WO2010019721A2 - Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device - Google Patents

Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device Download PDF

Info

Publication number
WO2010019721A2
WO2010019721A2 PCT/US2009/053623 US2009053623W WO2010019721A2 WO 2010019721 A2 WO2010019721 A2 WO 2010019721A2 US 2009053623 W US2009053623 W US 2009053623W WO 2010019721 A2 WO2010019721 A2 WO 2010019721A2
Authority
WO
WIPO (PCT)
Prior art keywords
drug
stent
everolimus
clobetasol
coating
Prior art date
Application number
PCT/US2009/053623
Other languages
French (fr)
Other versions
WO2010019721A3 (en
Inventor
Jin Chen
Stephen Dugan
Gordon Stewart
Gina Zhang
Nancy Kirsten
Paul Consigny
Christopher Feezor
Gene Park
Wouter Roorda
Syed F. A. Hossainy
Original Assignee
Abbott Cardiovascular Systems Inc.
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
Application filed by Abbott Cardiovascular Systems Inc. filed Critical Abbott Cardiovascular Systems Inc.
Publication of WO2010019721A2 publication Critical patent/WO2010019721A2/en
Publication of WO2010019721A3 publication Critical patent/WO2010019721A3/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2/00Filters 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
    • A61F2/82Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90Stents 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
    • A61F2/91Stents 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/4738Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148Materials at least partially resorbable by the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067Means for introducing or releasing pharmaceutical products into the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F2250/00Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067Means for introducing or releasing pharmaceutical products into the body
    • A61F2250/0068Means for introducing or releasing pharmaceutical products into the body the pharmaceutical product being in a reservoir
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/22Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
    • A61L2300/222Steroids, e.g. corticosteroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • This invention generally relates to a drug combination including an anti-proliferative drug such as everolimus and an anti-inflammatory agent such as clobetasol for the treatment of a disorder such as restenosis and vulnerable plaque.
  • plaque has been associated with stenosis and restenosis. While treatments of plaque-induced stenosis and restenosis have advanced significantly over the last few decades, the morbidity and mortality associated with vascular plaques have remained significant. Recent work suggests that plaque may generally fall into one of two different general types: standard stenotic plaques and vulnerable plaques. Stenotic plaque, which is sometimes referred to as thrombosis-resistant plaque, can generally be treated effectively by the known intravascular lumen opening techniques. Although plaques induce stenoses, these atherosclerotic plaques themselves are often benign and are an effectively treatable disease.
  • plaque As plaque matures, narrowing of a blood vessel by a proliferation of smooth muscle cells, matrix synthesis, and lipid accumulation may result in formation of a plaque which is quite different than a standard stenotic plaque. Such atherosclerotic plaque becomes thrombosis-prone, and can be highly dangerous. This thrombosis-prone or vulnerable plaque may be a frequent cause of acute coronary syndrome. While the known procedures for treating plaque have gained wide acceptance and have shown good efficacy for treatment of standard stenotic plaques, they may be ineffective (and possibly dangerous) when thrombotic conditions are superimposed on atherosclerotic plaques.
  • biodegradable implantable medical devices it may be desirable for PTI treatments to employ biodegradable implantable medical devices.
  • the presence of a stent in a body may be necessary for a limited period of time until its intended function of, for example, maintaining vascular patency and/or drug delivery is accomplished. Therefore, stents fabricated from biodegradable, bioabsorbable, and/or bioerodable materials such as bioabsorbable polymers should be configured to completely erode only after the clinical need for them has ended.
  • bioabsorbable stents are adequately suppressing acute or chronic inflammatory responses triggered by the degradation of the stent.
  • the vascular response to a fully bioabsorbable stent can be much different than that of a metal or polymer coated stent.
  • Anti-proliferative drugs are often sufficient to reduce neointimal formation, but do not have the ability to adequately suppress inflammation. This is reflected by the large number of granulomas often seen in chronic porcine studies with drug eluting stents.
  • a drug-delivery device, system or platform comprising at least 100 ⁇ g of everolimus and clobetasol, such that the ratio of everolimus to clobetasol is at least 10: 1 (w/w) or the amount of everolimus by weight is at least 10 times more than clobetasol.
  • the system is a stent.
  • the system can be a polymeric coated stent, such that the everolimus and clobetasol are in the polymeric coating.
  • the coating can include 2 layers or regions such that the everolimus is in one layer or region and the clobetasol is in another layer or region.
  • the drugs can be released in sequence, simultaneously or a combination of both.
  • the drug release profile can include at least a period of overlapping or simultaneous release profile of the everolimus and clobetasol.
  • the ratio of the everolimus to the clobetasol can be 10: 1 to 100: 1 (w/w).
  • a stent comprising a radially expandable body and a combination of (a) a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus), 40-O-(3-hydroxy)propylrapamycin, 40-O-[2-(2- hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and 40-epi-(Nl- tetrazol
  • the stent can include a coating carrying the first and second drugs.
  • the coating can include at least two layers such that the first drug is in one layer and the second drug is in another layer.
  • the stent can be polymeric, metallic or combination of both.
  • at least one of the drugs is in the body of the stent and at least one of the drugs is in a coating disposed over the surface of the stent.
  • a method of treating restenosis or vulnerable plaque of a blood vessel comprising locally administering to a patient a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2 -hydro xy)ethylrapamycin (everolimus), 40-O-(3 -hydro xy)propylrapamycin, 40-O- [2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and 40-epi-(Nl- tetrazolyl)rapamycin, and locally administering to the patient a second drug consisting of clobetasol, wherein the minimum amount of the first drug that is locally administered is 100 ⁇ g, and wherein
  • FIG. 1 depicts an illustration of a stent.
  • FIG. 2 depicts an illustration of a section of a stent.
  • FIGs. 3A-B depict cross-sections of a strut illustrating geometries of depots.
  • FIGs. 4A-B depicts cross-sections of a strut with a coating.
  • Figure 5 shows the results of 28 day quantitative coronary angioplasty (QCA) of a porcine implant study on drug-delivery systems described herein.
  • QCA quantitative coronary angioplasty
  • Figure 6 shows 28 day histology data of a porcine implant study on drug-delivery systems described herein.
  • Figure 7 shows the 28 day morphometry data of a porcine implant study on drug-delivery systems described herein.
  • FIG. 8 shows the results of 28 day quantitative coronary angioplasty (QCA) of a porcine implant study on drug-delivery systems described herein.
  • FIG. 9 depicts a proliferation assay that shows a dose dependent inhibition of vascular smooth muscle proliferation.
  • FIG. 10 depicts a proliferation assay with everolimus which also shows inhibition of vascular smooth muscle proliferation.
  • FIG. 11 depicts results of a proliferation assay with varying ratios of everolimus and clobetasol.
  • treatment includes prevention, reduction, delay or elimination of the vascular disorder.
  • treatment also includes repairing damage caused by the disorder and/or the mechanical intervention
  • the drug-delivery system has two or more drugs for treating a vascular disorder or a related disorder.
  • the drugs can be a combination of at least one anti-proliferative agent, at least one anti-inflammatory agent, and optionally a third bioactive agent.
  • the drug-delivery system consists only of two drugs, an anti-proliferative agent and an anti- inflammatory agent.
  • the drugs can include or only consist of everolimus and clobetasol. Everolimus is available under the trade name CerticanTM, Novartis Pharma AG, Germany and clobetasol is available under the trade name TemovateTM, Glaxosmithkline, UK.
  • the amount of the anti-proliferative agent or everolimus included or carried by the system can be at least 100 ⁇ g and the ratio of the anti-proliferative agent or everolimus to the anti-inflammatory agent or clobetasol can be at least 10: 1 (w/w). In one preferred embodiment, the ratio is 10: 1 to 100: 1 (w/w).
  • the system includes a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus), 40-O-(3-hydroxy)propylrapamycin, 40-O-[2-(2- hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and 40-epi-(Nl- tetrazolyl)rapamycin, and a second drug consisting of clobetasol.
  • rapamycin sirolimus
  • Biolimus A9 deforolimus
  • AP23572 tacrolimus
  • temsirolimus pimecrolimus
  • zotarolimus ABT-578
  • the minimum amount of the first drug carried by the system (e.g., stent) is 100 ⁇ g and the ratio of the first drug to the second drug is 10: 1 to 100: 1 (w/w).
  • the system consists solely of the first and second drug combination with no other drugs present.
  • a medical composition such as in a liquid carrier, is described including an effective amount of at least one anti- inflammatory agent and an effective amount of an anti-proliferative agent.
  • the composition described herein includes an effective amount of an agent which is effective both as an antiinflammatory agent and as an anti-proliferative agent.
  • the composition can, for example, be administered orally, intravenously, or formed into a coating for an implantable medical device such as a stent or a balloon of a catheter.
  • the anti-proliferative agent can be everolimus or others described herein, and the anti-inflammatory agent can be clobetasol.
  • the anti-proliferative agent and the anti- inflammatory agent can be in the form of a coating with or without a polymer matrix on a medical device (e.g., stent) or at least one of the agents can be administered in a separate dose form such as bolus dose of a free drug, optionally with fluoroscopic dye, or bolus dose of a gel encapsulating the drug.
  • the drug- delivery system or composition may further include a third agent such as a high-density lipoproptein mimetic (HDL-mimetic).
  • HDL-mimetic high-density lipoproptein mimetic
  • an anti-inflammatory agent such as clobetasol can be delivered along with the catheter based delivery of a HDL-mimetic while everolimus is administered by a stent.
  • the drug-delivery system or composition disclosed herein can be used to treat a disorder such as thrombosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, restenosis and progression of atherosclerosis in patient subsets including type I diabetics, type II diabetics, metabolic syndrome and syndrome X, vulnerable lesions including those with thin-capped fibroatheromatous lesions, systemic infections including gingivitis, hellobacteria, and cytomegalovirus, and combinations thereof.
  • a disorder such as thrombosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction
  • a common disorder in association with mechanical modification of a vessel, such as by a balloon or stenting is restenosis.
  • a number of cellular mechanisms have been proposed that lead to restenosis of a vessel. Two of these mechanisms are (1) the migration and proliferation of smooth muscle cells to and at the site of injury, and (2) the acute and chronic inflammatory response to injury and foreign body presence.
  • Inflammation is a defensive, biological response to injury, infection or an abrupt change in tissue homeostasis. Inflammation can occur anywhere in the body, and most of the time is confined to that part of the body. Well-known indicators of inflammation are pain, redness, warmth, swelling, and loss of function. In nature, inflammatory responses are designed to destroy, dilute and isolate injurious agents and then lead to recovery and repair of the affected tissue. The intensity of an inflammatory response can vary from one that is self-limiting, which requires minor therapeutic intervention, to one that is life threatening, which requires intense intervention. One drawback of the inflammatory process is its ability to become progressive, meaning tissue damage continues after the stimulus is neutralized or removed.
  • vascular inflammation is the first stage of the inflammatory response, developing after the initial contact with the stimulus and continuing sometimes for several days.
  • the presence of a stimulatory agent in the blood or in the tissue triggers the body's response through endothelial cells.
  • the endothelial cell layer is the innermost layer of larger vessels and the only cell layer of the smallest vessels, the capillaries.
  • Endothelial cells produce substances called chemokines that attract neutrophils and other white blood cells to the site of injury. Within the site, neutrophils and endothelium relay information back and forth across cell membranes through presentation of adhesion molecules and cytokines. Cellular cross-talk promotes physical interaction between the "inflamed" neutrophil and the "inflamed" endothelium.
  • Biodegradation refers generally to changes in physical and chemical properties that occur (e.g., in a polymer) upon exposure to bodily fluids as in a vascular environment.
  • the changes in properties may include a decrease in molecular weight, deterioration of mechanical properties, and decrease in mass due to erosion or absorption.
  • the decrease in molecular weight may be caused by chemical reactions of bodily fluids with the polymer, for example, hydrolysis and/or metabolic processes. By-products of such degradation reactions can be responsible for inciting inflammation.
  • by-products of hydrolysis are produced when polymer molecules are cleaved into component parts by the addition of water.
  • Various byproducts of degradation of biodegradable polymers are known to incite an inflammatory response.
  • lactic acid a degradation by-product of poly(lactic acid) polymers, is known to cause an inflammatory response.
  • the release of by-products into the body from a biodegradable device occurs continuously from the time of first exposure to bodily fluids to a time when the device is either completely degraded and eliminated or removed from the body. It follows that throughout this time frame, the body is continuously exposed to inflammation-inciting by-products. Therefore, in some embodiments, it is desirable to have a sustained release of an anti-inflammatory agent from a degrading implanted device throughout this time frame.
  • endothelial cell swelling Another important pathological feature of vascular inflammation is endothelial cell swelling. This action reduces the functional vessel diameter such that the speed of blood flow falls significantly and the vessel becomes congested. When these conditions predominate, inflamed neutrophils are induced to plug the vessel. As a result, endothelial cells lose their tight connections allowing neutrophils to transmigrate into the surrounding tissue. Within hours of the initial stimulus, neutrophils begin to enter the tissue and may continue transmigration for many days. The appearance of inflammatory cells in the surrounding tissue marks the beginning of tissue damage. In some inflammatory conditions, tissue damage is caused by direct injury of the vessels and amplified by the subsequent recruitment of neutrophils into the tissue.
  • tissue repair is the third and final stage of inflammation. It may take several days for tissue destruction to reach full intensity before tapering off. Until then, the tissue repair process that consists of growth of new blood vessels and entry of monocytes to clean up the debris is delayed. Fibroblasts also enter the local tissue to replace the extracellular matrix and collagen. The process of tissue repair is stringently controlled within the tissue site. If the process becomes dysregulated, inappropriate tissue repair will lead to excessive scarring. Depending on the tissue and the intensity/duration of the inflammatory condition, the amount of scarring can be significant.
  • VP vulnerable plaque
  • Previous studies have demonstrated that inflammation promotes proliferation at sites of balloon angioplasty and stent placement in pigs (Kornowski, et al, Coron Artery Dis. 12(6):513-5 (2001)). Since sites of vulnerable plaque have a higher density of macrophages and lymphocytes than other types of atherosclerotic lesions, it is expected that these sites, when stented, will produce elevated amounts of the cytokines (IL- 1 , TNF-alpha) that promote smooth muscle cell proliferation.
  • Another example of disorders that vessel inflammation is involved is diabetes.
  • the system, device or platform of the present invention can be a medical device, preferably an implantable medical device.
  • implantable medical device is intended to include self-expandable stents, balloon-expandable stents, stent-grafts, and grafts.
  • An implantable medical device also includes a body structure, substrate, or scaffolding for medical use that can be permanently or temporarily implanted in a subject.
  • the structure of the device can be of virtually any design.
  • a stent for example, may include a pattern or network of interconnecting structural elements or struts.
  • FIG. 1 depicts an example of a three-dimensional view of a stent 10.
  • the stent may have a pattern that includes a number of interconnecting elements or struts 15.
  • the embodiments disclosed herein are not limited to stents or to the stent pattern illustrated in FIG. 1.
  • the cross-section of a strut may be rectangular, (as pictured in Fig. 1), circular, oval, etc.
  • the struts of the stent in FIG. 1 may further be described as having abluminal (outer) faces 20, luminal (inner) faces 25, and sidewalls 30.
  • the embodiments are easily applicable to other patterns and other devices. In general, the variations in the structure of patterns are virtually unlimited. As shown in FIG. 1 the geometry or shape of stents vary throughout its structure.
  • a stent may be formed from a tube by laser cutting the pattern of struts into the tube.
  • the stent may also be formed by laser cutting a polymeric or metallic sheet, rolling the pattern into the shape of the cylindrical stent, and providing a longitudinal weld to form the stent.
  • Other methods of forming stents are well known and include chemically etching a sheet and rolling and then welding it to form the stent.
  • a polymeric or metallic wire may also be coiled to form the stent.
  • the stent may be formed by injection molding of a thermoplastic or reaction injection molding of a thermoset polymeric material. Filaments of the compounded polymer may be extruded or melt spun.
  • the underlying structure or substrate of an implantable medical device such as a stent can be completely or at least in part be made from a biodegradable polymer or combination of biodegradable polymers, a biostable polymer or combination of biostable polymers, or a combination of biodegradable and biostable polymers.
  • a polymer-based coating for a surface of a device can be a biodegradable polymer or combination of biodegradable polymers, a biostable polymer or combination of biostable polymers, or a combination of biodegradable and biostable polymers.
  • the coating can include any number of layer or regions such as primer layer, reservoir layer including the drugs, multiple reservoir layers each including a drug, top coat layer or any combination of these layers.
  • both the anti-proliferative and anti- inflammatory agent are included or mixed in a single reservoir layer of polymer(s).
  • a bottom reservoir layer can include the anti-proliferative and the top reservoir layer can include the anti-inflammatory agent.
  • implantable devices include artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads.
  • the device e.g., stent
  • the device can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N,” “MP20N,” ELASTINITE (Mtinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof.
  • cobalt chromium alloy ELGILOY
  • stainless steel 316L
  • high nitrogen stainless steel e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N,” “MP20N,” ELASTINITE (Mtinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or
  • MP35N and MP20N are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co., Jenkintown, PA.
  • MP35N consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum.
  • MP20N consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.
  • Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention.
  • the implantable device is a stent, which can be degradable stents, biodurable stents, depot stents, and metallic stents such as stents made of stainless steel or nitinol.
  • the anti-proliferative agent can be a natural proteineous agent such as a cytotoxin or a synthetic molecule.
  • the active agents include anti-proliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, WI 53233; or COSMEGEN available from Merck) (synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin Ii, actinomycin Xi, and actinomycin Ci), all taxoids such as taxols, docetaxel, and paclitaxel, paclitaxel derivatives, all olimus drugs such as macrolide antibiotics, rapamycin, everolimus, structural derivatives and functional analogues of rapamycin, structural derivatives and functional analogues of everolimus, FKBP- 12 mediated mTOR inhibitors,
  • the drug is rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus), 40-O-(3- hydroxy)propylrapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, and 40-O- tetrazolylrapamycin and 40-epi-(Nl-tetrazolyl)rapamycin, prodrugs thereof, co-drugs thereof, and combinations thereof.
  • rapamycin sirolimus
  • Biolimus A9 deforolimus
  • AP23572 tacrolimus
  • temsirolimus pimecrolimus
  • zotarolimus ABT-578
  • 40-O-(2-hydroxy)ethylrapamycin everolimus
  • the anti-proliferative agent is everolimus.
  • Everolimus acts by first binding to FKBP 12 to form a complex (Neuhhaus, P., et al, Liver Transpl. 2001 7(6):473-84 (2001) (Review)).
  • the everolimus /FKBP12 complex then binds to mTOR and blocks its activity (Id.). By blocking mTOR activity, cells are unable to pass through Gl of the cell cycle and as a result, proliferation is inhibited. mTOR inhibition has also been shown to inhibit vascular smooth muscle migration.
  • anti-inflammatory drugs can be a steroidal anti-inflammatory agent, a nonsteroidal antiinflammatory agent, or a combination thereof.
  • anti- inflammatory drugs include, but are not limited to, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone a
  • the anti- inflammatory agent is clobetasol.
  • Clobetasol is a corticosteroid that binds to corticosteroid receptors, a class of nuclear receptor. The binding of clobetasol to the corticosteroid receptor subsequently alters gene expression in such a way that inflammation is inhibited.
  • corticosteroids inhibit the activation of NFkB, the nuclear factor that is responsible for changes in gene expression that promote inflammation. The reduction in inflammation may also inhibit the mechanisms that promote small muscle cell (SMC) hyper proliferation.
  • SMC small muscle cell
  • dexamethasone a less potent glucocorticoid as compared to clobetasol, reduces the production of PGDF and thus has anti-proliferative properties.
  • Clobetasol acts through similar pathways and is more potent than dexamethasone.
  • the dosage or concentration of the anti-proliferative and anti- inflammatory agents required to produce a favorable therapeutic effect should be less than the level at which the bioactive agent produces toxic effects and greater than the level at which non-therapeutic results are obtained.
  • the dosage or concentration of the agents required can depend upon factors such as the particular circumstances of the patient, the nature of the trauma, the nature of the therapy desired, the time over which the ingredient administered resides at the vascular site, and if other active agents are employed, the nature and type of the substance or combination of substances.
  • Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies.
  • the bioactive agents can be incorporated into polymeric coating
  • the stent in a percent loading of between about 0.01% and less than about 100% by weight, more preferably between about 5% and about 50% by weight of the total drug- load that includes greater than about 0% to about 100% of the anti-proliferative agent and less than about 100% to greater than about 0% of the anti-inflammatory agent.
  • the relative amount of the anti-proliferative agent and anti- inflammatory agent can be determined by the type of lesions to be treated.
  • the relative amount of everolimus and clobetasol can be varied for different types of lesions, that is, the relative amount of everolimus can be higher for more proliferative lesions, and on the other hand, the relative amount of clobetasol can be higher for more inflammatory lesions.
  • the amount of everolimus (or the other listed anti-proliferative agents) carried by the stent is not less than 100 ⁇ g and the ratio of everolimus (or the other listed anti-proliferative agents) to clobetasol (or the other listed anti- inflammatory agents) is at least 10: 1 (w/w). In one embodiment the ratio is 10: 1 to 100: 1 (w/w).
  • bioactive agents can be any agent which is a therapeutic, prophylactic, or diagnostic agent.
  • agents can also have anti-proliferative and/or anti-inflammmatory properties or can have other properties such as antineoplastic, antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic, antioxidant as well as cystostatic agents.
  • suitable therapeutic and prophylactic agents include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities.
  • Nucleic acid sequences include genes, antisense molecules which bind to complementary DNA to inhibit transcription, and ribozymes.
  • Some other examples of other bioactive agents include antibodies, receptor ligands, enzymes, adhesion peptides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy.
  • antineoplastics and/or antimitotics examples include methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin ® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin ® from Bristol-Myers Squibb Co., Stamford, Conn.).
  • antiplatelets examples include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe- pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein Ilb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, thrombin inhibitors such as Angiomax a (Biogen, Inc., Cambridge, Mass.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3 -fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor ® from Merck &
  • cytostatic substance examples include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten ® and Capozide ® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil ® and Prinzide ® from Merck & Co., Inc., Whitehouse Station, NJ).
  • An example of an antiallergic agent is permirolast potassium.
  • Other therapeutic substances or agents which may be appropriate include alpha-interferon, and genetically engineered epithelial cells. The foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable.
  • compositions comprising both anti-proliferative agent and the anti-inflammatory agent can be formulated into any formulation suitable for delivery by any mode of delivery.
  • the composition can be formed into a coating on an implantable medical device to provide controlled release of the anti-proliferative agent and the antiinflammatory agent.
  • they are included in a polymeric coating on a stent.
  • the composition can also be formulated into other suitable formulations for example, bolus dose of free drug, optionally with a fluoroscopic dye, bolus dose of gel-encapsulated drug.
  • the gel can be formed of a gel- forming material or polymer such as hyaluronic acid, carboxymethyl cellulose, pectin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, polyethylene oxide, acacia, tragacanth, guar gum, xanthan gum, locust bean gum, CarbopolTM acidic carboxy polymer, polycarbophil, polyethylene oxide, poly(hydroxyalkyl methacrylate), poly(electrolyte complexes), polyvinyl acetate) cross-linked with hydrolyzable bonds, water-swellable N-vinyl lactams polysaccharides, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, arbinogla
  • the gel- forming material or polymer can be hydropropyl methylcellulose having 19-24% methoxyl substitution and 7-12% hydroxypropyl substitution and a number average molecular weight of at least 20,000.
  • Such polymers include those sold by Dow Chemical Co. under the tradenames Methocel K4M, Methocel K15M and Methocel KlOOM.
  • the anti-inflammatory drug such as clobetasol is formulated into a bolus dose of free drug with, optionally, a fluoroscopic dye.
  • the anti-proliferative drug such as everolimus can be formulated into a coating composition with a polymeric material and then coated onto an implantable device (e.g., stent).
  • the bolus dose of antiinflammatory drug is administered first and then the anti-proliferative drug is delivered by release from the implantable device such as a drug-delivery stent.
  • the composition may further include a third agent such as a HDL (high density lipoprotein)-mimic as described in U.S. Patent No. 6,367,479.
  • HDL-mimic can be delivered by the stent.
  • the anti- inflammatory drug such as clobetasol is formulated into a bolus dose of gel.
  • the anti-proliferative drug such as everolimus can be formulated into a coating composition with a polymeric material and then coated onto an implantable device.
  • the bolus dose of the anti- inflammatory drug is administered first and then the anti-proliferative drug is delivered by release from the implantable device such as a drug- delivery stent.
  • the anti-inflammatory drug and the anti-proliferative drug can be included in a polymeric matrix and then coated onto a medical device such as a stent.
  • the coating can be a single layer or include multiple layers or regions.
  • One layer or region can include the anti-proliferative drug (e.g., everolimus) and another layer or region can include the anti- inflammatory drug (e.g., clobetasol).
  • the medical device coating can be designed to have a variety of different release parameters for each of the drugs included in the coating. Methods of coating stents with drug/polymer combinations are well known in the art.
  • a drug-delivery system having a sustained release of an anti-inflammatory agent from an implanted device are described.
  • Certain embodiments of a drug-delivery system may include an effective amount of an anti-proliferative agent.
  • the drug delivery system may further include a body structure of an implantable medical device.
  • the body structure may be a substrate or scaffolding of an implantable medical device, such as stent.
  • the substrate or scaffolding may be a biostable or bioabsorbable polymer.
  • An embodiment of the drug- delivery system may further include an effective amount of a steroidal anti- inflammatory agent or a non steroidal anti- inflammatory agent within the body structure of the device.
  • An anti- inflammatory agent within a biodegradable body structure may allow for sustained release of the inflammatory agent throughout the degradation process of the body structure.
  • at least some of the anti-proliferative agent may be contained in a coating on the body structure of the device. The coating may be pure or substantially pure agent or mixed or dispersed in a biostable or bioabsorbable polymer matrix. Alternatively, at least some of the anti-proliferative agent may be delivered in some other local manner or systemically.
  • An embodiment of a method of treating restenosis or vulnerable plaque of a blood vessel may include administering to a patient an effective amount of an anti-proliferative agent (e.g., everolimus or other listed drugs) either through a coating on a device, systemically, and/or some other local method.
  • the method may further include allowing an effective amount of a steroidal anti- inflammatory agent or a non steroidal anti-inflammatory agent (e.g, clobetasol) to elute to a vessel from within a body structure the device.
  • At least a portion of the anti- inflammatory agent in at least one depot and/or anti- inflammatory agent mixed or dispersed within the body structure may elute from a surface of the body structure.
  • the anti- inflammatory agent may elute through a coating containing at least a portion of the anti-proliferative agent. In one embodiment, at least a portion of the anti- inflammatory agent may elute from the body structure and suppress inflammation of a blood vessel during all or a majority of the degradation of the body structure.
  • the properties of the coating may influence the rate of release of the anti- inflammatory agent from the device. Some embodiments may include controlling the release rate of anti-proliferative agent by modifying the properties of the coating.
  • at least a portion of the anti- inflammatory agent within the body structure may be contained in at least one depot or cavity on at least a portion of a surface of the body structure.
  • the agent in the depot may be pure or substantially pure agent.
  • the agent in the depot may be mixed or dispersed in a polymer matrix.
  • Depots may be placed at one or more arbitrary locations on a device.
  • depots may be selectively distributed at or near portions of a device that are adjacent to regions of a vessel in need of treatment for inflammation.
  • the center portion of the lesion may be more inflamed than the ends of the lesion.
  • the greater inflammation may arise from a larger concentration of degradation products closer to the center of the stent than the ends of the stent.
  • the center of the lesion may require more anti- inflammatory agent than the ends of the lesion.
  • the ends of the lesion may be more inflamed due to mechanical stresses causing irritation or injury to the ends of the lesion.
  • a stent may include depots or more depots in regions of a stent adjacent portions of a lesion having more inflammation.
  • depots may be selectively disposed on abluminal faces, luminal faces, and/or sidewalls of a stent. For example it may be desirable to have depots on abluminal faces since they may be in contact with inflamed portions of a vessel. However, depots may be placed at any location on a stent that could be clinically beneficial in treating restinosis.
  • FIG. 2 depicts a section 50 of stent 10 from FIG. 1. In section 50, depots 55 are disposed on an abluminal face 20 and depots 60 are disposed on a sidewall 30.
  • the geometrical parameters that characterize depots such as size (e.g., depth, diameter, etc.) and shape may be configured to facilitate treatment of an inflammatory response.
  • the geometry of depots may be configured to maximize sustained delivery of anti-inflammatory agent throughout the degradation of a device to counteract the inflammatory effect of degradation by-products.
  • a single depot or plurality of depots may be formed as a laser trench or laser trenches on a body of an implantable medical device such as stent 10 by exposing a surface of the device to an energy discharge from a laser, such as an excimer laser.
  • Alternative methods of forming depots include, but are not limited to physical or chemical etching techniques. Techniques of laser fabrication or etching to form depots are well-known to one of ordinary skill in the art. Depots can be formed in virtually any stent structure and not merely the above-described structure.
  • FIGs. 3A-B depict cross-sections of a strut illustrating geometries of depots.
  • depot 70 has a generally cylindrical shape.
  • Depot 70 has a depth Di and diameter D2.
  • the appropriate values for Di and D2 depend on factors such as the effective amount of agent, mechanical integrity of the strut, density of depots, and the desired time frame of release of active agent. For instance, the greater the effective amount of agent, the larger either or both depth Di and diameter D 2 may need to be.
  • a higher density of depots disposed on a strut may decrease a required amount of agent in an individual strut, and thus a necessary size of a depot.
  • the mechanical strength of the strut may decrease.
  • a diameter D 2 of cylindrical depot 70 may have a range from about 10% to about 95%, about 20% to about 80%, 30% to about 70%, or about 40% to about 60% of width W 1 .
  • FIG. 3B illustrates a depot 75 which is generally conical in shape.
  • Conical shaped depot 75 has an open end 80 and a closed end 85.
  • Open end 80 is the end that contacts a surface of a tissue since open end 80 is at ab luminal face 20.
  • a diameter D3 of conical shaped depot 75 is shown to decrease from closed end 85 to open end 80.
  • the largest diameter D 3 ' is at the closed end 85 of conical shaped depot 75.
  • D 3 ' may have a range from about 10% to about 95%, about 20% to about 80%, 30% to about 70%, or about 40% to about 60% of width Wi.
  • the smallest diameter D3" at open end 80 of conical shaped depot 75 may have a range from about 1% to about 70%, about 5% to about 70%, about 15% to about 60% of about 30% to about 50% of width Wi.
  • the reduced size of opening 80 of conical shaped depot 75, as compared to that of the cylindrical shaped depot 70, may reduce the rate at which the anti-inflammatory agent is released once the stent is implanted at the desired location of treatment.
  • the depots can have a variety of other geometrical shapes, such as elongated trenches (not illustrated).
  • the anti-inflammatory agent within the body structure may be mixed or dispersed within the body structure of the device.
  • the antiinflammatory agent mixed or dispersed within a biodegradable body structure may elute into a vessel at substantially the same rate as the body structure degrades.
  • the anti-inflammatory agent may be incorporated (mixed or dispersed) within the body structure during fabrication of the device.
  • the agent may be mixed with polymer in a molten state before, during, and/or after a fabrication process such as extrusion or injection molding.
  • the temperature of a molten polymer may be controlled to be below a degradation temperature or degradation temperature range.
  • FIGs. 4A-B depict cross-sections of struts having anti-inflammatory agent within that is below a coating 105 and 115.
  • Coating 105 and 115 may include an anti-proliferative agent.
  • a composition 100 that is pure anti-inflammatory agent or antiinflammatory agent dispersed within a polymer matrix is deposited within depot 70.
  • Anti- inflammatory agent is configured to elute through coating 105 to treat inflamed portions of vessels.
  • FIG. 4B depicts an anti- inflammatory agent 110 dispersed within the strut.
  • Antiinflammatory agent 110 is configured to elute through coating 115 to treat inflamed portions of vessels.
  • An anti-inflammatory can have one or a combination of release profiles that include a pulse release, fast or burst release, and a sustained release.
  • the anti-proliferative drug can have one or a combination of release profiles that include a pulse release, fast or burst release, and a sustained release from the stent.
  • the combination can be delivered simultaneously or at least during the drug treatment period there is at lease some overlap between the release of the drugs.
  • the anti- inflammatory can be completely released prior to the release to the anti-proliferative or can be partially released with some or significant overlap between the release of both drugs.
  • Pulse release generally refers to a release profile of a drug that features a sudden surge of the release rate of the drug. The release rate surge of the drug would then disappear within a period. A more detailed definition of the term can be found in Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., Culinary and Hospitality Industry Publications Services.
  • the term “fast release” in one embodiment refers to a release profile of a drug that features a release rate in the range between about 15 to about 40 ⁇ g per day for a 18 mm stent, about 10 ⁇ g to about 27 ⁇ g per day for a 13 mm stent, and about 6.7 ⁇ g to about 17.2 ⁇ g per day for a 8 mm stent. Equivalent profiles can be derived by one having ordinary skill in the art for stents having other sizes. In another embodiment, the term “fast release” refers to an approximately 20% release in 24 hours of a drug.
  • sustained release generally refers to a release profile of a drug that can include zero-order release, exponential decay, step-function release or other release profiles that carry over a period of time, for example, ranging from several days to several years.
  • zero-order release “exponential decay” and “step-function release” as well as other sustained release profiles are well known in the art (see, for example, Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., Culinary and Hospitality Industry Publications Services).
  • At least one of the anti-inflammatory agent (e.g., clobetasol) and anti-proliferative agent (e.g., everolimus) is administered via a stent while the other is administered by other local means of administration (e.g., coated balloon or drug delivery balloon) or alternatively, the other is administered systemically. In other embodiments, both are administered locally, by means other than a stent, or alternatively systemically.
  • Systemic administration can be accomplished orally or parenterally including intravascularly, rectally, intranasally, intrabronchially, or transdermally.
  • Liquid carriers which are sterile solutions or suspensions can be injected intramuscularly, intraperitoneally, subcutaneous Iy, and intravenously.
  • Rectal administration can be in the form of conventional suppository.
  • the drug can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
  • the drug can be administered transdermally through the used of a transdermal patch and a carrier that is inert to and mutually compatible with the active component, is non-toxic to the skin, and allows for the delivery of the drug for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams, ointments, pastes, and gels.
  • the creams and ointments may be viscous liquids or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes made of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active component may also be suitable. Other devices capable of releasing the drug into the blood stream include semi-permeable membranes covering a reservoir containing the drug, with or without a carrier.
  • Local administration can be accomplished by a variety of techniques which administer the active component at or near the target site.
  • local administration is by a stent.
  • the following examples of local delivery techniques are provided for illustrative purposes and are not intended to be limiting. Examples include local delivery catheters, site specific carriers, particles, implants, direct application, or direct injection. Local delivery by a catheter allows for the administration of the drug directly to the target site.
  • Local delivery by site specific carriers is conducted by attaching the drug to a carrier which will direct or link the drug to the target cells.
  • a carrier such as a protein ligand, a monoclonal antibody or a membrane anchored linker.
  • Local delivery by an implant is the placement of a matrix carrying the drug at the site.
  • the matrix can release the active component by, for example, diffusion, degradation, chemical reaction, solvent activators, etc.
  • One example of local delivery by an implant can include direct injection of vesicles or micro-particles. These micro-particles may be composed of substances such as proteins, lipids, carbohydrates or synthetic polymers. The micro-particles can have the drug impregnated therein and/or coated thereon.
  • Application via implants is not limited to the above described routes and other techniques such as grafts, micropumps or application of a fibrin glue or hydrogel containing the active component around the exterior of a designated region of the vessel can also be implemented by one of ordinary skill in the art.
  • liquid carrier containing the drug directly into the site.
  • the liquid carrier should be inert to and mutually compatible with the drug.
  • the component can be in true solution or suspended in fine particles in the carrier.
  • a suitable example of an inert carrier includes a sterile saline solution.
  • polymers can be biostable, bioabsorbable, biodegradable, or bioerodable.
  • Biostable refers to polymers that are not biodegradable.
  • biodegradable, bioabsorbable, and bioerodable, as well as degraded, eroded, and absorbed are used interchangeably and refer to polymers that are capable of being completely eroded or absorbed when exposed to bodily fluids such as blood and can be gradually resorbed, absorbed and/or eliminated by the body.
  • polymers that may be used to fabricate an implantable medical device, to coat an implantable medical device, or to provide a drug delivery particle with the anti-proliferative drug and/or anti-inflammatory drug include, but are not limited to, poly(N-acetylglucosamine) (Chitin), Chitosan, poly(3 -hydroxyvalerate), poly(lactide-co- glycolide), poly(3 -hydroxybutyrate), poly(4-hydroxybutyrate), poly(3 -hydroxybutyrate-co- 3-hydroxyvalerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide), poly(L- lactide-co-D,L-lactide), poly(caprolactone), poly(L-lactide-co-caprolactone), poly(D,L- lactide-co-caprolactone
  • PEO/PLA polyphosphazenes
  • biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid
  • polyurethanes silicones
  • polyesters polyolefins, polyisobutylene and ethylene-alphaolefin copolymers
  • acrylic polymers and copolymers other than polyacrylates vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidene halides (such as polyvinylidene chloride), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters (such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon 66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,
  • polymers that may be especially well suited for use in fabricating embodiments of implantable medical devices disclosed herein include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOH or by the trade name EVAL), poly(butyl methacrylate), poly(vinylidene fluoride-co- hexafluoropropene) (e.g., SOLEF 21508, available from Solvay Solexis PVDF, Thorofare, NJ), polyvinylidene fluoride (otherwise known as KYNAR, available from ATOFINA Chemicals, Philadelphia, PA), ethylene-vinyl acetate copolymers, poly(vinyl acetate), styrene-isobutylene-styrene triblock copolymers, and polyethylene glycol.
  • EVAL ethylene vinyl alcohol copolymer
  • poly(butyl methacrylate) poly(vinylidene fluoride-co- hexafluoropropene)
  • the coating described herein can be formed by spray coating or any other coating process available in the art, such as dipping.
  • the coating involves dissolving or suspending the composition (e.g. polymer and drug), or one or more components thereof, in a solvent or solvent mixture to form a solution, suspension, or dispersion of the composition or one or more components thereof, applying the solution or suspension to an implantable device, and removing the solvent or solvent mixture to form a coating or a layer of coating.
  • Suspensions or dispersions of the composition described herein can be in the form of latex or emulsion of microparticles having a size between 1 nanometer and 100 microns, preferably between 1 nanometer and 10 microns.
  • Heat and/or pressure treatment can be applied to any of the steps involved herein.
  • the coating described here can be subjected to further heat and/or pressure treatment.
  • Some additional exemplary processes of coating an implantable device that may be used are described in, for example, Lambert TL, et al. Circulation, 1994, 90: 1003-1011; Hwang CW, et al. Circulation, 2001; 104: 600-605; Van der Giessen WJ, et al. Circulation, 1996; 94: 1690-1697; Lincoff AM, et al. J Am Coll Cardiol 1997; 29: 808-816; Grube E.
  • solvent refers to a liquid substance or composition that is compatible with the polymer and is capable of dissolving or suspending the polymeric composition or one or more components thereof at a desired concentration.
  • solvents include chloroform, acetone, water (buffered saline), dimethylsulfoxide (DMSO), propylene glycol monomethyl ether (PM,) iso-propylalcohol (IPA), n-propyl alcohol, methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide (DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane, nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol, 2-butanone, cyclohexanone, dioxane, methylene chloride, carbon tetrachloride, tetrachloroethylene, te
  • a coating of the various described embodiments can be formed on an implantable device or prosthesis, e.g., a stent.
  • the agent will be retained on the medical device such as a stent during delivery and expansion of the device, and released at a desired rate and for a predetermined duration of time at the site of implantation.
  • the medical device is a stent.
  • a stent having the above-described coating is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways.
  • a stent having the above-described coating is particularly useful for treating occluded regions of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis.
  • Stents may be placed in a wide array of blood vessels, both arteries and veins. Representative examples of sites include the iliac, renal, and coronary arteries.
  • an angiogram is first performed to determine the appropriate positioning for stent therapy.
  • An angiogram is typically accomplished by injecting a radiopaque contrasting agent through a catheter inserted into an artery or vein as an x-ray is taken.
  • a guidewire is then advanced through the lesion or proposed site of treatment.
  • Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway.
  • the delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance.
  • a stent having the above- described coating may then be expanded at the desired area of treatment.
  • a post- insertion angiogram may also be utilized to confirm appropriate positioning.
  • the implantable device comprising a coating described herein can be used to treat an animal having a condition or disorder that requires a treatment.
  • Such an animal can be treated by, for example, implanting a device described herein in the animal.
  • the animal is a human being.
  • Exemplary disorders or conditions that can be treated by the method disclosed herein include, but not limited to, thrombosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, restenosis and progression of atherosclerosis in patient subsets including type I diabetics, type II diabetics, metabolic syndrome and syndrome X, vulnerable lesions including those with thin-capped fibroatheromatous lesions, systemic infections including gingivitis, hellobacteria, and cytomegalovirus, and combinations thereof.
  • EXAMPLES EXAMPLES
  • Example 1 Porcine implant study Described in this example is a 28 day porcine implant study that compared the 200 ⁇ g/cm 2 dose stent Lemans (a stent based on PVDF-co-HFP) with a clobetasol-only delivery stent, an everolimus-only stent, and an everolimus-clobetasol combination drug delivery stent. The study was performed using three different drug delivery stents, Arm 1, Arm 2, and Arm 3. Arm 1 is a Lemans stent that included 105 ⁇ g everolimus and used as a control. Arm 2 was loaded with 185 ⁇ g clobetasol only, with no everolimus. Arm 3 is loaded with 105 ⁇ g everolimus and 80 ⁇ g clobetasol.
  • stent Lemans a stent based on PVDF-co-HFP
  • Arm 1 is a Lemans stent that included 105 ⁇ g everolimus and used as a control.
  • Arm 2
  • Overstretch model refers to the technique of over-expanding the animal arteries by up to 30% (using the stent and balloon) over their natural diameter so that the stent is more likely to cause injury and thus greater restenosis. This sometimes helps differentiate between efficacy of various stent systems.
  • the release rate data are shown in Table 2. As can be seen from Table 2, a coating based on SolefTM is capable of simultaneous release of both everolimus and clobetasol. Table 2. Release rate data
  • Neointimal Area is the total amount of neointima as measured by a cross-sectional vessel section. This is essentially the area inside the Internal Elastic Lamina (IEL) minus the total area of the vessel lumen.
  • Neointima refers to the new intimal growth that forms after stenting which resides between the IEL and the vessel lumen.
  • Neointimal Thickness is the average distance between the IEL and the lumen. This is essentially the average thickness of the new intima that grows inside the stent after stenting.
  • Trauma Injury Score is a standardized scoring system that scores the amount of injury created in the vessel by the stent implantation. Currently, we use a range of 0 to 4 where 0 is no injury and 4 is the highest injury. There are specific quantitative and qualitative criteria for assigning a given score to a vessel. Table 3. 28 Day morphometry data from FIG. 7
  • the p values from a t-test of the data from FIG. 7 are summarized in Table 4.
  • a "t-test” returns the probability associated with a Student's t-Test that determines whether two samples are likely to have come from the same two underlying populations that have the same mean.
  • the value returned from the test, "p" is the probability that the two groups of data come from the same population, p Values less than or equal to 0.10 or 0.05 are generally considered significant (Zar, JH. Biostatistical Analysis. Englewood Cliffs, NJ: Prentice-Hall Inc, 1974. pp 101-108).
  • Described in this example is a 28 day porcine implant study that compared an everolimus-only stent, an everolimus-clobetasol combination drug delivery stent, and a clobetasol-only stent.
  • the drugs were dispersed in a Solef polymer matrix, available from Solvay Solexis PVDF, Thorofare, NJ.
  • the study was performed using three different drug delivery stents, Arm 1, Arm 2, and Arm 3.
  • Arm 1 is Lemans stent (a stent based on PVDF -co- HFP coating) that included 64 ⁇ g everolimus with a drug-polymer ratio of 1 :4.9, which was used as a control.
  • Arm 2 is loaded with 64 ⁇ g everolimus and 32 ⁇ g clobetasol with a drug- polymer ratio of 1 :4.
  • Arm 3 was loaded with 32 ⁇ g clobetasol only with a drug-ratio of 1 :4, with no everolimus.
  • Table 5 shows the coating design of the stents used in this study. The Arm 1, Arm 2, and Arm 3 stents were implanted in a 30% overstretch model.
  • the release rate data are shown in Table 6. As can be seen from Table 6, a coating based on SolefTM is capable of simultaneous release of both everolimus and clobetasol. Table 6. Release rate data
  • Clobetasol is non-toxic even at the highest concentrations typically tested in cell culture (10 ⁇ 6 M).
  • FIG. 9 depicts a proliferation assay that shows a dose dependent inhibition of vascular smooth muscle proliferation and a low EC50 value of 3 x 10 "11 M. The Efficacy of the drug is 25%.
  • a proliferation assay is a cell culture assay in which smooth muscle cells are exposed to various concentrations of a given drug.
  • the y-axis is a measure of the total number of DNA strands or cell nuclei. If cells are dividing (proliferating), the amount of DNA increases.
  • EC50 is the concentration of drug that causes half the total effect. For example, if the greatest amount of proliferation reduction is 60% reduction as compared to no drug, then the EC50 is the concentration of drug that causes a 30% reduction in proliferation. Efficacy refers to the effectiveness of the drug in preventing proliferation of smooth muscle cells.
  • FIG. 10 depicts a proliferation assay with everolimus only, which also shows inhibition of vascular smooth muscle proliferation.
  • the efficacy of the drug is 62%.
  • FIG. 11 depicts results of a proliferation assay with varying ratios of everolimus and clobetasol.
  • FIG. 11 illustrates a plot of the efficacy of inhibition of vascular smooth muscle proliferation versus the logarithm of the everolimus- clobetasol ratio.
  • the circled portion of the curve in FIG. 11 shows that everolimus and clobetasol have a synergistic effect that results in a higher efficacy within a range of the ratio of the two drugs.
  • Two safety studies, one 28-day and one 90-day were designed to include three arms: 100 ⁇ g everolimus alone; 100 ⁇ g everolimus: 10 ⁇ g clobetasol (100: 10) and 100 ⁇ g everolimus: 1 ⁇ g clobetasol (100: 1).
  • the 28-day study showed a 32.7 + 12.0% in-stent stenosis rate in everolimus arm, 17.9 + 5.0% in the 100: 10 arm, and 16.9 + 5.9% in the 100: 1 arm.
  • the in-stent stenosis rates were 45.2 + 21.5%, 14.2 + 7.9% and 16.1 + 8.6% in the everolimus 100, 100: 10 and 100: 1, respectively.
  • the data show that both doses of combination drug significantly (p ⁇ 0.05) reduced % stenosis versus everolimus 100 at both 28 and 90 days post implant. Evaluation via light microscopy and SEM at 28 days revealed that low dose (100:1) had near complete re-endothelialization, which was comparable to everolimus alone.

