WO2016107366A1 - 可降解铁基合金支架 - Google Patents

可降解铁基合金支架 Download PDF

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Publication number
WO2016107366A1
WO2016107366A1 PCT/CN2015/096212 CN2015096212W WO2016107366A1 WO 2016107366 A1 WO2016107366 A1 WO 2016107366A1 CN 2015096212 W CN2015096212 W CN 2015096212W WO 2016107366 A1 WO2016107366 A1 WO 2016107366A1
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Prior art keywords
degradable
iron
based alloy
acid
polymer
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PCT/CN2015/096212
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English (en)
French (fr)
Inventor
陈丽萍
孙宏涛
张德元
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先健科技(深圳)有限公司
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Priority to EP15875044.8A priority Critical patent/EP3241572A4/en
Priority to US15/534,406 priority patent/US10632232B2/en
Publication of WO2016107366A1 publication Critical patent/WO2016107366A1/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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/041—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—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

Definitions

  • the present invention belongs to the field of biodegradable implantable medical devices, and relates to an iron-based alloy stent that can be rapidly degraded.
  • implanted medical devices are typically made from metals and their alloys, ceramics, polymers, and related composite materials.
  • metal-based implanted medical devices are particularly popular for their superior mechanical properties, such as high strength and high toughness.
  • Iron is an important element in the human body and participates in many biochemical processes, such as the transport of oxygen.
  • Corrosive pure iron stents made by laser engraving and similar in shape to clinically used metal stents were implanted into the descending aorta of 16 New Zealand rabbits. The results of this animal experiment showed that there was no thrombotic complication within 6-18 months, and no adverse events occurred.
  • Pathological examination confirmed that there was no inflammatory reaction in the local vascular wall, and there was no obvious proliferation of smooth muscle cells. It is preliminarily indicating that the degradable iron stent is safe and reliable. Has a good application prospects.
  • the study found that the corrosion rate of pure iron in the in vivo environment is slow, which can not meet the clinical requirements for the degradation of degradable scaffolds. Therefore, it is necessary to increase the corrosion rate of iron.
  • the technical problem to be solved by the present invention is to provide a degradable iron-based alloy stent which can maintain good mechanical properties at an early stage after being implanted into the body, in view of the defects of the prior art. Can corrode quickly.
  • the degradable iron-based alloy stent comprises an iron-based alloy substrate and a degradable polyamino acid in contact with the surface of the substrate, and the degradable polyamino acid is degraded to produce an acidic amino acid.
  • the polyamino acid has a weight average molecular weight of [1,100] and a polydispersity coefficient between [1.0, 50].
  • the degradable iron-based alloy stent comprises an iron-based alloy substrate and a degradable polymer in contact with the surface of the substrate, the degradable polymer comprising an acidic amino acid capable of degrading a mixture of a polyamino acid and a degradable polyester, or a copolymer of the degradable polyamine monomer and the monomer of the degradable polyester, the weight average molecular weight of the degradable polymer is [1, 100 Between 10,000, the polydispersity coefficient is between [1.0, 50].
  • the degradable iron-based alloy stent comprises an iron-based alloy substrate and a degradable polymer in contact with the surface of the iron-based alloy substrate, and the degradable polymer comprises after degradation a mixture of a polyamino acid capable of producing an acidic amino acid and a degradable polymer which does not produce an acidic product after degradation, or a copolymer of a monomer of the degradable amino acid and a monomer of the degradable polymer which does not produce an acidic product after degradation Things.
  • the degradable polymer which does not produce an acidic product after degradation may be starch, cellulose, polysaccharide, chitin, chitosan or a derivative thereof or the like.
  • the degradable polymer has a weight average molecular weight of [1,100] and a polydispersity coefficient of (1.0, 50).
  • the degradable iron-based alloy stent comprises an iron-based alloy substrate and a degradable polymer in contact with the surface of the iron-based alloy substrate, and the degradable polymer includes after degradation a mixture of a degradable polyamino acid producing an acidic amino acid, a degradable polyester, and a degradable polymer which does not produce an acidic product after degradation, or a monomer of the degradable polyacid and a monomer of the degradable polyester a copolymer of a monomer of a degradable polymer that does not produce an acidic product after degradation, or any two of the degradable polyamino acid, the degradable polyester, and a degradable polymer that does not produce an acidic product after degradation A mixture of a copolymer of a monomer and a remaining one of the three substances, the degradable polyamine degrading to produce an acidic amino acid.
  • the degradable polymer has a weight
  • the iron-based alloy matrix in the present invention refers to an iron-based alloy bare stent, and the iron-based alloy matrix material is selected from pure iron or a medical iron-based alloy. Nutrients and harmless elements in the human body, or less toxic elements, such as c,
  • At least one of N, 0, S, P, Mn, Pd, Si, W, Ti, Co, Cr, Cu, and Re may be incorporated into pure iron to form the medical iron-based alloy.
  • the degradable polymer in contact with the surface of the substrate comprises a mixture of at least two polymers, each of which satisfies a weight average molecular weight of [1,100] million.
  • the polydispersity coefficient is between (1.0, 50).
  • the degradable polymer in contact with the surface of the substrate contains a polyamino acid capable of degrading to produce an acidic amino acid and is degradable.
  • the mixture of polyesters, the polyamino acid and the degradable polyester have a weight average molecular weight of [1,100] and a polydispersity coefficient between [1. 0, 50].
  • the rapid corrosion means that the degradable polymer can accelerate the corrosion of the iron-based alloy matrix, so that the iron-based alloy matrix can be completely corroded within 10 years after being implanted into the body.
  • the complete corrosion means that the mass loss rate of the iron-based alloy stent is W ⁇ 90%.
  • the complete corrosion was characterized by a mass loss test of an animal experiment.
  • the mass loss test was carried out by: massing the iron-based alloy matrix (i.e., the bare stent not including the degradable polymer) to M.
  • the iron-based alloy stent is implanted into the abdominal aorta of the rabbit, and the iron-based alloy stent implanted in the animal and the tissue in which it is implanted are taken out at a predetermined observation point, and then the tissue is immersed in a certain concentration of the solution together with the stent (eg Lmol / L sodium hydroxide solution), the tissue is digested, and then the stent rod is taken out from the solution, and the stent rod is placed in a certain concentration of solution (such as 3% tartaric acid solution, and / or organic solution) to make the surface of the stent
  • the corrosion products are all detached or dissolved in the solution, and the remaining stent rods in the solution are taken out, and the s
  • the early good mechanical properties of the stent in the implant are determined according to specific clinical needs. Generally speaking, “early” refers to within 1 month, or within 3 months, or within 6 months after implantation in the body.
