Pharmaceutical compositions, patches containing s-2-(2-fluoro-4-biphenylyl)propionic acid and methods of making the same

Abstract

The present application provides a long-term stable S-2-(2-fluoro-4-biphenyl) propionic acid-containing pharmaceutical composition, and a S-2-(2-fluoro-4-biphenyl) propionic acid-containing patch and a preparation method thereof, the pharmaceutical composition comprising: S-2-(2-fluoro-4-biphenyl) propionic acid or a pharmaceutically acceptable salt thereof, menthol oil and a stabilizer, the stabilizer being selected from at least one of isopropyl myristate, crotamiton and laurocapram. The S-2-(2-fluoro-4-biphenyl) propionic acid-containing pharmaceutical composition of the present application, with at least one of isopropyl myristate, crotamiton and laurocapram as a stabilizer added to the composition of S-2-(2-fluoro-4-biphenyl) propionic acid and menthol oil, can significantly improve the storage stability of the composition, compared with the prior art, the content of the active ingredient S-2-(2-fluoro-4-biphenyl) propionic acid is further inhibited from decreasing over time.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and specifically relates to a pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid that is stable for long-term storage, as well as a patch made from the pharmaceutical composition and its preparation method. Background Technology

[0002] 2-(2-fluoro-4-biphenyl)propionic acid is a nonsteroidal anti-inflammatory drug with anti-inflammatory and analgesic effects. It is used as an active ingredient in topical preparations, mostly in racemic form. S-2-(2-fluoro-4-biphenyl)propionic acid, obtained by optically resolving the S-body of the active compound, exhibits superior anti-inflammatory and analgesic effects compared to the racemic form.

[0003] Japanese Patent JP3782834B2 discloses a topical composition containing peppermint oil and SEFSOL as transdermal absorption enhancers. However, this topical composition shows a decrease in active ingredient content over time during storage due to the chemical reaction of the active ingredient S-2-(2-fluoro-4-biphenyl)propionic acid. Japanese Patent JP6023358B2 proposes that for topical compositions containing S-2-(2-fluoro-4-biphenyl)propionic acid and peppermint oil as a transdermal absorption enhancer, the decrease in active ingredient content over time is suppressed only when combined with one or more medium-chain fatty acid esters of certain specific polyols, namely esters selected from those with two medium-chain fatty acids bonded to propylene glycol and esters with three medium-chain fatty acids bonded to glycerol, and the active ingredient remains stable even under long-term storage. However, we have found that in this topical composition, the content of the active ingredient still shows a significant decrease with further extended storage time. Summary of the Invention

[0004] The purpose of this invention is to provide a pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid with further improved stability.

[0005] Another object of the present invention is to provide a patch comprising the above-described pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid and a method for preparing the patch.

[0006] According to one aspect of the present invention, a pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid is provided, comprising: S-2-(2-fluoro-4-biphenyl)propionic acid or a pharmaceutically acceptable salt thereof, peppermint oil, and a stabilizer selected from isopropyl myristate, clomiphene, and lauryl cyanide. At least one of the ketones.

[0007] Furthermore, in the composition, the amount of stabilizer is 0.5 to 3 times that of S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt.

[0008] Furthermore, the pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid is a topical preparation.

[0009] Furthermore, the pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid is a patch, plaster, ointment, liniment, gel, lotion, or cream.

[0010] According to another aspect of the present invention, a patch containing S-2-(2-fluoro-4-biphenyl)propionic acid is provided, comprising S-2-(2-fluoro-4-biphenyl)propionic acid or a pharmaceutical salt thereof, peppermint oil, a stabilizer, a matrix, a tackifier, and a plasticizer, wherein the stabilizer is selected from isopropyl myristate, clomiphene, and lauryl cyanide. At least one of the ketones.

[0011] Further, the patch containing S-2-(2-fluoro-4-biphenyl)propionic acid, by weight, comprises:

[0012]

[0013] Furthermore, in the patch containing S-2-(2-fluoro-4-biphenyl)propionic acid, the amount of stabilizer is 0.5 to 3 times that of S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt.

