WO2013044605A1 - 一种介入医疗器械及其制备方法 - Google Patents

一种介入医疗器械及其制备方法 Download PDF

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Publication number
WO2013044605A1
WO2013044605A1 PCT/CN2012/070455 CN2012070455W WO2013044605A1 WO 2013044605 A1 WO2013044605 A1 WO 2013044605A1 CN 2012070455 W CN2012070455 W CN 2012070455W WO 2013044605 A1 WO2013044605 A1 WO 2013044605A1
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WIPO (PCT)
Prior art keywords
stent
drug
medical device
stent body
interventional medical
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Application number
PCT/CN2012/070455
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English (en)
French (fr)
Inventor
蔡煦
张大东
胡燕
黄鹏
李俊菲
乐承筠
唐智荣
罗七一
Original Assignee
上海微创医疗器械（集团）有限公司
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Application filed by 上海微创医疗器械（集团）有限公司 filed Critical 上海微创医疗器械（集团）有限公司
Priority to US14/348,815 priority Critical patent/US20150004207A1/en
Priority to IN2580CHN2014 priority patent/IN2014CN02580A/en
Priority to BR112014007585A priority patent/BR112014007585A2/pt
Priority to JP2014532220A priority patent/JP2014531933A/ja
Priority to EP12837098.8A priority patent/EP2762111A4/en
Publication of WO2013044605A1 publication Critical patent/WO2013044605A1/zh

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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
    • 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
    • A61L31/146—Porous materials, e.g. foams or sponges
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05B—SPRAYING APPARATUS; ATOMISING APPARATUS; NOZZLES
    • B05B17/00—Apparatus for spraying or atomising liquids or other fluent materials, not covered by the preceding groups
    • B05B17/04—Apparatus for spraying or atomising liquids or other fluent materials, not covered by the preceding groups operating with special methods
    • B05B17/06—Apparatus for spraying or atomising liquids or other fluent materials, not covered by the preceding groups operating with special methods using ultrasonic or other kinds of vibrations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00—Processes for applying liquids or other fluent materials
    • B05D1/02—Processes for applying liquids or other fluent materials performed by spraying
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
    • B05D1/00—Processes for applying liquids or other fluent materials
    • B05D1/18—Processes for applying liquids or other fluent materials performed by dipping
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • 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
    • A61F2/0077—Special surfaces of prostheses, e.g. for improving ingrowth
    • A61F2002/0086—Special surfaces of prostheses, e.g. for improving ingrowth for preferentially controlling or promoting the growth of specific types of cells or tissues
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/06—Coatings containing a mixture of two or more compounds

Definitions

  • the present application relates to the field of medical device technology, and in particular to an interventional medical device containing a drug and a preparation method thereof.
  • Background technique
  • a drug-coated coating is applied to the stent implanted in the human body.
  • Most of the drug stents currently used are drugs that inhibit the intimal or mesenteric proliferation, such as: rapamycin, paclitaxel, and derivatives thereof.
  • the stent carrying the above drugs is implanted into the human body, the stent will be Drugs that inhibit the intimal or medial hyperplasia are continuously released to the vessel wall to reduce the incidence of in-stent restenosis.
  • intravascular restenosis is not only related to intimal or mesenteric hyperplasia after vascular injury, but also related to vascular remodeling, and vascular remodeling is the main factor in the formation of in-stent restenosis, which may account for restenosis. Seventy percent of the causes, and endocardial or medial hyperplasia accounted for only 30% of the possible causes of restenosis.
  • intimal or medial hyperplasia are not able to minimize the incidence of in-stent restenosis.
  • inhibition of intimal or medial hyperplasia can also cause problems with delayed endothelialization, whereas incomplete endothelialization of blood vessels may cause late thrombosis.
  • the embodiments of the present application provide an interventional medical device and a preparation method thereof, which can reduce the proliferation of the outer membrane fibroblasts, promote the compensatory expansion of the blood vessels, and reduce the incidence of in-stent restenosis. .
  • An interventional medical device comprises: a stent body, a surface of the stent body is provided with a drug releasing structure, and the drug in the drug releasing structure is a drug for inhibiting proliferation of outer membrane fibroblasts.
  • the drug release structure is a high molecular polymer and inhibits proliferation of outer membrane fibroblasts The dense mixed layer formed by the drug.
