CN101028538B - 含有雷帕霉素类似物的医疗装置 - Google Patents
含有雷帕霉素类似物的医疗装置 Download PDFInfo
- Publication number
- CN101028538B CN101028538B CN200710093679.3A CN200710093679A CN101028538B CN 101028538 B CN101028538 B CN 101028538B CN 200710093679 A CN200710093679 A CN 200710093679A CN 101028538 B CN101028538 B CN 101028538B
- Authority
- CN
- China
- Prior art keywords
- polymer
- compound
- medicine
- support
- 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.)
- Expired - Lifetime
Links
- 0 CC=N[C@](C1[C@](*)C[C@](CC[C@](CC(CC=C([C@]([C@](C([C@](*)C[C@](*)C=CC=CC=C(*)[C@@](C[C@](CC[C@@]2*)O[C@]22O)*=C)=*)N)O)N)=O)*C([C@]3C4CCCC3)=*=C2C4=O)CC1)*=NC Chemical compound CC=N[C@](C1[C@](*)C[C@](CC[C@](CC(CC=C([C@]([C@](C([C@](*)C[C@](*)C=CC=CC=C(*)[C@@](C[C@](CC[C@@]2*)O[C@]22O)*=C)=*)N)O)N)=O)*C([C@]3C4CCCC3)=*=C2C4=O)CC1)*=NC 0.000 description 1
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
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- 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
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
-
- 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
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
-
- 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
- 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
- A61L31/148—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- 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
- A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/426—Immunomodulating agents, i.e. cytokines, interleukins, interferons
-
- 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
- A61L2300/604—Biodegradation
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Surgery (AREA)
- Transplantation (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
- Prostheses (AREA)
Abstract
包含一个表面有涂层的支撑结构的医疗装置，该涂层含有治疗物质，例如一种药物。适合用于本发明的医疗装置的支撑结构包括，但不限于，冠状动脉支架，外周支架，导管，动-静脉移植物，支路移植物，和用于脉管系统的药物递送球囊。适用于本发明的药物包括，但不限于化学式。
Description
本申请是中国专利申请号为02822319.5(PCT/US2002/028798)于(国际)申请日2002年9月10日提交的发明专利申请的分案申请。原申请的发明名称为“含有雷帕霉素类似物的医疗装置”。
下面申请是1999年11月2日递交的美国申请系列号No.09/433,001的连续部分，而美国申请系列号No.09/433,001本身是1998年9月24日递交的美国申请系列号No.09/159,945，现在为美国专利No.6,015,815的连续部分，引入本文作为参考。
技术领域
本发明涉及具有免疫调节活性的新化合物和用于制备新化合物的合成中间体，特别是大环内酯免疫调节剂。更具体地说，本发明涉及雷帕霉素的半合成类似物，及其制备用工具，含有这样的化合物的药物组合物，和使用所述的物质进行治疗的方法。
背景技术
自从引入到器官移植和免疫调节领域，已经发现环孢菌素类化合物(环孢菌素A)有广泛的用途，并且已经导致移植操作的成功率显著增加。近来，已经发现几个种类的大环的化合物具有有效的免疫调节活性。Okuhara等人在1986年6月11日出版的欧洲专利申请No.184,162中公开许多从链霉菌属分离的大环的化合物，包括免疫抑制FK-506，一种23-员环的大环内酯，它是从S.tsukubaensis菌株分离的。
从吸水链霉菌yakushimnaensis中已经分离了其他的相关的天然产品，例如FR-900520和FR-900523，它们在C-21的烷基取代基不同于FK-506。由S.tsukubaensis产生的另一种类似物FR-900525不同于FK-506，以脯氨酸基团替代apipecolic acid成分。与cyclosporine和FK-506关联的不令人满意的副作用已经导致对具有改善的功效和安全的免疫抑制的化合物包括局部有效的，但是全身无效的免疫抑制剂的连续的研究(美国专利No.5,457,111)。
雷帕霉素是吸水链霉菌产生的大环的三烯抗生素，发现它在体外和 体内具有抗真菌的活性，特别是抗白色念珠菌(C.Vezina等人，J.Antibiot.1975，28，721；S.N.Sehgal等人J.Antibiot.1975，28，727；H.A.Baker等人，J.Antibiot.1978，31，539；美国专利No.3,929,992；和美国专利No.3,993,749)。
雷帕霉素
已经证明单独的雷帕霉素(美国专利No.4,885,171)或与picibanil联合(美国专利No.4,401,653)具有抗肿瘤活性。在1977年，雷帕霉素还显示在变应性的脑脊髓炎实验模型，一种多样的硬化症模型中，在辅助的关节炎模型，一种类风湿关节炎中，有效地作为免疫抑制剂；并且证明可有效地抑制IgE-类似的抗体的形成(R.Martel等人，Can.J.Physio.Pharmacol.，1977，55，48)。
在FASEB，1989，3，3411也已经公开了雷帕霉素的免疫抑制作用，如在组织不相容的啮齿动物中，能够延长器官移植的存活时间(R.Morris，Med.Sci.Res.，1989，17，877)。由M.Strauch公开了雷帕霉素抑制T-细胞活化的能力(FASEB，1989，3，3411)。在TransplantationReviews，1992，6，39-87中评论了雷帕霉素的这些和其他生物学作用。
已经证明雷帕霉素在动物模型中减少内膜(neointimal)增殖，在人体中减少再狭窄(restenosis)的速度。已经公开的证据显示雷帕霉素也显示抗炎性的作用，支持其选择为治疗类风湿关节炎的药剂的特性。因为细胞增殖和炎症被认为是气囊血管成形术和支架放置之后形成再狭窄损害的成因因素，雷帕霉素和其类似物已经被推荐为用于预防再狭窄。
已经证明雷帕霉素的一酯和二酯衍生物(在31和42位酯化)可用作为抗真菌剂(美国专利No.4,316,885)和作为水溶性的雷帕霉素前药(美国专利No.4,650,803)。
雷帕霉素和30-二甲氧基雷帕霉素的发酵和纯化已经在文献中描述(C.Vezina等人J.Antibiot.(Tokyo)，1975，28(10)，721；S.N.Sehgal等人，J.Antibiot.(Tokyo)，1975，28(10)，727；1983，36(4)，351；N.L.Pavia等人，J.Natural Products，1991，54(1)，167-177)。
已经尝试了许多化学修饰的雷帕霉素。这些包括雷帕霉素的一酯和二酯衍生物(WO 92/05179)，雷帕霉素的27-肟(EPO 467606)；雷帕霉素的42-氧代类似物(美国专利No.5,023,262)；二环雷帕霉素(美国专利No.5,120,725)；雷帕霉素二聚体(美国专利No.5,120,727)；雷帕霉素甲硅烷基醚(美国专利No.5,120,842)；和芳香基磺酸盐和氨基磺酸盐(美国专利No.5,177,203)的制备。近来已经合成了其天然存在的enantiomeric形式的雷帕霉素(K.C.Nicolaou等人，J.Am.Chem.Soc.，1993，115，4419-4420；S.L.Schreiber，J.Am.Chem.Soc.，1993，115，7906-7907；S.J.Danishefsky，J.Am.Chem.Soc.，1993，115，9345-9346)。
已知雷帕霉素，如FK-506与FKBP-12结合(Siekierka，J.J.；Hung，S.H.Y.；Poe，M.；Lin，C.S.；Si gal，N.H.Nature，1989，341，755-757；Harding，M.W.；Galat，A.；Uehling，D.E.；Schreiber，S.L.Nature1989，341，758-760；Dumont，F.J.；Melino，M.R.；Staruch，M.J.；Koprak，S.L.；Fi scher，P.A.；Si gal，N.H.J.Immunol.1990，144，1418-1424；Bierer，B.E.；Schreiber，S.L.；Burakoff，S.J.Eur.J.Immunol.1991，21，439-445；Fretz，H.；Albers，M.W.；Galat，A.；Standaert，R.F.；Lane，W.S.；Burakoff，S.J.；Bierer，B.E.；Schre iber，S.L.J.Am.Chem.Soc.1991，113，1409-1411)。近来已近发现雷帕霉素/FKBP-12复合物还结合到另一个蛋白质，该蛋白质与calcineurin不同，FK-506/FKBP-12复合物抑制该蛋白质(Brown，E.J.；Albers，M.W.；Shin，T.B.；Ichikawa，K.；Keith，C.T.；Lane，W.S.；Schreiber，S.L.Nature 1994，369，756-758；Sabatini，D.M.；Erdjument-Bromage，H.；Lui，M.；Tempest，P.；Snyder，S.H.Cell，1994，78，35-43)。
1970年代Andreas Gruntzig研制了经皮transluminal冠状的血管形成术(PTCA)。1975年9月24日进行了第一个犬齿冠状的扩张术；此后一年的美国心脏病协会的年会上提供了有关PTCA的应用的研究。此后不久，在瑞士的苏黎世研究了第一个患者，随后在旧金山和纽约研究了第一个美国人患者。就治疗引起闭塞的冠状动脉疾病的患者而言，该方案改变了干涉心脏病学的惯例，该方案没有提供长久的解决办法。患者仅仅得到了与血管闭合相关的胸部疼痛的临时减轻；通常需要重复该操作。确定了再狭窄(restenosis)损害的存在严重限制了新的操作的有用性。在1980年代后期，将支架导入用于维持脉管在血管成形术之后开放。今天在90％的血管形成术中使用支架技术。在支架导入之前，用气囊血管形成术的30％到50％的比率范围的患者发生再狭窄。在所选择的患者组中支架内再狭窄(in-stent restenosis)扩张术之后再现率可以是高至70％，而新形成的支架中脉搏描记术的再狭窄比率可以是20％。支架的放置将再狭窄比率减少到15％至20％。该百分数几乎代表了用纯粹的机械支架获得的最好的结果。再狭窄损害主要由内膜(neointimal)增生引起，其时间过程和组织病理表象明显地不同于动脉粥样硬化疾病。再狭窄是损坏了的冠状的动脉的壁的愈合过程，即内膜组织对管腔壁有相当程度的增生(impinging)。血管近程放射治疗似乎更能有效抵抗支架内再狭窄损害。可是放射受到实用性和费用的限制，并且其安全和持久性存在问题。
因此，需要将目前的再狭窄率至少减少到50％的程度。为此，通过介入(interventional)设备共同体进行许多尝试以建造和评估药物洗脱支架(drug-eluting stents)。如果成功，这样的装置有许多优点，主要地表现在不论是periprocedural技术或者是慢性的口部的药物疗法形式，这样的系统不需要辅助的治疗。
附图简述
附图1显示所给猴子的含有四唑(tetrazole)-的雷帕霉素类似物剂量的血浓度±SEM(n＝3)。
附图2是适用于本发明中的一个塞条凸起时的侧视图。
附图3A是脉管片段的横切面视图，该片段被放置了一个仅仅包被了聚合物的支架。
附图3B是脉管片段的横切面视图，该片段被放置了一个包被了聚合物和药物的支架。
发明概述
本发明的一个方面公开了由结构式代表的化合物：
或其药学可接受盐或其前药。
本发明的另一个目的是提供了从发酵获得的起始材料制备这样的化合物的合成过程，以及用于这样的合成过程的化学的中间体。
本发明的再一个目的是提供含有作为活性成分的至少上述化合物之一的药物组合物。
本发明的又一目的是提供治疗各种疾病状态的方法，包括再狭窄(restenosis)，移植后组织排斥，免疫和自身免疫的机能障碍，真菌生长和恶性肿瘤。
在另一个方面，本发明提供了一种医疗装置，包括其表面有一涂层的支撑结构，该涂层含有一种治疗物质，例如一种药物。适用于本发明的医药的装置的支撑结构包括，但不限于冠状动脉支架，外周支架，导管，动-静脉支架，旁路移植物，和用于脉管系统的药物递送球囊。适用于本发明的药物包括，但不限于
或其药物可接受盐或其前药，包括
其药学可接受的盐或前药，(或者下文中称之为A-179578)，和
或其药学可接受的盐或前药；
或其药学可接受的盐或前药，(或者下文中称之为SDZ RAD或40-O-(2-氢氧基乙基)-雷帕霉素)；
或其药学可接受的盐或其前药，(或者下文称之为A-94507)。
适用于本发明的涂层包括但不限于，包含任何聚合物材料的聚合涂层，治疗剂即药物可相当程度地溶于其中。该涂层可以是亲水的，疏水的，生物可降解的或者非生物可降解的。在脉管系统中该医疗装置减少了restenosis。预期冠状动脉直接递送药物如A-179578，将再狭窄的发生率降低到约0％到25％的水平。
本发明的详细描述
术语的定义
本文所用术语“前药″是指在体内通过血液中水解快速转化到为上述通式的母本化合物的化合物。由T.Higuchi和V.Stella在A.C.S.Symposium Series的第14期中″作为新的递送系统的前药″，和Edward B.Roche，ed.，American Pharmaceutical Association and PergamonPre ss，1987的″药物设计中生物可逆性的载体″中进行了彻底的讨论，两者引入本文作为参考。
本文的术语″药学可接受的前药″是指本发明的化合物的前药，以及如果可能，本发明化合物的两性离子的形态，在合理的医学的判断范围内它适用于与人类和低等哺乳动物的组织接触而没有过度的毒性，辐射，和变应性的应答，具有合理的效益/风险比率，可有效地用于预期的目的。特别优选的本发明的药学可接受前药是本发明化合物的C-31羟基的前药酯。
本文的术语″前药酯″是指任何的几个酯形成基团，它们在生理学的环境下被水解。前药酯基团的例子包括乙酰基，乙酰基，新戊酰，新戊酰氧甲基，乙酰氧基甲基，肽基，甲氧基甲基，2，3-二氢化茚基等等，以及来源于天然的或非天然的氨基酸与本发明化合物的恶C-31羟基基团结合衍生的酯基团。
术语“支撑结构″是指能够包含或支撑药学的可接受载体或赋形剂的构架组织，其中载体或赋形剂可以含有治疗剂，例如一种前药或另一种化合物。通常该支撑结构是金属或聚合物的材料形成的。
具体的实施方案
本发明的一个具体实施方案是具有下列通式的化合物
本发明的另一个具体实施方案是具有下列通式的化合物
本发明化合物的制备
结合下面的合成的方案可以更好地理解本发明的化合物和方法，这些方案举例说明了用于制备本发明化合物的方法。
可以采用各种各样的合成的途径制备本发明的化合物。典型的操作显示于方案1。
方案1
差向(立体)异构体混合物
如方案1所示，雷帕霉素的C-42羟基转变为三氟代甲烷磺酸盐或氟 代磺酸盐保留基团得到A。在hindered，非亲核的碱例如2，6-二甲基吡啶，或优选的是二异丙基乙基胺存在下用四唑取代保留基团，得到差向异构体B和C，采用闪烁柱层析法将它们分离和纯化。
合成方法
参照下面的实施例可以更好地理解前面的描述，这些实施例阐明了制备本发明的化合物的方法并且不限于所附的权利要求书定义的范围内。
实施例1
42-Epi-(四唑基)-雷帕霉素(较差极性的异构体)
实施例1A
在78℃，氮气氛中依次用2，6-二甲基吡啶(53uL，0.46mmol，4.3eq.)和三氟代甲烷磺酸基的酸酐(37uL，0.22mmol)处理溶于二氯甲烷(0.6mL)中的雷帕霉素(100mg，0.11mmol)溶液，之后搅拌15分钟，加温到室温，穿过一个二氧化硅凝胶(6mL)用二乙基醚洗脱。将含有triflate的馏分合并，浓缩以提供琥珀色的泡沫形式的指定化合物。
实施例1B
42-Epi-(四唑基)-雷帕霉素(较差极性的异构体)
二异丙基乙基胺(87DL，0.5mmol)和1H-四唑(35mg，0.5mmol)依次处理溶于醋酸异丙酯的实施例1A的溶液(0.3mL)，之后搅拌18小时。将该混合物在水(10mL)和醚(10mL)之间分配。用用盐水(10mL)和干(Na2SO4)洗涤有机物。浓缩的有机物是有粘性的黄色固体，是通过二氧化硅凝胶(3.5g，70-230网眼)层析法用己烷(10mL)，己烷∶醚(4∶1(10mL)，3∶1(10mL)，2∶1(10mL)，1∶1(10mL))，醚(30mL)，己烷∶丙酮(1∶1(30mL))洗脱纯化的。收集醚馏分形式的异构体之一。MS(ESI)m/e966(M)-；
实施例2
42-Epi-(四唑基)-雷帕霉素(程度较大的极性的异构体)
实施例2A
42-Epi-(四唑基)-雷帕霉素(程度较大的极性的异构体)
在实施例1B中利用己烷∶丙酮(1∶1)移动相从层析柱收集较慢的移 动谱带得到指定的化合物。
MS(ESI)m/e966(M)-。
生物学活性的体外测定
将本发明的化合物的免疫抑制活性与雷帕霉素和两个雷帕霉素类似物比较：40-表-N-[2’-羟基吡啶]-雷帕霉素和40-表-N-[4’-羟基吡啶]-雷帕霉素，两个类似物公开于美国专利No.5,527,907。利用Kino，T.等人在Transplantation Proceedings，XIX(5)：36-39，增刊6(1987)描述的人的混合的淋巴细胞反应(MLR)测定法测定活性。分析结果证明本发明的化合物在纳摩尔浓度时是有效的免疫调节剂，如表1所示。
表1
| 实施例 | 人MLR IC50±S.E.M.(nM) |
| 雷帕霉素 | 0.91±0.36 |
| 2-羟基吡啶 | 12.39±5.3 |
| 4-羟基吡啶 | 0.43±0.20 |
| 实施例1 | 1.70±0.48 |
| 实施例2 | 0.66±0.19 |
对实施例1和实施例2中的药物动力学的行为是对短尾猴(n＝3每组)以2.5mg/kg静脉内的剂量给药之后进行标定。各个化合物是以2.5mg/mL的水溶液溶于含20％乙醇∶30％丙烯乙二醇∶2％聚氧乙烯蓖麻油(Cremophor EL)∶48％葡萄糖共5％的溶液中。在猴子的隐静脉以缓慢的大丸剂形式(～1-2分钟)的1mL/kg静脉内的剂量给药。在给药之前和给药之后0.1(仅仅IV)，0.25，0.5，1，1.5，2，4，6，9，12，24，和30小时之后从每个动物的股骨的动脉或静脉获得血样本。将EDTA保存的样品彻底地混合和提取以用于后来的分析。
用溶于含有内部的标准的水(0.5ml)的20％甲醇使血样品(1.0mL)中的血细胞溶解。用乙酸乙酯和己烷(1∶1(v/v)，6.0mL)的混合物提取发生溶血的样品。在室温下用氮流将有机层蒸发至干燥。在甲醇∶水(1∶1，150uL)中重新构成样品。利用反相HPLC和UV检测从污染物中分离主题化合物(50uL注射液)。在进行期间将样品保持在冷却(4℃)状态。将每 个研究的所有的样品作为单批量进行HPLC分析。
利用Sciex MacQuanTTM软件测定实施例1，实施例2和内部的标准的曲线(AUC)量度的面积。利用有穗的血标准的峰值区域比率对理论的浓度的最少平方线性回归，从有穗的血标准的峰值区域比率(根源药物/内在的标准)获得校准曲线。对于超过标准曲线(相关性＞0.99)范围的两种化合物，该方法是线形的，估计的定量界限为0.1ng/mL。可以直接从观察到的血浓度-时间数据读出最大血浓度(CMAX)和获得最大血浓度(TMAX)的时间。利用CSTRIP将血浓度数据提交到多指数曲线装置以获得药物动力学参数的估计量。进一步利用NONLIN84对估计的参数进行定义。利用表示血液-时间概况的线性trapeziodal规则计算以所示剂量(AUC0-t)给药后0-t小时(最终的可测量的血液浓度时间点)血液浓度-时间曲线下面积。如由末端排除率常数(j 3)除于最后的测定的血液浓度(Ct)，并且加入到AUC0-t以产生曲线下总面积(AUC0-t)所测定的，推断剩余的面积为无限大。
