CN1735402A - 含大环三烯化合物的聚合物组合物 - Google Patents

含大环三烯化合物的聚合物组合物 Download PDF

Info

Publication number
CN1735402A
CN1735402A CNA03809309XA CN03809309A CN1735402A CN 1735402 A CN1735402 A CN 1735402A CN A03809309X A CNA03809309X A CN A03809309XA CN 03809309 A CN03809309 A CN 03809309A CN 1735402 A CN1735402 A CN 1735402A
Authority
CN
China
Prior art keywords
support
polymer
coating
compositions
rapamycin
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
CNA03809309XA
Other languages
English (en)
Inventor
J·E·舒尔泽
R·E·贝茨
D·R·萨维吉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biosensor International Group Co., Ltd.
Original Assignee
Sun Biomedical Ltd
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=29268785&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1735402(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Sun Biomedical Ltd filed Critical Sun Biomedical Ltd
Publication of CN1735402A publication Critical patent/CN1735402A/zh
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2/07—Stent-grafts
    • A61F2002/072—Encapsulated stents, e.g. wire or whole stent embedded in lining
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/91533—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other characterised by the phase between adjacent bands
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/9155—Adjacent bands being connected to each other
    • A61F2002/91575—Adjacent bands being connected to each other connected peak to trough
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00—Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0002—Two-dimensional shapes, e.g. cross-sections
    • A61F2230/0028—Shapes in the form of latin or greek characters
    • A61F2230/0054—V-shaped
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Surgery (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Neurosurgery (AREA)
  • Inorganic Chemistry (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Materials For Medical Uses (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Prostheses (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

本发明描述了用于向个体递送大环三烯化合物的聚合物组合物。所述聚合物组合物由含大环三烯化合物40－O－羟基烷基雷帕霉素衍生物(其中的烷基含有7－11个碳原子)的聚合物底材组成。该组合物可用于治疗对雷帕霉素和依维莫司有反应的任何症状。本发明还描述了用聚合物组合物治疗疾病的方法。

