WO2024099433A1 - 一种药涂球囊涂覆液、涂层材料、药涂球囊、制备方法及应用 - Google Patents

一种药涂球囊涂覆液、涂层材料、药涂球囊、制备方法及应用 Download PDF

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WO2024099433A1
WO2024099433A1 PCT/CN2023/130996 CN2023130996W WO2024099433A1 WO 2024099433 A1 WO2024099433 A1 WO 2024099433A1 CN 2023130996 W CN2023130996 W CN 2023130996W WO 2024099433 A1 WO2024099433 A1 WO 2024099433A1
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polyoxyethylene
glycerol
drug
sirolimus
core
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PCT/CN2023/130996
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English (en)
French (fr)
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熊丹
李爽爽
吕萌
李超
张莹
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凯诺威医疗科技(武汉)有限公司
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Publication of WO2024099433A1 publication Critical patent/WO2024099433A1/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
    • 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
    • A61L29/16—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
    • A61L2300/20—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
    • A61L2300/416—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
    • A61L2300/60—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
    • 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
    • A61L2300/626—Liposomes, micelles, vesicles
    • 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
    • A61L2420/04—Coatings containing a composite material such as inorganic/organic, i.e. material comprising different phases

Definitions

  • the present invention relates to the field of interventional therapy instruments, and in particular to a drug-coated balloon coating material, a drug-coated balloon, a drug-coated balloon coating liquid, and a preparation method and application thereof.
  • Nanocrystals can effectively increase the solubility of poorly soluble drugs, and have a high drug loading capacity, which can theoretically reach 100%. Oswald ripening causes the system to be unstable. As the storage time increases, nanocrystals gradually re-deposit into larger particles, resulting in unstable particle size and physical properties during storage. Due to the high surface energy and fast dissolution rate, nanocrystals are more unstable in the complex environment of the body as the surface erodes and the spatial stability of the nanocrystals gradually disappears. At the same time, drug-coated balloons made only of nanocrystals have the problem of uncontrollable dissolution and release in the body. Liposomes can control drug release.
  • Nanocarriers have good biocompatibility, can quickly enter tissues, and have good stability. Because poorly soluble drugs are retained in the phospholipid bilayer, the drug loading capacity of liposomes is low, which limits their use. Nanocrystal-liposome complexes combine the advantages of both, with high drug loading capacity, strong stability, and controllable drug release rate.
  • An embodiment of the present invention provides a coating liquid for a drug-coated balloon, wherein the coating liquid includes an aqueous solvent, and the coating liquid also includes a plurality of core-shell structures formed by a phospholipid bilayer encapsulating a drug, wherein the core-shell structure is dispersed in the aqueous solvent, wherein the inner core of the core-shell structure includes a plurality of particles loaded with the drug, the outer shell of the core-shell structure is the phospholipid bilayer, the phospholipid bilayer includes an outer layer of hydrophilic groups and an inner layer of hydrophobic groups, and the plurality of particles loaded with the drug include a plurality of nanocrystalline particles containing the drug.
  • the particle size of the core-shell structure is 200-900 nm
  • the particle size d50 of the nanocrystalline particles is 150-900 nm; wherein the preparation process of the nanocrystalline particles uses a surfactant;
  • the surfactant is selected from the group consisting of polyethylene glycol succinate of vitamin E, poloxamer 188, poloxamer 407, tyloxapol, sodium docusate, polyethylene glycol 15-hydroxystearate, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (40) castor oil, polyoxyethylene (35) castor oil, polyoxyethylene (20) castor oil, polyoxyethylene (10) castor oil, polyethylene glycol cetostearyl ether 20, polyethylene glycol cetostearyl ether 12, monocetyl alcohol polyoxyethylene ether (Cetearyl alcohol) th-10), polyoxyethylene (10) lauryl ether (Brij 56), polyoxyethylene (20) lauryl ether (Brij 58), polyoxyethylene (23) lauryl ether (Brij 35), polyoxyethylene (2) lauryl ether (Brij 52), polyoxyethylene (25) oleate (Myrj
  • the drug includes sirolimus, zotarolimus, everolimus, tacrolimus, temsirolimus, prurigo (Pimecrolimus), Deforolimus, Ridaforolimus;
  • the raw materials for preparing the phospholipid bilayer include phospholipids and cholesterol;
  • the phospholipids include egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, cephalin, phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), stearylamide (SA), sunflower lecithin, 1,2-diformyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn- Glycerol-3-phosphocholine, 1,2-dierucyl-sn-glycerol-3-phosphocholine, 1-dipalmitoyl-dioleoyl-sn-glycerol-3-phosphocholine, 1,2-diformyl-sn-glycerol-3-phospho-rac-glycerol sodium salt, 1,2-dipalmitoy
  • the cholesterol includes cholesterol and DC cholesterol
  • the mass ratio of phospholipids to cholesterol is 40:1-1:2, more preferably 30:1-1:1.
  • the present invention also provides a drug-coated balloon coating material, which includes a plurality of core-shell structures formed by a phospholipid bilayer wrapping a drug, wherein the inner core of the core-shell structure includes a plurality of particles loaded with the drug, the outer shell of the core-shell structure is the phospholipid bilayer, the phospholipid bilayer includes an outer layer of hydrophilic groups and an inner layer of hydrophobic groups, and the plurality of particles loaded with the drug include a plurality of nanocrystalline particles containing the drug.
  • the particle size of the core-shell structure is 200-900 nm
  • the particle size d50 of the nanocrystalline particles is 150-900 nm; wherein the preparation process of the nanocrystalline particles uses a surfactant;
  • the surfactant is selected from the group consisting of vitamin E succinate polyethylene glycol ester, poloxamer 188, poloxamer 407, tyloxapol, docusate sodium, 15-hydroxystearate polyethylene glycol ester, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (40) castor oil, polyoxyethylene (35) castor oil, polyoxyethylene (20) castor oil, polyoxyethylene (10) castor oil, polyethylene glycol cetostearyl ether 20, polyethylene glycol cetostearyl ether 12, monocetyl alcohol polyoxyethylene ether (Cetearyl alcohol) th-10), polyoxyethylene (10) lauryl ether (Brij 56), polyoxyethylene (20) lauryl ether (Brij 58), polyoxyethylene (23) lauryl ether (Brij 35), polyoxyethylene (2) lauryl ether (Brij 52), polyoxyethylene (25) oleate (
  • the drug includes sirolimus, zotarolimus, everolimus, tacrolimus, temsirolimus, prurigo (Pimecrolimus), Deforolimus, Ridaforolimus;
  • the raw materials for preparing the phospholipid bilayer include phospholipids and cholesterol;
  • the phospholipids include egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, cephalin, phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), stearylamide (SA), sunflower lecithin, 1,2-diformyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3- Phosphocholine, 1,2-dierucyl-sn-glycero-3-phosphocholine, 1-dipalmitoyl-dioleoyl-sn-glycero-3-phosphocholine, 1,2-diformyl-sn-glycero-3-phospho-rac-glycerol sodium salt, 1,2-dipalmitoyl
  • the mass ratio of phospholipids to cholesterol is 40:1-1:2, more preferably 30:1-1:1.
  • the present invention also provides a drug-coated balloon, the surface of which is coated with any one of the above materials.
  • the present invention also provides a use of a drug-coated balloon in treating atherosclerosis, stenosis and/or restenosis of coronary arteries, peripheral blood vessels or intracranial arteries.
  • the present invention also provides a method for preparing a drug-coated balloon coating liquid, the method comprising the following steps:
  • the method for preparing the nanocrystalline particles comprises: an anti-solvent method, a high-pressure homogenization method or a microfluidization method;
  • the coating liquid includes an aqueous solvent, and the coating liquid also includes a plurality of core-shell structures formed by drugs wrapped in phospholipid bilayers, and the core-shell structures are dispersed in the aqueous solvent, wherein the inner core of the core-shell structure includes a plurality of particles loaded with drugs, and the outer shell of the core-shell structure is the phospholipid bilayer, and the phospholipid bilayer includes hydrophilic groups in the outer layer and hydrophobic groups in the inner layer.
  • the method further comprises: (4) adding a thickener to the above solution, stirring with a magnetic stirrer and mixing evenly to obtain a drug-coated balloon coating solution;
  • the thickener comprises sodium alginate
  • step (2) after magnetic stirring, the mixture is homogenized 5-10 times by a high pressure homogenizer or a microfluidizer to obtain a milky white solution;
  • the drug in step S1 includes sirolimus, and the organic solvent includes methanol;
  • the mass ratio of sirolimus to sodium lauryl sulfate is 5:1-1:2;
  • the anti-solvent method comprises the following steps:
  • the particle size d50 of the nanocrystalline particles is 150-900 nm, and the mass ratio of sirolimus to sodium dodecyl sulfate is 5:1-1:2;
  • the high pressure homogenization method comprises the following steps:
  • the particle size d50 of the nanocrystalline particles is 150-900 nm
  • the homogenization pressure is 1000-2000 bar
  • the number of homogenizations is 5-10 times
  • the mass ratio of sirolimus to sodium dodecyl sulfate is 5:1-1:2;
  • the microfluidization method comprises the following steps:
  • the particle size d50 of the nanocrystalline particles is 150-900 nm
  • the microjet pressure is 1000-2000 bar
  • the homogenization times are 5-10 times
  • the mass ratio of sirolimus to sodium dodecyl sulfate is 5:1-1:2.
