WO2017117923A1 - 可吸收铁基合金植入医疗器械 - Google Patents

可吸收铁基合金植入医疗器械 Download PDF

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WO2017117923A1
WO2017117923A1 PCT/CN2016/087302 CN2016087302W WO2017117923A1 WO 2017117923 A1 WO2017117923 A1 WO 2017117923A1 CN 2016087302 W CN2016087302 W CN 2016087302W WO 2017117923 A1 WO2017117923 A1 WO 2017117923A1
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zinc
iron
based alloy
medical device
acid
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PCT/CN2016/087302
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English (en)
French (fr)
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齐海萍
林文娇
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先健科技(深圳)有限公司
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Priority to US16/068,124 priority Critical patent/US11020514B2/en
Priority to EP16883064.4A priority patent/EP3400970B1/en
Publication of WO2017117923A1 publication Critical patent/WO2017117923A1/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
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/04—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • 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
    • A61L27/12—Phosphorus-containing materials, e.g. apatite
    • 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
    • A61L27/14—Macromolecular materials
    • A61L27/18—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61L31/08—Materials for coatings
    • A61L31/082—Inorganic materials
    • A61L31/086—Phosphorus-containing materials, e.g. apatite
    • A—HUMAN NECESSITIES
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    • 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
    • A61L31/082—Inorganic materials
    • A61L31/088—Other specific inorganic materials not covered by A61L31/084 or A61L31/086
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • 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
    • A61L31/148—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
    • 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
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/06—Coatings containing a mixture of two or more compounds
    • 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 absorbable implantable medical devices, and more particularly to an absorbable iron-based alloy implanted medical device.
  • the most widely used materials for implantable medical device substrates include polymers, magnesium-based alloys and iron-based alloys.
  • polylactic acid is the most widely used, and its advantage is that it can be completely degraded and absorbed.
  • the degradation products are carbon dioxide and water.
  • the disadvantage is that the mechanical properties are insufficient.
  • the polymer The size of the base device needs to be larger than that of the metal based device, which limits the application of polymer based devices.
  • Magnesium-based alloys and iron-based alloys have the advantages of easy processing and shaping, and high mechanical strength.
  • the corrosion rate of magnesium-based alloys in the human body is too fast and hydrogen is generated along with corrosion, which can only be achieved by increasing the size of magnesium-based alloy instruments. Meeting the early mechanical properties of the implant will also limit the application of magnesium-based alloy devices.
  • the absorbable implanted medical device has completed its intended use, the lesion has healed and returned to normal morphology and function (ie, healed), without causing new biocompatibility issues, The shorter the time the device is completely degraded and absorbed by the body, the better.
  • the healing period is 1-6 months, during which time the device needs to maintain structural integrity and sufficient mechanical properties.
  • the iron-based alloy has good biocompatibility, but the iron-based alloy corrodes slowly in the body, which causes the iron-based alloy device to take a long time to completely corrode after the healing period. Therefore, it is necessary to speed up the corrosion rate to shorten the iron-based alloy device. Corrosion cycle.
  • the amount of degradable polyester coating, the type and nature of the degradable polyester determine the corrosion rate of the iron-based alloy and whether it can be completely corroded.
  • the type and nature of the degradable polyester are selected and the amount of degradable polyester sufficient to completely corrode the iron-based alloy matrix is determined.
  • Excessive corrosion rate of iron-based alloys or severe local corrosion will affect the structural integrity and mechanical properties of the iron-based alloy implants in the early stage (1-6 months, ie the healing period described above), resulting in the device being difficult to meet clinical requirements. Application requirements.
  • the degradation products of the degradable polyester coating are acidic, and the degradable polyester tends to have small molecular residues with rapid degradation rate (such as the monomer residue standard of polylactic acid is ⁇ 2%).
  • the iron-based alloy matrix will corrode faster in the early stage of implantation, such as about 1-7 days after implantation of the coronary artery.
  • Corrosion too fast and accumulation of corrosion products lead to incomplete endothelialization of the instrument surface, increasing acute and subacute thrombosis
  • the risk of (2) the degradation of the degradable polyester easily leads to uneven corrosion of the iron-based alloy matrix, and the local corrosion is too fast to break, which makes it difficult to meet the requirements of early structural integrity and mechanical properties.
  • the method of reducing the amount of the degradable polyester coating can be used to prevent the excessive corrosion of the iron-based alloy device in the early stage, the corrosion cycle of the iron-based alloy device is prolonged. Therefore, for an iron-based alloy device including a degradable polyester, in the case where the type and nature of the degradable polyester, the ratio of the degradable polyester to the iron-based alloy are determined, it is necessary to explore an acidic environment formed by the degradable polyester. In the middle, how to reduce the early corrosion rate of the iron-based alloy matrix to ensure the early mechanical properties of the instrument implantation.
  • the object of the present invention is to provide an absorbing iron-based alloy implanted medical device which is slow in corrosion (or within 1-6 months) in the early stage of implantation (or within 1-6 months) or even completely non-corrosive, and can meet clinical requirements during this period of time.
  • Early mechanical properties requirements for instrument implantation are to provide an absorbing iron-based alloy implanted medical device which is slow in corrosion (or within 1-6 months) in the early stage of implantation (or within 1-6 months) or even completely non-corrosive, and can meet clinical requirements during this period of time.
  • the absorbable iron-based alloy implanted medical device comprises an iron-based alloy substrate and a degradable polymer disposed on the surface of the iron-based alloy substrate, and a zinc-containing protective body disposed on the surface of the iron-based alloy substrate.
  • the zinc-containing protective body may cover the entire surface of the iron-based alloy substrate, or may cover a part of the surface of the iron-based alloy substrate.
  • the degradable polymer covers at least a portion of the surface of the zinc-containing protective body when the zinc-containing protective body covers the entire surface of the iron-based alloy substrate.
  • the degradable polymer may cover only at least part of the surface of the zinc-containing protective body, or may be covered with the zinc-containing protective body so as to be offset from each other.
  • the different surfaces of the iron-based alloy substrate may also cover at least a portion of the surface of the zinc-containing protective body while covering at least a portion of the uncovered regions.
  • the zinc-containing protective body may be directly coated on the surface of the iron-based alloy substrate or embedded in the iron-based alloy matrix in a block or granular shape.
  • the zinc-containing protective body is selected from the group consisting of a zinc compound, or a mixture of at least one of a phosphate-containing compound, a degradable binder or a water-soluble binder and a zinc compound, wherein the weight percentage of the zinc compound in the mixture is greater than or equal to 20% and less than 100%.
  • the iron-based alloy matrix may be selected from the group consisting of pure iron or an iron-based alloy having a carbon content of not more than 2.11 wt.%, such as a product of pure iron after nitriding and/or carburizing.
  • the degradable polymer degrades to form an acidic environment in which the active drug can be mixed.
  • the present invention provides an absorbing iron-based alloy implanted medical device that adds a zinc-containing protective body.
  • the zinc-containing protective body can directly act as a preservative (such as zinc phosphate), or dissolve ionized or react in the body fluid to form zinc ions and further react to form zinc phosphate to avoid corrosion of the iron-based alloy matrix.
  • the iron-based alloy matrix begins to rapidly corrode when the substance with antiseptic effect is completely removed by the body, thereby ensuring that the iron-based alloy body meets the clinical mechanical performance requirements at the early stage of implantation.
  • the absorbable iron-based alloy implanted medical device of the present invention has a smaller design size, produces less corrosion products after implantation, and has a shorter complete absorption period.
  • FIG. 1 is a schematic cross-sectional view of an absorbable implantable medical device along its length, in which a zinc-containing protective body completely covers the entire surface of an iron-based alloy substrate.
