WO2023236188A1 - 一种药物涂层、药物涂层球囊及其制备方法 - Google Patents

一种药物涂层、药物涂层球囊及其制备方法 Download PDF

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WO2023236188A1
WO2023236188A1 PCT/CN2022/098130 CN2022098130W WO2023236188A1 WO 2023236188 A1 WO2023236188 A1 WO 2023236188A1 CN 2022098130 W CN2022098130 W CN 2022098130W WO 2023236188 A1 WO2023236188 A1 WO 2023236188A1
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drug
core
coating
positively charged
shell structure
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PCT/CN2022/098130
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English (en)
French (fr)
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刘扬扬
赵丽晓
马翠杰
张毅
胡晓君
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乐普（北京）医疗器械股份有限公司
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Priority to PCT/CN2022/098130 priority Critical patent/WO2023236188A1/zh
Priority to EP22859512.0A priority patent/EP4321183A1/en
Publication of WO2023236188A1 publication Critical patent/WO2023236188A1/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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A61L2300/608—Coatings having two or more layers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants

Definitions

  • the invention relates to the technical field of medical devices, and in particular to a drug coating, a drug-coated balloon and a preparation method thereof.
  • Coronary heart disease is the most common cause of death in the world today, killing more people than all cancers combined. According to incomplete statistics, the number of patients with coronary heart disease in my country has exceeded 11 million, and the number is increasing by 1 million every year. In 2018, a total of more than 900,000 percutaneous coronary intervention (PCI) surgeries were performed in China. Against the background of younger age of coronary heart disease, aging population, and continuous advancement of hierarchical diagnosis and treatment, it is expected that PCI procedures will remain at 13 per year in the next 3-5 years. %-16% growth.
  • Drug-coated balloon (DCB, referred to as drug balloon) is a coronary intervention technology developed in recent years. The surface of the drug balloon is coated with a drug coating.
  • the drug coating After being delivered to the lesion, the drug coating is transferred to the blood vessel wall within a short expansion period.
  • the drug coating releases anti-proliferative drugs to inhibit the proliferation of vascular smooth muscle cells. Rapamycin and other drugs are relatively safe in the human body, but due to their poor lipophilicity, slow tissue absorption and low bioavailability, the above shortcomings need to be overcome when applied in the field of drug balloons.
  • the current drug balloons mainly have the following problems: a large amount of drug is lost during the delivery process. Blood erosion or dissolution and falling off of the drug coating causes a large amount of drug coating loss on the surface of the balloon, which affects the transfer of the drug coating to the lesion. The amount of drug on the blood vessel wall. According to research, 80% or more of the drug in the drug-coated capsules in the prior art is lost during the drug delivery process, reducing the amount of drug transferred to the blood vessel wall, thereby reducing the efficacy; these lost drugs enter the human body The circulatory system increases the risk of downstream vascular embolism and increases the toxic and side effects of drug-coated balloons. Therefore, how to reduce the amount of drug delivered and increase the transfer to the blood vessel wall, thereby improving the efficacy, is still an urgent problem that researchers need to solve.
  • the technical problem to be solved by the present invention is to overcome the shortcomings of the prior art drug balloons in transferring the drug to the blood vessel wall, thereby providing a new type of drug-coated balloon and its preparation method.
  • the present invention provides a drug coating, which includes a drug active coating and a positively charged hydrophobic modification layer sequentially attached to the surface of a substrate, and the positively charged hydrophobic modification layer includes a positively charged modified substance and a hydrophobic substance.
  • the drug active coating includes a core-shell structure layer and/or a drug nanoparticle layer; wherein,
  • the core-shell structure layer includes core-shell structure particles, the core-shell structure particles have a core and a shell wrapping the core, the core is a drug particle, and the shell is a polymer shell;
  • the drug nanoparticle layer includes drug nanoparticles.
  • the particle size D50 of the core-shell structure particles is 100 nm-9 ⁇ m; preferably, the particle size D50 of the core-shell structure particles is 300 nm-6 ⁇ m.
  • the particle size D50 of the drug nanoparticles is 100nm-600nm.
  • the drug coating includes a core-shell structure layer, a drug nanoparticle layer and a positively charged hydrophobic modification layer sequentially attached to the surface of the substrate.
  • the drug coating also satisfies at least one of the following A-E:
  • the core-shell structural layer also includes a binder.
  • the binder is selected from polyvinyl alcohol, polyvinylpyrrolidone, Tween 80, poloxamer, egg yolk lecithin, soybean lecithin and formazan.
  • the polymer shell is an amphiphilic polymer shell.
  • the amphiphilic polymer includes a hydrophilic block and a hydrophobic block.
  • the hydrophilic block is polyethylene glycol or polyethylene glycol monomethyl ether,
  • the hydrophobic block is at least one of polyoxypropylene, polystyrene, polyamino acid, polylactic acid, polyglycolic acid and polycaprolactone polyglycolide lactide; preferably, a core-shell structure
  • the mass ratio of the drug particles and the polymer shell in the particles is 0.5-5:0.5-50;
  • the drug nanoparticle layer also includes a binder.
  • the binder is selected from polyvinyl alcohol, polyvinylpyrrolidone, Tween 80, poloxamer, egg yolk lecithin, soybean lecithin and formazan.
  • the ratio of the drug content (mass content) in the core-shell structure layer and the drug content (mass content) in the drug nanoparticle layer is 1-5:1-5; preferably 1-2:1-2;
  • the drug is a drug for preventing and treating coronary heart disease.
  • the drug for preventing and treating coronary heart disease is selected from rapamycin and/or rapamycin derivatives.
  • Rapamycin derivatives include common derivatives such as everolimus and zotarolimus;
  • the drug content in the core-shell structure layer is 1-5 ⁇ g/mm 2 ; and/or the drug content in the drug nanoparticle layer is 1-5 ⁇ g/mm 2 .
  • polyamino acids in the present invention include but are not limited to common polyamino acids such as polyglutamic acid, polyaspartic acid, and polyornithine.
  • the drug nanoparticle layer is also provided with a positively charged hydrophobic modification layer on the side away from the core-shell structure layer.
  • the positively charged hydrophobic modification layer includes positively charged lipid substances and hydrophobic substances. ; More preferably, the positively charged hydrophobic modification layer also satisfies at least one of the following (1)-(3):
  • the mass ratio of positively charged lipid substances and hydrophobic substances is 10-20:10-20;
  • the hydrophobic substance is selected from fatty acids, natural phospholipids or synthetic phospholipids.
  • the hydrophobic substance is selected from the group consisting of nervonic acid, phytanic acid, palmitic acid, linolenic acid, caprylic acid, vaccenic acid, hard acid, etc.
  • Fatty acid palmitic acid, lauric acid, arachidonic acid, eicosapentaenoic acid, cephalin, lecithin, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, phosphatidylglycerol, dimyristoylphosphatidyl At least one of ethanolamine, dilauroyl lecithin and 1-stearoyl-2-myristoyl lecithin;
  • the positively charged modifying substance is a positively charged lipid, preferably DC-cholesterol, dioleoylphosphatidylethanolamine, 2-dioleoylhydroxypropyl-3-N,N,N-trimethylammonium chloride, 1,2- At least one of dioctadecyloxy-3-methylammonium propane and 4-(N,N-dimethylamino)butyric acid (dilinoleyl)methyl ester;
  • the hydrophobic substance is phytanic acid
  • the positively modified substance is dioleoylphosphatidylethanolamine
  • the content of the positively charged hydrophobic modified layer is 0.1-1 ⁇ g/mm 2 .
  • the core-shell structure particles include the following raw materials: 0.5-5 parts by weight of drug, 0.5-50 parts by weight of amphiphilic polymer, 1-50 parts by volume of oil phase, and 100-2000 parts by volume of aqueous solution containing emulsifier; wherein , the ratio between parts by weight and parts by volume is g/mL; optionally, the oil phase is selected from at least one of methylene chloride, acetone or a combination thereof.
  • the drug nanoparticles include the following raw materials: 0.5-2 parts by weight of drug, 5-20 parts by volume of oil phase, and 5-100 parts by volume of aqueous solution containing emulsifier; wherein, the ratio between parts by weight and parts by volume is: g/mL; optionally, the oil phase selects at least one of methanol, ethanol or a combination thereof.
  • the emulsifier is selected from polyvinyl alcohol, polyvinylpyrrolidone, poloxamer, bovine serum albumin, Tween 80, poloxamer, egg yolk lecithin, soy lecithin and methylcellulose. At least one; and/or, the mass volume percentage of the emulsifier in the aqueous solution containing the emulsifier is 0.01-2% (w/v).
  • the present invention also provides a drug-coated balloon, which includes a balloon body and a drug coating attached to the outside of the balloon body.
  • the drug coating is any one of the above-mentioned drug coatings.
