A transdermal patch for non-steroidal anti-inflammatory drugs and its preparation process

Abstract

The present invention discloses a non-steroidal anti-inflammatory drug transdermal patch, which comprises a backing layer, a plaster layer and a release liner. The raw materials of the plaster layer are: indomethacin, amphiphilic cholesterol derivatives, isopropyl myristate, menthol, modified polyacrylate adhesive solution, tackifier, crosslinking agent, main drug solvent, wherein the modified polyacrylate adhesive solution uses ethyl acetate as a reaction solvent, and polyethylene glycol and zinc-based zeolitic imidazolate framework materials are respectively introduced during the polymerization of isooctyl acrylate, methyl acrylate and dimethylaminoethyl methacrylate; the present invention also discloses a preparation process of the non-steroidal anti-inflammatory drug transdermal patch. The non-steroidal anti-inflammatory drug transdermal patch of the present invention has air permeability, moderate adhesion, no skin irritation, can be administered locally, has a high transdermal permeation amount and a low residual drug amount, helps to improve the bioavailability and efficacy of the drug, and reduces the number of drug administrations and the drug dosage.

Description

Technical Field

[0001] The present invention belongs to the technical field of transdermal patches, and particularly relates to a non-steroidal anti-inflammatory drug transdermal patch and its preparation process. Background Art

[0002] Indomethacin, namely 2-methyl-1-(4-chlorobenzoyl)-5-methoxy-1H-indole-3-acetic acid, is a non-steroidal anti-inflammatory drug and belongs to the second category of "low solubility and high permeability" in the biopharmaceutics classification system. Indomethacin reduces the synthesis of prostaglandins by inhibiting cyclooxygenase, and stops the formation of pain nerve impulses in inflammatory tissues, thereby exerting antipyretic, anti-inflammatory, and analgesic effects. Indomethacin has many adverse reactions, especially gastrointestinal system irritation and tissue damage are the most common. In order to reduce the toxic and side effects of its oral administration, indomethacin is made into a topical preparation, and the local drug concentration is increased through transdermal administration.

[0003] Traditional transdermal drug delivery often has the following problems: poor transdermal absorption of the main drug, insufficient water resistance and adhesiveness of the drug-loading matrix. For indomethacin, in order to solve the problem of main drug absorption, a patent with the publication number CN102526001B discloses a transdermal patch of indomethacin salt, which includes a backing layer, a drug reservoir and a release liner. The drug reservoir includes the main drug indomethacin salt, a pressure-sensitive adhesive, and a transdermal absorption promoter. The indomethacin salt is formed by dispersing indomethacin and an organic amine in acetone, followed by mixing and crystallization; this method effectively improves its transdermal permeation amount by forming a salt of indomethacin, but the crystalline salt precipitated by indomethacin and the organic amine in the acetone system is unstable, and it is easy to separate different acid-base free states in the solution. Moreover, indomethacin and acetone will produce a metastable crystalline solvate, which affects the stability of the product quality. At the same time, the yield of the improved main drug is not high, resulting in waste of indomethacin. In order to solve the problems of water resistance and adhesion of the drug-loading matrix, a patent with the publication number CN114106746B discloses a mesoporous silica-modified pressure-sensitive adhesive, which is made of mesoporous silica nanoparticles, modified mesoporous silica nanoparticles, soft monomers, hard monomers, functional monomers, initiators and solvents. The modified mesoporous silica nanoparticles are obtained by surface treatment of mesoporous silica nanoparticles with hexamethyldisilazane. This mesoporous silica-modified pressure-sensitive adhesive can be used to prepare indomethacin transdermal patches; the pressure-sensitive adhesive prepared by this patent has improved bonding performance, good water resistance, high peel strength, low water absorption rate, and high air permeability, but this pressure-sensitive adhesive has a high retardation effect on indomethacin and a low drug release rate (70% released in 3 days).

[0004] Therefore, on the basis of not changing the chemical structure and pharmacological activity of indomethacin, how to overcome the deficiencies of the pressure-sensitive adhesive, improve the stability of drug release and the transdermal penetration rate still needs to be studied and solved. Summary of the Invention

[0005] Based on the deficiencies of the prior art, the present invention provides a transdermal patch for non-steroidal anti-inflammatory drugs. By introducing polyethylene glycol and zinc-based zeolitic imidazolate framework material during the preparation process of the polyacrylate adhesive solution, and then combining with a tackifier and a cross-linking agent as the drug-loading matrix of the patch, the bonding performance and drug controlled-release effect of the transdermal patch are improved. And through the compounding of amphiphilic cholesterol derivatives, isopropyl myristate and menthol, the transdermal permeability of indomethacin is increased; the present invention also discloses the preparation process of the transdermal patch for non-steroidal anti-inflammatory drugs.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] A transdermal patch for non-steroidal anti-inflammatory drugs, comprising a backing layer, a plaster layer and a release liner. The plaster layer is made of the following raw materials in parts by weight: 3-12 parts of indomethacin, 12-36 parts of amphiphilic cholesterol derivatives, 10-20 parts of isopropyl myristate, 8-15 parts of menthol, 180-240 parts of modified polyacrylate adhesive solution, 10-40 parts of tackifier, 1-3 parts of cross-linking agent, and 80-180 parts of main drug solvent;

[0008] The modified polyacrylate adhesive solution is prepared by the following steps:

[0009] Disperse isooctyl acrylate, methyl acrylate, and dimethylaminoethyl methacrylate in ethyl acetate to obtain a monomer solution; disperse the zinc-based zeolitic imidazolate framework material in ethyl acetate to obtain a metal-organic solution; under nitrogen protection, add polyethylene glycol to the monomer solution, stir and mix evenly, heat up to 70-80 °C, add an initiator, stir and react for 6-8 h, cool down to 40-50 °C, add the metal-organic solution, stir for 1-2 h, and cool to room temperature to obtain it; wherein, the mass ratio of isooctyl acrylate, methyl acrylate, dimethylaminoethyl methacrylate, polyethylene glycol and zinc-based zeolitic imidazolate framework material is 60:(36-38):(2-4):(8-12):(1-2), the mass fraction of isooctyl acrylate in the monomer solution is 30-40%, and the mass fraction of zinc-based zeolitic imidazolate framework material in the metal-organic solution is 10-15%.