  • FIG. 2 is a schematic view showing the outer surface of the absorbable implantable medical device after the removal of the degradable polymer in the axial direction after being cut in the axial direction, wherein the zinc-containing protective body covers a part of the surface of the iron-based alloy substrate.
  • FIG 3 is a schematic view of an absorbable implantable medical device after removing a degradable polymer according to still another embodiment of the present invention, wherein the zinc-containing protective body penetrates the substrate along a thickness direction of the iron-based alloy substrate.
  • the main idea of the present invention is to increase the zinc-containing protective body on the surface of the iron-based alloy substrate, and to utilize the anti-corrosion property of the zinc-containing protective body or to dissolve and ionize zinc ions or react to form zinc ions in the body fluid environment at the implantation site, and then further generate Zinc phosphate with anti-corrosion effect to controlly reduce the corrosion of iron-based alloy matrix, and achieve the early structural integrity of the iron-based alloy substrate without corrosion during the early stage of implantation (1-6 months) And has sufficient mechanical properties without prolonging the corrosion cycle of the iron-based alloy matrix.
  • the zinc-containing protective body can effectively and controlly reduce the corrosion of the iron-based alloy matrix, the iron-based alloy matrix does not substantially corrode during the protection period of the zinc-containing protective body, and the mechanical properties thereof are not substantially changed, so the present invention can be
  • the absorption of iron-based alloy implanted medical devices only needs to ensure that the initial mechanical properties before implantation reach the lower limit of the clinical requirements for early implantation, and there is no need to have strong mechanical properties after the healing period is exceeded. Therefore, compared with the prior art, the design of the absorbing iron-based alloy implanted medical device of the present invention is smaller, correspondingly reducing the amount of the iron-based alloy, thereby achieving the purpose of reducing iron corrosion products.
  • an absorbable iron-based alloy implanted medical device of the present invention comprises an iron-based alloy substrate 11, a zinc-containing protective body 12 disposed on the iron-based alloy substrate 11, and an iron-based alloy substrate. 11 and a degradable polymer coating 13 over the zinc-containing protective body 12.
  • the iron-based alloy substrate 11 may be a pure iron or an iron-based alloy having a carbon content of not more than 2.11 wt.%, such as a product of pure iron after carburizing and/or nitriding.
  • the material of the zinc-containing protective body 12 may be a zinc compound or a mixture of at least one of a phosphate-containing compound, a degradable binder, and a water-soluble binder and a zinc compound.
  • the zinc compound may be zinc phosphate which has antiseptic effect, or zinc sulfate, zinc chloride, zinc nitrate, zinc gluconate, zinc licorice, zinc lactate which can dissolve and ionize zinc ions in a neutral environment.
  • Zinc acetate, zinc citrate, zinc amino acid, yeast zinc, etc. may also be zinc carbonate, basic zinc carbonate, zinc oxide, zinc hydroxide or the like which can react to form zinc ions in an acidic environment.
  • the mass percentage of the zinc compound is 20% or more and less than 100%.
  • the phosphate-containing compound can ionize the phosphate ion in the body fluid, and can accelerate the formation rate of the zinc phosphate to achieve better protection of the iron matrix without corrosion.
  • the phosphate-containing compound can be phosphate or basic.
  • Phosphate such as sodium phosphate, sodium dihydrogen phosphate, sodium monohydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, may also be other compounds that can react to form phosphate, such as trimeric Phosphorus At least one of sodium carbonate, potassium tripolyphosphate, sodium hexaphosphate, potassium hexaphosphate, ammonium polyphosphate, sodium metaphosphate, potassium metaphosphate, sodium pyrophosphate, and potassium pyrophosphate. After the implant is implanted in the body, the zinc compound can be exposed by degrading or dissolving in a short time.
  • the binder may be polyethylene glycol, polyvinyl alcohol, starch, cyclodextrin or a water soluble inorganic salt.
  • the zinc-containing protective body 12 can be prepared on an iron-based alloy substrate by spraying, dip coating, brush coating, electrospinning, inlaying or the like.
  • the zinc-containing protective body 12 There are various relative positional relationships between the zinc-containing protective body 12 and the iron-based alloy substrate 11. As an embodiment, as shown in FIG. 1, the zinc-containing protective body 12 completely covers the surface of the iron-based alloy substrate 11, and the degradable polymer layer directly covers the zinc-containing protective body 12 directly. As another embodiment, the apparatus shown in FIG. 2 removes the structural diagram after the degradable polymer, and the zinc-containing protective body 12 covers a part of the surface of the iron-based alloy substrate 11 to expose the surface of the portion of the iron-based alloy substrate 11. As still another embodiment, the apparatus shown in FIG.
  • the zinc-containing protective body 12 is embedded in the iron-based alloy substrate 11 and penetrates the substrate along the thickness direction of the iron-based alloy substrate 11.
  • the portion of the iron-based alloy substrate 11 that is not penetrated is referred to as an uncovered region.
  • the zinc-containing protective body 12 can also be connected to the iron-based alloy substrate 11 in other forms, for example, non-penetratingly embedded in the iron-based alloy substrate 11, and the exposed end faces thereof can be flush with the surface of the iron-based alloy substrate 11. Flat, it is also possible to protrude or lower than the surface of the iron-based alloy substrate 11.
  • the zinc-containing protective body 12 dissolves and ionizes the zinc ion Zn 2+ after contact with the body fluid, or hydrogen in an acidic environment degraded by the degradable polymer. Ion reaction generates zinc ion Zn 2+ , and zinc ion Zn 2+ further reacts with phosphate PO 4 3- in the body to form insoluble zinc phosphate Zn 3 (PO 4 ) 2 .
  • the reaction equations are as shown in (1) and (2). Show:
  • Zn 3 (PO 4 ) 2 has antiseptic effect.
  • the specific mechanism is as follows: On the one hand, zinc phosphate dissociates to form phosphate ions, and condensed phosphate ions react with the surface of the iron-based alloy matrix to form complex and adherent Fe-Zn-P 2
  • the O 5 compound covers the film to passivate the iron-based alloy matrix; on the other hand, the zinc phosphate reacts with the carboxyl group generated by the ionization of the polylactic acid to form a complex which can react with the iron corrosion product in the iron
  • the surface of the base alloy matrix forms a tight protective film to isolate the iron-based alloy matrix from the internal environment and inhibit iron corrosion.
  • the zinc-containing compound 12 As the zinc-containing compound 12 is consumed, the newly formed zinc ion Zn 2+ decreases, the equilibrium of the reaction (2) shifts to the left, that is, the zinc phosphate is gradually dissolved, and the iron-based alloy matrix is gradually exposed, at which time the iron-based alloy matrix begins. Slowly corrode until the zinc phosphate is consumed, the iron-based alloy matrix is completely exposed to the acidic environment and begins to corrode quickly.
  • the zinc alloy is directly diffused to reach the uncovered region or the zinc ions are diffused to the uncovered region to form zinc phosphate to slow the corrosion rate of the uncovered iron matrix.
  • the amount (weight or volume) of the zinc-containing protective body 12 is independent of the amount (weight or volume) of the iron-based alloy substrate 11, and the kind, properties (such as crystallinity, molecular weight, and polydispersity coefficient), and thickness of the degradable polymer ( Or quality) and the time required to protect the iron-based alloy substrate 11.
  • the amount of zinc-containing protective body 12 can be flexibly selected to adjust the duration of protection of the zinc-containing protective body 12 to approximately iron.
  • the base alloy matrix 11 is expected to match the time required to maintain structural integrity and sufficient mechanical properties.
  • the degradable polymer layer comprises at least one degradable polymer, which degrades to produce an acidic degradation product such as a carboxylic acid, which may be selected from the group consisting of a degradable polyester and/or a degradable polyanhydride selected from the group consisting of a degradable polyester and a degradable polyester.
  • the degradable polymer coating can also include an active drug that releases the therapeutic drug during degradation.