  • the high molecular polymer comprises: polylactic acid, polyethylene glycol, styrene butene copolymer, polycaprolactone, polybutyl methacrylate, polyethyl methacrylate, ethyl acetate ethyl acetate , polyurethane, polyvinylpyrrolidone, poly-tartrate, silk fibroin, gelatin, chitin and/or hyaluronic acid.
  • the drug release structure is a microporous coating structure formed on the surface of the stent body or formed on the surface of the stent body, and is contained in the ⁇ : pore structure or the microporous coating structure. Into the drug.
  • the drug for inhibiting proliferation of outer membrane fibroblasts comprises tanshinone, asiaticoside, centella asiatica, and chuanxiong. At least one of Qin, hemodin, sulvastatin, and angiotensin.
  • the stent body comprises: a coronary artery stent, an intracranial vascular stent, a peripheral vascular stent, an intraoperative stent, a heart valve stent, a biliary stent, an esophageal stent, an intestinal stent, a pancreatic duct stent, a urethral stent or a tracheal stent. .
  • a method of preparing an interventional medical device comprising:
  • the interventional medical device is obtained by drying the stent body.
  • the microporous structure is prepared on the surface of the stent body, specifically:
  • Micropores are formed on the surface of the stent body by anodization, micro-arc oxidation, and/or chemical etching.
  • the microporous structure is prepared on the surface of the stent body, specifically:
  • a coating having micropores is prepared on the surface of the stent body.
  • the drug in the formulated solution is loaded into the microporous structure, specifically: loading the drug in the solution into the opening by ultrasonic spraying, air spraying and/or dip coating Or in a coating with micropores.
  • a method of preparing an interventional medical device comprising:
  • the interventional medical device is obtained by drying the stent body.
  • the coating comprises: ultrasonic spraying, air spraying, and/or dip coating.
  • the drug carried on the outer membrane fibroblast proliferation can be slowly released into the blood vessel wall cells in contact with the stent body, and further It can inhibit the proliferation of adventitial fibroblasts, inhibit the proliferation of fibroblasts, and play a role in vascular remodeling, which is beneficial to the compensatory expansion of damaged vessels, thereby reducing the incidence of in-stent restenosis.
  • the interventional medical device compared with the existing drug stents using rapamycin, paclitaxel and its derivatives, the interventional medical device provided by the embodiments of the present application not only has a lower inhibition rate on endothelial cells, but also promotes endothelial cells. Growing, speeding up the process of endothelialization.
  • FIG. 1 is a schematic structural view of a specific embodiment of an interventional medical device provided by the present application
  • FIG. 2 is a statistical diagram of the inhibition rate of asiaticoside, paclitaxel and rapamycin on human umbilical vein endothelial cells HUVEC provided by the present application;
  • FIG. 3 is a schematic structural view of another embodiment of the interventional medical device provided by the present application
  • FIG. 4 is a schematic structural view of another embodiment of the interventional medical device provided by the present application; a process flow of a preparation method
  • FIG. 6 is another process flow of the method for preparing an interventional medical device provided by the present application
  • FIG. 7 is still another process flow of the method for preparing an interventional medical device provided by the present application.
  • An embodiment of the present application provides an interventional medical device, comprising: a stent body, wherein: a drug dry release structure is disposed on a surface of the stent body, and the drug in the drug front-release structure is for inhibiting the outer membrane fiber formation and proliferation drug.
  • FIG. 1 is a schematic structural view of a specific embodiment of an interventional medical device provided by the present application.
  • 1 is a stent body
  • 2 is a drug release coating
  • a drug release coating 2 is coated on the outer surface of the stent body 1, wherein:
  • the stent body 1 may be a coronary stent, an intracranial stent, a peripheral vascular stent, an intraoperative stent, a heart valve stent, a biliary stent, an esophageal stent, an intestinal stent, a pancreatic duct stent, a urethral stent, or a tracheal stent.
  • the material of the stent body 1 may be stainless steel, a cobalt-based alloy, a nickel-based alloy, a titanium alloy, a degradable magnesium alloy or a polymer material having good biocompatibility and mechanical properties.
  • the drug release coating 2 is a dense mixed layer formed of a high molecular polymer and a drug for inhibiting the proliferation of the outer membrane fibroblasts, that is, the drug release coating 2 as a carrier, so that the surface of the stent body 1 carries the outer membrane fiber.
