WO2006044989A1 - Dispositifs et methodes pour l'administration de pimecrolimus et d'autres agents therapeutiques - Google Patents

Dispositifs et methodes pour l'administration de pimecrolimus et d'autres agents therapeutiques Download PDF

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Publication number
WO2006044989A1
WO2006044989A1 PCT/US2005/037658 US2005037658W WO2006044989A1 WO 2006044989 A1 WO2006044989 A1 WO 2006044989A1 US 2005037658 W US2005037658 W US 2005037658W WO 2006044989 A1 WO2006044989 A1 WO 2006044989A1
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WO
WIPO (PCT)
Prior art keywords
therapeutic agent
rate
primary therapeutic
agents
pimecrolimus
Prior art date
Application number
PCT/US2005/037658
Other languages
English (en)
Inventor
Vinayak D. Bhat
John Yan
Ashok A. Shah
Original Assignee
Avantec Vascular Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/993,935 external-priority patent/US20050125054A1/en
Application filed by Avantec Vascular Corporation filed Critical Avantec Vascular Corporation
Publication of WO2006044989A1 publication Critical patent/WO2006044989A1/fr

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Classifications

    • 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
    • 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
    • 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
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
    • 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
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers

Definitions

  • the present invention relates generally to medical devices and methods. More particularly, the present invention relates to intracorporeal devices, such as vascular stents or grafts, which inhibit restenosis and hyperplasia.
  • intracorporeal devices such as vascular stents or grafts, which inhibit restenosis and hyperplasia.
  • a number of percutaneous intravascular procedures have been developed for treating stenotic atherosclerotic regions of a patient's vasculature to restore adequate blood flow.
  • PTA percutaneous transluminal angioplasty
  • a catheter having an expandable distal end usually in the form of an inflatable balloon, is positioned in the blood vessel at the stenotic site. The expandable end is expanded to dilate the vessel to restore adequate blood flow beyond the diseased region.
  • Restenosis refers to the re-narrowing of an artery after an initially successful angioplasty. Restenosis afflicts approximately up to 50% of all angioplasty patients and is the result of injury to the blood vessel wall during the lumen opening angioplasty procedure. In some patients, the injury initiates a repair response that is characterized by smooth muscle cell proliferation referred to as "hyperplasia" in the region traumatized by the angioplasty. This proliferation of smooth muscle cells re-narrows the lumen that was opened by the angioplasty within a few weeks to a few months, thereby necessitating a repeat PTA or other procedure to alleviate the restenosis.
  • the present invention is directed to an intracorporeal device which has an expandable structure or scaffolding, such as a stent or graft.
  • an expandable structure or scaffolding such as a stent or graft.
  • a primary therapeutic agent which includes pimecrolimus or a therapeutically effective pro-drug, analog, derivative or metabolite thereof to reduce restenosis and provide other therapeutic effects, hi addition to inhibiting the occurrence of restenosis
  • devices and method of the present invention also allow for the generation of a small amount of cellularization, endothelialization, or neointima, preferably, in a controlled manner.
  • the intracorporeal device embodying features of the present invention comprises a luminal delivery device which has a structure or scaffolding which is implantable in a body lumen and associated therewith a deliverable amount of pimecrolimus which is releasable from the structure or scaffolding.
  • the structure or scaffolding may be in the form of a stent, which additionally may also maintain luminal patency, or may be in the form of a graft, which may protect or enhance the strength of a luminal wall.
  • the structure or scaffolding may be radially expansible by a balloon or other expansion means and/or self-expanding and is preferably suitable for luminal placement in a body lumen.
  • the structure or scaffolding is preferably expandable but it may have a substantially constant transverse size or diameter, or alternatively depending on the application and use, it may be contractable to a smaller configuration.
  • a suitable stent for use in a device embodying features of the present invention is described in U.S. Patent No. 6,602,282, assigned to the assignee of the present application, the full disclosure of which is incorporated herein by reference.
  • the device is configured to be implantable within a corporeal body which includes a susceptible tissue site or it may be configured for implanting, with or without expansion, at a targeted corporeal site.
  • a susceptible tissue site refers to a tissue site that is injured, or may become injured as a result of an impairment (e.g., disease, medical condition), or may become injured during or following an interventional procedure such as an intravascular intervention which is susceptible to the therapeutic agent for treatment.
  • the susceptible tissue site may include tissues associated with intracorporeal lumens, organs, or localized tumors.
  • the targeted corporeal site may include the susceptible tissue site or may be another corporeal site (e.g., other body organs or lumens).
  • the corporeal site may comprise the targeted intracorporeal site, such as an artery, which supplies blood to the susceptible tissue site.
  • the structure or scaffolding is configured for placement within a body lumen such as a patient's coronary, carotid, or other peripheral artery.
  • the device may be a scaffold formed with an open lattice or it may have an essentially closed surface.
  • the expandable structure may be formed of any suitable material such as metals, polymers, or a combination thereof.
  • the expandable structure may be formed of an at least partially biodegradable material selected from the group consisting of polymeric material, metallic materials, or combinations thereof.
  • the at least partially biodegradable material preferably degrades over time.
  • polymeric material include poly-L-lactic acid, having a delayed degradation to allow for the recovery of the vessel before the structure is degraded.
  • metallic material include metals or alloys degradable in the corporeal body, such as stainless steel.
  • Primary and/or secondary therapeutic agents associated with the structure may be directly or indirectly coupled to, connected to, disposed on, disposed within, attached to, adhered to, bonded to, adjacent to, entrapped in, absorbed in, absorbed on, or otherwise secured to the structure or scaffolding.
  • the therapeutic agent may be secured in such a manner as to become available to the tissue site, immediately or after a delayed period, upon introduction of the device to the site.
  • a source of the primary therapeutic agent may be disposed or formed proximate to one or more surfaces of the structure or scaffolding of the device. The source may be disposed on an exterior or interior surface or within the interior of the structure itself between the interior and exterior surfaces, or any combination thereof.
  • the association of the primary and/or secondary therapeutic agent with the structure or scaffolding may be continuous or in discrete segments.
  • the structure or scaffolding may have one or more secondary therapeutic agents which augment the function of the primary therapeutic agent or perform another therapeutic or diagnostic function.
  • the one or more secondary therapeutic agents may be selected from the group consisting of immunosuppressants, antiinflammatories, anti-pro liferatives, anti- migratory agents, anti-fibrotic agents, proapoptotics, vasodilators, calcium channel blockers, anti-neoplasties, anti-cancer agents, antibodies, anti-thrombotic agents, anti-platelet agents, Ilb/IIIa agents, antiviral agents, MTOR (mammalian target of rapamycin) inhibitors, non- imniunosuppressant agents, tyrosine kinase inhibitors, CDK inhibitors, chemotherapeutic agents, thrombolytics, antimicrobials, antibiotics, antimitotics, growth factor antagonists, free radical scavengers, radiotherapeutic agents, radiopaque agents, radiolabeled agents, anti ⁇ coagulants,
  • the one or more secondary therapeutic agents may enable and/or enhance either or both the release and efficacy of the therapeutic agent or provide other therapeutic or diagnostic effects.
  • the secondary therapeutic agent may be associated with the expandable structure in the same or different manner as the primary therapeutic agent.
  • one secondary therapeutic agent may reduce generation of endothelial cells while another secondary therapeutic agent may allow for more endothelialization to be achieved.
  • the one or more secondary therapeutic agent may be released prior to, concurrent with, or subsequent to, the primary therapeutic agent, at similar or different rates, times, layers, and phases.
  • the luminal prosthesis makes available one or more therapeutic agents to one or more selected locations within a patient's vasculature, including the susceptible tissue site, to reduce the formation or progression of restenosis and/or hyperplasia.
  • the term "make available” means to have provided the substance (e.g., therapeutic agent) at the time of release or administration, including having made the substance available at a corporeal location such as an intracorporeal location or target site, regardless of whether the substance is in fact delivered, used by, or incorporated into the intended site, such as the susceptible tissue site.
  • the therapeutic agents may be therapeutic as it is introduced to the subject under treatment, or it may become therapeutic after being introduced to the subject under treatment.
  • the therapeutic agent may become therapeutic by way of a native or non-native substance or condition, or another introduced substance or condition.
  • native conditions include pH (e.g., acidity), chemicals, temperature, salinity, osmolality, and conductivity.
  • non-native conditions include magnetic fields, electromagnetic fields (such as radiofrequency and microwave), and ultrasound.
  • the primary and/or secondary therapeutic agents may be made available to the susceptible tissue site as a native environment of the area where the device is implanted changes. For example, a change in a pH of the area where the device is implanted may change over time so as to bring about the release of one or more of the therapeutic agents.
