A medical balloon multiple release control drug-loaded coating and a preparation method thereof

Abstract

The application discloses a medical balloon multiple release control drug-loaded coating and a preparation method thereof, and relates to the technical field of cardiovascular repair materials.The coating is formed by ultrasonic spraying of an ultralow-viscosity multiple drug-loaded coating liquid; the multiple drug-loaded coating liquid takes an organic solvent as a solvent, and the mass percentage of each component in the organic solvent is as follows: 3-7% of a non-ionic surfactant, 0.2-0.8% of a hydrophobic surfactant, 0.5-1.6% of an alcohol, 0.05-1% of a smooth muscle proliferation inhibiting drug, 0.5-3% of a NO donor drug, 6-12% of urea and 0.5-2% of deionized water.The medical balloon multiple release control drug-loaded coating and the preparation method thereof increase the adhesion on the surface of the balloon by adding macromolecules into the coating liquid; the added urea can inhibit paclitaxel crystallization, and the hydrophobic surfactant can make the coating surface more uniform and smooth.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of cardiovascular repair materials, in particular to a medical balloon multi-release controlled drug delivery coating and a preparation method thereof. BACKGROUND

[0002] Common cardiovascular diseases include hypertension, coronary heart disease, and arteriosclerosis. Although the development of arteriosclerosis is slow and gradual, atherosclerosis (AS) is the main lethal factor of global cardiovascular diseases. At present, balloon dilatation stents (DES) are commonly used for treatment. However, the initial damage caused by implantation and the reaction of the blood vessel to the implanted metal prosthesis lead to excessive proliferation of neointima and in-stent restenosis. Moreover, there are still many challenges in DES implantation, such as arterial injury, vascular proliferation cascade, smooth muscle cell proliferation and migration, neointimal hyperplasia, delayed vascular endothelial healing, poor late stent apposition, and in-stent thrombosis. Due to the clinical effectiveness of drug-coated balloons (DCB) and the avoidance of permanent metal implants (such as stents) and the advantages over traditional uncoated balloon angioplasty, drug-coated balloons (DCB) are gradually becoming an important means of clinical intervention for AS.

[0003] DCB is a drug-coated balloon in which a drug-loaded coating is coated on a conventional balloon. When the balloon is expanded, the PTX in the coating contacts the lesion intima of the blood vessel and rapidly penetrates into the blood vessel wall, thereby inhibiting the proliferation and migration of smooth muscle cells and hindering the process of restenosis. Compared with DES, DCB can uniformly release drugs to the contacted blood vessel wall while ensuring the integrity of the blood vessel anatomy, reducing the probability of abnormal blood flow dynamics and restenosis and thrombosis, avoiding stent fracture and metal allergy, and overcoming the problems of immediate vascular burden and neointimal hyperplasia after stent implantation. Moreover, the drug delivery per square millimeter of the surface of the balloon has greater theoretical advantages. The ease of use and high delivery of the balloon-based drug delivery system provide opportunities for use in coronary artery regions where DES may have problems or have not been proven to be particularly effective, and may improve the results in non-coronary artery regions where DES has been proven to be ineffective so far.

[0004] To firmly attach the coating to the surface of the balloon material, immersion coupling and surface plasma treatment methods are commonly used, which do not meet the demand for simple and efficient preparation process. Moreover, the coating surface requires uniformity and flatness to avoid the formation of debris on the coating surface during packaging and storage. Within 1-2 min from the transportation of the balloon from the guide wire to the damaged part of the blood vessel to the inflation and expansion in contact with the inner wall of the blood vessel, the transfer efficiency of DCB is generally <8%, which is far from enough compared with the drug release rate from the balloon (>90). The accumulation of the drug in the distal part of the body due to the flushing of the drug with blood flow and blood circulation leads to the occurrence of adverse symptoms, which is a problem of balloon technology.

[0005] To this end, the present application provides a medical balloon multiple release control drug-loaded coating and a preparation method thereof to solve the above-mentioned problems. SUMMARY

[0006] (I) Technical problems solved

[0007] In view of the deficiencies in the prior art, the present application provides a medical balloon multiple release control drug-loaded coating and a preparation method thereof to solve the above-mentioned problems in the background art.

[0008] (II) Technical solutions

[0009] To achieve the above object, the present application is implemented by the following technical solutions: a medical balloon multiple release control drug-loaded coating, which is formed by ultrasonic spraying of an ultralow-viscosity multiple drug-loaded coating liquid; the multiple drug-loaded coating liquid takes an organic solvent as a solvent, and the mass percentage of each component in the organic solvent is: 3-7% of a non-ionic surfactant, 0.2-0.8% of a hydrophobic surfactant, 0.5-1.6% of an alcohol, 0.05-1% of a smooth muscle proliferation inhibiting drug, 0.5-3% of a NO donor drug, 6-12% of urea, and 0.5-2% of deionized water.

[0010] Preferably, the non-ionic surfactant is selected from one or more of poloxamer 188 and poloxamer 407.

[0011] Preferably, the hydrophobic surfactant is selected from one or more of polyoxyethylene-polyoxypropylene monobutyl ether L61 and O-butyryl citric acid trihexyl ester.

[0012] Preferably, the alcohol is selected from one or more of glycerol and 1,4-butanediol.

[0013] Preferably, the smooth muscle proliferation inhibiting drug is selected from one or more of paclitaxel and rapamycin.

[0014] Preferably, the NO donor drug is selected from one or more of nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate.

[0015] Preferably, the organic solvent is selected from one or more of methanol and chloroform.

[0016] A preparation method of a medical balloon multiple release control drug-loaded coating: the components are mixed in proportion to obtain a first solution, the first solution is pumped into an ultrasonic spraying machine after the smooth muscle proliferation inhibiting drug is completely dissolved; the parameters of the ultrasonic spraying machine are adjusted, and the nozzle is aimed at the center position of the expanded balloon for spraying; after the spraying is completed, the organic solvent is completely volatilized, and the multiple release control drug-loaded coating is obtained.

