Pharmaceutical composition, interventional medical device, drug delivery device, preparation method, and use

Abstract

Provided are a pharmaceutical composition, an interventional medical device, a drug delivery device, a preparation method, and use. The pharmaceutical composition herein comprises liposome microspheres. The liposome microspheres comprise: drug microspheres, comprising a drug and a degradable material; and liposomes, comprising a phospholipid bilayer and encapsulating the drug microspheres, wherein the phospholipid bilayer comprises phospholipid. The pharmaceutical composition herein enables the liposome microspheres comprising the drug microspheres to firmly adhere to the blood vessel wall so that the microspheres will not be washed away by blood flow, and can facilitate the entry of the microspheres into the blood vessel wall.

Description

Pharmaceutical composition, interventional medical device, drug delivery device, preparation method and application

[0001] This application claims the priority of the Chinese Invention Patent Application with the application date of September 4, 2024, the application number of 202411238984.7, and the invention name of "Pharmaceutical composition, interventional medical device, drug delivery device, preparation method and application". TECHNICAL FIELD

[0002] The present application relates to the field of medical devices, in particular to a pharmaceutical composition, an interventional medical device, a drug delivery device, a preparation method and application. BACKGROUND

[0003] The main means of treating vascular stenosis is to implant a drug-eluting stent. After implanting the stent, the patient needs to take anti-thrombotic drugs for a long time, which affects the subsequent surgical treatment, and there is a problem of late stent thrombosis. Therefore, "intervention without implantation" as a new concept of interventional medicine is being accepted by more and more clinicians and patients, and the drug-eluting balloon (DCB) is a new product under this concept of interventional treatment.

[0004] The drug-eluting balloon is a new type of intravascular drug release technology. The anti-proliferative drug is coated on the surface of the balloon. When the balloon reaches the diseased blood vessel and is expanded and dilated, it contacts the intima of the blood vessel wall. The drug carried on the surface of the balloon is quickly transferred to the blood vessel wall and remains for a period of time, thereby inhibiting the intimal hyperplasia of the blood vessel. Human clinical studies have confirmed that the restenosis of the diseased blood vessel usually occurs 1 to 3 months after balloon angioplasty, and the restenosis reaches the highest point at about 3 months, which requires the drug on the balloon to penetrate into the blood vessel wall and maintain an effective drug concentration for a long enough time to minimize restenosis.

[0005] At present, the drug balloon on the market mainly uses paclitaxel as an anti-proliferative drug, among which the paclitaxel releasing balloon catheter SeQuent Please of Germany's B. Braun is the representative. Sirolimus can form a complex with intracellular FKBP-12, bind to the mammalian target of rapamycin, and reversibly inhibit the cell cycle transition of proliferating smooth muscle cells. It is mainly used in the G1 phase of vascular smooth muscle mitosis, so that the cell mitosis stops in the resting phase G0. As an anti-proliferative drug, it is mainly used on the stent coating. Due to the poor liposolubility of sirolimus and the reversibility of the combination of sirolimus and FKBP-12, the retention time in the tissue is short, so it is difficult to be applied to drug balloons. At present, the drug balloon on the market mainly uses paclitaxel. However, paclitaxel itself achieves the purpose of inhibiting the proliferation of smooth muscle cells by causing apoptosis or death of cells, that is, paclitaxel has a certain cytotoxicity. Sirolimus and its derivatives achieve the purpose of anti-proliferation by a cell inhibition mechanism, that is, by acting on cells to make them stop growing. In view of the overall safety of sirolimus being superior to that of paclitaxel, the safety of sirolimus has been proven in clinical practice, and it has been widely used in drug stents.

[0006] Therefore, developing a drug balloon dilatation catheter with sirolimus as the coating drug will have a wide range of application scenarios. SUMMARY

[0007] In order to solve the problem of poor liposolubility of sirolimus and short retention time in the tissue, two technical routes are mainly adopted at home and abroad at present: (1) the Magic Touch balloon catheter of Concept Medical is taken as a representative to use sirolimus nanocrystals as an anti-proliferative drug for a drug balloon. Sirolimus nanocrystals, phospholipids and polyethylene glycol are mixed and dispersed in water, and ultrasonic is performed; and (2) the Selution balloon catheter of M.A. Medical Joint Company is taken as a representative to use a degradable material to wrap sirolimus to form microspheres. The microspheres, phospholipids, PEGylated lipids, cholesterol and other auxiliary materials are dispersed in heptane, and a spraying method is used. Due to the rapid volatilization of heptane, phospholipids are precipitated and attached to the surface of the microspheres.

[0008] The inventors of the present application found that when the first technical route is adopted, the phospholipids cannot be well attached to the surface of the nanocrystals, and the retention time in the tissue is short. When the second technical route is adopted, the phospholipid film formed on the surface of the microspheres is a monolayer phospholipid, not a bilayer film in the form of liposomes. There are disadvantages such as small binding force between phospholipids and microspheres, and easy to be washed away by blood flow.

[0009] The inventors of the present application found that the key technical point of sirolimus and its derivative drug balloon is how to improve the adhesion of the drug and the vascular intima. Therefore, a new drug balloon catheter coating is developed to solve the problem of adsorption and absorption of sirolimus and its derivatives to the blood vessels.

[0010] This application provides a pharmaceutical composition, an interventional medical device, a drug delivery device, a preparation method, and an application, which solves the problems of low lipid solubility of drugs, poor adsorption capacity to the vascular endothelium, and easy flushing away by blood flow, and achieves controllable drug release cycle, enabling drugs to be retained in the blood vessel wall for a long time.

[0011] In one aspect, a pharmaceutical composition is provided, the pharmaceutical composition comprising drug microspheres, the drug microspheres comprising a drug and a biodegradable material; and

[0012] Liposomes comprising a phospholipid bilayer containing phospholipids; wherein the liposomes encapsulate the drug microspheres to form liposome microspheres.

[0013] In some embodiments, the weight ratio of the drug microspheres to the phospholipid bilayer is 1:5 to 20:1. In some embodiments, the drug composition is used as a coating for an interventional medical device. In some embodiments, the drug is dispersed in a biodegradable material. In some embodiments, the biodegradable material is one or more of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, and glycosaminoglycans.

[0014] In some embodiments, the diameter of the drug microspheres ranges from 0.1 to 10 μm. In some embodiments, the in vitro degradation time of the biodegradable material is 2-12 months. In some embodiments, the biodegradable material is one or more of polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), and polycaprolactone (PCL). In some embodiments, the drug is one or more of eutrimoxil, sirolimus, everolimus, zotamoxetine, paclitaxel, and their analogues.

[0015] In some embodiments, the phospholipid is one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. In some embodiments, the phosphatidylcholine is one or more of egg phosphatidylcholine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diacyl-sn-glycero-3-phosphocholine (HSPC), 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dierucoyl-sn-glycero-3-phosphocholine (DEPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-myristoyl-2-palmitoyl-SN-glycero-3-phosphocholine (MPPC), 1-myristoyl-2-stearoyl-SN-glycero-3-phosphocholine (MSPC), and 1-stearoyl-2-myristoyl-SN-glycero-3-phosphocholine (SMPC). In some embodiments, the phosphatidylethanolamine is one or more of 1,2-dioleoyl-SN-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine (DMPE), 1,2-dipalmitoyl-SN-glycero-3-phosphoethanolamine (DPPE), and 1,2-distearoyl-SN-glycero-3-phosphoethanolamine (DSPE). In some embodiments, the phosphatidylserine is one or more of 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) and its sodium salts, dipalmitoyl phosphatidylserine sodium (DPPS), distearoyl phosphatidylserine sodium (DSPS), 1,2-dilauroyl-sn-glycero-3-phospho-L-serine sodium (DLPS), dioleoyl phosphatidylserine sodium (DOPS). In some embodiments, the phospholipid comprises phospholipids having acyl chain lengths of less than or equal to 20 carbons, preferably 10 to 18 carbons. In some embodiments, the phospholipid comprises phospholipids having acyl chain lengths of 10 to 18 carbons, or 40% to 100% of the molar amount of the phospholipids having acyl chain lengths of 10 to 18 carbons relative to the total molar amount of phospholipids.

[0016] In some embodiments, the liposome microspheres are dispersed in the pharmaceutically acceptable excipient. In some embodiments, the weight ratio of the excipient to the drug microspheres is 1:3-5:1. In some embodiments, the excipient is one or more of polyethylene glycol, polyethylene oxide, DC-cholesterol, butylated hydroxytoluene, probucol, iopromide, iohexol, iopamidol, urea, mannitol, PEGylated lipids, cationic lipids, hyaluronic acid, vitamin E, polysorbate, xanthan gum, puerarin, inosine, gelatin, gum arabic, butylated hydroxyanisole, chitosan, polyethylene glycol-poly caprolactone, dextran, and shellac.

[0017] In some embodiments, the excipient is one or more of polyethylene oxide, cationic lipids, and gum arabic. In some embodiments, the PEGylated lipid is one or more of 1,2- distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE- mPEG2000), 1,2-distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine-N- methoxy(polyethylene glycol)-2000 (DMPE-mPEG2000), 1,2-dimyristoyl-SN-glycero-3- phosphoethanolamine-N-methoxy(polyethylene glycol)-5000 (DMPE-mPEG5000), 1,2- dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DPPE- mPEG2000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-5000 (DPPE-mPEG5000).

[0018] In some embodiments, the phospholipid bilayer further comprises one or more of cholesterol and a cationic lipid. In some embodiments, the cholesterol comprises 0% to 55% of the mole ratio of the liposome. In some embodiments, the cationic lipid comprises 0% to 50% of the mole ratio of the liposome. In some embodiments, the cholesterol is one or more of 3β-hydroxy-5-cholesten (ordinary cholesterol) and 3β-[N-(N',N'-dimethylaminoethane)-formyl]cholesterol (also known as dimethylaminoethane-carbamoylcholesterol, or DC-Cholesterol). In some embodiments, the cationic lipid is one or more of (2,3-dioleoyl-propyl)-trimethylamine (DOTAP), DC-Cholesterol, dimyristylglycerol-polyethyleneglycol 2000 (DMG-PEG 2000), 1,2-dioleoyl-3-dimethylamino-propane (DODMA), 1,2-dioleoyloxy-3-methylammoniumpropane (DOTMA), 4-(N,N-dimethylamino)butanoic acid (dilinoleyl) methyl ester (DLin-MC3-DMA).

[0019] In some embodiments, the phospholipid bilayer is prepared by a method comprising the step of dissolving the lipophilic material in an organic solvent and performing rotary evaporation at a temperature greater than 30°C, preferably 30°C to 60°C. In one embodiment, the organic solvent is one or more of dichloromethane, trichloromethane, methanol, ethanol, acetone, and diethyl ether. In one embodiment, the lipophilic material comprises a phospholipid, or a phospholipid and cholesterol, or a phospholipid and a cationic lipid, or a phospholipid and cholesterol and a cationic lipid. In some embodiments, the liposome microspheres are prepared by a method comprising the step of mixing the phospholipid bilayer, the drug microspheres, and water or an aqueous buffer solution in a water bath at 30°C to 55°C. In one embodiment, the aqueous buffer solution is a citrate buffer solution, a phosphate buffer solution, a borate buffer solution, or a tris buffer solution.