  • Agent release may be direct, as for example when a polymeric drug acts as a matrix including both the therapeutic agent and a rate-sustaining or rate-controlling element. Agent release may alternatively be indirect, as for example by affecting the erosion or diffusion characteristic of the rate-sustaining or rate-controlling element or coating as either or both the matrix or non-matrix. Additionally, as the pH increases or decreases, the erosion of the rate-sustaining or rate-controlling element or coating changes allowing for initial and subsequent phase releases.
  • the primary and/or secondary therapeutic agent may be responsive to an external form of energy (non-native condition) to effect or modify the release of the therapeutic agent.
  • the responsive compound may be associated with the therapeutic agent, a rate-sustaining or rate-controlling element, coating or matrix, the expandable structure, or a combination thereof.
  • the energy to effect release of one or more of the therapeutic agents include ultrasound, magnetic resonance imaging, magnetic field, radio frequency, temperature change, x-ray, vibration, gamma radiation, microwave and the like.
  • the energy source may be directed at the device after implantation to effect release of one or more of the therapeutic agents.
  • the devices of the present invention may be configured to release or make available the therapeutic agents 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, hi one embodiment, the primary therapeutic agent, pimecrolimus, may be released over a predetermined time pattern comprising an initial phase wherein the delivery rate is below a threshold level and a subsequent phase wherein the delivery rate is above a threshold level.
  • Time delayed substance release can be programmed to impact restenosis substantially at the onset of events leading to smooth muscle cell proliferation (hyperplasia).
  • the present invention can further minimize substance washout by timing substance release to occur after at least initial cellularization and/or endothelialization which creates a barrier over the stent to reduce loss of the substance directly into the bloodstream.
  • the predetermined time pattern may reduce substance loading and/or substance concentration as well as potentially providing minimal to no hindrance to endothelialization of the vessel wall due to the minimization of drug washout and the increased efficiency of substance release.
  • the total amount of therapeutic agent made available to the tissue depends in part on the level and amount of desired therapeutic result.
  • the therapeutic agent may be made available at one or more phases, each phase having similar or different release rate and duration as the other phases.
  • the one or more release rates may be substantially constant, decreasing, increasing, substantially non-releasing over one or more time periods.
  • the release rates, concentrations, time durations, and other characteristics for the primary and secondary therapeutic agents may be the same or different depending upon their effects.
  • the total amount of primary therapeutic agent made available or released may be in an amount ranging from about 0.1 ⁇ g (microgram) to about 1O g (grams), generally from about 10 ⁇ g to about 1 mg (milligram), usually from about 100 ⁇ g to about 500 ⁇ g.
  • the primary therapeutic agent may be released in a time period, as measured from the time of implanting of the device, ranging from about 1 day to about 200 days, preferably from about 1 day to about 45 days, and most preferably from about 7 days to about 21 days.
  • the release rate of the primary therapeutic agent per day may generally range from about 0.001 ng (nanogram) to about 500 ⁇ g, typically from about 100 ng to about 100 ⁇ g, usually from about 1 ⁇ g to about 50 ⁇ g.
  • the concentration of the primary therapeutic agent within the receiving tissue will be within a range generally from about 0.001 ng of agent/mg of tissue to about 600 ⁇ g of agent/mg of tissue, typically from about 0.001 ng of agent/mg of tissue to about 100 ⁇ g of agent/mg of tissue, and usually from about 0.1 ng of agent/mg of tissue to about 10 ⁇ g of agent/mg of tissue.
  • the delivery of the primary therapeutic agent may be over an initial phase and one or more subsequent phases.
  • the rate of delivery during an initial phase will generally range from about 0.001 ng per day to about 500 ⁇ g per day, typically from about 0.001 ng to about 50 ⁇ g per day, and usually from about 0.1 ⁇ g per day to about 50 ⁇ g per day.
  • the rate of delivery at the subsequent phase may range from about 0.01 ng per day to about 500 ⁇ g per day, typically from about 0.01 ⁇ g per day to about 200 ⁇ g per day, usually from about 1 ⁇ g per day to about 100 ⁇ g per day.
  • the primary therapeutic agent may be made available to the susceptible tissue site in a programmed, sustained, and/or controlled manner with increased efficiency and/or efficacy. There may also be additional phase(s) for release of the one or more secondary therapeutic agents.
  • the duration of the initial, subsequent, and any other additional phases may vary.
  • the release of the therapeutic agent may be delayed from the initial implantation of the device.
  • the delay is sufficiently long to allow the generation of sufficient cellularization or endothelialization at the treated site to inhibit loss of the therapeutic agent into the vascular lumen.
  • the duration of the initial phase will be sufficiently long to allow initial cellularization or endothelialization of at least part of the surface covered by the device.
  • the duration of the initial phase, whether being a delayed phase or a release phase is from about 1 hour to about 24 weeks, usually less than about 12 weeks, and preferably about 1 hour to about 8 weeks.
  • the durations of the one or more subsequent phases may also vary, typically being from about 4 hours to about 24 weeks, usually from about 1 hour to about 12 weeks.
  • the device preferably includes a rate-sustaining or rate-controlling element, coating or matrix for affecting the rate of release of the primary and/or secondary therapeutic agents.
  • the rate-sustaining or rate-controlling element, coating or matrix may be disposed on or formed adjacent to the structure.
  • the rate-sustaining or rate-controlling element may be disposed or formed adjacent at least a portion of the one or more surfaces of the structure (e.g., luminal or abluminal surfaces), or within the interior of the structure, or any combination thereof.
  • the primary and/or secondary therapeutic agent may be disposed adjacent the rate-sustaining or rate-controlling element. Additionally and/or alternatively, the primary and/or secondary therapeutic agent may be mixed with the rate-sustaining or rate- controlling element incorporating the therapeutic agent in a matrix.
  • the rate-sustaining or rate-controlling element may comprise multiple adjacent layers formed from the same or different material and any one of the layers may include the primary and/or secondary therapeutic agent.
  • the rate-sustaining or rate-controlling element may be formed of a non-degradable material, partially degradable material, substantially degradable material, or a combination thereof.
  • the material may be synthetic, natural, non-polymeric, polymeric, metallic, bio- active, non bio-active, or a combination thereof.
  • a non-metallic material that at least partially degrades with time may be used as the rate-sustaining or rate-controlling element.
  • Non-polymers having large molecular weights, polar or non-polar functional groups, electrical charge, steric hindrance groups, hydrophobic, hydrophilic, or amphiphilic moieties may also be used.
  • the rate-sustaining or rate-controlling element, coating or matrix may have a sufficient thickness so as to provide the desired release rate of the therapeutic agent.
  • the rate-sustaining or rate-controlling element, coating or matrix will generally have a total thickness in a range from about 10 nm to about 100 ⁇ m.
  • the thickness may also range from about 50 nm to about 100 ⁇ m, typically from about 100 nm to about 50 ⁇ m, and usually from about 100 nm to 10 ⁇ m.
  • the primary and/or secondary therapeutic agent may be associated with or otherwise directly or indirectly secured to at least a portion of the implantable structure or scaffolding using coating methods such as spraying, dipping, deposition (vapor or plasma), painting, or chemical bonding. Such coatings may be continuously or intermittently applied to the structure or may be applied in a random or pre-determined pattern.
  • a biocompatible (e.g., blood compatible) layer may be formed over the source and/or the most outer layer of the device, to make or enhance the biocompatibility of the device.
  • the devices embodying features of the present invention having at least the primary therapeutic agent pimecrolimus associated therewith are delivered in a suitable manner to a tissue site, such as a blood vessel, where the primary therapeutic agent is released and/or made available to the susceptible tissue site.
  • the therapeutic agent is made available to the susceptible tissue site, preferably, in a sustained or controlled manner over a period of time.
  • the primary and/or secondary therapeutic agent may be directly or indirectly coupled to, connected to, disposed on, disposed within, attached to, adhered to, bonded to, adjacent to, entrapped in, absorbed in, absorbed on, or otherwise secured to or within a gelatinous substance.
  • the gelatin substance may control or sustain release of the therapeutic agent from the device.
  • the gelatinous substance is bonded, normally covalently bonded, to a silane coupling agent formed adjacent the surface of the device.
  • the silane compound forms a bond with the surface of the device.
  • the primary and/or secondary therapeutic agent is associated with the gelatinous substance in such a manner as to become available, immediately or after a delayed period, to the tissue site upon introduction of the device to the site.
  • the device such as a metallic stent, may be prepared for a silylation process by undergoing a passivation process.
