JP2016145179A - Minoxidil-containing liquid medicine for external use, and manufacturing method of liquid medicine for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a clear liquid medicine for external use containing minoxidil, which has performance excellent in storage stability such as causing no crystallization even in low-temperature atmosphere storage for a long period of time, and suppressing temporal discoloration in relatively warm atmosphere at about 50°C.SOLUTION: A liquid medicine for external use contains at least (A) minoxidil, (B) glycerin, (C) absolute ethanol, and (D) water, has 2.5 times or more of glycerin than minoxidil with respect to the total amount of a composition, and contains 10 to 35 wt.% of glycerin, has a clear state in which minoxidil is uniformly dissolved, and has suppressed crystallization in low-temperature storage, and furthermore, a liquid medicine for external use containing discoloration-preventing agent, pH regulator, l-menthol, eucalyptus oil can also be embodied.SELECTED DRAWING: None

Description

Detailed Description of the Invention

  The present invention relates to an external liquid preparation containing minoxidil and a method for producing the external liquid preparation.

Minoxidil has a chemical name of 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxamid and has an effect of hair growth, hair growth, hair growth, etc. (hereinafter referred to as hair growth) by external use. The application as a hair restorer is disclosed in US Pat. No. 4,139,619. In recent years, external preparations containing minoxidil have been widely used for hair growth and the like, and various external compositions containing minoxidil have also been proposed.
In general, for example, by applying a solution-form external preparation containing minoxidil to the scalp, components such as minoxidil effective for hair growth penetrate into the dermis of the scalp and wrap the hair root in the scalp to grow the hair. It is known that it acts directly on the hair follicles it controls to promote hair growth and the like. In order for minoxidil as an active ingredient such as hair growth to penetrate into the dermis and promote hair growth, etc., the form in which minoxidil is contained in the form of a solution instead of a solid form is effective for hair growth, etc. It is also known to promote the effect of hair growth and the like by containing an optimal transdermal absorption enhancer.
Minoxidil 1% solution is used as an over-the-counter drug for "Efficacy of preventing hair growth, hair growth and hair loss progression in juvenile alopecia". Approved as OTC). In recent years, liquids containing 5% minoxidil have also been approved and widely used as major pharmaceuticals in major countries and the like as having further enhanced efficacy effects such as hair growth.

A liquid preparation containing minoxidil and other components in a dissolved state tends to be discolored over time due to the other components contained and the causes caused by oxidation deterioration, light deterioration, and other atmospheric conditions. In addition, minoxidil has poor solubility in a solvent, and therefore, a solution in which minoxidil is dissolved tends to precipitate crystals, particularly when stored at a low temperature. Thus, the commercial value tends to decrease with time depending on other components contained and the conditions such as the atmosphere and temperature to be stored. In particular, a liquid agent containing a high concentration of minoxidil tends to cause remarkable deterioration of the liquid agent such as discoloration with time and crystal precipitation under low temperature storage.
In order to suppress such deterioration of the liquid agent such as discoloration over time and crystal precipitation under low temperature storage, a minoxidil-containing liquid agent containing various compositions has been proposed.

  Japanese Patent Application Laid-Open No. 63-150211 (Patent Document 1) discloses an external preparation obtained by adding polyhydric alcohols of both glycerin and propylene glycol to minoxidil, and discloses that the percutaneous absorbability of minoxidil is enhanced. .

  JP-A-61-165312 (Patent Document 2) proposes a hair nourishing cosmetic containing minoxidil and an antiandrogenic agent as a hair nourishing ingredient, and minoxidil (0.5% by weight) and glycerin (5% by weight). , Ethanol (50 wt%), water (44.5 wt%) were disclosed, and minoxidil (0.5 wt%), glycerin (5 wt%), ethanol (50 wt%), water (44.0 wt%), stilbestrol (0.5 wt%), l-menthol (0.4 wt%), capsicum tincture (1.0 wt%), resorcin (0. 5% by weight), perfume (1.5% by weight), discoloring agent (appropriate amount), water (appropriate amount to make the whole 100%) are disclosed. It is disclosed that a hair nourishing cosmetic containing minoxidil and an antiandrogenic agent has an excellent hair nourishing effect.

  WO2001 / 078662 (Patent Document 3) includes (A) 2 to 6% by mass of minoxidil, (B-1) 5 to 30% by mass of 1,3 butylene glycol and glycerin, or (B-2) dioxygen. It has been disclosed and proposed that a composition containing a mixture of propylene glycol and glycerin exhibits an excellent long-lasting hair-growth effect. In this composition, in particular, (a) a composition having a pH of 5.5 to 9.5, (b) a composition having a pH of 5.5 to 6.5, (c) an acid and / or a pH regulator It is disclosed that a composition containing a base, (d) a composition containing citric acid, hydrochloric acid, lactic acid or phosphoric acid as a pH adjusting agent, (e) a composition containing menthol and pantothenyl ethyl ether, etc. are desirable. Has been.

  WO2001 / 076541 (Patent Document 4) contains (A) 1,3-butylene glycol, (B-1) 1, in a preparation containing 10 to 50% by mass of water and 3% by mass or more of minoxidil. A hair restoration composition containing 8 to 30% by mass of a polyhydric alcohol such as 3-butylene glycol and glycerin or (B-2) dipropylene glycol and glycerin and having a pH of 5.5 to 6.5. It has been disclosed and proposed that crystals are less likely to precipitate and have an effect of high stability.

  In JP 2002-308740 (Patent Document 5), in the minoxidil-containing composition, one or two selected from the group consisting of dibutylhydroxytoluene and butylhydroxyanisole are blended, and the pH is 5.7-6. 4, a method for preventing discoloration of the composition is disclosed.

  WO2003 / 030844 (Patent Document 6) includes (A) 1 to 5 W / V% minoxidil of the whole preparation, (B) polyethylene glycol, and (C) one selected from 1,3-butylene glycol and glycerin. Alternatively, a long-lasting hair growth preparation containing two types has been proposed, and it is disclosed that an excellent hair-restoring action can be obtained by application once a day and that it has excellent durability in use.

  In JP-A-11-349451 (Patent Document 7), volatile solvent (ethyl alcohol or isopropyl alcohol) 50 to 99 V / V%, water, polyhydric alcohol (diethylene glycol, propylene glycol, 1,3-butylene glycol, dipropylene) 1 or more selected from the group consisting of glycol, glycerin, sorbitol, and polyethylene glycol having a molecular weight of 200 to 600), a pH adjuster, and a hair growth agent consisting of minoxidil, which is excellent in storage stability and particularly It is disclosed that a hair growth agent having a pH of 4.8 or less when diluted 10-fold with purified water has an effect of being excellent in absorbability from the scalp and penetrating into the hair papilla during administration. On the other hand, minoxidil is an unstable drug in the solution, and its tendency becomes strong particularly when the pH is weakly acidic or lower. Therefore, the pH of the minoxidil solution is preferably 5 or more from the viewpoint of storage stability of minoxidil. Is also disclosed.

  Japanese Patent Application Laid-Open No. 2011-68695 (Patent Document 8) discloses that in a minoxidil-containing composition having a minoxidil concentration of 3 to 10% by mass, dibutylhydroxytoluene, butylhydroxyanisole, erythorbic acid, EDTA-2Na, isopropyl citrate, and gallic acid. Propyl acid, guaiac acid, alpha thioglycerin, potassium dichloroisocyanurate, 2,6-di-tert-butyl-4-methylphenol, soybean lecithin, sodium thioglycolate, sodium thiomalate, ascorbyl palmitate, 2- Discoloration of the composition containing one or more selected from the group consisting of mercaptobenzimidazole and oxyquinoline sulfate and 1,3-butylene glycol, and having a pH of 5.5 to 7.0 A prevention method is disclosed.

  JP 2012-25770 (Patent Document 9) contains 8 to 30% of one or more polyhydric alcohols in a preparation containing 10 to 50% by weight of water and 3% by weight or more of minoxidil. It is disclosed that the hair-growing composition having a pH of 5.5 to 6.5 is highly stable because crystals are hardly precipitated. Here, as the polyhydric alcohol, 1,3-butylene glycol, glycerin, dipropylene glycol, macrogol and the like can be used. In particular, 1,3-butylene glycol is preferable, and two or more kinds of polyhydric alcohols can be used. As combinations of monohydric alcohols, combinations in which 1,3-butylene glycol and glycerin are in a weight ratio of 10: 1 to 1: 4 and dipropylene glycol and glycerin are in a weight ratio of 10: 1 to 1: 4 are disclosed. ing.

  JP 2014-214097 (Patent Document 10) contains 3 to 10% by weight of minoxidil, contains propylene glycol so that the weight ratio of minoxidil: propylene glycol is 1: 3 to 1: 9, and includes A composition for external use having a pH of 6.5 to 7.5 has been proposed. Japanese Patent Application Laid-Open No. 2014-214098 (Patent Document 11) contains 3 to 10% by weight of minoxidil and has a weight ratio of butylene glycol to propylene glycol (propylene A composition for external use containing propylene glycol and butylene glycol so that the ratio of glycol: butylene glycol) is 1: 3.5 to 3.5: 1 has been proposed. Japanese Patent Application Laid-Open No. 2014-214099 (Patent Document 12) 3 to 8% by weight of minoxidil and 24 to 35% by weight of butylene glycol, respectively, based on the total amount of And topical compositions containing 45-60 wt% ethanol and water, and having a pH of 6.6-8, and in each of these compositions, minoxidil crystal precipitation, and It is disclosed that a general discoloration is suppressed and an excellent effect in use feeling is achieved.

On the other hand, various external preparations containing eucalyptus oil have been proposed as external preparations having effects such as hair growth.
JP-A-2005-206536 (Patent Document 13) discloses the following components (A) to (E), that is, (A) Eucalyptus extract, (B) polyhydric alcohol, (C) blood circulation promoter, (D) hair. A hair restorer composition containing a dressing activator and (E) a polar oil agent has been proposed, and a hair restorer having a high hair-growth effect, low irritation to the scalp, and excellent stability over time of the preparation is disclosed.

  JP 2001-2532 (Patent Document 14) proposes a hair growth agent containing one or more components selected from a blood circulation promoter and a hair follicle activator and a polar solvent extract of eucalyptus, and JP 2001-139435 A. (Patent Document 15) includes A: a process of extracting an extract from Eucalyptus plants with a polar organic solvent, removing the polar organic solvent to obtain a crude extract; and B: separating the crude extract from water. A method for producing a neutral fraction of eucalyptus extract, which comprises a step of dissolving in an organic solvent and partitioning and extracting with an alkaline aqueous solution to remove an acidic fraction and a phenolic fraction, has been proposed.

  JP-A-2001-316234 (Patent Document 16) contains an essential oil having an anti-androgenic action such as eucalyptus oil and one or more plant extracts having a skin astringent action and a capillary contraction action, A hair loss inhibitor for body hair such as breasts and wrinkles has been proposed.

  Japanese Patent Application Laid-Open No. 2005-200383 (Patent Document 17) proposes a hair-growth composition comprising eucalyptus oil as a hair-growth active ingredient containing 0.01% by mass or more.

  JP-A-2005-206538 (Patent Document 18) proposes a hair-restoring agent composition containing an eucalyptus extract, a polyhydric alcohol, a blood circulation promoter, a hair follicle activator and a polar oil, and JP-A-2006-143640 (Patent Document 19). ) Proposed hair restoration and hair growth amount containing 0.0001 to 0.5% by weight of eucalyptus extract, JP 2008-208117 (Patent Document 20), hair restoration containing eucalyptus extract 0.00001 to 1% by mass An agent composition is proposed, and JP 2010-1000066 (Patent Document 21) proposes a hair restorer composition containing 0.0006 to 0.5% by weight of eucalyptus extract.

JP 63-150211 JP-A-61-165312 WO2001 / 078662 WO2001 / 076541 JP 2002-308740 A WO2003 / 030844 JP-A-11-349451 JP2011-68695A JP2012-25770 JP2014-214097 JP2014-214098 JP2014-214099 JP 2005-206536 A JP2001-2532 JP 2001-139435 A JP 2001-316234 A JP 2005-200383 JP 2005-206538 A JP 2006-143640 A JP2008-208117 JP2010-1000066

As described in JP-A-63-150211, generally, the percutaneous absorption rate of minoxidil is low, and a measure for improving the percutaneous absorption rate of minoxidil is necessary in order to exhibit the hair growth effect. is there.
This is also described in JP-A-11-349451 (Patent Document 7). That is, the hair growth is controlled by the hair papilla of the hair bulb portion, and it is necessary to obtain the higher hair-growth effect by allowing the minoxidil to efficiently reach the part and stay in the hair papilla. For this reason, various percutaneous absorption promoting components having various absorption promoting capabilities have been proposed, but some of the percutaneous absorption promoting components have the effect of penetrating into the skin through the stratum corneum. Since minoxidil tends to move to the whole body by riding in the bloodstream, it is difficult to retain minoxidil in the scalp while improving absorbability. It is also disclosed that the absorbability of minoxidil into the skin and the permeability to the hair papilla are preferably weakly acidic or lower, preferably at least pH 4.8 or lower.

  On the other hand, as described in JP-A-11-349451 (Patent Document 7), a solution containing minoxidil may cause minoxidil to precipitate during low-temperature storage or during long-term storage, depending on the type and content of the solvent. It is also known that it is an unstable drug that tends to discolor and change. For example, it is disclosed that the tendency of crystal precipitation becomes strong when the pH is weakly acidic or lower, and therefore, from the viewpoint of storage stability of minoxidil in the solution, the pH of the hair restorer is preferably 5 or more. ing.

  Various studies have been made from such a viewpoint, and as disclosed in the above-mentioned Patent Documents 1, 3, 4, 6, 7, and 9 to 12, polyvalents such as ethylene glycol, propylene glycol, butylene glycol, and glycerin. It is disclosed that alcohol has a skin absorption promoting action that promotes the action of absorbing minoxidil into the skin. In addition, as disclosed in Patent Documents 3, 4, 6, 7, and 9 to 12, depending on the type, combination, content, content ratio, other coexisting substances, pH, etc. of these polyhydric alcohols to be used. It is also known that crystal precipitation occurs or discoloration over time occurs.

According to THE MERCK INDEX 13th edition, the properties of minoxidil are as follows: melting point 248 ° C., solubility in absolute ethanol 29 mg / ml, solubility in 2-propanol 6.7 mg / ml, solubility in water Solid with properties of 2 mg / ml. That is, minoxidil has a solubility of about 29 mg / ml in absolute ethanol and is only slightly soluble in water.
In order to apply minoxidil to the human skin and achieve effects such as hair growth, it is necessary for minoxidil to penetrate inside the genus, and for this purpose, clear minoxidil dissolved in a solvent instead of minoxidil solid It is desirable to exist in the form of a solution.
Therefore, in order to prepare a clear solution in which minoxidil is dissolved, it is necessary to select an appropriate solvent, and at the same time, a solution that does not precipitate dissolved minoxidil in the form of crystals even after low-temperature storage. A prescription is required.

  In addition, in order to provide a hair growth agent that is excellent in the absorption efficiency of minoxidil into the skin and at the same time has the effect of staying as long as possible in the hair papilla of the hair bulb part, at the same time, in order to provide a hair growth agent that is also satisfactory in storage stability, It is necessary to design a hair growth agent that is suitable by a formulation-like device such as a transdermal absorption enhancer, a discoloration inhibitor, a pH of the solution such as acidity and alkalinity, and a production method. Also, when other components are added to improve the feeling of use by suppressing discomfort during use, there is no precipitation of crystals even during long-term storage, and further discoloration is suppressed, etc. It is desired to design a hair growth agent that is suitable, for example, having excellent performance in storage stability.

The present invention is a solution containing minoxidil, which solves problems such as crystallization over time, at least minoxidil as an active ingredient such as hair growth is uniformly dissolved and mixed, and is a clear external solution, A liquid preparation for external use and a topical product that has no storage of crystals during storage for a long period of time, has excellent storage stability, and has a comfortable feeling when applied to human skin, with a feeling of stickiness being suppressed. A method for producing a liquid preparation is provided. In addition, in the composition in which the precipitation of crystals over time is suppressed, an external liquid preparation having excellent storage stability in which discoloration is suppressed during long-term storage and a method for producing the external liquid preparation are provided.
Moreover, in the external liquid agent which has said effect, the manufacturing method of the external liquid agent which can manufacture easily the clear liquid agent by which minoxidil was melt | dissolved in the solvent is provided, without deteriorating minoxidil during manufacture.
In particular, the present invention provides a clear external liquid solution in which minoxidil is uniformly dissolved and mixed, and in the external liquid solution having a pH of 7.1 or more, the external liquid solution and the method for producing the external liquid solution exhibiting the above effects.
In particular, in a clear external liquid preparation in which about 0.3 to 8% by weight of minoxidil is uniformly dissolved and mixed, an external liquid preparation and a method for producing the external liquid liquid having the above effects are provided.

