WO2002085253A1 - Plate-forme d'administration de medicaments et procedes d'inhibition de la formation de la neointima - Google Patents
Plate-forme d'administration de medicaments et procedes d'inhibition de la formation de la neointima Download PDFInfo
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- WO2002085253A1 WO2002085253A1 PCT/US2002/012091 US0212091W WO02085253A1 WO 2002085253 A1 WO2002085253 A1 WO 2002085253A1 US 0212091 W US0212091 W US 0212091W WO 02085253 A1 WO02085253 A1 WO 02085253A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L31/00—Materials 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
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/145—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
- A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
- A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
- A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
- A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
- A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L31/00—Materials 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
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
- A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
- A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
- A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
- A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
- A61F2002/91533—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other characterised by the phase between adjacent bands
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
- A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
- A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
- A61F2250/0068—Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
Definitions
- Stents and other prosthetic devices have provided the means to clinically treat many conditions.
- Stents are commonly used to open blood vessels, e.g. clearing obstructions, preventing restenosis, providing support at the site of an aneurysm, and to repair damage to vascular tissues, e.g. arteries and veins.
- vascular tissues e.g. arteries and veins.
- other vessels of the body may be repaired with a stent, including the trachea for breathing disorders, renal and urethral tubules, fallopian tubes for the treatment of infertility, eustachian tubes for the treatment of chronic ear infection and other hearing disorders, large and small intestines where the vessels may be occluded with tumor cells, etc.
- stent designs are known and in clinical use. For example, they can be cut from a tube or formed from a wire that has been bent back and forth in a zig-zag pattern and wound in a circumferential direction to form one or more loops of a pre-determined circumference.
- the stent is radially expandable from a collapsed condition. Once in position, it is expanded to the predetermined size, to support and reinforce the lumen.
- stents One of the largest fields for the use of stents is in the treatment of cardiovascular disease.
- Treatment by balloon angioplasty, percutaneous transluminal angioplasty (PTA) has been shown to improve life expectancy after occlusion of blood vessels, but up to 40% of patients encounter restenosis within 6 months. Since angioplasty alone is marked by progressive luminal compromise (negative remodeling), stenting has become the leading interventional strategy with current application in 60-70% of PTAs.
- Stent use offers a number of advantages over simple PTA, including decreased early in-hospital complications, increase in luminal diameter, decreased negative remodeling, and sealing of intimal flaps.
- arteries treated with stents also encounter dramatically accelerated rates of in- stent restenosis, which are clinically significant in up to 40% of cases.
- U.S. Patent no. 6,004,346, "Intralumenal drug eluting prosthesis" discloses a drug eluting stent.
- U.S. Patent no. 5,972,027 discloses a porous stent drug delivery system.
- a drug eluting stent is described in U.S. Patent 5,697,967.
- U.S. Patent no. 6,335,029 is directed to polymeric coatings for controlled delivery of active agents. Other coatings for localized delivery of drug agents are disclosed in U.S. Patent no. 6,280,411. Brown et al., U.S. Patent no. 6,071,305 relates to a directional drug delivery stent.
- a drug delivery stent for liquid formulations is disclosed by Leone et al., U.S. Patent no. 5,891,108.
- the stent comprises a matrix, where the matrix has entrapped a pharmaceutical agent of interest.
- the matrix for example microspheres, etc. resides within a channel formed on one or both of the abluminal or adluminal surfaces of the stent, and allows for release, usually sustained release, of the entrapped agent.
- the stent and matrix is encased with a gel covalently bound to the stent surface and optionally also covalently bound to the matrix, which prevents loss of the matrix during transport and implantation of the stent, and which affects the release of the biologically active agent, through degradation and diffusion characteristics.
- the delivery system of the invention finds use in the delivery of pharmaceutical agents, particularly where a localized concentration of the agent is desirable.
- the stent is a cardiovascular stent, where the pharmacologic agent is an anti- restenotic agent, e.g. to prevent in-stent restenosis.
- the stent is a gastrointestinal stent that prevents obstruction due to tumor ingrowth or reactive hyperplasia, and which also delivers a chemotherapeutic agent for treatment of hyperplasia.
- the delivery system of the invention also find use in the evaluation of candidate agents by providing both efficient delivery and low perturbation at the site of implantation.
- the efficiency of drug delivery provided by the drug delivery stent allows a sensitive comparison of the effect of an agent on, for example, restenosis, hyperplasia, and the like.
- the matrix is formed into microspheres or other discrete particles that entrap the agent to be delivered.
- the matrix may be biodegradable, bioerodible, or biocompatible, non-biodegradable compositions. In all cases the matrix will provide for release of the entrapped agent over time.
- the matrix is loaded into the channels, and then ensheathed in a gel bound to the stent surface, e.g. by derivatization of a metal oxide surface with methoxysilane, by binding to a plastic surface, binding to a biodegradable or bioerodible stent surface, and the like.
- the pharmaceutical agent is not directly bound to the stent surface.
- compositions and methods are provided for preventing restenosis through local delivery of anti-restenotic agents.
- Figure 1A is a diagram of a channeled stent.
- Figure 1B is a cross-sectional view of the stent and channels.
- Figure 1 C is a close-up view of the stent.
- Figure 2 is a graph depicting size-dependent flow retention. Microspheres of 50 ⁇ m
- Figure 3 is a graph depicting hybrid retention in vitro and in vivo. Microspheres of 10 ⁇ m were loaded onto a stent to complete fill density, and combined with pluronic gel (MS- plu), stent-anchored PEG-methacrylate gel (MS-gel) or stent- and MS-anchored PEG- methacrylate gel (MS-meac-gel).
- MS- plu pluronic gel
- MS-gel stent-anchored PEG-methacrylate gel
- MS-meac-gel stent- and MS-anchored PEG- methacrylate gel
- Figures 4A and 4B are representative digital subtraction angiograms after in vivo MS- gel deployment. No immediate post-deployment (Figure 4A) or late (pre-harvest, Figure 4B) mechanical failures or complications are present.
- Figures 5A, 5B and 5C are photographs depicting early in-stent plaque formation.
- compositions and methods are provided for a stent based drug delivery system.
- a biological agent of interest is entrapped within a matrix 130.
- the matrix is loaded into channels 110 on the surface of a stent 100, which channels are formed on one or both of the stent abluminal or adluminal surfaces.
- the matrix allows for release, usually sustained release, of the entrapped agent.
- the stent and matrix is sheathed with a covalently bound gel 140, which may help retain the matrix during transport and implantation of the stent.
- the stent surface may be derivatized 120 to improve covalent binding.
- the stent is used to deliver therapeutic agents to a patient, providing the advantage of efficient delivery and sustained release of an agent at a localized site.
- the system provides the additional advantage of low perturbation at the site of implantation.
- the advantages of the drug delivery system allow for testing and comparison of candidate drugs in an in vivo setting.
- compositions and methods are also provided for preventing restenosis through local delivery of anti-restenotic agents.
- agents useful as anti-restenotic agents include angiotensin converting enzyme inhibitors; nicotine receptor agonists, agents that increase concentrations of nitric oxide, anti-angiogenic agents, agonists of the TGF-beta receptor; death domain receptor ligands; rapamycin; antiplatelet agents; GPIIb/llla inhibitors; DNA; ribozymes; RNA; and thrombin inhibitors.
- the localized delivery is effected through the use of a stent modified for delivery of the agent at the site of injury from balloon angioplasty.
- a microsphere includes a plurality of such microspheres and reference to “the stent” includes reference to one or more stents and equivalents thereof known to those skilled in the art, and so forth.
- dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. , . . . . .