[0014] Furthermore, the matrix is ​​selected from styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butene-styrene block copolymer, or styrene-ethylene-propylene-styrene block copolymer, polyisobutylene, and polybutene; the tackifier is selected from rosin resin, terpene resin, terpene phenolic resin, and petroleum resin; and the plasticizer is selected from liquid paraffin, peanut oil, and olive oil.

[0015] Furthermore, in the patch containing S-2-(2-fluoro-4-biphenyl)propionic acid, the matrix is ​​a styrene-isoprene-styrene block copolymer and polyisobutylene, the tackifier is hydrogenated rosin glycerol ester, and the plasticizer is liquid paraffin.

[0016] According to another aspect of the present invention, a method for preparing the above-described patch containing S-2-(2-fluoro-4-biphenyl)propionic acid is also provided, comprising the following steps:

[0017] S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, peppermint oil, stabilizer, matrix, thickener, and plasticizer are combined under high temperature conditions to prepare a paste. The paste is then applied to a release layer and a backing material and cut to obtain the patch.

[0018] The beneficial effects of this invention are:

[0019] The pharmaceutical composition of the present invention containing S-2-(2-fluoro-4-biphenyl)propionic acid, wherein isopropyl myristate, clomiphene, and lauryl cyanide are used. Adding at least one of the ketones as a stabilizer to the combination of S-2-(2-fluoro-4-biphenyl)propionic acid and peppermint oil can significantly improve the storage stability of the combination of S-2-(2-fluoro-4-biphenyl)propionic acid and peppermint oil. Compared with the prior art, the content of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl)propionic acid is further inhibited from decreasing over time. Attached Figure Description

[0020] Figure 1 This is a schematic diagram showing the results of the embodiment and comparative example in Experiment Example 1. Detailed Implementation

[0021] This invention provides a pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid, comprising: S-2-(2-fluoro-4-biphenyl)propionic acid or a pharmaceutically acceptable salt thereof, peppermint oil, and a stabilizer selected from isopropyl myristate, clomiphene, and lauryl cyanide. At least one of the ketones. For the composition of S-2-(2-fluoro-4-biphenyl)propionic acid and peppermint oil, due to the chemical reaction of S-2-(2-fluoro-4-biphenyl)propionic acid, the content of the active pharmaceutical ingredient decreases over time during storage, resulting in poor stability. The present invention has screened out three stabilizers that can significantly improve the storage stability of the pharmaceutical composition.

[0022] Preferably, in the pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid of the present invention, the amount of stabilizer is 0.5 to 3 times that of S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt. This ratio balances the long-term storage stability and usability of the pharmaceutical composition.

[0023] Pharmaceutical salts of S-2-(2-fluoro-4-biphenyl)propionic acid, such as sodium salts and potassium salts.

[0024] The content of S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt is generally 0.1-10% relative to the total pharmaceutical composition, preferably 0.2-3%.

[0025] The content of peppermint oil relative to the total pharmaceutical composition is typically 0.1% to 10%, preferably 0.2% to 3%.

[0026] The pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid of the present invention can be prepared into topical formulations, such as patches, ointments, liniments, gels, lotions, creams, etc., with patches and ointments being particularly preferred. The topical formulations containing S-2-(2-fluoro-4-biphenyl)propionic acid are prepared by adding some functional excipients of the topical formulation to the above-mentioned pharmaceutical composition.