  • the present invention also provides a drug-coated balloon coating liquid, the coating liquid includes an aqueous solvent, the coating liquid also includes a plurality of core-shell structures formed by phospholipid bilayers encapsulating drugs, the core-shell structures are dispersed in the aqueous solvent, wherein the core of the core-shell structure includes a plurality of particles loaded with drugs, the outer shell of the core-shell structure is the phospholipid bilayer, the phospholipid bilayer includes an outer layer of hydrophilic groups and an inner layer of hydrophobic groups, the plurality of particles loaded with drugs include a plurality of nanocrystalline particles containing drugs,
  • the raw materials for preparing the nanocrystalline particles include a surfactant, and the surfactant is selected from the group consisting of polyethylene glycol succinate vitamin E, poloxamer 188, poloxamer 407, tyloxapol, sodium docusate, polyethylene glycol 15-hydroxystearate, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (40) castor oil, polyoxyethylene (35) castor oil, polyoxyethylene (20) castor oil, polyoxyethylene (10) castor oil, polyethylene glycol cetostearyl ether 20, polyethylene glycol cetostearyl ether 12, monocetyl alcohol polyoxyethylene ether (Ceteth-10), polyoxyethylene (10) lauryl ether (Brij 56), polyoxyethylene (20) lauryl ether (Brij 58), polyoxyethylene (23) lauryl ether (Brij 35), polyoxyethylene (2) lauryl ether (Brij 52), polyoxyethylene (2
  • the method for preparing the nanocrystalline particles includes: an anti-solvent method, a high-pressure homogenization method or a microfluidization method;
  • the anti-solvent method comprises the following steps:
  • the particle size d50 of the nanocrystalline particles is 150-900 nm, and the mass ratio of sirolimus to surfactant is 5:1-1:2;
  • the high pressure homogenization method comprises the following steps:
  • the particle size d50 of the nanocrystalline particles is 150-900 nm
  • the homogenization pressure is 1000-2000 bar
  • the number of homogenizations is 5-10 times
  • the mass ratio of sirolimus to surfactant is 5:1-1:2;
  • the microfluidization method comprises the following steps:
  • the particle size d50 of the nanocrystalline particles is 150-900 nm
  • the microjet pressure is 1000-2000 bar
  • the homogenization times are 5-10 times
  • the mass ratio of sirolimus to surfactant is 5:1-1:2.
  • the present invention has the following technical effects: nanocrystals are combined with liposomes to combine the advantages of the two drug carriers; the formed phospholipid bilayer increases the solubility of poorly soluble drugs, has a high drug loading capacity, good stability, and controllable drug release rate.
  • the present invention also provides use of the drug-coated balloon in intracranial artery stenosis, wherein the dosage of the drug is less than or equal to 3 ⁇ g/mm 2 , more preferably less than or equal to 1.5 ⁇ g/mm 2 .
  • the present invention also provides a use of a sirolimus drug-coated balloon in intracranial artery stenosis, wherein the dosage of the drug is less than or equal to 3 ⁇ g/mm 2 , more preferably less than or equal to 1.5 ⁇ g/mm 2 .
  • the present invention combines nanocrystals with liposomes, combining the advantages of the two drug carriers; the formed phospholipid bilayer increases the solubility of the poorly soluble drugs on the drug-coated balloon, has a high drug loading capacity, good drug carrier stability and stable drug crystal form, so that the drug release rate is controllable.
  • FIG. 1 is a schematic diagram showing a nanocrystal-liposome composite nanocarrier of the present invention.
  • FIG. 2 shows an electron microscopic image of the surface of the sirolimus drug-coated balloon of the present invention.
  • FIG. 3 shows a distribution diagram of nanocrystal particle size in the present invention.
  • FIG. 4 shows the particle size distribution of the nanocrystal-liposome composite nanocarrier of the present invention.
  • FIG5 shows the crystal form spectra of nanocrystal-liposome composite nanocarriers prepared by different prescriptions and different processes before and after sterilization in the present invention (different prescriptions: polyoxyethylene (35) castor oil: EL35; 15-hydroxystearate polyethylene glycol ester: HS15; Tyloxapol; different processes: antisolvent method, microfluidization method)
  • FIG6 shows the crystal form of the nanocrystal-liposome composite nanocarrier prepared by different processes using sodium dodecyl sulfate: SDS as a surfactant before and after sterilization and the nanocrystal-liposome composite nanocarrier prepared by using HS15 after sterilization.
  • a nanocrystal containing a drug is first prepared, wherein the drug includes sirolimus, zotarolimus or everolimus.
  • the drug includes sirolimus, zotarolimus or everolimus.
  • sirolimus is used as an example for description.
  • the preparation method of the nanocrystal includes: an anti-solvent method, a high-pressure homogenization method or a microfluidization method.
  • the anti-solvent method used in the sirolimus nanocrystals comprises the following steps:
  • phase B solution (2) accurately weighing sodium dodecyl sulfate and aqueous phase solvent respectively, and stirring by magnetic stirring until transparent and uniform, to obtain a phase B solution;
  • the anti-solvent method may specifically include the following steps, wherein the specific amount of each raw material is shown in the following table:
  • phase A (2) Accurately weigh sirolimus and methanol respectively, and stir magnetically for 10 minutes until the mixture becomes transparent and uniform, which is phase A;
  • phase B (2) Accurately weigh sodium dodecyl sulfate and water respectively, and stir magnetically for 10 minutes until the mixture becomes transparent and uniform, which is phase B;
  • Phase A is quickly added to phase B and magnetically stirred for 10 minutes to obtain a nanocrystal suspension
  • the high-pressure homogenization method used for the sirolimus nanocrystals comprises the following steps:
  • the specific high pressure homogenization method may specifically include the following steps, wherein the specific amount of each raw material is shown in the following table:
  • the microfluidization method used in the sirolimus nanocrystals may specifically include the following steps, wherein the specific amount of each raw material is shown in the following table:
  • the anti-solvent method used in the sirolimus nanocrystals comprises the following steps:
  • phase B solution (2) Accurately weigh Tween 80 and aqueous phase solvent respectively, and stir magnetically until transparent and uniform to obtain phase B solution;
  • the anti-solvent method may specifically include the following steps, wherein the specific amount of each raw material is shown in the following table:
  • phase A (2) Accurately weigh sirolimus and methanol respectively, and stir magnetically for 10 minutes until the mixture becomes transparent and uniform, which is phase A.
  • phase B (2) Accurately weigh Tween 80 and water respectively, and stir magnetically for 10 minutes until the mixture becomes transparent and uniform, which is phase B.
  • Phase A is quickly added to phase B and magnetically stirred for 10 minutes to obtain a nanocrystal suspension.
  • the high-pressure homogenization method used for the sirolimus nanocrystals comprises the following steps:
  • the high pressure homogenization method may specifically include the following steps, wherein the specific amount of each raw material is shown in the following table:
  • the microfluidization method used for the sirolimus nanocrystals may specifically include the following steps, wherein the specific amount of each raw material is shown in the following table:
  • sirolimus nanocrystals (2) Freeze-drying to obtain sirolimus nanocrystals.
  • the high-pressure nano-microfluidization method used for the sirolimus nanocrystals may specifically include the following steps, wherein the specific amount of each raw material is shown in the following table:
  • sirolimus nanocrystals (2) Freeze-drying to obtain sirolimus nanocrystals.
  • the nanocrystal-liposome composite nanocarriers can be prepared by a high-pressure homogenization method or a microfluidization method, and the high-pressure homogenization method or the microfluidization method can be a two-step method or a one-step method.
  • the specific amount of each raw material is shown in the following table:
  • the two-step method of high pressure homogenization may include the following steps:
  • the particle size of the nanocrystal-liposome composite nanocarrier is 200-900 nm, and the mass ratio of lecithin: cholesterol is 40:1-1:2, more preferably 30:1-1:1.
  • the two-step method of microfluidization may include the following steps:
  • the particle size of the nanocrystal-liposome composite nanocarrier is 200-900 nm, and the mass ratio of lecithin: cholesterol is 40:1-1:2, more preferably 30:1-1:1.
  • the one-step method of high pressure homogenization may include the following steps:
  • the homogenization pressure is 1000-2000 bar, the homogenization times are 5-10 times, and the nanocrystal-liposome composite nanocarrier is obtained by freeze-drying.
  • the particle size of the nanocrystal-liposome composite nanocarrier is 200-900 nm, and the mass ratio of lecithin or soybean lecithin: cholesterol is 40:1-1:2, more preferably 30:1-1:1.
  • the one-step method of microfluidization may include the following steps:
  • the colostrum is placed in a microfluidizer for homogenization at a homogenization pressure of 1000-2000 bar and a homogenization frequency of 5-10 times, and then freeze-dried to obtain the nanocrystal-liposome composite nanocarrier.
  • the particle size of the nanocrystal-liposome composite nanocarrier is 200-900 nm, and the mass ratio of lecithin: cholesterol is 40:1-1:2, more preferably 30:1-1:1.
  • the phospholipids of the present application can be egg yolk phospholipids, soybean phospholipids, sunflower phospholipids, hydrogenated soybean phospholipids, hydrogenated egg yolk phospholipids, 1,2-diformyl-sn-glycero-3-phosphocholine, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, 1,2-dierucoyl-sn-glycero-3-phosphocholine, 1-dipalmitoyl-dioleoyl-sn-glycero-3-phosphocholine, 1,2-diformyl-sn-glycero-3-phospho-rac-glycero sodium salt, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-glycero sodium salt, 1,2-distearoyl-sn-
  • the nanocrystal-liposome composite nanocarrier prepared by the above-mentioned preparation method of the present invention has a core-shell structure, the inner core of the core-shell structure includes a plurality of particles loaded with drugs, the outer shell of the core-shell structure is the phospholipid bilayer, and the phospholipid bilayer includes an outer layer of hydrophilic groups and an inner layer of hydrophobic groups.
  • the specific structure of the core-shell structure is shown in Figure 1.
  • the nanocrystal-liposome composite nanocarrier freeze-dried powder is re-dissolved in pure water to form a coating liquid, which is atomized by high-frequency ultrasound, and the generated mist forms an aerosol with the air.
  • the aerosol is pushed out from the nozzle by nitrogen.
  • the balloon is connected to the support module by a clamp, and the balloon moves radially and axially at a uniform speed in the airflow.
  • the atomized particles carried in the airflow contact the balloon surface and are deposited on the balloon surface to form a liquid film. After drying, the desired coating structure of the drug-coated balloon is obtained.
