Ibuprofen-containing transdermal patch as well as preparation method and application thereof

Abstract

The invention relates to an ibuprofen-containing transdermal patch as well as a preparation method and application thereof. The ibuprofen-containing transdermal patch comprises a polymer matrix layer, the polymer matrix layer comprises ibuprofen, a compound at least containing one amino group and a pressure-sensitive adhesive, and based on the weight of the polymer matrix layer, the ibuprofen accounts for 10-30% by weight, the compound at least containing one amino group accounts for 0.1-5% by weight, and the pressure-sensitive adhesive accounts for 0.1-5% by weight. The weight content of the pressure-sensitive adhesive is 45%-84%, the pressure-sensitive adhesive is composed of a silicone pressure-sensitive adhesive and an acrylate pressure-sensitive adhesive, and the weight ratio of the silicone pressure-sensitive adhesive to the acrylate pressure-sensitive adhesive is 1: 1-15: 1. According to the transdermal patch, the penetration capacity of ibuprofen is remarkably improved, particularly, the early-stage medicine penetration rate is higher, the medicine utilization rate is greatly improved, meanwhile, the patch is good in application performance, free of skin irritation, free of crystallization in the long-term storage process, good in stability and capable of better meeting the clinical medication requirement.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biological medicine, in particular to a transdermal patch containing ibuprofen and a preparation method and use thereof. BACKGROUND

[0002] Transdermal drug delivery system (transdermal patch) is a common drug delivery method, which delivers active ingredients into the body through the skin or mucosa to achieve local or systemic effect. Since the first scopolamine patch (Transderm Scop®) was launched in 1979, many attempts have been made to develop more transdermal drug delivery systems with therapeutic effects. Currently, several patch products have been successfully commercialized. According to the combination of active ingredients and other excipients in the patch, the patch can be generally divided into reservoir type and drug-in-adhesives type. The drug-in-adhesives type patch uniformly dissolves or disperses the active ingredients in a semi-solid composition composed of one or more high molecular materials and other pharmaceutically acceptable excipients, forming a uniform drug-containing polymer matrix. If the high molecular material used is a pressure-sensitive adhesive, the polymer matrix serves as both a drug carrier and an adhesive to the skin of the patch site.

[0003] Ibuprofen is a non-steroidal anti-inflammatory drug (NSAIDs), the chemical name is 2-(4-isobutylphenyl) propionic acid, the molecular formula is C 13 H 18 O2, the molecular weight is 206.3, which is a white crystalline powder. Ibuprofen is a chiral drug with S and R two isomers, i.e. S- ibuprofen and R -ibuprofen, wherein S -ibuprofen is also known as dexibuprofen, R -ibuprofen is also known as levobuprofen, and the racemic ibuprofen contains equal amounts of S -ibuprofen and R -ibuprofen, and the chemical structural formula is as follows. The melting point of racemic ibuprofen is 74.5-77.5℃. S The melting point of dexibuprofen is 50-54℃, which is about 25℃ lower than that of racemic ibuprofen.

[0004]

[0005] Studies have found that the pharmacological activity of ibuprofen mainly comes from S dexibuprofen, S -ibuprofen has direct anti-inflammatory, analgesic and antipyretic effects, and is the main pharmacologically active ingredient, which can directly bind to target sites such as COX enzymes, and has a faster effect; R- Ibuprofen itself has no significant pharmacological effect, and needs to be converted into S - Ibuprofen to take effect, conversion efficiency varies from person to person, which may affect the stability and onset time of drug efficacy. Ibuprofen is mainly used to relieve mild to moderate pain, including headache, toothache, muscle pain and joint pain. In addition, it is also commonly used to relieve fever and inflammation. Common dosage forms of ibuprofen include tablets, capsules, granules, injections, etc.

[0006] So far, various transdermal patches of the same non-steroidal anti-inflammatory drugs with a daily dose of less than 200 mg except ibuprofen have been marketed, such as diclofenac (inorganic salt, organic salt or free acid), diflunisal, flurbiprofen, ketoprofen, indomethacin, loxoprofen (inorganic salt form), etc. have been marketed.

[0007] As the safest drug in this class of drugs, ibuprofen is the only drug recommended by WHO and FDA for fever reduction in children. Although a large number of patents and open literature have reported research work on the transdermal penetration of ibuprofen, so far there is no transdermal drug product. One of the main reasons is that the daily dose requirement of ibuprofen is large, and the maximum daily oral dose can exceed 1000 mg. If the amount of ibuprofen transdermally penetrated to achieve a therapeutic effect is large. But considering the practicability of the patch and the total body surface area, the effective drug delivery area cannot be too large, which leads to the difficulty of developing ibuprofen transdermal patches.

[0008] The present inventors disclosed a multi-layer transdermal drug delivery system containing ibuprofen or its structural analogs in an early Chinese patent CN 109432061 B. By salifying all or part of ibuprofen with an amino compound, all or part of ibuprofen is kept in a uniformly dissolved state in the polymer matrix, greatly improving the solubility and drug loading of ibuprofen in the pressure-sensitive adhesive matrix material, and significantly improving the drug penetration capacity and crystallization stability.

[0009] However, the transdermal patch provided in this patent has a slow drug penetration rate in the early stage, resulting in a slow onset time. Therefore, it is necessary to develop a transdermal patch containing ibuprofen with a fast drug penetration rate in the early stage, a fast onset, and a high overall penetration to meet the clinical needs. SUMMARY

[0010] The purpose of the present application is to provide a transdermal patch containing ibuprofen with a fast drug penetration rate in the early stage, a fast onset, and a high overall penetration, as well as a preparation method and use thereof. The transdermal patch has good adhesion performance, high safety, and does not crystallize during long-term storage, with good stability.

[0011] TERMS EXPLANATION : Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The following definitions are applied to the descriptions and claims herein.

[0012] The term "transdermal patch" or "transdermal delivery system" as used herein refers to a system for transdermal delivery of an active ingredient, which generally comprises a backing layer and a release liner, and a polymer matrix layer in between. Depending on the combination of active ingredient and other components in the polymer matrix layer, it can be classified as a reservoir type or a gel-medicine mixed type. Transdermal delivery system can also be referred to as patch or transdermal patch, and these terms can be used interchangeably in this application.

[0013] The term "polymer matrix layer" as used herein refers to a combination of polymer pressure sensitive adhesive, active ingredient, and other pharmaceutically acceptable excipients included in the transdermal delivery system. Generally, the polymer matrix layer is located in between the release liner and the backing film. The polymer matrix layer serves as the delivery layer of the transdermal delivery system, forming a gel-medicine mixed type of transdermal delivery system.

[0014] The term "permeation capacity" as used herein refers to the passive diffusion of a drug through the skin or mucosa, driven by the concentration difference of the active ingredient on both sides of the skin. The cumulative permeation amount per unit time and unit area can be used as an evaluation index of the permeation capacity of the patch, generally denoted as Flux, with the unit of μg / cm 2 / h. The cumulative permeation amount per unit area at each time point can also be used for evaluation, generally denoted as Q t , with the unit of μg / cm 2 .