[0017] (III) Beneficial effects

[0018] The present application provides a medical balloon multiple release control drug-loaded coating and a preparation method thereof. Compared with the prior art, the medical balloon multiple release control drug-loaded coating and the preparation method thereof have the following beneficial effects: the medical balloon multiple release control drug-loaded coating and the preparation method thereof increase the adhesion on the surface of the balloon by adding macromolecules to the coating liquid; the added urea can inhibit the crystallization of paclitaxel, and the combination of the hydrophobic surfactant makes the coating surface more uniform and smooth; the re-wetting material and deionized water increase the toughness of the coating, so that the coating as a whole does not break when it is folded, contracted and inflated, thereby avoiding the generation of fragments falling from the surface of the balloon. Due to the addition of a small amount of water to the organic system, the solubility of the hydrophobic active drug is greatly affected, and the added double surfactant can help to increase the solubility of paclitaxel, so that a transparent ultra-low viscosity spraying liquid is finally obtained, which is atomized after ultrasonic treatment and uniformly attached to the surface of the balloon. And the addition of NO donor drugs can release NO immediately when contacting the damaged blood vessel site, dilate the blood vessel, and cooperate with the synchronous loading of active drugs in the coating to inhibit the proliferation of smooth muscle cells and achieve the effect of long-term treatment of atherosclerosis. The coating liquid can be stored stably and uniformly in a closed low-temperature dark environment. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 It is a macroscopic schematic diagram of an ultrasonic spraying machine;

[0020] Figure 2 It is a macroscopic schematic diagram of a medical balloon multiple release control drug-loaded coating;

[0021] Figure 3 It is a schematic diagram of successful atomization of the spraying liquid and clogging of the nozzle of the ultrasonic spraying machine;

[0022] Figure 4 It is a schematic diagram of drug-loaded coatings containing 0.335% BTHC and containing 0.8% BTHC while keeping the content of other components unchanged;

[0023] Figure 5 It is a schematic diagram of drug-loaded coatings containing 6% urea and containing 10% urea while keeping the content of other components unchanged. DETAILED DESCRIPTION

[0024] The technical solutions in the embodiments of the present application will be described clearly and completely below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0025] Example 1

[0026] Preparation of the medical balloon multiple release control drug-loaded coating:

[0027] At room temperature, 2 g Urea, 1 g P407, 0.067 g BTHC, 0.12 g Glycerol (GLY), 0.1 g PTX, 0.4 g NTG, 0.2 g DIW were dissolved in 20 g MeOH. After 20 min ultrasonic, the solution was sprayed into the ultrasonic spray machine, the flow rate was set at 2 mL / min, the feeding speed was 3 mm / s, the rotation speed was 3 rev / s, the spraying times was 10, the drying speed was 10 mm / s, and the drying time was 6.0 s.

[0028] Example 2

[0029] In this example, chloroform (CHCl3) was used to replace methanol (MeOH) in the preparation of coating solution, and the other operations were the same as in Example 1.

[0030] Example 2 was prepared according to the method of Example 1, and the operations were the same as in Example 1, except that the types of organic solvents were different. The profile arithmetic mean deviation of the drug-loaded coating prepared by different organic solvents, the relative standard deviation of the functional group signal intensity for measuring the uniformity of the composition content, the residual rate of the coating after friction and wear test, the peeling rate of the coating after expansion and contraction cycle test, and the hemolysis rate were measured, as shown in Table 1.

[0031] Table 1 Performance analysis of drug-loaded coatings prepared by different types of organic solvents

[0032] Example Organic solvent class Ra (pm) Ingredient RSD (%) Coating residual rate (%) Coating flaking rate (%) Hemolysis rate (%) 1 MeOH 0.10 3 95 3 1.1 2 CHCl3 0.15 4 95 4 1.2

[0033] Ra: profile arithmetic mean deviation; RSD: relative standard deviation.

[0034] As can be seen from the data in Table 1, compared with methanol (MeOH), the multiple controlled-release drug-loaded coating prepared by chloroform (CHCl3) also showed very excellent surface uniformity, anti-friction and wear performance, almost no peeling of the balloon surface coating after the expansion and contraction cycle test, and excellent biocompatibility after the organic solvent was completely volatilized. By using chloroform and methanol to dissolve each component, the viscosity of the coating solution was maintained at 0.4 mPa•s~0.5 mPa•s, which ensured that it could be completely atomized by the ultrasonic spray machine and would not gather into droplets at the nozzle.

[0035] Example 3

[0036] In this example, 1,4-butanediol (BDO) was used to replace glycerol (GLY) in the preparation of coating solution, and the other operations were the same as in Example 1.

[0037] Example 4

[0038] In the preparation of the coating solution of this example, the hydrophobic surfactant was replaced with polyoxyethylene-polyoxypropylene monobutyl ether L61 (L61) instead of O-butyryl trihexyl citrate (BTHC), and the other components were the same as in Example 1.

[0039] Example 5

[0040] In the preparation of the coating solution of this example, the hydrophobic surfactant was replaced with polyoxyethylene-polyoxypropylene monobutyl ether L61 (L61) instead of O-butyryl trihexyl citrate (BTHC), and 1,4-butanediol (BDO) was used instead of glycerol (GLY), and the other components were the same as in Example 1.

[0041] Example 6

[0042] In the preparation of the coating solution of this example, the nonionic surfactant was replaced with poloxamer 188 (P188) instead of poloxamer 407 (P407), and the other components were the same as in Example 1.

[0043] Example 7

[0044] In the preparation of the coating solution of this example, the nonionic surfactant was replaced with poloxamer 188 (P188) instead of poloxamer 407 (P407), the alcohol was replaced with 1,4-butanediol (BDO) instead of glycerol (GLY), and the other components were the same as in Example 1.

[0045] Example 8

[0046] In the preparation of the coating solution of this example, the nonionic surfactant was replaced with poloxamer 188 (P188) instead of poloxamer 407 (P407), the hydrophobic surfactant was replaced with polyoxyethylene-polyoxypropylene monobutyl ether L61 (L61) instead of O-butyryl trihexyl citrate (BTHC), and the other components were the same as in Example 1.

[0047] Example 9

[0048] In the preparation of the coating solution of this example, the nonionic surfactant was replaced with poloxamer 188 (P188) instead of poloxamer 407 (P407), the hydrophobic surfactant was replaced with polyoxyethylene-polyoxypropylene monobutyl ether L61 (L61) instead of O-butyryl trihexyl citrate (BTHC), and 1,4-butanediol (BDO) was used instead of glycerol (GLY), and the other components were the same as in Example 1.

[0049] Examples 3-9 were prepared according to the method of Example 1, with the same procedure as Example 1, except that only the type of non-ionic surfactant, hydrophobic surfactant and moisturizing alcohol used in the coating solution was changed, and the profile arithmetic mean deviation of the coating prepared from different types of non-ionic surfactant, hydrophobic surfactant and moisturizing alcohol was measured, the relative standard deviation of the functional group signal intensity was measured to measure the uniformity of the ingredient content, the coating residual rate after the friction and wear test, the coating shedding rate after the expansion and contraction cycle test, and the hemolysis rate, as shown in Table 2.