  • the mechanical properties can be verified by animal experiments. It is indicated by early OCT follow-up or radial support force test. When OCT is followed up, there is no significant difference between the surrounding area of the stent and the surrounding area of the implanted orbital implant, or the radial support force test. The radial support force is above 23.3 kPa (175 mm Hg), indicating that the stent is implanted early in the body. Has good mechanical properties.
  • the mass ratio of the iron-based alloy matrix to the degradable polymer is between [1, 200]. Further, the mass ratio of the iron-based alloy matrix to the degradable polymer may be between [5, 50]
  • the degradable polymer is applied to the surface of the iron-based alloy substrate in the form of a coating.
  • the wall thickness of the iron-based alloy substrate may be between [30, 50) ⁇ , and the thickness of the degradable polymer coating is [3, 5 ) between ⁇ , or between [5, 10) ⁇ , or [10,
  • the wall thickness of the iron-based alloy substrate may be between [50, 100) ⁇ , and the thickness of the degradable polymer coating is [5, 10] ) between ⁇ , or between [10, 15) ⁇ , or [
  • the wall thickness of the iron-based alloy substrate is between [100, 200) ⁇
  • the thickness of the degradable polymer coating is [10, 15) Between ⁇ , or between [15, 20) ⁇ , or [2
  • the wall thickness of the iron-based alloy substrate is between [200, 300] ⁇
  • the thickness of the degradable polymer coating is [10, 15) Between ⁇ , or between [15, 20) ⁇ , or [2
  • the degradable polyamino acid may be a combination of any one or two of polyaspartic acid, polyglutamic acid or a copolymer of both monomers. .
  • the coating contains a degradable polyester ruthenium
  • the degradable polyester may be polylactic acid, polyglycolic acid, polysuccinate, poly ( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer, polyhydroxybutyrate valerate copolymer
  • a blend of one or more of a polyhydroxyalkyl alcohol ester, a poly( ⁇ -malate) species, or a copolymerization of at least two monomers e.g., a blend of one or more of a polyhydroxyalkyl alcohol ester, a poly( ⁇ -malate) species, or a copolymerization of at least two monomers.
  • the mass ratio of the degradable polyamino acid to the degradable polyester or the ratio of the comonomer of the two is between [1: 1, 10: 1].
  • the degradable polymer which does not generate an acidic product after degradation may be a lake.
  • the content of the degradable polyamino acid, the degradable polyester, and the degradable polymer which does not produce an acidic product after degradation or the content of the three comonomers are respectively [ 10% , 80
  • the iron-based alloy substrate may further be provided with a slit or a groove, and the degradable polymer is disposed in the slit or the groove; or the iron base
  • the alloy matrix has an inner cavity into which the degradable polymer is filled.
  • the mixture may be a mixture of at least two polymers before Contacting the blend with the iron-based alloy in a coating or in the foregoing manner with an iron-based alloy substrate, or first forming a coating on the surface of the iron-based alloy substrate with one of the polymers, and then laminating the coating on the coating layer A coating formed of the remaining polymer, or a coating formed of a different polymer in different regions of the surface of the iron-based alloy substrate.
  • the mixture may be formed by first forming a coating on the surface of the iron-based alloy substrate with one of the polymers, and then sequentially laminating the coating formed of the remaining polymer on the coating, or Different polymer coatings are placed in different regions of the surface of the iron-based alloy substrate.
  • the degradable polymer may further be mixed with an active drug, and the mass ratio of the degradable polymer to the drug is between [0.1, 20].
  • the active drug may be a drug that inhibits vascular proliferation such as paclitaxel, rapamycin and its derivatives, or an anti-platelet drug selected from cilostazol, or an antithrombotic drug such as heparin, or an anti-inflammatory drug such as a celite.
  • Rice pine can also be a mixture of the aforementioned drugs.
  • the mass ratio of the degradable polymer to the drug is between [0.5, 10].
  • the degradable iron-based alloy stent provided by the invention adopts a specific degradable polymer, so that the iron-based alloy matrix mainly undergoes a chemical reaction under the action of the degradable polymer, thereby Accelerating the corrosion rate of iron can meet the clinical requirements for the early mechanical properties of the stent.
  • FIG. 1 is a schematic cross-sectional view showing an iron-based alloy stent and a coated stent rod according to Embodiment 5 of the present invention.
  • the degradable iron-based alloy stent provided by the invention adopts an animal experiment to verify that the iron-based alloy stent can be rapidly corroded under the action of the degradable polymer, mainly through early mechanical properties and Whether it is completely corroded in a certain time zone, the mass loss test is used to judge whether the iron-based stent is rapidly corroded.
  • the test is performed at a predetermined observation point.
  • the surrounding area of the stent rod is not significantly different from the implanted sputum, or the animal is euthanized, the stent and its tissue are removed from the body, and the stent is attached to the stent.
  • the blood vessel is tested for radial support force to determine whether the stent meets the early mechanical properties.
  • the stent sample is taken out to measure the mass loss of the stent to determine whether the stent has completely corroded.
  • the radial support force test can be performed using a radial support force tester RX550-100 produced by MSI Corporation, including taking the stent implanted in the animal body together with the blood vessel at a predetermined observation point, and directly testing. The radial support force is obtained.
  • the complete corrosion was characterized by a mass loss test of an animal experiment.
  • the mass of the iron-based alloy matrix i.e., the bare stent not including the degradable polymer
  • the iron-based alloy stent is implanted into the abdominal aorta of the rabbit, and the iron-based alloy stent implanted in the animal and the tissue in which it is implanted are taken out at a predetermined observation point, and then the tissue is immersed in a certain concentration of the solution together with the stent (eg Lmol / L sodium hydroxide solution), the tissue is digested, and then the stent rod is taken out from the solution, and the stent rod is placed in a certain concentration of solution (such as 3% tartaric acid solution, and / or organic solution) to make the surface of the stent
  • the corrosion products are all detached or dissolved in the solution, and the remaining stent rods in the solution are taken out, and the stent rods are dry and weighed, and the
  • W quality loss rate
  • the mass loss rate of the stent is W ⁇ 90% ⁇ , it indicates that the iron-based alloy stent is completely corroded.