- Stent As used . herein, the term stent is used as is known in the art, to. refer to a prosthesis which can be inserted and held, when desired, in a lumen of a vessel ;or organ in the, body. Uses. include the support of blood vessels, the trachea, renal and urethral tubules, fallopian tubes, eustachian, large and small intestines, etc. Materials commonly used in stent construction include biologically compatible metals, e.g. stainless steel, titanium, tantalum, gold, platinum, copper and the like, as well as alloys of these metals; low shape memory plastic; a shape-memory plastic or alloy, such as nitinol; and the like. Any of these materials can be fabricated to form channels for use in the present invention, and can form, or be derivatized to form, covalent bonds with the matrix.
- biologically compatible metals e.g. stainless steel, titanium, tantalum, gold, platinum, copper and the like,
- Non-limiting examples of commercially available stents include the Gianturco-Roubin stent and the Palmaz-Schatz stent, commonly used for tandem short segment stenotic lesions; Wallstent (Boston Scientific, Natick, Mass), a self expanding stainless stent used for long lesions; Mammotherm stent, Symphony stent, Smart stent, all of self expanding nitinol; the balloon exapandable Perflex, AVE, Intrastent, and Herculink stents, self-expanding Instent, Gianturco Z-stent (Wilson-Cook, Winston-Salem, NC), Ultraflex nitinol mesh stent (Microinvasive, Natick, Mass), and Esophacoil (IntraTherapeutics, Eden Prairie, Minn).
- Tracheobronchial stents include the Gianturco Z tracheobronchial tree stent and the Wallstent tracheobronchial endoprosthesis.
- the stent may be self-expanding, or may be expandable with a balloon, as is known in the art.
- Additional platforms for the invention include polymeric biodegradable stents, anastomotic devices, and scaffolds, including synthetic biodegradable or bioerodible porous scaffolds produced using solid free-form fabrication techniques which include selective laser sintering, three-dimensional printing, fused deposition manufacturing, and stereolithography for micro- or nano-fabrication.
- a stent 100 comprises channels 110 on the surface, which may be on either or both of the abluminal (toward the wall) or adluminal (toward the lumen) surfaces.
- the channels may extend to the end of the stent, forming an open channel, or may be a closed channel.
- the channels are on the adluminal surface and direct delivery to the cells of the vessel wall.
- a matrix 130 which is covalently bound to the stent surface, which may be derivatized 120 for that purpose.
- the dimensions of the channel will be dictated by the requirements for the specific use, and will be sufficient to contain the unit size of the matrix, e.g. microspheres of 1 to 100 ⁇ m diameter, and will not be of a depth so great that it compromises the integrity of the stent's structural integrity.
- the depth will usually be at least about 10 ⁇ m, more usually at least about 20 ⁇ m, usually not more than about 200 ⁇ m, more usually not more than about 100 ⁇ m, and preferably are about 45 to 65 ⁇ m iri depth.
- the depth is usually greater than : " about 10% of the total depth of the stent structure, usually greater than about 50% of the totai depth of the stent stru ⁇ ure, usuaiiy not more than about 80% of the total depth of the stent structure.
- the length and width of the channel may vary greatly depending on the tissue intended for deployment, for example a cardiovascular stent may have smaller dimensions than an enteral stent.
- the length of the channel may be up to and including the length of the stent, or where the stent has a strut pattern, along the entire circumference, or a fraction thereof.
- the width of the channel will be sufficient to contain the unit size of the matrix and still maintain the structural integrity of the stent.
- the channels are usually at least about 10 ⁇ m in width, more usually at least about 20 ⁇ m in width, preferably at least about 45 ⁇ m in width, where the upper boundary of width is determined by the specific stent design, but is generally not more than about 50 to 75% of the total width of the element, i.e. strut, tube, efc., but could be up to 100% of the width in the case of tapered channels, such as one can get from laser machining the channels.
- Channels may be tapered in cross-section, such that the width at the stent surface is wider than the width at the bottom of the channel, e.g. a V shape, a U shape, a V shape with a flat bottom, etc.
- the tapered channel is usually more than about 10% of the strut width, usually more than about 50 or more than about 75% of the surface width, and may be as much as 100% of the surface width.
- Depth for tapered channels are as described above for a non-tapered channel. The degree of taper will determine the width of the channel at the bottom, where a V-shaped taper will result in a width of about 0 to about 10% of the width of the stent structure. A broader bottom may also find use, where the width of the channel at the bottom will be from about 10% to about 50% of the width of the stent.
- Channel dimensions and architecture are designed to achieve the desired percent coverage and delivery location while preserving mechanical integrity.
- Channels may be fabricated into a stent using known micro- or non-fabrication techniques known in the art, including electro-discharge machining (EDM), laser machining e.g. photolithography, thin-film deposition, wet chemical etching, reactive ion etching, inductively coupled plasma deep silicon etching, laser ablation, air abrasion techniques, injection molding, embossing, and other techniques.
- Stents may also be comprised of polymeric materials, e.g., plastics, biodegradable polymers, and the like. Such substrates are readily manufactured from microfabricated masters, using well known molding techniques, such as injection molding, embossing or stamping, or by polymerizing the polymeric precursor . material withjn the mold. These polymeric materials . may include, treated surfaces, e.g., derivatized-or coated. surfaces, to enhance their utility in the.system. . •
- the gel is covalently bound to the channel.surface.
- The' stent surface may be derivatized for covalent binding of a highly viscous agent or component of a gel-forming composition, which can be applied in the absence or presence of channels described above. Where the surface is a meta), it may be first modified with an adhesion agent.
- silane coupling reagents especially those of the formula R'Si(OR) 3 in which R' is typically an aliphatic group with a terminal amine and R is a lower alkyl or chloro group, to attach a macromolecule or polymer covalently to a solid support is well known in the art.
- Alkoxy or chloro leaving groups are particularly reactive towards hydroxyl groups found on metal oxide surfaces, where trichlorosilanes are much more reactive than trialkoxysilanes, and appear to form the densest films.
- Other organosilanes include 3- methacryloxypropyltrimethoxysilane; aminopropyltriethoxysilane (APTES); 3- mercaptopropyltriethoxysilane (MPS); glycidoxypropyltriethoxysilane (GOPS), and the like.
- APTES aminopropyltriethoxysilane
- MPS 3- mercaptopropyltriethoxysilane
- GOPS glycidoxypropyltriethoxysilane
- succinnic anhydride can be used to change the amino functionality to carboxylic acid which is then attached to an amino-linked nucleic acid via carbodiimide coupling.
- MPS can be used to form disulfide linkages with thiol-containing biomolecules.
- GOPS has been used in schemes using long polyether chains to provide greater distance and flexibility between the surface and the matrix.
- Bifunctional trichlorosilanes have been made so that other molecules can be later attached to the silanized surface.
- 1-thioacetato-16-(trichlorosilyl)-hexadecane and related analogs have been described as a linking agent for biomolecules.
- the active silane monomer can also be diluted with a monomer which does not contain the linking group, to effectively "space-out" the active silane monomers that deposit on the surface.
- the degree of surface coverage depends on several variables such as reaction time, temperature, degree of hydration of the substrates, nature of the solvent, the cleaning procedure utilized prior to silanization of substrates and the nature/morphology of the oxide layer on the substrate.
- Methyl terminated diluent silanes provide a hydrophobic alternative to polar materials.
- Other diluents can be used to provide other functionalities to the surface, for example, the diluent may contain alcohol groups to increase hydrophilicity.
- the number of carbons in the diluent may also be varied to control the steric environment around the active silane's functional moiety.
- Polymer coating of plastic surfaces may be achieved with polyvinyl alcohol, polyethyleneimine, polyacrolein, polyacrylic acid, etc.
- Direct chemical modification of plastic surfaces includes graft polymerization; halomethylation; plasma deposition of amines, alcohols, and carboxylic acids; nitration followed by reduction; and oxidation.
