WO2024022532A1 - 一种医疗器械用涂层 - Google Patents

一种医疗器械用涂层 Download PDF

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Publication number
WO2024022532A1
WO2024022532A1 PCT/CN2023/110241 CN2023110241W WO2024022532A1 WO 2024022532 A1 WO2024022532 A1 WO 2024022532A1 CN 2023110241 W CN2023110241 W CN 2023110241W WO 2024022532 A1 WO2024022532 A1 WO 2024022532A1
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Prior art keywords
drug
layer
coating
polymer
loaded
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PCT/CN2023/110241
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English (en)
French (fr)
Inventor
李云飞
张德元
齐海萍
张万谦
李海锋
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元心科技(深圳)有限公司
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Priority to CN202380009885.9A priority Critical patent/CN117794587A/zh
Publication of WO2024022532A1 publication Critical patent/WO2024022532A1/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
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials

Definitions

  • the invention belongs to the technical field of medical devices, and specifically relates to a coating for medical devices, and more specifically to a degradable coating for medical devices.
  • Medical devices especially implantable or interventional medical devices, are not only required to have basic therapeutic functions, but also have to be loaded with drugs on their surfaces to prevent rejection, proliferation, thrombosis, inflammation and other reactions at the implantation site. Therefore, currently common medical devices usually add some coatings on their surfaces to load drugs or control drug release.
  • Such as vascular stents after being implanted in blood vessels, they must not only expand the blood vessels and have sufficient support for a certain period of time to ensure that the blood vessels remain open, but also prevent blood vessel proliferation, prevent thrombosis at the implantation site, and later restenosis and other problems. Therefore, vascular stents currently on the market usually add one or more layers of coatings to the surface to load drugs and control drug release to prevent some abnormal reactions after the stent is implanted in the human body, affecting its basic therapeutic effect.
  • the coating on the surface of the device has very strict requirements in terms of drug loading and drug release. It is necessary to control both the drug load and the drug release rate. If the drug load is too large, too much drug will be absorbed by the human body. It will bring greater toxic side effects and increase the risk of drug toxicity in the body. If the dose is too small, it will not have a good preventive and therapeutic effect. When the total dose of the medical device is constant, if the drug release rate is too slow, the drug will be insufficient throughout the drug release stage, and the drug's preventive and therapeutic effect will be limited. If the drug release rate is too fast, too high a local drug concentration will produce toxic side effects, and the drug will cause side effects in the initial stage.
  • patent CN107496996B discloses a drug coating for a vascular stent.
  • the coating includes three layers, each layer containing drugs and drug carriers.
  • the outer coating plays a role in controlling the release of the inner coating, so that The burst release of the drug in the inner layer becomes smaller, reducing the possibility of acute toxic reactions.
  • the outer layer of the drug coating is also loaded with two kinds of drugs, and the molecular weight of the drug-loaded PLGA is relatively small, only about 2000.
  • the mass fraction ratio of rapamycin, curcumin and PLGA carrier loaded in the outer coating is 5:2:13.
  • the molecular weight of the polymer in the outer coating is small, the proportion of polymer is low, and the drug A large proportion.
  • the entire coating design does not have a good sustained release effect on the drug in the outer layer, and a large amount of rapamycin loaded in the outer layer will also cause burst release; both the middle layer and the outer layer are loaded with a large amount of rapamycin, It may cause the drug loading amount to significantly exceed the demand and produce additional toxic side effects on the human body; in addition, the base material of the vascular stent is stainless steel, so the design of the drug coating in the patent application does not need to consider the degradation of the matrix. Therefore, its The polymer used is a small molecular weight polymer and is not suitable for medical devices with degradable substrates.
  • this application provides a coating for medical devices, especially a coating for degradable medical devices.
  • this coating ensures that the loading amount of the drug is within an appropriate effective range. , which makes the coating have very excellent performance in controlled drug release, and can also effectively control the corrosion of the matrix.
  • the technical solution of the present invention provides a coating for medical devices.
  • the coating has very excellent performance in controlling drug release.
  • the preparation process of the coating and the process of preparing the coating are improved.
  • the solvents used, as well as the crystal form and size of the drug in the final coating, are more inclusive.
  • the coating includes a drug-loaded layer and a drug-controlled release layer covering the drug-loaded layer. Both the drug-loaded layer and the drug-controlled release layer contain polymers.
  • the drug-controlled release layer medium polymer The molecular weight retention rate m, the weight average molecular weight Mw of the polymer for controlled release and the thickness of the polymer X for controlled release satisfy the following relationship:
  • a 1 is the fitting constant, which is 823;
  • a 2 is the fitting constant, which is 79.9;
  • k is the fitting constant, which is 1.5;
  • b is the fitting constant, ranging from 0 ⁇ b ⁇ 2;
  • the Mw controlled release is the weight average molecular weight of the polymer in the drug controlled release layer, the unit is kilodaltons, and the unit of X is ⁇ m.
  • b in the above technical solution formula can be any value within the range of 0-2.
  • b can be 0.2, 0.5, 0.55, 0.6, 0.65, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.85, 1.9, 1.95 or 2.0.
  • b can be It is an interval composed of any two values in the range of 0-2, such as 0.2-1.9, 0.5-1.5, 0.3-1.6, 0.3-1.2, 0.55-1.95, 0.6-1.95, 0.6-1.9, 0.6-1.85, 0.6 -1.8, 0.6-1.7, 0.7-1.8, 0.75-1.6, 0.8-1.95, 0.8-1.9, 0.8-1.85, 0.8-1.8, 0.8-1.7 or 0.8-1.6 etc.
  • the present invention finds out the inherent correlation or regularity among the three variables of the outer drug controlled release layer: coating thickness, polymer type and polymer molecular weight, and determines the specific properties of the outer drug controlled release layer.
  • coating thickness Depending on the polymer and the molecular weight of a specific polymer, there must be a relatively optimal polymer thickness range corresponding to it. Within this optimal polymer thickness range, the performance of the coating in drug release can be greatly improved.
  • the present invention innovatively summarizes the relationship between the optimal thickness range of the drug-controlled release layer and the type of polymer and the molecular weight of the polymer through a large number of experimental results.
  • this application has correspondingly relaxed the requirements on the process of the drug in the drug coating, the solvent used, and the final drug crystal form, and enabled the release of the drug.
  • the rate and curve basically meet the requirements of the corresponding medical devices.
  • the above-mentioned medical device coating provided by the present invention is a relatively universal drug coating.
  • the coating is suitable for both degradable medical devices and controlled release of drugs in non-degradable medical devices.
  • the above coating is suitable for biodegradable medical devices.
  • the weight average molecular weight Mw of the polymer in the drug controlled release layer for controlled release is 20-900 kDa.
  • the molecular weight of the polymer in the drug controlled release layer of the technical solution of the present invention can be any value from 20 to 900 kDa.
  • the molecular weight of the polymer in the drug controlled release layer is 21 kDa; in other embodiments, the drug controlled release layer has a molecular weight of 21 kDa.
  • the molecular weight of the release layer polymer is 898 kDa; in some other embodiments, the molecular weight of the drug controlled release layer polymer is 800 kDa; in still other embodiments, the molecular weight of the drug controlled release layer polymer is 700 kDa.
  • the molecular weight retention rate m of the drug controlled release layer polymer is 50%-80%.
  • each polymer has different molecular weight retention rates at the same time point under the same conditions. That is, in this application, each molecular weight retention rate represents a specific polymer, and different molecular weight retention rates represent different polymers.
  • the drug-carrying layer described in the present invention may be one layer or multiple layers, and the same drug-carrying layer may contain one type of medicine or multiple types of medicines.
  • the drug-loaded layer is one layer, and the drug loaded is one kind; in other embodiments, the drug-loaded layer is three layers, and each layer is loaded with a different drug; in other embodiments, In this example, the drug-loaded layer is two layers, one layer is loaded with one drug, and the other layer is loaded with two different drugs, that is, the drug-loaded layer is loaded with a total of three drugs; in some embodiments, the drug-loaded layer is The layers are two layers, one layer is loaded with two drugs, and the other layer is loaded with two different drugs. The two drugs loaded in each of the two layers can be completely different, partially the same, or completely identical.
  • the mass ratio of drugs and polymers in the drug-loaded layer is 1:0.1-50; further, the mass ratio of drugs and polymers in the drug-loaded layer is 1:( 0.1-30) or 1:0.1-20; further, the mass ratio of the drug to the polymer in the drug-loaded layer is 1:(0.2-18), 1:(0.5-18), 1:(0.6- 15), 1: (0.8-18), 1: (0.8-16), 1: (0.8-15), 1: (0.5-12), 1: (0.5-8), 1: (0.5-6) , 1: (0.2-16), 1: (0.2-12), 1: (0.1-12), 1: (0.2-10), 1: (0.1-10), 1: (0.2-8), 1 :(0.1-8), 1:(0.2-5), 1:(0.2-4), 1:(0.2-3), 1:(0.1-5), 1:(0.1-4) or 1:( 0.5-4).
  • the particle size of the drug particles in the drug-loaded layer is r ⁇ 0.8 ⁇ m.
  • the crystal form of the drug in the drug-loaded layer may be crystalline, amorphous, or semi-crystalline. That is, in some embodiments of the present invention, the drug in the drug-loaded layer is Crystalline. In other embodiments, the drug in the drug-loaded layer is amorphous. In still other embodiments, the drug in the drug-loaded layer is semi-crystalline.
  • the present invention does not have high requirements on the crystal form or the size of the crystal grains of the drug in the drug-loaded layer, that is, regardless of whether the drug in the drug-loaded layer is Whether in crystalline form, amorphous form, or semi-crystalline form, when the particle size of the drug is controlled below 0.8 ⁇ m, the drug release rate can meet the corresponding needs. Therefore, this application uses the outer layer
  • the special design of the drug-controlled release layer and the drug-loading layer has relatively significantly reduced the requirements for the drug-loading process and solvents in the drug-loading layer, so that the drug coating formed through different processes and solvents can be used as long as the particle size of the drug is not very large. , the dispersion is relatively uniform, and the drug release rate is within a relatively ideal range.
  • the particle size of the drug particles in the drug-loaded layer is r ⁇ 0.8 ⁇ m; in other embodiments of the present invention, the particle size of the drug particles in the drug-loaded layer is r ⁇ 0.6 ⁇ m; in other embodiments of the invention, In some embodiments, the particle size of the drug particles in the drug-loaded layer is r ⁇ 0.45 ⁇ m.
  • the particle size mentioned in the present invention refers to the average particle size.
  • the particle size r of the drug particles in the drug-loading layer is 0.6 ⁇ m
  • the average particle size of the drug particles in the drug-loading layer is 0.6 ⁇ m.
  • the particle size of the drug particles is the particle size of the crystal form.
  • the particle size of the drug is the particle size of the drug clusters dispersed in the polymer.
  • the sum of the thicknesses of the drug-loaded layer and the drug-controlled release layer is not less than 2.5 ⁇ m; further, the sum of the thicknesses of the drug-loaded layer and the drug-controlled release layer is not less than 5 ⁇ m; Furthermore, the sum of the thicknesses of the drug-loaded layer and the drug-controlled release layer is between (5 ⁇ m, 38 ⁇ m].
  • the sum of the thicknesses of the drug-loaded layer and the drug-controlled release layer is is 5.1 ⁇ m, 5.5 ⁇ m, 5.2 ⁇ m or 6 ⁇ m; in some embodiments of the present invention, the sum of the thicknesses of the drug-loaded layer and the drug-controlled release layer is 7 ⁇ m, 7.5 ⁇ m or 8 ⁇ m.
  • the molecular weight of the polymer in the drug-loaded layer is 30-1000kDa; further, the molecular weight of the inner and middle layer polymers is 40-1000kDa, 50-1000kDa, 60-1000kDa; further, the molecular weight of the drug-loading layer polymer is 70-1000kDa, 80 -1000kDa.
  • the inner layer of the drug-loaded layer also includes a corrosion control layer, and the molecular weight of the polymer in the corrosion control layer is 50-1000kDa; further, the polymers of the inner layer and the middle layer The molecular weight is 60-1000kDa, 70-1000kDa, 80-1000kDa; further, the molecular weight of the drug-loading layer polymer is 90-1000kDa, 100-1000kDa.
