topical pharmaceutical preparations

Abstract

To provide a minoxidil-containing pharmaceutical preparation 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: The present disclosure provides a pharmaceutical preparation for external use that contains (a) 5 w / v% or more minoxidil, (b) isopropylmethylphenol, (c) lower alcohol, and (d) water and is a solution, lotion, tonic, gel, or aerosol.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an external pharmaceutical preparation containing minoxidil.

[0002] Minoxidil, whose chemical name is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, is known for its application as a hair growth agent (Patent Document 1), and has been reported in many reports as a drug that exhibits excellent hair growth and hair regrowth effects. The basic performance required for a hair growth agent containing minoxidil is excellent absorption of minoxidil from the scalp (Patent Document 2). For minoxidil in a minoxidil-containing formulation to be efficiently absorbed through the scalp, it is preferable that the minoxidil in the formulation be in a dissolved state and not crystallize. It is also important that the minoxidil-containing formulation blends and spreads on the scalp surface. However, formulations containing a large amount of water tend to remain in a droplet form and are less likely to spread on the skin surface due to the surface free energy generated between the formulation and the hydrophobic skin. Techniques for improving skin blending have been proposed, such as the use of polyether-modified silicone or polyglycerin-modified silicone, and sucrose fatty acid esters (Patent Document 3). Patent Document 4 also shows that increasing the minoxidil concentration worsens the sensation of the formulation spreading on the scalp. However, none of the above Patent Documents 1 to 4 contain any description suggesting that the configuration of the present invention be adopted to obtain the present invention, which is a minoxidil-containing external pharmaceutical preparation that is compatible with the skin. [Prior art documents] [Patent documents]

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

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

[0005] In order to solve the above problems, the present invention provides an external pharmaceutical preparation in a specific dosage form containing (a) 5 w / v% or more minoxidil, (b) isopropylmethylphenol, (c) a lower alcohol, and (d) water. That is, the present invention provides: (1) A pharmaceutical preparation for external use, which is a liquid, lotion, tonic, gel, or aerosol containing (a) 5 w / v % or more minoxidil, (b) isopropylmethylphenol, (c) a lower alcohol, and (d) water. (2) The pharmaceutical preparation for external application according to (1), wherein the lower alcohol is a lower alcohol having 1 to 5 carbon atoms. (3) The pharmaceutical preparation for external use according to either (1) or (2), wherein the content of the lower alcohol is 20 to 80 w / v%. (4) The topical pharmaceutical preparation according to any one of (1) to (3), further comprising a polyhydric alcohol. (5) The pharmaceutical preparation for external application according to (4), wherein the content of the polyhydric alcohol is 3 to 30 w / v%. (6) The topical pharmaceutical preparation according to (5) or (6), 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. (7) The pharmaceutical preparation for external use according to any one of (1) to (6), further comprising a pH adjuster. (8) The pharmaceutical preparation for external application according to (7), 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. (9) The pharmaceutical preparation for external application according to (1), wherein the water content is 5 to 75 w / w%. (10) Use of isopropylmethylphenol for the production of an external pharmaceutical preparation containing 5 w / v % or more minoxidil and preferably further containing a lower alcohol. (11) Use of isopropylmethylphenol to improve skin compatibility of an external pharmaceutical preparation containing 5 w / v% or more minoxidil and preferably further containing a lower alcohol. is. [Effects of the Invention]

[0006] According to the present invention, it is possible to provide a minoxidil-containing topical pharmaceutical preparation that is highly compatible with the skin by combining (a) 5 w / v % or more minoxidil, (b) isopropylmethylphenol, (c) a lower alcohol, and (d) water and formulating the formulation into a liquid, lotion, tonic, gel, or aerosol. DETAILED DESCRIPTION OF THE INVENTION

[0007] The minoxidil used in the topical pharmaceutical preparation of the present invention can be of the same quality as that used in ordinary pharmaceuticals. The content of minoxidil used in the present invention is 5 w / v% or more relative to the total topical pharmaceutical preparation, which increases the issue of skin compatibility. Specifically, it is preferably 5 to 15 w / v%, more preferably 5 to 10 w / v%.

[0008] The isopropyl methylphenol of the present invention may be of the same quality as that used in ordinary pharmaceuticals. In terms of the effects of the present invention, the content of isopropyl methyl phenol in the topical pharmaceutical preparation of the present invention is preferably 0.01 to 10 w / v%, more preferably 0.1 to 5 w / v%.