  • the weight average molecular weight of the degradable polymer and its polydispersity coefficient were measured by an eight-angle laser light scattering instrument manufactured by Wyatt, USA.
  • a pure iron stent comprising a pure iron matrix and a degradable polymer coating applied to the surface of the pure iron substrate.
  • the mass ratio of the pure iron matrix to the degradable polymer is 10:1.
  • the degradable polymer is polyglutamic acid, the weight average molecular weight is 15,000, the polydispersity coefficient is 1.5, and the wall thickness of the iron matrix is 80-90 ⁇ m, and the thickness of the degradable polymer coating is 10-15 ⁇ m.
  • the stent was implanted into the abdominal aorta of the rabbit. After 3 months of implantation, the stent and its tissue were removed for radial support testing with a test result of 70 kPa. After 2 years, the sample was again sampled for mass loss testing. The mass loss rate of the stent was 95%, indicating that the stent was completely corroded.
  • a degradable polymer coating having a thickness of 8-10 micrometers on a surface of a nitriding pure iron bare stent (ie, a nitriding pure iron matrix) having a wall thickness of 50 to 70 micrometers, wherein the nitriding pure iron
  • the mass percentage of the matrix and the degradable polymer is 25, and the degradable polymer coating is a polyaspartic acid-lactic acid copolymer coating having a weight average molecular weight of 100,000 and a polydispersity coefficient of 3, wherein aspartic acid and The lactic acid copolymerization ratio is 1:1, and after the coating is dried, a degradable iron-based alloy stent is obtained.
  • the iron-based alloy stent is implanted into the porcine coronary artery. After 3 months, OCT follow-up found that there was no significant difference between the surrounding area of the stent rod and the implanted sputum. After 1 year, the stent was removed and the mass loss test was performed. The mass loss rate of the stent was 92%, indicating that the stent was completely corroded.
  • the surface of the electrodeposited pure iron (550 ° C annealed) bare stent (ie, electrodeposited pure iron matrix) having a wall thickness of 40 to 50 ⁇ m is uniformly coated with a polyglycine coating of 3 to 5 ⁇ m thick.
  • the polyglutamic acid coating was coated with a 5-8 micron thick polycaprolactone (PCL) rapamycin mixed coating.
  • the mixing ratio of polycaprolactone to rapamycin is 2: 1, the mass ratio of electrodeposited pure iron matrix to degradable polymer is 35:1, wherein polycaprolactone has a weight average molecular weight of 30,000, a polydispersity coefficient of 1.3, a polyglutamic acid weight average molecular weight of 80,000, and a polydisperse The coefficient is 1.6, and the mass ratio is 1:1.
  • a degradable iron-based alloy stent is obtained.
  • the iron-based alloy stent was implanted into the abdominal aorta of the rabbit, the stent was taken out at the corresponding observation point, the stent surface was observed with a microscope, and the radial support force and mass loss percentage of the stent were tested.
  • the test results show that the radial support force of 3 months is 60 kPa; after 1 year, the test mass loss rate is 98%, indicating that the stent has completely corroded.
  • the surface of the outer wall of the carburized iron bare stent (ie, the carburized iron matrix) is coated with a mixed coating of polyaspartic acid and starch, and the wall thickness of the carburized iron matrix is 140-160 micrometers, and the coating layer is coated.
  • the thickness is 30 to 35 microns, and the mass ratio of the carburized iron matrix to the degradable polymer is 30:1.
  • the coating is divided into two layers, the bottom layer is polyaspartic acid with a molecular weight of 400,000, and the top layer is a chitosan coating with a molecular weight of 300,000, and the polydispersity coefficient is 1.2.
  • the two degradable polymer coatings have a mass ratio of 5:1.
  • the stent was implanted into the abdominal aorta of the rabbit, and the stent was taken out at the intercondylar point. The stent surface was observed with a microscope, and the weight loss percentage and radial support force of the stent were tested. The test results show that the radial support force of 6 months is 50 kPa, and the mass loss rate of the stent is 93% after 5 years.
  • the bracket rod 1 of the bracket has a thickness of 100-120 micrometers, and the surface of the bracket rod 1 is provided. Groove 2.
  • a mixture of two layers of degradable polymer 3 is uniformly applied to the surface of the stent rod 1 and the groove 2.
  • the coating of the degradable polyester polymer is a polyglutamic acid-caprolactone copolymer having a weight average molecular weight of 500,000, which is copolymerized by mass ratio of 2:1, and the polymer is polydisperse.
  • the coefficient is 10
  • the thickness of the mixture coating is 20-25 microns
  • the mass ratio of the iron-based alloy matrix to the degradable polymer is 40:1.
  • a degradable iron-based alloy stent is obtained.
  • the stent was implanted into the porcine coronary artery, and the stent was taken out at the intercondylar point to test the mass loss rate and radial support force of the stent.
  • the 3-month test results showed that the radial support force was 60 kPa, and the mass loss test after 4 years showed that the mass loss rate of the stent was 95%.
  • the surface of the sulphurized iron bare stent (ie, the sulphur-iron-based alloy substrate) having a wall thickness of 250 to 270 micrometers is relatively uniformly coated with a degradable polymer coating having a thickness of 35 to 45 micrometers, and the coating is divided into Two layers, the bottom layer is coated with chitosan Layer, molecular weight is 500,000, polydispersity coefficient is 10, top layer is polyglutamic acid lactic acid glycol copolymer coating
  • the copolymerization ratio is 1:1
  • the molecular weight is 300,000
  • the polydispersity coefficient is 5
  • the mass ratio of the sulphurized iron-based alloy matrix to the degradable polymer is 50:1
  • the mass ratio of the two coatings is 1:2.
  • the coating is dried to produce a degradable iron-based alloy stent.
  • the stent was implanted into the abdominal aorta of the pig, and the stent was taken out at the corresponding observation point to conduct a mass loss test on the iron-based alloy stent.
  • the radial support force of the stent was 50 kPa for 6 months
  • the mass loss rate of the stent was 90% after 5 years.
  • a surface of a carburized iron bare bracket ie, a carburized iron substrate
  • a polyaspartic acid and heparin mixed coating having an average thickness of 12 to 15 micrometers, wherein The ratio is 5:1, the molecular weight of aspartic acid is 1 million, the polydispersity coefficient is 20.
