WO2015070814A1 - 一种药物球囊及其制备方法 - Google Patents

一种药物球囊及其制备方法 Download PDF

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WO2015070814A1
WO2015070814A1 PCT/CN2014/091292 CN2014091292W WO2015070814A1 WO 2015070814 A1 WO2015070814 A1 WO 2015070814A1 CN 2014091292 W CN2014091292 W CN 2014091292W WO 2015070814 A1 WO2015070814 A1 WO 2015070814A1
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Prior art keywords
drug
balloon
layer
adhesive
polymer layer
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PCT/CN2014/091292
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English (en)
French (fr)
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张鹏
张琳琳
郭芳
王长松
史增佐
李中华
罗七一
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微创心脉医疗科技（上海）有限公司
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Publication of WO2015070814A1 publication Critical patent/WO2015070814A1/zh

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    • 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
    • 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
    • A61L29/148—Materials at least partially resorbable by the body

Definitions

  • the invention belongs to the field of medical instruments, and in particular relates to a drug balloon and a preparation method thereof.
  • vascular stenosis is the leading cause of morbidity and mortality.
  • the most common treatment currently used is drug-eluting stent (DES) interventional therapy.
  • DES is a drug that is mixed with a polymer matrix and applied to the surface of the stent to form a local drug slow release system.
  • the drug When the stent is implanted into the blood vessel, the drug will be slowly released for several weeks to several months. Together with the support of the stent, it can effectively treat the stenosis or occlusion of the blood vessel. It is one of the most commonly used and most effective interventional devices.
  • DES also has many shortcomings. For example, the polymer will produce a local chronic inflammatory reaction; the presence of the stent requires long-term antiplatelet therapy; the drug coating is unevenly distributed; after stent thrombosis, it is not suitable to implant the stent again.
  • DEB drug-eluting balloon
  • the current degradable stent partially overcomes the limitations of traditional DES, does not cause inflammatory reactions and re-endothelialization, and can release drugs slowly relative to DEB. But because of its release surface The product is limited, and the support strength of the stent is not ideal, and it is easy to break, and the expected effect cannot be achieved. Therefore, it is necessary to synthesize a uniform drug release in the drug balloon and a long-term slow release in the drug stent to develop a new drug-containing coating.
  • WO 2012/039884 A1 discloses a transferable polymer coating by dissolving a water-soluble material and a degradable polymer on a surface of a conventional balloon, respectively, and then immersing the entire coating in an aqueous solution for a period of time to dissolve the water solubility of the inner layer.
  • the material forms a structure in which a layer of degradable polymer is nested outside the balloon.
  • the disadvantages of the invention are: (1) the inner layer water-soluble material is tightly coated by the outer layer degradable polymer, and it is difficult for water molecules to cross the outer layer barrier. In many cases, the inner layer water-soluble material cannot be immersed for a long time.
  • the polymer layer is a very thin film, which does not support the support like a stent, and does not actively adhere to the wall once the balloon is withdrawn. After the release, the film remaining on the inner wall of the blood vessel is easily washed away by the bloodstream, and not only does not serve the purpose of treating the disease, but even causes severe blood vessel embolism.
  • Chinese Patent Application No. 200610025200.8 discloses a double-layer balloon catheter in which an inner balloon in the two-layer balloon functions to expand a blood vessel, and an outer balloon is made of a unique microporous membrane, which can be treated.
  • the acting gene or drug is infiltrated by the outer balloon into the blood vessel wall and the target organ.
  • the invention effectively overcomes the loss of the drug during the delivery of the contrast catheter, reduces the system toxicity, but does not achieve the purpose of long-term sustained release.
  • the present invention contemplates a coating of a drug balloon that is combined with a special double layer balloon.
  • the inner balloon is first angioplasty, then the outer balloon expansion.
  • a solution such as physiological saline oozes out from the pores of the outer balloon wall to dissolve the water-soluble underlayer, so that the action of the underlayer changes from the connecting layer to the lubricating layer, and the drug-containing degradable polymer layer (film) ) detaches from the surface of the outer balloon and withdraws the balloon from the body.
  • the drug-containing degradable polymer layer uniformly releases the drug throughout the lesion over a period of minutes to months.