[0009] The lower alcohol of the present invention is preferably one having 1 to 5 carbon atoms, such as ethanol or isopropanol. Two or more types of lower alcohol may be used in combination. In the present invention, the incorporation of a lower alcohol is highly significant from the viewpoint of providing a refreshing feeling when used. The content of the lower alcohol in the topical pharmaceutical preparation of the present invention is preferably 20 w / v% or more of the total preparation, more preferably 30 w / v% or more, even more preferably 35 w / v% or more, and even more preferably 50 w / v% or more. The upper limit is preferably 80 w / v%.

[0010] In terms of the effects of the present invention, the water content of the topical pharmaceutical composition 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 topical pharmaceutical composition of the present invention can be measured by the Karl Fischer method.

[0011] The topical pharmaceutical preparation of the present invention may contain a pH adjuster as needed. 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. The pH of the topical pharmaceutical preparation of the present invention is preferably adjusted to 5 to 8, more preferably 5 to 7, and even more preferably 6 to 6.5.

[0012] If necessary, a polyhydric alcohol can be blended into the topical pharmaceutical preparation of the present invention. Examples of polyhydric alcohols include 1,3-butylene glycol, dipropylene glycol, propylene glycol, glycerin, polyethylene glycol, etc., with 1,3-butylene glycol, propylene glycol, and glycerin being preferred, and 1,3-butylene glycol being more preferred. These may be used alone or in combination. The content of the polyhydric alcohol in the topical pharmaceutical preparation 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, and more preferably 10 w / v% or more. Taking into consideration the feel during use, such as reduced stickiness, the upper limit is preferably 30 w / v% or less.

[0013] The topical pharmaceutical preparation 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 cutaneous absorption of minoxidil, it is preferable that the preparation is substantially free of surfactants.

[0014] In addition to the above-mentioned components, the topical pharmaceutical preparation of the present invention may contain other active ingredients and auxiliary ingredients as needed, provided that the effects of the present invention are not impaired. Examples of medicinal ingredients that are preferably added or blended into the topical pharmaceutical preparation of the present invention include one or more components selected from the group consisting of menthol, vitamin E acetate, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, and diphenhydramine hydrochloride. The amounts of these ingredients added are not particularly limited and can be determined experimentally, taking into consideration the feel when used, the stability of minoxidil, the composition of the solvent system, and the like.

[0015] In addition to the above-mentioned ingredients, the topical pharmaceutical preparation of the present invention can 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 polyglutamum, etc.), vasodilators (carpronium chloride, benzyl nicotinate, Swertia japonica extract, Panax ginseng extract, Panax ginseng tincture, Capsicum tincture, etc.), antihistamines (isothipendyl hydrochloride, etc.), anti-inflammatory agents (guaiazulene, etc.), keratolytic agents (salicylic acid, etc.), disinfectants (chlorhexidine gluconate, isopropylmethylphenol, quaternary ammonium salts, piroctone olamine, etc.), moisturizers (hyaluronic acid or its salts, chondroitin sulfate, etc.), various plants and animals (yew, moutan pith, licorice, St. John's wort, aconite, loquat, artemisonia capillaris, comfrey, angelica tree, saffron, Sanshi, It can contain commonly used ingredients such as extracts of (e.g., shiitake mushroom, rosemary, sage, bamboo shoots, bamboo shoots, hops, placenta, saw palmetto, pumpkin seed, etc.), vitamins (ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, etc.), antioxidants (dibutylhydroxytoluene, sodium metabisulfite, 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 such as carboxyvinyl polymers, etc.), adhesives, fragrances, fresheners (peppermint oil, camphor, etc.), dyes, etc.

[0016] The topical pharmaceutical preparation of the present invention may be a liquid, a lotion, a tonic, a gel obtained by adding a gelling agent to a liquid to make it viscous, or an aerosol prepared from a concentrate and a propellant, but is preferably a liquid, a lotion, or a tonic.

[0017] The viscosity of the topical pharmaceutical preparation of the present invention is preferably 50 mPa·s or less at 25°C. This is because the effects of the present invention are particularly pronounced at low viscosities. The viscosity of the topical pharmaceutical preparation of the present invention is preferably 1 to 50 mPa·s at 25°C. The viscosity of the topical pharmaceutical preparation of the present invention is measured using a vibration viscometer. In this application, a VISCOMATE VM-100A (Yamaichi Electric Co., Ltd.) is used, and the conditions, such as the probe to be used, are selected in accordance with the instruction manual for the instrument, and the viscosity is measured at 25°C.