  • the mass ratio of the carburized iron-based alloy matrix to the cocoa-degradable polymer is 30, and the degradable iron-based alloy stent is implanted into the pig. Coronary artery, the iron-based alloy stent was taken out at the corresponding observation point, and the mass loss test and the radial support force test were performed. As a result, the radial support force of 3 months was 60 kPa, and the mass loss rate of the stent was 98% in 4 years.
  • a bare iron stent (pure iron matrix, i.e., the surface is not covered with any coating) having a wall thickness of 60 to 70 microns is implanted into the abdominal aorta of the rabbit. After three months, the bracket was taken out and the radial support force was tested. The radial support force was 120kP a. After 3 years, the bracket was taken out for mass loss test. The mass loss rate of the bracket was 25%, indicating the corrosion rate of the bare pure iron bracket. slow.
  • the surface of the pure iron bare bracket ie, pure iron substrate
  • a polylactic acid coating having a thickness of 25 to 35 micrometers, and the mass ratio of the pure iron matrix to the polylactic acid is 10:1.
  • the polylactic acid had a weight average molecular weight of 15,000 and a polydispersity coefficient of 1.8.
  • Dry, an iron-based stent was prepared and implanted into the abdominal aorta of the rabbit. After 3 months, the radial support force test result is 20 kPa, 6 months ⁇ , the bracket mass loss test shows that the bracket mass loss rate is 100%, indicating that the bracket has been completely corroded, and the corrosion is too fast, not expected. The point meets the mechanical properties required for clinical use.
  • the corrosion-resistant iron-based alloy stent provided by the present invention has a weight average molecular weight of [2,100] million, and more A degradable polymer with a dispersion coefficient between (1.0, 50), which achieves complete corrosion of the iron-based alloy matrix within 10 years of implantation in the body.

Abstract

可降解铁基合金支架，包括铁基合金基体和与该基体表面接触的可降解聚合物，所述可降解聚合物的重均分子量在[1，100]万之间，且多分散系数在(1.0，50]之间，所述可降解聚合物选自降解后产生酸性氨基酸的可降解聚氨基酸；或所述可降解聚氨基酸与可降解聚酯的混合物，或两者单体的共聚物；或所述可降解聚氨基酸与降解后不产生酸性产物的可降解聚合物的混合物，或两者单体的共聚物；或所述可降解聚氨基酸与可降解聚酯以及降解后不产生酸性产物的可降解聚合物的混合物，或三者单体的共聚物，或三者中任两种的单体共聚后与剩余一种的混合物。

Description

可降解铁基合金支架
技术领域
[0001] 本发明属于可降解植入医疗器械领域， 涉及一种可快速降解的铁基合金支架。
背景技术
[0002] 当前， 植入医疗器械通常采用金属及其合金、 陶瓷、 聚合物和相关复合材料制 成。 其中， 金属材料基植入医疗器械以其优越的力学性能， 如高强度、 高韧性 等， 尤为受人青睐。
[0003] 铁作为人体内的重要元素， 参与到诸多生物化学过程中， 如氧的搬运。 Peuster M等采用激光雕刻方法制成的、 与临床使用的金属支架形状相似的易腐蚀性纯铁 支架， 植入到 16只新西兰兔的降主动脉处。 此动物实验结果表明， 在 6-18个月内 没有血栓并发症， 亦无不良事件发生， 病理检査证实局部血管壁无炎症反应， 平滑肌细胞无明显增殖， 初步说明可降解铁支架安全可靠， 具有良好的应用前 景。 但该研究同吋发现， 纯铁在体内环境下的腐蚀速率较慢， 无法满足临床上 对可降解支架的降解吋间要求， 因此需要提高铁腐蚀速度。
技术问题
[0004] 研究同吋发现， 纯铁在体内环境下的腐蚀速率较慢， 无法满足临床上对可降解 支架的降解吋间要求， 因此需要提高铁腐蚀速度。
问题的解决方案
技术解决方案
