Preparation method of medicine balloon coated medicine

Abstract

The invention provides a preparation method of a medicine balloon coating medicine, in particular to a medicine balloon for vascular restenosis, which is prepared from the following raw materials in parts by mass: 1 part of rapamycin, 1-20 parts of phospholipid and cholesterol. Wherein the mass ratio of cholesterol to phosphatide is (1: 3)-(1: 8). According to the rapamycin liposome disclosed by the invention, the solubility of rapamycin in a water phase is greatly improved. The lipidosome coating can promote adhesion of nanoparticles to the surface of a blood vessel wall, has a slow release effect, and reduces toxic and side effects. And phospholipids and cholesterol as the rapamycin carriers can be degraded under in-vivo physiological conditions, and have good biocompatibility and high safety. The preparation method is simple, stable in process, suitable for large-scale production, stable in product and long in quality guarantee period.

Description

Technical Field

[0001] The present invention relates to the field of medical devices, in particular to the field of balloon catheters and coated catheter material technology, and in particular to a drug-coated drug balloon, a drug balloon and a preparation method thereof. Background Art

[0002] Since the 1970s, coronary artery (CO) intervention technology has been booming. From the initial percutaneous balloon angioplasty (POBA) to the placement of bare metal stents (BMS) and drug-eluting stents (DES). DES significantly reduced the restenosis rate, but brought another thorny problem: in-stent restenosis (ISR). ISR is a pathophysiological evolution process, and its histological manifestation is different from restenosis, characterized by the formation of new intima.

[0003] The incidence of in-stent restenosis in coronary arteries is about 10% in patients receiving DES implantation and more than 30% in patients receiving BMS implantation. The new technology that has emerged in recent years, drug-eluting balloon (DEB), is one of the more promising technologies to overcome ISR.

[0004] As a product of the combination of traditional balloon angioplasty and advanced drug elution technology, the unique structure of DEB avoids the side effects caused by long-term retention of metal frames and polymer carriers, and coats the drug on the blood vessel wall in a specific area, concentrating the drug locally without causing systemic side effects.

[0005] In 2003, Scheller et al. from Germany published the first animal experiment results in the Journal of the American College of Cardiology showing that intracoronary injection of a mixture of iopromide and paclitaxel can effectively inhibit in-stent restenosis. Please drug-eluting balloons have completed animal experiments and the PACCOCATH-ISR study, the first human application of DEB to treat in-stent restenosis, which confirmed that DEB is significantly better than the conventional balloon POBA in treating in-stent restenosis. Please balloon has been clinically studied, and other DEB products have also been launched. At present, more than ten drug-containing balloons have been launched in the world, and most of the DEBs on the market use paclitaxel-based drug coatings. This is because paclitaxel is lipid-soluble and can more easily enter vascular endothelial cells. Cell culture shows that smooth muscle cells can maintain long-term inhibitory effects after a brief contact with paclitaxel compounds. For example, the Dior balloon system uses nanoporous technology to directly bind paclitaxel to the balloon surface. However, on the other hand, paclitaxel has potential risks due to its strong cytotoxicity, long-term embolism caused by the shedding of coating particles, and poor performance in calcified blood vessels. At present, rapamycin has been proven to be a safe and effective cell inhibitory drug. Its anti-restenosis ability and safety factor are better than paclitaxel, and have been fully verified in the field of coronary artery rapamycin drug stents; at the same time, compared with paclitaxel, it has higher safety and a wider treatment range, and has anti-inflammatory effects. It is recognized as the next generation of highly advantageous new drugs.

