WO2017063372A1 - 可吸收铁基合金植入医疗器械及其制备方法 - Google Patents

可吸收铁基合金植入医疗器械及其制备方法 Download PDF

Info

Publication number
WO2017063372A1
WO2017063372A1 PCT/CN2016/085046 CN2016085046W WO2017063372A1 WO 2017063372 A1 WO2017063372 A1 WO 2017063372A1 CN 2016085046 W CN2016085046 W CN 2016085046W WO 2017063372 A1 WO2017063372 A1 WO 2017063372A1
Authority
WO
WIPO (PCT)
Prior art keywords
iron
based alloy
acid
medical device
chemical conversion
Prior art date
Application number
PCT/CN2016/085046
Other languages
English (en)
French (fr)
Inventor
齐海萍
刘自强
秦莉
张德元
林文娇
Original Assignee
先健科技(深圳)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 先健科技(深圳)有限公司 filed Critical 先健科技(深圳)有限公司
Priority to US15/767,610 priority Critical patent/US10543296B2/en
Priority to EP16854758.6A priority patent/EP3363475B1/en
Publication of WO2017063372A1 publication Critical patent/WO2017063372A1/zh

Links

Images

Classifications

    • 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
    • A61L27/14—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
    • A61L27/28—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
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • 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
    • A61L31/02—Inorganic materials
    • A61L31/022—Metals or alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—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
    • A61L31/12—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/424—Anti-adhesion agents
    • 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

