WO2004002367A1 - Stent eluant des medicaments - Google Patents

Stent eluant des medicaments Download PDF

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Publication number
WO2004002367A1
WO2004002367A1 PCT/CN2003/000489 CN0300489W WO2004002367A1 WO 2004002367 A1 WO2004002367 A1 WO 2004002367A1 CN 0300489 W CN0300489 W CN 0300489W WO 2004002367 A1 WO2004002367 A1 WO 2004002367A1
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WO
WIPO (PCT)
Prior art keywords
drug
stent according
eluting stent
layer
stent
Prior art date
Application number
PCT/CN2003/000489
Other languages
English (en)
French (fr)
Inventor
Yi Zhang
Jianke Wang
Zhirong Tang
Shuiying He
Shunhua Zhou
Runlin Gao
Junfei Li
Ying Zhang
Qiyi Luo
Original Assignee
Microport Medical (Shanghai) Co., 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
Priority claimed from CN 02146905 external-priority patent/CN100471469C/zh
Priority claimed from CNB021551383A external-priority patent/CN1306917C/zh
Priority claimed from CNB031155960A external-priority patent/CN100435880C/zh
Priority claimed from CNA031160638A external-priority patent/CN1533813A/zh
Priority claimed from CNB031289061A external-priority patent/CN100346850C/zh
Application filed by Microport Medical (Shanghai) Co., Ltd. filed Critical Microport Medical (Shanghai) Co., Ltd.
Priority to JP2004548875A priority Critical patent/JP2005531391A/ja
Priority to AU2003280437A priority patent/AU2003280437A1/en
Priority to EP03739968A priority patent/EP1516597A4/en
Publication of WO2004002367A1 publication Critical patent/WO2004002367A1/zh
Priority to US10/943,636 priority patent/US20050043788A1/en
Priority to US10/943,633 priority patent/US20050033414A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • 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
    • 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
    • A61L31/048—Macromolecular materials obtained 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
    • A61L31/14—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
    • 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
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • 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
    • A61F2002/075—Stent-grafts the stent being loosely attached to the graft material, e.g. by stitching
    • 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
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A61L2300/61—Coatings having two or more layers containing two or more active agents in different layers

Definitions

  • the invention relates to the field of medical devices, and in particular to a drug-eluting stent with a multi-layer coating.
  • Arterial stent is the main method for interventional treatment of cardiovascular and peripheral vascular occlusive lesions. Since Sigwart et al. Placed the first coronary stent (PTCA stent) in the human body in 1986, the application of this technology has been spreading rapidly. More than 80% of the disease treatment.
  • the biggest disadvantage of this technique is the occurrence of post-stent restenosis.
  • the incidence of post-stent restenosis is currently about 20%.
  • the cause of restenosis after the stent is that the blood vessel is damaged by the expansion of the blood vessel, which induces the excessive proliferation of vascular smooth muscle cells (VSMC) and migrates to the intima, and eventually causes the restenosis of the blood vessel.
  • VSMC vascular smooth muscle cells
  • the technical problem to be solved by the present invention is to further optimize and improve on the basis of Chinese patent application 02112242.3, to provide a stent with more uniform coating, firmness, no cracking and peeling, and at the same time, it can prevent multiple postoperative complications. .
  • Yet another technical problem to be solved by the present invention is to disclose a method for preparing the above-mentioned drug stent.
  • Another technical problem to be solved by the present invention is to disclose the application of the above-mentioned stent in interventional treatment of cardiovascular, nerve and peripheral vascular occlusive diseases.
  • the novel stent disclosed by the present invention is composed of a stent and a coating covering the surface of the stent, which is characterized by having 1 to 4 layers of coating on the surface of the stent, at least two of which are drug-carrying layers; It is composed of 0.5-99% polymer, 0-10% additive and 0.5-99% active ingredient.
  • the bottom layer may be a bottom layer between the drug-loaded layer and the stent to improve the binding force between the drug-loaded layer and the stent.
  • the bottom layer is composed of one or several polymers.
  • a surface layer may be coated on the surface of the drug-loading layer.
  • the surface layer may be composed of 0.5-99% polymer, 0-10% additive and 0-99% active ingredient.
  • the present invention further provides a dense control-release layer outside the coating.
  • This coating is made of Parylene (the trade name of Parylene, Parylene) or its derivative, polytetrafluoroethylene (PTFE), etc.
  • the controlled release layer also includes an appropriate amount of Antithrombotic drugs: such as cilostazol, ticlopidine, or clopirolide, and its thickness is controlled between 0.01 and 20 microns.
  • the active ingredient in the surface layer may be the same as or different from the active ingredient in the drug-loaded layer.
  • Surface layer can be loaded or unloaded
  • the drug as a release barrier layer, is used to adjust the release rate curve of the active ingredient according to the needs of different conditions, and can also be used to prevent the formation of acute and subacute thrombosis.
  • each coating according to the present invention is 0.1-100 micrometers.