[0006] Rapamycin (trade name rapamune, also known as sirolimus) was isolated from soil samples of Easter Island, Chile, by Ayerst, a Canadian pharmaceutical company. It was first studied as a low-toxic antifungal drug. In 1977, researchers discovered that rapamycin has an immunosuppressive effect. In 1989, rapamycin was used as a new drug for the treatment of organ transplant rejection. Rapamycin is a new macrolide immunosuppressant. It blocks signal transduction through different cytokine receptors, blocking the process of T lymphocytes and other cells from the G1 phase to the S phase, thereby exerting an immunosuppressive effect. From the perspective of clinical application, rapamycin has a good anti-rejection effect and has a good synergistic effect with immunosuppressants such as cyclosporine A (CsA) and FK506. It is a new immunosuppressant with good efficacy, low toxicity, and no nephrotoxicity. Rapamycin has extremely poor water solubility, which affects its absorption rate in the gastrointestinal tract, resulting in low bioavailability of oral solution and tablets, so the efficacy of systemic administration is poor. The method of coating drugs on stents has been widely used in the treatment of atherosclerosis-related diseases. Rapamycin stents can also effectively inhibit the proliferation and migration of vascular smooth muscle cells after vascular injury, thereby reducing the occurrence of vascular restenosis. Summary of the invention

[0007] In view of this, an embodiment of the present invention provides a drug-coated balloon. The raw materials for preparing the coated drug include, by mass: 1 part of rapamycin, 1-20 parts of phospholipids, and cholesterol; wherein the mass ratio of cholesterol to phospholipids is 1:3-1:8.

[0008] Optionally, the phospholipids include one or more of egg yolk lecithin, hydrogenated soybean lecithin, cephalin, phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), and stearamide (SA).

[0009] Optionally, the coated drug comprises a cationic lipid material.

[0010] Optionally, the cationic lipid material includes one or more of (2,3-dioleoyl-propyl)-trimethylamine (DOTAP), dimethylaminoethane-carbamoyl cholesterol (DC-cholesterol), N-[1-(2,3-dioleoyl)propyl]-N,N,N-trimethylammonium chloride (DOTMA), and trimethyldodecyl ammonium bromide (DTAB).

[0011] Optionally, the cholesterol comprises DC cholesterol.

[0012] Optionally, the drug further comprises a lyoprotectant, and the lyoprotectant is selected from one or more of mannitol, glucose, sucrose, and trehalose.

[0013] Optionally, the mass ratio of the lyophilized protective agent to the mass ratio of the rapamycin liposome is 5%-10%.

[0014] Optionally, the average particle size of the coated drug is 200-400 nm, the drug loading is 1%-4%, and the encapsulation efficiency is 40%-90%.

[0015] Optionally, the drug further comprises a spinning aid, and the spinning aid is selected from one or more of carbomer, gelatin, and PEO.

[0016] The present invention also provides a drug balloon, the surface of which is coated with any of the above-mentioned drugs.

[0017] The present invention also provides a method for preparing a drug-coated drug balloon, the method comprising the following steps:

[0018] Prepare the following raw materials by weight: 1 part of rapamycin, 1-20 parts of phospholipids, and cholesterol; wherein the mass ratio of cholesterol to phospholipids is 1:3-1:8;

[0019] The above raw materials are dissolved in an organic solvent, and the organic solvent is removed by rotary evaporation; an aqueous phase solution is added; the rapamycin liposome is obtained after homogenization; and the liposome is freeze-dried.

[0020] The present invention also provides a method for preparing a drug balloon, the method comprising the following steps:

[0021] Prepare the following raw materials by weight: 1 part of rapamycin, 1-20 parts of phospholipids, and cholesterol; wherein the mass ratio of cholesterol to phospholipids is 1:3-1:8;

[0022] The above raw materials are dissolved in an organic solvent, and the organic solvent is removed by rotary evaporation; an aqueous solution is added; the rapamycin liposomes are obtained after homogenization; and lyophilization is performed;

[0023] The liposomes are re-dissolved with a spinning aid, transferred into a syringe, and electrostatically sprayed onto the balloon surface to obtain a drug-loaded liposome drug balloon.

