Composition for external use

Abstract

To provide a minoxidil-containing composition for external use, blended with pyridoxine, which suppresses the precipitation caused by minoxidil which may occur after application, and also suppresses deterioration of stability of the pyridoxine.SOLUTION: There is provided a composition for external use which comprises minoxidil, pyridoxine and / or a salt thereof, propylene glycol and at least one acid selected from the group consisting of phosphoric acid, citric acid, lactic acid, hydrochloric acid, acetic acid, sulfuric acid, nitric acid, tartaric acid and maleic acid and / or a salt thereof. It can be used as a composition for external use such as a lotion, an aerosol, a tonic agent, a cream agent, an ointment and a gelling agent and the most preferable formulation of it is a lotion.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an external composition containing minoxidil as an active ingredient. More specifically, it relates to a technique for suppressing precipitation derived from minoxidil that may occur by applying an external composition containing minoxidil blended with pyridoxine.

Background Art

[0002] Minoxidil is called 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide in chemical name and is known to be applicable as a hair growth agent (Patent Document 1), and there are many reports as a drug that exhibits an excellent hair growth and hair follicle-stimulating effect. Since an external composition containing minoxidil is used daily on the head for a long period of time, an excellent composition is required in terms of the feeling of use. When using a composition with a higher concentration of minoxidil, precipitation derived from minoxidil rarely occurs after application and may look like dandruff. Therefore, in an external composition containing minoxidil, a composition that suppresses precipitation derived from minoxidil that may occur after application is desired. In addition, pyridoxine has been reported to have an effect of suppressing lipid synthesis (Non-Patent Document 1) and is used in many hair growth agents.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Non-Patent Documents

[0004]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a minoxidil-containing topical composition containing pyridoxine, which suppresses precipitation derived from minoxidil that may occur after application. **Means for Solving the Problems**

[0006] As a result of intensive studies to solve the above problems, the present inventors have found that a composition containing minoxidil, pyridoxine, a specific polyhydric alcohol, and a specific acid can suppress precipitation derived from minoxidil, and have completed the present invention.

[0007] That is, the present invention is (1) A topical composition characterized by containing 1) minoxidil, 2) pyridoxine and / or its salt, 3) propylene glycol, and 4) at least one acid selected from the group consisting of phosphoric acid, citric acid, lactic acid, hydrochloric acid, acetic acid, sulfuric acid, nitric acid, tartaric acid, and maleic acid and / or salts thereof. (2) The topical composition according to (1), wherein the concentration of minoxidil is 5 w / w% or more. It is. **Effects of the Invention**

[0008] According to the present invention, in a minoxidil-containing topical composition containing pyridoxine, it has become possible to suppress precipitation derived from minoxidil that may occur after application. Furthermore, unexpectedly, it can be provided as a clear minoxidil-containing composition in which no precipitate is formed in the preparation, and it can suppress a decrease in the stability of pyridoxine and / or its salt over time. **Modes for Carrying Out the Invention**

[0009] According to the present invention, a topical composition containing minoxidil, pyridoxine and / or its salt, propylene glycol, and a specific acid and / or its salt suppresses precipitation derived from minoxidil that may occur after application, does not form a precipitate in the preparation, and suppresses a decrease in the stability of pyridoxine.

[0010] In the topical composition of the present invention, minoxidil that is of a quality usually used in pharmaceuticals can be appropriately used. Further, according to the present invention, as the content of minoxidil increases, the problem of precipitation that may occur after applying the preparation becomes more significant. Therefore, the higher the concentration of minoxidil in the topical composition, the greater the significance of implementing the present invention. Specifically, it is 1 w / w% or more in the topical composition of the present invention, more preferably 3 w / w% or more, and even more preferably 5 w / w% or more.

[0011] The specific acid and / or its salt in the topical composition of the present invention is phosphoric acid, citric acid, lactic acid, hydrochloric acid, acetic acid, sulfuric acid, nitric acid, tartaric acid, maleic acid, or a salt thereof, preferably phosphoric acid, citric acid, lactic acid, tartaric acid, from the viewpoint of the effect of the present invention of obtaining a clear preparation without precipitation. These acids and / or their salts are components that adjust the liquidity of the topical composition of the present invention to 7 or less, and all of them are inorganic acids or their salts or organic acids having 6 or less carbon atoms or their salts. The specific acid and / or its salt of the present invention may be used alone or in combination of two or more.

