WO2024016498A1 - 一种药物涂层球囊及其制备方法和应用 - Google Patents

一种药物涂层球囊及其制备方法和应用 Download PDF

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WO2024016498A1
WO2024016498A1 PCT/CN2022/126117 CN2022126117W WO2024016498A1 WO 2024016498 A1 WO2024016498 A1 WO 2024016498A1 CN 2022126117 W CN2022126117 W CN 2022126117W WO 2024016498 A1 WO2024016498 A1 WO 2024016498A1
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drug
balloon
glycolic acid
polylactic acid
acid copolymer
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PCT/CN2022/126117
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English (en)
French (fr)
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夏洁
崔取金
郭力友
赵晟
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苏州中天医疗器械科技有限公司
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    • 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
    • A61M25/1002—Balloon catheters characterised by balloon shape
    • 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
    • A61L29/04—Macromolecular materials
    • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L29/148—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • 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
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • 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
    • A61M25/104—Balloon catheters used for angioplasty
    • 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
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation
    • 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
    • A61L2300/62—Encapsulated active agents, e.g. emulsified droplets
    • A61L2300/624—Nanocapsules
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/02—Methods for coating medical devices
    • 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
    • A61L2420/00—Materials or methods for coatings medical devices
    • A61L2420/08—Coatings comprising two or more layers
    • 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
    • A61M25/1027—Making of balloon catheters
    • A61M25/1029—Production methods of the balloon members, e.g. blow-moulding, extruding, deposition or by wrapping a plurality of layers of balloon material around a mandril
    • A61M2025/1031—Surface processing of balloon members, e.g. coating or deposition; Mounting additional parts onto the balloon member's surface
    • 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
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
    • 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
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/1075—Balloon catheters with special features or adapted for special applications having a balloon composed of several layers, e.g. by coating or embedding
    • 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
    • A61M2207/00—Methods of manufacture, assembly or production

Definitions

  • the present application relates to the technical field of drug-coated balloons, and in particular to a drug-coated balloon and its preparation method and application.
  • Ischemic stroke is one of the major diseases that endangers human health.
  • One of its main causes is the stenosis of intracranial arteries caused by atherosclerosis, which in turn leads to stroke due to insufficient blood supply.
  • Atherosclerosis is an important cause of arterial stenosis.
  • Focal fibrosis of the intima of blood vessels leads to the formation of atherosclerotic plaques, which causes the blood vessel wall to harden and the lumen to narrow, thereby causing a series of secondary pathologies.
  • the treatment options include drug therapy and intravascular stent therapy.
  • the incidence of stroke in patients treated conservatively with drugs is still high, and the long-term efficacy of endovascular stent therapy is controversial.
  • the main risks of stent implantation for treatment of intracranial artery stenosis are as follows: (1) vessel rupture; (2) reperfusion injury; (3) thrombosis; (4) perforating artery occlusion; (5) cortical artery perforation ; (6) Restenosis.
  • the stent cannot reach the diseased site. The reason is that the intracranial and extracranial blood vessels are excessively tortuous and angular and cannot be in place.
  • balloon angioplasty provides an effective solution to the above problems, which is an established method of treating vascular disease by physically dilating atherosclerosis, areas of reduced lumen diameter or narrowing in diseased blood vessels. , compared with stents, balloons are softer and smaller in diameter, and can reach small blood vessels that stents cannot reach.
  • DCB Drug-coated balloon
  • interventional technologies such as balloon dilatation or balloon angioplasty. Its principle is to inhibit blood vessels in the diseased area through active drugs in the coating. Excessive proliferation of smooth muscle cells prevents vascular restenosis.
  • an interventional method is used to locally deliver drugs to the affected area through the active drug-loaded coating on the surface of the balloon catheter. It has strong clinical operability and can overcome the insufficient drug loading and uneven drug distribution caused by the small surface area of intravascular drug-coated stents. , poor tissue compatibility and high cost, it also avoids endothelialization disorders caused by continuous drug contact.
  • CN113476669A discloses a pharmaceutical coating composition, which includes the following components: excipient, bioactive drug for treating vascular inner wall reproliferation, polymer, excipient solvent, bioactive drug solvent and polymer solvent.
  • the coating process is: fully mix the excipient and the excipient solvent to prepare an excipient solution with a concentration of 0.1 mg/mL to 10g/mL; combine the bioactive drug for treating vascular inner wall reproliferation with the bioactive drug solvent. Mix thoroughly to prepare a bioactive drug solution with a concentration of 0.1 mg/mL to 10 g/mL; spray or dip-coat the excipient solution and bioactive drug solution onto the surface of the medical device according to the predetermined coating method.
  • the disclosed drug coating composition can reduce the loss of the drug during the process of entering the blood vessel and avoid the shedding of the drug coating during the process of entering the blood vessel.
  • the drug coating of the balloon acts on the lesion, and the drug can be quickly absorbed by vascular tissue cells, which can effectively inhibit cell proliferation and achieve very good therapeutic effects.
  • the first is the adhesive force of the coating.
  • the adhesive force is too small, the coating can easily fall off when the balloon is delivered to the lesion, causing drug loss; and the adhesive force If it is too large, the coating will not be released or will not be released quickly and in sufficient amount after the balloon is expanded. Both situations will result in an insufficient amount of drug being delivered to the affected area, thereby affecting the effectiveness of the treatment.
  • the active drug loaded in the coating has poor lipid solubility or the drug has a large molecular weight, it cannot effectively penetrate the affected tissues and cells on the inner wall of the blood vessel and enter the cells through the cell membrane within tens of seconds of balloon expansion. Internally, the actual bioavailability of drugs entering the body will be extremely low, and drugs that have been released by the balloon but not absorbed by the tissue may also produce systemic toxicity, causing new problems.
  • This application provides a drug-coated balloon and its preparation method and application.
  • the particle size of the drug-coated balloon is small and uniform, and can be quickly absorbed through the cell membrane after the balloon is expanded, greatly improving the bioavailability of the drug.
  • all materials in the drug-coated balloon are biodegradable and will not cause systemic toxicity to the human body.
  • the preparation process of the method is simple, efficient, stable and convenient to operate.
  • the present application provides a drug-coated balloon, which includes a balloon body and a hydrophilic coating and a drug-loaded layer sequentially provided on the surface of the balloon body;
  • the drug-loaded layer includes additives with binding and excipient functions and nanomedicine carriers;
  • the nanomedicine carrier includes a combination of polylactic acid-glycolic acid copolymer, macrolide drugs and polyvinyl alcohol.
  • the nanomedicine carrier includes a combination of polylactic acid-glycolic acid copolymer, macrolide drugs and polyvinyl alcohol, and a combination of polylactic acid-glycolic acid copolymer and polyvinyl alcohol, both of which have a synergistic effect.
  • the particle size of the drug-coated balloon formed is small and uniform, and can be quickly absorbed through the cell membrane after the balloon is expanded, greatly improving the bioavailability of the drug.
  • all materials in the drug-coated balloon are biodegradable. It will not cause systemic toxicity to the human body.
  • polylactic acid-glycolic acid copolymer is a biodegradable polymer with good performance. It is an aliphatic polyester and has been introduced in 2008 due to its excellent biodegradability, biocompatibility and non-toxic properties. Approved for human use by the U.S. Food and Drug Administration (FDA).
  • FDA Food and Drug Administration
  • Polylactic acid-glycolic acid copolymer is polymerized from polylactic acid and polyglycolic acid monomers in a certain ratio. It is not only biodegradable, biocompatible, and nontoxic, but also has the function of protecting the activity of biological macromolecules. . Polylactic acid-glycolic acid copolymer breaks into small molecular substances during the biodegradation process, enters the tricarboxylic acid cycle in the form of lactic acid, etc., and eventually degrades into carbon dioxide and water. The acid-base balance system in the body can quickly neutralize and decompose the acidic substances released by polylactic acid-glycolic acid copolymer, so that the local pH does not change significantly. Therefore, polylactic acid-glycolic acid copolymer nanoparticles can safely and effectively encapsulate and deliver various drugs (including hydrophilic and hydrophobic macromolecules), gene fragments, etc. in biological applications.