[0005] 本发明要解决的技术问题， 在于针对现有技术的缺陷， 提供一种可降解的铁基 合金支架， 该铁基合金支架植入体内后既能在早期保持良好的力学性能， 又能 快速地腐蚀。
[0006] 作为本发明采用的第一种技术方案， 该可降解铁基合金支架包括铁基合金基体 和与该基体表面接触的可降解聚氨基酸， 所述可降解聚氨基酸降解产生酸性氨 基酸。 该聚氨基酸的重均分子量在 [1， 100]万之间， 多分散系数在 [1.0， 50]之间 [0007] 作为本发明采用的第二种技术方案， 该可降解铁基合金支架包括铁基合金基体 和与该基体表面接触的可降解聚合物， 该可降解聚合物包含能降解产生酸性氨 基酸的聚氨基酸与可降解聚酯的混合物， 或所述可降解聚氨酸的单体与所述可 降解聚酯的单体的共聚物， 所述可降解聚合物的重均分子量在 [1， 100]万之间， 多分散系数在 [1.0， 50]之间。
[0008] 作为本发明采用的第三种技术方案， 该可降解铁基合金支架包括铁基合金基体 和与该铁基合金基体表面接触的可降解聚合物， 所述可降解聚合物包含降解后 能产生酸性氨基酸的聚氨基酸和降解后不产生酸性产物的可降解聚合物的混合 物， 或者所述可降解氨基酸的单体与所述降解后不产生酸性产物的可降解聚合 物的单体的共聚物。 所述降解后不产生酸性产物的可降解聚合物可以是淀粉、 纤维素、 聚糖、 甲壳素、 壳聚糖或其衍生物等。 所述的可降解聚合物的重均分 子量在 [1， 100]万之间， 多分散系数在 (1.0， 50]之间。
[0009] 作为本发明采用的第四种技术方案， 该可降解铁基合金支架包括铁基合金基体 和与该铁基合金基体表面接触的可降解聚合物， 所述可降解聚合物包括降解后 产生酸性氨基酸的可降解聚氨酸、 可降解聚酯和降解后不产生酸性产物的可降 解聚合物的混合物， 或者所述可降解聚氨酸的单体与所述可降解聚酯的单体和 降解后不产生酸性产物的可降解聚合物的单体的共聚物， 或者所述可降解聚氨 基酸、 所述可降解聚酯、 与降解后不产生酸性产物的可降解聚合物中的任意两 种的单体的共聚物与该三种物质中剩余的一种的混合物， 所述可降解聚氨酸降 解后产生酸性氨基酸。 所述的可降解聚合物的重均分子量在 [1， 100]万之间， 多 分散系数在 (1.0， 50]之间。
[0010] 本发明中所述铁基合金基体指铁基合金裸支架， 所述铁基合金基体材质选自纯 铁或医用铁基合金。 人体内营养元素和无害元素， 或毒性较小的元素， 例如 c、
N、 0、 S、 P、 Mn、 Pd、 Si、 W、 Ti、 Co、 Cr、 Cu、 Re中的至少一种， 都可以 惨杂入纯铁中形成所述医用铁基合金。
[0011] 所述各数值区间遵照数学常识， 即 [a， b]指大于或等于 a， 且小于或等于 b; (a
， b]指大于 a， 且小于或等于 b; [a, b) 指大于或等于 a， 小于 b， 全文下同， 不 再赘述。 [0012] 上述第二至第四种技术方案中， 凡与该基体表面接触的可降解聚合物包括至少 两种聚合物的混合物吋， 各聚合物均满足重均分子量在 [1， 100]万之间， 多分散 系数在 (1.0， 50]之间。 以第二种技术方案为例， 该方案中， 与该基体表面接触的 可降解聚合物包含能降解产生酸性氨基酸的聚氨基酸与可降解聚酯的混合物， 该聚氨基酸和该可降解聚酯的重均分子量皆在 [1， 100]万之间， 多分散系数在 [1. 0， 50]之间。
[0013] 所述快速腐蚀， 是指该可降解聚合物能够加速铁基合金基体的腐蚀， 使得该铁 基合金基体在植入体内后 10年内， 能够完全腐蚀。
[0014] 所述完全腐蚀， 是指铁基合金支架的质量损失率 W≥90%。
[0015] 所述完全腐蚀通过动物实验的质量损失测试来表征。 所述质量损失测试通过如 下方式进行： 将铁基合金基体 （即未包括可降解聚合物的裸支架） 质量为 M。的 铁基合金支架植入兔子腹主动脉， 在预定观察吋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一定浓度的溶液 中 （如 lmol/L氢氧化钠溶液） ， 使组织消解， 然后从溶液中取出支架杆， 将支架 杆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， 使支架表 面的腐蚀产物全部脱落或溶解于溶液中， 取出溶液中剩余的支架杆， 将支架杆 干燥称重， 质量为 M t。 质量损失率 W用腐蚀清洗后支架杆重量损失的差值占铁 基合金基体的重量的百分比来表示， 如公式 1-1所示：
[0016] W=[( M 0- M t)/ M 0]xl00% (公式 1-1)
[0017] W——质量损失率
[0018] M t——腐蚀后剩余支架杆的质量
[0019] M 0——铁基合金基体的质量
[0020] 当支架质量损失率 W≥90%吋， 则表明该铁基合金支架完全腐蚀。
[0021] 支架在植入体内的早期良好的力学性能， 根据具体临床需要来确定。 一般来讲 ， "早期 "是指植入体内后的 1个月内， 或 3个月内， 或 6个月内。 力学性能可采用 动物实验方式验证， 通过早期 OCT随访或径向支撑力测试来表示， 当 OCT随访 吋， 支架环绕面积与刚植入吋支架环绕面积无明显差异， 或者径向支撑力测试 吋， 径向支撑力在 23.3kPa (175mm汞柱） 以上， 则表明该支架在植入体内早期 有良好的力学性能。
[0022] 前述四种技术方案中， 所述铁基合金基体与可降解聚合物的质量比在 [1， 200] 之间。 进一步地， 所述铁基合金基体与可降解聚合物的质量比可在 [5， 50]之间
[0023] 前述四种种技术方案中， 所述可降解聚合物以涂层形式涂覆于所述铁基合金基 体表面。
[0024] 前述第一至第四种技术方案中， 所述铁基合金基体的壁厚可在 [30， 50)μηι之间 吋， 所述可降解聚合物涂层的厚度在 [3， 5)μηι之间， 或 [5， 10)μηι之间， 或 [10，
15)μηι之间， 或 [15， 20]μηι之间。
[0025] 前述第一至第四种技术方案中， 所述铁基合金基体的壁厚可在 [50， 100)μηι之 间吋， 所述可降解聚合物涂层的厚度在 [5， 10)μηι之间， 或 [10， 15)μηι之间， 或[
15， 20)μηι之间， 或 [20， 25]μηι之间。
[0026] 前述第一至第四种技术方案中， 所述铁基合金基体的壁厚在 [100， 200)μηι之间 吋， 所述可降解聚合物涂层的厚度在 [10， 15)μηι之间， 或 [15， 20)μηι之间， 或 [2
0， 25)μηι之间， 或 [25， 35]μηι之间。