Definitions

  • the invention belongs to the field of absorbable implant medical devices, in particular to an absorbable iron-based alloy implanted medical device and a preparation method thereof.
  • Implantable medical device matrix materials mainly include polymers and magnesium-based alloys, 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 alloy devices.
  • Fe-based alloys are used as implantable medical device matrix materials, 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 heal It will take a long time to completely corrode after the period, so it is necessary to speed up the corrosion rate to shorten the corrosion cycle of the iron-based alloy.
  • 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. In the case where 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, the corrosion rate of the iron-based alloy is too fast or the local corrosion is severe, which will affect the iron-based alloy device.
  • the structural integrity and mechanical properties of the early stage (1-6 months, the healing period described above), which makes it difficult for the device to meet the requirements of clinical applications.
  • degradable polyester coating The degradation products 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 ⁇ 2%), which will cause the iron-based matrix to corrode faster in the early stage of implantation, such as planting. About 1-7 days after entering the coronary artery, excessive corrosion and accumulation of corrosion products lead to incomplete endothelialization of the device surface, increasing the risk of acute and subacute thrombosis; (2) unevenness of degradation of degradable polyester is easy to cause The corrosion of the iron-based alloy matrix is uneven, and the local corrosion is too fast, and the fracture may occur, 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 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 has a slow or no corrosion rate within 1-6 months after implantation in the body, and can be used in this section.
  • the mechanical performance requirements for early instrument implantation are met in the time.
  • An absorbable iron-based alloy implanted medical device comprising: an iron-based alloy substrate and a degradable polymer layer disposed on a surface of the iron-based alloy substrate; and a tannic acid chemical conversion film disposed on the surface of the iron-based alloy substrate .
  • the tannic acid chemical conversion film 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 layer covers at least a portion of the surface of the tannic acid chemical conversion film when the tannic acid chemical conversion film covers the entire surface of the iron-based alloy substrate.
  • the degradable polymer layer may cover only at least part of the surface of the tannic acid chemical conversion film, or may be The tannic acid chemical conversion coatings cover the different surfaces of the iron-based alloy substrate in a staggered manner, and may cover at least part of the surface of the tannic acid chemical conversion film while covering at least a portion of the uncovered regions.
  • the iron-based alloy matrix may be selected from iron-based alloys or pure iron having a carbon content of not more than 2.11 wt.%, such as products of pure iron after nitriding and/or carburizing.
  • the tannic acid chemical conversion film is a product formed by reacting tannic acid with an iron-based alloy matrix.
  • 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, and polysuccinate , physics of at least two of poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer, and polyhydroxybutyrate valerate copolymer Blend, or selected from the group consisting of forming polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid Copolymer and polyhydroxybutyrate Any one of copo
  • the degradable polymer may be mixed with an active drug, such as an anti-intimal proliferative drug, an anticoagulant drug, an anti-platelet adhesion drug, an anti-infective drug, an antibacterial drug or an anti-tumor drug for treating vascular restenosis.
  • an active drug such as an anti-intimal proliferative drug, an anticoagulant drug, an anti-platelet adhesion drug, an anti-infective drug, an antibacterial drug or an anti-tumor drug for treating vascular restenosis.
  • the implanted medical device is a cardiac implant such as an occluder, a vascular implant such as a stent, a gynecological implant, a male implant, a respiratory implant or an orthopedic implant.
