Topical pharmaceutical composition

Abstract

The present invention provides a topical pharmaceutical composition that contains a nonsteroidal anti-inflammatory drug, a lower alcohol, vitamin E derivatives, and water, without the harmful effects caused by high concentrations of alcohol, and without suppressing the precipitation of insoluble substances. [Solution] The topical pharmaceutical composition of the present invention contains (A) a nonsteroidal anti-inflammatory drug, (B) a nonionic surfactant with an HLB value greater than 6.5, (C) 30-45% by weight of a lower alcohol, (D) an antihistamine, (E) 0.1-2% by weight of vitamin E derivatives, (F) 3-6% by weight of monoterpenes, and (G) water.

Description

Technical Field

[0001] The present invention relates to an external pharmaceutical composition containing a non-steroidal anti-inflammatory drug as a main drug. More specifically, the present invention relates to an external pharmaceutical composition that contains a non-steroidal anti-inflammatory drug, a lower alcohol and vitamin E derivatives at a specific concentration, water, etc., and in which precipitation of insoluble matter is suppressed.

Background Art

[0002] External preparations containing non-steroidal anti-inflammatory drugs, such as patches, tapes, solutions, gels, etc., are commercially available and widely used clinically. So far, for example, an external pharmaceutical composition containing diclofenac, 0.1 to 1% by weight of tocopherol, menthol, water, and 50 to 75% by weight of a lower alcohol is known (Patent Document 1). By using a large amount of the lower alcohol, this external pharmaceutical composition suppresses the formation of cloudiness and precipitates caused by diclofenac and tocopherol.

[0003] Also, in an external pharmaceutical composition containing diclofenac and / or its salt, tocopherol and / or its derivative, and water, an invention is known in which by adding 60 to 70% by weight of a lower alcohol, the formation of cloudiness and precipitates is suppressed (Patent Document 2).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] Patent documents 1 and 2 disclose topical pharmaceutical compositions containing 50-75% by weight of lower alcohol. However, topical pharmaceutical compositions containing 50% or more by weight of lower alcohol have drawbacks such as skin irritation due to alcohol, respiratory irritation due to alcohol volatilization, flammability, and high cost. Therefore, there is a need for topical pharmaceutical compositions with reduced alcohol content. However, reducing the alcohol content leads to problems such as inability to solubilize, resulting in clouding or the formation of precipitates.

[0006] The object of the present invention is to provide a topical pharmaceutical composition that contains a nonsteroidal anti-inflammatory drug, a lower alcohol, vitamin E derivatives, and water, while reducing the alcohol content to eliminate the harmful effects caused by high concentrations of alcohol and suppress the precipitation of insoluble substances. [Means for solving the problem]

[0007] The present inventors conducted diligent studies to solve the aforementioned problems and discovered that by incorporating a specific nonionic surfactant into an external pharmaceutical composition containing a nonsteroidal anti-inflammatory drug (NSAID) which is a combination of a relatively low concentration of lower alcohol, a relatively high concentration of vitamin E, and menthol, the precipitation of insoluble matter is significantly suppressed, thus completing the present invention.

[0008] The topical pharmaceutical composition of the present invention has the following composition. (A) Nonsteroidal anti-inflammatory drugs (B) Nonionic surfactants with an HLB value exceeding 6.5 (C) Lower alcohol 30-45% by weight (D) Antihistamines (E) Vitamin E derivatives 0.1-2% by weight (F) Monoterpenes 3-6% by weight (G)Water

[0009] The topical pharmaceutical composition of the present invention also encompasses the following embodiments. (1) The component (A) comprises at least one selected from diclofenac, loxoprofen, indomethacin, felbinac and / or a pharmaceutically acceptable salt thereof. (2) The component (B) contains 2.0 to 35% by weight of at least one selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, and polyethylene glycol fatty acid ester. (3) The component (C) is ethanol and / or isopropanol. (4) The component (D) is 0.1% by weight of chlorpheniramine and / or a pharmaceutically acceptable salt thereof. (5) The above-mentioned component (E) is 1-2% by weight of tocopherol acetate. (6) The above-mentioned component (F) is menthol. (7)(H)Contains a pH adjusting agent, and the pH is 5.5 to 7.5. (8) The formulation is in the form of an external liquid or gel. [Effects of the Invention]

[0010] According to the present invention, it is possible to provide a topical pharmaceutical composition that contains a nonsteroidal anti-inflammatory drug, a lower alcohol, vitamin E derivatives, and water, without the harmful effects caused by high concentrations of alcohol, and with suppressed precipitation of insoluble substances. [Modes for carrying out the invention]

[0011] The main components incorporated into the topical pharmaceutical composition of the present invention will now be described. In this specification, the amount of each component is given in weight percent, and even when simply referred to as weight percent, it refers to the amount relative to the total amount of the composition.