[0050] Table 2 Performance analysis of drug-loaded coatings prepared from different types of surfactants and alcohols

[0051] Example Non-ionic surfactant Hydrophobic surfactant Alcohol Ra (pm) Ingredient RSD (%) Coating residual rate (%) Coating flaking rate (%) Hemolysis rate (%) 1 P407 BTHC GLY 0.10 3 95 3 1.1 3 P407 BTHC BDO 0.11 3 93 5 1.1 4 P407 L61 GLY 0.14 4 92 4 1.2 5 P407 L61 BDO 0.15 4 90 5 1.2 6 P188 BTHC GLY 0.11 3 94 3 1.1 7 P188 BTHC BDO 0.11 3 93 5 1.1 8 P188 L61 GLY 0.13 4 93 4 1.1 9 P188 L61 BDO 0.15 4 90 6 1.1

[0052] As can be seen from the data in Table 2, compared with non-ionic surfactant P407, the drug-loaded coatings formed by P188 combined with BTHC and L61 and GLY and BDO also exhibit very excellent surface uniformity, anti-friction and wear performance and good expansion and contraction cycle coating retention rate. Compared with hydrophobic surfactant BTHC, L61 can also make the coating surface uniform and smooth. Compared with GLY, BDO can also make the coating have good anti-friction and wear performance. Compared with BTHC and GLY, the anti-friction and wear performance of the coating formed by L61 and BDO is slightly weaker, but the coating residual rate after the friction and wear test is still ≥90.

[0053] Example 10

[0054] In the preparation of the coating solution of this example, the addition amount of O-butyryl trihexyl citrate (BTHC) is 0.04 g, and the addition amounts of other components are the same as in Example 1.

[0055] Example 11

[0056] In the preparation of the coating solution of this example, the addition amount of O-butyryl trihexyl citrate (BTHC) is 0.1 g, and the addition amounts of other components are the same as in Example 1.

[0057] Example 12

[0058] In the preparation of the coating solution of this example, the addition amount of O-butyryl trihexyl citrate (BTHC) is 0.13 g, and the addition amounts of other components are the same as in Example 1.

[0059] Example 13

[0060] In the preparation of the coating solution of this example, the addition amount of O-butyryl trihexyl citrate (BTHC) is 0.16 g, and the addition amounts of other components are the same as in Example 1.

[0061] Example 14

[0062] In the preparation of the coating solution of this example, the amount of glycerol (GLY) added was 0.1 g, and the amounts of the other components added were the same as in Example 1.

[0063] Example 15

[0064] In the preparation of the coating solution of this example, the amount of glycerol (GLY) added was 0.14 g, and the amounts of the other components added were the same as in Example 1.

[0065] Example 16

[0066] In the preparation of the coating solution of this example, the amount of glycerol (GLY) added was 0.16 g, and the amounts of the other components added were the same as in Example 1.

[0067] Example 17

[0068] In the preparation of the coating solution of this example, the amount of glycerol (GLY) added was 0.18 g, and the amounts of the other components added were the same as in Example 1.

[0069] Example 18

[0070] In the preparation of the coating solution of this example, the amount of glycerol (GLY) added was 0.2 g, and the amounts of the other components added were the same as in Example 1.

[0071] Example 19

[0072] In the preparation of the coating solution of this example, the amount of glycerol (GLY) added was 0.24 g, and the amounts of the other components added were the same as in Example 1.

[0073] Example 20

[0074] In the preparation of the coating solution of this example, the amount of glycerol (GLY) added was 0.28 g, and the amounts of the other components added were the same as in Example 1.

[0075] Example 21

[0076] In the preparation of the coating solution of this example, the amount of glycerol (GLY) added was 0.32 g, and the amounts of the other components added were the same as in Example 1.

[0077] Examples 10-21 were prepared according to the method of Example 1, with the same operations as in Example 1, except that the amounts of the hydrophobic surfactant and the moisturizing alcohol were changed. The profile arithmetic mean deviation of the drug-loaded coating prepared with different amounts of the hydrophobic surfactant and the moisturizing alcohol was measured, the relative standard deviation of the functional group signal intensity was measured to evaluate the uniformity of the ingredient content, the coating residual rate after the friction-wear test was measured, the coating shedding rate after the expansion-contraction cycle test was measured, and the hemolysis rate was measured, as shown in Table 3.

[0078] Table 3 Performance analysis of drug-loaded coatings prepared with different proportions of hydrophobic surfactant and alcohol

[0079] Example W BTHC W MeOH (w%)]]> W GLY W MeOH (w%)]]> Ra (pm) Ingredient RSD (%) Coating residual rate (%) Coating flaking rate (%) Hemolysis rate (%) 1 0.335 0.6 0.10 3 95 3 1.1 10 0.2 0.6 0.18 5 93 4 1.1 11 0.5 0.6 0.15 4 94 4 1.1 12 0.65 0.6 0.18 5 92 5 1.2 13 0.8 0.6 2.0 6 90 7 1.3 14 0.335 0.5 0.10 3 92 5 1.1 15 0.335 0.7 0.12 3 94 4 1.1 16 0.335 0.8 0.14 4 93 4 1.2 17 0.335 0.9 0.15 4 92 5 1.3 18 0.335 1.0 0.16 5 92 5 1.3 19 0.335 1.2 0.16 6 91 6 1.3 20 0.335 1.4 0.17 6 89 7 1.4 21 0.335 1.6 0.19 7 85 9 1.6

[0080] From the data in Table 3, it can be seen that Examples 1, 10, 11, 12, 13 show that a small amount of hydrophobic surfactant has no great influence on the surface properties of the coating, an appropriate amount of hydrophobic surfactant can help the hydrophobic drug paclitaxel to disperse, making the coating surface more smooth and uniform, and a large amount of hydrophobic surfactant will aggregate to form a hydrophobic microzone, resulting in a rough coating surface and a decrease in the anti-friction and wear resistance. Examples 1, 14, 15, 16, 17, 18, 19, 20, 21 show that a small amount of glycerol has no influence on the properties of the coating, an appropriate amount of glycerol can increase the toughness of the coating and its adhesion to the balloon, and when a large amount of glycerol is added, the viscosity of the system increases, the coating liquid cannot be completely atomized when the ultrasonic atomizer is in use, the coating liquid drops are formed and fall on the surface of the balloon, the surface is slightly sticky and rough, and even delamination occurs, resulting in a significant decrease in the anti-friction and wear resistance of the balloon. Therefore, the preferred range of BTHC in the methanol solution is 0.2% to 0.5%, and the preferred range of GLY in the methanol solution is 0.5% to 0.8%.

[0081] Example 22

[0082] In this example, the antiproliferative drug rapamycin (RAPA) is used instead of paclitaxel (PTX) in the preparation of the coating liquid, and the other operations are the same as in Example 1.