  • the active drug can inhibit hyperintimal hyperplasia after stent implantation and reduce the incidence of intravascular restenosis.
  • the active drug may be a drug that inhibits vascular proliferation such as paclitaxel, rapamycin and its derivatives, or an anti-platelet drug selected from cilostazol, or an antithrombotic drug such as heparin, or an anti-drug.
  • Inflammatory drugs such as dexamethasone, or anti-sensitizing drugs such as calcium gluconate, chlorpheniramine, and cortisone may also be a mixture of the foregoing drugs.
  • the antiallergic drug may be selected from at least one of an antihistamine antiallergic drug, an anti-leukotriene drug, a mast cell membrane stabilizer, a glucocorticoid antiallergic drug, or a modulating immune antiallergic drug.
  • the antiallergic drug is selected from the group consisting of chlorpheniramine, diphenhydramine, promethazine hydrochloride, cetirizine, loratadine, mizolastine, ebastine, astemizole, terfena Ding, desloratadine, fexofenadine, cyproheptadine, ketotifen, levocetirizine, meclizine, epiflucysine, carbendazim, azelastine, go Chloroquinol, chlorcycline, amlexidine, avastin, azastatin, mequitazine, levocastine, statin, sirnadine, dipyridamole, phenylthiophene Pyridinium, pyridinium, ranitidine, ezetine, eplesine, promethazine, montelukast, zafirlukast, tokasti, zileuton, aurora
  • the method for preparing the degradable polymer layer is as follows: firstly dissolving the degradable polymer and the drug in an organic solvent (such as ethyl acetate, chloroform, etc.) to form a mixed solution, and then applying the mixed solution to the zinc-containing protection that has been prepared The entire surface or partial surface of the iron-based alloy substrate 11 of the body 12 is dried to form a film.
  • the method used may be spray coating, dip coating, brush coating, electrospinning, preferably spraying.
  • the absorbable iron-based alloy implantable medical device of the present invention may be a vascular stent, an orthopedic implant, a gynecological implant, a male implant, a respiratory implant or an orthopedic implant.
  • vascular stent an orthopedic implant
  • gynecological implant a male implant
  • respiratory implant or an orthopedic implant.
  • present invention will be further described in detail by taking an iron-based alloy coronary stent as an example, but the scope of protection of the present invention is not limited thereto.
  • the following examples use animal experiments to show that under the action of the zinc-containing protective body, the iron-based alloy stent can hardly corrode within 1-6 months of implantation, mainly by implanting the animal in the stent.
  • the animals are euthanized at different observation time points after the body, such as 3 months, 6 months, 12 months, etc., and the stent and the tissue at the location thereof are taken out from the body, and the stent is placed along with the blood vessel segment where the stent is located.
  • Radial support strength and mass loss tests are used to characterize the in vivo corrosion of iron-based alloy stents and to meet early mechanical performance requirements.
  • the test of the radial support strength is carried out by using a radial support force tester produced by MSI, and the stent implanted in the animal body is taken out together with the blood vessel segment, and the surface moisture is absorbed and directly tested, thereby obtaining the stent after implantation. Radial support strength at different points in time.
  • the mass loss test is carried out by implanting an iron-based alloy stent (including a degradable polymer) comprising an iron-based alloy matrix of mass M 0 (referred to as a bare stent not including a degradable polymer) into a rabbit belly Artery, the iron-based alloy stent implanted in the animal and the tissue in which it is implanted are taken out at a predetermined observation time point, and then the tissue is immersed in a 1 mol/L sodium hydroxide solution together with the stent to digest the tissue, and then taken out from the solution.
  • an iron-based alloy stent including a degradable polymer
  • M 0 iron-based alloy matrix of mass M 0
  • An iron-based alloy stent or a fragment thereof which is ultrasonically placed in a solution of a certain concentration (such as a 3% tartaric acid solution, and/or an organic solution) to cause corrosion products on the surface, residual zinc-containing protective bodies (if any), and The polymer layer is completely detached or dissolved in the solution, and the uncorroded iron-based alloy stent or its fragments remain in the solution, and are dry and weighed, and the mass is M t .
  • the mass loss rate is expressed as a percentage of the weight loss of the support rod after corrosion cleaning, as a percentage of the weight of the iron-based alloy matrix, as shown in Equation 3:
  • mass loss rate of the iron-based alloy matrix when the mass loss rate of the iron-based alloy matrix is less than 5%, it is defined as non-corrosive; when the mass loss rate of the iron-based alloy stent substrate is W ⁇ 90%, it is defined as complete corrosion.
  • normal coronary vasodilation low pressure
  • systolic blood pressure high pressure
  • systolic blood pressure in hypertensive patients can reach 175 mm Hg, or 23.3 kPa.
  • the vasoconstriction pressure of coronary vasospasm is 400 mmHg, which is 55 kPa.
  • Psychological stress, cold stimulation, strenuous exercise, coronary atherosclerosis, local angiography of coronary angiography, and a large amount of smoking or alcohol abuse can induce coronary spasm.
  • effective support for coronary vessels means that the stent can withstand at least 23.3 kPa of systolic blood pressure during coronary vascular pulsation, and preferably has a systolic pressure of 55 kPa when vasospasm is experienced.
  • the iron-based alloy coronary stents provided in the following embodiments are designed to meet the following clinical requirements: within a predetermined time from the date of implantation (eg, within 1 month, within 2 months, 3 months, or less than 3) During the other months of the month, the iron-based alloy matrix hardly corrodes; it can effectively support for 3 months after implantation, the radial support strength after implantation for 3 months is ⁇ 55kPa, and the corrosion period is greater than 6 months less than or equal to 24 Months.
  • the 30008 specification brackets in the following embodiments are defined as follows: the bracket has a nominal diameter of 3 mm and a nominal length of 8 mm under the action of a nominal expansion pressure of 8 atm.
  • the monitored stents are completely due to the normal fluctuations in the performance of the stent product within the design permission range, the individual differences of the animals, the insufficient sampling points of the design, and the systematic errors that are inevitably introduced by the test method.
  • the time points of non-corrosion, the radial strength data, and the time point of complete corrosion will fluctuate within a certain range in actual tests.
  • An absorbable iron-based alloy support comprising a zinc-containing protective body can delay the corrosion of the iron-based alloy substrate within 2 months of implantation, and the preparation method is as follows: taking the original radial support strength of 145 kPa and the mass of 4.5-5 mg The 30008-size nitriding iron stent was sprayed with a zinc phosphate-polyethylene glycol (weight average molecular weight 4000)-chloroform suspension on the entire stent surface and then dried to obtain a zinc phosphate-polyethylene glycol coating having a thickness of 4 ⁇ m. Wherein the volume fraction of zinc phosphate is 80%.
  • a polybutyl lactic acid-ethyl acetate solution having a molecular weight of 200,000 was sprayed to completely cover the entire surface of the zinc phosphate-polyethylene glycol coating, and after drying, an absorbable iron-based alloy stent having a polylactic acid coating thickness of 12 ⁇ m was obtained.
  • the stent was implanted into the abdominal aorta of rabbits and removed after 2 months. The stent was not corroded. After 3 months, the radial support strength was 120 kPa, which was in accordance with the mechanical properties of the early 3 months. After 12 months of removal, the stent was completely corroded.
  • An absorbing iron-based alloy stent comprising a zinc-containing protective body can delay the corrosion of the iron-based alloy matrix within 1 month of implantation, and the preparation method is as follows: taking the original radial support strength of 145 kPa and the mass of 4.5-5 mg The 30008 specification nitriding iron stent is sprayed with a suspension solution of zinc sulfate-cyclodextrin-ethanol on the outer surface and side of the stent, and then dried to obtain a zinc sulfate-cyclodextrin coating having a thickness of 12 micrometers, wherein the volume of zinc sulfate is The score is 90%.
