Pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid, patch and preparation method thereof

Abstract

The invention provides a long-term stable pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid, a patch containing S-2-(2-fluoro-4-biphenyl) propionic acid and a preparation method of the patch, and the pharmaceutical composition comprises S-2-(2-fluoro-4-biphenyl) propionic acid or a pharmaceutical salt thereof, dementholized peppermint oil and a stabilizer, the stabilizing agent is selected from at least one of isopropyl myristate, crotamiton and laurocapram # imgabs0 # ketone. According to the pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid disclosed by the invention, at least one of isopropyl myristate, crotamiton and laurinol # imgabs 1 # ketone is used as a stabilizer to be added into the composition of S-2-(2-fluoro-4-biphenyl) propionic acid and dementholized peppermint oil, so that the storage stability of the composition can be obviously improved, and compared with the prior art, the pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid has the advantages that the storage stability of the composition is obviously improved; the content of the active ingredient S-2-(2-fluoro-4-biphenyl) propionic acid is further inhibited along with the reduction of time.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a long-term stable pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid, a patch made from the pharmaceutical composition and a preparation method thereof. Background Art

[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 external preparations and is mostly used in the form of a racemate. S-2-(2-Fluoro-4-biphenyl)propionic acid obtained by optically resolving the S-isomer of the active entity has better anti-inflammatory and analgesic effects than the racemate.

[0003] Japanese patent JP3782834B2 proposes a topical composition containing peppermint oil and SEFSOL as a transdermal absorption accelerator. However, the topical composition is confirmed to reduce the effective ingredient over time due to the chemical reaction of the active ingredient S-2-(2-fluoro-4-biphenyl) propionic acid during storage. Japanese patent JP6023358B2 proposes that for a topical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid and peppermint oil as a transdermal absorption accelerator, only when the medium-chain fatty acid esters of certain specific polyols, i.e., selected from esters with two medium-chain fatty acids bonded to propylene glycol and esters with three medium-chain fatty acids bonded to glycerol, the content of the active ingredient is suppressed over time, and the active ingredient remains stable even in the case of long-term storage. However, we found that in the topical composition, as time is further extended, the content of the active ingredient is still significantly reduced. Summary of the invention

[0004] The object of the present 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 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, which comprises: S-2-(2-fluoro-4-biphenyl) propionic acid or a pharmaceutically acceptable salt thereof, peppermint oil and a stabilizer, wherein the stabilizer is selected from isopropyl myristate, crotamiton, lauryl nitrogen At least one of ketones.

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

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

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

[0010] According to another aspect of the present invention, there is provided a patch 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, a stabilizer, a matrix, a tackifier and a plasticizer, wherein the stabilizer is selected from isopropyl myristate, crotamiton, lauryl nitrogen At least one of ketones.

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

[0012]

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

[0014] Furthermore, the matrix is ​​selected from styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butylene-styrene block copolymer or styrene-ethylene-propylene-styrene block copolymer, polyisobutylene, polybutene, the tackifier is selected from rosin resin, terpene resin, terpene phenolic resin, 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 ​​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, there is also provided a method for preparing the above-mentioned patch containing S-2-(2-fluoro-4-biphenyl)propionic acid, comprising the following steps:

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

[0018] Beneficial effects of the present invention:

[0019] The pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid of the present invention is prepared by using isopropyl myristate, crotamiton, lauryl nitrogen At least one of the ketones is added as a stabilizer to the combination of S-2-(2-fluoro-4-biphenyl)propionic acid and peppermint oil, which can significantly improve the storage stability of the composition of S-2-(2-fluoro-4-biphenyl)propionic acid and peppermint oil. Compared with the prior art, the decrease in the content of the active ingredient S-2-(2-fluoro-4-biphenyl)propionic acid over time is further suppressed. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Schematic diagram of the results of the embodiment and comparative example in Experimental Example 1. DETAILED DESCRIPTION

[0021] The invention provides a pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid, which comprises: S-2-(2-fluoro-4-biphenyl) propionic acid or a pharmaceutically acceptable salt thereof, peppermint oil and a stabilizer, wherein the stabilizer is selected from isopropyl myristate, crotamiton, lauryl nitrogen 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 ingredient of the medicine will decrease over time during storage, and the stability is not very good. The present invention screens out three stabilizers, which 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 the stabilizer is 0.5 to 3 times the amount of S-2-(2-fluoro-4-biphenyl)propionic acid or a pharmaceutically acceptable salt thereof. At this ratio, both the long-term storage stability and the usability of the pharmaceutical composition are taken into account.

