WO2019128453A1 - 可吸收铁基植入式器械 - Google Patents

可吸收铁基植入式器械 Download PDF

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Publication number
WO2019128453A1
WO2019128453A1 PCT/CN2018/112861 CN2018112861W WO2019128453A1 WO 2019128453 A1 WO2019128453 A1 WO 2019128453A1 CN 2018112861 W CN2018112861 W CN 2018112861W WO 2019128453 A1 WO2019128453 A1 WO 2019128453A1
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Prior art keywords
iron
implantable device
absorbable
anhydride
antioxidant
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PCT/CN2018/112861
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English (en)
French (fr)
Inventor
林文娇
陈丽萍
秦莉
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先健科技(深圳)有限公司
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Priority to US16/957,202 priority Critical patent/US20200390943A1/en
Priority to EP18897186.5A priority patent/EP3733222B1/en
Publication of WO2019128453A1 publication Critical patent/WO2019128453A1/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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—Metals or alloys
    • A61L27/042—Iron or iron alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/28—Materials for coating prostheses
    • A61L27/34—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/505—Stabilizers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by 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
    • 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
    • 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
    • A61L31/06—Macromolecular materials obtained otherwise than 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
    • A61L31/08—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
    • A61L31/143—Stabilizers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/43—Hormones, e.g. dexamethasone
    • 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
    • A61L2400/18—Modification of implant surfaces in order to improve biocompatibility, cell growth, fixation of biomolecules, e.g. plasma treatment
    • 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
    • A61L2420/08—Coatings comprising two or more layers

Definitions

  • the present invention relates to the field of implantable medical devices, and more particularly to an absorbable iron-based implantable device.
  • absorbable implantable medical device materials are mainly degradable polymers and absorbable metal materials.
  • Absorbable metal materials include magnesium-based alloys, iron-based alloys, zinc-based alloys, and pure iron.
  • iron-based alloys and pure iron have excellent mechanical properties comparable to those of permanently implanted medical metal materials such as stainless steel, cobalt-chromium alloys and platinum-chromium alloys. Compared with other absorbable materials, they can be made smaller.
  • Implanted medical devices with superior mechanical properties ensure better clinical operability and effectiveness.
  • the ideal design concept of absorbable medical devices is that during the recovery period of the lesion, effective support can be provided.
  • the implantable medical device After the lesion is cured, the implantable medical device should be corroded or degraded as soon as possible and absorbed by the body.
  • an unsolved problem that iron-based alloys can absorb medical devices and pure iron absorbable medical devices for a long time is that the main corrosion products of iron are hardly soluble in body fluids, and these corrosion products can pass through the flow of intercellular fluids. Absorption and metabolism by macrophage phagocytosis, but this process takes a long time, resulting in a large number of corrosion products persist in the tissue for a long time, may bring long-term biological risks.
  • the generated Fe 3+ ions preferentially react with hydroxide to form Fe(OH) 3 precipitates, and the iron phosphate is stable under the environment of pH ⁇ 5, and the pH of the body fluid is usually >5. Therefore, Fe 3+ and PO 4 3- ions in the body are difficult to form iron phosphate precipitates.
  • the Fe 2+ ions corroded by the iron-based scaffold consume the phosphate in the local tissue fluid at the implantation site, the phosphate in the other tissue fluid needs to be diffused and replenished, and the diffusion process takes a certain time.
  • the local tissue site of implantation in the OH - ion concentration lower than the concentration of phosphate ions, but OH - can be isolated by water electrolysis in situ quickly added, easier kinetically formed ferrous hydroxide.
  • the solubility products of Fe(OH) 2 and Fe(OH) 3 are 7.19 ⁇ 10 -17 and 1.22 ⁇ 10 -38 , respectively.
  • the concentration of free Fe 2+ when the Fe(OH) 2 precipitate reaches the equilibrium of dissolution is about 60 mg/L, while the concentration of free Fe 3+ after the equilibrium of Fe(OH) 3 is more than ten orders of magnitude lower than that of Fe 2+ .
  • phagocytic cells such as macrophages.
  • the phagocytic cells can only contact the outermost layer of the corrosion product, and the efficiency of engulfing and transporting the solid corrosion products will be lower. Therefore, the Fe(OH) 3 solid corrosion product will be removed more slowly, resulting in a longer absorption period.
  • the corrosion product of iron is difficult to absorb in the body and has a long absorption period.
  • the prior art adopts an antioxidant method to promote the formation of corrosion products of soluble iron, such as water-soluble polyphenols, tocopherols, sodium tripolyphosphate, etc.
  • the above antioxidants have the following problems: 1. Poor stability, chemical properties are easily changed under illumination, oxygen enrichment or specific pH to lose antioxidant effect; 2. Water-soluble antioxidants during and after implantation Dissolved in blood and aqueous tissue fluids, causing a large loss, while fat-soluble antioxidants are difficult to dissolve in water-soluble tissue fluids, so the antioxidant effect is not good, and it is difficult to promote the corrosion product Fe of iron with higher solubility product ( The effect of the formation of OH) 2 ; 3.
  • antioxidants start to release quickly, and iron-based alloy implantable medical devices usually start to corrode a lot of corrosion in about 3 months in order to ensure the stability of the early mechanical properties. Therefore, the above-mentioned antioxidant has not been consumed, and the above-mentioned antioxidant has not been used to promote the absorption of iron.
  • An absorbable iron-based implant device comprising an iron-based substrate, further comprising an iron-promoting absorber attached to the iron-based substrate, the iron-absorbing absorbent being a polymer, and the iron-absorbing absorbent molecular chain Contains an antioxidant structural unit.
  • the iron-promoting absorbent is capable of degrading to release an antioxidant.
  • the antioxidant is selected from at least one of ascorbic acid, proanthocyanidins, vitamin E, glutathione, and lipoic acid.
  • the iron-absorbing absorbent has a weight average molecular weight of from 1,000 to 500,000.
  • the iron propellant is a proanthocyanidin polymer.
  • the iron propellant further comprises at least one degradable polymer structural unit.
  • the iron-promoting absorber further comprises at least one non-degradable polymer structural unit.
  • the degradable polymer is selected from at least one of a degradable polyester, a polyamino acid, a polyanhydride, and a dextran.
  • the degradable polyester is selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, and polyethylene adipate. At least one of the esters.
  • the polyamino acid is selected from at least one of polylysine, polyaspartic acid, polycysteine, polymethionine, polyornithine, and polyglutamic acid.
  • the polyanhydride is selected from the group consisting of polyoxoic anhydride, polysuccinic anhydride, polyadipate anhydride, polysebacic anhydride, polydodoic anhydride, polycitric anhydride, polymalic anhydride, polysuccinic anhydride, At least one of polytartaric anhydride, polyitaic anhydride, and polymaleic anhydride.
  • the non-degradable polymer is selected from the group consisting of ethylene glycol, polyacrylate, polysuccinate, polycarbonate, polyvinyl acetate, polybutyl methacrylate, polystyrene, At least one of polyvinylidene fluoride, polyvinylpyrrolidone and polyhexafluoroethylene.
  • the mass ratio of the iron-promoting agent to the iron in the iron-based matrix is from 0.05 to 3:1.
  • the mass ratio of the iron-promoting agent to the iron in the iron-based matrix is from 0.15 to 1:1.
  • the iron-promoting absorber is attached to a surface of the iron-based substrate; or the iron-absorbing absorbent is filled inside the iron-based substrate.
  • the absorbable iron-based implantable device is a cardiovascular stent, a cerebrovascular stent, a peripheral vascular stent, a biliary stent, an esophageal stent, an airway stent, an occluder, or an orthopedic implant.
  • the absorbable iron-based implantable device further comprises an active drug attached to the iron-based substrate, the active drug selected from the group consisting of a drug that inhibits angiogenesis, an anti-platelet drug, and an antithrombotic device. At least one of a drug, an anti-inflammatory drug, and an anti-allergic drug.
