WO2017067181A1 - 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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WO2017067181A1
WO2017067181A1 PCT/CN2016/085188 CN2016085188W WO2017067181A1 WO 2017067181 A1 WO2017067181 A1 WO 2017067181A1 CN 2016085188 W CN2016085188 W CN 2016085188W WO 2017067181 A1 WO2017067181 A1 WO 2017067181A1
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iron
based alloy
acid
corrosion
medical device
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PCT/CN2016/085188
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English (en)
French (fr)
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林文娇
秦莉
张德元
孙宏涛
张贵
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先健科技(深圳)有限公司
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Priority to EP16856622.2A priority Critical patent/EP3366325B1/en
Priority to US15/763,329 priority patent/US10857267B2/en
Publication of WO2017067181A1 publication Critical patent/WO2017067181A1/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
    • 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
    • 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
    • A61L31/08—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
    • 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
    • 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
    • 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

Definitions

  • the invention belongs to the field of absorbable implant medical devices, in particular to an absorbable iron-based alloy implanted medical device.
  • bioabsorbable implantable medical device materials mainly include polymers and magnesium-based alloys and iron-based alloys.
  • polymers polylactic acid is the most widely used, and its advantage is that it can be completely degraded and absorbed, and the degradation products are carbon dioxide and water, and the disadvantage is that the mechanical properties are insufficient.
  • metal-based devices polymer-based devices need to be larger than metal-based devices if they meet the same mechanical properties, which limits the use 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, it can only meet the early stage of implantation by increasing the size of magnesium-based alloy instruments. Mechanical properties will also limit the application of magnesium-based alloys.
  • 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.
  • Iron-based alloys have good biocompatibility, and iron ions help to inhibit smooth muscle and promote endothelial cell growth, but iron-based alloys are slowly corroded in the body, causing iron-based alloy devices to take a long time to complete after the healing period. Corrosion, so it is necessary to speed up the corrosion rate to shorten the corrosion cycle of iron-based alloys.
  • the degradation products of some degradable polymers are acidic, and coating such degradable polymers on the surface of iron-based alloys can improve the corrosion rate of iron-based alloys.
  • the degradation of the degradable polymer in the body causes the pH of the local microenvironment near the implanted position of the device to decrease, forming a local slightly acidic environment, and the iron-based alloy can corrode more quickly in this acidic environment, generating corrosion products such as iron. Salt and / or iron oxides and / or iron hydroxides.
  • the amount, type and nature of the degradable polymer determine the corrosion rate and corrosion cycle of the iron-based alloy matrix.
  • the amount of degradable polymer will be relatively large, because the degradation products are acidic, which increases the risk of inflammatory reaction.
  • the corrosion rate of the iron-based alloy is too fast or local corrosion is severe, which will affect the iron base.
  • the degradation products of degradable polymers are acidic, and the degradable polymers tend to have small molecular residues with rapid degradation rate (such as the monomer residue standard of polylactic acid is ⁇ 2%), causes the iron-based alloy matrix to corrode quickly in the early stage of implantation, such as 1-7 days after implantation of the coronary artery, excessive corrosion and accumulation of corrosion products lead to incomplete endothelium inner surface of the instrument, increasing the risk of acute and subacute thrombosis
  • the non-uniformity of degradation of the degradable polymer tends to cause 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 degradable polymer 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 polymer, in the case where the type and nature of the degradable polymer and the ratio of the amount of the iron-based alloy are determined, it is necessary to explore how to reduce in the acidic environment formed by the degradable polymer. The early corrosion rate of the iron-based alloy matrix to ensure the early mechanical properties of the instrument implantation; and how to effectively use the degradable polymer to reduce its amount.
  • the present invention provides an absorbing iron-based implantable medical device which has a slower or even no corrosion rate within 1-6 months after implantation in the body, and can satisfy clinically during this period of time.
  • Early mechanical properties of the device implant while reducing the amount of degradable polymer while maintaining its intended corrosion cycle.
  • An absorbable iron-based alloy implanted medical device comprising: an iron-based alloy substrate and a degradable polymer disposed on a surface of the iron-based alloy substrate; and corrosion inhibition provided on the surface of the iron-based alloy substrate and the degradable polymer Floor.
  • the degradable polymer may cover the entire surface of the iron-based alloy substrate, and may also cover a part of the surface of the iron-based alloy substrate.
  • the corrosion inhibiting layer covers at least a portion of the surface of the degradable polymer when the degradable polymer covers the entire surface of the iron-based alloy substrate.
  • the corrosion-inhibiting layer may cover only at least part of the surface of the degradable polymer, or may overlap the iron with the degradable polymer
  • the different surfaces of the base alloy substrate may also cover at least a portion of the surface of the degradable polymer while covering at least a portion of the uncovered regions.
  • the iron-based alloy base material is an iron-based alloy or pure iron having a carbon content of not more than 2.11 wt.%.
