WO2015062546A1 - 一种可吸收铁基合金支架 - Google Patents

一种可吸收铁基合金支架 Download PDF

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Publication number
WO2015062546A1
WO2015062546A1 PCT/CN2014/090107 CN2014090107W WO2015062546A1 WO 2015062546 A1 WO2015062546 A1 WO 2015062546A1 CN 2014090107 W CN2014090107 W CN 2014090107W WO 2015062546 A1 WO2015062546 A1 WO 2015062546A1
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Prior art keywords
iron
based alloy
degradable
degradable polyester
polymer
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PCT/CN2014/090107
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English (en)
French (fr)
Inventor
张德元
孙宏涛
陈丽萍
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先健科技(深圳)有限公司
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Priority to US15/033,227 priority Critical patent/US20160279303A1/en
Priority to EP14857514.5A priority patent/EP3064232B1/en
Priority to KR1020167014075A priority patent/KR102201025B1/ko
Priority to CN201480056254.3A priority patent/CN105636618B/zh
Priority to JP2016526948A priority patent/JP2016534807A/ja
Priority to AU2014344307A priority patent/AU2014344307B2/en
Priority to NZ720002A priority patent/NZ720002A/en
Publication of WO2015062546A1 publication Critical patent/WO2015062546A1/zh

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    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
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    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
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    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/86—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure
    • A61F2/90—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure
    • A61F2/91—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes
    • A61F2/915—Stents in a form characterised by the wire-like elements; Stents in the form characterised by a net-like or mesh-like structure characterised by a net-like or mesh-like structure made from perforated sheet material or tubes, e.g. perforated by laser cuts or etched holes with bands having a meander structure, adjacent bands being connected to each other
    • A61F2002/9155—Adjacent bands being connected to each other
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    • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
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Definitions

  • the invention belongs to the field of biodegradable implant medical devices and relates to an absorbable iron-based alloy device which can be rapidly and controllably degraded within a predetermined time period.
  • 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.
  • the literature also points out that in the degradation process of iron-based alloys, it is accompanied by two processes of oxygen absorption corrosion and hydrogen evolution corrosion, and because the highest oxygen absorption corrosion rate of the solution in the local slightly acidic environment is constant, it is difficult to increase oxygen absorption corrosion.
  • Speed to improve the corrosion rate of iron-based alloys that is, the literature believes that the corrosion rate of iron-based alloys can only be improved by hydrogen evolution corrosion in the degradation of iron-based alloys.
  • this document only provides experimental data showing that the iron-based alloy accelerates the corrosion rate under the action of polyester, and the molecular weight and molecular weight distribution of the polymer are not disclosed, that is, the compatibility of degradation of the degradable polymer with the corrosion of the iron-based alloy substrate is not disclosed.
  • the large amount of hydrogen produced by hydrogen evolution corrosion can cause clinical risk of tissue tolerance such as the formation of a gas plug, which can cause the stent to be clinically unusable.
  • Our early experiments showed that iron-based alloy rot after denitrification in a corrosive environment The etch rate is greatly reduced, that is, the iron-based alloy in the body does not undergo hydrogen evolution corrosion as described in the aforementioned literature.
  • the corrosion rate of iron is too fast, it is easy to cause the structure of the iron-based alloy stent to be incomplete (such as 3 months) after implantation, and it is difficult to achieve the radial support force required for the clinical blood vessel, resulting in the loss of clinical application value of the stent. .
  • the technical problem to be solved by the present invention is to provide an absorbable iron-based alloy stent which can be quickly and controllably corroded within a predetermined period of time after being implanted into the body in view of the defects of the prior art.
  • the absorbable iron-based alloy stent comprises an iron-based alloy substrate and a degradable polyester in contact with the surface of the substrate, and the weight average molecular weight of the degradable polyester is [2,100 Between 10,000, the polydispersity coefficient is between [1.2, 30].
  • the absorbable iron-based alloy stent comprises an iron-based alloy substrate and a degradable polyester in contact with the surface of the substrate, and the weight average molecular weight of the degradable polyester is [2, 100] Between ten thousand, the polydispersity coefficient is between (1.0, 1.2) or (30, 50).
  • the absorbable 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 weight average molecular weight of the degradable polymer is [ Between 2,100 million, the polydispersity coefficient is between (1.0, 50), and the degradable polymer degrades to produce a carboxyl group after the iron-based alloy stent is implanted in the body.
  • the degradable polymer may be a degradable polyester, a blend of a degradable polyester and a degradable polyanhydride, or a copolymer copolymerized with a monomer that forms a degradable polyester and a degradable polyanhydride.
  • 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 medical iron-based alloy. a nutrient element and a harmless element in the human body, or an element having less toxicity, such as at least one of C, N, O, S, P, Mn, Pd, Si, W, Ti, Co, Cr, Cu, Re, Both of these may be doped into pure iron to form the medical iron-based alloy.
  • Each numerical interval follows mathematical common sense, that is, [a, b] means greater than or equal to a, and less than or equal to b; (a, b) means greater than a, and less than or equal to b; [a, b) means greater than or Equal to a, less than b, the same text is the same, no longer repeat.
  • the rapid means that the degradable polyester can accelerate the corrosion of the iron-based alloy matrix, so that the iron-based alloy matrix can be completely corroded within 5 years after being implanted into the body.
  • the controllable refers to the corrosion of the degradable polyester to the iron-based alloy matrix, which can ensure the implantation of the iron-based alloy stent.
  • Early in the body has good mechanical properties, and the stent can generate a small amount of hydrogen or no hydrogen at all during the entire corrosion process.
  • a small amount of hydrogen refers to the amount of hydrogen that is insufficient to form a risk of clinical embolism.
  • 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 in an animal experiment.
  • the mass loss test is carried out by implanting an iron-based alloy substrate (ie, a bare stent not including a degradable polymer) with an iron-based alloy stent of mass M 0 into a rabbit abdominal aorta, which is implanted at a predetermined observation time point.
  • the iron-based alloy stent and the tissue in the animal body are taken out, and then the tissue and the stent are immersed in a certain concentration of solution (such as 1 mol/L sodium hydroxide solution) to digest the tissue, and then the stent rod is taken out from the solution.
  • a certain concentration of solution such as 1 mol/L sodium hydroxide solution
  • stent rod Inserting the stent rod into a solution of a certain concentration (such as 3% tartaric acid solution, and / or organic solution), so that the corrosion products on the surface of the stent are all detached or dissolved in the solution, and the remaining stent rods in the solution are taken out, and the stent is removed.
  • the rod is dry and weighed with a mass of M t .
  • the mass loss rate is expressed as a percentage of the weight loss of the support rod after corrosion cleaning, as a percentage of the weight of the iron-based alloy matrix, as shown in Equation 1-1:
  • 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 stent when it is implanted, or when the radial support force is tested. The radial support force above 23.3 kPa (175 mm Hg) indicates that the stent has good mechanical properties in the early stage of implantation.
  • the iron-based alloy stent provided by the invention does not generate hydrogen at all during the whole corrosion process, or only generates a small amount of hydrogen, which is specifically verified by an animal experiment.
  • an iron-based alloy stent is implanted into the rabbit abdominal aorta at a predetermined observation time, such as 1 month, 3 months, 6 months, 2 years, 3 years, or 5 years after implantation in the body, using a microscope. Observing the circumference of the stent rod at the same magnification, if a small amount of stent rod coating is slightly bulged, it indicates that the stent generates a small amount of hydrogen during corrosion. If the stent rod is uniformly corroded and there are no bubbles around it, it indicates that the stent has no corrosion during the corrosion process. Hydrogen is produced.
  • the weight average molecular weight of the degradable polyester may be between [2, 10) million, or Between [10,25) million, or between [25,40) million, or between [40,60) million, or [60,100] million.
  • the polydispersity coefficient of the degradable polyester is between [1.2, 2), or between [2, 3) or [3, 5), or [5, 10). Between, or between [10, 20), or between [20, 30].
  • the polydispersity coefficient is between [1.2, 2), or between [2, 3) or [3, 5), or between [5, 10), or [ Between 10, 20), or between [20, 30), or between [30, 50].
  • the mass ratio of the iron-based alloy substrate to the degradable polyester is between [1, 200]. Further, in the foregoing first and second technical solutions, the mass ratio of the iron-based alloy substrate to the degradable polyester may be between [5, 50].
  • the mass ratio of the iron-based alloy matrix to the degradable polymer is between [1,200].
  • the mass ratio of the iron-based alloy matrix to the degradable polymer is between [5, 50].
  • the degradable polyester is coated on the surface of the iron-based alloy substrate in the form of a coating.
  • the degradable polymer is applied to the surface of the iron-based alloy substrate in the form of a coating.
  • the thickness of the degradable polyester coating or the degradable polymer coating is Between [3, 5) ⁇ m, or between [5, 10) ⁇ m, or between [10, 15) ⁇ m, or between [15, 20] ⁇ m.
  • the thickness of the degradable polyester coating or the degradable polymer coating is Between [5, 10) ⁇ m, or between [10, 15) ⁇ m, or between [15, 20) ⁇ m, or between [20, 25] ⁇ m.
  • the thickness of the degradable polyester coating or the degradable polymer coating is [ 10, 15) between ⁇ m, or between [15, 20) ⁇ m, or between [20, 25) ⁇ m, or between [25, 35] ⁇ m.
  • the thickness of the degradable polyester coating or the degradable polymer coating is [ 10, 15) between ⁇ m, or between [15, 20) ⁇ m, or between [20, 25) ⁇ m, or between [25, 35) ⁇ m, or between [35, 45] ⁇ m.