  • the invention also provides a preparation method of an absorbing iron-based alloy implanted medical device, comprising the following steps:
  • the concentration of the tannic acid solution is 2-10 g/L
  • the reaction temperature is 15-45 ° C
  • the reaction time is 5-60 min.
  • the preparation method further comprises: sealing the substrate on which the tannic acid chemical conversion film has been formed with boiling water, and sealing time is 20-30 min.
  • the present invention provides an absorbable iron-based alloy implanted medical device comprising a tannic acid chemical conversion film.
  • the tannic acid conversion film protects the covered iron-based alloy substrate from contact with the body fluid, so that the iron matrix does not corrode, and the tannic acid chemical conversion film is protected after being completely consumed.
  • the iron-based alloy matrix begins to corrode quickly, thereby ensuring that the device meets the clinical mechanical performance requirements early in the implant.
  • the absorbable iron-based alloy implanted medical device of the present invention has a smaller design size, produces less corrosion products after implantation, and facilitates faster absorption or metabolism of the corrosion product.
  • 1 is a schematic cross-sectional view of an absorbable implantable medical device along its length, in which 11 is an iron-based alloy substrate, 12 is a tannic acid chemical conversion film, and 13 is a polymer layer.
  • the tannic acid chemical conversion film 12 completely covers the surface of the iron-based alloy substrate 11, and the degradable polymer layer 13 also directly covers the tannic acid chemical conversion film 12.
  • the main idea of the present invention is to provide a tannic acid chemical conversion film on the surface of an existing absorbable iron-based alloy implanted medical device, and the use of the tannic acid chemical conversion film can hinder the contact of the iron-based alloy substrate with the acidic environment, thereby controllably At the point of time when the iron-based alloy matrix begins to corrode, the iron-based alloy matrix is not corroded at the early stage of implantation (1-6 months) to ensure the structural integrity and sufficient mechanics of the absorbing iron-based alloy implanted device. Performance, and does not extend the corrosion cycle of the iron-based alloy matrix.
  • the absorbing iron-based alloy implanted medical device of the invention only needs to ensure that the initial mechanical properties before implantation reach the lower limit of clinical requirements for early implantation, and it is not necessary to have strong mechanical properties after exceeding the healing period. . Therefore, compared with the prior art, the design of the absorbable iron-based alloy implanted medical device of the present invention is smaller, correspondingly reducing the amount of iron, thereby achieving the purpose of reducing iron corrosion products.
  • the reaction between the tannic acid chemical conversion film and the hydrogen ion formed by degradation of the degradable polymer is slower than the reaction between the iron-based alloy and the hydrogen ion formed by degradation of the degradable polymer; and the tannic acid chemical conversion film With polyphenolic hydroxyl structure, the product reacted with acid has reducibility, combined with protein, alkaloid and polysaccharide in vivo, which can further alleviate the corrosion of iron-based alloy matrix in acidic environment; in addition, the reaction of tannic acid chemical conversion film with acid The product tannic acid is degraded into carbon dioxide and water under the action of enzymes in the body, and has no effect on the human body. Therefore, the formation of a tannic acid chemical conversion film on the surface of an implanted medical device iron-based alloy substrate can effectively delay early corrosion in the early stage of medical device implantation.
  • the present invention can adjust the reaction conditions of the iron-based alloy substrate and the tannic acid, for example, by reacting. Time to control the thickness of the tannic acid chemical conversion film, so that the time for the initiation of corrosion of the iron-based alloy implanted medical device can be adjusted; and the corrosion rate of the iron-based alloy substrate can be adjusted by adjusting the type and thickness (mass) of the polymer layer.
