JP2022177246A - Composition for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: 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

COPYRIGHT: (C)2023,JPO&INPIT

Description

The present invention relates to an external composition containing minoxidil as an active ingredient. More particularly, it relates to a technique for suppressing minoxidil-derived precipitation that may occur due to the application of a minoxidil-containing topical composition containing pyridoxine.

Minoxidil, whose chemical name is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, is known to be applied as a hair restorer (Patent Document 1), and has excellent hair growth and growth effects. There are many reports as a drug that exerts
Since minoxidil-containing topical compositions are used on the head every day for a long period of time, there is a demand for compositions that are excellent in feeling during use. When a composition with a high concentration of minoxidil is used, minoxidil-derived precipitation rarely occurs after application, and it may look like dandruff. Therefore, in a composition for external use containing minoxidil, a composition that suppresses minoxidil-derived precipitation that may occur after application is desired.
Pyridoxine has also been reported to have a lipid synthesis inhibitory effect (Non-Patent Document 1), and is used in many hair restorers.

U.S. Pat. No. 4,139,619

Effects of drugs on lipid synthesis capacity of sebaceous glands

An object of the present invention is to provide a minoxidil-containing topical composition containing pyridoxine that suppresses minoxidil-derived precipitation that may occur after application.

The present inventors have made intensive studies to solve the above problems, and as a result, found that a composition containing minoxidil, pyridoxine, a specific polyhydric alcohol, and a specific acid can suppress minoxidil-derived precipitation. I have perfected my invention.

That is, the present invention
(1) selected from the group consisting of 1) minoxidil, 2) pyridoxine and/or salts thereof, 3) propylene glycol, and 4) phosphoric acid, citric acid, lactic acid, hydrochloric acid, acetic acid, sulfuric acid, nitric acid, tartaric acid, and maleic acid. Composition for external use, characterized in that it contains at least one acid and / or a salt thereof,
(2) The topical composition according to (1), wherein the concentration of minoxidil is 5 w/w% or more;
is.

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to suppress minoxidil-derived precipitation that may occur after application in a minoxidil-containing topical composition containing pyridoxine. Furthermore, unexpectedly, it is possible to provide a clear minoxidil-containing composition in which no sediment occurs in the formulation, and to suppress deterioration in the stability of pyridoxine and/or a salt thereof over time.

According to the present invention, an external composition containing minoxidil, pyridoxine and/or salts thereof, propylene glycol, and a specific acid and/or salts thereof suppresses minoxidil-derived precipitation that may occur after application. , the formulation does not form a precipitate and suppresses a decrease in the stability of pyridoxine.

As for minoxidil used in the composition for external use of the present invention, minoxidil of a quality commonly used in pharmaceuticals can be appropriately used. In addition, according to the present invention, the higher the minoxidil content, the greater the problem of precipitation that may occur after application of the formulation. is large. Specifically, it is 1 w/w% or more, more preferably 3 w/w% or more, and still more preferably 5 w/w% or more in the composition for external use of the present invention.

The specific acids and/or salts thereof in the composition for external use of the present invention are phosphoric acid, citric acid, lactic acid, hydrochloric acid, acetic acid, sulfuric acid, and nitric acid, from the viewpoint of the effect of the present invention that a clear formulation without precipitation is obtained. , tartaric acid, maleic acid, or salts thereof, preferably phosphoric acid, citric acid, lactic acid, or tartaric acid. These acids and/or salts thereof are components for adjusting the liquid properties of the composition for external use of the present invention to 7 or less, and are inorganic acids or salts thereof, or organic acids or salts thereof having 6 or less carbon atoms. be. The specific acids and/or salts thereof of the present invention may be used singly or in combination of two or more.

In addition, the polyhydric alcohol used in the composition for external use of the present invention is propylene glycol because it does not cause precipitation derived from minoxidil after application, which is the effect of the present invention. The blending amount of propylene glycol is preferably 2 to 55 w/w%, more preferably 5 to 35 w/w%, in the total composition. The composition for external use of the present invention may contain a polyhydric alcohol other than propylene glycol as long as it does not impair the effects of the present invention. From the viewpoint of the effect of the present invention, it is most preferable to blend only propylene glycol.

In addition, the composition for external use of the present invention has a pH of 4.0 to 9.5 from the viewpoints of the stability of minoxidil, which is the main ingredient, the feeling of irritation to the skin during use, the permeability of the drug, the feeling of use, etc. It is preferable to adjust it within a range, more preferably 5.0 to 7.0. Furthermore, the upper limit of the pH is preferably less than 6.5, more preferably 6.3 or less, still more preferably 6.1 or less.

