Drug balloon, drug coating and preparation method thereof

Abstract

The invention relates to the technical field of drug balloons, in particular to a drug balloon, a drug coating and a preparation method thereof, the drug coating comprises a nano-drug, the nano-drug sequentially comprises drug-loaded nanoparticles, an elastin layer and an adhesion layer from inside to outside, and the adhesion layer comprises a polydopamine coating and a cationic polymer coating. The invention provides the drug particle with excellent adhesion to the target blood vessel, the polydopamine and cationic polymer coating is prepared on the surface of the drug particle, the adhesion can be maintained in a dynamic washing environment, and meanwhile, the elastin with excellent elastic buffering performance is adopted as the middle layer of the drug particle, so that the adhesion of the drug particle can be maintained in a dynamic washing environment. The drug can adapt to periodic expansion, contraction and shear force change of blood vessels, close contact between the drug and blood vessel walls can be kept under blood vessel pulsation and blood flow impact, the adhesion stability of the drug is further enhanced, and the retention rate of the drug in target blood vessels is greatly increased.

Description

Technical Field

[0001] The present invention relates to the technical field of drug balloons, and in particular to a drug balloon, a drug coating and a preparation method thereof. Background Art

[0002] The existing drug-eluting balloon is a balloon that is made of drugs and covered with a drug film. It is used in the treatment of coronary and peripheral vascular atherosclerosis, stenosis and / or restenosis. After the target vessel is dilated, the drug film can cover the inner wall of the target vessel. However, due to the pulsation of the arterial blood vessels and the flushing of blood flow, less drugs remain in the target vessel, resulting in insufficient drug concentration at the target site, affecting the treatment effect. Summary of the invention

[0003] The purpose of the present invention is to provide a drug balloon, a drug coating and a preparation method thereof to improve the above problems. In order to achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0004] A drug coating comprises nano-drugs, wherein the nano-drugs comprise drug-loaded nano-particles, an elastin layer and an adhesion layer in sequence from the inside to the outside, wherein the adhesion layer comprises a polydopamine coating and a cationic polymer coating.

[0005] Optionally, the components of the elastin layer include at least one of silk fibroin or spider silk protein.

[0006] Optionally, the components of the cationic polymer coating include at least one of polyethyleneimine, poly-L-lysine, chitosan and poly-β-amino ester.

[0007] Optionally, the surface of the nanodrug is further modified with at least one of an NHS group, an aldehyde group, an isothiocyanate group, and a phenylboronic acid group.

[0008] The present application also provides a drug balloon, the surface of which is covered with the above-mentioned drug coating.

[0009] The present application also provides a method for preparing the above-mentioned drug coating, comprising:

[0010] The drug-loaded nanoparticles are mixed with the elastin solution to obtain a protein mixture, and the cross-linking agent solution is slowly added dropwise to the protein mixture to obtain a PLGA-protein intermediate;

[0011] adding the PLGA-protein intermediate to a dopamine solution to obtain a polydopamine-encapsulated intermediate after reaction;

[0012] adding the polydopamine-encapsulated intermediate into a cationic polymer solution to obtain a nano drug after reaction;

[0013] The nano drug is covered on the balloon surface by ultrasonic atomization spraying or electrostatic self-assembly to obtain a drug coating.

[0014] Optionally, the drug-loaded nanoparticles are mixed with an elastin solution to obtain a protein mixture, and a crosslinker solution is slowly added dropwise to the protein mixture to obtain a PLGA-protein intermediate, comprising:

[0015] Dissolving elastin in water to prepare an elastin solution with a concentration of 1-5%, adding drug-loaded nanoparticles to the elastin solution, stirring and reacting at room temperature to obtain a protein mixture;

[0016] Dissolving the crosslinking agent in a water / ethanol mixture to obtain a crosslinking agent solution with a concentration of 0.5-2%;

[0017] The cross-linking agent solution is added dropwise to the protein mixture, and the reaction is stirred at room temperature for 8-15 hours. After the reaction, the mixture is centrifuged, washed and freeze-dried to obtain a PLGA-protein intermediate; the cross-linking agent includes at least one of genipin or glutaraldehyde.

[0018] Optionally, the PLGA-protein solid is added to a dopamine solution to obtain a polydopamine-coated solid after reaction, comprising:

[0019] Add dopamine to Tris buffer to prepare a dopamine solution with a concentration of 0.5-2 mg / mL;

[0020] The PLGA-protein intermediate is added to the dopamine solution, and the mixture is stirred at room temperature for 4-8 hours. After the reaction, the mixture is centrifuged and washed to obtain a polydopamine-coated solid.

[0021] Optionally, the polydopamine-encapsulated intermediate is added to a cationic polymer solution to obtain a nano drug after reaction, comprising:

[0022] Adding the cationic polymer to a Tris buffer to prepare a cationic polymer solution having a concentration of 1-4 mg / mL;

[0023] The polydopamine-coated intermediate is added to the cationic polymer solution, and the reaction is stirred at room temperature for 1-3 hours. After the reaction, the reaction is centrifuged and washed to obtain a polydopamine-coated solid.

[0024] Optionally, the drug-loaded nanoparticles are PLGA drug-loaded nanoparticles, and the preparation method thereof includes:

[0025] preparing a first aqueous phase solution;

[0026] The PLGA polymer is mixed with the drug solution to obtain an organic phase;

[0027] Adding the first aqueous phase solution to the organic phase for full emulsification to obtain a reverse emulsion;

[0028] The reverse emulsion is added into the second aqueous phase solution, fully stirred for emulsification, and centrifuged to obtain PLGA drug-loaded nanoparticles.

[0029] The beneficial effects of the present invention are:

[0030] The present invention provides a drug particle with excellent target blood vessel adhesion ability. Polydopamine and cationic polymer coatings are coated on the surface of the drug particle, so that the drug can maintain adhesion in a dynamic flushing environment. At the same time, elastin with excellent elastic buffering performance is used as the middle layer of the drug particle, so that the drug can adapt to the periodic expansion, contraction and shear force changes of the blood vessel, and can maintain close contact between the drug and the blood vessel wall under blood vessel pulsation and blood flow impact, further enhancing the adhesion stability of the drug, and greatly improving the retention rate of the drug in the target blood vessel.

[0031] Other features and advantages of the present invention will be set forth in the following description, and in part will become apparent from the description, or may be understood by practicing embodiments of the present invention. DETAILED DESCRIPTION

[0032] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments.

[0033] In this application, when it comes to numerical ranges, unless otherwise specified, the above numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0034] Although drug-eluting balloons have been used in the treatment of cardiovascular and cerebrovascular diseases, current drug-eluting balloons still have the following problems:

[0035] 1. Water-soluble drug coatings cannot be used, as water-soluble drugs usually dissolve quickly in the blood.