  • the drug for inhibiting the proliferation of the outer membrane fibroblasts includes at least one of tanshinone, asiaticoside, hydroxysalicum, ligustrazine, scutellarin, sulvastatin, angiotensin, in the present application, Preferred is asiaticoside.
  • the high molecular polymer in the drug front coating layer 2 may be a high molecular polymer having biocompatibility and controlled release properties, such as polylactic acid, polyethylene glycol, styrene butene copolymer, polyhexene. Ester, polybutyl methacrylate, polyethyl methacrylate, ethyl acetate ethyl acetate, polyurethane, polyvinylpyrrolidone, polycholine, silk fibroin, gelatin, chitin and/or hyaluronic acid.
  • biocompatibility and controlled release properties such as polylactic acid, polyethylene glycol, styrene butene copolymer, polyhexene. Ester, polybutyl methacrylate, polyethyl methacrylate, ethyl acetate ethyl acetate, polyurethane, polyvinylpyrrolidone, polycholine, silk fibroin, gelatin,
  • Centella asiatica is a total extract of Centella asiatica, which can inhibit the pathological action of TGF- ⁇ and inhibit the proliferation of fibroblasts by increasing the expression of Smad7, which inhibits Smad transduction. It plays a role in vascular remodeling, which is beneficial to the compensatory expansion of damaged blood vessels, thereby inhibiting restenosis.
  • HUVEC Human Umbilical Vein Endothelial Cells
  • Figure 2 is a statistical diagram of the inhibition rate of asiaticoside, paclitaxel and rapamycin on HUVEC provided by the present application.
  • asiaticoside HUVEC inhibition rate was lower than the drug paclitaxel and rapamycin, and the concentration in the range of 10- 12 ⁇ 10- 9 M, asiaticoside almost no HUVEC Inhibition.
  • asiaticoside also has the effect of promoting endothelial cell growth and accelerating the endothelialization process.
  • PCI classification number R541.4 article number: 1671-8259 (2005) 05-0477-03.
  • the interventional medical device not only has a lower inhibition rate on endothelial cells, but also promotes endothelium compared with the existing drug stents using rapamycin, paclitaxel and its derivatives. The growth of cells accelerates the process of endothelialization.
  • FIG. 3 is a schematic structural view of another embodiment of the interventional medical device provided by the present application.
  • 1 is a stent body
  • 3 is a micropore formed on the surface of the stent.
  • the drug dry release structure is a hole 3, and the ⁇ : hole 3 can be obtained by oxidizing or etching the surface of the stent body 1.
  • the micropores 3 may be loaded with a drug for inhibiting the proliferation of the outer membrane fibroblasts, so that the surface of the stent body 1 carries a drug which inhibits the proliferation of the outer membrane fibroblasts.
  • FIG. 4 is a schematic structural view of still another embodiment of the interventional medical device provided by the present application.
  • the micropores 3 are obtained by directly oxidizing or etching the surface of the stent body 1.
  • a microporous layer may be prepared on the surface of the stent body 1.
  • Coating, as shown in Figure 3, 1 is the stent body, 4 is a microporous coating.
  • FIG. 5 is a process flow of a method for preparing an interventional medical device provided by the present application.
  • the stent body is exemplified by a metal stent
  • the preparation method of the interventional medical device includes:
  • Step S101 Cleaning the stent body and drying.
  • Step S102 preparing micropores on the surface of the stent body.
  • Electroporation and/or chemical etching are used to form micropores on the surface of the stent body, wherein electro-chemical corrosion includes anodization, micro-arc oxidation, and the like. Through this step, micropores can be formed on the surface of the stent body, and a schematic structural view thereof is shown in FIG.
  • Step S103 A solution containing a drug that inhibits proliferation of outer membrane fibroblasts is prepared.
  • the drug for inhibiting the proliferation of the outer membrane fibroblast is preferably asiaticoside, and 50 mg of asiaticoside is dissolved in 10 ml of an ethanol solution at the time of preparation, and uniformly mixed.
  • Step S104 Loading the drug in the prepared solution into the microwell of the stent body.
  • the stent body having the surface microporous obtained in step S102 is immersed in the solution prepared in the step S103, so that the drug in the solution can be loaded in the micropores on the surface of the stent body.