  • 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 iron-based alloy stent can hardly corrode within the first 1-6 months of implantation under the action of the tannic acid chemical conversion membrane, mainly through stenting. Not after entering the animal At the observation time point, such as 3 months, 6 months, 12 months, 2 years, 3 years, etc., the animal is euthanized, and the stent and the tissue at the location thereof are taken out from the body, and the stent is placed together with the stent. The vascular segment was 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.
  • 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 radial strength test method of the support strength 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.
  • 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, and then the iron-based alloy stent is taken out from the solution.
  • 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 polylactic acid coating completely covers the tannic acid chemical conversion film and is 6 ⁇ m thick.
  • the stent was implanted into the abdominal aorta of rabbits and removed after 3 months. The stent had a certain degree of corrosion, and the stent was completely endothelialized without early thrombosis and inflammation.
  • the results of the radial support strength test and the complete corrosion cycle data of the same group of animal experiments are shown in Table 1.
  • Polylactic acid forms a discontinuous coating on the surface of the tannic acid chemical conversion film and is 8 ⁇ m thick.
  • the stent was implanted into the abdominal aorta of rabbits and removed after 3 months. The stent had a certain degree of corrosion, and the stent was completely endothelialized without early thrombosis and inflammation.
  • the results of the radial support strength test and the complete corrosion cycle data of the same group of animal experiments are shown in Table 1.
  • the polylactic acid coating completely covers the tannic acid chemical conversion film and is 12 ⁇ m thick.
  • the stent was implanted into the abdominal aorta of rabbits and removed after 3 months. The stent had a certain degree of corrosion, and the stent was completely endothelialized without early thrombosis and inflammation.
  • the results of the radial support strength test and the complete corrosion cycle data of the same group of animal experiments are shown in Table 1.
  • the polylactic acid drug coating completely covers the tannic acid chemical conversion film, and the coating contains 0.01 mg of rapamycin and a thickness of 12-16 ⁇ m.
  • the stent was implanted into the abdominal aorta of rabbits and removed after 3 months. The stent had a certain degree of corrosion, and the stent was completely endothelialized without early thrombosis and inflammation.
  • the radial support strength test results and the complete set of animal test monitoring complete corrosion cycle data are shown in Table 1.
  • the iron-based alloy coronary stent after polishing with 30008 specification has an original radial strength of 175 kPa and a weight of 5.5 mg.
  • the surface is sprayed with a polychlorolactic acid-ethyl acetate solution having a molecular weight of 200,000, and dried to obtain an absorbable iron.
  • the base alloy bracket, the polylactic acid coating completely covers the surface of the iron-based alloy support, and the coating thickness is 8 ⁇ m.
  • the stent was implanted into the abdominal aorta of rabbits and taken out after 3 months. There was a certain degree of corrosion.
  • the results of radial support strength test and the complete corrosion cycle data of the same group of animals were shown in Table 1.
  • the stents provided in Examples 1-4 of the present invention satisfy the design requirements for the radial support strength and the corrosion period after 3 months of implantation.
  • the stent has a desired support strength at 3 months after implantation by providing a tannic acid chemical conversion film between the iron-based alloy substrate and the polylactic acid coating.
  • the amount of iron-based alloy matrix is less, thus reducing the stent rot
  • the amount of etched product, the period of complete absorption is shorter.
  • Example 3 compared with Comparative Example 2, a tannic acid chemical conversion film was disposed between the iron-based alloy substrate and the polylactic acid coating in the case where the original specifications of the stent were the same, and the iron-based alloy substrate was delayed in the initial stage of implantation ( Corrosion within 3 months) ensures the structural integrity and good mechanical properties of the stent at the initial stage of implantation.