  • the invention also provides a method for preparing a drug-coated balloon, which includes the following steps:
  • Step S1 Spray the drug-containing coating solution on the outside of the balloon body and dry to form a drug-active coating
  • Step S2 Mix a positively charged modified substance, a hydrophobic substance and an organic solvent to prepare a positively charged hydrophobic modified layer coating liquid. Spray the positively charged hydrophobic modified layer coating liquid on the outside of the drug active coating and dry to form a positively charged hydrophobic modified layer. , to prepare drug-coated balloons.
  • the drying method for forming the coating may be common drying such as air drying and oven drying.
  • the organic solvent is selected from at least one of alkanes, alcohols and water; and/or the ratio of the mass of the positively modified substance, the mass of the hydrophobic substance and the volume of the organic solvent is 10-20mg:10 -20mg: 5mL.
  • the exemplary organic solvent is selected from at least one of n-heptane, n-hexane, n-pentane, methanol, ethanol and water.
  • the drug-containing coating liquid includes a core-shell structure layer coating liquid and/or a drug nanoparticle layer coating liquid
  • the preparation of the core-shell structural layer coating liquid includes: mixing core-shell structural particles with an organic solvent to prepare a core-shell structural layer coating liquid;
  • the preparation of the drug nanoparticle layer coating liquid includes mixing the drug nanoparticles with an organic solvent to prepare the drug nanoparticle layer coating liquid.
  • the organic solvent is selected from at least one of alkanes, alcohols and water; and/or, in the core-shell structure layer coating liquid, the ratio of the mass of the core-shell structure particles added to the volume of the organic solvent It is 2.1g:3-12mL; and/or, in the drug nanoparticle layer coating liquid, the ratio of the mass of the added drug nanoparticles to the volume of the organic solvent is 150mg:3-12mL.
  • the exemplary organic solvent is selected from at least one of n-heptane, n-hexane, n-pentane, methanol, ethanol and water.
  • the core-shell structure particles in the present invention can be produced by existing conventional methods.
  • the drug and the amphiphilic polymer can be dissolved in an oil phase, and the oil phase can be added dropwise to an aqueous solution containing an emulsifier, and then heated under high pressure.
  • At least one or a combination of homogenization, ultrasonic homogenization, solvent evaporation and membrane emulsification, centrifugation, removing the supernatant, and drying to obtain core-shell structure particles.
  • the drug nanoparticles in the present invention can be prepared by existing conventional methods.
  • the drug can be dissolved in an oil phase, the oil phase can be added dropwise to an aqueous solution containing an emulsifier, stirred or ultrasonicated, and dried to obtain Drug nanoparticles.
  • Core-shell structured particles and drug nanoparticles can be dried using existing conventional methods such as spray drying, freeze drying, and vacuum drying.
  • One or two freeze-drying protective agents are added before freeze-drying.
  • the types include but are not limited to: mannitol. , trehalose, sucrose, glucose, lactose, etc., the percentage of the quality of the freeze-dried protective agent in the quality of the drug can be 0.1%-10%, or 1-10%.
  • the drug coating provided by the present invention includes a drug active coating and a positively charged hydrophobic modification layer sequentially attached to the surface of a substrate, and the positively charged hydrophobic modification layer includes a positively charged modified substance and a hydrophobic substance.
  • the setting of the positively charged hydrophobic modification layer including positively charged modified substances and hydrophobic substances makes the entire drug coating surface positively charged and hydrophobic.
  • the positively charged characteristics enable it to strongly bind to the negatively charged inner wall of blood vessels, allowing the drug coating to Durable adsorption to the inner wall of blood vessels, combined with hydrophobic properties, can effectively resist the erosion of the drug coating by blood flow during the delivery process.
  • the drug coating with the above structure can not only reduce the loss of the drug during the delivery process of the drug balloon, but also reduce the loss of the drug during the delivery process. The loss during balloon expansion and contraction also increases the amount of drug transferred to the inner wall of the blood vessel.
  • the drug coating provided by the present invention is composed of drug nanoparticles and/or core-shell structural layers.
  • the drug coating includes a core-shell structural layer, a drug nanoparticle layer and a positively charged hydrophobic layer attached to the surface of the substrate in sequence.
  • the drug nanoparticles are more firmly bound to the surface of the balloon and are not easy to fall off, which greatly reduces the amount of drug loss during the delivery process in the body, increases the amount of drug transferred to the blood vessel wall, and thereby improves the efficacy.
  • the drug nanoparticles are arranged in the drug nanoparticle layer and the drug particles are arranged in the core-shell structure layer, so that the drug located in the drug nanoparticle layer can be quickly released after reaching the affected area to achieve rapid onset of action, and the core-shell structure layer
  • the slow release of the drug achieves a sustained release effect, prolongs the action time, and further improves the efficacy; the drug release can also be adjusted to achieve the purpose of regulating the drug release by adjusting the drug content of the core-shell structure layer and the drug nanoparticle layer.
  • the drug coating provided by the present invention can regulate the drug to have a reasonable release cycle by controlling the particle size D50 of the core-shell structure particles to 100 nm to 9 ⁇ m, and maintain a high therapeutic level of drug concentration in the target tissue, especially when controlled at 300nm ⁇ 6 ⁇ m allows the drug to be released in about 90 days.
  • the particle size of the drug nanoparticles is 100-600 nm.
  • the nano-scale drug particles can quickly penetrate into the target diseased tissue and exert immediate drug effect.
  • the core-shell structural layer further includes a binder.
  • the binder is selected from polyvinyl alcohol, polyvinylpyrrolidone, Tween 80, poloxamer, and egg yolk. At least one of lecithin, soy lecithin and methylcellulose; alternatively, the drug nanoparticle layer also includes a binder.
  • the binder is selected from polyvinyl alcohol, polyvinylpyrrolidone, polyvinylpyrrolidone, etc.
  • the drug coating provided by the present invention can further reduce the coating by using the hydrophobic substances and positively charged modifying substances listed in the present invention, especially by using the hydrophobic substance as phytanic acid and the positively charged modifying substance as dioleoylphosphatidylethanolamine. Loss rate, increase the amount of transferred blood vessel wall.
  • Figure 1 is a scanning electron microscope image of core-shell structure particles prepared in Example 1 of the present invention.
  • Figure 2 is a scanning electron microscope image of the drug nanoparticles prepared in Example 1 of the present invention.
  • Figure 3 is a scanning electron microscope image of the drug balloon prepared in Example 1 of the present invention.
  • the polyethylene glycol-polycaprolactone block copolymer (PEG-PCL) used in the present invention is purchased from: Shanghai Zhenzhun Biotechnology Co., Ltd., the number average molecular weight of PEG: 2000, and the number average molecular weight of PCL: 2000.
  • Polyethylene glycol-polylactide block copolymer (PEG-PLA) was purchased from: Shanghai Zhenzhun Biotechnology Co., Ltd., PEG number average molecular weight: 2000, PLA viscosity: 0.9-1.2dl/g.
  • PEG-PLGA Polyethylene glycol-polyglycolide lactide block copolymer
  • PEG number average molecular weight 2000
  • PLGA 75:25
  • viscosity 0.5-0.8dl/g
  • PLGA 50:50
  • Viscosity 0.3-0.5dl/g, all purchased from: Xi'an Ruixi Biotechnology Co., Ltd.
  • Polyvinyl alcohol (PVA) was purchased from: Tianrun Pharmaceutical Co., Ltd., model: 4-88; sodium alginate was purchased from: Qingdao Huanghai Biopharmaceutical Co., Ltd.; trehalose was purchased from: Jiangsu Hanston Pharmaceutical Co., Ltd. Specifications: Injection grade; Poloxamer 188, purchased from: Sigma Aldrich (Shanghai) Trading Co., Ltd.; Lactose was purchased from Jiangsu Hanstone Pharmaceutical Co., Ltd., specifications: Injection grade. Egg yolk lecithin was purchased from Lipoid Company, specifications: injection grade; the balloon was provided by Lepu (Beijing) Medical Equipment Co., Ltd., 3.5mm diameter ⁇ 20mm length;
  • the drug loading test method of the core-shell structure particles in the present invention is as follows: take 50 mg of the core-shell structure particles, add 5 mL acetonitrile, ultrasonic for 10 minutes, add acetonitrile to make the volume to 10 mL, centrifuge, take the supernatant, and inject it into a high-performance liquid chromatograph.
  • the content of the drug (rapamycin) in the core-shell structure particles was determined by high performance liquid chromatography, using octadecylsilane bonded silica gel as the filler, and methanol-acetonitrile.
  • Particle size D50 test Take 10 mg of core-shell structure particles or drug nanoparticles, add 5 ml of purified water to disperse evenly, and then test with a particle size distribution analyzer; take the average of three consecutive measurements.