[0018] The topical pharmaceutical preparation of the present invention is prepared by incorporating the above-mentioned components in accordance with a conventional method.

[0019] The thus obtained external pharmaceutical preparation of the present invention can be used as a skin application preparation such as a preparation for hair, eyelashes, or eyebrows.

[0020] 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 to these Examples. The water content in the Examples, Comparative Examples, and Reference Examples was measured using a Karl Fischer moisture meter. All viscosity values ​​were measured at 25°C. [Example]

[0021] Example 1 5 g of minoxidil, 0.5 g of isopropylmethylphenol, 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 topical pharmaceutical preparation (liquid) with a pH of 6.16 and a viscosity of 2.8 mPa·s.

[0022] (Comparative Example 1) 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 an external pharmaceutical preparation (liquid) with a pH of 6.16.

[0023] The formulations of Example 1 and Comparative Example 1, as well as the water content and pH after preparation, are shown in Table 1.

[0024] [Table 1]

[0025] (Skin compatibility evaluation) 100 μL of each test liquid from Example 1 and Comparative Example 1 was measured using a micropipette (manufactured by Eppendorf) and dropped onto a Bioskin plate (#40, manufactured by Beaulux). 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 1]. The calculated results are shown in Table 2. [Equation 1] Skin compatibility improvement rate (%) = (skin compatibility score of each test liquid / skin compatibility score of Comparative Example 1) × 100

[0026] [Table 2] As shown in Table 2, the topical pharmaceutical preparation of Example 1 of the present invention had improved compatibility with the skin compared to the topical pharmaceutical preparation of Comparative Example 1 which did not contain component (b).

[0027] (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 an external pharmaceutical preparation (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 an external pharmaceutical preparation (liquid) with a pH of 6.13.

[0028] The formulations of Reference Examples 1 and 2, as well as the water content and pH after preparation, are shown in Table 3.

[0029] [Table 3]

[0030] 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% lower than that of Reference Example 1, and the results showed that the higher the concentration of minoxidil, the worse the compatibility with skin.

[0031] Example 2 5 g of minoxidil, 0.5 g of isopropylmethylphenol, 14 g of 1,3-butylene glycol, 14 g of propylene glycol, 13 g of purified water, an appropriate amount of tartaric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a topical pharmaceutical preparation (liquid) with a pH of 6.75 and a viscosity of 4.6 mPa·s.

[0032] (Comparative Example 2) 5 g of minoxidil, 14 g of 1,3-butylene glycol, 14 g of propylene glycol, 13 g of purified water, an appropriate amount of tartaric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a topical pharmaceutical preparation (liquid) with a pH of 6.75 and a viscosity of 4.5 mPa·s.

[0033] (Comparative Example 3) 5 g of minoxidil, 1 g of pantothenyl ethyl ether, 14 g of 1,3-butylene glycol, 14 g of propylene glycol, 13 g of purified water, an appropriate amount of tartaric 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 preparation (liquid) with a pH of 6.75 and a viscosity of 4.6 mPa·s.

[0034] Comparative Example 4 5 g of minoxidil, 1 g of panthenol, 14 g of 1,3-butylene glycol, 14 g of propylene glycol, 13 g of purified water, an appropriate amount of tartaric acid, and ethanol were added to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a topical pharmaceutical preparation (liquid) with a pH of 6.75 and a viscosity of 4.7 mPa·s.

[0035] Table 4 shows the formulations of Example 2 and Comparative Examples 2 to 4, as well as the water content and pH after preparation.

[0036] [Table 4]

[0037] (Skin compatibility evaluation) 100 μL of each test liquid from Example 2 and Comparative Examples 2 to 4 was measured using a micropipette (manufactured by Eppendorf) and dropped onto a Bioskin plate (#40, manufactured by Beaulux). 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 calculated results are shown in Table 5. [Equation 2] Skin compatibility improvement rate (%) = (skin compatibility score of each test liquid / skin compatibility score of Comparative Example 2) × 100

[0038] [Table 5] As shown in Table 5, the topical pharmaceutical preparation of Example 2 of the present invention had improved compatibility with the skin compared to the topical pharmaceutical preparation of Comparative Example 2 which did not contain component (b).

