Paclitaxel drug coating balloon dilatation catheter as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medical instruments, in particular to a paclitaxel drug coating balloon dilatation catheter and a preparation method and application thereof.The paclitaxel drug coating comprises a substrate layer, a middle layer and an outer layer; the substrate layer comprises paclitaxel and a hydrophilic excipient; the middle layer comprises a lipophilic excipient and a temperature response type polymer; and the outer layer comprises a pH sensitive polymer. The substrate layer is combined with the surface of the balloon, so that excellent conveying stability is provided, the medicine is effectively prevented from falling off prematurely in the conveying process of the catheter, and the firmness of the coating is improved; a micropore network structure is formed in the middle layer, the network structure is expanded under the body temperature condition, the porosity is increased, slow release of the medicine is achieved, the absorption amount of the medicine on the blood vessel wall is effectively increased, and the medicine effect time is prolonged; the solubility of the outer layer is improved in a slightly acidic blood vessel wall environment, so that the release of the medicine is further promoted, and the effective release of the medicine on the blood vessel wall is ensured.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, specifically to a paclitaxel-coated balloon dilation catheter, its preparation method, and its uses. Background Technology

[0002] Drug-eluting balloons are a novel intravascular drug delivery technology developed based on interventional techniques such as balloon dilation and balloon angioplasty. They involve coating the surface of a balloon with anti-proliferative drugs such as paclitaxel and rapamycin. When the balloon reaches the diseased blood vessel and expands, contacting the vessel's intima, the carried drugs are rapidly transferred to the vessel wall and remain there long-term, inhibiting intimal hyperplasia and preventing postoperative restenosis.

[0003] However, existing drug-eluting balloons still have shortcomings in terms of therapeutic efficacy and drug utilization, specifically including low drug coating adhesion, uniform drug release rate, and insufficient drug absorption by the blood vessel wall. These problems limit their application effectiveness, thus necessitating the development of novel drug coating designs to improve drug efficacy and safety. Summary of the Invention

[0004] This invention provides a paclitaxel-coated balloon dilation catheter, its preparation method, and its uses, in order to solve the problems of low drug coating adhesion, single drug release rate, and insufficient drug absorption in the blood vessel wall.

[0005] In a first aspect, the present invention provides a paclitaxel drug coating comprising: a base layer, an intermediate layer, and an outer layer; The base layer includes paclitaxel and a hydrophilic excipient; The intermediate layer comprises a lipophilic excipient and a temperature-responsive polymer; The outer layer comprises a pH-sensitive polymer.

[0006] In one optional embodiment, the hydrophilic excipient is selected from any one of polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyurethane, polyacrylic acid, and urea; preferably polyvinylpyrrolidone. In one optional embodiment, the lipophilic excipient is selected from any one of triglycerides, polylactic acid (PLA), polylactic-co-glycolic acid copolymer (PLGA), polyethylene glycol (PEG), and polycaprolactone (PCL); preferably, triglycerides. In one optional embodiment, the temperature-responsive polymer is selected from any one of poly(N-isopropylacrylamide), polyoxyethylene ether polymers, and polyethylene glycol-acrylic acid copolymer (PEG-PAA); preferably poly(N-isopropylacrylamide); In one optional embodiment, the pH-sensitive polymer is selected from any one of poly(methacrylate-co-methyl methacrylate) copolymer, amino-polyethylene glycol polyacrylate copolymer (NH2-PEG-PA), and polyhistidine (Phis); preferably poly(methacrylate-co-methyl methacrylate) copolymer.

[0007] Secondly, the present invention provides a method for preparing the above-mentioned paclitaxel drug coating, comprising the following steps: S1. Prepare the nanocrystal composite of the base layer and the mixed microemulsion of the intermediate layer respectively; S2. The nanocrystal composite and the mixed microemulsion are mixed, placed in a container carrier with a hydrophilic bottom, and dried to obtain the inner layer composite coating material; S3. Dissolve the pH-sensitive polymer in a solvent, dry it, and obtain the outer layer material; S4. Coat the surface of the outer layer material prepared in step S3 with the inner layer composite coating material prepared in step S2, and dry.

[0008] In an optional embodiment, in step S1, the preparation method of the nanocrystalline composite of the substrate layer is to mix a hydrophilic excipient with paclitaxel, add a solvent, and sonicate for 30-60 minutes with an ultrasonic power of 50-300W. In one optional embodiment, the intermediate layer mixed microemulsion is prepared by mixing a lipophilic excipient with a temperature-responsive polymer, adding a solvent and an emulsifier, and stirring at high speed for 30-60 minutes at a speed of 1000-3000 rpm.

[0009] In one optional embodiment, the solvent includes at least one selected from water, anhydrous ethanol, ethyl acetate, butyl acetate, dichloromethane, acetone, and acetonitrile. In one alternative embodiment, the emulsifier includes any one of polyvinyl alcohol, Tween 80, polyethylene glycol succinate, and polyoxyethylene polyoxypropylene ether block copolymer.

