuis et al., Chem. Biol. Pteridines, Proe. Int. Sy mp. Pteridines Folic Acid Deriv., 1027-30, .1989), γ- tetrazole methotrexate analogue (Kalman ef al., Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv. , 1154-7, 1989), N-(L-α- aminoacyl) methotrexate derivatives (Cheung et al., Heterocycles 2δ(2):751- 8, 1989), meta and ortho isomers of aminopterin (Rosowsky ef al., J. Med. Chem. 32(12):2582, 1989), hydroxymethy Methotrexate (DE 267495), γ- fluoromethotrexate (McGuire et al., Cancer Res. 49(16):4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar ef a/., Cancer Res. 46(10):5020-3, 1986), gem-diphosphonate methotrexate analogues (WO 88/06158), α- and γ-substituted methotrexate analogues (Tsushima et al., Tetrahedron 44(17) :5375-87, 1988), 5-methyl~5-deaza methotrexate analogues (4,725,687), Nδ-acyl-Nα-(4-amino-4-deoxypteroyl)-L-ornithine derivatives (Rosowsky et al., J. Med. Chem. 37(7): 1332-7, 1988), 8-deaza methotrexate analogues (Kuehl ef al., Cancer Res. 4S(6):1481-8, 1988), acivicin methotrexate analogue (Rosowsky et al., J. Med. Chem. 30(8): 1463-9, 1987), polymeric platinol methotrexate derivative (Carraher ef al., Polym. ScI. Technol. (Plenum), 35(Adv. Biomed. Po/y/7?.J:311-24, 1987), methotrexate-γ-dimyristoylphophatidylethanolamine (Kinsky et al., Biochim. Biophys. Acta 977(2):211-18, 1987), methotrexate polyglutamate analogues (Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 985-8, 1986), poly-γ-glutamyl methotrexate derivatives (Kisliuk et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 989-92, 1986), deoxyuridylate methotrexate derivatives (Webber et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 659-62, 1986), iodoacetyl lysine methotrexate analogue (Delcamp et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv.: Chem., Biol. Clin. Aspects: 807-9, 1986), 2,.omega.-diaminoalkanoid acid-containing methotrexate analogues (McGuire et al., Biochem. Pharmacol. 35(15):2607-13, 1986), polyglutamate methotrexate derivatives (Kamen & Winick, Methods Enzymol. 722(Vitam. Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza analogues (Piper et al., J. Med. Chem. 29(6): 1080-7, 1986), quinazoline methotrexate analogue (Mastropaolo et al., J. Med. Chem. 29(1):155-8, 1986), pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl. Chem. 22(1):5-6, 1985), cysteic acid and homocysteic acid methotrexate analogues (4,490,529), γ-tert-butyl methotrexate esters (Rosowsky et al., J. Med. Chem. 28(5):660-7, 1985), fluorinated methotrexate analogues (Tsushima et al., Heterocycles 23(1):45-9, 1985), folate methotrexate analogue (Trombe, J. Bacteήol. 760(3):849-53, 1984), phosphonoglutamic acid analogues (Sturtz & Guillamot, Eur. J. Med. Chem.-Chim. Ther. 19(3):267-73, 1984), poly (L-lysine) methotrexate conjugates (Rosowsky et al., J. Med. Chem. 27(7):888-93, 1984), dilysine and trilysine methotrexate derivates (Forsch & Rosowsky, J. Org. Chem. 49(7): 1305-9, 1984), 7-hydroxymethotrexate (Fabre et al., Cancer Res. 43(10):4648-52, 1983), poly-γ-glutamyl methotrexate analogues (Piper & Montgomery, Adv. Exp. Med. Biol., 163(FoIyI Antifolyl Polyglutamates):95-W0, 1983), β'.δ1- dichloromethotrexate (Rosowsky & Yu, J. Med. Chem. 26(10): 1448-52, 1983), diazoketone and chloromethylketone methotrexate analogues (Gangjee et al., J. Pharm. ScL 77(6):717-19, 1982), 10- propargylaminopterin and alkyl methotrexate homologs (Piper et al., J. Med. Chem. 25(7):877-80, 1982), lectin derivatives of methotrexate (Lin et al., JNCI 66(3):523-8, 1981), polyglutamate methotrexate derivatives (Galivan, MoI. Pharmacol. 17(1): 105-10, 1980), halogentated methotrexate derivatives (Fox, JNCI 58(4):J955-8, 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky et al., J. Med. Chem. 20(10):J 1323-7, 1977), 7-methyl methotrexate derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med. Chem. 77(12):J1308-11, 1974), lipophilic methotrexate derivatives and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem. 76(10):J1190-3, 1973), deaza amethopterin analogues (Montgomery et al., Ann. N.Y. Acad. Sci. 786:J227-34, 1971), MX068 (Pharma Japan, 1658:18, 1999) and cysteic acid and homocysteic acid methotrexate analogues (EPA 0142220).

These compounds are believed to act as antimetabolites of folic acid.

4) Podophyllotoxins

In another aspect, the anti-infective therapeutic agent is a podophyllotoxin, or a derivative or an analogue thereof. Exemplary compounds of this type are etoposide or teniposide, which have the following structures:

Figure imgf000104_0001
Other representative examples of podophyllotoxins include Cu(II)-VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6(7): 1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide analogues (Ji et al., Bioorg. Med. Chem. Lett. 7(5):607-612, 1997), 4β-amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), γ-lactone ring-modified arylamino etoposide analogues (Zhou et al., J. Med. Chem. 37(2):287-92, 1994), N-glucosyl etoposide analogue (Allevi et al., Tetrahedron Lett. 34(45):7313-16, 1993), etoposide A-ring analogues (Kadow ef al., Bioorg. Med. Chem. Lett. 2(1):17-22, 1992), 4'-deshydroxy-4'- methyl etoposide (Saulnier et al., Bioorg. Med. Chem. Lett. 2(10):1213-18, 1992), pendulum ring etoposide analogues (Sinha et al., Eur. J. Cancer 26(5):590-3, 1990) and E-ring desoxy etoposide analogues (Saulnier et al., J. Med. Chem. 32(7): 1418-20, 1989).

These compounds are believed to act as topoisomerase Il inhibitors and/or DNA cleaving agents.

5) Camptothecins

In another aspect, the anti-infective therapeutic agent is camptothecin, or an analogue or derivative thereof. Camptothecins have the following general structure.

Figure imgf000105_0001

In this structure, X is typically O, but can be other groups, e.g., NH in the case of 21-lactam derivatives. Ri is typically H or OH, but may be other groups, e.g., a terminally hydroxylated C1-3 alkane. R2 is typically H or an amino containing group such as (CHs)2NHCH2, but may be other groups e.g., NO2, NH2, halogen (as disclosed in, e.g., U.S. Patent 5,552,156) or a short alkane containing these groups. R3 is typically H or a short alkyl such as C2H5. R4 is typically H but may be other groups, e.g., a methylenedioxy group with R1.

Exemplary camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin, 10- hydroxycamptothecin. Exemplary compounds have the structures:

Figure imgf000106_0001

SN-38: OH H C2H5

X: O for most analogs, NH for 21 -lactam analogs

Camptothecins have the five rings shown here. The ring labeled E must be intact (the lactone rather than carboxylate form) for maximum activity and minimum toxicity.

Camptothecins are believed to function as topoisomerase I inhibitors and/or DNA cleavage agents.

6) Hydroxyureas

The anti-infective therapeutic agent of the present invention may be a hydroxyurea. Hydroxyureas have the following general structure:

Figure imgf000106_0002

Suitable hydroxyureas are disclosed in, for example, U.S. Patent No. 6,080,874, wherein Ri is:

Figure imgf000107_0001
and R2 is an alkyl group having 1-4 carbons and R3 is one of H, acyl, methyl, ethyl, and mixtures thereof, such as a methylether.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,665,768, wherein R1 is a cycloalkenyl group, for example N-(3-(5-(4- fluorophenylthio)-furyl)-2-cyclopenten-1-yl)N-hydroxyurea; R2 is H or an alkyl group having 1 to 4 carbons and R3 is H; X is H or a cation.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 4,299,778, wherein Ri is a phenyl group substituted with one or more fluorine atoms; R2 is a cyclopropyl group; and R3 and X is H.

Other suitable hydroxyureas are disclosed in, e.g., U.S. Patent No. 5,066,658, wherein R2 and R3 together with the adjacent nitrogen form:

Figure imgf000107_0002

where in m is 1 or 2, n is 0-2 and Y is an alkyl group.

In one aspect, the hydroxyurea has the structure:

Figure imgf000107_0003

Hydroxyurea

These compounds are thought to function by inhibiting DNA synthesis. 7) Platinum complexes

In another aspect, the anti-infective therapeutic agent is a platinum compound. In general, suitable platinum complexes may be of Pt(II) or Pt(IV) and have this basic structure:

Figure imgf000108_0001
wherein X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen; R1 and R2 are alkyl, amine, amino alkyl any may be further substituted, and are basically inert or bridging groups. For Pt(II) complexes Z1 and Z2 are non-existent. For Pt(IV) Z1 and Z2 may be anionic groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See, e.g., U.S. Patent Nos. 4,588,831 and 4,250,189.

Suitable platinum complexes may contain multiple Pt atoms. See, e.g., U.S. Patent Nos. 5,409,915 and 5,380,897. For example bisplatinum and triplatinum complexes of the type:

Figure imgf000109_0001

Exemplary platinum compounds are cisplatin, carboplatin, oxaliplatin, and miboplatin having the structuresf

Figure imgf000109_0002

Cisplatin Carboplatin

Figure imgf000109_0003

Oxaliplatin

Figure imgf000109_0004

Other representative platinum compounds include (CPA)2Pt(DOLYM) and (DACH)Pt(DOLYM) cisplatin (Choi et al., Arch. Pharmacal Res. 22(2):151-156, 1999), Cis-(PtCI2(4,7-H-5-methyl-7- oxo)1, 2,4(triazolo(1,5-a)pyrimidine)2) (Navarro et al., J. Med. Chem. 47(3):332-338, 1998), (Pt(cis-1 ,4-DACH)(trans-CI2)(CBDCA)) . Y2MeOH cisplatin (Shamsuddin et al., Inorg. Chem. 36(25):5969-5971 , 1997), 4- pyridoxate diammine hydroxy platinum (Tokunaga et al., Pharm. Sci. 3(7):353-356, 1997), Pt(II) ... Pt(II) (Pt2(NHCHN(C(CH2)(CH3)))4) (Navarro et al., Inorg. Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue (Koga et al., Neurol. Res. 78(3):244-247, 1996), o-phenylenediamine ligand bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Inorg. Biochem. 62(4):281-298, 1996), trans, cis-(Pt(OAc)2l2(en)) (Kratochwil et al., J. Med. Chem. 39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenediamine ligand (with sulfur-containing amino acids and glutathione) bearing cisplatin analogues (Bednarski, J. Inorg. Biochem. 62(1):75, 1996), cis-1 ,4- diaminocyclohexane cisplatin analogues (Shamsuddin et al., J. Inorg. Biochem. 67(4):291-301 , 1996), 5' orientational isomer of cis-(Pt(NH3)(4- aminoTEMP-O){d(GpG)}) (Dunham & Lippard, J. Am. Chem. Soc. 777(43): 10702-12, 1995), chelating diamine-bearing cisplatin analogues (Koeckerbauer & Bednarski, J. Pharm. Sci. 84(7):819-23, 1995), 1 ,2- diarylethyleneamine ligand-bearing cisplatin analogues (Otto et al., J. Cancer Res. Clin. Oncol. 727(1 ):31 -8, 1995), (ethylenediamine)platinum(ll) complexes (Pasini et al., J. Chem. Soc, Dalton Trans. 4:579-85, 1995), Cl- 973 cisplatin analogue (Yang et al., Int. J. Oncol. 5(3):597-602, 1994), cis- diaminedichloroplatinum(ll) and its analogues cis-1 ,1- cyclobutanedicarbosylato(2R)-2-methyl-1 ,4-butanediamineplatinum(ll) and cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J. Inorg. Biochem. 26(4):257-67, 1986; Fan et al., Cancer Res. 48(11):3135-9, 1988; Heiger- Bernays et al., Biochemistry 29(36):8461-6, 1990; Kikkawa et al., J. Exp. Clin. Cancer Res. 72(4):233-40, 1993; Murray et a/., Biochemistry 37(47):11812-17, 1992; Takahashi et al., Cancer Chemother. Pharmacol. 33(1):31-5, 1993), cϊs-amine-cyclohexylamine-dichloroplatinum(ll) (Yoshida et al., Biochem. Pharmacol. 48(4):793-9, 1994), gem-diphosphonate cisplatin analogues (FR 2683529), (meso-1,2-bis(2,6-dichloro-4- hydroxyplenyl)ethylenediamine) dichloroplatinum(ll) (Bednarski et al., J. Med. Chem. 35(23):4479-85, 1992), cisplatin analogues containing a tethered dansyl group (Hartwig et al., J. Am. Chem. Soc. 774(21):8292-3, 1992), platinum(ll) polyamines (Siegmann et al., Inorg. Met.-Containing Polym. Mater., (Proc. Am. Chem. Soc. Int. Symp.), 335-61 , 1990), cis- (3H)dichloro(ethylenediamine)platinum(ll) (Eastman, Anal. Biochem. 797(2):311-15, 1991), trans-diamminedichloroplatinum(ll) and cis- (Pt(NH3)2(N3-cytosine)CI) (Bellon & Lippard, Biophys. Chem. 35(2-3): 179- 88, 1990), 3H-cis-1,2-diaminocyclohexanedichloroplatinum(ll) and 3H-cis- 1 ,2-diaminocyclohexanemalonatoplatinum (II) (Oswald etal., Res. Commun. Chem. Pathol. Pharmacol. 64(1):41-58, 1989), diaminocarboxylatoplatinum (EPA 296321), trans-(D,1)-1 ,2-diaminocyclohexane carrier ligand-bearing platinum analogues (Wyrick & Chaney, J. Labelled Compd. Radiopharm. 25(4):349-57, 1988), aminoalkylaminoanthraquinone-derived cisplatin analogues (Kitov et al., Eur. J. Med. Chem. 23(4):381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen et al., Eur. J. Cancer Clin. Oncol. 24(8): 1309-12, 1988), bidentate tertiary diamine- containing cisplatinum derivatives (Orbell et al., Inorg. Chim. Acta 152(2): 125-34, 1988), platinum(ll), platinum(IV) (Liu & Wang, Shandong Yike Daxue Xuehao 24(1):35-41 , 1986), cis-diammine(1,1- cyclobutanedicarboxylato-)platinum(ll) (carboplatin, JM8) and ethylenediammine-malonatoplatinum(ll) (JM40) (Begg et al., Radiother. Oncol. 9(2):157-65, 1987), JM8 and JM9 cisplatin analogues (Harstrick et al., Int. J. Androl. 70(1); 139-45, 1987), (NPr4)2((PtCL4).cis-(PtCI2- (NH2Me)2)) (Brammer et al., J. Chem. Soc, Chem. Commun. 6:443-5, 1987), aliphatic tricarboxylic acid platinum complexes (EPA 185225), and cis-dichloro(amino acid)(tert-butylamine)platinum(ll) complexes (Pasini & Bersanetti, Inorg. Chim. Acta 107(4)259-67, 1985). These compounds are thought to function by binding to DNA, i.e., acting as alkylating agents of DNA. 8) Other Anti-Infective Agents

In another aspect, the anti-infective therapeutic agent is a quinolone antibacterial agent. Representative examples of quinolone antibacterial agents include garenoxacin (Schering Plough) or an analogue or derivative thereof.

Dosages of Anti-Infective Agents

The drug dose administered from the present compositions for prevention or inhibition of infection in accordance with the present invention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used .at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single anti-infective systemic dose application. In certain aspects, the anti- infective agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days.

The exemplary anti-infective agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-infective agent in the composition can be in the range of about 0.01 μg-1 μg, or about 1 μg-10 μg, or about 10 μg-1 mg, or about 1 mg to 10 mg, or about 10 mg-100 mg, or about 100 mg to 250 mg, or about 250 mg-1000 mg. The dose (amount) of anti-infective agent per unit area of device or tissue surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or about 1 μg/mm2 - 10 μg/mm2, or about 10 μg/mm2 - 100 μg/mm2, or about 100 μg/mm2 to 250 μg/mm2, or about 250 μg/mm2 - 1000 μg/mm2. As different compositions will release the anti-infective agent at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the composition such that a minimum concentration of about 10"8 M to 10"7 M, or about 10"7 M to lO'6 M about 10"6 M to 10"5 M or about 10"5 M to 10'4 M of the agent is maintained on the tissue surface.

(a) Anthracvclines. Utilizing the anthracycline doxorubicin as an example, whether applied as a polymer coating, incorporated into the polymers which make up the implant components, or applied without a carrier polymer, the total dose of doxorubicin applied to the device or implant should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.01 μg - 100 μg per mm2 of surface area. In a particularly preferred embodiment, doxorubicin should be applied to the implant surface at a dose of 0.1 μg/mm2 - 10 μg/mm2. As different polymer and non-polymer coatings will release doxorubicin at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10"7- 10"4 M of doxorubicin is maintained on the surface. It is necessary to insure that surface drug concentrations exceed concentrations of doxorubicin known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10"4 M; although for some embodiments lower concentrations are sufficient). In a preferred embodiment, doxorubicin is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of doxorubicin (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as doxorubicin is administered at half the above parameters, a compound half as potent as doxorubicin is administered at twice the above parameters, etc.).

Utilizing mitoxantrone as another example of an anthracycline, whether applied as a polymer coating, incorporated into the polymers which make up the device or implant, or applied without a carrier polymer, the total dose of mitoxantrone applied should not exceed 5 mg (range of 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of- 0.-1 μg to 1 mg. The dose per unit area (i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.01 μg - 20 μg per mm2 of surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the implant surface at a dose of 0.05 μg/mm2 - 3 μg/mm2. As different polymer and non-polymer coatings will release mitoxantrone at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10"5 - 10"6 M of mitoxantrone is maintained. It is necessary to insure that drug concentrations on the implant surface exceed concentrations of mitoxantrone known to be lethal to multiple species of bacteria and fungi (i.e., are in excess of 10"5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, mitoxantrone is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of mitoxantrone (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as mitoxantrone is administered at half the above parameters, a compound half as potent as mitoxantrone is administered at twice the above parameters, etc.).

(b) Fluoropyrimidines Utilizing the fluoropyrimidine 5- fluorouracil as an example, whether applied as a polymer coating, incorporated into the polymers which make up the device or implant, or applied without a carrier polymer, the total dose of 5-fluorouracil applied should not exceed 250 mg (range of 1.0 μg to 250 mg). In a particularly preferred-embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.1 μg - 1 mg per mm2 of surface area. In a particularly preferred embodiment, 5- fluorouracil should be applied to the implant surface at a dose of 1.0 μg/mm2 - 50 μg/mm2. As different polymer and non-polymer coatings will release 5- fluorouracil at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a minimum concentration of 10"4- 10"7 M of 5-fluorouracil is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of 5-fluorouracil known to be lethal to numerous species of bacteria and fungi (Ae., are in excess of 10"4 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, 5-fluorouracil is released from the implant surface such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of 5-fluorouracil (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as 5-fluorouracil is administered at half the above parameters, a compound half as potent as 5-fluorouracil is administered at twice the above parameters, etc.).

(c) Podophylotoxins Utilizing the podophylotoxin etoposide as an example, whether applied as a polymer coating, incorporated into the polymers which make up the device or implant, or applied without a carrier polymer, the total dose of etoposide applied should not exceed 25 mg (range of 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (i.e., the amount of drug as a function of the surface area of the portion of the implant to which drug is applied and/or incorporated) should fall within the range of 0.01 μg - 100 μg per mm2 of surface area. In a particularly preferred embodiment, etoposide should be applied to the implant surface at a dose of 0.1 μg/mm2 - 10 μg/mm2. As different polymer and non-polymer coatings will release etoposide at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the implant surface such that a concentration of 10"5 - 10~6 M of etoposide is maintained. It is necessary to insure that surface drug concentrations exceed concentrations of etoposide known to be lethal to a variety of bacteria and fungi (i.e., are in excess of 10"5 M; although for some embodiments lower drug levels will be sufficient). In a preferred embodiment, etoposide is released from the surface of the implant such that anti-infective activity is maintained for a period ranging from several hours to several months. In a particularly preferred embodiment the drug is released in effective concentrations for a period ranging from 1 week - 6 months. It should be readily evident based upon the discussions provided herein that analogues and derivatives of etoposide (as described previously) with similar functional activity can be utilized for the purposes of this invention; the above dosing parameters are then adjusted according to the relative potency of the analogue or derivative as compared to the parent compound (e.g., a compound twice as potent as etoposide is administered at half the above parameters, a compound half as potent as etoposide is administered at twice the above parameters, etc.).

It should be readily evident based upon the discussions provided herein that combinations of anthracyclines (e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexate), podophylotoxins (e.g., etoposide), and/or quinolones can be utilized to enhance the antibacterial activity of the composition.

Polymers _ . . . _ .

The therapeutic agents useful in the present invention may also include various polymers. Such polymers may be used alone to be effective in certain applications (e.g., treating or preventing surgical adhesions) or in combination of an anti-fibrosis agent and/or an anti- infective agent to facilitate the delivery of, or to provide a sustained release formulation of, the anti-fibrosis agent and/or the anti-infective agent. Detailed descriptions of exemplary polymers are provided below in the section regarding pharmaceutical compositions, especially in the section regarding sustained release formulations.

Pharmaceutical Compositions

The present invention, in another aspect, provides pharmaceutical compositions that comprise a fibrosis-inhibiting agent and/or anti-infective agent. In certain embodiments, the pharmaceutical compositions further comprise a polymer, an additional therapeutic agent, a pharmaceutical excipient, and/or an agent that facilitates the delivery of the therapeutic agents or compositions.

Compositions That Comprise Polymers

In certain embodiments, the compositions of the present invention may comprise a polymer that itself is a therapeutic agent. In certain other embodiments, the compositions of the present invention may comprise a polymer that facilitates the delivery of a therapeutic agent or forms a sustained release formuation for a therapeutic agent. In certain embodiments, compositions that comprise polymers may further comprise additional agents (e.g., pharmaceutical exicipents, echogenic agents, etc.).

For instance, the composition may be or include a hydrophilic polymer gel that has anti-thrombogenic properties. Such a composition can be in the form of a coating that can comprise a hydrophilic, biodegradable polymer that is physically removed from the surface of the device over time, thus reducing adhesion of platelets to the device surface. The gel composition can include a polymer or a blend of polymers. Representative examples include alginates, chitosan and chitosan sulfate, hyaluronic acid, dextran sulfate, PLURONIC polymers (e.g., F-127 or F87), chain extended PLURONIC polymers, various polyester-polyether block copolymers of various configurations (e.g., AB, ABA, or BAB, where A is a polyester such as PLA, PGA, PLGA, PCL or the like), examples of which include MePEG- PLA, PLA-PEG-PLA, and the like). In one embodiment, the anti-thrombotic composition can include a crosslinked gel formed from a combination of molecules (e.g., PEG) having two or more terminal electrophilic groups and two or more nucleophilic groups.

Sustained-Release Preparations of Therapeutic Agents In certain embodiments, desired therapeutic agents may be admixed with, blended with, conjugated to, or, otherwise modified to contain a polymer composition (which may be either biodegradable or non- biodegradable) or a non-polymeric composition in order to release the therapeutic agent over a prolonged period of time. For many of the aforementioned embodiments, localized delivery as well as localized sustained delivery of the fibrosis-inhibiting and/or anti-infective agent may be required. For example, a desired therapeutic agent may be admixed with, blended with, conjugated to, or, otherwise modified to contain a polymeric composition (which may be either biodegradable or nonbiodegradable) or non-polymeric composition in order to release the therapeutic agent over a period of time.

Representative examples of biodegradable polymers suitable for the delivery of the aforementioned therapeutic agents include albumin, collagen, gelatin, hyaluronic acid, starch, cellulose and cellulose derivatives (e.g., regenerated cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate), casein, dextrans, polysaccharides, fibrinogen, poly(ether ester) multiblock copolymers, based on poly(ethylene glycol) and polyφutylene terephthalate), tyrosine-derived polycarbonates (e.g., U.S. Patent No. 6,120,491), poly(hydroxyl acids), poly(D,L-lactide), poly(D,L-lactide-co- glycolide), poly(glycolide), poly(hydroxybutyrate), polydioxanone, poly(alkylcarbonate) and poly(orthoesters), polyesters, poly(hydroxyvaleric acid), polydioxanone, polyesters, poly(malic acid), poly(tartronic acid), poly(acrylamides), polyanhydrides, polyphosphazenes, poly(amino acids), poly(alkylene oxide)-poly(ester) block copolymers (e.g., X-Y, X-Y-X, Y-X-Y, R-(Y-X)n, or R-(X-Y)n, where X is a polyalkylene oxide (e.g., poly(ethylene glycol, polyφropylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e- caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y- decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one (e.g., PLGA, PLA, PCL, polydioxanone and copolymers thereof) and R is a multifunctional initiator), and the copolymers as well as blends thereof (see generally, Ilium, L., Davids, S. S. (eds.) "Polymers in Controlled Drug Delivery" Wright, Bristol, 1987; Arshady, J. Controlled Release 17:1-22, 1991 ; Pitt, Int. J. Phar. 59:173-196, 1990; Holland et al., J. Controlled Release 4:155-0180, 1986).

Representative examples of non-degradable polymers suitable for the delivery of fibrosis-inhibiting agents include poly(ethylene-co-vinyl acetate) ("EVA") copolymers, non-degradable polyesters, such as poly(ethylene terephthalate), silicone rubber, acrylic polymers (polyacrylate, polyacrylic acid, polymethylacrylic acid, polymethylmethacrylate, poly(butyl methacrylate)), poly(alkylcynoacrylate) (e.g., poly(ethylcyanoacrylate), poly(butylcyanoacrylate) poly(hexylcyanoacrylate) poly(octylcyanoacrylate)), -acrylic resin, polyethylene, polypropylene, polyamides (nylon 6,6), polyurethanes (e.g., CHRONOFLEX AR, CHRONOFLEX AL, BIONATE, and PELLETHANE), poly(ester urethanes), poly(ether urethanes), poly(ester-urea), cellulose esters (e.g., nitrocellulose), polyethers (poly(ethylene oxide), polyφropylene oxide), polyoxyalkylene ether block copolymers based on ethylene oxide and propylene oxide such as the PLURONIC polymers (e.g., F-127 or F87) from BASF Corporation (Mount Olive, NJ), and poly(tetramethylene glycol), styrene-based polymers (polystyrene, poly(styrene sulfonic acid), poly(styrene)-block- poly(isobutylene)-block-poly(styrene), poly(styrene)-poly(isoprene) block copolymers), and vinyl polymers (polyvinylpyrrolidone, polyvinyl alcohol), polyvinyl acetate phthalate) as well as copolymers and blends thereof. Polymers may also be developed which are either anionic (e.g., alginate, carrageenan, carboxymethyl cellulose, poly(acrylamido-2-methyl propane sulfonic acid) and copolymers thereof, poly(methacrylic acid and copolymers thereof and poly(acrylic acid) and copolymers thereof, as well as blends thereof, or cationic (e.g., chitosan, poly-L-lysine, polyethylenimine, and poly(allyl amine)) and blends, copolymers and branched polymers thereof (see generally, Dunn et al., J. Applied Polymer ScL 50:353-365, 1993; Cascone et al., J. Materials Sci.: Materials in Medicine 5:770-77 '4, 1994; Shiraishi et al., Biol. Pharm. Bull. 76(11):1164-1168, 1993; Thacharodi and Rao, Int'I J. Pharm. -/20:115-118, 1995; Miyazaki et al., InVU. Pharm. 118:257-263, 1995).

Some examples of preferred polymeric carriers include poly(ethylene-co-vinyl acetate), polyurethanes (e.g., CHRONOFLEX AR, CHRONOFLEX AL, BIONATE, and PELLETHANE), poly (D,L-lactic acid) oligomers and polymers, poly (L-lactic acid) oligomers and polymers, poly (glycolic acid), copolymers of lactic acid and glycolic acid, poly (caprolactone), poly (valerolactone), polyanhydrides, copolymers of poly (caprolactone) or poly (lactic acid) with a polyethylene glycol (e.g., MePEG), poly(alkylene oxide)-poly(ester) block copolymers (e.g., X-Y, X-Y-X or Y-X- Y, R-(Y-X)n, R-(X-Y)n where X is a polyalkylene oxide and Y is a polyester (e.g., polyester can comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta- butyrolactone, gamma-butyrolactone, gamma-valerolactone, v- decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one.), R is a multifunctional initiator and copolymers as well as blends thereof), nitrocellulose, silicone rubbers, poly(styrene)block-poly(isobutylene)-block-poly(styrene), poly(acrylate) polymers and blends, admixtures, or co-polymers of any of the above. Other preferred polymers include collagen, poly(alkylene oxide)-based polymers, polysaccharides such as hyaluronic acid, chitosan and fucans, and copolymers of polysaccharides with degradable polymers, as well as blends thereof.

Other representative polymers capable of sustained localized delivery of anti-infective and/or fibrosis-inhibiting therapeutic agents include carboxylic polymers, polyacetates, polycarbonates, polyethers, polyethylenes, polyvinylbutyrals, polysilanes, polyureas, polyoxides, polystyrenes, polysulfides, polysulfones, polysulfonides, polyvinylhalides, pyrrolidones, rubbers, thermal-setting polymers, cross-linkable acrylic and methacrylic polymers, ethylene acrylic acid copolymers, styrene acrylic copolymers, vinyl acetate polymers and copolymers, vinyl acetal polymers and copolymers, epoxies, melamines, other amino resins, phenolic polymers, and copolymers thereof, water-insoluble cellulose ester polymers (including cellulose acetate propionate, cellulose acetate, cellulose acetate butyrate, cellulose nitrate, cellulose acetate phthalate, and mixtures thereof), polyvinylpyrrolidone, polyethylene glycols, polyethylene oxide, polyvinyl alcohol, polyethers, polysaccharides, hydrophilic polyurethane, polyhydroxyacrylate, dextran, xanthan, hydroxypropyl cellulose, and homopolymers and copolymers of N-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinyl caprolactam, other vinyl compounds having polar pendant groups, acrylate and methacrylate having hydrophilic esterifying groups, hydroxyacrylate, and acrylic acid, and combinations thereof; cellulose esters and ethers, ethyl cellulose, hydroxyethyl cellulose, cellulose nitrate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, natural and synthetic elastomers, rubber, acetal, styrene polybutadiene, acrylic resin, polyvinylidene chloride, polycarbonate, homopolymers and copolymers of vinyl compounds, polyvinylchloride, and polyvinylchloride acetate.

Representative examples of patents relating to drug-delivery polymers and their preparation include PCT Publication Nos. WO 98/19713, WO 01/17575, WO 01/41821, WO 01/41822, and WO 01/15526 (as well as the corresponding U.S. applications), U.S. Patent Nos. 4,500,676, 4,582,865, 4,629,623, 4,636,524, 4,713,448, 4,795,741 , 4,913,743, 5,069,899, 5,099,013, 5,128,326, 5,143,724, 5,153,174, 5,246,698, 5,266,563, 5,399,351, 5,525,348, 5,800,412, 5,837,226, 5,942,555, 5,997,517, 6,007,833, 6,071 ,447, 6,090,995, 6,106,473, 6,110,483, 6,121 ,027, 6,156,345, 6,214,901 , 6,368,611 6,630,155, 6,528,080, RE37.950, 6,46,1631 , 6,143,314, 5,990,194, 5,792,469, 5,780,044, 5,759,563, 5,744,153, 5,739,176, 5,733,950, 5,681 ,873, 5,599,552, 5,340,849, 5,278,202, 5,278,201 , 6,589,549, 6,287,588, 6,201 ,072, 6,117,949, 6,004,573, 5,702,717, 6,413,539, 5,714,159, 5,612,052, and U.S. Patent Application Publication Nos. 2003/0068377, 2002/0192286, 2002/0076441, and 2002/0090398.

It should be obvious to one of skill in the art that the polymers as described herein can also be blended or copolymerized in various compositions as required to deliver therapeutic doses of fibrosis-inhibiting agents.

It should be also obvious to one of skill in the art that the polymers as described herein can also be blended or copolymerized in various compositions as required to deliver therapeutic doses of biologically active agents (such as anit-infective agents).

Polymeric carriers for anti-infective and/or fibrosis-inhibiting therapeutic agents can be fashioned in a variety of forms, with desired release characteristics and/or with specific properties depending upon the composition being utilized. For example, polymeric carriers may be fashioned to release a therapeutic agent upon exposure to a specific triggering event such as pH (see, e.g., Heller et al., "Chemically Self- Regulated Drug Delivery Systems," in Polymers in Medicine III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp. 175-188; Kang et al., J. Applied Polymer ScL 48:343-354, 1993; Dong et al., J. Controlled Release 19:171-178, 1992; Dong and Hoffman, J. Controlled Release 75:141-152, 1991; Kim et al., J. Controlled Release 28:143-152, 1994; Comejo-Bravo et al., J. Controlled Release 33:223-229, 1995; Wu and Lee, Pharm. Res. 70(10):1544-1547, 1993; Serres et al., Pharm. Res. 73(2): 196-201 , 1996; Peppas, "Fundamentals of pH- and Temperature-Sensitive Delivery Systems," in Gurny et al. (eds.), Pulsatile Drug Delivery, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp. 41-55; Doelker, "Cellulose Derivatives," 1993, in Peppas and Langer (eds.), Biopolymers I, Springer- Verlag, Berlin). Representative examples of pH-sensitive polymers include poly (acrylic acid) and its derivatives (including for example, homopolymers such as poly(aminocarboxylic acid); poly(acrylic acid); poly(methyl acrylic acid), copolymers of such homopolymers, and copolymers of poly(acrylic acid) and/or acrylate or acrylamide lmonomers such as those discussed above. Other pH sensitive polymers include polysaccharides such as cellulose acetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; cellulose acetate trimellilate; and chitosan. Yet other pH sensitive polymers include any mixture of a pH sensitive polymer and a water-soluble polymer.

Likewise, ant-infective and/or fibrosis-inhibiting therapeutic agents can be delivered via polymeric carriers which are temperature sensitive (see, e.g., Chen et al., "Novel Hydrogels of a Temperature- Sensitive PLURONIC Grafted to a Bioadhesive Polyacrylic Acid Backbone for Vaginal Drug Delivery," in Proceed. Intern. Symp. Control. ReI. Bioact. Mater. 22:167-168, Controlled Release Society, Inc., 1995; Okano, "Molecular Design of Stimuli-Responsive Hydrogels for Temporal Controlled Drug Delivery," in Proceed. Intern. Symp. Control. ReI. Bioact. Mater. 22:111-112, Controlled Release Society, Inc., 1995; Johnston et al., Pharm. Res. 9(3):425-433, 1992; Tung, Int'l J. Pharm. 707:85-90, 1994; Harsh and Gehrke, J. Controlled Release 77:175-186, 1991; Bae et al., Pharm. Res. 8(4):531-537, 1991 ; Dinarvand and D'Emanuele, J. Controlled Release 36:221-227, 1995; Yu and Grainger, "Novel Thermo-sensitive Amphiphilic Gels: Poly N-isopropylacrylamide-co-sodium acrylate-co-n-N- alkylacrylamide Network Synthesis and Physicochemical Characterization," Dept. of Chemical & Biological ScL, Oregon Graduate Institute of Science & Technology, Beaverton, OR, pp. 820-821; Zhou and Smid, "Physical Hydrogels of Associative Star Polymers," Polymer Research Institute, Dept. of Chemistry, College of Environmental Science and Forestry, State Univ. of New York, Syracuse, NY, pp. 822-823; Hoffman et al., "Characterizing Pore Sizes and Water 'Structure' in Stimuli-Responsive Hydrogels," Center for Bioengineering, Univ. of Washington, Seattle, WA, p. 828; Yu and Grainger, "Thermo-sensitive Swelling Behavior in Crosslinked N-isopropylacrylamide Networks: Cationic, Anionic and Ampholytic Hydrogels," Dept. of Chemical & Biological Sci., Oregon Graduate Institute of Science & Technology, Beaverton, OR, pp. 829-830; Kim et al., Pharm. Res. 9(3):283-290, 1992; Bae et al., Pharm. Res. 8(5):624-628, 1991; Kono et al., J. Controlled Release 30:69-75, 1994; Yoshida et al., J. Controlled Release 32:97-102, 1994; Okano et al., J. Controlled Release 36:125-133, 1995; Chun and Kim, J. Controlled Release 38:39-47, 1996; D'Emanuele and Dinarvand, Int'l J. Pharm. 118:237-242, 1995; Katono et al., J. Controlled Release 76:215-228, 1991; Hoffman, "Thermally Reversible Hydrogels Containing Biologically Active Species," in Migliaresi et al. (eds.), Polymers in Medicine III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp. 161-167; Hoffman, "Applications of Thermally Reversible Polymers and Hydrogels in Therapeutics and Diagnostics," in Third International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, UT, Feb. 24-27, 1987, pp. 297-305; Gutowska et al., J. Controlled Release 22:95-104, 1992; Palasis and Gehrke, J. Controlled Release 78:1-12, 1992; Paavola et al., Pharm. Res. 72(12): 1997-2002, 1995).

Representative examples of thermogelling polymers, and the gelatin temperature (LCST (0C)) include homopolymers such as poly(N-methyl-N-n-propylacrylamide), 19.8; poly(N-n-propylacrylamide), 21.5; poly(N-methyl-N-isopropylacrylamide), 22.3; poly(N-n-propylmethacrylamide), 28.0; poIy(N-isopropylacrylamide), 30.9; poly(N, n-diethylacrylamide), 32.0; poly(N-isopropylmethacrylamide), 44.0; poly(N-cyclopropylacrylamide), 45.5; poly(N-ethylmethyacrylamide), 50.0; poly(N-methyl-N-ethylacrylamide), 56.0; poly(N-cyclopropylmethacrylamide), 59.0; poly(N-ethylacrylamide), 72.0. Moreover thermogelling polymers may be made by preparing copolymers between (among) monomers of the above, or by combining such homopolymers with other water-soluble polymers such as acrylmonomers (e.g., acrylic acid and derivatives thereof, such as methylacrylic acid, acrylate monomers and derivatives thereof, such as butyl methacrylate, butyl acrylate, lauryl acrylate, and acrylamide monomers and derivatives thereof, such as N-butyl acrylamide and acrylamide).

Other representative examples of thermogelling polymers include cellulose ether derivatives such as hydroxypropyl cellulose, 410C; methyl cellulose, 55°C; hydroxypropylmethyl cellulose, 66°C; and ethylhydroxyethyl cellulose, polyalkylene oxide-polyester block copolymers of the structure X-Y, Y-X-Y and X-Y-X where X in a polyalkylene oxide and Y is a biodegradable polyester (e.g., PLG-PEG-PLG) and PLURONICs such as F-127, 10 - 15°C; L-122, 190C; L-92, 260C; L-81 , 200C; and L-61 , 24°C.

Representative examples of patents relating to thermally gelling polymers and the preparation include U.S. Patent Nos. 6,451,346; 6,201 ,072; 6,117,949; 6,004,573; 5,702,717; and 5,484,610; and PCT Publication Nos. WO 99/07343; WO 99/18142; WO 03/17972; WQ . . 01/82970; WO 00/18821 ; WO 97/15287; WO 01/41735; WO 00/00222 and WO 00/38651.

Anti-infective and/or fibrosis-inhibiting therapeutic agents may be linked by occlusion in the polymer matrix, dissolution in the polymer, bound by covalent linkages, bound by ionic interactions, or encapsulated in microcapsules. Within certain embodiments of the invention, therapeutic compositions are provided in non-capsular formulations such as microspheres (ranging from nanometers to micrometers in size), pastes, threads of various size, films, or sprays. In one aspect, the anti-scarring agent may be incorporated into biodegradable magnetic nanospheres. The nanospheres may be used, for example, to replenish an anti-scarring agent into an implanted intravascular device, such as a stent containing a weak magnetic alloy (see, e.g., Z. Forbes, B. B. Yellen, G. Friedman, K. Barbee. "An approach to targeted drug delivery based on uniform magnetic fields," IEEE Trans. Magn. 39(5): 3372-3377 (2003)). Within certain aspects of the present invention, therapeutic compositions of anti-infective and/or fibrosis-inhibiting agents may be fashioned in the form of microspheres, microparticles and/or nanoparticles having any size ranging from 50 nm to 500 μm, depending upon the particular use. These compositions can be. These compositions can be formed by spray-drying methods, milling methods, coacervation methods, W/O emulsion methods, W/O/W emulsion methods, and solvent evaporation methods. In other aspects, these compositions can include microemulsions, emulsions, liposomes and micelles. Alternatively, such compositions may also be readily applied as a "spray", which solidifies into a film or coating for use as a device/implant surface coating or to line the tissues of the implantation site. Such sprays may be prepared from microspheres of a wide array of sizes, including for example, from 0.1 μm to 3 μm, from 10 μm to 30 μm, and from 30 μm to 100 μm.

Therapeutic compositions that include anti-infective and/or anti-fibrosis agents may also be prepared in a variety of "paste" or gel forms. For example, within one embodiment of the invention, therapeutic compositions are provided which are liquid at one temperature {e.g., temperature greater than 37°C, such as 400C, 45°C, 5O0C, 550C or 600C), and solid or semi-solid at another temperature (e.g., ambient body temperature, or any temperature lower than 37°C). Such "thermopastes" may be readily made utilizing a variety of techniques (see, e.g., PCT Publication WO 98/24427). Other pastes may be applied as a liquid, which solidify in vivo due to dissolution of a water-soluble component of the paste and precipitation of encapsulated drug into the aqueous body environment. These "pastes" and "gels" containing therapeutic agents are particularly useful for application to the surface of tissues that will be in contact with the implant or device.

Within yet other aspects of the invention, the therapeutic compositions of the present invention may be formed as a film or tube. These films or tubes can be porous or non-porous. Preferably, such films or tubes are generally less than 5, 4, 3, 2, or 1 mm thick, more preferably less than 0.75 mm, 0.5 mm, 0.25 mm, or, 0.10 mm thick. Films or tubes can also be generated of thicknesses less than 50 μm, 25 μm or 10 μm. Such films are preferably flexible with a good tensile strength (e.g., greater than 50, preferably greater than 100, and more preferably greater than 150 or 200 N/cm2), good adhesive properties (Ae., adheres to moist or wet surfaces), and have controlled permeability. Fibrosis-inhibiting agents contained in polymeric films are particularly useful for application to the surface of a device or implant as well as to the surface of tissue, cavity or an organ.

Within further aspects of the present invention, polymeric carriers are provided which are adapted to contain and release a hydrophobic ant-infective and/or fibrosis-inhibiting compound, and/or the carrier containing the hydrophobic compound in combination with a carbohydrate, protein or polypeptide. Within certain embodiments, the polymeric carrier contains or comprises regions, pockets, or granules of one or more hydrophobic compounds. For example, within one embodiment of the invention, hydrophobic compounds may be incorporated within a matrix which contains the hydrophobic therapeutic compound, followed by incorporation of the matrix within the polymeric carrier. A variety of matrices can be utilized in this regard, including for example, carbohydrates and polysaccharides such as starch, cellulose, dextran, methylcellulose, sodium alginate, heparin, chitosan and hyaluronic acid, proteins or polypeptides such as albumin, collagen and gelatin. Within alternative embodiments, hydrophobic compounds may be contained within a hydrophobic core, and this core contained within a hydrophilic shell.

The anti-infective and/or fibrosis-inhibiting therapeutic agent may be delivered as a solution. The therapeutic agent can be incorporated directly into the solution to provide a homogeneous solution or dispersion. In certain embodiments, the solution is an aqueous solution. The aqueous solution may further include buffer salts, as well as viscosity modifying agents (e.g., hyaluronic acid, alginates, carboxymethylcellulose (CMC), and the like). In another aspect of the invention, the solution can include a biocompatible solvent or liquid oligomers and/or polymers, such as ethanol, DMSO, glycerol, PEG-200, PEG-300 or NMP. These compositions may further comprise a polymer such a degradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta- butyrolactone, gamma-butyrolactone, gamma-valerolactone, y- decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one, or block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X (where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator).

Within another aspect of the invention, the therapeutic anti- infective and/or fibrosis-inhibiting agent can further comprise a secondary carrier. The secondary carrier can be in the form of microspheres (e.g., PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate)), nanospheres (PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate)), liposomes, emulsions, microemulsions, micelles (SDS, block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X (where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polyφropylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator), zeolites or cyclodextrins. Other carriers that may likewise be utilized to contain and deliver anti-infective and/or fibrosis-inhibiting therapeutic agents described herein include: hydroxypropyl cyclodextrin (Cserhati and Hollo, Int. J. Pharm. 108:69-75, 1994), liposomes (see, e.g., Sharma et al., Cancer Res. 53:5877-5881, 1993; Sharma and Straubinger, Pharm. Res. 11 (60):889- 896, 1994; WO 93/18751; U.S. Patent No. 5,242,073), liposome/gel (WO 94/26254), nanocapsules (Bartoli et a!., J. Microencapsulation 7(2):191-197, 1990), micelles (Alkan-Onyuksel et al., Pharm. Res. ; 11(2):206-212, 1994), implants (Jampel et al., Invest. Ophthalm. Vis. Science 34(11):3076-3083, 1993; Walter et al., Cancer Res. 54:22017-2212, 1994), nanoparticles (Violante and Lanzafame PAACR), nanoparticles - modified (U.S. Patent No. 5,145,684), nanoparticles (surface modified) (U.S. Patent No. 5,399,363), micelle (surfactant) (U.S. Patent No. 5,403,858), synthetic phospholipid compounds (U.S. Patent No. 4,534,899), gas borne dispersion (U.S. Patent No. 5,301,664), liquid emulsions, foam, spray, gel, lotion, cream, ointment, dispersed vesicles, particles or droplets solid- or liquid- aerosols, microemulsions (U.S. Patent No. 5,330,756), polymeric shell (nano- and micro- capsule) (U.S. Patent No. 5,439,686), emulsion (Tarr et al., Pharm Res. 4: 62-165, 1987), nanospheres (Hagan et al., Proc. Intern. Symp. Control ReI. Bioact. Mater. 22, 1995; Kwon et al., Pharm Res. 12(2): 192-195; Kwon et al., Pharm Res. 70(7):970-974; Yokoyama et al., J. Contr. ReI. 32:269-277, 1994; Gref et al., Science 263:1600-1603, 1994; Bazile et al., J. Pharm. Sci. 84:493-498, 1994) and implants (U.S. Patent No. 4,882,168).

Within another aspect of the present invention, polymeric carriers can be materials that are formed in situ. In one embodiment, the precursors can be monomers or macromers that contain unsaturated groups that can be polymerized and/or cross-linked. The monomers or macromers can then, for example, be injected into the treatment area or onto the surface of the treatment area and polymerized in situ using a radiation source (e.g., visible or UV light) or a free radical system (e.g., potassium persulfate and ascorbic acid or iron and hydrogen peroxide). The polymerization step can be performed immediately prior to, simultaneously to or post injection of the reagents into the treatment site. Representative examples of compositions that undergo free radical polymerization reactions are described in WO 01/44307, WO 01/68720, WO 02/072166, WO 03/043552, WO 93/17669, WO 00/64977; U.S. Patent Nos. 5,900,245, 6,051 ,248, 6,083,524, 6,177,095, 6,201 ,065, 6,217,894, 6,639,014, 6,352,710, 6,410,645, 6,531 ,147, 5,567,435, 5,986,043, 6,602,975; U.S. Patent Application Publication Nos. 2002/012796A1, 2002/0127266A1 , 2002/0151650A1, 2003/0104032A1 , 2002/0091229A1 , and 2003/0059906A1.

In certain aspects, it is desirable to use compositions that can be administered as liquids, but subsequently form hydrogels at the site of administration. Such in situ hydrogel forming compositions can be administered as liquids from a variety of different devices, and are more adaptable for administration to any site, since they are not preformed. Examples of in situ forming hydrogels include photoactivatable mixtures of water-soluble co-polyester prepolymers and polyethylene glycol to create hydrogel barriers. Block copolymers of polyalkylene oxide polymers (e.g., PLURONIC compounds from BASF Corporation, Mount Olive, NJ) and poloxamers have been designed that are soluble in cold water, but form insoluble hydrogels that adhere to tissues at body temperature (Leach, et al., Am. J. Obstet. Gynecol. 162:1317-1319 (1990)).

In certain embodiments, the present invention provides for polymeric crosslinked matrices, and polymeric carriers, that may be used to assist in the prevention of the formation or growth of fibrous connective tissue. The composition may contain and deliver fibrosis-inhibiting agents in the vicinity of the implanted device. The following compositions are particularly useful when it is desired to infiltrate around the device, with or without a fibrosis-inhibiting agent. Such polymeric materials may be prepared from, e.g., (a) synthetic materials, (b) naturally-occurring materials, or (c) mixtures of synthetic and naturally occurring materials. The matrix may be prepared from, e.g., (a) a one-component, i.e., self-reactive, compound, or (b) two or more compounds that are reactive with one another. Typically, these materials are fluid prior to delivery, and thus can be sprayed or otherwise extruded from a delivery device (e.g., a syringe) in order to deliver the composition. After delivery, the component materials react with each other, and/or with the body, to provide the desired affect. In some instances, materials that are reactive with one another must be kept separated prior to delivery to the patient, and are mixed together just prior to being delivered to the patient, in order that they maintain a fluid form prior to delivery. In a preferred aspect of the invention, the components of the matrix are delivered in a liquid state to the desired site in the body, whereupon in situ polymerization occurs.

First and Second Synthetic Polymers In one embodiment, crosslinked polymer compositions (in other words, crosslinked matrices) are prepared by reacting a first synthetic polymer containing two or more nucleophilic groups with a second synthetic polymer containing two or more electrophilic groups, where the electrophilic groups are capable of covalently binding with the nucleophilic groups. In one embodiment, the first and second polymers are each non-immunogenic. In another embodiment, the matrices are not susceptible to enzymatic cleavage by, e.g., a matrix metalloproteinase (e.g., collagenase) and are therefore expected to have greater long-term persistence in vivo than collagen-based compositions.

As used herein, the term "polymer" refers inter alia to polyalkyls, polyamino acids, polyalkyleneoxides and polysaccharides. Additionally, for external or oral use, the polymer may be polyacrylic acid or carbopol. As used herein, the term "synthetic polymer" refers to polymers that are not naturally occurring and that are produced via chemical synthesis. As such, naturally occurring proteins such as collagen and naturally occurring polysaccharides such as hyaluronic acid are specifically excluded. Synthetic collagen, and synthetic hyaluronic acid, and their derivatives, are included. Synthetic polymers containing either nucleophilic or electrophilic groups are also referred to herein as "multifunctionally activated synthetic polymers." The term "multifunctionally activated" (or, simply, "activated") refers to synthetic polymers which have, or have-been chemically modified to have, two or more nucleophilic or electrophilic groups which are capable of reacting with one another (i.e., the nucleophilic groups react with the electrophilic groups) to form covalent bonds. Types of multifunctionally activated synthetic polymers include difunctionally activated, tetrafunctionally activated, and star-branched polymers.

Multifunctionally activated synthetic polymers for use in the present invention must contain at least two, more preferably, at least three, functional groups in order to form a three-dimensional crosslinked network with synthetic polymers containing multiple nucleophilic groups (i.e., "multi- nucleophilic polymers"). In other words, they must be at least difunctionally activated, and are more preferably trifunctionally or tetrafunctionally activated. If the first synthetic polymer is a difunctionally activated synthetic polymer, the second synthetic polymer must contain three or more functional groups in order to obtain a three-dimensional crosslinked network. Most preferably, both the first and the second synthetic polymer contain at least three functional groups.

Synthetic polymers containing multiple nucleophilic groups are also referred to generically herein as "multi-nucleophilic polymers." For use in the present invention, multi-nucleophilic polymers must contain at least two, more preferably, at least three, nucleophilic groups. If a synthetic polymer containing only two nucleophilic groups is used, a synthetic polymer containing three or more electrophilic groups must be used in order to obtain a three-dimensional crosslinked network.

Preferred multi-nucleophilic polymers for use in the compositions and methods of the present invention include synthetic polymers that contain, or have been modified to contain, multiple nucleophilic groups such as primary amino groups and thiol groups. Preferred multi-nucleophilic polymers include: (i) synthetic polypeptides that have been synthesized to contain two or more primary amino groups or thiol groups; and (ii)_polyethylene glycols that have been-modified to contain two or more primary amino groups or thiol groups. In general, reaction of a thiol group with an electrophilic group tends to proceed more slowly than reaction of a primary amino group with an electrophilic group.

In one embodiment, the multi-nucleophilic polypeptide is a synthetic polypeptide that has been synthesized to incorporate amino acid residues containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine). Poly(lysine), a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000.

Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1 ,000 to about 300,000; more preferably, within the range of about 5,000 to about 100,000; most preferably, within the range of about 8,000 to about 15,000. Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.) and Aldrich Chemical (Milwaukee, Wl).

Polyethylene glycol can be chemically modified to contain multiple primary amino or thiol groups according to methods set forth, for example, in Chapter 22 of Poly(ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, N.Y. (1992). Polyethylene glycols which have been modified to contain two or more primary amino groups are referred to herein as "multi-amino PEGs." Polyethylene glycols which have been modified to contain two or more thiol groups are referred to herein as "multi-thiol PEGs." As used herein, the term "polyethylene glycol(s)" includes modified and or derivatized polyethylene glycol(s).

Various forms of multi-amino PEG are commercially available from Shearwater Polymers (Huntsville, Ala.) and from Huntsman Chemical Company (Utah) under the name "Jeffamine." Multi-amino PEGs useful in the present invention-include Huntsman's Jeffamine diamines ("D" series) and triamines ("T" series), which contain two and three primary amino groups per molecule, respectively.

Polyamines such as ethylenediamine (H2N-CH2-CH2-NH2), tetramethylenediamine (H2N-(C H2^-NH2), pentamethylenediamine (cadaverine) (H2N-(CH2)S-NH2), hexamethylenediamine (H2N-(CH2J6-NH2), di(2-aminoethyl)amine (HN-(CH2-CH2-NH2^), and tris(2-aminoethyl)amine (N-(CH2-CH2-NH2)3) may also be used as the synthetic polymer containing multiple nucleophillc groups.

Synthetic polymers containing multiple electrophilic groups are also referred to herein as "multi-electrophilic polymers." For use in the present invention, the multifunctionally activated synthetic polymers must contain at least two, more preferably, at least three, electrophilic groups in order to form a three-dimensional crosslinked network with multi- nucleophilic polymers. Preferred multi-electrophilic polymers for use in the compositions of the invention are polymers which contain two or more succinimidyl groups capable of forming covalent bonds with nucleophilic groups on other molecules. Succinimidyl groups are highly reactive with materials containing primary amino (NH2) groups, such as multi-amino PEG, poly(lysine), or collagen. Succinimidyl groups are slightly less reactive with materials containing thiol (SH) groups, such as multi-thiol PEG or synthetic polypeptides containing multiple cysteine residues.

As used herein, the term "containing two or more succinimidyl groups" is meant to encompass polymers which are preferably commercially available containing two or more succinimidyl groups, as well as those that must be chemically derivatized to contain two or more succinimidyl groups. As used herein, the term "succinimidyl group" is intended to encompass sulfosuccinimidyl groups and other such variations of the "generic" succinimidyl group. The presence of the sodium sulfite moiety on the sulfosuccinimidyl group serves to increase the solubility of the polymer.

Hydrophilic polymers and, in particular, various derivatized polyethylene glycols, are preferred for use in the compositions of the present invention. As used herein, the term "PEG" refers to polymers having the repeating structure (OCH2-CHb)n- Structures for some specific, tetrafunctionally activated forms of PEG are shown in FIGS. 4 to 13 of U.S. Patent 5,874,500, incorporated herein by reference. Examples of suitable PEGS include PEG succinimidyl propionate (SE-PEG), PEG succinimidyl succinamide (SSA-PEG), and PEG succinimidyl carbonate (SC-PEG). In one aspect of the invention, the crosslinked matrix is formed in situ by reacting pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) as reactive reagents. Structures for these reactants are shown in U.S. Patent 5,874,500. Each of these materials has a core with a structure that may be seen by adding ethylene oxide-derived residues to each of the hydroxyl groups in pentaerythritol, and then derivatizing the terminal hydroxyl groups (derived from the ethylene oxide) to contain either thiol groups (so as to form 4-armed thiol PEG) or N- hydroxysuccinimydyl groups (so as to form 4-armed NHS PEG), optionally with a linker group present between the ethylene oxide derived backbone and the reactive functional group, where this product is commercially available as COSEAL from Angiotech Pharmaceuticals Inc. Optionally, a group "D" may be present in one or both of these molecules, as discussed in more detail below.

As discussed above, preferred activated polyethylene glycol derivatives for use in the invention contain succinimidyl groups as the reactive group. However, different activating groups can be attached at sites along the length of the PEG molecule. For example, PEG can be derivatized to form functionally activated PEG propionaldehyde (A-PEG), or functionally activated PEG glycidyl ether (E-PEG), or functionally activated PEG-isocyanate (I-PEG), or functionally activated PEG-vinylsulfone (V- PEG).

Hydrophobic polymers can also be used to prepare the compositions of the present invention. Hydrophobic polymers for use in the present invention preferably contain, or can be derivatized to contain, two or more electrophilic groups, such as succinimidyl groups, most preferably, two, three, or four electrophilic groups. As used herein, the term "hydrophobic polymer" refers to polymers which contain a relatively small proportion of oxygen or nitrogen atoms.

Hydrophobic polymers which already contain two or more succinimidyl groups include, without limitation, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS3), dithiobis(succinimidylpropionate) (DSP), bis(2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'-dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives. The above-referenced polymers are commercially available from Pierce (Rockford, III.), under catalog Nos. 21555, 21579, 22585, 21554, and 21577, respectively.

Preferred hydrophobic polymers for use in the invention generally have a carbon chain that is no longer than about 14 carbons. Polymers having carbon chains substantially longer than 14 carbons generally have very poor solubility in aqueous solutions and, as such, have very long reaction times when mixed with aqueous solutions of synthetic polymers containing multiple nucleophilic groups.

Certain polymers, such as polyacids, can be derivatized to contain two or more functional groups, such as succinimidyl groups. Polyacids for use in the present invention include, without limitation, trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid). Many of these polyacids are commercially available from DuPont Chemical Company (Wilmington, DE). According to a general method, polyacids can be chemically derivatized to contain two or more succinimidyl groups by reaction with an appropriate molar amount of N-hydroxysuccinimide (NHS) in the presence of N1N1- dicyclohexylcarbodiimide (DCC).

Polyalcohols such as trimethylolpropane and di(trimethylol propane) can be converted to carboxylic acid form using various methods, then further derivatized by reaction with NHS in the presence of DCC to produce trifunctionally and tetrafunctionally activated polymers, respectively, as described in U.S. application Ser. No. 08/403,358. Polyacids such as heptanedioic acid (HOOC-(CH2)5-COOH), octanedioic acid (HOOC-(CH2)6- COOH), and hexadecanedioic acid (HOOC-(CH2)i4-COOH) are derivatized by the addition of succinimidyl groups to produce difunctionally activated polymers.

Polyamines such as ethylenediamine, tetramethylenediamine, pentamethylenediamine (cadaverine), hexamethylenediamine, bis (2- aminoethyl)amine, and tris(2-aminoethyl)amine can be chemically derivatized to polyacids, which can then be derivatized to contain two or more succinimidyl groups by reacting with the appropriate molar amounts of N-hydroxysuccinimide in the presence of DCC, as described in U.S. application Ser. No. 08/403,358. Many of these polyamines are commercially available from DuPont Chemical Company.

In a preferred embodiment, the first synthetic polymer will contain multiple nucleophilic groups (represented below as "X") and it will react with the second synthetic polymer containing multiple electrophilic groups (represented below as "Y"), resulting in a covalently bound polymer network, as follows:

Polymer-Xm + Polymer-Yn → Polymer-Z-Polymer wherein m < 2, n < 2, and m + n ≤ 5; where exemplary X groups include -NH2, -SH, -OH, -PH2, CO- NH-NH2, etc., where the X groups may be the same or different in polymer-

Xm! where exemplary Y groups include -CO2-N(COCH2^, -CO2H, - CHO, -CHOCH2 (epoxide), -N=C=O, -SO2-CH=CH2, -N(COCH)2 (i.e., a five- membered heterocyclic ring with a double bond present between the two CH groups), -S-S-(CsH4N), etc., where the Y groups may be the same or different in polymer-Yn; and where Z is the functional group resulting from the union of a nucleophilic group (X) and an electrophilic group (Y).

As noted above, it is also contemplated by the present invention that X and Y may be the same or different, i.e., a synthetic polymer may have two different electrophilic groups, or two different nucleophilic groups, such as with glutathione.

In one embodiment, the backbone of at least one of the synthetic polymers comprises alkylene oxide residues, e.g., residues from ethylene oxide, propylene oxide, and mixtures thereof. The term 'backbone' refers to a significant portion of the polymer.

For example, the synthetic polymer containing alkylene oxide residues may be described by the formula X-polymer-X or Y-polymer-Y, wherein X and Y are as defined above, and the term "polymer" represents - (CH2CH2 O)n- or -(CH(CH3)CH2 O)n- or -(CH2-CH2-O)n-(CH(CH3)CH2-O)n-. In these cases the synthetic polymer would be difunctional.

The required functional group X or Y is commonly coupled to the polymer backbone by a linking group (represented below as "Q"), many of which are known or possible. There are many ways to prepare the various functionalized polymers, some of which are listed below:

Polymer-Qi-X + Polymer-Q2-Y → Polymer-Qi-Z-Q2-Polymer

Exemplary Q groups include -O-(CH2)n-; -S-(CH2)n-; -NH- (CHz)n-; -O2C-NH-(CH2)n-; -O2C-(CH2)n-; -O2C-(CR1H)n-; and -0-R2-CO-NH-, which provide synthetic polymers of the partial structures: polymer-O- (CH2)n-(X or Y); polymer-S-(CH2)n-(X or Y); polymer-NH-(CH2)n-(X or Y); polymer-O2C-NH-(CH2)n-(X or Y); polymer-O2C-(CH2)n-(X or Y); polymer-O2C-(CR1 H)n-(X or Y); and polymer-O-R2-CO-NH-(X or Y), respectively. In these structures, n = 1-10, R1 = H or alkyl (Ae., CH3, C2H5, etc.); R2 = CH2, or CO-NH-CH2CH2; and Q1 and Q2 may be the same or different.

For example, when Q2 = OCH2CH2 (there is no Qi in this case); Y = -CO2-N(COCH2)2; and X = -NH2, -SH, or -OH, the resulting reactions and Z groups would be as follows:

Polymer-NH2 + Polymer-O-CH2-CH2-CO2-N(COCH2)2 → PoIymer-NH-CO-CH2-CH2-O-Polymer;

Polymer-SH + Polymer-O-CH2-CH2-CO2-N(COCH2)2 → Polymer-S-COCH2CH2-O-Polymer; and

Polymer-OH + Polymer-O-CH2-CH2-CO2-N(COCH2)2 → Polymer-O-COCH2CH2-O-Polymer.

An additional group, represented below as "D", can be inserted between the polymer and the linking group, if present. One purpose of such a D group is to affect the degradation rate of the crosslinked polymer composition in vivo, for example, to increase the degradation rate, or to decrease the degradation rate. This may be useful in many instances, for example, when drug has been incorporated into the matrix, and it is desired to increase or decrease polymer degradation rate so as to influence a drug delivery profile in the desired direction. An illustration of a crosslinking reaction involving first and second synthetic polymers each having D and Q groups is shown below.

Polymer-D-Q-X + Polymer-D-Q-Y → Polymer-D-Q-Z-Q-D- Polymer

Some useful biodegradable groups "D" include polymers formed from one or more α-hydroxy acids, e.g., lactic acid, glycolic acid, and the cyclization products thereof (e.g., lactide, glycolide), ε-caprolactone, and amino acids. The polymers may be referred to as polylactide, polyglycolide, poly(co-lactide-glycolide); poly-ε-caprolactone, polypeptide (also known as poly amino acid, for example, various di- or tri-peptides) and poly(anhydride)s.

In a general method for preparing the crosslinked polymer compositions used in the context of the present invention, a first synthetic polymer containing multiple nucleophilic groups is mixed with a second synthetic polymer containing multiple electrophilic groups. Formation of a three-dimensional crosslinked network occurs as a result of the reaction between the nucleophilic groups on the first synthetic polymer and the electrophilic groups on the second synthetic polymer.

The concentrations of the first synthetic polymer and the second synthetic polymer used to prepare the compositions of the present invention will vary depending upon a number of factors, including the types and molecular weights of the particular synthetic polymers used and the desired end use application. In general, when using multi-amino PEG as the first synthetic polymer, it is preferably used at a concentration in the range of about 0.5 to about 20 percent by weight of the final composition, while the second synthetic polymer is used at a concentration in the range of about 0.5 to about 20 percent by weight of the final composition. For example, a final composition having a total weight of 1 gram (1000 milligrams) would contain between about 5 to about 200 milligrams of multi- amino PEG, and between about 5 to about 200 milligrams of the second synthetic polymer.

Use of higher concentrations of both first and second synthetic polymers will result in the formation of a more tightly crosslinked network, producing a stiffer, more robust gel. Compositions intended for use in tissue augmentation will generally employ concentrations of first and second synthetic polymer that fall toward the higher end of the preferred concentration range. Compositions intended for use as bioadhesives or in adhesion prevention do not need to be as firm and may therefore contain lower polymer concentrations.