  • the active ingredient in the drug-loaded coating of the present invention is selected from one or more of the following drug therapeutic agents or carrier therapeutic genes: including anti-thrombogenic agents, anticancer drugs, microbial immunosuppressants, hormones, and Other anti-restenosis drugs.
  • the anticoagulant drug is selected from the group consisting of heparin, aspirin, hirudin, colchicine, an antiplatelet GPIIb / ma receptor-binding agent, such as tirofiban, abciximab, eptifibatide, Cilostazol (Cilostazol), ticlopidine, clopidogrel sulfate, etc .;
  • the anticancer drug is selected from methotrexate, purines, pyrimidines, phytoalkali (especially Taxol and Epothilone), tripterygium compounds, antibiotics (especially Actinomycin-D), hormones, antibodies, etc .:
  • the microbial immunosuppressant is selected from the group consisting of ciclosporinA (CsA), FK506 (and homologues), DSG (15-deoxyspergualin, 15-dos), MMF, rapamycin and derivatives thereof Object, CCI-779, FR 900520, FR 900523, NK86-1086, daclizumab, depsidomycin, kanglemycinC, spergualin, prodigiosin25- c, cammunomicin, demethomycin, tetranactl, tranilast, stevastelins, myriocin, gllooxin, FR 651814, SDZ214- Mycin C, bredinin, mycophenolic acid, brefeldin A, WS9482, glucocorticoids, etc .;
  • anti-restenosis drug is selected from the batima S t a t, metalloproteinase inhibitors (MMP inhibitory particularly homogeneous j!), 17 ⁇ - estradiol, NO donors, 2-chlorodeoxyadenosine, 2-deoxycoformycin , .
  • the vector therapy gene is selected from the group consisting of: Keratin 8 gene, VEGF gene, EGF gene, PTEN, urokinase precursor gene, mediated by cells, viruses, plasmids, tritium molecular materials and other vectors. Nitric oxide synthase (NOS) gene and antisense C-myc gene.
  • NOS Nitric oxide synthase
  • Drug therapies and vector therapy genes can prevent the vascular smooth muscle by inhibiting the excessive proliferation of vascular smooth muscle cells (VSMC), or promoting the growth of vascular endothelial cells, or preventing the migration of vascular smooth muscle cells, or inhibiting the excessive proliferation of extracellular matrix of vascular smooth muscle.
  • VSMC vascular smooth muscle cells
  • the polymer according to the present invention is selected from the group consisting of homopolymers of lactide, glycolide, and ⁇ -caprolactone, and copolymers of or in between, celluloses, polyvinylpyrrolidone, polyvinyl alcohol, Gum acacia, tragacanth, sodium alginate, gelatin, polymethyl methacrylate, polybutyl methacrylate, ethylene-vinyl alcohol copolymer, ethylene-vinyl acetate copolymer and mixtures of the above polymers .
  • the additives described in the present invention are selected from polymer cross-linking curing agents (curing catalysts), wetting and dispersing agents, plasticizers, and the like.
  • cross-linking curing agent or cross-linking curing catalyst
  • the role of the cross-linking curing agent is to provide a cross-linking active point or reduce the activation energy of the cross-linking reaction of the polymer, so that the polymer can be cured to form a coating film with certain physical and chemical properties, such as amide and carbamate. Acid esters, acids, bases, etc.
  • Wetting agents are used to improve the dispersion efficiency of polymers and improve the uniformity of polymer dispersion. These materials are mostly anionic or non-ionic surfactants, such as TweenSO.
  • Plasticizers are used to improve the mechanical properties of coatings. These materials are mostly linear polymer molecular materials, such as polyethers.
  • the method for preparing the drug-eluting stent disclosed in the present invention includes the following steps:
  • the solvent used in the preparation method of the present invention has the function of dispersing the polymer, active ingredient and additives into a uniform dispersion solution (or emulsion).
  • the solvent should be relatively stable and have the following characteristics: Do not react chemically with polymers, active ingredients and additives; Disperse polymers, active ingredients and additives into solutions (or emulsions); Do not affect the efficacy of active ingredients; and in coatings Easy to come off or escape during curing.
  • the solvents are mainly selected from the following categories: water; alcohols and ketones such as glycerol, isopropanol, acetone, cyclohexanone, methyl ethyl ketone, etc .: esters such as ethyl acetate, butyl acetate, etc .; alkanes such as N-hexane, chloroform, methylene chloride, etc .; aromatic hydrocarbons such as benzene, toluene, etc .; heterocyclic aromatic hydrocarbons such as tetrahydrofuran, etc .; amides such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide, etc. .
  • the dispersion method described in the preparation method of the present invention uses a strong stirring or ultrasonic emulsification dispersion method.
  • the dispersion liquid is uniformly coated on the surface of the stent according to the preparation method of the present invention, and can be used by dip coating or spray coating or a combination of the two methods.
  • the curing of the coating in the preparation method of the present invention can be cured by heat curing or radiation light.
  • the invention also relates to the application of the stent in the interventional treatment of cardiovascular, nerve and peripheral vascular occlusive diseases.