- the linkage may utilize a homo- or heterobifunctional linker having a group at one end capable of forming a stable linkage to the stent surface, and a group at the opposite end -capable of forming a stable linkage to the matrix.
- Illustrative entities include:
- azidobenzoyl hydrazide • N-[4-(p-azidosalicylamino)butyl]-3 2'-pyridyldithio]propionamide), bis-sulfosuccinimidyl suberate, dimethyladipimidate, disuccinimidyltartrate,.
- Matrix A biodegradable, bioerodible or biocompatible non-biodegradable matrix comprising a biologically active agent is placed within the channels of the stent surface.
- the matrix may be of any geometry including fibers, sheets, films, microspheres, circular discs, plaques and the like.
- the size and form of the matrix can be used to control the rate of released period of treatment, and drug concentration. In some situations mixtures of matrices may be utilized employing the same or different biologically active agents. In this way, in a single administration a course of drug treatment may be achieved, where the pattern of release may be greatly varied.
- the matrix is formed to discrete particles, e.g. fibers, spheres, etc., preferably microspheres.
- Microspheres are usually at least about 5 ⁇ m in diameter, more usually at least about 10 ⁇ m in diameter, and are usually not more than about 100 ⁇ m in diameter, more usually not more than about 50 ⁇ m in diameter. Certain drug/microsphere preparations necessitate smaller sizes, e.g. from about 5 ⁇ m to about 20 ⁇ m in diameter due to concentration, molecular charge and volume requirements. In addition, smaller sizes are desirable to ease manual loading or automate loading.
- Biodegradable polymers are generally subject to enzymatic or hydrolytic instability. Water soluble polymers may be cross-linked with hydrolytic or biodegradable unstable cross- links to provide useful water insoluble polymers. The degree of stability can be varied widely, depending upon the choice of monomer, whether a homopolymer or copolymer is employed, employing mixtures of polymers, where the polymers may be employed as varying layers or mixed.
- biodegradable polymers useful in the present invention include: hydroxyaliphatic carboxylic acids, either homo- or copolymers, such as polylactic acid, polyglycolic acid, polylactic glycolic acid; polysaccharides such as cellulose or cellulose derivatives such as ethyl cellulose, cross-linked or uncross-liriked sodium carb ⁇ xymethyl :
- cellulose sodium carboxyrriethylcellulose starch, cellulose ethers, cellulose esters such as cellulose acetate, cellulose acetate phthallate, hydroxypropylrriethyl cellulose.
- polymethacrylates polyanhydrides, polyvalerates, polycaprolactones such as poly-.epsil ⁇ n.- caprolactone, polydimethylsiloxane, polyamides, polyvinylpyrollidone, polyvinylalcohol phthallate, waxes such as paraffin wax and white beeswax, natural oils, shellac, zein, or a mixture thereof.
- polymers of hydroxyaliphatic carboxylic acids either homo- or copolymers, and polysaccharides. Included among the polyesters of interest are polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, and combinations thereof.
- the matrix may include small amounts of a compound capable of covalently bonding to the stent surface, e.g. including a PEG-dimethacrylate conjugate, or other linkers as described above.
- Polysaccharides useful as a matrix include calcium alginate, and functionalized celluloses, particularly carboxymethylcellulose esters characterized by being water insoluble, molecular weight of about 5 kD to 500 kD, etc.
- Other polymers of interest include polyvinyl alcohol, esters and ethers, which are biocompatible and may be biodegradable or soluble. For the most part, characteristics of the polymers will include biocompatibility, compatibility with the agent of interest, ease of encapsulation, a half-life in the physiological environment of at least 6 hrs; preferably greater than one day, water insoluble, and the like.
- Biocompatible, non-biodegradable polymeric compositions are also used as a matrix. Where a non-biodegradable polymer is employed, the rate of release of the drug will be 5 primarily solution/diffusion controlled. The rate of diffusion of drug through the non- biodegradable polymer may be affected by drug solubility, polymer hydrophilicity, extent of polymer cross-linking, expansion of the polymer upon water absorption so as to make the polymer more permeable to the drug, and the like. Diffusion of the drug from the implant may also be controlled by the structure of the implant.
- the non-biodegradable polymeric polymeric materials may be controlled by the structure of the implant.
- compositions employed may be varied according to the compatibility of the polymer with the drug or other active agent to be employed, ease of manufacture, the desired rate of release of the drug, desired density or porosity, and the like.
- Various non-biodegradable polymers which may be employed are described in U.S. Pat. Nos. 4,303,637; 4,304,765; 4,190,642; 4,186,184; 4,057,619; 4,052,505; 4,281,654; 4,959,217; 4,014,335; 4,668,506; 4,144,317.
- the non-biodegradable polymers may be homopolymers, copolymers, straight, branched- chain, or cross-linked derivatives.
- polystyrene resin graft copolymer
- non-biodegradable, polymers of particular interest include, * polycarbamates or . polyureas,. particularly, polyurethanes, polymers which may be * cross- linked to produce non-biodegradable polymers such as cross-linked poly(vinyl, acetate) and
- ethylene-vinyl ester copolymers aving ail ester content of 4 to 80% such as ethylene-vinyl acetate (EVA) copolymer, ethylene-vinyl hexanoate copolymer, ethylene-vinyl propionate copolymer, ethylene-vinyl butyrate copolymer, ethylene-vinyl pentantoate copolymer, ethylene-vinyl trimethyl acetate copolymer, ethylene-vinyl diethyl acetate copolymer, ethylene-vinyl 3-methyl butanoate
- EVA ethylene-vinyl acetate
- EVA ethylene-vinyl acetate copolymer
- ethylene-vinyl hexanoate copolymer ethylene-vinyl propionate copolymer
- ethylene-vinyl butyrate copolymer ethylene-vinyl pentantoate copolymer
- Additional naturally occurring or synthetic non-biodegradable polymeric materials include poly(methylmethacrylate), poly(butylmethacrylate), plasticized poly(vinylchloride), plasticized poly(amides), plasticized nylon, plasticized soft nylon, plasticized poly(ethylene
- Various techniques known in the art may be employed to entrap the anti-restenotic agent in the matrix.
- Useful techniques include solvent evaporation methods, phase separation methods, double emulsions methods, UV crosslinking, chemical crosslinking, self-assembling systems based upon covalent or noncovalent interactions, interfacial methods, extrusion methods, molding methods, injection molding methods, heat press methods and the like.
- the ratio of agent to polymer will vary with the desired rate of release, the amount of agent generally varying in the range of 1 to 80 weight percent of the polymer in addition to other agents present.
- the ratio of drug to polymer may be adjusted to produce optimized compositions.
- a preformed rate controlling polymer may be dissolved in a volatile substantially water-immiscible solvent, and the agent then added to the polymer-solvent solution.
- the agent dispersed in the viscous polymer-solvent mixture or a solid dispersion of drug particles, where the drug will have been pulverized to obtain a fine powder.
- the matrix may also be formed by mixing the agent with molten polymer at. the appropriate temperature, for example. for molten polylactic polymer.,. between _60° , to -90° C, .
- the resulting mixture can be cut, . molded, injection molded or extruded into any shape or size. - . ⁇ . . ' • *; • ⁇ - ' . . • •
- a coating can be formed around the layered solution to provide an encapsulated matrix for controlled, prolonged release of the active agent.
- an appropriate aqueous solution generally water
- aqueous solution is slowly poured over the surface.
- polymerization results in a membrane surrounding the drug or agent.
- the drug and polymer mixture may be extruded to provide, for example, a long rod or fiber.
- the dispersion or solution can alternatively be added to a rapidly stirred aqueous solution comprising water and a dispersion agent, which may be a protective colloid.
- the matrix may be formed by one of the methods described above, but in the absence of the active agent.