[0023] The pharmaceutically acceptable salt of S-2-(2-fluoro-4-biphenyl)propionic acid is, for example, sodium salt or potassium salt.

[0024] The content of S-2-(2-fluoro-4-biphenyl)propionic acid or a pharmaceutically acceptable salt thereof is generally 0.1 to 10%, preferably 0.2 to 3%, based on the total amount of the pharmaceutical composition.

[0025] The content of peppermint oil is usually 0.1 to 10%, preferably 0.2 to 3%, based on the total amount of the pharmaceutical composition.

[0026] The pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl) propionic acid of the present invention can be prepared into an external preparation, such as a patch, a plaster, an ointment, a liniment, a gel, a lotion, a cream, etc., and is particularly preferably made into a patch and a plaster. The external preparation containing S-2-(2-fluoro-4-biphenyl) propionic acid is prepared by adding some functional excipients of the external preparation to the above pharmaceutical composition.

[0027] For example: a patch containing S-2-(2-fluoro-4-biphenyl) propionic acid, calculated by weight, includes 0.2 to 1 parts of the active ingredient S-2-(2-fluoro-4-biphenyl) propionic acid or its pharmaceutical salt, 0.2 to 1 parts of peppermint oil, 0.1 to 3 parts of stabilizer, 20 to 60 parts of glycerol, 30 to 60 parts of purified water, 4 to 10 parts of skeleton material, 0.1 to 1 parts of cross-linking agent, 0.1 to 2 parts of cross-linking regulator, 2 to 15 parts of viscosity enhancer, 1 to 10 parts of filler, 0.1 to 3 parts of pH regulator, and 0 to 3 parts of antibacterial agent. The skeleton material can be selected from sodium polyacrylate, partially neutralized sodium polyacrylate, etc.; the cross-linking agent can be selected from aluminum trioxide, aluminum hydroxide, aluminum glycolate, etc.; the cross-linking regulator can be selected from disodium edetate, dicalcium edetate, etc.; the viscosity enhancer can be selected from gelatin, sodium carboxymethyl cellulose, carbomer, polyvinyl alcohol, etc.; the pH adjuster can be selected from tartaric acid, citric acid, sodium tartrate, etc.; the filler can be selected from kaolin, zinc oxide, etc.; the antibacterial agent can be selected from phenoxyethanol, methylparaben, ethylparaben, propylparaben, etc. The skeleton material, cross-linking agent, and filler are added to the glycerin phase and mixed evenly, the viscosity enhancer, cross-linking regulator, and antibacterial agent are added to the water phase and mixed evenly, the water phase and the oil phase are mixed evenly, and the pH adjuster, the active pharmaceutical ingredient, and the stabilizer are added, and the mixture is mixed to make a paste, and the paste is coated on the backing layer and the release layer, and the paste is cut and packaged.

[0028] The ointment comprises, by weight, 1 to 3 parts of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl) propionic acid or its pharmaceutically acceptable salt, 0.5 to 3 parts of peppermint oil, 0.5 to 9 parts of a stabilizer, 50 to 80 parts of white vaseline, 1 to 10 parts of octadecyl alcohol, 1 to 5 parts of ethylene glycol stearate, and 10 to 30 parts of anhydrous ethanol. The white vaseline, octadecyl alcohol, and ethylene glycol stearate are heated, stirred, and melted, and the mixture is kept warm as the oil phase for later use; the active pharmaceutical ingredient, stabilizer, and peppermint oil are added to anhydrous ethanol, and the mixture is stirred as the alcohol phase for later use; the alcohol phase is added to the oil phase, and the mixture is stirred and emulsified to obtain an ointment containing S-2-(2-fluoro-4-biphenyl) propionic acid or its pharmaceutically acceptable salt.