[0010] In one optional embodiment, the ratio of hydrophilic excipient, paclitaxel, and solvent in the nanocrystalline composite of the substrate layer is (3~6):(1~2.5):(50~100) (g:g:mL). In one optional embodiment, the ratio of lipophilic excipient, temperature-responsive polymer, emulsifier, and solvent in the mixed microemulsion of the intermediate layer is (1~2.5):(1~3):(0.1~0.5):(50~100) (g:g:g:mL). In one optional embodiment, in step S3, the ratio of pH-sensitive polymer to solvent is 1:(20~50) (g:mL). In one optional embodiment, the ratio of the sum of the mass of the hydrophilic excipient and paclitaxel to the sum of the mass of the lipophilic excipient, the temperature-responsive polymer, and the emulsifier in the inner composite coating material is (4~8.5):(2.1~6). In one optional embodiment, in step S4, the mass ratio of the outer layer material to the inner composite coating material is 1:(4~19) (g:g).

[0011] In one alternative embodiment, the drying includes freeze drying, vacuum drying, or spray drying; In one optional embodiment, in step S2 or S4, the product is freeze-dried at -50 to -20°C for 4 to 8 hours. In one optional embodiment, the product is vacuum dried at 50-80°C for 4-8 hours. In one optional embodiment, in step S3, spray drying is performed at 20~50°C for 1~3 seconds.

[0012] In an optional embodiment, in step S2, the nanocrystalline composite and the mixed microemulsion are mixed and placed in a container carrier with a hydrophilic bottom surface. This allows the hydrophilic portion of the nanocrystalline composite formed by the nanocrystalline composite and the mixed microemulsion to bond with the hydrophilic bottom surface, ensuring that the base layer is at the bottom and the intermediate layer is at the top. After freeze-drying and vacuum drying, an inner composite coating material with the base layer at the bottom and the intermediate layer at the top is obtained. The hydrophilic bottom surface is plasma-treated under the following conditions: oxygen flow rate (10~50 sccm), power (250~500W), time (200~400s), and vacuum degree (25~35pa).

[0013] Thirdly, the present invention provides an application of a paclitaxel-coated balloon dilation catheter or a paclitaxel-coated balloon dilation catheter prepared by the above-described preparation method in a balloon dilation catheter.

[0014] Fourthly, the present invention provides a paclitaxel-coated balloon dilation catheter, characterized in that the surface of the balloon dilation catheter is coated with the above-mentioned paclitaxel drug coating or the paclitaxel drug balloon composite coating prepared by the above-mentioned preparation method; In an optional embodiment, before coating the surface of the balloon dilation catheter with a paclitaxel drug coating, the step of performing a plasma treatment on the surface of the balloon dilation catheter is further included to bond the surface of the balloon dilation catheter with the base layer of the paclitaxel drug coating. In one optional embodiment, the coating method employs a precision spraying process to sequentially spray the solution of the base layer, the solution of the intermediate layer, and the solution of the outer layer onto the balloon dilation catheter. In one optional embodiment, the process parameters of the precision spray are as follows: a dual-channel or multi-channel ultrasonic nozzle with a nozzle diameter of 10~40μm, a spraying power of 2~10W, a flow rate of 0.3~10mL / min, a spraying temperature of 30~45℃, and a spraying pressure of 0.2~10MPa.

[0015] In an optional embodiment, before coating the surface of the balloon dilation catheter with the paclitaxel drug balloon composite coating, the step of plasma treatment of the surface of the balloon dilation catheter is further included, so that the surface of the balloon dilation catheter is bonded to the base layer of the paclitaxel drug balloon composite coating; optionally, the plasma treatment conditions are: oxygen flow rate (10~50 sccm), power (250~500W), time (200~400s), and vacuum degree (25~35pa).

[0016] In one optional embodiment, the total thickness of the paclitaxel drug coating on the surface of the balloon catheter is 5 ± 0.5 μm; In one optional embodiment, the base layer of the paclitaxel drug coating is a nanocrystalline composite formed of paclitaxel and a hydrophilic excipient, with a particle size of 500-800 nm. In one optional embodiment, the intermediate layer of the paclitaxel drug coating is prepared by a lipophilic excipient and a temperature-responsive polymer to form a microporous network structure with a pore size of 0.5~2μm; In one optional embodiment, the outer layer of the paclitaxel drug coating is obtained by spray drying a pH-sensitive polymer solution to obtain microparticles with a particle size of 1-2 μm.

[0017] The technical solution of this invention has the following advantages: 1. This invention provides a paclitaxel drug coating, comprising: a base layer, an intermediate layer, and an outer layer; the base layer comprises paclitaxel and a hydrophilic excipient; the intermediate layer comprises a lipophilic excipient and a temperature-responsive polymer; and the outer layer comprises a pH-sensitive polymer. A three-layer microstructure gradient-responsive composite coating system is employed. The base layer, comprising paclitaxel and a hydrophilic excipient, binds to the balloon surface via hydrogen bonds, providing excellent delivery stability and effectively preventing premature drug detachment during catheter delivery, thus improving the coating's adhesion. The intermediate layer, copolymerized with a lipophilic excipient and a temperature-responsive polymer, forms a microporous network structure with a pore size of 0.5-2 μm. Under body temperature conditions, the network structure expands, increasing porosity and enabling slow drug release, effectively increasing drug absorption in the blood vessel wall and prolonging the duration of action. The outer layer, formed by a pH-sensitive polymer, exhibits increased solubility in the slightly acidic environment of the blood vessel wall (pH≈6.8), further promoting drug release and ensuring effective drug release in the blood vessel wall.

