External 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 a composition for external use that contains a nonsteroidal anti-inflammatory drug, 0.015% by weight or more of nonanoic acid vanillylamide, and 0.01% by weight or more of nicotinic acid benzyl ester, and that can inhibit browning that occurs over time. [Background technology]

[0002] Nonsteroidal anti-inflammatory drugs such as loxoprofen sodium, diclofenac sodium, indomethacin, etc. are widely used as active ingredients in external pharmaceutical compositions. Nonanoic acid vanillylamide is known to have effects such as warming sensation and blood circulation promotion, and is widely used as active ingredients in external pharmaceutical compositions. Nicotinic acid benzyl ester is known to have effects such as absorption promotion and blood circulation promotion, and is widely used as active ingredients in external pharmaceutical compositions.

[0003] Conventionally, various formulations of topical compositions containing nonsteroidal anti-inflammatory drugs, nonanoic acid vanillylamide, nicotinic acid benzyl ester, etc. as active ingredients have been proposed. For example, Patent Document 1 describes that a topical anti-inflammatory and analgesic composition containing 0.5-5% by weight of loxoprofen, nonanoic acid vanillylamide, and water can improve the anti-inflammatory and analgesic effect of loxoprofen. In addition, Patent Document 2 describes that a topical preparation containing indomethacin, nonanoic acid vanillylamide, and / or nicotinic acid benzyl ester can improve the storage stability of indomethacin. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2018-65878 A [Patent Document 2] Japanese Patent Application Publication No. 4-77425 Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventor has studied a formulation that contains a nonsteroidal anti-inflammatory drug, vanillylamide nonanoate, and benzyl nicotinate in an external composition, in order to effectively exert the efficacy of vanillylamide nonanoate and benzyl nicotinate.As a result, the inventor has found that when vanillylamide nonanoate is present at 0.015% by weight or more together with a nonsteroidal anti-inflammatory drug, browning occurs over time.Furthermore, the inventor has found that when vanillylamide nonanoate is present at 0.015% by weight or more together with benzyl nicotinate and benzyl nicotinate, browning occurs over time and becomes more pronounced.

[0006] Therefore, an object of the present invention is to provide a formulation technology that can suppress browning that occurs over time in an external composition containing a nonsteroidal anti-inflammatory drug, 0.015% by weight or more of nonanoic acid vanillylamide, and 0.01% by weight or more of nicotinic acid benzyl ester. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems and have found that browning occurring over time can be effectively suppressed by incorporating a monoterpene in an external pharmaceutical composition together with a nonsteroidal anti-inflammatory drug, 0.015% by weight or more of nonanoic acid vanillylamide, and 0.01% by weight or more of nicotinic acid benzyl ester. The present invention was completed based on this knowledge and further research.

[0008] That is, the present invention provides the following aspects. Item 1. A composition for external use comprising a nonsteroidal anti-inflammatory drug, 0.015% by weight or more of nonanoic acid vanillylamide, 0.01% by weight or more of nicotinic acid benzyl ester, and a monoterpene. Item 2. The composition for external use according to Item 1, wherein the nonsteroidal anti-inflammatory drug is at least one selected from the group consisting of loxoprofen, diclofenac, and salts thereof. Item 3. The composition for external use according to Item 1 or 2, wherein the monoterpene is menthol. Item 4. The composition for external use according to any one of Items 1 to 3, which is a liquid, cream, lotion, gel, or emulsion. Effect of the Invention

[0009] The topical composition of the present invention contains a nonsteroidal anti-inflammatory drug, 0.015% by weight or more of nonanoic acid vanillylamide, and 0.01% by weight or more of nicotinic acid benzyl ester, yet it can effectively inhibit browning that occurs over time, has excellent formulation stability, stably retains the contained ingredients during storage, and can maintain a good external appearance. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] 1. External composition The topical composition of the present invention is characterized by containing a nonsteroidal anti-inflammatory drug, 0.015% by weight or more of nonanoic acid vanillylamide, 0.01% by weight or more of nicotinic acid benzyl ester, and a monoterpene. The topical composition of the present invention will be described in detail below.

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

[0012] The type of non-steroidal anti-inflammatory drug used in the present invention is not particularly limited, and examples thereof include loxoprofen, diclofenac, indomethacin, felbinac, salicylic acid, acetylsalicylic acid, aspirin, salsalate, salicylamide, ethenzamide, ibuprofen, ketoprofen, naproxen, flurbiprofen, piroxicam, tiaprofenic acid, suprofen, tolmetin, aluminoprofen, benoxaprofen, benzydamine, sulindac, acemetacin, proglumetacin, amfenac, mofezolac, lornoxicam, ampiroxicam, fenoprofen, tiaprofenic acid, oxaprozin, mefenamic acid, flufenamic acid, azapropazone, fenbufen, etodolac, rofecoxib, diflunisal, zomepirac, celecoxib, zaltoprofen, ketorolac, nimesulide, and aceclofenac.

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

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

[0015] Specific examples of diclofenac salts 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, triethylamine, etc. Among these, alkali metal salts are preferred, and sodium salt is more preferred.