  • the degradable polymer is selected from the group consisting of a degradable polyester and/or a degradable polyanhydride selected from the group consisting of polylactic acid, polyglycolic acid, polylactic acid glycolic acid, polycaprolactone, polyhydroxyalkanoate, Any one of polyacrylate, polysuccinate, poly( ⁇ -hydroxybutyrate), and polyethylene adipate, or selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, Physical totality of at least two of poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer, and polyhydroxybutyrate valerate copolymer Mixture, or selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymerization And a copolymer obtained by copo
  • the degradable polymer may be mixed with an active drug or may not be mixed with an active drug, and the active drug may be a drug for inhibiting vascular proliferation such as paclitaxel, rapamycin and a derivative thereof, or an anti-platelet drug selected from the group consisting of Cilostazol, or an antithrombotic drug such as heparin, or an anti-inflammatory drug such as dexamethasone, may also be a mixture of the foregoing drugs.
  • the active drug may be a drug for inhibiting vascular proliferation such as paclitaxel, rapamycin and a derivative thereof, or an anti-platelet drug selected from the group consisting of Cilostazol, or an antithrombotic drug such as heparin, or an anti-inflammatory drug such as dexamethasone, may also be a mixture of the foregoing drugs.
  • the corrosion inhibiting layer material is an organic material containing at least one hydrophobic group.
  • the organic matter is selected from the group consisting of a mixture of solid alkanes and semi-solid alkanes, solid alkanes, semi-solid alkanes, higher fatty acid glycerides, lipids, higher alkanols, higher fatty acids, salts of higher fatty acids, organic acid esters, polyorganic A silicone, a fat-soluble vitamin, a silane coupling agent, a linear alkyl compound or an amino acid.
  • the higher fatty acid glyceride is selected from the group consisting of monoglycerides, diesters or triesters; the lipid is lecithin; the higher alkanol is selected from the group consisting of octacosanol and triacontanol; The salt thereof is selected from the group consisting of lauric acid, palmitic acid, stearic acid, magnesium stearate, and octadecylamine; the organic acid ester is selected from the group consisting of citrate, laurate, and sucrose dodecanoate; The organosiloxane is a silicone oil; the fat-soluble vitamin is selected from the group consisting of ⁇ -carotenoids, vitamin E, and vitamin A; the solid or semi-solid alkane is selected from the group consisting of paraffin wax, microcrystalline wax, and petrolatum; The base compound is selected from the group consisting of sodium dodecyl sulfate, sodium lauryl sulfate, do
  • the absorbable iron-based alloy implanted medical device further includes a drug carrying layer disposed on an outermost layer of the medical device, the drug loading layer comprising a degradable polymer and an active drug.
  • the present invention provides an absorbable iron-based alloy implanted medical device comprising a corrosion inhibiting layer.
  • the corrosion-inhibiting layer can effectively block the penetration of water molecules and inhibit the formation of a slightly acidic environment on the surface of the iron-based alloy matrix, thereby avoiding problems such as excessive corrosion of the iron alloy matrix in the early stage of implantation and serious local corrosion. It ensures that the iron-based alloy medical device meets the clinical mechanical performance requirements at the initial stage of implantation; the corrosion-resistant layer covering the degradable polymer can greatly reduce the degradation consumption of the degradable polymer in the body fluid environment at the initial stage of implantation, and improve the utilization rate thereof.
  • the amount of degradable polymer can be reduced, and the risk of inflammatoryness can be reduced.
  • the corrosion-inhibiting layer material is gradually degraded or metabolized, the degradable polymer on the surface of the iron-based alloy substrate is gradually hydrolyzed. Forming a slightly acidic environment, thereby accelerating the corrosion of the iron-based alloy substrate; the absorbing iron-based alloy implanted medical device of the present invention has a smaller design size, and produces less corrosion products after implantation, which is beneficial to the iron-based alloy substrate. The corrosion products are absorbed or metabolized faster.
  • FIG. 1 is a schematic cross-sectional view of an absorbable implantable medical device along its length in accordance with an embodiment of the present invention.
  • FIG. 2 is a schematic cross-sectional view of an absorbable implantable medical device along its length according to another embodiment of the present invention.
  • the degradable polymer coating 16 completely covers the surface of the iron-based alloy substrate 11, and the degradable polymer layer 16 can be mixed with an active drug, and the corrosion-inhibiting layer 12 is also completely covered and degradable. Polymer coating 16.
  • a drug-loading layer may also be disposed. As shown in FIG. 2, the drug-loading layer 13 completely covers the surface of the corrosion-inhibiting layer 12.
  • the material of 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 degradation of the degradable polymer in the body fluid environment produces an acidic carboxyl group to generate a local micro-acid environment, thereby accelerating the corrosion of the iron-based alloy substrate 11.