  • the iron-based substrate of the above-mentioned absorbable iron-based implantable device is attached with an iron-promoting absorbent, and the iron-absorbing absorbent is a polymer comprising an antioxidant structural unit, and the absorbable iron-based implantable device is implanted in the body.
  • the iron-promoting agent gradually degrades or slashes, and gradually releases an antioxidant, which acts to promote iron absorption for a long time.
  • An absorbing iron-based implantable device comprising an iron-based substrate and an iron-promoting agent attached to the iron-based substrate, the iron-absorbing absorbent is a polymer, and the iron-absorbing absorbent molecular chain comprises an antioxidant structural unit.
  • the iron-promoting agent is capable of degrading to release an antioxidant.
  • the iron-based matrix may be a pure iron matrix or an iron-based alloy matrix.
  • the material of the iron-based alloy matrix is an iron-based alloy having a carbon content of not more than 2.11 wt.%.
  • the iron-promoting agent may be attached to the surface of the iron-based substrate in a film-forming manner. For example, it is attached to the outer surface, the inner surface or the side surface of the iron-based substrate. Alternatively, it is attached to the outer surface, the inner surface, and the side surface of the iron-based substrate at the same time. Or attached to the outer and inner surfaces of the iron-based substrate, and the like. That is to say, the position of the film layer formed by the iron-promoting agent on the iron-based substrate is not limited. Also, the distribution of the iron-promoting agent on the surface of the iron-based substrate may be uniform or non-uniform.
  • the iron propellant may be filled in the interior of the iron-based matrix.
  • a slit, a hole, a groove, a through hole or an inner cavity may be formed on the iron-based substrate to fill the corresponding iron absorbing agent in the corresponding slit, pore, groove, through hole or inner cavity, so as to promote iron
  • the absorbent is filled inside the iron-based matrix.
  • the antioxidant is selected from at least one of ascorbic acid, proanthocyanidins, vitamin E, glutathione, and lipoic acid.
  • the antioxidant forms an iron-promoting agent by polymerization.
  • the antioxidant structural unit is a repeating unit, and the antioxidant structural unit is connected by a chemical bond. When the iron-promoting agent is degraded or broken, an antioxidant is released.
  • the antioxidant released by the iron-promoting agent is selected from at least one of ascorbic acid, proanthocyanidins, vitamin E, glutathione, and lipoic acid.
  • the antioxidant released by the iron-absorbing absorbent is a small molecular substance in the normal metabolism process of human tissue cells or a daily nutrient which can be safely ingested, so that the iron-absorbing absorbent degrades or releases the product in the body and the biological phase of the human body. It has good capacitance and does not produce substances harmful to the human body.
  • the antioxidants released when the above-mentioned iron-promoting agent is degraded are all antioxidants having strong reducing action, and when the iron-absorbing absorbent is degraded or broken in the body to release an antioxidant, the absorbable iron-based implantable type can be consumed.
  • the in-situ and nearby oxygen of the device ensures that the etched Fe 2+ is not immediately oxidized to Fe 3+ , but in the form of higher solubility Fe 2+ and its precipitate phase, which facilitates the diffusion of iron corrosion products. absorb.
  • the iron-promoting agent can delay the conversion of Fe 2+ to Fe 3+ , and the free Fe 2+ diffuses out with the tissue fluid.
  • the diffused Fe 2+ ions are continuously oxidized into Fe 3+ ions in the oxygen-rich structure away from the iron-based matrix, and precipitated into dispersed Fe(OH) 3 solid corrosion products in the surrounding structure where the iron-based matrix is implanted in situ. .
  • the more dispersed the Fe(OH) 3 solid corrosion product the more favorable it is to improve the efficiency of phagocytic phagocytosis handling and metabolism of ferric iron corrosion products, thereby shortening the absorption period of the absorbable iron-based implantable device in vivo.
  • the iron-promoting agent gradually degrades or sag, gradually releasing an antioxidant, thereby delaying the release rate of the antioxidant and increasing the antioxidant.
  • the utilization rate plays a long-term role in promoting iron absorption.
  • the iron-promoting agent can be gradually degraded or broken, and an antioxidant is gradually released.
  • the antioxidant which forms the iron-promoting absorbent can also be other antioxidants which have antioxidant properties and are biocompatible with the human body.
  • the molecular weight of the iron-promoting agent is too low, and the release rate of the antioxidant is fast, which is not conducive to increasing the long-term effect of the antioxidant to promote iron absorption.
  • the iron-absorbing absorbent has a weight average molecular weight of 1,000 to 500,000.
  • the iron-absorbing absorbent has a weight average molecular weight of from 3,000 to 300,000.
  • the above iron-promoting absorbent is a polymer containing an antioxidant structural unit, and has a high stability compared with most natural antioxidants.
  • oxygen enrichment or specific pH its chemical properties are difficult to change and can exist stably for a long time.
  • the iron-absorbing absorbent has poor solubility in water. Therefore, the iron-promoting agent can be stably present in the body.
  • the iron-absorbing absorbent is difficult to dissolve in the aqueous tissue fluid, and the loss is small, thereby enabling the long-term Effectively promote the role of iron absorption.
  • the stability of the iron-promoting absorbent is good, the environmental requirements for product storage are low, and the failure of the product due to the failure of the iron-absorbing absorbent during storage is not facilitated, thereby prolonging the shelf life.
  • the iron propellant further comprises at least one degradable polymer structural unit.
  • the iron-promoting absorbent is formed by polymerizing a degradable polymer monomer with the above antioxidant. On the iron-promoting agent molecular chain, the degradable polymer structural unit is linked to the antioxidant structural unit by a chemical bond.
  • the degradable polymer structural unit refers to a repeating unit in the molecular chain of the degradable polymer.
  • the degradable polymer is selected from the group consisting of at least one of forming a degradable polyester, a polyamino acid, a polyanhydride, and a dextran.
  • the degradable polyester is selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, and polyethylene adipate. At least one.
  • the polyamino acid is selected from at least one of polylysine, polyaspartic acid, polycysteine, polymethionine, polyornithine, and polyglutamic acid.
  • the polyanhydride is selected from the group consisting of polyoxoic anhydride, polysuccinic anhydride, polyadipate anhydride, polysebacic anhydride, polydodecanoic anhydride, poly citrate anhydride, polymalic anhydride, polysuccinic anhydride, polytartrate anhydride At least one of polytherapeutic anhydride and polymaleic anhydride.
  • the polymerization of the degradable polymer monomer and the antioxidant is beneficial to improve the stability of the antioxidant, further delaying the release rate of the antioxidant, and the antioxidant is gradually released slowly after the implantable iron-based implantable device is implanted into the body.
  • the segment formed by the degradable polymer can also be gradually degraded and absorbed.
  • degradable polymer monomers capable of polymerizing with an antioxidant to form an iron-promoting agent and having good biocompatibility with the human body are also It can be applied to the above-mentioned absorbable iron-based implantable device to achieve long-lasting iron absorption.
  • the iron propellant further comprises at least one non-degradable polymeric structural unit.
  • the non-degradable polymer structural unit is a repeating unit on the non-degradable polymer molecular chain.
  • the iron-promoting absorbent is polymerized from a non-degradable polymer monomer and an antioxidant to form an iron-promoting absorber.
  • the non-degradable polymer is polyethylene glycol, polyacrylate, polysuccinate, polycarbonate, polyvinyl acetate, polybutyl methacrylate, polystyrene, polyvinylidene fluoride. At least one of ethylene, polyvinylpyrrolidone and polyhexafluoroethylene.
  • the iron propellant further comprises at least one degradable polymer structural unit and at least one non-degradable polymeric structural unit.
  • the types of degradable polymer and non-degradable polymer are the same as those of the above-exemplified degradable polymer and non-degradable polymer, respectively.
  • non-degradable polymer structural units can improve the hydrophilicity, or hydrophobicity, or mechanical properties of the iron-promoting agent, or the stability and release rate of the antioxidant.