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

[0017] Among these nonsteroidal anti-inflammatory drugs, preferred are loxoprofen, diclofenac, and salts thereof. In particular, when loxoprofen and its salts are used as the nonsteroidal anti-inflammatory drug, browning that occurs over time can be more effectively suppressed.

[0018] The content of the nonsteroidal anti-inflammatory drug in the topical pharmaceutical composition of the present invention may be appropriately determined depending on the type of nonsteroidal anti-inflammatory drug used, the medicinal effect to be provided, and the like, and may be, for example, 0.1 to 15 wt %, preferably 0.5 to 10 wt %, more preferably 0.5 to 5 wt %, and even more preferably 1 to 1.5 wt %.

[0019] [Nonanoic acid vanillylamide] The topical composition of the present invention contains 0.015% by weight or more of nonanoic acid vanillylamide. Nonanoic acid vanillylamide is a type of capsaicinoid, and is a known ingredient known for its effects of providing a warming sensation, promoting blood circulation, etc.

[0020] The content of vanillylamide nonanoate in the composition for external use of the present invention may be 0.015% by weight or more, specifically 0.015-0.3% by weight, preferably 0.015-0.15% by weight, more preferably 0.02-0.15% by weight, and even more preferably 0.05-0.1% by weight. When vanillylamide nonanoate is present at 0.02% by weight or more together with a nonsteroidal anti-inflammatory drug and a benzyl nicotinate at 0.01% by weight or more, browning occurring over time tends to become more pronounced, but the composition for external use of the present invention can effectively suppress browning occurring over time even when vanillylamide nonanoate is present at 0.02% by weight or more.

[0021] In the topical composition of the present invention, the ratio of the non-steroidal anti-inflammatory drug to nonanoic acid vanillylamide may be within a range that satisfies the above-mentioned respective contents, and for example, the nonanoic acid vanillylamide may be 0.001 to 1 part by weight, preferably 0.01 to 0.3 parts by weight, and more preferably 0.015 to 0.1 parts by weight per part by weight of the non-steroidal anti-inflammatory drug.

[0022] [Nicotinic acid benzyl ester] The topical composition of the present invention contains 0.01% by weight or more of nicotinic acid benzyl ester, which is an ester of niacin and benzyl alcohol, and is a known ingredient known to have effects such as promoting absorption and blood circulation.

[0023] The content of nicotinic acid benzyl ester in the composition for external use of the present invention may be 0.01% by weight or more, specifically, 0.01-0.3% by weight, preferably 0.01-0.1% by weight, more preferably 0.01-0.1% by weight, even more preferably 0.02-0.1% by weight, and particularly preferably 0.04-0.1% by weight. In the prior art, when nicotinic acid benzyl ester is present at 0.015% by weight or more together with nicotinic acid benzyl ester at 0.01% by weight or more, browning occurs over time, but in the composition for external use of the present invention, even if nicotinic acid benzyl ester is contained at 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 nonsteroidal anti-inflammatory drug to the nicotinic acid benzyl ester may be within a range that satisfies the above-mentioned respective contents, and for example, the nicotinic acid benzyl ester may be 0.001 to 1 part by weight, preferably 0.005 to 0.3 parts by weight, and more preferably 0.008 to 0.1 part by weight per part by weight of the nonsteroidal anti-inflammatory drug.

[0025] [Monoterpene] The topical composition of the present invention contains monoterpene in addition to the above-mentioned components. The pharmaceutical composition of the present invention contains monoterpene together with nonsteroidal anti-inflammatory drug, nonanoic acid vanillylamide 0.015% by weight or more, and nicotinic acid benzyl ester 0.01% by weight or more, so that browning occurring over time can be effectively suppressed.

[0026] Monoterpenes are known components that have a structure containing two isoprene units in the molecule and have a cooling effect. The type of monoterpene used in the present invention is not particularly limited as long as it is pharmacologic acceptable, and examples of the monoterpenes include alcohol monoterpenes such as menthol, thymol, geraniol, linalool, borneol, cineole, and terpineol; aldehyde monoterpenes such as citral, citronellal, perillaldehyde, and safranal; and ketone monoterpenes such as camphor, menthone, carbomenthone, and ionone. When optical isomers exist, these monoterpenes may be d-, l-, or dl-isomers. These monoterpenes may be used alone or in combination of two or more.

[0027] In addition, in the present invention, as the monoterpene, an essential oil containing monoterpene may be used. The essential oil containing monoterpene can be appropriately selected from known ones and used, and for example, essential oil containing menthol includes peppermint oil, peppermint oil, spearmint oil, etc. In addition, the description of the content and ratio of monoterpene in this specification is the value converted into the amount of monoterpene contained in the essential oil when an essential oil containing monoterpene is used.

[0028] Among these monoterpenes, menthol is preferable, and 1-menthol is more preferable.

[0029] The content of monoterpenes in the topical composition of the present invention may be appropriately set depending on the type of monoterpene used, but may be, for example, 0.1 to 15% by weight in total of monoterpenes, and from the viewpoint of further suppressing browning that occurs over time, preferably 1 to 10% by weight, and more preferably 2 to 7% by weight.