[0018] 2. The method for preparing the paclitaxel drug coating provided by this invention controls the total thickness of the paclitaxel drug coating sprayed on the surface of the balloon dilation catheter to be 5±0.5μm. The balloon surface is first subjected to plasma pretreatment for hydrophilic modification and wetting, making the balloon surface easier to bond with the base layer. After drying, the composite coating is transferred to a temporary carrier membrane, covering the balloon surface with the inner layer facing outward to complete the transfer. This achieves uniformity and stability of the drug coating and improves the bonding force between the drug coating and the balloon surface. During balloon dilation, the contact area between the microstructure surface and the blood vessel wall increases, achieving a better drug adhesion rate, significantly improving the effective drug transfer efficiency, and enhancing the therapeutic effect. Attached Figure Description

[0019] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0020] Figure 1 This is a scanning electron microscope (SEM) image of the inner composite coating material in the paclitaxel drug coating prepared in Example 1 of the present invention; Figure 2 This is a scanning electron microscope (SEM) image of the paclitaxel drug coating prepared in Example 1 of the present invention; Figure 3 This is a diagram of the blood vessel model X2.4 in ASTM F2394-07 used in Experimental Examples 2-4 of this invention. Detailed Implementation

[0021] The following embodiments are provided to better understand the present invention, but the following embodiments do not constitute a limitation on the content and scope of protection of the present invention. Any product that is the same as or similar to the present invention, derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art, falls within the scope of protection of the present invention.

[0022] Unless otherwise specified, all experimental steps or conditions in the examples were performed according to conventional experimental procedures and conditions in the art. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0023] Paclitaxel was purchased from Jiangsu Taxus chinensis Pharmaceutical Co., Ltd.; triglycerides were purchased from Beijing Fengli Jingqiu Pharmaceutical Co., Ltd.; the molecular weights of polyvinylpyrrolidone (PVP) were 8000-1300000 Da; polyethylene glycol (PEG) was 2000-30000 Da; polyvinyl alcohol (PVA) was 20000-220000 Da; polyurethane (PU) was 5000-12000 Da; polyacrylic acid (PA) was 3000-10000 Da; polylactic acid (PLA) was 5000-60000 Da; polylactic acid-glycolic acid copolymer (PLGA) was 5000-30000 Da; polyethylene glycol (PEG) was 2000-30000 Da; polycaprolactone (PCL) was 1000-50000 Da; and poly(N-isopropylacrylamide) was 16... 500-300000 Da; the molecular weight of polyoxyethylene ether polymers is 5000-10000 Da; the molecular weight of polyethylene glycol-acrylic acid copolymer (PEG-PAA) is 5000-10000 Da; the molecular weight of poly(methacrylic acid-co-methyl methacrylate) copolymer is 10000-50000 Da; the molecular weight of amino polyethylene glycol polyacrylic acid copolymer (NH2-PEG-PA) is 5000-10000 Da; the molecular weight of polyhistidine (Phis) is 10000-50000 Da; the molecular weight of polyvinyl alcohol is 20000-220000 Da; the molecular weight of Tween 80 is 1309.68; the molecular weight of polyethylene glycol succinate is 400-2000 Da; the molecular weight of polyoxyethylene polyoxypropylene ether block copolymer is 5000-20000 Da.

[0024] The thickness of the paclitaxel drug coating and the pore size of the intermediate layer were detected using scanning electron microscopy and ultra-depth-of-field microscopy.

[0025] Example 1 This embodiment provides a method for preparing a paclitaxel-coated balloon dilation catheter, including the following steps: (1) Weigh 4.5g of polyvinylpyrrolidone (PVP) with a crosslinking degree of 85% and 1.75g ​​of paclitaxel respectively, mix them, add 75mL of anhydrous ethanol as solvent, and sonicate (power 200W) for 30min to obtain nanocrystalline composite with a particle size of 500~800nm. (2) Weigh 1.75g ​​of triglyceride and 2g of temperature-responsive poly(N-isopropylacrylamide) (PNIPAM) and mix them together. The transition temperature of PNIPAM is controlled at 37±0.5℃. Add 100mL of water and 0.25g of emulsifier (polyvinyl alcohol), and stir at high speed (2000rpm) for 30min to obtain a microemulsion. (3) The nanocrystal composite obtained in step (1) is added to the microemulsion obtained in step (2), and transferred to a container whose bottom surface has been plasma-treated (the plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), vacuum degree (30 Pa)). The mixture is then ultrasonically treated (power 200 W) for 15 min, freeze-dried at -50℃ for 4 h, and vacuum-dried at 50℃ for 4 h to obtain the inner composite coating material. Because the bottom surface of the container has undergone plasma pretreatment, hydrophilic modification, and wetting, it can combine with the hydrophilic substrate layer to form a substrate layer at the bottom and an intermediate layer at the top. After freeze-drying and vacuum drying, the inner composite coating material with a substrate layer at the bottom and an intermediate layer at the top is obtained, such as... Figure 1 As shown, (4) Dissolve 1g of pH-sensitive poly(methacrylic acid-co-methyl methacrylate) copolymer (pKa=5.8) in 50mL of ethyl acetate and prepare micro powder with a particle size of 1~2μm by spray drying at 35℃ (spray drying for 1~3s); (5) The 1g micro powder obtained in step (4) is uniformly coated with the 10g inner composite coating material obtained in step (3), and then freeze-dried at -20℃ for 4h and vacuum-dried at 80℃ for 8h to obtain the paclitaxel drug coating, as shown below. Figure 2 As shown in Table 1, the total coating thickness is as shown in Table 1, and the pore size of the intermediate layer is 0.5~2μm.