[0027] For example, a plaster containing S-2-(2-fluoro-4-biphenyl)propionic acid, by weight, includes 0.2-1 parts of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, 0.2-1 parts of peppermint oil, 0.1-3 parts of stabilizer, 20-60 parts of glycerin, 30-60 parts of purified water, 4-10 parts of matrix material, 0.1-1 parts of crosslinking agent, 0.1-2 parts of crosslinking regulator, 2-15 parts of thickener, 1-10 parts of filler, 0.1-3 parts of pH adjuster, and 0-3 parts of antibacterial agent. The matrix material can be sodium polyacrylate, partially neutralized sodium polyacrylate, etc.; the crosslinking agent can be alumina, aluminum hydroxide, aluminum hydroxyl, etc.; the crosslinking regulator can be disodium edetate, dicalcium edetate, etc.; the thickener can be gelatin, sodium carboxymethyl cellulose, carbomer, polyvinyl alcohol, etc.; the pH adjuster can be tartaric acid, citric acid, sodium tartrate, etc.; the filler can be kaolin, zinc oxide, etc.; the antibacterial agent can be phenoxyethanol, methylparaben, ethylparaben, propylparaben, etc. The matrix material, crosslinking agent, and filler are added to the glycerol phase and mixed evenly. The thickener, crosslinking regulator, and antibacterial agent are added to the aqueous phase and mixed evenly. After the aqueous and oil phases are mixed evenly, the pH adjuster, active pharmaceutical ingredient, and stabilizer are added, and the mixture is prepared into an ointment. The ointment is then coated onto the backing layer and release layer, slit, and packaged to obtain the final product.

[0028] The ointment, by weight, comprises 1-3 parts of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, 0.5-3 parts of peppermint oil, 0.5-9 parts of stabilizer, 50-80 parts of white petrolatum, 1-10 parts of stearyl alcohol, 1-5 parts of ethylene glycol stearate, and 10-30 parts of anhydrous ethanol. The white petrolatum, stearyl alcohol, and ethylene glycol stearate are heated and stirred until melted, and kept warm as the oil phase. The active pharmaceutical ingredient, stabilizer, and peppermint oil are added to anhydrous ethanol, and stirred as the alcohol phase. The alcohol phase is then added to the oil phase, stirred, homogenized, and emulsified to obtain the ointment containing S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt.

[0029] The liniment, by weight, comprises 1-3 parts of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, 1-3 parts of peppermint oil, 0.5-9 parts of stabilizer, 5-40 parts of dimethyl sulfoxide, 10-30 parts of glycerin, and 10-50 parts of purified water, prepared by uniformly mixing the active pharmaceutical ingredient, peppermint oil, stabilizer, dimethyl sulfoxide, glycerin, and purified water.

[0030] The gel, by weight, comprises 1-3 parts of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, 1-3 parts of peppermint oil, 0.5-9 parts of stabilizer, 40-90 parts of purified water, 0.2-5 parts of thickener, 0-20 parts of humectant, 0-5 parts of pH adjuster, and 0-2 parts of antibacterial agent. The pH adjuster can be sodium hydroxide, potassium hydroxide, triethanolamine, etc.; the thickener can be carbomer, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, etc.; the humectant can be glycerin, propylene glycol, 1,3-butanediol, etc.; and the antibacterial agent can be phenoxyethanol, methylparaben, ethylparaben, propylparaben, etc. It is prepared by adding the active pharmaceutical ingredient, peppermint oil, stabilizer, pH adjuster, thickener, humectant, and antibacterial agent to purified water and mixing thoroughly.

[0031] The lotion, by weight, comprises 1-3 parts of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, 1-3 parts of peppermint oil, 0.5-9 parts of stabilizer, 2-20 parts of calamine, 2-10 parts of zinc oxide, 5-30 parts of glycerin, and 40-80 parts of purified water. The calamine and zinc oxide are finely ground, sieved, and mixed. Then, the active pharmaceutical ingredient, stabilizer, glycerin, peppermint oil, and purified water are added and stirred until homogeneous.

[0032] For creams, by weight, the following components are included: 1-3 parts of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt; 1-3 parts of peppermint oil; 0.5-9 parts of stabilizer; 8-20 parts of petrolatum; 2-10 parts of stearyl alcohol; 5-20 parts of glycerin; 50-80 parts of purified water; and 1-3 parts of dimethyl sulfoxide. The petrolatum is melted by heating in a water bath to form the oil phase. Stearyl alcohol, glycerin, and purified water are heated and stirred until homogeneous to form the aqueous phase. The aqueous phase is slowly added to the oil phase while continuously stirring, followed by the stabilizer, peppermint oil, active pharmaceutical ingredient, and dimethyl sulfoxide. After condensation, a cream containing S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt is obtained.