Abstract

A drug-delivery system is provided including at least 100 μg of everolimus and clobetasol, such that the ratio of everolimus to clobetasol is at least 10:1 (w/w) or the amount of everolimus by weight is at least 10 times more than clobetasol. The system can be a stent. Also provided a method of treating restenosis or vulnerable plaque of a blood vessel, the method includes locally administering to a patient a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2- hydroxy)ethylrapamycin (everolimus), 40-O-(3-hydroxy)propylrapamycin, 40-O-[2-(2- hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and 40-epi-(N1 - tetrazolyl)rapamycin, and locally administering to a patient a second drug consisting of clobetasol, wherein the minimum amount of the first drug that is locally administered is 100 μg, and wherein the ratio of the first drug to the second drug is, for example, 10:1 to 100:1 (w/w).

Description

ANTI-PROLIFERATIVE AND ANTI-INFLAMMATORY AGENT COMBINATION FOR TREATMENT OF VASCULAR DISORDERS WITH AN IMPLANTABLE
MEDICAL DEVICE
BACKGROUND OF THE INVENTION Field of the Invention
This invention generally relates to a drug combination including an anti-proliferative drug such as everolimus and an anti-inflammatory agent such as clobetasol for the treatment of a disorder such as restenosis and vulnerable plaque. Description of the Background
Plaques have been associated with stenosis and restenosis. While treatments of plaque-induced stenosis and restenosis have advanced significantly over the last few decades, the morbidity and mortality associated with vascular plaques have remained significant. Recent work suggests that plaque may generally fall into one of two different general types: standard stenotic plaques and vulnerable plaques. Stenotic plaque, which is sometimes referred to as thrombosis-resistant plaque, can generally be treated effectively by the known intravascular lumen opening techniques. Although plaques induce stenoses, these atherosclerotic plaques themselves are often benign and are an effectively treatable disease. Unfortunately, as plaque matures, narrowing of a blood vessel by a proliferation of smooth muscle cells, matrix synthesis, and lipid accumulation may result in formation of a plaque which is quite different than a standard stenotic plaque. Such atherosclerotic plaque becomes thrombosis-prone, and can be highly dangerous. This thrombosis-prone or vulnerable plaque may be a frequent cause of acute coronary syndrome. While the known procedures for treating plaque have gained wide acceptance and have shown good efficacy for treatment of standard stenotic plaques, they may be ineffective (and possibly dangerous) when thrombotic conditions are superimposed on atherosclerotic plaques. Specifically, mechanical stresses caused by primary treatments like percutaneous transluminal intervention (PTI), such as stenting, may actually trigger release of fluids and/or solids from a vulnerable plaque into the blood stream, thereby potentially causing a coronary thrombotic occlusion. For example, rupture of the fibrous cap that overlies the thrombogenic necrotic core is presently believed to play an important role in acute ischemic events, such as stroke, transient ischemic attack, myocardial infarction, and unstable angina (Virmani R, et al. Arterioscler Thromb Vase Biol. 20: 1262-1275 (2000)). There is evidence that fibrous cap can be ruptured during stent deployment. Human data from various sources have indicated that lipid rich and/or positively remodeled and/or echolucent lesions in sysmptomatic coronary atherosclerosis have higher likelihood for restenosis (See, for example, J. Am. Coll. Cardiol. 21(2):298-307 (1993); Am. J. Cardiol. 89(5):505 (2002); Circ. 94(12):3098-102 (1996)). Therefore, there is a need for the treatment of vulnerable plaques and restenosis.
Furthermore, it may be desirable for PTI treatments to employ biodegradable implantable medical devices. In many treatment applications, the presence of a stent in a body may be necessary for a limited period of time until its intended function of, for example, maintaining vascular patency and/or drug delivery is accomplished. Therefore, stents fabricated from biodegradable, bioabsorbable, and/or bioerodable materials such as bioabsorbable polymers should be configured to completely erode only after the clinical need for them has ended.
However, one of the major clinical challenges of bioabsorbable stents is adequately suppressing acute or chronic inflammatory responses triggered by the degradation of the stent. The vascular response to a fully bioabsorbable stent can be much different than that of a metal or polymer coated stent. Anti-proliferative drugs are often sufficient to reduce neointimal formation, but do not have the ability to adequately suppress inflammation. This is reflected by the large number of granulomas often seen in chronic porcine studies with drug eluting stents.
The embodiments of the present invention address these and other needs.
SUMMARY OF THE INVENTION
In accordance with one aspect of the invention a drug-delivery device, system or platform is provided, comprising at least 100 μg of everolimus and clobetasol, such that the ratio of everolimus to clobetasol is at least 10: 1 (w/w) or the amount of everolimus by weight is at least 10 times more than clobetasol. In one embodiment the system is a stent. For example, the system can be a polymeric coated stent, such that the everolimus and clobetasol are in the polymeric coating. The coating can include 2 layers or regions such that the everolimus is in one layer or region and the clobetasol is in another layer or region. The drugs can be released in sequence, simultaneously or a combination of both. For example the drug release profile can include at least a period of overlapping or simultaneous release profile of the everolimus and clobetasol. The ratio of the everolimus to the clobetasol can be 10: 1 to 100: 1 (w/w). In accordance with another aspect of the invention a stent is provided, comprising a radially expandable body and a combination of (a) a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus), 40-O-(3-hydroxy)propylrapamycin, 40-O-[2-(2- hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and 40-epi-(Nl- tetrazolyl)rapamycin, and (b) a second drug consisting of clobetasol, carried by the stent, wherein the minimum amount of the first drug carried by the stent is 100 μg, and wherein the ratio of the first drug to the second drug is 10: 1 to 100: 1 (w/w). The stent can include a coating carrying the first and second drugs. The coating can include at least two layers such that the first drug is in one layer and the second drug is in another layer. The stent can be polymeric, metallic or combination of both. In some embodiments at least one of the drugs is in the body of the stent and at least one of the drugs is in a coating disposed over the surface of the stent.
In accordance with another aspect of the invention a method of treating restenosis or vulnerable plaque of a blood vessel is provided, comprising locally administering to a patient a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2 -hydro xy)ethylrapamycin (everolimus), 40-O-(3 -hydro xy)propylrapamycin, 40-O- [2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and 40-epi-(Nl- tetrazolyl)rapamycin, and locally administering to the patient a second drug consisting of clobetasol, wherein the minimum amount of the first drug that is locally administered is 100 μg, and wherein the ratio of the first drug to the second drug is at least 10: 1 (w/w). The ratio of the first drug to the second drug can be 10: 1 to 100: 1 (w/w). In some embodiments, local administration is by a stent such as a polymer coated stent or a bioabsorbable stent.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 depicts an illustration of a stent.
FIG. 2 depicts an illustration of a section of a stent.
FIGs. 3A-B depict cross-sections of a strut illustrating geometries of depots. FIGs. 4A-B depicts cross-sections of a strut with a coating. Figure 5 shows the results of 28 day quantitative coronary angioplasty (QCA) of a porcine implant study on drug-delivery systems described herein.
Figure 6 shows 28 day histology data of a porcine implant study on drug-delivery systems described herein. Figure 7 shows the 28 day morphometry data of a porcine implant study on drug-delivery systems described herein.
FIG. 8 shows the results of 28 day quantitative coronary angioplasty (QCA) of a porcine implant study on drug-delivery systems described herein.
FIG. 9 depicts a proliferation assay that shows a dose dependent inhibition of vascular smooth muscle proliferation.
FIG. 10 depicts a proliferation assay with everolimus which also shows inhibition of vascular smooth muscle proliferation.
FIG. 11 depicts results of a proliferation assay with varying ratios of everolimus and clobetasol.
DETAILED DESCRIPTION
Anti-proliferative Agents and Anti-inflammatory Agents In accordance with one embodiment, described herein are drug-delivery systems, devices or platforms and methods of using the drug-delivery systems, devices or platforms for the treatment of a vascular disorder. The term "treatment" includes prevention, reduction, delay or elimination of the vascular disorder. In some embodiments, treatment also includes repairing damage caused by the disorder and/or the mechanical intervention
(e.g., stenting, balloon dilation, etc.). The drug-delivery system has two or more drugs for treating a vascular disorder or a related disorder. The drugs can be a combination of at least one anti-proliferative agent, at least one anti-inflammatory agent, and optionally a third bioactive agent. In one embodiment, the drug-delivery system consists only of two drugs, an anti-proliferative agent and an anti- inflammatory agent. In one embodiment, the drugs can include or only consist of everolimus and clobetasol. Everolimus is available under the trade name Certican™, Novartis Pharma AG, Germany and clobetasol is available under the trade name Temovate™, Glaxosmithkline, UK. The amount of the anti-proliferative agent or everolimus included or carried by the system can be at least 100 μg and the ratio of the anti-proliferative agent or everolimus to the anti-inflammatory agent or clobetasol can be at least 10: 1 (w/w). In one preferred embodiment, the ratio is 10: 1 to 100: 1 (w/w).
In a preferred embodiment, the system includes a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus), 40-O-(3-hydroxy)propylrapamycin, 40-O-[2-(2- hydroxy)ethoxy]ethylrapamycin, 40-O-tetrazolylrapamycin and 40-epi-(Nl- tetrazolyl)rapamycin, and a second drug consisting of clobetasol. The minimum amount of the first drug carried by the system (e.g., stent) is 100 μg and the ratio of the first drug to the second drug is 10: 1 to 100: 1 (w/w). In one preferred embodiment, the system consists solely of the first and second drug combination with no other drugs present.
In one embodiment, a medical composition, such as in a liquid carrier, is described including an effective amount of at least one anti- inflammatory agent and an effective amount of an anti-proliferative agent. In another embodiment, the composition described herein includes an effective amount of an agent which is effective both as an antiinflammatory agent and as an anti-proliferative agent. The composition can, for example, be administered orally, intravenously, or formed into a coating for an implantable medical device such as a stent or a balloon of a catheter. The anti-proliferative agent can be everolimus or others described herein, and the anti-inflammatory agent can be clobetasol. The anti-proliferative agent and the anti- inflammatory agent can be in the form of a coating with or without a polymer matrix on a medical device (e.g., stent) or at least one of the agents can be administered in a separate dose form such as bolus dose of a free drug, optionally with fluoroscopic dye, or bolus dose of a gel encapsulating the drug. The drug- delivery system or composition may further include a third agent such as a high-density lipoproptein mimetic (HDL-mimetic). For example, an anti-inflammatory agent such as clobetasol can be delivered along with the catheter based delivery of a HDL-mimetic while everolimus is administered by a stent.
The drug-delivery system or composition disclosed herein can be used to treat a disorder such as thrombosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, restenosis and progression of atherosclerosis in patient subsets including type I diabetics, type II diabetics, metabolic syndrome and syndrome X, vulnerable lesions including those with thin-capped fibroatheromatous lesions, systemic infections including gingivitis, hellobacteria, and cytomegalovirus, and combinations thereof.
Inflammation in stenting a vessel
A common disorder in association with mechanical modification of a vessel, such as by a balloon or stenting is restenosis. A number of cellular mechanisms have been proposed that lead to restenosis of a vessel. Two of these mechanisms are (1) the migration and proliferation of smooth muscle cells to and at the site of injury, and (2) the acute and chronic inflammatory response to injury and foreign body presence.
Inflammation is a defensive, biological response to injury, infection or an abrupt change in tissue homeostasis. Inflammation can occur anywhere in the body, and most of the time is confined to that part of the body. Well-known indicators of inflammation are pain, redness, warmth, swelling, and loss of function. In nature, inflammatory responses are designed to destroy, dilute and isolate injurious agents and then lead to recovery and repair of the affected tissue. The intensity of an inflammatory response can vary from one that is self-limiting, which requires minor therapeutic intervention, to one that is life threatening, which requires intense intervention. One drawback of the inflammatory process is its ability to become progressive, meaning tissue damage continues after the stimulus is neutralized or removed.
Vascular inflammation is the first stage of the inflammatory response, developing after the initial contact with the stimulus and continuing sometimes for several days. The presence of a stimulatory agent in the blood or in the tissue triggers the body's response through endothelial cells. The endothelial cell layer is the innermost layer of larger vessels and the only cell layer of the smallest vessels, the capillaries. Endothelial cells produce substances called chemokines that attract neutrophils and other white blood cells to the site of injury. Within the site, neutrophils and endothelium relay information back and forth across cell membranes through presentation of adhesion molecules and cytokines. Cellular cross-talk promotes physical interaction between the "inflamed" neutrophil and the "inflamed" endothelium.
Additionally, the presence of a biodegradable foreign body, such as a biodegradable implantable medical device (e.g., a stent), in a vessel can lead to or aggravate an inflammatory response, thus leading to a more aggressive restenotic process. Biodegradation refers generally to changes in physical and chemical properties that occur (e.g., in a polymer) upon exposure to bodily fluids as in a vascular environment. The changes in properties may include a decrease in molecular weight, deterioration of mechanical properties, and decrease in mass due to erosion or absorption. The decrease in molecular weight may be caused by chemical reactions of bodily fluids with the polymer, for example, hydrolysis and/or metabolic processes. By-products of such degradation reactions can be responsible for inciting inflammation. For example, by-products of hydrolysis are produced when polymer molecules are cleaved into component parts by the addition of water. Various byproducts of degradation of biodegradable polymers are known to incite an inflammatory response. For example, lactic acid, a degradation by-product of poly(lactic acid) polymers, is known to cause an inflammatory response.
Furthermore, the release of by-products into the body from a biodegradable device occurs continuously from the time of first exposure to bodily fluids to a time when the device is either completely degraded and eliminated or removed from the body. It follows that throughout this time frame, the body is continuously exposed to inflammation-inciting by-products. Therefore, in some embodiments, it is desirable to have a sustained release of an anti-inflammatory agent from a degrading implanted device throughout this time frame.
Another important pathological feature of vascular inflammation is endothelial cell swelling. This action reduces the functional vessel diameter such that the speed of blood flow falls significantly and the vessel becomes congested. When these conditions predominate, inflamed neutrophils are induced to plug the vessel. As a result, endothelial cells lose their tight connections allowing neutrophils to transmigrate into the surrounding tissue. Within hours of the initial stimulus, neutrophils begin to enter the tissue and may continue transmigration for many days. The appearance of inflammatory cells in the surrounding tissue marks the beginning of tissue damage. In some inflammatory conditions, tissue damage is caused by direct injury of the vessels and amplified by the subsequent recruitment of neutrophils into the tissue. Activated by local mediators, neutrophils and tissue macrophages are triggered to release agents that destroy toxins and clean up dead cells in the area. Unfortunately, these same agents also cause collateral damage to healthy cells, which further extends the borders of the initial tissue destruction. Tissue repair is the third and final stage of inflammation. It may take several days for tissue destruction to reach full intensity before tapering off. Until then, the tissue repair process that consists of growth of new blood vessels and entry of monocytes to clean up the debris is delayed. Fibroblasts also enter the local tissue to replace the extracellular matrix and collagen. The process of tissue repair is stringently controlled within the tissue site. If the process becomes dysregulated, inappropriate tissue repair will lead to excessive scarring. Depending on the tissue and the intensity/duration of the inflammatory condition, the amount of scarring can be significant.
An example of disorders that vessel inflammation is involved is vulnerable plaque (VP) rupture. Previous studies have demonstrated that inflammation promotes proliferation at sites of balloon angioplasty and stent placement in pigs (Kornowski, et al, Coron Artery Dis. 12(6):513-5 (2001)). Since sites of vulnerable plaque have a higher density of macrophages and lymphocytes than other types of atherosclerotic lesions, it is expected that these sites, when stented, will produce elevated amounts of the cytokines (IL- 1 , TNF-alpha) that promote smooth muscle cell proliferation. Another example of disorders that vessel inflammation is involved is diabetes.
Studies have shown that patients with type-2 diabetes have higher rates of restenosis than the general population. The diabetic patient is in pro-inflammatory state that can amplify restenosis because diabetic lesions contain a large number of inflammatory cells (e.g., macrophages, lymphocytes, etc.). Implantable Medical Devices
The system, device or platform of the present invention can be a medical device, preferably an implantable medical device. The term "implantable medical device" is intended to include self-expandable stents, balloon-expandable stents, stent-grafts, and grafts. An implantable medical device also includes a body structure, substrate, or scaffolding for medical use that can be permanently or temporarily implanted in a subject. The structure of the device can be of virtually any design. A stent, for example, may include a pattern or network of interconnecting structural elements or struts. FIG. 1 depicts an example of a three-dimensional view of a stent 10. The stent may have a pattern that includes a number of interconnecting elements or struts 15. The embodiments disclosed herein are not limited to stents or to the stent pattern illustrated in FIG. 1. For example, the cross-section of a strut may be rectangular, (as pictured in Fig. 1), circular, oval, etc. The struts of the stent in FIG. 1 may further be described as having abluminal (outer) faces 20, luminal (inner) faces 25, and sidewalls 30. The embodiments are easily applicable to other patterns and other devices. In general, the variations in the structure of patterns are virtually unlimited. As shown in FIG. 1 the geometry or shape of stents vary throughout its structure.
In some embodiments, a stent may be formed from a tube by laser cutting the pattern of struts into the tube. The stent may also be formed by laser cutting a polymeric or metallic sheet, rolling the pattern into the shape of the cylindrical stent, and providing a longitudinal weld to form the stent. Other methods of forming stents are well known and include chemically etching a sheet and rolling and then welding it to form the stent. A polymeric or metallic wire may also be coiled to form the stent. The stent may be formed by injection molding of a thermoplastic or reaction injection molding of a thermoset polymeric material. Filaments of the compounded polymer may be extruded or melt spun. These filaments can then be cut, formed into ring elements, welded closed, corrugated to form crowns, and then the crowns welded together by heat or solvent to form the stent. Lastly, hoops or rings may be cut from tubing stock, the tube elements stamped to form crowns, and the crowns connected by welding or laser fusion to form the stent. The underlying structure or substrate of an implantable medical device, such as a stent can be completely or at least in part be made from a biodegradable polymer or combination of biodegradable polymers, a biostable polymer or combination of biostable polymers, or a combination of biodegradable and biostable polymers.
Additionally, a polymer-based coating for a surface of a device can be a biodegradable polymer or combination of biodegradable polymers, a biostable polymer or combination of biostable polymers, or a combination of biodegradable and biostable polymers. The coating can include any number of layer or regions such as primer layer, reservoir layer including the drugs, multiple reservoir layers each including a drug, top coat layer or any combination of these layers. In one embodiment, both the anti-proliferative and anti- inflammatory agent are included or mixed in a single reservoir layer of polymer(s). In another embodiment, a bottom reservoir layer can include the anti-proliferative and the top reservoir layer can include the anti-inflammatory agent.
Examples of other implantable devices include artificial heart valves, cerebrospinal fluid shunts, pacemaker electrodes, and endocardial leads. The device (e.g., stent) can be made of a metallic material or an alloy such as, but not limited to, cobalt chromium alloy (ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, "MP35N," "MP20N," ELASTINITE (Mtinol), tantalum, nickel-titanium alloy, platinum-iridium alloy, gold, magnesium, or combinations thereof. "MP35N" and "MP20N" are trade names for alloys of cobalt, nickel, chromium and molybdenum available from Standard Press Steel Co., Jenkintown, PA. "MP35N" consists of 35% cobalt, 35% nickel, 20% chromium, and 10% molybdenum. "MP20N" consists of 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum. Devices made from bioabsorbable or biostable polymers could also be used with the embodiments of the present invention. In one embodiment, the implantable device is a stent, which can be degradable stents, biodurable stents, depot stents, and metallic stents such as stents made of stainless steel or nitinol.
Anti-Proliferative Agents
Any drugs having anti-proliferative effects can be used in the present invention. The anti-proliferative agent can be a natural proteineous agent such as a cytotoxin or a synthetic molecule. The active agents include anti-proliferative substances such as actinomycin D, or derivatives and analogs thereof (manufactured by Sigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, WI 53233; or COSMEGEN available from Merck) (synonyms of actinomycin D include dactinomycin, actinomycin IV, actinomycin Ii, actinomycin Xi, and actinomycin Ci), all taxoids such as taxols, docetaxel, and paclitaxel, paclitaxel derivatives, all olimus drugs such as macrolide antibiotics, rapamycin, everolimus, structural derivatives and functional analogues of rapamycin, structural derivatives and functional analogues of everolimus, FKBP- 12 mediated mTOR inhibitors, biolimus, perfenidone, prodrugs thereof, co-drugs thereof, and combinations thereof. Preferably the drug is rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2-hydroxy)ethylrapamycin (everolimus), 40-O-(3- hydroxy)propylrapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, and 40-O- tetrazolylrapamycin and 40-epi-(Nl-tetrazolyl)rapamycin, prodrugs thereof, co-drugs thereof, and combinations thereof.
In one embodiment, the anti-proliferative agent is everolimus. Everolimus acts by first binding to FKBP 12 to form a complex (Neuhhaus, P., et al, Liver Transpl. 2001 7(6):473-84 (2001) (Review)). The everolimus /FKBP12 complex then binds to mTOR and blocks its activity (Id.). By blocking mTOR activity, cells are unable to pass through Gl of the cell cycle and as a result, proliferation is inhibited. mTOR inhibition has also been shown to inhibit vascular smooth muscle migration. Anti-inflammatory Agents
Any drugs having anti-inflammatory effects can be used in the present invention. The anti- inflammatory drug can be a steroidal anti-inflammatory agent, a nonsteroidal antiinflammatory agent, or a combination thereof. In some embodiments, anti- inflammatory drugs include, but are not limited to, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, deflazacort, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate, momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylic acid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus, pimecorlimus, prodrugs thereof, co-drugs thereof, and combinations thereof.
In one embodiment, the anti- inflammatory agent is clobetasol. Clobetasol is a corticosteroid that binds to corticosteroid receptors, a class of nuclear receptor. The binding of clobetasol to the corticosteroid receptor subsequently alters gene expression in such a way that inflammation is inhibited. For example, corticosteroids inhibit the activation of NFkB, the nuclear factor that is responsible for changes in gene expression that promote inflammation. The reduction in inflammation may also inhibit the mechanisms that promote small muscle cell (SMC) hyper proliferation. This is shown in that dexamethasone, a less potent glucocorticoid as compared to clobetasol, reduces the production of PGDF and thus has anti-proliferative properties. Clobetasol acts through similar pathways and is more potent than dexamethasone.
Dosage The dosage or concentration of the anti-proliferative and anti- inflammatory agents required to produce a favorable therapeutic effect should be less than the level at which the bioactive agent produces toxic effects and greater than the level at which non-therapeutic results are obtained. The dosage or concentration of the agents required can depend upon factors such as the particular circumstances of the patient, the nature of the trauma, the nature of the therapy desired, the time over which the ingredient administered resides at the vascular site, and if other active agents are employed, the nature and type of the substance or combination of substances. Therapeutic effective dosages can be determined empirically, for example by infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the agent and its effects, or by conducting suitable in vitro studies. In one embodiment, the bioactive agents can be incorporated into polymeric coating
(e.g., of the stent) in a percent loading of between about 0.01% and less than about 100% by weight, more preferably between about 5% and about 50% by weight of the total drug- load that includes greater than about 0% to about 100% of the anti-proliferative agent and less than about 100% to greater than about 0% of the anti-inflammatory agent. The relative amount of the anti-proliferative agent and anti- inflammatory agent can be determined by the type of lesions to be treated. For example, where everolimus is used as the anti-proliferative agent and clobetasol is used as the anti- inflammatory agent, the relative amount of everolimus and clobetasol can be varied for different types of lesions, that is, the relative amount of everolimus can be higher for more proliferative lesions, and on the other hand, the relative amount of clobetasol can be higher for more inflammatory lesions.
Preferably the amount of everolimus (or the other listed anti-proliferative agents) carried by the stent is not less than 100 μg and the ratio of everolimus (or the other listed anti-proliferative agents) to clobetasol (or the other listed anti- inflammatory agents) is at least 10: 1 (w/w). In one embodiment the ratio is 10: 1 to 100: 1 (w/w). Other Bioactive Agents
In some embodiments, other agents can be used in combination with the antiproliferative agent and the anti-inflammatory agent. These bioactive agents can be any agent which is a therapeutic, prophylactic, or diagnostic agent. These agents can also have anti-proliferative and/or anti-inflammmatory properties or can have other properties such as antineoplastic, antiplatelet, anti-coagulant, anti-fibrin, antithrombonic, antimitotic, antibiotic, antiallergic, antioxidant as well as cystostatic agents. Examples of suitable therapeutic and prophylactic agents include synthetic inorganic and organic compounds, proteins and peptides, polysaccharides and other sugars, lipids, and DNA and RNA nucleic acid sequences having therapeutic, prophylactic or diagnostic activities. Nucleic acid sequences include genes, antisense molecules which bind to complementary DNA to inhibit transcription, and ribozymes. Some other examples of other bioactive agents include antibodies, receptor ligands, enzymes, adhesion peptides, blood clotting factors, inhibitors or clot dissolving agents such as streptokinase and tissue plasminogen activator, antigens for immunization, hormones and growth factors, oligonucleotides such as antisense oligonucleotides and ribozymes and retroviral vectors for use in gene therapy. Examples of antineoplastics and/or antimitotics include methotrexate, azathioprine, vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin® from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g. Mutamycin® from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of such antiplatelets, anticoagulants, antifibrin, and antithrombins include sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclin analogues, dextran, D-phe- pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein Ilb/IIIa platelet membrane receptor antagonist antibody, recombinant hirudin, thrombin inhibitors such as Angiomax a (Biogen, Inc., Cambridge, Mass.), calcium channel blockers (such as nifedipine), colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega 3 -fatty acid), histamine antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station, NJ), monoclonal antibodies (such as those specific for Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxide donors, super oxide dismutases, super oxide dismutase mimetic, 4-amino-2,2,6,6-tetramethylpiperidine-l-oxyl (4-amino-TEMPO), estradiol, anticancer agents, dietary supplements such as various vitamins, and a combination thereof. Examples of such cytostatic substance include angiopeptin, angiotensin converting enzyme inhibitors such as captopril (e.g. Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril (e.g. Prinivil® and Prinzide® from Merck & Co., Inc., Whitehouse Station, NJ). An example of an antiallergic agent is permirolast potassium. Other therapeutic substances or agents which may be appropriate include alpha-interferon, and genetically engineered epithelial cells. The foregoing substances are listed by way of example and are not meant to be limiting. Other active agents which are currently available or that may be developed in the future are equally applicable.
Delivery Formulations The composition comprising both anti-proliferative agent and the anti-inflammatory agent can be formulated into any formulation suitable for delivery by any mode of delivery. For example, the composition can be formed into a coating on an implantable medical device to provide controlled release of the anti-proliferative agent and the antiinflammatory agent. Preferably, they are included in a polymeric coating on a stent. The composition can also be formulated into other suitable formulations for example, bolus dose of free drug, optionally with a fluoroscopic dye, bolus dose of gel-encapsulated drug. The gel can be formed of a gel- forming material or polymer such as hyaluronic acid, carboxymethyl cellulose, pectin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, polyethylene oxide, acacia, tragacanth, guar gum, xanthan gum, locust bean gum, Carbopol™ acidic carboxy polymer, polycarbophil, polyethylene oxide, poly(hydroxyalkyl methacrylate), poly(electrolyte complexes), polyvinyl acetate) cross-linked with hydrolyzable bonds, water-swellable N-vinyl lactams polysaccharides, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, arbinoglactan, amylopectin, gelatin, hydrophilic colloids such as carboxylmethyl cellulose gum or alginate gum, including both non-crosslinked and crosslinked alginate gums, where the crosslinked alginate gums maybe crosslinked with di- or trivalent ions, polyols such as propylene glycol, or other crosslinking agents, Cyanamer™ polyacrylamides, Good-rite™ polyacrylic acid, starch graft copolymers, Aqua- Keeps™ acrylate polymer, ester crosslinked polyglucan, and the like, and combinations thereof. Some of the gel-forming materials are discussed in U.S. patents, U.S. Patent Nos. 3,640,741, 3,865,108, 3,992,562, 4,002,173, 4,014,335, and 4,207,893. Hydrogels also are discussed in the Handbook of Common Polymers, by Scott and Roff, published by the Chemical Rubber Company, Cleveland, Ohio. For any given gel-forming material or polymer, use of a material with higher average molecular weight provides higher viscosity in aqueous solution of any given concentration. Therefore, using a higher molecular weight generally enables use of a lesser quantity of polymer to accomplish the required retardation of dissolution. In some embodiments, the gel- forming material or polymer can be hydropropyl methylcellulose having 19-24% methoxyl substitution and 7-12% hydroxypropyl substitution and a number average molecular weight of at least 20,000. Such polymers include those sold by Dow Chemical Co. under the tradenames Methocel K4M, Methocel K15M and Methocel KlOOM.