  • nanocrystals are combined with liposomes to combine the advantages of the two drug carriers; the formed phospholipid bilayer increases the solubility of poorly soluble drugs, has a high drug loading capacity, good stability, and controllable drug release rate.
  • the drug-coated balloon coating liquid of the present invention uses an aqueous solvent.
  • the use of an aqueous phase to form the drug-coated balloon coating liquid can achieve the following technical effects: first, good firmness, second, less organic solvent residue, and third, it can be expanded to water-soluble and water-insoluble drugs.
  • the preparation method of the nanocrystal-liposome composite nanocarrier is the same as that of the nanocrystal-liposome composite nanocarrier, except that cholesterol is not added, thereby obtaining a nanocrystal-phospholipid complex, wherein the nanocrystal-phospholipid complex encapsulates a monolayer liposome.
  • the results of Example 1 and Comparative Example 1 are compared as follows:
  • Test example intracranial drug-coated balloon dose verification
  • MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
  • the required dosage of the test sample and positive control was calculated according to different groups, dissolved in pure DMSO, and then added with serum-containing culture medium to adjust the DMSO concentration to 0.1%, 10 ml per group.
  • the culture medium was adjusted into three subgroups: 100%, 50% and 25%.
  • Negative control solution add serum-containing medium to 0.01 ml pure DMSO to adjust the DMSO concentration to 0.1%. Prepare 10 ml of negative control solution.
  • Medium control solution take 10 ml of serum-containing medium as medium control solution.
  • L-929, C6, and HT22 cells were inoculated in 96-well plates and cultured for 24 hours. After a nearly confluent cell layer was formed, they were exposed to the corresponding test sample, control sample, and medium control solution. After incubating the cells for 24 hours, the supernatant was removed and MTT solution was added to each well. After incubating the cell culture plate for 2 hours, the MTT solution was removed and 100uL of isopropanol was added. The culture plate was placed in a microplate reader, and the absorbance was read at a wavelength of 570nm as the detection wavelength and 650nm as the reference wavelength. Cytotoxicity was detected by measuring cell viability, and cell viability depended on the percentage of OD570 (OD570 average) of each dosing group relative to the medium control.
  • the deviations of the average OD570 values of L929 cells on the left side (second column) and the right side (eleventh column) of the microplate in the A, B, and C formulas relative to the average values on both sides were 8.59%, 5.06%, and 10.27%, respectively.
  • the deviations of the average OD570 values of C6 cells on the left side (second column) and the right side (eleventh column) of the microplate in the A, B, and C formulas relative to the average values on both sides were 3.54%, 6.13%, and 5.65%, respectively, all less than 15%.
  • the cell viability of the negative control group of L929 cells in the A, B, and C formulas were 98.45%, 102.47%, and 97.37%, respectively; the cell viability of the negative control group of HT22 cells in the A, B, and C formulas were 100.44%, 98.96%, and 101.52%, respectively. According to the above results, this experiment is effective.
  • the cell viability of L929 cells in TA1 and TA2 groups at 25% was 77.64% and 64.08% respectively; the cell viability of C6 cells in TA1 and TA2 groups at 25% was 79.33% and 75.71% respectively.
  • the coating drug concentration should be within the range of 1-2 ⁇ g/ mm2 to achieve an inhibitory effect on fibroblasts, but has no effect on nerve cells.
  • formulas A, B, and C can inhibit fiber cells at less than or equal to 1.5 ⁇ g/mm 2 , but have no effect on nerve cells.
  • the inhibitory dose of sirolimus-coated balloon on intracranial vascular restenosis is less than or equal to 1.5 ⁇ g/mm 2 .
  • the experimental group had 24 animals implanted in the bilateral iliac arteries, and each group of animals received 6 test products (using the implementation Example 2B) of the preparation of nanocrystals of Example 1A-F, 12 rats were dissected immediately after surgery and 12 rats were dissected 7 days (7d) after surgery.
  • control group 1 (comparative example 1)
  • the implantation site was bilateral iliac arteries.
  • One control balloon catheter was placed in each group of animals, and two animals were dissected immediately after surgery and two animals were dissected 7 days after surgery.
  • Control group 2 (comparative example 2 - commercially available Magic touch sirolimus-coated balloon) was implanted in 4 animals at the bilateral iliac arteries. 2 animals were dissected immediately after surgery and 2 animals were dissected 7 days after surgery.
  • sodium heparin injection is given intravenously to monitor the coagulation time and ensure that the ACT is greater than 500 during the operation.
  • the electrocardiogram is monitored in real time, and the blood pressure, heart rate and other indicators are observed.
  • the drug-coated balloon dilatation is performed in accordance with the standard operating procedures of this laboratory.
  • After reaching the target position of the iliac artery use a pressure pump to expand the balloon with appropriate pressure so that the drug components are attached to the blood vessel wall. Record the distance between the balloon and the bifurcation of the blood vessel. After maintaining the pressure for 60 seconds, withdraw the balloon pressure, and then withdraw the balloon delivery system from the body.
  • control group 1 (2 animals) and control group 2 (2 animals) were dissected in situ, the skin layer was cut, the target blood vessels were exposed, and the target blood vessel tissue was cut 2-3 mm upstream and downstream of the surgical operation site. After anesthesia recovery, the experimental animals were transferred to the ICU for monitoring.
  • Example 2B The content of the spherical balloon in Example 2B, Comparative Example 1 and Comparative Example 2 was about 1.5 ⁇ g/mm 2 .
  • the nanocrystal-phospholipid complex was a single molecular layer, and the nanocrystal-liposome composite nanocarrier was a double molecular layer.
  • the experimental results shown in the following table were obtained:
  • the content of the nanocrystal-liposome composite nanocarrier (Example 2) in the tissue at 7 days is significantly higher than that of Comparative Example 1 (nanocrystal-phospholipid complex) and Comparative Example 2.
  • the average drug content per unit tissue of the nanocrystal-liposome composite nanocarrier at 7 days is more than 2 times higher than that of the comparative example. Therefore, the nanocrystal-liposome composite nanocarrier of the present invention has a better drug sustained release effect.
  • the present invention also systematically compares and contrasts various parameters of nanocrystals and liposomes under different prescriptions and processes, and verifies that their crystal forms are basically stable.
  • the specific experimental conditions and results are shown in the following table and text:
  • phase B solution (2) accurately weighing the surfactant and the aqueous phase solvent respectively, and stirring them magnetically until they are transparent and uniform to obtain a phase B solution;
  • the suspension is passed through a microfluidizer at a microfluidizer pressure of 1600-2000 bar and homogenized 30-40 times to obtain a nanocrystalline suspension.
  • the microfluidizer is used for homogenization 15-25 times at a microfluidizer pressure of 1200-1500 bar to obtain a nanocrystal-liposome composite nanocarrier.
  • the antisolvent method and the microfluidization method can be used to prepare carriers with particle sizes below 1000nm, which is in line with the typical nano-preparation range.
  • the carrier particle size prepared for HS15 is slightly larger than 1000nm, and the carrier prepared by the microfluidization method is below 1000nm, which is in line with the typical nano-preparation range.
  • the antisolvent method and the microfluidization method can be used to prepare carriers with the same crystal form as the raw material before and after sterilization, and they remain stable.
  • the carrier prepared by the antisolvent method is amorphous before sterilization and mixed crystal after sterilization. Therefore, EL35 and tyloxapol are most suitable for preparing sirolimus nanocrystal-liposome nanocarriers.
  • the present invention also systematically verifies the stability of the nanocrystal-liposome composite nanocarrier crystal form, confirming the stability of its crystal form, which provides a guarantee for the sustained release of sibirolimus. As shown in the following table:
  • the nanocrystal-liposome composite nanocarriers were placed under accelerated conditions (temperature 40°C ⁇ 2°C, relative humidity 75% ⁇ 5%) and long-term conditions (temperature 25°C ⁇ 2°C, relative humidity 60% ⁇ 5%) after commercial packaging of the balloons, and the content and crystal form were examined for 0 and 3 months respectively.
  • the experiment proved that the nanocrystal-liposome composite nanocarriers were stable for 3 months under accelerated conditions and long-term conditions.