[0012] (A) Nonsteroidal anti-inflammatory drugs Preferred nonsteroidal anti-inflammatory drugs (NSAIDs) for the present invention include diclofenac, loxoprofen, indomethacin, felbinac, and pharmaceutically acceptable salts thereof. Examples of these salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts; salts with ammonia; salts with primary, secondary, or tertiary alkylamines such as dimethylamine, diethylamine, trimethylamine, and triethylamine; and salts with primary, secondary, or tertiary alkanolamines such as monoethanolamine, diethanolamine, diisopropanolamine, triethanolamine, and triisopropanolamine. Among these, alkali metal salts are preferred, and sodium salts are more preferred. These NSAIDs may be used individually or in combination of two or more.

[0013] In particular, from the viewpoint of more significantly exhibiting the effects of the present invention, a combination of one or more of diclofenac sodium, loxoprofen sodium hydrate, indomethacin, and felbinac is preferred. The amount of each is 0.5 to 3.0% by weight, preferably 1.0 to 3.0% by weight, based on the total amount of the composition.

[0014] (B) Nonionic surfactants Examples of nonionic surfactants include polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester (e.g., polysorbate 60, polysorbate 80, etc.), polyoxyethylene sorbit fatty acid ester, polyoxyethylene glycerin fatty acid ester, glycerin fatty acid ester (e.g., glycerin monostearate, etc.), polyglycerin fatty acid ester, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene sterol, polyoxyethylene hydrogenated sterol, polyoxyethylene polyoxypropylene alkyl ether, polyethylene glycol fatty acid ester (e.g., polyoxyl 40 stearate, etc.), sucrose fatty acid ester, polyoxyethylene alkyl aryl ether, polyoxyethylene styryl phenyl ether, polyoxyethylene phenyl ether polymer, polyoxyethylene alkylene aryl phenyl ether, and the like.

[0015] Particularly preferred nonionic surfactants include one or a combination of two or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbit fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, and polyethylene glycol fatty acid ester.

[0016] As nonionic surfactants, those having an HLB value (Hydrophile-lipophile balance value, a value representing the degree of affinity between water and an organic compound insoluble in water for nonionic surfactants) exceeding 6.5 are preferred from the viewpoint of the effect of reducing the content of lower alcohols. Also, nonionic surfactants having an HLB value exceeding 6.5 are preferred in that the amount of surfactant added can be reduced and the content of active ingredients such as nonsteroidal anti-inflammatory analgesics in the whole preparation can be increased.

[0017] Table 1 shows the preferred nonionic surfactants of the present invention and their HLB values.

Table 1

[0018] The content of the nonionic surfactant varies depending on its HLB value, the content of active ingredients such as lower alcohols and nonsteroidal anti-inflammatory drugs. However, from the perspective of more significantly achieving the effects of the present invention, it is 0.1 to 40.0% by weight, preferably 1.0 to 40.0% by weight, more preferably 2.0 to 40.0% by weight, and even more preferably 2.0 to 35.0% by weight based on the total amount of the composition. In particular, when a nonionic surfactant with an HLB value exceeding 6.5 is used, its content is 7.0 to 15.0% by weight.

[0019] (C) Lower alcohol As the lower alcohol, for example, a monohydric lower alcohol can be used. The monohydric lower alcohol refers to a monohydric alcohol having 1 to 5 carbon atoms. The type of the monohydric lower alcohol is not particularly limited as long as it is pharmaceutically acceptable. Examples include monohydric lower alcohols having 1 to 4 carbon atoms such as ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, and tert-butanol. These monohydric lower alcohols may be used alone or in combination of two or more. Among these monohydric lower alcohols, ethanol and / or isopropanol are preferably used. When it is ethanol and / or isopropanol, to effectively remove the adverse effects of the alcohol, its content is preferably 30 to 45% by weight, more preferably 30 to 40% by weight based on the total amount of the composition.