  • the degradable polymer layer (film) may further comprise an adhesive which adheres to the inner wall of the blood vessel and has a certain toughness, and does not break like a stent due to an external force such as compression or torsion of the blood vessel, and does not fall off from the lesion.
  • the present invention provides a drug balloon comprising a double-layer balloon, characterized in that a coating layer is provided on the outer balloon surface of the double-layer balloon, and the coating sequentially comprises a water-soluble primer layer. And a biodegradable polymer layer containing the drug.
  • the drug is dispersed in the biodegradable polymer layer, or the drug-containing biodegradable polymer layer comprises a further coating of a drug layer over the biodegradable polymer layer.
  • the drug-containing biodegradable polymer layer further contains an adhesive.
  • the drug-containing biodegradable polymer layer is a layer structure comprising a biodegradable polymer, an adhesive and a drug, or a double layer structure comprising any combination of a polymer, an adhesive and a drug, Or a three-layer structure in which a polymer, an adhesive, and a drug are separately coated.
  • the one-layer structure is obtained by blending a biodegradable polymer, an adhesive and a drug together on a water-soluble underlayer.
  • the two-layer structure may be arbitrarily combined as long as it includes a biodegradable polymer, an adhesive, and a drug.
  • the two-layer structure may be a structure in which a degradable polymer and an adhesive form a structure, and the drug alone constitutes another layer structure, or the degradable polymer separately constitutes a layer structure, and the adhesive and the drug constitute another layer structure, Or the degradable polymer and the adhesive form a structure, and the drug and the adhesive constitute another structure, or the degradable polymer and the drug form a structure, and the adhesive separately constitutes a structure, or a degradable polymer, an adhesive And the drug constitutes a layer of structure, while the adhesive and / or drug and / or degradable polymerization The object constitutes another layer structure or the like.
  • the three-layer structure may be arranged in any order, for example, in turn, a biodegradable polymer structural layer, an adhesive structural layer, and a drug structural layer.
  • the adhesive-containing structural layer is exposed in whole or in part to dissolve in the water-soluble bottom layer. It can be in contact with the inner wall of the blood vessel after release.
  • the present invention also provides a method of preparing a drug balloon comprising providing a double layer balloon, making a water soluble primer layer on the outer balloon surface thereof, and then forming a biodegradable polymer layer containing the drug and optionally an adhesive.
  • the biodegradable polymer layer may be attached to the inner wall of the blood vessel of the lesion area to release the drug for a period of several minutes to several months.
  • the double-layered balloon is completely identical to the balloon disclosed in Chinese Patent Application No. 200610025200.8.
  • the water-soluble bottom layer also known as the hydrophilic bottom layer, has a certain adhesive strength in the anhydrous state, and is used for connecting the surface of the balloon and the degradable polymer layer containing the drug and the optional adhesive; Dissolved to form a lubricating layer to smoothly release the degradable polymer layer.
  • the water-soluble materials include natural water-soluble polymers such as starch, cellulose, vegetable gum and animal glue; modified starch and modified cellulose; carboxymethyl starch, acetic acid starch, hydroxymethyl cellulose, and carboxymethyl Chemically modified natural polymers such as cellulose; synthetic polymers such as polyacrylamide (PAM), hydrolyzed polyacrylamide (HPAM), and polyvinylpyrrolidone (PVP).
  • the biodegradable polymer layer containing the drug and optionally the adhesive can be rapidly degraded or dissolved, for example, even a few days after surgery, for example, 5 minutes to 24 hours after surgery. In other cases, the degradable polymer layer may degrade or dissolve slowly, for example from 5 days to 6 months. In this process, the degradable polymer layer is attached to the inner wall of the diseased vessel until the drug is completely absorbed or the coating is completely degraded. Thickness of the drug-containing degradable polymer layer The degree can be appropriately adjusted depending on the desired degradation time, generally less than 10 ⁇ m, for example, 0.2 ⁇ m to 9 ⁇ m or 0.5 ⁇ m to 8.5 ⁇ m.
  • the biodegradable polymer may be polyhydroxyalkanoate (PHA), polyhydroxybutyrate compound, poly(glycerol-sebacic acid), polypeptide, polylactic acid (PLA), etc. poly- ⁇ - A hydroxy acid compound, a polyglycolic acid (PGA), a polylactic acid-glycolic acid copolymer (PLGA), a polydioxanone, a polylactic acid-polyethylene oxide copolymer, hyaluronic acid or the like.
