JP7569019B2 - External Composition - Google Patents

Description

The present invention relates to a topical composition containing minoxidil as an active ingredient. More specifically, the present invention relates to a technology for suppressing coloration over time of a topical composition containing minoxidil that contains at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or its salts, pantothenyl ethyl ether, panthenol, hinokitiol, and diphenhydramine and/or its salts.

Minoxidil has the chemical name 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, and is known to be useful as a hair growth agent (Patent Document 1). There are many reports of minoxidil as a drug that exhibits excellent hair growth and hair regrowth effects.
In addition, it has been reported that glycyrrhetinic acid has an anti-inflammatory effect (Patent Document 2), pantothenyl ethyl ether has a cell activation effect (Patent Document 3), panthenol has a wound healing promoting effect (Patent Document 4), hinokitiol has an antibacterial effect (Patent Document 5), and diphenhydramine has an itching suppressing effect (Patent Document 6), and these compounds are used in many hair growth agents.

U.S. Pat. No. 4,139,619 JP 2009-221190 A WO2007/074602 publication JP 2012-126733 A JP 2000-1432 A Patent No. 5008162

In order to develop an excellent hair growth agent, the present inventors produced a minoxidil-containing topical composition by blending a specific active ingredient, namely, glycyrrhetinic acid, pantothenyl ethyl ether, panthenol, hinokitiol, or diphenhydramine hydrochloride, with a composition containing minoxidil and an acid, and evaluated the stability. Surprisingly, it was found that the blending of a specific active ingredient caused more discoloration than a preparation containing minoxidil alone. The present invention aims to provide a minoxidil-containing topical composition blended with at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or a salt thereof, pantothenyl ethyl ether, panthenol, hinokitiol, diphenhydramine and/or a salt thereof, which suppresses discoloration of the preparation.

There have been no reports to date of whether or not there is an interaction between minoxidil at 2 w/w% or more and glycyrrhetinic acid and/or its salts, pantothenyl ethyl ether, panthenol, hinokitiol, or diphenhydramine and/or its salts that could affect the discoloration of the formulation.

As a result of intensive research conducted by the present inventors to solve the above problems, they discovered that when producing a minoxidil-containing topical composition containing glycyrrhetinic acid and/or a salt thereof, pantothenyl ethyl ether, panthenol, hinokitiol, or diphenhydramine and/or a salt thereof, by selecting a specific polyhydric alcohol, it is possible to produce a minoxidil-containing topical composition that suppresses discoloration of the formulation over time, and thus completed the present invention.

That is, the present invention provides:
(1) a) 2 w/w% or more of minoxidil;
b) at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or a salt thereof, pantothenyl ethyl ether, panthenol, hinokitiol, diphenhydramine and/or a salt thereof;
A composition for external use, comprising: c) propylene glycol; and d) an acid.
(2) The composition for external use according to (1), wherein the concentration of minoxidil is 5 w/w% or more.
(3) a) 2 w/w% or more of minoxidil;
b) at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or a salt thereof, pantothenyl ethyl ether, panthenol, hinokitiol, diphenhydramine and/or a salt thereof;
c) propylene glycol, and d) an acid to prepare a mixture;
a method for producing a composition for external use, comprising the steps of: adding e) water and f) a lower alcohol to the mixture to prepare a total amount of the composition;
It is.

The present invention makes it possible to provide a minoxidil-containing topical composition containing 2 w/w% or more of minoxidil, which contains at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or its salts, pantothenyl ethyl ether, panthenol, hinokitiol, and diphenhydramine and/or its salts, and which suppresses discoloration of the formulation over time.

According to the present invention, a topical composition containing 2 w/w% or more of minoxidil, at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or its salts, pantothenyl ethyl ether, panthenol, hinokitiol, diphenhydramine and/or its salts, propylene glycol, and acid suppresses discoloration of minoxidil preparations.

The minoxidil used in the topical composition of the present invention may be of the same quality as that used in ordinary pharmaceuticals. According to the present invention, the minoxidil content is 2 w/w% or more, more preferably 3 w/w% or more, and even more preferably 5 w/w% or more. If the content is 5 w/w% or more, the coloring of the preparation will progress more, so it is very meaningful to carry out the present invention within this range.

The polyhydric alcohol used in the topical composition of the present invention is propylene glycol from the viewpoint of suppressing coloration of the preparation over time, which is an effect of the present invention. The amount of propylene glycol in the total composition is preferably 2 to 55 w/w%, more preferably 2 to 35 w/w%, and even more preferably 2 to 15 w/w%. The topical composition of the present invention may contain polyhydric alcohols other than propylene glycol within a range that does not impair the effect of the present invention, but it is preferable from the viewpoint of the effect of the present invention not to include glycerin, polyethylene glycol, or dipropylene glycol, and it is most preferable from the viewpoint of the effect of the present invention to include only propylene glycol.

