WO2017113634A1 - 铁基合金植入医疗器械及其制备方法 - Google Patents

铁基合金植入医疗器械及其制备方法 Download PDF

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WO2017113634A1
WO2017113634A1 PCT/CN2016/086118 CN2016086118W WO2017113634A1 WO 2017113634 A1 WO2017113634 A1 WO 2017113634A1 CN 2016086118 W CN2016086118 W CN 2016086118W WO 2017113634 A1 WO2017113634 A1 WO 2017113634A1
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drug
iron
based alloy
polymer
medical device
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PCT/CN2016/086118
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English (en)
French (fr)
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孙宏涛
陈丽萍
胡军
张德元
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先健科技(深圳)有限公司
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Priority to EP16880442.5A priority Critical patent/EP3398623A4/en
Priority to US15/779,805 priority patent/US20200230296A1/en
Publication of WO2017113634A1 publication Critical patent/WO2017113634A1/zh
Priority to IN201817025322A priority patent/IN201817025322A/xx

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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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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    • 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
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    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
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Definitions

  • the invention belongs to the field of biodegradable implant medical devices, and relates to an iron-based alloy drug-loading medical device with controlled drug release and a preparation method thereof.
  • implanted medical devices are typically made from metals and their alloys, ceramics, polymers, and related composite materials.
  • metal-based implanted medical devices are particularly popular because of their superior mechanical properties, such as high strength and high toughness.
  • iron participates in many biochemical processes, such as the handling of oxygen.
  • Peuster M and other laser-engraving methods of corrosive pure iron stents similar in shape to clinically used metal stents were implanted into the descending aorta of 16 New Zealand rabbits. The results of this animal experiment showed that there was no thrombotic complication within 6-18 months, and no adverse events occurred.
  • Pathological examination confirmed that there was no inflammatory reaction in the local vascular wall, and there was no obvious proliferation of smooth muscle cells. It is preliminarily indicating that the degradable iron stent is safe and reliable. Good application prospects.
  • the degradable polymer drug-loaded coating is disposed on the implanted medical device, and the drug therapeutic effect can be further exerted after the device is implanted into the body.
  • the active drug component for restenosis is added to the bare stent, the lumen restenosis rate can be greatly reduced after the stent is implanted into the blood vessel.
  • the release rate of the active drug plays a crucial role in the therapeutic effect of the drug-loaded medical device. When the total dose of the device is constant, if the drug release rate is too slow, the therapeutic effect of the drug is limited. If the drug is released too quickly, the local drug concentration is too high, which may cause toxic side effects. Therefore, for an iron-based alloy implanted medical device, it is necessary to have a suitable drug release rate in addition to the suitable corrosion rate as described in the patent CN201310533266.6, filed on Oct. 31, 2013.
  • the technical problem to be solved by the present invention is to provide an iron-based alloy implanted medical device using a polymer of a specific molecular weight range as a drug carrier for a drug-loaded coating according to the defects of the prior art. Controlled drug release can be achieved after implantation in the body.
  • An iron-based alloy implanted medical device comprising an iron-based alloy substrate and a drug-loaded coating, the drug-loaded coating comprising a polymer and an active drug, the polymer having a weight average molecular weight of [5,100] Meanwhile, micropores having a pore diameter of not more than 10 ⁇ m are formed in the drug-loaded coating.
  • the weight average molecular weight of the polymer is preferably between [10, 50] million.
  • the pores of the micropores are no more than 1 micron; further no more than 0.1 micron.
  • the amount of the active drug per unit area of the iron-based alloy substrate is between [5,500] ⁇ g/cm 2 , and further, between [50, 300] ⁇ g/cm 2 .
  • the mass ratio of the polymer to the active drug is between [50:1, 0.1:1], further, between [10:1, 0.2:1].
  • the thickness of the drug-loaded coating is between [2, 50] micrometers. Further, when micropores having a pore diameter of not more than 1 micrometer are formed in the drug-loaded coating layer, the thickness of the drug-loaded coating layer is [5] between 30 micrometers, the drug-loaded coating may be a layer or a combination of layers, which may be a uniform coating or a non-uniform coating such as an asymmetric coating, a discontinuous coating or a single side. coating.
  • the drug loading coating can be applied to at least a portion of the surface of the iron-based alloy substrate. When the iron-based alloy has slits, grooves or cavities, the drug-loaded coating may be applied to the surface of the iron-based alloy substrate, and may be coated in the slit, the groove or the cavity.