[0083] Example 22 is prepared according to the method of Example 1, and the operations are the same as in Example 1, except that the antiproliferative drug is RAPA. The drug release efficiency and hemolysis rate of the coating prepared with different antiproliferative drugs are measured, as shown in Table 4.

[0084] Table 4 Analysis of the properties of the drug-loaded coating with different types of antiproliferative drugs

[0085] Example Antiproliferative drug IRE 1day (%)]] Hemolysis rate (%) 1 PTX 100 1.1 22 RAPA 100 1.1

[0086] IRE1day: One-day in vitro drug release efficiency (%).

[0087] Compared with Example 22, the one-day in vitro release efficiency of rapamycin in the coating can also reach 100%, meeting the requirements of anti-endothelial cell proliferation and having good biocompatibility.

[0088] Example 23

[0089] In this example, the NO donor drug isosorbide dinitrate (ISDN) is used instead of nitroglycerin (NTG) in the preparation of the coating liquid, and the other operations are the same as in Example 1.

[0090] Example 24

[0091] In this embodiment, the NO donor drug is replaced by isosorbide mononitrate (ISMN) in the coating solution preparation, and other components are the same as in Example 1.

[0092] Examples 23-24 were prepared according to the method of Example 1, and the operations were the same as in Example 1, except that the type of NO donor drug used in the drug-loaded coating was changed. The drug release efficiency and hemolysis rate of the coating prepared with different NO donor drugs were measured, as shown in Table 5.

[0093] Table 5 Performance analysis of drug-loaded coatings prepared with different NO donor drugs

[0094] Example NO donor drug IRE 1day (%)]] Hemolysis rate (%) 1 NTG 100 1.1 23 ISDN 100 1.3 24 ISMN 100 1.4

[0095] As can be seen from the data in Table 5, the in vitro release efficiency of ISDN and ISMN within one day can still reach 100%, achieving the effect of relaxing blood vessels and having good biocompatibility.

[0096] Example 25

[0097] In this embodiment, the amount of poloxamer 407 (P407) added in the coating solution preparation was 0.6 g, the amount of paclitaxel (PTX) added was 0.01 g, and the amount of deionized water (DIW) added was 0.1 g. The amounts of other components were the same as in Example 1.

[0098] Example 26

[0099] In this embodiment, the amount of poloxamer 407 (P407) added in the coating solution preparation was 0.8 g, the amount of paclitaxel (PTX) added was 0.055 g, and the amount of deionized water (DIW) added was 0.15 g. The amounts of other components were the same as in Example 1.

[0100] Example 27

[0101] In this embodiment, the amount of poloxamer 407 (P407) added in the coating solution preparation was 1 g, the amount of paclitaxel (PTX) added was 0.1 g, and the amount of deionized water (DIW) added was 0.15 g. The amounts of other components were the same as in Example 1.

[0102] Example 28

[0103] In this embodiment, the amount of poloxamer 407 (P407) added in the coating solution preparation was 1 g, the amount of paclitaxel (PTX) added was 0.1 g, and the amount of deionized water (DIW) added was 0.24 g. The amounts of other components were the same as in Example 1.

[0104] Example 29

[0105] In the preparation of the coating solution of this example, the amount of poloxamer 407 (P407) added was 1 g, the amount of paclitaxel (PTX) added was 0.1 g, the amount of deionized water (DIW) added was 0.3 g, and the amounts of the other components added were the same as in Example 1.

[0106] Example 30

[0107] In the preparation of the coating solution of this example, the amount of poloxamer 407 (P407) added was 1 g, the amount of paclitaxel (PTX) added was 0.055 g, the amount of deionized water (DIW) added was 0.2 g, and the amounts of the other components added were the same as in Example 1.

[0108] Example 31

[0109] In the preparation of the coating solution of this example, the amount of poloxamer 407 (P407) added was 1 g, the amount of paclitaxel (PTX) added was 0.15 g, the amount of deionized water (DIW) added was 0.2 g, and the amounts of the other components added were the same as in Example 1.

[0110] Example 32

[0111] In the preparation of the coating solution of this example, the amount of poloxamer 407 (P407) added was 0.6 g, the amount of paclitaxel (PTX) added was 0.1 g, the amount of deionized water (DIW) added was 0.2 g, and the amounts of the other components added were the same as in Example 1.

[0112] Example 33

[0113] In the preparation of the coating solution of this example, the amount of poloxamer 407 (P407) added was 0.8 g, the amount of paclitaxel (PTX) added was 0.1 g, the amount of deionized water (DIW) added was 0.2 g, and the amounts of the other components added were the same as in Example 1.

[0114] Example 34

[0115] In the preparation of the coating solution of this example, the amount of poloxamer 407 (P407) added was 1.2 g, the amount of paclitaxel (PTX) added was 0.1 g, the amount of deionized water (DIW) added was 0.2 g, and the amounts of the other components added were the same as in Example 1.

[0116] Example 35

[0117] In the preparation of the coating solution of this example, the amount of poloxamer 407 (P407) added was 1.2 g, the amount of paclitaxel (PTX) added was 0.15 g, the amount of deionized water (DIW) added was 0.3 g, and the amounts of the other components added were the same as in Example 1.

[0118] Example 36

[0119] In the preparation of the coating solution, the amount of poloxamer 407 (P407) added was 1.4 g, the amount of paclitaxel (PTX) added was 0.2 g, and the amount of deionized water (DIW) added was 0.4 g. The amounts of the other components were the same as in Example 1.

[0120] Examples 25-36 were prepared according to the method of Example 1, with the same procedure as in Example 1, except that the amount of non-ionic surfactant, paclitaxel, and deionized water used in the coating solution was varied. The profile arithmetic mean deviation of the drug-loaded coating prepared with different amounts of non-ionic surfactant, paclitaxel, and deionized water was measured, and the relative standard deviation of the functional group signal intensity, which measures the uniformity of the content of the components, the residual rate of the coating after the friction-wear test, the shedding rate of the coating after the expansion-contraction cycle test, the drug content, and the hemolysis rate were measured. The results are shown in Table 6.