  • the more the amount of the degradable polymer coating 16, the iron-based alloy matrix The faster the corrosion rate of 11 is, the adjustment of the material, thickness, molecular weight, crystallinity and other parameters of the degradable polymer coating 16 can adjust the corrosion cycle of the iron-based alloy implanted medical device.
  • the corrosion-inhibiting layer 12 can effectively block the penetration of water molecules, inhibit the formation of a slightly acidic environment on the surface of the iron-based alloy substrate, and avoid problems such as excessive corrosion of the iron-based alloy substrate 11 and severe local corrosion.
  • the mechanical properties of the medical device at the early stage of implantation are ensured; the corrosion-inhibiting layer 12 is disposed on the outer layer of the degradable polymer, which can be isolated from the water, can effectively delay the degradation of the degradable polymer, and improve the utilization rate thereof, thereby Reduce the amount of degradable polymer.
  • the corrosion-inhibiting layer 12 As the implantation time is extended, the corrosion-inhibiting layer 12 is gradually consumed, and the degradable polymer is gradually degraded to produce a slightly acidic environment, which can accelerate the corrosion rate in the late stage of medical device implantation.
  • the thickness of the corrosion-inhibiting layer 12 By adjusting the thickness of the corrosion-inhibiting layer 12, the effective support time of the medical device can be adjusted.
  • the drug-loading layer 13 functions to carry the drug, and can further treat the implantation site, and the drug-loading layer includes the degradable polymer and the active drug.
  • the degradable polymer coating 16 and the degradable polymer material in the drug-loading layer 13 are at least one degradable polymer which degrades to produce an acidic degradation product such as a carboxylic acid, which may be selected from degradable poly Ester and/or degradable polyanhydride.
  • the degradable polyester is selected from the group consisting of polylactic acid, polyglycolic acid, polylactic acid glycolic acid, polycaprolactone, polyhydroxyalkanoate, polyacrylate, polysuccinate, poly( ⁇ -hydroxybutyrate), Any one of polyethylene adipate, or selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyadipate B a physical blend of at least two of a glycol ester, a polylactic acid-glycolic acid copolymer, and a polyhydroxybutyrate valerate copolymer, or selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, At least two of monomers of poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer, and polyhydroxybutyrate valerate copolymer Any one of copolymerized copo
  • the active drug may be a drug that inhibits angiogenesis 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-inflammatory drug such as a celite.
  • Rice pine can also be a mixture of the aforementioned drugs.
  • the coating method of the degradable polymer coating, the corrosion-inhibiting layer and the drug-loading layer may be spray coating, dip coating, brush coating, or electrospinning.
  • 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.
  • the following examples use animal experiments to show that under the action of corrosion-inhibiting layer, the iron-based alloy stent can corrode very slowly in the first 1-6 months after implantation, mainly after the stent is implanted into the animal.
  • the animals are euthanized, and the stent and the tissue at its location are removed from the body, by placing the stent together with the stent.
  • the vascular segments were tested for radial support strength and mass loss to characterize the in vivo corrosion of the iron-based alloy stent and to meet early mechanical performance requirements.
  • 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.
  • 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 radial strength test method of the bracket is as follows: the radial pressure is uniformly applied to the bracket by the compression module, and the bracket is compressed to generate uniform deformation. The radial pressure applied when the radial (outer diameter) of the stent is 10% deformed is defined as the radial strength of the stent.
  • the radial support strength test is performed by using a radial support strength tester (RX550-100) produced by MSI, and the stent implanted in the animal body is taken out together with the blood vessel, and the surface moisture is absorbed and directly tested to obtain the stent graft. Radial support strength at different points in time after entry.
  • RX550-100 radial support strength tester
  • the weight loss test method is as follows: an iron-based alloy stent (including a degradable polymer) including an iron-based alloy matrix of mass M 0 (referred to as a bare stent not including a degradable polymer) is implanted into the rabbit abdominal aorta, at a predetermined time At the observation time point, the iron-based alloy stent implanted in the animal and the tissue in which it is implanted are taken out, and then the tissue and the stent are immersed in a 1 mol/L sodium hydroxide solution to digest the tissue, such as tannic acid on the surface of the iron-based substrate.
  • the chemical conversion film remains, the remaining tannic acid chemical conversion film is removed, and then the iron-based alloy stent or its fragments are taken out from the solution and placed in a solution of a certain concentration (such as 3% tartaric acid solution, and/or organic solution).
  • a certain concentration such as 3% tartaric acid solution, and/or organic solution.
  • the corrosion products and polymer layers on the surface are completely detached or dissolved in the solution, and the uncorroded iron-based alloy stent or fragments thereof are taken out in the solution, and dried 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 matrix, as shown in Equation 1:
  • 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.
  • the design goals of the iron-based alloy stents provided in the following embodiments are to meet the following clinical requirements: 3 months after implantation, 3 days after implantation, ⁇ 55 kPa, and more than 6 corrosion cycles. Months are less than or equal to 24 months.