如附图1和表2所示，当与雷帕霉素比较时，实施例1和实施例2具有惊人的实质上更短的末端除去半衰期(t1/2)，因此仅仅本发明的化合物提供了足够的功效(表1)和较短的末端半衰期(表2)。
表2
| 化合物 | AUC ng.hr/mL | t1/2 (小时) |
| 雷帕霉素 | 6.87 | 16.7 |
| 2-羟基吡啶 | 2.55 | 2.8 |
| 4-羟基吡啶 | 5.59 | 13.3 |
| 实施例1 | 2.35 | 5.0 |
| 实施例2 | 2.38 | 6.9 |
治疗方法
本发明的化合物，包括但不限于本实施例中例举的那些，在哺乳动物(尤其是人)中具有免疫调节的活性。至于免疫抑制剂，本发明的化合物可用于治疗和预防免疫介导的疾病例如器官或组织如心脏，肾，肝脏，骨髓，皮肤，角膜，肺，胰腺，肠tenue，四肢，肌肉，神经质，十二指 肠，小肠，胰腺的岛细胞等等移植产生的抗性；由骨髓移植引起的移植-对-宿主的疾病；自身免疫的疾病如类风湿关节炎，全身性红斑狼疮，Hashimoto’s甲状腺炎，多数的硬化症，重肌无力，I型糖尿病，眼色素层炎，变应性的脑脊髓炎，肾小球性肾炎等。进一步的用途包括由本发明的化合物靶击的炎性的和过度增殖的皮肤疾病和皮肤上表现的免疫学的介导的疾病如牛皮癣，主题皮肤炎，接触皮肤炎和进一步地湿疹性的皮肤炎，皮脂溢皮炎，地衣平坦的，天疱疮，大疱天疱疮样的，表皮松解大疱，荨麻疹，血管神经性肿胀，血管炎，红斑，皮肤上的嗜曙红细胞增多，全身性红斑狼疮，痤疮和脱发areata，各种眼睛疾病(自身免疫和别的方式)如角膜结膜炎，青春的结膜炎，葡萄膜炎关联的Behcet’s疾病，角膜炎，疱疹的角膜炎，圆锥的角膜，营养不良epithelialiscorneae，角膜白斑，眼睛的天疱疮的的治疗和预防。除了可逆的引起阻塞的导气管疾病，所述的疾病包括状态如哮喘(例如，支气管哮喘，变应性的哮喘，内部的哮喘，外部的哮喘和尘埃哮喘)，特别是慢性的或慢性顽固性的哮喘(例如，晚哮喘和导气管超响应能力)，支气管炎，变应性的鼻炎等的治疗和预防。粘膜和血管炎症例如胃溃疡，由局部缺血的疾病和血栓的形成引起的血管损坏。而且，过度增殖血管疾病例如内膜的光滑肌细胞增生，再狭窄和血管闭合，特别是在生物学或机械介到的血管损坏可以用本发明的化合物治疗或预防。可以将本文描述的化合物或药物应用到已经包被了聚合的化合物的支架上。通过将聚合物包被的支架浸泡在含有化合物或药物的溶液中足够的时间(例如5分钟)，然后干燥该包被的支架，优选的是借助于空气干燥足够的时间(例如30分钟)。然后通过从球囊导管中展开将含有化合物或药物的聚合物包被的支架释放到冠状动脉。除了支架，可以将本发明的药物导入到脉管系统的其他装置包括，但不限于移植物，导管和球囊。另外，可以与本发明的药物一起使用的其他化合物或药物包括，但不限于A-94507和SDZ RAD)。当用于本发明时，涂层可以包括任何的聚合材料，其中治疗剂即药物基本上是可溶的。包被的目的是作为治疗剂的可控制释放的赋形剂或作为治疗剂的储藏库以便在损伤位点释放。涂层可以是聚合物，进一步可以是亲水的，疏水的，生物可降解的或非生物可降解的。作为聚合的涂层的材料可以选自于下列组：多羧酸的酸，纤维质聚合物，明胶，聚乙烯吡咯烷酮，马来酸酐聚合物，聚酰胺，聚乙烯醇，聚乙烯氧化物，糖胺聚 糖，多糖，聚酯，聚尿烷，有机硅氧聚合物，聚原酸酯，聚酐类，聚碳酸酯，聚丙烯，聚乳酸，聚乙醇酸，聚己内酯，聚羟基丁酯戊酸盐，聚丙烯酰胺，聚醚，和前面所述的物质的混合物和共聚物。从聚合分散体例如聚氨酯分散体(BAYHYDROL，等)和丙烯酸酸胶乳分散体制备的涂层也可以与本发明的治疗剂一起使用。
可以用于本发明的生物可降解聚合物包括聚合物例如聚(L-乳酸)，聚(DL-乳酸)，聚己内酯，聚(羟基丁酸酯)，聚乙交酯，聚(diaxanone)，聚(羟基戊酸酯)，聚原酸酯；共聚物例如聚(环二酯-co-乙交酯)，聚羟基(丁酸盐-共-戊酸盐)，聚乙交酯-co-三甲烯碳酸盐；聚酐类；聚磷酸酯；聚磷酸酯-尿烷；聚氨基酸；聚腈基丙烯酸酯；生物分子例如纤维蛋白，血纤蛋白原，纤维素，淀粉，胶原，和透明质酸；和前面所述的物质的混合物。适用于本发明的生物稳定的物质包括聚合物例如聚氨酯，有机硅氧聚合物，聚酯，聚烯烃，聚酰胺，聚己内酰胺，聚酰亚胺，聚乙烯基的氯化物，聚乙烯基的甲基醚，聚乙烯醇，丙烯酸的聚合物和共聚物，聚丙烯腈，乙烯基单体与石蜡的聚苯乙烯共聚物(例如苯乙烯丙烯腈共聚物，异丁烯酸乙烯甲酯共聚物，乙酸乙烯乙烯酯)，聚醚，人造纤维，纤维素类(例如纤维素乙酸盐，纤维素硝酸盐，纤维素丙酸盐等等)，聚对亚苯基二甲基和其衍生物；以及前面共聚物的混合物。
可用于本发明的另一个聚合物是聚(MPCw∶LAMx∶HPMAy∶TSMAz)，其中w，x，y，和z代表在制备聚合物的原料中使用的单体的摩尔比和MPC代表2-methacryoyl oxy乙基磷酰胆碱单元，LMA代表异丁烯酸月桂酯单元，HPMA代表异丁烯酸2-羟丙酯单元，和TSMA代表3-异丁烯酸三甲氧基甲硅烷丙酯单元。可将浸透药物的支架用于维持以前由血栓关闭的冠状动脉的开放和/或动脉粥样硬化血小板。抗增殖剂的释放降低支架内再狭窄的比例。
其他的tratable条件包括但不限于局部缺血的肠疾病，炎性的肠疾病，引起坏死的小肠结肠炎，肠内的炎症/变应性例如腹腔的疾病，直肠炎，嗜曙红的肠胃炎，mastocytosis，Crohn’s疾病和溃疡结肠炎；神经的疾病例如多样的肌炎，Guillain-Barre并发位，Meniere’s疾病，多神经炎，多样的神经炎，单神经炎和神经根病；内分泌腺疾病例如甲状腺功能亢进症和Basedow’s疾病血液的疾病；例如纯的红细胞发育不全，再生障碍的贫血，再生不良的贫血，原发的thrombocytopenic紫癜， 自身免疫的溶血的贫血，粒细胞缺乏症，恶性的贫血，巨幼红细胞贫血和红细胞发生不能；骨疾病例如骨质疏松症；呼吸的疾病例如肉样瘤病，纤维瘤肺和原发的间质的肺炎；皮肤疾病例如皮肤肌炎，leukodermavulgaris，普通的鱼鳞癣，光敏感性和皮肤上的T细胞淋巴瘤；循环的疾病例如动脉硬化，动脉粥样硬化，主动脉炎综合征，多动脉炎nodosa和非炎性心肌病；胶原疾病例如硬皮病，Wegener’s肉芽瘤和Sjogren’s综合征；肥胖症；嗜曙红的筋膜炎；牙周膜的疾病例如龈，牙周组织损害，牙槽的骨头和质ossea dentis；肾变病的综合征例如肾小球性肾炎；通过预防脱毛或提供头发发芽和/或促进头发生殖和头发生长的男性型脱发或早衰脱发；肌肉发达的营养障碍；脓皮病和Sezary’s综合征；Addison’s疾病；活性氧-介导的疾病，如防腐，移植或局部缺血的疾病(例如，血栓形成和心脏的梗塞)的器官损伤例如器官的局部缺血-再灌注损伤(例如心脏，肝脏，肾和消化道)；肠的疾病例如内毒素-休克，假膜的结肠炎和药物或照射引起的结肠炎；肾脏的疾病例如局部缺血的急性的肾脏的机能不全和慢性的肾脏的机能不全；肺的疾病例如由肺氧或药物引起的毒素病(例如，paracort和博莱霉素)，肺癌和肺的肺气肿；眼睛的疾病例如白内障，血铁过多，视网膜炎，眼点，老年的有斑点的退化，vitreal瘢痕形成和角膜的碱性的灼伤；皮肤炎例如红斑multiforme，线形的IgA ballous皮肤炎和胶接剂皮肤炎；和其他例如齿龈炎，牙周炎，脓毒病，腺，由环境污染引起的疾病(例如，空气污染)，老化，致癌作用，癌和低气压病转移；由组胺或白三烯-C4释放引起的疾病；Behcet’s疾病例如肠的，vasculo-或neuro-Behcet’s疾病，和也影响口腔，皮肤，眼睛，外阴，接合，附睾，肺，肾等的Behcet’s。此外，本发明的化合物可用于治疗和预防肝脏的疾病例如致免疫的疾病(例如，慢性的自身免疫的肝病例如自身免疫的肝炎，原发的胆汁的肝硬化和致硬化的胆管炎)，部份的肝脏切除术，急性的肝脏坏死(例如由毒素，病毒的肝炎，休克或缺氧症引起的坏死)，B-病毒肝炎，非A/非-B肝炎，肝硬化(例如醇的肝硬化)和肝脏的衰竭例如暴发的肝脏的衰竭，晚期起始的肝脏的衰竭和″急性的合并慢性的″肝脏衰竭(对慢性的肝脏疾病的急性的肝脏衰竭)，和而且可用于各式各样的疾病，因为有用的活性例如化学疗法效应的augmention，巨细胞病毒感染，尤其是HCMV感染，抗炎性的活性，致硬化的和纤维变性的疾病例如肾变病，硬皮病， 肺的纤维变性，动脉硬化，充血的心脏衰竭，心室的肥大，外科手术后的粘连和瘢痕形成，发作，心肌的梗塞和局部缺血关联的损伤和再灌注等。
另外，本发明的化合物FK-506拮抗药特性。因此可将本发明的化合物用于治疗免疫阻抑或包括免疫阻抑的紊乱。参与免疫阻抑的紊乱的例子包括AIDS，癌症，真菌感染，高龄痴呆，损伤(包括创伤愈合，手术和休克)慢性病患者细菌感染，和中央神经系统紊乱。由免疫抑制的大环化合物，例如12-(2-环己烷-1-甲基乙烯基)-13，19，21，27-四甲基-11，28-dioxa-4-azatricyclo[22.3.1.04，9]octacos-18-ene 例如FK-506或雷帕霉素的衍生物配药过量引起的待治疗的免疫阻抑。患者使用配药量过多的这样的药物是十分普通的，在实际用药时患者已经忘记按照规定时间服药，并且能够导致严重的副作用。
可以根据在Bunchman ET和CA Brookshire，TransplantationProceed.23967-968(1991)；Yamagishi，等人Biochem.Biophys.Res.Comm.191 840-846(1993)；和Shichiri，等人J.Clin.Invest.871867-1871(1991)描述的方法中证明本发明的化合物治疗增殖疾病的能力。增殖疾病包括光滑的肌肉增殖，全身的硬化，肝硬化，成人的呼吸窘迫症，原发的心肌痛，全身性红斑狼疮，糖尿病的视网膜病或其他视网膜病，牛皮藓，硬皮病，前列腺增生，心脏增生，动脉损伤之后的restenosis或其他血管的病理学的狭窄。另外，这些化合物引起细胞对几个生长因子的反抗应答，并且因此具有抗血管形成性质，制备可用的药剂以控制或逆转某些肿瘤的生长，以及肺，肝脏和肾的纤维化疾病。
本发明的含水液体组合物特别适用于治疗和预防各种眼睛疾病例如自体免疫疾病(包括例如，圆锥形的角膜，角膜炎，dysophiaepithelialis corneae，角膜白斑，Mooren’s溃疡，sclevitis和Graves’，眼病)和角膜的移植的排斥。
当用于上面或其他的治疗时，也可以使用纯化形式或者如果存在这样的形式，药物可接受盐，酯或前药形式的本发明的化合物之一的药物有效量。或者，可以将该化合物以含有与一种或多种药物学可接受的赋形剂结合的所需要的化合物的药物组合物形式给药。术语本发明的化合物的″治疗有效量″是指在用于任何医学治疗的合理的效益/风险比例时该化合物治疗紊乱的足够量。但是应该了解本发明的化合物和组合物的 总每日用法将由主治医师在可靠的医学判断范围内作出决定。对于特定病人的特异性的治疗有效剂量水平将取决于各种因素包括需治疗的紊乱和紊乱的严重程度；所使用的特异性化合物的活性；所使用的特定化合物；患者的年龄，体重，总的健康，性别和饮食习惯；给药的时间，给药的方式和所使用的特定化合物的排出比例；治疗的持续时间；与所使用的特定化合物结合或相一致的药物；以及其他医学领域熟知的因素。例如在低于获得预期的治疗效果所需的水平时该化合物开始给药的剂量和逐渐增加到获得预期效果的剂量是本领域内技术人员熟知的。
给人或较低动物的本发明的化合物的总每日剂量可以是从约0.01到约10mg/kg/天。为了口服给药的目的，更优选的剂量可以是在约0.001到约3mg/kg/day的范围内。对于从支架局部释放的目的，患者将接受的每日剂量取决于支架的长度。例如，一个15毫米的冠状支架可以含有从约1到约120微克范围的量的药物并且在几个小时到几个星期的范围的时间期限内释放该药物。如果需要，可以将有效的每日剂量划分为多个剂量进行给药；因此，单剂量组合物可以含有这样的量或者其约数以达到每日剂量。局部的给药可以包括0.001到3％mg/kg/day范围的剂量，这取决于用药位点。
药物组合物
本发明的药物组合物包括本发明的一个组合物和药物学可接受的载体或赋形剂，该组合物可以口服，直肠的，非肠道，脑池内的，阴道内的，腹膜内的，局部的(散剂，油膏，滴剂或透皮片形式)，口部，口服或鼻喷雾，或局部性的，或在置于脉管系统内的支架内的形式给药。术语″药物学可接受的载体″是指无毒性固体，办固体或液体填充剂，稀释剂，左成胶囊的材料或任何形式的配制辅助物。本文使用的术语″非肠道的″是指给药方式，包括静脉内，动脉内的，肌内的，腹膜内的，胸骨内的，皮下的和动脉内的注射，浸泡，和放置，例如在脉管系统中。
用于非肠道注射的本发明药物组合物包括药物可接受的无菌含水的或不含水的溶液，分散体，悬浮体或乳剂以及无菌粉剂以便在刚使用之前重构建成无菌可注射的溶液或分散剂。适当的含水或不含水的载体，稀释剂，溶剂或赋形剂的例子包括水，乙醇，多元醇(例如甘油，丙烯乙二醇，聚乙烯乙二醇等等)，羧甲基纤维素和其合适的混合物，植物油(例如橄榄油)，和可注射的有机酯例如油酸乙酯。例如通过使用涂层材料例 如卵磷脂，对于分散体通过保持必需的颗粒大小，通过使用表面活性剂，可以维持适当的流动性。
这些组合物也含有助剂例如防腐剂，润湿剂，乳化剂和分散剂。通过包埋各式各样的抗细菌和抗真菌剂，例如paraben，三氯叔丁醇，苯酚山梨酸等等可以确保阻止微生物作用。包括等渗剂例如糖，氯化钠等等也可以是令人满意的。通过包埋延迟吸收的试剂例如一硬脂酸铝和明胶可以引起可注射的药物形式的长时间的吸收。
在某些情况下，为了延长药物的作用，将皮下的或肌内注射的药物的吸收放慢也是令人满意的。使用具有低劣的水溶解性的晶体或非晶形的物质的液体悬浮液可以完成该过程。那时药物的吸收率取决于其溶解速率，依次取决于晶体大小和结晶的形式。或者，通过将药物溶解于或悬浮于油载体中完成非肠道给药药物形式的延迟吸收。
通过将药物在生物可降解的聚合物例如聚交酯-聚乙交酯中形成微胶囊基体制备可注射的贮藏库形式。基于药物与聚合物的比率，和所使用的特定的聚合物的特性，可以控制药物的释放比率。其他的生物可降解的聚合物的例子包括聚(原酸酯)和聚(酸酐)。贮藏库可注射的配方也可以通过将药物陷入与身体组织相容的脂质体或微乳液来制备。
例如通过用留住细菌的滤器进行过滤，或在刚刚使用之前通过掺入无菌固体组合物形式的灭菌剂将可注射的配方灭菌，所述的灭菌剂可以溶于或分散于无菌水或其他的无菌的可注射的介质。
适用于口服给药的固体剂量形式包括胶囊，片剂，丸剂，粉末，和颗粒。对于这样固体剂量形式，将活性化合物与至少一个惰性的，药物可接受的赋形剂或载体例如柠檬酸钠或磷酸二钙和/或a)充填剂或膨胀剂例如淀粉，乳糖，蔗糖，葡萄糖，甘露糖醇和硅酸，b)粘合剂例如羧甲基纤维素，藻酸盐，明胶，聚乙烯吡咯烷酮，蔗糖和阿拉伯胶，c)湿润剂例如甘油，d)分解剂例如琼脂-琼脂，碳酸钙，马铃薯或木薯淀粉淀粉，藻蛋白酸，硅酸盐，和碳酸钠，e)延缓溶解的药剂例如石蜡，吸收加速剂例如四元铵化合物，g)润湿剂例如十六烷基酒和一硬脂酸丙三酯，h)吸收剂例如高岭土和皂土粘土，和i)润滑剂例如滑石，硬脂酸钙，硬脂酸镁，固体聚乙烯乙二醇，十二烷基硫酸钠，和其混合物进行混合。对于胶囊，片剂和丸剂，剂量形式也可以包括缓冲剂。
在柔软的半固体和坚硬的装满明胶的胶囊或装满液体的胶囊，利用 赋形剂如乳糖或奶糖以及高分子量的聚乙烯乙二醇等也可以将相似类型的固体组合物用作为充填剂。
用涂层和外壳例如肠涂层和其他药物制备领域内熟知的涂层可以制备固体剂量形式的片剂，糖衣丸，胶囊，丸剂和颗粒。选择性地他们含有乳浊剂和也可以是仅仅或优选地在肠道的某些部分，非强制性地以延迟方式释放活性成分的组合物。可以使用的包埋组合物的例子包括聚合物的物质和蜡。可以将含有药物的那些包埋组合物置于医学的装置，例如支架，移植物，导管和球囊。
如果合适，活性化合物也可以是具有一个或多个上面提到的赋形剂的微胶囊包着的形式。
适用于口服给药的液体剂量形式包括药物可接受的乳状液，溶液，悬浮液，糖浆和酏剂。对于活性化合物，液体剂量形式可以含有一般用于本领域的惰性稀释剂例如水或其他的溶剂，增溶剂和乳化剂例如乙醇，异丙基醇，碳酸乙酯，乙酸乙酯，苯甲基醇，苯甲酸苯甲酯，丙烯乙二醇，1，3-丁烯乙二醇，二甲基甲酰胺，油类(特别是，棉籽，落花生，玉米，胚芽，橄榄，海狸和芝麻油类)，甘油，四氢化糠基醇，聚乙烯乙二醇和脱水山梨糖醇脂肪酸酯，和其混合物。
除惰性稀释剂之外，口服组合物也可以包括助剂例如润湿剂，乳化和悬浮剂，甜味剂，调味料和香味剂。
除了活性化合物，悬浮液可以包括悬浮剂，例如乙氧化的异十八烷酰醇，聚环氧乙烷山梨醇和脱水山梨糖醇酯，微晶的纤维素，meta氢氧化物铝，皂土，琼脂-琼脂，和黄芪胶和其混合物。
局部给药包括对皮肤或粘膜给药，包括肺和眼睛的表面。用于局部给药的组合物，包括吸入剂可以制备成为被增压或非增压的干粉形式。对于非增压的粉末组合物，仔细地粉碎形式的活性成分可以与较大的与大小排列的药物可接受的惰性载体混合，所述的载体包括大小例如直径高达100微米的颗粒。合适的惰性载体包括糖例如乳糖。令人满意的是，活性成分的颗粒的至少95％重量具有有效颗粒大小在0.01到10微米范围。皮肤上局部使用的组合物还包括油膏，乳液，洗液和凝胶。
或者，可以将组合物增压和含有压缩的气体，例如氮或液化气体推进剂。液化推进剂介质和真正地总的组成优选的是活性成分在其中没有实质程度的溶解。增压的组合物可以含有表面活性剂。表面活性剂可以 是液体或固体非离子的表面活性剂或可以是固体阴离子的表面活性剂。使用钠盐形式的固体阴离子的表面活性剂是优选的。
局部给药的其他形式是给眼睛用药，例如治疗眼睛的免疫介导的情况例如自体免疫疾病，过敏的或炎性的状况和角膜的移植。将本发明的化合物在药物可接受的眼用的赋形剂中释放，以便该化合物保持与眼睛的表面接触足够时期允许该化合物穿透眼睛的角膜的和内部的区域，例如前腔，后面的腔，玻璃体，含水的体液，玻璃体的体液，角膜，虹膜/睫状，透镜，脉络膜/视网膜和巩膜。药物可接受的眼用的赋形剂可以例如是软膏，植物油或做成胶囊的材料。
优选的是用于直肠或阴道给药的组合物是栓剂或潴留灌肠剂，通过将本发明的化合物与合适的非刺激的赋形剂或载体例如可可豆黄油，聚乙烯乙二醇或栓剂蜡混合可以制备这些组合物，所述的载体在室温下是固体但是在体温是液体，并且其因此在直肠或阴道腔熔化并且释放该活性化合物。
本发明的化合物也可以脂质体形式给药。如本领域内技术人员已知的，通常脂质体来源于磷脂体或其他的脂类物质。由分散于含水的介质中的单一或片状的水合液体晶体形成脂质体。可以使用能够形成脂质体的任何无毒的，生理学的可接受的和可代谢的脂类。除了本发明的化合物以外，脂质体形式的本发明的化合物可以含有稳定剂，防腐剂，赋形剂等等。优选的脂类是天然的和合成的磷脂和磷脂酰胆碱(卵磷脂)。形成脂质体的方法是本领域已知的，参见例如Prescott，Ed.，Methods inCell Biology，Volume XIV，学术出版社，纽约，N.Y.(1976)，p.33et seq。
本发明的化合物还可以与一个或多个免疫抑制剂共给药。本发明范围内的免疫抑制剂包括，但不限于 硫唑嘌呤钠，brequinar钠， gus perimus三盐酸盐(已知也称为deoxy spergualin)，mizoribine(已知也称为布雷青霉素)， mycophenolatemofetil， Cylosporin A(市场上有商标为SANDIMMUNE的不同的环孢霉素A制剂)， 他克莫斯(也称为FK-506)，sirolimus和 ，来氟米特(leflunomide)(也称为HWA-486)，糖皮质激素，例如氢化泼尼松和其衍生物，抗体疗法例如orthoclone(OKT3)和赛尼哌(Zenapax)，和抗thymyocyte球蛋白，例 如即复宁(thymoglobulins)。
实施例3
本实施例的目的是为了测定在含有支架的猪冠状动脉中雷帕霉素类似物对内膜形成的作用。该实施例描述了在猪冠状动脉中，当从生物相容性BiodiviYsio PC冠状支架复合和释放时，雷帕霉素类似物A-179578对内膜增生和腔大小有利的影响。该结果暗示如果通过限制内膜增生而适当地应用于人中这样的结合可能对临床效益极为有利。
药剂A-179578是雷帕霉素类似物。本实施例中提出的研究被指定用于评价雷帕霉素类似物A-179578在猪冠状动脉模型中降低内膜增生的能力。该模型中A-179578的功效暗示其在经皮的血管再形成之后在支架中用于限制和治疗冠状restenosis的临床潜力。可以使用家养猪，因为与用于研究限制人患者中neointimal增生的其他调查相比，该模型似乎产生效果。
该实施例测试了从置于未成年农场猪中的冠状支架洗脱的A-179578，并且将这些结果与对照支架比较。对照支架具有仅仅覆盖其支柱的聚合物。这是重要的，对于聚合物本身必须实质上不刺激内膜增生。当洗脱的药物消失时，可以想象对聚合物的炎性应答将导致后来的″catch-up现象″，而再狭窄过程没有停止，只是更慢了。这种现象导致人患者中晚期的再狭窄出现。
在各个猪两个血管中植入支架。通常用于该模型中的猪为2-4个月龄并且重量为30-40千克。因此通过视觉观察评价Anormalα支架：动脉比例1.1-1.2，将两个冠状支架植入各个猪。
从该程序启动开始，给猪口服阿斯匹林(每天325mg)和该过程的其余时间继续服用。借助于肌内注射，随后静脉内氯胺酮(30mg/kg)和甲苯噻嗪(3mg/kg)给药进行常规的麻醉。诱导时使用的其他药物包括以阿托平(1mg)和flocillin(1g)肌内给药。在放置支架程序中，以动脉节点内的10,000单位的肝素大丸团给药。
