Drug balloon with effect of enhancing vascular wall adhesion and preparation method thereof

Abstract

The invention discloses a drug balloon with a function of enhancing blood vessel wall adhesion and a preparation method thereof, the drug balloon is characterized in that the surface of balloon equipment is provided with a drug-loaded microsphere coating, the drug-loaded microsphere is prepared by the following steps: carrying out surface modification on a drug-loaded degradable polymer microsphere through polycation, adding the drug-loaded degradable polymer microsphere into a monomer solution of an adhesion layer, and carrying out surface modification on the drug-loaded degradable polymer microsphere through polycation to obtain the drug-loaded microsphere. And performing ultraviolet radiation to perform in-situ polymerization on the surface of the microsphere to form a PAN adhesion layer, namely forming a coating on the surface of the drug-loaded degradable polymer microsphere, and coating the surface of the balloon equipment with the drug-loaded microsphere to form a drug-loaded microsphere coating. The degradable polymer particles are subjected to surface modification and covalent interaction is introduced, so that a chemical bonding adhesion strategy is formed by utilizing groups such as amino groups and carboxyl groups naturally existing on the surface of vascular wall tissue, and the adhesion of the degradable polymer particles to the vascular wall is effectively improved by taking the degradable polymer particles as a balloon coating.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology and relates to a drug balloon, in particular to a drug balloon having the function of enhancing blood vessel wall adhesion and a preparation method thereof. Background Art

[0002] Degradable polymers such as PLGA (polylactic acid-co-glycolic acid) are approved by the FDA for a variety of medical applications due to their excellent biosafety and degradability, especially as a long-acting sustained-release platform and a carrier of a variety of hydrophobic drugs. However, existing methods often rely mainly on physical mechanical embedding and van der Waals forces, and the mechanism of action is relatively simple, for example: the patent application with publication number CN113813449A discloses a method for preparing a nanoparticle-loaded rapamycin drug-coated balloon, prepares hollow mesoporous silica nanoparticles (MSNs) of rapamycin (RPM), and then coats it on the balloon surface by polylactic acid-polyglycolic acid (PLGA). The patent application with publication number CN115414538A discloses a lipid nanocapsule drug-loaded particle with uniform particle size, a drug balloon, and a preparation method and application thereof, wherein the drug is mixed with a nonionic surfactant for ultrasonic emulsification to prepare a nanocapsule with uniform particle size, and realizes drug delivery and sustained release in vivo.

[0003] Although these methods can effectively achieve drug encapsulation to a certain extent, achieving efficient drug transfer and long-term retention and sustained release within a few minutes of balloon expansion is still a major challenge. In fact, there are challenges in the application of intravascular retention and sustained release of degradable polymers. For example, due to their hydrophobicity and biological inertness, PLGA microspheres or particles lack specific interactions with tissues, are not suitable for long-term existence in the blood and withstand shear forces, and are difficult to achieve stable tissue adhesion and drug retention in a long-term blood flow environment. Therefore, it is necessary to enhance the interaction between degradable polymers and vascular walls to facilitate their application. Summary of the invention

[0004] The purpose of the present invention is to provide a drug balloon with enhanced blood vessel wall adhesion and a preparation method thereof in view of the deficiencies of the prior art. By modifying the surface of degradable polymer particles and introducing covalent interactions, a chemically bonded adhesion strategy is formed by utilizing naturally existing amino and carboxyl groups on the surface of blood vessel wall tissue, and using it as a balloon coating effectively improves its adhesion to the blood vessel wall.

[0005] The technical solution adopted by the present invention is as follows:

[0006] A drug-loaded balloon with enhanced vascular adhesion is a balloon device with a drug-loaded microsphere coating on its surface. The drug-loaded microspheres are prepared by first surface-modifying drug-loaded degradable polymer microspheres with polycations, then adding them to a monomer solution of an adhesion layer, and irradiating them with ultraviolet light to polymerize them in situ on the microsphere surfaces to form a PAN adhesion layer, i.e., forming a coating on the surfaces of the drug-loaded degradable polymer microspheres. The drug-loaded microspheres are coated on the balloon device surface to form a drug-loaded microsphere coating.

