Water-based external components

Abstract

To provide pharmaceutical formulation in which separation can be suppressed in an aqueous external composition containing 0.005 pt.wt. or more of ester derivative of nicotinic acid for 1 pt.wt. of ester derivative of myristic acid.SOLUTION: An aqueous external composition contains (A) ester derivative of nicotinic acid and (B) ester derivative of myristic acid, where the content of the (A) component for 1 pt.wt. of the (B) component is 0.005 pt.wt. or more, and separation of the aqueous external composition is suppressed when menthol (C) is allowed to coexist with the components (A) and (B).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an aqueous external composition in which separation is suppressed despite containing a nicotinic acid ester derivative and a myristic acid ester derivative in water at a predetermined ratio.

Background Art

[0002] Nicotinic acid ester derivatives such as benzyl nicotinate are known as agents having a blood circulation promoting effect, and are also used as external compositions. In addition, since nicotinic acid ester derivatives are hardly soluble in water, they are formulated as aqueous compositions using ethanol or isopropanol, as shown in Patent Documents 1 and 2 and the like.

[0003] Further, myristic acid ester derivatives such as isopropyl myristate are oily components known as percutaneous absorption promoters, and as shown in Patent Documents 3 and 4 and the like, they are used by being blended together with active ingredients in external patches and the like.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of Invention

Problems to be Solved by the Invention

[0005] The inventors designed an aqueous topical composition containing a nicotinic acid ester derivative together with a monohydric lower alcohol to enhance the efficacy of the nicotinic acid ester derivative, by incorporating a myristic acid ester derivative, which is a transdermal penetration enhancer, while also increasing the content of the nicotinic acid ester derivative. However, despite both the nicotinic acid ester derivative and the myristic acid ester derivative being soluble in the lower monohydric alcohol, the inventors encountered the problem that significant separation occurs when the ratio of the nicotinic acid ester derivative to the myristic acid ester derivative reaches 0.005 parts by weight or more.

[0006] Therefore, the present invention aims to provide a formulation that can suppress separation in an aqueous topical composition containing 0.005 parts by weight or more of a nicotinic acid ester derivative per 1 part by weight of a myristic acid ester derivative. [Means for solving the problem]

[0007] As a result of diligent research, the inventors have found that separation can be suppressed by incorporating menthol into an aqueous topical composition containing 0.005 parts by weight or more of a nicotinic acid ester derivative per 1 part by weight of a myristic acid ester derivative. 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. An aqueous external composition comprising (A) an ester derivative of nicotinic acid, (B) an ester derivative of myristic acid, and (C) menthol, wherein the content of component (A) is 0.005 parts by weight or more per 1 part by weight of component (B). Item 2. The aqueous topical composition according to Item 1, wherein the component (A) is benzyl nicotinate. Item 3. The aqueous topical composition according to item 1 or 2, wherein the (B) component is isopropyl myristate. Item 4. An aqueous topical composition according to any one of items 1 to 3, wherein the content of component (A) is 0.011% by weight or more. Item 5. The aqueous topical composition according to any one of items 1 to 4, wherein the content of component (C) is 4 parts by weight or more per 1 part by weight of component (A). Item 6. An aqueous topical composition according to any one of items 1 to 5, which is a lotion, emulsion, gel, or cream. [Effects of the Invention]

[0009] According to the present invention, a formulation is provided in which separation can be suppressed in an aqueous topical composition containing 0.005 parts by weight or more of a nicotinic acid ester derivative per 1 part by weight of a myristic acid ester derivative. [Modes for carrying out the invention]

[0010] The aqueous topical composition of the present invention comprises (A) an ester derivative of nicotinic acid (hereinafter sometimes referred to as "component (A)"), (B) an ester derivative of myristic acid (hereinafter sometimes referred to as "component (B)"), and (C) menthol (hereinafter sometimes referred to as "component (C)"), characterized in that the content of component (A) is 0.005 parts by weight or more per 1 part by weight of component (B). The aqueous topical composition of the present invention will be described in detail below.

[0011] (A) Ester derivative of nicotinic acid The aqueous topical composition of the present invention contains a nicotinic acid ester derivative as component (A). Nicotinic acid ester derivatives are known components that have effects such as promoting blood circulation and activating cells.

[0012] Nicotinic acid ester derivatives are esters of nicotinic acid with alcohols, and specific examples include benzyl nicotinate, β-butoxyethyl nicotinate, and methyl nicotinate. These nicotinic acid ester derivatives may be used individually or in combination of two or more. Among these nicotinic acid ester derivatives, benzyl nicotinate is preferred.