Modes of Delivery
In one embodiment, the anti-inflammatory drug such as clobetasol is formulated into a bolus dose of free drug with, optionally, a fluoroscopic dye. The anti-proliferative drug such as everolimus can be formulated into a coating composition with a polymeric material and then coated onto an implantable device (e.g., stent). The bolus dose of antiinflammatory drug is administered first and then the anti-proliferative drug is delivered by release from the implantable device such as a drug-delivery stent. The composition may further include a third agent such as a HDL (high density lipoprotein)-mimic as described in U.S. Patent No. 6,367,479. Alternatively, HDL-mimic can be delivered by the stent.
In another embodiment, the anti- inflammatory drug such as clobetasol is formulated into a bolus dose of gel. The anti-proliferative drug such as everolimus can be formulated into a coating composition with a polymeric material and then coated onto an implantable device. The bolus dose of the anti- inflammatory drug is administered first and then the anti-proliferative drug is delivered by release from the implantable device such as a drug- delivery stent.
In a further embodiment, the anti-inflammatory drug and the anti-proliferative drug can be included in a polymeric matrix and then coated onto a medical device such as a stent. The coating can be a single layer or include multiple layers or regions. One layer or region can include the anti-proliferative drug (e.g., everolimus) and another layer or region can include the anti- inflammatory drug (e.g., clobetasol). The medical device coating can be designed to have a variety of different release parameters for each of the drugs included in the coating. Methods of coating stents with drug/polymer combinations are well known in the art. As indicated above, the release of inflammation-inciting by-products into the body from a biodegradable device can occur continuously while the device is degrading within the body. Therefore, embodiments of a drug-delivery system having a sustained release of an anti-inflammatory agent from an implanted device are described. Certain embodiments of a drug-delivery system may include an effective amount of an anti-proliferative agent. The drug delivery system may further include a body structure of an implantable medical device. In some embodiments, the body structure may be a substrate or scaffolding of an implantable medical device, such as stent. The substrate or scaffolding may be a biostable or bioabsorbable polymer. An embodiment of the drug- delivery system may further include an effective amount of a steroidal anti- inflammatory agent or a non steroidal anti- inflammatory agent within the body structure of the device. An anti- inflammatory agent within a biodegradable body structure may allow for sustained release of the inflammatory agent throughout the degradation process of the body structure. In one embodiment, at least some of the anti-proliferative agent may be contained in a coating on the body structure of the device. The coating may be pure or substantially pure agent or mixed or dispersed in a biostable or bioabsorbable polymer matrix. Alternatively, at least some of the anti-proliferative agent may be delivered in some other local manner or systemically.
An embodiment of a method of treating restenosis or vulnerable plaque of a blood vessel may include administering to a patient an effective amount of an anti-proliferative agent (e.g., everolimus or other listed drugs) either through a coating on a device, systemically, and/or some other local method. The method may further include allowing an effective amount of a steroidal anti- inflammatory agent or a non steroidal anti-inflammatory agent (e.g, clobetasol) to elute to a vessel from within a body structure the device. At least a portion of the anti- inflammatory agent in at least one depot and/or anti- inflammatory agent mixed or dispersed within the body structure may elute from a surface of the body structure. In some embodiments, the anti- inflammatory agent may elute through a coating containing at least a portion of the anti-proliferative agent. In one embodiment, at least a portion of the anti- inflammatory agent may elute from the body structure and suppress inflammation of a blood vessel during all or a majority of the degradation of the body structure.
Moreover, the properties of the coating, such as thickness and porosity, may influence the rate of release of the anti- inflammatory agent from the device. Some embodiments may include controlling the release rate of anti-proliferative agent by modifying the properties of the coating. In one embodiment, at least a portion of the anti- inflammatory agent within the body structure may be contained in at least one depot or cavity on at least a portion of a surface of the body structure. The agent in the depot may be pure or substantially pure agent. Alternatively, the agent in the depot may be mixed or dispersed in a polymer matrix.
Numerous embodiments of implantable medical devices with depots configured to hold an agent are possible. Depots may be placed at one or more arbitrary locations on a device. In some embodiments, depots may be selectively distributed at or near portions of a device that are adjacent to regions of a vessel in need of treatment for inflammation. For example, in long lesions, the center portion of the lesion may be more inflamed than the ends of the lesion. The greater inflammation may arise from a larger concentration of degradation products closer to the center of the stent than the ends of the stent. Thus, the center of the lesion may require more anti- inflammatory agent than the ends of the lesion. Alternatively, the ends of the lesion may be more inflamed due to mechanical stresses causing irritation or injury to the ends of the lesion. Thus, a stent may include depots or more depots in regions of a stent adjacent portions of a lesion having more inflammation. Additionally, depots may be selectively disposed on abluminal faces, luminal faces, and/or sidewalls of a stent. For example it may be desirable to have depots on abluminal faces since they may be in contact with inflamed portions of a vessel. However, depots may be placed at any location on a stent that could be clinically beneficial in treating restinosis. FIG. 2 depicts a section 50 of stent 10 from FIG. 1. In section 50, depots 55 are disposed on an abluminal face 20 and depots 60 are disposed on a sidewall 30.
Additionally, the geometrical parameters that characterize depots such as size (e.g., depth, diameter, etc.) and shape may be configured to facilitate treatment of an inflammatory response. For example, the geometry of depots may be configured to maximize sustained delivery of anti-inflammatory agent throughout the degradation of a device to counteract the inflammatory effect of degradation by-products.
A single depot or plurality of depots may be formed as a laser trench or laser trenches on a body of an implantable medical device such as stent 10 by exposing a surface of the device to an energy discharge from a laser, such as an excimer laser. Alternative methods of forming depots include, but are not limited to physical or chemical etching techniques. Techniques of laser fabrication or etching to form depots are well-known to one of ordinary skill in the art. Depots can be formed in virtually any stent structure and not merely the above-described structure.
FIGs. 3A-B depict cross-sections of a strut illustrating geometries of depots. Referring to FIG. 3A, depot 70 has a generally cylindrical shape. Depot 70 has a depth Di and diameter D2. The appropriate values for Di and D2 depend on factors such as the effective amount of agent, mechanical integrity of the strut, density of depots, and the desired time frame of release of active agent. For instance, the greater the effective amount of agent, the larger either or both depth Di and diameter D2 may need to be. A higher density of depots disposed on a strut may decrease a required amount of agent in an individual strut, and thus a necessary size of a depot. Furthermore, as the size and density of the depots increase, the mechanical strength of the strut may decrease. Additionally, a longer sustained release of active agent may be facilitated by a larger depth Di. A diameter D2 of cylindrical depot 70 may have a range from about 10% to about 95%, about 20% to about 80%, 30% to about 70%, or about 40% to about 60% of width W1.
FIG. 3B illustrates a depot 75 which is generally conical in shape. Conical shaped depot 75 has an open end 80 and a closed end 85. Open end 80 is the end that contacts a surface of a tissue since open end 80 is at ab luminal face 20. A diameter D3 of conical shaped depot 75 is shown to decrease from closed end 85 to open end 80. The largest diameter D3' is at the closed end 85 of conical shaped depot 75. D3' may have a range from about 10% to about 95%, about 20% to about 80%, 30% to about 70%, or about 40% to about 60% of width Wi. The smallest diameter D3" at open end 80 of conical shaped depot 75 may have a range from about 1% to about 70%, about 5% to about 70%, about 15% to about 60% of about 30% to about 50% of width Wi. The reduced size of opening 80 of conical shaped depot 75, as compared to that of the cylindrical shaped depot 70, may reduce the rate at which the anti-inflammatory agent is released once the stent is implanted at the desired location of treatment. The depots can have a variety of other geometrical shapes, such as elongated trenches (not illustrated).
In other embodiments, at least a portion of the anti-inflammatory agent within the body structure may be mixed or dispersed within the body structure of the device. The antiinflammatory agent mixed or dispersed within a biodegradable body structure may elute into a vessel at substantially the same rate as the body structure degrades. In one embodiment, the anti-inflammatory agent may be incorporated (mixed or dispersed) within the body structure during fabrication of the device. For example, the agent may be mixed with polymer in a molten state before, during, and/or after a fabrication process such as extrusion or injection molding. However, it is important to control the temperature of an molten polymer containing agent during a mixing process to inhibit or prevent degradation of the active agent. The temperature of a molten polymer may be controlled to be below a degradation temperature or degradation temperature range. Some agents tend to degrade at temperatures above about 80 0C. Others may tend to degrade above about 100 0C.
FIGs. 4A-B depict cross-sections of struts having anti-inflammatory agent within that is below a coating 105 and 115. Coating 105 and 115 may include an anti-proliferative agent. In FIG. 4A, a composition 100 that is pure anti-inflammatory agent or antiinflammatory agent dispersed within a polymer matrix is deposited within depot 70. Anti- inflammatory agent is configured to elute through coating 105 to treat inflamed portions of vessels. FIG. 4B depicts an anti- inflammatory agent 110 dispersed within the strut. Antiinflammatory agent 110 is configured to elute through coating 115 to treat inflamed portions of vessels.
An anti-inflammatory can have one or a combination of release profiles that include a pulse release, fast or burst release, and a sustained release. Similarly, the anti-proliferative drug can have one or a combination of release profiles that include a pulse release, fast or burst release, and a sustained release from the stent. In some embodiments, the combination can be delivered simultaneously or at least during the drug treatment period there is at lease some overlap between the release of the drugs. In some embodiments, the anti- inflammatory can be completely released prior to the release to the anti-proliferative or can be partially released with some or significant overlap between the release of both drugs. "Pulse release" generally refers to a release profile of a drug that features a sudden surge of the release rate of the drug. The release rate surge of the drug would then disappear within a period. A more detailed definition of the term can be found in Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., Culinary and Hospitality Industry Publications Services.
As used herein, the term "fast release" in one embodiment refers to a release profile of a drug that features a release rate in the range between about 15 to about 40 μg per day for a 18 mm stent, about 10 μg to about 27 μg per day for a 13 mm stent, and about 6.7 μg to about 17.2 μg per day for a 8 mm stent. Equivalent profiles can be derived by one having ordinary skill in the art for stents having other sizes. In another embodiment, the term "fast release" refers to an approximately 20% release in 24 hours of a drug. The term "fast release" is used interchangeably with the term "burst release." As used herein, the term "sustained release" generally refers to a release profile of a drug that can include zero-order release, exponential decay, step-function release or other release profiles that carry over a period of time, for example, ranging from several days to several years. The terms "zero-order release", "exponential decay" and "step-function release" as well as other sustained release profiles are well known in the art (see, for example, Encyclopedia of Controlled Drug Delivery, Edith Mathiowitz, Ed., Culinary and Hospitality Industry Publications Services).
In one embodiment, at least one of the anti-inflammatory agent (e.g., clobetasol) and anti-proliferative agent (e.g., everolimus) is administered via a stent while the other is administered by other local means of administration (e.g., coated balloon or drug delivery balloon) or alternatively, the other is administered systemically. In other embodiments, both are administered locally, by means other than a stent, or alternatively systemically. Systemic administration can be accomplished orally or parenterally including intravascularly, rectally, intranasally, intrabronchially, or transdermally. Liquid carriers which are sterile solutions or suspensions can be injected intramuscularly, intraperitoneally, subcutaneous Iy, and intravenously. Rectal administration can be in the form of conventional suppository. For adminsitration by intranasal or intrabronchial inhalation or insufflation, the drug can be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol. The drug can be administered transdermally through the used of a transdermal patch and a carrier that is inert to and mutually compatible with the active component, is non-toxic to the skin, and allows for the delivery of the drug for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams, ointments, pastes, and gels. The creams and ointments may be viscous liquids or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes made of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active component may also be suitable. Other devices capable of releasing the drug into the blood stream include semi-permeable membranes covering a reservoir containing the drug, with or without a carrier.
Local administration can be accomplished by a variety of techniques which administer the active component at or near the target site. Preferably, local administration is by a stent. The following examples of local delivery techniques are provided for illustrative purposes and are not intended to be limiting. Examples include local delivery catheters, site specific carriers, particles, implants, direct application, or direct injection. Local delivery by a catheter allows for the administration of the drug directly to the target site.
Local delivery by site specific carriers is conducted by attaching the drug to a carrier which will direct or link the drug to the target cells. Examples of this delivery technique include the use of carrier such as a protein ligand, a monoclonal antibody or a membrane anchored linker.
Local delivery by an implant (other than a stent) is the placement of a matrix carrying the drug at the site. The matrix can release the active component by, for example, diffusion, degradation, chemical reaction, solvent activators, etc. One example of local delivery by an implant can include direct injection of vesicles or micro-particles. These micro-particles may be composed of substances such as proteins, lipids, carbohydrates or synthetic polymers. The micro-particles can have the drug impregnated therein and/or coated thereon. Application via implants is not limited to the above described routes and other techniques such as grafts, micropumps or application of a fibrin glue or hydrogel containing the active component around the exterior of a designated region of the vessel can also be implemented by one of ordinary skill in the art.
Local delivery by direct injection describes injecting a liquid carrier containing the drug directly into the site. The liquid carrier should be inert to and mutually compatible with the drug. The component can be in true solution or suspended in fine particles in the carrier. A suitable example of an inert carrier includes a sterile saline solution. Biocompatible and Bioabsorbable Polymers
In general, polymers can be biostable, bioabsorbable, biodegradable, or bioerodable. Biostable refers to polymers that are not biodegradable. The terms biodegradable, bioabsorbable, and bioerodable, as well as degraded, eroded, and absorbed, are used interchangeably and refer to polymers that are capable of being completely eroded or absorbed when exposed to bodily fluids such as blood and can be gradually resorbed, absorbed and/or eliminated by the body.
Representative examples of polymers that may be used to fabricate an implantable medical device, to coat an implantable medical device, or to provide a drug delivery particle with the anti-proliferative drug and/or anti-inflammatory drug include, but are not limited to, poly(N-acetylglucosamine) (Chitin), Chitosan, poly(3 -hydroxyvalerate), poly(lactide-co- glycolide), poly(3 -hydroxybutyrate), poly(4-hydroxybutyrate), poly(3 -hydroxybutyrate-co- 3-hydroxyvalerate), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide), poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide), poly(L- lactide-co-D,L-lactide), poly(caprolactone), poly(L-lactide-co-caprolactone), poly(D,L- lactide-co-caprolactone), poly(glycolide-co-caprolactone), poly(trimethylene carbonate), polyester amide, poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes, biomolecules (such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid), polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers other than polyacrylates, vinyl halide polymers and copolymers (such as polyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether), polyvinylidene halides (such as polyvinylidene chloride), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such as polystyrene), polyvinyl esters (such as polyvinyl acetate), acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon 66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides, polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, and carboxymethyl cellulose. Additional representative examples of polymers that may be especially well suited for use in fabricating embodiments of implantable medical devices disclosed herein include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOH or by the trade name EVAL), poly(butyl methacrylate), poly(vinylidene fluoride-co- hexafluoropropene) (e.g., SOLEF 21508, available from Solvay Solexis PVDF, Thorofare, NJ), polyvinylidene fluoride (otherwise known as KYNAR, available from ATOFINA Chemicals, Philadelphia, PA), ethylene-vinyl acetate copolymers, poly(vinyl acetate), styrene-isobutylene-styrene triblock copolymers, and polyethylene glycol. Method of Coating A Device
The coating described herein can be formed by spray coating or any other coating process available in the art, such as dipping. Generally, the coating involves dissolving or suspending the composition (e.g. polymer and drug), or one or more components thereof, in a solvent or solvent mixture to form a solution, suspension, or dispersion of the composition or one or more components thereof, applying the solution or suspension to an implantable device, and removing the solvent or solvent mixture to form a coating or a layer of coating. Suspensions or dispersions of the composition described herein can be in the form of latex or emulsion of microparticles having a size between 1 nanometer and 100 microns, preferably between 1 nanometer and 10 microns. Heat and/or pressure treatment can be applied to any of the steps involved herein. In addition, if desirable, the coating described here can be subjected to further heat and/or pressure treatment. Some additional exemplary processes of coating an implantable device that may be used are described in, for example, Lambert TL, et al. Circulation, 1994, 90: 1003-1011; Hwang CW, et al. Circulation, 2001; 104: 600-605; Van der Giessen WJ, et al. Circulation, 1996; 94: 1690-1697; Lincoff AM, et al. J Am Coll Cardiol 1997; 29: 808-816; Grube E. et al, J American College Cardiology Meeting, March 6 2002, ACCIS2002, poster 1174-15; Grube E, et al, Circulation, 2003, 107: 1, 38-42; Bullesfeld L, et al. Z Kardiol, 2003, 92: 10, 825-832; and Tanabe K, et al. Circulation 2003, 107: 4, 559-64. As used herein, the term "solvent" refers to a liquid substance or composition that is compatible with the polymer and is capable of dissolving or suspending the polymeric composition or one or more components thereof at a desired concentration. Representative examples of solvents include chloroform, acetone, water (buffered saline), dimethylsulfoxide (DMSO), propylene glycol monomethyl ether (PM,) iso-propylalcohol (IPA), n-propyl alcohol, methanol, ethanol, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl acetamide (DMAC), benzene, toluene, xylene, hexane, cyclohexane, heptane, octane, nonane, decane, decalin, ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, butanol, diacetone alcohol, benzyl alcohol, 2-butanone, cyclohexanone, dioxane, methylene chloride, carbon tetrachloride, tetrachloroethylene, tetrachloro ethane, chlorobenzene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, formamide, hexafluoroisopropanol, 1,1,1-trifluoroethanol, and hexamethyl phosphoramide and a combination thereof.
Method of Use In accordance with embodiments of the invention, a coating of the various described embodiments can be formed on an implantable device or prosthesis, e.g., a stent. For coatings including one or more active agents, the agent will be retained on the medical device such as a stent during delivery and expansion of the device, and released at a desired rate and for a predetermined duration of time at the site of implantation. Preferably, the medical device is a stent. A stent having the above-described coating is useful for a variety of medical procedures, including, by way of example, treatment of obstructions caused by tumors in bile ducts, esophagus, trachea/bronchi and other biological passageways. A stent having the above-described coating is particularly useful for treating occluded regions of blood vessels caused by abnormal or inappropriate migration and proliferation of smooth muscle cells, thrombosis, and restenosis. Stents may be placed in a wide array of blood vessels, both arteries and veins. Representative examples of sites include the iliac, renal, and coronary arteries.
For implantation of a stent, an angiogram is first performed to determine the appropriate positioning for stent therapy. An angiogram is typically accomplished by injecting a radiopaque contrasting agent through a catheter inserted into an artery or vein as an x-ray is taken. A guidewire is then advanced through the lesion or proposed site of treatment. Over the guidewire is passed a delivery catheter which allows a stent in its collapsed configuration to be inserted into the passageway. The delivery catheter is inserted either percutaneously or by surgery into the femoral artery, brachial artery, femoral vein, or brachial vein, and advanced into the appropriate blood vessel by steering the catheter through the vascular system under fluoroscopic guidance. A stent having the above- described coating may then be expanded at the desired area of treatment. A post- insertion angiogram may also be utilized to confirm appropriate positioning.
The implantable device comprising a coating described herein can be used to treat an animal having a condition or disorder that requires a treatment. Such an animal can be treated by, for example, implanting a device described herein in the animal. Preferably, the animal is a human being. Exemplary disorders or conditions that can be treated by the method disclosed herein include, but not limited to, thrombosis, high cholesterol, hemorrhage, vascular dissection or perforation, vascular aneurysm, vulnerable plaque, chronic total occlusion, claudication, anastomotic proliferation for vein and artificial grafts, bile duct obstruction, ureter obstruction, tumor obstruction, restenosis and progression of atherosclerosis in patient subsets including type I diabetics, type II diabetics, metabolic syndrome and syndrome X, vulnerable lesions including those with thin-capped fibroatheromatous lesions, systemic infections including gingivitis, hellobacteria, and cytomegalovirus, and combinations thereof. EXAMPLES
The embodiments of the present invention will be illustrated by the following set forth examples. All parameters and data are not to be construed to unduly limit the scope of the embodiments of the invention.
Example 1. Porcine implant study Described in this example is a 28 day porcine implant study that compared the 200μg/cm2 dose stent Lemans (a stent based on PVDF-co-HFP) with a clobetasol-only delivery stent, an everolimus-only stent, and an everolimus-clobetasol combination drug delivery stent. The study was performed using three different drug delivery stents, Arm 1, Arm 2, and Arm 3. Arm 1 is a Lemans stent that included 105 μg everolimus and used as a control. Arm 2 was loaded with 185 μg clobetasol only, with no everolimus. Arm 3 is loaded with 105 μg everolimus and 80 μg clobetasol.
The Arm 1, Arm 2, and Arm 3 stents were implanted in a 30% overstretch model. Overstretch model refers to the technique of over-expanding the animal arteries by up to 30% (using the stent and balloon) over their natural diameter so that the stent is more likely to cause injury and thus greater restenosis. This sometimes helps differentiate between efficacy of various stent systems.
Nine samples of each Arm stent were implanted, one for each coronary artery. 24 hr release data in porcine serum were gathered. 3, 7 and 28 day in vivo release data were gathered (from the mammary arteries), as was 28 day quantitative coronary angioplasty (QCA), histology and morphometry.
In this study, 12mm Vision Small stents were used. All drug solutions were sprayed in a 2% Solef™ in acetone/ cyclohexanone formulation. All stents had a 100 μg PBMA primer. Table 1 shows the coating design of the stents used in this study.
Table 1. Coating design
Figure imgf000035_0001
The release rate data are shown in Table 2. As can be seen from Table 2, a coating based on Solef™ is capable of simultaneous release of both everolimus and clobetasol. Table 2. Release rate data
Figure imgf000036_0001
The results of 28 day QCA are shown in FIG. 5, the 28 day histology data are in FIG. 6, and the 28 day morphometry data are shown in FIG. 7 and summarized in Table 3 below.
Neointimal Area is the total amount of neointima as measured by a cross-sectional vessel section. This is essentially the area inside the Internal Elastic Lamina (IEL) minus the total area of the vessel lumen. Neointima refers to the new intimal growth that forms after stenting which resides between the IEL and the vessel lumen. Neointimal Thickness is the average distance between the IEL and the lumen. This is essentially the average thickness of the new intima that grows inside the stent after stenting.
Injury Score is a standardized scoring system that scores the amount of injury created in the vessel by the stent implantation. Currently, we use a range of 0 to 4 where 0 is no injury and 4 is the highest injury. There are specific quantitative and qualitative criteria for assigning a given score to a vessel. Table 3. 28 Day morphometry data from FIG. 7
Figure imgf000036_0002
The p values from a t-test of the data from FIG. 7 are summarized in Table 4. A "t-test" returns the probability associated with a Student's t-Test that determines whether two samples are likely to have come from the same two underlying populations that have the same mean. The value returned from the test, "p", is the probability that the two groups of data come from the same population, p Values less than or equal to 0.10 or 0.05 are generally considered significant (Zar, JH. Biostatistical Analysis. Englewood Cliffs, NJ: Prentice-Hall Inc, 1974. pp 101-108). Table 4. p Values from a t-test of the data from FIG. 7
Figure imgf000037_0001
Example 2. Porcine implant study
Described in this example is a 28 day porcine implant study that compared an everolimus-only stent, an everolimus-clobetasol combination drug delivery stent, and a clobetasol-only stent. The drugs were dispersed in a Solef polymer matrix, available from Solvay Solexis PVDF, Thorofare, NJ. The study was performed using three different drug delivery stents, Arm 1, Arm 2, and Arm 3. Arm 1 is Lemans stent (a stent based on PVDF -co- HFP coating) that included 64 μg everolimus with a drug-polymer ratio of 1 :4.9, which was used as a control. Arm 2 is loaded with 64 μg everolimus and 32 μg clobetasol with a drug- polymer ratio of 1 :4. Arm 3 was loaded with 32 μg clobetasol only with a drug-ratio of 1 :4, with no everolimus. Table 5 shows the coating design of the stents used in this study. The Arm 1, Arm 2, and Arm 3 stents were implanted in a 30% overstretch model.
Nine samples of each Arm stent were implanted, one for each coronary artery. 24 hr release data in porcine serum were gathered. 3, 7 and 28 day in vivo release data were gathered (from the mammary arteries), as was 28 day quantitative coronary angioplasty (QCA), histology and morphometry. 28 day QCA, histology, and morphometry were collected from coronary arteries.
In this study, 12mm Vision Small stents were used. All drug solutions were sprayed in a 2% Solef™ in acetone/ cyclohexanone formulation. All stents had a 100 μg PBMA primer.
Table 5. Coating design
Figure imgf000038_0001
The release rate data are shown in Table 6. As can be seen from Table 6, a coating based on Solef™ is capable of simultaneous release of both everolimus and clobetasol. Table 6. Release rate data
Figure imgf000038_0002
The results of the 28 day morphometry data are shown in Figure 8 and summarized in Table 7 below. Table 7. 28 Day morphometry data from FIG. 8
Figure imgf000038_0003
The p values from a t-test of the data from FIG. 8 are summarized in Table 8. Table 8. p Values from a t-test of the data from Figure 8
Figure imgf000039_0001
Clobetasol is non-toxic even at the highest concentrations typically tested in cell culture (10~6 M). FIG. 9 depicts a proliferation assay that shows a dose dependent inhibition of vascular smooth muscle proliferation and a low EC50 value of 3 x 10"11 M. The Efficacy of the drug is 25%.
A proliferation assay is a cell culture assay in which smooth muscle cells are exposed to various concentrations of a given drug. The y-axis is a measure of the total number of DNA strands or cell nuclei. If cells are dividing (proliferating), the amount of DNA increases. EC50 is the concentration of drug that causes half the total effect. For example, if the greatest amount of proliferation reduction is 60% reduction as compared to no drug, then the EC50 is the concentration of drug that causes a 30% reduction in proliferation. Efficacy refers to the effectiveness of the drug in preventing proliferation of smooth muscle cells.
FIG. 10 depicts a proliferation assay with everolimus only, which also shows inhibition of vascular smooth muscle proliferation. The efficacy of the drug is 62%.
FIG. 11 depicts results of a proliferation assay with varying ratios of everolimus and clobetasol. FIG. 11 illustrates a plot of the efficacy of inhibition of vascular smooth muscle proliferation versus the logarithm of the everolimus- clobetasol ratio. The circled portion of the curve in FIG. 11 shows that everolimus and clobetasol have a synergistic effect that results in a higher efficacy within a range of the ratio of the two drugs. Example 3
The results of additional preclinical dosing studies (porcine 10% safety) are presented to demonstrate the continued efficacy in reducing neointimal proliferation and inflammation at both 28 and 90 days, while achieving appropriate vascular healing (as assessed by vascular re-endothelialization).
Two safety studies, one 28-day and one 90-day were designed to include three arms: 100 μg everolimus alone; 100 μg everolimus: 10 μg clobetasol (100: 10) and 100 μg everolimus: 1 μg clobetasol (100: 1).
The 28-day study showed a 32.7 + 12.0% in-stent stenosis rate in everolimus arm, 17.9 + 5.0% in the 100: 10 arm, and 16.9 + 5.9% in the 100: 1 arm. In the 90-day study, the in-stent stenosis rates were 45.2 + 21.5%, 14.2 + 7.9% and 16.1 + 8.6% in the everolimus 100, 100: 10 and 100: 1, respectively. The data show that both doses of combination drug significantly (p<0.05) reduced % stenosis versus everolimus 100 at both 28 and 90 days post implant. Evaluation via light microscopy and SEM at 28 days revealed that low dose (100:1) had near complete re-endothelialization, which was comparable to everolimus alone. Furthermore, histopathological evaluation at 90 days demonstrated that both drug combination arms maintained vascular healing with reduced stenosis and inflammation, as compared to everolimus alone. In conclusion, 100: 1 arm appears to be very effective in reducing and maintaining reduced vascular stenosis while also showing a good safety profile at 28 and 90 days in the porcine safety (10%) coronary arterial model.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true spirit and scope of this invention.