[0020] In another aspect, a method of making a pharmaceutical composition according to the present disclosure is provided, comprising the steps of dissolving a lipophilic material in an organic solvent, and rotary evaporation at a temperature greater than 30°C, preferably 30°C to 60°C to form a phospholipid bilayer membrane, and mixing the phospholipid bilayer membrane, the drug microspheres, and water or an aqueous buffer solution in a container in a water bath at 30°C to 55°C to form the liposome microspheres. In one embodiment, the lipophilic material comprises a phospholipid, or a phospholipid and cholesterol, or a phospholipid and a cationic lipid, or a phospholipid and cholesterol and a cationic lipid. In one embodiment, the organic solvent is one or more of dichloromethane, trichloromethane, methanol, ethanol, acetone, and diethyl ether. In one embodiment, the aqueous buffer solution is a citrate buffer solution, a phosphate buffer solution, a borate buffer solution, or a tris buffer solution.

[0021] In one embodiment, the method comprises:

[0022] (1) making drug microspheres of a degradable material and a drug, preferably by emulsification solvent evaporation method;

[0023] (2) placing a phospholipid, a cationic lipid, and cholesterol in a container, adding an organic solvent to dissolve, rotary evaporation to dry, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane; or, placing a phospholipid and a cationic lipid in a container, adding an organic solvent to dissolve, rotary evaporation to dry, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane; or, placing a phospholipid alone in a container, adding an organic solvent to dissolve, rotary evaporation to dry, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane; or, placing a phospholipid and cholesterol in a container, adding an organic solvent to dissolve, rotary evaporation to dry, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane;

[0024] (3) mixing the drug microspheres, the phospholipid bilayer membrane, and water or the aqueous buffer solution in a water bath by ultrasonic mixing, and then by magnetic stirring to obtain a solution containing the liposome microspheres.

[0025] In another aspect, an interventional medical device is provided, comprising a balloon, a catheter connected to the balloon, and a drug coating, the drug coating comprising a pharmaceutical composition according to the present disclosure, the drug coating being disposed at least on a portion of the surface of the balloon.

[0026] In another aspect, a method of making a drug coated balloon dilatation catheter is provided, the interventional medical device being a balloon dilatation catheter, and after obtaining the solution containing the liposome microspheres, the method further comprises one or more of the following steps:

[0027] (4) mixing the pharmaceutically acceptable excipient with the liposome microsphere solution to obtain a coating drug solution;

[0028] (5) performing plasma treatment on the surface of the balloon dilatation catheter;

[0029] (6) folding the balloon of the balloon dilatation catheter to form a plurality of wing petals, the plurality of wing petals having a plurality of "V" shaped spaces therebetween;

[0030] (7) applying the coating drug solution to the plurality of "V" shaped spaces to form a balloon dilatation catheter having a drug coating.

[0031] Optionally, the method further comprises one or more of the following steps:

[0032] (8) after the drug coating is dried, winding the balloon and vacuum drying with a protective sleeve;

[0033] (9) loading the balloon dilatation catheter into a coil, and then loading the coil into a dialysis paper bag for sterilization;

[0034] (10) loading the dialysis paper bag together with a desiccant and an oxygen absorber into an aluminum foil bag, and then loading the aluminum foil bag into a packaging box.

[0035] In another aspect, a drug delivery device comprising the pharmaceutical composition described herein or the pharmaceutical composition prepared by the method described herein is provided. For example, the drug delivery device is a drug-loaded balloon dilatation catheter, a drug-eluting stent, a drug delivery micro-robot, etc.

[0036] In yet another aspect, the use of the pharmaceutical composition described herein, the pharmaceutical composition prepared by the method described herein in the preparation of a medicament or an apparatus for the dilation of a blood vessel, or the treatment of atherosclerosis, a stenosis or restenosis in a diseased blood vessel is provided.

[0037] In yet another aspect, the use of the pharmaceutical composition described herein, the pharmaceutical composition prepared by the method described herein, the interventional medical device, the interventional medical device prepared by the method described herein, or the drug delivery device in the preparation of a kit for the dilation of a blood vessel, or the treatment of atherosclerosis, a stenosis or restenosis in a diseased blood vessel is provided.

[0038] In yet another aspect, the pharmaceutical composition described herein, the interventional medical device, or the drug delivery device is provided for the dilation of a blood vessel, or the treatment of atherosclerosis, a stenosis or restenosis in a diseased blood vessel.

[0039] In yet another aspect, a method for vasodilation, or treatment of atherosclerosis, stenosis or restenosis in a diseased blood vessel, comprising administering to a subject in need thereof a pharmaceutical composition, an interventional medical device, or a drug delivery device. In this context, the subject is a human or a mammal.

[0040] Advantages of the present application include:

[0041] 1. The present application provides a pharmaceutical composition with good resistance to blood flow flushing and adhesion. The pharmaceutical composition comprises liposome microspheres, the liposome microspheres comprise drug microspheres and liposomes formed by phospholipid bilayer membrane wrapping the drug microspheres, which can firmly adhere the drug microspheres to the blood vessel wall and not be flushed away by blood flow, and promote the drug microspheres to enter the blood vessel wall.

[0042] 2. The drug (such as sirolimus and its derivatives) and the degradable material (such as PLGA, PCL or PLA) form drug microspheres, and the drug is uniformly distributed in the interior of the drug microspheres, and the drug is slowly released with the continuous degradation of the drug microspheres.

[0043] 3. The present application solves the problems of poor liposolubility of sirolimus and its derivatives, low adhesion to the blood vessel intima, and short tissue retention time in the prior art, and has wide application value. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 shows sirolimus microspheres wrapped by phospholipid bilayer (dry state) according to an embodiment of the present application.

[0045] Figure 2 shows the appearance of a balloon drug coating according to an embodiment of the present application, specifically the appearance after the drug coating is coated on the surface of the balloon and dried.

[0046] Figure 3 shows a schematic diagram of the structure of liposome microspheres formed by phospholipid bilayer wrapping drug microspheres according to an embodiment of the present application. DETAILED DESCRIPTION

[0047] In order to make the technical problems, technical solutions and beneficial effects of the present application more clear, the following specific embodiments further illustrate the present application in detail.

[0048] A drug composition is provided, in which drug microspheres are coated with a phospholipid bilayer membrane to form liposome microspheres. Specifically, drug and degradable material are made into microspheres, and the phospholipid bilayer membrane is coated on the surface of the drug microspheres to make liposome microspheres. The preparation method can use a modified film dispersion method; a coating liquid containing an excipient and liposome microspheres is mixed and coated on the surface of an interventional medical device such as a balloon of a balloon catheter to make a balloon catheter including a drug coating. The drug composition can also include an excipient, and the liposome microspheres are dispersed in a pharmaceutically acceptable excipient, which can transfer and adhere the drug-loaded liposome microspheres to the blood vessel wall when the interventional medical device is close to the blood vessel wall, such as the balloon is expanded at the blood vessel lesion site.

[0049] Drug composition

[0050] A drug composition is disclosed herein that can be used for coating an expandable portion of a balloon catheter. The balloon catheter is designed for insertion into a living body to locally deliver at least one drug. The coating including the drug composition is formulated and configured for minimal dissolution and dispersion into the blood stream or body fluid when the catheter is placed into a target blood vessel or body lumen for treatment, or after the coating is delivered to the tissue at the treatment site, such as the blood vessel wall or lumen wall. The coating is configured to transfer to the lumen surface or lumen wall that the coating contacts when the expandable portion is expanded. In some blood vessels or body lumens, the inner surface of the blood vessel or body lumen can be diseased and can have irregular structures such as due to plaque, lesions or previous interventions. The coating is configured to transfer to the lumen surface including the irregular structures. The drug can be delivered to the blood vessel to prevent or minimize the restenosis after balloon angioplasty. In some embodiments, the expandable portion can be a balloon of a balloon catheter. In other embodiments, the expandable portion can also be a vascular stent, a lumen occluder, a heart valve prosthesis, etc. body lumen implantation device.

[0051] The drug composition described herein can be present on the surface of a balloon catheter as the only component in a coating or with a base layer and / or a protective layer. The drug composition can include liposome microspheres, in which the liposome microspheres include drug microspheres and liposomes. The coating can also include an excipient.

[0052] Drug microspheres

[0053] The drug microspheres of the pharmaceutical compositions herein do not require that the microspheres be regular spherical in shape, they can be spherical, spheroidal, polyhedral or any spheroid-like or other shape, so long as they encapsulate a drug in their structure. The drug microspheres can comprise a drug and a degradable material. The drug and the degradable material can each be distributed in different layers, for example the drug microspheres can comprise a shell and a drug encapsulated within the shell, so that the degradable material is not intermixed with the drug. Alternatively, the drug can be dispersed in the degradable material, the drug microspheres can also be made of a degradable material doped with a drug, the drug microspheres can also be made of a degradable material chemically linked to a drug. The drug microspheres, also known as microreservoirs, can be manufactured by any known method for particle manufacture, including spray drying, coacervation, micro-molding and milling. All such methods start with dissolving the drug and the polymer together in a suitable solvent, then removing the solvent in a controlled manner that produces a uniform microspherical morphology. The drug microspheres can be further shaped by mechanical methods. Methods that produce a microspherical morphology with a size distribution that has a coefficient of variation of 10% or less are particularly useful to provide a more consistent release rate of the active agent. Methods to produce microspheres of uniform size are described by forming an emulsion of the microspherical material and extruding the emulsion through a substrate with a controlled size of through holes, as described in US 7,972,543 and US 8,100,348. In this context, it is preferred to use the emulsification solvent evaporation method to make the microspheres. The drug microspheres herein can have a diameter in the range of 0.1-10 μm, for example 0.1 μm, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm or any range in between.

[0054] Degradable materials are known herein to refer to materials that are capable of disintegrating or decomposing in an ecological environment or in a living organism, and the products generated are harmless to the environment or the living organism, including degradable polymers, degradable alloys, etc. In the context herein, degradable materials also encompass biodegradable or bioerodible polymers. These polymers can provide controlled and extended release of active agents. The polymers can act as a barrier to drug diffusion, thereby providing a release profile that is tailored to the pharmacokinetics of the active agent to be effective on the treated vessel. For example, the drug can be mixed and distributed in the polymer in a solid solution. The polymer can provide controlled release by slowing down drug diffusion or by coupling drug release to the biodegradation, dissolution or bioerodibility of the polymer. In some embodiments, the biodegradable or bioerodible polymer is selected from one or more of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan and glycosaminoglycans. In some embodiments, the drug microspheres are microspheres comprising the same drug, or a mixture of microspheres comprising different drugs. The drug microspheres can comprise one drug or can comprise two or more drugs. The drug microspheres can be microspheres of one biodegradable or bioerodible polymer, or a mixture of microspheres of two or more biodegradable or bioerodible polymers.