[0015] The term "adhesion performance" as used herein refers to the tightness of the adhesion between the transdermal patch and the skin at the application site during the application process, as well as the degree of cold flow, stringing, and delamination of the drug-containing gel.

[0016] The term "crystallization stability" as used herein is used to evaluate the risk of crystallization of the transdermal patch over time during storage. High crystallization stability indicates a low risk of crystallization of the transdermal patch over time.

[0017] The term "ibuprofen" as used herein includes ibuprofen racemate, dexibuprofen ( S -ibuprofen), levobuprofen ( R -ibuprofen), and mixtures thereof.

[0018] The term "amino compound" or "amino compound" as used herein can be a primary, secondary, or tertiary amine that is capable of forming a salt of ibuprofen-amino compound (or referred to as an ion pair of ibuprofen-amino compound) with the active ingredient ibuprofen. In the transdermal patch of the present invention, the amino compound is included and combined with ibuprofen and exists in the form of a salt of ibuprofen-amino compound. The term "amino" as used herein includes primary amino groups (-NH2), secondary amino groups (-NH-), and tertiary amino groups, and specifically refers to a nitrogen-containing functional group formed by the covalent bonding of a nitrogen atom with two hydrogen atoms and one carbon atom, with one hydrogen atom and two carbon atoms, or with three carbon atoms.

[0019] The term "salt of ibuprofen-amino compound" or "ion pair of ibuprofen-amino compound" as used herein can be used generically to refer to the reaction of ibuprofen with an amino compound to form an ibuprofenate ion (-COO - ) and an amino cation (such as -NH3 + , -NRH2 + , or NR3H + ). In the polymer matrix layer, these ions are combined and stabilized by electrostatic attraction, hydrogen bonding, or other weaker interactions. Through this reaction and interaction, the physicochemical properties and permeation ability of ibuprofen are improved. It should be understood that the "salt of ibuprofen-amino compound" or "ion pair of ibuprofen-amino compound" described in the present invention encompasses this structure formed in the polymer matrix layer through different process routes, including but not limited to: (a) adding ibuprofen and an amino compound separately to the pressure-sensitive adhesive composition and reacting to form during mixing or drying; and (b) adding a pre-synthesized salt of ibuprofen-amino compound to the pressure-sensitive adhesive composition and finally dispersed in the polymer matrix layer to form through the process of dissolution and drying.

[0020] The term "pressure-sensitive adhesive" as used herein refers to a class of viscoelastic polymeric materials that, when brought into contact with the surface of most other materials, adhere upon contact with very little pressure and maintain a strong attachment for a long period of time. The main function of the pressure-sensitive adhesive is to adhere the patch to the skin for the prescribed treatment time, and it also serves as the polymer matrix to hold the drug and any excipients in the formulation. The pressure-sensitive adhesive has satisfactory physical properties at room temperature, such as good skin adhesion, maintenance of adhesion over time, ability to be peeled off without damaging the skin, and controlled degree of cold flow to meet the requirements of patching. Generally, it includes acrylate pressure-sensitive adhesives, silicone pressure-sensitive adhesives, and polyisobutylene pressure-sensitive adhesives, etc., as well as new mixed pressure-sensitive adhesives formed by physically mixing or chemically combining the above pressure-sensitive adhesives to adjust the properties of the pressure-sensitive adhesive to meet special requirements.

[0021] The term "silicone pressure sensitive adhesive" as used herein refers to a polymer formed by condensation polymerization of low viscosity polydimethylsiloxane and silicone resin. Silicone pressure sensitive adhesive has a softening point close to the temperature of human skin, and has good flowability, flexibility and adhesion at normal body temperature. Silicone pressure sensitive adhesive also has the characteristics of heat oxidation resistance, low temperature resistance, hydrophobicity, low cohesion and low drug solubility. Commercially available silicone pressure sensitive adhesives include products of DuPont, such as Liveo™ BIO-PSA 7-4101, Liveo™ BIO-PSA 7-4102, Liveo™ BIO-PSA 7-4201, Liveo™ BIO-PSA 7-4202, Liveo™ BIO-PSA 7-4301, Liveo™ BIO-PSA 7-4302, Liveo™ BIO-PSA 7-4401, Liveo™ BIO-PSA 7-4402, Liveo™ BIO-PSA 7-4501, Liveo™ BIO-PSA 7-4502, Liveo™ BIO-PSA 7-4601 and Liveo™ BIO-PSA 7-4602, etc.

[0022] The term "acrylate pressure sensitive adhesive" as used herein includes dimeric, trimeric and polymeric pressure sensitive adhesives. Monomers that can be used to prepare acrylate pressure sensitive adhesives include acrylic monomers (such as acrylic acid, acrylate and acrylamide, etc.) and non-acrylic monomers (such as vinyl acetate, etc.). Commercially available acrylate pressure sensitive adhesives include Duro-Tak products of Henkel, such as DURO-TAK 87-2852, DURO-TAK 87-235A, DURO-TAK 87-900A, DURO-TAK 87-2677, DURO-TAK 87-2287, DURO-TAK 87-2074, DURO-TAK 387-2510 / 87-2510, DURO-TAK 387-2516 / 87-2516, DURO-TAK 387-2051 / 87-2051, DURO-TAK 387-2052 / 87-2052, DURO-TAK 387-2054 / 87-2054, DURO-TAK 87-2196 and DURO-TAK 87-4098, etc.

[0023] The term "a weight content of … is … based on the weight of the high molecular matrix layer" as used herein refers to the dry weight ratio of each component to the high molecular matrix layer.

[0024] The term "backing layer" or "backing film" used in the present application refers to a layer through which the drug in the transdermal patch cannot pass. One surface of the backing layer is directly connected to the high polymer matrix layer, and in use, the backing layer protects the high polymer matrix layer from contact with the surrounding environment, preventing drug loss. The material of the backing layer generally includes polyester, polyethylene polyvinyl acetate composite film, polyvinyl chloride, polyurethane, metal foil composite film, non-woven fabric, and elastic cloth, etc., and the thickness is generally 10-200 μm. For example, ScotchPak TM 9730, 9701, 9720, 9723, 9733, 9754, 1109, China Xiaoshan elastic cloth 6015A, Japan treasure non-woven fabric EW2080, EW2083, or Shanghai winning PE3601, etc. The backing layer or backing film of the present application has the same meaning and can be used interchangeably.