  • non-degradable polymer monomers in addition to the above-described non-degradable polymer monomers, other can be polymerized with antioxidant polymerization or with antioxidant and degradable polymer monomers to form an iron-promoting agent, and with human organisms.
  • Compatible non-degradable polymer monomers can also be used in the above-mentioned absorbable iron-based implantable devices to improve the hydrophilicity or hydrophobicity, or mechanical properties of the iron-absorbing absorbent, or the stability of antioxidants. And the effect of the release rate.
  • the antioxidant is copolymerized with the degradable polymer monomer and/or the non-degradable polymer monomer, and can be copolymerized by random copolymerization, alternating copolymerization, block copolymerization or graft copolymerization.
  • the iron-promoting agent formed by the polymerization can gradually release the antioxidant.
  • the quality of the iron-promoting agent is too low, and the effect of promoting iron absorption is not obvious.
  • the iron-absorbing absorbent has high quality and good iron absorption effect, but due to its high quality and large volume, it will seriously affect the physical properties of the absorbable iron-based implantable device. Therefore, the combined iron absorption effect and physical properties, the mass ratio of the iron-absorbing absorbent to the iron in the iron-based matrix is 0.05 to 3:1. In one embodiment, the mass ratio of the iron-promoting agent to the iron in the iron-based matrix is from 0.15 to 1:1.
  • the absorbable iron-based implantable device further comprises an active drug.
  • the active drug may be directly applied to the iron-based substrate, or may be filled on the iron-based substrate, or may be dispersed in the film layer formed by the iron-absorbing absorbent, or dispersed in the degradable polymer layer.
  • the active drug is selected from at least one of a drug for inhibiting angiogenesis, an antiplatelet drug, an antithrombotic drug, an anti-inflammatory drug, and an anti-sensitizer.
  • the drug for inhibiting angiogenesis is selected from at least one of paclitaxel, rapamycin, and rapamycin derivatives.
  • the antiplatelet drug is cilostazol.
  • the antithrombotic drug is heparin.
  • the anti-inflammatory drug is dexamethasone.
  • the anti-sensitizing drug is selected from at least one of calcium gluconate, chlorpheniramine and cortisone.
  • the iron-based substrate of the above-mentioned absorbable iron-based implantable device has an iron-promoting agent attached thereto, and the iron-promoting absorbent is a polymer containing an antioxidant structural unit.
  • the absorbable iron-based implantable device gradually degrades gradually, gradually releases an antioxidant, exerts a long-acting effect, effectively delays the release rate of the antioxidant, and promotes iron absorption during the gradual corrosion of the iron-based matrix.
  • the antioxidant released by the agent can more fully interact with the iron corrosion products, thereby promoting the absorption of iron corrosion products.
  • the above-mentioned absorbable iron-based implantable devices are cardiovascular stents, cerebrovascular stents, peripheral vascular stents, biliary stents, esophageal stents, airway stents, occluders or orthopedic implants.
  • an iron-based matrix is prepared according to a method known to those skilled in the art, and then an iron-promoting agent and/or a metal-based matrix is formed on the iron-based substrate by a method known to those skilled in the art.
  • a degradable polymer layer of the drug and the like.
  • a lumen iron-based substrate is formed by laser cutting, and then an iron-promoting agent and/or a drug-containing degradable polymer layer is formed on the iron-based substrate by plasma spraying, ultrasonic atomization spraying, or the like.
  • the above iron-promoting absorbers are obtained by polymerization or by polymerization using a polymerization method known to those skilled in the art.
  • the antioxidant and the polymer monomer are copolymerized by a melt polymerization method to form an iron-promoting absorbent, for example, polymerized by a melt polymerization method to form a polylactic acid vitamin E copolymer.
  • a ring-opening polymerization method is used to form a copolymer of an antioxidant and a polymer monomer, such as using ascorbic acid as an initiator to initiate ring-opening polymerization of caprolactone to synthesize an ascorbyl polycaprolactone copolymer.
  • vitamin C ascorbic acid
  • anhydrous potassium carbonate N,N-dimethylformamide
  • N,N-dimethylformamide N,N-dimethylformamide
  • the benzyl protected vitamin C precursor was dissolved in dichloromethane, and then an acrylamide solution was slowly added dropwise to synthesize an acrylate-modified benzyl-protected vitamin C monomer.
  • the L-type lactide is ring-opened to synthesize a polylactic acid homopolymer.
  • the block copolymer is synthesized by synthesizing the homopolymer with the vitamin C precursor under the conditions of copper bromide and anhydrous toluene, and then the block copolymer is debenzylated by hydrogen to obtain a polylactic acid block polyascorbic acid acrylate copolymer.
  • an iron-based alloy vascular stent containing an iron-promoting agent As an example, the iron absorption in the blood vessel of the iron-based alloy vascular stent was examined by implanting an iron-based alloy stent containing an iron-promoting agent into a healthy miniature pig coronary artery model. /Percentage of metabolism, the iron absorption absorption effect of the iron-promoting agent in the body was evaluated by the absorption/metabolism percentage of iron.
  • the specific method is to measure the mass M 0 of the iron in the implanted iron-based alloy vascular stent, and then implant the iron-based alloy vascular stent containing the iron-promoting agent of the same batch size into the porcine coronary artery, and take the iron after 36 months.
  • Base alloy vascular stent and its vascular segment carefully trim the adipose tissue around the adventitia and myocardial tissue, and ensure that the length of the blood vessel is equivalent to the length of the iron-based alloy vascular stent implanted therein.
  • the iron-based alloy is measured.
  • the vascular stent and the vascular segment where the stent is located have an iron content of M 1 , and the iron ion content in the blank blood vessel is very low, which is ignored here.
  • the specific method for testing the iron content is to digest the stent or the stent together with the blood vessel in the microwave digestion apparatus with concentrated nitric acid, and then use an Agilent 240FS atomic absorption spectrometer at a wavelength of 248.3 nm, a slit of 0.2 nm, and acetylene as a combustion gas.
  • the concentration of iron ions in the solution was measured under a flow rate of 2.0 L/min, and the mass of iron in the sample was calculated.
  • the absorption/metabolism percentage of iron is generally within 15% after 36 months of implantation of porcine coronary arteries. After the addition of the high-molecular iron-absorbing absorbent, the iron absorption/metabolism percentage is more than 15%, and the most desirable iron-absorbing effect is that the iron absorption/metabolism percentage is 100%.
  • the weight average molecular weight of the polymer was measured by a GPC-multi-angle laser light scattering instrument combined with a molecular weight test system by Wyatt, USA.
  • the test system includes Agilent's liquid pump and sampler from the United States, Agilent's Agilent PL MIXED-C GPC column (size: 7.5 ⁇ 300mm, 5 microns), Wyatt's multi-angle laser light scattering instrument and Differential detector.
  • the detection conditions were: mobile phase: tetrahydrofuran; pump flow rate: 1 mL/min; injection amount: 100 ⁇ L; laser wavelength: 663.9 nm; test temperature: 35 °C.
  • the proanthocyanidin polymer having a weight average molecular weight of 1000 was dissolved in ethyl acetate to prepare a solution having a proanthocyanidin polymer concentration of 10 mg/mL, and the solution was uniformly sprayed on iron having a nominal diameter of 4.0 mm and a wall thickness of 60 ⁇ m.
  • the inner and outer surfaces of the base alloy coronary stent base form a 5 micron thick iron-promoting absorbent layer to obtain an iron-based alloy coronary stent.
  • the mass ratio of iron in the iron-absorbing alloy to the iron-based alloy coronary stent matrix is 0.05:1.
  • a 3 ⁇ m thick polylactic acid (weight average molecular weight of 20,000)-loaded rapamycin layer was continuously sprayed on the surface of the iron-absorbing absorbent coating to obtain an iron-based alloy coronary stent.