  • PHA polyhydroxyalkanoate
  • PHA polyhydroxybutyrate compound
  • poly(glycerol-sebacic acid) polypeptide
  • PLA polylactic acid
  • PLA polylactic acid
  • poly- ⁇ - A hydroxy acid compound a polyglycolic acid (PGA), a polylactic acid-glycolic acid copolymer (PLGA), a polydioxanone, a polylactic acid-polyethylene oxide copolymer, hyaluronic acid or the like
  • the adhesive can adhere the polymer layer to the inner wall tissue of the blood vessel to prevent shedding, including gelatin, starch, agar, mannan, alginic acid, polyacrylic acid, polyacrylate adhesive, dextrin, methyl cellulose. , methyl vinyl ether, copolymer of maleic anhydride, gum arabic, scutellaria gum, paulownia gum, locust bean gum, cyanoacrylate adhesive, polyurethane adhesive, silicone adhesive, fibrin Adhesive, mussel mucin adhesive, etc.
  • the drug is antithrombotic, proliferative, anti-inflammatory, anti-inflammatory, anti-proliferative, anti-tumor, anti-mitotic, cytostatic, cytotoxic, anti-angiogenic, anti-restenosis, inhibition of microtubule, anti-metastatic or antithrombotic Substance, preferably acemetacin, aescin, aminopterin, antimycotics, arsenic trioxide, aristolochic acid, aspirin, berberine, ginkgo phenol, rapamycin and its derivatives, paclitaxel, docei Paclitaxel, antibiotics (especially actinomycin-D), hormones, and antibody-based cancer drugs.
  • the invention solves the problems that the absorption time of the medicine in the traditional drug balloon is short, the absorption amount is low, and the individual difference is large.
  • the polymer layer carries the drug to the lesion and uniformly releases the drug from 5 minutes to 6 months.
  • the drug balloon of the invention has the following beneficial effects: (1) the coating is combined with a special double-layer balloon, and a solution such as physiological saline is exuded from the balloon wall during the expansion of the outer balloon to dissolve the water-soluble bottom layer. It converts the connection function into a lubrication function to control the release of the drug-containing degradable polymer layer; (2) the polymer layer can uniformly release the drug to the entire diseased tissue for a long time, and maintain sufficient surrounding of the diseased cells for a long period of time.
  • degradable polymer layer may also contain Adhesive, which is more conducive to adhesion to the inner wall of the blood vessel and has certain toughness, and will not break like a stent due to external forces such as compression and torsion of the blood vessel; (4) no stent exists in the human body for a long time, and the coating can be relatively short. Degradation or dissolution in time does not affect re-endothelialization; (5) Compared with the conventional drug-eluting balloon technique, the present invention reduces the amount of drug loss, increases the amount of drug absorption, requires less drug loading, and has less toxicity to the system.
  • FIG. 1 is a schematic view showing a cross-sectional structure of a drug balloon after an inner balloon is expanded according to an embodiment of the present invention.
  • the inner balloon acts as an angioplasty, in which case the degradable polymer layer remains firmly bonded to the outer wall of the balloon.
  • FIG. 2 is a schematic view showing a cross-sectional structure of a drug balloon according to an embodiment of the present invention, in which the inner and outer balloons are expanded.
  • its expansion fluid such as saline
  • saline can penetrate the pores in the outer wall of the balloon to dissolve the water-soluble bottom layer, thereby degrading the polymer layer containing the drug and optional adhesive. Separated from the balloon.
  • FIG. 3 is a schematic structural view of a longitudinal section of a drug balloon according to an embodiment of the present invention.
  • FIG. 4 is a schematic structural view of a drug balloon in a process of withdrawing a balloon according to an embodiment of the present invention. As shown, the balloon is withdrawn from the body and a layer of degradable polymer containing the drug and optional adhesive adheres to the inner wall of the blood vessel, releasing the drug to adjacent tissue over a period of minutes to months of dissolution or degradation.
  • a double-layered balloon was prepared according to the method described in Chinese Patent Application No. 200610025200.8 owned by the present applicant.