[0010] In the present invention, isooctyl acrylate is selected as the hard monomer, methyl acrylate as the soft monomer, and dimethylaminoethyl methacrylate as the functional monomer. The introduction of amino groups can increase the crosslinking density, thereby enhancing the cohesive strength, improving the adhesion performance, and avoiding the residue of the skin patch on the skin surface due to insufficient cohesive force. The introduction of hydrophilic polyethylene glycol can improve the fluidity of the polymerization system, contribute to the uniform composition of the modified polyacrylate adhesive solution, and form a polyacrylate-polyethylene glycol interpenetrating network structure, improving the wettability of the plaster layer on the surface of the adherend and skin affinity. The introduction of a zinc-based zeolitic imidazolate framework material with good compatibility with the polymer can stabilize the three-dimensional network of the polymer, and the structure and active sites of the zinc-based zeolitic imidazolate framework material itself can not only enhance the permeability and mechanical stability of the plaster layer, but also form an inclusion complex with the drug. By introducing polyethylene glycol and zinc-based zeolitic imidazolate framework material during the polymerization of polyacrylate monomers, the controlled release of the drug is achieved. By adding tackifiers and crosslinking agents, the cohesive force of the plaster layer can be further improved, which helps to enhance the holding viscosity and reduce the decrease in the initial viscosity. The amphiphilic cholesterol derivative synergistically promotes the transdermal release of indomethacin with isopropyl myristate and menthol, increases the transdermal permeation amount of indomethacin, reduces drug waste, and helps to improve the drug absorption effect. The transdermal patch prepared by the reasonable compounding of each raw material in the present invention has good adhesion and antibacterial properties, low retardation to indomethacin, and high drug release rate.

[0011] In order to stably polymerize the polyacrylate monomer, when preparing the modified polyacrylate adhesive solution, azobisisobutyronitrile is selected as the initiator, and the dosage of the initiator is 0.5-0.6% of the mass of the monomer solution. In order to optimize the performance of the modified polyacrylate adhesive solution, the zinc-based zeolitic imidazolate framework material is prepared by the following steps: using zinc nitrate hexahydrate as the zinc source, imidazole or imidazole derivative as the organic ligand, and methanol as the reaction medium. The zinc source and the organic ligand are dispersed in the reaction medium, stirred for 16-24 h, then solid-liquid separated, and the solid is taken, washed and dried to obtain; wherein, the molar ratio of the zinc source to the organic ligand is 1:7-12.

[0012] In order to promote the transdermal permeation amount of indomethacin, an amphiphilic cholesterol derivative is used to improve the amphiphilicity of indomethacin. The structural formula of the amphiphilic cholesterol derivative is:

[0013]

[0014] An ester group and a quaternary ammonium salt group are introduced into the structure of the amphiphilic cholesterol derivative, which not only makes the amphiphilic cholesterol derivative have certain hydrophilicity, contributing to transdermal absorption, but also makes the amphiphilic cholesterol derivative carry a positive charge, improving the antibacterial property of the plaster layer and at the same time helping to enhance the penetration power to the skin.

[0015] The amphiphilic cholesterol derivative is prepared by the following steps:

[0016] (1) Cholesterol is dispersed in tetrahydrofuran. Under a nitrogen atmosphere, potassium hydroxide and 4-bromobutyric acid are successively added. The temperature is raised to 70 - 80 °C, and after stirring and refluxing for 16 - 24 h, it is cooled to room temperature. After filtration, the filtrate is taken, concentrated, dispersed in dichloromethane, an aqueous KHCO3 solution is added and stirred, the organic phase is separated, an aqueous HCl solution is added and stirred, the organic phase is separated, concentrated and dried to obtain Intermediate 1. The structural formula of Intermediate 1 is:

[0017]

[0018] (2) 1,3-Dichloropropanol is dispersed in tetrahydrofuran. Under a nitrogen atmosphere, sulfuric acid and Intermediate 1 are successively added, and the temperature is raised to 55 - 65 °C. After stirring and reacting for 4 - 6 h, it is cooled to room temperature. After concentration, it is dispersed in dichloromethane, an aqueous KHCO3 solution is added and stirred, the organic phase is separated, concentrated and dried to obtain Intermediate 2. The structural formula of Intermediate 2 is:

[0019]

[0020] (3) Under a nitrogen atmosphere, triethylamine and Intermediate 2 are dispersed in ethanol, potassium iodide is added, the temperature is raised to 60 - 70 °C, stirred and reacted for 6 - 10 h, cooled to room temperature, concentrated, dispersed in dichloromethane, saturated brine is added and stirred, the organic phase is separated, pure water is added and stirred, the organic phase is separated, concentrated and dried to obtain the product.

[0021] The synthetic route of the above amphiphilic cholesterol derivative is as follows:

[0022]

[0023] To ensure the product yield of the above synthetic reaction, in step (1), the molar ratio of cholesterol, 4-bromobutyric acid and potassium hydroxide is 1:(3 - 5):(3 - 4), and the addition amount of cholesterol in tetrahydrofuran is 0.3 - 0.4 mol / L; in step (2), the molar ratio of Intermediate 1, 1,3-dichloropropanol and sulfuric acid is 1:(2 - 3):(0.8 - 1.4), and the addition amount of 1,3-dichloropropanol in tetrahydrofuran is 0.6 - 1.2 mol / L; in step (3), the molar ratio of Intermediate 2, triethylamine and potassium iodide is 1:(2.2 - 2.5):(0.3 - 0.4), and the addition amount of triethylamine in ethanol is 0.6 - 1.0 mol / L; the pH of the aqueous HCl solution in step (1) is 3 - 4, and the concentration of the aqueous KHCO3 solution in steps (1) and (2) is 0.8 - 1.2 mol / L.

[0024] To ensure the adhesion performance of the non-steroidal anti-inflammatory transdermal patch, the tackifier is selected as terpene resin; the crosslinking agent is selected as butyl titanate.

[0025] To ensure the uniform dispersion of indomethacin in the non-steroidal anti-inflammatory transdermal patch, the main drug solvent is selected as a mixed solution of methanol, ethanol and ethyl acetate, and the volume ratio of methanol, ethanol and ethyl acetate is (1-2):(0.6-1):1.

[0026] To obtain a transparent patch and be suitable for the patch for relieving local pain, both the backing layer and the anti-adhesive layer are made of polyester film. The thickness of the backing layer is 20-100 μm, and the thickness of the anti-adhesive layer is 30-120 μm. The content of the plaster layer in the non-steroidal anti-inflammatory transdermal patch is 9.9-10.9 mg / cm 2 。

[0027] The preparation method of the non-steroidal anti-inflammatory transdermal patch includes the following steps:

[0028] S1. Prepare each raw material by weight; add indomethacin and amphiphilic cholesterol derivatives to the main drug solvent, and stir for 20-40 min to obtain a drug-loaded solution; add the crosslinking agent to the modified polyacrylate adhesive solution, and stir for 40-80 min to obtain a matrix adhesive solution;

[0029] S2. Add the drug-loaded solution to the matrix adhesive solution, stir for 80-120 min, then add isopropyl myristate and menthol, stir for 60-80 min, and then add the tackifier, and continue to stir for 60-90 min to obtain a drug-containing adhesive paste;

[0030] S3. After removing air bubbles from the drug-containing adhesive paste under vacuum, uniformly coat it on the anti-adhesive layer, dry it at 60-120 °C to form a plaster layer, laminate the backing layer on the plaster layer, and wind it up to obtain a patch roll;

[0031] S4. Punch holes and slice the patch roll to obtain the non-steroidal anti-inflammatory transdermal patch.