Description

含大环三烯化合物的聚合物组合物
发明领域：
本发明涉及聚合物组合物，其由含有40-O-羟基烷基-雷帕霉素衍生物的聚合物底材组成，其中的烷基具有7-11个碳原子。
发明背景：
雷帕霉素是大环三烯化合物，最初是从东岛土壤样品中分离出的链霉菌(吸水链霉菌)提取出来的(Vezina等人，J.Antibiot. 28：721(1975)；美国专利号：3,929,992；3,993,749)。雷帕霉素具有以下分子结构：
雷帕霉素原被用做抗真菌剂(美国专利：3,929,992)，随后发现它对于其它疾病和病症也是有效的活性剂，包括用于治疗癌症和肿瘤(美国专利：4,885,171)、用于预防实验性免疫性疾病(实验性过敏性脑炎和佐剂关节炎；Martel，R.，Can.J.Physiol.， 55：48(1977)、移植排斥的抑制(美国专利5,100,899)和抑制平滑肌细胞的增殖(Morris，R.，J.Heart Lung Transplant，11(pt.2)(1992))。
然而这一化合物作为药物的应用由于它的极低且易变的生物利用度和很高的毒性而受到限制。此外，雷帕霉素仅微溶于水，如20mg/ml，因此很难配制成适于体内递送的稳定的组合物。为克服这些问题，化合物的前药和衍生物已被合成出来。通过将雷帕霉素结构的31和40位形成甘氨酸酯、丙酸酯、吡咯烷基丁酸酯，这种前药已有记载(美国专利：4,650,803)。现有技术酯记载了多种雷帕霉素的衍生物，包括单酰基和二酰基衍生物(美国专利：4,316,885)、乙缩醛衍生物(美国专利：5,151,413)、甲硅烷醚(美国专利：5,120,842)、羟基酯(美国专利：5,362,718)，及烷基、芳基、链烯基和炔基衍生物(美国专利：5,665,772；5,258,389；6,384,046；WO97/35575)。
发明概述
一方面，本发明包括用于将大环三烯化合物递送到个体体内的靶点的聚合物组合物。该组合物含有：(i)20-70％重量的聚合物底材和(ii)30-80％重量的大环三烯化合物，该化合物具有以下结构式：
Figure A0380930900051
其中R是CH2-X-OH，X是含有6-10个碳原子的直链或支链的烷基。当所述组合物被放置到靶点与细胞接触时，可有效地使摄入靶点细胞内的化合物的量明显多于含有雷帕霉素或依维莫司(everolimis)大环三烯化合物的同样的聚合物底材。
在一个实施方案中，该组合物用于治疗靶点的实体瘤、炎症或创伤，并且由可注射微粒的混悬液组成，可通过在靶点注射而局部化。
在另一个实施方案中，组合物中的聚合物底材由生物可降解聚合物形成。
在又一个实施方案中，组合物用于治疗靶点的实体瘤、炎症或创伤，并且是由聚合物底材和化合物形成的贴剂的形式。将含药贴剂置于组织结构的表面，例如器官或肿瘤的外表面、或血管的外或内表面。
该组合物还可用于治疗发炎的组织或伤口，其中的聚合物底材为用于在有需要的组织上涂抹的药膏的形式。
该组合物还可用于在血管壁损伤部位抑制再狭窄，其中的组合物包括可扩张血管支架中与血管壁接触的部分所携带的涂层。
在另一个实施方案中，该组合物用于向粘膜表面的细胞递送大环三烯化合物。组合物中的聚合物底材具有一个粘膜粘附性表面涂层，适于放置在粘膜组织处。
在任意或所有这些用途中，在一个实施方案中，化合物具有如下结构：其中R是CH2-X-OH，X是含有6-10个碳原子的直链烷基。在另一个实施方案中，R是CH2-X-OH，X是含有6个碳原子的直链基团。
在另一个实施方案中，聚合物底材由生物可降解聚合物组合物。生物可降解聚合物的实例包括：聚乳酸、聚羟基乙酸和它们的共聚物。适宜的聚乳酸包括：聚-l-丙交酯、聚-d-丙交酯和聚-dl-丙交酯。
在另一个实施方案中，大环三烯化合物的初始浓度为总组合物重量的35-80％(重量)。
通过以下结合附图对本发明的详细描述，本发明的这些以及其它的目的和特点将更加清楚。
附图概述
图1是几种化合物的相对疏水性(Rm值)相对丙酮浓度(平衡水)的半-对数函数图。实心圆圈是40-O-羟基庚基；空心正方形是依维莫司(40-O-羟基乙基雷帕霉素)；实心菱形是雷帕霉素；空心三角形是紫杉醇；实心正方形是地塞米松。
图2和图3显示了按照本发明的一个实施方案形成的具有金属丝体的血管内支架，图2是支架的收缩状态；图3是支架的扩张状态。
图4是图2的支架中涂层的金属丝的横断面放大图。
图5是一个带有涂层的可降解聚合物支架的横断面放大图。
图6A和6B是适用于生产聚合物涂层支架的聚合物涂层方法的示意图。
图7显示生物可降解聚合物支架被安装在用于送至血管部位的导管上。
图8A和8B是从带有聚合物涂层的支架释放依维莫司的函数图。
图9是支架置入血管部位后的横断面图。
图10A-10C是置入裸金属支架28天后的血管组织学切片。
图11A-11C是置入含聚合物涂层的金属丝支架28天后的血管组织学切片。
图12A-12C和13A-13C是置入含依维莫司的聚合物涂层金属丝支架28天后的血管组织学切片。
图14是一个放大的血管组织学切片，其中可见图12A-12C所用支架的细丝，该细丝上长满新的组织，形成愈合的血管壁。
图15是各种支架置入后28天时，狭窄的面积与损伤度的函数图。
图16显示一个校正函数图，Y轴为损伤度，X轴为支架置入时B/A(球囊/动脉)的比率。
图17是从支架的聚合物底材(聚-dl-乳酸)上释放的药物总量(μg)相对时间(小时)的函数图。实心圆圈代表依维莫司(40-O-羟基乙基雷帕霉素)；实心四方形代表40-O-羟基庚基雷帕霉素。
发明详述
I、定义：
在此使用的“雷帕霉素”指的是具有如下结构的化合物：
Figure A0380930900071
该化合物也称为“西罗莫司”。
“40-O-羟基烷基取代的雷帕霉素”化合物是指将雷帕霉素化合物中40位的羟基用羟基烷基取代所形成的化合物。例如，对40-O进行修饰，用(CH2)7OH代替羟基上的氢就产生了40-O-羟基庚基雷帕霉素。
“依维莫司”指具有如下结构的化合物：
Figure A0380930900081
其中R是CH2CH2OH(羟基乙烷基)。
“有效量”是指足以对所治疗的疾病或病症提供治疗作用的剂量。这会随着患者、疾病、所进行治疗而变化，但很容易由所涉及的疾病或病症所特有的临床标记来确定。如：在支架植入后，测量植入后在支架内新组织生长的横截面的面积和由于球囊的过度膨胀的拉伸使血管的损伤的面积就提供了再狭窄的临床标记。用一定剂量的活性药在肿瘤部位上，肿瘤的减少或稳定就提供了肿瘤治疗的临床的标记。关于器官移植或血管移植手术的临床标记就要观察器官正在运行的情况或同种异体移植的延续的效力。对于皮肤的伤口，临床标记是观察红肿、肉芽形成或纤维化的发炎标记的变化。对于前列腺增大，临床标记就是监视输尿管堵塞复发的任何减少。
II、聚合物组合物
本发明涉及一种聚合物组合物，该组合物含有40-O-羟基烷基(C7-C11)取代的雷帕霉素化合物。以上已讨论过，雷帕霉素和它的许多衍生物的生物利用度很低，这限制了它作为药物的应用。在本发明中，某些40-O-羟基烷基雷帕霉素衍生物当配入聚合物结构中时，在与所治疗的组织相接触时可以提供改善的生物利用度。用在聚合物中的雷帕霉素化合物是在40-O的位置进行了如下修饰的化合物：
Figure A0380930900091
其中R是CH2-X-OH，X是含有6-10个碳原子的直链或支链烷基。其一个实施方案中，X是含有6-10个碳原子的直链或支链烷基，或者，在另一个实施方案中，X含有7-11个碳原子。在一个优选的实施方案中，X是含有6个碳原子的直链烷基。其中R是CH2-X-OH，X是6、7、8、9、10个碳的烷基的化合物在本文中分别称为40-O-羟基庚基、40-O-羟基辛基、40-O-羟基壬基、40-O-羟基癸基和40-O-羟基十一烷基。
图1是显示几种药物的相对疏水性(Rm值)的半-对数函数图。Rm用于衡量疏水性(Biagi G.等人.，J.Medicinal Chem.， 18(9)：873(1975)；Ichihaski，T.等人，Pharm.Res.，11(4)：508(1994))。Rm值使用通用的Biagi法，用反相-薄层色谱技术确定。此方法是把测试的化合物在极性的流动相和非极性的固定相之间分配。测每个化合物的相对迁移率得Rm值。反向色谱采用HPTLC-RP18F单十八烷改性硅胶薄层色谱盘(Alltech63077)。移动相由水与丙酮的各种浓度的溶液(v/v)组成。在紫外光254nm下观察。见图1，以下几种化合物的结果(RM值)：实心圆圈代表40-O-羟基庚基雷帕霉素；空心正方形是依维莫司(40-O-羟基乙基雷帕霉素)；实心菱形是雷帕霉素；空心三角形是紫杉醇；实心正方形是地塞米松。见表-1各化合物的Y轴截距值。
                       表-1
  化合物   Y轴截距值1
  40-O-羟基庚基雷帕霉素   4.667
  40-O-羟基乙基雷帕霉素(依维莫司)   3.966
  雷帕霉素   3.860
  紫杉醇   2.659
  地塞米松   2.341
1由图1数据做的线性回归分析得出
Y截距值是对数，所以40-O-羟基庚基雷帕霉素的疏水性大约比40-O-羟基乙基雷帕霉素(依维莫司)大7倍；40-O-羟基乙基雷帕霉素大约比雷帕霉素大1倍。以这些数据为基础得到几种化合物的相对水溶性的顺序为：地塞米松＞＞紫杉醇＞＞＞雷帕霉素＞依维莫司＞＞＞＞＞40-O-羟基庚基雷帕霉素
相对于40-O-羟基庚基雷帕霉素，雷帕霉素和依维莫司的可溶性彼此更相近，那么这两种的生物利用度也更相近。由于40-O-羟基庚基雷帕霉素水溶性很低，使它的生物利用度差，也就难于掌控其配制，所以也就不会被选定作为药物。但是，正如以下将要证实的，此化合物与雷帕霉素的40-O-羟基烷基衍生物可以配制成用于在治疗位点给药的药物。
因此，一方面，本发明提供了一种用于向患者的体内位点递送40-O-羟基烷基(C7-C11)取代的雷帕霉素化合物的聚合物组合物。该聚合物组合物一般含有20-70％重量的被选聚合物和30-80％重量的40-O-羟基烷基取代的雷帕霉素化合物。或者，该组合物可以含有30-70％重量的被选聚合物和30-70％重量的40-O-羟基烷基取代的雷帕霉素化合物。
正如上面所提到的，可以采用多种聚合物及其配方，以下将更详细地讨论几个具体的例子。通常，聚合物组合物起到一种药物储库的作用，其含有化合物并在放入靶点后释放化合物。
聚合物颗粒
一种示例性聚合物组合物以聚合物颗粒形式存在，此颗粒可以通过用某一工具如导管注射或沉淀放到活的有机体中。聚合物颗粒可以是多微孔、大孔或没孔的，它能储存溶水性很差的40-O-雷帕霉素化合物。
多孔聚合物颗粒有许多相连的孔，这些孔开到颗粒的外表，使颗粒外与内空间相连通。可制的颗粒用于形成这种大孔的储存器被描述在美国专利：5,135,740，这引为参考。简要地说，就是通过聚合，如液-液系统悬浮聚合，生成多孔的颗粒。通常，先制有单体和聚合催化剂的溶液，此溶液不溶于水；加一种可溶于此溶液但不溶于水的惰性溶剂于溶液中；此溶液在水溶液中悬浮，一般水溶液中有表面活性剂和分散剂类的添加剂，以促进悬浮或乳化。一旦希望的不连续的小颗粒形成，通过加温或照射激活反应剂使聚合反应奏效。一旦聚合完成，生成固体的颗粒，颗粒是固体的、球型、多孔结构。由于聚合物是围绕惰性液体生成的，因而，形成多孔的网络，惰性溶剂作为助孔剂占据了颗粒的孔。此孔剂而后被去除。
大孔颗粒可以通过可生物降解或不可生物降解的聚合物的溶剂蒸发制得。溶剂蒸发工艺：1、需蒸发的聚合物在一有机溶剂中被溶解，然后将溶液倒过一氯化钠结晶(希望尺寸结晶颗粒)层(见穆尼，等人，保尔木..玛特.研究杂志 37：413-42，(1997)。溶剂一般通过蒸发去除，得到的聚合物浸在水中滤出氯化钠，产生多孔聚合物储存体。2、或，氯化钠结晶体被分散在聚合物溶液中，搅拌得到氯化钠结晶体均衡的分散作用；分散体然后逐滴被挤到非溶剂中，而搅拌使聚合物颗粒沉淀到氯化钠晶体的周围。固态的聚合物颗粒通过过滤或离心过滤后被浸入水中以滤出氯化钠，得到多孔的聚合物储存体。氯化钠可以用任何一种无毒、可溶于水的盐或低分子量的、可溶于水的聚合物所替代。
多孔化合物在颗粒形成过程中或形成后，可以加载一或多种药物以使聚合物中含化合物。例如，在颗粒形成后加载药物的过程：在一可溶解药物化合物，但不能溶解聚合物的溶剂中把药溶解，放入聚合物，搅拌使颗粒和药物溶剂混合，药溶液被颗粒吸附产生自由流动的粉末。颗粒按需要去除溶剂。
另一种可制的聚合物颗粒是无孔颗粒，如：微胶囊体和微颗粒，其化合物可以被包或分散在其中。微胶囊和微颗粒在制药和药物传导业被众所周知(见例，巴克，R.W.，控制生物助剂的释放，纽约，约翰威利&儿子们，1987；雷纳达.V和郝林格，M.，药物传导系统，CRC出版，1996)。微胶囊作为活性助剂的储存体周围被聚合物隔膜壳包裹。微颗粒是将治疗助剂分散整个颗粒的单一系统。然而，在这两个定义中还有许多形式，如：微胶囊凝聚，这些形式这儿也适用。
可用生物可降解或非生物降解聚合物制成微胶囊体和微颗粒。微胶囊可通过几个方法制成，包括凝聚、界面间的聚合、溶剂蒸发和物理的压缩(巴克，R.W.，控制生物助剂的释放，纽约，约翰威利&山斯，1987)。微颗粒配制有许多方法，简单方法把含有分散治疗助剂的聚合物膜磨成合适的尺寸。另一方法是从聚合物溶液喷洒干的药物助剂颗粒。生物活性助剂的密封压缩的详细程序在美国专利4,675,189和专利应用20010033868，这儿引入作为参考。
聚合物的颗粒形式是多种并变化的。一般的选择标准是聚合物能容40-O-羟基-烷基雷帕霉素。这些聚合物的例子包括但不限于：聚(d，l-乳酸)、聚(l-乳酸)、聚(d-乳酸)、甲基丙烯酸酯聚合物，如聚甲基丙烯酸丁酯等、乙烯乙烯醇共聚物(EVOH)、ε-己内酯、乙基乙烯基羟基化乙酸酯(EVA)、聚乙烯醇(PVA)、聚氧化乙烯(PEO)、聚酯酰胺和其共聚物和混合物。所有这些聚合物都有用于系统循环的安全和低炎症史。一般由占20-70％重量的聚合物和30-80％的40-O-羟基-烷基雷帕霉素化合物结合形成聚合混合物。
颗粒无论是有孔和无孔，在尺寸上相差很大，直径范围从0.1-100微米，最合适的是从0.5-40微米.这些颗粒可以作为净颗粒使用或制成胶、浆、药膏、软膏或粘性液体被用于目标处。
本发明聚合物组合物能被分散或放在目标处使聚合物组合物与目标处的机体组织相接触。其实混合物与目标组织接触仅是聚合物颗粒诸多应用的一种，聚合物可以携带疏水化合物形成薄膜、片、浆、膏或胶放在或分散在目的处。例如：一个简单的载有40-O-羟基-烷基雷帕霉素化合物的聚合物片可以被放在需治疗的机体组织的表面。这个组织表面可以是血管、器官、肿瘤或受伤或被伤的身体表面。
粘膜粘附性聚合物组合物
聚合物组合物的另一形式，聚合物组合物是由有粘膜粘合特性的聚合物衬层，以放在连接粘膜组织的位置。在身体的粘膜位指：眼睛的盲管、口腔内、鼻子、直肠、阴道、牙周、肠和结肠。粘膜输导系统展示服用含化合物的粘膜聚合物对粘膜组织的粘合。
各种聚合混合物被用于做粘膜传导体。尤其，用40-O-羟基烷基雷帕霉素使粘膜粘合剂具有亲水和疏水双重性。粘合剂是胶质、凝胶和羟基甲基纤维素在一有粘性的聚合体内的混合物，粘合到口粘膜。其他有亲水和疏水性的粘膜粘合剂如包括：聚(甲基乙烯基醚/顺丁烯二酐)和凝胶，被分散在软膏内像矿物油含被分散的聚乙烯(见美国专利：4,948,580)。另一个亲水和疏水系统在美国专利5,413,702有叙述，即揭示了一个糊状的聚硅氧烷和一溶水聚合材料。
在本发明中，聚合物组合物有粘膜粘合聚合物衬层和本发明的40-O-羟基-烷基雷帕霉素化合物。粘膜聚合物组分被传导放到连接粘膜的表面，然后化合物从聚合物中被洗脱出进入粘膜组织。可以采用聚合物的补片，把补片放到被治疗组织的表面。组织可以是一个器官、一个血管、一个肿瘤或需治疗的身体表面。
血管内支架
本发明的聚合物组合物的另一用途是在一个可扩张血管支架上的聚合物涂层。图2和3是一个血管内涂层支架的示意图，涂层是含40-O-取代的雷帕霉素化合物的聚合物组合物。在这些图中，示出了支架20的收缩状态(图2)和扩张状态(图3)。支架包括结构件或结构体22和一个携带和释放化合物的外涂层，以下参照图3和图4将做进一步描述。
在图2和图3所示的实施方案中，支架体是由多个通过细丝相连的管状件，如件24和26组成。每个件具有可扩张的Z型锯齿或正弦波结构。各件体通过轴向连接件，例如将相邻部件的波峰和波谷相连的连接件28、30连接。可以理解，此结构使支架可以从收缩状态(如图2所示)扩张到扩张状态(如图3所示)，而支架的长度不变或有少许改变。同时，相邻管状件的峰谷之间相对较少的连接使得支架可以弯曲。此特性对于支架在导管中或导管上以收缩状态被导入血管部位特别重要。支架有一个0.5-2mm的典型收缩状态直径(图2)，更优选0.71-1.65mm，长度为5-100mm。在支架的扩张状态(见图3)，支架的直径至少是它收缩状态的2倍，甚至可达到8-9倍。因此，一个收缩态直径在0.7-1.5mm的支架可放射状地扩张到直径为2-8mm或更大的选定扩张状态。
具有这样的由相连的、可扩张的管状件构成的支架体的支架是已知的，如PCT公布号WO99/07308所述，该专利申请与本申请属于同一申请人，并且引入本文作为参考。其它的例子记载于美国专利6,190,406、6,042,606、5,860,999、6,129,755或5,902,317中，这些专利引入本文作为参考。或者，支架的结构件也可能是连续的螺旋状丝带结构，即，支架体是由单一的连续的丝带样螺旋构成。支架体的基本要求是在放置于血管损伤部位时可以扩张，并且在其外表面能涂覆含药物的涂层，能将涂层中所含的药物输送到血管靶点内层的血管壁(如：组织的中膜、外膜和内皮层)内。优选地，支架体还具有网状或开放结构，允许内皮细胞穿过支架从外向内生长。
在支架丝上涂有可释放药物的涂层，该涂层由聚合物基质和分布在基质内的40-O-羟基烷基取代的雷帕霉素化合物组成，用于在至少数周、一般是4-8周，有时持续2-3个月或更长的时期内从支架上释放出药物。
图4以放大的断面图的方式显示了具有涂层32的支架丝24，所述涂层完全覆盖了细丝的所有面，即顶部(形成支架体外表面的细丝侧面)、底部(形成支架体内表面的细丝侧面)和相对的细丝侧面。正如以下将要进一步讨论的，涂层的厚度通常为3-30微米，该厚度取决于构成涂层的聚合物基质材料的性质和聚合物基质与活性化合物的相对量。理想的是，涂层尽可能的薄，如15微米或更小，以使支架在血管损伤部位的轮廓最小。
上(外)表面涂层的厚度也应该相对均匀，以促进释放的药物在靶点的均匀分布。在支架丝上产生相对均匀厚度的涂层的方法将在下面讨论。
图4显示了在支架丝和涂层间有一层聚合物底层34。底层的目的是帮助支架体细丝与涂层间的粘合，即稳定细丝上的涂层。以下会看到，此功能在形成涂层的聚合物底材中含有高百分比的抗再狭窄化合物(如：35-80％重量的化合物)时特别有价值。一种底层聚合物的例子是聚对亚苯基二甲基，其用以连接由可生物降解的聚-dl-丙交酯形成的聚合物底材。其它适用的聚合物底层为乙烯乙烯醇共聚物(EVOH)、paryLASTTM、聚对亚苯基二甲基、聚硅氧烷、TEFLONTM和其它含氟聚合物，它们可以通过等离子涂覆、其它涂覆或沉淀工艺沉积在金属支架表面。底层厚度一般为1-5微米。
形成底材的聚合物可以是任何生物相容性聚合物材料，其中所包含的化合物可以通过扩散和/或通过聚合物基质的降解而释放。两种公知的不可降解的用于涂层底材的聚合物是聚甲基丙烯酸甲酯、乙烯乙烯醇共聚物。制备适用于支架体的这些聚合物的方法描述在US2001/0027340A1和WO00/145763中，这两篇申请引入本文作为参考。通常，加入聚合物的药物限量是约20-40％重量。
可生物降解的聚合物，特别是聚-dl-丙交酯，也适合作为涂层底材材料。在本发明中的一个的实施方案中，涂层是可生物降解的聚-dl-丙交酯聚合物底材，即聚-dl-乳酸聚合物，其可容高达80％(干重)的活性化合物分散在聚合物底材内。更一般的，涂层含35-80％干重的活性化合物和20-65％干重的聚合物。示例性的涂层含25-50％干重的聚合物基质和50-75％重量的活性化合物。关于用于沉淀于支架丝上的聚合物和药物的合成的详细说明见以下描述。
一种优选的涂层由25-50％重量的聚-dl-丙交酯聚合物底材和50-75％重量的大环三烯免疫抑制化合物形成，涂层厚度为3-15微米。底层是聚对亚苯基二甲基，厚度为1-5微米。该实施方案中，化合物的含量相当于15μg药物/mm支架长。
在另一个实施方案中，涂层由15-35％重量的可降解或不可降解的聚合物底材和65-85％重量的40-O-羟基烷基取代的雷帕霉素化合物形成。涂层厚度优选为10-30微米，支架还可以含1-5微米的聚合物底层，如聚对亚苯基二甲基底层。在该实施方案中，化合物的含量相当于约15μg药物/mm支架长。
涂层还可以含有第二种生物活性剂，该生物活性剂可有效治疗所涉及的疾病或病症或治疗任何可能出现的第二种病症。例如：如果40-O-羟基烷基取代的雷帕霉素被用于治疗再狭窄，就可以含有第二种可以将血液相关事件例如可能由原血管损伤或支架的存在刺激形成的凝血降至最小或改善血管损伤的愈合的生物活性剂。第二种活性剂的例子包括抗血小板剂、纤维蛋白溶解剂或可溶结晶形式的溶栓剂，或可刺激内皮细胞愈合和控制平滑肌细胞生长的NO供体。抗血小板剂、纤维蛋白溶解剂或溶栓剂的实例是肝素、阿司匹林、水蛭素、噻氯匹定、eptifibatide、尿激酶、链激酶、组织纤溶酶原激活物(TPA)或它们的混合物。如果40-O-羟基烷基取代的雷帕霉素被用做抗肿瘤剂，则可以包含常用于肿瘤化疗的第二种活性剂。第二种化疗剂的例子包括：紫杉醇、铂化合物、阿糖胞苷、5-氟尿嘧啶、替尼泊苷、依托泊苷、甲氨碟呤、阿霉素等。第二活性剂在支架涂层中的含量由需要该活性剂提供治疗益处的时期的长短来决定。第二活性剂可以根据已知的方法包含在准备涂在支架体细丝上的涂层配方中。
可生物降解支架
在另一个实施方案中，支架体和聚合物涂层均由可生物降解聚合物构成，经一定时间支架被完全吸收。支架优选是一个可扩张的螺旋支架，它具有由螺旋带状细丝形成的支架体(无图示)。在美国专利4,990,155中记载了用于植入血管的自扩张螺旋支架，在此引为参考。
螺旋支架可以用预成形的支架来制备，预成形支架的最终扩张直径略大于拟用此螺旋支架治疗的血管内腔尺寸(对于冠状动脉常见的是3.5mm外径(OD)±1mm)。通常，支架可以通过如下方式制备：铸模扩张状态下的支架，再以支架的长轴为轴拧支架使其处于收缩状态或径向压支架让其处于收缩状态，以便安装在导管尖端上送至血管。支架的总厚度优选为100-1000微米，总长度为0.4-10cm。事实上，该类型可生物降解支架的一个重要的优点是，相对较长的支架、如长度超过3cm的支架，能容易地送入并放置在血管损伤部位。
关于用可生物降解聚合物(如聚-l-丙交酯)的编结丝形成可扩张球囊支架的方法已有报道(美国专利6,080,177)。也有一种形式的装置已被用于释放药物(美国5,733,327)。
一种优选的用于形成支架的聚合物材料是聚-l-或聚-dl-丙交酯(美国专利6,080,177)。如上所述，支架体和涂层可以是一体的，成为一个在整个支架中含有抗再狭窄化合物的可扩张丝支架。或者，可生物降解涂层可以被涂到预制的可生物降解体中，详见以下第二部分的描述。按后者，支架体可以由一种可生物降解聚合物如聚-l-丙交酯形成，涂层由第二种聚合物如聚-dl-丙交酯聚合物形成。涂层如果是被涂到预制支架上的，则涂层具有与以上描述基本相同的组成和厚度特征。
图5显示了一个刚描述的可生物降解支架中的细丝、例如螺旋丝带的横断面图，它具有分别形成的支架体和涂层。图中显示了一个内部的可生物降解的支架细丝36，在其所有侧面均涂有可生物降解的涂层38。一种示例性的涂层是由聚-dl-丙交酯形成的，含有20-40％重量的40-O羟烷基-雷帕霉素和60-80％重量的聚合物底材。在另一个实施方案中，涂层含45-75％重量的化合物和25-55％重量的聚合物底材。
可生物降解的支架有一个独特的优势，就是用一个装置治疗整个血管，它既可以和球囊成形术结合使用以便在有大的堵塞存在时预扩张血管，也可以作为预防性植入物放入将来可能发生堵塞的高风险患者体内。由于支架是可完全生物降解的，它不会像“全金属衣”、即一串含金属底材的药物洗脱支架那样影响患者以后在血管做非复杂手术的机会。
如以上所说，可以在涂层上掺入第二种活性剂，用于在植入后在希望的一定时间内从涂层中释放。或者，如果使用了第二种活性剂，若涂到支架体的涂层没有覆盖支架体的内表面，则可将第二种活性剂掺入到支架体细丝中。在以下第二部分叙述的关于金属丝支架体的涂层方法也适用于聚合物丝支架体。
支架涂层方法
更详细地参考附图，图5A和5B是本发明的支架涂层工艺的示意图。在可相容的溶剂中溶解聚合物得到聚合物溶液40。将40-O-取代的化合物和，如果需要的话，第二种活性剂，以混悬液或溶液的形式用同种溶剂或不同的溶剂加入聚合物溶液中。将整个混合物置于加压储存器42中。储存器上连有一个液体加压泵44。
加压泵可以采用任何压力来源，只要能把混合溶剂以一个设计的速度推过溶液传输管46。正如精密给料系统领域所公知的，加压泵44由微型控制器(没图示)控制。例如：这样一个微型控制器可以含有4-轴自动给料装置(4-Axis Dispensing Robot，型号为I&J500-R和I&J750-R，可从FairLawn，NJ的I&J Fisnar公司获得，它可通过RS-232C交换界面由个人电脑控制；或精密给料系统如Automove A-400，其来自加拿大卡尔斯拜的Asymtek。一个用于控制RS232C界面的合适的软件程序可从包括Fluidmove系统，其也可由加拿大卡尔斯拜的Asymtek得到。
与储存器42相连的，例如与储存器的底部相连的是溶液导管48，它把溶剂混合物传输到支架的表面。可加压储存器42和导管48被装在一个可移动的支架上(没图示)，它可使溶剂导管以微小的步长移动，例如每步0.2mm，或连续地沿支架的长轴方向移动(如图中箭头X1所示)。加压储存器42和导管46的可移动支架也能将导管的尖部(远端)沿Y1所示的方向以微小的步长移向或远离细丝的表面。
未涂层的支架被卡在转动的卡夹上，卡夹至少有一端与支架的内表面相接触。通过步进电机带动卡夹可以使支架以微小的角度沿轴向旋转，如每次0.5度，以使支架结构的最外表面可以被导管涂层，这是本领域公知的。如果需要，支架也可连续转动。精确定位低量液体传导装置的方法在X-Y-Z溶剂给料系统领域是公知的，可以用于本发明。
液体加压泵的活动、液体导管X1和Y1向定位以及支架R1向定位都是由数字控制器和计算机软件来控制，这样定量的溶液被精确地涂到支架表面所需要的地方，然后，溶剂可以被蒸发，支架表面剩下变硬的聚合物和活性剂涂层。溶剂混合物的粘度通常随溶剂的量变化，其范围2-2000厘泊，通常可能为300-700厘泊。或者，可将导管固定在固定的位置，支架除转动外还可沿其长轴方向移动完成涂层工艺。
X-Y-Z定位台和可移动的支架可以从I&J Fisnar采购。溶液导管尺寸最好是18-28计量规格的不锈钢注射管，连有可被锁定的连接器。这种导管可以从RI，East Providence的EFD公司得到。见EFD的特别用途的注射针选择指南。优选的注射针是再订购号从5118-1/4-B到5121-1/4-B的“无泊尔钝化不锈钢针，长度1/4”快速点对点注射充颗粒或稠的材料”；再订购号为51150VAL-B的“椭圆的不锈钢针，在平带状沉积物上涂抹稠的浆料、密封剂和环氧物”；再订购号从5121-TLC-B到5125-TLC-B的“抗氰基丙烯酸酯凝结并为低粘度液体提供附加的沉积控制。压纹和衬聚四氟乙烯”。一种可任意使用的加压溶液储存器也可以从EFD得到，库存号1000Y5148到1000Y5152F。用于本发明的另一种针头是玻璃毛细管，内径约0.0005-0.002英寸，如约0.001英寸，在VWR目录中可以得到，目录号15401-560“微血球比溶剂管”，长度60mm，内径0.5-0.6mm。
在本生灯下，管子被进一步拉伸，得到用于精确涂层聚合物/药物/溶剂混合物的希望的尺寸。用于操作步进电机的可编程的微控制器和XYZ台可从Asymtek公司获得。本发明还包括使用一个以上的液体给料管共同形成涂层，或在同一涂层工艺中，使用一个以上的装配有不同注射针或含不同粘度的溶液或由多种溶液组成的不同的化学剂的可移动溶液储存器。卡夹和步进电机系统可以从NJ，Barrigton的Edmund Scientific购买。
如上所述，涂层通常被直接涂在支架的外支撑面，可能覆盖或不覆盖支架内表面的全部或一(或多)部分，覆盖的情况取决于如何控制以上所述的本发明的涂层系统，如图6A和6B所示。后图是用涂层材料52涂细丝50的顶部和侧面区域。或者，涂层或涂层混合物也可以直接涂到支架的内表面。一个细的导针可以穿过支架壁的一个或多个缺口处(即：窗户)，从而使涂层混合物直接涂到支架内表面希望的位置。用此方法，就可以实现用含不同药物成分的不同涂层材料涂到细丝的内和外面。例如，细丝外表面涂层可含40-O-取代的雷帕霉素化合物，细丝的内表面涂层可含有上面所提的第二活性剂之一或另一种40-O-取代的雷帕霉素化合物。如果支架有足够大的直径，细的“L-型”导针能沿支架的长轴方向插入到支架的开放端以将支架的内表面涂层。