[0027] 前述第一至第四种技术方案中， 所述铁基合金基体的壁厚在 [200， 300]μηι之间 吋， 所述可降解聚合物涂层的厚度在 [10， 15)μηι之间， 或 [15， 20)μηι之间， 或 [2
0， 25)μηι之间， 或 [25， 35)μηι之间， 或 [35， 45]μηι之间。
[0028] 前述第一至第四种技术方案中， 所述可降解聚氨基酸可以为聚天冬氨酸， 聚谷 氨酸中的任意一种或两种的共混或两者单体的共聚。
[0029] 前述第二种技术方案中， 以及第四种技术方案中涂层中含有可降解聚酯吋， 所 述可降解聚酯可以是聚乳酸、 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， 聚羟基丁酸酯戊酸酯共聚物
， 聚羟基烷基醇酯、 聚 （β-苹果酸酯） 种的一种或几种的共混或至少两种的单体 的共聚。
[0030] 进一步地， 前述第二种技术方案中， 可降解聚氨基酸与可降解聚酯的质量比或 者两者共聚单体的比例介于 [1: 1， 10: 1]。
[0031] 前述第三种技术方案中， 所述降解后不产生酸性产物的可降解聚合物可以是淀 粉、 纤维素、 聚糖、 甲壳素、 壳聚糖或其衍生物等， 涂层中聚氨基酸与降解后 不产生酸性产物的可降解聚合物的质量比或两者共聚单体的比例介于 [1:1， 10:1]
[0032] 前述第四种技术方案中， 所述可降解聚氨基酸， 可降解聚酯和所述降解后不产 生酸性产物的可降解聚合物三者的含量或三者共聚单体的含量分别为 [ 10%， 80
<¾]、 [10% , 80%] [10%, 60%]=
[0033] 前述第一至第四种技术方案中， 所述铁基合金基体还可以设有缝隙或凹槽， 所 述可降解聚合物设于所述缝隙或凹槽中； 或者所述铁基合金基体具有内腔， 所 述可降解聚合物填充在所述内腔内。 当与所述铁基合金基体表面接触的可降解 聚合物为至少两种聚合物的混合物吋， 对相互可以相溶的聚合物而言， 该混合 物可以是先将至少两种聚合物混合后再将共混物与所述铁基合金按涂层或前述 方式与铁基合金基体接触， 或者是先以其中一种聚合物在铁基合金基体表面形 成涂层， 再在该涂层上依次层叠由其余聚合物形成的涂层， 或者是在铁基合金 基体表面的不同区域设置不同的聚合物形成的涂层。 对相互不相溶的聚合物， 该混合物可以是是先以其中一种聚合物在铁基合金基体表面形成涂层， 再在该 涂层上依次层叠由其余聚合物形成的涂层， 或者是在铁基合金基体表面的不同 区域设置不同的聚合物涂层。
[0034] 前述第一至第四种技术方案中， 所述可降解聚合物中还可混有活性药物， 所述 可降解聚合物与药物的质量比在 [0.1， 20]之间。 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。 进一步地， 所述可降解聚合物与药物的质量比在 [0.5， 10]之间。
发明的有益效果
有益效果
[0035] 与现有技术相比， 本发明提供的可降解铁基合金支架采用特定的可降解聚合物 ， 使铁基合金基体在该可降解聚合物的作用下主要发生化学反应， 从而既可以 加速铁的腐蚀速度， 又能满足临床上对支架早期的力学性能要求。
对附图的简要说明 附图说明
[0036] 图 1是本发明实施例 5提供的铁基合金支架及涂层支架杆截面示意图。
实施该发明的最佳实施例
本发明的最佳实施方式
[0037] 需要说明的是， 本发明提供的可降解铁基合金支架采用动物实验的方式来验证 在可降解聚合物的作用下， 铁基合金支架能够快速的腐蚀， 主要通过早期的力 学性能和在一定吋间内是否完全地腐蚀， 通过质量损失测试来判断该铁基支架 是否快速腐蚀。
[0038] 具体地， 把该含有可降解聚合物的铁基合金支架植入动物体内后， 在预定的观 察吋间点， 分别进行测试。 例如， 植入体内 3个月吋 OCT随访测试， 支架杆的环 绕面积与刚植入吋， 无明显差异， 或对动物进行安乐处死， 从其体内取出支架 及其所在的组织， 将支架连同支架所在的血管， 进行径向支撑力测试， 来判断 支架是否满足早期力学性能； 2年吋取出支架样品测量支架质量损失， 来判断支 架是否已经完全腐蚀。
[0039] 所述径向支撑力的测试可使用 MSI公司生产的径向支撑力测试仪 RX550-100进 行， 包括在预定观察吋间点将植入动物体内的支架连同血管取出， 直接进行测 试， 即可得所述径向支撑力。
[0040] 所述完全腐蚀通过动物实验的质量损失测试来表征。 将铁基合金基体 （即未包 括可降解聚合物的裸支架） 质量为 M。的铁基合金支架植入兔子腹主动脉， 在预 定观察吋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一定浓度的溶液中 （如 lmol/L氢氧化钠溶液） ， 使组织消 解， 然后从溶液中取出支架杆， 将支架杆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， 使支架表面的腐蚀产物全部脱落或溶解于溶液中 ， 取出溶液中剩余的支架杆， 将支架杆干燥称重， 质量为 M t。 质量损失率 W用 腐蚀清洗后支架杆重量损失的差值占铁基合金基体的重量的百分比来表示， 如 公式 1-1所示：
[0041] W=[( M 0- M t)/ M 0]xl00% (公式 1-1)
[0042] W——质量损失率 [0043] M t——腐蚀后剩余支架杆的质量
[0044] M 0——铁基合金基体的质量
[0045] 当支架质量损失率 W≥90%吋， 则表明该铁基合金支架完全腐蚀。 所述可降解 聚合物重均分子量大小及其多分散系数采用美国怀雅特公司生产的八角度激光 光散射仪进行检测。
[0046] 以下结合附图和实施例对本发明提供的可降解铁基合金支架作进一步说明。 可 以理解的是， 下述各实施例仅为本发明的较佳实施例， 并不用以限制本发明， 凡在本发明的精神和原则之内所作的任何修改、 等同替换和改进等， 均应包含 在本发明的保护范围之内。
[0047] 实施例 1
[0048] 一种纯铁支架， 包括纯铁基体和涂覆在所述纯铁基体表面的可降解聚合物涂层 。 其中， 所述纯铁基体与可降解聚合物质量比为 10:1。 所述可降解聚合物为聚谷 氨酸， 重均分子量为 1.5万， 多分散系数为 1.5， 且铁基体的壁厚为 80~90μηι， 可 降解聚合物涂层厚度为 10~15μηι。 将该支架植入兔子腹主动脉。 植入 3个月后取 出支架及其所在的组织， 进行径向支撑力测试， 测试结果为 70kPa。 2年后再次 取样， 进行质量损失测试， 该支架质量损失率为 95%， 表明支架已经完全腐蚀。
[0049] 实施例 2