[0012] Also, the polyhydric alcohol used in the topical composition of the present invention is propylene glycol from the viewpoint that it does not cause precipitation derived from minoxidil after application, which is an effect of the present invention. The blending amount of propylene glycol is preferably 2 to 55 w / w% in the total composition, and more preferably 5 to 35 w / w%. In the topical composition of the present invention, polyhydric alcohols other than propylene glycol may be included as long as the effects of the present invention are not impaired, but it is preferable from the viewpoint of the effects of the present invention not to blend glycerin and polyethylene glycol, and it is most preferable from the viewpoint of the effects of the present invention to blend only propylene glycol.

[0013] In addition, in terms of the stability of the main drug component minoxidil, the irritation to the skin during use, the drug permeability, the usability, etc. of the external composition of the present invention, it is preferable to adjust its pH to the range of 4.0 to 9.5, and the range of 5.0 to 7.0 is more preferable. Further, as the upper limit of the pH, it is preferably less than 6.5, more preferably 6.3 or less, and even more preferably 6.1 or less.

[0014] Regarding the compounding amount of pyridoxine used in the external composition of the present invention, from the viewpoint of the effects of the present invention, 0.01 to 2 w / w% in the external composition is preferable, 0.03 to 0.1 w / w% is more preferable, and 0.03 to 0.05 w / w% is even more preferable.

[0015] Higher alcohols can be further added to the external composition of the present invention as needed. Examples of higher alcohols include diacetone alcohol, caproyl alcohol, caprylyl alcohol, capryl alcohol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, hexyl decanol, isocetyl alcohol, cetostearyl alcohol, heptadecanol, stearyl alcohol, oleyl alcohol, isostearyl alcohol, octyl decanol, nonadecanol, arachyl alcohol, octyldodecanol, heneicosanol, behenyl alcohol, and decyltetradecanol with 6 to 24 carbon atoms, among which diacetone alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, hexyl decanol, cetostearyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, arachyl alcohol, octyldodecanol, behenyl alcohol, and decyltetradecanol are more preferable. Among them, diacetone alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, hexyl decanol, cetostearyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, arachyl alcohol, octyldodecanol, behenyl alcohol, and decyltetradecanol are even more preferable. The higher alcohols of the present invention may be used alone or in combination of two or more. The compounding amount of the higher alcohol is preferably 0.05 to 2 w / w% in the whole composition, more preferably 0.1 to 1.5 w / w%, and even more preferably 0.25 to 1.5 w / w%.

[0016] In the external composition of the present invention, lower alcohols and water can be further added if necessary. As the lower alcohol, those having 1 to 5 carbon atoms are preferred, for example, ethanol, isopropanol, etc. are preferred, and these may be used in combination. The blending amount of the lower alcohol is preferably 20 w / w% or more in the total composition, more preferably 30 w / w% or more, still more preferably 35 w / w% or more, and even more preferably 50 w / w% or more. The blending amount of water is preferably 2 to 75 w / w%, more preferably 5 to 50 w / w%.

[0017] In the external composition of the present invention, higher fatty acids can be further added if necessary. As examples of the higher fatty acid, those having 10 to 22 carbon atoms are preferred, for example, isostearic acid, oleic acid, stearic acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, linoleic acid, linolenic acid, elaidic acid, arachidic acid, arachidonic acid, behenic acid, eicosapentaenoic acid, docosahexaenoic acid, etc. can be mentioned, and one or a combination of two or more of these may be used. Among these, those having 18 carbon atoms are preferred, and isostearic acid or oleic acid is particularly preferred. The blending amount of the higher fatty acid is preferably 0.1 to 10 w / w% in the total composition, more preferably 1 to 6 w / w%.

[0018] In the external composition of the present invention, surfactants can be further added if necessary. However, the addition of surfactants may affect the usability and the skin absorption of minoxidil. In the external composition of the present invention, since the solubility of minoxidil can be ensured without adding surfactants, it is preferably substantially free of surfactants.