  • the degradable polymer when the degradable polymer is a degradable polyester, the degradable polyester is polylactic acid, polyglycolic acid, polysuccinate, poly Any one of ( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer, and polyhydroxybutyrate valerate copolymer.
  • the degradable polyester comprises at least two homogenous degradable polyester polymers.
  • the same type refers to a general term for polymers having the same structural unit (i.e., the monomers are the same) but having different weight average molecular weights.
  • the weight average molecular weight of the first degradable polyester polymer is between [2,10) million, and the weight average molecular weight of the second degradable polyester polymer is between [10,100] million, by mass.
  • the ratio of the first and second degradable polyester polymers is [1:9, 9:1], and the same type of degradable polyester polymer is selected from the group consisting of polylactic acid, polyglycolic acid, and poly Succinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer or polyhydroxybutyrate valerate copolymer.
  • the at least two different weight average molecular weight homogeneous degradable polyester polymers may each be coated on the surface of the stent, or may be uniformly mixed and coated on the surface of the stent.
  • the quality of the first and second degradable polyester polymers is the same when the degradable polymer is a degradable polyester
  • the ratio is between [1:5, 5:1].
  • the degradable polyester comprises at least two high molecular weight degradable polyester polymers
  • the weight average molecular weight of the at least two high molecular weight degradable polyester polymers is between [10,20) million, or [20,40) million, or [40,60) million, Or between [60,100] million.
  • the degradable polyester is polylactic acid, polyglycolic acid, polysuccinate, poly Physical blending of at least two of ( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer and polyhydroxybutyrate valerate copolymer Or by forming polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer a copolymer obtained by copolymerizing at least two of the monomers of the polyhydroxybutyrate valerate copolymer.
  • the degradable polyester may include polylactic acid (PLA) and polylactic acid glycolic acid (PLGA), wherein the PLGA has a weight average molecular weight of [2,30] million and a PLA weight average molecular weight of [2,100] million. According to the mass ratio, the content ratio of the two is between [1:9, 9:1].
  • PLA polylactic acid
  • PLGA polylactic acid glycolic acid
  • the degradable polyester is at least two kinds of degradable polyester polymerizations having different crystallinity. a mixture of the compounds, wherein the content of the degradable polyester polymer having a crystallinity of [5%, 50%] is between [10%, 90%], and the degradable polyester polymerization
  • the material is selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer or polyhydroxyl Butyrate valerate copolymer.
  • the at least two degradable polyester-based polymers having different crystallinity comprise: the degradable polyester may be a mixture of crystalline and amorphous degradable polyester polymers, or may have low crystallinity and high crystallization. Degree of degradable polyester polymer Mixed.
  • the degradable polyester includes polylactic acid having a crystallinity of 5 to 50%, and the content of polylactic acid is between 10% and 90%.
  • the above polylactic acid may be poly- or poly-L-lactic acid.
  • the degradable polymer when the degradable polymer is a blend of a degradable polyester and a degradable polyanhydride, or a copolymer of a degradable polyester and a degradable polyanhydride, When the copolymer is degraded, the weight average molecular weight of the degradable polyester and the degradable polyanhydride are between [2,100] million, and the polydispersity coefficient is between (1.0, 50), the polyanhydride Selected from poly1,3-bis(p-carboxyphenoxy)propane-sebacic acid, polyerucic acid dimer-sebacic acid or polyfumaric acid-sebacic acid; the degradable polyester is selected from the group consisting of Lactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), polycaprolactone, polyethylene adipate, polylactic acid-glycolic acid copolymer, polyhydroxybutyrate Any one of the acid ester cop
  • the degradable polyester or the degradable polyanhydride having a crystallinity of [5%, 50%] by mass percentage
  • the content of the degradable polyester polymer is selected from the group consisting of polylactic acid, polyglycolic acid, polysuccinate, poly( ⁇ -hydroxybutyrate), and poly An ester, a polyethylene adipate, a polylactic acid-glycolic acid copolymer or a polyhydroxybutyrate valerate copolymer, the polyanhydride being selected from the group consisting of poly1,3-bis(p-carboxyphenoxy)propane - azelaic acid, polyerucic acid dimer-sebacic acid or polyfumaric acid-sebacic acid.
  • the degradable polyester or the degradable polymer may also be in contact with the surface of the iron-based alloy substrate in a non-coated form, such as the iron-based alloy substrate provided with a slit or a concave surface. a groove, the degradable polyester or degradable polymer is disposed in the slit or groove; or the iron-based alloy substrate has a lumen, and the degradable polyester or degradable polymer is filled therein Inside the cavity. At least one of the above-exemplified non-coating contact means and coating forms may be selected.
  • the "surface” in the “contact with the surface of the substrate” means not only the outer surface, but also the degradable polyester or degradable polymer and the iron.
  • the base alloy substrate may have a contact point or a contact surface.
  • the degradable polyester or the degradable polymer may further be mixed with an active drug, the degradable polyester or the mass ratio of the degradable polymer to the drug.
  • 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 (Cilostazol), or an antithrombotic drug such as heparin, or an anti-inflammatory drug.
  • cilostazol cilostazol
  • an antithrombotic drug such as heparin
  • an anti-inflammatory drug such as dexamethasone
  • the mass ratio of the degradable polyester or the degradable polymer to the drug is between [0.5, 10].
  • the absorbing iron-based alloy stent provided by the invention adopts a specific degradable polymer, so that the iron-based alloy matrix mainly undergoes oxygen absorption corrosion under the action of the degradable polymer, resulting in little or no
  • the generation of hydrogen can not only avoid the clinical risk of clinical thrombosis caused by a large amount of hydrogen generated by hydrogen evolution corrosion, but also meet the clinical early stage of stenting.
  • FIG. 1 is a schematic cross-sectional view showing a stent rod of an iron-based alloy stent coated with a degradable polyester coating according to Embodiment 5 of the present invention
  • Figure 2 is a photomicrograph of a small amount of hydrogen produced by the stent rod in Example 7 of the present invention.
  • Figure 3 is a photomicrograph of a small amount of hydrogen produced by the stent rod in Example 9 of the present invention.
  • Figure 4 is a photomicrograph of a small amount of hydrogen produced by a stent rod in Example 12 of the present invention.
  • Fig. 5 is a micrograph showing the generation of a small amount of hydrogen gas in the stent rod in the thirteenth embodiment of the present invention.
  • Figure 6 is a photomicrograph of a small amount of hydrogen produced by a stent rod in Example 14 of the present invention.
  • Fig. 7 is a micrograph showing the generation of a large amount of hydrogen during the corrosion of the stent rod in Comparative Example 2.
  • the absorbable iron-based alloy stent uses an animal experiment to verify that the iron-based alloy stent can be rapidly and controllably corroded under the action of the degradable polymer, mainly through early mechanical properties and Whether a large amount of hydrogen gas is generated at a predetermined observation time point to judge whether the iron-based alloy support is corroded or not, and the mass loss test is used to judge whether the iron-based support is rapidly corroded.
  • the test is performed at predetermined observation time points. For example, in the OCT follow-up test at 3 months after implantation, there is no significant difference between the surrounding area of the stent rod and the freshly implanted, 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. At 2 years, the stent sample is taken out to measure the mass loss of the stent to observe the corrosion of the stent, and the stent is axially dissected at each sampling time. A large amount of hydrogen gas was generated during the corrosion of the stent by using a microscope and observing the circumference of the stent rod at the same magnification.
  • the test of the radial support force can be carried out by using the radial support force tester RX550-100 produced by MSI, including taking out the stent implanted in the animal body together with the blood vessel at a predetermined observation time point, and directly testing the plant. Radial support force.
  • the complete corrosion was characterized by a mass loss test in an animal experiment.
  • An iron-based alloy stent having an iron-based alloy matrix ie, a bare stent not including a degradable polymer
  • M 0 an iron-based alloy stent implanted in the animal at a predetermined observation time and The tissue is taken out, and then the tissue is immersed in a certain concentration of solution (such as 1 mol / L sodium hydroxide solution) to disintegrate the tissue, and then the stent rod is taken out from the solution, and the stent rod is placed in a certain concentration of the solution.
  • a certain concentration of solution such as 1 mol / L sodium hydroxide solution
  • the mass loss rate is expressed as a percentage of the weight loss of the support rod after corrosion cleaning, as a percentage of the weight of the iron-based alloy matrix, as shown in Equation 1-1:
  • the mass loss rate of the stent When 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 are detected by an eight-angle laser light scattering instrument produced 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 5:1.
  • the degradable polymer is polyglycolic acid, the weight average molecular weight is 200,000, the polydispersity coefficient is 1.8, the wall thickness of the iron matrix is 80-90 ⁇ m, and the thickness of the degradable polymer coating is 15-20 ⁇ m.
  • the test result was 70 kPa, indicating that the degradable polymer and the iron-based alloy matrix were well matched, and the early mechanical properties of the stent were ensured. No hydrogen bubbles were found around the stent rod. After 2 years, the sample was again sampled for mass loss test. The mass loss rate of the stent was 95%, indicating that the stent was completely corroded. The surrounding of the stent rod was observed with a microscope, and no hydrogen bubbles were found.
  • a degradable polymer coating having a thickness of 10 to 12 ⁇ m is uniformly coated on the surface of a nitriding pure iron bare stent (ie, a nitrided pure iron matrix) having a wall thickness of 65 to 75 ⁇ m, wherein the nitrided pure iron matrix and the nitriding iron matrix
  • the mass percentage of the degraded polymer is 25, and the degradable polymer coating is a poly- chlorolactic acid coating having a weight average molecular weight of 100,000 and a polydispersity coefficient of 3, and dried to obtain an absorbing iron-based alloy stent.
  • the iron-based alloy stent is implanted into the porcine coronary artery.