[0032] The non-steroidal anti-inflammatory transdermal patch prepared by the present invention has the following characteristics:

[0033] (1) It is transparent, odorless, non-irritating to the skin, has good flexibility, air permeability, moderate adhesion and long-lasting application;

[0034] (2) The preparation process is simple, the cost is low, and there is no pollution; when used, it can be directly applied to the affected area to relieve local pain and has a rapid onset;

[0035] (3) Indomethacin can be continuously and stably released from the plaster layer within 12 hours, has a high percutaneous permeation amount and a low residual drug amount, and is used once a day, reducing the number of drug administrations and the drug dosage. Specific Embodiments

[0036] To make the technical objectives, technical solutions, and beneficial effects of the present invention clearer, the following further illustrates the technical solutions of the present invention in conjunction with specific embodiments. However, the embodiments are intended to explain the present invention and should not be construed as limiting the present invention. For those without specific technologies or conditions noted in the embodiments, they shall be carried out according to the technologies or conditions described in the literature in this field or according to the product specifications.

[0037] All raw materials used in the following embodiments are ordinary commercially available products. Among them, the backing layer and the anti-sticking layer are both made of transparent polyester film (TPEE breathable film, hydrophobic, dust-proof, breathable and moisture-permeable). The thickness of the backing layer is 40μm, and the thickness of the anti-sticking layer is 60μm; the terpene resin is purchased from Shenzhen Yoshida Chemical Co., Ltd., with the model T-100.

[0038] A non-steroidal anti-inflammatory drug transdermal patch includes a backing layer, a plaster layer, and an anti-sticking layer. The plaster layer is made of the following raw materials in parts by weight: 3 - 12 parts of indomethacin, 12 - 36 parts of amphiphilic cholesterol derivative, 10 - 20 parts of isopropyl myristate, 8 - 15 parts of menthol, 180 - 240 parts of modified polyacrylate adhesive solution, 10 - 40 parts of terpene resin, 1 - 3 parts of tetrabutyl titanate, and 80 - 180 parts of the main drug solvent (a mixture of methanol, ethanol, and ethyl acetate in a volume ratio of (1 - 2):(0.6 - 1):1).

[0039] The amphiphilic cholesterol derivative is prepared by the following steps:

[0040] (1) Cholesterol is dispersed in tetrahydrofuran. Under a nitrogen atmosphere, ground potassium hydroxide and 4-bromobutyric acid are sequentially added. The temperature is raised to 70 - 80°C, and after stirring and refluxing for 16 - 24 hours, it is cooled to room temperature. After filtration, the filtrate is taken, concentrated, dispersed in dichloromethane, 1mol / L aqueous KHCO3 solution is added and stirred, the organic phase is separated, then an aqueous HCl solution with a pH of 3 - 4 is added and stirred, the organic phase is separated, concentrated, and dried to obtain intermediate 1; among them, the molar ratio of cholesterol, 4-bromobutyric acid, and potassium hydroxide is 1:(3 - 5):(3 - 4), and the addition amount of cholesterol in tetrahydrofuran is 0.3 - 0.4mol / L;

[0041] (2) 1,3 - dichloropropanol is dispersed in tetrahydrofuran. Under a nitrogen atmosphere, sulfuric acid and intermediate 1 are added successively, and the temperature is raised to 55 - 65 °C. After stirring and reacting for 4 - 6 h, it is cooled to room temperature. After concentration, it is dispersed in dichloromethane. 1 mol / L aqueous solution of KHCO3 is added and stirred. The organic phase is separated, concentrated and dried to obtain intermediate 2. Among them, the molar ratio of intermediate 1, 1,3 - dichloropropanol and sulfuric acid is 1:(2 - 3):(0.8 - 1.4), and the addition amount of 1,3 - dichloropropanol in tetrahydrofuran is 0.6 - 1.2 mol / L;

[0042] (3) Under a nitrogen atmosphere, triethylamine and intermediate 2 are dispersed in ethanol, potassium iodide is added, and the temperature is raised to 60 - 70 °C. After stirring and reacting for 6 - 10 h, it is cooled to room temperature. After concentration, it is dispersed in dichloromethane. Saturated brine is added and stirred. The organic phase is separated, pure water is added and stirred, and the organic phase is separated. After concentration and drying, the amphiphilic cholesterol derivative is obtained. Among them, the molar ratio of intermediate 2, triethylamine and potassium iodide is 1:(2.2 - 2.5):(0.3 - 0.4), and the addition amount of triethylamine in ethanol is 0.6 - 1.2 mol / L.

[0043] The modified polyacrylate adhesive solution is prepared by the following steps:

[0044] 1) Isooctyl acrylate, methyl acrylate, and dimethylaminoethyl methacrylate are dispersed in ethyl acetate according to the mass ratio of 60:(36 - 38):(2 - 4) to obtain a monomer solution, and the mass fraction of isooctyl acrylate in the monomer solution is 30 - 40%;

[0045] 2) Using zinc nitrate hexahydrate as the zinc source, imidazole or an imidazole derivative as the organic ligand, and methanol as the reaction medium, the zinc source and the organic ligand are dispersed in the reaction medium according to a molar ratio of 1:7 - 12, stirred for 16 - 24 h, and then solid - liquid separated. The solid is washed and dried to obtain a zinc - based zeolitic imidazolate framework material. The zinc - based zeolitic imidazolate framework material is dispersed in ethyl acetate to obtain a metal - organic solution (the mass fraction of the zinc - based zeolitic imidazolate framework material is 10 - 15%);

[0046] 3) Under nitrogen protection, polyethylene glycol (the mass ratio of isooctyl acrylate to polyethylene glycol is 60:(8 - 12)) is added to the monomer solution, stirred and mixed evenly, the temperature is raised to 70 - 80 °C, azobisisobutyronitrile (the dosage is 0.5 - 0.6% of the mass of the monomer solution) is added, stirred and reacted for 6 - 8 h, the temperature is lowered to 40 - 50 °C, the metal - organic solution (the mass ratio of isooctyl acrylate to the zinc - based zeolitic imidazolate framework material is 60:(1 - 2)) is added, stirred for 1 - 2 h, and cooled to room temperature to obtain the product.