[0036] 2. After a conventional drug balloon enters a blood vessel, it is generally required to reach the target lesion and open within 15-30 seconds. Otherwise, the drug will dissolve and release in the blood, and the local drug concentration cannot be guaranteed.

[0037] 3. The retention rate of existing drug coatings in target blood vessels is very low, only about 10-20%.

[0038] In order to solve the existing technical problems, the present application provides a method for preparing a drug coating, comprising:

[0039] S100, preparing drug-loaded nanoparticles;

[0040] Drugs are generally divided into hydrophobic drugs and hydrophilic drugs. Different encapsulation materials need to be designed for different drugs to ensure that the drugs can be concentrated in the target blood vessels and released at an appropriate rate;

[0041] The present application provides a hydrophobic drug-loaded PLGA nanoparticle, and the preparation method thereof comprises:

[0042] A PBS solution was prepared as the first aqueous phase solution, and the PLGA polymer and the drug solution were mixed as the organic phase.

[0043] The first aqueous phase solution is added to the organic phase and fully emulsified to obtain a reverse emulsion.

[0044] The reverse emulsion is added to the second aqueous phase solution, and the mixture is stirred and emulsified until the organic solvent is completely volatilized. The large particle precipitate is removed by centrifugation, and the supernatant is centrifuged again to obtain PLGA drug-loaded nanoparticles. By adjusting the PLGA concentration, the ratio of the organic phase to the aqueous phase, and the speed during stirring, particles of different particle sizes (ranging from 100 to 1000 nm) can be obtained.

[0045] The present application also provides a hydrophilic drug-loaded calcium phosphate nanoparticle, the preparation method of which comprises:

[0046] The organic phase was prepared by using surfactant Igepal CO-520 and cyclohexane in a mass ratio of 3:7; two reverse emulsions A and B were prepared. Reverse emulsion A contained CaCl 2 and hydrophilic drugs; inverse emulsion B contains Na 2 HPO 4 (25mM, pH=9) and DOPA. The two reverse emulsions A and B were added to the organic phase, mixed and stirred, centrifuged and ethanol was used for times, and the obtained precipitate was dissolved in chloroform together with soybean lecithin and cholesterol, and then hydrated after spin drying to obtain calcium phosphate nanoparticles encapsulating hydrophilic drugs.

[0047] The drug-loaded nanoparticles of the present application can encapsulate water-soluble drugs and fat-soluble drugs (such as colchicine). Water-soluble drugs usually dissolve quickly in the blood and cannot act locally. Fat-soluble drugs (such as rapamycin and paclitaxel) do not dissolve in the blood. After contacting with tissues, they are absorbed by the endothelial cells or smooth muscle cells of the coronary vessels. In the field of drug balloons, existing drugs are all fat-soluble drugs, and there are no water-soluble drugs. The present application can encapsulate water-soluble drugs so that they can successfully reach the target blood vessels and play a therapeutic role.

[0048] S200, mixing the drug-loaded nanoparticles with the elastin solution to obtain a protein mixture, and slowly dropping the crosslinker solution into the protein mixture to obtain a PLGA-protein intermediate; specifically:

[0049] Dissolving elastin in water to prepare an elastin solution with a concentration of 1-5%, adding drug-loaded nanoparticles to the elastin solution, stirring and reacting at room temperature to obtain a protein mixture;

[0050] Dissolving the crosslinking agent in a water / ethanol mixture to obtain a crosslinking agent solution with a concentration of 0.5-2%;

[0051] The cross-linking agent solution is added dropwise to the protein mixture, and the reaction is stirred at room temperature for 8-15 hours. After the reaction, the mixture is centrifuged, washed and freeze-dried to obtain a PLGA-protein intermediate; the cross-linking agent includes at least one of genipin or glutaraldehyde.

[0052] PLGA-protein intermediates with different properties can be obtained by adjusting the mass ratio of elastin to cross-linking agent.

[0053] S300, adding the PLGA-protein intermediate to the dopamine solution to obtain a polydopamine-encapsulated intermediate after reaction; specifically:

[0054] Add dopamine to Tris buffer to prepare a dopamine solution with a concentration of 0.5-2 mg / mL;

[0055] The PLGA-protein intermediate is added to the dopamine solution, and the mixture is stirred at room temperature for 4-8 hours. After the reaction, the mixture is centrifuged and washed to obtain a polydopamine-coated solid.

[0056] S400, adding the polydopamine-encapsulated intermediate into a cationic polymer solution to obtain a nanomedicine after reaction;

[0057] Adding the cationic polymer to a Tris buffer to prepare a cationic polymer solution having a concentration of 1-4 mg / mL;

[0058] The polydopamine-encapsulated intermediate is added to the cationic polymer solution, stirred for reaction at room temperature for 1-3 hours, and centrifuged and washed after the reaction to obtain the nano drug.

[0059] Dopamine can form polydopamine through oxidation self-polymerization under alkaline conditions. The catechol structure in the structure interacts with the cell surface through hydrogen bonds, π-π stacking and other forces. The quinone group formed after oxidation of catechol covalently bonds with amino groups, thiol groups and other groups on the cell membrane surface, thereby exhibiting good adhesion properties.

[0060] However, due to the rapid blood flow in the coronary arteries, protein adsorption in the blood vessels, enzymatic hydrolysis, etc., it is difficult for polydopamine alone to achieve sufficient adhesion. The present application further modifies dopamine nanoparticles with materials such as polyacetimide, polylysine, chitosan, hyaluronic acid, chondroitin sulfate, and benzoic acid, or groups such as NHS, aldehyde, phenylboronic acid, and isothiocyanate to enhance the vascular adhesion of dopamine nanoparticles through multiple forces such as electrostatic adsorption and covalent binding, thereby greatly improving the retention rate of the drug.

[0061] S500, covering the surface of the balloon with the nano drug by ultrasonic atomization spraying or electrostatic self-assembly to obtain a drug coating;

[0062] The ultrasonic atomization spraying process includes: preparing a nano drug solution of a certain concentration, degassing it and spraying it onto the balloon surface by ultrasonic atomization. The spraying drug flow rate is 0.02-0.05mL / min, preferably 0.03mL / min; the ultrasonic power of the spraying is 1.0-3.0W, preferably 1.5W; the number of spraying cycles is 4 to 10 times. The nano drug solution is a mixed solution of nano drug and one or more auxiliary materials such as polyacrylic acid and polylysine, wherein the concentration of the nano drug is 0.5 to 5wt%.

