WO2024007830A1 - 球囊导管涂层及其制备方法、球囊导管 - Google Patents

球囊导管涂层及其制备方法、球囊导管 Download PDF

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Publication number
WO2024007830A1
WO2024007830A1 PCT/CN2023/100094 CN2023100094W WO2024007830A1 WO 2024007830 A1 WO2024007830 A1 WO 2024007830A1 CN 2023100094 W CN2023100094 W CN 2023100094W WO 2024007830 A1 WO2024007830 A1 WO 2024007830A1
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Prior art keywords
balloon catheter
drug
coating
sirolimus
catheter coating
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PCT/CN2023/100094
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English (en)
French (fr)
Inventor
王森
于绍兴
王鼎曦
戴志豪
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上海申淇医疗科技有限公司
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Publication of WO2024007830A1 publication Critical patent/WO2024007830A1/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
    • A61L29/08—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
    • A61L29/08—Materials for coatings
    • 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
    • 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
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This application belongs to the field of medical technology, such as a balloon catheter coating and its preparation method, and a balloon catheter.
  • rapamycin-medicated balloon catheter a drug that is released into the blood vessel to counteract the inflammatory and healing responses
  • Rapamycin and its analogues have both antiproliferative and anti-inflammatory activities and better biosafety.
  • the existing rapamycin drug balloon catheter releases the drug too quickly and cannot effectively inhibit vascular thrombosis and restenosis; the non-lipophilic rapamycin coating is difficult to adhere to the balloon surface and is difficult to be absorbed by the vascular tissue. Absorption; and this coating is easily washed away by blood. Even if a small amount of rapamycin is absorbed, the therapeutic effect can only last for a few days.
  • the purpose of this application is to provide a balloon catheter coating, a preparation method thereof, and a balloon catheter.
  • the balloon catheter coating of the present application solves the coating stability problem of non-lipophilic drug balloon catheters, as well as the adsorption and absorption problems of non-lipophilic substances and blood vessels, and achieves a controllable drug release cycle, allowing the drug to be released for a long time.
  • the balloon catheter coating of the present application solves the coating stability problem of non-lipophilic drug balloon catheters, as well as the adsorption and absorption problems of non-lipophilic substances and blood vessels, and achieves a controllable drug release cycle, allowing the drug to be released for a long time.
  • the present application provides a balloon catheter coating, which includes drug-loaded microspheres and a lipophilic material, and the drug-loaded microspheres are dispersed in the lipophilic material;
  • the drug-loaded microspheres include sirolimus drugs and a shell that wraps the drug, and the shell includes polylactic acid-glycolic acid copolymer;
  • the lipophilic material includes a phase change temperature above 25°C (for example, it can be 25°C, 26°C, 28°C, 30°C, 32°C, 34°C, 36°C, 38°C, 40°C, 50°C, 60°C, 80°C, 100°C, etc.) phospholipid compounds.
  • sirolimus also known as "rapamycin” drugs are selected.
  • Sirolimus and its analogues have both anti-proliferative and anti-inflammatory activities, and have better biological properties. Safety, but sirolimus and its analogues are released too quickly and are easily washed away by the blood. Even if a small amount of the drug is absorbed, the therapeutic effect can only last for a few days. Therefore, this application chooses to coat it with polylactic acid-glycolic acid copolymer (PLGA for short). Drug-loaded microspheres of different sizes made from PLGA with different molecular weights will have different release cycles. Control the release cycle of the microspheres. The release cycle of the drug in the balloon catheter coating can be controlled.
  • PLGA polylactic acid-glycolic acid copolymer
  • the lipophilic material includes phospholipid compounds with a phase transition temperature above 25°C.
  • this type of lipophilic material can help the drug to better adhere to the wall and absorb; on the other hand, at normal temperature or higher Under temperature storage conditions, phospholipid compounds with a phase transition temperature above 25°C can be stored in solid form exists, the coating is more stable, the drug-loaded microspheres are dispersed in this type of lipophilic material, and there is less loss during the delivery process.
  • the sirolimus drugs include sirolimus and/or sirolimus derivatives.
  • the sirolimus derivatives include everolimus and/or zotarolimus.
  • the relative molecular mass of the polylactic acid-glycolic acid copolymer is 30000-140000, for example, it can be 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 110000, 120000, 130000, 140000, etc. .
  • the relative molecular mass of the polylactic acid-glycolic acid copolymer is 30000-50000, for example, it can be 30000, 32000, 34000, 36000, 38000, 40000, 42000, 44000, 46000, 48000, 50000, etc., so
  • the in vitro release half-life of the drug-loaded microspheres is 30-100 days, for example, it can be 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, etc.;
  • the relative molecular mass of the polylactic acid-glycolic acid copolymer is 50000-100000, for example, it can be 50000, 60000, 70000, 80000, 90000, 100000, etc.
  • the in vitro release half-life of the drug-loaded microsphere is 100-300 Days, for example, can be 100 days, 120 days, 140 days, 160 days, 180 days, 200 days, 220 days, 240 days, 260 days, 280 days, 300 days, etc.;
  • the relative molecular mass of the polylactic acid-glycolic acid copolymer is 100000-140000, for example, it can be 100000, 110000, 120000, 130000, 140000, etc.
  • the in vitro release half-life of the drug-loaded microsphere is 300-1000 days, For example, it can be 300 days, 400 days, 500 days, 600 days, 700 days, 800 days, 900 days, and 1000 days.
  • the particle size of the drug-loaded microspheres is 100nm-10 ⁇ m, for example, it can be 100nm, 200nm, 300nm, 400nm, 500nm, 600nm, 700nm, 800nm, 900nm, 1 ⁇ m, 2 ⁇ m, 3 ⁇ m, 4 ⁇ m, 5 ⁇ m, 6 ⁇ m, 7 ⁇ m, 8 ⁇ m, 9 ⁇ m, 10 ⁇ m, etc.
  • the mass ratio of the polylactic acid-glycolic acid copolymer and the sirolimus drug is (0.5-5):1, for example, it can be 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4.5:1, 5:1 etc.; and/or the mass ratio of the sirolimus drug and the lipophilic material is (0.1-5):1, for example, it can be 0.1:1, 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4.5:1, 5:1, etc.