[0047] The preparation method of the non-steroidal anti-inflammatory drug transdermal patch comprises the following steps:

[0048] S1. Prepare each raw material by weight; add indomethacin and the amphiphilic cholesterol derivative into the main drug solvent, and stir for 20 - 40 min to obtain the drug-loaded solution; add the cross-linking agent into the modified polyacrylate adhesive solution, and stir for 40 - 80 min to obtain the matrix adhesive solution;

[0049] S2. Add the drug-loaded solution into the matrix adhesive solution, stir for 80 - 120 min, then add isopropyl myristate and menthol, stir for 60 - 80 min, and then add the tackifier, and continue to stir for 60 - 90 min to obtain the medicated adhesive paste;

[0050] S3. After removing air bubbles from the medicated adhesive paste under vacuum, uniformly coat it on the anti-adhesive layer, dry it at 60 - 120 °C to form a plaster layer, laminate the backing layer on the plaster layer, and wind it up to obtain a patch roll;

[0051] S4. Punch holes and slice the patch roll to obtain the non-steroidal anti-inflammatory drug transdermal patch, and the content of the plaster layer is 9.9 - 10.9 mg / cm 2 .

[0052] Example 1

[0053] An amphiphilic cholesterol derivative is prepared by the following steps:

[0054] (1) Disperse cholesterol (6.5 g, 16.81 mmol) in 50 mL of tetrahydrofuran. Under a nitrogen atmosphere, sequentially add ground potassium hydroxide (3.3 g, 58.82 mmol) and 4-bromobutyric acid (11.23 g, 67.24 mmol), heat up to 75 °C, stir and reflux for 20 h, then cool to room temperature, filter, take the filtrate, concentrate it, disperse it in 50 mL of dichloromethane, add 50 mL of 1 mol / L KHCO3 aqueous solution and stir for 1 min, separate the organic phase, then add 50 mL of HCl aqueous solution with a pH of 3 - 4 and stir for 1 min, separate the organic phase, concentrate it under reduced pressure and dry it under vacuum to obtain Intermediate 1;

[0055] (2) Disperse 1,3-dichloropropanol (5.16 g, 40.0 mmol) in 50 mL of tetrahydrofuran. Under a nitrogen atmosphere, sequentially add sulfuric acid (1.57 g, 16.0 mmol) and Intermediate 1 (7.56 g, 16.0 mmol), and heat up to 55 - 65 °C, stir and react for 4 - 6 h, then cool to room temperature, concentrate it, disperse it in 50 mL of dichloromethane, add 32 mL of 1 mol / L KHCO3 aqueous solution and stir for 1 min, separate the organic phase, concentrate it under reduced pressure and dry it under vacuum to obtain Intermediate 2;

[0056] (3) Under a nitrogen atmosphere, triethylamine (3.64 g, 36.0 mmol) and intermediate 2 (8.76 g, 15.0 mmol) were dispersed in 50 mL of ethanol, potassium iodide (0.9 g, 5.5 mmol) was added, the temperature was raised to 60 - 70 °C, and the mixture was stirred and reacted for 6 - 10 h. After cooling to room temperature, it was concentrated and then dispersed in 50 mL of dichloromethane. 20 mL of saturated brine was added and stirred for 1 min. The organic phase was separated, 50 mL of pure water was added and stirred for 1 min (the pure water can be added in two portions, separating the organic phase after the first addition and then adding the second portion), the organic phase was separated, and after concentration under reduced pressure and vacuum drying, the amphiphilic cholesterol derivative was obtained.

[0057] Example 2

[0058] A modified polyacrylate adhesive solution was prepared by the following steps:

[0059] 1) Isooctyl acrylate, methyl acrylate, and dimethylaminoethyl methacrylate were dispersed in ethyl acetate according to a mass ratio of 60:37:3 to obtain a monomer solution, and the mass fraction of isooctyl acrylate in the monomer solution was 35%;

[0060] 2) Using zinc nitrate hexahydrate as the zinc source, imidazole or an imidazole derivative as the organic ligand, and methanol as the reaction medium, the zinc source and the organic ligand were dispersed in the reaction medium (the concentration of the zinc source in the reaction medium was 25.21 mmol / L) according to a molar ratio of 1:8. After stirring for 18 h, solid-liquid separation was carried out. The solid was washed with methanol and vacuum dried to obtain a zinc-based zeolitic imidazolate framework material; the zinc-based zeolitic imidazolate framework material was dispersed in ethyl acetate to obtain a metal-organic solution with a mass fraction of 12%;

[0061] 3) Under nitrogen protection, polyethylene glycol (the mass ratio of isooctyl acrylate to polyethylene glycol was 60:10) was added to the monomer solution, stirred and mixed evenly, the temperature was raised to 75 °C, azobisisobutyronitrile (the dosage was 0.5% of the mass of the monomer solution) was added, and the mixture was stirred and reacted for 7 h. The temperature was lowered to 50 °C, the metal-organic solution (the mass ratio of isooctyl acrylate to the zinc-based zeolitic imidazolate framework material was 60:1.2) was added, and the mixture was stirred for 2 h. After cooling to room temperature, the product was obtained.

[0062] Example 3

[0063] A modified polyacrylate adhesive solution was prepared by the following steps:

[0064] 1) Isooctyl acrylate, methyl acrylate, and dimethylaminoethyl methacrylate were dispersed in ethyl acetate according to a mass ratio of 60:38:2 to obtain a monomer solution, and the mass fraction of isooctyl acrylate in the monomer solution was 40%;

[0065] 2) Prepare a metal-organic solution with a mass fraction of 12% according to the method in step 2) of Example 2;

[0066] 3) Under nitrogen protection, add polyethylene glycol (the mass ratio of isooctyl acrylate to polyethylene glycol is 60:8) to the monomer solution, stir and mix evenly, heat up to 75 °C, add azobisisobutyronitrile (the dosage is 0.5% of the mass of the monomer solution), stir and react for 7 h, cool down to 50 °C, add the metal-organic solution (the mass ratio of isooctyl acrylate to zinc-based zeolitic imidazolate framework material is 60:2), stir for 2 h, and cool to room temperature to obtain the product.

[0067] Example 4

[0068] A modified polyacrylate adhesive solution is prepared by the following steps:

[0069] 1) Disperse isooctyl acrylate, methyl acrylate, and dimethylaminoethyl methacrylate in ethyl acetate according to a mass ratio of 60:36:4 to obtain a monomer solution, and the mass fraction of isooctyl acrylate in the monomer solution is 30%;

[0070] 2) Prepare a metal-organic solution with a mass fraction of 12% according to the method in step 2) of Example 2;

[0071] 3) Under nitrogen protection, add polyethylene glycol (the mass ratio of isooctyl acrylate to polyethylene glycol is 60:12) to the monomer solution, stir and mix evenly, heat up to 75 °C, add azobisisobutyronitrile (the dosage is 0.5% of the mass of the monomer solution), stir and react for 7 h, cool down to 50 °C, add the metal-organic solution (the mass ratio of isooctyl acrylate to zinc-based zeolitic imidazolate framework material is 60:1), stir for 2 h, and cool to room temperature to obtain the product.