  • various drugs including hydrophilic and hydrophobic macromolecules
  • the thickness of the hydrophilic coating is 0.05-0.2 ⁇ m, such as 0.1 ⁇ m, 0.12 ⁇ m, 0.14 ⁇ m, 0.16 ⁇ m or 0.18 ⁇ m, etc.
  • the drug-loading capacity of the drug-coated balloon is 1-10 ⁇ g/mm 2 , such as 2 ⁇ g/mm 2 , 4 ⁇ g/mm 2 , 6 ⁇ g/mm 2 , 8 ⁇ g/mm 2 or 10 ⁇ g/mm 2 , etc.
  • this application provides a method for preparing the drug-coated balloon described in the first aspect, the preparation method comprising the following steps:
  • polylactic acid-glycolic acid copolymer is broken into small molecular substances during the biodegradation process, enters the tricarboxylic acid cycle in the form of lactic acid, etc., and is eventually degraded into carbon dioxide and water, without biological toxicity;
  • polyvinyl alcohol is amphiphilic Polymers, the addition of polyvinyl alcohol during the synthesis process can stabilize emulsion droplets and reduce the coalescence and aggregation of newly formed nanoparticles in the aqueous phase.
  • amphiphilic PVA can enhance the binding of active drugs to nanoparticles through hydrophobic interactions. in the package.
  • the nanoparticles prepared by this application have uniform particle sizes, ensuring drug loading while also ensuring that the particles can be quickly absorbed by cells; moreover, the drug-coated balloons prepared by the method described in this application have precise and controllable drug loading, avoiding the need for drug loading. Insufficient medicine fails to achieve the therapeutic target and excessive drug loading causes waste and produces systemic toxicity in the human body.
  • the mixing includes: dropping a solution containing polylactic acid-glycolic acid copolymer and macrolide drugs into the polyvinyl alcohol solution, and ultrasonic emulsification to form an emulsion.
  • the particle size of the solute is ⁇ 650nm, such as 580nm, 560nm, 540nm, 520nm or 500nm, etc.
  • the dripping tool includes a microsyringe pump.
  • the dropping rate is 0.01-99.99mL/min, such as 0.1mL/min, 0.5mL/min, 1mL/min, 5mL/min, 10mL/min, 20mL/min, 30mL/min, 40mL/min. min, 50mL/min, 60mL/min, 70mL/min, 80mL/min or 90mL/min, etc.
  • the concentration of the polyvinyl alcohol solution is 1-10 mg/mL, such as 2 mg/mL, 4 mg/mL, 6 mg/mL or 8 mg/mL, and more preferably 3-8 mg/mL.
  • the solvent in the polyvinyl alcohol solution includes water.
  • the solvent in the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs includes an organic solvent.
  • the organic solvent includes methylene chloride.
  • the mass ratio of lactic acid and glycolic acid is 1: (1-6), wherein 1-6 can be 2, 3, 4, 5, etc., and 1: is further preferred. 1.
  • the polylactic acid-glycolic acid copolymer has different molecular weights and different physical and chemical properties due to different ratios of lactic acid and glycolic acid.
  • the content of lactic acid directly affects its mechanical strength, swelling behavior, hydrolysis ability and biodegradation rate.
  • Lactic acid is more hydrophobic than glycolic acid, so PLA-co-glycolic acid with higher lactic acid content is less hydrophilic, absorbs less water, and degrades more slowly.
  • the molecular weight of the polylactic acid-glycolic acid copolymer is 5,000-300,000 Daltons, such as 10,000 Daltons, 50,000 Daltons, 100,000 Daltons, 150,000 Daltons, 200,000 Daltons, and 250,000 Daltons. Dayton et al.
  • the concentration of polylactic acid-glycolic acid copolymer is 6-13 mg/mL, such as 7 mg/mL, 8 mg/mL. , 9mg/mL, 10mg/mL, 11mg/mL or 12mg/mL, etc.
  • the concentration of polylactic acid-glycolic acid copolymer is controlled in the range of 6-13mg/mL, and the polylactic acid-glycolic acid copolymer is If the concentration of polylactic acid-glycolic acid copolymer is too high, it will not be fully dissolved in the solvent, and excessive polylactic acid-glycolic acid copolymer will have an adverse effect on subsequent experimental steps; if the concentration of polylactic acid-glycolic acid copolymer is too low, it will not be fully dissolved in the solvent. Macrolides form a coating or the coating amount is insufficient, and cannot play the role of drug carriers in transporting drugs into cells. At the same time, the drug encapsulation rate is too low, resulting in drug waste.
  • the concentration of the macrolide drugs is 2-5 mg/mL, such as 2.5 mg/mL, 3 mg/mL. , 3.5mg/mL, 4mg/mL, 4.5mg/mL, etc.
  • the volume ratio of the polyvinyl alcohol solution and the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs is (2-10):1, where 2-10 can be 4, 6, 8, etc., more preferably (2-7):1, still more preferably (2-4):1.
  • the volume ratio of the polyvinyl alcohol solution and the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs is in the range of (2-10):1. If the mass ratio of the two is too high, it will As a result, the relative content of macrolide drugs in the coating per unit mass of the balloon surface is too low, and the therapeutic effect cannot be achieved or the therapeutic effect is poor; the mass ratio between the two is too low, which will result in the relative content of the carrier being too low and the drug package If the sealing rate is too low, the ability to pass through the cell membrane will also be reduced.
  • the macrolide drug includes rapamycin, everolimus, zotarolimus, dexamethasone, paclitaxel, docetaxel, probucol, colchicine, heparin, aspirin or Any one or a combination of at least two of doxorubicin, where typical but non-limiting combinations include: a combination of rapamycin and everolimus, zotarolimus, dexamethasone, paclitaxel and docetaxel Combinations of docetaxel, probucol, colchicine, heparin, aspirin and doxorubicin, etc.
  • the stirring and heating temperature is 30-50°C, such as 32°C, 34°C, 36°C, 38°C, 40°C, 42°C, 44°C, 46°C or 48°C, etc.
  • the stirring and heating are performed until the organic solvent in the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs is completely volatilized.
  • the purification includes filtration, dialysis and centrifugation in sequence.
  • the filtering tool includes a microporous filter membrane.
  • the pore diameter of the microporous filter membrane is 0.4-1.0 ⁇ m, such as 0.5 ⁇ m, 0.6 ⁇ m or 0.8 ⁇ m, and more preferably 0.45 ⁇ m and 0.8 ⁇ m.
  • the dialysis tool includes a dialysis membrane.
  • the molecular weight cutoff of the dialysis membrane is 500-7000 Daltons, such as 1000 Daltons, 1500 Daltons, 2000 Daltons, 2500 Daltons, 3000 Daltons, 3500 Daltons, 4000 Daltons Dalton, 4500 Dalton, 5000 Dalton, 5500 Dalton, 6000 Dalton or 6500 Dalton, etc., further preferably 500 Dalton, 1000 Dalton, 3500 Dalton or 7000 Dalton pause.
  • the centrifugal speed is 10000-30000r/min, such as 12000r/min, 14000r/min, 16000r/min, 18000r/min, 20000r/min, 22000r/min, 24000r/min, 26000r/min or 28000r/min. Min et al.
  • the centrifugation time is 10-60 min, such as 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min or 55 min, etc.
  • the particle size of the nanomedicine carrier is 30nm-300nm, such as 160nm, 180nm, 200nm, 220nm, 240nm, 260nm or 280nm, etc.
  • step (4) includes: first dispersing the nanomedicine carrier in a solvent, and then mixing it with additives.
  • the solvent includes water.
  • the concentration of nano drug carrier is 13-40 mg/mL, such as 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL or 35mg/mL etc.
  • the mass parts of the additive are 1-20 parts, such as 2 parts, 4 parts, 6 parts, 8 parts, 10 parts, 12 parts, 14 parts, 16 servings or 18 servings etc.