  • the 30008 specification bracket is 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 rack diameter is monitored due to the normal fluctuation of the performance of the stent product within the design permission range, the individual differences of the animal, the insufficient sampling point of the design, and the systematic error that the test method inevitably introduces.
  • the intensity data and the time point of complete corrosion will fluctuate within a certain range in the actual test.
  • the 30008-size polished nitriding iron-based alloy coronary stent was prepared with an original radial strength of 145 kPa and a mass of 4.5 mg.
  • the surface of the stent substrate was sprayed with a poly- lactic acid-ethyl acetate solution and dried.
  • a degradable poly-polylactic acid coating having a thickness of 6 ⁇ m completely covering the surface of the stent; spraying the octacosanol-trichloromethane solution on the surface of the stent prepared in the above step to form a thickness completely covering the degradable racemic lactic acid coating It is a 2 ⁇ m octacosanol corrosion inhibitor.
  • the iron-based absorbable stent prepared in the above procedure was implanted into the abdominal aorta of rabbit, and was taken out after 3 months.
  • the stent was completely endothelialized, without early thrombosis and inflammation.
  • the radial support strength was 80 kPa, and the animals in the same group were completely corroded.
  • the cycle is 12 months.
  • the iron-based absorbable stent prepared in the above procedure was implanted into the abdominal aorta of rabbit, and was taken out after 3 months.
  • the stent was completely endothelialized, without early thrombosis and inflammation.
  • the radial support strength was 80 kPa, and the animals in the same group were completely corroded.
  • the cycle is 6 months.
  • the 30008-size polished nitriding iron-based alloy coronary stent matrix has an original radial strength of 145 kPa and a mass of 4.5 mg.
  • the surface of the stent substrate is sprayed with a poly- lactic acid-ethyl acetate solution, which is completely covered after drying.
  • the surface of the stent has a thickness of 6 ⁇ m of a degradable poly- lactic acid coating; the surface of the stent prepared in the above step is sprayed with a octacosanol-trichloromethane solution to form a fully covered degradable poly- lactic acid lactic acid coating having a thickness of 5 ⁇ m.
  • the octacosanol corrosion inhibitory layer is used to form a fully covered degradable poly- lactic acid lactic acid coating having a thickness of 5 ⁇ m.
  • the absorbable iron-based stent prepared in the above procedure was implanted into the abdominal aorta of rabbit, and was taken out after 3 months.
  • the stent was completely endothelialized, without early thrombosis and inflammation.
  • the radial support strength was 110 kPa, and the same group of animals were monitored for complete corrosion.
  • the cycle is 18 months.
  • the 30008-size polished nitriding iron-based alloy coronary stent matrix has an original radial strength of 145 kPa and a mass of 4.5 mg.
  • the surface of the stent substrate is sprayed with a poly- lactic acid-ethyl acetate solution, which is completely covered after drying.
  • the surface of the stent has a thickness of 6 ⁇ m of a degradable poly-polylactic acid coating; the surface of the stent prepared in the above step is coated with vitamin E oil to form a 2 ⁇ m thick vitamin E oil corrosion-inhibiting coating completely covering the degradable poly-polylactic acid coating.
  • the 30008-size polished nitriding iron-based alloy coronary stent matrix has an original radial strength of 145 kPa and a mass of 4.5 mg.
  • the surface of the stent substrate is sprayed with a poly- lactic acid-ethyl acetate solution, which is completely covered after drying.
  • the surface of the stent has a thickness of 6 ⁇ m of a degradable poly- lactic acid coating; the surface of the stent prepared in the above step is sprayed with a lecithin-ethanol solution to form a 2 ⁇ m thick lecithin covering 90% of the surface of the degradable poly-polylactic acid coating. Corrosion inhibition layer.
  • the absorbable iron-based stent prepared in the above procedure was implanted into the abdominal aorta of rabbit, and was taken out after 3 months.
  • the stent was completely endothelialized, and there was no early thrombosis or inflammation.
  • the radial support strength was 80 kPa, and the animals in the same group were completely corroded.
  • the cycle is 12 months.
  • the 30008-size polished nitriding iron-based alloy coronary stent matrix has an original radial strength of 145 kPa and a mass of 4.5 mg.
  • the surface of the stent substrate is sprayed with a poly- lactic acid-ethyl acetate solution, and dried to obtain a surface covering the stent.
  • the thickness is 2 ⁇ m of sodium stearate corrosion-inhibiting layer; 80% of it covers the surface of the degradable poly- lactic acid-coated coating, and 10% directly covers the surface of the iron stent.
  • the absorbable iron-based stent prepared in the above procedure was implanted into the abdominal aorta of rabbit, and was taken out after 3 months. The stent was completely endothelialized, and there was no early thrombosis or inflammation. The radial support strength was 80 kPa, and the animals in the same group were completely corroded. The cycle is 18 months.
