External pharmaceutical composition

Abstract

To provide a minoxidil-containing pharmaceutical composition for external use that has good skin compatibility as it is important for a minoxidil-containing pharmaceutical to agree with the surface of scalp and spread well so that minoxidil in the pharmaceutical is efficiently absorbed from the scalp.SOLUTION: A pharmaceutical composition for external use contains (a) 5 w / v% or more minoxidil, (b) dipotassium glycyrrhizinate, (c) polyhydric alcohol, and (d) water. The pharmaceutical composition is suitably used as a solution, lotion or tonic.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for external use containing minoxidil.

[0002] Minoxidil, whose chemical name is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, is known for its application as a hair restorer (Patent Document 1), and there are many reports of it being a drug that exhibits excellent hair growth and hair regrowth effects. The basic performance required for a hair restorer containing minoxidil is excellent absorption of minoxidil from the scalp (Patent Document 2). In order for minoxidil in a formulation containing minoxidil to be efficiently absorbed from the scalp, it is preferable that the minoxidil in the formulation is in a dissolved state and does not crystallize. It is important that the formulation containing minoxidil blends with and spreads on the surface of the scalp. However, a formulation containing a lot of water maintains the state of droplets and does not spread easily on the skin surface due to the surface free energy acting between the formulation and the hydrophobic skin. As a technique for improving the blending with the skin, for example, a method using polyether-modified silicone or polyglycerin-modified silicone, and sucrose fatty acid ester has been proposed (Patent Document 3). In addition, Patent Document 4 shows that the feeling of the formulation spreading on the scalp worsens as the concentration of minoxidil increases. However, none of the above Patent Documents 1 to 4 contain any description that suggests the use of the configuration of the present invention in order to obtain the present invention, which is a minoxidil-containing pharmaceutical composition for external use that is compatible with the skin. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] U.S. Pat. No. 4,139,619 [Patent Document 2] Japanese Patent Application Publication No. 11-349451 [Patent Document 3] JP 2016-84323 A [Patent Document 4] JP 2019-142851 A Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention aims to provide a minoxidil-containing topical pharmaceutical composition that is compatible with the skin. [Means for solving the problem]

[0005] In order to solve the above problems, the present invention provides a pharmaceutical composition for external application containing (a) 5 w / v % or more minoxidil, (b) dipotassium glycyrrhizinate, (c) a polyhydric alcohol, and (d) water. That is, the present invention provides: (1) A pharmaceutical composition for external application, comprising (a) 5 w / v% or more minoxidil, (b) dipotassium glycyrrhizinate, (c) a polyhydric alcohol, and (d) water; (2) The pharmaceutical composition for external application according to (1), wherein the polyhydric alcohol is at least one selected from the group consisting of 1,3-butylene glycol, dipropylene glycol, propylene glycol, glycerin, and polyethylene glycol. (3) The pharmaceutical composition for external application according to (1) or (2), wherein the content of the polyhydric alcohol is 5 to 30 w / v%. (4) The pharmaceutical composition for external application according to any one of (1) to (3), further comprising a lower alcohol. (5) The pharmaceutical composition for external application according to (4), wherein the lower alcohol is a lower alcohol having 1 to 5 carbon atoms. (6) The pharmaceutical composition for external application according to any one of (1) to (4), further comprising a pH adjuster. (7) The pharmaceutical composition for external application according to (6), wherein the pH adjuster is at least one selected from the group consisting of citric acid, malic acid, lactic acid, tartaric acid, phosphoric acid, hydrochloric acid, and sulfuric acid. (8) The pharmaceutical composition for external application according to (1), wherein the water content is 5 to 75 w / w%. (9) The pharmaceutical composition for external application according to any one of (1) to (8), which is in the form of a liquid, a lotion, a tonic, a gel, or an aerosol. (10) Use of dipotassium glycyrrhizinate for the manufacture of a pharmaceutical composition for external application containing 5 w / v % or more of minoxidil and preferably further containing a polyhydric alcohol; (11) Use of dipotassium glycyrrhizinate to improve skin compatibility of an external pharmaceutical composition containing 5 w / v % or more minoxidil and preferably further containing a polyhydric alcohol; It is. Effect of the Invention

[0006] According to the present invention, it is possible to provide a minoxidil-containing topical pharmaceutical composition that is highly compatible with the skin by combining and formulating (a) 5 w / v % or more minoxidil, (b) dipotassium glycyrrhizinate, (c) a polyhydric alcohol, and (d) water. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] The minoxidil used in the topical pharmaceutical composition of the present invention can be of the quality generally used in pharmaceuticals. The content of minoxidil used in the present invention is preferably 5-15 w / v%, more preferably 5-10 w / v%, based on the total content of the topical pharmaceutical composition. In the topical pharmaceutical composition of the present invention, the higher the content of minoxidil, the greater the problem of skin compatibility. Therefore, the higher the concentration of minoxidil in the topical pharmaceutical composition, the greater the significance of carrying out the present invention.

