WO2022105849A1 - 药物涂层球囊及其制备方法 - Google Patents

药物涂层球囊及其制备方法 Download PDF

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Publication number
WO2022105849A1
WO2022105849A1 PCT/CN2021/131619 CN2021131619W WO2022105849A1 WO 2022105849 A1 WO2022105849 A1 WO 2022105849A1 CN 2021131619 W CN2021131619 W CN 2021131619W WO 2022105849 A1 WO2022105849 A1 WO 2022105849A1
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WIPO (PCT)
Prior art keywords
drug
coating
cholesterol
coated balloon
combination
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PCT/CN2021/131619
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English (en)
French (fr)
Inventor
王森
于绍兴
王占军
戴志豪
王鼎曦
Original Assignee
上海申淇医疗科技股份有限公司
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Application filed by 上海申淇医疗科技股份有限公司 filed Critical 上海申淇医疗科技股份有限公司
Priority to EP21893996.5A priority Critical patent/EP4249033A1/en
Publication of WO2022105849A1 publication Critical patent/WO2022105849A1/zh

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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
    • A61M25/1027—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
    • 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
    • A61L29/08—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
    • 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
    • A61L2300/606—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
    • 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
    • A61L2420/06—Coatings containing a mixture of two or more compounds
    • 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

Definitions

  • the present application relates to the technical field of medical devices, in particular to a drug-coated balloon and a preparation method thereof.
  • Drug-coated balloon is a new therapeutic balloon drug release technology developed on the basis of interventional techniques such as balloon dilation or balloon angioplasty. On the surface, when the balloon reaches the lesion and is stretched and expanded, and contacts the intima of the blood vessel wall, the drug is rapidly released and the drug is transferred into the local blood vessel wall. Prevention of vascular restenosis after vascular intervention. On the one hand, the drug-coated balloon can effectively inhibit the excessive proliferation of smooth muscle cells and reduce the incidence of restenosis. Dual antiplatelet time, reduced bleeding risk.
  • drug coating is very important.
  • the firmness of the drug coating in the blood vessel, the drug release ability in the artery, and the ability of the drug to be absorbed by the blood vessel are all determined by the drug coating.
  • the fastness of the drug coating is not high, and there will be large losses during the passage and expansion of the drug balloon, and the utilization rate of the drug is not high.
  • the blood washes away more drugs; (2) the drug adheres to the wall for a short time, and it is difficult to be absorbed by the blood vessel wall in large quantities, so that a better therapeutic effect cannot be achieved; (3) the drug coating is easy to fall off and produce particles, which is easy to produce thrombosis.
  • a drug-coated balloon having excellent coating firmness, drug release capability and drug absorption capability by blood vessels and a preparation method thereof are provided.
  • a drug-coated balloon includes a balloon body and a drug coating disposed on the outer surface of the balloon body, wherein the drug coating includes a bottom coating, an interlayer coating and a top coating that are stacked in sequence.
  • the bottom coating layer includes a high molecular polymer material
  • the interlayer coating layer includes a drug and a lipophilic material
  • the top layer coating layer includes a high molecular polymer material
  • the primer layer comprises polylactic acid-glycolic acid copolymer, polyethylene glycol, povidone, polyvinyl alcohol, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose Or any one of polycaprolactone or a combination of at least two.
  • the top coat includes any one or a combination of at least two of dibutylhydroxytoluene, butylhydroxyanisole, chitosan or polycaprolactone.
  • the lipophilic material comprises any one or a combination of at least two of cholesterol, phospholipids or fatty acids.
  • the lipophilic material includes cholesterol and phospholipid, and the mass ratio of cholesterol to phospholipid is 0.2-10.
  • the lipophilic material includes phospholipids and fatty acids, and the mass ratio of the phospholipids to fatty acids is 0.2-10.
  • the lipophilic material includes cholesterol and fatty acid, and the mass ratio of cholesterol to fatty acid is 0.04-100.
  • the drug comprises any one or a combination of at least two of sirolimus, a derivative of sirolimus, paclitaxel or a derivative of paclitaxel.
  • the mass ratio of the drug to the lipophilic material is 0.1-10; the mass ratio of the high molecular polymer material in the bottom layer to the drug is 0.05-20; the high molecular polymer in the top interlayer The mass ratio of the material to the drug is 0.05-20.
  • the cholesterol comprises DC-cholesterol and/or cholesterol.
  • the phospholipids include 1,2-dioleoyl lecithin, dipalmitoyl phosphatidyl choline, distearoyl phosphatidyl choline, dimyristoyl phosphatidyl choline, 1-palmitoyl-2-oleoyl lecithin Any one or a combination of at least two of phospholipids, distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, or dipalmitoylphosphatidylethanolamine.
  • 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 application also provides a preparation method of the above-mentioned drug-coated balloon, comprising the following steps:
  • the spraying operation is performed using an ultrasonic atomization spraying equipment and a multi-layer spraying superposition technique.
  • the drug-coated balloon includes a drug coating disposed on the outer surface of the balloon body, and the drug coating has a bottom coating layer, an interlayer coating layer and a top coating layer that are stacked in sequence, that is, a "sandwich" type structure.
  • the bottom coating is used to increase the adhesion and firmness of the drug coating to the balloon body, reduce the loss of the drug during the delivery process, and improve the utilization rate of the drug; while ensuring the rapid release of the drug, the delivery process will not More drugs are washed away by the blood; and the drug coating is not easy to fall off to produce particles, and it is not easy to produce thrombus.
  • the interlayer coating is used to load the drug and at the same time help the drug to be better absorbed by the tissue.
  • the top coating is used to promote the adhesion of the drug coating to the intima of the blood vessel wall, which is more conducive to the tissue absorption capacity of the drug, so as to achieve the effect that the adherent drug can be absorbed by the blood vessel wall in a short time.
  • the present application provides a drug-coated balloon, comprising a balloon body and a drug coating disposed on the outer surface of the balloon body.
  • the drug coating includes a bottom coating layer, an interlayer coating layer and a top layer coating layer which are successively stacked from the outer surface of the balloon body.
  • the bottom coating is used to increase the adhesion of the drug coating to the balloon body and improve the firmness of the drug coating;
  • the interlayer coating is used to load the drug and help the drug to be better absorbed by the tissue;
  • the top coating is used to promote The adhesion of the coating to the inner membrane of the cell is more conducive to the tissue absorption capacity of the drug.