It is known that an acid is used to dissolve minoxidil in a base. The acid used in the topical composition of the present invention is preferably a component that adjusts the liquidity of the topical composition of the present invention to 7 or less, and examples of such acids include inorganic acids and organic acids with 6 or less carbon atoms. Specific examples include phosphoric acid, citric acid, lactic acid, hydrochloric acid, acetic acid, sulfuric acid, nitric acid, tartaric acid, maleic acid, malic acid, and gluconic acid, and preferably phosphoric acid, citric acid, lactic acid, and tartaric acid. These acids may be used alone or in combination of two or more.

The pH of the topical composition of the present invention is preferably adjusted to a range of 4.0 to 9.5, more preferably 5.0 to 7.0, from the standpoints of the stability of the main ingredient minoxidil, the sensation of irritation to the skin during use, the permeability of the drug, the feeling of use, etc. Furthermore, the upper limit of the pH is preferably less than 6.5, more preferably 6.3 or less, and even more preferably 6.1 or less.

The amount of glycyrrhetinic acid and/or its salt used in the topical composition of the present invention is preferably 0.01 to 1 w/w% in the topical composition, more preferably 0.02 to 0.5 w/w%, even more preferably 0.05 to 0.1 w/w%, and preferably 0.02 parts by mass or more per part by mass of minoxidil, from the viewpoint of the problem of suppressing discoloration of the present invention. The amount of pantothenyl ethyl ether is preferably 0.1 to 5 w/w% in the topical composition, more preferably 0.2 to 2 w/w%, even more preferably 0.2 to 1 w/w%, and preferably 0.2 parts by mass or more per part by mass of minoxidil, from the viewpoint of the problem of suppressing discoloration of the present invention. The amount of panthenol in the composition for external use is preferably 0.1 to 5 w/w%, more preferably 0.2 to 2 w/w%, even more preferably 0.2 to 1 w/w%, and is preferably 0.2 parts by mass or more per part by mass of minoxidil. The amount of hinokitiol in the composition for external use is preferably 0.01 to 0.1 w/w%, more preferably 0.01 to 0.05 w/w%, even more preferably 0.02 to 0.05 w/w%, and is preferably 0.01 parts by mass or more per part by mass of minoxidil, from the viewpoint of the object of the present invention to suppress discoloration. From the viewpoint of the objective of the present invention of suppressing discoloration, the amount of diphenhydramine and/or its salt in the topical composition is preferably 0.01 to 1 w/w%, more preferably 0.02 to 0.5 w/w%, and even more preferably 0.05 to 0.1 w/w%, and is preferably 0.02 parts by mass or more per part by mass of minoxidil.

The topical composition of the present invention may further contain a higher alcohol if necessary. Examples of higher alcohols include diacetone alcohol, caproyl alcohol, caprylyl alcohol, capryl alcohol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, hexyldecanol, isocetyl alcohol, cetostearyl alcohol, heptadecanol, stearyl alcohol, oleyl alcohol, isostearyl alcohol, octyldecanol, nonadecanol, arachyl alcohol, octyldodecanol, henicosanol, behenyl alcohol, and decyltetradecanol, which have 6 to 24 carbon atoms. Of these, diacetone alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, hexyldecanol, cetostearyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, arachyl alcohol, octyldodecanol, behenyl alcohol, and decyltetradecanol are even more preferred. The higher alcohols of the present invention may be used alone or in combination of two or more. The content of higher alcohol in the topical composition is preferably 0.05 to 10 w/w%, more preferably 0.1 to 5 w/w%, and even more preferably 0.25 to 1.5 w/w%.

The topical composition of the present invention may further contain a lower alcohol or water, if necessary. The lower alcohol is preferably one having 1 to 5 carbon atoms, such as ethanol or isopropanol, and these may be used in combination. The content of the lower alcohol is preferably 20 w/w% or more of the total composition, more preferably 30 w/w% or more, more preferably 35 w/w% or more, and even more preferably 50 w/w% or more. The amount of water to be added is preferably 2 to 75 w/w%, more preferably 5 to 50 w/w%.

The topical composition of the present invention may further contain a higher fatty acid if necessary. Examples of higher fatty acids include those having 10 to 22 carbon atoms, such as 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, and docosahexaenoic acid, and these may be used alone or in combination. Of these, those having 18 carbon atoms are preferred, and isostearic acid or oleic acid are particularly preferred. The amount of higher fatty acid to be contained in the composition is preferably 0.1 to 10 w/w%, more preferably 1 to 6 w/w%.

The topical composition of the present invention may further contain a surfactant if necessary. However, the addition of a surfactant may affect the feel of use and the dermal absorption of minoxidil. Since the topical composition of the present invention can ensure the solubility of minoxidil without the inclusion of a surfactant, it is preferable that the topical composition of the present invention does not substantially contain a surfactant.