[0025] The term "release film" used in the present application can also be referred to as a protective layer, which is directly connected to the other surface of the high polymer matrix layer. The release film is removed before use of the transdermal patch. Commonly used release films are mainly divided into silicon-coated release films, fluorine release films (or fluorine-coated release films) and non-silicon non-fluorine-coated release films. For example, ScotchPak TM 1022, 9709, 9744, 9755, various specifications of release film from Fujimori Industries Co., Ltd., 75u transparent release film from Taiwan Province of China Xiangwei Technology Co., Ltd., various specifications of release film from Taiwan Province of China Seno Technology Co., Ltd., N75 400 release film and 75u PET release film from Wuxi Zhongxing New Material Technology Co., Ltd., release film with model number 5192 from Naiheng (Guangzhou) Paper Products Co., Ltd., fluorine release film from Guangdong Desheng New Material Technology Co., Ltd., fluorine release film from Nantong Huakai New Material Technology Co., Ltd., medical PET release film from Zhejiang Sili Anti-adhesive Paper Manufacturing Co., Ltd., various specifications of release film from Jiangsu Shuangguan New Material Technology Co., Ltd., polyester pharmaceutical release film from Shenyang Zhongjia Plastic Products Co., Ltd., polyester release film from Shanghai Yifang Medical Composite Materials Co., Ltd., various specifications of release film from Anhui Meike Medical Technology Co., Ltd., and silicon-coated release film such as BD type release film from Fujimori Industries Co., Ltd., various specifications of release film from LOPAREX BV, various specifications of release film from Jiangsu Shuangguan New Material Technology Co., Ltd., and XL8016W type release film from Zhejiang Sili Anti-adhesive Paper Manufacturing Co., Ltd.

[0026] The term "transdermal effective dose" or "transdermal amount effective to achieve a therapeutic effect" as used herein means that the active ingredient is capable of being delivered through the skin in an amount sufficient to achieve the desired amount for local or systemic effect to achieve a particular pharmacological effect, such as curing, reducing or controlling a disease or symptoms, when the transdermal patch is in use. These terms are used interchangeably in the present invention.

[0027] The solubility of ibuprofen in silicone pressure sensitive adhesive is small, and crystals are easily precipitated during storage, and the adhesion of the patch is small, and the patching performance is poor. The solubility of ibuprofen in acrylate pressure sensitive adhesive is larger, but the permeability is lower. In order to achieve the purpose of fast initial drug permeation rate, fast onset and high overall permeation, the present application attempts to further increase the proportion of silicone pressure sensitive adhesive in the mixed glue on the basis of the patent CN 109432061 B. It is unexpectedly found through further research that by using a mixed glue of silicone pressure sensitive adhesive and acrylate pressure sensitive adhesive with a weight percentage of silicone pressure sensitive adhesive of 50% or more (especially a mixed glue of silicone pressure sensitive adhesive and acrylate pressure sensitive adhesive with a weight ratio of 1:1 to 15:1), and by adjusting the addition amount of ibuprofen and amino compound, the problems of permeation, crystallization, irritation and patching performance can be well balanced. The patch obtained can significantly improve the permeability of ibuprofen, especially the faster initial drug permeation rate to achieve a faster onset time, and can greatly improve the drug utilization rate. At the same time, the patch obtained has good patching performance, no skin irritation, no crystal precipitation during long-term storage, good stability, and can better meet the clinical drug demand.

[0028] Further, it is found in the research that due to the presence of amino compounds in the patch, when using a mixed glue with a high content of silicone pressure sensitive adhesive, the prepared patch will have a problem of significantly increased release force of the protective layer during long-term storage, which will cause the protective layer of the patch product to fail to be normally peeled off, and in serious cases, will cause peeling failure. The growth rate of the release force of the protective layer is positively correlated with the content of the amino compound and the content of the silicone pressure sensitive adhesive in the prescription, especially when the proportion of the silicone pressure sensitive adhesive in the mixed glue is greater than 50%, the growth is obvious. Without any theory, it is possible that there is an interaction between the silicone pressure sensitive adhesive, the amino compound and the release agent of the protective layer in the patch, which causes the release force of the protective layer to grow faster. The present application finds that the addition of cellulose derivatives and / or fillers can significantly reduce the growth rate of the release force of the protective layer, and the more the amount of cellulose derivatives and / or fillers, the slower the growth of the release force of the protective layer. Further research finds that the simultaneous use of cellulose derivatives and fillers can produce a synergistic effect, significantly improving the release force of the protective layer, the patching performance of the glue, the drug permeability and the stability of crystallization, and the product has excellent performance in all aspects.

[0029] In the preparation process of the patch of the present application, it is found that, due to the use of mixed glue with high content of silicone pressure sensitive adhesive, the incompatibility of glue solution caused by the difference in properties of the two pressure sensitive adhesives will bring about the problems of uniformity of glue solution and coating quality, which will cause the problems of glue solution wall-hanging and obvious layering when mixed with ibuprofen, amino compounds and optional cellulose derivatives and / or fillers, and thus cannot be uniformly mixed and coated, and finally lead to uneven and uneven flatness of the dried product, thereby affecting the controllability of product quality. The present application can well solve the above problems by using the preferred solvent for preparation.

[0030] The object of the present application is achieved by the following technical solutions: The present application provides a transdermal patch containing ibuprofen, which comprises a high molecular matrix layer, wherein the high molecular matrix layer comprises ibuprofen, at least one amino-containing compound and pressure sensitive adhesive, wherein the weight content of the ibuprofen is 10% to 30%, the weight content of the at least one amino-containing compound is 0.1% to 5%, and the weight content of the pressure sensitive adhesive is 45% to 84% based on the weight of the high molecular matrix layer, wherein the pressure sensitive adhesive is composed of silicone pressure sensitive adhesive and acrylate pressure sensitive adhesive, and the weight ratio of the silicone pressure sensitive adhesive to the acrylate pressure sensitive adhesive is 1:1 to 15:1.

[0031] For example, the ibuprofen can have a weight content of 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%, 22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%, 28%, 28.5%, 29%, 29.5%, 30%, or any decimal or integer value within a range of the foregoing, by weight of the polymeric matrix layer; the at least one amino-containing compound can have a weight content of 0.1%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or any decimal or integer value within a range of the foregoing; the pressure sensitive adhesive can have a weight content of 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, or any decimal or integer value within a range of the foregoing; and the silicone pressure sensitive adhesive to acrylate pressure sensitive adhesive can have a weight ratio of 1:1, 2:1, 7:3, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, or any decimal or integer value within a range of the foregoing.

[0032] Preferably, the ibuprofen has a weight content of 20% to 30%, by weight of the polymeric matrix layer.

[0033] More preferably, the ibuprofen has a weight content of 20% to 25%, by weight of the polymeric matrix layer.

[0034] Preferably, the polymeric matrix layer further comprises a cellulose derivative.

[0035] More preferably, the cellulose derivative has a weight content of 1% to 10%, by weight of the polymeric matrix layer. For example, the cellulose derivative can have a weight content of 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, or any decimal or integer value within a range of the foregoing, by weight of the polymeric matrix layer.

[0036] Further preferably, the weight content of the cellulose derivative is 3% to 5% by weight of the polymeric matrix layer.

[0037] Further preferably, the cellulose derivative is selected from one or more of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, hydroxypropyl cellulose acetate.

[0038] Still further preferably, the cellulose derivative is a hydrophobic cellulose derivative.

[0039] Preferably, the polymeric matrix layer further comprises a filler.

[0040] More preferably, the weight content of the filler is 4% to 15% by weight of the polymeric matrix layer. For example, the weight content of the filler can be 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13, 13.5%, 14%, 14.5%, 15% or any decimal or integer value within the range by weight of the polymeric matrix layer.

[0041] Further preferably, the weight content of the filler is 8% to 15% by weight of the polymeric matrix layer.