[0033] This invention also provides a patch containing S-2-(2-fluoro-4-biphenyl)propionic acid, comprising the pharmaceutically active ingredient S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutically acceptable salt, peppermint oil, stabilizer, matrix, tackifier, and plasticizer, wherein the stabilizer is selected from isopropyl myristate, clomiphene, and lauryl cyanide. At least one of the ketones.

[0034] Preferably, the patch containing S-2-(2-fluoro-4-biphenyl)propionic acid of the present invention comprises, by weight parts:

[0035]

[0036]

[0037] Preferably, in the patch containing S-2-(2-fluoro-4-biphenyl)propionic acid of the present invention, the amount of stabilizer is 0.5 to 3 times that of S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt.

[0038] Preferably, the patch containing S-2-(2-fluoro-4-biphenyl)propionic acid of the present invention is a hot-melt patch. The hot-melt patch includes a matrix, a tackifier, and a plasticizer. The matrix can be selected from styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, styrene-ethylene-butene-styrene block copolymers, or styrene-ethylene-propylene-styrene block copolymers, polyisobutylene, polybutene, etc., preferably styrene-isoprene-styrene block copolymers and polyisobutylene. The tackifier can be selected from rosin resins, terpene resins, terpene phenolic resins, petroleum resins, etc., preferably rosin resins, more preferably hydrogenated rosin glycerol esters. The plasticizer can be a substance with good compatibility with the matrix components, such as liquid paraffin, peanut oil, olive oil, etc. One or more of these can be used in combination, with liquid paraffin being particularly preferred.

[0039] Preferably, the plasters, ointments, liniments, gels, lotions, creams, patches, etc. containing S-2-(2-fluoro-4-biphenyl)propionic acid may also selectively add solubilizers, penetration enhancers, antioxidants, fillers, pH adjusters, anti-irritants, antibacterial agents, fragrances and flavors as needed, within the range that does not affect the overall quality and efficiency of the preparation.

[0040] According to another aspect of the present invention, a method for preparing the above-mentioned patch containing S-2-(2-fluoro-4-biphenyl)propionic acid is also provided, comprising the following steps: heating and mixing S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, peppermint oil, stabilizer, matrix, tackifier and plasticizer to prepare a paste, applying the paste to a release layer and a backing material and cutting it to obtain the patch.

[0041] The present application will be further described in detail below through specific embodiments. The following embodiments are only for further illustration of the present application and should not be construed as limiting the present application.

[0042] The reagents and raw materials used in this invention are all commercially available.

[0043] Experimental Example 1

[0044] According to the composition in Table 1 below, the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl)propionic acid, peppermint oil, and stabilizers (isopropyl myristate, lauryl nitrate) are added. Ketones, clomiphene, propylene glycol dicaprylate, propylene glycol monolaurate, glyceryl monooleate, oleic acid, and diethylene glycol monoethyl ether were mixed in a 1:1:2 ratio and incubated at 60°C. Samples were taken at 1, 2, and 3 months to determine the content of the active pharmaceutical ingredient (API). The residual rate (%) of the API was calculated to evaluate stability. The results are shown in Table 2 and... Figure 1 As shown.

[0045] Table 1

[0046]

[0047] Table 2

[0048]

[0049] Table 2 and Figure 1 The results show that the stabilizers used in this invention (isopropyl myristate, lauryl nitrate) are effective. Ketones and clomiphene have a significant effect on improving the stability of pharmaceutical compositions.

[0050] Experiment Example 2

[0051] The pharmaceutical compositions of the present invention containing S-2-(2-fluoro-4-biphenyl)propionic acid, peppermint oil, and stabilizers were prepared into plasters, ointments, liniments, lotions, gels, and creams according to the composition ratios in Table 3. After packaging, the stability was investigated under constant temperature conditions of 25°C. After 6 months, samples were taken to determine the residual content (%) of the active pharmaceutical ingredient (S-2-(2-fluoro-4-biphenyl)propionic acid) to evaluate the stability. The test results are shown in Table 4.

