Topical composition

Abstract

To provide a topical composition with improved percutaneous penetration of felbinac and menthol.SOLUTION: A topical composition contains (A) felbinac, (B) menthol, (C) ethanol and (D) water, where the content of component (C) does not exceed 64 wt.%. The topical composition enables improved percutaneous absorption of component (A) and component (B).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition for external use having improved permeability of felbinac and menthol. [Background technology]

[0002] Felbinac is a nonsteroidal anti-inflammatory analgesic that has antipyretic, analgesic, and anti-inflammatory effects, and is used in external compositions. Monoterpenes such as menthol provide a cooling sensation, and are used to improve the usability of external compositions, and may be incorporated in anti-inflammatory analgesic compositions to enhance the usability.

[0003] For example, Patent Document 1 describes that a pharmaceutical composition for external use containing a nonsteroidal anti-inflammatory drug such as felbinac and a monoterpene such as menthol contains more than 10% by weight of propylene glycol to improve the cooling sensation.

[0004] Patent Document 2 describes that a transdermal patch containing an adhesive base, a terpene such as menthol, a sebacic acid ester, an alkyl glyceryl ether, and a non-steroidal analgesic anti-inflammatory drug such as felbinac, has excellent transdermal absorbability of the non-steroidal analgesic anti-inflammatory drug. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Patent Publication No. 2022-096994 [Patent Document 2] JP 2008-013494 A Summary of the Invention [Problem to be solved by the invention]

[0006] The topical preparations disclosed in Patent Documents 1 and 2 can contain a combination of felbinac and menthol. Such topical preparations still have room for improvement in terms of the percutaneous permeability of the blended ingredients. Therefore, an object of the present invention is to provide a composition for topical use in which the percutaneous permeability of felbinac and menthol is improved. [Means for solving the problem]

[0007] As a result of intensive research, the present inventors have found that the percutaneous absorbability of felbinac and menthol is improved by adding a predetermined amount of ethanol to a composition for external use containing felbinac and menthol in water. They have also found that the percutaneous absorbability is further improved by adding camphor and / or eucalyptus oil to a composition for external use with improved percutaneous absorbability. The present invention has been completed based on these findings and through further research.

[0008] That is, the present disclosure provides the inventions of the following aspects. Item 1. A composition for external use comprising (A) felbinac, (B) menthol, (C) ethanol and (D) water, wherein the amount of component (C) does not exceed 64% by weight. Item 2. The composition for external use according to Item 1, wherein the content of the component (C) is 30 to 64% by weight. Item 3. The composition for external use according to Item 1 or 2, further comprising (E) camphor. Item 4. The composition for external use according to Item 3, wherein the content of the component (E) is 0.01 part by weight or more per 1 part by weight of the component (A). Item 5. The composition for external use according to Item 3 or 4, wherein the content of the component (E) is 0.005 part by weight or more per 1 part by weight of the component (B). Item 6. The composition for external use according to any one of Items 1 to 5, further comprising (F) eucalyptus oil. Item 7. The composition for external use according to Item 6, wherein the content of the component (F) is 0.005 part by weight or more per 1 part by weight of the component (A). Item 8. The composition for external use according to Item 6 or 7, wherein the content of the component (F) is 0.0025 part by weight or more per part by weight of the component (B). Item 9. The composition for external use according to any one of Items 1 to 8, further comprising glycyrrhetinic acid, and / or chlorpheniramine and / or a salt thereof. Effect of the Invention

[0009] According to the present invention, there is provided a composition for external use having improved percutaneous permeability of felbinac and menthol. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The topical composition of the present disclosure comprises (A) felbinac (hereinafter also referred to as "component (A)"), (B) menthol (hereinafter also referred to as "component (B)"), (C) ethanol (hereinafter also referred to as "component (C)"), and (D) water (hereinafter also referred to as "component (D)"), characterized in that the amount of component (C) does not exceed 64% by weight. The topical composition of the present disclosure may further comprise (E) camphor (hereinafter also referred to as "component (E)") and / or (F) eucalyptus oil (hereinafter also referred to as "component (F)").

[0011] (A) Felbinac The topical composition of the present disclosure contains felbinac as component (A), which is a known phenylacetic acid-based nonsteroidal anti-inflammatory drug.

[0012] The content of component (A) in the topical composition of the present disclosure may be set appropriately depending on the desired medicinal effect, etc., and may be, for example, 0.1 to 15 wt %, preferably 0.5 to 10 wt %, more preferably 1 to 5 wt %, and even more preferably 2 to 4 wt %.