[0024] Optionally, the phospholipids include one or more of egg yolk lecithin, hydrogenated soybean lecithin, cephalin, phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), and stearamide (SA).

[0025] Optionally, the rapamycin liposomes comprise a cationic lipid material.

[0026] Optionally, the cationic lipid material includes one or more of (2,3-dioleoyl-propyl)-trimethylamine (DOTAP), dimethylaminoethane-carbamoyl cholesterol (DC-cholesterol), N-[1-(2,3-dioleoyl)propyl]-N,N,N-trimethylammonium chloride (DOTMA), and trimethyldodecyl ammonium bromide (DTAB).

[0027] Optionally, the cholesterol comprises DC cholesterol.

[0028] Optionally, the lyoprotectant used in the freeze-drying is selected from one or more of mannitol, glucose, sucrose, and trehalose, and the mass ratio of the lyoprotectant to the mass ratio of the rapamycin liposome is 5%-10%.

[0029] Optionally, the average particle size of the coated drug is 200-400 nm, the drug loading is 1%-4%, and the encapsulation efficiency is 40%-90%.

[0030] Optionally, the spinning aid is selected from one or more of carbomer, gelatin, and PEO.

[0031] Optionally, the injection rate of the spray is 0.2-1 ml / h; the needle specification of the syringe is 20-23G, the voltage connected to the needle is 15-30 kv, and the rotation rate of the balloon is above 20 rpm.

[0032] Compared with existing rapamycin pharmaceutical products, the present invention has the following advantages:

[0033] 1. The rapamycin liposomes of the present invention greatly improve the solubility of rapamycin in the aqueous phase.

[0034] 2. The cationic liposome coating of the present invention can promote the adhesion of nanoparticles to the surface of the blood vessel wall, has a sustained release effect, and reduces toxic side effects. Phospholipids and cholesterols as rapamycin carriers can be degraded under physiological conditions in the body, have good biocompatibility, and are highly safe.

[0035] 3. The preparation method is simple, the process is stable, suitable for large-scale production, the product is stable and has a long shelf life. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The features and advantages of the present invention will be more clearly understood by referring to the accompanying drawings, which are schematic and should not be construed as limiting the present invention in any way. In the accompanying drawings:

[0037] Figure 1 is a particle size diagram of the liposome in Example 1 of the present invention;

[0038] Figure 2 is a particle size diagram of the liposome in Example 6 of the present invention;

[0039] Figure 3 is a graph showing the particle size of the liposomes in Example 7 of the present invention;

[0040] Figure 4 This is the in vitro release diagram of the liposomes in Example 8 of the present invention;

[0041] Figure 5 is a particle size diagram of the liposome in Example 8 of the present invention;

[0042] Figure 6 is the potential diagram of the liposome in Example 8 of the present invention;

[0043] Figure 7 The rapamycin liposome capsule prepared in Example 8 of the present invention;

[0044] Figure 8 This is a diagram showing the particle size of the liposomes in Example 9 of the present invention. DETAILED DESCRIPTION

[0045] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0046] Rapamycin (sirolimus, sirolimus, rapamycin) has broad application prospects in the field of treating cardiovascular and cerebrovascular diseases with atherosclerosis and vascular intimal hyperplasia as etiologies, but sirolimus is a poorly soluble drug with poor bioavailability. Since liposomes as drug carriers have the advantages of targeting, cell affinity and tissue compatibility, the present invention encapsulates rapamycin in liposomes to improve its stability and improve its shortcomings of poor absorption and low bioavailability.

[0047] Example 1: 5 mg of rapamycin, 100 mg of egg yolk lecithin, and 20 mg of DC cholesterol were accurately weighed and dissolved in a mixture of 6 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS was added for hydration. The mixture was oscillated in a water bath until the film was hydrolyzed, and then homogenized by ultrasound and centrifuged to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and lyophilized. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn = 300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasound was applied for 5 minutes to uniformly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 26 kV, distance between the needle and the balloon 10 cm, flow rate 0.2 mL / h, rotation speed about 20 rpm, and needle specification 21G. The particle size analysis was performed using a particle size analyzer (90Plus PALS). The specific test results are as follows: Figure 1 As shown, the figure shows the particle size distribution diagram of three measurements. It can be seen from the figure that the particle size distribution is uniform, basically normal distribution, and the average particle size is 311.04nm.

