Interventional medical instrument

Abstract

The invention provides an interventional medical instrument, particularly relates to a drug balloon for inhibiting restenosis, particularly relates to the technical field of materials of catheters and coated catheters, and particularly relates to a drug balloon and a preparation method thereof. The coating comprises a coating liquid, the coating liquid comprises a mixed solvent system, and the mixed solvent system comprises water, ethanol and N, N-dimethylformamide (DMF); the coating liquid further comprises a rapamycin bulk drug, a drug sustained-release carrier, a hydrophilic high-molecular material, a spinning aid and a drug release regulator. Wherein the drug release regulator comprises sodium hyaluronate (SH). According to the invention, the rapamycin can present quick release and slow drug release effects in different media, the inner layer is the PLGA microspheres, and the PLGA is used as a rapamycin carrier and realizes continuous and slow release of the rapamycin at the same time.

Description

Technical Field

[0001] The present invention relates to interventional medical devices, in particular to the technical field of materials for catheters and coated catheters, and specifically to a drug balloon coating liquid, a drug balloon coating material, a drug balloon and a preparation method thereof. Background Art

[0002] Rapamycin is a new type of immunosuppressant and antifungal drug with good efficacy, low toxicity and no nephrotoxicity. It is a specific inhibitor of mTOR protein. After binding to the intracellular receptor FKBP-12 to form a complex, it directly acts on the FRB (FKBP-12-rapamycin binding) domain in mTOR to inhibit protein activity. It is often used as a drug to maintain the immune capacity of transplanted organs (especially kidney transplantation) to slow down the immune rejection reaction after organ transplantation surgery. As a potent immunosuppressant, rapamycin blocks signal transduction through different cytokine receptors, blocks the process of T lymphocytes and other cells from G1 phase to S phase, and thus exerts an immunosuppressive effect. Rapamycin is a white solid crystal with a melting point of 183-185°C. It is lipophilic and soluble in organic solvents such as methanol, ethanol, acetone, and chloroform. It is very slightly soluble in water and almost insoluble in ether.

[0003] The currently available rapamycin dosage forms are mainly oral tablets and injections, but traditional tablets and liquid preparations cannot solve the problem of low bioavailability of rapamycin due to poor water solubility, nor can they achieve targeted and long-term release of rapamycin at the treatment site. To solve the above problems, a new dosage form that has been launched on the market, microspheres, can be used as formulation carriers. The particle size of microspheres is generally 1-250μm. It is a microparticle dispersion system formed by drug dispersion or adsorption in a high molecular polymer matrix. It is a commonly used drug carrier with targeted effects. In order to reduce the number of rapamycin doses and achieve long-term release of rapamycin at the treatment site, polylactic acid-glycolic acid copolymer (PLGA) is widely used as a carrier of microspheres in the medical field. PLGA is a degradable functional macromolecular organic compound with good biocompatibility, non-toxicity, and good encapsulation and film-forming properties. It is widely used in pharmaceutical, medical engineering materials and modern industrial fields. At the same time, PLGA microspheres, as sustained-release carriers for various drugs such as proteins and enzymes, have been a hot topic of research in recent years, and the preparation and application of various PLGA drug microspheres have been reported.

[0004] At the same time, innovations in clinical medical technology combine simple drug delivery with the intervention of medical devices. In recent years, there have been many studies and applications on clinical point-of-care interventional treatments for contact transfer using intraluminal expandable catheters. The preparation of rapamycin into a microsphere-type drug microreservoir can effectively solve problems such as targeted drug delivery and absorption barriers. However, the difficulty of its preparation lies in the long drug release time of the commonly used PLGA carrier, the need to improve its cell affinity and contact transfer requirements, and how to achieve drug coating. Summary of the invention

[0005] The purpose of the present invention is to provide a rapamycin PLGA sustained-release microsphere containing sodium hyaluronate. The microsphere has a core-shell structure, and the outer layer is a sodium hyaluronate layer. Due to the material properties of sodium hyaluronate, rapamycin can exhibit rapid release and slow release effects in different media. The inner layer is a PLGA microsphere. PLGA serves as a rapamycin carrier and realizes the sustained slow release of rapamycin.

[0006] Another object of the present invention is to provide a coating method for rapamycin microspheres, which uses electrostatic spraying technology to achieve stable coating of the rapamycin microsphere system containing sodium hyaluronate, and provides an optimized coating process for the rapamycin microsphere coating.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] The present invention provides a drug balloon coating liquid, the coating liquid comprises a mixed solvent system, the mixed solvent system comprises: water, ethanol and N,N-dimethylformamide (DMF); the coating liquid also comprises: rapamycin raw material, drug sustained-release carrier, hydrophilic polymer material, spinning aid and drug release regulator; wherein the drug release regulator comprises sodium hyaluronate (SH).