[0013] (B) Menthol The topical composition of the present disclosure contains menthol as component (B). The menthol may be any of d-, l-, and dl-forms, but is preferably l-form. In addition, essential oils containing menthol may be used as menthol. Examples of essential oils containing menthol include peppermint oil, peppermint oil, and spearmint oil.

[0014] The content of component (B) in the topical composition of the present disclosure is not particularly limited and may be appropriately set depending on the cooling sensation to be imparted, and may be, for example, 0.5 to 10% by weight, preferably 1 to 9% by weight, more preferably 3 to 8% by weight, even more preferably 4 to 7% by weight, and even more preferably 5 to 6.5% by weight. Note that, when an essential oil containing menthol is used in the formulation of component (B), the description of the content and ratio of (B) in this specification is a value converted into the amount of menthol contained in the essential oil.

[0015] (C) Ethanol The topical composition of the present disclosure contains ethanol as component (C). In the topical composition of the present disclosure, component (C) is contained in an amount not exceeding 64% by weight in order to obtain the desired effect of improving transdermal absorbability.

[0016] In the topical composition of the present disclosure, from the viewpoint of further improving transdermal absorbability, the content of component (C) is preferably 30 to 64 wt%, 34 to 64 wt%, or 36 to 64 wt%, preferably 42 to 64 wt%, 46 to 64 wt%, 48 to 64 wt%, or 52 to 64 wt%, and more preferably 56 to 62 wt% or 58 to 62 wt%.

[0017] In the topical composition of the present disclosure, the ratio of component (A) to component (C) is determined depending on the content of each of the above components, but from the viewpoint of further improving transdermal absorbability, the content of component (C) per 1 part by weight of component (A) is preferably not more than 21 parts by weight, more preferably 10 to 21 parts by weight, 11 to 21 parts by weight, 12 to 21 parts by weight, even more preferably 14 to 21 parts by weight, 15 to 21 parts by weight, 16 to 21 parts by weight, 17 to 21 parts by weight, and even more preferably 18 to 20 parts by weight or 19 to 20 parts by weight.

[0018] In the topical composition of the present disclosure, the ratio of component (B) to component (C) is determined depending on the content of each of the above components. From the viewpoint of further improving transdermal absorbability, the content of component (C) per part by weight of component (B) is preferably not more than 10.5 parts by weight, more preferably 5 to 10.5 parts by weight, 5.5 to 10.5 parts by weight, 6 to 10.5 parts by weight, even more preferably 7 to 10.5 parts by weight, 7.5 to 10.5 parts by weight, 8 to 10.5 parts by weight, 8.5 to 10.5 parts by weight, and even more preferably 9 to 10.3 parts by weight or 9.5 to 10.3 parts by weight.

[0019] (D)Water The topical composition of the present disclosure contains water as component (D). The amount of component (D) in the topical composition of the present disclosure is not particularly limited, but may be, for example, 15 to 60% by weight, preferably 17 to 40% by weight, more preferably 19 to 30% by weight, and even more preferably 20 to 25% by weight.

[0020] (E) Camphor The topical composition of the present disclosure may further contain camphor as component (E) for the purpose of improving the transdermal absorbability of components (A) and (B).

[0021] Camphor may be in the d-, l- or dl-form, with the d-form being preferred.

[0022] The content of the (E) component in the composition for external use of the present disclosure is not particularly limited, but the content of the (E) component per 1 part by weight of the (A) component is, for example, 0.01 parts by weight or more, and from the viewpoint of further improving the transdermal absorbability, preferably 0.03 parts by weight or more, more preferably 0.06 parts by weight or more, and even more preferably 0.08 parts by weight or more. The content of the (E) component per 1 part by weight of the (A) component is not particularly limited in its upper limit, but for example, 0.3 parts by weight or less, 0.25 parts by weight or less, 0.2 parts by weight or less, 0.15 parts by weight or less, or 0.12 parts by weight or less.

[0023] In addition, in the topical composition of the present disclosure, the content of the (E) component per 1 part by weight of the (B) component is, for example, 0.005 parts by weight or more, and from the viewpoint of further improving the transdermal absorbability, preferably 0.015 parts by weight or more, more preferably 0.03 parts by weight or more, and even more preferably 0.04 parts by weight or more. The content of the (E) component per 1 part by weight of the (B) component is not particularly limited in its upper limit, and may be, for example, 0.15 parts by weight or less, 0.12 parts by weight or less, 0.1 parts by weight or less, 0.08 parts by weight or less, or 0.06 parts by weight or less.