  • the polychlorolactic acid-ethyl acetate solution having a molecular weight of 200,000 was sprayed to completely cover the entire surface of the zinc sulfate-cyclodextrin coating layer and the exposed surface of the iron-based alloy stent, and dried to obtain a polylactic acid coating layer having a thickness of 8 ⁇ m.
  • An absorbable iron-based alloy support comprising a zinc-containing protective body capable of retarding an iron-based alloy substrate It is not corroded within 1 month.
  • the preparation method is as follows: on the 30008-size nitriding iron support rod with the original radial strength of 145 kPa and the mass of 4.5-5 mg, the groove is set with zinc phosphate powder block, all inlaid zinc phosphate. The ratio of the exposed area of the powder to the surface area of the iron matrix is 1:1.
  • a surface of the stent was sprayed with a molecular weight of 200,000 poly- lactic acid-ethyl acetate solution to completely cover the exposed zinc phosphate powder block and the surface of the iron-based stent, and after drying, the thickness of the poly- lactic acid coating was 6 micrometers.
  • Absorbable iron-based alloy brackets The stent was implanted into the abdominal aorta of rabbits and taken out after 1 month. The iron-based stents were not corroded; after 3 months, the radial support strength was measured to be 110 kPa. After 24 months of removal, the stent was completely corroded.
  • An absorbable iron-based alloy stent comprising a zinc-containing protective body can delay the corrosion of the iron-based alloy matrix within 1 month of implantation, and the preparation method is as follows: the original radial strength is 145 kPa, and the mass is 4.5-5 mg.
  • the surface of the 30008-size nitriding iron stent is protected by a zinc chloride-polyethylene glycol (weight average molecular weight 4000)-ethanol solution on the inner surface and part of the side surface of the stent, and then dried to obtain a thickness of 12 micrometers.
  • a zinc chloride-polyethylene glycol coating in which the volume fraction of zinc chloride is 80%.
  • An absorbable iron-based alloy stent comprising a zinc-containing protective body can delay the corrosion of the iron-based alloy matrix within 1 month of implantation, and the preparation method is as follows: the original radial strength is 145 kPa, and the mass is 4.5-5 mg.
  • the surface of the 30008 nitriding iron stent was sprayed with an aqueous solution of zinc gluconate on the entire surface of the stent. After drying, the zinc gluconate coating was measured to have a thickness of 3 ⁇ m. Subsequently, an aqueous solution of sodium tripolyphosphate was sprayed on the surface of the zinc gluconate coating, and the coating of the sodium tripolyphosphate was measured to have a thickness of 3 ⁇ m.
  • a polymorphic lactic acid-rapamycin-ethyl acetate solution having a molecular weight of 200,000 was sprayed on the surface of sodium tripolyphosphate, and the mass ratio of poly- lactic acid to rapamycin was 4:1, and dried to obtain a poly An absorbable iron-based alloy stent having a lactic acid-rapamycin coating thickness of 5 microns.
  • the stent was implanted into the abdominal aorta of rabbits and taken out after 1 month.
  • the iron-based stents were not corroded; after 3 months, the radial support strength was measured to be 80 kPa, which met the mechanical performance requirements of the early 3 months of implantation. 24 after implantation After a month of removal, the mass loss test indicated complete corrosion of the stent.
  • This comparative example provides a 30008 gauge nitriding iron bare stent (ie, a stent that does not include a degradable polymer and a zinc-containing protective body) having an original radial strength of 145 kPa and a mass of 4.5-5 mg.
  • the stent was implanted into the abdominal aorta of the rabbit. After 3 months, the mass loss test showed that the stent was slightly corroded, and the radial support strength of the stent was measured to be 140 kPa, which satisfies the mechanical performance requirements of the early 3 months of implantation. After 24 months after implantation, the mass loss test indicated that the stent was not completely corroded, indicating that the corrosion cycle of the nitriding iron stent without the degradable polymer layer was too long.
  • the present comparative example provides an absorbable iron-based stent prepared by spraying a polychlorolactic acid having a molecular weight of 200,000 on the surface of a 30008-size nitrided iron stent having an original radial strength of 145 kPa and a mass of 4.5 to 5 mg.
  • the ethyl acetate solution completely covers the entire surface of the stent, and after drying, an absorbable iron-based alloy stent having a thickness of 12 micrometers of a poly- lactic acid coating is obtained.
  • the stent was implanted into the abdominal aorta of rabbits. After 2 months, the stent rods were corroded very seriously and fractured at multiple locations.
  • the stents were measured and the radial support strength was less than 55 kPa. After 6 months of implantation, the mass was measured. The loss test showed that the stent was completely corroded, indicating that the corrosion was too fast and could not meet the early mechanical properties.
  • the present comparative example provides an absorbable iron-based stent prepared by spraying a polychlorolactic acid having a molecular weight of 200,000 on the surface of a 30008-sized nitrided iron stent having an original radial strength of 175 kPa and a mass of 5.5-6 mg.
  • the ethyl acetate solution completely covered the entire surface of the stent, and after drying, an absorbable iron-based alloy stent having a thickness of 10 ⁇ m of a poly- lactic acid coating was obtained.
  • the stent was implanted into the abdominal aorta of rabbits. After 1 month, the stent rods were removed to a certain extent.
  • the stents were taken out and the radial support strength was 80 kPa, which satisfied the mechanical properties of the early 3 months of implantation. Requirements; taken 12 months after implantation, the mass loss test indicated complete corrosion of the stent.
  • the absorbing iron-based alloy stent of the present invention has a zinc-containing protective body, and the iron-based alloy matrix is less corroded in the early stage of implantation, and the radial support strength is decreased, but still meets the early stage. Mechanical performance requirements for 3 months of implantation.
  • the amount of the zinc-containing protective body By adjusting the amount of the zinc-containing protective body, the amount of time consumed in the body corresponding to the amount of the zinc-containing protective body is substantially matched with the length of time that the iron-based alloy is not corroded by the intended setting. Adjust the length of time the stent does not corrode early in the implant.
  • the stents provided in Examples 1-5 had a shorter corrosion cycle than Comparative Example 1.
  • the stent provided in Example 1 was less corrosive in the early stage of implantation, maintaining structural integrity and sufficient mechanical support at 3 months of implantation.
  • the stent provided in Example 2 has a smaller amount of iron matrix under the premise of ensuring the same corrosion cycle and sufficient mechanical support at 3 months, and it is expected that the amount of corrosion products generated subsequently will be less. The period of complete absorption is shorter.