[0048] Example 2: 5 mg of rapamycin, 75 mg of cephalin, and 15 mg of DC cholesterol were accurately weighed and dissolved in a mixture of 6 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS was added for hydration. The film was hydrolyzed in an oscillating water bath, and then homogenized by ultrasound and centrifuged to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and lyophilized. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn = 300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasound was applied for 5 minutes to evenly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 30 kV, distance between the needle and the balloon 10 cm, flow rate 1 mL / h, rotation speed about 20 rpm, and needle specification 23G.

[0049] Example 3: 5 mg of rapamycin, 50 mg of stearylethanolamine, and 10 mg of DC cholesterol were accurately weighed and dissolved in a mixture of 6 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS was added for hydration. The film was hydrolyzed in an oscillating water bath, and then homogenized by ultrasound and centrifuged to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and lyophilized. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn = 300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasound was applied for 5 minutes to uniformly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 15 kV, distance between the needle and the balloon 10 cm, flow rate 0.2 mL / h, rotation speed about 20 rpm, and needle specification 20G.

[0050] Example 4: 5 mg of rapamycin, 100 mg of stearylamine, and 12.5 mg of DC cholesterol were accurately weighed and dissolved in a mixture of 6 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS was added for hydration. The mixture was oscillated in a water bath until the film was hydrolyzed, and then homogenized by ultrasound and centrifuged to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and lyophilized. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn = 300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasound was applied for 5 minutes to uniformly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 30 kV, distance between the needle and the balloon 10 cm, flow rate 0.2 mL / h, rotation speed about 20 rpm, and needle specification 21G.

[0051] Example 5: 5 mg of rapamycin, 100 mg of DOTMA, and 33 mg of cholesterol were accurately weighed and dissolved in a mixture of 6 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS was added for hydration. The film was hydrolyzed in an oscillating water bath, and then homogenized by ultrasound and centrifuged to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and lyophilized. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn = 300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasound was applied for 5 minutes to evenly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 20 kV, distance between the needle and the balloon 10 cm, flow rate 0.4 mL / h, rotation speed about 20 rpm, and needle specification 23G.

[0052] Example 6: 5 mg of rapamycin, 100 mg of DOTAP, and 20 mg of cholesterol were accurately weighed and dissolved in a mixture of 6 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS was added for hydration. The film was hydrolyzed in an oscillating water bath, and then homogenized by ultrasound and centrifuged to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and lyophilized. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn = 300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasound was applied for 5 minutes to evenly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 26 kV, distance between the needle and the balloon 10 cm, flow rate 0.2 mL / h, rotation speed about 20 rpm, and needle specification 21G. The particle size analysis was performed using a particle size analyzer (90Plus PALS). The specific test results are as follows: Figure 2 As shown in the figure, the particle size distribution diagram is measured three times. It can be seen from the figure that the particle size distribution is uniform, basically normally distributed, and the average particle size is 378.57nm.

[0053] Example 7: 5 mg of rapamycin, 100 mg of HSPC, and 20 mg of DC cholesterol were accurately weighed and dissolved in a mixture of 6 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS was added for hydration. The film was hydrolyzed in an oscillating water bath, and then ultrasonically dispersed and centrifuged to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and lyophilized. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn = 300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasonicated for 5 minutes to evenly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 26 kV, distance between the needle and the balloon 10 cm, flow rate 0.2 mL / h, rotation speed about 20 rpm, needle specification 21G. The particle size analysis was performed using a particle size analyzer (90Plus PALS). The specific test results are as follows: Figure 3 As shown, the figure shows the particle size distribution diagram of three measurements. It can be seen from the figure that the particle size distribution is uniform, basically normally distributed, and the average particle size is 457.71nm.