[0007] In the above technical solution, further, the preparation method of the drug balloon includes the following:

[0008] The desired loaded drug and the degradable polymer are dissolved in an organic solvent to form an organic phase, and the organic phase is added to an emulsifier aqueous solution, and ultrasonically emulsified to form colostrum; the colostrum is then added to an emulsifier aqueous solution for hardening, stirred and volatilized overnight, centrifuged, washed, and then freeze-dried to obtain polymer drug-loaded particles;

[0009] Adding the polymer drug-loaded particles into the polycation solution, stirring and incubating, centrifuging and washing, and freeze-drying to obtain polymer particles modified with the intermediate layer;

[0010] The modified polymer particles of the intermediate layer are added to the monomer solution of the adhesion layer, and in-situ polymerization is carried out by ultraviolet irradiation, and then freeze-dried after centrifugal washing to obtain the drug-loaded microspheres. The monomer solution of the adhesion layer contains acrylic acid AA, succinimidyl ester NHS (acrylic acid-N-succinimidyl ester can also be used), a photoinitiator and a crosslinking agent.

[0011] The drug-loaded microspheres are coated on a balloon to obtain the drug balloon.

[0012] Furthermore, the degradable polymer is one or more of polylactic acid PLA, polylactic acid-glycolic acid copolymer PLGA, polyglycolic acid PGA, polycaprolactone PCL, polyglycolic acid PELA, and polyamino acid;

[0013] Furthermore, the organic solvent is one or more of dichloromethane, chloroform, benzene, toluene, ethyl acetate, and acetone.

[0014] Furthermore, the emulsifier is one or a combination of Tween 20, Tween 80, PVA, polyoxyethylene (16) sorbitan monotoleate, polyoxyethylene (10) sorbitan monolaurate, polyoxyethylene (20) sorbitan dioleate, polyoxyethylene (18) sorbitan monostearate, polyoxyethylene (3,8) glycerol monolaurate, sodium oleate, sodium rosinate, C14-18 alkyl sodium sulfate, sodium dodecylbenzene sulfonate, and dialkyl sulfosuccinate.

[0015] Furthermore, the concentration of the emulsifier is 0.5% to 5%, and the concentration of the hardening emulsifier is 0.1% to 2%. Preferably, the concentration ratio of the two is 1.5 to 10:1.

[0016] Furthermore, the volume ratio of the organic phase to the emulsifier aqueous solution is 1:2-20, and the volume ratio of the colostrum to the hardening emulsifier aqueous solution is 1:2-10.

[0017] Furthermore, the polycation is one or more of polyethyleneimine, chitosan, methacrylamide chitosan, gelatin, and peptides, and the concentration of the polycation is 0.1 to 20 mg / mL.

[0018] Furthermore, in the monomer solution of the adhesion layer, the concentration of acrylic acid is 0.1-0.8 mol / L, and the molar ratio of AA to NHS is preferably 1-10:1. If the ratio is too low or too high, it will have a great impact on the final effect and is not conducive to the application of the balloon; the molar ratio of the photoinitiator to the monomer is 1:50-200, and the molar ratio of the crosslinker to the monomer is 1:100-500.

[0019] Furthermore, the drug can generally be one or more of rapamycin, paclitaxel, and zotarolimus, and can also load most hydrophobic drugs, such as tacrolimus, dexamethasone, indomethacin, triamcinolone acetonide, ibuprofen, ketoconazole, diazepam, chloramphenicol, etc.

[0020] Furthermore, the coating includes: dispersing the drug-loaded microspheres in water, and then coating the drug-loaded microspheres on the balloon surface by ultrasonic spraying, immersion drying, spray drying, micro-pipetting, coating, etc.

[0021] The beneficial effects of the present invention are at least as follows:

[0022] The drug balloon device with surface-modified drug-loaded microsphere coating provided by the present invention further improves the efficiency and durability of drug delivery, especially in the release and long-term retention of drugs such as rapamycin, by optimizing the surface chemical modification of polymer particles. Through this technology, the present invention not only improves the interaction between the balloon and the blood vessel wall, but also improves the stability and effectiveness of the drug release system in the complex environment within the blood vessel. Specifically:

[0023] (1) The preparation method of introducing an intermediate layer and in-situ polymerization provided by the present invention realizes the modification of the adhesion layer on the surface of the degradable polymer particles through electrostatic interaction and ultraviolet light-induced in-situ polymerization. The preparation process is simple and efficient, biosafe, and has universal applicability, and is applicable to various drugs, various negatively charged surface particles, and various adhesion application requirements, which is very beneficial to production and application.