[0055] After the drug composition is in contact with the luminal wall in vivo, the kinetics of drug release is controlled by the release of the drug from the drug microspheres into the surrounding medium, thereby enabling sustained elution of the active agent to penetrate into the vessel wall. The in vitro degradation time of the degradable material is 2-12 months.

[0056] The drug contained in the drug microspheres can be any suitable drug, including but not limited to anti-proliferative agents, anti-inflammatory agents, anti-neoplastic agents, anti-coagulants, anti-fibrin agents, anti-thrombotic agents, anti-mitotic agents, antibiotic agents, anti-allergic agents and anti-oxidants, anti-proliferative agents, estrogens, protease inhibitors, antibodies, immunosuppressive agents, cytostatic agents, cytotoxic agents, calcium channel blockers, phosphodiesterase inhibitors, prostaglandin inhibitors, etc. Preferably, the drug is a poorly lipid-soluble drug. For example, the drug is one or more of everolimus, sirolimus, evirolimus and zotarolimus or analogs thereof, etc.

[0057] Liposomes

[0058] The coating described herein contains liposomes. The liposomes contain a phospholipid bilayer membrane. In the present invention, in an aqueous environment, the dry phospholipid bilayer membrane can close through exposed edges under external force (e.g. mechanical stirring, ultrasound) to form liposomes, unless otherwise specified.

[0059] Phospholipid bilayer membranes can be prepared from lipophilic materials (e.g., phospholipids, cationic lipids, or cholesterol). Specifically, the lipophilic materials are dissolved in an organic solvent and the step of rotary evaporation is performed at a temperature greater than 30°C, preferably 30°C to 60°C (e.g., 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, or any range therebetween). The organic solvent can be one or more of dichloromethane, trichloromethane, methanol, ethanol, acetone, and diethyl ether. For example, phospholipids, cationic lipids, and cholesterol can be placed in a container, dissolved with an organic solvent, rotary evaporated to dryness, and dried in a vacuum desiccator to obtain a phospholipid bilayer membrane; or phospholipids and cationic lipids can be placed in a container, dissolved with an organic solvent, rotary evaporated to dryness, and dried in a vacuum desiccator to obtain a phospholipid bilayer membrane; or phospholipids alone can be placed in a container, dissolved with an organic solvent, rotary evaporated to dryness, and dried in a vacuum desiccator to obtain a phospholipid bilayer membrane.

[0060] The class of phospholipids is not particularly limited, for example, it can be a phospholipid comprising an acyl chain length of 10 to 34 carbons (e.g., 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 carbons or any range therebetween). However, it is preferred that the phospholipids in the present application comprise phospholipids having an acyl chain length of less than or equal to 20 carbons, preferably comprising phospholipids having an acyl chain length of 10 to 18 carbons. When there are two or more different phospholipids, the proportion of each phospholipid present in the lipid bilayer membrane is readily determined by the skilled person. The inventors have found that phospholipids having an acyl chain length of less than or equal to 20 carbons, preferably 10 to 18 carbons, or even more preferably when 40% to 100% (e.g., 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) of the molar amount of phospholipids having an acyl chain length of 10 to 18 carbons relative to the total molar amount of phospholipids, can achieve even more superior drug residual rate and tissue drug concentration. In some embodiments, the phospholipids consist of phospholipids having an acyl chain length of less than or equal to 20 carbons. The phospholipids can be one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. Preferably, the phosphatidylcholine is one or more of egg phosphatidylcholine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diacyl-sn-glycero-3-phosphocholine (HSPC), 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dierucoyl-sn-glycero-3-phosphocholine (DEPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-myristoyl-2-palmitoyl-SN-glycero-3-phosphocholine (MPPC), 1-myristoyl-2-stearoyl-SN-glycero-3-phosphocholine (MSPC), and 1-stearoyl-2-myristoyl-SN-glycero-3-phosphocholine (SMPC). Preferably, the phosphatidylethanolamine is one or more of 1,2-dioleoyl-SN-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine (DMPE), 1,2-dipalmitoyl-SN-glycero-3-phosphoethanolamine (DPPE), and 1,2-distearoyl-SN-glycero-3-phosphoethanolamine (DSPE). Preferably, the phosphatidylserine is one or more of 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS) and its sodium salts, dipalmitoyl phosphatidylserine sodium (DPPS), distearoyl phosphatidylserine sodium (DSPS), 1,2-dilauroyl-sn-glycero-3-phospho-L-serine sodium (DLPS), dioleoyl phosphatidylserine sodium (DOPS).The phospholipid can comprise 20-100% of the total liposome by molar ratio, such as 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, or any range therebetween.

[0061] The phospholipid bilayer membrane can comprise cholesterol and / or a cationic lipid in addition to the phospholipid. The cholesterol can be one or more of cholesterol and dimethylaminoethane-carbamoylcholesterol (DC-Cholesterol). The cholesterol can comprise 0-55% of the total liposome by molar ratio, such as 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, or any range therebetween. It is understood that the last significant figure in the values recited herein is rounded; specifically, for example, when the cholesterol comprises 17.4% of the liposome by molar ratio, the value under the percent sign is rounded to 17% with the last significant figure being "4", and for example, when the cholesterol comprises 17.6% of the liposome by molar ratio, the value under the percent sign is rounded to 18% with the last significant figure being "6". The same understanding applies to the recitation of other parameter values in the detailed description section of the application, unless otherwise specified.

[0062] The cationic lipid can be one or more of (2,3-dioleoyl-propyl)-trimethylamine (DOTAP), dimyristylglycerol-polyethylene glycol 2000 (DMG-PEG2000), 1,2-dioleoyl-3-dimethylamino-propane (DODMA), 1,2-dioleoxy-3-methylammonium propane (DOTMA), 4-(N,N-dimethylamino)butanoic acid (dilinoleyl) methyl ester (DLin-MC3-DMA). The molar ratio of cationic lipid to liposome can be 0-50%, for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or any range therebetween.

[0063] The phospholipid bilayer, drug microspheres, and water or aqueous buffer solution can be mixed in a container to form liposome microspheres in a water bath at 30-55°C (e.g., 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, or any range therebetween). The weight ratio of drug microspheres to lipophilic material (or phospholipid bilayer) can be 1:5-20:1, for example, 1:5, 2:5, 1:2, 3:5, 4:5, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, or any range therebetween. The weight ratio of drug microspheres to lipophilic material (or phospholipid bilayer) can be 0.2-20, also 0.2, 0.3, 0.4, 0.5, 0.7, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or any range therebetween. The amount of water or aqueous buffer solution added to make the liposomes is known in the art and will ultimately be removed in the drying step.

[0064] In some embodiments, the phospholipid bilayer membrane comprises DEPC, DSPC, and 3 -hydroxy-5-cholesten. In some embodiments, the phospholipid bilayer membrane comprises DMPC, HSPC, and 3 -hydroxy-5-cholesten. In some embodiments, the phospholipid bilayer membrane comprises DOTAP, DOPE, HSPC, and 3 -hydroxy-5-cholesten. In some embodiments, the phospholipid bilayer membrane comprises DLin-MC3-DMA, DOPE, and 3 -hydroxy-5-cholesten. In some embodiments, the phospholipid bilayer membrane comprises DEPC, DPPC, DODMA, and 3 -hydroxy-5-cholesten. In some embodiments, the phospholipid bilayer membrane comprises DOTAP, HSPC, and 3 -hydroxy-5-cholesten. In some embodiments, the phospholipid bilayer membrane comprises DOTAP and HSPC. The phospholipid bilayer membrane comprises DOTAP and HSPC. In some embodiments, the phospholipid bilayer membrane comprises DOTAP, HSPC, and DPPC. In some embodiments, the phospholipid bilayer membrane comprises DEPC, HSPC, and DPPC. In some embodiments, the phospholipid bilayer membrane comprises DEPC, HSPC, and DOTAP.

[0065] Coating solution

[0066] The coating solution herein comprises a pharmaceutical composition, and can further comprise an aqueous solvent. The pharmaceutical composition comprises liposome microspheres. The pharmaceutical composition can further comprise an excipient. The drug-loaded liposome microspheres can be dispersed (e.g., uniformly or substantially uniformly) in the excipient. The excipient can facilitate rapid transfer of the drug-loaded liposome microspheres to the vessel wall when the balloon is expanded at the site of the vascular lesion. The weight ratio of the excipient to the drug microspheres can be 1:3-5:1, such as 1:3, 1:2, 2:3, 1:1, 2:1, 3:1, 4:1, 5:1, or any range therebetween. The weight ratio of the excipient to the drug microspheres can be 0.33-5, and can also be 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.51, 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.6, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.9, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, or any range therebetween. It is understood that the last significant figure of the enumerated values herein is rounded. Specifically, for example, when the weight ratio of the excipient to the drug microspheres is 0.552, the number "2" beyond the two significant figures is rounded to 0.55. For another example, when the weight ratio of the excipient to the drug microspheres is 0.557, the number "7" beyond the two significant figures is rounded to 0.56. The same understanding applies to other enumerated values of parameters in the DETAILED DESCRIPTION section of the present application, unless otherwise specified.

[0067] The excipient or dispersant can be one or more of polyethylene glycol, polyethylene oxide, DC-Cholesterol, butylated hydroxytoluene, probucol, iopromide, iohexol, iopamidol, urea, mannitol, PEGylated lipids, cationic lipids, hyaluronic acid, vitamin E, polysorbate, xanthan gum, acacia, puerarin, inosine, gelatin, butylated hydroxyanisole, chitosan, polyethylene glycol-poly caprolactone, dextran, and shellac. Preferably, the PEGylated lipid is one or more of 1,2-distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-mPEG2000), 1,2-distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DMPE-mPEG2000), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-5000 (DMPE-mPEG5000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DPPE-mPEG2000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-5000 (DPPE-mPEG5000). More preferably, the excipient is one or more of polyethylene oxide, cationic lipids, and acacia.

[0068] The solvent in the coating drug solution herein can be an aqueous solvent, such as a phosphate solution, a citrate solution, and other pharmaceutically acceptable other aqueous solution, and the solvent in the coating drug solution herein can also be water. When the solvent in the coating drug solution is an aqueous solvent, under suitable process operation, the liposome microspheres formed by the liposome-encapsulated drug microspheres containing the lipophilic material have a phospholipid bilayer membrane outer layer. The inventors of the present application have found that the drug-coated balloon catheter prepared by using the liposome-encapsulated drug microspheres as the coating drug solution has better advantages in adhesion, resistance to flushing, and increasing tissue drug concentration.