通过切开外部颈动脉的右边并且放置8F护套产生动脉入口。在该程序之后，用普通的食物供养动物，食物中没有胆固醇或其他特定的补充剂。
使用nominal脉管靶大小为3.0mm的BiodivYsio支架。参见附图 2。随机给每个猪指定两个冠状动脉以展开支架。该支架或者是洗脱药物的支架(聚合物和药物支架)或者是仅仅包被了聚合物的支架(仅仅是聚合物支架)。借助于标准的引导导管和丝线释放该支架。在不到30秒内将支架球囊充气膨胀到合适大小。
每个猪有分别放置于冠状动脉的一个单纯的聚合物支架和一个聚合物和药物支架，以便每个猪有一个支架用于释放药物，另一个用于作为对照。
选择总共20头猪的样品大小以检测方案inneointimal厚度差异为0.2mm，标准偏差为0.15mm，功率为0.95和β0.02。
在28天时将动物杀死以进行组织病理学检查和定量分析。在从灌注泵系统移走心脏之后，移走左动脉附件以进入到邻近的冠状动脉。将带伤口的冠状动脉节片分割与心外膜分开。分离含有损伤的节片，从而允许足够的组织在任一端含有uninvolved血管。借助于标准的整形包埋技术将各个长度约为2.5cm的前面的节段包埋，和处理。随后将组织处理并且用苏木紫-曙红和elastic-van Gieson技术染色。
使用低倍和高倍功率光学显微镜代替平面显微观察，借助于校准标线和与使用校准分析软件的电脑连接的数字显微镜系统，对其长度进行测量。
采用校准的数字显微镜测量脉管损伤的严重程度和内膜应答。内部的弹性薄片的完整性的重要性是本邻域内技术人员熟知的。已经验证支架血管中组织病理学损伤评分为非常接近内膜厚度。该分数与损伤的深度相关，如下所述：
评分 损伤的描述
0 内部的弹性薄片完整；通常内皮剥落，
血管中层被压缩但是没有划破。
1 内部的弹性薄片被划破；
血管中层被压缩但是没有划破。
2 内部的弹性薄片被划破；
血管中层有可见的划破，
外部弹性薄片完整但是被压缩。
3 外部弹性薄片被划破；通常延伸过外
部弹性薄片的血管中层有大的划破；
线圈丝有时残留于外膜。
对每个支架区段的所有支架丝的损伤进行定量测量评价。也可以将校准的数字图像用于在每个支架丝位置测量内膜厚度。也测量腔区域，包含在内部的弹性的薄片的区域，外部弹性的薄片内的区域。
对于给定的节段的每个支架丝，测量内膜厚度的平均值以获得每个区段的平均损伤等级。在支架丝的abluminal侧面测量内膜厚度，因为所有情况下内膜包括该厚度。
将中间的支架片段用于测量，分析和比较。也记录近中心的和末梢的片段的相关数据(和包括在本报告的数据部分)。
本项研究的数据分析方法不必考虑治疗/对照组的可变的动脉的损伤，因为轻的到中等的损伤敏感到足以检测治疗差异。进行成对的t-测试以比较单一的聚合物支架(对照组)和聚合物加药物支架(治疗组)的可变性。在本项研究中在安排的时间点之前没有动物死亡。
表3显示所使用的猪和动脉。在表3，LCX是指左边的冠状的动脉的卷曲的分支，LAD是指左边的前面的下行的冠状的动脉，和RCA是指右边冠状的动脉。
表3
所使用的猪和脉管
| 1 | 2000-G-693 | RCA-对照 |
| 2000-G-693 | LCX-测试 | |
| 2 | 2000-G-698 | RCA-Test |
| 2000-G-698 | LAD-Control | |
| 3 | 2000-G-702 | RCA-Test |
| 2000-G-702 | LAD-Control | |
| 4 | 2000-G-709 | RCA-Control |
| 2000-G-709 | LAD-Test | |
| 5 | 2000-G-306 | RCA-Control |
| 2000-G-306 | LAD-Test | |
| 2000-G-306 | *LCX-Test | |
| 6 | 2000-G-672 | RCA-Test |
| 2000-G-672 | LAD-Control | |
| 7 | 2000-G-712 | RCA-Control |
| 2000-G-712 | LCX-Test | |
| 8 | 2000-G-735 | RCA-Control |
| 2000-G-735 | LAD-Test | |
| 9 | 2000-G-736 | RCA-Control |
| 2000-G-736 | LCX-Test | |
| 10 | 2000-G-740 | RCA-Test |
| 2000-G-740 | LAD-Control | |
| 11 | 2000-G-742 | LAD-Test |
| 2000-G-742 | OM(LCX)-Control | |
| 12 | 2000-G-744 | RCA-Test |
| 2000-G-744 | LAD-Control | |
| 13 | 2000-G-748 | RCA-Test |
| 2000-G-748 | LAD-Control | |
| 14 | 2000-G-749 | RCA-Control |
| 2000-G-749 | LCX-Test | |
| 15 | 2000-G-753 | RCA-Control |
| 2000-G-753 | LAD-Test | |
| 16 | 2000-G-754 | RCA-Test |
| 2000-G-754 | LCX-Control | |
| 17 | 2000-G-755 | RCA-Control |
| 2000-G-755 | LAD-Test | |
| 18 | 2000-G-756 | RCA-Test |
| 2000-G-756 | LAD-Control | |
| 19 | 2000-G-757 | LAD-Control |
| 2000-G-757 | LCX-Test | |
| 20 | 2000-G-760 | LAD-Test |
| 2000-G-760 | LCX-Control |
表4显示了各个支架包括近中心的，中间的和末梢的节片的平均损 伤和内膜厚度的所有数据概要结果。
表4还显示了由内部弹性薄片(IEL)和外部弹性薄片(EEL)测定的腔大小，狭窄的百分数，和动脉大小。
表4
概述：所有测量值(末梢，中间，近中心的)
| ID | 近中心 参考 | 末梢参考 | 管 | IEL | EEL | 损伤 均值 | ％ 狭窄 | Neointimal 区 | NIT |
| 对照 | 末梢 | ||||||||
| 均值 | 4.46 | 3.96 | 4.88 | 7.66 | 9.00 | 0.22 | 36.10 | 2.79 | 0.41 |
| SD | 1.20 | 1.16 | 1.30 | 1.15 | 1.10 | 0.26 | 15.41 | 1.29 | 0.17 |
| 对照 | 中间 | ||||||||
| 均值 | 4.46 | 3.96 | 4.94 | 7.71 | 9.08 | 0.08 | 36.23 | 2.77 | 0.38 |
| SD | 1.20 | 1.16 | 1.44 | 1.07 | 1.15 | 0.14 | 14.93 | 1.20 | 0.16 |
| 对照 | 近中心的 | ||||||||
| 均值 | 4.46 | 3.96 | 5.11 | 7.89 | 9.30 | 0.15 | 35.35 | 2.78 | 0.38 |
| SD | 1.20 | 1.16 | 1.38 | 1.33 | 1.42 | 0.22 | 11.94 | 1.04 | 0.12 |
| 测试 | 末梢 | ||||||||
| 均值 | 4.26 | 3.41 | 6.04 | 7.70 | 9.01 | 0.26 | 22.35 | 1.66 | 0.25 |
| SD | 1.26 | 0.96 | 1.55 | 1.49 | 1.47 | 0.43 | 8.58 | 0.58 | 0.06 |
| 测试 | 中间 | ||||||||
| 均值 | 4.26 | 3.41 | 6.35 | 7.75 | 8.98 | 0.04 | 18.71 | 1.41 | 0.22 |
| SD | 1.26 | 0.96 | 1.29 | 1.18 | 1.31 | 0.07 | 5.68 | 0.33 | 0.05 |
| 测试 | 近中心的 | ||||||||
| 均值 | 2.56 | 2.15 | 3.31 | 4.06 | 4.66 | 0.19 | 16.79 | 1.29 | 0.18 |
| SD | 1.66 | 1.37 | 2.39 | 3.48 | 4.15 | 0.13 | 9.97 | 0.80 | 0.12 |
对于测试组(聚合物和药物支架)或对照组(单纯的聚合物支架)其穿过近中心的，中间的或末梢的节片的内膜区域或厚度没有统计学上的明显的差异。该结果与以前的研究非常一致，并且因此允许使用唯一的中央的片段进行测试装置(聚合物加药物的支架)vs.对照装置(单产量的聚合物支架)的统计学的比较。
表5显示测试组和对照组的统计的t-测试比较。inneointimal厚度，内膜区域，腔大小，和腔狭窄百分率，明显受惠的药物洗脱支架具有统 计学上显著的差异。相反，测试组(聚合物加药物支架)和对照组(单纯的聚合物支架)之间，其平均损伤程度，外部弹性的薄层，或内部的弹性的薄片区域没有统计学上显著差异。
表5
测试vs.对照参数：中间的区段数据的统计比较
观察相关的支架片段的动脉近中心的和末梢，并且定量分析。在所有病例中这些脉管显示正常，在对照组(单纯的聚合物支架)和测试组(聚合物加药物支架)未受伤。参见附图3A和3B。下面的数据显示对照组的支架和测试组的支架之间大小没有统计学上的显著差异。
近中心的参考 末梢的参考
直径(mm) 直径(mm)
对照
(均值+SD) 4.46+1.20 3.96+1.16
测试
(均值+SD) 4.26～1.26 3.41+0.96
该资料显示存在统计学上的显著差异，这些差异证实支架洗脱A-179578。本发明的支架导致产生较小的内膜区域，较低的内膜厚度，和较大的腔区域。测试组(聚合物加药物支架)和对照组(单纯的聚合物支架)内的neointimal或损伤参数没有显著差异。与测试组比较对照组的动脉大小(包括支架)没有明显差异。这些后面的发现暗示含有聚合物的涂层的药物的动脉的改型特性没有明显差异。
在聚合物加药物支架和单纯的聚合物支架之间，几乎全部发现轻微的炎症。该结果暗示该聚合物显示令人满意的生物相容性，甚至没有药物填料。其他的研究显示当药物已经完全从聚合物离开，聚合物本身引起足够炎症导致neointima。该现象可能负责临床晚期再狭窄的晚期扣锁器械现象。因为本实施例中的聚合物没有引起冠状动脉的炎症，在药物用尽之后后期问题与聚合物相关是不太可能的。
可以得出结论，在猪模型中当置于冠状动脉中时含有具有一个聚合物的A-179578化合物的支架显示inneointimal增生减少。
实施例4
本实施例的目的是为了测定A-179578药物从含有磷酸胆硷侧基的生物相容性聚合物包被的316L电抛光的不锈钢样片释放的速率。
从小瓶移走HPLC小瓶的盖子的橡皮隔膜，并且置于玻璃小瓶以便″Teflon″侧面向上。这些隔膜用作为测试样本的支撑物。测试样本是先前用含有磷酸胆硷侧基的生物相容性聚合物(PC聚合物)包被的316L不锈钢样片，通常冠状动脉支架由316L不锈钢制备并且用PC聚合物覆盖以提供装填药物的贮存位置。将用于模仿支架的包被的样片置于隔膜上。利用玻璃Hamilton注射器，将A-179578和乙醇(10μl)溶液应用到每个样片的表面。该溶液含有溶于100％乙醇(3.0ml)的A-179578(30.6mg)。在每个应用之间将注射器用乙醇清洁。玻璃小瓶的盖子松弛地置于小瓶上，从而确保适当的通风。将样片干燥最少1.5小时。以这种方式负载12个(12)样片-将6个用于测定负载到装置的平均药物量，6个用于测量从装置释放药物需要的时间。
为了测定负载到样片的A-179578总量，将样片从小瓶移走，并且置于50/50乙腈/0.01M磷酸盐缓冲液(pH 6.0，5.0ml)。将样片置于5210Branson超声仪中1小时。然后将样片从溶液移走，由HPLC分析该溶液。
通过在下面各个时间间隔5，15，30和60分钟将单个样片从0.01M磷酸盐缓冲液，pH为6.0的新鲜的等分试样(10.0ml)沉浸和移走进行时间释放研究。对于剩余的时间点120，180，240，300，360分钟，使用5.0ml的缓冲液的体积。为了在药物释放阶段推进混合，将样本置于低速率的Eberbach震动器。在完成最后的样品的测试之后采用HPLC分析所有溶液等分试样。
用Hewlett Packard 1100系列仪器进行HPLC分析，该仪器具有下列设定：
注射体积＝100微升
获得时间＝40分钟
流速＝1.0ml/分钟
柱温度＝40℃
波长＝278nm
流动相＝65％乙腈/35％H2O
柱＝YMC ODS-A S5微米，4.6x 250mm Part No.A12052546WT。
上面试验的结果显示下列的释放数据：
表6
| 时间 (min.) | 释放百分率 | 标准离差 |
| 0.00 | 0.00 | 0.00 |
| 5.00 | 1.87 | 1.12 |
| 15.00 | 2.97 | 1.47 |
| 30.00 | 3.24 | 1.28 |
| 60.00 | 3.29 | 1.29 |
| 120.00 | 3.92 | 1.28 |
| 180.00 | 4.36 | 1.33 |
| 240.00 | 4.37 | 1.35 |
| 300.00 | 6.34 | 2.07 |
| 360.00 | 7.88 | 1.01 |
实施例5
本实施例的目的是为了测定A-179578从15mm BiodivYsio药物递送支架装填和释放。
为了将药物负载到支架，制备浓度为50mg/ml的溶于乙醇中的A-179578溶液并且分配到十二个小瓶。将十二个独立的聚合物包被的支 架置于计划用于将支架保持在垂直位置的固定装置上，并且将支架垂直地沉浸于药物溶液中5分钟。将支架和固定夹紧装置从小瓶移走并且通过将支架与吸收材料接触将过量药物溶液吸干。然后将支架以倒置的垂直位置在空气中干燥30分钟。
从混合物中移走支架，将各个支架置于50/50乙腈/磷酸盐缓冲液(pH 5.1，2.0ml)和超声处理一小时。
从溶液移走支架，分析溶液的药物浓度，利用该浓度可以计算支架的原始的药物量。该结果独立地证明该方法从支架涂层上除去至少95％的药物。平均来说，支架含有60微克的药物±20微克。
将负载药物的支架置于固定物并且在单个小瓶中置于0.01M磷酸盐缓冲液(pH＝6.0，1.9ml)。将这些样品置于低速的Eberbach震动器装置以提供向后-和-往前的振荡。为了避免在缓冲液中接近药物饱和度，在下列时间点：15，30，45，60，120，135，150，165，180，240，390分钟定期地将支架转移到新鲜的缓冲液小瓶。在药物释放时期研究的末端采用HPLC评价溶解缓冲液小瓶的药物浓度。下面以表的形式显示表示药物的％累积的释放与时间函数的数据：
表7
| 时间(min) | ％药物的累积释放 |
| 15 | 0.3 |
| 30 | 1.1 |
| 45 | 2.1 |
| 60 | 3.2 |
| 120 | 4.3 |
| 135 | 5.9 |
| 150 | 6.3 |
| 165 | 6.8 |
| 180 | 7.4 |
| 240 | 10.8 |
| 390 | 13.2 |
可以理解，前面说明书的详细描述的内容和相应的实施例仅仅是为了说明本发明而不是限制发明范围，本发明要求保护的范围由所附的权利要求书及其等效物界定。对公开的实施方案进行不同的变化和改进， 对于本领域内的技术人员是显而易见的。而且这些改进和变化，包括但不限于本发明所涉及的化学结构，取代基，衍生物，中间体，合成物，制剂和/或方法，都落入要求保护的本发明的范围内。
Claims (3)
1.一种医疗装置，包含在其表面上具有涂层的支撑结构,所述的涂层含有下式治疗物质
或其药学可接受的盐或前药,
其中所述前药为所述治疗物质的C-31羟基与选自如下的基团之间形成的酯：乙酰基、新戊酰、新戊酰氧甲基、乙酰氧基甲基、肽基、甲氧基甲基，2,3-二氢化茚基和天然或非天然氨基酸；
其中，所述支撑结构是一15毫米的冠状动脉支架，所述涂层是聚合物，并包含从1到120微克范围的量的治疗物质或其药学可接受的盐或前药，和
所述医疗装置在几小时到几周的时间内提供可控地释放所述治疗物质或其药学可接受的盐或前药。
2.根据权利要求1所述的医疗装置，其中所述的聚合物涂层是生物稳定的。
3.根据权利要求1所述的医疗装置，其中所述的聚合物涂层是能进行生物降解的。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/950,307 US6890546B2 (en) | 1998-09-24 | 2001-09-10 | Medical devices containing rapamycin analogs |
| US09/950307 | 2001-09-10 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028223195A Division CN1318102C (zh) | 2001-09-10 | 2002-09-10 | 含有雷帕霉素类似物的医疗装置 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101028538A CN101028538A (zh) | 2007-09-05 |
| CN101028538B true CN101028538B (zh) | 2015-06-17 |
Family
ID=25490254
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910168208.3A Expired - Lifetime CN101637624B (zh) | 2001-09-10 | 2002-09-10 | 含有雷帕霉素类似物的医疗装置 |
| CNB028223195A Expired - Lifetime CN1318102C (zh) | 2001-09-10 | 2002-09-10 | 含有雷帕霉素类似物的医疗装置 |
| CN2007100936789A Expired - Lifetime CN101081315B (zh) | 2001-09-10 | 2002-09-10 | 形成含有雷帕霉素类似物的医疗装置的方法 |
| CN200710093679.3A Expired - Lifetime CN101028538B (zh) | 2001-09-10 | 2002-09-10 | 含有雷帕霉素类似物的医疗装置 |
Family Applications Before (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200910168208.3A Expired - Lifetime CN101637624B (zh) | 2001-09-10 | 2002-09-10 | 含有雷帕霉素类似物的医疗装置 |
| CNB028223195A Expired - Lifetime CN1318102C (zh) | 2001-09-10 | 2002-09-10 | 含有雷帕霉素类似物的医疗装置 |
| CN2007100936789A Expired - Lifetime CN101081315B (zh) | 2001-09-10 | 2002-09-10 | 形成含有雷帕霉素类似物的医疗装置的方法 |
Country Status (13)
| Country | Link |
|---|---|
| US (4) | US6890546B2 (zh) |
| EP (3) | EP3153188A1 (zh) |
| JP (1) | JP5025887B2 (zh) |
| CN (4) | CN101637624B (zh) |
| AR (2) | AR036458A1 (zh) |
| AU (2) | AU2002335732C1 (zh) |
| BR (1) | BR0212434A (zh) |
| CA (1) | CA2460036C (zh) |
| ES (1) | ES2588853T3 (zh) |
| HK (1) | HK1068006A1 (zh) |
| PL (1) | PL209153B1 (zh) |
| TW (1) | TWI295179B (zh) |
| WO (1) | WO2003022324A1 (zh) |
Families Citing this family (175)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6774278B1 (en) * | 1995-06-07 | 2004-08-10 | 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 |
| US6884429B2 (en) * | 1997-09-05 | 2005-04-26 | Isotechnika International Inc. | Medical devices incorporating deuterated rapamycin for controlled delivery thereof |