[0026] (6) The prepared paclitaxel drug coating is transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter undergoes plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), and vacuum degree (30 Pa).

[0027] Example 2 This embodiment provides a method for preparing a paclitaxel-coated balloon dilation catheter, including the following steps: (1) Weigh 3g of polyvinylpyrrolidone (PVP) with a crosslinking degree of 85% and 2.5g of paclitaxel respectively, mix them, add 100mL of dichloromethane as solvent, and sonicate (power 50W) for 45min to obtain nanocrystal composite with a particle size of 500~800nm. (2) Weigh 2.5g of triglyceride and mix it with 1g of temperature-responsive poly(N-isopropylacrylamide) (PNIPAM), wherein the transition temperature of PNIPAM is controlled at 37℃. Add 50mL of water and 0.1g of polyethylene glycol succinate as emulsifier, and stir at high speed (1000rpm) for 45min to obtain microemulsion. (3) Add the nanocrystal composite obtained in step (1) to the microemulsion obtained in step (2), transfer it to a container whose bottom surface has been plasma treated (the plasma treatment conditions are: oxygen flow rate (10 sccm), power (500 W), time (200 s), vacuum degree (25 Pa)), ultrasonic treatment (power 50 W) for 20 min, freeze-drying at -45℃ for 6 h, vacuum drying at 80℃ for 6 h, and obtain the inner layer composite coating material; (4) Dissolve 1g of pH-sensitive poly(methacrylic acid-co-methyl methacrylate) copolymer (pKa=5.8) in 35mL of butyl acetate, and prepare micro powder with a particle size of 1~2μm by spray drying at 20℃ (spray drying for 1~3s); (5) The 1g micro powder obtained in step (4) is uniformly covered on the surface of the 4g inner layer composite coating material obtained in step (3), and then freeze-dried at -45℃ for 6h and vacuum-dried at 65℃ for 6h to obtain the paclitaxel drug coating. The total thickness is shown in Table 1, and the pore size of the middle layer is 0.5~2μm. (6) The prepared paclitaxel drug coating is transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter undergoes plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions are: oxygen flow rate (10 sccm), power (500 W), time (200 s), and vacuum degree (25 Pa).

[0028] Example 3 This embodiment provides a method for preparing a paclitaxel-coated balloon dilation catheter, including the following steps: (1) Weigh 12g of polyvinylpyrrolidone (PVP) with a crosslinking degree of 85% and mix it with 2g of paclitaxel. Add 100mL of acetone as a solvent and sonicate (power 300W) for 60min to obtain a nanocrystal composite with a particle size of 500~800nm. (2) Weigh 2g of triglyceride and 6g of temperature-responsive poly(N-isopropylacrylamide) (PNIPAM) and mix them. The transition temperature of PNIPAM is controlled at 36.5℃. Add 150mL of water and 1g of polyoxyethylene polyoxypropylene ether block copolymer as emulsifier. Stir at high speed (3000rpm) for 60min to obtain microemulsion. (3) Add the nanocrystal composite obtained in step (1) to the microemulsion obtained in step (2), transfer it to a container whose bottom surface has been plasma treated (the plasma treatment conditions are: oxygen flow rate (50 sccm), power (250 W), time (400 s), vacuum degree (35 Pa)), ultrasonic treatment (power 300 W) for 30 min, freeze-dry at -50℃ for 8 h, and vacuum dry at 65℃ for 8 h to obtain the inner layer composite coating material; (4) 1g of pH-sensitive poly(methacrylic acid-co-methyl methacrylate) copolymer (pKa=5.8) was dissolved in 20mL of a mixed solvent of ethyl acetate and acetonitrile (7:3, v / v), and micro powder with a particle size of 1~2μm was prepared by spray drying at 50℃. (5) The 1g micro powder obtained in step (4) is uniformly covered with the 19g inner layer composite coating material obtained in step (3), and then freeze-dried at -30℃ for 8h and vacuum-dried at 65℃ for 8h to obtain the paclitaxel drug coating. The total thickness is shown in Table 1, and the pore size of the middle layer is 0.5~2μm. (6) The prepared paclitaxel drug coating is transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter undergoes plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions are: oxygen flow rate (50 sccm), power (250 W), time (400 s), and vacuum degree (35 Pa).