  • the drug loading amount of sirolimus drugs in the coating is 0.1-4 ⁇ g/mm 2 , for example It can be 0.1 ⁇ g/mm 2 , 0.2 ⁇ g/mm 2 , 0.4 ⁇ g/mm 2 , 0.6 ⁇ g/mm 2 , 0.8 ⁇ g/ mm 2 , 1 ⁇ g/mm 2 , 1.5 ⁇ g/mm 2 , 2 ⁇ g/mm 2 , 2.5 ⁇ g /mm 2 , 3 ⁇ g/mm 2 ,
  • the lipophilic material also includes cholesterol and/or fatty acids.
  • the lipophilic material is a combination of a phospholipid compound and cholesterol with a phase transition temperature above 25°C, and the mass ratio of the phospholipid compound and cholesterol is (0.2-5):1, for example It is 0.2:1, 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4.5:1, 5:1, etc., preferably (4-5): 1.
  • the lipophilic material is a combination of a phospholipid compound and a fatty acid with a phase transition temperature above 25°C.
  • the mass ratio of the phospholipid compound and the fatty acid is (0.2-5):1.
  • it can It is 0.2:1, 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4.5:1, 5:1, etc., preferably (2-3): 1.
  • the cholesterol includes DC-cholesterol and/or cholesterol.
  • the fatty acid includes any one or a combination of at least two of palmitic acid, stearic acid, lauric acid, myristic acid or arachidic acid.
  • the phospholipid compound is an amphiphilic phospholipid compound.
  • the phospholipid compound includes any one of dipalmitate phosphatidylcholine, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylethanolamine or A combination of at least two.
  • the dispersion density of the drug-loaded microspheres is 10 3 -10 5 /mm 2 , for example, 10 3 pieces/mm 2 , 5 ⁇ 10 3 pieces/mm 2 , 10 4 pieces/mm 2 , 5 ⁇ 10 4 pieces/mm 2 , 10 5 pieces/mm 2 , etc.
  • the balloon catheter coating also includes PEG-lipid and/or hydrophilic pharmaceutical excipients.
  • adding a small amount of PEG-lipid can increase coating firmness and biocompatibility.
  • adding a small amount of hydrophilic pharmaceutical excipients can make the coating of the balloon easier to melt during the expansion process, thereby increasing the drug absorption rate of blood vessels.
  • the PEG-lipids include 1,2-dioleoyl-sn-glyceryl-3-phosphoethanolamine-N-methoxy (polyethylene glycol) and/or 1,2-disulfonate Fatty acyl-sn-glyceryl-3-phosphoethanolamine-N-methoxy (polyethylene glycol).
  • the number average molecular weight of the polyethylene glycol is 300-5000, for example, it can be 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, etc.
  • the mass ratio of the PEG-lipid and the phospholipid compound is (1-20):100, for example, it can be 1:100, 2:100, 4:100, 6:100, 8: 100, 10:100, 12:100, 14:100, 16:100, 18:100, 20:100, etc.
  • the mass ratio of the hydrophilic pharmaceutical excipient and the phospholipid compound is (5 -40):100, for example, it can be 5:100, 6:100, 8:100, 10:100, 12:100, 14:100, 16:100, 18:100, 20:100, 25:100, 30 :100, 35:100, 40:100, etc.
  • hydrophilic pharmaceutical excipients include any one or a combination of at least two of hyaluronic acid, mannitol or water-soluble crystalline sugar.
  • This application also provides a preparation method for the balloon catheter coating as described above, which preparation method includes the following steps:
  • the mixing temperature is 0-37°C, for example, it can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 37°C °C, etc.
  • the mixing time is 1-10 min, for example, it can be 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, etc.
  • the concentration of drug-loaded microspheres in the coating solution is 10-30g/L, for example, it can be 10g/L, 12g/L, 14g/L, 16g/L, 18g/L, 20g/L, 22g/L, 24g/L, 26g/L, 28g/L, 30g/L, etc.
  • the concentration of the lipophilic material is 10-30g/L, for example, it can be 10g/L, 12g/L, 14g/L, 16g/L, 18g/L, 20g/L, 22g/L, 24g/L, 26g/L, 28g/L, 30g/L, etc.
  • the solvent includes methanol, ethanol, acetone, isopropyl alcohol, dimethyl sulfoxide, ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, n-heptane, n-hexane, Any one or a combination of at least two of cyclohexane or water.
  • each preparation raw material for the balloon catheter coating needs to be dried before preparing the coating solution.
  • the stirring speed is 500-10000rpm, for example, it can be 500rpm, 1000rpm, 2000rpm, 3000rpm, 4000rpm, 5000rpm, 6000rpm, 7000rpm, 8000rpm, 9000rpm, 10000rpm, etc.
  • step (2) the spraying is ultrasonic atomization spraying.
  • the power of the spraying is 0.2-5W, for example, it can be 0.2W, 0.5W, 0.8W, 1W, 1.5W, 2W, 2.5W, 3W, 5W, etc.
  • the temperature is 20-50°C, for example, it can be 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 50°C, etc.
  • the air pressure is 0.01-0.3MPa, for example, it can be 0.01MPa, 0.05MPa, 0.1MPa, 0.15 MPa, 0.2MPa, 0.25MPa, 0.3MPa, etc.
  • the spraying range is 10-300mm, for example, it can be 10mm, 20mm, 30mm, 40mm, 50mm, 300mm, etc.
  • the sprayed drug solution flow rate is preferably 0.1-1.0mL/min, for example, it can be 0.1mL/min, 0.2mL/min, 0.5mL/min, 0.8mL/min, 1.0mL/min, etc.
  • the relative humidity of the spraying environment is 45-60%, for example, it can be 45%, 46%, 48%, 50%, 52%, 54%, 56%, 58% , 60%, etc.
  • step (2) after the coating of the balloon catheter is formed, it needs to be dried, and the balloon body part is compressed by a folding and winding machine to obtain a size suitable for entering human blood vessels.
  • the size of the blood vessels entering the human body is 0.1-2.0mm, for example, it can be 0.1mm, 0.2mm, 0.4mm, 0.6mm, 0.8mm, 1.0mm, 1.2mm, 1.4mm, 1.6mm, 1.8mm , 2.0mm, etc.
  • the coating solution also includes PEG-lipid and/or hydrophilic pharmaceutical excipients.
  • the present application also provides a balloon catheter, which includes the balloon catheter coating as described above.