  In the present invention, the phrase “clear” means a liquid agent state similar to “transparent”, and means a state in which phenomena such as turbidity, suspension, and precipitated solid are not observed. Further, the phrases “solvent” and “solvent” have the same meaning and mean “a liquid that dissolves a solid”. “Liquid” means “solvent”, “solvent”, or “liquid agent in a state where a solid is dissolved in a solvent or a solvent”.

  The composition for external use of the composition of the present invention is at least one selected from the group consisting of (A) minoxidil and (B) glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, and polyethylene glycol. A polyhydric alcohol, (C) absolute ethanol, and (D) water, and the content of the polyhydric alcohol is 2.5 times or more of the minoxidil by weight, It is characterized by containing 10 to 35% by weight based on the total amount, having a clear state in which the minoxidil is uniformly dissolved, and crystal precipitation during storage is suppressed.

  Preferably, the content of the minoxidil is 0.3 to 8% by weight based on the total amount of the composition, the polyhydric alcohol is glycerin, and the content of the glycerin is based on the total amount of the composition. And 12 to 30% by weight.

  Desirably, the absolute ethanol content is in the range of 30 to 60% by weight with respect to the total amount of the composition, and is in the range of 1 to 4 times the content of the glycerin by weight.

  Desirably, the content of the water is in the range of 10 to 40% by weight with respect to the total amount of the composition, and is 0.1 to 0. 0 of the total amount of the glycerin and the absolute ethanol by weight. It is in the range of 9 times and in the range of 10 to 40% by weight with respect to the total amount of the composition.

  Preferably, the polyhydric alcohol is glycerin and does not contain any polyhydric alcohol other than the glycerin.

  Desirably, it further contains (E) eucalyptus oil.

  Desirably, it further contains (E) 0.001 to 1% by weight of eucalyptus oil based on the total amount of the composition.

  Desirably, it further contains (F) 1-menthol.

Desirably, it further contains (G) a discoloration inhibitor.

  Preferably, the discoloration inhibitor is at least one selected from the group consisting of dibutylhydroxytoluene, benzotriazole, gluconolactone, thymol, polyoxyethylene hydrogenated castor oil, polysorbate, and citric acid.

Desirably, it further contains (H) a pH adjusting agent, and the pH is in the range of 7.1 to 8.1.

  Preferably, the pH adjuster is at least one selected from the group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide.

  Preferably, it further contains (E) eucalyptus oil, (F) 1-menthol, (G) dibutylhydroxytoluene as a discoloration inhibitor, and (H) citric acid as a pH regulator. These components have a clear state in which they are uniformly dissolved, and both crystal precipitation and discoloration over time are suppressed.

  Desirably, the pH is adjusted to a range of 7.1 to 8.1.

  Desirably, (A) 0.3-8 wt% minoxidil, (B) 12-30 wt% glycerin, (C) 30-60 wt% absolute ethanol, (D) based on the total amount of the composition 10-40 wt% water, (E) 0.001-1.0 wt% eucalyptus oil, (F) 0.001-1.0 wt% l-menthol, (G) 0.05-2. Containing 0% by weight of dibutylhydroxytoluene and (H) 0.005 to 2.0% by weight of citric acid, having a pH in the range of 7.1 to 8.1, and these components are homogeneous It is dissolved and mixed, and both crystal precipitation over time and discoloration over time are suppressed.

  The method for producing an external liquid preparation of the present invention comprises (a) a step of preparing minoxidil, glycerin, absolute ethanol, and water, and (b) mixing the glycerin and the absolute ethanol, thereby separating them. A step of preparing a uniformly mixed liquid mixture, and (c) adding and dissolving solid minoxidil to the mixed liquid solution of glycerin and absolute ethanol, thereby dissolving minoxidil Preparing a clear solution, whereby at least 0.3 to 8 wt% minoxidil, 12 to 30 wt% glycerin and 30 to 60 wt% of the total amount of the composition An absolute ethanol, and a clear minoxidil-containing solution in which the minoxidil is dissolved, and has a clear state in which crystal precipitation during storage is suppressed. Characterized in that it.

  Desirably, in the step (b), (b-1) is a step further containing the water, wherein the glycerin, the absolute ethanol, and the water are mixed and mixed uniformly without separation. In the step (c), (c-1) adding and dissolving solid minoxidil in the mixture of glycerin, absolute ethanol and water, Preparing a clear solution in which minoxidil is dissolved, whereby at least 0.3 to 8 wt% minoxidil and 12 to 30 wt% glycerin with respect to the total amount of the composition 30 to 60 wt% absolute ethanol and 10 to 40 wt% water, comprising a clear minoxidil-containing solution in which the minoxidil is dissolved, and crystals at the time of storage Out with a clear state is suppressed.

  Preferably, further, (d) the water is added to a solution obtained by dissolving the minoxidil in a mixed solution of the glycerin and the absolute ethanol, and mixed to prepare a clear solution uniformly mixed without separation. A process, whereby at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, And a clear minoxidil-containing solution in which the minoxidil is dissolved, and has a clear state in which crystal precipitation during storage is suppressed.

  Preferably, the method further comprises the step of (e) adding and mixing eucalyptus oil to prepare a uniformly mixed clear solution without separation, whereby at least 0.3 to 8% by weight of minoxidil And 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 0.001-1 wt% eucalyptus oil, and a clear minoxidil-containing solution in which the minoxidil is dissolved , It has a clear state in which crystal precipitation during storage is suppressed.

  Preferably, the method further comprises the step of adding (f) l-menthol and mixing to prepare a uniformly mixed clear solution without separation, whereby at least 0.3-8 wt% A clear minoxidil-containing solution containing minoxidil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, and 0.001-1 wt% l-menthol, wherein the minoxidil is dissolved And has a clear state in which crystal precipitation during storage is suppressed.

  Preferably, (g) dibutylhydroxytoluene, nicotinamide, sodium bisulfite, sodium sulfite, sodium pyrosulfite, benzotriazole, tetrasodium edetate, gluconolactone, sodium thiosulfate, thymol, and polyoxyethylene Adding at least one anti-discoloring agent selected from the group consisting of hydrogenated castor oil and polysorbate, and mixing to prepare a uniformly mixed clear solution without separation, whereby at least Containing 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and 0.05 to 2.0% by weight of an anti-discoloring agent, Crystal clear precipitation during storage with clear minoxidil-containing solution with dissolved minoxidil Having a clear state in which color change is suppressed while being suppressed.

Preferably, (fg) dibutylhydroxytoluene, nicotinamide, sodium bisulfite, sodium sulfite, sodium pyrosulfite, benzotriazole, tetrasodium edetate, gluconolactone, sodium thiosulfate, thymol, And at least one discoloration inhibitor selected from the group consisting of polyoxyethylene hydrogenated castor oil and polysorbate and l-menthol are added and mixed to prepare a discoloration inhibitor / menthol-containing ethanol solution, and the discoloration A step of adding an inhibitor / menthol-containing ethanol solution and mixing to prepare a uniformly mixed clear solution without separation,
Thus, at least 0.3-8 wt% minoxidil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 0.001-1 wt% l-menthol, And a clear minoxidil-containing solution containing the minoxidil dissolved therein, and having a clear state in which crystal precipitation during storage is suppressed and discoloration is suppressed. Have.

  Preferably, (h) at least one pH regulator selected from the group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide is added. Mixing and adjusting the pH to 7.1-8.1 to prepare a uniformly mixed clear solution without separation, whereby at least 0.3-8% by weight And a clear minoxidil-containing solution containing 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and a pH adjuster in which the minoxidil is dissolved. It is adjusted to 1 to 8.1 and has a clear state while suppressing crystal precipitation during storage.

  Desirably, further, (h) at least one pH adjustment selected from the group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide in water. A pH adjusting agent-containing aqueous solution was prepared by adding and mixing the agent, and the pH adjusting agent-containing aqueous solution was added and mixed to adjust the pH to 7.1 to 8.1, and uniformly mixed without separation. Preparing a clear solution, whereby at least 0.3-8 wt% minoxidil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, water, pH And a clear minoxidil-containing liquid solution in which the minoxidil is dissolved, the pH is adjusted to 7.1 to 8.1, crystal precipitation during storage is suppressed, and the solution has a clear state .

  In another method for producing an external liquid preparation of the present invention, (a) a step of preparing minoxidil, glycerin, absolute ethanol, and water, and (b) mixing the glycerin, the absolute ethanol, and the water, Thereby, a step of preparing a mixed solvent / liquid agent uniformly mixed without separation, (e) eucalyptus oil is added to the mixed solvent / liquid agent obtained by the step (b) and mixed to be uniform without separation (C) the step of preparing a clear solution mixed with the above, (c) adding and dissolving solid minoxidil in the mixed solvent / solution obtained in the step (b) or (e), and thereby minoxidil A clear solution in which is dissolved, (f) l-menthol solution in which l-menthol is dissolved in absolute ethanol is obtained by the step (b), the step (c) or the step (e). (G) a dibutylhydroxytoluene solution prepared by dissolving dibutylhydroxytoluene in absolute ethanol (b) ) Step, (c) step, (e) step or (f) added to the mixed solvent / liquid obtained in step (f) and mixed to prepare a clear liquid that is uniformly mixed without separation. Step (h) A citric acid solution obtained by dissolving citric acid in water is mixed with the step (b), the step (c), the step (e), the step (f) or the step (g). Adding to the solvent / solution, mixing, adjusting the pH to 7.1-8.1 to prepare a uniformly mixed clear solution without separation, whereby 0.3 ~ 8 wt% minoxidil, 0.00 ˜1 wt% eucalyptus oil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 10-40 wt% water, 0.001-1 wt% l-menthol, 0.05 to 2.0% by weight of dibutylhydroxytoluene and 0.005 to 2% by weight of citric acid, the pH is adjusted to 7.1 to 8.1, and crystal precipitation during storage It has a clear state in which discoloration is suppressed while being suppressed.

  According to another method for producing an external liquid of the present invention, (a) a step of preparing minoxidil, glycerin, absolute ethanol, and water, respectively (bc) mixing the glycerin and the absolute ethanol, A step of preparing a mixed solvent / solution mixed uniformly without separation, and then adding and dissolving solid minoxidil to the mixed solvent / solution, thereby preparing a clear solution in which minoxidil is dissolved; (C) adding the water to the glycerin in which the minoxidil is dissolved and the absolute ethanol solution, thereby preparing a clear solution, (e) the step (bc) or the step (c) A step of adding eucalyptus oil to the mixed solvent / liquid obtained and mixing to prepare a clear liquid that is uniformly mixed without separation; (f) l-menthol is anhydrous L-Menthol solution dissolved in ethanol was added to the mixed solvent / solution obtained in the step (bc), the step (c) or the step (e), mixed, and mixed uniformly without separation. A step of preparing a clear solution, and (g) a dibutylhydroxytoluene solution prepared by dissolving dibutylhydroxytoluene in absolute ethanol by the step (bc), the step (c), the step (e) or the step (f). Adding (h) a citric acid solution in which citric acid is dissolved in water to the obtained mixed solvent / solution to prepare a clear solution that is mixed and mixed uniformly without separation; Steps, (c), (e), (f), or (g) is added to the mixed solvent / liquid obtained in step (g) and mixed to obtain a pH of 7.1-8. Adjust to 1 and separate Preparing a uniformly mixed clear solution, whereby 0.3 to 8 wt% minoxidil, 0.001 to 1 wt% eucalyptus oil, and 12 to 30 wt% glycerin; 30 to 60% by weight absolute ethanol, 10 to 40% by weight water, 0.001 to 1% by weight l-menthol, 0.05 to 2.0% by weight dibutylhydroxytoluene, 005 to 2% by weight of citric acid, having a clear state in which pH is adjusted to 7.1 to 8.1, crystal precipitation during storage is suppressed, and discoloration is suppressed. Features.

  In another method for producing an external liquid preparation of the present invention, (a) a step of preparing minoxidil, glycerin, absolute ethanol, and water, and (b) mixing the glycerin, the absolute ethanol, and the water, (E) adding eucalyptus oil to the mixed solvent / solution, mixing, and mixing to obtain a clear solution uniformly mixed without separation. (Fg) Dibutylhydroxytoluene and l-menthol are added to and mixed with the absolute ethanol to prepare a dibutylhydroxytoluene / menthol-containing ethanol solution, and then the dibutylhydroxytoluene / menthol-containing ethanol solution is prepared. A step of preparing a clear liquid agent mixed with the mixed solvent / liquid agent and uniformly mixed without separation, (c) fg) adding the solid minoxidil to the mixed solution / solution in the clear solution prepared in the step and dissolving it, thereby preparing a clear solution in which the minoxidil is dissolved, (h) Citric acid is dissolved in water to prepare a citric acid aqueous solution, and then the citric acid aqueous solution is added to and mixed with the liquid prepared in the step (c) to prepare a clear liquid. Comprising 0.3 to 8% by weight of minoxidil, 0.001 to 1% by weight of eucalyptus oil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and 10 to 40%. Containing, by weight, water, 0.001-1 wt% l-menthol, 0.05-2.0 wt% dibutylhydroxytoluene, and 0.005-2 wt% citric acid, pH is 7.1-8. It is adjusted to have a clear state discoloration is suppressed with crystallization during storage is suppressed, characterized in that.

  Preferably, the minoxidil, the eucalyptus oil, the glycerin, the absolute ethanol, the water, the l-menthol, the dibutylhydroxytoluene, and the production member that contacts the citric acid are made of a resin or ceramic that does not contain a metal. It is characterized by preparing using a manufactured manufacturing member.

  Preferably, the glycerin, the absolute ethanol, and the water are prepared at a temperature in the range of about 15 ° C to about 35 ° C.

  Desirably, a polyhydric alcohol other than the glycerin is not contained.

A clear external liquid solution in which at least minoxidil as an active ingredient such as hair growth is uniformly dissolved and mixed, and there is no precipitation of crystals even when stored in a low temperature atmosphere for a long time. Thus, a liquid for external use having excellent storage stability, such as suppression of discoloration with time in a warm atmosphere, can be obtained. Therefore, in the distribution application to tropical and cold regions and storage in summer and winter, quality deterioration such as discoloration suppression and crystal precipitation is suppressed, and further, when applied to human skin, stickiness is suppressed. Thus, an external liquid preparation containing high-concentration minoxidil having excellent commercial value such as providing a comfortable feeling of use can be obtained.
Moreover, in the external liquid agent which exhibits said effect, the manufacturing method of the external liquid agent which can melt | dissolve minoxidil in a solvent efficiently and can manufacture a clear liquid agent easily is obtained during manufacture, without deteriorating.

  The external liquid preparation of the present invention is at least from the group consisting of (A) minoxidil and (B) glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, and polyethylene glycol with respect to the total amount of the composition. At least one selected polyhydric alcohol, (C) absolute ethanol, and (D) water, and the content of the polyhydric alcohol is 2.5 times or more of the minoxidil by weight. And 10 to 35% by weight, having a clear state in which the minoxidil is uniformly dissolved, and crystal precipitation during storage is suppressed.

  In the external liquid preparation of the present invention, desirably, the content of minoxidil is 0.3 to 8% by weight, the polyhydric alcohol is glycerin, and the content of glycerin is based on the total amount of the composition, It contains 12 to 30% by weight.

According to THE MERCK INDEX 13th edition, the properties of minoxidil have a melting point of 248 ° C., a solubility in propylene glycol of 75 mg / ml, a solubility in absolute ethanol of 29 mg / ml, and a solubility in 2-propanol of 6.7 mg / ml. , A solid having a property of 2.2 mg / ml in water (however, solubility in diglycerin, dipropylene glycol, butylene glycol and polyethylene glycol is not described). Further, according to the experiments by the inventors, it has a property that it is easily discolored by light and is colorless at room temperature. That is, minoxidil has a solubility of about 29 mg / ml in absolute ethanol and is only slightly soluble in water.
As described in the above [Background Art] section, minoxidil was developed as an oral hypertension treatment drug having a vasodilatory effect according to known literature, but a medical external hair growth agent that is applied to the skin and used. Has been approved as a general pharmaceutical, and about 0.5% by weight of a minoxidil-containing solution has been proposed for a long time to prevent hair loss, and in recent years, it contained a relatively high concentration of about 5% by weight of minoxidil. The containing liquid is generally widely used as a medical external hair restorer with enhanced effects such as hair growth, hair growth, and hair growth.