[0013] The amount of component (A) in the aqueous topical composition of the present invention is 0.005 parts by weight or more per 1 part by weight of component (B). In an aqueous topical composition, if component (A) is present in an amount of 0.005 parts by weight or more per 1 part by weight of component (B), separation would normally occur, but separation is suppressed in the aqueous topical composition of the present invention.

[0014] Because the aqueous external composition of the present invention exhibits excellent separation-inhibiting effects, separation can be effectively suppressed even if the content of component (A) relative to 1 part by weight of component (B) is high. From this viewpoint, preferred examples of the content of component (A) relative to 1 part by weight of component (B) include 0.007 parts by weight or more, 0.009 parts by weight or more, 0.012 parts by weight or more, 0.02 parts by weight or more, 0.03 parts by weight or more, 0.04 parts by weight or more, 0.05 parts by weight or more, 0.06 parts by weight or more, 0.07 parts by weight or more, or 0.08 parts by weight or more.

[0015] There is no particular upper limit to the content of component (A) per 1 part by weight of component (B), but examples include 0.2 parts by weight or less, 0.15 parts by weight or less, 0.1 parts by weight or less, or 0.09 parts by weight or less.

[0016] The specific content of component (A) in the aqueous topical composition of the present invention may be set appropriately according to the therapeutic effect to be provided to the aqueous topical composition, but for example, it may be 0.005% by weight or more, preferably 0.008% by weight or more, more preferably 0.011% by weight or more, even more preferably 0.018% by weight or more, and even more preferably 0.03% by weight or more. The specific upper limit of the content of component (A) may be 0.5% by weight or less, preferably 0.1% by weight or less, more preferably 0.05% by weight or less, and even more preferably 0.03% by weight or less.

[0017] (B) Ester derivatives of myristic acid The aqueous topical composition of the present invention contains a myristic acid ester derivative as component (B). The myristic acid ester derivative is a known component known to have transdermal penetration promoting effects, etc.

[0018] The ester derivative of myristic acid is an ester of myristic acid and an alcohol, and specific examples thereof include isopropyl myristate, butyl myristate, octyldodecyl myristate, and the like. These ester derivatives of myristic acid may be used singly or in combination of two or more. Among these ester derivatives of myristic acid, isopropyl myristate is preferred.

[0019] The content of component (B) in the aqueous external composition of the present invention is determined according to the content of component (A) (parts by weight) relative to 1 part by weight of the aforementioned component (B) and the specific content of component (A) (% by weight), and is, for example, 1 to 8% by weight, preferably 2 to 6% by weight.

[0020] (C) Menthol The aqueous external composition of the present invention contains menthol as component (C). The menthol may be any of d-form, l-form, and dl-form. In addition, for the incorporation of menthol, an essential oil containing menthol may be incorporated.

[0021] The content of component (C) in the aqueous external composition of the present invention is not particularly limited, and is, for example, 1% by weight or more. From the viewpoint of further enhancing the separation inhibitory effect, the content is preferably 2.5% by weight or more, more preferably 3.5% by weight or more, still more preferably 4.5% by weight or more, and even more preferably 5.5% by weight or more. The upper limit of the content of component (C) is not particularly limited, and is, for example, 8% by weight or less, 7% by weight or less, or 6.5% by weight or less.

[0022] In the aqueous external composition of the present invention, the ratio of component (A) to component (C) is determined according to the content of each component, but from the viewpoint of further enhancing the separation suppression effect, the content of component (C) per 1 part by weight of component (A) is preferably 4 parts by weight or more, more preferably 10 parts by weight or more, even more preferably 50 parts by weight or more, even more preferably 70 parts by weight or more, even more preferably 100 parts by weight or more, 150 parts by weight or more, 200 parts by weight or more, 250 parts by weight or more, 300 parts by weight or more, 400 parts by weight or more, or 500 parts by weight or more. There is no particular upper limit to the content of component (C) per 1 part by weight of component (A), but examples include 600 parts by weight or less, 550 parts by weight or less, 450 parts by weight or less, 350 parts by weight or less, or 250 parts by weight or less.

[0023] water The aqueous topical composition of the present invention contains water. The water is not particularly limited and includes purified water, distilled water, ion-exchanged water, ultrapure water, and sterile water, with purified water being preferred.

[0024] The water content is not particularly limited as long as it does not hinder the effects of the present invention, but for example, it is 5 to 0% by weight, preferably 10 to 30% by weight.