[0029] Example 4 This embodiment provides a method for preparing a paclitaxel-coated balloon dilation catheter, including the following steps: (1) Weigh out 4g of polyethylene glycol and 1.2g of paclitaxel respectively, mix them, add 100mL of ethyl acetate as solvent, and sonicate (power 200W) for 60min to obtain nanocrystal composite with a particle size of 500~800nm; (2) Weigh 2g of polylactic acid (PLA) and 2.5g of temperature-responsive polyoxyethylene ether polymer and mix them. The transition temperature of the polyoxyethylene ether polymer is controlled at 25℃. Add 50mL of water and 0.3g of polyethylene glycol succinate as emulsifier and stir at high speed (2000rpm) for 45min. (3) Add the nanocrystal composite obtained in step (1) to the microemulsion obtained in step (2), transfer it to a container whose bottom surface has been plasma treated (the plasma treatment conditions are: oxygen flow rate (10 sccm), power (500 W), time (200 s), vacuum degree (25 Pa)), ultrasonic treatment (power 200 W) for 20 min, freeze-dry at -30℃ for 6 h, and vacuum dry at 75℃ for 6 h to obtain the inner layer composite coating material; (4) Dissolve 1g of pH-sensitive amino-polyethylene glycol polyacrylic acid copolymer (NH2-PEG-PA) in 35mL of butyl acetate and prepare micro powder with a particle size of 1~2μm by spray drying at 45℃; (5) The 1g micro powder obtained in step (4) is uniformly covered on the surface of the 6g inner layer composite coating material obtained in step (3), and then freeze-dried at -50℃ for 6h and vacuum-dried at 65℃ for 6h to obtain the paclitaxel drug coating. The total thickness is shown in Table 1, and the pore size of the middle layer is 0.5~2μm. (6) The prepared paclitaxel drug coating is transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter undergoes plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), and vacuum degree (30 Pa).

[0030] Example 5 This embodiment provides a method for preparing a paclitaxel-coated balloon dilation catheter, including the following steps: (1) Weigh 4.5g of polyvinyl alcohol and 1.3g of paclitaxel respectively, mix them, add 80mL of dichloromethane as solvent, and sonicate (power 200W) for 45min to obtain nanocrystal composite with a particle size of 500~800nm; (2) Weigh 2g of polylactic acid-glycolic acid copolymer (PLGA) and 2.8g of polyethylene glycol-acrylic acid copolymer (PEG-PAA) and mix them. The transition temperature of polyethylene glycol-acrylic acid copolymer (PEG-PAA) is controlled at 34℃. Add 50mL of water and 0.3g of polyethylene glycol succinate as emulsifier and stir at high speed (2000rpm) for 45min. (3) Add the nanocrystal composite obtained in step (1) to the microemulsion obtained in step (2), transfer it to a container whose bottom surface has been plasma treated (the plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), vacuum degree (30 Pa)), ultrasonic treatment (power 200 W) for 20 min, freeze drying for 6 h, vacuum drying at 60 °C for 6 h, to obtain the inner layer composite coating material; (4) Dissolve 1g of pH-sensitive polyhistidine (Phis) in 35mL of butyl acetate and prepare micro powder with a particle size of 1~2μm by spray drying at 25℃; (5) The 1g micro powder obtained in step (4) is uniformly covered on the surface of the 10g inner layer composite coating material obtained in step (3), and then freeze-dried for 6h and vacuum-dried at 60℃ for 6h to obtain the paclitaxel drug coating. The total thickness is shown in Table 1, and the pore size of the middle layer is 0.5~2μm. (6) The prepared paclitaxel drug coating is transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter undergoes plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), and vacuum degree (30 Pa).

[0031] Example 6 This embodiment provides a method for preparing a paclitaxel-coated balloon dilation catheter, including the following steps: (1) Weigh 10g of polyurethane and 3g of paclitaxel respectively, mix them, add 160mL of dichloromethane as solvent, and sonicate (power 200W) for 45min to obtain a nanocrystal composite with a particle size of 500~800nm, and spray it on the balloon dilation catheter.

[0032] (2) Weigh 4.6g of polyethylene glycol (PEG) and 2g of temperature-responsive poly(N-isopropylacrylamide) (PNIPAM) and mix them. The transition temperature of PNIPAM is controlled at 37℃. Add 100mL of water and 0.6g of polyethylene glycol succinate as emulsifier. Stir at high speed (2000rpm) for 45min to obtain a microemulsion with a particle size of 1.2μm. Then spray it onto the balloon dilation catheter in step (1). (3) Dissolve 1g of pH-sensitive poly(methacrylic acid-co-methyl methacrylate) copolymer (pKa=5.8) in 35mL of butyl acetate, and then spray it onto the balloon dilation catheter of step (2); The spraying process in steps (1), (2), and (3) above is as follows: a dual-channel ultrasonic nozzle with a nozzle diameter of 10 μm, a spraying power of 5 W, a flow rate of 0.3 mL / min, a spraying temperature of 45 °C, and a spraying pressure of 10 MPa.

[0033] Example 7 This embodiment provides a method for preparing a paclitaxel-coated balloon dilatation catheter. The specific preparation steps and process parameters are the same as in Example 1, except that polyvinylpyrrolidone (PVP) with a crosslinking degree of 85% is replaced with an equal amount of polyacrylic acid; and triglycerides are replaced with an equal amount of polycaprolactone (PCL). The process is as follows: (1) Weigh 4.5g of polyacrylic acid and 1.75g ​​of paclitaxel respectively, mix them, add 75mL of anhydrous ethanol as solvent, and sonicate (power 200W) for 30min to obtain a nanocrystal composite with a particle size of 500~800nm, and spray it on the balloon dilation catheter. (2) Weigh 1.75g ​​of polycaprolactone (PCL) and 2g of temperature-responsive poly(N-isopropylacrylamide) (PNIPAM) and mix them. The transition temperature of PNIPAM is controlled at 37±0.5℃. Add 100mL of water and 0.25g of emulsifier (polyvinyl alcohol), and stir at high speed (2000rpm) for 30min to obtain a microemulsion. Then spray it onto the balloon dilation catheter in step (1). (3) Dissolve 1g of pH-sensitive poly(methacrylic acid-co-methyl methacrylate) copolymer (pKa=5.8) in 50mL of ethyl acetate, and then spray it onto the balloon dilation catheter of step (2); The spraying process in steps (1), (2), and (3) above is to use a multi-channel ultrasonic nozzle with a nozzle diameter of 40 μm, a spraying power of 2 W, a flow rate of 5 mL / min, a spraying temperature of 45 °C, and a spraying pressure of 5 MPa.