[0030] In the topical composition of the present invention, the ratio of the nonsteroidal anti-inflammatory drug to the monoterpene may be within a range that satisfies the above-mentioned respective contents, but for example, the monoterpene may be 0.01 to 500 parts by weight per 1 part by weight of the nonsteroidal anti-inflammatory drug, and from the viewpoint of further suppressing browning that occurs over time, the ratio is preferably 0.1 to 50 parts by weight, and more preferably 1 to 5 parts by weight.

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

[0032] The type of monohydric lower alcohol is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include ethanol, n-propanol, isopropanol, etc. Among these monohydric lower alcohols, ethanol is preferred.

[0033] When the topical pharmaceutical composition of the present invention contains a monohydric lower alcohol, the content thereof is not particularly limited, but may be, for example, 0.1 to 90% by weight, preferably 25 to 80% by weight, and more preferably 50 to 80% by weight.

[0034] [water] The topical composition of the present invention may further contain water. When the topical pharmaceutical composition of the present invention contains water, the content of water is not particularly limited, and may be, for example, 0.1 to 80% by weight, preferably 1 to 50% by weight, more preferably 10 to 40% by weight, and even more preferably 15 to 30% by weight.

[0035] [Other ingredients] In addition to the above-mentioned components, the composition for external use of the present invention may contain other additives that are commonly used as necessary.Such additives include, for example, surfactants, vegetable oils, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, polyhydric alcohols, higher alcohols, pH regulators, buffers, solubilizers, preservatives, preservatives, antioxidants, stabilizers, fragrances, etc.When these additives are contained in the composition for external use of the present invention, their content can be appropriately set according to the type of additives used, etc.

[0036] In addition, the topical composition of the present invention may contain pharmacological components in addition to the above-mentioned components. Examples of such pharmacological components include antihistamines, local anesthetics, moisturizers, bactericides, antibacterial agents, antipruritic agents, skin protectants, blood circulation promoters, vitamins, etc. These pharmacological components may be used alone or in combination of two or more. In addition, when these pharmacological components are contained in the topical composition of the present invention, the concentration of the pharmacological components may be appropriately set according to the type of pharmacological components used, the expected effect, etc.

[0037] [Formulation] The topical composition of the present invention is not particularly limited in its formulation form as long as it is a dosage form that can be applied transdermally, and may be either liquid or semi-solid (gel, ointment, paste), but is preferably in liquid form.

[0038] Specific examples of the formulation of the topical composition of the present invention include liquids, creams, lotions, gels, emulsions, and aerosols. Among these, preferred are liquids, creams, lotions, gels, and emulsions. Preparation into these formulations can be carried out by formulating the composition using additives appropriate for the formulation according to the known method described in the General Provisions for Preparations of the Japanese Pharmacopoeia, 17th Edition, etc. EXAMPLES

[0039] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these.

[0040] Test Example 1: Evaluation of topical compositions containing loxoprofen sodium hydrate External compositions (liquids) with the compositions shown in Tables 1 and 2 were prepared. All of the obtained external compositions had a colorless and transparent appearance immediately after preparation. The obtained external compositions were filled into transparent glass bottles and stored in a dark place at 50°C and a relative humidity of 60%RH for 2 months. The external appearance of the external compositions after storage was visually observed, and the degree of browning was evaluated according to the following criteria. <Criteria for determining the degree of browning> ◎: No browning is observed, and the product is colorless and transparent. ◯: A very slight amount of browning is observed, but it is not a problem for practical use. △: Some browning is observed. ×: Obvious browning is observed. ××: Significant browning was observed, presenting a dark brown color.

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

[0042] [Table 1]

[0043] [Table 2]

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

[0045] The results are shown in Tables 3 and 4. Even when diclofenac sodium was used as a nonsteroidal anti-inflammatory drug, browning occurred when nonanoic acid vanillylamide was contained at 0.015% by weight or more, and further browning occurred when nonanoic acid vanillylamide was contained at a content of 0.02% by weight or more. Furthermore, when nicotinic acid benzyl ester was coexisted at 0.01% by weight or more, significant browning was observed (Comparative Examples 8 to 14), but by adding l-menthol in addition to these components, browning could be suppressed and an appearance that was practically acceptable could be maintained even after storage (Examples 13 to 24). Furthermore, when the content of l-menthol in Examples 13 to 24 was changed to 6% by weight, browning was significantly suppressed compared to Examples 13 to 24, and a colorless and transparent appearance could be maintained even after storage.

[0046] [Table 3]

[0047] [Table 4]

Claims

1. A composition for external use comprising at least one nonsteroidal anti-inflammatory drug selected from the group consisting of diclofenac and its salts, 0.015% by weight or more of nonanoic acid vanillylamide, 0.01% by weight or more of nicotinic acid benzyl ester, and menthol.

2. The composition for topical application according to claim 1 , which is a liquid, cream, lotion, gel, or emulsion.

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