[0054] Example 8: 20 mg of rapamycin, 400 mg of egg yolk lecithin, and 80 mg of cholesterol were accurately weighed and dissolved in 24 ml of a mixture of dichloromethane and methanol. The organic mixture was then evaporated at 37°C to remove the organic solvent, and 5 ml of PBS was added for hydration. The mixture was shaken in a water bath until a thin film was hydrolyzed, and then dispersed by ultrasound and centrifuged to obtain rapamycin liposomes.

[0055] In vitro release: Cut a 5 cm dialysis bag (molecular weight cutoff Mw = 20,000), put it into boiling water for 20 minutes, and wash it with distilled water. Quickly transfer a liposome suspension containing about 8 mg of drug, put it into the dialysis bag, tie both ends with dialysis clamps, and put it into a beaker containing 150 mL of dialysis medium. The dialysis medium is a mixed solution of 50% acetonitrile and 50% phosphate buffer (pH = 7.4, containing 2% SDS). Place the beaker on a magnetic stirring stirrer (Jintan HJ-6B), keep stirring, and take out 1 ml of dialysis medium at specific sampling points, and add 1 ml of rehydration solution. The removed dialysis medium is filtered with a 0.45 μm organic microporous filter membrane, and a high performance liquid chromatograph (Shimadzu LC-20AT) is used to determine the drug in the dialysis medium, and the cumulative release rate of the drug is calculated. Figure 4 As shown, the liposomes prepared by the method of this example released 50% within 24 hours, having a sustained-release property.

[0056] Particle size and potential: Take 200 μl of liposomes, dilute to 4 ml with PBS (pH 7.4), and measure the particle size with a laser particle size analyzer (90Plus PALS). The specific test results are as follows: Figure 5 As shown in the figure, the particle size distribution diagram of three measurements is shown. It can be seen from the figure that the particle size distribution is uniform and basically normal, and the average particle size is 184.62nm. The potential is detected by a laser particle size analyzer (Nano ZS90). The specific test results are as follows Figure 6 As shown, the figure shows the potential values ​​measured three times, and the average potential is 45.9mV.

[0057] Stability: The prepared lipid liposome suspension was sealed and placed vertically in a refrigerator.

[0058] Freeze-drying: Take an appropriate amount of the prepared liposome suspension and add 10% trehalose, stir to dissolve, and freeze-dry.

[0059] Electrostatic spray: Absorb a certain amount of liposome freeze-dried powder, re-dissolve, and then add PEO (Mn = 300,000) to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasonicate for 5 minutes to evenly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 26kV, distance between needle and balloon 10cm, flow rate 0.2mL / h, rotation speed about 20 rpm, needle specification 21G. Figure 7 As shown, the surface of the balloon is coated with a layer of yellow oily substance, and there are obvious particles adhering to it, which has a good coating effect.

[0060] Example 9: 20 mg of rapamycin, 100 mg of HSPC, and 20 mg of DC cholesterol were accurately weighed and dissolved in a mixture of 24 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37°C to remove the organic solvent, and 5 ml of PBS containing 1% (w / v) Tween 80 was added for hydration. The mixture was oscillated in a water bath until the film was hydrolyzed, and then ultrasonically dispersed and passed through a 0.8 μm aqueous microporous filter membrane to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and freeze-dried. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn=300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasonicated for 5 minutes to evenly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 26kV, distance between needle and balloon 10cm, flow rate 0.2mL / h, rotation speed about 20 rpm, needle specification 21G. Particle size analysis was performed using a particle size analyzer (90Plus PALS). The specific test results are as follows: Figure 8 As shown, the figure shows the particle size distribution diagram of three measurements. It can be seen from the figure that the particle size distribution is uniform, basically normally distributed, and the average particle size is 452.42nm.