  • the thickness ratio of the base coating to the interlayer coating may be 0.05-10, and the thickness ratio of the interlayer coating to the top coating may be 0.01-20.
  • the thickness ratio of the base coating to the interlayer coating can be selected from 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.
  • the thickness ratio of the interlayer coating to the top coating layer may be 0.01, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, etc.
  • the thickness of the interlayer coating may be 1-20 ⁇ m, such as 1 ⁇ m, 2 ⁇ m, 4 ⁇ m, 5 ⁇ m, 8 ⁇ m, 10 ⁇ m, 12 ⁇ m, 14 ⁇ m, 15 ⁇ m, 16 ⁇ m, 18 ⁇ m, 20 ⁇ m, and the like. Other specific point values within the above numerical range can be selected, which will not be repeated here.
  • the primer coating includes a high molecular polymer material.
  • the primer layer comprises polylactic acid-glycolic acid copolymer, polyethylene glycol, povidone, polyvinyl alcohol, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose or polycaprolactone any one or a combination of at least two.
  • the high-molecular polymer material used in the underlying coating is preferably a high-viscosity high-molecular polymer material, which is beneficial to promote the adhesion of the drug coating and the balloon body, so that the drug-coated balloon will not be damaged during the delivery process. More drugs are washed away by the blood, and the utilization rate of drugs is higher.
  • the primer layer can be a combination of at least two high molecular polymer materials, such as a combination of polylactic acid-glycolic acid copolymer and polyethylene glycol, a combination of polyethylene glycol and povidone, a combination of polyvinyl alcohol and methyl cellulose. combination, polylactic acid-glycolic acid copolymer, polyethylene glycol and povidone, hydroxymethyl cellulose, hydroxypropyl cellulose and polycaprolactone, etc. Any other combination can be selected. This will not be repeated one by one.
  • the top coat includes a high molecular polymer material.
  • the top coating comprises any one or a combination of at least two of dibutylhydroxytoluene, butylhydroxyanisole, chitosan or polycaprolactone.
  • the high-molecular polymer material used in the top coating is preferably a lipophilic high-molecular polymer material, which is conducive to promoting the adhesion of the drug coating to the intracellular membrane, and is more conducive to the tissue absorption capacity of the drug.
  • the top coat can be a combination of at least two high molecular polymer materials, such as a combination of dibutylhydroxytoluene and butylated hydroxyanisole, a combination of butylated hydroxyanisole and chitosan, The combination of caprolactone, etc., other arbitrary combinations can be selected, and will not be repeated here.
  • the interlayer coating includes a drug and a lipophilic material.
  • the lipophilic material may comprise any one or a combination of at least two of cholesterol, phospholipids or fatty acids. These lipophilic materials coexist with the drug in the interlayer coating, which can help the drug better adherent absorption.
  • the cholesterol may include DC-cholesterol and/or cholesterol.
  • the phospholipid may include 1,2-dioleoyl lecithin, dipalmitoyl phosphatidyl choline, distearoyl phosphatidyl choline, dimyristoyl phosphatidyl choline, 1-palmitoyl-2-oleoyl Any one or a combination of at least two of lecithin, distearoylphosphatidylethanolamine, dioleoylphosphatidylethanolamine, or dipalmitoylphosphatidylethanolamine.
  • the fatty acid may include any one or a combination of at least two of palmitic acid, stearic acid, lauric acid, myristic acid, or arachidic acid.
  • the lipophilic material can be a combination of at least two materials, such as a combination of cholesterol and phospholipids, a combination of phospholipids and fatty acids, a combination of cholesterol and fatty acids, and a combination of cholesterol, phospholipids and fatty acids, etc. Any other combination is acceptable. The choice will not be repeated here.
  • the lipophilic material can be a combination of 1,2-dioleoyl lecithin and dipalmitate phosphatidyl choline, a combination of distearoyl phosphatidyl choline and dimyristoyl phosphatidyl choline, And the combination of 1,2-dioleoyl lecithin, 1-palmitoyl-2-oleoyl lecithin and distearoyl phosphatidyl ethanolamine, etc., any other combination can be selected, and they will not be listed here. Repeat.
  • the lipophilic material can also be a combination of palmitic acid and stearic acid, a combination of stearic acid and lauric acid, a combination of myristic acid and arachidic acid, and a combination of palmitic acid, stearic acid and lauric acid, etc., Other arbitrary combinations can be selected, which will not be repeated here.
  • the mass ratio of cholesterol and phospholipid is 0.2-10, such as 0.2, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc., other specific point values within the above range can be selected, and will not be repeated here.
  • the mass ratio of the phospholipid to the fatty acid is 0.2-10, such as 0.2, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.
  • the point values can be selected, which will not be repeated here. Other specific point values within the above range can be selected, and will not be repeated here.
  • the mass ratio of cholesterol and fatty acid is 0.04-100, for example, 0.04, 0.05, 0.1, 0.5, 1, 5, 10, 20, 50, 60, 70, 100, etc. , and other specific point values within the above range can be selected, which will not be repeated here.
  • the interlayer coating also includes a drug, which may include any one or a combination of at least two of sirolimus, a derivative of sirolimus, paclitaxel, or a derivative of paclitaxel.
  • a drug which may include any one or a combination of at least two of sirolimus, a derivative of sirolimus, paclitaxel, or a derivative of paclitaxel.
  • Combinations of said at least two such as combinations of sirolimus and derivatives of sirolimus, combinations of paclitaxel and derivatives of paclitaxel, combinations of derivatives of sirolimus and derivatives of paclitaxel, combinations of sirolimus and derivatives of paclitaxel Combination, etc., other arbitrary combination methods can be selected, which will not be repeated here.
  • the sirolimus derivatives are, for example, everolimus, zotarolimus and the like.
  • the paclitaxel derivatives are, for example, docetaxel, pac
  • the mass ratio of the drug to the lipophilic material is preferably 0.1-10, such as 0.1, 0.2, 0.5, 1, 2, 5, 7, 9, 10, etc., other specific point values within the above range can be selected, and will not be repeated here. If the proportion of lipophilic materials is further increased, it will lead to excessive amount of pharmaceutical excipients and cause adverse reactions. If the proportion of lipophilic materials is further reduced, the hardness of the coating will change, and at the same time, it will not help the drug adherent absorption.