The amount of pyridoxine used in the topical composition of the present invention is preferably 0.01 to 2 w/w%, more preferably 0.03 to 0.1 w/w%, in terms of the effects of the present invention. 0.03 to 0.05 w/w% is more preferred.

The composition for external use of the present invention may further contain a higher alcohol if necessary. Examples of higher alcohols include diacetone alcohol having 6 to 24 carbon atoms, caproyl alcohol, caprylyl alcohol, capryl alcohol, lauryl alcohol, tridecanol, myristyl alcohol, pentadecanol, cetyl alcohol, hexyldecanol, isocetyl alcohol, More preferred are cetostearyl alcohol, heptadecanol, stearyl alcohol, oleyl alcohol, isostearyl alcohol, octyldecanol, nonadecanol, arachyl alcohol, octyldodecanol, henicosanol, behenyl alcohol and decyltetradecanol, of which diacetone alcohol, More preferred are lauryl alcohol, myristyl alcohol, cetyl alcohol, hexyldecanol, cetostearyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, arachyl alcohol, octyldodecanol, behenyl alcohol and decyltetradecanol. You may use the higher alcohol of this invention 1 type or in combination of 2 or more types. The blending amount of the higher alcohol is preferably 0.05 to 2 w/w%, more preferably 0.1 to 1.5 w/w%, and still more preferably 0.25 to 1.5 w/w% in the total composition. be.

The composition for external use of the present invention may further contain a lower alcohol or water, if necessary. As the lower alcohol, those having 1 to 5 carbon atoms are preferred, such as ethanol and isopropanol, and these may be used in combination. The amount of the lower alcohol is preferably 20 w/w% or more, more preferably 30 w/w% or more, more preferably 35 w/w% or more, and still more preferably 50 w/w% or more in the entire composition. be. The blending amount of water is preferably 2 to 75 w/w%, more preferably 5 to 50 w/w%.

The composition for external use of the present invention may further contain a higher fatty acid if necessary. Examples of higher fatty acids preferably have 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, and elaidic acid. , arachidic acid, arachidonic acid, behenic acid, eicosapentaenoic acid, docosahexaenoic acid and the like, and these may be used singly or in combination of two or more. 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%, more preferably 1 to 6 w/w%, in the total composition.

The composition for external use of the present invention may further contain a surfactant, if necessary. However, the addition of surfactants may affect the feeling of use and skin absorption of minoxidil, and in the composition for external use of the present invention, the solubility of minoxidil can be ensured without blending surfactants. , preferably substantially free of surfactants.

In addition to the components described above, the composition for external use of the present invention can contain necessary active ingredients and auxiliary ingredients within a range that does not impair the effects of the present invention. Medicinal ingredients that are preferably added to or blended with the lotion of the present invention include ingredients selected from the group consisting of menthol, vitamin E acetate, pantothenyl ethyl ether, hinokitiol, glycyrrhetinic acid, diphenhydramine hydrochloride, and panthenol. .
The amount of these optional components to be added is not particularly limited, and can be determined experimentally while considering the feel of use, the stability of minoxidil, the composition of the solvent system, and the like.

In the composition for external use of the present invention, in addition to the above 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 ingredients (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, Hekkei bird, etc.), vasodilators (carpronium chloride, benzyl nicotinate, assembly extract, panax ginseng extract, ginseng 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, piroctoneola) min, etc.), moisturizing agents (hyaluronic acid or its salts, chondroitin sulfate, etc.), various animals and plants (yew, botanpi, licorice, hypericum perforatum, Bushi, loquat, artemisia var. , Seymong, hops, placenta, saw palmetto, pumpkin seed, etc.), vitamins (retinol acetate, ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, etc.), antioxidants (dibutyl hydroxytoluene, sodium pyrosulfite, tocopherol, edet) sodium acid, 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 (highly water-soluble molecules, etc.), adhesives, fragrances, refreshing agents (mint oil, camphor, etc.), dyes, and other commonly used ingredients can be blended.

The topical composition of the present invention can be a suitable topical composition such as lotions, aerosols, tonics, creams, ointments, gels and the like. Among these, the most preferable dosage form is a lotion.

The composition for external use of the present invention is prepared according to a conventional method by containing each of the above components.

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

EXAMPLES Examples, comparative examples and test examples are given below to describe the present invention in more detail, but the present invention is not limited by these examples.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.0.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.1.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.1.

(Example 4)
Minoxidil 5 g, pyridoxine hydrochloride 0.05 g, propylene glycol 15 g, hydrochloric acid appropriate amount, purified water 20 g appropriate amount, ethanol was added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain an external composition having a pH of 6.0.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.1.