[0009] Optionally, the coating liquid comprises, by mass, rapamycin raw material: drug sustained-release carrier: hydrophilic polymer material: spinning aid: drug release regulator = 1:16:40-50:8:6-8.

[0010] Optionally, the drug sustained-release carrier comprises polylactic-co-glycolic acid (PLGA);

[0011] Preferably, the drug sustained-release carrier comprises one or more of PLGA 75 / 25 (0.22 dl / l), PLGA 50 / 50 (0.1 dl / l), PLGA 50 / 50 (0.2 dl / l), and PLGA 50 / 50 (0.23 dl / l).

[0012] Optionally, the hydrophilic polymer material includes polyvinyl alcohol;

[0013] Preferably, the hydrophilic polymer material includes polyvinyl alcohol 403 (PVA403).

[0014] Optionally, the spinning aid is polyethylene oxide (PEO);

[0015] Preferably, the number average molecular weight of the polyethylene oxide (PEO) is Mn=10,000, Mn=50,000 or Mn=100,000.

[0016] Optionally, the number average molecular weight of the sodium hyaluronate (SH) is Mn=10,000, or Mn=100,000-400,000.

[0017] Optionally, the volume ratio of water, ethanol and N,N-dimethylformamide in the mixed solvent system is 2:1:1.

[0018] The present invention also provides a drug balloon coating material, which includes rapamycin sustained-release microspheres containing sodium hyaluronate, wherein the microspheres are core-shell structures, wherein the core-shell structure includes an outer layer coating rapamycin, wherein the outer layer includes a sodium hyaluronate layer, and the inner core of the core-shell structure includes rapamycin and PLGA.

[0019] Optionally, the material includes rapamycin API: PLGA: sodium hyaluronate = 1:16:6-8 by mass.

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

[0021] (1) adding a hydrophilic polymer material to pure water under stirring and fully dissolving it to prepare a solution ①; dissolving a drug sustained-release carrier in an organic solvent first, vortexing and ultrasonically stirring it to fully dissolve it, and then adding the rapamycin raw material to prepare a solution ② by vortexing and ultrasonically stirring it; pouring solution ② into solution ① and ultrasonically stirring it to fully emulsify it, and continuing to stir at room temperature to volatilize the organic solvent; then adding anhydrous ethanol and N,N-dimethylformamide (DMF) thereto and stirring it fully; then adding a spinning aid to the solution under stirring and stirring it fully, and after stirring it fully, adding a drug release regulator thereto, stirring it fully and ultrasonically stirring it to make the solution uniformly dispersed, thereby obtaining a microsphere electrostatic spray working solution; wherein the drug release regulator comprises sodium hyaluronate (SH);

[0022] (2) The microsphere electrostatic spray working solution is placed in a syringe and slowly discharged by a constant current pump. The solution spray rate is 0.2-0.8 mL / h and the voltage range is 10-25 KV. The solution is sprayed through the nozzle to a receiving device at a receiving distance of 10-20 cm. The powdered drug balloon coating material is collected.

[0023] Optionally, the organic solvent in step (1) comprises dichloromethane.

[0024] Optionally, the microsphere electrostatic spray working fluid comprises, by mass, rapamycin raw material: drug sustained-release carrier: hydrophilic polymer material: spinning aid: drug release regulator = 1:16:40-50:8:6-8.

[0025] Optionally, the drug sustained-release carrier comprises polylactic-co-glycolic acid (PLGA);

[0026] Preferably, the drug sustained-release carrier comprises one or more of PLGA 75 / 25 (0.22 dl / l), PLGA 50 / 50 (0.1 dl / l), PLGA 50 / 50 (0.2 dl / l), and PLGA 50 / 50 (0.23 dl / l).

[0027] Optionally, the hydrophilic polymer material includes polyvinyl alcohol;

[0028] Preferably, the hydrophilic polymer material includes polyvinyl alcohol 403 (PVA403).

[0029] Optionally, the spinning aid is polyethylene oxide (PEO);

[0030] Preferably, the number average molecular weight of the polyethylene oxide (PEO) is Mn=10,000, Mn=50,000 or Mn=100,000.

[0031] Optionally, the number average molecular weight of the sodium hyaluronate (SH) is Mn=10,000, or Mn=100,000-400,000.

[0032] Beneficial Effects

[0033] The present invention has the following beneficial effects:

[0034] 1. The present invention solves the problem of poor water solubility of rapamycin. By using a hydrophilic carrier and a microparticle delivery system, a rapamycin microsphere preparation with adjustable drug release rate is prepared. In vitro dissolution experiments show that the rapamycin microsphere can release 80% after one day in water, and can be slowly and continuously released within 7 days in a pH 7.4 phosphate buffer. The rapamycin microsphere preparation prepared by this method has an adjustable and controllable drug release rate in different media.