[0121] Table 6 Performance analysis of the adhesion outer layer prepared with different adhesion monomers

[0122] Example W P407 W MeOH (%)]]> W PTX / W MeOH (%)]]> W DIW W MeOH (%)]]> Ra (pm) Ingredient RSD (%) Coating residual rate (%) Coating flaking rate (%) Drug content (ug / mm 2 )]> Hemolysis rate (%) 1 5 0.5 1 0.10 3 95 3 3.1 1.1 25 3 0.05 0.5 0.10 2 97 2 0.3 1.0 26 4 0.275 0.75 0.10 3 96 3 1.6 1.1 27 5 0.5 0.75 0.10 3 94 5 3.1 1.1 28 5 0.5 1.2 0.11 3 97 2 2.9 1.1 29 5 0.5 1.5 0.17 5 92 7 2.5 1.0 30 5 0.275 1 0.10 2 98 2 1.7 1.0 31 5 0.75 1 0.20 5 90 8 4.5 1.2 32 3 0.5 1 0.20 5 87 9 1.9 1.1 33 4 0.5 1 0.15 4 92 7 2.9 1.1 34 6 0.5 1 0.12 3 95 2 3.1 1.2 35 6 0.75 1.5 0.12 4 94 4 4.6 1.2 36 7 1 2 0.13 4 94 4 6 1.5

[0123] As can be seen from the data in Table 6, Examples 1, 27, 28, 29 show that a small amount of water is added to the coating liquid, at which time paclitaxel can be completely dissolved, the residual rate of the coating after the friction and wear test is improved, and the coating shedding rate after the expansion-contraction cycle test is reduced, because at this time the surfactant in the coating liquid is sufficient to wrap paclitaxel, does not affect the complete dissolution of paclitaxel, at the same time increases the toughness of the coating, and prevents the coating from breaking and falling off. When excessive deionized water is added to the coating liquid, the surfactant in the system is not sufficient to wrap all the paclitaxel, which affects the complete dissolution of the hydrophobic drug paclitaxel, a small amount of particles is precipitated, which makes the ultrasonic atomization incomplete, the surface spraying uneven, and the surface friction increased, so that the residual rate of the coating during the friction and wear test is reduced, and the coating shedding rate during the expansion-contraction cycle test is increased, but the addition of water does not affect the biocompatibility of the coating, and the coating liquid has good biosafety. Examples 1, 30, 31 show that when the mass fraction of other components remains different, the mass fraction of PTX is increased, the surface roughness is increased, the element distribution is uneven, and the residual rate of the coating during the friction and wear test is reduced. This is because the addition of part of deionized water in the coating liquid limits the solubility of paclitaxel in methanol, and excessive paclitaxel blocks the spray head of the ultrasonic spray head machine, so that the coating liquid cannot be completely atomized continuously and stably, and the droplets accumulate and fall on the surface of the coating, resulting in uneven surface. Examples 1, 32, 33, 34 show that with the increase of the surfactant, the coating surface is more uniform, and the proportion of high molecules in the system is increased, which increases the adhesion of the coating on the balloon and the anti-friction and wear performance. Therefore, the preferred range of P407 in the methanol solution is 3% to 6%, the preferred range of PTX in the methanol solution is 0.275% to 0.5%, and the preferred range of DIW in the methanol solution is 0.75% to 1.2%.

[0124] Example 37

[0125] In the preparation of the coating liquid of this example, the amount of urea (Urea) is 1.2 g, and the others are the same as in Example 1.

[0126] Example 38

[0127] In the preparation of the coating liquid of this example, the amount of urea (Urea) is 1.6 g, and the others are the same as in Example 1.

[0128] Example 39

[0129] In the preparation of the coating liquid of this example, the amount of urea (Urea) is 2.4 g, and the others are the same as in Example 1.

[0130] Examples 37-39 were prepared according to the method of Example 1, with the same procedure as Example 1, except that the urea concentration was changed, and the profile arithmetic mean deviation of the drug-loaded coating prepared at different urea concentrations was measured, the relative standard deviation of the functional group signal intensity was measured to evaluate the uniformity of the composition, the coating residual rate after the friction-wear test, the coating shedding rate after the expansion-contraction cycle test, the drug content, the one-day in vitro release efficiency, the hemolysis rate, as shown in Table 7.

[0131] Table 7 Performance analysis of drug-loaded coatings prepared at different urea amounts

[0132] Example W Urea W MeOH (%)]]> Ra (pm) Ingredient RSD (%) Coating residual rate (%) Coating flaking rate (%) Drug content (ug / mm 2 )]> IRE 1day (%)]] Hemolysis rate 1 10 0.10 3 95 3 3.1 100 1.1 37 6 0.18 5 90 8 2.8 95 1.0 38 8 0.15 4 92 6 2.9 98 1.1 39 12 0.10 3 95 3 3.1 100 1.1

[0133] As can be seen from the data in Table 7, as the mass fraction of urea in the coating solution increases, the surface uniformity of the coating increases, and the one-day in vitro release efficiency of paclitaxel gradually increases to 100%. This is because urea can inhibit the aggregation of paclitaxel crystals, and after the balloon is expanded at the site of action, urea quickly dissolves due to its strong hydrophilicity, and at the same time generates a local osmotic pressure, promoting the penetration of paclitaxel to the atherosclerotic site. Therefore, the preferred range of urea in the methanol solution is 8% to 12%.

[0134] Example 40

[0135] In the preparation of the coating solution of this example, the amount of nitroglycerin (NTG) added was 0.1 g, and the amounts of the other components were the same as in Example 1.

[0136] Example 41

[0137] In the preparation of the coating solution of this example, the amount of nitroglycerin (NTG) added was 0.2 g, and the amounts of the other components were the same as in Example 1.

[0138] Example 42

[0139] In the preparation of the coating solution of this example, the amount of nitroglycerin (NTG) added was 0.3 g, and the amounts of the other components were the same as in Example 1.

[0140] Example 43

[0141] In the preparation of the coating solution of this example, the amount of nitroglycerin (NTG) added was 0.5 g, and the amounts of the other components were the same as in Example 1.

[0142] Example 44

[0143] In the preparation of the coating solution of this example, the amount of nitroglycerin (NTG) added was 0.6 g, and the amounts of the other components were the same as in Example 1.

[0144] Examples 40-44 were prepared according to the method of Example 1, with the same procedure as Example 1, except that the amount of nitroglycerin used in the coating solution was varied. The drug content on the balloon surface, the one-day in-vitro release efficiency, the profile arithmetic mean deviation, the relative standard deviation of the functional group signal intensity measuring the uniformity of the ingredient content, the coating residual rate after friction-wear test, the coating shedding rate after expansion-contraction cycle test, and the hemolysis rate of the drug-loaded coatings prepared with different amounts of nitroglycerin were measured, as shown in Table 8.