  • This embodiment provides a drug-coated balloon, which includes a balloon body and a core-shell structural layer, a drug nanoparticle layer and a positively charged hydrophobic modification layer sequentially attached to the outside of the balloon body, wherein the core-shell structural layer includes Core-shell structure particles, the core-shell structure particles have a core and a shell wrapping the core, the core is rapamycin particles, the shell is a PEG-PCL shell; the drug nanoparticle layer includes drug nanoparticles , the drug nanoparticles are rapamycin nanoparticles.
  • the positively charged hydrophobic modified layer includes a positively charged modified substance (DC-cholesterol) and a hydrophobic modified substance (stearic acid).
  • the preparation method of the above-mentioned drug-coated balloon includes the following steps:
  • Rapamycin drug nanoparticles were prepared using antisolvent precipitation method. Weigh 0.5g of rapamycin and dissolve it in 5ml of methanol as the oil phase. Add this oil phase dropwise to 15ml of aqueous solution containing 2% (w/v) poloxamer 188. After ultrasonic for 30 minutes, add 25mg of trehalose to disperse evenly. , freeze-drying to obtain drug nanoparticles. After testing, the particle size D50 of the drug nanoparticles was 481 nm.
  • the first spraying Use a balloon spraying machine to spray the core-shell structure layer coating liquid onto the balloon surface.
  • the spraying parameters of the balloon spraying machine are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, so that the balloon surface The concentration of rapamycin reaches 1.0 ⁇ g/mm 2 and is dried;
  • Second spraying Use a balloon sprayer to spray the drug nanoparticle layer coating liquid onto the balloon surface.
  • the spraying parameters of the balloon sprayer are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, so that the balloon surface The concentration of rapamycin reaches 2.0 ⁇ g/mm 2 and is dried;
  • the third spraying Use a balloon sprayer to spray the positive hydrophobic modification layer coating onto the balloon surface.
  • the spraying parameters of the balloon sprayer are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, and dry.
  • the average weight gain of the third spray-coated balloon is 0.2 ⁇ g/mm 2 .
  • This embodiment provides a drug-coated balloon and a preparation method thereof.
  • the difference from Example 1 is only in the composition and preparation method of the positively charged hydrophobic modified layer coating liquid.
  • the positively charged hydrophobic modified layer coating liquid adopts 20 mg of DC-cholesterol and 10 mg of stearic acid were added to 5 ml of ethanol and dispersed evenly by ultrasonic to obtain a positively charged hydrophobic modification layer coating liquid.
  • This embodiment provides a drug-coated balloon and a preparation method thereof.
  • the only difference from Example 1 is that the average weight gain of the balloon after the third spraying is 0.1 ⁇ g/mm 2 .
  • This embodiment provides a drug-coated balloon and a preparation method thereof.
  • the difference from Example 1 is only in the composition and preparation method of the positively charged hydrophobic modification layer coating liquid and the difference in spray weight gain.
  • This embodiment is positively charged and hydrophobic.
  • the modification layer coating liquid uses 20 mg of dioleoylphosphatidylethanolamine (DOPE) and 20 mg of phytanic acid, added to 5 ml of ethanol, and dispersed evenly by ultrasonic to obtain a positively charged and hydrophobic modification layer coating liquid for later use.
  • DOPE dioleoylphosphatidylethanolamine
  • phytanic acid 20 mg
  • the average weight gain of the balloon after the third spraying was 0.1 ⁇ g/mm 2 .
  • This embodiment provides a drug-coated balloon and a preparation method thereof.
  • the difference from Example 1 is only in the composition and preparation method of the positively charged hydrophobic modified layer coating liquid.
  • the positively charged hydrophobic modified layer coating liquid adopts 20 mg of DOPE and 10 mg of phytanic acid were added to 5 ml of ethanol and dispersed evenly by ultrasonic to obtain a positively charged hydrophobic modification layer coating liquid for later use.
  • This embodiment provides a drug-coated balloon and a preparation method thereof.
  • the difference from Example 1 is only in the composition and preparation method of the positively charged hydrophobic modified layer coating liquid.
  • the positively charged hydrophobic modified layer coating liquid adopts 20 mg of DOPE and 20 mg of phytanic acid were added to 5 ml of ethanol and dispersed evenly by ultrasonic to obtain a positively charged hydrophobic modification layer coating liquid for later use.
  • This embodiment provides a drug-coated balloon and a preparation method thereof.
  • the only difference from Example 1 lies in the preparation methods of the core-shell structural layer coating liquid and the drug nanoparticle layer coating liquid.
  • take 2.1 g core-shell structure particles add them to 12 ml of ethanol, and disperse evenly with ultrasonic to obtain a core-shell structure layer coating liquid.
  • Take 150 mg of drug nanoparticles add it to 12 ml of ethanol, and disperse evenly by ultrasonic to obtain a drug nanoparticle layer coating liquid.
  • This embodiment provides a drug-coated balloon, which includes a balloon body and a core-shell structural layer, a drug nanoparticle layer and a positively charged hydrophobic modification layer sequentially attached to the outside of the balloon body, wherein the core-shell structural layer includes Core-shell structure particles, the core-shell structure particles have a core and a shell wrapping the core, the core is rapamycin particles, the shell is a PEG-PLA shell; the drug nanoparticle layer includes drug nanoparticles , the drug nanoparticles are rapamycin nanoparticles.
  • the positively charged hydrophobic modification layer includes DC-cholesterol and stearic acid.
  • the preparation method of the above-mentioned drug-coated balloon includes the following steps:
  • Rapamycin drug nanoparticles were prepared using antisolvent precipitation method. Weigh 2g of rapamycin and dissolve it in 20ml of ethanol as the oil phase. Add this oil phase dropwise to 100ml of aqueous solution containing 2% (w/v) poloxamer 188. After ultrasonic for 30 minutes, add 25mg of mannitol and disperse evenly. Freeze-drying to obtain drug nanoparticles. After testing, the particle size D50 of the drug nanoparticles was 593 nm.
  • the first spraying Use a balloon spraying machine to spray the core-shell structure layer coating liquid onto the balloon surface.
  • the spraying parameters of the balloon spraying machine are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, so that the balloon surface The concentration of rapamycin reaches 1.0 ⁇ g/mm 2 and is dried;
  • Second spraying Use a balloon sprayer to spray the drug nanoparticle layer coating liquid onto the surface of the balloon.
  • the spraying parameters of the balloon sprayer are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, so that the balloon The concentration of rapamycin on the surface reaches 2.0 ⁇ g/mm 2 and is left to dry;
  • the third spraying Use a balloon sprayer to spray the positive hydrophobic modification layer coating onto the balloon surface.
  • the spraying parameters of the balloon sprayer are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, and dry.
  • the average weight gain of the third spray-coated balloon is 0.2 ⁇ g/mm 2 .
  • This embodiment provides a drug-coated balloon and a preparation method thereof.
  • the drug nanoparticles, the drug nanoparticle layer coating liquid and the positively charged hydrophobic modification layer coating liquid are prepared according to the method of Example 1;
  • the first spraying Use a balloon sprayer to spray the drug nanoparticle layer coating liquid onto the surface of the balloon.
  • the spraying parameters of the balloon sprayer are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, so that the balloon The concentration of rapamycin on the surface reaches 2.0 ⁇ g/mm 2 and is left to dry;
  • Second spraying Use a balloon sprayer to spray the positive hydrophobic modification layer coating onto the balloon surface.
  • the spraying parameters of the balloon sprayer are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, and let dry.
  • the average weight gain of the second spray-coated balloon is 0.2 ⁇ g/mm 2 .
  • the average weight gain of the balloon after the second spraying (the weight of the balloon after drying after the second spraying - the weight after drying after the first spraying)/balloon surface area.
  • This embodiment provides a drug-coated balloon and a preparation method thereof.
  • the core-shell structure particles, the core-shell structure layer coating liquid, and the positively charged hydrophobic modification layer coating liquid are prepared according to the method of Example 1;
  • the first spraying Use a balloon spraying machine to spray the core-shell structure layer coating liquid onto the balloon surface.
  • the spraying parameters of the balloon spraying machine are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, so that the balloon surface The concentration of rapamycin reaches 2.0 ⁇ g/mm 2 and is dried;
  • Second spraying Use a balloon sprayer to spray the positive hydrophobic modification layer coating onto the balloon surface.
  • the spraying parameters of the balloon sprayer are: drip flow rate: 3.6ml/h, ultrasonic power: 0.05W, and let dry.
  • the average weight gain of the second spray-coated balloon is 0.2 ⁇ g/mm 2 .
  • This comparative example provides a drug-coated balloon, including a balloon body and a core-shell structural layer and a drug nanoparticle layer sequentially attached to the outside of the balloon body, wherein the core-shell structural layer includes core-shell structural particles,
  • the core-shell structure particles have a core and a shell wrapping the core, the core is rapamycin particles, and the shell is a PEG-PCL shell;
  • the drug nanoparticle layer includes drug nanoparticles, and the drug nanoparticles The particles are rapamycin nanoparticles.