用于本发明的聚合物包括但并不仅限于：聚(d，l-乳酸)、聚(l-乳酸)、聚(d-乳酸)、乙烯乙烯醇共聚物(EVOH)、ε-己内酯、乙基乙烯基羟基化乙酸酯(EVA)、聚乙烯醇(PVA)、聚氧化乙烯(PEO)和其共聚物和混合物，被溶解于氯仿或丙酮或其他适用的溶剂中。所有这些聚合物都有用于系统循环的安全和低炎症史。
一种非聚合物涂层也可用于本发明，如通过离子连接涂到金属支架表面的40-O-取代的雷帕霉素化合物。
使用描述的涂层系统，会发现给支架表面涂层无论上、侧或里面都是可行的。通过仔细选择溶剂和聚合物的合适比率，可以调整溶液的粘度，从而使一些溶液可以沿着支柱的侧面向下移动，并在凝固前占据底部表面，见图6B。通过控制导管接近支架边缘的停留时间，聚合物被涂到支架边缘或底部的量就会被增减。在图4所示的实施方案中，首先将由纯聚合物和溶剂组成的底层34用本发明的涂层系统涂到支架表面24，然后将溶剂蒸发掉。然后涂上含生物活性剂的第二层聚合物涂层32。
如上所述，第二活性剂也可以被加入聚合物的混合物中。如：结晶形式的肝素可以被加入涂层中。将肝素结晶微粒化到粒度约为1-5微米，然后以悬浮液的形式加入聚合物溶液中。当按照本发明的工艺涂层时，肝素的适宜形式是那些在哺乳动物中显示生物活性的结晶态，包括肝素盐(即：肝素钠和低分子量肝素及其盐)。当药物释放型支架被放入血管壁时，如图9所示，靠近凝固的聚合物涂层表面的肝素晶体开始溶解，增加了聚合物的孔。当聚合物慢慢溶解，更多的肝素和生物活性剂以受控的方式被释放。
然而，参见图9，应注意到，并不总是需要在支架内表面涂层。例如，在支架内表面涂层增加了支架起皱的传导轮廓，使在小血管内的可操作性变小。并且，植入血管后内表面直接被通过支架的血流冲洗，导致支架内表面释放的药物流失在系统循环中。所以，在图4和图5所示的实施方案中，凝固的聚合物和活性剂大部分被涂在支架支撑的圆周的外面，其次是在侧面上。在一个优选的实施方案中，仅最小量的聚合物和活性剂被涂在支架的内表面。若需要，也可至少有一部分支架内表面不被涂层或裸露。
此外，图4和图5的涂层也可以有选择地涂到支架丝的表面。涂层的厚度应与用于组织中的生物活性涂层的体积相对应。限制一些范围的涂层是有利的，因为这些范围的涂层会导致放支架时的高损伤。
先在支架的表面均匀地涂上底层，以促进含生物活性剂涂层与支架的粘合，和/或帮助稳定在支架上的聚合物涂层。最初的涂层可以用本领域已知的任何方法涂层，或用本发明的精确给料系统涂层。使用不同的聚合物材料涂最初的涂层也在本发明内，如使用聚对亚苯基二甲基(聚(二氯-对-二甲苯))，或任何其他可以使金属底材和含生物活性剂的涂层能很好粘合的材料。聚对亚苯基二甲基(聚(二氯-对-二甲苯))可以采用等离子沉积或蒸气沉积技术，此技术是本领域公知的(见美国专利6,299,604)。在本发明的一个实施方案中，含肝素的不连续或连续的涂层涂在支架的内表面，而含本发明上述抗增殖药物的涂层涂在支架外表面。
当需要在金属支架底材上形成具有高的药物/聚合物底材比例，如药物含量占涂层重量40-80％的涂层时，最好在支架丝上涂一底层来稳定并牢固地将涂层粘在底材上。在沉积涂层材料前，底层可通过在一种合适的溶剂中溶胀来进一步处理，溶剂可以是例如丙酮、氯仿、二甲苯或它们的混合物。在实施例5中描述了该方法，用于制备具有高的依维莫司/聚-dl-丙交酯比例的支架。
其中，通过等离子沉积法在支架丝上形成聚对亚苯基二甲基底层，然后将该底层在二甲苯中溶胀，最后沉积涂层材料。该方法可用于生产在聚-dl-丙交酯聚合物底材中含50％药物或75％药物的涂层，涂层厚度仅为5-10微米。
如上所述，使用本发明的涂层系统生产完全可生物降解的支架也在本发明的范围内。先用顶部开放的“C-形”螺旋状槽以将要制造的支架形状制一个管状预制件，可以用给料系统向该槽内注入聚合物。预制件的外径是开放的，以便聚合物可被放入预制件中，通常用注射管的一个通道，若需要也可有多个；并同时建立支架均匀一致的边缘，因为聚合物会受预制件的限制。预制件可溶于一种溶剂中，但由此产生的可生物降解支架不溶于此溶剂。在注入聚合物并且聚合物溶液的溶剂已被蒸发后，可将装配组合放入可溶解预制件的溶液中，释放出完整的支架结构。用于制备预制件的有代表性的原料是蔗糖，它可以用标准的注塑技术制成希望的预制件形状。预制件的代表性溶剂是水。
III、使用方法
40-O-羟基烷基取代的雷帕霉素化合物可用于治疗对雷帕霉素和依维莫司有反应的任何病症。这包括与伤口愈合有关的任何病症，例如涉及血管或器官移植术的术后伤口愈合；肿瘤疾病，在该疾病中，把聚合物组合物直接放到癌症部位例如实体瘤上。发炎和感染也可用40-O-羟基烷基取代的雷帕霉素衍生物进行治疗。另外，这种化合物还可用于动脉血管的治疗中，尤其是再狭窄。将化合物配到用于向个体的体内位点给药的聚合物底材中，示例性的聚合物底材配方如上所述。被涂到可扩张支架上的聚合物涂层的聚合物组合物特别适用于治疗再狭窄。
关于血管损伤的治疗，用含有40-O-羟基烷基取代的雷帕霉素化合物的聚合物组合物可以减小有局部血管损伤或血管闭塞风险的患者再狭窄的危险和/或程度。典型的血管损伤是在血管造影术过程中打开部分闭塞的血管如冠状动脉或外周动脉时造成的。在血管造影术中，球囊导管被放于闭塞处，球囊远端充气和放气一或多次，迫使闭塞的血管打开。这种血管的扩张尤其涉及血管壁的表面创伤，可使其上的斑块移动，经常造成局部创伤，足以使血管随时间的过去而产生细胞增殖和再闭合反应。不奇怪，再狭窄的发生率和严重程度经常与血管造影术中所涉及的血管被牵拉的程度有关。特别是过度拉伸到35％或更高时，再狭窄的发生频率很高并且经常是很严重的，即血管闭塞。
将支架以其收缩状态置于导管的远端，可以在导管腔内，或者以其收缩状态置于球囊的远端。然后将导管远端引导到损伤处或潜在闭合点并从导管上释放支架，例如，如果支架是自扩张型的，用拉发线释放支架到位点，或者，在球囊上通过球囊充气使支架扩张，直到支架与血管壁相接触，从而将支架植入血管壁组织。
图7显示了一个可完全生物降解的支架和将支架置入心血管系统的血管如冠状动脉内的导管。图中显示了部分放松状态的支架53，称作“药物螺旋支架”。该支架是自扩张的螺旋型支架，由聚乳酸形成并且含有一种或多种生物活性剂。
该螺旋支架用所述的预制件制成，预制件的最终扩张直径被设定为略大于用此螺旋支架治疗的血管内腔尺寸。除去预制件后，通过将药物螺旋支架的两端向反方向拧使其到较小半径，这样压缩其全长至一个可滑动鞘下，使螺旋的传输直径大约为最终扩张直径的1/3(在体温下)。药物螺旋支架的厚度足够小(约25-125微米)，使其易于弯曲到更小的半径，形成与鞘的内径相当的压缩的螺旋。鞘被滑动地放在导管55上，该导管适于将压缩状态的支架导入目标血管。鞘54在其近端有一个把手56，通过它，血管成形术的操作者可以在导管尖端到达血管的适当位置时把鞘向后拉，从而完全释放药物螺旋。
导管55中央有一个直径约为0.014″的内腔，带有柔韧尖端58的导丝57可以在其内滑动。导管还有一个卢尔毂59，用于连接内腔到Y接头和止血阀，这是血管成形术领域公知的。有可滑动鞘的导管的外径范围在2-4F(法国尺寸)；若治疗外周动脉会更大。
由于药物螺旋支架是可完全生物降解的，它不影响患者以后接受不复杂血管外科手术的机会，不像全金属衣那样。在某些神经和血管应用领域，裸金属螺旋支架放入血管中经常会产生血栓栓塞，甚至是完全闭塞，而令人惊奇的是，已经发现，已揭示结构中的生物相容性聚合物聚(dl-乳酸)(PDLA)及其混合物，可以提供合适的机械强度以支撑血管成形术后损伤的血管，并且不产生栓塞；因此是用于生产本发明药物螺旋支架的示例性材料。
支架一旦入位即开始释放活性化合物到血管内层的细胞中以抑制细胞增殖。图8A显示依维莫司从两个支架释放的动力学，每个支架有大约10微米厚的涂层(涂黑的正方形)。药物释放动力学是通过将支架浸入25％的乙醇溶液中得到的，该溶液可大大加快药物从支架涂层释放的速度。曲线图显示体内可预期的药物释放动力学，但经历的时间要长的多。
图8B显示从金属支架上的聚合物涂层释放依维莫司的图形。上面的一组曲线显示直接涂到金属表面的涂层的药物释放。下面一组曲线(显示缓慢释放)是通过在金属支架表面先涂一层聚对亚苯基二甲基底层或初级涂层，然后再在表面上涂层获得的。可以看出，涂有底层使涂层与支架表面的机械粘附增加，使可生物降解涂层的分解减慢，药物释放也减慢。当需要强粘附的支架涂层以经得住药物洗脱支架在导管和/或血管内弯曲操作时反复的磨损时；和/或需要支架置入后在置入部位药物释放的速度减慢以延长对动脉粥样硬化过程的治疗时，这样的结构是有用的。
图9显示一个横截面图，图中可以看到已植入一个支架62的血管区域60，所述支架的涂层丝例如丝64带有涂层66。该图显示活性化合物从每个丝区域释放到周围的血管壁区域。经过一段时间，形成的血管壁的平滑肌细胞开始在支架内或穿过支架网或螺旋空隙生长，最后形成吞没支架双面的连续的内细胞层。如果支架植入是成功的，以后在支架位置的血管的闭塞程度将小于50％，即在血管内保持血流通道的横截面直径至少是植入时已扩张支架直径的50％。
在如Schwartz等人所述的猪再狭窄动物模型(“球囊血管成形术后再狭窄--一个猪冠状动脉的实用的增殖模型”，Circulation 82：(6)2190-2200，1990年12月)中进行的试验证实了本发明的支架限制再狭窄程度的能力，以及该支架优于现有的和经过测试的支架的优越性，尤其对严重的血管损伤的病例，即血管的拉伸大于35％的病例。研究在实施例4中进行了总结。
简言之，研究比较了几种支架在植入28天后再狭窄的程度，支架包括：裸金属支架、聚合物涂层支架、包含高或低浓度的雷帕霉素和依维莫司的聚合物涂层支架。
实施例4的表1显示雷帕霉素(Rapa-高或Rapa-低)和依维莫司(C-高或C-低)支架大大减少了再狭窄的水平，高剂量依维莫司支架的再狭窄最小。在低损伤动物研究中获得了同样的结果(表2)。
图10A-10C是植入裸金属S-支架(从加洲Bewport Beach的Biosensores International Inc获得)后28天新生内膜的支架横断面图例。图11A-11C是聚合物涂层(无药)S-支架的新内膜形成的例子。图12A-12C和图13A-13C是依维莫司/聚合物涂层支架的新内膜形成。总的来说，依维莫司涂层支架所治疗的血管愈合良好，内皮层建立良好，28天血管完全愈合并达到血管稳态。图14是一个放大91倍的血管横断面，显示支架植入后28天血管腔内愈合和建立的内皮层。
照片显示，在28天消除再狭窄的最佳结合是C-高或C-U高(见实施例4)，它们在18.7mm长的支架上分别含325mg和275mg依维莫司。对远系繁殖的幼猪随访28天的数据预测，与目前市场上的裸金属支架(S-支架)相比，再狭窄率减少50％。数据也显示，在同样的支架/聚合物传输平台上，依维莫司优于或至少相当于180mg雷帕霉素。形态度量分析(实施例4)支持这些结果。
图15显示选择涂到S-支架上的聚合物中的药物剂量的“最佳拟合”线性回归曲线，损伤度与随访时狭窄面积相关。“狭窄面积”是一个由形态度量分析确定的新内膜形成的精确指标。从图上可看出，在测试的样品组中仅高含量的依维莫司涂层支架相对损伤度增加显示负性斜率。此分析提示C-高涂层可能能够在损伤的冠状动脉中控制再狭窄，这实际上与损伤度无关。其它涂层配方均不能显示这一独特特性。
图16显示了在动物实验中，血管被球囊过度拉伸(通过球囊/对动脉比率，即(B/A比率)来测量)和血管损伤的关系。该数据显示了用过度扩张的血管成形术球囊造成高度控制的血管损伤是在猪模型中造成可预测和已知的血管损伤的合理的精确方法。
图17是一个从金属支架的PDLLA聚合物涂层释放依维莫司(实心圆和40-O-羟烷基取代雷帕霉素(实心正方型)的曲线图。曲线是由相对时间测量从聚合物释放到乙醇与水(25/75比)的溶液中的化合物量而得到。在8小时时候释放的40-O-羟烷基取代雷帕霉素的量大约是依维莫司的1.7倍；在8小时后的时间，释放40-O羟烷基取代雷帕霉素约是依维莫司的1.5倍。由此可以说，在室温下，由聚合物衬层和40-O-羟烷基取代雷帕霉素化合物组成的聚合物组合物在乙醇/水中释放化合物的速度至少是聚合物和依维莫司组成的混合物释放化合物的速度的1.5倍。
从前述中，可以看到，此发明能满足多个目的，并有多种特点。含40-O-羟烷基取代雷帕霉素化合物的聚合物结构的RM值实际比依维莫司或雷帕霉素的RM值高，所以，此聚合物结构能被置于一个被治疗的目标点。当这样的聚合物的混合物被放到与需治疗的组织相接触，40-O-羟烷基取代雷帕霉素化合物会从聚合物衬中释放到组织处，它能治疗雷帕霉素和依维莫司能治疗的任何病症，包括：肿瘤、发炎、感染、创伤愈合、移植排斥反应和再狭窄。也能治疗那些聚合物可局部放置需要治疗的地方，如创伤、肿中瘤或再狭窄，发炎或感染处。
                         实施例
以下实施例举例说明了本发明的支架制造和使用的各方面。但本发明不仅限于这些范围。
                         实施例1
                 依维莫司及其衍生物的制备
步骤A、2-(叔丁基二甲基硅烷基)氧基乙醇(TBS乙二醇)的合成
将154ml无水THF和1.88g NaH在氮气氛下在带有冷凝器的500ml圆底烧瓶中搅拌。向烧瓶中加入4.4ml无水乙二醇，搅拌45分钟后生成大量沉淀物。向烧瓶中加入11.8g叔丁基二甲基氯硅烷并继续剧烈搅拌45分钟。将形成的混合物倒入950ml乙醚中。用420ml盐水洗乙醚，溶液用硫酸钠干燥。将产物通过真空蒸发乙醚进行浓缩，然后通过快速色谱法用27×5.75cm充硅胶柱进行纯化，用己烷/Et2O(75∶25 v/v)溶剂系统洗脱。将产品在0℃保存。
步骤B、2-(叔丁基二甲基硅烷基)氧基乙醇三氟甲磺酸酯(TBS乙二醇Trif)的合成
氮气氛及剧烈搅拌下，将4.22g TBS乙二醇和5.2g 2，6-二甲基吡啶在装有冷凝器的100ml双颈烧瓶中混合。在35-45分钟内缓慢加入10.74g三氟甲磺酸酐，生成黄棕色溶液。然后加入1ml盐水结束反应，溶液用100ml盐水洗5次，最终pH值为6-7。将溶液用硫酸钠干燥，在真空中蒸发二氯甲烷进行浓缩。将产物通过快速色谱法用24×3cm充硅胶柱进行纯化，用己烷/Et2O(85∶15 v/v)溶剂系统洗脱，然后在0℃下保存。
步骤C、40-O-[2-(叔丁基二甲基硅烷基)氧基]乙基-雷帕霉素(TBS Rap)的合成
在50ml烧瓶中，将400mg雷帕霉素、10ml甲苯和1.9ml 2，6-二甲基吡啶混合并在55-57℃下搅拌。在另一个3ml的隔膜小瓶中加入1ml甲苯，再加入940μl 2，6-二甲基吡啶，接着加入2.47g的TBS乙二醇Trif。把小瓶内的混合物加到50ml的烧瓶中，反应在搅拌下进行1.5小时。向反应烧瓶中再加入480μL 2，6-二甲基吡啶和另加的1.236g TBS乙二醇Trif，继续搅拌反应1小时。最后再加入480μL 2，6--二甲基吡啶和1.236g TBS乙二醇Trif到混合物中，将混合物再搅拌1-1.5小时。将生成的棕色溶液用真空多孔玻璃过滤器过滤。用甲苯洗涤结晶状的沉淀物直到所有颜色被去掉。然后用60ml饱和NaHCO3溶液洗涤滤液2次，然后再用盐水洗。溶液用硫酸钠干燥，真空浓缩。用少量己烷/EtOAc(40∶60 v/v)溶剂溶解产物，用33×2cm快速硅胶色谱柱纯化，用同样的溶剂洗脱。真空除去溶剂，将产物在5℃下存放。
步骤D、40-O-(2-羟基)乙基-雷帕霉素(依维莫司)的合成工艺
向耐热玻璃碟(150×75mm)中加满冰并放置在搅拌盘上。加入少量水。先在一个小的玻璃瓶中用8ml甲醇溶解60-65mg的TBS-雷帕霉素。向小瓶中加入0.8ml 1N的HCl，将溶液搅拌45分钟，然后加3ml饱和NaHCO3水溶液进行中和。向溶液中加入5ml盐水，然后加入20ml EtOAc，产生两相的混合物。混合两相，再用分液漏斗排掉水层。剩下的溶液用盐水洗直到最终pH为6-7，然后用硫酸钠干燥。用多孔玻璃过滤器除去硫酸钠，然后真空蒸除溶剂。将得到的浓缩物溶于EtOAc/甲醇(97∶3)中，然后用23×2cm快速硅胶色谱柱纯化，用同样的溶剂洗脱。真空除去溶剂，将产物在5℃下存放。
                        实施例2
        制备在聚-d，l-丙交酯涂层中含依维莫司的支架
在室温下将100mg的聚-d，l-丙交酯溶于2ml丙酮。将5mg依维莫司放在小瓶中，加入400μL丙交酯溶液。用微处理器控制的注射泵精确给料10μL含药物的丙交酯溶液到支架支柱的顶面。溶剂蒸发后在支架上产生均匀的含药物的单一聚合物层。
以同样的方法将15μL溶液涂到支架支柱的顶面和侧面，产生涂在支架支柱顶部和侧面的单层涂层。
                         实施例3
在体外从在聚-d，l-丙交酯涂层中含依维莫司的支架上释放药物
将涂层支架放入2ml pH 7.4的含25％ETOH的磷酸盐缓冲液中，用0.05％(w/v)叠氮化钠防腐并将温度维持在37℃，构建体外药物释放。定时抽出全部缓冲液进行取样以进行药物测量，同时放入同体积的新的缓冲液(无限沉淀)。图8图示了从2个用此方法涂单一聚合物涂层的相似支架的药物释放情况。
                       实施例4
                     动物植入实验
A、猪的安全性和剂量研究的QCA结果
药物洗脱支架治疗最具挑战性的病症是严重损伤的血管，因为已知血管损伤程度的增加直接导致再狭窄(新内膜形成)程度的增加。实验是在猪身上进行的，药物涂层支架植入的靶血管用血管成形术球囊严重损伤(血管过度拉伸损伤平均约36％)。这引起血管内膜层和中间层的严重撕裂和拉伸，导致植入支架28后的血管充溢再狭窄。用这种方法，可以在同一金属支架/聚合物平台上评估各种不同剂量的药物以及药物与聚合物的不同重量比率在支架植入28天后对减少再狭窄的相对有效性。
试验平台缩写：
“裸支架”指18.7mm裸金属波纹环支架(即，目前市场上由BiosensorsIntl.Inc制造的“S-支架”)；
“C-高”指18.7mm的支架，在PDLA(聚-dl-乳酸)聚合物涂层中含有325mg的依维莫司。
“C-低”指18.7mm的支架，在PDLA聚合物涂层中含有180mg依维莫司。
“雷帕霉素-高”指18.7mm的支架，在PDLA聚合物涂层中含有325mg雷帕霉素。
“雷帕霉素-低”指18.7mm的支架，在PDLA聚合物涂层中含有180mg雷帕霉素。
“C-U高”指18.7mm的支架，在极薄的PDLA聚合物涂层中含有275mg依维莫司(药物与聚合物的重量比是37％)。
“C-U低”指18.7mm的支架，在极薄的PDLA聚合物涂层中含有180mg依维莫司或等同物(药物与聚合物的重量比是37％)。
“聚合物支架”指仅有PDLA聚合物涂层的18.7mm的S-支架。
“B/A”：最终扩张的球囊与动脉血管的比率，表示血管被过度拉伸的程度。
“平均内腔损失(MLL)”：植入时测量支架内腔3次，3次数据的平均值减去随访造影时3次测量的平均值的差，反映了支架内新内膜的形成量。
方法：
将由波状环的金属线网支架(即S-支架)和聚合物涂层组成的药物洗脱支架植入到远系繁殖的幼猪(也可植入犹卡塔小猪持续超过28天)，涂层使用不同剂量的依维莫司或雷帕霉素。在植入时，用QCA(定量冠脉造影)测定植入支架前后的血管直径。在28天或在下表规定的更长时间，在安乐死之前对动物在支架区再做造影。
动物按许可的方案安乐死后，取出动物的心脏，用甲醛溶液加压注入冠状动脉。含支架的冠状动脉部分从心脏的表面被切除随后被固定在丙烯酸塑料板上，用钻石锯切割出横断面。含有血管最近端、中间、最远端的各50微米厚的丙烯酸材料切片经光学磨光后安装在显微镜的滑片上。
用一个带有数码像机的显微镜摄出安装在滑片上的血管横断面的高分辨率图象。图象按以下程序做组织形态分析。
使用计算机图象处理系统Image Pro Plus 4.0通过基于PC系统的A.G.Heinze显微镜进行组织形态的分析。
1、平均横截面面积和内腔厚度(由内膜/新内膜-内腔边划定的面积)；新内膜(在内腔和内弹性薄层即IEL间的面积，当IEL消失，则为内腔和残留的中间膜或外弹性薄层EEL间的面积)；中间(IEL和EEL间的面积)；血管尺寸(由EEL圈定的面积，但不包括外膜面积)；外膜面积(在周边外膜组织，脂肪组织和心肌以及EEL之间的面积)。
2、损伤度。为量化血管损伤的程度，使用以不同血管壁结构撕裂的长度和量为基础的评分。损伤度被计算如下：
0＝完整的IEL；
1＝IEL被轻度撕裂，暴露了表中层(较小损伤)；
2＝IEL被中度撕裂，暴露了更深的中层(中度切开)；
3-EEL被撕裂，暴露了外层。mm2
下表是QCA分析的结果(测量由于再狭窄产生的平均内腔损失)。下表“新内膜面积”列中的数据显示了随访时从猪取下的血管和支架的形态学分析结果
                        表1“高损伤”实验的结果
装置说明 (B/A)比(平均)  随访时间  平均内腔损失(mm)  新内膜面积(mm2) 支架号
裸金属支架 1.33  28  1.69  5.89 31，39，40，45，47，50
聚合物涂层支架 1.36  28  2.10  5.82 32，41，43，48，51，60
RAPA-高 1.39  28  1.07  3.75 42，44，49，65，69，73
RAPA-低 1.42  28  0.99  2.80 52，56，61，64，68，72
C-高 1.37  28  0.84  3.54 54，55，59，63
C-低 1.36  28  1.54  3.41 53，57，58，62，66，70，74
C-U高 1.36  28  0.85  2.97 67，75，92，103
B、低损伤研究：
为进一步确定在轻度损伤的血管中依维莫司的最佳剂量，尤其是对简单的冠状动脉疾病和单一的未处理过病变的患者，植入依维莫司药物洗脱支架造成中度到低度的过度拉伸损伤(约15％)。用农场猪进行30天的实验，用成年尤卡塔小猪进行植入3个月的安全性研究。血管造影结果如下：
                       表2“低损伤”实验的QCA结果
装置说明 (B/A)比  植入后的天数  平均内腔损失(mm)  新内膜面积(mm2) 支架号
裸金属支架 1.14  28  0.95  2.89 20，22，26，29
裸金属支架 1.13  90 76，80，84，87，91
C-U高 1.15  28  0.60  2.14 94，96，98，102
C-U低 1.09  28  0.49  2.26 93，95，97，100，101
C-U高 1.15  90 77，81，85，86，90
以上数据预示，依维莫司的C-U低或C-U高剂量可在低至中度损伤的血管中降低新内膜形成45-48％。
C、形态测量分析
用计算机测量每个支架内总的截面面积和在支架内形成的新组织(新内膜)的截面面积，计算出狭窄面积百分比。每种药物和聚合物配方的平均血管损伤度、新内膜面积和狭窄面积百分比(每一支架测量三张片子，取平均值)，显示在下表中。
                      表3“高损伤”实验结果
 装置说明 损伤度  随访时间  新内膜面积(mm2)  狭窄面积(％) 支架号
 裸金属支架 1.9  28  5.89  0.72 31，39，40，45，47，50
 聚合物涂层支架 2.11  28  5.82  0.70 32，41，43，48，51，60
 RAPA-高 2.10  28  3.75  0.55 42，44，49，65，69，73
 RAPA-低 1.90  28  2.80  0.43 52，56，61，64，68，72
 C-高 1.89  28  3.54  0.38 54，55，59，63
 C-低 2.1  28  3.41  0.53 53，57，58，62，66，70，74
 C-U高 2.13  28  2.97  0.45 67，75，92，103
形态测量分析是在猪冠状动脉模型中测量支架内再狭窄的高度精确的方法。在高损伤的模型中，C-高配方在高度损伤实验28天时产生最低量的新内膜形成；而C-U高组有最高的损伤程度，但仍能维持低百分比的狭窄面积--0.45。因此，此数据独立的证实了QCA分析的发现，支持人体实验优选的配方应是C-U高。
D、组织学分析
将C-U高和雷帕霉素-低的幻灯片呈给一个有经验的心脏病理学家，对血管横切面新愈合的血管内腔的炎症、纤维素蛋白、内皮化情况进行审视。未发现由雷帕霉素和依维莫司洗脱支架引起的组织学变化有不同。总的来说，28天时血管已形成完好的内皮层恢复其平衡，达到完全愈合。图14是一个放大91倍的血管横断面例子，显示支架植入28天后血管内腔的愈合及内皮层的建立。
E、与已发表结果的比较
Carter等人已发表了使用Palmaz Schatz金属支架的雷帕霉素涂层支架在猪身上实验的结果。下表是已发表的Carter的结果和Biosensors实验结果的比较：
                                  表-4
  装置说明 血管过度拉伸(％)   平均后期损失(mm)   标准偏差(mm)  新内膜截面面积(mm2)
  S-支架裸金属对照 33.5％±9.2％   1.80   ±0.5  7.6
  S-支架仅涂聚合物 34.9％±4.8％   2.02   ±0.8  8.5
  S-支架聚合物/雷帕霉素(325mg) 32.9％±10.1％   0.66   ±0.2  3.27(对照的-57％)
  S-支架聚合物/依维莫司(325mg) 36.8％±8.5％   0.74   ±0.3  3.61(对照的-50％)
  PS支架BARE*对照 10-20％   1.19   ---  4.5
  PS支架仅涂聚合物 10-20％   1.38   ---  5.0
  PS雷帕霉素洗脱支架*166mg 10-20％   0.70   ---  2.9(对照的-33.5％)
  PS雷帕霉素洗脱支架*166mg(缓释) 10-20％   0.67   ---  2.8(对照的-37.7％)
  PS雷帕霉素洗脱支架*450mg 10-20％   0.75   ---  3.1(对照的-31.1％)
                      实施例5
                高药物含量支架的制备
先用等离子沉积工艺在市售的14.6mm长的金属波状环支架(Biosensors Intl的S-支架，波状环设计)上涂上约2微米厚的聚对亚苯基二甲基“C”底层。然后将涂有聚对亚苯基二甲基的支架放在二甲苯中在环境温度下过夜。通过将100mg的聚乳酸(PDLA)溶解在2ml丙酮中制备含有50μg/μL PDLA的聚-d，l-乳酸储备液。
为了制备药物与聚合物的比率为50％的涂层支架，将5mg依维莫司溶于100μL PDLA储备液。另加20μL丙酮以促进溶液的分散。从二甲苯中取出支架，小心地把溶剂蘸干。在每个支架的外表面给料总共5.1μL涂层溶液。将支架在室温下干燥并置于干燥器中干燥过夜。由此使每个支架在212μg PDLA中含有212μg依维莫司。
为了制备药物与聚合物的比率为75％的涂层支架，将5mg依维莫司与33.3μL PDLA储备液混合。另加33.3μL丙酮使混合物溶解。按照以上描述从二甲苯中取出支架并蘸干。在每个支架的外表面给料总共2.8μL涂层溶液。将支架在室温下干燥并置于干燥器中干燥过夜。由此使每个支架在70μg PDLA中含有212μg依维莫司。
成品支架的依维莫司/PDLA涂层厚度为约5微米，或呈现浅乳白色外观，该涂层在顶面和侧面平滑分布并且与金属支柱表面牢固连接。
权利要求书
(按照条约第19条的修改)
7、用于向粘膜表面的细胞递送大环三烯化合物的根据权利要求1的组合物，其中所述聚合物底材具有一个粘膜粘附性表面涂层。
8、根据权利要求1-7任意一项所述的组合物，其中R是CH2-X-OH，X是含有6-10个碳原子的直链烷基。
9、根据权利要求1-7任意一项所述的组合物，其中R是CH2-X-OH，X是含有6个碳原子的直链烷基。
10、根据权利要求1的组合物，其中所述的聚合物底材是由可生物降解的聚合物组合物的。
11、根据权利要求10的组合物，其中所述可生物降解的聚合物选自聚乳酸、聚羟基乙酸和它们的共聚物。
12、根据权利要求11的组合物，其中所述的聚乳酸选自聚-l-丙交酯、聚-d-丙交酯和聚-dl-丙交酯。
13、根据权利要求12的组合物，其中所述化合物的初始浓度为所述组合物重量的35-80％。