[0063] The process of electrostatic self-assembly is as follows: First, the balloon is immersed in a solution containing polycations, then washed with deionized water and dried with nitrogen, thereby forming a coating with positive polycation charges on the balloon surface. Then, the balloon is immersed in a mixed solution containing nanomedicine and polyanions, and repeatedly washed and dried to form a nanomedicine coating with negative polyanion charges on the balloon surface. By alternating the above steps 4 to 6 times, a drug coating alternating between polyanions and polycations can be formed on the balloon surface.

[0064] Preferably, the solution containing polycations is 0.5-1.0 mg / mL polyethyleneimine, polylysine or chitosan, etc., preferably 0.8 mg / mL polyethyleneimine; the mixed solution of nanodrugs and polyanions is 2.0-5.0 mg / mL of nanodrugs mixed with one or more of polyacrylic acid, hyaluronic acid, polyaspartic acid, etc., preferably 3.5 mg / mL of a mixed solution of nanoparticles and polyacrylic acid.

[0065] The present application is not limited thereto, and other suitable methods may also be used to prepare the drug coating.

[0066] Based on the same inventive concept, the present application also provides a drug coating, which includes a nano drug, wherein the nano drug includes drug-loaded nanoparticles, an elastin layer, and an adhesion layer from the inside to the outside, wherein the adhesion layer includes a polydopamine coating and a cationic polymer coating. The drug coating can be prepared by the preparation method of the drug coating of the present application.

[0067] In the nanomedicine, the composition of the elastin layer includes at least one of silk fibroin or spider silk protein. Elastin has excellent elastic buffering properties and can adapt to the dynamic changes of the blood vessel wall. Therefore, it is introduced into the structure to construct a three-layer structure consisting of a drug-loaded core + an elastin middle layer (elastic buffer) + dopamine and a PEI coating, which imitates physiological elasticity and constitutes a super-adhesive preparation.

[0068] In the nanomedicine, the components of the cationic polymer coating include at least one of polyethyleneimine, poly-L-lysine, chitosan and poly-β-amino ester. Positively charged cationic polymers such as polyethyleneimine (PEI) and negatively charged cell membranes (phospholipid head groups, glycoproteins) interact with each other through electrostatic adsorption, and can also form hydrogen bonds with polar groups such as hydroxyl groups and carboxyl groups in biological molecules to enhance biological adhesion.

[0069] The surface of the nano drug is also modified with at least one of NHS group, aldehyde group, isothiocyanate group and phenylboronic acid group. NHS group, aldehyde group, isothiocyanate group and other groups can covalently bind to amino group, hydroxyl group and the like on the cell membrane surface in the blood vessel, and phenylboronic acid and the cis-diol structure in the glycoprotein on the cell membrane surface can form a borate ester bond, thereby significantly improving the adhesion of the nanoparticles to the inner wall of the blood vessel. In addition, chitosan, chondroitin sulfate and the like can also bind to the integrin receptor on the cell membrane surface to improve adhesion.

[0070] In the nanomedicine, the thickness ratio of the elastin layer, the polydopamine coating and the cationic polymer coating is (4-6):3:(1-3); preferably 5:3:2.

[0071] The present application also provides a drug-eluting balloon, the surface of which is covered with the drug coating of the present application. The drug-eluting balloon is used in the treatment of coronary and peripheral vascular atherosclerosis, stenosis and / or restenosis; when in use, the drug coating is coated on the balloon and carried to the target blood vessel site by the balloon. After the balloon is expanded, the drug coating adheres to the inner wall of the blood vessel and slowly releases the drug, thereby achieving continuous treatment.

[0072] The drug balloon of the present application can effectively improve the retention rate of drugs in the target blood vessels, and the implementation principle is mainly in three aspects:

[0073] (1) The adhesion layer can ensure that the drug adheres to the vascular tissue and has more retention in the target blood vessel;

[0074] (2) Using elastin with buffering properties as the middle layer of drug particles allows the drug to maintain close contact with the inner wall of irregular blood vessels and will not separate from the blood vessels due to the pulsation of the blood vessels.

[0075] (3) The use of elastin and an adhesive layer to wrap nanodrugs can regulate the timeline of drug release, thereby prolonging the sustained release of drugs in the target blood vessels.

[0076] Specific examples are provided below to illustrate the embodiments of the present invention.

[0077] Example 1

[0078] A method for preparing a drug coating, comprising:

[0079] S100, preparation of drug-loaded nanoparticles:

[0080] Prepare PBS solution (10 mg / mL, pH 7.4) as the first aqueous phase solution;

[0081] 5 mL of PLGA polymer solution (lactic acid:glycolic acid=50:50, molecular weight 10000 kDa, 10 mg / mL) was mixed with 2.5 mg of colchicine in dichloromethane as an organic phase.

[0082] The first aqueous phase solution was added to the organic phase, and treated with a probe ultrasonic emulsifier (80% power, ultrasonic 0.5s, interval 0.5s) for 15 seconds under ice bath to fully emulsify it to obtain a reverse emulsion.

[0083] The reverse emulsion was added to 50 mL of the second aqueous phase solution (1 wt% PVA aqueous solution), and the mixture was stirred and emulsified at 800 rpm until the organic solvent was completely volatilized. The large particles were removed by centrifugation at 2000 g for 5 min, and the supernatant was centrifuged at 12000 g for 30 min to obtain nanoparticles, which were washed three times by centrifugation with ultrapure water to remove excess PVA, and resuspended in 2 mL of ultrapure water to obtain drug-loaded nanoparticles.

[0084] S200, mixing the drug-loaded nanoparticles with the elastin solution to obtain a protein mixture, and slowly dropping the crosslinker solution into the protein mixture to obtain a PLGA-protein intermediate:

[0085] Dissolve an appropriate amount of silk fibroin in 10 mL of deionized water to prepare a 2 wt% elastin solution;

[0086] Add 2 mL of drug-loaded nanoparticles (2 mg / mL) into the elastin solution and stir for 1 h at room temperature to fully mix to obtain a protein mixture;

[0087] Dissolving a cross-linking agent (genipin) in a water / ethanol mixture to obtain a cross-linking agent solution having a concentration of 1%;

[0088] The cross-linking agent solution was slowly added dropwise to the protein mixture, stirred at room temperature for 12 h, centrifuged at 12000 g for 30 min, washed with ultrapure water for 3 times and freeze-dried to obtain the PLGA-protein intermediate.

[0089] S300, adding the PLGA-protein intermediate to the dopamine solution, and obtaining a polydopamine-encapsulated intermediate after reaction:

[0090] Add dopamine to Tris buffer (50 mM, pH = 8.5), wherein the dopamine concentration is 1 mg / mL, to obtain a dopamine solution;

[0091] 10 mg of PLGA-protein intermediate was added to 10 mL of dopamine solution and stirred at room temperature for 6 hours. The solution gradually turned dark brown. After that, the solution was centrifuged at 12000 g for 30 min and the precipitate was washed with ultrapure water for 3 times to obtain the polydopamine-encapsulated intermediate.