  • the drug loading in the interlayer coating may be 0.1-8 ⁇ g/mm 2 , such as 0.1 ⁇ g/mm 2 , 0.2 ⁇ g/mm 2 , 0.5 ⁇ g/mm 2 , 1 ⁇ g/mm 2 , 2 ⁇ g/mm 2 2 , 3 ⁇ g/mm 2 , 4 ⁇ g/mm 2 , 5 ⁇ g/mm 2 , 6 ⁇ g/mm 2 , 7 ⁇ g/mm 2 , 8 ⁇ g/mm 2 , etc.
  • Other specific point values within the above range can be selected, and will not be repeated here. Describe them one by one.
  • the mass ratio of the macromolecular polymer material in the bottom coating to the drug in the interlayer coating can be 0.05-20, such as 0.05, 0.1, 0.2, 0.5, 1, 5, 10, 15, 20, etc.
  • the point value can be selected and will not be repeated here.
  • the mass ratio of the high molecular polymer material in the top coating to the drug in the interlayer coating can be 0.05-20, such as 0.05, 0.1, 0.2, 0.5, 1, 5, 10, 15, 20, etc. Other specific points within the above range Values can be selected, and will not be repeated here.
  • the application also provides a preparation method of the above-mentioned drug-coated balloon, comprising the following steps:
  • step (1) the raw materials for preparing the bottom coating, the interlayer coating and the top coating are respectively mixed and dissolved with a solvent to prepare the bottom coating solution, the interlayer coating solution and the top coating solution.
  • the solvent includes methanol, ethanol, acetone, isopropanol, dimethyl sulfoxide, ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, n-heptane, n-hexane, cyclohexane or any one or at least one of water. combination of the two.
  • the combination of the at least two kinds can be a combination of ethanol and n-heptane, a combination of ethanol, n-heptane and dimethyl sulfoxide, etc., and other arbitrary combinations can be selected, which will not be repeated here.
  • ultrasonic atomization spraying equipment is used to perform the spraying operation, and the ultrasonic atomization spraying equipment can use the multi-layer spraying superposition technology to perform the spraying operation, or use other existing spraying techniques to perform the spraying operation. the spraying operation.
  • the ultrasonic power is preferably 0.2-5W, such as 0.2W, 0.5W, 0.8W, 1W, 1.5W, 2W, 2.5W, 3W, 5W, etc.;
  • the temperature is preferably 20-50°C, such as 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 50°C, etc.;
  • the air pressure is preferably 0.01-0.3MPa, such as 0.01MPa, 0.05MPa, 0.1MPa, 0.15MPa, 0.2 MPa, 0.25MPa, or 0.3MPa, etc., other specific point values within the above-mentioned numerical range can be selected, which will not be repeated here.
  • the spraying range is preferably 10-60mm, such as 10mm, 20mm, 30mm, 40mm, 50mm or 60mm, etc.; the flow rate of the drug solution is preferably 0.01-1mL/min, For example, 0.01mL/min, 0.02mL/min, 0.05mL/min, 0.08mL/min, 0.1mL/min, 0.2mL/min, 0.5mL/min, 0.8mL/min or 1.0mL/min, etc., within the above range Other specific point values of , can be selected, and will not be repeated here.
  • the drug-coated balloon includes a balloon body and a drug coating disposed on the outer surface of the balloon body.
  • the bottom coating, the interlayer coating and the top coating, the thicknesses of the bottom coating, the interlayer coating and the top coating are 4 ⁇ m, 6 ⁇ m and 4 ⁇ m, respectively.
  • the preparation raw material of the bottom coating is hydroxymethyl cellulose
  • the preparation raw material of the top coating is butylated hydroxyanisole
  • the preparation raw material of the interlayer coating is sirolimus and lipophilic materials (DC-cholesterol, 1,2-dihydroxyanisole). oleoyl lecithin, stearic acid).
  • the mass ratio of DC-cholesterol, 1,2-dioleoyl lecithin and stearic acid is 2:1:1; the mass ratio of sirolimus to lipophilic material is 1:1; The mass ratio of roolimus was 1:1.5; the mass ratio of butylated hydroxyanisole to sirolimus was 1:1.5; the drug loading amount of sirolimus in the interlayer coating was 3 ⁇ g/mm 2 .
  • the preparation method of the drug-coated balloon is as follows:
  • the drug-coated balloon includes a balloon body and a drug coating disposed on the outer surface of the balloon body, and the drug coating includes bottom layers that are stacked in sequence.
  • the coating layer, the interlayer coating layer and the top layer coating layer, the thicknesses of the bottom layer coating layer, the interlayer coating layer and the top layer coating layer are respectively 4 ⁇ m, 8 ⁇ m and 4 ⁇ m.
  • the preparation raw material of the bottom coating is hydroxypropyl cellulose
  • the preparation raw material of the top coating is dibutyl hydroxytoluene
  • the preparation raw material of the interlayer coating is sirolimus and lipophilic material DC-cholesterol, dipalmitic acid phosphatidyl bile alkali, lauric acid).
  • the mass ratio of DC-cholesterol, dipalmitate phosphatidylcholine, and lauric acid is 1:1:1; the mass ratio of sirolimus to lipophilic material is 2:1; hydroxypropyl cellulose to sirolimus The mass ratio of 2:5; the mass ratio of dibutylhydroxytoluene and sirolimus was 2:5; the drug loading amount of sirolimus in the interlayer coating was 2 ⁇ g/mm 2 .
  • the preparation method of the drug-coated balloon is as follows:
  • dibutylhydroxytoluene is dissolved in n-heptane to form a transparent solution, i.e. a top coating solution;
  • the present embodiment provides a drug-coated balloon and a preparation method thereof.
  • the drug-coated balloon includes a balloon body and a drug coating disposed on the outer surface of the balloon body, and the drug coating includes a bottom layer stacked in sequence.
  • the thickness of the coating layer, the interlayer coating layer and the top layer coating layer are respectively 5 ⁇ m, 5 ⁇ m and 5 ⁇ m.
  • the preparation raw material of the bottom coating is a combination of equal quality hydroxypropyl cellulose and polylactic acid-glycolic acid copolymer
  • the preparation raw material of the top coating is a combination of equal quality dibutyl hydroxytoluene and butylated hydroxyanisole
  • the preparation raw materials of the interlayer coating are paclitaxel and lipophilic materials (DC-cholesterol, distearoylphosphatidylcholine, myristic acid).