  • the molecular weight of the polymer of the drug-controlled release layer can fluctuate within a wide range, and the drug-loaded layer and the corrosion control layer have a higher influence on the polymer molecular weight than the drug-controlled release layer.
  • the polymer in the drug-loaded layer is the carrier of the active drug. Its type, molecular weight, thickness of the drug-loaded coating, and mass ratio to the drug all have an important impact on the drug release rate.
  • the degradable metal part corrodes rapidly in the early stage and does not meet the requirements of mechanical properties, or causes premature degradation of the polymer and then cannot effectively control the rapid corrosion of the degradable metal part in the device in the later stage.
  • the total thickness of the corrosion control layer, the drug-loading layer and the drug-controlled release layer is 3.5-45 ⁇ m; further, the corrosion control layer, the drug-loading layer and the drug-controlled release layer are The total thickness is 5.5-40 ⁇ m; further, the total thickness of the corrosion control layer, drug-loading layer and drug-controlled release layer is 5.8-36 ⁇ m.
  • the thickness ratio of the corrosion control layer, the drug-loaded layer and the drug-controlled release layer is 1:(0.5-15):(0.2-13).
  • the thickness of the drug controlled release layer is 0.2-8 ⁇ m; further, the thickness of the corrosion control layer is 0.5-7 ⁇ m; further, the thickness of the corrosion control layer is 0.8-6.6 ⁇ m.
  • the thickness of the corrosion control layer is 0.2-6 ⁇ m; further, the thickness of the corrosion control layer is 0.5-5 ⁇ m; further, the thickness of the corrosion control layer The thickness is 0.8-3 ⁇ m.
  • the thickness of the drug-loaded layer is 1-8 ⁇ m; further, the thickness of the corrosion control layer is 1.5-7 ⁇ m; further, the thickness of the corrosion control layer is 1.5 -6 ⁇ m.
  • At least one layer of the three-layer structure of the coating also includes a corrosion promoter, a corrosion retarder or an antioxidant.
  • the coating further includes a metal isolation layer located inside the corrosion control layer.
  • the metal isolation layer is a coating containing more active metal elements than the base material of the medical device.
  • the metal coating can be densely and evenly distributed on the degradable device through methods such as electroplating, spray plating, or chemical plating. substrate surface.
  • the metal isolation layer can be used to delay corrosion of the medical device base.
  • the electronegativity of at least one metal in the metal isolation layer is smaller than the electronegativity of the base metal of the degradable medical device, that is, at least one metal in the metal isolation layer More active than the base metal of the degradable medical device, the metal isolation layer may be a pure metal or a metal alloy; when the metal isolation layer is a pure metal, the electronegativity of the metal is higher than that of the degradable medical device.
  • the electronegativity of the base metal is small, that is, the metal is more active than the base metal of the degradable medical device.
  • the metal isolation layer is pure zinc or pure magnesium; when the metal is When the isolation layer is a metal alloy, the main metal element in the metal alloy, that is, one or more elements with higher content, is more active or less electronegative than the base metal of the degradable medical device.
  • the metal isolation layer is zinc alloy or magnesium alloy.
  • the metal isolation layer may be an isolation layer containing metal oxide. In some other embodiments of the present invention, the metal isolation layer may be any other metal-containing coating that can prevent corrosion of the medical device substrate.
  • the metal isolation layer when the metal in the absorbable metal matrix is pure iron or iron-based alloy, the metal isolation layer includes pure magnesium, magnesium-containing alloy, pure zinc or zinc-containing alloy; when When the metal in the absorbable metal matrix is pure zinc or zinc-containing alloy, the metal isolation layer includes pure magnesium or magnesium-containing alloy.
  • the metal in the metal isolation layer is relatively more active than the metal constituting the device base material, electrochemical protection can be formed in the microenvironment of the body.
  • the relatively active metal in the isolation layer corrodes preferentially, while the supporting device base material does not. Being protected can delay its corrosion.
  • the device base material is iron or iron alloy
  • covering the surface of the device with a metal coating composed of zinc or zinc alloy will form a galvanic cell in the microenvironment of the body, composed of zinc or zinc alloy.
  • the metal coating serves as the negative electrode and loses electrons to become zinc ions, which are corroded first, while the iron or iron alloy device base material serves as the positive electrode and is temporarily protected from corrosion.
  • the drug controlled release layer and the drug-loaded layer in the present invention or the drug controlled release layer, the drug-loaded layer and the corrosion control layer, or the drug controlled-release layer, the drug-loaded layer and the metal isolation layer, or the drug controlled-release layer, the drug-loaded layer.
  • the four schemes of , corrosion control layer and metal isolation layer can realize both controlling drug release and controlling the corrosion of the substrate.
  • the parameters of each layer of the coating can be coordinated and matched with each other to realize the invention.
  • the coating for medical devices is a drug controlled release layer and a drug-loaded layer from the outside to the inside, or a drug controlled release layer, a drug-loaded layer and a corrosion control layer.
  • the polymer type, polymer molecular weight, coating thickness, and drug loading in each layer are adjusted within the corresponding range, so that the final coating has both excellent drug release performance and excellent corrosion control performance. This ensures that after the device is implanted into the corresponding site, neither proliferation nor inflammation will occur. At the same time, it will not corrode or corrode slowly in the first 1-6 months, and corrode rapidly after 6 months.
  • the thickness of the metal isolation layer is ⁇ 0.6 ⁇ m, and further, the thickness of the metal isolation layer is between 0.6-3.8 ⁇ m.
  • the thickness of the metal isolation layer is sufficient, it can effectively prevent premature corrosion of the base metal of the degradable medical device, thereby ensuring that the base body can be corrosion-free within the first 1-6 months, and the thickness of the metal isolation layer cannot be too large. , otherwise it will not be completely corroded within 2 years, and ultimately the degradable medical devices will not be corroded quickly after 6 months, and will not be completely corroded within 2 years.
  • the polymer in the coating is at least one of degradable polyester or degradable polyanhydride; further, the polymer in the present invention is selected from polyracemic lactic acid , poly-L-lactic acid, poly-D-lactic acid, polyhydroxyethyl ester, polyurethane, polyamino acid, poly(lactic acid diglycolic acid) acid, poly-D,L-lactide, polypropylene glycol, polyglycolic acid, polylactic acid glycolic acid , polysalicylic anhydride, polytrimethylene carbonate, polycaprolactone, polycaprolactone, polyhydroxyalkanoate, polyacrylate, polybutylene Diacid ester, poly( ⁇ -hydroxybutyrate) and polyethylene adipate, poly1,3-bis(p-carboxyphenoxy)propane-sebacic acid, polyerucic acid dimer- At least one of sebacic acid and polyfumaric acid-sebacic acid.
  • the polymer in the coating can be a specific one of the above-mentioned polymers, such as the drug controlled release layer, the corrosion control layer and the polymer in the corrosion control layer in the coating.
  • the polymers are all polyracemic lactic acid; in other embodiments of the present invention, the polymer in the coating can be a mixture of two or more of the above polymers, such as poly-L-lactic acid, poly-D-lactic acid.
  • a mixture of two or more of lactic acid, polyurethane, polysalicylic anhydride, polytrimethylene carbonate or polycaprolactone; the mixture of two or more can be a layer containing two or more at the same time. polymers, or each single layer may contain only one different polymer.
  • the polymer in the outer drug-release controlled layer of the coating is polymer L-lactic acid
  • the polymer in the drug-loaded layer is polyracemic lactic acid
  • the polymer in the corrosion control layer is polyurethane
  • the drug-controlled release layer in the coating, corrosion control layer are both polyurethane and polysalicylic anhydride ester, or a mixture of polyracemic lactic acid, poly-L-lactic acid, and poly-D-lactic acid
  • the coating The polymer of the drug controlled release layer and the corrosion control layer is polyracemic lactic acid
  • the polymer in the corrosion control layer is a mixture of polyhydroxyalkanoate and polyacrylate.
  • the drug loaded in the coating is at least one of a drug that inhibits blood vessel proliferation, an anti-inflammatory drug, an anti-thrombotic drug and a sensitizing drug;
  • the anti-thrombotic drug Drugs include antiplatelet drugs and anticoagulant drugs.
  • the drugs loaded in the coating are only drugs that inhibit vascular proliferation; in other embodiments, the drugs loaded in the coating are drugs that inhibit vascular proliferation, anti-inflammatory drugs, and anti-inflammatory drugs. A combination of any two or more drugs from thrombotic drugs and sensitizing drugs.
  • the drug that inhibits vascular proliferation described in the present invention is selected from at least one of paclitaxel, rapamycin and its derivatives; antiplatelet drugs include cilostazol; antithrombotic drugs include heparin ;
  • the anti-inflammatory drug is dexamethasone; the anti-allergenic drug is at least one selected from calcium gluconate, chlorpheniramine and cortisone.
  • the drugs loaded in the drug-loaded layer are paclitaxel, rapamycin, cilostazol, heparin, tacrolimus, everolimus, dexamethasone, glucose At least one of calcium phosphate, chlorpheniramine, or cortisone.
  • the medical device is a degradable metal medical device Or degradable non-metallic medical devices, where the metal is pure metal or metal alloy.
  • the degradable medical device is a medical device that at least partially includes iron-based, zinc-based, polymer and magnesium-based medical devices.
  • the base body of the degradable medical device is composed of a metal or metal alloy, for example, the entire degradable medical device is an iron-based medical device; in other embodiments of the present invention, the The matrix of degradable medical devices is composed of two or more materials, such as part iron-based and part zinc-based, or part metal-based and part non-metal-based.
  • the medical devices include vascular stents, heart valves, non-vascular intraluminal stents, occluders, orthopedic implants, dental implants, respiratory implants, and gynecological implants. any of the following: implants, male implants, sutures or bolts.
  • the stent of the present invention is an intravascular stent or a stent for heart valves; further, the stent of the present invention is a ball-expandable stent or a self-expanding stent; further, the present invention
  • the stent includes a coronary stent, a below-knee stent, a superficial femoral stent, an intracranial stent, a carotid artery stent, a pulmonary artery stent or a renal artery stent.
  • the base material of the degradable medical device is pure iron or an iron-based alloy with a carbon content of no more than 2.11wt%.
  • the metals in the above-mentioned iron-based, zinc-based or magnesium-based materials refer to the main components in the matrix.
  • the iron base includes pure iron or iron alloy, that is, the iron base means that the main component of the base material is iron.
  • the present invention controls the release of drugs in the drug-loaded layer through the relationship or internal logic between the polymer type, polymer molecular weight and polymer thickness of the drug-controlled release layer.
  • the drug-controlled release layer provided in the invention It can effectively prevent the drug in the drug-loaded layer from being released rapidly under the erosion of blood when the stent is first implanted into the human body, resulting in too fast drug release in the early stage and insufficient drug release in the later period, resulting in the inability to carry out sustained and effective drug release.
  • the controlled drug release layer in the present invention not only has a certain protective effect on the drug-loaded layer, but also can regulate the release rate of the drug loaded in the drug-loaded layer.
  • the present invention adds a special drug-controlled release layer outside the drug-loaded layer.
  • the drug in the drug-loaded layer will gradually increase the contact between the drug-loaded layer and the blood only after the polymer of the drug-controlled release layer has degraded to a certain extent. area, so it can effectively control the problem of drug burst release in the early stage of stent implantation.
  • the drug controlled release layer and the drug-carrying layer in the present invention work together to control the release of the drug.
  • it is effective Control the release rate of the drug at each stage to ensure that the amount of drug released at each stage just meets the demand; on the other hand, the drug-loaded layer should be loaded with an appropriate amount of drug as much as possible to prevent excessive drug loading from having certain harmful effects on the human body.
  • Toxic and side effects that is, controlling drug release to ensure that the amount of drug just meets the demand while reducing the total drug load as much as possible.
  • the drug controlled release layer, drug-loading layer and corrosion promotion layer in the present invention all contain polymers.
  • the thickness and molecular weight of the polymers in the three coatings work together to control the device matrix, or the device matrix and the metal isolation layer. of corrosion.
  • the type and molecular weight of the polymers in the drug-loading layer and the corrosion control layer can be adjusted so that It satisfies requirements such as increasing the molecular weight of the polymers in the drug-loaded layer and corrosion control layer while selecting polymers with relatively slow degradation rates.
