Topical composition

Abstract

To provide formulation technology with which it is possible to suppress browning that occurs over time in a topical composition containing a non-steroidal anti-inflammatory, 0.015 wt.% or more of vanillylamide nonanoate, and 0.01 wt.% or more of benzyl nicotinate.SOLUTION: In this topical drug composition, the browning that occurs over time can be suppressed effectively by blending a monoterpene with a non-steroidal anti-inflammatory, 0.015 wt.% or more of vanillylamide nonanoate, and 0.01 wt.% or more of benzyl nicotinate.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an external composition containing a non-steroidal anti-inflammatory drug, 0.015% by weight or more of vanillyl amide nonanoate, and 0.01% by weight or more of benzyl nicotinate, which can suppress browning that occurs over time.

Background Art

[0002] Non-steroidal anti-inflammatory drugs represented by loxoprofen sodium, diclofenac sodium, indomethacin, etc. are widely used as active ingredients in external pharmaceutical compositions. In addition, vanillyl amide nonanoate is known to have effects such as imparting a warming sensation and promoting blood circulation, and is widely used as an active ingredient in external pharmaceutical compositions. Furthermore, benzyl nicotinate is known to have effects such as promoting absorption and promoting blood circulation, and is widely used as an active ingredient in external pharmaceutical compositions.

[0003] Conventionally, various formulations of external compositions containing non-steroidal anti-inflammatory drugs, vanillyl amide nonanoate, benzyl nicotinate, etc. as active ingredients have been proposed. For example, Patent Document 1 describes that an external anti-inflammatory and analgesic composition containing 0.5 to 5% by weight of loxoprofen, vanillyl amide nonanoate, and water can improve the anti-inflammatory and analgesic action of loxoprofen. In addition, Patent Document 2 describes that an external preparation containing indomethacin and vanillyl amide nonanoate and / or benzyl nicotinate can improve the storage stability of indomethacin.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] The inventor has advanced the study on a formulation with increased contents of both components in an external composition containing a non-steroidal anti-inflammatory drug, vanillyl amide nonanoate, and benzyl nicotinate in order to effectively exert the efficacy of vanillyl amide nonanoate and benzyl nicotinate. As a result, it was found that when 0.015% by weight or more of vanillyl amide nonanoate coexists with the non-steroidal anti-inflammatory drug, browning occurs over time. Furthermore, it was found that when 0.015% by weight or more of vanillyl amide nonanoate and 0.01% by weight or more of benzyl nicotinate coexist with the non-steroidal anti-inflammatory drug, the browning occurring over time becomes remarkable.

[0006] Therefore, an object of the present invention is to provide a pharmaceutical formulation technology capable of suppressing browning occurring over time in an external composition containing a non-steroidal anti-inflammatory drug, 0.015% by weight or more of vanillyl amide nonanoate, and 0.01% by weight or more of benzyl nicotinate.

Means for Solving the Problem

[0007] The inventor has conducted intensive studies to solve the above problems and found that by containing a monoterpene together with a non-steroidal anti-inflammatory drug, 0.015% by weight or more of vanillyl amide nonanoate, and 0.01% by weight or more of benzyl nicotinate in an external pharmaceutical composition, browning occurring over time can be effectively suppressed. The present invention has been completed by further studies based on such findings.

[0008] That is, the present invention provides the inventions of the following aspects. Item 1. An external composition containing a non-steroidal anti-inflammatory drug, 0.015% by weight or more of vanillyl amide nonanoate, 0.01% by weight or more of benzyl nicotinate, and a monoterpene. Item 2. The external composition according to Item 1, wherein the non-steroidal anti-inflammatory drug is at least one selected from the group consisting of loxoprofen, diclofenac, and salts thereof. Item 3. The external composition according to Item 1 or 2, wherein the monoterpene is menthol. Item 4. The external composition according to any one of Items 1 to 3, which is a liquid preparation, a cream preparation, a lotion preparation, a gel preparation, or an emulsion preparation.

Advantages of the Invention

[0009] The external composition of the present invention can effectively suppress browning that occurs over time, has excellent formulation stability, can stably retain the contained components during storage, and can maintain a good external shape, although it contains a non-steroidal anti-inflammatory drug, 0.015% by weight or more of vanillylamide nonanoate, and 0.01% by weight or more of benzyl nicotinate.

Modes for Carrying Out the Invention

[0010] 1. External composition The external composition of the present invention is characterized by containing a non-steroidal anti-inflammatory drug, 0.015% by weight or more of vanillylamide nonanoate, 0.01% by weight or more of benzyl nicotinate, and a monoterpene. Hereinafter, the external composition of the present invention will be described in detail.