[0052] Table 3

[0053]

[0054]

[0055] Table 4

[0056]

[0057] The above results indicate that the pharmaceutical compositions of the present invention containing S-2-(2-fluoro-4-biphenyl)propionic acid, peppermint oil, and stabilizers exhibit good storage stability when formulated into plasters, ointments, liniments, lotions, gels, and creams.

[0058] Experimental Example 3

[0059] The pharmaceutical composition of the present invention, containing S-2-(2-fluoro-4-biphenyl)propionic acid, menthol oil, and stabilizer, was prepared into a patch, and the stability of the patch was investigated.

[0060] Preparation method: According to the composition in Table 5, S-2-(2-fluoro-4-biphenyl)propionic acid, peppermint oil, stabilizer, matrix, tackifier and plasticizer are mixed under high temperature to prepare a paste, which is then applied to the release layer and backing material and cut to obtain a patch containing S-2-(2-fluoro-4-biphenyl)propionic acid.

[0061] Test method: The prepared patch was sealed in an aluminum-plastic composite film bag and placed under constant temperature conditions of 60℃ and 25℃ respectively. Samples were taken at 60℃ for 1 month, 2 months and 3 months respectively, and at 25℃ for 6 months. The residual content (%) of the active pharmaceutical ingredient (S-2-(2-fluoro-4-biphenyl)propionic acid) was determined to evaluate the stability. The test results are shown in Table 6.

[0062] Table 5

[0063]

[0064] Note: In this invention, "appropriate amount" refers to adding up to a total of 100 portions.

[0065] Table 6

[0066]

[0067] The above results indicate that the stabilizers of this invention (isopropyl myristate, crombutin, and lauryl nitrate) The ketone significantly improves the stability of compositions containing S-2-(2-fluoro-4-biphenyl)propionic acid and peppermint oil, and its effect is superior to that of propylene glycol dioctanoate disclosed in JP6023358B2.

[0068] The present invention contains stabilizers (isopropyl myristate, clomiphene, and lauryl nitrate). The topical formulation of S-2-(2-fluoro-4-biphenyl)propionic acid and menthol oil exhibits good long-term stability.

[0069] The above description, in conjunction with specific embodiments, provides a further detailed explanation of this application and should not be construed as limiting the specific implementation of this application to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of this application, and all such modifications or substitutions should be considered within the scope of protection of this application.

Claims

1. A pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid, characterized in that, Contains: S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, peppermint oil, and a stabilizer selected from at least one of clomiphene and laurocapram; The amount of the stabilizer is 0.5 to 3 times that of S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt.

2. The pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 1, characterized in that, It is a topical preparation.

3. The pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 2, characterized in that, These include patches, plasters, ointments, liniments, gels, lotions, and creams.

4. A patch containing S-2-(2-fluoro-4-biphenyl)propionic acid, characterized in that, By weight, it includes: 1 to 3 parts of S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt 1-3 parts peppermint oil Stabilizer 0.5-9 parts, 20-50 parts of matrix, 10-30 parts of thickener Plasticizer 20-60 parts; The stabilizer is selected from at least one of clomiphene and laurocapram; the amount of stabilizer used is 0.5 to 3 times that of S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt.

5. The patch containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 4, characterized in that, The matrix is ​​selected from styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butene-styrene block copolymer, or styrene-ethylene-propylene-styrene block copolymer, polyisobutylene, and polybutene. The tackifier is selected from rosin resins, terpene resins, terpene phenolic resins, and petroleum resins. The plasticizer is selected from liquid paraffin, peanut oil, and olive oil.

6. The method for preparing the patch containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 4 or 5, characterized in that, Includes the following steps: S-2-(2-fluoro-4-biphenyl)propionic acid or its pharmaceutical salt, peppermint oil, stabilizer, matrix, thickener, and plasticizer are combined under high temperature conditions to prepare a paste. The paste is then applied to the release layer and backing material and cut to obtain the final product.

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