In the external use liquid preparation of the present invention, the content ratio of minoxidil is not particularly limited. For example, the range is preferably from 0.3% by weight to 8% by weight, more preferably from 0.9% by weight based on the total amount of the composition. % To 7% by weight. In general, according to known literature, the effect of hair growth and the like tends to decrease as the content of minoxidil decreases. When the content of minoxidil exceeds 8% by weight, side effects on the human body are a concern, and safety for the human body has not been confirmed. Further, when the content of minoxidil exceeds 8% by weight, it is necessary to increase the content of the solvent capable of dissolving minoxidil, so that the solubility of minoxidil, the viscosity of the liquid agent, the evaporation property during use of the liquid agent, It is necessary to select the optimum conditions in the design of liquid component such as stickiness, and in addition, some minoxidil remains in the solvent in a solid state without completely dissolving the minoxidil in the solvent (or solvent). Even when dissolved in a solvent at a high temperature, the tendency to become turbid or to precipitate crystals at a low temperature of room temperature or less becomes strong.
From such a viewpoint, in the present invention, the content ratio of minoxidil is more preferably in the range of 0.3 wt% to 8 wt%, and the types and contents of other components were examined.

  Anhydrous ethanol is widely used as a solvent for external liquids such as cosmetics. Absolute ethanol can be used as a solvent capable of dissolving minoxidil at a rate of 29 mg / ml (described in the above-mentioned THE MERCK INDEX). As described in the 15th revision Japanese Pharmacopoeia (edited by the Japan Public Writings Association, published on April 25, 2006 by Jiho Co., Ltd.), absolute ethanol is a colorless and clear liquid with a boiling point of 78-79 ° C. However, it has the property of being miscible with water. In addition, the Cosmetic Raw Material Dictionary (Chuo Printing Co., Ltd., issued on November 29, 1991) describes that it has a bactericidal effect when water is present, and is mixed with water and glycerin at an arbitrary ratio. Yes. In the present invention, absolute ethanol having a purity of about 99.5% is used. Note that, instead of musui ethanol, diluted ethanol composed of absolute ethanol and water can also be used.

As described in the above background art, generally, an external solution containing anhydrous ethanol, water, a butylene glycol multi-valued alcohol, and minoxidil is generally used.
Also in the present invention, it is assumed that a solvent containing anhydrous ethanol and water is used as the solvent / solvent. Although it does not specifically limit as water, Purified water is desirable. As purified water, for example, purified water purified by distillation of pharmacopoeia normal water, purified water purified through an ion exchange resin, or purified water purified by ultrafiltration is desirable. “Purified water” is also called “pure water”. The above-mentioned cosmetic raw material dictionary describes that “purified water is colorless and transparent, has no smell (odor or smell), has no taste, and has a pH of 5.0 to 7.0”.

In the external preparation of the present invention, a polyhydric alcohol such as glycerin, propylene glycol, dipropylene glycol, 1,3 butylene glycol, or polyethylene glycol is desirable as a solvent for dissolving minoxidil. These polyhydric alcohols have a property of mixing without separation from absolute ethanol.
According to the description of the 15th revision of the Japanese Pharmacopoeia mentioned above, glycerin is a colorless and clear viscous liquid called glycerol or propane-1,2,3-triol, which has a sweet and hygroscopic nature that is miscible with water or ethanol. A liquid. As described in the aforementioned cosmetic raw material dictionary, glycerin is a colorless odorless, syrupy liquid having a melting point of 18.2 ° C., a boiling point of 290 ° C., a viscosity of 945 cp (25 ° C.), water The alcohol is mixed in an arbitrary ratio. In the cosmetic field, it is used in cosmetics for the purpose of improving skin humectants, skin softeners, and product slipping and stretching.
Propylene glycol has a slightly transparent, boiling point of 188 ° C. with a little viscosity, a viscosity of 56 cp (20 ° C.), and is soluble in water and ethanol.
Dipropylene glycol is a viscous liquid having a boiling point of 231 ° C. and a melting point of −40 ° C. and relatively little stickiness, and is freely mixed with water, ethanol, fats and oils, and the like.
1,3-butylene glycol has a slightly transparent and transparent boiling point of 207 ° C., a viscosity of 104 cp (25 ° C.), and is soluble in water and ethanol. It is said that it has a lighter feeling than glycerin and has less stickiness.
Polyethylene glycol, which is also called macrocol, is water-soluble, there are those having a molecular weight of 200 to 1000 having different polymerization weights and different molecular weights, and as the molecular weight increases, the water-solubility decreases and the viscosity with a molecular weight of 200-600. Higher liquids, and more than that have properties close to solids.
The viscosity (viscosity) of these polyhydric alcohols is 56 cp for propylene glycol, no data for dipropylene glycol, 104 cp for 1,3-butylene glycol, 945 cp for glycerin, and polyethylene glycol varies depending on the degree of polymerization. The viscosity of propylene glycol, dipropylene glycol, and 1,3-butylene glycol is relatively low, and the viscosity of glycerin is high.
In addition, publicly known literature data relating to the solubility of minoxidil in these polyhydric alcohols could not be found.

These polyhydric alcohols have a significantly higher viscosity than absolute ethanol. Therefore, it takes a long time to dissolve minoxidil at room temperature, or it is necessary to lower the viscosity at high temperature to make it easier to dissolve. . However, at high temperatures, minoxidil tends to deteriorate and is inappropriate.
In order to prepare a minoxidil-containing liquid agent containing these polyhydric alcohols with suppressed crystal precipitation at low temperatures, the content ratio with minoxidil, the content ratio with other mixed solvents such as anhydrous ethanol and water, It needs to be carefully examined and determined.

As described in the background art above, generally contains minoxidil, absolute ethanol and water, and further contains a predetermined number of polyhydric alcohols such as propylene glycol, 1,3-butylene glycol, polyethylene glycol and glycerin. It is known that a liquid preparation for external use contained in a proportion exhibits a skin absorption promoting action that promotes the action of absorbing minoxidil into the skin.
On the other hand, especially in the presence of a mixed solution of polyhydric alcohol and water, depending on the conditions such as the type of these polyhydric alcohols, the type of polyhydric alcohol used in combination, the content, the content ratio, etc. It is also known that crystal precipitation occurs or discoloration over time occurs.

In the liquid formulation containing minoxidil, absolute ethanol, and water, the use of polyhydric alcohols that have the effect of promoting skin absorption of minoxidil was experimentally examined. 1,3-butylene glycol or polyethylene glycol was found to suppress crystal precipitation during low-temperature storage and to suppress discoloration over time.
Mixed solvents made by adding low-viscosity anhydrous ethanol to high-viscosity polyhydric alcohols have a low viscosity, can easily dissolve minoxidil even at room temperature, and can suppress crystal precipitation even during long-term low-temperature storage. I found. Further, in addition to polyhydric alcohol and absolute ethanol, in a mixed solvent containing a predetermined ratio of water, minoxidil can be easily dissolved at room temperature. It was found that crystal precipitation was suppressed.

The content of polyhydric alcohol capable of dissolving minoxidil in such a mixed solvent of polyhydric alcohol, absolute ethanol and water varies depending on the type of polyhydric alcohol, but is about 2.5 times or more that of minoxidil by weight. In addition, a liquid agent containing 10 to 35% by weight is desirable, and more desirably, a liquid agent that is about 3.0 times or more and contains 12 to 30% by weight. In this range, (i) Minoxidil can be easily dissolved at room temperature, and it is a clear solution for external use, and has excellent storage stability such as no crystal precipitation even during storage in a low-temperature atmosphere for a long period of time. The effect of “having an effect having performance” is obtained.
When the content of polyhydric alcohol with respect to minoxidil is less than 2.5 times by weight and less than 10% by weight, (a) Minoxidil cannot be completely dissolved during production, and a clear external liquid is obtained. (B) Even when minoxidil can be completely dissolved, there is a tendency that minoxidil crystals precipitate during low-temperature storage.
When the content of polyhydric alcohol with respect to minoxidil exceeds 35% by weight, (a) when a liquid preparation for external use is applied to the human skin, a sticky feeling due to the highly viscous polyhydric alcohol remains and the feeling of use remains It tends to decrease. (B) In the process of dissolving minoxidil in the polyhydric alcohol-containing solvent, it becomes impossible to reduce the viscosity of the polyhydric alcohol-containing solvent because the amount of absolute ethanol or water that can dilute the polyhydric alcohol decreases. , There is a tendency to require a long time or to be unable to dissolve minoxidil near room temperature.

In the external preparation of the present invention, glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol or polyethylene glycol can be used as the polyhydric alcohol, and glycerin is particularly desirable.
As described above, glycerin has a melting point of 18.2 ° C., a boiling point of 290 ° C., and a viscosity of 945 cP (25 ° C.). It is used in cosmetics for the purpose of improving product sliding and elongation.
Glycerin has a higher viscosity than polyhydric alcohols such as propylene glycol, dipropylene glycol, and 1,3-butylene glycol. Therefore, minoxidil cannot be easily dissolved at room temperature.
Although no known literature data on the solubility of minoxidil in glycerin could be found, according to the preliminary experiments by the present inventors, minoxidil was not easily dissolved in glycerin at 25 ° C at room temperature in a short time. It was confirmed that 5 g of minoxidil was completely dissolved in 100 g of glycerol heated. It was also confirmed that no minoxidil crystal precipitation was observed even when the solution was stored in a low temperature atmosphere at about 4 ° C. for 5 days.

It is known that a liquid preparation containing anhydrous ethanol and water is suitable from the viewpoint of use feeling in using an external liquid preparation containing minoxidil applied to the skin. It is also known that polyhydric alcohol has the effect as a skin absorption enhancer of the minoxidil component of the minoxidil-containing external liquid.
On the premise of this, “(Effective b) A clear external liquid solution in which minoxidil as an active ingredient such as hair growth is uniformly dissolved and mixed, and even when stored in a low temperature atmosphere for a long time, It has the effect of having excellent performance in storage stability without precipitation, and “(Effective B) When applied to human skin, it provides a comfortable feeling of use with reduced stickiness, etc. Obtaining a commercial solution containing a high-concentration minoxidil having commercial value "and" (Effect C) Along with suppression of crystal precipitation, discoloration with time in a relatively warm atmosphere of about 50 ° C is suppressed ", etc. It has a function as a skin absorption enhancer for the purpose of `` to obtain a liquid preparation for external use containing high-concentration minoxidil having an excellent commercial value with excellent storage stability ''. And polyhydric alcohols having a viscosity, and absolute ethanol having a low viscosity, the content ratio and a manufacturing method of a mixed solvent containing a gentle water human skin and various experimental study.

As a result of various experimental studies, the following knowledge was obtained.
As a result of studying various polyhydric alcohols, a composition containing “predetermined proportion of glycerin” dissolves minoxidil well and is mixed with each other to have a clear state and suppress crystallization at low temperature In addition, the present inventors have found an externally applied liquid agent that has no significant stickiness when applied to human skin and does not feel uncomfortable during use. In addition, the present inventors have found an external liquid preparation that suppresses discoloration over time even in a composition that suppresses crystal precipitation at low temperatures.

  In the external preparation of the present invention, desirably, the external preparation of the present invention contains at least (A) 0.3 to 8% by weight of minoxidil, (B) glycerin, and (C) with respect to the total amount of the composition. Anhydrous ethanol and (D) water are contained, and the content of the glycerin is 2.5% or more of the minoxidil in a weight ratio, and is 12 to 30% with respect to the total amount of the composition. It is desirable that the liquid preparation for external use has a clear state in which the minoxidil is uniformly dissolved and crystal precipitation during storage is suppressed.

  Considering from the viewpoint of effects such as hair growth, the content ratio of minoxidil with respect to the total amount of the composition is preferably in the range of 0.3 to 8% by weight. It is known from the above-mentioned known literature that an external liquid preparation containing minoxidil within this range has excellent effects such as hair loss prevention, hair growth, and hair growth. Although it has not been confirmed by experiments, generally, for example, in the case of a liquid preparation for external use containing a range of about 0.3 to about 2.0% by weight of minoxidil, hair loss is prevented by continuous use. The effect can be expected. Further, in the case of an external liquid preparation containing a minoxidil content of about 2.0 to about 8.0% by weight, effects such as hair growth and hair growth can be expected. In the case of a liquid preparation having a minoxidil content of less than 0.3% by weight, the effects of hair growth tend to decrease, and in the case of a liquid preparation having a minoxidil content of more than 8% by weight, the human body is adversely affected. It is expected that side effects will occur.

  In an external liquid preparation having a clear state in which 0.3 to 8% by weight of minoxidil is uniformly dissolved and mixed in the glycerin mixed liquid, the content of glycerin with respect to minoxidil is 2.5 times or more by weight. In addition, a liquid agent containing 10 to 35% by weight is desirable. More desirably, a liquid agent having a glycerin content of 3 times or more by weight ratio of the minoxidil content and containing 12 to 30% by weight is desirable, and more desirably 15 to 25% by weight.

  As a result, “(Effect A) is a clear external liquid preparation, and has an effect of having excellent performance in storage stability such as no crystal precipitation even during storage in a low-temperature atmosphere for a long time”. In addition, an effect such as “(Effect B) can be used comfortably without any discomfort such as stickiness when applied to human skin” is obtained.

When the content of glycerin with respect to minoxidil is less than 2.5 times by weight and less than 10% by weight, (a) Minoxidil cannot be completely dissolved during production, and a clear external preparation cannot be obtained. b) Even when minoxidil can be completely dissolved, the liquid preparation for external use is put in a glass sealed container and stored in a refrigerator at about 4 ° C. for 5 days. is there. No change in discoloration of the liquid is observed.
When the content of glycerin exceeds 35% by weight, in the appearance of the liquid form after storage in a refrigerator at about 4 ° C. for 5 days, no precipitation of minoxidil crystals and no change in discoloration of the liquid form are observed. a) When a liquid for external use is applied to human skin, a sticky feeling due to glycerin having a high viscosity remains, and the feeling of use tends to decrease. (B) Since the amount of absolute ethanol or water that can dilute glycerin decreases, the viscosity of the glycerin-containing solvent cannot be lowered, and a long time is required in the process of dissolving minoxidil in the glycerin-containing solvent. Or, there is a tendency that minoxidil cannot be dissolved around room temperature.

In the external liquid preparation having a clear state in which minoxidil is uniformly dissolved and mixed in the glycerin mixed liquid of the present invention, the absolute ethanol content is in the range of 30 to 60% by weight with respect to the total amount of the composition. In addition, an external liquid preparation in the range of 1 to 4 times the content of glycerin by weight is desirable.
More desirably, the absolute ethanol content is in the range of 35 to 55% by weight with respect to the total amount of the composition, and is in the range of 1.5 to 2.5 times the glycerin content by weight. Liquids are particularly desirable.
The external solution within this range is “(Effective b) A clear external solution, and has an effect of having excellent storage stability such as no crystal precipitation even during storage in a low-temperature atmosphere for a long period of time. In addition, there are effects such as “(Effect B) There is no discomfort such as stickiness when applied to human skin, and it can be used comfortably”. In addition, “(Effect D) It is possible to easily prepare a solution in which minoxidil is dissolved at a room temperature of about 25 ° C. without increasing the temperature of the solution to be used at the time of manufacturing an external solution, thereby improving mass productivity. The effect such as “Yes” is obtained.

As described above, glycerin easily dissolves minoxidil (minoxidil was not easily dissolved in glycerin at room temperature at 25 ° C in a short time, but 5 g of minoxidil was completely dissolved in 100 g of glycerol heated at 60 ° C. And has a high viscosity of 945 cP (25 ° C.). That is, as the reason why minoxidil was not easily dissolved in glycerin at room temperature at 25 ° C. in a short time, due to the high viscosity of glycerin at room temperature at 25 ° C., the miscibility between minoxidil (powder) and glycerin was poor. It is conceived.
Further, as described above, absolute ethanol has a property of dissolving about 30 mg / ml (about 3 g / 100 cc) of minoxidil and has a relatively low viscosity.
That is, minoxidil has a solubility that dissolves well in glycerin but slightly dissolves in absolute ethanol. Moreover, glycerin and absolute ethanol have the property of mixing well without being separated from each other. In consideration of these properties, a mixed liquid in which glycerin and absolute ethanol are mixed has a viscosity that is significantly lower than that of glycerin alone, and on the contrary, without reducing the solubility of minoxidil. It has been found that, due to the low viscosity of the mixed solution, minoxidil can be easily and easily dissolved at room temperature of 25 ° C. Further, even when a predetermined amount of water is added to a mixed solution of glycerin and absolute ethanol in which minoxidil is dissolved, no cloudiness or crystal precipitation is observed. Further, even when such an external liquid preparation is refrigerated at about 4 ° C., crystal precipitation is suppressed.