[0092] S400, adding the polydopamine-encapsulated intermediate to a cationic polymer solution, and obtaining a nano drug after reaction:

[0093] PEI (25 kDa) was added to Tris buffer (50 mM, pH = 8.5), wherein the PEI concentration was 2 mg / mL, to obtain a cationic polymer solution;

[0094] 1 mL of polydopamine-encapsulated intermediate (5 mg / mL) was added to 10 mL of cationic polymer solution, stirred at room temperature for 2 h, centrifuged at 12000 g for 30 min, and the precipitate was washed 3 times with ultrapure water to obtain nanomedicine.

[0095] S500, covering the surface of the balloon with the nano drug by ultrasonic atomization spraying to obtain a drug coating:

[0096] A 2 wt% nanoparticle solution was prepared with polyacrylic acid, and after degassing, it was sprayed onto the balloon surface by ultrasonic atomization. The spraying drug flow rate was 0.02 mL / min; the spraying ultrasonic power was 1.0 W; the spraying cycle number was 6 times to obtain a drug coating.

[0097] Example 2

[0098] S100, preparation of drug-loaded nanoparticles:

[0099] The organic phase was prepared by using surfactant Igepal CO-520 and cyclohexane in a ratio of 3:7;

[0100] Prepare 25 mL of each of the two inverse emulsions A and B. Emulsion A contains 500 uL CaCl 2 (2.5M), and 1mg hydrophilic drug; emulsion B contains 500uLNa 2 HPO 4 (25 mM, pH 9) and 3 mg DOPA;

[0101] The two reverse emulsions A and B were added to the organic phase, mixed and stirred for 30 minutes, centrifuged at 12000g for 20 minutes and washed with ethanol three times. The obtained precipitate was dissolved in 2 mL of chloroform with 3 mg of soybean lecithin and 0.3 mg of cholesterol, and then hydrated after spin drying to obtain calcium phosphate nanoparticles (drug-loaded nanoparticles) encapsulating hydrophilic drugs.

[0102] S200, mixing the drug-loaded nanoparticles with the elastin solution to obtain a protein mixture, and slowly dropping the crosslinker solution into the protein mixture to obtain a PLGA-protein intermediate:

[0103] Dissolve an appropriate amount of silk fibroin in 10 mL of deionized water to prepare a 1.5 wt% elastin solution;

[0104] Add 2 mL of drug-loaded nanoparticles (3 mg / mL) to the elastin solution and stir for 1 h at room temperature to fully mix to obtain a protein mixture;

[0105] Dissolve the crosslinking agent (glutaraldehyde) in a water / ethanol mixture to obtain a crosslinking agent solution with a concentration of 2%;

[0106] The cross-linking agent solution was slowly added dropwise to the protein mixture, stirred at room temperature for 10 h, centrifuged at 12000 g for 30 min, washed with ultrapure water for 3 times and freeze-dried to obtain the PLGA-protein intermediate.

[0107] S300, adding the PLGA-protein intermediate to the dopamine solution, and obtaining a polydopamine-encapsulated intermediate after reaction:

[0108] Add dopamine to Tris buffer (50 mM, pH=8.5), wherein the dopamine concentration is 2 mg / mL, to obtain a dopamine solution;

[0109] 10 mg of PLGA-protein intermediate was added to 10 mL of dopamine solution and stirred at room temperature for 8 hours. The solution gradually turned dark brown. After that, the solution was centrifuged at 12000 g for 30 min and the precipitate was washed with ultrapure water for 3 times to obtain the polydopamine-encapsulated intermediate.

[0110] S400, adding the polydopamine-encapsulated intermediate to a cationic polymer solution, and obtaining a nano drug after reaction:

[0111] Add PEI to Tris buffer (50 mM, pH = 8.5), wherein the PEI concentration is 3 mg / mL, to obtain a cationic polymer solution;

[0112] 1 mL of polydopamine-encapsulated intermediate (4 mg / mL) was added to 10 mL of cationic polymer solution, stirred at room temperature for 3 h, centrifuged at 12000 g for 30 min, and the precipitate was washed 3 times with ultrapure water to obtain nanomedicine.

[0113] S500, covering the surface of the balloon with the nano drug by ultrasonic atomization spraying to obtain a drug coating:

[0114] A 5wt% nanoparticle solution was prepared with polyacrylic acid and polylysine, and after degassing, it was sprayed onto the balloon surface by ultrasonic atomization. The spraying drug flow rate was 0.03mL / min; the spraying ultrasonic power was 1.5W; the spraying cycle number was 8 times to obtain a drug coating.

[0115] Example 3

[0116] A method for preparing a drug coating, comprising:

[0117] S100, preparation of drug-loaded nanoparticles:

[0118] Prepare PBS solution (10 mg / mL, pH 7.4) as the first aqueous phase solution;

[0119] 5 mL of PLGA polymer solution (8 mg / mL) was mixed with 2.0 mg of paclitaxel in dichloromethane as the organic phase.

[0120] The first aqueous phase solution was added to the organic phase, and treated with a probe ultrasonic emulsifier (80% power, ultrasonic 0.5s, interval 0.5s) for 15 seconds under ice bath to fully emulsify it to obtain a reverse emulsion.

[0121] The reverse emulsion was added to 40 mL of the second aqueous phase solution (1 wt% PVA aqueous solution), and the mixture was stirred and emulsified at 800 rpm until the organic solvent was completely volatilized. The large particles were removed by centrifugation at 2000 g for 5 min, and the supernatant was centrifuged at 12000 g for 30 min to obtain nanoparticles, which were washed three times by centrifugation with ultrapure water to remove excess PVA, and resuspended in 2 mL of ultrapure water to obtain drug-loaded nanoparticles.

[0122] S200, mixing the drug-loaded nanoparticles with the elastin solution to obtain a protein mixture, and slowly dropping the crosslinker solution into the protein mixture to obtain a PLGA-protein intermediate:

[0123] Dissolve an appropriate amount of silk fibroin in 10 mL of deionized water to prepare a 4 wt% elastin solution;

[0124] Add 2 mL of drug-loaded nanoparticles (1.5 mg / mL) to the elastin solution and stir for 1 h at room temperature to fully mix to obtain a protein mixture;

[0125] Dissolving a cross-linking agent (genipin) in a water / ethanol mixture to obtain a cross-linking agent solution having a concentration of 0.5%;

[0126] The cross-linking agent solution was slowly added dropwise to the protein mixture, stirred at room temperature for 15 h, centrifuged at 12000 g for 30 min, washed with ultrapure water for 3 times and freeze-dried to obtain the PLGA-protein intermediate.

