JP7518466B2 - External pharmaceutical composition - Google Patents

Description

The present invention relates to a pharmaceutical composition for external use that contains minoxidil and retinol or a derivative thereof.

Minoxidil has the chemical name 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide and is known for its use as a hair growth agent (Patent Document 1), with numerous reports of it being a drug with 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). To ensure absorption of minoxidil from the scalp, it is preferable that minoxidil in the formulation is present in a dissolved state, and it is required that crystal precipitation does not occur in the formulation. Minoxidil has poor solubility in water and most oils, and in order to ensure solubility of minoxidil, especially at high concentrations, it is common to add ethanol or an acid such as phosphoric acid or citric acid to adjust the pH of the formulation (Patent Documents 3 and 4).

On the other hand, retinol or its derivatives are components known to normalize the functions of the skin and mucous membranes (Patent Document 5). Retinol and its derivatives are highly lipid-soluble components that dissolve in oil.

U.S. Pat. No. 4,139,619 Japanese Patent Application Publication No. 11-349451 WO2001/76541 JP 2012-25770 A Patent Publication 2017-075111

While minoxidil has poor solubility in oil, retinol or its derivatives are highly lipid-soluble and dissolve in oil. The inventors found that when they prepared a formulation containing these ingredients, the formulation immediately became cloudy and oil droplets derived from retinol remained. In other words, the means of blending minoxidil and retinol or its derivatives are different, and it was found that it was necessary to consider a stable formulation that does not separate or become cloudy immediately after blending the two ingredients and is free of oil droplets.

The present invention has been made in consideration of the above circumstances, and aims to provide a transparent topical pharmaceutical composition that combines minoxidil and retinol or a derivative thereof.

As a result of extensive research aimed at solving the above problems, the inventors unexpectedly discovered that by combining minoxidil, retinol or a derivative thereof, a specific nonionic surfactant, and a lower alcohol, a transparent formulation can be obtained that does not become cloudy immediately after preparation and does not leave oil droplets derived from retinol palmitate, leading to the completion of the present invention.

That is, the present invention provides:
(1) A pharmaceutical composition for external application, comprising (a) minoxidil, (b) retinol or a derivative thereof, (c) polyoxyethylene hydrogenated castor oil, and (d) a lower alcohol;
(2) The pharmaceutical composition for external application according to (1), wherein the concentration of minoxidil is 5 w/v% or more.
(3) The pharmaceutical composition for external application according to (1), wherein the concentration of retinol or a derivative thereof is 1,000 to 1,000,000 units/100 mL.
(4) The pharmaceutical composition for external application according to any one of (1) to (3), which is in the form of a liquid, a lotion, an aerosol, a tonic, or a gel.
It is.

The present invention makes it possible to provide a transparent topical pharmaceutical composition that contains minoxidil and retinol or a derivative thereof.

The minoxidil used in the topical pharmaceutical composition of the present invention may be of the quality normally used in pharmaceuticals. In addition, in the topical pharmaceutical composition of the present invention, as the minoxidil content increases, the problem of minoxidil solubility becomes greater, so the higher the concentration of minoxidil in the topical pharmaceutical composition, the greater the significance of implementing the present invention. Specifically, the concentration of minoxidil in the topical pharmaceutical composition of the present invention is preferably 3 w/v% or more, more preferably 5 w/v% or more, with the upper limit being 15 w/v%.

Examples of retinol or a derivative thereof in the topical pharmaceutical composition of the present invention include retinol, retinol palmitate, retinol acetate, vitamin A oil, etc. The content of retinol or a derivative thereof in the topical pharmaceutical composition of the present invention is preferably 1,000 to 1,000,000 units/100 mL, more preferably 10,000 to 200,000 units/100 mL, from the viewpoint of the effects of the present invention. Furthermore, from the viewpoint of formulation stability during low-temperature storage, it is even more preferably 10,000 to 120,000 units/100 mL, even more preferably 10,000 to 50,000 units/100 mL.

The specific surfactant in the topical pharmaceutical composition of the present invention is polyoxyethylene hydrogenated castor oil. Examples of the polyoxyethylene hydrogenated castor oil of the present invention include polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60. The content of the polyoxyethylene hydrogenated castor oil of the present invention is preferably 0.001 w/v% or more in the topical pharmaceutical composition of the present invention in terms of the effect of low temperature stability of the present invention, and more preferably 0.005 w/v% or more. In addition, the upper limit is preferably 3 w/v% or less, and more preferably 2 w/v% or less, taking into consideration safety such as skin irritation and dermal absorption of minoxidil. The content of the polyoxyethylene hydrogenated castor oil of the present invention is more preferably 1 to 50 parts by weight per 1 part by weight of retinol or its derivative in terms of the effect of the present invention.

The lower alcohol of the present invention 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 of the present invention in the topical pharmaceutical composition of the present invention is preferably 20 w/v% or more, 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%.

The pH of the topical pharmaceutical composition of the present invention can be adjusted using a commonly used pH adjuster, and specific examples 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. From the viewpoint of formulation stability during low-temperature storage, organic acids other than tartaric acid and inorganic acids are preferred. The pH of the topical pharmaceutical composition of the present invention is preferably adjusted to 5 to 8.1.

The topical pharmaceutical composition of the present invention may contain a polyhydric alcohol, specific examples of which include 1,3-butylene glycol, propylene glycol, glycerin, and polyethylene glycol. The content of the polyhydric alcohol in the topical pharmaceutical composition of the present invention is 0.1 w/v% or more, preferably 5 w/v% or more, and more preferably 10 w/v% or more, with the upper limit being preferably 30 w/v% or less, taking into consideration the feeling of use, such as reduced stickiness.