  • the additives include dextran, polysorbate, sorbitol, fructose, sucrose, lactose, maltose, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, Any of fucotol, iditol, inositol, heptaptol, isomalt, maltitol, lactitol, maltotriitol, voglibose, xylitol or polyethylene glycol
  • One or a combination of at least two, wherein typical but non-limiting combinations include: a combination of dextran, polysorbate and sorbitol, ribitol, mannitol, galactitol, fucoitol, and idodol , combination of myo-inositol, heptaptol, isomalt and maltitol, arabitol,
  • the curing temperature is 40-70°C, such as 45°C, 50°C, 55°C, 60°C or 65°C.
  • the preparation method includes the following steps:
  • the suspension is first filtered through a microporous filter membrane with a pore size of 0.4-1.0 ⁇ m, and then dialyzed using a dialysis membrane with a molecular weight cutoff of 500-7000 Daltons, and then centrifuged at a speed of 10000-30000r/min for 10- 60 minutes to form a nano drug carrier with a particle size of 30-300nm;
  • this application provides a drug-coated balloon described in the first aspect, or the use of a drug-coated balloon prepared by the method described in the second aspect in intracranial drug-coated balloons.
  • the particle size of the drug-coated balloon is small and uniform, and can be quickly absorbed through the cell membrane after expansion of the balloon, greatly improving the bioavailability of the drug.
  • all particles in the drug-coated balloon The materials are all biodegradable and will not cause systemic toxicity to the human body.
  • the drug-loading amount of the drug-coated balloon prepared in this application is accurately controllable, which avoids the waste caused by insufficient drug loading to achieve the treatment target and excessive drug loading, and the generation of systemic toxicity in the human body.
  • the average particle size of the drug-coated balloon described in this application is within 276.4nm, the particle size distribution is between 30-1260nm, the drug encapsulation rate is between 9-73%, and the unit time (0.5h)
  • the drug absorption ratio is between 4-25%.
  • Figure 1 is a schematic structural diagram of the drug-coated balloon described in Example 1;
  • 1-balloon body 2-hydrophilic coating
  • 3-drug-loading layer 2-hydrophilic coating
  • Figure 2 is a particle size distribution diagram of PLGA-PVA copolymer drug-loaded nanoparticles in the suspension before purification after ultrasonic emulsification and complete solvent evaporation during preparation according to the method described in Example 1.
  • Balloon body Pebax material, selected from Suzhou Zhongtian Medical products
  • Polylactic acid-glycolic acid copolymer purchased from Shenzhen Boli Biomaterials Co., Ltd.;
  • Polyvinyl alcohol (PVA) purchased from Aladdin Reagent (Shanghai) Co., Ltd.;
  • Polyvinylpyrrolidone purchased from Sinopharm Chemical Reagent Co., Ltd.;
  • Microporous filter membrane Purchased from Tianjin Test Equipment Co., Ltd., it is a needle sample filter, made of PES, with pore sizes including 0.45 ⁇ m and 0.8 ⁇ m;
  • Dialysis membrane purchased from Seventh Port Biological Laboratory, specifications are MD55 1000, MD55 3500.
  • This embodiment provides a drug-coated balloon, the structural schematic diagram of which is shown in Figure 1.
  • the drug-coated balloon includes a balloon body 1 and a hydrophilic coating 2 and 2 that are sequentially provided on the surface of the balloon body.
  • the drug-loaded layer includes additives and nanomedicine carriers
  • the nanomedicine carrier includes a combination of polylactic acid-glycolic acid copolymer, macrolide drugs and polyvinyl alcohol.
  • the balloon body is made of Pebax material
  • the thickness of the hydrophilic coating is 0.1 ⁇ m
  • the drug-loading capacity of the drug-coated balloon is 2 ⁇ g/mm 2 .
  • the drug-coated balloon is prepared by the following method, which includes the following steps:
  • the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs was added dropwise to the polyvinyl alcohol solution at a rate of 0.1 mL/min through a microsyringe pump, and ultrasonically emulsified for 20 minutes to form an emulsion;
  • the suspension is first filtered through a microporous filter membrane with a pore size of 0.8 ⁇ m, and then dialyzed using a dialysis membrane with a molecular weight cutoff of 1000 Daltons (specification: MD55 1000), and then centrifuged at a speed of 20000r/min for 15min. Discard the supernatant and take the precipitate to form a nano drug carrier;
  • hydrophilic treatment Perform hydrophilic treatment on the balloon body.
  • the specific process of hydrophilic treatment is as follows: spray polyacrylamide (Xilong Scientific Chemical, Mw 3 million) with a mass concentration of 1% evenly on the surface of the balloon through spraying equipment. The spraying amount is 20 ⁇ g/mm 2. After the spraying is completed, it is placed in a vacuum drying oven and dried at 0.5atm and 60°C for 24h;
  • This embodiment provides a drug-coated balloon, which includes a balloon body and a hydrophilic coating and a drug-loaded layer sequentially provided on the surface of the balloon body;
  • the drug-loaded layer includes additives and nanomedicine carriers
  • the nanomedicine carrier includes a combination of polylactic acid-glycolic acid copolymer, macrolide drugs and polyvinyl alcohol.
  • the balloon body is made of Pebax material
  • the thickness of the hydrophilic coating is 0.1 ⁇ m
  • the drug-loading capacity of the drug-coated balloon is 2 ⁇ g/mm 2 .
  • the drug-coated balloon is prepared by the following method, which includes the following steps:
  • the suspension is first filtered through a microporous filter membrane with a pore size of 0.8 ⁇ m, and then dialyzed using a dialysis membrane with a molecular weight cutoff of 3500 Daltons (specification: MD55 3500), and then centrifuged at a speed of 20000r/min for 15 minutes. Discard the supernatant and take the precipitate to form a nano drug carrier;
  • hydrophilic treatment Perform hydrophilic treatment on the balloon body.
  • the specific process of hydrophilic treatment is as follows: spray polyacrylamide (Xilong Scientific Chemical, Mw 3 million) with a mass concentration of 1% evenly on the surface of the balloon through spraying equipment. The spraying amount is 20 ⁇ g/mm 2. After the spraying is completed, it is placed in a vacuum drying oven and dried at 0.5atm and 60°C for 24h;
  • This embodiment provides a drug-coated balloon, which includes a balloon body and a hydrophilic coating and a drug-loaded layer sequentially provided on the surface of the balloon body;
  • the drug-loaded layer includes additives and nanomedicine carriers
  • the nanomedicine carrier includes a combination of polylactic acid-glycolic acid copolymer, macrolide drugs and polyvinyl alcohol.
  • the balloon body is made of Pebax material
  • the thickness of the hydrophilic coating is 0.1 ⁇ m
  • the drug-loading capacity of the drug-coated balloon is 2 ⁇ g/mm 2 .
  • the drug-coated balloon is prepared by the following method, which includes the following steps:
  • the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs was added dropwise to the polyvinyl alcohol solution at a rate of 0.1 mL/min through a microsyringe pump, and ultrasonically emulsified for 20 minutes to form an emulsion;
  • the suspension is first filtered through a microporous filter membrane with a pore size of 0.45 ⁇ m, and then dialyzed using a dialysis membrane with a molecular weight cutoff of 1000 Daltons (specification: MD55 1000), and then centrifuged at a speed of 20000 r/min for 15 minutes. Discard the supernatant and take the precipitate to form a nano drug carrier;
  • hydrophilic treatment Perform hydrophilic treatment on the balloon body.
  • the specific process of hydrophilic treatment is as follows: spray polyacrylamide (Xilong Scientific Chemical, Mw 3 million) with a mass concentration of 1% evenly on the surface of the balloon through spraying equipment. The spraying amount is 20 ⁇ g/mm 2. After the spraying is completed, it is placed in a vacuum drying oven and dried at 0.5atm and 60°C for 24h;
  • Example 1 The difference between this embodiment and Example 1 is that the concentration of the polyvinyl alcohol solution is 15 mg/mL, and the rest are the same as Example 1.