Because polymers containing multiple electrophilic groups will also react with water, the second synthetic polymer is generally stored and used in sterile, dry form to prevent the loss of crosslinking ability due to hydrolysis which typically occurs upon exposure of such electrophilic groups to aqueous media. Processes for preparing synthetic hydrophilic polymers containing multiple electrophylic groups in sterile, dry form are set forth in U.S. Patent 5,643,464. For example, the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or, preferably, e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates. In contrast, polymers containing multiple nucleophilic groups are generally not water-reactive and can therefore be stored in aqueous solution.

In certain embodiments, one or both of the electrophilic- or nucleophilic-terminated polymers described above can be combined with a synthetic or naturally occurring polymer. The presence of the synthetic or naturally occurring polymer may enhance the mechanical and/or adhesive properties of the in situ forming compositions. Naturally occurring polymers, and polymers derived from naturally occurring polymer that may be included in in situ forming materials include naturally occurring proteins, such as collagen, collagen derivatives (such as methylated collagen), fibrinogen, thrombin, albumin, fibrin, and derivatives of and naturally occurring polysaccharides, such as glycosaminoglycans, including deacetylated and desulfated glycosaminoglycan derivatives.

In one aspect, a composition comprising naturally-occurring protein and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising collagen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising methylated collagen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrinogen and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising thrombin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising albumin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrin and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising naturally occurring polysaccharide and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising deacetylated glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising desulfated glycosaminoglycan and both of the first and second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.

In one aspect, a composition comprising naturally-occurring protein and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising collagen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising methylated collagen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrinogen and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising thrombin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising albumin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrin and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising naturally occurring polysaccharide and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising deacetylated glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising desulfated glycosaminoglycan and the first synthetic polymer as described above is used to form the crosslinked matrix according to the present invention.

In one aspect, a composition comprising naturally-occurring protein and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising collagen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising methylated collagen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrinogen and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising thrombin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising albumin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising fibrin and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising naturally occurring polysaccharide and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising deacetylated glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. In one aspect, a composition comprising desulfated glycosaminoglycan and the second synthetic polymer as described above is used to form the crosslinked matrix according to the present invention. The presence of protein or polysaccharide components which contain functional groups that can react with the functional groups on multiple activated synthetic polymers can result in formation of a crosslinked synthetic polymer-naturally occurring polymer matrix upon mixing and/or crosslinking of the synthetic polymer(s). In particular, when the naturally occurring polymer (protein or polysaccharide) also contains nucleophilic groups such as primary amino groups, the electrophilic groups on the second synthetic polymer will react with the primary amino groups on these components, as well as the nucleophilic groups on the first synthetic polymer, to cause these other components to become part of the polymer matrix. For example, lysine-rich proteins such as collagen may be especially reactive with electrophilic groups on synthetic polymers.

In one aspect, the naturally occurring protein is polymer may be collagen. As used herein, the term "collagen" or "collagen material" refers to all forms of collagen, including those which have been processed or otherwise modified and is intended to encompass collagen of any type, from any source, including, but not limited to, collagen extracted from tissue or produced recombinantly, collagen analogues, collagen derivatives, modified collagens, and denatured collagens, such as gelatin.

In general, collagen from any source may be included in the compositions of the invention; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced. The preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. U.S. Patent No. 5,428,022 discloses methods of extracting and purifying collagen from the human placenta. U.S. Patent No. 5,667,839, discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows. Collagen of any type, including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred. Either atelopeptide or telopeptide-containing collagen may be used; however, when collagen from a xenogeneic source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.

Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the compositions of the invention, although previously crosslinked collagen may be used. Non-crosslinked atelopeptide fibrillar collagen is commercially available from lnamed Aesthetics (Santa Barbara, CA) at collagen concentrations of 35 mg/ml and 65 mg/ml under the trademarks ZYDERM I Collagen and ZYDERM Il Collagen, respectively. Glutaraldehyde crosslinked atelopeptide fibrillar collagen is commercially available from lnamed Corporation (Santa Barbara, CA) at a collagen concentration of 35 mg/ml under the trademark ZYPLAST Collagen.

Collagens for use in the present invention are generally in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml; preferably, between about 30 mg/ml to about 90 mg/ml.

Because of its tacky consistency, nonfibrillar collagen may be preferred for use in compositions that are intended for use as bioadhesives. The term "nonfibrillar collagen" refers to any modified or unmodified collagen material that is in substantially nonfibrillar form at pH 7, as indicated by optical clarity of an aqueous suspension of the collagen.

Collagen that is already in nonfibrillar form may be used in the compositions of the invention. As used herein, the term "nonfibrillar collagen" is intended to encompass collagen types that are nonfibrillar in native form, as well as collagens that have been chemically modified such that they are in nonfibrillar form at or around neutral pH. Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, Vl, and VII.

Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen and methylated collagen, both of which can be prepared according to the methods described in U.S. Pat. No. 4,164,559, issued Aug. 14, 1979, to Miyata et al., which is hereby incorporated by reference in its entirety. Due to its inherent tackiness, methylated collagen is particularly preferred for use in bioadhesive compositions, as disclosed in U.S. application Ser. No. 08/476,825.

Collagens for use in the crosslinked polymer compositions of the present invention may start out in fibrillar form, then be rendered nonfibrillar by the addition of one or more fiber disassembly agent. The fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above. Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids (e.g., arginine), inorganic salts (e.g., sodium chloride and potassium chloride), and carbohydrates (e.g., various sugars including sucrose).

In one aspect, the polymer may be collagen or a collagen derivative, for example methylated collagen. An example of an in situ forming composition uses pentaerythritol poly(ethylene glycol)ether tetra- sulfhydryl] (4-armed thiol PEG), pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG) and methylated collagen as the reactive reagents. This composition, when mixed with the appropriate buffers can produce a crosslinked hydrogel. (See, e.g., U.S. Patent Nos. 5,874,500; 6,051,648; 6,166,130; 5,565,519 and 6,312,725J.

In another aspect, the naturally occurring polymer may be a glycosaminoglycan. Glycosaminoglycans, e.g., hyaluronic acid, contain both anionic and cationic functional groups along each polymeric chain, which can form intramolecular and/or intermolecular ionic crosslinks, and are responsible for the thixotropic (or shear thinning) nature of hyaluronic acid.

In certain aspects, the glycosaminoglycan may be derivatized. For example, glycosaminoglycans can be chemically derivatized by, e.g., deacetylation, desulfation, or both in order to contain primary amino groups available for reaction with electrophilic groups on synthetic polymer molecules. Glycosaminoglycans that can be derivatized according to either or both of the aforementioned methods include the following: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chitin (can be derivatized to chitosan), keratan sulfate, keratosulfate, and heparin. Derivatization of glycosaminoglycans by deacetylation and/or desulfation and covalent binding of the resulting glycosaminoglycan derivatives with synthetic hydrophilic polymers is described in further detail in commonly assigned, allowed U.S. patent application Ser. No. 08/146,843, filed Nov. 3, 1993.

In general, the collagen is added to the first synthetic polymer, then the collagen and first synthetic polymer are mixed thoroughly to achieve a homogeneous composition. The second synthetic polymer is then added and mixed into the collagen/first synthetic polymer mixture, where it will covalently bind to primary amino groups or thiol groups on the first synthetic polymer and primary amino groups on the collagen, resulting in the formation of a homogeneous crosslinked network." Various deacetylated and/or desulfated glycosaminoglycan derivatives can be incorporated into the composition in a similar manner as that described above for collagen. In addition, the introduction of hydrocolloids such as carboxymethylcellulose may promote tissue adhesion and/or swellability.

Administration of the Crosslinked Synthetic Polymer

Compositions

The compositions of the present invention having two synthetic polymers may be administered before, during or after crosslinking of the first and second synthetic polymer. Certain uses, which are discussed in greater detail below, such as tissue augmentation, may require the compositions to be crosslinked before administration, whereas other applications, such as tissue adhesion, require the compositions to be administered before crosslinking has reached "equilibrium." The point at which crosslinking has reached equilibrium is defined herein as the point at which the composition no longer feels tacky or sticky to the touch.

In order to administer the composition prior to crosslinking, the first synthetic polymer and second synthetic polymer may be contained within separate barrels of a dual-compartment syringe. In this case, the two synthetic polymers do not actually mix until the point at which the two polymers are extruded from the tip of the syringe needle into the patient's tissue. This allows the vast majority of the crosslinking reaction to occur in situ, avoiding the problem of needle blockage which commonly occurs if the two synthetic polymers are mixed too early and crosslinking between the two components is already too advanced prior to delivery from the syringe needle. The use of a dual-compartment syringe, as described above, allows for the use of smaller diameter needles, which is advantageous when performing soft tissue augmentation in delicate facial tissue, such as that surrounding the eyes.

Alternatively, the first synthetic polymer and second synthetic polymer may be mixed according to the methods described above prior to delivery to the tissue site, then injected to the desired tissue site immediately (preferably, within about 60 seconds) following mixing.

In another embodiment of the invention, the first synthetic polymer and second synthetic polymer are mixed, then extruded and allowed to crosslink into a sheet or other solid form. The crosslinked solid is then dehydrated to remove substantially all unbound water. The resulting dried solid may be ground or comminuted into particulates, then suspended in a nonaqueous fluid carrier, including, without limitation, hyaluronic acid, dextran sulfate, dextran, succinylated noncrosslinked collagen, methylated noncrosslinked collagen, glycogen, glycerol, dextrose, maltose, triglycerides of fatty acids (such as corn oil, soybean oil, and sesame oil), and egg yolk phospholipid. The suspension of particulates can be injected through a small-gauge needle to a tissue site. Once inside the tissue, the crosslinked polymer particulates will rehydrate and swell in size at least five-fold. Hydrophilic Polymer + Plurality of Crosslinkable

Components

As mentioned above, the first and/or second synthetic polymers may be combined with a hydrophilic polymer, e.g., collagen or methylated collagen, to form a composition useful in the present invention. In one general embodiment, the compositions useful in the present invention include a hydrophilic polymer in combination with two or more crosslinkable components. This embodiment is described in further detail in this section.

The Hydrophilic Polymer Component:

The hydrophilic polymer component may be a synthetic or naturally occurring hydrophilic polymer. Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen and derivatives thereof, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred; carboxylated polysaccharides such as -polymannuronic acid and polygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives. Collagen (e.g., methylated collagen) and glycosaminoglycans are preferred naturally occurring hydrophilic polymers for use herein.

In general, collagen from any source may be used in the composition of the method; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced. The preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. See, e.g., U.S. Pat. No. 5,428,022, to Palefsky et al., which discloses methods of extracting and purifying collagen from the human placenta. See also U.S. Patent No. 5,667,839, to Berg, which discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows. Unless otherwise specified, the term "collagen" or "collagen material" as used herein refers to all forms of collagen, including those that have been processed or otherwise modified.

Collagen of any type, including, but not limited to, types I, II, III, IV, or any combination thereof, may be used in the compositions of the invention, although type I is generally preferred. Either atelopeptide or telopeptide-containing collagen may be used; however, when collagen from a source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen.

Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the compositions of the invention, although previously crosslinked collagen may be used. Non-crosslinked atelopeptide fibrillar collagen is commercially available from McGhan Medical Corporation (Santa Barbara, Calif.) at collagen concentrations of 35 mg/ml and 65 mg/ml under the trademarks ZYDERM® I Collagen and ZYDERM® Il Collagen, respectively. Glutaraldehyde-crosslinked atelopeptide fibrillar collagen is commercially available from McGhan Medical Corporation at a collagen concentration of 35 mg/ml under the trademark ZYPLAST®.

Collagens for use in the present invention are generally, although not necessarily, in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml, preferably between about 30 mg/ml to about 90 mg/ml.

Although intact collagen is preferred, denatured collagen, commonly known as gelatin, can also be used in the compositions of the invention. Gelatin may have the added benefit of being degradable faster than collagen.

Because of its greater surface area and greater concentration of reactive groups, nonfibrillar collagen is generally preferred. The term "nonfibrillar collagen" refers to any modified or unmodified collagen material that is in substantially nonfibrillar form at pH 7, as indicated by optical clarity of an aqueous suspension of the collagen.

Collagen that is already in nonfibrillar form may be used in the compositions of the invention. As used herein, the term "nonfibrillar collagen" is intended to encompass collagen types that are nonfibrillar in native form, as well as collagens that have been chemically modified such that they are in nonfibrillar form at or around neutral pH. Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, Vl, and VII.

Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen, propylated collagen, ethylated collagen, methylated collagen, and the like, both of which can be prepared according to the methods described in U.S. Pat. No. 4,164,559, to Miyata et al., which is hereby incorporated by reference in its entirety. Due to its inherent tackiness, methylated collagen is particularly preferred, as disclosed in U.S. Patent No. 5,614,587 to Rhee et al. Gollagens-for use in the crosslinkable compositions of the present invention may start out in fibrillar form, then be rendered nonfibrillar by the addition of one or more fiber disassembly agents. The fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above. Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids, inorganic salts, and carbohydrates, with biocompatible alcohols being particularly preferred. Preferred biocompatible alcohols include glycerol and propylene glycol. Non-biocompatible alcohols, such as ethanol, methanol, and isopropanol, are not preferred for use in the present invention, due to their potentially deleterious effects on the body of the patient receiving them. Preferred amino acids include arginine. Preferred inorganic salts include sodium chloride and potassium chloride. Although carbohydrates, such as various sugars including sucrose, may be used in the practice of the present invention, they are not as preferred as other types of fiber disassembly agents because they can have cytotoxic effects in vivo.

As fibrillar collagen has less surface area and a lower concentration of reactive groups than nonfibrillar, fibrillar collagen is less preferred. However, as disclosed in U.S. Patent 5,614,587, fibrillar collagen, or mixtures of nonfibrillar and fibrillar collagen, may be preferred for use in compositions intended for long-term persistence in vivo, if optical clarity is not a requirement.

Synthetic hydrophilic polymers may also be used in the present invention. Useful synthetic hydrophilic polymers include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol and poly(ethylene oxide)-poly(propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri- pplyoxyethylated glycerol,, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and analogs and copolymers thereof, such as polyacrylic acid perse, polymethacrylic acid, poly(hydroxyethyl-methacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide methacrylate), poly(methylalkylsulfoxide acrylate) and copolymers of any of the foregoing, and/or with additional acrylate species such as aminoethyl acrylate and mono-2-(acryloxy)-ethyl succinate; polymaleic acid; poly(acrylamides) such as polyacrylamide perse, poly(methacrylamide), poly(dimethylacrylamide), and poly(N-isopropyl- acrylamide); poly(olefinic alcohol)s such as polyvinyl alcohol); poly(N-vinyl lactams) such as polyvinyl pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof; polyoxazolines, including poly(methyloxazoline) and poly(ethyloxazoline); and polyvinylamines. It must be emphasized that the aforementioned list of polymers is not exhaustive, and a variety of other synthetic hydrophilic polymers may be used, as will be appreciated by those skilled in the art.

The Crosslinkable Components:

The compositions of the invention also comprise a plurality of crosslinkable components. Each of the crosslinkable components participates in a reaction that results in a crosslinked matrix. Prior to completion of the crosslinking reaction, the crosslinkable components provide the necessary adhesive qualities that enable the methods of the invention.

The crosslinkable components are selected so that crosslinking gives rise to a biocompatible, nonimmunogenic matrix useful in a variety of contexts including adhesion prevention, biologically active agent delivery, tissue augmentation, and other applications. The crosslinkable components of the invention comprise: a component A, which has m nucleophilic groups, wherein m > 2 and a component B, which has n electrophilic groups capable of reaction with the m nucleophilic groups, wherein n > 2 and m + n > 4. An optional third component, optional component C, which has at least one functional group that is either electrophilic and capable of reaction with the nucleophilic groups of component A, or nucleophilic and capable of reaction with the electrophilic groups of component B may also be present. Thus, the total number of functional groups present on components A, B and C, when present, in combination is > 5; that is, the total functional groups given by m + n + p must be > 5, where p is the number of functional groups on component C and, as indicated, is > 1. Each of the components is biocompatible and nonimmunogenic, and at least one component is comprised of a hydrophilic polymer. Also, as will be appreciated, the composition may contain additional crosslinkable components D, E, F, etc., having one or more reactive nucleophilic or electrophilic groups and thereby participate in formation of the crosslinked biomaterial via covalent bonding to other components.

The m nucleophilic groups on component A may all be the same, or, alternatively, A may contain two or more different nucleophilic groups. Similarly, the n electrophilic groups on component B may all be the same, or two or more different electrophilic groups may be present. The functional group(s) on optional component C, if nucleophilic, may or may not be the same as the nucleophilic groups on component A, and, conversely, if electrophilic, the functional group(s) on optional component C may or may not be the same as the electrophilic groups on component B.

Accordingly, the components may be represented by the structural formulae

(I) R 1HQ1 ]q-X)m (component A),

(H) R 2HQ2 IrY)n (component B), and

(III) R 3HQ3 VFn)p (optional component C), wherein:

R1, R2 and R3 are independently selected from the group consisting of C2 to C14 hydrocarbyl, heteroatom-containing C2 to Ci4 hydrocarbyl, hydrophilic polymers, and hydrophobic polymers, providing that at least one of R1, R2 and R3 is a hydrophilic polymer, preferably a synthetic hydrophilic polymer;

X represents one of the m nucleophilic groups of component A, and the various X moieties on A may be the same or different;

Y represents one of the n electrophilic groups of component B, and the various Y moieties on A may be the same or different;

Fn represents a functional group on optional component C;

Q1, Q2 and Q3 are linking groups; m ≥ 2, n ≥ 2, m + n is > 4, q, and r are independently zero or 1 , and when optional component C is present, p ≥ 1 , and s is independently zero or 1. Reactive Groups:

X may be virtually any nucleophilic group, so long as reaction can occur with the electrophilic group Y. Analogously, Y may be virtually any electrophilic group, so long as reaction can take place with X. The only limitation is a practical one, in that reaction between X and Y should be fairly rapid and take place automatically upon admixture with an aqueous medium, without need for heat or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although not essential that reaction occur without need for ultraviolet or other radiation. Ideally, the reactions between X and Y should be complete in under 60 minutes, preferably under 30 minutes. Most preferably, the reaction occurs in about 5 to 15 minutes or less.

Examples of nucleophilic groups suitable as X include, but are not limited to, -NH2, -NHR4, -N(R4)2, -SH, -OH, -COOH, -C6H4-OH, -PH2, - PHR5, -P(R5)2, -NH-NH2, -CO-NH-NH2, -C5H4N, etc. wherein R4 and R5 are hydrocarbyl, typically alkyl or monocyclic aryl, preferably alkyl, and most preferably lower alkyl. Organometallic moieties are also useful nucleophilic groups for the purposes of the invention, particularly those that act as carbanion donors. Organometallic nucleophiles are not, however, preferred. Examples of organometallic moieties include: Grignard functionalities - R6MgHaI wherein R6 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromo, iodo or chloro, preferably bromo; and lithium- containing functionalities, typically alkyllithium groups; sodium-containing functionalities.

It will be appreciated by those of ordinary skill in the art that certain nucleophilic groups must be activated with a base so as to be capable of reaction with an electrophile. For example, when there are nucleophilic sulfhydryl and hydroxyl groups in the crosslinkable composition, the composition must be admixed with an aqueous base in order to remove a proton and provide an -S" or -O" species to enable reaction with an electrophile. Unless it is desirable for the base to participate in the crosslinking reaction, a nonnucleophilic base is preferred. In some embodiments, the base may be present as a component of a buffer solution. Suitable bases and corresponding crosslinking reactions are described infra in Section E.

The selection of electrophilic groups provided within the crosslinkable composition, i.e., on component B, must be made so that reaction is possible with the specific nucleophilic groups. Thus, when the X moieties are amino groups, the Y groups are selected so as to react with amino groups. Analogously, when the X moieties are sulfhydryl moieties, the corresponding electrophilic groups are sulfhydryl-reactive groups, and the like.

By way of example, when X is amino (generally although not necessarily primary amino), the electrophilic groups present on Y are amino reactive groups such as, but not limited to: (1) carboxylic acid esters, including cyclic esters and "activated" esters; (2) acid chloride groups (-CO- Cl); (3) anhydrides (-(CO)-O-(CO)-R); (4) ketones and aldehydes, including α,β-unsaturated aldehydes and ketones such as -CH=CH-CH=O and - CH=CH-C(CH3)=O; (5) halides; (6) isocyanate (-N=C=O); (7) isothiocyanate (-N=C=S); (8) epoxides; (9) activated hydroxyl groups (e.g., activated with conventional activating agents such as carbonyldiimidazole or sulfonyl chloride); and (10) olefins, including conjugated olefins, such as ethenesulfonyl (-SO2CH=CH2) and analogous functional groups, including acrylate (-CO2-C=CH2), methacrylate (-CO2-C(CH3)=CH2)), ethyl acrylate (- CO2-C(CH2CHs)=CH2), and ethyleneimino (-CH=CH-C=NH). Since a carboxylic acid group perse is not susceptible to reaction with a nucleophilic amine, components containing carboxylic acid groups must be activated so as to be amine-reactive. Activation may be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU). For example, a carboxylic acid can be reacted with an alkoxy-substituted N-hydroxy- succinimide or N-hydroxysulfosuccinimide in the presence of DCC to form reactive electrophilic groups, the N-hydroxysuccinimide ester and the N- hydroxysulfosuccinimide ester, respectively. Carboxylic acids may also be activated by reaction with an acyl halide such as an acyl chloride (e.g., acetyl chloride), to provide a reactive anhydride group. In a further example, a carboxylic acid may be converted to an acid chloride group using, e.g., thionyl chloride or an acyl chloride capable of an exchange reaction. Specific reagents and procedures used to carry out such activation reactions will be known to those of ordinary skill in the art and are described in the pertinent texts and literature.

Analogously, when X is sulfhydryl, the electrophilic groups present on Y are groups that react with a sulfhydryl moiety. Such reactive groups include those that form thioester linkages upon reaction with a sulfhydryl group, such as those described in PCT Publication No. WO 00/62827 to Wallace et al. As explained in detail therein, such "sulfhydryl reactive" groups include, but are not limited to: mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p- nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N- hydroxysulfosuccinimide esters, and N-hydroxyglutarimide esters; esters of 1 -hydroxybenzotriazole; 3-hydroxy-3,4-dihydro-benzotriazin-4-one; 3- hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates. With these sulfhydryl reactive groups, auxiliary reagents can also be used to facilitate bond formation, e.g., 1-ethyl- 3-[3-dimethylaminopropyl]carbodiimide can be used to facilitate coupling of sulfhydryl groups to carboxyl-containing groups.

In addition to the sulfhydryl reactive groups that form thioester linkages, various other sulfhydryl reactive functionalities can be utilized that form other types of linkages. For example, compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups. Alternatively, sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups; such groups generally have the structure -S- S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron-withdrawing moiety, such that Ar may be, for example, 4- pyridinyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2- nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc. In such instances, auxiliary reagents, i.e., mild oxidizing agents such as hydrogen peroxide, can be used to facilitate disulfide bond formation.

Yet another class of sulfhydryl reactive groups forms thioether bonds with sulfhydryl groups. Such groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and α,β-unsaturated aldehydes and ketones. This class of sulfhydryl reactive groups are particularly preferred as the thioether bonds may provide faster crosslinking and longer in vivo stability.

When X is -OH, the electrophilic functional groups on the remaining component(s) must react with hydroxy! groups. The hydroxyl group may be activated as described above with respect to carboxylic acid groups, or it may react directly in the presence of base with a sufficiently reactive electrophile such as an epoxide group, an aziridine group, an acyl halide, or an anhydride.

When X is an organometallic nucleophile such as a Grignard functionality or an alkyllithium group, suitable electrophilic functional groups for reaction therewith are those containing carbonyl groups, including, by way of example, ketones and aldehydes.

It will also be appreciated that certain functional groups can react as nucleophiles or as electrophiles, depending on the selected reaction partner and/or the reaction conditions. For example, a carboxylic acid group can act as a nucleophile in the presence of a fairly strong base, but generally acts as an electrophile allowing nucleophilic attack at the carbonyl carbon and concomitant replacement of the hydroxyl group with the incoming nucleophile.

The covalent linkages in the crosslinked structure that result upon covalent binding of specific nucleophilic components to specific electrophilic components in the crosslinkable composition include, solely by way of example, the following (the optional linking groups Q1 and Q2 are omitted for clarity):

TABLE

Figure imgf000161_0001
Figure imgf000162_0001

Linking Groups:

The functional groups X and Y and FN on optional component C may be directly attached to the compound core (R1, R2 or R3 on optional component C, respectively), or they may be indirectly attached through a linking group, with longer linking groups also termed "chain extenders." In structural formulae (I), (II) and (III), the optional linking groups are represented by Q1, Q2 and Q3, wherein the linking groups are present when q, r and s are equal to 1 (with R, X, Y, Fn, m n and p as defined previously).

Suitable linking groups are well known in the art. See, for example, International Patent Publication No. WO 97/22371. Linking groups are useful to avoid steric hindrance problems that are sometimes associated with the formation of direct linkages between molecules. Linking groups may additionally be used to link several multifunctionally activated compounds together to make larger molecules. In a preferred embodiment, a linking group can be used to alter the degradative properties of the compositions after administration and resultant gel formation. For example, linking groups can be incorporated into components A, B, or optional component C to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation.

Examples of linking groups that provide hydrolyzable sites, include, inter alia: ester linkages; anhydride linkages, such as obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide linkages; phosphoester linkages; α-hydroxy acid linkages, such as may be obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as may be obtained by incorporation of caprolactone, valerolactone, y- butyrolactone and p-dioxanone; and amide linkages such as in a dimeric, oligomeric, or poly(amino acid) segment. Examples of non-degradable linking groups include succinimide, propionic acid and carboxymethylate linkages. See, for example, PCT WO 99/07417. Examples of enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin.

Linking groups can also enhance or suppress the reactivity of the various nucleophilic and electrophilic groups. For example, electron- withdrawing groups within one or two carbons of a sulfhydryl group would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity. Carbon-carbon double bonds and carbonyl groups will also have such an effect. Conversely, electron-withdrawing groups adjacent to a carbonyl group (e.g., the reactive carbonyl of glutaryl-N- hydroxysuccinimidyl) would increase the reactivity of the carbonyl carbon with respect to an incoming nucleophile. By contrast, sterically bulky groups in the vicinity of a functional group can be used to diminish reactivity and thus coupling rate as a result of steric hindrance.

By way of example, particular linking groups and corresponding component structure are indicated in the following Table:

TABLE

Figure imgf000164_0001

Figure imgf000165_0001

In the above Table, n is generally in the range of 1 to about 10, R7 is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and most preferably lower alkyl, and R8 is hydrocarbylene, heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom- containing hydrocarbylene) typically alkylene or arylene (again, optionally substituted and/or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (e.g., -(CO)-NH-CH2).

Other general principles that should be considered with respect to linking groups are as follows: If higher molecular weight components are to be used, they preferably have biodegradable linkages as described above, so that fragments larger than 20,000 mol. wt. are not generated during resorption in the body. In addition, to promote water miscibility and/or solubility, it may be desired to add sufficient electric charge or hydrophilicity. Hydrophilic groups can be easily introduced using known chemical synthesis, so long as they do not give rise to unwanted swelling or an undesirable decrease in compressive strength. In particular, polyalkoxy segments may weaken gel strength. The Component Core:

The "core" of each crosslinkable component is comprised of the molecular structure to which the nucleophilic or electrophilic groups are bound. Using the formulae (I) R1-[Q1]q-X)m, for component A, (II) R2(-[Q2]r Y)n for component B, and (III)

R3(-[Q3]S-Fn)p for optional component C, the "core" groups are R1, R2 and R3. Each molecular core of the reactive components of the crosslinkable composition is generally selected from synthetic and naturally occurring hydrophilic polymers, hydrophobic polymers, and C2-C14 hydrocarbyl groups zero to 2 heteroatoms selected from N, O and S, with the proviso that at least one of the crosslinkable components A, B, and optionally C, comprises a molecular core of a synthetic hydrophilic polymer. In a preferred embodiment, at least one of A and B comprises a molecular core of a synthetic hydrophilic polymer.

Hydrophilic Crosslinkable Components - In one aspect, the crosslinkable component(s) is (are) hydrophilic polymers. The term "hydrophilic polymer" as used herein refers to a synthetic polymer having an average molecular weight and composition effective to render the polymer "hydrophilic" as defined above. As discussed above, synthetic crosslinkable hydrophilic polymers useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol and poly(ethylene oxide)-poly(propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; acrylic acid polymers and analogs and copolymers thereof, such as polyacrylic acid perse, polymethacrylic acid, poly(hydroxyethyl-methacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide methacrylate), poly(methylalkylsulfoxide acrylate) and copolymers of any of the foregoing, and/or with additional acrylate species such as aminoethyl acrylate and mono-2-(acryloxy)-ethyl succinate; polymaleic acid; poly(acrylamides) such as polyacrylamide perse, poly(methacrylamide), poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide); poly(olefinic alcohol)s such as polyvinyl alcohol); poly(N-vinyl lactams) such as polyvinyl pyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof; polyoxazolines, including poly(methyloxazoline) and poly(ethyloxazoline); and polyvinylamines. It must be emphasized that the aforementioned list of polymers is not exhaustive, and a variety of other synthetic hydrophilic polymers may be used, as will be appreciated by those skilled in the art.

The synthetic crosslinkable hydrophilic polymer may be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer. In addition, the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer. The polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer. Biodegradable segments are those that degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ. Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc. Larger biodegradable "blocks" will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer. Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like. Other suitable synthetic crosslinkable hydrophilic polymers include chemically synthesized polypeptides, particularly polynucleophilic polypeptides that have been synthesized to incorporate amino acids containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine). Poly(lysine), a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000. Poly(lysine)s for use in the present invention preferably have a molecular weight within the range of about 1 ,000 to about 300,000, more preferably within the range of about 5,000 to about 100,000, and most preferably, within the range of about 8,000 to about 15,000. Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).

The synthetic crosslinkable hydrophilic polymer may be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer. In addition, the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer. The polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer. Biodegradable segments are those that degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ. Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc. Larger biodegradable "blocks" will generally be composed of oligomeric or polymeric segments incorporated within the hydrophilic polymer. Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like.

Although a variety of different synthetic crosslinkable hydrophilic polymers can be used in the present compositions, as indicated above, preferred synthetic crosslinkable hydrophilic polymers are polyethylene glycol (PEG) and polyglycerol (PG), particularly highly branched polyglycerol. Various forms of PEG are extensively used in the modification of biologically active molecules because PEG lacks toxicity, antigenicity, and immunogenicity (i.e., is biocompatible), can be formulated so as to have a wide range of solubilities, and do not typically interfere with the enzymatic activities and/or conformations of peptides. A particularly preferred synthetic crosslinkable hydrophilic polymer for certain applications is a polyethylene glycol (PEG) having a molecular weight within the range of about 100 to about 100,000 mol. wt., although for highly branched PEG, far higher molecular weight polymers can be employed — up to 1 ,000,000 or more - providing that biodegradable sites are incorporated ensuring that all degradation products will have a molecular weight of less than about 30,000. For most PEGs, however, the preferred molecular weight is about 1,000 to about 20,000 mol. wt., more preferably within the range of about 7,500 to about 20,000 mol. wt. Most preferably, the polyethylene glycol has a molecular weight of approximately 10,000 mol. wt.

Naturally occurring crosslinkable hydrophilic polymers include, but are not limited to: proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, and fibrin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives. Collagen and glycosaminoglycans are examples of naturally occurring hydrophilic polymers for use herein, with methylated collagen being a preferred hydrophilic polymer. Any of the hydrophilic polymers herein must contain, or be activated to contain, functional groups, i.e., nucleophilic or electrophilic groups, which enable crosslinking. Activation of PEG is discussed below; it is to be understood, however, that the following discussion is for purposes of illustration and analogous techniques may be employed with other polymers.

With respect to PEG, first of all, various functionalized polyethylene glycols have been used effectively in fields such as protein modification (see Abuchowski et al., Enzymes as Drugs, John Wiley & Sons: New York, N.Y. (1981) pp. 367-383; and Dreborg et al., Crit. Rev. Therap. Drug Carrier Syst. (1990) 6:315), peptide chemistry (see Mutter et al., The Peptides, Academic: New York, N.Y. 2:285-332; and Zalipsky et al., Int. J. Peptide Protein Res. (1987) 30:740), and the synthesis of polymeric drugs (see Zalipsky et al., Eur. Polym. J. (1983) 19:1177; and Ouchi et al., J. Macromol. Sci. Chem. (1987) A24:1011).

Activated forms of PEG, including multifunctionally activated PEG, are commercially available, and are also easily prepared using known methods. For example, see Chapter 22 of Poly(ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992); and Shearwater Polymers, Inc. Catalog, Polyethylene Glycol Derivatives, Huntsville, Alabama (1997-1998).

Structures for some specific, tetrafunctionally activated forms of PEG are shown in FIGS. 1 to 10 of U.S. Patent 5,874,500, as are generalized reaction products obtained by reacting the activated PEGs with multi-amino PEGs, i.e., a PEG with two or more primary amino groups. The activated PEGs illustrated have a pentaerythritol (2,2-bis(hydroxymethyl)- 1 ,3-propanediol) core. Such activated PEGs, as will be appreciated by those in the art, are readily prepared by conversion of the exposed hydroxyl groups in the PEGylated polyol (i.e., the terminal hydroxyl groups on the PEG chains) to carboxylic acid groups (typically by reaction with an anhydride in the presence of a nitrogenous base), followed by esterification with N-hydroxysuccinimide, N-hydroxysulfosuccinimide, or the like, to give the polyfunctionally activated PEG.

Hydrophobic Polymers:

The crosslinkable compositions of the invention can also include hydrophobic polymers, although for most uses hydrophilic polymers are preferred. Polylactic acid and polyglycolic acid are examples of two hydrophobic polymers that can be used. With other hydrophobic polymers, only short-chain oligomers should be used, containing at most about 14 carbon atoms, to avoid solubility-related problems during reaction.

Low Molecular Weight Components:

As indicated above, the molecular core of one or more of the crosslinkable components can also be a low molecular weight compound, Ae., a C2-C14 hydrocarbyl group containing zero to 2 heteroatoms selected from N, O, S and combinations thereof. Such a molecular core can be substituted with nucleophilic groups or with electrophilic groups.

When the low molecular weight molecular core is substituted with primary amino groups, the component may be, for example, ethylenediamine (H2N-CH2CH2-NH2), tetramethylenediamine (H2N-(CH4)- NH2), pentamethylenediamine (cadaverine) (H2N-(CH5)-NH2), hexamethylenediamine (H2N-(CH6)-NH2), bis(2-aminoethyl)amine (HN- [CH2CH2-NH2I2), or tris(2-aminoethyl)amine (N-[CH2CH2-NH2J3).

Low molecular weight diols and polyols include trimethylolpropane, di(trimethylol propane), pentaerythritol, and diglycerol, all of which require activation with a base in order to facilitate their reaction as nucleophiles. Such diols and polyols may also be functionalized to provide di- and poly-carboxylic acids, functional groups that are, as noted earlier herein, also useful as nucleophiles under certain conditions. Polyacids for use in the present compositions include, without limitation, trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid), all of which are commercially available and/or readily synthesized using known techniques.

Low molecular weight di- and poly-electrophiles include, for example, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS3), dithiobis(succinimidylpropionate) (DSP), bis(2- succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'- dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives. The aforementioned compounds are commercially available from Pierce (Rockford, III.). Such di- and poly-electrophiles can also be synthesized from di- and polyacids, for example by reaction with an appropriate molar amount of N-hydroxysuccinimide in the presence of DCC. Polyols such as trimethylolpropane and di(trimethylol propane) can be converted to carboxylic acid form using various known techniques, then further derivatized by reaction with NHS in the presence of DCC to produce trifunctionaϊly and tetrafunctionally activated polymers.

Delivery Systems:

Suitable delivery systems for the homogeneous dry powder composition (containing at least two crosslinkable polymers) and the two buffer solutions may involve a multi-compartment spray device, where one or more compartments contains the powder and one or more compartments contain the buffer solutions needed to provide for the aqueous environment, so that the composition is exposed to the aqueous environment as it leaves the compartment. Many devices that are adapted for delivery of multi- component tissue sealants/hemostatic agents are well known in the art and can also be used in the practice of the present invention. Alternatively, the composition can be delivered using any type of controllable extrusion system, or it can be delivered manually in the form of a dry powder, and exposed to the aqueous environment at the site of administration. The homogeneous dry powder composition and the two buffer solutions may be conveniently formed under aseptic conditions by placing each of the three ingredients (dry powder, acidic buffer solution and basic buffer solution) into separate syringe barrels. For example, the composition, first buffer solution and second buffer solution can be housed separately in a multiple-compartment syringe system having a multiple barrels, a mixing head, and an exit orifice. The first buffer solution can be added to the barrel housing the composition to dissolve the composition and form a homogeneous solution, which is then extruded into the mixing head. The second buffer solution can be simultaneously extruded into the mixing head. Finally, the resulting composition can then be extruded through the orifice onto a surface.

For example, the syringe barrels holding the dry powder and the basic buffer may be part of a dual-syringe system, e.g., a double barrel syringe as described in U.S. Patent 4,359,049 to Redl et al. In this embodiment, the acid buffer can be added to the syringe barrel that also holds the dry powder, so as to produce the homogeneous solution. In other words, the acid buffer may be added (e.g., injected) into the syringe barrel holding the dry powder to thereby produce a homogeneous solution of the first and second components. This homogeneous solution can then be extruded into a mixing head, while the basic buffer is simultaneously extruded into the mixing head. Within the mixing head, the homogeneous solution and the basic buffer are mixed together to thereby form a reactive mixture. Thereafter, the reactive mixture is extruded through an orifice and onto a surface (e.g., tissue), where a film is formed, which can function as a sealant or a barrier, or the like. The reactive mixture begins forming a three- dimensional matrix immediately upon being formed by the mixing of the homogeneous solution and the basic buffer in the mixing head. Accordingly, the reactive mixture is preferably extruded from the mixing head onto the tissue very quickly after it is formed so that the three-dimensional matrix forms on, and is able to adhere to, the tissue. Other systems for combining two reactive liquids are well known in the art, and include the systems described in U.S. Patent Nos. 6,454,786 to Holm et al.; 6,461 ,325 to Delmotte et al.; 5,585,007 to Antanavich et al.; 5,116,315 to Capozzi et al.; and 4,631,055 to Redl et al.

Storage and Handling:

Because crosslinkable components containing electrophilic groups react with water, the electrophilic component or components are generally stored and used in sterile, dry form to prevent hydrolysis. Processes for preparing synthetic hydrophilic polymers containing multiple electrophilic groups in sterile, dry form are set forth in commonly assigned U.S. Patent No. 5,643,464 to Rhee et al. For example, the dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or, preferably, e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates.

Components containing multiple nucleophilic groups are generally not water-reactive and can therefore be stored either dry or in aqueous solution. If stored as a dry, particulate, solid, the various components of the crosslinkable composition may be blended and stored in a single container. Admixture of all components with water, saline, or other aqueous media should not occur until immediately prior to use.

In an alternative embodiment, the crosslinking components can be mixed together in a single aqueous medium in which they are both unreactive, i.e., such as in a low pH buffer. Thereafter, they can be sprayed onto the targeted tissue site along with a high pH buffer, after which they will rapidly react and form a gel.

Suitable liquid media for storage of crosslinkable compositions include aqueous buffer solutions such as monobasic sodium phosphate/dibasic sodium phosphate, sodium carbonate/sodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM. In general, a sulfhydryl-reactive component such as PEG substituted with maleimido groups or succinimidyl esters is prepared in water or a dilute buffer, with a pH of between around 5 to 6. Buffers with pKs between about 8 and 10.5 for preparing a polysulfhydryl component such as sulfhydryl-PEG are useful to achieve fast gelation time of compositions containing mixtures of sulfhydryl-PEG and SG-PEG. These include carbonate, borate and AMPSO (3-[(1 ,1-dimethyl-2-hydroxyethyl)amino]2-hydroxy-propane-sulfonic acid). In contrast, using a combination of maleimidyl PEG and sulfhydryl- PEG, a pH of around 5 to 9 is preferred for the liquid medium used to prepare the sulfhydryl PEG.

Collagen + Fibrinogen and/or Thrombin (e.g., Costasis) In yet another aspect, the polymer composition may include collagen in combination with fibrinogen and/or thrombin. (See, e.g., U.S. Patent Nos. 5,290,552; 6,096,309; and 5,997,811). For example, an aqueous composition may include a fibrinogen and FXIII, particularly plasma, collagen in an amount sufficient to thicken the composition, thrombin in an amount sufficient to catalyze polymerization of fibrinogen present in the composition, and Ca2+ and, optionally, an antifibrinolytic agent in amount sufficient to retard degradation of the resulting adhesive clot. The composition may be formulated as a two-part composition that may be mixed together just prior to use, in which fibrinogen/FXIII and collagen constitute the first component, and thrombin together with an antifibrinolytic agent, and Ca2+ constitute the second component.

Plasma, which provides a source of fibrinogen, may be obtained from the patient for which the composition is to be delivered. The plasma can be used "as is" after standard preparation which includes centrifuging out cellular components of blood. Alternatively, the plasma can be further processed to concentrate the fibrinogen to prepare a plasma cryoprecipitate. The plasma cryoprecipitate can be prepared by freezing the plasma for at least about an hour at about -20 0C, and then storing the frozen plasma overnight at about 4 0C. to slowly thaw. The thawed plasma is centrifuged and the plasma cryoprecipitate is harvested by removing approximately four-fifths of the plasma to provide a cryoprecipitate comprising the remaining one-fifth of the plasma. Other fibrinogen/FXIII preparations may be used, such as cryoprecipitate, patient autologous fibrin sealant, fibrinogen analogs or other single donor or commercial fibrin sealant materials. Approximately 0.5 ml to about 1.0 ml of either the plasma or the plasma-cryoprecipitate provides about 1 to 2 ml of adhesive composition which is sufficient for use in middle ear surgery. Other plasma proteins (e.g., albumin, plasminogen, von Willebrands factor, Factor VIII, etc.) may or may not be present in the fibrinogen/FXII separation due to wide variations in the formulations and methods to derive them.

Collagen, preferably hypoallergenic collagen, is present in the composition in an amount sufficient to thicken the composition and augment the cohesive properties of the preparation. The collagen may be atelbpeptide collagen or telopeptide collagen, e.g., native collagen. In addition to thickening the composition, the collagen augments the fibrin by acting as a macromolecular lattice work or scaffold to which the fibrin network adsorbs. This gives more strength and durability to the resulting glue clot with a relatively low concentration of fibrinogen in comparison to the various concentrated autogenous fibrinogen glue formulations (i.e., AFGs).

The form of collagen which is employed may be described as at least "near native" in its structural characteristics. It may be further characterized as resulting in insoluble fibers at a pH above 5; unless crosslinked or as part of a complex composition, e.g., bone, it will generally consist of a minor amount by weight of fibers with diameters greater than 50 nm, usually from about 1 to 25 volume % and there will be substantially little, if any, change in the helical structure of the fibrils. In addition, the collagen composition must be able to enhance gelation in the surgical adhesion composition. A number of commercially available collagen preparations may be used. ZYDERM Collagen Implant (ZCI) has a fibrillar diameter distribution consisting of 5 to 10 nm diameter fibers at 90% volume content and the remaining 10% with greater than about 50 nm diameter fibers. ZCI is available as a fibrillar slurry and solution in phosphate buffered isotonic saline, pH 7.2, and is injectable with fine gauge needles. As distinct from ZCI1 cross-linked collagen available as ZYPLAST may be employed. ZYPL-AST is essentially an exogenously crosslinked (glutaraldehyde) version of ZCI. The material has a somewhat higher content of greater than about 50 nm diameter fibrils and remains insoluble over a wide pH range. Crosslinking has the effect of mimicking in vivo endogenous crosslinking found in many tissues.

Thrombin acts as a catalyst for fibrinogen to provide fibrin, an insoluble polymer and is present in the composition in an amount sufficient to catalyze polymerization of fibrinogen present in the patient plasma. Thrombin also activates FXIII, a plasma protein that catalyzes covalent crosslinks in fibrin, rendering the resultant clot insoluble. Usually the thrombin is present in the adhesive composition in concentration of from about 0.01 to about 1000 or greater NIH units (NlHu) of activity, usually about i to about 500 NIHu, most usually about 200 to about 500 NIHu. The thrombin can be from a variety of host animal sources, conveniently bovine. Thrombin is commercially available from a variety of sources including Parke-Davis, usually lyophilized with buffer salts and stabilizers in vials which provide thrombin activity ranging from about 1000 NIHu to 10,000 NIHu. The thrombin is usually prepared by reconstituting the powder by the addition of either sterile distilled water or isotonic saline. Alternately, thrombin analogs or reptile-sourced coagulants may be used.

The composition may additionally comprise an effective amount of an antifibrinolytic agent to enhance the integrity of the glue clot as the healing processes occur. A number of antifibrinolytic agents are well known and include aprotinin, C1 -esterase inhibitor and ε-amino-n-caproic acid (EACA). ε-amino-n-caproic acid, the only antifibrinolytic agent approved by the FDA, is effective at a concentration of from about 5 mg/ml to about 40 mg/ml of the final adhesive composition, more usually from about 20 to about 30 mg/ml. EACA is commercially available as a solution having a concentration of about 250 mg/ml. Conveniently, the commercial solution is diluted with distilled water to provide a solution of the desired concentration. That solution is desirably used to reconstitute lyophilized thrombin to the desired thrombin concentration.

Other examples of in situ forming materials based on the crosslinking of proteins are described, e.g., in U.S. Patent Nos. RE38158; 4,839,345; 5,514,379, 5,583,114; 6,458,147; 6,371 ,975; 5,290,552; 6,096,309; U.S. Patent Application Publication Nos. 2002/0161399; 2001/0018598 and PCT Publication Nos. WO 03/090683; WO 01/45761 ; WO 99/66964 and WO 96/03159).

Self-Reactive Compounds

In one aspect, the therapeutic agent is released from a crosslinked matrix formed, at least in part, from a self-reactive compound. As used herein, a self-reactive compound comprises a core substituted with a minimum of three reactive groups. The reactive groups may be directed attached to the core of the compound, or the reactive groups may be indirectly attached to the compound's core, e.g., the reactive groups are joined to the core through one or more linking groups.

Each of the three reactive groups that are necessarily present in a self-reactive compound can undergo a bond-forming reaction with at least one of the remaining two reactive groups. For clarity it is mentioned that when these compounds react to form a crosslinked matrix, it will most often happen that reactive groups on one compound will reactive with reactive groups on another compound. That is, the term "self-reactive" is not intended to mean that each self-reactive compound necessarily reacts with itself, but rather that when a plurality of identical self-reactive compounds are in combination and undergo a crosslinking reaction, then these compounds will react with one another to form the matrix. The compounds are "self-reactive" in the sense that they can react with other compounds having the identical chemical structure as themselves.

The self-reactive compound comprises at least four components: a core and three reactive groups. In one embodiment, the self-reactive compound can be characterized by the formula (I), where R is the core, the reactive groups are represented by X1, X2 and X3, and a linker (L) is optionally present between the core and a functional group.

Figure imgf000179_0001

The core R is a polyvalent moiety having attachment to at least three groups (i.e., it is at least trivalent) and may be, or may contain, for example, a hydrophilic polymer, a hydrophobic polymer, an amphiphilic polymer, a C2-I4 hydrocarbyl, or a C2-14 hydrocarbyl which is heteroatom- containing. The linking groups L1, L2, and L3 may be the same or different. The designators p, q and r are either 0 (when no linker is present) or 1 (when a linker is present). The reactive groups X1, X2 and X3 may be the same or different. Each of these reactive groups reacts with at least one other reactive group to form a three-dimensional matrix. Therefore X1 can react with X2 and/or X3, X2 can react with X1 and/or X3, X3 can react with X1 and/or X2 and so forth. A trivalent core will be directly or indirectly bonded to three functional groups, a tetravalent core will be directly or indirectly bonded to four functional groups, etc.

Each side chain typically has one reactive group. However, the invention also encompasses self-reactive compounds where the side chains contain more than one reactive group. Thus, in another embodiment of the invention, the self-reactive compound has the formula (II): [ X' - (L4)a - Y' - (L5)b ] c R1 where: a and b are integers from 0-1; c is an integer from 3-12; R1 is selected from hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C2-i4 hydrocarbyls, and heteroatom-containing C2-M hydrocarbyls; X' and Y' are reactive groups and can be the same or different; and L4 and L5 are linking groups. Each reactive group inter-reacts with the other reactive group to form a three-dimensional matrix. The compound is essentially non-reactive in an initial environment but is rendered reactive upon exposure to a modification in the initial environment that provides a modified environment such that a plurality of the self-reactive compounds inter-react in the modified environment to form a three-dimensional matrix. In one preferred embodiment, R is a hydrophilic polymer. In another preferred embodiment, X' is a nucleophilic group and Y' is an electrophilic group.

Jne L following self-reactive compound is one example of a compound of formula (II):

Figure imgf000180_0001
where R4 has the formula:

Figure imgf000180_0002

Thus, in formula (II), a and b are 1; c is 4; the core R' is the hydrophilic polymer, tetrafunctionally activated polyethylene glycol, (C(CH2- O-)4; X1 is the electrophilic reactive group, succinimidyl; Y' is the nucleophilic reactive group -CH-NH2; L4 is -C(O)-O-; and L5 is -(CH2- C H2-O-C H2)x-C H2-

0-C(O)-(CHz)2-.

The self-reactive compounds of the invention are readily synthesized by techniques that are well known in the art. An exemplary synthesis is set forth below:

Figure imgf000181_0001

Mitsunobo or DCC

Figure imgf000181_0002
H2, Pd/C

Figure imgf000182_0001

The reactive groups are selected so that the compound is essentially non-reactive in an initial environment. Upon exposure to a specific modification in the initial environment, providing a modified environment, the compound is rendered reactive and a plurality of self- reactive compounds are then able to inter-react in the modified environment to form a three-dimensional matrix. Examples of modification in the initial environment are detailed below, but include the addition of an aqueous medium, a change in pH, exposure to ultraviolet radiation, a change in temperature, or contact with a redox initiator. The core and reactive groups can also be selected so as to provide a compound that has one of more of the following features: are biocompatible, are non-immunogenic, and do not leave any toxic, inflammatory or immunogenic reaction products at the site of administration. Similarly, the core and reactive groups can also be selected so as to provide a resulting matrix that has one or more of these features.

In one embodiment of the invention, substantially immediately or immediately upon exposure to the modified environment, the self-reactive compounds inter-react form a three-dimensional matrix. The term "substantially immediately" is intended to mean within less than five minutes, preferably within less than two minutes, and the term "immediately" is intended to mean within less than one minute, preferably within less than 30 seconds.

In one embodiment, the self-reactive compound and resulting matrix are not subject to enzymatic cleavage by matrix metalloproteinases such as collagenase, and are therefore not readily degradable in vivo. Further, the self-reactive compound may be readily tailored, in terms of the selection and quantity of each component, to enhance certain properties, e.g., compression strength, swellability, tack, hydrophilicity, optical clarity, and the like.

In one preferred embodiment, R is a hydrophilic polymer. In another preferred embodiment, X is a nucleophilic group, Y is an electrophilic group and Z is either an electrophilic or a nucleophilic group. Additional embodiments are detailed below.

A higher degree of inter-reaction, e.g., crosslinking, may be useful when a less swellable matrix is desired or increased compressive strength is desired. In those embodiments, it may be desirable to have n be an integer from 2-12. In addition, when a plurality of self-reactive compounds are utilized, the compounds may be the same or different. a. Reactive Groups

Prior to use, the self-reactive compound is stored in an initial environment that insures that the compound remain essentially non-reactive until use. Upon modification of this environment, the compound is rendered reactive and a plurality of compounds will then inter-react to form the desired matrix. The initial environment, as well as the modified environment, is thus determined by the nature of the reactive groups involved.

The number of reactive groups can be the same or different. However, in one embodiment of the invention, the number of reactive groups are approximately equal. As used in this context, the term "approximately" refers to a 2:1 to 1 :2 ratio of moles of one reactive group to moles of a different reactive groups. A 1 :1 :1 molar ratio of reactive groups is generally preferred.

In general, the concentration of the self-reactive compounds in the modified environment, when liquid in nature, will be in the range of about 1 to 50 wt%, generally about 2 to 40 wt%. The preferred concentration of the compound in the liquid will depend on a number of factors, including the type of compound (Ae., type of molecular core and reactive groups), its molecular weight, and the end use of the resulting three-dimensional matrix. For example, use of higher concentrations of the compounds, or using highly functionalized compounds, will result in the formation of a more tightly crosslinked network, producing a stiffer, more robust gel. As such, compositions intended for use in tissue augmentation will generally employ concentrations of self-reactive compounds that fall toward the higher end of the preferred concentration range. Compositions intended for use as bioadhesives or in adhesion prevention do not need to be as firm and may therefore contain lower concentrations of the self-reactive compounds. i) Electrophilic and Nucleophilic Reactive Groups In one embodiment of the invention, the reactive groups are electrophilic and nucleophilic groups, which undergo a nucleophilic substitution reaction, a nucleophilic addition reaction, or both. The term "electrophilic" refers to a reactive group that is susceptible to nucleophilic attack, i.e., susceptible to reaction with an incoming nucieophilic group. Electrophilic groups herein are positively charged or electron-deficient, typically electron-deficient. The term "nucleophilic" refers to a reactive group that is electron rich, has an unshared pair of electrons acting as a reactive site, and reacts with a positively charged or electron-deficient site. For such reactive groups, the modification in the initial environment comprises the addition of an aqueous medium and/or a change in pH.

In one embodiment of the invention, X1 (also referred to herein as X) can be a nucleophilic group and X2 (also referred to herein as Y) can be an electrophilic group or vice versa, and X3 (also referred to herein as Z) can be either an electrophilic or a nucleophilic group.

X may be virtually any nucleophilic group, so long as reaction can occur with the electrophilic group Y and also with Z, when Z is electrophilic (ZEL). Analogously, Y may be virtually any electrophilic group, so long as reaction can take place with X and also with Z when Z is nucleophilic (ZNU)- The only limitation is a practical one, in that reaction between X and Y, and X and ZEL, or Y and ZNu should be fairly rapid and take place automatically upon admixture with an aqueous medium, without need for heat or potentially toxic or non-biodegradable reaction catalysts or other chemical reagents. It is also preferred although not essential that reaction occur without need for ultraviolet or other radiation. In one embodiment, the reactions between X and Y, and between either X and ZEL or Y and ZNU, are complete in under 60 minutes, preferably under 30 minutes. Most preferably, the reaction occurs in about 5 to 15 minutes or less. Examples of nucleophilic groups suitable as X or FΓINU include, but are not limited to: -NH2, -NHR1, -N(R1)2, -SH, -OH, -COOH, -C6H4-OH, -H, -PH2,

-PHR1, -P(R1)2, -NH-NH2, -CO-NH-NH2, -C5H4N, etc. wherein R1 is a hydrocarbyl group and each R1 may be the same or different. R1 is typically alkyl or monocyclic aryl, preferably alkyl, and most preferably lower alkyl. Organometallic moieties are also useful nucleophilic groups for the purposes of the invention, particularly those that act as carbanion donors. Examples of organometallic moieties include: Grignard functionalities - R2MgHaI wherein R2 is a carbon atom (substituted or unsubstituted), and Hal is halo, typically bromo, iodo or chloro, preferably bromo; and lithium- containing functionalities, typically alkyllithium groups; sodium-containing functionalities.

It will be appreciated by those of ordinary skill in the art that certain nucleophilic groups must be activated with a base so as to be capable of reaction with an electrophilic group. For example, when there are nucleophilic sulfhydryl and hydroxyl groups in the self-reactive compound, the compound must be admixed with an aqueous base in order to remove a proton and provide an -S" or -O" species to enable reaction with the electrophilic group. Unless it is desirable for the base to participate in the reaction, a non-nucleophilic base is preferred. In some embodiments, the base may be present as a component of a buffer solution. Suitable bases and corresponding crosslinking reactions are described herein.

The selection of electrophilic groups provided on the self- reactive compound, must be made so that reaction is possible with the specific nucleophilic groups. Thus, when the X reactive groups are amino groups, the Y and any ZEL groups are selected so as to react with amino groups. Analogously, when the X reactive groups are sulfhydryl moieties, the corresponding electrophilic groups are sulfhydryl-reactive groups, and the like. In general, examples of electrophilic groups suitable as Y or ZEL include, but are not limited to, -CO-CI, -(CO)-O-(CO)-R (where R is an alkyl group), -CH=CH-CH=O and -CH=CH-C(CH3)=O, halo, -N=C=O, -N=C=S, -SO2CH=CH2, -0(CO)-C=CH2, -O(CO)-C(CH3)=CH2, -S-S-(C5H4N), -0(CO)-C(CH2CHs)=CH2, -CH=CH-C=NH, -COOH, -(CO)O-N(COCH2)2, -CHO, -(CO)O-N(COCH2)2-S(O)2OH, and -N(COCH)2.

When X is amino (generally although not necessarily primary amino), the electrophilic groups present on Y and ZEL are amine-reactive groups. Exemplary amine-reactive groups include, by way of example and not limitation, the following groups, or radicals thereof: (1) carboxylic acid esters, including cyclic esters and "activated" esters; (2) acid chloride groups (-CO-CI); (3) anhydrides (-(CO)-O-(CO)-R, where R is an alkyl group); (4) ketones and aldehydes, including α,β-unsaturated aldehydes and ketones such as -CH=CH-CH=O and -CH=CH-C(CH3)=O; (5) halo groups; (6) isocyanate group (-N=C=O); (7) thioisocyanato group (-N=C=S); (8) epoxides; (9) activated hydroxyl groups (e.g., activated with conventional activating agents such as carbonyldiimidazole or sulfonyl chloride); and (10) olefins, including conjugated olefins, such as ethenesulfonyl (-SO2CH=CH2) and analogous functional groups, including acrylate (-0(CO)-C=CH2), methacrylate (-O(CO)-C(CH3)=CH2), ethyl acrylate (-O(CO)-C(CH2CH3)=CH2), and ethyleneimino (-CH=CH-C=NH).

In one embodiment the amine-reactive groups contain an electrophilically reactive carbonyl group susceptible to nucleophilic attack by a primary or secondary amine, for example the carboxylic acid esters and aldehydes noted above, as well as carboxyl groups (-COOH).

Since a carboxylic acid group per se is not susceptible to reaction with a nucleophilic amine, components containing carboxylic acid groups must be activated so as to be amine-reactive. Activation may be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU). For example, a carboxylic acid can be reacted with an alkoxy-substituted N- hydroxy-succinimide or N-hydroxysulfosuccinimide in the presence of DCC to form reactive electrophilic groups, the N-hydroxysuccinimide ester and the N-hydroxysulfosuccinimide ester, respectively. Carboxylic acids may also be activated by reaction with an acyl halide such as an acyl chloride (e.g., acetyl chloride), to provide a reactive anhydride group. In a further example, a carboxylic acid may be converted to an acid chloride group using, e.g., thionyl chloride or an acyl chloride capable of an exchange reaction. Specific reagents and procedures used to carry out such activation reactions will be known to those of ordinary skill in the art and are described in the pertinent texts and literature.

Accordingly, in one embodiment, the amine-reactive groups are selected from succinimidyl ester (-O(CO)-N(COCH2)2), sulfosuccinimidyl ester (-O(CO)-N(COCH2)2-S(O)2OH), maleimido (-N(COCH)2), epoxy, isocyanato, thioisocyanato, and ethenesulfonyl.

Analogously, when X is sulfhydryl, the electrophilic groups present on Y and ZEL are groups that react with a sulfhydryl moiety. Such reactive groups include those that form thioester linkages upon reaction with a sulfhydryl group, such as those described in WO 00/62827 to Wallace et al. As explained in detail therein, sulfhydryl reactive groups include, but are not limited to: mixed anhydrides; ester derivatives of phosphorus; ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluorophenol; esters of substituted hydroxylamines, including N-hydroxyphthalimide esters, N- hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N- hydroxyglutarimide esters; esters of 1-hydroxybenzotriazole; 3-hydroxy-3,4- dihydro-benzotriazin-4-one; 3-hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole derivatives; acid chlorides; ketenes; and isocyanates. With these sulfhydryl reactive groups, auxiliary reagents can also be used to facilitate bond formation, e.g., 1-ethyl-3-[3- dimethylaminopropyljcarbodiimide can be used to facilitate coupling of sulfhydryl groups to carboxyl-containing groups.

In addition to the sulfhydryl reactive groups that form thioester linkages, various other sulfhydryl reactive functionalities can be utilized that form other types of linkages. For example, compounds that contain methyl imidate derivatives form imido-thioester linkages with sulfhydryl groups. Alternatively, sulfhydryl reactive groups can be employed that form disulfide bonds with sulfhydryl groups; such groups generally have the structure -S- S-Ar where Ar is a substituted or unsubstituted nitrogen-containing heteroaromatic moiety or a non-heterocyclic aromatic group substituted with an electron-withdrawing moiety, such that Ar may be, for example, 4- pyridinyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2- nitro-4-benzoic acid, 2-nitro-4-pyridinyl, etc. In such instances, auxiliary reagents, Ae., mild oxidizing agents such as hydrogen peroxide, can be used to facilitate disulfide bond formation.

Yet another class of sulfhydryl reactive groups forms thioether bonds with sulfhydryl groups. Such groups include, inter alia, maleimido, substituted maleimido, haloalkyl, epoxy, imino, and aziridino, as well as olefins (including conjugated olefins) such as ethenesulfonyl, etheneimino, acrylate, methacrylate, and α,β-unsaturated aldehydes and ketones.

When X is -OH, the electrophilic functional groups on the remaining component(s) must react with hydroxyl groups. The hydroxyl group may be activated as described above with respect to carboxylic acid groups, or it may react directly in the presence of base with a sufficiently reactive electrophilic group such as an epoxide group, an aziridine group, an acyl halide, an anhydride, and so forth.

When X is an organometallic nucleophilic group such as a Grignard functionality or an alkyllithium group, suitable electrophilic functional groups for reaction therewith are those containing carbonyl groups, including, by way of example, ketones and aldehydes.

It will also be appreciated that certain functional groups can react as nucleophilic or as electrophilic groups, depending on the selected reaction partner and/or the reaction conditions. For example, a carboxylic acid group can act as a nucleophilic group in the presence of a fairly strong base, but generally acts as an electrophilic group allowing nucleophilic attack at the carbonyl carbon and concomitant replacement of the hydroxyl group with the incoming nucleophilic group.

These, as well as other embodiments are illustrated below, where the covalent linkages in the matrix that result upon covalent binding of specific nucleophilic reactive groups to specific electrophilic reactive groups on the self-reactive compound include, solely by way of example, the following Table:

Table

Figure imgf000190_0001

Figure imgf000191_0001

For self-reactive compounds containing electrophilic and nucleophilic reactive groups, the initial environment typically can be dry and sterile. Since electrophilic groups react with water, storage in sterile, dry form will prevent hydrolysis. The dry synthetic polymer may be compression molded into a thin sheet or membrane, which can then be sterilized using gamma or e-beam irradiation. The resulting dry membrane or sheet can be cut to the desired size or chopped into smaller size particulates. The modification of a dry initial environment will typically comprise the addition of an aqueous medium.

In one embodiment, the initial environment can be an aqueous medium such as in a low pH buffer, i.e., having a pH less than about 6.0, in which both electrophilic and nucleophilic groups are non-reactive. Suitable liquid media for storage of such compounds include aqueous buffer solutions such as monobasic sodium phosphate/dibasic sodium phosphate, sodium carbonate/sodium bicarbonate, glutamate or acetate, at a concentration of 0.5 to 300 mM. Modification of an initial low pH aqueous environment will typically comprise increasing the pH to at least pH 7.0, more preferably increasing the pH to at least pH 9.5. In another embodiment the modification of a dry initial environment comprises dissolving the self-reactive compound in a first buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous solution, and (ii) adding a second buffer solution having a pH within the range of about 6.0 to 11.0 to the homogeneous solution. The buffer solutions are aqueous and can be any pharmaceutically acceptable basic or acid composition. The term "buffer" is used in a general sense to refer to an acidic or basic aqueous solution, where the solution may or may not be functioning to provide a buffering effect (i.e., resistance to change in pH upon addition of acid or base) in the compositions of the present invention. For example, the self-reactive compound can be in the form of a homogeneous dry powder. This powder is then combined with a buffer solution having a pH within the range of about 1.0 to 5.5 to form a homogeneous acidic aqueous solution, and this solution is then combined with a buffer solution having a pH within the range of about 6.0 to 11.0 to form a reactive solution. For example, 0.375 grams of the dry powder can be combined with 0.75 grams of the acid buffer to provide, after mixing, a homogeneous solution, where this solution is combined with 1.1 grams of the basic buffer to provide a reactive mixture that substantially immediately forms a three-dimensional matrix.

Acidic buffer solutions having a pH within the range of about 1.0 to 5.5, include by way of illustration and not limitation, solutions of: citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, AMPSO (3-[(1,1- dimethyl-2-hydroxyethyl)amino]2-hydroxy-propane-sulfonic acid), acetic acid, lactic acid, and combinations thereof. In a preferred embodiment, the acidic buffer solution, is a solution of citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, and combinations thereof. Regardless of the precise acidifying agent, the acidic buffer preferably has a pH such that it retards the reactivity of the nucleophilic groups on the core. For example, a pH of 2.1 is generally sufficient to retard the nucleophilicity of thiol groups. A lower pH is typically preferred when the core contains amine groups as the nucleophilic groups. In general, the acidic buffer is an acidic solution that, when contacted with nucleophilic groups, renders those nucleophilic groups relatively non-nucleophilic.