  • the above drug-coated balloon was prepared according to the method of Example 1. The only difference was that the surface of the balloon was not sprayed for the third time, that is, the positively charged hydrophobic modification layer coating liquid was not sprayed.
  • the release medium is PBS (pH7.4) solution containing 0.03% (w/v) SDS, volume 40ml; sampling time points: 1 day, 4 days, 7 days, 14 days, 28 days, 60 days, 90 days. Take samples according to the sampling time points, with a sampling volume of 1.5ml each time and a rehydration volume of 1.5ml.
  • the solution to be tested is passed through a 0.5um filter membrane before use.
  • the content of rapamycin in the test solution was determined by high performance liquid chromatography.
  • Octadecylsilane bonded silica gel was used as the filler, and methanol-acetonitrile-water (volume The ratio is 60:17:23) as the mobile phase, the detection wavelength is 280nm, the flow rate is 1mL/min, and the column temperature is 40°C.
  • test groups 2-4 have better sustained release effect and better effect of extending the drug action time.
  • test group 1 released the drug faster due to its smaller particle size and could release 100% in 28 days, while test group 5 only released 69.9% in 90 days due to its larger particle size and the drug release cycle was too long.
  • the preferred particle size D50 of the core-shell structure particles in the present invention is 300 nm to 6 ⁇ m.
  • the drug balloons prepared in each Example and Comparative Example were used to simulate the drug loss and expansion process during the withdrawal and expansion of the drug balloon in the body using in vitro simulation transport equipment (see the pharmaceutical industry standard "YY/T 0807-2010").
  • the Chinese medicine coating is transferred to the inner wall of the blood vessel to indirectly evaluate the effectiveness, safety and anti-erosion ability of the coating.
  • Test method Heat the water bath of the in vitro simulated transport equipment and maintain the temperature at 37°C. Connect the end of the equipment to the silicone simulated blood vessel (provided by Shanghai Purin Medical Technology Co., Ltd., diameter 3.0mm), and insert the drug balloon product into the equipment. When the balloon body enters the simulated blood vessel, press and inflate the balloon to a pressure of 8 atm. After maintaining the pressure for 1 minute, after pumping the negative pressure, collect the liquid in the simulated blood vessel, the simulated blood vessel, the liquid in the in vitro simulated transport equipment and the fluid after expansion in sequence. sacculus. Test the rapamycin content as follows.
  • octadecylsilane bonded silica gel as the filler
  • methanol-acetonitrile-water volume ratio 60:17:23
  • the detection wavelength is 280nm
  • the flow rate is 1mL/min
  • the column temperature is 40 °C
  • record the chromatogram calculate the total mass of rapamycin in the simulated intravascular liquid, simulated blood vessel, liquid in the in vitro simulated transport device and the expanded balloon, and calculate the percentage of rapamycin in each part of the total mass.
  • Example 1 Comparing Example 1 with Example 7, it can be seen that in the preferred solution of the present invention, adding an adhesive to the core-shell structure layer and adding an adhesive to the nanoparticle layer can further increase the amount of drug transferred to the blood vessel wall and reduce the delivery process. loss and balloon expansion and contraction loss.
  • the transfer to the blood vessel wall can be further improved by arranging a core-shell structure layer, a drug nanoparticle layer and a positively charged hydrophobic modification layer sequentially attached to the surface of the substrate.
  • the amount of medicine is reduced, and the loss during the delivery process and the loss during balloon expansion and contraction are reduced.