[0069] Method of preparing a pharmaceutical composition

[0070] The method of preparing the pharmaceutical composition herein can comprise the steps of dissolving the lipophilic material in an organic solvent and rotary evaporation at a temperature greater than 30°C, preferably 30-60°C (e.g. 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60°C or any range therebetween) to form a phospholipid bilayer membrane, and mixing the phospholipid bilayer membrane, drug microspheres and water or aqueous buffer solution in a container in a water bath at 30-55°C (e.g. 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55°C or any range therebetween) to form a solution containing liposome microspheres. The organic solvent can be one or more of dichloromethane, trichloromethane, methanol, ethanol, acetone and diethyl ether. The aqueous buffer solution is a citrate buffer solution, a phosphate buffer solution, a borate buffer solution or a tris buffer solution.

[0071] In particular, the method comprises:

[0072] (1) preparing drug microspheres from the degradable material and the drug, preferably by emulsion solvent evaporation method;

[0073] (2) placing phospholipid, cationic lipid and cholesterol in a container, adding an organic solvent to dissolve, rotary evaporation to dryness, and drying in a vacuum drying oven to obtain a phospholipid bilayer membrane; or placing phospholipid and cationic lipid in a container, adding an organic solvent to dissolve, rotary evaporation to dryness, and drying in a vacuum drying oven to obtain a phospholipid bilayer membrane; or placing phospholipid alone in a container, adding an organic solvent to dissolve, rotary evaporation to dryness, and drying in a vacuum drying oven to obtain a phospholipid bilayer membrane; or placing phospholipid and cholesterol in a container, adding an organic solvent to dissolve, rotary evaporation to dryness, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane;

[0074] (3) mixing the drug microspheres, the phospholipid bilayer membrane and water or an aqueous buffer solution in a water bath by ultrasonic mixing and then magnetic stirring to obtain a solution containing liposome microspheres.

[0075] Specific process for preparing a drug-coated balloon dilatation catheter

[0076] The specific process for preparing a drug-coated balloon dilatation catheter herein comprises the following steps:

[0077] (1) The degradable material and the drug are prepared into drug microspheres by emulsification solvent evaporation method;

[0078] (2) The phospholipid, the cationic lipid and the cholesterol are placed in a flask, an organic solvent is added to dissolve, rotary evaporation is performed until dry, and drying is performed in a vacuum drying box to obtain a phospholipid bilayer membrane; or the phospholipid and the cationic lipid are placed in a flask, an organic solvent is added to dissolve, rotary evaporation is performed until dry at a certain temperature, and drying is performed in a vacuum drying box to obtain the phospholipid bilayer membrane; or the phospholipid is placed in a flask alone, an organic solvent is added to dissolve, rotary evaporation is performed until dry, and drying is performed in a vacuum drying box to obtain the phospholipid bilayer membrane; or the phospholipid and the cholesterol are placed in a container, an organic solvent is added to dissolve, rotary evaporation is performed until dry, and drying is performed in a vacuum drying box to obtain the phospholipid bilayer membrane;

[0079] (3) The drug microspheres prepared in step (1) are added to the flask in step (2), water or an aqueous buffer solution is added, ultrasonic treatment is performed in a water bath, and then magnetic stirring is performed to obtain a solution containing liposome microspheres;

[0080] (4) The excipient is added to the flask in step (3), and then magnetic stirring is performed to obtain a coating liquid;

[0081] (5) The balloon dilatation catheter is taken and the balloon is cleaned, and after the balloon is dried, the balloon of the balloon dilatation catheter is treated by plasma treatment; the purpose of cleaning the balloon is to remove surface dust, and the plasma treatment of the balloon can improve the hydrophilicity of the surface of the balloon;

[0082] (6) The balloon of the balloon dilatation catheter is folded by using a balloon folding machine, so that the balloon forms a plurality of folded wing petals, and has a plurality of "V" shaped spaces; preferably, the number of folded wings is three;

[0083] (7) A fixed volume of the coating liquid prepared in step (4) is sucked by using a flat-head micro-syringe, and is injected into the plurality of "V" shaped spaces of the balloon in sequence;

[0084] (8) After the drug coating is dried, the balloon is wound and a protective sleeve is sleeved, and vacuum drying is performed for 24 hours;

[0085] (9) The balloon dilatation catheter is loaded into a coil, and then the coil is loaded into a dialysis paper bag for sterilization;

[0086] (10) The dialysis paper bag is loaded into an aluminum foil bag together with a drying agent and an oxygen absorber, and a packaging box is sleeved.

[0087] The degradable material for preparing the drug microspheres in step (1) is polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL) and a combination thereof.

[0088] The drug of step (1) is one or more of everolimus (BA9), temsirolimus (Rapa), sirolimus, zotarolimus, paclitaxel.

[0089] The phospholipid of step (2) is selected from one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol.

[0090] The cholesterol of step (2) is selected from one or more of 3β-hydroxy-5-cholestene (ordinary cholesterol), 3β-[N-(N',N'-dimethylaminoethane)-formyl]cholesterol (also known as DC-Cholesterol).

[0091] The organic solvent of step (2) is selected from one or more of dichloromethane, trichloromethane, methanol, ethanol, acetone, diethyl ether.

[0092] The phosphatidylcholine of step (2) is selected from one or more of egg phosphatidylcholine, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diacyl-sn-glycero-3-phosphocholine (HSPC), 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dierucoyl-sn-glycero-3-phosphocholine (DEPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-myristoyl-2-palmitoyl-SN-glycero-3-phosphocholine (MPPC), 1-myristoyl-2-stearoyl-SN-glycero-3-phosphocholine (MSPC), 1-stearoyl-2-myristoyl-SN-glycero-3-phosphocholine (SMPC).

[0093] The phosphatidylethanolamine of step (2) is selected from one or more of 1,2-dioleoyl-SN-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine (DMPE), 1,2-dipalmitoyl-SN-glycero-3-phosphoethanolamine (DPPE), 1,2-distearoyl-SN-glycero-3-phosphoethanolamine (DSPE).

[0094] The phosphatidylserine of step (2) is selected from one or more of 1,2-dimyristoyl-SN-glycero-3-phospho-L-serine (sodium salt) (DMPS), dipalmitoyl phosphatidylserine sodium (DPPS), distearoyl phosphatidylserine sodium (DSPS), 1,2-dilauroyl-sn-glycero-3-phospho-L-serine sodium (DLPS), dioleoyl phosphatidylserine sodium (DOPS).

[0095] The cationic lipid in step (2) is selected from one or more of (2,3-dioleoyl-propyl)-trimethylamine (DOTAP), dimyristoylglycerol-polyethylene glycol 2000 (DMG-PEG 2000), 1,2-dioleoyl-3-dimethylamino-propane (DODMA), 1,2-dioleoxy-3-methylammonium propane (DOTMA), 4-(N,N-dimethylamino)butyric acid (dilinoleyl) methyl ester (DLin-MC3-DMA).

[0096] The solvent in step (3) is selected from one or more of water, buffer solutions with water as solvent, such as one or more of borate, citrate, phosphate and tris buffer solutions.

[0097] The excipient in step (4) is one or more of polyethylene glycol, polyethylene oxide, DC-Cholesterol, butylated hydroxytoluene (BHT), probucol, iopromide, iohexol, iopamidol, urea, mannitol, PEGylated lipids, hyaluronic acid, vitamin E, polysorbate, xanthan gum, gum arabic, puerarin, inosine, gelatin, butylated hydroxyanisole, chitosan, polyethylene glycol-poly caprolactone, dextran, shellac.

[0098] The PEGylated lipid in step (4) is selected from one or more of 1,2-distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-mPEG2000), 1,2-distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DMPE-mPEG2000), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-5000 (DMPE-mPEG5000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DPPE-mPEG2000), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-5000 (DPPE-mPEG5000).

[0099] The diameter of the drug microspheres in step (1) is in the range of 0.1-10 μm, and can also be selected as any one of the following diameters or an interval formed by any two of the following diameters: for example, 0.1 μm, 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, or any range therebetween.

[0100] The temperature of the rotary evaporation of step (2) is from 30 °C to 60 °C, for example 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C, 45 °C, 46 °C, 47 °C, 48 °C, 49 °C, 50 °C, 51 °C, 52 °C, 53 °C, 54 °C, 55 °C, 56 °C, 57 °C, 58 °C, 59 °C, 60 °C, or any range therein.

[0101] The temperature of the water bath of step (3) is from 30 °C to 55 °C, for example 30 °C, 31 °C, 32 °C, 33 °C, 34 °C, 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C, 41 °C, 42 °C, 43 °C, 44 °C, 45 °C, 46 °C, 47 °C, 48 °C, 49 °C, 50 °C, 51 °C, 52 °C, 53 °C, 54 °C, 55 °C, or any range therein.

[0102] The proportion of the number of moles of cholesterol of step (2) to the total number of moles of the phospholipid bilayer is from 0% to 50%, for example 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, or any range therein.

[0103] The proportion of the number of moles of the cationic lipid of step (2) to the total number of moles of the phospholipid bilayer can be from 0% to 50%, for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, or any range therein.

[0104] The weight ratio of the drug microspheres and the phospholipid bilayer membrane in step (3) is 1:5-20:1, for example, 1:5, 2:5, 1:2, 3:5, 4:5, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, or any range therebetween.

[0105] The weight ratio of the excipient and the drug microspheres in step (4) is 1:3-5:1, for example, 1:3, 1:2, 2:3, 1:1, 2:1, 3:1, 4:1, 5:1, or any range therebetween.

[0106] The in vitro degradation time of the degradable material in step (1) is 2-12 months.

[0107] The technical solutions of the present application are further illustrated by specific embodiments. Those skilled in the art should understand that the embodiments are only used to help understand the present application and should not be regarded as specific limitations of the present application.

[0108] Embodiments

[0109] All raw materials in the following examples and comparative examples are commercially available.

[0110] Example 1: Preparation of sirolimus microspheres (drug microspheres)

[0111] I. Raw materials

[0112] 1. PLGA (75% DL-lactide / 25% glycolide);

[0113] 2. Sirolimus;

[0114] 3. Dichloromethane;

[0115] 4. Polyvinyl alcohol (PVA) solution: weigh 10 g of polyvinyl alcohol into a 1 L beaker, add 400 mL of water, ultrasonically dissolve, transfer to a 1 L volumetric flask, and add water to constant volume to obtain.

[0116] II. Preparation method

[0117] 1. Weigh 400.0 mg of PLGA and 200 mg of sirolimus into 4 mL of dichloromethane, shake to dissolve, to obtain a drug-containing polymer solution.

[0118] 2. Measure 160 mL PVA solution into a 1000 mL plastic beaker, then place the beaker into a blender, and turn on the blender (800 rpm). Measure 20 mL PVA solution into a 50 mL plastic centrifuge tube, homogenize (homogenization speed 12000 rpm / min), and drop the polymer solution into the centrifuge tube within 1 min, continue homogenizing for 3 min to obtain a microemulsion. After homogenization, immediately pour the microemulsion in the centrifuge tube into the 1000 mL beaker, and stir for 2 h.

[0119] 3. After stirring, transfer the solution into a centrifuge tube, centrifuge at 4000 rpm for 10 min, discard the supernatant, add purified water to shake and wash the micro-nuclei, centrifuge, and repeat 3 times to wash away the PVA and obtain the precipitate (drug microsphere precursor).