An exemplary acidic buffer is a solution of hydrochloric acid, having a concentration of about 6.3 mM and a pH in the range of 2.1 to 2.3. This buffer may be prepared by combining concentrated hydrochloric acid with water, i.e., by diluting concentrated hydrochloric acid with water. Similarly, this buffer A may also be conveniently prepared by diluting 1.23 grams of concentrated hydrochloric acid to a volume of 2 liters, or diluting 1.84 grams of concentrated hydrochloric acid to a volume to 3 liters, or diluting 2.45 grams of concentrated hydrochloric acid to a volume of 4 liters, or diluting 3.07 grams concentrated hydrochloric acid to a volume of 5 liters, or diluting 3.68 grams of concentrated hydrochloric acid to a volume to 6 liters. For safety reasons, the concentrated acid is preferably added to water.

Basic buffer solutions having a pH within the range of about 6.0 to 11.0, include by way of illustration and not limitation, solutions of: glutamate, acetate, carbonate and carbonate salts (e.g., sodium carbonate, sodium carbonate monohydrate and sodium bicarbonate), borate, phosphate and phosphate salts (e.g., monobasic sodium phosphate monohydrate and dibasic sodium phosphate), and combinations thereof. In a preferred embodiment, the basic buffer solution is a solution of carbonate salts, phosphate salts, and combinations thereof.

In general, the basic buffer is an aqueous solution that neutralizes the effect of the acidic buffer, when it is added to the homogeneous solution of the compound and first buffer, so that the nucleophilic groups on the core regain their nucleophilic character (that has been masked by the action of the acidic buffer), thus allowing the nucleophilic groups to inter-react with the electrophilic groups on the core.

An exemplary basic buffer is an aqueous solution of carbonate and phosphate salts. This buffer may be prepared by combining a base solution with a salt solution. The salt solution may be prepared by combining 34.7 g of monobasic sodium phosphate monohydrate, 49.3 g of sodium carbonate monohydrate, and sufficient water to provide a solution volume of 2 liter. Similarly, a 6 liter solution may be prepared by combining 104.0 g of monobasic sodium phosphate monohydrate, 147.94 g of sodium carbonate monohydrate, and sufficient water to provide 6 liter of the salt solution. The basic buffer may be prepared by combining 7.2 g of sodium hydroxide with 180.0 g of water. The basic buffer is typically prepared by adding the base solution as needed to the salt solution, ultimately to provide a mixture having the desired pH, e.g., a pH of 9.65 to 9.75.

In general, the basic species present in the basic buffer should be sufficiently basic to neutralize the acidity provided by the acidic buffer, but should not be so nucleophilic itself that it will react substantially with the electrophilic groups on the core. For this reason, relatively "soft" bases such as carbonate and phosphate are preferred in this embodiment of the invention.

To illustrate the preparation of a three-dimensional matrix of the present invention, one may combine an admixture of the self-reactive compound with a first, acidic, buffer (e.g., an acid solution, e.g., a dilute hydrochloric acid solution) to form a homogeneous solution. This homogeneous solution is mixed with a second, basic, buffer (e.g., a basic solution, e.g., an aqueous solution containing phosphate and carbonate salts) whereupon the reactive groups on the core of the self-reactive compound substantially immediately inter-react with one another to form a three-dimensional matrix.

//) Redox Reactive Groups

In one embodiment of the invention, the reactive groups are vinyl groups such as styrene derivatives, which undergo a radical polymerization upon initiation with a redox initiator. The term "redox" refers to a reactive group that is susceptible to oxidation-reduction activation. The term "vinyl" refers to a reactive group that is activated by a redox initiator, and forms a radical upon reaction. X, Y and Z can be the same or different vinyl groups, for example, methacrylic groups.

For self-reactive compounds containing vinyl reactive groups, the initial environment typically will be an aqueous environment. The modification of the initial environment involves the addition of a redox initiator.

Hi) Oxidative Coupling Reactive Groups In one embodiment of the invention, the reactive groups undergo an oxidative coupling reaction. For example, X, Y and Z can be a halo group such as chloro, with an adjacent electron-withdrawing group on the halogen-bearing carbon (e.g., on the "L" linking group). Exemplary electron-withdrawing groups include nitro, aryl, and so forth.

For such reactive groups, the modification in the initial environment comprises a change in pH. For example, in the presence of a base such as KOH, the self-reactive compounds then undergo a de-hydro, chloro coupling reaction, forming a double bond between the carbon atoms, as illustrated below:

Cl

I H I

Ar-C R C-Ar I

A1 I ^OH Ar-C R C-Ar

Cl C| KOH c, T,

+ ci c"Ar

C-Ar

I Ar-C R CH-Ar

Ar-C R C-Ar Cl Cl

Cl Cl

For self-reactive compounds containing oxidative coupling reactive groups, the initial environment typically can be can be dry and sterile, or a non-basic medium. The modification of the initial environment will typically comprise the addition of a base. /V) Photoinitiated Reactive Groups In one embodiment of the invention, the reactive groups are photoinitiated groups. For such reactive groups, the modification in the initial environment comprises exposure to ultraviolet radiation.

In one embodiment of the invention, X can be an azide (-N3) group and Y can be an alkyl group such as -CH(CH3)2 or vice versa. Exposure to ultraviolet radiation will then form a bond between the groups to provide for the following linkage: -NH-C(CH3)2-CH2-. In another embodiment of the invention, X can be a benzophenone (-(C6H4)-C(O)- (CeH5)) group and Y can be an alkyl group such as -CH(CH3)2 or vice versa. Exposure to ultraviolet radiation will then form a bond between the groups to provide for the following linkage:

Figure imgf000196_0001

For self-reactive compounds containing photoinitiated reactive groups, the initial environment typically will be in an ultraviolet radiation- shielded environment. This can be for example, storage within a container that is impermeable to ultraviolet radiation.

The modification of the initial environment will typically comprise exposure to ultraviolet radiation.

v) Temperature-sensitive Reactive Groups In one embodiment of the invention, the reactive groups are temperature-sensitive groups, which undergo a thermochemical reaction. For such reactive groups, the modification in the initial environment thus comprises a change in temperature. The term "temperature-sensitive" refers to a reactive group that is chemically inert at one temperature or temperature range and reactive at a different temperature or temperature range. In one embodiment of the invention, X, Y, and Z are the same or different vinyl groups.

For self-reactive compounds containing reactive groups that are temperature-sensitive, the initial environment typically will be within the range of about 10 to 3O0C.

The modification of the initial environment will typically comprise changing the temperature to within the range of about 20 to 4O0C.

b. Linking Groups

The reactive groups may be directly attached to the core, or they may be indirectly attached through a linking group, with longer linking groups also termed "chain extenders." In the formula (I) shown above, the optional linker groups are represented by L1, L2, and L3, wherein the linking groups are present when p, q and r are equal to 1.

Suitable linking groups are well known in the art. See, for example, WO 97/22371 to'Rhee et"al. Linking groups are useful to avoid steric hindrance problems that can sometimes associated with the formation of direct linkages between molecules. Linking groups may additionally be used to link several self-reactive compounds together to make larger molecules. In one embodiment, a linking group can be used to alter the degradative properties of the compositions after administration and resultant gel formation. For example, linking groups can be used to promote hydrolysis, to discourage hydrolysis, or to provide a site for enzymatic degradation.

Examples of linking groups that provide hydrolyzable sites, include, inter alia: ester linkages; anhydride linkages, such as those obtained by incorporation of glutarate and succinate; ortho ester linkages; ortho carbonate linkages such as trimethylene carbonate; amide linkages; phosphoester linkages; α-hydroxy acid linkages, such as those obtained by incorporation of lactic acid and glycolic acid; lactone-based linkages, such as those obtained by incorporation of caprolactone, valerolactone, y- butyrolactone and p-dioxanone; and amide linkages such as in a dimeric, oligomeric, or poly(amino acid) segment. Examples of non-degradable linking groups include succinimide, propionic acid and carboxymethylate linkages. See, for example, WO 99/07417 to Coury et al. Examples of enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase; and Gly-Pro-Lys, which is degraded by plasmin.

Linking groups can also be included to enhance or suppress the reactivity of the various reactive groups. For example, electron- withdrawing groups within one or two carbons of a sulfhydryl group would be expected to diminish its effectiveness in coupling, due to a lowering of nucleophilicity. Carbon-carbon double bonds and carbonyl groups will also have such an effect. Conversely, electron-withdrawing groups adjacent to a carbonyl group (e.g., the reactive carbonyl of glutaryl-N- hydroxysuccinimidyl) would increase the reactivity of the carbonyl carbon with respect to an incoming nucleophilic group. By contrast, sterically bulky groups in the vicinity of a reactive group can be used to diminish reactivity and thus reduce the coupling rate as a result of steric hindrance.

By way of example, particular linking groups and corresponding formulas are indicated in the following Table:

Table

Figure imgf000198_0001
Figure imgf000199_0001

In the above Table, x is generally in the range of 1 to about 10; R2 is generally hydrocarbyl, typically alkyl or aryl, preferably alkyl, and most preferably lower alkyl; and R3 is hydrocarbylene, heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom- containing hydrocarbylene) typically alkylene or arylene (again, optionally substituted and/or containing a heteroatom), preferably lower alkylene (e.g., methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (e.g., -(CO)-NH-CH2). Other general principles that should be considered with respect to linking groups are as follows. If a higher molecular weight self- reactive compound is to be used, it will preferably have biodegradable linkages as described above, so that fragments larger than 20,000 mol. wt. are not generated during resorption in the body. In addition, to promote water miscibility and/or solubility, it may be desired to add sufficient electric charge or hydrophilicity. Hydrophilic groups can be easily introduced using known chemical synthesis, so long as they do not give rise to unwanted swelling or an undesirable decrease in compressive strength. In particular, polyalkoxy segments may weaken gel strength.

c. The Core

The "core" of each self-reactive compound is comprised of the molecular structure to which the reactive groups are bound. The molecular core can a polymer, which includes synthetic polymers and naturally occurring polymers: In one embodfment, the core is a polymer containing repeating monomer units. The polymers can be hydrophilic, hydrophobic, or amphiphilic. The molecular core can also be a low molecular weight components such as a C2-U hydrocarbyl or a heteroatom-containing C2-14 hydrocarbyl. The heteroatom-containing C2-I4 hydrocarbyl can have 1 or 2 heteroatoms selected from N, O and S. In a preferred embodiment, the self- reactive compound comprises a molecular core of a synthetic hydrophilic polymer.

/) Hydrophilic Polymers

As mentioned above, the term "hydrophilic polymer" as used herein refers to a polymer having an average molecular weight and composition that naturally renders, or is selected to render the polymer as a whole "hydrophilic." Preferred polymers are highly pure or are purified to a highly pure state such that the polymer is or is treated to become pharmaceutically pure. Most hydrophilic polymers can be rendered water soluble by incorporating a sufficient number of oxygen (or less frequently nitrogen) atoms available for forming hydrogen bonds in aqueous solutions.

Synthetic hydrophilic polymers may be homopolymers, block copolymers including di-block and tri-block copolymers, random copolymers, or graft copolymers. In addition, the polymer may be linear or branched, and if branched, may be minimally to highly branched, dendrimeric, hyperbranched, or a star polymer. The polymer may include biodegradable segments and blocks, either distributed throughout the polymer's molecular structure or present as a single block, as in a block copolymer. Biodegradable segments preferably degrade so as to break covalent bonds. Typically, biodegradable segments are segments that are hydrolyzed in the presence of water and/or enzymatically cleaved in situ. Biodegradable segments may be composed of small molecular segments such as ester linkages, anhydride linkages, ortho ester linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc. Larger biodegradable "blocks" will generally be composed of όligomeric or polymeric segments incorporated within the hydrophilic polymer. Illustrative oligomeric and polymeric segments that are biodegradable include, by way of example, poly(amino acid) segments, poly(orthoester) segments, poly(orthocarbonate) segments, and the like. Other biodegradable segments that may form part of the hydrophilic polymer core include polyesters such as polylactide, polyethers such as polyalkylene oxide, polyamides such as a protein, and polyurethanes. For example, the core of the self-reactive compound can be a diblock copolymer of tetrafunctionally activated polyethylene glycol and polylactide.

Synthetic hydrophilic polymers that are useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycol (PEG) and poly(ethylene oxide)-poly(propylene oxide) copolymers, including block and random copolymers; polyols such as glycerol, polyglycerol (PG) and particularly highly branched polyglycerol, propylene glycol; poly(oxyalkylene)-substituted diols, and poly(oxyalkylene)-substituted polyols such as mono-, di- and tri-polyoxyethylated glycerol, mono- and di- polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol; polyoxyethylated sorbitol, polyoxyethylated glucose; poly(acrylic acids) and analogs and copolymers thereof, such as polyacrylic acid perse, polymethacrylic acid, poly(hydroxyethylmethacrylate), poly(hydroxyethylacrylate), poly(methylalkylsulfoxide methacrylates), poly(methylalkylsulfoxide acrylates) and copolymers of any of the foregoing, and/or with additional acrylate species such as aminoethyl acrylate and mono-2-(acryloxy)-ethyl succinate; polymaleic acid; poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide), poly(dimethylacrylamide), poly(N-isopropyl-acrylamide), and copolymers thereof; poly(olefinic alcohols) such as polyvinyl alcohols) and copolymers thereof; poly(N-vinyl lactams) such as polyvinyl pyrrolidones), poly(N-vinyl caprolactams), and copolymers thereof; polyoxazolines, including poly(methyloxazoline) and poly(ethyloxazoline); and polyvinylamines; as well as copolymers of any of the foregoing. It must be emphasized that the aforementioned list of polymers is not exhaustive, and a variety of other synthetic hydrophilic polymers may be used, as will be appreciated by those skilled in the art.

Those of ordinary skill in the art will appreciate that synthetic polymers such as polyethylene glycol cannot be prepared practically to have exact molecular weights, and that the term "molecular weight" as used herein refers to the weight average molecular weight of a number of molecules in any given sample, as commonly used in the art. Thus, a sample of PEG 2,000 might contain a statistical mixture of polymer molecules ranging in weight from, for example, 1 ,500 to 2,500 daltons with one molecule differing slightly from the next over a range. Specification of a range of molecular weights indicates that the average molecular weight may be any value between the limits specified, and may include molecules outside those limits. Thus, a molecular weight range of about 800 to about 20,000 indicates an average molecular weight of at least about 800, ranging up to about 20 kDa. Other suitable synthetic hydrophilic polymers include chemically synthesized polypeptides, particularly polynucleophilic polypeptides that have been synthesized to incorporate amino acids containing primary amino groups (such as lysine) and/or amino acids containing thiol groups (such as cysteine). Poly(lysine), a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly(lysine)s have been prepared having anywhere from 6 to about 4,000 primary amino groups, corresponding to molecular weights of about 870 to about 580,000. Poly(Iysine)s for use in the present invention preferably have a molecular weight within the range of about 1 ,000 to about 300,000, more preferably within the range of about 5,000 to about 100,000, and most preferably, within the range of about 8,000 to about 15,000. Poly(lysine)s of varying molecular weights are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).

Although a variety of different synthetic hydrophilic polymers can be used in the present compounds, preferred synthetic hydrophilic polymers are PEG and PG, particularly highly branched PG. Various forms of PEG are extensively used in the modification of biologically active molecules because PEG lacks toxicity, antigenicity, and immunogenicity (Ae., is biocompatible), can be formulated so as to have a wide range of solubilities, and does not typically interfere with the enzymatic activities and/or conformations of peptides. A particularly preferred synthetic hydrophilic polymer for certain applications is a PEG having a molecular weight within the range of about 100 to about 100,000, although for highly branched PEG, far higher molecular weight polymers can be employed, up to 1 ,000,000 or more, providing that biodegradable sites are incorporated ensuring that all degradation products will have a molecular weight of less than about 30,000. For most PEGs, however, the preferred molecular weight is about 1 ,000 to about 20,000, more preferably within the range of about 7,500 to about 20,000. Most preferably, the polyethylene glycol has a molecular weight of approximately 10,000. Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen, fibronectin, albumins, globulins, fibrinogen, fibrin and thrombin, with collagen particularly preferred; carboxylated polysaccharides such as polymannuronic acid and polygalacturonic acid; aminated polysaccharides, particularly the glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin; and activated polysaccharides such as dextran and starch derivatives. Collagen and glycosaminoglycans are preferred naturally occurring hydrophilic polymers for use herein.

Unless otherwise specified, the term "collagen" as used herein refers to all forms of collagen, including those, which have been processed or otherwise modified. Thus, collagen from any source may be used in the compounds of the invention; for example, collagen may be extracted and purified from human or other mammalian source, such as bovine or porcine corium and human placenta, or may be recombinantly or otherwise produced. The preparation of purified, substantially non-antigenic collagen in solution from bovine skin is well known in the art. For example, U.S. Patent No. 5,428,022 to Palefsky et al. discloses methods of extracting and purifying collagen from the human placenta, and U.S. Patent No. 5,667,839 to Berg discloses methods of producing recombinant human collagen in the milk of transgenic animals, including transgenic cows. Non-transgenic, recombinant collagen expression in yeast and other cell lines) is described in U.S. Patent No. 6,413,742 to Olsen et al., 6,428,978 to Olsen et al., and 6,653,450 to Berg et al.

Collagen of any type, including, but not limited to, types I1 II1 III, IV, or any combination thereof, may be used in the compounds of the invention, although type I is generally preferred. Either atelopeptide or telopeptide-containing collagen may be used; however, when collagen from a natural source, such as bovine collagen, is used, atelopeptide collagen is generally preferred, because of its reduced immunogenicity compared to telopeptide-containing collagen. Collagen that has not been previously crosslinked by methods such as heat, irradiation, or chemical crosslinking agents is preferred for use in the invention, although previously crosslinked collagen may be used.

Collagens for use in the present invention are generally, although not necessarily, in aqueous suspension at a concentration between about 20 mg/ml to about 120 mg/ml, preferably between about 30 mg/ml to about 90 mg/ml. Although intact collagen is preferred, denatured collagen, commonly known as gelatin, can also be used. Gelatin may have the added benefit of being degradable faster than collagen.

Nonfibrillar collagen is generally preferred for use in compounds of the invention, although fibrillar collagens may also be used. The term "nonfibrillar collagen" refers to any modified or unmodified collagen material that is in substantially nonfibrillar form, i.e., molecular collagen that is not tightly associated with other collagen molecules so as to form fibers. Typically, a solution of nonfibrillar collagen is more transparent than is a solution of fibrillar collagen. Collagen types that are nonfibrillar (or microfibrillar) in native form include types IV, Vl, and VII.

Chemically modified collagens that are in nonfibrillar form at neutral pH include succinylated collagen and methylated collagen, both of which can be prepared according to the methods described in U.S. Patent No. 4,164,559 to Miyata et al. Methylated collagen, which contains reactive amine groups, is a preferred nucleophile-containing component in the compositions of the present invention. In another aspect, methylated collagen is a component that is present in addition to first and second components in the matrix-forming reaction of the present invention. Methylated collagen is described in, for example, in U.S. Patent No. 5,614,587 to Rhee et al.

Collagens for use in the compositions of the present invention may start out in fibrillar form, then can be rendered nonfibrillar by the addition of one or more fiber disassembly agent. The fiber disassembly agent must be present in an amount sufficient to render the collagen substantially nonfibrillar at pH 7, as described above. Fiber disassembly agents for use in the present invention include, without limitation, various biocompatible alcohols, amino acids, inorganic salts, and carbohydrates, with biocompatible alcohols being particularly preferred. Preferred biocompatible alcohols include glycerol and propylene glycol. Non- biocompatible alcohols, such as ethanol, methanol, and isopropanol, are not preferred for use in the present invention, due to their potentially deleterious effects on the body of the patient receiving them. Preferred amino acids include arginine. Preferred inorganic salts include sodium chloride and potassium chloride. Although carbohydrates, such as various sugars including sucrose, may be used in the practice of the present invention, they are not as preferred as other types of fiber disassembly agents because they can have cytotoxic effects in vivo.

Fibrillar collagen is less preferred for use in the compounds of the invention. However, as disclosed in U.S. Patent No. 5,614,587 to Rhee et'al., fibrillar collagen, or mixtures of nonfibrillar and fibrillar collagen, may be preferred for use in compounds intended for long-term persistence in vivo.

H) Hydrophobic Polymers

The core of the self-reactive compound may also comprise a hydrophobic polymer, including low molecular weight polyfunctional species, although for most uses hydrophilic polymers are preferred. Generally, "hydrophobic polymers" herein contain a relatively small proportion of oxygen and/or nitrogen atoms. Preferred hydrophobic polymers for use in the invention generally have a carbon chain that is no longer than about 14 carbons. Polymers having carbon chains substantially longer than 14 carbons generally have very poor solubility in aqueous solutions and, as such, have very long reaction times when mixed with aqueous solutions of synthetic polymers containing, for example, multiple nucleophilic groups. Thus, use of short-chain oligomers can avoid solubility-related problems during reaction. Polylactic acid and polyglycolic acid are examples of two particularly suitable hydrophobic polymers.

Hi) Amphiphilic Polymers

Generally, amphiphilic polymers have a hydrophilic portion and a hydrophobic (or lipophilic) portion. The hydrophilic portion can be at one end of the core and the hydrophobic portion at the opposite end, or the hydrophilic and hydrophobic portions may be distributed randomly (random copolymer) or in the form of sequences or grafts (block copolymer) to form the amphiphilic polymer core of the self-reactive compound. The hydrophilic and hydrophobic portions may include any of the aforementioned hydrophilic and hydrophobic polymers.

Alternately, the amphiphilic polymer core can be a hydrophilic polymer that has been modified with hydrophobic moieties (e.g., alkylated PEG or a hydrophilic polymer modified with one or more fatty chains ), or a hydrophobic polymer that has been modified with hydrophilic moieties (e.g., "PEGylated" phospholipids such as polyethylene glycolated phospholipids).

iv) Low Molecular Weight Components As indicated above, the molecular core of the self-reactive compound can also be a low molecular weight compound, defined herein as being a C2-M hydrocarbyl or a heteroatom-containing C2-U hydrocarbyl, which contains 1 to 2 heteroatoms selected from N, O, S and combinations thereof. Such a molecular core can be substituted with any of the reactive groups described herein.

Alkanes are suitable C2-U hydrocarbyl molecular cores. Exemplary alkanes, for substituted with a nucleophilic primary amino group and a Y electrophilic group, include, ethyleneamine (H2N-CH2CH2-Y), tetramethyleneamine (H2N-(C H4)-Y), pentamethyleneamine (H2N-(CH5)-Y), and hexamethyleneamine (H2N-(CHe)-Y). Low molecular weight diols and polyols are also suitable C2-I4 hydrocarbyls and include trimethylolpropane, di(trimethylol propane), pentaerythritol, and diglycerol. Polyacids are also suitable C2-I4 hydrocarbyls, and include trimethylolpropane-based tricarboxylic acid, di(trimethylol propane)-based tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid), and hexadecanedioic acid (thapsic acid).

Low molecular weight di- and poly-electrophiles are suitable heteroatom-containing C2-14 hydrocarbyl molecular cores. These include, for example, disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl) suberate (BS3), dithiobis(succinimidylpropionate) (DSP), bis(2- succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES), and 3,3'- dithiobis(sulfosuccinimidylpropionate (DTSPP), and their analogs and derivatives.

In one embodiment of the invention, the self-reactive compound of the invention comprises a low-molecular weight material core, with a plurality of acrylate moieties and a plurality of thiol groups.

d. Preparation

The self-reactive compounds are readily synthesized to contain a hydrophilic, hydrophobic or amphiphilic polymer core or a low molecular weight core, functionalized with the desired functional groups, i.e., nucleophilic and electrophilic groups, which enable crosslinking. For example, preparation of a self-reactive compound having a polyethylene glycol (PEG) core is discussed below. However, it is to be understood that the following discussion is for purposes of illustration and analogous techniques may be employed with other polymers.

With respect to PEG, first of all, various functionalized PEGs have been used effectively in fields such as protein modification (see Abuchowski et a!., Enzymes as Drugs, John Wiley & Sons: New York, N.Y. (1981) pp. 367-383; and Dreborg et al. (1990) Crit Rev. Therap. Drug Carrier Syst. 6:315), peptide chemistry (see Mutter et al., The Peptides, Academic: New York, N.Y. 2:285-332; and Zalipsky et al. (1987) Int. J. Peptide Protein Res. 30:740), and the synthesis of polymeric drugs (see Zalipsky et al. (1983) Eur. Polym. J. 19:1177; and Ouchi et al. (1987) J. Macromol. Sci. Chem. A24:1011).

Functionalized forms of PEG, including multi-functionalized PEG, are commercially available, and are also easily prepared using known methods. For example, see Chapter 22 of Poly(ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, ed., Plenum Press, NY (1992).

Multi-functionalized forms of PEG are of particular interest and include, PEG succinimidyl glutarate, PEG succinimidyl propionate, succinimidyl butylate, PEG succinimidyl acetate, PEG succinimidyl succinamide, PEG succinimidyl carbonate, PEG propionaldehyde, PEG glycidyl ether, PEG-isocyanate, and PEG-vinylsulfone. Many such forms of PEG are described in U.S. Patent No. 5,328,955 and 6,534,591 , both to Rhee et al. Similarly, various forms of mϋlti-amino PEG are commercially available from sources such as PEG Shop, a division of SunBio of South Korea (www.sunbio.com), Nippon Oil and Fats (Yebisu Garden Place Tower, 20-3 Ebisu 4-chome, Shibuya-ku, Tokyo), Nektar Therapeutics (San Carlos, California, formerly Shearwater Polymers, Huntsville, Alabama) and from Huntsman's Performance Chemicals Group (Houston, Texas) under the name Jeffamine® polyoxyalkyleneamines. Multi-amino PEGs useful in the present invention include the Jeffamine diamines ("D" series) and triamines ("T" series), which contain two and three primary amino groups per molecule. Analogous poly(sulfhydryl) PEGs are also available from Nektar Therapeutics, e.g., in the form of pentaerythritol poly(ethylene glycol) ether tetra-sulfhydryl (molecular weight 10,000). These multi-functionalized forms of PEG can then be modified to include the other desired reactive groups.

Reaction with succinimidyl groups to convert terminal hydroxyl groups to reactive esters is one technique for preparing a core with electrophilic groups. This core can then be modified include nucleophilic groups such as primary amines, thiols, and hydroxyl groups. Other agents to convert hydroxyl groups include carbonyldiimidazole and sulfonyl chloride. However, as discussed herein, a wide variety of electrophilic groups may be advantageously employed for reaction with corresponding nucleophilic groups. Examples of such electrophilic groups include acid chloride groups; anhydrides, ketones, aldehydes, isocyanate, isothiocyanate, epoxides, and olefins, including conjugated olefins such as ethenesulfony! (-SO2CH=CH2) and analogous functional groups.

Other in situ Crosslinkinq Materials

Numerous other types of in situ forming materials have been described which may be used in combination with an anti-scarring agent in accordance with the invention. The in situ forming material may be a biocompatible crosslinked polymer that is formed from water soluble precursors having electrophilic and nucleophilic groups capable of reacting" and crosslinking in situ (see, e.g., U.S. Patent No. 6,566,406). The in situ forming material may be hydrogel that may be formed through a combination of physical and chemical crosslinking processes, where physical crosslinking is mediated by one or more natural or synthetic components that stabilize the hydrogel-forming precursor solution at a deposition site for a period of time sufficient for more resilient chemical crosslinks to form (see, e.g., U.S. Patent No. 6,818,018). The in situ forming material may be formed upon exposure to an aqueous fluid from a physiological environment from dry hydrogel precursors (see, e.g., U.S. Patent No. 6,703,047). The in situ forming material may be a hydrogel matrix that provides controlled release of relatively low molecular weight therapeutic species by first dispersing or dissolving the therapeutic species within relatively hydrophobic rate modifying agents to form a mixture; the mixture is formed into microparticles that are dispersed within bioabsorbable hydrogels, so as to release the water soluble therapeutic agents in a controlled fashion (see, e.g., 6,632,457). The in situ forming material may be a multi-component hydrogel system (see, e.g., U.S. Patent No. 6,379, 373). The in situ forming material may be a multi-arm block copolymer that includes a central core molecule, such as a residue of a polyol, and at least three copolymer arms covalently attached to the central core molecule, each copolymer arm comprising an inner hydrophobic polymer segment covalently attached to the central core molecule and an outer hydrophilic polymer segment covalently attached to the hydrophobic polymer segment, wherein the central core molecule and the hydrophobic polymer segment define a hydrophobic core region (see, e.g., 6,730,334). The in situ forming material may include a gel-forming macromer that includes at least four polymeric blocks, at least two of which are hydrophobic and at least one of which is hydrophilic, and including a crosslinkable group (see, e.g., 6,639,014). The in situ forming material may be a water-soluble macromer that includes at least one hydrolysable linkage formed from carbonate or dioxanone groups, at least one water-soluble polymeric block, and at least one polymerizable group (see, e.g., U.S. Patent No. 6,177,095). The in situ forming material may comprise polyoxyalkylene block copolymers that form weak physical crosslinks to provide gels having a paste-like consistency at physiological temperatures, (see, e.g., U.S. Patent No. 4,911,926). The in situ forming material may be a thermo-irreversible gel made from polyoxyalkylene polymers and ionic polysaccharides (see, e.g., U.S. Patent No. 5,126,141). The in situ forming material may be a gel forming composition that includes chitin derivatives (see, e.g., U.S. Patent No. 5,093,319), chitosan-coagulum (see, e.g., U.S. Patent No. 4,532,134), or hyaluronic acid (see, e.g., U.S. Patent No. 4,141 ,973). The in situ forming material may be an in situ modification of alginate (see, e.g., U.S. Patent No. 5,266,326 ). The in situ forming material may be formed from ethylenically unsaturated water soluble macromers that can be crosslinked in contact with tissues, cells, and bioactive molecules to form gels (see, e.g., U.S. Patent No. 5,573,934). The in situ forming material may include urethane prepolymers used in combination with an unsaturated cyano compound containing a cyano group attached to a carbon atom, such as cyano(meth)acrylic acids and esters thereof (see, e.g., U.S. Patent No. 4,740,534). The in situ forming material may be a biodegradable hydrogel that polymerizes by a photoinitiated free radical polymerization from water soluble macromers (see, e.g., U.S. Patent No. 5,410,016). The \n situ forming material may be formed from a two component mixture including a first part comprising a serum albumin protein in an aqueous buffer having a pH in a range of about 8.0-11.0, and a second part comprising a water- compatible or water-soluble bifunctional crosslinking agent, (see, e.g., U.S. Patent No. 5,583,114).

In another aspect, in situ forming materials that can be used include those based on the crosslinking of proteins. For example, the in situ forming material may be a biodegradable hydrogel composed of a recombinant or natural human serum albumin and poly(ethylene) glycol polymer solution whereby upon mixing the solution cross-links to form a mechanical non-liquid covering structure which acts as a sealant. See e.g., U.S. Patent No. 6,458,147 and 6,371 ,975. The in situ forming material may be composed of two separate mixtures based on fibrinogen and thrombin which are dispensed together to form a biological adhesive when intermixed either prior to or on the application site to form a fibrin sealant. See e.g., U.S. Patent No. 6,764,467. The in situ forming material may be composed of ultrasonically treated collagen and albumin which form a viscous material that develops adhesive properties when crosslinked chemically with glutaraldehyde and amino acids or peptides. See e.g., U.S. Patent No. 6,310,036. The in situ forming material may be a hydrated adhesive gel composed of an aqueous solution consisting essentially of a protein having amino groups at the side chains (e.g., gelatin, albumin) which is crosslinked with an N-hydroxyimidoester compound. See e.g., U.S. Patent No. 4,839,345. The in situ forming material may be a hydrogel prepared from a protein or polysaccharide backbone (e.g., albumin or polymannuronic acid) bonded to a cross-linking agent (e.g., polyvalent derivatives of polyethylene or polyalkylene glycol). See e.g., U.S. Patent No. 5,514,379. The in situ forming material may be composed of a polymerizable collagen composition that is applied to the tissue and then exposed to an initiator to polymerize the collagen to form a seal over a wound opening in the tissue. See e.g., U.S. Patent No. 5,874,537. The in situ forming material may be a two component mixture composed of a protein (e.g., serum albumin) in an aqueous buffer having a pH in the range of about 8.0-11.0 and a water- soluble bifunctional polyethylene oxide type crosslinking agent, which transforms from a liquid to a strong, flexible bonding composition to seal tissue in situ. See e.g., U.S. Patents 5,583,114 and RE38158 and PCT Publication No. WO 96/03159. The in situ forming material may be composed of a protein, a surfactant, and a lipid in a liquid carrier, which is crosslinked by adding a crosslinker and used as a sealant or bonding agent in situ. See e.g., U.S. Patent Application No. 2004/0063613A1 and PCT Publication Nos. WO 01/45761 and WO 03/090683. The in situ forming material may be composed of two enzyme-free liquid components that are mixed by dispensing the components into a catheter tube deployed at the vascular puncture site, wherein, upon mixing, the two liquid components chemically cross-link to form a mechanical non-liquid matrix that seals a vascular puncture site. See e.g., U.S. Patent Application Nos. 2002/0161399A1 and 2001 /0018598A1. The in situ forming material may be a cross-linked albumin composition composed of an albumin preparation and a carbodiimide preparation which are mixed under conditions that permit crosslinking of the albumin for use as a bioadhesive or sealant. See e.g., PCT Publication No. WO 99/66964. The in situ forming material may be composed of collagen and a peroxidase and hydrogen peroxide, such that the collagen is crosslinked to from a semi-solid gel that seals a wound. See e.g., PCT Publication No. WO 01/35882.

In another aspect, in situ forming materials that can be used include those based on isocyanate or isothiocyanate capped polymers. For example, the in situ forming material may be composed of isocyanate- capped polymers that are liquid compositions which form into a solid adhesive coating by in situ polymerization and crosslinking upon contact with body fluid or tissue. See e.g., PCT Publication No. WO 04/021983. The in situ forming material may be a moisture-curing sealant composition composed of an active isocyanato-terminated isocyanate prepolymer containing a polyol component with a molecular weight of 2,000 to 20,000 and an isocyanurating catalyst agent. See e.g., U.S. Patent No. 5,206,331.

In another embodiment, the reagents can undergo an electrophilic-nucleophilic reaction to produce a crosslinked matrix. Polymers containing and/or terminated with nucleophilic groups such as amine, sulfhydryl, hydroxyl, -PH2 or CO-NH-NH2 can be used as the nucleophilic reagents and polymers containing and/or terminated with electrophilic groups such as succinimidyl, carboxylic acid, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis can be used as the electrophilic reagents. For example, a 4-armed thiol derivatized poly(ethylene glycol) (e.g., pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl) can be reacted with a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) under basic conditions (pH > about 8). Representative examples of compositions that undergo such electrophilic-nucleophilic crosslinking reactions are described, for example, in U.S. Patent. Nos. 5,752,974; 5,807,581; 5,874,500; 5,936,035; 6,051 ,648; 6,165,489; 6,312,725; 6,458,889; 6,495,127; 6,534,591; 6,624,245; 6,566,406; 6,610,033; 6,632,457; and PCT Application Publication Nos. WO 04/060405 and WO 04/060346.

In another embodiment, the electrophilic- or nucleophilic- terminated polymers can further comprise a polymer that can enhance the mechanical and/or adhesive properties of the in situ forming compositions. This polymer can be a degradable or non-degradable polymer. For example, the polymer may be collagen or a collagen derivative, for example methylated collagen. An example of an in situ forming composition uses pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl) (4-armed thiol PEG), pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) (4-armed NHS PEG) and methylated collagen as the reactive reagents. This composition, when mixed with the appropriate buffers can produce a crosslinked hydrogel. (See, e.g., U.S. Patent Nos. 5,874,500; 6,051 ,648; 6,166,130; 5,565,519 and 6,312,725J.

In another embodiment, the reagents that can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(CsH4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In the preferred embodiment, the 4 armed NHS-derivatized polyethylene glycol is applied to the tissue under basic conditions (pH > about 8). Other representative examples of compositions of this nature that may be used are disclosed in PCT Application Publication No. WO 04/060405 and WO 04/060346, and U.S. Patent Application No. 10/749,123.

In another embodiment, the in situ forming material polymer can be a polyester. Polyesters that can be used in in situ forming compositions include poly(hydroxyesters). In another embodiment, the polyester can comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta- butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ~ decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxane-2- one or 1 ,5-dioxepan-2one. Representative examples of these types of compositions are described in U.S. Patent. Nos. 5,874,500; 5,936,035; 6,312,725; 6,495,127 and PCT Publication Nos. WO 2004/028547. In another embodiment, the electrophilic-terminated polymer can be partially or completely replaced by a small molecule or oligomer that comprises an electrophilic group (e.g., disuccinimidyl glutarate).

In another embodiment, the nucleophilic-terminated polymer can be partially or completely replaced by a small molecule or oligomer that comprises a nucleophilic group (e.g., dicysteine, dilysine, trilysine, etc.).

Other examples of in situ forming materials that can be used include those based on the crosslinking of proteins (described in, for example, U.S. Patent Nos. RE38158; 4,839,345; 5,514,379, 5,583,114; 6,310,036; 6,458,147; 6,371 ,975; US Patent Application Publication Nos. 2004/0063613A1 , 2002/0161399A1 , and 2001/0018598A1 , and PCT Publication Nos. WO 03/090683, WO 01/45761 , WO 99/66964, and WO 96/03159) and those based on isocyanate or isothiocyanate capped polymers (see, e.g., PCT Publication No. WO 04/021983).

Other examples of in situ forming materials can include reagents that comprise one or more cyanoacrylate groups. These reagents can be used to prepare a poly(alkylcyanoacrylate) or poly(carboxyalkylcyanoacrylate) (e.g., poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(hexylcyanoacrylate), poly(methoxypropylcyanoacrylate), and poly(octylcyanoacrylate)).

Examples of commercially available cyanoacrylates that can be used in the present invention include DERMABOND, INDERMIL, GLUSTITCH, VETBOND, HISTOACRYL, TISSUMEND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT.

In another embodiment, the cyanoacrylate compositions may further comprise additives to stabilize the reagents and/or alter the rate of reaction of the cyanoacrylate, and/or plasticize the poly(cyanoacrylate), and/or alter the rate of degradation of the poly(cyanoacrylate). For example, a trimethylene carbonate based polymer or an oxalate polymer of poly(ethylene glycol) or a ε-caprolactone based copolymer may be mixed with a 2-alkoxyalkylcyanoacrylate (e.g., 2-methoxypropyIcyanoacrylate). Representative examples of these compositions are described in U.S. Patent Nos. 5,350,798 and 6,299,631.

In another embodiment, the cyanoacrylate composition can be prepared by capping heterochain polymers with a cyanoacrylate group. The cyanoacrylate-capped heterochain polymer preferably has at least two cyanoacrylate ester groups per chain. The heterochain polymer can comprise an absorbable poly(ester), poly(ester-carbonate), poly(ether- carbonate) and poly(ether-ester). The poly(ether-ester)s described in U.S. Patent Nos. 5,653,992 and 5,714,159 can also be used as the heterochain polymers. A triaxial poly(ε-caprolactone-co-trimethylene carbonate) is an example of a poly(ester-carbonate) that can be used. The heterochain polymer may be a polyether. Examples of polyethers that can be used include poly(ethylene glycol), polyφropylene glycol) and block copolymers of poly(ethylene glycol) and poly(propylene glycol) (e.g., PLURONICS group of polymers including but not limited to PLURONIC F127 or F68). Representative examples of these compositions are described in U.S. Patent No. 6,699,940.

Within another aspect of the invention, the biologically active ant-infective and/or fibrosis-inhibiting agent can be delivered with a non- polymeric compound (e.g., a carrier). These non-polymeric carriers can include sucrose derivatives (e.g., sucrose acetate isobutyrate, sucrose oleate), sterols such as cholesterol, stigmasterol, β-sitosterol, and estradiol; cholesteryl esters such as cholesteryl stearate; Ci2 -C24 fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid; Ci8 -C36 mono-, di- and triacylglycerides such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerol tristearate and mixtures thereof; sucrose fatty acid esters such as sucrose distearate and sucrose palmitate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; Ci6 -C18 fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty alcohols and fatty acids such as cetyl palmitate and cetearyl palmitate; anhydrides of fatty acids such as stearic anhydride; phospholipids including phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and lysoderivatives thereof; sphingosine and derivatives thereof; spingomyelins such as stearyl, palmitoyl, and tricosanyl spingomyelins; ceramides such as stearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolin alcohols, calcium phosphate, sintered and unscintered hydoxyapatite, zeolites; and combinations and mixtures thereof.

Representative examples of patents relating to non-polymeric delivery systems and the preparation include U.S. Patent Nos. 5,736,152; 5,888,533; 6,120,789; 5,968,542; and 5,747,058.

Within certain embodiments of the invention, the therapeutic compositions are provided that include (i) a fibrosis-inhibiting agent and/or (ii) an anti-infective agent. The therapeutic compositions may include one or more additional therapeutic agents (such as described above), for example, anti-inflammatory agents, anti-thrombotic agents, and/ or anti-platelet agents. Other agents that may be combined with the therapeutic compositions include, e.g., additional ingredients such as surfactants (e.g., PLURONICS, such as F-127, L-122, L-101, L-92, L-81 , and L-61), preservatives, anti-oxidants.

In one aspect, the present invention provides compositions comprising i) an anti-fibrotic agent and ii) a polymer or a compound that forms a polymer in situ. The following are some, but by no means all, of the preferred anti-fibrotic agents and classes of anti-fibrotic agents that may be included in the inventive compositions:

1a) an anti-fibrotic agent that inhibits cell regeneration, 2a) an anti-fibrotic agent that inhibits angiogenesis, 3a) an anti-fibrotic agent that inhibits fibroblast migration, 4a) an anti-fibrotic agent that inhibits fibroblast proliferation, 5a) an anti-fibrotic agent that inhibits deposition of extracellular matrix,

6a) an anti-fibrotic agent inhibits tissue remodeling, 7a) an adensosine A2A receptor antagonist, 8a) an AKT inhibitor,

9a) an alpha 2 integrin antagonist, wherein the alpha 2 integrin antagonist is Pharmaprojects No. 5754 (Merck KgaA), 10a) an alpha 4 integrin antagonist, 11a) an alpha 7 nicotinic receptor agonist, 12a) an angiogenesis inhibitor selected from the group consisting of AG-12,958 (Pfizer), ATN-161 (Attenuon LLC), neovastat, an angiogenesis inhibitor from Jerina AG (Germany), NM-3 (Mercian), VGA- 1155 (Taisho), FCE-26644 (Pfizer), FCE-26950 (Pfizer), FPMA (Meiji Daries), FR-111142 (Fujisawa), GGTI-298, GM-1306 (Ligand), GPA-1734 (Novartis), NNC-47-0011 (Novo Nordisk), herbamycin (Nippon Kayaku), lenalidomide (Celegene), IP-10 (NIH), ABT-828 (Abbott), KIN-841 (Tokushima University, Japan), SF-1126 (Semafore Pharmaceuticals), laminin technology (NIH), CHIR-258 (Chiron), NVP-AEW541 (Novartis), NVP-AEW541 (Novartis), Vt16907 (Alchemia), OXI-8007 (Oxigene), EG- 3306 (Ark Therapeutics), Maspin (Arriva), ABT-567 (Abbott), PPI-2458 (Praecis Pharmaceuticals), CC-5079, CC-4089 (Celgene), HIF-1 alpha inhibitors (Xenova), S-247 (Pfizer), AP-23573 (Ariad), AZD-9935 (Astra Zeneca), mebendazole (Introgen Therapeutics), MetAP-2 inhibitors (GlaxoSmithKline), AG-615 (Angiogene Pharmaceuticals), Tie-2 antagonists (Hybrigenics), NC-381 , CYC-381 , NC-169, NC-219, NC-383, NC-384, NC- 407 (Lorus Therapeutics), ATN-224 (Attenuon), ON-01370 (Onconova), Vitronectin antagonists (Amgen), SDX-103 (Salmedix), Vitronectin antagonists (Shire), CHP (Riemser), TEK (Amgen), Anecortave acetate (Alcon), T46.2 (Matrix Therapeutics), HG-2 (Heptagen), TEM antagonists (Genzyme), Oxi-4500 (Oxigene), ATN-161 (Attenuon), WX-293 (Wilex), M- 2025 (Metris Therapeutics), Alphastatin (BioActa), YH-16 (Yantai Rongchang), BIBF-1120 (Boehringer Ingelheim), BAY-57-9352 (Bayer), AS- 1404 (Cancer Research Technology), SC-77964 (Pfizer), glycomimetics (BioTie Therapies), TIE-2 Inhibitors (Ontogen), DIMI, Octamer (Octamer), ABR-215050 (Active Biotech), ABT-518 (Abbott), KDR inhibitors (Abbott), BSF-466895 (Abbott), SCH-221153 (Schering-Plough), DAC:antiangiogenic (ConjuChem), TFPI (EntreMed), AZD-2171 (Astra-Zenaca), CDC-394 (Celgene), LY290293 (EIi Lilly), IDN-5390 (Indena), Kdr Kinase Inhibitors (Merck), CT-113020, CT-116433, CT-116563, CT-31890, CT-32228) (Cell Therapeutics), A-299620 (Abbott), TWEAK Inhibitor (Amgen), VEGF modulators (Johnson and Johnson), Tum-N53, tumstatin (Genzyme), Thios- 1 , Thios-2 (Thios Pharmaceuticals), MV-6401 (Miravant Medical Technologies), Spisulosine (PharmaMar), CEP-7055 (Cephalon), AUV-201 (Auvation),~LM-609 (EIi Lilly), SKF-106615 (AnorMED), Oglufanide disodium (Cytran), BW-114 (Pharminox), Calreticulin (NIH), WX-678 (Wilex), SD-7784 (Pfizer), WX-UK1 (Wilex), SH-268 (Schering AG), 2-Me-PGA (Celgene), S- 137 (Pfizer), ZD-6126 (Angiogene Pharmaceuticals), SG-292 (SignalGen), Benefin (Lane Labs), A6, A36 (Angstrom), SB-2723005 (GlaxoSmithKline), SC-7 (Cell Therapeutics), ZEN-014 (AEterna Zentaris), 2-methoxyestradiol (EntreMed), NK-130119 (Nippon Kayaku), CC-10004 (Celgene), AVE- 8062A (Ajinomoto), Tacedinaline (Pfizer), Actinonin (Tokyo Metropolitan Institute of Medical Science), Lenalidomide (Celgene), VGA-1155, BTO-956 (SRI International), ER-68203-00 (Eisai), CT-6685 (UCB), JKC-362 (Phoenix Pharmaceuticals), DMI-3798 (DMI Biosciences, Angiomate (Ipsen), ZD-6474 (AstraZeneca), CEP-5214 (Cephalon), Canstatin (Genzyme), NM-3 (Mercian), Oridigm (MediQuest Therapeutics), Exherin (Adherex), BLS-0597 (Boston Life Sciences), PTC-299 (PTC Therapeutics), NPI-2358 (Nereus Pharmaceuticals), CGP-79787 (Novartis), AEE-788 (Novartis), CKD-732 (Chong Kun Dang), CP-564959 (OSI Pharmaceuticals), CM-101 (CarboMed), CT-2584, CT3501 (Cell Therapeutics), combretastatin and analogues and derivatives thereof (Oxigene), Rebimastat (Bristol-Meyers Squibb), Dextrin 2-sulfate (ML Laboratories), Cilengitide (Merk KGaA), NSC-706704 (Pharminox), KRN- 951 (Kirin Brewery), Ukrain, NSC-631570 (Nowicky Pharma), Tecogalan sodium (Daiichi Pharmaceutical), Tz-93 (Tsumura), TBC-1635 (Encysive Pharmaceuticals), TAN-1120 (Takeda), Semaxanib (Pfizer), BDI-7800 (Biopharmacopae), SD-186, SD-983 (Bristol-Meyers Squibb), SB-223245 (GlaxoSmithKline), SC-236 (Pfizer), RWJ-590973 (Johnson and Johnson), ILX-1850 (Genzyme), SC-68488, S-836 (Pfizer), CG-55069-11 (CuraGen), Ki-23057 (Kirin Brewery), CCX-700 (Chemoentryx), Pegaptanib octasodium (Giled Sciences), ANGIOCOL (available from Biostratum Inc.), or an analogue or derivative thereof,

13a) an apoptosis antagonist,

14a) an apoptosis activator,

15a) a beta 1 integrin antagonist,

16a) a beta tubulin inhibitor,

17a) a blocker of enzyme production in Hepatitis C,

18a) a Bruton's tyrosine kinase inhibitor,

19a) a calcineurin inhibitor,

20a) a caspase 3 inhibitor,

21a) a CC chemokine receptor antagonist,

22a) a cell cycle inhibitor selected from the group consisting of SNS-595 (Sunesis), synthadotin, KRX-0403, homoharringtonine, and an analogue or derivative thereof,

23a) a cathepsin B inhibitor,

24a) a cathepsin K inhibitor, wherein the cathepsin K inhibitor is 462795 (GlaxoSmithKline), INPL-022-D6 (Amura Therapeutics), or an analogue or derivative thereof,

25a) a cathepsin L inhibitor,

26a) a CD40 antagonist, 27a) a chemokine receptor agonist,

28a) a chymase inhibitor,

29a) a collagenase antagonist,

30a) a CXCR antagonist,

31a) a cyclin dependent kinase inhibitor selected from the group consisting of a CDK-1 inhibitor, a CDK-2 inhibitor, a CDK- 4 inhibitor, a CDK-6 inhibitor, a CAK1 inhibitor from GPC Biotech and Bristol-Myers Squibb, RGB-286199 (GPC Biotech), an anticancer agent from Astex Technology, a CAK1 inhibitor from GPC Biotech, a CDK inhibitor from Sanofi-Aventis, a CDK1/CDK2 inhibitor from Amgen, a CDK2 inhibitor from SUGEN-2 (Pfizer), a hearing loss therapy agent (Sound Pharmaceuticals), PD-0332991 (Pfizer), RGB-286199 (GPC Biotech), Ro-0505124 (Hoffmann- La Roche), a Ser/Thr kinase inhibitor from Lilly (EIi Lilly), CVT-2584 (CAS No. 199986-75-9) (CV Therapeutics), CGP 74514A, bohemine, olomoucine (CAS No. 101622-51-9), indole-3-carbinol (CAS No. 700-06-1), and an analogue or derivative thereof,

32a) a cyclooxygenase 1 inhibitor,

33a) a DHFR inhibitor,

34a) a dual integrin inhibitor,

35a) an elastase inhibitor,

36a) an elongation factor-1 alpha inhibitor,

37a) an endothelial growth factor antagonist,

38a) an endothelial growth factor receptor kinase inhibitor selected from the group consisting of sorafenib tosylate (Bayer), AAL-993 (Novartis), ABP-309 (Novartis), BAY-57-9352 (Bayer), BIBF-1120 (Boehringer Ingelheim), E-7080 (Eisai), EG-3306 (Ark Therapeutics), EXEL- 2880 (Exelixis), GW-654652 (GlaxoSmithKline), lavendustin A (CAS No. 125697-92-9), a KDR inhibitor from LG Life Sciences, CT-6685 and CT- 6729 (UCB), KRN-633 and KRN-951 (Kirin Brewery), OSI-930 (OSI Pharmaceuticals), SP-5.2 (Supratek Pharma), SU-11657 (Pfizer), a Tie-2 antagonist (Hybrigenics), SU 1498 (a VEGF-R inhibitor), a VEGFR-2 kinase inhibitor (Bristol-Myers Squibb), XL-647 (Exelixis), a KDR inhibitor from Abbott Laboratories, sorafenib tosylate, and an analogue or derivative thereof,

39a) an endotoxin antagonist,

40a) an epothilone and tubulin binder,

41a) an estrogen receptor antagonist,

42a) an FGF inhibitor,

43a) a famexyl transferase inhibitor,

44a) a famesyltransferase inhibitor selected from the group of A-197574 (Abbott), a famesyltransferase inhibitor from Servier, FPTIII (Strathclyde Institute for Drug R), LB-42908 (LG Life Sciences), Pharmaprojects No. 5063 (Genzyme), Pharmaprojects No. 5597 (Ipsen), Yissum Project No. B-1055 (Yissum), and an analogue or derivative thereof,

45a) an FLT-3 kinase inhibitor,

46a) an FGF receptor kinase inhibitor,

47a) a fibrinogen antagonist selected from the group consisting of AUV-201 (Auvation), MG-13926 (Sanofi-Aventis), plasminogen activator (CAS No. 105913-11-9) (from Sanofi-Aventis or UCB), plasminogen activator-2 (tPA-2) (Sanofi-Aventis), pro-urokinase (CAS No. 82657-92-9) (Sanofi-Aventis), mevastatin, and an analogue or derivative thereof,

48a) a heat shock protein 90 antagonist selected from the group consisting of SRN-005 (Sirenade), geldanamycin, NSC-33050 (17- allylaminogeldanamycin; 17-AAG), 17-dimethylaminoethylamino-17- demethoxy-geldanamycin (17-DMAG), rifabutin (rifamycin XIV, 1',4- didehydro-1-deoxy-1 ,4-dihydro-5'-(2-methylpropyl)-1-oxo-), radicicol from Humicola fuscoatra (CAS No. 12772-57-5), and an analogue or derivative thereof,

49a) a histone deacetylase inhibitor,

50a) an HMGCoA reductase inhibitor selected from the group consisting of an atherosclerosis therapeutic from Lipid Sciences, ATI-16000 (ARYx Therapeutics), KS-01-019 (Kos Pharmaceuticals), Pharmaprojects No. 2197 (Sanofi-Aventi), RP 61969 (Sanofi-Aventis), cerivastatin Na (CAS No. 143201-11-0), and an analogue or derivative thereof,

51a) an ICAM inhibitor,

52a) an IL, ICE and IRAK antagonist, wherein the antagonist is a CJ-14877, CP-424174 (Pfizer), NF-61 (Negma-Lerads), and an analogue or derivative thereof,

53a) an IL-2 inhibitor,

54a) an immunosuppressant selected from the group consisting of teriflunomide (Sanofi Aventis), chlorsulfaquinoxalone (NSC- 339004), chlorsulfaquinoxalone sulfate, CS-712 (Sankyo), ismomultin alfa (CAS No. 457913-93-8) (Akzo Nobel), antiallergics from GenPat77, antiinflammatories or AT-005 (Androclus Therapeutics), autoimmune disease therapeutics from EpiVax, BN-007 (Bone), budesonide (CAS No. 51333-22- 3) (MAP Pharmaceuticals), CO-14 (Genzyme), edratide (CAS No. 433922- 67-9) (Teva), EP-314 (Enanta), eprovafen (CAS No. 101335-99-3) (Sanofi- Aventis), HWA-131 (CAS No. 118788-41-3) (Sanofi-Aventis), immunomodulators from MerLion Pharmaceuticals, immunosuppressives from Alchemia, IPL-12 (Inflazyme), MDL-9563 (CAS No. 27086-86-8) (Sanofi-Aventis), Pharmaprojects No. 2330 (Sanofi-Aventis), Pharmaprojects No. 6426 (Abgenix), PXS-25 (Pharmaxis), rosmarinic acid (CAS No. 20283-92-5) (Sanofi-Aventis), RP 42927 or RP 54745 (CAS No. 135330-08-4) (Sanofi-Aventis), SGN-35 (Seattle Genetics), ST-1959 (Sigma-Tau), type I diabetes therapy from SYNX Pharma, UNIL-88 (Debiopharm), VP-025 (Vasogen), VR-694 (Vectura), PRTX-001 (Protalex), and an analogue or derivative thereof,

55a) an IMPDH (inosine monophosphate),

56a) an integrin antagonist,

57a) an interleukin antagonist,

58a) an inhibitor of type III receptor tyrosine kinase, 59a) an irreversible inhibitor of enzyme methionine aminopeptidase type 2,

60a) an isozyme selective delta protein kinase C inhibitor,

61a) a JAK3 enzyme inhibitor,

62a) a JNK inhibitor,

63a) a kinase inhibitor,

64a) a kinesin antagonist,

65a) a leukotriene inhibitor and antagonist selected from the group consisting of ambicromil (CAS No. 58805-38-2) (Sanofi-Aventis), amelubant (CAS No. 346735-24-8) (Boehringer Ingelheim), DW-1141 (Dong Wha), ebselen (Daiichi Pharmaceutical), ibudilast (Kyorin), leucotriene inhibitors from Sanofi-Aventis, lymphotoxin-beta receptor (LT-β) from Biogen Idee, Pharmaprojects No. 1535 and 2728 (CAS No. 119340-33-9) (Sanofi- Aventis), R-112 (Rigel), Rev-5367 (CAS No. 92532-05-3) (Sanofi-Aventis), RG-14893 (CAS No. 141835-49-6) (Sanofi-Aventis), RG-5901-A (CAS No. 101910-24-1), 92532-23-5, RP 66153 (CAS No. 142422-79-5), RP 66364 (CAS No.186912-92-5), RP 69698 (CAS No. 141748-00-7) (Sanofi-Aventis), SC-411930 (Pfizer), SC-41930 (CAS No. 120072-59-5) (Pfizer), SC-50605 (CAS No. 138828-39-4) (Pfizer), SC-51146 (CAS No. 141059-52-1), SC- 53228 (CAS No. 153633-01-3) (Pfizer), spaglumic acid (ZY-15106) (CAS No.3106-85-2), 80619-64-3 (Novartis), tipredane (CAS No. 85197-77-9) (Bristol-Myers Squibb), U-75302 (CAS No. 119477-85-9) (Pfizer), and analogue or derivative thereof,

66a) a MAP kinase inhibitor,

67a) a matrix metalloproteinase inhibitor,

68a) an MCP-CCR2 inhibitor,

69a) an mTOR inhibitor,

70a) an mTOR kinase inhibitor,

71a) a microtubule inhibitor selected from the group consisting of antibody-maytansinoid conjugates from Biogen Idee, colchicines (MantiCore Pharmaceuticals), anticancer immunoconjugates from Johnson & Johnson, DIME from Octamer, gni-1f (GNI), huC242-DM4, huMy9-6-DM1 (ImmunoGen), IDN-5404 (Indena), IMO-098, IMOderm (Imotep), mebendazole (Introgen Therapeutics), microtubule poisons from Cambridge Enterprise, paclitaxel such as LOTAX from Aphios (CAS No. 33069-62-4), Genexol-PM from Samyang, Pharmaprojects No. 6383 (Tapestry Pharmaceuticals), RPR-112378 (Sanofi-Aventis), SGN-75 (Seattle Genetics), SPL-7435 (Starpharma), SSR-250411 (Sanofi-Aventis), trastuzumab-DM1 (Genentech), vinorelbine, dolastatin 15 (CAS No. 123884-00-4), vincamine, and an analogue or derivative thereof,

72a) an MIF inhibitor,

73a) an MMP inhibitor,

74a) a neurokinin (NK) antagonist selected from the group consisting of anthrotainin (CAS No. 148084-40-6) (Sanofi-Aventis), an IBS thereapeutic from ArQuIe, MDL-105212A (CAS No. 167261-60-1) (Ssanofi- Aventis), Pharmaprojects No. 2744, 3258 (CAS No. 139167-47-8) 4006, 4201 , or 5986 (Sanofi-Aventis), RP 67580 (CAS No. 135911-02-3), SR- 144190 (CAS No. 201152-86-5), SSR-240600, SSR-241586 (Sanofi- Aventis), TKA-457 (Novartis), vestipitant mesylate (CAS No. 334476-64-1) (GlaxoSmithKline), Win-64821 (Sanofi-Aventis), PRX-96026 (Predix Pharmaceuticals), and an analogue or derivative thereof,

75a) an NF kappa B inhibitor selected from the group consisting of emodin (CAS No. 518-82-1), AVE-0545 or AVE-0547 (Sanofi- Aventis), bortezomib (CAS No. 179324-69-7) (Millennium Pharmaceuticals), dexanabinol (CAS No. 112924-45-5) (Pharmos), dexlipotam (Viatris), Pharmaprojects No. 6283 (INDRA) (OXiGENE), IPL-576092 (CAS No. 137571-30-3) (Inflazyme), NFKB decoy (Corgentech), NFKB decoy oligo (AnGes MG), NFKB's from Ariad, osteoporosis treatments or S5 (F005) from Fulcrum Pharmaceuticals, P61 (Phytopharm), R-flurbiprofen (CAS No. 5104-49-4) (Encore Pharmaceuticals), Bay 11-7085, and an analogue or derivative thereof,

76a) a nitric oxide agonist, 77a) an ornithine decarboxylase inhibitor, 78a) a p38 MAP kinase inhibitor selected from the group consisting of AZD-6703 (AstraZeneca), JX-401 (Jexys Pharmaceuticals), BMS-2 (Bristol-Myers Squibb), a p38 MAP kinase inhibitor from Novartis, a p38-alpha MAP kinase inhibitor from Amphora, Pharmaprojects No. 5704 (Pharmacopeia), SKF86002 (CAS No. 72873-74-6), RPR-200765A (Sanofi- Aventis), SD-282 (Johnson & Johnson), TAK-715 (Takeda), and an analogue or derivative thereof,

79a) a palmitoyl-protein thioesterase inhibitor, 80a) a PDGF receptor kinase inhibitor selected from the group consisting of AAL-993, AMN-107, or ABP-309 (Novartis), AMG-706 (Amgen), BAY-57-9352 (Bayer), CDP-860 (UCB), E-7080 (Eisai), imatinib (CAS No. 152459-95-5) (Novartis), OSI-930 (OSI Pharmaceuticals), RPR- 127963E (Sanofi-Aventis), RWJ-540973 (Johnson & Johnson), sorafenib tosylate (Bayer), SU-11657 (Pfizer), tandutinib (CAS No. 387867-13-2) (Millennium Pharmaceuticals), vatalanib (Novartis), ZK-CDK (Schering AG), and an analogue or derivative thereof,

81a) a peroxisome proliferators-activated receptor agonist selected from the group consisting of (-)-halofenate (Metabolex), AMG-131 (Amgen), antidiabetics from Japan Tobacco, AZD-4619, AZD-8450, AZD- 8677 (AstraZeneca), DRF-10945, balaglitazone (Dr Reddy's), CS-00088, CS-00098 (Chipscreen Biosciences), E-3030 (Eisai), etalocib (CAS No. 161172-51-6) (EIi Lilly), GSK-641597 (Ligand), GSK-677954 (GlaxoSmithKline), GW-409544 (Ligand), GW-590735 (GlaxoSmithKline), K- 111 (Hoffmann-La Roche), LY-518674 (EIi Lilly), LY-674 (Ligand), LY-929 (Ligand), MC-3001 , MC-3002 (MaxoCore Pharmaceuticals), metformin HCI + pioglitazone (CAS No. 1115-70-4 and 112529-15-4), ACTOPLUS MET from Andrx), muragiitazar (CAS No. 331741-94-7) (Bristol-Myers Squibb), naveglitazar (Ligand), oleoylethanolamide (Kadmus Pharmaceuticals), ONO-5129, pioglitazone hydrochloride (CAS No. 111025-46-8 and 112529- 15-4) (Takeda), PLX-204 (Plexxikon), PPAR agonists from Genfit, PPAR delta agonists from EIi Lilly, PPAR-alpha agonists from CrystalGenomics, PPAR-gamma modulators and PPAR-β modulators from CareX, rosiglitazone maleate (CAS No. 122320-73-4 or 155141-29-0) (GlaxoSmithKline), rosiglitazone maleate/glimepir (CAS No. 155141-29-0 and 93479-97-1), AVANDARYL, rosiglitazone maleate/metformin extend (CAS No. 155141-29-0 and 657-24-9), AVANDAMET, rosiglitazone maieate+metformin, AVANDAMET (GlaxoSmithKline), tesaglitazar (AstraZeneca), LBM642, WY-14,643 (CAS No. 50892-23-4), GW7647, fenofibric acid (CAS No. 42017-89-0), MCC-555 (CAS No. 161600-01-7), GW9662, GW1929, GW501516, L-165,041 (CAS No. 79558-09-1), and an analogue or derivative thereof,

82a) a phosphatase inhibitor,

83a) a phosphodiesterase (PDE) inhibitor selected from the group consisting of avanafil (Tanabe Seiyaku), dasantafil (CAS No. 569351- 91-3) (Schering-Plough), A-906119 (CAS No. 134072-58-5), DL-850 (Sanofi-Aventis)rGRC-3015, GRC-3566, GRC-3886 (Glenmark), HWA-153 (CAS No. 56395-66-5) (Sanofi-Aventis), hydroxypumafentrine (Altana), IBFB-130011 , IBFB-14-016, IBFB-140301 , IBFB-150007, IBFB-211913 (IBFB Pharma), L-826141 (Merck & Co), medorinone (CAS No. 88296-61-1) (Sanofi-Aventis), MEM-1917 (Memory Pharmaceuticals), ND-1251 (Neuro3d), PDE inhibitors from ICOS, PDE IV inhibitors from Memory Pharmaceuticals and CrystalGenomics, Pharmaprojects No. 2742 and 6141 (Sanofi-Aventis), QAD-171 (Novartis), RHC-2963 (CAS No. 76993-12-9 and 76993-14-1), RPR-117658, RPR-122818 derivatives, SR-24870 , and RPR- 132294 (Sanofi-Aventis), SK-350 (ln2Gen), stroke therapy agents from deCODE Genetics, TAS-203 (Taiho), tofimilast (CAS No. 185954-27-2) (Pfizer), UK-371800 (Pfizer), WIN-65579 (CAS No. 158020-82-7) (Sanofi- Aventis), IBFB-130020 (IBFB Pharma), OPC-6535 (CAS No. 145739-56-6) (Otsuka), theobromine (CAS No. 83-67-0), papverine hydrochloride (CAS No. 61-25-6), quercetin dehydrate (CAS No. 6151-25-3), YM 976 (CAS No. 191219-80-4), irsogladine (CAS No. 57381-26-7), a phosphodiesterase III inhibitor, enoximone, a phosphodiesterase IV inhibitor, fosfosal, Atopik (Barrier Therapeutics), triflusal, a phosphodiesterase V inhibitor, and an analogue or derivative thereof,