  • the metal isolation layer introduced in the technical solution of the present invention can control the corrosion rate of the device base material together with the above-mentioned polymer-containing coating to ensure that the device does not corrode in the early stage of implantation (1-6 months), but when the blood vessel is repaired After completion, the device substrate is allowed to degrade quickly.
  • the corrosion control layer and the metal isolation layer are degraded at the same time.
  • the degradable polyester that constitutes the corrosion control layer will produce acidic substances when it degrades. When the degradation accumulates to a certain extent, a local acidic environment can be formed, which can aggravate the metal Corrosion and degradation of barrier layers and medical device substrates.
  • This process can be controlled by the thickness and molecular weight of the degradable polyester of the corrosion control layer. The lower the molecular weight, the thicker the degradable polyester, and the faster the metal isolation layer and bracket will corrode and degrade.
  • the polymers in the corrosion control layer, the drug-loaded layer and the drug-controlled release layer work together to control the corrosion of the device base or the device base and the metal isolation layer.
  • the corrosion control layer can also isolate the device base and the metal.
  • the metal ions produced during the corrosion process of the layer and the human body environment prevent the metal ions from being combined with active drugs from being transferred unhindered into the human blood vessels, thereby causing hemolysis, or preventing excessive metal ions from coming into direct contact with the human body, causing Local poisoning or thrombosis.
  • Figure 1 is a Raman spectrum chart of the thickness test of each layer in the stent coating in Example 1, where: 1-metal isolation layer, 2-corrosion control layer, 3-drug-loading layer, 4-drug controlled release layer, 5 -Inlay sample material epoxy polyester;
  • Figure 2 is an SEM image of the particle size test of drug particles in the drug-loaded layer of Examples 1 and 6, wherein Figure 2-1 is a cross-section of the ethyl acetate solvent spray coating at zero time in Example 6; Figure 2- 2 is a cross section after leaching the drug from the ethyl acetate solvent spray coating in Example 6; Figure 2-3 is a cross section after leaching the drug from the chloroform solvent spray coating in Example 1;
  • Figure 3 is the XRD pattern of the drug crystallinity test in the drug-loaded layer of Example 1 and Example 6;
  • Figure 4 is a drug release rate diagram of the absorbable stent coating in Examples 1-7 and Comparative Examples 1-5;
  • Figure 5 is a graph showing the mass loss percentage of the absorbable scaffold in Examples 1-7 and Comparative Examples 1-5 in animals;
  • Figure 6 is a graph showing the radial support strength test of the absorbable stents in Examples 1-7 and Comparative Examples 1-5 in animals.
  • the GPC-multi-angle laser light scattering instrument combined with the molecular weight testing system of Wyatt Company in the United States was used for detection.
  • the test system includes the liquid phase pump and injector of the American Agilent Company, the Agilent PL MIXED-C GPC column (size: 7.5 ⁇ 300mm, 5 microns) of the American Agilent Company, the multi-angle laser light scattering instrument of the American Wyatt Company and Differential detector.
  • the detection conditions are:
  • Mobile phase tetrahydrofuran; pump flow rate: 1mL/min; injection volume: 100 ⁇ L; laser wavelength: 663.9nm; test temperature: 35°C.
  • Measurement using the scanning electron microscope method First, fix the stent sample to be tested for coating thickness on the sample stage, then place the sample stage in the JFC-1600 gold spray equipment to spray platinum. After spraying once, rotate 180° and spray again to ensure all The location was sprayed. Place the sample with the surface sprayed with platinum into the Buehler room-temperature resin curing agent mixture reagent prepared at a ratio of 5:1, and let it sit for more than 8 hours before it can be separated from the sample sealing case. Divide the sealed sample into 3 equal sections, and use a semi-automatic grinding and polishing machine to polish each section according to the sample polishing procedure. The section of the sample to be measured should be polished until there is no wear mark. Fix the polished sample to the stage of the scanning electron microscope, place the entire stage into the JFC-1600 gold spraying equipment, and spray gold for 20 seconds. Place the gold-sprayed sample into a JSM-6510 scanning electron microscope for thickness measurement.
  • Thermo DXR2 uses the micro-Raman spectrometer Thermo DXR2 to scan the cross-section of the coating part of the multi-layer coating medical device.
  • the laser energy parameters are: 6.0mW, the exposure time is 20Hz, the number of exposures is 50 times, and the magnification is 500 times.
  • the component distribution map of the cross-section can be obtained.
  • the content of the drug and polylactic acid in different areas can be qualitatively analyzed and the thickness of each coating can be tested.
  • Coating solutions made of different solvents were evenly sprayed onto the stainless steel plate using spray equipment, and vacuum dried at room temperature for 24 hours to prepare drug/polymer coatings made of different solvents. layer of film.
  • XRD testing (Bruker D2PHASER) of drug/polymer films made of different solvents was performed. The samples were scanned in ⁇ -2 ⁇ linkage mode. The scanning angle range was 3-40°; the scanning step was 0.02°; the scanning speed was 4°. /min.
  • Multi-layer coated medical devices were implanted into the blood vessels of healthy rabbits, and the cells were observed at predetermined observation time points, such as 7 hours, 1 day, 3 days, 7 days, 14 days, 28 days, 60 days, 90 days, and 180 days.
  • the rabbits were sacrificed and the multilayer-coated medical devices were removed. After removing as much tissue as possible from the medical device, place it into a brown glass bottle and add an appropriate amount of acetonitrile to the volume.
  • the volume can be determined according to specific specifications to ensure that the stent can be completely immersed in the solution.
  • the drug release amount of the stent is the initial drug amount on the stent minus the residual drug amount on the stent after soaking (test drug amount).
  • the drug release percentage is the ratio of the drug release amount to the initial drug amount.
  • Multi-layer coated medical devices were implanted into the blood vessels of healthy rabbits, and the cells were observed at predetermined observation time points, such as 7 hours, 1 day, 3 days, 7 days, 14 days, 28 days, 60 days, 90 days, and 180 days.
  • the rabbits were sacrificed and the multilayer-coated medical devices were removed. After removing as much tissue as possible from the medical device, use a liquid chromatograph to test the remaining drug content of the stent. Use ethyl acetate solution to clean the stent after testing the dose so that the polymer coating on it is completely dissolved.
  • Micro-CT inspection was performed on the above-mentioned cleaned stent to conduct a qualitative analysis of the corrosion of the iron-based matrix. After that, the stent was placed in a tartaric acid solution and cleaned ultrasonically to remove the surface corrosion product layer. After drying, the stent was weighed as m after corrosion .
  • the mass loss rate m% of the device is the difference between the mass m of the device before corrosion and the mass m of the device after corrosion and treatment, and the ratio of the mass m of the device before corrosion multiplied by 100%, that is :
  • the stent is expanded with a suitable balloon (or distal component) to a nominal pressure so that the outer diameter of the stent sample reaches a predetermined size.
  • the radial support strength is expressed as a numerical value (unit: kPa) that defines the force value per unit length when the nominal diameter of the stent is compressed by 10% as the radial anti-extrusion performance of the stent.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 0.6 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use bracket spray Equipment, evenly spray a corrosion control layer with an average thickness of 3 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 600kDa.
  • the solvent is chloroform; after the corrosion control layer is dry, use a stent spraying equipment to evenly spray a layer with an average thickness of 3 ⁇ m.
  • the coating is made of polyracemic lactic acid, the molecular weight is 400kDa, the solvent is chloroform, the drug contained is sirolimus, the mass ratio of sirolimus to polyracemic lactic acid in the drug-loaded layer is 1 :0.5, the average particle size of the drug particles is 0.25 ⁇ m, and the drug particles are amorphous (see Figure 3); after the drug-loaded layer is dry, use stent spray equipment to evenly spray a drug release control layer with an average thickness of 3 ⁇ m.
  • the coating is made of polyracemic lactic acid, with a one-month molecular weight retention rate of 74%, a molecular weight of 200kDa, and ethyl acetate as the solvent.
  • the drug release rate of the stent in the body is shown in Figure 4
  • the mass loss of the stent is shown in Figure 5
  • the radial support strength of the stent is shown in Figure 6.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 2 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use stent spraying equipment to evenly spray a drug-loaded layer with an average thickness of 10 ⁇ m.
  • the coating is polyracemic lactic acid with a molecular weight of 400kDa.
  • the solvent is chloroform.
  • the drug contained is sirolimus.
  • the mass ratio of sirolimus to polyracemic lactic acid in the drug-loaded layer is 1:8, the average particle size of the drug particles is 0.35 ⁇ m, and the drug particles are amorphous; after the drug-loaded layer is dry, use stent spraying equipment to evenly A drug release control layer with an average thickness of 1.8 ⁇ m is sprayed on the ground.
  • the coating is made of polyracemic lactic acid.
  • the one-month molecular weight retention rate is 79%.
  • the molecular weight is 400kDa.
  • the solvent is chloroform.
  • the drug release rate of the stent in the body is shown in Figure 4
  • the mass loss of the stent is shown in Figure 5
  • the radial support strength of the stent is shown in Figure 6.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 3 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use bracket spraying equipment to evenly spray a corrosion control layer with an average thickness of 6 ⁇ m.
  • the coating is PLGA (50:50), the molecular weight is 50kDa, and the solvent is chloroform; after the corrosion control layer is dry, Use stent spraying equipment to evenly spray a drug-loaded layer with an average thickness of 5 ⁇ m.
  • the coating is made of PLGA (50:50) with a molecular weight of 50kDa.
  • the solvent is chloroform.
  • the drug is sirolimus.
  • the drug-loaded layer is Chinese and Western.
  • the mass ratio of lolimus to PLGA is 1:1.25, the average particle size of the drug particles is 0.45 ⁇ m, and the drug particles are amorphous; after the drug-loaded layer is dry, use stent spraying equipment to evenly spray the drug particles with an average thickness of 6 ⁇ m.
  • the coating is made of PLGA (50:50), the molecular weight is 50kDa, the one-month molecular weight retention rate is 61%, and the solvent is chloroform.
  • the drug release rate of the stent in the body is shown in Figure 4
  • the mass loss of the stent is shown in Figure 5
  • the radial support strength of the stent is shown in Figure 6.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 3.8 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use bracket spraying equipment to evenly spray a corrosion control layer with an average thickness of 5 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 400kDa and ethyl acetate as the solvent. After the corrosion control layer is dry, use the bracket Spray equipment to evenly spray a drug-loaded layer with an average thickness of 4 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 200 kDa.
  • the solvent is ethyl acetate.
  • the drug contained is sirolimus.
  • the drug-loaded layer contains sirolimus and
  • the mass ratio of polyracemic lactic acid is 1:2, the average particle size of the drug particles is 0.2 ⁇ m, and the drug particles are in a semi-crystalline state; after the drug-loaded layer is dry, use stent spraying equipment to evenly spray the drug particles with an average thickness of 0.8 ⁇ m.
  • Drug release control layer the coating is made of polyracemic lactic acid, the one-month molecular weight retention rate is 81%, and the molecular weight is 800kDa.
  • the solvent used was chloroform.
  • the drug release rate of the stent in the body is shown in Figure 4
  • the mass loss of the stent is shown in Figure 5
  • the radial support strength of the stent is shown in Figure 6.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 1 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use bracket spraying equipment to evenly spray a corrosion control layer with an average thickness of 3.5 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 200kDa and ethyl acetate as the solvent. After the corrosion control layer is dry, use The stent spraying equipment uniformly sprays a drug-loaded layer with an average thickness of 5 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 100 kDa.
  • the solvent is ethyl acetate.
  • the drug contained is sirolimus.
  • the drug-loaded layer contains sirolimus.
  • the mass ratio to polyracemic lactic acid is 1:1.5, the average particle size of the drug particles is 0.7 ⁇ m, and the drug particles are semi-crystalline; after the drug-loaded layer is dry, use stent spraying equipment to evenly spray with an average thickness of 5.8 ⁇ m
  • the drug release control layer uses polyracemic lactic acid as the coating, with a molecular weight of 50kDa, a one-month molecular weight retention rate of 63%, and ethyl acetate as the solvent.