[0034] Example 8 This embodiment provides a method for preparing a paclitaxel-coated balloon dilatation catheter. The specific preparation steps and process parameters are the same as in Example 1, except that urea is used in an equal amount to replace polyvinylpyrrolidone (PVP) with a crosslinking degree of 85%. The process is as follows: (1) Weigh 4.5g of urea and 1.75g ​​of paclitaxel respectively, mix them, add 75mL of anhydrous ethanol as solvent, and sonicate (power 200W) for 30min to obtain nanocrystal composite with a particle size of 500~800nm, and spray it on the balloon dilation catheter. (2) Weigh 1.75g ​​of triglyceride and 2g of temperature-responsive poly(N-isopropylacrylamide) (PNIPAM) and mix them. The transition temperature of PNIPAM is controlled at 37±0.5℃. Add 100mL of water and 0.25g of emulsifier (polyvinyl alcohol), and stir at high speed (2000rpm) for 30min to obtain a microemulsion. Then spray it onto the balloon dilation catheter in step (1). (3) Dissolve 1g of pH-sensitive poly(methacrylic acid-co-methyl methacrylate) copolymer (pKa=5.8) in 50mL of ethyl acetate, and then spray it onto the balloon dilation catheter of step (2); The spraying process in steps (1), (2), and (3) above is as follows: a dual-channel ultrasonic nozzle with a nozzle diameter of 25 μm, a spraying power of 10 W, a flow rate of 10 mL / min, a spraying temperature of 30 °C, and a spraying pressure of 0.2 MPa.

[0035] Comparative Example 1 This comparative example provides a method for preparing a paclitaxel-coated balloon dilation catheter, which is basically similar to that of Example 1, except that step (4) is omitted. The specific steps are as follows: (1) Weigh out 9g and 3.5g of polyvinylpyrrolidone (PVP) with a crosslinking degree of 85% and paclitaxel respectively, mix them, add 150mL of anhydrous ethanol as solvent, and sonicate (power 200W) for 30min to obtain nanocrystalline composite with a particle size of 500~800nm. (2) Weigh 3.5g of triglyceride and 4g of temperature-responsive poly(N-isopropylacrylamide) (PNIPAM) and mix them together. The transition temperature of PNIPAM is controlled at 37±0.5℃. Add 200mL of water and 0.5g of emulsifier (polyvinyl alcohol), and stir at high speed (2000rpm) for 30min to obtain a microemulsion. (3) Add the nanocrystal composite obtained in step (1) to the microemulsion obtained in step (2), sonicate for 15 min, transfer to a container with a plasma-treated bottom, freeze-dry for 4 h, vacuum-dry for 4 h, and obtain the inner composite coating material. (4) The 11g inner layer composite coating material obtained in step (3) was freeze-dried for 4 hours and vacuum-dried for 8 hours to obtain the paclitaxel drug coating. (5) The prepared paclitaxel drug coating is transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter undergoes plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), and vacuum degree (30 Pa).

[0036] Comparative Example 2 This comparative example provides a method for preparing a paclitaxel-coated balloon dilation catheter, which is basically similar to that of Example 1, except that step (2) is omitted. The specific steps are as follows: (1) Weigh 9g of polyvinylpyrrolidone (PVP) with a crosslinking degree of 85% and 3.5g of paclitaxel respectively, mix them, add 150mL of anhydrous ethanol as solvent, and sonicate for 30min to obtain a nanocrystal composite with a particle size of 500~800nm. (3) The nanocrystal composite obtained in step (1) was freeze-dried at -50℃ for 4h and vacuum-dried at 50℃ for 4h to obtain the inner coating material. (3) Dissolve 1g of pH-sensitive poly(methacrylic acid-co-methyl methacrylate) copolymer (pKa=5.8) in 50mL of ethyl acetate and prepare micro powder with a particle size of 0.5-1μm by spray drying at 35℃; (4) The 1g micro powder obtained in step (3) is evenly coated with the 10g inner coating material obtained in step (3), and then freeze-dried at -20℃ for 4h and vacuum-dried at 80℃ for 8h to obtain the paclitaxel drug coating. (5) The prepared paclitaxel drug coating is transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter undergoes plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), and vacuum degree (30 Pa).

[0037] Comparative Example 3 This comparative example provides a method for preparing a paclitaxel-coated balloon dilation catheter, which is basically similar to Example 1, except that steps (2) and (4) are omitted. The specific steps are as follows: (1) Weigh 9g of polyvinylpyrrolidone (PVP) with a crosslinking degree of 85% and 3.5g of paclitaxel respectively, mix them, add 150mL of anhydrous ethanol as solvent, and sonicate (power 200W) for 30min to obtain nanocrystalline composite with a particle size of 500~800nm. (2) The prepared paclitaxel drug balloon coating was transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter underwent plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions were: oxygen flow rate (30 sccm), power (350 W), time (300 s), and vacuum degree (30 Pa).