[0020] (D) Antihistamine Antihistamines that can be used include chlorpheniramine, isotipendyl, ketotifen, bepotastine, dimenhydrinate, cyproheptadine, diphenylpyraline, promethazine, iproheptine, emedastine, clemastine, azelastine, levocabastine, hydroxyzine, mequitazine, loratadine, fexofenadine, cetirizine, oxatomide, terfenadine, epinastine, astemizole, ebastine, diphenylimidazole, diphenhydramine, or salts of these compounds.

[0021] Preferred antihistamines include diphenhydramine, diphenylpyraline, chlorpheniramine, diphenylimidazole, or salts thereof; more preferred examples are chlorpheniramine, diphenhydramine, or salts thereof; and even more preferred examples are chlorpheniramine, chlorpheniramine maleate, diphenhydramine, or diphenhydramine hydrochloride. One or more of these agents can be used in appropriate combinations. For example, when the antihistamine is chlorpheniramine maleate, the content of chlorpheniramine maleate is preferably 0.05 to 2% by weight, and more preferably 0.1 to 1% by weight, relative to the total amount of the composition, from the viewpoint of more significantly exhibiting the effects of the present invention.

[0022] (E) Vitamin E derivatives As for vitamin E derivatives, dl-α-tocopherol, dl-α-tocopherol succinate, dl-α-tocopherol succinate calcium, dl-α-tocopherol acetate (tocopherol acetate), and dl-α-tocopherol nicotinate are more preferred, with dl-α-tocopherol acetate being particularly preferred. One or more of these agents can be used in appropriate combinations. For example, when the vitamin E derivative is tocopherol acetate, from the viewpoint of more significantly exhibiting the effects of the present invention, the content of tocopherol acetate is preferably 0.1 to 2% by weight, and more preferably 1 to 2% by weight, based on the total amount of the composition.

[0023] (F) Monoterpenes The monoterpenes used in the present invention are not particularly limited as long as they are monoterpenes commonly used in pharmaceuticals, quasi-drugs, and cosmetics, but examples include menthol, camphor, borneol, eugenol, cineole, thymol, bisabolol, α-pinene, or limonene. Menthol or camphor is preferred, and menthol is more preferred. These monoterpenes can be natural or synthetic, and may be d-isomers, l-isomers, or dl-isomers. Among these, l-menthol or dl-camphor is preferred, and l-menthol is more preferred. These monoterpenes can also be used as essential oils containing monoterpenes, and examples include eucalyptus oil, peppermint oil, clove oil, cinnamon oil, peppermint oil, mint oil, tea tree oil, chamomile oil, rosemary oil, lemon oil, orange oil, thyme oil, sage oil, clove oil, etc. Preferably, eucalyptus oil, peppermint oil, or tea tree oil may be used, and more preferably, eucalyptus oil or peppermint oil, etc. These monoterpenes can be used individually or in combination of two or more. The content of monoterpenes can be in the range of 0.001 to 20% by weight, preferably 1 to 10% by weight, and particularly preferably 3 to 6% by weight, based on the total amount of the composition.

[0024] (H) pH adjuster Examples of pH adjusters include adipic acid, citric acid, trisodium citrate, glucono delta-lactone, gluconic acid, potassium gluconate, sodium gluconate, succinic acid, monosodium succinate, disodium succinate, sodium acetate, DL-tartaric acid, L-tartaric acid, DL-potassium bitartrate, L-potassium bitartrate, DL-sodium tartrate, L-sodium tartrate, potassium carbonate (anhydrous), sodium bicarbonate, sodium carbonate, carbon dioxide, lactic acid, potassium lactate, sodium lactate, glacial acetic acid, disodium dihydrogen pyrophosphate, fumaric acid, monosodium fumarate, DL-malic acid, sodium DL-malate, phosphoric acid, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. Furthermore, examples include alkanolamine bases such as diisopropanolamine, triisopropanolamine, triethanolamine, isopropanolamine, diethanolamine, and monoethanolamine; alkylamine bases such as dimethylamine, diethylamine, trimethylamine, and triethylamine; and inorganic bases such as ammonia, aqueous ammonia, sodium hydroxide, and potassium hydroxide. In particular, citric acid hydrate is preferred because it dissolves readily in water and lower alcohols contained in the composition of the present invention. When citric acid hydrate is used as a pH adjusting agent, its content is 0.01 to 5.0% by weight, preferably 0.1 to 1.0% by weight, based on the total amount of the composition, from the viewpoint of more significantly exhibiting the effects of the present invention.