  • Example 1 The difference between this embodiment and Example 1 is that the added amount of zotarolimus is 60 mg, and the rest are the same as Example 1.
  • Example 1 The difference between this embodiment and Example 1 is that the added amount of PLGA is 260 mg, and the rest are the same as Example 1.
  • Example 1 The difference between this embodiment and Example 1 is that the volume of the polyvinyl alcohol solution is 10 mL, that is, the volume ratio of the polyvinyl alcohol solution and the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs is 1: 1, the rest are the same as Example 1.
  • Example 1 The difference between this embodiment and Example 1 is that the volume of the polyvinyl alcohol solution is 80 mL, that is, the volume ratio of the polyvinyl alcohol solution and the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs is 8: 1, the rest are the same as Example 1.
  • Embodiment 1 The difference between this embodiment and Embodiment 1 is that no filtering operation is performed in step (3), and the rest are the same as Embodiment 1.
  • Embodiment 1 The difference between this embodiment and Embodiment 1 is that no dialysis operation is performed in step (3), and the rest are the same as Embodiment 1.
  • Example 1 The difference between this embodiment and Example 1 is that the zotarolimus is replaced by an equal mass of rapamycin, and the rest are the same as in Example 1.
  • Example 1 The difference between this embodiment and Example 1 is that the zotarolimus is replaced by everolimus of equal mass, and the rest are the same as in Example 1.
  • Example 1 The difference between this comparative example and Example 1 is that the polyvinyl alcohol is replaced by polyvinylpyrrolidone of equal mass, and the rest are the same as Example 1.
  • Example 1 The difference between this comparative example and Example 1 is that the polylactic acid-glycolic acid copolymer is replaced by an equal mass of polyvinylpyrrolidone, and the rest are the same as Example 1.
  • Example 1 The difference between this comparative example and Example 1 is that the polyvinyl alcohol was replaced with fructose of equal mass (purchased from Sigma Aldrich (Shanghai) Trading Co., Ltd.), and the rest were the same as Example 1.
  • Example 1 The difference between this comparative example and Example 1 is that the polylactic acid-glycolic acid copolymer is replaced by an equal mass of fructose, and the rest are the same as Example 1.
  • the average particle size of the drug-coated balloon described in the present application is within 185.3 nm, the particle size distribution is between 30-630 nm, and the encapsulation rate is between 43% and 47%.
  • Figure 2 is a particle size distribution diagram of PLGA-PVA copolymer drug-loaded nanoparticles after ultrasonic emulsification and complete solvent evaporation before purification. It can be seen from the figure that the particle size of the drug-coated balloon described in this application is Small and uniform.
  • Comparative Examples 1-4 shows that the performance of Comparative Examples 1-4 is not as good as Example 1, proving that in the drug-loaded layer, polyvinyl alcohol and polylactic acid-glycolic acid copolymer are used together, and the two have a synergistic effect. If any one of them is replaced with other compounds of the same type, or if only one of them is set, the drug encapsulation rate of the drug-coated balloon formed is too low (for cost reasons, in vitro simulation experiments were not performed).
  • Example 4 shows that the performance of Example 4 is not as good as that of Example 1, which proves that the drug-coated balloon formed by controlling the concentration of the polyvinyl alcohol solution in the range of 3-8 mg/mL during preparation has better performance.
  • Example 5 shows that the performance of Example 5 is not as good as that of Example 1, which proves that during preparation, in the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs, the macrolide