  • the novel stent disclosed in the present invention includes a balloon-expandable stent and a self-expanding stent, which are mainly used for obstruction of coronary arteries, cerebral arteries, carotid arteries, pulmonary arteries, renal arteries or other blood vessels, and diseases of the nervous system.
  • the stent coating disclosed in the present invention is uniformly distributed on the surface of the stent without cracking and peeling; the coating maintains the original morphological structure in the blood at 37 ° C; the original morphological structure is maintained after the stent is expanded; the active ingredient in the coating can prevent the The occurrence of complications or treatment of local lesions and injuries.
  • Figure 1 shows the sustained-release effect of Parylene coating on different molecular weights.
  • Figure 2 shows the controlled release of small molecular weight drugs by different parylene coating thicknesses.
  • Figure 3 shows the results of an in vitro expansion experiment without a stent.
  • Figure 4 shows the results of an in vitro expansion experiment with a bottom stent.
  • ethylene-vinyl alcohol copolymer 0.5 g was added with 10 ml of N, N-dimethylacetamide, dispersed uniformly at 80 ° C, sprayed on the surface of the stent, the stent was placed in a 120 ⁇ vacuum oven, and cured for 2 hours, and the stent was ready for use.
  • Controlled release layer-a method for preparing parylene coatings Controlled release layer-a method for preparing parylene coatings.
  • the controlled-release body disclosed in the present invention is parylene or a derivative thereof.
  • Parylene is a new coating material developed and applied by Union Carbide Co. in the United States in the mid-1960s. It is prepared by para-xylene vacuum vapor deposition. Para-xylene is heated to '950 ° C to produce para-xylene dimer, which is then cracked at 680 ° C to form monomer vapor.
  • the matrix stainless steel scaffold was placed in a room temperature deposition chamber, and monomer vapor was passed into it to form a uniform and dense polymer on the surface of the matrix. The molecular weight of the polymer was estimated to be about 500,000.
  • Parylene is a chemically inert and highly biocompatible high-purity coating material. It has been approved by the US FDA for various types of implants in the body. The device coated by it can improve the surface lubrication and biological phase. Capacitive.
  • the process of monomer cracking is the same as in Example 2. While introducing monomer vapor into the matrix deposition chamber, dust of platelet antagonists (such as Cilostazol, Ticlid, Plavix, etc.) was introduced, thereby forming a dense and dense layer on the surface of the matrix. Controlled release layer with anti-platelet aggregation function.
  • platelet antagonists such as Cilostazol, Ticlid, Plavix, etc.
  • Example 1 Take 0.1 g of ethylene-vinyl acetate copolymer and 0.2 g of polybutyl methacrylate and add 10 ml of isopropanol to disperse uniformly at room temperature, and then add 0.2 g of colchicine to disperse uniformly at room temperature. B ⁇ was coated on the surface of Example 1 Then, the stent is cured at 80 ° C for 2 hours. According to Example 3, a 0.5 micron controlled release layer was applied.
  • Example 3 a 0.05 micron controlled release layer was applied.
  • Example 2 Dissolve 1 part of polybutyl methacrylate and 1 part of ethylene-vinyl acetate copolymer in 100 parts of tetrahydrofuran, and then add 1 part of a small molecular weight drug (such as 10-hydroxycamptothecin). Disperse uniformly at room temperature. Spray on In Example 1, the surface of the stent was dried in a vacuum oven at 30 ° C. According to Example 2, the parylene coating was used to observe the controlled release of small-molecular-weight drugs by different coating thicknesses (eg, 0.05 ⁇ m, 0.1 ⁇ m, 0.2 ⁇ m, 0.4 ⁇ m, and 0.5 ⁇ m) (see Figure 2).
  • a small molecular weight drug such as 10-hydroxycamptothecin
  • Parylene coating can effectively control the slow release of small molecular weight drugs.
  • Example 1 0.20 g of polybutyl methacrylate and 0.20 g of ethylene-vinyl acetate copolymer were added to 10 ml of trichloroacetamidine, mixed and dispersed, and then 0.10 g of paclitaxel was added, dispersed uniformly at room temperature, and then sprayed on in Example 1. Bracket surface. Cured in air for 60min. Repeat the above operation until the drug load reaches 100 pg / cm 2 . The stand was then dried in a vacuum oven. A mixture of parylene and cilostazol was coated on the outside of the drug-loaded layer by vapor deposition according to Example 3 to a thickness of 0.5 ⁇ m.
  • Example 3 a mixture of parylene and Ticlid was coated on the outside of the drug-loaded layer by vapor deposition to a thickness of 0.3 ⁇ m.
  • the drug stent was immersed in 37 ° C physiological saline for 10 minutes, and then the electron microscope was observed.