[0042] Further preferably, the filler is selected from one or more of talc, magnesium trisilicate, bentonite, kaolin, hydrophobic colloidal silica and montmorillonite.

[0043] Preferably, the polymeric matrix layer further comprises a filler having a weight content of 4% to 15% by weight of the polymeric matrix layer and a cellulose derivative having a weight content of 1% to 10% by weight of the polymeric matrix layer.

[0044] More preferably, the polymeric matrix layer further comprises a filler having a weight content of 8% to 15% by weight of the polymeric matrix layer and a cellulose derivative having a weight content of 3% to 5% by weight of the polymeric matrix layer.

[0045] Preferably, the ibuprofen is ibuprofen racemate, dexibuprofen and / or levobuprofen.

[0046] Preferably, the compound containing at least one amino group forms an ibuprofen-amino compound salt with the ibuprofen.

[0047] Preferably, the compound containing at least one amino group is a primary, secondary or tertiary amine.

[0048] More preferably, the at least one amino group containing compound is a fatty amine.

[0049] Further more preferably, the at least one amino group containing compound is selected from one or more of diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, propylenediamine.

[0050] Preferably, the silicone pressure sensitive adhesive is selected from one or more of Liveo™ BIO-PSA 7-4101, Liveo™ BIO-PSA 7-4102, Liveo™ BIO-PSA 7-4201, Liveo™ BIO-PSA 7-4202, Liveo™ BIO-PSA 7-4301, Liveo™ BIO-PSA 7-4302, Liveo™ BIO-PSA 7-4401, Liveo™ BIO-PSA 7-4402, Liveo™ BIO-PSA 7-4501, Liveo™ BIO-PSA 7-4502, Liveo™ BIO-PSA 7-4601, and Liveo™ BIO-PSA 7-4602.

[0051] Preferably, the acrylate pressure sensitive adhesive is selected from one or more of DURO-TAK 87-2852, DURO-TAK 87-235A, DURO-TAK 87-900A, DURO-TAK 87-2677, DURO-TAK 87-2287, DURO-TAK 87-2074, DURO-TAK 387-2510 / 87-2510, DURO-TAK 387-2516 / 87-2516, DURO-TAK 387-2051 / 87-2051, DURO-TAK 387-2052 / 87-2052, DURO-TAK 387-2054 / 87-2054, DURO-TAK 87-2196, and DURO-TAK 87-4098.

[0052] Preferably, the molar ratio of ibuprofen to the at least one amino group in the at least one amino-containing compound in the polymeric matrix layer is 2: 1 to 20: 1. For example, the molar ratio of ibuprofen to the at least one amino group in the at least one amino-containing compound in the polymeric matrix layer is 2: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1, 4.5: 1, 5: 1, 5.5: 1, 6: 1, 6.5: 1, 7: 1, 7.5: 1, 8: 1, 8.5: 1, 9: 1, 9.5: 1, 10: 1, 10.5: 1, 11: 1, 11.5: 1, 12: 1, 12.5: 1, 13: 1, 13.5: 1, 14: 1, 14.5: 1, 15: 1, 15.5: 1, 16: 1, 16.5: 1, 17: 1, 17.5: 1, 18: 1, 18.5: 1, 19: 1, 19.5: 1, 20: 1, or any fraction or whole number within the ranges.

[0053] More preferably, the molar ratio of ibuprofen to the at least one amino group in the at least one amino-containing compound in the polymeric matrix layer is 5: 2 to 5: 1.

[0054] Preferably, the amount of ibuprofen contained in the transdermal patch is 0.2 mg to 2.4 mg per square centimeter, for example, the amount of ibuprofen contained in the transdermal patch can be 0.20 mg, 0.25 mg, 0.30 mg, 0.35 mg, 0.40 mg, 0.45 mg, 0.50 mg, 0.55 mg, 0.60 mg, 0.65 mg, 0.70 mg, 0.75 mg, 0.80 mg, 0.85 mg, 0.90 mg, 0.95 mg, 1.00 mg, 1.05 mg, 1.10 mg, 1.15 mg, 1.20 mg, 1.25 mg, 1.30 mg, 1.35 mg, 1.40 mg, 1.45 mg, 1.50 mg, 1.55 mg, 1.60 mg, 1.65 mg, 1.70 mg, 1.75 mg, 1.80 mg, 1.85 mg, 1.90 mg, 1.95 mg, 2.00 mg, 2.05 mg, 2.10 mg, 2.15 mg, 2.20 mg, 2.25 mg, 2.30 mg, 2.35 mg, 2.40 mg, or any fraction or whole number within the ranges.

[0055] More preferably, the administration area of the transdermal patch is 5 cm 2 ~100 cm 2For example, the administration area of ​​the transdermal patch can be 5cm², 10cm², 15cm², 20cm², 25cm², 30cm², 35cm², 40cm², 45cm², 50cm², 55cm², 60cm², 65cm², 70cm², 75cm², 80cm², 85cm², 90cm², 95cm², 100cm², or any decimal or integer value within the above range.

[0056] Preferably, the transdermal patch further comprises a backing layer and a protective layer; the polymer matrix layer is located between the backing layer and the protective layer.

[0057] More preferably, the protective layer is a fluorine release film.

[0058] More preferably, the fluorinated release film is selected from ScotchPak from 3M Company, USA. TM Release films 9744, 9709, and 9755; 5192 / 5195 release films from Naiheng Paper Products Co., Ltd.; and DC150 release films from Nantong Huakai New Material Technology Co., Ltd.

[0059] A second aspect of the present invention provides a method for preparing the ibuprofen-containing transdermal patch described in the first aspect of the present invention, comprising the following steps: S1: Mix the prescribed amount of ibuprofen, a compound containing at least one amino group, pressure-sensitive adhesive, and optional cellulose derivatives and / or fillers in an organic solvent to obtain an adhesive solution; S2: Apply the adhesive obtained in step S1 onto the protective layer and dry it; S3: Combine the product obtained in step S2 with the backing layer, cut it, and obtain the transdermal patch.

[0060] Preferably, the organic solvent in step S1 is selected from ethanol, ethyl acetate and / or dimethyl sulfoxide.

[0061] More preferably, the organic solvent in step S1 is a mixture of ethyl acetate and dimethyl sulfoxide.

[0062] More preferably, the organic solvent comprises dimethyl sulfoxide in a weight content of 1% to 10% and ethyl acetate in a weight content of 90% to 99%. For example, the organic solvent can comprise the dimethyl sulfoxide in a weight content of 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or any decimal or integer value within the range; and the organic solvent can comprise the ethyl acetate in a weight content of 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99% or any decimal or integer value within the range.

[0063] More preferably, the organic solvent comprises dimethyl sulfoxide in a weight content of 1% to 10% and ethyl acetate in a weight content of 90% to 99%. For example, the organic solvent can comprise the dimethyl sulfoxide in a weight content of 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or any decimal or integer value within the range; and the organic solvent can comprise the ethyl acetate in a weight content of 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.5%, 99% or any decimal or integer value within the range.