Abstract

一种可吸收铁基合金植入医疗器械，包括铁基合金基体(11)和设于铁基合金基体(11)表面的可降解聚合物(13)，以及设于所述铁基合金基体(11)表面的含锌保护体(12)。含锌保护体(12)选自锌化合物，或包括含磷酸根化合物、可降解粘结剂、水溶性粘结剂中的至少一种与锌化合物的混合物。混合物中锌化合物的重量百分比≥20％且<100％。含锌保护体(12)可在器械植入早期延缓该铁基合金基体(11)腐蚀。铁基合金基体(11)在植入早期基本不腐蚀且满足临床上对器械植入早期的力学性能要求。

Description

可吸收铁基合金植入医疗器械 技术领域
本发明涉及可吸收植入医疗器械领域，特别是涉及一种可吸收铁基合金植入医疗器械。
背景技术
目前可吸收植入医疗器械基体应用最广泛的材料包括聚合物、镁基合金与铁基合金。聚合物中以聚乳酸应用最多，其优点为可完全降解吸收，降解产物为二氧化碳和水，其缺点是机械性能不足，相对金属基器械而言，若两者要满足相同的机械性能，聚合物基器械的尺寸需要比金属基器械大，这限制了聚合物基器械的应用。镁基合金和铁基合金的优点是易加工塑形，机械强度大，但镁基合金在人体内的腐蚀速度太快且伴随腐蚀会生成氢气，只能通过增大镁基合金器械的尺寸来满足植入早期的力学性能，同样会限制镁基合金器械的应用。
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。
有研究表明在铁基合金表面涂覆可降解聚酯涂层，可提高铁基合金的腐蚀速度。该可降解聚酯涂层在体内的降解会使得器械植入位置附近的局部微环境的pH值下降，形成局部微酸性环境，铁基合金在此酸性环境中能更快地腐蚀，生成腐蚀产物铁盐和/或铁氧化物和/或铁氢氧化物。
对于预定规格的铁基合金器械，可降解聚酯涂层的用量、可降解聚酯种类和性质决定铁基合金的腐蚀速度以及最终是否可完全腐蚀。在选定可降解聚酯种类和性质并确定好足以使铁基合金基体完全腐蚀的可降解聚酯用量的情况下， 铁基合金腐蚀速度过快或局部腐蚀严重将会影响该铁基合金器械植入早期(1-6个月，即前文所述痊愈期)的结构完整性和力学性能，从而导致器械难以满足临床应用的要求。这些缺陷具体表现在：(1)可降解聚酯涂层的降解产物呈酸性，且可降解聚酯往往有降解速度较快的小分子残留(如聚乳酸的单体残留标准为<2％)，将导致铁基合金基体在植入早期腐蚀较快，比如植入冠脉后1-7天左右，腐蚀过快和腐蚀产物的积累导致器械内表面内皮化不完整，增加急性和亚急性血栓的风险；(2)可降解聚酯降解的不均匀性容易导致铁基合金基体的腐蚀不均匀，局部腐蚀过快有可能出现断裂，从而导致其难以满足早期结构完整性和力学性能的要求。虽可采用减少可降解聚酯涂层用量的方法来防止铁基合金器械植入早期过快腐蚀，但会延长铁基合金器械的腐蚀周期。因此，对于包括可降解聚酯的铁基合金器械，在可降解聚酯种类和性质、可降解聚酯与铁基合金的用量比确定的情况下，需探索在可降解聚酯形成的酸性环境中，如何降低铁基合金基体的早期腐蚀速度来保证器械植入早期的力学性能。
发明内容
本发明的目的在于，提供可吸收铁基合金植入医疗器械，其在植入体内早期(例如1-6个月内)腐蚀速度较慢甚或是完全不腐蚀，可在此段时间内满足临床上对器械植入早期的力学性能要求。
本技术方案提供的可吸收铁基合金植入医疗器械包括铁基合金基体和设于铁基合金基体表面的可降解聚合物，以及设于所述铁基合金基体表面的含锌保护体。
所述含锌保护体可以覆盖所述铁基合金基体的全部表面，也可以覆盖所述铁基合金基体的部分表面。当所述含锌保护体覆盖所述铁基合金基体的全部表面时，所述可降解聚合物覆盖所述含锌保护体的至少部分表面。当所述含锌保护体未完全覆盖铁基合金基体表面时，所述可降解聚合物可仅覆盖所述含锌保护体的至少部分表面，也可与所述含锌保护体相互错开地覆盖所述铁基合金基体的不同表面，还可既覆盖所述含锌保护体的至少部分表面，又同时覆盖至少部分所述未覆盖区。所述含锌保护体可以直接覆盖在铁基合金基体表面，或以块状或粒状镶嵌在铁基合金基体中。
所述含锌保护体选自锌化合物，或含磷酸根化合物、可降解粘结剂或水溶性粘结剂中的至少一种与锌化合物的混合物，所述混合物中锌化合物的重量百分比大于等于20％且小于100％。
所述铁基合金基体可选自纯铁或碳含量不高于2.11wt.％的铁基合金，例如纯铁经渗氮和/或渗碳后的产物。
所述可降解聚合物降解后形成酸性环境，其内可混有活性药物。
相比现有技术，本发明提供的可吸收铁基合金植入医疗器械增加了含锌保护体。器械植入体内后，所述含锌保护体可以直接起到防腐作用(例如磷酸锌)，或者在体液中溶解电离或反应生成锌离子并进一步反应生成磷酸锌避免铁基合金基体腐蚀，待所述具有防腐作用的物质几乎完全被机体清除走后铁基合金基体才开始快速腐蚀，由此确保了铁基合金体在植入早期满足临床上的力学性能要求。另外，本发明的可吸收铁基合金植入医疗器械具有更小的设计尺寸，植入后产生的腐蚀产物更少，完全吸收周期更短。
附图说明
图1是本发明一实施例提供的可吸收植入医疗器械沿其长度方向的剖面示意图，其中含锌保护体完全覆盖铁基合金基体的全部表面。
图2是本发明又一实施例提供的可吸收植入医疗器械除去可降解聚合物后的外表面沿轴向剪开后展开的示意图，其中含锌保护体覆盖铁基合金基体的部分表面。
图3是本发明再一实施例提供的可吸收植入医疗器械除去可降解聚合物后的示意图，其中含锌保护体沿铁基合金基体的厚度方向贯通所述基体。
具体实施方式
为了便于理解本发明，下面将参照相关附图对本发明进行更全面的描述。附图中给出了本发明的首选实施例。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对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。
本发明的主要思想在于，在铁基合金基体表面增加含锌保护体，利用含锌保护体自身的防腐性能或者在植入部位体液环境中溶解电离出锌离子或反应生成锌离子，然后进一步生成具有防腐作用的磷酸锌来可控地减缓铁基合金基体腐蚀，达成铁基合金基体在植入早期(1-6个月)不腐蚀而确保可吸收铁基合金植入器械早期的结构完整性和具有足够的力学性能，且不延长铁基合金基体的腐蚀周期。
由于含锌保护体可以有效并可控地减缓铁基合金基体腐蚀，在含锌保护体的保护期内，铁基合金基体基本不腐蚀，其力学性能基本不会发生改变，故本发明的可吸收铁基合金植入医疗器械只需要保证植入前的初始力学性能达到临床上对植入早期的要求的下限即可，无需在超出痊愈期后仍具有较强的力学性能。因此，相对于现有技术，本发明的可吸收铁基合金植入医疗器械的设计尺寸更小，相应地减少了铁基合金的用量，进而达到减少铁腐蚀产物的目的。
请参见图1，本发明的可吸收铁基合金植入医疗器械包括铁基合金基体11、设置于所述铁基合金基体11上的含锌保护体12，和设于所述铁基合金基体11和含锌保护体12之上的可降解聚合物涂层13。所述的铁基合金基体11可以是纯铁或碳含量不高于2.11wt.％的铁基合金，例如纯铁经渗碳和/或渗氮后的产物。