[0061] Comparative Example 1: Accurately weigh 5 mg of rapamycin, 100 mg of HSPC, and 100 mg of DC cholesterol, and dissolve them in a mixture of 6 ml of dichloromethane-methanol. Then, the organic mixture is evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS is added for hydration. Oscillate in a water bath until the film is hydrolyzed, then disperse by ultrasound and centrifuge to obtain rapamycin liposomes. Add 10% trehalose to the prepared liposome suspension, stir to dissolve, and freeze-dry. Take a certain amount of liposome freeze-dried powder, re-dissolve, and then add PEO (Mn = 300,000) to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasonicate for 5 minutes to evenly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 26 kV, distance between needle and balloon 10 cm, flow rate 0.2 mL / h, rotation speed about 20 rpm, needle specification 21G.

[0062] Comparative Example 2: 5 mg of rapamycin, 100 mg of HSPC, and 50 mg of DC cholesterol were accurately weighed and dissolved in a mixture of 6 ml of dichloromethane-methanol. The organic mixture was then evaporated at 37 ° C to remove the organic solvent, and 4 ml of PBS was added for hydration. The film was hydrolyzed in an oscillating water bath, and then ultrasonically dispersed and centrifuged to obtain rapamycin liposomes. 10% trehalose was added to the prepared liposome suspension, stirred to dissolve, and lyophilized. A certain amount of liposome freeze-dried powder was taken, re-dissolved, and PEO (Mn = 300,000) was added to the solution at a ratio of 1:3 (liposome: PEO) under stirring. After sufficient stirring, ultrasonic 5 min was used to evenly disperse the solution to obtain an electrostatic spray prescription. Electrostatic spray conditions: voltage 26 kV, distance between the needle and the balloon 10 cm, flow rate 0.2 mL / h, rotation speed about 20 rpm, needle specification 21G.

[0063] The performance parameters of the drug balloons obtained in various embodiments and comparative examples are shown in Table 1:

[0064] Table 1

[0065]

[0066]

[0067] It can be seen from Table 1 that when the mass ratio of phospholipid to cholesterol is above 3:1, the comprehensive performance parameters are very good, especially the drug loading capacity. When the mass ratio of phospholipid to cholesterol is above 3:1, the drug loading capacity is above 1.73%.

[0068] Experimental example

[0069] The drug balloons of the embodiment were implanted in New Zealand rabbits, with a total of 20 animals implanted.

[0070] Experimental group: 12 New Zealand rabbits were implanted in the bilateral iliac arteries. Each group of animals was implanted with drug balloons, and 6 rabbits were dissected immediately after surgery (0 days) and 7 days after surgery. The balloon catheters described in Examples 1, 3, and 6 were implanted in the experimental group rabbits.

[0071] Control group: Two New Zealand rabbits were implanted in the bilateral iliac arteries. Two blank control balloon catheters were placed in each group of animals. One was dissected immediately after surgery and the other was dissected 7 days after surgery.

[0072] New Zealand rabbits were given intravenous heparin before surgery, and blood pressure, heart rate and other indicators were monitored. Using a guide catheter and a 0.014 guidewire, the drug balloon was delivered through the carotid artery to the target position of the iliac artery, and then the drug balloon was expanded with appropriate pressure. The pressure was maintained for 60 seconds and then the balloon pressure was withdrawn. The position of the balloon from the vascular bifurcation was recorded, and all instruments and equipment were removed from the experimental animals at the end of the operation. Immediately after surgery (0 days), 4 days after surgery, and 7 days after surgery, the New Zealand map was dissected in situ to expose the target blood vessels, and the target vascular tissue was cut 2-3 mm upstream and downstream of the surgical operation site.