  • surface contaminants such as oils, greases, or lubricants are first removed from the surface of the device by general degreasing and cleaning methods.
  • the device is thereafter subjected to a passivation solution (e.g., placed in the passivation solution), normally comprising an acidic solution such as a nitric acid-based solution, usually for a period of time from about 10 to about 15 minutes. Consequently, a metal oxide film is formed on the surface of the device.
  • a passivation solution e.g., placed in the passivation solution
  • an acidic solution such as a nitric acid-based solution
  • the device is subjected to the silylation process preferably after it has undergone passivation.
  • the passivated device is exposed to a silane coupling agent.
  • Silane e.g., compounds of silicon and hydrogen of formula Si n H 2n+2
  • other monomelic silicon compounds have the ability to bond inorganic materials such as glass, mineral fillers, metals, and metallic oxides to organic materials such as polymers, resins, or other organic compounds.
  • the silane coupling agents normally comprise one or more organo-functional groups and one or more functional groups which can undergo hydrolysis to become silanols ("silanol forming group").
  • the one or more organo-functionality can react with functional groups in polymers such as industrial polymers, bio-molecules (e.g., peptides), and proteins (e.g., gelatin).
  • the silanol forming groups can either or both react with one another forming oligomeric variations and/or react with active surfaces, normally surfaces having hydroxyl (-OH) groups.
  • organo-functional groups include — NH 2 , -SH, -NCO, -CHO, epoxy, vinyl groups (e.g., aliphatic including but not limited to acrylates, aromatic including but not limited to styrenated groups such as amino styrene).
  • silanol forming groups normally tri-functional groups, include halo groups such as -Cl or alkoxy groups such as methoxy (-(OCH 3 ) or ethoxy (-(OC 2 H 5 ).
  • the silylation process normally involves the reaction between the silanol forming portion and the inorganic material (e.g., the metallic oxide of the passivated metal stent surface), usually forming a covalent bond, while the one or more organo-functional group reacts with the organic material such as gelatin having amino, carboxyl, or styrene groups (e.g., styrenated gelatin).
  • the silane coupling agent is styrenated, it can be prepared by reacting an epoxy-terminated silane with an amino-styrene.
  • the gelatinous substance (either as the gelatinous substance or as the source including the gelatinous substance and the primary and/or secondary therapeutic agent (e.g., pre-mixed source)) is disposed (e.g., coated) on the silylated device.
  • disposed does not imply a particular order in the process.
  • the device may be immersed in a solution or mixture comprising the gelatinous substance or the gelatinous substance may be sprayed or coated on the device.
  • the gelatinous substance is bonded to the silylated device through functional groups such as carboxylic groups, amine groups or styrene groups (e.g., when the silane coupling agent itself is a stryrenated agent).
  • the gelatinous substance may be acid treated (e.g., acidic gelatin) with or without styrene functionalities.
  • the gelatinous substance is styrenated prior to being disposed on the silylated device, which may or may not be itself styrenated, as discussed above.
  • the rate-controlling element or coating may be disposed on or formed adjacent to the structure and/or the source (e.g., primary and/or secondary therapeutic agent associated with the gelatinous substance) for sustaining or controlling release of the therapeutic agent from the gelatinous substance.
  • the rate-sustaining or rate-controlling element may be disposed or formed adjacent at least a portion of the luminal, abluminal, or interior surfaces of the structure.
  • the source of the primary and/or secondary therapeutic agents may be disposed adjacent the rate-sustaining or rate-controlling element.
  • the one or more therapeutic primary and/or secondary therapeutic agents may be mixed with the rate-sustaining or rate-controlling element and thereafter associated with the gelatinous substance.
  • the rate-sustaining or rate-controlling element may comprise multiple adjacent layers formed from the same or different material and any one of the layers may include the one or more therapeutic agent with or without the gelatinous substance.
  • deployment may be carried out in a patient's veins, aorta, or in previously implanted grafts, shunts, fistulas, and the like. Additionally, the device may be deployed in other body lumens, such as the biliary duct, which are subject to excessive neoplastic cell growth.
  • the device may further incorporate cardiac pacemaker leads or lead tips, cardiac defibrillator leads or lead tips, heart valves, sutures, needles, pacemakers, orthopedic devices, appliances, implants or replacements, or portions of any of the above.
  • the devices of the present invention may further be provided together with instructions for use (IFU), separately or as part of a kit.
  • the kit may include a pouch or any other suitable package, such as a tray, box, tube, or the like, to contain the device and the IFU, where the IFU may be printed on a separate sheet or other media of communication and/or on the packaging itself, hi one embodiment, the kit may also include a mounting hook, such as a crimping device and/or an expansible inflation member, which may be permanently or releaseably coupled to the device of the present invention.
  • the kit may comprise the device and an IFU regarding use of a second compound prior to, concurrent with, or subsequent to, the interventional procedure or first therapeutic agent, and optionally the second compound.
  • FIGS. IA through 1C are cross-sectional views of a device embodying features of the present invention which has been implanted in a body lumen.
  • FIGS. 2 A through 2N are cross-sectional views of various embodiments of the device of FIG. IA taken along line 2-2.
  • FIG. 3 is a schematic representation of a stent for use as the device of the present invention.
  • FIGS. 4A through 4C are graphical representations of various release profiles of a therapeutic agent over a predetermined time period.
  • FIGS. 5A through 51 illustrate a method for positioning the device of FIGS. 1 A-IC in a blood vessel.
  • FIG. 6 illustrates what is believed to be the molecular structure of pimecrolimus.
  • FIG. 7 is a representation of a stent surface having an oxide layer.
  • FIG. 8 is a representation of a reaction for forming a styrenated silane coupling agent.
  • FIG. 9 is a representation of a reaction between the passivated metal stent surface of FIG. 9 and a silane coupling agent after a hydrolysis/condensation reaction.
  • FIG. 10 is a representation of a gelatin structure.
  • FIG. 1 IA through 11C are representations of reactions between the gelatinous substance and different silane coupling agents.
  • FIG. 12 is a graphical representation of the proliferation of human smooth muscle cells in contact with various concentrations of pimecrolimus.
  • FIG. 13 is bar graph representing the viability of human smooth muscle cells at various amounts of pimecrolimus.
  • FIG. 14 is a graphical representation of pimecrolimus release profiles from various parylene coated stents over a predetermined time period.
  • FIGS. 15A and 15B are histologic slides illustrating bare stents after 28 days of implantation.
  • FIGS. 16A and 16B are histologic slides illustrating stents coated with pimecrolimus after 28 days of implantation.
  • FIGS. IA through 1C and cross-sectional drawings FIGS. 2A through 2N illustrate a device 10, such as a stent 13, embodying features of the present invention.
  • the device 10 generally comprises an expandable structure 16 implanted in an intracorporeal body and a source 25 proximate to the structure 16 including the primary therapeutic agent 28, pimecrolimus.
  • the source 25, as depicted in the figures is disposed proximate to a surface of the stent 13, the term "proximate" is not intended to be limited by the figures or descriptions herein.
  • the device 10, as shown, is disposed in a body lumen 19 including a susceptible tissue site 22. It will be appreciated that the following depictions are for illustration purposes only and do not necessarily reflect the actual shape, size, configuration, or distribution of the device 10.
  • the prosthesis 13 may have a continuous structure or an intermittent structure as the case may be with many stents (e.g., a cross section of a stent does not entirely include a substrate forming the expandable structure, for example, some stents have a screen or mesh like cross section).
  • the expandable structure 16 generally has a tissue facing surface 31, a luminal facing surface 34, and optionally an interior 37 which may include a lumen as shown
  • the source 25 may be disposed or formed adjacent at least a portion of either or both the luminal facing surface 34, as shown in FIG. IB, the tissue facing surface 31, as shown in FIG. 1C, within the interior 37 of the expandable structure, and/or any combination thereof, hi one embodiment, devices 10 may be configured to make available to the tissue the most suitable therapeutic amount of the therapeutic agent while minimizing the presence
  • the source 25 for making the therapeutic agent available is associated with the expandable structure 16 in one or more configurations.
  • the source as shown in FIGS. 2A and 2B, is within the expandable structure 16.
  • a matrix 40 may be formed by the expandable structure 16 and the therapeutic agent 28, or the therapeutic agent 28 may be
  • the source 25 may further comprise a rate-sustaining or rate-controlling element 43 formed over at least a portion of the expandable structure 16 for sustaining or controlling the release of the therapeutic agent 28 from the matrix 40 or the interior 37 of the expandable structure.