  • the mass ratio of DC-cholesterol, distearoylphosphatidylcholine and myristic acid is 1:3:4; the mass ratio of paclitaxel to lipophilic material is 1:2; the mass ratio of bottom coating raw material to paclitaxel is 2:2: 4.
  • the mass ratio of the top coating material and paclitaxel is 2:4; the drug loading amount of paclitaxel in the interlayer coating is 2 ⁇ g/mm 2 .
  • the preparation method of the drug-coated balloon is as follows:
  • the drug-coated balloon includes a balloon body and a drug coating disposed on the outer surface of the balloon body.
  • Bottom coating, interlayer coating and top coating, the thickness of bottom coating, interlayer coating and top coating are 2 ⁇ m, 6 ⁇ m and 2 ⁇ m respectively.
  • the preparation raw material of the bottom coating is a combination of polyethylene glycol and povidone of equal quality
  • the preparation raw material of the top coating is butylated hydroxyanisole
  • the preparation raw material of the interlayer coating is paclitaxel and lipophilic materials (DC-cholesterol, dimethicone, etc.). Stearoylphosphatidylethanolamine).
  • the mass ratio of DC-cholesterol and distearoyl phosphatidylethanolamine is 1:1; the mass ratio of paclitaxel and lipophilic material is 1:1; the mass ratio of bottom coating material and paclitaxel is 2:1; the top coating material is The mass ratio to paclitaxel was 2:1; the drug loading of the paclitaxel in the interlayer coating was 4 ⁇ g/mm 2 .
  • the preparation method is as follows:
  • hydroxypolyethylene glycol and povidone are dissolved in ethanol to form a colorless and transparent solution, i.e. a bottom coating solution;
  • the drug-coated balloon includes a balloon body and a drug coating disposed on the outer surface of the balloon body.
  • Bottom coating, interlayer coating and top coating, the thickness of bottom coating, interlayer coating and top coating are 2 ⁇ m, 6 ⁇ m and 2 ⁇ m respectively.
  • the preparation raw materials of the bottom coating are polylactic acid-glycolic acid copolymer and polyethylene glycol in equal mass ratios
  • the preparation raw materials of the top coating are dibutyl hydroxytoluene
  • the preparation raw materials of the interlayer coating are the drug rapamycin and prophil.
  • Lipid material DC-cholesterol and dipalmitate phosphatidylcholine.
  • the mass ratio of lipophilic material DC-cholesterol to dipalmitate phosphatidylcholine is 1:1; the mass ratio of drug to lipophilic material is 1:1; the mass ratio of bottom coating raw material and drug is 1:3; the top layer The mass ratio of the coating raw material to the drug is 1:3; the drug loading amount of the drug in the interlayer coating is 3 ⁇ g/mm 2 .
  • the preparation method is as follows:
  • the present application illustrates the drug-coated balloon provided by the present application and the preparation method thereof by the above-mentioned embodiments, but the present application is not limited to the above-mentioned embodiments, that is to say, it does not mean that the present application must rely on the above-mentioned embodiments for implementation. .
  • Those skilled in the art should understand that any improvement to the application, the equivalent replacement of each raw material of the product of the application, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the application.

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Abstract

一种药物涂层球囊及其制备方法，所述药物涂层球囊包括球囊本体和设置于球囊本体外表面的药物涂层，所述药物涂层包括依次相叠的底层涂层、夹层涂层和顶层涂层。底层涂层用来增加药物涂层对球囊本体的粘附性和牢固性，降低了输送过程的药物损耗，提高药物的利用率；夹层涂层用于负载药物，同时帮助药物更好地被组织吸收；顶层涂层用于促进药物涂层与血管壁内膜的贴合，更有利于药物的组织吸收能力。

Description

药物涂层球囊及其制备方法
相关申请的交叉引用
本申请要求于2020年11月19日提交中国专利局、申请号为202011303535.8、发明名称为“一种药物涂层球囊及其制备方法”的中国专利申请和于2021年10月25日提交中国专利局、申请号为202111242947.X、发明名称为“一种药物涂层球囊及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请涉及医疗器械技术领域，具体涉及一种药物涂层球囊及其制备方法。
技术背景
药物涂层球囊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，它是将抗增生性的药物，如紫杉醇，涂层于球囊表面，当球囊到达病变部位被撑开、扩张，与血管壁内膜接触时，药物快速释放、转移药物在局部血管壁内的技术，药物在局部起到抗血管内膜增生的作用，从而预防血管介入术后的血管再狭窄。药物涂层球囊一方面药物能有效抑制平滑肌细胞过度增生从而降低再狭窄发生率，另一方面无需置入支架，从而减少了血管内膜的炎症反应、降低了支架内血栓形成风险、缩短了双联抗血小板时间、减少了出血风险。另外，在冠状动脉疾病的临床研究中，药物球囊在治疗支架内再狭窄、小血管病变、分叉病变时显示出更好的有效性和安全性，并且还适用于高出血风险患者、正在口服抗凝药物或近期进行外科手术的患者。
作为药物涂层球囊的重要技术指标，药物涂层至关重要。在血管内的药物涂层牢固度、在动脉的药物释放能力、药物被血管吸收的能力均由药物涂 层所决定。从目前公开的专利和文献中也可以看出，药物涂层的牢度不高，在药物球囊穿越和扩张过程中会有较大损失，药物利用率不高。也有涂层技术是在涂层外面设置保护膜，从而减少输送过程的药物损失，但设计的保护膜过于封闭，药物被隔离无法直接与血管壁接触，过小的接触面积同样对药物的组织吸收能力造成不利影响。
药物涂层快速释放的同时，输送过程也会被血液冲刷掉较多药物，作用于局部的药物非常少。通过增大球囊涂层的载药量能够在局部增加药物吸收量，但大量多余药物流向血管远端，影响患者健康。由于普通药物球囊扩张导管扩张时间短，药物并不好被释放，所以目前普通药物球囊扩张导管所面临的问题和难点有：(1)药物涂层快速释放的同时，输送过程也会被血液冲刷掉较多药物；(2)药物短时间贴壁，难以大量被血管壁吸收，从而达不到较好的治疗效果；(3)药物涂层易脱落产生微粒，易产生血栓。
发明内容
根据本申请的各种实施例，提供一种具有优异的涂层牢固度、药物释放能力和药物被血管吸收能力的药物涂层球囊及其制备方法。
为达到此申请目的，本申请采用以下技术方案：
一种药物涂层球囊，包括球囊本体和设置于所述球囊本体外表面的药物涂层，所述药物涂层包括依次相叠的底层涂层、夹层涂层和顶层涂层。
在其中一个实施例中，所述底层涂层包括高分子聚合物材料；所述夹层涂层包括药物和亲脂性材料；所述顶层涂层包括高分子聚合物材料。
在其中一个实施例中，所述底层涂层包括聚乳酸-羟基乙酸共聚物、聚乙二醇、聚维酮、聚乙烯醇、甲基纤维素、羟甲基纤维素、羟丙基纤维素或聚己内酯中的任意一种或至少两种的组合。所述顶层涂层包括二丁基羟基甲苯、丁基羟基茴香醚、壳聚糖或聚己内酯中的任意一种或至少两种的组合。
在其中一个实施例中，所述亲脂性材料包括胆固醇、磷脂或脂肪酸中的任意一种或至少两种的组合。
在其中一个实施例中，所述亲脂性材料包括胆固醇和磷脂，所述胆固醇与磷脂的质量比为0.2-10。
在其中一个实施例中，所述亲脂性材料包括磷脂与脂肪酸，所述磷脂与脂肪酸的质量比为0.2-10。
在其中一个实施例中，所述亲脂性材料包括胆固醇与脂肪酸，所述胆固醇与脂肪酸的质量比为0.04-100。
在其中一个实施例中，所述药物包括西罗莫司、西罗莫司衍生物、紫杉醇或紫杉醇衍生物中的任意一种或至少两种的组合。所述药物与所述亲脂性材料的质量比为0.1-10；所述底层涂层中的高分子聚合物材料与所述药物的质量比为0.05-20；所述顶层夹层中的高分子聚合物材料与所述药物的质量比为0.05-20。
在其中一个实施例中，所述胆固醇包括DC-胆固醇和/或胆固醇。所述磷脂包括1,2-二油酰基卵磷脂、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、1-棕榈酰基-2-油酰基卵磷脂、二硬脂酰基磷脂酰乙醇胺、二油酰磷脂酰乙醇胺或二棕榈酰磷脂酰乙醇胺中的任意一种或至少两种的组合。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。
本申请还提供了上述药物涂层球囊的制备方法，包括如下步骤：