[0025] (I) Formulation The formulation form of the topical pharmaceutical composition of the present invention is not particularly limited, as long as it is applicable transdermally. Examples include liquid formulations (including lotions, sprays, aerosols, and emulsions), foam formulations, ointments, plasters, creams, gels, and patches. Among these, liquid formulations or gel formulations are preferred. These formulations can be prepared by compounding them using additives appropriate to the formulation form, in accordance with known methods described in the General Provisions for Formulations of the 18th Revised Japanese Pharmacopoeia, etc. [Examples]

[0026] Examples and comparative examples of the topical pharmaceutical compositions of the present invention are shown below. Each example and comparative example demonstrates that by using the following four types of nonsteroidal anti-inflammatory drugs (NSAIDs) and adding various nonionic surfactants, the occurrence of precipitates and clouding can be suppressed even when the lower alcohol content is reduced. This fact is not limited to a specific NSAID, but is applicable to NSAIDs in general that are widely used in topical pharmaceutical compositions. 1. Diclofenac sodium 2. Felbinac 3. Indomethacin 4. Loxoprofen sodium hydrate

[0027] Each example and comparative example demonstrates that the effects of adding nonionic surfactants can be fully realized by presenting examples in which the amounts of l-menthol and antihistamines, which are commonly added to topical pharmaceutical compositions, are varied, and furthermore, by presenting examples in which ethanol is used as a lower alcohol in addition to isopropanol.

[0028] This specification provides a detailed description of the components, preparation method, and evaluation method for 1. Diclofenac sodium, while other examples and comparative examples are presented in tables showing the amounts added and their evaluation for each composition. Unless otherwise specified, the examples and comparative examples were carried out using the same methods as for 1. Diclofenac sodium.

[0029] The present invention is not limited to the embodiments described below, but encompasses all external pharmaceutical compositions described in the claims and embodiments of the specification.

[0030] 1. Nonsteroidal anti-inflammatory drugs: Diclofenac sodium (1) Isopropanol 45% by weight, l-menthol 3% by weight, nonionic surfactant 7% by weight fixed [Examples 1-14, Comparative Examples 0-4] These examples and comparative examples are characterized by the addition of 1% by weight of diclofenac sodium as a nonsteroidal anti-inflammatory drug and 45% by weight of isopropanol as a lower alcohol. In these examples and comparative examples, with respect to the solvent (G) water, (A) Nonsteroidal anti-inflammatory drug: Diclofenac sodium 1% by weight (F) Monoterpenes: l-menthol 3% by weight (E) Vitamin E derivatives: Tocopherol acetate 2% by weight (D) Antihistamine: Chlorpheniramine maleate 0.1% by weight (C) Lower alcohol: Isopropanol 45% by weight Tables 2 and 3 show each (B) nonionic surfactant in 7% by weight. (H) pH adjuster: Citric acid hydrate 0.2% by weight The substances were dissolved to prepare the topical pharmaceutical compositions of Examples 1 to 14 and Comparative Examples 0 to 5 shown in Tables 2 to 3. In Comparative Example 0, the amount of (B) nonionic surfactant added was set to 0.

[0031] Specifically, a liquid topical pharmaceutical composition was obtained by adding predetermined amounts of diclofenac sodium, l-menthol, tocopherol acetate, chlorpheniramine maleate, surfactant, pH adjuster, and water to isopropanol and stirring.

[0032] The external pharmaceutical compositions of each example and comparative example were evaluated for their appearance and properties according to the following criteria. ○: No precipitate formation or cloudiness was observed, and the sample was clear. △: Slight cloudiness was observed. ×: The sample was opaque with noticeable clouding.