  • the polymer is selected from a degradable polyester-based polymer, or a blend of the degradable polyester-based polymer and a non-degradable polyester-based polymer, or at least one forms the degradable polyester a copolymer of a monomer of the polymer and at least one monomer forming the non-degradable polyester-based polymer, the degradable polyester-based polymer being selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate Any one or at least one of poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polyvalerate, polyhydroxyalkyl alcohol ester, poly(malate) a physical blend of two, or a copolymer of at least two of the monomers forming the aforementioned degradable polyester-based polymer; the non-degradable polyester-based polymer is selected from the group consisting of starch, chitosan, Cellulose, polysaccharides, glycans and their derivatives
  • the active drug is selected from at least one of an anti-angiogenic drug, an anti-platelet drug, an anti-thrombotic drug, an anti-inflammatory drug, and an anti-sensitizing drug, and the anti-angiogenic drug is selected from the group consisting of paclitaxel and rapamycin.
  • the antiplatelet drug is selected from the group consisting of cilostazol; the antithrombotic drug is selected from the group consisting of heparin; the anti-inflammatory drug is selected from the group consisting of dexamethasone;
  • the drug is selected from the group consisting of diphenhydramine, chlorpheniramine, promethazine, hydrocortisone, triamcinolone acetonide, methylprednisolone, loratadine, fexofenadine, levocetirizine, At least one of mizolastine and ebastine.
  • the iron-based alloy implanted medical device may be a vascular stent, a non-vascular endoluminal stent, an occluder, other cardiovascular implants, an orthopedic implant, a gynecological implant, a male implant, a respiratory implant. Things.
  • the iron-based alloy substrate is an iron-based alloy or pure iron having a carbon content of not more than 2.11 wt.%.
  • the release percentage of the active drug is between [4t 1/2 -1, 6.9t 1/2 +63], t ⁇ (0, 28), and t is the sampling time/day.
  • the present invention also provides a method for preparing an iron-based alloy implanted medical device, comprising the steps of: dissolving the polymer and the active drug in an organic solvent to form a solution, and then coating the solution on an iron base On the alloy substrate, such as at least part of a surface, a slit, a groove or a cavity, the polymer has a weight average molecular weight of [5,100] million, and the organic solvent is selected from the group consisting of chloroform, dichloromethane, At least one of ethyl acetate, tetrahydrofuran, acetone, methanol, ethanol, acetonitrile, 1, 4-dioxane, dimethylformamide, and isopropanol.
  • the iron-based implanted medical device of the present invention selects a polymer in a molecular weight range of [5,100] million as a drug carrier, and a micropore having a pore diameter of not more than 10 ⁇ m is formed in the drug-loaded coating, and the active drug is formed.
  • the release percentage is between [4t 1/2 -1, 6.9t 1/2 +63], where t ⁇ (0,28), t is the sampling time/day, with a suitable drug release rate.
  • the release rate of the active drug in the drug-loaded coating of the iron-based alloy implanted medical device of the present invention is affected by various factors, including:
  • drug release is mainly achieved by dissolution, diffusion, and degradation of drug carriers such as polymers.
  • the size of the pore size in the drug-loaded coating directly affects the rate of dissolution and diffusion of the drug, and also affects the degradation rate of the polymer.
  • the invention thus controls the rate of drug release directly by controlling the molecular weight range of the polymer and the pore size of the drug-loaded coating.
  • the present invention can obtain a carrier having a different pore size by selecting a polymer having a weight average molecular weight of [5,100] million and adjusting the molecular weight of the polymer, the kind of the drug and the solvent, and the ratio of the polymer to the drug within this range.
  • the size of the pore size of the drug-loaded coating is independent of the substrate.
  • the drug release rate of the device of the invention is characterized by animal experiments.
  • the iron-based alloy device with the drug-loading mass S is implanted into the abdominal aorta of the rabbit, and the device and its tissue are taken out at a predetermined time, and the remaining drug in the device and the tissue is extracted with a volume V (such as acetonitrile). Constant volume, ultrasound, the drug is completely dissolved in the extraction solvent to obtain a drug extraction solution.
  • the drug-loaded stent was implanted into the abdominal aorta of the rabbit, and samples were taken at 1, 7 days, 14 days, and 28 days, respectively, if the percentage of drug release Y% was 3 to 70%, 9 to 81%, respectively. ⁇ 89%, in the range of 20% to 99%, the stent is considered to have controllable drug release properties.
  • the molecular weight of the high molecular weight polymer refers to a weight average molecular weight, which is detected by an eight-angle laser light scattering instrument manufactured by Wyatt, USA.
  • the method for testing the pore size of the drug-loaded coating is mainly to obtain a complete coating cross section of the original drug-loaded coating stent, and then use a scanning electron microscope to observe the pores of the coating and measure the pore diameter. If the scanning electron microscope is enlarged to 8000 times and the apparent pore diameter cannot be observed, it is regarded as a pore diameter of less than 0.1 ⁇ m.