所述的含锌保护体12的材质可以是锌化合物，也可以是含磷酸根化合物、可降解粘结剂、水溶性粘结剂中的至少一种与锌化合物的混合物。所述的锌化合物可以是自身具有防腐作用的磷酸锌，也可以是在中性环境下能溶解电离出锌离子的硫酸锌、氯化锌、硝酸锌、葡萄糖酸锌、甘草锌、乳酸锌、醋酸锌、柠檬酸锌、氨基酸锌、酵母锌等，还可以是在酸性环境下能反应生成锌离子的碳酸锌、碱式碳酸锌、氧化锌、氢氧化锌等。所述的锌化合物与含磷酸根化合物或/和粘结剂的混合物中，锌化合物的质量百分比大于等于20％，且小于100％。所述含磷酸根化合物在体液中能电离出磷酸根离子，能加快磷酸锌的生成速度，以达到更好的保护铁基体不腐蚀的效果，所述含磷酸根化合物可以是磷酸盐或碱式磷酸盐，如磷酸钠、磷酸二氢钠、磷酸一氢钠，磷酸钾、磷酸二氢钾、磷酸一氢钾、磷酸二氢钾，还可以是可反应生成磷酸根的其它化合物，如三聚磷 酸钠、三聚磷酸钾、六聚磷酸钠、六聚磷酸钾、高聚磷酸铵，偏磷酸钠、偏磷酸钾、焦磷酸钠、焦磷酸钾中的至少一种。所述粘结剂在器械植入体内后，可以在短时间内降解或溶解而将锌化合物暴露出来。该粘结剂可以是聚乙二醇、聚乙烯醇、淀粉、环糊精或水溶性无机盐。所述含锌保护体12可以通过喷涂、浸涂、刷涂、静电纺丝、镶嵌等方法制备在铁基合金基体上。
含锌保护体12与铁基合金基体11之间的相对位置关系有多种。作为一种实施方式，如图1所示，含锌保护体12完全直接覆盖铁基合金基体11的表面，可降解聚合物层也直接完全覆盖含锌保护体12。作为另一种实施方式，如图2所示的器械除去可降解聚合物后的结构图，含锌保护体12覆盖铁基合金基体11的部分表面，暴露出部分铁基合金基体11的表面。作为再一种实施方式，如图4所示的器械除去可降解聚合物后的结构图，含锌保护体12镶嵌在铁基合金基体11中并沿铁基合金基体11的厚度方向贯通该基体，相应地，未被贯通的铁基合金基体11的部分称为未被覆盖的区域。可以理解的是，含锌保护体12还可以其他形式与铁基合金基体11连接，例如非贯通地镶嵌在铁基合金基体11中，其暴露出的端面可与铁基合金基体11的表面齐平，也可以凸出或低于所述铁基合金基体11的表面。
当含锌保护体12完全覆盖所述铁基合金基体11时，含锌保护体12与体液接触后会溶解并电离出锌离子Zn2+，或者与可降解聚合物降解出的酸性环境中氢离子反应生成锌离子Zn2+，锌离子Zn2+进一步与体内的磷酸根PO4 3-反应生成难溶的磷酸锌Zn3(PO4)2，反应方程式如(1)和(2)所示：
ZnxR2＝xZn2++2Rx-       (1)
Figure PCTCN2016087302-appb-000001
Zn3(PO4)2具有防腐作用，具体机理如下：一方面，磷酸锌离解生成磷酸离子，缩合磷酸离子与铁基合金基体表面反应，形成复杂的有粘附性的Fe-Zn-P2O5化合物覆盖膜，使铁基合金基体钝化；另一方面，磷酸锌与由聚乳酸电离产生的羧基发生反应，生成络合物，该络合物能与铁腐蚀产物发生反应，在铁基合金基体表面形成紧密的保护膜，从而隔绝铁基合金基体与体内环境，遏制铁腐蚀。随着含锌化合物12被消耗，新生成的锌离子Zn2+减少，反应(2)的平衡 左移，即磷酸锌逐渐被溶解，铁基合金基体逐渐暴露出，此时铁基合金基体开始缓慢腐蚀，直至磷酸锌消耗完，铁基合金基体完全暴露于酸性环境中，开始快速腐蚀。
当含锌化合物12未完全覆盖铁基合金基体表面，通过磷酸锌直接扩散到达未覆盖区或者锌离子扩散到未覆盖区后再形成磷酸锌来减缓未覆盖区铁基体的腐蚀速度。
含锌保护体12的用量(重量或体积)与铁基合金基体11的用量(重量或体积)无关，与可降解聚合物的种类、性质(例如结晶度、分子量和多分散系数)、厚度(或质量)及需要保护铁基合金基体11的时间有关。可根据器械的种类与规格、器械的临床性能要求和预期需保持结构完整和足够力学性能的时长，灵活选择含锌保护体12的用量来调节含锌保护体12起保护作用的时长大致与铁基合金基体11的预期需保持结构完整和足够力学性能的时间相匹配。
所述可降解聚合物层至少包括一种可降解聚合物，其降解后产生酸性的降解产物如羧酸，可选自可降解聚酯和/或可降解聚酸酐，该可降解聚酯选自聚乳酸、聚乙醇酸、聚乳酸乙醇酸、聚己内酯、聚羟基脂肪酸酯、聚丙烯酸酯、聚丁二酸酯、聚(β-羟基丁酸酯)、聚己二酸乙二醇酯中的任意一种，或者选自聚乳酸、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、聚乳酸-乙醇酸共聚物和聚羟基丁酸酯戊酸酯共聚物中的至少两种的物理共混物，或者选自由形成聚乳酸、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、聚乳酸-乙醇酸共聚物和聚羟基丁酸酯戊酸酯共聚物的单体中的至少两种共聚而成的共聚物中的任一种；所述可降解聚酸酐选自聚1，3-双(对羧基苯氧基)丙烷-癸二酸、聚芥酸二聚体-癸二酸或聚富马酸-癸二酸中的至少一种；或者所述可降解聚合物为形成前述可降解聚酯与可降解聚酸酐的单体中的至少两种共聚而成的共聚物。
该可降解聚合物涂层还可包括活性药物，可在降解过程中释放治疗性药物。例如对于血管支架，该活性药物可抑制支架植入后的内膜过度增生，减少血管内再狭窄的发生率。活性药物可以是抑制血管增生的药物如紫杉醇、雷帕霉素及其衍生物，或抗血小板类药物选自西洛他唑，或抗血栓类药物如肝素，或抗 炎症反应的药物如地塞米松，或抗致敏的药物，如葡萄糖酸钙、扑尔敏、可的松，也可以是前述几种药物的混合物。所述抗过敏药物可选自抗组胺类抗过敏药物、抗白三烯药物、肥大细胞膜稳定剂、糖皮质激素类抗过敏药物或调节免疫类抗过敏药物中的至少一种。例如，所述抗过敏药物选自氯苯吡胺、苯海拉明、盐酸异丙嗪、西替利嗪、氯雷他定、咪唑斯汀、依巴斯汀、阿司咪唑、特非那定、地氯雷他定、非索非那定、赛庚啶、酮替芬、左旋西替利嗪、氯苯甲嗪、乙氟利嗪、卡依巴斯丁、氮卓斯汀、去氯羟嗪、氯环利嗪、氨来仙司、阿伐斯丁、阿扎他丁、甲喹吩嗪、左卡斯汀、赛他斯丁、斯喹那定、地普托品、苯噻啶、吡拉明、雷尼替丁、依美斯汀、依匹斯汀、异丙嗪、孟鲁司特、扎鲁司特、托卡司特、齐留通、氨来洛斯、伊布拉特、泊米司特、多塞平、维鲁司特、多西苯醌、色甘酸钠、色羟丙钠、尼多考米钠、曲尼司特、噻拉米特、瑞吡司特、丁氮菲酸、苯氮嘌呤酮、塔赞司特、奥萨格雷、瑞吡司特、地塞米松、甲基强的松龙、氢化可的松、曲安奈德、皮质类固醇、维他命C、钙剂、辅酶Q10或糜胰蛋白酶中的至少一种。
所述可降解聚合物层制备方法如下：先将可降解聚合物和药物溶解于有机溶剂(如乙酸乙酯、氯仿等)中形成混合溶液，随后将该混合溶液涂于已经制备了含锌保护体12的铁基合金基体11的整个表面或局部表面，干燥后成膜。采用的方法可以是喷涂、浸涂、刷涂、静电纺丝，优选喷涂。
本发明的可吸收铁基合金植入医疗器械可以是血管支架、骨科植入物、妇科植入物、男科植入物、呼吸科植入物或骨科植入物。以下结合具体实施例，以铁基合金冠脉支架为例，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。
