Topical pharmaceutical composition

Abstract

The object of the present invention is to provide a formulation technology that improves the cooling sensation exhibited by topical pharmaceutical compositions containing nonsteroidal anti-inflammatory drugs and monoterpenes. [Solution] By adding propylene glycol in a content of more than 10% by weight to a topical pharmaceutical composition containing a nonsteroidal anti-inflammatory drug and a monoterpene, the cooling sensation can be improved.

Description

【Technical Field】 【0001】 The present invention relates to an external pharmaceutical composition containing a non-steroidal anti-inflammatory drug and a monoterpene, and having an improved cooling sensation. 【Background Art】 【0002】 Non-steroidal anti-inflammatory drugs represented by loxoprofen sodium, diclofenac sodium, felbinac, etc. are widely used as active ingredients of external pharmaceutical compositions. In addition, monoterpenes such as menthol are used for the purpose of improving the usability of external pharmaceutical compositions because they exhibit a cooling sensation. 【0003】 Conventionally, various reports have been made on the formulation of external pharmaceutical compositions containing a non-steroidal anti-inflammatory drug and a monoterpene. For example, Patent Document 1 describes that an external pharmaceutical composition containing loxoprofen and / or its salt, menthol, ethanol, and water can suppress clouding. Patent Document 2 describes that an external pharmaceutical composition containing diclofenac and / or its salt, tocopherol and / or its derivative, menthol, and water can suppress the formation of clouding and precipitates and can have excellent appearance properties. Patent Document 3 describes that an oil-in-water emulsion type external preparation having felbinac, l-menthol, a polyhydric alcohol, and a triglyceride and having a pH of 6.5 to 8.0 can suppress a decrease in the content of felbinac. 【0004】 In recent years, consumers' demands for improving the usability and functionality of external pharmaceutical compositions have been increasing. In order to meet such consumer needs, the development of a formulation technology for further improving the cooling sensation of external pharmaceutical compositions containing a non-steroidal anti-inflammatory drug and a monoterpene has been demanded. 【Prior Art Documents】 【Patent Documents】 【0005】 【Patent Document 1】 Japanese Patent Application Laid-Open No. 2020-59666 [Patent Document 2] Japanese Patent Publication No. 2015-189760 [Patent Document 3] Japanese Patent Publication No. 2019-178110 [Overview of the Initiative] [Problems that the invention aims to solve] 【0006】 The object of the present invention is to provide a technology for improving the cooling sensation exhibited by topical pharmaceutical compositions containing nonsteroidal anti-inflammatory drugs and monoterpenes. [Means for solving the problem] 【0007】 The inventors of the present invention conducted diligent research to solve the aforementioned problems and found that the cooling sensation can be improved by including propylene glycol in a content of more than 10% by weight in a topical pharmaceutical composition containing a nonsteroidal anti-inflammatory drug and a monoterpene. The present invention was completed by further research based on this finding. 【0008】 In other words, the present invention provides inventions in the following embodiments. Item 1. (A) Nonsteroidal anti-inflammatory drugs, (B) Monoterpenes, and (C) Propylene glycol, A topical pharmaceutical composition having a content of component (C) of more than 10% by weight. Item 2. The topical pharmaceutical composition according to Item 1, wherein component (A) is at least one selected from the group consisting of loxoprofen, diclofenac, felbinac, and salts thereof. Item 3. A method for improving the cooling sensation of a topical pharmaceutical composition containing a nonsteroidal anti-inflammatory drug and a monoterpene, A method for improving the cooling sensation of an external pharmaceutical composition, comprising (A) a nonsteroidal anti-inflammatory drug, (B) a monoterpene, and (C) propylene glycol in an amount exceeding 10% by weight. [Effects of the Invention] 【0009】 According to the present invention, the cooling sensation exhibited by topical pharmaceutical compositions containing nonsteroidal anti-inflammatory drugs and monoterpenes can be improved, resulting in a superior user experience. Furthermore, according to the present invention, a superior cooling sensation can be achieved even when the monoterpene content is set to a low level (e.g., 5% by weight or less) that is less likely to cause skin irritation, thus enabling formulations with low skin irritation. [Modes for carrying out the invention] 【0010】 1. Topical pharmaceutical composition The topical pharmaceutical composition of the present invention comprises (A) a nonsteroidal anti-inflammatory drug, (B) a monoterpene, and (C) propylene glycol, characterized in that the content of component (C) is greater than 10% by weight. The topical pharmaceutical composition of the present invention will be described in detail below. 