  • the present invention can further increase the amount of drug transferred to the blood vessel wall by controlling the mass ratio of the positively charged modifying substance and the hydrophobic substance within a preferred range.
  • Example 5 Twelve white pigs were randomly divided into 2 groups, the experimental group and the control group, with 6 white pigs in each group.
  • One drug balloon of Example 5 was inserted into the coronary vessels LAD (left anterior descending artery), LCX (left circumflex artery) and RCA (right coronary artery) of white pigs in the control group to prepare a balloon of Comparative Example 1, and the balloon was expanded. 1 time ⁇ 60S, retracement.
  • the animals in the experimental group and the control group were killed on days 0 (after intervention), 7 days, and 28 days respectively.
  • Two animals in each group were killed at each time point, and the blood vessels at the balloon expansion site were dissected and stored, and they were frozen and stored at -80°C.

Abstract

一种药物涂层、药物涂层球囊及其制备方法，所述药物涂层包括依次附着于基体表面的药物活性涂层和正电疏水修饰层，包括正电修饰物质和疏水性物质的正电疏水修饰层的设置使得整个药物涂层表面带正电且具有疏水性，正电特性使得其与带负电荷的血管内壁能够强力结合，让药物涂层持久吸附于血管内壁，搭配疏水特性能够有效抵抗输送过程中血流对药物涂层的冲刷影响，通过上述结构的药物涂层不仅能够降低药物球囊输送过程中药物的损失，还能降低药物在球囊扩张收缩过程中的损失，同时提高药物转移到血管内壁上的量。

Description

一种药物涂层、药物涂层球囊及其制备方法 技术领域
本发明涉及医疗器械技术领域，具体涉及一种药物涂层、药物涂层球囊及其制备方法。
背景技术
冠心病是当今全球最常见的死因，它的致死人数甚至超过所有肿瘤死亡人数的总和。据不完全统计，我国的冠心病患者已超过1100万人，同时以每年100万的人数增加。2018年中国经皮冠状动脉介入治疗(PCI)手术共超过90万例，在冠心病低龄化、人口老龄化、分级诊疗不断推进的背景下，预计未来3-5年PCI术仍将维持每年13％-16％左右的增长。药物涂层球囊(DCB，简称药物球囊)是近年来发展起来的一项冠状动脉介入治疗技术。药物球囊的表面涂覆药物涂层，输送到病变部位后在短暂的扩张时间内把药物涂层转移到血管壁，药物涂层释放抗增生药物来抑制血管平滑肌细胞增生。雷帕霉素等药物在人体内安全性较高，但因其亲脂性差、组织吸收慢和生物利用度低，应用到药物球囊领域需克服上述缺点。
但是，目前药物球囊主要存在如下问题：输送过程中药物损失量多，血液冲刷或药物涂层的溶解脱落使球囊表面的药物涂层损失量较大，从而影响了药物涂层转移到病变血管壁的药物量，据研究表明，现有技术中的药物涂层胶囊中80％及以上的药物损失在药物输送过程，降低转移到血管壁上药物量，从而降低疗效；这些损失药物进入人体循环系统，增加下游血管栓塞风险，增加药物涂层球囊的毒副作用，因此，如何降低输送提高转移血管壁的药量，从而提高疗效仍是研发人员亟需解决的问题。
发明内容
因此，本发明要解决的技术问题在于克服现有技术中的药物球囊转移血管壁的药量低下的缺陷，从而提供一种新型的药物涂层球囊及其制备方法。
为此，本发明提供了一种药物涂层，所述药物涂层包括依次附着于基体表面的药物活性涂层和正电疏水修饰层，所述正电疏水修饰层包括正电修饰物质和疏水性物质。
进一步地，所述药物活性涂层包括核壳结构层和/或药物纳米粒子层；其中，
所述核壳结构层包括核壳结构粒子，所述核壳结构粒子具有内核及包裹住该内核 的外壳，所述内核为药物粒子，所述外壳为聚合物外壳；
所述药物纳米粒子层包括药物纳米粒子。
进一步地，所述核壳结构粒子的粒径D50为100nm～9μm；优选地，所述核壳结构粒子的粒径D50为300nm～6μm。
进一步地，所述药物纳米粒子的粒径D50为100nm-600nm。
进一步地，所述药物涂层包括依次附着于基体表面的核壳结构层、药物纳米粒子层和正电疏水修饰层。
进一步地，所述药物涂层还满足如下A-E中的至少一项：
A、所述核壳结构层还包括粘结剂，优选地，所述粘结剂选自聚乙烯醇、聚乙烯吡咯烷酮、吐温80、泊洛沙姆、蛋黄卵磷脂、大豆卵磷脂和甲基纤维素中的至少一种，优选地，粘结剂与核壳结构粒子的质量比为1:1-26；
B、所述聚合物外壳为两亲聚合物外壳，所述两亲聚合物包括亲水嵌段和疏水嵌段，所述亲水嵌段为聚乙二醇或者聚乙二醇单甲醚，所述疏水嵌段为聚氧丙烯，聚苯乙烯，聚氨基酸，聚乳酸，聚羟基乙酸和聚己内酯聚乙交酯丙交酯中的至少一种；优选地，优选地，核壳结构粒子中所述药物粒子与聚合物外壳的质量比为0.5-5：0.5-50；
C、所述药物纳米粒子层还包括粘结剂，优选地，所述粘结剂选自聚乙烯醇、聚乙烯吡咯烷酮、吐温80、泊洛沙姆、蛋黄卵磷脂、大豆卵磷脂和甲基纤维素中的至少一种，优选地，粘结剂和第二纳米药物颗粒的质量比为1:1-25；
D、所述核壳结构层中药物含量(质量含量)与药物纳米粒子层中药物含量(质量含量)之比为1-5：1-5；优选为1-2：1-2；
E、所述药物为防治冠心病的药物，优选地，所述防治冠心病的药物选自雷帕霉素和/或雷帕霉素衍生物。雷帕霉素衍生物包括依维莫司、佐他莫司等常见衍生物；
F、所述核壳结构层中药物含量为1～5μg/mm 2；和/或，所述药物纳米粒子层中药物含量为1～5μg/mm 2。
其中，本发明中聚氨基酸包括但不局限于聚谷氨酸、聚天冬氨酸、聚鸟氨酸等常见聚氨基酸。
进一步地，所述药物纳米粒子层位于背离核壳结构层的一侧还设置有正电疏水修饰层，优选地，所述正电疏水修饰层包括带正电的脂质类物质和疏水性物质；更优选地，所述正电疏水修饰层还满足如下(1)-(3)中的至少一项：
(1)带正电的脂质类物质和疏水性物质的质量比为10-20:10-20；
(2)所述疏水性物质选自脂肪酸类、天然磷脂或合成磷脂类，优选地，所述疏水性物质选自神经酸、植烷酸、棕榈酸、亚麻酸、辛酸、异油酸、硬脂酸、棕榈酸、月桂酸、花生四烯酸、二十碳五烯酸、脑磷脂、卵磷脂、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、磷脂酰甘油，二肉豆蔻酰基磷脂酰乙醇胺、二月桂酰基卵磷脂和1-硬脂酰基-2-肉豆蔻酰基卵磷脂中的至少一种；
正电修饰物质为带正电的脂质，优选为DC-胆固醇、二油酰基磷脂酰乙醇胺、2-二油酰基羟丙基-3-N,N,N-三甲铵氯、1,2-双十八烯氧基-3-甲基铵丙烷和4-(N,N-二甲基氨基)丁酸(二亚油基)甲酯中的至少一种；
更优选地，所述疏水性物质为植烷酸，所述正电修饰物质为二油酰基磷脂酰乙醇胺；
(3)以正电修饰物质和疏水性物质的总质量计，正电疏水修饰层的含量为0.1-1μg/mm 2。
进一步地，所述核壳结构粒子包括如下原料：药物0.5-5重量份，两亲聚合物0.5-50重量份，油相1-50体积份、含乳化剂的水溶液100-2000体积份；其中，重量份与体积份的配比关系为g/mL；可选的，所述油相选自二氯甲烷、丙酮中的至少一种或其组合。
进一步地，所述药物纳米粒子包括如下原料：药物0.5-2重量份、油相5-20体积份、含乳化剂的水溶液5-100体积份；其中，重量份与体积份的配比关系为g/mL；可选的，所述油相选择甲醇、乙醇中的至少一种或其组合。
进一步地，所述乳化剂选自聚乙烯醇、聚乙烯吡咯烷酮、泊洛沙姆、牛血清白蛋白、吐温80、泊洛沙姆、蛋黄卵磷脂、大豆卵磷脂和甲基纤维素中的至少一种；和/或，含乳化剂的水溶液中乳化剂的质量体积百分数为0.01-2％(w/v)。
本发明还提供了一种药物涂层球囊，包括球囊本体和附着于球囊本体外的药物涂层，所述药物涂层为上述任一所述的药物涂层。
本发明还提供了一种药物涂层球囊的制备方法，包括如下步骤：
S1步骤：将含药物的涂液喷涂于球囊本体的外侧，干燥形成药物活性涂层；
S2步骤：取正电修饰物质、疏水性物质与有机溶剂混合制得正电疏水修饰层涂液，将正电疏水修饰层涂液喷涂于药物活性涂层的外侧，干燥形成正电疏水修饰层，制得药物涂层球囊。
本发明中，形成涂层的干燥方式可以是晾干、烘干等常见干燥。
进一步地，所述有机溶剂选自烷烃类、醇类和水中的至少一种；和/或，正电修饰物质的质量、疏水性物质的质量与有机溶剂的体积之比为10-20mg:10-20mg：5mL。示例性的所述有机溶剂选自正庚烷、正己烷、正戊烷、甲醇、乙醇和水中的至少一种。