  • Step S105 drying the stent body to obtain an interventional medical device.
  • FIG. 6 is another process flow of the method for preparing an interventional medical device provided by the present application.
  • the method for preparing the interventional medical device includes: Step S201: Cleaning the stent body and drying.
  • Step S202 preparing a coating having micropores on the surface of the stent body.
  • the specific operation procedure is as follows: the silk fibroin solution is covered on the surface of the stent body, denatured by heat or chemical reagent, and then infiltrated with pure water, then frozen and warmed to dry, and a coating having a microporous structure is formed on the surface of the stent body.
  • Floor the surface of the stent body.
  • Step S203 A solution containing a drug for inhibiting proliferation of outer membrane fibroblasts is prepared.
  • the drug for inhibiting the proliferation of the outer membrane fibroblast is preferably asiaticoside, and 50 mg of asiaticoside is dissolved in 10 ml of an ethanol solution at the time of preparation, and uniformly mixed.
  • Step S204 The drug in the formulated solution is loaded into the micropores of the coating on the surface of the stent body.
  • the stent body having the microporous coating on the surface obtained in the step S202 is immersed in the prepared solution so that the drug in the solution can be loaded in the micropores of the surface coating of the stent body.
  • Step S205 drying the stent body to obtain an interventional medical device.
  • Figure ⁇ is a further process flow of the method for preparing an interventional medical device provided by the present application.
  • the method for preparing the interventional medical device includes: Step S301: Cleaning the stent body and drying.
  • Step S302 preparing a mixed solution of a drug and a high molecular polymer which inhibit proliferation of outer membrane fibroblasts.