[0033] [Table 2]

[0034] [Table 3]

[0035] As can be seen from Tables 2 and 3, in Comparative Example 0, where 45% by weight of isopropanol was added as a lower alcohol and no nonionic surfactant was added, and in Comparative Examples 1-4, where a nonionic surfactant with an HLB value of 6.5 or less was added, turbidity occurred. In contrast, in Examples 38 and 1-14, where 45% by weight of isopropanol was added and 7% by weight of a nonionic surfactant with an HLB value of 7.5 or higher was added, no precipitate formation or turbidity was observed, and the solution remained clear.

[0036] (2) Increase or decrease in the amount of isopropanol 30% by weight, l-menthol 6% by weight, and nonionic surfactant added. [Examples 15-23, Comparative Examples 6-20] In the examples and comparative examples of (2) above, the amount of nonionic surfactant added was increased or decreased less than in (1) above. Generally, when the amount of lower alcohol added decreases, precipitates and turbidity tend to occur, but by increasing or decreasing the amount of nonionic surfactant added in the present invention, we confirmed what the lower limit of the amount of isopropanol to add should be.

[0037] [Table 4]

[0038] [Table 5]

[0039] [Table 6]

[0040] As can be seen from these examples, even if the amount of isopropanol added is reduced to 30% by weight, it is possible to prevent the formation of precipitates and turbidity by increasing the amount of nonionic surfactant added to, for example, 13% by weight. As a result, by further reducing the amount of isopropanol added, it is possible to further reduce the adverse effects caused by isopropanol.

[0041] (3) Increase or decrease in the amount of isopropanol 45% by weight, l-menthol 3% by weight, and nonionic surfactant added. [Examples 24-45, Comparative Examples 21-40] In these examples and comparative examples, the amount of l-menthol added was reduced to 3% by weight compared to (2). Generally, monoterpenes such as l-menthol are used as cooling agents and other active ingredients in topical pharmaceutical compositions. However, many of these monoterpenes are oil-soluble, and it is expected that the presence of lower alcohols, which are organic solvents, or the nonionic surfactant of the present invention will affect their effective dissolution. Therefore, we investigated how reducing the amount of l-menthol added to 3% by weight affects the amount of nonionic surfactant added in the present invention.

[0042] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11]

[0043] From these examples and comparative examples, it was found that even when the amount of l-menthol added is 3% by weight, similar to the 6% by weight l-menthol example in (2) above, in a topical pharmaceutical composition with 30% by weight of isopropanol added, even if turbidity occurred with 7% by weight of a nonionic surfactant, increasing the isopropanol to approximately 45% by weight makes it possible to prevent the formation of precipitates and turbidity. In other words, it was confirmed that the inhibitory effect on precipitates and turbidity by the addition of isopropanol in the present invention is exerted even with slight increases or decreases in the amount of monoterpenes such as l-menthol added.

[0044] Furthermore, when large amounts of nonionic surfactant were added, such as 30% or 40% by weight, precipitates and turbidity appeared, confirming that the upper limit for the amount of nonionic surfactant to be added is approximately 25% by weight.

[0045] (4) Increase or decrease in the amount of isopropanol 45% by weight, l-menthol 6% by weight, and nonionic surfactant added. [Examples 46-65, Comparative Examples 41-61] These examples and comparative examples were used to confirm whether the same trend as in (3) above would also appear when 6% by weight of l-menthol was added.

[0046] [Table 12]

[0047] [Table 13]

[0048] [Table 14]

[0049] [Table 15]

[0050] [Table 16]

[0051] These examples and comparative examples confirm that even when 6% by weight of l-menthol is added, the formation of precipitates and turbidity can be prevented in a topical pharmaceutical composition containing 45% by weight of isopropanol by increasing the amount of nonionic surfactant to approximately 25% by weight. Furthermore, it was confirmed that adding large amounts of nonionic surfactant, such as 30% or 40% by weight, resulted in the appearance of precipitates and turbidity, indicating that approximately 25% by weight is the upper limit for the amount of nonionic surfactant to be added.

[0052] 2. Nonsteroidal anti-inflammatory drugs: Felbinac (1) Isopropanol 45% by weight, l-menthol 3% by weight, nonionic surfactant 7% by weight fixed [Examples 66-79, Comparative Example 62] These examples and comparative examples correspond to the examples and comparative examples in (1) above, where the nonsteroidal anti-inflammatory drug in 1. is diclofenac sodium. Specifically, using 3% by weight of felbinac as the nonsteroidal anti-inflammatory drug, and with the amount of various nonionic surfactants fixed at 7% by weight, the amount of isopropanol, a lower alcohol, was reduced to 45% by weight, and the presence or absence of precipitates or turbidity was verified.