[0035] 2. The present invention provides a promising method for coating rapamycin microspheres. The rapamycin microspheres prepared by electrostatic spraying are in the form of dry powder and can be coated on a flat surface or a catheter surface. After the microsphere preparation is redissolved in water, the average particle size is 436.28 nm, the PDI is 0.238, and scanning electron microscopy shows that the particles are evenly distributed. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0037] Figure 1 This is a transmission electron microscopy result image of rapamycin microspheres in Example 5;

[0038] Figure 2 This is a scanning electron microscopy image of rapamycin microspheres in Example 5;

[0039] Figure 3 This is a transmission electron microscopy result image of rapamycin microspheres in Example 6;

[0040] Figure 4 This is a scanning electron microscopy image of rapamycin microspheres in Example 6;

[0041] Figure 5 This is a transmission electron microscopy result image of rapamycin microspheres in Example 8;

[0042] Figure 6 This is a scanning electron microscopy image of rapamycin microspheres in Example 8;

[0043] Figure 7 This is the particle size distribution diagram of rapamycin microspheres in Example 8;

[0044] Figure 8 This is a scanning electron microscopy image of rapamycin microspheres in Example 9;

[0045] Fig. 9 This is a scanning electron microscopy image of rapamycin microspheres in Example 10;

[0046] Fig.10 This is a curve chart of the in vitro drug release results of rapamycin microspheres in Example 8. DETAILED DESCRIPTION

[0047] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0048] The present invention adopts sodium hyaluronate as a drug release regulator of a drug balloon coating liquid, realizes microsphere molding and coating integration through electrostatic spraying technology, and prepares rapamycin PLGA sustained-release microspheres containing sodium hyaluronate.

[0049] Hyaluronic acid (HA), also known as hyaluronic acid and hyaluronic acid, is a mucopolysaccharide formed by alternating disaccharide units of glucuronic acid and N-acetylglucosamine. It is widely present in tissues such as the placenta, amniotic fluid, lens, articular cartilage, and skin dermis. Commercially available hyaluronic acid is presented in the form of its sodium salt, called sodium hyaluronate. Sodium hyaluronate is widely used in the pharmaceutical and cosmetic industries. It has the characteristics of high biocompatibility and good safety. It plays the role of water retention, maintaining extracellular space, regulating osmotic pressure, lubrication, and promoting cell repair in the body. Sodium hyaluronate, as a drug carrier, can prolong the retention time of the drug on the surface of the treatment site by increasing the viscosity of the drug, improve the bioavailability of the drug, and reduce the irritation of the drug to the treatment site. Sodium hyaluronate has a certain water absorption and storage capacity, good film-forming properties, and its strong permeability can effectively help the drug enter specific parts of the body and exert the efficacy of the drug. At the same time, the selection of sodium hyaluronate with different molecular weights can adjust the viscosity of the electrostatic or ultrasonic spraying working fluid, thereby optimizing the process parameters.

[0050] The present invention uses electrostatic spray technology to prepare rapamycin microsphere nanoparticles encapsulated by sodium hyaluronate. Compared with other methods for preparing microspheres such as emulsification, solvent volatilization, spray drying, etc., the electrostatic spray method has significant advantages, such as good controllability of preparation conditions, avoiding the heating process in the preparation process to reduce the loss of drugs, and the prepared microspheres have uniform and controllable particle size and controllable surface morphology. Compared with the traditional microsphere preparation process, the obvious advantages are: avoiding high temperature operation, simple preparation process, and omitting the second emulsion. The present invention uses electrostatic spray technology to solidify and mold the microsphere mother solution containing sodium hyaluronate after incubation. Sodium hyaluronate itself has a certain viscosity and the core-shell structure formed is easily destroyed at high or low temperatures. Therefore, it is difficult to solidify and obtain an ideal microsphere structure using traditional drying methods. The present invention successfully prepares preparations such as microspheres, nanoparticles, and nanogels using electrostatic spray technology.

[0051] The following are the main instruments and raw materials used in the examples:

[0052] Raw materials: Rapamycin API (Shanghai McLean Biochemical Technology Co., Ltd.); PLGA (Shenzhen Boli Biomaterials Co., Ltd.); PVA403 (BASF New Materials Co., Ltd.); PEO (BASF New Materials Co., Ltd.); sodium hyaluronate (Guangzhou Meiyi Biotechnology Co., Ltd.); ethanol (Sinopharm Chemical Reagent Co., Ltd.); N,N-dimethylformamide (Sinopharm Chemical Reagent Co., Ltd.).