[0024] (2) The present invention introduces a stable adhesion layer coating on the surface of polymer particles by adopting an in situ ultraviolet polymerization method, and introduces covalent interaction in the tissue adhesion design involving a complex vascular flushing environment through raw material screening and proportion adjustment, thereby significantly improving the immediate adhesion and long-term retention effect of the particles in the vascular area.

[0025] (3) The present invention introduces an adhesive coating on the surface of the degradable polymer particles, thereby effectively reducing the side effects during drug delivery and ensuring the safety of drug application. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Scanning electron microscope (SEM), transmission electron microscope (TEM) and laser confocal microscope images of the P@CS@PAN particles obtained in Example 1.

[0027] Figure 2 This is a comparison chart of the zeta potential data of P@CS@PAN, P and P@CS particles obtained in Example 1, Comparative Example 1 and Comparative Example 2.

[0028] Figure 3 This is a laser confocal microscope image of the P@PAN-1 particles obtained in Comparative Example 3.

[0029] Figure 4 This is a comparison chart of the vascular endothelial cell adhesion ability of P@CS@PAN and P particles obtained in Example 1 and Comparative Example 1.

[0030] Figure 5 This is a comparison chart of the adhesion ability of P@CS@PAN particles prepared in Example 1, P particles prepared in Comparative Example 1, P@CS@PAN-A particles prepared in Comparative Example 6, P@CS@PAN-A8N1 prepared in Example 2, and P@CS@PAN-A2N1 particles prepared in Example 3 on porcine blood vessels.

[0031] Figure 6 This is a scanning electron microscope (SEM) image of the P@CS@PAN particles prepared in Example 1 sprayed on a balloon by ultrasonic spraying. DETAILED DESCRIPTION

[0032] The technical solution of the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0033] Example 1

[0034] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0035] Step 2: 400 mg of PLGA microspheres were added to 40 mL of chitosan solution (10 mg / mL, MW=8k), stirred overnight, and centrifuged at least 3 times to obtain chitosan-modified PLGA microspheres (P@CS).

[0036] Step 3: Prepare a reaction solution with a molar ratio of AA:NHS = 4:1 and an acrylic acid monomer concentration of 0.49 mol / L: 200ul acrylic acid (2.92mmol), 8mg I2959, and 9.4mg NN-methylenebisacrylamide are added to 5600ul water, and 123.5mg acrylic acid-N-succinimidyl ester (0.73mmol) is dissolved in 200ul N,N-dimethylformamide and added to the above mixture.

[0037] Step 4: Add 200 mg of the prepared P@CS to the above 6 mL of the mixed solution and disperse evenly by ultrasonic. Initiate polymerization by ultraviolet irradiation for 300 s to obtain P@CS@PAN particles. After the polymerization is completed, centrifuge and wash at least three times. Freeze-dry and store at low temperature.

[0038] To verify the successful preparation of the adhesion layer modified particles, morphological tests were performed: the P@CS@PAN prepared in Example 1 was subjected to scanning electron microscopy (SEM) and transmission electron microscopy (TEM) tests. The blue fluorescent dye 7-amino-4-methylcoumarin was used to label the PAN adhesion layer, and the red fluorescent dye Nile red was used to label the PLGA particle core, and laser confocal microscopy was performed.

[0039] Results Figure 1 , showing that the P@CS@PAN particles were spherical, with uniform particle size and core-shell structure, indicating that the adhesion layer modified particles were successfully prepared.

[0040] In order to verify the effectiveness of the adhesion layer to modify the particle intermediate layer, a zeta potential test was performed: the P@CS@PAN prepared in Example 1 was dispersed in water at a concentration of 0.1 mg / mL, and a zeta potential test was performed using a nanoparticle size potential analyzer (DLS).

[0041] Results Figure 2, indicating that the surface charge of P@CS@PAN changes from negative to positive to negative during the preparation process, which corresponds to the charge properties of PLGA, CS and PAN. The results prove that the intermediate layer can effectively realize the charge transition from negative to positive on the surface of PLGA particles, which is an important guarantee for the adsorption of negatively charged monomers for in situ polymerization.