  • the high molecular polymer is selected to be polylactic acid
  • the drug for inhibiting the proliferation of fibroblasts is preferably asiaticoside.
  • a solution of polylactic acid and asiaticoside in a ratio of 1:1 to 1:4 was prepared. For example: Add 10 mg of asiaticoside and 20 mg of polylactic acid to 10 ml of tetrahydrofuran, dissolve well, and mix well.
  • Step S303 The mixed solution is coated on the surface of the stent body.
  • the mixed solution prepared in the step 302 may be applied to the stent body by ultrasonic spraying, air spraying or dip coating.
  • Step S304 drying the stent body to obtain an interventional medical device.

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  • Vascular Medicine (AREA)
  • Epidemiology (AREA)
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  • Heart & Thoracic Surgery (AREA)
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Abstract

一种介入医疗器械及其制备方法，该介入医疗器械包括：支架本体（1），所述支架本体（1）的表面设置有药物释放结构，所述药物释放结构中的药物为抑制外膜成纤维细胞增殖的药物。该介入医疗器械在使用时，当植入到人体后，其上携带的抑制外膜成纤维细胞增殖的药物可以缓慢释放到与支架本体（1）相接触的血管壁细胞中，进而可以抑制外膜成纤维细胞的增殖，促进血管的代偿性扩张，降低了支架内再狭窄的发生率。

Description

一种介入医疗器械及其制备方法
技术领域
本申请涉及医疗器械技术领域， 特别是涉及一种含有药物的介入医疗器 械及其制备方法。 背景技术
近年来， 为了避免介入治疗后支架内再狭窄的发生， 在植入人体的支架 上会涂覆有药物涂层。 目前应用的药物支架大多携带的药物为抑制血管内膜 或中膜增生的药物， 例如： 雷帕霉素、 紫杉醇及其衍生物等， 当携带有上述 药物的支架植入人体后， 支架就会持续向血管壁释放抑制血管内膜或中膜增 生的药物， 以降低支架内再狭窄的发生率。
研究表明， 血管内再狭窄的形成机制不仅与血管损伤后内膜或中膜增生 有关， 而且还与血管重构有关， 并且血管重构是支架内再狭窄形成的主要因 素， 约占再狭窄可能原因的七成， 而血管内膜或中膜增生仅占再狹窄可能原 因的三成。
因此现有的抑制内膜或中膜增生的药物支架无法最大程度低降低支架内 再狭窄的发生率。 另外， 抑制血管内膜或中膜增生还会带来血管内皮化延迟 的问题， 而血管不能完全内皮化则可能会引起晚期血栓。
发明内容
有鉴于此， 本申请实施例提供一种介入医疗器械及其制备方法， 该介入 医疗器械通过抑制外膜成纤维细胞的增殖， 促进血管的代偿性扩张， 以降低 支架内再狹窄的发生率。
为了实现上述目的， 本申请实施例提供的技术方案如下：
一种介入医疗器械， 包括： 支架本体， 所述支架本体的表面设置有药物 释放结构， 所述药物释放结构中的药物为抑制外膜成纤维细胞增殖的药物。
优选地， 所述药物释放结构为高分子聚合物与抑制外膜成纤维细胞增殖 的药物形成的致密混合层。
优选地， 所述高分子聚合物包括： 聚乳酸、 聚乙二醇、 苯乙烯丁烯共聚 物、 聚己内酯、 聚曱基丙烯酸丁酯、 聚曱基丙烯酸乙酯、 聚乙烯乙酸乙酯、 聚氨酯、 聚乙烯基吡咯烷酮、 聚磚酸胆碱、 蚕丝蛋白、 明胶、 曱壳素和 /或透 明质酸。
优选地， 所述药物释放结构为在所述支架本体表面制备^^孔或者在所述 支架本体表面形成的微孔涂层结构， 并在所述^:孔结构或微孔涂层结构中载 入药物。