[0053] Instruments: electronic balance (Sartorius BSA124S-CW, Germany); CNC ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.); constant temperature oscillator (Zhongda Instrument Factory, Jintan City, Jiangsu Province); 90Plus PALS particle size analyzer (Brookhaven Instruments, USA); LSP01-1A micro-injection pump (Hebei Baoding Lange Co., Ltd.); HB-Z303-1AC DC high-voltage power supply (Tianjin Haokai Technology Development Co., Ltd.); liquid chromatograph (including LC-20AD liquid phase pump, SIL-20AC injector, CTO-20AC column oven, SPD-M20A UV detector, symmetry C18 column) (Shimadzu, Japan).

[0054] Example 1 Rapamycin Microspheres

[0055] (1) Weigh 200 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 200 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 5 mg of rapamycin API and 80 mg of PLGA50 / 50 (0.23 dl / l) accurately with an electronic balance, dissolve 80 mg of PLGA50 / 50 (0.23 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 40 mg of PEO (Mn=100,000) was added to the solution under stirring, and then 75 mg of sodium hyaluronate (McLean) was added thereto after sufficient stirring. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to uniformly disperse the solution to obtain a microsphere electrostatic spray formulation.

[0056] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant current pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to a flat receiving plate and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0057] Example 2 Rapamycin Microspheres

[0058] (1) Weigh 250 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 250 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 5 mg of rapamycin API and 80 mg of PLGA50 / 50 (0.23 dl / l) accurately with an electronic balance, dissolve 80 mg of PLGA50 / 50 (0.23 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 40 mg of PEO (Mn=100,000) was added to the solution under stirring. After sufficient stirring, 75 mg of sodium hyaluronate (McLean) was added thereto. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to evenly disperse the solution to obtain a microsphere electrostatic spray prescription.

[0059] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant current pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to a flat receiving plate and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0060] Example 3 Rapamycin Microspheres

[0061] (1) Weigh 250 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 250 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 5 mg of rapamycin API and 80 mg of PLGA50 / 50 (0.23 dl / l) accurately with an electronic balance, dissolve 80 mg of PLGA50 / 50 (0.23 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 40 mg of PEO (Mn=50,000) was added to the solution under stirring. After sufficient stirring, 50 mg of sodium hyaluronate (McLean) was added thereto. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to evenly disperse the solution to obtain a microsphere electrostatic spray formulation.

[0062] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant current pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to a flat receiving plate and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0063] Example 4 Rapamycin Microspheres

[0064] (1) Weigh 250 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 250 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 5 mg of rapamycin API and 80 mg of PLGA50 / 50 (0.23 dl / l) accurately with an electronic balance, dissolve 80 mg of PLGA50 / 50 (0.23 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 40 mg of PEO (Mn=50,000) was added to the solution under stirring, and then 30 mg of sodium hyaluronate (Mn=100,000) was added thereto after sufficient stirring. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to uniformly disperse the solution to obtain a microsphere electrostatic spray prescription.

[0065] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant current pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to a flat receiving plate and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0066] Example 5 Rapamycin Microspheres

[0067] (1) Weigh 250 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 250 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 5 mg of rapamycin API and 80 mg of PLGA50 / 50 (0.2 dl / l) accurately with an electronic balance, dissolve 80 mg of PLGA50 / 50 (0.2 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 40 mg of PEO (Mn=50,000) was added to the solution under stirring. After sufficient stirring, 40 mg of sodium hyaluronate (McLean) was added thereto. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to evenly disperse the solution to obtain a microsphere electrostatic spray prescription.

[0068] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant current pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to a flat receiving plate and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0069] Example 6 Rapamycin Microspheres

[0070] (1) Weigh 250 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 250 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 5 mg of rapamycin API and 80 mg of PLGA50 / 50 (0.23 dl / l) accurately with an electronic balance, dissolve 80 mg of PLGA50 / 50 (0.23 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 40 mg of PEO (Mn = 100,000) was added to the solution under stirring. After sufficient stirring, 40 mg of sodium hyaluronate (Mn = 200,000 to 400,000) was added thereto. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to evenly disperse the solution to obtain a microsphere electrostatic spray prescription.

[0071] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant current pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to a flat receiving plate and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0072] Example 7 Rapamycin Microspheres

[0073] (1) Weigh 250 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 250 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 5 mg of rapamycin API and 80 mg of PLGA50 / 50 (0.1 dl / l) accurately with an electronic balance, dissolve 80 mg of PLGA50 / 50 (0.1 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 40 mg of PEO (Mn=10,000) was added to the solution under stirring, and then 40 mg of sodium hyaluronate (Mn=10,000) was added thereto after sufficient stirring. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to uniformly disperse the solution to obtain a microsphere electrostatic spray prescription.