[0011] [Non-steroidal anti-inflammatory drug] The external composition of the present invention contains a non-steroidal anti-inflammatory drug. A non-steroidal anti-inflammatory drug is a general term for anti-inflammatory drugs other than glucocorticoids.

[0012] The types of non-steroidal anti-inflammatory drugs used in the present invention are not particularly limited. For example, loxoprofen, diclofenac, indomethacin, felbinac, salicylic acid, acetylsalicylic acid, aspirin, salsalate, salicylamide, ethenzamide, ibuprofen, ketoprofen, naproxen, flurbiprofen, piroxicam, tiaprofenic acid, suprofen, tolmetin, alminoprofen, benoxaprofen, benzydamine, sulindac, acemetacin, progulmetacin, anfenac, mofezolac, lornoxicam, ampiroxicam, fenoprofen, tiaprofenic acid, oxaprozin, mefenamic acid, flufenamic acid, azapropazone, fenbufen, etodolac, rofecoxib, diflunisal, zomepirac, celecoxib, zaltoprofen, ketorolac, nimesulide, aceclofenac may be mentioned.

[0013] In addition, when the non-steroidal anti-inflammatory drug can take the form of a salt, it may be in the form of a salt. Examples of the non-steroidal anti-inflammatory drug in the form of a salt include salts of loxoprofen, salts of diclofenac, and the like.

[0014] Specific examples of the salt of loxoprofen include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt. Among these, alkali metal salts are preferred, and sodium salt is more preferred. Further, the salt of loxoprofen may be a hydrate.

[0015] Specific examples of the salt of diclofenac include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; salts with ammonia; salts with primary, secondary or tertiary alkylamines such as dimethylamine, diethylamine, trimethylamine, and triethylamine. Among these, alkali metal salts are preferred, and sodium salt is more preferred.

[0016] These non-steroidal anti-inflammatory drugs may be used alone or in combination of two or more kinds.

[0017] Among these non-steroidal anti-inflammatory drugs, preferably, loxoprofen, diclofenac, and salts thereof are mentioned. In particular, when loxoprofen and its salts are used as the non-steroidal anti-inflammatory drug, it becomes possible to more effectively suppress the browning that occurs over time.

[0018] The content of the non-steroidal anti-inflammatory drug in the external pharmaceutical composition of the present invention may be appropriately set according to the type of the non-steroidal anti-inflammatory drug to be used, the medicinal effects to be provided, etc. For example, 0.1 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 0.5 to 5% by weight, and still more preferably 1 to 1.5% by weight can be mentioned.

[0019] [Vanillylamide nonanoate] The external composition of the present invention contains 0.015% by weight or more of vanillylamide nonanoate. Vanillylamide nonanoate is a kind of capsaicinoid and is a known component having effects such as imparting a warming sensation and promoting blood circulation.

[0020] The content of vanillylamide nonanoate in the external composition of the present invention may be 0.015% by weight or more. Specifically, 0.015 to 0.3% by weight, preferably 0.015 to 0.15% by weight, more preferably 0.02 to 0.15% by weight, and still more preferably 0.05 to 0.1% by weight can be mentioned. When 0.02% by weight or more of vanillylamide nonanoate coexists with 0.01% by weight or more of the non-steroidal anti-inflammatory drug and benzyl nicotinate, the browning that occurs over time tends to become prominent. However, in the external composition of the present invention, even if it contains 0.02% by weight or more of vanillylamide nonanoate, the browning that occurs over time can be effectively suppressed.

[0021] In the topical composition of the present invention, the ratio of the non-steroidal anti-inflammatory drug to vanillylamide nonanoate may be within the range that satisfies each of the aforementioned contents. For example, per 1 part by weight of the non-steroidal anti-inflammatory drug, vanillylamide nonanoate is 0.001 to 1 part by weight, preferably 0.01 to 0.3 part by weight, more preferably 0.015 to 0.1 part by weight.

[0022] [Benzyl nicotinate] The topical composition of the present invention contains 0.01% by weight or more of benzyl nicotinate. Benzyl nicotinate is an ester of niacin and benzyl alcohol and is a known component with known effects such as absorption promotion and blood circulation promotion.

[0023] The content of benzyl nicotinate in the topical composition of the present invention may be 0.01% by weight or more. Specifically, it is 0.01 to 0.3% by weight, preferably 0.01 to 0.1% by weight, more preferably 0.01 to 0.1% by weight, still more preferably 0.02 to 0.1% by weight, and particularly preferably 0.04 to 0.1% by weight. In the prior art, when benzyl nicotinate of 0.01% by weight or more coexists with a non-steroidal anti-inflammatory drug and 0.015% by weight or more of vanillylamide nonanoate, browning occurs over time. However, in the topical composition of the present invention, even when benzyl nicotinate is contained in a high content of 0.01% by weight or more, browning occurring over time can be effectively suppressed.