  • the prepared iron-based alloy coronary stent was implanted into the coronary artery of a miniature pig, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 20%.
  • Tocopherol polyethylene glycol maleate having a weight average molecular weight of 5000 was dissolved in ethyl acetate to prepare a solution having a tocopherol polyethylene glycol maleate concentration of 10 mg/mL, and the solution was uniformly sprayed.
  • a 10 ⁇ m thick iron-promoting absorbent layer was formed to obtain an iron-based alloy coronary stent.
  • the mass ratio of iron in the iron-absorbing alloy to the iron-based alloy coronary stent matrix is 0.15:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary artery of a miniature pig, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 26%.
  • the polylactic acid block polycysteine-conjugated glutathione having a weight average molecular weight of 10,000 was dissolved in ethyl acetate to prepare a solution having a concentration of 5 mg/mL, and the solution was uniformly sprayed at a nominal diameter of 3 mm.
  • the inner and outer surfaces of the iron-based alloy coronary stent base having a wall thickness of 50 ⁇ m form a 15 ⁇ m thick iron-absorbing absorbent layer to obtain an iron-based alloy coronary stent.
  • the mass ratio of the iron-absorbing absorbent to the iron in the iron-based alloy stent matrix is 0.25:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 30%.
  • the polylactic acid vitamin E copolymer having a weight average molecular weight of 50,000 was dissolved in dichloromethane to prepare a solution having a concentration of 5 mg/mL, and the solution was uniformly sprayed on an iron base having a nominal diameter of 3.0 mm and a wall thickness of 50 ⁇ m.
  • the inner and outer surfaces of the alloy coronary stent base form a 15 micron thick iron-promoting absorbent layer, and a 3 micron thick polylactic acid (weight average molecular weight of 20,000)-loaded paclitaxel drug layer is continuously sprayed on the iron-absorbing absorbent layer.
  • An iron-based alloy coronary stent is obtained.
  • the mass ratio of iron in the iron-absorbing alloy to the iron-based alloy coronary stent matrix is 0.25:1.
  • the prepared stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 35%.
  • the poly(lysine poly(lysine) polyethylene glycol copolymer having a weight average molecular weight of 100,000 was dissolved in ethyl acetate to prepare a solution having a concentration of 10 mg/mL, and the solution was uniformly sprayed at a nominal diameter of 3 mm and a wall thickness.
  • the inner and outer surfaces of a 50 micron iron-based alloy coronary stent base form a 25 micron thick layer of iron-promoting absorber to obtain an iron-based alloy coronary stent.
  • the mass ratio of the iron-promoting agent to the iron in the iron-based alloy stent matrix is 0.5:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 40%.
  • the ascorbic acid polycaprolactone copolymer having a weight average molecular weight of 300,000 and the polylactic acid having a weight average molecular weight of 100,000 and dexamethasone are dissolved in ethyl acetate at a mass ratio of 1:1:1, and are prepared.
  • a solution with a total concentration of 6 mg/mL was sprayed evenly on the inner and outer surfaces of an iron-based alloy coronary stent base having a nominal diameter of 3 mm and a wall thickness of 50 ⁇ m to form a 25 ⁇ m thick mixture containing iron-promoting absorbent. Coating to obtain an iron-based alloy coronary stent.
  • the mass ratio of the iron-promoting agent to the iron in the iron-based alloy coronary stent matrix is 0.5:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 45%.
  • the polylactic acid block polyascorbic acid acrylate having a weight average molecular weight of 500,000 was dissolved in chloroform to prepare a solution of polylactic acid block polyascorbic acid acrylate having a concentration of 1.5 mg/mL, and the solution was uniformly sprayed in the name.
  • the inner and outer surfaces of the iron-based alloy coronary stent base having a diameter of 2.5 mm and a wall thickness of 40 ⁇ m form a 33 ⁇ m thick iron-absorbing absorbent layer to obtain an iron-based alloy coronary stent.
  • the mass ratio of iron in the iron-absorbing alloy to the iron-based alloy coronary stent matrix is 1:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 55%.
  • the lipoic acid dextran copolymer having a weight average molecular weight of 500,000 was dissolved in ethyl acetate to prepare a solution of a lipoic acid dextran copolymer having a concentration of 2 mg/mL, and the solution was uniformly sprayed at a nominal diameter of 2.5.
  • the inner and outer surfaces of the matrix of the iron-based alloy coronary stent with mm and wall thickness of 40 ⁇ m form a 50 ⁇ m thick iron-absorbing absorbent layer to obtain an iron-based alloy coronary stent.
  • the mass ratio of iron in the iron-absorbing alloy to the iron-based alloy coronary stent matrix is 2:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 60%.
  • the polyaspartic acid polyglycol copolymer (prepared by the method disclosed in CN105524272A) having a weight average molecular weight of 100,000 is dissolved in ethyl acetate to prepare a solution having a concentration of 10 mg/mL.
  • the solution was uniformly sprayed on the inner and outer surfaces of an iron-based alloy coronary stent base having a nominal diameter of 2.5 mm and a wall thickness of 30 ⁇ m to form a 50 ⁇ m thick iron-absorbing absorbent layer, thereby obtaining an iron-based alloy coronary stent.
  • the mass ratio of iron in the iron-absorbing alloy to the iron-based alloy coronary stent matrix is 3:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 60%.
  • the proanthocyanidin with a molecular weight of 594 was dissolved in ethanol to prepare a solution of proanthocyanidin at a concentration of 10 mg/mL, and the solution was uniformly sprayed on an iron-based alloy coronary stent base having a nominal diameter of 4.0 mm and a wall thickness of 60 ⁇ m.
  • a 5 micron thick layer of iron-promoting absorber is formed to obtain an iron-based alloy coronary stent.
  • the mass ratio of iron in the proanthocyanidin and iron-based alloy support matrix is 0.05:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 10%.
  • the vitamin C is dissolved in purified water to prepare a solution having a vitamin C concentration of 10 mg/mL, and the solution is uniformly sprayed on the inner and outer surfaces of an iron-based alloy coronary stent base having a nominal diameter of 2.5 mm and a wall thickness of 40 ⁇ m.
  • a 33 micron thick layer of iron propellant was formed to obtain an iron-based alloy coronary stent.
  • the mass ratio of vitamin C to iron in the iron-based alloy stent matrix is 1:1.
  • the prepared iron-based alloy coronary stent was implanted into the coronary vessels of miniature pigs, and the over-expansion range was maintained from 1.1:1 to 1.2:1 during implantation. After 36 months of implantation, the residual iron-based alloy coronary stent and its surrounding vascular tissue were removed, and the percentage of iron metabolized by the tissue tested according to the aforementioned method was 15%.