[0008] The dipotassium glycyrrhizinate of the present invention may be of a quality generally used in pharmaceuticals. In the present invention, the content of dipotassium glycyrrhizinate in the pharmaceutical composition for external use of the present invention is preferably 0.01 to 10 w / v%, more preferably 0.1 to 5 w / v%, from the viewpoint of the effects of the present invention.

[0009] Examples of the polyhydric alcohol of the present invention include 1,3-butylene glycol, dipropylene glycol, propylene glycol, glycerin, polyethylene glycol, etc., and preferably 1,3-butylene glycol, propylene glycol, and glycerin, more preferably 1,3-butylene glycol and propylene glycol, and these may be used in combination of one or more. Among these, the most preferred is the combined use of 1,3-butylene glycol and propylene glycol from the viewpoint of the solubility of both components, minoxidil and dipotassium glycyrrhizinate. In the present invention, the content of the polyhydric alcohol in the external pharmaceutical composition of the present invention is preferably 3 w / v% or more, more preferably 5 w / v% or more, more preferably 8 w / v% or more, more preferably 10 w / v% or more, and even more preferably 12 w / v% or more, and the upper limit is preferably 30 w / v% or less in consideration of the feeling of use, such as less stickiness.

[0010] In terms of the effects of the present invention, the water content in the pharmaceutical composition for external use of the present invention is preferably 1 to 75 w / w%, more preferably 5 to 50 w / w%, even more preferably 8 to 30 w / w%, and most preferably 15 to 30 w / w%. The water content in the pharmaceutical composition for external use of the present invention can be measured by the Karl Fischer method.

[0011] The topical pharmaceutical composition of the present invention may contain a pH adjuster as necessary. Examples of pH adjusters include organic acids such as citric acid, malic acid, lactic acid, and tartaric acid, and inorganic acids such as phosphoric acid, hydrochloric acid, and sulfuric acid, and tartaric acid is preferred from the viewpoint of the solubility of both components, minoxidil and dipotassium glycyrrhizinate. The pH of the topical pharmaceutical composition of the present invention is preferably adjusted to 5 to 8, more preferably 5.6 to 7, and even more preferably 6 to 7.

[0012] The pharmaceutical composition for external application of the present invention may contain a lower alcohol as required. Examples of the lower alcohol preferably include those having 1 to 5 carbon atoms, such as ethanol and isopropanol. Two or more types of lower alcohol may be used in combination. The content of the lower alcohol in the pharmaceutical composition for external application of the present invention is preferably 20 w / v% or more of the total composition, more preferably 30 w / v% or more, and even more preferably 35 w / v% or more. The upper limit is preferably 80 w / v%.

[0013] The topical pharmaceutical composition of the present invention may further contain a surfactant if necessary. However, since the addition of a surfactant may affect the feel during use and the dermal absorption of minoxidil, it is preferable that the composition is substantially free of surfactants.

[0014] In addition to the above-mentioned components, the topical pharmaceutical composition of the present invention may contain active ingredients or auxiliary ingredients as necessary, as long as the effects of the present invention are not impaired. Examples of medicinal ingredients that are preferably added or blended into the topical pharmaceutical composition of the present invention include one or more ingredients selected from the group consisting of menthol, vitamin E acetate, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, and diphenhydramine hydrochloride. There are no particular restrictions on the amount of these ingredients to be added, and they can be determined experimentally while taking into consideration the feel when used, the stability of minoxidil, the composition of the solvent system, etc.

[0015] In the topical pharmaceutical composition of the present invention, in addition to the above-mentioned ingredients, various active ingredients and auxiliary ingredients used in general topical preparations can be blended within the range that does not impair the effects of the present invention. For example, excipients, hair growth ingredients (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, Polygonum polymorpha, 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 (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, saxifraga, etc.), It is possible to blend in commonly used ingredients such as extracts of flan, Sanshishi, rosemary, sage, Saussurea japonica, Seimokko, hops, placenta, saw palmetto, pumpkin seed, etc., vitamins (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.), dyes, etc.

[0016] In addition, the topical pharmaceutical composition of the present invention is preferably in a liquid dosage form, and can be made into a suitable topical pharmaceutical composition such as a liquid, lotion, tonic, gel, or aerosol, and is preferably a liquid, lotion, or tonic.

[0017] The pharmaceutical composition for external application of the present invention can be prepared by incorporating the above-mentioned components in a conventional manner.

[0018] The thus obtained pharmaceutical composition for external application of the present invention can be used as a preparation for application to the skin, such as an agent for hair, eyelashes, eyebrows, etc.

