Coating solution for drug-coated balloons, coating material, drug-coated balloons, preparation method and use

Abstract

The present invention relates to a coating material for drug-coated balloons, drug-coated balloons, and a coating solution for drug-coated balloons, as well as their preparation and application. The coating solution comprises an aqueous solvent and a plurality of core-shell structures dispersed in the aqueous solvent, each of which comprises a lipid bilayer coated with a drug. The core of the core-shell structure contains a plurality of drug-loaded particles, and the shell of the core-shell structure is a lipid bilayer with an outer hydrophilic group and an inner hydrophobic group. The drug-loaded particles comprise a plurality of drug-loaded nanocrystalline particles. The combination of nanocrystals and liposomes combines the advantages of these two types of drug carriers. The resulting lipid bilayer improves the solubility of poorly soluble drugs in drug-coated balloons, resulting in a high drug loading capacity, high drug carrier stability, and stable drug crystal form, allowing for controllable drug release rates.

Description

[Technical Field]

[0001] The present invention relates to the field of interventional treatment devices, and more particularly to a coating material for a drug-coated balloon, a drug-coated balloon, a coating solution for a drug-coated balloon, and a preparation method and application thereof. [Background technology]

[0002] Nanocrystals can effectively improve the solubility of poorly soluble drugs, achieving high drug loadings, theoretically reaching 100%. Ostwald ripening causes system instability. Nanocrystals gradually redeposit into larger particles with prolonged storage, causing the particle size and physical properties to become unstable during storage. Due to their high surface energy and rapid dissolution rate, nanocrystals become less stable in the complex in vivo environment as their surface erodes and their spatial stability gradually decreases. Furthermore, drug-coated balloons composed solely of nanocrystals suffer from uncontrollable dissolution and release in vivo. Liposomes enable controlled drug release. Nanocarriers are highly biocompatible, can rapidly penetrate tissues, and have good stability. Because poorly soluble drugs are retained in the lipid bilayer, liposomes have low drug loadings, limiting their applications. Nanocrystal-liposome complexes combine the advantages of both, achieving high drug loadings, high stability, and controllable drug release rates. Summary of the Invention

[0003] An embodiment of the present invention provides a coating solution for a drug-coated balloon, the coating solution comprising an aqueous solvent and a plurality of core-shell structures dispersed in the aqueous solvent, the core of the core-shell structure comprising a plurality of drug-loaded particles, the shell of the core-shell structure being the lipid bilayer comprising an outer layer of hydrophilic groups and an inner layer of hydrophobic groups, and the drug-loaded particles comprising a plurality of nanocrystalline particles containing the drug.

[0004] Preferably, the particle diameter of the core-shell structure is 200-900 nm, and preferably, the particle diameter d50 of the nanocrystalline particles is 150-900 nm, wherein a surfactant is used in the manufacturing process of the nanocrystalline particles, and preferably, the surfactant is tocophersolan, poloxamer 188, poloxamer 407, tyloxapol, docusate sodium, polyethylene glycol (15)-hydroxystearic acid, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 60, polyoxyethylene castor oil 40, polyoxyethylene 35 castor oil, polyoxyethylene castor oil 20, polyoxyethylene castor oil 10, polyethylene glycol cetostearyl ether 20 (KOLLIPHOR® CS 20), polyethylene glycol cetostearyl ether 12 (KOLLIPHOR® CS 12), Polyoxyethylene cetyl ether (Ceteth-10), Polyoxyethylene (10) lauryl ether (Brij56), Polyoxyethylene (20) lauryl ether (Brij58), Polyoxyethylene (23) lauryl ether (Brij35), Polyoxyethylene (2) lauryl ether (Brij52), Polyoxyethylene (25) oleic acid ester (Myrj49), Polyoxyethylene (40) palmitic acid ester (Myrj52), Sodium lauryl sulfate, Tween 80, Tween 60, Tween 40, propylene glycol monolaurate, polyoxyethylene (20) lauryl ether, and polyoxyethylene cetyl ether, and preferably, the drug includes sirolimus, zotarolimus, everolimus, tacrolimus, temsirolimus, pimecrolimus, deforolimus, and ridaforolimus, and preferably, the raw materials for producing the lipid bilayer include phospholipids and cholesterols, and preferably, the phospholipids include egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, cephalin,Phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), stearylamine (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-dierucoyl-sn-glycero-3-phosphocholine, 1-dipalmitoyl-dioleoyl-sn-glycero-3-phosphocholine, 1 ,2-Diformyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1-dipalmitoyl-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-diformyl N-(carbonyl-methoxypolyethylene glycol)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine sodium salt, 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt, N-(carbonyl-methoxypolyethylene glycol-5000)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine The lipid composition contains one or more of n-glycero-3-phosphoethanolamine sodium salt, N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-4-phosphoethanolamine sodium salt, and 1,2-dioleyl-3-trimethylpropaneammonium chloride, and the cholesterols include cholesterol and DC cholesterol. Preferably, the mass ratio of the phospholipid to the cholesterols is 40:1 to 1:2, and more preferably 30:1 to 1:1.

[0005] The present invention further provides a coating material for a drug-coated balloon, the material comprising a plurality of core-shell structures formed by a lipid bilayer coated with a drug, wherein the core of the core-shell structure comprises a plurality of drug-loaded particles, the shell of the core-shell structure is the lipid bilayer comprising an outer layer of hydrophilic groups and an inner layer of hydrophobic groups, and the drug-loaded particles comprise a plurality of nanocrystalline particles containing the drug.

[0006] Preferably, the particle diameter of the core-shell structure is 200-900 nm, and preferably, the particle diameter d50 of the nanocrystalline particles is 150-900 nm, wherein a surfactant is used in the manufacturing process of the nanocrystalline particles, and preferably, the surfactant is tocophersolan, poloxamer 188, poloxamer 407, tyloxapol, docusate sodium, polyethylene glycol (15)-hydroxystearic acid, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 60, polyoxyethylene castor oil 40, polyoxyethylene 35 castor oil, polyoxyethylene castor oil 20, polyoxyethylene castor oil 10, KOLLIPHOR CS 20, polyethylene glycol cetostearyl ether 12, polyoxyethylene cetyl ether (Ceteth-10), polyoxyethylene (10) lauryl ether (Brij56), polyoxyethylene (20) lauryl ether (Brij58), polyoxyethylene (23) lauryl ether (Brij35), polyoxyethylene (2) lauryl ether (Brij52), polyoxyethylene (25) oleic acid ester (Myrj49), polyoxyethylene (40) palmitic acid ester (Myrj52), sodium lauryl sulfate, Tween 80, Tween 60, Tween 40, propylene glycol monolaurate, polyoxyethylene (20) lauryl ether, and polyoxyethylene monocetyl ether, and preferably, the drug includes sirolimus, zotarolimus, everolimus, tacrolimus, temsirolimus, pimecrolimus, deforolimus, and ridaforolimus, and preferably, the raw materials for preparing the lipid bilayer include phospholipids and cholesterols, and preferably, the phospholipids include egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, cephalin, phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), stearylamine (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-dierucoyl-sn-glycero-3-phosphocholine, 1-dipalmitoyl-dioleoyl-sn-glycero-3-phosphocholine, 1,2-diformyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium Salt, 1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-Distearoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-Dioleoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1-Dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-Diformyl-sn-glycero-3-phosphoethanolamine, 1,2 -Dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine sodium salt, 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt, N-(carbonyl-methoxypolyethylene glycol-5000)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine The phospholipid composition contains one or more of ethanolamine sodium salt, N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-4-phosphoethanolamine sodium salt, and 1,2-dioleyl-3-trimethylpropane ammonium chloride, and the cholesterols include cholesterol and DC cholesterol, and the mass ratio of the phospholipid to the cholesterols is preferably 40:1 to 1:2, and more preferably 30:1 to 1:1.