[0072] Example 5

[0073] A non-steroidal anti-inflammatory drug transdermal patch includes a backing layer, a plaster layer, and a release liner. The plaster layer is made of the following raw materials in parts by weight: 9 parts of indomethacin, 27 parts of the amphiphilic cholesterol derivative obtained in Example 1, 15 parts of isopropyl myristate, 12 parts of menthol, 210 parts of the modified polyacrylate adhesive solution obtained in Example 2, 25 parts of terpene resin, 2 parts of polybutyl titanate, and 150 parts of the main drug solvent (a mixture of methanol, ethanol, and ethyl acetate in a volume ratio of 2:1:1).

[0074] Example 6

[0075] A transdermal patch for non-steroidal anti-inflammatory drugs, comprising a backing layer, a plaster layer and a release liner. The plaster layer is made from the following raw materials in parts by weight: 9 parts of indomethacin, 18 parts of the amphiphilic cholesterol derivative obtained in Example 1, 20 parts of isopropyl myristate, 15 parts of menthol, 215 parts of the modified polyacrylate adhesive solution obtained in Example 3, 20 parts of terpene resin, 3 parts of butyl titanate, and 150 parts of the main drug solvent (a mixture of methanol, ethanol and ethyl acetate in a volume ratio of (1-2):(0.6-1):1).

[0076] Example 7

[0077] A transdermal patch for non-steroidal anti-inflammatory drugs, comprising a backing layer, a plaster layer and a release liner. The plaster layer is made from the following raw materials in parts by weight: 9 parts of indomethacin, 36 parts of the amphiphilic cholesterol derivative obtained in Example 1, 10 parts of isopropyl myristate, 8 parts of menthol, 205 parts of the modified polyacrylate adhesive solution obtained in Example 4, 30 parts of terpene resin, 2 parts of butyl titanate, and 150 parts of the main drug solvent (a mixture of methanol, ethanol and ethyl acetate in a volume ratio of 1.6:0.8:1).

[0078] The preparation method of the transdermal patch for non-steroidal anti-inflammatory drugs according to Examples 5 to 7 comprises the following steps:

[0079] S1. Prepare each raw material according to the parts by weight; add indomethacin and the amphiphilic cholesterol derivative to the main drug solvent, and stir for 30 min to obtain a drug-loaded solution; add the cross-linking agent to the modified polyacrylate adhesive solution, and stir for 60 min to obtain a matrix adhesive solution;

[0080] S2. Add the drug-loaded solution to the matrix adhesive solution, stir for 90 min, then add isopropyl myristate and menthol, stir for 60 min, and then add the tackifier, and continue to stir for 90 min to obtain a drug-containing adhesive paste;

[0081] S3. After removing air bubbles from the drug-containing adhesive paste under vacuum, uniformly coat it on the release liner, dry it at 100 °C to form a plaster layer, laminate the backing layer on the plaster layer, and wind it up to obtain a patch roll;

[0082] S4. Punch holes (punching spacing 5 mm × 5 mm) and slice the patch roll to obtain the transdermal patch for non-steroidal anti-inflammatory drugs, and the content of the plaster layer is 10.5 mg / cm 2 .

[0083] Comparative Example 1

[0084] A non-steroidal anti-inflammatory drug transdermal patch, comprising a backing layer, a plaster layer and a release liner. The plaster layer is made from the following raw materials in parts by weight: indomethacin 9 parts, isopropyl myristate 15 parts, menthol 12 parts, the modified polyacrylate adhesive solution obtained in Example 2, 210 parts, terpene resin 25 parts, tetrabutyl titanate 2 parts, main drug solvent (methanol, ethanol and ethyl acetate mixed in a volume ratio of 2:1:1) 150 parts; the preparation method of this non-steroidal anti-inflammatory drug transdermal patch is the same as that of Example 5.

[0085] Comparative Example 1 is different from Example 5 in that: the amphiphilic cholesterol derivative obtained in Example 1 is not added.

[0086] Comparative Example 2

[0087] A non-steroidal anti-inflammatory drug transdermal patch, comprising a backing layer, a plaster layer and a release liner. The plaster layer is made from the following raw materials in parts by weight: indomethacin 9 parts, the amphiphilic cholesterol derivative obtained in Example 1, 27 parts, the modified polyacrylate adhesive solution obtained in Example 2, 210 parts, terpene resin 25 parts, tetrabutyl titanate 2 parts, main drug solvent (methanol, ethanol and ethyl acetate mixed in a volume ratio of 2:1:1) 150 parts; the preparation method of this non-steroidal anti-inflammatory drug transdermal patch is the same as that of Example 5.

[0088] Comparative Example 2 is different from Example 5 in that: isopropyl myristate and menthol are not added.

[0089] Comparative Example 3

[0090] A non-steroidal anti-inflammatory drug transdermal patch, comprising a backing layer, a plaster layer and a release liner. The plaster layer is made from the following raw materials in parts by weight: indomethacin 9 parts, the amphiphilic cholesterol derivative obtained in Example 1, 27 parts, isopropyl myristate 15 parts, menthol 12 parts, polyacrylate adhesive solution 210 parts, terpene resin 25 parts, tetrabutyl titanate 2 parts, main drug solvent (methanol, ethanol and ethyl acetate mixed in a volume ratio of 2:1:1) 150 parts; the preparation method of this non-steroidal anti-inflammatory drug transdermal patch is the same as that of Example 5.

[0091] The modified polyacrylate adhesive solution described in Comparative Example 3 is prepared by the following steps:

[0092] 1) Disperse isooctyl acrylate, methyl acrylate, dimethylaminoethyl methacrylate in ethyl acetate according to a mass ratio of 60:37:3 to obtain a monomer solution, and the mass fraction of isooctyl acrylate in the monomer solution is 35%.

[0093] 2) Under nitrogen protection, polyethylene glycol (mass ratio of isooctyl acrylate to polyethylene glycol is 60:10) was added to the monomer solution, stirred and mixed evenly, heated to 75 °C, azobisisobutyronitrile (dosage is 0.5% of the mass of the monomer solution) was added, stirred and reacted for 7 h, cooled to 50 °C, stirred and reacted for 2 h, and then cooled to room temperature to obtain the product.