  • PVP polyvinylpyrrolidone
  • IPA isopropyl alcohol
  • PLGA polylactic acid-glycolic acid copolymer
  • THF tetrahydrofuran
  • the thickness of the degradable polymer layer was 6 ⁇ m.
  • a double-layered balloon was prepared according to the method described in Chinese Patent Application No. 200610025200.8 owned by the present applicant.
  • the thickness of the degradable polymer layer including the drug layer was 8.5 ⁇ m in total.
  • the isolated porcine artery vascular segment which is similar in diameter to the balloon, was immediately immersed in pig blood supplemented with anticoagulant, kept at 37 ° C, and the drug balloon was passed through the 6F catheter in a folded state for 1 minute, then the balloon entered the blood vessel.
  • the inner balloon first expands (12 atm) to achieve the purpose of blood vessel formation, and then the outer balloon is infused with physiological saline, and the water-soluble bottom layer dissolves and disappears (about 1 minute) to withdraw the balloon, and the degradable polymer layer forms a
  • the layer film adheres to the inner wall of the blood vessel.
  • the drug balloon entered the lumen of the latex hose in a folded state, and the inner balloon first expanded (12 atm). Then, the outer balloon is infused with physiological saline, and after the water-soluble bottom layer dissolves and disappears (about 1 minute), the balloon is withdrawn, and the polymer layer is degraded to form a film adhered to the inner cavity of the latex tube, and the latex tube is degradable.
  • PBS constant temperature phosphate buffer

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Abstract

一种球囊及其制备方法。该药物球囊包括双层球囊，其外层表面依次涂覆有水溶性底层以及含药物的生物可降解聚合物层。该药物球囊扩张的过程中会有生理盐水等溶液从球囊壁渗出，溶解水溶性底层，从而控制含药物的可降解聚合物层的释放。