  • the balloon catheter coating described in this application can control the release cycle of the drug in the body by controlling the molecular weight and diameter of the wrapped drug microspheres;
  • This application uses a coating constructed from a combination of amphiphilic phospholipids with a phase transition temperature above 25°C to ensure that the phospholipids exist in a solid state under normal temperature storage conditions.
  • the coating is more stable, with less loss during the delivery process, and the suspension used for spraying is The liquid needs to be constantly stirred to make the spraying result more uniform and stronger;
  • This application adds a small amount of hydrophilic pharmaceutical excipients to make the coating of the balloon easier to melt during the expansion process, thereby increasing the drug absorption rate of blood vessels.
  • Figure 1 is an appearance diagram of the drug balloon provided in Example 1.
  • Figure 2 is an appearance diagram of the drug balloon provided in Comparative Example 1.
  • the balloon catheter coating includes drug-loaded microspheres and a lipophilic material.
  • the drug-loaded microspheres are dispersed in the lipophilic material.
  • the dispersion density of the drug-loaded microspheres is is 1 ⁇ g/mm 2 ;
  • the core of the drug-loaded microsphere is sirolimus, and the outer shell is polylactic acid-glycolic acid copolymer (relative molecular weight is 40,000); the particle size of the drug-loaded microsphere is 5 ⁇ m; the lipophilic material is dime Myristoylphosphatidylcholine;
  • the balloon catheter coating also includes DSPE-mPEG 650 accounting for 10% of the mass of the dimyristoylphosphatidylcholine, and hyaluronic acid accounting for 25% of the mass of the dimyristoylphosphatidylcholine;
  • the power of the spraying is 2W
  • the temperature is 30°C
  • the air pressure is 0.1MPa
  • the range of the spraying is 40mm
  • the flow rate of the sprayed drug solution is preferably 0.5mL/min
  • the relative humidity of the spraying environment is 50% ;
  • the balloon catheter coating includes drug-loaded microspheres and a lipophilic material.
  • the drug-loaded microspheres are dispersed in the lipophilic material.
  • the dispersion density of the drug-loaded microspheres is is 1 ⁇ g/mm 2 ;
  • the core of the drug-loaded microsphere is sirolimus, and the outer shell is polylactic acid-glycolic acid copolymer (relative molecular weight: 40,000); the particle size of the drug-loaded microsphere is 2 ⁇ m; the lipophilic material is dipalmit acid phosphatidylcholine;
  • the balloon catheter coating also includes DSPE-mPEG 5000 accounting for 5% of the mass of the dipalmitic acid phosphatidylcholine, and hyaluronic acid accounting for 15% of the mass of the dipalmitic acid phosphatidylcholine;
  • the power of the spraying is 3W
  • the temperature is 40°C
  • the air pressure is 0.2MPa
  • the range of the spraying is 40mm
  • the flow rate of the sprayed drug solution is preferably 0.6mL/min
  • the relative humidity of the spraying environment is 45% ;
  • the balloon catheter coating includes drug-loaded microspheres and a lipophilic material.
  • the drug-loaded microspheres are dispersed in the lipophilic material.
  • the dispersion density of the drug-loaded microspheres is is 1 ⁇ g/mm 2 ;
  • the core of the drug-loaded microsphere is zotarmus, and the outer shell is polylactic acid-glycolic acid copolymer (relative molecular weight is 40000); the particle size of the drug-loaded microsphere is 8 ⁇ m; the lipophilic material is dipalmit acid phosphatidylcholine;
  • the balloon catheter coating also includes DOPE-mPEG 2000, which accounts for 3% of the mass of the dipalmitate phosphatidylcholine, and mannitol, which accounts for 10% of the mass of the dipalmitate phosphatidylcholine;
  • the power of the spraying is 4W
  • the temperature is 20°C
  • the air pressure is 0.3MPa
  • the range of the spraying is 40mm
  • the flow rate of the sprayed drug solution is preferably 0.8mL/min
  • the relative humidity of the spraying environment is 60% ;
  • This embodiment provides a balloon catheter coating.
  • the only difference from Example 1 is that the relative molecular weight of the polylactic acid-glycolic acid copolymer in the outer shell of the drug-loaded microsphere is 45,000.
  • This embodiment provides a balloon catheter coating.
  • the only difference from Example 1 is that the relative molecular weight of the polylactic acid-glycolic acid copolymer in the outer shell of the drug-loaded microsphere is 90,000.
  • This embodiment provides a balloon catheter coating.
  • the only difference from Example 1 is that the relative molecular weight of the polylactic acid-glycolic acid copolymer in the outer shell of the drug-loaded microsphere is 15,000.
  • This embodiment provides a balloon catheter coating.
  • the only difference from Example 1 is that the relative molecular weight of the polylactic acid-glycolic acid copolymer in the outer shell of the drug-loaded microsphere is 120,000.
  • This embodiment provides a balloon catheter coating.
  • the lipophilic material is a combination of dimyristoylphosphatidylcholine and DC-cholesterol with a mass ratio of 1:1.
  • This embodiment provides a balloon catheter coating.
  • the only difference from Example 1 is that the lipophilic material is a combination of dimyristoylphosphatidylcholine and palmitic acid with a mass ratio of 2.5:1.
  • This embodiment provides a balloon catheter coating.
  • the only difference from Example 1 is that DSPE-mPEG 650 is not added, and dimyristoylphosphatidylcholine is supplemented to 88 mg.
  • This embodiment provides a balloon catheter coating.
  • the only difference from Example 1 is that hyaluronic acid is not added and dimyristoylphosphatidylcholine is supplemented to 100 mg.
  • This embodiment provides a balloon catheter coating.
  • the only difference from Embodiment 1 is that drying is not performed in step (a).
  • the other steps are the same as Embodiment 1.
  • Example 1 provides a balloon catheter coating, the only difference from Example 1 is that dimyristoyl phosphatidylcholine is replaced by an equal mass of egg yolk lecithin (PC-98T, phase transition temperature is -8°C) , other steps are the same as Example 1.
  • PC-98T egg yolk lecithin
  • This comparative example provides a balloon catheter coating.
  • the only difference from Example 1 is that dimyristoyl phosphatidylcholine is replaced by equal mass of 1-stearoyl-2-oleoyl lecithin (SOPC, phase 1).
  • SOPC 1-stearoyl-2-oleoyl lecithin
  • the temperature was changed to 6°C), and other steps were the same as in Example 1.