[0094] Comparative Example 4

[0095] A non-steroidal anti-inflammatory drug transdermal patch, comprising a backing layer, a plaster layer and a release liner. The plaster layer is made of the following raw materials in parts by weight: indomethacin 9 parts, the amphiphilic cholesterol derivative obtained in Example 1 27 parts, isopropyl myristate 15 parts, menthol 12 parts, modified polyacrylate adhesive solution 210 parts, terpene resin 25 parts, tetrabutyl titanate 2 parts, main drug solvent (methanol, ethanol and ethyl acetate are mixed according to a volume ratio of 2:1:1) 150 parts; the preparation method of this non-steroidal anti-inflammatory drug transdermal patch is the same as that of Example 5.

[0096] The modified polyacrylate adhesive solution described in Comparative Example 4 was prepared by the following steps:

[0097] 1) Isooctyl acrylate, methyl acrylate, and dimethylaminoethyl methacrylate were dispersed in ethyl acetate according to a mass ratio of 60:37:3 to obtain a monomer solution, and the mass fraction of isooctyl acrylate in the monomer solution was 35%;

[0098] 2) A metal-organic solution with a mass fraction of 12% was prepared according to the method of step 2) in Example 2;

[0099] 3) Under nitrogen protection, the monomer solution was heated to 75 °C, azobisisobutyronitrile (dosage is 0.5% of the mass of the monomer solution) was added, stirred and reacted for 7 h, cooled to 50 °C, the metal-organic solution (mass ratio of isooctyl acrylate to zinc-based zeolitic imidazolate framework material is 60:1.2) was added, stirred and reacted for 2 h, and then cooled to room temperature to obtain the product.

[0100] Comparative Example 5

[0101] A non-steroidal anti-inflammatory drug transdermal patch, comprising a backing layer, a plaster layer and a release liner. The plaster layer is made of the following raw materials in parts by weight: indomethacin 9 parts, the amphiphilic cholesterol derivative obtained in Example 1 27 parts, isopropyl myristate 15 parts, menthol 12 parts, polyacrylate adhesive solution 210 parts, terpene resin 25 parts, tetrabutyl titanate 2 parts, main drug solvent (methanol, ethanol and ethyl acetate are mixed according to a volume ratio of 2:1:1) 150 parts; the preparation method of this non-steroidal anti-inflammatory drug transdermal patch is the same as that of Example 5.

[0102] The polyacrylate adhesive solution described in Comparative Example 5 was prepared by the following steps:

[0103] 1) The isooctyl acrylate, methyl acrylate, and dimethylaminoethyl methacrylate were dispersed in ethyl acetate according to a mass ratio of 60:37:3 to obtain a monomer solution, and the mass fraction of isooctyl acrylate in the monomer solution was 35%;

[0104] 2) Under nitrogen protection, the monomer solution was heated to 75 °C, azobisisobutyronitrile (used in an amount of 0.5% of the mass of the monomer solution) was added, and the mixture was stirred and reacted for 7 h, then cooled to 50 °C and stirred and reacted for 2 h, and then cooled to room temperature to obtain the product.

[0105] Performance test:

[0106] (1) Wetting performance

[0107] Using deionized water as the test medium, the contact angles between the non-steroidal anti-inflammatory drug transdermal patches prepared in Examples 5-7 and Comparative Examples 3-5 and deionized water were measured by the droplet method. The water droplets were dropped at different positions on the surface of the plaster layer, and the average value was taken after 5 measurements. The results are shown in Table 1.

[0108] Table 1 Wetting performance of the non-steroidal anti-inflammatory drug transdermal patches described in Examples 5-7 and Comparative Examples 3-5

[0109]

[0110]

[0111] As can be seen from Table 1, during the polyacrylate polymerization process, only polyethylene glycol was introduced to improve the hydrophilicity of the transdermal patch, and only the zinc-based zeolitic imidazolate framework material was introduced to improve the hydrophobicity of the transdermal patch. When both polyethylene glycol and the zinc-based zeolitic imidazolate framework material were introduced, the wetting performance of the transdermal patch was improved, but it was not significantly hydrophilic, which contributed to the stability of the transdermal patch in a humid environment.

[0112] (2) Water vapor transmission performance

[0113] 100 mL of deionized water was placed in a 150 mL beaker (the area of the beaker mouth is S), weighed and recorded as W0. The beaker was sealed with a transdermal patch (directly cut from the patch roll, without punching) and placed in a dry constant temperature oven at 37 °C for 24 h. After taking it out, the transdermal patch was removed and weighed as W n , then the water vapor transmission rate was (W0 - W n ) / 24S, with the unit of g·m -2 ·h -1 . The non-steroidal anti-inflammatory drug transdermal patches prepared in Examples 5-7 and Comparative Examples 3-5 were tested respectively, and the results are shown in Table 2.

[0114] Table 2 Water vapor transmission performance of the non-steroidal anti-inflammatory drug transdermal patches described in Examples 5-7 and Comparative Examples 3-5

[0115] Performance indicators Example 5 Example 6 Example 7 Comparative Example 3 Comparative Example 4 Comparative Example 5 Water vapor transmission performance 22.30 20.77 21.84 12.96 7.16 2.62

[0116] As can be seen from Table 2, the introduction of polyethylene glycol and zinc-based zeolitic imidazolate framework material into the polyacrylate adhesive solution can significantly improve the water vapor permeability. Polyethylene glycol itself has good water absorption performance, but it may swell after water absorption, blocking the polymer network, so it is not conducive to long-term water vapor permeation; while the zinc-based zeolitic imidazolate framework material has a certain rigid structure, which can stabilize the polymer network, but the hydrophobicity of the polymer will hinder water vapor permeation. Through the combined action of polyethylene glycol and zinc-based zeolitic imidazolate framework material, the water vapor permeability of the transdermal patch prepared by the present invention reaches 20 g·m -2 ·h -1 or more. Coupled with the punching design, it can fully meet the requirements of body surface ventilation and moisture permeability. By improving the wetting performance and water vapor permeability, the comfort of using the transdermal patch is improved.

[0117] (3) Adhesive performance

[0118] According to the relevant regulations of the Chinese Pharmacopoeia (2015 Edition) on patches, the adhesive performance of the non-steroidal anti-inflammatory drug transdermal patches prepared in Examples 5 to 7 and Comparative Examples 3 to 5 before and after immersion in water was tested. Among them, after immersion in water means taking out after soaking in deionized water for 12 h and blotting the surface moisture with filter paper. According to GB4852-84, the initial tack was tested by the inclined plane rolling ball method. The test method was as follows: the inclined plate was inclined at 30°, the assisting rolling section was 1 cm, the adhesive surface was upward, and the largest ball number that could be adhered represented its initial tack value. According to GB4851-84, the holding tack was tested by the hanging weight method. The test method was as follows: the transdermal patch was cut into a standard specimen of 4 cm × 5 cm, the anti-adhesive layer was removed, and it was pasted on two special test steel plates, and placed at room temperature for 20 min. During the test, a 1 kg weight was hung at the lower part, and the time until the final detachment was the holding tack of the pressure-sensitive adhesive. According to GB2972-81, the 180° peel strength was tested by an electronic peeling tester. The test method was as follows: the patch paste was cut into 20 cm × 2.5 cm, and tested 20 min after pasting on the steel plate, and the peeling speed was 300 mm / min. Each sample was tested three times and the average value was taken. The results are shown in Table 3.