Description

一种药物球囊及其制备方法 技术领域
本发明属于医疗器械领域，具体涉及一种药物球囊及其制备方法。
背景技术
血管狭窄是发病和死亡的主要原因，目前最常用的治疗方式是采用药物洗脱支架(DES)介入治疗。DES是将药物与聚合物基质混合后涂覆于支架表面，形成一个局部药物缓慢释放系统。当支架植入血管后，药物会慢慢释放持续数周至数月时间，加上支架的支撑作用，可以有效治疗血管的狭窄或闭塞，是目前最为常用且最为有效的介入器械之一。然而DES也有许多不足之处，例如，聚合物会产生局部慢性炎症反应；支架的存在需要长期抗血小板药物治疗；药物涂层分布不均匀；支架内血栓形成后，不宜再次植入支架等。
为了克服上述不足，尤其是在寻求解决支架内再狭窄、下肢动脉疾病、血管分叉处及小血管的狭窄等问题时诞生了的一种新型产品--药物洗脱球囊(DEB)。DEB技术是一种改进的球囊血管再造术，该技术在球囊外表面附加药物，通过导管将球囊送到病变位置，并在球囊扩张的短暂时间内(0-2min)释放药物，起到扩张血管，治疗狭窄或闭塞的作用。即使病变血管发生再狭窄堵塞，也可通过DEB进行二次治疗。
但是，目前的药物球囊要求用于治疗疾病的药物必须具有这样的效果：即通过单次大剂量给药达到治疗治病的目的，重复给药是非必须的。这极大地限制了药物的选择，并且一次性大剂量给药后药物进入循环系统容易引起急性毒性反应。
目前的可降解支架部分克服了传统DES的限制因素，不会引起炎症反应和再内皮化困难，相对于DEB能够缓慢地释放药物。但是因为其释药面 积有限，并且支架的支撑强度不理想、容易断裂等因素，也不能达到预期效果。所以，有必要综合药物球囊中药物均匀释放的特点和药物支架中长期缓慢释放的特点，从而开发一种新的含药涂层。
WO2012/039884A1公开了一种可转移聚合物涂层，通过将水溶性材料和可降解聚合物分别涂覆在普通球囊表面，然后将整个涂层浸入水溶液中一段时间，溶解里层的水溶性材料，从而形成一个在球囊外侧嵌套一个可降解聚合物层的结构。该发明的缺点在于：(1)里层水溶性材料被外层可降解聚合物紧紧包被，水分子很难越过外层屏障，很多情况下即使长时间浸泡，内层水溶性材料也不能溶解；另一方面，即使里层的水溶性材料溶解，它的水溶液也很难完全随水分子流出，虽然有水存在的条件下此种溶液具有一定的润滑性，但一旦涂层干燥之后，又将球囊与外层粘连；(2)即使通过浸泡处理，里层被完全去除，球囊壁与可降解聚合物层之间没有实体连接，这直接造成药物涂覆以及后期的折叠压握等处理过程中聚合物层的移动，甚至脱落；(3)另外，聚合物层为很薄的一层膜，起不到像支架一样的支撑作用，也不会主动贴壁，一旦球囊撤出之后，留存于血管内壁处的薄膜很容易被血流冲走，不仅起不到治疗疾病的目的，甚至引起严重的血管栓塞。
中国发明专利申请No.200610025200.8公开一种双层球囊导管，两层球囊中内层球囊起到扩张血管的作用，而外层球囊由独特的微孔膜制成，能将起治疗作用的基因或者药物由外层球囊渗透作用于血管壁、靶器官上。该发明有效地克服了药物在造影导管内输送过程中的损失，降低了系统毒性，但是没有达到长效缓释的目的。
发明内容
为了解决以上难题，本发明设计了一种药物球囊的涂层，该涂层配合特殊的双层球囊。手术时，首先内层球囊进行血管成形术，然后外层球囊 扩张。在此过程中，生理盐水等溶液从外层球囊壁的小孔中渗出，溶解水溶性底层，从而使底层的作用由连接层变为润滑层，含药物的可降解聚合物层(薄膜)从外层球囊的表面脱离，再将球囊撤出体外。含药物的可降解聚合物层在数分钟到数月的时间内在整个病变部位均匀释放药物。可降解聚合物层(薄膜)还可包含胶粘剂，使其粘附在血管内壁并具有一定的韧性，不会因血管的压迫、扭转等外力而像支架一样断裂，也不会从病变部位脱落。
具体而言，本发明提供一种药物球囊，包括双层球囊，其特征在于，所述双层球囊的外层球囊表面上设置有涂层，所述涂层依次包括水溶性底层以及含药物的生物可降解聚合物层。