  • Test samples the balloon catheter coating provided in Examples 1-12, and the balloon catheter coating provided in Comparative Examples 1-2;
  • Test method Fold and roll the sprayed balloon, test the drug load on the balloon surface before and after folding, and calculate the shedding percentage during the process.
  • Figure 1 is the appearance of the drug balloon of the phospholipid with a phase change temperature above 25°C provided in Example 1 (opened after being folded and rolled);
  • Figure 2 is the appearance of the drug balloon of the phospholipid with a phase transition temperature below 25°C in Comparative Example 1.
  • the phospholipid with a phase change temperature of 25°C or above in Example 1 can ensure that the phospholipid exists in a solid state under normal or higher temperature storage conditions, and the coating More stable
  • Comparative Example 1 uses phospholipids with a phase transition temperature below 25°C, the drug balloon showed coating peeling off in many places.
  • Test samples the balloon catheter coating provided in Examples 1-12, and the balloon catheter coating provided in Comparative Examples 1-2;
  • Test method Using liquid chromatography (HPLC) detection method, each group of samples is implanted into the blood vessels of rabbits corresponding to the animal numbers, and then the drugs detected in the tissues of domestic pigs 1 hour after implantation are detected;
  • HPLC liquid chromatography
  • the coating of the drug balloon in the embodiment is relatively stable, and stable drug-loaded microspheres are transferred to the blood vessel wall.
  • the results of the comparative example show that a coating using a phospholipid with a phase transition temperature lower than 25°C transfers a smaller amount of drug-loaded microspheres to blood vessels, and the data fluctuates greatly. This may be due to the instability of the coating, which has lost most of the drug-loaded microspheres during the delivery process.
  • Microspheres prepared from PLGA of different molecular weights were subjected to simulated in vitro release experiments as follows:
  • the molecular weight of PLGA in microsphere 1 is 40,000; the molecular weight of PLGA in microsphere 2 is 60,000; the molecular weight of PLGA in microsphere 3 is 75,000; the molecular weight of PLGA in microsphere 3 is 75,000; The molecular weight of PLGA in 4 is 120000), place it in a 10ml centrifuge tube, and add 6.0mL PBS-0.1% SDS (pH 7.4, 37°C). Place in a constant temperature oscillator, control the temperature at (37 ⁇ 0.5)°C, and the rotation speed is 200r/min.
  • a single rapamycin has been proven to only maintain an effective concentration in the body for a few days, which cannot meet the long-term therapeutic effect of the drug balloon. Therefore, it needs to be wrapped with polymers to achieve a long-term sustained release effect.
  • microspheres The release process of microspheres was simulated through in vitro experiments.