进一步地，所述含药物的涂液包括核壳结构层涂液和/或药物纳米粒子层涂液；
所述核壳结构层涂液的制备包括，取核壳结构粒子与有机溶剂混合，制得核壳结构层涂液；
所述药物纳米粒子层涂液的制备包括，取药物纳米粒子与有机溶剂混合，制得药物纳米粒子层涂液。
进一步地，所述有机溶剂选自烷烃类、醇类和水中的至少一种；和/或，核壳结构层涂液中，加入的所述核壳结构粒子的质量与有机溶剂的体积之比为2.1g:3-12mL；和/或，药物纳米粒子层涂液中，加入的所述药物纳米粒子的质量与有机溶剂的体积之比为150mg:3-12mL。示例性的所述有机溶剂选自正庚烷、正己烷、正戊烷、甲醇、乙醇和水中的至少一种。
本发明中的核壳结构粒子可采用现有的常规方法制得，示例地，可以取药物和两亲聚合物溶解于油相中，将油相滴加至含乳化剂的水溶液中，经高压均质、超声均质、溶剂挥发和膜乳化中的至少一种或组合，离心，去除上清液，干燥，得到核壳结构粒子。
本发明中的药物纳米粒子可采用现有的常规方法制得，示例地，可以取药物溶解于油相中，将油相滴加至含乳化剂的水溶液中，经搅拌或者超声，干燥，得到药物纳米粒子。
核壳结构粒子和药物纳米粒子的干燥均可采用喷雾干燥、冷冻干燥和真空干燥等现有常规方式，在冷冻干燥前加入冻干保护剂一种或两种，种类包括但不限于：甘露醇、海藻糖、蔗糖、葡萄糖、乳糖等，冻干保护剂质量占药物质量的百分数可以为0.1％-10％，也可以是1-10％。
本发明技术方案，具有如下优点：
1.本发明提供的药物涂层，所述药物涂层包括依次附着于基体表面的药物活性涂层和正电疏水修饰层，所述正电疏水修饰层包括正电修饰物质和疏水性物质。包括正电修饰物质和疏水性物质的正电疏水修饰层的设置整个药物涂层表面带正电且具有疏水性，正电特性使得其与带负电荷的血管内壁能够强力结合，让药物涂层持久吸附于 血管内壁，搭配疏水特性能够有效抵抗输送过程中血流对药物涂层的冲刷影响，通过上述结构的药物涂层不仅能够降低药物球囊输送过程中药物的损失，还能降低药物在球囊扩张收缩过程中的损失，同时提高药物转移到血管内壁上的量。
2.本发明提供的药物涂层，通过药物纳米粒子和/或核壳结构层的设置，尤其是所述药物涂层包括依次附着于基体表面的核壳结构层、药物纳米粒子层和正电疏水修饰层时，一方面，使得药物纳米粒子更加牢固地结合在球囊表面，不易脱落，大大降低在体内输送过程中药物损失量，提高转移到血管壁的药量，进而提高疗效，另一方面，将药物纳米粒子设置于药物纳米粒子层内和将药物粒子设置于核壳结构层内，使得位于药物纳米粒子层的药物到达患处后快速释放达到快速起效的目的，而核壳结构层的药物缓慢释放达到缓释作用，延长作用时间，进一步提高疗效；还可以通过调整核壳结构层和药物纳米粒子层的含药量来调整实现调控药物释放的目的。
3.本发明提供的药物涂层，通过将核壳结构粒子的粒径D50控制在100nm～9μm可以调控药物具有合理的释放周期，维持靶组织药物浓度控制较高的治疗水平，尤其是控制在300nm～6μm使得药物在90天左右完成释放。
4.本发明提供的药物涂层，药物纳米粒子的粒径为100-600nm，纳米级药物颗粒能快速渗透进入靶病变组织，起到即刻发挥药效的作用。
5.本发明提供的药物涂层，所述核壳结构层还包括粘结剂，优选地，所述粘结剂选自聚乙烯醇、聚乙烯吡咯烷酮、吐温80、泊洛沙姆、蛋黄卵磷脂、大豆卵磷脂和甲基纤维素中的至少一种；或者，所述药物纳米粒子层还包括粘结剂，优选地，所述粘结剂选自聚乙烯醇、聚乙烯吡咯烷酮、吐温80、泊洛沙姆、蛋黄卵磷脂、大豆卵磷脂和甲基纤维素中的至少一种；粘附剂的加入增加核壳粒子间粘结力，使得输送和扩张过程中涂层损失更低，增加涂层与血管壁的亲和力，使得涂层转移量更高；增加药物亲脂性，药物更快进入靶组织。
6.本发明提供的药物涂层，通过采用本发明所列举的疏水性物质和正电修饰物质，尤其是采用疏水性物质为植烷酸，正电修饰物质为二油酰基磷脂酰乙醇胺能够进一步降低损失率，提升转移血管壁用量。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性 劳动的前提下，还可以根据这些附图获得其他的附图。
图1是本发明实施例1制备得到的核壳结构粒子的扫描电镜图；
图2是本发明实施例1制备得到的药物纳米粒子的扫描电镜图；
图3是本发明实施例1制备得到的药物球囊的扫描电镜图。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明，并不局限于所述最佳实施方式，不对本发明的内容和保护范围构成限制，任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品，均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者，按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规试剂产品。
例如，本发明采用的聚乙二醇-聚己内酯嵌段共聚物(PEG-PCL)购自：上海甄准生物科技有限公司，PEG数均分子量：2000，PCL数均分子量：2000。聚乙二醇-聚丙交酯嵌段共聚物(PEG-PLA)购自：上海甄准生物科技有限公司，PEG数均分子量：2000，PLA粘度：0.9-1.2dl/g。聚乙二醇-聚乙交酯丙交酯嵌段共聚物(PEG-PLGA)，PEG数均分子量：2000，PLGA(75:25)粘度：0.5-0.8dl/g，PLGA(50:50)粘度：0.3-0.5dl/g，均购自：西安瑞禧生物科技有限公司。
聚乙烯醇(PVA)购自：天润药业有限公司，型号：4-88；海藻酸钠购自：青岛黄海生物制药有限责任公司；海藻糖购自：江苏汉斯通药业有限公司，规格：注射级；泊洛沙姆188，购自：西格玛奥德里奇(上海)贸易有限公司；乳糖购自江苏汉斯通药业有限公司，规格：注射级。蛋黄卵磷脂购自Lipoid公司，规格：注射级；球囊由乐普(北京)医疗器械股份有限公司提供，3.5mm直径×20mm长度；
本发明中核壳结构粒子的载药量测试方法如下：取核壳结构粒子50mg，加5mL乙腈，超声10分钟，加乙腈定容至10mL，离心，取上清液，分别注入高效液相色谱仪，按中华人民共和国药典(2020年版)通则0512高效液相色谱法测定核壳结构粒子中药物(雷帕霉素)的含量，以十八烷基硅烷键合硅胶为填充剂，以甲醇-乙腈-水(60：17：23)为流动相，检测波长280nm，流速1mL/min，柱温40℃。粒径D50测试：取核壳结构粒子或者药物纳米粒子10mg，加入5ml纯化水分散均匀后，通过粒度分布测定仪进行测试；取连续测量3次的平均值。
实施例1
本实施例提供了一种药物涂层球囊，包括球囊本体以及依次附着于球囊本体外侧的核壳结构层、药物纳米粒子层和正电疏水修饰层，其中，所述核壳结构层包括核壳结构粒子，所述核壳结构粒子具有内核及包裹住该内核的外壳，所述内核为雷帕霉素粒子，所述外壳为PEG-PCL外壳；所述药物纳米粒子层包括药物纳米粒子，所 述药物纳米粒子为雷帕霉素纳米粒子。正电疏水修饰层包括正电修饰物质(DC-胆固醇)与疏水修饰物质(硬脂酸)。
上述药物涂层球囊的制备方法包括如下步骤：
(1)核壳结构粒子的制备
称取1g雷帕霉素和2g PEG-PCL溶解于30mL油相(二氯甲烷：丙酮的体积比＝8：2)中，在搅拌(常温，1000r/min)下，逐滴(1mL/min)注入200ml含0.1％(w/v)PVA的纯化水，搅拌12h(35℃，750r/min)，在-4℃、12000r/min下低温高速离心30min，去除上清液，底部沉淀洗涤两次，每次加入纯化水200ml，离心，冷冻干燥处理，得到核壳结构粒子。经检测该核壳结构粒子粒径D50：312nm，载药量6.83％。
(2)药物纳米粒子的制备
采用反溶剂沉淀方法制备雷帕霉素药物纳米粒子。称取0.5g雷帕霉素用5ml甲醇溶解作为油相，将此油相滴加到15ml含有2％(w/v)泊洛沙姆188水溶液中，超声30min后，加入25mg海藻糖分散均匀，冷冻干燥，得到药物纳米粒子。经检测，该该药物纳米粒子的粒径D50为481nm。
(3)涂层喷涂液的制备
取2.1g核壳结构粒子和83.6mg蛋黄卵磷脂，加入到12ml乙醇中，超声分散均匀，得到核壳结构层涂液。取150mg药物纳米粒子，7.1mg蛋黄卵磷脂，加到12ml乙醇中，超声分散均匀，得到药物纳米粒子层涂液。将DC-胆固醇20mg和硬脂酸20mg加入5ml乙醇中，超声分散均匀，得到正电疏水修饰层涂液。
(4)药物球囊的制备
第一次喷涂：采用球囊喷涂机将核壳结构层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，使得球囊表面雷帕霉素的浓度达到1.0μg/mm 2，晾干；
第二次喷涂：采用球囊喷涂机将药物纳米粒子层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，使得球囊表面雷帕霉素的浓度达到2.0μg/mm 2，晾干；
第三次喷涂：采用球囊喷涂机将正电疏水修饰层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，晾干，使得第三次喷涂球囊的平均增重为0.2μg/mm 2。本发明中第三次喷涂球囊的平均增重为：第三次喷涂球囊的平均增重＝(球囊经第三次喷涂晾干后的重量-经第二次喷涂晾干后的重量)/球囊表面积。
实施例2
本实施例提供了一种药物涂层球囊及其制备方法，与实施例1的区别仅在于正电疏水修饰层涂液的组成和制备方法不同，本实施例正电疏水修饰层涂液采用DC-胆固醇20mg和硬脂酸10mg加入5ml乙醇中，超声分散均匀，得到正电疏水修饰层涂液。