[0145] Table 8 Performance analysis of drug-loaded coatings prepared with different amounts of nitroglycerin

[0146] Example W NTG W MeOH (%)]]> Drug content (ug / mm 2 )]> IRE 1day (%)]] Ra (pm) Ingredient RSD (%) Coating residual rate (%) Coating flaking rate (%) Hemolysis rate Example Ra (pm) Ingredient RSD (%) Coating residual rate (%) Coating flaking rate (%) Hemolysis rate 1 2 12.4 100 0.1 3 95 3 1.1 40 0.5 3.1 100 0.15 4 94 4 1.1 41 1 6.2 100 0.13 3 95 3 1.1 42 1.5 9.3 100 0.11 3 95 3 1.1 43 2.5 15.3 96 0.3 6 90 9 1.4 44 3 18.2 91 0.4 7 86 10 1.6

[0147] As can be seen from the data in Table 8, a small amount of NTG does not have much effect on the coating, and as a small molecule, it fills the pores on the surface of the coating, making the coating surface uniform and complete. However, an excessive amount of NTG will form droplets during the rapid evaporation of methanol during the drying process due to the high concentration, resulting in coarse pores, cracks, or surface precipitates in the coating, causing the coating surface to be rough and the structure to be loose, leading to a decrease in the anti-friction and wear properties of the coating, and a rapid initial release rate (a large amount of NTG is directly dissolved through the loose structure or the surface), resulting in a "burst effect" and possibly causing excessive dilation of the blood vessel due to the high local concentration. Therefore, the preferred range of NTG in the methanol solution is 1% to 2.5%.

[0148] The above describes the preferred embodiments of the present application, but the present application is not limited to the specific details of the above-described embodiments, and various simple modifications can be made to the technical solutions of the present application within the technical concept of the present application, and these simple modifications all belong to the protection scope of the present application. In addition, various different embodiments of the present application can also be combined arbitrarily, as long as they do not deviate from the idea of the present application, and they should also be considered as disclosed by the present application.

[0149] In addition, the characterization method of the double-layer vascular patch prepared by the present application is as follows:

[0150] 1. Profile arithmetic mean deviation (Ra) test:

[0151] The test strictly follows GB / T 3505-2009 (surface structure), YY / T 0285 (vascular implant standards), and the operation specification of the micro stylus roughness tester.

[0152] After the balloon surface coating is completely dried, inflate it to expand it. To avoid deformation during testing, maintain the inflation pressure at 0.8-1.2 mPa. Use a balloon-specific clamp to fix the expanded balloon at both ends on a rotating support, ensuring that the balloon axis is horizontal and that the test area is free of tensile / compressive stress. Along the balloon axis: select three regions near the proximal end, the middle, and the distal end (avoiding the sealing area at both ends of the balloon by ≥3 mm), and along the balloon circumference: select three evenly distributed points in each axial region (a total of nine test points) to ensure that the coating is covered overall and that the data are statistically representative. The stylus radius is 5 μm to reduce scratching of the coating. After the machine is preheated, calibrate it with a curved standard block matching the Ra range of the coating to be tested (Ra=0.2 μm arc-shaped block), set the sampling length (lr) to 0.8 mm, the evaluation length (ln) to 5xlr, the stylus pressure to ≤0.002 N, the scanning speed to 3-5 mm / s, and the scanning direction to circumferential scanning along the balloon. Place the clamp with the fixed balloon smoothly on the roughness meter workbench, adjust the workbench height and clamp position so that the test point is directly below the instrument stylus, confirm that the stylus is perpendicular to the surface of the balloon coating, fine-tune the balloon rotating support to ensure that the first test point is unobstructed, has no wrinkles, and is ≥3 mm from the balloon edge. Select the "automatic light touch mode", slowly lower the stylus until the instrument displays "contact success" (at this time the stylus pressure is ≤0.002 N, and no drug shedding marks are observed on the coating surface);

[0153] Perform one pre-scan (without recording data): scan along the set circumferential path to confirm that the stylus smoothly follows the curved surface without jamming or coating damage, and that the scanning trajectory completely coincides with the curved surface. Start the formal scan, and move the stylus along the balloon circumference within the evaluation length. The instrument collects profile curve data in real time and automatically calculates the Ra value of the test point.

[0154] Repeat the scanning at the same test point twice (with an interval of 10 seconds to avoid local coating damage caused by continuous scanning), and take the average of the two data as the Ra value of the point (to reduce random errors). Move the stylus / adjust the balloon position according to the planned nine test points (three axial regions x three circumferential points), repeat the above scanning steps, record the Ra value of each point, and calculate and record the Ra average value of the nine test points.

[0155] 2. Relative standard deviation of functional group signal intensity

[0156] Prepare 3 drug-loaded balloon coatings that are completely dry. Turn on the FT-IR spectrometer and preheat for at least 30 min. Perform baseline calibration and background scan according to the instrument operation procedure. Ensure that the surface of the ATR crystal is clean and free of any contaminants during the background scan. Install the device capable of fixing the drug-loaded balloon on the sample stage of the ATR accessory, adjust the height and angle of the device so that the balloon can be placed with the coating surface in close and uniform contact with the ATR crystal, and the contact pressure is consistent (monitored by the instrument pressure display module, set the pressure value and record it, and keep the pressure unchanged in subsequent tests). Fix the first sample on the fixing device, ensure that the coating surface is in good contact with the ATR crystal, and record the positioning parameters of the current balloon (such as the rotation angle, axial position, etc.). Start the spectrum acquisition program and set the scan parameters: resolution 4 cm - , number of scans 32, scan range 4000-400 cm -1 , and collect the infrared spectrum at this position. Keep the fixing device stationary, rotate the balloon 30° around the axis (or other fixed angle, ensure that the test positions are evenly distributed), adjust the position of the balloon to the same contact pressure as in the above steps, and collect the spectrum. Repeat the above steps to collect the spectrum at 6 different positions on the first sample, with consistent angle between each position and covering the main area of the balloon coating. After the test is completed, wipe the ATR crystal with anhydrous ethanol, perform a background scan, and prepare the next sample for testing. Test sample 2 and sample 3 according to the above steps, and collect the spectrum at 6 different positions for each sample. Note that after completing the test of each sample, clean the ATR crystal and perform a background scan to ensure no cross-contamination. Open the infrared spectrum analysis software and import all the collected spectra. Determine the position of the characteristic absorption peak according to the characteristic wave number of the target functional group.

[0157] Use the peak area integration function or peak height measurement function of the software to quantify the signal intensity of the characteristic peak of the target functional group in each spectrum. If peak area is used, set the integration range (with the baseline on both sides of the characteristic peak as the boundary); if peak height is used, measure the vertical distance from the peak vertex to the baseline based on the baseline. Record the signal intensity values (peak area or peak height) of all spectra. The relative standard deviation calculation formula is:

[0158] ;

[0159] where S is the standard deviation, and the average value of the signal intensity.