Claims

CLAIMSWhat is claimed is:
1. A drug-delivery system, comprising: at least 100 μg of everolimus; and clobetasol, such that the amount of everolimus by weight is at least 10 times more than clobetasol.
2. The drug-delivery system of claim 1, wherein the system is a stent.
3. The drug-delivery system of claim 1 , where the system is a polymeric coated stent, such that the everolimus and clobetasol are in the polymeric coating.
4. The drug-delivery system of claim 3, wherein the coating includes 2 layers or regions such that the everolimus is in one layer or region and the clobetasol is in another layer or region.
5. The drug-delivery system of claim 1, wherein the drugs are released in sequence.
6. The drug-delivery system of claim 1, wherein the drugs are released simultaneously.
7. The drug-delivery system of claim 1, wherein the drug release profile includes at least a period of overlapping or simultaneous release profile of the everolimus and clobetasol.
8. The drug-delivery system of claim 1, wherein the ratio of the everolimus to the clobetasol is 10: 1 to 100: 1 (w/w).
9. A stent, comprising: a radially expandable body; and a combination of (a) a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2 -hydro xy)ethylrapamycin (everolimus), 40-O-(3- hydroxy)propylrapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O- tetrazolylrapamycin and 40-epi-(Nl-tetrazolyl)rapamycin, and (b) a second drug consisting of clobetasol, carried by the stent, wherein the minimum amount of the first drug carried by the stent is 100 μg, and wherein the ratio of the first drug to the second drug 10: 1 to 100: 1 (w/w).
10. The stent of claim 9, wherein the stent includes a coating carrying the first and second drugs.
11. The stent of claim 9, wherein the coating includes at least two layers such that the first drug is in one layer and the second drug is on another layer.
12. The stent of claim 9, wherein the stent is a bioabsorbable stent.
13. The stent of claim 12, wherein at least one of the drugs is in the body of the bioabsorbable stent and at least one of the drugs is in a coating on the bioabsorbable stent.
14. A method of treating a vascular disorder comprising delivering the system of claim
1 to a patient in need thereof, wherein the disorder is restenosis, vulnerable plaque, and/or progression of atherosclerosis in patient subsets including type I diabetics and type II diabetics.
15. A method of treating a vascular disorder comprising delivering the system of claim
2 to a patient in need thereof, wherein the disorder is restenosis, vulnerable plaque, and/or progression of atherosclerosis in patient subsets including type I diabetics and type II diabetics.
16. A method of treating a vascular disorder comprising delivering the stent of claim 9 to a patient in need thereof, wherein the disorder is restenosis, vulnerable plaque, and/or progression of atherosclerosis in patient subsets including type I diabetics and type II diabetics.
17. A method of treating restenosis or vulnerable plaque of a blood vessel comprising: locally administering to a patient a first drug selected from a group consisting of rapamycin (sirolimus), Biolimus A9, deforolimus, AP23572, tacrolimus, temsirolimus, pimecrolimus, zotarolimus (ABT-578), 40-O-(2 -hydro xy)ethylrapamycin (everolimus), 40- O-(3 -hydro xy)propylrapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethylrapamycin, 40-O- tetrazolylrapamycin and 40-epi-(Nl-tetrazolyl)rapamycin, and locally administering to a patient a second drug consisting of clobetasol, wherein the minimum amount of the first drug that is locally administered is 100 μg, and wherein the amount of the first drug by weight is at least 10 times more than the second drug.
18. The method of claim 17, wherein the ratio of the first drug to the second drug is 10: 1 to 100: 1 (w/w).
19. The method of claim 17, wherein local administration is by a stent.
PCT/US2009/053623 2008-08-13 2009-08-12 Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device WO2010019721A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12/191,209 US8435550B2 (en) 2002-12-16 2008-08-13 Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US12/191,209 2008-08-13

Publications (2)

Publication Number Publication Date
WO2010019721A2 true WO2010019721A2 (en) 2010-02-18
WO2010019721A3 WO2010019721A3 (en) 2010-10-07

Family

ID=41151795

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/053623 WO2010019721A2 (en) 2008-08-13 2009-08-12 Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device

Country Status (2)

Country Link
US (1) US8435550B2 (en)
WO (1) WO2010019721A2 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014070322A1 (en) * 2012-11-02 2014-05-08 Abbott Cardiovascular Systems Inc. Method of treating vascular disease in diabetic patients
US9138337B2 (en) 2004-06-30 2015-09-22 Abbott Cardiovascular Systems Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US9750627B2 (en) 2012-03-30 2017-09-05 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a stent and locally administered adjunctive therapy

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6790228B2 (en) * 1999-12-23 2004-09-14 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US7807211B2 (en) * 1999-09-03 2010-10-05 Advanced Cardiovascular Systems, Inc. Thermal treatment of an implantable medical device
US7758881B2 (en) 2004-06-30 2010-07-20 Advanced Cardiovascular Systems, Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US20110319987A1 (en) 2009-05-20 2011-12-29 Arsenal Medical Medical implant
US8992601B2 (en) 2009-05-20 2015-03-31 480 Biomedical, Inc. Medical implants
US9309347B2 (en) 2009-05-20 2016-04-12 Biomedical, Inc. Bioresorbable thermoset polyester/urethane elastomers
US8888840B2 (en) * 2009-05-20 2014-11-18 Boston Scientific Scimed, Inc. Drug eluting medical implant
CA3186201A1 (en) * 2009-05-20 2010-11-25 Lyra Therapeutics, Inc. Self-expandable medical device comprising polymeric strands and coatings thereon
US9265633B2 (en) * 2009-05-20 2016-02-23 480 Biomedical, Inc. Drug-eluting medical implants
US8562670B2 (en) * 2010-04-01 2013-10-22 Abbott Cardiovascular Systems Inc. Implantable prosthesis with depot retention feature
US9220759B2 (en) 2012-02-23 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a drug eluting stent and adjunctive therapy
WO2013148537A1 (en) * 2012-03-29 2013-10-03 Ning Xi Substituted spirobicyclic compounds and methods of use
US9254212B2 (en) * 2012-04-06 2016-02-09 Abbott Cardiovascular Systems Inc. Segmented scaffolds and delivery thereof for peripheral applications
US20130303496A1 (en) * 2012-05-08 2013-11-14 Abbott Cardiovascular Systems Inc. Method Of Treating Vascular Lesions
IN2013MU02532A (en) 2013-07-31 2015-06-26 Sahajanand Medical Technologies Pvt Ltd
US9839644B2 (en) 2014-09-09 2017-12-12 ARKAY Therapeutics, LLC Formulations and methods for treatment of metabolic syndrome
JP2017000724A (en) * 2015-06-05 2017-01-05 国立大学法人東北大学 Micro needle and micro array and method for producing the same
KR101653535B1 (en) * 2016-05-31 2016-09-05 전남대학교병원 Polymer-Free Everolimus-Eluting Coronary Stent Fabricated by Electrospinning Technique

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006014270A2 (en) * 2004-06-30 2006-02-09 Advanced Cardiovascular Systems, Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders
US20060105019A1 (en) * 2002-12-16 2006-05-18 Gordon Stewart Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders
WO2007149825A2 (en) * 2006-06-22 2007-12-27 Cardiac Pacemakers, Inc. Coating on shocking coil of tachy lead
WO2008016528A2 (en) * 2006-08-01 2008-02-07 Abbott Cardiovascular Systems Inc. Drug delivery after biodegradation of the stent scaffolding