[0050] 在壁厚为 50~70微米的渗氮纯铁裸支架 （即渗氮纯铁基体） 表面均匀全涂覆厚 度为 8~10微米的可降解聚合物涂层， 其中渗氮纯铁基体与可降解聚合物的质量 百分比为 25， 可降解聚合物涂层为重均分子量为 10万、 多分散系数为 3的聚天冬 氨酸 -乳酸共聚物涂层， 其中天冬氨酸与乳酸共聚比例为 1:1， 涂层干燥后， 制得 可降解铁基合金支架。 将该铁基合金支架植入猪冠脉。 3个月吋， OCT随访发现 支架杆环绕面积与刚植入吋无明显差异， 1年吋取出支架， 进行质量损失测试， 测得支架质量损失率为 92%， 表明支架已经完全腐蚀。
[0051] 实施例 3
[0052] 将壁厚为 40~50微米的电沉积纯铁 （550°C退火） 裸支架 （即电沉积纯铁基体） 表面均匀全涂覆 3~5微米厚的聚谷氨酸涂层， 聚谷氨酸涂层上又涂覆 5-8微米厚的 聚己内酯 （PCL) 雷帕霉素混合涂层。 其中聚己内酯与雷帕霉素的混合比例为 2: 1， 电沉积纯铁基体与可降解聚合物质量比为 35:1， 其中聚己内酯重均分子量为 3 万， 多分散系数为 1.3， 聚谷氨酸重均分子量为 8万， 多分散系数为 1.6， 两者质 量比 1:1。 干燥后， 制得可降解铁基合金支架。 将该铁基合金支架植入兔子腹主 动脉， 在相应观察吋间点取出支架， 用显微镜观察支架表面， 并测试支架径向 支撑力和质量损失百分比。 测试结果表明， 3个月径向支撑力为 60kPa; 1年后测 试支架质量损失率为 98%， 表明支架已经完全腐蚀。
[0053] 实施例 4
[0054] 在热处理后的渗碳铁裸支架 （即渗碳铁基体） 外壁表面涂覆聚天冬氨酸与淀粉 的混合涂层， 渗碳铁基体的壁厚为 140~160微米， 涂层厚度为 30~35微米， 且渗 碳铁基体与可降解聚合物的质量比为 30:1。 该涂层分为两层， 底层为分子量为 40 万的聚天冬氨酸， 顶层为分子量为 30万的壳聚糖涂层， 多分散系数为 1.2。 该两 种可降解聚合物涂层质量比为 5:1。 干燥， 制得可降解铁基合金支架。 将支架植 入兔子腹主动脉， 相应观察吋间点取出支架， 用显微镜观察支架表面， 测试支 架重量损失百分比和径向支撑力。 测试结果表明， 6个月径向支撑力为 50kPa， 5 年后该支架质量损失率为 93%。
[0055] 实施例 5
[0056] 打磨铁锰合金裸支架 （即铁锰合金基体） ， 使支架表面分布凹槽， 如图 1所示 ， 该支架的支架杆 1厚度为 100~120微米， 且支架杆 1表面设有凹槽 2。 在支架杆 1 表面和凹槽 2内均匀涂覆有两层可降解聚合物的混合物涂层 3。 按质量比计， 该 可降解聚酯类聚合物的涂层为重均分子量为 50万的聚谷氨酸酸-己内酯共聚物， 按质量比 2:1共聚而成， 聚合物多分散系数为 10， 该混合物涂层厚度为 20~25微米 ， 铁基合金基体与可降解聚合物的质量比为 40:1。 干燥后， 制得可降解铁基合金 支架。 将支架植入猪冠脉， 相应观察吋间点取出支架， 测试支架质量损失率和 径向支撑力。 3个月测试结果表明， 径向支撑力为 60kPa， 4年后质量损失测试， 该支架质量损失率为 95%。
[0057] 实施例 6
[0058] 在壁厚为 250~270微米的渗硫铁裸支架 （即渗硫铁基合金基体） 表面相对均匀 地涂覆厚度 35~45微米的可降解聚合物涂层， 该涂层分为两层， 底层为壳聚糖涂 层， 分子量为 50万， 多分散系数为 10， 顶层为聚谷氨酸乳酸乙醇酸共聚物涂层
(共聚比例为 1:1) ， 分子量为 30万， 多分散系数为 5， 渗硫铁基合金基体与可降 解聚合物质量比为 50:1， 两涂层质量比为 1:2， 。 涂层干燥， 制得可降解铁基合 金支架。 将支架植入猪腹主动脉， 在相应观察吋间点取出支架， 对铁基合金支 架进行质量损失测试。 结果为， 6个月支架径向支撑力为 50kPa， 5年后支架质量 损失率为 90%。
[0059] 实施例 7
[0060] 在壁厚为 50~70微米的渗碳铁裸支架 （即渗碳铁基体） 表面， 涂覆平均厚度为 1 2~15微米的聚天冬氨酸与肝素混合涂层， 其中二者比例为 5:1， 天冬氨酸分子量 为 100万， 多分散系数为 20， 渗碳铁基合金基体与可可降解聚合物的质量比为 30 ， 将该可降解铁基合金支架植入猪冠脉， 在相应观察吋间点取出铁基合金支架 ， 进行质量损失测试和径向支撑力测试。 结果为， 3个月径向支撑力为 60kPa， 在 4年吋支架质量损失率为 98%。
[0061] 对比例 1
[0062] 将壁厚为 60~70微米的纯铁裸支架 （纯铁基体， 即表面未覆盖有任何涂层） 植 入兔子腹主动脉。 三个月后， 取出支架， 测试径向支撑力， 径向支撑力为 120kP a, 3年吋取出支架进行质量损失测试， 此吋支架质量损失率为 25%， 说明裸的纯 铁支架腐蚀速度慢。
[0063] 对比例 2
[0064] 在壁厚为 60~70微米的纯铁裸支架 (即纯铁基体)表面涂覆厚度为 25~35微米的聚 乳酸涂层， 纯铁基体与聚乳酸质量比为 10:1， 聚乳酸重均分子量为 1.5万， 多分 散系数为 1.8。 干燥， 制得铁基支架， 将其植入兔子腹主动脉。 3个月吋， 径向支 撑力测试结果为 20kPa， 6个月吋， 支架质量损失测试表明， 支架质量损失率为 1 00% , 说明该支架已经完全腐蚀， 且腐蚀过快， 没有在预期吋间点满足临床所需 的力学性能。
[0065] 从以上实施例 1-7和对比实施例 1-2的试验结果可以看出， 本发明提供的可腐蚀 铁基合金支架采用重均分子量在 [2， 100]万之间， 且多分散系数在（1.0， 50]之间 的可降解聚合物， 既实现了铁基合金基体在植入体内 10年内完全腐蚀， 同吋满 足临床上对可降解支架腐蚀周期的要求； 在 OCT随访吋， 支架环绕面积与刚植 入吋支架环绕面积无明显差异， 或者早期径向支撑力均在 23.3kPa (175mm汞柱
) 以上， 满足了临床上对支架植入体内的早期力学性能要求。

Claims

权利要求书
[权利要求 1] 一种可降解铁基合金支架， 包括铁基合金基体和与该基体表面接触的 可降解聚合物， 所述可降解聚合物重均分子量在 [1， 100]万之间， 多 分散系数在 [1.0， 50]之间， 所述可降解聚合物选自：
降解后产生酸性氨基酸的可降解聚氨基酸； 或
所述可降解聚氨基酸与可降解聚酯的混合物； 或 所述可降解聚氨酸的单体与所述可降解聚酯的单体的共聚物； 或 所述可降解聚氨基酸与降解后不产生酸性产物的可降解聚合物的混合 物； 或
所述可降解聚氨基酸的单体与降解后不产生酸性产物的可降解聚合物 的单体的共聚物； 或
所述可降解聚氨基酸与可降解聚酯以及降解后不产生酸性产物的可降 解聚合物的混合物； 或