[0007] The present invention further provides a drug-coated balloon, the surface of which is coated with any one of the materials described above.

[0008] The present invention further provides for the use of the drug coated balloon in the treatment of atherosclerosis, stenosis and / or restenosis of coronary, peripheral or intracranial arterial vessels.

[0009] The present invention further provides a method for preparing a coating solution for a drug-coated balloon, comprising: step (1) of preparing a plurality of drug-loaded nanocrystalline particles, the method comprising antisolvent, high-pressure homogenization, or microfluidics; step (2) of accurately weighing cholesterols, phospholipids, and an aqueous solvent, and magnetically stirring the mixture to obtain a milky white solution; and step (3) of adding the nanocrystalline particles to the milky white solution and uniformly mixing the mixture with magnetic stirring to obtain a coating solution for a drug-coated balloon, the coating solution comprising an aqueous solvent and a plurality of core-shell structures dispersed in the aqueous solvent, the core of the core-shell structure comprising a plurality of drug-loaded particles, and the shell of the core-shell structure being the lipid bilayer comprising an outer layer of hydrophilic groups and an inner layer of hydrophobic groups.

[0010] Preferably, after step (3), the method further comprises step (4) of adding a thickener to the solution and uniformly mixing it by magnetic stirring to obtain a coating solution for drug-coated balloons, preferably the thickener comprises sodium alginate, preferably in step (2), after magnetic stirring, the solution is further homogenized 5 to 10 times by a high-pressure homogenizer or a microfluidic device to obtain a milky white solution, preferably the drug in step (1) comprises sirolimus, and the organic solvent comprises methanol, preferably a mixture of sirolimus and sodium lauryl sulfate. The ratio of the amounts is 5:1 to 1:2, and preferably, the anti-solvent method includes step S1 of accurately weighing sirolimus and an organic solvent, respectively, and magnetically stirring them until they are transparent and uniform, thereby obtaining an A-phase solution; step S2 of accurately weighing sodium lauryl sulfate and an aqueous phase solvent, respectively, and magnetically stirring them until they are transparent and uniform, thereby obtaining a B-phase solution; step S3 of quickly adding the A-phase solution to the B-phase solution, and magnetically stirring them to obtain a nanocrystalline suspension; and step S4 of adding water to the suspension, mixing them uniformly, and freeze-drying to obtain the nanocrystalline particles, and preferably, the nanocrystalline particles have a particle size d5. Preferably, the high-pressure homogenization method comprises the steps of: Step S1: accurately weighing sirolimus, an aqueous solvent, and sodium lauryl sulfate, and magnetically stirring them to obtain a suspension; Step S2: homogenizing the suspension multiple times with a high-pressure homogenizer to obtain a nanocrystalline suspension; and Step S3: freeze-drying the suspension to obtain sirolimus nanocrystals; and preferably, the particle size d50 of the nanocrystalline particles is 150 to 900 nm, the homogenization pressure is 1000 to 2000 bar, and the homogenization the number of times is 5 to 10, and the mass ratio of sirolimus to sodium lauryl sulfate is 5:1 to 1:2; preferably, the microfluidic method includes a step S1 of accurately weighing sirolimus, an aqueous solvent, and sodium lauryl sulfate, and magnetically stirring them to obtain a suspension; a step S2 of homogenizing the suspension multiple times using a microfluidic device to obtain a nanocrystalline suspension; and a step S3 of freeze-drying to obtain sirolimus nanocrystals; preferably, the particle size d50 of the nanocrystalline particles is 150 to 900 nm, and the microfluidic pressure is 1000 to 2000 bar;The number of homogenization times is 5 to 10, and the mass ratio of sirolimus to sodium lauryl sulfate is 5:1 to 1:2.

[0011] The present invention provides a coating solution for a drug-coated balloon, the coating solution comprising an aqueous solvent and a plurality of core-shell structures, each of which comprises a lipid bilayer coated with a drug and is dispersed in the aqueous solvent, wherein the core of the core-shell structure comprises a plurality of particles loaded with a drug, and the shell of the core-shell structure is the lipid bilayer comprising an outer layer of hydrophilic groups and an inner layer of hydrophobic groups, and the plurality of drug-loaded particles comprise a plurality of nanocrystalline particles containing the drug, wherein raw materials for producing the nanocrystalline particles include tocophersolan, poloxamer 188, poloxamer 407, tyloxapol, docusate sodium, polyethylene glycol (15)-hydroxystearic acid, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 60, polyoxyethylene castor oil 40, polyoxyethylene 35 castor oil, polyoxyethylene castor oil 20, polyoxyethylene castor oil 10, and KOLLIPHOR CS.

[0013] Further provided is a coating solution for a drug-coated balloon, comprising a surfactant selected from the group consisting of polyethylene glycol cetostearyl ether-12, polyoxyethylene cetyl 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 (25) oleate (Myrj 49), polyoxyethylene (40) palmitate (Myrj 52), sodium lauryl sulfate, Tween 80, Tween 60, Tween 40, propylene glycol monolaurate, polyoxyethylene (20) lauryl ether, and polyoxyethylene monocetyl ether.