  • the OCT follow-up showed that there was no significant difference between the surrounding area of the stent rod and the freshly implanted one.
  • the stent was taken out and the mass loss test was performed. The mass loss rate of the stent was 92%, indicating that the stent was completely corroded.
  • the stent was taken out and observed around the stent rod with a microscope, and no hydrogen bubbles were generated.
  • 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 mixture of 3 to 5 ⁇ m thick polycaprolactone (PCL) and paclitaxel. coating.
  • the mass ratio of the electrodeposited pure iron matrix to the degradable polymer is 35:1, and the polycaprolactone has a weight ratio of 1:2 by two polycaprolactones having a weight average molecular weight of 30,000 and a weight average molecular weight of 80,000.
  • the mixed polycaprolactone polydispersity coefficient was 25, and the mass ratio of polycaprolactone to paclitaxel was 2:1.
  • an absorbing iron-based alloy stent After drying, an absorbing iron-based alloy stent is obtained.
  • the iron-based alloy stent was implanted into the abdominal aorta of the rabbit, the stent was taken at the corresponding observation time 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; the test mass loss rate is 98% after 1 year, indicating that the stent has completely corroded, and there is no hydrogen bubble formation around the stent rod under the microscope at the two sampling time points. .
  • the surface of the outer wall of the carburized iron bare stent (ie, the carburized iron matrix) is coated with a poly-L-lactic acid coating, the wall thickness of the carburized iron substrate is 140-160 micrometers, and the thickness of the poly-L-lactic acid coating is 30-35. Micron, and the mass ratio of the carburized iron matrix to the poly-L-lactic acid is 120.
  • the coating is divided into two layers, the bottom layer is PLLA with 50% crystallinity, and the top layer is PLLA coating with 5% crystallinity.
  • the two layers of poly-L-lactic acid have a weight average molecular weight of 600,000 and a polydispersity coefficient of 1.2.
  • the two crystallinity degradable polymer coatings have a mass ratio of 1:1. Drying produces an absorbable iron-based alloy stent.
  • the stent was implanted into the abdominal aorta of the rabbit, and the stent was taken out at the time of observation. 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 6-month radial support force is 45 kPa, and the mass loss rate of the stent is 92% after 3 years. No hydrogen bubbles are generated around the stent rod at the above two sampling time points.
  • polishing the iron-manganese alloy bare bracket ie, the iron-manganese alloy base
  • the bracket rod 1 of the bracket has a thickness of 100-120 micrometers
  • the surface of the bracket rod 1 is provided with a groove 2 .
  • a mixture coating 3 of a degradable polyester-based polymer is uniformly applied to the surface of the stent rod 1 and the groove 2.
  • the coating of the degradable polyester polymer is a poly L-lactic acid having a weight average molecular weight of 1,000,000 and a weight average molecular weight of 20,000 polylactic acid glycolic acid (the molar ratio of lactic acid to glycolic acid is 50:50).
  • the polylactic acid polydispersity coefficient after mixing is 10
  • the thickness of the mixture coating is 20-25 micrometers
  • the mass ratio of the iron-based alloy matrix to the degradable polymer is 40:1.
  • an absorbing iron-based alloy stent is obtained.
  • the stent was implanted into the porcine coronary artery, and the stent was taken out at the corresponding observation time to test the stent mass loss rate and the radial support force.
  • the test results of 3 months showed that the radial support force was 60 kPa.
  • the mass loss rate of the stent was 95%. No hydrogen bubbles were generated around the stent rod at the above two sampling time points.
  • the outer surface of an iron-carbon alloy bare stent ie, iron-carbon alloy substrate
  • the wall is uniformly coated with a polysuccinate coating having a thickness of 5 to 8 ⁇ m, the ratio of the mass of the iron-carbon alloy substrate to the polysuccinate is 12:1, and the weight average molecular weight of the polysuccinate is 60,000.
  • the polydispersity coefficient is 2, and drying is performed to obtain an absorbable iron-based alloy stent.
  • the stent was implanted into the abdominal aorta of the rabbit, and the stent was taken out at the corresponding observation time point, and the stent was subjected to a mass loss test and a radial support force test.
  • the radial support force of the stent was 50 kPa at 1 month, and the mass loss rate of the stent was 99% after 1.5 years. No hydrogen bubbles were observed around the stent by the microscope at the above two sampling time points.
  • the surface of the sulphurized iron bare stent ie, the sulphur-iron-based alloy substrate
  • a degradable polymer coating having a thickness of 35 to 45 micrometers
  • the sulphur-iron-based alloy matrix and the The degradable polymer has a mass ratio of 50:1.
  • the degradable polymer is a blend of polylactic acid and PLGA, wherein the polylactic acid has a weight average molecular weight of 300,000, a crystallinity of 40%, a content of 90%, and a polydispersity coefficient of 1.8, PLGA weight average molecular weight of 30,000, polydispersity coefficient of 4, crystallinity of 5%, content of 10%. Drying produces an absorbable 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 time to test the mass loss of the iron-based alloy stent. As a result, the radial support force of the 6-month stent was 50 kPa.
  • the circumference of the iron-based alloy support rod was observed with a microscope. As shown in Fig. 2, a small amount of bulging around the support rod was found, that is, a small amount of hydrogen was generated; The loss rate was 90%, and no hydrogen bubbles were found.
  • a coating having a thickness of 15 to 20 ⁇ m is applied to the surface of the iron-manganese alloy bare stent (ie, the iron-manganese alloy substrate) having a wall thickness of 120 to 150 ⁇ m.
  • the coating is formed by mixing poly( ⁇ -hydroxybutyrate), polyfumaric acid-sebacic acid and heparin at a mass ratio of 8:1:1, wherein the iron-based alloy matrix and the degradable polymer are The mass ratio of the sum of poly( ⁇ -hydroxybutyrate) and polyfumaric acid-sebacic acid is 80, the weight average molecular weight of PLLA is 300,000, the crystallinity is 30%, the polydispersity coefficient is 2, and the PLGA weight average The molecular weight is 100,000 and the polydispersity coefficient is 45.
  • the stent was implanted into the abdominal aorta of the rabbit, and the iron-based alloy stent was taken out at the corresponding observation time point, and the radial support force test and the mass loss test were performed on the iron-based alloy stent.
  • the radial support force of the 3-month iron-based alloy stent was 60 kPa, and the mass loss rate of the stent was 95% after 3 years.
  • the surrounding of the stent rod was observed with a microscope, and no hydrogen bubbles were observed at both time points.
  • Spinning lactic acid (PDLLA) and rapamycin are mixed at a mass ratio of 2:1, wherein PDLLA has a weight average molecular weight of 200,000 and a polydispersity factor of 1.6.
  • the mass ratio of the carburized iron matrix to the degradable polymer coating Is 30. Drying produces an absorbable iron-based alloy stent.
  • the iron-based alloy stent was implanted into the porcine coronary artery, and the iron-based alloy stent was taken at the corresponding observation time point for mass loss test and radial support force test.
  • the result is that The radial support force of 3 months was 60 kPa.
  • the circumference of the iron-based alloy support rod was observed with a microscope. As shown in Fig. 3, it was found that a small amount of hydrogen was generated in the local support rod, and a small number of iron-based alloy support coatings had slight bulging. At 2 years, the mass loss rate of the stent was 98%, and no hydrogen bubbles were found.
  • the surface of the pure iron bare bracket (ie pure iron matrix) with a wall thickness of 50-60 micrometers is coated with a degradable polymer coating having a thickness of 8-12 micrometers, and the mass ratio of the pure iron matrix to the degradable polymer coating is 20:1, the bottom degradable polymer in the degradable polymer coating is PLLA having a weight average molecular weight of 300,000, a thickness of about 6 to 8 micrometers, and a top layer of PDLLA having a weight average molecular weight of 30,000.
  • the polydispersity coefficient of the degraded polymer coating was 15. Drying to produce an iron-based alloy stent.
  • the iron-based alloy stent was implanted into the porcine coronary artery and followed up for 3 months.
  • the results of OCT test showed that the surrounding area of the stent rod of the iron-based alloy stent was not significantly different from that of the newly implanted; 2.5 years later, sampling was performed.
  • the mass loss test of the stent was carried out, and the mass loss rate of the stent was 98%. Samples were observed around the stent rod at the above two time points, and no hydrogen gas bubbles were found.
  • a nitriding iron bare stent ie, a nitriding iron matrix
  • a nitriding iron matrix having a wall thickness of 60 to 90 ⁇ m with a thickness of 10-15 ⁇ m, a weight average molecular weight of 400,000, and a polyhydroxybutyrate of 3 with a polydispersity factor of 3.
  • the acid ester coating is then sprayed with a mixed coating comprising polylactic acid, polyerucic acid dimer-sebacic acid and cilostazol.
  • the hybrid coating has a thickness of about 10 microns and is primarily applied to the outer and sidewalls of the nitriding iron matrix.
  • polylactic acid has a weight average molecular weight of 50,000 and a polydispersity coefficient of 1.6.
  • the polyorucic acid dimer-sebacic acid has a weight average molecular weight of 20,000 and a polydispersity coefficient of 10.
  • the mass ratio of polylactic acid to polyerucic acid dimer-sebacic acid and cilostazol is 1:1: 1.
  • the ratio of the nitriding iron matrix to the sum of the masses of the two degradable polymer coatings described above was 35:1. Drying produces an absorbable iron-based alloy stent.
  • the iron-based alloy stent was implanted into the porcine coronary artery.
  • the OCT test showed that the lumen area of the iron-based alloy stent was not significantly different from that of the newly implanted; at 1.5 years, the stent mass loss rate was 95%. At the two time points, no hydrogen bubbles were found around the stent rod.