[0074] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant current pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to a flat receiving plate and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0075] Example 8 Rapamycin Microspheres

[0076] (1) Weigh 250 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 250 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 5 mg of rapamycin API and 80 mg of PLGA50 / 50 (0.1 dl / l) accurately with an electronic balance, dissolve 80 mg of PLGA50 / 50 (0.1 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 40 mg of PEO (Mn=10,000) was added to the solution under stirring, and then 30 mg of sodium hyaluronate (Mn=10,000) was added thereto after sufficient stirring. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to uniformly disperse the solution to obtain a microsphere electrostatic spray prescription.

[0077] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant flow pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to the balloon catheter device and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0078] Example 9 Rapamycin Microspheres

[0079] (1) Weigh 45 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 45 mg of PVA403 to the pure water under stirring, and fully dissolve to prepare solution ①. Then weigh 25 mg of rapamycin API and 50 mg of PLGA50 / 50 (0.1 dl / l) accurately with an electronic balance, dissolve 50 mg of PLGA50 / 50 (0.1 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 30 mg of PEO (Mn=10,000) was added to the solution under stirring, and then 40 mg of sodium hyaluronate (Mn=10,000) was added thereto after sufficient stirring. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to uniformly disperse the solution to obtain a microsphere electrostatic spray prescription.

[0080] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant flow pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to the balloon catheter device and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0081] Example 10 Rapamycin Microspheres

[0082] (1) Weigh 25 mg of PVA403 accurately with an electronic balance, take 5 mL of pure water, add 25 mg of PVA403 to the pure water while stirring, and fully dissolve to prepare solution ①. Then weigh 25 mg of rapamycin API and 25 mg of PLGA50 / 50 (0.1 dl / l) accurately with an electronic balance, dissolve 25 mg of PLGA50 / 50 (0.1 dl / l) in 1 mL of dichloromethane, vortex and sonicate for 5 min to fully dissolve it, then add 5 mg of rapamycin API, vortex and sonicate to prepare solution ②. Pour solution ② into solution ① and sonicate for 5 min to fully emulsify it, and continue stirring at room temperature for 1 h to volatilize the organic reagent. Then add 2.5 mL of anhydrous ethanol and 2.5 mL of N,N-dimethylformamide (DMF) and stir well. Then, 30 mg of PEO (Mn=10,000) was added to the solution under stirring, and then 30 mg of sodium hyaluronate (Mn=10,000) was added thereto after sufficient stirring. After sufficient stirring, ultrasonic treatment was performed for 5 minutes to uniformly disperse the solution to obtain a microsphere electrostatic spray prescription.

[0083] (2) About 10 mL of the microsphere working solution was placed in a syringe and slowly discharged by a constant flow pump. The solution spray rate was 0.4 mL / h, the voltage range was 15 KV, and the nozzle specification was 22G. The solution was sprayed through the nozzle to the balloon catheter device and collected to obtain a powdered rapamycin microsphere preparation. The receiving distance was 15 cm.

[0084] Results and Discussion

[0085] The morphology and particle size distribution of the rapamycin microspheres prepared in Example 5 were studied:

[0086] (1) Morphological observation using a transmission electron microscope (TEM). Scrape an appropriate amount of rapamycin microspheres from aluminum foil and fully disperse them in pure water. Pipette them with a micropipette and drop them on a carbon film copper grid. Stain them with phosphomolybdic acid for 30 seconds. Then dry the sample under an infrared lamp. The process from dispersion to drying takes about 30 minutes. Push the sample into the sample rod and use TEM to observe the morphological characteristics of the sample. The results are shown in Figure 1 As can be seen from the figure, the microspheres are evenly distributed and are in the form of oval particles. Sodium hyaluronate fails to form a shell to wrap the microspheres, and unevenly dispersed sodium hyaluronate can be seen in the gray shadows, indicating that the viscosity of sodium hyaluronate itself causes the adhesion between the microspheres. The particle size of the black microspheres is 200-300nm.

[0087] (2) Morphological observation using scanning electron microscopy (SEM). Scrape an appropriate amount of rapamycin microspheres from aluminum foil and place them on a sample holder. Use conductive glue to fix them on a sample plate. Use SEM to observe their surface morphology under vacuum conditions. The results are shown in Figure 2 As can be seen from the figure, the microspheres are unevenly distributed, the particle sizes of the microspheres are not uniform, and there is obvious adhesion between the microspheres. The particle size is 400-800nm.

[0088] (3) Particle size distribution. Take an appropriate amount of rapamycin microspheres, add an appropriate amount of distilled water, vortex and completely dissolve them, and then use a 90Plus PALS particle size analyzer (Brookhaven Instruments, USA) to measure the particle size distribution of the microspheres. The results show that the particle size of the rapamycin microspheres is 763.67 nm and the PDI index is 0.341.