需要说明的是，以下各实施例采用动物实验的方式说明在含锌保护体的作用下，铁基合金支架能够在植入早期1-6个月内几乎不腐蚀，主要通过在支架植入动物体内后的不同观察时间点，诸如3个月、6个月、12个月等，对动物进行安乐处死，从其体内取出支架及其所在位置的组织，通过将支架连同支架所在的血管段进行径向支撑强度和质量损失测试来表征铁基合金支架的体内腐蚀状况以及是否满足早期力学性能要求。
所述径向支撑强度的测试使用MSI公司生产的径向支撑力测试仪进行，将植入动物体内的支架连同血管段取出，吸干表面水分后直接进行测试，即可得到支架植入后的不同时间点的径向支撑强度。
所述质量损失测试通过如下方式进行：将包括质量为M0的铁基合金基体(指未包括可降解聚合物的裸支架)的铁基合金支架(包括可降解聚合物)植入兔子腹主动脉，在预定观察时间点将植入动物体内的铁基合金支架及其所在的组织截取出来，然后将组织连同支架浸泡在1mol/L氢氧化钠溶液中，使组织消解，然后从溶液中取出铁基合金支架或其碎片，将其放入一定浓度的溶液(如3％酒石酸溶液，和/或有机溶液)中超声，使其表面的腐蚀产物、残留的含锌保护体(若有)和聚合物层全部脱落或溶解于溶液中，取出溶液中剩余未腐蚀的铁基合金支架或其碎片，干燥称重，质量为Mt。质量损失率W用腐蚀清洗后支架杆重量损失的差值占铁基合金基体的重量的百分比来表示，如公式3所示：
W＝(Mt-M0)/M0×100％    (3)
W——质量损失率
Mt——腐蚀后剩余铁基合金支架基体的质量
M0——铁基合金支架基体的初始质量
其中，当铁基合金基体的质量损失率W<5％时，定义为不腐蚀；铁基合金支架基体的质量损失率W≥90％时，定义为完全腐蚀。
临床上，正常人的冠脉血管舒张压(低压)和收缩压(高压)范围为60-120mmHg，高血压病人的收缩压可达到175mm汞柱，即23.3kPa。发生冠脉痉挛时血管收缩压为400mmHg，即55kPa。心理应激状态、寒冷刺激、剧烈运动、冠脉粥样硬化、冠脉造影对冠脉的局部刺激以及一次性大量吸烟或酗酒均可诱发冠脉痉挛。故实现对冠脉血管的有效支撑是指支架至少能经受冠脉血管脉动时的收缩压23.3kPa，最好能经受血管痉挛时的收缩压55kPa。
以下各实施例提供的铁基合金冠脉支架的设计目标是需满足以下临床要求：自植入日起预定时间内(例如1个月内、2个月内、3个月或少于3个月的其他时长内)，铁基合金基体几乎不腐蚀；在植入后能有效支撑3个月，植入3个月后的径向支撑强度≥55kPa，腐蚀周期大于6个月小于或等于24个月。
以下各实施例中30008规格支架定义如下：支架在名义扩张压8atm作用下，扩开后的公称直径3mm，公称长度为8mm。
需要指出的是，以下各实施例中，由于支架产品自身性能在设计许可范围内的正常波动、动物个体差异、设计的取样点不够频密以及测试方法不可避免引入的系统误差，监测到的支架完全不腐蚀的时间点、径向强度数据以及完全腐蚀的时间点在实际测试中会在一定范围内波动。
实施例1
一种可吸收铁基合金支架，其包括的含锌保护体可延缓铁基合金基体在植入2个月内不腐蚀，制备方法如下：取原始径向支撑强度为145kPa、质量为4.5-5mg的30008规格的渗氮铁支架，在整个支架表面喷涂磷酸锌-聚乙二醇(重均分子量4000)-氯仿的悬浮液然后干燥制得厚度为4微米的磷酸锌-聚乙二醇涂层，其中磷酸锌的体积分数为80％。随后喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液完全覆盖整个磷酸锌-聚乙二醇涂层表面，干燥后制得聚乳酸涂层厚度为12微米的可吸收铁基合金支架。将支架植入兔子腹主动脉，2个月后取出，支架腐蚀不腐蚀；3个月后取出，测得径向支撑强度为120kPa，符合植入早期3个月的力学性能要求。12个月取出，支架完全腐蚀。
实施例2
一种可吸收铁基合金支架，其包括的含锌保护体可延缓铁基合金基体在植入1个月内不腐蚀，制备方法如下：取原始径向支撑强度为145kPa、质量为4.5-5mg的30008规格的渗氮铁支架，在支架外表面和侧面喷涂硫酸锌-环糊精-乙醇的悬浮溶液，然后干燥制得厚度为12微米的硫酸锌-环糊精涂层，其中硫酸锌体积分数为90％。随后喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液完全覆盖整个硫酸锌-环糊精涂层表面和暴露出来的铁基合金支架表面，干燥后制得聚乳酸涂层厚度为8微米的可吸收铁基合金支架。将支架植入兔子腹主动脉，1个月后取出，铁基支架不腐蚀；3个月后取出，测得径向支撑强度为80kPa，满足植入早期3个月的力学性能要求；12个月取出，支架完全腐蚀。
实施例3
一种可吸收铁基合金支架，其包括的含锌保护体可延缓铁基合金基体在植 入1个月内不腐蚀，制备方法如下：在原始径向强度为145kPa、质量为4.5-5mg的30008规格的渗氮铁支架杆上，设置凹槽镶嵌磷酸锌粉块，所有镶嵌的磷酸锌粉块露出来的面积与铁基体表面积的比值为1:1。随后在支架的表面喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液完全覆盖露出来的磷酸锌粉块和铁基支架表面，干燥后制得聚消旋乳酸涂层厚度为6微米的可吸收铁基合金支架。将支架植入兔子腹主动脉，1个月后取出，铁基支架不腐蚀；3个月后取出，测得径向支撑强度为110kPa。24个月取出，支架完全腐蚀。
实施例4
一种可吸收铁基合金支架，其包括的含锌保护体可延缓铁基合金基体在植入1个月内不腐蚀，制备方法如下：在原始径向强度为145kPa、质量为4.5-5mg的30008规格的渗氮铁支架表面，保护支架部分表面后，在支架内表面和部分侧面浸涂氯化锌-聚乙二醇(重均分子量4000)-乙醇溶液，然后干燥制得厚度为12微米的氯化锌-聚乙二醇涂层，其中氯化锌的体积分数为80％。随后喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液完全覆盖暴露出来的铁基支架表面，干燥后制得聚乳酸涂层厚度为15微米的可吸收铁基合金支架。将支架植入兔子腹主动脉，1个月后取出，铁基支架不腐蚀；3个月后取出测得径向支撑强度为80kPa，满足植入早期3个月的力学性能要求。植入后24个月后取出，质量损失测试表明支架完全腐蚀。
实施例5
一种可吸收铁基合金支架，其包括的含锌保护体可延缓铁基合金基体在植入1个月内不腐蚀，制备方法如下：在原始径向强度为145kPa、质量为4.5-5mg的30008规格的渗氮铁支架表面，在整个支架表面喷涂葡萄糖酸锌水溶液，干燥后测得葡萄糖酸锌涂层厚3微米。随后在葡萄糖酸锌涂层表面喷涂三聚磷酸钠水溶液，干燥测得三聚磷酸钠涂层厚3微米。随后喷涂分子量为20万的聚消旋乳酸-雷帕霉素-乙酸乙酯溶液于三聚磷酸钠表面，聚消旋乳酸与雷帕霉素的质量比为4:1，干燥后制得聚乳酸-雷帕霉素涂层厚度为5微米的可吸收铁基合金支架。将支架植入兔子腹主动脉，1个月后取出，铁基支架不腐蚀；3个月后取出测得径向支撑强度为80kPa，满足植入早期3个月的力学性能要求。植入后24 个月后取出，质量损失测试表明支架完全腐蚀。