  • the concentration of drug-like drugs is in the range of 2-5mg/mL, and the encapsulation rate of the drug is higher.
  • Example 6 shows that the performance of Example 6 is not as good as that of Example 1, which proves that during preparation, in the solution containing polylactic acid-glycolic acid copolymer and macrolide drugs, the polylactic acid-hydroxyacetic acid copolymer
  • concentration of acetic acid copolymer is in the range of 6-13mg/mL, and the drug encapsulation rate is higher.
  • Example 1 shows that the performance of Examples 7-8 is not as good as Example 1, which proves that during preparation, the polyvinyl alcohol solution and the polylactic acid-glycolic acid copolymer and macrolide drugs are controlled.
  • the volume ratio of the solution is in the range of (2-7):1, and it is further preferred that the drug-coated balloon formed by (2-4):1 has better performance.
  • Example 1 shows that although the drug encapsulation rate in Examples 9-10 is not lower than that of Example 1, the availability of the drug in the in vitro simulation experiment is significantly lower than that of Example 1, proving that purification adopts filtration, The material-coated balloons formed by dialysis and centrifugation operations have better performance.

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Abstract

本申请涉及一种药物涂层球囊及其制备方法和应用，所述药物涂层球囊包括球囊本体以及依次设置于所述球囊本体表面的亲水涂层和载药层；其中，所述载药层包括具有粘结、赋形作用的添加剂和纳米药物载体；所述纳米药物载体包括聚乳酸-羟基乙酸共聚物、大环内酯类药物和聚乙烯醇的组合。本申请中，所述药物涂层球囊粒径小而均匀，可在球囊扩张后快速穿过细胞膜被吸收，大幅提高药物的生物利用度，同时，药物涂层球囊中所有材料均可生物降解，不会对人体产生周身毒性。所述方法制备工艺简单、高效、稳定，操作便捷。

Description

一种药物涂层球囊及其制备方法和应用 技术领域
本申请涉及药物涂层球囊技术领域，尤其涉及一种药物涂层球囊及其制备方法和应用。
背景技术
缺血性卒中是目前危害人类健康的重大疾病之一，其主要发病原因之一是动脉粥样硬化造成颅内动脉狭窄进而供血不足引发卒中。动脉粥样硬化是动脉狭窄的重要病因，血管内膜灶状纤维化，形成粥样斑块，导致血管壁变硬、管腔变窄，从而引起一系列继发性病变。
对于症状性颅内动脉狭窄，其治疗方案有药物治疗及血管内支架治疗，其中药物保守治疗患者其脑卒中发生率依然较高，而血管内支架治疗的远期疗效存在一定争议。颅内动脉狭窄支架置入治疗的主要风险有以下几个方面:(1)血管破裂；(2)再灌注损伤；(3)血栓形成；(4)穿支动脉闭塞；(5)皮层动脉穿孔；(6)再狭窄。同时有个别报道指出，存在支架不能到达病变部位的现象，原因均为颅内外血管过度迂曲成角而不能到位。
球囊血管成形术的存在给上述问题提供了有效解决方案，这是一种通过物理扩张动脉粥样硬化、病变血管中的管腔直径减小或狭窄的区域来治疗血管疾病的已建立的方法，相对于支架，球囊更加柔软且直径更小，能够到达支架无法到达的细小血管。
药物涂层球囊(DCB)是在球囊扩张术或球囊成形术等介入技术基础上发展起来的新型治疗性球囊药物释放技术，其原理是通过涂层中的活性药物抑制病变区域血管平滑肌细胞的过度增殖避免血管再狭窄。具体是用介入方法通过球囊导管表面负载活性药物的涂层局部输送药物至患处，临床可操作性强，能克服血管内药物涂层支架表面积小而导致的载药量不足、药物分布不均、组织相容性差和造价昂贵等特点，也避免了药物持续接触所造成的内皮化障碍。
CN113476669A公开了一种药物涂层组合物，包括以下组分：赋形剂、治疗血管内壁再增生类生物活性药、聚合物、赋形剂溶剂、生物活性药溶剂和聚合物溶剂。其涂覆工艺为：将赋形剂与赋形剂溶剂充分混合，配制浓度为0.1 mg/mL～10g/mL的赋形剂溶液；将治疗血管内壁再增生类生物活性药与生物活性药溶剂充分混合，配制浓度为0.1mg/mL～10g/mL的生物活性药溶液；将赋形剂溶液和生物活性药溶液按照预定涂覆方法喷涂至或浸涂至医疗器械表面。其公开的药物涂层组合物可以减少药物在进入血管过程中的损失，避免在进入血管过程中药物涂层的脱落。另外，球囊药物涂层作用在病变处，药物能够快速被血管组织细胞吸收，能够很好地抑制细胞增生，达到非常好的治疗效果。
但药物涂层球囊也存在一些问题，首先是涂层粘结力方面，当粘结力过小时，涂层很容易在球囊输送至病变部位是发生脱落，造成药物损失；而粘结力如果过大，会出现球囊扩张后涂层无法释放或者无法快速、足量释放的现象。两种情况都会造成输送至患处的药量不足，从而影响治疗效果。与此同时，若涂层中负载的活性药物脂溶性较差，或者药物的分子量较大，无法有效穿透血管内壁的患处组织、细胞并在球囊扩张的数十秒时间内通过细胞膜进入细胞内部，会导致进入体内的药物实际的生物利用度极低，且已被球囊释放但未被组织吸收的药物还可能产生周身毒性，引发新的问题。
综上所述，开发一种能载药量可控、释放运输快的药物涂层球囊是至关重要的。
发明内容
本申请提供了一种药物涂层球囊及其制备方法和应用，所述药物涂层球囊粒径小而均匀，可在球囊扩张后快速穿过细胞膜被吸收，大幅提高药物的生物利用度，同时，药物涂层球囊中所有材料均可生物降解，不会对人体产生周身毒性。所述方法制备工艺简单、高效、稳定，操作便捷。
第一方面，本申请提供一种药物涂层球囊，所述药物涂层球囊包括球囊本体以及依次设置于所述球囊本体表面的亲水涂层和载药层；
其中，所述载药层包括具有粘结、赋形作用的添加剂和纳米药物载体；
所述纳米药物载体包括聚乳酸-羟基乙酸共聚物、大环内酯类药物和聚乙烯醇的组合。
本申请中，所述纳米药物载体包括聚乳酸-羟基乙酸共聚物、大环内酯类药物和聚乙烯醇的组合，聚乳酸-羟基乙酸共聚物和聚乙烯醇的配合，二者具有协同作用，形成的药物涂层球囊粒径小而均匀，可在球囊扩张后快速穿过细胞膜 被吸收，大幅提高药物的生物利用度，同时，药物涂层球囊中所有材料均可生物降解，不会对人体产生周身毒性。
其中，聚乳酸-羟基乙酸共聚物是一种性能良好的可生物降解聚合物，是一种脂肪族聚酯，由于其出色的生物降解性、生物相容性和无毒特性，已于2008年被美国食品和药物管理局(FDA)批准应用于人体。
聚乳酸-羟基乙酸共聚物是由聚乳酸和聚乙醇酸单体按照一定的比例聚合而成，不仅具生物可降解性、生物相容性、无毒特性，还具有保护生物大分子活性的作用。聚乳酸-羟基乙酸共聚物在生物降解过程中断裂为小分子物质，以乳酸等形式进入三羧酸循环，最终降解为二氧化碳和水。机体内的酸碱平衡系统可以快速中和并分解聚乳酸-羟基乙酸共聚物释放的酸性物质，使局部pH不发生较大变化。因此，聚乳酸-羟基乙酸共聚物纳米粒子可安全、有效地在生物应用领域包载和输送各种药物(包括亲水性和疏水性大分子等)、基因片段等。
优选地，所述亲水涂层的厚度为0.05-0.2μm，例如0.1μm、0.12μm、0.14μm、0.16μm或0.18μm等。
优选地，所述药物涂层球囊的载药量为1-10μg/mm 2，例如2μg/mm 2、4μg/mm 2、6μg/mm 2、8μg/mm 2或10μg/mm 2等。
第二方面，本申请提供一种第一方面所述的药物涂层球囊的制备方法，所述制备方法包括如下步骤：
(1)将聚乙烯醇溶液和含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液混合，形成乳液；
(2)将乳液搅拌加热，蒸发有机溶剂，形成悬浮液；
(3)将悬浮液进行纯化，形成纳米药物载体；
(4)将纳米药物载体、添加剂和溶剂混合，形成聚合物载药纳米粒子悬液以及；