84a) a PKC inhibitor,

85a) a platelet activating factor antagonist,

86a) a platelet-derived growth factor receptor kinase inhibitor,

87a) a prolyl hydroxylase inhibitor,

88a) a polymorphonuclear neutrophil inhibitor,

89a) a protein kinase B inhibitor,

90a) a protein kinase C stimulant,

91a) a purine nucleoside analogue,

92a) a purinoreceptor P2X antagonist,

93a) a Raf kinase inhibitor,

94a) a reversible inhibitor of ErbB1 and ErbB2,

95a) a ribonucleoside triphosphate reductase inhibitor,

96a) an SDF-T antagonist,

97a) a sheddase inhibitor,

98a) an SRC inhibitor,

99a) a stromelysin inhibitor,

100a) an Syk kinase inhibitor,

101a) a telomerase inhibitor,

102a) a TGF beta inhibitor selected from the group consisting of pirfenidone (CAS No. 53179-13-8) (MARNAC), tranilast (CAS No. 53902- 12-8) (Kissei), IN-1130 (ln2Gen), mannose-6-phosphate (BTG), TGF-β antagonists from Inflazyme (Pharmaprojects No. 6075), TGF-β antagonists from Sydney, non-industrial source), TGF-β I receptor kinase inhibitors from EIi Lilly, TGF-β receptor inhibitors from Johnson & Johnson, and an analogue or derivative thereof,

103a) a TNFα antagonist or TACE inhibitor selected from the group consisting of adalimumab (CAS No. 331731-18-1) (Cambridge Antibody Technology), AGIX-4207 (AtheroGenics), AGT-1 (Advanced Biotherapy), an anti-inflammatory from Borean Pharma, Cellzome, or Paradigm Therapeutics, anti-inflammatory vaccine (TNF-alpha kinoid) from Neovacs, humanized anti-TNF antibody or an anti-TNF MAb (CB0006) Celltech (UCB), apratastat (CAS No. 287405-51-0) (Wyeth), BMS-561392 (Bristol-Myers Squibb), BN-006 (Bone), certolizumab pegol (CAS No. 428863-50-7 or CH-138 (UCB), cilomilast (CAS No. 153259-65-5) (GlaxoSmithKline), CR-1 (Nuada Pharmaceuticals), CRx-119 (CombinatoRx), D-5410 (UCB), dacopafant (CAS No. 125372-33-0) (Sanofi- Aventis), dersalazine (CAS No. 188913-57-7/188913-58-8) (Uriach), etanercept (CAS No. 185243-69-0) (Amgen), ethyl pyruvate (Critical (Critical Therapeutics), golimumab (CAS No. 476181-74-5) (Johnson & Johnson), hormono-immunotherapy from Ipsen, CDP571 (e.g., Humicade from UCB), IC-485 (ICOS), infliximab (CAS No. 170277-31-3) (Johnson & Johnson), IP- 751 (Manhattan Pharmaceuticals), ISIS-104838 (CAS No. 250755-32-9) (ISIS Pharmaceuticals), lenalidomide (CAS No. 191732-72-6) (Celgene), lentinan (CAS No. 37339-90-5) (Ajinomoto), MDL-201112 (CAS No. 142130-73-2) (Sanofi-Aventis), medroxyprogesterone (CAS No. 520-85-4) (InKine Pharmaceutical), N-acetylcysteine (CAS No. 616-91-1) (Zambon), NBE-P2 (DIREVO Biotech), nerelimomab (CAS No. 162774-06-3) (Chiron), OM-294DP (OM PHARMA), onercept (CAS No. 199685-57-9) (Yeda), PASSTN F-alpha (Verigen), pentoxifylline or oxypentifylline (Sanofi-Aventis), Pharmaprojects No. 4091 , 4241 , 4295, or 4488 (Sanofi-Aventis), Pharmaprojects No. 5480 (Amgen), Pharmaprojects No. 6749 (Cengent), pirfenidone (CAS No. 53179-13-8) (MARNAC), RPR-132294 (Sanofi- Aventis), S5 (F002) (Fulcrum Pharmaceuticals), simvastatin (CAS No. 79902-63-9) (Merck & Co), STA-6292 (Synta Pharmaceuticals), tacrolimus (CAS No. 104987-11-3) (Fujisawa LifeCycle Pharma), talactoferrin alfa (CAS No. 308240-58-6) (Agennix), thalidomide (CAS No. 50-35-1) (Celgene), TNF antagonists form ProStrakan, and Synergen, TNF inhibitors (Amgen), TNF-alpha antagonists from Dynavax Technologies and Jerina AG (Germany), TNF-alpha inhibitors from IBFB Pharma and Xencor (Xencor), torbafylline (CAS No. 105102-21-4) (Sanofi-Aventis), UR-1505 (Uriach), VT-346 (Viron Therapeutics), YSIL6 (Y's Therapeutics), YSTH2 (Y's Therapeutics), NPI-1302a-3 (Nereus Pharmaceuticals, a TNF antagonist from Jerina AG (Germany), dersalazine, and an analogue or derivative thereof,

104a) a tumor necrosis factor antagonist,

105a) a Toll receptor inhibitor,

106a) a tubulin antagonist,

107a) a tyrosine kinase inhibitor selected from the group consisting of SU-011248, SUTENT from Pfizer Inc. (New York, NY), BMS- 354825, PN-355 (Paracelsian Pharmaceuticals), AGN-199659 (Allergan), AAL-993 or ABP-309 (Novartis), adaphostin (NIH), AEE-788 (Novartis), AG- 013736 (OSI Pharmaceuticals), AG-13736 (Pfizer), ALT-110 (Alteris Therapeutics), AMG-706 (Amgen), anticancer MAbs from Xencor, anti- EGFrvlll MAbs from Abgenix, anti-HER2 MAb from Abiogen, AZD-2171 or AZD-9935 (AstraZeneca), BAY-57-9352 (Bayer), BIBF-1120 (Boehringer Ingelheim), CEP-5214 (Cephalon), CEP-7055 (Cephalon), cetuximab (ImClone Systems), CHIR-200131 and CHIR-258 (Chiron), CP-547632 (OSI Pharmaceuticals), CP-724714 (Pfizer), CT-301 (Creabilis Therapeutics), D- 69491 (Baxter International), E-7080 (Eisai), EG-3306 (Ark Therapeutics), EGFR/ErbB2 inhibitors from Array BioPharma, erlotinib (CAS No. 183319- 69-9) (OSI Pharmaceuticals), EXEL-2880 (Exelixis), FK-778 (Sanofi- Aventis) , gefitinib (CAS No. 184475-35-2) (AstraZeneca), GW-2286 or GW- 654652 (GlaxoSmithKline), her2/neu antigen from AlphaVax, HER-2/neu inhibitor from Generex, Herzyme (Medipad) (Sirna Therapeutics), HKI-272 (Wyeth), HuMax-EGFr (Genmab), idronoxil (CAS No. 81267-65-4) (Novogen), IGF-1 inhibitors from Ontogen, IMC-11F8 (ImClone Systems), kahalalide F (CAS No. 149204-42-2) (PharmaMar), KDR inhibitor from LG Life Sciences, KDR inhibitors from Abbott Laboratories, KDR kinase inhibitors (UCB), Kdr kinase inhibitors from Merck & Co, KRN-633 and KRN- 951 (Kirin Brewery), KSB-102 (Xenova), lapatinib ditosylate (CAS No. 388082-78-8) (GlaxoSmithKline), matuzumab (Merck KGaA), MDX-214 (Medarex), ME-103 (Pharmexa), MED-A300 (Gerolymatos), MNAC-13 (Lay Line Genomics), nimotuzumab (Center of Molecular Immunology), NSC- 330507 or NSC-707545 (NIH), NV-50 (Novogen), OSI-930 (OSI Pharmaceuticals), panitumumab (Abgenix), pelitinib (CAS No. 287933-82-7) (Wyeth), pertuzumab (CAS No. 380610-27-5) (Genentech), Pharmaprojects No. 3985 (Sanofi-Aventis), prostate cancer therapeutics from Sequenom (SQPC35, SQPC36, SQPC90), removab and remoxab (Trion Pharma), RG- 13022 (CAS No. 136831-48-6), RG-13291 (CAS No. 138989-50-1), or RG- 14620 (CAS No. 136831-49-7) (Sanofi-Aventis), RM-6427 (Romark), RNAi breast cancer therapy from Benitec, RP 53801 (CAS No. 125882-88-4) (Sanofi-Aventis), sorafenib tosylate (Bayer), SU-11657 (Pfizer), Tie-2 antagonists from Semaia (Hybrigenics), Tie-2 inhibitors from Ontogen, trastuzumab (CAS No. 180288-69-1) (Genentech), tyrosine kinase inhibitors from Sanofi-Aventis, U3-1287, U3-1565, U3-1784, U3-1800 (U3 Pharma), vatalanib (Novartis), VEGFR-2 kinase inhibitor from Bristol-Myers Squibb, XL-647 (Exelixis), ZD-6474 (AstraZeneca), ZK-CDK (Schering AG), an EGFR tyrosine kinase inhibitor, EKB-569 (Wyeth), herbimycin A, and an analogue or derivative thereof,

108a) a VEGF inhibitor,

109a) a vitamin D receptor agonist,

110a) ZD-6474 (an angiogenesis inhibitor),

111a) AP-23573 (an mTOR inhibitor),

112a) synthadotin (a tubulin antagonist),

113a) S-0885 (a collagenase inhibitor),

114a) aplidine (an elongation factor-1 alpha inhibitor),

115a) ixabepilone (an epithilone),

116a) IDN-5390 (an angiogenesis inhibitor and an FGF inhibitor),

117a) SB-2723005 (an angiogenesis inhibitor),

118a) ABT-518 (an angiogenesis inhibitor), 119a) combretastatin (an angiogenesis inhibitor),

120a) anecortave acetate (an angiogenesis inhibitor),

121a) SB-715992 (a kinesin antagonist),

122a) temsirolimus (an mTOR inhibitor),

123a) adalimumab (a TNFα antagonist),

124a) erucylphosphocholine (an ATK inhibitor),

125a) alphastatin (an angiogenesis inhibitor),

126a) bortezomib (an NF Kappa B inhibitor),

127a) etanercept (a TNFα antagonist and TACE inhibitor),

128a) humicade (a TNFα inhibitor),

129a) gefitinib (a tyrosine kinase inhibitor),

130a) a histamine receptor antagonist selected from the group consisting of phenothiazines (e.g., promethazine), alkylamines (e.g., chlorpheniramine (CAS No. 7054-11-7), brompheniramine (CAS No. 980- 71-2), fexofenadine hydrochloride, promethazine hydrochloride, loratadine, ketotifen fumarate salt, and acrivastine), methylxanthines (e.g., theophylline, theobromine, and caffeine), cimetidine (available under the tradename TAGAMET from SmithKline Beecham Phamaceutical Co., Wilmington, DE), ranitidine (available under the tradename ZANTAC from Warner Lambert Company, Morris Plains, NJ), famotidine (available under the tradename PEPCID from Merck & Co., Whitehouse Station, NJ), nizatidine (available under the tradename AXID from Reliant Pharmaceuticals, Inc., Liberty Corner, NJ), nizatidine, and roxatidine acetate (CAS No. 78628-28-1), H3 receptor antagonists (e.g., thioperamide and thioperamide maleate salt), and anti-histamines (e.g., tricyclic dibenozoxepins, ethanolamines, ethylenediamines, piperizines, piperidines, and pthalazinones),

131a) an alpha adrenergic receptor antagonist,

132a) an anti-psychotic compound,

133a) a CaM kinase Il inhibitor,

134a) a G protein agonist, 135a) an antibiotic selected from the group consisting of apigenin (Cas No. 520-36-5), ampicillin sodium salt (CAS No. 69-52-3), puromycin, and an analogue or derivative thereof,

136a) an anti-microbial agent,

137a) a DNA topoisomerase inhibitor selected from the group consisting of β-lapachone (CAS No. 4707-32-8), (-)-arctigenin (CAS No. 7770-78-7), aurintricarboxylic acid, and an analogue or derivative thereof,

138a) a thromboxane A2 receptor inhibitor selected from the group consisting of BM-531 (CAS No. 284464-46-6), ozagrel hydrochloride (CAS No. 78712-43-3), and an analogue or derivative thereof,

139a) a D2 dopamine receptor antagonist,

140a) a Peptidyl-Prolyl Cis/Trans lsomerase Inhibitor,

141a) a dopamine antagonist, an anesthetic compound,

142a) a clotting factor,

143a) a lysyl hydrolase inhibitor,

144a) a muscarinic receptor inhibitor,

145a) a superoxide anion generator,

146a) a steroid,

147a) an anti-proliferative agent selected from the group consisting of silibinin (CAS No. 22888-70-6), silymarin (CAS No. 65666-07- 1), 1 ,2-hexanediol, dioctyl phthalate (CAS No. 117-81-7), zirconium (IV) oxide, glycyrrhizic acid, spermidine trihydrochloride, tetrahydrochloride, CGP 74514, spermine tetrahydrochloride, NG-methyl-L-arginine acetate salt, galardin, and an analogue or derivative thereof,

148a) a diuretic,

149a) an anti-coagulant,

150a) a cyclic GMP agonist,

151a) an adenylate cyclase agonist,

152a) an antioxidant,

153a) a nitric oxide synthase inhibitor, 154a) an anti-neoplastic agent selected from tirapazamine (CAS No. 27314-97-2), fludarabine (CAS No. 21679-14-1), cladribine, imatinib mesilate, and an analogue or derivative thereof,

155a) a DNA synthesis inhibitor,

156a) a DNA alkylating agent selected from dacarbazine (CAS No. 4342-03-4), temozolomide, procarbazine HCI, and an analogue or derivative thereof,

157a) a DNA methylation inhibitor,

158a) a NSAID agent,

159a) a peptidylglycine alpha-hydroxylating monooxygenase inhibitor,

160a) an MEK1/MEK 2 inhibitor,

161a) a NO synthase inhibitor,

162a) a retinoic acid receptor antagonist selected from isotretinoin (CAS No. 4759-48-2) and an analogue or derivative thereof, ~ 163a) an ACE inhibitor;

164a) a glycosylation inhibitor,

165a) an intracellular calcium influx inhibitor,

166a) an anti-emetic agent,

167a) an acetylcholinesterase inhibitor,

168a) an ALK-5 receptor antagonist,

169a) a RAR/RXT antagonist,

170a) an elF-2a inhibitor,

171a) an S-adenosyl-L-homocysteine hydrolase inhibitor,

172a) an estrogen agonist,

173a) a serotonin receptor inhibitor,

174a) an anti-thrombotic agent,

175a) a tryptase inhibitor,

176a) a pesticide,

177a) a bone mineralization promoter, 178a) a bisphosphonate compound selected from risedronate and an analogue or derivative thereof,

179a) an anti-inflammatory compound, 180a) a DNA methylation promoter, 181a) an anti-spasmodic agent, 182a) a protein synthesis inhibitor, 183a) an α-glucosidase inhibitor, 184a) a calcium channel blocker, 185a) a pyruvate dehydrogenase activator, 186a) a prostaglandin inhibitor, 187a) a sodium channel inhibitor, 188a) a serine protease inhibitor, 189a) an intracellular calcium flux inhibitor, 190a) a JAK2 inhibitor; 191a) an androgen inhibitor, ~ 192a) an aromatase inhibitor, 193a) an anti-viral agent, 194a) a 5-HT inhibitor, 195a) an FXR antagonist,

196a) an actin polymerization and stabilization promoter, 197a) an AXOR12 agonist, 198a) an angiotensin Il receptor agonist, 199a) a platelet aggregation inhibitor, 200a) a CB1/CB2 receptor agonist, 201a) a norepinephrine reuptake inhibitor, 202a) a selective serotonin reuptake inhibitor, 203a) a reducing agent, 204a) isotretinoin, 205a) radicicol, 206a) clobetasol propionate, 207a) homoharringtonine, 208a) trichostatin A, 209a) brefeldin A, 210a) thapsigargin, 211a) dolastatin 15, 212a) cerivastatin, 213a) jasplakinolide, 214a) herbimycin A, 215a) pirfenidone, 216a) vinorelbine, 217a) 17-DMAG, 218a) tacrolimus, 219a) loteprednol etabonate, 220a) juglone, 221a) prednisolone, 222a) pυromycin, 223a) 3-BAABE, 224a) cladribine, 225a) mannose-6-phosphate, 226a) 5-azacytidine, 227a) Ly333531 (ruboxistaurin), 228a) simvastatin, and

229a) an immuno-modulator selected from Bay 11-7085, (-)- arctigenin, idazoxan hydrochloride, and an analogue or derivative thereof.

As mentioned above, the present invention provides compositions comprising each of the foregoing 229 (i.e., 1a through 229a) listed anti-fibrotic agents or classes of anti-fibrotic agents, with each of the following 97 (i.e., 1b through 97b) polymers and compounds:

1b. A crosslinked polymer.

2b. A polymer that reacts with mammalian tissue.

3b. A polymer that is a naturally occurring polymer.

4b. A polymer that is a protein. 5b. A polymer that is a carbohydrate.

6b. A polymer that is biodegradable.

7b. A polymer that is crosslinked and biodegradable.

8b. A polymer that nonbiodegradable.

9b. Collagen.

10b. Methylated collagen.

11b. Fibrinogen.

12b. Thrombin.

13b. Albumin.

14b. Plasminogen.

15b. von Willebrands factor.

16b. Factor VIII.

17b. Hypoallergenic collagen.

18b. Atelopeptidic collagen.

19b. Telopeptide collagen.

20b. Crosslinked collagen.

21b. Aprotinin.

22b. Gelatin.

23b. A protein conjugate.

24b. A gelatin conjugate.

25b. Hyaluronic acid.

26b. A hyaluronic acid derivative.

27b. A synthetic polymer.

28b. A polymer formed from reactants comprising a synthetic isocyanate-containing compound.

29b. A synthetic isocyanate-containing compound.

30b. A polymer formed from reactants comprising a synthetic thiol-containing compound.

31 b. A synthetic thiol-containing compound.

32b. A polymer formed from reactants comprising a synthetic compound containing at least two thiol groups. 33b. A synthetic compound containing at least two thiol groups.

34b. A polymer formed from reactants comprising a synthetic compound containing at least three thiol groups.

35b. A synthetic compound containing at least three thiol groups.

36b. A polymer formed from reactants comprising a synthetic compound containing at least four thiol groups.

37b. A synthetic compound containing at least four thiol groups.

38b. A polymer formed from reactants comprising a synthetic amino-containing compound.

39b. A synthetic amino-containing compound.

40b. A polymer formed from reactants comprising a synthetic compound containing at least two amino groups.

41b. A synthetic compound containing at least two amino groups.

42b. A polymer formed from reactants comprising a synthetic compound containing at least three amino groups.

43b. A synthetic compound containing at least three amino groups.

44b. A polymer formed from reactants comprising a synthetic compound containing at least four amino groups.

45b. A synthetic compound containing at least four amino groups.

46b. A polymer formed from reactants comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group.

47b. A synthetic compound comprising a carbonyl-oxygen- succinimidyl group.

48b. A polymer formed from reactants comprising a synthetic compound comprising at least two carbonyl-oxygen-succinimidyl groups. 49b. A synthetic compound comprising at least two carbonyl- oxygen-succinimidyl groups.

50b. A polymer formed from reactants comprising a synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

51b. A synthetic compound comprising at least three carbonyl-oxygen-succinimidyl groups.

52b. A polymer formed from reactants comprising a synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

53b. A synthetic compound comprising at least four carbonyl-oxygen-succinimidyl groups.

54b. A polymer formed from from reactants comprising a synthetic polyalkylene oxide-containing compound.

55b. A synthetic polyalkylene oxide-containing compound.

56b. A polymer formed from reactants comprising a synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks. - - - . _

57b. A synthetic compound comprising both polyalkylene oxide and biodegradable polyester blocks.

58b. A polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive amino groups.

59b. A synthetic polyalkylene oxide-containing compound having reactive amino groups.

60b. A polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive thiol groups.

61b. A synthetic polyalkylene oxide-containing compound having reactive thiol groups.

62b. A polymer formed from reactants comprising a synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen- succinimidyl groups.

63b. A synthetic polyalkylene oxide-containing compound having reactive carbonyl-oxygen-succinimidyl groups. 64b. A polymer formed from reactants comprising a synthetic compound comprising a biodegradable polyester block.

65b. A synthetic compound comprising a biodegradable polyester block.

66b. A polymer formed from reactants comprising a synthetic polymer formed in whole or part from lactic acid or lactide.

67b. A synthetic polymer formed in whole or part from lactic acid or lactide.

68b. A polymer formed from reactants comprising a synthetic polymer formed in whole or part from glycolic acid or glycolide.

69b. A synthetic polymer formed in whole or part from glycolic acid or glycolide.

70b. A polymer formed from reactants comprising polylysine.

71b. Polylysine.

72b. A polymer formed from reactants comprising (a) protein and (b) a compound comprising a polyalkylene oxide portion.

73b. A polymer formed from reactants comprising (a) protein and (b) polylysine.

74b. A polymer formed from reactants comprising (a) protein and (b) a compound having at least four thiol groups.

75b. A polymer formed from reactants comprising (a) protein and (b) a compound having at least four amino groups.

76b. A polymer formed from reactants comprising (a) protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.

77b. A polymer formed from reactants comprising (a) protein and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon- caprolactone.

78b. A polymer formed from reactants comprising (a) collagen and (b) a compound comprising a polyalkylene oxide portion. 79b. A polymer formed from reactants comprising (a) collagen and (b) polylysine.

80b. A polymer formed from reactants comprising (a) collagen and (b) a compound having at least four thiol groups.

81b. A polymer formed from reactants comprising (a) collagen and (b) a compound having at least four amino groups.

82b. A polymer formed from reactants comprising (a) collagen and (b) a compound having at least four carbonyl-oxygen- succinimide groups.

83b. A polymer formed from reactants comprising (a) collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon-caprolactone.

84b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound comprising a polyalkylene oxide portion.- -. . . . .

85b. A polymer formed from reactants comprising (a) methylated collagen and (b) polylysine.

86b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four thiol groups.

87b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four amino groups.

88b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound having at least four carbonyl- oxygen-succinimide groups.

89b. A polymer formed from reactants comprising (a) methylated collagen and (b) a compound having a biodegradable region formed from reactants selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon-caprolactone.

90b. A polymer formed from reactants comprising hyaluronic acid. 91 b. A polymer formed from reactants comprising a hyaluronic acid derivative.

92b. A polymer formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl of number average molecular weight between 3,000 and 30,000.

93b. Pentaerythritol poly(ethylene glycol)ether tetra- sulfhydryl of number average molecular weight between 3,000 and 30,000.

94b. A polymer formed from reactants comprising pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

95b. Pentaerythritol poly(ethylene glycol)ether tetra-amino of number average molecular weight between 3,000 and 30,000.

96b. A polymer formed from reactants comprising (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

97b. A mixture of (a) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple nucleophilic groups, and (b) a synthetic compound having a number average molecular weight between 3,000 and 30,000 and comprising a polyalkylene oxide region and multiple electrophilic groups.

As mentioned above, the present invention provides compositions comprising each of the foregoing 229 (1a through 229a) listed anti-fibrotic agents or classes of anti-fibrotic agents, with each of the foregoing 97 (1b through 97b) polymers and compounds: Thus, in separate aspects, the invention provides 229 times 97 = 22213 described compositions. In other words, each of the following is a distinct aspect of the present invention: 1a+1b, 2a+1b, 3a+1b, 4a+1b, 5a+1b, 6a+1b, 7a+1b, 8a+1b, 9a+1b, 10a+1b, 11a+1b, 12a+1b, 13a+1b, 14a+1b, 15a+1b, 16a+1b, 17a+1b, 18a+1b, 19a+1b, 20a+1b, 21a+1b, 22a+1b, 23a+1b, 24a+1b, 25a+1b, 26a+1b, 27a+1b, 28a+1b, 29a+1b, 30a+1b, 31a+1b, 32a+1b, 33a+1b, 34a+1b, 35a+1b, 36a+1b, 37a+1b, 38a+1b, 39a+1b, 40a+1b, 41a+1b, 42a+1b, 43a+1b, 44a+1b, 45a+1b, 46a+1b, 47a+1b, 48a+1b, 49a+1b, 50a+1b, 51a+1b, 52a+1b, 53a+1b, 54a+1b, 55a+1b, 56a+1b, 57a+1b, 58a+1b, 59a+1b, 60a+1b, 61a+1b, 62a+1b, 63a+1b, 64a+1b, 65a+1b, 66a+1b, 67a+1b, 68a+1b, 69a+1b, 70a+1b, 71a+1b, 72a+1b, 73a+1b, 74a+1b, 75a+1b, 76a+1b, 77a+1b, 78a+1b, 79a+1b, 80a+1b, 81a+1b, 82a+1b, 83a+1b, 84a+1b, 85a+1b, 86a+1b, 87a+1b, 88a+1b, 89a+1b, 90a+1b, 91a+1b, 92a+1b, 93a+1b, 94a+1b, 95a+1b, 96a+1b, 97a+1b, 98a+1b, 99a+1b, 100a+1b, 101a+1b, 102a+1b, 103a+1b, 104a+1b, 105a+1b, 106a+1b, 107a+1b, 108a+1b, 109a+1b, 110a+1b, 111a+1b, 112a+1b, 113a+1b, 114a+1b, 115a+1b, 116a+1b, 117a+1b, 118a+1b, 119a+1b, 120a+1b, 121a+1b, 122a+1b, 123a+1b, 124a+1b, 125a+1b, 126a+1b, 127a+1b, 128a+1b, 129a+1b, 130a+1b, 131a+1b, 132a+1b, 133a+1b, 134a+1b, 135a+1b, 136a+1b, 137a+1b, 138a+1b, 139a+1b, 140a+1b, 141a+1b, 142a+1b, 143a+1b, 144a+1b, 145a+1b, 146a+1b, 147a+1b, 148a+1b, 149a+1b, 150a+1b, 151a+1b, 152a+1b, 153a+1b, 154a+1b, 155a+1b, 156a+1b, 157a+1b, 158a+1b, 159a+1b, 160a+1b, 161a+1b, 162a+1b, 163a+1b, 164a+1b, 165a+1b, 166a+1b, 167a+1b, 168a+1b, 169a+1b, 170a+1b, 171a+1b, 172a+1b, 173a+1b, 174a+1b, 175a+1b, 176a+1b, 177a+1b, 178a+1b, 179a+1b, 180a+1b, 181a+1b, 182a+1b, 183a+1b, 184a+1b, 185a+1b, 186a+1b, 187a+1b, 188a+1b, 189a+1b, 190a+1b, 191a+1b, 192a+1b, 193a+1b, 194a+1b, 95a+1b, 96a+1b, 97a+1b, 98a+1b, 99a+1b, 200a+1b, 201a+1b, 202a+1b, 203a+1b, 204a+1b, 205a+1b, 206a+1b, 207a+1b, 208a+1b, 209a+1b, 210a+1b, 211a+1b, 212a+1b, 213a+1b, 214a+1b, 215a+1b, 216a+1b, 217a+1b, 218a+1b, 219a+1b, 220a+1b, 221a+1b, 222a+1b, 223a+1b, 224a+1b, 225a+1b, 226a+1b, 227a+1b, 228a+1b, 229a+1b, 1a+2b, 2a+2b, 3a+2b, 4a+2b, 5a+2b, 6a+2b, 7a+2b, 8a+2b, 9a+2b, 10a+2b, 11a+2b, 12a+2b, 13a+2b, 14a+2b, 15a+2b, 16a+2b, 17a+2b, 18a+2b, 19a+2b, 20a+2b, 21a+2b, 22a+2b, 23a+2b, 24a+2b, 25a+2b, 26a+2b, 27a+2b, 28a+2b, 29a+2b, 30a+2b, 31a+2b, 32a+2b, 33a+2b, 34a+2b, 35a+2b, 36a+2b, 37a+2b, 38a+2b, 39a+2b, 40a+2b, 41a+2b, 42a+2b, 43a+2b, 44a+2b, 45a+2b, 46a+2b, 47a+2b, 48a+2b, 49a+2b, 50a+2b, 51a+2b, 52a+2b, 53a+2b, 54a+2b, 55a+2b, 56a+2b, 57a+2b, 58a+2b, 59a+2b, 60a+2b, 61a+2b, 62a+2b, 63a+2b, 64a+2b, 65a+2b, 66a+2b, 67a+2b, 68a+2b, 69a+2b, 70a+2b, 71a+2b, 72a+2b, 73a+2b, 74a+2b, 75a+2b, 76a+2b, 77a+2b, 78a+2b, 79a+2b, 80a+2b, 81a+2b, 82a+2b, 83a+2b, 84a+2b, 85a+2b, 86a+2b, 87a+2b, 88a+2b, 89a+2b, 90a+2b, 91a+2b, 92a+2b, 93a+2b, 94a+2b, 95a+2b, 96a+2b, 97a+2b, 98a+2b, 99a+2b, 100a+2b, 101a+2b, 102a+2b, 103a+2b, 104a+2b, 105a+2b, 106a+2b, 107a+2b, 108a+2b, 109a+2b, 110a+2b, 111a+2b, 112a+2b, 113a+2b, 114a+2b, 115a+2b, 116a+2b, 117a+2b, 118a+2b, 119a+2b, 120a+2b, 121a+2b, 122a+2b, 123a+2b, 124a+2b, 125a+2b, 126a+2b, 127a+2b, 128a+2b, 129a+2b, 130a+2b, 131a+2b, 132a+2b, 133a+2b, 134a+2b, 135a+2b, 136a+2b, 137a+2b, 138a+2b, 139a+2b, 140a+2b, 141a+2b, 142a+2b, 143a+2b, 144a+2b, 145a+2b, 146a+2b, 147a+2b, 148a+2b, 149a+2b, 150a+2b, 151a+2b, 152a+2b, 153a+2b, 154a+2b, 155a+2b, 156a+2b, 157a+2b, 158a+2b, 159a+2b, 160a+2b, 161a+2b, 162a+2b, 163a+2b, 164a+2b, 165a+2b, 166a+2b, 167a+2b, 168a+2b, 169a+2b, 170a+2b, 171a+2b, 172a+2b, 173a+2b, 174a+2b, 175a+2b, 176a+2b, 177a+2b, 178a+2b, 179a+2b, 180a+2b, 181a+2b, 182a+2b, 183a+2b, 184a+2b, 185a+2b, 186a+2b, 187a+2b, 188a+2b, 189a+2b, 190a+2b, 191a+2b, 192a+2b, 193a+2b, 194a+2b, 95a+2b, 96a+2b, 97a+2b, 98a+2b, 99a+2b, 200a+2b, 201a+2b, 202a+2b, 203a+2b, 204a+2b, 205a+2b, 206a+2b, 207a+2b, 208a+2b, 209a+2b, 210a+2b, 211a+2b, 212a+2b, 213a+2b, 214a+2b, 215a+2b, 216a+2b, 217a+2b, 218a+2b, 219a+2b, 220a+2b, 221a+2b, 222a+2b, 223a+2b, 224a+2b, 225a+2b, 226a+2b, 227a+2b, 228a+2b, 229a+2b, etc.

Compositions That Comprise Additional Therapeutic Agents

In addition to incorporation of the above-mentioned therapeutic agents (Ae., anti-infective agents or fibrosis-inhibiting agents), one or more other pharmaceutically active agents can be incorporated into the present compositions to improve or enhance efficacy. In one aspect, the composition may further include a compound which acts to have an inhibitory effect on pathological processes in or around the treatment site. Representative examples of additional therapeutically active agents include, by way of example and not limitation, anti-thrombotic agents, antiproliferative agents, anti-inflammatory agents, neoplastic agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antimicrobial agents, antibodies, cytokine inhibitors, IMPDH (inosine monophosplate dehydrogenase) inhibitors tyrosine kinase inhibitors, MMP inhibitors, p38 MAP kinase inhibitors, immunosuppressants, apoptosis antagonists, caspase inhibitors, and JNK inhibitors.

In certain embodiments, the composition may further include an antithrombotic agent and/or antiplatelet agent and/or a thrombolytic agent, which reduces the likelihood of thrombotic events upon implantation of a medical implant. Representative examples of anti-thrombotic and/or antiplatelet and/or thrombolytic agents include heparin, heparin fragments, organic salts of heparin, heparin complexes (e.g., benzalkonium heparinate, tridodecylammonium heparinate), dextran, sulfonated carbohydrates such as dextran sulfate, Coumadin, coumarin, heparinoid, danaparoid, argatroban chitosan sulfate, chondroitin sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, acetylsalicylic acid, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, streptokinase, factor Xa inhibitors, such as DX9065a, magnesium, and tissue plasminogen activator. Further examples include plasminogen, lys- plasminogen, alpha-2-antiplasmin, urokinase, aminocaproic acid, ticlopidine, clopidogrel, trapidil (triazolopyrimidine), naftidrofuryl, auriritricarboxylic acid and glycoprotein llb/llla inhibitors such as abcixamab, eptifibatide, and tirogiban. Other agents capable of affecting the rate of clotting include glycosaminoglycans, danaparoid, 4-hydroxycourmarin, warfarin sodium, dicumarol, phenprocoumon, indan-1 ,3-dione, acenocoumarol, anisindione, and rodenticides including bromadiolone, brodifacoum, diphenadione, chlorophacinone, and pidnone.

The polymeric formulation may further include an agent from one of the following classes of compounds: anti-inflammatory agents (e.g., dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone, 6α- methylprednisolone, triamcinolone, betamethasone, and aspirin); MMP inhibitors (e.g., batimistat, marimistat, TIMP's representative examples of which are included in U.S. Patent Nos. 5,665,777; 5,985,911 ; 6,288,261; 5,952,320; 6,441 ,189; 6,235,786; 6,294,573; 6,294,539; 6,563,002; - 6,071 ;903; 6,358,980; 5,852,213; 6,124,502; 6,160,132; 6,197,791; 6,172,057; 6,288,086; 6,342,508; 6,228,869; 5,977,408; 5,929,097; 6,498,167; 6,534,491; 6,548,524; 5,962,481 ; 6,197,795; 6,162,814; 6,441 ,023; 6,444,704; 6,462,073; 6,162,821 ; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861 ,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 6,444,639; 6,262,080; 6,486,193; 6,329,550; 6,544,980; 6,352,976; 5,968,795; 5,789,434; 5,932,763; 6,500,847; 5,925,637; 6,225,314; 5,804,581; 5,863,915; 5,859,047; 5,861 ,428; 5,886,043; 6,288,063; 5,939,583; 6,166,082; 5,874,473; 5,886,022; 5,932,577; 5,854,277; 5,886,024; 6,495,565; 6,642,255; 6,495,548; 6,479,502; 5,696,082; 5,700,838; 5,861 ,436; 5,691 ,382; 5,763,621 ; 5,866,717; 5,902,791; 5,962,529; 6,017,889; 6,022,873; 6,022,898; 6,103,739; 6,127,427; 6,258,851; 6,310,084; 6,358,987; 5,872,152; 5,917,090; 6,124,329; 6,329,373; 6,344,457; 5,698,706; 5,872,146; 5,853,623; 6,624,144; 6,462,042; 5,981 ,491 ; 5,955,435; 6,090,840; 6,114,372; 6,566,384; 5,994,293; 6,063,786; 6,469,020; 6,118,001 ; 6,187,924; 6,310,088; 5,994,312; 6,180,611 ; 6,110,896; 6,380,253; 5,455,262; 5,470,834; 6,147,114; 6,333,324; 6,489,324; 6,362,183; 6,372,758; 6,448,250; 6,492,367; 6,380,258; 6,583,299; 5,239,078; 5,892,112; 5,773,438; 5,696,147; 6,066,662; 6,600,057; 5,990,158; 5,731 ,293; 6,277,876; 6,521 ,606; 6,168,807; 6,506,414; 6,620,813; 5,684,152; 6,451 ,791 ; 6,476,027; 6,013,649; 6,503,892; 6,420,427; 6,300,514; 6,403,644; 6,177,466; 6,569,899; 5,594,006; 6,417,229; 5,861 ,510; 6,156,798; 6,387,931 ; 6,350,907; 6,090,852; 6,458,822; 6,509,337; 6,147,061 ; 6,114,568; 6,118,016; 5,804,593; 5,847,153; 5,859,061 ; 6,194,451 ; 6,482,827; 6,638,952; 5,677,282; 6,365,630; 6,130,254; 6,455,569; 6,057,369; 6,576,628; 6,110,924; 6,472,396; 6,548,667; 5,618,844; 6,495,578; 6,627,411 ; 5,514,716; 5,256,657; 5,773,428; 6,037,472; 6,579,890; 5,932,595; 6,013,792; 6,420,415; 5,532,265; 5,639,746; 5,672,598; 5,830,915; 6,630,516; 5,324,634; 6,277,061 ; 6,140,099; 6,455,570; 5,595,885; 6,093,398; 6,379,667; 5,641 ,636; 5,698,404; 6,448,058; 6,008,220; 6,265,432; 6,169,103; 6,133,304; 6,541 ,521 ; 6,624,196; 6,307,089; 6,239,288; 5,756,545; 6,020,366; 6,117,869; 6,294,674; 6,037,361; 6,399,612; 6,495,568; 6,624,177; 5,948,780; 6,620,835; 6,284,513; 5,977,141 ; 6,153,612; 6,297,247; 6,559,142; 6,555,535; 6,350,885; 5,627,206; 5,665,764; 5,958,972; 6,420,408; 6,492,422; 6,340,709; 6,022,948; 6,274,703; 6,294,694; 6,531 ,499; 6,465,508; 6,437,177; 6,376,665; 5,268,384; 5,183,900; 5,189,178; 6,511 ,993; 6,617,354; 6,331 ,563; 5,962,466; 5,861 ,427; 5,830,869; and 6,087,359), cytokine inhibitors (chlorpromazine, mycophenolic acid, rapamycin, 1α- hydroxy vitamin D3), IMPDH (inosine monophosplate dehydrogenase) inhibitors (e.g., mycophenolic acid, ribaviran, aminothiadiazole, thiophenfurin, tiazofurin, viramidine) (Representative examples are included in U.S. Patent, Nos. 5,536,747; 5,807,876; 5,932,600; 6,054,472; 6,128,582; 6,344,465; 6,395,763; 6,399,773; 6,420,403; 6,479,628; 6,498,178; 6,514,979; 6,518,291 ; 6,541 ,496; 6,596,747; 6,617,323; and 6,624,184, U.S. Patent Application Nos. 2002/0040022A1 , 2002/0052513A1 , 2002/0055483A1 , 2002/0068346A1 , 2002/0111378A1 , 2002/0111495A1 , 2002/0123520A1 , 2002/0143176A1 , 2002/0147160A1 , 2002/0161038A1 , 2002/0173491 A1 , 2002/0183315A1 , 2002/0193612A1 , 2003/0027845A1 , 2003/0068302A1 , 2003/0105073A1 , 2003/0130254A1, 2003/0143197A1 , 2003/0144300A1 , 2003/0166201 A1 , 2003/0181497A1 , 2003/0186974A1, 2003/0186989A1 , and 2003/0195202A1 , and PCT Publication Nos. WO 00/24725A1 , WO 00/25780A1 , WO 00/26197A1 , WO 00/51615A1 , WO 00/56331 A1 , WO 00/73288A1 , WO 01/00622A1 , WO 01/66706A1 , WO 01/79246A2, WO 01/81340A2, WO 01/85952A2, WO 02/16382A1 , WO 02/18369A2, WO 02/051814A1 , WO 02/057287A2, WO 02/057425A2, WO 02/060875A1 , WO 02/060896A1 , WO 02/060898A1 , WO 02/068058A2, WO 03/020298A1 , WO 03/037349A1 , WO 03/039548A1 , WO 03/045901A2, WO 03/047512A2, WO 03/053958A1 , WO 03/055447A2, WO 03/059269A2, WO 03/063573A2, WO 03/087071 A1, WO 99/001545A1, WO 97/40028A1 , WO 97/41211A1, WO 98/40381A1 , and WO 99/55663A1), p38 MAP kinase inhibitors (MAPK) (e.g., GW-2286, CGP-52411 , BIRB-798, SB220025, RO- 320-1195, RWJ-67657, RWJ-68354, SCIO-469) (Representative examples are included in U.S. Patent Nos. 6,300,347; 6,316,464; 6,316,466; 6,376,527; 6,444,696; 6,479,507; 6,509,361 ; 6,579,874, and 6,630,485, and U.S. Patent Application Publication Nos. 2001/0044538A1, 2002/0013354A1 , 2002/0049220A1 , 2002/0103245A1 , 2002/0151491 A1 , 2002/0156114A1 , 2003/0018051 A1 , 2003/0073832A1 , 2003/0130257A1 , 2003/0130273A1 , 2003/0130319A1 , 2003/0139388A1 , 2003/0139462A1, 2003/0149031A1 , 2003/0166647A1 , and 2003/0181411A1, and PCT Publication Nos. WO 00/63204A2, WO 01/21591A1 , WO 01/35959A1, WO 01/74811A2, WO 02/18379A2, WO 02/064594A2, WO 02/083622A2, WO 02/094842A2,WO 02/096426A1 , WO 02/101015A2, WO 02/103000A2, WO 03/008413A1 , WO 03/016248A2, WO 03/020715A1 , WO 03/024899A2, WO 03/031431 A1, WO 03/040103A1 , WO 03/053940A1 , WO 03/053941 A2, WO 03/063799A2, WO 03/079986A2, WO 03/080024A2, WO 03/082287A1 , WO 97/44467A1 , WO 99/01449A1 , and WO 99/58523A1), and immunomodulatory agents (rapamycin, everolimus, ABT-578, azathioprine azithromycin, analogues of rapamycin, including tacrolimus and derivatives thereof (e.g., EP 0184162B1 and those described in U.S. Patent No. 6,258,823) and everolimus and derivatives thereof (e.g., U.S. Patent No. 5,665,772). Further representative examples of sirolimus analogues and derivatives include ABT-578 and those found in PCT Publication Nos. WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691, WO 95/15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, WO 92/14737, and WO 92/05179 and in U.S. Patent Nos. 6,342,507; 5,985,890; 5,604,234; 5,597,715; 5,583,139; 5,563,172; 5,561 ,228; 5,561 ,137; 5,541,193; 5,541 ,189; 5,534,632; 5,527,907; 5,484,799; 5,457,194; 5,457,182; 5,362,735; 5,324,644; 5,318,895; 5,310,903; 5,310,901; 5,258,389; 5,252,732; 5,247,076; 5,225,403; 5,221 ,625; 5,210,030; 5,208,241 ; 5,200,411 ; 5,198,421 ; 5,147,877; 5,140,018; 5,116,756; 5,109,112; 5,093,338; and 5,091 ,389.

Other examples of biologically active agents which may be included in the compositions of the invention include tyrosine kinase inhibitors, such as imantinib, ZK-222584, CGP-52411 , CGP-53716, NVP- AAK980-NX, CP-127374, CP-564959, PD-171026, PD-173956, PD-180970, SU-0879, and SKI-606; MMP inhibitors such as nimesulide, PKF-241-466, PKF-242-484, CGS-27023A, SAR-943, primomastat, SC-77964, PNU- 171829, AG-3433, PNU-142769, SU-5402, and dexlipotam; p38 MAP kinase inhibitors such as include CGH-2466 and PD-98-59; immunosuppressants such as argyrin B, macrocyclic lactone, ADZ-62-826, CCI-779, tilomisole, amcinonide, FK-778, AVE-1726, and MDL-28842; cytokine inhibitors such as TNF-484A, PD-172084, CP-293121 , CP-353164, and PD-168787; NFKB inhibitors, such as, AVE-0547, AVE-0545, and IPL- 576092; HMGCoA reductase inhibitors, such as, pravestatin, atorvastatin, fluvastatin, dalvastatin, glenvastatin, pitavastatin, CP-83101 , U-20685; apoptosis antagonist (e.g., troloxamine, TCH-346 (N-methyl-N-propargyl-10- aminomethyl-dibenzo(b,f)oxepin); and caspase inhibitors (e.g., PF-5901 (benzenemethanol, alpha-pentyl-3-(2-quinolinylmethoxy)-), and JNK inhibitors (e.g., AS-602801).

In another aspect, the composition may further include an antibiotic (e.g., amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxicillin-clavulanate, cefprozil, cefuroxime, cefpodoxime, or cefdinir).

In certain aspects, a polymeric composition comprising a fibrosis-inhibiting agent is combined with an agent that can modify metabolism of the agent In vivo to enhance efficacy of the fibrosis-inhibiting agent. One class of therapeutic agents that can be used to alter drug metabolism includes agents capable of inhibiting oxidation of the anti- scarring agent by cytochrome P450 (CYP). In one embodiment, compositions are provided that include a fibrosis-inhibiting agent (e.g., ZD- 6474, AP-23573, synthadotin, S-0885, aplidine, Ixabepilone, IDN-5390, SB- 2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, rapamycin, everolimus, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5- azacytidine, Ly333531 (ruboxistaurin), and simvastatin) and a CYP inhibitor, which may be combined (e.g., coated) with any of the devices described herein, including, without limitation, stents, grafts, patches, valves, wraps, and films. Representative examples of CYP inhibitors include flavones, azole antifungals, macrolide antibiotics, HIV protease inhibitors, and anti- sense oligomers. Devices comprising a combination of a fibrosis-inhibiting agent and a CYP inhibitor may be used to treat a variety of proliferative conditions that can lead to undesired scarring of tissue, including intimal hyperplasia, surgical adhesions, and tumor growth.

In another aspect, a composition comprising an anti-infective agent {e.g., anthracyclines {e.g., doxorubicin or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists (e.g., methotrexate), quinolone antibacterial agents, and/or podophylotoxins (e.g., etoposide)) can be combined with traditional antibiotic and/or antifungal agents to enhance efficacy. The anti-infective agent may be further combined with anti-thrombotic and/or antiplatelet agents (for example, heparin, dextran sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2- chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban, streptokinase, and/or tissue plasminogen activator) to enhance efficacy.

Although the above therapeutic agents have been provided for the purposes of illustration, it should be understood that the present invention is not so limited. For example, although agents are specifically referred to above, the present invention should be understood to include analogues, derivatives and conjugates of such agents. As an illustration, ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatinshould be understood to refer to not only the common chemically available form of ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT- 518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin, but analogues, derivatives or conjugates (e.g., -PEG, - Dextran, -xylos conjugates) of the aforementioned compounds. In addition, as will be evident to one of skill in the art, although the agents set forth above may be noted within the context of one class, many of the agents listed in fact have multiple biological activities. Further, more than one therapeutic agent may be utilized ata time (i.e., in combination), or delivered sequentially.

Compositions That Comprise Additional Components

Within certain embodiments of the invention, the composition can also comprise radio-opaque, echogenic materials and magnetic resonance imaging (MRI) responsive materials (i.e., MRI contrast agents) to aid in visualization of the composition under ultrasound, fluoroscopy and/or MRI. For example, a composition may be echogenic or radiopaque (e.g., made with echogenic or radiopaque with materials such as powdered tantalum, tungsten, barium carbonate, bismuth oxide, barium sulfate, metrazimide, iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, iotrolan, acetrizoic acid derivatives, diatrizoic acid derivatives, iothalamic acid derivatives, ioxithalamic acid derivatives, metrizoic acid derivatives, iodamide, lypophylic agents, iodipamide and ioglycamic acid or, by the addition of microspheres or bubbles which present an acoustic interface). For visualization under MRI1 contrast agents (e.g., gadolinium (III) chelates or iron oxide compounds) may be incorporated into the composition.

The compositions may, alternatively, or in addition, be visualized under visible light, using fluorescence, or by other spectroscopic means. Visualization agents that can be included for this purpose include dyes, pigments, and other colored agents. In one aspect, the composition may further include a colorant to improve visualization of the composition in vivo and/or ex vivo. Frequently, compositions can be difficult to visualize upon delivery into a host, especially at the margins of an implant or tissue. A coloring agent can be incorporated into a composition to reduce or eliminate the incidence or severity of this problem. The coloring agent provides a unique color, increased contrast, or unique fluorescence characteristics to the composition. In one aspect, a composition is provided that includes a colorant such that it is readily visible (under visible light or using a fluorescence technique) and easily differentiated from its implant site. In another aspect, a colorant can be included in a liquid or semi-solid composition. For example, a single component of a two component mixture may be colored, such that when combined ex-vivo or in-vivo, the mixture is sufficiently colored.

The coloring agent may be, for example, an endogenous compound (e.g., an amino acid or vitamin) or a nutrient or food material and may be a hydrophobic or a hydrophilic compound. Preferably, the colorant has a very low or no toxicity at the concentration used. Also preferred are colorants that are safe and normally enter the body through absorption such as β-carotene. Representative examples of colored nutrients (under visible light) include fat soluble vitamins such as Vitamin A (yellow); water soluble vitamins such as vitamin B12 (pink-red) and folic acid (yellow-orange); carotenoids such as β-carotene (yellow-purple) and lycopene (red). Other examples of coloring agents include natural product (berry and fruit) extracts such as anthrocyanin (purple) and saffron extract (dark red). The coloring agent may be a fluorescent or phosphorescent compound such as α- tocopherolquinol (a vitamin E derivative) or L-tryptophan.

In one aspect, the compositions of the present invention include one or more coloring agents, also referred to as dyestuffs, which will be present in an effective amount to impart observable coloration to the composition, e.g., the gel. Examples of coloring agents include dyes suitable for food such as those known as F. D. & C. dyes and natural coloring agents such as grape skin extract, beet red powder, beta carotene, annato, carmine, turmeric, paprika, and so forth. Derivatives, analogues, and isomers of any of the above colored compound also may be used. The method for incorporating a colorant into an implant or therapeutic composition may be varied depending on the properties of and the desired location for the colorant. For example, a hydrophobic colorant may be selected for hydrophobic matrices. The colorant may be incorporated into a carrier matrix, such as micelles. Further, the pH of the environment may be ^controlled to further control the color and intensity.

In one aspect, the compositions of the present invention include one or more preservatives or bacteriostatic agents present in an effective amount to preserve the composition and/or inhibit bacterial growth in the composition, for example, bismuth tribromophenate, methyl hydroxybenzoate, bacitracin, ethyl hydroxybenzoate, propyl hydroxybenzoate, erythromycin, chlorocresol, benzalkonium chlorides, and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. In one aspect, the compositions of the present invention include one or more bactericidal (also known as bacteriacidal) agents.

In one aspect, the compositions of the present invention include one or more antioxidants, present in an effective amount. Examples of the antioxidant include sulfites, alpha-tocopherol, beta-carotene and ascorbic acid. Characteristics of Certain Compositions

In certain embodiments, compositions of the present invention may have a stable shelf-life of at least several months and capable of being produced and maintained under sterile conditions. The composition may be sterile either by preparing them under aseptic environment and/or they may be terminally sterilized using methods known in the art. A combination of both of these methods may also be used to prepare the composition in the sterile form. Sterilization may also occur by terminally using gamma radiation or electron beam sterilization methods.

In one aspect, the compounds and compositions of the present invention are sterile. Many pharmaceuticals are manufactured to be sterile and this criterion is defined by the USP XXII <1211>. The term "USP" refers to U.S. Pharmacopeia (see www.usp.org, Rockville, MD). Sterilization in this embodiment may be accomplished by a number of means accepted in the industry and listed in the USP XXII <1211>, including gas sterilization, ionizing radiation or, when appropriate, filtration. Sterilization may be maintained by what is termed asceptic processing, defined also in USP XXII <1211>. Acceptable gases used for gas sterilization include ethylene oxide. Acceptable radiation types used for ionizing radiation methods include gamma, for instance from a cobalt 60 source and electron beam. A typical dose of gamma radiation is 2.5 MRad. Filtration may be accomplished using a filter with suitable pore size, for example 0.22 μm and of a suitable material, for instance polytetrafluoroethylene (e.g., TEFLON from E. I. DuPont De Nemours and Company, Wilmington, DE).

In another aspect, the compositions of the present invention are contained in a container that allows them to be used for their intended purpose, i.e., as a pharmaceutical composition. Properties of the container that are important are a volume of empty space to allow for the addition of a constitution medium, such as water or other aqueous medium, e.g., saline, acceptable light transmission characteristics in order to prevent light energy from damaging the composition in the container (refer to USP XXII <661>), an acceptable limit of extractables within the container material (refer to USP XXII), an acceptable barrier capacity for moisture (refer to USP XXII <671>) or oxygen. In the case of oxygen penetration, this may be controlled by including in the container, a positive pressure of an inert gas, such as high purity nitrogen, or a noble gas, such as argon.

Typical materials used to make containers for pharmaceuticals include USP Type I through III and Type NP glass (refer to USP XXII <661>), polyethylene, TEFLON, silicone, and gray-butyl rubber. For parenterals, USP Types I to III glass and polyethylene are preferred.

Within certain aspects of the present invention, the therapeutic composition should be biocompatible, and release one or more fibrosis- inhibiting agents and/or anti-infective agents over a period of several hours, days, or, months. As described above, "release of an agent" refers to any statistically significant presence of the agent, or a subcomponent thereof, which has disassociated from the compositions and/or remains active on the surface of (or within) the composition. The compositions of the present invention may release the anti-scarring agent at one or more phases, the one or more phases having similar or different performance (e.g., release) profiles. The therapeutic agent may be made available to the tissue at amounts which may be sustainable, intermittent, or continuous; in one or more phases; and/or rates of delivery; effective to reduce or inhibit any one or more components of fibrosis (or scarring), including: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue).

Thus, release rate may be programmed to impact fibrosis (or scarring) by releasing an anti-scarring agent at a time such that at least one of the components of fibrosis is inhibited or reduced. Moreover, the predetermined release rate may reduce agent loading and/or concentration as well as potentially providing minimal drug washout and thus, increases efficiency of drug effect. Any one of the at least one anti-scarring agents may perform one or more functions, including inhibiting the formation of new blood vessels (angiogenesis), inhibiting the migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), inhibiting the deposition of extracellular matrix (ECM), and inhibiting remodeling (maturation and organization of the fibrous tissue). In one embodiment, the rate of release may provide a sustainable level of the anti- scarring agent to the susceptible tissue site. In another embodiment, the rate of release is substantially constant. The rate may decrease and/or increase over time, and it may optionally include a substantially non-release period. The release rate may comprise a plurality of rates. In an embodiment, the plurality of release rates may include rates selected from the group consisting of substantially constant, decreasing, increasing, substantially non-releasing.

The total amount of anti-scarring agent made available on, in or near the device may be in an amount ranging from about 0.01 μg (micrograms) to about 2500 mg (milligrams). Generally, the anti-scarring agent may be in the amount ranging from 0.01 μg to about 10 μg; or from 10 μg to about 1 mg; or from 1 mg to about 10 mg; or from 10 mg to about 100 mg; or from 100 mg to about 500 mg; or from 500 mg to about 2500 mg.

The total surface amount of anti-scarring agent on, in or near the device may be in an amount ranging from less than 0.01 μg to about 2500 μg per mm2 of device surface area. Generally, the anti-scarring agent may be in the amount ranging from less than 0.01 μg; or from 0.01 μg to about 10 μg; or from 10 μg to about 250 μg; or from 250 μg to about 2500 μg,

The anti-scarring agent that is on, in or near the device may be released from the composition in a time period that may be measured from the time of implantation, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 7 days; from 7 days to about 14 days; from 14 days to about 28 days; from 28 days to about 56 days; from 56 days to about 90 days; from 90 days to about 180 days.

The amount of anti-scarring agent released from the composition as a function of time may be determined based on the in vitro release characteristics of the agent from the composition. The in vitro release rate may be determined by placing the anti-scarring agent within the composition or device in an appropriate buffer such as 0.1 M phosphate buffer (pH 7.4)) at 370C. Samples of the buffer solution are then periodically removed for analysis by HPLC, and the buffer is replaced to avoid any saturation effects.

Based on the in vitro release rates, the release of anti-scarring agent per day may range from an amount ranging from about 0.01 μg (micrograms) to about 2500 mg (milligrams). Generally, the antwscarring agent that may be released in a day may be in the amount ranging from 0.01 μg to about 10 μg; or from -10 μg to about 1 mg; or from 1 mg to about 10 mg; or from 10 mg to about 100 mg; or from 100 mg to about 500 mg; or from 500 mg to about 2500 mg.

In one embodiment, the anti-scarring agent is made available to the susceptible tissue site in a programmed, sustained, and/or controlled manner which results in increased efficiency and/or efficacy. Further, the release rates may vary during either or both of the initial and subsequent release phases. There may also be additional phase(s) for release of the same substance(s) and/or different substance(s).

Delivery of Therapeutic Agents or Compositions

The present invention provides various compositions which can be used to inhibit fibrosis and/or infection of tissue in the vicinity of a treatment site (e.g., a surgical site). Within various embodiments, fibrosis and/or infection is inhibited by local or systemic release of specific pharmacological agents that become localized at the site or intervention. Within other embodiments, fibrosis and/or infection can be inhibited by local or systemic release of specific pharmacological agents that become localized adjacent to a device or implant that has been introduced into a host. In certain embodiments, compositions are provided which inhibit fibrosis in and around an implanted device, or prevent "stenosis" of a device/implant in situ, thus enhancing the efficacy. In other embodiments, anti-infective compositions are provided which inhibit or prevent infection in and around an implanted device.

There are numerous methods available for optimizing delivery of the therapeutic agent to the site of the intervention. Several of these are described below.

Systemic, Regional and Local Delivery of Therapeutic Agents A variety of drug-delivery technologies are available for systemic, regional and local delivery of anti-infective and/or anti-fibrosis therapeutic agents.

For systemic delivery of therapeutic agents, several routes of administration would be suitable to provide systemic exposure of the therapeutic agent, including: (a) intravenous, (b) oral, (c) subcutaneous, (d) intraperitoneal, (e) intrathecal, [T) inhaled and intranasal, (g) sublingual or transbuccal, (h) rectal, (i) intravaginal, (j) intra-arterial, (k) intracardiac, (I) transdermal, (m) intraocular and (n) intramuscular. The therapeutic agent may be administered as a sustained low dose therapy to prevent disease progression, prolong disease remission, or decrease symptoms in active disease. Alternatively, the therapeutic agent may be administered in higher doses as a "pulse" therapy to induce remission in acutely active disease. The minimum dose capable of achieving these endpoints can be used and can vary according to patient, severity of disease, formulation of the administered agent, potency and tolerability of the therapeutic agent, and route of administration. For regional and local delivery of therapeutic agents, several techniques would be suitable to achieve preferentially elevated levels of therapeutic agents in the vicinity of the area to be treated. These include: (a) using drug-delivery catheters and/or a syringe and needle for local, regional or systemic delivery of ftbrosis-inhibiting agents to the tissue surrounding the device or implant (typically, drug delivery catheters are advanced through the circulation or inserted directly into tissues under radiological guidance until they reach the desired anatomical location; the fibrosis-inhibiting agent can then be released from the catheter lumen in high local concentrations in order to deliver therapeutic doses of the drug to the tissue surrounding the device or implant); (b) drug localization techniques such as magnetic, ultrasonic or MRI-guided drug delivery; (c) chemical modification of the therapeutic drug or formulation designed to increase uptake of the agent into damaged tissues (e.g., antibodies directed against damaged or healing tissue components such as macrophages, neutrophils, smooth muscle cells, fibroblasts, extracellular matrix components, neovascular tissue); (d) chemical modification of the therapeutic drug or formulation designed to localize the drug to areas of bleeding or disrupted vasculature; and/or (e) direct injection, for example subcutaneous, intramuscular, intra-articular, etc, of the therapeutic agent, for example, under normal or endoscopic vision.

Infiltration of Therapeutic Agents into the Tissue Surrounding a

Device or Implant

Alternatively, the tissue cavity or surgical pocket into which a device or implant is placed can be treated with an anti-infective and/or fibrosis-inhibiting therapeutic agent or a composition that comprises an anti- infective and/or fibrosis-inhibiting therapeutic agent prior to, during, or after the procedure. This can be accomplished in several ways including: (a) topical application of the agent into the anatomical space or surface where the device will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the agent over a period ranging from several hours to several weeks. Compositions that can be used for this application include, e.g., fluids, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release a therapeutic agent into the region where the device or implant will be implanted); (b) microparticulate forms of the therapeutic agent are also useful for directed delivery into the implantation site; (c) sprayable collagen-containing formulations such as COSTASIS and crosslinked derivatized poly(ethylene glycol) -collagen compositions (described, e.g., in U.S. Patent Nos. 5,874,500 and 5,565,519 and referred to herein as "CT3" (both from Angiotech Pharmaceuticals, Inc., Canada), either alone, or loaded with a therapeutic agent, applied to the implantation site (or the implant/device surface); (d) sprayable PEG-containing formulations such as COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), SPRAYGEL or DURASEAL (both from Confluent Surgical, Inc., Boston, MA), either alone, or loaded with a. therapeutic agent, applied to the implantation site (or the implant/device surface); (e) fibrin-containing formulations such as FLOSEAL or TISSEEL (both from Baxter Healthcare Corporation, Fremont, CA), applied to the implantation site (or the implant/device surface); (f) hyaluronic acid-containing formulations such as RESTYLANE or PERLANE (both from Q-Med AB, Sweden), HYLAFORM (Inamed Corporation (Santa Barbara, CA)), SYNVISC (Biomatrix, Inc., Ridgefield, NJ), SEPRAFILM or SEPRACOAT (both from Genzyme Corporation, Cambridge, MA) loaded with a therapeutic agent applied to the implantation site (or the implant/device surface); (g) polymeric gels for surgical implantation such as REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOGEL (Baxter Healthcare Corporation) loaded with a therapeutic agent applied to the implantation site (or the implant/device surface); (h) orthopedic "cements" used to hold prostheses and tissues in place with a therapeutic agent applied to the implantation site (or the implant/device surface); (i) surgical adhesives containing cyanoacrylates such as DERMABOND (Johnson & Johnson, Inc., New Brunswick, NJ), INDERMIL (U.S. Surgical Company, Norwalk, CT), GLUSTITCH (Blacklock Medical Products Inc., Canada), TISSUMEND Il (Veterniary Products Laboratories,, Phoenix, AZ), VETBOND (3M Company, St. Paul, MN), HISTOACRYL BLUE (Davis & Geek, St. Louis, MO) and ORABASE SMOOTHE-N-SEAL Liquid Protectant (Colgate-Palmolive Company, New York, NY) loaded with a therapeutic agent, applied to the implantation site (or the implant/device surface); and/or (j) protein-based sealants or adhesives such as BIOGLUE (Cryolife, Inc.) and TISSUEBOND (TissueMed, Ltd.) loaded with a therapeutic agent, applied to the implantation site (or the implant/device surface).

An exemplary polymeric matrix which can be used to help prevent the formation of fibrous tissue, either alone or in combination with a fibrosis inhibiting agent/composition, is formed from reactants comprising either one or both of pentaerythritol poly(ethylene glycol)ether tetra- sulfhydryl] (4-armed thiol PEG, which includes structures having a linking group(s) between a sulfhydryl group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra- succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents. Another preferred composition comprises either one or both of pentaerythritol poly(ethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking group(s) between an amino group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents. Chemical structures for these reactants are shown in, e.g., U.S. Patent 5,874,500. Optionally, collagen or a collagen derivative (e.g., methylated collagen) is added to the poly(ethylene glycol)-containing reactant(s) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a stand-alone composition to help prevent the formation of fibrous tissue.

Additional descriptions of infiltrating tissues around medical devices or implants with the therapeutic agents of the present invention are provided below in connection of using therapeutic agents or pharmaceutical compositions of the present invention.

Delivery of Theraputic Agents via Medical Devices or Implants

In certain embodiments, the therapeutic agents or compositions of the present invention may be delivered via medical devices or implants, for example, as a coating or otherwise a component of the devices or implants. The therapeutic agents may, or may not, be released from the devices or implants.

A medical device or implants useful in delivering the therapeutic agents may be made by (a) directly affixing to the implant or device a desired therapeutic agent or composition containing the therapeutic agent (e.g., by either spraying or electrospraying the medical implant with a drug and/or carrier (polymeric or non-polymeric)-drug composition to create a film and/or coating on all, or parts of the internal or external surface of the device; by dipping the implant or device into a drug and/or carrier (polymeric or non-polymeric)-drug solution to coat all or parts of the device or implant; or by other covalent or noncovalent attachment of the therapeutic agent to the device or implant surface); (b) by coating the medical device or implant with a substance such as a hydrogel which either contains or which will in turn absorb the desired fibrosis-inhibiting agent or composition; (c) by interweaving a "thread" composed of, or coated with, the fibrosis-inhibiting agent into the medical implant or device {e.g., a polymeric strand composed of materials that inhibit fibrosis (e.g., paclitaxel, mitoxantrone, doxorubicin, epithilone B, etoposide, TAXOTERE, Tubercidin, vinblastine, geldanamycin, simvastatin, halifuginone, sirolimus, everolimus, mycophenolic acid, 1- alpha-25 dihydroxy vitamin D3, bay 11-7082, SB202190, sulconizole polymerized drug compositions) or polymers which release a fibrosis- inhibiting agent from the thread}; (d) by covering all, or portions of the device or implant with a sleeve, cover, electrospun fabric or mesh containing a fibrosis-inhibiting agent (i.e., a covering comprised of a fibrosis-inhibiting agent - paclitaxel, mitoxantrone, doxorubicin, epithilone B, etoposide, TAXOTERE, tubercidin, vinblastine, geldanamycin, simvastatin, halifuginone, sirolimus, everolimus, mycophenolic acid, 1-alpha-25 dihydroxy vitamin D3, Bay 11-7082, SB202190, sulconizole or polymerized compositions containing fibrosis-inhibiting agents); (e) constructing all, or parts of the device or implant itself with the desired agent or composition (e.g., paclitaxel, mitoxantrone, doxorubicin, epithilone B, etoposide, TAXOTERE, tubercidin, vinblastine, geldanamycin, simvastatin, halifuginone, sirolimus, everolimus, mycophenolic acid, 1-alpha-25 dihydroxy vitamin D3, bay 11-7082, SB202190, sulconizole or polymerized compositions olfibrosis-inhibiting agents); (f) otherwise impregnating the device or implant with the desired fibrosis-inhibiting agent or composition; (g) composing all, or parts, of the device or implant from metal alloys that inhibit fibrosis; (h) constructing all, or parts of the device or implant itself from a degradable or non-degradable polymer that releases one or more fibrosis-inhibiting agents; (i) utilizing specialized multi-drug releasing medical device systems (for example, U.S. Patent. Nos. 6,527,799; 6,293,967; 6,290,673; 6241762, U.S. Application Publication Nos. 2003/0199970A1 and 2003/0167085A1 , and PCT Publication WO 03/015664) to deliver fibrosis-inhibiting agents alone or in combination.