  • polylactic acid-glycolic acid with a weight average molecular weight of 100,000 and paclitaxel were mixed and dissolved in ethyl acetate in a mass ratio of 3:1, and the solution was coated on the surface of a pure iron stent to form a drug.
  • the coating, the drug-loaded coating had a thickness of 15 ⁇ m, a pore size of 0.2 ⁇ m, and the amount of paclitaxel on the substrate area of the stent was 200 ⁇ g/cm 2 .
  • the prepared drug-loaded stent was implanted into the rabbit abdominal aorta and sampled at 1 day, 7 days, 14 days, and 28 days, respectively. The percentage of drug release on the stent was 20%, 40%, 50%, and 65%, respectively.
  • the experimental results show that the stent drug-loaded coating prepared in this example has controllable drug release properties.
  • Polybutylsuccinate with a weight average molecular weight of 200,000 and rapamycin were dissolved in a chloroform solution at a ratio of 4:1, and sprayed on the surface of the stent to form a polysuccinate-rapamycin drug.
  • the solution was coated on the surface of the iron-zinc alloy stent substrate drug-coating layer as a top layer having a thickness of 10 ⁇ m and a pore diameter of less than 0.1 ⁇ m.
  • the prepared drug-loaded stent was implanted into the rabbit abdominal aorta and sampled at 1 day, 7 days, 14 days, and 28 days. The percentage of drug release was 15%, 35%, 50%, and 65%, respectively.
  • the stent drug-loaded coating prepared in this example has controllable drug release properties.
  • polychlorolactic acid having a weight average molecular weight of 300,000, polyglycolic acid and dexamethasone were dissolved therein at a mass ratio of 1:1:1, and the solution was coated on a nitriding iron having a cavity.
  • a drug-loaded coating is formed in the base cavity of the base alloy stent.
  • the drug-loaded coating has a thickness of 25 ⁇ m, a pore diameter of 2 ⁇ m, and an active drug amount of 300 ⁇ g/cm 2 on the substrate area of the stent.
  • the prepared drug-loaded stent was implanted into the abdominal aorta of rabbits and sampled at 1 day, 7 days, 14 days, and 28 days. The percentage of drug release was 40%, 50%, 60%, and 80%, respectively.
  • the stent drug-loaded coating prepared in this example has controllable drug release properties.
  • a polycaprolactone having a weight average molecular weight of 1,000,000 and a styrene copolymer were dissolved in a mass ratio of 10:1:1 with paclitaxel and promethazine, and the solution was coated on the surface of the galvanized iron support substrate.
  • a drug-loaded coating was formed having a drug-coated coating thickness of 50 ⁇ m, a pore diameter of 5 ⁇ m, and an active drug amount of 100 ⁇ g/cm 2 on the stent substrate area.
  • the prepared drug-loaded stent was implanted into the abdominal aorta of rabbits, and samples were taken at 1 day, 7 days, 14 days, and 28 days. The percentage of drug release was 20%, 30%, 40%, and 60%, respectively.
  • the stent drug-loaded coating prepared in this example has controllable drug release properties.
  • a polysuccinate having a weight average molecular weight of 600,000 and levocetirizine and rapamycin were dissolved in a mass ratio of 100:1:1, and the solution was coated on iron.
  • a drug-loaded coating was formed in the gap of the manganese alloy stent substrate.
  • the drug-loaded coating had a thickness of 10 ⁇ m, a pore diameter of 0.1 ⁇ m, and an active drug amount of 10 ⁇ g/cm 2 on the stent substrate area.
  • the prepared drug-loaded stent was implanted into the abdominal aorta of rabbits and sampled at 1 day, 7 days, 14 days, and 28 days. The percentage of drug release was 10%, 25%, 35%, and 45%, respectively.
  • the stent drug-loaded coating prepared in this example has controllable drug release properties.
  • a polyvalerate-starch copolymer having a weight average molecular weight of 50,000 and triamcinolone acetonide were dissolved therein at a mass ratio of 1:5, and the solution was applied only to the outer wall of the iron-titanium alloy support substrate and The side wall surface was formed with a single-sided drug-loaded coating having a thickness of 15 ⁇ m, a pore size of 0.8 ⁇ m, and an active drug amount of 200 ⁇ g/cm 2 on the substrate area of the stent.
  • the prepared drug-loaded stent was implanted into the rabbit abdominal aorta and sampled at 1 day, 7 days, 14 days, and 28 days. The percentage of drug release was 45%, 55%, 65%, and 90%, respectively.
  • the stent drug-loaded coating prepared in this example has controllable drug release properties.