- the drug-free matrix may then be loaded with drug by, for example, immersing the matrix in a solution comprising the active agent for a time sufficient for absorption of the drug.
- the drug-filled matrix may then be dried or partially dried for storage until use. This method may find particular application where the activity of the drug of choice is sensitive to exposure to solvents, heat or other aspects of the conventional solvent-evaporation, molding, extrusion or other methods. Gel.
- the gel is selected to be a polymeric compound that will fill the spaces between the matrix and the channel, that can be covalently bound to the stent surface and optionally covalently bound to the matrix, and that provides a porous protective barrier between the matrix and the environment, for example during storage, implantation, flow conditions, etc.
- the gel may contribute to the control of drug release through its characteristics of degradation and diffusion.
- the gel may comprise a biologically active agent that is the same or different from the biologically active agent present in the matrix.
- Suitable polymers for the gel include poly(methylmethacrylate), poly(butylmethacrylate), plasticized poly(vinylchloride), plasticized poly(amides), plasticized nylon, plasticized soft nylon, plasticized poly(ethylene terephthalate), natural rubber, silicone, poly(isoprene), poly(isobutylene), poly(butadiene), poly(ethylene), poly(tetrafluoroethylene), poly(vinylidene chloride), poly(acrylonitrile, cross-linked poly(vinylpyrrolidone), poly(trifluorochloroethylene), chlorinated poly(ethylene), poly(4,4'-isopropylidene diphenylene carbonate), vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone, silicone rubbers (especially the medical grade), poly(dimethylsiloxanes), ethylene-propylene rubber, silicone-carbonate copolymers-
- the gel is cross-linked to the stent through the chemistry described above.
- the polymer may be molded, wrapped, etc. around the stent to provide a protective covering.
- the biologically active agent delivered to the targeted tissue may be any exogenous agent, particularly agents where it is desirable to achieve a localized concentration, e.g. anti-restenotic agents, anti-tumor agents, etc. Included are pharmacologically active drugs, e.g. antibodies, cytokines, hormones, growth factors, etc.; nucleic acids, e.g. anti-sense oligonucleotides, plasmids, viral genomes, mRNA, etc.; viruses; pro-drugs; pro-drug activators; etc. When drugs are delivered locally via the prosthesis of the invention, they may be at therapeutic levels at the diseased site while at the lower limits of detectability in the bloodstream.
- pharmacologically active drugs e.g. antibodies, cytokines, hormones, growth factors, etc.
- nucleic acids e.g. anti-sense oligonucleotides, plasmids, viral genomes, mRNA, etc.
- viruses pro-drugs
- Compounds of interest include chemotherapeutic agents for neoplastic tissues, anti- inflammatory agents for ischemic or inflamed tissues, hormones or hormone antagonists for endocrine tissues, ion channel modifiers for cardiovascular or other tissues, and neuroactive agents for the central nervous system.
- Agents may be in, the form of simple drugs, peptides, peptide
- the method of the invention can be exploited as a platform for delivery of genetic materials and thus is useful in a variety of applications.
- Nucleic acids that correct genetic deficiencies can be introduced into a targeted tissue, e.g. blood vessels, intestines, etc.
- Specific agents of interest include therapeutic agents that inhibit in-stent restenosis.
- Such agents may include rapamycin; antiplatelet agents; GPIIb/llla inhibitors, e.g. RheoPro; DNA; ribozymes; RNA; antiplatelet drugs- e.g. aspirin and dipyridamole; anticoagulant drugs,
- ⁇ including heparin, coumadin, protamine,* and.hirudin; antimitotics (cytotoxic agents) that work directly to prevent cell mitosis. (replication) and antimetabolites .that prevent replication, e.g..
- glucocorticoids e.g. dexamethasone, betamethasone, etc. can also be useful to locally suppress inflammation caused by injury to luminal tissue during angioplasty.
- Angiotensin converting enzyme inhibitors (ACE-I) are used for antihypertensive and
- ACE inhibitor include, but are not limited to, captopril, benazepril, enalapril, fosinopril, lisinopril, quinapril, Ramipril, imidapril, perindopril, erbumine, and trandolapril.
- ACE receptor blockers may also be used in place of or as well as ACE inhibitors, and these include losartan, irbesartan, candesartan, cilexetil, and valsartan.
- Nicotine receptor agonist e.g. nicotine (S-3-(1-methyl-2-pyrrolidinyl)pyridine) and
- Nicotine receptor agonists encompass naturally-occurring compounds (including, but not limited to, small molecules, polypeptides, peptides, etc., particularly naturally-occurring plant alkaloids, and the like), endogenous ligands (e.g., purified from a natural source, recombinantly produced, or synthetic, and further including
- the term "nicotine” further includes any pharmacologically acceptable derivative or metabolite of nicotine which exhibits pharmacotherapeutic properties similar to nicotine.
- Such derivatives, metabolites, and derivatives of metabolites are known in the art, and include, but are not necessarily limited to, cotinine, norcotinine, nornicotine, nicotine N-oxide, cotinine N-oxide, 3-hydroxycotinine and 5-hydroxycotinine or pharmaceutically acceptable salts thereof.
- Agents that increase nitric oxide are of interest as anti-restonic agents, e.g.
- nitric oxide may also be modulated by cytokines, such as ⁇ -interferon, tumor necrosis factor, IL-1, IL-2 and endotoxin due to their effect on the enzyme, nitric oxide synthase.
- cytokines such as ⁇ -interferon, tumor necrosis factor, IL-1, IL-2 and endotoxin due to their effect on the enzyme, nitric oxide synthase.
- the inducible form of NO synthase is increased by cytokines and the constitutive form seems to be decreased by cytokines.
- HMG-CoA reductase inhibitors have been found to upregulate endothelial cell NOS activity, as described by United States Patent 6,147,109, Liao et al. Any of the forms of nitric oxide synthase can be utilized, as the protein or an active fragment derived therefrom, or as a DNA construct for expression. Also of interest for the inhibition of restenosis are compounds with an anti-angiogenic effect. These include the anti-angiogenic polypeptides: angiostatiri (O'Reilly et al. (1994) Cell 79:315-328); endostatin (O'Reilly et al.
- anti-angiogenic - anti-thrombin 111- (Bock et ah* (1982) Nucleic Acids Res. 10 (24), 8113-8125);»and.the, like, arid further include functionally active variants and derivatives thereof.
- Other anti-angiogenic agents include inhibitors. of matrix metalloproteases, e.g. amifostine, WR-.1065; marimastat, primomastat, alpha-1 antitrypsin; and the like. ' • .. "
- compounds that block thrombin, and other anti-coagulants may be used to inhibit restenosis, such compounds based on the tripeptide motif D-Phe-Pro-Arg; e.g. LY287045, etc.
- Many compounds, such as inogatran and melagatran, are known in the art. For non-limiting examples, see U.S. Patent nos. 6,326,386; 6,232,315; 6,201 ,006; 6,174,855; 6,060,451; and 5,985,833; among others.
- TGF-beta receptor Type I and type II mediate most activities of TGF-beta (Ebner et al. (1993) Science 260:1344-1348; and Franzen et al. (1993) Cell 75: 681-692).
- Ligands include TGF- ⁇ , and mimetics and biologically active derivatives thereof.
- agents of interest include death domain receptor ligands, which are compounds, usually polypeptide compounds, that bind to mammalian cell surface receptors comprising a death domain, or homologs or orthologs thereof, and that, by binding so deliver a signal for apoptosis to the cell.
- the intracellular protein interactions triggered by these receptors can be attributed to binding interactions of the death domain, which is homologous to an approximately 80 amino acid domain near the C-terminus of TNF-R1, and is responsible for signaling cytotoxicity (Huang et al. (1996) Nature 384:372-5).