Additional descriptions of making or using various medical devices or implants that comprise the therapeutic agents of the present invention are provided below in connection with using the therapeutic agents and pharmaceutical compositions of the present invention. Uses of Therapeutic Agents and Pharmaceutical Compositions

The compositions of the present invention can be used in a variety of different applications. For example, the compositions may be used for (a) preventing tissue adhesions; (b) treating or preventing inflammatory arthritis; (c) prevention of cartilage loss; (d) treating or preventing hypertrophic scars and keloids; (e) treating or preventing vascular disease; (f) combining with medical implants or devices, and (g) infiltrating tissues around medical devices or implants. A more detailed description of several specific applications is given below.

(a) Adhesion Preventions

The present invention provides compositions for use in the prevention of adhesions (e.g., surgical adhesions). The compositions may include one or more therapeutically active agents (e.g., anti-scarring agents), which provide pharmacological alteration of cellular and/ or non- cellular processes involved in the development and/or progression of surgical adhesions. Therapeutically active agents are described that can reduce surgical adhesions by inhibiting the formation of fibrous or scar tissue. In another aspect, the present invention provides surgical adhesion barriers that include an anti-scarring agent or a composition that includes an anti-scarring agent.

Surgical adhesions are abnormal, fibrous bands of scar tissue that can form inside the body as a result of the healing process that follows any open or minimally invasive surgical procedure including abdominal, gynecologic, cardiothoracic, spinal, plastic, vascular, ENT, ophthalmologic, urologic, neuro, or orthopedic surgery. Surgical adhesions are typically connective tissue structures that form between adjacent injured areas within the body. Briefly, localized areas of injury trigger an inflammatory and healing response that culminates in healing and scar tissue formation. If scarring results in the formation of fibrous tissue bands or adherence of adjacent anatomical structures (that should be separate), surgical adhesion formation is said to have occurred. Adhesions can range from flimsy, easily separable structures to dense, tenacious fibrous structures that can only be separated by surgical dissection. While many adhesions are benign, some can cause significant clinical problems and are a leading cause of repeat surgical intervention. Surgery to breakdown adhesions (adhesiolysis) often results in failure and recurrence because the surgical trauma involved in breaking down the adhesion triggers the entire process to repeat itself. Surgical breakdown of adhesions is a significant clinical problem and it is estimated that there were 473,000 adhesiolysis procedures in the US in 2002. According to the Diagnosis-Related Groups (DRGs), the total hospital charges for these procedures is likely to be at least US $10 billion annually.

Since all interventions involve a certain degree of trauma to the operative tissues, virtually any procedure (no matter how well executed) has the potential to result in the formation of clinically significant adhesion formation. Adhesions can be triggered by surgical trauma such as cutting, manipulation,, retraction or suturing, as well as from inflammation, infection (e.g., fungal or mycobacterium), bleeding or the presence of a foreign body. Surgical trauma may also result from tissue drying, ischemia, or thermal injury. Due to the diverse etiology of surgical adhesions, the potential for formation exists regardless of whether the surgery is done in a so-called minimally invasive fashion (e.g., catheter-based therapies, laparoscopy) or in a standard open technique involving one or more relatively large incisions. Although a potential complication of any surgical intervention, surgical adhesions are particularly problematic in Gl surgery (causing bowel obstruction), gynecological surgery (causing pain and/or infertility), tendon repairs (causing shortening and flexion deformities), joint capsule procedures (causing capsular contractures), and nerve and muscle repair procedures (causing diminished or lost function).

Surgical adhesions may cause various, often serious and unpredictable clinical complications; some of which manifest themselves only years after the original procedure was completed. Complications from surgical adhesions are a major cause of failed surgical therapy and are the leading cause of bowel obstruction and infertility. Other adhesion-related complications include chronic back or pelvic pain, intestinal obstruction, urethral obstruction and voiding dysfunction. Relieving the post-surgical complications caused by adhesions generally requires another surgery. However, the subsequent surgery is further complicated by adhesions formed as a result of the previous surgery. In addition, the second surgery is likely to result in further adhesions and a continuing cycle of additional surgical complications.

The placement of medical devices and implants also increases the risk that surgical adhesions will occur. In addition to the above mechanisms, an implanted device can trigger a "foreign body" response where the immune system recognizes the implant as foreign and triggers an inflammatory reaction that ultimately leads to scar tissue formation. A specific form of foreign body reaction in response to medical device placement is complete enclosure ("walling off') of the implant in a capsule of scar tissue (encapsulation). Fibrous encapsulation of implanted devices and implants can complicate any procedure, but breast augmentation and reconstruction surgery, joint replacement surgery, hernia repair surgery, artificial vascular graft surgery, stent placement, and neurosurgery are particularly prone to this complication. In each case, the implant becomes encapsulated by a fibrous connective tissue capsule which compromises or impairs the function of the surgical implant (e.g., breast implant, artificial joint, surgical mesh, vascular graft, stent or dural patch).

Adhesions generally begin to form within the first several days after surgery. Generally, adhesion formation is an inflammatory reaction in which factors are released, increasing vascular permeability and resulting in fibrinogen influx and fibrin deposition. This deposition forms a matrix that bridges the abutting tissues. Fibroblasts accumulate, attach to the matrix, deposit collagen and induce angiogenesis. If this cascade of events can be prevented within 4 to 5 days following surgery, then adhesion formation may be inhibited.

Various modes of adhesion prevention have been examined, including (1) prevention of fibrin deposition, (2) reduction of local tissue inflammation and (3) removal of fibrin deposits. Fibrin deposition is prevented through the use of physical barriers that are either mechanical or comprised of viscous solutions. Barriers have the added advantage of physically preventing adjacent tissues from contacting each other and thereby reducing the probability that they will scar together. Although many investigators and commercial products utilize adhesion prevention barriers, a number of technical difficulties exist and significant failure rates have been reported. Inflammation is reduced by the administration of drugs such as corticosteroids and non-steroidal anti-inflammatory drugs. However, the results from the use of these drugs in animal models have not been encouraging due to the extent of the inflammatory response and dose restriction due to systemic side effects. Finally, the removal of fibrin deposits has been investigated using proteolytic and fibrinolytic enzymes. A potential complication to the clinical use of these enzymes is the possibility for post-surgical excessive bleeding (surgical hemostasis is critical for procedural success).

Numerous polymeric compositions for use in the prevention of surgical adhesions (e.g., surgical adhesion barriers) may be used in the practice of the invention, either alone, or in combination with one or more anti-scarring agents. It should be noted that certain polymeric compositions can themselves help prevent the formation of fibrous tissue at a surgical site. In certain embodiments, the polymer composition can form a barrier between the tissue surfaces or organs.

For example, the surgical adhesion barrier may be coated onto tissue surfaces and may be composed of an aqueous solution of a hydrophilic, polymeric material (e.g., polypeptides or polysaccharide) having greater than 50,000 molecular weight and a concentration range of 0.01% to 15% by weight. See e.g., U.S. Patent No. 6,464,970. The surgical adhesion barrier may be a crosslinkable system with at least three reactive compounds each having a polymeric molecular core with at least one functional group. See e.g., U.S. Patent No. 6,458,889. The surgical adhesions barrier may be composed of a non-gelling polyoxyalkylene composition with or without a therapeutic agent. See e.g., U.S. Patent No. 6,436,425. The surgical adhesions barrier may be composed of an anionic polymer having an acid sulfate and sulfur content greater than 5% which acts to inhibit monocyte or macrophage invasion. See e.g., U.S. Patent No. 6,417,173. The surgical adhesions barrier may be an aqueous composition including a surfactant, pentoxifylline and a polyoxyalkylene polyether. See e.g., U.S. Patent No. 6,399,624. The surgical adhesions barrier may be composed by crosslinking two synthetic polymers, one having nucleophilic groups and the other having electrophilic groups, such that they form a matrix that may be used to incorporate a biologically active compound. See e.g., U. S. Patent Nos. 6,323,278; 6,166,130; 6,051 ,648 and 5,874,500. The surgical adhesion barrier may be composed of hyaluronic acid compositions such as those described in U.S. Patents Nos. 6,723,709; 6,531 ,147; and 6,464,970. The surgical adhesions barrier may be a polymeric tissue coating which is formed by applying a polymerization initiator to the tissue and then covering it with a water-soluble macromer that is polymerizable using free radical initiators under the influence of UV light. See e.g., U.S. Patent Nos. 6,177,095 and 6,083,524. The surgical adhesions barrier may be composed of fluent prepolymeric material that is emitted to the tissue surface and then exposed to activating energy in situ to initiate conversion of the applied material to non-fluent polymeric form. See e.g., U.S. Patent Nos. 6,004,547 and 5,612,050. The surgical adhesions barrier may be a hydrogel-forming, self-solvating, absorbable polyester copolymers capable of selective, segmental association into compliant hydrogels mass upon contact with an aqueous environment. See e.g., U.S. Patent No. 5,612,052. The surgical adhesions barrier may be an anionic polymer effective to inhibit cell invasion or fibrosis (e.g., dermatan sulfate, dextran sulfate, pentosan polysulfate, or alginate), and a pharmaceutically effective carrier, in which the carrier may be semi-solid. See e.g., U.S. Patent Nos. 6,756,362; 6,127,348 and 5,994,325. The surgical adhesions barrier may be an acidified hydrogel comprising a carboxypolysaccharide and a polyether having a pH in the range of about 2.0 to about 6.0. See e.g., U.S. Patent No. 6,017,301. The surgical adhesions barrier may be composed of dextran sulfate having a molecular weight about 40,000 to 500,000 Daltons which is used to inhibit neurite outgrowth. See e.g., U.S. Patent No. 5,705,178. The surgical adhesions barrier may be a fragmented biocompatible hydrogel which is at least partially hydrated and is substantially free from an aqueous phase, wherein said hydrogel comprises gelatin and will absorb water when delivered to a moist tissue target site. See e.g., U.S. Patent No. 6,066,325. The surgical adhesions barrier may be a water-soluble, degradable macromer that is composed of at least two-crosslinkable substituents that may -crosslink to other macromers at a localized site when under the influence of a polymerization initiator. See e.g., U.S. Patent No. 6,465,001. The surgical adhesions barrier may be a biocompatible adhesive composition comprising at least one alkyl ester cyanoacrylate monomer and a polymerization initiator or accelerator. See e.g., U.S. Patent No. 6,620,846.

In one embodiment, the polymers that can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8). The fibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS-derivatized polyethylene glycol, the acidic solution or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, the acidic solution and/or the basic buffer. Secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. Degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta- butyrolactone, gamma-butyrolactone, gamma-valerolactone, y- decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X (where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator).

In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis-inhibiting agent may then be applied to the coated tissue. The fibrosis-inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. Secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma- caprolactone, hydroxyvaleric acid, hydroxy butyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ-decanolactone, δ- decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan- 2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X (where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG-PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof. A preferred polymeric matrix which can be used to help prevent the formation of fibrous tissue, either alone or in combination with a fibrosis inhibiting agent/composition, is formed from reactants comprising either one or both of pentaerythritol poly(ethylene glycol)ether tetra- sulfhydryl] (4-armed thiol PEG, which includes structures having a linking group(s) between a sulfhydryl group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra- succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents. Another preferred composition comprises either one or both of pentaerythritol poly(ethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking group(s) between an amino group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents. Chemical structures for these reactants are shown in, e.g., U.S. Patent 5,874,500. Optionally, collagen or a collagen derivative (e.g., methylated collagen) is added to the poly(ethylene glycol)-containing reactant(s) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a stand-alone composition to help prevent the formation of fibrous tissue.

Surgical adhesion barriers, which may be combined with one or more anti-scarring agents according to the present invention, also include commercially available products. Examples of surgical adhesion barrier compositions into which a fibrosis agent can be incorporated include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3 (Angiotech Pharmaceuticals, Inc., Canada); (b) sprayable PEG-containing formulations such as COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), SPRAYGEL or DURASEAL (both from Confluent Surgical, Inc., Boston, MA) or FOCALSEAL (Genzyme Corporation, Cambridge, MA); (c) hyaluronic acid-containing formulations such as RESTYLANE or PERLANE (both from Q-Med AB, Sweden), HYLAFORM (Inamed Corporation, Santa Barbara, CA), SYNVISC (Biomatrix, Inc., Ridgefield, NJ), SEPRAFILM or SEPRACOAT (both from Genzyme Corporation), (d) fibrinogen-containing formulations such as FLOSEAL or TISSEAL (both from Baxter Healthcare Corporation, Fremont, CA); (e) polymeric gels such as REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOWGEL (Baxter Healthcare Corporation, Deerfield, IL), (f) surgical adhesives containing cyanoacrylates such as DERMABOND (Johnson & Johnson, Inc., New Brunswick, NJ), INDERMIL (U.S. Surgical Company, Norwalk, CT), GLUSTITCH (Blacklock Medical Products Inc., Canada), TISSUMEND (Veterinary Products Laboratories, Phoenix, AZ), VETBOND (3M Company, St. Paul, MN), HISTOACRYL BLUE (Davis & Geek, St. Louis, MO) and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT (Colgate-Palmolive Company, New York, NY); (g) dextran sulfate gels such as the ADCON range of products (available from Wright Medical Technology, Inc. Arlington, TN), (h) lipid based compositions such as ADSURF (Britannia Pharmaceuticals Ltd., United Kingdom) and (j) film compositions such as INTERCEED (Ethicon, Inc., Somerville, NJ) and HYDROSORB (MacroPore Biosurgery, Inc., San Diego, CA /Medtronic Sofamor Danek, Memphis, TN).

For greater clarity, several specific applications and treatments will be described in greater detail including:

i) Adhesion Prevention in Spinal and Neurosurgical Procedures

Back pain is the number one cause of healthcare expenditures in the United States and accounts for over $50 billion in costs annually ($100 billion worldwide). Over 12 million people in the U.S. have some form of degenerative disc disease (DDD) and 10% of them (1.2 million) will require surgery to correct their problem.

In healthy individuals, the vertebral column is composed of vertebral bone plates separated by intervertebral discs that form strong joints and absorb spinal compression during movement. The intervertebral disc is comprised of an inner gel-like substance called the nucleus pulposus which is surrounded by a tough fibrocartilagenous capsule called the annulus fibrosis. The nucleus pulposus is composed of a loose framework of collagen fibrils and connective tissue cells (resembling fibroblasts and chondrocytes) embedded in a gelatinous matrix of glycosaminoglycans and water. The annulus fibrosus is composed of numerous concentric rings of fibrocartilage that anchor into the vertebral bodies. The most common cause of DDD occurs when tears in the annulus fibrosis create an area of localized weakness that allow bulging, herniation or sequestration of the nucleus pulposis and annulus fibrosis into the spinal canal and/or spinal foramena. The bulging or herniated disc often compresses nerve tissue such as spinal cord fibers or spinal cord nerve root fibers. Pressure on the spinal cord or nerve roots from the damaged intervertebral disc results in neuronal dysfunction (numbness, weakness, tingling), crippling pain, bowel or bladder disturbances and can frequently cause long-term disability. Although many cases of DDD will spontaneously resolve, a significant number of patients will require surgical intervention in the form of minimally invasive procedures, microdiscectomy, major surgical resection of the disc, spinal fusion (fusion of adjacent vertebral bone plates using various techniques and devices), and/or implantation of an artificial disc. The present invention provides for the application of an anti-adhesion or anti- fibrosis agent inihe surgical management of DDD.

Spinal disc removal is mandatory and urgent in cauda equine syndrome when there is a significant neurological deficit; particularly bowel or bladder dysfunction. It is also performed electively to relieve pain and eliminate lesser neurological symptoms. The spinal nerve roots exit the spinal canal through bony spinal foramena (a bony opening between the vertebra above and the vertebra below) that is a common site of nerve entrapment. To gain access to the spinal foramen during back surgeries, vertebral bone tissue is often resected; a process known as laminectomy.

In open surgical resection of a ruptured lumbar disc or entrapped spinal nerve root (laminectomy) the patient is placed in a modified kneeling position under general anesthesia. An incision is made in the posterior midline and the tissue is dissected away to expose the appropriate interspace; the ligamentum flavum is dissected and in some cases portions of the bony lamina are removed to allow adequate visualization. The nerve root is carefully retracted away to expose the herniated fragment and the defect in the annulus. Typically, the cavity of the disc is entered from the tear in the annulus and the loose fragments of the nucleus pulposus are removed with pituitary forceps. Any additional fragments of disc sequestered inside or outside of the disc space are also carefully removed and the disc space is forcefully irrigated to remove to remove any residual fragments. If tears are present in the dura, the dura is closed with sutures that are often augmented with fibrin glue. The tissue is then closed with absorbable sutures.

Microlumbar disc excision (microdiscectomy) can be performed as an outpatient procedure and has largely replaced laminectomy as the intervention of choice for herniated discs or root entrapment. A one inch incision is made from the spinous process above the disc affected to the spinous process below. Using an operating microscope, the tissue is dissected down to the ligamentum flavum and bone is removed from the lamina until the nerve root can be clearly identified. The nerve root is carefully retracted and the tears in the annulus are visualized under magnification. Microdisc forceps are used to remove disc fragments through the annular tear and any sequestered disc fragments are also removed. As with laminectomy, the disc space is irrigated to remove any disc fragments, any dural tears are repaired and the tissue is closed with absorbable sutures. It should be noted that anterior (abdominal) approaches can also be used for both open and endoscopic lumbar disc excision. Cervical and thoracic disc excisions are similar to lumbar procedures and can also be performed from a posterior approach (with laminectomy) or as an anterior discectomy with fusion.

Back surgeries, such as laminectomies, discectomies and microdiscectomies, often leave the spinal dura exposed and unprotected. As a result, scar tissue frequently forms between the dura and the surrounding tissue. This scar is formed from the damaged erector spinae muscles that overlay the laminectomy site. The result is adhesion development between the muscle tissue and the fragile dura, thereby, reducing mobility of the spine and the nerve roots that exit from it, leading to pain, persistent neurological symptoms and slow post-operative recovery. Similarly, adhesions that occur in the epidural and dural tissue cause complications in spinal injury (e.g., compression and crush injuries) cases. In addition, scar and adhesion formation within the dura and around nerve roots has been implicated in rendering subsequent (revision and repeat) spine operations technically more difficult to perform.

To circumvent adhesion development, a scar-reducing barrier may be inserted between the dural sleeve and the paravertebral musculature post-laminectomy. Alternatively (or in addition to this), the adhesion barrier, either alone or containing a fibrosis-inhibiting agent, can be coated on (or infiltrated into the tissues around) the spinal nerve as it exits the spinal canal and traverses the space between the bony vertebra (Ae., the laminectomy site). This reduces cellular and vascular invasion into the epidural space from the overlying muscle and exposed cancellous bone and j.hus,_reduc.es the complications associated with scarring of the canal housing, spinal chord and/or nerve roots. In microdiscectomy procedures it is important that the barrier be deliverable as a spray, gel or fluid material that can be administered via the delivery port of an endoscope. Once again, the adhesion barrier, either alone or containing a fibrosis-inhibiting agent, can be sprayed onto the spinal nerve (or infiltrated into the tissues around it) as it exits the spinal canal and traverses the space between the bony vertebra (i.e., the laminectomy site). The present invention discloses barrier compositions, used either alone or combined with a fibrosis-inhibiting agent, that can be delivered during surgical disc resection and microdiscectomy either directly, using specialized delivery catheters, via an endoscope, or through a needle or other applicator. When dural defects are present, the fibrosis-inhibiting agent will assist in the healing of the dura and prevent complications such as blockage of CSF flow.

In another aspect, adhesion formation may be associated with a neurosurgical (brain) procedure. Neurosurgical procedures are fraught with potentially severe post-operative complications that are often attributed to surgical trauma and unwanted fibrosis or gliosis (gliosis is scar tissue formation in the brain as a result of glial cell activity). Increased intracranial bleeding, infection, cerebrospinal fluid leakage and pain are but some complications resulting from adhesions following neurosurgery. For example, if scar tissue interrupts the normal circulation of cerebrospinal fluid (CSF) following brain or spinal surgery, the fluid can accumulate and exert pressure on surrounding tissues (causing increased intracranial pressure) leading to severe complications (such as uncal herneation, brain damage and/or death). Here the adhesion barrier alone, or combined with a fibrosis- inhibiting agent, can be used to prevent excessive dural scarring and adhesion formation in a variety of neurosurgical procedures.

There are numerous compositions that may be used alone or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent or an anti- infective agent), applied to a spinal or neurosurgical site (or to an implant surface placed in the spine - such as an artificial disc, rods, screws, spinal cages, drug-delivery pumps, neurostimulation devices; or to an implant placed in the brain - such as drains, shunts, drug-delivery pumps, neurostimulation devices) for the prevention of surgical adhesions in neurosurgical procedures. It should be noted that certain polymeric compositions can themselves help prevent the formation of fibrous tissue at a spinal or neurosurgical site. These compositions are particularly useful for the practice of this embodiment, either alone, or in combination with a fibrosis-inhibiting composition.

Various polymeric compositions can be infiltrated into the spinal or neurosurgical site (e.g., onto tissue at the surgical site or in the vicinity of the implant-tissue interface) with or without an additional therapeutic agent for the prevention of surgical adhesions.

In one embodiment, the polymers that can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8). The antifibrosisfibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, the acidic solution or the basic buffer.

In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, the acidic solution and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X (where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) {e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta- butyrolactone, gamma-butyrolactone, gamma-valerolactone, y- decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one (e.g., PLG-PEG-PLG) and R is a multifunctional initiator).

In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis-inhibiting agent may then be applied to the coated tissue. The fibrosis-inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - polypropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma- caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ-decanolactone, δ- decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan- 2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, Y-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG-PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof. A preferred polymeric matrix which can be used to help prevent the formation of fibrous tissue that leads to surgical adhesions, either alone or in combination with a fibrosis inhibiting agent/composition, is formed from reactants comprising either one or both of pentaerythritol poly(ethylene glycol)ether tetra-sulfhydryl] (4-armed thiol PEG, which includes structures having a linking group(s) between a sulfhydryl group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4-armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents. Another preferred composition comprises either one or both of pentaerythritol poly(ethylene glycol)ether tetra-amino] (4-armed amino PEG, which includes structures having a linking group(s) between an amino group(s) and the terminus of the polyethylene glycol backbone) and pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate] (4- armed NHS PEG, which again includes structures having a linking group(s) between a NHS group(s) and the terminus of the polyethylene glycol backbone) as reactive reagents. Chemical structures for these reactants are shown in, e.g., U.S. Patent 5,874,500. Optionally, collagen or a collagen derivative (e.g., methylated collagen) is added to the poly(ethylene glycol)-containing reactant(s) to form a preferred crosslinked matrix that can serve as a polymeric carrier for a therapeutic agent or a stand-alone composition to help prevent the formation of fibrous tissue.

Other examples of polymeric compositions that can be infiltrated into the spinal or neurosurgical site (e.g., onto tissue at the surgical site or in the vicinity of the implant-tissue interface) with or without an additional fibrosis-inhibiting (and/or an anti-infective) therapeutic agent for the prevention of surgical adhesions, include a variety of commercial products. For example, Confluent Surgical, Inc. makes their DURASEAL which is a synthetic hydrogel designed to augment sutured dura closures following cranial surgical procedures. Products that are being developed by Confluent Surgical, Inc. are described in, for example, U.S. Patent No. 6,379,373. FzioMed, Inc. (San Luis Obispo, CA) makes OXIPLEX/SP Gel which is being sold as an adhesion barrier for spine surgery. OXIPLEX/SP Gel is being used for the reduction of pain and radiculopathy in laminectomy, laminotomy and discectomy surgeries. Products being developed by FzioMed, Inc. are described in, for example, U.S. Patent Nos. 6,566,345 and 6,017,301. Anika Therapeutics, Inc. (Woburn, MA) is developing INCERT-S for the prevention of internal adhesions or scarring following spinal surgery. INCERT-S is part of a potential family of bioabsorbable, chemically modified hyaluronic acid therapies. Products being developed by Anika Therapeutics, Inc. are described in, for example, U.S. Patent Nos. 6,548,081; 6,537,979; 6,096,727; 6,013,679; 5,502,081 and 5,356,883. Life Medical Sciences, Inc. (Little Silver, NJ) is developing RELIEVE as a bio-resorbable polymer designed to prevent or reduce the formation of adhesions that can follow spinal surgery. Products being developed by Life Medical Sciences, Inc. are described in, for example, U.S. Patent Nos. 6,696,499; 6,399,624; 6,211 ,249; 6,136,333 and 5,711 ,958. Wright Medical Technology, Inc. is selling the ADCON range of products which are dextran sulfate gels originally developed by Gliatech, Inc. (Beachwood, OH) to inhibit postsurgical peridural fibrosis that occurs in posterior lumbar laminectomy or laminotomy procedures where nerve routes are exposed. ADCON provides a barrier between the spinal cord and nerve roots and the surrounding muscle and bone following lumbar spine surgeries. The ADCON range of products may be described in, for example, U.S. Patent Nos. 6,417,173; 6,127,348; 6,083,930; 5,994,325 and 5,705,178.

Other commercially available materials that may be used alone or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent and/or an anti-infective agent), applied to or infiltrated into a spinal or neurosurgical site (or to an implant surface) for the prevention of adhesions include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3; (b) sprayable PEG-containing formulations such as COSEAL, ADHIBIT, FOCALSEAL, or SPRAYGEL; (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL (both from Baxter Healthcare Corporation, Fremont, CA); (d) hyaluronic acid-containing formulations such as RESTYLANE, PERLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT; (e) polymeric gels for surgical implantation such as REPEL or FLOWGEL; (f) surgical adhesives containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT; (h) lipid based compositions such as ADSURF, and G) film compositions such as INTERCEED (Ethicon, Inc., Somerville, NJ) and HYDROSORB (MacroPore Biosurgery, Inc., San Diego, CA /Medtronic Sofamor Danek, Memphis, TN). It should be obvious to one of skill in the art that commercial compositions not specifically cited above as well as next- generation and/or subsequently-developed commercial products are to be anticipated and are suitable for use under the present invention.

As described above, the compositions for the prevention of surgical adhesions can be applied directly or indirectly to the tissue in a spinal or neurosurgical site. The polymeric compositions (either with or without a therapeutic agent) can be administered in any manner described herein. Exemplary methods include either direct application at the time of surgery, with endoscopic, ultrasound, CT, MRI, or fluoroscopic guidance, and/or in conjunction with the placement of a device or implant at the surgical site. Representative examples of devices or implants for use in spinal and neurosurgical procedures includes, without limitation, dural patches, spinal prostheses (e.g., artificial discs, injectable filling or bulking agents for discs, spinal grafts, spinal nucleus implants, intervertebral disc spacers), fusion cages, neurostimulation devices, implantable drug-delivery pumps, shunts, drains, electrodes, and bone fixation devices (e.g., anchoring plates and bone screws). The polymeric composition, with or without a fibrosis-inhibiting agent, may be applied during open or endoscopic procedures: (a) to the surface of the operative site (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after the surgical procedure; (b) to the surface of the tissue surrounding the operative site (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during or after the surgical procedure; (c) by topical application of the composition into an anatomical space (such as the subdural space or intrathecally) at the surgical site (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where the device will be inserted); (d) via percutaneous injection into the tissue in and around the operative site as a solution, as an infusate, or as a sustained release preparation; and/or (e) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used.

In certain applications involving the placement of a medical device or implant, it may be desirable to apply the anti-fibrosis (and/or anti- infective) composition at a site that is adjacent to an implant (preferably near the implant-tissue interface). This can be accomplished during open or endoscopic procedures by applying the polymeric composition, with or without a fibrosis-inhibiting agent: (a) to the implant surface (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) before, during, or after the implantation procedure; (b) to the surface of the adjacent tissue (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) immediately prior to, during, or after implantation of the implant; (c) to the surface of the implant and the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after implantation of the implant; (d) by topical application of the composition into the anatomical space (such as the sudural space or intrathecally) where the implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where the device will be inserted); (e) via percutaneous injection into the tissue surrounding the implant as a solution, as an infusate, or as a sustained release preparation; and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used.

In one aspect, the polymeric composition may be delivered to the tissue (or device/tissue interface) in the form of a spray or gel during open, endoscopic or catheter-based procedures. The fibrosis-inhibiting agent can be incorporated directly into the surgical adhesion barrier or it can be incorporated into a secondary carrier (polymeric or non-polymeric), as described above, that is then incorporated into the adhesion barrier. Examples of polymer compositions that may be in the form of a spray or gel include poly(ethylene glycol)-based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as the final composition or they can be applied as materials that form a crosslinked gel in situ.

In another aspect, an activated polymer is dissolved in a biologically acceptable buffer that has a pH lower that 6.8. The resultant solution is then applied to the desired tissue surface in the presence of a second biologically acceptable buffer that has a pH greater than 7.5. Application of the reaction mixture to the tissue site may be by extrusion, brushing, spraying or by any other convenient means. Following application of the composition to the surgical site, any excess solution may be removed from the surgical site if deemed necessary. At this point in time, the surgical site can be closed using conventional means (e.g., sutures, staples, or a bioadhesive). In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8). The antifibrosisfibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, the acidic solution or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS- derivatized polyethylene glycol, the acidic solution and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one, and block copolymers of the form X-Y1 Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poiyφropylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decano!actone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) {e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one {e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

In yet another aspect, an activated polymer can be applied to the surgical site in the solid state. The activated polymer can react with the tissue surface to which it was applied as the polymer hydrates. A biologically acceptable buffer, with a pH greater than 7.5 can be applied to the tissue before and/or after the solid activated polymer has been applied. In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form. The antifibrosisfibrosis- inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e- caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ~ decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof

ii) Adhesion Prevention in Gynecological Procedures In one aspect, adhesion formation may be associated with a gynecological surgical procedure. The post-operative adhesions occur in 60 to 90% of patients undergoing major gynecologic surgery and represent one of the most common causes of infertility in the industrialized world. Adhesions can form between the ovaries, the fallopian tubes, the bowel or the walls of the pelvis. Fibrous bands can connect to the normally mobile adnexal structures (ovaries and fallopian tubes) to other tissues, causing them to lose mobility, kink or twist. If the adhesions tighten around, constrict or twist the fallopian tubes themselves, they can block the passage of an ovum from the ovaries into and through the fallopian tube leading to infertility. Adhesions around the fallopian tubes can also interfere with sperm transport to the ovum and also cause infertility. Other adhesion- related complications include chronic pelvic pain, dysparunia, urethral obstruction and voiding dysfunction.

Several products are available commercially or under development for the management of gynecological adhesions. Life Medical Sciences, Inc. is producing the products, REPEL, REPEL-CV, RESOLVE and RELIEVE that are in various stages of development and may be used to prevent surgical adhesions in gynecological and other surgeries. Products being developed by Life Medical Sciences, Inc. are described in, for example, U.S. Patent Nos. 6,696,499; 6,399,624; 6,211,249; 6,136,333 and 5,711 ,958. Confluent Surgical, Inc. makes their SPRAYGEL which is a unique sprayable adhesion barrier that is being developed for use in pelvic and intrauterine surgical procedures. Products that are being developed by Confluent Surgical, Inc. are described in, for example, U.S. Patent No. 6,379,373. Closure Medical Corp. (Raleigh, NC) is developing a cyanoacrylate-based internal adhesives that may be used to seal internal surgical incisions or grafts which may be compatible in gynecology and general surgical specialties. Products that are being developed by Closure Medical, Corp. are described in, for example, U.S. Patent Nos. 6,620,846; 6,579,469; 6,565,840; 6,547,467 and 5,981,621.

Other commercially available materials that may be used alone, or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent and/or an anti-infective agent), applied to or infiltrated into a gynecological surgical site (or to the surface of a device or implant) for the prevention of adhesions in open or endoscopic gynecologic surgery include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3; (b) sprayable PEG-containing formulations such as COSEAL, ADHIBIT, FOCALSEAL or DURASEAL; (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL; (d) hyaluronic acid-containing formulations such as RESTYLANE or PERLANE, HYLAFORM, SYNVlSC, SEPRAFILM or SEPRACOAT; (e) polymeric gels for surgical implantation such as FLOWGEL; (f) surgical adhesives containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT; (g) dextran sulfate gels such as the ADCON series of gels; and (h) lipid based compositions such as ADSURF. It should be obvious to one of skill in the art that commercial compositions not specifically cited above as well as next-generation and/or subsequently-developed commercial products are to be anticipated and are suitable for use under the present invention.

Gynecological procedures are performed for a variety of medical conditions including hysterectomy (removal of the uterus), myomectomy (removal of uterine fibroids), endometriosis (ablation procedures), infertility (in vitro fertilization, adhesiolysis), birth control (tubal ligation), reversal of sterilization, pain, dysmennorrhea, dysfunctional uterine bleeding, ectopic pregnancy, ovarian cysts, gynecologic malignancies and numerous other conditions. Although many procedures are still performed through open surgical techniques, increasingly, gynecologic surgery is performed via an endoscope inserted through the umbilicus (belly button). Virtually any manipulation of the pelvic organs or pelvic sidewall can trigger a cascade that ultimately results in the formation of pelvic adhesions. In many instances, the adhesions must be broken down during a repeat surgical intervention for the treatment of pain or infertility. An adhesion barrier, either alone or containing a fibrosis-inhibiting agent (and/or an anti- infective agent), is best applied directly to the affected areas (as a solid, a film, a paste, a gel, a liquid or another such formulation) during the open or endoscopic procedure. In a preferred embodiment, the barrier (alone or containing an anti-fibrotic and/or anti-infective agent) is sprayed under direct endoscopic vision during the procedure onto the pelvic organs (and bowel, pelvic and abdominal sidewall) that are operated on, or manipulated, during the intervention. Since adhesions often occur in areas at a distance from the tissues actually instrumented during a surgical intervention, it is recommended that the barrier (with or without a therapeutic agent) be applied to a wide area in the pelvis (potentially even the entire adnexa, pelvic sidewall and pelvic surface of the uterus). Preferred barriers include liquids, gels, pastes, sprays or other formulations that can be delivered through an endoscope, adhere to the tissues treated, and remain in place long enough to deliver the therapeutic agent and/or prevent adhesion formation. As an alternative, the therapeutic agent can be delivered directly into the peritoneal cavity as an injectable (either before, during or after the procedure) such that the drug is delivered in doses high enough and long enough (multiple dosing and/or sustained release preparations are preferred) to prevent adhesions and the complications arising from them. An ideal adhesion therapy will reduce the incidence, number and tenacity of adhesions and improve patient outcome by reducing pain, improving fertility and limiting the need for repeat interventions.

As described above, the compositions for the prevention of surgical adhesions can be applied directly or indirectly to the tissue in a gynecological site. The polymeric compositions (either with or without an anti-fibrotic or anti-infective therapeutic agent) can be administered in any manner described herein. Exemplary methods include either direct application at the time of surgery or with endoscopic, ultrasound, CT, MRI, or fluoroscopic guidance. If an implanted device is being placed, the composition for the prevention of adhesions can be applied to the surface of the implant, or to the surrounding tissues, in conjunction with placement of a medical device or implant at the surgical site. Representative examples of implants for use in gynecological procedures includes, without limitation, genital-urinary stents, bulking agents, sterilization devices (e.g., valves, clips and clamps), and tubal occlusion implants and plugs.

The polymeric composition,, with or without a fibrosis-inhibiting agent, may be applied during open or endoscopic gynecological surgery: (a) to the tissue surface of the pelvic side wall, adnexa, uterus and any adjacent affected tissues (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) during the surgical procedure; (b) to the surface of an implanted device or implant and/or the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after the surgical procedure; (c) by intraperitoneal or endoscopic injection of the composition into the anatomical space (i.e., the peritoneal or pelvic cavity) at the surgical site (particularly useful for this embodiment is the use of injectable compositions containing polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where there is a risk of adhesion formation); (d) via percutaneous injection into the tissue as a solution as an infusate or as a sustained release preparation; (e) by guided catheter or hysteroscopic injection of the composition into the lumen of the fallopian tubes (i.e., inserting a catheter or an endoscope via the vagina, cervix and uterus until it can be advanced into the lumen of the fallopian tube) at the desired tubal location (particularly useful for this embodiment is the use of injectable compositions containing polymeric carriers which release the fibrosis- inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent can be delivered into the areas of the fallopian tube where there is a risk of adhesion formation); and/or (f) by any combination of the aforementioned methods. Combination therapies (Ae., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used in the manner described above.

In. certain applications involving the placement of a gynecological medical device or implant, it may be desirable to apply the anti-fibrosis (and/or anti-infective) composition at a site that is adjacent to an implant (preferably near the implant-tissue interface). This can be accomplished during open or endoscopic procedures by applying the polymeric composition, with or without a fibrosis-inhibiting agent: (a) to the implant surface (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) before, during, or after the implantation procedure; (b) to the surface of the adjacent tissue (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) immediately prior to, during, or after implantation of the implant; (c) to the surface of the implant and the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after implantation of the implant; (d) by topical application of the composition into the anatomical space (such as the lumen of the fallopian tube, the uterine cavity, the peritoneal cavity, or the pelvic cavity) where the implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis- inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where the device will be inserted); (e) via percutaneous injection into the tissue surrounding the implant as a solution, as an infusate, or as a sustained release preparation; and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used.

In one aspect, the polymeric composition may be delivered to the female pelvic tissue (or device/tissue interface) in the form of a spray or gel during open, endoscopic or catheter-based procedures. The fibrosis- inhibiting agent can be incorporated directly into the surgical adhesion barrier or it can be incorporated into a secondary carrier (polymeric or non- polymeric), as described above, that is then incorporated into the adhesion barrier. Examples of polymer compositions that may be in the form of a spray or gel include poly(ethylene glycol)-based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as the final composition or they can be applied as materials that form a crosslinked gel in situ.

In another aspect, an activated polymer is dissolved in a biologically acceptable buffer that has a pH lower that 6.8. The resultant solution is then applied to the desired tissue surface in the presence of a second biologically acceptable buffer that has a pH greater than 7.5. Application of the reaction mixture to the tissue site may be by extrusion, brushing, spraying or by any other convenient means. Following application of the composition to the surgical site, any excess solution may be removed from the surgical site if deemed necessary. At this point in time, the surgical site can be closed using conventional means (e.g., sutures, staples, or a bioadhesive). In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(CsH4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol {e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8). The antifibrosisfibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, the acidic solution or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS- derivatized polyethylene glycol, the acidic solution and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2~one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

In yet another aspect, an activated polymer can be applied to the surgical site in the solid state. The activated polymer can react with the tissue surface to which it was applied as the polymer hydrates. A biologically acceptable buffer, with a pH greater than 7.5 can be applied to the tissue before and/or after the solid activated polymer has been applied. In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form. The antifibrosisfibrosis- inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e- caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y- decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxane-2- one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxy butyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, Y-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one, and block copolymers of the form X-Y1 Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

iii) Adhesion Prevention in Abdominal Procedures In one aspect, adhesions may be associated with an abdominal surgical procedure. Following abdominal surgery, the formation of adhesions may cause loops of intestines become entangled or twisted about fibrous bands of tissue that impair the normal fluid movement of the bowel. The entanglements can cause partial or total flow obstruction through the bowel, scar can constrict around the bowel, volvulus (twisting) can occur, or blood flow to and from the bowel can be compromised. With entanglement, volvulus or fibrous banding the result is typically partial or complete bowel obstruction; a condition that requires immediate decompression, may require surgery and can cause death. Infarction (interruption of blood flow to the bowel) from adhesions or volvulus is a medical emergency that usually requires surgical removal of the affected bowel and can also lead to death if not treated aggressively. Peritoneal adhesions (adhesions between the abdominal wall and the underlying organs) represent another major health care problem causing pain, bowel obstruction and other potentially serious post-operative complications and they are associated with all types of abdominal surgery (incidence of 50- 90% for laparotomies).

As described previously, adhesion barriers are frequently used in the management of abdominal adhesions following open or endoscopic procedures. A variety of commercially available adhesion barriers are suitable for combining with a fibrosis-inhibitor (and/or an anti-infective agent) in the management of abdominal adhesions. Confluent Surgical, Inc. makes their SPRAYGEL which is a unique sprayable adhesion barrier that is being developed for use in abdominal and pelvic surgical procedures. Products that are being developed by Confluent Surgical, Inc. are described in, for example, U.S. Patent No. 6,379,373. Closure Medical Corp. (Raleigh, NC) is developing a cyanoacrylate-based internal adhesives that may be used to seal internal surgical incisions or grafts which may be compatible in gastrointestinal, oncology and general surgical specialties. Products that are being developed by Closure Medical, Corp. are described in, for example, U.S. Patent Nos. 6,620,846; 6,579,469; 6,565,840; 6,547,467 and 5,981 ,621. Genzyme Corporation has developed hyaluronic acid-containing biomaterials, such as SEPRAFILM and SEPRACOAT, to reduce the incidence of adhesions following abdominal and pelvic surgeries (see, e.g., U.S. Patent Nos. 6,780,427; 6,531 ,147; 6,521 ,223 and 6,010,692.

Other commercially available materials that may be used alone, or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent or an anti-infective agent), applied to or infiltrated into an abdominal site (or to the surface of an implanted device or implant) for the prevention of adhesions during open or endoscopic abdominal procedures include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3; (b) sprayable PEG-containing formulations such as COSEAL, ADHIBIT, FOCALSEAL or DURASEAL; (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL; (d) hyaluronic acid-containing formulations such as RESTYLANE or PERLANE, HYLAFORM, or SYNVISC; (e) polymeric gels for surgical implantation such as REPEL or FLOWGEL; (f) surgical adhesives containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT; (g) dextran sulfate gels such as the ADCON series of gels; and (h) lipid based compositions such as ADSURF. It should be obvious to one of skill in the art that commercial compositions not specifically cited above as well as next- generation and/or subsequently-developed commercial products are to be anticipated and are suitable for use under the present invention. Abdominal surgical procedures are performed for a variety of medical conditions including hernia repair (abdominal, ventral, inguinal, incisional), bowel obstruction, inflammatory bowel disease (ulcerative colitis, Crohn's disease), appendectomy, trauma (penetrating wounds, blunt tauma), tumor resection, infections (abscesses, peritonitis), cholecystectomy, gastroplasty (bariatric surgery), esophageal and pyloric strictures, colostomy, diversion iliostomy, anal-rectal fistulas, hemorrhoidectomies, splenectomy, hepatic tumor resection, pancreatitis, bowel perforation, upper and lower Gl bleeding, and ischemic bowel. Although many procedures are still performed through open surgical techniques, increasingly, abdominal surgery is performed via an endoscope inserted through the umbilicus (belly button). Virtually any manipulation of the abdominal viscera or peritoneum can trigger a cascade that ultimately results in the formation of abdominal adhesions. In many instances, the adhesions must be broken down during a repeat surgical intervention for the treatment of pain or bowel obstruction. An adhesion barrier, either alone or containing a fibrosis-inhibiting agent (and/or an anti-infective agent), is best applied directly to the affected areas (as a solid, a film, a paste, a gel, a liquid or another such formulation) during the open or endoscopic procedure. In a preferred embodiment, the barrier (alone or containing an anti-fibrotic and/or anti-infective agent) is sprayed under direct or endoscopic vision during the procedure onto the abdominal organs (such as the large and small bowel, stomach, liver, spleen, gall bladder etc.), visceral peritoneum and abdominal (wall) peritoneum that are operated on, or manipulated, during the intervention. Since adhesions often occur in areas at a distance from the tissues actually instrumented during a surgical intervention, it is recommended that the barrier (with or without a therapeutic agent) be applied to a wide area in the abdomen (potentially even the entire viscera and abdominal wall). Preferred barriers include films, liquids, gels, pastes, sprays or other formulations that can be delivered during open procedures or through an endoscope, adhere to the tissues treated, and remain in place long enough to deliver the therapeutic agent and/or prevent adhesion formation. As an alternative, the therapeutic agent can be delivered directly into the peritoneal cavity as an injectable (either before, during or after the procedure) such that the drug is delivered in doses high enough and long enough (multiple dosing and/or sustained release preparations are preferred) to prevent adhesions and the complications arising from them. An ideal adhesion therapy will reduce the incidence, number and tenacity of adhesions and improve patient outcome by reducing pain, preventing bowel obstruction and limiting the need for repeat interventions.

As described above, the compositions for the prevention of surgical adhesions can be applied directly or indirectly to the tissue in an abdominal procedure. The polymeric compositions (either with or without an anti-fibrotic or anti-infective therapeutic agent) can be administered in any manner described herein. Exemplary methods include either direct application at the time of surgery or with endoscopic, ultrasound, CT, MRI, or fluoroscopic guidance. If an implanted device is being placed, the composition for the prevention of adhesions can be applied to the surface of the implant, or to the surrounding tissues, in conjunction with placement of a medical device or implant at the surgical site. Representative examples of implants for use in abdominal procedures includes, without limitation, hernia meshes, restriction devices for obesity, implantable sensors, implantable pumps, peritoneal dialysis catheters, peritoneal drug-delivery catheters, Gl tubes for drainage or feeding, portosystemic shunts, shunts for ascites, gastrostomy or percutaneous feeding tubes, jejunostomy endoscopic tubes, colostomy devices, drainage tubes, biliary T-tubes, hemostatic implants, enteral feeding devices, colonic and biliary stents, low profile devices, gastric banding implants, capsule endoscopes, anti-reflux devices, and esophageal stents.

The polymeric composition, with or without a fibrosis-inhibiting agent, may be applied during open or endoscopic abdominal surgery: (a) to the tissue surface of the peritoneal cavity, visceral peritneum, abdominal organs, abdominal wall and any adjacent affected tissues (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) during the surgical procedure; (b) to the surface of an implanted device or implant and/or the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after the surgical procedure; (c) by intraperitoneal or endoscopic injection of the composition into the anatomical space (i.e., the peritoneal cavity) at the surgical site (particularly useful for this embodiment is the use of injectable compositions containing polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where there is a risk of adhesion formation); (d) via percutaneous injection into the tissue as a solution as an infusate or as a sustained release preparation; (e) by guided catheter or endoscopic (gastroscope, ERCP, colonoscope) injection of the composition into the lumen of the Gl tract at the desired location (particularly useful for this embodiment is the use of injectable compositions containing polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent can be delivered into the areas of the Gl tract where there is a risk of adhesion formation); and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used in the manner described above.

In certain applications involving the placement of an abdominal or gastrointestinal medical device or implant, it may be desirable to apply the anti-fibrosis (and/or anti-infective) composition at a site that is adjacent to an implant (preferably near the implant-tissue interface). This can be accomplished during open or endoscopic procedures by applying the polymeric composition, with or without a fibrosis-inhibiting agent: (a) to the implant surface (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) before, during, or after the implantation procedure; (b) to the surface of the adjacent tissue {e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) immediately prior to, during, or after implantation of the implant; (c) to the surface of the implant and the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after implantation of the implant; (d) by topical application of the composition into the anatomical space (such as the lumen of the Gl tract or the peritoneal cavity) where the implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where the device will be inserted); (e) via percutaneous injection into the tissue surrounding the implant as a solution, as an infusate, or as a sustained release preparation; and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used.

In one aspect, the polymeric composition may be delivered to the abdomen (or device/tissue interface) in the form of a spray or gel during open, endoscopic or catheter-based procedures. The fibrosis-inhibiting agent can be incorporated directly into the surgical adhesion barrier or it can be incorporated into a secondary carrier (polymeric or non-polymeric), as described above, that is then incorporated into the adhesion barrier. Examples of polymer compositions that may be in the form of a spray or gel include poly(ethylene glycol)-based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as the final composition or they can be applied as materials that form a crosslinked gel in situ.

In another aspect, an activated polymer is dissolved in a biologically acceptable buffer that has a pH lower that 6.8. The resultant solution is then applied to the desired tissue surface in the presence of a second biologically acceptable buffer that has a pH greater than 7.5. Application of the reaction mixture to the tissue site may be by extrusion, brushing, spraying or by any other convenient means. Following application of the composition to the surgical site, any excess solution may be removed from the surgical site if deemed necessary. At this point in time, the surgical site can be closed using conventional means (e.g., sutures, staples, or a bioadhesive). In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide; -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8). The antifibrosisfibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, the acidic solution or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS- derivatized polyethylene glycol, the acidic solution and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxy butyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator.. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - polyφropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

In yet another aspect, an activated polymer can be applied to the surgical site in the solid state. The activated polymer can react with the tissue surfacelo which it was. applied as the polymer hydrates. A biologically acceptable buffer, with a pH greater than 7.5 can be applied to the tissue before and/or after the solid activated polymer has been applied. In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form. The antifibrosisfibrosis- inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e- caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ~ decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - polyφropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethy!ene glycol, polypropylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - polyφropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof. . - . -

iv) Adhesion Prevention in Cardiac Procedures In one aspect, adhesions may be associated with a cardiac surgical procedure. In the case of cardiac surgery involving transplants, vascular repair, coronary artery bypass grafting (CABG), congenital heart defects, and valve replacements, staged procedures and reoperations (particularly repeat CABG surgery) are very common. As such, cardiac surgeons frequently must operate on tissues that have been surgically traumatized previously and have thick fibrous adhesions present which make dissection difficult. Post-operative pericardial adhesions (adhesions between the two surfaces of the pericardial sac) from initial surgery are common. Pericardial adhesions can cause symptoms by restricting the normal movement and filling of the heart during the cardiac cycle and can subject patients undergoing repeat cardiac surgery to elevated procedural risks. Restemotomy (re-opening the chest wall incision and surgical exposure of the heart) and dissection of the adhesions that accompany it, increases the risk of potential injury to the heart, great vessels and extracardiac grafts, increases operative time (including increasing the time the patient is on heart-lung bypass), and can increase procedural morbidity and mortality. Resternotomy is associated with as much as a 6% incidence of major vascular injury and a greater than 35% mortality has been reported for patients experiencing major hemorrhage during resternotomy. A 50% mortality has been reported for associated injuries to aortocoronary grafts. Staged pediatric open-heart surgery (repeat procedures required as the heart grows) is also associated with a very high incidence of complications due to reoperations.

As described previously, adhesion barriers are frequently used in the management of adhesions following open-heart procedures. A variety of commercially available adhesion barriers are suitable for combining with a fibrosis-inhibitor (and/or an anti-infective agent) in the management of cardiac surgery adhesions. Life Medical Sciences, Inc: is developing the products, REPEL, REPEL-CV, RESOLVE and RELIEVE that are in various stages of development and may be used to prevent surgical adhesions of open heart and other surgeries. Products being developed by Life Medical Sciences, Inc. are described in, for example, U.S. Patent Nos. 6,696,499; 6,399,624; 6,211 ,249; 6,136,333 and 5,711,958. Closure Medical Corp. (Raleigh, NC) is developing a cyanoacrylate-based internal adhesives that may be used to seal internal surgical incisions or grafts which may be compatible in pulmonary and general surgical specialties. Products that are being developed by Closure Medical, Corp. are described in, for example, U.S. Patent Nos. 6,620,846; 6,579,469; 6,565,840; 6,547,467 and 5,981 ,621. Genzyme Corporation has developed hyaluronic acid-containing biomaterials, such as SEPRAFILM and SEPRACOAT, to reduce the incidence of adhesions following cardiothoracic surgeries (see, e.g., U.S. Patent Nos. 6,780,427; 6,531 ,147; 6,521 ,223 and 6,010,692. Other commercially available materials that may be used alone, or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent or an anti-infective agent), applied to or infiltrated into cardiac surgery site (or to the surface of an implanted device or implant) for the prevention of adhesions during open or endoscopic heart surgery include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3; (b) sprayable PEG-containing formulations such as COSEAL, ADHIBIT, FOCALSEAL or DURASEAL; (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL; (d) hyaluronic acid-containing formulations such as RESTYLANE or PERLANE, HYLAFORM, or SYNVISC; (e) polymeric gels for surgical implantation such as REPEL or FLOWGEL; (f) surgical adhesives containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT; (g) dextran sulfate gels such as the ADCON series of gels; and (h) lipid based compositions such as ADSURF. It should be obvious to one of skill in the art that commercial compositions not specifically cited above as well as next- generation and/or subsequently-developed commercial products are to be anticipated and are suitable for use under the present invention.

Virtually any manipulation of the chest wall, pericardium and heart can trigger a cascade that ultimately results in the formation of adhesions. In many instances, the adhesions must be broken down during repeat open-heart interventions. An adhesion barrier, either alone or containing a fibrosis-inhibiting agent (and/or an anti-infective agent), is best applied directly to the affected areas (as a solid, a film, a paste, a gel, a liquid or another such formulation) during open or endoscopic cardiac procedures. In a preferred embodiment, the barrier (alone or containing an anti-fibrotic and/or anti-infective agent) is sprayed under direct or endoscopic vision during the procedure onto the heart, pericardium, pleura and chest wall that are operated on, or manipulated, during the intervention. Since adhesions often occur in areas at a distance from the tissues actually instrumented during a surgical intervention, it is recommended that the barrier (with or without a therapeutic agent) be applied to a wide area in the chest (potentially even the entire cardiopulmonary viscera and infiltrated throughout the pericardial sac). Preferred barriers include films, liquids, gels, pastes, sprays or other formulations that can be delivered during open procedures or through an endoscope, adhere to the tissues treated, and remain in place long enough to deliver the therapeutic agent and/or prevent adhesion formation. As an alternative, the therapeutic agent can be delivered directly into the pericardial sac as an injectable (either before, during or after the procedure) such that the drug is delivered in doses high enough and long enough (multiple dosing and/or sustained release preparations are preferred) to prevent adhesions and the complications arising from them. An ideal adhesion therapy will reduce the incidence, number and tenacity of adhesions and improve patient outcome by reducing the complications of repeat interventions.

- As described above, the compositions for the prevention of surgical adhesions can be applied directly or indirectly to the tissue in a cardiac surgery procedure. The polymeric compositions (either with or without an anti-fibrotic or anti-infective therapeutic agent) can be administered in any manner described herein. Exemplary methods include either direct application at the time of surgery or with endoscopic, ultrasound, CT, MRI, or fluoroscopic guidance. If an implanted device is being placed, the composition for the prevention of adhesions can be applied to the surface of the implant, or to the surrounding tissues, in conjunction with placement of a medical device or implant at the surgical site. Representative examples of implants for use in cardiac procedures includes, without limitation, heart valves (porcine, artificial), ventricular assist devices, cardiac pumps, artificial hearts, stents, bypass grafts (artificial and endogenous), patches, cardiac electrical leads, defibrillators and pacemakers. The polymeric composition, with or without a fibrosis-inhibiting agent, may be applied during open or endoscopic heart surgery: (a) to the tissue surface of the pericardium (or infiltrated into the pericardial sac), heart, great vessels, pleura, lungs, chest wall and any adjacent affected tissues (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) during the surgical procedure; (b) to the surface of an implanted device or implant and/or the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after the surgical procedure; (c) by intraperitoneal or endoscopic injection of the composition into the anatomical space (i.e., the pericardial sac) at the surgical site (particularly useful for this embodiment is the use of injectable compositions containing polymeric carriers which release the fibrosis- inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where there is - a risk of adhesion formation); (d) via percutaneous injection into the tissue as a solution as an infusate or as a sustained release preparation (intrapericardial injection); (e) by guided catheter or endoscopic injection of the composition into the lumen or the walls of the atria, ventricles, great vessels, coronary arteries or the pericardial sac (particularly useful for this embodiment is the use of injectable compositions containing polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent can be delivered into the areas of the heart where there is a risk of adhesion formation); and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used in the manner described above. In certain applications involving the placement of a cardiac medical device or implant, it may be desirable to apply the anti-fibrosis (and/or anti-infective) composition at a site that is adjacent to an implant (preferably near the implant-tissue interface). This can be accomplished during open, endoscopic or catheter-based procedures by applying the polymeric composition, with or without a fibrosis-inhibiting agent: (a) to the implant surface (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) before, during, or after the implantation procedure; (b) to the surface of the adjacent tissue (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) immediately prior to, during, or after implantation of the implant; (c) to the surface of the implant and the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after implantation of the implant; (d) by topical application of the composition into the anatomical space (pericardial sac, intracardiac, intra-arterial) where the implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent can be delivered into the region where the device will be inserted); (e) via percutaneous injection into the tissue surrounding the implant as a solution, as an infusate, or as a sustained release preparation; and/or (f) by any combination of the aforementioned methods. Combination therapies (Ae., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used.

In one aspect, the polymeric composition may be delivered to the heart (or device/tissue interface) in the form of a spray or gel during open, endoscopic or catheter-based procedures. The fibrosis-inhibiting agent can be incorporated directly into the surgical adhesion barrier or it can be incorporated into a secondary carrier (polymeric or non-polymeric), as described above, that is then incorporated into the adhesion barrier. Examples of polymer compositions that may be in the form of a spray or gel include poly(ethylene glycol)-based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as the final composition or they can be applied as materials that form a crosslinked gel in situ.

In another aspect, an activated polymer is dissolved in a biologically acceptable buffer that has a pH lower that 6.8. The resultant solution is then applied to the desired tissue surface in the presence of a second biologically acceptable buffer that has a pH greater than 7.5. Application of the reaction mixture to the tissue site may be by extrusion, brushing, spraying or by any other convenient means. Following application of the composition to the surgical site, any excess solution may be removed from the surgical site if deemed necessary. At this point in time, the surgical site can be closed using conventional means (e.g., sutures, staples, or a bioadhesive). In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8). The fibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS-derivatized polyethylene glycol, the acidic solution or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, the acidic solution and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e- caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ~ decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - polyφropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

In yet another aspect, an activated polymer can be applied to the surgical site in the solid state. The activated polymer can react with the tissue surface to which it was applied as the polymer hydrates. A biologically acceptable buffer, with a pH greater than 7.5 can be applied to the tissue before and/or after the solid activated polymer has been applied. In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form. The fibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS-derivatized polyethylene glycol, or the basic buffer. In another embodiment, the fibrosis- inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma- caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ-decanolactone, δ- decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan- 2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG-PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis-inhibiting agent may then be applied to the coated tissue. The fibrosis-inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - polyφropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta- butyrolactone, gamma-butyrolactone, gamma-valerolactone, y- decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polyφropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

v) Adhesion Prevention in Orthopedic Procedures In one aspect, adhesions may be associated with an orthopedic surgical procedure. Many orthopedic surgical interventions are performed as a result of injury or trauma (fractures; torn ligaments, cartilage, tendons or muscles) that cause significant tissue damage that can lead to excessive scarring and adhesion formation. As a result, orthopedic procedures often result in potentially severe post-operative complications which may be attributed to the trauma which caused the injury or to the trauma from the surgery itself. In general, excessive scarring and adhesion formation in orthopedic conditions follows certain patterns: (a) in joint injuries, it can result in a deformity such that the joint cannot fully extend, flex, or rotate (contractures); (b) in tendon injuries, it can prevent normal movement and lead to shortening; (c) in cartilage injuries, it can lead to the conversion of hyaline cartilage to fibrocartilage with a resultant loss of function and joint instability; (d) in muscle injuries, it can cause adhesion to adjacent tissues, loss of strength and loss of function; (e) in nerve injuries, it can result in loss of conduction and function; if the nerve becomes entrapped (encircled and constricted) by scar, it can cause pain, sensory impairment and loss of motor function; and (f) in tendons and ligaments, it can cause shortening, loss of range of motion and impaired function. The complications of adhesions can be wide spread; for example, adhesions formed after spinal surgery may produce low back pain, leg pain and sphincter disturbance (bladder and bowel). For this reason strategies designed to reduce adhesion formation in musculoskeletal surgery is a significant clinical problem. The local administration of anti-adhesive compositions, alone or loaded with a fibrosis-inhibiting agent, can be utilized in a wide array of clinical situations and conditions to improve patient outcomes following emergency or elective orthopedic interventions.

As described previously, adhesion barriers are frequently used in the management of adhesions following orthopedic procedures. A variety of commercially available adhesion barriers are suitable for combining with a fibrosis-inhibitor (and/or an anti-infective agent) in the management of orthopedic surgery adhesions. Closure Medical Corp. (Raleigh, NC) is developing a cyanoacrylate-based internal adhesives that may be used to seal internal surgical incisions or grafts which may be compatible in orthopedic and general surgical specialties. Products that are being developed by Closure Medical, Corp. are described in, for example, U.S. Patent Nos. 6,620,846; 6,579,469; 6,565,840; 6,547,467 and 5,981 ,621. Life Medical Sciences, Inc. is developing the products, REPEL, REPEL-CV, RESOLVE and RELIEVE that are in various stages of development and may be used to prevent surgical adhesions in orthopedic and spinal surgeries. Products being developed by Life Medical Sciences, Inc. are described in, for example, U.S. Patent Nos. 6,696,499; 6,399,624; 6,211 ,249; 6,136,333 and 5,711 ,958.

Other commercially available materials that may be used alone, or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent or an anti-infective agent), applied to or infiltrated into an orthopedic site (or to the surface of an implanted device or implant) for the prevention of adhesions in open or endoscopic orthopedic surgery include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3; (b) sprayable PEG-containing formulations such as COSEAL, ADHIBIT, FOCALSEAL, SPRAYGEL or DURASEAL; (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL; (d) hyaluronic acid-containing formulations such as RESTYLANE1 HYLAFORM1 PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, INTERGEL, or LUBRICOAT; (e) polymeric gels for surgical implantation such as REPEL or FLOWGEL; (f) orthopedic "cements" used to hold prostheses and tissues in place, such as OSTEOBOND (Zimmer), LVC (Wright Medical Technology), SIMPLEX P (Stryker), PALACOS (Smith & Nephew), and ENDURANCE (Johnson & Johnson, Inc.); (g) surgical adhesives containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT; (g) implants containing hydroxyapatite (or synthetic bone material such as calcium sulfate, VITOSS (Orthovita) and CORTOSS (Orthovita)); (h) other biocompatible tissue fillers, such as those made by BioCure, 3M Company and Neomend; (i) polysacharride gels such as the ADCON series of gels; (j) films, sponges or meshes such as INTERCEED, VICRYL mesh, and GELFOAM; (o) lipid based compositions such as ADSURF; and (p) OSSIGEL, a viscous formulation of hyaluronic acid (HA) and basic fibroblast growth factor (bFGF) designed to accelerate bone fracture healing (Orquest, Inc.). It should be obvious to one of skill in the art that commercial compositions not specifically cited above as well as next-generation and/or subsequently-developed commercial products are to be anticipated and are suitable for use under the present invention.

Orthopedic surgical procedures are performed for a variety of conditions including fractures (open and closed), sprains, joint dislocations, crush injuries, ligament and muscle tears, tendon injuries, nerve injuries, congenital deformities and malformations, total joint or partial joint replacement, and cartilage injuries. Although many procedures are still performed through open surgical techniques, increasingly, numerous orthopedic procedures are being performed via an arthroscope inserted into the joint. Virtually any musculoskeletal (muscle, tendon, joint, bone, cartilage) injury, traumatic injury, or orthopedic surgical intervention can trigger a cascade that ultimately results in the formation of adhesions. In many instances, the adhesions must be broken down during repeat surgical interventions (e.g., capsulotomies, tendon releases, nerve entrapment releases, frozen joints, etc.). An adhesion barrier, either alone or containing a fibrosis-inhibiting agent (and/or an anti-infective agent), is best applied directly to the affected areas (as a solid, a film, a paste, a gel, a liquid or another such formulation) during open or arthroscopic orthopedic procedures. In a preferred embodiment, the barrier (alone or containing an anti-fibrotic and/or anti-infective agent) is sprayed under direct or arthrocopic vision onto the affected musculoskeletal tissue during the intervention. Since adhesions often occur in areas at a distance from the tissues actually instrumented during a surgical intervention, it is recommended that the barrier (with or without a therapeutic agent) be applied to a wide area around the injured or repaired tissues. Preferred barriers include films, liquids, gels, pastes, sprays or other formulations that can be delivered during open procedures or through an endoscope, adhere to the tissues treated, and remain in place long enough to deliver the therapeutic agent and/or prevent adhesion formation. An ideal adhesion therapy will reduce the incidence, number and tenacity of adhesions and improve patient outcome by reducing pain, weakness and sensory abnormalities, preventing contractures, increasing range of motion, improving function, limiting physical deformity and disability, and reducing the need for repeat interventions.