  • the support rod of the nitriding iron bare bracket (ie, nitriding iron matrix) having a wall thickness of 220-240 micrometers is treated to form micropores and grooves, and the polybutans are relatively uniformly filled in the micropores and the grooves.
  • the acid ester had a weight average molecular weight of 150,000 and a polydispersity coefficient of 5, and the mass ratio of the nitriding iron base to the polysuccinate was 5:1. Drying produces an absorbable iron-based alloy stent.
  • the stent is implanted into the rabbit.
  • the iron-based alloy stent was taken at the corresponding observation time point for mass loss test and radial support force test. At 2 months, the radial support force was 75 kPa.
  • a small amount of bubbles were observed around the stent rod with a microscope. As shown in Fig. 4, the mass loss rate of the iron-based alloy stent was 90% at 3 years, and no stent was found. There are hydrogen
  • An iron-cobalt alloy stent comprising an iron-cobalt alloy substrate and a degradable polymer coating overlying the surface of the substrate.
  • the iron-cobalt alloy substrate has a wall thickness of between 280 and 300 micrometers
  • the degradable polymer coating is a copolymer coating formed by copolymerization of a monomer forming PLLA and PGA, and the two are formed by mass ratio.
  • the mass ratio of the monomer of the degradable polymer was 9:1, the weight average molecular weight of the copolymer was 50,000, the polydispersity coefficient was 1.1, the crystallinity was 50%, and the copolymer coating thickness was 35-45 ⁇ m.
  • the copolymer coating further contains rapamycin, the mass ratio of the two polymers to the mass of the drug is 0.1:1, and the mass ratio of the iron-cobalt alloy matrix to the copolymer coating is 25:1.
  • the iron-cobalt alloy stent was implanted into the abdominal aorta of the pig, and the radial support force was sampled at 3 months and 4.5 years, respectively, and the circumference of the stent rod was observed with a microscope. The test result is that at 3 months, the radial support force of the iron-based alloy support is 45 kPa. As shown in Fig. 5, a small amount of hydrogen bubbles are generated around the support rod. At 5 years, the mass loss rate of the support rod is 90%. There are no hydrogen bubbles around the rod.
  • the surface of the iron-carbon alloy bare stent (ie, the iron-carbon alloy substrate) is coated with a degradable polyester coating, wherein the iron-carbon alloy substrate has a wall thickness of 180-200 micrometers, and the degradable polyester coating has a thickness of 20-25 micrometers.
  • the polysuccinate and the polyglycolic acid were blended in a mass ratio of 9:1, and the blend had a weight average molecular weight of 250,000 and a polydispersity coefficient of 2.
  • Heparin may also be mixed in the degradable polyester coating, wherein the mass ratio of the degradable polyester to heparin is 20:1, and the mass ratio of the iron-carbon alloy matrix to the degradable polyester is 40:1.
  • the iron-based alloy stent was implanted into the abdominal aorta of the pig, and the radial support force was sampled at 3 and 3 years, respectively, and the circumference of the stent rod was observed with a microscope. The test results show that at 3 months, the radial support force is 75 kPa. As shown in Fig. 6, a small amount of hydrogen is generated around the stent rod. At 3 years, the mass loss rate of the stent is 95%, and there is no hydrogen bubble around the stent rod.
  • An iron-nitrogen alloy stent includes an iron-nitrogen alloy substrate and a degradable polymer coating covering the surface of the substrate.
  • the iron-nitrogen alloy substrate has a wall thickness of 90-100 micrometers
  • the degradable polymer coating layer has a thickness of 15-20 micrometers.
  • the coating is formed by physically mixing polylactic acid and polyethylene adipate in a mass ratio of 1:5, and the weight average molecular weights of polylactic acid and polyethylene adipate are 500,000 and 300,000, respectively.
  • the degradable polyester coating has a polydispersity factor of 3 and a mass ratio of the iron-nitrogen alloy substrate to the degradable polyester coating of 10:1.
  • the iron-based alloy stent was implanted into the abdominal aorta of the rabbit, and the radial support force was sampled at 3 and 3 years, respectively, and the circumference of the stent rod was observed with a microscope.
  • the test results show that the radial support force of the iron-based alloy support is 50 kPa at 3 months, and no hydrogen bubbles are generated around the support rod. At 3 years, the weight loss of the support rod is 95%, and no hydrogen bubbles are generated around the support rod.
  • An iron-palladium alloy stent comprising an iron-palladium alloy substrate and a degradable polymer coating overlying the surface of the substrate. Its
  • the iron-palladium alloy substrate has a wall thickness of between 70 and 90 microns and the degradable polyester coating has a thickness of from 10 to 15 microns.
  • the degradable polyester coating is physically mixed by polylactic acid and polyglycolic acid, the mass ratio of the two is 5:1, and the weight average molecular weights of polylactic acid and polyglycolic acid are 800,000 and 20,000, respectively.
  • the mixture had a polydispersity factor of 50 and a mass ratio of the iron-palladium alloy matrix to the degradable polyester coating of 15:1.
  • the iron-based alloy stent was implanted into the abdominal aorta of the rabbit, and the radial support force was sampled at 2 and 2 years, respectively, and the circumference of the stent rod was observed with a microscope.
  • the test results show that at 2 months, the radial support force of the stent is 80 kPa, and no hydrogen bubbles are generated around the stent rod. At 2 years, the mass loss rate of the stent is 98%, and no hydrogen bubbles are generated around the stent rod.
  • each of the absorbable iron-based alloy stents has a thickness difference in each part during preparation
  • the thickness of the coating in the above embodiments 1-16 and the wall thickness of the iron-based alloy substrate are an interval value.
  • a pure iron bare stent (pure iron matrix, ie, the surface is not covered with any coating) having a wall thickness of 60 to 70 micrometers 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 120 kPa. At 3 years, the bracket was taken out for mass loss test. At this time, the mass loss rate of the bracket was 25%, indicating that the bare pure iron stent was slow in corrosion. .
  • the mass ratio of the pure iron matrix to the polylactic acid is 10:1, and the polylactic acid is heavy.
  • the average molecular weight was 15,000 and the polydispersity coefficient was 1.8.
  • an iron-based stent was prepared and implanted into the abdominal aorta of the rabbit. After 1 month, the stent was taken out and cut along the axial direction of the stent. The circumference of the stent rod was observed with a microscope at the magnification of the foregoing embodiments. As shown in Fig.
  • the absorbable iron-based alloy stent provided by the present invention has a weight average molecular weight of [2,100] million and a polydispersity coefficient at The degradable polymer between (1.0, 50) realizes that the iron-based alloy matrix does not produce or produces only a small amount of hydrogen in the implant for 5 years, that is, oxygen absorption corrosion mainly occurs, and it is improved by oxygen corrosion.
  • the corrosion rate in the body overcomes the prior art that "the degradation of iron-based alloys can only improve the corrosion rate of iron-based alloys by hydrogen evolution corrosion, and it is difficult to increase the degradation rate of iron-based alloys by increasing the oxygen absorption corrosion rate.”
  • the technical prejudice also circumvents the risk of clinical air embolism caused by the large amount of hydrogen generated by the iron-based alloy matrix in the prior art due to hydrogen evolution corrosion.
  • the mass loss of the absorbable iron-based alloy stent of the present invention in the implant for 5 years The rate is not less than 90%, which meets the clinical requirements for the corrosion cycle of the degradable stent; at the OCT follow-up, there is no significant difference between the surrounding area of the stent and the surrounding area of the stent immediately after implantation, or the early radial support force is 23.3 kPa (175 mm).
  • Mercury column above meets the clinical requirements for early mechanical properties of stent implantation in vivo.