[0053] [Table 17]

[0054] [Table 18]

[0055] As shown in the above examples and comparative examples, when 3% by weight of felbinac is used as a nonsteroidal anti-inflammatory drug and 7% by weight of a nonionic surfactant is added, it was confirmed that no precipitates or turbidity occurred even when the amount of isopropanol added was reduced to 45% by weight. Therefore, it was confirmed that felbinac can be used as a nonsteroidal anti-inflammatory drug in the composition of the present invention in the same way as diclofenac sodium in 1.

[0056] (2) Increase or decrease in the amount of isopropanol 45% by weight, l-menthol 3% by weight, and nonionic surfactant added. [Examples 80-107, Comparative Examples 63-74] These examples and comparative examples correspond to (3) of diclofenac sodium in 1., and verify how increasing or decreasing the amount of nonionic surfactant added affects the effects of the present invention.

[0057] [Table 19]

[0058] [Table 20]

[0059] [Table 21]

[0060] [Table 22]

[0061] [Table 23]

[0062] As can be seen from these examples, when felbinac is used as a nonsteroidal anti-inflammatory drug, even if the amount of isopropanol added is reduced to 45% by weight, it is possible to prevent the formation of precipitates and turbidity by increasing the amount of nonionic surfactant added. As a result, by further reducing the amount of isopropanol added, it is possible to further reduce the adverse effects caused by isopropanol.

[0063] (3) Increase or decrease in the amount of isopropanol 45% by weight, l-menthol 6% by weight, and nonionic surfactant added. [Examples 108-136, Comparative Examples 75-81] These examples and comparative examples correspond to (4) of diclofenac sodium in 1., and verify how increasing or decreasing the amount of nonionic surfactant added affects the effects of the present invention.

[0064] [Table 24]

[0065] [Table 25]

[0066] [Table 26]

[0067] [Table 27]

[0068] [Table 28]

[0069] From these examples and comparative examples, it can be seen that even when the amount of l-menthol added is 6% by weight, similar to the 6% by weight l-menthol example in (4) above, it is possible to prevent the formation of precipitates and turbidity by increasing the amount of nonionic surfactant added to approximately 35% by weight in the topical pharmaceutical composition containing 45% by weight isopropanol. In other words, it has been confirmed that the inhibitory effect on precipitates and turbidity by the addition of nonionic surfactants in the present invention can be exerted even with slight increases or decreases in the amount of monoterpenes such as l-menthol added.

[0070] Furthermore, even when the nonsteroidal anti-inflammatory drug (NSAID) is felbinac, adding a large amount of nonionic surfactant, such as 40% by weight, to the NSAID described in 1. above, similar to diclofenac sodium, resulted in the appearance of precipitates and turbidity. Therefore, it was confirmed that the upper limit for the amount of nonionic surfactant to be added is approximately 35% by weight.

[0071] 3. Nonsteroidal anti-inflammatory drugs: Indomethacin (1) Isopropanol 45% by weight, l-menthol 3% by weight, nonionic surfactant 7% by weight fixed [Examples 137-150, Comparative Example 82] These examples and comparative examples correspond to the examples and comparative examples in (1) above, where the nonsteroidal anti-inflammatory drug (NSAID) in 1. is diclofenac sodium. Specifically, using 1% by weight of indomethacin as the NSAID, and with the amount of various nonionic surfactants fixed at 7% by weight, the amount of isopropanol, a lower alcohol, was reduced to 45% by weight, and the presence or absence of precipitates or turbidity was verified.

[0072] [Table 29]

[0073] [Table 30]

[0074] As shown in the above examples and comparative examples, when 1% by weight of indomethacin is used as a nonsteroidal anti-inflammatory drug and 7% by weight of a nonionic surfactant is added, it was confirmed that no precipitates or turbidity occurred even when the amount of isopropanol added was reduced to 45% by weight. Therefore, it was confirmed that indomethacin can be used as a nonsteroidal anti-inflammatory drug in the composition of the present invention in the same way as diclofenac sodium in 1.