[0012] Preferably, the method for producing the nanocrystalline particles includes an anti-solvent method, a high-pressure homogenization method, or a microfluidic method. Preferably, the anti-solvent method includes step S1 of accurately weighing sirolimus and an organic solvent, and magnetically stirring them to make them transparent and uniform, to obtain an A-phase solution; step S2 of accurately weighing a surfactant and an aqueous phase solvent, and magnetically stirring them to make them transparent and uniform, to obtain a B-phase solution; step S3 of rapidly adding the A-phase solution to the B-phase solution and magnetically stirring them to obtain a nanocrystalline suspension; and step S4 of adding water to the suspension to mix uniformly, freeze-drying, and obtaining the nanocrystalline particles. Preferably, the nanocrystalline particles have a particle size d50 of 150 to 900 nm, and a mass ratio of sirolimus to surfactant of 5:1 to 1:2. Preferably, the high-pressure homogenization method includes step S1 of accurately weighing sirolimus, an aqueous phase solvent, and a surfactant, and magnetically stirring them to obtain a suspension, and then lyophilizing the suspension using a high-pressure homogenizer. The method includes step S2 of homogenizing the nanocrystalline particles multiple times with a microfluidic device to obtain a nanocrystalline suspension, and step S3 of freeze-drying the nanocrystalline particles to obtain sirolimus nanocrystals. Preferably, the nanocrystalline particles have a particle size d50 of 150-900 nm, the homogenization pressure is 1000-2000 bar, the number of homogenizations is 5-10, and the mass ratio of sirolimus to surfactant is 5:1-1:2. Preferably, the microfluidic method accurately mixes sirolimus, an aqueous solvent, and a surfactant. and magnetically stirring to obtain a suspension; step S2, homogenizing the suspension multiple times using a microfluidic device to obtain a nanocrystal suspension; and step S3, freeze-drying to obtain sirolimus nanocrystals, wherein the nanocrystal particles preferably have a particle size d50 of 150-900 nm, a microfluidic pressure of 1000-2000 bar, the number of homogenizations is 5-10, and the mass ratio of sirolimus to surfactant is 5:1-1:2.

[0013] The present invention combines the advantages of two types of drug carriers by combining nanocrystals and liposomes, and the formed lipid bilayer has the technical effects of improving the solubility of poorly soluble drugs, increasing drug loading, improving drug stability, and enabling the control of drug release rate.

[0014] The present invention further provides a use of the drug-coated balloon in the treatment of intracranial arterial stenosis, wherein the drug dose is 3 μg / mm 2 ≤ 1.5 μg / mm 2 More preferably, it is:

[0015] The present invention further provides a use of a drug-coated balloon for sirolimus in the treatment of intracranial arterial stenosis, wherein the drug dose is 3 μg / mm 2 ≤ 1.5 μg / mm 2 More preferably, it is:

[0016] The present invention combines the advantages of two types of drug carriers by combining nanocrystals and liposomes: the formed lipid bilayer improves the solubility of poorly soluble drugs in the drug-coated balloon, leading to a high drug loading, high stability of the drug carrier, and stable drug crystal form, thereby enabling the drug release rate to be controlled. [Brief explanation of the drawings]

[0017] The features and advantages of the present invention can be more clearly understood by reference to the drawings, which are illustrative and should not be construed as limiting the present invention in any way.

[0018] [Figure 1] 1 shows a schematic diagram of a nanocrystal-liposome composite nanocarrier according to the present invention. [Figure 2] 1 shows an electron microscope image of the surface of a drug-coated balloon for sirolimus according to the present invention. [Figure 3] 1 shows a particle size distribution diagram of nanocrystals in the present invention. [Figure 4] 1 shows a particle size distribution diagram of the nanocrystal-liposome composite nanocarrier of the present invention. [Figure 5]The crystal form spectra of nanocrystal-liposome composite nanocarriers manufactured using different formulations and processes in the present invention are shown before and after sterilization (different formulations: polyoxyethylene 35 castor oil: EL35; polyethylene glycol (15)-hydroxystearic acid: HS15; tyloxapol; different processes: antisolvent method, microfluidic method). [Figure 6] The crystal form spectra of nanocrystal-liposome composite nanocarriers prepared by different processes using sodium lauryl sulfate (SDS) as a surfactant before and after sterilization in this invention, and the nanocrystal-liposome composite nanocarriers prepared by HS15 after sterilization are shown. DETAILED DESCRIPTION OF THE INVENTION

[0019] In order to make the objectives, technical solutions and advantages of the embodiments of the present invention clearer, the following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the drawings in the embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and are not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without any creative efforts fall within the protection scope of the present invention.

[0020] In an embodiment of the present invention, nanocrystals containing a drug are first prepared, where the drug includes sirolimus, zotarolimus, or everolimus. In the following examples, sirolimus is used as an example. The preparation method of the nanocrystals includes an antisolvent method, a high-pressure homogenization method, or a microfluidic method.

[0021] Example 1A Here, the anti-solvent method for sirolimus nanocrystals includes the following steps: (1) accurately weighing sirolimus and an organic solvent, and magnetically stirring until a transparent and uniform solution is obtained to obtain an A-phase solution; (2) accurately weighing sodium lauryl sulfate and an aqueous solvent, and magnetically stirring until a transparent and uniform solution is obtained to obtain a B-phase solution; (3) rapidly adding the A-phase solution to the B-phase solution and magnetically stirring until a nanocrystal suspension is obtained; and (4) adding water to the suspension, mixing uniformly, and freeze-drying to obtain the nanocrystal particles.

[0022] In a specific embodiment, the anti-solvent method specifically includes the following steps: wherein the specific dosage of each raw material is as shown in the table below.

[0023] [Table 1]

[0024] In step (1), sirolimus and methanol are each accurately weighed, and magnetically stirred for 10 minutes until the mixture becomes transparent and homogeneous, yielding phase A. In step (2), sodium lauryl sulfate and water are each accurately weighed, and magnetically stirred for 10 minutes until the mixture becomes transparent and homogeneous, yielding phase B. In step (3), phase A is quickly added to phase B, and magnetically stirred for 10 minutes to yield a nanocrystal suspension. In step (4), 150 g of water is added, mixed homogeneously, and freeze-dried to yield sirolimus nanocrystals.

[0025] The measured particle size of the sirolimus nanocrystals was d50 = 340 nm.

[0026] Example 1B Here, the high-pressure homogenization method for sirolimus nanocrystals includes the steps of: (1) accurately weighing sirolimus, an aqueous solvent, and sodium lauryl sulfate, and magnetically stirring to obtain a suspension; (2) homogenizing the suspension multiple times with a high-pressure homogenizer to obtain a nanocrystal suspension; and (3) freeze-drying to obtain sirolimus nanocrystals.

[0027] A specific high-pressure homogenization method specifically includes the following steps: wherein the specific dosage of each ingredient is as shown in the table below.

[0028] [Table 2]

[0029] In step (1), sirolimus, water, and sodium lauryl sulfate are accurately weighed and magnetically stirred for 10 minutes to obtain a suspension. In step (2), the suspension is homogenized eight times using a high-pressure homogenizer at a homogenization pressure of 1300 bar to obtain a nanocrystal suspension. In step (3), the suspension is freeze-dried to obtain sirolimus nanocrystals.

[0030] The measured particle size of the sirolimus nanocrystals was d50 = 512 nm.

[0031] Example 1C The microfluidic method for preparing sirolimus nanocrystals specifically includes the following steps: wherein the specific dosage of each raw material is as shown in the table below.

[0032] [Table 3]

[0033] In step (1), sirolimus, water, and sodium lauryl sulfate are accurately weighed and magnetically stirred for 10 minutes to obtain a suspension. In step (2), the suspension is homogenized eight times using a microfluidic device at a microfluidic pressure of 1600 bar to obtain a nanocrystal suspension. In step (3), the suspension is freeze-dried to obtain sirolimus nanocrystals.