[0064] The third aspect of the present application provides use of the transdermal patch of the first aspect of the present application in the preparation of a medicament for treating fever, pain and / or inflammation in adults and / or children.

[0065] Compared with the prior art, the present application has the following beneficial effects: The present application provides a transdermal patch containing ibuprofen, a preparation method and use thereof. The transdermal patch significantly improves the permeation capacity of ibuprofen, especially the faster permeation rate of prodrugs, greatly improves the drug utilization rate, has good patching performance and no skin irritation, does not crystallize during long-term placement, has good stability, and can better meet the clinical drug demand. BRIEF DESCRIPTION OF DRAWINGS

[0066] The drawings described herein are used to provide further understanding of the present application, form a part of the present application, the illustrative embodiments of the present application and the description thereof are used to explain the present application, and do not constitute improper limitation on the present application. In the drawings: Figure 1 Fig. 6 shows the 24 h average cumulative permeation amount-time curve of the patch of prescription 6-8, 10 and 12 of Example 1 of the present application; Figure 2 Fig. 7 shows the 24 h average permeation rate-time curve of the patch of prescription 6-8, 10 and 12 of Example 1 of the present application; Figure 3 Fig. 8 shows the photos of the influence of different organic solvents / additives on the coating performance in Example 1 of the present application; Figure 4The 24 h average cumulative permeation amount-time curve of the patch of the present application embodiment 2 prescription 29-33 is shown (the molar ratio shown in the figure is dexibuprofen / diethylamine molar ratio); Figure 5 The 24 h average permeation rate-time curve of the patch of the present application embodiment 2 prescription 29-33 is shown (the molar ratio shown in the figure is dexibuprofen / diethylamine molar ratio); Figure 6 The blood concentration-time curve of the pig administered with buprofen suspension by gavage and the buprofen transdermal patch of the present application by transdermal administration is shown. DETAILED DESCRIPTION

[0067] In order to make the technical solutions and beneficial effects of the present application more obvious and easy to understand, the following will be described in detail by combining the drawings and listing specific examples. It should be understood that these examples are only used to illustrate the basic principles, main features and advantages of the present application, and the present application is not limited in scope by the following examples. The implementation conditions used in the examples can be further adjusted according to specific requirements, and the specific technology or conditions not specified are usually carried out according to the conventional technology or conditions described in the literature in the art, or according to the product instructions. The reagents, materials or instruments used are commercially available unless otherwise specified.

[0068] In the following description, a large number of specific details are given in order to provide a more thorough understanding of the present application. However, it is obvious to those skilled in the art that the present application can be implemented without one or more of these details. In other examples, in order to avoid obscuring the present application, some technical features known in the art are not described; that is, not all features of the actual implementation examples are described, and well-known functions and steps are not described in detail.

[0069] In the following examples, the types, models and abbreviations of pressure-sensitive adhesives are shown in Table 1.

[0070] Table 1 Types, models and abbreviations of pressure-sensitive adhesives

[0071] For the sake of writing convenience, the model numbers of each pressure-sensitive adhesive are represented by abbreviated numbers in the following examples of the present application.

[0072] 2. Preparation method of the patch

[0073] The preparation method of the patch in the present application embodiment is as follows: The prescription amount of ibuprofen, at least one amino-containing compound, pressure-sensitive adhesive and optional cellulose derivative and / or filler are mixed uniformly in an organic solvent to obtain a glue solution. The prepared glue solution is coated on a selected protective layer, the coating thickness is determined according to the use requirement, and the coated polymer matrix is dried. Then the dried intermediate product and a selected backing film are compounded, and cut into appropriate size and shape according to the use requirement. In order to facilitate comparison, the patches prepared in the following examples all use the same coating thickness, and the protective layer model is ScotchPak TM 9744 (purchased from 3M Company), and the backing film model is ScotchPak TM 1109 (purchased from 3M Company).

[0074] 3. Investigation method of patch adhesion performance and skin irritation Take a rectangular patch with an area of 15 cm 2 × 15 cm, remove the release film, and respectively adhere to the back of a depilated Bama miniature pig, and remove the patch after 12 hours to investigate the adhesion, stringing, delamination, cold flow and other conditions and record. Among them, if the patch is easy to peel off and has appropriate adhesion, and there is no stringing, delamination, cold flow (with a black circle around the periphery) and other phenomena, it is recorded as good adhesion performance; if the patch has excessive or insufficient peeling adhesion, obvious stringing, delamination, cold flow and other conditions, the specific problems are recorded.

[0075] After removing the patch, observe whether there is skin irritation such as redness and swelling, and record.

[0076] 4. Investigation method of crystallization stability of patch Visual method, place the patch naked at room temperature, and observe whether crystals are precipitated regularly.

[0077] 5. Evaluation method of patch permeability In vitro transdermal experiment (IVPT): The in vitro transdermal experiment is determined by Franz diffusion cell. The skin of healthy naked mice is confirmed to be intact before the experiment. The LOGAN SYSTEM 918-12 automatic transdermal diffusion system is used, each group of samples is parallel to 3, the receiving liquid is pH 7.4 phosphate aqueous solution, the diffusion cell volume is 12 ml, the penetration diameter is 15 mm, the sampling volume is 12 ml, the temperature is 32℃, the full emptying mode is used, the rotation speed is 600 revolutions per minute, the operation is carried out according to the law, and the sample is taken at the predetermined time point.

[0078] The cumulative transdermal amount and the transdermal flux of the drug can be calculated according to the following formula:

[0079] In the formula: A 供 = peak area of test sample A 对 = peak area of control sample C 对 = concentration of control sample V 对 = volume of control sample injection amount V 供 = volume of test sample injection amount

[0080] 6. Method for determining the peel force of the protective layer of a patch

[0081] Determined according to the method for determining adhesion (Method III, Chinese Pharmacopoeia 2020, Vol. 4, General Rules 0952). Before testing, the patch (together with the packaging material) is placed at 18-25°C and a relative humidity of 40%-70% for more than 2 hours. Take 3 test samples, cut them to a width of 25 mm, and fix the back of the test sample to the test plate with double-sided tape, so that the test sample is flatly attached to the plate. Fold the free end of the release film in half (180°), and clamp the free end of the film and the test plate on the test machine, respectively, on the top and bottom. The peeling surface should be aligned with the test machine line. Determine using the 180° peel strength test method. The test machine continuously peels at a downward speed of 300 mm / min±10 mm / min, and the peel curve is drawn by an automatic recorder.

[0082] In the following examples, the content of each component is the theoretical dry weight ratio of each component to the high molecular matrix layer.

[0083] Example 1: Effect of different types and content ratios of pressure-sensitive adhesives on the performance of ibuprofen patches The patching performance, skin irritation, crystallization stability, and permeability of each patch were investigated according to the aforementioned “Method for investigating the patching performance and skin irritation of a patch”, “Method for investigating the crystallization stability of a patch”, and “Method for evaluating the permeability of a patch”, respectively. The experimental results are shown in Table 2.