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Abstract

一种药涂球囊涂覆液、涂层材料、药涂球囊、制备方法及应用。所述药涂球囊涂覆液，包括水相溶剂，所述涂覆液还包括多个由磷脂双分子层包裹药物形成的核壳结构，所述核壳结构分散于所述水相溶剂中，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团，所述多个装载有药物的颗粒包括包含有药物的多个纳米晶颗粒。将纳米晶与脂质体组合，结合两种药物载体优势；形成的磷脂双分子层增加了药涂球囊上的难溶性药物的溶解度，载药量高，药物载体稳定性好且药物晶型稳定，因而药物释放速率可控。

Description

一种药涂球囊涂覆液、涂层材料、药涂球囊、制备方法及应用 技术领域
本发明涉及介入治疗器械领域，具体涉及一种药涂球囊涂层材料、药涂球囊、药涂球囊涂覆液及其制备方法和应用。
背景技术
纳米晶可有效增大难溶性药物的溶剂度，且载药量高，理论可达100％。奥斯瓦尔德熟化导致其体系不稳定。纳米晶随保存时间延长，逐渐重新沉积为较大颗粒，导致颗粒粒径与物理性质在储存期间不稳定。由于表面能高，溶解速率快，随纳米晶表面侵蚀与空间稳定性逐渐流失，纳米晶在体内复杂环境中更加不稳定。同时，仅仅是由纳米晶制成的药涂球囊存在体内溶出、释放不可控的问题。脂质体可使药物释放受控。纳米载体生物相容性好，可快速进入组织，稳定性良好。因难溶性药物滞留磷脂双分子层，脂质体载药量低，限制了使用。纳米晶-脂质体复合物将两者优势相结合，载药量高，稳定性强，可控制药物释放速率。
发明内容
本发明实施例提供了一种药涂球囊涂覆液，所述涂覆液包括水相溶剂，所述涂覆液还包括多个由磷脂双分子层包裹药物形成的核壳结构，所述核壳结构分散于所述水相溶剂中，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团，所述多个装载有药物的颗粒包括包含有药物的多个纳米晶颗粒。
优选的是，所述核壳结构的粒径为200-900nm；
优选的是，所述纳米晶颗粒的粒径d50为150-900nm；其中纳米晶颗粒的制备过程采用表面活性剂；
优选的是，所述表面活性剂选自维生素E琥珀酸聚乙二醇酯、泊洛沙姆188、泊洛沙姆407、泰洛沙泊、多库酯钠、15-羟基硬脂酸聚乙二醇酯、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(60)氢化蓖麻油、聚氧乙烯(60)蓖麻油、聚氧乙烯(40)蓖麻油、聚氧乙烯(35)蓖麻油、聚氧乙烯(20)蓖麻油、聚氧乙烯(10)蓖麻油、聚乙二醇十六十八醇醚20、聚乙二醇十六十八醇醚12、单鲸蜡醇聚氧乙烯醚(Ceteth-10)、聚氧乙烯(10)月桂醚(Brij 56)、聚氧乙烯(20)月桂醚(Brij 58)、聚氧乙烯(23)月桂醚(Brij 35)、聚氧乙烯(2)月桂醚(Brij 52)、聚氧乙烯(25)油酸酯(Myrj 49)、聚氧乙烯(40)棕榈酸酯(Myrj 52)、十二烷基硫酸钠、吐温80、吐温60、吐温40、丙二醇单月桂酸酯、聚氧乙烯(20)月桂醇醚、单鲸蜡醇聚氧乙烯醚其中的一种或多种；
优选的是，所述药物包括西罗莫司(Sirolimus)、佐他莫司(Zotarolimus)和依维莫司(Everolimus)、塔克罗莫司(Tacrolimus)、利莫司(Temsirolimus)、普鲁克沙 (Pimecrolimus)、德芙利莫司(Deforolimus)、雷帕霉素酯(Ridaforolimus)；
优选的是，制备所述磷脂双分子层的原料包括磷脂和胆固醇类；
优选的是，所述磷脂包括蛋黄卵磷脂、大豆磷脂、氢化蛋黄卵磷脂、氢化大豆磷脂、脑磷脂、磷脂酰乙醇胺、二肉豆蔻酰卵磷脂(DMPC)、硬脂酰胺(SA)、向日葵磷脂、1，2-二甲酰基-sn-甘油-3-磷酸胆碱、1，2-二棕榈酰基-sn-甘油-3-磷酸胆碱、1，2-二硬酯酰基-sn-甘油-3-磷酸胆碱、1，2-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二芥酰基-sn-甘油-3-磷酸胆碱、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二甲酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二硬酯酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二甲酰基-sn-甘油-3-磷酸乙醇胺、1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺、1，2-二硬酯酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸-L-丝氨酸钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸单钠盐、N-(羰基-甲氧基聚乙二醇-5000)-1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺钠盐、N-(羰基-甲氧基聚乙二醇-2000)-1，2-二硬脂酰基-sn-甘油-4-磷酸乙醇胺钠盐、1，2-二油酰基-3-三甲基丙烷基氯化铵中的其中一种或多种；
所述胆固醇类包括胆固醇和DC胆固醇；
优选的是，所述的磷脂和胆固醇类的质量比为40∶1-1∶2，更优选30∶1-1∶1。
本发明还提供一种药涂球囊涂层材料，所述材料包括多个由磷脂双分子层包裹药物形成的核壳结构，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团，所述多个装载有药物的颗粒包括包含有药物的多个纳米晶颗粒。
优选的是，所述核壳结构的粒径为200-900nm；
优选的是，所述纳米晶颗粒的粒径d50为150-900nm；其中纳米晶颗粒的制备过程采用表面活性剂；
优选的是，所述表面活性剂选自维生素E琥珀酸聚乙二醇酯、泊洛沙姆188、泊洛沙姆407、泰洛沙泊、多库酯钠、15-羟基硬脂酸聚乙二醇酯、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(60)氢化蓖麻油、聚氧乙烯(60)蓖麻油、聚氧乙烯(40)蓖麻油、聚氧乙烯(35)蓖麻油、聚氧乙烯(20)蓖麻油、聚氧乙烯(10)蓖麻油、聚乙二醇十六十八醇醚20、聚乙二醇十六十八醇醚12、单鲸蜡醇聚氧乙烯醚(Ceteth-10)、聚氧乙烯(10)月桂醚(Brij 56)、聚氧乙烯(20)月桂醚(Brij 58)、聚氧乙烯(23)月桂醚(Brij 35)、聚氧乙烯(2)月桂醚(Brij 52)、聚氧乙烯(25)油酸酯(Myrj 49)、聚氧乙烯(40)棕榈酸酯(Myrj 52)、十二烷基硫酸钠、吐温80、吐温60、吐温40、丙二醇单月桂酸酯、聚氧乙烯(20)月桂醇醚、单鲸蜡醇聚氧乙烯醚其中的一种或多种；
优选的是，所述药物包括西罗莫司(Sirolimus)、佐他莫司(Zotarolimus)和依维莫司(Everolimus)、塔克罗莫司(Tacrolimus)、利莫司(Temsirolimus)、普鲁克沙 (Pimecrolimus)、德芙利莫司(Deforolimus)、雷帕霉素酯(Ridaforolimus)；
优选的是，制备所述磷脂双分子层的原料包括磷脂和胆固醇类；
优选的是，所述磷脂包括蛋黄卵磷脂、大豆磷脂、氢化蛋黄卵磷脂、氢化大豆磷脂、脑磷脂、磷脂酰乙醇胺、二肉豆蔻酰卵磷脂(DMPC)、硬脂酰胺(SA)、向日葵磷脂、1，2-二甲酰基-sn-甘油-3-磷酸胆碱、1，2-二棕榈酰基-sn-甘油-3-磷酸胆碱、1，2-二硬酯酰基-sn-甘油-3-磷酸胆碱、1，2-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二芥酰基-sn-甘油-3-磷酸胆碱、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二甲酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二硬酯酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二甲酰基-sn-甘油-3-磷酸乙醇胺、1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺、1，2-二硬酯酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸-L-丝氨酸钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸单钠盐、N-(羰基-甲氧基聚乙二醇-5000)-1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺钠盐、N-(羰基-甲氧基聚乙二醇-2000)-1，2-二硬脂酰基-sn-甘油-4-磷酸乙醇胺钠盐、1，2-二油酰基-3-三甲基丙烷基氯化铵中的其中一种或多种；所述胆固醇类包括胆固醇和DC胆固醇；
优选的是，所述的磷脂和胆固醇类的质量比为40∶1-1∶2，更优选30∶1-1∶1。
本发明还提供一种药涂球囊，所述药涂球囊表面涂覆有上述任意一种材料。
本发明还提供一种药涂球囊在治疗冠状动脉、外周血管或颅内动脉血管动脉粥样硬化、狭窄和/或再狭窄中的应用。
本发明还提供一种药涂球囊涂覆液的制备方法，所述方法包括如下步骤：
(1)制备包含有多个装载有药物的纳米晶颗粒；制备所述纳米晶颗粒的方法包括：反溶剂法、高压均质法或微射流法；
