External composition containing minoxidil, and method for preventing deposition of minoxidil

Abstract

To provide an external composition containing minoxidil of 3-10 w / v%, wherein deposition of minoxidil is suppressed.SOLUTION: An external composition contains (A) minoxidil, (B) dibutylhydroxytoluene and (C) pantothenyl ethyl ether, with a concentration of minoxidil of 3-10 w / v%.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a topical composition containing minoxidil and a method for preventing precipitation of minoxidil. [Background technology]

[0002] Minoxidil (2,4-diamino-6-piperidinopyrimidine 3-oxide) is widely used as a drug to improve alopecia because it has excellent hair growth and nourishing effects when applied topically. However, minoxidil has problems in that it is poorly soluble in water and ethanol, and is prone to crystallization, especially when stored at low temperatures.

[0003] Various studies have been conducted to date to improve the solubility of minoxidil. For example, Patent Document 1 (JP 2014-214098 A) discloses a topical composition that contains a high proportion of propylene glycol or a similar glycol to suppress precipitation of minoxidil. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] JP 2014-214098 A Summary of the Invention [Problem to be solved by the invention]

[0005] However, because glycols have relatively high viscosity and adhesion, if the glycol content in the composition is high, it may lead to a decrease in the feeling of use, such as stickiness on the scalp, etc. For this reason, there has been a demand for the development of a topical composition that does not contain a large amount of glycols and that inhibits the precipitation of minoxidil.

[0006] The present invention relates to a composition for external use containing 3 to 10 w / v% minoxidil, The objective of the present invention is to provide a composition for external use in which precipitation of aldehydes is suppressed. [Means for solving the problem]

[0007] [1] A composition for external use containing (A) minoxidil, (B) dibutylhydroxytoluene, and (C) pantothenyl ethyl ether, wherein the concentration of minoxidil is 3 to 10 w / v%.

[0008] [2] The composition for external use according to [1], wherein the concentration of (B) dibutylhydroxytoluene is 0.01 to 1.0 w / v%.

[0009] [3] (C) The composition for external use described in [1] or [2], wherein the concentration of pantothenyl ethyl ether is 0.1 to 2.0 w / v%.

[0010] [4] The composition for external use according to any one of [1] to [3], further comprising at least one selected from pyridoxine hydrochloride, tocopherol acetate, and menthol.

[0011] [5] The composition for external use described in any one of [1] to [4], having a pH of 5.0 to 8.0.

[0012] [6] The composition for external use described in any one of [1] to [5], which is filled in a container made of a resin whose main component is polyethylene terephthalate.

[0013] [7] A method for preventing precipitation of minoxidil, comprising adding dibutylhydroxytoluene and pantothenyl ethyl ether to a topical composition containing 3 to 10 w / v% minoxidil. Effect of the Invention

[0014] According to the present invention, it is possible to provide a composition for external use that contains 3 to 10 w / v % minoxidil and in which precipitation of minoxidil is inhibited. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The topical composition of the present invention contains (A) minoxidil, (B) dibutylhydroxytoluene, and (C) pantothenyl ethyl ether, and the concentration of minoxidil is 3 to 10 w / v %.

[0016] Minoxidil (including its salts) is a known compound, and may be obtained as a commercially available product, for example, from Tokyo Chemical Industry Co., Ltd. Examples of minoxidil salts include inorganic acid salts such as hydrochloride and sulfate, and organic acid salts such as acetate, citrate, succinate, benzoate, and lactate.

[0017] The content of minoxidil is 3w / v% or more, preferably 4w / v% or more, more preferably 4.5w / v% or more, based on the total amount of the composition. In general, in compositions containing minoxidil, precipitation of minoxidil is likely to occur within this range, so the effect of the present invention is useful within this range. In addition, the content of minoxidil is 10w / v% or less, preferably 9w / v% or less, more preferably 7w / v% or less, based on the total amount of the composition. If it exceeds this range, it may not be possible to fully suppress the crystal precipitation of minoxidil, or the composition may become colored over time.

[0018] (B) Dibutylhydroxytoluene contained in the topical composition of the present invention is a type of aromatic compound also called 2,6-di-tert-butyl-p-cresol, and is generally known as an antioxidant. In the topical composition of the present invention, the concentration of dibutylhydroxytoluene is preferably 0.01 to 1.0 w / v%, more preferably 0.03 to 0.9 w / v%, and even more preferably 0.05 to 0.8 w / v%.

[0019] The pantothenyl ethyl ether (C) contained in the topical composition of the present invention is a compound also called (2R)-N-(3-ethoxypropyl)-2,4-dihydroxy-3,3-dimethylbutanamide. In the topical composition of the present invention, the concentration of pantothenyl ethyl ether is preferably 0.1 to 2.0 w / v%, more preferably 0.3 to 1.5 w / v%, and even more preferably 0.5 to 1.0 w / v%.