  • Figure 3 shows the drug-free stent without peeling, and peeling occurs after expansion;
  • Figure 4 shows drug-free stent with peeling, without peeling. -

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Description

一种具有多层涂层的药物洗脱支架 技本领域
本发明涉及医疗器械领域， 具体涉及一种具有多层涂层的药物洗脱支架。
背景技术
动脉血管支架是心血管及外周血管阻塞病变进行介入治疗的主要手段， 自 1986年 Sigwart等在人体放置第一例冠状动脉支架 (PTCA支架)以来， 该技术的应用普及速度 飞快， 目前已占该疾治疗的 80%以上。
但同时该技术的最大缺点是支架后再狭窄的发生， 支架后再狭窄发生率目前为 20 %左右。 产生支架后再狭窄的原因在于血管经支架扩张后造成血管损伤， 从而诱导血 管平滑肌细胞 (VSMC)过度增殖并向内膜迁移， 最终导致血管的再狭窄。
本申请人在中国专利申请 02112242. 3 中公开了一种具有含活性成份涂层的防再 狭窄血管支架， 该支架有效地减少了血管阻塞病人介入治疗后再狭窄的发生率。
发明内容
本发明所要解决的技术问题是在中国专利申请 02112242.3的基础上进一步优化和 改进， 提供一种涂层更为均勾、 牢固、 无开裂、 剥落现象， 同时能防止多种术后并发 症的支架。
本发明所要解决的再一技术问题是公开上述药物支架的制备方法。
本发明所要解决的另一技术问题是公开上述支架在心血管、 神经及外周血管阻塞 病变介入治疗中的应用。
本发明公开的新型支架由支架和覆盖在支架表面的涂层构成， 其特点是在支架的 表面具有 1~4层涂层， 其中至少有两层为载药层； 载药层由重量比为 0.5-99%聚合物， 0~10%添加剂和 0.5-99%活性成分组成。
在载药层与支架之间可具有一底层， 以提高载药层与支架的结合力， 底层由一种 或几种聚合物组成。
在载药层.的表面可再涂覆一层表层，表层可由重量百分比为 0.5-99%聚合物， 0~10 %添加剂和 0-99%活性成分组成。
药物支架起始阶段的爆释现象， 会影响 （延缓）血管的内皮化过程。 为防止药物 在起始阶段的爆释， 更有效的控制释放速度， 本发明在上述涂层外再设置一层致密的 控制释放层。 这种涂层由派瑞林（聚对二甲苯的商品名， Parylene) 或其衍生物、 聚四 氟乙烯 （PTFE) 等， 同时为改善器械的血栓源性， 控制释放层中还包括适量的抗血栓 药物： 如西洛他唑、 噻氯匹定或氯比咯雷等， 其厚度控制在 0.01~20微米之间。
表层中的活性成份可以与载药层中的活性成份相同或不同。 表层可载药也可不载 药， 作为一种释放障碍层用于根据不同病症的需求而调节活性成分的释放速率曲线， 同时可用于防止急、 亚急性血栓的形成等。
本发明所述的各涂层厚度为 0.1— 100微米。
本发明载药涂层中的活性成份选自下述一种或多种药物治疗剂或载体治疗基因： 包括抗凝血剂 (Anti-thrombogenic agents)、 抗癌药物、 微生物免疫抑制剂、 激素以及其 他抗再狭窄药物等。
所述的抗凝血药物选自肝素、阿斯匹林、水蛭素、秋水仙碱、抗血小板 GPIIb / ma 受体结抗剂， 如替罗非班 (tirofiban)、 阿昔单抗、 eptifibatide, 西洛他唑 （ Cilostazol )， 噻氯吡啶， 硫酸氯吡格雷等；
所述的抗癌药物选白甲氨蝶吟， 嘌吟类、 嘧啶类、 植物碱类 (特别是紫杉醇 (Taxol) 和埃坡破霉素 (Epothilone)类、 雷公藤系列化合物、 抗生素 (特别是放线菌素 -D)、 激素、 抗体治癌药物 (antibody)等：
所述的微生物免疫抑制剂选自环孢霉素 A(ciclosporinA， CsA)， FK506(及同系物)， DSG(15-deoxyspergualin, 15-dos), MMF, 雷帕霉素 (Rapamycin)及其衍生物， CCI-779, FR 900520 , FR 900523 , NK86-1086, daclizumab , depsidomycin, kanglemycinC , spergualin , prodigiosin25- c， cammunomicin , demethomycin , tetranactl , tranilast , stevastelins, myriocin, gllooxin, FR 651814， SDZ214-104, 环抱霉素 C， bredinin, 麦 考酚酸， 布雷菲德菌素 A， WS9482, 糖皮质类固醇等；