| US20030129215A1 (en) * | 1998-09-24 | 2003-07-10 | T-Ram, Inc. | Medical devices containing rapamycin analogs |
| US7399480B2 (en) * | 1997-09-26 | 2008-07-15 | Abbott Laboratories | Methods of administering tetrazole-containing rapamycin analogs with other therapeutic substances using medical devices |
| US6890546B2 (en) * | 1998-09-24 | 2005-05-10 | Abbott Laboratories | Medical devices containing rapamycin analogs |
| US8257726B2 (en) * | 1997-09-26 | 2012-09-04 | Abbott Laboratories | Compositions, systems, kits, and methods of administering rapamycin analogs with paclitaxel using medical devices |
| US8257725B2 (en) * | 1997-09-26 | 2012-09-04 | Abbott Laboratories | Delivery of highly lipophilic agents via medical devices |
| US7357942B2 (en) * | 1997-09-26 | 2008-04-15 | Abbott Laboratories | Compositions, systems, and kits for administering zotarolimus and paclitaxel to blood vessel lumens |
| US8029561B1 (en) * | 2000-05-12 | 2011-10-04 | Cordis Corporation | Drug combination useful for prevention of restenosis |
| US7960405B2 (en) * | 1998-09-24 | 2011-06-14 | Abbott Laboratories | Compounds and methods for treatment and prevention of diseases |
| US20060240070A1 (en) * | 1998-09-24 | 2006-10-26 | Cromack Keith R | Delivery of highly lipophilic agents via medical devices |
| US7807211B2 (en) | 1999-09-03 | 2010-10-05 | Advanced Cardiovascular Systems, Inc. | Thermal treatment of an implantable medical device |
| US20070032853A1 (en) | 2002-03-27 | 2007-02-08 | Hossainy Syed F | 40-O-(2-hydroxy)ethyl-rapamycin coated stent |
| US8236048B2 (en) | 2000-05-12 | 2012-08-07 | Cordis Corporation | Drug/drug delivery systems for the prevention and treatment of vascular disease |
| US6953560B1 (en) | 2000-09-28 | 2005-10-11 | Advanced Cardiovascular Systems, Inc. | Barriers for polymer-coated implantable medical devices and methods for making the same |
| MXPA03002871A (es) | 2000-09-29 | 2004-12-06 | Johnson & Johnson | Dispositivos medicos recubiertos. |
| GB0100761D0 (en) | 2001-01-11 | 2001-02-21 | Biocompatibles Ltd | Drug delivery from stents |
| DE10115740A1 (de) | 2001-03-26 | 2002-10-02 | Ulrich Speck | Zubereitung für die Restenoseprophylaxe |
| US7862495B2 (en) * | 2001-05-31 | 2011-01-04 | Advanced Cardiovascular Systems, Inc. | Radiation or drug delivery source with activity gradient to minimize edge effects |
| US7247313B2 (en) * | 2001-06-27 | 2007-07-24 | Advanced Cardiovascular Systems, Inc. | Polyacrylates coatings for implantable medical devices |
| US6656216B1 (en) * | 2001-06-29 | 2003-12-02 | Advanced Cardiovascular Systems, Inc. | Composite stent with regioselective material |
| US20080145402A1 (en) * | 2001-09-10 | 2008-06-19 | Abbott Cardiovascular Systems Inc. | Medical Devices Containing Rapamycin Analogs |
| TW200306826A (en) * | 2002-01-10 | 2003-12-01 | Novartis Ag | Drug delivery systems for the prevention and treatment of vascular diseases |
| DE10223310A1 (de) * | 2002-05-24 | 2003-12-11 | Biotronik Mess & Therapieg | Verfahren zum Beschichten von Implantaten mit einer Polysaccharid-Lage |
| WO2004002367A1 (fr) * | 2002-06-27 | 2004-01-08 | Microport Medical (Shanghai) Co., Ltd. | Stent eluant des medicaments |
| EP1521603B1 (en) * | 2002-07-12 | 2011-01-19 | Cook Incorporated | Coated medical device |
| JP3980446B2 (ja) * | 2002-08-13 | 2007-09-26 | 富士通株式会社 | 生分解性樹脂組成物、並びに、生分解性樹脂組成物用充填材及び成形体 |
| KR101012605B1 (ko) * | 2002-09-06 | 2011-02-10 | 아보트 러보러터리즈 | 수화 억제제를 포함하는 의료용 장치 |
| AU2003272471B2 (en) | 2002-09-18 | 2010-10-07 | Trustees Of The University Of Pennsylvania | Method of inhibiting choroidal neovascularization |
| DE10244847A1 (de) | 2002-09-20 | 2004-04-01 | Ulrich Prof. Dr. Speck | Medizinische Vorrichtung zur Arzneimittelabgabe |
| US7149587B2 (en) | 2002-09-26 | 2006-12-12 | Pacesetter, Inc. | Cardiovascular anchoring device and method of deploying same |
| JP2006500996A (ja) * | 2002-09-26 | 2006-01-12 | エンドバスキュラー デバイセス インコーポレイテッド | 溶出性生体適合性移植可能医療器具を介してマイトマイシンを送達するための装置および方法 |
| CA2633589A1 (en) * | 2002-09-26 | 2004-04-08 | Angiotech International Ag | Perivascular wraps |
| US8303511B2 (en) * | 2002-09-26 | 2012-11-06 | Pacesetter, Inc. | Implantable pressure transducer system optimized for reduced thrombosis effect |
| US7208190B2 (en) | 2002-11-07 | 2007-04-24 | Abbott Laboratories | Method of loading beneficial agent to a prosthesis by fluid-jet application |
| 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 |
| 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 |
| ATE485847T1 (de) * | 2003-02-21 | 2010-11-15 | Sorin Biomedica Cardio Srl | Verfahren zur herstellung eines stents und entsprechender stent |
| 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 |
| US7641643B2 (en) * | 2003-04-15 | 2010-01-05 | Abbott Cardiovascular Systems Inc. | Methods and compositions to treat myocardial conditions |
| US20050118344A1 (en) | 2003-12-01 | 2005-06-02 | Pacetti Stephen D. | Temperature controlled crimping |
| US20050064038A1 (en) * | 2003-08-13 | 2005-03-24 | Dinh Thomas Q. | Active agent delivery systems including a single layer of a miscible polymer blend, medical devices, and methods |
| CA2539324A1 (en) * | 2003-09-18 | 2005-03-31 | Macusight, Inc. | Transscleral delivery |
| US7198675B2 (en) | 2003-09-30 | 2007-04-03 | Advanced Cardiovascular Systems | Stent mandrel fixture and method for selectively coating surfaces of a stent |
| AR045957A1 (es) * | 2003-10-03 | 2005-11-16 | Novartis Ag | Composicion farmaceutica y combinacion |
| US20060182778A1 (en) * | 2003-10-06 | 2006-08-17 | Nilesh Balar | Suture and graft delivery systems |
| US20090232866A1 (en) * | 2003-10-07 | 2009-09-17 | Mariann Pavone-Gyongyosi | Oligopeptides as coating material for medical products |
| US8828416B2 (en) * | 2004-03-09 | 2014-09-09 | Cordis Corporation | Local vascular delivery of topotecan in combination with rapamycin to prevent restenosis following vascular injury |
| EP1735042B1 (en) * | 2004-03-19 | 2011-11-23 | Abbott Laboratories | Multiple drug delivery from a balloon and a prosthesis |
| US20070027523A1 (en) * | 2004-03-19 | 2007-02-01 | Toner John L | Method of treating vascular disease at a bifurcated vessel using coated balloon |
| US8431145B2 (en) | 2004-03-19 | 2013-04-30 | Abbott Laboratories | Multiple drug delivery from a balloon and a prosthesis |
| US20100030183A1 (en) * | 2004-03-19 | 2010-02-04 | Toner John L | Method of treating vascular disease at a bifurcated vessel using a coated balloon |
| US20050208093A1 (en) * | 2004-03-22 | 2005-09-22 | Thierry Glauser | Phosphoryl choline coating compositions |
| US8778014B1 (en) | 2004-03-31 | 2014-07-15 | Advanced Cardiovascular Systems, Inc. | Coatings for preventing balloon damage to polymer coated stents |
| US20060182783A1 (en) * | 2004-04-30 | 2006-08-17 | Allergan, Inc. | Sustained release intraocular drug delivery systems |
| US8591885B2 (en) * | 2004-04-30 | 2013-11-26 | Allergan, Inc. | Carbonic anhydrase inhibitor sustained release intraocular drug delivery systems |
| US20050244472A1 (en) * | 2004-04-30 | 2005-11-03 | Allergan, Inc. | Intraocular drug delivery systems containing excipients with reduced toxicity and related methods |
| US9561309B2 (en) | 2004-05-27 | 2017-02-07 | Advanced Cardiovascular Systems, Inc. | Antifouling heparin coatings |
| 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 |
| WO2006017275A1 (en) | 2004-07-13 | 2006-02-16 | The University Of Tennessee Research Foundation | Adhesive composition for carrying therapeutic agents as delivery vehicle on coatings applied to vascular grafts |
| US7494665B1 (en) * | 2004-07-30 | 2009-02-24 | Advanced Cardiovascular Systems, Inc. | Polymers containing siloxane monomers |
| US7648727B2 (en) | 2004-08-26 | 2010-01-19 | Advanced Cardiovascular Systems, Inc. | Methods for manufacturing a coated stent-balloon assembly |
| US7604818B2 (en) | 2004-12-22 | 2009-10-20 | Advanced Cardiovascular Systems, Inc. | Polymers of fluorinated monomers and hydrocarbon monomers |
| DE102004062394B4 (de) * | 2004-12-23 | 2008-05-29 | Siemens Ag | Intravenöse Herzschrittmacherelektrode und Verfahren zu deren Herstellung |
| US8007775B2 (en) | 2004-12-30 | 2011-08-30 | Advanced Cardiovascular Systems, Inc. | Polymers containing poly(hydroxyalkanoates) and agents for use with medical articles and methods of fabricating the same |
| US8663639B2 (en) | 2005-02-09 | 2014-03-04 | Santen Pharmaceutical Co., Ltd. | Formulations for treating ocular diseases and conditions |
| US8637070B2 (en) * | 2005-02-09 | 2014-01-28 | Santen Pharmaceutical Co., Ltd. | Rapamycin formulations and methods of their use |
| WO2006102378A2 (en) * | 2005-03-21 | 2006-09-28 | Macusight, Inc. | Drug delivery systems for treatment of diseases or conditions |
| EP1868663B1 (en) * | 2005-03-23 | 2011-11-16 | Abbott Laboratories | Delivery of highly lipophilic agents via medical devices |
| US20080125745A1 (en) | 2005-04-19 | 2008-05-29 | Shubhayu Basu | Methods and compositions for treating post-cardial infarction damage |
| US9539410B2 (en) | 2005-04-19 | 2017-01-10 | Abbott Cardiovascular Systems Inc. | Methods and compositions for treating post-cardial infarction damage |
| US7795467B1 (en) | 2005-04-26 | 2010-09-14 | Advanced Cardiovascular Systems, Inc. | Bioabsorbable, biobeneficial polyurethanes for use in medical devices |