[0073] After weighing the blood vessel sample, cut it into pieces and homogenize it in a ratio of tissue: 50% methanol = 1:4 (w:v). Part of the homogenate is frozen and stored below -20°C. Use a pipette to accurately transfer 20 μL of the homogenate into a 1.5mL EP tube, add 180 μL of blank matrix and mix well for use. Take 100 μL of the standard curve sample and quality control sample and add the precipitant in a ratio of sample: precipitant = 1:3 (v:v), mix well, centrifuge at 12000 rpm for 10 min at 4°C, and determine the sirolimus content (unit ng / mg) in the tissue by liquid chromatography-mass spectrometry.

[0074] Chromatographic conditions: Chromatographic column: ZORBAX Extend-C18 column, 2.1*50mm 3.5μm, flow rate: 0.9mL / min, injection volume: 20μL, column temperature: 40°C, mobile phase A: 0.1% formic acid ultrapure aqueous solution (10mmol ammonium formate), mobile phase B: 0.1% formic acid methanol solution (10mmol ammonium formate), gradient elution measurement data are shown in Table 2 below.

[0075] Table 2 Sirolimus content in vascular tissue of animals in each group

[0076]

[0077] It can be seen that the drug balloons described in Examples 1, 3, and 6 can take sirolimus into the blood vessel wall and continue to work within 7 days. The above technical effects are also applicable to other embodiments and will not be repeated here.

[0078] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Those skilled in the art may make various modifications and variations without departing from the spirit and scope of the present invention. Such modifications and variations shall all fall within the scope defined by the appended claims.

Claims

1. A method for preparing a drug-coated drug balloon, The following steps are involved: Rapamycin, phospholipid and cholesterol are prepared in a mass ratio of 1:3-1:8 and dissolved in an organic solvent; The organic solvent is removed by rotary evaporation, and the aqueous phase solution is added and homogenized to obtain rapamycin liposomes; and lyophilized under the condition of adding a lyophilization protective agent; The liposome and the spinning aid are re-dissolved and mixed, and then electrostatically sprayed to form a uniform drug coating, so that the drug balloon can achieve sustained release of the drug within 7 days.

2. The method for preparing the drug-coated drug balloon according to claim 1, Features The cationic lipid material is selected from one or more of (2,3-dioleoyl-propyl)-trimethylamine (DOTAP), dimethylaminoethane-carbamoyl cholesterol (DC-cholesterol), N-[1-(2,3-dioleoyl)propyl]-N,N,N-trimethylammonium chloride (DOTMA), and trimethyldodecyl ammonium bromide (DTAB).

3. The method for preparing the drug-coated drug balloon according to claim 1 or 2, It is characterized in that The phospholipids include one or more of egg yolk lecithin, hydrogenated soybean lecithin, cephalin, phosphatidylethanolamine, dimyristoylphosphatidylcholine (DMPC), and stearamide (SA).

4. The method for preparing the drug-coated drug balloon according to claim 1 or 2, It is characterized in that The cholesterol includes DC cholesterol.

5. The method for preparing the drug-coated drug balloon according to claim 1 or 2, Features The spinning aid is selected from one or more of carbomer, gelatin and PEO.

6. The method for preparing the drug-coated drug balloon according to claim 1 or 2, It is characterized in that The lyophilization protective agent is selected from one or more of mannitol, glucose, sucrose and trehalose.

7. The method for preparing the drug-coated drug balloon according to claim 1 or 2, It is characterized in that The parameters of the electrostatic spraying are: voltage 15-30 kV; injection rate 0.2-1 ml / h; rotation rate above 20 rpm.

8. The method for preparing the drug-coated drug balloon according to any one of claims 1 to 6, It is characterized in that The mass ratio of the lyophilized protective agent to the mass ratio of the rapamycin liposome is 5%-10%.

9. The method for preparing the drug-coated drug balloon according to any one of claims 1 to 6, It is characterized in that The average particle size of the coated medicine is 200-400nm, the drug loading is 1%-4%, and the encapsulation rate is 40%-90%.

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