所述可降解聚氨基酸的单体与可降解聚酯的单体以及降解后不产生酸 性产物的可降解聚合物的单体的共聚物； 或
所述可降解聚氨基酸、 所述可降解聚酯、 与降解后不产生酸性产物的 可降解聚合物中的任意两种的单体的共聚物与该三种物质中剩余的一 种的混合物。
[权利要求 2] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述可降解 聚合物的重均分子量在 [1， 10) 万之间， 或 [10， 25) 万之间， 或 [25 ， 40) 万之间， 或 [40， 60) 万之间， 或 [60， 100]万之间。
[权利要求 3] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述可降解 聚合物多分散系数在 [1.0， 2)之间， 或 [2, 3)
之间， 或 [3， 5)之间， 或 [5， 10) 之间， 或 [10， 20) 之间， 或 [20， 5 0]之间。
[权利要求 4] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述铁基合 金基体与所述可降解聚合物的质量比在 [1， 200]之间。
[权利要求 5] 如权利要求 4所述的可降解铁基合金支架， 其特征在于， 所述铁基合 金基体与所述可降解聚合物的质量比在 [5， 50]之间。
[权利要求 6] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述可降解 聚合物以涂层形式涂覆于所述铁基合金基体表面； 或 所述铁基合金基体设有缝隙或凹槽， 所述可降解聚合物设于所述缝隙 或凹槽中； 或
所述铁基合金基体具有内腔， 所述可降解聚合物填充在所述内腔内。
[权利要求 7] 如权利要求 6所述的可降解铁基合金支架， 其特征在于， 在所述可降 解聚合物以涂层形式涂覆于所述铁基合金基体表面吋， 所述铁基合金 基体的壁厚在 [30， 50)μηι之间， 所述可降解聚合物涂层的厚度在 [3， 5)μηι之间， 或 [5， 10)μηι之间， 或 [10， 15)μηι之间， 或 [15， 20]μηι之 间；
或者所述铁基合金基体的壁厚在 [50， 100)μηι之间， 所述可降解聚合 物涂层的厚度在 [5， 10)μηι之间， 或 [10， 15)μηι之间， 或 [15， 20)μηι 之间， 或 [20， 25]μηι之间；
或者所述铁基合金基体的壁厚在 [100， 200)μηι之间， 所述可降解聚合 物涂层的厚度在 [10， 15)μηι之间， 或 [15， 20)μηι之间， 或 [20， 25)μηι 之间， 或 [25， 35]μηι之间；
或者所述铁基合金基体的壁厚在 [200， 300]μηι之间， 所述可降解聚合 物涂层的厚度在 [10， 15)μηι之间， 或 [15， 20)μηι之间， 或 [20， 25)μηι 之间， 或 [25， 35)μηι之间， 或 [35， 45]μηι之间。
[权利要求 8] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述可降解 聚氨基酸选自聚天冬氨酸或聚谷氨酸， 或聚天冬氨酸与聚谷氨酸的混 合物， 或聚天冬氨酸的单体与聚谷氨酸的单体的共聚物。
[权利要求 9] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述降解后 不产生酸性产物的可降解聚合物选自淀粉、 纤维素、 聚糖、 甲壳素、 壳聚糖或其衍生物。
[权利要求 10] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 当所述可降 解聚合物为可降解聚氨基酸和可降解聚酯的混合物， 或者可降解聚氨 基酸的单体和可降解聚酯的单体的共聚物吋， 所述聚氨基酸和所述可 降解聚酯混合比例或者共聚单体的比例为 [1:1， 10:1]。
[权利要求 11] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 当所述可降 解聚合物为可降解聚氨基酸和降解后不产生酸性产物的可降解聚合物 的混合物或所述可降解聚氨基酸的单体和降解后不产生酸性产物的可 降解聚合物的单体的共聚物吋， 所述可降解聚氨基酸和降解后不产生 酸性产物的可降解聚合物混合或共聚单体的比例为 [1:1， 10:1]。
[权利要求 12] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 当所述可降 解聚合物为可降解聚氨基酸与可降解聚酯以及降解后不产生酸性产物 的可降解聚合物的混合物， 或者是可降解聚氨基酸的单体与可降解聚 酯的单体以及降解后不产生酸性产物的可降解聚合物的单体的共聚物 ， 或者是所述可降解聚氨基酸、 所述可降解聚酯、 与降解后不产生酸 性产物的可降解聚合物中的任意两种的单体的共聚物与该三种物质中 剩余的一种的混合物吋， 所述可降解聚氨基酸与可降解聚酯以及降解 后不产生酸性产物的可降解聚合物或三者共聚单体的含量范围分别是
[10%, 80%] [10% , 80%] [10% , 60%]=
[权利要求 13] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述可降解 聚酯是聚乳酸、 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， 或者是由形成聚乳酸、 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。
[权利要求 14] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述可降解 聚合物中混有活性药物， 所述可降解聚合物与药物的质量比在 [0.1， 2 0]之间。
[权利要求 15] 如权利要求 14所述的可降解铁基合金支架， 其特征在于， 所述可降解 聚合物与药物的质量比在 [0.5， 10]之间。 [权利要求 16] 如权利要求 1所述的可降解铁基合金支架， 其特征在于， 所述铁基合 金基体材质选自纯铁或在纯铁中惨杂有 C、 N、 0、 S、 P、 Mn、 Pd、 Si、 W、 Ti、 Co、 Cr、 Cu、 Re中至少一种形成的铁基合金。
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US20170340780A1 (en) 2017-11-30

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