| US8778375B2 (en) | 2005-04-29 | 2014-07-15 | Advanced Cardiovascular Systems, Inc. | Amorphous poly(D,L-lactide) coating |
| US8021676B2 (en) | 2005-07-08 | 2011-09-20 | Advanced Cardiovascular Systems, Inc. | Functionalized chemically inert polymers for coatings |
| US7785647B2 (en) | 2005-07-25 | 2010-08-31 | Advanced Cardiovascular Systems, Inc. | Methods of providing antioxidants to a drug containing product |
| EP1940484A1 (en) * | 2005-08-25 | 2008-07-09 | Medtronic Vascular, Inc. | Controlled radical polymerization-derived block copolymer compositions for medical device coatings |
| WO2007046935A2 (en) * | 2005-10-14 | 2007-04-26 | Abbott Laboratories | Compositions, systems, kits, and methods of administering rapamycin analogs with paclitaxel using medical devices |
| US7700614B2 (en) * | 2005-12-14 | 2010-04-20 | Abbott Laboratories | One pot synthesis of tetrazole derivatives of rapamycin |
| US7976891B1 (en) | 2005-12-16 | 2011-07-12 | Advanced Cardiovascular Systems, Inc. | Abluminal stent coating apparatus and method of using focused acoustic energy |
| US7867547B2 (en) | 2005-12-19 | 2011-01-11 | Advanced Cardiovascular Systems, Inc. | Selectively coating luminal surfaces of stents |
| US7906134B2 (en) | 2005-12-21 | 2011-03-15 | Abbott Laboratories | Room temperature-curable polymers |
| EP2001438A2 (en) * | 2006-02-09 | 2008-12-17 | Macusight, Inc. | Stable formulations, and methods of their preparation and use |
| US20070196428A1 (en) | 2006-02-17 | 2007-08-23 | Thierry Glauser | Nitric oxide generating medical devices |
| US20070225313A1 (en) * | 2006-02-28 | 2007-09-27 | Zhao Jonathon Z | Epimers and isomers of tetrazole containing rapamycin analogs, methods of making and using the same |
| US7713637B2 (en) | 2006-03-03 | 2010-05-11 | Advanced Cardiovascular Systems, Inc. | Coating containing PEGylated hyaluronic acid and a PEGylated non-hyaluronic acid polymer |
| ES2563288T3 (es) | 2006-03-23 | 2016-03-14 | Santen Pharmaceutical Co., Ltd | Rapamicina en dosis bajas para el tratamiento de enfermedades relacionadas con la permeabilidad vascular |
| DE102006015013B4 (de) * | 2006-03-31 | 2010-06-02 | Siemens Ag | Implantierbarer Herzschrittmacher |
| WO2007127488A1 (en) * | 2006-04-27 | 2007-11-08 | Shenoy Narmada R | Compositions and methods for treating or preventing diseases of body passageways |
| US8304012B2 (en) | 2006-05-04 | 2012-11-06 | Advanced Cardiovascular Systems, Inc. | Method for drying a stent |
| US8003156B2 (en) | 2006-05-04 | 2011-08-23 | Advanced Cardiovascular Systems, Inc. | Rotatable support elements for stents |
| US7985441B1 (en) | 2006-05-04 | 2011-07-26 | Yiwen Tang | Purification of polymers for coating applications |
| US20080003254A1 (en) * | 2006-05-23 | 2008-01-03 | Abbott Laboratories | Systems and methods for delivering a rapamycin analog that do not inhibit human coronary artery endothelial cell migration |
| US7775178B2 (en) | 2006-05-26 | 2010-08-17 | Advanced Cardiovascular Systems, Inc. | Stent coating apparatus and method |
| US9561351B2 (en) | 2006-05-31 | 2017-02-07 | Advanced Cardiovascular Systems, Inc. | Drug delivery spiral coil construct |
| US8568764B2 (en) | 2006-05-31 | 2013-10-29 | Advanced Cardiovascular Systems, Inc. | Methods of forming coating layers for medical devices utilizing flash vaporization |
| US8703167B2 (en) | 2006-06-05 | 2014-04-22 | Advanced Cardiovascular Systems, Inc. | Coatings for implantable medical devices for controlled release of a hydrophilic drug and a hydrophobic drug |
| US8778376B2 (en) | 2006-06-09 | 2014-07-15 | Advanced Cardiovascular Systems, Inc. | Copolymer comprising elastin pentapeptide block and hydrophilic block, and medical device and method of treating |
| US8114150B2 (en) | 2006-06-14 | 2012-02-14 | Advanced Cardiovascular Systems, Inc. | RGD peptide attached to bioabsorbable stents |
| US8603530B2 (en) | 2006-06-14 | 2013-12-10 | Abbott Cardiovascular Systems Inc. | Nanoshell therapy |
| US8048448B2 (en) | 2006-06-15 | 2011-11-01 | Abbott Cardiovascular Systems Inc. | Nanoshells for drug delivery |
| US8017237B2 (en) | 2006-06-23 | 2011-09-13 | Abbott Cardiovascular Systems, Inc. | Nanoshells on polymers |
| US9028859B2 (en) | 2006-07-07 | 2015-05-12 | Advanced Cardiovascular Systems, Inc. | Phase-separated block copolymer coatings for implantable medical devices |
| US8685430B1 (en) * | 2006-07-14 | 2014-04-01 | Abbott Cardiovascular Systems Inc. | Tailored aliphatic polyesters for stent coatings |
| US8703169B1 (en) | 2006-08-15 | 2014-04-22 | Abbott Cardiovascular Systems Inc. | Implantable device having a coating comprising carrageenan and a biostable polymer |
| US9242005B1 (en) | 2006-08-21 | 2016-01-26 | Abbott Cardiovascular Systems Inc. | Pro-healing agent formulation compositions, methods and treatments |
| US20080085293A1 (en) * | 2006-08-22 | 2008-04-10 | Jenchen Yang | Drug eluting stent and therapeutic methods using c-Jun N-terminal kinase inhibitor |
| US10695327B2 (en) | 2006-09-13 | 2020-06-30 | Elixir Medical Corporation | Macrocyclic lactone compounds and methods for their use |
| US8088789B2 (en) * | 2006-09-13 | 2012-01-03 | Elixir Medical Corporation | Macrocyclic lactone compounds and methods for their use |
| WO2008033956A2 (en) * | 2006-09-13 | 2008-03-20 | Elixir Medical Corporation | Macrocyclic lactone compounds and methods for their use |
| US9005672B2 (en) | 2006-11-17 | 2015-04-14 | Abbott Cardiovascular Systems Inc. | Methods of modifying myocardial infarction expansion |
| US20080276935A1 (en) | 2006-11-20 | 2008-11-13 | Lixiao Wang | Treatment of asthma and chronic obstructive pulmonary disease with anti-proliferate and anti-inflammatory drugs |
| US8998846B2 (en) | 2006-11-20 | 2015-04-07 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
| US8414910B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
| US8414525B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
| US9737640B2 (en) | 2006-11-20 | 2017-08-22 | Lutonix, Inc. | Drug releasing coatings for medical devices |
| US8414909B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Drug releasing coatings for medical devices |
| US9700704B2 (en) | 2006-11-20 | 2017-07-11 | Lutonix, Inc. | Drug releasing coatings for balloon catheters |
| US8414526B2 (en) | 2006-11-20 | 2013-04-09 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising oils, fatty acids, and/or lipids |
| US8425459B2 (en) | 2006-11-20 | 2013-04-23 | Lutonix, Inc. | Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent |
| US8597673B2 (en) | 2006-12-13 | 2013-12-03 | Advanced Cardiovascular Systems, Inc. | Coating of fast absorption or dissolution |
| US20100196355A1 (en) * | 2007-01-29 | 2010-08-05 | Wyeth | Immunophilin Ligands and Methods for Modulating Immunophilin and Calcium Channel Activity |
| US8718795B2 (en) * | 2007-03-20 | 2014-05-06 | Cochlear Limited | Securing an implanted medical device in a patient |
| US20080265343A1 (en) * | 2007-04-26 | 2008-10-30 | International Business Machines Corporation | Field effect transistor with inverted t shaped gate electrode and methods for fabrication thereof |
| US11078262B2 (en) | 2007-04-30 | 2021-08-03 | Allergan, Inc. | High viscosity macromolecular compositions for treating ocular conditions |
| US7673379B1 (en) | 2007-05-11 | 2010-03-09 | Abbott Cardiovascular Systems Inc. | Method of producing a stent-balloon assembly |
| US8147769B1 (en) | 2007-05-16 | 2012-04-03 | Abbott Cardiovascular Systems Inc. | Stent and delivery system with reduced chemical degradation |
| US9056155B1 (en) | 2007-05-29 | 2015-06-16 | Abbott Cardiovascular Systems Inc. | Coatings having an elastic primer layer |
| US8048441B2 (en) | 2007-06-25 | 2011-11-01 | Abbott Cardiovascular Systems, Inc. | Nanobead releasing medical devices |
| US8109904B1 (en) | 2007-06-25 | 2012-02-07 | Abbott Cardiovascular Systems Inc. | Drug delivery medical devices |
| US8617114B2 (en) * | 2007-07-13 | 2013-12-31 | Abbott Cardiovascular Systems Inc. | Drug coated balloon catheter |
| US8690823B2 (en) | 2007-07-13 | 2014-04-08 | Abbott Cardiovascular Systems Inc. | Drug coated balloon catheter |
| US8182829B2 (en) * | 2007-07-27 | 2012-05-22 | Abbott Cardiovascular Systems Inc. | Drug eluting implantable medical device with hemocompatible and/or prohealing topcoat |
| US8216600B2 (en) | 2007-11-14 | 2012-07-10 | Cordis Corporation | Polymeric materials for medical devices |
| US20090209527A1 (en) * | 2008-02-19 | 2009-08-20 | Wyeth | Methods for Using Rapamycin Analogues in the Treatment of Neurological Disorders |
| WO2010024898A2 (en) | 2008-08-29 | 2010-03-04 | Lutonix, Inc. | Methods and apparatuses for coating balloon catheters |
| US8092822B2 (en) * | 2008-09-29 | 2012-01-10 | Abbott Cardiovascular Systems Inc. | Coatings including dexamethasone derivatives and analogs and olimus drugs |
| DE102008060549A1 (de) | 2008-12-04 | 2010-06-10 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Wirkstoff-Peptid-Konstrukt zur extrazellulären Anreicherung |
| KR20120061081A (ko) * | 2009-04-10 | 2012-06-12 | 하이얀 치 | 새로운 노화 방지 물질 및 그 확인 방법 |
| US20110144577A1 (en) * | 2009-12-11 | 2011-06-16 | John Stankus | Hydrophilic coatings with tunable composition for drug coated balloon |
| US8480620B2 (en) * | 2009-12-11 | 2013-07-09 | Abbott Cardiovascular Systems Inc. | Coatings with tunable solubility profile for drug-coated balloon |