[0042] Example 2

[0043] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0044] Step 2: 400 mg of PLGA microspheres were added to 40 mL of chitosan solution (10 mg / mL, MW=8k), stirred overnight, and centrifuged at least 3 times to obtain chitosan-modified PLGA microspheres (P@CS).

[0045] Step 3: Prepare a reaction solution with a molar ratio of AA:NHS = 8:1 and an acrylic acid monomer concentration of 0.49 mol / L: 200ul acrylic acid (2.92mmol), 7mg I2959, and 8.4mg NN-methylenebisacrylamide are added to 5600ul water, and 60mg acrylic acid-N-succinimidyl ester (0.36mmol) is dissolved in 200ul N,N-dimethylformamide and added to the above mixture.

[0046] Step 4: Add 200 mg of the prepared P@CS to the above 6 mL mixed solution and disperse evenly by ultrasonic. Initiate polymerization by UV irradiation for 300 s to obtain P@CS@PAN-A8N1 particles. After the polymerization is completed, centrifuge and wash at least three times. Freeze-dry and store at low temperature.

[0047] Example 3

[0048] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0049] Step 2: 400 mg of PLGA microspheres were added to 40 mL of chitosan solution (10 mg / mL, MW=8k), stirred overnight, and centrifuged at least 3 times to obtain chitosan-modified PLGA microspheres (P@CS).

[0050] Step 3: Prepare a reaction solution with a molar ratio of AA:NHS = 2:1 and an acrylic acid monomer concentration of 0.49 mol / L: 200ul acrylic acid (2.92mmol), 9.4mg I2959, and 11.4mg NN-methylenebisacrylamide are added to 5600ul water, and 247mg acrylic acid-N-succinimidyl ester (1.46mmol) is dissolved in 200ul N,N-dimethylformamide and added to the above mixture.

[0051] Step 4: Add 200 mg of the prepared P@CS to the above 6 mL mixed solution and disperse evenly by ultrasonic. Initiate polymerization by ultraviolet irradiation for 300 s to obtain P@CS@PAN-A2N1 particles. After the polymerization is completed, centrifuge and wash at least three times. Freeze-dry and store at low temperature.

[0052] Example 4

[0053] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0054] Step 2: 400 mg of PLGA microspheres were added to 40 mL of chitosan solution (10 mg / mL, MW=8k), stirred overnight, and centrifuged at least 3 times to obtain chitosan-modified PLGA microspheres (P@CS).

[0055] Step 3: Prepare a reaction solution with a molar ratio of AA:NHS = 4:1 and an acrylic acid monomer concentration of 0.24 mol / L: 100ul acrylic acid (1.46mmol), 4mg I2959, and 4.7mg NN-methylenebisacrylamide are added to 5800ul water, and 60mg acrylic acid-N-succinimidyl ester (0.36mmol) is dissolved in 100ul N,N-dimethylformamide and added to the above mixture.

[0056] Step 4: Add 200 mg of the prepared P@CS to the above 6 mL mixed solution and disperse evenly by ultrasonic. Initiate polymerization by ultraviolet irradiation for 300 s to obtain P@CS@PAN-2 particles. After the polymerization is completed, centrifuge and wash at least three times. Freeze-dry and store at low temperature.

[0057] Comparative Example 1

[0058] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0059] Comparative Example 2

[0060] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0061] Step 2: 400 mg of PLGA microspheres were added to 40 mL of chitosan solution (10 mg / mL, MW=8k), stirred overnight, and centrifuged at least 3 times to obtain chitosan-modified PLGA microspheres (P@CS).

[0062] Comparative Example 3

[0063] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0064] Step 2: Prepare a reaction solution with a molar ratio of AA:NHS = 4:1 and an acrylic acid monomer concentration of 0.49 mol / L: 200ul acrylic acid (2.92mmol), 8mg I2959, and 9.4mg NN-methylenebisacrylamide are added to 5600ul water, and 123.5mg acrylic acid-N-succinimidyl ester (0.73mmol) is dissolved in 200ul N,N-dimethylformamide and added to the above mixture.

[0065] Step 3: Add 200 mg of the prepared PLGA particles to the above 6 mL mixed solution and disperse them evenly by ultrasonic. Irradiate with UV light for 300 s to initiate polymerization, and obtain particles (P@PAN-1) that are directly in situ UV-polymerized without an intermediate layer. After the polymerization is completed, centrifuge and wash at least three times. Freeze-dry and store at low temperature.