  • the source may be the rate-sustaining or rate-controlling element itself when
  • the therapeutic agent is a polymeric therapeutic agent.
  • FIG. 2D illustrates features of an embodiment having the therapeutic agent 28 disposed between one of the tissue or luminal facing surfaces 31, 34 of the expandable structure 16 and the rate-sustaining or rate-controlling element 43.
  • the source 25 includes the rate-sustaining or rate-controlling element 43 formed adjacent at least 30. a portion of one of the tissue or luminal facing surfaces 31, 34 of the expandable structure 16 and forming the matrix 40 with the therapeutic agent 28.
  • the therapeutic agent 28 may itself act as a rate-sustaining or rate-controlling element, as for example, when the polymeric therapeutic agent forms a matrix.
  • the matrix 40 may be formed between the rate-sustaining or rate-controlling element 43 and the expandable structure 16.
  • FIGS. 2F and 2G A matrix interface 46 between the rate-sustaining or rate-controlling element 43 and the expandable structure 16 and/or between the therapeutic agent 28 and the rate-sustaining or rate-controlling element 43, is shown in FIGS. 2F and 2G respectively.
  • an outer most layer of the prosthesis 13 may be formed of the therapeutic agent with or without a matrix interface 46. For example, this may be desirable to effect a bolus release of the therapeutic agent.
  • the therapeutic agent 28 is shown in most figures as discrete particles, it may form a smooth layer or a layer of particles, as for example as part of the matrix interface 46 as shown in FIG. 2H.
  • At least one layer of a second rate-sustaining or rate-controlling element 49 is formed over the matrix 40, further affecting the release rate of the therapeutic agent 28 to the susceptible tissue site 22.
  • the second rate-sustaining or rate-controlling element 49 may be of the same or different material than that forming the first rate-sustaining or rate-controlling element 43.
  • the source may comprise a plurality of compounds, as for example the first therapeutic agent 28 and an optional another compound, such as a secondary therapeutic agent 50 or an enabling compound 61 (FIG. 2N).
  • Each of the plurality of compounds may be in the same or different area of the source.
  • the first therapeutic agent 28 may be present in matrix 40 while the second therapeutic agent 50 is in a second matrix 52 formed by the second therapeutic agent 50 and a second rate-sustaining or rate-controlling element 55.
  • the rate-sustaining or rate-controlling elements 43 and 55 may be formed from the same or different material.
  • the second therapeutic agent may act in synergy with the first therapeutic agent.
  • the second therapeutic agent may compensate for the possible reactions and metabolites that can be generated by the first therapeutic agent.
  • the first therapeutic agent may reduce generation of desired endothelial cells while the second therapeutic agent may allow for more endothelialization to be achieved.
  • the secondary therapeutic agent may be released prior to, concurrent with, or subsequent to, the primary therapeutic agent, at similar or different rates and phases.
  • the therapeutic agent 28 is disposed within the interior or on the exterior of expandable structure 16 within a reservoir 58.
  • the rate-sustaining or rate-controlling element 43 may be disposed adjacent the reservoir 58 and/or the therapeutic agent 28 for affecting the release of the therapeutic agent.
  • the figures and descriptions herein are not intended to limit the term "adjacent.”
  • the optional another compound may comprise an enabling compound 61 responsive to an external form of energy, or native condition, to effect the release of the first therapeutic agent 28.
  • the responsive compound 61 may be associated with the first therapeutic agent 28, the rate- sustaining or controlling element 43, the expandable structure 16, or a combination thereof. As shown in FIG. 2N, the responsive compound 61 is associated with the first therapeutic agent 28.
  • the enabling compound 61 may be formed from magnetic particles coupled to the therapeutic agent 28.
  • the energy source may be a magnetic source for directing a magnetic field at the prosthesis 13 after implantation to effect release of the therapeutic agent 28.
  • the magnetic particles 61 may be formed from magnetic beads and will typically have a size in a range from about 1 nm to about 100 nm.
  • the magnetic source exposes the prosthesis 13 to its magnetic field at an intensity typically in the range from about 0.01T to about 2T, which will activate the magnetic particles 61 and thereby effect release of the therapeutic agent 28 from the prosthesis 13.
  • the another enabling compound 61 may be present in other configurations of the prosthesis 13 as described above.
  • Other suitable external energy sources which may or may not require an enabling compound or their performance may not be affected by the presence or absence of an enabling compound, include ultrasound, magnetic resonance imaging, magnetic field, radio frequency, temperature change, electromagnetic, x-ray, radiation, heat, gamma, vibration, microwave, and a combination thereof.
  • an external ultrasound energy source may be used having a frequency in a range from 20 IcHz (kilohertz) to 100 MHz (megahertz), preferably in a range from 0.1 MHz to 20 MHz, and an intensity level in a range from 0.05 W/cm 2 (Watts per centimeter square) to 10 W/cm 2 , preferably in a range from 0.5 W/cm 2 to 5 W/cm 2 .
  • the ultrasound energy may be directed at the prosthesis 13 from a distance in a range from 1 mm (millimeters) to 30 cm (centimeters), preferably in a range from 1 cm to 20 cm.
  • the ultrasound may be continuously applied or pulsed, for a time period in a range from 5 seconds to 30 minutes, preferably in a range from 1 minute to 15 minutes.
  • the temperature of the prosthesis 13 during this period will be in a range from 36°C (degree Celsius) to 48 0 C.
  • the ultrasound may be used to increase a porosity of the prosthesis 13, thereby allowing release of the therapeutic agent 28 from the prosthesis 13.
  • Other sources of energy such as heat or vibrational energy, may also be used to increase the porosity or alter the configuration of at least a portion of the prosthesis.
  • the expandable structure 16 may comprise a stent 70 or a graft: (not shown).
  • the expandable structure 16 will usually comprise at least two radially expandable, usually cylindrical, ring segments 73 as shown in FIG. 3.
  • the expandable structure 16 will have at least four, and often five, six, seven, eight, ten, or more ring segments 73. At least some of the ring segments 73 will be adjacent to each other but others may be separated by other non-ring structures.
  • the description of stent structures herein is not intended to be exhaustive and it should be appreciated that other variations of stent designs may be used in the present invention.
  • the stent 70 generally comprises from 4 to 50 ring segments 73, with eight being illustrated. Each ring segment 73 is joined to the adjacent ring segment by at least one of sigmoidal links 76, with three being illustrated. Each ring segment 73 includes a plurality of strut/hinge units, e.g., six strut/hinge units, and three out of each six strut/hinge structures on each ring segment 73 will be joined by the sigmoidal links 76 to the adjacent ring segment. As shown in FIG. 3, stent 70 is in a collapsed or non-expanded configuration. The stent 70 is described in more detail in U.S. Patent No. 6,602,281, assigned to the assignee of the present application, the full disclosure of which is incorporated herein by reference.
  • radially expandable includes segments that can be converted from a small diameter configuration to a larger diameter radially expanded, usually cylindrical, configuration which is achieved when the expandable structure 16 is implanted at a desired target site.
  • the expandable structure 16 may be minimally resilient, e.g., malleable, thus requiring the application of an internal force to expand and set it at the target site.
  • the expansive force can be provided by a balloon, such as the balloon of an angioplasty catheter for vascular procedures.
  • the expandable structure 16 preferably provides sigmoidal links 76 between successive unit segments to enhance flexibility and crimpability of the stent 70.
  • the expandable structure 16 maybe self-expanding.
  • Self-expanding structures are provided by utilizing a resilient material, such as a tempered stainless steel or a superelastic alloy such as a NITDSfOLTM alloy, and forming the body segment so that it possesses a desired radially-expanded diameter when it is unconstrained, i.e., released from the radially constraining forces of a sheath, hi order to remain anchored in the body lumen, the expandable structure 16 will remain partially constrained by the lumen.
  • the self- expanding expandable structure 16 can be tracked and delivered in its radially constrained configuration, e.g., by placing the expandable structure 16 within a delivery sheath or tube and removing the sheath at the target site.
  • the dimensions of the expandable structure 16 will depend on its intended use. Typically, the expandable structure will have a length in a range from about 5 mm to about 100 mm, usually being from about 8 mm to about 50 mm, for vascular applications.
  • the diameter of a cylindrically shaped expandable structure for vascular applications, in a non- expanded configuration typically ranges from about 0.5 mm to about 10 mm, usually from about 0.8 mm to about 8 mm.
  • the diameter in an expanded configuration typically ranges from about 1.0 mm to about 100 mm, usually from about 2.0 mm to about 30 mm.
  • the expandable structure usually will have a thickness in a range from about 0.025 mm to 2.0 mm, usually from about 0.05 mm to about 0.5 mm.