[0019] In the external composition of the present invention, in addition to the above-described components, necessary active ingredients and auxiliary components can be added within a range that does not impair the effects of the present invention. As medicinal ingredients preferably added to and blended in the lotion of the present invention, components selected from the group consisting of menthol, vitamin E acetate, pantothenyl ethyl ether, hinokitiol, glycyrrhetinic acid, diphenhydramine hydrochloride, and panthenol can be mentioned. There are no particular restrictions on the addition amounts of these selected components, and they can be determined experimentally while considering the feel of use, the stability of minoxidil, the solvent system composition, etc.

[0020] In the external composition of the present invention, in addition to the above-described components, various active ingredients and auxiliary components used in general external preparations can be blended within a range that does not impair the effects of the present invention. For example, excipients, hair growth components (6-benzylaminopurine, adenosine, glyceryl pentadecanoate, fleeceflower root, etc.), vasodilators (calpronium chloride, benzyl nicotinate, assembly extract, wild angelica extract, Chinese rhubarb tincture, capsicum tincture, etc.), antihistamines (isothipendyl hydrochloride, etc.), anti-inflammatory agents (guaiazulene, etc.), keratolytic agents (urea, salicylic acid, etc.), bactericides (chlorhexidine gluconate, isopropylmethylphenol, quaternary ammonium salts, piroctone olamine, etc.), moisturizing agents (hyaluronic acid or its salts, chondroitin sulfate, etc.), extracts of various animals and plants (Japanese yew, button mushroom, licorice, speedwell, aconite, loquat, wild mugwort, comfrey, ashitaba, saffron, ginseng, rosemary, sage, mokko, seimokko, hops, placenta, saw palmetto, pumpkin seed, etc.), vitamins (retinol acetate, ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, etc.), antioxidants (dibutylhydroxytoluene, sodium pyrosulfite, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.), solubilizing aids (diisopropyl adipate, isopropyl myristate, various vegetable oils, various animal oils, alkyl glyceryl ethers, hydrocarbons, etc.), metabolic activators, gelling agents (water-soluble polymers, etc.), adhesives, fragrances, cooling agents (peppermint oil, camphor, etc.), dyes, and other commonly used components can be blended.

[0021] The external composition of the present invention can be made into a suitable external composition such as a lotion, aerosol, tonic, cream, ointment, gel, etc. Among these, the most preferred dosage form is a lotion.

[0022] The external composition of the present invention is prepared by containing the above components according to a conventional method.

[0023] The external composition of the present invention thus obtained can be used as a skin application preparation such as a hair preparation, an eyelash preparation, an eyebrow preparation, etc.

[0024] Examples, comparative examples and test examples are described below to further specifically explain the present invention, but the present invention is not limited by these examples and the like.

Examples

[0025] (Example 1) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of phosphoric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0026] (Example 2) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of citric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.1.

[0027] (Example 3) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of lactic acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.1.

[0028] (Example 4) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of hydrochloric acid, an appropriate amount of 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0029] (Example 5) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of acetic acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.1.

[0030] (Example 6) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of sulfuric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0031] (Example 7) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of nitric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0032] (Example 8) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of tartaric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.1.

[0033] (Example 9) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of maleic acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0034] (Example 10) 1 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of phosphoric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0035] (Example 11) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of citric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0036] (Example 12) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of lactic acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0037] (Example 13) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of tartaric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0038] (Comparative Example 1) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of polyethylene glycol 400, an appropriate amount of phosphoric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.3.

[0039] (Comparative Example 2) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of dl - malic acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to prepare an external composition.

[0040] (Comparative Example 3) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of boric acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to prepare an external composition.

[0041] (Comparative Example 4) 5 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of gluconic acid, 20 g of purified water, and the total amount was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0042] (Comparative Example 5) 1 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of propylene glycol, an appropriate amount of gluconic acid, 20 g of purified water, and the total volume was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0043] (Comparative Example 6) 1 g of minoxidil, 0.05 g of pyridoxine hydrochloride, 15 g of polyethylene glycol 400, an appropriate amount of phosphoric acid, 20 g of purified water, and the total volume was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0044] (Comparative Example 7) 1 g of minoxidil, 15 g of propylene glycol, an appropriate amount of phosphoric acid, 20 g of purified water, and the total volume was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0045] (Comparative Example 8) 5 g of minoxidil, 15 g of propylene glycol, an appropriate amount of citric acid, 20 g of purified water, and the total volume was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.1.