[0119] Table 3 Adhesive performance of the non-steroidal anti-inflammatory drug transdermal patches described in Examples 5 to 7 and Comparative Examples 3 to 5

[0120]

[0121] As can be seen from Table 3, compared with the comparative examples, the initial tack of the transdermal patches prepared in the examples slightly decreased before immersion in water, but the initial tack after immersion in water was better than that of the comparative examples. The holding tack and peel strength of the transdermal patches prepared in the examples before and after immersion in water were significantly better than those of the comparative examples, and the changes before and after immersion in water were small, indicating that the transdermal patches prepared by the present invention have good water resistance.

[0122] (4) Antibacterial performance

[0123] The antibacterial rates of the matrices of the non-steroidal anti-inflammatory drug transdermal patches (without indomethacin, amphiphilic cholesterol derivatives, isopropyl myristate and menthol) prepared in Examples 5 to 7 were tested with reference to WS / T 650-2019. The results showed that the antibacterial rates against Staphylococcus aureus, Escherichia coli and Candida albicans were all greater than 99%.

[0124] (5) Skin irritation test

[0125] New Zealand white rabbits were selected for the skin irritation test. 24 hours before the test, the hair on both sides of the dorsal part of the animal was removed with a pet grooming shear, and the hair removal area was 5 cm × 5 cm without damaging the epidermis. The non-steroidal anti-inflammatory drug transdermal patches prepared in Examples 5 to 7 were cut and directly applied to the depilated skin on one side of the animal (one side was used as a blank control). After 12 hours of application, the skin where the drug was administered was washed with water, and it was applied once a day for 7 consecutive days. The erythema and edema conditions on the surface of the skin where the drug was administered were observed every day. After scoring, it was found that the non-steroidal anti-inflammatory drug transdermal patches prepared in Examples 5 to 7 had no obvious skin irritation.

[0126] (6) In vitro drug release test

[0127] The in vitro release test was carried out by the rotating cylinder method. Using isopropyl alcohol phosphate buffer as the release medium, the transdermal patches described in Examples 5 to 7 were respectively placed in the release medium, stirred at a speed of 80 - 120 rpm, and the temperature was controlled at 28 - 34°C. After 3 - 24 hours, samples were taken every 3 hours and filtered to obtain the test solution, and fresh release medium was replenished; another 8 - 14 mg of indomethacin reference substance was taken and placed in a 100 mL volumetric flask, dissolved with ethanol and diluted to the mark, shaken well, accurately measured 2 mL, placed in a 20 mL volumetric flask, diluted to the mark with the release medium, shaken well and filtered to obtain the control solution; accurately measured 50 μL of each of the above test solution and control solution, and determined according to the high performance liquid chromatography method (General Principles 0512, Fourth Part of the Chinese Pharmacopoeia 2015 Edition). Using an octadecylsilane chemically bonded silica chromatographic column (4.6 × 250 mm, 5 μm), using 0.1 mol / L glacial acetic acid solution - acetonitrile (42:58) as the mobile phase, the detection wavelength was 228 nm, and the column temperature was 35°C for determination to obtain the dissolution amount, and then the release degree (release percentage, %) was calculated. The results are shown in Table 4.

[0128] Table 4 In vitro drug release results of the non-steroidal anti-inflammatory drug transdermal patches described in Examples 5-7

[0129] Release degree / % 3h 6h 9h 12h 15h 18h 21h 24h Example 5 40.35 56.07 66.60 73.35 80.13 84.63 88.47 91.17 Example 6 33.67 50.99 62.88 71.72 78.87 83.49 87.33 90.03 Example 7 27.39 46.29 58.28 68.76 77.54 83.43 88.53 92.59

[0130] As can be seen from Table 4, the transdermal patches prepared in the present invention meet the relevant regulations for patches (the release rate at 3 h should be 15-45%, and not less than 70% at 24 h), and have a controlled release effect on indomethacin, showing a stable release within 12 h. After 12 h, the release rate reaches more than 68%, and the release rate at 24 h reaches more than 90%.

[0131] (7) In vitro transdermal test

[0132] The in vitro transdermal test was carried out using the Franz diffusion cell method. The dorsal skin of female Nunu mice at 6-7 weeks was used, and the transdermal patches described in Example 5 and Comparative Examples 1 and 2 were cut into appropriate sizes. After testing and calculation, the cumulative permeation amount was obtained, and the results are shown in Table 5.

[0133] Table 5 In vitro transdermal results of the non-steroidal anti-inflammatory drug transdermal patches described in Example 5 and Comparative Examples 1 and 2

[0134] Transmission amount / % 3h 6h 9h 12h 15h 18h 21h 24h Example 5 38.67 53.72 63.93 70.40 76.91 81.23 84.91 87.52 Comparative Example 1 28.47 39.56 46.99 51.76 56.54 59.71 62.42 64.33 Comparative Example 2 32.63 44.95 53.21 58.51 63.80 66.32 69.34 71.28

[0135] As can be seen from Table 5, the transdermal patches prepared in the present invention can permeate through the skin at a relatively stable rate, indicating that the amphiphilic cholesterol derivative can increase the transdermal permeation amount of indomethacin and has a synergistic effect with isopropyl myristate and menthol.

[0136] In summary, the non-steroidal anti-inflammatory drug transdermal patches prepared in the present invention have moderate adhesiveness, breathability, can stably release drugs, and have a low residual drug amount, which helps to improve the bioavailability and efficacy of drugs. They are used to relieve local pain, such as muscle pain, joint pain, and pain and swelling caused by strains, sprains and sports injuries, and can also be used for the symptomatic treatment of rheumatoid arthritis, rheumatic arthritis and scapulohumeral periarthritis.