[0024] The specific content of the (E) component in the topical composition of the present disclosure is, for example, 0.03% by weight or more, and from the viewpoint of further improving the transdermal absorbability, is preferably 0.09% by weight or more, more preferably 0.18% by weight or more, and even more preferably 0.25% by weight or more. The content of the (E) component is not particularly limited in its upper limit, and may be, for example, 0.9% by weight or less, 0.75% by weight or less, 0.6% by weight or less, 0.45% by weight or less, or 0.35% by weight or less.

[0025] (F) Eucalyptus oil The topical composition of the present disclosure may further contain eucalyptus oil as component (F) for the purpose of improving the transdermal absorbability of components (A) and (B).

[0026] Eucalyptus oil is an essential oil obtained by steam distillation of the leaves of Eucalyptus globulus, such as E. globulus Labillardiere, or other closely related plants (Myrtaceae). In the present disclosure, the essential oil of E. globulus Labillardiere is preferably used.

[0027] The eucalyptus oil preferably includes one containing cineole as a main component, and more preferably includes, in addition to the main component cineole, at least one of monoterpene hydrocarbons such as α-pinene, limonene, p-cymene, etc.; monoterpene alcohols such as pinocarveol, α-terpineol, etc.; sesquiterpene alcohols such as globulol, ledol, etc.; terpene ketones, etc. The content of cineole in the eucalyptus oil is, for example, 55% by weight or more, preferably 65% ​​by weight or more, more preferably 70% by weight or more, and even more preferably 75% by weight or more or 80% by weight or more, and the upper limit is 90% by weight or less, preferably 85% by weight or less.

[0028] The content of the (F) component in the topical composition of the present disclosure is not particularly limited, but the content of the (F) component per 1 part by weight of the (A) component is, for example, 0.005 parts by weight or more, and from the viewpoint of further improving transdermal absorbability, preferably 0.015 parts by weight or more, more preferably 0.03 parts by weight or more, and even more preferably 0.04 parts by weight or more. The content of the (F) component per 1 part by weight of the (A) component is not particularly limited in its upper limit, but for example, 0.15 parts by weight or less, 0.12 parts by weight or less, 0.1 parts by weight or less, 0.08 parts by weight or less, or 0.06 parts by weight or less.

[0029] In addition, in the topical composition of the present disclosure, the content of the (F) component per 1 part by weight of the (B) component is, for example, 0.0025 parts by weight or more, and from the viewpoint of further improving the transdermal absorbability, preferably 0.008 parts by weight or more, more preferably 0.015 parts by weight or more, and even more preferably 0.02 parts by weight or more. The content of the (F) component per 1 part by weight of the (B) component is not particularly limited in its upper limit, and may be, for example, 0.08 parts by weight or less, 0.06 parts by weight or less, 0.05 parts by weight or less, 0.04 parts by weight or less, or 0.03 parts by weight or less.

[0030] The specific content of the (F) component in the topical composition of the present disclosure is, for example, 0.015% by weight or more, and from the viewpoint of further improving the transdermal absorbability, preferably 0.045% by weight or more, more preferably 0.09% by weight or more, and even more preferably 0.12% by weight or more. The content of the (F) component is not particularly limited in its upper limit, and may be, for example, 0.45% by weight or less, 0.35% by weight or less, 0.3% by weight or less, 0.23% by weight or less, or 0.17% by weight or less.

[0031] Other Ingredients The topical composition of the present disclosure may or may not further contain additives and / or bases depending on the formulation form in addition to the above-mentioned components (A) to (D) and optionally the blended components (E) and / or (F). The additives and bases, which may or may not be contained, are not particularly limited as long as they are pharma- ceutically acceptable, and examples of such additives and bases include excipients, binders, disintegrants, lubricants, isotonicity agents, plasticizers, dispersants, emulsifiers, solubilizers, wetting agents, stabilizers, suspending agents, adhesives, coating agents, glossing agents, oily bases [e.g., fats and oils (glycerin esters of fatty acids), mineral oils, waxes or waxes, ester oils (e.g., cetyl isooctanoate, isopropyl myristate, isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, etc.), higher (carbon number 10-24) fatty acids, higher (carbon number 10-24) fatty acids and monovalent lower (carbon number 1-5) alcohols and esters, higher (carbon number 10-24) alcohols, etc.], water-soluble polymers, surfactants, Examples of the additives include metal soaps, monohydric lower alcohols (having 3 to 5 carbon atoms) other than the component (C), polyhydric alcohols (e.g., aliphatic polyhydric alcohols such as propylene glycol, octanediol, 1,3-butanediol, ethylene glycol, polyethylene glycol, glycerin, and D-sorbitol), organic acids (e.g., acetic acid, citric acid, malic acid, fumaric acid, tartaric acid, and adipic acid) or salts thereof, aminoalcohols (ethanolamine, diethanolamine, triethanolamine, N-methyldiethanolamine, N,N-dibutylethanolamine, N-aminoethylethanolamine, n-propanolamine, diisopropanolamine, and triisopropanolamine), pH adjusters, buffers, antioxidants, ultraviolet light inhibitors, preservatives, flavorings, fragrances, powders, thickeners, colorants, and chelating agents. These additives may be used alone or in combination of two or more. The content of these additives and bases is appropriately set depending on the types of additives and bases used, the formulation form of the topical composition of the present invention, etc.