  • the stent was implanted into the abdominal aorta of rabbits. After 3 months, the stent was completely endothelialized, with no early thrombosis and inflammation. The radial support force was 80 kPa. The complete corrosion period of the same group of animals was 12 months.
  • the absorbing iron-based alloy stent of each embodiment has a corrosion-inhibiting layer, and the corrosion of the iron-based alloy matrix is retarded during the protection of the corrosion-inhibiting layer, and both It can meet the mechanical performance requirements of early implantation for 3 months.
  • the stents provided in Examples 1-6 were able to ensure structural integrity and sufficient mechanical support within 3 months of implantation by adjusting the amount of corrosion-inhibiting layer compared to Comparative Example 1.
  • the stents provided in Examples 1, 3, 4, 5, and 6 can ensure the structural integrity of the implant within 3 months and have sufficient mechanical support, and the amount of degradable polymer is more. less.
  • the stents provided in Examples 1, 2, 4 and 5 were able to ensure the structural integrity of the implant within 3 months and have sufficient mechanical support, and the quality of the iron-based alloy matrix was smaller. It is expected that the amount of corrosion products subsequently produced will be less and the period of complete absorption will be shorter.

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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）、设于铁基合金基体（11）表面的可降解聚合物涂层（16）和设于所述铁基合金基体（11）表面的缓蚀层（12）。该缓蚀层（12）可以延缓铁基合金基体（11）的早期腐蚀，保证医疗器械植入早期的力学性能，阻止聚合物在医疗器械植入早期的降解，减少可降解聚合物的用量，从而降低炎性反应风险。

Description

可吸收铁基合金植入医疗器械
【技术领域】
本发明属于可吸收植入医疗器械领域，尤其涉及一种可吸收铁基合金植入医疗器械。
【背景技术】
目前生物可吸收植入医疗器械材料主要包括聚合物及镁基合金、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，但由于镁基合金在人体内的腐蚀速度太快，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。铁基合金具有良好的生物相容性，且铁离子有助于抑制平滑肌而促进内皮细胞生长，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的腐蚀周期。
一些可降解聚合物的降解产物呈酸性，在铁基合金表面涂覆此类可降解聚合物，可提高铁基合金的腐蚀速度。该可降解聚合物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，生成腐蚀产物如铁盐和/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，可降解聚合物的用量、种类和性质决定了铁基合金基体的腐蚀速度和腐蚀周期。为了确保铁基合金基体在预定时间内完全腐蚀，可降解聚合物的用量会比较大，因其降解产物呈酸性，会增加炎性反应风险。此外，在选定可降解聚合物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合物用量的情况下，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）可降解聚合物的降解产物呈酸性，且可降解聚合物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）可降解聚合物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合物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，对于包括可降解聚合物的铁基合金器械，在可降解聚合物种类和性质及与铁基合金的用量比确定的情况下，需探索在可降解聚合物形成的酸性环境中，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；以及如何有效利用可降解聚合物，减少其用量。