(2)分别准确称量胆固醇类、磷脂和水相溶剂，磁力搅拌，得到乳白色溶液；
(3)向所述乳白色溶液加入所述纳米晶颗粒，磁力搅拌并混合均匀以得到所述药涂球囊涂覆液；
其中，所述涂覆液包括水相溶剂，所述涂覆液还包括多个由磷脂双分子层包裹药物形成的核壳结构，所述核壳结构分散于所述水相溶剂中，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团。
优选的是，在步骤(3)之后还包括：(4)向上述溶液加入增稠剂，磁力搅拌并混合均匀即得药涂球囊涂覆液；
优选的是，所述增稠剂包括海藻酸钠；
优选的是，步骤(2)在磁力搅拌后还通过高压均质机或微射流机，均质5-10次，得到乳白色溶液；
优选的是，步骤S1中的药物包括西罗莫司，所述有机溶剂包括甲醇；
优选的是，西罗莫司与十二烷基硫酸钠的质量比为5∶1-1∶2；
优选的是，所述反溶剂法包括如下步骤：
S1、分别准确称量西罗莫司和有机溶剂，磁力搅拌至透明均匀，得到A相溶液；
S2、分别准确称量十二烷基硫酸钠和水相溶剂，磁力搅拌至透明均匀，得到B相溶液；
S3、将A相溶液快速加入B相溶液，磁力搅拌得到纳米晶悬浊液；
S4、向所述悬浊液加水并混合均匀，冻干即得所述纳米晶颗粒；
优选的是，所述纳米晶颗粒的粒径d50为150-900nm，西罗莫司与十二烷基硫酸钠的质量比为5∶1-1∶2；
优选的是，所述高压均质法包括如下步骤：
S1、分别准确称量西罗莫司、水相溶剂和十二烷基硫酸钠，磁力搅拌得到混悬液；
S2、将混悬液通过高压均质机，均质多次，即得纳米晶悬浊液；
S3、冻干即得西罗莫司纳米晶；
优选的是，所述纳米晶颗粒的粒径d50为150-900nm，均质压力为1000-2000bar，均质次数为5-10次，西罗莫司与十二烷基硫酸钠的质量比为5∶1-1∶2；
优选的是，所述微射流法包括如下步骤：
S1、分别准确称量西罗莫司、水相溶剂和十二烷基硫酸钠，磁力搅拌得到混悬液；
S2、将混悬液通过微射流机，均质多次，即得纳米晶悬浊液；
S3、冻干即得西罗莫司纳米晶；
优选的是，所述纳米晶颗粒的粒径d50为150-900nm，微射流压力为1000-2000bar，均质次数为5-10次，西罗莫司与十二烷基硫酸钠的质量比为5∶1-1∶2。
本发明还提供一种药涂球囊涂覆液，所述涂覆液包括水相溶剂，所述涂覆液还包括多个由磷脂双分子层包裹药物形成的核壳结构，所述核壳结构分散于所述水相溶剂中，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团，所述多个装载有药物的颗粒包括包含有药物的多个纳米晶颗粒，
其中，制备所述纳米晶颗粒的原料包括表面活性剂，所述表面活性剂选维生素E琥珀酸聚乙二醇酯、泊洛沙姆188、泊洛沙姆407、泰洛沙泊、多库酯钠、15-羟基硬脂酸聚乙二醇酯、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(60)氢化蓖麻油、聚氧乙烯(60)蓖麻油、聚氧乙烯(40)蓖麻油、聚氧乙烯(35)蓖麻油、聚氧乙烯(20)蓖麻油、聚氧乙烯(10)蓖麻油、聚乙二醇十六十八醇醚20、聚乙二醇十六十八醇醚12、单鲸蜡醇聚氧乙烯醚(Ceteth-10)、聚氧乙烯(10)月桂醚(Brij 56)、聚氧乙烯(20)月桂醚(Brij 58)、聚氧乙烯(23)月桂醚(Brij 35)、聚氧乙烯(2)月桂醚(Brij 52)、聚氧乙烯(25)油酸酯(Myrj 49)、聚氧乙烯(40)棕榈酸酯(Myrj 52)、十二烷基硫酸钠、吐温80、吐温60、吐温40、丙二醇单月桂酸酯、聚氧乙烯(20)月桂醇醚、单鲸蜡醇聚氧乙烯醚 其中的一种或多种。
优选的是，制备所述纳米晶颗粒的方法包括：反溶剂法、高压均质法或微射流法；
优选的是，所述反溶剂法包括如下步骤：
S1、分别准确称量西罗莫司和有机溶剂，磁力搅拌至透明均匀，得到A相溶液；
S2、分别准确称量表面活性剂和水相溶剂，磁力搅拌至透明均匀，得到B相溶液；
S3、将A相溶液快速加入B相溶液，磁力搅拌得到纳米晶悬浊液；
S4、向所述悬浊液加水并混合均匀，冻干即得所述纳米晶颗粒；
优选的是，所述纳米晶颗粒的粒径d50为150-900nm，西罗莫司与表面活性剂的质量比为5∶1-1∶2；
优选的是，所述高压均质法包括如下步骤：
S1、分别准确称量西罗莫司、水相溶剂和表面活性剂，磁力搅拌得到混悬液；
S2、将混悬液通过高压均质机，均质多次，即得纳米晶悬浊液；
S3、冻干即得西罗莫司纳米晶；
优选的是，所述纳米晶颗粒的粒径d50为150-900nm，均质压力为1000-2000bar，均质次数为5-10次，西罗莫司与表面活性剂的质量比为5∶1-1∶2；
优选的是，所述微射流法包括如下步骤：
S1、分别准确称量西罗莫司、水相溶剂和表面活性剂，磁力搅拌得到混悬液；
S2、将混悬液通过微射流机，均质多次，即得纳米晶悬浊液；
S3、冻干即得西罗莫司纳米晶；
优选的是，所述纳米晶颗粒的粒径d50为150-900nm，微射流压力为1000-2000bar，均质次数为5-10次，西罗莫司与表面活性剂的质量比为5∶1-1∶2。
本发明具有如下技术效果：将纳米晶与脂质体组合，结合两种药物载体优势；形成的磷脂双分子层增加了难溶性药物的溶解性，载药量高，稳定性好，药物释放速率可控。
本发明还提供上述药涂球囊在颅内动脉狭窄的应用，其中药物的剂量为小于等于3μg/mm2，更优选小于等于1.5μg/mm2。
本发明还提供一种西罗莫司药涂球囊在颅内动脉狭窄的应用，其中药物的剂量为小于等于3μg/mm2，更优选小于等于1.5μg/mm2。
本发明将纳米晶与脂质体组合，结合两种药物载体优势；形成的磷脂双分子层增加了药涂球囊上的难溶性药物的溶解度，载药量高，药物载体稳定性好且药物晶型稳定，因而药物释放速率可控。
附图说明
通过参考附图会更加清楚的理解本发明的特征和优点，附图是示意性的而不应理解为对本发明进行任何限制，在附图中：
图1显示为本发明中纳米晶-脂质体复合纳米载体的示意图。
图2显示为本发明中西罗莫司药涂球囊表面电镜图
图3显示为本发明中的纳米晶粒径分布图
图4显示为本发明中的纳米晶-脂质体复合纳米载体粒径分布图
图5显示为本发明中灭菌前后不同处方不同工艺制备得到的纳米晶-脂质体复合纳米载体的晶型图谱(不同处方：聚氧乙烯(35)蓖麻油：EL35；15-羟基硬脂酸聚乙二醇酯：HS15；泰诺沙泊；不同工艺：反溶剂法、微射流法)
图6显示为本发明中灭菌前后采用十二烷基硫酸钠：SDS作为表面活性剂不同工艺制备得到的纳米晶-脂质体复合纳米载体与灭菌后采用HS15制备的纳米晶-脂质体复合纳米载体的晶型图谱
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
在本发明的实施例中，首先制备出包含药物的纳米晶，其中，所述药物包括西罗莫司、佐他莫司或依维莫司。在以下的实施例中，以西罗莫司为例进行说明。所述纳米晶的制备方法包括：反溶剂法、高压均质法或微射流法。
实施例1A
其中，所述西罗莫司纳米晶采用的反溶剂法包括如下步骤：
(1)分别准确称量西罗莫司和有机溶剂，磁力搅拌至透明均匀，得到A相溶液；
(2)分别准确称量十二烷基硫酸钠和水相溶剂，磁力搅拌至透明均匀，得到B相溶液；
(3)将A相溶液快速加入B相溶液，磁力搅拌得到纳米晶悬浊液；
(4)向所述悬浊液加水并混合均匀，冻干即得所述纳米晶颗粒。
在具体的实施例中，反溶剂法可具体包括如下步骤，其中，各原料的具体用量如下表所示：
表1
(1)分别准确称量西罗莫司、甲醇，磁力搅拌10分钟，至透明均匀，为A相；
(2)分别准确称量十二烷基硫酸钠、水，磁力搅拌10分钟，至透明均匀，为B相；
(3)A相快速加入B相，磁力搅拌10分钟，为纳米晶悬浊液；
(4)加水150g，混合均匀，冻干即得西罗莫司纳米晶。
实测西罗莫司纳米晶粒径d50＝340nm。
实施例1B
其中，所述西罗莫司纳米晶采用的高压均质法包括如下步骤：
(1)分别准确称量西罗莫司、水相溶剂和十二烷基硫酸钠，磁力搅拌得到混悬液；
(2)将混悬液通过高压均质机，均质多次，即得纳米晶悬浊液；
(3)冻干即得西罗莫司纳米晶。
在具体的高压均质法可具体包括如下步骤，其中，各原料的具体用量如下表所示：
表2
(1)分别准确称量西罗莫司、水和十二烷基硫酸钠，磁力搅拌10分钟，为混悬液；
(2)将混悬液通过高压均质机，均质压力1300bar，均质8次，即得纳米晶悬浊液；
(3)冻干即得西罗莫司纳米晶。
实测西罗莫司纳米晶粒径d50＝512nm。
实施例1C
所述西罗莫司纳米晶采用的微射流法可具体包括如下步骤，其中，各原料的具体用量如下表所示：
表3
(1)分别准确称量西罗莫司、水和十二烷基硫酸钠，磁力搅拌10分钟，为混悬液。
(2)将混悬液通过微射流机，微射流压力1600bar，均质8次，即得纳米晶悬浊液。
(3)冻干即得西罗莫司纳米晶。
实测西罗莫司纳米晶粒径d50＝160nm。
实施例1D
其中，所述西罗莫司纳米晶采用的反溶剂法包括如下步骤：
(1)分别准确称量西罗莫司和有机溶剂，磁力搅拌至透明均匀，得到A相溶液；
(2)分别准确称量吐温80和水相溶剂，磁力搅拌至透明均匀，得到B相溶液；
(3)将A相溶液快速加入B相溶液，磁力搅拌得到纳米晶悬浊液；
(4)向所述悬浊液加水并混合均匀，冻干即得所述纳米晶颗粒。
在一个具体的实施例中，反溶剂法可具体包括如下步骤，其中，各原料的具体用量如下表所示：
表4
(1)分别准确称量西罗莫司、甲醇，磁力搅拌10分钟，至透明均匀，为A相。
(2)分别准确称量吐温80、水，磁力搅拌10分钟，至透明均匀，为B相。
(3)A相快速加入B相，磁力搅拌10分钟，为纳米晶悬浊液。
(4)加水150g，混合均匀，冻干即得西罗莫司纳米晶。
实测西罗莫司纳米晶粒径d50＝776nm。
实施例1E
其中，所述西罗莫司纳米晶采用的高压均质法包括如下步骤：