  • the ring segments 73, and other components of the expandable structure 16, may be formed from conventional materials used for body lumen stents and grafts, typically being formed from malleable metals or alloys, such as 300 series stainless steel, resilient metals, such as superelastic and shape memory alloys (e.g., NITINOLTM alloys, spring stainless steels, and the like), non-metallic materials, such as polymeric materials, or a combination thereof.
  • the polymeric materials may include those polymeric materials that are substantially non-degradable, biodegradable, or substantially biodegradable, such as those described in relation to the materials of choice for the rate-sustaining or rate-controlling element.
  • the expandable structure 16 may function both as the prosthesis 13 and the direct source of the therapeutic agent 28.
  • the device 10 may comprise a biodegradable structure with a polymeric source, such as a polymeric therapeutic agent.
  • Suitable materials for use as the structure 16 include carbon or carbon fiber, cellulose acetate, cellulose nitrate, silicone, polyethylene terphthalate, polyurethane, polyamide, polyester, polyorthoester, polyanhydride, polyether sulfone, polycarbonate, polytetrafluoroethylene, polycaprolactone, polyhydroxybutyrate valerate, another biocompatible/biodegradable polymer, protein, extracellular matrix components, collagen, fibrin, another biologic agent, or a suitable mixture or copolymer of any of the materials listed above, degradable, non-degradable, metallic, or otherwise. Additional structures that may be incorporated into the expandable structure 16 of the present invention are illustrated in U.S. Patent Nos. 5,195,417, 5,102,417, and 4,776,337, the full disclosures of which are incorporated herein by reference.
  • FIG. 4A a graphical representation of one embodiment of therapeutic agent release over a predetermined time period is shown.
  • the predetermined rate pattern shown in FIG. 4 A improves the efficacy of the delivery of the therapeutic agent 28 to the susceptible tissue 22 site by making the therapeutic agent available at none to some lower delivery rate during an initial phase. Once a subsequent phase is reached, the delivery rate of the therapeutic agent may be substantially higher.
  • Time delayed therapeutic agent release can be programmed to impact restenosis (or other targeted conditions as the case may be) when there is at least a partial formation of the initial cellular deposition or proliferation (hyperplasia).
  • the present invention can further reduce any washout of the therapeutic agent by timing the release of the therapeutic agent to occur after at least initial cellularization.
  • the predetermined rate pattern may reduce loading and/or concentration of the therapeutic agent.
  • the predetermined rate pattern may further provide limited, reduced, or no hindrance to endothelialization of the vessel wall due to the minimization of washout of the therapeutic agent and the increased efficiency of its release.
  • FIGS. 4B and 4C represent further graphical representations of various release profiles of the therapeutic agent over a predetermined time period.
  • the rate of release of the therapeutic agent may exhibit a steeper or higher rate release slope during the initial phase as compared to the slope of rate release during the subsequent phase.
  • FIG. 4B illustrates a steeper or higher slope of release during the initial phase as that compared to the slope of release during the initial phase depicted in FIG. 4C.
  • FIGS. 5 A through 5F illustrate a method for making a therapeutic agent 28 available to a susceptible tissue site 22. As shown in FIG.
  • an intravasculature balloon catheter 100 having a tubular body 103 is introduced through a guiding catheter 106 via hemostatic valve and sheath (not shown) and through the femoral artery to the coronary vasculature over the aortic arch 112.
  • a guidewire 115 will usually be positioned at the target site 118 including the susceptible tissue site 22, which typically includes a region of stenosis to be treated by balloon angioplasty.
  • the balloon catheter 100 and guidewire 115 will be introduced together with the guidewire 115 being periodically extended distally of the catheter 100 until the target site 118 is reached.
  • a balloon 121 is inflated to expand the occlusion at the target site 118 as shown in FIGS. 5 C and 5D.
  • the balloon 121 will be deflated, with guidewire 115 remaining in place.
  • the balloon 121 may then be removed over guidewire 115, again with the guidewire 115 remaining in place as seen in FIGS. 5E and 5F.
  • a second balloon assembly 100' including a device 10 according to present invention is then introduced over the catheter body 103 as shown in FIG. 5G.
  • the device such as stent 10 which is in place over the second balloon assembly 100', may be deployed by inflating balloon 121' as shown in FIG.
  • the device of the present invention may be introduced to the site during the introduction of the first balloon catheter without the need for pre-dilatation.
  • Pimecrolimus is the 33-epi-chloro-derivative of the macrolactam ascomycin. It has an empirical formula of C 43 H 68 CINO 11 and a molecular weight of 810.48. Pimecrolimus is a cell-selective inhibitor of the production and release of pro-inflammatory cytokines. It is believed that pimecrolimus binds to macrophilin-12 and inhibits the Ca- dependent phosphatase calcineurin.
  • pimecrolimus is believed to block the synthesis of inflammatory cytokines in T cells at the level of gene transcription and in particular, regulates both Thl-(IL-2 and- TNf-) and Th2-(IL-4, IL-5, IL-10) type cytokine synthesis.
  • pimecrolimus is believed to prevent the release of cytokines and pro ⁇ inflammatory mediators from activated mast cells.
  • Pimecrolimus does not appear to effect the growth of keratinocyte or endothelial cell lines.
  • Pimecrolimus exhibits high anti- inflammatory activity in animal models of skin inflammation after both topical and systemic application.
  • Pimecrolimus appears to combine high anti-inflammatory activity with a low potential to impair local and systemic immunosurveillance.
  • the structure or scaffolding 16 may have one or more secondary therapeutic agents 50 which augment the function of the primary therapeutic agent 28 or perform another therapeutic or diagnostic function.
  • the secondary therapeutic agent 50 may be selected from a list comprising a variety of agents.
  • the therapeutic agent examples include mycophenolic acid, mycophenolic acid derivatives (e.g., 2-methoxymethyl derivative, 2-methyl derivative), VX-148, VX-944, mycophenolate mofetil, mizoribine, methylprednisolone, dexamethasone, CERTIC ANTM (e.g., everolimus, RAD), rapamycin, 32-deoxorapamycin (e.g., SAR943), ABT-578, ABT-773, ABT-797, TRIPTOLIDETM, METHOTREXATETM, phenylalkylamines (e.g., verapamil), benzothiazepines (e.g., diltiazem), 1,4-dihydropyridines (e.g., benidipine, nifedipine, nicarrdipine, isradipine, felodipine, amlodipine, nilvadipine, nisoldip
  • the "chemical name" of any of the therapeutic agents or other compounds is used to refer to the compound itself and to pro-drugs (precursor substances that are converted into an active form of the compound in the body), and/or pharmaceutical derivatives, analogues, or metabolites thereof (bio-active compound to which the compound converts within the body directly or upon introduction of other agents or conditions (e.g., enzymatic, chemical, energy), or environment (e.g., pH)).
  • pro-drugs precursor substances that are converted into an active form of the compound in the body
  • pharmaceutical derivatives, analogues, or metabolites thereof bio-active compound to which the compound converts within the body directly or upon introduction of other agents or conditions (e.g., enzymatic, chemical, energy), or environment (e.g., pH)).
  • the device 16 preferably includes a rate-sustaining or rate-controlling element or coating 43 for affecting the rate of release of the primary and/or secondary therapeutic agents 28, 50.
  • the rate-sustaining or rate-controlling element 43 may be formed of a non-degradable material, partially degradable material, substantially degradable material, or a combination thereof.
  • the material may be synthetic, natural, non-polymeric, polymeric, metallic, bio-active, non bio-active, or a combination thereof.
  • Suitable biodegradable rate-sustaining or rate-controlling element or coating 43 materials include, but are not limited to, poly(lactic acid), poly(glycolic acid), poly dioxanone, poly(ethyl glutamate), poly(hydroxybutyrate), polyhydroxyvalerate, polycaprolactone, polyanhydride, poly(ortho esters), poly (iminocarbonates), polyester- amids, polycyanoacrylates, polyphosphazenes, aliphatic polyesters, poly-L-lactic acid, poly- e-caprolactone, mixtures, copolymers, and combinations thereof.
  • biodegradable rate-sustaining or rate-controlling elements or coatings 43 include polyamide esters made from amino acids (e.g., L-lysine, 1-leucine) along with other building blocks such as diols (e.g., hexanediol) and diacids (e.g., sebacic acid).
  • amino acids e.g., L-lysine, 1-leucine
  • other building blocks such as diols (e.g., hexanediol) and diacids (e.g., sebacic acid).