【发明内容】
基于此，本发明提供了一种可吸收铁基植入医疗器械，其在植入体内后1-6个月内腐蚀速度较慢甚至是完全不腐蚀，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；同时在维持其预定腐蚀周期的情况下，可以减少可降解聚合物的用量。
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，以及设于所述铁基合金基体和可降解聚合物表面的缓蚀层。
所述可降解聚合物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。当所述可降解聚合物覆盖所述铁基合金基体的全部表面时，所述缓蚀层覆盖所述可降解聚合物的至少部分表面。当可降解聚合物未完全覆盖铁基合金基体表面时，所述缓蚀层可仅覆盖所述可降解聚合物的至少部分表面，也可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，还可既覆盖所述可降解聚合物的至少部分表面，又同时覆盖至少部分所述未覆盖区。
所述的铁基合金基体材料为碳含量不高于2.11wt.%的铁基合金或纯铁。
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。
所述可降解聚合物内可混有活性药物，也可不混有活性药物，所述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，也可以是前述几种药物的混合物。
所述缓蚀层材料为含至少一个疏水基团的有机物。
所述有机物选自固态烷烃及半固态烷烃的混合物、固态烷烃、半固态烷烃、高级脂肪酸甘油酯、类脂、高级烷醇类、高级脂肪酸、高级脂肪酸的盐类、有机酸酯化物，聚有机硅氧烷、脂溶性维生素、硅烷偶联剂、直链烷基化合物或氨基酸。
所述高级脂肪酸甘油酯选自甘油单酯、二酯或三酯；所述类脂为卵磷脂；所述高级烷醇类选自二十八烷醇、三十烷醇；所述高级脂肪酸及其盐类选自月桂酸、棕榈酸、硬脂酸、硬脂酸镁、十八胺；所述有机酸酯化物选自柠檬酸酯、月桂酸酯、蔗糖十二烷酸酯；所述聚有机硅氧烷为硅油；所述脂溶性维生素选自β-类胡萝卜素、维生素E、微生素A；所述固态或半固态烷烃选自石蜡、微晶蜡、凡士林；所述直链烷基化合物选自十二烷基磺酸钠、十二烷基硫酸钠、十二烷基二甲基苄基氯化铵、十六烷基三甲基氯化铵；所述氨基酸选自亮氨酸、丙氨酸。
所述可吸收铁基合金植入医疗器械还包括载药层，所述的载药层设于所述医疗器械最外层，所述载药层包括可降解聚合物和活性药物。
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包括缓蚀层。当器械植入体内一段时间后，缓蚀层能够有效阻挡水分子渗透，抑制铁基合金基体表面微酸性环境的形成，从而避免铁合金基体在植入早期出现腐蚀过快以及局部腐蚀严重等问题，保证了铁基合金医疗器械植入初期满足临床上的力学性能要求；缓蚀层覆盖可降解聚合物可以大大减少植入初期可降解聚合物在体液环境中的降解消耗，提高了其利用率，在保证同样的腐蚀周期的前提下，可以减少可降解聚合物的用量，降低了炎性风险；随着缓蚀层材料逐渐降解消耗或代谢转移，铁基合金基体表面的可降解聚合物逐渐水解形成微酸环境，从而加快了铁基合金基体的腐蚀；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，有利于铁基合金基体的腐蚀产物更快被吸收或代谢。
【附图说明】
图1为本发明一实施方式提供的可吸收植入医疗器械沿其长度方向的剖面示意图。
图2为本发明另一实施方式提供的可吸收植入医疗器械沿其长度方向的剖面示意图。
【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。
可降解聚合物与铁基合金基体之间的位置关系有多种，缓蚀层与可降解聚合物和铁基合金基体之间的位置关系也有多种。作为一种实施方式，如图1所示，可降解聚合物涂层16完全覆盖铁基合金基体11的表面，可降解聚合物层16中可以混合活性药物，缓蚀层12也完全覆盖可降解聚合物涂层16。
在上述可吸收铁基合金植入医疗器械表面的最外层，还可以设置载药层，如图2所示，载药层13完全覆盖在缓蚀层12的表面。
铁基合金基体11的材料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。
可降解聚合物在体液环境中降解会产生具有酸性的羧基基团而产生局部微酸环境，从而加速铁基合金基体11的腐蚀，可降解聚合物涂层16的量越多，铁基合金基体11的腐蚀速度越快，通过调整可降解聚合物涂层16的材料、厚度及分子量、结晶度等参数，可以调整铁基合金植入医疗器械的腐蚀周期。
在医疗器械植入早期，缓蚀层12可以有效阻挡水分子渗透，抑制在铁基合金基体表面形成微酸性环境，避免了铁基合金基体11早期的腐蚀过快和局部腐蚀严重等问题，从而保证了医疗器械在植入早期的力学性能；缓蚀层12设置在可降解聚合物的外层，可以将其与水隔离，能够有效延缓可降解聚合物的降解，提高其的利用率，从而减少可降解聚合物的用量。随着植入时间的延长，缓蚀层12逐渐消耗，可降解聚合物逐渐降解产生微酸环境，可以加快医疗器械植入后期的腐蚀速度。通过调整缓蚀层12的厚度，可以对医疗器械的有效支撑时间进行调整。
载药层13的作用在于载药，可以对植入部位起到进一步的治疗作用，载药层包括可降解聚合物和活性药物。
所述可降解聚合物涂层16和载药层13中的可降解聚合物的材料是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。