- the TNF receptor death domain family includes TNF-R1, Fas (CD95), TRAMP (wsl/Apo- 3/DR-3), TRAIL-R1 (DR-4) and TRAIL-R2 (DR-5, TRICK2, KILLER).
- Death domain ligands include proteins that regulate cellular proliferation and differentiation by binding to specific death domain receptors. These ligands include the TNF family, e.g. TNF, lymphotoxin, CD30 ligand, 4-1 BB ligand, CD40 ligand, CD27 ligand, and TRAIL (TNF-related apoptosis- inducing ligand), and homologs and analogs thereof.
- TNF TNF-related apoptosis- inducing ligand
- Lymphotoxin ⁇ a member of the TNF family, consists of a heterotrimer of one (lymphotoxin- , or TNF- ⁇ ) and two ⁇ chains (lymphotoxin- ⁇ ) on the membrane.
- Anti-restenotic polypeptides and peptides can be administered in their native form, or through the administration of nucleic acids encoding the molecule of interest. Administration of nucleic acids results in genetic alteration of targeted cells.
- the nucleic acid materials for delivery to targeted tissue encodes a gene product for which expression is desired, and a promoter for expression of the gene product.
- nucleic acid of interest is meant any DNA, RNA, ribozyme, hybrid or analog thereof that encodes a polypeptide or other gene product that is desirable for expression in tissue of a subject.
- the gene product can include a polypeptide, an anti-sense mRNA,* or other gene product that is desirably expressed.
- DNA of interest ⁇ r''DNA
- the nucleic acid delivered to the tissue in vivo can take any number of forms.
- the nucleic acid can be introduced as a linear or circular molecule, preferably a circular molecule (e.g., a circular plasmid or other construct).
- nucleic acid of interest and the promoter are operably linked to provide a construct, or vector for expression.
- construct will refer to a nucleic acid molecule that facilitates expression of a gene product encoded by the nucleic acid to be introduced.
- operably linked is meant that a DNA sequence and a regulatory sequence(s) (e.g., a promoter sequence) are connected in such a way as to permit transcription when the appropriate molecules (e.g., transcriptional activator proteins) are bound to the regulatory sequence(s).
- the amount of DNA to accomplish expression of an anti-restenotic gene product at an effective level will vary according to the desired effect, as well as with other variables such as the age of the subject, the tissue to be genetically altered, the gene product to be expressed and the desired level of its expression, etc.
- the amount of DNA administered is an amount sufficient to provide for transformation of a number of cells that in turn provides for a level of gene product expression from the introduced DNA to provide for a desired effect.
- Dosages are routinely determined in the art, and can be extrapolated from the amounts of DNA effective in an animal mode (e.g., a rodent (mouse or rat) or other mammalian animal model), in which factors such as the efficiency of transformation and the levels of gene product expression achieved can be readily assessed and extrapolated to other vertebrate subjects.
- an animal mode e.g., a rodent (mouse or rat) or other mammalian animal model
- the nucleic acid of interest can be obtained from any of a variety of sources or methods well known in the art, e.g. isolated from suitable cells, produced using synthetic techniques, etc., and the constructs prepared using recombinant techniques well known in the art. Likewise, techniques for obtaining expression of DNA or RNA sequences in a genetically altered host cell are known in the art (see, for example, Kormal et al., Proc. Natl.
- Expression of the introduced nucleic acid can be short-term, i.e. a few hours to several hours to a few days, or permanent or long-term i.e. from a week to several weeks to a few months or more.
- gene product expression from the introduced nucleic acid ranges from at least about 1 to 2 days, or 3 to 5 days, to about 1 week, generally about 1 to
- expression of the gene product can be* maintained. by using a.retroviral; construct having inactivated LTRs .and an internal, promoter in the construct to . drive. gene product expression. . . . ⁇ * ., . * . • ⁇ . ., .-*. . •
- An anticoagulant or antiplatelet may be included in the outermost surface of the device in order to elute off very quickly for the first several days.
- Antiinflammatories and antireplicates can be formulated into the device to continue to elute later, when in contact with non-blood cells after neointima overgrowth has surrounded the device.
- the drug elution rate does not need to be uniform, and may be tailored to fit the need of the patient.
- Restenosis Several clinical definitions of restenosis are available. The condition may be defined as a reduction of minimal luminal diameter in a vessel to less than 50% of the normal lumen diameter, or loss of at least 50% of the initial gain achieved in angioplasty. Another useful measure of restenosis is the ratio of intimal area to medial area of a vessel after a suitable period of time, usually at least about 2 weeks after initiation of treatment, more usually at least about 4 weeks after initiation of treatment.
- the anti-restenotic agents used in the methods of the invention provide for a statistically significant reduction on the intimal/medial ratio as compared to a control treatment in which the anti-restenotic agents agent is not present.
- the decrease in intimal/medial area ratio is at least about 10% in the presence of the agent compared to a control, more usually a decrease of at least about 20%, and may decrease by as much as about 25%, or more.
- compounds are used that inhibit restenosis. While the methods of the invention are not limited by any hypothesis of action, it is believed that restenosis is a natural healing process in response to the arterial injury that occurs during all types of angioplasty procedures. This very complex healing process results in intimal hyperplasia, more specifically migration and proliferation of medial smooth muscle cells (SMC) from the medial to the intimal area of the vessel.
- SMC medial smooth muscle cells
- restenosis is not a re- deposition of the plaque-like cholesterol material that originally occluded the artery.
- Prevention of restenosis is tied to an inhibition of SMC proliferation, through release of a pharmacologic agent at the site of injury, e.g. angioplasty.
- the pharmacologic agent is released locally, e.g. through a drug delivery stent positioned at the angioplasty site. The process of restenosis may be initiated shortly after injury to the vessel and may continue for a period of from about 3 to 6 months.
- the anti-restenotic agent is released immediately after the prosthesis is secured to the lumen wall to lessen cell proliferation.
- the drug should then continue to elute for up to about three to six, months- jn total. .... • ⁇ ⁇ * .* , ⁇ ..;. ,.
- anti-restenosis agents are delivered to a targeted site. in the vessel, usually the i site of an injury, such as angioplasty, where it is expected that neointimal hyperplasia will- occur.
- a useful device for such delivery is a stent modified for drug delivery* where the term
- stent is used as is known in the art, to refer to a prosthesis which can be inserted and held, when desired, in a lumen of a blood vessel for the treatment of restenosis, e.g. following angioplasty.
- Methods of particular interest provide for release of the anti-restenotic agents to inhibit in-stent restenosis.
- other devices may be used for targeted drug delivery.
- the anti-restenotic agent is formulated as a liquid for release from a stent.
- a stent may include a chamber with a drug transport wall, where the anti-restenotic agent is loaded into the chamber, then selectively transported through the wall (see U.S. Patent no.
- stents are described in the art as having side walls facing outwardly having holes for delivery of the liquid formulation to the targeted site, where the stent is implanted (U.S. Patent no. 5,891 ,108).
- the anti-restenotic agent may be diffused from a reservoir directly to the walls of a blood vessel, through directional delivery openings arranged on an outer surface of the stent.
- Such devices may also comprise an osmotic engine assembly for controlling the delivery of the agent from the reservoir (U.S. patent no. 6,071,305).
- stents that comprise a drug compounded to the device itself.
- the stent itself is formed of a polymeric material comprising the anti-restenotic agent, where the stent is biodegradable or bioabsorbable (see U.S. Patent no. 6,004,346).
- the prostheses may be biostable in which case the drug is diffused out from the biostable materials in which it is incorporated.
- the device can include a drug-carrying coating overlying at least a portion of the metal.
- a porous stent can be made from a powdered metal or polymer, where the anti-restenotic agents are then compressed into the pores of the stent (see U.S. Patent nos. 5,972,027; and 6,273,913).