【0011】 [(A) Nonsteroidal anti-inflammatory drugs] The topical pharmaceutical composition of the present invention contains a nonsteroidal anti-inflammatory drug (sometimes referred to as component (A)). A nonsteroidal anti-inflammatory drug is a general term for anti-inflammatory drugs other than glucocorticoids. 【0012】 The types of nonsteroidal anti-inflammatory drugs used in the present invention are not particularly limited, but examples include loxoprofen, diclofenac, felbinac, salicylic acid, acetylsalicylic acid, aspirin, salsalate, salicylamide, ethenzamide, ibuprofen, ketoprofen, naproxen, flurbiprofen, piroxicam, tiaprofenic acid, suprofen, tolmetin, aluminoprofen, benoxaprofen, benzydamine, sulindac, acemetacin, proglummetacin, amfenac, mofezolac, lornoxicam, ampiroxicam, fenoprofen, tiaprofenic acid, oxaprozin, mefenamic acid, flufenamic acid, azapropazon, fenbufen, etodolac, lofecoxib, diflunisal, zomepirac, celecoxib, zaltoprofen, ketrolac, nimeslid, and aceclofenac. 【0013】 In addition, when a non-steroidal anti-inflammatory drug can take a salt form, it may be in the salt form. Examples of the non-steroidal anti-inflammatory drug in the salt form 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, and the like. 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, and the like. 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. 【0017】 Among these non-steroidal anti-inflammatory drugs, loxoprofen, diclofenac, felbinac, and their salts are preferred. 【0018】 The content of component (A) in the external pharmaceutical composition of the present invention may be appropriately set according to the type of component (A) used, the medicinal effects to be provided, and the like. For example, it may be 0.1 to 15% by weight, preferably 0.5 to 10% by weight, more preferably 0.5 to 5% by weight. 【0019】 [(B) Monoterpene] The external pharmaceutical composition of the present invention contains a monoterpene (which may also be referred to as component (B)). A monoterpene is a known component having a structure containing two isoprene units in the molecule and having a cooling effect and the like. 【0020】 Regarding the types of monoterpenes used in the present invention, there is no particular limitation as long as they are pharmaceutically acceptable. For example, alcohol-based monoterpenes such as menthol, thymol, geraniol, linalool, borneol, cineole, terpineol, etc.; aldehyde-based monoterpenes such as citral, citronellal, perillaldehyde, safranal, etc.; ketone-based monoterpenes such as camphor, mentone, carvone, ionone, etc. may 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. 【0021】 In addition, in the present invention, essential oils containing monoterpenes may be used as monoterpenes. The essential oils containing monoterpenes can be appropriately selected from known ones and used. For example, as essential oils containing menthol, peppermint oil, spearmint oil, etc. may be mentioned. Note that 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 monoterpenes. 【0022】 Among these monoterpenes, preferably menthol, geraniol, d-borneol, dl-camphor, and more preferably l-menthol may be mentioned. 【0023】 Regarding the content of the component (B) in the external pharmaceutical composition of the present invention, it may be appropriately set according to the type of the component (B), the cooling sensation to be provided, etc. For example, the total amount of the component (B) is 0.01 to 10% by weight, preferably 0.1 to 8% by weight, more preferably 1 to 6% by weight, still more preferably 2 to 5% by weight, and particularly preferably 2 to 4% by weight. In the external pharmaceutical composition of the present invention, since the propylene glycol described later is contained at a content of more than 10% by weight together with the non-steroidal anti-inflammatory drug and the monoterpene, the cooling sensation is improved. Therefore, even when the content of the component (B) is about 5% by weight or less which is unlikely to cause skin irritation, it can have an excellent cooling sensation. 【0024】 In the topical pharmaceutical composition of the present invention, the ratio of component (B) to component (A) is determined according to the respective content of these components, but for example, per 1 part by weight of component (A), component (B) may be 0.001 to 100 parts by weight, preferably 0.01 to 10 parts by weight, and more preferably 0.1 to 10 parts by weight. 