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，也可以是前述几种药物的混合物。
所述的可降解聚合物涂层、缓蚀层、载药层的涂覆方法可以是喷涂、浸涂、刷涂、静电纺丝。
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缓蚀层作用下，铁基合金支架能够在植入早期1-6个月内腐蚀很慢，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、2年、3年等，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。
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。支架的径向强度测试方法如下：通过压缩模块均匀地对支架施加径向压力，使支架压缩，产生均匀变形。定义支架径向（外径）发生10%变形时所施加的径向压强大小为支架的径向强度。所述径向支撑强度测试使用MSI公司生产的径向支撑强度测试仪（RX550-100）进行，将植入动物体内的支架连同血管取出，吸干表面水分后直接进行测试，即可得到支架植入后不同时间点的径向支撑强度。
重量损失测试方法如下：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，如铁基基体表面有单宁酸化学转化膜残留，则去除剩余的单宁酸化学转化膜，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基体的重量的百分比来表示，如公式1所示：
W = (Mt-M0) / M0×100% （1）
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。
以下各实施例提供的铁基合金支架的设计目标是需满足以下临床要求：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个月且小于或等于24个月。
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
选取30008规格的抛光后经渗氮处理的铁基合金冠脉支架，其原始径向强度为145kPa，质量为4.5mg，在支架基体表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得完全覆盖在支架表面的厚度为6μm的可降解聚消旋乳酸涂层；在上述步骤制备的支架表面喷涂二十八烷醇-三氯甲烷溶液，形成完全覆盖可降解消旋乳酸涂层的厚度为2μm的二十八烷醇缓蚀层。将上述步骤制备的铁基可吸收支架植入兔子腹主动脉，3个月后取出，支架内皮化完全，无早期血栓、炎症现象，其径向支撑强度为80kPa，同组动物实验监测完全腐蚀周期为12个月。
实施例2
取30008规格的抛光后经渗氮处理的铁基合金冠脉支架基体，其原始径向强度145kPa，重量4.5mg，在支架基体表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得完全覆盖在支架表面的厚度为10μm的可降解聚消旋乳酸涂层；在上述步骤制备的支架表面喷涂三硬脂酸甘油酯-三氯甲烷溶液，形成完全覆盖可降解聚消旋乳酸涂层的厚度为2μm的三硬脂酸甘油酯缓蚀层。将上述步骤制备的铁基可吸收支架植入兔子腹主动脉，3个月后取出，支架内皮化完全，无早期血栓、炎症现象，其径向支撑强度为80kPa，同组动物实验监测完全腐蚀周期为6个月。
实施例3
取30008规格的抛光后渗氮铁基合金冠脉支架基体，其原始径向强度145kPa，质量为4.5mg，在支架基体表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得完全覆盖在支架表面的厚度为6μm的可降解聚消旋乳酸涂层；在上述步骤制备的支架表面喷涂二十八烷醇-三氯甲烷溶液，形成完全覆盖可降解聚消旋乳酸涂层的厚度为5μm的二十八烷醇缓蚀层。将上述步骤制备的可吸收铁基支架植入兔子腹主动脉，3个月后取出，支架内皮化完全，无早期血栓、炎症现象，其径向支撑强度为110kPa，同组动物实验监测完全腐蚀周期为18个月。
实施例4
取30008规格的抛光后渗氮铁基合金冠脉支架基体，其原始径向强度145kPa，质量为4.5mg，在支架基体表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得完全覆盖在支架表面的厚度为6μm的可降解聚消旋乳酸涂层；在上述步骤制备的支架表面刷涂维生素E油，形成完全覆盖可降解聚消旋乳酸涂层的厚为2μm的维生素E油缓蚀层；在维生素E油缓蚀层表面喷涂聚消旋乳酸-雷帕霉素-乙酸乙酯溶液，聚消旋乳酸与雷帕霉素质量比为2:1，干燥后制得厚度为3μm 的聚消旋乳酸-雷帕霉素载药层。将上述步骤制备的可吸收铁基支架植入兔子腹主动脉，3个月后取出，支架内皮化完全，无早期血栓、炎症现象，其径向支撑强度为80kPa，同组动物实验监测完全腐蚀周期为12个月。
实施例5
取30008规格的抛光后渗氮铁基合金冠脉支架基体，其原始径向强度145kPa，质量为4.5mg，在支架基体表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得完全覆盖在支架表面的厚度为6μm的可降解聚消旋乳酸涂层；在上述步骤制备的支架表面喷涂卵磷脂-乙醇溶液，形成覆盖可降解聚消旋乳酸涂层表面90%区域的厚为2μm卵磷脂缓蚀层。将上述步骤制备的可吸收铁基支架植入兔子腹主动脉，3个月后取出，支架内皮化完全，无早期血栓、炎症现象，其径向支撑强度为80kPa，同组动物实验监测完全腐蚀周期为12个月。
实施例6