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Abstract

一种可吸收铁基合金支架，其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[2,100]万之间，且多分散系数在(1.0, 50]之间，所述可降解聚合物在所述铁基合金支架植入体内后降解产生羧基。该可降解支架植入人体后，以吸氧腐蚀为主，既能在早期起到力学支撑作用，又能逐渐降解，且降解过程中不会产生足以引起气栓风险的氢气量。

Description

一种可吸收铁基合金支架 技术领域
本发明属于可降解植入医疗器械领域，涉及一种可在预定时段内快速、可控降解的可吸收铁基合金器械。
背景技术
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。
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，病理检查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。但该研究同时发现，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时间要求，因此需要提高铁腐蚀速度。
各种提高铁腐蚀速度的技术已不断被开发，包括合金化、改变铁金相结构，或在铁基合金支架表面涂覆可降解聚酯类涂层。对于聚酯加快铁基材料腐蚀速度的方法，有文献揭露，可降解聚酯类涂层在人体内的降解过程中会产生带有羧基的产物，使得支架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，从而降低铁基合金基体表面析氢反应的过电位，铁基合金基体产生析氢腐蚀，生成降解产物铁盐。该文献同时指出，在铁基合金降解过程中，伴随着吸氧腐蚀和析氢腐蚀两个过程，且由于局部微酸性环境中溶液的最高吸氧腐蚀速度是定值，难以通过增大吸氧腐蚀速度来提高铁基合金腐蚀速度，即该文献认为，铁基合金降解中仅能通过析氢腐蚀提高铁基合金的腐蚀速度。另外，该文献仅提供实验数据表明铁基合金在聚酯作用下加快了腐蚀速度，未公开聚合物的分子量及分子量分布，即未揭露可降解聚合物降解与铁基合金基体腐蚀的匹配性，致使本领域技术人员无法对该聚合物进行确认，该文献也未提供任何实验数据证明该铁基合金支架植入人体后能满足临床上的早期力学性能，亦未揭露该支架的腐蚀周期，导致本领域技术人员无法知悉该支架是否满足临床上对支架的性能要求。
事实上，析氢腐蚀产生的大量氢气会在临床上会引起诸如形成气栓的组织耐受性风险，会造成支架在临床上无法使用。我们早期实验表明，在腐蚀环境中通氮去氧后，铁基合金腐 蚀速度大大降低，即在体内铁基合金并非发生如前述文献认为的析氢腐蚀。并且，如果铁的腐蚀速度过快，容易造成铁基合金支架植入后早期(如3个月)的结构不完整，难以达到临床上血管所需的径向支撑力，致使支架失去临床应用价值。反之，若聚合物对铁的腐蚀速度提升有限，会导致铁基合金腐蚀周期较长，较难满足前述临床对可降解支架的降解时间要求。因此，有必要采用特定的可降解聚合物来匹配铁基合金基体，实现铁基合金快速可控的腐蚀，进而获得可满足临床要求的可吸收铁基合金支架。
发明内容
本发明要解决的技术问题，在于针对现有技术的缺陷，提供一种可吸收铁基合金支架，该铁基合金支架植入体内后能在预定时间段内快速可控地腐蚀。
作为本发明采用的第一种技术方案，该可吸收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酯，所述可降解聚酯的重均分子量在[2，100]万之间，多分散系数在[1.2，30]之间。
作为本发明采用的第二种技术方案，该可吸收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酯，所述可降解聚酯重均分子量在[2，100]万之间，多分散系数在(1.0，1.2)或(30，50]之间。
作为本发明采用的第三种技术方案，该可吸收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，所述可降解聚合物的重均分子量在[2，100]万之间，多分散系数在(1.0，50]之间，所述可降解聚合物在所述铁基合金支架植入体内后降解产生羧基。该第三种技术方案中，所述可降解聚合物可以是可降解聚酯、还可以为可降解聚酯与可降解聚酸酐的共混物、或形成可降解聚酯与可降解聚酸酐的单体共聚后的共聚物。
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、O、S、P、Mn、Pd、Si、W、Ti、Co、Cr、Cu、Re中的至少一种，都可以掺杂入纯铁中形成所述医用铁基合金。
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。
所述快速，是指该可降解聚酯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5年内，能够完全腐蚀。
所述可控，是指该可降解聚酯对铁基合金基体的腐蚀，既能保证该铁基合金支架在植入 体内的早期有良好的力学性能，又能使得该支架在整个腐蚀过程中产生少量氢气或完全不产生氢气。少量氢气是指不足以在临床上形成气栓风险的氢气量。
所述完全腐蚀，是指铁基合金支架的质量损失率W≥90％。
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M0的铁基合金支架植入兔子腹主动脉，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一定浓度的溶液中(如1mol/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Mt。质量损失率W用腐蚀清洗后支架杆重量损失的差值占铁基合金基体的重量的百分比来表示，如公式1-1所示：
Figure PCTCN2014090107-appb-000001
(公式1-1)
W——质量损失率
Mt——腐蚀后剩余支架杆的质量
M0——铁基合金基体的质量
当支架质量损失率W≥90％时，则表明该铁基合金支架完全腐蚀。
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随访时，支架环绕面积与刚植入时支架环绕面积无明显差异，或者径向支撑力测试时，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。
与现有技术相比，本发明提供的铁基合金支架在整个腐蚀过程中完全不产生氢气，或只产生少量氢气，具体采用动物实验方式验证。例如：将铁基合金支架植入兔子腹主动脉，在预定的观察时间点，比如植入体内后1个月、3个月、6个月、2年、3年或5年，采用显微镜并在相同放大倍数下观察支架杆周围，若有少量支架杆涂层轻微隆起，则表明该支架在腐蚀时产生少量氢气，若支架杆均匀腐蚀，周围没有气泡，则表明支架在腐蚀过程中完全没有氢气产生。
前述第一至第三种技术方案中，所述可降解聚酯的重均分子量可在[2，10)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。
前述第一种技术方案中，所述可降解聚酯的多分散系数介于[1.2，2)之间，或[2，3)之间或[3，5)之间，或[5，10)之间，或[10，20)之间，或[20，30]之间。
前述第三种技术方案中，所述多分散系数介于[1.2，2)之间，或[2，3)之间或[3，5)之间，或[5，10)之间，或[10，20)之间，或[20，30)之间，或[30，50]之间。
前述第一和第二种技术方案中，所述铁基合金基体与可降解聚酯的质量比在[1，200]之间。进一步地，前述第一和第二技术方案中，所述铁基合金基体与可降解聚酯的质量比可在[5，50]之间。
前述第三种方案中，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，前述第三种方案中，所述铁基合金基体与可降解聚合物的质量比在[5，50]之间。
前述第一和第二技术方案中，所述可降解聚酯以涂层形式涂覆在所述铁基合金基体表面。前述第三种技术方案中，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。
前述第一至第三种技术方案中，所述铁基合金基体的壁厚可在[30，50)μm之间时，所述可降解聚酯涂层或可降解聚合物涂层的厚度在[3，5)μm之间，或[5，10)μm之间，或[10，15)μm之间，或[15，20]μm之间。
前述第一至第三种技术方案中，所述铁基合金基体的壁厚可在[50，100)μm之间时，所述可降解聚酯涂层或可降解聚合物涂层的厚度在[5，10)μm之间，或[10，15)μm之间，或[15，20)μm之间，或[20，25]μm之间。
前述第一至第三种技术方案中，所述铁基合金基体的壁厚在[100，200)μm之间时，所述可降解聚酯涂层或可降解聚合物涂层的厚度在[10，15)μm之间，或[15，20)μm之间，或[20，25)μm之间，或[25，35]μm之间。
前述第一至第三种技术方案中，所述铁基合金基体的壁厚在[200，300]μm之间时，所述可降解聚酯涂层或可降解聚合物涂层的厚度在[10，15)μm之间，或[15，20)μm之间，或[20，25)μm之间，或[25，35)μm之间，或[35，45]μm之间。
前述第一至第二种技术方案中，以及第三种技术方案中可降解聚合物为可降解聚酯时，所述可降解聚酯为聚乳酸、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中的任意一种。
前述第一至第二种技术方案中，以及第三种技术方案中可降解聚合物为可降解聚酯时， 所述可降解聚酯包括至少两种同类可降解聚酯类聚合物。所述同类，是指具有相同的结构单元(即单体相同)，但重均分子量不同的聚合物的统称。其中第一种可降解聚酯类聚合物的重均分子量在[2，10)万之间，第二种可降解聚酯类聚合物重均分子量在[10，100]万之间，按质量比，该第一与第二种可降解聚酯类聚合物的比例介于[1∶9，9∶1]，所述同类可降解聚酯类聚合物选自聚乳酸、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-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物。所述至少两种不同重均分子量的同类可降解聚酯类聚合物可以各自分别涂覆在支架表面，也可混合均匀后涂覆在支架表面。
进一步地，前述第一至第二种技术方案中，以及第三种技术方案中可降解聚合物为可降解聚酯时，所述第一和第二种同类可降解聚酯类聚合物的质量比介于[1∶5，5∶1]。
前述第一至第二种技术方案中，以及第三种技术方案中可降解聚合物为可降解聚酯时，所述可降解聚酯包括至少两种高分子量的可降解聚酯类聚合物，所述至少两种高分子量的可降解聚酯类聚合物的重均分子量介于[10，20)万之间，或[20，40)万之间，或[40，60)万之间，或[60，100]万之间。
前述第一至第二种技术方案中，以及第三种技术方案中可降解聚合物为可降解聚酯时，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。作为一种举例，该可降解聚酯可以包括聚乳酸(PLA)和聚乳酸乙醇酸(PLGA)，其中，PLGA重均分子量[2，30]万，PLA重均分子量[2，100]万，按质量比计，两者含量比例介于[1∶9，9∶1]。
前述第一至第二种技术方案中，以及第三种技术方案中可降解聚合物为可降解聚酯时，所述可降解聚酯为至少两种具有不同结晶度的可降解聚酯类聚合物的混合物，其中，按质量百分比计，结晶度为[5％，50％]的可降解聚酯类聚合物的含量在[10％，90％]之间，所述可降解聚酯类聚合物选自聚乳酸、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-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物。
所述至少两种具有不同结晶度的可降解聚酯类聚合物包含：所述可降解聚酯可为结晶与非结晶可降解聚酯类聚合物的混合，也可为低结晶度与高结晶度的可降解聚酯类聚合物的共 混。例如按质量百分比计，该可降解聚酯包括结晶度为5-50％的聚乳酸，且聚乳酸的含量在10％-90％之间。优选地，上述聚乳酸可以是聚消旋乳酸或聚左旋乳酸。
前述第三种技术方案中，当所述可降解聚合物为可降解聚酯与可降解聚酸酐的共混物，或者为形成可降解聚酯与可降解聚酸酐的单体共聚而成的可降解共聚物时，所述可降解聚酯和所述可降解聚酸酐的重均分子量皆在[2，100]万之间，多分散系数皆在(1.0，50]之间，所述聚酸酐选自聚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；所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、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中的任一种，按质量比计，所述可降解聚酯与所述聚酸酐的比例介于[1∶9，9∶1]。