[0066] Morphological test of particles directly polymerized in situ without an intermediate layer: P@PAN-1 prepared in Comparative Example 3 was subjected to laser confocal test, in which the blue fluorescent dye 7-amino-4-methylcoumarin was used to label the PAN adhesion layer, and the red fluorescent dye Nile red was used to label the PLGA particle core.

[0067] Results Figure 3 , showing that the P@PAN-1 particles are spherical, but their core-shell structure is not obvious, and no obvious PAN adhesion layer is shown. It can be seen that the introduction of the intermediate layer plays a very important role and necessity for the in-situ polymerization of the adhesion layer. The reason may be that the introduction of the intermediate layer can be adsorbed on the PLGA particles and can effectively adsorb negatively charged monomers to make the local monomer concentration on the particle surface higher, which is conducive to the in-situ polymerization of monomers on the particle surface.

[0068] Comparative Example 4:

[0069] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0070] Step 2: Prepare a reaction solution with a molar ratio of AA:NHS = 25:1 and an acrylic acid monomer concentration of 0.49 mol / L: 200ul acrylic acid (2.92mmol), 6mg I2959, and 8mg NN-methylenebisacrylamide are added to 5600ul water, and 20.3mg acrylic acid-N-succinimidyl ester (0.12mmol) is dissolved in 200ul N,N-dimethylformamide and added to the above mixture.

[0071] Step 3: Add 200 mg of the prepared PLGA particles to the above 6 mL mixed solution and disperse them evenly by ultrasonic. Irradiate with UV light for 300 s to initiate polymerization, and obtain particles (P@PAN-2) that are directly in situ UV-polymerized without an intermediate layer. After the polymerization is completed, centrifuge and wash at least three times. Freeze-dry and store at low temperature.

[0072] The particles obtained in this example have poor adhesion in application.

[0073] Comparative Example 5

[0074] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0075] Step 2: 400 mg of PLGA microspheres were added to 40 mL of chitosan solution (10 mg / mL, MW=8k), stirred overnight, and centrifuged at least 3 times to obtain chitosan-modified PLGA microspheres (P@CS).

[0076] Step 3: Prepare pure NHS reaction solution: 1.6 mg I2959 and 2 mg NN-methylenebisacrylamide were added to 5800 ul water, 123.5 mg acrylic acid-N-succinimidyl ester (0.73 mmol) was dissolved in 200 ul N,N-dimethylformamide and then added to the above mixture.

[0077] Step 4: Add 200 mg of the prepared P@CS to the above 6 mL of the mixed solution and disperse it evenly by ultrasonic. Irradiate with UV light for 300 s to initiate polymerization and obtain P@CS@PAN-3 particles.

[0078] The particles obtained in this example are easy to agglomerate into white lumps, which is not conducive to subsequent processing and application.

[0079] Comparative Example 6

[0080] Step 1: Preparation of PLGA drug-loaded particles: Weigh 120 mg of rapamycin and 400 mg of PLGA (50:50, Mw = 20k) and dissolve them in 4 mL of dichloromethane. Add the solution to 20 mL of 1% PVA (polyvinyl alcohol 1788) solution, sonicate for 30 seconds, add colostrum to 60 mL of 0.5% PVA solution, stir and evaporate overnight. Wash and centrifuge at least 3 times, freeze-dry and store to obtain PLGA particles (P) with a particle size of 1 to 10 μm.

[0081] Step 2: 400 mg of PLGA microspheres were added to 40 mL of chitosan solution (10 mg / mL, MW=8k), stirred overnight, and centrifuged at least 3 times to obtain chitosan-modified PLGA microspheres (P@CS).

[0082] Step 3: Prepare a reaction solution with an acrylic acid monomer concentration of 0.49 mol / L: add 200 ul of acrylic acid (2.92 mmol), 6.3 mg of I2959, and 7.5 mg of NN-methylenebisacrylamide into 5800 ul of water.

[0083] Step 4: Add 200 mg of the prepared P@CS particles to the above 6 mL mixed solution and disperse them evenly by ultrasonic. Initiate polymerization by ultraviolet irradiation for 300 s to obtain P@CS@PAN-A particles. After the polymerization is completed, centrifuge and wash at least three times. Freeze-dry and store at low temperature.