所述的其他抗再狭窄的药物选自 batimaStat、 金属蛋白抑制剂 (特别是 MMP抑制 齐 !j)、 17 β -雌二醇、 NO供体、 2-chlorodeoxyadenosine、 2-deoxycoformycin、 . FTY720、 Myfortic、 ISA(TX)247、 AGI—1096、 OKT3、 Medimmune, ATG、 Zenapax、 Simulect、 DAB486-IL-2、 Anti-ICAM- Thymoglobulin、 Enverolimus、 NeoraK Azathipprine(AZA)、 Cyclophosphamide、 Methotrexate、 Brequinar Sodium、 Leflunomide、 Mizoribine等； 所述的载体治疗基因选自： 由细胞、 病毒、 质粒、 髙分子材料及其他载体介导的 Keratin 8基因、 VEGF基因、 EGF基因、 PTEN、尿激酶前体基因、一氧化氮合酶 (NOS) 基因和反义 C-myc基因等。
药物治疗剂和载体治疗基因， 通过抑制血管平滑肌细胞 (VSMC)的过度增殖， 或者 促进血管内皮细胞的生长， 或者阻止血管平滑肌细胞的迁移， 或者抑制血管平滑肌细 胞外基质过度增生， 达到防止血管冉狭窄的门的。
本发明所述的聚合物选白丙交酯、 乙交酯、 ε _己内酯的均聚物和两者之间或三者 的共聚物、 纤维素类、 聚乙烯吡咯酮、 聚乙烯醇、 阿拉伯胶、 西黄蓍胶、 海藻酸钠、 白明胶、 聚甲基丙烯酸甲酯、 聚甲基丙稀酸丁酯、 乙烯-乙烯醇共聚物、 乙烯一醋酸乙 烯共聚物以及上述聚合物的混合物。 本发明所述的添加剂选自聚合物交联固化剂 (固化催化剂)、 润湿分散剂及增塑剂 等。
交联固化剂 (或交联固化催化剂)的作用在于提供交联活性点或降低聚合物产生交 联反应的活化能， 使聚合物产生固化生成具有一定物化性能的涂膜， 如酰胺、 氨基甲 酸酯、 酸、 碱等。
润湿剂 (Wetting agent)用于提高聚合物的分散效率， 使聚合物分散的均匀性得到提 高。 该类材料多为阴离子型或非离子型表面活性剂， 如 TweenSO等。
增塑剂 ( asticizer)用于改善涂层的力学性能， 该类物质多为线形聚合物分子材料， 如聚醚等。
本发明公开的药物洗脱支架的制备方法包括如下步骤：
按上述支架涂层处方加入处方总量 2~1000倍溶剂， 置于容器中分散； 将分散液均 匀涂覆于支架表面， 再将带有涂层的支架放于真空干燥箱中， 在 20-20(TC干燥 0.5-72 小时固化； 支架可多次重复上述过程或重复涂覆不同组成的分散液。
然后再采用真空气相沉积制备， 将对二甲苯涂布于药物涂层表面。
本发明所述的制备方法中所用的溶剂， 其作用是将聚合物、 活性成分和添加剂分 散为均一的分散溶液 (或乳液)。 溶剂应相对稳定， 具有如下特点： 不与聚合物、 活性 成分和添加剂发生化学反应； 可将聚合物、 活性成分和添加剂分散为溶液 (或乳液)； 不影响活性成分的疗效； 并在涂层固化时易于脱出或逃逸等。 所述的溶剂主要选自以 下几类： 水； 醇酮类如丙三醇、 异丙醇、 丙酮、 环己酮、 丁酮等： 酯类如醋酸乙酯、 醋酸丁酯等； 烷烃类如正己垸、 氯仿、 二氯甲垸等； 芳烃类如苯、 甲苯等； 杂环芳烃 类如四氢呋喃等； 酰胺类如 Ν,Ν-二甲基甲酰胺、 Ν,Ν-二甲基乙酰胺等。
本发明的制备方法所述的分散方法叮采用强力搅拌或超声乳化分散法。
本发明的制备方法所述的将分散液均匀涂覆于支架表面， 可采用浸涂或喷涂或两 种方法的结合使用。
本发明的制备方法中所述的涂层固化可采用热固化或辐射光固化。
本发明还涉及上述支架在心血管、 神经及外周血管阻塞病变介入治疗中的应用。 本发明公开的新型支架包括球囊扩张支架和自扩张支架， 它们主要要用于冠状动 脉、 脑动脉、 颈动脉、 肺动脉、 肾动脉或其他血管的阻塞以及神经系统的病变。
本发明公开的支架涂层在支架表面分布均匀， 无开裂、 剥落现象； 涂层在 37°C 血液中保持原形态结构； 在支架扩张后保持原形态结构； 通过涂层中的活性成分能防 止并发症的发生或治疗局部的病变、 损伤。
附图说明
图 1为派瑞林涂层对不同分子量的缓释效果。 图 2为不同派瑞林涂层厚度对小分子量药物的控制释放。
图 3为无底层支架体外扩张实验结果。
图 4为有底层支架体外扩张实验结果。
具体实施方式
实施例 1
支架底层处理方法。
0.5g乙烯 -乙烯醇共聚物加入 10mlN,N-二甲基乙酰胺， 在 80°C条件下分散均匀， 喷涂于支架表面， 将支架置于 120Ό真空烘箱中， 固化 2小时， 支架待用。
实施例 2
控制释放层一一派瑞林涂层的制备方法。