[0034] The measured particle size of the sirolimus nanocrystals was d50 = 160 nm.

[0035] Example 1D Here, the anti-solvent method for sirolimus nanocrystals includes the following steps: (1) accurately weighing sirolimus and an organic solvent, and magnetically stirring until a transparent and uniform solution is obtained to obtain an A-phase solution; (2) accurately weighing Tween 80 and an aqueous phase solvent, and magnetically stirring until a transparent and uniform solution is obtained to obtain a B-phase solution; (3) rapidly adding the A-phase solution to the B-phase solution and magnetically stirring until a nanocrystal suspension is obtained; and (4) adding water to the suspension, mixing uniformly, and freeze-drying to obtain the nanocrystal particles.

[0036] In one specific embodiment, the anti-solvent method specifically includes the following steps: wherein the specific dosage of each raw material is as shown in the table below.

[0037] [Table 4]

[0038] In step (1), sirolimus and methanol are each accurately weighed and magnetically stirred for 10 minutes until transparent and homogeneous, yielding phase A. In step (2), Tween 80 and water are each accurately weighed and magnetically stirred for 10 minutes until transparent and homogeneous, yielding phase B. In step (3), phase A is quickly added to phase B and magnetically stirred for 10 minutes to yield a nanocrystal suspension. In step (4), 150 g of water is added, mixed homogeneously, and freeze-dried to yield sirolimus nanocrystals.

[0039] The measured particle size of the sirolimus nanocrystals was d50 = 776 nm.

[0040] Example 1E Here, the high-pressure homogenization method for sirolimus nanocrystals includes the steps of: (1) accurately weighing sirolimus, an aqueous solvent, and poloxamer 188, and magnetically stirring to obtain a suspension; (2) homogenizing the suspension multiple times with a high-pressure homogenizer to obtain a nanocrystal suspension; and (3) freeze-drying to obtain sirolimus nanocrystals.

[0041] In one specific embodiment, the high-pressure homogenization method specifically includes the following steps: wherein the specific dosage of each ingredient is as shown in the table below.

[0042] [Table 5]

[0043] In step (1), sirolimus, water, and poloxamer 188 were accurately weighed and magnetically stirred for 10 minutes to obtain a suspension. In step (2), the suspension was homogenized 10 times using a high-pressure homogenizer at a microfluidic pressure of 2000 bar to obtain a nanocrystal suspension. In step (3), the suspension was freeze-dried to obtain sirolimus nanocrystals.

[0044] The measured particle size of the sirolimus nanocrystals was d50 = 225 nm.

[0045] Example 1F In one specific embodiment, the microfluidic method for sirolimus nanocrystals specifically includes the following steps: wherein the specific dosage of each ingredient is as shown in the table below.

[0046] [Table 6]

[0047] In step (1), sirolimus, water, and poloxamer 407 are accurately weighed and magnetically stirred for 10 minutes to obtain a suspension. In step (2), the suspension is homogenized twice using a microfluidic device at a microfluidic pressure of 1800 bar to obtain a nanocrystal suspension. In step (3), the suspension is freeze-dried to obtain sirolimus nanocrystals. The measured particle size of the sirolimus nanocrystals is d50 = 530 nm.

[0048] Example 1G In one specific embodiment, the high-pressure nano-microfluidization method for sirolimus nanocrystals specifically includes the following steps: wherein the specific dosage of each raw material is as shown in the table below.

[0049] [Table 7]

[0050] In step (1), sirolimus, water, and polyoxyethylene 35 castor oil are each accurately weighed and magnetically stirred at 800 rpm for 15 minutes to obtain a suspension. In step (2), the suspension is homogenized using a high-pressure nano / microfluidization device, homogenized 35 times at a pressure of 1800 bar, to obtain a nanocrystal suspension. In step (3), the suspension is freeze-dried to obtain sirolimus nanocrystals. The measured particle size of the sirolimus nanocrystals is d50 = 520 nm.

[0051] Example 2 After preparing the drug-containing nanocrystalline particles in Examples 1A to 1G (the measured particle size of the sirolimus nanocrystals was d50 = 150 to 900 nm), they were then prepared into nanocrystal-liposome composite nanocarriers, which have a core-shell structure in which the drug is coated with a lipid bilayer. High-pressure homogenization or microfluidic methods can be used to prepare the nanocrystal-liposome composite nanocarriers, and both the high-pressure homogenization method and the microfluidic method can be two-step or one-step methods.

[0052] The specific amounts of each raw material are as shown in the table below.

[0053] [Table 8]

[0054] In another specific embodiment, the specific dosage of each ingredient is as shown in the table below.

[0055] [Table 9]

[0056] 1. The two-step high-pressure homogenization method may include step (1) of accurately weighing cholesterols, lecithin, and water, and then performing magnetic stirring at 60°C for 40 minutes, followed by homogenization 5 to 10 times using a high-pressure homogenizer at a homogenization pressure of 1000 to 2000 bar; and step (2) of accurately weighing and adding nanocrystals, and performing magnetic stirring at 60°C for 2 hours to mix uniformly, thereby obtaining nanocrystal-liposome composite nanocarriers.

[0057] Here, the particle size of the nanocrystal-liposome composite nanocarrier is 200 to 900 nm, and the mass ratio of lecithin:cholesterols is 40:1 to 1:2, more preferably 30:1 to 1:1.

[0058] 2. The two-step microfluidic method may include step (1) of accurately weighing cholesterols, lecithin, and water, and then magnetically stirring at 60°C for 40 minutes, followed by homogenization 5 to 10 times using a microfluidic device at a microfluidic pressure of 1000 to 2000 bar; and step (2) of accurately weighing and adding nanocrystals, and then magnetically stirring at 60°C for 2 hours to mix uniformly, thereby obtaining nanocrystal-liposome composite nanocarriers.

[0059] Here, the particle size of the nanocrystal-liposome composite nanocarrier is 200 to 900 nm, and the mass ratio of lecithin:cholesterols is 40:1 to 1:2, more preferably 30:1 to 1:1.

[0060] 3. The one-step method of high-pressure homogenization may include the following steps: (1) accurately weighing cholesterols and lecithin and dissolving them uniformly at 60°C to obtain an oil phase; (2) accurately weighing freeze-dried nanocrystalline powder and water and uniformly stirring them magnetically at 60°C to obtain an aqueous phase; (3) adding the aqueous phase to the oil phase and mixing at 60°C for 20 minutes to obtain an emulsion; and (4) homogenizing 5 to 10 times at a homogenization pressure of 1000 to 2000 bar, freeze-drying, and obtaining a nanocrystal-liposome composite nanocarrier.

[0061] Here, the particle size of the nanocrystal-liposome composite nanocarrier is 200 to 900 nm, and the mass ratio of lecithin or soybean lecithin to cholesterols is 40:1 to 1:2, more preferably 30:1 to 1:1.