Family Cites Families (525)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR732895A (en) * 1932-10-18 1932-09-25 Consortium Elektrochem Ind Articles spun in polyvinyl alcohol
US2386454A (en) 1940-11-22 1945-10-09 Bell Telephone Labor Inc High molecular weight linear polyester-amides
US3849514A (en) 1967-11-17 1974-11-19 Eastman Kodak Co Block polyester-polyamide copolymers
GB1237035A (en) 1969-08-20 1971-06-30 Tsi Travmatologii I Ortopedii Magnesium-base alloy for use in bone surgery
US3900632A (en) 1970-02-27 1975-08-19 Kimberly Clark Co Laminate of tissue and random laid continuous filament web
US3773737A (en) 1971-06-09 1973-11-20 Sutures Inc Hydrolyzable polymers of amino acid and hydroxy acids
US3839743A (en) 1972-04-21 1974-10-08 A Schwarcz Method for maintaining the normal integrity of blood
US4104410A (en) 1973-12-21 1978-08-01 Malecki George J Processing of green vegetables for color retention in canning
US4110497A (en) 1976-07-02 1978-08-29 Snyder Manufacturing Co., Ltd. Striped laminate and method and apparatus for making same
JPS6037735B2 (en) * 1978-10-18 1985-08-28 住友電気工業株式会社 Artificial blood vessel
DE2928007A1 (en) 1979-07-11 1981-01-15 Riess Guido Dr BONE IMPLANT BODY FOR PROSTHESES AND BONE CONNECTORS AND METHOD FOR THE PRODUCTION THEREOF
US4329383A (en) 1979-07-24 1982-05-11 Nippon Zeon Co., Ltd. Non-thrombogenic material comprising substrate which has been reacted with heparin
SU790725A1 (en) 1979-07-27 1983-01-23 Ордена Ленина Институт Элементоорганических Соединений Ан Ссср Process for preparing alkylaromatic polyimides
US4226243A (en) 1979-07-27 1980-10-07 Ethicon, Inc. Surgical devices of polyesteramides derived from bis-oxamidodiols and dicarboxylic acids
SU811750A1 (en) 1979-08-07 1983-09-23 Институт Физиологии Им.С.И.Бериташвили Bis-bicarbonates of aliphatic diols as monomers for preparing polyurethanes and process for producing the same
SU872531A1 (en) 1979-08-07 1981-10-15 Институт Физиологии Им.И.С.Бериташвили Ан Гсср Method of producing polyurethans
SU876663A1 (en) 1979-11-11 1981-10-30 Институт Физиологии Им. Академика И.С.Бериташвили Ан Гсср Method of producing polyarylates
US4346028A (en) 1979-12-14 1982-08-24 Monsanto Company Asbestiform crystalline calcium sodium or lithium phosphate, preparation and compositions
US4343931A (en) 1979-12-17 1982-08-10 Minnesota Mining And Manufacturing Company Synthetic absorbable surgical devices of poly(esteramides)
SU1016314A1 (en) 1979-12-17 1983-05-07 Институт Физиологии Им.И.С.Бериташвили Process for producing polyester urethanes
US4529792A (en) 1979-12-17 1985-07-16 Minnesota Mining And Manufacturing Company Process for preparing synthetic absorbable poly(esteramides)
SU905228A1 (en) 1980-03-06 1982-02-15 Институт Физиологии Им. Акад.И.С. Бериташвили Ан Гсср Method for preparing thiourea
DE3019996A1 (en) 1980-05-24 1981-12-03 Institute für Textil- und Faserforschung Stuttgart, 7410 Reutlingen HOHLORGAN
US4902289A (en) * 1982-04-19 1990-02-20 Massachusetts Institute Of Technology Multilayer bioreplaceable blood vessel prosthesis
US4473665A (en) 1982-07-30 1984-09-25 Massachusetts Institute Of Technology Microcellular closed cell foams and their method of manufacture
US4656083A (en) 1983-08-01 1987-04-07 Washington Research Foundation Plasma gas discharge treatment for improving the biocompatibility of biomaterials
US5197977A (en) * 1984-01-30 1993-03-30 Meadox Medicals, Inc. Drug delivery collagen-impregnated synthetic vascular graft
US4633873A (en) * 1984-04-26 1987-01-06 American Cyanamid Company Surgical repair mesh
US4596574A (en) 1984-05-14 1986-06-24 The Regents Of The University Of California Biodegradable porous ceramic delivery system for bone morphogenetic protein
CH671337A5 (en) 1984-06-19 1989-08-31 Ceskoslovenska Akademie Ved
US4879135A (en) 1984-07-23 1989-11-07 University Of Medicine And Dentistry Of New Jersey Drug bonded prosthesis and process for producing same
IT1186142B (en) * 1984-12-05 1987-11-18 Medinvent Sa TRANSLUMINAL IMPLANTATION DEVICE
SU1293518A1 (en) 1985-04-11 1987-02-28 Тбилисский зональный научно-исследовательский и проектный институт типового и экспериментального проектирования жилых и общественных зданий Installation for testing specimen of cross-shaped structure
US4656242A (en) 1985-06-07 1987-04-07 Henkel Corporation Poly(ester-amide) compositions
US4718907A (en) * 1985-06-20 1988-01-12 Atrium Medical Corporation Vascular prosthesis having fluorinated coating with varying F/C ratio
US4818559A (en) 1985-08-08 1989-04-04 Sumitomo Chemical Company, Limited Method for producing endosseous implants
US4733665C2 (en) 1985-11-07 2002-01-29 Expandable Grafts Partnership Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft
US4611051A (en) 1985-12-31 1986-09-09 Union Camp Corporation Novel poly(ester-amide) hot-melt adhesives
US4743252A (en) 1986-01-13 1988-05-10 Corvita Corporation Composite grafts
EP0257091B1 (en) 1986-02-24 1993-07-28 Robert E. Fischell An intravascular stent and percutaneous insertion system
US4878906A (en) 1986-03-25 1989-11-07 Servetus Partnership Endoprosthesis for repairing a damaged vessel
EP0241838B1 (en) 1986-04-07 1992-04-15 Agency Of Industrial Science And Technology Antithrombogenic material
US4882168A (en) 1986-09-05 1989-11-21 American Cyanamid Company Polyesters containing alkylene oxide blocks as drug delivery systems
US4740207A (en) 1986-09-10 1988-04-26 Kreamer Jeffry W Intralumenal graft
US4723549A (en) * 1986-09-18 1988-02-09 Wholey Mark H Method and apparatus for dilating blood vessels
US4722335A (en) * 1986-10-20 1988-02-02 Vilasi Joseph A Expandable endotracheal tube
JPH0696023B2 (en) 1986-11-10 1994-11-30 宇部日東化成株式会社 Artificial blood vessel and method for producing the same
US5721131A (en) * 1987-03-06 1998-02-24 United States Of America As Represented By The Secretary Of The Navy Surface modification of polymers with self-assembled monolayers that promote adhesion, outgrowth and differentiation of biological cells
US4800882A (en) 1987-03-13 1989-01-31 Cook Incorporated Endovascular stent and delivery system
US6387379B1 (en) 1987-04-10 2002-05-14 University Of Florida Biofunctional surface modified ocular implants, surgical instruments, medical devices, prostheses, contact lenses and the like
US4816339A (en) * 1987-04-28 1989-03-28 Baxter International Inc. Multi-layered poly(tetrafluoroethylene)/elastomer materials useful for in vivo implantation
US5059211A (en) 1987-06-25 1991-10-22 Duke University Absorbable vascular stent
US5527337A (en) 1987-06-25 1996-06-18 Duke University Bioabsorbable stent and method of making the same
US4894231A (en) 1987-07-28 1990-01-16 Biomeasure, Inc. Therapeutic agent delivery system
US4886062A (en) 1987-10-19 1989-12-12 Medtronic, Inc. Intravascular radially expandable stent and method of implant
US4877030A (en) 1988-02-02 1989-10-31 Andreas Beck Device for the widening of blood vessels
US5019096A (en) 1988-02-11 1991-05-28 Trustees Of Columbia University In The City Of New York Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
JP2561309B2 (en) 1988-03-28 1996-12-04 テルモ株式会社 Medical material and manufacturing method thereof
US5192311A (en) * 1988-04-25 1993-03-09 Angeion Corporation Medical implant and method of making
US4994298A (en) * 1988-06-07 1991-02-19 Biogold Inc. Method of making a biocompatible prosthesis
US4931287A (en) 1988-06-14 1990-06-05 University Of Utah Heterogeneous interpenetrating polymer networks for the controlled release of drugs
US5502158A (en) 1988-08-08 1996-03-26 Ecopol, Llc Degradable polymer composition
US5328471A (en) 1990-02-26 1994-07-12 Endoluminal Therapeutics, Inc. Method and apparatus for treatment of focal disease in hollow tubular organs and other tissue lumens
US5019090A (en) 1988-09-01 1991-05-28 Corvita Corporation Radially expandable endoprosthesis and the like
US5085629A (en) * 1988-10-06 1992-02-04 Medical Engineering Corporation Biodegradable stent
US4977901A (en) 1988-11-23 1990-12-18 Minnesota Mining And Manufacturing Company Article having non-crosslinked crystallized polymer coatings
CH678393A5 (en) 1989-01-26 1991-09-13 Ulrich Prof Dr Med Sigwart
DE69030811T2 (en) 1989-01-27 1997-10-02 Au Membrane & Biotech Res Inst RECEPTOR MEMBRANES AND SELECTIVE CONTROL OF THE ION FLOW BY IONOPHORES
US5163958A (en) 1989-02-02 1992-11-17 Cordis Corporation Carbon coated tubular endoprosthesis
US5540931A (en) 1989-03-03 1996-07-30 Charles W. Hewitt Methods for inducing site-specific immunosuppression and compositions of site specific immunosuppressants
US5289831A (en) * 1989-03-09 1994-03-01 Vance Products Incorporated Surface-treated stent, catheter, cannula, and the like
NZ228382A (en) 1989-03-17 1992-08-26 Carter Holt Harvey Plastic Pro Drug administering coil-like device for insertion in body cavity of animal
US5108755A (en) 1989-04-27 1992-04-28 Sri International Biodegradable composites for internal medical use
US5100429A (en) * 1989-04-28 1992-03-31 C. R. Bard, Inc. Endovascular stent and delivery system
IL90193A (en) 1989-05-04 1993-02-21 Biomedical Polymers Int Polurethane-based polymeric materials and biomedical articles and pharmaceutical compositions utilizing the same
US5272012A (en) 1989-06-23 1993-12-21 C. R. Bard, Inc. Medical apparatus having protective, lubricious coating
US5084065A (en) * 1989-07-10 1992-01-28 Corvita Corporation Reinforced graft assembly
US5971954A (en) 1990-01-10 1999-10-26 Rochester Medical Corporation Method of making catheter
US5496557A (en) 1990-01-30 1996-03-05 Akzo N.V. Article for the controlled delivery of an active substance, comprising a hollow space fully enclosed by a wall and filled in full or in part with one or more active substances
ATE120377T1 (en) 1990-02-08 1995-04-15 Howmedica INFLATABLE DILATATOR.
US5545208A (en) 1990-02-28 1996-08-13 Medtronic, Inc. Intralumenal drug eluting prosthesis
US5156623A (en) 1990-04-16 1992-10-20 Olympus Optical Co., Ltd. Sustained release material and method of manufacturing the same
US5123917A (en) 1990-04-27 1992-06-23 Lee Peter Y Expandable intraluminal vascular graft
US5298260A (en) * 1990-05-01 1994-03-29 Mediventures, Inc. Topical drug delivery with polyoxyalkylene polymer thermoreversible gels adjustable for pH and osmolality
US5292516A (en) * 1990-05-01 1994-03-08 Mediventures, Inc. Body cavity drug delivery with thermoreversible gels containing polyoxyalkylene copolymers
US5300295A (en) 1990-05-01 1994-04-05 Mediventures, Inc. Ophthalmic drug delivery with thermoreversible polyoxyalkylene gels adjustable for pH
US5306501A (en) 1990-05-01 1994-04-26 Mediventures, Inc. Drug delivery by injection with thermoreversible gels containing polyoxyalkylene copolymers
US5290271A (en) * 1990-05-14 1994-03-01 Jernberg Gary R Surgical implant and method for controlled release of chemotherapeutic agents
WO1991017724A1 (en) 1990-05-17 1991-11-28 Harbor Medical Devices, Inc. Medical device polymer
US5279594A (en) * 1990-05-23 1994-01-18 Jackson Richard R Intubation devices with local anesthetic effect for medical use
WO1991019529A1 (en) 1990-06-15 1991-12-26 Cortrak Medical, Inc. Drug delivery apparatus and method
US6060451A (en) 1990-06-15 2000-05-09 The National Research Council Of Canada Thrombin inhibitors based on the amino acid sequence of hirudin
CA2038605C (en) 1990-06-15 2000-06-27 Leonard Pinchuk Crack-resistant polycarbonate urethane polymer prostheses and the like
US5236447A (en) 1990-06-29 1993-08-17 Nissho Corporation Artificial tubular organ
US5342395A (en) 1990-07-06 1994-08-30 American Cyanamid Co. Absorbable surgical repair devices
US5112457A (en) 1990-07-23 1992-05-12 Case Western Reserve University Process for producing hydroxylated plasma-polymerized films and the use of the films for enhancing the compatiblity of biomedical implants
US5455040A (en) 1990-07-26 1995-10-03 Case Western Reserve University Anticoagulant plasma polymer-modified substrate
DE69114505T2 (en) 1990-08-28 1996-04-18 Meadox Medicals Inc SELF-SUPPORTING WOVEN VESSEL TRANSPLANT.
US5108417A (en) 1990-09-14 1992-04-28 Interface Biomedical Laboratories Corp. Anti-turbulent, anti-thrombogenic intravascular stent
US5258020A (en) * 1990-09-14 1993-11-02 Michael Froix Method of using expandable polymeric stent with memory
US5163952A (en) 1990-09-14 1992-11-17 Michael Froix Expandable polymeric stent with memory and delivery apparatus and method
US6248129B1 (en) 1990-09-14 2001-06-19 Quanam Medical Corporation Expandable polymeric stent with memory and delivery apparatus and method
US5462990A (en) 1990-10-15 1995-10-31 Board Of Regents, The University Of Texas System Multifunctional organic polymers
DE69116130T2 (en) 1990-10-18 1996-05-15 Ho Young Song SELF-EXPANDING, ENDOVASCULAR DILATATOR
US5104410A (en) 1990-10-22 1992-04-14 Intermedics Orthopedics, Inc Surgical implant having multiple layers of sintered porous coating and method
GB9027793D0 (en) 1990-12-21 1991-02-13 Ucb Sa Polyester-amides containing terminal carboxyl groups
US5163951A (en) 1990-12-27 1992-11-17 Corvita Corporation Mesh composite graft
EP0525210A4 (en) * 1991-02-20 1993-07-28 Tdk Corporation Composite bio-implant and production method therefor
WO1992015342A1 (en) 1991-03-08 1992-09-17 Keiji Igaki Stent for vessel, structure of holding said stent, and device for mounting said stent
US5383925A (en) 1992-09-14 1995-01-24 Meadox Medicals, Inc. Three-dimensional braided soft tissue prosthesis
US5330768A (en) 1991-07-05 1994-07-19 Massachusetts Institute Of Technology Controlled drug delivery using polymer/pluronic blends
US5356433A (en) 1991-08-13 1994-10-18 Cordis Corporation Biocompatible metal surfaces
US6515009B1 (en) * 1991-09-27 2003-02-04 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5811447A (en) 1993-01-28 1998-09-22 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5500013A (en) 1991-10-04 1996-03-19 Scimed Life Systems, Inc. Biodegradable drug delivery vascular stent
US5234457A (en) 1991-10-09 1993-08-10 Boston Scientific Corporation Impregnated stent
US5282860A (en) * 1991-10-16 1994-02-01 Olympus Optical Co., Ltd. Stent tube for medical use
US5545408A (en) 1991-10-21 1996-08-13 Peptide Technology Limited Biocompatible implant for the timing of ovulation in mares
US5167614A (en) 1991-10-29 1992-12-01 Medical Engineering Corporation Prostatic stent
US5516781A (en) 1992-01-09 1996-05-14 American Home Products Corporation Method of treating restenosis with rapamycin
US5756476A (en) 1992-01-14 1998-05-26 The United States Of America As Represented By The Department Of Health And Human Services Inhibition of cell proliferation using antisense oligonucleotides
CA2087132A1 (en) 1992-01-31 1993-08-01 Michael S. Williams Stent capable of attachment within a body lumen
US5573934A (en) * 1992-04-20 1996-11-12 Board Of Regents, The University Of Texas System Gels for encapsulation of biological materials
US5599352A (en) 1992-03-19 1997-02-04 Medtronic, Inc. Method of making a drug eluting stent
GB9206736D0 (en) 1992-03-27 1992-05-13 Sandoz Ltd Improvements of organic compounds and their use in pharmaceutical compositions
DE69332950T2 (en) 1992-03-31 2004-05-13 Boston Scientific Corp., Natick BLOOD VESSEL FILTER
US5219980A (en) 1992-04-16 1993-06-15 Sri International Polymers biodegradable or bioerodiable into amino acids
DE69325845T2 (en) 1992-04-28 2000-01-05 Terumo Corp Thermoplastic polymer composition and medical devices made therefrom
DE4224401A1 (en) 1992-07-21 1994-01-27 Pharmatech Gmbh New biodegradable homo- and co-polymer(s) for pharmaceutical use - produced by polycondensation of prod. from heterolytic cleavage of aliphatic polyester with functionalised (cyclo)aliphatic cpd.
US5306294A (en) 1992-08-05 1994-04-26 Ultrasonic Sensing And Monitoring Systems, Inc. Stent construction of rolled configuration
US5514379A (en) 1992-08-07 1996-05-07 The General Hospital Corporation Hydrogel compositions and methods of use
US5853408A (en) 1992-08-20 1998-12-29 Advanced Cardiovascular Systems, Inc. In-vivo modification of the mechanical properties of surgical devices
US5342621A (en) 1992-09-15 1994-08-30 Advanced Cardiovascular Systems, Inc. Antithrombogenic surface
US5770609A (en) 1993-01-28 1998-06-23 Neorx Corporation Prevention and treatment of cardiovascular pathologies
US5830461A (en) 1992-11-25 1998-11-03 University Of Pittsburgh Of The Commonwealth System Of Higher Education Methods for promoting wound healing and treating transplant-associated vasculopathy
US5342348A (en) 1992-12-04 1994-08-30 Kaplan Aaron V Method and device for treating and enlarging body lumens
FR2699168B1 (en) 1992-12-11 1995-01-13 Rhone Poulenc Chimie Method of treating a material comprising a polymer by hydrolysis.
US5443458A (en) 1992-12-22 1995-08-22 Advanced Cardiovascular Systems, Inc. Multilayered biodegradable stent and method of manufacture
EP0604022A1 (en) 1992-12-22 1994-06-29 Advanced Cardiovascular Systems, Inc. Multilayered biodegradable stent and method for its manufacture
US5981568A (en) 1993-01-28 1999-11-09 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
FI92465C (en) 1993-04-14 1994-11-25 Risto Tapani Lehtinen A method for handling endo-osteal materials
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US5441515A (en) 1993-04-23 1995-08-15 Advanced Cardiovascular Systems, Inc. Ratcheting stent
US5824048A (en) 1993-04-26 1998-10-20 Medtronic, Inc. Method for delivering a therapeutic substance to a body lumen
US20020055710A1 (en) 1998-04-30 2002-05-09 Ronald J. Tuch Medical device for delivering a therapeutic agent and method of preparation
US5464650A (en) 1993-04-26 1995-11-07 Medtronic, Inc. Intravascular stent and method
JPH0767895A (en) 1993-06-25 1995-03-14 Sumitomo Electric Ind Ltd Antimicrobial artificial blood vessel and suture yarn for antimicrobial operation
US5994341A (en) * 1993-07-19 1999-11-30 Angiogenesis Technologies, Inc. Anti-angiogenic Compositions and methods for the treatment of arthritis
EG20321A (en) 1993-07-21 1998-10-31 Otsuka Pharma Co Ltd Medical material and process for producing the same
DE69330132T2 (en) 1993-07-23 2001-11-15 Cook Inc FLEXIBLE STENT WITH A CONFIGURATION MOLDED FROM A MATERIAL SHEET
DE4327024A1 (en) 1993-08-12 1995-02-16 Bayer Ag Thermoplastically processable and biodegradable aliphatic polyesteramides
DK0716610T3 (en) 1993-08-26 2006-09-04 Genetics Inst Llc Human bone morphogenetic proteins for use in neural regeneration
US5380299A (en) 1993-08-30 1995-01-10 Med Institute, Inc. Thrombolytic treated intravascular medical device
WO1995010989A1 (en) 1993-10-19 1995-04-27 Scimed Life Systems, Inc. Intravascular stent pump
DK0659389T3 (en) 1993-10-20 1999-02-15 Schneider Europ Ag endoprosthesis
US5723004A (en) 1993-10-21 1998-03-03 Corvita Corporation Expandable supportive endoluminal grafts
US5389106A (en) 1993-10-29 1995-02-14 Numed, Inc. Impermeable expandable intravascular stent
US5599301A (en) 1993-11-22 1997-02-04 Advanced Cardiovascular Systems, Inc. Motor control system for an automatic catheter inflation system
SE501288C2 (en) 1993-11-30 1995-01-09 Corimed Gmbh Process for preparing ceramic implant material, preferably hydroxylapatite having ceramic implant material
WO1995019796A1 (en) 1994-01-21 1995-07-27 Brown University Research Foundation Biocompatible implants
US6051576A (en) 1994-01-28 2000-04-18 University Of Kentucky Research Foundation Means to achieve sustained release of synergistic drugs by conjugation
US5626611A (en) 1994-02-10 1997-05-06 United States Surgical Corporation Composite bioabsorbable materials and surgical articles made therefrom
US5556413A (en) 1994-03-11 1996-09-17 Advanced Cardiovascular Systems, Inc. Coiled stent with locking ends
CA2190121A1 (en) 1994-03-15 1995-09-21 Edith Mathiowitz Polymeric gene delivery system
AU704549B2 (en) 1994-03-18 1999-04-29 Lynx Therapeutics, Inc. Oligonucleotide N3'-P5' phosphoramidates: synthesis and compounds; hybridization and nuclease resistance properties
US5726297A (en) 1994-03-18 1998-03-10 Lynx Therapeutics, Inc. Oligodeoxyribonucleotide N3' P5' phosphoramidates
US5599922A (en) * 1994-03-18 1997-02-04 Lynx Therapeutics, Inc. Oligonucleotide N3'-P5' phosphoramidates: hybridization and nuclease resistance properties
US5399666A (en) 1994-04-21 1995-03-21 E. I. Du Pont De Nemours And Company Easily degradable star-block copolymers
US5693085A (en) 1994-04-29 1997-12-02 Scimed Life Systems, Inc. Stent with collagen
US5567410A (en) 1994-06-24 1996-10-22 The General Hospital Corporation Composotions and methods for radiographic imaging
US5629077A (en) 1994-06-27 1997-05-13 Advanced Cardiovascular Systems, Inc. Biodegradable mesh and film stent
US5857998A (en) * 1994-06-30 1999-01-12 Boston Scientific Corporation Stent and therapeutic delivery system
US5670558A (en) 1994-07-07 1997-09-23 Terumo Kabushiki Kaisha Medical instruments that exhibit surface lubricity when wetted
US5788979A (en) 1994-07-22 1998-08-04 Inflow Dynamics Inc. Biodegradable coating with inhibitory properties for application to biocompatible materials
US5554120A (en) 1994-07-25 1996-09-10 Advanced Cardiovascular Systems, Inc. Polymer blends for use in making medical devices including catheters and balloons for dilatation catheters
US5817327A (en) * 1994-07-27 1998-10-06 The Trustees Of The University Of Pennsylvania Incorporation of biologically active molecules into bioactive glasses