[0127] S300, adding the PLGA-protein intermediate to the dopamine solution, and obtaining a polydopamine-encapsulated intermediate after reaction:

[0128] Add dopamine to Tris buffer (50 mM, pH=8.5), wherein the dopamine concentration is 2 mg / mL, to obtain a dopamine solution;

[0129] 10 mg of PLGA-protein intermediate was added to 10 mL of dopamine solution and stirred at room temperature for 4 hours. The solution gradually turned dark brown. After that, the solution was centrifuged at 12000 g for 30 min and the precipitate was washed with ultrapure water for 3 times to obtain the polydopamine-encapsulated intermediate.

[0130] S400, adding the polydopamine-encapsulated intermediate to a cationic polymer solution, and obtaining a nano drug after reaction:

[0131] Add PEI to Tris buffer (50 mM, pH = 8.5), wherein the PEI concentration is 2 mg / mL, to obtain a cationic polymer solution;

[0132] 1 mL of polydopamine-encapsulated intermediate (5 mg / mL) was added to 10 mL of cationic polymer solution, stirred at room temperature for 1.5 h, centrifuged at 12000 g for 30 min, and the precipitate was washed 3 times with ultrapure water to obtain nanomedicine.

[0133] S500, covering the surface of the balloon with the nano drug by electrostatic self-assembly to obtain a drug coating:

[0134] The balloon was immersed in a 0.8 mg / mL polyethyleneimine solution, then washed with deionized water and dried with nitrogen to form a coating with a positive charge of polycations on the balloon surface. Then, the balloon was immersed in a mixed solution containing nanoparticles and polyanions, the mixed solution being 3.0 mg / mL of nanoparticles mixed with polyacrylic acid.

[0135] Repeat the washing and drying to form a nanoparticle coating with negative charges of polyanions on the balloon surface. By alternately performing the above steps 4 times, a drug coating of alternating polyanions and polycations can be formed on the balloon surface.

[0136] Example 4

[0137] A method for preparing a drug coating, comprising:

[0138] S100, preparation of drug-loaded nanoparticles:

[0139] Prepare PBS solution (10 mg / mL, pH 7.4) as the first aqueous phase solution;

[0140] 5 mL of PLGA polymer solution (8 mg / mL) was mixed with 5.0 mg of paclitaxel in dichloromethane as the organic phase.

[0141] The first aqueous phase solution was added to the organic phase, and treated with a probe ultrasonic emulsifier (80% power, ultrasonic 0.5s, interval 0.5s) for 15 seconds under ice bath to fully emulsify it to obtain a reverse emulsion.

[0142] The reverse emulsion was added to 60 mL of the second aqueous phase solution (1 wt% PVA aqueous solution), and the mixture was stirred and emulsified at 800 rpm until the organic solvent was completely volatilized. The large particles were removed by centrifugation at 2000 g for 5 min, and the supernatant was centrifuged at 12000 g for 30 min to obtain nanoparticles, which were washed three times by centrifugation with ultrapure water to remove excess PVA, and resuspended in 2 mL of ultrapure water to obtain drug-loaded nanoparticles.

[0143] S200, mixing the drug-loaded nanoparticles with the elastin solution to obtain a protein mixture, and slowly dropping the crosslinker solution into the protein mixture to obtain a PLGA-protein intermediate:

[0144] Dissolve an appropriate amount of silk fibroin in 10 mL of deionized water to prepare a 4 wt% elastin solution;

[0145] Add 2 mL of drug-loaded nanoparticles (3 mg / mL) to the elastin solution and stir for 1 h at room temperature to fully mix to obtain a protein mixture;

[0146] Dissolving a cross-linking agent (genipin) in a water / ethanol mixture to obtain a cross-linking agent solution having a concentration of 2%;

[0147] The cross-linking agent solution was slowly added dropwise to the protein mixture, stirred at room temperature for 8 h, centrifuged at 12000 g for 30 min, washed with ultrapure water for 3 times and freeze-dried to obtain the PLGA-protein intermediate.

[0148] S300, adding the PLGA-protein intermediate to the dopamine solution, and obtaining a polydopamine-encapsulated intermediate after reaction:

[0149] Add dopamine to Tris buffer (50 mM, pH=8.5), wherein the dopamine concentration is 2 mg / mL, to obtain a dopamine solution;

[0150] 10 mg of PLGA-protein intermediate was added to 10 mL of dopamine solution and stirred at room temperature for 7 hours. The solution gradually turned dark brown. After that, the solution was centrifuged at 12000 g for 30 min and the precipitate was washed with ultrapure water for 3 times to obtain the polydopamine-encapsulated intermediate.

[0151] S400, adding the polydopamine-encapsulated intermediate to a cationic polymer solution, and obtaining a nano drug after reaction:

[0152] Add PEI to Tris buffer (50 mM, pH = 8.5), wherein the PEI concentration is 2 mg / mL, to obtain a cationic polymer solution;

[0153] 1 mL of polydopamine-encapsulated intermediate (3 mg / mL) was added to 10 mL of cationic polymer solution, stirred at room temperature for 3 h, centrifuged at 12000 g for 30 min, and the precipitate was washed 3 times with ultrapure water to obtain nanomedicine;

[0154] BS(PEG)5 of PEGylated di(sulfosuccinimidyl) suberate was dissolved in DMSO to prepare a 20 mg / mL stock solution, which was then added dropwise to 20 mL of PBS buffer to a final concentration of 2.5 mg / mL. 1 mL of the nanodrug (1 mg / mL) was slowly added dropwise to the PBS buffer containing BS(PEG)5, stirred at room temperature for 30 min, centrifuged at 12000 g for 30 min, and the precipitate was washed 3 times with ultrapure water to obtain NHS-modified nanodrugs.

[0155] S500, covering the surface of the balloon with the nano drug by ultrasonic atomization spraying to obtain a drug coating:

[0156] A 5wt% nanoparticle solution was prepared with polyacrylic acid, and after degassing, it was sprayed onto the balloon surface by ultrasonic atomization. The spraying drug flow rate was 0.05mL / min; the spraying ultrasonic power was 3.0W; the spraying cycle number was 4 times to obtain a drug coating.

[0157] Example 5

[0158] A method for preparing a drug coating, comprising:

[0159] S100, preparation of drug-loaded nanoparticles:

[0160] Prepare PBS solution (7 mg / mL, pH 7.4) as the first aqueous phase solution;

[0161] 5 mL of PLGA polymer solution (12 mg / mL) was mixed with 3.5 mg of paclitaxel in dichloromethane as the organic phase.

[0162] The first aqueous phase solution was added to the organic phase, and treated with a probe ultrasonic emulsifier (80% power, ultrasonic 0.5s, interval 0.5s) for 15 seconds under ice bath to fully emulsify it to obtain a reverse emulsion.