[0038] Comparative Example 4 This comparative example provides a method for preparing a paclitaxel-coated balloon dilation catheter, comprising the following steps: (1) Weigh 13.5g of triglyceride and 5.25g of paclitaxel respectively, mix them, add 225mL of anhydrous ethanol as solvent, and sonicate for 30min to obtain the base layer solution; (2) Weigh 5.25g of polyvinylpyrrolidone (PVP) with a crosslinking degree of 85% and 6g of pH-sensitive poly(methacrylic acid-co-methyl methacrylate) copolymer (pKa=5.8) and mix them. The transition temperature of PNIPAM is controlled at 37±0.5℃. Add 300mL of water and 0.75g of emulsifier (Tween 80) and stir at high speed (2000rpm) for 30min to obtain the intermediate layer solution. (3) Add the base layer solution obtained in step (1) to the intermediate layer solution obtained in step (2), transfer it to a container whose bottom surface has been plasma treated (the plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), vacuum degree (30 Pa)), ultrasonic treatment (power 200 W) for 15 min, freeze-dry at -50℃ for 4 h, vacuum dry at 50℃ for 4 h, and obtain the inner layer composite coating material; (4) Dissolve 1g of temperature-responsive poly(N-isopropylacrylamide) (PNIPAM) in 50mL of ethyl acetate and prepare micro powder with a particle size of 0.5-1μm by spray drying at 35℃; (5) The 1g of micro powder obtained in step (4) is uniformly covered with the 10g of inner layer composite coating material obtained in step (3), and then freeze-dried at -20℃ for 4h and vacuum-dried at 80℃ for 8h to obtain an outer layer with a thickness of 2μm. (6) The prepared paclitaxel drug coating is transferred onto a temporary carrier membrane and applied to the outer wall of the plasma-treated balloon dilation catheter from the inner layer to the outer layer. Because the outer wall of the balloon dilation catheter undergoes plasma pretreatment, hydrophilic modification, and wetting, it can firmly bond with the hydrophilic substrate layer. The plasma treatment conditions are: oxygen flow rate (30 sccm), power (350 W), time (300 s), and vacuum degree (30 Pa).

[0039] Experimental Example 1 Total thickness of paclitaxel drug coating The total thickness of the paclitaxel drug coating was determined using scanning electron microscopy and ultra-depth-of-field microscopy.

[0040] Experimental Example 2 Paclitaxel drug coating adhesion test Under water bath conditions of (37±2)℃, and guided by a guidewire, the balloon catheters prepared in the examples and comparative examples were passed through a guiding catheter and a vascular model (e.g., X2.4) according to ASTM F2394-07. Figure 3 The tubing (as shown) is inserted, delivered, and withdrawn, and the withdrawn balloon is collected for drug content testing.

[0041] The adhesion is calculated by determining the drug content in the coating, as shown in the following formula: Firmness (%) = Drug content on the surface of the balloon catheter after simulated push / Initial drug content × 100%.

[0042] Experimental Example 3 Drug release rate test in paclitaxel drug coating Under water bath conditions of (37±2)℃, and guided by a guidewire, the balloon catheters prepared in the examples and comparative examples were passed through a guiding catheter and a vascular model (e.g., X2.4) according to ASTM F2394-07. Figure 3 The tubing (as shown) is inserted, delivered, expanded, depressurized, and withdrawn. The withdrawn balloon is then collected for drug content testing.

[0043] The release rate is calculated by determining the drug content in the remaining coating of the catheter, as shown in the following formula: Release rate (%) = (1 - Residual drug content on the surface of the balloon catheter after simulated use / Initial drug content) × 100%.

[0044] Experiment Example 4 Drug absorption rate test in blood vessel walls Under water bath conditions of (37±2)℃, and guided by a guidewire, the balloon catheters prepared in the examples and comparative examples were passed through a guiding catheter and a vascular model (e.g., X2.4) according to ASTM F2394-07. Figure 3 The tubing (as shown) is inserted, delivered, expanded, depressurized, and withdrawn. The withdrawn balloon is then collected for drug content testing.

[0045] The adhesion rate is calculated by determining the drug content in the vascular model, using the following formula: Adhesion rate (%) = (1 - Remaining drug content on the surface of the balloon catheter after simulated use / Initial drug content - Free drug content in the vascular model / Initial drug content) × 100%.

[0046] The test results for composite coating thickness, adhesion, drug release rate, and drug adhesion rate are shown in Table 1.

[0047] Table 1 Test Results

[0048] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A paclitaxel drug coating, characterized in that, The application relates to a paclitaxel drug coating and a preparation method thereof. The coating comprises a base layer, an intermediate layer and an outer layer. The base layer comprises paclitaxel and a hydrophilic excipient. The intermediate layer comprises a lipophilic excipient and a temperature-responsive polymer. The outer layer comprises a pH-sensitive polymer.