Abstract

一种可吸收铁基合金植入医疗器械及其制备方法，所述的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层(13)，以及设于所述铁基合金基体（11）表面的单宁酸化学转化膜(12)。所述的医疗器械植入体内后，单宁酸化学转化膜（12）保护其覆盖的铁基合金基体（11）不与体液接触，由此确保了器械在植入早期满足临床上的力学性能要求，另外，所述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，有利于腐蚀产物更快被吸收或代谢。

Description

可吸收铁基合金植入医疗器械及其制备方法 技术领域
本发明属于可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及其制备方法。
背景技术
目前可吸收植入医疗器械基体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。铁基合金用作植入医疗器械基体材料，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。
有研究表明在铁基合金表面涂覆可降解聚酯涂层，可提高其腐蚀速度。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
针对现有技术的不足，本发明的目的在于，提供可吸收铁基合金植入医疗器械，其在植入体内后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。
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层，以及设于所述铁基合金基体表面的单宁酸化学转化膜。
所述单宁酸化学转化膜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。当所述单宁酸化学转化膜覆盖所述铁基合金基体的全部表面时，所述可降解聚合物层覆盖所述单宁酸化学转化膜的至少部分表面。当所述单宁酸化学转化膜未覆盖所述铁基合金基体的全部表面时，所述可降解聚合物层可仅覆盖所述单宁酸化学转化膜的至少部分表面，也可与所述单宁酸化学转化膜相互错开地覆盖所述铁基合金基体的不同表面，还可既覆盖所述单宁酸化学转化膜的至少部分表面，又同时覆盖至少部分所述未覆盖区。所述的铁基合金基体可选自或碳含量不高于2.11wt.％的铁基合金或纯铁，例如纯铁经渗氮和/或渗碳后的产物。
所述的单宁酸化学转化膜为单宁酸与铁基合金基体反应生成的产物。
所述可降解聚合物选自可降解聚酯和/或可降解聚酸酐，所述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，如用于治疗血管再狭窄的抗内膜增生药物、抗凝血药物、抗血小板粘附药物、抗感染药物、抗菌药物或抗肿瘤药物。
所述植入医疗器械为心脏植入体如封堵器、血管植入体如支架、妇科植入体、男科植入体、呼吸科植入体或骨科植入物。
本发明还提供了一种可吸收铁基合金植入医疗器械的制备方法，包括以下步骤：
(1)将铁基合金基体浸泡在单宁酸溶液中反应形成单宁酸化学转化膜；
(2)在上述步骤制备的可吸收铁基合金植入医疗器械表面制备可降解聚合物层。
其中，所述单宁酸溶液的浓度为2-10g/L，反应温度为15-45℃，反应时间5-60min。
该制备方法还包括，对表面已形成单宁酸化学转化膜的基体以沸水封孔，封孔时间为20-30min。
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单宁酸化学转化膜。器械植入体内后，所述单宁酸转化膜保护其覆盖的铁基合金基体不与体液接触，从而使铁基体不腐蚀，待所述单宁酸化学转化膜几乎完全被消耗掉后所保护的铁基合金基体才开始快速腐蚀，由此确保了器械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，有利于腐蚀产物更快被吸收或代谢。
附图说明
图1为本发明可吸收植入医疗器械沿其长度方向的剖面示意图，图中，11为铁基合金基体、12为单宁酸化学转化膜，13为聚合物层。
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。
单宁酸化学转化膜与铁基合金基体之间的位置关系有多种，可降解聚合物层与单宁酸化学转化膜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，单宁酸化学转化膜12完全直接覆盖铁基合金基体11的表面，可降解聚合物层13也直接完全覆盖单宁酸化学转化膜12。
本发明的主要思想在于，在现有可吸收铁基合金植入医疗器械表面设置单宁酸化学转化膜，利用单宁酸化学转化膜可以阻碍铁基合金基体与酸性环境接触，从而可控地延后铁基合金基体开始腐蚀的时间点，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。
由于单宁酸化学转化膜可以起到延后铁基合金基体开始腐蚀的时间点，在单宁酸化学转化膜的保护期内，铁基合金基体的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，相应地减少了铁的用量，进而达到减少铁腐蚀产物的目的。
具体地，相比铁基合金与可降解聚合物降解形成的氢离子之间的反应，单宁酸化学转化膜与可降解聚合物降解形成的氢离子反应较为缓慢；且单宁酸化学转化膜具有多酚羟基结构，与酸反应的产物具有还原性，与体内蛋白质、生物碱、多糖结合，能进一步减缓酸性环境对铁基合金基体的腐蚀；此外，单宁酸化学转化膜与酸的反应产物单宁酸在体内酶的作用下降解为二氧化碳和水，对人体不产生影响。因此，在植入医疗器械铁基合金基体表面形成单宁酸化学转化膜，能够有效延缓医疗器械植入初期的早期腐蚀。