  • a polyglycolic acid-cellulose copolymer having a weight average molecular weight of 1,000,000 and rapamycin were dissolved therein in a mass ratio of 1:1 using dichloromethane as a solvent, and the solution was coated on the surface of the iron-cobalt alloy support substrate.
  • a drug-loaded coating layer was formed, the drug-loaded coating layer was 30 ⁇ m thick, the pore diameter was 0.5 ⁇ m, and the amount of the active drug on the stent substrate area was 100 ⁇ g/cm 2 .
  • the prepared drug-loaded stent was implanted into the abdominal aorta of rabbits and sampled at 1 day, 7 days, 14 days, and 28 days. The percentage of drug release was 15%, 35%, 50%, and 65%, respectively. It is shown that the stent drug-loaded coating prepared in this example has controllable drug release properties.
  • ethyl acetate a solvent
  • polylactic acid and rapamycin having a weight average molecular weight of 200,000 were dissolved in a mass ratio of 2:1, and the solution was coated on the surface of the pure iron support substrate to form a drug-loaded coating.
  • the drug coating thickness was 10 ⁇ m
  • the pore diameter was less than 0.1 ⁇ m
  • the amount of the active drug on the stent substrate area was 150 ⁇ g/cm 2 .
  • the prepared drug-loaded stent was implanted into the abdominal aorta of rabbits and sampled at 1 day, 7 days, 14 days, and 28 days. The percentage of drug release was 30%, 45%, 55%, and 70%, respectively. It is shown that the stent drug-loaded coating prepared in this example has controllable drug release properties.
  • polyglycolic acid and rapamycin having a weight average molecular weight of 30,000 were dissolved at a ratio of 1:1, and the solution was coated on the surface of the pure iron support substrate to form a completely covered drug-loaded coating.
  • the drug-loaded coating had a thickness of 40 ⁇ m, a pore diameter of 12 ⁇ m, and an active drug amount of 50 ⁇ g/cm 2 on the substrate area of the stent.
  • the prepared drug-loaded stent was implanted into the rabbit abdominal aorta, and samples were taken at different time points to test the drug release profile of the stent coating. At 1 day, the drug release percentage was already greater than 80%.