(5)在含有亲水涂层的球囊本体表面设置聚合物纳米药物载体悬液，干燥，形成载药层，得到药物涂层球囊。
本申请中，聚乳酸-羟基乙酸共聚物在生物降解过程中断裂为小分子物质，以乳酸等形式进入三羧酸循环，最终降解为二氧化碳和水，无生物毒性；聚乙烯醇属于两亲性聚合物，在合成过程中加入聚乙烯醇可以稳定乳化液滴，减少新形成的纳米粒子在水相中的聚结和聚集，此外，两亲性PVA可以通过疏水相 互作用增强活性药物在纳米粒子中的包封。本申请制备出的纳米粒子粒径均匀，保证载药量的同时还保证粒子可以被细胞快速吸收；而且，本申请所述方法制备的药物涂层球囊载药量精确可控，避免了载药不足达不到治疗目标以及过量载药造成的浪费、在人体内产生周身毒性。
优选地，步骤(1)中，所述混合包括：将含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液滴加至聚乙烯醇溶液中，超声乳化，形成乳液。
优选地，所述乳液中，溶质的粒径≤650nm，例如580nm、560nm、540nm、520nm或500nm等。
优选地，所述滴加的工具包括微量注射泵。
优选地，所述滴加的速率为0.01-99.99mL/min，例如0.1mL/min、0.5mL/min、1mL/min、5mL/min、10mL/min、20mL/min、30mL/min、40mL/min、50mL/min、60mL/min、70mL/min、80mL/min或90mL/min等。
优选地，所述聚乙烯醇溶液的浓度为1-10mg/mL，例如2mg/mL、4mg/mL、6mg/mL或8mg/mL等，进一步优选3-8mg/mL。
优选地，所述聚乙烯醇溶液中的溶剂包括水。
优选地，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中的溶剂包括有机溶剂。
优选地，所述有机溶剂包括二氯甲烷。
优选地，所述聚乳酸-羟基乙酸共聚物中，乳酸和羟基乙酸的质量比为1：(1-6)，其中，1-6可以为2、3、4、5等，进一步优选1:1。
本申请中，聚乳酸-羟基乙酸共聚物因乳酸和乙醇酸的比例不同而具有不同的分子量和不同的物理化学特性，乳酸的含量直接影响其机械强度、溶胀行为、水解能力及生物降解速率。乳酸比乙醇酸更具疏水性，因此乳酸含量较高的聚乳酸-羟基乙酸共聚物亲水性更差，吸收的水更少，降解速率也会更慢。通过调整聚乳酸-羟基乙酸共聚物乳酸和乙醇酸的配比，可在一定范围内选择适当的药物释放和降解、吸收周期。
优选地，所述聚乳酸-羟基乙酸共聚物的分子量为5000-300000道尔顿，例如10000道尔顿、50000道尔顿、100000道尔顿、150000道尔顿、200000道尔顿、250000道尔顿等。
优选地，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中，所 述聚乳酸-羟基乙酸共聚物的浓度为6-13mg/mL，例如7mg/mL、8mg/mL、9mg/mL、10mg/mL、11mg/mL或12mg/mL等。
本申请中，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中，控制聚乳酸-羟基乙酸共聚物的浓度在6-13mg/mL范围内，聚乳酸-羟基乙酸共聚物的浓度过高，会导致无法在溶剂中充分溶解，过量的聚乳酸-羟基乙酸共聚物对后续实验步骤造成不利影响；聚乳酸-羟基乙酸共聚物的浓度过低，会导致无法充分地对大环内酯类药物形成包覆或包覆量不足，无法起到药物载体应有的作用将药物输送至细胞内部，同时导致药物包封率过低，造成药物的浪费。
优选地，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中，所述大环内酯类药物的浓度为2-5mg/mL，例如2.5mg/mL、3mg/mL、3.5mg/mL、4mg/mL、4.5mg/mL等。
优选地，所述聚乙烯醇溶液和含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液的体积比为(2-10):1，其中，2-10可以为4、6、8等，进一步优选(2-7):1，更进一步优选(2-4):1。
本申请中，所述聚乙烯醇溶液和含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液的体积比在(2-10):1范围内，二者质量比过高，会导致球囊表面单位质量的涂层中大环内酯类药物的相对含量过低，起不到治疗作用或治疗效果不好；二者质量比过低，会导致载体相对含量过低，药物包封率过低，通过细胞膜的能力也会降低。
优选地，所述大环内酯类药物包括雷帕霉素、依维莫司、佐他莫司、地塞米松、紫杉醇、多西他赛、普罗布考、秋水仙碱、肝素、阿司匹林或阿霉素中的任意一种或至少两种的组合，其中典型但非限制性的组合包括：雷帕霉素和依维莫司的组合，佐他莫司、地塞米松、紫杉醇和多西他赛的组合，多西他赛、普罗布考、秋水仙碱、肝素、阿司匹林和阿霉素的组合等。
优选地，步骤(2)中，所述搅拌加热的温度为30-50℃，例如32℃、34℃、36℃、38℃、40℃、42℃、44℃、46℃或48℃等。
优选地，所述搅拌加热至含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中的有机溶剂完全挥发。
优选地，步骤(3)中，所述纯化依次包括过滤、透析和离心。
优选地，所述过滤的工具包括微孔滤膜。
优选地，所述微孔滤膜的孔径为0.4-1.0μm，例如0.5μm、0.6μm或0.8μm等，进一步优选0.45μm和0.8μm。
优选地，所述透析的工具包括透析膜。
优选地，所述透析膜的截留分子量为500-7000道尔顿，例如1000道尔顿、1500道尔顿、2000道尔顿、2500道尔顿、3000道尔顿、3500道尔顿、4000道尔顿、4500道尔顿、5000道尔顿、5500道尔顿、6000道尔顿或6500道尔顿等，进一步优选500道尔顿、1000道尔顿、3500道尔顿或7000道尔顿。
优选地，所述离心的转速为10000-30000r/min，例如12000r/min、14000r/min、16000r/min、18000r/min、20000r/min、22000r/min、24000r/min、26000r/min或28000r/min等。
优选地，所述离心的时间为10-60min，例如15min、20min、25min、30min、35min、40min、45min、50min或55min等。
优选地，所述纳米药物载体的粒径为30nm-300nm，例如160nm、180nm、200nm、220nm、240nm、260nm或280nm等。
优选地，步骤(4)包括：先将纳米药物载体分散于溶剂中，再与添加剂混合。
优选地，所述溶剂包括水。
优选地，步骤(4)中，所述聚合物载药纳米粒子悬液中，纳米药物载体的浓度为13-40mg/mL，例如15mg/mL、20mg/mL、25mg/mL、30mg/mL或35mg/mL等。
优选地，以纳米药物载体的总质量为100份计，所述添加剂的质量份数为1-20份，例如2份、4份、6份、8份、10份、12份、14份、16份或18份等。
示例性地，所述添加剂包括葡聚糖、聚山梨醇、山梨糖醇、果糖、蔗糖、乳糖、麦芽糖、赤藓醇、苏糖醇、阿拉伯糖醇、核糖醇、甘露醇、半乳糖醇、岩藻糖醇、艾杜醇、肌醇、庚七醇、异麦芽酮糖醇、麦芽糖醇、乳糖醇、麦芽三糖醇、伏格列波糖、木糖醇或聚乙二醇中的任意一种或至少两种的组合，其中典型但非限制性的组合包括：葡聚糖、聚山梨醇和山梨糖醇的组合，核糖醇、甘露醇、半乳糖醇、岩藻糖醇、艾杜醇、肌醇、庚七醇、异麦芽酮糖醇和麦芽糖醇的组合，阿拉伯糖醇、核糖醇、甘露醇、半乳糖醇、岩藻糖醇、艾杜醇、肌醇、庚七醇、异麦芽酮糖醇、麦芽糖醇、乳糖醇、麦芽三糖醇、伏格列波糖、 木糖醇和聚乙二醇的组合等。
优选地，步骤(5)中，所述固化的温度为40-70℃，例如45℃、50℃、55℃、60℃或65℃等。
作为优选的技术方案，所述制备方法包括如下步骤：
(1)将含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液通过微量注射泵以0.01-99.99mL/min的速率滴加至聚乙烯醇溶液中，超声乳化至溶质的粒径≤650nm，形成乳液；
(2)将乳液在30-50℃下搅拌加热，至乳液中的有机溶剂完全挥发，形成悬浮液；
(3)将悬浮液先采用孔径为0.4-1.0μm的微孔滤膜过滤，再采用截留分子量为500-7000道尔顿的透析膜透析，然后在10000-30000r/min的转速下离心10-60min，形成粒径为30-300nm的纳米药物载体；
(4)将纳米药物载体分散于水中，再与添加剂混合，形成聚合物载药纳米粒子悬液；以及
(5)在含有亲水涂层的球囊本体表面设置聚合物纳米药物载体悬液，在40-70℃下干燥，形成载药层，得到药物涂层球囊。
第三方面，本申请提供一种第一方面所述的药物涂层球囊，或第二方面所述的方法制备的药物涂层球囊在颅内药物涂层球囊中的应用。
相对于现有技术，本申请具有以下有益效果：
(1)本申请中，所述药物涂层球囊粒径小而均匀，可在球囊扩张后快速穿过细胞膜被吸收，大幅提高药物的生物利用度，同时，药物涂层球囊中所有材料均可生物降解，不会对人体产生周身毒性。
(2)本申请制备的药物涂层球囊载药量精确可控，避免了载药不足达不到治疗目标以及过量载药造成的浪费、在人体内产生周身毒性。