As described above, the compositions for the prevention of surgical adhesions can be applied directly or indirectly to the tissue in an orthopedic surgery procedure. The polymeric compositions (either with or without an anti-fibrotic or anti-infective therapeutic agent) can be administered in any manner described herein. Exemplary methods include either direct application at the time of surgery or with arthroscopic, ultrasound, CT, MRI, or fluoroscopic guidance. If an implanted device is being placed, the composition for the prevention of adhesions can be applied to the surface of the implant, or to the surrounding tissues, in conjunction with placement of a medical device or implant at the surgical site. Representative examples of implants for use in orthopedic procedures include plates, rods, screws, pins, wires, total and partial joint prostheses (artificial hips, knees, shoulders, phalangeal joints), reinforcement patches, tissue fillers, synthetic bone fillers, bone cement, synthetic graft material, allograft material, autograft material, artificial discs, spinal cages, and intermedulary rods.

The polymeric composition, with or without a fibrosis-inhibiting agent, may be applied during open or arthroscopic orthopedic surgery: (a) to the tissue surface of the bone, joint, muscle, tendon, ligament, cartilage and any adjacent affected tissues (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) during the surgical procedure; (b) to the surface of an implanted orthopedic device or implant and/or the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after the surgical procedure; (c) by intra-articular or endoscopic administration of the composition into the anatomical space (e.g., the joint space, tendon sheath, nerve root, spinal canal) at the surgical site (particularly useful for this embodiment is the use of injectable compositions containing polymeric carriers which release the fibrosis- inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where there is a risk of adhesion formation); (d) via percutaneous injection into the tissue as a solution as an infusate or as a sustained release preparation (intramuscular or intra-articular injection); (e) by guided catheter injection of the composition into the tissues and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used in the manner described above.

In certain applications involving the placement of an orthopedic medical device or implant, it may be desirable to apply the anti- fibrosis (or anti-infective) composition at a site that is adjacent to an implant (preferably near the implant-tissue interface). This can be accomplished during open, endoscopic or catheter-based orthopedic procedures by applying the polymeric composition, with or without a fibrosis-inhibiting agent: (a) to the implant surface (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) before, during, or after the implantation procedure; (b) to the surface of the adjacent tissue (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) immediately prior to, during, or after implantation of the orthopedic implant; (c) to the surface of the implant and the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after implantation of the implant; (d) by topical application of the composition into the anatomical space (joint capsule, spinal canal, marrow, tendon sheath etc.) where the implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis- inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent can be delivered into the region where the device will be inserted); (e) via percutaneous injection into the tissue surrounding the orthopedic implant as a solution, as an infusate, or as a sustained release preparation; and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used.

In one aspect, the polymeric composition may be delivered to the musculoskeletal tissue (or device/tissue interface) in the form of a spray or gel during open, endoscopic or catheter-based procedures. The fibrosis- inhibiting (and/or anti-infective) agent can be incorporated directly into the surgical adhesion barrier or it can be incorporated into a secondary carrier (polymeric or non-polymeric), as described above, that is then incorporated into the adhesion barrier. Examples of polymer compositions that may be in the form of a spray or gel include poly(ethylene glycol)-based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as the final composition or they can be applied as materials that form a crosslinked gel in situ.

In another aspect, an activated polymer is dissolved in a biologically acceptable buffer that has a pH lower that 6.8. The resultant solution is then applied to the desired tissue surface in the presence of a second biologically acceptable buffer that has a pH greater than 7.5. Application of the reaction mixture to the tissue site may be by extrusion, brushing, spraying or by any other convenient means. Following application of the composition to the surgical site, any excess solution may be removed from the surgical site if deemed necessary. At this point in time, the surgical site can be closed using conventional means (e.g., sutures, staples, or a bioadhesive). In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(CsH4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8). The fibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS-derivatized polyethylene glycol, the acidic solution or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, the acidic solution and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glyeolide, glycolic acid, e- caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, y- decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polyφropylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

In yet another aspect, an activated polymer can be applied to the surgical site in the solid state. The activated polymer can react with the tissue surface to which it was applied as the polymer hydrates. A biologically acceptable buffer, with a pH greater than 7.5 can be applied to the tissue before and/or after the solid activated polymer has been applied. In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form. The antifibrosisfibrosis- inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e- caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ~ decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2- one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene. carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof. vi) Adhesion Prevention in Reconstructive and Cosmetic Procedures

In one aspect, adhesions may be associated with a cosmetic or reconstructive surgical procedure. The use of soft tissue implants for cosmetic applications (aesthetic and reconstructive) is common in breast augmentation, breast reconstruction after cancer surgery, craniofacial procedures, reconstruction after trauma, congenital craniofacial reconstruction and oculoplastic surgical procedures to name a few.

The clinical function of a soft tissue implant depends upon the implant being able to effectively maintain its shape over time. In many instances, when these devices are implanted in the body, they are subject to a "foreign body" response from the surrounding host tissues. The body recognizes the implanted device as foreign, which triggers an inflammatory response followed by encapsulation of the implant with fibrous connective tissue (adhesion formation). Encapsulation of surgical implants complicates a variety of reconstructive and cosmetic surgeries, but is particularly problematic in the case of breast reconstruction surgery where the breast implant becomes surrounded by a fibrous capsule that alters anatomy and function. Scar capsules that harden and contract (known as "capsular contractures") are the most common complication of breast implant or reconstructive surgery. Capsular (fibrous) contractures can result in hardening of the breast, loss of the normal anatomy and contour of the breast, discomfort, weakening and rupture of the implant shell, asymmetry, infection, and patient dissatisfaction. Further, fibrous encapsulation of any soft tissue implant can occur even after a successful implantation if the device is manipulated or irritated by the daily activities of the patient. Bleeding in and around the implant can also trigger a biological cascade that ultimately leads to excess scar tissue formation. Furthermore, certain types of implantable prostheses (such as breast implants) include gel fillers (e.g., silicone) that tend to leak through the membrane envelope of the implant and can potentially cause a chronic inflammatory response in the surrounding tissue (which encourages tissue encapsulation and contracture formation). The effects of unwanted scarring in the vicinity of the implant are the leading cause of additional surgeries to correct defects, break down scar tissue (capsulotomy or capsulaectomy), to replace the implant, or remove the implant. The local administration of anti-adhesive compositions, alone or loaded with a fibrosis-inhibiting agent, can be utilized in a wide array of cosmetic and reconstructive procedures to improve patient outcomes.

Soft tissue implants are used in a variety of cosmetic, plastic, and reconstructive surgical procedures and may be delivered to many different parts of the body, including, without limitation, the face, nose, breast, chin, buttocks, chest, lip and cheek. Soft tissue implants are used for the reconstruction of surgically or traumatically created tissue voids, augmentation of tissues or organs, contouring of tissues, the restoration of bulk to aging tissues, and to correct soft tissue folds or wrinkles (rhytides). Of all soft tissue implantation procedures, breast implant placement for augmentation or breast reconstruction after mastectomy is the most frequently performed cosmetic surgery implant procedure. For example, in 2002 alone, over 300,000 women had breast implant surgery. Of these, approximately 80,000 were breast reconstructions following a mastectomy due to cancer.

The process for failure of all soft tissue implants is similar regardless of anatomical placement. However, since breast implants have been the most widely studied soft tissue implant, they will be used to illustrate the present invention. In general, breast augmentation or reconstructive surgery involves the placement of a commercially available breast implant, consisting of a capsule filled with either saline or silicone, into the tissues underneath the mammary gland. Four different incision sites have historically been used for breast implantation: axillary (armpit), periareolar (around the underside of the nipple), inframamary (at the base of the breast where it meets the chest wall) and transumbilical (around the belly button). The tissue is dissected away through the small incision, often with the aid of an endoscope (particularly for axillary and transumbilical procedures where tunneling from the incision site to the breast is required). A pocket for placement of the breast implant is created in either the subglandular or the subpectorial region. For subglandular implants, the tissue is dissected to create a space between the glandular tissue and the pectoralis major muscle that extends down to the inframammary crease. For subpectoral implants, the fibers of the pectoralis major muscle are carefully dissected to create a space beneath the pectoralis major muscle and superficial to the rib cage. Careful hemostasis is essential (since it can contribute to complications such as capsular contractures), so much so that minimally invasive procedures (axillary, transumbilical approaches) must be converted to more open procedures (such as periareolar) if bleeding control is inadequate. Depending upon the type of surgical approach selected, the breast implant is often deflated and rolled up for placement in the patient. After accurate positioning is_achieved, the implant can then be filled or expanded to the desired size.

Although many patients are satisfied with the initial procedure, significant percentages suffer from complications that frequently require a repeat intervention to correct. Encapsulation of a breast prosthesis that creates a periprosthetic shell (called capsular contracture) is the most common complication reported after breast enlargement, with up to 50% of patients reporting some dissatisfaction. Calcification can occur within the fibrous capsule adding to its firmness and complicating the interpretation of mammograms. Multiple causes of capsular contracture have identified including: foreign body reaction, migration of silicone gel molecules across the capsule and into the tissue, autoimmune disorders, genetic predisposition, infection, hematoma, and the surface characteristics of the prosthesis. Although no specific etiology has been repeatedly identified, at the cellular level, abnormal fibroblast activity stimulated by a foreign body is a consistent finding. Periprosthetic capsular tissues contain macrophages and occasional T- and B-lymphocytes, suggesting an inflammatory component to the process. Implant surfaces have been made both smooth and textured in an attempt to reduce encapsulation, however, neither has been proven to produce consistently superior results. Animal models suggest that there is an increased tendency for increased capsular thickness and contracture with textured surfaces that encourage fibrous tissue ingrowth on the surface. Placement of the implant in the subpectoral location appears to decrease the rate of encapsulation in both smooth and textured implants.

From a patient's perspective, the biological processes described above lead to a series of commonly described complaints. Implant malposition, hardness and unfavorable shape are the most frequently sited complications and are most often attributed to capsular contracture. When the surrounding scar capsule begins to harden and contract, it results in discomfort, weakening of the shell, asymmetry, skin dimpling and malpositioning. True capsular contractures will occur in approximately 10% of patients after augmentation, and in 25% to 30% of reconstruction cases, with most patients reporting dissatisfaction with the asthetic outcome. Scarring leading to asymmetries occurs in 10% of augmentations and 30% of reconstructions and is the leading cause of revision surgery. Skin wrinkling (due to the contracture pulling the skin in towards the implant) is a complication reported by 10% to 20% of patients. Scarring has even been implicated in implant deflation (1-6% of patients; saline leaking out of the implant and "deflating" it), when fibrous tissue ingrowth into the diaphragmatic valve (the access site used to inflate the implant) causes it to become incontinent and leak. In addition, over 15% of patients undergoing augmentation will suffer from chronic pain and many of these cases are ultimately attributable to scar tissue formation. Other complications of breast augmentation surgery include late leaks, hematoma (approximately 1-6% of patients), seroma (2.5%), hypertrophic scarring (2- 5%) and infections (about 1-4% of cases). Correction can involve several options including removal of the implant, capsulotomy (cutting or surgically releasing the capsule), capsulectomy (surgical removal of the fibrous capsule), or placing the implant in a different location (i.e., from subglandular to subpectoral). Ultimately, additional surgery (revisions, capsulotomy, removal, reimplantation) is required in over 20% of augmentation patients and in over 40% of reconstruction patients, with scar formation and capsular contracture being far and away the most common cause. Procedures to break down the scar may not be sufficient, and approximately 8% of augmentations and 25% of reconstructions ultimately have the implant surgically removed.

A fibrosis-inhibiting agent or composition delivered locally from the soft tissue implant or administered locally into the tissue surrounding the soft tissue implant can minimize fibrous tissue formation, encapsulation and capsular contracture. Application of a fibrosis-inhibiting composition onto the surface of a soft tissue implant or incorporated into a soft tissue implant (e.g., the agent is incorporated into the saline, gel or silicone within the implant and passively diffuses across the capsule into the surrounding tissue) may minimize or prevent fibrous contracture. Infiltration of a fibrosis- inhibiting agent or composition into the tissue surrounding the soft tissue implant, or into the surgical pocket where the implant will be placed, is another strategy for preventing the formation of scar and capsular contracture in augmentation and reconstructive surgery.

As described previously, adhesions and fibrous encapsulation of cosmetic implants is a common complication of asthetic and reconstructive surgery. A variety of commercially available adhesion barriers are suitable for combining with a fibrosis-inhibitor (and/or an anti- infective agent) in the management of this complication. Commercially available materials that may be used alone or loaded with a therapeutic agent (e.g., a fibrosis-inhibiting agent or an anti-infective agent), applied to the surface of a soft tissue implant, contained within the "filler" (typically saline, silicone or gel) of a soft tissue implant, or infiltrated into the tissue surrounding the implantation site for the prevention of adhesions in cosmetic surgery include: (a) sprayable collagen-containing formulations such as COSTASIS or CT3; (b) sprayable PEG-containing formulations such as COSEAL, ADHIBIT, FOCALSEAL, SPRAYGEL or DURASEAL; (c) fibrinogen-containing formulations such as FLOSEAL or TISSEAL; (d) hyaluronic acid-containing formulations such as RESTYLANE or PERLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT; (e) polymeric gels for surgical implantation such as REPEL or FLOWGEL; (f) surgical adhesives containing cyanoacrylates such as DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYL BLUE and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT; (g) dextran sulfate gels such as the ADCON series of gels; and (h) lipid based compositions such as ADSURF. Several of the above agents (e.g., formulations containing PEG, collagen, or fibrinogen such as COSEAL, CT3, ADHIBIT, COSTASIS, FOCALSEAL, SPRAYGEL, DURASEAL, TISSEAL AND FLOSEAL) have the added benefit of being hemostats and vascular sealants, which given the suspected role of inadequate hemostasis in the development of capsular contracture, should also be of benefit in the practice of this invention. It should be obvious to one of skill in the art that commercial compositions not specifically cited above as well as next- generation and/or subsequently-developed commercial products are to be anticipated and are suitable for use under the present invention.

As described above, the compositions for the prevention of surgical adhesions can be applied directly or indirectly to the tissue around the cosmetic implant site. The polymeric compositions (either with or without a therapeutic agent) can be administered in any manner described herein. Exemplary methods include either direct application at the time of surgery or with endoscopic, ultrasound, CT, MRI, or fluoroscopic guidance and in conjunction with placement of a cosmetic implant at the surgical site. Representative examples of implants for use in cosmetic procedures include, without limitation, saline breast implants, silicone breast implants, chin and mandibular implants, nasal implants, cheek implants, lip implants, other facial implants, pectoral and chest implants, malar and submalar implants, tissue fillers, and buttocks implants.

The polymeric composition, with or without a fibrosis-inhibiting agent, may be applied during open or endoscopic cosmetic surgery: (a) to the soft tissue implant surface (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) before, during, or after the implantation procedure; (b) to the surface of the tissue (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) of the implantation pocket immediately prior to, or during implantation of the soft tissue implant; (c) to the surface of the soft tissue implant and/or the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after implantation of the soft tissue implant; (d) by topical application of the anti-fibrosis agent into the anatomical space where the soft tissue implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks - fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent and can be delivered into the region where the implant will be inserted); (e) via percutaneous injection into the tissue surrounding the implant as a solution, as an infusate, or as a sustained release preparation; and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used.

A composition that includes an anti-scarring agent can be infiltrated into the space (surgically created pocket) where the soft tissue implant will be implanted. In certain applications involving the placement of a cosmetic soft tissue implant, it may be desirable to apply the anti-fibrosis (or anti-infective) composition at a site that is adjacent to an implant (preferably near the implant-tissue interface). This can be accomplished during open, endoscopic or catheter-based cosmetic procedures by applying the polymeric composition, with or without a fibrosis-inhibiting agent: (a) to the implant surface (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) before, during, or after the implantation procedure; (b) to the surface of the adjacent tissue (e.g., as an injectable, solution, paste, gel, in situ forming gel, or mesh) immediately prior to, during, or after implantation of the soft tissue implant; (c) to the surface of the soft tissue implant and the tissue surrounding the implant (e.g., as an injectable, solution, paste, gel, in situ forming gel or mesh) before, during, or after implantation of the implant; (d) by topical application of the composition into the anatomical space (surgical pocket; for example, in breast implants this is the subglandular or subpectoral space) where the soft tissue implant will be placed (particularly useful for this embodiment is the use of polymeric carriers which release the fibrosis-inhibiting agent over a period ranging from several hours to several weeks -fluids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticulates, sprays, aerosols, solid implants and other formulations which release the agent can be delivered into the region where the device will be inserted); (e) via percutaneous injection into the tissue surrounding the soft tissue implant as a solution, as an infusate, or as a sustained release preparation; and/or (f) by any combination of the aforementioned methods. Combination therapies (i.e., combinations of therapeutic agents and combinations with antithrombotic, anti-infective, and/or antiplatelet agents) can also be used. In one aspect, the polymeric composition may be delivered to the soft tissue implant (or implant/tissue interface) in the form of a spray or gel during open, endoscopic or catheter-based procedures. The fibrosis- inhibiting (and/or anti-infective) agent can be incorporated directly into the surgical adhesion barrier or it can be incorporated into a secondary carrier (polymeric or non-polymeric), as described above, that is then incorporated into the adhesion barrier. Examples of polymer compositions that may be in the form of a spray or gel include poly(ethylene glycol)-based systems, fibrinogen-containing systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as the final composition or they can be applied as materials that form a crosslinked gel in situ.

In another aspect, an activated polymer is dissolved in a biologically acceptable buffer that has a pH lower that 6.8. The resultant solution is then applied to the desired tissue surface in the presence of a second biologically acceptable buffer that has a pH greater than 7.5. Application of the reaction mixture to the tissue site may be by extrusion, brushing, spraying or by any other convenient means. Following application of the composition to the surgical site, any excess solution may be removed from the surgical site if deemed necessary. At this point in time, the surgical site can be closed using conventional means (e.g., sutures, staples, or a bioadhesive). In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form or in a solution form. In this embodiment, the 4 armed NHS-derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and is then co-applied to the tissue using a basic buffer (pH > about 8). The antifibrosisfibrosis-inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, the acidic solution or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS- derivatized polyethylene glycol, the acidic solution and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of poly(ethylene oxide) and polyφropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxane-2-one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - poly(propylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

In yet another aspect, an activated polymer can be applied to the surgical site in the solid state. The activated polymer can react with the tissue surface to which it was applied as the polymer hydrates. A biologically acceptable buffer, with a pH greater than 7.5 can be applied to the tissue before and/or after the solid activated polymer has been applied. In one embodiment, the activated polymer can form a covalent bond with the tissue to which it is applied may be used. Polymers containing and/or terminated with electrophilic groups such as succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, maleimide, -S-S-(C5H4N) or activated esters, such as are used in peptide synthesis may be used as the reagents. For example, a 4 armed NHS-derivatized polyethylene glycol (e.g., pentaerythritol poly(ethylene glycol)ether tetra-succinimidyl glutarate) may be applied to the tissue in the solid form. The antifibrosisfibrosis- inhibiting agent(s) may be incorporated directly into either the 4 armed NHS- derivatized polyethylene glycol, or the basic buffer. In another embodiment, the fibrosis-inhibiting agent may be incorporated into a secondary carrier that may then be incorporated into the 4 armed NHS-derivatized polyethylene glycol, and/or the basic buffer. The secondary carriers may include microparticles and/or microspheres which are made from degradable polymers. The degradable polymers may include polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e- caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, v- decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxane-2- one or 1 ,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R- (Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polyφropylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator. In another embodiment, the tissue reactive polymer may be applied initially and then the fibrosis- inhibiting agent may then be applied to the coated tissue. The fibrosis- inhibiting agent may be applied directly to the tissue or it may be incorporated into a secondary carrier. The secondary carriers may include microspheres (as described above), microparticles (as described above), gels (e.g., hyaluronic acid, carboxymethyl cellulose, dextran, poly(ethylene oxide) - polyφropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof) and films (degradable polyesters, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, hyaluronic acid, carboxymethyl cellulose, dextranτ poly(ethylene oxide) - polypropylene oxide) block copolymers as well as blends, association complexes and crosslinked compositions thereof.

vii) Agents and Dosages of Fibrosis-lnhibitors In certain aspects of the invention, compositions are provided that can release a therapeutic agent able to reduce scarring (i.e., a fibrosis- inhibiting agent) at a surgical site. Within one embodiment of the invention, surgical adhesion barriers may include or be adapted to release an agent that inhibits one or more of the five general components of the process of fibrosis (or scarring), including: inflammatory response and inflammation, migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), formation of new blood vessels (angiogenesis), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue). By inhibiting one or more of the components of fibrosis (or scarring), the overgrowth of scar tissue may be inhibited or reduced.

Examples of fibrosis-inhibiting agents for use in surgical adhesion barriers include the following: ZD-6474, AP-23573, synthadotin, S- 0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, as well as analogues and derivatives of the aforementioned.

Additional examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1- 10OnM IC50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC50 range) such as 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin.

The drug dose administered from the present compositions for surgical adhesion prevention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single systemic dose application. In certain aspects, the anti-scarring agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. In one aspect, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

The exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in the composition can be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg. The dose (amount) of anti-scarring agent per unit area of surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or 1 μg/mm2 - 10 μg/mm2, or 10 μg/mm2 - 250 μg/mm2, 250 μg/mm2 - 1000 μg/mm2, or 1000 μg/mm2 - 2500 μg/mm2. - -

For high potency drugs, the total dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per unit area of 0.01 μg - 100 μg per mm2; preferably 0.1 μg/mm2 - 20 μg/mm2; and minimum concentration of 10~8- 10"4 M of agent should be maintained on the implant or barrier surface. For mid-potency drugs, the total dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per unit area of 0.01 μg - 200 μg per mm2, preferably 0.1 μg/mm2 - 40 μg/mm2; and minimum concentration of 10" 8- 10"4 M of agent should be maintained on the implant or barrier surface. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit area of 0.01 μg - 500 μg per mm2; preferably 0.1 μg/mm2 - 100 μg/mm2; and minimum concentration of 10"8- 10"4 M of agent should to be maintained on the implant or barrier surface. Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with compositions for treating or preventing surgical adhesions in accordance with the invention.

(A) Angiogenesis inhibitors including alphastatin, ZD-6474, IDN-5390, SB- 2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface.

(B) mTOR inhibitors including AP-23573 and temsirolimus, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface.

(C) Tubulin antagonists including synthadotin, analogues and derivatives thereofhtotal dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 108 - 10"4 M of agent is to be maintained on the implant or barrier surface. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10~8- 10"4 M of agent is to be maintained on the implant or barrier surface. (E) Kinesin antagonists including SB-715992 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (F) TNF alpha antagonists including etanercept, humicade, adalimumab and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of -JO'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10"8 - 10"4 M of agent is to be maintained on the implant or barrier surface. (J) NF Kappa B Inhibitors including Bortezomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (K) Elongation factor-1 alpha inhibitors including aplidine and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 108 - 104 M of agent is to be maintained on the implant or barrier surface. (L) Tyrosine kinase inhibitors including Gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface.

According to another aspect, any anti-infective agent described above may be used in combination with the present compositions for surgical adhesion prevention. Exemplary anti-infective agents include (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin), as well as analogues and derivatives of the aforementioned.

The drug dose administered from the present compositions for prevention or inhibition of infection in accordance with the present invention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single anti-infective systemic dose application. In certain aspects, the anti- infective agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. W

The drug dose administered from the present compositions for prevention or inhibition of infection in accordance with the present invention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single anti-infective systemic dose application. In certain aspects, the anti-infective agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about .14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days.

The exemplary anti-infective agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-infective agent in the composition can be in the range of about 0.01 μg-1 μg, or about 1 μg-10 μg, or about 10 μg-1 mg, or about 1 mg to 10 mg, or about 10 mg-100 mg, or about 100 mg to 250 mg, or about 250 mg-1000 mg. The dose (amount) of anti-infective agent per unit area of device or tissue surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or about 1 μg/mm2 - 10 μg/mm2, or about 10 μg/mm2 - 100 μg/mm2, or about 100 μg/mm2 to 250 μg/mm2, or about 250 μg/mm2 - 1000 μg/mm2. As different compositions will release the anti-infective agent at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the composition such that a minimum concentration of about 10 s M to 1(T7 M, or about 1(T7 M to 1(T6 M about 10"6 M to 1(T5 M or about 10"5 M to 10"4 M of the agent is maintained on the tissue surface.

(b) Inflammatory Arthritis

In one aspect, the present invention provides compositions for the treatment and prevention of inflammatory arthritis. The compositions of the present invention can comprise one or more polymeric carriers and an anti-scarring agent.

Inflammatory arthritis is a serious health problem in developed countries, particularly given the increasing number of aged individuals and includes a variety of conditions including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), mixed connective tissue disease, Sjogren's syndrome, ankylosing spondylitis, Behcet's syndrome, sarcoidosis, and osteoarthritis - all of which feature inflamed and/or painful joints as a prominent symptom.

In one aspect, the present compositions may be used to treat or prevent osteoarthritis (OA). Osteoarthritis is a common, debilitating, costly, and currently incurable disease. The disease is characterized by abnormal functioning of chondrocytes and their terminal differentiation, leading ultimately to the initiation of OA and the breakdown of the cartilage matrix in the articular cartilage of affected joints. Age is the most powerful risk factor for OA, but major joint trauma, excessive weight, and repetitive joint use are also important risk factors for OA. The pattern of joint involvement in OA is also influenced by prior vocational or avocational overload.

OA can be of primary (idiopathic) and secondary types. Primary OA is most commonly related to age. Repetitive use of the joints, particularly the weight-bearing joints such as hips, knees, feet and back, irritates and inflames the joints and causes joint pain and swelling. Eventually, cartilage begins to degenerate by flaking or forming tiny crevasses. In advanced cases, there is a total loss of the cartilage cushion between the bones of the joints. Loss of the cartilage cushion causes friction between the bones, leading to pain and limitation of joint mobility. Inflammation of the cartilage can also stimulate new bone outgrowths (spurs) to form around the joints.

Secondary OA is pathologically indistinguishable from idiopathic OA but is attributable to another disease or condition. Conditions that can lead to secondary OA include obesity, repeated trauma (e.g., ligament tears, cartilage tears), surgery to the joint structures (ligament repairs, menisectomy, cartilage removal), abnormal joints at birth (congenital abnormalities), gout, diabetes, and other metabolic disorders.

In one aspect, the present compositions may be used to treat or prevent rheumatoid arthritis (RA). Rheumatoid arthritis is a multisystem chronic, relapsing, inflammatory disease of unknown cause. Although many organs can be affected, RA is basically a severe form of chronic synovitis that sometimes leads to destruction and ankylosis of affected joints (Robbins Pathological Basis of Disease, by R. S. Cotran, V. Kumar, and S. L. Robbins, W.B. Saunders Co., 1989). Pathologically the disease is characterized by a marked thickening of the synovial membrane which forms villous projections that extend into the joint space, multilayering of the synoviocyte lining (synoviocyte proliferation), infiltration of the synovial membrane with white blood cells (macrophages, lymphocytes, plasma cells, and lymphoid follicles; called an "inflammatory synovitis"), and deposition of fibrin with cellular necrosis within the synovium. The tissue formed as a result of this process is called pannus and eventually the pannus grows to fill the joint space. The pannus develops an extensive network of new blood vessels through the process of angiogenesis which is essential to the evolution of the synovitis. Digestive enzymes (matrix metalloproteinases such as collagenase and stromelysin) and other mediators of the inflammatory process (e.g., hydrogen peroxide, superoxides, lysosomal enzymes, and products of arachadonic acid metabolism) released from the cells of the pannus tissue break down the cartilage matrix and cause progressive destruction of the cartilage. The pannus invades the articular cartilage leading to erosions and fragmentation of the cartilage tissue. Eventually there is erosion of the subchondral bone with fibrous ankylosis and ultimately bony ankylosis, of the involved joint.

It is generally believed, but not conclusively proven, that RA is an autoimmune disease, and that many different arthrogenic stimuli activate the immune response in the immunogenetically susceptible host. Both exogenous infectious agents (Ebstein-Barr virus, rubella virus, cytomegalovirus, herpes virus, human T-cell lymphotropic virus, mycoplasma, and others) and endogenous proteins (collagen, proteoglycans, altered immunoglobulins) have been implicated as the causative agent which triggers an inappropriate host immune response. Regardless of the inciting agent, autoimmunity plays a role in the progression of the disease. In particular, the relevant antigen is ingested by antigen-presenting cells (macrophages or dendritic cells in the synovial membrane), processed, and presented to T lymphocytes. The T cells initiate a cellular immune response and stimulate the proliferation and differentiation of B lymphocytes into plasma cells. The end result is the production of an excessive, inappropriate immune response directed against the host tissues (e.g., antibodies directed against type Il collagen, antibodies directed against the Fc portion of autologous IgG (called "Rheumatoid Factor")). This further amplifies the immune response and hastens the destruction of the cartilage tissue. Once this cascade is initiated, numerous mediators of cartilage destruction are responsible for the progression of rheumatoid arthritis.

In rheumatoid arthritis, articular cartilage is destroyed when it is invaded by pannus tissue (which is composed of inflammatory cells, blood vessels, and connective tissue). Generally, chronic inflammation in itself is insufficient to result in damage to the joint surface, but a permanent deficit is created once fibrovascular tissue digests the cartilage tissue. The abnormal growth of blood vessels and pannus tissue may be inhibited by treatment with fibrosis-inhibiting compositions, or fibrosis-inhibiting agents. Incorporation of an anti-scarring agent into these compositions or other intra-articular formulations, can provide an approach that can reduce the rate of progression of the disease.

Thus, within one aspect of the present invention, methods are provided for treating or preventing inflammatory arthritis comprising the step of administering to a patient in need thereof a therapeutically effective amount of an anti-scarring agent or a composition comprising an anti- scarring agent. Inflammatory arthritis includes a variety of conditions including, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), mixed connective tissue disease, Sjogren's syndrome, ankylosing spondylitis, Behcet's syndrome, sarcoidosis, and osteoarthritis - all of which feature inflamed and/or painful joints as a prominent symptom.

An effective anti-scarring therapy for inflammatory arthritis will accomplish one or more of the following: (i) decrease the severity of symptoms (pain, swelling and tenderness of affected joints; morning stiffness, weakness, fatigue, anorexia, weight loss); (ii) decrease the severity of clinical signs of the disease (thickening of the joint capsule, synovial hypertrophy, joint effusion, soft tissue contractures, decreased range of motion, ankylosis and fixed joint deformity); (iii) decrease the extraarticular manifestations of the disease (rheumatic nodules, vasculitis, pulmonary nodules, interstitial fibrosis, pericarditis, episcleritis, iritis, Felty's syndrome, osteoporosis); (iv) increase the frequency and duration of disease remission/symptom-free periods; (v) prevent fixed impairment and disability; and/or (vi) prevent/attenuate chronic progression of the disease.

According to the present invention, any anti-scarring agent described above could be utilized in the practice of this invention. Within certain embodiments of the invention, the composition may release an agent that inhibits one or more of the general components of the process of fibrosis (or scarring) associated with inflammatory arthritis, including: (a) formation of new blood vessels (angiogenesis), (b) migration and/or proliferation of connective tissue cells (such as fibroblasts or synoviocytes), (c) destruction of the cartilage matrix by metalloproteinase activity, (d) inflammatory response by cytokines (such as IL-1 , TNFα, FGF, VEGF). By inhibiting one or more of the components of fibrosis (or scarring), cartilage loss may be inhibited or reduced.

In one aspect, the composition includes an anti-scarring agent and a polymeric carrier suitable for application to treat inflammatory arthritis. Numerous polymeric and non-polymeric delivery systems and compositions containing an anti-scarring agent for use in the treatment of inflammatory arthritis have been described above. An anti-scarring agent may be administered systemically (orally, intravenously, or by intramuscular or subcutaneous injection) in the minimum dose to achieve the above mentioned results. For patients with only a small number of joints affected, or with disease more prominent in a limited number of joints, the anti- scarring agent can be directly injected into the affected joint (intra-articular injection) via percutaneous needle insertion into the joint capsule, or as part of an arthroscopic procedure performed on the joint. In a preferred embodiment, the intra-articular formulation containing a fibrosis-inhibitor is administered to a joint following an injury with a high probability of inducing subsequent arthritis (e.g., cruciate ligament tears in the knee, meniscal tears in the knee). The agent is administered for a period sufficient (either through sustained release preparations and/or repeated injections) to protect the cartilage from breakdown as a result of the injury (or the surgical procedure used to treat it).

The anti-scarring agent can be administered in any manner described herein. However, preferred methods of administration include intravenous, oral, subcutaneous injection, or intramuscular injection. A particularly preferred embodiment involves the administration of the fibrosis- inhibiting compound as an intra-articular injection (directly, via arthroscopic or radiologic guidance, or irrigated into the joint as part of an open surgical procedure). The anti-scarring agent can be administered as a chronic low dose therapy to prevent disease progression, prolong disease remission, or decrease symptoms in active disease. Alternatively, the therapeutic agent can be administered in higher doses as a "pulse" therapy to induce remission in acutely active disease; such as the acute inflammation that follows a traumatic joint injury (intra-articular fractures, ligament tears, meniscal tears, as described below). The minimum dose capable of achieving these endpoints can be used and can vary according to patient, severity of disease, formulation of the administered agent, potency and/or tolerability of the agent, clearance of the agent from the joint, and route of administration.

In one preferred embodiment, the fibrosis-inhibiting composition can be an intra-articular injectable hyaluronic acid-based composition. Hyaluronic acid, which is a normal element of joint synovial fluid, lubricates the joint surface during normal activities (resting, walking) and helps prevent mechanical damage and decrease shock on the joint in high impact activities (such as running, jumping). In patients with OA, the elasticity and viscosity of the synovial fluid and the synovial hyaluronic acid concentration are reduced. It is believed that this contributes to the breakdown of the articular cartilage within the joint. Intra-articularly administered HA (typically sodium hyaluronate) penetrates the articular cartilage surface, the synovial tissue, and the capsule of the joint for a period of time after injection. By injecting hyaluronic acid into the joint (known as visco-supplementation), it is possible to partially restore the normal environment of the synovial fluid, reduce pain, and potentially prevent further damage and disability. Representative examples of hyaluronic acid compositions used in visco-supplementation are described in U.S. Patents Nos. 6,654,120, 6,645,945, and 6,635,287. As such, HA- containing materials are administered as an intra-articular injection (as either a single treatment or a course of repeated treatment cycles) for the treatment of painful osteoarthritis of the knee in patients who have insufficient pain relief from conservative therapies. Occasionally other joints such as hips (injected under fluoroscopy), ankles, shoulders and elbow joints, are also injected with HA to relieve the symptoms of the disease in those particular joints. Depending upon the particular commercial product, the HA material is injected into the joint once a week for 5 to 6 consecutive weeks. When effective, patients may report that they receive symptomatic relief for a period of 6 months or more - at which time the cycle may be repeated to prolong the activity of the therapy. Despite the sustained benefit in some patients, the injected HA is rapidly cleared (removed) from the joint by the body over a period of several days. Prolonging the residence time of the HA in the joint by inhibiting its breakdown may be expected to enhance its efficacy and increase the duration of symptomatic relief. By adding a fibrosis-inhibiting agent to the HA, the intra-articular injection has the added benefit of helping to prevent cartilage breakdown (i.e., it is "chondroprotective").

A variety of commercially available HA compositions for the treatment of inflammatory arthritis may be combined with one or more agents according to the present invention including: SYNVISC (Biomatrix, Inc., Ridgefield, NJ) - an elastoviscous fluid containing hylan (a derivative of sodium hyaluronate (hyaluronan)) polymers derived from rooster combs, HYALGAN (Sanofi-Synthelabo Inc. New York, NY), and ORTHOVISC (Ortho Biotech Products, Bridgewater, NJ) - a highly purified, high molecular weight, high viscosity injectable form of HA intended to relieve pain and to improve joint mobility and range of motion in patients suffering from osteoarthritis (OA) of the knee. ORTHOVISC is injected into the knee to restore the elasticity and viscosity of the synovial fluid. HYVISC is a high molecular weight, injectable HA product developed by Anika Therapeutics (Wobum, MA) currently being used to treat osteoarthritis and lameness in racehorses. Other HA-based viscosupplementation products for the treatment of osteoarthritis include SUPARTZ from Seikagaku Corp. (Japan), SUPLASYN from Bioniche Life Sciences, Inc. (Canada), ARTHREASE from DePuy Orthopaedics, Inc. (Warsaw, IN), and DUROLANE from Q-Med AB (Sweden).

In one aspect, the compositions of the present invention may be used for the management of osteoarthritis in animals (e.g., horses). It should be noted that some HA products (notably HYVISC by Boehringer lngelheim Vetmedica, St. Joseph, MO) are used in veterinary applications (typically in horses to treat osteoarthritis and lameness).

Other intra-articular compositions used to treat arthritis include corticosteroids. The most common corticosteroids currently used for inflammatory arthritis are methylprednisolone acetate (DEPO-MEDROL, Pharmacia & Upjohn Company, Kalamazoo, Ml), and triacinolone acetonide (KENALOG, Bristol-Myers Squibb, New York, NY). By adding a fibrosis- inhibiting agent to the intra-articular corticosteroid injection, the intra- articular injection has the added benefit of helping to prevent cartilage breakdown [i.e., it is "chondroprotective").

Formulations that can be used in these applications include solutions, topical formulations (e.g., solution, cream, ointment, gel) emulsions, micellar solutions, gels (crosslinked and non-crosslinked), suspensions and/or pastes. One form of the formulation is as an injectable composition. For compositions that further contain a polymer to increase the viscosity of the formulation, hyaluronic acid (crosslinked, derivatized and/or non-crosslinked) is an exemplary material. These formulations can further comprise additional polymers (e.g., collagen, poly(ethylene glycol) or dextran) as well as biocompatible solvents (e.g., ethanol, DMSO, or NMP). In one embodiment, the fibrosis-inhibiting therapeutic agent can be incorporated directly into the formulation. In another embodiment, the fibrosis-inhibiting therapeutic agent can be incorporated into a secondary carrier (e.g., micelles, liposomes, emulsions, microspheres, nanospheres etc, as described above). The microsphere and nanospheres may be comprised of degradable polymers. Degradable polymers that can be used include poly(hydroxyl esters) {e.g., PLGA, PLA, PCL, and the like), as well as polyanhydrides, polyorthoesters and polysaccharides (e.g., chitosan and alginates).

In one embodiment, the fibrosis-inhibiting agent further comprises a polymer where the polymer is a degradable polymer. The degradable polymers may include polyesters where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma- , caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ-decanolactone, δ- decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan- 2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG-PEG-PLG) and R is a multifunctional initiator. In another embodiment, the fibrosis-inhibiting agent/composition may further comprise a solvent, a liquid oligomer or liquid polymer such that the final composition may be passed through a 18G needle. The reagents that may be used include ethanol, NMP, PEG 200, PEG 300 and low molecular weight liquid polymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator.

In another embodiment, the fibrosis-inhibiting agent may be in the form of a solution or suspension in an organic solvent, a liquid oligomer or a liquid polymer. In this embodiment, reagents such as ethanol, NMP, PEG 200, PEG 300 and low molecular weight liquid polymers of the form X- Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polyφropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, may be used.

Examples of fibrosis-inhibiting agents for use in the treatment of inflammatory arthritis include the following: ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT- 518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, as well as analogues and derivatives of the aforementioned.

Additional examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1- 10OnM IC50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC50 range) such as 5-azacytidine, Ly333531(ruboxistaurin), and simvastatin.

The drug dose administered from the present compositions for the treatment of inflammatory arthritis will depend on a variety of factors, including the type of formulation and treatment site. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. For local application, drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single systemic dose application. In certain aspects, the anti-scarring agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. In one aspect, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

The exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in the composition can be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg. The dose (amount) of anti-scarring agent per unit area of surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or 1 μg/mm2 - 10 μg/mm2, or 10 μg/mm2 - 250 μg/mm2, 250 μg/mm2 - 1000 μg/mm2, or 1000 μg/mm2 - 2500 μg/mm2.

Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with compositions for the treatment of inflammatory arthritis in accordance with the invention. The following dosages are particularly useful for intra-articular administration: (A) Angiogenesis inhibitors including Alphastatin, ZD-6474, IDN-5390, SB- 2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per ml_; preferred dose of 0.1 μg/mL - 30 mg/mL (B) mTOR inhibitors including AP-23573 and Temsirolimus, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per ml_; preferred dose of 0.1 μg/ ml_ - 20 mg/ ml_. (C) Tubulin antagonists including synthadotin, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 μg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/mL - 20 mg/ mL. (E) Kinesin antagonists including SB-715992 and analogues and derivatives thereof: tota single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (F) TNF alpha antagonists including Etanercept, humicade, adalimumab and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ ml_ - 20 mg/ mL (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 300 mg per mL; preferred dose of 0.1 μg/ mL - 100 mg/ mL (J) NF KAPPA B Inhibitors including Bortezomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (K) Elongation factor-1 alpha inhibitors including aplidine and analogues and derivatives thereof: total single dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 100 mg/ mL. (L) Tyrosine kinase inhibitors including Gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 300 mg per mL; preferred dose of 0.1 μg/ mL - 100-μg/ mL. In another aspect, systemic treatment may be administered when severe exacerbations or systemic disease (e.g., RA) are present. Anti- scarring agents that are delivered systemically should be dosed according to the level of drug required to inhibit the pathologies of inflammatory arthritis as described above. These systemic doses may vary according to patient, severity of disease, formulation of the administered agent, potency and/or tolerability of the agent, and route of administration. For example, for ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, 1DN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, doiastatin 15, cerivastatin, jaspiakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), simvastatin, and an analogue or derivatives of the aforementioned, preferred embodiments would be 10 to 175 mg/m2 once every 1 to 4 weeks, 10 to 75 mg/m2 daily, as tolerated, or 10 to 175 mg/m2 weekly, as tolerated or until symptoms subside. To treat severe acute exacerbations, higher doses of 50 to 250 mg/m2 of ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT- 518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, doiastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), or simvastatin, may be administered as a "pulse" systemic therapy. Other anti-scarring agents can be administered at equivalent doses adjusted for the potency and tolerability of the agent.

For specific high potency drugs, the total single dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per volume of 0.01 μg - 100 mg per ml_; preferably 0.1 μg/mL - 20 mg/mL For mid-potency drugs, the total single dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per volume of 0.01 μg - 200 mg per ml_, preferably 0.1 μg/mL - 40 mg/mL. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit volume of 0.01 μg - 300 mg per mL; preferably 0.1 μg/mm2 - 100 mg/mL

According to another aspect, any anti-infective agent described above may be used in conjunction with compositions for the treatment of inflammatory arthritis. Exemplary anti-infective agents include (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin), as well as analogues and derivatives of the aforementioned.

The drug dose administered from the present compositions for prevention or inhibition of infection in accordance with the present invention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single anti-infective systemic dose application. In certain aspects, the anti-infective agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. The exemplary anti-infective agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-infective agent in the composition can be in the range of about 0.01 μg-1 μg, or about 1 μg-10 μg, or about 10 μg-1 mg, or about 1 mg to 10 mg, or about 10 mg-100 mg, or about 100 mg to 250 mg, or about 250 mg-1000 mg. The dose (amount) of anti-infective agent per unit area of device or tissue surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or about 1 μg/mm2 - 10 μg/mm2, or about 10 μg/mm2 - 100 μg/mm2, or about 100 μg/mm2 to 250 μg/mm2, or about 250 μg/mm2 - 1000 μg/mm2. As different compositions will release the anti-infective agent at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the composition such that a minimum concentration of about 10"8 M to 10"7 M, or about 10"7 M to 10"6 M about 10"6 M to 10"5 M or about 10'5 M to 10"4 M of the agent is maintained on the tissue surface.

(c) Prevention of Cartilage Loss ("Chondroprotection")

In another aspect, polymeric compositions can be used to prevent or reduce the loss of cartilage loss following an injury (e.g., cruciate ligament tear and/or meniscal tear). It has been known for a long time that damage to a joint can predispose a patient to develop osteoarthritis in the joint at a subsequent point in time, but there has been no effective treatment to prevent this occurrence. Instead most of the focus from the medical community and researchers has been on the treatment of the arthritis after it has become established. Treatments for established disease include antiinflammatory drugs (non-steroidal and steroidal), lubricants or synovial fluid replacements, surgery and joint replacement for severe disease.

Trauma to a joint can take many forms, ranging from a simple sprain which can heal spontaneously to a fracture that creates so many bone fragments that it is almost impossible to reconstruct the joint. The focus for treatment of these injuries revolves around restoring the joint to its normal anatomical state and to resume regular motion. Risk factors for developing arthritis are related to the extent of trauma, the extent of the joint disruption, the degree of the fracture or dislocations, whether or not it is a weight bearing joint, and the characteristic of the joint itself. In general, the greater the trauma to the joint, the greater the risk that the patient will develop osteoarthritis later in life. Surgical correction of a joint to its pre- injury anatomy does not guarantee the prevention of arthritis. In the case of an intra-articular fracture, for example a plateau fracture of the tibia, the treatment is to surgically reconstruct the joint so that it reverts back to a congruent, smooth and intact joint surface with no "step defects" or pieces out of place that would interfere with the gliding of the femur on its surface. Despite improved surgical techniques in repairing these fractures, patients with such fractures have a very high probability of developing degenerative arthritis later on in life.

Anterior cruciate ligament (ACL) injuries in the knee represent a classic example of an injury that predisposes patients to potentially severe degenerative arthritis. The ACL is the ligament that joins the anterior tibial plateau to the posterior femoral intercondylar notch. It is composed of multiple non-parallel fibers with variable fiber lengths that function in bundles to provide tension and mechanical stability to the knee throughout its range of motion. The ACL's stabilizing role has four main functions, including (a) restraining anterior translation of the tibia; (b) preventing hyperextension of the knee; (c) acting as a secondary stabilizer to the valgus stress, reinforcing the medial collateral ligament; and (d) controlling rotation of the tibia on the femur during femoral extensions, and thus, controlling movements such as side-stepping and pivoting. Generally, ACL deficiency results in subluxation of the tibia on the femur causing stretching of the enveloping capsular ligaments and abnormal shear forces on the menisci and on the articular cartilage. Delay in diagnosis and treatment gives rise to increased intra-articular damage as well as stretching of the secondary stabilizing capsular structures. Despite the known high risk for developing osteoarthritis, patients generally have no associated fractures and have normal x-rays at the time of presentation post-ACL injury. Yet it is well documented that anyone who suffers an ACL injury has a high probability of developing arthritis: 50% by 10 years and 80% by 20 years post-injury. Generally after an ACL rupture patients suffer from instability since the ligament is critical in stabilizing the joint during pivoting and rotation. For example, it is not only required for demanding pivoting sports such as basketball, it is also required for daily activity such as a mother holding her baby as she pivots to get an item from the fridge.

The typical treatment and management of an ACL tear is reconstruction using a graft to replace the torn ACL. The graft may be taken from elsewhere in the patient's extremity (autograft), harvested from a cadaver (allograft) or may be made from a synthetic material. Autograft is the most widely performed orthopedic ACL reconstruction. The technique involves harvesting the patient's own tissue, which may be the mid-third of the patellar tendon with bone attached at both ends, one or two medial hamstrings, or the quadriceps tendon with bone at one end. Synthetic materials have the advantage of being readily available, however, there is a higher failure rate of synthetic grafts compared to autografts and allografts and they have mechanical properties that do not closely resemble the normal ligament. Successful ACL reconstruction is dependent on a number of factors, including surgical technique, post-operative rehabilitation and associated secondary ligament instability. During the surgical procedure, arthroscopy is used to determine whether there are any other associated injuries, which may be treated at the same time, such as meniscal tears or chondral trauma. The surgical procedure is done through a small accessory incision, whereby a tunnel is drilled through the tibia and femur so that the graft may be inserted and fixed.

Surgical reconstruction was initially thought to provide a permanent solution: re-establish a stable knee and prevent degeneration. But other studies demonstrated that after joint injury, there is a cascade of inflammatory activity that once initiated, can be destructive to the joint. This explains why surgical repair itself would have not impact on the prevention of degeneration in traumatized joints; stabilizing a joint or the macro reconstruction of a joint does not address the fundamental underlying biology. Unfortunately, although long-term data has shown that surgery is indeed successful in stabilizing the knee and getting people back to normal activity; it has no impact on the subsequent rate of development of osteoarthritis. As a result, the standard of care to day is to repair the joint acutely and treat the arthritis when it ultimately develops. It should be noted that all joints (in addition to knees) have the potential to become arthritic after trauma, but joints typically involved include; fingers, thumbs, metacarpal (wrist), elbow, shoulder, spine joints (facets, sacro-iliac), temperomandibular, otic bones, hips, ankles, tarsal and toes, especially the hallux.

Fibrosis-inhibiting agents such as ZD-6474,J\P-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT- 518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatinmay demonstrate in animal experiments an ability to prevent cartilage breakdown following cruciate ligament tears. This effect has been seen with antifibrotic agents both in an inflammatory model and biomechanical model of joint injury. Hartley Guinea pigs subjected to surgical transaction of the anterior cruciate ligament represent a mechanical model for arthritis. Typically after the anterior cruciate is severed, the animals develop arthritis within several weeks. The introduction of the fibrosis-inhibiting agents such as ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin, into the joint may greatly retard the arthritic process and protect not only the cartilage, but also the underlying bone, from breakdown.

The present invention addresses a significant unmet medical need: the prevention of progressive joint degeneration after traumatic injury. Introduction of a composition containing a fibrosis-inhibiting agent into a damaged joint shortly after injury, (e.g., through intra-articular injection, peri- articular administration, via arthroscope, as a joint lavage during open surgical procedures) will impact the cascade of events that lead to joint destruction, such as inhibiting inflammation and preventing cartilage matrix destruction. Most ligament injuries are severe enough or painful enough that patients seek immediate medical attention (within the first 24 to 48 hours); long before irreversible changes have occurred in the joint. If at the time of initial presentation to a health care professional, an intra-articular injection of a fibrosis-inhibitor can be administered into the joint to stop or slow down the destructive activity (in the joint and the tissues surrounding the joint), the articular cartilage can be protected from breakdown. Early introduction of the agents of the present invention intervention will slow, decrease or eliminate the cascade of events that lead to osteoarthritis. The invention can be administered immediately after injury, repeated during the period leading up to stabilization surgery, and/or can be administered after surgery is completed. Thus, within one aspect of the present invention, methods are provided for treating or preventing cartilage loss, comprising the step of administering to a patient in need thereof a therapeutically effective amount of an anti-scarring agent or a composition comprising an anti-scarring agent.

An effective anti-scarring therapy for cartilage loss will accomplish one or more of the following: (i) decrease the severity of symptoms (pain, swelling and tenderness of affected joints; (ii) decrease the severity of clinical signs of the disease (thickening of the joint capsule, synovial hypertrophy, joint effusion, soft tissue contractures, decreased range of motion, ankylosis and fixed joint deformity); (iii) increase the frequency and duration of disease remission/symptom-free periods; (iv) delay or prevent the onset of clinically significant arthritis in a joint that has previously been injured; and/or (v) prevent or reduce fixed impairment and disability.

According to the present invention, any anti-scarring agent described above could be utilized in the practice of this invention. Within, certain embodiments of the invention, the composition may release an agent that inhibits one or more of the general components of the process of fibrosis (or scarring) associated with joint damage, including: (a) formation of new blood vessels (angiogenesis), (b) migration and/or proliferation of connective tissue cells (such as fibroblasts or synoviocytes), (c) deposition and remodeling of extracellular matrix (ECM) by matrix metalloproteinase activity, (d) inflammatory response by cytokines (such as IL-1 , TNFα, FGF, VEGF). By inhibiting one or more of the components of fibrosis (or scarring), joint damage and osteoarthritis development may be reduced or prevented in a previously injured joint..

In one aspect, the composition includes an anti-scarring agent and a polymeric carrier suitable for application to treat an injured joint. Numerous polymeric and non-polymeric delivery systems and compositions containing an anti-scarring agent for use in the prevention of cartilage loss have been described above. An anti-scarring agent may be administered systemically (orally, intravenously, or by intramuscular or subcutaneous injection) in the minimum dose to achieve the above mentioned results. For patients with only a small number of joints affected, or with disease more prominent in a limited number of joints, the anti-scarring agent can be applied onto tissue within a joint or directly injected into the affected joint (intraarticular injection).

The anti-scarring agent can be administered in any manner described herein. However, preferred methods of administration include intravenous, oral, or subcutaneous, intramuscular or intra-articular injection. The anti-scarring agent can be directly injected into the affected joint (intra- articular injection) via percutaneous needle insertion into the joint capsule, or as part of an arthroscopic procedure performed on the joint. In a preferred embodiment, the intra-articular formulation containing a fibrosis- inhibitor is administered to a joint following an injury with a high probability of inducing subsequent arthritis (e.g., cruciate ligament tears in the knee, meniscal tears in the knee). The fibrosis-inhibiting agent is administered for a period sufficient (either through sustained release preparations and/or repeated injections) to protect the cartilage from breakdown as a result of the injury (or the surgical procedure used to treat it). The anti-scarring agent can be administered as a chronic low dose therapy to prevent disease progression, prolong disease remission, or decrease symptoms in active disease. Alternatively, the therapeutic agent can be administered in higher doses as a "pulse" therapy to induce remission in acutely active disease (such as in the period immediately following a joint injury). The minimum dose capable of achieving these endpoints can be used and can vary according to patient, severity of disease, formulation of the administered agent, clearance from the joint, potency and/or tolerability of the agent, and route of administration.

A variety of commercially available HA compositions for intra- articular injection may be combined with one or more agents according to the present invention including: SYNVISC (Biomatrix, Inc., Ridgefield, NJ) - an elastoviscous fluid containing hylan (a derivative of sodium hyaluronate (hyaluronan)) polymers derived from rooster combs, HYALGAN (Sanofi- Synthelabo Inc. New York, NY)1 and ORTHOVISC (Ortho Biotech Products, Bridgewater, NJ) - a highly purified, high molecular weight, high viscosity injectable form of HA intended to relieve pain and to improve joint mobility and range of motion in patients suffering from osteoarthritis (OA) of the knee. ORTHOVISC is injected into the knee to restore the elasticity and viscosity of the synovial fluid. HYVISC is a high molecular weight, injectable HA product developed by Anika Therapeutics (Woburn, MA) currently being used to treat osteoarthritis and lameness in racehorses. Other HA-based viscosupplementation products for intra-articular injection include SUPARTZ from Seikagaku Corp. (Japan), SUPLASYN from Bioniche Life Sciences, Inc. (Canada), ARTHREASE from DePuy Orthopaedics, Inc. (Warsaw, IN), and DUROLANE from Q-Med AB (Sweden). By adding a fibrosis-inhibiting agent to the HA, the intra-articular injection has the added benefit of helping to prevent cartilage breakdown (i.e., it is "chondroprotective").

In one aspect, the compositions of the present invention may be used for the management of osteoarthritis in animals (e.g., horses). It should be noted that some HA products (notably HYVISC by Boehringer lngelheim Vetmedica, St. Joseph, MO) are used in veterinary applications (typically in horses to treat osteoarthritis and lameness).

Fibrosis-inhibiting formulations that can be used for the treatment or prevention of cartilage loss may be in the form of solutions, topical formulations (e.g., solution, cream, ointment, gel) emulsions, micellar solutions, gels (crosslinked and non-crosslinked), suspensions and/or pastes. One form for the formulation is as an injectable composition for intra-articular or arthroscopic delivery. For compositions that further contain a polymer to increase the viscosity of the formulation, hyaluronic acid (crosslinked, derivatized and/or non-crosslinked) is an exemplary material. These formulations can further comprise additional polymers (e.g., collagen, poly(ethylene glycol) or dextran) as well as biocompatible solvents (e.g., ethanol, DMSO, or NMP). In one embodiment, the fibrosis-inhibiting therapeutic agent can be incorporated directly into the formulation. In another embodiment, the fibrosis-inhibiting therapeutic agent can be incorporated into a secondary carrier {e.g., micelles, liposomes, emulsions, microspheres, nanospheres etc, as described above). The microsphere and nanospheres may be comprised of degradable polymers. Degradable polymers that can be used include poly(hydroxyl esters) (e.g., PLGA, PLA, PCL, and the like), as well as polyanhydrides, polyorthoesters and polysaccharides (e.g., chitosan and alginates).

In one embodiment, the fibrosis-inhibiting agent further comprises a polymer where the polymer is a degradable polymer. The degradable polymers may include polyesters where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma- caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, garηma-butyrolactone, gamma-valerolactone, γ-decanolactone, δ- - decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan- 2one, and block copolymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and polypropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma- valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG-PEG-PLG) and R is a multifunctional initiator. In another embodiment, the fibrosis-inhibiting agent/composition may further comprise a solvent, a liquid oligomer or liquid polymer such that the final composition may be passed through a 18G needle. The reagents that may be used include ethanol, NMP, PEG 200, PEG 300 and low molecular weight liquid polymers of the form X-Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, polypropylene glycol) and block copolymers of poly(ethylene oxide) and polyφropylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxy valeric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator.

In another embodiment, the fibrosis-inhibiting agent may be in the form of a solution or suspension in an organic solvent, a liquid oligomer or a liquid polymer. In this embodiment, reagents such as ethanol, NMP, PEG 200, PEG 300 and low molecular weight liquid polymers of the form X- Y, Y-X-Y, R-(Y-X)n, R-(X-Y)n and X-Y-X where X in a polyalkylene oxide (e.g., poly(ethylene glycol, poly(propylene glycol) and block copolymers of poly(ethylene oxide) and poly(propylene oxide) (e.g., PLURONIC and PLURONIC R series of polymers from BASF Corporation, Mount Olive, NJ) and Y is a biodegradable polyester, where the polyester may comprise the residues of one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, gamma-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma- butyrolactone, gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2one (e.g., PLG- PEG-PLG) and R is a multifunctional initiator, may be used.

Examples of fibrosis-inhibiting agents for use in the treatment of, or prevention of, cartilage loss following traumatic injury include the following: ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB- 715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), simvastatin, as well as analogues and derivatives of the aforementioned.

Additional examples of anti-scarring agents which can be used include those having a high potency in selected assays described herein (approximately 1-10OnM IC50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, and tacrolimus; those having a mid- potency in selected assays described herein (approximately 100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in selected assays described herein (approximately 500-1 OOOnm range IC50 range) such as 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin.

The drug dose administered from the present compositions for the treatment of cartilage loss will depend on a variety of factors, including the type of formulation and treatment site. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. For local application (such as intra-articular or endoscopic administration), drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1 % of the concentration typically used in a single systemic dose application. In certain aspects, the anti-scarring agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. In one aspect, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

The exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in the composition can be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg.

Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with compositions for the treatment of inflammatory arthritis in accordance with the invention. The following dosages are particularly useful for intra-articular administration: (A) Angiogenesis inhibitors including Alphastatin, ZD-6474, IDN-5390, SB- 2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/mL - 30 mg/mL (B) mTOR inhibitors including AP-23573 and Temsirolimus, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (C) Tubulin antagonists including synthadotin, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 μg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per ml_; preferred dose of 0.1 μg/mL - 20 mg/ mL (E) Kinesin antagonists including SB-715992 and analogues and derivatives thereof: tota single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (F) TNF alpha antagonists including Etanercept, humicade, adalimumab and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 300 mg per mL; preferred dose of 0.1 μg/ mL - 100 mg/ mL (J) NF KAPPA B Inhibitors including Bortezomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (K) Elongation factor-1 alpha inhibitors including aplidine and analogues and derivatives thereof: total single dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 100 mg/ mL. (L) Tyrosine kinase inhibitors including Gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 300 mg per mL; preferred dose of 0.1 μg/ ml_ - 100 μg/ mL In another aspect, systemic treatment may be administered when severe exacerbations or systemic disease (e.g., RA) are present. Anti- scarring agents that are delivered systemically should be dosed according to the level of drug required to inhibit the pathologies of inflammatory arthritis as described above. These systemic doses may vary according to patient, severity of disease, formulation of the administered agent, potency and/or tolerability of the agent, and route of administration. For example, for ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, lDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, . - . puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), simvastatin, and an analogue or derivatives of the aforementioned, preferred embodiments would be 10 to 175 mg/m2 once every 1 to 4 weeks, 10 to 75 mg/m2 daily, as tolerated, or 10 to 175 mg/m2 weekly, as tolerated or until symptoms subside. To treat severe acute exacerbations, higher doses of 50 to 250 mg/m2 of ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT- 518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), simvastatin, may be administered as a "pulse" systemic therapy. Other anti-scarring agents can be administered at equivalent doses adjusted for the potency and tolerability of the agent.

For specific high potency drugs, the total single dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per volume of 0.01 μg - 100 mg per mL; preferably 0.1 μg/mL - 20 mg/mL For mid-potency drugs, the total single dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per volume of 0.01 μg - 200 mg per mL, preferably 0.1 μg/mL - 40 mg/mL. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit volume of 0.01 μg - 300 mg per mL; preferably 0.1 μg/mm2 - 100 mg/mL.

According to another aspect, any anti-infective agent described above may be used in conjunction with formulations for the treatment or prevention of cartilage loss. Exemplary antynfective agents - include (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin), as well as analogues and derivatives of the aforementioned.

The drug dose administered from the present compositions for prevention or inhibition of infection in accordance with the present invention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single anti-Infective systemic dose application. In certain aspects, the anti-infective agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days.

The exemplary anti-infective agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-infective agent in the composition can be in the range of about 0.01 μg-1 μg, or about 1 μg-10 μg, or about 10 μg-1 mg, or about 1 mg to 10 mg, or about 10 mg-100 mg, or about 100 mg to 250 mg, or about 250 mg-1000 mg. The dose (amount) of anti-infective agent per unit area of device or tissue surface to which the agent is applied may ' be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or about 1 μg/mm2 - 10 μg/mm2, or about 10 μg/mm2 - 100 μg/mm2, or about 100 μg/mm2 to 250 μg/mm2, or about 250 μg/mm2 - 1000 μg/mm2. As different compositions will release the anti-infective agent at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the composition such that a minimum concentration of about 10"8 M to 10-7 M, or about 10 M to 10"6 M about 10"6 M to 10"5 M or about lO"5 M to 10"4 M of the agent is maintained on the tissue surface.

(d) Hypertrophic Sears/Keloids

In another aspect of the invention, compositions containing a therapeutically active agent (e.g., a fibrosis-inhibiting agent) and methods are provided for treating hypertrophic scars and keloids.

Hypertrophic scars and keloids are an overgrowth of dense fibrous tissue that is the result of an excessive fibroproliferative wound healing process. Hypertrophic scars and keloids usually develop after healing of a skin injury. Briefly, healing of wounds and scar formation occurs in three phases: inflammation, proliferation, and maturation. The first phase, inflammation, occurs in response to an injury which is severe enough to break the skin. During this phase, which lasts 3 to 4 days, blood and tissue fluid form an adhesive coagulum and fibrinous network which serves to bind the wound surfaces together. This is then followed by a proliferative phase in which there is ingrowth of capillaries and connective tissue from the wound edges, and closure of the skin defect. Finally, once capillary and fibroblastic proliferation has ceased, the maturation process begins wherein the scar contracts and becomes less cellular, less vascular, and appears flat and white. This final phase may take between 6 and 12 months.

If too much connective tissue is produced and the wound remains persistently cellular, the scar may become red and raised. If the scar remains within the boundaries of the original wound it is referred to as a hypertrophic scar, but if it extends beyond the original scar and into the - surrounding tissue, the lesion is referred to as a keloid. Hypertrophic scars and keloids are produced during the second and third phases of scar formation. Several wounds are particularly prone to excessive endothelial and fibroblastic proliferation, including burns, open wounds, and infected wounds. With hypertrophic scars, some degree of maturation occurs and gradual improvement occurs. In the case of keloids however, an actual tumor is produced which can become quite large. Spontaneous improvement in such cases rarely occurs.

Keloids and hypertrophic scars located at most sites are primarily of cosmetic concern; however, some keloids or hypertrophic scars can cause contractures, which may result in a loss of function if overlying a joint, or they can cause significant disfigurement if located on the face. Both keloids and hypertrophic scars can be painful or pruritic.

Within one embodiment of the present invention the compositions are directly injected into a hypertrophic scar or keloid, in order to prevent the progression of these lesions. The frequency of injections will depend upon the release kinetics of the polymer used, and the clinical response. This therapy is of particular value in the prophylactic treatment of conditions which are known to result in the development of hypertrophic scars and keloids (e.g., burns, the excision site of a keloid or hypertrophic scar, wounds on the chest and back of predisposed patients, etc.), and is preferably initiated prior to, or during the proliferative phase (from day 1 forward), but before hypertrophic scar or keloid development (i.e., within the first 3 months post-injury).

In one aspect, the present invention provides topical and injectable compositions that include an anti-scarring agent and a polymeric carrier suitable for application on or into hypertrophic scars or keloids. Numerous polymeric and non-polymeric delivery systems for use in treating hypertrophic scars or keloids have been described above.

Incorporation of a fibrosis-inhibiting agent into a topical formulation or an injectable formulation is one approach to treat this condition. The topical formulation can be in the form of a solution, a suspension, an emulsion, a gel, an ointment, a cream, film or mesh. The injectable formulation can be in the form of a solution, a suspension, an emulsion or a gel. Polymeric and non-polymeric components that can be used to prepare these topical or injectable compositions are described above.

In another embodiment, the fibrosis-inhibiting therapeutic agent can be incorporated into a secondary carrier (e.g., micelles, liposomes, emulsions, microspheres, nanospheres etc, as described above). Microsphere and nanospheres may include degradable polymers. Degradable polymers that can be used include poly(hydroxyl esters) (e.g., PLGA, PLA, PCL, and the like) as well as polyanhydrides, polyorthoesters and polysaccharides (e.g., chitosan and alginates).