  • the drug release rate of the stent in the body is shown in Figure 4
  • the mass loss of the stent is shown in Figure 5
  • the radial support strength of the stent is shown in Figure 6.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 2.5 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use bracket spraying equipment to evenly spray a corrosion control layer with an average thickness of 2.5 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 300kDa and ethyl acetate as the solvent. After the corrosion control layer is dry, use Bracket spray equipment, Uniformly spray a drug-loaded layer with an average thickness of 8 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 300kDa.
  • the solvent is ethyl acetate.
  • the drug contained is sirolimus.
  • Sirolimus and polyracemic lactic acid are used in the drug-loaded layer.
  • the mass ratio of lactic acid is 1:6, the average particle size of the drug particles is 0.35 ⁇ m, and the drug particles are in a semi-crystalline state (see Figure 3); after the drug-loaded layer is dry, use stent spray equipment to evenly spray with an average thickness of 2.6
  • the ⁇ m drug release control layer has a molecular weight of 600kDa, a one-month molecular weight retention rate of 80%, and chloroform is used as the solvent.
  • the drug release rate of the stent in the body is shown in Figure 4
  • the mass loss of the stent is shown in Figure 5
  • the radial support strength of the stent is shown in Figure 6.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 1.5 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use bracket spraying equipment to evenly spray a corrosion control layer with an average thickness of 2 ⁇ m.
  • the coating is polyracemic lactic acid with a molecular weight of 200kDa and acetone as the solvent. After the corrosion control layer is dry, use bracket spraying equipment. , evenly spray a drug-loaded layer with an average thickness of 3 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 600kDa.
  • the solvent is acetone.
  • the drug contained is sirolimus.
  • Sirolimus and polyracemic lactic acid are used in the drug-loaded layer.
  • the mass ratio is 1:1.5, and the average particle size of the drug particles is 0.6 ⁇ m; after the drug-loaded layer is dry, use stent spraying equipment to evenly spray a drug release control layer with an average thickness of 6.6 ⁇ m and a molecular weight of 100kDa, one month
  • the molecular weight retention rate was 65%, and acetone was used as the solvent.
  • the drug release rate of the stent in the body is shown in Figure 4
  • the mass loss of the stent is shown in Figure 5
  • the radial support strength of the stent is shown in Figure 6.
  • This embodiment uses an iron-based bracket with a specification of 3.0mm ⁇ 8mm.
  • the electroplating method is used to coat the surface of the base material.
  • a zinc layer with an average thickness of 1 ⁇ m is plated as a metal isolation layer.
  • bracket spraying equipment to evenly spray a corrosion control layer with an average thickness of 3 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 400kDa and ethyl acetate as the solvent.
  • the coating is made of polyracemic lactic acid with a molecular weight of 200 kDa.
  • the solvent is ethyl acetate.
  • the drug contained is sirolimus.
  • the drug-loaded layer contains sirolimus and
  • the mass ratio of polyracemic lactic acid is 1:2, the average particle size of the drug particles is 0.3 ⁇ m, and the
  • the drug release rate of the stent in the body in this comparative example is shown in Figure 4. It can be seen from Figure 4 that the stent in this comparative example bursts out in the early stage, and most of the drug is released in the early stage of stent implantation, resulting in insufficient drug release in the middle and later stages. , at the 90-day time point, the blood vessel where the stent was located showed signs of serious proliferation.
  • the mass loss results of the stent are shown in Figure 5, and the radial support strength of the stent is shown in Figure 6.
  • the corrosion rate of the stent in the body is normal, and it can still provide effective support at the 6-month time point.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 1.5 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use bracket spraying equipment to evenly spray a corrosion control layer with an average thickness of 5 ⁇ m.
  • the coating is polyracemic lactic acid with a molecular weight of 200kDa and chloroform as the solvent. After the corrosion control layer is dry, use the bracket Spray equipment to evenly spray a drug-loaded layer with an average thickness of 5 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 200 kDa.
  • the solvent is chloroform.
  • the drug contained is sirolimus.
  • the drug-loaded layer contains sirolimus and The mass ratio of polyracemic lactic acid is 1:1.25; the coating is polyracemic lactic acid, the molecular weight is 400kDa, the solvent is chloroform, the drug contained is sirolimus, the average particle size of the drug particles is 0.35 ⁇ m, and the drug The particles are amorphous.
  • the drug release rate of the stent in the body in this comparative example is shown in Figure 4. It can be seen from Figure 4 that the stent in this comparative example bursts out in the early stage, and most of the drug is released in the early stage of stent implantation, resulting in insufficient drug release in the middle and later stages. , at the 90-day time point, serious signs of proliferation and thrombus were observed in the blood vessel where the stent was located.
  • the mass loss rate of the stent is shown in Figure 5, and the radial support strength of the stent is shown in Figure 6.
  • the corrosion rate of the stent in the body is normal, and it can still provide effective support at the 6-month time point.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 1 ⁇ m on the surface of the base material as a metal isolation layer. Outside the metal isolation layer, use bracket spraying equipment to evenly spray a corrosion control layer with an average thickness of 4 ⁇ m.
  • the coating is polyracemic lactic acid with a molecular weight of 800kDa and chloroform as the solvent. After the corrosion control layer is dry, use the bracket Spraying equipment, evenly spray a drug-loaded layer with an average thickness of 4 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 400kDa.
  • the drug contained is sirolimus.
  • the mass of sirolimus and polyracemic lactic acid in the drug-loaded layer The ratio is 1:2, the average particle size of the drug particles is 0.35 ⁇ m, the drug particles are in a semi-crystalline state, and ethyl acetate is used as the solvent.
  • the coating is made of polyracemic lactic acid, with a molecular weight retention rate of 74% in one month and a molecular weight of 200kDa.
  • the solvent is ethyl acetate. ester.
  • the drug release rate of the stent in the body in this comparative example is shown in Figure 4. It can be seen from Figure 4 that the stent in this comparative example has insufficient drug release in the early stage and cannot play a therapeutic role in the early stage of implantation. At the 14-day time point, There are signs of blood clots in the blood vessel where the stent is located.
  • the mass loss of the stent is shown in Figure 5, and the radial support strength of the stent is shown in Figure 6.
  • the coating thickness increases, the amount of polylactic acid also increases accordingly, which causes the stent to corrode faster in the body, and the drug is released slowly in the early stage.
  • an iron-based bracket is used, with a specification of 3.0 mm ⁇ 8 mm.
  • An electroplating method is used to plate a zinc layer with an average thickness of 0.6 ⁇ m on the surface of the base material as a metal isolation layer.
  • use stent spraying equipment to evenly spray a corrosion control layer with an average thickness of 2.5 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 200kDa and chloroform as the solvent; after the corrosion control layer is dry, use Bracket spraying equipment Prepare the equipment and evenly spray a drug-loaded layer with an average thickness of 8 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 200kDa.
  • the solvent is chloroform.
  • the drug contained is sirolimus.
  • Sirolimus and poly(racemic lactic acid) are used in the drug-loaded layer.
  • the mass ratio of racemic lactic acid is 1:8, the average particle size of the drug particles is 0.35 ⁇ m, and the drug particles are amorphous; after the drug-loaded layer is dry, use stent spray equipment to evenly spray the drug with an average thickness of 0.2 ⁇ m
  • the coating is made of polyracemic lactic acid, the molecular weight is 100kDa, the one-month molecular weight retention rate is 68%, and the solvent is ethyl acetate.
  • the drug release rate of the stent in the body is shown in Figure 4
  • the mass loss of the stent is shown in Figure 5
  • the radial support strength of the stent is shown in Figure 6.
  • the corrosion rate of the stent in the body is normal, and it can still provide effective
  • the drug release control layer of the stent in this comparative example is too thin, the drug is released in an early stage, and most of the drug is released in the early stage of stent implantation, resulting in insufficient drug release in the middle and later stages.
  • the blood vessel where the stent is located There are signs of more serious proliferation.
  • This embodiment uses an iron-based stent with a specification of 3.0mm ⁇ 8mm.
  • stent spraying equipment On the surface of the metal substrate, use stent spraying equipment to evenly spray a coating with an average thickness of 2.5 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 100kDa.
  • the solvent is chloroform; after the corrosion control layer is dry, use stent spraying equipment to evenly spray a drug-loaded layer with an average thickness of 5 ⁇ m.
  • the coating is polyracemic lactic acid with a molecular weight of 100kDa.
  • the solvent is chloroform.
  • Sirolimus is selected as the drug.
  • the mass ratio of sirolimus to polyracemic lactic acid in the drug-loaded layer is 1:0.5.
  • the average particle size of the drug particles is 0.25 ⁇ m.
  • the drug particles are amorphous; after the drug-loaded layer is dried, , use stent spraying equipment to evenly spray a drug release control layer with an average thickness of 0.2 ⁇ m.
  • the coating is made of polyracemic lactic acid with a molecular weight of 100kDa. The one-month molecular weight retention rate is 68%.
  • the solvent is ethyl acetate.
  • the drug release rate of the stent in the body is shown in Figure 4, the mass loss of the stent is shown in Figure 5, and the radial support strength of the stent is shown in Figure 6.
  • the stent matrix corroded too quickly, and the stent rod was in the early stage of implantation. Breakage occurs, resulting in accelerated drug release, and most of the drug is released in the early stage of stent implantation. After 60 days of implantation, it is no longer able to maintain its normal shape and cannot provide effective support. There was obvious thrombosis on the stent rod at 30 days, and the color of the tissue around the stent rod was abnormal. The blood vessel restenosis was severe 90 days after the stent was implanted. The lumen area is lost by more than 60%.
  • Comparative Example 1 experienced drug burst release, releasing a large amount of drug in a short period of time, resulting in a rather long period of time in the middle and late stages. The drug is released very little over time and the drug utilization rate is low.
  • Comparative Example 1 has the same mass ratio of drug to polyester as Example 4, because Comparative Example 1 lacks a drug controlled release layer, a large amount of drug is released in a short period of time, resulting in a considerable amount of drug release in the middle and later stages. Little release and poor drug utilization.
  • Comparative Example 2 the shape of the drug particles and the type of solvent in Comparative Example 2 are different, but both are due to the lack of a controlled drug release layer, which leads to burst release of the drug in the body.
  • Comparative Example 3 Compared with Example 4, Comparative Example 3 has the same solvent and drug particle morphology, but because the drug controlled release layer is too thick, the drug release is insufficient in the early and mid-term, resulting in blood vessel proliferation and restenosis, and the drug treatment effect is also not achieved.
  • the polylactic acid coating was too thick and the content of polylactic acid increased, which caused the stent to corrode faster in the body. It could no longer maintain its normal shape after 60 days of implantation and could not provide effective support, exacerbating vascular thrombosis and restenosis. symptoms.
  • Comparative Example 4 and Comparative Example 5 both have a drug controlled release layer, due to the insufficient thickness of the drug controlled release layer, a large amount of drug is also released in a short period of time after the surface polylactic acid is degraded, resulting in a very long period of time in the middle and late stages. The drug is released very little over time and the drug utilization rate is low.
  • Comparative Example 5 lacks a metal isolation layer and does not match the corresponding polymer type and polymer molecular weight. Therefore, the polymer is in direct contact with the stent base material. The stent base corrodes too quickly, and the stent rod breaks early in the implantation process. As a result, the drug release is also accelerated, and it is no longer able to maintain its normal shape and provide effective support 60 days after implantation.