When the content of absolute ethanol is less than the glycerin content (the content ratio of the weight ratio of glycerin: absolute ethanol is less than 1: 1), since the glycerin content ratio increases, when applying an external preparation on the human skin, There is a tendency to be inferior to the feeling of use such as a sticky feeling remaining. In addition, the viscosity of the liquid mixture is not sufficiently lowered, and when minoxidil is added and dissolved in a glycerin / anhydrous ethanol mixed solution, a phenomenon in which minoxidil cannot be completely dissolved or a long time is required to dissolve minoxidil. There is a tendency for problems such as to occur.
When the absolute ethanol content exceeds 4.0 times the glycerin content (the content ratio of the weight ratio of glycerin: absolute ethanol exceeds 1: 4), the absolute ethanol content ratio inferior to the minoxidil solubility increases. For this reason, when the content of minoxidil is large, the solubility of minoxidil is lowered, and minoxidil cannot be completely dissolved during production, and there is a tendency that a clear external liquid preparation cannot be obtained.

When the content of absolute ethanol is less than 30% by weight with respect to the total amount of the composition, from the viewpoint of the glycerin content ratio, the glycerin content capable of dissolving a large amount of minoxidil decreases, so that minoxidil can be completely dissolved. There is an internal tendency.
When the content of absolute ethanol exceeds 60% by weight with respect to the total amount of the composition, when the external preparation is applied to the human skin, the amount of evaporation and the rate of evaporation of absolute ethanol increase, resulting in discomfort due to the smell of ethanol. In addition, the dissolved minoxidil crystals are precipitated and the amount of minoxidil penetrating into the skin is reduced, leading to a reduction in effects such as hair growth.

In the external preparation having a clear state in which minoxidil is uniformly dissolved and mixed in the glycerin mixed solution, the water content is in the range of 10 to 40% by weight with respect to the total amount of the composition, External preparations that are in the range of 0.1 to 0.9 times the total amount of glycerin and absolute ethanol by weight are desirable. More desirably, the water content is in the range of 15 to 35% by weight with respect to the total amount of the composition, and is 0.2 to 0.8 times the total amount of glycerin and absolute ethanol by weight. A liquid preparation for external use that falls within the range is particularly desirable.
With this configuration, “(Effective E) 0.3 to 8% by weight of minoxidil can be efficiently and easily dissolved to obtain a minoxidil solution having a clear state”, and further, “(Effect A) 12 to 30 Even in liquid formulations containing weight percent glycerin, no white turbidity or solid precipitation of minoxidil or crystal precipitation during low-temperature storage is observed '' and it has a clear state with excellent storage stability and good productivity. The effect that the liquid for external use which it has is obtained is acquired.

As described above, glycerin has a high viscosity of 945 cP (25 ° C.), and no known data on the solubility of minoxidil can be found. According to the inventors' experiment, 100 g of glycerin is at least 5 g. It has the property of dissolving the above minoxidil. Further, absolute ethanol has a relatively low viscosity, has a property of dissolving about 29 mg / ml (2.9 g / 100 cc) of minoxidil, and has a property of being relatively easily evaporated. On the other hand, water has the property of dissolving about 2.2 mg / ml (0.22 g / 100 cc) of minoxidil according to known materials. In other words, glycerin and anhydrous ethanol can dissolve minoxidil relatively well. Especially, a mixture of glycerin with high viscosity and anhydrous ethanol with low viscosity dissolves minoxidil by reducing the viscosity of glycerin. At the time of work, it has a property that it can be easily dissolved in a short time without heating, whereas water has a property that can slightly dissolve minoxidil.
When the water content is less than 0.1 times the total amount of glycerin and absolute ethanol by weight, when applied to human skin, the glycerin having a high boiling point and high viscosity due to evaporation of absolute ethanol As a result of the increase in the remaining ratio, inconveniences such as a lot of stickiness and poor usability tend to occur.
When the water content exceeds 0.9 times the total amount of glycerin and absolute ethanol by weight, (a) Minoxidil cannot be completely dissolved during production, and a clear external preparation cannot be obtained. (B) Even when minoxidil can be completely dissolved, minoxidil crystals are precipitated during storage at low temperature. There is a tendency to cause inconveniences such as precipitation (as a result, although not confirmed, it is expected that the content of minoxidil in the solution decreases and the penetration of minoxidil into the skin decreases).

In a solution for external use having a clear state in which minoxidil is uniformly dissolved and mixed in a glycerin mixed solution, the content ratio of water: absolute ethanol in the weight ratio is 1: 1.4 to 1: 3.0 (in other words, 1 to 1.4 or 3.0, or the content of anhydrous ethanol relative to 1 part by weight of water means 1.4 to 3.0 parts by weight) It is desirable to use a mixed solution containing a larger proportion than water. More desirably, in a liquid preparation for external use containing 0.3 to 8% by weight of minoxidil in a mixed solution of absolute ethanol and water, the content ratio of water: anhydrous ethanol is 1: 1.5 to 1: 2. More preferred is a mixed solution having a content ratio in the range of .2 and containing more absolute ethanol than water.
Thereby, “(e) 0.3 to 8% by weight of minoxidil can be efficiently and easily dissolved to obtain a minoxidil solution having a clear state”, and “(i) 12 to 30% by weight of Even in liquid formulations containing glycerin, no white turbidity / solid precipitation of minoxidil or crystal precipitation during low-temperature storage is observed, etc., and a liquid preparation for external use having a clear state with excellent storage stability and good productivity Can be obtained.

As described above, minoxidil has a property of being easily dissolved in anhydrous ethanol with a solubility of 29 mg / ml and hardly soluble in water with a solubility of 2.2 mg / ml (slightly soluble). On the other hand, the boiling point of water is 100 ° C., and the boiling point of absolute ethanol is 78 to 8.1 ° C., which is easier to evaporate than water.
When the content ratio of water: absolute ethanol is less than “1: 1.4” (that is, the absolute ethanol content is less than 1.4 times that of water), (a) Minoxidil cannot be completely dissolved during production. A clear external preparation cannot be obtained, (b) Minoxidil crystals are precipitated even when minoxidil is completely dissolved, and (c) Minoxidil dissolves by evaporation of absolute ethanol when applied to human skin. Minoxidil crystals precipitate as a result of the decrease in the properties (as a result, although not confirmed, it is expected that the content of minoxidil in the solution decreases and the penetration of minoxidil into the skin decreases) The inconvenience tends to occur.
When the water: anhydrous ethanol weight ratio exceeds 1: 3.0 (ie, the absolute ethanol content exceeds 3.0 times water), (d) when applied to the human skin, As a result of the increase in the residual ratio of glycerin having a high boiling point and high viscosity due to evaporation, there is a tendency that inconveniences such as a lot of stickiness and poor usability are generated.

In the external liquid preparation of the present invention having a clear state in which minoxidil is uniformly dissolved and mixed in the glycerin mixed liquid, the total amount of absolute ethanol and water is preferably 60 to 85% by weight. More preferably, in the external preparation containing 0.3 to 8% by weight of minoxidil in a mixed solution of absolute ethanol and water, the total of absolute ethanol and water is more preferably 65 to 80% by weight. E) The viscosity of a mixed solution obtained by mixing anhydrous ethanol and water with glycerin having a high viscosity is lowered, so that minoxidil is easily dissolved, and a clear minoxidil-containing glycerin solution can be easily produced. Further, “(a) Even if the obtained external liquid preparation is stored at a low temperature, an external liquid preparation with excellent storage stability in which crystal precipitation is suppressed” is obtained. Furthermore, effects such as “(b) When an externally applied solution is applied to human skin, a sticky feeling is reduced and an externally applied solution with excellent usability” can be obtained.

When the total of absolute ethanol and water is less than 60% by weight, (a) when a liquid for external use is applied to human skin, a sticky feeling due to glycerin having a high viscosity remains, and the feeling of use tends to decrease.
When the sum of absolute ethanol and water exceeds 85% by weight, (b) the content ratio of glycerin having high minoxidil solubility cannot necessarily be increased. There is a tendency that a clear external preparation cannot be obtained. (C) Even when minoxidil can be completely dissolved, minoxidil crystals are precipitated during low-temperature storage. (D) Minoxidil crystals are precipitated due to evaporation of anhydrous ethanol when applied to human skin, resulting in precipitation of minoxidil crystals. Tend to.

(E) Description of Eucalyptus Oil According to the description of the 15th revision of the Japanese Pharmacopoeia, eucalyptus oil is colorless to slightly yellow, has a unique aroma, is a neutral liquid, and is diluted with diluted ethanol. Mix thoroughly. Moreover, as explained in the above-mentioned [Background Art] column, it is generally known that an external liquid preparation containing eucalyptus oil has effects such as hair growth. Further, according to preliminary experiments, eucalyptus oil is hardly soluble in water and has a property of separating from water.
In the external preparation having a clear state in which minoxidil is uniformly dissolved and mixed in the glycerin mixed liquid of the present invention, (E) an external liquid containing eucalyptus oil is desirable. Desirably, a topical solution containing 0.001 to 1% by weight of eucalyptus oil is desirable, and particularly desirably 0.01 to 0.1% by weight of eucalyptus oil, based on the total amount of the composition of the topical solution for external use. It is further desirable to use an external liquid.
In the liquid preparation for external use having a clear state in which minoxidil is uniformly dissolved and mixed in a liquid mixture of glycerin, ethanol and water according to the present invention, the eucalyptus oil is not separated even in the liquid preparation containing eucalyptus oil. A clear liquid uniformly mixed is obtained.
In the external preparation containing eucalyptus oil in addition to minoxidil, an effect of “(Effect 1) When applying the external preparation onto the human body, it emits a unique aroma and improves the feeling of use” is obtained. Moreover, although it is not confirmed in the experiment by the inventor, as is apparent from the above-mentioned publicly known literature, an externally applied liquid containing about 0.001 to about 1% by weight of eucalyptus oil can exhibit effects such as hair growth. It is known, and in addition to the effect of hair growth by minoxidil, it is expected to exhibit the effect of hair growth by eucalyptus oil. Further, it is presumed that the hair restoration effect of the minoxidil-containing external preparation is not reduced by containing an appropriate amount of eucalyptus oil in combination. In addition, in a liquid for external use having a clear state in which minoxidil is uniformly dissolved and mixed in a liquid mixture of glycerin, even in a liquid for external use to which about 0.001 to 1% by weight of eucalyptus oil is added, crystals at low temperature storage No precipitation is observed.

When the content of eucalyptus oil is less than 0.001% by weight, the above-mentioned effect of "dispersing a specific aroma when applied to the human body to improve the feeling of use" cannot be obtained sufficiently. The effect tends to decrease.
When the content of eucalyptus oil exceeds 1% by weight, the strength of the unique fragrance caused by eucalyptus oil is remarkably increased when an external solution is applied to the human body, and some users may feel uncomfortable. There is a tendency to cause harmful effects.

(F) Description of l-menthol According to the description of the 15th revision Japanese Pharmacopoeia described above, l-menthol is a colorless crystal, very easily soluble in ethanol, hardly soluble in water, and gradually sublimates at room temperature. Has properties.
In the external liquid preparation having a clear state in which minoxidil is uniformly dissolved and mixed in the glycerin mixed liquid of the present invention, an external liquid containing (F) 1-menthol is further desirable. Desirably, a topical solution containing 0.001 to 1% by weight of 1-menthol based on the total amount of the composition of the topical solution is desirable, and particularly desirably 0.01 to 0.1% by weight of l-menthol. It is further desirable to use a liquid preparation for external use.
Thereby, the effect of improving the feeling of use such as a refreshing feeling and a refreshing feeling when the externally applied liquid preparation is applied to the human body is obtained. In addition, in a solution for external use having a clear state that is uniformly dissolved and mixed in a glycerin mixed solution, l-menthol is easily mixed with glycerin when 0.001 to 1% by weight of l-menthol is added and mixed. A solution for external use having a clear state can be obtained by completely dissolving in the solution. In addition, even in an external liquid preparation to which about 0.001 to 1% by weight of l-menthol is added, crystal precipitation during low-temperature storage is not observed.

When the content of l-menthol is less than 0.001% by weight, the above-mentioned effect of “improving feeling of use such as refreshing feeling and refreshing feeling when applied to the human body” cannot be obtained sufficiently. The effect tends to decrease.
When the content of l-menthol exceeds 1% by weight, there is a tendency to strongly feel irritation to the skin due to l-menthol when the liquid for external use is applied to the human body. On the contrary, it may cause adverse effects such as feeling uncomfortable. Moreover, when there is too much content of 1-menthol, l-menthol does not melt | dissolve at the time of manufacture of an external solution, and a clear external solution may not be obtained.

(G) Description of anti-discoloring agent In a liquid preparation for external use having a clear state in which minoxidil is uniformly dissolved and mixed in a liquid mixture of glycerin, when the liquid preparation for external use is stored for a long time, the liquid preparation for external use is yellow to brown There is a tendency to discolor. It is conceivable that the cause of discoloration is due to some degradation of dissolved minoxidil.
In the external liquid preparation having a clear state in which minoxidil is uniformly dissolved and mixed in the glycerin mixed liquid agent of the present invention, (G) an external liquid solution containing a discoloration inhibitor is further desirable. The discoloration inhibitor is preferably at least one selected from the group consisting of dibutylhydroxytoluene, benzotriazole, gluconolactone, thymol, polyoxyethylene hydrogenated castor oil, and polysorbate.
The content of the discoloration preventing agent varies depending on the type of the discoloration preventing agent, but is preferably 0.05 to 2.0% by weight, more preferably 0.1 to 1.0% by weight based on the total amount of the composition. %. When the content of the discoloration inhibitor is less than 0.05% by weight, the effect of suppressing discoloration / discoloration of the external liquid solution tends to decrease. When the content of the discoloration inhibitor exceeds 2.0% by weight, depending on the type of the discoloration inhibitor used, crystals may precipitate during low-temperature storage, or adverse side effects may occur on the human body. Therefore, it is desirable to set the content of the discoloration preventing agent to the minimum content that can exhibit the discoloration preventing effect.

As the discoloration inhibitor, dibutylhydroxytoluene is particularly desirable. In the glycerin mixed solution containing 0.3 to 8% by weight of minoxidil, the content of dibutylhydroxytoluene is desirably 0.05 to 2.0% by weight with respect to the total amount of the composition, 1.0% by weight is particularly desirable.
According to the description of the aforementioned cosmetic raw material dictionary, dibutylhydroxytoluene is an odorless colorless crystal or white crystalline powder having a melting point of about 70 ° C., is insoluble in water and glycerin, and is soluble in ethanol at a ratio of about 25%. And is widely used as an antioxidant in cosmetics.
When the dibutylhydroxytoluene content is less than 0.05% by weight, the effect of suppressing discoloration / discoloration of the external solution tends to decrease. When the dibutylhydroxytoluene content exceeds 2.0% by weight, in order to maintain the discoloration preventing effect even when the content increases, the minimum amount capable of exhibiting the discoloration preventing effect is desirable from the viewpoint of side effects.

(H) Description of pH regulator In general, the pH of human skin (skin, skin membrane) is weakly acidic from about 4.5 to about 6.5, and the pH of healthy skin is about 5.5. In addition, it is said that the human skin is naturally provided with a self-purifying action that can naturally maintain weak acidity. For example, even when the skin is washed with a weak alkaline soap having a pH of about 9.5 to 10.5, it is said that the skin function returns to weak acidity in about 10 minutes to about 3 hours due to normal functioning of the skin. ing.
In general, soap that cleans the skin is generally weakly alkaline, and it is a weakly alkaline detergent that temporarily softens the skin and gives it elasticity. It is said that it also has the effect of dropping. Acidic cosmetics are said to have an action of tightening skin and an action of suppressing secretion of sweat and sebum, and an action of returning weakly alkaline skin to normal weakly acidic skin.