由于单宁酸化学转化膜可以对铁基合金基体起到缓蚀的作用，且厚度增加，缓蚀的时间会延长，因此本发明可以通过调整铁基合金基体与单宁酸的反应条件例如反应时间来控制单宁酸化学转化膜的厚度，从而可以调整铁基合金植入医疗器械开始腐蚀的时间；通过调整聚合物层的种类、厚度(质量)又能调整铁基合金基体的腐蚀速率。
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单宁酸化学转化膜的作用下，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、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。
支撑强度临床上，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。
支撑强度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，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
取30008规格抛光后的铁基合金冠脉支架，其原始径向强度145kPa，重量为4.5mg，将其浸泡在质量分数4g/L单宁酸溶液中，温度20℃，时间20min，处理后以沸水封孔30min，得到覆盖铁基基体表面的厚0.4-0.5μm的单宁酸化学转化膜，覆盖率为95％，经无水乙醇脱水后在支架表面浸涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液，干燥后制得可吸收铁基合金支架。聚乳酸涂层完全覆盖单宁酸化学转化膜，厚6μm。将支架植入兔子腹主动脉，3个月后取出，支架有一定程度的腐蚀,支架内皮化完全，无早期血栓、炎症现象。其径向支撑强度测试结果及同组动物实验监测完全腐蚀周期数据见表1。
实施例2
取30008规格抛光后的铁基合金冠脉支架，其原始径向强度145kPa，重量4.5mg，将其浸泡在质量分数为4g/L单宁酸溶液中，温度20℃，时间40min，处理后以沸水封孔30min，得到完全覆盖铁基基体表面的厚0.8-1.0μm的单宁酸化学转化膜，经无水乙醇脱水后在支架表面喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液，干燥后制得可吸收铁基合金支架。聚乳酸在单宁酸化学转化膜表面形成不连续的涂层，厚8μm。将支架植入兔子腹主动脉，3个月后取出，支架有一定程度的腐蚀，支架内皮化完全，无早期血栓、炎症现象。其径向支撑强度测试结果及同组动物实验监测完全腐蚀周期数据见表1。
实施例3
取30008规格抛光后的铁基合金冠脉支架，其原始径向强度145kPa，重量4.5mg，将其浸泡在质量分数为6g/L单宁酸溶液中，温度20℃，时间60min，处理后以沸水封孔30min，得到完全覆盖铁基基体表面的厚1.6-1.8μm的单宁酸化学转化膜，经无水乙醇脱水后在支架表面刷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液，干燥后制得可吸收铁基合金支架。聚乳酸涂层完全覆盖单宁酸化学转化膜，厚12μm。将支架植入兔子腹主动脉，3个月后取出，支架有一定程度的腐蚀，支架内皮化完全，无早期血栓、炎症现象。其径向支撑强度测试结果及同组动物实验监测完全腐蚀周期数据见表1。
实施例4
取30008规格抛光后的铁基合金冠脉支架，其原始径向强度145kPa，重量4.5mg，将其 浸泡在质量分数为6g/L单宁酸溶液中，温度20℃，时间60min，处理后以沸水封孔30min，得到完全覆盖铁基基体表面的厚1.6-1.8μm的单宁酸化学转化膜，经无水乙醇脱水后在支架表面喷涂分子量为20万的聚消旋乳酸-雷帕霉素-乙酸乙酯溶液，干燥后制得可吸收铁基合金药物支架。聚乳酸药物涂层完全覆盖单宁酸化学转化膜，涂层中含雷帕霉素0.01mg，厚12-16μm。将支架植入兔子腹主动脉，3个月后取出，支架有一定程度的腐蚀，支架内皮化完全，无早期血栓、炎症现象。用径向支撑强度测试仪测量，其径向支撑强度测试结果及同组动物实验监测完全腐蚀周期数据见表1。
对比例1
取30008规格抛光后的铁基合金冠脉支架，其原始径向强度175kPa，重量5.5mg，在其表面喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液，干燥后制得可吸收铁基合金支架，聚乳酸涂层完全覆盖铁基合金支架表面，涂层厚8μm。将该支架植入兔子腹主动脉，3个月后取出，有一定程度的腐蚀，其径向支撑强度测试结果及同组动物实验监测完全腐蚀周期数据见表1。
对比例2
取30008规格抛光后的铁基合金冠脉支架，其原始径向强度145kPa，重量4.5mg，在其表面喷涂分子量为20万的聚消旋乳酸-乙酸乙酯溶液，干燥后制得可吸收铁基支架，聚乳酸涂层完全覆盖铁支架表面，涂层厚12μm。将该支架植入兔子腹主动脉，3个月后取出，支架腐蚀严重，用径向支撑强度测试仪测量，其径向支撑强度测试结果及同组动物实验监测完全腐蚀周期数据见表1。
表1实施例1-4及对比例1-2的实验结果
Figure PCTCN2016085046-appb-000001
从表1可以看出，与对比例2相比，本发明实施例1-4提供的支架在植入3个月后的径向支撑强度和腐蚀周期均满足设计要求。其中实施例2与对比例1相比，支架由于通过在铁基合金基体与聚乳酸涂层之间设置了单宁酸化学转化膜，在保证在植入后3个月具有理想的支撑强度的基础上，支架的设计尺寸更小，铁基合金基体的用量更少，从而减少了支架腐 蚀产物的量，完全吸收的周期更短。实施例3与对比例2相比，在支架原始规格相同的情况下，在铁基合金基体与聚乳酸涂层之间设置单宁酸化学转化膜，能够延缓铁基合金基体在植入初期(3个月内)的腐蚀，保证了支架在植入初期的结构完整性和良好的力学性能。