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Abstract

一种医疗器械用涂层，该涂层包括载药层和覆盖在载药层外的药物控释层，所述药物控释层中聚合物的分子量保留率m、聚合物的重均分子量Mw 控释和聚合物的厚度X 控释满足以下关系式；其中：A1、A2、k和b均为拟合常数。该涂层设计既可以提升药物的释放性能，又可以有效的控制基体的腐蚀，使可降解医疗器械的基体满足1-6个月内不降解或缓慢的降解，6个月之后快速的降解。

Description

一种医疗器械用涂层 技术领域
本发明属于医疗器械技术领域，具体涉及一种医疗器械用涂层，更具体的涉及一种可降解医疗器械用涂层。
背景技术
医疗器械，尤其是植入或介入型医疗器械，不仅要求其具有基本治疗的功能，还得在其表面负载药物，预防在器械植入位置出现一些排斥、增生、血栓、炎症等反应。因此目前常见的医疗器械通常都会在其表面增加一些涂层来负载药物或控制药物释放。如血管支架，在植入血管之后既要起到扩开血管并在一定时期内具有足够的支撑力确保血管保持畅通，同时还得防止血管增生，防止植入部位出现血栓以及后期再狭窄等问题，因此目前市面上的血管支架通常会在表面增加一层或多层涂层来负载药物和控制药物释放以防止支架在植入人体后发生一些异常反应，影响其基本的治疗效果。
器械对其表面的涂层在负载药物和药物释放方面有非常严格的要求，既要控制药物的负载量，又要控制药物的释放速度，如果载药量过大，过多的药物在人体会带来较大的毒副作用，增加药物在体内的毒性风险，如果药量过少，又不能起到很好的防治效果。当医疗器械总药量一定时，如果药物释放速度太慢，整个释药阶段药物均不足，药物的防治效果有限，如果药物释放速度太快，局部药物浓度过高会产生毒副作用，而且药物初期释放过快，不能持久有效地进行药物释放，会导致后期释放的药物量不足，两种情况在植入部位均会出现增生并最终引起血管再狭窄。由此可见，医疗器械表面的药物负载量和药物控释是在设计药物涂层时的关键难点。而对于可降解医疗器械来说，涂层不仅要负载药物、控制药物释放，还扮演着控制器械基体腐蚀的角色，因此，可降解器械用涂层的设计更是一个很大的难题和挑战。
目前，虽然已有大量药物涂层相关的研究成果公开，但现有的医疗器械用涂层绝大多数都只考虑了药物释放，并未考虑涂层对器械基材腐蚀的影响。因此，目前已公开的药物涂层的设计方案基本都不适合用于可降解医疗器械。一 方面，目前的一些常用涂层在释药方面还不是很完美，还存在一些缺陷，另一方面，当将可降解医疗器械的腐蚀需求考虑在涂层的设计中之后，涂层中聚合物的种类和分子量都会发生很大的变化，而不同种类和不同分子量的聚合物在药物控释方面均会存在非常大的差别，进而整个涂层的设计方案均会发生很大的变化。如专利CN107496996B中公开了一种血管支架的药物涂层，该涂层包括3层，每层中均含有药物和药物载体，外层的涂层对内层涂层起到了控制释放的作用，使得内层药物的突释性变小，降低了急性毒性反应的可能性，但该药物涂层的外层中也负载有2种药物，且载药的PLGA的分子量比较小，仅在2000左右，同时该外层涂层中负载的雷帕霉素、姜黄素和PLGA载体的质量分数之比为5:2:13，该外层涂层中聚合物的分子量小，聚合物的比例低，药物占比大。整个涂层设计对外层的药物并没有很好的缓释作用，外层所负载的大量雷帕霉素也会出现暴释的现象；中间层和外层均负载有大量的雷帕霉素，可能会导致载药量明显超出需求，对人体产生额外的毒副作用；此外，该血管支架的基材为不锈钢，因此该专利申请中的药物涂层的设计也不用考虑基体的降解，因此，其所使用的聚合物为小分子量的聚合物，不适用于可降解基材的医疗器械。
发明内容
基于此，本申请提供了一种医疗器械用涂层，尤其是一种可降解医疗器械用涂层，该涂层通过独特的涂层的设计，既确保药物的负载量在一个合适有效范围内，又使得涂层在药物控释方面具有非常优异的性能，还可有效的控制基体的腐蚀。
本发明的技术方案提供了一种医疗器械用涂层，该涂层在控制药物释放方面具有非常优异的性能，通过该涂层的特殊设计，对涂层的制备工艺、制备涂层过程中所使用的溶剂，以及最终涂层中药物的晶型和尺寸大小都更具有包容性。
本发明上述技术方案中，所述涂层包括载药层和覆盖在载药层外的药物控释层，所述载药层和药物控释层中均含有聚合物，所述药物控释层中聚合物的 分子量保留率m、聚合物的重均分子量Mw控释和聚合物的厚度X控释满足以下关系式：
其中：
A1为拟合常数，为823；
A2为拟合常数，为79.9；
k为拟合常数，为1.5；
b为拟合常数，范围为0≤b≤2；
所述Mw控释为药物控释层中聚合物的重均分子量，单位为千道尔顿，X的单位为μm。
需要特别说明的是，上述技术方案公式中的b可以为0-2区间范围内的任意一取值，如在本发明的一些实施例中，b可以为0.2、0.5、0.55、0.6、0.65、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.85、1.9、1.95或2.0中的任意一取值，在本发明的另一些实施例中，b可以为0-2区间范围内的任意两值所组成的区间，如0.2-1.9，0.5-1.5，0.3-1.6，0.3-1.2，0.55-1.95，0.6-1.95，0.6-1.9，0.6-1.85，0.6-1.8，0.6-1.7，0.7-1.8，0.75-1.6，0.8-1.95，0.8-1.9，0.8-1.85，0.8-1.8，0.8-1.7或0.8-1.6等。
本发明根据大量的实验记录找出外层药物控释层的涂层厚度、聚合物种类和聚合物分子量三个变量间存在内在的相互关联性或规律性，确定出外层药物控释层中特定的聚合物、特定聚合物的分子量，一定会有一个相对比较优的聚合物的厚度范围与其对应，在该最优的聚合物厚度范围内，可以大幅的提升涂层在药物释放方面的性能，本发明通过大量的实验结果并创新性的总结出了药物控释层最优厚度范围与聚合物的种类和聚合物分子量之间的关系式。也即本申请通过上述特殊的外层药物控释层的设计，对药物涂层中药物的工艺、所使用的溶剂以及最终药物晶型的要求方面都相对应的进行了放宽，并使得药物释放的速率和曲线都基本满足相应医疗器械的要求。
本发明所提供的上述医疗器械涂层是一种相对比较普适性的药物涂层，该涂层既适用于可降解医疗器械，又适用于不可降解医疗器械中的药物控释。优 选的，上述涂层适用于可降解医疗器械。
根据本发明所提供的上述技术方案，所述药物控释层中聚合物的重均分子量Mw控释为20-900kDa。本发明技术方案药物控释层中聚合物的分子量可以为20-900kDa中的任意一值，在一些实施例中，药物控释层聚合物的分子量为21kDa；在另外一些实施例中，药物控释层聚合物的分子量为898kDa；在其他一些实施例中，药物控释层聚合物的分子量为800kDa；在还有一些实施例中，药物控释层聚合物的分子量为700kDa。
根据本发明所提供的上述技术方案，所述药物控释层聚合物的分子量保留率m为50％-80％。本发明中所述聚合物的分子量保留率m是指聚合物涂层置于37℃浓度的PBS溶液(pH＝7.4)中放置1个月时间点时聚合物的分子量的保留率，即分子量保留率m＝Mw控释1个月时/Mw控释×100％，其中Mw控释1个月时是指聚合物涂层置于37℃的PBS溶液(pH＝7.4)中放置1个月时间点时聚合物的分子量，Mw控释为药物控释层聚合物的分子量。每一种聚合物在同样条件下同一时间点的分子量保留率不一样，也即在本申请中每一分子量保留率代表一种具体的聚合物，不同分子量保留率代表着不同的聚合物。
本发明中所述的载药层可以为一层，也可以为多层，且同一载药层所负载的药物可以为一种，也可以为多种。如在一些实施例中，载药层为一层，所负载的药物为一种；在其他一些实施例中，载药层为三层，每层各负载一种不同的药物；在另外一些实施例中，载药层为两层，其中一层负载一种药物，而另一层负载两种不同的药物，也即载药层总共负载三种药物；在还有一些实施例中，载药层为两层，其中一层负载两种药物，而另一层负载两种不同的药物，其中两层各所负载的两种药物可以完全不同，或部分相同或完全相同。
根据本发明所提供的上述技术方案，所述载药层中药物与聚合物的质量比为1:0.1-50；进一步的，所述载药层中药物与聚合物的质量比为1:(0.1-30)或1:0.1-20；更进一步的，所述载药层中药物与聚合物的质量比为1:(0.2-18)、1:(0.5-18)、1:(0.6-15)、1:(0.8-18)、1:(0.8-16)、1:(0.8-15)、1:(0.5-12)、1:(0.5-8)、1:(0.5-6)、1:(0.2-16)、1:(0.2-12)、1:(0.1-12)、1:(0.2-10)、1:(0.1-10)、1:(0.2-8)、1:(0.1-8)、1:(0.2-5)、1:(0.2-4)、1:(0.2-3)、1:(0.1-5)、1:(0.1-4)或1:(0.5-4)。
根据本发明所提供的上述技术方案，所述载药层中药物颗粒的粒径r≤0.8μm。所述载药层中的药物的晶型可以是结晶态的，也可以是非结晶态的，还可以是半结晶态的，也即在本发明的一些实施例中，载药层中的药物是结晶态的，在另一些实施例中，载药层中的药物是非结晶态的，在还有一些实施例中，载药层中的药物是半结晶态的。由于本发明所提供的特殊外层涂层的设计，使得本发明中对载药层中药物的晶型或者晶粒的大小等均没有太高的要求，也即不论载药层中的药物是结晶形态的，还是非结晶形态的，亦或是半结晶态的，当将药物的粒径控制在0.8μm以下时，其药物释放的速率都能满足相应的需求，因此，本申请通过对外层药物控释层、载药层特殊的设计，使得对载药层载药的工艺、溶剂的要求相对大幅的降低，使得通过不同工艺、溶剂形成的药物涂层，只要药物的粒径不是很大，分散相对比较均匀，药物释放的速率都在一个相对比较理想的范围内。
在本发明的一些实施例中，载药层药物颗粒的粒径r≤0.8μm；在本发明的另外一些实施例中，载药层药物颗粒的粒径r≤0.6μm；在本发明的其他一些实施例中，载药层药物颗粒的粒径r≤0.45μm。
需要说明的是，本发明中所述的粒径是指平均粒径，如“载药层中药物颗粒的粒径r为0.6μm”是指载药层中药物颗粒的平均粒径为0.6μm，其中会存在某些药物颗粒的粒径大于0.6μm，也存在某些颗粒小于0.6μm。
另需要说明的是，当载药层中的药物为结晶形态时，药物颗粒的粒径即为晶型的粒径，当载药层中的药物为非结晶形态或者半结晶态形态时，药物颗粒的粒径即为分散在聚合物中的药物团簇的粒径。
根据本发明所提供的上述技术方案，所述载药层和药物控释层的厚度之和不小于2.5μm；进一步的，所述载药层和药物控释层的厚度之和不小于5μm；更进一步的，所述载药层和药物控释层的厚度之和在(5μm，38μm]之间。在本发明的一些实施例中，所述载药层和药物控释层的厚度之和为5.1μm、5.5μm、5.2μm或6μm；在本发明的一些实施例中，所述载药层和药物控释层的厚度之和为7μm、7.5μm或8μm。
根据本发明所提供的上述技术方案，所述载药层中聚合物的分子量为 30-1000kDa；进一步的，所述内层和中间层聚合物的分子量为40-1000kDa、50-1000kDa、60-1000kDa；更进一步的，所述载药层聚合物的分子量为70-1000kDa，80-1000kDa。
根据本发明所提供的上述技术方案，所述载药层内测还包括腐蚀控制层，所述腐蚀控制层中聚合物的分子量为50-1000kDa；进一步的，所述内层和中间层聚合物的分子量为60-1000kDa、70-1000kDa、80-1000kDa；更进一步的，所述载药层聚合物的分子量为90-1000kDa，100-1000kDa。
在本发明所提供的上述技术方案中，药物控释层聚合物的分子量可以在很宽的范围内波动，而载药层和腐蚀控制层相对于药物控释层对聚合物分子量有更高的要求。载药层中的聚合物为活性药物的载体，其种类、分子量、载药涂层厚度，以及与药物的质量比等都对药物释放速度有重要影响。聚合物分子量越高，聚合物与药物之间物相分离越明显，药物释放速度越快；聚合物的质量与药物质量比值越小，聚合物对药物的约束能力越弱，药物释放速度越快；载药涂层越薄，药物扩散释放路径越短，药物释放速度越快；在腐蚀控制层，聚合物的分子量相对比较高，分子量太小，其在早期的腐蚀速度快，容易导致器械中可降解金属部分在早期快速的腐蚀而不满足力学性能的要求，或导致聚合物过早的降解之后在后期不能有效的调控器械中可降解金属部分快速的腐蚀。
根据本发明所提供的上述技术方案，所述腐蚀控制层、载药层和药物控释层的总厚度为3.5-45μm；进一步的，所述腐蚀控制层、载药层和药物控释层的总厚度为5.5-40μm；更进一步的，所述腐蚀控制层、载药层和药物控释层的总厚度为5.8-36μm。
根据本发明所提供的上述技术方案，所述腐蚀控制层、载药层和药物控释层的厚度比为1:(0.5-15):(0.2-13)。
根据本发明所提供的上述技术方案，所述药物控释层的厚度为0.2-8μm；进一步的，所述腐蚀控制层的厚度为0.5-7μm；更进一步的，所述腐蚀控制层的厚度为0.8-6.6μm。