[0084] Application Example 1

[0085] In order to explore whether the modification of the adhesion layer can enhance the adhesion to vascular endothelial cells, the P@CS@PAN particles prepared in Example 1 and the P particles prepared in Comparative Example 1 were subjected to cell adhesion tests:

[0086] When the vascular endothelial cells EC grew to 80% to 90% confluence, they were digested and centrifuged, dispersed in the culture medium, and seeded into a 24-well cell culture plate at a density of 50,000 cells per well. Cell experiments were performed after 24 hours of adhesion.

[0087] 60μg / mL P and P@CS@PAN particles were incubated with endothelial cells for two hours, washed three times with PBS buffer, and fluorescent images were taken. Among them, the red fluorescent dye Nile Red labeled the particles, the blue fluorescent dye Hochest labeled the cell nucleus, and the green fluorescent dye CellTracker Green CMFDA labeled the cytoplasm.

[0088] 60μg / mL P and P@CS@PAN particles were incubated with endothelial cells for two hours and washed three times with PBS buffer. The cells were fixed with paraformaldehyde overnight and dehydrated step by step with ethanol. The cell samples were photographed by scanning electron microscopy (SEM).

[0089] Results Figure 4 , cell fluorescence images ( Figure 4 A) and SEM images ( Figure 4 B) shows that compared with the P particles prepared in Comparative Example 1 without adhesion layer modification, the adhesion layer modified particles P@CS@PAN prepared in Example 1 show stronger fluorescence signals and more adhesion numbers on cells, indicating that the adhesion layer modified particles have better cell adhesion effect.

[0090] Application Example 2

[0091] In order to explore whether the modification of the adhesion layer can improve the adhesion of particles to vascular tissue, the P@CS@PAN particles prepared in Example 1, the P particles prepared in Comparative Example 1, the P@CS@PAN-A particles prepared in Comparative Example 6, the P@CS@PAN-A8N1 prepared in Example 2, and the P@CS@PAN-A2N1 particles prepared in Example 3 were subjected to vascular tissue adhesion tests:

[0092] The particles were coated on a thermoplastic polyurethane (TPU) substrate by ultrasonic spraying to obtain a particle coating (0.6 mg / cm 2 ). The coated sheet (0.5 cm wide and 1.2 cm long) was placed on fresh, moistened porcine vascular tissue. A vertical force of 5 N was applied for 3 minutes. The fluorescence intensity on the vascular tissue was detected using a fluorescence microscope, where the red fluorescent dye Nile red labeled the particles.

[0093] Results Figure 5 The fluorescence images show that compared with the P particles prepared in Comparative Example 1 and the P@CS@PAN-A particles prepared in Comparative Example 6, the P@CS@PAN particles prepared in Example 1, the P@CS@PAN-A8N1 particles prepared in Example 2, and the P@CS@PAN-A2N1 particles prepared in Example 3 show stronger fluorescence signals on the vascular tissue, indicating that the adhesion layer modified particles have better tissue adhesion effect.

[0094] Application Example 3

[0095] In order to explore whether the particles modified with the adhesion layer can be effectively used in non-implantable balloon devices, the P@CS@PAN particles prepared in Example 1 were sprayed on the balloon by ultrasonic spraying, and a scanning electron microscope (SEM) observation test was performed:

[0096] A balloon with a diameter of 1.5 cm was fixed on a rotating shaft. P@CS@PAN (15 mg / mL) was dispersed in water and sprayed onto the surface of a polyetheramide block (PEBAX) balloon. The liquid inflow was controlled at 6 μL / min for 20 minutes. After the balloon dried, the surface and cross-section of the coating were observed by SEM.

[0097] Results Figure 6 ,SEM images show that P@CS@PAN particles can form a uniform coating on the balloon surface by ultrasonic spraying, indicating that P@CS@PAN particles can be effectively used in non-implantable balloons and other devices.

[0098] The above-described embodiments are only some of the preferred solutions of the present invention, but they are not intended to limit the present invention. A person skilled in the relevant technical field may make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, any technical solution obtained by equivalent replacement or equivalent transformation falls within the protection scope of the present invention.