[0163] The reverse emulsion was added to 50 mL of the second aqueous phase solution (aqueous solution of 2 wt% PVA), and the mixture was stirred and emulsified at 800 rpm until the organic solvent was completely volatilized. The large particles were removed by centrifugation at 2000 g for 5 min, and the supernatant was centrifuged at 12000 g for 30 min to obtain nanoparticles, which were washed three times by centrifugation with ultrapure water to remove excess PVA, and resuspended in 2 mL of ultrapure water to obtain drug-loaded nanoparticles.

[0164] S200, mixing the drug-loaded nanoparticles with the elastin solution to obtain a protein mixture, and slowly dropping the crosslinker solution into the protein mixture to obtain a PLGA-protein intermediate:

[0165] Dissolve an appropriate amount of silk fibroin in 10 mL of deionized water to prepare a 1.5 wt% elastin solution;

[0166] Add 2 mL of drug-loaded nanoparticles (3 mg / mL) to the elastin solution and stir for 1 h at room temperature to fully mix to obtain a protein mixture;

[0167] Dissolving a cross-linking agent (genipin) in a water / ethanol mixture to obtain a cross-linking agent solution having a concentration of 1.5%;

[0168] The cross-linking agent solution was slowly added dropwise to the protein mixture, stirred at room temperature for 8 h, centrifuged at 12000 g for 30 min, washed with ultrapure water for 3 times and freeze-dried to obtain the PLGA-protein intermediate.

[0169] S300, adding the PLGA-protein intermediate to the dopamine solution, and obtaining a polydopamine-encapsulated intermediate after reaction:

[0170] Add dopamine to Tris buffer (50 mM, pH = 8.5), wherein the dopamine concentration is 3.5 mg / mL, to obtain a dopamine solution;

[0171] 10 mg of PLGA-protein intermediate was added to 10 mL of dopamine solution and stirred at room temperature for 8 hours. The solution gradually turned dark brown. After that, the solution was centrifuged at 12000 g for 30 min and the precipitate was washed with ultrapure water for 3 times to obtain the polydopamine-encapsulated intermediate.

[0172] S400, adding the polydopamine-encapsulated intermediate to a cationic polymer solution, and obtaining a nano drug after reaction:

[0173] Add PEI to Tris buffer (50 mM, pH = 8.5), wherein the PEI concentration is 3 mg / mL, to obtain a cationic polymer solution;

[0174] PEI25K was dissolved in methanol, and 4-(bromomethyl)phenylboronic acid was added, with a molar ratio of PEI to phenylboronic acid of 1:0.3. The reaction was carried out at 60°C for 12 hours. After the reaction was completed, the product was added dropwise to ice ether for precipitation. The reaction was repeated three times to obtain PEI-PBA.

[0175] Prepare PBS buffer containing PEI-PBA (2 mg / mL), add 1 mL of polydopamine-encapsulated intermediate (5 mg / mL) into 10 mL of PEI-PBA buffer, stir at room temperature for 2 h, centrifuge at 12000 g for 30 min, and wash the precipitate with ultrapure water three times to obtain phenylboronic acid-modified nanodrug;

[0176] S500, covering the surface of the balloon with the nano drug by ultrasonic atomization spraying to obtain a drug coating:

[0177] A 4wt% nanoparticle solution was prepared with polyacrylic acid, and after degassing, it was sprayed onto the balloon surface by ultrasonic atomization. The spraying drug flow rate was 0.04mL / min; the ultrasonic power of the spraying was 2.5W; the spraying cycle number was 5 times to obtain a drug coating.

[0178] Comparative Example 1

[0179] This comparative example prepares a nanomedicine with a drug-loaded core + adhesion layer structure, which does not contain an elastin layer;

[0180] S100, preparation of drug-loaded nanoparticles:

[0181] Prepare PBS solution (10 mg / mL, pH 7.4) as the first aqueous phase solution;

[0182] 5 mL of PLGA polymer solution (lactic acid:glycolic acid=50:50, molecular weight 10000 kDa, 10 mg / mL) was mixed with 2.5 mg of colchicine in dichloromethane as an organic phase.

[0183] The first aqueous phase solution was added to the organic phase, and treated with a probe ultrasonic emulsifier (80% power, ultrasonic 0.5s, interval 0.5s) for 15 seconds under ice bath to fully emulsify it to obtain a reverse emulsion.

[0184] The reverse emulsion was added to 50 mL of the second aqueous phase solution (1 wt% PVA aqueous solution), and the mixture was stirred and emulsified at 800 rpm until the organic solvent was completely volatilized. The large particles were removed by centrifugation at 2000 g for 5 min, and the supernatant was centrifuged at 12000 g for 30 min to obtain nanoparticles, which were washed three times by centrifugation with ultrapure water to remove excess PVA, and resuspended in 2 mL of ultrapure water to obtain drug-loaded nanoparticles.

[0185] S300, adding the drug-loaded nanoparticles to a dopamine solution, and obtaining a polydopamine-encapsulated intermediate after reaction:

[0186] Add dopamine to Tris buffer (50 mM, pH = 8.5), wherein the dopamine concentration is 1 mg / mL, to obtain a dopamine solution;

[0187] 5 mg of drug-loaded nanoparticles were added to 10 mL of dopamine solution and stirred at room temperature for 6 hours. The solution gradually turned dark brown. After that, the solution was centrifuged at 12000 g for 30 min and the precipitate was washed with ultrapure water for 3 times to obtain a polydopamine-encapsulated intermediate.

[0188] S400, adding the polydopamine-encapsulated intermediate to a cationic polymer solution, and obtaining a nano drug after reaction:

[0189] PEI (25 kDa) was added to Tris buffer (50 mM, pH = 8.5), wherein the PEI concentration was 2 mg / mL, to obtain a cationic polymer solution;

[0190] 1 mL of polydopamine-encapsulated intermediate (5 mg / mL) was added to 10 mL of cationic polymer solution, stirred at room temperature for 2 h, centrifuged at 12000 g for 30 min, and the precipitate was washed 3 times with ultrapure water to obtain nanomedicine.

[0191] S500, covering the surface of the balloon with the nano drug by ultrasonic atomization spraying to obtain a drug coating:

[0192] A 2 wt% nanoparticle solution was prepared with polyacrylic acid, and after degassing, it was sprayed onto the balloon surface by ultrasonic atomization. The spraying drug flow rate was 0.02 mL / min; the spraying ultrasonic power was 1.0 W; the spraying cycle number was 6 times to obtain a drug coating.