本发明公开的控制释放体是派瑞林或其衍生物， 派瑞林是六十年代中期美国 Union Carbide Co. 开发应用的一种新型涂敷材料， 由对二甲苯真空气相沉积制备， 首先将对 二甲苯加热至 ' 950°C， 生成对二甲苯二聚体， 然后在 680°C下裂解， 形成单体蒸汽。 将 基质不锈钢支架放在室温沉积室内， 通入单体蒸汽， 在基质表面形成一层均匀致密的聚 合物， 聚合物的分子量估计在 500,000左右。
派瑞林是一种化学惰性又具有良好生物相容性的高纯涂层材料， 已经通过美国 FDA 认可， 用于各类体内植入， 经它涂敷的器械可改善表面润滑型、 生物相容性。
实施例 3
具有抗血小板聚集功能的控制释放层的制备方法。
单体裂解等过程同实施例 2， 在向基质沉积室通入单体蒸汽的同时， 通入血小板拮 抗剂 （如 Cilostazol, Ticlid, Plavix等）粉尘， 从而在基质表面形成一层均勾致密的具 有抗血小板聚集功能的控制释放层。
实施例 4
0.2g聚甲基丙烯酸丁酯加入 10ml混合溶剂 (N，N-二甲基乙酰胺：乙酸乙酯 = 1:4)， 室温分散均匀， 再加入 0.2g雷帕霉素 （Rapamycin), 室温分散均匀， 喷涂于实施例 1 支架表面， 将支架置于 40 °C真空烘箱中， 固化 2小时。 根据实施例 2， 再涂覆 0.2微 米的控制释放层。
实施例 5
取 O.lg乙烯 -醋酸乙烯共聚物和 0.2g聚甲基丙烯酸丁酯加入 10ml异丙醇， 室温分 散均匀， 再加入 0.2g秋水仙碱， 室温分散均匀， B贲涂于实施例 1 支架表面， 再将支架 于 80°C固化 2小时。 根据实施例 3， 再涂覆 0.5微米的控制释放层。
实施例 6
0.3g丙交酯 -ε-己内酯共聚物加入 5ml氯仿， 混合分散均匀， 再加入 O.lg放线菌素 -D， 室温条件下分散均匀， 然后将支架浸入分散液中 1-30分钟， 再将支架取出于 60 °C真空烘箱中固化 2小时。 根据实施例 3， 再涂覆 0.05微米的控制释放层。
实施例 7
将 1份聚乳酸、 1份聚己内酯溶解于 100份氯仿中， 再加入 1份小分子量药物 （如 Cilostazol)和 1 份大分子量药物（如 Rapamycin), 室温条件下分散均匀， 喷涂于支架 表面， 在 30°C真空烘箱中烘干。 根据实施例 2涂覆上派瑞林涂层， 观察派瑞林涂层对 不同分子量的缓释效果 （见图 1 )。 结果表明： 在派瑞林涂层厚度相同的情况下， 不同 分子量的药物其释放速度不同， 分子量越大， 释放越缓慢。 且随着涂层厚度的增加， 其 释放速度变慢。
实施例 8
将 1份聚甲基丙烯酸丁酯、 1份乙烯一醋酸乙烯共聚物溶解于 100份四氢呋喃中， 再加入 1份小分子量药物 （如 10—羟基喜树碱)， 室温条件下分散均匀， 喷涂于实施例 1支架表面， 在 30°C真空烘箱中烘干。 根据实施例 2， 用派瑞林涂层处理， 观察不同的 涂层厚度 （如 0.05微米， 0.1微米， 0.2微米， 0.4微米， 0.5微米）对小分子量药物的 控制释放 （见图 2)。 结果表明： 派瑞林涂层能够有效地控制小分子量药物的缓慢释放。 涂层越厚， 空隙越少， 药物释放速度越慢， 即可以通过控制派瑞林涂层的厚度来达到预 期药物释放速度的目的。
实施例 9
将 2份丙交酯己内酯共聚物溶解于 100份氯仿溶液中，再加入 2份小分子量药物（如 FTY720), 喷涂于实施例 1支架的表面， 30Ό真空烘干后， 用派瑞林气相沉积聚合处理。 体外释放实验表明，用派瑞林处理的药物支架与对照组支架（没有用派瑞林处理的支架) 相比， 释放速度得到良好的控制， 可以达到药物长期缓释治疗的目的。
实施例 10
将 2份聚甲基丙烯酸丁酯溶解于 100份乙酸正丁酯中， 再加入 1份小分子量药物 (Epo-D), 室温条件下分散均勾， 喷涂于实施例 1支架表面， 在 30°C真空烘箱中烘干。 然后， 用派瑞林涂层处理。 结果表明： 派瑞林涂层能够有效地控制小分子量药物的缓慢 释放。 释放时间可以从 1天到 90天。
实施例 11
将 2份丙交酯己内酯共聚物溶解于 100份氯仿溶液中，再加入 2份小分子量药物（如 雷公藤）， 喷涂于经实施例 1 处理的颅内支架的表面， 30°C真空烘千后， 用派瑞林气相 沉积聚合处理。 体外释放实验表明， 用派瑞林处理的药物支架与对照组支架（没有用派 瑞林处理的支架）相比， 释放速度得到良好的控制， 可以达到药物长期缓释治疗的目的。
在植入患有胶质瘤动物模型的颅内动脉后， 能有效抑制直至胶质瘤消亡。 实施例 12