[0084] Table 2: Preparation and performance investigation of transdermal patches with different prescription compositions

[0085] As can be seen from the results of Table 2, the solubility of ibuprofen in the silicone pressure-sensitive adhesive alone (e.g. Formulations 1 and 5) is small, it crystallizes during the placement process, and the adhesive of the patch prepared in the silicone pressure-sensitive adhesive alone has small adhesion and poor placement performance. The solubility of ibuprofen in the acrylate pressure-sensitive adhesive is large, but the permeation capacity is low (e.g. Formulations 2 and 6). In order to achieve the purposes of fast initial drug permeation rate, fast onset, and high overall permeation, the present application attempts to further increase the proportion of silicone pressure-sensitive adhesive in the mixed adhesive on the basis of the patent CN 109432061 B. It is found through a large number of experiments that when the weight ratio of the silicone pressure-sensitive adhesive to the acrylate pressure-sensitive adhesive contained is 1:1~15:1 (e.g. Formulations 4 and 8-13), not only the solubility of ibuprofen can be improved, the crystallization stability can be improved, but also the permeation capacity and the placement performance can be significantly improved, and the problems of permeation, crystallization, irritation, and placement performance can be well balanced. Compared with the mixed pressure-sensitive adhesive with the weight ratio of silicone to acrylate pressure-sensitive adhesive of 2:25 disclosed in the patent CN 109432061 B (Formulations 3 and 7), the permeation capacity of ibuprofen is greatly improved, wherein the average permeation rate of Formulation 4 in 12h is about 5 times that of Formulation 3, and the average permeation rate of Formulations 8-13 in 12h is about 1.4~2.7 times that of Formulation 7, and it does not crystallize during the storage period. However, when the weight ratio of silicone to acrylate pressure-sensitive adhesive further reaches 20:1 (Formulation 14), the adhesive of the patch is small, the placement performance is poor, and it crystallizes during the placement process.

[0086] Figure 1 The 24 h average cumulative permeation amount-time curve of the patch of Formulations 6-8, 10, and 12 is shown in FIG. 1, Figure 2 The 24 h average permeation rate-time curve of the patch of Formulations 6-8, 10, and 12 is shown in FIG. 2.

[0087] From the results of Table 2, it can be seen that the solubility of ibuprofen in the silicone pressure-sensitive adhesive alone (e.g. Formulations 1 and 5) is small, it crystallizes during the placement process, and the adhesive of the patch prepared in the silicone pressure-sensitive adhesive alone has small adhesion and poor placement performance. The solubility of ibuprofen in the acrylate pressure-sensitive adhesive is large, but the permeation capacity is low (e.g. Formulations 2 and 6). In order to achieve the purposes of fast initial drug permeation rate, fast onset, and high overall permeation, the present application attempts to further increase the proportion of silicone pressure-sensitive adhesive in the mixed adhesive on the basis of the patent CN 109432061 B. It is found through a large number of experiments that when the weight ratio of the silicone pressure-sensitive adhesive to the acrylate pressure-sensitive adhesive contained is 1:1~15:1 (e.g. Formulations 4 and 8-13), not only the solubility of ibuprofen can be improved, the crystallization stability can be improved, but also the permeation capacity and the placement performance can be significantly improved, and the problems of permeation, crystallization, irritation, and placement performance can be well balanced. Compared with the mixed pressure-sensitive adhesive with the weight ratio of silicone to acrylate pressure-sensitive adhesive of 2:25 disclosed in the patent CN 109432061 B (Formulations 3 and 7), the permeation capacity of ibuprofen is greatly improved, wherein the average permeation rate of Formulation 4 in 12h is about 5 times that of Formulation 3, and the average permeation rate of Formulations 8-13 in 12h is about 1.4~2.7 times that of Formulation 7, and it does not crystallize during the storage period. However, when the weight ratio of silicone to acrylate pressure-sensitive adhesive further reaches 20:1 (Formulation 14), the adhesive of the patch is small, the placement performance is poor, and it crystallizes during the placement process. Figure 1 and Figure 2 From the results of Table 2, it can be seen that the solubility of ibuprofen in the silicone pressure-sensitive adhesive alone (e.g. Formulations 1 and 5) is small, it crystallizes during the placement process, and the adhesive of the patch prepared in the silicone pressure-sensitive adhesive alone has small adhesion and poor placement performance. The solubility of ibuprofen in the acrylate pressure-sensitive adhesive is large, but the permeation capacity is low (e.g. Formulations 2 and 6). In order to achieve the purposes of fast initial drug permeation rate, fast onset, and high overall permeation, the present application attempts to further increase the proportion of silicone pressure-sensitive adhesive in the mixed adhesive on the basis of the patent CN 109432061 B. It is found through a large number of experiments that when the weight ratio of the silicone pressure-sensitive adhesive to the acrylate pressure-sensitive adhesive contained is 1:1~15:1 (e.g. Formulations 4 and 8-13), not only the solubility of ibuprofen can be improved, the crystallization stability can be improved, but also the permeation capacity and the placement performance can be significantly improved, and the problems of permeation, crystallization, irritation, and placement performance can be well balanced. Compared with the mixed pressure-sensitive adhesive with the weight ratio of silicone to acrylate pressure-sensitive adhesive of 2:25 disclosed in the patent CN 109432061 B (Formulations 3 and 7), the permeation capacity of ibuprofen is greatly improved, wherein the average permeation rate of Formulation 4 in 12h is about 5 times that of Formulation 3, and the average permeation rate of Formulations 8-13 in 12h is about 1.4~2.7 times that of Formulation 7, and it does not crystallize during the storage period. However, when the weight ratio of silicone to acrylate pressure-sensitive adhesive further reaches 20:1 (Formulation 14), the adhesive of the patch is small, the placement performance is poor, and it crystallizes during the placement process.

[0088] In the present embodiment, ethyl acetate is used as the organic solvent in the preparation of the patch containing single pressure-sensitive adhesive, and a mixed organic solvent of ethyl acetate and dimethyl sulfoxide (DMSO) is used in the preparation of the patch containing mixed pressure-sensitive adhesive. It is found through research that, due to the incompatibility of the glue liquid caused by the difference in the properties of the two pressure-sensitive adhesives, silicone and acrylate, the uniformity of the glue liquid and the coating quality are affected. Specifically, in the preparation of the patch using mixed pressure-sensitive adhesive of silicone and acrylate, in the process of mixing the pressure-sensitive adhesive with ibuprofen, amino compounds and other auxiliary materials, the glue liquid wall-hanging phenomenon occurs and obvious stratification occurs when using conventional solvents (for example, using only ethyl acetate), which cannot be uniformly mixed and coated, especially when the proportion of silicone pressure-sensitive adhesive in the mixed pressure-sensitive adhesive is large, the above wall-hanging and stratification phenomenon is more obvious, which finally leads to uneven and uneven flatness of the dried product, thereby affecting the controllability of the product quality. In order to improve the coating performance in the preparation of the patch containing high content of silicone mixed pressure-sensitive adhesive, different organic solvents or additives are tried, and it is unexpectedly found that the use of a mixed organic solvent of ethyl acetate and dimethyl sulfoxide can well solve the above problems (see Table 3 and Figure 3 ). Preferably, the content of dimethyl sulfoxide in the mixed organic solvent is 1-10%, more preferably 3-5%.