[0020] By blending both dibutylhydroxytoluene and pantothenyl ethyl ether in a topical composition containing 3 to 10 w / v% minoxidil, the precipitation of minoxidil (particularly at low temperatures) can be suppressed more than when they are blended alone. In addition, since the precipitation of minoxidil can be prevented without containing a large amount of glycols, a topical composition with good usability and excellent storage stability can be obtained. In addition, the same effect can be expected when panthenol, hinokitiol, diphenhydramine or a salt thereof, or salicylic acid or a salt thereof is used instead of pantothenyl ethyl ether.

[0021] The topical composition of the present invention preferably further contains at least one selected from pyridoxine hydrochloride, tocopherol acetate, and menthol. The amounts of these components added are not particularly limited and can be determined experimentally while taking into consideration the feel of use and the stability of minoxidil. For example, it is preferable to mix pyridoxine hydrochloride at 0.01-0.1 w / v%, tocopherol acetate at 0.01-0.1 w / v%, and menthol at 0.1-0.5 w / v% in the topical composition.

[0022] (solvent) The composition for external use of the present invention may contain a pharma- ceutical or physiologically acceptable solvent used in external medicines, quasi-drugs, cosmetics, etc. The composition for external use of the present invention preferably contains one or more solvents selected from the group consisting of water, lower alcohols (particularly ethanol), and polyhydric alcohols. Examples of polyhydric alcohols include glycols such as propylene glycol, dipropylene glycol, and 1,3-butylene glycol, glycerin, macrogol 300, macrogol 400, and macrogol 600, and preferably propylene glycol, 1,3-butylene glycol, and glycerin, and more preferably propylene glycol and 1,3-butylene glycol. The polyhydric alcohols may be used alone or in combination of two or more. There are no particular restrictions on the amount of each solvent in the composition for external use, but the amount of water in the final composition is preferably 5 to 40 w / v%, more preferably 10 to 35 w / v%, and even more preferably 15 to 30 w / v%. The amount of the lower alcohol is preferably 25 to 70 w / v%, more preferably 35 to 60 w / v%, and even more preferably 40 to 55 w / v%. The amount of the polyhydric alcohol (glycols) is preferably 1 to 30 w / v%, more preferably 5 to 25 w / v%, and even more preferably 8 to 20 w / v%. Within these ranges, a topical composition having good solubility of minoxidil and excellent usability can be obtained.

[0023] (Additives) The composition for external use of the present invention may contain pharma- ceutical or physiologically acceptable additives used in external medicines, quasi-drugs, cosmetics, etc. Examples of such additives include antioxidants, surfactants, thickeners, preservatives, pH adjusters, stabilizers, irritation reducers, preservatives, colorants, fragrances, dissolution aids, etc. These additives may be used alone or in combination of two or more. Examples of pH adjusters that may be used include organic acids such as lactic acid, sodium lactate, citric acid, sodium citrate, malic acid, sodium malate, succinic acid, sodium succinate, tartaric acid, and sodium tartrate, and inorganic acids such as phosphoric acid, hydrochloric acid, and sulfuric acid. In addition, organic bases such as triethanolamine, diisopropanolamine, and triisopropanolamine, and inorganic bases such as potassium hydroxide and sodium hydroxide may be used as pH adjusters. The pH adjusters may be used alone or in combination of two or more.

[0024] (Pharmacologically active ingredients / biologically active ingredients) The topical composition of the present invention may contain pharmacologically or physiologically active ingredients used in topical pharmaceuticals, quasi-drugs, cosmetics, etc. other than minoxidil. Examples of such ingredients include blood circulation promoting ingredients, angiogenesis promoting factors, moisturizing ingredients, anti-inflammatory ingredients, antibacterial ingredients, vitamins, peptides or derivatives thereof, amino acids or derivatives thereof, cell activating ingredients, anti-aging ingredients, keratin softening or keratin dissolving ingredients, skin whitening ingredients, astringent ingredients, vasodilating ingredients, antihistamine ingredients, antioxidant ingredients, metabolic activators, and cooling agents. In addition, hair growth ingredients other than minoxidil, such as spiranolactone, Swertia japonica extract, capsaicinoid, keratinocyte growth factor (KGF; FGF-7), glycyrrhizinate, glycyrrhetinic acid, and ginseng extract, may also be included. The pharmacologically or physiologically active ingredients may be used alone or in combination of two or more.

[0025] (Dosage form) The form of the composition for external use of the present invention is not particularly limited, and examples thereof include liquid, suspension, emulsion, cream, gel, liniment, lotion, aerosol, etc. In addition, when the composition contains water to an extent that minoxidil can be dissolved, it can be made into an ointment. Among these, liquid, suspension, emulsion, lotion, or aerosol is preferred, and liquid, lotion, or aerosol is more preferred. The composition for external use of the present invention can be produced, for example, by mixing each component according to or in accordance with the General Provisions of the Japanese Pharmacopoeia. In addition, the composition for external use of the present invention can be incorporated into cosmetic compositions such as lotions, creams, skin lotions, milky lotions, foams, shampoos, rinses, conditioners, hair tonics, hair creams, and hair liquids.