[0062] 4. The one-step microfluidic method may include the following steps: (1) accurately weighing cholesterols and lecithin, dissolving them uniformly at 60°C to obtain an oil phase; (2) accurately weighing freeze-dried nanocrystalline powder and water, and uniformly dissolving them under magnetic stirring at 60°C to obtain an aqueous phase; (3) adding the aqueous phase to the oil phase and mixing at 60°C for 20 minutes to obtain an emulsion; and (4) homogenizing the emulsion in a microfluidic device 5 to 10 times at a homogenization pressure of 1000 to 2000 bar, freeze-drying, and obtaining a nanocrystal-liposome composite nanocarrier.

[0063] Here, the particle size of the nanocrystal-liposome composite nanocarrier is 200 to 900 nm, and the mass ratio of lecithin:cholesterols is 40:1 to 1:2, more preferably 30:1 to 1:1.

[0064] Instead of the phospholipids of the present application, egg yolk phospholipid, soybean lecithin, sunflower lecithin, hydrogenated soybean lecithin, hydrogenated egg yolk phospholipid, 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-(1-glycerin) sodium salt, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1-dipalmitoyl-dioleoyl-s n-Glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-diformyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine sodium salt, 1,2-dipalmitoyl-sn One or more of N-glycero-3-phosphate monosodium salt, N-(carbonyl-methoxypolyethylene glycol-5000)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine sodium salt, N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-4-phosphoethanolamine sodium salt, and 1,2-dioleyl-3-trimethylpropane ammonium chloride may be employed.

[0065] The nanocrystal-liposome composite nanocarrier produced by the above-mentioned production method of the present invention has a core-shell structure, the core of the core-shell structure contains multiple particles carrying a drug, and the shell of the core-shell structure is a lipid bilayer comprising hydrophilic groups in the outer layer and hydrophobic groups in the inner layer, and the specific structure of the core-shell structure is as shown in Figure 1.

[0066] The freeze-dried nanocrystal-liposome composite nanocarrier powder is redissolved in pure water to form a coating solution, which is then atomized using high-frequency ultrasound. The resulting mist is then mixed with air to form an aerosol. At a stable pressure, the aerosol is propelled by nitrogen gas and expelled from a nozzle. The balloon is connected to a holder mounting module via a clamp, and the balloon moves at a constant speed in the radial and axial directions in the airflow. The atomized particles carried by the airflow come into contact with the balloon surface and are deposited on the balloon surface, forming a liquid film. After a drying process, the desired drug-coated balloon coating structure is obtained.

[0067] In this invention, the combination of nanocrystals and liposomes combines the advantages of two types of drug carriers: the formed lipid bilayer improves the solubility of poorly soluble drugs, leading to higher drug loading, improved drug stability, and controllable drug release rate.

[0068] It is particularly important to note that the coating solution for drug-coated balloons according to the present invention uses an aqueous solvent, which has the following technical advantages: high durability, reduced residual organic solvent, and compatibility with both water-soluble and water-insoluble drugs.

[0069] Comparative Example 1 A nanocrystal-phospholipid complex was obtained by following the same manufacturing method as the nanocrystal-liposome complex nanocarrier, except that cholesterols were not added. The nanocrystal-phospholipid complex is a monolayer liposome that covers the nanocrystals. The results of Example 1 and Comparative Example 1 are as follows:

[0070] [Table 10]

[0071] Test Example - Verification of the dosage of a drug-coated balloon in the intracranial space The purpose of this study (MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide)) was to quantitatively evaluate the cytotoxicity of sirolimus drug coatings with different drug concentrations and different coating formulations on L-929 cells, C6 cells, and HT22 cells.

[0072] The desired doses of the test substance and positive standard substance were calculated for each group. Then, after dissolving them in pure DMSO, serum-containing medium was added to adjust the DMSO concentration to 0.1%, and 10 ml was added per group. Serum-containing medium was added to each group solution by volume, and three subgroups were prepared: 100%, 50%, and 25%.

[0073] As a negative standard solution, 0.01 ml of pure DMSO was added to serum-containing medium to adjust the DMSO concentration to 0.1%, and 10 ml of serum-containing medium was used as a medium standard solution.

[0074] L-929, C6, and HT22 cells were seeded into 96-well plates and cultured for 24 hours to form a nearly confluent cell layer, after which they were exposed to the corresponding test substance, standard, or vehicle standard. After 24 hours of incubation, the supernatant was removed and MTT solution was added to each well. After 2 hours of incubation, the cell culture plate was removed and 100 μL of isopropyl alcohol was added. The culture plate was placed in a microplate reader and absorbance values ​​were read using a detection wavelength of 570 nm and a reference wavelength of 650 nm. Cell activity was measured to detect cytotoxicity. Cell activity was determined by the percentage of the OD570 (mean OD570) of each treatment group compared to the vehicle control group.

[0075] In Test 1, the deviations of the mean OD570 values ​​on the left (column 2) and right (column 11) sides of the L929 and C6 cell microplates from the mean values ​​of both sides were less than 15%, at 2.61% and 4.14%, respectively. The cell viabilities of the negative control were 101.51% and 95.30%, respectively.

[0076] In Test 2, the deviations of the mean OD570 values ​​on the left (column 2) and right (column 11) sides of the L929 cell microplates in the A, B, and C formulations from the mean values ​​of both sides were 8.59%, 5.06%, and 10.27%, respectively. The deviations of the mean OD570 values ​​on the left (column 2) and right (column 11) sides of the C6 cell microplates in the A, B, and C formulations from the mean values ​​of both sides were all less than 15%, at 3.54%, 6.13%, and 5.65%, respectively. The cell viabilities of the negative control L929 cells in the A, B, and C formulations were 98.45%, 102.47%, and 97.37%, respectively. The cell viabilities of the negative control HT22 cells in the A, B, and C formulations were 100.44%, 98.96%, and 101.52%, respectively. These results demonstrate the validity of this test.

[0077] The cell viability of L929 cells at 25% was 77.64% and 64.08% in the TA1 and TA2 groups, respectively, and the cell viability of C6 cells at 25% was 79.33% and 75.71% in the TA1 and TA2 groups, respectively. This was due to the fact that the coating drug concentration was 1-2 μg / mm 2 It has been shown that within this range, an inhibitory effect can be achieved on fiber cells, but there is no effect on nerve cells.

[0078] In two cell lines, L929 and HT22, the concentrations were 1.0, 1.5, and 2.0 μg / mm 2 Secondary screening was performed at a concentration of 0.01g, and cell toxicity tests were performed using three types of coated drug formulations (A: sirolimus + shellac ammonium salt; B: nanocrystals + lecithin + cholesterol (Example 2); C: PLGA + lecithin + cholesterol).

[0079] The results showed that the three ingredients were 1.0-2 μg / mm 2 In the case of 1.0 and 1.5 μg / mm 2 When the concentration is 2.0 μg / mm 2 It was shown that when the concentration of ingredients A, B, and C was 1.5 μg / mm 2 In the following cases, an inhibitory effect on fiber cells can be achieved, but there is no effect on nerve cells.