| US8951595B2 (en) * | 2009-12-11 | 2015-02-10 | Abbott Cardiovascular Systems Inc. | Coatings with tunable molecular architecture for drug-coated balloon |
| CN102933658A (zh) | 2009-12-18 | 2013-02-13 | 界面生物公司 | 从自组装涂层局部递送药物 |
| US8696738B2 (en) | 2010-05-20 | 2014-04-15 | Maquet Cardiovascular Llc | Composite prosthesis with external polymeric support structure and methods of manufacturing the same |
| DE102010022588A1 (de) * | 2010-05-27 | 2011-12-01 | Hemoteq Ag | Ballonkatheter mit einer partikelfrei Wirkstoff-abgebenden Beschichtung |
| US8389041B2 (en) | 2010-06-17 | 2013-03-05 | Abbott Cardiovascular Systems, Inc. | Systems and methods for rotating and coating an implantable device |
| WO2012072074A1 (de) | 2010-12-04 | 2012-06-07 | Ruebben Alexander | Beschichtung und beschichtungsverfahren für den ballon eines ballonkatheters sowie ballonkatheter mit beschichtetem ballon |
| DE102011000340A1 (de) * | 2010-12-04 | 2012-06-06 | Alexander Rübben | Beschichtung und Beschichtungsverfahren für den Ballon eines Ballonkatheters sowie Ballonkatheter mit beschichtetem Ballon |
| MY172699A (en) | 2011-10-10 | 2019-12-10 | Ampio Pharmaceuticals Inc | Implantable medical devices with increased immune tolerance, and methods for making and implanting |
| WO2013055734A1 (en) | 2011-10-10 | 2013-04-18 | Ampio Pharmaceuticals, Inc. | Treatment of degenerative joint disease |
| US9220759B2 (en) | 2012-02-23 | 2015-12-29 | Abbott Cardiovascular Systems Inc. | Treatment of diabetic patients with a drug eluting stent and adjunctive therapy |
| US9220584B2 (en) | 2012-03-30 | 2015-12-29 | Abbott Cardiovascular Systems Inc. | Treatment of diabetic patients with a stent and locally administered adjunctive therapy |
| CN107043561B (zh) | 2012-10-29 | 2019-10-11 | 阿里斯特医疗有限责任公司 | 聚合物涂料组合物和涂覆的产品 |
| CN103845290A (zh) * | 2012-12-03 | 2014-06-11 | 曼丽国际有限公司 | Umirolimus及其衍生物用于治疗癌症的用途 |
| US9474834B2 (en) | 2014-04-11 | 2016-10-25 | Abbott Cardiovascular Systems Inc. | Stent with albumin coating for enhanced thromboresistance |
| WO2015164524A1 (en) | 2014-04-22 | 2015-10-29 | Ariste Medical, Inc. | Methods and processes for application of drug delivery polymeric coatings |
| WO2016028790A1 (en) | 2014-08-18 | 2016-02-25 | Ampio Pharmaceuticals, Inc. | Treatment of joint conditions |
| US11389512B2 (en) | 2015-06-22 | 2022-07-19 | Ampio Pharmaceuticals, Inc. | Use of low molecular weight fractions of human serum albumin in treating diseases |
| US10537599B2 (en) | 2015-12-02 | 2020-01-21 | Memorial Sloan-Kettering Cancer Center | Seneca valley virus (SVV) cellular receptor targeted oncotherapy |
| CN105879130A (zh) * | 2016-06-08 | 2016-08-24 | 刘厂辉 | 新型药物涂层支架 |
| BR112018077259A2 (pt) | 2016-06-30 | 2019-06-18 | Durect Corporation | formulações depot |
| US10682340B2 (en) | 2016-06-30 | 2020-06-16 | Durect Corporation | Depot formulations |
| CN107759616B (zh) * | 2016-08-23 | 2020-11-17 | 上海微创医疗器械（集团）有限公司 | 一种化合物及其制备方法和用途 |
| EA201990127A1 (ru) | 2016-12-30 | 2020-08-18 | Дьюрект Корпорейшн | Депо-препарат |
| CA3066361A1 (en) | 2017-06-07 | 2018-12-13 | Shifamed Holdings, Llc | Intravascular fluid movement devices, systems, and methods of use |
| WO2019059348A1 (ja) * | 2017-09-21 | 2019-03-28 | テルモ株式会社 | 薬剤コート層の形成方法および形成装置 |
| US11511103B2 (en) | 2017-11-13 | 2022-11-29 | Shifamed Holdings, Llc | Intravascular fluid movement devices, systems, and methods of use |
| WO2019152875A1 (en) | 2018-02-01 | 2019-08-08 | Shifamed Holdings, Llc | Intravascular blood pumps and methods of use and manufacture |
| CN112638436A (zh) * | 2018-05-22 | 2021-04-09 | 界面生物公司 | 用于将药物递送至血管壁的组合物和方法 |
| JP2022540616A (ja) | 2019-07-12 | 2022-09-16 | シファメド・ホールディングス・エルエルシー | 血管内血液ポンプならびに製造および使用の方法 |
| WO2021016372A1 (en) | 2019-07-22 | 2021-01-28 | Shifamed Holdings, Llc | Intravascular blood pumps with struts and methods of use and manufacture |
| WO2021062265A1 (en) | 2019-09-25 | 2021-04-01 | Shifamed Holdings, Llc | Intravascular blood pump systems and methods of use and control thereof |
| WO2021062270A1 (en) | 2019-09-25 | 2021-04-01 | Shifamed Holdings, Llc | Catheter blood pumps and collapsible pump housings |
| CN117258050B (zh) * | 2023-11-22 | 2024-02-23 | 杭州亿科医疗科技有限公司 | 一种药物球囊及其制备方法 |
Family Cites Families (170)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA737247B (en) | 1972-09-29 | 1975-04-30 | Ayerst Mckenna & Harrison | Rapamycin and process of preparation |
| US3993749A (en) | 1974-04-12 | 1976-11-23 | Ayerst Mckenna And Harrison Ltd. | 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 |
| US4401653A (en) | 1981-03-09 | 1983-08-30 | Ayerst, Mckenna & Harrison Inc. | Combination of rapamycin and picibanil for the treatment of tumors |
| US4894366A (en) | 1984-12-03 | 1990-01-16 | Fujisawa Pharmaceutical Company, Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
| US4580568A (en) | 1984-10-01 | 1986-04-08 | Cook, Incorporated | Percutaneous endovascular stent and method for insertion thereof |
| US4733665C2 (en) | 1985-11-07 | 2002-01-29 | Expandable Grafts Partnership | Expandable intraluminal graft and method and apparatus for implanting an expandable intraluminal graft |
| 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 |
| US4916193A (en) | 1987-12-17 | 1990-04-10 | Allied-Signal Inc. | Medical devices fabricated totally or in part from copolymers of recurring units derived from cyclic carbonates and lactides |
| US5283201A (en) | 1988-05-17 | 1994-02-01 | Advanced Power Technology, Inc. | High density power device fabrication process |
| US5092877A (en) | 1988-09-01 | 1992-03-03 | Corvita Corporation | Radially expandable endoprosthesis |
| US4994071A (en) | 1989-05-22 | 1991-02-19 | Cordis Corporation | Bifurcating stent apparatus and method |
| US5304121A (en) | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
| US5202750A (en) | 1990-04-09 | 1993-04-13 | U.S. Philips Corp. | MOS-gated thyristor |
| WO1991017724A1 (en) | 1990-05-17 | 1991-11-28 | Harbor Medical Devices, Inc. | Medical device polymer |
| JPH04230389A (ja) | 1990-07-16 | 1992-08-19 | American Home Prod Corp | ラパマイシン誘導体 |
| US5023262A (en) | 1990-08-14 | 1991-06-11 | American Home Products Corporation | Hydrogenated rapamycin derivatives |
| US5163952A (en) | 1990-09-14 | 1992-11-17 | Michael Froix | Expandable polymeric stent with memory and delivery apparatus and method |
| US6248129B1 (en) | 1990-09-14 | 2001-06-19 | Quanam Medical Corporation | Expandable polymeric stent with memory and delivery apparatus and method |
| PT98990A (pt) | 1990-09-19 | 1992-08-31 | American Home Prod | Processo para a preparacao de esteres de acidos carboxilicos de rapamicina |
| US5120842A (en) | 1991-04-01 | 1992-06-09 | American Home Products Corporation | Silyl ethers of rapamycin |
| US5120725A (en) | 1991-05-29 | 1992-06-09 | American Home Products Corporation | Bicyclic rapamycins |
| US5120727A (en) | 1991-05-29 | 1992-06-09 | American Home Products Corporation | Rapamycin dimers |
| US5705583A (en) | 1991-07-05 | 1998-01-06 | Biocompatibles Limited | Polymeric surface coatings |
| US6090901A (en) | 1991-07-05 | 2000-07-18 | Biocompatibles Limited | Polymeric surface coatings |
| US5457111A (en) | 1991-09-05 | 1995-10-10 | Abbott Laboratories | Macrocyclic immunomodulators |
| US5516781A (en) * | 1992-01-09 | 1996-05-14 | American Home Products Corporation | Method of treating restenosis with rapamycin |
| US5177203A (en) | 1992-03-05 | 1993-01-05 | American Home Products Corporation | Rapamycin 42-sulfonates and 42-(N-carboalkoxy) sulfamates useful as immunosuppressive agents |
| US5288711A (en) * | 1992-04-28 | 1994-02-22 | American Home Products Corporation | Method of treating hyperproliferative vascular disease |
| KR100284210B1 (ko) * | 1992-04-28 | 2001-03-02 | 이건 이. 버그 | 과증식성 혈관 질환 치료용 배합 제제 |
| US5283456A (en) | 1992-06-17 | 1994-02-01 | International Business Machines Corporation | Vertical gate transistor with low temperature epitaxial channel |
| US5449382A (en) * | 1992-11-04 | 1995-09-12 | Dayton; Michael P. | Minimally invasive bioactivated endoprosthesis for vessel repair |
| US5260300A (en) | 1992-11-19 | 1993-11-09 | American Home Products Corporation | Rapamycin carbonate esters as immuno-suppressant agents |
| US5324673A (en) | 1992-11-19 | 1994-06-28 | Motorola, Inc. | Method of formation of vertical transistor |
| US5355832A (en) | 1992-12-15 | 1994-10-18 | Advanced Surface Technology, Inc. | Polymerization reactor |
| WO1994015583A1 (en) | 1993-01-08 | 1994-07-21 | Pdt Systems, Inc. | Medicament dispensing stents |
| US5322802A (en) | 1993-01-25 | 1994-06-21 | North Carolina State University At Raleigh | Method of fabricating silicon carbide field effect transistor |
| US5283012A (en) | 1993-03-15 | 1994-02-01 | The Marley Cooling Tower Company | Self-balancing hot water distribution system for multi-level cooling tower |
| JPH08507715A (ja) | 1993-03-18 | 1996-08-20 | シーダーズ サイナイ メディカル センター | 生体人工部材のための薬剤導入性および放出性重合性コーティング |
| US5474563A (en) * | 1993-03-25 | 1995-12-12 | Myler; Richard | Cardiovascular stent and retrieval apparatus |
| 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 |
| US5380299A (en) | 1993-08-30 | 1995-01-10 | Med Institute, Inc. | Thrombolytic treated intravascular medical device |