[0032] In the topical composition of the present disclosure, among the above additives and bases, from the viewpoint of further enhancing the transdermal absorbability of component (A) and / or component (B), preferably, polyhydric alcohols (more preferably, propylene glycol, octanediol, 1,3-butanediol, ethylene glycol, glycerin, D-sorbitol, and even more preferably, propylene glycol) and / or amino alcohols (more preferably, ethanolamine, diethanolamine, triethanolamine, N-methyldiethanolamine, N,N-dibutylethanolamine, N-aminoethylethanolamine, n-propanolamine, diisopropanolamine, triisopropanolamine, and even more preferably, diisopropanolamine) are used.

[0033] When the topical composition of the present disclosure contains the polyhydric alcohol, the content of the polyhydric alcohol is, for example, 1 to 9% by weight, preferably 3 to 8.5% by weight, more preferably 5 to 8% by weight, and even more preferably 6 to 7.5% by weight. When the topical composition of the present disclosure contains the amino alcohol, the content of the amino alcohol is, for example, 0.5 to 2.5% by weight, preferably 1 to 2.2% by weight, and even more preferably 1.5 to 2% by weight.

[0034] The topical composition of the present disclosure may or may not contain a medicinal ingredient capable of exerting a pharmaceutical or cosmetic physiological function, in addition to the above-mentioned components (A) to (D) and the optional components (E) and / or (F). Examples of the medicinal ingredient, which may or may not be contained, include steroids, antihistamines, local anesthetics, anti-inflammatory agents, bactericides, antipruritic agents, moisturizers, blood circulation promoting ingredients, vitamins, mucopolysaccharides, etc. These medicinal ingredients may be used alone or in combination of two or more. When these medicinal ingredients are contained in the emulsion composition of the present invention, the content thereof may be appropriately set according to the type of medicinal ingredient used, the expected effect, etc.

[0035] In the topical composition of the present disclosure, among the above-mentioned medicinal ingredients, from the viewpoint of further enhancing the transdermal absorbability of component (A) and / or component (B), particularly the effect of component (A), it is preferable to contain at least one of chlorpheniramines selected from the group consisting of glycyrrhetinic acid and chlorpheniramine and its salts (including organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate, preferably maleate), and it is more preferable to contain both glycyrrhetinic acid and chlorpheniramines. When the topical composition of the present disclosure contains glycyrrhetinic acid, and when the topical composition of the present disclosure contains chlorpheniramines, the content of each of the glycyrrhetinic acid and chlorpheniramines is preferably 0.03 to 0.2% by weight, preferably 0.05 to 0.15% by weight, and more preferably 0.07 to 0.12% by weight; the content of each of the glycyrrhetinic acid and chlorpheniramines per part by weight of the (A) component is preferably 0.01 to 0.06 parts by weight, preferably 0.015 to 0.05 parts by weight, and more preferably 0.02 to 0.04 parts by weight; the content of each of the glycyrrhetinic acid and chlorpheniramines per part by weight of the (B) component is preferably 0.005 to 0.03 parts by weight, preferably 0.007 to 0.025 parts by weight, and more preferably 0.01 to 0.02 parts by weight.

[0036] Formulation The formulation form of the topical composition of the present disclosure is not particularly limited as long as it can be administered transdermally, and examples thereof include liquids (non-suspensions, suspensions), foams, ointments, creams, gels, etc. Among these, liquids (non-suspensions) are preferred. These formulation forms can be prepared by formulating them using additives appropriate for the formulation form according to the known methods described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 17th Edition, etc.