[0089] Table 3 Influence of different organic solvents / additives on the state of the glue liquid after mixing and coating performance

[0090] Further investigation of the influence of different types of pressure-sensitive adhesive combinations on the performance of the patch, the specific prescription and experimental results are shown in Table 4 below: Table 4 Preparation and performance investigation of transdermal patches with different prescription compositions

[0091] It can be seen from the results in Table 4 that within the range of the present application, the performance of the patch prepared by mixing different types of silicone pressure-sensitive adhesive and acrylate pressure-sensitive adhesive is good.

[0092] Example 2 Influence of ibuprofen and amino compound dosage on the performance of the patch This embodiment investigates the influence of the dosage of ibuprofen and amino compound on the performance of the patch.

[0093] According to the aforementioned "patch preparation method", a transdermal patch containing ibuprofen is prepared by using a mixed organic solvent of ethyl acetate and dimethyl sulfoxide to dissolve each component, and the performance of the patch is investigated. The components and contents of the specific prescription and the experimental results are shown in Tables 5-6.

[0094] Table 5 Preparation and performance investigation of transdermal patches with different active ingredient contents

[0095] As can be seen from the experimental results in Table 5, the permeation ability gradually increases as the ibuprofen content increases, and the permeation ability significantly increases when the ibuprofen content is greater than 20%, but the patch performance becomes poor and the risk of drug crystallization increases when the ibuprofen content is greater than 30%. In addition, when the patch is prepared using the mixed glue with a high content of silicone pressure-sensitive adhesive, the surface of the patch with an ibuprofen content of 20% or more is smoother than that of the patch with a lower ibuprofen content, which may be due to the tackifying effect of ibuprofen itself improving the compatibility of the mixed glue, thereby improving the appearance of the patch. Therefore, when the content of silicone pressure-sensitive adhesive in the mixed glue is greater than or equal to 50%, the content of ibuprofen is preferably 20% to 30%, and more preferably the content of ibuprofen is 20% to 25%.

[0096] Table 6 Preparation and performance evaluation of transdermal patches with different contents of amino compounds

[0097] As can be seen from the results in Table 6, the molar ratio of dexibuprofen / diethylamine is closely related to the patch performance, skin irritation, crystallization stability, and drug permeation ability of the patch. The amino compound can combine with ibuprofen to increase its solubility in the pressure-sensitive adhesive, thereby reducing the risk of crystallization. In the case of a high content of ibuprofen (e.g., greater than 20%), a larger proportion of amino compounds needs to be added to prevent ibuprofen from crystallizing during long-term storage due to the increased risk of crystallization. However, as the amount of amino compound added increases, the intrinsic solubility of ibuprofen increases, resulting in the active ingredient not reaching or approaching the saturated solubility, and the thermodynamic diffusion ability decreases, which will lead to a decrease in the permeation ability of ibuprofen; too much amino compound added also easily causes skin irritation and leads to poor patch performance. Therefore, the molar ratio of ibuprofen to the amino group in the amino compound is preferably 2:1 to 20:1, and more preferably 5:2 to 5:1. Within the above preferred molar ratio range, the patch not only has good patch performance, high crystallization stability, and no skin irritation, but also has significantly improved permeation ability (see Figure 4 and Figure 5 ).

[0098] Example 3 Improvement of the release force of the protective layer of the patch The currently marketed protective layer (release film) suitable for transdermal patches mainly includes silicone-coated release film, fluorine release film and non-silicone and non-fluorine coated release film. A large number of experimental studies have found that the fluorine release film is suitable for the ibuprofen patch prepared from the mixed glue containing a high proportion of silicone pressure-sensitive glue, and can play a role in preventing adhesion, while other types of protective layers (such as silicone-coated release film and non-silicone and non-fluorine release film) cannot play a role in preventing adhesion. However, since the patch of the present application contains an amino compound, in the high content silicone pressure-sensitive glue polymer matrix, the patch using fluorine release film will have a problem of significantly increased release force of the protective layer during long-term storage, resulting in the failure of the protective layer of the patch product to be normally peeled off, and in serious cases, the peeling failure, and the release force of the protective layer increases at a speed positively correlated with the content of the amino compound in the prescription and the content of the silicone pressure-sensitive glue, especially when the content of the silicone pressure-sensitive glue is high. Research has found that the addition of cellulose derivatives and / or fillers in the prescription can significantly reduce the release force growth rate of the protective layer, and the specific prescription and experimental results are shown in Table 7 below: Table 7 Effect of cellulose derivatives and / or fillers on the release force of the protective layer of the patch

[0099] As can be seen from the results of Table 7, the more the amount of cellulose derivatives and / or fillers, the slower the release force of the protective layer increases during long-term storage, but since the hydrophobic colloidal silica and other fillers are inorganic solid fine powders, they can only be dispersed in, but not dissolved in organic solvents, and too much filler is easy to agglomerate, which increases the difficulty of the preparation process and affects the coating effect, resulting in a grainy, non-smooth surface of the patch, thereby affecting the product quality. The cellulose derivatives can be well dissolved in the high molecular matrix, and have good compatibility; they can increase the stability of the glue solution during preparation, and improve the adhesive properties, but too much cellulose derivative will reduce the permeability of the ibuprofen patch. In order to better solve the problem of fast release force growth of the protective layer of the patch during long-term storage, while taking into account easy preparation and maintaining high permeability, the present application preferably uses an appropriate amount of cellulose derivatives and fillers in combination, and the obtained product can simultaneously significantly improve the release force of the protective layer, the adhesive properties, the drug permeability and the crystallization stability, and the product has excellent performance in all aspects. The present application preferably uses cellulose derivatives with a content of 1% to 10% and fillers with a content of 4% to 15% in combination, more preferably uses cellulose derivatives with a content of 3% to 5% and fillers with a content of 8% to 15% in combination.

[0100] Example 4: Pharmacokinetic experiment on bama miniature pigs 1. Drug information Ibuprofen suspension: batch number: 230112043, specification: 20mg / ml, manufacturer: Johnson & Johnson Pharmaceutical Co., Ltd.

[0101] Ibuprofen patch: Ibuprofen patch of prescription number 7 and 41 of the present application; cutting size: 3 cm x 5 cm, patch area 15 cm 2 .

[0102] 2. Test animals Healthy Bama mini-pigs, 3, male, 30 days old, body weight: 2.5-3.5 kg.

[0103] 3. Dosing regimen The Bama mini-pigs were divided into an ibuprofen gavage group (1) and an ibuprofen transdermal patch group (2).

[0104] The ibuprofen gavage group was given a single oral gavage of ibuprofen solution to the Bama mini-pigs at a dose of 10 mg / kg.

[0105] The ibuprofen transdermal patch (3 cm x 5 cm, 15 cm 2 ) group had the following dosing regimen: The patch site was depilated before the animal was patched. The backing film was peeled off with a disposable gun head, and the adhesive side of the backing film was patched on the skin prepared in advance, and pressed gently for 2-3 times. The administration was stopped after 12 h of continuous patching, the patch was removed and placed in a wide-mouth bottle for subsequent analysis and processing.