  • An example of a biodegradable material of the present invention is a copolymer of poly-L-lactic acid (having an average molecular weight of about 200,000 daltons) and poly-e- caprolactone (having an average molecular weight of about 30,000 daltons).
  • Poly-e- caprolactone (PCL) is a semi crystalline polymer with a melting point in a range from 59 0 C to 64 0 C and a degradation time of about 2 years.
  • PCL poly-1-lactic acid
  • a preferred ratio of PLLA to PCL is 75:25 (PLLA/PCL).
  • a 75:25 PLLA/PCL copolymer blend exhibits sufficient strength and tensile properties to allow for easier coating of the PLLA/PLA matrix on the expandable structure. Additionally, a 75:25 PLLA/PCL copolymer matrix allows for sustained or controlled drug delivery over a predetermined time period as a lower PCL content makes the copolymer blend less hydrophobic while a higher PLLA content leads to reduced bulk porosity.
  • the intracorporeal life span of the 75% PLLA- 25% PCL copolymer is about 1 to 2 years.
  • Suitable nondegradable or slow degrading rate-sustaining or rate-controlling element 43 materials include, but are not limited to, polyurethane, polyethylene, polyethylene imines, cellulose acetate butyrate, ethylene vinyl alcohol copolymer, silicone, polytetrafluorethylene (PTFE), parylene, parylene C, N, D, or F, parylene C, PARYLASTTM, PARYLAST CTM, poly (methyl methacrylate butyrate), poly-N-butyl methacrylate, poly (methyl methacrylate), poly 2-hydroxy ethyl methacrylate, poly ethylene glycol methacrylates, poly vinyl chloride, poly(dimethyl siloxane), poly(tetrafluoroethylene), poly (ethylene oxide), poly ethylene vinyl acetate, poly carbonate, poly acrylamide gels, N-vinyl- 2-pyrrolidone, maleic anhydride, nylon, cellulose acetate butyrate (CAB), synthetic or natural polymeric substances,
  • the rate-sustaining or rate-controlling element 43 is formed from a material selected from the group consisting of silicone, polytetrafluoroethylene, parylene, parylene C, non-porous parylene C, PARYLASTTM, PARYLAST CTM, polyurethane, cellulose acetate butyrate, mixtures, copolymers and combinations thereof.
  • These polymers can have a foam structure, porous structure, nano-porous structure, non-porous structure, structure with mechanical disruption (e.g., fractures, cracks, openings, fissures, perforations or combinations thereof).
  • Suitable natural material for the rate-sustaining or rate-controlling element 43 include, but are not limited to, fibrin, albumin, collagen, gelatin, glycosoaminoglycans, oligosaccharides and poly saccharides, chondroitin, phosholipids, phosphorylcholine, glycolipids, proteins, oligomers, amino acids, peptides, cellulose, mixtures, copolymers, or combinations thereof.
  • Other suitable materials for the rate-sustaining or rate-controlling element 43 include titanium, chromium, NITINOLTM, gold, stainless steel, metal alloys, or a combination thereof.
  • Non-polymer compounds having large molecular weights, polar or non-polar functional groups, electrical charge, steric hindrance groups, hydrophobic, hydrophilic, or amphiphilic moieties may also be used for the rate-sustaining or rate- controlling element 43.
  • the degradable material may degrade by bulk degradation or hydrolysis.
  • the rate-sustaining or rate-controlling element 43 degrades or hydrolyzes throughout, or by surface degradation or hydrolysis, in which a surface of the rate-sustaining or rate-controlling element 43 degrades or hydrolyzes over time while maintaining bulk integrity.
  • hydrophobic rate-sustaining or rate-controlling elements 43 are preferred as they tend to release therapeutic agent 28 at desired release rates.
  • a non-degradable rate-sustaining or rate-controlling element 43 may release the therapeutic agent by diffusion, hi still another embodiment, if the rate-sustaining or rate-controlling element 43 is formed of non-polymeric material, the therapeutic agent 28 may be released as a result of the interaction (e.g., chemical reaction, high molecular weight, steric hindrance, hyrophobicity, hydrophilicity, amphilicity, heat) of the therapeutic agent with the rate-sustaining or rate-controlling element material (e.g, a non-polymer compound).
  • the rate-sustaining or rate-controlling element material e.g, a non-polymer compound
  • the therapeutic agent 28 may be released by diffusion through the rate-sustaining or rate-controlling element.
  • a rate-sustaining or rate-controlling element having low molecular weight and/or relatively high hydrophilicity in the tissue or blood may diffuse through the source (e.g., a matrix). This increases the surface area or volume for the therapeutic agent to be released from, thus, affecting the release rate of the therapeutic agent.
  • the therapeutic agent 28 may be released either from a reservoir 58 or a matrix comprising any of the polymers 43 described herein (FIGS. 2L and 2M).
  • the therapeutic agents may be covalently attached to amino acids and released as the polymer biodegrades.
  • Other biodegradable poly ester urethanes made from copolymers of poly lactide, poly capro lactone, poly ethylene glycol, polyester- amid, and poly acrylic acid can also be used to release the therapeutic agent as described above.
  • the devices 10 of the present invention may be configured to release or make available the therapeutic agent 28 at one or more phases, the one or more phases having similar or different performance release profiles (e.g., rates of delivery).
  • the duration of the initial, subsequent, and any other additional phases may vary.
  • the release of the therapeutic agent may be delayed from the initial implantation of the device. Typically, the delay is sufficiently long to allow sufficient cellularization, endothelialization, or fibrin deposition at the treated site and/or on at least a part of the device after implantation.
  • 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 effective to reduce any one or more of smooth muscle cell proliferation, inflammation, immune response, hypertension, or those complementing the activation of the same. Any one of the at least one therapeutic agents may perform one or more functions, including preventing or reducing proliferative/restenotic activity, reducing or inhibiting thrombus formation, reducing or inhibiting platelet activation, reducing or preventing vasospasm, or the like.
  • the device 10 includes a source 25 having a plurality of therapeutic agents including piniecrolimus as a primary therapeutic agent 28 and one or more optional secondary therapeutic agents 50
  • the plurality of therapeutic agents may be released at different times and/or rates, from the same or different layers.
  • Each of the plurality of agents maybe made available independently of one another (e.g., sequential), simultaneous with one another, or concurrently with and/or subsequent to the interventional procedure.
  • the primary therapeutic agent e.g., pimecrolimus
  • the secondary therapeutic agent e.g, mycophenolic acid
  • the structure or scaffolding 16 of the device 10 may incorporate the primary therapeutic agent 28 and/or the optional secondary therapeutic agent 50, by coating, spraying, dipping, deposition (vapor or plasma), or painting the therapeutic agent onto the prosthesis.
  • the therapeutic agent is dissolved in a solvent.
  • Suitable solvents include aqueous solvents (e.g., water with pH buffers, pH adjusters, organic salts, and inorganic salts), alcohols (e.g., methanol, ethanol, propanol, isopropanol, hexanol, and glycols), nitriles (e.g., acetonitrile, benzonitrile, and butyronitrile), amides (e.g., formamide and N- dimethylformamide), ketones, esters, ethers, dimethyl sulfoxide (DMSO), gases (e.g., CO 2 ), and the like.
  • the device may be sprayed with or dipped in the solution and dried so that therapeutic crystals are left on a surface thereof.
  • a matrix solution including a rate-sustaining or rate-controlling element material 43 and the therapeutic agent 28 may be prepared by dissolving the rate- sustaining or rate-controlling element material and the therapeutic agent in a solution.
  • the expandable structure 16 may then be coated with the matrix solution by spraying, dipping, deposition, or painting the matrix onto the prosthesis.
  • the matrix solution is finely sprayed on the prosthesis while the prosthesis is rotating on a mandrel.
  • the thickness of the matrix coating may be controlled by the time period of spraying and a speed of rotation of the mandrel.
  • the thickness of the matrix-agent coating is typically in a range from about 0.01 ⁇ m to about 100 ⁇ m, preferably in a range from about 0.1 ⁇ m to about 50 ⁇ m.
  • the device 10 comprising a metallic stent 16, 70 (FIG. 3) and a source 25 including primary and/or secondary therapeutic agents 28, 50 associated with the gelatinous substance may be prepared by undergoing a silylation process.
  • the stent device 16 is first subjected to a cleaning process during which the surface contaminants such as oils, greases, or lubricants are removed from the surface of the device by general degreasing and cleaning methods.
  • the device is thereafter subjected to a passivation solution, such as a nitric acid-based solution, for a period of time in a range from 10 to 15 minutes.
  • a metal oxide film is formed on the surface of the device 16, as generally depicted in FIG. 7.