  • polylactic acid having a weight average molecular weight of 20,000 and paclitaxel were dissolved at a mass ratio of 10:1, and the solution was coated on the surface of the pure iron support substrate to form a drug-loaded coating layer.
  • the pore diameter is less than 0.1 ⁇ m
  • the amount of the active drug on the substrate area of the stent is 50 ⁇ g/cm 2
  • the prepared drug-loading stent is implanted into the abdominal aorta of the rabbit, and samples are taken at different time points to test the coating of the stent.
  • the iron-based alloy provided by the present invention is implanted into a medical device drug-loaded coating, and the polymer having a weight average molecular weight of [5,100] million
  • a drug-loaded coating having micropores having a pore diameter of not more than 10 ⁇ m is formed on the surface of the implanted medical device by adjusting the ratio of the polymer to the drug, the thickness of the drug-loaded coating, the amount of the drug, and the type of the solvent, thereby achieving controllable Drug release.

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Abstract

一种铁基合金植入医疗器械，包括铁基合金基体和载药涂层，载药涂层包括聚合物及活性药物，聚合物的重均分子量在[5，100]万之间，载药涂层中形成有孔径不大于10微米的微孔。铁基合金植入医疗器械上活性药物的释放百分比位于[4t 1/2-1，6.9t 1/2+63]之间，其中t∈(0，28]，t为取样时间/天。

Description

铁基合金植入医疗器械及其制备方法 技术领域
本发明属于可降解植入医疗器械领域，涉及一种可控药物释放的铁基合金载药植入医疗器械及其制备方法。
背景技术
当前，植入医疗器械通常采用金属及其合金、陶瓷、聚合物和相关复合材料制成。其中，金属材料基植入医疗器械因其优越的力学性能，如高强度、高韧性等，尤为受人青睐。
铁作为人体的重要元素，参与到诸多生物化学过程中，如氧的搬运。Peuster M等采用激光雕刻方法制成的、与临床使用的金属支架形状相似的易腐蚀性纯铁支架，植入到16只新西兰兔的降主动脉处。此动物实验结果表明，在6-18个月内没有血栓并发症，亦无不良事件发生，病理检查证实局部血管壁无炎症反应，平滑肌细胞无明显增殖，初步说明可降解铁支架安全可靠，具有良好的应用前景。
从临床应用的角度来说，当可吸收植入医疗器械完成了其预期用途，病变部位痊愈并恢复正常形态和功能(即痊愈)后，在不引起新的生物相容性问题的前提下，器械完全腐蚀或降解并被机体吸收的时间越短越好。根据临床上器械应用的部位不同，一般认为痊愈期为1-6个月，这段时间内器械需保持结构完整性和具有足够的力学性能。铁基合金的生物相容性良好，但铁基合金在体内腐蚀缓慢，导致铁基合金器械在痊愈期后仍需很长时间才能完全腐蚀，因此需加快其腐蚀速度以缩短铁基合金器械的腐蚀周期。有报道指出，在铁基合金(包括纯铁与医用铁基合金)表面涂覆可降解聚酯类涂层，可以加快铁基合金的腐蚀速度。
在植入医疗器械上设置可降解聚合物载药涂层，可在器械植入体内后进一步发挥药物治疗作用。例如，若在裸支架的基础上增加治疗再狭窄的活性药物成分，在支架植入血管后，能够大大降低管腔再狭窄率。活性药物的释放速度对载药植入医疗器械的治疗效果起着至关重要的作用。当器械总药量范围一定时，如果药物释放速度太慢，则药物的治疗效果有限，如果药物释放速度太快，局部药物浓度过高会产生毒副作用。因此，对于铁基合金植入医疗器械，除了需要如本申请人于2013年10月31日申请的CN201310533266.6号专利所述具有适合的腐蚀速度外，还必须具有合适药物释放速度。
发明内容
本发明要解决的技术问题在于，针对现有技术的缺陷，提供一种铁基合金植入医疗器械，该铁基合金植入医疗器械使用特定分子量范围的聚合物作为载药涂层的药物载体，在植入体内后能实现可控的药物释放。