[0024] In the topical composition of the present invention, the ratio of the non-steroidal anti-inflammatory drug to benzyl nicotinate may be within the range that satisfies each of the aforementioned contents. For example, per 1 part by weight of the non-steroidal anti-inflammatory drug, benzyl nicotinate is 0.001 to 1 part by weight, preferably 0.005 to 0.3 part by weight, more preferably 0.008 to 0.1 part by weight.

[0025] [Monoterpene] In addition to the aforementioned components, the external composition of the present invention contains a monoterpene. In the pharmaceutical composition of the present invention, by including a monoterpene together with a non-steroidal anti-inflammatory drug, vanillylamide nonanoate at 0.015% by weight or more, and benzyl nicotinate at 0.01% by weight or more, it becomes possible to effectively suppress browning that occurs over time.

[0026] A monoterpene is a known component having a structure containing two isoprene units in the molecule and having a cooling effect or the like. The type of monoterpene used in the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, alcohol-based monoterpenes such as menthol, thymol, geraniol, linalool, borneol, cineole, and terpineol; aldehyde-based monoterpenes such as citral, citronellal, perillaldehyde, and safranal; ketone-based monoterpenes such as camphor, menthone, carvone, and ionone can be mentioned. When there are optical isomers for these monoterpenes, they may be any of the d-form, l-form, or dl-form. These monoterpenes may be used alone or in combination of two or more.

[0027] Also, in the present invention, an essential oil containing a monoterpene may be used as the monoterpene. The essential oil containing a monoterpene can be appropriately selected and used from known ones. For example, as essential oils containing menthol, there are peppermint oil, peppermint oil, and spearmint oil. In addition, the descriptions regarding the content and ratio of monoterpenes in this specification are values converted to the amount of monoterpenes contained in the essential oil when using an essential oil containing a monoterpene.

[0028] Among these monoterpenes, preferably menthol, and more preferably l-menthol, can be mentioned.

[0029] Regarding the content of the monoterpene in the external composition of the present invention, it may be appropriately set according to the type of the monoterpene used, etc. For example, in terms of the total amount of the monoterpene, it is 0.1 to 15% by weight, preferably 1 to 10% by weight, and more preferably 2 to 7% by weight from the viewpoint of further suppressing the browning that occurs over time.

[0030] In the external composition of the present invention, regarding the ratio of the non-steroidal anti-inflammatory drug to the monoterpene, it may be within the range that satisfies each of the above-described contents. For example, per 1 part by weight of the non-steroidal anti-inflammatory drug, the monoterpene is 0.01 to 500 parts by weight, preferably 0.1 to 50 parts by weight, and more preferably 1 to 5 parts by weight from the viewpoint of further suppressing the browning that occurs over time.

[0031] [Monohydric lower alcohol] The external composition of the present invention may contain a monohydric lower alcohol in addition to the above-described components. In the present invention, the monohydric lower alcohol refers to a monohydric alcohol having 1 to 5 carbon atoms.

[0032] The type of the monohydric lower alcohol is not particularly limited as long as it is pharmaceutically acceptable. For example, ethanol, n-propanol, isopropanol, etc. may be mentioned. Among these monohydric lower alcohols, ethanol is preferably mentioned.

[0033] When the external pharmaceutical composition of the present invention contains a monohydric lower alcohol, its content is not particularly limited. For example, it is 0.1 to 90% by weight, preferably 25 to 80% by weight, and more preferably 50 to 80% by weight.

[0034] [Water] The external composition of the present invention may further contain water. When the external pharmaceutical composition of the present invention contains water, its content is not particularly limited. For example, it is 0.1 to 80% by weight, preferably 1 to 50% by weight, more preferably 10 to 40% by weight, and still more preferably 15 to 30% by weight.

[0035] [Other components] In addition to the components described above, the external composition of the present invention may contain other commonly used additives as required. Examples of such additives include surfactants, vegetable oils, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, polyhydric alcohols, higher alcohols, pH regulators, buffers, solubilizers, antiseptics, preservatives, antioxidants, stabilizers, fragrances, and the like. When these additives are contained in the external composition of the present invention, the content thereof may be appropriately set according to the type of additive used and the like.

[0036] Furthermore, in addition to the components described above, the external composition of the present invention may contain pharmacological components. Examples of such pharmacological components include antihistamines, local anesthetics, moisturizers, bactericides, antibacterial agents, antipruritics, skin protectants, blood circulation promoting components, vitamins, and the like. These pharmacological components may be used alone or in combination of two or more. Also, when these pharmacological components are contained in the external composition of the present invention, the concentration thereof may be appropriately set according to the type of pharmacological component used, the expected effect, and the like.