[0193] Comparative Example 2

[0194] This comparative example prepares a nanomedicine with a drug-loaded core + elastin layer + polydopamine layer structure, which does not contain a cationic polymer layer;

[0195] S100, preparation of drug-loaded nanoparticles:

[0196] Prepare PBS solution (10 mg / mL, pH 7.4) as the first aqueous phase solution;

[0197] 5 mL of PLGA polymer solution (lactic acid:glycolic acid=50:50, molecular weight 10000 kDa, 10 mg / mL) was mixed with 2.5 mg of colchicine in dichloromethane as an organic phase.

[0198] The first aqueous phase solution was added to the organic phase, and treated with a probe ultrasonic emulsifier (80% power, ultrasonic 0.5s, interval 0.5s) for 15 seconds under ice bath to fully emulsify it to obtain a reverse emulsion.

[0199] The reverse emulsion was added to 50 mL of the second aqueous phase solution (1 wt% PVA aqueous solution), and the mixture was stirred and emulsified at 800 rpm until the organic solvent was completely volatilized. The large particles were removed by centrifugation at 2000 g for 5 min, and the supernatant was centrifuged at 12000 g for 30 min to obtain nanoparticles, which were washed three times by centrifugation with ultrapure water to remove excess PVA, and resuspended in 2 mL of ultrapure water to obtain drug-loaded nanoparticles.

[0200] S200, mixing the drug-loaded nanoparticles with the elastin solution to obtain a protein mixture, and slowly dropping the crosslinker solution into the protein mixture to obtain a PLGA-protein intermediate:

[0201] Dissolve an appropriate amount of silk fibroin in 10 mL of deionized water to prepare a 2 wt% elastin solution;

[0202] Add 2 mL of drug-loaded nanoparticles (2 mg / mL) into the elastin solution and stir for 1 h at room temperature to fully mix to obtain a protein mixture;

[0203] Dissolving a cross-linking agent (genipin) in a water / ethanol mixture to obtain a cross-linking agent solution having a concentration of 1%;

[0204] The cross-linking agent solution was slowly added dropwise to the protein mixture, stirred at room temperature for 12 h, centrifuged at 12000 g for 30 min, washed with ultrapure water for 3 times and freeze-dried to obtain the PLGA-protein intermediate.

[0205] S300, adding the PLGA-protein intermediate to the dopamine solution, and obtaining a polydopamine-encapsulated intermediate after reaction:

[0206] Add dopamine to Tris buffer (50 mM, pH = 8.5), wherein the dopamine concentration is 1 mg / mL, to obtain a dopamine solution;

[0207] 10 mg of PLGA-protein intermediate was added to 10 mL of dopamine solution and stirred at room temperature for 6 hours. The solution gradually turned dark brown. After that, the solution was centrifuged at 12000 g for 30 min and the precipitate was washed with ultrapure water for 3 times to obtain polydopamine-encapsulated nanomedicine.

[0208] S500, covering the surface of the balloon with the nano drug by ultrasonic atomization spraying to obtain a drug coating:

[0209] A 2 wt% nanoparticle solution was prepared with polyacrylic acid, and after degassing, it was sprayed onto the balloon surface by ultrasonic atomization. The spraying drug flow rate was 0.02 mL / min; the spraying ultrasonic power was 1.0 W; the spraying cycle number was 6 times to obtain a drug coating.

[0210] Comparative Example 3

[0211] This comparative example prepares a nanomedicine with a drug-loaded core + elastin layer + PEI layer structure, which does not contain a polydopamine layer;

[0212] A method for preparing a drug coating, comprising:

[0213] S100, preparation of drug-loaded nanoparticles:

[0214] Prepare PBS solution (10 mg / mL, pH 7.4) as the first aqueous phase solution;

[0215] 5 mL of PLGA polymer solution (lactic acid:glycolic acid=50:50, molecular weight 10000 kDa, 10 mg / mL) was mixed with 2.5 mg of colchicine in dichloromethane as an organic phase.

[0216] The first aqueous phase solution was added to the organic phase, and treated with a probe ultrasonic emulsifier (80% power, ultrasonic 0.5s, interval 0.5s) for 15 seconds under ice bath to fully emulsify it to obtain a reverse emulsion.

[0217] The reverse emulsion was added to 50 mL of the second aqueous phase solution (1 wt% PVA aqueous solution), and the mixture was stirred and emulsified at 800 rpm until the organic solvent was completely volatilized. The large particles were removed by centrifugation at 2000 g for 5 min, and the supernatant was centrifuged at 12000 g for 30 min to obtain nanoparticles, which were washed three times by centrifugation with ultrapure water to remove excess PVA, and resuspended in 2 mL of ultrapure water to obtain drug-loaded nanoparticles.

[0218] S200, mixing the drug-loaded nanoparticles with the elastin solution to obtain a protein mixture, and slowly dropping the crosslinker solution into the protein mixture to obtain a PLGA-protein intermediate:

[0219] Dissolve an appropriate amount of silk fibroin in 10 mL of deionized water to prepare a 2 wt% elastin solution;

[0220] Add 2 mL of drug-loaded nanoparticles (2 mg / mL) into the elastin solution and stir for 1 h at room temperature to fully mix to obtain a protein mixture;

[0221] Dissolving a cross-linking agent (genipin) in a water / ethanol mixture to obtain a cross-linking agent solution having a concentration of 1%;

[0222] The cross-linking agent solution was slowly added dropwise to the protein mixture, stirred at room temperature for 12 h, centrifuged at 12000 g for 30 min, washed with ultrapure water for 3 times and freeze-dried to obtain the PLGA-protein intermediate.

[0223] S300, adding the PLGA-protein intermediate to the cationic polymer solution, and obtaining the nano drug after the reaction:

[0224] PEI (25 kDa) was added to Tris buffer (50 mM, pH = 8.5), wherein the PEI concentration was 2 mg / mL, to obtain a cationic polymer solution;

[0225] 1 mL of PLGA-protein intermediate (5 mg / mL) was added to 10 mL of cationic polymer solution, stirred at room temperature for 2 h, centrifuged at 12000 g for 30 min, and the precipitate was washed 3 times with ultrapure water to obtain nanomedicine.

[0226] S500, covering the surface of the balloon with the nano drug by ultrasonic atomization spraying to obtain a drug coating:

[0227] A 2 wt% nanoparticle solution was prepared with polyacrylic acid, and after degassing, it was sprayed onto the balloon surface by ultrasonic atomization. The spraying drug flow rate was 0.02 mL / min; the spraying ultrasonic power was 1.0 W; the spraying cycle number was 6 times to obtain a drug coating.

[0228] The various indicators of the drug coatings of Examples 1-5 and Comparative Examples 1-3 were tested, and the drugs were fluorescently labeled and the adhesion retention rate (retention rate) of the drugs at the target site was detected. Each sample was tested 5 times, and the retention rate was averaged. The test results are shown in Table 1.