[0137] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A transdermal patch for non-steroidal anti-inflammatory drugs, comprising a backing layer, a plaster layer and a release liner, characterized in that, The plaster layer is made from the following raw materials in parts by weight: 3 - 12 parts of indometacin, 12 - 36 parts of amphiphilic cholesterol derivative, 10 - 20 parts of isopropyl myristate, 8 - 15 parts of menthol, 180 - 240 parts of modified polyacrylate adhesive solution, 10 - 40 parts of tackifier, 1 - 3 parts of crosslinking agent, and 80 - 180 parts of main drug solvent; The modified polyacrylate adhesive solution is prepared by the following steps: Disperse isooctyl acrylate, methyl acrylate, and dimethylaminoethyl methacrylate in ethyl acetate to obtain a monomer solution; disperse zinc-based zeolitic imidazolate framework material in ethyl acetate to obtain a metal-organic solution; Under nitrogen protection, add polyethylene glycol to the monomer solution, stir and mix evenly, heat up to 70 - 80 °C, add an initiator, stir and react for 6 - 8 h, cool down to 40 - 50 °C, add the metal-organic solution, stir for 1 - 2 h, and cool to room temperature to obtain it; wherein, the mass ratio of isooctyl acrylate, methyl acrylate, dimethylaminoethyl methacrylate, polyethylene glycol, and zinc-based zeolitic imidazolate framework material is 60:(36 - 38):(2 - 4):(8 - 12):(1 - 2), the mass fraction of isooctyl acrylate in the monomer solution is 30 - 40%, and the mass fraction of zinc-based zeolitic imidazolate framework material in the metal-organic solution is 10 - 15%; The structural formula of the amphiphilic cholesterol derivative is: 。 2. The transdermal patch for non-steroidal anti-inflammatory drugs according to claim 1, wherein: When preparing the modified polyacrylate adhesive solution, the initiator selected is azobisisobutyronitrile, and the dosage of the initiator is 0.5 - 0.6% of the mass of the monomer solution.

3. The transdermal patch of non-steroidal anti-inflammatory drug according to claim 2, characterized in that, The zinc-based zeolitic imidazolate framework material is prepared by the following steps: Using zinc nitrate hexahydrate as the zinc source, imidazole as the organic ligand, and methanol as the reaction medium, disperse the zinc source and the organic ligand in the reaction medium, stir for 16 - 24 h, then perform solid-liquid separation, take the solid, wash and dry it to obtain it; wherein, the molar ratio of the zinc source to the organic ligand is 1:7 - 12.

4. The transdermal patch of non-steroidal anti-inflammatory drug according to claim 1, characterized in that: The amphiphilic cholesterol derivative is prepared by the following steps: (1) Disperse cholesterol in tetrahydrofuran, under a nitrogen atmosphere, sequentially add potassium hydroxide and 4-bromobutyric acid, heat up to 70 - 80 °C, stir and reflux for 16 - 24 h, then cool to room temperature, filter and take the filtrate, after concentration, disperse it in dichloromethane, add an aqueous KHCO3 solution and stir, separate the organic phase, then add an aqueous HCl solution and stir, separate the organic phase, and after concentration and drying, obtain intermediate 1; (2) Disperse 1,3-dichloropropanol in tetrahydrofuran, under a nitrogen atmosphere, sequentially add sulfuric acid and intermediate 1, and heat up to 55 - 65 °C, stir and react for 4 - 6 h, then cool to room temperature, after concentration, disperse it in dichloromethane, add an aqueous KHCO3 solution and stir, separate the organic phase, and after concentration and drying, obtain intermediate 2; (3)Under a nitrogen atmosphere, triethylamine and intermediate 2 are dispersed in ethanol, potassium iodide is added, the temperature is raised to 60 - 70 °C, and the mixture is stirred and reacted for 6 - 10 h. After cooling to room temperature, it is concentrated, dispersed in dichloromethane, saturated brine is added and stirred, the organic phase is separated, pure water is added and stirred, the organic phase is separated, and after concentration and drying, the product is obtained.

5. The transdermal patch of non-steroidal anti-inflammatory drug according to claim 4, wherein: In step (1), the molar ratio of cholesterol, 4-bromobutyric acid, and potassium hydroxide is 1:(3 - 5):(3 - 4); in step (2), the molar ratio of intermediate 1, 1,3-dichloropropanol, and sulfuric acid is 1:(2 - 3):(0.8 - 1.4); in step (3), the molar ratio of intermediate 2, triethylamine, and potassium iodide is 1:(2.2 - 2.5):(0.3 - 0.4).

6. The transdermal patch for non-steroidal anti-inflammatory drugs according to claim 5, wherein: In step (1), the addition amount of cholesterol in tetrahydrofuran is 0.3 - 0.4 mol / L; the pH of the HCl aqueous solution in step (1) is 3 - 4, and the concentration of the KHCO3 aqueous solution in steps (1) and (2) is 0.8 - 1.2 mol / L; in step (2), the addition amount of 1,3-dichloropropanol in tetrahydrofuran is 0.6 - 1.2 mol / L; in step (3), the addition amount of triethylamine in ethanol is 0.6 - 1.0 mol / L.

7. The transdermal patch of non-steroidal anti-inflammatory drug according to claim 1, characterized in that: The tackifier is terpene resin; the crosslinking agent is tetrabutyl titanate.

8. The transdermal patch of non-steroidal anti-inflammatory drug according to claim 1, characterized in that: The main drug solvent is a mixed solution of methanol, ethanol, and ethyl acetate, and the volume ratio of methanol, ethanol, and ethyl acetate is (1 - 2):(0.6 - 1):

1.

9. The transdermal patch of non-steroidal anti-inflammatory drug according to claim 1, wherein: Both the backing layer and the anti-adhesive layer are made of polyester film. The thickness of the backing layer is 20 - 100 μm, and the thickness of the anti-adhesive layer is 30 - 120 μm. The content of the plaster layer in the non-steroidal anti-inflammatory drug transdermal patch is 9.9 - 10.9 mg / cm 2 .

10. The preparation process of the transdermal patch of the non-steroidal anti-inflammatory drug according to any one of claims 1 to 9, characterized in that, It includes the following steps: S1. Prepare each raw material by weight; indomethacin and the amphiphilic cholesterol derivative are added to the main drug solvent and stirred for 20 - 40 min to obtain a drug-loaded solution; The crosslinking agent is added to the modified polyacrylate adhesive solution and stirred for 40 - 80 min to obtain a matrix adhesive solution; S2. The drug-loaded solution is added to the matrix adhesive solution, stirred for 80 - 120 min, isopropyl myristate and menthol are added, stirred for 60 - 80 min, and then the tackifier is added and stirring is continued for 60 - 90 min to obtain a medicated adhesive paste; S3. After the medicated adhesive paste is degassed under vacuum, it is evenly coated on the anti-adhesive layer and dried at 60 - 120 °C to form a plaster layer. The backing layer is laminated on the plaster layer and wound up to obtain a patch roll; S4. The patch roll is punched and sliced to obtain the non-steroidal anti-inflammatory drug transdermal patch.

Images