[0037] [Formulation form] The external composition of the present invention is not particularly limited with respect to its formulation form as long as it is a dosage form applicable to the skin, and it may be either liquid or semi-solid (gel-like, ointment-like, paste-like), with liquid being preferred.

[0038] Specific examples of the formulation form of the external composition of the present invention include solutions, creams, lotions, gels, emulsions, aerosols, and the like. Among these, solutions, creams, lotions, gels, and emulsions are preferred. The preparation of these formulation forms can be carried out by formulating using additives corresponding to the formulation form according to known methods described in the General Rules of Formulations of the Japanese Pharmacopoeia, 17th Revision.

Examples

[0039] Examples are shown below to more specifically explain the present invention, but the present invention is not limited thereto.

[0040] Test Example 1: Evaluation of an external composition containing loxoprofen sodium hydrate External compositions (liquids) having the compositions shown in Tables 1 and 2 were prepared. All of the obtained external compositions exhibited a colorless and transparent appearance immediately after preparation. The obtained external compositions were filled into transparent glass bottles and stored in the dark at 50°C and a relative humidity of 60% RH for 2 months. The appearance of the external compositions after storage was visually observed, and the degree of browning was evaluated according to the following criteria. <Criteria for judging the degree of browning> ◎: No browning is observed, and it is colorless and transparent. 〇: Slight browning is observed, but it is at a level that is not a problem in practical use. △: Some browning is observed. ×: Obvious browning is observed. ××: Marked browning is observed, and it exhibits a dark brown color.

[0041] The results are shown in Tables 1 and 2. When vanillylamide nonanoate was contained alone at 0.01% by weight, slight browning was observed after storage (Reference Example 1). Also, when loxoprofen sodium hydrate and vanillylamide nonanoate were contained at 0.01% by weight, almost no browning was observed after storage (Reference Example 2). On the other hand, when vanillylamide nonanoate was contained at 0.015% by weight or more together with loxoprofen sodium hydrate, browning occurred, and when the content of vanillylamide nonanoate was 0.02% by weight or more, further browning occurred. Furthermore, when benzyl nicotinate was contained at 0.01% by weight or more, the browning was remarkable (Comparative Examples 1 to 7). In contrast, when l-menthol was contained together with loxoprofen sodium hydrate, vanillylamide nonanoate at 0.015% by weight or more, and benzyl nicotinate at 0.01% by weight or more, the browning could be sufficiently suppressed, and a colorless and transparent appearance could be maintained even after storage. Also, even when the content of l-menthol in Examples 1 to 12 was changed to 6% by weight, the browning could be sufficiently suppressed in the same manner as in Examples 1 to 12, and a colorless and transparent appearance could be maintained even after storage.

[0042]

Table 1

[0043]

Table 2

[0044] Test Example 2: Evaluation of an external composition containing diclofenac sodium External compositions (liquids) having the compositions shown in Tables 3 and 4 were prepared. All of the obtained external compositions exhibited a colorless and transparent appearance immediately after preparation. The degree of browning after storage of the obtained external compositions was evaluated in the same manner as in Test Example 1 above.

[0045] The results are shown in Tables 3 and 4. Even when diclofenac sodium was used as a non-steroidal anti-inflammatory drug, browning occurred when vanillyl amide of nonanoic acid was contained at 0.015% by weight or more, and further browning occurred when the content of vanillyl amide of nonanoic acid was 0.02% by weight or more. Furthermore, remarkable browning was observed when 0.01% by weight or more of benzyl nicotinate coexisted (Comparative Examples 8 to 14). However, by containing l-menthol in addition to these components, browning could be suppressed and an appearance with no practical problems could be maintained even after storage (Examples 13 to 24). Also, when the content of l-menthol in Examples 13 to 24 was changed to 6% by weight, browning could be remarkably suppressed as compared with Examples 13 to 24, and a colorless and transparent appearance could be maintained even after storage.

[0046]

Table 3

[0047]

Table 4

Claims

**Claim 1** An external composition containing a non-steroidal anti-inflammatory drug, vanillylamide of nonanoic acid at 0.015% by weight or more, benzyl nicotinate at 0.01% by weight or more, and menthol (except when containing chlorpheniramine maleate). **Claim 2** The external composition according to claim 1, wherein the content of vanillylamide of nonanoic acid is 0.05 to 0.1% by weight. **Claim 3** The external composition according to claim 1 or 2, wherein the content of benzyl nicotinate is 0.04 to 0.1% by weight. **Claim 4** The external composition according to any one of claims 1 to 3, wherein the non-steroidal anti-inflammatory drug is at least one selected from the group consisting of loxoprofen, diclofenac, and salts thereof. **Claim 5** The external composition according to any one of claims 1 to 4, which is a liquid preparation, a cream preparation, a lotion preparation, a gel preparation, or an emulsion preparation.

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