取30008规格的抛光后渗氮铁基合金冠脉支架基体，其原始径向强度145kPa，质量为4.5mg，在支架基体表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得覆盖支架表面90%区域的厚度为6μm的可降解聚消旋乳酸涂层；在上述步骤制备的支架表面喷涂硬脂酸钠-三氯甲烷溶液溶液，形成覆盖可降解聚消旋乳酸涂层表面90%区域的厚度为2μm的硬脂酸钠缓蚀层；其中80%覆盖在可降解聚消旋乳酸涂层表面，10%直接覆盖在铁支架表面。将上述步骤制备的可吸收铁基支架植入兔子腹主动脉，3个月后取出，支架内皮化完全，无早期血栓、炎症现象，其径向支撑强度为80kPa，同组动物实验监测完全腐蚀周期为18个月。
对比例1
取30008规格的抛光后经渗氮处理的铁基合金冠脉支架基体，其原始径向强度145kPa，质量为4.5mg，在支架表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得完全覆盖在支架表面的厚度为6μm的可降解聚消旋乳酸涂层；将该支架植入兔子腹主动脉，3个月后取出，支架局部腐蚀严重，其径向支撑力<55kPa，同组动物实验监测完全腐蚀周期为11个月。
对比例2
取30008规格的抛光后经渗氮处理的铁基合金冠脉支架基体，其原始径向强度145kPa，质量为4.5mg，在支架表面喷涂三硬脂酸甘油酯-三氯甲烷溶液溶液，形成完全覆盖支架表面的厚为2μm的三硬脂酸甘油酯缓蚀层；在上述步骤制备的三硬脂酸甘油酯缓蚀层表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得厚度为10μm可降解聚消旋乳酸涂层，且涂层覆盖整个三硬脂酸甘油酯缓蚀层表面。将该支架植入兔子腹主动脉，3个月后取出，支架内皮化完全，无早期血栓、炎症现象，其径向支撑力为80kPa，同组动物实验监测完全腐蚀周期为12个月。
对比例3
取30008规格的抛光后经渗氮处理的铁基合金冠脉支架基体，其原始径向强度175kPa，质量为5.5mg，在支架表面喷涂聚消旋乳酸-乙酸乙酯溶液，干燥后制得厚度为10μm的完全覆盖支架表面的可降解聚消旋乳酸涂层；将该支架植入兔子腹主动脉，3个月后取出，支架局部腐蚀严重，其径向支撑力为80kPa，同组动物实验监测完全腐蚀周期为12个月。
由以上各实施例可以看出，各实施例的可吸收铁基合金支架由于设置了缓蚀层，都实现了在缓蚀层起保护作用的期间内延缓了铁基合金基体的腐蚀，并都能满足早期植入3个月的力学性能要求。各实施例通过调节缓蚀层的用量，与对比例1相比，实施例1-6提供的支架能够保证植入3个月内的结构完整性并具有足够的力学支撑。与对比例2相比，实施例1、3、4、5、6提供的支架能够保证植入3个月内的结构完整性并具有足够的力学支撑的前提下，可降解聚合物的用量更少。与对比例3相比，实施例1、2、4和5提供的支架能够保证植入3个月内的结构完整性并具有足够的力学支撑的前提下，铁基合金基体的质量更小，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 (10)

  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，还包括设于所述铁基合金基体表面的缓蚀层。
  2. 根据权利要求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铁基合金基体的全部表面，所述缓蚀层覆盖所述可降解聚合物的至少部分表面。
  3. 根据权利要求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铁基合金基体部分表面，所述缓蚀层覆盖所述可降解聚合物的至少部分表面，或所述可降解聚合物与所述缓蚀层相互错开地覆盖所述铁基合金基体的不同表面，或者所述缓蚀层既覆盖所述可降解聚合物的至少部分表面，又同时覆盖至少部分未被所述可降解聚合物覆盖的区域。
  4. 根据权利要求1所述的可吸收铁基合金植入医疗器械，其特征在于，所述的铁基合金基体材料为碳含量不高于2.11wt.%的铁基合金或纯铁。
  5. 根据权利要求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。
  6. 根据权利要求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。
  7. 根据权利要求1所述的可吸收铁基合金植入医疗器械，其特征在于，所述缓蚀层材料为含至少一个疏水基团的有机物。
  8. 根据权利要求7所述的可吸收铁基合金植入医疗器械，其特征在于，所述有机物选自固态烷烃及半固态烷烃的混合物、固态烷烃、半固态烷烃、高级脂肪酸甘油酯、类脂、高级烷醇类、高级脂肪酸、高级脂肪酸的盐类、有机酸酯化物，聚有机硅氧烷、脂溶性维生素、硅烷偶联剂、直链烷基化合物或氨基酸。
  9. 根据权利要求8所述的可吸收铁基合金植入医疗器械，其特征在于，所述高级脂肪酸甘油酯选自甘油单酯、二酯或三酯；所述类脂优选卵磷脂；所述高级烷醇类选自二十八烷醇、三十烷醇；所述高级脂肪酸及其盐类选自月桂酸、棕榈酸、硬脂酸、硬脂酸镁、十八胺；所述有机酸酯化物选自柠檬酸酯、月桂酸酯、蔗糖十二烷酸酯；所述聚有机硅氧烷优选硅油；所述脂溶性维生素选自β-类胡萝卜素、维生素E、微生素A；所述固态或半固态烷烃选自石蜡、微晶蜡、凡士林；所述直链烷基化合物选自十二烷基磺酸钠、十二烷基硫酸钠、十二烷基二甲基苄基氯化铵、十六烷基三甲基氯化铵；所述氨基酸选自亮氨酸、丙氨酸。
  10. 根据权利要求1所述的可吸收铁基合金植入医疗器械，其特征在于，包括设于所述植入医疗器械最外层的载药层，所述载药层包括可降解聚合物和活性药物。
PCT/CN2016/085188 2015-10-19 2016-06-08 可吸收铁基合金植入医疗器械 WO2017067181A1 (zh)

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