The topical composition of the present invention may contain various active ingredients and auxiliary ingredients used in general topical preparations, provided that the effects of the present invention are not impaired. For example, excipients, hair growth ingredients (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, Polygonum polycutrum, etc.), vasodilators (carpronium chloride, benzyl nicotinate, Swertia japonica extract, Panax ginseng extract, Panax ginseng tincture, Capsicum anguicum 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.), moisturizers (hyaluronic acid or its salts, chondroitin sulfate, etc.), various plants and animals (yew, moutan pi, licorice, Hypericum perforatum, aconite, loquat, artemisonia japonica, comfrey, angelica tree, saffron, etc.). It can contain commonly used ingredients such as extracts of Japanese laurel, rosemary, sage, bamboo shoots, Japanese laurel, hops, placenta, saw palmetto, pumpkin seeds, etc., vitamins (retinol acetate, ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, etc.), antioxidants (dibutylhydroxytoluene, sodium pyrosulfite, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.), solubilizers (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, refreshing agents (peppermint oil, camphor, etc.), and dyes.

Examples of the dosage form of the topical composition of the present invention include liquids, lotions, and the like.
The composition for external use of the present invention can be prepared by incorporating the above-mentioned components in a conventional manner.

The thus obtained composition for external use of the present invention can be used as a preparation for application to the skin, such as for hair, eyelashes, eyebrows, etc.

Examples of methods for producing the topical composition of the present invention include a) a method of mixing 2 w/w% or more of minoxidil, b) at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or its salts, pantothenyl ethyl ether, panthenol, hinokitiol, diphenhydramine and/or its salts, c) propylene glycol, and d) an acid to prepare a mixture, and then adding e) water and f) a lower alcohol to the mixture to prepare the total amount; and a method of mixing a) 2 w/w% or more of minoxidil, b) at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or its salts, pantothenyl ethyl ether, panthenol, hinokitiol, diphenhydramine and/or its salts, c) propylene glycol, d) an acid, and e) water to prepare a mixture, and then adding f) a lower alcohol to the mixture to prepare the total amount.

The present invention will be explained in more detail below with reference to examples, comparative examples, and reference examples, but the present invention is not limited in any way by these examples.

(Examples 1 to 10, Comparative Examples 1 to 17, and Reference Example 1)
The formulations of Examples 1 to 10, Comparative Examples 1 to 17 and Reference Example 1 are shown in Tables 1 and 2. The components shown in Tables 1 and 2 were mixed, stirred and dissolved, and ethanol was added to make up a total amount of 100 g to prepare preparations.

(Test method 1: Thermal stability test-1)
The test solutions of Example 1, Comparative Examples 1 to 3 and Reference Example 1 were stored at 65° C. (relative humidity constant) for 3 days, and then the preparations were visually observed to confirm the color tone.

(result)
As is clear from Table 3, the coloring of the minoxidil-containing preparation in which propylene glycol was blended with a polyhydric alcohol (Example 1) did not progress over time (colorless), but the coloring of the minoxidil-containing preparations in which a polyhydric alcohol other than propylene glycol was blended (Comparative Examples 1 to 3) progressed over time (faint yellow).

(Test method 2: Thermal stability test-2)
The test solutions of Example 2 and Comparative Examples 4 and 5 were stored at 65° C. (relative humidity constant) for 5 days, and then the preparations were visually observed to confirm the color tone.

(result)
As is clear from Table 4, the coloring of the minoxidil-containing preparation in which propylene glycol was blended with a polyhydric alcohol (Example 2) did not progress over time (colorless), but the coloring of the minoxidil-containing preparations in which a polyhydric alcohol other than propylene glycol was blended (Comparative Examples 4 to 5) progressed over time (faint yellow).

In addition, even with the same faint yellow color, the formulation with a higher concentration of glycyrrhetinic acid showed a stronger color.

(Test method 3: Thermal stability test-3)
The test solutions of Examples 3 to 10, Comparative Examples 6 to 17 and Reference Example 1 were stored at 65° C. (relative humidity constant) for 5 days, and then the preparations were visually observed to confirm the color tone.

(result)
As is clear from Table 5, the coloring of the minoxidil-containing preparations in which propylene glycol was blended with a polyhydric alcohol (Examples 3 to 10) did not progress over time (colorless), but the coloring of the minoxidil-containing preparations in which a polyhydric alcohol other than propylene glycol was blended (Comparative Examples 6 to 17) progressed over time (faint yellow or yellow).

The present invention makes it possible to provide a minoxidil-containing topical composition containing at least one active ingredient selected from the group consisting of glycyrrhetinic acid and/or its salts, pantothenyl ethyl ether, panthenol, hinokitiol, diphenhydramine and/or its salts, which suppresses discoloration of the formulation over time.

Claims (2)

a) 2% or more w/w of minoxidil;
b) hinokitiol,
A composition for external use having a pH of 5.0 to 7.0, comprising: c) propylene glycol; and d) an acid. The topical composition according to claim 1, wherein the concentration of minoxidil is 5 w/w% or more.