| JPH07122749A (ja) | 1993-09-01 | 1995-05-12 | Toshiba Corp | 半導体装置及びその製造方法 |
| US5527907A (en) | 1993-11-19 | 1996-06-18 | Abbott Laboratories | Macrolide immunomodulators |
| WO1995014023A1 (en) | 1993-11-19 | 1995-05-26 | Abbott Laboratories | Semisynthetic analogs of rapamycin (macrolides) being immunomodulators |
| KR0141218B1 (ko) | 1993-11-24 | 1998-07-15 | 윤종용 | 고집적 반도체장치의 제조방법 |
| US5519042A (en) * | 1994-01-13 | 1996-05-21 | Hoechst Aktiengesellschaft | Method of treating hyperproliferative vascular disease |
| CA2134997C (en) | 1994-11-03 | 2009-06-02 | Ian M. Penn | Stent |
| US5641694A (en) | 1994-12-22 | 1997-06-24 | International Business Machines Corporation | Method of fabricating vertical epitaxial SOI transistor |
| FR2730231B1 (fr) * | 1995-02-02 | 1997-04-04 | Fournier Sca Lab | Association de fenofibrate et de vitamine e, utilisation en therapeutique |
| US5605696A (en) | 1995-03-30 | 1997-02-25 | Advanced Cardiovascular Systems, Inc. | Drug loaded polymeric material and method of manufacture |
| US5837313A (en) | 1995-04-19 | 1998-11-17 | Schneider (Usa) Inc | Drug release stent coating process |
| US6120536A (en) * | 1995-04-19 | 2000-09-19 | Schneider (Usa) Inc. | Medical devices with long term non-thrombogenic coatings |
| US6099562A (en) | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
| US5869079A (en) * | 1995-06-02 | 1999-02-09 | Oculex Pharmaceuticals, Inc. | Formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents |
| 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 |
| EP0830109B1 (en) | 1995-06-08 | 2003-10-15 | Ave Galway Limited | Bifurcated endovascular stent |
| GB9522332D0 (en) | 1995-11-01 | 1996-01-03 | Biocompatibles Ltd | Braided stent |
| US5637898A (en) | 1995-12-22 | 1997-06-10 | North Carolina State University | Vertical field effect transistors having improved breakdown voltage capability and low on-state resistance |
| US6015816A (en) * | 1996-02-29 | 2000-01-18 | The Research Foundation Of State University Of New York | Antimicrobial compositions |
| GB9606452D0 (en) | 1996-03-27 | 1996-06-05 | Sandoz Ltd | Organic compounds |
| AU716764B2 (en) | 1996-06-04 | 2000-03-09 | Cook Incorporated | Implantable medical device |
| CA2261666C (en) * | 1996-07-30 | 2010-09-14 | Novartis Ag | Pharmaceutical compositions for the treatment of transplant rejection, autoimmune or inflammatory conditions comprising cyclosporin a and 40-0-(2-hydroxiethyl)-rapamycin |
| JP2001500126A (ja) | 1996-09-09 | 2001-01-09 | アメリカン・ホーム・プロダクツ・コーポレイション | アルキル化ラパマイシン誘導体 |
| AU4246197A (en) | 1996-09-09 | 1998-03-26 | American Home Products Corporation | Rapamycin derivatives with unnatural stereochemistries |
| ZA9710342B (en) | 1996-11-25 | 1998-06-10 | Alza Corp | Directional drug delivery stent and method of use. |
| US6495579B1 (en) | 1996-12-02 | 2002-12-17 | Angiotech Pharmaceuticals, Inc. | Method for treating multiple sclerosis |
| US5827321A (en) | 1997-02-07 | 1998-10-27 | Cornerstone Devices, Inc. | Non-Foreshortening intraluminal prosthesis |
| KR100526913B1 (ko) | 1997-02-20 | 2005-11-09 | 쿡 인코포레이티드 | 코팅된 이식가능한 의료 장치 |
| EP0916362B1 (en) * | 1997-03-31 | 2009-07-08 | Kabushikikaisha Igaki Iryo Sekkei | Stent for vessels |
| US6709873B1 (en) | 1997-04-09 | 2004-03-23 | Isodiagnostika Inc. | Method for production of antibodies to specific sites of rapamycin |
| US6240616B1 (en) | 1997-04-15 | 2001-06-05 | Advanced Cardiovascular Systems, Inc. | Method of manufacturing a medicated porous metal prosthesis |
| US5843172A (en) | 1997-04-15 | 1998-12-01 | Advanced Cardiovascular Systems, Inc. | Porous medicated stent |
| US6273913B1 (en) * | 1997-04-18 | 2001-08-14 | Cordis Corporation | Modified stent useful for delivery of drugs along stent strut |
| WO1998056312A1 (en) | 1997-06-13 | 1998-12-17 | Scimed Life Systems, Inc. | Stents having multiple layers of biodegradable polymeric composition |
| US6110483A (en) * | 1997-06-23 | 2000-08-29 | Sts Biopolymers, Inc. | Adherent, flexible hydrogel and medicated coatings |
| US6306166B1 (en) | 1997-08-13 | 2001-10-23 | Scimed Life Systems, Inc. | Loading and release of water-insoluble drugs |
| US5854382A (en) | 1997-08-18 | 1998-12-29 | Meadox Medicals, Inc. | Bioresorbable compositions for implantable prostheses |
| US20060198867A1 (en) * | 1997-09-25 | 2006-09-07 | Abbott Laboratories, Inc. | Compositions and methods of administering rapamycin analogs using medical devices for long-term efficacy |
| US20030129215A1 (en) | 1998-09-24 | 2003-07-10 | T-Ram, Inc. | Medical devices containing rapamycin analogs |
| US6015815A (en) | 1997-09-26 | 2000-01-18 | Abbott Laboratories | Tetrazole-containing rapamycin analogs with shortened half-lives |
| US6890546B2 (en) | 1998-09-24 | 2005-05-10 | Abbott Laboratories | Medical devices containing rapamycin analogs |
| US8257726B2 (en) * | 1997-09-26 | 2012-09-04 | Abbott Laboratories | Compositions, systems, kits, and methods of administering rapamycin analogs with paclitaxel using medical devices |
| US8394398B2 (en) * | 1997-09-26 | 2013-03-12 | Abbott Laboratories | Methods of administering rapamycin analogs with anti-inflammatories using medical devices |
| TW557297B (en) * | 1997-09-26 | 2003-10-11 | Abbott Lab | Rapamycin analogs having immunomodulatory activity, and pharmaceutical compositions containing same |
| US7378105B2 (en) * | 1997-09-26 | 2008-05-27 | Abbott Laboratories | Drug delivery systems, kits, and methods for administering zotarolimus and paclitaxel to blood vessel lumens |
| US5972027A (en) | 1997-09-30 | 1999-10-26 | Scimed Life Systems, Inc | Porous stent drug delivery system |
| US6623521B2 (en) | 1998-02-17 | 2003-09-23 | Md3, Inc. | Expandable stent with sliding and locking radial elements |
| US6096726A (en) | 1998-03-11 | 2000-08-01 | Surface Solutions Laboratories Incorporated | Multicomponent complex for use with substrate |
| RU2214244C9 (ru) * | 1998-03-26 | 2020-07-29 | Астеллас Фарма Инк. | Препараты с замедленным высвобождением |
| AU3212199A (en) | 1998-03-31 | 1999-10-18 | Scimed Life Systems, Inc. | Temperature controlled solute delivery system |
| US20010029351A1 (en) | 1998-04-16 | 2001-10-11 | Robert Falotico | Drug combinations and delivery devices for the prevention and treatment of vascular disease |
| US8029561B1 (en) | 2000-05-12 | 2011-10-04 | Cordis Corporation | Drug combination useful for prevention of restenosis |
| ES2179646T3 (es) * | 1998-04-27 | 2003-01-16 | Surmodics Inc | Revestimiento que libera un agente bioactivo. |
| US6225165B1 (en) | 1998-05-13 | 2001-05-01 | Micron Technology, Inc. | High density SRAM cell with latched vertical transistors |
| US6104045A (en) | 1998-05-13 | 2000-08-15 | Micron Technology, Inc. | High density planar SRAM cell using bipolar latch-up and gated diode breakdown |
| US6280411B1 (en) | 1998-05-18 | 2001-08-28 | Scimed Life Systems, Inc. | Localized delivery of drug agents |
| US6229161B1 (en) | 1998-06-05 | 2001-05-08 | Stanford University | Semiconductor capacitively-coupled NDR device and its applications in high-density high-speed memories and in power switches |
| US6153252A (en) * | 1998-06-30 | 2000-11-28 | Ethicon, Inc. | Process for coating stents |
| 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 |
| US6033562A (en) * | 1998-08-28 | 2000-03-07 | Budeit; Donald A | Apparatus for aerating wastewater from pressurized or gravity flow sources |
| US7455853B2 (en) | 1998-09-24 | 2008-11-25 | Abbott Cardiovascular Systems Inc. | Medical devices containing rapamycin analogs |
| US7662409B2 (en) | 1998-09-25 | 2010-02-16 | Gel-Del Technologies, Inc. | Protein matrix materials, devices and methods of making and using thereof |
| JP2000120869A (ja) * | 1998-10-15 | 2000-04-28 | Teikoku Piston Ring Co Ltd | 摺動部材及びその製造方法 |
| US6187024B1 (en) | 1998-11-10 | 2001-02-13 | Target Therapeutics, Inc. | Bioactive coating for vaso-occlusive devices |
| US6665728B1 (en) * | 1998-12-30 | 2003-12-16 | Intel Corporation | Establishing optimal latency in streaming data applications that use data packets |
| US6419692B1 (en) | 1999-02-03 | 2002-07-16 | Scimed Life Systems, Inc. | Surface protection method for stents and balloon catheters for drug delivery |
| US6730349B2 (en) | 1999-04-19 | 2004-05-04 | Scimed Life Systems, Inc. | Mechanical and acoustical suspension coating of medical implants |
| US6607598B2 (en) | 1999-04-19 | 2003-08-19 | Scimed Life Systems, Inc. | Device for protecting medical devices during a coating process |
| DE60026513T2 (de) * | 1999-05-27 | 2006-10-05 | Biocompatibles Uk Ltd., Farnham | Lokale arzneistoffabgabe |
| US6258121B1 (en) | 1999-07-02 | 2001-07-10 | Scimed Life Systems, Inc. | Stent coating |
| US6713119B2 (en) | 1999-09-03 | 2004-03-30 | Advanced Cardiovascular Systems, Inc. | Biocompatible coating for a prosthesis and a method of forming the same |
| US6077733A (en) | 1999-09-03 | 2000-06-20 | Taiwan Semiconductor Manufacturing Company | Method of manufacturing self-aligned T-shaped gate through dual damascene |
| US6663606B1 (en) | 1999-10-28 | 2003-12-16 | Scimed Life Systems, Inc. | Biocompatible medical devices |
| US6702849B1 (en) | 1999-12-13 | 2004-03-09 | Advanced Cardiovascular Systems, Inc. | Method of processing open-celled microcellular polymeric foams with controlled porosity for use as vascular grafts and stent covers |