[0080] Therefore, the dose of sirolimus-coated balloon to prevent intracranial restenosis was 1.5 μg / mm 2 It can be determined that the following is true.

[0081] Animal testing 1. Grouping of test animals Conduct vascular implantation experiments in New Zealand rabbits. In the test group, 24 animals were implanted, and the implantation sites were bilateral iliac arteries. Six test products (Example 2B made with nanocrystals of Examples 1A-F) were implanted in each group of animals, and 12 animals were dissected immediately after surgery and 12 animals were dissected on the 7th day (7d) after surgery.

[0082] In control group 1 (Comparative Example 1), implantation was performed on four animals, the implantation sites were the bilateral iliac arteries, and one standard balloon catheter was implanted in each animal of the group, two animals were dissected immediately after surgery and two animals were dissected on the seventh day after surgery.

[0083] In control group 2 (Comparative Example 2 - commercially available Magic Touch sirolimus drug-coated balloon), implantation was performed on four animals, with the implantation sites being the bilateral iliac arteries. Two animals were dissected immediately after surgery and two animals were dissected on the seventh day after surgery.

[0084] 2. Surgical procedure Before the surgical procedure began, heparin sodium injection was administered intravenously, and clotting time was monitored throughout the procedure to ensure an ACT of over 500. During the procedure, electrocardiograms were monitored in real time, and indicators such as blood pressure and heart rate were observed. Drug-coated balloon dilation was performed according to the laboratory's standard operating procedures. Using a guiding catheter and a 0.014 guidewire, the drug-coated balloon was advanced into the blood vessel via the carotid artery and guided to the target location in the iliac artery. The balloon was then inflated to the appropriate pressure using a pressure pump, allowing the drug components to adhere to the blood vessel wall. The balloon's position relative to the vessel bifurcation point was recorded. The balloon pressure was maintained for 60 seconds before being released, and the balloon delivery system was then removed from the body. After the procedure was completed, all machines and devices were removed from the test animals' bodies.

[0085] Immediately after surgery, the test group (12 animals), control group 1 (2 animals), and control group 2 (2 animals) were dissected on the spot, and the skin layer was incised to expose the target blood vessels. The target vascular tissue was excised 2-3 mm upstream and downstream of the surgical site. After waking from anesthesia, the test animals were transferred to the ICU for monitoring and protection.

[0086] 3. Extraction of tissue samples Rabbit vascular samples were weighed, minced, and homogenized in a tissue:50% methanol ratio of 1:4 (w:v). A portion of the homogenized solution was frozen and stored at -20°C or below. 20 μL of the homogenized solution was accurately pipetted into a 1.5 mL EP tube, and 180 μL of blank matrix was added and mixed thoroughly for storage. 100 μL of standard curve and quality control samples were taken, and precipitant was added at a sample:precipitant ratio of 1:3 (v:v). Mix thoroughly and centrifuged at 12,000 rpm at 4°C for 10 minutes. An appropriate amount of the supernatant was transferred to a new 96-well plate for storage.

[0087] The balloon content in Example 2B, Comparative Example 1, and Comparative Example 2 was about 1.5 μg / mm 2The nanocrystal-phospholipid complex was a monolayer, while the nanocrystal-liposome complex nanocarrier was a bilayer. This resulted in the experimental results shown in the table below.

[0088] [Table 11]

[0089] As can be seen from the table above, the content of nanocrystal-liposome composite nanocarriers (Example 2) in the tissue after 7 days was significantly higher than that of Comparative Example 1 (nanocrystal-phospholipid complex) and Comparative Example 2, and the average drug content of nanocrystal-liposome composite nanocarriers in unit tissue after 7 days was more than twice as high as that of the comparative example. Therefore, the drug sustained release effect of the nanocrystal-liposome composite nanocarriers of the present invention is higher.

[0090] Test Example: Verification test of particle size and crystal form of the present invention In the present invention, the parameters of nanocrystals and liposomes in different formulations and processes were systematically compared and contrasted, and the crystal form was found to be almost stable. The specific experimental conditions and results are shown in the table and contents below.

[0091] Nanocrystal manufacturing process: In the antisolvent method, in step (1), sirolimus and methanol were each accurately weighed and magnetically stirred until a transparent, homogeneous solution was obtained, yielding a phase A solution; in step (2), surfactant and solvent were each accurately weighed and magnetically stirred until a transparent, homogeneous solution was obtained, yielding a phase B solution; and in step (3), phase A solution was quickly added to phase B solution and magnetically stirred to obtain a nanocrystal suspension.

[0092] In the microfluidic method, in step (1), sirolimus, surfactant, and water were each accurately weighed and magnetically stirred for 5 to 15 minutes to obtain a suspension. In step (2), the suspension was homogenized 30 to 40 times using a microfluidic device at a microfluidic pressure of 1600 to 2000 bar to obtain a nanocrystal suspension.

[0093] Liposome preparation process: In step (1), cholesterols, phospholipids, and water were each accurately weighed and uniformly dissolved at 50-80°C before being added to the nanocrystal suspension. In step (2), the mixture was homogenized 15-25 times using a microfluidic device at a microfluidic pressure of 1200-1500 bar to obtain nanocrystal-liposome composite nanocarriers.

[0094] [Table 12]

[0095] As shown in the table above, the crystal form spectra of sirolimus nanocrystal-liposome nanocarriers manufactured using different formulations and different processes are shown in Figures 5 and 6. In Figure 5, from top to bottom, these are Formulation 6, Formulation 5, Formulation 4, Formulation 3, Formulation 2, and Formulation 1 after sterilization, respectively. In Figure 6, from top to bottom, these are Formulation 0 before sterilization, Formulation 2 after sterilization, and Formulation 0 after sterilization, respectively.

[0096] As can be seen from Table 12, for SDS, EL35, and tyloxapol, the antisolvent and microfluidic methods can produce carriers with particle sizes of 1000 nm or less, which is consistent with the typical nanoformulation range. The particle size of the carrier produced with HS15 is slightly larger than 1000 nm, while the carrier produced by the microfluidic method is 1000 nm or less, which is consistent with the typical nanoformulation range. For HS15, EL35, and tyloxapol, the antisolvent and microfluidic methods can produce carriers, and the crystalline form of the drug before and after sterilization is the same as that of the drug substance, maintaining stability. For SDS, the carrier produced by the antisolvent method is amorphous before sterilization and becomes a mixed crystal after sterilization. Therefore, EL35 and tyloxapol are ideal for producing sirolimus nanocrystal-liposome nanocarriers.

[0097] The above test examples are merely intended to demonstrate the feasibility of manufacturing process technology and are not intended to limit the scope. In the above examples, products with similar mass indices can be obtained as long as the sirolimus:surfactant ratio is in the range of 1.5:1 to 300:1. Similarly, by changing the formulation information such as the ratio of sirolimus to phospholipids and the ratio of phospholipids to cholesterol, products with similar mass indices can be produced.