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Abstract

一种可吸收铁基植入式器械，包括铁基基体和附着于铁基基体上的促铁吸收剂。促铁吸收剂为分子链上包含抗氧化剂结构单元的聚合物。抗氧化剂随着促铁吸收剂的逐渐降解或断链而逐渐释放出来，能够起到促进铁吸收的作用。

Description

可吸收铁基植入式器械 技术领域
本发明涉及植入式医疗器械领域，特别是涉及一种可吸收铁基植入式器械。
背景技术
目前，可吸收植入医疗器械材料主要有可降解聚合物和可吸收金属材料。可吸收金属材料有镁基合金、铁基合金、锌基合金和纯铁等。其中铁基合金和纯铁因具有可媲美永久植入医用金属材料如不锈钢、钴铬合金和铂铬合金等出色的力学性能，相比于其它几种可吸收材料，可以制备出体积更小但力学性能更优异的植入医疗器械，从而能保证更好的临床操作性和有效性。理想的可吸收医疗器械设计理念是，在病变部位恢复期内，可以提供有效的支撑，病变部位痊愈后，可吸收植入医疗器械应尽快腐蚀或降解并被机体吸收。然而，长久以来，铁基合金可吸收医疗器械和纯铁可吸收医疗器械的一个尚未得到解决的突出问题是铁主要的腐蚀产物难溶于体液中，这些腐蚀产物虽然可以通过细胞间液的流动和巨噬细胞吞噬进行吸收和代谢，但该过程历时较长，导致大量腐蚀产物长期存留在组织中，可能带来远期生物学风险。
研究表明，在铁基支架植入体内后，首先腐蚀生成Fe 2+，在有氧的环境下，Fe 2+容易被氧化成Fe 3+。组织液中同时存在PO 4 3-离子和OH -离子，从热力学上来说，生成的Fe 2+会优先和PO 4 3-离子形成更难溶的磷酸亚铁Fe 3(PO 4) 2沉淀，当组织局部的磷酸根离子消耗完后才会和OH -离子生成Fe(OH) 2沉淀，并进一步氧化成氢氧化铁Fe(OH) 3沉淀。而从热力学上来说，生成的Fe 3+离子会优先和氢氧根反应生成Fe(OH) 3沉淀，磷酸铁要在pH<5的环境下才会稳定，通常情况下体液的pH>5，因此体内Fe 3+和PO 4 3-离子很难形成磷酸铁沉淀。铁基支架腐蚀出来的Fe 2+离子将植入部位的局部组织液中的磷酸根消耗完以后，需要其它部位组织液中的磷酸根扩散过来补给，扩 散过程需要一定的时间。相反，虽然植入部位的局部组织中的OH -离子浓度比磷酸根离子浓度低，但OH -可以通过原位的水电离迅速补充，动力学上更易于形成氢氧化亚铁。
因此，铁基支架植入体内后固态腐蚀产物绝大部分都是铁的氢氧化物及后期脱水后形成的氧化物，极少量腐蚀产物是磷酸亚铁。在pH＝7.4,温度为37℃的环境下(体内环境)，Fe(OH) 2和Fe(OH) 3的溶度积分别为7.19×10 -17和1.22×10 -38，即在这种环境下，Fe(OH) 2沉淀达到溶解平衡时的游离Fe 2+的浓度约为60mg/L，而Fe(OH) 3溶解平衡后的游离Fe 3+浓度比Fe 2+低十几个数量级，约为4.3×10 -14mg/L，接近于0。所以当铁基支架腐蚀出来的Fe 2+往外围富氧区扩散过程中被氧化成Fe 3+后，极易迅速在当地形成Fe(OH) 3固体腐蚀产物，且因为其溶度积非常低，导致溶解平衡后游离的Fe 3+浓度非常低，后续很难再通过Fe 3+扩散并被组织吸收代谢走后Fe(OH) 3的溶解平衡右移电离出新的铁离子来逐渐溶解并代谢Fe(OH) 3腐蚀产物。机体清除Fe(OH) 3这种难溶固体腐蚀产物的唯一方式就是通过吞噬细胞的吞噬和搬运，如巨噬细胞。此外，若Fe(OH) 3固体腐蚀产物团聚在一起，吞噬细胞只能接触腐蚀产物的最外层，吞噬和搬运固体腐蚀产物的效率将变得更低。故，Fe(OH) 3固体腐蚀产物清除速度会更慢，导致吸收周期更长。
针对铁的腐蚀产物在体内吸收困难、吸收周期长的问题，现有技术采用加入抗氧化剂的方法来促进可溶性铁的腐蚀产物的生成，例如水溶性多酚、生育酚、三聚磷酸钠等，然而上述的抗氧化剂存在以下问题：1.稳定性差，在光照、富氧或者特定pH情况下化学性质很容易发生改变从而失去抗氧化功效；2.水溶性抗氧化剂在输送过程中及植入后溶解于血液及水性的组织液中导致大量流失，而脂溶性的抗氧化剂很难溶解在水溶性的组织液中故而抗氧化效果不佳，难以起到促进溶度积更高的铁的腐蚀产物Fe(OH) 2的生成的作用；3.这些抗氧化剂大多起始释放速度快，而铁基合金植入式医疗器械通常为了保证前期力学性能稳定，通常会在3个月左右才开始大量腐蚀。因此，还没等铁基体腐蚀，上述抗氧化剂已经消耗完，没有起到促进铁吸收的作用。
发明内容
基于此，有必要提供一种能够起到长效促进铁吸收的可吸收铁基植入式器械。
一种可吸收铁基植入器械，包括铁基基体，还包括附着于所述铁基基体上的促铁吸收剂，所述促铁吸收剂为聚合物，所述促铁吸收剂分子链上包含抗氧化剂结构单元。
在其中一个实施例中，所述促铁吸收剂能够降解释放出抗氧化剂。
在其中一个实施例中，所述抗氧化剂选自抗坏血酸、原花青素、维生素E、谷胱甘肽及硫辛酸中的至少一种。
在其中一个实施例中，所述促铁吸收剂的重均分子量为1千～50万。
在其中一个实施例中，所述促铁吸收剂为原花青素聚合物。
在其中一个实施例中，所述促铁吸收剂还包含至少一种可降解聚合物结构单元。
在其中一个实施例中，所述促铁吸收剂还包含至少一种不可降解聚合物结构单元。
在其中一个实施例中，所述可降解聚合物选自可降解聚酯、聚氨基酸、聚酸酐及葡聚糖中的至少一种。
在其中一个实施例中，所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯及聚己二酸乙二醇酯中的至少一种。
在其中一个实施例中，所述聚氨基酸选自聚赖氨酸、聚天冬氨酸、聚半胱氨酸、聚蛋氨酸、聚鸟氨酸及聚谷氨酸中的至少一种。
在其中一个实施例中，所述聚酸酐选自聚乙二酸酐、聚丁二酸酐、聚己二酸酐、聚癸二酸酐、聚十二酸酐、聚柠檬酸酐、聚苹果酸酐、聚琥珀酸酐、聚酒石酸酐、聚衣康酸酐及聚马来酸酐中的至少一种。
在其中一个实施例中，所述不可降解聚合物选聚乙二醇、聚丙烯酸酯、聚琥珀酸酯、聚碳酸酯、聚乙烯醋酸乙烯酯、聚甲基丙烯酸正丁酯、聚苯乙烯、聚偏氟乙烯、聚乙烯基吡咯烷酮及聚六氟乙烯中至少一种。
在其中一个实施例中，所述促铁吸收剂与所述铁基基体中铁的质量比为 0.05～3:1。
在其中一个实施例中，所述促铁吸收剂与所述铁基基体中铁的质量比为0.15～1:1。
在其中一个实施例中，所述促铁吸收剂附着于所述铁基基体的表面；或者，所述促铁吸收剂填充于所述铁基基体的内部。
在其中一个实施例中，所述可吸收铁基植入式器械为心血管支架、脑血管支架、外周血管支架、胆道支架、食道支架、气道支架、封堵器或骨科植入物。
在其中一个实施例中，所述可吸收铁基植入式器械还包括附着于所述铁基基体上的活性药物，所述活性药物选自抑制血管增生的药物、抗血小板类药物、抗血栓类药物、抗炎症反应药物及抗致敏药物中的至少一种。
上述可吸收铁基植入式器械的铁基基体上附着有促铁吸收剂，促铁吸收剂为包含抗氧剂结构单元的聚合物，该可吸收铁基植入式器械植入体内后，促铁吸收剂逐渐降解或断链，逐渐释放出抗氧化剂，起到长效促进铁吸收的作用。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。
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。本文中在本发明的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。