[0106] 4. Sample collection The ibuprofen gavage group collected whole blood at 0 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h after gavage administration, and the ibuprofen transdermal patch group collected whole blood at 0 h, 1 h, 3 h, 6 h, 8 h, 10 h, 12 h (patch removed), 13 h, 14 h, 16 h, 20 h, 24 h after patch administration. About 0.4 mL of whole blood was collected at each time point and placed in a blood collection tube containing EDTA.K2. The whole blood was centrifuged at 2-8 ℃, 2000 g, 10 min within 1 hour of collection, and then the plasma was taken into a new EP tube with a volume of not less than 200 µL. The plasma was placed in an ultra-low temperature freezer, and the plasma samples were transferred to the biological laboratory and stored in the ultra-low temperature freezer after the end of the experiment.

[0107] Sample collection followed the relevant SOP (standard operating procedure).

[0108] 5. Analysis of biological samples The collected samples were detected by the LC-MS / MS sample detection method verified for feasibility.

[0109] The residual patch was detected by the HPLC detection analysis method verified for feasibility.

[0110] 6. Data statistics The test data were statistically analyzed by using WinNonlin software, and the pharmacokinetic parameters were calculated, and the results were shown in Table 2. Figure 6 .

[0111] 7. Results Figure 6 The results showed that the Cmax of the bama mini-pig with the transdermal patch of prescription No. 41 was significantly higher than that of the transdermal patch of prescription No. 7. Compared with the intragastric administration group, the blood drug concentration of the transdermal patch group was more stable. The Cmax of the transdermal patch of prescription No. 41 was close to half of the oral administration, and was significantly higher than the blood drug concentration of the intragastric administration group at 4 h, which could meet the treatment needs.

[0112] It should be understood that the above examples are all exemplary, and are not used to include all possible embodiments contained in the claims. Various modifications and changes can also be made on the basis of the above examples without departing from the scope of the disclosure. Similarly, any combination of the technical features of the above examples can also be made to form additional embodiments of the application that can not be explicitly described. Therefore, the above examples only express several embodiments of the application, and do not limit the protection scope of the patent of the application.

Claims

1. A transdermal patch containing ibuprofen, comprising a high molecular matrix layer, wherein the high molecular matrix layer comprises ibuprofen, a compound containing at least one amino group, and a pressure-sensitive adhesive, wherein the weight content of the ibuprofen is 10% to 30%, the weight content of the compound containing at least one amino group is 0.1% to 5%, and the weight content of the pressure-sensitive adhesive is 45% to 84%, based on the weight of the high molecular matrix layer, wherein the pressure-sensitive adhesive consists of a silicone pressure-sensitive adhesive and an acrylate pressure-sensitive adhesive, and the weight ratio of the silicone pressure-sensitive adhesive to the acrylate pressure-sensitive adhesive is 1:1 to 15:

1.

2. The transdermal patch according to claim 1, wherein the high molecular matrix layer further comprises a cellulose derivative; preferably, the weight content of the cellulose derivative is 1% to 10%, more preferably 3% to 5%, based on the weight of the high molecular matrix layer; preferably, the cellulose derivative is selected from one or more of methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, hydroxypropyl cellulose acetate; preferably, the cellulose derivative is a hydrophobic cellulose derivative.

3. The transdermal patch according to claim 1 or 2, wherein the high molecular matrix layer further comprises a filler; preferably, the weight content of the filler is 4% to 15%, more preferably 8% to 15%, based on the weight of the high molecular matrix layer; preferably, the filler is selected from one or more of talc, magnesium trisilicate, bentonite, kaolin, hydrophobic colloidal silica, and montmorillonite.

4. The transdermal patch according to any one of claims 1 to 3, wherein the ibuprofen is ibuprofen racemate, dexibuprofen, and / or levobuprofen; preferably, the compound containing at least one amino group forms an ibuprofen-amino compound salt with the ibuprofen; preferably, the compound containing at least one amino group is a primary amine, a secondary amine, or a tertiary amine; more preferably, the compound containing at least one amino group is a fatty amine, preferably selected from one or more of diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, propylene diamine.

5. The transdermal patch according to any one of claims 1 to 4, wherein the silicone pressure-sensitive adhesive is selected from one or more of Liveo™ BIO-PSA 7-4101, Liveo™ BIO-PSA 7-4102, Liveo™ BIO-PSA 7-4201, Liveo™ BIO-PSA 7-4202, Liveo™ BIO-PSA 7-4301, Liveo™ BIO-PSA 7-4302, Liveo™ BIO-PSA 7-4401, Liveo™ BIO-PSA 7-4402, Liveo™ BIO-PSA 7-4501, Liveo™ BIO-PSA 7-4502, Liveo™ BIO-PSA 7-4601, and Liveo™ BIO-PSA 7-4602; and / or The acrylate pressure sensitive adhesive is selected from one or more of DURO-TAK 87-2852, DURO-TAK 87-235A, DURO-TAK 87-900A, DURO-TAK 87-2677, DURO-TAK 87-2287, DURO-TAK 87-2074, DURO-TAK 387-2510 / 87-2510, DURO-TAK 387-2516 / 87-2516, DURO-TAK 387-2051 / 87-2051, DURO-TAK 387-2052 / 87-2052, DURO-TAK 387-2054 / 87-2054, DURO-TAK 87-2196, and DURO-TAK 87-4098.

6. The transdermal patch according to any one of claims 1 to 5, wherein the molar ratio of ibuprofen to the amino group in the at least one compound containing one amino group in the high polymer matrix layer is 2:1 to 20:1, preferably 5:2 to 5:

1.

7. The transdermal patch according to any one of claims 1 to 6, wherein the amount of ibuprofen contained in the transdermal patch per square centimeter is 0.2 mg to 2.4 mg; preferably, the administration area of the transdermal patch is 5 cm 2 100 cm 2 .

8. The transdermal patch according to any one of claims 1 to 7, further comprising a backing layer and a protective layer; the high polymer matrix layer is located between the backing layer and the protective layer. Preferably, the protective layer is a fluorine release film.

9. A method for preparing the transdermal patch according to any one of claims 1 to 8, comprising the following steps: S1: uniformly mixing the prescription amount of ibuprofen, the at least one compound containing one amino group, the pressure sensitive adhesive, and optionally the cellulose derivative and / or the filler in an organic solvent to obtain a glue solution; S2: coating the glue solution obtained in step S1 on a protective layer and drying; S3: combining the product obtained in step S2 with a backing layer, cutting to obtain the transdermal patch; Preferably, the organic solvent in step S1 is selected from ethanol, ethyl acetate and / or dimethyl sulfoxide, further preferably, the organic solvent in step S1 is a mixture of ethyl acetate and dimethyl sulfoxide; more preferably, the organic solvent contains 1% to 10% by weight of dimethyl sulfoxide and 90% to 99% of ethyl acetate.

10. Use of the transdermal patch according to any one of claims 1 to 8 in the preparation of a medicament for treating fever, pain and / or inflammation in adults and / or children.

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