根据本发明所提供的上述技术方案，所述腐蚀控制层的厚度为0.2-6μm；进一步的，所述腐蚀控制层的厚度为0.5-5μm；更进一步的，所述腐蚀控制层 的厚度为0.8-3μm。
根据本发明所提供的上述技术方案，所述载药层的厚度为1-8μm；进一步的，所述腐蚀控制层的厚度为1.5-7μm；更进一步的，所述腐蚀控制层的厚度为1.5-6μm。
根据本发明所提供的上述技术方案，所述涂层的三层结构中，至少有一层中还包括有促腐蚀剂、延缓腐蚀剂或抗氧化剂。
根据本发明所提供的上述技术方案，所述涂层还包括位于腐蚀控制层内侧的金属隔离层。所述金属隔离层为含比医疗器械基材更活泼的金属元素的涂层，金属涂层可通过电镀法、喷镀法、或者化学镀等方法使金属涂层致密均匀地分布在可降解器械基材表面。
根据本发明所提供的上述技术方案，所述金属隔离层可用于延缓医疗器械基体的腐蚀。
在本发明的一些实施例中，所述金属隔离层中至少有一种金属的电负性小于所述可降解医疗器械的基体金属的电负性，也即所述金属隔离层中至少有一种金属比所述可降解医疗器械的基体金属更活泼，所述金属隔离层可以是纯金属，也可以是金属合金；当金属隔离层为纯金属时，该金属的电负性比可降解医疗器械的基体金属的电负性小，也即该金属比可降解医疗器械的基体金属更活泼，如当可降解医疗器械的基体为铁基时，所述金属隔离层为纯锌或纯镁；当金属隔离层为金属合金时，金属合金中的主要金属元素也即含量较高的一种或多种元素的活性比可降解医疗器械的基体金属更活动，或电负性更小，如当可降解医疗器械的基体为铁基时，所述金属隔离层为锌合金或镁合金。在本发明的另外一些实施例中，所述金属隔离层可以是含金属氧化物的隔离层。在本发明的其他一些实施例中，所述金属隔离层可以是任何其他的可防止医疗器械基体腐蚀的含金属的涂层。
根据本发明所提供的上述技术方案，当所述可吸收金属基体中的金属为纯铁或铁基合金时，所述金属隔离层包括纯镁、含镁合金、纯锌或含锌合金；当所述可吸收金属基体中的金属为纯锌或含锌合金时，所述金属隔离层包括纯镁、含镁合金。
由于金属隔离层中的金属比构成器械基材的金属相对更加活泼，所以在体内微环境中可以形成电化学保护，隔离层中的相对活泼的金属优先腐蚀，而起支撑作用的器械基材却被保护起来可以延缓其腐蚀，例如当器械基材为铁或者铁合金时，在器械表面覆盖由锌或者锌合金构成的金属涂层，会在体内微环境中形成原电池，锌或者锌合金构成的金属涂层作为负极，失去电子变成锌离子，优先被腐蚀，而铁或者铁合金的器械基材则作为正极暂时被保护起来不会被腐蚀。
本发明中的药物控释层、载药层，或药物控释层、载药层和腐蚀控制层，或药物控释层、载药层和金属隔离层，或药物控释层、载药层、腐蚀控制层和金属隔离层四种方案均可以实现既控制药物释放又控制基体的腐蚀，每种方案中涂层的各层的各项参数之间互相协同、互相搭配均可以实现本发明的发明目的。如在本发明的一些实施例中，所述医疗器械用涂层从外到内为药物控释层和载药层，或药物控释层、载药层和腐蚀控制层，通过分别对上述涂层中各层中的聚合物种类、聚合物分子量和涂层厚度，以及载药量在相应区间内调整，使得最终的涂层既能具有优异的释药性能，又具有优异的腐蚀调控性能，使得器械在植入到相应部位后，既不会出现增生、又不会出现炎症，同时在前1-6个月不会腐蚀或慢速腐蚀，在6个月后快速腐蚀。
根据本发明所提供的上述技术方案，所述金属隔离层的厚度≥0.6μm，进一步的，所述金属隔离层的厚度为0.6-3.8μm之间。当金属隔离层的厚度足够时，可以有效的防止可降解医疗器械的基体金属过早的腐蚀，从而确保基体能满足前1-6个月内不腐蚀，而金属隔离层的厚度也不能过大，否则在2年内不能全部腐蚀，最终导致可降解医疗器械6个月之后不能快速被腐蚀，2年之内也不能完全腐蚀。
根据本发明所提供的上述技术方案，所述涂层中的聚合物为可降解聚酯或可降解聚酸酐中的至少一种；进一步的，本发明中所述聚合物选自聚消旋乳酸、聚左旋乳酸、聚右旋乳酸、聚羟乙酯、聚氨酯、聚氨基酸、聚(乳酸二乙醇酸)酸、聚-D,L-丙交酯、聚丙二醇、聚乙醇酸、聚乳酸乙醇酸、聚水杨酸酐酯、聚三亚甲基碳酸酯、聚己内酯、聚已内酯、聚羟基脂肪酸酯、聚丙烯酸酯、聚丁 二酸酯、聚(β-羟基丁酸酯)及聚己二酸乙二醇酯中、聚1，3-双(对羧基苯氧基)丙烷-癸二酸、聚芥酸二聚体-癸二酸及聚富马酸-癸二酸中的至少一种。在本发明的一些实施例中，所述涂层中的聚合物可以为上述聚合物中的具体一种，如所述涂层中的药物控释层、腐蚀控制层和腐蚀控制层中的聚合物均为聚消旋乳酸；在本发明的另一些实施例中，所述涂层中的聚合物可以为上述聚合物中的两种或多种的混合物，如为聚左旋乳酸、聚右旋乳酸、聚氨酯、聚水杨酸酐酯、聚三亚甲基碳酸酯或聚己内酯中的两种或多种的混合物；所述两种或多种的混合物，可以是某一层中同时含有两种聚合物，也可以是每个单层中均仅含一种互不相同聚合物，如在本发明的一些实施例中所述涂层中的外层药物控释层中的聚合物为聚左旋乳酸，载药层中的聚合物为聚消旋乳酸，而腐蚀控制层中的聚合物为聚氨酯；而在本发明的另一些实施例中，所述涂层中的药物控释层、腐蚀控制层和腐蚀控制层中的聚合物均为聚氨酯和聚水杨酸酐酯，或聚消旋乳酸、聚左旋乳酸、聚右旋乳酸的混合物；在还有一些实施例中，所述涂层中的药物控释层、腐蚀控制层的聚合物为聚消旋乳酸，腐蚀控制层中聚合物为聚羟基脂肪酸酯和聚丙烯酸酯的混合物。
根据本发明所提供的上述技术方案，所述涂层中所负载的药物为抑制血管增生的药物、抗炎症反应药物、抗血栓类药物和致敏药物中的至少一种；所述抗血栓类药物包括抗血小板药物、抗凝血类药物。在本发明的一些实施例中，涂层中所载药物仅为抑制血管增生的药物；在其他一些实施例中，涂层中所负载的药物为抑制血管增生的药物、抗炎症反应药物、抗血栓类药物和致敏药物中的任意两种或两种以上的药物的组合。更为具体的，本发明中所述的抑制血管增生的药物选自紫杉醇、雷帕霉素及其衍生物中的至少一种；抗血小板类药物包括西洛他唑；抗血栓类药物包括肝素；抗炎症反应药物为地塞米松；抗致敏药物选自葡萄糖酸钙、扑尔敏及可的松的至少一种。
根据本发明所提供的上述技术方案，所述载药层中所负载的药物为紫杉醇、雷帕霉素、西洛他唑、肝素、他克莫司、依维莫司、地塞米松、葡萄糖酸钙、扑尔敏或可的松中的至少一种。
根据本发明所提供的上述技术方案，所述医疗器械为可降解金属医疗器械 或可降解非金属医疗器械，所述金属为纯金属或金属合金。进一步的，所述的可降解医疗器械为至少部分包括铁基、锌基、聚合物和镁基的医疗器械。在本发明的一些实施例中，所述可降解医疗器械的基体由一种金属或金属合金组成，如整个可降解医疗器械为铁基医疗器械；在本发明的另外一些实施例中，所述可降解医疗器械的基体是由两种或多种材质组成，如部分为铁基，部分为锌基，或者部分为金属基，部分为非金属基。
根据本发明所提供的上述技术方案，所述医疗器械包括血管支架、心脏瓣膜、非血管腔内支架、封堵器、骨科植入物、齿科植入物、呼吸科植入物、妇科植入物、男科植入物、缝合线或者螺栓中的任意一种。
根据本发明所提供的上述技术方案，本发明所述的支架为血管内支架或心脏瓣膜用支架；进一步的，本发明所述支架为球扩式支架或自扩张支架；更进一步的，本发明所述支架包括冠脉支架、膝下支架、股浅支架、颅内支架、颈动脉支架、肺动脉支架或肾动脉支架。
根据本发明所提供的上述技术方案，所述的可降解医疗器械的基材为纯铁或含碳量不高于2.11wt％的铁基合金。
需要特殊说明的是，上述的铁基、锌基或者镁基，其中的金属均是指基体中主要成分。如铁基包括纯铁或铁合金，也即铁基是指该种基材中的主要成分为铁。
本发明通过药物控释层的聚合物种类、聚合物分子量和聚合物的厚度三者之间的关系或存在的内在逻辑来控制载药层药物的释放，本发明中所提供的药物控释层可有效的防止支架在刚植入人体时，载药层内的药物在血液的冲刷下，急剧地释放，导致早期药物释放过快，而后期药物释放不足，不能持久有效地进行药物释放，从而避免引起血管再狭窄，也即本发明中的药物控释层既对载药层有一定的保护作用，同时又可以调控载药层中所负载药物的释放速度。本发明通过在载药层外面增加一层特殊的药物控释层，载药层的药物只有在药物控释层的聚合物降解到一定程度之后，才会逐渐增大载药层与血液的接触面积，因此可以有效控制支架植入早期药物暴释的问题。
本发明中的药物控释层和载药层一起协同控制药物的释放，一方面，有效 的控制药物在各个阶段的释放速度，确保各个阶段所释放的药物的量刚好满足需求；另一方面使载药层中尽可能的载适量的药，防止载药量过大对人体有一定的毒副作用，也即在控制药物释放确保药物量刚好满足需求的同时尽可能的减少总载药量。
本发明中的药物控释层、载药层和腐蚀促进层中均含有聚合物，通过三种涂层中聚合物的厚度和分子量共同协同作用，一起控制器械基体，或器械基体和金属隔离层的腐蚀。在本发明所提供的一些实施例中，当药物控释层的聚合物分子量比较小时，为了控制最终器械基体综合的腐蚀速度，可以调控载药层和腐蚀控制层中聚合物的种类和分子量使其满足要求，如提高载药层和腐蚀控制层的聚合物的分子量，同时选择降解速率相对比较慢的聚合物。
本发明的技术方案中所引入的金属隔离层可以和上述含聚合物的涂层一起控制器械基材的腐蚀速度，确保器械在植入早期(1-6个月)不腐蚀，但当血管修复完成后，再让器械基材迅速降解。在体内环境下，腐蚀控制层和金属隔离层同时进行降解，构成腐蚀控制层的可降解聚酯降解时会产生酸性物质，当降解积累至一定程度后，可以形成局部酸性环境，从而可以加剧金属隔离层和医疗器械基体的腐蚀和降解。这一过程可以通过腐蚀控制层的可降解聚酯厚度以及分子量来控制。分子量越低，可降解聚酯厚度越厚，金属隔离层和支架的腐蚀和降解越快。
本发明中的腐蚀控制层、载药层和药物控释层中的聚合物一起协同的控制器械基体或器械基体和金属隔离层的腐蚀，同时腐蚀控制层还可以起到隔离器械基体和金属隔离层在腐蚀过程中所产生的金属离子和人体环境的作用，防止金属离子与活性药物结合之后不受阻碍的转移至人体血管内，从而导致溶血，或者防止过量的金属离子与人体直接接触，引发局部中毒或者血栓现象。
应理解的是，文中使用的术语仅出于描述特定示例实施方式的目的，而无意于进行限制。除非上下文另外明确地指出，否则如文中使用的单数形式“一”、“一个”以及“所述”也可以表示包括复数形式。术语“包括”、“包含”、“含有”以及“具有”是包含性的，并且因此指明所陈述的特征、步骤、操作、元件和/或部件的存在，但并不排除存在或者添加一个或多个其它特征、步骤、操作、元件、 部件、和/或它们的组合。文中描述的方法步骤、过程、以及操作不解释为必须要求它们以所描述或说明的特定顺序执行，除非明确指出执行顺序。还应当理解，可以使用另外或者替代的步骤。
附图说明
通过阅读下文优选实施方式的详细描述，各种其它的优点和益处对于本领域普通技术人员将变得清楚明了。附图仅用于示出优选实施方式的目的，而并不认为是对本发明的限制。而且在整个附图中，用相同的附图标记表示相同的部件。其中：
图1为实施例1中支架涂层中各分层厚度测试的拉曼光谱图，其中：1-金属隔离层，2-腐蚀控制层，3-载药层，4-药物控释层，5-镶嵌样品材料环氧聚酯；
图2为实施例1和实施例6的载药层中药物颗粒粒径测试的SEM图，其中图2-1为实施例6中乙酸乙酯溶剂喷涂涂层零时刻的横截面；图2-2为实施例6中乙酸乙酯溶剂喷涂涂层药物浸提后的横截面；图2-3为实施例1中三氯甲烷溶剂喷涂涂层药物浸提后的横截图；
图3为实施例1和实施例6的载药层中药物结晶度测试的XRD图；
图4为实施例1-7和对比例1-5中的可吸收支架涂层的药物释放速率图；
图5为实施例1-7和对比例1-5中的可吸收支架在动物体内的质量损失百分比图；
图6为实施例1-7和对比例1-5中的可吸收支架在动物体内的径向支撑强度测试图。
具体实施方式
以下所述的仅为本发明的优选实施方式，本发明所保护的不限于以下优选实施方式，如实施例中均以支架为示例进行说明，但并不代表本发明的技术方案仅适用于支架。应当指出，对于本领域的技术人员来说在此发明创造构思的基础上，做出的若干变形和改进，都属于本发明的保护范围。所用试剂或仪器未注明生产商者，均为可以通过市购获得的常规产品。
测试方法
1、聚合物的重均分子量测定
使用美国Wyatt公司的GPC-多角度激光光散射仪联用分子量测试系统进行检测。该测试系统包括美国安捷伦公司的液相泵和进样器、美国安捷伦公司的Agilent PL MIXED-C型GPC柱(尺寸：7.5×300mm，5微米)、美国Wyatt公司的多角度激光光散射仪及示差检测器。检测条件为：
流动相：四氢呋喃；泵流速：1mL/min；进样量：100μL；激光波长：663.9nm；测试温度：35℃。
2、金属隔离层厚度的测定
X射线荧光镀层测厚仪法测定金属隔离层厚度：首先将需要使用对应元素的标准块对设备进行校准，校准完成后，将测试金属隔离层厚度的支架样品固定到样品台上，放入X射线荧光镀层测厚仪，设置涂层和基底金属类型，设置测量时间为10～15s，厚度单位μm等参数。点击确定即可测试金属隔离层厚度。
3、聚合物涂层总厚度的测定