[0120] 4. Place the precipitate (drug microsphere precursor) into a vacuum drying oven, and dry at room temperature for 48 h to obtain the drug microspheres (PLGA / sirolimus) with a drug loading of 30.2% sirolimus by weight.

[0121] Example 2: Preparation of everolimus microspheres (drug microspheres)

[0122] I. Raw materials

[0123] 1. PLA;

[0124] 2. Everolimus (BA9);

[0125] 3. Dichloromethane;

[0126] 4. Polyvinyl alcohol (PVA) solution: weigh 10 g polyvinyl alcohol into a 1 L beaker, add 400 mL water, and ultrasonically dissolve, then transfer into a 1 L volumetric flask, and add water to constant volume.

[0127] II. Preparation method

[0128] 1. Weigh 500.0 mg PLA and 237.5 mg everolimus into 8 mL dichloromethane, and shake to dissolve.

[0129] 2. Measure 160 mL PVA solution into a 1000 mL plastic beaker, then place the beaker into a blender, and turn on the blender (800 rpm). Measure 20 mL PVA solution into a 50 mL plastic centrifuge tube, homogenize (homogenization speed 12000 rpm / min), and drop the polymer solution into the centrifuge tube within 1 min, continue homogenizing for 3 min. After homogenization, immediately pour the microemulsion in the centrifuge tube into the 1000 mL beaker, and stir for 2 h.

[0130] 3. After stirring, the solution was transferred to a centrifuge tube, centrifuged at 4000 rpm for 10 min, the supernatant was discarded, and the micro-nuclei were washed with purified water, centrifuged, and repeated 3 times.

[0131] 4. The drug microspheres were placed in a vacuum drying oven and dried at room temperature for 48 h, and the drug loading was 31% by weight.

[0132] Example 3: Preparation of sirolimus microsphere liposome coated balloon

[0133] I. Raw materials

[0134] 1. Drug microspheres: sirolimus (Rapa) PLGA microspheres prepared in Example 1;

[0135] 2. Lipophilic materials: DEPC, DSPC, 3β-hydroxy-5-cholesterol;

[0136] 3. Excipient: DSPE-mPEG2000;

[0137] 4. Solvent: water.

[0138] II. Preparation method

[0139] 1. 5.0 mg of DEPC (5.57 x 10 -6 mol), 5.2 mg of DSPC (6.58 x 10 -6 mol), and 0.27 mg of 3β-hydroxy-5-cholesterol (ordinary cholesterol) (6.98 x 10 -7 mol) were weighed into a 250 mL tomato-shaped bottle, 5 mL of chloroform was added, and ultrasonic dissolution was performed, and rotary evaporation was performed at 60°C until dryness, and drying was performed in a vacuum drying oven for 12 h to obtain a phospholipid bilayer membrane. The number of moles of cholesterol accounts for about 5% of the number of moles of the phospholipid bilayer membrane.

[0140] 2. 209.4 mg of sirolimus PLGA microspheres (drug microspheres) were weighed into the tomato-shaped bottle of step 1, 10 mL of water was added, ultrasonic dissolution was performed in a 60°C water bath for 10 min, and then magnetic stirring was performed for 40 min to obtain a liposome microsphere solution, wherein the weight ratio of sirolimus microspheres and phospholipid bilayer membrane is 20:1;

[0141] 3. 69.8 mg of DSPE-mPEG2000 was weighed into the tomato-shaped bottle of step 2, and magnetic stirring was performed for 10 min to obtain a coating drug solution, and the weight ratio of excipient and sirolimus PLGA microspheres was 1:3;

[0142] 4. The balloon was folded into 3 wings with a folding machine, and the coating drug solution was coated into the V-shaped groove of the folded balloon by needle coating;

[0143] 5. After the drug coating is dried, the balloon is wound up, a protective sleeve is put on, and vacuum dried for 24 h;

[0144] 6. The balloon expandable catheter is loaded into a coil, and then the coil is loaded into a dialysis paper bag for sterilization;

[0145] 7. The dialysis paper bag is loaded into an aluminum foil bag together with a desiccant and an oxygen absorber, and a packaging box is put on.

[0146] Example 4: Preparation of everolimus microsphere liposome coated balloon

[0147] I. Raw materials

[0148] 1. Drug microspheres: everolimus (BA9) PLA microspheres prepared in Example 2;

[0149] 2. Lipophilic material: DMPC, HSPC, 3β-hydroxy-5-cholesterol;

[0150] 3. Excipient: DC-cholesterol;

[0151] 4. Solvent: water.

[0152] II. Preparation method

[0153] 1. 50 mg of DMPC (7.38 x 10 -5 mol), 56.2 mg of HSPC (7.37 x 10 -5 mol), and 24.4 mg of 3β-hydroxy-5-cholesterol (ordinary cholesterol) (6.31 x 10 -5 mol) are weighed into a 250 mL tomato-shaped bottle, 5 mL of chloroform / methanol (7:3, V / V) is added, and ultrasonic dissolution is performed, 55°C rotary evaporation is performed until dryness, and drying is performed in a vacuum drying box for 12 h to obtain a phospholipid bilayer membrane. The number of moles of cholesterol is about 30% of the number of moles of the phospholipid bilayer membrane.

[0154] 2. 261.2 g of everolimus PLA microspheres are weighed into the tomato-shaped bottle of step 1, 10 mL of water is added, ultrasonic dissolution is performed in a 50°C water bath for 10 min, and then magnetic stirring is performed for 40 min, and the weight ratio of everolimus microspheres to phospholipid membrane is 2:1;

[0155] 3. 653 mg of DC-cholesterol (1.22 x 10 -3 mol) (excipient) is weighed into the tomato-shaped bottle of step 2, and magnetic stirring is performed for 10 min to obtain a coating drug solution, and the weight ratio of excipient to drug microspheres is 2.5:1;

[0156] 4. The balloon is folded into 3 wings with a folding machine, and the coating drug solution is coated into the V-shaped groove of the folded balloon by needle coating;

[0157] 5. After the drug coating is dried, the balloon is wound and a protective sleeve is vacuum dried for 24 hours;

[0158] 6. The balloon dilatation catheter is loaded into a coil, and then the coil is loaded into a dialysis paper bag for sterilization;

[0159] 7. The dialysis paper bag is loaded into an aluminum foil bag together with a desiccant and an oxygen absorber, and a packaging box is sleeved.

[0160] Example 5: Preparation of everolimus microsphere liposome coated balloon

[0161] I. Raw materials

[0162] 1. Drug microspheres: everolimus (BA9) microspheres prepared in Example 2;

[0163] 2. Lipophilic materials: DOTAP, DOPE, HSPC; 3β-hydroxy-5-cholesterol;

[0164] 3. Excipients: PEG4000;

[0165] 4. Solvent: water.

[0166] II. Preparation method

[0167] 1. 37 mg of DOTAP (4.78 x 10 -5 mol), 39 mg of DOPE (5.24 x 10 -5 mol), 60 mg of HSPC (7.87 x 10 -5 mol), and 71.2 mg (1.84 x 10 -5 mol) of 3β-hydroxy-5-cholesterol (ordinary cholesterol) are weighed into a 250 mL tomato-shaped bottle, 5 mL of chloroform is added, and it is ultrasonically dissolved, 50°C rotary evaporation to dryness, and dried in a vacuum drying oven for 12 hours to obtain a phospholipid bilayer membrane. The number of moles of cholesterol accounts for about 50% of the number of moles of the phospholipid bilayer membrane, and the number of moles of cationic lipid accounts for 13% of the number of moles of the phospholipid bilayer membrane;

[0168] 2. 41.4 mg of everolimus microspheres is weighed into the tomato-shaped bottle of step 1, 10 mL of water is added, ultrasonically treated for 10 min in a 50°C water bath, and then magnetically stirred for 40 min. The weight ratio of everolimus microspheres to phospholipid membrane is 1:5;

[0169] 3. 41.4 mg of PEG4000 is weighed into the tomato-shaped bottle of step 2, and magnetically stirred for 10 min to obtain a coating drug solution, and the weight ratio of excipient to drug microspheres is 1:1;

[0170] 4. The balloon is folded into 3 wings with a folding machine, and the coating drug solution is coated into the V-shaped groove of the folded balloon by needle coating.

[0171] 5. After the drug coating is dried, the balloon is wound and a protective sleeve is vacuum dried for 24 hours;

[0172] 6. The balloon dilatation catheter is loaded into a coil, and then the coil is loaded into a dialysis paper bag for sterilization;

[0173] 7. The dialysis paper bag is loaded into an aluminum foil bag together with a desiccant and an oxygen absorber, and a packaging box is sleeved.

[0174] Example 6: Preparation of sirolimus microsphere liposome coated balloon

[0175] I. Raw materials

[0176] 1. Drug microspheres: sirolimus microspheres prepared in Example 1;

[0177] 2. Lipophilic material: DLin-MC3-DMA, DOPE, 3β-hydroxy-5-cholesterol;

[0178] 3. Excipient: iopromide;

[0179] 4. Solvent: water.

[0180] II. Preparation method

[0181] 1. 30 mg of DLin-MC3-DMA (4.67 x 10 -5 mol), 34 mg of DOPE (4.57 x 10 - 5 mol), and 36 mg of 3β-hydroxy-5-cholesterol (ordinary cholesterol) (9.31 x 10 -5 mol) are weighed into a 250 mL flask, 5 mL of dichloromethane / ethanol (1:1, V / V) is added, and it is ultrasonically dissolved, and then it is rotary evaporated at 30°C until dry, and then it is dried in a vacuum drying box for 12 hours, and the molar number of cholesterol accounts for about 50% of the molar number of the phospholipid bilayer membrane, and the molar number of the cationic lipid accounts for 25% of the molar number of the phospholipid bilayer membrane;

[0182] 2. 100 mg of sirolimus microspheres are weighed into the flask of step 1, 10 mL of water is added, and it is ultrasonically dissolved in a 30°C water bath for 10 minutes, and then it is magnetically stirred for 40 minutes, and the weight ratio of sirolimus microspheres to phospholipid membrane is 1:1;

[0183] 3. 50 mg of iopromide is weighed into the flask of step 2, and it is magnetically stirred for 10 minutes to obtain a coating drug solution, and the weight ratio of excipient to drug microspheres is 1:2;

[0184] 4. The balloon is folded into 3 wings with a folding machine, and the coating drug solution is coated into the V-shaped groove of the folded balloon by needle coating;

[0185] 5. After the drug coating is dried, the balloon is wound and a protective sleeve is vacuum dried for 24 hours;

[0186] 6. The balloon expandable catheter is loaded into a coil, and the coil is loaded into a dialysis paper bag for sterilization;

[0187] 7. The dialysis paper bag is loaded into an aluminum foil bag together with a desiccant and an oxygen absorber, and a packaging box is attached.