(1)分别制得底层涂层溶液、夹层涂层溶液和顶层涂层溶液；
(2)将所述底层涂层溶液、夹层涂层溶液和顶层涂层溶液依次喷涂到球囊本体表面，形成所述药物涂层。
在其中一个实施例中，上述步骤(2)中，使用超声雾化喷涂设备并采用多层喷涂叠加技术执行所述喷涂操作。
与现有技术相比，本申请具有如下有益效果：
本申请提供的药物涂层球囊包括设置于球囊本体外表面的药物涂层，药物涂层具有依次相叠的底层涂层、夹层涂层和顶层涂层，即“三明治”型结构。底层涂层用来增加药物涂层对球囊本体的粘附性和牢固性，降低了输送 过程中药物的损耗，提高了药物的利用率；保证了药物快速释放的同时，输送过程也不会被血液冲刷掉较多药物；且药物涂层不易脱落产生微粒，不易产生血栓。夹层涂层用于负载药物，同时帮助药物更好地被组织吸收。顶层涂层用于促进药物涂层与血管壁内膜的贴合，更有利于药物的组织吸收能力，以达到短时间贴壁药物能被血管壁吸收的效果。
具体实施方式
为更进一步阐述本申请所采取的技术方案及其效果，以下结合本申请的具体实施例来进一步说明本申请的技术方案，但本申请并非局限在以下实施例范围内。
本申请提供了一种药物涂层球囊，包括球囊本体和设置于球囊本体外表面的药物涂层。药物涂层包括自球囊本体的外表面起依次相叠的底层涂层、夹层涂层和顶层涂层。底层涂层用来增加药物涂层对球囊本体的粘附性，提高药物涂层的牢固性；夹层涂层用于负载药物，同时帮助药物更好地被组织吸收；顶层涂层用于促进涂层与细胞内膜的贴合，更有利于药物的组织吸收能力。
在一些实施例中，底层涂层与夹层涂层的厚度比可以为0.05-10，夹层涂层与顶层涂层的厚度比可以为0.01-20。具体的，底层涂层与夹层涂层的厚度比可选择0.05、0.1、0.5、1、2、3、4、5、6、7、8、9、10等。夹层涂层与顶层涂层的厚度比可以为0.01、0.1、0.5、1、2、3、4、5、6、7、8、9、10、15、20等。进一步地，夹层涂层的厚度可以为1-20μm，例如1μm、2μm、4μm、5μm、8μm、10μm、12μm、14μm、15μm、16μm、18μm、20μm等。以上数值范围内的其他具体点值均可选择，在此便不再一一赘述。
在一些实施例中，底层涂层包括高分子聚合物材料。优选地，底层涂层包括聚乳酸-羟基乙酸共聚物、聚乙二醇、聚维酮、聚乙烯醇、甲基纤维素、羟甲基纤维素、羟丙基纤维素或聚己内酯中的任意一种或至少两种的组合。用于底层涂层中的高分子聚合物材料优选为高粘度型的高分子聚合物材料， 有利于促进药物涂层与球囊本体的贴合，使药物涂层球囊在输送过程中不会被血液冲刷掉较多药物，药物利用率较高。
底层涂层可以为至少两种高分子聚合物材料的组合，例如聚乳酸-羟基乙酸共聚物和聚乙二醇的组合、聚乙二醇和聚维酮的组合、聚乙烯醇和甲基纤维素的组合、聚乳酸-羟基乙酸共聚物、聚乙二醇和聚维酮的组合、羟甲基纤维素、羟丙基纤维素和聚己内酯的组合等，其他任意的组合方式均可选择，在此便不再一一赘述。
在一些实施例中，顶层涂层包括高分子聚合物材料。优选的，顶层涂层包括二丁基羟基甲苯、丁基羟基茴香醚、壳聚糖或聚己内酯中的任意一种或至少两种的组合。用于顶层涂层中的高分子聚合物材料优选为亲脂性的高分子聚合物材料，有利于促进药物涂层与细胞内膜的贴合，更有利于药物的组织吸收能力。
顶层涂层可以为至少两种高分子聚合物材料的组合，例如二丁基羟基甲苯和丁基羟基茴香醚的组合、丁基羟基茴香醚和壳聚糖的组合、二丁基羟基甲苯和聚己内酯的组合等，其他任意的组合方式均可选择，在此便不再一一赘述。
在一些实施例中，夹层涂层包括药物和亲脂性材料。所述亲脂性材料可以包括胆固醇、磷脂或脂肪酸中的任意一种或至少两种的组合。这些亲脂性材料与药物共存于夹层涂层中，能够帮助药物更好地贴壁吸收。
所述胆固醇可以包括DC-胆固醇和/或胆固醇。所述磷脂可以包括1,2-二油酰基卵磷脂、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、1-棕榈酰基-2-油酰基卵磷脂、二硬脂酰基磷脂酰乙醇胺、二油酰磷脂酰乙醇胺或二棕榈酰磷脂酰乙醇胺中的任意一种或至少两种的组合。所述脂肪酸可以包括软脂酸、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。
所述亲脂性材料可以为至少两种材料的组合，例如胆固醇和磷脂的组合、磷脂和脂肪酸的组合、胆固醇和脂肪酸的组合，以及胆固醇、磷脂和脂肪酸 的组合等，其他任意的组合方式均可选择，在此便不再一一赘述。
具体的，所述亲脂性材料可以为1,2-二油酰基卵磷脂和二棕榈酸磷脂酰胆碱的组合、二硬脂酰磷脂酰胆碱和二肉豆蔻酰磷脂酰胆碱的组合，以及1,2-二油酰基卵磷脂、1-棕榈酰基-2-油酰基卵磷脂和二硬脂酰基磷脂酰乙醇胺的组合等，其他任意的组合方式均可选择，在此便不再一一赘述。
所述亲脂性材料还可以为软脂酸和硬脂酸的组合、硬脂酸和月桂酸的组合、豆蔻酸和花生酸的组合，以及软脂酸、硬脂酸和月桂酸的组合等，其他任意的组合方式均可选择，在此便不再一一赘述。
其中，当亲脂性材料中同时包含胆固醇与磷脂时，所述胆固醇与磷脂的质量比为0.2-10，例如0.2、0.5、1、1.5、2、3、4、5、6、7、8、9、10等，上述范围内的其他具体点值均可选择，在此便不再一一赘述。
优选地，所述磷脂与脂肪酸的质量比为0.2-10，例如0.2、0.5、1、1.5、2、3、4、5、6、7、8、9、10等，上述范围内的其他具体点值均可选择，在此便不再一一赘述等，上述范围内的其他具体点值均可选择，在此便不再一一赘述。
当亲脂性材料中同时包含胆固醇与脂肪酸时，所述胆固醇与脂肪酸的质量比为0.04-100，例如0.04、0.05、0.1、0.5、1、5、10、20、50、60、70、100等，上述范围内的其他具体点值均可选择，在此便不再一一赘述。
夹层涂层还包括药物，所述药物可以包括西罗莫司、西罗莫司衍生物、紫杉醇或紫杉醇衍生物中的任意一种或至少两种的组合。所述至少两种的组合例如西罗莫司和西罗莫司衍生物的组合、紫杉醇和紫杉醇衍生物的组合、西罗莫司衍生物和紫杉醇衍生物的组合、西罗莫司和紫杉醇的组合等，其他任意的组合方式均可选择，在此便不再一一赘述。所述西罗莫司衍生物例如依维莫司、佐他莫斯等。所述紫杉醇衍生物例如多西紫杉醇、紫杉醇脂质体、白蛋白紫杉醇等。