使用扫描电镜法测量：首先将需要测试涂层厚度的支架样品固定到样品台上，然后将样品台放到JFC-1600喷金设备中喷铂金，喷完一次后旋转180°再喷一次保证所有位置被喷到。将表面喷好铂金的样品放置到按5:1的比例调配好的标乐常温树脂固化剂混合试剂中，静置8个小时以上才可以脱离封样壳。将封好的样品平均分为3段，每段用半自动磨抛机按照样品抛磨的程序进行抛磨，要将需要测量的样品截面抛光到无磨痕。将抛磨好的样品固定到扫描电镜的载物台上，将整个载物台放置到JFC-1600喷金设备中进行喷金20s。将喷好金的样品放到JSM-6510扫描电镜中进行厚度测量。
4、多层药物涂层各层厚度测试方法
首先将需要测试多层药物涂层表征的支架样品固定到样品台上，然后将样品台放到JFC-1600喷金设备中喷铂金，喷完一次后旋转180°再喷一次保证所有位置被喷到。将表面喷好金的样品放置到按5:1的比例调配好的标乐常温树脂固化剂混合试剂中，静置8个小时以上才可以脱离封样壳。将封好的样品平均 分为3段，每段用半自动磨抛机按照样品抛磨的程序进行抛磨，要将需要测量的样品截面抛光到无磨痕。将抛磨好的样品固定到扫描电镜的载物台上，将整个载物台放置到JFC-1600喷金设备中进行喷金20s。
使用显微拉曼光谱仪Thermo DXR2，对多层涂层医疗器械涂层部分的横截面进行扫描，激光能量参数：6.0mW，曝光时间20Hz，曝光次数50次，放大倍数：500倍。
通过YZ截面扫描，可以得到横截面的成分分布图，通过药物以及聚乳酸的特征峰可以定性分析出不同区域的药物以及聚乳酸含量并测试各涂层厚度。
5、涂层中药物颗粒的粒径测试方法
将不同溶剂制成的涂层在室温下真空干燥24小时后，将其放入盛有5mL异丙醇溶液的中，在37℃下以100rpm的转速震荡30分钟，待药物被异丙醇充分浸提后，将涂层取出并真空干燥24小时，再放入液氮进行脆断涂层处理，将脆断涂层处理后的样品固定到扫描电镜的载物台上，将整个载物台放置到JFC-1600喷金设备中进行喷金20s，将喷好金的样品放到JSM-6510扫描电镜中测量药物浸提后留下的孔径大小，可测出药物颗粒的粒径大小。
6、涂层中药物结晶度测试方法
将不同溶剂(乙酸乙酯、三氯甲烷)制成的涂层溶液，使用喷涂设备将溶液均匀地喷涂到不锈钢板，室温下真空干燥24小时，制得不同溶剂制成的药物/聚合物涂层薄膜。
对不同溶剂制成的药物/聚合物薄膜进行XRD测试(布鲁克D2PHASER)，采用θ-2θ联动模式对样品进行扫描，扫描角度范围为3-40°；扫描步长0.02°；扫描速度为4°/min。
7、多层涂层医疗器械在动物体内药物释放率的测试方法
将多层涂层医疗器械植入健康家兔体内血管，在预定观察时间点，诸如7小时、1天、3天、7天、14天、28天、60天、90天、180天分别将兔子处死，并取出多层涂层医疗器械。将医疗器械上的组织尽可能的去除后，放入棕色玻璃瓶内，并加入适量乙腈定容，可根据具体规格确定容体积，确保支架能够被溶液完全浸没。超声处理15分钟，用0.22μm尼龙有机系滤膜过滤，然后装入色谱 仪进样瓶内，使用液相色谱仪测试支架的剩余药量。支架的药物释放量为支架上的初始药量减去浸泡后支架上的残余药量(测试药量)，药物释放百分比为药物释放量与初始药量的比值。
色谱条件：乙腈:水＝65:35溶液为流动相，流速1.0ml/min，检测波长278nm，柱温50℃，进样量10.0μl。
8、可吸收支架动物体内质量损失测试
将多层涂层医疗器械植入健康家兔体内血管，在预定观察时间点，诸如7小时、1天、3天、7天、14天、28天、60天、90天、180天分别将兔子处死，并取出多层涂层医疗器械。将医疗器械上的组织尽可能的去除后，使用液相色谱仪测试支架的剩余药量。使用乙酸乙酯溶液清洗测试药量后的支架，使其上的聚合物涂层完全溶解。
对上述清洗后的支架进行micro-CT检查，对铁基基体腐蚀情况作定性分析。之后，将支架置入酒石酸溶液中经超声清洗，去除表面腐蚀产物层，干燥后称重为m腐蚀后。
器械的质量损失率m％为器械腐蚀前的质量m腐蚀前与器械腐蚀后并经过处理后的质量m腐蚀后之差，与器械腐蚀前的质量m腐蚀前的比值乘以100％，也即：
9、支架径向支撑强度测试
将支架配合合适的球囊(或者远端组件)进行扩张，扩张至名义压力下，使得支架样品外径达到既定尺寸。
使用三维显微镜测量支架长度，然后以压缩50％位移为终点，进行支撑力曲线测试。径向支撑强度以定义支架名义直径被压缩10％时的单位长度上的力值为支架的径向抗挤压性能的数值表示(单位：kPa)。
实施例1
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为0.6μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂 设备，均匀地喷涂平均厚度为3μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为600kDa，溶剂采用三氯甲烷；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为5μm的载药层，涂层采用聚消旋乳酸，分子量为400kDa，溶剂采用三氯甲烷，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:0.5，药物颗粒的平均粒径为0.25μm，药物颗粒为无定形态(见图3)；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为3μm的药物释放控制层，涂层采用聚消旋乳酸，一个月分子量保留率为74％，分子量为200kDa，溶剂采用乙酸乙酯。
该实施例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，整个植入阶段支架所在血管未观察到血栓，并且管腔畅通，无再狭窄。涂层能确保支架在6个月内有足够的支撑力，并在2年内完全降解。
实施例2
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为2μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为10μm的载药层，涂层采用聚消旋乳酸，分子量为400kDa，溶剂采用三氯甲烷，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:8，药物颗粒的平均粒径为0.35μm，药物颗粒为无定形态；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为1.8μm的药物释放控制层，涂层采用聚消旋乳酸，一个月分子量保留率为79％，分子量为400kDa，溶剂采用三氯甲烷。
该实施例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，整个植入阶段支架所在血管未观察到血栓，并且管腔畅通，无再狭窄。涂层能确保支架在6个月内有足够的支撑力，并在2年内完全降解。
实施例3
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为3μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为6μm的腐蚀控制层，涂层采用PLGA(50：50)，分子量为50kDa，溶剂采用三氯甲烷；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为5μm的载药层，涂层采用PLGA(50：50)，分子量为50kDa，溶剂采用三氯甲烷，所载药物选用西罗莫司，载药层中西罗莫司与PLGA的质量比为1:1.25，药物颗粒的平均粒径为0.45μm，药物颗粒为无定形态；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为6μm的药物释放控制层，涂层采用PLGA(50：50)，分子量为50kDa，一个月分子量保留率为61％，溶剂采用三氯甲烷。
该实施例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，整个植入阶段支架所在血管未观察到血栓，并且管腔畅通，无狭窄。涂层能确保支架在6个月内有足够的支撑力，并在2年内完全降解。
实施例4
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为3.8μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为5μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为400kDa，溶剂采用乙酸乙酯；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为4μm的载药层，涂层采用聚消旋乳酸，分子量为200kDa，溶剂采用乙酸乙酯，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:2，药物颗粒的平均粒径为0.2μm，药物颗粒为半结晶态；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为0.8μm的药物释放控制层，涂层采用聚消旋乳酸，一个月分子量保留率为81％，分子量为800kDa， 溶剂采用三氯甲烷。
该实施例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，整个植入阶段支架所在血管未观察到血栓，并且管腔畅通，无再狭窄。涂层能确保支架在6个月内有足够的支撑力，并在2年内完全降解。
实施例5
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为1μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为3.5μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为200kDa，溶剂采用乙酸乙酯；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为5μm的载药层，涂层采用聚消旋乳酸，分子量为100kDa，溶剂采用乙酸乙酯，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:1.5，药物颗粒的平均粒径为0.7μm，药物颗粒为半结晶态；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为5.8μm的药物释放控制层，涂层采用聚消旋乳酸，分子量为50kDa，一个月分子量保留率为63％，溶剂采用乙酸乙酯。
该实施例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，整个植入阶段支架所在血管未观察到血栓，并且管腔畅通，无再狭窄。涂层能确保支架在6个月内有足够的支撑力，并在2年内完全降解。
实施例6
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为2.5μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为2.5μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为300kDa，溶剂采用乙酸乙酯；待腐蚀控制层干燥后，使用支架喷涂设备， 均匀地喷涂平均厚度为8μm的载药层，涂层采用聚消旋乳酸，分子量为300kDa，溶剂采用乙酸乙酯，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:6，药物颗粒的平均粒径为0.35μm，药物颗粒为半结晶态(见图3)；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为2.6μm的药物释放控制层，分子量为600kDa，一个月分子量保留率为80％，溶剂采用三氯甲烷。
该实施例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，整个植入阶段支架所在血管未观察到血栓，并且管腔畅通，无再狭窄。
实施例7
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为1.5μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为2μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为200kDa，溶剂采用丙酮；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为3μm的载药层，涂层采用聚消旋乳酸，分子量为600kDa，溶剂采用丙酮，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:1.5，药物颗粒的平均粒径为0.6μm；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为6.6μm的药物释放控制层，分子量为100kDa，一个月分子量保留率为65％，溶剂采用丙酮。