Taking these into consideration, the external liquid preparation having a clear state in which the minoxidil of the present invention is uniformly dissolved and mixed in the glycerin mixed liquid, further contains (H) a pH adjuster, and has a pH of 7. An external solution in the range of 1 to 8.1 is desirable, and an external solution in which the pH is in the range of 7.3 to 8.0 is particularly desirable.
In such an external liquid preparation having a pH in the range of 7.1 to 8.1, about 0.3 to 8% by weight of minoxidil as the above-mentioned “(Effect I) at least an active ingredient such as hair growth is uniformly dissolved. It is a mixed clear external preparation that maintains the effect of having no performance of crystal precipitation and excellent storage stability even when stored in a low-temperature atmosphere for a long period of time. Furthermore, in an external solution containing an additive for adding discoloration, it has excellent storage stability such as “(Effect C) Suppression of crystal precipitation and discoloration over time in a relatively warm atmosphere of about 50 ° C.”. The effect of obtaining a liquid preparation for external use containing high-concentration minoxidil having excellent commercial value with excellent performance ”is maintained.
Further, it has been found that by containing citric acid, an unexpected effect of suppressing discoloration deterioration when the minoxidil-containing external preparation is stored at 50 ° C. for 1 month is also achieved.

When the pH is less than 7.1, it is considered to have an advantage that the skin is gentle to the human skin because it is close to the human skin. However, since the effect of softening the skin is inferior, the active ingredient of minoxidil It is conceivable that the effect of penetrating the hair into the hair papilla inside the skin is reduced, and therefore the effect of promoting the action of hair growth and the like tends to be reduced. Moreover, when pH exceeds 9.0, the tendency for the disadvantages, such as damaging a human body skin, to arise is conceived. In addition, when an external preparation having a pH in the range of 7.1 to 8.1 is applied to human skin, the skin becomes temporarily soft and the active ingredient of minoxidil penetrates into the skin, but within a few hours thereafter Furthermore, since the pH of the skin naturally returns to around a weakly acidic pH of 5.5, it is conceivable that the human skin is not affected by side effects or the like.
Accordingly, in the present invention, attention is paid to the development of a minoxidil-containing liquid agent having a pH in the range of 7.1 to 8.1. In this pH range, crystal precipitation in low-temperature storage is suppressed, and in long-term storage. In addition, various experiments were conducted in order to obtain a liquid for external use in which discoloration is suppressed.

The pH adjusting agent that adjusts the pH to 7.1 to 8.1 is selected from the group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide. At least one of these is desirable.
In particular, the pH adjuster is preferably 0.005 to 2.0% by weight of citric acid, particularly preferably 0.001 to 1.0% by weight of citric acid, based on the total amount of the composition. According to the description of the 15th revision Japanese Pharmacopoeia described above, citric acid is a colorless crystal or crystalline powder, and is very soluble in water and easily soluble in ethanol. Therefore, even when added to an external liquid preparation having a clear state in which minoxidil is uniformly dissolved and mixed in the glycerin mixed liquid of the present invention, it is easily dissolved in the glycerin mixed liquid and becomes a clear external liquid. Can be prepared. The above-mentioned “(effect i) crystal precipitation inhibiting effect” is also maintained in the external liquid preparation containing citric acid. Moreover, the above-mentioned “(Effect C) Crystal precipitation suppression effect and discoloration suppression effect” is maintained even in an externally applied liquid preparation further containing a discoloration preventing agent.

The method for producing a clear external liquid preparation of the present invention includes (a) a step of preparing minoxidil, glycerin, absolute ethanol, and water, respectively, (b) mixing the glycerin and the absolute ethanol, Thereby, a step of preparing a mixed solution uniformly mixed without separation, and (c) adding and dissolving solid minoxidil to the mixed solution, thereby obtaining a clear solution in which minoxidil is dissolved. Preparing, whereby, based on the total amount of the composition, at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, and 30 to 60% by weight of absolute ethanol, And a clear minoxidil-containing solution in which the minoxidil is dissolved, and has a clear state in which crystal precipitation during storage is suppressed.
By mixing glycerin and absolute ethanol in the above-described mixing ratio at about 15 to 35 ° C. at room temperature without heating, a clear glycerin mixed solution uniformly mixed without being separated from each other can be obtained. Next, 0.3 to 8% by weight of solid minoxidil is added to the obtained glycerin mixed solution and mixed to obtain a clear minoxidil-containing solution in which minoxidil is dissolved. In this case, it is desirable that the solid minoxidil is easy to dissolve the powder minoxidil. In this way, a clear external liquid preparation is prepared.

With this configuration, “(Effective E) 0.3 to 8% by weight of minoxidil can be efficiently and easily dissolved to obtain a minoxidil solution having a clear state”, and further, “(Effect A) 12 to 30 Even in liquid formulations containing weight percent glycerin, no white turbidity or solid precipitation of minoxidil or crystal precipitation during low-temperature storage is observed '' and it has a clear state with excellent storage stability and good productivity. The effect that the liquid for external use which it has is obtained is acquired.
As described above, glycerin has a high viscosity of 945 cP (25 ° C.), and 100 g of glycerol heated to about 60 ° C. has a property of dissolving at least 5 g of minoxidil (inventors and others). By experiment). On the other hand, in general, glycerin has a high viscosity and therefore requires a long stirring time to dissolve minoxidil at a temperature near room temperature. In addition, absolute ethanol has a relatively low viscosity and has a property of dissolving about 29 mg / ml (2.9 g / 100 cc) of minoxidil. In other words, glycerin and absolute ethanol can dissolve minoxidil relatively well. It has the property that it can be easily dissolved during heating in a short time without heating.

  In the method for producing an external liquid preparation of the present invention, desirably, in the step (b), (b-1) further containing the water, mixing the glycerin, the absolute ethanol, and the water, A step of preparing a mixed solution uniformly mixed without separation, and in the step (c), in the step (c-1), the liquid mixture of the glycerin, the absolute ethanol, and the water is solid. Adding and dissolving the form of minoxidil, thereby preparing a clear solution in which the minoxidil is dissolved, whereby at least 0.3-8% by weight relative to the total amount of the composition A clear minoxidil containing minoxidil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, and 10-40 wt% water, wherein the minoxidil is dissolved Comprising a closed liquid is configured to have a clear state crystallization during storage is suppressed.

  As described above, minoxidil has a property of being easily dissolved in anhydrous ethanol with a solubility of 29 mg / ml and hardly soluble in water with a solubility of 2.2 mg / ml (slightly soluble). On the other hand, the boiling point of water is 100 ° C., and the boiling point of absolute ethanol is 78 to 79 ° C., which is easier to evaporate than water. Therefore, according to the above configuration, “(Effect) 0.3 to 8% by weight of minoxidil can be efficiently and easily dissolved to obtain a minoxidil solution having a clear state”, and “(Effect (B) Even in a liquid preparation containing 12 to 30% by weight of glycerin, it has a clear state excellent in storage stability such as “no cloudiness / solid precipitation of minoxidil or crystal precipitation during low-temperature storage”. By suppressing the flammability of absolute ethanol which is easily flammable by evaporation, an effect that can be produced safely and satisfactorily is obtained.

In the production method of the present invention, “in addition to the steps (a), (b), and (c), (d) a solution obtained by dissolving the minoxidil in a mixed solution of the glycerin and the absolute ethanol” In addition, a method for producing a solution for external use, which includes the step of adding and mixing the water to prepare a clear solution uniformly mixed without separation is desirable.
As described above, minoxidil has a property of being slightly soluble in water with a solubility of 2.2 mg / ml (slightly soluble), however, 12-30% by weight of glycerin having 0.3-8% by weight of minoxidil dissolved therein. A clear solution in which 10 to 40% by weight of water is added to and mixed with 30 to 60% by weight of absolute ethanol, and no reprecipitation of minoxidil is observed, and the mixture is uniformly mixed without separation Is obtained.

In the production method of the present invention, “in addition to (b) or (b-1) or (d) step, (c) step, (e) eucalyptus oil is added and mixed; Preparing a uniformly mixed clear solution without separation, whereby at least 0.3-8% by weight minoxidil, 12-30% by weight glycerin, and 30-60% by weight anhydrous A clear minoxidil-containing solution containing ethanol, 10 to 40% by weight of water, and 0.001 to 1% by weight of eucalyptus oil, in which the minoxidil is dissolved, and crystal precipitation during storage is suppressed. A “method for producing a liquid preparation for external use having a clear state” is desirable.
As a step of adding eucalyptus oil, (b) a step of adding eucalyptus oil to a mixed solution in which the glycerin and the absolute ethanol are mixed and mixed uniformly without separation, or (b-1) the glycerin and the above A step of adding eucalyptus oil to a mixed solution obtained by mixing absolute ethanol and water and mixing uniformly without separation; or (c) adding and dissolving solid minoxidil in a mixed solution of glycerin and absolute ethanol. Adding eucalyptus oil to a clear solution in which minoxidil is dissolved, or (c-1) adding and dissolving solid minoxidil in a mixed solution of glycerin, absolute ethanol and water to dissolve minoxidil Any method of adding eucalyptus oil to the clear liquid obtained can be carried out.
Thereby, eucalyptus oil is completely melt | dissolved in a liquid mixture, without isolate | separating, and a clear liquid agent is obtained. In addition, a liquid for external use having a clear state in which crystal precipitation is suppressed even during storage can be obtained.

In the production method of the present invention, in addition to (b), (b-1), (d) step, (c) step, or (e), (f) 1-menthol And mixing to prepare a uniformly mixed clear solution without separation, whereby at least 0.3 to 8 wt% minoxidil and 12 to 30 wt% glycerin and 30 to 60% by weight absolute ethanol, 10 to 40% by weight water, and 0.001 to 1% by weight l-menthol, and a clear minoxidil-containing solution in which the minoxidil is dissolved. The method for producing a liquid preparation for external use having a clear state in which crystal precipitation during storage is suppressed is desirable.
l-Menthol is a colorless crystal and is very easily soluble in ethanol and hardly soluble in water. However, in this step, a liquid preparation in which l-menthol is completely dissolved is obtained. In addition, a liquid preparation for external use having a clear state in which crystal precipitation of l-menthol or minoxidil is suppressed during storage can also be obtained.

  In the production method of the present invention, “in addition to (b), (b-1), (d) step, (c) step, (e) step, or (f) step, (G) dibutylhydroxytoluene, nicotinamide, sodium bisulfite, sodium sulfite, sodium pyrosulfite, benzotriazole, tetrasodium edetate, gluconolactone, sodium thiosulfate, thymol, and polyoxyethylene hydrogenated castor oil, And adding at least one anti-discoloring agent selected from the group consisting of polysorbates and mixing to prepare a uniformly mixed clear solution without separation, whereby at least 0.3 to 8 wt% minoxidil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 10-4 % By weight of water, containing, and 0.05 to 2.0 wt% of anti-tarnish agents, the production method of the liquid for external use with a clear minoxidil-containing liquid preparation wherein the minoxidil is dissolved "is desirable. Of these discoloration inhibitors, dibutylhydroxytoluene is particularly desirable. Thereby, the liquid for external use which has the clear state where the crystal precipitation at the time of storage was suppressed and discoloration was suppressed can be prepared.

In the production method of the present invention, “in addition to (b), (b-1), (d) step, (c) step, or (e) step, (fg) said anhydrous Ethanol, dibutylhydroxytoluene, nicotinamide, sodium bisulfite, sodium sulfite, sodium pyrosulfite, benzotriazole, tetrasodium edetate, gluconolactone, sodium thiosulfate, thymol, and polyoxyethylene hydrogenated castor oil, and At least one discoloration inhibitor selected from the group consisting of polysorbate and l-menthol are added and mixed to prepare a discoloration inhibitor / menthol-containing ethanol solution, and the discoloration inhibitor / menthol-containing ethanol solution is added. Mixing and preparing a uniformly mixed clear solution without separation. Thereby, at least 0.3-8 wt% minoxidil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 10-40 wt% water, 0.001-1 wt% % Of 1-menthol and 0.05 to 2.0% by weight of an anti-discoloring agent, and a method for producing an externally applied solution comprising a clear minoxidil-containing solution in which the minoxidil is dissolved is desirable. Of these discoloration inhibitors, dibutylhydroxytoluene is particularly desirable.
Thereby, it is possible to prepare a liquid for external use having a clear state in which crystal precipitation during storage is suppressed and discoloration with time is suppressed.

  In the production method of the present invention, “the (b), the (b-1), the (d) step, the (c) step, the (e) step, the (f) step, the (g) step, Or, in addition to the step (fg), (h) selected from the group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide. Adding at least one pH adjusting agent and mixing to adjust the pH to 7.1-8.1 to prepare a homogeneously mixed clear solution without separation, thereby comprising at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, 10 to 40% by weight of water, and a pH regulator, Clear minoxidil-containing solution in which minoxidil is dissolved Method of manufacturing a liquid for external use "provided is preferable. Of these pH regulators, citric acid is particularly desirable. Thereby, it has pH 7.1-8.1, and can prepare the liquid for external use which has the clear state where the crystal deposition at the time of storage was suppressed and the discoloration with time was suppressed.

In the production method of the present invention, “the (b), the (b-1), the (d) step, the (c) step, the (e) step, the (f) step, the (g) step, Alternatively, in addition to the step (fg), (h) a group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide in water At least one pH adjusting agent selected from the above is added and mixed to prepare a pH adjusting agent-containing aqueous solution, and the pH adjusting agent-containing aqueous solution is added and mixed to adjust the pH to 7.1 to 8.1. Preparing a clear solution uniformly mixed without separation, whereby at least 0.3-8% by weight minoxidil, 12-30% by weight glycerin, and 30-60% by weight Absolute ethanol, 10-40% by weight water, pH adjustment Agent and contains a method for producing a liquid for external use with a clear minoxidil-containing liquid preparation wherein the minoxidil is dissolved "is desirable. Of these pH regulators, citric acid is particularly desirable. Thereby, it has pH 7.1-8.1, and can prepare the liquid for external use which has the clear state where the crystal deposition at the time of storage was suppressed and the discoloration with time was suppressed.
As described above, even in an external liquid preparation whose pH is adjusted to 7.1 to 8.1, “(Effect) 0.3 to 8% by weight of minoxidil is easily dissolved efficiently and has a clear state. In addition, “(Effect I) Even in a liquid preparation containing 12 to 30% by weight of glycerin, no cloudiness or solid precipitation of minoxidil or crystal precipitation during low-temperature storage is not observed” Thus, an external liquid preparation having a clear state excellent in storage stability and good productivity can be obtained.

In the method for producing an external liquid preparation of the present invention, preferably, (a) a step of preparing minoxidil, glycerin, absolute ethanol, and water, respectively, (b) the glycerin, the absolute ethanol, and the water are prepared. (E) adding eucalyptus oil to the mixed solvent / solution, mixing and mixing, and mixing the mixture to obtain a clear mixture uniformly mixed without separation A step of preparing a liquid preparation, (c) adding and dissolving solid minoxidil in the mixed solvent / solution, and thereby preparing a solution in which minoxidil is dissolved, and (f) adding l-menthol. A step of preparing a clear solution uniformly mixed without separation, and (g) a clear solution uniformly mixed without separation by adding and mixing dibutylhydroxytoluene And (h) adding citric acid and mixing to adjust the pH to 7.1-8.1 to prepare a homogeneously mixed clear solution without separation, comprising 0.3 to 8% by weight of minoxidil, 0.001 to 1% by weight of eucalyptus oil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and 10 to 40% by weight of Contains water, 0.001-1 wt% l-menthol, 0.05-2.0 wt% dibutylhydroxytoluene, 0.005-2 wt% citric acid, and has a pH of 7 A manufacturing method that is adjusted to .1 to 8.1 is desirable.
As a result, “(effect e) 0.3 to 8 wt% of minoxidil can be dissolved efficiently and easily to obtain a minoxidil solution having a clear state” and “(effect i) 12 to 30 wt. Even in a liquid preparation containing 1% glycerin, no cloudiness / solid precipitation of minoxidil or crystal precipitation during low-temperature storage is observed, etc., and it has a clear state with excellent storage stability and good productivity. A liquid for external use is obtained.