[0188] Example 7: Preparation of everolimus microsphere liposome coated balloon

[0189] I. Raw materials

[0190] 1. Drug microspheres: everolimus microspheres prepared in Example 2;

[0191] 2. Lipophilic material: DEPC, DPPC, DODMA, 3β-hydroxy-5-cholesterol;

[0192] 3. Excipient: polyethylene oxide (molecular weight 300,000);

[0193] 4. Solvent: 0.01M phosphate buffer solution.

[0194] II. Preparation method

[0195] 1. Weigh 20mg DEPC (2.23x10 -5 mol), 16.3mg DPPC (2.22x10 -5 mol), 15.6mg DOTMA (2.33x10 -5 mol) and 6.5mg 3β-hydroxy-5-cholesterol (ordinary cholesterol) (1.68x10 -5 mol) into a 250mL flask, add 5mL chloroform, ultrasonic dissolution, rotary evaporation at 45°C until dry, dry in a vacuum drying oven for 12h, the molar number of cholesterol accounts for about 20% of the phospholipid bilayer membrane, and the molar number of cationic lipid accounts for 28% of the molar number of phospholipid bilayer membrane;

[0196] 2. Weigh 175mg sirolimus microspheres into the flask of step 1, add 10mL 0.01M phosphate buffer solution, ultrasonic for 10min in 40°C water bath, then magnetic stirring for 40min, the weight ratio of sirolimus microspheres and phospholipid membrane is 3:1;

[0197] 3. Weigh 350mg polyethylene oxide into the flask of step 2, magnetic stirring for 60min, to get the coating drug solution, the weight ratio of excipient and drug microspheres is 2:1;

[0198] 4. Fold the balloon into 3 wings with a folding machine, and coat the coating liquid into the V-shaped groove of the folded balloon by pin coating;

[0199] 5. After the drug coating is dried, the balloon is wound and a protective sleeve is sleeved for vacuum drying for 24 h;

[0200] 6. The balloon dilatation catheter is loaded into a coil, and then the coil is loaded into a dialysis paper bag for sterilization;

[0201] 7. The dialysis paper bag is loaded into an aluminum foil bag together with a desiccant and an oxygen absorber, and a packaging box is sleeved.

[0202] Example 8: Preparation of sirolimus microsphere liposome coated balloon

[0203] I. Raw materials

[0204] 1. Drug microspheres: sirolimus microspheres prepared in Example 1;

[0205] 2. Lipophilic material: DOTAP, HSPC, 3β-hydroxy-5-cholesterol;

[0206] 3. Excipient: DC-cholesterol;

[0207] 4. Solvent: water.

[0208] II. Preparation method

[0209] 1. Weigh 4.8 mg of DOTAP (6.20 x 10 -6 mol), 13.4 mg of HSPC (1.76 x 10 -5 mol) and 4.06 mg of 3β-hydroxy-5-cholesterol (ordinary cholesterol) (1.05 x 10 -5 mol) into a 250 mL tomato-shaped bottle, add 5 mL of chloroform, ultrasonic dissolution, rotary evaporation at 55°C until dry, dry in a vacuum drying box for 12 h, the molar number of cholesterol accounts for about 30% of the phospholipid bilayer membrane, and the molar number of cationic lipid accounts for 18% of the molar number of phospholipid bilayer membrane;

[0210] 2. Weigh 182.2 mg of sirolimus microspheres into the tomato-shaped bottle of step 1, add 10 mL of water, ultrasonic for 10 min in a 40°C water bath, then magnetic stirring for 40 min, the weight ratio of sirolimus microspheres and phospholipid membrane is about 8:1;

[0211] 3. Weigh 182.2 mg of DC-cholesterol into the tomato-shaped bottle of step 2, and magnetically stir for 60 min to obtain a coating liquid, and the weight ratio of excipient and drug microspheres is 1:1;

[0212] 4. Use the folding machine to fold the balloon into 3 wings, and use needle coating to coat the coating liquid into the V-shaped groove of the folded balloon;

[0213] 5. After the drug coating is dried, the balloon is wound and the protective sleeve is vacuum dried for 24 h;

[0214] 6. The balloon dilation catheter is loaded into the coil, and then the coil is loaded into the dialysis paper bag for sterilization;

[0215] 7. The dialysis paper bag is loaded into the aluminum foil bag together with the desiccant and oxygen absorber, and the packaging box is sleeved.

[0216] Example 9: Preparation of everolimus microsphere liposome coated balloon

[0217] I. Raw materials

[0218] 1. Drug microspheres: everolimus (BA9) microspheres prepared in Example 2;

[0219] 2. Lipophilic material: DOTAP, HSPC;

[0220] 3. Excipient: gum arabic;

[0221] 4. Solvent: water.

[0222] II. Preparation method

[0223] 1. Weigh 20.88 mg of DOTAP (2.70 x 10 -5 mol) and 20.88 mg of HSPC (2.74 x 10 -5 mol) into a 250 mL tomato-shaped bottle, add 5 mL of chloroform, ultrasonic dissolution, rotary evaporation at 55°C until dry, dry in a vacuum drying box for 12 h, to obtain a phospholipid bilayer membrane; wherein the number of moles of cationic lipids accounts for 50% of the number of moles of phospholipid bilayer membrane;

[0224] 2. Weigh 334 mg of everolimus microspheres into the tomato-shaped bottle of step 1, add 10 mL of water, ultrasonic for 10 min in 45°C water bath, then magnetic stirring for 40 min, the weight ratio of everolimus microspheres and phospholipid membrane is about 8:1;

[0225] 3. Weigh 222.67 mg of gum arabic into the tomato-shaped bottle of step 2, and magnetically stir for 10 min to obtain a coating liquid, the weight ratio of excipient and drug microspheres is 2:3;

[0226] 4. Use the folding machine to fold the balloon into 3 wings, and use needle coating to coat the coating liquid into the V-shaped groove of the folded balloon;

[0227] 5. After the drug coating is dried, the balloon is wound and the protective sleeve is vacuum dried for 24 h;

[0228] 6. The balloon dilatation catheter is loaded into the coil, which is then loaded into a dialysis paper bag for sterilization;

[0229] 7. The dialysis paper bag is loaded into an aluminum foil bag together with a desiccant and an oxygen absorber, and a packaging box is put on.

[0230] Example 10: Preparation of everolimus microsphere liposome-coated balloon

[0231] I. Raw materials

[0232] 1. Drug microspheres: everolimus (BA9) microspheres prepared in Example 2;

[0233] 2. Lipophilic materials: DOTAP, HSPC;

[0234] 3. Excipients: polyethylene oxide (molecular weight 300,000), gum arabic;

[0235] 4. Solvent: water.

[0236] II. Preparation method

[0237] 1. 33.4 mg of DOTAP (4.31 x 10 -5 mol) and 33.4 mg of HSPC (4.38 x 10 -5 mol) are weighed into a 250 mL flask, 5 mL of chloroform is added, and ultrasonic dissolution is performed, followed by rotary evaporation at 55°C until dryness, and drying in a vacuum drying box for 12 h to obtain a phospholipid bilayer membrane; wherein the number of moles of cationic lipids accounts for 50% of the number of moles of the phospholipid bilayer membrane;

[0238] 2. 334 mg of everolimus microspheres are weighed into the flask of step 1, 10 mL of water is added, ultrasonic dissolution is performed in a 45°C water bath for 10 min, and then magnetic stirring is performed for 40 min, with a weight ratio of everolimus microspheres to phospholipid membrane of 5:1;

[0239] 3. 445 mg of polyethylene oxide and 56 mg of gum arabic are weighed into the flask of step 2, and magnetic stirring is performed for 10 min to obtain a coating drug solution, with a weight ratio of excipients to drug microspheres of 3:2; wherein gum arabic accounts for about 11% of the weight of the excipients;

[0240] 4. The balloon is folded into 3 wings using a folding machine, and the coating drug solution is coated into the V-shaped groove of the folded balloon using a needle coating method;

[0241] 5. After the drug coating is dry, the balloon is wound and a protective sleeve is put on, and vacuum drying is performed for 24 h;

[0242] 6. The balloon dilatation catheter is loaded into the coil, which is then loaded into a dialysis paper bag for sterilization;

[0243] 7. Put the dialysis paper bag together with the desiccant, oxygen absorber into an aluminum foil bag, and cover with a packaging box.

[0244] Example 11: Preparation of everolimus microsphere liposome coated balloon

[0245] I. Raw materials

[0246] 1. Drug microspheres: everolimus (BA9) microspheres prepared in Example 2;

[0247] 2. Lipophilic materials: DOTAP, HSPC, DPPC;

[0248] 3. Excipients: polyethylene oxide (molecular weight 300,000), gum arabic;

[0249] 4. Solvent: water.

[0250] II. Preparation method

[0251] 1. Weigh 8.0 mg of DOTAP (1.03 x 10 -5 mol) and 8.0 mg of HSPC (1.05 x 10 -5 mol) and 8.0 mg of DPPC (1.09 x 10 -5 mol) into a 250 mL tomato-shaped bottle, add 5 mL of chloroform, ultrasonic dissolution, rotary evaporation at 55°C until dry, dry in a vacuum drying box for 12 h, to obtain a phospholipid bilayer membrane; wherein the number of moles of cationic lipids accounts for 33% of the number of moles of phospholipid bilayer membrane;

[0252] 2. Weigh 240 mg of everolimus microspheres into the tomato-shaped bottle of step 1, add 10 mL of water, ultrasonic for 10 min in a 40°C water bath, then magnetic stirring for 40 min, the weight ratio of everolimus microspheres and phospholipid membrane is 10:1;

[0253] 3. Weigh 300 mg of polyethylene oxide and 60 mg of gum arabic into the tomato-shaped bottle of step 2, magnetic stirring for 10 min, to obtain a coating drug solution, the weight ratio of excipients and drug microspheres is 3:2; wherein gum arabic accounts for about 17% of the weight of the excipients;

[0254] 4. Fold the balloon into 3 wings with a folding machine, and use needle coating to coat the coating drug solution into the V-shaped groove of the folded balloon;

[0255] 5. After the drug coating is dry, the balloon is wound and covered with a protective sleeve and vacuum dried for 24 h;

[0256] 6. The balloon catheter is loaded into the coil, and then the coil is loaded into the dialysis paper bag for sterilization;

[0257] 7. Put the dialysis paper bag together with the desiccant, oxygen absorber into an aluminum foil bag, and cover with a packaging box.

[0258] Example 12: Preparation of everolimus microsphere liposome coated balloon

[0259] I. Raw materials

[0260] 1. Drug microspheres: everolimus (BA9) microspheres prepared in Example 2;

[0261] 2. Lipophilic materials: DEPC, HSPC, DPPC;

[0262] 3. Excipients: polyethylene oxide (molecular weight 300,000), gum arabic;

[0263] 4. Solvent: water.

[0264] II. Preparation method

[0265] 1. Weigh 8.0 mg of DEPC (8.91 x 10 -6 mol) and 8.0 mg of HSPC (1.05 x 10 -5 mol) and 8.0 mg of DPPC (1.09 x 10 -5 mol) into a 250 mL tomato flask, add 5 mL of chloroform, ultrasonic dissolution, rotary evaporation at 55°C until dry, dry in a vacuum drying box for 12 h, to obtain phospholipid bilayer membrane.