  • the results in Table 3 show that the release rate of microspheres can be effectively controlled by controlling the molecular weight of PLGA microspheres and the size of microsphere preparation, so that the rapamycin microspheres transferred to the blood vessel wall can be effectively controlled.
  • the ball has a slow release effect.

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Abstract

本申请提供一种球囊导管涂层及其制备方法、球囊导管。所述球囊导管涂层包括载药微球和亲脂性材料，所述载药微球分散于亲脂性材料中；所述载药微球包括西罗莫司类药物和包裹所述药物的外壳，所述外壳包括聚乳酸-羟基乙酸共聚物；所述亲脂性材料包括相变温度40℃以上的磷脂类化合物。本申请所述涂层稳定，递送过程损失更少，且均匀更牢固。

Description

球囊导管涂层及其制备方法、球囊导管 技术领域
本申请属于医药技术领域，例如一种球囊导管涂层及其制备方法、球囊导管。
背景技术
随着人口老龄化和饮食结构改变，动脉粥样硬化(atherosclerosis,AS)所致动脉闭塞性疾病(心、脑血管)已成为人类死亡的首要原因。目前，经皮经腔血管球囊成形术和血管内支架置入术已成为治疗血管狭窄的主要手段。球囊进入病灶部位高压扩张之后会对血管造成一定的物理损伤，例如内皮细胞破坏、内弹性膜破裂和血管中膜的剥离，损伤也常常延伸到外动脉外膜中。尽管球囊的植入使得血管通路恢复到正常，但是由于机械损伤，再狭窄是难以避免的。
目前，减少再狭窄反应的一个策略是联合球囊扩张治疗，将药物释放到血管中以抵消炎性反应和愈合反应，例如使用雷帕霉素药物球囊导管。雷帕霉素及其类似物既具有抗增殖活性又具有抗炎活性，且具有更好的生物安全性。但是现有的雷帕霉素药物球囊导管的药物释放过快，不能有效抑制血管血栓及再狭窄；非亲脂性的雷帕霉素涂层难以黏附在球囊表面，也很难被血管组织吸收；而且这种涂层容易被血液冲刷，即使少量雷帕霉素被吸收，治疗效果也只能维持几天。
因此，开发一种新的药物球囊导管，并同时解决非亲脂性药物与血管的吸附和吸收问题是本领域研究的重点。
发明内容
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的 保护范围。
针对现有技术的不足，本申请的目的在于提供一种球囊导管涂层及其制备方法和球囊导管。本申请的球囊导管涂层解决了非亲脂性药物球囊导管的涂层稳定性问题，以及非亲脂性物质与血管的吸附和吸收问题，并实现了药物释放周期可控，使得药物能够长期在体内发挥功效。
为达到此申请目的，本申请采用以下技术方案：
本申请提供一种球囊导管涂层，所述球囊导管涂层包括载药微球和亲脂性材料，所述载药微球分散于所述亲脂性材料中；
所述载药微球包括西罗莫司类药物和包裹所述药物的外壳，所述外壳包括聚乳酸-羟基乙酸共聚物；
所述亲脂性材料包括相变温度在25℃以上(例如可以是25℃、26℃、28℃、30℃、32℃、34℃、36℃、38℃、40℃、50℃、60℃、80℃、100℃等)的磷脂类化合物。
在本申请中，选择西罗莫司(又名“雷帕霉素”)类药物，西罗莫司及其类似物的药物既具有抗增殖活性又具有抗炎活性，且具有更好的生物安全性，但西罗莫司及其类似物的药物释放过快，而且容易被血液冲刷，即使少量药物被吸收，治疗效果也只能维持几天。因此，本申请选择以聚乳酸-羟基乙酸共聚物(简称：PLGA)对其进行包覆，不同分子量的PLGA制成不同尺寸的载药微球会有着不同的释放周期，控制微球的释放周期就可以控制球囊导管涂层中药物的释放周期。
在本申请中，所述亲脂性材料包括相变温度在25℃以上的磷脂类化合物，一方面，该类亲脂性材料能够帮助药物更好地贴壁吸收；另一方面，在常温或较高温度的储存条件下，相变温度在25℃以上的磷脂类化合物能够以固态形式 存在，涂层更稳定，载药微球分散于该类亲脂性材料中，递送过程损失更少。
在本申请中，所述西罗莫司类药物包括西罗莫司和/或西罗莫司衍生物。
在本申请中，所述西罗莫司衍生物包括依维莫司和/或佐他莫斯。
在本申请中，所述聚乳酸-羟基乙酸共聚物的相对分子质量为30000-140000，例如可以是30000、40000、50000、60000、70000、80000、90000、100000、110000、120000、130000、140000等。
在本申请中，所述聚乳酸-羟基乙酸共聚物的相对分子质量为30000-50000，例如可以是30000、32000、34000、36000、38000、40000、42000、44000、46000、48000、50000等，所述载药微球的体外释放半衰期为30-100天，例如可以是30天、40天、50天、60天、70天、80天、90天、100天等；
或者，所述聚乳酸-羟基乙酸共聚物的相对分子质量为50000-100000，例如可以是50000、60000、70000、80000、90000、100000等，所述载药微球的体外释放半衰期为100-300天，例如可以是100天、120天、140天、160天、180天、200天、220天、240天、260天、280天、300天等；
或者，所述聚乳酸-羟基乙酸共聚物的相对分子质量为100000-140000，例如可以是100000、110000、120000、130000、140000等，所述载药微球的体外释放半衰期为300-1000天，例如可以是300天、400天、500天、600天、700天、800天、900天、1000天。
在本申请中，所述载药微球的粒径为100nm-10μm，例如可以是100nm、200nm、300nm、400nm、500nm、600nm、700nm、800nm、900nm、1μm、2μm、3μm、4μm、5μm、6μm、7μm、8μm、9μm、10μm等。
在本申请中，所述聚乳酸-羟基乙酸共聚物和所述西罗莫司类药物的质量比为(0.5-5):1，例如可以是0.5:1、1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4.5:1、5:1 等；和/或所述西罗莫司类药物和所述亲脂性材料的质量比为(0.1-5):1，例如可以是0.1:1、0.5:1、1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4.5:1、5:1等，所述西罗莫司类药物在涂层中的载药量为0.1-4μg/mm2，例如可以是0.1μg/mm2、0.2μg/mm2、0.4μg/mm2、0.6μg/mm2、0.8μg/mm2、1μg/mm2、1.5μg/mm2、2μg/mm2、2.5μg/mm2、3μg/mm2、3.5μg/mm2、4μg/mm2等。