根据本发明，所述药物分散于生物可降解聚合物层中，或者所述含药物的生物可降解聚合物层包括在生物可降解聚合物层之上另涂布一层药物层。
根据本发明，所述含药物的生物可降解聚合物层进一步含有胶粘剂。在此情形下，所述含药物的生物可降解聚合物层是包含生物可降解聚合物、胶粘剂和药物的一层结构，或者是包含聚合物、胶粘剂和药物的任意组合的双层结构，又或者是分别涂布聚合物、胶粘剂和药物的三层结构。
根据本发明，所述一层结构是将生物可降解聚合物、胶粘剂和药物掺混后，一起涂布在水溶性底层上。
根据本发明，所述双层结构可以任意组合，只要组合后，包括生物可降解聚合物、胶粘剂和药物就行。例如，所述双层结构可以是可降解聚合物和胶粘剂构成一层结构，而药物单独构成另一层结构，或者可降解聚合物单独构成一层结构，而胶粘剂和药物构成另一层结构，或者可降解聚合物和胶粘剂构成一层结构，而药物和胶粘剂构成另一层结构，或者可降解聚合物和药物构成一层结构，而胶粘剂单独构成一层结构，或者是可降解聚合物、胶粘剂和药物构成一层结构，而胶粘剂和/或药物和/或可降解聚合 物构成另一层结构等。
根据本发明，所述三层结构可以任意顺序排列，例如，依次是生物可降解聚合物结构层、胶粘剂结构层和药物结构层。
本领域技术人员能够理解，无论是双层结构或三层结构，为了保证双层或三层结构粘附于血管内壁，含胶粘剂的结构层是整体或部分暴露在外，以便在水溶性底层溶解、释放后能与血管内壁接触。
本发明还提供一种药物球囊的制备方法，包括提供双层球囊，在其外层球囊表面制作水溶性底层，然后制作含药物和任选胶粘剂的生物可降解聚合物层。
所述的生物可降解聚合物层可以附着于病变区域的血管内壁，在数分钟到数月不等的时间内释放药物。
所述的双层球囊与中国发明专利申请No.200610025200.8公开的球囊完全一致。
所述的水溶性底层亦称亲水底层，在无水的状态下具有一定的粘附强度，用于连接球囊表面和含药物和任选胶粘剂的可降解聚合物层；一旦遇水能迅速溶解，形成润滑层，从而顺利将可降解聚合物层释放。所述的水溶性材料包括淀粉类、纤维素、植物胶、动物胶等天然水溶性高分子；改性淀粉和改性纤维素；羧甲基淀粉、醋酸淀粉、羟甲基纤维素、羧甲基纤维素等化学改性天然聚合物；聚丙烯酰胺(PAM)、水解聚丙烯酰胺(HPAM)、聚乙烯吡咯烷酮(PVP)等合成聚合物。
所述含药物和任选胶粘剂的生物可降解聚合物层可快速降解或者溶解，例如在术后几天甚至更少，又例如术后5分钟到24小时。在另外一些情况下，所述的可降解聚合物层可缓慢降解或者溶解，例如从5天到6个月不等。在这个过程中，可降解聚合物层联合药物贴附在病变血管内壁直到药物被完全吸收或者涂层完全降解。所述含药物的可降解聚合物层的厚 度根据所需的降解时间可做适当调整，一般小于10μm，例如，0.2μm-9μm或者0.5μm-8.5μm。
所述的生物可降解聚合物可以是聚羟基脂肪酸酯(PHA)、聚羟基丁酸酯类化合物、聚(丙三醇-癸二酸)、多肽、聚乳酸(PLA)等聚-α-羟基酸类化合物、聚羟基乙酸(PGA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚对二氧环己酮、聚乳酸-聚环氧乙烷共聚物、透明质酸等。
所述的胶粘剂可将聚合物层粘附于血管内壁组织处，防止脱落，包括明胶、淀粉、琼脂、甘露聚糖、海藻酸、聚丙烯酸、聚丙烯酸盐类胶粘剂、糊精、甲基纤维素、甲基乙烯基醚、顺丁烯二酸酐的共聚物、阿拉伯胶、西黄耆胶、梧桐胶、槐树豆胶，氰基丙烯酸酯类胶粘剂、聚氨酯类胶粘剂、有机硅系列胶粘剂，纤维蛋白胶粘剂、贻贝粘蛋白胶粘剂等。
所述的药物为抗血栓、增殖、抗炎、消炎、抗增生、抗肿瘤、抗有丝分裂、抑制细胞、具有细胞毒、抗血管生成、抗再狭窄、抑制微管、抗转移或者抗血栓形成的物质，优选为阿西美辛、七叶皂苷、氨基蝶呤、抗霉菌素、三氧化二砷、马兜铃酸、阿司匹林、小糪碱、银杏酚、雷帕霉素及其衍生物、紫杉醇、多西紫杉醇、抗生素(特别是放线菌素-D)、激素、抗体治癌药物。
本发明解决了传统药物球囊中存在的药物吸收时间短，吸收量低，个体差异大的问题。介入手术后，聚合物层携带药物粘附于病变部位从5分钟-6个月不等的时间内均匀释放药物。