一实施方式的可吸收铁基植入式器械，包括铁基基体和附着于铁基基体上的促铁吸收剂，促铁吸收剂为聚合物，促铁吸收剂分子链上包含抗氧化剂结构单元，促铁吸收剂能够降解释放出抗氧化剂。
铁基基体可以为纯铁基体，也可以为铁基合金基体。优选地，铁基合金基体的材料为碳含量不高于2.11wt.％的铁基合金。
促铁吸收剂可以以成膜的方式附着于铁基基体的表面。例如附着于铁基基体的外表面、内表面或侧面。或者，同时附着于铁基基体的外表面、内表面和侧面。或者附着于铁基基体的外表面和内表面等等。也就是说，促铁吸收剂所形成的膜层在铁基基体上的位置不限。并且，促铁吸收剂在铁基基体表面上的分布可以是均匀的，也可以是非均匀的。
在另外的实施方式中，促铁吸收剂可以填充于铁基基体的内部。可以在铁基基体上开设有缝隙、孔隙、凹槽、通孔或内腔等，以将促铁吸收剂填充于相应的缝隙、孔隙、凹槽、通孔或内腔中，以使促铁吸收剂填充于铁基基体的内部。
优选地，抗氧化剂选自抗坏血酸、原花青素、维生素E、谷胱甘肽及硫辛酸中的至少一种。抗氧化剂通过聚合反应形成促铁吸收剂，在促铁吸收剂分子链上，抗氧化剂结构单元为重复单元，抗氧化剂结构单元通过化学键相连。当促铁吸收剂降解或断链时，释放出抗氧化剂。
促铁吸收剂释放的抗氧化剂选自抗坏血酸、原花青素、维生素E、谷胱甘肽及硫辛酸中的至少一种。该促铁吸收剂释放的抗氧化剂为人体组织细胞正常代谢过程中的小分子物质或可以被安全摄入的日常营养物质，使得该促铁吸收剂在体内的降解或释放产物与人体的生物相容性较好，不会产生对人体有害的物质。
上述促铁吸收剂降解时释放的抗氧化剂均为具有强还原作用的抗氧化剂，当促铁吸收剂在体内降解或断链而释放出抗氧剂时，能够消耗该可吸收铁基植入式器械原位及附近的氧，保证腐蚀出来的Fe 2+不会立即被氧化成Fe 3+，而是以溶解度更高的Fe 2+及其沉淀相形式存在，从而利于铁的腐蚀产物的扩散吸收。并且，该促铁吸收剂可以延迟Fe 2+向Fe 3+的转化，游离出的Fe 2+会随组织液扩散出去。离铁基基体越远，组织中的氧离子浓度越高，直至恢复到正常组织中的氧浓度水平。扩散出来的Fe 2+离子在远离铁基基体的富氧组织中不断被氧化成Fe 3+离子，在铁基基体植入原位的周围组织中沉淀 成分散的Fe(OH) 3固体腐蚀产物。Fe(OH) 3固体腐蚀产物越分散，越有利于提高吞噬细胞吞噬搬运和代谢三价铁腐蚀产物的效率，从而缩短可吸收铁基植入式器械在体内的吸收周期。
并且，在生理环境下，如上述可吸收铁基植入式器械植入体内后，促铁吸收剂逐渐降解或断链，逐渐释放出抗氧化剂，从而延缓抗氧化剂的释放速度、提高抗氧化剂的利用率，起到长效促进铁吸收的作用。
在模拟生理环境下，如生理盐溶液下，促铁吸收剂亦可逐渐降解或断链，逐渐释放出抗氧化剂。
可以理解，形成促铁吸收剂的抗氧化剂，还可以为其他具有抗氧化性、且与人体生物相容性好的抗氧化剂。
促铁吸收剂的分子量过低，抗氧化剂释放速度快，不利于提高抗氧化剂促进铁吸收的长效效果，然而促铁吸收剂分子量太大时，合成困难，且力学性能差，难以涂覆于铁基基体的表面。因此，促铁吸收剂的重均分子量为1千～50万。优选地，促铁吸收剂的重均分子量为3千～30万。
同时，上述促铁吸收剂为含有抗氧化剂结构单元的聚合物，与大多数天然的抗氧化剂相比，具有稳定性高的优点。在光照、富氧或者特定pH环境下，其化学性质较难发生改变，能够长效稳定地存在。并且，该促铁吸收剂在水中的溶解性较差。因此，该促铁吸收剂能够在体内较稳定地存在，当可吸收铁基植入式器械植入体内后，促铁吸收剂在水性的组织液中难以溶解，流失较少，因而能够起到长效促进铁吸收的作用。
并且，由于促铁吸收剂的稳定性较好，对产品储存的环境要求较低，不会因为在储存时促铁吸收剂的失效而导致产品的失效，有利于延长货架寿命。
在一实施方式中，促铁吸收剂还包含至少一种可降解聚合物结构单元。促铁吸收剂由可降解聚合物单体与上述抗氧化剂聚合而成。在促铁吸收剂分子链上，可降解聚合物结构单元与抗氧化剂结构单元通过化学键相连。其中，可降解聚合物结构单元是指可降解聚合物分子链中的重复单元。
在一实施方式中，可降解聚合物选自形成可降解聚酯、聚氨基酸、聚酸酐及葡聚糖中的至少一种。
在一实施方式中，可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯及聚己二酸乙二醇酯中的至少一种。
在一实施方式中，聚氨基酸选自聚赖氨酸、聚天冬氨酸、聚半胱氨酸、聚蛋氨酸、聚鸟氨酸及聚谷氨酸中的至少一种。
在一实施方式中，聚酸酐选自聚乙二酸酐、聚丁二酸酐、聚己二酸酐、聚癸二酸酐、聚十二酸酐、聚柠檬酸酐、聚苹果酸酐、聚琥珀酸酐、聚酒石酸酐、聚衣康酸酐及聚马来酸酐中的至少一种。
将可降解聚合物单体与抗氧化剂进行聚合，有利于提高抗氧化剂的稳定性，进一步延缓了抗氧化剂的释放速度，使得可吸收铁基植入式器械植入体内后抗氧化剂逐渐缓慢释放，以尽可能与铁基基体的降解周期保持一致，能够发挥长效作用，最大限度地促进铁吸收，且在抗氧化剂释放的同时，可降解聚合物形成的链段同样可以逐渐降解吸收。
可以理解，在其他实施方式中，除上述所列举的可降解聚合物单体外，其他能够与抗氧化剂聚合形成促铁吸收剂，且与人体生物相容性好的可降解聚合物单体也能应用于上述可吸收铁基植入式器械中，以达到长效促铁吸收的效果。
在另外的实施方式中，促铁吸收剂还包含至少一种不可降解聚合物结构单元。不可降解聚合物结构单元为不可降解聚合物分子链上的重复单元。所述促铁吸收剂由不可降解聚合物单体与抗氧化剂聚合形成促铁吸收剂。在一实施方式中，不可降解聚合物为聚乙二醇、聚丙烯酸酯、聚琥珀酸酯、聚碳酸酯、聚乙烯醋酸乙烯酯、聚甲基丙烯酸正丁酯、聚苯乙烯、聚偏氟乙烯、聚乙烯基吡咯烷酮及聚六氟乙烯中至少一种。
在一实施方式中，促铁吸收剂还包含至少一种可降解聚合物结构单元和至少一种不可降解聚合物结构单元。优选地，可降解聚合物和不可降解聚合物的种类分别与上述所列举的可降解聚合物和不可降解聚合物的种类相同。
不可降解聚合物结构单元的加入，可以改善促铁吸收剂的亲水性，或疏水性，或力学性能，或抗氧化剂的稳定性和释放速率。
可以理解，在其他实施方式中，除上述所列举的不可降解聚合物单体外， 其他能够与抗氧化聚合或与抗氧化及可降解聚合物单体聚合形成促铁吸收剂，且与人体生物相容好的不可降解聚合物单体也可以用于上述可吸收铁基植入式器械中，以达到改善促铁吸收剂的亲水性或疏水性、或力学性能，或抗氧化剂的稳定性和释放速率的效果。
具体地，抗氧化剂与可降解聚合物单体和/或不可降解聚合物单体共聚，可以通过无规则共聚、交替共聚、嵌段共聚或接枝共聚的方式共聚而成。聚合形成的促铁吸收剂，能够逐渐释放出抗氧化剂。
促铁吸收剂的质量太低，促铁吸收的效果不明显。促铁吸收剂的质量高，促铁吸收效果好，但是由于质量高，体积太大，会严重影响可吸收铁基植入式器械的物理性能。因此，综合铁吸收效果与物理性能，促铁吸收剂与铁基基体中铁的质量比为0.05～3:1。在一实施方式中，促铁吸收剂与铁基基体中铁的质量比为0.15～1:1。
在一实施方式中，可吸收铁基植入式器械还包括活性药物。活性药物可以直接涂覆于铁基基体上，或填充于铁基基体上，也可以分散于促铁吸收剂形成的膜层中，或者分散于可降解聚合物层中。
活性药物选自抑制血管增生的药物、抗血小板类药物、抗血栓类药物、抗炎症反应药物及抗致敏药物中的至少一种。