若亲脂性材料的占比进一步增加会导致药用辅料过量，引起不良反应，若亲脂性材料的占比进一步减少会导致涂层软硬发生变化，同时不能够帮助药物贴壁吸收。
在本申请中，所述亲脂性材料还包括胆固醇和/或脂肪酸。
在本申请中，所述亲脂性材料为相变温度在25℃以上的磷脂类化合物和胆固醇的组合，所述磷脂类化合物和所述胆固醇的质量比为(0.2-5):1，例如可以是0.2:1、0.5:1、1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4.5:1、5:1等，优选为(4-5):1。
在本申请中，所述亲脂性材料为相变温度在25℃以上的磷脂类化合物和脂肪酸的组合，所述磷脂类化合物和所述脂肪酸的质量比为(0.2-5):1，例如可以是0.2:1、0.5:1、1:1、1.5:1、2:1、2.5:1、3:1、3.5:1、4.5:1、5:1等，优选为(2-3):1。
在本申请中，所述胆固醇包括DC-胆固醇和/或胆固醇。
在本申请中，所述脂肪酸包括软脂酸、硬脂酸、月桂酸、豆蔻酸或花生酸中的任意一种或至少两种的组合。
在本申请中，所述磷脂类化合物为双亲性磷脂类化合物。
在本申请中，所述磷脂类化合物包括二棕榈酸磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二硬脂酰基磷脂酰乙醇胺中的任意一种或至少两种的组合。
在本申请中，在所述亲脂性材料中，所述载药微球的分散密度为103-105个 /mm2，例如可以是103个/mm2、5×103个/mm2、104个/mm2、5×104个/mm2、105个/mm2等。
在本申请中，所述球囊导管涂层还包括PEG-脂质和/或亲水性药用辅料。
在本申请中，增加少量的PEG-脂质可以增加涂层牢固度和生物相容性。
在本申请中，增加少量的亲水性药用辅料，可以使得球囊在扩张过程涂层更容易化开，从而增加血管的药物吸收率。
在本申请中，所述PEG-脂质包括1,2-二油酰基-sn-甘油基-3-磷酸乙醇胺-N-甲氧基(聚乙二醇)和/或1,2-二硬脂酰基-sn-甘油基-3-磷酸乙醇胺-N-甲氧基(聚乙二醇)。
在本申请中，所述聚乙二醇的数均分子量为300-5000，例如可以是300、400、500、600、700、800、900、1000、2000、3000、4000、5000等。
在本申请中，所述PEG-脂质和所述磷脂类化合物的质量比为(1-20):100，例如可以是1:100、2:100、4:100、6:100、8:100、10:100、12:100、14:100、16:100、18:100、20:100等，和/或所述亲水性药用辅料和所述磷脂类化合物的质量比为(5-40):100，例如可以是5:100、6:100、8:100、10:100、12:100、14:100、16:100、18:100、20:100、25:100、30:100、35:100、40:100等。
在本申请中，所述亲水性药用辅料包括透明质酸、甘露醇或水溶性结晶糖中的任意一种或至少两种的组合。
本申请还提供了一种如上所述的球囊导管涂层的制备方法，所述制备方法包括以下步骤：
(1)配置涂层溶液：将载药微球、亲脂性材料与溶剂混合，得到涂层溶液；
(2)喷涂：在搅拌状态下，将步骤(1)得到的涂层溶液喷涂到球囊导管囊体表面，形成所述球囊导管涂层。
在本申请中，步骤(1)中，所述混合的温度为0-37℃，例如可以是0℃、5℃、10℃、15℃、20℃、25℃、30℃、35℃、37℃等，所述混合的时间为1-10min，例如可以是1min、2min、3min、4min、5min、6min、7min、8min、9min、10min等。
在本申请中，步骤(1)中，所述涂层溶液中，载药微球的浓度为10-30g/L，例如可以是10g/L、12g/L、14g/L、16g/L、18g/L、20g/L、22g/L、24g/L、26g/L、28g/L、30g/L等，所述亲脂性材料的浓度为10-30g/L，例如可以是10g/L、12g/L、14g/L、16g/L、18g/L、20g/L、22g/L、24g/L、26g/L、28g/L、30g/L等。
在本申请中，步骤(1)中，所述溶剂包括甲醇、乙醇、丙酮、异丙醇、二甲基亚砜、乙酸乙酯、乙腈、四氢呋喃、二氯甲烷、正庚烷、正己烷、环己烷或水中的任意一种或至少两种的组合。
在本申请中，步骤(1)中，在配置涂层溶液前需将球囊导管涂层的各制备原料进行干燥。
在本申请中，步骤(2)中，所述搅拌的转速为500-10000rpm，例如可以是500rpm、1000rpm、2000rpm、3000rpm、4000rpm、5000rpm、6000rpm、7000rpm、8000rpm、9000rpm、10000rpm等。
在本申请中，步骤(2)中，所述喷涂为超声雾化喷涂。
在本申请中，步骤(2)中，所述喷涂的功率为0.2-5W，例如可以是0.2W、0.5W、0.8W、1W、1.5W、2W、2.5W、3W、5W等，温度为20-50℃，例如可以是20℃、25℃、30℃、35℃、40℃、45℃或50℃等，气压为0.01-0.3MPa，例如可以是0.01MPa、0.05MPa、0.1MPa、0.15MPa、0.2MPa、0.25MPa、0.3MPa等。
在本申请中，步骤(2)中，所述喷涂的范围为10-300mm，例如可以是10mm、20mm、30mm、40mm、50mm、300mm等。
在本申请中，步骤(2)中，所述喷涂的药物溶液流量优选为0.1-1.0mL/min，例如可以是0.1mL/min、0.2mL/min、0.5mL/min、0.8mL/min、1.0mL/min等。
在本申请中，步骤(2)中，所述喷涂的环境相对湿度为45-60％，例如可以是45％、46％、48％、50％、52％、54％、56％、58％、60％等。
在本申请中，步骤(2)中，形成所述球囊导管涂层后，还需进行干燥，并经折叠卷绕机压缩球囊囊体部分，得到进入人体血管的尺寸。
在本申请中，所述进入人体血管的尺寸为0.1-2.0mm，例如可以是0.1mm、0.2mm、0.4mm、0.6mm、0.8mm、1.0mm、1.2mm、1.4mm、1.6mm、1.8mm、2.0mm等。
在本申请中，所述涂层溶液中还包括PEG-脂质和/或亲水性药用辅料。
本申请还提供了一种球囊导管，所述球囊导管包括如上所述的球囊导管涂层。
相对于现有技术，本申请具有以下有益效果：
(1)本申请所述的球囊导管涂层可以通过控制包裹药物微球的分子量及直径来控制药物在体内的释放周期；
(2)本申请采用相变温度在25℃以上的双亲性磷脂组合构建的涂层，保证在常温储存条件下磷脂成固态存在，涂层更稳定，递送过程损失更少，且喷涂所用悬浊液需要不断搅拌，喷涂所得更均匀更牢固；
(3)本申请增加少量的亲水性的药用辅料赋性剂，使得球囊在扩张过程涂层更容易化开，从而增加血管的药物吸收率。
在阅读并理解了附图和详细描述后，可以明白其他方面。
附图说明
附图用来提供对本文技术方案的进一步理解，并且构成说明书的一部分，与本申请的实施例一起用于解释本文的技术方案，并不构成对本文技术方案的限制。
图1为实施例1提供的药物球囊表观图。