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

[0030] The gel, by weight, includes 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 moisturizer, 0-5 parts of pH regulator, and 0-2 parts of antibacterial agent. The pH regulator can be selected from sodium hydroxide, potassium hydroxide, triethanolamine, etc., the thickener can be selected from carbomer, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, etc., the moisturizer can be selected from glycerin, propylene glycol, 1,3-butylene glycol, etc., and the antibacterial agent can be selected from phenoxyethanol, methylparaben, ethylparaben, propylparaben, etc. The active pharmaceutical ingredient, peppermint oil, stabilizer, pH regulator, thickener, moisturizer and antibacterial agent are added to purified water and mixed evenly.

[0031] The lotion comprises, by weight, 1 to 3 parts of a pharmaceutically active ingredient, S-2-(2-fluoro-4-biphenyl) propionic acid or a pharmaceutically acceptable salt thereof, 1 to 3 parts of peppermint oil, 0.5 to 9 parts of a stabilizer, 2 to 20 parts of calamine, 2 to 10 parts of zinc oxide, 5 to 30 parts of glycerol, and 40 to 80 parts of purified water. The lotion is prepared by grinding calamine and zinc oxide, sieving and mixing, then adding the pharmaceutically active ingredient, stabilizer, glycerol, peppermint oil and purified water, and stirring evenly.

[0032] For the cream, by weight, it includes 1-3 parts of the active pharmaceutical ingredient S-2-(2-fluoro-4-biphenyl) propionic acid or its pharmaceutically acceptable salt, 1-3 parts of peppermint oil, 0.5-9 parts of stabilizer, 8-20 parts of vaseline, 2-10 parts of octadecyl alcohol, 5-20 parts of glycerol, 50-80 parts of purified water, and 1-3 parts of dimethyl sulfoxide. The vaseline is heated and melted in a water bath to serve as the oil phase; the octadecyl alcohol, glycerol, and purified water are heated and stirred evenly to serve as the water phase; the water phase is slowly added to the oil phase under continuous stirring, and then the stabilizer, peppermint oil, active pharmaceutical ingredient, and dimethyl sulfoxide are added, and after condensation, a cream containing S-2-(2-fluoro-4-biphenyl) propionic acid or its pharmaceutically acceptable salt is obtained.

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

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

[0035]

[0036]

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

[0038] Preferably, the patch containing S-2-(2-fluoro-4-biphenylyl) propionic acid of the present invention is a hot-melt patch, and the hot-melt patch includes substrate, tackifier, plasticizer, and substrate can be selected as styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butylene-styrene block copolymer or styrene-ethylene-propylene-styrene block copolymer, polyisobutylene, polybutene etc., preferably styrene-isoprene-styrene block copolymer and polyisobutylene. Tackifier can be selected as rosin-based resin, terpene resin, terpene phenolic resin, petroleum resin etc., preferably rosin-based resin, more preferably hydrogenated rosin glyceride. Plasticizer can be selected and substrate component compatible material, such as liquid paraffin, peanut oil, olive oil etc. Can adopt 1 or more mixed use, wherein particularly preferably liquid paraffin.

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

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

[0041] The present application is further described in detail below through specific examples. The following examples are only used to further illustrate the present application and should not be construed as limiting the present application.

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

[0043] Experimental Example 1

[0044] According to the composition in Table 1 below, the active ingredient S-2-(2-fluoro-4-biphenyl) propionic acid, peppermint oil, stabilizer (isopropyl myristate, lauryl nitrogen) Ketone, crotamiton, propylene glycol dicaprylate, propylene glycol monolaurate, glyceryl monooleate, oleic acid, diethylene glycol monoethyl ether) were mixed in a ratio of 1:1:2 and kept at a constant temperature of 60°C. Samples were taken at 1 month, 2 months and 3 months to determine the content of the active ingredient of the drug, and the residual rate (%) of the active ingredient of the drug was calculated to evaluate the stability. The results are shown in Table 2 and Figure 1 shown.

[0045] Table 1

[0046]

[0047] Table 2

[0048]

[0049] Table 2 and Figure 1 The results show that the stabilizers used in the present invention (isopropyl myristate, lauryl nitrogen Ketone, crotamiton) have a significant improvement effect on the stability of the pharmaceutical composition.