[0019] The present invention will be explained in more detail below with reference to Examples, Comparative Examples, Reference Examples, and Test Examples, but the present invention is not limited by these Examples, etc. The moisture contents in the Examples, Comparative Examples, and Reference Examples were measured using a Karl Fischer moisture meter. EXAMPLES

[0020] Example 1 5 g of minoxidil, 0.1 g of dipotassium glycyrrhizinate, 14 g of 1,3-butylene glycol, 11 g of propylene glycol, 40 g of ethanol, an appropriate amount of tartaric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a liquid with a pH of 6.55.

[0021] Comparative Example 1 5 g of minoxidil, 14 g of 1,3-butylene glycol, 11 g of propylene glycol, 40 g of ethanol, an appropriate amount of tartaric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a liquid preparation with a pH of 6.54.

[0022] The formulations of Example 1 and Comparative Example 1, as well as the water content and pH after preparation, are shown in Table 1.

[0023] [Table 1]

[0024] (Skin compatibility evaluation) 100 μL of each test liquid in Example 1 and Comparative Example 1 was measured using a micropipette (manufactured by Eppendorf) and dropped onto a Bioskin plate (#40, manufactured by Bealux). 30 seconds after dropping, the major axis and minor axis of the spread liquid were measured, and the multiplied value was used as a skin compatibility score. The skin compatibility improvement rate was calculated according to the following [Equation 1]. The calculated results are shown in Table 2. [Formula 1] Skin compatibility improvement rate (%) = (skin compatibility score of each test liquid / skin compatibility score of Comparative Example 1) x 100

[0025] [Table 2] As shown in Table 2, the composition of Example 1 of the present invention exhibited improved compatibility with the skin compared to the composition of Comparative Example 1 not containing component (b).

[0026] (Reference example 1) 1 g of minoxidil, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use (liquid) with a pH of 5.81. (Reference example 2) 5 g of minoxidil, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use (liquid) with a pH of 6.13.

[0027] The formulations of Reference Examples 1 and 2 and the water contents and pH values ​​after preparation are shown in Table 3.

[0028] [Table 3]

[0029] As a result of evaluating the compatibility of Reference Examples 1 and 2 with skin, the skin compatibility score of Reference Example 2 was 88%, which was lower than that of Reference Example 1, and the results showed that the higher the concentration of minoxidil, the worse the skin compatibility.

[0030] Example 2 5 g of minoxidil, 0.1 g of dipotassium glycyrrhizinate, 10 g of 1,3-butylene glycol, 20 g of purified water, an appropriate amount of phosphoric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use (liquid) with a pH of 5.98.

[0031] Comparative Example 2 5 g of minoxidil, 10 g of 1,3-butylene glycol, 20 g of purified water, an appropriate amount of phosphoric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use (liquid) with a pH of 5.97.

[0032] Comparative Example 3 5 g of minoxidil, 1 g of panthenol, 10 g of 1,3-butylene glycol, 20 g of purified water, an appropriate amount of phosphoric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use (liquid) with a pH of 5.98.

[0033] Table 4 shows the formulations of Example 2 and Comparative Examples 2 and 3, as well as the water content and pH after preparation.

[0034] [Table 4]

[0035] (Skin compatibility evaluation) 100 μL of each test liquid from Example 2 and Comparative Examples 2 to 3 was measured using a micropipette (manufactured by Eppendorf) and dropped onto a Bioskin plate (#40, manufactured by Bealux). 30 seconds after dropping, the major and minor axes of the spread liquid were measured, and the multiplied value was used as a skin compatibility score. The skin compatibility improvement rate was calculated according to the following [Equation 2]. The calculation results are shown in Table 5. [Formula 2] Skin compatibility improvement rate (%) = (skin compatibility score of each test liquid / skin compatibility score of Comparative Example 2) x 100

[0036] [Table 5] As shown in Table 5, the composition of Example 2 of the present invention exhibited improved compatibility with the skin compared to the composition of Comparative Example 2 which did not contain component (b).

[0037] Example 3 5 g of minoxidil, 0.1 g of dipotassium glycyrrhizinate, 1 g of 1,3-butylene glycol, 13 g of glycerin, 18 g of purified water, an appropriate amount of lactic acid, an appropriate amount of citric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition (liquid) with a pH of 6.93.

[0038] Comparative Example 4 5 g of minoxidil, 1 g of 1,3-butylene glycol, 13 g of glycerin, 18 g of purified water, an appropriate amount of lactic acid, an appropriate amount of citric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use (liquid) with a pH of 6.92.

[0039] Comparative Example 5 5 g of minoxidil, 1 g of pantothenyl ethyl ether, 1 g of 1,3-butylene glycol, 13 g of glycerin, 18 g of purified water, an appropriate amount of lactic acid, an appropriate amount of citric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition (liquid) with a pH of 6.93.