本发明的药物球囊具有以下有益效果：(1)其涂层配合特殊的双层球囊，在外层球囊扩张的过程中会有生理盐水等溶液从球囊壁渗出，溶解水溶性底层使其由连接功能转变为润滑功能，从而控制含药物的可降解聚合物层的释放；(2)聚合物层可长期向整个病变组织均匀释放药物，在相当长的时间内维持病变细胞周围足够的药物浓度；(3)可降解聚合物层(薄膜)还可含有 胶粘剂，从而更利于粘附在血管内壁并具有一定的韧性，不会因血管的压迫、扭转等外力而像支架一样断裂；(4)无支架长期存在于人体，涂层可在相对较短的时间内降解或者溶解，不影响再内皮化；(5)相对于传统的药物洗脱球囊技术，本发明减少药物损失量，增加药物吸收量，所需载药量小，对系统毒性小。
附图说明
为了更清楚地描述本发明的技术方案，下面将结合附图作简要介绍。显而易见，这些附图仅是本申请记载的一些具体实施方式。本发明包括但不限于这些附图。
图1为本发明实施例提供的一种药物球囊，其内层球囊扩张后的横切面结构示意图。如图所示，内层球囊可起到血管成形术的作用，此时可降解聚合物层仍牢固地结合于球囊外壁。
图2为本发明实施例提供的一种药物球囊，其内外层球囊均扩张后的横切面结构示意图。如图所示，当外层球囊扩张时，其扩充液(如生理盐水)可透过球囊外壁的小孔从而将水溶性底层溶解，从而含药物和任选胶粘剂的可降解聚合物层与球囊分离。
图3为本发明实施例提供的一种药物球囊纵切面结构示意图。
图4为本发明实施例提供的一种药物球囊在球囊撤出过程中的结构示意图。如图所示，球囊撤出体内，含药物和任选胶粘剂的可降解聚合物层粘附于血管内壁，在数分钟到数月不等的溶解或降解时间内向邻近组织释放药物。
具体实施方式
为了进一步理解本发明，下面将结合实施例对本发明的优选方案进行描述。这些描述只是举例说明本发明药物球囊的特征和优点，而非限制本 发明的保护范围。
实施例1
1.双层球囊制备
根据本申请人拥有的中国发明专利申请No.200610025200.8的所述方法制备一个双层球囊。
2.涂层制备
称取2g聚乙烯吡咯烷酮(PVP，分子量1万)，加入到5ml异丙醇(IPA)溶液中，充分搅拌直至PVP完全溶解。将双层球囊内层扩张，浸入上述溶液中，然后40℃烘箱中干燥，形成水溶性底层，卡规测得球囊中间部位外径为30.109mm.
称取2g聚乳酸-羟基乙酸共聚物(PLGA)(50/50)，0.01g氰基丙烯酸酯和300mg紫杉醇溶于10ml四氢呋喃(THF)溶液中，充分搅拌直至所有成分完全溶解。然后将涂有水溶性底层的球囊浸入上述溶液中，40℃烘箱中干燥，重复浸入3次。干燥后，在卡规测得球囊中间部位外径为30.121mm。
通过计算可知，可降解聚合物层的厚度为6μm。
实施例2
1.双层球囊制备
根据本申请人拥有的中国发明专利申请No.200610025200.8所述方法，制备一个双层球囊。
2.涂层制备
称取2g PVP(分子量1万)，加入到5ml IPA溶液中，充分搅拌直至PVP完全溶解。将双层球囊内层扩张，浸入上述溶液中，然后40℃烘箱中干燥，形成水溶性底层，卡规测得球囊中间部位外径为30.109mm。
称取2g PLGA(50/50)，0.01g氰基丙烯酸酯溶于10mlTHF溶液中，充 分搅拌直至所有成分完全溶解。继续将涂有水溶性底层的球囊浸入上述溶液中，然后40℃烘箱中干燥，重复浸入2次，完全干燥。最后，在聚合物层表面采用超声喷涂技术喷涂一层紫杉醇，为确保聚合物涂层与血管的有效粘合，在该涂层两端各预留1mm的长度不喷涂药物。卡规测得球囊中间部位外径为30.126mm。
通过计算可知，包括药物层在内的可降解聚合物层的厚度合计为8.5μm。
实施例3
取与球囊直径相近的离体猪动脉血管段，立即浸入添加抗凝剂的猪血中，保持37℃恒温，药物球囊在折叠状态下通过6F导管并保持1分钟，然后球囊进入血管内腔，内层球囊首先扩张(12atm)达到血管成型的目的，然后外层球囊注入生理盐水，水溶性底层溶解消失后(约1分钟)撤出球囊，可降解聚合物层形成一层薄膜粘附在血管内壁处。