  • silane coupling agent preferably after the device has undergone passivation, the device 16 is exposed to a silane coupling agent.
  • Silanes and other monomelic silicon compounds have the ability to bond inorganic materials such as glass, mineral fillers, metals, and metallic oxides to organic materials such as polymers, resins, or other organic compounds.
  • the silane coupling agents normally comprise one or more organo-functional groups and one or more functional groups which can undergo hydrolysis to become silanols.
  • Silane coupling agents typically have a molecular structure as shown in formula #1 below:
  • R 1 includes R 3 and optionally R 4;
  • R 4 is (CH 2 ) n wherein n ranges from 0 to about 15, preferably 3;
  • R 2 is a silanol forming group, normally a tri-functional group, usually selected from the group consisting of halo groups such as -Cl 3 and alkoxy groups (-OCH 3 ) n , wherein n ranges from about 1 to about 6, preferably 1 (methoxy (-(OCH 3 )) or 2 (ethoxy (- (OC 2 H 5 )).
  • the silane coupling agent when the silane coupling agent is styrenated, it can be prepared by reacting an epoxy-terminated silane with amino-styrene.
  • the silylation process normally involves the reaction between the silanol forming portion and the inorganic material (e.g., the metallic oxide of the passivated metal stent surface) while the one or more organo- functional group reacts with the organic material such as the gelatin (including a plurality of amino and carboxyl groups).
  • the gelatin is a styrenated gelatin as disclosed by Nakayama et al.
  • the gelatinous substance is disposed (e.g., bonded) on the silylated device through functional groups of the gelatinous substance such as carboxylic groups, amine groups, or styrene groups (if the silane coupling agent itself is a stryrenated agent).
  • Gelatin has a structure generally depicted in FIG. 10.
  • the gelatinous substance may be acid treated with or without styrene functionalities, and is generally depicted as formula #3, below:
  • FIGS. 1 IA through 11C Some reactions between the gelatinous substance and different silane coupling agents are shown in FIGS. 1 IA through 11C. It will be appreciated that the mechanisms of reaction between the various functional groups follow typical organic reactions.
  • the gelatinous substance may control or sustain release of the primary and/or secondary therapeutic agent 28, 50 from the stent 16.
  • the therapeutic agent is mixed with the gelatinous substance and thereafter disposed on the device.
  • the device may be sprayed with or dipped in the solution/mixture comprising the therapeutic agent and the gelatinous substance and then dried so that source is left on a surface thereof.
  • the gelatinous substance may be disposed on the device and the therapeutic agent is disposed between this layer and a subsequent layer of the gelatinous substance.
  • Example 1 A stainless steel DURAFLEXTM stent (available from Avantec Vascular Corporation, the assignee of the present application) having dimensions of 3.0 mm x 14 mm was sprayed with a solution of 25 mg/ml of pimecrolimus in a 100% ethanol solvent. The stent was dried and the ethanol was evaporated leaving pimecrolimus on the stent surface.
  • a 75:25 PLLA/PCL copolymer (sold commercially by Polysciences) was prepared in a 1, 4 Dioxane solvent (sold commercially by Aldrich Chemicals).
  • the pimecrolimus loaded stent was mounted on a mandrel rotated at 200 rpm, and coated by spraying with a spray gun (sold commercially by Binks Manufacturing).
  • the copolymer solution was finely sprayed onto the pimecrolimus loaded stent as it was rotated for a time period of 10 to 30 seconds.
  • the stent was then placed in an oven and maintained at 25° to 35°C for up to 24 hours to complete evaporation of the solvent.
  • the stent was then ready for implantation within a patient in a conventional fashion.
  • Example 2 The surface of a DURAFLEXTM stent having dimensions of 3.0 mm x 14 mm was roughened to increase the surface area of the stent. In addition to the surface roughening, the surface area and the volume of the stent was further increased by creating 10 ran wide by 5 run deep grooves along the links of the stent strut. The grooves were created in those stent areas experiencing low stress during expansion so as not to compromise the stent radial strength. Pimecrolimus was loaded onto the stent and in the stent grooves by dipping the stent in a solution of pimecrolimus and a low surface tension solvent (e.g., isopropyl alcohol, ethanol, or methanol).
  • a low surface tension solvent e.g., isopropyl alcohol, ethanol, or methanol
  • the stent was then dried with pimecrolimus remaining on the stent surface and in the grooves which served as a reservoir.
  • a parylene coating is then vacuum deposited onto the stent to serve as a rate-sustaining or rate-controlling element.
  • pimecrolimus is eluted from the stent over a period of time in the range from 1 day to 45 days.
  • Example 3 Pimecrolimus was dissolved in methanol and sprayed onto a DURAFLEXTM stent having dimensions of 3.0 mm x 14 mm. The stent was left to dry with the solvent evaporating, leaving pimecrolimus on the stent.
  • a rate-sustaining or rate- controlling coating e.g., silicone, polyurethane, polytetrafluorethylene, parylene, parylene C, non-porous parylene C, PARYLASTTM, PARYLASTTMC
  • the amount of pimecrolimus on the stent varied from about 10 ⁇ g to 2 mg.
  • the coated stent was then placed within a patient's vasculature and the release rates for the pimecrolimus ranged from 1 day to 45 days.
  • Example 4 A matrix solution including the matrix polymer and pimecrolimus was coated onto the stent of Example 2. The stent was then coated or sprayed with a top coat of a second rate-sustaining or rate-controlling element, hi another similar example, the pimecrolimus was coated on the stent via a rate-sustaining or rate-controlling element, and then covered with a top coat of a matrix material without a drag. Top coats provide further sustained or controlled release rates, improved biocompatibility, and/or resistance to scratching and cracking upon stent delivery or expansion within a body lumen.
  • Example 5 Pimecrolimus was combined with another or secondary therapeutic agent (e.g., rapamycin and/or its analogs). Pimecrolimus was coupled to a first coating while the secondary therapeutic agent was coupled to a second coating. The pimecrolimus was released for a time period of about 1 day to about 45 days after being implanted within a vessel, while the second therapeutic agent was released for a longer period in one instance and a shorter period in another instance. By way of example, when the second therapeutic agent was rapamycin, the second therapeutic agent was released at a shorter period.
  • another or secondary therapeutic agent e.g., rapamycin and/or its analogs
  • Example 6 The anti-proliferative properties of pimecrolimus were measured using a standard thymidine incorporation proliferation assay.
  • Cultured human smooth muscle cells (HSMCs) were exposed to varying concentration doses of pimecrolimus, ranging from 0.01 ⁇ mol to 10 ⁇ mol, for a period of 2 hours.
  • a positive control of HSMCs with no pimecrolimus exposure was also carried out for control purposes.
  • the cells were then exposed to tritiated-thymidine, which gets incorporated in proliferating cells. The thymidine was measured using a scintillation counter.
  • the extent of proliferation in absence (controls) and presence of pimecrolimus was measured and the IC50 (e.g., concentration at which 50 % (percent) of cells were prevented from proliferating) of the drug was calculated.
  • the proliferation assay enables the evaluation of the potency of an anti-proliferative agent.
  • the IC50 of pimecrolimus for HSMCs was between 0.01 ⁇ mol to 0.1 ⁇ mol, which indicates that pimecrolimus has potent anti-proliferative effects.
  • the undesirable proliferation of HSMCs decreases.
  • the % proliferation dipped below the 50% mark at 0.03 ⁇ mol and greater concentrations of pimecrolimus, the % proliferation dipped below the 50% mark, at 0.2 ⁇ mol and greater concentrations of pimecrolimus, the % proliferation dipped below the 40% mark, and at 0.5 ⁇ mol and greater concentrations of pimecrolimus, the % proliferation dipped below the 30% mark
  • Example 7 The effect of the pimecrolimus on the viability of human smooth muscle cells was evaluated using the standard trypan blue viability assay.
  • Cultured HSMCs were exposed to varying concentration doses of pimecrolimus, ranging from an amount of 10 ⁇ g (12 ⁇ mol) to about 600 ⁇ g (727 ⁇ mol), for a period of 2 hours.
  • a positive control of HSMCs with no pimecrolimus exposure was also carried out for control purposes.
  • the cells were then exposed to trypan blue, which incorporates into dead cells.
  • the viability was expressed as a percentage of live cells remaining after two hours at each concentration.
  • the viability assay enables the evaluation of the toxicity of the drug. As shown in FIG.
  • pimecrolimus provided high viability (e.g., 80% viability or greater) at concentrations up to 600 ⁇ g, indicating that although pimecrolimus has anti-proliferative effects, it is not due to toxicity; pimecrolimus is a cytostatic agent.