[0046] (Comparative Example 9) 5 g of minoxidil, 15 g of propylene glycol, an appropriate amount of lactic acid, 20 g of purified water, and the total volume was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0047] (Comparative Example 10) 5 g of minoxidil, 15 g of propylene glycol, an appropriate amount of tartaric acid, 20 g of purified water, and the total volume was made up to 100 g with ethanol, and stirred for about 1 hour to obtain an external composition with a pH of 6.0.

[0048] (Test Example 1: Precipitation Test - 1) Regarding Example 1 and Comparative Example 1, 100 μL of each external composition was dropped onto a glass petri dish, and after 24 hours, the precipitation of crystals derived from minoxidil was visually evaluated. The test was carried out 3 times.

[0049] As a result of the test, compared with Comparative Example 1 in which polyethylene glycol was blended as the polyhydric alcohol, in Example 1 using the polyhydric alcohol of the present invention, the precipitation of crystals derived from minoxidil was suppressed three times.

[0050] <Test Example 2: Precipitation Test - 2> Regarding Examples 10 to 13 and Comparative Examples 6 to 10, 100 μL of each external composition was dropped onto a glass petri dish, and after 24 hours, the precipitation of crystals derived from minoxidil was visually evaluated.

[0051] As a result of the test, compared with Comparative Example 6 in which polyethylene glycol was blended as the polyhydric alcohol, in Example 10 using the polyhydric alcohol of the present invention, the precipitation of crystals derived from minoxidil was suppressed. Also, compared with Comparative Example 7 in which pyridoxine hydrochloride was not blended, in Example 10 of the present invention in which pyridoxine hydrochloride was blended, the precipitation of crystals derived from minoxidil was suppressed.

[0052] Furthermore, similarly, in the preparations using different types of acids of the present invention, the precipitation of crystals derived from minoxidil was suppressed (Examples 11 to 13 and Comparative Examples 8 to 10).

[0053] <Test Example 3: Preparation Test of Lotion> Regarding Examples 1 to 10 and Comparative Examples 2 to 5, a preparation test of lotion was carried out. After preparation, the lotion in the beaker was visually confirmed, and those that obtained a clear preparation without precipitate were marked as ○, and those that had precipitate in the lotion were marked as ×. The results are shown in Table 1.

[0054] <Test Example 4: Stability Test of Pyridoxine Hydrochloride> Regarding Examples 1 to 10 and Comparative Examples 4 to 5, a stability test of pyridoxine hydrochloride was carried out. The stability test was performed by quantifying the content of pyridoxine hydrochloride by liquid chromatography after allowing each composition to stand in a thermostat at 65°C for 2 weeks. Comparing with the content of pyridoxine hydrochloride immediately after preparation, those with a decrease in pyridoxine hydrochloride of 0 to 5% were rated as ◎, those with 6% to 7% were rated as ○, those with 8 to 9% were rated as △, and those with a decrease of 10% or more were rated as ×. The results are shown in Table 1.

[0055]

Table 1

[0056] As is clear from Table 1, in Examples 1 to 10 using the acid of the present invention, clear lotions in which all the compounding components were dissolved and there was no precipitate were obtained. On the other hand, when malic acid or boric acid among the acids was used, precipitates were formed in the lotion after preparation (Comparative Examples 2 and 3). Also, in Comparative Examples 4 and 5 using gluconic acid as the acid, although lotions could be prepared, the content of pyridoxine hydrochloride decreased significantly. On the other hand, in the lotions of Examples 1 to 10 using the acid of the present invention, the decrease in the content of pyridoxine hydrochloride was lower than 10%. In particular, when phosphoric acid, hydrochloric acid, acetic acid, sulfuric acid, or nitric acid was used, the decrease in the content of pyridoxine hydrochloride could be suppressed to 5% or less, which was a favorable result.

Industrial Applicability

[0057] According to the present invention, in a minoxidil-containing topical composition containing pyridoxine, it is possible to provide an excellent minoxidil-containing topical composition that suppresses precipitation derived from minoxidil that may occur after application, suppresses precipitate formation in the topical composition, and suppresses a decrease in the stability of pyridoxine and / or its salt.

Claims

【Claim 1】 The invention described in this specification.

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