[0098] The present invention further conducted a systematic study on the stability of the crystalline form of the nanocrystal-liposome composite nanocarrier, and the stability of the crystalline form was demonstrated, which ensures the sustained release of sirolimus, as shown in the table below.

[0099] [Table 13]

[0100] In accordance with the "Guidelines for Stability Guidance of Drug Substances and Preparations" in the Chinese Pharmacopoeia (2020 edition), nanocrystal-liposome composite nanocarriers were balloon-packaged for sale, and then the content and crystalline form were examined at 0 and 3 months 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%). The results of the tests demonstrated that the nanocrystal-liposome composite nanocarriers were stable for 3 months under both accelerated and long-term conditions.

Claims

1. A coating solution for a drug-coated balloon, comprising: the coating solution comprises an aqueous phase solvent and a plurality of core-shell structures, each of which has a lipid bilayer coating a drug, dispersed in the aqueous phase solvent; the core of the core-shell structure comprises a plurality of particles loaded with a drug, and the shell of the core-shell structure is the lipid bilayer comprising an outer layer of hydrophilic groups and an inner layer of hydrophobic groups; the drug-loaded particles include a plurality of nanocrystalline particles comprising a drug; A coating solution for a drug-coated balloon.

2. The particle size of the core-shell structure is 200 to 900 nm, Preferably, the nanocrystalline particles have a particle size d50 of 150 to 900 nm, and a surfactant is used in the process for producing the nanocrystalline particles; Preferably, the surfactant is tocophersolan, poloxamer 188, poloxamer 407, tyloxapol, docusate sodium, polyethylene glycol (15)-hydroxystearic acid, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 60, polyoxyethylene castor oil 40, polyoxyethylene 35 castor oil, polyoxyethylene castor oil 20, polyoxyethylene castor oil 10, polyethylene glycol cetostearyl ether 20 (KOLLIPHOR® CS 20), polyethylene glycol cetostearyl ether 12 (KOLLIPHOR® CS 12), polyoxyethylene cetyl 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 (25) oleate (Myrj 49), polyoxyethylene (40) stearate (Myrj 52), sodium lauryl sulfate, Tween 80, Tween 60, Tween 40, propylene glycol monolaurate, and polyoxyethylene (20) lauryl ether; Preferably, the drug comprises Sirolimus, Zotarolimus, Everolimus, Tacrolimus, Temsirolimus, Pimecrolimus, Deforolimus, and Ridaforolimus; Preferably, the raw materials for producing the lipid bilayer include phospholipids and cholesterols, Preferably, the phospholipid is egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, cephalin, phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), stearylamine (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, or 1,2-dioleoyl-sn-glycero-3-phosphocholine. 1,2-Diercoyl-sn-glycero-3-phosphocholine, 1-Dipalmitoyl-dioleoyl-sn-glycero-3-phosphocholine, 1,2-Diformyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt, 1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt, 1,2-Distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt, 1,2-Dioleoyl-sn-glycero-3-phospho-rac-( 1-glycerin) sodium salt, 1-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-diformyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine sodium salt, 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt, N-(carbonyl-methoxypolyethylene glycol-5000)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine sodium salt, N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-4-phosphoethanolamine sodium salt, and 1,2-dioleyl-3-trimethylpropane ammonium chloride; The cholesterols include cholesterol and DC cholesterol, Preferably, the mass ratio of the phospholipid to the cholesterol is 40:1 to 1:2, more preferably 30:1 to 1:

1.

2. The coating solution for a drug-coated balloon according to claim 1.

3. The drug-coated core-shell structure comprises a lipid bilayer. the core of the core-shell structure comprises a plurality of particles loaded with a drug, and the shell of the core-shell structure is the lipid bilayer comprising an outer layer of hydrophilic groups and an inner layer of hydrophobic groups; the drug-loaded particles include a plurality of nanocrystalline particles comprising a drug; A coating material for a drug-coated balloon.

4. The particle size of the core-shell structure is 200 to 900 nm, Preferably, the nanocrystalline particles have a particle size d50 of 150 to 900 nm, and a surfactant is used in the process for producing the nanocrystalline particles; Preferably, the surfactant is tocophersolan, poloxamer 188, poloxamer 407, tyloxapol, docusate sodium, polyethylene glycol (15)-hydroxystearic acid, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 60, polyoxyethylene castor oil 40, polyoxyethylene 35 castor oil, polyoxyethylene castor oil 20, polyoxyethylene castor oil 10, polyethylene glycol cetostearyl ether 20 (KOLLIPHOR® CS 20), polyethylene glycol cetostearyl ether 12 (KOLLIPHOR® CS 12), polyoxyethylene cetyl 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 (25) oleate (Myrj 49), polyoxyethylene (40) stearate (Myrj 52), sodium lauryl sulfate, Tween 80, Tween 60, Tween 40, propylene glycol monolaurate, polyoxyethylene (20) lauryl ether, and polyoxyethylene cetyl ether; Preferably, the drug comprises Sirolimus, Zotarolimus, Everolimus, Tacrolimus, Temsirolimus, Pimecrolimus, Deforolimus, and Ridaforolimus; Preferably, the raw materials for producing the lipid bilayer include phospholipids and cholesterols, Preferably, the phospholipid is egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, cephalin, phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), stearylamine (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, or 1,2-dioleoyl-sn-glycero-3-phosphocholine. 1,2-Diercoyl-sn-glycero-3-phosphocholine, 1-Dipalmitoyl-dioleoyl-sn-glycero-3-phosphocholine, 1,2-Diformyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt, 1,2-Dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt, 1,2-Distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt, 1,2-Dioleoyl-sn-glycero-3-phospho-rac-( 1-glycerin) sodium salt, 1-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerin) sodium salt, 1,2-diformyl-sn-glycero-3-phosphoethanolamine, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-L-serine sodium salt, 1,2-dipalmitoyl-sn-glycero-3-phosphate monosodium salt, N-(carbonyl-methoxypolyethylene glycol-5000)-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine sodium salt, N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-4-phosphoethanolamine sodium salt, and 1,2-dioleyl-3-trimethylpropane ammonium chloride; The cholesterols include cholesterol and DC cholesterol, Preferably, the mass ratio of the phospholipid to the cholesterol is 40:1 to 1:2, more preferably 30:1 to 1:

1.

4. The coating material for a drug-coated balloon according to claim 3.

5. The surface of the drug-coated balloon is coated with the coating solution for a drug-coated balloon according to any one of claims 1 and 2 or the coating material for a drug-coated balloon according to any one of claims 3 and 4. A drug-coated balloon.

6. 10. Use of the drug-coated balloon according to claim 5 in the treatment of atherosclerosis, stenosis and / or restenosis of coronary, peripheral or intracranial arterial vessels.