(1)分别准确称量西罗莫司、水相溶剂和泊洛沙姆188，磁力搅拌得到混悬液；
(2)将混悬液通过高压均质机，均质多次，即得纳米晶悬浊液；
(3)冻干即得西罗莫司纳米晶。
在一个具体的实施例中，高压均质法可具体包括如下步骤，其中，各原料的具体用量如下表所示：
表5
(1)分别准确称量西罗莫司、水和泊洛沙姆188，磁力搅拌10分钟，为混悬液。
(2)将混悬液通过高压均质机，微射流压力2000bar，均质10次，即得纳米晶悬浊液。
(3)冻干即得西罗莫司纳米晶。
实测西罗莫司纳米晶粒径d50＝225nm。
实施例1F
在一个具体的实施例中，所述西罗莫司纳米晶采用的微射流法可具体包括如下步骤，其中，各原料的具体用量如下表所示：
表6
(1)分别准确称量西罗莫司、水和泊洛沙姆407，磁力搅拌10分钟，为混悬液。
(2)将混悬液通过微射流机，微射流压力1800bar，均质2次，即得纳米晶悬浊液。
(3)冻干即得西罗莫司纳米晶。实测西罗莫司纳米晶粒径d50＝530nm。
实施例1G
在一个具体的实施例中，所述西罗莫司纳米晶采用的高压纳米微流化法可具体包括如下步骤，其中，各原料的具体用量如下表所示：
表7
(1)分别准确称量西罗莫司、水和聚氧乙烯(35)蓖麻油，磁力搅拌15分钟，旋转速度800rpm，为混悬液。
(2)将混悬液通过高压纳米微流化器进行均质，压力1800bar，均质35次，即得纳米晶悬浊液。
(3)冻干即得西罗莫司纳米晶。实测西罗莫司纳米晶粒径d50＝520nm。
实施例2
在实施例1A-G制备出包含药物的纳米晶颗粒后(实测西罗莫司纳米晶粒径d50＝150-900nm)，再将其制备成纳米晶-脂质体复合纳米载体，所述纳米晶-脂质体复合纳米载体为由磷脂双分子层包裹药物形成的核壳结构。可以采用高压均质法或微射流法制备纳米晶-脂质体复合纳米载体，所述高压均质法或微射流法均可以两步法或一步法。
其中，各原料的具体用量如下表所示：
表8-实施例2A
在另一个具体的实施例中，各原料的具体用量如下表所示：
表9-实施例2B
1、高压均质法的两步法可包括如下步骤：
(1)分别准确称量胆固醇类、卵磷脂、水，60℃磁力搅拌40分钟，后通过高压均质机，均质压力1000-2000bar，均质次数5-10次；
(2)准确称量并加入纳米晶，60℃磁力搅拌2h，混合均匀，即得纳米晶-脂质体复合纳米载体。
其中，纳米晶-脂质体复合纳米载体粒径200-900nm，卵磷脂∶胆固醇类的质量比为40∶1-1∶2，更优选30∶1-1∶1。
2、微射流法的两步法可包括如下步骤：
(1)分别准确称量胆固醇类、卵磷脂、水，60℃磁力搅拌40分钟，后通过微射流机，微射流压力1000-2000bar，均质次数5-10次；
(2)准确称量并加入纳米晶，60℃磁力搅拌2h，混合均匀，即得纳米晶-脂质体复合纳米载体。
其中，纳米晶-脂质体复合纳米载体粒径200-900nm，卵磷脂∶胆固醇类的质量比为40∶1-1∶2，更优选30∶1-1∶1。
3、高压均质法的一步法可包括如下步骤：
(1)分别准确称量胆固醇类、卵磷脂，60℃溶解均匀，为油相；
(2)分别准确称量纳米晶冻干粉、水，60℃磁力搅拌均匀，为水相；
(3)将水相加入油相，60℃混合20分钟得初乳；
(4)均质压力1000-2000bar，均质次数5-10次，冻干即得纳米晶-脂质体复合纳米载体。
其中，纳米晶-脂质体复合纳米载体粒径200-900nm，卵磷脂或大豆磷脂∶胆固醇类的质量比为40∶1-1∶2，更优选30∶1-1∶1。
4、微射流法的一步法可包括如下步骤：
(1)分别准确称量胆固醇类、卵磷脂，60℃溶解均匀，为油相；
(2)分别准确称量纳米晶冻干粉、水，60℃磁力搅拌均匀，为水相；
(3)将水相加入油相，60℃混合20分钟得初乳；
(4)将初乳放入微射流机进行均质，均质压力1000-2000bar，均质次数5-10次，冻干即得纳米晶-脂质体复合纳米载体。
其中，纳米晶-脂质体复合纳米载体粒径200-900nm，卵磷脂∶胆固醇类的质量比为40∶1-1∶2，更优选30∶1-1∶1。
本申请磷脂可以采用蛋黄磷脂、大豆磷脂、向日葵磷脂、氢化大豆磷脂、氢化蛋黄磷脂、1，2-二甲酰基-sn-甘油-3-磷酸胆碱、1，2-二棕榈酰基-sn-甘油-3-磷酸胆碱、1，2-二硬酯酰基-sn-甘油-3-磷酸胆碱、1，2-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二芥酰基-sn-甘油-3-磷酸胆碱、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二甲酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二硬酯酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二甲酰基-sn-甘油-3-磷酸乙醇胺、1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺、1，2-二硬酯酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸-L-丝氨酸钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸单钠盐、N-(羰基-甲氧基聚乙二醇-5000)-1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺钠盐、N-(羰基-甲氧基 聚乙二醇-2000)-1，2-二硬脂酰基-sn-甘油-4-磷酸乙醇胺钠盐、1，2-二油酰基-3-三甲基丙烷基氯化铵中的一种或多种进行替代。
采用本发明的上述制备方法制备纳米晶-脂质体复合纳米载体具有核壳结构，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团，如图1所示为所述核壳结构的具体结构。
将纳米晶-脂质体复合纳米载体冻干粉复溶于纯水，形成涂覆液，利用高频超声波雾化，产生的雾气与空气形成气溶胶。在稳定的压力下，气溶胶被氮气推动从喷头喷出。利用夹具与载支架模块相连，球囊在气流中匀速地径向和轴向运动，气流中携带的雾化颗粒与球囊表面接触，沉积于球囊表面上形成液态薄膜，经干燥处理得到所需药涂球囊的涂层结构。
在本发明中，将纳米晶与脂质体组合，结合两种药物载体优势；形成的磷脂双分子层增加了难溶性药物的溶解性，载药量高，稳定性好，药物释放速率可控。
尤其需要强调的是，本发明所述药涂球囊涂覆液采用水相溶剂。采用水相来形成药涂球囊涂覆液可取得如下的技术效果包括：其一是牢固度好，其二是有机溶剂残留少，第三可以扩展到水溶性和非水溶性药物。
对比例1
与纳米晶-脂质体复合纳米载体制备方法相同，仅不加胆固醇类，由此得到的是纳米晶-磷脂复合物，所述纳米晶-磷脂复合物包裹纳米晶的是单分子层的脂质体。实施例1与对比例1的结果对比如下：
表10
试验例-颅内药涂球囊剂量验证
本试验(MTT(3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴盐))目的是通过定量的方法评估不同药物浓度、不同涂层配方的西罗莫司药物涂层对L-929细胞、C6细胞、HT22细胞的细胞毒性。
供试品及阳性对照品根据不同组别，计算对应所需的药量，将其溶于纯DMSO后，加入含血清培养基调整DMSO浓度为0.1％，每组10ml。向每组溶液中根据体积比加入含血清培 养基，调整为100％、50％、25％三个亚组。
阴性对照品溶液：向0.01ml纯DMSO中加入含血清培养基，调整DMSO浓度为0.1％。制得阴性对照品溶液10ml。介质对照溶液：取10ml含血清培养基作为介质对照溶液。
将L-929、C6、HT22细胞接种于96孔板并培养24小时后，待形成近汇合的细胞层，然后暴露于相应供试品、对照品、介质对照溶液。孵育细胞24小时后，将上清液移除并向每孔加入MTT溶液。将细胞培养板孵育2小时后，移出MTT溶液加100uL异丙醇。培养板放于酶标仪，以570nm波长为检测波长，以650nm波长为参比波长读取吸光值。通过测量细胞活力检测细胞毒性，而细胞活力取决于各给药组OD570(OD570平均值)相对于介质对照的百分比。
试验一中L929及C6细胞微孔板左侧(第二列)与右侧(第十一列)的OD570平均值相对于两侧平均值的偏差分别为2.61％、4.14％，小于15％。阴性对照的细胞活力分别为：101.51％、95.30％。
试验二中L929细胞在A、B、C配方中微孔板左侧(第二列)与右侧(第十一列)的OD570平均值相对于两侧平均值的偏差分别为8.59％、5.06％、10.27％，C6细胞在A、B、C配方中微孔板左侧(第二列)与右侧(第十一列)的OD570平均值相对于两侧平均值的偏差分别为3.54％、6.13％、5.65％，均小于15％。L929细胞在A、B、C配方中阴性对照组的细胞活力分别为：98.45％、102.47％、97.37％；HT22细胞在A、B、C配方中阴性对照组的细胞活力分别为：100.44％、98.96％、101.52％。根据以上结果，本试验是有效的。
L929细胞在TA1、TA2组中25％时细胞活力分别为：77.64％、64.08％；C6细胞在TA1、TA2组中25％时细胞活力分别为：79.33％、75.71％。这说明了该涂层药物浓度应当在1-2μg/mm2范围内对纤维细胞可达到抑制作用，而对神经细胞无影响。
在两种细胞系：L929、HT22中对1.0、1.5、2.0μg/mm2浓度进行二次筛选，采用三种配方(A：西罗莫司+紫胶铵盐；B：纳米晶+卵磷脂+胆固醇(实施例2)；C：PLGA+卵磷脂+胆固醇)涂层药物对细胞进行毒性试验。