[0025] Other ingredients The aqueous topical composition of the present invention may contain other pharmacological components in addition to the components described above, as necessary, as long as they do not interfere with the effects of the present invention. Other pharmacological components that can be incorporated into the aqueous topical composition of the present invention are not particularly limited, but examples include: anti-inflammatory agents such as glycyrrhetinic acid, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, stearyl glycyrrhizinate, indomethacin, felbinac, diclofenac sodium, and loxoprofen sodium; antihistamines such as diphenylimidazole, diphenhydramine and pharmaceutically acceptable salts thereof, and chlorpheniramine maleate; lidocaine and pharmaceutically acceptable salts thereof, dibucaine and its pharmaceutically acceptable salts Examples include locally anesthetics such as salts and ethyl aminobenzoate that are generally acceptable; capsaicinoids (specifically vanillylamide nonanoate; and capsaicin derivatives such as capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin, etc.); blood circulation promoters such as tocopherol acetate (other than the above component (A)); and crude drugs such as arnica tincture, Phellodendron amurense extract, Gardenia fruit extract, Aesculus hippocastanum extract, Belladonna extract, Angelica acutiloba extract, Lithospermum erythrorhizon extract, and Zanthoxylum piperitum extract.

[0026] Furthermore, in addition to the components described above, the aqueous topical composition of the present invention may optionally contain solvents and other additives commonly used in aqueous topical compositions. Examples of such solvents include monohydric lower alcohols having 1 to 5 carbon atoms, such as ethanol, propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, and pentanol, with ethanol and isopropanol being preferred, and ethanol being more preferred. In the aqueous topical composition of the present invention, the content of the above monohydric lower alcohol is not particularly limited as long as it does not hinder the effects of the present invention, but for example, it may be 60 to 80% by weight. Examples of additives include pH adjusters, surfactants, emulsifiers, solubilizers, preservatives, antioxidants, stabilizers, chelating agents, thickeners, fragrances, and colorants.

[0027] Formulation The formulation form of the aqueous topical composition of the present invention is not particularly limited, as long as it is applicable transdermally. Since separation is suppressed in the aqueous topical composition of the present invention, the active ingredient is well soluble, and as a result, the active ingredient can act effectively regardless of the formulation form.

[0028] Specific examples of the aqueous topical composition of the present invention include liquid formulations (such as lotions, sprays, aerosols, and emulsions), foams, ointments, gels, creams, and patches, with lotions, emulsions, gels, or creams being 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 Edition of the Japanese Pharmacopoeia, etc. [Examples]

[0029] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0030] Test Example 1 Aqueous topical compositions (lotions) with the compositions shown in Tables 2-4 were prepared, and the degree of separation at the time of preparation was evaluated according to the following criteria.

[0031] [Evaluation of separation-inhibiting effect] Ten g of the prepared aqueous topical composition was placed in a transparent screw tube with a diameter of 21 mm, and its appearance was visually inspected from the side. The separation inhibition effect was evaluated based on the criteria in Table 1. A score of 5 or higher indicates that the predetermined separation inhibition effect was achieved, with higher scores indicating a greater separation inhibition effect. The results are shown in Tables 2 to 4.

[0032] [Table 1]

[0033] [Table 2]

[0034] [Table 3]

[0035] [Table 4]

[0036] As shown in Tables 2-4, no significant separation occurred when the ratio of benzyl nicotinate to isopropyl myristate (the value indicated as "(A) / (B)" in the table) was as shown in Reference Examples 2-4. However, when the ratio reached the levels shown in Comparative Examples 1-5, separation became significant. In particular, separation was especially pronounced in Comparative Examples 3-5, where the ratio of benzyl nicotinate to isopropyl myristate, (A) / (B), was 0.01 or higher. On the other hand, by adding menthol to compositions with the ratio shown in Comparative Examples 1-5, a high separation inhibition effect was achieved, as shown in Examples 1-13. Furthermore, the same separation inhibition effect was achieved when the ethanol content in Examples 1-13 was changed to 60% or 80% by weight.

Claims

1. (A) benzyl nicotinate, (B) isopropyl myristate, (C) menthol, and a monohydric lower alcohol having 1 to 5 carbon atoms, The content of component (A) is 0.02% by weight or more, The content of component (A) relative to 1 part by weight of component (B) is 0.01 parts by weight or more. The content of component (C) relative to 1 part by weight of component (A) is 10 parts by weight or more. An aqueous topical composition wherein the monohydric lower alcohol is ethanol.

2. The aqueous external composition according to claim 1, which is a lotion, emulsion, gel, or cream.

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