优选地， 所述抑制外膜成纤维细胞增殖的药物包括丹参酮、 积雪草苷、 羟基积雪草甙、 川芎。秦、 血竭素、 舒伐他汀、 血管紧张素中的至少一种。
优选地， 所述支架本体包括： 冠状动脉血管支架、 颅内血管支架、 外周 血管支架、 术中支架、 心脏瓣膜支架、 胆道支架、 食道支架、 肠道支架、 胰 管支架、 尿道支架或气管支架。
一种介入医疗器械的制备方法， 包括：
在支架本体的表面制备微孔结构；
配制含有抑制外膜成纤维细胞增殖的药物的溶液；
将配制的所述溶液中的药物装载在所述敖孔结构中；
将所述支架本体干燥后得到所述介入医疗器械。
优选地， 在支架本体的表面制备微孔结构， 具体为：
采用阳极氧化、微弧氧化和 /或化学腐蚀的方法在支架本体表面形成微孔。 优选地， 在支架本体的表面制备微孔结构， 具体为：
在所述支架本体的表面上制备具有微孔的涂层。
优选地， 将配制的所述溶液中的药物装载在所述微孔结构中， 具体为： 采用超声喷涂、 空气喷涂和 /或浸涂的方式将所述溶液中的药物装载在所 述啟孔或具有微孔的涂层中。
一种介入医疗器械的制备方法， 包括：
配制抑制外膜成纤维细胞增殖的药物与高分子聚合物的混合溶液； 将所述混合溶液涂覆在支架本体的表面；
将所述支架本体干燥后得到所述介入医疗器械。 优选地， 所述涂覆包括： 超声喷涂、 空气喷涂和 /或浸涂。
由以上技术方案可见， 该介入医疗器械在使用时， 当植入到人体后， 其 上携带的抑制外膜成纤维细胞增殖的药物可以緩慢释放到与支架本体相接触 的血管壁细胞中， 进而可以抑制外膜成纤维细胞的增殖， 使成纤维细胞增殖 受阻而在血管重构中发挥作用， 有利于受损血管的代偿性扩张， 从而能够降 低支架内再狭窄的发生率。
另外， 与现有的采用雷帕霉素、 紫杉醇及其衍生物的药物支架相比， 本 申请实施例提供的该介入医疗器械不仅对内皮细胞的抑制率较低， 而且还会 促进内皮细胞的生长， 加快内皮化的进程。
附图说明
为了更清楚地说明本申请实施例或现有技术中的技术方案， 下面将对实 施例或现有技术描述中所需要使用的附图作简单地介绍， 显而易见地， 下面 描述中的附图仅仅是本申请中记载的一些实施例， 对于本领域普通技术人员 来讲， 在不付出创造性劳动的前提下， 还可以根据这些附图获得其他的附图。
图 1为本申请提供的介入医疗器械的一个具体实施方式的结构示意图； 图 2为本申请提供的积雪草苷、 紫杉醇和雷帕霉素对人脐静脉内皮细胞 HUVEC的抑制率统计图；
图 3为本申请提供的介入医疗器械的另一具体实施方式的结构示意图； 图 4为本申请提供的介入医疗器械的另一具体实施方式的结构示意图； 图 5为本申请提供的介入医疗器械制备方法的一种工艺流程；
图 6为本申请提供的介入医疗器械制备方法的另一种工艺流程； 图 7为本申请提供的介入医疗器械制备方法的又一种工艺流程。 具体实施方式
为了使本技术领域的人员更好地理解本申请中的技术方案， 下面将结合 本申请实施例中的附图， 对本申请实施例中的技术方案进行清楚、 完整地描 述， 显然， 所描述的实施例仅仅是本申请一部分实施例， 而不是全部的实施 例。 基于本申请中的实施例， 本领域普通技术人员在没有做出创造性劳动前 提下所获得的所有其他实施例， 都应当属于本申请保护的范围。 本申请实施例提供了一种介入医疗器械， 包括： 支架本体， 其中： 在支 架本体的表面设置有药物幹放结构， 并且药物锋放结构中的药物为抑制外膜 成纤维细^ >增殖的药物。
一个实施例：
图 1为本申请提供的介入医疗器械的一个具体实施方式的结构示意图。 如图 1所示， 1为支架本体， 2为药物释放涂层， 药物释放涂层 2涂覆在 支架本体 1的外表面上， 其中：
支架本体 1 可以为冠状动脉血管支架、 颅内血管支架、 外周血管支架、 术中支架、 心脏瓣膜支架、 胆道支架、 食道支架、 肠道支架、 胰管支架、 尿 道支架或气管支架。 另外， 支架本体 1 的材料可以为具有良好生物相容性及 力学特性的不锈钢、 钴基合金、 镍基合金、 钛合金、 可降解镁合金或者聚合 物材料等。
药物释放涂层 2是由高分子聚合物与抑制外膜成纤维细胞增殖的药物形 成的致密混合层， 即药物释放涂层 2作为载体， 可以使得支架本体 1的表面 携带有抑制外膜成纤维细胞增殖的药物。 抑制外膜成纤维细胞增殖的药物包 括丹参酮、 积雪草苷、 羟基积雪草甙、 川芎嗪、 血竭素、 舒伐他汀、 血管紧 张素中的至少一种， 在本申请实施例中， 优选为积雪草苷。 另外， 药物锋放 涂层 2中的高分子聚合物可以为具有生物相容性及控释性能的高分子聚合物， 例如聚乳酸、 聚乙二醇、 苯乙烯丁烯共聚物、 聚己内酯、 聚曱基丙烯酸丁酯、 聚甲基丙烯酸乙酯、 聚乙烯乙酸乙酯、 聚氨酯、 聚乙烯基吡咯烷酮、 聚 酸 胆碱、 蚕丝蛋白、 明胶、 甲壳素和 /或透明质酸。