In addition, a variety of other compositions and approaches for treating hypertrophic scars and keloids may be used in accordance with the invention. For example, treatment may include the administration of an effective amount of angiogenesis inhibitor (e.g., fumagillol, thalidomide) as a systemic or local treatment to decrease excessive scarring. See, e.g., U.S. Patent No. 6,638,949. The treatment may be a copolymer composed of a hydrophilic polymer, such as polyethylene glycol, that is bound to a polymer that adsorbs readily to the surfaces of body tissues, such as phenylboronic acid. See, e.g., U.S. Patent No. 6,596,267. The treatment may include a cryoprobe containing cryogen whereby it is positioned within the hypertrophic scar or keloid to freeze the tissue. See, e.g., U.S. Patent No. 6,503,246. The treatment may be a method of locally administering an amount of botulinum toxin in or in close proximity to the skin wound, such that the healing is enhanced. See, e.g., U.S. Patent No. 6,447,787. The treatment may be a liquid composition composed of a film-forming carrier such as a collodion which contains one or more active ingredients such as a topical steroid, silicone gel and vitamin E. See, e.g., U.S. Patent No. 6,337,076. The treatment may be a method of administering an antifibrotic amount of fluoroquinolone to prevent or treat scar tissue formation. See, e.g., U.S. Patent No. 6,060,474. The treatment may be a composition of an effective amount of calcium antagonist and protein synthesis inhibitor sufficient to cause matrix degradation at a scar site so as to control scar formation. See, e.g., U.S. Patent No. 5,902,609. The treatment may be a composition of non-biodegradable microspheres with a substantial surface charge in a pharmaceutically acceptable carrier. See, e.g., U.S. Patent No. 5,861 ,149. The treatment may be a composition of endothelial cell growth factor and heparin which may be administered topically or by intralesional injection. See, e.g., U.S. Patent No. 5,500,409.

Treatments and compositions for hypertrophic scars and keloids, which may be combined with one or more fibrosis-inhibiting agents according to the present invention, include commercially available products. Representative products include, for example, PROXIDERM External Tissue Expansion product for wound healing from Progressive Surgical Products (Westbury, NY)1 CICA-CARE Gel Sheet dressing product from Smith & Nephew Healthcare Ltd (India), and MEPIFORM Self-Adherent Silicone Dressing from Molnlycke Health Care (Eddystone, PA).

In one aspect, the present invention provides topical and injectable compositions that include an anti-scarring agent and a polymeric carrier suitable for application on or into hypertrophic scars or keloids or sites that are prone to forming hypertrophic scars or keloids.

Within one embodiment of the present invention either anti- scarring agents alone, or anti-scarring compositions as described above, are directly injected into a hypertrophic scar or keloid, in order to prevent the progression of these lesions. The frequency of injections will depend upon the release kinetics of the polymer used (if present), and the clinical response. This therapy is of particular value in the prophylactic treatment of conditions which are known to result in the development of hypertrophic scars and keloids (e.g., burns, the excision site of a keloid or hypertrophic scar, wounds on the chest and back of predisposed patients, etc.), and is preferably initiated prior to, or during the proliferative phase (from day 1 forward), but before hypertrophic scar or keloid development (i.e., within the first 3 months post-injury).

According to the present invention, any fibrosis-inhibiting agent described above could be utilized alone or in combination in the practice of this embodiment. Within one embodiment of the invention, compositions for treating hypertrophic scars or keloids may release an agent that inhibits one or more of the four general components of the process of fibrosis (or scarring), including: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue).

Examples of fibrosis-inhibiting agents for use in composition for treating hypertrophic scars and keloids include the following: ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB- 2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, as well as analogues and derivatives of the aforementioned.

Additional examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1- 10OnM IC5O range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC50 range) such as 5-azacytidine, Ly333531(ruboxistaurin), and simvastatin.

The drug dose administered from the present compositions for the treatment of hypertrophic scars and keloids will depend on a variety of factors, including the type of formulation and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single systemic dose application. In certain aspects, the anti- scarring agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. In one aspect, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

The exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in the composition can be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg. The dose (amount) of anti-scarring agent per unit area of surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or 1 μg/mm2 - 10 μg/mm2, or 10 μg/mm2 - 250 μg/mm2, 250 μg/mm2 - 1000 μg/mm2, or 1000 μg/mm2 - 2500 μg/mm2.

Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with compositions for the treatment of inflammatory arthritis in accordance with the invention. The following dosages are particularly useful for intra-articular administration: . , (A) Angiogenesis inhibitors including Alphastatin, ZD-6474, IDN-5390, SB- 2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per ml_; preferred dose of 0.1 μg/mL - 30 mg/mL. (B) mTOR inhibitors including AP-23573 and Temsirolimus, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per ml_; preferred dose of 0.1 μg/ ml_ - 20 mg/ ml_. (C) Tubulin antagonists including synthadotin, analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 μg per ml_; preferred dose of 0.1 μg/ ml_ - 20 mg/ ml_. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/mL - 20 mg/ mL (E) Kinesin antagonists including SB-715992 and analogues and derivatives thereof: tota single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (F) TNF alpha antagonists including Etanercept, humicade, adalimumab and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total single dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 300 mg per mL; preferred dose of 0.1 μg/ mL - 100 mg/ mL (J) NF KAPPA B Inhibitors including Bortezomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 20 mg/ mL. (K) Elongation factor-1 alpha inhibitors including aplidine and analogues and derivatives thereof: total single dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 100 mg per mL; preferred dose of 0.1 μg/ mL - 100 mg/ mL. (L) Tyrosine kinase inhibitors including Gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit volume of 0.01 μg - 300 mg per mL; preferred dose of 0.1 μg/ mL - 100 μg/ ml_. In another aspect, systemic treatment may be administered when severe exacerbations or systemic disease (e.g., RA) are present. Anti- scarring agents that are delivered systemically should be dosed according to the level of drug required to inhibit the pathologies of inflammatory arthritis as described above. These systemic doses may vary according to patient, severity of disease, formulation of the administered agent, potency and/or tolerability of the agent, and route of administration. For example, for ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), simvastatin, and an analogue or derivatives of the aforementioned, preferred embodiments would be 10 to 175 mg/m2 once every 1 to 4 weeks, 10 to 75 mg/m2 daily, as tolerated, or 10 to 175 mg/m2 weekly, as tolerated or until symptoms subside. To treat severe acute exacerbations, higher doses of 50 to 250 mg/m2 of ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT- 518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), or simvastatin may be administered as a "pulse" systemic therapy. Other anti-scarring agents can be administered at equivalent doses adjusted for the potency and tolerability of the agent. For specific high potency drugs, the total single dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per volume of 0.01 μg - 100 mg per ml_; preferably 0.1 μg/mL - 20 mg/mL For mid-potency drugs, the total single dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per volume of 0.01 μg - 200 mg per ml_, preferably 0.1 μg/mL - 40 mg/mL. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit volume of 0.01 μg - 300 mg per mL; preferably 0.1 μg/mm2 - 100 mg/mL.

According to another aspect, any anti-infective agent described above may be used in conjunction with formulations for the treatment or prevention of hypertrophic scars and keloids. Exemplary anti- infective agents include (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin), as well as analogues and derivatives of the aforementioned.

The drug dose administered from the present compositions for prevention or inhibition of infection in accordance with the present invention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single anti-infective systemic dose application. In certain aspects, the anti-infective agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days.

The exemplary anti-infective agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-infective agent in the composition can be in the range of about 0.01 μg-1 μg, or about 1 μg-10 μg, or about 10 μg-1 mg, or about 1 mg to 10 mg, or about 10 mg-100 mg, or about 100 mg to 250 mg, or about 250 mg-1000 mg. The dose (amount) of anti-infective agent per unit area of device or tissue surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or about 1 μg/mm2 - 10 μg/mm2, or about 10 μg/mm2 - 100 μg/mm2, or about 100 μg/mm2 to 250 μg/mm2, or about 250 μg/mm2 - 1000 μg/mm2. As different compositions will release the anti-infective agent at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the composition such that a minimum concentration of about 10~8 M to 10~7 M, or about 10"7 M to 10"6 M about 10"6 M to 10'5 M or about 10"5 M to 10"4 M of the agent is maintained on the tissue surface.

(e) Vascular Diseases

In one aspect, the present invention provides for the use of a polymer composition comprising a polymeric carrier and one or more fibrosis-inhibiting agents for the treatment of vascular disease (e.g., stenosis, restenosis, or atherosclerosis).

Perivascular Delivery

A further aspect of the invention provides therapeutic compositions which may be delivered perivascularly (e.g., to an external portion of a blood vessel or directly into the adventitia of a blood vessel) for the treatment or prevention of a vascular disease (e.g., stenosis, restenosis, or atherosclerosis).

Perivascular drug delivery involves percutaneous administration of localized (often sustained release) therapeutic formulations using a needle or catheter directed via ultrasound, CT, fluoroscopic, MRI or endoscopic guidance to the adventitial surface of a targeted blood vessel (arteries, veins, autologous bypass grafts, synthetic bypass grafts, AV fistulas). Alternatively the procedure can be performed intra-operatively (e.g., during bypass surgery, hemodialysis access surgery) under direct vision or with additional imaging guidance. Such a procedure can also be performed in conjunction with endovascular procedures such as angioplasty, atherectomy, or stenting or in association with an operative arterial procedure such as endarterectomy, vessel or graft repair or graft insertion. For example, within one embodiment, polymeric formulations of for example, ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5- azacytidine, Ly333531 (ruboxistaurin), and simvastatin, can be injected into the vascular wall or applied to the adventitial surface of a blood vessel allowing drug concentrations to remain highest in regions where biological activity is most needed. This has the potential to reduce local "washout" of the drug that can be accentuated by continuous blood flow over the surface of an endovascular drug delivery device (such as a drug-coated stent). Administration of effective fibrosis-inhibiting agents to the external surface of the vessel can reduce obstruction of the artery, vein or graft and reduce the risk of complications associated with intravascular manipulations (such as restenosis, embolization, thrombosis, plaque rupture, and systemic drug toxicity).

For example, in a patient with narrowing of the superficial femoral artery, balloon angioplasty would be performed in the usual manner (i.e., passing a balloon angioplasty catheter down the artery over a guide wire and inflating the balloon across the lesion). Prior to, at the time of, or after angioplasty, a needle would be inserted through the skin under ultrasound, fluoroscopic, or CT guidance and a fibrosis-inhibiting agent or composition (e.g., ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17-DMAG, tacrolimus, loteprednol etabonate, juglone, - prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5- azacytidine, Ly333531 (ruboxistaurin), and simvastatin) impregnated into a slow release polymer) would be infiltrated through the needle or catheter in a circumferential manner directly around the area of narrowing in the artery. This could be performed around any artery, vein or graft, but ideal candidates for this intervention include diseases of the carotid, coronary, iliac, common femoral, superficial femoral and popliteal arteries and at the site of graft anastomosis. Logical venous sites include infiltration around veins in which indwelling catheters are inserted. Similarly at the time of endoscopic or open coronary bypass surgery, peripheral bypass surgery or hemodialysis access surgery, a fibrosis-inhibiting agent or composition (e.g., ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, tacrolimus, loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, mannose-6-phosphate, 5-azacytidine, Ly333531 (ruboxistaurin), and simvastatin) impregnated into a slow release polymer) would be infiltrated, sprayed or wrapped in a circumferential manner in the region of the anastomosis where there is an increased incidence of restenosis. This could be performed around any artery, vein or graft, but ideal candidates for this intervention include diseases of the carotid, coronary, iliac, common femoral, superficial femoral and popliteal arteries and at the site of AV graft anastomosis.

According to the present invention, any anti-scarring agent described above can be utilized in the practice of this invention. Within one embodiment, compositions for perivascular drug delivery may be adapted to release an agent that inhibits one or more of the five general components of the process of fibrosis (or scarring), including: inflammatory response and" inflammation, migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), formation of new blood vessels (angiogenesis), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue). By inhibiting one or more of the components of fibrosis (or scarring), the overgrowth of neointimal tissue may be inhibited or reduced.

The drug dose of the fibrosis-inhibiting agent administered from the present compositions for perivascular delivery will depend on a variety of factors, including the type of formulation and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single systemic dose application. In certain aspects, the anti- scarring agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days. In one aspect, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

Several examples of fibrosis-inhibiting agents for use with compositions for perivascular drug delivery include the following: ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB- 2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, as well as analogues and derivatives of the aforementioned.

Additional specific examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1-10OnM IC50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC5O range) such as 5-azacytidine, Ly333531(ruboxistaurin), and simvastatin.

The exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in the composition can be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg. The dose (amount) of anti-scarring agent per unit area of surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or 1 μg/mm2 - 10 μg/mm2, or 10 μg/mm2 - 250 μg/mm2, 250 μg/mm2 - 1000 μg/mm2, or 1000 μg/mm2 - 2500 μg/mm2.

Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with perivascular administration in accordance with the invention. (A) Angiogenesis inhibitors including Alphastatin, ZD-6474, IDN-5390, SB-2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (B) mTOR inhibitors including AP-23573 and Temsirplimus, analogues and derivatives thereof." total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10~8- 10"4 M of agent is to be maintained on the implant or barrier surface. (C) Tubulin antagonists including synthadotin, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10 s - 10"4 M of agent is to be maintained on the implant or barrier surface. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (E) Kinesin antagonists including SB- 715992 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (F) TNF alpha antagonists including etanercept, humicade, adalimumab and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10'8- 10'4 M of agent is to be maintained on the implant or barrier surface. (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8 - 10"4 M of agent is to be maintained on the implant or barrier surface. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (J) NF KAPPA B Inhibitors including Bortezomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (K) Elongation factor- 1 alpha inhibitors including aplidine and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (L) Tyrosine kinase inhibitors including Gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface.

For high potency drugs, the total dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per unit area of 0.01 μg - 100 μg per mm2; preferably 0.1 μg/mm2 - 20 μg/mm2; and minimum concentration of 108 - 10'4 M of agent should be maintained on the implant or barrier surface. For mid-potency drugs, the total dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per unit area of 0.01 μg - 200 μg per mm2, preferably 0.1 μg/mm2 - 40 μg/mm2; and minimum concentration of 10" 8 - 10"4 M of agent should be maintained on the implant or barrier surface. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit area of 0.01 μg - 500 μg per mm2; preferably 0.1 μg/mm2 - 100 μg/mm2; and minimum concentration of 10^ - 10"4 M of agent should to be maintained on the implant or barrier surface.

According to another aspect, any anti-infective agent described above may be used alone or in conjunction with an anti-fibrosing agent in the practice of the present embodiment. Exemplary anti-infective agents include (A) anthracyclines (e.g., doxorubicin and mitoxantrone), (B) fluoropyrimidines (e.g., 5-FU), (C) folic acid antagonists (e.g., methotrexate), (D) podophylotoxins (e.g., etoposide), (E) camptothecins, (F) hydroxyureas, and (G) platinum complexes (e.g., cisplatin), as well as analogues and derivatives of the aforementioned. The drug dose administered from the present compositions for prevention or inhibition of infection in accordance with the present invention will depend on a variety of factors, including the type of formulation, the location of the treatment site, and the type of condition being treated. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the treatment site), total drug dose administered can be measured and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 50%, 20%, 10%, 5%, or even less than 1% of the concentration typically used in a single anti-infective systemic dose application. In certain aspects, the anti-infective agent is released from the composition in effective concentrations in a time period that may be measured from the time of infiltration into tissue adjacent to the device, which ranges from about less than 1 day to about 180 days. Generally, the release time may also be from about less than 1 day to about 180 days; from about 7 days to about 14 days; from about 14 days to about 28 days; from about 28 days to about 56 days; from about 56 days to about 90 days; from about 90 days to about 180 days.

The exemplary anti-infective agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-infective agent in the composition can be in the range of about 0.01 μg-1 μg, or about 1 μg-10 μg, or about 10 μg-1 mg, or about 1 mg to 10 mg, or about 10 mg-100 mg, or about 100 mg to 250 mg, or about 250 mg-1000 mg. The dose (amount) of anti-infective agent per unit area of device or tissue surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or about 1 μg/mm2 - 10 μg/mm2, or about 10 μg/mm2 - 100 μg/mm2, or about 100 μg/mm2 to 250 μg/mm2, or about 250 μg/mm2 - 1000 μg/mm2. As different compositions will release the anti-infective agent at differing rates, the above dosing parameters should be utilized in combination with the release rate of the drug from the composition such that a minimum concentration of about 10'8 M to 10"7 M, or about 10"7 M to 10'6 M about 10"6 M to 1(T5 M or about 10'5 M to 10"4 M of the agent is maintained on the tissue surface.

(f) Combining With Medical Devices or Implants

The fibrosis-inhibiting agents and/or anti-infective agents and compositions of the present invention can also be combined with an implant or an implantable medical device, (e.g., artificial joints, retaining pins, cranial plates, and the like, of metal, plastic and/or other materials), breast implants (e.g., silicone gel envelopes, foam forms, and the like), implanted catheters and cannulas intended for long-term use (beyond about three days), artificial organs and vessels (e.g., artificial hearts, pancreases, kidneys, blood vessels, and the like), drug delivery devices (including monolithic implants, pumps and controlled release devices such as ALZET minipumps (DURECT Corporation, Cupertino, California), steroid pellets for anabolic growth or contraception, and the like, sutures for dermal or internal use, periodontal membranes, ophthalmic shields, corneal lenticules, and the like.

A range of polymeric and non-polymeric materials can be used to incorporate the fibrosis-inhibiting agent onto or into a device. The anti- fibrosing agent composition can be incorporated into or onto the device in a variety of ways. Coating of the device with the fibrosis-inhibiting agent containing composition or with the fibrosis-inhibiting agent only is one process that can be used to incorporate the fibrosis-inhibiting agent into or onto the device. The anti-fibrosing agent or anti-fibrosing composition may be coated onto the entire device or a portion of the device using a method, such as by dipping, spraying, painting or vacuum deposition, that is appropriate for the particular type of device. B. Dip coating

Dip coating is one coating process that can be used. In one embodiment, the fibrosis-inhibiting agent is dissolved in a solvent for the fibrosis agent and is then coated onto the device.

Fibrosis-inhibiting agent with an inert-solvent In one embodiment, the solvent is an inert solvent for the device such that the solvent does not dissolve the medical device to any great extent and is not absorbed by the device to any great extent. The device can be immersed, either partially or completely, in the fibrosis- inhibiting agent/solvent solution for a specific period of time. The rate of immersion into the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The device can then be removed from the solution. The rate at which the device can be withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated device can be air-dried. The dipping process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent being coated on the surface of the device.

Fibrosis-inhibiting agent with a swelling solvent In one embodiment, the solvent is one that will not dissolve the device but will be absorbed by the device. These solvents can thus swell the device to some extent. The device can be immersed, either partially or completely, in the fibrosis-inhibiting agent/solvent solution for a specific period of time (seconds to days). The rate of immersion into the fibrosis- inhibiting agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The device can then be removed from the solution. The rate at which the device can be withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated device can be air-dried. The clipping process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent being adsorbed into the medical device. The fibrosis-inhibiting agent may also be present on the surface of the device. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated device into a solvent for the fibrosis-inhibiting agent or by spraying the coated device with a solvent for the fibrosis-inhibiting agent.

Fibrosis-inhibiting agent with a solvent

In one embodiment, the solvent is one that will be absorbed by the device and that will dissolve the device. The device can be immersed, either partially or completely, in the fibrosis-inhibiting agent/solvent solution for a specific period of time (seconds to hours). The rate of immersion into the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The device can then be removed from the solution. The rate at which the device can be withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated device can be air-dried. The dipping process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent being adsorbed into the medical device as well as being surface associated. In the preferred embodiment, the exposure time of the device to the solvent can be such that there are no significant permanent dimensional changes to the device. The fibrosis-inhibiting agent may also be present on the surface of the device. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated device into a solvent for the fibrosis-inhibiting agent or by spraying the coated device with a solvent for the fibrosis-inhibiting agent.

In the above description the device can be a device that has not been modified as well as a device that has been further modified by coating with a polymer, surface treated by plasma treatment, flame treatment, corona treatment, surface oxidation or reduction, surface etching, mechanical smoothing or roughening, or grafting prior to the coating process.

In one embodiment, the fibrosis-inhibiting agent and a polymer are dissolved in a solvent, for both the polymer and the fibrosis -inhibiting agent, and are then coated onto the device.

In any one the above dip coating methods, the surface of the device can be treated with a plasma polymerization method prior to coating of the scarring agent or scarring agent containing composition, such that a thin polymeric layer is deposited onto the device surface. Examples of such methods include parylene coating of devices and the use of various monomers such hydrocyclosiloxane monomers. Parylene coating may be especially advantageous if the device, or portions of the device, is composed of materials (e.g., stainless steel, nitinol) that do not allow incorporation of the therapeutic agent(s) into the surface layer using one of the above methods. A parylene primer layer may be deposited onto the device using a parylene coater (e.g., PDS 2010 LABCOTER2 from Cookson Electronics) and a suitable reagent (e.g., di-p-xylylene or dichloro-di-p- xylylene) as the coating feed material. Paryiene compounds are commercially available, for example, from Specialty Coating Systems, Indianapolis, IN), including PARYLENE N (di-p-xylylene), PARYLENE C (a monchlorinated derivative of PARYLENE N, and PARYLENE D, a dichlorinated derivative of PARYLENE N).

Fibrosis-inhibiting agent/polymer with an inert-solvent In one embodiment, the solvent is an inert solvent for the device such that the solvent does not dissolve the medical device to any great extent and is not absorbed by the device to any great extent. The device can be immersed, either partially or completely, in the fibrosis- inhibiting agent/polymer/solvent solution for a specific period of time. The rate of immersion into the fibrosis-inhibiting agent/polymer/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The device can then be removed from the solution. The rate at which the device can be withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated device can be air-dried. The dipping process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent/polymer being coated on the surface of the device.

Fibrosis-inhibiting agent/polymer with a swelling solvent In one embodiment, the solvent is one that will not dissolve the device but will be absorbed by the device. These solvents can thus swell the device to some extent. The device can be immersed, either partially or completely, in the fibrosis-inhibiting agent/polymer/solvent solution for a specific period of time (seconds to days). The rate of immersion into the fibrosis-inhibiting agent/polymer/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The device can then be removed from the solution. The rate at which the device can be withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated device can be air-dried. The dipping process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent/polymer being coated onto the surface of the device as well as the potential for the fibrosis-inhibiting agent being adsorbed into the medical device. The fibrosis-inhibiting agent may also be present on the surface of the device. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated device into a solvent for the fibrosis-inhibiting agent or by spraying the coated device with a solvent for the fibrosis-inhibiting agent. Fibrosis-inhibiting agent/polymer with a solvent

In one embodiment, the solvent is one that will be absorbed by the device and that will dissolve the device. The device can be immersed, either partially or completely, in the fibrosis-inhibiting agent/solvent solution for a specific period of time (seconds to hours). The rate of immersion into the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The device can then be removed from the solution. The rate at which the device can be withdrawn from the solution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). The coated device can be air-dried. The dipping process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. In the preferred embodiment, the exposure time of the device to the solvent can be such that there are not significant permanent dimensional changes to the device (other than those associated with the coating itself). The fibrosis-inhibiting agent may also be present on the surface of the device. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated device into a solvent for the fibrosis-inhibiting agent or by spraying the coated device with a solvent for the fibrosis-inhibiting agent.

In the above description the device can be a device that has not been modified as well as a device that has been further modified by coating with a polymer (e.g., parylene), surface treated by plasma treatment, flame treatment, corona treatment, surface oxidation or reduction, surface etching, mechanical smoothing or roughening, or grafting prior to the coating process.

In another embodiment, a suspension of the fibrosis-inhibiting agent in a polymer solution can be prepared. The suspension can be prepared by choosing a solvent that can dissolve the polymer but not the fibrosis-inhibiting agent or a solvent that can dissolve the polymer and in which the fibrosis-inhibiting agent is above its solubility limit. In similar processes described above, a device can be dipped into the suspension of the fibrosis-inhibiting and polymer solution such that the device is coated with a polymer that has a fibrosis-inhibiting agent suspended within it.

C. Spray coating

Spray coating is another coating process that can be used. In the spray coating process, a solution or suspension of the fibrosis-inhibiting agent, with or without a polymeric or non-polymeric carrier, is nebulized and directed to the device to be coated by a stream of gas. One can use spray devices such as an air-brush (for example models 2020, 360, 175, 100, 200, 150, 350, 250, 400, 3000, 4000, 5000, 6000 from Badger Air-brush Company, Franklin Park, IL), spray painting equipment, TLC reagent sprayers (for example Part # 14545 and 14654, Alltech Associates, Inc. Deerfield, IL, and ultrasonic spray devices (for example those available from Sono-Tek, Milton, NY). One can also use powder sprayers and electrostatic sprayers.

In one embodiment, the fibrosis-inhibiting agent is dissolved in a solvent for the fibrosis agent and is then sprayed onto the device.

Fibrosis-inhibiting agent with an inert-solvent In one embodiment, the solvent is an inert solvent for the device such that the solvent does not dissolve the medical device to any great extent and is not absorbed by the device to any great extent. The device can be held in place or the device can be mounted onto a mandrel or rod that has the ability to move in an X, Y or Z plane or a combination of these planes. Using one of the above described spray devices, the device can be spray coated such that the device is either partially or completely coated with the fibrosis-inhibiting agent/solvent solution. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 mL per sec to 10 mL per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained. The coated device can be air-dried. The spray coating process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis- inhibiting agent being coated on the surface of the device.

Fibrosis-inhibiting agent with a swelling solvent In one embodiment, the solvent is one that will not dissolve the device but will be absorbed by the device. These solvents can thus swell the device to some extent. The device can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/solvent solution. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 mL per sec to 10 ml_ per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained. The coated device can be air-dried. The spray coating process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis- inhibiting agent being adsorbed into the medical device. The fibrosis- inhibiting agent may also be present on the surface of the device. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated device into a solvent for the fibrosis-inhibiting agent or by spraying the coated device with a solvent for the fibrosis-inhibiting agent.

Fibrosis-inhibiting agent with a solvent

In one embodiment, the solvent is one that will be absorbed by the device and that will dissolve the device. The device can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/solvent solution. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 mL per sec to 10 mL per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained. The coated device can be air-dried. The spray coating process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent being adsorbed into the medical device as well as being surface associated. In the preferred embodiment, the exposure time of the device to the solvent can be such that there are not significant permanent dimensional changes to the device. The fibrosis-inhibiting agent may also be present on the surface of the device. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated device into a solvent for the fibrosis-inhibiting agent or by spraying the coated device with a solvent for the fibrosis-inhibiting agent.

In the above description the device can be a device that has not been modified as well as a device that has been further modified by coating with a polymer (e.g., parylene), surface treated by plasma treatment, flame treatment, corona treatment, surface oxidation or reduction, surface etching, mechanical smoothing or roughening, or grafting prior to the coating process.

In one embodiment, the fibrosis-inhibiting agent and a polymer are dissolved in a solvent, for both the polymer and the anti-fibrosing agent, and are then spray coated onto the device.

Fibrosis-inhibiting agent/polymer with an inert-solvent In one embodiment, the solvent is an inert solvent for the device such that the solvent does not dissolve the medical device to any great extent and is not absorbed by the device to any great extent. The device can be spray coated, either partially or completely, in the fibrosis- inhibiting agent/polymer/solvent solution for a specific period of time. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 ml. per sec to 10 ml_ per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained. The coated device can be air-dried. The spray coating process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent/polymer being coated on the surface of the device. Fibrosis-inhibitinq agent/polymer with a swelling solvent In one embodiment, the solvent is one that will not dissolve the device but will be absorbed by the device. These solvents can thus swell the device to some extent. The device can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/polymer/solvent solution. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 ml_ per sec to 10 mL per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained. The coated device can be air-dried. The spray coating process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. This process will result in the fibrosis-inhibiting agent/polymer being coated onto the surface of the device as well as the potential for the fibrosis-inhibiting agent being adsorbed into the medical device. The fibrosis-inhibiting agent may also be present on the surface of the device. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated device into a solvent for the fibrosis-inhibiting agent or by spraying the coated device with a solvent for the fibrosis-inhibiting agent.

Fibrosis-inhibiting agent/polymer with a solvent In one embodiment, the solvent is one that will be absorbed by the device and that will dissolve the device. The device can be spray coated, either partially or completely, in the fibrosis-inhibiting agent/solvent solution. The rate of spraying of the fibrosis-inhibiting agent/solvent solution can be altered (e.g., 0.001 mL per sec to 10 mL per sec) to ensure that a good coating of the fibrosis-inhibiting agent is obtained. The coated device can be air-dried. The spray coating process can be repeated one or more times depending on the specific application. The device can be dried under vacuum to reduce residual solvent levels. In the preferred embodiment, the exposure time of the device to the solvent can be such that there are not significant permanent dimensional changes to the device (other than those associated with the coating itself). The fibrosis-inhibiting agent may also be present on the surface of the device. The amount of surface associated fibrosis-inhibiting agent may be reduced by dipping the coated device into a solvent for the fibrosis-inhibiting agent or by spraying the coated device with a solvent for the fibrosis-inhibiting agent.

In the above description the device can be a device that has not been modified as well as a device that has been further modified by coating with a polymer (e.g., parylene), surface treated by plasma treatment, flame treatment, corona treatment, surface oxidation or reduction, surface etching, mechanical smoothing or roughening, or grafting prior to the coating process.

In another embodiment, a suspension of the fibrosis-inhibiting agent in a polymer solution can be prepared. The suspension can be prepared by choosing a solvent that can dissolve the polymer but not the fibrosis-inhibiting agent or a solvent that can dissolve the polymer and in which the fibrosis-inhibiting agent is above its solubility limit. In similar processes described above, the suspension of the fibrosis-inhibiting and polymer solution can be sprayed onto the device such that the device is coated with a polymer that has a fibrosis-inhibiting agent suspended within it.

In a general method for coating a surface of a synthetic implant, the multifunctional compounds are exposed to the modified environment, and a thin layer of the composition is then applied to a surface of the implant before substantial inter-reaction has occurred. In one embodiment, in order to minimize cellular and fibrous reaction to the coated implant, the compounds are selected so as to result in a matrix that has a net neutral charge. Application of the compounds to the implant surface may be by extrusion, brushing, spraying, or by any other convenient means. Following application of the compounds to the implant surface, inter-reaction is allowed to continue until complete and the three-dimensional matrix is formed. Although this method can be used to coat the surface of any type of synthetic implant, it is particularly useful for implants where reduced thrombogenicity is an important consideration, such as artificial blood vessels and heart valves, vascular grafts, vascular stents, anastomotic connector devices, and stent/graft combinations. The method may also be used to coat implantable surgical membranes (e.g., monofilament polypropylene) or meshes (e.g., for use in hernia repair). Breast implants may also be coated using the above method in order to minimize capsular contracture.

The fibrosis-inhibiting compounds and compositions can also be coated on a suitable fibrous material, which can then be wrapped around a bone to provide structural integrity to the bone. The term "suitable fibrous material" as used herein, refers to a fibrous material which is substantially insoluble in water, non-immunogenic, biocompatible, and immiscible with the crosslinkable compositions of the invention. The fibrous material may comprise any of a variety of materials having these characteristics and may be combined with crosslinkable compositions herein in order to form and/or provide structural integrity to various implants or devices used in connection with medical and pharmaceutical uses.

The fibrosis-inhibiting compounds and compositions of the present invention may also be used to coat lenticules, which are made from either naturally occurring or synthetic polymers.

In yet another example, the device can be coated with a polyurethane and then allowed to partially dry such that the surface is still tacky. A particulate form of the fibrosis-inhibiting agent or fibrosis-inhibiting agent/secondary carrier can then be applied to all or a portion of the tacky coating after which the device is dried.

In yet another example, the device can be coated with one of the coatings described above. A thermal treatment process can then be used to soften the coating, afterwhich the fibrosis-inhibiting agent or the fibrosis-inhibiting agent/secondary carrier is applied to the entire device or to a portion of the device (e.g., outer surface).

In one embodiment, all or a portion of the device is coated with a primer (bonding) layer and a drug release layer, as described in U.S. Patent application entitled, "Stent with Medicated Multi-Layer Hybrid Polymer Coating," filed September 16, 2003 (U.S. Serial No. 10/662,877).

In order to develop a hybrid polymer delivery system for targeted therapy, it is desirable to be able to control and manipulate the properties of the system both in terms of physical and drug release characteristics. The active agents can be imbibed into a surface hybrid polymer layer, or incorporated directly into the hybrid polymer coating solutions. Imbibing drugs into surface polymer layers is an efficient method for evaluating polymer-drug performance in the laboratory, but for commercial production it may be preferred for the polymer and drug to be premixed in the casting mixture. Greater efficacy can be achieved by combining the two elements in the coating mixtures in order to control the ratio of active agent to polymer in the coatings. Such ratios are important parameters to the final properties of the medicated layers, i.e., they allow for better control of active agent concentration and duration of pharmacological activity.

Typical polymers used in the drug-release system can include water-insoluble cellulose esters, various polyurethane polymers including hydrophilic and hydrophobic versions, hydrophilic polymers such as polyethylene glycol (PEG), polyethylene oxide (PEO), polyvinylpyrrolidone (PVP), PVP copolymers such as vinyl acetate, hydroxyethyl methacrylate (HEMA) and copolymers such as methylmethacrylate (PMMA-HEMA), and other hydrophilic and hydrophobic acrylate polymers and copolymers containing functional groups such as carboxyl and/or hydroxyl.

Cellulose esters such as cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, and cellulose nitrate may be used. In one aspect of the invention, the therapeutic agent is formulated with a cellulose ester. Cellulose nitrate is a preferred cellulose ester because of its compatibility with the active agents and its ability to impart non-tackiness and cohesiveness to the coatings. Cellulose nitrate has been shown to stabilize entrapped drugs in ambient and processing conditions. Various grades of cellulose nitrate are available and may be used in a coating on a device, including cellulose nitrate having a nitrogen content = 11.8-12.2%. Various viscosity grades, including 3.5, 0.5 or 0.25 seconds, may be used in order to provide proper rheological properties when combined with the coating solids used in these formulations. Higher or lower viscosity grades can be used. However, the higher viscosity grades can be more difficult to use because of their higher viscosities. Thus, the lower viscosity grades, such as 3.5, 0.5 or 0.25 seconds, are generally preferred. Physical properties such as tensile strength, elongation, flexibility, and softening point are related to viscosity (molecular weight) and can decrease with the lower molecular weight species, especially below the 0,25 second grades.

The cellulose derivatives comprise hydroglucose structures. Cellulose nitrate is a hydrophobic, water-insoluble polymer, and has high water resistance properties. This structure leads to high compatibility with many active agents, accounting for the high degree of stabilization provided to drugs entrapped in cellulose nitrate. The structure of nitrocellulose is given below:

Figure imgf000413_0001
nitrocellulose

Cellulose nitrate is a hard, relatively inflexible polymer, and has limited adhesion to many polymers that are typically used to make medical devices. Also, control of drug elution dynamics is limited if only one polymer is used in the binding matrix. Accordingly, in one embodiment of the invention, the therapeutic agent is formulated with two or more polymers before being associated with the device. In one aspect, the agent is formulated with both polyurethane ((e.g., CHRONOFLEX AR, CHRONOFLEX AL, and BIONATE, PELLETHANE) and cellulose nitrate to provide a hybrid polymer drug loaded matrix. Polyurethanes provide the hybrid polymer matrix with greater flexibility and adhesion to the device, particularly when the device has been pre-coated with a primer. Polyurethanes can also be used to slow or hasten the drug elution from coatings. Aliphatic, aromatic, polytetramethylene ether glycol, and polycarbonate are among the types of polyurethanes, which can be used in the coatings. In one aspect, an anti-scarring agent (e.g., ZD-6474, AP- 23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib. as well as^analogues and derivatives of the aforementioned) may be incorporated into a carrier that includes a polyurethane and a cellulose derivative. Additional examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1- 10OnM IC5O range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC50 range) such as 5-azacytidine, Ly333531(ruboxistaurin), and simvastatin.

A heparin complex, such as benzalkonium heparinate or tridodecylammonium heparinate), may optionally be included in the formulation. From the structure below, it is possible to see how more or less hydrophilic polyurethane polymers may be created based on the number of hydrophilic groups contained in the polymer structures. In one aspect of the invention, the device is associated with a formulation that includes therapeutic agent, cellulose ester, and a polyurethane that is water- insoluble, flexible, and compatible with the cellulose ester.

Figure imgf000415_0001

Polyvinylpyrrolidone (PVP) is a polyamide that possesses unusual complexing and colloidal properties and is essentially physiologically inert. PVP and other hydrophilic polymers are typically biocompatible. PVP may be incorporated into drug loaded hybrid polymer compositions in order to increase drug release rates. In one embodiment, the concentration of PVP that is used in drug loaded hybrid polymer compositions can be less than 20%. This concentration can not make the layers bioerodable or lubricious. In general, PVP concentrations from <1% to greater than 80% are deemed workable. In one aspect of the invention, the therapeutic agent that is associated with an device is formulated with a PVP polymer.

Figure imgf000415_0002
polyvinylpyrrolidone

Acrylate polymers and copolymers including polymethylmethacrylate (PMMA) and polymethylmethacrylate hydroxyethyl

Figure imgf000415_0003
methacrylate (PMMA/HEMA) are known for their biocompatibility as a result of their widespread use in contact and intraocular lens applications. This class of polymer generally provokes very little smooth muscle and endothelial cell growth, and very low inflammatory response (Bar). These polymers/copolymers are compatible with drugs and the other polymers and layers of the instant invention. Thus, in one aspect, the device is associated with a composition that comprises an anti-scarring agent as described above, and an acrylate polymer or copolymer.

Methylmethacrylate Hydroxyethylmethacrylate Copolymer

Within another aspect of the invention, the coated device which inhibits or reduces an in vivo fibrotic reaction is further coated with a compound or compositions which delay the release of and/or activity of the fibrosis-inhibiting agent. Representative examples of such agents include biologically inert materials such as gelatin, PLGA/MePEG film, PLA, polyurethanes, silicone rubbers, surfactants, lipids, or polyethylene glycol, as well as biologically active materials such as heparin (e.g., to induce coagulation).

For example, in one embodiment of the invention, the active agent on the device is top-coated with a physical barrier. Such barriers can include non-degradable materials or biodegradable materials such as gelatin, PLGA/MePEG film, PLA, or polyethylene glycol among others. In one embodiment, the rate of diffusion of the therapeutic agent in the barrier coat is slower that the rate of diffusion of the therapeutic agent in the coating layer. In the case of PLGA/ MePEG, once the PLGA/ MePEG becomes exposed to the bloodstream, the MePEG can dissolve out of the PLGA, leaving channels through the PLGA layer to an underlying layer containing the fibrosis-inhibiting agent, which then can then diffuse into the vessel wall and initiate its biological activity. In another embodiment of the invention, a particulate form of the active agent may be coated onto any of the devices described below) using a polymer (e.g., PLG, PLA, aor a polyurethane). A second polymer, that dissolves slowly or degrades (e.g., MePEG-PLGA or PLG) and that does not contain the active agent, may be coated over the first layer. Once the top layer dissolves or degrades, it exposes the under coating which allows the active agent to be exposed to the treatment site or to be released from the coating.

Within another aspect of the invention, the outer layer of the coating of a coated device, which inhibits an in vivo fibrotic response, is further treated to crosslink the outer layer of the coating. This can be accomplished by subjecting the coated device to a plasma treatment process. The degree of crosslinking and nature of the surface modification can be altered by changing the RF power setting, the location with respect to the plasma, the duration of treatment as well as the gas composition introduced into the plasma chamber.

Protection of a biologically active surface can also be utilized by coating the device surface with an inert molecule that prevents access to the active site through steric hindrance, or by coating the surface with an inactive form of the fibrosis-inhibiting agent, which is later activated. For example, the device can be coated with an enzyme, which causes either release of the fibrosis-inhibiting agent or activates the fibrosis-inhibiting agent.

In another embodiment, the device is coated with a fibrosis- inhibiting agent and then further coated with a composition that comprises an anticoagulant such as heparin. As the anticoagulant dissolves away, the anticoagulant activity slows or stops, and the newly exposed fibrosis- inhibiting agent is available to inhibit or reduce fibrosis from occurring in the adjacent tissue.

The device can be coated with an inactive form of the fibrosis- inhibiting agent, which is then activated once the device is deployed. Such activation can be achieved by injecting another material into the treatment area after the device (as desribed below) is deployed or after the fibrosis- inhibiting agent has been administered to the treatment area (via, e.g., injections, spray, wash, drug delivery catheters or balloons). For example, the device can be coated with an inactive form of the fibrosis-inhibiting agent. Once the device is deployed, the activating substance is injected or applied into or onto the treatment site where the inactive form of the fibrosis- inhibiting agent has been applied. For example, a device can be coated with a biologically active fibrosis-inhibiting agent and a first substance having moieties that capable of forming an ester bond with another material. The coating can be covered with a second substance such as polyethylene glycol. The first and second substances can react to form an ester bond via, e.g., a condensation reaction. Prior to the deployment of the device, an esterase is injected into the treatment site around the outside of the device, which can cleave the bond between the ester and the fibrosis-inhibiting agent, allowing the agent to initiate fibrosis-inhibition.

In another aspect, a medical device may include a plurality of reservoirs within its structure, each reservoir configured to house and protect a therapeutic drug. The reservoirs may be formed from divets in the device surface or micropores or channels in the device body. In one aspect, the reservoirs are formed from voids in the structure of the device. The reservoirs may house a single type of drug or more than one type of drug. The drug(s) may be formulated with a carrier (e.g., a polymeric or non- polymeric material) that is loaded into the reservoirs. The filled reservoir can function as a drug delivery depot which can release drug over a period of time dependent on the release kinetics of the drug from the carrier. In certain embodiments, the reservoir may be loaded with a plurality of layers. Each layer may include a different drug having a particular amount (dose) of drug, and each layer may have a different composition to further tailor the amount of drug that is released from the substrate. The multi-layered carrier may further include a barrier layer that prevents release of the drug(s). The barrier layer can be used, for example, to control the direction that the drug elutes from the void.

As described above, the anti-fibrosing agent can be associated with a medical device using the polymeric carriers or coatings described above. In addition to the compositions and methods described above, there are various other compositions and methods that are known in the art. Representative examples of these compositions and methods for applying (e.g., coating) these compositons to devices are described in U.S. Patent. Nos. 6,610,016; 6,358,557; 6,306,176; 6,110,483; 6,106,473; 5,997,517; 5,800,412; 5,525,348; 5,331 ,027; 5,001,009; 6,562,136; 6,406,754; 6,344,035; 6,254,921 ; 6,214,901; 6,077,698; 6,603,040; 6,278,018; 6,238,799; 6,096,726, 5,766,158, 5,599,576, 4,119,094; 4,100,309; 6,599,558; 6,369,168; 6,521 ,283; 6,497,916; 6,251 ,964; 6,225,431 ; 6,087,462; 6,083,257; 5,739,237; 5,739,236; 5,705,583; 5,648,442; 5,645,883; 5,556,710; 5,496,581; 4,689,386; 6,214,115; 6,090,901 ; 6,599,448; 6,054,504; 4,987,182; 4,847,324; and 4,642,267; U.S. Patent Application Publication Nos. 2002/0146581, 2003/0129130, 2003/0129130, 2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631 ; 2003/0190405; 2002/0146581 ; 2003/020399; 2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405; and 2003/020399; and PCT Publication Nos. WO 02/055121; WO 01/57048; WO 01/52915; and WO 01/01957.

Representative examples of medical devices which may be coated using the compositions of the invention and are described in more detail below include vascular stents, gastrointestinal stents, tracheal/bronchial stents, genital-urinary stents, ENT stents, intra-articular implants, intraocular lenses, implants for hypertrophic scars and keloids, vascular grafts, anastomotic connector devices, implantable sensors, implantable pumps, implantable electrical devices, such as implantable neurostimulators, implantable electrical leads, surgical adhesion barriers, glaucoma drainage devices, film or mesh, prosthetic heart valves, tympanostomy tubes, penile implants, endotracheal and tracheostomy tubes, peritoneal dialysis catheters, intracranial pressure monitors, vena cava filters, central venous cathethers (CVCs), ventricular assist devices (e.g., LVAD's), spinal prostheses, urinary (Foley) catheters, prosthetic bladder sphincters, orthopedic implants, and gastrointestinal drainage tubes. There are numerous medical devices where the occurrence of a fibrotic reaction will adversely affect the functioning of the device or the biological problem for which the device was implanted or used. Representative examples of implants or devices that can be coated with or otherwise constructed to contain and/or release the therapeutic agents provided herein include cardiovascular devices (e.g., implantable venous catheters, venous ports, tunneled venous catheters, chronic infusion lines or ports, including hepatic artery infusion catheters, pacemakers and pacemaker leads, implantable defibrillators; neurologic/neurosurgical devices (e.g., ventricular peritoneal shunts, ventricular atrial shunts, dural patches and implants to prevent epidural fibrosis post-laminectomy, devices for continuous subarachnoid infusions); gastrointestinal devices (e.g., chronic indwelling catheters, feeding tubes, portosystemic shunts, shunts for ascites, peritoneal implants for drug delivery, peritoneal dialysis catheters, and suspensions or solid implants to prevent surgical adhesions); genitourinary devices (e.g., uterine implants, including intrauterine devices (IUDs) and devices to prevent endometrial hyperplasia, fallopian tubal implants, including reversible sterilization devices, fallopian tubal stents, ureteric stents, chronic indwelling catheters, bladder augmentations, or wraps or splints for vasovasostomy, central venous catheters, urinary catheters; prosthetic heart valves, vascular grafts, ophthalmologic implants (e.g., multino implants and other implants for neovascular glaucoma, drug eluting contact lenses for pterygiums, splints for failed dacrocystalrhinostomy, drug eluting contact lenses for corneal neovascularity, implants for diabetic retinopathy, drug eluting contact lenses for high risk corneal transplants); otolaryngology devices (e.g., ossicular implants, Eustachian tube splints or stents for glue ear or chronic otitis as an alternative to transtempanic drains); catheter cuffs and orthopedic implants (e.g., cemented orthopedic prostheses).

Other examples of implants include drainage tubes, biliary T- tubes, clips, sutures, braids, meshes (e.g., hernia meshes, tissue support meshes), barriers (for the prevention of adhesions), anastomotic devices, anastomotic connectors, ventrical assist devices (e.g., LVAD's), artificial hearts, artificial joints, conduits, irrigation fluids, packing agents, stents, staples, inferior vena cava filters, pumps (e.g., for the delivery of therapeutics), hemostatic implants (e.g., sponges), tissue fillers, surgical adhesion barriers (e.g., INTERCEED, degradable polyester films (e.g., PLLA/PDLLA), CMC/PEO association complexes (e.g., OXIPLEX from Fziomed), hyaluronic acid/CMC films (e.g., SEPRAFILM from Genzyme Corporation), bone grafts, skin grafts, tissue sealants, intrauterine devices (IUD), ligatures, titanium implants (particularly for use in dental applications), chest tubes, nasogastric tubes, percutaneous feeding tubes, colostomy devices, bone wax, and Penrose drains, hair plugs, ear rings, nose rings, and other piercing-associated implants, as well as anaesthetic solutions.

The coating of fibrosis-inhibiting agent(s) onto or incorporation of a fibrosis-inhibiting agent(s) into medical devices provides a solution to the clinical problems that can be encountered with these devices. Alternatively, or additional, compositions that comprise anti-scarring agents can be infiltrated in to the space or onto tissue surrounding the area where medical devices are implanted either before, during or after implantation of the devices.

Described below are examples of medical devices whose functioning can be improved by the use of a fibrosis-inhibiting agent as well as methods for incorporating fibrosis-inhibiting agents into or onto these devices and methods for using such devices. Intravascular Devices

The present invention provides for the combination of an anti- scarring agent and an intravascular device. "Intravascular devices" refers to devices that are implanted at least partially within the vasculature (e.g., blood vessels). Examples of intravascular devices that can be used to deliver anti-scarring agents to the desired location include, e.g., catheters, balloon catheters, balloons, stents, covered stents, stent grafts, anastomotic connectors, and guidewires.

In one aspect, the present invention provides for the combination of an anti-scarring agent or a composition comprising an anti- scarring agent and an intravascular stent.

"Stent" refers to devices comprising a cylindrical tube (composed of a metal, textile, non-degradable or degradable polymer, and/or other suitable material (such as biological tissue) which maintains the flow of blood from one portion of a blood vessel to another. In one aspect, a stent is an endovascular scaffolding which maintains the lumen of a body passageway (e.g., an artery) and allows bloodflow. Representative examples of stents that can benefit from being coated with or having incorporated therein, a fibrosis-inhibiting agent include vascular stents, such as coronary stents, peripheral stents, and covered stents.

Stents that can be used in the present invention include metallic stents, polymeric stents, biodegradable stents and covered stents. Stents may be self-expandable or balloon-expandable, composed of a variety of metal compounds and/or polymeric materials, fabricated in innumerable designs, used in coronary or peripheral vessels, composed of degradable and/or nondegradable components, fully or partially covered with vascular graft materials (so called "covered stents") or "sleeves", and can be bare metal or drug-eluting.

Stents may be comprise a metal or metal alloy such as stainless steel, spring tempered stainless steel, stainless steel alloys, gold, platinum, super elastic alloys, cobalt-chromium alloys and other cobalt- containing alloys (including ELGILOY (Combined Metals of Chicago, Grove Village, IL), PHYNOX (Alloy Wire International, United Kingdom) and CONICHROME (Carpenter Technology Corporation, Wyomissing, PA)), titanium-containing alloys, platinum-tungsten alloys, nickel-containing alloys, nickel-titanium alloys (including nitinol), malleable metals (including tantalum); a composite material or a clad composite material and/or other functionally equivalent materials; and/or a polymeric (non-biodegradable or biodegradable) material. Representative examples of polymers that may be included in the stent construction include polyethylene, polypropylene, polyurethanes, polyesters, such as polyethylene terephthalate (e.g., DACRON or MYLAR (E. I. DuPont De Nemours and Company, Wilmington, DE)), polyamides, polyaramids (e.g., KEVLAR from E.I. DuPont De Nemours and Company), polyfluorocarbons such as poly(tetrafluoroethylene with and without copolymerized hexafluoropropylene) (available, e.g., under the trade name TEFLON (E. I. DuPont De Nemours and Company), silk, as well as the mixtures, blends and copolymers of these polymers. Stents also may be made with engineering plastics, such as thermotropic liquid crystal polymers (LCP), such as those formed from p,p'-dihydroxy-polynuclear- aromatics or dicarboxy-polynuclear-aromatics.

Further types of stents that can be used with the described therapeutic agents are described, e.g., in PCT Publication No. WO 01/01957 and U.S. Patent Nos. 6,165, 210; 6,099,561; 6,071 ,305; 6,063,101 ; 5,997,468; 5,980,551; 5,980,566; 5,972,027; 5,968,092; 5,951 ,586; 5,893,840; 5,891,108; 5,851 ,231; 5,843,172; 5,837,008; 5,766,237; 5,769,883; 5,735,811; 5,700,286; 5,683,448; 5,679,400; 5,665,115; 5,649,977; 5,637,113; 5,591 ,227; 5,551 ,954; 5,545,208; 5,500,013; 5,464,450; 5,419,760; 5,411 ,550; 5,342,348; 5,286,254; and 5,163,952. Removable drug-eluting stents are described, e.g., in Lambert, T. (1993) J. Am. Coll. Cardiol.: 21: 483A. Moreover, the stent may be adapted to release the desired agent at only the distal ends, or along the entire body of the stent. Balloon over stent devices, such as are described in Wilensky, R.L (1993) J. Am. Coll. Cardiol.: 21: 185A, also are suitable for local delivery of a fibrosing agent to a treatment site.

In addition to using the more traditional stents, stents that are specifically designed for drug delivery can be used. Examples of these specialized drug delivery stents as well as traditional stents include those from Conor Medsystems (Palo Alto, CA) (e.g., U.S. Patent. Nos. 6,527,799; 6,293,967; 6,290,673; 6,241,762; U.S. Patent Application Publication Nos. 2003/0199970 and 2003/0167085; and PCT Publication No. WO 03/015664).

Examples of intravascular stents, which may be combined with one or more therapeutic agents according to the present invention, include commercially available products. The stent may be self-expanding or balloon expandable (e.g., STRECKER stent by Medi-Tech/Boston Scientific Corporation), or implanted by a change in temperature (e.g., nitinol stent). Self-expanding stents that can be used include the coronary WALLSTENT and the SCIMED RADIUS stent from Boston Scientific Corporation (Natick, MA) and the GIANTURCO stents from Cook Group, Inc. (Bloomington, IN). Examples of balloon expandable stents that can be used include the CROSSFLEX stent, BX-VELOCITY stent and the PALMAZ-SCHATZ crown and spiral stents from Cordis Corporation (Miami Lakes, FL), the V-FLEX PLUS stent by Cook Group, Inc., the NIR, EXPRESS and LIBRERTE stents from Boston Scientific Corporation, the ACS MULTILINK, MULTILINK PENTA, SPIRIT, and CHAMPION stents from Guidant Corporation, and the Coronary Stent S670 and S7 by Medtronic, Inc. (Minneapolis, MN).

Other examples of stents that can be combined with a fibrosing agent in accordance with the invention include those from Boston Scientific Corporation, (e.g., the drug-eluting TAXUS EXPRESS2 drug- Eluting Coronary Stent System; over the wire stent stents such as the Express2 Coronary Stent System and NIR Elite OTW Stent System; rapid exchange stents such as the EXPRESS2 Coronary Stent System and the NIR ELITE MONORAIL Stent System; and self-expanding stents such as the MAGIC WALLSTENT Stent System and RADIUS Self Expanding Stent); Medtronic, Inc. (Minneapolis, MN) (e.g., DRIVER ABT578-eluting stent, DRIVER ZIPPER MX Multi-Exchange Coronary Stent System and the DRIVER Over-the-Wire Coronary Stent System; the S7 ZIPPER MX Multi- Exchange Coronary Stent System; S7, S670, S660, and BESTENT2 with Discrete Technology Over-the-Wire Coronary Stent System); Guidant Corporation (e.g., cobalt chromium stents such as the MULTI-LINK VISION Coronary Stent System; MULTI-LINK ZETA Coronary Stent System; MULTI- LINK PIXEL Coronary Stent System; MULTI-LINK ULTRA Coronary Stent System; and the MULTI-LINK FRONTIER); Johnson & Johnson/Cordis Corporation (e.g., CYPHER sirolimus-eluting Stent; PALMAZ-SCHATZ Balloon Expandable Stent; and S.M.A.R.T. Stents); Abbott Vascular (Redwood City, California) (e.g., MATRIX LO Stent; TRIMAXX Stent; and DEXAMET stent); Conor Medsystems (Menlo Park, California) (e.g., MEDSTENT and COSTAR stent); AMG GmbH (Germany) (e.g., PICO Elite stent); Biosensors International (Singapore) (e.g., MATRIX stent, CHAMPION Stent (formerly the S-STENT), and CHALLENGE Stent); Biotronik (Switzerland) (e.g., MAGIC AMS stent); Clearstream Technologies (Ireland) (e.g., CLEARFLEX stent); Cook Inc. (Bloomington, Indiana) (e.g., V-FLEX PLUS stent, ZILVER PTX self-expanding vascular stent coating, LOGIX PTX stent (in development); Devax (e.g., AXXESS stent) (Irvine, CA); DISA Vascular (Pty) Ltd (South Africa) (e.g., CHROMOFLEX Stent, S- FLEX Stent, S-FLEX Micro Stent, and TAXOCHROME DES); lntek Technology (Baar, Switzerland) (e.g., APOLLO stent); Orbus Medical Technologies (Hoevelaken, The Netherlands) (e.g., GENOUS); Sorin Biomedica (Saluggia, Italy) (e.g., JANUS and CARBOSTENT); and stents from Bard/Angiomed GmbH Medizintechnik KG (Murray Hill, NJ), and Blue Medical Supply & Equipment (Mariettta, GA), Aachen Resonance GmbH (Germany); Eucatech AG (Germany), Eurocor GmbH (Bonn, Gemany), Prot, Goodman, Terumo (Japan), Translumina GmbH (Germany), MIV Therapeutics (Canada), Occam International B.V. (Eindhoven, The Netherlands), Sahajanand Medical Technologies PVT LTD. (India); AVI Biopharma/Medtronic/ Interventional Technologies (Portland, OR) (e.g., RESTEN NG-coated stent); and Jomed (e.g., FLEXMASTER drug-eluting stent) (Sweden).

Generally, stents are inserted in a similar fashion regardless of the site or the disease being treated. Briefly, a preinsertion examination, usually a diagnostic imaging procedure, endoscopy, or direct visualization at the time of surgery, is generally first performed in order to determine the appropriate positioning for stent insertion. A guidewire is then advanced through the lesion or proposed site of insertion, and over this is passed a delivery catheter which allows a stent in its collapsed form to be inserted. Intravascular stents may be inserted into an artery such as the femoral artery in the groin and advanced through the circulation under radiological guidance until they reach the anatomical location of the plaque in the coronary or peripheral circulation. Typically, stents are capable of being compressed, so that they can be inserted through tiny cavities via small catheters, and then expanded to a larger diameter once they are at the desired location. The delivery catheter then is removed, leaving the stent standing on its own as a scaffold. Once expanded, the stent physically forces the walls of the passageway apart and holds them open. A post insertion examination, usually an x-ray, is often utilized to confirm appropriate positioning.

Stents are typically maneuvered into place under, radiologic or direct visual control, taking particular care to place the stent precisely within the vessel being treated. In certain aspects, the stent can further include a radio-opaque, echogenic material, or MRI responsive material (e.g., MRI contrast agent) to aid in visualization of the device under ultrasound, fluoroscopy and/or magnetic resonance imaging. The radio-opaque or MRI visible material may be in the form of one or more markers (e.g., bands of material that are disposed on either end of the stent) that may be used to orient and guide the device during the implantation procedure.

In another aspect, the present invention provides for the combination of an anti-scarring agent or a composition comprising an anti- scarring agent and an intravascular catheter.

"Intravascular Catheter" refers to any intravascular catheter containing one or more lumens suitable for the delivery of aqueous, microparticulate, fluid, or gel formulations into the bloodstream or into the vascular wall. These formulations may contain a biologically active agent (e.g., an anti-scarring agent). Numerous intravascular catheters have been described for direct, site-specific drug delivery (e.g., microinjector catheters, catheters placed within or immediately adjacent to the target tissue), regional drug delivery (i.e., catheters placed in an artery that supplies the target organ or tissue), or systemic drug delivery (i.e., intra-arterial and intravenous catheters placed in the peripheral circulation). For example, catheters and balloon catheters can deliver anti-fibrosing agents from an end orifice, through one or more side ports, through a microporous outer structure, or through direct injection into the desired tissue or vascular location.

A variety of catheters are available for regional or localized arterial drug-delivery. Intravascular balloon and non-balloon catheters for delivering drugs are described, for example, in U.S. Patent Nos. 5,180,366; 5,171,217; 5,049,132; 5,021,044; 6,592,568; 5,304,121; 5,295,962; 5,286,254; 5,254,089; 5,112,305; PCT Publication Nos WO 93/08866, WO 92/11890, and WO 92/11895; and Riessen et at. (1994) JACC 23: 1234- 1244, Kandarpa K. (2000) J. Vase. Interv. Radio. 11 (suppl.): 419-423, and Yang, X. (2003) Imaging of Vascular Gene Therapy 228(1): 36-49.

Representative examples of drug delivery catheters include balloon catheters, such as the CHANNEL and TRANSPORT balloon catheters from Boston Scientific Corporation (Natick, MA) and Stack Perfusion Coronary Dilitation catheters from Advanced Cardiovascular Systems, Inc. (Santa Clara, CA). Other examples of drug delivery catheters include infusion catheters, such as the CRESCENDO coronary infusion catheter available from Cordis Corporation (Miami Lakes, FL), the Cragg- McNamara Valved Infusion Catheter available from Microtherapeutics, Inc. (San Clemente, CA), the DISPATCH catheter from Boston Scientific Corporation, the GALILEO Centering Catheter from Guidant Corporation (Houston, TX), and infusion sleeve catheters, such as the INFUSASLEEVE catheter from LocalMed, Inc. (Sunnyvale, CA). Infusion sleeve catheters are described in, e.g., U.S. Patent Nos. 5,318,531 ; 5,336,178; 5,279,565; 5,364,356; 5,772,629; 5,810,767; and 5,941 ,868. Catheters that mechanically or electrically enhance drug delivery include, for example, pressure driven catheters (e.g., needle injection catheters having injector ports, such as the INFILTRATOR catheter available from Interventional Technologies, Inc. (San Diego, CA)) (see, e.g., U.S. Patent No. 5,354,279) and ultrasonically assisted (phonophoresis) and iontophoresis catheters (see, e.g., Singh, J., et al. (1989) Drug Des. Deliv.: 4: 1-12 and U.S. Patent . Nos. 5,362,309; 5,318,014; 5,315,998; 5,304,120; 5,282,785; and 5,267,985).

In one aspect, the present invention provides for the combination of an anti-scarring agent or a composition comprising an anti- scarring agent and a drug delivery balloon.

"Drug-Delivery Balloon" refers to an intra-arterial balloon (typically based upon percutaneous angioplasty balloons) suitable for insertion into a peripheral artery (typically the femoral artery) and manipulated via a catheter to the treatment site (either in the coronary or peripheral circulation). Numerous drug delivery balloons have been developed for local delivery of therapeutic agents to the arterial wall such as "sweaty balloons," "channel balloons," "microinjector balloons," "double balloons," "spiral balloons" and other specialized drug-delivery balloons. Other examples of balloons include BHP balloons and Transurethral and Radiofrequency Needle Ablation (TUNA or RFNA)) balloons for prostate applications.

In addition, numerous drug delivery balloons have been developed for local delivery of therapeutic agents to the arterial wall. Representative examples of drug delivery balloons include porous (WOLINSKY) balloons, available from Advanced Polymers (Salem, NH), described in, e.g., U.S. Patent No. 5,087,244. Microporous and macroporous balloons (Ae., "sweaty balloons") for use in infusion catheters are described in, e.g., Lambert, CR. etal. (1992) Circ. Res. 71: 27-33. Other types of specialized drug delivery balloons include hydrogel coated balloons (e.g., ULTRATHIN GLIDES from Boston Scientific Corporation) (see, e.g., Fram, D.B. et al. (1992) Circulation: 86 Suppl. I: 1-380), "channel balloons" (see, e.g., U.S. Patent Nos. 5,860,954; 5,843,033; and 5,254,089, and Hong, M.K., et al. (1992) Circulation: 86 Suppl. 1: 1-380), "microinjector balloons" (see, e.g., U.S. Patent Nos. 5,681,281 and 5,746,716), "double balloons," described in, e.g., U.S. Patent No. 6,544,221 , and double-layer channeled perfusion balloons (such as the REMEDY balloon from Boston Scientific Corportion), and "spiral balloons" (see, e.g., U.S. Patent Nos. 6,527,739 and 6,605,056). Drug delivery catheters that include helical (i.e., spiral) balloons are described in, e.g., U.S. Patent Nos. 6,190,356; 5,279,546; 5236424, 5,226,888; 5,181,911 ; 4,824,436; and 4,636,195.

The balloon catheter systems that can be used include systems in which the balloon can be inflated at the desired location the desired fibrosis-inducing agents can be delivered through holes that are located in the balloon wall. Other balloon catheters that can be used include systems that have a plurality of holes that are located between two balloons. The system can be guided into the desired location such that the inflatable balloon components are located on either side of the specific site that is to be treated. The balloons can then be inflated to isolate the treatment area. The compositions containing the fibrosing agent are then injected into the isolated area through the plurality of holes between the two balloons. Representative examples of these types of drug delivery balloons are described in U.S. Patent. Nos. 5,087,244, 6,623,452, 5,397,307, 4,636,195 and 4,994,033.

The compositions of the invention can be delivered using a catheter that has the ability to enhance uptake or efficacy of the compositions of the invention. The stimulus for enhanced uptake can include the use of heat, the use of cooling, the use of electrical fields or the use of radiation (e.g., ultraviolet light, visible light, infrared, microwaves, ultrasound or X-rays). Further Representative examples of catheter systems that can be used are described in U.S. Patent. Nos. 5,362,309 and 6,623,444; U.S. Patent Application Publication Nos. 2002/0138036 and 2002/0068869; and PCT Publication Nos. WO 01/15771; WO 94/05361 ; WO 96/04955 and WO 96/22111.

In another aspect of the invention, the compositions of the inventions can be delivered into the treatment site and/or into the tissue surrounding the treatment site by using catheter systems that have one or more injectors that can penetrate the surrounding tissue. Following insertion into the appropriate vessel, the catheter can be maneuvered into the desired position such that the injectors are aligned with or adjacent to the tissue. The injector(s) are inserted into the desired location, for example by direct insertion into the tissue, by inflating the balloon or mechanical rotation of the injector, and the composition of the invention is injected into the desired location. Representative examples of catheters that can be used for this application are described in and U.S. Patent Application Publication No. 2002/0082594 and U.S. Patent. Nos. 6,443,949; 6,488,659; 6,569,144; 5,609,151; 5,385,148; 5,551,427; 5,746,716; 5,681,281 ; and 5,713,863.

In another aspect of the invention, the catheter may be adapted to deliver a thermoreversible polymer composition. For the site- specific delivery of these materials, a catheter delivery system has the ability to either heat the composition to above body temperature or to cool the composition to below body temperature such that the composition remains in a fluent state within the catheter delivery system. The catheter delivery system can be guided to the desired location and the composition of the invention can be delivered to the surface of the surrounding tissue or can be injected directly into the surrounding tissue. A representative example of a catheter delivery system for direct injection of a thermoreversible material is described in U.S. Patent. No. 6,488,659. Representative examples of catheter delivery systems that can deliver the thermoreversible compositions to the surface of the vessel are described in U.S. Patent. Nos. 6,443,941 ; 6,290,729; 5,947,977; 5,800,538; and 5,749,922.