结果显示，三种配方在1.0-2μg/mm2时对L929细胞存在抑制作用，而配方A、B、C在1.0、1.5μg/mm2时对HT22无抑制作用，在2.0μg/mm2时对HT22细胞具有抑制作用。因此配方A、B、C在小于等于1.5μg/mm2时对纤维细胞可达到抑制作用，而对神经细胞无影响。
因此，可以判定，西罗莫司药涂球囊在颅内血管再狭窄的抑制剂量为小于等于1.5μg/mm2。
动物试验
1、试验动物分组
试验进行新西兰兔血管植入实验：
试验组植入24只动物，植入部位为双侧髂动脉，每组动物置入测试产品6个(采用实施 例1A-F的纳米晶制备的实施例2B)，术后即刻解剖12只，术后7天(7d)解剖12只。
对照组1(对比例1)植入4只动物，植入部位为双侧髂动脉，每组动物置入对照球囊导管1个，术后即刻解剖2只，术后7天解剖2只。
对照组2(对比例2-市售Magic touch西罗莫司药涂球囊)植入4只动物，植入部位为双侧髂动脉，术后即刻解剖2只，术后7天解剖2只。
2、手术步骤
在手术操作开始前通过静脉给予肝素钠注射液，监测凝血时间，确保手术过程中ACT大于500。手术过程中，实时监测心电图，观察血压、心率等指标。药涂球囊扩张术按照本试验室标准操作规范进行。使用导引导管和0.014导丝引导药涂球囊经颈动脉进入血管，到达髂动脉目标位置后，用压力泵以适当压力扩开球囊，使药物成分贴于血管壁上。记录球囊距血管分叉位置。保压60s后撤出球囊压力，然后将球囊输送系统从体内撤出。手术结束，从试验动物体内撤除一切器械、设备。
术后即刻原位解剖试验组(12只)、对照组1(2只)和对照组2(2只)，切开皮肤层，暴露目标血管，在手术操作部位上下游2-3mm处截取目的血管组织。麻醉复苏后，试验动物转移至ICU监护。
3、组织样本提取
兔子血管样品称重后，剪碎，按照组织∶50％甲醇＝1∶4(w∶v)的比例进行匀浆，部分匀浆液在-20℃以下冻留样贮存，用移液器精确移取20μL匀浆液于1.5mL的EP管中，加入180μL空白基质后混匀，备用。取100μL标准曲线样品和质控样品按照样品∶沉淀剂＝1∶3(v∶v)的比例加入沉淀剂，混匀，4℃下以12000rpm离心10分钟，移取适量上清液至新的96孔板中备用。
在实施例2B、对比例1和对比例2中的球囊含量均约为1.5μg/mm2。纳米晶-磷脂复合物为单分子层，纳米晶-脂质体复合纳米载体为双分子层。由此得到如下表所示的实验结果：
表11

由上表可知，纳米晶-脂质体复合纳米载体(实施例2)在7天组织内含量明显高于对比例1(纳米晶-磷脂复合物)以及对比例2，纳米晶-脂质体复合纳米载体在7天的单位组织含药平均值相对于对比例提高了2倍以上，因而本发明的纳米晶-脂质体复合纳米载体的药物缓释效果更好。
试验例-本发明的粒径和晶型的验证试验
本发明中还对不同处方及工艺下的纳米晶、脂质体的各项参数进行了系统比对和对照，验证了其晶型基本稳定，具体实验条件和结果见下表和文字：
纳米晶制备工艺：
反溶剂法：
(1)分别准确称量西罗莫司和甲醇，磁力搅拌至透明均匀，得到A相溶液；
(2)分别准确称量表面活性剂和水相溶剂，磁力搅拌至透明均匀，得到B相溶液；
(3)将A相溶液快速加入B相溶液，磁力搅拌得到纳米晶悬浊液；
微射流法：
(1)分别准确称量西罗莫司、表面活性剂和水，磁力搅拌5-15分钟，为混悬液。
(2)将混悬液通过微射流机，微射流压力1600-2000bar，均质30-40次，即得纳米晶悬浊液。
脂质体制备工艺：
(1)分别准确称量胆固醇类、磷脂与水，50-80℃溶解均匀后加入纳米晶悬浊液；
(2)通过微射流机，微射流压力1200-1500bar，均质15-25次，即得纳米晶-脂质体复合纳米载体。
由此表12可知，对于SDS、EL35、泰洛沙泊，采用反溶剂法、微射流法均可制备得到载体粒径均在1000nm以下，符合典型纳米制剂范围。对于HS15制备得到的载体粒径略大于1000nm，采用微射流法制备得到载体在1000nm以下，符合典型纳米制剂范围。对于HS15、EL35、泰洛沙泊采用反溶剂法、微射流法均可制备得到载体在灭菌前后晶型均与原料药相同，保持稳定。对于SDS，反溶剂法制备得到的载体在灭菌前为无定形，灭菌后为混晶。因此，EL35与泰洛沙泊等最合适与制备西罗莫司纳米晶-脂质体纳米载体。
以上试验例仅作为制备工艺技术可行性展示，不代表为限定范围。以上实施例中西罗莫司∶表面活性剂为1.5∶1-300∶1范围内均可得到质量指标类似的产物。西罗莫司与磷脂的比例，磷脂与胆固醇的比例等处方信息也同样可以改变而制备得到质量指标类似的产物。
本发明还对纳米晶-脂质体复合纳米载体晶型的稳定性进行了系统验证，确证了其晶型的稳定，这为西本罗莫司的持续释放提供了保证。如下表所示：
表13
按照中国药典(2020版)中″原料药物与制剂稳定性指导原则″，将纳米晶-脂质体复合纳米载体按照球囊商业包装后分别置于加速条件(温度40℃±2℃、相对湿度75％±5％)、长期条件(温度25℃±2℃、相对湿度60％±5％)下，分别在0，3月考察含量、晶型。试验证明纳米晶-脂质体复合纳米载体在加速条件、长期条件下3个月稳定。

Claims (11)

  1. 一种药涂球囊涂覆液，其特征在于，所述涂覆液包括水相溶剂，所述涂覆液还包括多个由磷脂双分子层包裹药物形成的核壳结构，所述核壳结构分散于所述水相溶剂中，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团，所述多个装载有药物的颗粒包括包含有药物的多个纳米晶颗粒。
  2. 根据权利要求1所述的涂覆液，其特征在于，所述核壳结构的粒径为200-900nm；
    优选的是，所述纳米晶颗粒的粒径d50为150-900nm；其中纳米晶颗粒的制备过程采用表面活性剂；
    优选的是，所述表面活性剂选自维生素E琥珀酸聚乙二醇酯、泊洛沙姆188、泊洛沙姆407、泰洛沙泊、多库酯钠、15-羟基硬脂酸聚乙二醇酯、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(60)氢化蓖麻油、聚氧乙烯(60)蓖麻油、聚氧乙烯(40)蓖麻油、聚氧乙烯(35)蓖麻油、聚氧乙烯(20)蓖麻油、聚氧乙烯(10)蓖麻油、聚乙二醇十六十八醇醚20、聚乙二醇十六十八醇醚12、单鲸蜡醇聚氧乙烯醚(Ceteth-10)、聚氧乙烯(10)月桂醚(Brij 56)、聚氧乙烯(20)月桂醚(Brij 58)、聚氧乙烯(23)月桂醚(Brij 35)、聚氧乙烯(2)月桂醚(Brij 52)、聚氧乙烯(25)油酸酯(Myrj 49)、聚氧乙烯(40)棕榈酸酯(Myrj 52)、十二烷基硫酸钠、吐温80、吐温60、吐温40、丙二醇单月桂酸酯、聚氧乙烯(20)月桂醇醚、单鲸蜡醇聚氧乙烯醚其中的一种或多种；
    优选的是，所述药物包括西罗莫司(Sirolimus)、佐他莫司(Zotarolimus)和依维莫司(Everolimus)、塔克罗莫司(Tacrolimus)、利莫司(Temsirolimus)、普鲁克沙(Pimecrolimus)、德芙利莫司(Deforolimus)、雷帕霉素酯(Ridaforolimus)；
    优选的是，制备所述磷脂双分子层的原料包括磷脂和胆固醇类；
    优选的是，所述磷脂包括蛋黄卵磷脂、大豆磷脂、氢化蛋黄卵磷脂、氢化大豆磷脂、脑磷脂、磷脂酰乙醇胺、二肉豆蔻酰卵磷脂(DMPC)、硬脂酰胺(SA)、向日葵磷脂、1，2-二甲酰基-sn-甘油-3-磷酸胆碱、1，2-二棕榈酰基-sn-甘油-3-磷酸胆碱、1，2-二硬酯酰基-sn-甘油-3-磷酸胆碱、1，2-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二芥酰基-sn-甘油-3-磷酸胆碱、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二甲酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二硬酯酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二甲酰基-sn-甘油-3-磷酸乙醇胺、1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺、1，2-二硬酯酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸-L-丝氨酸钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸单钠盐、N-(羰基-甲氧基聚乙二醇-5000)-1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺钠盐、N-(羰基-甲氧基聚乙二醇-2000)-1，2-二硬脂酰基-sn-甘油-4-磷酸乙醇胺钠盐、1，2-二油酰基-3-三甲基丙烷基氯化铵中的其中一种或多种；
    所述胆固醇类包括胆固醇和DC胆固醇；
    优选的是，所述的磷脂和胆固醇类的质量比为40∶1-1∶2，更优选30∶1-1∶1。
  3. 一种药涂球囊涂层材料，其特征在于，所述材料包括多个由磷脂双分子层包裹药物形成的核壳结构，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团，所述多个装载有药物的颗粒包括包含有药物的多个纳米晶颗粒。
  4. 根据权利要求3所述的材料，其特征在于，所述核壳结构的粒径为200-900nm；
    优选的是，所述纳米晶颗粒的粒径d50为150-900nm；其中纳米晶颗粒的制备过程采用表面活性剂；