| WO2001049338A1 (en) | 1999-12-30 | 2001-07-12 | Li Wei Pin | Controlled delivery of therapeutic agents by insertable medical devices |
| EP2298299A3 (en) * | 2000-01-14 | 2012-02-29 | The Trustees Of The University Of Pennsylvania | O-methylated rapamycin derivatives for alleviation and inhibition of lymphoproliferative disorders |
| SE0000363A0 (sv) | 2000-02-04 | 2001-08-05 | Zoucas Kirurgkonsult Ab | Belagd medicinsk anordning |
| WO2001087267A1 (en) | 2000-02-28 | 2001-11-22 | Gel-Del Technologies, Inc. | Protein matrix materials, devices and methods of making and using thereof |
| WO2001085064A1 (en) | 2000-05-05 | 2001-11-15 | The Board Of Trustees Of The Leland Stanford Junior University | Multilayer stents having enhanced flexibility and hoop strength |
| US20020007214A1 (en) | 2000-05-19 | 2002-01-17 | Robert Falotico | Drug/drug delivery systems for the prevention and treatment of vascular disease |
| US20020005206A1 (en) | 2000-05-19 | 2002-01-17 | Robert Falotico | Antiproliferative drug and delivery device |
| US20020007213A1 (en) | 2000-05-19 | 2002-01-17 | Robert Falotico | Drug/drug delivery systems for the prevention and treatment of vascular disease |
| WO2001087375A1 (en) | 2000-05-12 | 2001-11-22 | Cordis Corporation | Delivery devices for treatment of vascular disease |
| US20020007215A1 (en) | 2000-05-19 | 2002-01-17 | Robert Falotico | Drug/drug delivery systems for the prevention and treatment of vascular disease |
| US6776796B2 (en) | 2000-05-12 | 2004-08-17 | Cordis Corportation | Antiinflammatory drug and delivery device |
| ATE317709T1 (de) | 2000-05-16 | 2006-03-15 | Ortho Mcneil Pharm Inc | Verfahren zur beschichtung von medizinischen geräten unter verwendung von superkritischem kohlendioxid |
| US20020077693A1 (en) | 2000-12-19 | 2002-06-20 | Barclay Bruce J. | Covered, coiled drug delivery stent and method |
| US6974473B2 (en) | 2000-06-30 | 2005-12-13 | Vascular Architects, Inc. | Function-enhanced thrombolytic AV fistula and method |
| US6506408B1 (en) | 2000-07-13 | 2003-01-14 | Scimed Life Systems, Inc. | Implantable or insertable therapeutic agent delivery device |
| US6746773B2 (en) | 2000-09-29 | 2004-06-08 | Ethicon, Inc. | Coatings for medical devices |
| MXPA03002871A (es) | 2000-09-29 | 2004-12-06 | Johnson & Johnson | Dispositivos medicos recubiertos. |
| US7261735B2 (en) | 2001-05-07 | 2007-08-28 | Cordis Corporation | Local drug delivery devices and methods for maintaining the drug coatings thereon |
| AU1129902A (en) | 2000-09-29 | 2002-04-08 | Cordis Corp | Coated medical devices |
| US6758859B1 (en) | 2000-10-30 | 2004-07-06 | Kenny L. Dang | Increased drug-loading and reduced stress drug delivery device |
| EP1330273B1 (en) | 2000-10-31 | 2007-07-25 | Cook Incorporated | Coated implantable medical device |
| US6517888B1 (en) | 2000-11-28 | 2003-02-11 | Scimed Life Systems, Inc. | Method for manufacturing a medical device having a coated portion by laser ablation |
| US6545097B2 (en) | 2000-12-12 | 2003-04-08 | Scimed Life Systems, Inc. | Drug delivery compositions and medical devices containing block copolymer |
| DE60130032D1 (de) * | 2000-12-22 | 2007-09-27 | Avantec Vascular Corp | Vorrichtung zur Abgabe von therapeutischen Wirkstoffen |
| GB0100760D0 (en) * | 2001-01-11 | 2001-02-21 | Biocompatibles Ltd | Drug delivery from stents |
| RU2345719C2 (ru) | 2001-01-16 | 2009-02-10 | Васкулар Терапиез, Ллс. | Способ предотвращения или лечения уменьшения доступа для гемодиализа сосудов и устройство для его осуществления и другие сосудистые графты |
| US6752829B2 (en) | 2001-01-30 | 2004-06-22 | Scimed Life Systems, Inc. | Stent with channel(s) for containing and delivering a biologically active material and method for manufacturing the same |
| DE10107795B4 (de) * | 2001-02-13 | 2014-05-15 | Berlex Ag | Gefäßstütze mit einem Grundkörper, Verfahren zur Herstellung der Gefäßstütze, Vorrichtung zur Beschichtung der Gefäßstütze |
| US20020119178A1 (en) | 2001-02-23 | 2002-08-29 | Luc Levesque | Drug eluting device for treating vascular diseases |
| US20020127263A1 (en) | 2001-02-27 | 2002-09-12 | Wenda Carlyle | Peroxisome proliferator-acitvated receptor gamma ligand eluting medical device |
| US6462359B1 (en) | 2001-03-22 | 2002-10-08 | T-Ram, Inc. | Stability in thyristor-based memory device |
| US6780424B2 (en) | 2001-03-30 | 2004-08-24 | Charles David Claude | Controlled morphologies in polymer drug for release of drugs from polymer films |
| US6787179B2 (en) | 2001-06-29 | 2004-09-07 | Ethicon, Inc. | Sterilization of bioactive coatings |
| EP1273314A1 (en) | 2001-07-06 | 2003-01-08 | Terumo Kabushiki Kaisha | Stent |
| US6669980B2 (en) | 2001-09-18 | 2003-12-30 | Scimed Life Systems, Inc. | Method for spray-coating medical devices |
| US6805703B2 (en) | 2001-09-18 | 2004-10-19 | Scimed Life Systems, Inc. | Protective membrane for reconfiguring a workpiece |
| US7195640B2 (en) | 2001-09-25 | 2007-03-27 | Cordis Corporation | Coated medical devices for the treatment of vulnerable plaque |
| US7033389B2 (en) | 2001-10-16 | 2006-04-25 | Scimed Life Systems, Inc. | Tubular prosthesis for external agent delivery |
| US6764709B2 (en) | 2001-11-08 | 2004-07-20 | Scimed Life Systems, Inc. | Method for making and measuring a coating on the surface of a medical device using an ultraviolet laser |
| US6517889B1 (en) | 2001-11-26 | 2003-02-11 | Swaminathan Jayaraman | Process for coating a surface of a stent |
| US7014654B2 (en) | 2001-11-30 | 2006-03-21 | Scimed Life Systems, Inc. | Stent designed for the delivery of therapeutic substance or other agents |
| US6945994B2 (en) | 2001-12-05 | 2005-09-20 | Boston Scientific Scimed, Inc. | Combined balloon-expanding and self-expanding stent |
| TW200306826A (en) | 2002-01-10 | 2003-12-01 | Novartis Ag | Drug delivery systems for the prevention and treatment of vascular diseases |
| 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 |
| US20030204168A1 (en) | 2002-04-30 | 2003-10-30 | Gjalt Bosma | Coated vascular devices |
| US7754238B2 (en) | 2002-05-03 | 2010-07-13 | Avi Biopharma, Inc. | Delivery of microparticle-conjugated drugs for inhibition of stenosis |
| US6945995B2 (en) | 2002-08-29 | 2005-09-20 | Boston Scientific Scimed, Inc. | Stent overlap point markers |
| WO2005027973A2 (en) | 2003-09-23 | 2005-03-31 | Novartis Ag | Combinations of a vegf receptor inhibitor with other therapeutic agents |
| US20080085902A1 (en) | 2003-09-23 | 2008-04-10 | Guido Bold | Combination Of A Vegf Receptor Inhibitor Or With A Chemotherapeutic Agent |
| US7758908B2 (en) * | 2006-03-28 | 2010-07-20 | Boston Scientific Scimed, Inc. | Method for spray coating a medical device using a micronozzle |
-
2001
- 2001-09-10 US US09/950,307 patent/US6890546B2/en not_active Expired - Lifetime
-
2002
- 2002-08-12 TW TW091118099A patent/TWI295179B/zh not_active IP Right Cessation
- 2002-09-09 AR ARP020103398A patent/AR036458A1/es not_active Application Discontinuation
- 2002-09-10 PL PL368603A patent/PL209153B1/pl not_active IP Right Cessation
- 2002-09-10 CN CN200910168208.3A patent/CN101637624B/zh not_active Expired - Lifetime
- 2002-09-10 AU AU2002335732A patent/AU2002335732C1/en not_active Expired
- 2002-09-10 EP EP16183878.4A patent/EP3153188A1/en not_active Withdrawn
- 2002-09-10 WO PCT/US2002/028798 patent/WO2003022324A1/en active Application Filing
- 2002-09-10 ES ES02770496.4T patent/ES2588853T3/es not_active Expired - Lifetime
- 2002-09-10 CN CNB028223195A patent/CN1318102C/zh not_active Expired - Lifetime
- 2002-09-10 CN CN2007100936789A patent/CN101081315B/zh not_active Expired - Lifetime
- 2002-09-10 EP EP10181379.8A patent/EP2258415B1/en not_active Expired - Lifetime
- 2002-09-10 AU AU2002330012A patent/AU2002330012B2/en not_active Expired
- 2002-09-10 JP JP2003526451A patent/JP5025887B2/ja not_active Expired - Lifetime
- 2002-09-10 EP EP02770496.4A patent/EP1427457B1/en not_active Expired - Lifetime
- 2002-09-10 BR BR0212434-3A patent/BR0212434A/pt not_active Application Discontinuation
- 2002-09-10 CN CN200710093679.3A patent/CN101028538B/zh not_active Expired - Lifetime
- 2002-09-10 CA CA2460036A patent/CA2460036C/en not_active Expired - Lifetime
-
2004
- 2004-08-06 US US10/914,055 patent/US20050032826A1/en not_active Abandoned
- 2004-12-07 HK HK04109690.0A patent/HK1068006A1/zh not_active IP Right Cessation
-
2008
- 2008-03-03 US US12/041,537 patent/US20080175884A1/en not_active Abandoned
-
2014
- 2014-05-22 AR ARP140102032A patent/AR096391A2/es not_active Application Discontinuation
-
2016
- 2016-04-05 US US15/091,473 patent/US10058641B2/en not_active Expired - Lifetime
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101028538B (zh) | 含有雷帕霉素类似物的医疗装置 | |
| CN100548236C (zh) | 含有雷帕霉素类似物的医疗装置 | |
| US8153150B2 (en) | Methods of administering tetrazole-containing rapamycin analogs with other therapeutic substances for treatment of vascular disorder | |
| AU2002330012A1 (en) | Medical devices containing rapamycin analogs | |
| US7455853B2 (en) | Medical devices containing rapamycin analogs | |
| US20080145402A1 (en) | Medical Devices Containing Rapamycin Analogs | |
| US8569333B2 (en) | Compounds and methods for treatment and prevention of diseases |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CX01 | Expiry of patent term |
Granted publication date: 20150617 |
|
| CX01 | Expiry of patent term |