积雪草苷是伞形科植物积雪草中提取的总甙， 积雪草苷能够通过增加抑 制性 Smad转导信号的 Smad7的表达， 抑制 TGF- β的病理作用， 使成纤维细 胞增殖受阻而在血管重构中发挥作用， 有利于受损血管的代偿性扩张， 从而 能够抑制再狭窄。
另外，在体外细胞试验中，利用 HUVEC( Human Umbilical Vein Endothelial Cells, 人脐静脉内皮细胞）分别测试积雪草苷、 紫杉醇和雷帕霉素对 HUVEC 的抑制率， 图 2为本申请提供的积雪草苷、 紫杉醇和雷帕霉素对 HUVEC的 抑制率统计图。 从图 2中可以看出， 积雪草苷对 HUVEC的抑制率明显低于 紫杉醇及雷帕霉素药物， 并且浓度范围在 10-12~10—9M 内， 积雪草苷几乎对 HUVEC无抑制作用。
同时， 有研究发现， 积雪草苷还具有促进内皮细胞生长， 加快内皮化进 程的作用。 具体文献请参见《积雪草苷防治 PCI术后再狭窄的实验研究》（分 类号 R541.4 文章编号： 1671-8259 ( 2005 ) 05-0477-03 )。
由此可见， 与现有的采用雷帕霉素、 紫杉醇及其衍生物的药物支架相比， 本申请实施例提供的该介入医疗器械不仅对内皮细胞的抑制率较低 , 而且还 会促进内皮细胞的生长， 加快内皮化的进程。 另一个实施例：
图 3为本申请提供的介入医疗器械的另一个具体实施方式的结构示意图。 如图 3所示， 1为支架本体， 3为支架表面形成的微孔。
在本申请实施例中， 药物幹放结构为 孔 3, ^：孔 3可以通过氧化或腐蚀 支架本体 1 的表面得到。 在微孔 3 内可以装载有抑制外膜成纤维细胞增殖的 药物， 这样就可以使得支架本体 1 的表面携带有抑制外膜成纤维细胞增殖的 药物。 又一个实施例：
图 4为本申请提供的介入医疗器械的又一个具体实施方式的结构示意图。 在图 3所示的介入医疗器械中， 微孔 3是直接氧化或腐蚀支架本体 1的 表面得到的， 而在本申请实施例中， 还可以在支架本体 1 的表面制备一层具 有微孔的涂层， 如图 3所示， 1为支架本体， 4为微孔涂层。 这样就无需氧化 或腐蚀支架本体 1的表面， 而是直接在支架本体 1的表面制备微孔涂层 4， 即 可得到装载药物的微孔。 又一个实施例：
图 5为本申请提供的介入医疗器械的制备方法的一种工艺流程。 如图 5所示， 在本申请实施例中， 支架本体以金属支架为例， 该介入医 疗器械的制备方法包括：
步骤 S101 : 清洗支架本体并干燥。
在制备介入医疗器械时， 为了避免支架本体上残留的污渍影响介入医疗 器械的质量， 需要首先对支架本体进行清洗。
步骤 S102: 在支架本体的表面制备微孔。
采用电化学腐蚀和 /或化学腐蚀的方法在支架本体表面形成微孔， 其中电 化学腐蚀包括阳极氧化、 微弧氧化等。 通过该步骤可以在支架本体的表面形 成微孔， 其结构示意图如图 2所示。
步骤 S103: 配制含有抑制外膜成纤维细胞增殖的药物的溶液。
在本申请实施例中， 抑制外膜成纤维细胞增殖的药物优选为积雪草苷， 在配制时， 将 50mg的积雪草苷溶解于 10ml的乙醇溶液中， 并混合均匀。
步骤 S104: 将配制的溶液中的药物装载在支架本体的微孔中。
将步 S102中得到的表面为微孔的支架本体浸没于步骤 S103配制得到 的溶液中， 使得溶液中的药物可以装载在支架本体表面的微孔中。
步骤 S105: 将支架本体进行干燥， 即可得到介入医疗器械。 又一个实施例：
图 6为本申请提供的介入医疗器械的制备方法的另一种工艺流程。
如图 6所示， 在本申请实施例中， 该介入医疗器械的制备方法包括： 步骤 S201 : 清洗支架本体并干燥。
步骤 S202: 在支架本体的表面上制备具有微孔的涂层。
具体操作流程为： 将蚕丝蛋白溶液均勾地覆盖在支架本体的表面， 进行 热或化学试剂变性， 再用纯水浸润， 然后进行冷冻和升温干燥， 在支架本体 表面形成具有微孔结构的涂层。
步骤 S203: 配制含有抑制外膜成纤维细胞增殖的药物的溶液。
在本申请实施例中， 抑制外膜成纤维细胞增殖的药物优选为积雪草苷， 在配制时， 将 50mg的积雪草苷溶解于 10ml的乙醇溶液中， 并混合均匀。
步骤 S204:将配制的溶液中的药物装载在支架本体表面的涂层的微孔中。 将步骤 S202中得到的表面具有微孔涂层的支架本体浸没于配制得到的溶 液中 , 使得溶液中的药物可以装载在支架本体表面涂层的微孔中。