【0025】 [(C) Propylene Glycol] The topical pharmaceutical composition of the present invention contains, in addition to the above-mentioned components, propylene glycol (sometimes referred to as component (C)) in an amount exceeding 10% by weight. In the topical pharmaceutical composition of the present invention, by including propylene glycol in an amount exceeding 10% by weight, together with nonsteroidal anti-inflammatory drugs and monoterpenes, it is possible to improve the cooling sensation. Propylene glycol is a divalent lower alcohol also known as propane-1,2-diol. 【0026】 The content of component (C) in the topical pharmaceutical composition of the present invention may be more than 10% by weight, but specifically, it may be more than 10% by weight and 50% by weight or less. From the viewpoint of further improving the cooling sensation, the content of component (C) in the topical pharmaceutical composition of the present invention is preferably 11 to 40% by weight, more preferably 13 to 30% by weight, and even more preferably 15 to 30% by weight. 【0027】 In the topical pharmaceutical composition of the present invention, the ratio of component (C) to component (A) is determined according to the content of each component, but for example, per 1 part by weight of component (A), component (C) is 0.1 to 100 parts by weight, preferably 0.5 to 100 parts by weight, and more preferably 1 to 40 parts by weight. 【0028】 [Monovalent lower alcohol] The topical pharmaceutical composition of the present invention may further contain a monohydric lower alcohol. In the present invention, a monohydric lower alcohol refers to a monohydric alcohol having 1 to 5 carbon atoms. 【0029】 The types of monohydric lower alcohols are not particularly limited, as long as they are pharmaceutically acceptable, but examples include ethanol, n-propanol, isopropanol, etc. These monohydric lower alcohols may be used individually or in combination of two or more. 【0030】 Among these monohydric lower alcohols, ethanol is preferred. 【0031】 When the topical pharmaceutical composition of the present invention contains a monohydric lower alcohol, the amount is not particularly limited, but for example, it is 0.1 to 88% by weight, preferably 25 to 80% by weight, and more preferably 50 to 80% by weight. 【0032】 [Other ingredients] In addition to the components described above, the topical pharmaceutical composition of the present invention may contain other commonly used additives as needed. Examples of such additives include water, surfactants, vegetable oils, animal oils, mineral oils, fatty acid alkyl esters, fatty acids, higher alcohols, pH adjusters, buffers, solubilizers, preservatives, antioxidants, stabilizers, fragrances, colorants, and the like. When these additives are included in the topical pharmaceutical composition of the present invention, their content may be appropriately determined depending on the type of additive used. 【0033】 Furthermore, the topical pharmaceutical composition of the present invention may also contain pharmacological components in addition to the components described above. Examples of such pharmacological components include antihistamines, local anesthetics, moisturizers, disinfectants, antibacterial agents, antipruritics, skin protectants, blood circulation promoting components, vitamins, and the like. These pharmacological components may be used individually or in combination of two or more. When these pharmacological components are included in the topical pharmaceutical composition of the present invention, their concentrations may be appropriately set according to the type of pharmacological component used, the expected effect, etc. 【0034】 [Formulation] The topical pharmaceutical composition of the present invention is not particularly limited in terms of its formulation form, as long as it is a dosage form that can be applied transdermally. It may be in liquid or semi-solid form (gel, ointment, or paste), but liquid is preferred. 【0035】 Furthermore, specific formulations of the topical pharmaceutical composition of the present invention include liquids, creams, lotions, gels, emulsions, aerosols, and the like. Among these, liquids are preferred. These formulations can be prepared by compounding them using additives appropriate to the formulation, in accordance with known methods described in the General Provisions for Formulations of the Seventeenth Revised Japanese Pharmacopoeia, etc. 【0036】 2. Methods to improve the feeling of coolness The present invention further provides a method for improving the cooling sensation of a topical pharmaceutical composition containing a nonsteroidal anti-inflammatory drug and a monoterpene, characterized in that the topical pharmaceutical composition is blended with (A) a nonsteroidal anti-inflammatory drug, (B) a monoterpene, and (C) propylene glycol in an amount of more than 10% by weight. 