Claims (13)

1、用于将大环三烯化合物递送到个体体内靶点的聚合物组合物，该组合物含有：
(i)20-70％重量的聚合物底材和
(ii)30-80％重量的大环三烯化合物，该化合物具有以下结构式：
Figure A038093090002C1
其中R是CH2-X-OH，X是含有6-10个碳原子的直链或支链的烷基；当所述组合物被放置到靶点与细胞接触时，可有效地使摄入靶点细胞内的化合物的量明显多于含有雷帕霉素或依维莫司大环三烯化合物的同样的聚合物底材。
2、用于治疗靶点的实体瘤、炎症或创伤的根据权利要求1的组合物，其中的组合物包含可注射颗粒的混悬液，其可通过在靶点注射而局部化。
3、根据权利要求2的组合物，其中，组合物中的聚合物底材由可生物降解的聚合物形成。
4、用于治疗靶点的实体瘤、炎症或创伤的根据权利要求1的组合物，其中所述聚合物底材是用于贴在组织结构的外表面的贴剂。
5、用于治疗发炎的组织或伤口的根据权利要求1的组合物，其中所述聚合物底材是用于在需要治疗的组织上涂抹的药膏的形式。
6、用于在血管壁损伤部位抑制再狭窄的根据权利要求1的组合物，其中所述组合物包括可扩张血管支架中与血管壁接触的部分所携带的涂层。
7、用于向粘膜表面的细胞递送大环三烯化合物的根据权利要求1的组合物，其中所述聚合物底材具有一个粘膜粘附性表面涂层。
8、根据权利要求1-8任意一项所述的组合物，其中R是CH2-X-OH，X是含有6-10个碳原子的直链烷基。
9、根据权利要求1-8任意一项所述的组合物，其中R是CH2-X-OH，X是含有6个碳原子的直链烷基。
10、根据权利要求1的组合物，其中所述的聚合物底材是由可生物降解的聚合物组合物的。
11、根据权利要求10的组合物，其中所述可生物降解的聚合物选自聚乳酸、聚羟基乙酸和它们的共聚物。
12、根据权利要求11的组合物，其中所述的聚乳酸选自聚-l-丙交酯、聚-d-丙交酯和聚-dl-丙交酯。
13、根据权利要求12的组合物，其中所述化合物的初始浓度为所述组合物重量的35-80％。
CNA03809309XA 2002-04-24 2003-04-24 含大环三烯化合物的聚合物组合物 Pending CN1735402A (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10/133,814 US6939376B2 (en) 2001-11-05 2002-04-24 Drug-delivery endovascular stent and method for treating restenosis
PCT/US2003/012750 WO2003090818A2 (en) 2002-04-24 2003-04-24 Drug-delivery endovascular stent and method for treating restenosis

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN2008101905439A Division CN101467921B (zh) 2001-11-05 2003-04-24 药物洗脱支架的生产方法

Publications (1)

Publication Number Publication Date
CN1735402A true CN1735402A (zh) 2006-02-15

Family

ID=29268785

Family Applications (3)

Application Number Title Priority Date Filing Date
CN2010102003218A Expired - Lifetime CN101862233B (zh) 2002-04-24 2003-04-24 药物释放型血管内支架和治疗再狭窄的方法
CN038093111A Expired - Lifetime CN1649551B (zh) 2002-04-24 2003-04-24 药物释放型血管内支架
CNA03809309XA Pending CN1735402A (zh) 2002-04-24 2003-04-24 含大环三烯化合物的聚合物组合物

Family Applications Before (2)

Application Number Title Priority Date Filing Date
CN2010102003218A Expired - Lifetime CN101862233B (zh) 2002-04-24 2003-04-24 药物释放型血管内支架和治疗再狭窄的方法
CN038093111A Expired - Lifetime CN1649551B (zh) 2002-04-24 2003-04-24 药物释放型血管内支架

Country Status (10)

Country Link
US (6) US6939376B2 (zh)
EP (6) EP2316377B1 (zh)
JP (6) JP4315817B2 (zh)
CN (3) CN101862233B (zh)
AT (1) ATE451075T1 (zh)
AU (3) AU2003231757B2 (zh)
DE (1) DE60330455D1 (zh)
ES (4) ES2523870T3 (zh)
HK (3) HK1177882A1 (zh)
WO (2) WO2003090818A2 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104478898A (zh) * 2014-11-18 2015-04-01 连云港恒运医药科技有限公司 依维莫司及其中间体的制备方法