  • Example 8 The elution characteristics of pimecrolimus were evaluated. Specifically, the concentration and degradation of pimecrolimus over time was measured using high performance liquid chromatography (HPLC) with UV detection. Five DURAFLEXTM stents having dimensions of 3 mm x 14 mm were coated with pimecrolimus.
  • the normal (1) and normal (2) stents were identically coated with a parylene sublimation temperature rise of 0.5 °C/min, the faster (2) stent was coated with a parylene sublimation temperature rise of 1.0 °C/min, the faster (1) stent was coated with a parylene sublimation temperature rise of 2.0 °C/min, and the slowest stent was coated with a parylene sublimation temperature rise of 0.25 °C/min.
  • the drug elution properties of these pimecrolimus parylene coated stents was measured using the HPLC method. As clearly seen in FIG.
  • the pimecrolimus release profiles from the various parylene coated stents described above all exhibited a steeper or higher slope of pimecrolimus rate release during an initial phase (e.g., up to 3 days) as compared to the slope of pimecrolimus rate release during the subsequent phase (e.g., after 3 days). It is believed that upon stent crimping and expansion, the non-porous parylene coating cracks, fractures, or other mechanical disruptions in the coating structure allow the pimecrolimus to elute or move from the stent.
  • Example 9 DURAFLEXTM stents having dimensions of 3 mm x 14 mm were coated with pimecrolimus and placed in porcine coronary arteries of juvenile farm pigs weighing between about 20 kgs (kilograms) and 50 kgs.
  • One or two pimecrolimus loaded stents were implanted per animal along with a bare metal stent without a therapeutic agent to serve as a control.
  • stents were loaded with 200 ⁇ g of pimecrolimus without a rate delaying or controlling coating.
  • Stents were implanted in the major epicardial vessels of the chosen pigs.
  • the appropriate vasculature was accessed via the right or left femoral artery and the stents were implanted and sized to approximately a 1.25:1 balloon to artery ratio by angiographic analysis. All stents were carefully tracked during implantation to assure precise recording of sample group and location. Animals were then followed for 28 days by quantitative coronary angiography (QCA) before euthanasia.
  • QCA quantitative coronary angiography
  • Animal preparation began by daily administration of ASA 650 mg p.o. and Ticlid 500 mg p.o. to the animal starting one week prior to anesthesia. Following an overnight fast, the pigs were anesthetized with Ketamine 20 mg/kg, Xylazine 2 mg/kg, and Atropine 0.6 mg, which was administered intramuscularly. General anesthesia was induced by administering 1-3% Isoflurane. A 7 French or 8 French introducer sheath was placed into the animal's femoral artery. A 0.035" (inch) guidewire was then introduced into the animal's femoral artery through the introducer sheath and advanced therein through the animal's aorta and into the appropriate coronary ostium.
  • a guiding catheter was advanced over the guidewire through the ascending aorta and into the appropriate coronary ostium. The guidewire was then removed.
  • the stents were mounted on a delivery balloon catheter and advanced over the in-place guiding catheter until the stent was in the desired location within the animal vasculature.
  • the balloon on the catheter was inflated to deploy the stent at the target site.
  • the balloon was inflated to a pressure required to achieve a 1.25:1 ratio of stent to artery size. After stent deployment, the balloon was deflated and the catheters were removed from the animal. Further angiography was performed to determine appropriate stent sizing and expansion.
  • the animals were administrated a daily dose of ASA 650 mg p.o. and Ticlid 500 mg p.o. and followed by QCA for 28 days. After this time period, the animals were euthanized with an overdose of potassium chloride. The thorax of each animal was opened by a left lateral intercostal incision and the heart removed. The entire heart was infused with 1000 ml of saline solution followed by 2 liters of formalin under a pressure of about 120 mm Hg. All stents were subjected to histological evaluations, including morphometric and histopathologic analysis.
  • the niorphometric analysis of each stent segment measured the % stenosis and neointimal area of both the pimecrolimus coated stents and the bare metal control stents.
  • the % stenosis measured a mean value of 17.03 with a standard deviation of 7.00 and the neointimal area measured a mean value of 1.13 with a standard deviation of 0.53 for 24 pimecrolimus coated stents.
  • 27 bare metal control stents measured a % stenosis mean value of 25.56 with a standard deviation of the 16.94 and a neointimal area mean value of 1.97 with a standard deviation of 1.40.
  • FIGS. 15A and 15B are histologic slides illustrating bare metal stents after 28 days of implantation.
  • FIGS. 16A and 16B are histologic slides illustrating stents coated with pimecrolimus after 28 days of implantation.
  • the body lumens 19 implanted with pimecrolimus coated stents exhibit a significantly reduced stenotic build up (e.g., reduced stenotic percentage) as compared to the body lumens 19 implanted with bare metal control stents.
  • Example 10 An amino propyltriethoxysilane was attached to a passivated stainless steel DURAFLEXTM stent having dimensions of 3.0 mm x 14 mm, evolving ethanol as a by ⁇ product. The silylated stent was then reacted with acidic gelatin. The primary and/or secondary therapeutic agent was added to the gelatinous substance prior to the gelatinous substance being applied to the stent. In a similar example, the primary and/or secondary therapeutic agent was applied after the stent had been coated with the gelatinous substance.
  • Example 11 Propanoldehyde triethoxysilane was attached to a passivated stainless steel stent by condensation reaction evolving ethanol as a by-product. Type B amino terminated gelatin was reacted with the aldehyde functional group of the silylated stent.
  • the primary and/or secondary therapeutic agent was added to the gelatinous substance prior to the gelatinous substance being applied to the stent, hi a similar example, the primary and/or secondary therapeutic agent was applied after the stent had been coated with the gelatinous substance.
  • Example 12 A styrenated tri-ethoxysilane coupling agent was attached to a passivated stainless steel stent by condensation reaction evolving alcohol (e.g., methanol or ethanol) as a by-product. Styrenated gelatin was applied to the silylated stent. The primary and/or secondary therapeutic agent was added to the gelatinous substance prior to the gelatinous substance being applied to the stent. In a similar example, the primary and/or secondary therapeutic agent was applied after the stent had been coated with the gelatinous substance.
  • condensation reaction evolving alcohol e.g., methanol or ethanol
  • the coated stent was then subjected to visible light in presence of carboxylated camporquinone initiator, causing the reaction between the styrene groups of the gelatin and the styrene groups present on the of the silylated stent. It is believed that this reaction formed cross-linked covalent bonds between gelatin and the groups on the silylated stent.
  • the cross-link density may be controlled by adjusting the amount of styrenation in the gelatin molecule. It is further believed that controlling the cross-link density of the coating will help control the release or elution of the therapeutic agent from the coated stent.

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Abstract

La présente invention concerne un dispositif intracorporel, tel qu'une endoprothèse, ainsi que des méthodes destinées à réduire, inhiber ou traiter une resténose et une hyperplasie par introduction d'un dispositif intracorporel dans le corps d'un patient, ce dispositif étant revêtu d'un enrobage d'un agent thérapeutique primaire, tel que le pimécrolimus, pouvant être libéré de manière régulée ou prolongée. Le dispositif peut être une structure ou un échafaudage, la source de l'agent thérapeutique étant située au voisinage de cette structure ou de cet échafaudage en vue d'une libération de l'agent thérapeutique dans le corps du patient. Ce dispositif peut être utilisé dans le système vasculaire d'un patient, et notamment dans les artères coronaires, carotides et périphériques du patient.
PCT/US2005/037658 2004-10-18 2005-10-17 Dispositifs et methodes pour l'administration de pimecrolimus et d'autres agents therapeutiques WO2006044989A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008024626A2 (fr) * 2006-08-21 2008-02-28 Innovational Holdings Llc Endoprothèse biorésorbable avec libération prolongée d'agent anti-resténose in vivo

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6240616B1 (en) * 1997-04-15 2001-06-05 Advanced Cardiovascular Systems, Inc. Method of manufacturing a medicated porous metal prosthesis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6240616B1 (en) * 1997-04-15 2001-06-05 Advanced Cardiovascular Systems, Inc. Method of manufacturing a medicated porous metal prosthesis

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008024626A2 (fr) * 2006-08-21 2008-02-28 Innovational Holdings Llc Endoprothèse biorésorbable avec libération prolongée d'agent anti-resténose in vivo
WO2008024626A3 (fr) * 2006-08-21 2008-10-30 Innovational Holdings Llc Endoprothèse biorésorbable avec libération prolongée d'agent anti-resténose in vivo

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