7. (1) producing a plurality of nanocrystalline particles carrying a drug, wherein the method for producing the nanocrystalline particles comprises an antisolvent method, a high-pressure homogenization method, or a microfluidic method; Step (2) of accurately weighing cholesterols, phospholipids, and an aqueous solvent, and magnetically stirring the mixture to obtain a milky white solution; and (3) adding the nanocrystalline particles to the milky white solution and mixing them uniformly by magnetic stirring to obtain a coating solution for drug-coated balloons; The coating solution comprises an aqueous solvent and a plurality of core-shell structures, each having a lipid bilayer coating a drug, dispersed in the aqueous solvent, wherein the core of the core-shell structure comprises a plurality of particles carrying the drug, and the shell of the core-shell structure is the lipid bilayer comprising an outer layer of hydrophilic groups and an inner layer of hydrophobic groups.

1. A method for preparing a coating solution for a drug-coated balloon, comprising:

8. After step (3), The method further includes step (4) of adding a thickener to the solution and uniformly mixing the solution by magnetic stirring to obtain a coating solution for drug-coated balloons; Preferably, the thickening agent comprises sodium alginate; Preferably, in step (2), after magnetic stirring, the mixture is further homogenized 5 to 10 times using a high-pressure homogenizer or a microfluidic device to obtain a milky white solution; Preferably, the drug in step (1) comprises sirolimus, and the organic solvent comprises methanol; Preferably, the mass ratio of sirolimus to sodium lauryl sulfate is 5:1 to 1:2; Preferably, the anti-solvent method comprises: Step S1: accurately weighing sirolimus and an organic solvent, and magnetically stirring them to obtain a transparent and homogeneous solution in phase A; Step S2: accurately weighing sodium lauryl sulfate and an aqueous phase solvent, and magnetically stirring the mixture to obtain a transparent and uniform solution of phase B; Step S3: rapidly adding the phase A solution to the phase B solution and magnetically stirring to obtain a nanocrystal suspension; and step S4 of adding water to the suspension to mix uniformly, and freeze-drying the mixture to obtain the nanocrystalline particles. Preferably, the particle size d50 of the nanocrystalline particles is 150 to 900 nm, and the mass ratio of sirolimus to sodium lauryl sulfate is 5:1 to 1:2; Preferably, the high pressure homogenization method comprises: Step S1: accurately weighing sirolimus, an aqueous solvent, and sodium lauryl sulfate, and magnetically stirring the mixture to obtain a suspension; Step S2: homogenizing the suspension multiple times with a high-pressure homogenizer to obtain a nanocrystal suspension; and step S3 of freeze-drying to obtain sirolimus nanocrystals; Preferably, 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, and the mass ratio of sirolimus to sodium lauryl sulfate is 5:1-1:2; Preferably, the microfluidic method comprises: Step S1: accurately weighing sirolimus, an aqueous solvent, and sodium lauryl sulfate, and magnetically stirring the mixture to obtain a suspension; Step S2: homogenizing the suspension multiple times by a microfluidic device to obtain a nanocrystal suspension; and step S3 of freeze-drying to obtain sirolimus nanocrystals; Preferably, the particle size d50 of the nanocrystalline particles is 150-900 nm, the microfluidic pressure is 1000-2000 bar, the number of homogenization times is 5-10, and the mass ratio of sirolimus to sodium lauryl sulfate is 5:1-1:

2.

8. The method for preparing a coating solution for a drug-coated balloon according to claim 7.

9. A coating solution for a drug-coated balloon, comprising: the coating solution comprises an aqueous phase solvent and a plurality of core-shell structures, each of which has a lipid bilayer coating a drug, dispersed in the aqueous phase solvent; the core of the core-shell structure comprises a plurality of particles loaded with a drug, and the shell of the core-shell structure is the lipid bilayer comprising an outer layer of hydrophilic groups and an inner layer of hydrophobic groups; the drug-loaded particles include a plurality of nanocrystalline particles comprising a drug; The raw materials for producing the nanocrystalline particles are tocophersolan, poloxamer 188, poloxamer 407, tyloxapol, docusate sodium, polyethylene glycol (15)-hydroxystearic acid, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene castor oil 60, polyoxyethylene castor oil 40, polyoxyethylene 35 castor oil, polyoxyethylene castor oil 20, polyoxyethylene castor oil 10, KOLLIPHOR CS. 20, polyethylene glycol cetostearyl ether 12, polyoxyethylene cetyl ether (Ceteth-10), polyoxyethylene (10) cetyl ether (Brij 56), polyoxyethylene (20) cetyl ether (Brij 58), polyoxyethylene (23) lauryl ether (Brij 35), polyoxyethylene (2) cetyl ether (Brij 52), polyoxyethylene (25) oleate (Myrj 49), polyoxyethylene (40) stearate (Myrj 52), sodium lauryl sulfate, Tween 80, Tween 60, Tween 40, propylene glycol monolaurate, polyoxyethylene (20) lauryl ether, and polyoxyethylene cetyl ether, A coating solution for a drug-coated balloon.

10. The method for producing the nanocrystalline particles includes an anti-solvent method, a high-pressure homogenization method, or a microfluidic method; Preferably, the anti-solvent method comprises: Step S1: accurately weighing sirolimus and an organic solvent, and magnetically stirring them to obtain a transparent and homogeneous solution in phase A; Step S2: accurately weighing the surfactant and the aqueous phase solvent, and magnetically stirring the mixture to obtain a transparent and uniform solution of phase B; Step S3: rapidly adding the phase A solution to the phase B solution and magnetically stirring to obtain a nanocrystal suspension; and step S4 of adding water to the suspension to mix uniformly, and freeze-drying the mixture to obtain the nanocrystalline particles. Preferably, the nanocrystalline particles have a particle size d50 of 150 to 900 nm, and the mass ratio of sirolimus to surfactant is 5:1 to 1:2; Preferably, the high pressure homogenization method comprises: Step S1: accurately weighing sirolimus, an aqueous solvent, and a surfactant, and magnetically stirring the mixture to obtain a suspension; Step S2: homogenizing the suspension multiple times with a high-pressure homogenizer to obtain a nanocrystal suspension; and step S3 of freeze-drying to obtain sirolimus nanocrystals; Preferably, 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, and the mass ratio of sirolimus to surfactant is 5:1-1:2; Preferably, the microfluidic method comprises: Step S1: accurately weighing sirolimus, an aqueous solvent, and a surfactant, and magnetically stirring the mixture to obtain a suspension; Step S2: homogenizing the suspension multiple times by a microfluidic device to obtain a nanocrystal suspension; and step S3 of freeze-drying to obtain sirolimus nanocrystals; Preferably, the particle size d50 of the nanocrystalline particles is 150-900 nm, the microfluidic pressure is 1000-2000 bar, the number of homogenization times is 5-10, and the mass ratio of sirolimus to surfactant is 5:1-1:

2. The coating solution for a drug-coated balloon according to claim 9 .

11. The drug dose was 3 μg / mm ２ 1.5 μg / mm ２ More preferably, the use of a drug coated balloon for sirolimus in the treatment of intracranial arterial stenosis.

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