实施例3
本实施例提供了一种药物涂层球囊及其制备方法，与实施例1的区别仅在于经第三次喷涂球囊的平均增重为0.1μg/mm 2。
实施例4
本实施例提供了一种药物涂层球囊及其制备方法，与实施例1的区别仅在于正电疏水修饰层涂液的组成和制备方法不同以及喷涂增重不同，本实施例正电疏水修饰层涂液采用二油酰基磷脂酰乙醇胺(DOPE)20mg和植烷酸20mg加入5ml乙醇中，超声分散均匀，得到正电疏水修饰层涂液，备用。本实施例经第三次喷涂球囊的平均增重为0.1μg/mm 2。
实施例5
本实施例提供了一种药物涂层球囊及其制备方法，与实施例1的区别仅在于正电疏水修饰层涂液的组成和制备方法不同，本实施例正电疏水修饰层涂液采用DOPE20mg和植烷酸10mg加入5ml乙醇中，超声分散均匀，得到正电疏水修饰层涂液，备用。
实施例6
本实施例提供了一种药物涂层球囊及其制备方法，与实施例1的区别仅在于正电疏水修饰层涂液的组成和制备方法不同，本实施例正电疏水修饰层涂液采用DOPE20mg和植烷酸20mg加入5ml乙醇中，超声分散均匀，得到正电疏水修饰层涂 液，备用。
实施例7
本实施例提供了一种药物涂层球囊及其制备方法，与实施例1的区别仅在于核壳结构层涂液和药物纳米粒子层涂液的制备方法不同，本实施例中，取2.1g核壳结构粒子，加入到12ml乙醇中，超声分散均匀，得到核壳结构层涂液。取150mg药物纳米粒子，加到12ml乙醇中，超声分散均匀，得到药物纳米粒子层涂液。
实施例8
本实施例提供了一种药物涂层球囊，包括球囊本体以及依次附着于球囊本体外侧的核壳结构层、药物纳米粒子层和正电疏水修饰层，其中，所述核壳结构层包括核壳结构粒子，所述核壳结构粒子具有内核及包裹住该内核的外壳，所述内核为雷帕霉素粒子，所述外壳为PEG-PLA外壳；所述药物纳米粒子层包括药物纳米粒子，所述药物纳米粒子为雷帕霉素纳米粒子。正电疏水修饰层包括DC-胆固醇与硬脂酸。
上述药物涂层球囊的制备方法包括如下步骤：
(1)核壳结构粒子的制备
称取0.5g雷帕霉素和0.5gPEG-PLA溶解于1mL油相(丙酮)中，在搅拌(常温，1000r/min)下，逐滴(1mL/min)注入100ml含0.01％(w/v)PVA的纯化水，搅拌12h(35℃，750r/min)，在-4℃、12000r/min下低温高速离心30min，去除上清液，底部沉淀洗涤两次，每次加入纯化水200ml，离心，冷冻干燥处理，得到核壳结构粒子。经检测该核壳结构粒子的粒径D50：579nm，载药量5.92％。
(2)药物纳米粒子的制备
采用反溶剂沉淀方法制备雷帕霉素药物纳米粒子。称取2g雷帕霉素用20ml乙醇溶解作为油相，将此油相滴加到100ml含有2％(w/v)泊洛沙姆188水溶液中，超声30min后，加入25mg甘露醇分散均匀，冷冻干燥，得到药物纳米粒子。经检测，该该药物纳米粒子的粒径D50为593nm。
(3)涂层喷涂液的制备
取2.1g核壳结构粒子和2.1g吐温80，加入到3ml水中，超声分散均匀，得到核壳结构层涂液。取150mg药物纳米粒子和150mg泊洛沙姆188，加到3ml水中，超声分散均匀，得到药物纳米粒子层涂液。将DC-胆固醇20mg和硬脂酸20mg加入5ml正己 烷中，超声分散均匀，得到正电疏水修饰层涂液。
(4)药物球囊的制备
第一次喷涂：采用球囊喷涂机将核壳结构层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，使得球囊表面雷帕霉素的浓度达到1.0μg/mm 2，晾干；
第二次喷涂：采用球囊喷涂机将药物纳米粒子层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，使得使得球囊表面雷帕霉素的浓度达到2.0μg/mm 2，晾干；
第三次喷涂：采用球囊喷涂机将正电疏水修饰层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，晾干，使得第三次喷涂球囊的平均增重为0.2μg/mm 2。
实施例9
本实施例提供了一种药物涂层球囊及其制备方法，按照实施例1的方法制备药物纳米粒子、药物纳米粒子层涂液以及正电疏水修饰层涂液；
第一次喷涂：采用球囊喷涂机将药物纳米粒子层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，使得使得球囊表面雷帕霉素的浓度达到2.0μg/mm 2，晾干；
第二次喷涂：采用球囊喷涂机将正电疏水修饰层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，晾干，使得第二次喷涂球囊的平均增重为0.2μg/mm 2。第二次喷涂球囊的平均增重＝(球囊经第二次喷涂晾干后的重量-经第一次喷涂晾干后的重量)/球囊表面积。
实施例10
本实施例提供了一种药物涂层球囊及其制备方法，按照实施例1的方法制备核壳结构粒子、核壳结构层涂液以及正电疏水修饰层涂液；
第一次喷涂：采用球囊喷涂机将核壳结构层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，使得球囊表面雷帕霉素的浓度达到2.0μg/mm 2，晾干；
第二次喷涂：采用球囊喷涂机将正电疏水修饰层涂液喷涂到球囊表面，球囊喷涂机喷涂参数为，滴注流速：3.6ml/h，超声功率：0.05W，晾干，使得第二次喷涂球囊的平均增重为0.2μg/mm 2。
对比例1
本对比例提供了一种药物涂层球囊，包括球囊本体以及依次附着于球囊本体外侧的核壳结构层和药物纳米粒子层，其中，所述核壳结构层包括核壳结构粒子，所述核壳结构粒子具有内核及包裹住该内核的外壳，所述内核为雷帕霉素粒子，所述外壳为PEG-PCL外壳；所述药物纳米粒子层包括药物纳米粒子，所述药物纳米粒子为雷帕霉素纳米粒子。
上述药物涂层球囊按照实施例1的方法制备，区别仅在于，球囊表面未经第三次喷涂，即未喷涂正电疏水修饰层涂液。
实验例1考察不同粒径的核壳结构粒子的体外药物释放情况
考察不同粒径的核壳结构粒子的体外释放情况，共分为5组实验，各组实验采用的雷帕霉素与PEG-PCL的质量、油相体积、油相中二氯甲烷与丙酮体积比以及搅拌转速见下表1所示，分别按照下表处方称取雷帕霉素和PEG-PCL，按下表处方量取二氯甲烷和丙酮混合制备油相，将雷帕霉素和PEG-PCL溶解于油相中，得到含药物的油相。然后在常温下以表格中相应的转速搅拌该含药物的油相，在搅拌下逐滴(1mL/min)注入含0.1％(w/v)PVA的水溶液200ml，注入完毕之后，在转速750r/min，温度为35℃的条件下继续搅拌12h。接着在转速为12000r/min、温度为-4℃下低温高速离心30min，去除上清液，底部沉淀加入纯化水洗涤两次，每次加水200ml，离心，冷冻干燥处理，得到核壳结构粒子。
表1不同处方与工艺条件的核壳结构粒子及其粒径
Figure PCTCN2022098130-appb-000001
然后通过下述方法测试核壳结构粒子的体外药物释放情况。
取核壳结构粒子10mg，加释放介质适量，振摇使均匀分散，并全量转移置 1000ml量瓶中，用释放介质稀释至刻度，摇匀。采用摇瓶法，160转/分钟，释放介质是含0.03％(w/v)SDS的PBS(pH7.4)溶液，体积40ml；取样时间点：1天、4天、7天、14天、28天、60天、90天。按照取样时间点取样品，每次取样量1.5ml，补液量1.5ml。待测溶液过0.5um滤膜后备用。按中华人民共和国药典(2020年版)通则0512高效液相色谱法测定供试品溶液中雷帕霉素的含量，以十八烷基硅烷键合硅胶为填充剂，以甲醇-乙腈-水(体积比为60：17：23)为流动相，检测波长280nm，流速1mL/min，柱温40℃。
表2累积释放度(％)
Figure PCTCN2022098130-appb-000002
由上表可知，相比于试验组1来说，试验组2-4具有更好的缓释作用，延长药物作用时间的效果更好。而试验组1因粒径较小而导致药物释放的较快，28天即可释放100％，而试验组5因粒径较大药物释放周期过长，90天仅释放69.9％，因此，本发明优选核壳结构粒子的粒径D50为300nm～6μm。
实验例2
取各实施例和对比例制得的药物球囊使用体外模拟运输设备(参见医药行业标准《YY/T 0807-2010》)模拟药物球囊在体内输送回撤、扩张过程中药物损失和扩张过程中药物涂层转移到血管内壁，间接评估涂层的有效性和安全性、抗冲刷能力。
测试方法：将体外模拟运输设备水浴加热，维持温度在37℃，将设备末端连接硅胶模拟血管(由上海璞临医疗科技有限公司提供，直径3.0mm)，将药物球囊产品插入此设备中，在囊体部位进入模拟血管中时，打压充起球囊至8atm压力，保压后1min后，抽负压后，依次收集模拟血管内液体、模拟血管、体外模拟运输设备中的液体和扩张后的球囊。按照如下方法测试其中雷帕霉素的含量。取待测样品加溶剂乙腈使雷帕霉素溶解并定量稀释，离心，取上清液，分别注入液相色谱仪，按中华人民共和国药典(2020年版)通则0512高效液相色谱法测定雷帕霉素的含量，以十八烷基硅烷键合硅胶为填充剂，以甲醇-乙腈-水(体积比为60：17：23)为流动相，检测波长280nm，流速1mL/min，柱温40℃，记录色谱图，计算模拟血管内液体、模拟血管、体外模拟运输设备中的液体和扩张后的球囊中雷帕霉素的总质量，计算各部分雷帕霉 素占总质量的百分数。
结果见表3所示。