- Stents for drug delivery can also comprise multiple coatings, where the rate of release is different for the two coatings (see U.S. Patent no. 6,258,121), where one of the anti-restenotic agents can be present in both coatings to provide for an extended release profile; or where two or more anti-restenotic agents are differentially released.
- composite coatings include at least one composite layer of the anti-restenotic agent and a polymer material, and at least a barrier layer positioned over the composite layer, and being of thickness- adequate to provide a controlled release of the bioactive agent (see U.S., Patent 6,335,029).
- The, sheath over the, coating containing the anti-restenotic agent can also be perforated', so that when; the stent is compressed, the perforation is closed. Upon placement in the vessel, the stent is expanded, and the perforation is opened. (see U.S. Patent no. 6,280,411).
- the drug delivery system of the present invention is useful for any vascular surgery, such as may be used in any situation in which the flow of blood through a vessel has been compromised.
- Occlusive vascular conditions of interest include atherosclerosis, graft coronary vascular disease after transplantation, vein graft stenosis, peri-anastomatic prosthetic graft stenosis, restenosis after angioplasty, coronary artery disease, peripheral vascular disease or other forms of occlusive arterial disease, and the like.
- a therapeutic strategy may involve multiple therapeutic factors, e.g. released with multiple time courses.
- Strategies may utilize combinations of microspheres and gels containing different agents and/or that are formulated for different release profiles. Due to their versatility, the controlled release materials can be adapted and combined to provide the desired time course and dose- response for each stent and application.
- Other uses include conditions affecting the gastrointestinal tract. Malignant obstruction of the stomach, eosophagus, or duodenum causes nausea, vomiting, esophagitis, electrolyte imbalance, poor nutrition, and severe dehydration.
- Causes include primary tumors of the stomach and duodenum, malignant infiltration by neoplasms from adjacent organs (e.g., pancreas), and compression by malignant regional lymphadenopathy.
- Expandable stents offer a nonsurgical alternative for treatment. These are particularly useful in poor surgical candidates with malignant obstruction of the gastric outlet.
- the ability to treat duodenal obstruction secondary to extrinsic compression from pancreatic cancer further expands the spectrum of indications of stent placement for primary nonsurgical palliation.
- Stents have also been used in patients with benign gastroduodenal strictures when conventional surgical resection or bypass was not possible or wanted.
- stents In patients with benign disease, coexistent morbid factors involving the cardiopulmonary systems may limit surgical options, which makes the use of metallic stents more attractive. In all cases, the ability to provide therapeutic agents in addition to the stent provides enhanced benefits. .
- Other vessels of the body may be repaired with a stent, including the trachea for breathing disorders, renal and urethral tubules, fallopian tubes for the treatment of infertility, eustachian tubes for the treatment of chronic , ear infection and other hearing disorders, etc ,
- the drug delivery platform ofthe present invention finds use in the evaluation 'of drug candidates, for example to test efficacy in preventing in-stent restenosis.
- a test sample comprising a candidate drug is entrapped within a matrix, and used in the drug delivery platform as described above.
- the stent is then implanted in a biologically relevant model, e.g. an animal model of injury after balloon angioplasty, and the effect on the condition of interest evaluated after a period of time sufficient to observe an effect.
- the results may be compared to various controls, including stents lacking pharmacologic agents; stents comprising an agent with known efficacy; combinations of matrix polymers, combinations of gel polymers, variations in stent design, and the like.
- the results can be entered into a data processor for reference, and algorithms used for the comparison and analysis of results obtained under different conditions. Mathematical systems can be used to provide quantitative measures of similarities and differences between results.
- the translation profiles in the database can be analyzed by pattern recognition algorithms or clustering methods, e.g. hierarchical or k-means clustering, etc., that use statistical analysis to quantify relatedness. These methods can be modified by weighting, employing classification strategies, etc. to optimize the ability of a translation profile to discriminate different functional effects.
- a plurality of assays may be run in parallel with different agent concentrations to obtain a differential response to the various concentrations.
- determining the effective concentration of an agent typically uses a range of concentrations resulting from 1:10, or other log scale, dilutions.
- the concentrations may be further refined with a second series of dilutions, if necessary.
- one of these concentrations serves as a negative control, i.e. at zero concentration or below the level of detection of the agent or at or below the concentration of agent that does not give a detectable change in the phenotype.
- Kits for the use of the drug delivery platform in clinical use or in compound testing will comprise at least a channeled stent, which may be derivatized for covalent bonding of the gel; and polymers for the matrix and gel.
- the components may be previously assembled, including a biologically active agent of interest; or may be provided in component form for addition of an agent of interest.
- kits may further comprise packaging, e.g. to prevent damage during shipping; and instructions for use.
- Kits for compound testing may further comprise agents of known activity for use as controls, and the like. . ' ⁇ * ⁇ ..
- the stent design for this initial example is based on the Palmaz-Schatz coronary stent.
- the stainless steel stent is 1.6 mm in diameter and 10 mm in length and has 10 longitudinal struts evenly spaced circumferentially, and it is designed to be balloon expandable up to 5 mm diameter.
- Its basic slotted tube design was modified by electro-discharge machining (EDM) channels 80 microns wide by 60 microns deep along the length of the abluminal (toward the wall) side of each strut.
- EDM electro-discharge machining
- the stent is designed to provide abluminal (toward the wall) but not adluminal (toward the lumen) delivery.
- the channels cover 8.5% of the lumen wall area when deployed to a nominal diameter of 3 mm.
- the channels were machined from end to end in order to allow drug delivery both to the wall and to the tissue surrounding the stent end which both represent critical sights for neointima formation.
- Microspheres which can hold and release therapeutic agents (for example, see Yuksel et al. (2000) Plast Reconstr Sum. 105(5):1721-9; Waugh et al. (1999) Circ Res. 84(1):84-92 were mechanically loaded into these channels. Excess microspheres were removed with a needle and short bursts of air from a compressed air canister. The corresponding design and post-manufacture stent appear as Figures 1A to 1C.
- Stent channels were filled by manual loading with PLGA (75:25)-PEG-buffer microspheres with a mean diameter of 50 ⁇ m. Predetermination of microsphere size can be difficult for certain drug-loads, and smaller microspheres are more readily loaded. As a result, quantitative evaluation of stent filling as percent of total channel was subsequently evaluated for both large and small microspheres.
- Microsphere preparation Bioerodible polyethylene glycol-polylactide-co-glyc ⁇ lide (PLGA, Polysciences, Warrington, PA) microspheres (MS) were prepared as a modification of- previously described techniques (Yuksel, et al., supra.) A mixture of 8:1::PLGA" (75:25): PEG-8000 (polyethylene glycol, MW 8000, Sigma, St Louis, MO) was employed with the double emulsion technique to generate microspheres (MS) of final diameter 50 or 10 ⁇ m. Additionally, a pH buffer of 7.4 was incorporated in all MS preparations as a modification of other techniques to limit local pH changes (Zhu ef al. (2000) Nature Biotechnology 18:52-7. Separately, MS containing PEG-dimethacrylate instead of PEG were also prepared to a final size of 10 ⁇ m.
- PLGA Bioerodible polyethylene glycol-polylactide-co-glyc ⁇ lide
- MS microsphere
- each channel was photographed with single composite photographs of each generated and employed in ImagePro Image analysis suite. Stents were examined on a Nikon E600 microscope with plan apochromat lenses at a total magnification of 40X. High resolution digital images were acquired using a Diagnostic Instruments true color SPOT camera. The entire length of each channel was photographed with single composite 5 photographs of each generated and employed in ImagePro image analysis suite to determine the mean percent of total channel filled with MS.