[0040] Comparative Example 6 5 g of minoxidil, 1 g of panthenol, 1 g of 1,3-butylene glycol, 13 g of glycerin, 18 g of purified water, an appropriate amount of lactic acid, an appropriate amount of citric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain an external pharmaceutical composition (liquid) with a pH of 6.93.

[0041] Table 6 shows the formulations of Example 3 and Comparative Examples 4 to 6, as well as the water content and pH after preparation.

[0042] [Table 6]

[0043] (Skin compatibility evaluation) 100 μL of each test liquid from Example 3 and Comparative Examples 4 to 6 was measured using a micropipette (manufactured by Eppendorf) and dropped onto a Bioskin plate (#40, manufactured by Bealux). 30 seconds after dropping, the major and minor axes of the spread liquid were measured, and the multiplied value was used as a skin compatibility score. The skin compatibility improvement rate was calculated according to the following [Equation 3]. The calculation results are shown in Table 7. [Formula 3] Skin compatibility improvement rate (%) = (skin compatibility score of each test liquid / skin compatibility score of Comparative Example 4) x 100

[0044] [Table 7] As shown in Table 7, the composition of Example 3 of the present invention exhibited improved compatibility with the skin compared to the composition of Comparative Example 4 which did not contain the component (b).

[0045] Another embodiment of the composition for external use may contain, for example, 0.1 to 10 w / v% minoxidil, and as active ingredients or auxiliary ingredients, 0.1 to 5 w / v% menthol, 0.001 to 1 w / v% vitamin E acetate, 0.001 to 1 w / v% pyridoxine hydrochloride, 0.001 to 1 w / v% hinokitiol, 0.001 to 1 w / v% glycyrrhetinic acid, 0.001 to 1 w / v% diphenhydramine hydrochloride, 0.001 to 1 w / v% pantothenyl ethyl ether or panthenol, 0.1 to 5 w / v% dipotassium glycyrrhizinate, 0.1 to 1 w / v% % w / v, 1,3-butylene glycol 2-30 w / v%, glycerin 1-30 w / v%, ethanol 20-70 w / v%, antioxidant (dibutylhydroxytoluene, dibutylhydroxyanisole, sodium pyrosulfate, sodium edetate, or propyl gallate) 0.001-1 w / v%, phosphoric acid in an appropriate amount, glycine 0.00001-1 w / v%, L-arginine 0.00001-1 w / v%, ascorbic acid 0.000001-1 w / v%, and the remaining amount is water. These active ingredients and auxiliary ingredients can be appropriately blended in consideration of the feeling of use, the stability of minoxidil, the solvent system composition, etc. An example of the formulation of this topical composition is shown in Table 8.

[0046] [Table 8] [Industrial Applicability]

[0047] The present invention makes it possible to provide a minoxidil-containing topical pharmaceutical composition that is compatible with the skin.

Claims

1. A pharmaceutical composition for external application, comprising (a) 5 w / v % or more minoxidil, (b) dipotassium glycyrrhizinate, (c) a polyhydric alcohol, and (d) water (excluding a composition for external application in which 0.1 mL to 2 mL of the composition for external application is contained in a single-use container).

2. 2. The pharmaceutical composition for external application according to claim 1, wherein the polyhydric alcohol is at least one selected from the group consisting of 1,3-butylene glycol, dipropylene glycol, propylene glycol, glycerin, and polyethylene glycol.

3. 3. The pharmaceutical composition for external application according to claim 1, wherein the content of the polyhydric alcohol is 5 to 30 w / v %.

4. The pharmaceutical composition for external application according to any one of claims 1 to 3, further comprising a lower alcohol.

5. The composition for external use according to claim 4, wherein the lower alcohol is a lower alcohol having 1 to 5 carbon atoms.

6. The pharmaceutical composition for external application according to any one of claims 1 to 5, further comprising a pH adjuster.

7. The pharmaceutical composition for external application according to claim 6, wherein the pH adjuster is at least one selected from the group consisting of citric acid, malic acid, lactic acid, tartaric acid, phosphoric acid, hydrochloric acid, and sulfuric acid.

8. 2. The pharmaceutical composition for external application according to claim 1, wherein the water content is 5 to 75 w / w %.

9. The pharmaceutical composition for external application according to any one of claims 1 to 8, which is in the form of a liquid, a lotion, a tonic, a gel, or an aerosol.

10. Use of dipotassium glycyrrhizinate for the manufacture of a pharmaceutical composition for external use containing 5 w / v % or more of minoxidil (excluding a composition for external use in which 0.1 mL to 2 mL of the composition for external use is contained in a single-use container).

11. Use of dipotassium glycyrrhizinate to improve skin compatibility of an external pharmaceutical composition containing 5 w / v % or more minoxidil.

Images