[0037] In addition, the topical composition of the present disclosure can be contained in any container that can be administered transdermally, depending on the formulation form, etc. When the topical composition of the present disclosure is a liquid, specific examples of the container include a container with an inner cap (specifically, a cap with a liquid-absorbent material (brush, cloth, sponge, etc.)) having a communication part that allows liquid to leak from inside the container to outside the container, and a roll-on type container, as an easily applicable container. EXAMPLES

[0038] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0039] (1) Preparation of topical composition A non-suspension pharmaceutical composition for external use was prepared by mixing the components in the proportions shown in Tables 1 and 2. The eucalyptus oil used was an essential oil of Eucalyptus globulus Labillardiere, containing 82% by weight of cineole.

[0040] (2) Permeability test (2-1)(A) Felbinac permeability test The permeability of felbinac was quantified by Franz cell test using the skin of a hairless mouse. Specifically, 0.1 mL of the topical pharmaceutical composition in Table 1 was applied to the skin of a hairless mouse set in a Franz cell, and 0.3 mL was collected from the receptor solution after 1 hour, and felbinac was quantified by HPLC. The relative value of each Example was calculated, assuming that the quantitative value of the topical pharmaceutical composition in Comparative Example 1 was 1. The results are shown in Table 1.

[0041] (2-2)(B) Menthol permeability test The amount of menthol that penetrated into the inner side of the upper arm of a human was quantified by tape stripping method. Specifically, 4 g of the topical pharmaceutical composition shown in Table 1 was applied to an area of ​​2.0 x 2.0 cm on the inner side of the upper arm of a human, and after 5 minutes, the skin (keratin) was peeled off with cellophane tape, and the amount of l-menthol in the peeled skin (keratin) was quantified by gas chromatography. The relative value of each example was derived when the quantitative value of the topical pharmaceutical composition of Comparative Example 1 was set to 1. The results are shown in Table 1.

[0042] [Table 1]

[0043] (3) Analgesic effect test Ten subjects with stiff shoulders were asked to apply the topical pharmaceutical composition shown in Table 2 to the affected area, and the analgesic effect after five minutes was evaluated using a five-point visual analog scale (VAS), with 5 points for when the patient felt that the pain had improved, 3 points for when they could not say either way, and 1 point for when they felt that the pain had not improved, and the number of subjects who gave the VAS a score of 5 was calculated. The results are shown in Table 2.

[0044] [Table 2]

[0045] (Result 1) As is clear from Table 1, the percutaneous absorbability of the components (A) and (B) was improved by blending the component (C) in an amount limited in Examples 1 to 7 with a topical composition containing the components (A) and (B) in the component (D). In particular, as shown in Examples 4 to 7, the percutaneous absorbability of the components (A) and (B) was further improved by further blending the component (E) and / or the component (F).

[0046] Furthermore, the effect of improving the transdermal absorbability of component (A) by limiting the amount of ethanol was also reflected in the improvement of the analgesic effect of component (A) as shown in Table 2. In particular, the improvement of the analgesic effect of the topical pharmaceutical composition of Example 9 was significantly more remarkable.

[0047] (Result 2) In the topical pharmaceutical compositions of Tables 1 and 2, component (A) was replaced with other anti-inflammatory analgesics, i.e., loxoprofen sodium or diclofenac sodium, and similar evaluations were performed. As a result, when component (A) was used as an anti-inflammatory analgesic, the effect of improving the permeability of components (A) and (B) was higher, and the effect of improving the analgesic effect was also higher.

Claims

1. 1. A composition for external use comprising (A) felbinac, (B) menthol, (C) ethanol and (D) water, the amount of said component (C) being not more than 64% by weight.

2. The composition for external use according to claim 1, wherein the content of component (C) is 30 to 64% by weight.

3. The composition for external use according to claim 1 , further comprising (E) camphor.

4. The composition for external use according to claim 3 , wherein the content of the (E) component is 0.01 part by weight or more per 1 part by weight of the (A) component.

5. The composition for external use according to claim 3 , wherein the content of the (E) component is 0.005 part by weight or more per 1 part by weight of the (B) component.

6. The topical composition according to claim 1, further comprising (F) eucalyptus oil.

7. The composition for external use according to claim 6 , wherein the content of the (F) component is 0.005 part by weight or more per 1 part by weight of the (A) component.

8. The composition for external use according to claim 6, wherein the content of the (F) component is 0.0025 part by weight or more per 1 part by weight of the (B) component.

9. The composition for external use according to claim 1 , further comprising glycyrrhetinic acid, and / or chlorpheniramine and / or a salt thereof.

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