(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 ethanol were added to bring the total amount to 100 g.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.0.

(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 ethanol were added to bring the total amount to 100 g.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.0.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.0.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.0.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain an external composition having a pH of 6.0.

(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 ethanol were added to bring the total amount to 100 g.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.3.

(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 ethanol to bring the total amount to 100 g, and stirred for about 1 hour to prepare a composition for external use.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to prepare a composition for external use.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.0.

(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 ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use with a pH of 6.0.

(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 ethanol to bring the total amount to 100 g, and stirred for about 1 hour to obtain a composition for external use with a pH of 6.0.

(Comparative Example 7)
1 g of minoxidil, 15 g of propylene glycol, an appropriate amount of phosphoric acid, 20 g of purified water and ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain an external composition having a pH of 6.0.

(Comparative Example 8)
5 g of minoxidil, 15 g of propylene glycol, an appropriate amount of citric acid, 20 g of purified water and ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain an external composition having a pH of 6.1.

(Comparative Example 9)
5 g of minoxidil, 15 g of propylene glycol, an appropriate amount of lactic acid, 20 g of purified water, and ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain a composition for external use having a pH of 6.0.

(Comparative Example 10)
5 g of minoxidil, 15 g of propylene glycol, an appropriate amount of tartaric acid, 20 g of purified water and ethanol were added to bring the total amount to 100 g, and the mixture was stirred for about 1 hour to obtain an external composition having a pH of 6.0.

<Test Example 1: Precipitation Test-1>
Regarding Example 1 and Comparative Example 1, 100 μL of each topical composition was dropped onto a glass petri dish, and minoxidil-derived crystal precipitation was visually evaluated after 24 hours. The test was performed in triplicate.

As a result of the test, in comparison 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, minoxidil-derived crystal precipitation was suppressed all three times.

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

As a result of the test, minoxidil-derived crystal precipitation was suppressed in Example 10 using the polyhydric alcohol of the present invention as compared with Comparative Example 6 in which polyethylene glycol was blended as the polyhydric alcohol. In addition, as compared with Comparative Example 7, which did not contain pyridoxine hydrochloride, minoxidil-derived crystal precipitation was suppressed in Example 10, which contained pyridoxine hydrochloride of the present invention.

Furthermore, the precipitation of minoxidil-derived crystals was similarly suppressed in formulations using different kinds of acids of the present invention (Examples 11 to 13 and Comparative Examples 8 to 10).

<Test Example 3: Preparation test of lotion>
For Examples 1 to 10 and Comparative Examples 2 to 5, lotion preparation tests were conducted. After preparation, the lotion in the beaker was visually checked, and the case where a clear formulation without sediment was obtained was rated as ◯, and the case where sediment was generated in the lotion was rated as x. Table 1 shows the results.

<Test Example 4: Stability test of pyridoxine hydrochloride>
A stability test of pyridoxine hydrochloride was performed for Examples 1-10 and Comparative Examples 4-5. A stability test was performed by allowing each composition to stand in a thermostat at 65° C. for 2 weeks, and then quantifying the content of pyridoxine hydrochloride by liquid chromatography. Compared to the content of pyridoxine hydrochloride immediately after preparation, ⊚ indicates that the decrease in pyridoxine hydrochloride was 0 to 5%, ◯ indicates that it decreased by 6% to 7%, and 8 to 9% decreases. △, and those with a decrease of 10% or more were evaluated as ×. Table 1 shows the results.

As is clear from Table 1, in Examples 1 to 10 using the acid of the present invention, all the ingredients were dissolved and a clear lotion without sediments was obtained. On the other hand, when malic acid or boric acid was used among the acids, a precipitate was formed in the lotion after preparation (Comparative Examples 2 and 3).
In Comparative Examples 4 and 5, in which gluconic acid was used as an acid, lotions could be prepared, but the content of pyridoxine hydrochloride was significantly reduced. On the other hand, the lotions of Examples 1 to 10 using the acid of the present invention showed less than 10% decrease in pyridoxine hydrochloride content. In particular, when phosphoric acid, hydrochloric acid, acetic acid, sulfuric acid, or nitric acid was used, the decrease in pyridoxine hydrochloride content could be suppressed to 5% or less, which was a favorable result.

According to the present invention, in a minoxidil-containing external composition containing pyridoxine, minoxidil-derived precipitation that may occur after application is suppressed, precipitation in the external composition is suppressed, and pyridoxine and / or a salt thereof are suppressed. It has become possible to provide an excellent minoxidil-containing topical composition that suppresses a decrease in stability.

Claims (1)

The inventions described herein.