该实施例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，整个植入阶段支架所在血管未观察到血栓，并且管腔畅通，无再狭窄。涂层能确保支架在6个月内有足够的支撑力，并在2年内完全降解。
对比例1
本实施例选用铁基支架，规格为3.0mm×8mm，：采用电镀法在基材表面 镀平均厚度为1μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为3μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为400kDa，溶剂采用乙酸乙酯；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为5μm的载药层，涂层采用聚消旋乳酸，分子量为200kDa，溶剂采用乙酸乙酯，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:2，药物颗粒的平均粒径为0.3μm，药物颗粒为半结晶态。
该对比例中支架在体内的药物释放速率见图4，从图4中可以看出，该对比例中支架在早期发生暴释，在支架植入前期释放大部分药物，导致中后期药物释放不足，在90天时间点时，支架所在血管出现比较严重的增生迹象。支架质量损失结果见图5，支架径向支撑强度见图6，支架在体内腐蚀速度正常，在6个月的时间点仍能够提供有效支撑。
对比例2
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为1.5μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为5μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为200kDa，溶剂采用三氯甲烷；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为5μm的载药层，涂层采用聚消旋乳酸，分子量为200kDa，溶剂采用三氯甲烷，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:1.25；涂层采用聚消旋乳酸，分子量为400kDa，溶剂采用三氯甲烷，所载药物选用西罗莫司，药物颗粒的平均粒径为0.35μm，药物颗粒为无定形态。
该对比例中支架在体内的药物释放速率见图4，从图4中可以看出，该对比例中支架在早期发生暴释，在支架植入前期释放大部分药物，导致中后期药物释放不足，在90天时间点时，支架所在血管观察到比较严重的增生迹象以及血栓。
支架质量损失率见图5，支架径向支撑强度见图6，支架在体内腐蚀速度正常，在6个月的时间点仍能够提供有效支撑。
对比例3
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为1μm的锌层，作为金属隔离层。在金属隔离层外，使用支架喷涂设备，均匀地喷涂平均厚度为4μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为800kDa，溶剂采用三氯甲烷；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为4μm的载药层，涂层采用聚消旋乳酸，分子量为400kDa，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:2，药物颗粒的平均粒径为0.35μm，药物颗粒为半结晶态，溶剂采用乙酸乙酯。待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为15μm的药物释放控制层，涂层采用聚消旋乳酸，一个月分子量保留率为74％，分子量为200kDa，溶剂采用乙酸乙酯。
该对比例中支架在体内的药物释放速率见图4，从图4中可以看出，该对比例种支架在早期药物释放不足，植入前期不能起到治疗作用，在14天时间点时，支架所在血管出现血栓迹象。
支架质量损失情况见图5，支架径向支撑强度见图6，由于涂层厚度增加，聚乳酸量也相应增加，导致支架在体内腐蚀速度加快，药物在前期释放速度慢，植入60天后已无法维持正常形态，也无法提供有效支撑力。30天支架杆上有明显血栓形成，支架植入90天后血管再狭窄严重，管腔面积丢失超过60％。
对比例4
本实施例选用铁基支架，规格为3.0mm×8mm，采用电镀法在基材表面镀平均厚度为0.6μm的锌层，作为金属隔离层。在金属隔离层表面，使用支架喷涂设备，均匀地喷涂平均厚度为2.5μm的腐蚀控制层，涂层采用聚消旋乳酸，分子量为200kDa，溶剂采用三氯甲烷；待腐蚀控制层干燥后，使用支架喷涂设 备，均匀地喷涂平均厚度为8μm的载药层，涂层采用聚消旋乳酸，分子量为200kDa，溶剂采用三氯甲烷，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:8，药物颗粒的平均粒径为0.35μm，药物颗粒为无定形态；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为0.2μm的药物释放控制层，涂层采用聚消旋乳酸，分子量为100kDa，一个月分子量保留率为68％，溶剂采用乙酸乙酯。
该对比例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，支架在体内腐蚀速度正常，在6个月的时间点仍能够提供有效支撑，但由于该对比例中支架药物释放控制层过薄，药物在早期发生暴释，在支架植入前期释放大部分药物，导致中后期药物释放不足，在90天时间点时，支架所在血管出现比较严重的增生迹象。
对比例5
本实施例选用铁基支架，规格为3.0mm×8mm，在金属基材表面，使用支架喷涂设备，均匀地喷涂平均厚度为2.5μm的涂层，涂层采用聚消旋乳酸，分子量为100kDa，溶剂采用三氯甲烷；待腐蚀控制层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为5μm的载药层，涂层采用聚消旋乳酸，分子量为100kDa，溶剂采用三氯甲烷，所载药物选用西罗莫司，载药层中西罗莫司与聚消旋乳酸的质量比为1:0.5，药物颗粒的平均粒径为0.25μm，药物颗粒为无定形态；待载药层干燥后，使用支架喷涂设备，均匀地喷涂平均厚度为0.2μm的药物释放控制层，涂层采用聚消旋乳酸，分子量为100kDa，一个月分子量保留率为68％，溶剂采用乙酸乙酯。
该对比例中支架在体内的药物释放速率见图4，支架质量损失情况见图5，支架径向支撑强度见图6，因缺少金属隔离层，支架基体腐蚀过快，支架杆在植入早期就出现断裂，导致药物释放也加快，支架植入前期释放大部分药物。植入60天后已无法维持正常形态，也无法提供有效支撑力。30天支架杆上有明显血栓形成，支架杆周围组织颜色异常，支架植入90天后血管再狭窄严重， 管腔面积丢失超过60％。
由上可以看出，与实施例4及对比例1相比，由于缺少药物控释层，对比例1发生了药物暴释，在短时间内释放了大量的药量，导致在中后期相当长的时间药物释放很少，药物利用率低下。
对比例1虽然与实施例4有同样的药物与聚酯的质量比例，但是因为对比例1缺少药物控释层，在短时间内释放了大量的药量，导致在中后期相当长的时间药物释放很少，药物利用率低下。而相比较对比例2，对比例2的药物颗粒形态与溶剂种类都不同，却都是因为缺少药物控释层，导致了药物在体内的暴释。
对比例3和实施例4相比，虽然有相同的溶剂和药物颗粒形态，但是因为药物控释层过厚，前中期药物释放不足，导致血管发生增生和再狭窄，同样起不到药物治疗作用，对比例3因为聚乳酸涂层过厚，聚乳酸的含量增加，导致支架在体内腐蚀速度加快，植入60天后已无法维持正常形态，也无法提供有效支撑力，加剧了血管血栓和再狭窄的症状。
对比例4与对比例5，虽然都具有药物控释层，但是由于药物控释层厚度不够，在表面聚乳酸降解后，同样在短时间内释放了大量的药量，导致在中后期相当长的时间药物释放很少，药物利用率低下。
而对比例5因缺少金属隔离层，同时也没有搭配相应的聚合物种类和聚合物分子量，因此聚合物直接与支架基材接触，支架基体腐蚀过快，支架杆在植入早期就出现断裂，导致药物释放也加快，植入60天后已无法维持正常形态，也无法提供有效支撑力。
而实施例1-7，虽然分子量不同，聚合物材料也有不同，试剂不同，结晶度不同和药物颗粒粒径不同，但是在配制了厚度合适的药物控释层后，均没有发生药物早期暴释，并在释放周期中合适地释放，比较合适地配合了支架基材的降解周期。
本发明还可有其它多种实施例，在不背离本发明精神及其实质的情况下，熟悉本领域的技术人员当可根据本发明做出各种相应的改变和变形，但这些相应的改变和变形都应属于本发明所附的权利要求的保护范围。

Claims (16)

  1. 一种医疗器械用涂层，其特征在于，所述涂层包括载药层和覆盖在载药层外的药物控释层，所述载药层和药物控释层中均含有聚合物，其特征在于，所述药物控释层中聚合物的分子量保留率m、聚合物的重均分子量Mw控释和聚合物的厚度X控释满足以下关系式：
    其中：
    A1为拟合常数，为823；
    A2为拟合常数，为79.9；
    k为拟合常数，为1.5；
    b为拟合常数，范围为0≤b≤2；
    所述Mw控释为药物控释层中聚合物的重均分子量，单位为千道尔顿，X控释的单位为μm。
  2. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述药物控释层中聚合物的重均分子量Mw控释为20-900kDa；聚合物的分子量保留率m为50％-80％。
  3. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述载药层中药物与聚合物的质量比为1:(0.1-50)。
  4. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述载药层中药物颗粒的粒径r≤0.8μm。
  5. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述载药层和药物控释层的厚度之和不小于2.5μm。
  6. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述载药层聚合物的分子量为30-1000kDa。
  7. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述载药层内侧还包括腐蚀控制层；所述腐蚀控制层中聚合物的分子量为50-1000kDa。
  8. 根据权利要求7所述的医疗器械用涂层，其特征在于，所述腐蚀控制层、载药层和药物控释层的总厚度为3.5-45μm。
  9. 根据权利要求7所述的医疗器械用涂层，其特征在于，所述腐蚀控制层、 载药层和药物控释层的厚度比为1:(0.5-15):(0.2-13)。
  10. 根据权利要求7所述的医疗器械用涂层，其特征在于，所述涂层还包括位于腐蚀控制层内侧的金属隔离层。
  11. 根据权利要求10所述的医疗器械用涂层，其特征在于，所述金属隔离层的厚度≥0.6μm。
  12. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述聚合物为可降解聚酯或可降解聚酸酐中的至少一种；所述聚合物选自聚消旋乳酸、聚左旋乳酸、聚右旋乳酸、聚羟乙酯、聚氨酯、聚氨基酸、聚(乳酸二乙醇酸)酸、聚-D,L-丙交酯、聚丙二醇、聚乙醇酸、聚乳酸乙醇酸、聚水杨酸酐酯、聚三亚甲基碳酸酯、聚己内酯、聚已内酯、聚羟基脂肪酸酯、聚丙烯酸酯、聚丁二酸酯、聚(β-羟基丁酸酯)及聚己二酸乙二醇酯中、聚1，3-双(对羧基苯氧基)丙烷-癸二酸、聚芥酸二聚体-癸二酸及聚富马酸-癸二酸中的至少一种。
  13. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述载药层中所负载的药物为抑制血管增生的药物、抗炎症反应药物、抗血栓类药物和致敏药物中的至少一种。
  14. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述载药层中所负载的药物为紫杉醇、雷帕霉素、西洛他唑、肝素、地塞米松、他克莫司、依维莫司、葡萄糖酸钙、扑尔敏或可的松中的至少一种。
  15. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述医疗器械为可降解医疗器械；所述医疗器械为可降解金属医疗器械或可降解非金属医疗器械。
  16. 根据权利要求1所述的医疗器械用涂层，其特征在于，所述可降解医疗器械包括血管支架、心脏瓣膜、非血管腔内支架、封堵器、骨科植入物、齿科植入物、呼吸科植入物、妇科植入物、男科植入物、缝合线或者螺栓中的任意一种。
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