The topical pharmaceutical composition of the present invention may further contain water as necessary. The content of water in the topical pharmaceutical composition of the present invention is preferably 2 to 75 w/v%, more preferably 5 to 50 w/v%, and even more preferably 5 to 30 w/v%.

In addition to the above-mentioned components, the topical pharmaceutical composition of the present invention may contain necessary active ingredients and auxiliary ingredients within the scope of not impairing the effects of the present invention. Examples of medicinal ingredients that are preferably added or blended into the topical pharmaceutical composition of the present invention include ingredients selected from the group consisting of menthol, vitamin E acetate, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, diphenhydramine hydrochloride, and pantothenyl ethyl ether.

There are no particular restrictions on the amounts of these optional ingredients that can 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.

In addition to the above-mentioned ingredients, the topical pharmaceutical 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 polycuta, 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, artemisia capillaris, comfrey, angelica tree, It can contain commonly used ingredients such as extracts of saffron, 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.), and dyes.

The topical pharmaceutical composition of the present invention is preferably in a liquid dosage form, and can be in the form of a suitable topical pharmaceutical composition, such as a liquid, lotion, aerosol, tonic, or gel.

The topical pharmaceutical composition of the present invention is prepared by incorporating the above-mentioned components according to a conventional method.

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

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

Example 1
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.14.

Example 2
5 g of minoxidil, 200,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.15.

Example 3
5 g of minoxidil, 50,000 units of retinol palmitate, 0.0268 g of polyoxyethylene hydrogenated castor oil 40, 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 with a pH of 6.16.

Example 4
5 g of minoxidil, 10,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 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 with a pH of 6.12.

Example 5
5 g of minoxidil, 120,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.16.

Example 6
5 g of minoxidil, 10,000 units of retinol palmitate, 0.00536 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.12.

(Example 7)
5 g of minoxidil, 50,000 units of retinol acetate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.17.

(Example 8)
5 g of minoxidil, 50,000 units of retinol, 1 g of polyoxyethylene hydrogenated castor oil 40, 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 with a pH of 6.16.

Example 9
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of concentrated glycerin, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 5.98.

Example 10
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of propylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.09.

(Example 11)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of concentrated glycerin, 10 g of propylene glycol, 50 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 5.84.

Example 12
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 50, 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 with a pH of 6.11.

(Example 13)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 60, 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 with a pH of 6.16.

(Example 14)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of citric 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 with a pH of 6.34.

(Example 15)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 60 g of ethanol, an appropriate amount of lactic 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 with a pH of 6.24.

(Example 16)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 0.2 g of polyethylene glycol, 60 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 6.16.

(Example 17)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 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 pharmaceutical composition for external use with a pH of 6.38.

(Example 18)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyethylene hydrogenated castor oil 40, 10 g of 1,3-butylene glycol, 10 g of concentrated glycerin, 50 g of ethanol, an appropriate amount of phosphoric acid, and purified water were added to bring the total volume to 100 mL, and the mixture was stirred and dissolved to obtain a pharmaceutical composition for external use with a pH of 8.03.

(Comparative Example 1)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polysorbate 60, 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. Even after stirring, the preparation remained cloudy, and a transparent preparation could not be prepared.

(Comparative Example 2)
5 g of minoxidil, 200,000 units of retinol palmitate, 1 g of polysorbate 60, 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. Even after stirring, the preparation remained cloudy, and a transparent preparation could not be prepared.

(Comparative Example 3)
5 g of minoxidil, 50,000 units of retinol palmitate, 1 g of polyoxyl 40 stearate, 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. Even after stirring, the preparation was cloudy and oil droplets of retinol palmitate remained, and a transparent preparation could not be prepared.

(Comparative Example 4)
5 g of minoxidil, 200,000 units of retinol palmitate, 1 g of polyoxyl 40 stearate, 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. Even after stirring, the preparation was cloudy and oil droplets of retinol palmitate remained, and a transparent preparation could not be prepared.

The formulations and post-preparation pH for Examples 1 to 18 and Comparative Examples 1 to 4 are shown in Tables 1 and 2.

(Appearance of the formulation)
The appearance of the preparations immediately after preparation was evaluated for Examples 1 to 18 and Comparative Examples 1 to 4. Preparations with a transparent appearance were rated as ◯, and those with a non-transparent appearance were rated as ×. The results are shown in Tables 3 and 4.

The formulations of Comparative Examples 1 and 2 were cloudy, and a transparent formulation could not be prepared. The formulations of Comparative Examples 3 and 4 were cloudy, and oil droplets derived from retinol palmitate were also observed. On the other hand, the formulations of Examples 1 to 18 solubilized minoxidil, retinol palmitate, retinol acetate, and retinol, and a transparent formulation was obtained.

(Low temperature stability)
25 mL of each of the formulations of Examples 1 to 18 was filled into a 30 mL transparent PET bottle and stored at 5°C for 1 week. As a result, white granular precipitates were observed on the bottom of the container for the formulation of Example 2, but no precipitates were observed for the formulations of the other Examples.

These results show that a concentration of retinol or a derivative in the formulation of up to 120,000 units/100 mL is the most favorable for providing good formulation stability when stored at low temperatures.

The present invention makes it possible to provide a topical pharmaceutical composition containing minoxidil and retinol or its derivatives, which has excellent formulation stability.

Claims (2)

A pharmaceutical composition for external application, comprising: (a) 5 w/v % or more of minoxidil; (b) 0.1 to 120,000 units of retinol , retinol palmitate, retinol acetate, or vitamin A oil ; (c) 0.001 to 2 w/v % of polyoxyethylene hydrogenated castor oil; and (d) 20 to 80 w/v % of a lower alcohol. The pharmaceutical composition for external application according to claim 1, wherein the dosage form is a liquid, a lotion, an aerosol, a tonic, or a gel.