Claims (11)

  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层，其特征在于，还包括设于所述铁基合金基体表面的单宁酸化学转化膜。
  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，所述单宁酸化学转化膜覆盖所述铁基合金基体的全部表面，所述可降解聚合物层覆盖所述单宁酸化学转化膜的至少部分表面。
  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，所述单宁酸化学转化膜覆盖所述铁基合金基体部分表面，所述可降解聚合物层覆盖所述单宁酸化学转化膜的至少部分表面，或所述单宁酸化学转化膜与所述可降解聚合物层相互错开地覆盖所述铁基合金基体的不同表面，或者所述可降解聚合物层既覆盖所述单宁酸化学转化膜的至少部分表面，又同时覆盖至少部分所述未覆盖区。
  4. 根据权利要求1所述的可吸收铁基合金植入医疗器械，所述铁基合金基体为碳含量不高于2.11wt.％的铁基合金或纯铁。
  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，所述单宁酸化学转化膜为单宁酸与铁基合金基体反应生成的产物。
  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，所述可降解聚合物选自可降解聚酯和/或可降解聚酸酐，所述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。
  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，所述可降解聚合物层包括活性药物，所述活性药物为用于治疗血管再狭窄的抗内膜增生药物、抗凝血药物、抗血小板粘附药物、抗感染药物、抗菌药物或抗肿瘤药物。
  8. 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，所述植入医疗器械为心脏植入体、血管植入体、妇科植入体、男科植入体、呼吸科植入体或骨科植入物。
  9. 一种可吸收铁基合金植入医疗器械的制备方法，其特征在于，包括以下步骤：
    (1)将铁基合金基体浸泡在单宁酸溶液中反应形成单宁酸化学转化膜；
    (2)在上述步骤制备的可吸收铁基合金植入医疗器械表面制备可降解聚合物层。
  10. 根据权利要求9所述的可吸收铁基合金植入医疗器械的制备方法，其特征在于，所述单宁酸溶液的浓度为2-10g/L，反应温度为15-45℃，反应时间5-60min。
  11. 根据权利要求10所述的可吸收铁基合金植入医疗器械的制备方法，其特征在于，该制备方法还包括，对表面已形成单宁酸化学转化膜的铁基合金基体以沸水封孔，封孔时间为20-30min。
PCT/CN2016/085046 2015-10-14 2016-06-07 可吸收铁基合金植入医疗器械及其制备方法 WO2017063372A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US15/767,610 US10543296B2 (en) 2015-10-14 2016-06-07 Absorbable iron-based alloy medical instrument implant and manufacturing method
EP16854758.6A EP3363475B1 (en) 2015-10-14 2016-06-07 Absorbable iron-based alloy medical instrument implant and manufacturing method

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510663121.9 2015-10-14
CN201510663121.9A CN106581778B (zh) 2015-10-14 2015-10-14 可吸收铁基合金植入医疗器械及其制备方法

Publications (1)

Publication Number Publication Date
WO2017063372A1 true WO2017063372A1 (zh) 2017-04-20

Family

ID=58517123

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/085046 WO2017063372A1 (zh) 2015-10-14 2016-06-07 可吸收铁基合金植入医疗器械及其制备方法

Country Status (4)

Country Link
US (1) US10543296B2 (zh)
EP (1) EP3363475B1 (zh)
CN (1) CN106581778B (zh)
WO (1) WO2017063372A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109954171A (zh) * 2017-12-26 2019-07-02 先健科技(深圳)有限公司 可吸收植入式器械
CN111329632B (zh) * 2018-12-19 2021-10-22 元心科技(深圳)有限公司 可吸收金属支架
CN113116615B (zh) * 2019-12-31 2022-11-18 元心科技(深圳)有限公司 可吸收金属器械

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1572210A (en) * 1977-03-22 1980-07-23 Pyrene Chemical Services Ltd Treating metal surfaces
CN101078114A (zh) * 2006-05-26 2007-11-28 佛山市顺德区汉达精密电子科技有限公司 镁合金表面化学转化处理工艺
CN102027157A (zh) * 2008-03-11 2011-04-20 凯密特尔有限责任公司 用钝化剂涂覆金属表面的方法，该钝化剂及其用途
CN104207866A (zh) * 2013-05-30 2014-12-17 先健科技(深圳)有限公司 生物可吸收的医疗器械或其可吸收部件的制作方法
CN104587534A (zh) * 2013-10-31 2015-05-06 先健科技(深圳)有限公司 可吸收铁基合金支架