[0075] (2) Increase or decrease in the amount of isopropanol 45% by weight, l-menthol 3% by weight, and nonionic surfactant added. [Examples 151-168, Comparative Examples 83-92] These examples and comparative examples correspond to (3) of diclofenac sodium in 1., and verify how increasing or decreasing the amount of nonionic surfactant added affects the effects of the present invention.

[0076] [Table 31]

[0077] [Table 32]

[0078] [Table 33]

[0079] [Table 34]

[0080] [Table 35]

[0081] As can be seen from these examples, even when indomethacin is used as a nonsteroidal anti-inflammatory drug, it is possible to prevent the formation of precipitates and turbidity by increasing the amount of nonionic surfactant added, even if the amount of isopropanol added is reduced to 45% by weight. As a result, by further reducing the amount of isopropanol added, it is possible to further reduce the adverse effects caused by isopropanol.

[0082] (3) Increase or decrease in the amount of isopropanol 45% by weight, l-menthol 6% by weight, and nonionic surfactant added. [Examples 169-190, Comparative Examples 93-99] These examples and comparative examples correspond to (4) of diclofenac sodium in 1., and verify how increasing or decreasing the amount of nonionic surfactant added affects the effects of the present invention when indomethacin is used as a nonsteroidal anti-inflammatory drug.

[0083] [Table 36]

[0084] [Table 37]

[0085] [Table 38]

[0086] [Table 39]

[0087] From these examples and comparative examples, it can be seen that even when indomethacin is used as a nonsteroidal anti-inflammatory drug, and even when the amount of l-menthol added is 6% by weight, it is possible to prevent the formation of precipitates and turbidity in a topical pharmaceutical composition containing 45% by weight of isopropanol, similar to the 6% by weight l-menthol composition in (4) above, by increasing the amount of nonionic surfactant added to about 35% by weight.

[0088] Furthermore, even when the nonsteroidal anti-inflammatory drug is indomethacin, if the nonsteroidal anti-inflammatory drug is diclofenac sodium as described in 1. above, adding a large amount of nonionic surfactant, such as 40% by weight, can conversely cause precipitates or turbidity. Therefore, depending on the type of nonionic surfactant, it is preferable to limit the amount added to about 35% by weight.

[0089] 4. Nonsteroidal anti-inflammatory drugs: Loxoprofen sodium hydrate 1.13% by weight (1) Isopropanol 45% by weight, l-menthol 3% by weight. Nonionic surfactant 7% by weight fixed (only polyethylene glycol monolaurate (MYL-10) is 15% by weight) [Examples 191-202, Example A, Comparative Examples 100-102] These examples and comparative examples correspond to the examples and comparative examples in (1) above, where the nonsteroidal anti-inflammatory drug in 1. is diclofenac sodium. Specifically, using 1.13% by weight of loxoprofen sodium hydrate as the nonsteroidal anti-inflammatory drug, and with the amount of various nonionic surfactants fixed at 7% by weight, the amount of isopropanol, a lower alcohol, was reduced to 45% by weight, and the presence or absence of precipitates or turbidity was verified.

[0090] [Table 40]

[0091] [Table 41]

[0092] As is clear from the above examples and comparative examples, even when loxoprofen sodium hydrate is used as the nonsteroidal anti-inflammatory drug, it is possible to reduce the amount of isopropanol, a lower alcohol, to 45% by weight. Regarding polyethylene glycol monolaurate (MYL-10), turbidity occurred at 7% by weight, but increasing the amount to 15% by weight prevented the occurrence of precipitates and turbidity. This also confirms that, by increasing or decreasing the amount of nonionic surfactant around 7% by weight in response to the occurrence of precipitates and turbidity, it is possible to prevent the occurrence of precipitates and turbidity when loxoprofen sodium hydrate is used as the nonsteroidal anti-inflammatory drug, similar to the other nonsteroidal anti-inflammatory drugs mentioned above, by limiting the amount of isopropanol to 45% or less.

[0093] (2) Increase or decrease in the amount of isopropanol 45% by weight, l-menthol 3% by weight, and nonionic surfactant added. [Examples 203-219, Comparative Examples 103-118] These examples and comparative examples correspond to (3) of diclofenac sodium in 1., and use 1.13% by weight of loxoprofen sodium hydrate as a nonsteroidal anti-inflammatory drug to verify how increasing or decreasing the amount of nonionic surfactant added affects the effects of the present invention.