[0089] The morphology and particle size distribution of the rapamycin microspheres prepared in Example 6 were studied:

[0090] (1) Morphological observation using a transmission electron microscope (TEM). Scrape an appropriate amount of rapamycin microspheres from aluminum foil and fully disperse them in pure water. Pipette them with a micropipette and drop them on a carbon film copper grid. Stain them with phosphomolybdic acid for 30 seconds. Then dry the sample under an infrared lamp. The process from dispersion to drying takes about 30 minutes. Push the sample into the sample rod and use TEM to observe the morphological characteristics of the sample. The results are shown in Figure 3 As can be seen from the figure, the microspheres are unevenly distributed, but the microspheres are in a relatively regular round particle shape. Sodium hyaluronate can form a shell to wrap the microspheres, but there is adhesion between the microspheres, and unevenly dispersed sodium hyaluronate can be seen around the microspheres. The particle size of the microspheres is 800-1000nm.

[0091] (2) Morphological observation using scanning electron microscopy (SEM). Scrape an appropriate amount of rapamycin microspheres from aluminum foil and place them on a sample holder. Use conductive glue to fix them on a sample plate. Use SEM to observe their surface morphology under vacuum conditions. The results are shown in Figure 4 As can be seen from the figure, the microsphere particles are unevenly distributed, the microsphere particle size is extremely uneven, and there is obvious adhesion between the microspheres. The particle size is 800-2500nm.

[0092] (3) Particle size distribution. Take an appropriate amount of rapamycin microspheres, add an appropriate amount of distilled water, vortex and completely dissolve them, and then use a 90Plus PALS particle size analyzer (Brookhaven Instruments, USA) to measure the particle size distribution of the microspheres. The results show that the particle size of the rapamycin microspheres is 1143.64 nm and the PDI index is 0.286.

[0093] The morphology and particle size distribution of the rapamycin microspheres prepared in Example 8 were studied:

[0094] (1) Morphological observation using a transmission electron microscope (TEM). Scrape an appropriate amount of rapamycin microspheres from aluminum foil and fully disperse them in pure water. Pipette them with a micropipette and drop them on a carbon film copper grid. Stain them with phosphomolybdic acid for 30 seconds. Then dry the sample under an infrared lamp. The process from dispersion to drying takes about 30 minutes. Push the sample into the sample rod and use TEM to observe the morphological characteristics of the sample. The results are shown in Figure 5 As can be seen from the figure, the microspheres are evenly distributed and are in the form of spherical particles. The surface of the microspheres is coated with a sodium hyaluronate layer, and the particle size is 300-400nm.

[0095] (2) Morphological observation using scanning electron microscopy (SEM). Scrape an appropriate amount of rapamycin microspheres from aluminum foil and place them on a sample holder. Use conductive glue to fix them on a sample plate. Use SEM to observe their surface morphology under vacuum conditions. The results are shown in Figure 6 As can be seen from the figure, the microspheres are evenly distributed and are in the form of regular spherical particles. The microspheres are slightly adhered to each other, and the particle size is 300-400nm.

[0096] (3) Particle size distribution. Take an appropriate amount of rapamycin microspheres, add an appropriate amount of distilled water, vortex and completely dissolve them, and then use a 90Plus PALS particle size analyzer (Brookhaven Instruments, USA) to measure the particle size distribution of the microspheres. Figure 7The results showed that the particle size of the rapamycin microspheres was 436.28 nm and the PDI was 0.238.

[0097] Study on the morphology and particle size distribution of rapamycin microspheres prepared in Example 9:

[0098] (1) Morphological observation using scanning electron microscopy (SEM). Scrape an appropriate amount of rapamycin microspheres from aluminum foil and place them on a sample holder. Use conductive glue to fix them on a sample plate. Use SEM to observe their surface morphology under vacuum conditions. The results are shown in Figure 8 As can be seen from the figure, the microspheres are evenly distributed, but some are spherical particles, some are long strips, and there is a slight adhesion between the microspheres. The particle size is 300-800nm.

[0099] (2) Particle size distribution. Take an appropriate amount of rapamycin microspheres, add an appropriate amount of distilled water, vortex and completely dissolve them, and then use a 90Plus PALS particle size analyzer (Brookhaven Instruments, USA) to measure the particle size distribution of the microspheres. The results show that the particle size of the rapamycin microspheres is 791.64 nm and the PDI is 0.361.

[0100] Study on the morphology and particle size distribution of rapamycin microspheres prepared in Example 10:

[0101] (1) Morphological observation using scanning electron microscopy (SEM). Scrape an appropriate amount of rapamycin microspheres from aluminum foil and place them on a sample holder. Use conductive glue to fix them on a sample plate. Use SEM to observe their surface morphology under vacuum conditions. The results are shown in Fig. 9 As can be seen from the figure, the microspheres are evenly distributed and are in the form of regular spherical particles. The microspheres are slightly adhered to each other, and the particle size is 400-900nm.