在夹层涂层中，所述药物与亲脂性材料的质量比优选为0.1-10，例如0.1、0.2、0.5、1、2、5、7、9、10等，上述范围内的其他具体点值均可选择，在 此便不再一一赘述。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。所述药物在所述夹层涂层中的载药量可以为0.1-8μg/mm 2，例如0.1μg/mm 2、0.2μg/mm 2、0.5μg/mm 2、1μg/mm 2、2μg/mm 2、3μg/mm 2、4μg/mm 2、5μg/mm 2、6μg/mm 2、7μg/mm 2、8μg/mm 2等，上述范围内的其他具体点值均可选择，在此便不再一一赘述。底层涂层中高分子聚合物材料与夹层涂层中药物的质量比为可以为0.05-20，例如0.05、0.1、0.2、0.5、1、5、10、15、20等，上述范围内的其他具体点值均可选择，在此便不再一一赘述。顶层涂层中高分子聚合物材料与夹层涂层中药物的质量比可以为0.05-20，例如0.05、0.1、0.2、0.5、1、5、10、15、20等，上述范围内的其他具体点值均可选择，在此便不再一一赘述。
本申请还提供一种如上所述的药物涂层球囊的制备方法，包括如下步骤：
(1)分别制得底层涂层溶液、夹层涂层溶液和顶层涂层溶液；
(2)将所述底层涂层溶液、夹层涂层溶液和顶层涂层溶液依次喷涂到球囊本体表面，形成所述药物涂层。
其中，步骤(1)中，将用于制备底层涂层、夹层涂层和顶层涂层的原料分别与溶剂混合溶解，制得底层涂层溶液、夹层涂层溶液和顶层涂层溶液。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。所述至少两种的组合可以为乙醇和正庚烷的组合、乙醇、正庚烷和二甲基亚砜的组合等，其他任意的组合方式均可选择，在此便不再一一赘述。
其中，所述步骤(2)中使用超声雾化喷涂设备执行所述喷涂操作，所述超声雾化喷涂设备可以采用多层喷涂叠加技术执行所述喷涂操作，或者采用现有的其他喷涂技术执行所述喷涂操作。所述超声雾化喷涂设备执行所述喷涂操作时，超声功率优选为0.2-5W，例如0.2W、0.5W、0.8W、1W、1.5W、2W、2.5W、3W、5W等；温度优选为20-50℃，例如20℃、25℃、30℃、 35℃、40℃、45℃或50℃等；气压优选为0.01-0.3MPa，例如0.01MPa、0.05MPa、0.1MPa、0.15MPa、0.2MPa、0.25MPa或0.3MPa等，上述数值范围内的其他具体点值均可选择，在此便不再一一赘述。
进一步地，所述超声雾化喷涂设备执行所述喷涂操作时，喷涂范围优选为10-60mm，例如10mm、20mm、30mm、40mm、50mm或60mm等；药物溶液流量优选为0.01-1mL/min，例如0.01mL/min、0.02mL/min、0.05mL/min、0.08mL/min、0.1mL/min、0.2mL/min、0.5mL/min、0.8mL/min或1.0mL/min等，上述范围内的其他具体点值均可选择，在此便不再一一赘述。
实施例1
本实施例提供一种药物涂层球囊及其制备方法，所述药物涂层球囊包括球囊本体和设置于球囊本体外表面的药物涂层，所述药物涂层包括依次相叠的底层涂层、夹层涂层和顶层涂层，所述底层涂层、夹层涂层和顶层涂层的厚度分别为4μm、6μm、4μm。
底层涂层的制备原料为羟甲基纤维素，顶层涂层的制备原料为丁基羟基茴香醚，夹层涂层的制备原料为西罗莫司和亲脂性材料(DC-胆固醇、1,2-二油酰基卵磷脂、硬脂酸)。
DC-胆固醇、1,2-二油酰基卵磷脂、硬脂酸的质量比为2:1:1；西罗莫司与亲脂性材料的质量比为1:1；羟甲基纤维素与西罗莫司的质量比为1:1.5；丁基羟基茴香醚与西罗莫司的质量比为1:1.5；西罗莫司在夹层涂层中的载药量为3μg/mm 2。
该药物涂层球囊的制备方法如下：
(1)将羟甲基纤维素溶于乙醇中，形成无色透明溶液，即底层涂层溶液；
(2)将DC-胆固醇、1,2-二油酰基卵磷脂、硬脂酸、西罗莫司溶解于正庚烷中，超声形成白色悬浮液，即夹层涂层溶液；
(3)将丁基羟基茴香醚溶于二甲基亚砜中，形成透明溶液，即顶层涂层溶液；
(4)在球囊本体的外表面用超声雾化喷涂设备依次喷涂底层涂层溶液2遍、夹层涂层溶液6遍和顶层涂层溶液2遍，其中超声功率为3.0W，注射泵输送药物溶液的流量为0.08mL/min，喷涂温度25℃，喷涂气压0.05MPa，喷涂范围为30mm。
实施例2
本实施例提供一种药物涂层球囊及其制备方法，所述药物涂层球囊包括球囊本体和设置于球囊本体外表面的药物涂层，该药物涂层包括依次相叠的底层涂层、夹层涂层和顶层涂层，所述底层涂层、夹层涂层和顶层涂层厚度分别为4μm、8μm、4μm。
底层涂层的制备原料为羟丙基纤维素，顶层涂层的制备原料为二丁基羟基甲苯，夹层涂层的制备原料为西罗莫司和亲脂性材料DC-胆固醇、二棕榈酸磷脂酰胆碱、月桂酸)。
DC-胆固醇、二棕榈酸磷脂酰胆碱、月桂酸的质量比为1:1:1；西罗莫司与亲脂性材料的质量比为2:1；羟丙基纤维素与西罗莫司的质量比为2:5；二丁基羟基甲苯与西罗莫司的质量比为2:5；西罗莫司在夹层涂层中的载药量为2μg/mm 2。
该药物涂层球囊的制备方法如下：
(1)将羟丙基纤维素溶于乙醇中，形成无色透明溶液，即底层涂层溶液；
(2)将DC-胆固醇、二棕榈酸磷脂酰胆碱、月桂酸、西罗莫司溶解于正庚烷中，超声形成白色悬浮液，即夹层涂层溶液；
(3)将二丁基羟基甲苯溶于正庚烷中，形成透明溶液，即顶层涂层溶液；
(4)在球囊本体的外表面用超声雾化喷涂设备依次喷涂底层涂层溶液2遍、夹层涂层溶液4遍和顶层涂层溶液4遍，其中超声功率为5.0W，注射泵输送药物溶液的流量为0.15mL/min，喷涂温度为25℃，喷涂气压为0.05MPa，喷涂范围为30mm。
实施例3
本实施例提供一种药物涂层球囊及其制备方法，所述药物涂层球囊包括 球囊本体和设置于球囊本体外表面的药物涂层，其药物涂层包括依次相叠的底层涂层、夹层涂层和顶层涂层，该底层涂层、夹层涂层和顶层涂层的厚度分别为5μm、5μm、5μm。
底层涂层的制备原料为等质量的羟丙基纤维素与聚乳酸-羟基乙酸共聚物的组合，顶层涂层的制备原料为等质量的二丁基羟基甲苯与丁基羟基茴香醚的组合，夹层涂层的制备原料为紫杉醇和亲脂性材料(DC-胆固醇、二硬脂酰磷脂酰胆碱、豆蔻酸)。
DC-胆固醇、二硬脂酰磷脂酰胆碱、豆蔻酸的质量比为1:3:4；紫杉醇与亲脂性材料的质量比为1:2；底层涂层原料与紫杉醇的质量比为2:4；顶层涂层原料与紫杉醇的质量比为2:4；紫杉醇在夹层涂层中的载药量为2μg/mm 2。
该药物涂层球囊的制备方法如下：
(1)将羟丙基纤维素与聚乳酸-羟基乙酸共聚物溶于乙醇中，形成无色透明溶液，即底层涂层溶液；
(2)将DC-胆固醇、二硬脂酰磷脂酰胆碱、豆蔻酸、紫杉醇溶解于正庚烷中，超声形成白色悬浮液，即夹层涂层溶液；