Claims

1. A drug-eluting balloon having a vascular adhesion enhancing effect, characterized in that: The surface of the balloon device is provided with a drug-loaded microsphere coating. The drug-loaded microspheres are prepared by first surface-modifying drug-loaded degradable polymer microspheres with polycations, then adding them into a monomer solution of an adhesion layer, and irradiating them with ultraviolet light to polymerize them in situ on the surface of the microspheres to form a PAN adhesion layer, i.e., forming a coating on the surface of the drug-loaded degradable polymer microspheres. The drug-loaded microspheres are coated on the surface of the balloon device to form a drug-loaded microsphere coating.

2. The method for preparing the drug balloon having the effect of enhancing blood vessel adhesion according to claim 1, characterized in that: These include: The desired loaded drug and the degradable polymer are dissolved in an organic solvent to form an organic phase, and the organic phase is added to an emulsifier aqueous solution, and ultrasonically emulsified to form colostrum; the colostrum is then added to an emulsifier aqueous solution for hardening, stirred and volatilized overnight, centrifuged, washed, and then freeze-dried to obtain polymer drug-loaded particles; Adding the polymer drug-loaded particles into the polycation solution, stirring and incubating, centrifuging and washing, and freeze-drying to obtain polymer particles modified with the intermediate layer; The polymer particles modified by the intermediate layer are added to the monomer solution of the adhesion layer, and in-situ polymerization is performed by ultraviolet irradiation, and then freeze-dried after centrifugal washing to obtain the drug-loaded microspheres; the monomer solution of the adhesion layer contains acrylic acid AA, succinimidyl ester NHS, a photoinitiator and a cross-linking agent; The drug-loaded microspheres are coated on a balloon to obtain the drug balloon.

3. The method for preparing the drug balloon having the effect of enhancing blood vessel adhesion according to claim 2, characterized in that: The degradable polymer is one or more of polylactic acid PLA, polylactic acid-glycolic acid copolymer PLGA, polyglycolic acid PGA, polycaprolactone PCL, polyglycolic acid PELA, and polyamino acid.

4. The method for preparing the drug balloon having the effect of enhancing blood vessel adhesion according to claim 2, characterized in that: The organic solvent is one or more of dichloromethane, chloroform, benzene, toluene, ethyl acetate and acetone.

5. The method for preparing the drug balloon having the effect of enhancing blood vessel adhesion according to claim 2, characterized in that: The emulsifier is one of Tween 20, Tween 80, PVA, polyoxyethylene (16) sorbitan monotolate, polyoxyethylene (10) sorbitan monolaurate, polyoxyethylene (20) sorbitan dioleate, polyoxyethylene (18) sorbitan monostearate, polyoxyethylene (3,8) glycerol monolaurate, sodium oleate, sodium rosinate, C14-18 alkyl sodium sulfate, sodium dodecylbenzene sulfonate, and dialkyl sulfosuccinate, or a combination thereof.

6. The method for preparing the drug balloon having the effect of enhancing blood vessel adhesion according to claim 2, characterized in that: The concentration of the emulsifier is 0.5% to 5%, and the concentration of the hardening emulsifier is 0.1% to 2%.

7. The method for preparing the drug balloon having the effect of enhancing blood vessel adhesion according to claim 2, characterized in that: The volume ratio of the organic phase to the emulsifier aqueous solution is 1:2-20, and the volume ratio of the colostrum to the hardening emulsifier aqueous solution is 1:2-10.

8. The method for preparing the drug balloon having the effect of enhancing blood vessel adhesion according to claim 2, characterized in that: The polycation is one or more of polyethyleneimine, chitosan, methacrylamide chitosan, gelatin and peptides, and the concentration of the polycation is 0.1-20 mg / mL.

9. The method for preparing the drug balloon having the function of enhancing blood vessel adhesion according to claim 2, characterized in that: In the monomer solution of the adhesion layer, the acrylic acid concentration is 0.1-0.8 mol / L, the molar ratio of AA to NHS is 1-10:1, the molar ratio of the photoinitiator to the monomer is 1:50-200, and the molar ratio of the crosslinking agent to the monomer is 1:100-500.

10. The method for preparing the drug balloon having the function of enhancing blood vessel adhesion according to claim 2, characterized in that: The drug is one or more of rapamycin, paclitaxel and zotarolimus.

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