图2为对比例1提供的药物球囊表观图。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。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。
以下实施例和对比例所有原料均可由市售购得。
实施例1
本实施例提供一种球囊导管涂层，所述球囊导管涂层包括载药微球和亲脂性材料，所述载药微球分散于亲脂性材料中，所述载药微球的分散密度为1μg/mm2；
所述载药微球的内核为西罗莫司，外壳为聚乳酸-羟基乙酸共聚物(相对分子量为40000)；所述载药微球的粒径为5μm；所述亲脂性材料为二肉豆蔻酰磷脂酰胆碱；
所述球囊导管涂层还包括占所述二肉豆蔻酰磷脂酰胆碱质量10％的DSPE-mPEG 650，以及占所述二肉豆蔻酰磷脂酰胆碱质量25％的透明质酸；
本实施例所述球囊导管涂层由以下制备方法得到：
(a)前处理：将载药微球、二肉豆蔻酰磷脂酰胆碱、DSPE-mPEG 650和透明质酸分别进行干燥；
(b)配置涂层溶液：将150mg的载药微球、80mg的二肉豆蔻酰磷脂酰胆碱、8mg的DSPE-mPEG 650和20mg的透明质酸于25℃下在10mg的正庚烷中混合并超声10min，得到涂层溶液；
(c)喷涂：以2000rpm的转速搅拌涂层溶液，并使用超声雾化喷涂设备执行所述喷涂操作，将涂层溶液喷涂到球囊导管囊体表面，形成所述球囊导管涂层；
其中，所述喷涂的功率为2W，温度为30℃，气压为0.1MPa；所述喷涂的范围为40mm；所述喷涂的药物溶液流量优选为0.5mL/min；喷涂的环境相对湿度为50％；
(d)后处理：形成所述球囊导管涂层后，还需进行干燥，并经折叠卷绕机压缩球囊囊体部分，得到进入人体血管的尺寸(具体尺寸为0.6mm)。
实施例2
本实施例提供一种球囊导管涂层，所述球囊导管涂层包括载药微球和亲脂性材料，所述载药微球分散于亲脂性材料中，所述载药微球的分散密度为1μg/mm2；
所述载药微球的内核为西罗莫司，外壳为聚乳酸-羟基乙酸共聚物(相对分子量为40000)；所述载药微球的粒径为2μm；所述亲脂性材料为二棕榈酸磷脂酰胆碱；
所述球囊导管涂层还包括占所述二棕榈酸磷脂酰胆碱质量5％的DSPE-mPEG 5000，以及占所述二棕榈酸磷脂酰胆碱质量15％的透明质酸；
本实施例所述球囊导管涂层由以下制备方法得到：
(a)前处理：将载药微球、二棕榈酸磷脂酰胆碱、DSPE-mPEG 5000和透明质酸分别进行干燥；
(b)配置涂层溶液：将150mg的载药微球、80mg的二棕榈酸磷脂酰胆碱、4mg的DSPE-mPEG 5000和12mg的透明质酸于25℃下在10mg的正庚烷中混合并超声10min，得到涂层溶液；
(c)喷涂：以1000rpm的转速搅拌涂层溶液，并使用超声雾化喷涂设备执行所述喷涂操作，将涂层溶液喷涂到球囊导管囊体导管囊体表面，形成所述球囊导管涂层；
其中，所述喷涂的功率为3W，温度为40℃，气压为0.2MPa；所述喷涂的范围为40mm；所述喷涂的药物溶液流量优选为0.6mL/min；喷涂的环境相对湿度为45％；
(d)后处理：形成所述球囊导管涂层后，还需进行干燥，并经折叠卷绕机压缩球囊囊体部分，得到进入人体血管的尺寸(具体尺寸直径为0.6mm)。
实施例3
本实施例提供一种球囊导管涂层，所述球囊导管涂层包括载药微球和亲脂性材料，所述载药微球分散于亲脂性材料中，所述载药微球的分散密度为1μg/mm2；
所述载药微球的内核为佐他莫斯，外壳为聚乳酸-羟基乙酸共聚物(相对分子量为40000)；所述载药微球的粒径为8μm；所述亲脂性材料为二棕榈酸磷脂酰胆碱；
所述球囊导管涂层还包括占所述二棕榈酸磷脂酰胆碱质量3％的DOPE-mPEG 2000，以及占所述二棕榈酸磷脂酰胆碱质量10％的甘露醇；
本实施例所述球囊导管涂层由以下制备方法得到：
(a)前处理：将载药微球、二棕榈酸磷脂酰胆碱、DOPE-mPEG 2000和甘露醇分别进行干燥；
(b)配置涂层溶液：将150mg的载药微球、80mg的二棕榈酸磷脂酰胆碱、2.4mg的DOPE-mPEG 2000和8mg的甘露醇于25℃下在10mg的正庚烷中混合并超声10min，得到涂层溶液；
(c)喷涂：以3000rpm的转速搅拌涂层溶液，并使用超声雾化喷涂设备执行所述喷涂操作，将涂层溶液喷涂到球囊导管囊体表面，形成所述球囊导管涂层；
其中，所述喷涂的功率为4W，温度为20℃，气压为0.3MPa；所述喷涂的范围为40mm；所述喷涂的药物溶液流量优选为0.8mL/min；喷涂的环境相对湿度为60％；
(d)后处理：形成所述球囊导管涂层后，还需进行干燥，并经折叠卷绕机压缩球囊囊体部分，得到进入人体血管的尺寸(具体尺寸为0.6mm)。
实施例4
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，所述载药微球的外壳的聚乳酸-羟基乙酸共聚物的相对分子量为45000。
实施例5
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，所述载药微球的外壳的聚乳酸-羟基乙酸共聚物的相对分子量为90000。
实施例6
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，所述载药微球的外壳的聚乳酸-羟基乙酸共聚物的相对分子量为15000。
实施例7
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，所述载药微球的外壳的聚乳酸-羟基乙酸共聚物的相对分子量为120000。
实施例8
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，所述亲脂性材料为质量比为1:1的二肉豆蔻酰磷脂酰胆碱和DC-胆固醇的组合。
实施例9
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，所述亲脂性材料为质量比为2.5:1的二肉豆蔻酰磷脂酰胆碱和软脂酸的组合。
实施例10
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，不添加DSPE-mPEG 650，二肉豆蔻酰磷脂酰胆碱补至88mg。
实施例11
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，不添加透明质酸，二肉豆蔻酰磷脂酰胆碱补至100mg。
实施例12
本实施例提供一种球囊导管涂层，与实施例1的区别仅在于，步骤(a)不进行干燥，其他步骤与实施例1相同。
对比例1
本对比例提供一种球囊导管涂层，与实施例1的区别仅在于，二肉豆蔻酰磷脂酰胆碱替换为等质量的蛋黄卵磷脂(PC-98T，相变温度为-8℃)，其他步骤与实施例1相同。
对比例2
本对比例提供一种球囊导管涂层，与实施例1的区别仅在于，二肉豆蔻酰磷脂酰胆碱替换为等质量的1-硬脂酰基-2-油酰基卵磷脂(SOPC，相变温度为6℃)，其他步骤与实施例1相同。
测试例1
折叠卷绕压缩稳定性试验
测试样品：实施例1-12提供的球囊导管涂层，对比例1-2提供的球囊导管涂层；