Families Citing this family (370)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2178541C (en) 1995-06-07 2009-11-24 Neal E. Fearnot Implantable medical device
US6241762B1 (en) 1998-03-30 2001-06-05 Conor Medsystems, Inc. Expandable medical device with ductile hinges
US7208010B2 (en) 2000-10-16 2007-04-24 Conor Medsystems, Inc. Expandable medical device for delivery of beneficial agent
US7208011B2 (en) * 2001-08-20 2007-04-24 Conor Medsystems, Inc. Implantable medical device with drug filled holes
US7713297B2 (en) 1998-04-11 2010-05-11 Boston Scientific Scimed, Inc. Drug-releasing stent with ceramic-containing layer
US6790228B2 (en) 1999-12-23 2004-09-14 Advanced Cardiovascular Systems, Inc. Coating for implantable devices and a method of forming the same
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
US7419678B2 (en) * 2000-05-12 2008-09-02 Cordis Corporation Coated medical devices for the prevention and treatment of vascular disease
HUP0300810A2 (hu) 2000-07-20 2003-08-28 M.G.V.S. Ltd. Mesterséges értranszplantátum, valamint ennek létrehozása és alkalmazása
US7175658B1 (en) * 2000-07-20 2007-02-13 Multi-Gene Vascular Systems Ltd. Artificial vascular grafts, their construction and use
IL155107A0 (en) 2000-10-16 2003-10-31 Conor Medsystems Inc Expandable medical device for delivery of beneficial agent
EP1258230A3 (en) * 2001-03-29 2003-12-10 CardioSafe Ltd Balloon catheter device
US6764505B1 (en) 2001-04-12 2004-07-20 Advanced Cardiovascular Systems, Inc. Variable surface area stent
US8741378B1 (en) 2001-06-27 2014-06-03 Advanced Cardiovascular Systems, Inc. Methods of coating an implantable device
US7247313B2 (en) * 2001-06-27 2007-07-24 Advanced Cardiovascular Systems, Inc. Polyacrylates coatings for implantable medical devices
US7056338B2 (en) * 2003-03-28 2006-06-06 Conor Medsystems, Inc. Therapeutic agent delivery device with controlled therapeutic agent release rates
US7842083B2 (en) 2001-08-20 2010-11-30 Innovational Holdings, Llc. Expandable medical device with improved spatial distribution
GB0121980D0 (en) * 2001-09-11 2001-10-31 Cathnet Science Holding As Expandable stent
US20030077310A1 (en) 2001-10-22 2003-04-24 Chandrashekhar Pathak Stent coatings containing HMG-CoA reductase inhibitors
US7682387B2 (en) 2002-04-24 2010-03-23 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US6939376B2 (en) * 2001-11-05 2005-09-06 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US20030135266A1 (en) * 2001-12-03 2003-07-17 Xtent, Inc. Apparatus and methods for delivery of multiple distributed stents
US7182779B2 (en) 2001-12-03 2007-02-27 Xtent, Inc. Apparatus and methods for positioning prostheses for deployment from a catheter
US7270668B2 (en) * 2001-12-03 2007-09-18 Xtent, Inc. Apparatus and methods for delivering coiled prostheses
US7294146B2 (en) 2001-12-03 2007-11-13 Xtent, Inc. Apparatus and methods for delivery of variable length stents
US7147656B2 (en) 2001-12-03 2006-12-12 Xtent, Inc. Apparatus and methods for delivery of braided prostheses
US8080048B2 (en) * 2001-12-03 2011-12-20 Xtent, Inc. Stent delivery for bifurcated vessels
US7351255B2 (en) * 2001-12-03 2008-04-01 Xtent, Inc. Stent delivery apparatus and method
US7137993B2 (en) 2001-12-03 2006-11-21 Xtent, Inc. Apparatus and methods for delivery of multiple distributed stents
US20040186551A1 (en) * 2003-01-17 2004-09-23 Xtent, Inc. Multiple independent nested stent structures and methods for their preparation and deployment
US7309350B2 (en) 2001-12-03 2007-12-18 Xtent, Inc. Apparatus and methods for deployment of vascular prostheses
US7892273B2 (en) 2001-12-03 2011-02-22 Xtent, Inc. Custom length stent apparatus
US20040024450A1 (en) * 2002-04-24 2004-02-05 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US6645547B1 (en) * 2002-05-02 2003-11-11 Labcoat Ltd. Stent coating device
US7270675B2 (en) * 2002-05-10 2007-09-18 Cordis Corporation Method of forming a tubular membrane on a structural frame
EP1516597A4 (en) * 2002-06-27 2010-11-10 Microport Medical Shanghai Co MEDICINES ELUTIONSSTENT
EP1539157B1 (en) 2002-09-18 2013-08-21 Trustees Of The University Of Pennsylvania Rapamycin for use in inhibiting or preventing choroidal neovascularization
US8303511B2 (en) 2002-09-26 2012-11-06 Pacesetter, Inc. Implantable pressure transducer system optimized for reduced thrombosis effect
US7149587B2 (en) 2002-09-26 2006-12-12 Pacesetter, Inc. Cardiovascular anchoring device and method of deploying same
US6971813B2 (en) * 2002-09-27 2005-12-06 Labcoat, Ltd. Contact coating of prostheses
WO2004034874A2 (en) * 2002-10-15 2004-04-29 Norbert Thompson Parylene-coated silicone t-tubes and method of use thereof
AU2003291470A1 (en) * 2002-11-08 2004-06-03 Innovational Holdings, Llc Expandable medical device and method for treating chronic total occlusions with local delivery of an angiogenic factor
US7169178B1 (en) * 2002-11-12 2007-01-30 Advanced Cardiovascular Systems, Inc. Stent with drug coating
US20060121080A1 (en) 2002-11-13 2006-06-08 Lye Whye K Medical devices having nanoporous layers and methods for making the same
US9770349B2 (en) * 2002-11-13 2017-09-26 University Of Virginia Patent Foundation Nanoporous stents with enhanced cellular adhesion and reduced neointimal formation
ATE402675T1 (de) * 2002-11-13 2008-08-15 Setagon Inc Medizinprodukte mit porösen schichten und herstellungsverfahren dafür
US20050070989A1 (en) * 2002-11-13 2005-03-31 Whye-Kei Lye Medical devices having porous layers and methods for making the same
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
US8435550B2 (en) 2002-12-16 2013-05-07 Abbot Cardiovascular Systems Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US20060002968A1 (en) * 2004-06-30 2006-01-05 Gordon Stewart Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders
US8715771B2 (en) * 2003-02-26 2014-05-06 Abbott Cardiovascular Systems Inc. Coated stent and method of making the same
US20090093875A1 (en) * 2007-05-01 2009-04-09 Abbott Laboratories Drug eluting stents with prolonged local elution profiles with high local concentrations and low systemic concentrations
EP1605863B1 (en) 2003-03-14 2016-09-07 Intersect ENT, Inc. Sinus delivery of sustained release therapeutics
US20040202692A1 (en) * 2003-03-28 2004-10-14 Conor Medsystems, Inc. Implantable medical device and method for in situ selective modulation of agent delivery
JP5596896B2 (ja) 2003-03-28 2014-09-24 イノヴェイショナル・ホールディングズ・エルエルシー 有益な薬剤の濃度勾配を有する、移植可能な医療装置の形成方法
US7241308B2 (en) * 2003-06-09 2007-07-10 Xtent, Inc. Stent deployment systems and methods
US7229979B2 (en) * 2003-06-23 2007-06-12 Immune Modulation, Inc. Hypoestoxides, derivatives and agonists thereof for use as stent-coating agents
US20050118344A1 (en) 2003-12-01 2005-06-02 Pacetti Stephen D. Temperature controlled crimping
US6840569B1 (en) * 2003-07-22 2005-01-11 Arthur Donald Leigh Caravan
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
US20050048194A1 (en) * 2003-09-02 2005-03-03 Labcoat Ltd. Prosthesis coating decision support system
US20050058768A1 (en) * 2003-09-16 2005-03-17 Eyal Teichman Method for coating prosthetic stents
WO2005037339A1 (en) * 2003-10-14 2005-04-28 Cube Medical A/S A balloon for use in angioplasty
US20050080475A1 (en) * 2003-10-14 2005-04-14 Xtent, Inc. A Delaware Corporation Stent delivery devices and methods
US7553324B2 (en) * 2003-10-14 2009-06-30 Xtent, Inc. Fixed stent delivery devices and methods
US7192440B2 (en) * 2003-10-15 2007-03-20 Xtent, Inc. Implantable stent delivery devices and methods
US20050100577A1 (en) * 2003-11-10 2005-05-12 Parker Theodore L. Expandable medical device with beneficial agent matrix formed by a multi solvent system
US7220755B2 (en) 2003-11-12 2007-05-22 Biosensors International Group, Ltd. 42-O-alkoxyalkyl rapamycin derivatives and compositions comprising same
US7403966B2 (en) * 2003-12-08 2008-07-22 Freescale Semiconductor, Inc. Hardware for performing an arithmetic function
US20070156225A1 (en) * 2003-12-23 2007-07-05 Xtent, Inc. Automated control mechanisms and methods for custom length stent apparatus
US7326236B2 (en) 2003-12-23 2008-02-05 Xtent, Inc. Devices and methods for controlling and indicating the length of an interventional element
EP1699527A1 (en) 2004-01-02 2006-09-13 Advanced Cardiovascular Systems, Inc. High-density lipoprotein coated medical devices
DE102004029611A1 (de) * 2004-02-06 2005-08-25 Restate Patent Ag Implantat zur Freisetzung eines Wirkstoffs in ein von einem Körpermedium durchströmtes Gefäß
MXPA06009770A (es) * 2004-02-28 2007-02-20 Hemoteq Gmbh Revestimiento biocompatible, metodo y utilizacion de superficies medicas.
DE602005011879D1 (de) * 2004-03-01 2009-02-05 Terumo Corp Verfahren zur Herstellung von O-alkylierten Rapamycinderivaten
US7695731B2 (en) * 2004-03-22 2010-04-13 Cordis Corporation Local vascular delivery of etoposide in combination with rapamycin to prevent restenosis following vascular injury
US7323006B2 (en) 2004-03-30 2008-01-29 Xtent, Inc. Rapid exchange interventional devices and methods
US8778014B1 (en) 2004-03-31 2014-07-15 Advanced Cardiovascular Systems, Inc. Coatings for preventing balloon damage to polymer coated stents
US20050228477A1 (en) * 2004-04-09 2005-10-13 Xtent, Inc. Topographic coatings and coating methods for medical devices
US8000784B2 (en) 2004-04-19 2011-08-16 The Invention Science Fund I, Llc Lumen-traveling device
US8024036B2 (en) 2007-03-19 2011-09-20 The Invention Science Fund I, Llc Lumen-traveling biological interface device and method of use
US7998060B2 (en) 2004-04-19 2011-08-16 The Invention Science Fund I, Llc Lumen-traveling delivery device
US8092549B2 (en) 2004-09-24 2012-01-10 The Invention Science Fund I, Llc Ciliated stent-like-system
US8361013B2 (en) 2004-04-19 2013-01-29 The Invention Science Fund I, Llc Telescoping perfusion management system
US9801527B2 (en) 2004-04-19 2017-10-31 Gearbox, Llc Lumen-traveling biological interface device
US9011329B2 (en) 2004-04-19 2015-04-21 Searete Llc Lumenally-active device
US7850676B2 (en) 2004-04-19 2010-12-14 The Invention Science Fund I, Llc System with a reservoir for perfusion management
US8353896B2 (en) 2004-04-19 2013-01-15 The Invention Science Fund I, Llc Controllable release nasal system
US8337482B2 (en) 2004-04-19 2012-12-25 The Invention Science Fund I, Llc System for perfusion management
US20060246109A1 (en) * 2005-04-29 2006-11-02 Hossainy Syed F Concentration gradient profiles for control of agent release rates from polymer matrices
US8293890B2 (en) * 2004-04-30 2012-10-23 Advanced Cardiovascular Systems, Inc. Hyaluronic acid based copolymers
US20070142339A1 (en) * 2004-05-10 2007-06-21 Novacea, Inc. Prevention of arterial restenosis with active vitamin d compounds
US20050255230A1 (en) * 2004-05-17 2005-11-17 Clerc Claude O Method of manufacturing a covered stent
US20050288766A1 (en) * 2004-06-28 2005-12-29 Xtent, Inc. Devices and methods for controlling expandable prostheses during deployment
US8317859B2 (en) 2004-06-28 2012-11-27 J.W. Medical Systems Ltd. Devices and methods for controlling expandable prostheses during deployment
US20050287184A1 (en) * 2004-06-29 2005-12-29 Hossainy Syed F A Drug-delivery stent formulations for restenosis and vulnerable plaque
US8709469B2 (en) 2004-06-30 2014-04-29 Abbott Cardiovascular Systems Inc. Anti-proliferative and anti-inflammatory agent combination for treatment of vascular disorders with an implantable medical device
US20060029720A1 (en) * 2004-08-03 2006-02-09 Anastasia Panos Methods and apparatus for injection coating a medical device
US8980300B2 (en) 2004-08-05 2015-03-17 Advanced Cardiovascular Systems, Inc. Plasticizers for coating compositions
US7901451B2 (en) 2004-09-24 2011-03-08 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US20060069424A1 (en) * 2004-09-27 2006-03-30 Xtent, Inc. Self-constrained segmented stents and methods for their deployment
US20060085065A1 (en) * 2004-10-15 2006-04-20 Krause Arthur A Stent with auxiliary treatment structure
US20060095122A1 (en) * 2004-10-29 2006-05-04 Advanced Cardiovascular Systems, Inc. Implantable devices comprising biologically absorbable star polymers and methods for fabricating the same
US8388677B2 (en) * 2004-10-29 2013-03-05 Boston Scientific Scimed, Inc. Anti-thrombogenic and anti-restenotic vascular medical devices
US7481835B1 (en) * 2004-10-29 2009-01-27 Advanced Cardiovascular Systems, Inc. Encapsulated covered stent
US20060127443A1 (en) * 2004-12-09 2006-06-15 Helmus Michael N Medical devices having vapor deposited nanoporous coatings for controlled therapeutic agent delivery
US7632307B2 (en) 2004-12-16 2009-12-15 Advanced Cardiovascular Systems, Inc. Abluminal, multilayer coating constructs for drug-delivery stents
US8057543B2 (en) * 2005-01-28 2011-11-15 Greatbatch Ltd. Stent coating for eluting medication
US7749553B2 (en) * 2005-01-31 2010-07-06 Boston Scientific Scimed, Inc. Method and system for coating a medical device using optical drop volume verification
BRPI0608152A2 (pt) 2005-02-09 2009-11-10 Macusight Inc formulações para tratamento ocular
US9381279B2 (en) 2005-03-24 2016-07-05 Abbott Cardiovascular Systems Inc. Implantable devices formed on non-fouling methacrylate or acrylate polymers
US7700659B2 (en) * 2005-03-24 2010-04-20 Advanced Cardiovascular Systems, Inc. Implantable devices formed of non-fouling methacrylate or acrylate polymers
EP2510908B1 (en) * 2005-03-31 2014-04-30 Innovational Holdings, LLC System and method for loading a beneficial agent into a medical device
MX2007012324A (es) 2005-04-04 2008-02-12 Sinexus Inc Dispositivo y metodo para tratar condiciones del seno paranasal.
US7402168B2 (en) * 2005-04-11 2008-07-22 Xtent, Inc. Custom-length stent delivery system with independently operable expansion elements
US8778375B2 (en) * 2005-04-29 2014-07-15 Advanced Cardiovascular Systems, Inc. Amorphous poly(D,L-lactide) coating
US20060257355A1 (en) * 2005-05-10 2006-11-16 Abiomed, Inc. Impregnated polymer compositions and devices using them
US8043323B2 (en) * 2006-10-18 2011-10-25 Inspiremd Ltd. In vivo filter assembly
WO2006126182A2 (en) 2005-05-24 2006-11-30 Inspire M.D Ltd. Stent apparatuses for treatment via body lumens and methods of use
US8961586B2 (en) 2005-05-24 2015-02-24 Inspiremd Ltd. Bifurcated stent assemblies
US20060282149A1 (en) * 2005-06-08 2006-12-14 Xtent, Inc., A Delaware Corporation Apparatus and methods for deployment of multiple custom-length prostheses (II)
US20090062909A1 (en) * 2005-07-15 2009-03-05 Micell Technologies, Inc. Stent with polymer coating containing amorphous rapamycin
AU2011256902B2 (en) * 2005-07-15 2015-03-12 Micell Technologies, Inc. Polymer coatings containing drug powder of controlled morphology
AU2006270221B2 (en) 2005-07-15 2012-01-19 Micell Technologies, Inc. Polymer coatings containing drug powder of controlled morphology
US20070020312A1 (en) * 2005-07-20 2007-01-25 Desnoyer Jessica R Method of fabricating a bioactive agent-releasing implantable medical device
WO2007040485A1 (en) * 2005-09-22 2007-04-12 Novovascular, Inc. Stent covered by a layer having a layer opening
US20070104753A1 (en) * 2005-11-04 2007-05-10 Aiden Flanagan Medical device with a coating comprising an active form and an inactive form of therapeutic agent(s)
US20070196423A1 (en) * 2005-11-21 2007-08-23 Med Institute, Inc. Implantable medical device coatings with biodegradable elastomer and releasable therapeutic agent
US9446226B2 (en) 2005-12-07 2016-09-20 Ramot At Tel-Aviv University Ltd. Drug-delivering composite structures
US20070142903A1 (en) * 2005-12-15 2007-06-21 Dave Vipul B Laser cut intraluminal medical devices
US7842312B2 (en) * 2005-12-29 2010-11-30 Cordis Corporation Polymeric compositions comprising therapeutic agents in crystalline phases, and methods of forming the same
WO2007081530A2 (en) * 2006-01-03 2007-07-19 Med Institute, Inc. Endoluminal medical device for local delivery of cathepsin inhibitors
US20070179587A1 (en) * 2006-01-30 2007-08-02 Xtent, Inc. Apparatus and methods for deployment of custom-length prostheses
WO2007089780A2 (en) * 2006-01-30 2007-08-09 Licentia, Ltd. Bmx/etk tyrosine kinase gene therapy materials and methods
JP2009525110A (ja) 2006-01-31 2009-07-09 マルチ ジーン バスキュラー システムズ， インコーポレイテッド 薬物溶出血管内プロテーゼおよび使用方法
US20070178137A1 (en) * 2006-02-01 2007-08-02 Toby Freyman Local control of inflammation
WO2007092620A2 (en) 2006-02-09 2007-08-16 Macusight, Inc. Stable formulations, and methods of their preparation and use
WO2007098270A2 (en) 2006-02-27 2007-08-30 Vertex Pharmaceuticals Incorporated Co-crystals comprising vx-950 and pharmaceutical compositions comprising the same
US7622477B2 (en) * 2006-02-28 2009-11-24 Cordis Corporation Isomers and 42-epimers of rapamycin alkyl ether analogs, methods of making and using the same
CA2646885A1 (en) 2006-03-20 2007-09-27 Xtent, Inc. Apparatus and methods for deployment of linked prosthetic segments
CN103127100A (zh) 2006-03-23 2013-06-05 参天制药株式会社 用于与血管通透性有关的疾病或病症的制剂和方法
US20070224235A1 (en) 2006-03-24 2007-09-27 Barron Tenney Medical devices having nanoporous coatings for controlled therapeutic agent delivery
US8187620B2 (en) 2006-03-27 2012-05-29 Boston Scientific Scimed, Inc. Medical devices comprising a porous metal oxide or metal material and a polymer coating for delivering therapeutic agents
WO2007119423A1 (ja) * 2006-03-30 2007-10-25 Terumo Kabushiki Kaisha 生体内留置物
JPWO2007116646A1 (ja) * 2006-04-04 2009-08-20 テルモ株式会社 生体内留置物
US8145295B2 (en) 2006-04-12 2012-03-27 The Invention Science Fund I, Llc Methods and systems for untethered autofluorescent imaging, target ablation, and movement of untethered device in a lumen
US9198563B2 (en) 2006-04-12 2015-12-01 The Invention Science Fund I, Llc Temporal control of a lumen traveling device in a body tube tree
US7879086B2 (en) * 2006-04-20 2011-02-01 Boston Scientific Scimed, Inc. Medical device having a coating comprising an adhesion promoter
US8852625B2 (en) 2006-04-26 2014-10-07 Micell Technologies, Inc. Coatings containing multiple drugs
US20070254003A1 (en) * 2006-05-01 2007-11-01 Pu Zhou Non-sticky coatings with therapeutic agents for medical devices
US20070276486A1 (en) * 2006-05-25 2007-11-29 E. Benson Hood Laboratories Coated tracheostomy tube and stoma stent or cannula
EP2020956A2 (en) 2006-05-26 2009-02-11 Nanyang Technological University Implantable article, method of forming same and method for reducing thrombogenicity
US9561351B2 (en) * 2006-05-31 2017-02-07 Advanced Cardiovascular Systems, Inc. Drug delivery spiral coil construct
US20070281117A1 (en) 2006-06-02 2007-12-06 Xtent, Inc. Use of plasma in formation of biodegradable stent coating
US20080095918A1 (en) * 2006-06-14 2008-04-24 Kleiner Lothar W Coating construct with enhanced interfacial compatibility
US8246973B2 (en) 2006-06-21 2012-08-21 Advanced Cardiovascular Systems, Inc. Freeze-thaw method for modifying stent coating
US8388573B1 (en) 2006-06-28 2013-03-05 Abbott Cardiovascular Systems Inc. Local delivery with a balloon covered by a cage
US8815275B2 (en) 2006-06-28 2014-08-26 Boston Scientific Scimed, Inc. Coatings for medical devices comprising a therapeutic agent and a metallic material
US8679573B2 (en) * 2006-06-28 2014-03-25 Advanced Cardiovascular Systems, Inc. Stent coating method and apparatus
CA2655793A1 (en) 2006-06-29 2008-01-03 Boston Scientific Limited Medical devices with selective coating
US8956640B2 (en) * 2006-06-29 2015-02-17 Advanced Cardiovascular Systems, Inc. Block copolymers including a methoxyethyl methacrylate midblock
US20080008736A1 (en) * 2006-07-06 2008-01-10 Thierry Glauser Random copolymers of methacrylates and acrylates
US8016879B2 (en) 2006-08-01 2011-09-13 Abbott Cardiovascular Systems Inc. Drug delivery after biodegradation of the stent scaffolding
US20080091262A1 (en) * 2006-10-17 2008-04-17 Gale David C Drug delivery after biodegradation of the stent scaffolding
CN100465209C (zh) * 2006-08-17 2009-03-04 同济大学 用于形状记忆管腔内支架的可降解高分子材料的制备方法
WO2008033711A2 (en) 2006-09-14 2008-03-20 Boston Scientific Limited Medical devices with drug-eluting coating
US20080069858A1 (en) * 2006-09-20 2008-03-20 Boston Scientific Scimed, Inc. Medical devices having biodegradable polymeric regions with overlying hard, thin layers
WO2008042909A2 (en) * 2006-10-02 2008-04-10 Micell Technologies Inc. Surgical sutures having increased strength
US10137015B2 (en) 2006-10-18 2018-11-27 Inspiremd Ltd. Knitted stent jackets
EP1913960A1 (en) * 2006-10-19 2008-04-23 Albert Schömig Coated implant
EP1916006A1 (en) * 2006-10-19 2008-04-30 Albert Schömig Implant coated with a wax or a resin
US20080097591A1 (en) * 2006-10-20 2008-04-24 Biosensors International Group Drug-delivery endovascular stent and method of use
US8067055B2 (en) * 2006-10-20 2011-11-29 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method of use
CN101678388B (zh) 2006-10-23 2013-12-11 米歇尔技术公司 用于在涂覆过程中为基底充电的保持器
US20080103584A1 (en) * 2006-10-25 2008-05-01 Biosensors International Group Temporal Intraluminal Stent, Methods of Making and Using
US7981150B2 (en) 2006-11-09 2011-07-19 Boston Scientific Scimed, Inc. Endoprosthesis with coatings
US20080294236A1 (en) * 2007-05-23 2008-11-27 Boston Scientific Scimed, Inc. Endoprosthesis with Select Ceramic and Polymer Coatings
CN102973343B (zh) 2006-11-22 2015-12-09 印斯拜尔Md有限公司 优化的支架套
WO2008088537A2 (en) * 2006-12-20 2008-07-24 Boston Scientific Limited Stent with a coating for delivering a therapeutic agent
EP2111184B1 (en) 2007-01-08 2018-07-25 Micell Technologies, Inc. Stents having biodegradable layers
US11426494B2 (en) 2007-01-08 2022-08-30 MT Acquisition Holdings LLC Stents having biodegradable layers
US8221496B2 (en) * 2007-02-01 2012-07-17 Cordis Corporation Antithrombotic and anti-restenotic drug eluting stent
US20080199510A1 (en) 2007-02-20 2008-08-21 Xtent, Inc. Thermo-mechanically controlled implants and methods of use
NZ579442A (en) 2007-02-27 2012-02-24 Vertex Pharma Co-crystals of VX-950 (telaprevir) and other components, and pharmaceutical compositions comprising the same