[0160] For single sample repeatability RSD calculation, substitute the signal intensity values of the 6 positions of sample 1 into the formula to calculate the repeatability RSD1 of this sample; similarly, calculate RSD2 of sample 2 and RSD3 of sample 3. Finally, combine the signal intensity values of the 18 positions of the 3 samples to calculate the total average value The total standard deviation Stotal is substituted into the formula to obtain the final RSD.

[0161] 3. High-performance liquid chromatography (HPLC) test

[0162] Paclitaxel content test: Accurately weigh 10 mg of paclitaxel standard, dissolve it in methanol and dilute to 100 mL to prepare a standard solution of 100 μg / mL. Dilute the standard solution sequentially to prepare a series of working standard solutions of 0.1 μg / mL, 0.5 μg / mL, 1 μg / mL, 5 μg / mL, 10 μg / mL, and 20 μg / mL.

[0163] A C18 column (250 mm × 4.6 mm) was used with a mobile phase of methanol-acetonitrile-water (18:42:40), a flow rate of 1.0 mL / min, a detection wavelength of 227 nm, a column temperature of 30 °C, and an injection volume of 10 μL. The peak areas of the standard solutions at various concentrations were measured. A standard curve was plotted with paclitaxel concentration (μg / mL) on the x-axis and peak area on the y-axis, and the regression equation was calculated. R0 was required. 2 ≥0.999.

[0164] Place the drug capsule into a centrifuge tube, add 50 mL of methanol, let stand for 20 min, sonicate for 10 min, and then filter through a 0.45 μm filter membrane to obtain the filtrate. Following the same procedure as above, obtain the peak area of ​​the filtrate in a high-performance liquid chromatograph (HPLC). Compare with a standard solution to determine the concentration of paclitaxel in the filtrate.

[0165] Rapamycin content assay: Accurately weigh 10 mg of rapamycin standard, dissolve it in PBS buffer and bring the volume to 100 mL to prepare a 100 μg / mL standard solution. Dilute the standard solution sequentially to prepare a series of working standard solutions of 0.1 μg / mL, 0.5 μg / mL, 1 μg / mL, 5 μg / mL, 10 μg / mL, and 20 μg / mL. Use a C18 column (250 mm × 4.6 mm), with acetic acid-water (50:50) as the mobile phase, a detection wavelength of 227.5 nm, a flow rate of 1 mL / min, and a column temperature of 30 °C. Measure the peak area of ​​each concentration of standard solution. Plot a standard curve with rapamycin concentration (μg / mL) on the x-axis and peak area on the y-axis, and calculate the regression equation. The R-value is required to be... 2 ≥0.999.

[0166] Place the drug capsule into a centrifuge tube, add 50 mL of methanol, let stand for 20 min, sonicate for 10 min, and then filter through a 0.45 μm filter membrane to obtain the filtrate. Following the same procedure as above, measure the peak area of ​​the filtrate in a high-performance liquid chromatograph (HPLC) and compare it with a standard solution to obtain the concentration of rapamycin in the filtrate.

[0167] 4. Friction-wear test

[0168] Three completely dried drug-coated balloons and one balloon without drug coating were selected as blank controls. Freshly prepared porcine aortic blood vessel segments were selected as counterpieces to simulate human blood vessels, washed with physiological saline three times to remove residual blood in the blood vessels and fixed on the sample table of the friction and wear tester. The initial total mass of drug of each balloon was determined by HPLC.

[0169] The drug-coated balloon coating fragments were fixed on the sample table of the tester, the coating surface was upward, and the counterpiece was aligned (the contact area between the counterpiece and the coating surface should be consistent, about 5mm x 5mm). Start the test, set the load of the friction and wear tester to 5N±0.1N; the friction frequency is 1Hz±0.01Hz; the friction stroke, i.e. the movement distance of the balloon in the blood vessel, is set to 5mm±0.1mm; the friction time is set to 30min, 60min, 120min (corresponding to short-term, medium-term and long-term wear respectively). Inject 37℃ PBS buffer solution into the friction chamber of the tester to ensure that the sample and the counterpiece are completely immersed, and the temperature is maintained at 37℃±0.5℃. After the experiment, turn off the tester and take out the sample, blow the surface of the sample with an ear cleaning ball to remove the residual wear debris and avoid secondary shedding of the coating. Repeat the above steps for the blank control sample, and perform at least 3 parallel tests under each experimental condition to ensure data reproducibility.

[0170] After wear, the sample was placed in 10mL PBS buffer solution and ultrasonically extracted for 30min (power 300W, frequency 40kHz). The extract was filtered through a 0.22μm filter membrane, and the drug concentration was detected by HPLC to calculate the drug retention rate = (mass of drug after wear / mass of initial drug) x 100%.

[0171] 5. Expansion-contraction cycle test

[0172] Three completely dried drug-coated balloons and one balloon without drug coating were selected as blank controls.

[0173] 50mL of 37℃ preheated PBS buffer solution was injected into the balloon expansion-contraction cycle pipeline, and the temperature control system was started. After the temperature in the pipeline stabilized at 37℃±0.5℃, the sealing of the pressure control system was checked (pressure maintained at 1.2mPa for 5min, pressure drop ≤0.02mPa was qualified). The catheter end of the drug-coated balloon was connected to the pressure interface of the balloon expansion-contraction cycle test system, ensuring that the balloon was completely placed in the test section of the cycle pipeline (the inner diameter of the pipeline matched the expanded diameter of the balloon), and the catheter position was fixed to avoid displacement of the balloon during the cycle.

[0174] Turn on the cyclic test system, set the expansion pressure to 1.1 mPa ± 0.01 mPa (the clinical commonly used expansion pressure), the expansion maintenance time to 30 s ± 1 s; the contraction pressure to 0.15 mPa ± 0.01 mPa, the contraction maintenance time to 10 s ± 1 s; the cycle number to 1, 3, 5, 10 times; the cycle rate to 1 cycle / 40 s (including expansion for 30 s and contraction for 10 s). Real-time observation of cycle number, pressure change curve and temperature. After the cycle is completed, turn off the system, keep the PBS medium in the pipeline for 5 min, and make the detached coating fragments fully suspended. Transfer all the PBS medium in the circulation pipeline to a clean 50 mL centrifuge tube, rinse the inner wall of the pipeline with 5 mL of PBS buffer for 3 times, combine the rinsing liquid to the centrifuge tube, and make the total volume to 55 mL. Replace the blank control balloon, repeat the above steps, collect the blank control liquid, and exclude the substrate interference. Calculate the drug concentration C (μg / mL) in the eluent, and convert it to the total detached drug mass M1 and the coating detachment rate:

[0175] ;

[0176] ;

[0177] wherein, the initial drug mass of the balloon, the drug mass measured in the blank control experiment, 3 parallel experiments are performed for each cycle number, and the average value of the detachment rate is calculated.