US5516881A (en) 1994-08-10 1996-05-14 Cornell Research Foundation, Inc. Aminoxyl-containing radical spin labeling in polymers and copolymers
US6015429A (en) 1994-09-08 2000-01-18 Gore Enterprise Holdings, Inc. Procedures for introducing stents and stent-grafts
US5593403A (en) 1994-09-14 1997-01-14 Scimed Life Systems Inc. Method for modifying a stent in an implanted site
US5578073A (en) 1994-09-16 1996-11-26 Ramot Of Tel Aviv University Thromboresistant surface treatment for biomaterials
US5649977A (en) 1994-09-22 1997-07-22 Advanced Cardiovascular Systems, Inc. Metal reinforced polymer stent
US5485496A (en) 1994-09-22 1996-01-16 Cornell Research Foundation, Inc. Gamma irradiation sterilizing of biomaterial medical devices or products, with improved degradation and mechanical properties
FR2724938A1 (en) 1994-09-28 1996-03-29 Lvmh Rech POLYMERS FUNCTIONALIZED BY AMINO ACIDS OR AMINO ACID DERIVATIVES, THEIR USE AS SURFACTANTS, IN PARTICULAR, IN COSMETIC COMPOSITIONS AND IN PARTICULAR NAIL POLISH.
US5682665A (en) 1994-10-11 1997-11-04 Svanberg; Gunnar K. Method for manufacturing a dental curette
EP0785774B1 (en) 1994-10-12 2001-01-31 Focal, Inc. Targeted delivery via biodegradable polymers
US5765682A (en) 1994-10-13 1998-06-16 Menlo Care, Inc. Restrictive package for expandable or shape memory medical devices and method of preventing premature change of same
US5836964A (en) 1996-10-30 1998-11-17 Medinol Ltd. Stent fabrication method
US5707385A (en) * 1994-11-16 1998-01-13 Advanced Cardiovascular Systems, Inc. Drug loaded elastic membrane and method for delivery
CA2301351C (en) 1994-11-28 2002-01-22 Advanced Cardiovascular Systems, Inc. Method and apparatus for direct laser cutting of metal stents
US5637113A (en) 1994-12-13 1997-06-10 Advanced Cardiovascular Systems, Inc. Polymer film for wrapping a stent structure
US5569198A (en) 1995-01-23 1996-10-29 Cortrak Medical Inc. Microporous catheter
CA2141092C (en) * 1995-01-25 1999-01-05 James F. White Communication between components of a machine
US5919570A (en) 1995-02-01 1999-07-06 Schneider Inc. Slippery, tenaciously adhering hydrogel coatings containing a polyurethane-urea polymer hydrogel commingled with a poly(N-vinylpyrrolidone) polymer hydrogel, coated polymer and metal substrate materials, and coated medical devices
US6017577A (en) 1995-02-01 2000-01-25 Schneider (Usa) Inc. Slippery, tenaciously adhering hydrophilic polyurethane hydrogel coatings, coated polymer substrate materials, and coated medical devices
US5869127A (en) * 1995-02-22 1999-02-09 Boston Scientific Corporation Method of providing a substrate with a bio-active/biocompatible coating
US5702754A (en) 1995-02-22 1997-12-30 Meadox Medicals, Inc. Method of providing a substrate with a hydrophilic coating and substrates, particularly medical devices, provided with such coatings
US6231600B1 (en) 1995-02-22 2001-05-15 Scimed Life Systems, Inc. Stents with hybrid coating for medical devices
US5854376A (en) 1995-03-09 1998-12-29 Sekisui Kaseihin Kogyo Kabushiki Kaisha Aliphatic ester-amide copolymer resins
US5876743A (en) 1995-03-21 1999-03-02 Den-Mat Corporation Biocompatible adhesion in tissue repair
US5605696A (en) * 1995-03-30 1997-02-25 Advanced Cardiovascular Systems, Inc. Drug loaded polymeric material and method of manufacture
US5837313A (en) 1995-04-19 1998-11-17 Schneider (Usa) Inc Drug release stent coating process
US20020091433A1 (en) 1995-04-19 2002-07-11 Ni Ding Drug release coated stent
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
RU2169742C2 (en) 1995-04-19 2001-06-27 Катаока Казунори Heterotelochelate block copolymer and method of preparation thereof
US6120536A (en) 1995-04-19 2000-09-19 Schneider (Usa) Inc. Medical devices with long term non-thrombogenic coatings
JP2795824B2 (en) * 1995-05-12 1998-09-10 オオタ株式会社 Surface treatment method for titanium-based implant and biocompatible titanium-based implant
US5674242A (en) 1995-06-06 1997-10-07 Quanam Medical Corporation Endoprosthetic device with therapeutic compound
US5954744A (en) 1995-06-06 1999-09-21 Quanam Medical Corporation Intravascular stent
US6129761A (en) 1995-06-07 2000-10-10 Reprogenesis, Inc. Injectable hydrogel compositions
US5820917A (en) * 1995-06-07 1998-10-13 Medtronic, Inc. Blood-contacting medical device and method
US5591199A (en) 1995-06-07 1997-01-07 Porter; Christopher H. Curable fiber composite stent and delivery system
US6774278B1 (en) * 1995-06-07 2004-08-10 Cook Incorporated Coated implantable medical device
CA2178541C (en) * 1995-06-07 2009-11-24 Neal E. Fearnot Implantable medical device
US6010530A (en) * 1995-06-07 2000-01-04 Boston Scientific Technology, Inc. Self-expanding endoluminal prosthesis
US5609629A (en) 1995-06-07 1997-03-11 Med Institute, Inc. Coated implantable medical device
US7550005B2 (en) * 1995-06-07 2009-06-23 Cook Incorporated Coated implantable medical device
US7611533B2 (en) * 1995-06-07 2009-11-03 Cook Incorporated Coated implantable medical device
US5667767A (en) 1995-07-27 1997-09-16 Micro Therapeutics, Inc. Compositions for use in embolizing blood vessels
US5877224A (en) 1995-07-28 1999-03-02 Rutgers, The State University Of New Jersey Polymeric drug formulations
GB9611437D0 (en) 1995-08-03 1996-08-07 Secr Defence Biomaterial
US5830879A (en) 1995-10-02 1998-11-03 St. Elizabeth's Medical Center Of Boston, Inc. Treatment of vascular injury using vascular endothelial growth factor
US5723219A (en) 1995-12-19 1998-03-03 Talison Research Plasma deposited film networks
US5736152A (en) 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US5607442A (en) * 1995-11-13 1997-03-04 Isostent, Inc. Stent with improved radiopacity and appearance characteristics
US5658995A (en) 1995-11-27 1997-08-19 Rutgers, The State University Copolymers of tyrosine-based polycarbonate and poly(alkylene oxide)
US5957899A (en) 1995-11-27 1999-09-28 Therox, Inc. High pressure transluminal fluid delivery device
DE19545678A1 (en) 1995-12-07 1997-06-12 Goldschmidt Ag Th Copolymers of polyamino acid esters
US6048964A (en) 1995-12-12 2000-04-11 Stryker Corporation Compositions and therapeutic methods using morphogenic proteins and stimulatory factors
DK2111876T3 (en) 1995-12-18 2011-12-12 Angiodevice Internat Gmbh Crosslinked polymer preparations and methods for their use
ATE290832T1 (en) 1996-01-05 2005-04-15 Medtronic Inc EXPANDABLE ENDOLUMINAL PROSTHESES
US6150630A (en) 1996-01-11 2000-11-21 The Regents Of The University Of California Laser machining of explosives
US6033582A (en) 1996-01-22 2000-03-07 Etex Corporation Surface modification of medical implants
US6054553A (en) 1996-01-29 2000-04-25 Bayer Ag Process for the preparation of polymers having recurring agents
EP1011889B1 (en) 1996-01-30 2002-10-30 Medtronic, Inc. Articles for and methods of making stents
JP2000509014A (en) 1996-03-11 2000-07-18 フォーカル,インコーポレイテッド Polymer delivery of radionuclides and radiopharmaceuticals
US5932299A (en) 1996-04-23 1999-08-03 Katoot; Mohammad W. Method for modifying the surface of an object
US6071266A (en) 1996-04-26 2000-06-06 Kelley; Donald W. Lubricious medical devices
US6241760B1 (en) 1996-04-26 2001-06-05 G. David Jang Intravascular stent
US6592617B2 (en) 1996-04-30 2003-07-15 Boston Scientific Scimed, Inc. Three-dimensional braided covered stent
US5955509A (en) 1996-05-01 1999-09-21 Board Of Regents, The University Of Texas System pH dependent polymer micelles
US5610241A (en) * 1996-05-07 1997-03-11 Cornell Research Foundation, Inc. Reactive graft polymer with biodegradable polymer backbone and method for preparing reactive biodegradable polymers
US5733326A (en) 1996-05-28 1998-03-31 Cordis Corporation Composite material endoprosthesis
US5876433A (en) 1996-05-29 1999-03-02 Ethicon, Inc. Stent and method of varying amounts of heparin coated thereon to control treatment
US5874165A (en) 1996-06-03 1999-02-23 Gore Enterprise Holdings, Inc. Materials and method for the immobilization of bioactive species onto polymeric subtrates
US5914182A (en) 1996-06-03 1999-06-22 Gore Hybrid Technologies, Inc. Materials and methods for the immobilization of bioactive species onto polymeric substrates
NL1003459C2 (en) * 1996-06-28 1998-01-07 Univ Twente Copoly (ester amides) and copoly (ester urethanes).
US5711958A (en) 1996-07-11 1998-01-27 Life Medical Sciences, Inc. Methods for reducing or eliminating post-surgical adhesion formation
JPH1033562A (en) 1996-07-25 1998-02-10 Injietsukusu:Kk Artificial dental root
US5830178A (en) 1996-10-11 1998-11-03 Micro Therapeutics, Inc. Methods for embolizing vascular sites with an emboilizing composition comprising dimethylsulfoxide
US5800516A (en) 1996-08-08 1998-09-01 Cordis Corporation Deployable and retrievable shape memory stent/tube and method
US6060518A (en) 1996-08-16 2000-05-09 Supratek Pharma Inc. Polymer compositions for chemotherapy and methods of treatment using the same
US6344271B1 (en) 1998-11-06 2002-02-05 Nanoenergy Corporation Materials and products using nanostructured non-stoichiometric substances
US5855618A (en) * 1996-09-13 1999-01-05 Meadox Medicals, Inc. Polyurethanes grafted with polyethylene oxide chains containing covalently bonded heparin
US5807404A (en) * 1996-09-19 1998-09-15 Medinol Ltd. Stent with variable features to optimize support and method of making such stent
US5783657A (en) 1996-10-18 1998-07-21 Union Camp Corporation Ester-terminated polyamides of polymerized fatty acids useful in formulating transparent gels in low polarity liquids
US6387121B1 (en) 1996-10-21 2002-05-14 Inflow Dynamics Inc. Vascular and endoluminal stents with improved coatings
US5868781A (en) 1996-10-22 1999-02-09 Scimed Life Systems, Inc. Locking stent
US6530951B1 (en) 1996-10-24 2003-03-11 Cook Incorporated Silver implantable medical device
US5833651A (en) 1996-11-08 1998-11-10 Medtronic, Inc. Therapeutic intraluminal stents
US5877263A (en) 1996-11-25 1999-03-02 Meadox Medicals, Inc. Process for preparing polymer coatings grafted with polyethylene oxide chains containing covalently bonded bio-active agents
US5728751A (en) 1996-11-25 1998-03-17 Meadox Medicals, Inc. Bonding bio-active materials to substrate surfaces
US5741881A (en) 1996-11-25 1998-04-21 Meadox Medicals, Inc. Process for preparing covalently bound-heparin containing polyurethane-peo-heparin coating compositions
US6120491A (en) 1997-11-07 2000-09-19 The State University Rutgers Biodegradable, anionic polymers derived from the amino acid L-tyrosine
JP3760533B2 (en) * 1996-11-29 2006-03-29 マツダ株式会社 Power steering operation abnormality detection device
IT1289728B1 (en) 1996-12-10 1998-10-16 Sorin Biomedica Cardio Spa SYSTEM AND EQUIPMENT DEVICE THAT INCLUDES IT
US5980972A (en) 1996-12-20 1999-11-09 Schneider (Usa) Inc Method of applying drug-release coatings
US5906759A (en) 1996-12-26 1999-05-25 Medinol Ltd. Stent forming apparatus with stent deforming blades
IT1291001B1 (en) 1997-01-09 1998-12-14 Sorin Biomedica Cardio Spa ANGIOPLASTIC STENT AND ITS PRODUCTION PROCESS
US5733330A (en) 1997-01-13 1998-03-31 Advanced Cardiovascular Systems, Inc. Balloon-expandable, crush-resistant locking stent
US5997517A (en) 1997-01-27 1999-12-07 Sts Biopolymers, Inc. Bonding layers for medical device surface coatings
DE69826639T2 (en) 1997-01-28 2005-10-06 United States Surgical Corp., Norwalk SURGICAL ARTICLES MADE FROM POLYESTERAMIDES WITH GROUPS DERIVED FROM AMINO ACIDS AND ALTERNATIVELY WITH GROUPS DERIVED FROM ALPHA HYDROXYLIC ACIDS
DE69828387T2 (en) 1997-01-28 2005-12-08 United States Surgical Corp., Norwalk POLYESTERAMIDE, ITS PRESENTATION AND SURGICAL FABRICATED SURGICAL ARTICLES
WO1998032779A1 (en) 1997-01-28 1998-07-30 United States Surgical Corporation Polyesteramide, its preparation and surgical devices fabricated therefrom
US6159951A (en) 1997-02-13 2000-12-12 Ribozyme Pharmaceuticals Inc. 2'-O-amino-containing nucleoside analogs and polynucleotides
US5954724A (en) 1997-03-27 1999-09-21 Davidson; James A. Titanium molybdenum hafnium alloys for medical implants and devices
US6210715B1 (en) 1997-04-01 2001-04-03 Cap Biotechnology, Inc. Calcium phosphate microcarriers and microspheres
US5874101A (en) * 1997-04-14 1999-02-23 Usbiomaterials Corp. Bioactive-gel compositions and methods
US5843172A (en) 1997-04-15 1998-12-01 Advanced Cardiovascular Systems, Inc. Porous medicated stent
US6240616B1 (en) 1997-04-15 2001-06-05 Advanced Cardiovascular Systems, Inc. Method of manufacturing a medicated porous metal prosthesis
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
FI103715B (en) 1997-04-21 1999-08-31 Vivoxid Oy New composite and its use
US5879697A (en) 1997-04-30 1999-03-09 Schneider Usa Inc Drug-releasing coatings for medical devices
US5741327A (en) 1997-05-06 1998-04-21 Global Therapeutics, Inc. Surgical stent featuring radiopaque markers
US6303901B1 (en) 1997-05-20 2001-10-16 The Regents Of The University Of California Method to reduce damage to backing plate
US5891192A (en) 1997-05-22 1999-04-06 The Regents Of The University Of California Ion-implanted protein-coated intralumenal implants
US6159978A (en) 1997-05-28 2000-12-12 Aventis Pharmaceuticals Product, Inc. Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases
US6245760B1 (en) 1997-05-28 2001-06-12 Aventis Pharmaceuticals Products, Inc Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases
US6180632B1 (en) * 1997-05-28 2001-01-30 Aventis Pharmaceuticals Products Inc. Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases
US6056993A (en) 1997-05-30 2000-05-02 Schneider (Usa) Inc. Porous protheses and methods for making the same wherein the protheses are formed by spraying water soluble and water insoluble fibers onto a rotating mandrel
US6110483A (en) 1997-06-23 2000-08-29 Sts Biopolymers, Inc. Adherent, flexible hydrogel and medicated coatings
US6211249B1 (en) 1997-07-11 2001-04-03 Life Medical Sciences, Inc. Polyester polyether block copolymers
US5980928A (en) 1997-07-29 1999-11-09 Terry; Paul B. Implant for preventing conjunctivitis in cattle
US5980564A (en) 1997-08-01 1999-11-09 Schneider (Usa) Inc. Bioabsorbable implantable endoprosthesis with reservoir
US6174330B1 (en) * 1997-08-01 2001-01-16 Schneider (Usa) Inc Bioabsorbable marker having radiopaque constituents
US6340367B1 (en) 1997-08-01 2002-01-22 Boston Scientific Scimed, Inc. Radiopaque markers and methods of using the same
US6245103B1 (en) 1997-08-01 2001-06-12 Schneider (Usa) Inc Bioabsorbable self-expanding stent
AU8901798A (en) 1997-08-08 1999-03-01 Procter & Gamble Company, The Laundry detergent compositions with amino acid based polymers to provide appearance and integrity benefits to fabrics laundered therewith
US6121027A (en) 1997-08-15 2000-09-19 Surmodics, Inc. Polybifunctional reagent having a polymeric backbone and photoreactive moieties and bioactive groups
US6316522B1 (en) * 1997-08-18 2001-11-13 Scimed Life Systems, Inc. Bioresorbable hydrogel compositions for implantable prostheses
US6117979A (en) 1997-08-18 2000-09-12 Medtronic, Inc. Process for making a bioprosthetic device and implants produced therefrom
US6129928A (en) 1997-09-05 2000-10-10 Icet, Inc. Biomimetic calcium phosphate implant coatings and methods for making the same
US6284333B1 (en) 1997-09-10 2001-09-04 Scimed Life Systems, Inc. Medical devices made from polymer blends containing low melting temperature liquid crystal polymers
US6010445A (en) * 1997-09-11 2000-01-04 Implant Sciences Corporation Radioactive medical device and process
WO1999016871A2 (en) 1997-09-22 1999-04-08 Max-Planck-Gesellschaft Zur Forderung Der Wissensc Nucleic acid catalysts with endonuclease activity
DE69838256T2 (en) 1997-09-24 2008-05-15 Med Institute, Inc., West Lafayette RADIAL EXPANDABLE STENT
US6890546B2 (en) 1998-09-24 2005-05-10 Abbott Laboratories Medical devices containing rapamycin analogs
US5972027A (en) 1997-09-30 1999-10-26 Scimed Life Systems, Inc Porous stent drug delivery system
US5976182A (en) 1997-10-03 1999-11-02 Advanced Cardiovascular Systems, Inc. Balloon-expandable, crush-resistant locking stent and method of loading the same
US6120788A (en) 1997-10-16 2000-09-19 Bioamide, Inc. Bioabsorbable triglycolic acid poly(ester-amide)s
US6015541A (en) 1997-11-03 2000-01-18 Micro Therapeutics, Inc. Radioactive embolizing compositions
DE19881727D2 (en) 1997-11-24 2001-01-04 Herbert P Jennissen Process for immobilizing mediator molecules on inorganic and metallic implant materials
US6093463A (en) 1997-12-12 2000-07-25 Intella Interventional Systems, Inc. Medical devices made from improved polymer blends
US5957975A (en) 1997-12-15 1999-09-28 The Cleveland Clinic Foundation Stent having a programmed pattern of in vivo degradation
US6626939B1 (en) 1997-12-18 2003-09-30 Boston Scientific Scimed, Inc. Stent-graft with bioabsorbable structural support
US5986169A (en) 1997-12-31 1999-11-16 Biorthex Inc. Porous nickel-titanium alloy article
WO1999034750A1 (en) * 1998-01-06 1999-07-15 Bioamide, Inc. Bioabsorbable fibers and reinforced composites produced therefrom
US6224626B1 (en) 1998-02-17 2001-05-01 Md3, Inc. Ultra-thin expandable stent
DK1062278T3 (en) 1998-02-23 2006-09-25 Mnemoscience Gmbh Polymers with shape memory
US5938697A (en) 1998-03-04 1999-08-17 Scimed Life Systems, Inc. Stent having variable properties
US6110188A (en) 1998-03-09 2000-08-29 Corvascular, Inc. Anastomosis method
US6258371B1 (en) 1998-04-03 2001-07-10 Medtronic Inc Method for making biocompatible medical article
US20030040790A1 (en) * 1998-04-15 2003-02-27 Furst Joseph G. Stent coating
US20010029351A1 (en) 1998-04-16 2001-10-11 Robert Falotico Drug combinations and delivery devices for the prevention and treatment of vascular disease
US7658727B1 (en) 1998-04-20 2010-02-09 Medtronic, Inc Implantable medical device with enhanced biocompatibility and biostability
EP1555036B1 (en) 1998-04-27 2010-05-05 Surmodics Inc. Bioactive agent release coating
US20020188037A1 (en) 1999-04-15 2002-12-12 Chudzik Stephen J. Method and system for providing bioactive agent release coating
US6113629A (en) 1998-05-01 2000-09-05 Micrus Corporation Hydrogel for the therapeutic treatment of aneurysms
KR100314496B1 (en) 1998-05-28 2001-11-22 윤동진 Non-thrombogenic heparin derivatives, process for preparation and use thereof
US6083258A (en) 1998-05-28 2000-07-04 Yadav; Jay S. Locking stent
EP0966979B1 (en) 1998-06-25 2006-03-08 Biotronik AG Implantable bioresorbable support for the vascular walls, in particular coronary stent
US6153252A (en) 1998-06-30 2000-11-28 Ethicon, Inc. Process for coating stents
WO2000010622A1 (en) 1998-08-20 2000-03-02 Cook Incorporated Coated implantable medical device
US6248127B1 (en) 1998-08-21 2001-06-19 Medtronic Ave, Inc. Thromboresistant coated medical device
US6335029B1 (en) * 1998-08-28 2002-01-01 Scimed Life Systems, Inc. Polymeric coatings for controlled delivery of active agents
US6123703A (en) 1998-09-19 2000-09-26 Tu; Lily Chen Ablation catheter and methods for treating tissues
US6011125A (en) * 1998-09-25 2000-01-04 General Electric Company Amide modified polyesters
US6358276B1 (en) 1998-09-30 2002-03-19 Impra, Inc. Fluid containing endoluminal stent
WO2000023123A1 (en) 1998-10-19 2000-04-27 Synthes Ag Chur Hardenable ceramic hydraulic cement
DE19855421C2 (en) 1998-11-02 2001-09-20 Alcove Surfaces Gmbh Implant
DE69822470T2 (en) 1998-11-12 2005-01-20 Takiron Co. Ltd. Biodegradable absorbable shape memory material
WO2000029501A1 (en) 1998-11-18 2000-05-25 Emory University Radioactive coating solutions, methods, and substrates
US6125523A (en) 1998-11-20 2000-10-03 Advanced Cardiovascular Systems, Inc. Stent crimping tool and method of use
US6530950B1 (en) 1999-01-12 2003-03-11 Quanam Medical Corporation Intraluminal stent having coaxial polymer member
DE60017363T2 (en) 1999-02-02 2006-03-02 Wright Medical Technology Inc., Arlington CONTROLLED RELEASE OF A COMPOSITE MATERIAL
US6419692B1 (en) 1999-02-03 2002-07-16 Scimed Life Systems, Inc. Surface protection method for stents and balloon catheters for drug delivery
US6143354A (en) 1999-02-08 2000-11-07 Medtronic Inc. One-step method for attachment of biomolecules to substrate surfaces
US6187045B1 (en) 1999-02-10 2001-02-13 Thomas K. Fehring Enhanced biocompatible implants and alloys
US6066156A (en) 1999-03-11 2000-05-23 Advanced Cardiovascular Systems, Inc. Temperature activated adhesive for releasably attaching stents to balloons
US6183505B1 (en) * 1999-03-11 2001-02-06 Medtronic Ave, Inc. Method of stent retention to a delivery catheter balloon-braided retainers
US6238491B1 (en) 1999-05-05 2001-05-29 Davitech, Inc. Niobium-titanium-zirconium-molybdenum (nbtizrmo) alloys for dental and other medical device applications
US6667049B2 (en) 1999-06-14 2003-12-23 Ethicon, Inc. Relic process for producing bioresorbable ceramic tissue scaffolds
US6312459B1 (en) 1999-06-30 2001-11-06 Advanced Cardiovascular Systems, Inc. Stent design for use in small vessels
US6258121B1 (en) 1999-07-02 2001-07-10 Scimed Life Systems, Inc. Stent coating
US6283947B1 (en) 1999-07-13 2001-09-04 Advanced Cardiovascular Systems, Inc. Local drug delivery injection catheter
US6494862B1 (en) * 1999-07-13 2002-12-17 Advanced Cardiovascular Systems, Inc. Substance delivery apparatus and a method of delivering a therapeutic substance to an anatomical passageway
US6177523B1 (en) * 1999-07-14 2001-01-23 Cardiotech International, Inc. Functionalized polyurethanes
US6569193B1 (en) 1999-07-22 2003-05-27 Advanced Cardiovascular Systems, Inc. Tapered self-expanding stent