US8070797B2 (en) 2007-03-01 2011-12-06 Boston Scientific Scimed, Inc. Medical device with a porous surface for delivery of a therapeutic agent
US8431149B2 (en) 2007-03-01 2013-04-30 Boston Scientific Scimed, Inc. Coated medical devices for abluminal drug delivery
US8486132B2 (en) 2007-03-22 2013-07-16 J.W. Medical Systems Ltd. Devices and methods for controlling expandable prostheses during deployment
US8067054B2 (en) 2007-04-05 2011-11-29 Boston Scientific Scimed, Inc. Stents with ceramic drug reservoir layer and methods of making and using the same
KR101158981B1 (ko) * 2007-04-17 2012-06-21 미셀 테크놀로지즈, 인코포레이티드 생체분해성 층을 갖는 스텐트
US7976915B2 (en) 2007-05-23 2011-07-12 Boston Scientific Scimed, Inc. Endoprosthesis with select ceramic morphology
US8084077B2 (en) * 2007-05-25 2011-12-27 Abbott Laboratories One-step phosphorylcholine-linked polymer coating and drug loading of stent
JP2010527746A (ja) * 2007-05-25 2010-08-19 ミセル テクノロジーズ、インコーポレイテッド メディカルデバイスコーティング用ポリマーフィルム
US20100070020A1 (en) 2008-06-11 2010-03-18 Nanovasc, Inc. Implantable Medical Device
US8002823B2 (en) 2007-07-11 2011-08-23 Boston Scientific Scimed, Inc. Endoprosthesis coating
US7942926B2 (en) 2007-07-11 2011-05-17 Boston Scientific Scimed, Inc. Endoprosthesis coating
JP2010533563A (ja) 2007-07-19 2010-10-28 ボストン サイエンティフィック リミテッド 吸着抑制表面を有する内部人工器官
DE102007034364A1 (de) * 2007-07-24 2009-01-29 Biotronik Vi Patent Ag Degradierbarer Metallstent mit wirkstoffhaltiger Beschichtung
US8815273B2 (en) 2007-07-27 2014-08-26 Boston Scientific Scimed, Inc. Drug eluting medical devices having porous layers
US7931683B2 (en) 2007-07-27 2011-04-26 Boston Scientific Scimed, Inc. Articles having ceramic coated surfaces
US8221822B2 (en) 2007-07-31 2012-07-17 Boston Scientific Scimed, Inc. Medical device coating by laser cladding
EP2185103B1 (en) 2007-08-03 2014-02-12 Boston Scientific Scimed, Inc. Coating for medical device having increased surface area
US20090041845A1 (en) * 2007-08-08 2009-02-12 Lothar Walter Kleiner Implantable medical devices having thin absorbable coatings
US20090043330A1 (en) * 2007-08-09 2009-02-12 Specialized Vascular Technologies, Inc. Embolic protection devices and methods
US20090043380A1 (en) * 2007-08-09 2009-02-12 Specialized Vascular Technologies, Inc. Coatings for promoting endothelization of medical devices
MX2010002407A (es) 2007-08-30 2010-03-26 Vertex Pharma Cocristales y composiciones farmaceuticas que los comprenden.
US8556880B2 (en) * 2007-09-06 2013-10-15 Boston Scientific Scimed, Inc. Methods and devices for local therapeutic agent delivery to heart valves
US8100855B2 (en) 2007-09-17 2012-01-24 Abbott Cardiovascular Systems, Inc. Methods and devices for eluting agents to a vessel
KR100930167B1 (ko) * 2007-09-19 2009-12-07 삼성전기주식회사 초광각 광학계
US20090076584A1 (en) * 2007-09-19 2009-03-19 Xtent, Inc. Apparatus and methods for deployment of multiple custom-length prostheses
US9814553B1 (en) 2007-10-10 2017-11-14 Abbott Cardiovascular Systems Inc. Bioabsorbable semi-crystalline polymer for controlling release of drug from a coating
US8661630B2 (en) * 2008-05-21 2014-03-04 Abbott Cardiovascular Systems Inc. Coating comprising an amorphous primer layer and a semi-crystalline reservoir layer
US8142490B2 (en) 2007-10-24 2012-03-27 Cordis Corporation Stent segments axially connected by thin film
US8642062B2 (en) 2007-10-31 2014-02-04 Abbott Cardiovascular Systems Inc. Implantable device having a slow dissolving polymer
US20090112239A1 (en) * 2007-10-31 2009-04-30 Specialized Vascular Technologies, Inc. Sticky dilatation balloon and methods of using
US8029554B2 (en) 2007-11-02 2011-10-04 Boston Scientific Scimed, Inc. Stent with embedded material
US20090118821A1 (en) * 2007-11-02 2009-05-07 Boston Scientific Scimed, Inc. Endoprosthesis with porous reservoir and non-polymer diffusion layer
US20090118812A1 (en) * 2007-11-02 2009-05-07 Boston Scientific Scimed, Inc. Endoprosthesis coating
US7938855B2 (en) 2007-11-02 2011-05-10 Boston Scientific Scimed, Inc. Deformable underlayer for stent
US8216632B2 (en) 2007-11-02 2012-07-10 Boston Scientific Scimed, Inc. Endoprosthesis coating
US8573150B2 (en) 2007-11-14 2013-11-05 Biosensors International Group, Ltd. Automated stent coating apparatus and method
TW200940527A (en) 2007-12-07 2009-10-01 Vertex Pharma Solid forms of 1-ethyl-3-(5-(5-fluoropyridin-3-yl)-7-(pyrimidin-2-yl)-1H-benzo[d]imidazol-2-yl)urea
AU2008338586B2 (en) 2007-12-18 2015-01-29 Intersect Ent, Inc. Self-expanding devices and methods therefor
US20090186068A1 (en) * 2008-01-18 2009-07-23 Chameleon Scientific Corporation Atomic plasma deposited coatings for drug release
US20090196900A1 (en) * 2008-02-01 2009-08-06 Medtronic Vascular, Inc. Use of Phosphodiesterase Inhibitor as a Component of Implantable Medical Devices
US9603980B2 (en) * 2008-02-26 2017-03-28 CARDINAL HEALTH SWITZERLAND 515 GmbH Layer-by-layer stereocomplexed polymers as drug depot carriers or coatings in medical devices
US9101503B2 (en) 2008-03-06 2015-08-11 J.W. Medical Systems Ltd. Apparatus having variable strut length and methods of use
US8377116B2 (en) * 2008-03-20 2013-02-19 Abbott Cardiovascular Systems Inc. Implantable medical device coatings with improved mechanical stability
CN101264351B (zh) * 2008-04-07 2011-08-24 易生科技(北京)有限公司 复合涂层心血管药物洗脱支架及其制备方法
US20100121435A1 (en) 2008-04-16 2010-05-13 Cardiovascular Technologies, Llc Percutaneous transvalvular intrannular band for mitral valve repair
US10456259B2 (en) 2008-04-16 2019-10-29 Heart Repair Technologies, Inc. Transvalvular intraannular band for mitral valve repair
US11083579B2 (en) 2008-04-16 2021-08-10 Heart Repair Technologies, Inc. Transvalvular intraanular band and chordae cutting for ischemic and dilated cardiomyopathy
US11013599B2 (en) 2008-04-16 2021-05-25 Heart Repair Technologies, Inc. Percutaneous transvalvular intraannular band for mitral valve repair
US20100121437A1 (en) 2008-04-16 2010-05-13 Cardiovascular Technologies, Llc Transvalvular intraannular band and chordae cutting for ischemic and dilated cardiomyopathy
JP5608160B2 (ja) 2008-04-17 2014-10-15 ミセル テクノロジーズ、インコーポレイテッド 生体吸収性の層を有するステント
US20090285873A1 (en) * 2008-04-18 2009-11-19 Abbott Cardiovascular Systems Inc. Implantable medical devices and coatings therefor comprising block copolymers of poly(ethylene glycol) and a poly(lactide-glycolide)
US8916188B2 (en) * 2008-04-18 2014-12-23 Abbott Cardiovascular Systems Inc. Block copolymer comprising at least one polyester block and a poly (ethylene glycol) block
WO2009131911A2 (en) 2008-04-22 2009-10-29 Boston Scientific Scimed, Inc. Medical devices having a coating of inorganic material
WO2009132176A2 (en) 2008-04-24 2009-10-29 Boston Scientific Scimed, Inc. Medical devices having inorganic particle layers
US9126025B2 (en) 2008-05-01 2015-09-08 Bayer Intellectual Property Gmbh Method of coating a folded catheter balloon
US8986728B2 (en) 2008-05-30 2015-03-24 Abbott Cardiovascular Systems Inc. Soluble implantable device comprising polyelectrolyte with hydrophobic counterions
WO2010036427A1 (en) 2008-06-17 2010-04-01 Brigham Young University Cationic steroid antimicrobial diagnostic, detection, screening and imaging methods
WO2009155328A2 (en) 2008-06-18 2009-12-23 Boston Scientific Scimed, Inc. Endoprosthesis coating
US8206635B2 (en) 2008-06-20 2012-06-26 Amaranth Medical Pte. Stent fabrication via tubular casting processes
US8206636B2 (en) 2008-06-20 2012-06-26 Amaranth Medical Pte. Stent fabrication via tubular casting processes
US10898620B2 (en) 2008-06-20 2021-01-26 Razmodics Llc Composite stent having multi-axial flexibility and method of manufacture thereof
US8562669B2 (en) * 2008-06-26 2013-10-22 Abbott Cardiovascular Systems Inc. Methods of application of coatings composed of hydrophobic, high glass transition polymers with tunable drug release rates
EP2313122B1 (en) 2008-07-17 2019-03-06 Micell Technologies, Inc. Drug delivery medical device
CA2732355A1 (en) 2008-08-01 2010-02-04 Intersect Ent, Inc. Methods and devices for crimping self-expanding devices
US8642063B2 (en) 2008-08-22 2014-02-04 Cook Medical Technologies Llc Implantable medical device coatings with biodegradable elastomer and releasable taxane agent
US20100055145A1 (en) * 2008-08-29 2010-03-04 Biosensors International Group Stent coatings for reducing late stent thrombosis
EP4147681A1 (en) 2008-09-25 2023-03-15 Advanced Bifurcation Systems Inc. Partially crimped stent
US12076258B2 (en) 2008-09-25 2024-09-03 Advanced Bifurcation Systems Inc. Selective stent crimping
US8821562B2 (en) 2008-09-25 2014-09-02 Advanced Bifurcation Systems, Inc. Partially crimped stent
US8828071B2 (en) 2008-09-25 2014-09-09 Advanced Bifurcation Systems, Inc. Methods and systems for ostial stenting of a bifurcation
US8808347B2 (en) 2008-09-25 2014-08-19 Advanced Bifurcation Systems, Inc. Stent alignment during treatment of a bifurcation
US11298252B2 (en) 2008-09-25 2022-04-12 Advanced Bifurcation Systems Inc. Stent alignment during treatment of a bifurcation
GB0819296D0 (en) * 2008-10-21 2008-11-26 Smith & Nephew Coating II
US20100119578A1 (en) * 2008-11-07 2010-05-13 Specialized Vascular Technologies, Inc. Extracellular matrix modulating coatings for medical devices
US8231980B2 (en) 2008-12-03 2012-07-31 Boston Scientific Scimed, Inc. Medical implants including iridium oxide
US8834913B2 (en) 2008-12-26 2014-09-16 Battelle Memorial Institute Medical implants and methods of making medical implants
MX2011008499A (es) 2009-02-13 2011-09-06 Vertex Pharma Formas solidas de 2-(2,4-difluorofenil)-6-(1-(2,6-difluorofenil)ur eido)nicotinamida.
US8071156B2 (en) 2009-03-04 2011-12-06 Boston Scientific Scimed, Inc. Endoprostheses
CA2756386C (en) * 2009-03-23 2019-01-15 Micell Technologies, Inc. Drug delivery medical device
CA2757276C (en) 2009-04-01 2017-06-06 Micell Technologies, Inc. Coated stents
CN102449094B (zh) * 2009-04-03 2014-10-22 亚什兰许可和知识产权有限公司 紫外辐射可固化压敏丙烯酸类粘合剂
EP2419058B1 (en) 2009-04-17 2018-02-28 Micell Technologies, Inc. Stents having controlled elution
US8287937B2 (en) 2009-04-24 2012-10-16 Boston Scientific Scimed, Inc. Endoprosthese
EP2429624B1 (en) 2009-05-15 2014-04-02 Intersect ENT, Inc. A combination of an expandable device and a delivery device.
WO2010135433A1 (en) * 2009-05-20 2010-11-25 Arsenal Medical, Inc. Medical implant
US9265633B2 (en) 2009-05-20 2016-02-23 480 Biomedical, Inc. Drug-eluting medical implants
EP2453834A4 (en) 2009-07-16 2014-04-16 Micell Technologies Inc MEDICAL DEVICE DISPENSING MEDICINE
CA2767994C (en) * 2009-09-30 2017-07-04 Terumo Kabushiki Kaisha Stent
US8628790B2 (en) 2009-10-09 2014-01-14 Pls Technologies, Llc Coating system and method for drug elution management
EP2338534A2 (de) * 2009-12-21 2011-06-29 Biotronik VI Patent AG Medizinisches Implantat, Beschichtungsverfahren sowie Implantationsverfahren
EP2531140B1 (en) 2010-02-02 2017-11-01 Micell Technologies, Inc. Stent and stent delivery system with improved deliverability
WO2011119536A1 (en) 2010-03-22 2011-09-29 Abbott Cardiovascular Systems Inc. Stent delivery system having a fibrous matrix covering with improved stent retention
CA2794080A1 (en) 2010-03-24 2011-09-29 Advanced Bifurcation Systems, Inc. System and methods for treating a bifurcation
AU2011232360B2 (en) 2010-03-24 2015-10-08 Advanced Bifurcation Systems Inc. Methods and systems for treating a bifurcation with provisional side branch stenting
US8795762B2 (en) 2010-03-26 2014-08-05 Battelle Memorial Institute System and method for enhanced electrostatic deposition and surface coatings
US8685433B2 (en) 2010-03-31 2014-04-01 Abbott Cardiovascular Systems Inc. Absorbable coating for implantable device
US8834560B2 (en) 2010-04-06 2014-09-16 Boston Scientific Scimed, Inc. Endoprosthesis
US10232092B2 (en) 2010-04-22 2019-03-19 Micell Technologies, Inc. Stents and other devices having extracellular matrix coating
DE102010018541A1 (de) * 2010-04-28 2011-11-03 Acandis Gmbh & Co. Kg Verfahren zur Herstellung einer medizinischen Vorrichtung
US20130032967A1 (en) * 2010-05-07 2013-02-07 Abbott Cardiovascular Systems Inc. Cold ethylene oxide sterilization of a biodegradable polymeric stent
CA2805631C (en) 2010-07-16 2018-07-31 Micell Technologies, Inc. Drug delivery medical device
CN102464669B (zh) * 2010-11-17 2014-04-16 浙江海正药业股份有限公司 无定形依维莫司及其制备方法
WO2012066502A1 (en) * 2010-11-19 2012-05-24 Biocon Limited Processes for preparation of everolimus and intermediates thereof
EP2663557B1 (en) 2011-01-14 2015-05-27 Vertex Pharmaceuticals Incorporated Pyrimidine gyrase and topoisomerase iv inhibitors
MX341342B (es) 2011-01-14 2016-08-17 Vertex Pharma Formas solidas del inhibidor de girasa (r)-1-etil-3-[6-fluoro-5-[2 -(1-hidroxi-1-metil-etil) pirimidin-5-il]-7-(tetrahidrofuran-2-il) -1h-benzimidazol-2-il]urea.
ES2635591T3 (es) 2011-02-04 2017-10-04 Synthon Bv Procedimiento de fabricación de everolimus
CA2826760A1 (en) 2011-02-08 2012-08-16 Advanced Bifurcation Systems, Inc. Multi-stent and multi-balloon apparatus for treating bifurcations and methods of use
CA2826769A1 (en) 2011-02-08 2012-08-16 Advanced Bifurcation Systems, Inc. System and methods for treating a bifurcation with a fully crimped stent
US9187953B2 (en) 2011-03-23 2015-11-17 Rytec Corporation Side column configuration for overhead roll-up door assemblies
US20120323311A1 (en) * 2011-04-13 2012-12-20 Micell Technologies, Inc. Stents having controlled elution
WO2012166819A1 (en) 2011-05-31 2012-12-06 Micell Technologies, Inc. System and process for formation of a time-released, drug-eluting transferable coating
JP5977344B2 (ja) 2011-06-20 2016-08-24 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ ジャイレースおよびトポイソメラーゼ阻害剤のリン酸エステル
CN102389585B (zh) * 2011-07-07 2014-04-23 中山大学 一种在生物医用材料表面负载活性分子的方法
WO2013012689A1 (en) 2011-07-15 2013-01-24 Micell Technologies, Inc. Drug delivery medical device
AU2012285816B2 (en) 2011-07-20 2015-07-23 Brigham Young University Hydrophobic ceragenin compounds and devices incorporating same
US8945217B2 (en) * 2011-08-25 2015-02-03 Brigham Young University Medical devices incorporating ceragenin-containing composites
US9155746B2 (en) 2011-09-13 2015-10-13 Brigham Young University Compositions and methods for treating bone diseases and broken bones
US9694019B2 (en) 2011-09-13 2017-07-04 Brigham Young University Compositions and methods for treating bone diseases and broken bones
US9603859B2 (en) 2011-09-13 2017-03-28 Brigham Young University Methods and products for increasing the rate of healing of tissue wounds
AU2012308526B2 (en) 2011-09-13 2016-04-21 Brigham Young University Compositions for treating bone diseases and broken bones
US10188772B2 (en) 2011-10-18 2019-01-29 Micell Technologies, Inc. Drug delivery medical device
EP2793832B1 (en) 2011-12-21 2018-05-23 Brigham Young University Oral care compositions
US9220759B2 (en) 2012-02-23 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a drug eluting stent and adjunctive therapy
US9533063B1 (en) 2012-03-01 2017-01-03 Brigham Young University Aerosols incorporating ceragenin compounds and methods of use thereof
US9220584B2 (en) 2012-03-30 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a stent and locally administered adjunctive therapy
US10039285B2 (en) 2012-05-02 2018-08-07 Brigham Young University Ceragenin particulate materials and methods for making same
CN102786534A (zh) * 2012-05-25 2012-11-21 上海现代制药股份有限公司 一种依维莫司的制备方法
PL2859001T3 (pl) * 2012-06-08 2016-08-31 Biotronik Ag 40-o-podstawiona pochodna estrowa rapamycyny i węglowodoru cyklicznego, kompozycje i metody
WO2014010759A1 (ko) * 2012-07-10 2014-01-16 주식회사 엠아이텍 인체에 삽입되는 루멘을 가진 원통형의 구조물
WO2014015105A1 (en) 2012-07-18 2014-01-23 Vertex Pharmaceuticals Incorporated Solid forms of (r)-2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1h-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl dihydrogen phosphate and salts thereof
US10285833B2 (en) * 2012-08-10 2019-05-14 Lombard Medical Limited Stent delivery systems and associated methods
CN102784418B (zh) * 2012-08-10 2014-04-16 中国医学科学院生物医学工程研究所 可程序性释放的生物药物纳米微孔血管支架及其制备方法与用途
EP2895211B1 (en) * 2012-09-12 2017-10-18 Boston Scientific Scimed, Inc. Adhesive stent coating for anti-migration
BR112015008804A2 (pt) 2012-10-17 2017-07-04 Univ Brigham Young tratamento e prevenção de mastite
EP2737894A1 (en) 2012-12-03 2014-06-04 Debiotech S.A. Smart coating for implantable devices
WO2014107740A2 (en) 2013-01-07 2014-07-10 Brigham Young University Methods for reducing cellular proliferation and treating certain diseases
CN110269959A (zh) 2013-03-12 2019-09-24 脉胜医疗技术公司 可生物吸收的生物医学植入物
AU2014236729B2 (en) 2013-03-14 2018-11-22 Intersect Ent, Inc. Systems, devices, and method for treating a sinus condition
US10568893B2 (en) 2013-03-15 2020-02-25 Brigham Young University Methods for treating inflammation, autoimmune disorders and pain
CN110420211A (zh) 2013-03-15 2019-11-08 布莱阿姆青年大学 治疗炎症、自身免疫性疾病和疼痛的方法
US11524015B2 (en) 2013-03-15 2022-12-13 Brigham Young University Methods for treating inflammation, autoimmune disorders and pain
US9387215B2 (en) 2013-04-22 2016-07-12 Brigham Young University Animal feed including cationic cholesterol additive and related methods
JP2016519965A (ja) 2013-05-15 2016-07-11 マイセル・テクノロジーズ，インコーポレイテッド 生体吸収性バイオメディカルインプラント
WO2015020527A1 (en) 2013-08-09 2015-02-12 Maastricht University Biodegradable radiopaque stents and other implants
SI3057953T1 (sl) 2013-10-17 2018-12-31 Vertex Pharmaceuticals Incorporated Ko-kristali(s)-n-metil-8-(1-((2'-metil-(4,5'-bipimiridin)-6-il)amino) propan-2-il)kinolin-4-karboksamida in njegovi devterirani derivati kot inhibitorji dna-pk
US11690855B2 (en) 2013-10-17 2023-07-04 Brigham Young University Methods for treating lung infections and inflammation
US9459193B2 (en) * 2013-12-18 2016-10-04 Abbott Cardiovascular Systems Inc. Stent holder having a reduced profile
US20150203527A1 (en) 2014-01-23 2015-07-23 Brigham Young University Cationic steroidal antimicrobials
CA2844321C (en) 2014-02-27 2021-03-16 Brigham Young University Cationic steroidal antimicrobial compounds
US10220045B2 (en) 2014-03-13 2019-03-05 Brigham Young University Compositions and methods for forming stabilized compositions with reduced CSA agglomeration
US9867836B2 (en) 2014-03-13 2018-01-16 Brigham Young University Lavage and/or infusion using CSA compounds for increasing fertility in a mammal
US9931350B2 (en) 2014-03-14 2018-04-03 Brigham Young University Anti-infective and osteogenic compositions and methods of use
WO2015160998A2 (en) 2014-04-17 2015-10-22 Abbott Cardiovascular Systems Inc. Coatings for braided medical devices and methods of forming same
WO2015163336A1 (ja) 2014-04-21 2015-10-29 株式会社 東芝 無線通信用集積回路
EP3136804B1 (en) 2014-04-21 2021-09-01 Kabushiki Kaisha Toshiba Base stations and wireless communication methods
US9686966B2 (en) 2014-04-30 2017-06-27 Brigham Young University Methods and apparatus for cleaning or disinfecting a water delivery system
US10441595B2 (en) 2014-06-26 2019-10-15 Brigham Young University Methods for treating fungal infections
US10238665B2 (en) 2014-06-26 2019-03-26 Brigham Young University Methods for treating fungal infections
EP3166950A1 (en) 2014-08-04 2017-05-17 Cipla Limited Process for the synthesis of everolimus and intermediates thereof
DE102014111117B4 (de) * 2014-08-05 2017-11-16 Acandis Gmbh & Co. Kg Medizinische Vorrichtung zur Behandlung von neurovaskulären Erkrankungen, System und Set mit einer derartigen Vorrichtung sowie Herstellungsverfahren
US10227376B2 (en) 2014-08-22 2019-03-12 Brigham Young University Radiolabeled cationic steroid antimicrobials and diagnostic methods
US10155788B2 (en) 2014-10-07 2018-12-18 Brigham Young University Cationic steroidal antimicrobial prodrug compositions and uses thereof
WO2016114216A1 (ja) * 2015-01-13 2016-07-21 テルモ株式会社 生分解性ステント
CN104592254B (zh) * 2015-02-08 2016-07-13 福建省微生物研究所 依维莫司的合成方法
WO2016172543A1 (en) 2015-04-22 2016-10-27 Savage Paul B Methods for the synthesis of ceragenins
WO2016172553A1 (en) 2015-04-22 2016-10-27 Savage Paul B Methods for the synthesis of ceragenins
US9434759B1 (en) 2015-05-18 2016-09-06 Brigham Young University Cationic steroidal antimicrobial compounds and methods of manufacturing such compounds
EP3352690B1 (en) * 2015-09-25 2023-09-13 Spirox, Inc. Nasal implants
CN105566348A (zh) * 2015-12-31 2016-05-11 哈药集团技术中心 一种依维莫司的制备方法
US10226550B2 (en) 2016-03-11 2019-03-12 Brigham Young University Cationic steroidal antimicrobial compositions for the treatment of dermal tissue
US20180161185A1 (en) * 2016-12-14 2018-06-14 eLum Technologies, Inc. Electrospun stents, flow diverters, and occlusion devices and methods of making the same
EP3558407B1 (en) * 2016-12-22 2023-03-15 Biotronik AG Drug releasing coatings for medical devices and methods of making same
JP2020501842A (ja) 2016-12-22 2020-01-23 ハート・リペアー・テクノロジーズ・インコーポレーテッド インプラントを心臓弁輪に固定する経皮的送達システム
US10959433B2 (en) 2017-03-21 2021-03-30 Brigham Young University Use of cationic steroidal antimicrobials for sporicidal activity
WO2019143717A1 (en) * 2018-01-16 2019-07-25 Sintra Medical Llc Stents with increased flexibility
CN108720971A (zh) * 2018-01-28 2018-11-02 杭州市第人民医院 一种可控抗菌气管支架
US11224512B2 (en) * 2018-03-21 2022-01-18 Edwards Lifesciences Corporation Coronary artery check valve
EP3700475B1 (en) 2018-03-29 2021-08-04 Sahajanand Medical Technologies Private Limited Stent
RU2686747C1 (ru) * 2018-11-08 2019-04-30 Федеральное государственное бюджетное учреждение науки Институт металлургии и материаловедения им. А.А. Байкова Российской академии наук (ИМЕТ РАН) Способ получения биодеградируемого полимерного покрытия на основе полилактида на проволоке TiNbTaZr
US11541152B2 (en) 2018-11-14 2023-01-03 Lutonix, Inc. Medical device with drug-eluting coating on modified device surface
CN114105836B (zh) * 2020-08-27 2024-03-15 鲁南制药集团股份有限公司 一种乙二醇的衍生化合物
CN115300195A (zh) * 2022-07-29 2022-11-08 宁波拜锐生物科技有限公司 血管支架
WO2024068153A1 (en) * 2022-09-30 2024-04-04 Biotronik Ag Macrocyclic triene immunosuppressive compounds for perivascular medical treatment of vascular access fistulas, grafts and other vascular conditions
CN116869715B (zh) * 2023-07-10 2024-02-09 上海心玮医疗科技股份有限公司 一种抗凝药物洗脱支架