[0102] (2) Particle size distribution. Take an appropriate amount of rapamycin microspheres, add an appropriate amount of distilled water, vortex and completely dissolve them, and then use a 90Plus PALS particle size analyzer (Brookhaven Instruments, USA) to measure the particle size distribution of the microspheres. The results show that the particle size of the rapamycin microspheres is 847.20 nm and the PDI is 0.281.

[0103] The drug loading and encapsulation efficiency of Example 8 were measured:

[0104] After spraying all the electrostatic spray microsphere working fluid, the drug-containing part of the front end of the balloon was placed in 2 mL of water to dissolve. Ultrasound was used to accelerate the dissolution process. After the sample was completely dissolved, 1 mL of acetonitrile was added at a ratio of 1:1 to break the emulsion. After vortexing for 30 seconds, a 0.45 μm nylon organic membrane was obtained to obtain sample 1. Another 1 mL was centrifuged at 8000 rpm for 10 minutes, and then 1 mL of acetonitrile was added to break the emulsion at a ratio of 1:1, and a 0.45 μm nylon organic membrane was obtained to obtain sample 2. 20 μL of samples from sample 1 and sample 2 were taken and analyzed by HPLC. The drug amount measured in sample 1 was the actual drug content, and the drug amount measured in sample 2 was the actual encapsulated drug amount. The actual encapsulated drug amount was converted to the drug loading amount, and (actual encapsulated drug amount / actual drug content) × 100% was the encapsulation rate. The final measured drug loading amount was 10.1 mg / g, and the encapsulation rate was 84.2%.

[0105] The rapamycin microspheres of Example 8 were subjected to an in vitro drug release experiment:

[0106] 100mL of distilled water solution was used as the dissolution medium, the temperature was 37±0.5℃, and the speed was 100rpm. The rapamycin microspheres prepared in Example 8 were placed in the dissolution medium water and pH7.4 phosphate buffer, and 1mL of the dissolution solution was taken out at 1h, 2h, 4h, 8h (hours), 1d, 2d, 3d, 4d, 5d, 6d, and 7d (days), respectively. At the same time, an equal amount of isothermal dissolution medium was added in time, centrifuged at 8000rpm, 500μL was taken and diluted with 500μL of chromatographic acetonitrile, and 20μL of the sample was taken and analyzed by HPLC, and the cumulative release rate of the drug was calculated. The results are shown in Fig.10 As can be seen from the figure, the cumulative release rate of rapamycin microspheres in water reaches 105% in 24 hours, and then begins to slowly decrease until the cumulative release rate reaches 45%. The cumulative release rate of rapamycin microspheres in pH 7.4 phosphate buffer reaches 38% in 24 hours, then immediately decreases, and then slowly increases until it reaches 50%.

[0107] Experimental example

[0108] The drug balloons of the embodiment were implanted in New Zealand rabbits, with a total of 20 animals implanted.

[0109] Experimental group: 18 New Zealand rabbits were implanted in the bilateral iliac arteries. Each group of animals was implanted with drug balloons, and 6 rabbits were dissected immediately after surgery (0 days), 4 days after surgery, and 7 days after surgery. The drug balloons described in Examples 8-10 were implanted in the experimental group rabbits.

[0110] Control group: Two New Zealand rabbits were implanted in the bilateral iliac arteries. Two blank control balloon catheters were placed in each group of animals. One was dissected immediately after surgery and the other was dissected 7 days after surgery.

[0111] New Zealand rabbits were given intravenous heparin before surgery, and blood pressure, heart rate and other indicators were monitored. Using a guide catheter and a 0.014 guidewire, the drug balloon was delivered through the carotid artery to the target position of the iliac artery, and then the drug balloon was expanded with appropriate pressure. The pressure was maintained for 60 seconds and then the balloon pressure was withdrawn. The position of the balloon from the vascular bifurcation was recorded, and all instruments and equipment were removed from the experimental animals at the end of the operation. Immediately after surgery (0 days), 4 days after surgery, and 7 days after surgery, the New Zealand map was dissected in situ to expose the target blood vessels, and the target vascular tissue was cut 2-3 mm upstream and downstream of the surgical operation site.

[0112] After weighing the blood vessel sample, cut it into pieces and homogenize it in a ratio of tissue: 50% methanol = 1:4 (w:v). Part of the homogenate is frozen and stored below -20°C. Use a pipette to accurately transfer 20 μL of the homogenate into a 1.5mL EP tube, add 180 μL of blank matrix and mix well for use. Take 100 μL of the standard curve sample and quality control sample and add the precipitant in a ratio of sample: precipitant = 1:3 (v:v), mix well, centrifuge at 12000 rpm for 10 min at 4°C, and determine the sirolimus content (unit ng / mg) in the tissue by liquid chromatography-mass spectrometry.