表3体外模拟运输实验结果
Figure PCTCN2022098130-appb-000003
由上表结果可知，相比于对比例1来说，本发明实施例1-10的药物涂层转移到血管壁的药物量显著提高，输送过程损失量明显减少。
实施例1与实施例7比较可知，本发明优选的方案中通过在核壳结构层中加入粘结剂以及在纳米粒子层加入粘结剂能够进一步提高转移到血管壁的药物量，降低输送过程损失量和球囊扩张收缩损失量。
实施例1与实施例9-10比较可知，本发明优选的方案中通过依次附着于基体表面的核壳结构层、药物纳米粒子层和正电疏水修饰层的设置，能够进一步提高转移到血管壁的药物量，降低输送过程损失量和球囊扩张收缩损失量。
实施例1-6比较可知，本发明优选的方案中通过采用植烷酸和二油酰基磷脂酰乙醇胺作为疏水性物质和正电修饰物质，能够进一步提高转移到血管壁的药物量，降低输送过程损失量和球囊扩张收缩损失量。
实施例1-3以及实施例4-6比较可知，本发明通过控制正电修饰物质和疏水性物质的质量比在优选的范围内能够进一步提高转移到血管壁的药物量。
实验例3体内药物代谢动力学实验
白猪12只，随机分为2组，实验组和对照组，每组6只白猪，实验组白猪冠脉血管LAD(左前降支)、LCX(左回旋支)和RCA(右冠状动脉)分别介入1个实施例5的药物球囊，对照组白猪冠脉血管LAD(左前降支)、LCX(左回旋支)和RCA (右冠状动脉)分别介入1个对比例1制备球囊，球囊扩张1次×60S，回撤。然后在0天(介入后)、7天、28天分别处死实验组和对照组的动物，每个时间点各组处死2只动物，解剖取出球囊扩张部位血管，-80℃冷冻储存。将血管壁组织样品室温解冻，采用LC-MS/MS法测试血管组织样品中雷帕霉素的平均浓度，结果见下表所示。
表4血管组织中的药物浓度/(ng/mg)
  0天 7天 28天
实验组 215.44 59.61 6.20
对照组 32.79 98.62 0.05
由药物代谢动力学研究的结果显示，本发明实施例5制得的药物球囊释放到血管组织中的药物量明显高于对比例药物球囊。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims (15)

  1. 一种药物涂层，其特征在于，所述药物涂层包括依次附着于基体表面的药物活性涂层和正电疏水修饰层，所述正电疏水修饰层包括正电修饰物质和疏水性物质。
  2. 根据权利要求1所述的药物涂层，其特征在于，所述药物活性涂层包括核壳结构层和/或药物纳米粒子层；其中，
    所述核壳结构层包括核壳结构粒子，所述核壳结构粒子具有内核及包裹住该内核的外壳，所述内核为药物粒子，所述外壳为聚合物外壳；
    所述药物纳米粒子层包括药物纳米粒子。
  3. 根据权利要求2所述的药物涂层，其特征在于，所述核壳结构粒子的粒径D50为100nm～9μm；优选地，所述核壳结构粒子的粒径D50为300nm～6μm。
  4. 根据权利要求2所述的药物涂层，其特征在于，所述药物纳米粒子的粒径D50为100nm-600nm。
  5. 根据权利要求2-4中任一所述的药物涂层，其特征在于，所述药物涂层包括依次附着于基体表面的核壳结构层、药物纳米粒子层和正电疏水修饰层。
  6. 根据权利要求2-5中任一所述的药物涂层，其特征在于，所述药物涂层还满足如下A-F中的至少一项：
    A、所述核壳结构层还包括粘结剂，优选地，所述粘结剂选自聚乙烯醇、聚乙烯吡咯烷酮、吐温80、泊洛沙姆、蛋黄卵磷脂、大豆卵磷脂和甲基纤维素中的至少一种，优选地，粘结剂与核壳结构粒子的质量比为1:1-26；
    B、所述聚合物外壳为两亲聚合物外壳，所述两亲聚合物包括亲水嵌段和疏水嵌段，所述亲水嵌段为聚乙二醇或者聚乙二醇单甲醚，所述疏水嵌段为聚氧丙烯、聚苯乙烯、聚氨基酸、聚羟基乙酸、聚丙交酯、聚己内酯和聚乙交酯丙交酯中的至少一种；优选地，核壳结构粒子中所述药物粒子与聚合物外壳的质量比为0.5-5：0.5-50；
    C、所述药物纳米粒子层还包括粘结剂，优选地，所述粘结剂选自聚乙烯醇、聚乙烯吡咯烷酮、吐温80、泊洛沙姆、蛋黄卵磷脂、大豆卵磷脂和甲基纤维素中的至少一种，优选地，粘结剂和药物纳米粒子的质量比为1:1-25；
    D、所述核壳结构层中药物含量与药物纳米粒子层中药物含量之比为1-5：1-5；优选为1-2：1-2；
    E、所述药物为防治冠心病的药物，优选地，所述防治冠心病的药物选自雷帕霉素和/或雷帕霉素衍生物；
    F、所述核壳结构层中药物含量为1～5μg/mm 2；和/或，所述药物纳米粒子层中药物含量为1～5μg/mm 2。
  7. 根据权利要求1-6中任一所述的药物涂层，其特征在于，所述正电疏水修饰层还满足如下(1)-(3)中的至少一项：
    (1)正电修饰物质和疏水性物质的质量比为10-20:10-20，优选为20:10；
    (2)所述疏水性物质选自脂肪酸类、天然磷脂或合成磷脂类，优选地，所述疏水性物质选自神经酸、植烷酸、棕榈酸、亚麻酸、辛酸、异油酸、硬脂酸、棕榈酸、月桂酸、花生四烯酸、二十碳五烯酸、脑磷脂、卵磷脂、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、二肉豆蔻酰基磷脂酰乙醇胺、二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二月桂酰基卵磷脂和1-硬脂酰基-2-肉豆蔻酰基卵磷脂中的至少一种；
    正电修饰物质为带正电的脂质，优选为DC-胆固醇、二油酰基磷脂酰乙醇胺、2-二油酰基羟丙基-3-N,N,N-三甲铵氯、1,2-双十八烯氧基-3-甲基铵丙烷和4-(N,N-二甲基氨基)丁酸(二亚油基)甲酯中的至少一种；
    更优选地，所述疏水性物质为植烷酸，所述正电修饰物质为二油酰基磷脂酰乙醇胺；
    (3)以正电修饰物质和疏水性物质的总质量计，正电疏水修饰层的含量为0.1-1μg/mm 2。
  8. 根据权利要求2-6中任一所述的药物涂层，其特征在于，所述核壳结构粒子包括如下原料：药物0.5-5重量份，两亲聚合物0.5-50重量份，油相1-50体积份、含乳化剂的水溶液100-2000体积份；其中，重量份与体积份的配比关系为g/mL；可选的，所述油相选自二氯甲烷、丙酮中的一种或其组合。
  9. 根据权利要求2-6中任一所述的药物涂层，其特征在于，所述药物纳米粒子包括如下原料：药物0.5-2重量份、油相5-20体积份、含乳化剂的水溶液5-100体积份；其中，重量份与体积份的配比关系为g/mL；可选的，所述油相选择甲醇、乙醇中的一种或其组合。
  10. 根据权利要求8或9所述的药物涂层，其特征在于，所述乳化剂选自聚乙烯醇、聚乙烯吡咯烷酮、泊洛沙姆、牛血清白蛋白、吐温80、泊洛沙姆、蛋黄卵磷脂、大豆卵磷脂和甲基纤维素中的至少一种；和/或，含乳化剂的水溶液中乳化剂的质量体积百分数为0.01-2％(w/v)。
  11. 一种药物涂层球囊，其特征在于，包括球囊本体和附着于球囊本体外的药物涂 层，所述药物涂层为权利要求1-10中任一所述的药物涂层。
  12. 一种权利要求11所述的药物涂层球囊的制备方法，其特征在于，包括如下步骤：
    S1步骤：将含药物的涂液喷涂于球囊本体的外侧，干燥形成药物活性涂层；
    S2步骤：取正电修饰物质、疏水性物质与有机溶剂混合制得正电疏水修饰层涂液，将正电疏水修饰层涂液喷涂于药物活性涂层的外侧，干燥形成正电疏水修饰层，制得药物涂层球囊。
  13. 根据权利要求12所述的药物涂层球囊的制备方法，其特征在于，所述有机溶剂选自烷烃类、醇类和水中的至少一种；和/或，正电修饰物质的质量、疏水性物质的质量与有机溶剂的体积之比为10-20mg:10-20mg：5mL。
  14. 根据权利要求12所述的药物涂层球囊的制备方法，其特征在于，所述含药物的涂液包括核壳结构层涂液和/或药物纳米粒子层涂液；
    所述核壳结构层涂液的制备包括，取核壳结构粒子与有机溶剂混合，制得核壳结构层涂液；
    所述药物纳米粒子层涂液的制备包括，取药物纳米粒子与有机溶剂混合，制得药物纳米粒子层涂液。
  15. 根据权利要求14所述的药物涂层球囊的制备方法，其特征在于，所述有机溶剂选自烷烃类、醇类和水中的至少一种；和/或，核壳结构层涂液中，加入的所述核壳结构粒子的质量与有机溶剂的体积之比为2.1g:3-12mL；和/或，药物纳米粒子层涂液中，加入的所述药物纳米粒子的质量与有机溶剂的体积之比为150mg:3-12mL。
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CHEN WEIPING, ZHAN HONG-BING, LI ZHAO-HUI: "Drug Loading Strategies and Applications of Drug Eluting Stents", CHINESE JOURNAL OF TISSUE ENGINEERING RESEARCH, ZHONGGUO KANGFU YIXUEHUI,, CN, vol. 14, no. 42, 15 October 2010 (2010-10-15), CN , pages 7878 - 7882, XP093046379, ISSN: 1673-8225, DOI: 10.3969/j.issn.1673-8225.2010.42.021 *

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