[0039] Example 3 5 g of minoxidil, 0.5 g of isopropylmethylphenol, 1 g of 1,3-butylene glycol, 13 g of glycerin, 12 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 topical pharmaceutical preparation (liquid) with a pH of 6.99 and a viscosity of 3.1 mPa·s.

[0040] (Comparative Example 5) 5 g of minoxidil, 1 g of 1,3-butylene glycol, 13 g of glycerin, 12 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 topical pharmaceutical preparation (liquid) with a pH of 6.99 and a viscosity of 3.1 mPa·s.

[0041] (Comparative Example 6) 5 g of minoxidil, 1 g of pantothenyl ethyl ether, 1 g of 1,3-butylene glycol, 13 g of glycerin, 12 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 preparation (liquid) with a pH of 7.03 and a viscosity of 3.2 mPa·s.

[0042] (Comparative Example 7) 5 g of minoxidil, 1 g of panthenol, 1 g of 1,3-butylene glycol, 13 g of glycerin, 12 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 topical pharmaceutical preparation (liquid) with a pH of 7.05 and a viscosity of 3.2 mPa·s.

[0043] Table 6 shows the formulations of Example 3 and Comparative Examples 5 to 7, as well as the water content and pH after preparation.

[0044] [Table 6]

[0045] (Skin compatibility evaluation) 100 μL of each test liquid from Example 3 and Comparative Examples 5 to 7 was measured using a micropipette (manufactured by Eppendorf) and dropped onto a Bioskin plate (#40, manufactured by Beaulux). 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 calculated results are shown in Table 7. [Equation 3] Skin compatibility improvement rate (%) = (skin compatibility score of each test liquid / skin compatibility score of Comparative Example 5) × 100

[0046] [Table 7] As shown in Table 7, the topical pharmaceutical preparation of Example 3 of the present invention had improved compatibility with the skin compared to the topical pharmaceutical preparation of Comparative Example 5 which did not contain component (b).

[0047] Another embodiment of the topical composition includes, 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, 0.1 to 5 w / v% pantothenyl ethyl ether or panthenol, and 0.02 to 0.5 w / v% isopropyl methylphenol. Examples of formulations include: 2-30 w / v% 1,3-butylene glycol, 1-30 w / v% glycerin, 20-70 w / v% ethanol, 0.001-1 w / v% antioxidant (dibutylhydroxytoluene, dibutylhydroxyanisole, sodium pyrosulfate, sodium edetate, or propyl gallate), an appropriate amount of phosphoric acid, 0.00001-1 w / v% glycine, 0.00001-1 w / v% L-arginine, and 0.000001-1 w / v% ascorbic acid, with the remainder being water. These active ingredients and auxiliary ingredients can be appropriately blended taking into consideration the feel of use, the stability of minoxidil, the solvent composition, etc. An example formulation for this topical composition is shown in Table 8.

[0048] [Table 8] [Industrial Applicability]

[0049] The present invention makes it possible to provide a minoxidil-containing topical pharmaceutical preparation that is compatible with the skin.

Claims

1. A pharmaceutical preparation for external application, characterized in that it is a liquid, lotion, or tonic containing (a) 5 w / v % or more minoxidil, (b) 0.1 to 5 w / v % isopropylmethylphenol, (c) a lower alcohol, and (d) 15 to 30 w / w % water.

2. The topical pharmaceutical preparation of claim 1, which is a liquid.

3. An external pharmaceutical preparation according to claim 1 or 2, wherein the lower alcohol is a lower alcohol having 1 to 5 carbon atoms.

4. An external pharmaceutical preparation according to any one of claims 1 to 3, wherein the content of lower alcohol is 20 to 80 w / v%.

5. An external pharmaceutical preparation according to any one of claims 1 to 4, further containing a polyhydric alcohol.

6. An external pharmaceutical preparation according to claim 5, wherein the content of polyhydric alcohol is 3 to 30 w / v%.

7. The topical pharmaceutical preparation according to claim 5, 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.

8. An external pharmaceutical preparation according to any one of claims 1 to 7, further comprising a pH adjuster.

9. The topical pharmaceutical preparation according to claim 8, 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.

10. Use of isopropylmethylphenol to improve the spread of an external pharmaceutical preparation containing 5 w / v% or more minoxidil onto the scalp surface.

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