Family Cites Families (109)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US517698A (en) 1894-04-03 Druggist s weighing-scale
ZA737247B (en) 1972-09-29 1975-04-30 Ayerst Mckenna & Harrison Rapamycin and process of preparation
US4885171A (en) 1978-11-03 1989-12-05 American Home Products Corporation Use of rapamycin in treatment of certain tumors
US4316885A (en) 1980-08-25 1982-02-23 Ayerst, Mckenna And Harrison, Inc. Acyl derivatives of rapamycin
US4650803A (en) 1985-12-06 1987-03-17 University Of Kansas Prodrugs of rapamycin
US5527337A (en) 1987-06-25 1996-06-18 Duke University Bioabsorbable stent and method of making the same
US5059211A (en) 1987-06-25 1991-10-22 Duke University Absorbable vascular stent
US5176908A (en) 1988-12-19 1993-01-05 American Cyanamid Company Method for the treatment of endotoxic shock in mammal
US4990155A (en) 1989-05-19 1991-02-05 Wilkoff Howard M Surgical stent method and apparatus
US5100899A (en) 1989-06-06 1992-03-31 Roy Calne Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof
JPH05502179A (ja) 1990-02-28 1993-04-22 メドトロニック　インコーポレーテッド 管状器官内薬剤溶出装具
US5545208A (en) * 1990-02-28 1996-08-13 Medtronic, Inc. Intralumenal drug eluting prosthesis
WO1991017724A1 (en) * 1990-05-17 1991-11-28 Harbor Medical Devices, Inc. Medical device polymer
US5258020A (en) * 1990-09-14 1993-11-02 Michael Froix Method of using expandable polymeric stent with memory
WO1992015342A1 (en) * 1991-03-08 1992-09-17 Keiji Igaki Stent for vessel, structure of holding said stent, and device for mounting said stent
US5120842A (en) 1991-04-01 1992-06-09 American Home Products Corporation Silyl ethers of rapamycin
US6515009B1 (en) 1991-09-27 2003-02-04 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
US5151413A (en) 1991-11-06 1992-09-29 American Home Products Corporation Rapamycin acetals as immunosuppressant and antifungal agents
CA2086642C (en) 1992-01-09 2004-06-15 Randall E. Morris Method of treating hyperproliferative vascular disease
US5516781A (en) * 1992-01-09 1996-05-14 American Home Products Corporation Method of treating restenosis with rapamycin
US6013853A (en) 1992-02-14 2000-01-11 The University Of Texas System Continuous release polymeric implant carrier
US5288711A (en) 1992-04-28 1994-02-22 American Home Products Corporation Method of treating hyperproliferative vascular disease
US5540712A (en) 1992-05-01 1996-07-30 Nitinol Medical Technologies, Inc. Stent and method and apparatus for forming and delivering the same
GB9221220D0 (en) 1992-10-09 1992-11-25 Sandoz Ag Organic componds
US5258389A (en) 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
US5342348A (en) 1992-12-04 1994-08-30 Kaplan Aaron V Method and device for treating and enlarging body lumens
US5443458A (en) * 1992-12-22 1995-08-22 Advanced Cardiovascular Systems, Inc. Multilayered biodegradable stent and method of manufacture
US6663881B2 (en) * 1993-01-28 2003-12-16 Neorx Corporation Therapeutic inhibitor of vascular smooth muscle cells
DE4303181A1 (de) 1993-02-04 1994-08-11 Angiomed Ag Implantierbarer Katheter
US5252579A (en) * 1993-02-16 1993-10-12 American Home Products Corporation Macrocyclic immunomodulators
US5824048A (en) 1993-04-26 1998-10-20 Medtronic, Inc. Method for delivering a therapeutic substance to a body lumen
US5464650A (en) * 1993-04-26 1995-11-07 Medtronic, Inc. Intravascular stent and method
PL314238A1 (en) * 1993-12-17 1996-09-02 Sandoz Ltd Rapamycin derivatives
US5362718A (en) 1994-04-18 1994-11-08 American Home Products Corporation Rapamycin hydroxyesters
US5649977A (en) * 1994-09-22 1997-07-22 Advanced Cardiovascular Systems, Inc. Metal reinforced polymer stent
EP1477132A3 (en) 1994-10-17 2009-09-09 Kabushikikaisha Igaki Iryo Sekkei Drug-releasing stent
US5707385A (en) 1994-11-16 1998-01-13 Advanced Cardiovascular Systems, Inc. Drug loaded elastic membrane and method for delivery
US5565772A (en) 1994-11-30 1996-10-15 Eastman Kodak Company High sensitivity magnetic viewer using anhysteretic transfer for viewing weak magnetic patterns
US5869127A (en) * 1995-02-22 1999-02-09 Boston Scientific Corporation Method of providing a substrate with a bio-active/biocompatible coating
US6179817B1 (en) * 1995-02-22 2001-01-30 Boston Scientific Corporation Hybrid coating for medical devices
US6231600B1 (en) 1995-02-22 2001-05-15 Scimed Life Systems, Inc. Stents with hybrid coating for medical devices
US6120536A (en) * 1995-04-19 2000-09-19 Schneider (Usa) Inc. Medical devices with long term non-thrombogenic coatings
US5837313A (en) * 1995-04-19 1998-11-17 Schneider (Usa) Inc Drug release stent coating process
US6099562A (en) 1996-06-13 2000-08-08 Schneider (Usa) Inc. Drug coating with topcoat
US5609629A (en) * 1995-06-07 1997-03-11 Med Institute, Inc. Coated implantable medical device
CA2178541C (en) 1995-06-07 2009-11-24 Neal E. Fearnot Implantable medical device
BE1009856A5 (fr) * 1995-07-14 1997-10-07 Sandoz Sa Composition pharmaceutique sous la forme d'une dispersion solide comprenant un macrolide et un vehicule.
GB9606452D0 (en) 1996-03-27 1996-06-05 Sandoz Ltd Organic compounds
WO1997037617A1 (en) * 1996-04-08 1997-10-16 Swaminathan Jayaraman Multiple interconnected stents and method of coating stents
EP1208847B8 (en) * 1996-07-30 2007-02-14 Novartis AG Pharmaceutical compositions for the treatment of transplant rejection, as well as autoimmune or inflammatory conditions
US6174329B1 (en) * 1996-08-22 2001-01-16 Advanced Cardiovascular Systems, Inc. Protective coating for a stent with intermediate radiopaque coating
US5980972A (en) 1996-12-20 1999-11-09 Schneider (Usa) Inc Method of applying drug-release coatings
EP0968013B1 (en) 1997-02-20 2005-10-19 Cook Incorporated Coated implantable medical device
US6273913B1 (en) 1997-04-18 2001-08-14 Cordis Corporation Modified stent useful for delivery of drugs along stent strut
US5879697A (en) * 1997-04-30 1999-03-09 Schneider Usa Inc Drug-releasing coatings for medical devices
US6670398B2 (en) * 1997-05-14 2003-12-30 Atherogenics, Inc. Compounds and methods for treating transplant rejection
AU7972498A (en) * 1997-06-18 1999-01-04 Boston Scientific Corporation Polycarbonate-polyurethane dispersions for thrombo-resistant coatings
US6174330B1 (en) * 1997-08-01 2001-01-16 Schneider (Usa) Inc Bioabsorbable marker having radiopaque constituents
EP1003444A4 (en) * 1997-08-08 2004-07-28 Sunscope International Inc MICROPOROUS STENT AND IMPLANTATION DEVICE
US6159488A (en) 1997-08-14 2000-12-12 Agricultural Research Org. Ministry Of Agriculture (Gov.) Intracoronary stents containing quinazolinone derivatives
US6042606A (en) 1997-09-29 2000-03-28 Cook Incorporated Radially expandable non-axially contracting surgical stent
US6190406B1 (en) 1998-01-09 2001-02-20 Nitinal Development Corporation Intravascular stent having tapered struts
US6129755A (en) 1998-01-09 2000-10-10 Nitinol Development Corporation Intravascular stent having an improved strut configuration
US7208011B2 (en) * 2001-08-20 2007-04-24 Conor Medsystems, Inc. Implantable medical device with drug filled holes
US20010029351A1 (en) 1998-04-16 2001-10-11 Robert Falotico Drug combinations and delivery devices for the prevention and treatment of vascular disease
EP1555036B1 (en) * 1998-04-27 2010-05-05 Surmodics Inc. Bioactive agent release coating
US6153252A (en) * 1998-06-30 2000-11-28 Ethicon, Inc. Process for coating stents
US20020038146A1 (en) * 1998-07-29 2002-03-28 Ulf Harry Expandable stent with relief cuts for carrying medicines and other materials
JP4898991B2 (ja) 1998-08-20 2012-03-21 クック メディカル テクノロジーズ エルエルシー 被覆付植込式医療装置
US6335029B1 (en) 1998-08-28 2002-01-01 Scimed Life Systems, Inc. Polymeric coatings for controlled delivery of active agents
WO2000015763A1 (de) 1998-09-14 2000-03-23 Vesifact Ag Verwendung von nanocells in kulturmedien-endprodukten
WO2000045763A1 (en) 1999-02-02 2000-08-10 The Procter & Gamble Company Elastic laminate including spunbonded nonwoven of polypropylene/polyethylene copolymer and disposable article using the same
US6368658B1 (en) * 1999-04-19 2002-04-09 Scimed Life Systems, Inc. Coating medical devices using air suspension
US6607598B2 (en) * 1999-04-19 2003-08-19 Scimed Life Systems, Inc. Device for protecting medical devices during a coating process
ATE264863T1 (de) * 1999-08-24 2004-05-15 Ariad Gene Therapeutics Inc 28-epirapaloge
US6790228B2 (en) * 1999-12-23 2004-09-14 Advanced Cardiovascular Systems, Inc. Coating for implantable devices 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
US6277983B1 (en) * 2000-09-27 2001-08-21 American Home Products Corporation Regioselective synthesis of rapamycin derivatives
IL133312A (en) 1999-12-05 2006-09-05 Orbotech Ltd Method for testing a printed circuit
WO2001045644A2 (en) * 1999-12-23 2001-06-28 Combe International Ltd. Dental adhesive device and method for producing same
AU3095601A (en) * 2000-01-14 2001-07-24 Univ Pennsylvania O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders
US7220276B1 (en) * 2000-03-06 2007-05-22 Surmodics, Inc. Endovascular graft coatings
MXPA02011427A (es) * 2000-05-16 2004-09-10 Johnson & Johnson Procedimiento para revestir dispositivos medicos utilizando dioxido de carbono supercritico.
US6569191B1 (en) * 2000-07-27 2003-05-27 Bionx Implants, Inc. Self-expanding stent with enhanced radial expansion and shape memory
DE10046448A1 (de) * 2000-09-18 2002-03-28 Daimler Chrysler Ag Verfahren zur Bestimmung des Momentes an der Kurbelwelle einer Brennkraftmaschine
AU2001288809A1 (en) * 2000-09-26 2002-04-08 Advanced Cardiovascular Systems Inc. A method of loading a substance onto an implantable device
US20020111590A1 (en) * 2000-09-29 2002-08-15 Davila Luis A. Medical devices, drug coatings and methods for maintaining the drug coatings thereon
US6746773B2 (en) 2000-09-29 2004-06-08 Ethicon, Inc. Coatings for medical devices
US6863685B2 (en) * 2001-03-29 2005-03-08 Cordis Corporation Radiopacity intraluminal medical device
AU1129902A (en) * 2000-09-29 2002-04-08 Cordis Corp Coated medical devices
US20020051730A1 (en) * 2000-09-29 2002-05-02 Stanko Bodnar Coated medical devices and sterilization thereof
IL155107A0 (en) * 2000-10-16 2003-10-31 Conor Medsystems Inc Expandable medical device for delivery of beneficial agent
US7083642B2 (en) * 2000-12-22 2006-08-01 Avantec Vascular Corporation Delivery of therapeutic capable agents
US20020082679A1 (en) * 2000-12-22 2002-06-27 Avantec Vascular Corporation Delivery or therapeutic capable agents
US20030033007A1 (en) * 2000-12-22 2003-02-13 Avantec Vascular Corporation Methods and devices for delivery of therapeutic capable agents with variable release profile
US7077859B2 (en) * 2000-12-22 2006-07-18 Avantec Vascular Corporation Apparatus and methods for variably controlled substance delivery from implanted prostheses
US20030050692A1 (en) * 2000-12-22 2003-03-13 Avantec Vascular Corporation Delivery of therapeutic capable agents
US7247338B2 (en) * 2001-05-16 2007-07-24 Regents Of The University Of Minnesota Coating medical devices
US6641611B2 (en) * 2001-11-26 2003-11-04 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
JP4393870B2 (ja) * 2001-09-24 2010-01-06 ボストン サイエンティフィック リミテッド 薬剤被覆ステントのための最適用量
US20030077310A1 (en) * 2001-10-22 2003-04-24 Chandrashekhar Pathak Stent coatings containing HMG-CoA reductase inhibitors
US8740973B2 (en) * 2001-10-26 2014-06-03 Icon Medical Corp. Polymer biodegradable medical device
US7179283B2 (en) * 2001-11-02 2007-02-20 Scimed Life Systems, Inc. Vapor deposition process for producing a stent-graft and a stent-graft produced therefrom
US20030088307A1 (en) * 2001-11-05 2003-05-08 Shulze John E. Potent coatings for stents
US7682387B2 (en) * 2002-04-24 2010-03-23 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US6939376B2 (en) * 2001-11-05 2005-09-06 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
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
US20040024450A1 (en) * 2002-04-24 2004-02-05 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7294145B2 (en) * 2004-02-26 2007-11-13 Boston Scientific Scimed, Inc. Stent with differently coated inside and outside surfaces