    优选的是，所述表面活性剂选自维生素E琥珀酸聚乙二醇酯、泊洛沙姆188、泊洛沙姆407、泰洛沙泊、多库酯钠、15-羟基硬脂酸聚乙二醇酯、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(60)氢化蓖麻油、聚氧乙烯(60)蓖麻油、聚氧乙烯(40)蓖麻油、聚氧乙烯(35)蓖麻油、聚氧乙烯(20)蓖麻油、聚氧乙烯(10)蓖麻油、聚乙二醇十六十八醇醚20、聚乙二醇十六十八醇醚12、单鲸蜡醇聚氧乙烯醚(Ceteth-10)、聚氧乙烯(10)月桂醚(Brij 56)、聚氧乙烯(20)月桂醚(Brij 58)、聚氧乙烯(23)月桂醚(Brij 35)、聚氧乙烯(2)月桂醚(Brij 52)、聚氧乙烯(25)油酸酯(Myrj 49)、聚氧乙烯(40)棕榈酸酯(Myrj 52)、十二烷基硫酸钠、吐温80、吐温60、吐温40、丙二醇单月桂酸酯、聚氧乙烯(20)月桂醇醚、单鲸蜡醇聚氧乙烯醚其中的一种或多种；
    优选的是，所述药物包括西罗莫司(Sirolimus)、佐他莫司(Zotarolimus)和依维莫司(Everolimus)、塔克罗莫司(Tacrolimus)、利莫司(Temsirolimus)、普鲁克沙(Pimecrolimus)、德芙利莫司(Deforolimus)、雷帕霉素酯(Ridaforolimus)；
    优选的是，制备所述磷脂双分子层的原料包括磷脂和胆固醇类；
    优选的是，所述磷脂包括蛋黄卵磷脂、大豆磷脂、氢化蛋黄卵磷脂、氢化大豆磷脂、脑磷脂、磷脂酰乙醇胺、二肉豆蔻酰卵磷脂(DMPC)、硬脂酰胺(SA)、向日葵磷脂、1，2-二甲酰基-sn-甘油-3-磷酸胆碱、1，2-二棕榈酰基-sn-甘油-3-磷酸胆碱、1，2-二硬酯酰基-sn-甘油-3-磷酸胆碱、1，2-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二芥酰基-sn-甘油-3-磷酸胆碱、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸胆碱、1，2-二甲酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二硬酯酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1-二棕榈酰基-二油酰基-sn-甘油-3-磷酸-rac-甘油钠盐、1，2-二甲酰基-sn-甘油-3-磷酸乙醇胺、1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺、1，2-二硬酯酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸乙醇胺、1，2-二油酰基-sn-甘油-3-磷酸-L-丝氨酸钠盐、1，2-二棕榈酰基-sn-甘油-3-磷酸单钠盐、N-(羰基-甲氧基聚乙二醇-5000)-1，2-二棕榈酰基-sn-甘油-3-磷酸乙醇胺钠盐、N-(羰基-甲氧基聚乙二醇-2000)-1，2-二硬脂酰基-sn-甘油-4-磷酸乙醇胺钠盐、1，2-二油酰基-3-三甲基丙烷基氯化铵中的其中一种或多种；
    所述胆固醇类包括胆固醇和DC胆固醇；
    优选的是，所述的磷脂和胆固醇类的质量比为40∶1-1∶2，更优选30∶1-1∶1。。
  5. 一种药涂球囊，其特征在于所述药涂球囊表面涂覆有权利要求1-2任意一项所述的涂敷液或权利要求3-4任意一项所述的材料。
  6. 一种如权利要求5所述的药涂球囊在治疗冠状动脉、外周血管或颅内动脉血管的动脉粥样硬化、狭窄和/或再狭窄中的应用。
  7. 一种药涂球囊涂覆液的制备方法，其特征在于，所述方法包括如下步骤：
    (1)制备包含有多个装载有药物的纳米晶颗粒；制备所述纳米晶颗粒的方法包括：反溶剂法、高压均质法或微射流法；
    (2)分别准确称量胆固醇类、磷脂和水相溶剂，磁力搅拌，得到乳白色溶液；
    (3)向所述乳白色溶液加入所述纳米晶颗粒，磁力搅拌并混合均匀以得到所述药涂球囊涂覆液；
    其中，所述涂覆液包括水相溶剂，所述涂覆液还包括多个由磷脂双分子层包裹药物形成的核壳结构，所述核壳结构分散于所述水相溶剂中，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团。
  8. 根据权利要求7所述的方法，其特征在于，在步骤(3)之后还包括：(4)向上述溶液加入增稠剂，磁力搅拌并混合均匀即得药涂球囊涂覆液；
    优选的是，所述增稠剂包括海藻酸钠；
    优选的是，步骤(2)在磁力搅拌后还通过高压均质机或微射流机，均质5-10次，得到乳白色溶液；
    优选的是，步骤S1中的药物包括西罗莫司，所述有机溶剂包括甲醇；
    优选的是，西罗莫司与十二烷基硫酸钠的质量比为5∶1-1∶2；
    优选的是，所述反溶剂法包括如下步骤：
    S1、分别准确称量西罗莫司和有机溶剂，磁力搅拌至透明均匀，得到A相溶液；
    S2、分别准确称量十二烷基硫酸钠和水相溶剂，磁力搅拌至透明均匀，得到B相溶液；
    S3、将A相溶液快速加入B相溶液，磁力搅拌得到纳米晶悬浊液；
    S4、向所述悬浊液加水并混合均匀，冻干即得所述纳米晶颗粒；
    优选的是，所述纳米晶颗粒的粒径d50为150-900nm，西罗莫司与十二烷基硫酸钠的质量比为5∶1-1∶2；
    优选的是，所述高压均质法包括如下步骤：
    S1、分别准确称量西罗莫司、水相溶剂和十二烷基硫酸钠，磁力搅拌得到混悬液；
    S2、将混悬液通过高压均质机，均质多次，即得纳米晶悬浊液；
    S3、冻干即得西罗莫司纳米晶；
    优选的是，所述纳米晶颗粒的粒径d50为150-900nm，均质压力为1000-2000bar，均 质次数为5-10次，西罗莫司与十二烷基硫酸钠的质量比为5∶1-1∶2；
    优选的是，所述微射流法包括如下步骤：
    S1、分别准确称量西罗莫司、水相溶剂和十二烷基硫酸钠，磁力搅拌得到混悬液；
    S2、将混悬液通过微射流机，均质多次，即得纳米晶悬浊液；
    S3、冻干即得西罗莫司纳米晶；
    优选的是，所述纳米晶颗粒的粒径d50为150-900nm，微射流压力为1000-2000bar，均质次数为5-10次，西罗莫司与十二烷基硫酸钠的质量比为5∶1-1∶2。
  9. 一种药涂球囊涂覆液，其特征在于，所述涂覆液包括水相溶剂，所述涂覆液还包括多个由磷脂双分子层包裹药物形成的核壳结构，所述核壳结构分散于所述水相溶剂中，其中，所述核壳结构的内核包括多个装载有药物的颗粒，所述核壳结构的外壳为所述磷脂双分子层，所述磷脂双分子层包括外层的亲水基团和内层的疏水基团，所述多个装载有药物的颗粒包括包含有药物的多个纳米晶颗粒，
    其中，制备所述纳米晶颗粒的原料包括表面活性剂，所述表面活性剂选自维生素E琥珀酸聚乙二醇酯、泊洛沙姆188、泊洛沙姆407、泰洛沙泊、多库酯钠、15-羟基硬脂酸聚乙二醇酯、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(60)氢化蓖麻油、聚氧乙烯(60)蓖麻油、聚氧乙烯(40)蓖麻油、聚氧乙烯(35)蓖麻油、聚氧乙烯(20)蓖麻油、聚氧乙烯(10)蓖麻油、聚乙二醇十六十八醇醚20、聚乙二醇十六十八醇醚12、单鲸蜡醇聚氧乙烯醚(Ceteth-10)、聚氧乙烯(10)月桂醚(Brij 56)、聚氧乙烯(20)月桂醚(Brij 58)、聚氧乙烯(23)月桂醚(Brij 35)、聚氧乙烯(2)月桂醚(Brij 52)、聚氧乙烯(25)油酸酯(Myrj 49)、聚氧乙烯(40)棕榈酸酯(Myrj 52)、十二烷基硫酸钠、吐温80、吐温60、吐温40、丙二醇单月桂酸酯、聚氧乙烯(20)月桂醇醚、单鲸蜡醇聚氧乙烯醚其中的一种或多种。
  10. 根据权利要求9所述的涂覆液，其特征在于，制备所述纳米晶颗粒的方法包括：反溶剂法、高压均质法或微射流法；
    优选的是，所述反溶剂法包括如下步骤：
    S1、分别准确称量西罗莫司和有机溶剂，磁力搅拌至透明均匀，得到A相溶液；
    S2、分别准确称量表面活性剂和水相溶剂，磁力搅拌至透明均匀，得到B相溶液；
    S3、将A相溶液快速加入B相溶液，磁力搅拌得到纳米晶悬浊液；
    S4、向所述悬浊液加水并混合均匀，冻干即得所述纳米晶颗粒；
    优选的是，所述纳米晶颗粒的粒径d50为150-900nm，西罗莫司与表面活性剂的质量比为5∶1-1∶2；
    优选的是，所述高压均质法包括如下步骤：
    S1、分别准确称量西罗莫司、水相溶剂和表面活性剂，磁力搅拌得到混悬液；
    S2、将混悬液通过高压均质机，均质多次，即得纳米晶悬浊液；
    S3、冻干即得西罗莫司纳米晶；
    优选的是，所述纳米晶颗粒的粒径d50为150-900nm，均质压力为1000-2000bar，均质次数为5-10次，西罗莫司与表面活性剂的质量比为5∶1-1∶2；
    优选的是，所述微射流法包括如下步骤：
    S1、分别准确称量西罗莫司、水相溶剂和表面活性剂，磁力搅拌得到混悬液；
    S2、将混悬液通过微射流机，均质多次，即得纳米晶悬浊液；
    S3、冻干即得西罗莫司纳米晶；
    优选的是，所述纳米晶颗粒的粒径d50为150-900nm，微射流压力为1000-2000bar，均质次数为5-10次，西罗莫司与表面活性剂的质量比为5∶1-1∶2。
  11. 西罗莫司药涂球囊在颅内动脉狭窄的应用，其中药物的剂量为小于等于3μg/mm2，更优选小于等于1.5μg/mm2。
PCT/CN2023/130996 2022-11-11 2023-11-10 一种药涂球囊涂覆液、涂层材料、药涂球囊、制备方法及应用 WO2024099433A1 (zh)

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