将 0.20g聚甲基丙烯酸丁酯和 0.20g乙烯-醋酸乙烯共聚物加入到 10ml三氯乙烷 中， 混合分散均匀， 再加入 0.10g紫杉醇及 0.20g西洛他唑， 室温条件下分散均匀， 然后喷涂于实施例 1支架表面。 空气中固化 60min。 重复上述操作直到载药量达到 300 W g/cm2。 再将支架置于真空烘箱中干燥。 根据实施例 2在载药层的外面通过气相沉积 涂覆派瑞林， 厚度为 0.1 μ ιη。
实施例 13
将 0.20g聚甲基丙烯酸丁酯和 0.20g乙烯-醋酸乙烯共聚物加入到 10ml三氯乙垸 中， 混合分散均勾， 再加入 0.10g紫杉醇， 室温条件下分散均匀， 然后喷涂于实施例 1 支架表面。 空气中固化 60min。 重复上述操作直到载药量达到 100 p g/cm2。 再将支 架置于真空烘箱中干燥。 根据实施例 3 在载药层的外面通过气相沉积涂覆派瑞林与西 洛他唑的混合物， 厚度为 0.5 μ m。
实施例 14
0.2g聚甲基丙烯酸丁酯加入 10ml N,N-二甲基甲酰胺， 混合分散均勾， 再加入 0.18 埃坡破霉素 -D， 室温条件下分散均勾。 将分散液喷涂于实施例 1 支架表面， 再将支架 置于 40~C真空烘箱中， 固化 2 4小时。 根据实施例 3在载药层的外面通过气相沉积涂 覆派瑞林与 Ticlid的混合物， 厚度为 0.3 μ m。
实施例 15~16
先将药物支架浸泡于 37°C生理盐水中 10分钟， 再撑开电镜观察。
图 3为无底层药物支架， 撑开后出现剥落； 图 4为有底层药物支架， 撑开后无剥 落。 -

Claims

权利要求书
1.一种具有多层涂层的药物洗脱支架， 其特征在于， 由支架和覆盖在支架表面的 1~4层涂层构成， 其中至少有两层为载药层； 载药层由重量比为 0.5-99%聚合物， 0~10 %添加剂和 0.5-99%活性成分组成。
2. 根据权利要求 1所述的药物洗脱支架， 其特征在于， 在载药层与支架之间具有 一底层， 底层由一种或几种聚合物组成。
3. 根据权利要求 2所述的药物洗脱支架， 其特征在于， 在载药层的表面可涂覆一 层表层， 表层由重量百分比为 0.5-99%聚合物， 0~10%添加剂和 0-99%活性成分组成。
4.根据权利要求 2所述的药物洗脱支架， 其特征在于， 在上述涂层外再设置一层 致密的控制释放层， 由派瑞林及其衍生物或聚四氟乙烯构成。
5. 根据权利要求 4所述的药物洗脱支架， 其特征在于， 控制释放层含有抗血栓药 物。
6. 根据权利要求 4所述的药物洗脱支架， 其特征在于， 控制释放层厚度为 0.01~20 微米。
7.根据权利要求 1所述的药物洗脱支架， 其特征在于， 在上述涂层外再设置一层 致密的控制释放层， 由派瑞林及其衍生物或聚四氟乙烯构成。
8.根据权利要求 7所述的药物洗脱支架， 其特征在于， 控制释放层含有抗血栓药 物。
9.根据衩利要求 7所述的药物洗脱支架， 其特征在于，控制释放层厚度为 0.01~20 微米。
10.根据权利要求 2所述的药物洗脱支架， 其特征在于， 表层中的活性成份可以 与载药层中的活性成份相同或不同。
11.根据权利要求 1所述的药物洗脱支架， 其特征在于， 所述的各涂层厚度为 0.1 一 100微米。
12.根据权利要求 1~11任一项所述的药物洗脱支架， 其特征在于， 载药涂层中的 活性成份选自一种或多种药物治疗剂或载体治疗基因：包括抗凝血剂 (Anti-thrombogenic agents), 抗癌药物、 微生物免疫抑制剂、 激素以及其他抗再狭窄药物。
13.根据权利要求 12所述的药物洗脱支架， 其特征在于， 所述的抗凝血药物选自 肝素、 阿斯匹林、 水蛭素、 秋水仙碱或抗血小板 GPIIb / nia受体结抗剂。
14.根据权利要求 12所述的药物洗脱支架， 其特征在于， 抗血小板 GPIIb / HIa 受体结抗剂包括替罗非班 (tirofiban；)、 阿昔单抗、 eptifibatide、 西洛他唑 （Cilostazol)、 噻氯吡啶或硫酸氯吡格雷。
15. 根据权利要求 12所述的药物洗脱支架， 其特征在于， 所述的抗癌药物选白甲 氨蝶吟， 嘌吟类、 嘧啶类、 植物碱类、 雷公藤系列化合物、 抗生素、 激素或抗体治癌 药物 (antibody)。
16. 根据权利要求 15所述的药物洗脱支架， 其特征在于， 抗生素选自放线菌素 -D， 植物碱类选自紫杉醇或埃坡破霉素。
17.根据权利要求 12所述的药物洗脱支架， 其特征在于， 所述的微生物免疫抑制 剂选自环孢霉素 A(ciclosporinA， CsA), FK506及同系物， DSG(15-deoxyspergualin， 15-dos), MMF, 雷帕霉素 (Rapamycin)及其衍生物， CCI-779, FR 900520， FR 900523, 86-1086, daclizumab, depsidomycin, kanglemycinC, spergualin, prodigiosin25- c, cammunomicin, demethomycin, tetranactln, tranilast, stevastelins, myriocin, gllooxin, FR 651814， SDZ214-104, 环抱霉素 C， bredinin,麦考酚酸， 布雷菲德菌素 A， WS9482 或糖皮质类固醇。