(3)将二丁基羟基甲苯与丁基羟基茴香醚溶于正庚烷中，形成透明溶液，即顶层涂层溶液；
(4)在球囊本体的外表面用超声雾化喷涂设备依次喷涂底层涂层溶液2遍、夹层涂层溶液4遍和顶层涂层溶液4遍，其中超声功率为2.0W，注射泵输送药物溶液的流量为0.05mL/min，喷涂温度25℃，喷涂气压0.2MPa，喷涂范围为20mm。
实施例4
本实施例提供一种药物涂层球囊及其制备方法，所述药物涂层球囊包括球囊本体和设置于球囊本体外表面的药物涂层，所述药物涂层包括依次相叠的底层涂层、夹层涂层和顶层涂层，底层涂层、夹层涂层和顶层涂层的厚度分别为2μm、6μm、2μm。
底层涂层的制备原料为等质量的聚乙二醇和聚维酮的组合，顶层涂层的 制备原料为丁基羟基茴香醚，夹层涂层的制备原料为紫杉醇和亲脂性材料(DC-胆固醇、二硬脂酰基磷脂酰乙醇胺)。
DC-胆固醇、二硬脂酰基磷脂酰乙醇胺的质量比为1:1；紫杉醇与亲脂性材料的质量比为1:1；底层涂层原料与紫杉醇的质量比为2:1；顶层涂层原料与紫杉醇的质量比为2:1；所述紫杉醇在所述夹层涂层中的载药量为4μg/mm 2。
制备方法如下：
(1)将羟聚乙二醇和聚维酮溶于乙醇中，形成无色透明溶液，即底层涂层溶液；
(2)将DC-胆固醇、二硬脂酰基磷脂酰乙醇胺、紫杉醇溶解于正庚烷中，超声形成白色悬浮液，即夹层涂层溶液；
(3)将丁基羟基茴香醚溶于正庚烷中，形成透明溶液，即顶层涂层溶液；
(4)在球囊本体的外表面用超声雾化喷涂设备依次喷涂底层涂层溶液3遍、夹层涂层溶液5遍和顶层涂层溶液3遍，其中超声功率为4.0W，注射泵输送药物溶液的流量为0.2mL/min，喷涂温度为30℃，喷涂气压为0.1MPa，喷涂范围为40mm。
实施例5
本实施例提供一种药物涂层球囊及其制备方法，所述药物涂层球囊包括球囊本体和设置于球囊本体外表面的药物涂层，所述药物涂层包括依次相叠的底层涂层、夹层涂层和顶层涂层，底层涂层、夹层涂层和顶层涂层的厚度分别为2μm、6μm、2μm。
底层涂层的制备原料为等质量比的聚乳酸-羟基乙酸共聚物和聚乙二醇，顶层涂层的制备原料为二丁基羟基甲苯，夹层涂层的制备原料为药物雷帕霉素和亲脂性材料DC-胆固醇和二棕榈酸磷脂酰胆碱。
亲脂性材料DC-胆固醇与二棕榈酸磷脂酰胆碱的质量比为1:1；药物与亲脂性材料的质量比为1:1；底层涂层原料与药物的质量比为1:3；顶层涂层原料与药物的质量比为1:3；所述药物在所述夹层涂层中的载药量为3μg/mm 2。
制备方法如下：
(1)将底层涂层的制备原料溶于乙醇中，形成无色透明溶液，即底层涂层溶液；
(2)将药物和亲脂性材料溶解于正庚烷中，超声形成白色悬浮液，即夹层涂层溶液；
(3)将顶层涂层的制备原料溶于正庚烷中，形成透明溶液，即顶层涂层溶液；
(4)在球囊本体的外表面用超声雾化喷涂设备依次喷涂底层涂层溶液2遍、夹层涂层溶液6遍和顶层涂层溶液2遍，其中超声功率为5.0W，注射泵输送药物溶液的流量为0.15mL/min，喷涂温度为25℃，喷涂气压为0.05MPa，喷涂范围为30mm。
申请人声明，本申请通过上述实施例来说明本申请提供的药物涂层球囊及其制备方法，但本申请并不局限于上述实施例，即不意味着本申请必须依赖上述实施例才能实施。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。
以上详细描述了本申请的优选实施方式，但是，本申请并不限于上述实施方式中的具体细节，在本申请的技术构思范围内，可以对本申请的技术方案进行多种简单变型，这些简单变型均属于本申请的保护范围。
另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合，为了避免不必要的重复，本申请对各种可能的组合方式不再另行说明。

Claims (10)

  1. 一种药物涂层球囊，包括球囊本体和设置于所述球囊本体外表面的药物涂层，所述药物涂层包括依次相叠的底层涂层、夹层涂层和顶层涂层。
  2. 如权利要求1所述的药物涂层球囊，其中，所述底层涂层包括高分子聚合物材料；所述夹层涂层包括药物和亲脂性材料；所述顶层涂层包括高分子聚合物材料。
  3. 如权利要求1所述的药物涂层球囊，其中，所述底层涂层包括聚乳酸-羟基乙酸共聚物、聚乙二醇、聚维酮、聚乙烯醇、甲基纤维素、羟甲基纤维素、羟丙基纤维素或聚己内酯中的任意一种或至少两种的组合；
    和/或，所述顶层涂层包括二丁基羟基甲苯、丁基羟基茴香醚、壳聚糖或聚己内酯中的任意一种或至少两种的组合。
  4. 如权利要求2所述的药物涂层球囊，其中，所述亲脂性材料包括胆固醇、磷脂或脂肪酸中的任意一种或至少两种的组合。
  5. 如权利要求4所述的药物涂层球囊，其中，所述亲脂性材料包括胆固醇和磷脂，所述胆固醇与磷脂的质量比为0.2-10；
    或者，所述亲脂性材料包括磷脂与脂肪酸，所述磷脂与脂肪酸的质量比为0.2-10；
    或者，所述亲脂性材料包括胆固醇与脂肪酸，所述胆固醇与脂肪酸的质量比为0.04-100。
  6. 如权利要求2所述的药物涂层球囊，其中，所述药物包括西罗莫司、西罗莫司衍生物、紫杉醇或紫杉醇衍生物中的任意一种或至少两种的组合。
  7. 如权利要求2所述的药物涂层球囊，其中，所述药物与所述亲脂性材料的质量比为0.1-10；所述底层涂层中的高分子聚合物材料与所述药物的质量比为0.05-20；所述顶层夹层中的高分子聚合物材料与所述药物的质量比为0.05-20。
  8. 如权利要求4所述的药物涂层球囊，其中，所述胆固醇包括DC-胆固醇和/或胆固醇；
    和/或，所述磷脂包括1,2-二油酰基卵磷脂、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、1-棕榈酰基-2-油酰基卵磷脂、二硬脂酰基磷脂酰乙醇胺、二油酰磷脂酰乙醇胺或二棕榈酰磷脂酰乙醇胺中的任意一种或至少两种的组合；
    和/或，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。
  9. 如权利要求1-8中任一项所述的药物涂层球囊的制备方法，其中，包括如下步骤：
    (1)分别制得底层涂层溶液、夹层涂层溶液和顶层涂层溶液；
    (2)将所述底层涂层溶液、夹层涂层溶液和顶层涂层溶液依次喷涂到球囊本体表面，形成所述药物涂层。
  10. 如权利要求9所述的药物涂层球囊的制备方法，其中，所述步骤(2)中，使用超声雾化喷涂设备并采用多层喷涂叠加技术执行所述喷涂操作。
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