对比例1
本对比例提供一种30008规格的渗氮铁裸支架(即不包括可降解聚合物和含锌保护体的支架)，其原始径向强度为145kPa、质量为4.5-5mg。将该支架植入兔子腹主动脉。3个月后取出，质量损失测试表明支架轻微腐蚀，测得支架径向支撑强度为140kPa，满足植入早期3个月的力学性能要求。植入后24个月后取出，质量损失测试表明支架未完全腐蚀，说明未设置可降解聚合物层的渗氮铁支架的腐蚀周期过长。
对比例2
本对比例提供一种可吸收铁基支架，其制备方法如下：在原始径向强度为145kPa、质量为4.5-5mg的30008规格的渗氮铁支架表面上喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液完全覆盖整个支架表面，干燥后制得聚消旋乳酸涂层厚度为12微米的可吸收铁基合金支架。将该支架植入兔子腹主动脉，2个月后取出，支架杆腐蚀非常严重，多处断裂；3个月后取出，测得支架径向支撑强度小于55kPa；植入后6个月，质量损失测试表明支架完全腐蚀，说明腐蚀过快，满足不了早期力学性能要求。
对比例3
本对比例提供一种可吸收铁基支架，其制备方法如下：在原始径向强度为175kPa、质量为5.5-6mg的30008规格的渗氮铁支架表面喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液完全覆盖整个支架表面，干燥后制得聚消旋乳酸涂层厚度为10微米的可吸收铁基合金支架。将该支架植入兔子腹主动脉，1个月后取出，支架杆有一定程度的腐蚀；3个月后取出，测得支架径向支撑强度为80kPa，满足植入早期3个月的力学性能要求；植入后12个月取出，质量损失测试表明支架完全腐蚀。
由以上各实施例可以看出，本发明的可吸收铁基合金支架由于设置了含锌保护体，在植入早期铁基合金基体腐蚀较少，径向支撑强度有所下降，但仍满足早期植入3个月的力学性能要求。通过调节含锌保护体的用量，使其用量对应的在体内被消耗的时长大致与预期设定的铁基合金不腐蚀的时长匹配，实现 了调节支架在植入早期不腐蚀的时间长短。与对比例1相比，实施例1-5提供的支架的腐蚀周期更短。与对比例2相比，实施例1提供的支架在植入早期腐蚀较轻微，在植入3个月时保持了结构完整性并具有足够的力学支撑。与对比例3相比，实施例2提供的支架在保证同样的腐蚀周期和3个月时足够的力学支撑的前提下，铁基体的用量更少，可以预期后续产生的腐蚀产物量更少，完全吸收的周期更短。
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 (12)

  1. 一种可吸收铁基合金植入医疗器械，包括铁基合金基体和设于铁基合金基体表面的可降解聚合物，其特征在于，所述医疗器械还包括设于所述铁基合金基体表面的含锌保护体，所述含锌保护体选自锌化合物，或包括含磷酸根化合物、可降解粘结剂、水溶性粘结剂中的至少一种与锌化合物的混合物，所述混合物中锌化合物的重量百分比≥20％且<100％。
  2. 如权利要求1所述的可吸收铁基合金植入医疗器械，其特征在于，所述含锌保护体覆盖所述铁基合金基体的表面，所述可降解聚合物覆盖所述含锌保护体的至少部分表面。
  3. 如权利要求1所述的可吸收铁基合金植入医疗器械，其特征在于，所述可降解聚合物覆盖所述含锌保护体的至少部分表面，或所述含锌保护体与所述可降解聚合物相互错开地覆盖所述铁基合金基体的不同表面，或者所述可降解聚合物既覆盖所述含锌保护体的至少部分表面，又同时覆盖至少部分所述未覆盖区。
  4. 如权利要求1-3任一项所述的可吸收铁基合金植入医疗器械，其特征在于，所述锌化合物为磷酸锌，或是能溶解电离出锌离子的锌化合物，或是能反应生成锌离子的锌化合物。
  5. 如权利要求4所述的可吸收铁基合金植入医疗器械，其特征在于，所述锌化合物选自硫酸锌、氯化锌、硝酸锌、碳酸锌、碱式碳酸锌、氧化锌、氢氧化锌、葡萄糖酸锌、甘草锌、乳酸锌、醋酸锌、柠檬酸锌、氨基酸锌、酵母锌中的至少一种。
  6. 如权利要求4所述的可吸收铁基合金植入医疗器械，其特征在于，所述含锌保护体直接与所述铁基合金基体表面接触。
  7. 如权利要求4所述的可吸收铁基合金植入医疗器械，其特征在于，所述含锌保护体镶嵌在所述铁基合金基体中。
  8. 如权利要求1所述的可吸收铁基合金植入医疗器械，其特征在于，所述铁基合金基体为纯铁或碳含量不高于2.11wt.％的铁基合金。
  9. 如权利要求1所述的可吸收铁基合金植入医疗器械，其特征在于，所述可降解聚合物中混有活性药物。
  10. 如权利要求9所述的可吸收铁基合金植入医疗器械，其特征在于，所述活性药物包括抗致敏药物，所述抗过敏药物选自抗组胺类抗过敏药物、抗白三烯药物、肥大细胞膜稳定剂、糖皮质激素类抗过敏药物或调节免疫类抗过敏药物中的至少一种。
  11. 根据权利要求10所述的可吸收铁基合金植入医疗器械，其特征在于，所述抗过敏药物选自氯苯吡胺、苯海拉明、盐酸异丙嗪、西替利嗪、氯雷他定、咪唑斯汀、依巴斯汀、阿司咪唑、特非那定、地氯雷他定、非索非那定、赛庚啶、酮替芬、左旋西替利嗪、氯苯甲嗪、乙氟利嗪、卡依巴斯丁、氮卓斯汀、去氯羟嗪、氯环利嗪、氨来仙司、阿伐斯丁、阿扎他丁、甲喹吩嗪、左卡斯汀、赛他斯丁、斯喹那定、地普托品、苯噻啶、吡拉明、雷尼替丁、依美斯汀、依匹斯汀、异丙嗪、孟鲁司特、扎鲁司特、托卡司特、齐留通、氨来洛斯、伊布拉特、泊米司特、多塞平、维鲁司特、多西苯醌、色甘酸钠、色羟丙钠、尼多考米钠、曲尼司特、噻拉米特、瑞吡司特、丁氮菲酸、苯氮嘌呤酮、塔赞司特、奥萨格雷、瑞吡司特、地塞米松、甲基强的松龙、氢化可的松、曲安奈德、皮质类固醇、维他命C、钙剂、辅酶Q10或糜胰蛋白酶中的至少一种。
  12. 如权利要求1所述的可吸收铁基合金植入医疗器械，其特征在于，所述可降解聚合物选自可降解聚酯和/或可降解聚酸酐，该可降解聚酯选自聚乳酸、聚乙醇酸、聚乳酸乙醇酸、聚己内酯、聚羟基脂肪酸酯、聚丙烯酸酯、聚丁二酸酯、聚(β-羟基丁酸酯)、聚己二酸乙二醇酯中的任意一种，或者选自聚乳酸、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、聚乳酸-乙醇酸共聚物和聚羟基丁酸酯戊酸酯共聚物中的至少两种的物理共混物，或者选自由形成聚乳酸、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、聚乳酸-乙醇酸共聚物和聚羟基丁酸酯戊酸酯共聚物的单体中的至少两种共聚而成的共聚物中的任一种；所述可降解聚酸酐选自聚1，3-双(对羧基苯氧基)丙烷-癸二酸、聚芥酸二聚体-癸二酸或聚富马酸-癸二酸中的至少一种；或者所述可降解聚合物为形成前述可降解聚酯与可降解聚酸酐的单体中的至少两种共聚而成的共聚物。
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