2. The paclitaxel drug coating of claim 1, wherein, The hydrophilic excipient is selected from any one of polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyurethane, polyacrylic acid and urea; preferably polyvinylpyrrolidone. Optionally, the lipophilic excipient is selected from any one of glycerol triacetate, polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL); preferably glycerol triacetate. Optionally, the temperature-responsive polymer is selected from any one of poly(N-isopropylacrylamide), polyoxyethylene ether polymer and polyethylene glycol-acrylic acid copolymer (PEG-PAA); preferably poly(N-isopropylacrylamide). Optionally, the pH-sensitive polymer is selected from any one of poly(methacrylic acid-co-methyl methacrylate) copolymer, amino polyethylene glycol polyacrylic acid copolymer (NH2-PEG-PA) and polyhistidine (Phis); preferably poly(methacrylic acid-co-methyl methacrylate) copolymer.

3. A method for the preparation of paclitaxel drug coating according to claim 1 or 2, characterized in that, The application further discloses a preparation method of the paclitaxel drug coating. S1. Preparing a nanocrystal composite of the base layer and a mixed microemulsion of the intermediate layer respectively; S2. Mixing the nanocrystal composite and the mixed microemulsion, placing them in a container carrier with a hydrophilic bottom surface, drying to obtain an inner layer composite coating material; S3. Dissolving the pH-sensitive polymer in a solvent, drying to obtain an outer layer material; S4. Coating the outer layer material prepared in step S3 on the surface of the inner layer composite coating material prepared in step S2, and drying.

4. The method of claim 3, wherein the paclitaxel drug coating is prepared by, In step S1, the preparation method of the nanocrystal composite of the base layer is mixing the hydrophilic excipient and paclitaxel, adding a solvent and ultrasonic treatment for 30-60 min at an ultrasonic power of 50-300 W. The preparation method of the mixed microemulsion of the intermediate layer is mixing the lipophilic excipient and the temperature-responsive polymer, adding a solvent and an emulsifier, and stirring at a high speed for 30-60 min at a rotating speed of 1000-3000 rpm.

5. The method of claim 3 or 4, wherein the paclitaxel drug coating is prepared by, The solvent comprises at least one of water, anhydrous ethanol, ethyl acetate, butyl acetate, dichloromethane, acetone and acetonitrile. The emulsifier comprises any one of polyvinyl alcohol, Tween 80, polyethylene glycol succinate and polyoxyethylene polyoxypropylene ether block copolymer.

6. The preparation method of the paclitaxel drug coating according to any one of claims 3-5, wherein In the nanocrystal composite of the base layer, the amount ratio of the hydrophilic excipient, paclitaxel and the solvent is (3-6):(1-2.5):(50-100) (g:g:mL); In the mixed microemulsion of the intermediate layer, the amount ratio of the lipophilic excipient, the temperature-responsive polymer, the emulsifier and the solvent is (1-2.5):(1-3):(0.1-0.5):(50-100) (g:g:g:mL). The ratio of the pH-sensitive polymer to the solvent in the step S3 is 1: (20-50) (g:mL); The ratio of the sum of the mass of the hydrophilic excipient and the paclitaxel to the sum of the mass of the lipophilic excipient, the temperature-responsive polymer and the emulsifier in the inner layer composite coating material is (4-8.5):(2.1-6); The mass ratio of the outer layer material to the inner layer composite coating material in the step S4 is 1: (4-19) (g:g).

7. The method of claim 3 or 4, wherein the paclitaxel drug coating is prepared by, The drying includes freeze drying, vacuum drying or spray drying; Optionally, in the step S2 or S4, the freeze drying is performed at -50--20℃ for 4-8h; and / or, the vacuum drying is performed at 50-80℃ for 4-8h; Optionally, in the step S3, the spray drying is performed at 20-50℃ for 1-3s.

8. A use of the paclitaxel drug coating balloon dilatation catheter of claim 1 or 2 or prepared by the preparation method of any one of claims 3-7 in a balloon dilatation catheter.

9. A paclitaxel drug coated balloon dilatation catheter characterized by, coating balloon dilatation catheter of claim 1 or 2 or prepared by the preparation method of claims 3-7 on the surface of a balloon dilatation catheter; Optionally, before the coating of the paclitaxel drug coating on the surface of the balloon dilatation catheter, the method further comprises a step of performing plasma treatment on the surface of the balloon dilatation catheter to bond the surface of the balloon dilatation catheter with the base layer of the paclitaxel drug coating; Optionally, the coating method uses a precision spraying process to sequentially spray the solution of the base layer, the solution of the intermediate layer and the solution of the outer layer onto the balloon dilatation catheter. Optionally, the process parameters of the precision spraying are as follows: an ultrasonic nozzle with double flow channels or multiple flow channels is used, the nozzle diameter is 10-40μm, the spraying power is 2-10W, the flow rate is 0.3-10mL / min, the spraying temperature is 30-45℃ and the spraying pressure is 0.2-10MPa.

10. The paclitaxel drug coated balloon dilatation catheter of claim 9, wherein, The total thickness of the paclitaxel drug coating coated on the surface of the balloon catheter is 5±0.5μm; Optionally, the base layer of the paclitaxel drug coating is formed of nanocrystal composites of paclitaxel and a hydrophilic excipient, and the particle size is 500-800nm; Optionally, the intermediate layer of the paclitaxel drug coating is formed of a microporous network structure prepared from a lipophilic excipient and a temperature-responsive polymer, and the pore size is 0.5-2μm; Optionally, the outer layer of the paclitaxel drug coating is formed of a pH-sensitive polymer solution after spray drying, and the particle size of the micropowder is 1-2μm.

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