18.根据权利要求 12所述的药物洗脱支架， 其特征在于， 所述的其他抗再狭窄的 药物选自 batimastat、金属蛋白抑制剂、 17 β -雌二醇、 NO供体、 2-chlorodeoxyadenosine、 2-deoxycoformycin> FTY720、 Myfortic、 ISA(TX)247、 AGI— 1096、 OKT3、 Medimmune、 ATG、 Zenapax、 Simulect、 DAB486-IL-2、 Anti-ICAM-K Thymoglobulin Enverolimus、 Neoral、 Azathipprine(AZA)、 Cyclophosphamide、 Methotrexate、 Brequinar Sodium或 Leflunomide、 Mizoribine。
19.根据权利要求 18所述的药物洗脱支架，其特征在于，金属蛋白抑制剂包括 MMP 抑制剂。
20.根据权利要求 12所述的药物洗脱支架， 其特征在于， 所述的载体治疗基因选 自由细胞、 病毒、 质粒、 高分子材料及其他载体介导的 Keratin 8基因、 VEGF基因、 EGF基因、 PTEN、 尿激酶前体基因、 一氧化氮合酶 (NOS)基因或反义 C-myc基因。
21. 根据权利要求 12所述的药物洗脱支架， 其特征在于， 聚合物选白丙交酯、 乙 交酯、 ε -己内酯的均聚物和两者之间或三者的共聚物、 纤维素类、 聚乙烯吡咯酮、 聚 乙烯醇、 阿拉伯胶、 西黄蓍胶、 海藻酸钠、 白明胶、 聚甲基丙烯酸甲酯、 聚甲基丙稀 酸丁酯、 乙熾' -乙烯醇共聚物、 乙烯一醋酸乙烯共聚物以及上述聚合物的混合物。
22.根据权利要求 12所述的药物洗脱支架， 其特征在于， 添加剂选自聚合物交联 固化剂、 润湿分散剂及增塑剂。
23. 根据权利要求 22所述的药物洗脱支架， 其特征在于， 交联固化剂包括酰胺、 氨基甲酸酯、 酸或碱。
24.根据权利要求 22所述的药物洗脱支架， 其特征在于， 润湿剂为阴离子型或非 离子型表面活性剂。
25.根据权利要求 22所述的药物洗脱支架， 其特征在于， 增塑剂为线形聚合物分 子材料。
26.根据权利要求 1~25任一项所述的药物洗脱支架的制备方法， 其特征在于， 包 括如下步骤：
将药物溶解于溶剂， 分散； 将分散液均匀涂覆于支架表面， 干燥， 固化。
27.根据权利要求 26所述的药物洗脱支架， 其特征在于， 采用真空气相沉积， 将 对二甲苯涂布于药物涂层表面。
28.根据权利要求 26所述的药物洗脱支架， 其特征在于， 溶剂选自水、 醇酮类、 酯类、 垸烃类、 芳烃类、 杂环芳烃类或酰胺类化合物。
29.权利要求 1~25任一项所述的支架在心血管、 神经及外周血管阻塞病变介入治 疗中的应用。
30.权利要求 1~25任一项所述的支架， 其特征在于包括球囊扩张支架和自扩张支 架。
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CN 02146905 CN100471469C (zh) 2002-06-27 2002-10-24 一种具有多层涂层的药物洗脱支架
CNB021551383A CN1306917C (zh) 2002-12-17 2002-12-17 一种通过复合作用机理预防/治疗血管内再狭窄的支架
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CNB031155960A CN100435880C (zh) 2003-02-28 2003-02-28 一种药物洗脱介入医疗器械及其制备方法
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CN105251062A (zh) * 2005-10-27 2016-01-20 科迪斯公司 局部给药雷帕霉素和西洛他唑的组合用于治疗血管疾病

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AU2003280437A1 (en) 2004-01-19
EP1516597A1 (en) 2005-03-23

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