[0094] [Table 42]

[0095] [Table 43]

[0096] [Table 44]

[0097] [Table 45]

[0098] [Table 46]

[0099] As can be seen from these examples, even when using 1.13% by weight of loxoprofen sodium hydrate as a nonsteroidal anti-inflammatory drug, it is possible to prevent the formation of precipitates and turbidity by increasing the amount of nonionic surfactant added, even when the amount of isopropanol added is reduced to 45% by weight. As a result, by further reducing the amount of isopropanol added, it is possible to further reduce the adverse effects caused by isopropanol.

[0100] 5. Lower alcohols: Ethanol 45% by weight, 30% by weight The following examples and comparative examples verify the difference in solubility with and without a nonionic surfactant at each concentration, adjusted to the upper and lower limits of ethanol (45% by weight, 30% by weight) when ethanol was used instead of isopropanol as the lower alcohol used in each of the examples and comparative examples in 1 to 4 above.

[0101] (1) Nonsteroidal anti-inflammatory drugs: Diclofenac sodium 1% by weight [Examples 220-225, Comparative Examples 119-120] These examples and comparative examples used 1% by weight diclofenac sodium as a nonsteroidal anti-inflammatory drug to compare the solubility of 30% by weight isopropanol and 30% and 45% by weight ethanol.

[0102] [Table 47]

[0103] As can be seen from Table 47, when 1% by weight of diclofenac sodium is used as a nonsteroidal anti-inflammatory drug, there is a slight difference in solubility between ethanol and isopropanol. However, by adjusting the type and amount of nonionic surfactant added, it was confirmed that no precipitates or turbidity occur when the amount of lower alcohol added is in the range of 30% to 45% by weight. Therefore, the effects of the present invention are fully exhibited even when other lower alcohols are used in the range of 30% to 45% by weight.

[0104] (2) Nonsteroidal anti-inflammatory drugs: Loxoprofen sodium hydrate 1.13% by weight [Examples 226-228, Comparative Examples 121-122] These examples and comparative examples used 1.13% by weight of loxoprofen sodium hydrate as a nonsteroidal anti-inflammatory drug to compare its solubility with 30% by weight of isopropanol and 30% and 45% by weight of ethanol.

[0105] [Table 48]

[0106] As can be seen from Table 48, even when the nonsteroidal anti-inflammatory drug is 1.13% by weight of loxoprofen sodium hydrate, although there is a slight difference in solubility between ethanol and isopropanol, it was confirmed that no precipitates or turbidity occur when the amount of lower alcohol added is in the range of 30% to 45% by weight by adjusting the type and amount of nonionic surfactant. Therefore, the effects of the present invention are fully exhibited even when other lower alcohols are used in the range of 30% to 45% by weight.

Claims

1. A topical pharmaceutical composition characterized by containing (A) a nonsteroidal anti-inflammatory drug, (B) a nonionic surfactant with an HLB value exceeding 6.5, (C) 30 to 45% by weight of a lower alcohol, (D) an antihistamine, (E) 0.1 to 2% by weight of vitamin E derivatives, (F) 3 to 6% by weight of monoterpenes, and (G) water.

2. The topical pharmaceutical composition according to claim 1, wherein the component (A) comprises at least one selected from diclofenac, loxoprofen, indomethacin, felbinac and / or a pharmaceutically acceptable salt thereof.

3. The topical pharmaceutical composition according to claim 1, wherein component (B) comprises 2.0 to 35% by weight of at least one selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene alkyl ether, and polyethylene glycol fatty acid ester.

4. The topical pharmaceutical composition according to claim 1, wherein the (C) component is ethanol and / or isopropanol.

5. The topical pharmaceutical composition according to claim 1, wherein component (D) is 0.1% by weight of chlorpheniramine and / or a pharmaceutically acceptable salt thereof.

6. The topical pharmaceutical composition according to claim 1, wherein the (E) component is 1 to 2% by weight of tocopherol acetate.

7. The topical pharmaceutical composition according to claim 1, wherein the (F) component is menthol.

8. (H) The topical pharmaceutical composition according to claim 1, comprising a pH adjusting agent and having a pH of 5.5 to 7.

5.

9. The topical pharmaceutical composition according to claim 1, wherein the formulation form is a topical liquid or gel.

Images