[0178] 6. Hemolysis test

[0179] First, take two 10 mL centrifuge tubes, add 1 mL of heparin anticoagulant 0.1N whole blood and 7 mL of PBS buffer (pH=7.4) to each, centrifuge at 1500 rpm for 5 minutes, then carefully aspirate the supernatant until blood filaments appear, then add PBS to 8 mL scale along the tube wall, repeat the above washing steps four times to obtain a purified red blood cell suspension. Prepare the purified red blood cells into 200 μL stock solution and 3 tubes of 10% red blood cell PBS working solution (each tube contains 200 μL of red blood cells and 1800 μL of PBS). Set up positive control group (50 μL of red blood cells + 950 μL of distilled water), negative control group (500 μL of 10% red blood cell PBS + 500 μL of PBS) and sample group (500 μL of 10% red blood cell PBS + 500 μL of PBS + drug-loaded coating fragments) during testing, and set up 3 parallel samples for each group. After incubation at 37°C for 1-1.5 hours, centrifuge at 2500 rpm for 5 minutes, take 100 μL of supernatant and add it to a 96-well plate (3 replicates per sample), use a microplate reader to measure the absorbance at 540 nm wavelength, and evaluate the hemolysis performance of the material by comparing the absorbance values of each group.

[0180] Hemolysis rate calculation:

[0181] .

[0182] 7. Drug content test

[0183] Paclitaxel content test: Put the drug balloon in folded state into a centrifuge tube. Accurately add 50 mL of methanol, stand for 20 min, ultrasonic for 10 min, then filter with 0.45 um filter membrane, take the filtrate for testing.

[0184] Take methanol-acetonitrile-water (18:42:40) as mobile phase, detection wavelength 227 nm, flow rate 1 mL / min, column temperature 30℃, injection volume 10 μL, the retention time of paclitaxel should be between 8.0±0.5 min. According to the high performance liquid chromatography HPLC (Appendix VD of the Second Part of the People's Republic of China Pharmacopoeia (2020 edition)), sample the test sample solution and the control sample solution respectively, and record the peak area. Put the paclitaxel peak area obtained by testing into the standard curve to calculate the paclitaxel content on the balloon.

[0185] Take methanol-acetonitrile-water (18:42:40) as mobile phase, detection wavelength 227 nm, flow rate 1 mL / min, column temperature 30℃, injection volume 10 μL, the retention time of paclitaxel should be between 8.0±0.5 min. According to the high performance liquid chromatography HPLC (Appendix VD of the Second Part of the People's Republic of China Pharmacopoeia (2020 edition)), sample the test sample solution and the control sample solution respectively, and record the peak area. Put the paclitaxel peak area obtained by testing into the standard curve to calculate the paclitaxel content on the balloon.

[0186] Put the drug-loaded balloon into 10 mL of methanol, ultrasonic for 20 min, transfer the solution to a dialysis bag, stir in 50 mL of methanol solution at 37℃, take samples after 24 h and determine the paclitaxel content in the solution by HPLC method to obtain the one-day in vitro release efficiency of paclitaxel.

[0187] Rapamycin content test: Put the drug balloon in folded state into a centrifuge tube. Accurately add 50 mL of PBS, stand for 20 min, ultrasonic for 10 min, then filter with 0.45 um filter membrane, take the filtrate for testing.

[0188] Take acetonitrile-water (50:50) as mobile phase, detection wavelength 227.5 nm, flow rate 1 mL / min, column temperature 30℃, injection volume 10 μL, the retention time of rapamycin should be between 8.0±0.5 min. According to the high performance liquid chromatography HPLC (Appendix VD of the Second Part of the People's Republic of China Pharmacopoeia (2020 edition)), record the peak area. Put the rapamycin peak area obtained by testing into the standard curve to calculate the rapamycin content on the balloon.

[0189] The drug loaded balloon was immersed in 10 mL PBS solution, and sonicated for 20 min. The whole solution was transferred to a dialysis bag, which was placed in a beaker containing 30 mL PBS solution, temperature 37 oC ± 1 oC, stirring rate about 50 rpm / min. After 24 h, the sample was taken, and the drug content in the release solution was determined by high performance liquid chromatography (HPLC), to obtain the one-day in vitro release efficiency of rapamycin.

[0190] While embodiments of the application have been shown and described, it is to be understood that the embodiments described are merely exemplary of the principles and application of the present application. Numerous modifications, changes, omissions, substitutions, and equivalents can be made by one of ordinary skill in the art without departing from the spirit and scope of the application, which is defined by the following claims and their equivalents.

Claims

1. A multi-release controlled-drug coating for a medical balloon, characterized in that: The coating is formed by ultrasonic spraying of an ultra-low viscosity multi-drug-loaded coating liquid; the multi-drug-loaded coating liquid uses an organic solvent as the solvent, and the mass percentage of each component in the organic solvent is as follows: nonionic surfactant 3%~7%, hydrophobic surfactant 0.2%~0.8%, alcohol 0.5%~1.6%, smooth muscle proliferation inhibitor 0.05%~1%, NO donor drug 0.5%~3%, urea 6%~12%, and deionized water 0.5%~2%; The nonionic surfactant is selected from one or more of poloxamer 188 and poloxamer 407; The hydrophobic surfactant is selected from one or more of polyoxyethylene-polyoxypropylene monobutyl ether L61 and O-butyryl trihexyl citrate. The alcohols are selected from one or more of glycerol and 1,4-butanediol.

2. The multi-release controlled-drug coating for a medical balloon according to claim 1, characterized in that: The drug that inhibits smooth muscle proliferation is selected from one or more of paclitaxel and rapamycin.

3. The multi-release controlled-drug coating for a medical balloon according to claim 1, characterized in that: The NO donor drug is selected from one or more of nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate.

4. The multi-release controlled-drug coating for a medical balloon according to claim 1, characterized in that: The organic solvent is selected from one or more of methanol and chloroform.

5. A method for preparing a multi-release controlled-drug coating for a medical balloon according to claim 1, characterized in that: The components are mixed in proportion to obtain a first solution. After the drug that inhibits smooth muscle proliferation is completely dissolved, the first solution is injected into an ultrasonic spraying machine. The parameters of the ultrasonic spraying machine are adjusted, and the nozzle is aligned with the center of the expanded balloon for spraying. After the spraying is completed, the organic solvent is allowed to completely evaporate to obtain the multi-release controlled drug-loaded coating.

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