具体地，抑制血管增生的药物选自紫杉醇、雷帕霉素及雷帕霉素衍生物中的至少一种。抗血小板类药物为西洛他唑。抗血栓类药物为肝素。抗炎症反应的药物为地塞米松。抗致敏药物选自葡萄糖酸钙、扑尔敏及可的松的至少一种。
上述可吸收铁基植入式器械的铁基基体上附着有促铁吸收剂，促铁吸收剂为包含抗氧化剂结构单元的聚合物。该可吸收铁基植入式器械植入体内后，逐渐缓慢降解，逐渐释放出抗氧化剂，发挥长效作用，有效延迟抗氧化剂的释放速度，在铁基基体逐渐腐蚀的过程中，促铁吸收剂释放出来的抗氧化剂能够更充分的与铁腐蚀产物相互作用，从而促进铁的腐蚀产物吸收。
上述可吸收铁基植入式器械为心血管支架、脑血管支架、外周血管支架、胆道支架、食道支架、气道支架、封堵器或骨科植入物等。
上述可吸收铁基植入式器械的制备，首先按本领域技术人员掌握的方法制备铁基基体，然后再采用本领域技术人员掌握的方法在铁基基体上形成促铁吸收剂和/或含药物的可降解聚合物层等。例如，采用激光切割的方法形成管腔铁基基体，然后采用等离子喷涂、超声雾化喷涂等方法在铁基基体上形成促铁吸收剂和/或含药物的可降解聚合物层。
上述促铁吸收剂为购买得到或采用本领域技术人员掌握的聚合方法聚合得到。例如，采用熔融聚合法将抗氧化剂和聚合物单体共聚形成促铁吸收剂，如采用熔融聚合法聚合形成聚乳酸维生素E共聚物。或者，采用开环聚合法聚合形成抗氧化剂和聚合物单体的共聚物，如将抗坏血酸作为引发剂，引发己内酯开环聚合合成抗坏血酸聚己内酯共聚物。又如，将维生素C(抗坏血酸)、无水碳酸钾与N,N-二甲基甲酰胺进行溶解混合反应，生成苄基保护的维生素C前体。将该苄基保护的维生素C前体用二氯甲烷溶解后缓慢滴加丙烯酰胺溶液，合成丙烯酸酯修饰苄基保护维生素C单体。将L型丙交酯开环聚合合成聚乳酸均聚物。将均聚物与维生素C前体在溴化铜和无水甲苯条件下合成嵌段共聚物，然后氢气将该嵌段共聚物脱苄基，便得到聚乳酸嵌段聚抗坏血酸丙烯酸酯共聚物。
以下通过具体实施例对上述可吸收铁基植入式器械进一步阐述。
以下实施例采用如下表征及测试方法：
1、促铁吸收效果的表征：
以含有促铁吸收剂的铁基合金血管支架为例，通过将含有促铁吸收剂的铁基合金支架植入健康小型猪冠状动脉模型的实验来检验铁基合金血管支架所在的血管中铁的吸收/代谢百分比，以铁的吸收/代谢百分比来评估该促铁吸收剂在体内的促铁吸收效果。具体方法为，测量植入的铁基合金血管支架中铁的质量M 0，然后将相同批次规格的含有促铁吸收剂的铁基合金血管支架植入猪冠状动脉，36个月后，取出铁基合金血管支架及其所在的血管段，仔细修剪血管外膜外围的脂肪组织及心肌组织之类的赘物，确保血管长度和植入其中的铁基合金血管支架长度相当，测量该铁基合金血管支架连同支架所在的血管段铁含量为M 1，空白血管中的铁离子含量很低，在此忽略不计。 那么该植入时间段，铁的吸收/代谢百分比为W，W＝(M 0-M 1)/M 0*100％。
其中铁含量的测试具体方法为，用浓硝酸将支架或支架连同所在血管在微波消解仪中消解，然后采用安捷伦240FS原子吸收光谱仪，在波长为248.3nm，狭缝为0.2nm，乙炔为助燃气，流速为2.0L/min的条件下测试该溶液中铁离子的浓度，进而计算出样品中铁的质量。
促铁吸收剂促进铁吸收的效果越好，则铁的吸收/代谢百分比越高。对于不加抗氧化剂的铁基合金植入器械或含有小分子抗氧化剂的铁基合金植入器械来说，植入猪冠状动脉36个月后，铁的吸收/代谢百分比一般在15％以内，而加入高分子的促铁吸收剂后，铁的吸收/代谢百分比则大于15％，最理想的促铁吸收效果是铁的吸收/代谢百分比为100％。
2、聚合物的重均分子量大小检测方法：
聚合物的重均分子量大小采用美国Wyatt公司的GPC-多角度激光光散射仪联用分子量测试系统进行检测。该测试系统包括美国安捷伦公司的液相泵和进样器、美国安捷伦公司的Agilent PL MIXED-C型GPC柱(尺寸：7.5×300mm，5微米)、美国Wyatt公司的多角度激光光散射仪及示差检测器。检测条件为：流动相：四氢呋喃；泵流速：1mL/min；进样量：100μL；激光波长：663.9nm；测试温度：35℃。
实施例1
将重均分子量为1000的原花青素聚合物溶于乙酸乙酯中，配制成原花青素聚合物的浓度为10mg/mL的溶液，并将该溶液均匀喷涂在名义直径为4.0mm、壁厚60微米的铁基合金冠脉支架基体的内外表面，形成5微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，促铁吸收剂与铁基合金冠脉支架基体中铁的质量比为0.05：1。在促铁吸收剂涂层表面继续喷涂3微米厚的聚乳酸(重均分子量为2万)载雷帕霉素层，得到铁基合金冠脉支架。将制备好的铁基合金冠脉支架植入小型猪的冠状动脉，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为20％。
实施例2
将重均分子量为5000的生育酚聚乙二醇马来酸酯溶于乙酸乙酯中，配制成生育酚聚乙二醇马来酸酯的浓度为10mg/mL的溶液，将该溶液均匀喷涂在名义直径为3.0mm、壁厚50微米的铁基合金冠脉支架基体的内外表面，形成10微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，促铁吸收剂与铁基合金冠脉支架基体中铁的质量比为0.15：1。将制备好的铁基合金冠脉支架植入小型猪的冠状动脉，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为26％。
实施例3
将重均分子量为1万的聚乳酸嵌段聚半胱氨酸偶联谷胱甘肽溶于乙酸乙酯中，配制成浓度为5mg/mL的溶液，将该溶液均匀喷涂在名义直径为3mm、壁厚50微米的铁基合金冠脉支架基体的内外表面，形成15微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，促铁吸收剂与铁基合金支架基体中铁的质量比为0.25：1。将制备好的铁基合金冠脉支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为30％。
实施例4
将重均分子量为5万的聚乳酸维生素E共聚物溶于二氯甲烷中，配制成浓度为5mg/mL的溶液，将该溶液均匀喷涂在名义直径为3.0mm、壁厚50微米的铁基合金冠脉支架基体的内外表面，形成15微米厚的促铁吸收剂层，在该促铁吸收剂层的上面继续喷涂3微米厚的聚乳酸(重均分子量为2万)载紫杉醇药物层，得到铁基合金冠脉支架。其中，促铁吸收剂与铁基合金冠脉支架基体中铁的质量比为0.25:1。将制备好的支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为35％。
实施例5
将重均分子量为10万的硫辛酸聚赖氨酸聚乙二醇共聚物溶于乙酸乙酯中，配制成浓度为10mg/mL的溶液，将该溶液均匀喷涂在名义直径为3mm、壁厚50微米的铁基合金冠脉支架基体的内外表面，形成25微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，促铁吸收剂与铁基合金支架基体中铁的质量比为0.5：1。将制备好的铁基合金冠脉支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为40％。
实施例6