  In the method for producing an external liquid preparation of the present invention, preferably, (a) a step of preparing minoxidil, glycerin, absolute ethanol, and water, respectively, (b) the glycerin, the absolute ethanol, and the water are prepared. (E) adding eucalyptus oil to the mixed solvent / solution, mixing and mixing, and mixing the mixture to obtain a clear mixture uniformly mixed without separation (Fg) Dibutylhydroxytoluene and l-menthol are added to and mixed with the absolute ethanol to prepare a discoloration inhibitor / menthol-containing ethanol solution, and then the discoloration inhibitor / menthol is contained. A step of mixing an ethanol solution with the mixed solvent / solution to prepare a clear solution uniformly mixed without separation; and (c) the step (fg). (H) a step of preparing a clear solution in which minoxidil is dissolved by adding and dissolving solid minoxidil in the mixed solvent / solution, and (h) citric acid. Dissolving in water to prepare a citric acid aqueous solution, and then adding the citric acid aqueous solution to the liquid preparation prepared in the step (c) and mixing to prepare a clear liquid preparation. 0.3 to 8% by weight of minoxidil, 0.001 to 1% by weight of eucalyptus oil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and 10 to 40% by weight of Contains water, 0.001-1 wt% l-menthol, 0.05-2.0 wt% dibutylhydroxytoluene, 0.005-2 wt% citric acid, and has a pH of 7 Adjusted from 1 to 8.1 Production method is desirable. As a result, “(effect e) 0.3 to 8 wt% of minoxidil can be dissolved efficiently and easily to obtain a minoxidil solution having a clear state” and “(effect i) 12 to 30 wt. Even in a liquid preparation containing 1% glycerin, no cloudiness / solid precipitation of minoxidil or crystal precipitation during low-temperature storage is observed, etc., and it has a clear state with excellent storage stability and good productivity. A liquid for external use is obtained.

  In the method for producing an external liquid preparation of the present invention, preferably, (a) a step of preparing minoxidil, glycerin, absolute ethanol and water, and (b) mixing the glycerin, the absolute ethanol and the water, respectively. , Thereby, a step of preparing a mixed solvent / solution uniformly mixed without separation, (e) a clear solution in which eucalyptus oil is added to the mixed solvent / solution, mixed, and uniformly mixed without separation (Fg) Dibutylhydroxytoluene and l-menthol are added to and mixed with the absolute ethanol to prepare a dibutylhydroxytoluene-menthol-containing ethanol solution, and then the dibutylhydroxytoluene-menthol-containing ethanol solution Is mixed with the mixed solvent / solution to prepare a clear solution that is uniformly mixed without separation. (C) To the clear solution prepared in the step (fg), solid minoxidil is added to and dissolved in the mixed solvent / solution, thereby preparing a clear solution in which minoxidil is dissolved. (H) Dissolving citric acid in water to prepare a citric acid aqueous solution, and then adding the citric acid aqueous solution to the liquid prepared in step (c) and mixing to obtain a clear liquid Preparing 0.3 to 8% by weight of minoxidil, 0.001 to 1% by weight of eucalyptus oil, 12 to 30% by weight of glycerin, and 30 to 60% by weight of anhydrous Ethanol, 10-40 wt% water, 0.001-1 wt% l-menthol, 0.05-2.0 wt% dibutylhydroxytoluene, 0.005-2 wt% citric acid And containing, pH It is adjusted to 7.1 to 8.1, the manufacturing method of the liquid for external use having clear state discoloration is suppressed with crystallization during storage is suppressed is desired. As a result, “(effect e) 0.3 to 8 wt% of minoxidil can be dissolved efficiently and easily to obtain a minoxidil solution having a clear state” and “(effect i) 12 to 30 wt. Even in a liquid preparation containing 1% glycerin, no cloudiness / solid precipitation of minoxidil or crystal precipitation during low-temperature storage is observed, etc., and it has a clear state with excellent storage stability and good productivity. A liquid for external use is obtained.

In the method for producing an external liquid preparation of the present invention, desirably, “a method for producing an external liquid preparation to be prepared at a temperature of about 15 ° C. to about 35 ° C. in the temperature of the glycerin, the absolute ethanol and the water” is desirable.
Thereby, while being a clear liquid agent by which the solid component was melt | dissolved in the liquid component, deterioration and evaporation of a contained component are prevented and an external solution can be prepared.
If these temperatures are less than about 15 ° C., the solid component tends to be completely insoluble in the liquid component, and if it exceeds about 35 ° C., the proportion of the component due to the evaporation of ethanol during the production process There is a tendency for fluctuations to occur, or for the thermal degradation of minoxidil and discoloration of the liquid agent to occur.
In the method for producing an external liquid preparation of the present invention, desirably, “the production contacting with the minoxidil, the eucalyptus oil, the glycerin, the anhydrous ethanol, the water, the l-menthol, the dibutylhydroxytoluene, and the citric acid” The member is preferably a “method for producing an external-use liquid preparation prepared using a resin-made or ceramic-made production member that does not contain a metal”.
In general, minoxidil dissolved in a solution tends to change color due to some chemical reaction with metal ions. It is desirable to use a resin or ceramic production container or a stirring member that does not release metal ions even in the liquid agent, thereby preventing degradation of minoxidil or discoloration of the liquid agent.

  In addition, in the above-described external liquid preparation and external liquid preparation method, a configuration in which the polyhydric alcohol is glycerin and no polyhydric alcohol other than the glycerin is contained is particularly desirable.

Hereinafter, typical examples of the external preparation and the method for producing the external preparation of the present invention will be described.
(Typical Example 1)
(A) A predetermined amount of minoxidil, glycerin as a polyhydric alcohol, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxytoluene, and citric acid are prepared.
Next, at a room temperature of about 25 ° C., (bc) a predetermined amount of glycerin and absolute ethanol are put into a resin container, and the mixture is stirred and mixed, thereby preparing a uniformly mixed solution without separation. . Next, solid minoxidil is added to the liquid mixture of glycerin and absolute ethanol and dissolved to prepare a clear liquid in which minoxidil is dissolved, and then (c) water is added. Then, stirring and mixing are performed, thereby preparing a mixed solution uniformly mixed without separation. Next, (e) Eucalyptus oil is added to and mixed with the obtained mixed solvent / solution to prepare a clear solution that is uniformly mixed without separation.
Separately, in another resin container, (f) l-menthol is added to and mixed with the absolute ethanol to prepare a menthol-containing ethanol solution. Then, the menthol-containing ethanol solution is mixed with the mixed solvent / liquid obtained in the step (e) to prepare a clear liquid uniformly mixed without separation.
Separately, in another resin container, (g) dibutylhydroxytoluene is added to and mixed with the absolute ethanol to prepare a dibutylhydroxytoluene-containing ethanol solution. Then, the dibutylhydroxytoluene-containing ethanol solution is mixed with the mixed solvent / liquid obtained in the step (e) to prepare a clear liquid that is uniformly mixed without separation.
Next, (h) an aqueous citric acid solution in which citric acid is dissolved in water is added to the liquid and mixed to prepare a clear liquid.
In this way, liquid preparations having various components such as minoxidil, glycerin, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxytoluene, and citric acid as shown in Table 1 were prepared. .

About each obtained liquid agent, the solubility and clarity of minoxidil after preparation were observed visually. Furthermore, a sticky feeling when applied to the human head was confirmed by hand feel.
Each obtained solution is put into a 30 mL colorless and transparent glass sample bottle, sealed with a lid, left to stand at room temperature for about 24 to 48 hours, and then placed in a low-temperature refrigerator at about 4 ° C. for 5 hours. It was put for one day and the presence or absence of crystal precipitation at that time (low-temperature crystal precipitation) was visually observed.
Put each of the obtained liquids in a 30 mL colorless and transparent glass sample bottle, seal with a lid, leave in a thermostatic chamber at 50 ° C. for 1 month, and leave at room temperature of about 25 ° C. for 1 month. Then, the degree of color change (temporal color change) of each solution was visually observed, and the result was shown as 0 to 5 color change degree. Color change 0 is colorless, color change 1 is slightly yellow, color change 2 is slightly yellow, color change 3 is slightly yellow, color change 4 is yellow, color change 5 is brown Judged as discoloration.
Based on the following criteria, comprehensive judgment is described in the comprehensive judgment column.
○: A clear solution in which minoxidil is completely dissolved is obtained.
No crystal precipitation is observed after low temperature storage at 4 ° C for 5 days,
Discoloration after long-term storage at 50 ° C for 1 month is 2 or less,
Discoloration after long-term storage at 25 ° C for 1 month is 1 or less,
No stickiness when applied to human skin,
Δ: A clear solution in which minoxidil is completely dissolved is obtained.
No crystal precipitation is observed after low temperature storage at 4 ° C for 5 days,
Discoloration after long-term storage at 50 ° C for 1 month is 2 or less,
Discoloration after long-term storage at 25 ° C for 1 month is 1 or less,
There may be a slight stickiness when applied to human skin,
X: A clear solution in which minoxidil is completely dissolved cannot be obtained, or
A clear solution in which minoxidil is completely dissolved is obtained, but crystal precipitation is observed after low-temperature storage at 4 ° C for 5 days, or
A clear solution in which minoxidil is completely dissolved is obtained, but the color change after long-term storage at 50 ° C for 1 month exceeds 2, or the color change after long-term storage at 25 ° C for 1 month Is less than 1, or
A sticky feeling is observed when applied to human skin,
These results are shown in Table 1. In Table 1, the unit of the amount of the contained component is “g”. Moreover, only content of glycerol is changed, content of other components is the same, and the total amount of each liquid composition is not necessarily 100 g.

In the liquid agents 1-6 of Table 1, content of glycerol differs from each other, and content of other components is the same. When the content of glycerin as the polyhydric alcohol was 0.6 times the content of minoxidil (solution 6), some of the minoxidil could not be dissolved and a clear solution was not obtained. When the content of glycerin was 1.0 times the content of minoxidil (solution 5), all the minoxidil was dissolved and a clear solution was obtained, but crystal precipitation was observed after storage at 4 ° C for 5 days. It was. When the content of glycerin was 8.0 times the content of minoxidil (Liquid 1), there was a slight stickiness when applied to the head of the human body. On the other hand, when the content of glycerin is 2.0 times (solution 4) and 3.0 times (solution 3) of the content of minoxidil, no crystal precipitation is observed after storage at 4 ° C for 5 days, Also, no stickiness was observed when applied to the human head.
In addition, each color of the liquid agents 1 to 5 in which minoxidil is dissolved is colorless and clear immediately after preparation, but the state after storage at 50 ° C. for one month has a color change degree of 2 (slightly yellow), 25 ° C., The state after storage for 1 month had a color change of 1 (very slightly yellow).

(Typical Example 2)
Solution 7 to solution containing a predetermined amount of minoxidil, glycerin as a polyhydric alcohol, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxytoluene, and citric acid by the same method as in Example 1. Twelve respective solutions were prepared.
In Solution 7 to Solution 12, the glycerin content is 15 to 25 g, the total content of glycerin, absolute ethanol, and water is 90.0 g, and the content ratios of these glycerin, absolute ethanol, and water are different. The contents of other components are the same.

With respect to each of the obtained liquid agents, the crystal precipitation property and the temporal discoloration property were observed in the same manner as in Example 1.
These implementation results are shown in Table 2. In Table 2, the unit of the amount of the contained component is “g”. The glycerin content is 15 g, 20 g, or 25 g, and the glycerin content is 3 times (solution 7), 4 times (solutions 8 to 11), 5 times (solution 12) of minoxidil, and glycerin and anhydrous The content ratio of ethanol and water is different, the total amount of glycerin, absolute ethanol and water is the same, and the content of other components is the same.

In solutions 7 to 12 in Table 2, solutions having an absolute ethanol content of less than 30 g and a water content of more than 40 g (solution 11 and solution 12) were incompletely soluble in minoxidil. In the case of other solutions (solutions 7 to 10), no crystal precipitation was observed after storage at 4 ° C. for 5 days, and no sticky feeling was observed when applied to the human head.
In addition, although each color of the liquid agents 7 to 10 in which minoxidil is dissolved is colorless and clear immediately after preparation, the state after storage at 50 ° C. for 1 month is a color change degree of 2 (slightly yellow), 25 ° C., The condition after storage for 1 month had a color change of 1 (very slightly yellow), and no sticky feeling was observed when applied to the human head.
However, when the absolute ethanol content is 67 g (Liquid 7), it feels rough within about 60 seconds when applied to the head of a human body, and this phenomenon makes it easy for crystals to precipitate due to evaporation of absolute ethanol. Therefore, it is presumed that the content of minoxidil dissolved in the liquid is reduced, and the effects such as hair growth are adversely affected.

(Typical Example 3)
Solution 13 to solution containing a predetermined amount of minoxidil, various polyhydric alcohols, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxyl-toluene, and citric acid by the same method as in Example 1. Twenty-four respective solutions were prepared.
In Solution 13 to Solution 24, glycerin, dipropylene glycol, polyethylene glycol 400 or 1,3-butylene glycol is contained as the polyhydric alcohol, and the content of components other than these polyhydric alcohols is the same. Each liquid preparation with different types and contents was prepared.

About each obtained liquid agent, the crystal precipitation property, discoloration with time, etc. were observed like the typical example 1.
These implementation results are shown in Tables 3 and 4. In Tables 3 and 4, the unit of the amount of the contained component is “g”. The total amount of each liquid composition is not necessarily 100 g.

In solutions 13 to 24 in Tables 3 and 4, when the polyhydric alcohol content was twice that of minoxidil (solutions 13, 16, and 19), crystal precipitation was observed after storage at 4 ° C for 5 days. When the polyhydric alcohol content was 8 times that of minoxidil (solutions 15, 18, and 21), a sticky feeling was also observed when applied to the human head. For the other liquids (liquids 14, 17, 20, 22, 23, 24), no crystal precipitation was observed after storage at 4 ° C. for 5 days, and no stickiness was observed when applied to the human head. It was.
In addition, each color of the liquid agents 13 to 24 in which minoxidil is dissolved is colorless and clear immediately after preparation, but the state after storage at 50 ° C. for 1 month has a color change degree of 2 (slightly yellow), 25 ° C., The condition after storage for 1 month had a color change of 1 (very slightly yellow), and no sticky feeling was observed when applied to the human head.

(Typical Example 4)
According to the same method as in Example 1, each of a predetermined amount of each of liquid 25 to liquid 30 containing minoxidil, glycerin, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxyl-toluene, and citric acid. A solution was prepared.
In liquid agent 25 to liquid agent 28, the content of dibutylhydroxytoluene contained as a discoloration preventing agent is different, and the contents of other components are the same. Liquid 29 is a liquid that does not contain eucalyptus oil, and liquid 30 is a liquid that does not contain l-menthol.
About each obtained liquid agent, the crystal precipitation property, discoloration with time, etc. were observed like the typical example 1.
These implementation results are shown in Table 5. In Table 5, the unit of the amount of the contained component is “g”.

  In Table 5, in the case of a solution containing no dibutylhydroxytoluene (solution 25), the color change immediately after preparation is colorless and clear, but the color after storage at 50 ° C. for 1 month is a color change of 3 (slightly yellow) Discolored). About the liquid agent (liquid agent 26-28) containing other dibutylhydroxytoluene, the liquid agent (liquid agent 29) which does not contain eucalyptus oil, and the liquid agent (liquid agent 30) which does not contain menthol, the color immediately after preparation is colorless and clear, 50 The discoloration degree after storage at 1 ° C. for 1 month was discoloration degree 2 (slightly discolored to yellow), and the discoloration degree after storage at 25 ° C. for 1 month was discoloration 1 (very slightly discolored to yellow) . The case where the color after 1 month at 50 ° C. was less than 2 (slightly discolored) and the color after 1 month at 25 ° C. was less than 1 (colored slightly slightly yellow) was evaluated as an acceptable range. That is, it turns out that the liquid agent which contains about 0.1 weight% dibutylhydroxytoluene has the effect which suppresses discoloration with time. Eucalyptus oil and menthol do not affect the degree of discoloration after storage.

(Typical Example 5)
According to the same method as in Example 1, each of liquid agents 31 to 36 containing a predetermined amount of minoxidil, glycerin, absolute ethanol, water, eucalyptus oil, l-menthol, citric acid, and various anti-discoloring agents A liquid was prepared.
In liquid agent 31 to liquid agent 36, the type and content of the discoloration preventing agent are different, and the content of other components is the same.
About each obtained liquid agent, the crystal precipitation property, discoloration with time, etc. were observed like the typical example 1.
These implementation results are shown in Table 6. In Table 6, the unit of the amount of the contained component is “g”.