[0266] 2. Weigh 240 mg of everolimus microspheres into the tomato flask of step 1, add 10 mL of water, ultrasonic for 10 min in a 40°C water bath, then magnetic stirring for 40 min, the weight ratio of everolimus microspheres and phospholipid membrane is 10:1;

[0267] 3. Weigh 300 mg of polyethylene oxide and 60 mg of gum arabic into the tomato flask of step 2, magnetic stirring for 10 min, to obtain the coating drug solution, the weight ratio of excipients and drug microspheres is 3:2; wherein, gum arabic accounts for about 17% of the weight of the excipients;

[0268] 4. Fold the balloon into 3 wings with a folding machine, and coat the coating drug solution into the V-shaped groove of the folded balloon by needle coating;

[0269] 5. After the drug coating is dry, the balloon is wound and covered with a protective sleeve and vacuum dried for 24 h;

[0270] 6. Put the balloon catheter into the coil, then put the coil into the dialysis paper bag, and sterilize;

[0271] 7. Put the dialysis paper bag together with the desiccant, oxygen absorber into an aluminum foil bag, and cover with a packaging box.

[0272] Example 13: Preparation of sirolimus microsphere liposome coated balloon

[0273] I. Raw materials

[0274] 1. Drug microspheres: sirolimus (BA9) microspheres prepared in Example 2;

[0275] 2. Lipophilic materials: DEPC, HSPC, DOTAP;

[0276] 3. Excipients: DOTAP, polyethylene oxide (molecular weight 300,000), gum arabic;

[0277] 4. Solvent: water.

[0278] II. Preparation method

[0279] 1. Weigh 8.0 mg of DEPC (8.91 x 10 -6 mol) and 8.0 mg of HSPC (1.05 x 10 -5 mol) and 8.0 mg of DPPC (1.09 x 10 -5 mol) into a 250 mL tomato flask, add 5 mL of chloroform, ultrasonic dissolution, rotary evaporation at 55°C to dryness, dry in a vacuum drying box for 12 h, to obtain a phospholipid bilayer membrane.

[0280] 2. Weigh 240 mg of sirolimus microspheres into the tomato flask of step 1, add 10 mL of water, ultrasonic for 10 min in a 40°C water bath, then magnetic stirring for 40 min, the weight ratio of sirolimus microspheres and phospholipid membrane is 10:1;

[0281] 3. Weigh 100 mg of DOTAP, 200 mg of polyethylene oxide and 60 mg of gum arabic into the tomato flask of step 2, magnetic stirring for 10 min to obtain a coating drug solution, the weight ratio of excipients and drug microspheres is 3:2; wherein gum arabic accounts for about 17% of the weight of the excipients;

[0282] 4. Fold the balloon into 3 wings with a folding machine, and coat the coating drug solution into the V-shaped groove of the folded balloon by needle coating;

[0283] 5. After the drug coating is dry, the balloon is wound and a protective sleeve is put on, and vacuum dried for 24 h;

[0284] 6. The balloon catheter is loaded into a coil, and then the coil is loaded into a dialysis paper bag for sterilization;

[0285] 7. The dialysis paper bag is loaded into an aluminum foil bag together with a desiccant and an oxygen absorber, and a packaging box is put on.

[0286] Comparative Example 1: Preparation of sirolimus microsphere coated balloon

[0287] I. Raw materials

[0288] 1. Drug microspheres: rapamycin (BA9) microspheres prepared in Example 2;

[0289] 2. Lipophilic material: DMPC, HSPC, 3β-hydroxy-5-cholesterol;

[0290] 3. Excipient: DC-cholesterol;

[0291] 4. Solvent: heptane.

[0292] II. Preparation method

[0293] 1. Weigh 50 mg of DMPC (7.38 x 10 -5 mol), 56.2 mg of HSPC (7.37 x 10 -5 mol), 24.4 mg of 3β-hydroxy-5-cholesterol (ordinary cholesterol) (6.31 x 10 -5 mol), and 653 mg of DC-cholesterol (1.22 x 10 -3 mol) (excipient) into a 50 mL glass bottle, add 20 mL of heptane, and dissolve by ultrasonic treatment in a 60°C water bath, and cool to room temperature;

[0294] 2. Weigh 261.2 mg of rapamycin microspheres into the glass bottle of Step 1, and disperse the drug microspheres by ultrasonic treatment for 5 min to obtain a coating drug solution;

[0295] 3. Use a pressure of 1-2 tam to expand the balloon catheter, and spray the coating drug solution of Step 2 onto the surface of the balloon in a uniform manner;

[0296] 4. After the drug coating is dry, roll up the balloon, and cover it with a protective cover and dry in a vacuum for 24 h;

[0297] 5. Load the balloon expansion catheter into a coil, and then load the coil into a dialysis paper bag, and sterilize;

[0298] 6. Load the dialysis paper bag together with a desiccant and an oxygen absorber into an aluminum foil bag, and cover it with a packaging box.

[0299] Comparative Example 2: Preparation of a rapamycin microsphere liposome coated balloon

[0300] I. Raw materials

[0301] 1. Drug microspheres: rapamycin (BA9) microspheres prepared in Example 2;

[0302] 2. Lipophilic material: DOTAP, HSPC;

[0303] 3. Excipient: gum arabic;

[0304] 4. Solvent: water.

[0305] II. Preparation method

[0306] 1. Take 20.88 mg of DOTAP (2.70 x 10 -5 mol) and 20.88 mg of HSPC (2.74 x 10 -5 mol) in a 250 mL tomato flask, add 5 mL of chloroform, ultrasonic dissolution, rotary evaporation at 25°C to dryness, dry in a vacuum drying oven for 12 h, to obtain a phospholipid bilayer membrane.

[0307] 2. Take 334 mg of everolimus microspheres in the tomato flask of step 1, add 10 mL of water, ultrasonic for 10 min in a 45°C water bath, then magnetic stirring for 40 min, the weight ratio of everolimus microspheres and phospholipid membrane is 8:1;

[0308] 3. Take 222.67 mg of gum arabic in the tomato flask of step 2, magnetic stirring for 10 min, to obtain a coating drug solution, the weight ratio of excipient and drug microspheres is 2:3;

[0309] 4. Fold the balloon into 3 wings with a folding machine, and coat the coating drug solution into the V-shaped groove of the folded balloon by needle coating;

[0310] 5. After the drug coating is dried, the balloon is wound and a protective sleeve is put on, and vacuum dried for 24 h;

[0311] 6. The balloon catheter is loaded into the coil, and then the coil is loaded into the dialysis paper bag for sterilization;

[0312] 7. The dialysis paper bag is loaded into an aluminum foil bag together with a desiccant and an oxygen absorber, and a packaging box is put on.

[0313] Comparative Example 3: Preparation of everolimus microsphere liposome coated balloon

[0314] I. Raw materials

[0315] 1. Drug microspheres: everolimus (BA9) microspheres prepared in Example 2;

[0316] 2. Lipophilic material: DOTAP, HSPC;

[0317] 3. Excipient: gum arabic;

[0318] 4. Solvent: water.

[0319] II. Preparation method

[0320] 1. Take 20.88 mg of DOTAP (2.70 x 10 -5mol) and 20.88 mg HSPC (2.74 x 10 -5 mol) and 20.88 mg HSPC (2.74 x 10

[0321] 2. Take 334 mg of everolimus microspheres into the flask of step 1, add 10 mL of water, ultrasonic for 10 min in 65°C water bath, then magnetic stirring for 40 min, the weight ratio of everolimus microspheres and phospholipid membrane is 8:1;

[0322] 3. Take 222.67 mg of gum arabic into the flask of step 2, magnetic stirring for 10 min, to get the coating liquid, the weight ratio of excipient and drug microspheres is 2:3;

[0323] 4. Fold the balloon into 3 wings with a folding machine, and coat the coating liquid into the V-shaped groove of the folded balloon by needle coating;

[0324] 5. After the drug coating is dried, the balloon is wound and the protective sleeve is put on and vacuum dried for 24 h;

[0325] 6. The balloon catheter is loaded into the coil, and then the coil is loaded into the dialysis paper bag for sterilization;

[0326] 7. The dialysis paper bag is loaded into an aluminum foil bag together with desiccant and oxygen absorber, and a packaging box is put on.

[0327] Example 14: Activity determination

[0328] Material

[0329] The drug-coated balloon catheters prepared in Examples 3-13 and Comparative Examples 1-3 above are evaluated for drug transfer / delivery characteristics at 1 d time point and target tissue uptake of the drug in vivo.

[0330] Experimental subjects and equipment

[0331] 1. Experimental animals

[0332] Experimental animals: Bama pigs; gender: male or female; body weight: 30-40 kg.

[0333] Total number of experimental animals: 14.

[0334] 2. Drug balloon

[0335] Model specifications: DCB-2520, DCB-3020

[0336] Experimental method

[0337] 1. Surgical procedure

[0338] 14 pigs, 3 drug coated balloon catheters implanted in each pig, 33 test groups of drug balloon catheters and 9 comparative examples of drug coated balloon catheters. The implantation position of each pig is:

[0339] (1) right coronary artery

[0340] (2) anterior descending branch

[0341] (3) circumflex branch

[0342] The appropriate balloon is selected according to the overexpansion ratio of 1.10-1.20, the balloon is expanded for 60 seconds, and then retracted.

[0343] 2. Animal treatment

[0344] Blood routine and biochemical tests are performed before and after the operation, and after the balloon implantation, the double-antibiotic drug (aspirin and clopidogrel) is orally administered for treatment until the end of the experiment. The sampling site: the blood vessel at the balloon expansion site, the length of which is equal to the length of the balloon.

[0345] Four tissue tests

[0346] After sampling, the blood vessel is immediately stored in dry ice and sent to a third-party testing agency for analysis.

[0347] The drug absorption results are shown in Table 1. The drug absorption effect is mainly investigated at the 1d time point. The tissue drug concentration of Comparative Example 1 is 28.16 ng / mg, and the balloon catheters of Examples 3-13 can achieve a tissue drug concentration of ≥ 159.21 ng / mg, among which the tissue drug concentration of Example 11 is the largest, reaching 989.2 ng / mg, which is much larger than that of Comparative Example 1. From the animal experiment results, it can be seen that first preparing a phospholipid bilayer membrane, and then using the phospholipid bilayer membrane to wrap the drug microspheres to make liposome microspheres can greatly improve the adhesion between the drug and the blood vessel intima, enhance the ability of the drug to resist blood flow flushing, and thus improve the drug absorption rate of the tissue.

[0348] As can be seen from Comparative Example 1, when the phospholipid and other lipophilic materials are mixed without water solvent and the excipient is added to the preparation process of the liposome, and the prepared drug coated balloon catheter is measured by the same active determination method, the tissue drug concentration is significantly lower than that in Example 4; as can be seen from Comparative Example 2, when the rotary evaporation temperature is lower than 30℃, the liposome membrane made is poor, and the tissue drug concentration is only 7.51 ng / mg; as can be seen from Comparative Example 3, when the water bath temperature is greater than 60℃, the structure of the liposome microspheres is destroyed, resulting in a tissue drug concentration of only 3.1 ng / mg.