步骤 S205: 将支架本体进行干燥， 即可后得到介入医疗器械。 又一个实施例：
图 Ί为本申请提供的介入医疗器械的制备方法的又一种工艺流程。
如图 7所示， 在本申请实施例中， 读介入医疗器械的制备方法包括： 步骤 S301 : 清洗支架本体并干燥。
步骤 S302: 配制抑制外膜成纤维细胞增殖的药物与高分子聚合物的混合 溶液。
在本申请实施例中， 高分子聚合物选择为聚乳酸， 抑制成纤维细胞增殖 的药物优选为积雪草苷。 配制聚乳酸与积雪草苷的比例为 1 :1〜1 :4的溶液。 例 如： 在 10ml 四氢呋喃中加入 10mg积雪草苷和 20mg聚乳酸， 充分溶解后并 混合均匀。
步骤 S303: 将混合溶液涂覆在支架本体的表面。
在本申请实施例中， 可以采用超声喷涂、 空气喷涂或浸涂的方式将步骤 302中配制得到的混合溶液涂覆到支架本体上。
步骤 S304: 将支架本体进行干燥， 即可后得到介入医疗器械。 以上所述仅是本申请的优选实施方式， 使本领域技术人 能够理解或实 现本申请。 对这些实施例的多种修改对本领域的技术人员来说将是显而易见 的， 本文中所定义的一般原理可以在不脱离本申请的精神或范围的情况下， 在其它实施例中实现。 因此， 本申请将不会被限制于本文所示的这些实施例， 而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims

权 利 要 求 书
1、 一种介入医疗器械， 其特征在于， 包括： 支架本体， 所述支架本体的 表面设置有药物释放结构， 所述药物释放结构中的药物为抑制外膜成纤维细 胞增殖的药物。
2、 根据权利要求 1所述的介入医疗器械， 其特征在于， 所述药物释放结 构为高分子聚合物与抑制外膜成紆维细胞增殖的药物形成的致密混合层。
3、 4艮据权利要求 2所述的介入医疗器械， 其特征在于， 所述高分子聚合 物包括： 聚乳酸、 聚乙二醇、 苯乙烯丁烯共聚物、 聚己内酯、 聚甲基丙烯酸 丁酯、 聚曱基丙烯酸乙酯、 聚乙烯乙酸乙酯、 聚氨酯、 聚乙烯基吡咯烷酮、 聚磷酸胆碱、 蚕丝蛋白、 明胶、 甲壳素和 /或透明质酸。
4、 根据权利要求 1所述的介入医疗器械， 其特征在于， 所述药物释放结 构为在所述支架本体表面制备微孔结构或者在所述支架本体表面形成的微孔 涂层结构， 并在所述^:孔结构或鼓孔涂层结构中载入药物。
5、 根据权利要求 1所述的介入医疗器械， 其特征在于， 所述抑制外膜成 纤维细胞增殖的药物包括丹参酮、 积雪草苷、 羟基积雪草甙、 川芎嗪、 血竭 素、 舒伐他汀、 血管紧张素中的至少一种。
6、 根据权利要求 1所述的介入医疗器械， 其特征在于， 所述支架本体包 括： 冠状动脉血管支架、 颅内血管支架、 外周血管支架、 术中支架、 心脏瓣 膜支架、 胆道支架、 食道支架、 肠道支架、 胰管支架、 尿道支架或气管支架。
7、 一种介入医疗器械的制备方法， 其特征在于， 包括：
在支架本体的表面制备微孔结构；
配制含有抑制外膜成纤维细胞增殖的药物的溶液；
将配制的所述溶液中的药物装载在所述^：孔结构中；
将所述支架本体干燥后得到所述介入医疗器械。
8、 根据权利要求 7所述的方法， 其特征在于， 在支架本体的表面制备微 孔结构， 具体为：
采用阳极氧化、微弧氧化和 /或化学腐蚀的方法在支架本体表面形成微孔。
9、 根据权利要求 7所述的方法， 其特征在于， 在支架本体的表面制备微 孔结构， 具体为：
在所述支架本体的表面上制备具有微孔的涂层。
10、 根据权利要求 7所述的方法， 其特征在于， 将配制的所述溶液中的 药物装载在所述微孔结构中， 具体为：
采用超声喷涂、 空气喷涂和 /或浸涂的方式将所述溶液中的药物装载在所 述微孔结构中。
11、 一种介入医疗器械的制备方法， 其特征在于， 包括：
配制抑制外膜成纤维细胞增殖的药物与高分子聚合物的混合溶液； 将所述混合溶液涂覆在支架本体的表面；
将所述支架本体干燥后得到所述介入医疗器械。
12、 根据权利要求 11所述的方法， 其特征在于， 所述涂覆包括： 超声喷 涂、 空气喷涂和 /或浸涂。
PCT/CN2012/070455 2011-09-29 2012-01-17 一种介入医疗器械及其制备方法 WO2013044605A1 (zh)

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US20150004207A1 (en) 2015-01-01
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