[0229] Table 1 Test results of Examples 1-5 and Comparative Examples 1-3

[0230]

[0231]

[0232] Among them, drug release response time refers to the time required for the drug to enter the body and begin to exert its therapeutic effect.

[0233] When drug-loaded nanoparticles are used to make drug films, their 6-hour retention rate is only 38%±5% due to the inability to strongly adhere to the structure of the blood vessel wall, and their targeting accuracy can only reach the tissue level. After the drug is encapsulated and modified using the method of the present application, its targeting accuracy can reach the cell substructure level and can bind to the specific structure of the cell. In addition, when drug-loaded nanoparticles are directly used as drug films, their continuous treatment time can only reach 2-3 hours, and the drug release response time is greater than 60min. The treatment effect is not ideal, a large amount of drugs will be lost in the bloodstream, and the off-target toxicity is large.

[0234] After a conventional drug balloon enters a blood vessel, it is generally required to reach the target lesion site and open the balloon within 15-30 seconds. This is because the drug is released too quickly in the blood vessel, and the drug balloon needs to be delivered to the target site as quickly as possible. The surface of the drug particles of the present application is coated with elastin and an adhesion layer, and the drug release rate can be adjusted and extended as needed, which can effectively extend the opening time of the drug balloon after entering the blood vessel, reduce drug distribution in non-target areas, and reduce surgical risks.

[0235] It can be seen from the test results in Table 1 that the retention rate of the drug coating of the present application can still be maintained at about 80% after 12 hours, and the duration of treatment can reach 2-4 weeks, indicating that in the complex environment of blood flow flushing and vascular expansion, contraction and shear force changes, the drug particles can maintain excellent adhesion, the drug concentration at the target site is high and can be released continuously, and reducing the loss of drugs in the bloodstream can reduce the risk of thrombosis and embolism, and can reduce the need for re-intervention due to drug loss, thereby reducing the medical burden on patients.

[0236] The drug of comparative example 1 has a slightly higher retention rate in the early stage than comparative examples 2 and 3 in the absence of an elastin layer, but after a period of time, as the expansion and contraction of the blood vessels change, a large number of drug particles will detach from the blood vessels and lose their adhesion ability, so the retention rate in the later stage will be significantly reduced. Comparative examples 2 and 3 are drugs that only coat polydopamine and PEI, respectively, and have a certain adhesion to the blood vessels, but are obviously not as good as the adhesion effect brought by the coordinated use of the two. It can be seen that the present application significantly improves the long-term adhesion performance of the drug coating in the blood vessels by designing the elastin intermediate layer and the polydopamine + PEI adhesion layer, and can sustainably maintain the drug concentration at the therapeutic level, prolong the action time of the drug, and effectively improve the therapeutic effect.

[0237] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A drug coating, characterized in that: The drug coating comprises nano-drugs, which sequentially comprise drug-loaded nano-particles, an elastin layer and an adhesion layer from the inside to the outside, and the adhesion layer comprises a polydopamine coating and a cationic polymer coating.

2. A drug coating according to claim 1, characterized in that: The components of the elastin layer include at least one of silk fibroin or spider silk protein.

3. A drug coating according to claim 1, characterized in that: The components of the cationic polymer coating include at least one of polyethyleneimine, poly-L-lysine, chitosan and poly-β-amino ester.

4. A drug coating according to claim 1, characterized in that: The surface of the nano drug is also modified with at least one of an NHS group, an aldehyde group, an isothiocyanate group, and a phenylboronic acid group.

5. A drug balloon, characterized in that: The surface of the drug balloon is covered with the drug coating according to any one of claims 1 to 4.

6. A method for preparing a drug coating according to any one of claims 1 to 4, characterized in that: include: The drug-loaded nanoparticles are mixed with the elastin solution to obtain a protein mixture, and the cross-linking agent solution is slowly added dropwise to the protein mixture to obtain a PLGA-protein intermediate; adding the PLGA-protein intermediate to a dopamine solution to obtain a polydopamine-encapsulated intermediate after reaction; adding the polydopamine-encapsulated intermediate into a cationic polymer solution to obtain a nano drug after reaction; The nano drug is covered on the balloon surface by ultrasonic atomization spraying or electrostatic self-assembly to obtain a drug coating.

7. The method for preparing a drug coating according to claim 6, characterized in that: The drug-loaded nanoparticles are mixed with an elastin solution to obtain a protein mixture, and a crosslinker solution is slowly added dropwise to the protein mixture to obtain a PLGA-protein intermediate, including: Dissolving elastin in water to prepare an elastin solution with a concentration of 1-5%, adding drug-loaded nanoparticles to the elastin solution, stirring and reacting at room temperature to obtain a protein mixture; Dissolving the crosslinking agent in a water / ethanol mixture to obtain a crosslinking agent solution with a concentration of 0.5-2%; The cross-linking agent solution is added dropwise to the protein mixture, and the reaction is stirred at room temperature for 8-15 hours. After the reaction, the mixture is centrifuged, washed and freeze-dried to obtain a PLGA-protein intermediate; the cross-linking agent includes at least one of genipin or glutaraldehyde.

8. The method for preparing a drug coating according to claim 76, characterized in that: The PLGA-protein solid is added to the dopamine solution to obtain a polydopamine-coated solid after reaction, comprising: Add dopamine to Tris buffer to prepare a dopamine solution with a concentration of 0.5-2 mg / mL; The PLGA-protein intermediate is added to the dopamine solution, and the mixture is stirred at room temperature for 4-8 hours. After the reaction, the mixture is centrifuged and washed to obtain a polydopamine-coated solid.

9. The method for preparing a drug coating according to claim 6, characterized in that: The polydopamine-encapsulated intermediate is added to a cationic polymer solution, and a nano drug is obtained after reaction, comprising: Adding the cationic polymer to a Tris buffer to prepare a cationic polymer solution having a concentration of 1-4 mg / mL; The polydopamine-coated intermediate is added to the cationic polymer solution, and the reaction is stirred at room temperature for 1-3 hours. After the reaction, the reaction is centrifuged and washed to obtain a polydopamine-coated solid.

10. The method for preparing a drug coating according to claim 6, characterized in that: The drug-loaded nanoparticles are PLGA drug-loaded nanoparticles, and the preparation method thereof comprises: preparing a first aqueous phase solution; The PLGA polymer is mixed with the drug solution to obtain an organic phase; Adding the first aqueous phase solution to the organic phase for full emulsification to obtain a reverse emulsion; The reverse emulsion is added into the second aqueous phase solution, fully stirred for emulsification, and centrifuged to obtain PLGA drug-loaded nanoparticles.

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