(3)本申请中，制备工艺简单、高效、稳定，操作便捷。
(4)本申请中所述药物涂层球囊的平均粒径在276.4nm以内，粒径分布在30-1260nm之间，药物包封率在9-73％之间，单位时间(0.5h)内的药物吸收比例在4-25％之间。
附图说明
图1是实施例1所述的药物涂层球囊的结构示意图；
其中，1-球囊本体；2-亲水涂层；3-载药层。
图2是实施例1所述方法制备时超声乳化且溶剂完全挥发后，纯化前，悬浮液中PLGA-PVA共聚物载药纳米粒子的粒度分布图。
具体实施方式
为便于理解本申请，本申请列举实施例如下。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
本申请中，各实施例的原料的购置信息如下：
球囊本体：Pebax材料，选自苏州中天医疗的产品；
聚乳酸-羟基乙酸共聚物(PLGA)：购于深圳市博立生物材料有限公司；
聚乙烯醇(PVA)：购于阿拉丁试剂(上海)有限公司；
聚乙烯吡咯烷酮：购于国药集团化学试剂有限公司；
微孔滤膜：购于天津试验设备有限公司，为针式样品过滤器，PES材质，孔径包括0.45μm、0.8μm；
透析膜：购于第七港口生物实验室，规格为MD55 1000、MD55 3500。
实施例1
本实施例提供一种药物涂层球囊，其结构示意图如图1所示，所述药物涂层球囊包括球囊本体1以及依次设置于所述球囊本体表面的亲水涂层2和载药层3；
所述载药层包括添加剂和纳米药物载体；
所述纳米药物载体包括聚乳酸-羟基乙酸共聚物、大环内酯类药物和聚乙烯醇的组合。
所述球囊本体为Pebax材料；
所述亲水涂层的厚度为0.1μm；
所述药物涂层球囊的载药量为2μg/mm 2。
所述药物涂层球囊由如下方法制备，所述制备方法包括如下步骤：
(1)配置5mg/mL的PVA水溶液20mL，形成聚乙烯醇溶液；
称取65mg PLGA，30mg佐他莫司溶于10mL二氯甲烷，形成含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液；
将含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液通过微量注射泵以0.1mL/min的速率滴加至聚乙烯醇溶液中，超声乳化20min，形成乳液；
(2)将乳液在37℃下搅拌加热，至乳液中的二氯甲烷完全挥发，形成悬浮液；
(3)将悬浮液先采用孔径为0.8μm的微孔滤膜过滤，再采用截留分子量为1000道尔顿的透析膜(规格为MD55 1000)透析，然后在20000r/min的转速下离心15min，弃上清，取沉淀，形成纳米药物载体；
(4)将纳米药物载体分散于水中，加入15mg添加剂甘露醇，形成聚合物载药纳米粒子悬液；
(5)将球囊本体进行亲水处理，亲水处理的过程具体为：将质量浓度为1％的聚丙烯酰胺(西陇科学化工，Mw 300万)通过喷涂设备均匀喷涂于球囊表面，喷涂量为20μg/mm 2，喷涂完成后置于真空干燥箱中在0.5atm、60℃条件下干燥24h；
在含有亲水涂层的球囊本体表面以超声喷涂设备均匀喷涂纳米药物载体悬液，在50℃下干燥，形成载药层，得到药物涂层球囊。
实施例2
本实施例提供一种药物涂层球囊，所述药物涂层球囊包括球囊本体以及依次设置于所述球囊本体表面的亲水涂层和载药层；
所述载药层包括添加剂和纳米药物载体；
所述纳米药物载体包括聚乳酸-羟基乙酸共聚物、大环内酯类药物和聚乙烯醇的组合。
所述球囊本体为Pebax材料；
所述亲水涂层的厚度为0.1μm；
所述药物涂层球囊的载药量为2μg/mm 2。
所述药物涂层球囊由如下方法制备，所述制备方法包括如下步骤：
(1)配置5mg/mL的PVA水溶液20mL，形成聚乙烯醇溶液；
称取130mg PLGA，30mg佐他莫司溶于10mL二氯甲烷，形成含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液；
将含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液通过微量注射泵以0.2mL/min的速率滴加至聚乙烯醇溶液中，超声乳化20min，形成乳液；
(2)将乳液在37℃下搅拌加热，至乳液中的二氯甲烷完全挥发，形成悬浮液；
(3)将悬浮液先采用孔径为0.8μm的微孔滤膜过滤，再采用截留分子量为3500道尔顿的透析膜透析(规格为MD55 3500)，然后在20000r/min的转速下离心15min，弃上清，取沉淀，形成纳米药物载体；
(4)将纳米药物载体分散于水中，加入15mg添加剂甘露醇，形成聚合物载药纳米粒子悬液；
(5)将球囊本体进行亲水处理，亲水处理的过程具体为：将质量浓度为1％的聚丙烯酰胺(西陇科学化工，Mw 300万)通过喷涂设备均匀喷涂于球囊表面，喷涂量为20μg/mm 2，喷涂完成后置于真空干燥箱中在0.5atm、60℃条件下干燥24h；
在含有亲水涂层的球囊本体表面以超声喷涂设备均匀喷涂纳米药物载体悬液，在40℃下干燥，形成载药层，得到药物涂层球囊。
实施例3
本实施例提供一种药物涂层球囊，所述药物涂层球囊包括球囊本体以及依次设置于所述球囊本体表面的亲水涂层和载药层；
所述载药层包括添加剂和纳米药物载体；
所述纳米药物载体包括聚乳酸-羟基乙酸共聚物、大环内酯类药物和聚乙烯醇的组合。
所述球囊本体为Pebax材料；
所述亲水涂层的厚度为0.1μm；
所述药物涂层球囊的载药量为2μg/mm 2。
所述药物涂层球囊由如下方法制备，所述制备方法包括如下步骤：
(1)配置5mg/mL的PVA水溶液20mL，形成聚乙烯醇溶液；
称取65mg PLGA，30mg佐他莫司溶于15mL二氯甲烷，形成含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液；
将含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液通过微量注射泵以0.1mL/min的速率滴加至聚乙烯醇溶液中，超声乳化20min，形成乳液；
(2)将乳液在37℃下搅拌加热，至乳液中的二氯甲烷完全挥发，形成悬浮液；
(3)将悬浮液先采用孔径为0.45μm的微孔滤膜过滤，再采用截留分子量为1000道尔顿的透析膜透析(规格为MD55 1000)，然后在20000r/min的转速下离心15min，弃上清，取沉淀，形成纳米药物载体；
(4)将纳米药物载体分散于水中，加入15mg添加剂甘露醇，形成聚合物载药纳米粒子悬液；
(5)将球囊本体进行亲水处理，亲水处理的过程具体为：将质量浓度为1％的聚丙烯酰胺(西陇科学化工，Mw 300万)通过喷涂设备均匀喷涂于球囊表面，喷涂量为20μg/mm 2，喷涂完成后置于真空干燥箱中在0.5atm、60℃条件下干燥24h；
在含有亲水涂层的球囊本体表面以超声喷涂设备均匀喷涂纳米药物载体悬液，在40℃下干燥，形成载药层，得到药物涂层球囊。
实施例4
本实施例与实施例1的区别在于所述聚乙烯醇溶液的浓度为15mg/mL，其余均与实施例1相同。
实施例5
本实施例与实施例1的区别在于所述佐他莫司的添加量为60mg，其余均与实施例1相同。
实施例6
本实施例与实施例1的区别在于所述PLGA的添加量为260mg，其余均与实施例1相同。
实施例7
本实施例与实施例1的区别在于所述聚乙烯醇溶液的体积为10mL，即聚乙烯醇溶液和含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液的体积比为1:1，其余均与实施例1相同。
实施例8
本实施例与实施例1的区别在于所述聚乙烯醇溶液的体积为80mL，即聚乙烯醇溶液和含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液的体积比为8:1，其余均与实施例1相同。
实施例9
本实施例与实施例1的区别在于步骤(3)中不进行过滤操作，其余均与实 施例1相同。
实施例10
本实施例与实施例1的区别在于步骤(3)中不进行透析操作，其余均与实施例1相同。
实施例11
本实施例与实施例1的区别在于将所述佐他莫司替换为等质量的雷帕霉素，其余均与实施例1相同。
实施例12
本实施例与实施例1的区别在于将所述佐他莫司替换为等质量的依维莫司，其余均与实施例1相同。
对比例1
本对比例与实施例1的区别在于将所述聚乙烯醇替换为等质量的聚乙烯吡咯烷酮，其余均与实施例1相同。
对比例2
本对比例与实施例1的区别在于将所述聚乳酸-羟基乙酸共聚物替换为等质量的聚乙烯吡咯烷酮，其余均与实施例1相同。
对比例3
本对比例与实施例1的区别在于将所述聚乙烯醇替换为等质量的果糖(购于西格玛奥德里奇(上海)贸易有限公司)，其余均与实施例1相同。
对比例4
本对比例与实施例1的区别在于将所述聚乳酸-羟基乙酸共聚物替换为等质量的果糖，其余均与实施例1相同。
性能测试
将实施例1-12和对比例1-4所述的药物涂层球囊进行如下测试：
(1)粒径分布及平均粒径测定：使用Masterriser 2000E+zs90激光粒度仪测定纳米粒子粒度分布及平均粒径。
(2)载药量测定：用甲醇将制备完成的药物涂层球囊上的药物涂层反复清洗并收集至容量瓶定容。利用HPLC测定容量瓶中的药物浓度，根据浓度即可计算出载药量。HPLC测试条件为：Agilent 1260InfinityⅡ高效液相色谱仪，色谱柱：Agilent C18，RRHD 1.8μm，3.0×50mm，流动相：水:乙腈＝10:90，柱温： 50℃，紫外检测波长：278nm，流速：0.6mL/min。