DE19938704C1 (en) 1999-08-14 2001-10-31 Ivoclar Vivadent Ag Process for the production of reaction systems for implantation in the human and animal body as a bone substitute, which i.a. Contain calcium and phosphorus
US6479565B1 (en) 1999-08-16 2002-11-12 Harold R. Stanley Bioactive ceramic cement
US6379381B1 (en) 1999-09-03 2002-04-30 Advanced Cardiovascular Systems, Inc. Porous prosthesis and a method of depositing substances into the pores
US6503556B2 (en) 2000-12-28 2003-01-07 Advanced Cardiovascular Systems, Inc. Methods of forming a coating for a prosthesis
US6749626B1 (en) 2000-03-31 2004-06-15 Advanced Cardiovascular Systems, Inc. Actinomycin D for the treatment of vascular disease
US6790228B2 (en) 1999-12-23 2004-09-14 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US6759054B2 (en) 1999-09-03 2004-07-06 Advanced Cardiovascular Systems, Inc. Ethylene vinyl alcohol composition and coating
US20040029952A1 (en) * 1999-09-03 2004-02-12 Yung-Ming Chen Ethylene vinyl alcohol composition and coating
US6503954B1 (en) * 2000-03-31 2003-01-07 Advanced Cardiovascular Systems, Inc. Biocompatible carrier containing actinomycin D and a method of forming the same
US6713119B2 (en) 1999-09-03 2004-03-30 Advanced Cardiovascular Systems, Inc. Biocompatible coating for a prosthesis and a method of forming the same
US6287628B1 (en) 1999-09-03 2001-09-11 Advanced Cardiovascular Systems, Inc. Porous prosthesis and a method of depositing substances into the pores
JP4172883B2 (en) 1999-09-08 2008-10-29 Hoya株式会社 Drug sustained release carrier and method for producing drug sustained release carrier
US6204245B1 (en) 1999-09-17 2001-03-20 The Regents Of The University Of California Treatment of narcolepsy with immunosuppressants
US6403663B1 (en) 1999-09-20 2002-06-11 North Carolina State University Method of making foamed materials using surfactants and carbon dioxide
US6203551B1 (en) * 1999-10-04 2001-03-20 Advanced Cardiovascular Systems, Inc. Chamber for applying therapeutic substances to an implant device
US6331313B1 (en) 1999-10-22 2001-12-18 Oculex Pharmaceticals, Inc. Controlled-release biocompatible ocular drug delivery implant devices and methods
US6551303B1 (en) 1999-10-27 2003-04-22 Atritech, Inc. Barrier device for ostium of left atrial appendage
DE19953771C1 (en) * 1999-11-09 2001-06-13 Coripharm Medizinprodukte Gmbh Absorbable bone implant material and method for producing the same
WO2001035928A1 (en) 1999-11-17 2001-05-25 Microchips, Inc. Microfabricated devices for the delivery of molecules into a carrier fluid
US6251136B1 (en) 1999-12-08 2001-06-26 Advanced Cardiovascular Systems, Inc. Method of layering a three-coated stent using pharmacological and polymeric agents
US6508832B1 (en) * 1999-12-09 2003-01-21 Advanced Cardiovascular Systems, Inc. Implantable nickel-free stainless steel stents and method of making the same
US6554854B1 (en) 1999-12-10 2003-04-29 Scimed Life Systems, Inc. Process for laser joining dissimilar metals and endoluminal stent with radiopaque marker produced thereby
US6494908B1 (en) 1999-12-22 2002-12-17 Ethicon, Inc. Removable stent for body lumens
US6338739B1 (en) 1999-12-22 2002-01-15 Ethicon, Inc. Biodegradable stent
US6613432B2 (en) * 1999-12-22 2003-09-02 Biosurface Engineering Technologies, Inc. Plasma-deposited coatings, devices and methods
US20050238686A1 (en) 1999-12-23 2005-10-27 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US6908624B2 (en) 1999-12-23 2005-06-21 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
US6283949B1 (en) 1999-12-27 2001-09-04 Advanced Cardiovascular Systems, Inc. Refillable implantable drug delivery pump
AU2599501A (en) 1999-12-29 2001-07-09 Advanced Cardiovascular Systems Inc. Device and active component for inhibiting formation of thrombus-inflammatory cell matrix
AU2623201A (en) 1999-12-30 2001-07-16 Kam W Leong Controlled delivery of therapeutic agents by insertable medical devices
US6375826B1 (en) 2000-02-14 2002-04-23 Advanced Cardiovascular Systems, Inc. Electro-polishing fixture and electrolyte solution for polishing stents and method
KR100371559B1 (en) 2000-04-03 2003-02-06 주식회사 경원메디칼 Calcium phosphate artificial bone as osteoconductive and biodegradable bone substitute material
US6527801B1 (en) 2000-04-13 2003-03-04 Advanced Cardiovascular Systems, Inc. Biodegradable drug delivery material for stent
JP4686006B2 (en) 2000-04-27 2011-05-18 大日本印刷株式会社 Halftone phase shift photomask, blank for halftone phase shift photomask, and method for manufacturing halftone phase shift photomask
US6270779B1 (en) 2000-05-10 2001-08-07 United States Of America Nitric oxide-releasing metallic medical devices
US7300662B2 (en) 2000-05-12 2007-11-27 Cordis Corporation Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020005206A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Antiproliferative drug and delivery device
US20020007213A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US6776796B2 (en) * 2000-05-12 2004-08-17 Cordis Corportation Antiinflammatory drug and delivery device
US20020007214A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US20020007215A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US20040243097A1 (en) 2000-05-12 2004-12-02 Robert Falotico Antiproliferative drug and delivery device
EP1153621A1 (en) 2000-05-12 2001-11-14 MERCK PATENT GmbH Biocements based on a mixture of TCP-PHA with improved compressive strength
US6395326B1 (en) 2000-05-31 2002-05-28 Advanced Cardiovascular Systems, Inc. Apparatus and method for depositing a coating onto a surface of a prosthesis
US6673385B1 (en) * 2000-05-31 2004-01-06 Advanced Cardiovascular Systems, Inc. Methods for polymeric coatings stents
US6585765B1 (en) 2000-06-29 2003-07-01 Advanced Cardiovascular Systems, Inc. Implantable device having substances impregnated therein and a method of impregnating the same
US20020077693A1 (en) 2000-12-19 2002-06-20 Barclay Bruce J. Covered, coiled drug delivery stent and method
US6555157B1 (en) 2000-07-25 2003-04-29 Advanced Cardiovascular Systems, Inc. Method for coating an implantable device and system for performing the method
WO2002009768A2 (en) 2000-07-27 2002-02-07 Rutgers, The State University Therapeutic polyesters and polyamides
US6569191B1 (en) 2000-07-27 2003-05-27 Bionx Implants, Inc. Self-expanding stent with enhanced radial expansion and shape memory
US6574851B1 (en) 2000-07-31 2003-06-10 Advanced Cardiovascular Systems, Inc. Stent made by rotational molding or centrifugal casting and method for making the same
US6451373B1 (en) 2000-08-04 2002-09-17 Advanced Cardiovascular Systems, Inc. Method of forming a therapeutic coating onto a surface of an implantable prosthesis
US6503538B1 (en) 2000-08-30 2003-01-07 Cornell Research Foundation, Inc. Elastomeric functional biodegradable copolyester amides and copolyester urethanes
US6585926B1 (en) 2000-08-31 2003-07-01 Advanced Cardiovascular Systems, Inc. Method of manufacturing a porous balloon
US6485512B1 (en) 2000-09-27 2002-11-26 Advanced Cardiovascular Systems, Inc. Two-stage light curable stent and delivery system
US6716444B1 (en) 2000-09-28 2004-04-06 Advanced Cardiovascular Systems, Inc. Barriers for polymer-coated implantable medical devices and methods for making the same
US6953560B1 (en) 2000-09-28 2005-10-11 Advanced Cardiovascular Systems, Inc. Barriers for polymer-coated implantable medical devices and methods for making the same
US6254632B1 (en) 2000-09-28 2001-07-03 Advanced Cardiovascular Systems, Inc. Implantable medical device having protruding surface structures for drug delivery and cover attachment
US20020111590A1 (en) 2000-09-29 2002-08-15 Davila Luis A. Medical devices, drug coatings and methods for maintaining the drug coatings thereon
US7261735B2 (en) 2001-05-07 2007-08-28 Cordis Corporation Local drug delivery devices and methods for maintaining the drug coatings thereon
US20020051730A1 (en) 2000-09-29 2002-05-02 Stanko Bodnar Coated medical devices and sterilization thereof
US6746773B2 (en) 2000-09-29 2004-06-08 Ethicon, Inc. Coatings for medical devices
US6492615B1 (en) 2000-10-12 2002-12-10 Scimed Life Systems, Inc. Laser polishing of medical devices
US6506437B1 (en) * 2000-10-17 2003-01-14 Advanced Cardiovascular Systems, Inc. Methods of coating an implantable device having depots formed in a surface thereof
US6558733B1 (en) 2000-10-26 2003-05-06 Advanced Cardiovascular Systems, Inc. Method for etching a micropatterned microdepot prosthesis
US6758859B1 (en) 2000-10-30 2004-07-06 Kenny L. Dang Increased drug-loading and reduced stress drug delivery device
US6517888B1 (en) * 2000-11-28 2003-02-11 Scimed Life Systems, Inc. Method for manufacturing a medical device having a coated portion by laser ablation
US6664335B2 (en) 2000-11-30 2003-12-16 Cardiac Pacemakers, Inc. Polyurethane elastomer article with “shape memory” and medical devices therefrom
US20020082679A1 (en) 2000-12-22 2002-06-27 Avantec Vascular Corporation Delivery or therapeutic capable agents
US6824559B2 (en) 2000-12-22 2004-11-30 Advanced Cardiovascular Systems, Inc. Ethylene-carboxyl copolymers as drug delivery matrices
US7077859B2 (en) 2000-12-22 2006-07-18 Avantec Vascular Corporation Apparatus and methods for variably controlled substance delivery from implanted prostheses
US6544543B1 (en) 2000-12-27 2003-04-08 Advanced Cardiovascular Systems, Inc. Periodic constriction of vessels to treat ischemic tissue
US6540776B2 (en) 2000-12-28 2003-04-01 Advanced Cardiovascular Systems, Inc. Sheath for a prosthesis and methods of forming the same
US6663662B2 (en) 2000-12-28 2003-12-16 Advanced Cardiovascular Systems, Inc. Diffusion barrier layer for implantable devices
US6565599B1 (en) 2000-12-28 2003-05-20 Advanced Cardiovascular Systems, Inc. Hybrid stent
US20020087123A1 (en) 2001-01-02 2002-07-04 Hossainy Syed F.A. Adhesion of heparin-containing coatings to blood-contacting surfaces of medical devices
US6645195B1 (en) 2001-01-05 2003-11-11 Advanced Cardiovascular Systems, Inc. Intraventricularly guided agent delivery system and method of use
US6544223B1 (en) 2001-01-05 2003-04-08 Advanced Cardiovascular Systems, Inc. Balloon catheter for delivering therapeutic agents
US6544582B1 (en) 2001-01-05 2003-04-08 Advanced Cardiovascular Systems, Inc. Method and apparatus for coating an implantable device
US6740040B1 (en) 2001-01-30 2004-05-25 Advanced Cardiovascular Systems, Inc. Ultrasound energy driven intraventricular catheter to treat ischemia
US20030032767A1 (en) * 2001-02-05 2003-02-13 Yasuhiro Tada High-strength polyester-amide fiber and process for producing the same
WO2002064014A2 (en) 2001-02-09 2002-08-22 Endoluminal Therapeutics, Inc. Endomural therapy
US6540777B2 (en) 2001-02-15 2003-04-01 Scimed Life Systems, Inc. Locking stent
US6490228B2 (en) 2001-02-16 2002-12-03 Koninklijke Philips Electronics N.V. Apparatus and method of forming electrical connections to an acoustic transducer
WO2002072014A2 (en) * 2001-03-08 2002-09-19 Volcano Therapeutics, Inc. Medical devices, compositions and methods for treating vulnerable plaque
US6613077B2 (en) 2001-03-27 2003-09-02 Scimed Life Systems, Inc. Stent with controlled expansion
US6645135B1 (en) 2001-03-30 2003-11-11 Advanced Cardiovascular Systems, Inc. Intravascular catheter device and method for simultaneous local delivery of radiation and a therapeutic substance
US6780424B2 (en) 2001-03-30 2004-08-24 Charles David Claude Controlled morphologies in polymer drug for release of drugs from polymer films
US6623448B2 (en) 2001-03-30 2003-09-23 Advanced Cardiovascular Systems, Inc. Steerable drug delivery device
US6625486B2 (en) 2001-04-11 2003-09-23 Advanced Cardiovascular Systems, Inc. Method and apparatus for intracellular delivery of an agent
US6764505B1 (en) 2001-04-12 2004-07-20 Advanced Cardiovascular Systems, Inc. Variable surface area stent
US6712845B2 (en) 2001-04-24 2004-03-30 Advanced Cardiovascular Systems, Inc. Coating for a stent and a method of forming the same
EP1383504A1 (en) * 2001-04-26 2004-01-28 Control Delivery Systems, Inc. Sustained release drug delivery system containing codrugs
US6660034B1 (en) 2001-04-30 2003-12-09 Advanced Cardiovascular Systems, Inc. Stent for increasing blood flow to ischemic tissues and a method of using the same
US8182527B2 (en) * 2001-05-07 2012-05-22 Cordis Corporation Heparin barrier coating for controlled drug release
US6656506B1 (en) 2001-05-09 2003-12-02 Advanced Cardiovascular Systems, Inc. Microparticle coated medical device
US7651695B2 (en) 2001-05-18 2010-01-26 Advanced Cardiovascular Systems, Inc. Medicated stents for the treatment of vascular disease
US7862495B2 (en) 2001-05-31 2011-01-04 Advanced Cardiovascular Systems, Inc. Radiation or drug delivery source with activity gradient to minimize edge effects
US6743462B1 (en) 2001-05-31 2004-06-01 Advanced Cardiovascular Systems, Inc. Apparatus and method for coating implantable devices
US6605154B1 (en) 2001-05-31 2003-08-12 Advanced Cardiovascular Systems, Inc. Stent mounting device
US6679980B1 (en) * 2001-06-13 2004-01-20 Advanced Cardiovascular Systems, Inc. Apparatus for electropolishing a stent
US6666880B1 (en) 2001-06-19 2003-12-23 Advised Cardiovascular Systems, Inc. Method and system for securing a coated stent to a balloon catheter
US6527938B2 (en) 2001-06-21 2003-03-04 Syntheon, Llc Method for microporous surface modification of implantable metallic medical articles
US6572644B1 (en) 2001-06-27 2003-06-03 Advanced Cardiovascular Systems, Inc. Stent mounting device and a method of using the same to coat a stent
US6695920B1 (en) 2001-06-27 2004-02-24 Advanced Cardiovascular Systems, Inc. Mandrel for supporting a stent and a method of using the mandrel to coat a stent
US6565659B1 (en) 2001-06-28 2003-05-20 Advanced Cardiovascular Systems, Inc. Stent mounting assembly and a method of using the same to coat a stent
US6673154B1 (en) * 2001-06-28 2004-01-06 Advanced Cardiovascular Systems, Inc. Stent mounting device to coat a stent
US6585755B2 (en) 2001-06-29 2003-07-01 Advanced Cardiovascular Polymeric stent suitable for imaging by MRI and fluoroscopy
US6706013B1 (en) 2001-06-29 2004-03-16 Advanced Cardiovascular Systems, Inc. Variable length drug delivery catheter
US6527863B1 (en) 2001-06-29 2003-03-04 Advanced Cardiovascular Systems, Inc. Support device for a stent and a method of using the same to coat a stent
US6656216B1 (en) 2001-06-29 2003-12-02 Advanced Cardiovascular Systems, Inc. Composite stent with regioselective material
EP1273314A1 (en) 2001-07-06 2003-01-08 Terumo Kabushiki Kaisha Stent
US6641611B2 (en) 2001-11-26 2003-11-04 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
IN2014DN10834A (en) 2001-09-17 2015-09-04 Psivida Inc
US20030083739A1 (en) 2001-09-24 2003-05-01 Robert Cafferata Rational drug therapy device and methods
US7195640B2 (en) 2001-09-25 2007-03-27 Cordis Corporation Coated medical devices for the treatment of vulnerable plaque
US20030059520A1 (en) 2001-09-27 2003-03-27 Yung-Ming Chen Apparatus for regulating temperature of a composition and a method of coating implantable devices
US6753071B1 (en) 2001-09-27 2004-06-22 Advanced Cardiovascular Systems, Inc. Rate-reducing membrane for release of an agent
US20030073961A1 (en) 2001-09-28 2003-04-17 Happ Dorrie M. Medical device containing light-protected therapeutic agent and a method for fabricating thereof
US20030065377A1 (en) 2001-09-28 2003-04-03 Davila Luis A. Coated medical devices
US6939376B2 (en) 2001-11-05 2005-09-06 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7585516B2 (en) 2001-11-12 2009-09-08 Advanced Cardiovascular Systems, Inc. Coatings for drug delivery devices
US6663880B1 (en) 2001-11-30 2003-12-16 Advanced Cardiovascular Systems, Inc. Permeabilizing reagents to increase drug delivery and a method of local delivery
US6752826B2 (en) 2001-12-14 2004-06-22 Thoratec Corporation Layered stent-graft and methods of making the same
US6709514B1 (en) 2001-12-28 2004-03-23 Advanced Cardiovascular Systems, Inc. Rotary coating apparatus for coating implantable medical devices
US7445629B2 (en) 2002-01-31 2008-11-04 Boston Scientific Scimed, Inc. Medical device for delivering biologically active material
US6887270B2 (en) 2002-02-08 2005-05-03 Boston Scientific Scimed, Inc. Implantable or insertable medical device resistant to microbial growth and biofilm formation
US6743463B2 (en) 2002-03-28 2004-06-01 Scimed Life Systems, Inc. Method for spray-coating a medical device having a tubular wall such as a stent
US20030203915A1 (en) 2002-04-05 2003-10-30 Xinqin Fang Nitric oxide donors, compositions and methods of use related applications
US20040024450A1 (en) 2002-04-24 2004-02-05 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7008979B2 (en) 2002-04-30 2006-03-07 Hydromer, Inc. Coating composition for multiple hydrophilic applications
US6865810B2 (en) 2002-06-27 2005-03-15 Scimed Life Systems, Inc. Methods of making medical devices
US20040054104A1 (en) 2002-09-05 2004-03-18 Pacetti Stephen D. Coatings for drug delivery devices comprising modified poly(ethylene-co-vinyl alcohol)
US20040063805A1 (en) 2002-09-19 2004-04-01 Pacetti Stephen D. Coatings for implantable medical devices and methods for fabrication thereof
US6818063B1 (en) 2002-09-24 2004-11-16 Advanced Cardiovascular Systems, Inc. Stent mandrel fixture and method for minimizing coating defects
US7087263B2 (en) 2002-10-09 2006-08-08 Advanced Cardiovascular Systems, Inc. Rare limiting barriers for implantable medical devices
US20040147999A1 (en) 2003-01-24 2004-07-29 Kishore Udipi Stent with epoxy primer coating
US8088404B2 (en) 2003-03-20 2012-01-03 Medtronic Vasular, Inc. Biocompatible controlled release coatings for medical devices and related methods
US20040230298A1 (en) 2003-04-25 2004-11-18 Medtronic Vascular, Inc. Drug-polymer coated stent with polysulfone and styrenic block copolymer
US6846323B2 (en) * 2003-05-15 2005-01-25 Advanced Cardiovascular Systems, Inc. Intravascular stent
EP1633280A4 (en) * 2003-06-16 2011-03-16 Univ Nanyang Tech Polymeric stent and method of manufacture
US7318944B2 (en) 2003-08-07 2008-01-15 Medtronic Vascular, Inc. Extrusion process for coating stents
US20050038497A1 (en) * 2003-08-11 2005-02-17 Scimed Life Systems, Inc. Deformation medical device without material deformation
US20050037052A1 (en) * 2003-08-13 2005-02-17 Medtronic Vascular, Inc. Stent coating with gradient porosity
US20050043786A1 (en) * 2003-08-18 2005-02-24 Medtronic Ave, Inc. Methods and apparatus for treatment of aneurysmal tissue
US20050049693A1 (en) 2003-08-25 2005-03-03 Medtronic Vascular Inc. Medical devices and compositions for delivering biophosphonates to anatomical sites at risk for vascular disease
US20050055078A1 (en) 2003-09-04 2005-03-10 Medtronic Vascular, Inc. Stent with outer slough coating
US7544381B2 (en) 2003-09-09 2009-06-09 Boston Scientific Scimed, Inc. Lubricious coatings for medical device
US20050054774A1 (en) 2003-09-09 2005-03-10 Scimed Life Systems, Inc. Lubricious coating
US20050060020A1 (en) 2003-09-17 2005-03-17 Scimed Life Systems, Inc. Covered stent with biologically active material
US7371228B2 (en) 2003-09-19 2008-05-13 Medtronic Vascular, Inc. Delivery of therapeutics to treat aneurysms
US20050065501A1 (en) 2003-09-23 2005-03-24 Scimed Life Systems, Inc. Energy activated vaso-occlusive devices
US7789891B2 (en) 2003-09-23 2010-09-07 Boston Scientific Scimed, Inc. External activation of vaso-occlusive implants
US7060319B2 (en) 2003-09-24 2006-06-13 Boston Scientific Scimed, Inc. method for using an ultrasonic nozzle to coat a medical appliance
US8801692B2 (en) 2003-09-24 2014-08-12 Medtronic Vascular, Inc. Gradient coated stent and method of fabrication
US7055237B2 (en) 2003-09-29 2006-06-06 Medtronic Vascular, Inc. Method of forming a drug eluting stent
US20050074406A1 (en) 2003-10-03 2005-04-07 Scimed Life Systems, Inc. Ultrasound coating for enhancing visualization of medical device in ultrasound images
US6984411B2 (en) 2003-10-14 2006-01-10 Boston Scientific Scimed, Inc. Method for roll coating multiple stents
EP1604697A1 (en) 2004-06-09 2005-12-14 J.A.C.C. GmbH Implantable device
US7563780B1 (en) * 2004-06-18 2009-07-21 Advanced Cardiovascular Systems, Inc. Heparin prodrugs and drug delivery stents formed therefrom
US7244443B2 (en) 2004-08-31 2007-07-17 Advanced Cardiovascular Systems, Inc. Polymers of fluorinated monomers and hydrophilic monomers
US6928878B1 (en) 2004-09-28 2005-08-16 Rosemount Aerospace Inc. Pressure sensor
US7166680B2 (en) 2004-10-06 2007-01-23 Advanced Cardiovascular Systems, Inc. Blends of poly(ester amide) polymers
US7214759B2 (en) 2004-11-24 2007-05-08 Advanced Cardiovascular Systems, Inc. Biologically absorbable coatings for implantable devices based on polyesters and methods for fabricating the same
US7202325B2 (en) 2005-01-14 2007-04-10 Advanced Cardiovascular Systems, Inc. Poly(hydroxyalkanoate-co-ester amides) and agents for use with medical articles
US20090004243A1 (en) 2007-06-29 2009-01-01 Pacetti Stephen D Biodegradable triblock copolymers for implantable devices
US20090035350A1 (en) 2007-08-03 2009-02-05 John Stankus Polymers for implantable devices exhibiting shape-memory effects
US20090110713A1 (en) 2007-10-31 2009-04-30 Florencia Lim Biodegradable polymeric materials providing controlled release of hydrophobic drugs from implantable devices