测试方法：对喷涂完的球囊进行折叠卷绕处理，测试折叠前后球囊表面的载药量，计算该过程脱落百分比，
具体测试结果如下表1所示：
表1

由表1测试结果可知，本申请所述球囊导管涂层在折叠卷绕脱落实验中表现优异，脱落百分比在10％以下；说明在常温储存条件下磷脂成固态存在，涂层更稳定，递送过程损失更少，且喷涂所用悬浊液需要不断搅拌，喷涂所得更均匀更牢固。
特别地，图1为实施例1提供的相变温度25℃以上磷脂的药物球囊表观(折叠卷绕后打开)；图2为对比例1相变温度25℃以下磷脂的药物球囊表观(折叠卷绕后打开)，从图1和图2的对比清楚可见，实施例1采用相变温度25℃以上磷脂能够保证在常温或较高温度的储存条件下磷脂成固态存在，涂层更稳定，而对比例1采用相变温度25℃以下磷脂，药物球囊表观多处显示涂层脱落。
测试例2
药物吸收测试
测试样品：实施例1-12提供的球囊导管涂层，对比例1-2提供的球囊导管涂层；
测试方法：通过液相色谱(HPLC)检测方法，将各组样品植入对应动物编号的兔子血管内，后检测植入家猪1小时后组织中检测到的药物；
具体测试结果如下表2所示：
表2


由表2测试结果可知，1h后血管检测的药物越多，证明球囊转移到血管壁上的微球越多，吸收越好。其中，实施例中药物球囊的涂层较为稳定，有稳定的载药微球转移到血管壁上。对比例的结果表明：使用相变温度低于25℃的磷脂的涂层转到血管上的载药微球量较少，且数据波动较大。这可能是由于涂层不稳定，在递送过程已经损失绝大部分载药微球。
测试例3
微球体外释放试验
不同分子量的PLGA制备的微球进行模拟体外释放实验，方法如下：
称取10mg载药微球(微球均为本司自制，其中，微球1中PLGA的分子量为40000；微球2中PLGA的分子量为60000；微球3中PLGA的分子量为75000；微球4中PLGA的分子量为120000)，置于10ml离心管中，分别加入6.0mL PBS-0.1％SDS(pH 7.4，37℃)。置恒温振荡器中，温度控制在(37±0.5)℃，转速为200r/min，分别于不同时间点取出离心管，3000r，10min离心后取上清5mL，及时补充等量恒温释放介质，用紫外分光光度法于279nm测定其释放量，计算7天累积释放百分率。采用Origin软件将不同粘度PLGA制备的微球7天的释放结果拟合成Higuchi方程，并计算不同分子量微球的半衰期。
具体结果如下表3所示：
表3
单一的雷帕霉素已经被证明在体内只能维持几天的有效浓度，不能满足药物球囊的长效治疗作用，所以需要通过高分子进行包裹达到长效的缓释效果。
通过体外试验模拟微球的释放过程，表3结果表明：通过控制微球PLGA的分子量以及微球制备的尺寸可以有效地控制微球的释放速率，从而使得转移到血管壁的雷帕霉素微球具有缓释效果。
申请人声明，本申请通过上述实施例来说明本申请的球囊导管涂层及其制备方法、球囊导管，但本申请并不局限于上述工艺步骤，即不意味着本申请必须依赖上述工艺步骤才能实施。所属技术领域的技术人员应该明了，对本申请的任何改进，对本申请所选用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 (15)

  1. 一种球囊导管涂层，所述球囊导管涂层包括载药微球和亲脂性材料，所述载药微球分散于所述亲脂性材料中；
    所述载药微球包括西罗莫司类药物和包裹所述药物的外壳，所述外壳包括聚乳酸-羟基乙酸共聚物；
    所述亲脂性材料包括相变温度在40℃以上的磷脂类化合物；
    所述聚乳酸-羟基乙酸共聚物的相对分子质量为30000-50000，所述载药微球的体外释放半衰期为30-100天；
    或者，所述聚乳酸-羟基乙酸共聚物的相对分子量为50000-100000，所述载药微球的体外释放半衰期为100-300天；
    或者，所述聚乳酸-羟基乙酸共聚物的相对分子量为100000-140000，所述载药微球的体外释放半衰期为300-1000天；
    所述球囊导管涂层还包括PEG-脂质和亲水性药用辅料，所述亲水性药用辅料包括透明质酸、甘露醇或水溶性结晶糖中的任意一种或至少两种的组合。
  2. 根据权利要求1所述的球囊导管涂层，其中，所述西罗莫司类药物包括西罗莫司和/或西罗莫司衍生物。
  3. 根据权利要求1所述的球囊导管涂层，其中，所述载药微球的粒径为100nm-10μm。
  4. 根据权利要求1所述的球囊导管涂层，其中，所述聚乳酸-羟基乙酸共聚物和所述西罗莫司类药物的质量比为(0.5-5):1；和/或所述西罗莫司类药物和所述亲脂性材料的质量比为(0.1-5):1，所述西罗莫司类药物在涂层中的载药量为0.1-4μg/mm2。
  5. 根据权利要求1所述的球囊导管涂层，其中，所述亲脂性材料还包括胆固醇和/或脂肪酸。
  6. 根据权利要求1所述的球囊导管涂层，其中，所述磷脂类化合物为双亲性磷脂类化合物。
  7. 根据权利要求1所述的球囊导管涂层，其中，在所述亲脂性材料中，所述载药微球的分散密度为103-105个/mm2。
  8. 根据权利要求1所述的球囊导管涂层，其中，所述PEG-脂质和所述磷脂类化合物的质量比为(1-20):100，和/或所述亲水性药用辅料和所述磷脂类化合物的质量比为(5-40):100。
  9. 根据权利要求1所述的球囊导管涂层，其中，所述相变温度在40℃以上的磷脂类化合物包括二棕榈酸磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二硬脂酰基磷脂酰乙醇胺中的任意一种或至少两种的组合。
  10. 一种根据权利要求1-9中任一项所述的球囊导管涂层的制备方法，所述制备方法包括以下步骤：
    (1)配置涂层溶液：将载药微球、亲脂性材料、PEG-脂质、亲水性药用辅料与溶剂混合，得到涂层溶液；
    (2)喷涂：在搅拌状态下，将步骤(1)得到的涂层溶液喷涂到球囊导管囊体表面，形成所述球囊导管涂层。
  11. 根据权利要求10所述的制备方法，其中，步骤(1)中，所述溶剂包括甲醇、乙醇、丙酮、异丙醇、二甲基亚砜、乙酸乙酯、乙腈、四氢呋喃、二氯甲烷、正庚烷、正己烷、环己烷或水中的任意一种或至少两种的组合；步骤(1)中，在配置涂层溶液前需将球囊导管涂层的各制备原料进行干燥。
  12. 根据权利要求10所述的制备方法，其中，步骤(2)中，所述搅拌的转速为500-10000rpm。
  13. 根据权利要求10所述的制备方法，其中，步骤(2)中，所述喷涂为 超声雾化喷涂；
    步骤(2)中，所述喷涂的功率为0.2-5W，温度为20-50℃，气压为0.01-0.3MPa，范围为10-300mm，环境相对湿度为45-60％；
    步骤(2)中，所述涂层溶液的喷涂流量为0.1-1.0mL/min。
  14. 根据权利要求10所述的制备方法，其中，步骤(2)中，形成所述球囊导管涂层后，还需进行干燥，并经折叠卷绕机压缩所述球囊导管的囊体部分，得到进入人体血管的尺寸。
  15. 一种球囊导管，包括如权利要求1-9中任一项所述的球囊导管涂层。
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