In Table 6, benzotriazole (Liquid 31), thymol (Liquid 32), polyoxyethylene hydrogenated castor oil (Liquid 33), polysorbate (Liquid 34), gluconolactone (Liquid 35), and polysorbate (Liquid 34) In the contained liquid, the color immediately after preparation is clear and colorless, and the color change after storage at 50 ° C. for 1 month is a color change degree 2 (slightly yellow), and the color change after storage at 25 ° C. for 1 month. The degree of color change was 1 (very slightly discolored to yellow). The case where the color after 1 month at 50 ° C. was less than 2 (slightly discolored) and the color after 1 month at 25 ° C. was less than 1 (colored slightly slightly yellow) was evaluated as an acceptable range. That is, it can be seen that the liquid agents 31 to 35 have the effect of suppressing discoloration over time.
However, the liquid containing sodium thiosulfate (Liquid 36) has a color change of 4 (changed to yellow) after 1 month at 50 ° C., and the color after 1 month at 25 ° C. with a color change of 2 (slightly yellow) Discoloration), a discoloration preventing effect cannot be obtained, and conversely, there is an adverse effect of promoting discoloration, and it cannot be used.

  Furthermore, in addition to the above experiments, the effects of other discoloration inhibitors were tested. A liquid agent having the same content of other components was prepared by changing the type and content of the anti-discoloring agent in the above composition. As a result, for the color after 1 month at 50 ° C., a solution containing 0.30 g of ascorbic acid has a color change degree of 5; a solution containing 0.10 g of tetrasodium edetate has a color change of 4 and 0.30 g of sodium bisulfite. The liquid containing contains a color change of 4, liquid containing 0.20 g of dry sodium sulfite has a color change of 4, and the liquid containing 0.15 g of sodium pyrosulfite has a color change of 4, and the discoloration inhibiting effect of each of these liquids is recognized. I couldn't.

(Typical Example 6)
According to the same method as in the exemplary embodiment 1, each of a predetermined amount of each of solutions 37 to 42 containing minoxidil, glycerin, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxyl-toluene, and citric acid. A solution was prepared.
In liquid agent 37 to liquid agent 42, the content of citric acid contained as a pH adjuster is different, and the content of other components is the same.
About each obtained liquid agent, the crystal precipitation property, discoloration with time, etc. were observed like the typical example 1. Table 7 shows the results of these implementations. In Table 7, the unit of the blending amount of the component is “g”.

In Table 7, the pH of the solution containing no citric acid (solution 37) is 8.5, and the pH decreases as the citric acid content increases and changes to the acidic side. Therefore, the pH of the solution can be adjusted by selecting the citric acid content. Moreover, in the liquid agent (liquid agent 38-42) containing citric acid, the color after one month at 50 ° C. has a color change degree of 2 (slightly changed to yellow), and the color after one month after 25 ° C. is discolored. Degree 1 (very slightly yellow).
On the other hand, in a solution containing no citric acid (solution 37), the color after 1 month at 50 ° C. has a color change degree of 3 (slightly changed to yellow), and the degree of color change is larger than that of a solution containing citric acid. Is required. In other words, it was found that citric acid has an effect of adjusting the pH of the liquid agent and also has an effect of suppressing discoloration of the liquid agent.

(Typical Example 7)
According to the same method as in the exemplary embodiment 1, each of the liquids 43 to 46 containing a predetermined amount of minoxidil, glycerin, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxyl-toluene, and citric acid. A solution was prepared.
In liquid agent 43 to liquid agent 46, the contents of minoxidil and glycerin are different, the contents of the other components are the same, and the total amount of each liquid agent composition is not necessarily 100 g.
About each obtained liquid agent, the crystal precipitation property, discoloration with time, etc. were observed like the typical example 1. Table 8 shows the results of these implementations. In Table 8, the unit of the amount of the contained component is “g”.

  In Table 8, in the liquid preparation (Liquid 43, Liquid 46) in which the content of glycerin is twice the content of minoxidil, the liquid state immediately after preparation is colorless and clear, but crystal precipitation was observed after storage at 4 ° C for 5 days. It was. Moreover, in the liquid agent (liquid agent 45, liquid agent 48) in which the content of glycerin exceeds 30.0 g, there was a sticky feeling when applied to the human body. In other liquids (Liquid 44, Liquid 47), no sticky feeling was observed when applied to the human body, no crystal precipitation was observed after storage at 4 ° C for 5 days, and discoloration over time after storage at 50 ° C and 25 ° C. The degree was also acceptable.

(Typical Example 8)
According to the same method as in Example 1, each of the liquid 49 to liquid 54 containing a predetermined amount of minoxidil, glycerin, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxyl-toluene, and citric acid. A solution was prepared.
In liquid agent 49 to liquid agent 54, the contents of l-menthol and eucalyptus oil are different, the contents of the other components are the same, and the total amount of each liquid composition is not necessarily 100 g.
About each obtained liquid agent, the crystal precipitation property, discoloration with time, etc. were observed like the typical example 1. Table 9 shows the results of these implementations. In Table 9, the unit of the blending amount of the component is “g”.

In Table 9, in all the liquid preparations, the liquid preparation state immediately after preparation was colorless and clear, no stickiness was observed at the time of application to the human body, no crystal precipitation was observed after storage at 4 ° C for 5 days, and 50 ° C and 25 ° C. The degree of temporal discoloration after storage at ° C. was also within an acceptable range.
That is, it can be seen that eucalyptus oil and l-menthol do not affect the crystal precipitation and the color change over time after low-temperature storage.

(Typical Example 9)
According to the same method as in Example 1, each of liquid agents 55 to 60 containing a predetermined amount of minoxidil, glycerin, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxyl-toluene, and a pH regulator. A liquid was prepared.
In Solution 55 to Solution 60, the type and content of the pH adjuster are different, and the content of the other components is the same. Moreover, after adding the aqueous solution of an acid component, sodium hydroxide aqueous solution was added and pH of the liquid agent was adjusted to 7.5.
About each obtained liquid agent, the crystal precipitation property, discoloration with time, etc. were observed like the typical example 1. These implementation results are shown in Table 10. In Table 10, the unit of the amount of the contained component is “g”.

    In Table 10, in all solutions, the solution state immediately after preparation was colorless and clear, no stickiness was observed when applied to the human body, no crystal precipitation was observed after storage at 4 ° C. for 5 days, and 50 ° C. and 25 ° C. The degree of temporal discoloration after storage at ° C. was also within an acceptable range.

(Typical Example 10)
In the same manner as in Example 1, each of the liquid 61 to liquid 72 containing a predetermined amount of minoxidil, glycerin, absolute ethanol, water, eucalyptus oil, l-menthol, dibutylhydroxyl-toluene, and citric acid was used. A solution was prepared.
In liquid 61 to liquid 72, the contents of minoxidil and glycerin are different, the contents of the other components are the same, and the total amount of each liquid composition is not necessarily 100 g.
About each obtained liquid agent, the crystal precipitation property, discoloration with time, etc. were observed like the typical example 1. These implementation results are shown in Tables 11 and 12. In Tables 11 and 12, the unit of the amount of the contained component is “g”.

  In Tables 11 and 12, in the case of a liquid agent (liquid agent 67) having a glycerin content lower than the minoxidil content, minoxidil was not completely dissolved. In the liquid preparations (Liquid 61, Liquid 68) whose glycerin content is less than 2.5 times the minoxidil content, the liquid state immediately after preparation is colorless and clear, but crystal precipitation is observed after storage at 4 ° C for 5 days. It was. In a liquid preparation (Liquid 71) in which the content of glycerin exceeds 30% by weight with respect to the total amount of the composition, there was a sticky feeling when applied to the human body. In the liquid preparation (liquid preparation 72) in which the content of musui ethanol was less than 3040% by weight and the water content was more than 40% by weight, some minoxidil was not dissolved. In other liquids, no sticky feeling was observed when applied to the human body, no crystal precipitation was observed after storage at 4 ° C for 5 days, and the temporal discoloration after storage at 50 ° C and 25 ° C was within the allowable range. It was.

(Typical Example 11)
A liquid preparation for external use was prepared as follows at room temperature of about 25 ° C. In production, a resin container and a resin experimental instrument were used.
(B) About 20 g of glycerin, about 40 g of absolute ethanol, and about 40 water are mixed, thereby preparing a mixed solvent / solution that is uniformly mixed without separation. Next, (e) about 0.05 g of eucalyptus oil is added to the mixed solvent / liquid obtained in the step (b) and mixed to prepare a clear liquid uniformly mixed without separation. Next, (c) about 5 g of solid minoxidil is added to and dissolved in the mixed solvent / solution obtained in (e) above, thereby preparing a clear solution in which minoxidil is dissolved. Next, (f) l-menthol solution prepared by dissolving about 0.05 g of l-menthol in about 3 g of absolute ethanol is added to the mixed solvent / solution obtained in the step (c) and mixed. Prepare a clear solution that is uniformly mixed without separation. Next, (g) a dibutylhydroxytoluene solution prepared by dissolving about 0.05 g of dibutylhydroxytoluene in about 2 g of absolute ethanol is added to the mixed solvent / solution obtained in the step (f) and mixed. Prepare a clear solution that is uniformly mixed without separation. Next, (h) a citric acid solution prepared by dissolving about 0.03 g of citric acid in about 5 g of water is added to the mixed solvent / solution obtained in the step (g) and mixed to obtain a pH of about Adjust to 7.5 to prepare a clear solution that is uniformly mixed without separation. Thus, about 5 g minoxidil, about 0.05 g eucalyptus oil, about 20 g glycerin, about 45 g absolute ethanol, about 25 g water, 0.05 g l-menthol, about 0 g. An external solution containing 0.5 g of dibutylhydroxytoluene and about 0.05 g of citric acid and having a pH adjusted to 7.5 was prepared.

About the obtained external preparation, by the same method as in Example 1, the presence or absence of stickiness when applied to the human head, crystal precipitation at low temperature storage at 4 ° C for 5 days, and 50 ° C for 1 month The color change over time and the color change over time after 1 month at 25 ° C. were observed.
As a result, there was no stickiness when applied to the human head. Crystal precipitation was not observed during low temperature storage at 4 ° C. for 5 days. The color after 50 ° C and 1 month has a color change of 2 (slightly changes to yellow), and the color after 25 ° C and 1 month has a color change of 1 (very slightly yellow) and is within an acceptable range. there were.

(Typical Example 12)
A liquid preparation for external use was prepared as follows at room temperature of about 25 ° C. In production, a resin container and a resin experimental instrument were used.
(B) About 20 g of glycerin, about 40 g of absolute ethanol, and about 40 water are mixed, thereby preparing a mixed solvent / solution that is uniformly mixed without separation. Next, (e) about 0.05 g of eucalyptus oil is added to the mixed solvent / liquid obtained in the step (b) and mixed to prepare a clear liquid uniformly mixed without separation. Separately, (fg) about 0.5 g of dibutylhydroxytoluene and about 0.05 g of l-menthol are added to and mixed with about 5 g of absolute ethanol to prepare a dibutylhydroxytoluene-menthol-containing ethanol solution. Subsequently, the dibutylhydroxytoluene / menthol-containing ethanol solution is mixed with the mixed solvent / liquid agent to prepare a clear liquid agent uniformly mixed without separation. Next, (c) obtained by (fg) above. About 5 g of solid minoxidil is added to and dissolved in the mixed solvent / solution, thereby preparing a clear solution in which minoxidil is dissolved. Next, (h) a citric acid solution prepared by dissolving about 0.03 g of citric acid in about 5 g of water is added to the mixed solvent / solution obtained in the step (g) and mixed to obtain a pH of about Adjust to 7.5 to prepare a clear solution that is uniformly mixed without separation. Thus, about 5 g minoxidil, about 0.05 g eucalyptus oil, about 20 g glycerin, about 45 g absolute ethanol, about 25 g water, 0.05 g l-menthol, about 0 g. An external solution containing 0.5 g of dibutylhydroxytoluene and about 0.05 g of citric acid and having a pH adjusted to 7.5 was prepared.

About the obtained external preparation, by the same method as in Example 1, the presence or absence of stickiness when applied to the human head, crystal precipitation at low temperature storage at 4 ° C for 5 days, and 50 ° C for 1 month The color change over time and the color change over time after 1 month at 25 ° C. were observed.
As a result, there was no stickiness when applied to the human head. Crystal precipitation was not observed during low temperature storage at 4 ° C. for 5 days. The color after 50 ° C and 1 month has a color change of 2 (slightly changes to yellow), and the color after 25 ° C and 1 month has a color change of 1 (very slightly yellow) and is within an acceptable range. there were.

(Typical Example 13)
A liquid preparation for external use was prepared as follows at room temperature of about 25 ° C. In production, a resin container and a resin experimental instrument were used.
(Bc) About 20 g of glycerin and about 40 g of absolute ethanol are mixed, thereby preparing a mixed solvent / solution that is uniformly mixed without separation, and then about 5 g of solid minoxidil is added to the mixed solvent / solution. Add and dissolve, thereby preparing a clear solution in which minoxidil is dissolved. Next, (c) about 25 g of water is added to the glycerol and absolute ethanol solution in which the minoxidil is dissolved, thereby preparing a clear solution. Next, (e) about 0.05 g of eucalyptus oil is added to the mixed solvent / liquid obtained in the step (c) and mixed to prepare a clear liquid uniformly mixed without separation. Next, (fg) 0.5 g of dibutylhydroxytoluene and 0.05 g of l-menthol are added to and mixed with about 5 g of absolute ethanol to prepare a dibutylhydroxytoluene / menthol-containing ethanol solution, A dibutylhydroxytoluene / menthol-containing ethanol solution is mixed with the mixed solvent / solution to prepare a clear solution uniformly mixed without separation. Next, (h) a citric acid solution prepared by dissolving about 0.03 g of citric acid in about 5 g of water is added to the mixed solvent / solution obtained in the step (fg) and mixed to adjust the pH. Adjust to about 7.5 to prepare a clear solution that is uniformly mixed without separation.
Thus, about 5 g minoxidil, about 0.05 g eucalyptus oil, about 20 g glycerin, about 45 g absolute ethanol, about 25 g water, 0.05 g l-menthol, about 0 g. An external solution containing 0.5 g of dibutylhydroxytoluene and about 0.05 g of citric acid and having a pH adjusted to 7.5 was prepared.

About the obtained external preparation, by the same method as in Example 1, the presence or absence of stickiness when applied to the human head, crystal precipitation at low temperature storage at 4 ° C for 5 days, and 50 ° C for 1 month The color change over time and the color change over time after 1 month at 25 ° C. were observed.
As a result, there was no stickiness when applied to the human head. Crystal precipitation was not observed during low temperature storage at 4 ° C. for 5 days. The color after 50 ° C and 1 month has a color change of 2 (slightly changes to yellow), and the color after 25 ° C and 1 month has a color change of 1 (very slightly yellow) and is within an acceptable range. there were.

(Typical Example 14)
In the above-mentioned typical example 11, a liquid preparation for external use containing 1 g of minoxidil was prepared instead of 5 g of minoxidil.
A liquid preparation for external use was prepared as follows at room temperature of about 25 ° C. In production, a resin container and a resin experimental instrument were used.
(B) About 20 g of glycerin, about 40 g of absolute ethanol, and about 40 water are mixed, thereby preparing a mixed solvent / solution that is uniformly mixed without separation. Next, (e) about 0.05 g of eucalyptus oil is added to the mixed solvent / liquid obtained in the step (b) and mixed to prepare a clear liquid uniformly mixed without separation. Next, (c) about 1 g of solid minoxidil is added to and dissolved in the mixed solvent / solution obtained in (e) above, thereby preparing a clear solution in which minoxidil is dissolved. Next, (f) l-menthol solution prepared by dissolving about 0.05 g of l-menthol in about 3 g of absolute ethanol is added to the mixed solvent / solution obtained in the step (c) and mixed. Prepare a clear solution that is uniformly mixed without separation. Next, (g) a dibutylhydroxytoluene solution prepared by dissolving about 0.05 g of dibutylhydroxytoluene in about 2 g of absolute ethanol is added to the mixed solvent / solution obtained in the step (f) and mixed. Prepare a clear solution that is uniformly mixed without separation. Next, (h) a citric acid solution prepared by dissolving about 0.03 g of citric acid in about 5 g of water is added to the mixed solvent / solution obtained in the step (g) and mixed to obtain a pH of about Adjust to 7.5 to prepare a clear solution that is uniformly mixed without separation. Thus, about 1 g minoxidil, about 0.05 g eucalyptus oil, about 20 g glycerin, about 45 g absolute ethanol, about 25 g water, 0.05 g l-menthol, about 0 g. An external solution containing 0.5 g of dibutylhydroxytoluene and about 0.05 g of citric acid and having a pH adjusted to 7.5 was prepared.