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060105019A1 (en) * 2002-12-16 2006-05-18 Gordon Stewart Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders
WO2006014270A2 (en) * 2004-06-30 2006-02-09 Advanced Cardiovascular Systems, Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders
WO2007149825A2 (en) * 2006-06-22 2007-12-27 Cardiac Pacemakers, Inc. Coating on shocking coil of tachy lead
WO2008016528A2 (en) * 2006-08-01 2008-02-07 Abbott Cardiovascular Systems Inc. Drug delivery after biodegradation of the stent scaffolding

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9138337B2 (en) 2004-06-30 2015-09-22 Abbott Cardiovascular Systems Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US9566373B2 (en) 2004-06-30 2017-02-14 Abbott Cardiovascular Systems Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US9750627B2 (en) 2012-03-30 2017-09-05 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a stent and locally administered adjunctive therapy
WO2014070322A1 (en) * 2012-11-02 2014-05-08 Abbott Cardiovascular Systems Inc. Method of treating vascular disease in diabetic patients

Also Published As

Publication number Publication date
WO2010019721A3 (en) 2010-10-07
US20090286761A1 (en) 2009-11-19
US8435550B2 (en) 2013-05-07

Similar Documents

Publication Publication Date Title
US7758881B2 (en) Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US8435550B2 (en) Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US8586069B2 (en) Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders
US9345816B2 (en) Methods of treatment with drug delivery after biodegradation of the stent scaffolding
US8398706B2 (en) Drug delivery after biodegradation of the stent scaffolding
AU2017378839B2 (en) Drug eluting stent and method of use of the same for enabling restoration of functional endothelial cell layers
US20080306584A1 (en) Implantable medical devices for local and regional treatment
US11660214B2 (en) Drug eluting stent and method of use of the same for enabling restoration of functional endothelial cell layers
WO2009073307A2 (en) Implantable medical devices for local and regional treatment
US9220759B2 (en) Treatment of diabetic patients with a drug eluting stent and adjunctive therapy
US9566373B2 (en) Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09791443

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09791443

Country of ref document: EP

Kind code of ref document: A2