- Stents were manually loaded with microspheres of mean diameter 50 ⁇ m (b-MS) or 10 ⁇ m (s-MS), loaded onto a balloon, and the entire length of each stent channel was photographed.
- Mean channel fill density was calculated as the percent of total channel filled
- Stents were either rinsed with saline or pretreated with 2% 3- methacryloxypropyltrimethoxysilane (meac) in 75% ethanol and heat cured for 60 minutes at
- Stents containing s-MS were again prepared as above and ensheathed en toto in silicone tubing. The spaces around the MS within each channel were filled with a rapid- . release gel formulation in an attempt to prevent loss of s-MS under flow conditions. The entire length of each stent channel was again photographed and mean channel fill density calculated. These sterits (MS/plu). were subsequently introduced into an in vitro flow loop,
- New stents were pretreated to form a metal oxide-methoxysilane- monomethacrylate link to the metal-oxide layer of the stent surface.
- Silane stents were then loaded with either s-MS containing PEG-dimethacrylate or s-MS with PEG as above.
- Stents were ensheathed and a 20% mixture of 3:2::PEG-dimethacrylate:PEG was introduced to fill unoccupied spaces within the channels. Gels were subsequently polymerized to form gel-stent links (MS-gel) or gel-stent-microsphere links (MS-meac-gel).
- Stent channel fill density was again evaluated after balloon loading, after in vitro flow loop exposure and after in vivo deployment in rabbit aortas.
- a solution for hybrid MS-retention is a gel that protects the microspheres from embolization during advancement and deployment.
- a crosslinked PEG-methacrylate gel was subsequently investigated. Initial experiments revealed that channel contents separated from the stent readily but did not fragment from one another.
- the stent channels .- were subsequently modified to add a methacrylate link to the metal-oxide layer of .the stent in order to enhance channel retention of the polymers.
- Small microspheres were either prepared as before, or modified to contain PEG r methacrylate.
- NOC-12 N-Ethyl-2-(1-ethyl-2-hydroxy-2-nitrosohydrazino) ethanamine
- mice underwent implantation of normal P-S stents, MS-gel stents containing polymer only (MS- gel), or MS-gel stents containing a therapeutic level of a nitric oxide donor as an anti- restenotic agent (MS-gel-NO).
- MS-gel-NO MS-gel stents containing a therapeutic level of a nitric oxide donor as an anti- restenotic agent
- Example 2 35 Stent-based release of an angiogenesis inhibitor limits in-stent plaque progression.
- Biodegradable poly(lactic-co-glycolic-acid)-polyethylene glycol (PLGA/PEG) microspheres were prepared as a modification of previously described techniques.
- a mixture of 8:1::PLGA(75:25):PEG-8000 was employed with the double emulsion technique to generate a final microsphere diameter of 10 microns, and a degradation time of approximately 4 weeks.
- a pH buffer of 7.4 was incorporated to limit local pH changes in order to stabilize incorporated drugs and render the microspheres more biocompatible.
- angiogenesis inhibitor angiostatin Calbiochem, La Jolla, CA
- 200 ml phosphate buffered saline 200 ml phosphate buffered saline
- Control microspheres blank microspheres
- Stents were prepared as above.
- the 28 days aortic specimens were fixed in 10% neutral buffered formalin and were embedded in PolyBed (Polysciences, Warrington, PA) for light microscopic and morphologic analysis. Morphological Analysis of Intima/Media (l/M) Ratios.
- angiogenesis inhibitor reduces plaque progression after stenting and stabilizes the plaque that does form so that plaque rupture, occlusion, and adverse long-term outcome are reduced in frequency. While this example presents use of angiostatin as a specific agent, any anti-angiogenic factor could be substituted with comparable result (i.e. the example demonstrates efficacy of the class of agents).
- microsphere/stent preparation Microspheres were prepared as above (example 2b) except loaded with 40 mg NOC-12 (Calbiochem, La Jolla, CA) in 200 ⁇ l phosphate buffered saline in place of angiostatin and stents were loaded as before. plaque formation. Plaque morphometry was assessed as in Example 2, with results summarized as Table 4.
- Example 4 Stent-based release of an elastase (or matrix metalloproteinase) inhibitor can limit in-stent plaque progression. Local prevention of post-stenting extracellular matrix remodeling can limit plaque progression. microsphere/stent preparation. Microspheres were prepared as above (Example 2) except loaded with 40 mg of the elastase inhibitor alpha-1-antitrypsin (Calbiochem, La Jolla, CA) in 200 ⁇ l phosphate buffered saline in place of angiostatin and stents were loaded as before. plaque formation. Plaque morphometry was assessed as in Example 2, with results summarized as Table 5. Table 5. Plaque formation after in vivo stent implantation and release of an elastase inhibitor.
- alpha-1-antitrypsin Calbiochem, La Jolla, CA
- Ratio of intimal area to medial area 28 days after stent implantation for control stents or stents releasing an elastase inhibitor (AAT), (mean ⁇ SE), * denotes P 0.0001 vs. controls.
- any factor to inhibit elastase or matrix metalloproteinases could be substituted with comparable result (i.e. the example demonstrates efficacy of the class of agents).
- Example 5 Stent-based release of nicotine or nicotinic receptor agonist limits in-stent plaque progression. microsphere/stent preparation. Microspheres were prepared as above (Example 2) . except loaded with SO-P r ⁇ g : Nicotine (Signia Chemical, St Louis, MO) (to achieve ' a calculated daily load release of 0.1 mg/ml) in 200 ⁇ l phosphate buffered saline in place of angiostatin and stents Were loaded as before. plaque ' formation. Plaque morphometry was assessed as in Example 2, with results summarized as Table 6.
- Stent based local release of nicotine reduces plaque progression after stenting.
- Example 6 Stent-based release of transforming growth factor ⁇ can limit in-stent plaque progression.
- microsphere/stent preparation Microspheres were prepared as above, except loaded with 2.0 ⁇ g TGF ⁇ l (Oncogene Research, Boston, MA) in 200 ⁇ l phosphate buffered saline in place of angiostatin and stents were loaded as before. plaque formation. Plaque morphometry was assessed as above, with results summarized as Table 7.
- Ratio of intimal area to medial area 28 days after stent implantation for control stents or stents releasing transforming growth factor ⁇ 1 (TGF ⁇ l), (mean ⁇ SE), * denotes P 0.004 vs. controls.
- Stent based local release of transforming growth factor ⁇ or other agonist of * transforming growth factor ⁇ receptors or downstream signaling reduces plaque progression after stenting.
- Example 7 Stent-based release of an angiotensin pathway inhibitor Release of an inhibitor of angiotensin converting enzyme, angiotensin, angiotensin II, or angiotensin II receptors can limit in-stent plaque progression.
- microsphere/stent preparation Microspheres were prepared as above except loaded with 1.2 mg of the angiotensin II receptor inhibitor perindoprilate in 200 ⁇ l phosphate buffered saline in place of angiostatin and stents were loaded as before. plaque formation. Plaque morphometry was assessed as above, with results summarized as Table 8.
- Ratio of intimal area to medial area 28 days after stent implantation for control stents or stents releasing of an angiotensin II receptor inhibitor, (ATIIr), (mean ⁇ SE), * denotes P 0.02 vs. controls.
- Stent based local release of an inhibitor of angiotensin converting enzyme, angiotensin, angiotensin II, or angiotensin II receptors or downstream signaling reduces plaque progression after stenting.
- Microspheres were prepared as above except loaded with 10 ⁇ g Fas ligand (Oncogene Research, Boston, MA) in 200 ⁇ l phosphate buffered saline in place of angiostatin and stents were loaded as before. plaque formation. Plaque morphometry was assessed as above, with results summarized as Table 9.
- Example 9 Stent-based release of fibroblast growth factor microsphere/stent preparation.