一种铁基合金植入医疗器械，包括铁基合金基体及载药涂层，所述载药涂层包括聚合物及活性药物，所述聚合物的重均分子量在[5，100]万之间，所述载药涂层中形成有孔径不大于10微米的微孔。所述聚合物的重均分子量优选在[10，50]万之间。所述微孔的孔径不大于1微米；进一步不大于0.1微米。所述活性药物在所述铁基合金基体单位面积上的量在[5，500]μg/cm2之间，进一步地，在[50，300]μg/cm2之间。所述聚合物与活性药物的质量比在[50:1，0.1:1]之间，进一步地，在[10:1，0.2:1]之间。
所述载药涂层的厚度在[2，50]微米之间，进一步地，当所述载药涂层中形成有孔径不大于1微米的微孔时，载药涂层的厚度在[5，30]微米之间，所述载药涂层可以是一层，也可以是多层组合，可以是均匀涂层，也可以是非均匀涂层如不对称涂层、不连续涂层或单面涂层。所述载药涂层可以涂覆在铁基合金基体的至少部分表面上。当铁基合金有缝隙、凹槽或腔体时，所述载药涂层除了可以涂覆在铁基合金基体的表面上，还可以涂覆在此缝隙、凹槽或腔体中。
所述聚合物选自可降解聚酯类聚合物，或所述可降解聚酯类聚合物与非可降解聚酯类聚合物的共混物，或至少一种形成所述可降解聚酯类聚合物的单体与至少一种形成所述非可降解聚酯类聚合物的单体的共聚物，所述可降解聚酯类聚合物选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚戊酸酯、聚羟基烷基醇酯、聚(苹果酸酯)中的任意一种或至少两种的物理共混物，或形成前述可降解聚酯类聚合物的单体中的至少两种单体的共聚物；所述非可降解聚酯类聚合物选自淀粉、壳聚糖、纤维素、聚糖、聚糖及其衍生物、聚氨酯(PU)、聚碳酸酯、聚甲基丙烯酸甲酯(PMMA)、聚苯乙烯(PS)、聚丁烯、聚甲基丙烯酸丁酯(PBMA)、聚丙烯酰胺中的任意一种或至少两种的物理共混物，或形成前述非可降解聚酯类聚合物的单体中的至少两种单体的共聚物。
所述活性药物选自抑制血管增生药物、抗血小板类药物、抗血栓类药物、抗炎症反应药物、抗致敏药物中的至少一种，所述抑制血管增生药物选自紫杉醇、雷帕霉素及其衍生物中的至少一种；所述抗血小板类药物选自西洛他唑；所述抗血栓类药物选自肝素；所述抗炎症反应药物选自地塞米松；所述抗致敏药物选自苯海拉明、氯苯那敏、异丙嗪、氢化可的松、曲安奈德，甲基强的松龙、氯雷他定、非索非那定、左西替利嗪、咪唑斯汀、依巴斯汀中的至少一种。
所述铁基合金植入医疗器械可以是血管支架、非血管腔内支架、封堵器、其它心血管植入物、骨科植入物、妇科植入物、男科植入物、呼吸科植入物。
所述铁基合金基体为碳含量不高于2.11wt.％的铁基合金或纯铁。
所述活性药物的释放百分比位于[4t1/2-1，6.9t1/2+63]之间，t∈(0，28]，t为取样时间/天。
本发明还提供了一种铁基合金植入医疗器械的制备方法，包括以下步骤：将所述聚合物及所述活性药物溶解在有机溶剂中形成溶液，然后将所述溶液涂覆在铁基合金基体上，例如至少部分表面、缝隙、凹槽或腔体上，所述聚合物的重均分子量在[5，100]万之间，所述有机溶剂选自三氯甲烷，二氯甲烷，乙酸乙酯，四氢呋喃，丙酮，甲醇，乙醇，乙腈，1、4二氧六烷，二甲基甲酰胺，异丙醇中的至少一种。
相比现有技术，本发明的铁基植入医疗器械选用[5，100]万分子量范围内聚合物作为药物载体，且载药涂层中形成有孔径不大于10微米的微孔，活性药物的释放百分比位于[4t1/2-1，6.9t1/2+63]之间，其中t∈(0，28]，t为取样时间/天，具有适宜的药物释放速。
具体实施方式
为了便于理解本发明，本发明给出了首选实施例。但是，本发明可以以许多不同的形式来实现，并不限于本文所描述的实施例。相反地，提供这些实施例的目的是使本发明的公开内容更加透彻全面。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
本发明的铁基合金植入医疗器械载药涂层中活性药物的释放速度受多种因素影响，包括：
(1)聚合物分子量越高，聚合物与药物之间物相分离越明显，药物释放速度越快；
(2)聚合物与药物比值越小，聚合物对药物的约束能力越弱，药物释放速度越快；
(3)载药涂层越薄，药物扩散释放路径越短，药物释放速度越快；
(4)制备方法中选用的溶剂的饱和蒸汽压越高，其挥发速率越快，从而使聚合物与药物之间的相互作用力越弱，药物释放速度越快。
从药物释放机制来看，药物释放主要是通过溶解、扩散以及药物载体(如聚合物)的降解等方式来实现的。而载药涂层中孔径的大小，直接影响到药物的溶解和扩散速度，也会影响到聚合物的降解速度。因此本发明直接通过控制聚合物分子量范围和载药涂层的孔径来控制药物释放速度。本发明通过选择重均分子量在[5，100]万之间的聚合物并在此范围内调整聚合物的分子量、药物及溶剂的种类、聚合物与药物比例，可以获得具有不同孔径大小的载 药涂层。载药涂层孔径的大小与基体无关。
本发明的器械的药物释放速度通过动物实验表征。将载药质量为S的铁基合金器械植入兔子腹主动脉，在预定时间将器械及其所在的组织截取出来，将器械及组织中剩余的药物用体积为V的萃取溶剂(如：乙腈)定容、超声，使药物完全溶解在萃取溶剂中，获得药物萃取溶液。采用安捷伦1260高效液相色谱仪测量药物萃取溶液中的药物浓度c，进而得到样品剩余药物质量S1＝cV，则样品在该时间点的药物释放百分比Y％＝(S-S1)/S*100％。