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070224244A1 (en) * 2006-03-22 2007-09-27 Jan Weber Corrosion resistant coatings for biodegradable metallic implants
US20070250155A1 (en) * 2006-04-24 2007-10-25 Advanced Cardiovascular Systems, Inc. Bioabsorbable medical device
CN101461964B (zh) * 2007-12-19 2013-03-13 中国科学院金属研究所 一种生物医用可降解镁合金的生物活性表面改性方法
DE102008006455A1 (de) * 2008-01-29 2009-07-30 Biotronik Vi Patent Ag Implantat mit einem Grundkörper aus einer biokorrodierbaren Legierung und einer korrosionshemmenden Beschichtung
CN102228721A (zh) * 2011-06-09 2011-11-02 中国科学院金属研究所 一种可降解冠脉支架及其制备方法
US10179114B2 (en) * 2013-01-24 2019-01-15 Northwestern University Phenolic coatings and methods of making and using same
US9155637B2 (en) * 2013-03-13 2015-10-13 Medtronic Vascular, Inc. Bioabsorbable stent with hydrothermal conversion film and coating
CN104195535A (zh) * 2014-08-12 2014-12-10 西南交通大学 一种提高生物医用镁基金属材料耐腐蚀性能与表面功能化的修饰方法
CN104784750B (zh) * 2015-04-03 2017-08-11 中国科学院金属研究所 提高变形性生物镁合金植入器件耐蚀性的表面改性方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1572210A (en) * 1977-03-22 1980-07-23 Pyrene Chemical Services Ltd Treating metal surfaces
CN101078114A (zh) * 2006-05-26 2007-11-28 佛山市顺德区汉达精密电子科技有限公司 镁合金表面化学转化处理工艺
CN102027157A (zh) * 2008-03-11 2011-04-20 凯密特尔有限责任公司 用钝化剂涂覆金属表面的方法，该钝化剂及其用途
CN104207866A (zh) * 2013-05-30 2014-12-17 先健科技(深圳)有限公司 生物可吸收的医疗器械或其可吸收部件的制作方法
CN104587534A (zh) * 2013-10-31 2015-05-06 先健科技(深圳)有限公司 可吸收铁基合金支架

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3363475A4 *

Also Published As

Publication number Publication date
CN106581778B (zh) 2020-07-21
EP3363475B1 (en) 2020-11-18
EP3363475A1 (en) 2018-08-22
CN106581778A (zh) 2017-04-26
EP3363475A4 (en) 2019-06-12
US10543296B2 (en) 2020-01-28
US20180303971A1 (en) 2018-10-25

Similar Documents

Publication Publication Date Title
WO2017117923A1 (zh) 可吸收铁基合金植入医疗器械
US10857267B2 (en) Absorbable iron-based alloy implantable medical device
WO2017117924A1 (zh) 可吸收铁基合金植入医疗器械
JP6009456B2 (ja) 生物分解性のマグネシウムベースの合金を含む医療用インプラントおよびその製造方法
WO2017063372A1 (zh) 可吸收铁基合金植入医疗器械及其制备方法
Liu et al. A novel biodegradable and biologically functional arginine-based poly (ester urea urethane) coating for Mg–Zn–Y–Nd alloy: enhancement in corrosion resistance and biocompatibility
CN106310372B (zh) 可降解镁基骨内植物可载药高分子/钙磷复合涂层及制备
WO2018121350A1 (zh) 可吸收铁基器械
WO2021135054A1 (zh) 可吸收铁基器械
EP3900749B1 (en) Absorbable implantable device
US10751445B2 (en) Iron-based absorbable and implantable medical device and manufacturing method thereof
WO2024022532A1 (zh) 一种医疗器械用涂层
KR20160122655A (ko) 비대칭적 pei/plga 이중 코팅을 통해 부식저항성 및 혈관재협착 억제효과를 갖는 마그네슘 스텐트 및 이의 제조방법
CN113491796A (zh) 含锌医疗器械
CN106039422A (zh) 一种颅颌面骨修复固定装置的制备

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16854758

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15767610

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2016854758

Country of ref document: EP