将重均分子量为30万的抗坏血酸聚己内酯共聚物与重均分子量为10万的聚乳酸以及地塞米松按质量比为1:1:1的共混比例溶于乙酸乙酯中，配制成总浓度为6mg/mL的溶液，并将该溶液均匀喷涂在名义直径为3mm、壁厚50微米的铁基合金冠脉支架基体的内外表面，形成25微米厚的含促铁吸收剂的混合涂层，得到铁基合金冠脉支架。其中促铁吸收剂与铁基合金冠脉支架基体中铁的质量比为0.5:1。将制备好的铁基合金冠脉支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为45％。
实施例7
将重均分子量为50万的聚乳酸嵌段聚抗坏血酸丙烯酸酯溶于三氯甲烷中，配制成聚乳酸嵌段聚抗坏血酸丙烯酸酯的浓度为1.5mg/mL的溶液，将该溶液均匀喷涂在名义直径为2.5mm、壁厚40微米的铁基合金冠脉支架基体的内外表面，形成33微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，促铁吸收剂与铁基合金冠脉支架基体中铁的质量比为1：1。将制备好的铁基合金冠脉支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为55％。
实施例8
将重均分子量为50万的硫辛酸葡聚糖共聚物溶于乙酸乙酯中，配制成硫辛酸葡聚糖共聚物的浓度为2mg/mL的溶液，将该溶液均匀喷涂在名义直径为2.5mm、壁厚40微米的铁基合金冠脉支架基体的内外表面，形成50微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，促铁吸收剂与铁基合金冠脉支架基体中铁的质量比为2：1。将制备好的铁基合金冠脉支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为60％。
实施例9
将重均分子量为10万的硫辛酸聚天冬氨酸聚乙二醇共聚物(制备方法按CN105524272A所公开的方法制备)溶于乙酸乙酯中，配制成浓度为10mg/mL的溶液，将该溶液均匀喷涂在名义直径为2.5mm、壁厚30微米的铁基合金冠脉支架基体的内外表面，形成50微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，促铁吸收剂与铁基合金冠脉支架基体中铁的质量比为3：1。将制备好的铁基合金冠脉支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为60％。
对比例1
然后将分子量为594的原花青素溶于乙醇中，配制成原花青素的浓度为10mg/mL的溶液，并将该溶液均匀喷涂在名义直径为4.0mm、壁厚60微米的铁基合金冠脉支架基体的内外表面，形成5微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，原花青素与铁基合金支架基体中铁的质量比为0.05:1。将制备好的铁基合金冠脉支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为10％。
对比例2
将维生素C溶于纯化水中，配制成维生素C的浓度为10mg/mL的溶液，并将该溶液均匀喷涂在名义直径为2.5mm、壁厚40微米的铁基合金冠脉支架基体的内外表面，形成33微米厚的促铁吸收剂层，得到铁基合金冠脉支架。其中，维生素C与铁基合金支架基体中铁的质量比为1：1。将制备好的铁基合金冠脉支架植入小型猪的冠脉血管，植入过程中保持过扩比范围为1.1:1至1.2:1。植入36个月后随访，取出残余的铁基合金冠脉支架及其周围的血管组织，按照前述方法测试的组织代谢的铁的百分比为15％。
可见，实施例1～实施例9的铁基合金冠脉支架植入后，组织代谢的铁的百分比明显高于对比例1和对比例2，说明实施例1～实施例9的促铁吸收剂的确起到了长效地促进铁吸收的效果。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述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 (17)

  1. 一种可吸收铁基植入器械，包括铁基基体，其特征在于，还包括附着于所述铁基基体上的促铁吸收剂，所述促铁吸收剂为聚合物，所述促铁吸收剂分子链上包含抗氧化剂结构单元。
  2. 根据权利要求1所述的可吸收铁基植入式器械，其特征在于，所述促铁吸收剂能够降解释放出抗氧化剂。
  3. 根据权利要求2所述的可吸收铁基植入式器械，其特征在于，所述抗氧化剂选自抗坏血酸、原花青素、维生素E、谷胱甘肽及硫辛酸中的至少一种。
  4. 根据权利要求1所述的可吸收铁基植入式器械，其特征在于，所述促铁吸收剂的重均分子量为1千～50万。
  5. 根据权利要求1所述的可吸收铁基植入式器械，其特征在于，所述促铁吸收剂为原花青素聚合物。
  6. 根据权利要求1所述的可吸收铁基植入式器械，其特征在于，所述促铁吸收剂还包含至少一种可降解聚合物结构单元。
  7. 根据权利要求1或6所述的可吸收铁基植入式器械，其特征在于，所述促铁吸收剂还包含至少一种不可降解聚合物结构单元。
  8. 根据权利要求6所述的可吸收铁基植入式器械，其特征在于，所述可降解聚合物选自可降解聚酯、聚氨基酸、聚酸酐及葡聚糖中的至少一种。
  9. 根据权利要求8所述的可吸收铁基植入式器械，其特征在于，所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯及聚己二酸乙二醇酯中的至少一种。
  10. 根据权利要求8所述的可吸收铁基植入式器械，其特征在于，所述聚氨基酸选自聚赖氨酸、聚天冬氨酸、聚半胱氨酸、聚蛋氨酸、聚鸟氨酸及聚谷氨酸中的至少一种。
  11. 根据权利要求8所述的可吸收铁基植入式器械，其特征在于，所述聚酸酐选自聚乙二酸酐、聚丁二酸酐、聚己二酸酐、聚癸二酸酐、聚十二酸酐、聚柠檬酸酐、聚苹果酸酐、聚琥珀酸酐、聚酒石酸酐、聚衣康酸酐及聚 马来酸酐中的至少一种。
  12. 根据权利要求7所述的可吸收植入式器械，其特征在于，所述不可降解聚合物选聚乙二醇、聚丙烯酸酯、聚琥珀酸酯、聚碳酸酯、聚乙烯醋酸乙烯酯、聚甲基丙烯酸正丁酯、聚苯乙烯、聚偏氟乙烯、聚乙烯基吡咯烷酮及聚六氟乙烯中至少一种。
  13. 根据权利要求1～6任一项所述的可吸收铁基植入式器械，其特征在于，所述促铁吸收剂与所述铁基基体中铁的质量比为0.05～3:1。
  14. 根据权利要求13所述的可吸收铁基植入式器械，其特征在于，所述促铁吸收剂与所述铁基基体中铁的质量比为0.15～1:1。
  15. 根据权利要求1～6任一项所述的可吸收铁基植入式器械，其特征在于，所述促铁吸收剂附着于所述铁基基体的表面；或者，所述促铁吸收剂填充于所述铁基基体的内部。
  16. 根据权利要求1～6任一项所述的可吸收铁基植入式器械，其特征在于，所述可吸收铁基植入式器械为心血管支架、脑血管支架、外周血管支架、胆道支架、食道支架、气道支架、封堵器或骨科植入物。
  17. 根据权利要求1～6任一项所述的可吸收铁基植入式器械，其特征在于，所述可吸收铁基植入式器械还包括附着于所述铁基基体上的活性药物，所述活性药物选自抑制血管增生的药物、抗血小板类药物、抗血栓类药物、抗炎症反应药物及抗致敏药物中的至少一种。
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