以下结合具体实施例，以载药铁基合金支架为例，对本发明作进一步详细说明，但是本发明保护的范围并不局限于此。
以下各实施例是将载药支架植入兔子腹主动脉，分别在1天、7天、14天、28天时取样，如其药物释放百分比Y％分别在3～70％，9～81％，14～89％，20～99％范围内，视为该支架具有可控的药物释放性能。
所述高分子量聚合物的分子量是指重均分子量，所述重均分子量大小采用美国怀雅特公司生产的八角度激光光散射仪进行检测。
所述的载药涂层孔径测试方法主要是通过获取原始载药涂层支架完整的涂层截面，然后使用扫描电镜，观察涂层的孔隙并测量孔隙直径。如果在扫描电镜放大至8000倍，仍无法观察出明显的孔径，则视作孔径低于0.1微米。
实施例1
以乙酸乙酯为溶剂，将重均分子量为10万的聚乳酸-乙醇酸与紫杉醇按3:1的质量比混合溶解在乙酸乙酯中，将溶液涂覆在纯铁支架基体表面形成载药涂层，载药涂层厚度为15μm，孔径大小为0.2μm，紫杉醇在支架基体面积上的量为200μg/cm2。将制备好的载药支架植入兔子腹主动脉，分别在1天、7天、14天、28天时取样，测试得到支架上药物释放百分比分别为20％、40％、50％、65％，实验结果表明本实施例制备的支架载药涂层具有可控的药物释放性能。
实施例2
将重均分子量为20万的聚丁二酸酯与雷帕霉素以4:1的比例分别溶解在三氯甲烷溶液中，喷涂在支架表面形成聚丁二酸酯-雷帕霉素载药涂层，该涂层厚度约为5μm，孔径为低于0.1μm，雷帕霉素在支架基体面积上的量为50μg/cm2；然后将分子量为6万聚丁二酸酯的三氯甲烷溶液涂覆在铁锌合金支架基体载药涂层表面，作为顶层，其厚度为10μm，孔径低于0.1μm。将制备好的载药支架植入兔子腹主动脉，在1天、7天、14天、28天时取样，测试得到药物释放百分比分别为15％、35％、50％、65％，实验结果表明本实施例制备的支架载药涂层具有可控的药物释放性能。
实施例3
以丙酮为溶剂，将重均分子量为30万的聚消旋乳酸，聚乙醇酸与地塞米松以1:1:1的质量比溶解于其中，将溶液涂覆在有空腔的渗氮铁基合金支架基体腔内，形成载药涂层，载药涂层厚度为25μm，孔径为2μm，活性药物在支架基体面积上的量为300μg/cm2。将制备好的载药支架植入兔子腹主动脉，在1天、7天、14天、28天时取样，测试得到药物释放百分比分别为40％、50％、60％、80％，实验结果表明本实施例制备的支架载药涂层具有可控的药物释放性能。
实施例4
以四氢呋喃为溶剂，将重均分子量为100万的聚己内酯与苯乙烯共聚物与紫杉醇、异丙嗪以10:1:1的质量比溶解于其中，将溶液涂覆在镀锌铁支架基体表面形成载药涂层，载药涂层厚度为50μm，孔径为5μm，活性药物在支架基体面积上的量为100μg/cm2。将制备好的载药支架植入兔子腹主动脉，在1天、7天、14天、28天时取样，测试得到药物释放百分比分别为20％、30％、40％、60％，实验结果表明本实施例制备的支架载药涂层具有可控的药物释放性能。
实施例5
以乙酸乙酯为溶剂，将重均分子量为60万的聚丁二酸酯与左西替利嗪、雷帕霉素以100:1:1的质量比溶解于其中，将溶液涂覆在铁锰合金支架基体的缝隙中形成载药涂层，载药涂层厚度为10μm，孔径为0.1μm，活性药物在支架基体面积上的量为10μg/cm2。将制备好的载药支架植入兔子腹主动脉，在1天、7天、14天、28天时取样，测试得到药物释放百分比分别为10％、25％、35％、45％，实验结果表明本实施例制备的支架载药涂层具有可控的药物释放性能。
实施例6
以四氢呋喃为溶剂，将重均分子量为5万的聚戊酸酯-淀粉共聚物、曲安奈德以1:5的质量比溶解于其中，将溶液仅涂覆在铁钛合金支架基体的外壁和侧壁表面，形成单面载药涂层，载药涂层厚度为15μm，孔径为0.8μm，活性药物在支架基体面积上的量为200μg/cm2。将制备好的载药支架植入兔子腹主动脉，在1天、7天、14天、28天时取样，测试得到药物释放百分比分别为45％、55％、65％、90％，实验结果表明本实施例制备的支架载药涂层具有可控的药物释放性能。
实施例7
以二氯甲烷为溶剂，将重均分子量为100万的聚乙醇酸-纤维素共聚物、雷帕霉素以1:1的质量比溶解于其中，将溶液涂覆在铁钴合金支架基体表面形成载药涂层，载药涂层厚度为 30μm，孔径为0.5μm，活性药物在支架基体面积上的量为100μg/cm2。将制备好的载药支架植入兔子腹主动脉，在1天、7天、14天、28天时分别取样，测试得到药物释放百分比分别为15％、35％、50％、65％，实验结果表明本实施例制备的支架载药涂层具有可控的药物释放性能。
实施例8
以乙酸乙酯为溶剂，将重均分子量为20万的聚乳酸、雷帕霉素以2:1的质量比溶解于其中，将溶液涂覆在纯铁支架基体表面形成载药涂层，载药涂层厚度为10μm，孔径低于0.1μm，活性药物在支架基体面积上的量为150μg/cm2。将制备好的载药支架植入兔子腹主动脉，在1天、7天、14天、28天时分别取样，测试得到药物释放百分比分别为30％、45％、55％、70％，实验结果表明本实施例制备的支架载药涂层具有可控的药物释放性能。
对比例1
以乙酸乙酯为溶剂，将重均分子量为3万的聚乙醇酸和雷帕霉素以1:1的比例溶解，将溶液涂覆在纯铁支架基体表面形成完全覆盖的载药涂层，载药涂层厚度为40μm，孔径为12μm，活性药物在支架基体面积上的量为50μg/cm2。将制备好的载药支架植入兔子腹主动脉，并在不同时间点取样，测试该支架涂层的药物释放曲线，1天时，药物释放百分比已经大于80％。