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104478898A (zh) * 2014-11-18 2015-04-01 连云港恒运医药科技有限公司 依维莫司及其中间体的制备方法

Also Published As

Publication number Publication date
EP2578186B1 (en) 2014-07-23
AU2003231757B2 (en) 2009-07-09
EP1518517B1 (en) 2009-12-09
US20030125800A1 (en) 2003-07-03
EP2316377B1 (en) 2014-11-05
AU2003231759A1 (en) 2003-11-10
JP2005523332A (ja) 2005-08-04
US7727275B2 (en) 2010-06-01
WO2003090818A2 (en) 2003-11-06
EP1505930B1 (en) 2014-07-30
ES2514391T3 (es) 2014-10-28
JP2005523119A (ja) 2005-08-04
EP2578186A2 (en) 2013-04-10
WO2003090684A2 (en) 2003-11-06
US20140200654A1 (en) 2014-07-17
US6939376B2 (en) 2005-09-06
AU2009201655B2 (en) 2011-03-24
US20100312328A1 (en) 2010-12-09
JP2009011847A (ja) 2009-01-22
ES2522277T3 (es) 2014-11-14
EP2113230A3 (en) 2010-06-23
EP2417943B1 (en) 2014-08-27
CN101862233A (zh) 2010-10-20
US8308795B2 (en) 2012-11-13
ES2335406T3 (es) 2010-03-26
JP5461624B2 (ja) 2014-04-02
US20130035754A1 (en) 2013-02-07
CN1649551B (zh) 2010-08-11
EP2316377A1 (en) 2011-05-04
WO2003090684A8 (en) 2004-12-16
JP2012205920A (ja) 2012-10-25
EP2578186A3 (en) 2013-05-22
ES2523870T3 (es) 2014-12-02
US20050038505A1 (en) 2005-02-17
JP4315817B2 (ja) 2009-08-19
EP1505930A2 (en) 2005-02-16
HK1177882A1 (zh) 2013-08-30
EP2417943A1 (en) 2012-02-15
HK1156494A1 (zh) 2012-06-15
JP5827355B2 (ja) 2015-12-02
JP2014087714A (ja) 2014-05-15
JP5113667B2 (ja) 2013-01-09
EP1505930A4 (en) 2006-05-03
US8715341B2 (en) 2014-05-06
EP1518517A2 (en) 2005-03-30
AU2009201655A1 (en) 2009-05-21
JP2008279278A (ja) 2008-11-20
JP5726777B2 (ja) 2015-06-03
US20030225450A1 (en) 2003-12-04
JP2012091032A (ja) 2012-05-17
WO2003090684A3 (en) 2004-02-26
DE60330455D1 (de) 2010-01-21
EP1518517A3 (en) 2005-12-14
AU2003231757A1 (en) 2003-11-10
AU2003231759B2 (en) 2009-02-05
HK1150229A1 (en) 2011-11-11
CN101862233B (zh) 2012-09-05
EP2113230A2 (en) 2009-11-04
JP2013121509A (ja) 2013-06-20
ATE451075T1 (de) 2009-12-15
WO2003090684B1 (en) 2004-05-13
WO2003090818A3 (en) 2003-12-04
CN1649551A (zh) 2005-08-03

Similar Documents

Publication Publication Date Title
CN1735402A (zh) 含大环三烯化合物的聚合物组合物
CN1684641A (zh) 用于递送丝裂霉素通过洗脱生物相容可移植医疗器件的装置和方法
CN1964748A (zh) 用于生物活性剂的涂料组合物
TWI435724B (zh) 組合物、系統、套組及使用醫藥裝置施加雷帕黴素（ｒａｐａｍｙｃｉｎ）類似物及紫杉醇之方法
CN1520297A (zh) 包含复合药物(codrugs)的缓释药物传递系统
CN1589166A (zh) 包被有持续释放药物递送系统的支架及其使用方法
JP2008526371A (ja) ブレンドを含む生分解性コーティング組成物
US20220047773A1 (en) Self-eliminating coatings
JP2008526322A (ja) 多層を含む生分解性コーティング組成物
TW200418538A (en) Medical devices incorporating deuterated rapamycin for controlled delivery thereof
CN104203959A (zh) 雷帕霉素40-o-环状烃酯、组合物和方法
CN102091355A (zh) 一种复合涂层冠脉药物洗脱支架及其制备方法
US8017143B2 (en) Coating agent for drug releasing stent, preparation method thereof and drug releasing stent coated therewith
CN1764482A (zh) 血管支架
CN107865967B (zh) 含氨来呫诺和mTOR抑制剂的药物组合物及其应用
CN101467921B (zh) 药物洗脱支架的生产方法
CN1964750A (zh) 用于医疗用具的生物活性的涂料组合物
CN1950115A (zh) 用于生物相容性表面的方法和系统
CN1750855A (zh) 支架
CN108904888B (zh) 静电纺丝法制备载普伐他汀血管组织工程支架材料的方法
US20240301093A1 (en) Triazole containing polymers and methods of use thereof
CN1565663A (zh) 药物改性心血管支架
EP4056207A1 (en) Drug-loaded implanted medical device and preparation method therefor
CN115024870A (zh) 一种涂层修饰的载药胆管支架及其制备方法和应用
CN1829550A (zh) 生物体内留置用支架

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
ASS Succession or assignment of patent right

Owner name: BIOSENSORS INTERNAT GROUP LTD

Free format text: FORMER OWNER: SOLAR BIO-MEDICAL CO.,LTD

Effective date: 20090410

C41 Transfer of patent application or patent right or utility model
TA01 Transfer of patent application right

Effective date of registration: 20090410

Address after: Bermuda (UK) Hamilton

Applicant after: Biosensor International Group Co., Ltd.

Address before: Bermuda (UK) Hamilton

Applicant before: Sun Biomedical Ltd.

C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20060215