前述第三种技术方案中，所述可降解聚酯与可降解聚酸酐的共混物中，按质量百分比计，结晶度为[5％，50％]的可降解聚酯或可降解聚酸酐的含量在[10％，90％]之间，所述可降解聚酯类聚合物选自聚乳酸、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-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物，所述聚酸酐选自聚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。
前述第一至第三种技术方案中，所述可降解聚酯或可降解聚合物还可以非涂层形式与所述铁基合金基体表面接触，比如所述铁基合金基体设有缝隙或凹槽，所述可降解聚酯或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，所述可降解聚酯或可降解聚合物填充在所述内腔内。上述举例的非涂层接触方式与涂层形式中至少可选择一种。即，前述第一至第三种方案中，所述“与该基体表面接触”中的“表面”，不仅仅指外表面，只要是所述可降解聚酯或可降解聚合物与所述铁基合金基体有接触点或接触面即可。
前述第一至第三种技术方案中，所述可降解聚酯或所述可降解聚合物中还可混有活性药物，所述可降解聚酯或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(Cilostazol)，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，所述可降解聚酯或所述可降解聚合物与药物的质量比在[0.5，10]之间。
与现有技术相比，本发明提供的可吸收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吸氧腐蚀，产生少量或完全不产生氢气，既可规避现有技术因析氢腐蚀产生的大量氢气带来的临床气栓风险，又能满足临床上对支架早期 的力学性能要求
附图说明
图1是本发明实施例5提供的铁基合金支架涂覆可降解聚酯涂层后支架杆截面示意图；
图2是本发明实施例7中支架杆产生少量氢气的显微镜图片。
图3是本发明实施例9中支架杆产生少量氢气的显微镜图片。
图4是本发明实施例12中支架杆产生少量氢气的显微镜图片。
图5是本发明实施例13中支架杆产生少量氢气的显微镜图片。
图6是本发明实施例14中支架杆产生少量氢气的显微镜图片。
图7是对比例2中支架杆腐蚀过程中产生大量氢气的显微镜图片。
具体实施方式
需要说明的是，本发明提供的可吸收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可控的腐蚀，主要通过早期的力学性能和在预定观察时间点是否产生大量氢气来判断铁基合金支架是否可控地腐蚀，通过质量损失测试来判断该铁基支架是否快速腐蚀。
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，在预定的观察时间点，分别进行测试。例如，植入体内3个月时OCT随访测试，支架杆的环绕面积与刚植入时，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年时取出支架样品测量支架质量损失，来观察支架腐蚀情况，且在各取样时间点沿轴向剖开支架，采用显微镜并在相同放大倍数下观察支架杆周围，来判断支架腐蚀过程中是否产生大量氢气。
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，包括在预定观察时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。
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M0的铁基合金支架植入兔子腹主动脉，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一定浓度的溶液中(如1mol/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Mt。质量损 失率W用腐蚀清洗后支架杆重量损失的差值占铁基合金基体的重量的百分比来表示，如公式1-1所示：
Figure PCTCN2014090107-appb-000002
(公式1-1)
W——质量损失率
Mt——腐蚀后剩余支架杆的质量
M0——铁基合金基体的质量
当支架质量损失率W≥90％时，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。
以下结合附图和实施例对本发明提供的可吸收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。
实施例1
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5∶1。所述可降解聚合物为聚乙醇酸，重均分子量为20万，多分散系数为1.8，且铁基体的壁厚为80～90μm，可降解聚合物涂层厚度为15～20μm。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，表明该可降解聚合物与铁基合金基体匹配良好，能够保证支架早期力学性能，用显微镜观察支架杆周围，未发现氢气泡。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，用显微镜观察支架杆周围，发现无氢气泡产生。
实施例2
在壁厚为65～75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10～12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的聚消旋乳酸涂层，干燥，制得可吸收铁基合金支架。将该铁基合金支架植入猪冠脉。3个月时，OCT随访发现支架杆环绕面积与刚植入时无明显差异，1年时取出支架，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。在3个月和1年时取出支架分别用显微镜观察支架杆周围，均没有氢气泡产生。
实施例3
将壁厚为40～50微米的电沉积纯铁(550℃退火)裸支架(即电沉积纯铁基体)表面均匀全涂覆3～5微米厚的聚己内酯(PCL)与紫杉醇的混合物涂层。其中电沉积纯铁基体与可降解聚合物质量比为35∶1，该聚己内酯由重均分子量为3万和重均分子量为8万的两种聚己内酯按质量比1∶2混合而成，混合后的聚己内酯多分散系数为25，聚己内酯与紫杉醇的质量比例均为2∶1。干燥后，制得可吸收铁基合金支架。将该铁基合金支架植入兔子腹主动脉，在相应观察时间点取出支架，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，在该两个取样时间点用显微镜观察支架杆周围均没有氢气泡形成。
实施例4
在热处理后的渗碳铁裸支架(即渗碳铁基体)外壁表面涂覆聚左旋乳酸涂层，渗碳铁基体的壁厚为140～160微米，该聚左旋乳酸涂层厚度为30～35微米，且渗碳铁基体与聚左旋乳酸质量比为120。该涂层分为两层，底层为结晶度50％的PLLA，顶层为结晶度5％的PLLA涂层，该两层聚左旋乳酸的重均分子量均为60万，多分散系数为1.2。该两种结晶度的可降解聚合物涂层质量比为1∶1。干燥，制得可吸收铁基合金支架。将支架植入兔子腹主动脉，相应观察时间点取出支架，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45kPa，3年后该支架质量损失率为92％，在上述两个取样时间点的支架杆周围均没有氢气泡产生。
实施例5
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内均匀涂覆可降解聚酯类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100万的聚左旋乳酸和重均分子量为2万聚乳酸乙醇酸(乳酸与乙醇酸的摩尔比为50∶50)按质量比5∶1混合而成，混合后的聚乳酸多分散系数为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，制得可吸收铁基合金支架。将支架植入猪冠脉，相应观察时间点取出支架，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，2年后质量损失测试，该支架质量损失率为95％，在上述两个取样时间点观察支架杆周围，没有氢气泡产生。
实施例6
在厚度为30～40微米的铁碳合金裸支架(即铁碳合金基体)外表面(不包括支架管腔内 壁)均匀涂覆厚度为5～8微米的聚丁二酸酯涂层，铁碳合金基体与聚丁二酸酯质量之比为12∶1，聚丁二酸酯重均分子量为6万，多分散系数为2，干燥，制得可吸收铁基合金支架。将该支架植入兔子腹主动脉，在相应观察时间点取出支架，对支架进行质量损失测试和径向支撑力测试。结果为，1个月时支架径向支撑力为50kPa，1.5年后支架质量损失率为99％，在上述两个取样时间点用显微镜观察支架周围均未发现有氢气泡产生。
实施例7
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，渗硫铁基合金基体与可降解聚合物质量比为50∶1，该可降解聚合物由聚乳酸和PLGA共混而成，其中聚乳酸重均分子量为30万，结晶度为40％，含量为90％，多分散系数为1.8，PLGA重均分子量为3万，多分散系数为4，结晶度为5％，含量为10％。干燥，制得可吸收铁基合金支架。将支架植入猪腹主动脉，在相应观察时间点取出支架，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，用显微镜观察铁基合金支架杆周围，如图2所示，发现少量支架杆周围有轻微鼓包，即有少量氢气产生；4.5年后支架质量损失率为90％，没有发现有氢气气泡。
实施例8
在壁厚为120～150微米的铁锰合金裸支架(即铁锰合金基体)表面涂覆厚度为15～20微米的涂层。该涂层由聚(β-羟基丁酸酯)、聚富马酸-癸二酸、肝素三者以质量比8∶1∶1混合而成，其中，铁基合金基体与可降解聚合物即聚(β-羟基丁酸酯)与聚富马酸-癸二酸质量之和的质量比为80，PLLA重均分子量为30万，结晶度为30％，多分散系数为2，PLGA重均分子量为10万，多分散系数为45。干燥，制得可吸收铁基合金支架。将支架植入兔子腹主动脉，在相应观察时间点取出铁基合金支架，对铁基合金支架进行径向支撑力测试和质量损失测试。结果为，3个月铁基合金支架径向支撑力为60kPa，3年后支架质量损失率为95％，用显微镜观察支架杆周围，在两个时间点均未发现有氢气气泡产生。
实施例9
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12～15微米的可降解聚合物涂层，该可降解聚合物涂层由聚消旋乳酸(PDLLA)和雷帕霉素按质量比2∶1混合而成，其中PDLLA重均分子量为20万，多分散系数为1.6，渗碳铁基体与该可降解聚合物涂层的质量比为30。干燥，制得可吸收铁基合金支架。将所述铁基合金支架植入猪冠脉，在相应观察时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，用显微镜观察铁基合金支架杆周围，如图3所示，发现局部支架杆有少量氢气产生，少数铁基合金支架涂层有轻微隆起。在2年时支架质量损失率为98％，没有发现氢气气泡。
实施例10
在壁厚为50～60微米的纯铁裸支架(即纯铁基体)表面涂覆厚度为8～12微米的可降解聚合物涂层，纯铁基体与可降解聚合物涂层的质量比为20∶1，所述可降解聚合物涂层中底层可降解聚合物为重均分子量为30万的PLLA，厚度约为6～8微米，顶层为重均分子量为3万的PDLLA，所述可降解聚合物涂层的多分散系数为15。干燥，制得铁基合金支架。将该铁基合金支架植入猪冠脉中，植入3个月后随访，OCT检测结果显示铁基合金支架所在的支架杆环绕面积与刚植入时无明显差异；2.5年后，取样进行支架质量损失测试，支架质量损失率为98％，在前述两个时间点取样观察支架杆周围，发现无氢气气泡产生。
实施例11