对比例2
以三氯甲烷为溶剂，将重均分子量为2万的聚乳酸与紫杉醇以10:1的质量比溶解，将溶液涂覆在纯铁支架基体表面形成载药涂层，载药涂层厚度为20μm，孔径低于0.1μm，活性药物在支架基体面积上的量为50μg/cm2，将制备好的载药支架植入兔子腹主动脉，并在不同时间点取样，测试该支架涂层的药物释放曲线，1天时，药物释放百分比小于3％。
从以上实施例1～8和对比例1～2的实验结果可以看出，本发明提供的铁基合金植入医疗器械载药涂层，以重均分子量为[5，100]万的聚合物作为药物载体，通过调节聚合物与药物比例、载药涂层厚度、药量、溶剂种类，在植入医疗器械表面形成具有不大于10微米孔径的微孔的载药涂层，实现了可控的药物释放。
以上实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (15)

  1. 一种铁基合金植入医疗器械，包括铁基合金基体和载药涂层，所述载药涂层包括聚合物及活性药物，所述聚合物的重均分子量在[5，100]万之间，其特征在于，所述载药涂层中形成有孔径不大于10微米的微孔。
  2. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述聚合物的重均分子量在[10，50]万之间。
  3. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述载药涂层的厚度在[2，50]微米之间。
  4. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述活性药物在所述铁基合金基体单位面积上的量在[5，500]μg/cm2之间。
  5. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述聚合物与活性药物的质量比在[50:1，0.1:1]之间。
  6. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述载药涂层为一层或多层。
  7. 根据权利要求2所述的铁基合金植入医疗器械，其特征在于，所述微孔的孔径不大于1微米，进一步不大于0.1微米。
  8. 根据权利要求7所述的铁基合金植入医疗器械，其特征在于，所述载药涂层的厚度在[5，30]微米之间。
  9. 根据权利要求8所述的铁基合金植入医疗器械，其特征在于，所述活性药物在所述铁基合金基体单位面积上的量在[50，300]μg/cm2之间。
  10. 根据权利要求9所述的铁基合金植入医疗器械，其特征在于，所述聚合物与活性药物的质量比在[10:1，0.2:1]之间。
  11. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述聚合物选自可降解聚酯类聚合物，或所述可降解聚酯类聚合物与非可降解聚酯类聚合物的共混物，或至少一种形成所述可降解聚酯类聚合物的单体与至少一种形成所述非可降解聚酯类聚合物的单体的共聚物，所述可降解聚酯类聚合物选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、聚己二酸乙二醇酯、聚戊酸酯、聚羟基烷基醇酯、聚(苹果酸酯)中的任意一种或至少两种的物理共混物，或形成前述可降解聚酯类聚合物的单体中的至少两种单体的共聚物；所述非可降解聚酯类聚合物选自淀粉、壳聚糖、纤维素、聚糖、聚糖及其衍生物、聚氨酯(PU)、聚碳酸酯、聚甲基丙烯酸甲酯(PMMA)、聚苯乙烯(PS)、聚丁烯、聚甲基丙烯酸丁 酯(PBMA)、聚丙烯酰胺中的任意一种或至少两种的物理共混物，或形成前述非可降解聚酯类聚合物的单体中的至少两种单体的共聚物。
  12. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述活性药物选自抑制血管增生药物、抗血小板类药物、抗血栓类药物、抗炎症反应药物、抗致敏药物中的至少一种，所述抑制血管增生药物选自紫杉醇、雷帕霉素及其衍生物中的至少一种；所述抗血小板类药物选自西洛他唑；所述抗血栓类药物选自肝素；所述抗炎症反应药物选自地塞米松；所述抗致敏药物选自苯海拉明、氯苯那敏、异丙嗪、地塞米松，氢化可的松、曲安奈德，甲基强的松龙、氯雷他定、非索非那定、左西替利嗪、咪唑斯汀、依巴斯汀中的至少一种。
  13. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述铁基合金基体为碳含量不高于2.11wt.％的铁基合金或纯铁。
  14. 根据权利要求1所述的铁基合金植入医疗器械，其特征在于，所述活性药物的释放百分比位于[4t1/2-1，6.9t1/2+63]之间，t∈(0，28]，t为取样时间/天。
  15. 一种如权利要求1-14任一项所述的铁基合金植入医疗器械的制备方法，包括以下步骤：将所述聚合物及所述活性药物溶解在有机溶剂中形成溶液；将所述溶液涂覆在所述铁基合金基体上，所述有机溶剂选自三氯甲烷，二氯甲烷，乙酸乙酯，四氢呋喃，丙酮，甲醇，乙醇，乙腈，1、4二氧六烷，二甲基甲酰胺，异丙醇中的至少一种。
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