[0026] (pH) The pH of the composition for external use of the present invention is preferably 5.0 or more, more preferably 5.5 or more, and even more preferably 6.0 or more.The pH of the composition of the present invention is preferably 8.0 or less, more preferably 7.5 or less, and even more preferably 7.0 or less.Within the above range, minoxidil is easily dissolved, and irritation to the scalp due to high pH can be avoided.The pH can be adjusted using the above pH adjuster.

[0027] (container) The container for filling the topical composition of the present invention is not particularly limited, and a container of a shape and material appropriately selected in the art according to the purpose of use can be used. The material of the container (main body, cap, discharge member, inner plug, sealing member, etc.) may be appropriately selected in consideration of the storage stability of the topical composition, the chemical resistance, strength, flexibility, weather resistance, etc. of the container. Examples of such materials include polyethylene, polypropylene, polyethylene terephthalate, polystyrene, aluminum, polyvinyl chloride, ABS resin, ethylene-vinyl alcohol resin, acrylonitrile styrene resin, epoxy resin, polyamideimide resin, glass, etc. A laminate using these resins may be used as the material of the container. Among these, it is preferable to use a resin containing polyethylene terephthalate as the main component as the material of the container. Here, the main component refers to the material with the highest content among the container materials, and the content is preferably 50 to 100% by mass, more preferably 80 to 100% by mass. The container may be of a multi-dose type that can be used multiple times (for example, 30 to 360 times, preferably 60 to 240 times), or may be of a unit-dose type that can be used up in a single use.

[0028] (How to use) The method of using the topical composition of the present invention varies depending on the condition of the hair, condition of the scalp, age, sex, etc. of the subject of use, but may be, for example, the following method. That is, an appropriate amount (for example, 0.5 to 2 g, or 0.5 to 2 mL) may be applied to the skin (for example, scalp) several times a day (for example, 1 to 5 times, preferably 1 to 3 times). The topical composition may be applied to the skin (for example, scalp) so that the daily usage amount of minoxidil is, for example, 1 to 1000 mg. The application method may be painting, spraying, etc., depending on the dosage form. The application period may be, for example, 7 days or more, and may be until a sufficient hair growth effect is obtained, for example, within 6 months, at least within 4 months.

[0029] In the present invention, the hair growth effect means having one or more of the following effects: hair growth, hair growth promotion, hair nourishment, hair loss prevention, etc. The effects of the topical composition of the present invention include hair growth, hair growth, hair growth promotion, hair growth promotion, and prevention of hair loss (hair loss, thinning hair) (progression), etc. EXAMPLES

[0030] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these.

[0031] The topical compositions shown in Tables 1 to 3 were prepared according to a conventional method. Each composition was filled into a 50 mL glass container, and the topical compositions shown in Tables 1 and 3 were left in an incubator at 4°C for 14 days, and the topical compositions shown in Table 2 were left in an incubator at -20°C for 12 days, after which crystal precipitation was visually observed. The results are shown in the "Low temperature stability" column of Tables 1 and 2. Here, those in which no precipitation was observed are indicated with "○", and those in which precipitation was observed are indicated with "×".

[0032] [Table 1]

[0033] [Table 2]

[0034] As shown in Tables 1 and 2, when dibutylhydroxytoluene (hereinafter sometimes abbreviated as BHT) and pantothenyl ethyl ether were added to a solution containing 5 g of minoxidil per 100 mL of solution, no precipitation of minoxidil was observed after low-temperature storage (Examples 1 to 5). However, when BHT or pantothenyl ethyl ether was added alone to the solution, precipitation of minoxidil was observed (Comparative Examples 1, 2, 5, and 6). In addition, when butylhydroxyanisole (BHA) or ascorbic acid, which are the same antioxidants as BHT, were used together with pantothenyl ethyl ether, precipitation of minoxidil was observed (Comparative Examples 3 and 4).

[0035] [Table 3]

[0036] The composition shown in Table 3 further contains pyridoxine hydrochloride, tocopherol acetate and l-menthol as active ingredients in addition to minoxidil and pantothenyl ethyl ether. Similar to the results in Tables 1 and 2, in the liquid preparation containing BHT and pantothenyl ethyl ether, no precipitation of minoxidil was observed after low-temperature storage (Example 6), whereas in the liquid preparation containing only BHT or pantothenyl ethyl ether, precipitation of minoxidil was observed (Comparative Examples 7 and 8).

[0037] The results shown in Tables 1 to 3 show that by incorporating both dibutylhydroxytoluene and pantothenyl ethyl ether into a topical composition containing 3 to 10 w / v% minoxidil, precipitation of minoxidil can be significantly inhibited compared to when either is incorporated alone or when an antioxidant other than dibutylhydroxytoluene is incorporated.

[0038] <Prescription Examples> Tables 4 and 5 below show examples of formulations for topical compositions of the present invention.

[0039] [Table 4]

[0040] [Table 5]

[0041] The embodiments and examples disclosed herein should be considered to be illustrative and not restrictive in all respects. The scope of the present invention is defined by the claims, not the above description, and is intended to include all modifications within the meaning and scope of the claims.

Claims

[Claim 1] The invention described in this specification.