在壁厚为60～90微米的渗氮铁裸支架(即渗氮铁基体)表面涂覆厚度为10-15微米，重均分子量为40万，多分散系数为3的聚羟基丁酸酯戊酸酯涂层，然后再喷涂包括聚乳酸、聚芥酸二聚体-癸二酸和西洛他唑的混合涂层。该混合涂层的厚度约为10微米，主要喷涂在渗氮铁基体的外壁和侧壁。其中，聚乳酸的重均分子量为5万，多分散系数为1.6。聚芥酸二聚体-癸二酸的重均分子量为2万，多分散系数为10，聚乳酸与聚芥酸二聚体-癸二酸和西洛他唑的质量比为1∶1∶1。渗氮铁基体与前述两可降解聚合物涂层质量之和的比例为35∶1。干燥，制得可吸收铁基合金支架。将该铁基合金支架植入猪冠脉，3个月随访，OCT检测结果显示铁基合金支架所在的管腔面积与刚植入时无明显差异；1.5年时，支架质量损失率为95％，在两个时间点取样均未发现支架杆周围有氢气泡产生。
实施例12
对壁厚为220-240微米的渗氮铁裸支架(即渗氮铁基体)的支架杆进行处理，使之形成微孔和凹槽，在微孔和凹槽中相对均匀的填充聚丁二酸酯，其重均分子量为15万，多分散系数为5，所述渗氮铁基体与聚丁二酸酯的质量比为5∶1。干燥，制得可吸收铁基合金支架。将支架植入兔子体内。在相应观察时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。2个月时，径向支撑力为75kPa，用显微镜观察支架杆周围，发现有少量气泡产生，如图4所示，3年时，该铁基合金支架质量损失率为90％，未发现支架杆周围有氢气泡存在。
实施例13
一种铁钴合金支架，包括铁钴合金基体和覆盖在所述基体表面的可降解聚合物涂层。其中，所述铁钴合金基体的壁厚在280-300微米之间，该可降解聚合物涂层为形成PLLA与PGA的单体共聚形成的共聚物涂层，按质量比计，形成该两种可降解聚合物的单体的质量比为9∶1，该共聚物重均分子量为5万，多分散系数为1.1，结晶度为50％，该共聚物涂层厚度为35-45微米。该共聚物涂层中还含有雷帕霉素，该两种聚合物质量之和与药物的质量比为0.1∶1，铁钴合金基体与该共聚物涂层的质量比为25∶1。将该铁钴合金支架植入猪腹主动脉，分别在3个月、4.5年取样测试径向支撑力和用显微镜观察支架杆周围。测试结果为，在3个月时，铁基合金支架径向支撑力为45kPa，如图5所示，支架杆周围有少量氢气泡产生，5年时，支架杆质量损失率为90％，支架杆周围无氢气泡。
实施例14
在铁碳合金裸支架(即铁碳合金基体)表面涂覆可降解聚酯涂层，其中铁碳合金基体的壁厚为180-200微米，可降解聚酯涂层厚度为20-25微米，由聚丁二酸酯与聚乙醇酸以9∶1的质量比共混而成，共混物重均分子量为25万，多分散系数为2。该可降解聚酯涂层中还可混有肝素，其中该可降解聚酯与肝素的质量比为20∶1，铁碳合金基体与可降解聚酯的质量比为40∶1。干燥，制得可吸收铁基合金支架。将该铁基合金支架植入猪腹主动脉，分别在3个月和3年取样测试径向支撑力和用显微镜观察支架杆周围。测试结果表明，3个月时，径向支撑力为75kPa，如图6所示，支架杆周围有少量氢气产生，3年时，支架质量损失率为95％，支架杆周围无氢气气泡。
实施例15
一种铁氮合金支架，包括铁氮合金基体和覆盖在所述基体表面的可降解聚合物涂层。其中，铁氮合金基体的壁厚为90-100微米，可降解聚合物涂层厚度为15-20微米。所述涂层由聚乳酸与聚己二酸乙二醇酯按质量比1∶5物理混合而成，聚乳酸与聚己二酸乙二醇酯的重均分子量分别为50万和30万，该可降解聚酯涂层的多分散系数为3，铁氮合金基体与可降解聚酯涂层的质量比为10∶1。将该铁基合金支架植入兔子腹主动脉，在3个月和3年时分别取样测试径向支撑力和用显微镜观察支架杆周围。测试结果表明，3个月时铁基合金支架径向支撑力为50kPa，在支架杆周围无氢气气泡产生，3年时，支架杆重量损失为95％，在支架杆周围无氢气气泡产生。
实施例16
一种铁钯合金支架，包括铁钯合金基体和覆盖在所述基体表面的可降解聚合物涂层。其 中，铁钯合金基体的壁厚在70-90微米之间，可降解聚酯涂层厚度为10-15微米。该可降解聚酯涂层由聚乳酸和聚乙醇酸物理混合而成，两者质量比为5∶1，聚乳酸和聚乙醇酸的重均分子量分别为80万和2万。该混合物的多分散系数为50，铁钯合金基体与可降解聚酯涂层的质量比为15∶1。将该铁基合金支架植入兔子腹主动脉，在2个月和2年时分别取样测试径向支撑力和用显微镜观察支架杆周围。测试结果表明，在2个月时，支架径向支撑力为80kPa，支架杆周围无氢气泡产生，在2年时，支架质量损失率为98％，支架杆周围无氢气泡产生。
特别说明的是，由于每个可吸收铁基合金支架在制备过程中，各部分会出现厚度差异，因此上述实施例1-16中涂层厚度和铁基合金基体的壁厚为一区间值，各实施例中显微镜以相同放大倍数观察各支架周围在所述预定的观察时间点是否有产生氢气泡。
对比例1
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120kPa，3年时取出支架进行质量损失测试，此时支架质量损失率为25％，说明裸的纯铁支架腐蚀速度慢。
对比例2
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。1个月后，取出支架，沿支架轴向剖开，用显微镜以同于前述各实施例的放大倍数观察支架杆周围，如图7所示，发现支架杆在腐蚀过程中有大量氢气产生，形成较多体积较大的氢气鼓包，表明有较大气栓形成风险。3个月时，径向支撑力测试结果为20kPa，6个月时，支架质量损失测试表明，支架质量损失率为100％，说明该支架已经完全腐蚀，且腐蚀过快，没有在预期时间点满足临床所需的力学性能。
从以上实施例1-16和对比实施例1-2的试验结果可以看出，本发明提供的可吸收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，实现了铁基合金基体在植入体内5年内完全不产生或仅产生少量氢气，即主要发生吸氧腐蚀，且其通过吸氧腐蚀的方式提高了在体内的腐蚀速度，既克服了现有技术认为的“铁基合金降解中仅能通过析氢腐蚀提高铁基合金的腐蚀速度，难以通过增大吸氧腐蚀速度来提高铁基合金降解速度”的技术偏见，又规避了现有技术中铁基合金基体因析氢腐蚀在体内产生大量氢气带来的临床气栓风险。另外，本发明的可吸收铁基合金支架在植入体内5年内的质量损失 率不小于90％，满足临床上对可降解支架腐蚀周期的要求；在OCT随访时，支架环绕面积与刚植入时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 (43)

  1. 一种可吸收铁基合金支架，包括铁基合金基体和与该基体表面接触的可降解聚酯，其特征在于，所述可降解聚酯重均分子量在[2，100]万之间，且多分散系数在[1.2，30]之间。
  2. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯的重均分子量在[2，10)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。
  3. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述多分散系数在[1.2，2)之间，或[2，3)之间，或[3，5)之间，或[5，10)之间，或[10，20)之间，或[20，30]之间。
  4. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体与所述可降解聚酯的质量比在[1，200]之间。
  5. 如权利要求4所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体与所述可降解聚酯的质量比在[5，50]之间。
  6. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯以涂层形式涂覆于所述铁基合金基体表面；
    或/和所述铁基合金基体设有缝隙或凹槽，所述可降解聚酯设于所述缝隙或凹槽中；
    或/和所述铁基合金基体具有内腔，所述可降解聚酯填充在所述内腔内。
  7. 如权利要求6所述的可吸收铁基合金支架，其特征在于，在所述可降解聚酯以涂层形式涂覆于所述铁基合金基体表面时，所述铁基合金基体的壁厚在[30，50)μm之间，所述可降解聚酯涂层的厚度在[3，5)μm之间，或[5，10)μm之间，或[10，15)μm之间，或[15，20]μm之间；
    或者所述铁基合金基体的壁厚在[50，100)μm之间，所述可降解聚酯涂层的厚度在[5，10)μm之间，或[10，15)μm之间，或[15，20)μm之间，或[20，25]μm之间；
    或者所述铁基合金基体的壁厚在[100，200)μm之间，所述可降解聚酯涂层的厚度在[10，15)μm之间，或[15，20)μm之间，或[20，25)μm之间，或[25，35]μm之间；
    或者所述铁基合金基体的壁厚在[200，300]μm之间，所述可降解聚酯涂层的厚度在[10，15)μm之间，或[15，20)μm之间，或[20，25)μm之间，或[25，35)μm之间，或[35，45]μm之间。
  8. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、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中的任一种。
  9. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯包括至少两种同类可降解聚酯类聚合物，其中第一种可降解聚酯类聚合物的重均分子量在[2，10)万之间，第二种可降解聚酯类聚合物分子量在[10，100]万之间，按质量比计，该第一种可降解聚酯类聚合物和第二种可降解聚酯类聚合物的比例介于[1∶9，9∶1]之间，所述同类可降解聚酯类聚合物选自聚乳酸、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、聚羟基丁酸酯戊酸酯共聚物中的任一种。
  10. 如权利要求9所述的可吸收铁基合金支架，其特征在于，按质量比计，所述第一种可降解聚酯类聚合物和第二种可降解聚酯类聚合物的比例介于[1∶5，5∶1]之间。
  11. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯包括至少两种高分子量的可降解聚酯类聚合物，所述至少两种高分子量的可降解聚酯类聚合物的重均分子量介于[10，20)万之间，或[20，40)万之间，或[40，60)万之间，或[60，100]万之间。
  12. 如权利要求1所述的可吸收铁基合金支架，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。
  13. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯为至少两种具有不同结晶度的可降解聚酯类聚合物的混合物，其中，按质量百分比计，结晶度为[5％，50％]的可降解聚酯类聚合物的含量在[10％，90％]之间，所述可降解聚酯类聚合物选自聚乳酸、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-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物。
  14. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯中混有活性药物，所述可降解聚酯与药物的质量比在[0.1，20]之间。
  15. 如权利要求14所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯与药物的质量比在[0.5，10]之间。
  16. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体材质选自纯铁中掺杂有C、N、O、S、P中至少一种形成的铁基合金。
  17. 如权利要求1所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体材质选自纯 铁或在纯铁中掺杂有Mn、Pd、Si、W、Ti、Co、Cr、Cu、Re中至少一种形成的铁基合金。
  18. 一种可吸收铁基合金支架，包括铁基合金基体和与该基体表面接触的可降解聚酯，其特征在于，所述可降解聚酯重均分子量在[2，100]万之间，且多分散系数在(1.0，1.2)或(30，50]之间。
  19. 如权利要求18所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯的重均分子量在[2，10)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。
  20. 如权利要求18所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体与可降解聚酯的质量比在[1，200]之间。
  21. 如权利要求20所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体与可降解聚酯的质量比在[5，50]之间。