- Microspheres were prepared as above except loaded with 200 ng acidic FGF (Calbiochem, La Jolla, CA) and 1280 units filtered endotoxin-free heparin (Sigma Chemical, St Louis, MO) as a stabilizer in 200 ⁇ l phosphate buffered saline in place of angiostatin and stents were loaded as before. plaque formation. Plaque morphometry was assessed as above, with results summarized as Table 10. Table 10 Plaque formation after in vivo stent implantation and release of acidic FGF.
- Ratio of intimal area to medial area 28 days after stent implantation for control stents or stents releasing of acidic FGF, (FGF), (mean ⁇ SE), * denotes P 0.004 vs. controls.
- any pro-endothelialization growth factor or related downstream signaling reduces plaque progression after stenting.
- Microspheres Stent-based release of thrombin pathway inhibitors microsphere/stent preparation.
- Microspheres are prepared as above, except loaded with D-Phe-Pro-Arg chloromethyl ketone (PPACK, Calbiochem), which is the prototype of a class of synthetic tripeptides that form covalent complexes with thrombin, (Calbiochem, La Jolla, CA) in 200 ⁇ l phosphate buffered saljrie in place of angiostatin.
- PPACK irreversibly inhibits thrombin by alkylati ⁇ g the active center histidine residue.
- thrombin and thrombin receptor-activating peptide* (TRAP)-induced DNA synthesis are potently inhibited by PD98059 (Calbiochem, La Jolla, CA), an inhibitor of ERK phosphorylation, this inhibitor br others of its class can be used alone or in combination to inhibit thrombin-mediated plaque progression after stenting.
- PD98059 is examined in the range from 100 nmol/l to 500 ⁇ mol/L daily release (optimal typically in the range of 10 ⁇ mol/L).
- PPACK is evaluated in a range from 0.1 nmol/L to 10 ⁇ mol/L daily release (with typical use at 10 nmol/L in vitro). plaque formation. Plaque morphometry is assessed as above.
- Microsphere/stent preparation Microspheres were prepared as above (example 2) except loaded with 200 ⁇ l of a 1.0 mg/ml solution of a plasmid encoding E. coli beta- galactosidase as a marker under the control of the cytomegalovirus promoter with a 2:1 charge ratio of Superfect (400 ⁇ l of stock 1.2 mg/ml, Qiagen) added as a transfection agent (10 ⁇ l undiluted) (Calbiochem, La Jolla, CA) in 200 ⁇ l phosphate buffered saline in place of angiostatin.
- Superfect 400 ⁇ l of stock 1.2 mg/ml, Qiagen
- Gene expression was confirmed functionally on cross-sections obtained as for plaque morphometry 7 days after stent deployment. Beta galactosidase expression was visualized using X-gal staining (Sigma, St. Louis, MO) and showed specific staining.
- Example 13 Stent-based gene transfer to limit plague progression. microsphere/stent preparation. Microspheres are prepared as above except loaded with 20 ⁇ l of a 1.0 mg/ml solution of a plasmid encoding human thrombomodulin under the control of the cytomegalovirus promoter with a 4:1 charge ratio of Superfect added as a transfection agent (10 ⁇ l undiluted) (Calbiochem, La Jolla, CA) in 200 ⁇ l phosphate buffered saline in place of angiostatin. plaque formation. Plaque morphometry is assessed as above, with gene expression •also confirmed antigenically or functionally. . , _., . . .: ; : . ⁇ ; .... -. ⁇ ,* .
- BX-velocity stents (Cordis, Miami, FL) are derivatized as above with a silane linker. The stent is placed within an outer tube which rests flush against the stent outer surface and is open at either end. A glycerol solution or other viscous solution is instilled to fill all spaces. The glycerol is allowed to drain by gravity and the stent is washed and immediately drained with sterile water, allowing some traces of glycerol to remain at the stent-tube interface.
- a polymerization chain blocker or terminator is instilled and linked to the exposed surface of the stent.
- a terminator is polyethylene glycol (PEG) monoacrylate (MW200), which is anchored under exposure to UV-A source for 15 minutes.
- PEG polyethylene glycol
- MW200 polyethylene glycol
- the stent is then removed from the cylinder and washed repeatedly to remove glycerol and unreacted chain blocker.
- the stent is then immersed in a sterile highly viscous solution containing PEG (MW 8000), PEG dimethacrylate (MW1200), and star-polymer PEG multi-methacrylates together with rapamycin at an effective dose for post-stenting restenosis.
- the stent is placed within an outer tube which allows a gap of 30 microns between the stent and the inner wall of the cylinder (although other thicknesses are valid as well).
- the gel is then polymerized under UV-A for 30 minutes to anchor rapamycin passively to the outer surface of the stent and the shoulders of the stent. Unreacted solution is removed by washing and the stent is lyophillized for use. plaque formation. Plaque morphometry is assessed as above, with gene expression also confirmed antigenically or functionally. 5
- Example 15 Stent-based delivery of chelated noncovalently bound rapamycin to limit plaque progression.
- stent preparation BX-velocity stents (Cordis, Miami, FL) are derivatized as above with a silane linker. The stent is placed within an outer tube which rests flush against the
- stent outer surface 10 stent outer surface and is open at either end.
- a glycerol solution or other viscous solution is instilled to fill all spaces.
- the glycerol is allowed to drain by gravity and the stent is washed and immediately drained with sterile water, allowing some traces of glycerol to remain at the stent-tube interface.
- the outer surface of the stent and the adjacent sites are thus blocked from incubation, as a solution with a polymerization chain blocker or terminator is instilled
- such a terminator is polyethylene glycol (PEG) monoacrylate (MW200), which is anchored under exposure to UV-A source for 15 minutes.
- PEG polyethylene glycol
- the stent js then removed from the cylinder and washed repeatedly to remove glycerol and unreacted chain blocker.
- the stent is then immersed in a . highly viscous solution containing PEG (MW 8000), PEG dimethacrylate (MW1200), and a
- the stent is lyophillized for use. plaque formation. Plaque morphometry is assessed as above, with gene expression also confirmed antigenically or functionally.
- Example 14 Stent-based delivery of noncovalently bound RheoPro to limit plaque progression.
- stent preparation BX-velocity stents (Cordis, Miami, FL) are derivatized as above with a silane linker. The stent is placed within an outer tube which rests flush against the stent outer surface and is open at either end. A glycerol solution or other viscous solution is instilled to fill all spaces. The glycerol is allowed to drain by gravity and the stent is washed 35 and immediately drained with sterile water, allowing some traces of glycerol to remain at the stent-tube interface.
- a polymerization chain blocker or terminator is instilled and linked to the exposed surface of the stent.
- a terminator is polyethylene glycol (PEG) monoacrylate (MW200), which is anchored under exposure to UV-A source for 15 minutes.
- PEG polyethylene glycol
- MW200 polyethylene glycol
- the stent is then removed from the cylinder and washed repeatedly to remove glycerol and unreacted chain blocker.
- the stent is then immersed in a sterile highly viscous solution containing PEG (MW 8000), PEG dimethacrylate (MW1200), and star-polymer PEG multi-methacrylates together with RheoPro at an effective dose for post-stenting restenosis.
- the stent is placed within an outer tube which allows a gap of 30 microns between the stent and the inner wall of the cylinder (although other thicknesses are valid as well).
- the gel is then polymerized under UV-A for 30 minutes to anchor RheoPro passively to the outer surface of the stent and the shoulders of the stent. Unreacted solution is removed by washing and the stent is lyophillized for use. plaque formation. Plaque morphometry is assessed as above, with gene expression also confirmed antigenically or functionally.
Abstract
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US10/101,453 US7048939B2 (en) | 2001-04-20 | 2002-03-11 | Methods for the inhibition of neointima formation |
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