[0349] Table 1 Drug tissue absorption results

[0350] Table 2 Summary of preparation parameters for examples and comparative examples

[0351] The above examples are the preferred embodiments of the present application, but the embodiments of the present application are not limited to the above examples, and any changes, modifications, substitutions, combinations, simplifications, etc. made without departing from the spirit and principles of the present application are equivalent replacement manners and are included in the protection scope of the present application.

Claims

1. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises: a drug microsphere comprising a drug and a degradable material; and a liposome comprising a phospholipid bilayer membrane comprising a phospholipid; wherein the liposome encapsulates the drug microsphere to form a liposome microsphere.

2. Pharmaceutical composition according to claim 1, characterized in that The weight ratio of the drug microsphere to the phospholipid bilayer membrane is 1:5-20:1; optionally, the pharmaceutical composition further satisfies one or more of the following: (a) the pharmaceutical composition is used as a coating of an interventional medical device; (b) the drug is dispersed in the degradable material; (c) the degradable material is one or more of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan and glycosaminoglycan.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that The pharmaceutical composition further satisfies one or more of the following: (d) the diameter of the drug microsphere ranges from 0.1 to 10 μm; (e) the in vitro degradation time of the degradable material is 2-12 months; and / or the degradable material is one or more of polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL); (f) the drug is one or more of everolimus, sirolimus, temsirolimus, zotarolimus, paclitaxel and their analogues.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further satisfies one or more of the following: (g) the phospholipid is one or more of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and phosphatidylinositol; optionally, the phosphatidylcholine is one or more of lecithin (L-α-phosphatidylcholine), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (HSPC), 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dierucoyl-sn-glycero-3-phosphocholine (DEPC), 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-myristoyl-2-palmitoyl-SN-glycero-3-phosphocholine (MPPC), 1-myristoyl-2-stearoyl-SN-glycero-3-phosphocholine (MSPC) and 1-stearoyl-2-myristoyl-SN-glycero-3-phosphocholine (SMPC); optionally, the phosphatidylethanolamine is one or more of 1,2-dioleoyl-SN-glycero-3-phosphoethanolamine (DOPE), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine (DMPE), 1,2-dipalmitoyl-SN-glycero-3-phosphoethanolamine (DPPE) and 1,2-distearoyl-SN-glycero-3-phosphoethanolamine (DSPE); Optionally, the phosphatidylserine is one or more of 1,2-dimyristoyl-sn-glycero-3- phospho-L-serine (DMPS) and its sodium salt, sodium di-palmitoyl phosphatidylserine (DPPS), sodium di-stearoyl phosphatidylserine (DSPS), sodium 1,2-dilauroyl-sn-glycero-3- phospho-L-serine (DLPS), sodium 1,2-dioleoyl phosphatidylserine (DOPS); (h) the phospholipid comprises 20-100% of the moles of the liposome; (i) the phospholipid comprises a phospholipid having an acyl chain length of less than or equal to 20 carbons; (j) the phospholipid comprises a phospholipid having an acyl chain length of 10 to 18 carbons, or 40-100% of the molar amount of a phospholipid having an acyl chain length of 10 to 18 carbons relative to the total molar amount of the phospholipid.

5. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition further comprises a pharmaceutically acceptable excipient; Optionally, the pharmaceutical composition further satisfies one or more of: (k) the liposome microspheres are dispersed in the pharmaceutically acceptable excipient; (l) the weight ratio of the excipient to the drug microspheres is 1:3-5:1; (m) the excipient is one or more of polyethylene glycol, polyethylene oxide, DC- cholesterol, butylated hydroxytoluene, probucol, iopromide, iohexol, iopamidol, urea, mannitol, PEGylated lipids, cationic lipids, hyaluronic acid, vitamin E, polysorbate, xanthan gum, puerarin, inosine, gelatin, gum arabic, butylated hydroxyanisole, chitosan, polyethylene glycol- poly caprolactone, dextran, and shellac; Preferably, the excipient is one or more of polyethylene oxide, cationic lipids, and gum arabic; Optionally, the PEGylated lipid is one or more of 1,2-distearoyl-SN-glycero-3- phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-mPEG2000), 1,2- distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE- mPEG1000), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DMPE-mPEG2000), 1,2-dimyristoyl-SN-glycero-3-phosphoethanolamine-N- methoxy(polyethylene glycol)-5000 (DMPE-mPEG5000), 1,2-dipalmitoyl-sn-glycero-3- phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DPPE-mPEG2000), 1,2- dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-5000 (DPPE- mPEG5000).

6. The pharmaceutical composition according to claim 1, characterized in that, The phospholipid bilayer further comprises one or more of cholesterol and cationic lipids; Optionally, the cholesterol comprises 0-55% of the moles of the liposome; Optionally, the cationic lipid comprises 0-50% of the moles of the liposome; Optionally, the cholesterol is one or more of 3β-hydroxy-5-cholestene and 3β-[N-(N',N'- dimethylaminoethane)-formyl]cholesterol (DC-Cholesterol); Optionally, the cationic lipid is one or more of (2,3-dioleoyl-propyl)-trimethylamine (DOTAP), dimyristylglycerol-polyethylene glycol 2000 (DMG-PEG2000), 1,2-dioleoyl-3-dimethylamino-propane (DODMA), 1,2-dioleoyloxy-3-methylammoniumpropane (DOTMA), 4-(N,N-dimethylamino)butanoic acid (dilinoleyl) methyl ester (DLin-MC3-DMA).

7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that, The phospholipid bilayer membrane is prepared by a method comprising the steps of dissolving a lipophilic material in an organic solvent, the lipophilic material comprising a phospholipid, or a phospholipid and a cholesterol, or a phospholipid and a cationic lipid, or a phospholipid and a cholesterol and a cationic lipid, and rotary evaporation at a temperature greater than 30°C, preferably 30°C to 60°C; optionally, the organic solvent is one or more of dichloromethane, trichloromethane, methanol, ethanol, acetone and diethyl ether; and / or, the liposomal microsphere is prepared by a method comprising the steps of mixing the phospholipid bilayer membrane, the drug microsphere and water or an aqueous buffer solution in a container in a water bath at 30°C to 55°C; optionally, the aqueous buffer solution is a citrate buffer solution, a phosphate buffer solution, a borate buffer solution or a tris-hydroxymethylmethane buffer solution.

8. Process for the preparation of a pharmaceutical composition according to any one of claims 1 to 7, characterized in that, The phospholipid bilayer membrane is prepared by a method comprising the steps of dissolving a lipophilic material in an organic solvent, the lipophilic material comprising a phospholipid, or a phospholipid and a cholesterol, or a phospholipid and a cationic lipid, or a phospholipid and a cholesterol and a cationic lipid, and rotary evaporation at a temperature greater than 30°C, preferably 30°C to 60°C; optionally, the organic solvent is one or more of dichloromethane, trichloromethane, methanol, ethanol, acetone and diethyl ether; Optionally, the method satisfies one or more of: (i) the phospholipid is present in a molar ratio of 20% to 100% of the liposome; (ii) the cholesterol is present in a molar ratio of 0% to 55% of the liposome; (iii) the cationic lipid is present in a molar ratio of 0% to 50% of the liposome; (iv) the cholesterol is one or more of 3β-hydroxy-5-cholestene and 3β-[N-(N',N'- dimethylaminoethane)-formyl]cholesterol (DC-Cholesterol); (v) the cationic lipid is one or more of (2,3-dioleoyl-propyl)-trimethylamine (DOTAP), dimyristylglycerol-polyethylene glycol 2000 (DMG-PEG2000), 1,2-dioleoyl-3-dimethylamino-propane (DODMA), 1,2-dioleoyloxy-3-methylammoniumpropane (DOTMA), 4-(N,N-dimethylamino)butanoic acid (dilinoleyl) methyl ester (DLin-MC3-DMA). (vi) the organic solvent is one or more of dichloromethane, trichloromethane, methanol, ethanol, acetone and diethyl ether; (vii) the aqueous buffer solution is a citrate buffer solution, a phosphate buffer solution, a borate buffer solution or a tris buffer solution; (viii) the weight ratio of the drug microspheres to the lipophilic material is 1:5-20:

1.

9. The method according to claim 8, comprising: (1) preparing drug microspheres of the degradable material and the drug, preferably by emulsification solvent evaporation method; (2) placing phospholipid, cationic lipid and cholesterol in a container, adding an organic solvent to dissolve, rotary evaporation to dryness, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane; or placing phospholipid and cationic lipid in a container, adding an organic solvent to dissolve, rotary evaporation to dryness, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane; or placing phospholipid alone in a container, adding an organic solvent to dissolve, rotary evaporation to dryness, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane; or placing phospholipid and cholesterol in a container, adding an organic solvent to dissolve, rotary evaporation to dryness, and drying in a vacuum drying oven to obtain the phospholipid bilayer membrane; (3) ultrasonically mixing the drug microspheres, the phospholipid bilayer membrane and water or the aqueous buffer solution in a water bath, and then magnetically stirring to obtain a solution containing the liposome microspheres.

10. An interventional medical device comprising a balloon, a catheter connected with the balloon and a drug coating, the drug coating comprising the drug composition according to any one of claims 1-7, the drug composition being arranged at least on part of the surface of the balloon.

11. A method for preparing the interventional medical device of claim 10, which comprises the method of claim 8 or 9, the interventional medical device being a balloon dilatation catheter, and after obtaining the solution containing the liposome microspheres, further comprising one or more of the following steps: (4) mixing a pharmaceutically acceptable excipient with the solution containing the liposome microspheres to obtain a coating drug solution; (5) performing plasma treatment on the surface of the balloon dilatation catheter; (6) folding the balloon of the balloon dilatation catheter so that the balloon forms a plurality of folded wing petals, the plurality of folded wing petals having a plurality of "V" shaped spaces therebetween; (7) coating the coating drug solution to the plurality of "V" shaped spaces to form a balloon dilatation catheter with a drug coating; Optionally, the method further comprises one or more of the following steps: (8) after the drug coating is dried, winding the balloon, sleeving a protective sleeve and vacuum drying; (9) loading the balloon dilatation catheter into a coil, then loading the coil into a dialysis paper bag for sterilization; (10) loading the dialysis paper bag together with a drying agent and an oxygen absorber into an aluminum foil bag, and sleeving a packaging box.

12. A drug delivery device comprising the drug composition according to any one of claims 1-7, or the drug composition prepared by the method of claim 8 or 9.

13. Use of a pharmaceutical composition according to any one of claims 1 to 7, or a pharmaceutical composition obtained by the process according to claim 8 or 9, for the manufacture of a medicament or device for the dilation of blood vessels, or for the treatment of atherosclerosis, stenosis or restenosis in a diseased blood vessel.

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