  22. 如权利要求18所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯以涂层形式涂覆于所述铁基合金基体表面；
    或/和所述铁基合金基体设有缝隙或凹槽，所述可降解聚酯设于所述缝隙或凹槽中；
    或/和所述铁基合金基体具有内腔，所述可降解聚酯填充在所述内腔内。
  23. 如权利要求22所述的可吸收铁基合金支架，其特征在于，在所述可降解聚酯以涂层形式涂覆于所述铁基合金基体表面时，所述铁基合金基体的壁厚在[30，50)μm之间，所述可降解聚酯涂层的厚度在[3，5)μm之间，或[5，10)μm之间，或[10，15)μm之间，或[15，20]μm之间；
    或者所述铁基合金基体的壁厚在[50，100)μm之间，所述可降解聚酯涂层的厚度在[5，10)μm之间，或[10，15)μm之间，或[15，20)μm之间，或[20，25]μm之间；
    或者所述铁基合金基体的壁厚在[100，200)μm之间，所述可降解聚酯涂层的厚度在[10，15)μm之间，或[15，20)μm之间，或[20，25)μm之间，或[25，35]μm之间；
    或者所述铁基合金基体的壁厚在[200，300]μm之间，所述可降解聚酯涂层的厚度在[10，15)μm之间，或[15，20)μm之间，或[20，25)μm之间，或[25，35)μm之间，或[35，45]μm之间。
  24. 如权利要求18所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、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中的任一种；
    或者所述可降解聚酯包括至少两种同类可降解聚酯类聚合物，其中第一种可降解聚酯类聚合物的重均分子量在[2，10)万之间，第二种可降解聚酯类聚合物重均分子量在[10，100]万之间，按质量比计，该第一种可降解聚酯类聚合物和第二种可降解聚酯类聚合物的比例介于[1∶9，9∶1]之间，所述同类可降解聚酯类聚合物选自聚乳酸、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-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物；
    或者所述可降解聚酯包括至少两种高分子量的可降解聚酯类聚合物，所述至少两种高分子量的可降解聚酯类聚合物的重均分子量介于[10，20)万之间，或[20，40)万之间，或[40，60)万之间，或[60，100]万之间；
    或者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-乙醇酸共聚物或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；
    或者所述可降解聚酯为至少两种具有不同结晶度的可降解聚酯类聚合物的混合物，其中，按质量百分比计，结晶度为[5％，50％]的可降解聚酯类聚合物的含量在[10％，90％]之间，所述可降解聚酯类聚合物选自聚乳酸、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-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物。
  25. 如权利要求24所述的可吸收铁基合金支架，其特征在于，在所述可降解聚酯包括至少两种同类可降解聚酯类聚合物时，所述第一种可降解聚酯类聚合物和第二种可降解聚酯类聚合物的质量比介于[1∶5，5∶1]之间。
  26. 如权利要求18所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯中混有活性药物，所述可降解聚酯与药物的质量比在[0.1，20]之间。
  27. 如权利要求26所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯与药物的质量比在[0.5，10]之间。
  28. 如权利要求18所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体材质选自纯铁或在纯铁中掺杂有C、N、O、S、P、Mn、Pd、Si、W、Ti、Co、Cr、Cu、Re中至少一种形成的铁基合金。
  29. 一种可吸收铁基合金支架，包括铁基合金基体和与该基体表面接触的可降解聚合物，其 特征在于，所述可降解聚合物的重均分子量在[2，100]万之间，多分散系数在(1.0，50]之间，且所述可降解聚合物在所述铁基合金基体植入体内后降解产生羧基。
  30. 如权利要求29所述的可吸收铁基合金支架，其特征在于，所述可降解聚合物为可降解聚酯；
    或者所述可降解聚合物为可降解聚酯与可降解聚酸酐的共混物；
    或者所述可降解聚合物为形成可降解聚酯与可降解聚酸酐的单体共聚而成的可降解共聚物，所述可降解聚酯和所述可降解聚酸酐的重均分子量皆在[2，100]万之间，多分散系数皆在(1.0，50]之间。
  31. 如权利要求30所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯和所述可降解聚酸酐的多分散系数皆介于[1.2，2)之间，或[2，3)之间或[3，5)之间，或[5，10)之间，或[10，20)之间，或[20，30)之间，或[30，50]之间。
  32. 如权利要求30所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体与可降解聚合物的质量比在[1，200]之间。
  33. 如权利要求32所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体与可降解聚合物的质量比在[5，50]之间。
  34. 如权利要求30所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯的重均分子量在[2，10)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。
  35. 如权利要求29所述的可吸收铁基合金支架，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/和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/和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。
  36. 如权利要求35所述的可吸收铁基合金支架，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时，所述铁基合金基体的壁厚在[30，50)μm之间，所述可降解聚合物的涂层厚度在[3，5)μm之间，或[5，10)μm之间，或[10，15)μm之间，或[15，20]μm之间；
    或者所述铁基合金基体的壁厚在[50，100)μm之间，所述可降解聚合物的涂层厚度在[5，10)μm之间，或[10，15)μm之间，或[15，20)μm之间，或[20，25]μm之间；
    或者所述铁基合金基体的壁厚在[100，200)μm之间，所述可降解聚合物的涂层厚度在[10， 15)μm之间，或[15，20)μm之间，或[20，25)μm之间，或[25，35]μm之间；
    或者所述铁基合金基体的壁厚在[200，300]μm之间，所述可降解聚合物的涂层厚度在[10，15)μm之间，或[15，20)μm之间，或[20，25)μm之间，或[25，35)μm之间，或[35，45]μm之间。
  37. 如权利要求30所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、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中的任一种；
    或者所述可降解聚酯包括至少两种同类可降解聚酯类聚合物，其中第一种可降解聚酯类聚合物的重均分子量在[2，10)万之间，第二种可降解聚酯类聚合物重均分子量在[10，100]万之间，按质量比计，该第一种可降解聚酯类聚合物和第二种可降解聚酯类聚合物的比例介于[1∶9，9∶1]之间，所述同类可降解聚酯类聚合物选自聚乳酸、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任一种；
    或者所述可降解聚酯包括至少两种高分子量的可降解聚酯类聚合物，所述至少两种高分子量的可降解聚酯类聚合物的重均分子量介于[10，20)万之间，或[20，40)万之间，或[40，60)万之间，或[60，100]万之间；
    或者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；
    或者所述可降解聚酯为至少两种具有不同结晶度的可降解聚酯类聚合物的混合物，其中，按质量百分比计，结晶度为[5％，50％]的可降解聚酯类聚合物的含量在[10％，90％]之间，所述可降解聚酯类聚合物选自聚乳酸、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-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物。
  38. 如权利要求37所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯包括至少两种同类可降解聚酯类聚合物时，所述第一种可降解聚酯类聚合物和第二种可降解聚酯类聚合物的质量比介于[1∶5，5∶1]之间。
  39. 如权利要求30所述的可吸收铁基合金支架，其特征在于，所述聚酸酐选自聚1，3-双(对 羧基苯氧基)丙烷-癸二酸、聚芥酸二聚体-癸二酸和聚富马酸-癸二酸中的任一种，所述可降解聚酯选自聚乳酸、聚乙醇酸、聚丁二酸酯、聚(β-羟基丁酸酯)、聚已内酯、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中的任一种，按质量比，所述可降解聚酯与所述聚酸酐的比例介于[1∶9，9∶1]。
  40. 如权利要求30所述的可吸收铁基合金支架，其特征在于，所述可降解聚酯与可降解聚酸酐的共混物中，按质量百分比计，结晶度为[5％，50％]的可降解聚酯或可降解聚酸酐的含量在[10％，90％]之间，所述可降解聚酯类聚合物选自聚乳酸、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-乙醇酸共聚物或聚羟基丁酸酯戊酸酯共聚物，所述聚酸酐选自聚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。
  41. 如权利要求29所述的可吸收铁基合金支架，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[0.1，20]之间。
  42. 如权利要求41所述的可吸收铁基合金支架，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。
  43. 如权利要求29所述的可吸收铁基合金支架，其特征在于，所述铁基合金基体材质选自纯铁或在纯铁中掺杂有C、N、O、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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KR20160094375A (ko) 2016-08-09
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AU2014344307A1 (en) 2016-06-02
EP3064233A1 (en) 2016-09-07
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US20160279303A1 (en) 2016-09-29
US20160263287A1 (en) 2016-09-15
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AU2014344308B2 (en) 2018-07-12
EP3064232A4 (en) 2017-07-19
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US10058639B2 (en) 2018-08-28
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