In another aspect, the present invention provides for the combination of an anti-scarring agent or a composition comprising an anti- scarring agent and an anastomotic connector device.

"Anasomotic connector device" refers to any vascular device that mechanizes the creation of a vascular anastomosis (i.e., artery-to- artery, vein-to-artery, artery-to-vein, artery-to-synthetic graft, synthetic graft- to-artery, vein-to-synthetic graft or synthetic graft-to-vein anastomosis) without the manual suturing that is typically done in the creation of an anastomosis. The term also refers to anastomotic connector devices (described below), designed to produce a facilitated semiautomatic vascular anastomosis without the use of suture and reduce connection time substantially (often to several seconds), where there are numerous types and designs of such devices. The term also refers to devices which facilitate attachment of a vascular graft to an aperture or orifice (e.g., in the side or at the end of a vessel) in a target vessel. Anastomotic connector devices may be anchored to the outside of a blood vessel, and/or into the wall of a blood vessel (e.g., into the adventitial, intramural, or intimal layer of the tissue), and/or a portion of the device may reside within the lumen of the vessel.

Anastomotic connector devices also may be used to create new flow from one structure to another through a channel or diversionary shunt. Accordingly, such devices (also referred to herein as "bypass devices") typically include at least one tubular structure, wherein a tubular structure defines a lumen. Anastomotic connector devices may include one tubular structure or a plurality of tubular structures through which blood can flow. At least a portion of the tubular structure resides external to a blood vessel (i.e., extravascular) to provide a diversionary passageway. A portion of the device also may reside within the lumen and/or within the tissue of the blood vessel.

Examples of anastomotic connector devices are described in co-pending application entitled, "Anastomotic Connector Devices", filed May 23, 2003 (U.S. Ser. No. 60/473,185). Representative examples of anastomotic connector devices include, without limitation, vascular clips, vascular sutures, vascular staples, vascular clamps, suturing devices, anastomotic coupling devices (i.e., anastomotic couplers), including couplers that include tubular segments for carrying blood, anastomotic rings, and percutaneous in situ coronary artery bypass (PISCAB and PICVA) devices. Broadly, anastomotic connector devices may be classified into three categories: (1) automated and modified suturing methods and devices, (2) micromechanical devices, and (3) anastomotic coupling devices.

(1) Automated and Modified Suturing Methods and Devices Automated sutures and modified suturing methods generally facilitate the rapid deployment of multiple sutures, usually in a single step, and eliminate the need for knot tying or the use of aortic side-biting clamps. Suturing devices include those devices that are adapted to be minimally invasive such that anastomoses are formed between vascular conduits and hollow organ structures by applying sutures or other surgical fasteners through device ports or other small openings. With these devices, sutures and other fasteners are applied in a relatively quick and automated manner within bodily areas that have limited access. By using minimally invasive means for establishing anastomoses, there is less blood loss and there is no need to temporarily stop the flow of blood distal to the operating site. For example, the suturing device may be composed of a shaft-supported vascular conduit that is adapted for anastomosis and a collar that is slideable on the shaft configured to hold a plurality of needles and sutures that passes through the vascular conduit. See, e.g., U.S. Patent No. 6,709,441. The suturing device may be composed of a carrier portion for inserting Λgraft, arm portions that extend to support the graft into position, and a needle assembly adapted to retain and advance coil fasteners into engagement with the vessel wall and the graft flange to complete the anastomosis. See, e.g., U.S. Patent No. 6,709,442. The suturing device may include two oblong interlinked members that include a split bush adapted for suturing (e.g., U.S. Patent No. 4,350,160).

One representative example of a suturing device is the HEARTFLOW device, made by Perclose-Abbott Labs, Redwood City, CA (see generally, U.S. Patent Nos. 6,358,258, 6,355,050, 6,190,396, and 6,036,699, and PCT Publication No. WO 01/19257)

The nitinol U-CLIP suture clip device by Coalescent Surgical (Sunnyvale, CA) consists of a self-closing nitinol wire loop attached to a flexible member and a needle with a quick release mechanism. This device facilitates the construction of anastomosis by simplifying suture management and eliminating knot tying (see generally, U.S. Patent Nos. 6,074,401 and 6,149,658, and PCT Publication Nos. WO 99/62406, WO 99/62409, WO 00/59380, WO 01/17441).

The ENCLOSE Anastomotic Assist Device (Novare Surgical Systems, Cupertino, CA) allows a surgeon to create a sutured anastomosis using standard suturing techniques but without the use of a partial occluding side-biting aortic clamp, avoiding aortic wall distortion (see U.S. Patent Nos. 6,312,445 and 6,165,186).

In one aspect, automated and modified suturing methods and devices can deliver a surgical fastener (e.g., a suture or suture clip) that comprises an anti-scarring agent. In another aspect, automated and modified suturing methods and devices can deliver a vascular graft that comprises an anti-scarring agent to complete an anastomosis.

(2) Micromechanical devices

Micromechanical devices are used to create an anastomosis and/or secure a graft vessel to the site of an anastomosis. Representative examples of micromechanical devices include staples (either penetrating or non-penetrating) and clips.

Anastomotic staple and clip devices may take a variety of forms and may be made from different types of materials. For example, staples and clips may be formed of a metal or metal alloy, such as titanium, nickel-titanium alloy, or stainless steel, or a polymeric material, such as silicone, poly(urethane), rubber, or a thermoplastic elastomer.

The polymeric material may be an absorbable or biodegradable material designed to dissolve after completion of the anastomosis. Biodegradable polymers include, for example, homopolymers and copolymers that comprise one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, ε-caprolactone, gamma- caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ-decanolactone, δ- decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan- 2one.

A variety of devices for guiding staples and clips into position also have been described.

One manufacturer of non-penetrating staples for use in the creation of anastomosis is United States Surgical Corp. (Norwalk, CT). The VCS system (Autosuture) is an automatic stapling device that applies nonpenetrating, titanium vascular clips which are usually used in an interrupted fashion to evert tissue edges with high compressive forces. (See, e.g., U.S. Patent Nos. 6,440,146, 6,391 ,039, 6,024,748, 5,833,698, 5,799,857, 5,779,718, 5,725,538, 5,725,537, 5,720,756, 5,360,154, 5,193,731 , and 5,005,749 for the description of anastomotic connector devices made by U.S. Surgical).

An anastomotic clip may be composed of a shape memory material, such as nitinol, which is self-closing between an open U-shaped configuration and a closed configuration. See, e.g., U.S. Patent No. 6,641,593. The anastomotic clip may be composed of a wire having a shape memory that defines a closed configuration which may be substantially spiral-shaped and having a needle that may be releasably attached to the clip. See, e.g., U.S. Patent No. 6,551 ,332. Other anastomotic clips are described in, e.g., U.S. Patent Nos. 6,461 ,365; and 6,514,265.

Automatic stapling devices are also made by Bypass/Ethicon, Inc. (Somerville, NJ) and are described in, e.g., U.S. Patent Nos. 6,193,129; 5,632,433; 5,609,285; 5,533,661 ; 5,439,156; 5,350,104; 5,333,773; 5,312,024; 5,292,053; 5,285,945; 5,275,322; 5,271,544; 5,271,543 and 5,205,459 and WO 03/02016. Resorbable surgical staples that include a polymer blend that is rich in glycolide (i.e., 65 to 85 weight % polymerized glycolide) are described in, e.g., U.S. Patent No. 4,741 ,337 and 4,889,119. Surgical staples made from a blend of lactide/glycolide-copolymer and poly(p-dioxanone) are described in U.S. Patent No. 4,646,741. Other types of stapling devices are described in, e.g., U.S. Patent Nos. 5,234,447; 5,904,697 and 6,565,582; and U.S. Publication No. 2002/0185517A1.

In another aspect, the micromechanical device may be an anastomotic clip. For example, an anastomotic clip may be composed of a shape memory material, such as nitinol, which is self-closing between an open U-shaped configuration and a closed configuration. See, e.g., U.S. Patent No. 6,641,593. The anastomotic clip may be composed of a wire having a shape memory that defines a closed configuration which may be substantially spiral-shaped and having a needle that may be releasably attached to the clip. See, e.g., U.S. Patent No. 6,551 ,332. Other anastomotic clips are described in, e.g., U.S. Patent Nos. 6,461,365; 6,187,019; and 6,514,265.

In one aspect, the present invention provides for the combination of a micromechanical anastomotic device (e.g., a staple or a clip) and an anti-scarring agent.

(3) Anastomotic Coupling Devices

Anastomotic coupling devices may be used to connect a first blood vessel to a second vessel, either with or without a graft vessel, for completion of an anastomosis. In one aspect, anastomotic coupling devices facilitate automated attachment of a graft or vessel to an aperture or orifice (e.g., in the side or at the end of a vessel) in a target vessel without the use of sutures or staples. In another aspect, the anastomotic coupling device comprises a tubular structure defining a lumen through which blood may flow (described below).

Anastomotic coupling devices that facilitate automated attachment of a graft or vessel to an aperture or orifice in a target vessel may take a variety of forms and may be made from a variety of materials. Typically, such devices are made of a biocompatible material, such as a polymer or a metal or metal alloy. For example, the device may be formed from a synthetic material, such as a fluoropolymer, such as expanded poly(tetrafluoroethylene) (ePTFE) (ePTFE) sold under the trade name GORE-TEX available from W.L. Gore & Associates, Inc. or fluorinated ethylene propylene (FEP), a polyurethane, polyethylene, polyamide (nylon), silicone, polypropylene, polysulfone, or a polyester.

Anastomotic coupling devices may include an absorbable or biodegradable material designed to dissolve after completion of the anastomosis. Biodegradable polymers include, for example, homopolymers and copolymers that comprise one or more of the monomers selected from lactide, lactic acid, glycolide, glycolic acid, ε-caprolactone, gamma- caprolactone, hydroxyvaleric acid, hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone, gamma-valerolactone, γ-decanolactone, δ- decanolactone, trimethylene carbonate, 1 ,4-dioxane-2-one or 1 ,5-dioxepan- 2one.

The device may include a metal or metal alloy (e.g., nitinol, stainless steel, titanium, iron, nickel, nickel-titanium, cobalt, platinum, tungsten, tantalum, silver, gold, molybdenum, chromium, and chrome), or a combination of a metal and a polymer.

The device may be anchored to the outside of a vessel, within the tissue that surrounds the lumen of a blood vessel, and/or a portion of the device may reside within the lumen of the vessel.

In one aspect, the anastomotic coupler may be an artificially formed aperture connector that is placed in the side wall of the target vessel so that the tubular graft conduit may be extended from the target vessel. The connector may include a plurality of tissue-piercing members and retention fingers disposed in a concentric annular array which may be passed through the side wall of the tubular graft conduit for securing and retaining the graft to the connector in a fluid-tight configuration. See, e.g., U.S. Patent No. 6,702,829 and 6,699,256.

In another aspect, the anastomotic coupler may be in the form of a frame. For example, the frame may be configured to be deformable and scissor-shaped such that spreading members are moveable to secure a graft vessel upon insertion into a target vessel. See, e.g., U.S. Patent No. 6,179,849.

In another aspect, the anastomotic coupler may be a ring-like device that is used as an anastomotic interface between a lumen of a graft and an opening in a lumen of a target vessel. For example, the anastomotic ring may be composed of stainless steel alloy, titanium alloy, or cobalt alloy and have a flange with an expandable diameter. See, e.g., U.S. Patent No. 6,699,257. Anastomosis rings are also described in, e.g., U.S. Patent No. 6,248,117.

In another aspect, the anastomotic coupler is resorbable. Resorbable anastomotic coupling devices may include, for example, a polymeric blend that is rich in glycolide (i.e., 65 to 85 weight % polymerized glycolide) (see, e.g., U.S. Patent No. 4,741 ,337 and 4,889,119) or a blend of lactide/glycolide-copolymer and poly(p-dioxanone) (see, e.g., U.S. Patent No. 4,646,741).

In another aspect, the anastomotic coupler includes a bioabsorbable, elastomeric material. Representative examples of elastomeric materials for use in resorbable devices are described in, e.g., U.S. Patent No. 5,468,253.

In another aspect, the anastomotic coupler may be used to connect a first blood vessel to a second vessel, either with or without a graft vessel. For example, the anastomotic coupler may be a device that serves to interconnect two vessels in a side-to-side anastomosis, such as when grafting two juxtaposed cardiac vessels. The anastomotic coupler may be configured as two partially opened cylindrical segments that are interconnected along the periphery by a flow opening whereby the device may be inserted in a minimally-invasive manner which then conforms to provide pressure against the interior wall when in the original configuration such that leakage is prevented. See, e.g., U.S. Patent Nos. 6,464,709; 6,458,140 and 6,251,116 and U.S. Application Publication No. 2003/0100920A1.

In another aspect, the anastomotic coupler may also be incorporated in the design of a vascular graft to eliminate the step of attaching the interface prior to deployment. For example, the anastomotic coupler may have a leading and rear petal for dilating the vessel opening during advancement, and a base which is configured for attachment to a graft while forming a seal with the opening of the vessel. See, e.g., U.S. Patent No. 6,702,828.

In another aspect, the anastomotic coupler may be in the form of a frame. For example, the anastomotic coupler may be composed of a deformable, scissor-shaped frame with spreading members that is inserted into a target vessel. See, e.g., U.S. Patent No. 6,179,849. In another aspect, the anastomotic coupling device may include a graft that incorporates fixation mechanisms (e.g., a collet or a grommet) at its opposite ends and a heating element to create a thermal bond between the graft and a blood vessel (see, e.g., U.S. Patent Nos. 6,652,544 and 6,293,955).

In another aspect, the anastomotic coupling device includes a compressible, expandable fitting for securing the ends of a bypass graft to two vessels. The fitting may be incorporated in the bypass graft design to eliminate the step of attaching the graft to the fitting prior to deployment (see, e.g., U.S. Patent No. 6,494,889).

In another aspect, the anastomotic coupling device includes a pair of coupling disc members for joining two vessels in an end-to-end or end-to-side fashion. One of the members includes hook members, while the other member has receptor cavities aligned with the hooks for locking everted tissue of the vessels together (see, e.g., U.S. Patent No. 4,523,592).

Representative examples of anastomotic connector devices of Bypass/Ethicon, Inc. are described in U.S. Application Publication Nos. US2002/0082625A1 and 2003/0100910A1 and U.S. Patent Nos. 6,036,703, 6,036,700, 6,015,416, and 5,346,501.

Other anastomotic coupling devices are those described in e.g., U.S. Patent No. 6,036,702; 6,508,822; 6,599,303; 6,673,084, 5,695,504; 6,569,173; 4,931 ,057; 5,868,763; 4,624,257; 4,917,090; 4,917,091 ; 5,697,943; 5,562,690; 5,454,825; 5,447,514; 5,437,684; 5,376,098; 6,652,542; 6,551 ,334; and 6,726,694 and U.S. Application Publication Nos. 2003/0120293A1 and 2004/0030348A1.

Anastomotic coupling devices may include proximal aortic connectors and distal coronary connectors. For example, aortic anastomotic connectors include devices such as the SYMMETRY Bypass Aortic Connector device made by St. Jude Medical, Inc. (Maple Grove, MN), which consists of an aortic cutter or hole punch assembly and a graft delivery system. The aortic hole punch is a cylindrical cutter with a barbed needle that provides an anchor and back pressure for the rotating cutter to core a round hole in the wall of the aorta. The graft delivery system is a radially expandable nitinol device that holds the vein graft with small hooks which pierce through vein graft wall. The graft is fixed to the aorta through use of an inner and outer ring of struts or flanges. This and other anastomotic connector devices by St. Jude are described in U.S. Patent Nos. 6,309,416, 6,302,905, 6,152,937, and PCT Publication Nos. WO 00/27312 and WO 00/27311.

The CORLINK Automated Anastomotic connector device, which is produced by the CardioVations division of Ethicon, Inc. (Johnson & Johnson, Somerville, NJ), uses a nitinol metal alloy fastener to connect the grafted vessel to the aorta. It consists of a central cylindrical body made of interconnected elliptical arches and two sets of several pins radiating from each end. The graft is loaded into a CORLINK insertion instrument and deployed to create an anastomosis in one step.

Further examples of anastomotic coupling devices include those made by Cardica (see, U.S. Patent Nos. 6,719,769; 6,419,681 and 6,537,287), Converge Medical (formerly Advanced Bypass Technologies), Onux Medical (see, e.g., PCT Publication No. WO 01/34037) and Ventrica, Menlo Park, CA (VENTRICA Magnetic Vascular Positioner) (see, e.g., U.S. Patent Nos. 6,719,768; 6,517,558 and 6,352,543).

As described above, an anastomotic coupling device may comprise a tubular structure defining a lumen through which blood may flow. These types of devices (also referred to herein as "bypass devices") can function as an artificial passageway or conduit for fluid communication between blood vessels and can be used to divert {i.e., shunt) blood from one part of a blood vessel (e.g., an artery) to another part of the same vessel, or to a second vessel (e.g., an artery or a vein) or to multiple vessels (e.g., a vein and an artery). In one aspect of the invention, the anastomotic device is a bypass device. Bypass devices may be used in a variety of end-to-end and end-to-side anastomotic procedures. The bypass device may be placed into a patient where it is desired to create a pathway between two or more vascular structures, or between two different parts of the same vascular structure. For example, bypass devices may be used to create a passageway which allows blood to flow around a blood vessel, such as an artery (e.g., coronary artery, carotid artery, or artery supplying the lower limb), which has become damaged or completely or partially obstructed. Bypass devices may be used in coronary artery bypass surgery to shunt blood from an artery, such as the aorta, to a portion of a coronary artery downstream from an occlusion in the artery.

Certain types of anastomotic coupling devices are configured to join two abutting vessels. The device can further include a tubular segment to shunt blood to another vessel. These types of connectors are often used for end-to-end anastomosis if a vessel is severed or injured.

Bypass devices include at least one tubular structure having a first end and a second end, which defines a single lumen through which blood can flow, or may include more than one tubular structure, defining multiple lumens through which blood can flow. The tubular structure includes an extravascular portion and may, optionally, include an intravascular portion. The extravascular portion resides external to the adventitial tissue of a blood vessel, whereas the intravascular portion may reside within the vessel lumen or within the intimal, medial, and/or adventitial tissue.

The configuration of the tubular segment may take a variety of forms. For example, the tubular portion may be generally straight, bent or curved (e.g., L-shaped or helical), tapered, branched (e.g., bifurcated or trifurcated), or may include a network of conduits through which blood may flow. Generally, straight or bent devices have a single lumen through which blood may flow, while branched conduits (e.g., generally T-shaped and Y- shaped devices) and conduit networks (described below) have two or more lumens through which blood may flow. A tubular structure may be in the form, for example, of a hollow cylinder and may or may not include a support structure, such as a mesh or porous framework. Depending on the procedure, the device may be biodegradable or non-biodegradable; expandable or rigid; metal and/or polymeric; and/or may include a shape- memory material (e.g., nitinol). In certain embodiments, the device may include a self-expanding stent structure.

Bypass devices typically are made of a biocompatible material. Any of the materials described above for other types of connectors may be used to make a bypass device, such as a synthetic or naturally-derived polymer, or a metal or metal alloy. For example, the device may be formed from a synthetic material, such as a fluoropolymer, such as expanded poly(tetrafluoroethylene) (ePTFE) or fluorinated ethylene propylene (FEP), a polyurethane, polyethylene, polyamide (nylon), silicone, polypropylene, polysulfone, or a polyester and/or a naturally derived material, such as collagen or a polysaccharide. The device may include a metal or metal alloy (e.g., nitinol, stainless steel, titanium, nickel, nickel-titanium, cobalt, platinum, iron, tungsten, tantalum, silver, gold, molybdenum, chromium and chrome), or a combination of a metal and a polymer. Other types of devices include a natural graft material (e.g., autologous vessel, homologous vessel, or xenograft), or a combination of a synthetic and a natural graft material. In another aspect, the bypass device may be formed of an absorbable or biodegradable material designed to dissolve after completion of the anastomosis (e.g., polylactide, polyglycolide, and copolymers of lactide and glycolide). In yet another aspect, demineralized bone may be used to provide a pliable tubular conduit (see, e.g., U.S. Patent No. 6,290,718).

The tubular structure(s) include a proximal end that may be configured for attachment to a proximal blood vessel and a distal end configured for attachment to a distal blood vessel. As described above, an anastomosis may be described as being either "proximal" or "distal" depending on its location relative to the vascular obstruction. The "proximal" anastomosis may be formed in a proximal blood vessel, and the "distal" anastomosis may be formed in a distal blood vessel, which may the same vessel or a different vessel than the proximal vessel. The terms "distal" and "proximal" may also be used to describe the direction that blood flows through a tubular structure from one vessel into another vessel. For example, blood may flow from a proximal vessel (e.g., the aorta) into a distal vessel, such as a coronary artery to bypass an obstruction in the coronary artery.

The tubular structure may be attached directly to a proximal or distal blood vessel. Alternatively, the bypass device may further include a graft vessel or be configured to receive a graft vessel, which can be connected to the same or a different blood vessel for completion of the anastomosis. Representative examples of graft vessels include, for example, vascular grafts or grafts used in hemodialysis applications (e.g., AV graft, AV shunt, or AV graft).

In one aspect, a tubular anastomotic coupler includes a proximal end that is attached to a proximal vessel and a distal end that is used to attach a bypass graft. The bypass graft can be secured to the distal vessel to complete the anastomosis. The direction of blood flow can be from the proximal blood vessel and into the proximal end of the tubular structure. Blood can exit through the distal end of the tubular structure and into the graft vessel.

In another aspect, the tubular anastomotic coupler includes a proximal end that is attached to a graft vessel, which is secured to the proximal blood vessel, and a distal end that is configured for attachment to a distal blood vessel. The direction of blood flow can be from the proximal vessel into the graft vessel and into the proximal end of the tubular structure. Blood can exit through the distal end of the tubular structure and into the distal vessel.

Anastomotic bypass devices may be anchored to a blood vessel in a variety of ways and may be attached to a blood vessel for the formation of an anastomosis with or without the use of sutures. Bypass devices may be attached to the outside of a blood vessel, and/or a portion of the device may be implanted into a vessel. For example, a portion of the implanted device may reside within the lumen of the vessel (i.e., endoluminally), and/or a portion of the implanted device may reside intravascularly (i.e., within the intimal, intramural, and/or adventitial tissue of the blood vessel). In one aspect, at least one of the tubular structures, or a portion thereof, may be inserted into the end of a vessel or into the side of a blood vessel. The device may be secured directly to the vessel using, for example, a fastener, such as sutures, staples, or clips and/or an adhesive. Bypass devices may include an interface to secure the conduit to a target vessel without the use of sutures. The interface may include means, such as, for example, hooks, barbs, pins, clamps, or a flange or lip for coupling the device to the site of an anastomosis.

Representative examples of anastomotic coupling devices that include at least one tubular portion include, without limitation, devices used for end-to-end anastomosis procedures (e.g., anastomotic stents and anastomotic sleeves) and end-to-side anastomosis procedures (e.g., single- lumen and multi-lumen bypass devices).

In one aspect of the invention, the anastomotic coupling device comprises a single tubular portion that may by used as a shunt to divert blood from a source vessel to a graft vessel (e.g., in an end-to-side anastomosis procedure). In one aspect, an end of the tubular portion may be connected directly or indirectly to a target vessel, as described above. The opposite end of the tubular portion may be attached to a graft vessel, where the graft vessel may be secured to a target vessel to complete the anastomosis.

The tubular portion(s) may be straight or may have a curved or bent shape (e.g., L-shaped or helical) and may be oriented orthogonally or at an angle relative to the vessel to which it is connected. In one aspect, the conduit may be secured into the site by, for example, a fastener, such as staples, clamps, or hooks, or by adhesives, radiofrequency sealing, or by other methods known to those skilled in the art.

In one aspect, the anastomotic coupling device may be, for example, a tubular metal braided graft with suture rings welded at the distal end to provide a means for securing in place to the target vessel. See, e.g., U.S. Patent No. 6,235,054. Other types of conduits that are secured into the site include, e.g., U.S. Patent Nos. 4,368,736 and 4,366,819.

In certain types of single-lumen coupling devices, the conduit terminates in a flange that resides within the lumen of the vessel. For example, the conduit may have a tubular body with a connector which has a plurality of extensions and is configured for disposition annularly within the inside of a tubular vessel. See, e.g., U.S. Patent No. 6,660,015. In other devices, the flange may be attached into or onto the surface of the adventitial tissue of the blood vessel.

Other types of single-lumen bypass devices are described, for example, in U.S. Patent Nos, 6,241 ,743; 6,428,550; 6,241 ,743; 6,428,550; 5,904,697; 5,290,298; 6,007,576; 6,361,559; 6,648,901, 4,931,057 and U.S. Application Publication Nos. 2004/0015180A1, 2003/0065344A1 , and 2002/0116018A1.

In one aspect of the invention, the anastomotic coupling device comprises more than one lumen through which blood may travel. Multi-lumen bypass devices may include two or more tubular portions configured to interconnect multiple (two or more) blood vessels. Multi-lumen coupling devices may be used in a variety of anastomosis procedures. For example, such devices may be used in coronary artery bypass graft (CABG) surgery to divert blood from an occluded proximal vessel (e.g., an artery) into one or more target (i.e., distal) vessels (e.g., an artery or vein).

In one aspect, at least one tubular portion may by used as a shunt for diverting blood between a source vessel and a target vessel. In another aspect, the device may be configured as an interface for securing a graft vessel to a target vessel for completion of an anastomosis. Depending on the procedure, the tubular arms may be of equal length and diameter or of unequal length and diameter and may include a tubular portion(s) that is expandable and/or includes a shape-memory material (e.g., nitinol). Furthermore, the tubular portions may be made of the same material or a different material.

In one aspect, one or more ends of a tubular portion may be inserted into the end or into the side of one or more blood vessels. In other embodiments, one or more tubular portions of the device may reside within the lumen of a blood or graft vessel. The device, optionally, may be secured to the blood vessel using a fastener or an adhesive, or another approach known to those skilled in the art.

At least one arm of the multi-lumen connector may be attached to a graft vessel. The graft vessel may be a synthetic graft, such as an ePTFE or polyester graft, or natural graft material (e.g., autologous vessel, homologous vessel, or xenograft), or a combination of a synthetic and a natural graft material. In certain embodiments, a graft vessel may be attached to an end of a tubular portion of the device, and a second graft vessel may be attached to the opposite end of the same tubular portion or to the end of another tubular portion. The graft vessel(s) may be further attached to a target vessel(s) for the completion of the anastomosis.

In one aspect, the device may include three or more tubular arms that extend from a junction site. For example, the multi-lumen device may be generally T-shaped or Y-shaped (i.e., having two or three lumens, respectively). For example, the multi-lumen device may be a T-shaped tubular graft connector having a longitudinal member that extends into the target vessel and a second section that is exterior to the vessel which provides a connection to an alternate tubular structure. See, e.g., U.S. Patent Nos. 6,152,945 and 5,972,017. Other multi-lumen devices are described in, (see, e.g., U.S. Patent Nos. 6,152,945; 6,451,033; 5,755,778; 5,922,022; 6,293,965; 6,517,558 and 6,626,914 and U.S. Publication No. 2004/0015180A1). In another aspect, the device may be a tube for bypassing blood flow directly from a portion of the heart (e.g., left ventricle) to a coronary artery. For example, the device may be a hollow tube that may be partially closable by a one-way valve in response to movement of the cardiac tissue during diastole while permitting blood flow during systole (see, e.g., U.S. Patent No. 6,641,610). The device may be an elongated rigid shunt body composed of a diversion tube having two apertures in which one may be disposed within the cyocardium of the left ventricle and the other may be disposed within the coronary artery (see, e.g., WO 00/15146 and U.S. Application Publication No. 2003/0055371A1). The device may be a valved, tubular apparatus that is L- or T-shaped which is adapted for insertion into the wall of the heart to provide blood communication from the heart to a coronary vessel (see, e.g., U.S. Patent No. 6,123,682).

In another aspect, the device may include a network of interconnected tubular conduits.. For example, the device may include two tubular portions that may be oriented generally axially or orthogonally relative to each other. See U.S. Patent No. 6,241 ,761 and 6,241 ,764. Communication between the two tubular structures may be achieved through a flow channel which facilitates blood to flow between the bores of each tube.

In another aspect, the anastomotic coupling device is a resorbable device that may be configured with two or three termini which provide a vessel interface without the need for sutures and provides a fluid communication through an intersecting lumen, such as a bypass graft or alternate vessel. See, e.g., U.S. Application Publication Nos. 2002/0052572A1 and PCT Publication No. WO 02/24114A2. An anastomotic connector may also be formed of a resorbable tubular structure configured to include snap-connectors or other components for securing it to the tissue as well as hemostasis inducing sealing rings to prevent blood leakage. See, e.g., U.S. Patent Nos. 6,056,762. The anastomotic connector may be designed with three legs whereby two legs are adapted to be inserted within the continuous blood vessel in a contracted state and then enlarged to form a tight fit and the third leg is adapted for connecting and sealing with a third conduit. See, e.g., U.S. Patent No. 6,019,788.

An example of a commercially available multi-lumen anastomotic coupling device is the SOLEM graft connector (made by Jomed, Sweden). This device, which is described in more detail in PCT Publication No. WO 01/13820, and U.S. Patent Nos. 6,179,848, D438618 and D429334, includes a T-shaped connector composed of nitinol and an ePTFE graft for completion of a distal anastomosis.

Another example of an anastomotic connector is the HOLLY GRAFT System (in development) for use in bypass surgery from CABG Medical, Inc. (Minneapolis, MN), which is described, e.g., in U.S. Patent Nos. 6,241,761 and 6,241 ,764.

In one aspect, the present invention provides for the combination of an anastomotic coupling device and an anti-scarring agent or a composition comprising an anti-scarring device. In one aspect, the anastomotic coupling device may be attached to a blood vessel for the formation of an anastomosis without the use of sutures or staples. In certain aspects, the anastomotic coupling device may comprise a tubular structure defining a lumen through which blood may flow, and an anti-scarring agent. The device may include one, two, three, or more lumens defined by one, two, three, or more tubular structures, depending on the number of vessels to be connected.

Introduction of an anastomotic connector into or onto an intramural, luminal, or adventitial portion of a blood vessel may irritate or damage the endothelial tissue of the blood vessel and/or may alter the natural hemodynamic flow through the vessel. This irritation or damage may stimulate a cascade of biological events resulting in a fibrotic response which can lead to the formation of scar tissue in the vessel. Incorporation of a therapeutic agent in accordance with the invention into or onto a portion of the device that is in direct contact with the blood vessel (e.g., a terminal portion or edge of the device) may inhibit one or more of the scarring processes described above (e.g., smooth muscle cell proliferation, cell migration, inflammation), making the vessel less prone to the formation of intimal hyperplasia and stenosis.

Thus, in one aspect, the therapeutic agent may be associated only with the portion of the device that is in contact with the blood or endothelial tissue. For example, the anti-scarring agent may be incorporated into only an intravascular portion (i.e., that portion that resides within the lumen of the vessel or in the vessel tissue) of the device. The anti-scarring agent may be incorporated onto all or a portion of the intravascular portion of the device. In other embodiments, the coating may reside on all or a portion of an extravascular portion of the device.

The anti-scarring agent or a composition that includes an anti- scarring agent may be coated onto a portion of or onto the entire surface of the device or may be incorporated into a portion of, or into the entire the structure of, the device (e.g., either within voids, reservoirs, or divets in the device or within the material used to construct the device). In other aspects, the agent or a composition comprising the agent is impregnated into or affixed onto the device surface.

As described above, the device may include a tubular portion that is disposed within the lumen of a blood vessel. The entire tubular portion may, for example, be coated with an anti-scarring agent or a composition comprising an anti-scarring. Alternatively, only a portion of the tubular portion may include the anti-scarring agent. For example, only an external (abluminal) surface or only the interior (endoluminal) surface of the tubular portion may be coated. In other embodiments, one or both termini of the tubular portion may be coated. For example, the endoluminal and/or abluminal surface of the tubular section through which blood enters into the device (Ae., proximal end) may be coated with the anti-scarring agent or composition comprising the anti-scarring agent. In another aspect, the endoluminal and/or abluminal surface of the tubular section through which blood exits (i.e., distal end) from the device may be coated with the anti- scarring agent or composition comprising the anti-scarring agent.

In another embodiment, the anti-scarring agent or composition comprising the anti-scarring agent is associated (e.g., coated onto or incorporated into) with an anchoring member (e.g., a fastener, such as a staple or clip) that secures the device to a blood vessel.

As described above, anastomotic connector devices can include a fibrosis-inhibiting agent as a means to improve the clinical efficacy of the device. In another approach, the fibrosis-inhibiting agent can be incorporated into or onto a film or mesh (described in further detail below) that is applied in a perivascular manner to an anastomotic site (e.g., at the junction of a graft vessel and the blood vessel). These films or wraps can be used with any of the anastomotic connector devices described above and, typically, are placed around the outside of the anastomosis at the time of surgery. In other embodiments, the agent may be delivered to the anastomotic site in the form of a spray, paste, gel, or the like. In yet another approach, the fibrosis-inhibiting agent can be incorporated into or onto the graft vessel that is secured to the blood vessel with the connector device.

In yet another aspect, other specialized intravascular devices, such as coronary drug infusion guidewires, such as those available from TherOx, Inc., grafts and balloon over stent devices, such as are described in Wilensky, R.L. (1993) J. Am. Coll. Cardiol.: 21 : 185A can also be utilized for local delivery of an anti-fibrosing agent.

As described above, the present invention provides intravascular devices (e.g., anastomotic connectors, stents, drug-delivery balloons, intravascular catheters) that include an anti-scarring agent or a composition that includes an anti-scarring agent. Numerous polymeric and non-polymeric delivery systems for use with intravascular devices have been described above. Methods for incorporating coating fibrosis-inhibiting agents and compositions onto or into intravascular devices include: (a) directly affixing to the intravascular device a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (b) directly incorporating into the device a fibrosis- inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier (c) by coating the device with a substance such as a hydrogel which will in turn absorb the fibrosis-inhibiting composition), (d) by interweaving fibrosis-inhibiting composition coated thread (or the polymer itself formed into a thread) into the device structure, (e) by inserting the device into a sleeve or mesh which contains or is coated with a fibrosis-inhibiting composition, (T) constructing the device itself or a portion of the device with a fibrosis-inhibiting composition, or (g) by covalently binding the fibrosis-inhibiting agent directly to the device surface or to a linker (small molecule or polymer) that is coated or attached to the device surface. For these devices, the coating process can be performed in such a manner as to (a) coat the external surface of the stent, (b) coat the internal (luminal) surface of the stent or (c) coat all or parts of both the internal and external surfaces of the stent.

The intravascular device (e.g., a stent) may be adapted to release the desired agent at only the distal ends, or along the entire body of the device.

According to the present invention, any fibrosis-inhibiting agent described above can be utilized in the practice of this embodiment. Within one embodiment of the invention, intravascular devices may be adapted to release an agent that inhibits one or more of the four general components of the process of fibrosis (or scarring), including: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue). By inhibiting one or more of the components of fibrosis (or scarring), the overgrowth of granulation tissue may be inhibited or reduced. As intravascular devices are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total drug dose administered, and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 10%, 5%, or even less than 1% of the concentration typically used in a single chemotherapeutic systemic dose application. Preferably, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

Several examples of agents for use in intravascular devices include the following: ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, as well as analogues and derivatives of the aforementioned.

Additional examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1- 10OnM IC50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC50 range) such as 5-azacytidine, Ly333531(ruboxistaurin), and simvastatin.

Regardless of the method of application of the drug to the intravascular device, the exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in or on the device may be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg. The dose (amount) of anti-scarring agent per unit area of device surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or 1 μg/mm2 - 10 μg/mm2, or 10 μg/mm2 - 250 μg/mm2, 250 μg/mm2 - 1000 μg/mm2, or 1000 μg/mm2 - 2500 μg/mm2.

Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with intravascular devices in accordance with the invention. (A) Angiogenesis inhibitors including Alphastatin, ZD-6474, IDN-5390, SB-2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (B) mTOR inhibitors including AP-23573 and temsirolimus, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (C) Tubulin antagonists including synthadotin, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (E) Kinesin antagonists including SB- 715992 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (F) TNF alpha antagonists including etanercept, humicade, adalimumab and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (J) NF Kappa B Inhibitors including Bortesomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 108 - 104 M of agent is to be maintained on the implant or barrier surface. (K) elongation factor- 1 alpha inhibitors including aplidine and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10"8- 10'4 M of agent is to be maintained on the implant or barrier surface. (L) Tyrosine kinase inhibitors including gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface.

For high potency drugs, the total dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per unit area of 0.01 μg - 100 μg per mm2; preferably 0.1 μg/mm2 - 20 μg/mm2; and minimum concentration of 10"8- 10"4 M of agent should be maintained on the implant or barrier surface. For mid-potency drugs, the total dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per unit area of 0.01 μg - 200 μg per mm2, preferably 0.1 μg/mm2 - 40 μg/mm2; and minimum concentration of 10" 8 - 10"4 M of agent should be maintained on the implant or barrier surface. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit area of 0.01 μg - 500 μg per mm2; preferably 0.1 μg/mm2 - 100 μg/mm2; and minimum concentration of 10"8- 10"4 M of agent should to be maintained on the implant or barrier surface.

Gastrointestinal Stents

The present invention provides for the combination of a drug and a gastrointestinal (Gl) stent. The term Gl stent refers to devices that are located in the gastrointestinal tract including the biliary duct, pancreatic duct, colon, and the esophagus. Gl stents are or comprise scaffoldings that are used to treat endoluminal body passageways that have become blocked due to disease or damage, including malignancy or benign disease. In one aspect, the Gl stent may be an esophageal stent used to keep the esophagus open whereby food is able to travel from the mouth to the stomach. For example, the esophageal stent may be composed of a cylindrical supporting mesh inner layer, retaining mesh outer layer and a semi-permeable membrane sandwiched between. See, e.g., U.S. Patent No. 6,146,416. The esophageal stent may be a radially, self-expanding stent of open weave construction with an elastomeric film formed along the stent to prevent tissue ingrowth and distal cuffs that resist stent migration. See, e.g., U.S. Patent No. 5,876,448. The esophageal stent may be composed of a flexible wire configuration to form a cylindrical tube with a deformed end portion increased to a larger diameter for anchoring pressure. See, e.g., U.S. Patent No. 5,876,445. The esophageal stent may be a flexible, self-expandable tubular wall incorporating at least one truncated conical segment along the longitudinal axis. See, e.g., U.S. Patent No. 6,533,810.

In another aspect, the Gl stent may be a biliary stent used to keep the biliary duct open whereby bile is able to drain into the small intestines. For example, the biliary stent may be composed of shape memory alloy. See, e.g., U.S. Patent No. 5,466,242. The biliary stent may be a plurality of radially extending wings with grooves which project from a helical core. See, e.g., U.S. Patent Nos. 5,776,160 and 5,486,191.

In another aspect, the Gl stent may be a colonic stent. For example, the colonic stent may be a hollow tubular body that may expand radially and be secured to the inner wall of the organ in a release fitting. See, e.g., European Patent Application No. EP1092400A2.

In another aspect, the Gl stent may be a pancreatic stent used to keep the pancreatic duct open to facilitate secretion into the small intestines. For example, the pancreatic stent may be composed of a soft biocompatible material which is resiliently compliant which conforms to the duct's curvature and contains perforations that facilitates drainage. See, e.g., U.S. Patent No. 6,132,471. Gl stents, which may be combined with one or more drugs according to the present invention, include commercially available products, such as the NIR Biliary Stent System and the WALLSTENT Endoprostheses from Boston Scientific Corporation.

In one aspect, the present invention provides Gl stents that include an anti-scarring agent or a composition that includes an anti-scarring agent. Numerous polymeric and non-polymeric delivery systems for use in Gl stents have been described above.

Methods for incorporating fibrosis-inhibiting agents or fibrosis- inhibiting compositions onto or into the Gl stents include: (a) directly affixing to the stent a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (b) directly incorporating into the stent a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (c) by coating the stent with a substance such as a hydrogel which will in turn absorb the fibrosis-inhibiting composition, (d) by interweaving fibrosis-inhibiting composition coated thread (or the polymer itself formed into a thread) into the stent structure, (e) by inserting the stent into a sleeve or mesh which is comprised of or coated with a fibrosis- inhibiting composition, (f) constructing the stent itself or a portion of the stent with a fibrosis-inhibiting composition, or (g) by covalently binding the fibrosis-inhibiting agent directly to the stent surface or to a linker (small molecule or polymer) that is coated or attached to the stent surface. For these devices, the coating process can be performed in such a manner as to (a) coat the external surface of the stent, (b) coat the internal (luminal) surface of the stent or (c) coat all or parts of both the internal and external surfaces of the stent.

In addition to coating the Gl stent with the fibrosis-inhibiting composition, the fibrosis-inhibiting agent can be mixed with the materials that are used to make the device such that the fibrosis-inhibiting agent is incorporated into the final device. This can include the Gl stent structure itself, the outer covering or sleeve, if applicable, or both the stent structure and the outer covering or sleeve.

According to the present invention, any fibrosis-inhibiting agent described above can be utilized in the practice of this embodiment. Within one embodiment of the invention, Gl stents may be adapted to release an agent that inhibits one or more of the four general components of the process of fibrosis (or scarring), including: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue). By inhibiting one or more of the components of fibrosis (or scarring), the overgrowth of granulation tissue may be inhibited or reduced.

As Gl stents are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total dose administered, and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 10%, 5%, or even less than 1 % of the concentration typically used in a single chemotherapeutic systemic dose application. Preferably, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

Several examples of scarring agents for use in Gl stents include the following: ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, as well as analogues and derivatives of the aforementioned.

Additional examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1- 10OnM IC50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC50 range) such as 5-azacytidine, Ly333531(ruboxistaurin), and simvastatin.

Regardless of the method of application of the drug to the Gl stent, the exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in or on the device may be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg. The dose (amount) of anti-scarring agent per unit area of device surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or 1 μg/mm2 - 10 μg/mm2, or 10 μg/mm2 - 250 μg/mm2, 250 μg/mm2 - 1000 μg/mm2, or 1000 μg/mm2 - 2500 μg/mm2.

Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with Gl stent devices in accordance with the invention. (A) Angiogenesis inhibitors including Alphastatin, ZD-6474, IDN-5390, SB-2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (B) mTOR inhibitors including AP-23573 and temsirolimus, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (C) Tubulin antagonists including synthadotin, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (E) Kinesin antagonists including SB- 715992 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (F) TNF alpha antagonists including etanercept, humicadβj adalimumab and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (J) NF KAPPA B Inhibitors including Bortezomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (K) Elongation factor-1 alpha inhibitors including aplidine and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (L) Tyrosine kinase inhibitors including Gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10"8- 10~4 M of agent is to be maintained on the implant or barrier surface.

For high potency drugs, the total dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per unit area of 0.01 μg - 100 μg per mm2; preferably 0.1 μg/mm2 - 20 μg/mm2; and minimum concentration of 10^ - 10"4 M of agent should be maintained on the implant or barrier surface. For mid-potency drugs, the total dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per unit area of 0.01 μg - 200 μg per mm2, preferably 0.1 μg/mm2 - 40 μg/mm2; and minimum concentration of 10' 8- 10"4 M of agent should be maintained on the implant or barrier surface. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit area of 0.01 μg - 500 μg per mm2; preferably 0.1 μg/mm2 - 100 μg/mm2; and minimum concentration of 10"8- 10"4 M of agent should to be maintained on the implant or barrier surface.

Tracheal and Bronchial Stents

The present invention provides for the combination of an anti- scarring agent and a tracheal or bronchial stent device.

Representative examples of tracheal or bronchial stents that can benefit from being coated with or having incorporated therein, a fibrosis- inhibiting agent include tracheal stents or bronchial stents, including metallic and polymeric tracheal or bronchial stents and tracheal or bronchial stents that have an external covering (e.g., polyurethane, poly(ethylene terephthalate), PTFE, or silicone rubber).

Tracheal and bronchial stents may be, for example, composed of an elastic plastic shaft with metal clasps that expands to form a lumen along the axis for opening the diseased portion of the trachea and having three sections to emulate the natural shape of the trachea. See, e.g., U.S. Patent No. 5,480,431. The tracheal/bronchial stent may be a T-shaped tube having a tracheotomy tubular portion that projects outwardly through a tracheotomy orifice which is configured to close and form a fluid seal. See, e.g., U.S. Patent Nos. 5,184,610 and 3,721,233. The tracheal/bronchial stent may be composed of a flexible, synthetic polymeric resin with a tracheotomy tube mounted on the wall with a bifurcated bronchial end that is configured in a T-Y shape with specific curves at the intersections to minimize tissue damage. See, e.g., U.S. Patent No. 4,795,465. The tracheal/bronchial stent may be a scaffolding configured to be substantially cylindrical with a shape-memory frame having geometrical patterns and having a coating of sufficient thickness to prevent epithelialization. See, e.g., U.S. Patent Application Publication No. 2003/0024534A1.

Tracheal/bronchial stents, which may be combined with one or more agents according to the present invention, include commercially available products, such as the WALLSTENT Tracheobronchial Endoprostheses and ULTRAFLEX Tracheobronchial Stent Systems from Boston Scientific Corporation and the DUMON Tracheobronchial Silicone Stents from Bryan Corporation (Woburn, MA).

In one aspect, the present invention provides tracheal and bronchial stents that include an anti-scarring agent or a composition that includes an anti-scarring agent. Numerous polymeric and non-polymeric delivery systems for use in tracheal and bronchial stents have been described above. Methods for incorporating fibrosis-inhibiting agents or fibrosis-inhibiting compositions onto or into the tracheal or bronchial stents include: (a) directly affixing to the stent a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (b) directly incorporating into the stent a fibrosis- inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier (c) by coating the stent with a substance such as a hydrogel which will in turn absorb the fibrosis-inhibiting composition), (d) by interweaving fibrosis-inhibiting composition coated thread (or the polymer itself formed into a thread) into the stent structure, (e) by inserting the stent into a sleeve or mesh which is comprised of or coated with a fibrosis-inhibiting composition, (f) constructing the stent itself or a portion of the stent with a fibrosis-inhibiting composition, or (g) by covalently binding the fibrosis-inhibiting agent directly to the stent surface or to a linker (small molecule or polymer) that is coated or attached to the stent surface. For these devices, the coating process can be performed in such a manner as to (a) coat the external surface of the stent, (b) coat the internal (luminal) surface of the stent or (c) coat all or parts of both the internal and external surfaces of the stent.

In addition to coating the device with the fibrosis-inhibiting composition, the fibrosis-inhibiting agent can be mixed with the materials that are used to make the device such that the fibrosis-inhibiting agent is incorporated into the final device. This can include the stent structure itself, the outer covering or sleeve, if applicable, or both the stent structure and the outer covering or sleeve.

According to the present invention, any fibrosis-inhibiting agent described above can be utilized in the practice of this embodiment. Within one embodiment of the invention, tracheal and bronchial stents may be adapted to release an agent that inhibits one or more of the four general components of the process of fibrosis (or scarring), including: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue). By inhibiting one or more of the components of fibrosis (or scarring), the overgrowth of granulation tissue may be inhibited or reduced.

As tracheal and bronchial stents are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in . the application of this art. Drug dose can be calculated as a function of dose per unit area (of the portion of the device being coated), total dose administered, and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 10%, 5%, or even less than 1 % of the concentration typically used in a single chemotherapeutic systemic dose application. Preferably, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

Several fibrosis-inhibiting agents for use in tracheal and bronchial stents include the following: ZD-6474, AP-23573, synthadotin, S- 0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, as well as analogues and derivatives of the aforementioned. Additional examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1- 10OnM IC50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC50 range) such as 5-azacytidine, Ly333531(ruboxistaurin), and simvastatin.

Regardless of the method of application of the drug to the tracheal or bronchial stent, the exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in or on the device may-be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg. The dose (amount) of anti-scarring agent per unit area of device surface to which the agent is applied may be in the range of about 0.01 μg/mm2 - 1 μg/mm2, or 1 μg/mm2 - 10 μg/mm2, or 10 μg/mm2 - 250 μg/mm2, 250 μg/mm2 - 1000 μg/mm2, or 1000 μg/mm2 - 2500 μg/mm2.

Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with tracheal and bronchial stent devices in accordance with the invention. (A) Angiogenesis inhibitors including alphastatin, ZD-6474, IDN-5390, SB-2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (B) mTOR inhibitors including AP-23573 and temsirolimus, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (C) Tubulin antagonists including synthadotin, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (E) Kinesin antagonists including SB- 715992 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0,1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10~s- 10"4 M of agent is to be maintained on the implant or barrier surface. (F) TNF alpha antagonists including Etanercept, humicade, adalimumab and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (J) NF KAPPA B Inhibitors including Bortezomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (K) Elongation factor-1 alpha inhibitors including aplidine and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10'8- 10'4 M of agent is to be maintained on the implant or barrier surface. (L) Tyrosine kinase inhibitors including gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10"s- 10"4 M of agent is to be maintained on the implant or barrier surface.

For high potency drugs, the total dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per unit area of 0.01 μg - 100 μg per mm2; preferably 0.1 μg/mm2 - 20 μg/mm2; and minimum concentration of 10^- 10"4 M of agent should be maintained on the implant or barrier surface. For mid-potency drugs, the total dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per unit area of 0.01 μg - 200 μg per mm2, preferably 0.1 μg/mm2 - 40 μg/mm2; and minimum concentration of 10' 8- 10'4 M of agent should be maintained on the implant or barrier surface. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit area of 0.01 μg - 500 μg per mm2; preferably 0.1 μg/mm2 - 100 μg/mm2; and minimum concentration of 10~8- 10'4 M of agent should to be maintained on the implant or barrier surface.

Genital-Urinary Stents

The present invention provides for the combination of an anti- scarring agent and genital-urinary (GU) stent device.

Representative examples genital-urinary (GU) stents that can benefit from being coated with or having incorporated therein, a fibrosis- inhibiting agent include ureteric and urethral stents, fallopian tube stents, prostate stents, including metallic and polymeric GU stents and GU stents that have an external covering (e.g., polyurethane, poly(ethylene terephthalate), PTFE or silicone rubber).

In one aspect, genital-urinary stents include ureteric and urethral stents. Ureteral stents are hollow tubes with holes along the sides and coils at either end to prevent migration. Ureteral stents are used to relieve obstructions (caused by stones or malignancy), to facilitate the passage of stones, or to allow healing of ureteral anastomoses or leaks following surgery or trauma. They are placed endoscopically via the bladder or percutaneously via the kidney.

Urethral stents are used for the treatment of recurrent urethral strictures, detruso-external sphincter dyssynergia and bladder outlet obstruction due to benign prostatic hypertrophy. In addition, procedures that are conducted for the prostate, such as external radiation or brachytherapy, may lead to fibrosis due to tissue insult resulting from these procedures. The incidence of urethral stricture in prostate cancer patients treated with external beam radiation is about 2%. Development of urethral stricture may also occur in other conditions such as following urinary catheterization or surgery, which results in damage to the epithelium of the urethra. The clinical manifestation of urinary tract obstruction includes decreased force and caliber of the urinary stream, intermittency, postvoid dribbling, hesitance and nocturia. Complete closure of the urethra can result in numerous problems including eventual kidney failure. To maintain patency in the urethra, urethral stents may be used. The stents are typically self- expanding and composed of metal superalloy, titanium, stainless steel or polyurethane.

For example, the ureteric/urethral stent may be composed of a main catheter body of flexible polymeric material having an enlarged entry end with a hydrophilic tip that dissolves when contacted with body fluids. See, e.g., U.S. Patent No. 5,401,257. The ureteric/urethral stent may be composed of a multi-sections including a closed section at that the bladder end which does not contain any fluid passageways such that it acts as an anti-reflux device to prevent reflux of urine back into the kidney. See, e.g., U.S. Patent No. 5,647,843. The ureteric/urethral stent may be composed of . a central catheter tube made of shape memory material that forms a stent with a retention coil for anchoring to the ureter. See, e.g., U.S. Patent No. 5,681 ,274. The ureteric/urethral stent may be a composed of an elongated flexible tubular stent with preformed set curls at both ends and an elongated tubular rigid extension attached to the distal end which allows the combination function as an externalized ureteral catheter. See, e.g., U.S. Patent Nos. 5,221,253 and 5,116,309. The ureteric/urethral stent may be composed of an elongated member, a proximal retention structure, and a resilient portion connecting them together, whereby they are all in fluid communication with each other with a slideable portion providing a retracted and expanded position. See, e.g., U.S. Patent No. 6,685,744. The ureteric/urethral stent may be a hollow cylindrical tube that has a flexible connecting means and locating means that expands and selectively contracts. See, e.g., U.S. Patent No. 5,322,501. The ureteric/urethral stent may be composed of a stiff polymeric body that affords superior columnar and axial strength for advancement into the ureter, and a softer bladder coil portion for reducing the risk of irritation. See, e.g., U.S. Patent No. 5,141 ,502. The ureteric/urethral stent may be composed of an elongated tubular segment that has a pliable wall at the proximal region and a plurality of members that prevent blockage of fluid drainage upon compression. See, e.g., U.S. Patent No. 6,676,623. The ureteric/urethral stent may be a catheter composed of a conduit which is part of an assembly that allows for non-contaminated insertion into a urinary canal by providing a sealing member that surrounds the catheter during dismantling. See, e.g., U.S. Patent Application Publication No. 2003/0060807A1.

In another aspect, genital-urinary stents include prostatic stents. For example, the prostatic stent may be composed of two polymeric rings constructed of tubing with a plurality of connecting arm members connecting the rings in a parallel manner. See, e.g., U.S. Patent No. 5,269,802. The prostatic stent may be composed of thermoplastic material and a circumferential reinforcing helical spring, which provides rigid mechanical support while being flexible to accommodate the natural anatomical bend of the prostatic urethra. See, e.g., U.S. Patent No. 5,069,169.

In another aspect, genital-urinary stents include fallopian stents and other female genital-urinary devices. For example, the genital- urinary device may be a female urinary incontinence device composed of a vaginal-insertable supporting portion that is resilient and flexible, which is capable of self-support by expansion against the vaginal wall and extending about the urethral orifice. See, e.g., U.S. Patent No. 3,661,155. The genital-urinary device may be a urinary evacuation device composed of a ovular bulbous concave wall having an opening to a body engaging perimetal edge integral with the wall and an attached tubular member with a pleated body. See, e.g., U.S. Patent No. 6,041,448.

Genital-urinary stents, which may be combined with one or more agents according to the present invention, include commercially available products, such as the UROLUME Endoprosthesis Stents from American Medical Systems, Inc. (Minnetonka, MN), the RELIEVE Prostatic/Urethral Endoscopic Device from InjecTx, Inc. (San Jose, CA), the PERCUFLEX Ureteral Stents from Boston Scientific Corporation, and the TARKINGTON Urethral Stents and FIRLIT-KLUGE Urethral Stents from Cook Group lnc (Bloomington, IN).

In one aspect, the present invention provides GU stents that include an anti-scarring agent or a composition that includes an anti-scarring agent. Numerous polymeric and non-polymeric delivery systems for use in GU stents have been described above. Methods for incorporating fibrosing agents or fibrosis-inhibiting compositions onto or into the GU stents include: (a) directly affixing to the stent a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (b) directly incorporating into the stent a fibrosis-inhibiting composition (e.g., by either a spraying process or dipping process as described above, with or without a carrier), (c) by coating the stent with a substance such as a hydrogel which will in turn absorb the fibrosis-inhibiting composition, (d) by interweaving fibrosis-inhibiting composition coated thread (or the polymer itself formed into a thread) into the stent structure, (e) by inserting the stent into a sleeve or mesh which is comprised of or coated with a fibrosis-inhibiting composition, (f) constructing the stent itself or a portion of the stent with a fibrosis-inhibiting composition, or (g) by covalently binding the fibrosis-inhibiting agent directly to the stent surface or to a linker (small molecule or polymer) that is coated or attached to the stent surface. For these devices, the coating process can be performed in such a manner as to (a) coat the external surface of the stent, (b) coat the internal (luminal) surface of the stent or (c) coat all or parts of both the internal and external surfaces of the stent.

In addition to coating the device with the fibrosis-inhibiting composition, the fibrosis-inhibiting agent can be mixed with the materials that are used to make the device such that the fibrosis-inhibiting agent is incorporated into the final device.

According to the present invention, any fibrosis-inhibiting agent described above can be utilized in the practice of this embodiment. Within one embodiment of the invention, GU stents may be adapted to release an agent that inhibits one or more of the four general components of the process of fibrosis (or scarring), including: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of the fibrous tissue). By inhibiting one or more of the components of fibrosis (or scarring), the overgrowth of granulation tissue may be inhibited or reduced.

As GU stents are made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in the application of this art. Drug dose can be calculated as a function of dose per unit area (of . the portion of the device being coated), total dose administered, and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 10%, 5%, or even less than 1% of the concentration typically used in a single chemotherapeutic systemic dose application. Preferably, the drug is released in effective concentrations for a period ranging from 1 - 90 days.

Several examples of scarring agents for use in GU stents include the following: ZD-6474, AP-23573, synthadotin, S-0885, aplidine, ixabepilone, IDN-5390, SB-2723005, ABT-518, combretastatin, anecortave acetate, SB-715992, temsirolimus, adalimumab, erucylphosphocholine, alphastatin, etanercept, humicade, gefitinib, as well as analogues and derivatives of the aforementioned.

Additional examples of anti-scarring agents which can be used include those having a high potency in the assays described herein (1- 10OnM IC50 range) such as isotretinoin, radicicol, clobetasol propionate, homoharringtonine, trichostatin A, brefeldin A, thapsigargin, dolastatin 15, cerivastatin, jasplakinolide, herbimycin A, pirfenidone, vinorelbine, 17- DMAG, and tacrolimus; those having a mid-potency in the assays described herein (100-500 nM IC50 range) such as loteprednol etabonate, juglone, prednisolone, puromycin, 3-BAABE, cladribine, and mannose-6-phosphate; and those having a low potency in the assays described herein (500- 1000nm range IC50 range) such as 5-azacytidine, Ly333531(ruboxistaurin), and simvastatin.

Regardless of the method of application of the drug to the GU stent, the exemplary anti-fibrosing agents, used alone or in combination, should be administered under the following dosing guidelines. The total amount (dose) of anti-scarring agent in or on the device may be in the range of about 0.01 μg-10 μg, or 10 μg-10 mg, or 10 mg-250 mg, or 250 mg-1000 mg, or 1000 mg-2500 mg. The dose (amount) of anti-scarring agent per unit area of device surface to which the agent is applied may be in the range of i about 0.01 μg/mm2 - 1 μg/mm2, or 1 μg/mm2 - 10 μg/mm2, or 10 μg/mm2 - . 250 μg/mm2, 250 μg/mm2 - 1000 μg/mm2, or 1000 μg/mm2 - 2500 μg/mm2.

Provided below are exemplary dosage ranges for various anti- scarring agents that can be used in conjunction with GU stent devices in accordance with the invention. (A) Angiogenesis inhibitors including Alphastatin, ZD-6474, IDN-5390, SB-2723005, ABT-518, combretastatin, and anecortane, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (B) mTOR inhibitors including AP-23573 and Temsirolimus, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (C) Tubulin antagonists including synthadotin, analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8 - 10"4 M of agent is to be maintained on the implant or barrier surface. (D) Epithilones including ixabepilone and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (E) Kinesin antagonists including SB- 715992 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (F) TNF alpha antagonists including Etanercept, humicade, adalimumab and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (G) AKT inhibitor including erucylphosphocholine and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^ - 10"4 M of agent is to be maintained on the implant or barrier surface. (H) FGF Inhibitors including IDN-5390 and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10^- 10"4 M of agent is to be maintained on the implant or barrier surface. (I) Collagenase Antagonists including S-0885 and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10'8- 10"4 M of agent is to be maintained on the implant or barrier surface. (J) NF KAPPA B Inhibitors including Bortezomib and analogues and derivatives thereof: total dose not to exceed 200 mg (range of 0.1 μg to 200 mg); preferred 1 μg to 100 mg. Dose per unit area of 0.01 μg - 100 μg per mm2; preferred dose of 0.1 μg/mm2 - 20 μg/mm2. Minimum concentration of 10"8- 10"4 M of agent is to be maintained on the implant or barrier surface. (K) Elongation factor-1 alpha inhibitors including aplidine and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10'8- 10'4 M of agent is to be maintained on the implant or barrier surface. (L) Tyrosine kinase inhibitors including Gefitinib and analogues and derivatives thereof: total dose not to exceed 1000 mg (range of 0.1 μg to 1000 mg); preferred 1 μg to 500 mg. Dose per unit area of 0.01 μg - 500 μg per mm2; preferred dose of 0.1 μg/mm2 - 100 μg/mm2. Minimum concentration of 10'8- 10'4 M of agent is to be maintained on the implant or barrier surface.

For high potency drugs, the total dose typically should not exceed 200 mg (range of 0.1 μg to 200 mg) and preferably 1 μg to 100 mg; dose per unit area of 0.01 μg - 100 μg per mm2; preferably 0.1 μg/mm2 - 20 μg/mm2; and minimum concentration of 10'8- 10"4 M of agent should be maintained on the implant or barrier surface. For mid-potency drugs, the total dose typically should not to exceed 500 mg (range of 1.0 μg to 500 mg) and preferably 1 μg to 200 mg; dose per unit area of 0.01 μg - 200 μg per mm2, preferably 0.1 μg/mm2 - 40 μg/mm2; and minimum concentration of 10' 8- 10"4 M of agent should be maintained on the implant or barrier surface. For low potency drugs, the total dose typically should not exceed 1000 mg (range of 0.1 μg to 1000 mg), preferably 1 μg to 500 mg; dose per unit area of 0.01 μg - 500 μg per mm2; preferably 0.1 μg/mm2 - 100 μg/mm2; and minimum concentration of 10'8- 10"4 M of agent should to be maintained on the implant or barrier surface.

Ear and Nose Stents

The present invention provides for the combination of an anti- scarring agent and an ear-nose-throat (ENT) stent device {e.g., a lacrimal duct stent, Eustachian tube stent, nasal stent, or sinus stent).

The sinuses are four pairs of hollow regions contained in the bones of the skull named after the bones in which they are located (ethmoid, maxillary, frontal and sphenoid). All are lined by respiratory mucosa which is directly attached to the bone. Following an inflammatory insult such as an upper respiratory tract infection or allergic rhinitis, a purulent form of sinusitis can develop. Occasionally secretions can be retained in the sinus due to altered ciliary function or obstruction of the opening (ostea) that drains the sinus. Incomplete drainage makes the sinus prone to infection typically with Haemophilus influenza, Streptococcus pneumoniae, Moraxella catarrhalis, Veillonella, Peptococcus, Corynebacterium acnes and certain species of fungi.

When initial treatment such as antibiotics, intranasal steroid sprays and decongestants are ineffective, it may become necessary to perform surgical drainage of the infected sinus. Surgical therapy often involves debridement of the ostea to remove anatomic obstructions and removal of parts of the mucosa. Occasionally a stent (a cylindrical tube which physically holds the lumen of the ostea open) is left in the osta to ensure drainage is maintained even in the presence of postoperative swelling. ENT stents, typically made of stainless steel or plastic, remain in place for several days or several weeks before being removed.

Representative examples of ENT stents that can benefit from being coated with or having incorporated therein a fibrosis-inhibiting agent include lacrimal duct stents, Eustachian tube stents, nasal stents, and sinus stents. In one aspect, the present invention provides for the combination of a lacrimal duct stent and a fibrosis-inhibiting agent or a composition comprising a fibrosis-inhibiting agent.

In another aspect, the present invention provides for the combination of a Eustachian tube stent and a fibrosis-inhibiting agent or a composition comprising a fibrosis-inhibiting agent.

In yet another aspect, the present invention provides for the combination of a sinus stent and a fibrosis-inhibiting agent or a composition comprising a fibrosis-inhibiting agent.

In yet another aspect, the present invention provides for the combination of a nasal stent and a fibrosis-inhibiting agent or a composition comprising a fibrosis-inhibiting agent.

The ENT stent may be a choanal atresia stent composed of two long hollow tubes that are bridged by a flexible transverse tube. See, e.g., U.S. Patent No. 6,606,995. The ENT stent may be an expandable nasal stent for postoperative nasal packing composed of a highly porous, pliable and absorbent foam material capable of expanding outwardly, which has a nonadherent surface. See, e.g., U.S. Patent No. 5,336,163. The ENT stent may be a nasal stent composed of a deformable cylinder with a breathing passageway that has a smooth outer non-absorbent surface used for packing the nasal cavity following surgery. See, e.g., U.S. Patent No. 5,601 ,594. The ENT stent may be a ventilation tube composed of a flexible, plastic, tubular vent with a rectangular flexible flange which is used for the nasal sinuses following endoscopic antrostomy. See, e.g., U.S. Patent No. 5,246,455. The ENT stent may be a ventilating ear tube composed of a shaft and an extended tab which is used for equalizing the pressure between the middle ear and outer ear. See, e.g., U.S. Patent No. 6,042,574. The ENT stent may be a middle ear vent tube composed of a non-compressible, tubular base and an eccentric flange. See, e.g., U.S. Patent No. 5,047,053. ENT stents, which may be combined with one or more agents according to the present invention, include commercially available products such as Genzyme Corporation (Ridgefield, NJ) SEPRAGEL Sinus Stents and MEROGEL Nasal Dressing and Sinus Stents from Medtronic Xomed Surgical Prod