[0050] Experimental Example 2

[0051] The pharmaceutical composition of the present invention containing S-2-(2-fluoro-4-biphenyl) propionic acid, peppermint oil and a stabilizer was prepared into a patch, an ointment, a liniment, a lotion, a gel and a cream according to the composition ratio in Table 3. After packaging, the stability was investigated under a constant temperature of 25° C. After 6 months, samples were taken to determine the residual rate (%) of the active 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 show that the pharmaceutical composition of the present invention containing S-2-(2-fluoro-4-biphenyl)propionic acid, peppermint oil and stabilizer has good storage stability when prepared 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, peppermint oil and a 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 conditions to prepare a paste, which is applied on a release layer and a 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 at constant temperatures of 60°C and 25°C, respectively. Samples were taken at 60°C at 1 month, 2 months and 3 months, and at 25°C at 6 months to determine the residual rate (%) of the active ingredient (S-2-(2-fluoro-4-biphenyl) propionic acid) to evaluate the stability. The test results are shown in Table 6.

[0062] Table 5

[0063]

[0064] Note: In the present invention, an appropriate amount refers to adding to a total amount of 100 parts.

[0065] Table 6

[0066]

[0067] The above results show that the stabilizer of the present invention (isopropyl myristate, crotamiton and lauryl nitrogen Ketone) has a significant improvement effect on the stability of the composition containing S-2-(2-fluoro-4-biphenyl)propionic acid and mint oil, and the effect is better than that of propylene glycol dicaprylate disclosed in JP6023358B2.

[0068] The present invention contains stabilizer (isopropyl myristate, crotamiton and lauryl nitrogen The external preparation composition of S-2-(2-fluoro-4-biphenyl)propionic acid and peppermint oil containing 1,2-difluoro-2-nitrophenyl propionic acid and 1,2-difluoro-2-nitrophenyl propionic acid has good long-term stability.

[0069] The above contents are further detailed descriptions of the present application in combination with specific implementation methods, and it cannot be determined that the specific implementation of the present application is limited to these descriptions. For ordinary technicians in the technical field to which the present application belongs, several simple deductions or substitutions can be made without departing from the concept of the present application, which should be deemed to fall within the scope of protection of the present application.

Claims

1. A pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid, It is characterized in that The invention comprises: S-2-(2-fluoro-4-biphenyl) propionic acid or a pharmaceutically acceptable salt thereof, peppermint oil and a stabilizer, wherein the stabilizer is selected from isopropyl myristate, crotamiton, lauryl nitrogen At least one of ketones.

2. The pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 1, It is characterized in that The dosage of the stabilizer is 0.5 to 3 times of S-2-(2-fluoro-4-biphenyl) propionic acid or its pharmaceutically acceptable salt.

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

4. The pharmaceutical composition containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 3, It is characterized in that It is a patch, a plaster, an ointment, a liniment, a gel, a lotion, a cream.

5. A patch containing S-2-(2-fluoro-4-biphenyl)propionic acid, It is characterized in that The invention comprises S-2-(2-fluoro-4-biphenyl) propionic acid or a pharmaceutically acceptable salt thereof, peppermint oil, a stabilizer, a matrix, a tackifier and a plasticizer, The stabilizer is selected from isopropyl myristate, crotamiton, lauryl nitrogen At least one of ketones.

6. The patch containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 5, It is characterized in that In parts by weight, it includes:

7. The patch containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 5 or 6, It is characterized in that The dosage of the stabilizer is 0.5 to 3 times of S-2-(2-fluoro-4-biphenyl) propionic acid or its pharmaceutically acceptable salt.

8. The patch containing S-2-(2-fluoro-4-biphenyl)propionic acid according to claim 5 or 6, It is characterized in that The matrix is ​​selected from styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-ethylene-butylene-styrene block copolymer or styrene-ethylene-propylene-styrene block copolymer, polyisobutylene, polybutylene, The tackifier is selected from rosin resin, terpene resin, terpene phenolic resin, petroleum resin, The plasticizer is selected from liquid paraffin, peanut oil and olive oil.

9. A method for preparing a patch containing S-2-(2-fluoro-4-biphenyl)propionic acid according to any one of claims 5 to 8, It is characterized in that The steps include: S-2-(2-fluoro-4-biphenyl) propionic acid or its pharmaceutical salt, peppermint oil, stabilizer, matrix, tackifier and plasticizer are mixed under high temperature to prepare a paste, and the paste is coated on a release layer and a backing material and cut to obtain the product.

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