另取与球囊直径相近的乳胶软管，浸入37℃恒温磷酸缓冲液(PBS，pH＝7.4)中，药物球囊在折叠状态下进入乳胶软管内腔，内层球囊首先扩张(12atm)，然后外层球囊注入生理盐水，水溶性底层溶解消失后(约1分钟)撤出球囊，可降解聚合物层形成一层薄膜粘附在乳胶管内腔，将此乳胶管与可降解薄膜置于药物溶出仪的转篮中，溶出介质为37℃±0.5℃的恒温PBS(pH＝7.4)，转速为100转/分钟，每隔1小时取样处理后，HPLC测试药物溶出情况。结果，可降解聚合物层在前24小时释放约40％药物。
以上实施例的说明只是用于帮助理解本发明的核心思想。应当指出，对于本领域的普通技术人员而言，在不脱离本发明原理的前提下，还可以对本发明球囊的药物涂层及其制备方法进行若干改进和修饰，但这些改进和修饰也落入本发明权利要求请求保护的范围内。

Claims (15)

  1. 一种药物球囊，包括双层球囊，其特征在于，所述双层球囊的外层球囊表面上设置有涂层，所述涂层依次包括水溶性底层以及含药物的生物可降解聚合物层。
  2. 如权利要求1所述的药物球囊，其特征在于，所述药物分散于生物可降解聚合物层中，或者所述含药物的生物可降解聚合物层包括在生物可降解聚合物层之上另涂布一层药物层。
  3. 如权利要求1所述的药物球囊，其特征在于，所述含药物的生物可降解聚合物层进一步含有胶粘剂。
  4. 如权利要求3所述的药物球囊，其特征在于，所述含药物的生物可降解聚合物层是包含生物可降解聚合物、胶粘剂和药物的一层结构，或者是包含聚合物、胶粘剂和药物的任意组合的双层结构，又或者是分别涂布聚合物、胶粘剂和药物的三层结构。
  5. 如权利要求1-4任一项所述的药物球囊，其特征在于，所述水溶性底层由水溶性材料制成，所述水溶性材料选自天然水溶性高分子、改性淀粉和改性纤维素、化学改性天然聚合物或合成聚合物。
  6. 如权利要求5所述的药物球囊，其特征在于，所述天然水溶性材料选自淀粉、纤维素、植物胶或动物胶，所述化学改性天然聚合物选自羧甲基淀粉、醋酸淀粉、羟甲基纤维素或羧甲基纤维素，以及所述合成聚合物选自聚丙烯酰胺、水解聚丙烯酰胺或聚乙烯吡咯烷酮。
  7. 如权利要求1-4任一项所述的药物球囊，其特征在于，所述含药物的生物可降解聚合物层的厚度小于10μm。
  8. 如权利要求7所述的药物球囊，其特征在于，所述含药物的生物可降解聚合物层的厚度为0.2μm-9μm。
  9. 如权利要求8所述的药物球囊，其特征在于，所述含药物的生物可 降解聚合物层的厚度为0.5μm-8.5μm。
  10. 如权利要求1-4任一项所述的药物球囊，其特征在于，所述生物可降解聚合物选自聚羟基脂肪酸酯、聚羟基丁酸酯类化合物、聚(丙三醇-癸二酸)、多肽、聚乳酸、聚羟基乙酸、聚乳酸-羟基乙酸共聚物、聚对二氧环己酮、聚乳酸-聚环氧乙烷共聚物或透明质酸。
  11. 如权利要求3或4所述的药物球囊，其特征在于，所述胶粘剂选自明胶、淀粉、琼脂、甘露聚糖、海藻酸、聚丙烯酸、聚丙烯酸盐类胶粘剂、糊精、甲基纤维素、甲基乙烯基醚、顺丁烯二酸酐的共聚物、阿拉伯胶、西黄耆胶、梧桐胶、槐树豆胶，氰基丙烯酸酯类胶粘剂、聚氨酯类胶粘剂、有机硅系列胶粘剂，纤维蛋白胶粘剂或贻贝粘蛋白胶粘剂。
  12. 如权利要求1-4任一项所述的药物球囊，其特征在于，所述药物选自抗血栓、抗炎、消炎、抗增生、抗肿瘤、抗有丝分裂、抑制细胞、具有细胞毒、抗血管生成、抗再狭窄、抑制微管、抗转移或者抗血栓形成的物质。
  13. 如权利要求12所述的药物球囊，其特征在于，所述药物选自阿西美辛、七叶皂苷、氨基蝶呤、抗霉菌素、三氧化二砷、马兜铃酸、阿司匹林、小糪碱、银杏酚、雷帕霉素及其衍生物、紫杉醇、多西紫杉醇、抗生素、激素或抗体治癌药物。
  14. 如权利要求13所述的药物球囊，其特征在于，所述抗生素为放线菌素D。
  15. 一种制备如前述权利要求任一项所述的药物球囊的方法，包括提供双层球囊，在其外层球囊表面制作水溶性底层，然后制作含药物和任选胶粘剂的生物可降解聚合物层。
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