[0113] Chromatographic conditions: Chromatographic column: ZORBAX Extend-C18 column, 2.1*50mm 3.5μm, flow rate: 0.9mL / min, injection volume: 20μL, column temperature: 40°C, mobile phase A: 0.1% formic acid ultrapure aqueous solution (10mmol ammonium formate), mobile phase B: 0.1% formic acid methanol solution (10mmol ammonium formate), gradient elution measurement data are shown in the table below.

[0114]

[0115]

[0116] It can be seen that the drug balloons described in Examples 8-10 can take sirolimus into the blood vessel wall and can continue to work within 7 days. The above technical effects are also applicable to other embodiments and will not be repeated here.

[0117] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the present invention. Those skilled in the art may make various modifications and variations without departing from the spirit and scope of the present invention. Such modifications and variations shall all fall within the scope defined by the appended claims.

Claims

1. A drug balloon coating solution, characterized in that: The coating liquid includes a mixed solvent system, which includes: water, ethanol and N,N-dimethylformamide (DMF); the coating liquid also includes: rapamycin raw material, drug sustained-release carrier, hydrophilic polymer material, spinning aid and drug release regulator; wherein the drug release regulator includes sodium hyaluronate (SH).

2. The coating liquid according to claim 1, characterized in that: The coating liquid comprises, by mass, rapamycin raw material: drug sustained-release carrier: hydrophilic polymer material: spinning aid: drug release regulator = 1:16:40-50:8:6-8.

3. The coating liquid according to claim 1 or 2, characterized in that: The drug sustained-release carrier comprises polylactic acid-co-glycolic acid (PLGA); Preferably, the drug sustained-release carrier comprises one or more of PLGA 75 / 25 (0.22 dl / l), PLGA 50 / 50 (0.1 dl / l), PLGA 50 / 50 (0.2 dl / l), and PLGA 50 / 50 (0.23 dl / l).

4. The coating liquid according to claim 1 or 2, characterized in that: The hydrophilic polymer material includes polyvinyl alcohol; Preferably, the hydrophilic polymer material includes polyvinyl alcohol 403 (PVA403).

5. The coating liquid according to claim 1 or 2, characterized in that: The spinning aid is polyethylene oxide (PEO); Preferably, the number average molecular weight of the polyethylene oxide (PEO) is Mn=10,000, Mn=50,000 or Mn=100,000.

6. The coating liquid according to claim 1 or 2, characterized in that: The number average molecular weight of the sodium hyaluronate (SH) is Mn=10,000, or Mn=100,000-400,000.

7. The coating liquid according to claim 1 or 2, characterized in that: The volume ratio of water, ethanol and N,N-dimethylformamide in the mixed solvent system is 2:1:

1.

8. A drug balloon coating material, characterized in that: The material comprises rapamycin sustained-release microspheres containing sodium hyaluronate, the microspheres are of a core-shell structure, the core-shell structure comprises an outer layer covering rapamycin, the outer layer comprises a sodium hyaluronate layer, and the inner core of the core-shell structure comprises rapamycin and PLGA.

9. The coating material according to claim 8, characterized in that The materials include rapamycin raw material: PLGA: sodium hyaluronate=1:16:6-8 by mass.

10. A method for preparing a drug balloon coating material, characterized in that: The method comprises the following steps: (1) adding a hydrophilic polymer material to pure water under stirring and fully dissolving it to prepare a solution ①; dissolving a drug sustained-release carrier in an organic solvent, vortexing it and then ultrasonically stirring it to fully dissolve it, then adding the rapamycin raw material, vortexing it and ultrasonically preparing a solution ②; pouring solution ② into solution ① and ultrasonically stirring it to fully emulsify it, and continuing to stir at room temperature to volatilize the organic solvent; then adding anhydrous ethanol and N,N-dimethylformamide (DMF) thereto and stirring it fully; then adding a spinning aid to the solution under stirring and stirring it fully, and after stirring it fully, adding a drug release regulator thereto, stirring it fully and then ultrasonically stirring it to make the solution uniformly dispersed, thereby obtaining a microsphere electrostatic spray working solution; wherein the drug release regulator comprises sodium hyaluronate (SH); (2) The microsphere electrostatic spray working solution is placed in a syringe and slowly discharged by a constant current pump. The solution spray rate is 0.2-0.8 mL / h and the voltage range is 10-25 KV. The solution is sprayed through the nozzle to a receiving device at a receiving distance of 10-20 cm. The powdered drug balloon coating material is collected.

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