【0037】 In the method for improving the cooling sensation of the present invention, the types of components (A) and (B), the amounts of components (A) to (C), the types and amounts of other components included, and the formulation form of the topical pharmaceutical composition are the same as in the case of "1. Topical Pharmaceutical Composition" described above. [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】 Topical pharmaceutical compositions (liquids) with the compositions listed in Tables 1-3 were prepared. The cooling sensation exhibited by each obtained topical pharmaceutical composition was evaluated. Specifically, 10 subjects applied approximately 2 g of each topical pharmaceutical composition to their inner arm, and 30 minutes after application, the cooling sensation at the application site was evaluated on a 20-point scale. The cooling sensation was evaluated on a 20-point scale from 1 to 20, with "no cooling sensation at all" being 1 point, "the cooling sensation felt when using the topical pharmaceutical composition of Reference Examples 1-1, 2-1, or 3-1" being 15 points, and "extremely good and high cooling sensation" being 20 points. The average score of the 10 subjects' scores was calculated. Then, the average score when using the topical pharmaceutical composition of Comparative Examples 1-1, 2-1, or 3-1 was set to 100, and the percentage of the average score when using each topical pharmaceutical composition was calculated, and the value was rounded to the first decimal place to obtain the cooling sensation score. 【0040】 The results are shown in Tables 1-3. In topical pharmaceutical compositions containing loxoprofen sodium, diclofenac sodium or felbinac, and l-menthol, the inclusion of dipropylene glycol or glycerin did not significantly improve the cooling sensation (Comparative Examples 1-2, 1-3, 2-2, 2-3, 3-2, and 3-3). 【0041】 On the other hand, although propylene glycol, dipropylene glycol, and glycerin do not exhibit a cooling sensation (Reference Examples 1-2 to 1-4, 2-2 to 2-4, and 3-2 to 3-4), when propylene glycol was included in topical pharmaceutical compositions containing loxoprofen sodium, diclofenac sodium, or felbinac, and l-menthol, a dramatic improvement in the cooling sensation was observed (Examples 1-1 to 1-4, 2-1 to 2-4, and 3-1 to 3-4). In particular, the topical pharmaceutical compositions of these examples exhibited a cooling sensation equivalent to or better than those of the topical pharmaceutical compositions of Reference Examples 1-1, 2-1, and 3-1, despite containing half the amount of l-menthol. Furthermore, in the topical pharmaceutical compositions of Examples 1-3, 2-3, and 3-3 in which the l-menthol content was changed to 6% by weight, an improvement in cooling sensation was observed compared to the topical pharmaceutical compositions of Examples 1-3, 2-3, and 3-3. In addition, in the topical pharmaceutical compositions of Examples 1-3, 2-3, and 3-3 in which l-menthol was replaced with geraniol, d-borneol, or dl-camphor, a dramatic improvement in cooling sensation was observed compared to these topical pharmaceutical compositions that did not contain propylene glycol. 【0042】 [Table 1] 【0043】 [Table 2] 【0044】 [Table 3] 【0045】 Prescription examples Topical pharmaceutical compositions with the compositions shown in Table 4 were prepared in the same manner as in Test Example 1, and the cooling sensation was evaluated in the same manner as in Test Example 1. In all of the topical pharmaceutical compositions from Formulation Examples 1 to 12, a dramatic improvement in cooling sensation was observed compared to the topical pharmaceutical compositions in Formulation Examples 1 to 12 in which propylene glycol was omitted. 【0046】 [Table 4]

Claims

[Claim 1] (A) Nonsteroidal anti-inflammatory drugs, (B) Monoterpenes, and (C) Propylene glycol are included. A topical pharmaceutical composition having a content of component (C) of more than 10% by weight. [Claim 2] The topical pharmaceutical composition according to claim 1, wherein component (A) is at least one selected from the group consisting of loxoprofen, diclofenac, felbinac, and salts thereof. [Claim 3] A method for improving the cooling sensation of a topical pharmaceutical composition containing a nonsteroidal anti-inflammatory drug and a monoterpene, A method for improving the cooling sensation of an external pharmaceutical composition, comprising (A) a nonsteroidal anti-inflammatory drug, (B) a monoterpene, and (C) propylene glycol in an amount of more than 10% by weight.

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