(3)体外实验中血管组织0.5h药物摄入量测定：用猪冠状血管模拟冠状动脉系统的靶血管进行体外模拟测试。将制备的药物涂层球囊导管插入模拟靶血管中，对球囊使用液体介质冲压至12atm。球囊直径与目标血管直径的比例约为1.1-1.2。球囊扩张时间为60s，然后泄压并从体外模拟系统中取出。收集靶血管组织，通过组织提取和HPLC，分析靶组织中的药物含量及球囊上的残余药量。
测试结果汇总于表1和图2中。
表1
Figure PCTCN2022126117-appb-000001
分析表1数据可知，本申请所述药物涂层球囊的平均粒径在276.4nm以内，粒径分布在30-1260nm之间，药物包封率在9-73％之间，单位时间(0.5h)内 吸收药物的比例在4-25％之间；本申请所述药物涂层球囊粒径小而均匀，可在球囊扩张后快速穿过细胞膜被吸收，大幅提高药物的生物利用度，同时，此方法中所有材料均可生物降解，不会对人体产生周身毒性。除此之外，本申请的制备工艺简单、高效、稳定，操作便捷。
在优选范围内，本申请所述药物涂层球囊的平均粒径在185.3nm以内，粒径分布在30-630nm之间，包封率在43％-47％之间。
以实施例1为例，图2为超声乳化且溶剂完全挥发后，纯化前，PLGA-PVA共聚物载药纳米粒子的粒度分布图，由图可知，本申请所述药物涂层球囊粒径小而均匀。
分析对比例1-4与实施例1可知，对比例1-4性能不如实施例1，证明载药层中，聚乙烯醇和聚乳酸-羟基乙酸共聚物配合使用，二者具有协同作用，将二者任意一种替换为其他同类型化合物，或，仅设置其中一种，所形成的药物涂层球囊药物包封率过低(考虑到成本原因，未进行体外模拟实验)。
分析实施例4与实施例1可知，实施例4性能不如实施例1，证明制备时，控制聚乙烯醇溶液的浓度在3-8mg/mL范围内形成的药物涂层球囊性能更佳。
分析实施例5与实施例1可知，实施例5性能不如实施例1，证明制备时，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中，所述大环内酯类药物的浓度在2-5mg/mL范围内，药物的包封率更高。
分析实施例6与实施例1可知，实施例6性能不如实施例1，证明制备时，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中，所述聚乳酸-羟基乙酸共聚物的浓度为6-13mg/mL范围内，药物的包封率更高。
分析实施例7-8与实施例1可知，实施例7-8性能不如实施例1，证明制备时，控制所述聚乙烯醇溶液和含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液的体积比在(2-7):1范围内，进一步优选(2-4):1形成的药物涂层球囊性能更佳。
分析实施例9-10与实施例1可知，实施例9-10虽然药物包封率不低于实施例1，但体外模拟实验中药物的利用度明显低于实施例1，证明纯化采用过滤、透析和离心操作形成的物涂层球囊性能更佳。
申请人声明，本申请通过上述实施例来说明本申请的详细方法，但本申请并不局限于上述详细方法，即不意味着本申请必须依赖上述详细方法才能实施。 所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本申请的保护范围和公开范围之内。

Claims (12)

  1. 一种药物涂层球囊，其包括球囊本体以及依次设置于所述球囊本体表面的亲水涂层和载药层；
    其中，所述载药层包括具有粘结、赋形作用的添加剂和纳米药物载体；
    所述纳米药物载体包括聚乳酸-羟基乙酸共聚物、大环内酯类药物和聚乙烯醇的组合。
  2. 根据权利要求1所述的药物涂层球囊，其中，所述亲水涂层的厚度为0.05-0.2μm。
  3. 根据权利要求1或2所述的药物涂层球囊，其中，所述药物涂层球囊的载药量为1-10μg/mm 2。
  4. 一种权利要求1-3任一项所述的药物涂层球囊的制备方法，其包括如下步骤：
    (1)将聚乙烯醇溶液和含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液混合，形成乳液；
    (2)将乳液搅拌加热，蒸发有机溶剂，形成悬浮液；
    (3)将悬浮液进行纯化，形成纳米药物载体；
    (4)将纳米药物载体、添加剂和溶剂混合，形成聚合物载药纳米粒子悬液；以及
    (5)在含有亲水涂层的球囊本体表面设置聚合物纳米药物载体悬液，固化，形成载药层，得到所述药物涂层球囊。
  5. 根据权利要求4所述的制备方法，其中，步骤(1)中，所述混合包括：将含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液滴加至聚乙烯醇溶液中，超声乳化，形成乳液；
    优选地，所述乳液中，溶质的粒径≤650nm；
    优选地，所述滴加的工具包括微量注射泵；
    优选地，所述滴加的速率为0.01-99.99mL/min；
    优选地，所述聚乙烯醇溶液的浓度为1-10mg/mL；
    优选地，所述聚乙烯醇溶液中的溶剂包括水；
    优选地，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中的溶剂包括有机溶剂；
    优选地，所述有机溶剂包括二氯甲烷。
  6. 根据权利要求4或5所述的制备方法，其中，所述聚乳酸-羟基乙酸共聚物中，乳酸和羟基乙酸的质量比为1：(1-6)；
    优选地，所述聚乳酸-羟基乙酸共聚物的分子量为5000-300000道尔顿；
    优选地，所述大环内酯类药物包括雷帕霉素、依维莫司、佐他莫司、地塞米松、紫杉醇、多西他赛、普罗布考、秋水仙碱、肝素、阿司匹林或阿霉素中的任意一种或至少两种的组合；
    优选地，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中，所述聚乳酸-羟基乙酸共聚物的浓度为6-13mg/mL；
    优选地，所述含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中，所述大环内酯类药物的浓度为2-5mg/mL；
    优选地，所述聚乙烯醇溶液和含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液的体积比为(2-10):1。
  7. 根据权利要求4-6任一项所述的制备方法，其中，步骤(2)中，所述搅拌加热的温度为30-50℃；
    优选地，所述搅拌加热至含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液中的有机溶剂完全挥发。
  8. 根据权利要求4-7任一项所述的制备方法，其中，步骤(3)中，所述纯化依次包括过滤、透析和离心；
    优选地，所述过滤的工具包括微孔滤膜；
    优选地，所述微孔滤膜的孔径为0.4-1.0μm；
    优选地，所述透析的工具包括透析膜；
    优选地，所述透析膜的截留分子量为500-7000道尔顿；
    优选地，所述离心的转速为10000-30000r/min；
    优选地，所述离心的时间为10-60min；
    优选地，所述纳米药物载体的粒径为30-300nm。
  9. 根据权利要求4-8任一项所述的制备方法，其中，步骤(4)包括：先将纳米药物载体分散于溶剂中，再与添加剂混合；
    优选地，所述溶剂包括水。
  10. 根据权利要求4-9任一项所述的制备方法，其中，步骤(4)中，所述聚合物载药纳米粒子悬液中，纳米药物载体的浓度为13-40mg/mL；
    优选地，以纳米药物载体的总质量为100份计，所述添加剂的质量份数为1-20份；
    优选地，步骤(5)中，所述固化的温度为40-70℃。
  11. 根据权利要求4-10任一项所述的制备方法，其中，所述制备方法包括如下步骤：
    (1)将含有聚乳酸-羟基乙酸共聚物和大环内酯类药物的溶液通过微量注射泵以0.01-99.99mL/min的速率滴加至聚乙烯醇溶液中，超声乳化至溶质的粒径≤650nm，形成乳液；
    (2)将乳液在30-50℃下搅拌加热，至乳液中的有机溶剂完全挥发，形成悬浮液；
    (3)将悬浮液先采用孔径为0.4-1.0μm的微孔滤膜过滤，再采用截留分子量为500-7000道尔顿的透析膜透析，然后在10000-30000r/min的转速下离心10-60min，形成粒径为30-300nm的纳米药物载体；
    (4)将纳米药物载体分散于水中，再与添加剂混合，形成聚合物载药纳米粒子悬液；以及
    (5)在含有亲水涂层的球囊本体表面设置聚合物纳米药物载体悬液，在40-70℃下固化，形成载药层，得到所述药物涂层球囊。
  12. 一种权利要求1-3任一项所述的药物涂层球囊，或，权利要求4-11任一项所述的方法制备的药物涂层球囊在颅内药物涂层球囊中的应用。
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CN115006605A (zh) * 2022-07-20 2022-09-06 苏州中天医疗器械科技有限公司 一种药物涂层球囊及其制备方法和应用

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