About the obtained external preparation, by the same method as in Example 1, the presence or absence of stickiness when applied to the human head, crystal precipitation at low temperature storage at 4 ° C for 5 days, and 50 ° C for 1 month The color change over time and the color change over time after 1 month at 25 ° C. were observed.
As a result, there was no stickiness when applied to the human head. Crystal precipitation was not observed during low temperature storage at 4 ° C. for 5 days. The color after 50 ° C and 1 month has a color change of 2 (slightly changes to yellow), and the color after 25 ° C and 1 month has a color change of 1 (very slightly yellow) and is within an acceptable range. there were.

(Typical Example 15)
In the above-mentioned typical example 12, a liquid preparation for external use containing 1 g of minoxidil was prepared instead of 5 g of minoxidil.

About the obtained external preparation, by the same method as in Example 1, the presence or absence of stickiness when applied to the human head, crystal precipitation at low temperature storage at 4 ° C for 5 days, and 50 ° C for 1 month The color change over time and the color change over time after 1 month at 25 ° C. were observed.
As a result, there was no stickiness when applied to the human head. Crystal precipitation was not observed during low temperature storage at 4 ° C. for 5 days. The color after 50 ° C and 1 month has a color change of 2 (slightly changes to yellow), and the color after 25 ° C and 1 month has a color change of 1 (very slightly yellow) and is within an acceptable range. there were.

(Comparison example 1 of a manufacturing method)
At room temperature of about 25 ° C., about 5 minutes of powdered minoxidil is gradually added to about 20 g of glycerin that is forcibly stirred using a resin container and a resin experimental device, and about 30 minutes. Stir and mix. Even after 30 minutes, the powdery minoxidil was not completely dissolved.

(Comparison example 2 of manufacturing method)
At room temperature of about 25 ° C., using a resin container and a resin experimental apparatus, about 1 g of powdered minoxidil is gradually added to about 20 g of glycerin that is forcibly stirred, and about 30 minutes. Stir and mix. Even after 30 minutes, the powdery minoxidil was not completely dissolved.

(Comparative Example 3 of Manufacturing Method)
About 5 g of minoxidil is gradually added to a mixed solution of about 10 g of glycerin and about 40 g of absolute ethanol with stirring at a room temperature of about 25 ° C. using a resin container and a resin laboratory instrument. After stirring and mixing for about 30 minutes, a colorless and clear solution in which minoxidil was completely dissolved was obtained. About 25 g of water was added to the colorless clear solution with stirring. As a result, a liquid preparation in which a cloudy solid was deposited was obtained.

(Comparative Example 4 of Manufacturing Method)
While stirring about 5 g of minoxidil in a mixed solution of about 10 g of glycerin, about 40 g of absolute ethanol, and about 25 g of water at room temperature of about 25 ° C. using a resin container and a resin experimental instrument. The mixture was gradually added and mixed with stirring for about 30 minutes. Even after 30 minutes, some of the powdered minoxidil was not completely dissolved.

(Comparative Example 3 of Manufacturing Method)
In the above-mentioned typical example 11, a liquid preparation for external use was prepared using a stainless steel container and a stainless steel experimental instrument instead of the resin container and the resin experimental instrument.
The color of the obtained liquid for external use was not colorless, but was in a clear state in which it was slightly colored yellow.

According to the present invention, minoxidil at least as an active ingredient such as hair growth is uniformly dissolved and mixed, and it is a clear external liquid solution, and there is no precipitation of crystals even during storage in a long-term low-temperature atmosphere. An external liquid preparation having performance excellent in storage stability such as suppression of discoloration with time in a relatively warm atmosphere of about 50 ° C. can be obtained. Therefore, in the distribution application to tropical and cold regions and storage in summer and winter, quality deterioration such as discoloration suppression and crystal precipitation is suppressed, and further, when applied to human skin, stickiness is suppressed. Thus, an external liquid preparation containing high-concentration minoxidil having excellent commercial value such as providing a comfortable feeling of use can be obtained.
Moreover, in the external liquid agent which exhibits said effect, the manufacturing method of the external liquid agent which can melt | dissolve minoxidil in a solvent efficiently and can manufacture a clear liquid agent easily is obtained during manufacture, without deteriorating.

Claims (30)

at least,
(A) minoxidil,
(B) at least one polyhydric alcohol selected from the group consisting of glycerin, propylene glycol, dipropylene glycol, 1,3-butylene glycol, and polyethylene glycol;
(C) absolute ethanol;
(D) water,
Containing
The content of the polyhydric alcohol is 2.5 times or more of the minoxidil by weight and contains 10 to 35% by weight with respect to the total amount of the composition.
A liquid preparation for external use characterized by having a clear state in which the minoxidil is uniformly dissolved and crystal precipitation during storage is suppressed. The content of minoxidil is 0.3 to 8% by weight based on the total amount of the composition,
The polyhydric alcohol is glycerin;
The external solution according to claim 1, wherein the content of the glycerin is 12 to 30% by weight based on the total amount of the composition.   The absolute ethanol content is in a range of 30 to 60% by weight with respect to the total amount of the composition, and is in a range of 1 to 4 times the content of the glycerin by weight. Item 3. A liquid preparation for external use according to Item 1 or 2.   The water content is in the range of 10 to 40% by weight with respect to the total amount of the composition, and is 0.1 to 0.9 times the total amount of the glycerin and the absolute ethanol by weight. The external liquid preparation according to any one of claims 1 to 3, wherein the liquid composition is in a range of 10 to 40% by weight with respect to the total amount of the composition.   The liquid for external use according to any one of claims 1 to 4, wherein the polyhydric alcohol is glycerin and does not contain any polyhydric alcohol other than the glycerin.   Furthermore, (E) Eucalyptus oil is contained, The liquid for external use in any one of the Claims 1 thru | or 5 characterized by the above-mentioned.   Furthermore, (E) 0.001-1 weight% of eucalyptus oil is contained with respect to the whole quantity of a composition, The external preparation in any one of the Claims 1 thru | or 5 characterized by the above-mentioned.   Furthermore, (F) 1-menthol is contained, The liquid for external use in any one of the Claims 1 thru | or 7 characterized by the above-mentioned.   Furthermore, (G) the discoloration prevention agent is contained, The external preparation liquid agent in any one of the Claims 1 thru | or 8 characterized by the above-mentioned.   The discoloration inhibitor is at least one selected from the group consisting of dibutylhydroxytoluene, benzotriazole, gluconolactone, thymol, polyoxyethylene hydrogenated castor oil, polysorbate, and citric acid. 9. An external liquid preparation according to 9.   The external liquid preparation according to any one of claims 1 to 10, further comprising (H) a pH adjusting agent and having a pH in the range of 7.1 to 8.1.   The pH regulator is at least one selected from the group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide. The external preparation of Claim 11. further,
(E) Eucalyptus oil,
(F) l-menthol,
(G) dibutylhydroxytoluene as a discoloration inhibitor;
(H) citric acid as a pH regulator;
Containing
6. The external preparation according to any one of claims 1 to 5, which has a clear state in which these components are uniformly dissolved, and both crystal precipitation and discoloration with time are suppressed. .   The liquid for external use according to any one of claims 1 to 13, wherein the pH is adjusted to a range of 7.1 to 8.1. For the total amount of the composition,
(A) 0.3-8% by weight of minoxidil,
(B) 12-30 wt% glycerin,
(C) 30-60% by weight absolute ethanol,
(D) 10 to 40% by weight of water,
(E) 0.001 to 1.0% by weight of eucalyptus oil,
(F) 0.001 to 1.0% by weight of 1-menthol,
(G) 0.05 to 2.0% by weight of dibutylhydroxytoluene, and
(H) 0.005 to 2.0% by weight of citric acid,
Containing
the pH is in the range of 7.1-8.1,
15. The external preparation according to any one of claims 1 to 14, wherein these components are uniformly dissolved and mixed to suppress both crystallization over time and discoloration over time. (A) a step of preparing minoxidil, glycerin, absolute ethanol, and water,
(B) mixing the glycerin and the absolute ethanol, thereby preparing a uniformly mixed solution without separation; and
(C) adding and dissolving solid minoxidil to the mixed solution of the glycerin and the absolute ethanol, thereby preparing a clear solution in which minoxidil is dissolved;
With
Thereby, it contains at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, and 30 to 60% by weight of absolute ethanol, based on the total amount of the composition,
A clear minoxidil-containing solution in which the minoxidil is dissolved,
The manufacturing method of the external preparation characterized by having a clear state in which the crystal precipitation at the time of storage was suppressed. In the step (b),
(B-1) Furthermore, it is a step containing the water, and the step of mixing the glycerin, the absolute ethanol and the water, thereby preparing a uniformly mixed solution without separation. ,
In the step (c),
(C-1) adding and dissolving solid minoxidil to a mixed solution of the glycerin, the absolute ethanol and the water, thereby preparing a clear solution in which minoxidil is dissolved,
Thereby, at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and 10 to 40% by weight of water based on the total amount of the composition. And containing
A clear minoxidil-containing solution in which the minoxidil is dissolved,
The method for producing an external liquid preparation according to claim 16, which has a clear state in which crystal precipitation during storage is suppressed. further,
(D) adding the water to a solution obtained by dissolving the minoxidil in a mixed solution of the glycerin and the absolute ethanol, mixing, and preparing a clear solution that is uniformly mixed without separation; and
Thereby, at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and 10 to 40% by weight of water based on the total amount of the composition. And containing
A clear minoxidil-containing solution in which the minoxidil is dissolved,
The method for producing an external liquid preparation according to claim 16, which has a clear state in which crystal precipitation during storage is suppressed. further,
(E) adding and mixing eucalyptus oil to prepare a clear solution that is uniformly mixed without separation;
With
Thus, at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and 0.001 to 1% by weight of eucalyptus oil are contained. ,
A clear minoxidil-containing solution in which the minoxidil is dissolved,
The method for producing an external liquid preparation according to any one of claims 16 to 18, which has a clear state in which crystal precipitation during storage is suppressed. further,
(F) adding l-menthol and mixing to prepare a uniformly mixed clear solution without separation,
Thereby, at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and 0.001 to 1% by weight of 1-menthol are contained. And
A clear minoxidil-containing solution in which the minoxidil is dissolved,
The method for producing an external liquid preparation according to any one of claims 16 to 19, which has a clear state in which crystal precipitation during storage is suppressed. further,
(G) dibutylhydroxytoluene, nicotinamide, sodium bisulfite, sodium sulfite, sodium pyrosulfite, benzotriazole, tetrasodium edetate, gluconolactone, sodium thiosulfate, thymol, and polyoxyethylene hydrogenated castor oil, and Adding at least one anti-discoloring agent selected from the group consisting of polysorbates, mixing, and preparing a clear liquid that is uniformly mixed without separation,
Thereby, at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, 0.05 to 2.0% by weight of an anti-discoloring agent, Containing
A clear minoxidil-containing solution in which the minoxidil is dissolved,
The method for producing an external preparation according to any one of claims 16 to 20, which has a clear state in which crystal precipitation during storage is suppressed and discoloration is suppressed. further,
(Fg) dibutylhydroxytoluene, nicotinamide, sodium bisulfite, sodium bisulfite, sodium pyrosulfite, benzotriazole, tetrasodium edetate, gluconolactone, sodium thiosulfate, thymol, and polyoxyethylene At least one discoloration inhibitor selected from the group consisting of hydrogenated castor oil and polysorbate and l-menthol are added and mixed to prepare a discoloration inhibitor / menthol-containing ethanol solution, which contains the discoloration inhibitor / menthol. Adding an ethanol solution and mixing to prepare a uniformly mixed clear solution without separation,
Thus, at least 0.3-8 wt% minoxidil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 0.001-1 wt% l-menthol, 05 to 2.0% by weight of an anti-discoloring agent,
A clear minoxidil-containing solution in which the minoxidil is dissolved,
20. The method for producing an external liquid preparation according to any one of claims 16 to 19, which has a clear state in which crystal precipitation during storage is suppressed and discoloration is suppressed. further,
(H) At least one pH adjuster selected from the group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide is added and mixed. Adjusting the pH to 7.1 to 8.1 to prepare a homogeneous solution that is uniformly mixed without separation,
Thereby, at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, and a pH regulator,
A clear minoxidil-containing solution in which the minoxidil is dissolved,
the pH is adjusted to 7.1-8.1,
The method for producing an external liquid preparation according to any one of claims 16 to 22, wherein the precipitation of crystals during storage is suppressed and the crystal has a clear state. further,
(H) Add and mix at least one pH adjuster selected from the group consisting of citric acid, malic acid, acetic acid, lactic acid, succinic acid, maleic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and sodium hydroxide into water. Then, a pH adjusting agent-containing aqueous solution is prepared, and the pH adjusting agent-containing aqueous solution is added and mixed to adjust the pH to 7.1 to 8.1, thereby preparing a clear liquid that is uniformly mixed without separation. Comprising the steps of:
Thereby, at least 0.3 to 8% by weight of minoxidil, 12 to 30% by weight of glycerin, 30 to 60% by weight of absolute ethanol, water, and a pH adjuster,
A clear minoxidil-containing solution in which the minoxidil is dissolved,
the pH is adjusted to 7.1-8.1,
The method for producing an external liquid preparation according to any one of claims 16 to 22, wherein the precipitation of crystals during storage is suppressed and the crystal has a clear state. (A) a step of preparing minoxidil, glycerin, absolute ethanol, and water,
(B) a step of mixing the glycerin, the absolute ethanol, and the water, thereby preparing a mixed solvent / solution mixed uniformly without separation;
(E) a step of adding a eucalyptus oil to the mixed solvent / liquid obtained in the step (b) and mixing to prepare a clear liquid that is uniformly mixed without separation;
(C) a step of adding a solid minoxidil to the mixed solvent / solution obtained in the step (b) or the step (e) and dissolving it, thereby preparing a clear solution in which the minoxidil is dissolved,
(F) Add 1-menthol solution prepared by dissolving l-menthol in absolute ethanol to the mixed solvent / solution obtained in step (b), step (c) or (e), and mix. A step of preparing a clear liquid uniformly mixed without separation,
(G) A dibutylhydroxytoluene solution obtained by dissolving dibutylhydroxytoluene in absolute ethanol is mixed into the mixed solvent / solution obtained in the step (b), the step (c), the step (e) or the step (f). Adding, mixing, and preparing a uniformly mixed clear solution without separation,
(H) A citric acid solution obtained by dissolving citric acid in water is a mixed solvent obtained by the step (b), the step (c), the step (e), the step (f) or the step (g). Adding to the solution, mixing, adjusting the pH to 7.1-8.1 to prepare a uniformly mixed clear solution without separation,
Thus, 0.3-8 wt% minoxidil, 0.001-1 wt% eucalyptus oil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 10-40 wt% Water, 0.001-1 wt% l-menthol, 0.05-2.0 wt% dibutylhydroxytoluene, and 0.005-2 wt% citric acid,
the pH is adjusted to 7.1-8.1,
It has a clear state in which crystal precipitation during storage is suppressed and discoloration is suppressed,
The manufacturing method of the external preparation of Claim 16 characterized by the above-mentioned. (A) a step of preparing minoxidil, glycerin, absolute ethanol, and water,
(Bc) Mixing the glycerin and the absolute ethanol, thereby preparing a mixed solvent / liquid agent uniformly mixed without separation, and then adding and dissolving solid minoxidil in the mixed solvent / liquid agent, Thereby, a step of preparing a clear solution in which minoxidil is dissolved,
(C) adding the water to the glycerin in which the minoxidil is dissolved and the anhydrous ethanol solution, thereby preparing a clear solution,
(E) adding a eucalyptus oil to the mixed solvent / liquid obtained in the step (bc) or the step (c) and mixing to prepare a clear liquid that is uniformly mixed without separation;
(F) An l-menthol solution prepared by dissolving l-menthol in absolute ethanol is added to the mixed solvent / liquid obtained in the step (bc), the step (c) or the step (e), and mixed. A step of preparing a clear liquid uniformly mixed without separation,
(G) A dibutylhydroxytoluene solution obtained by dissolving dibutylhydroxytoluene in absolute ethanol is mixed into the mixed solvent / solution obtained in the step (bc), the step (c), the step (e) or the step (f). Adding, mixing, and preparing a uniformly mixed clear solution without separation,
(H) A citric acid solution prepared by dissolving citric acid in water is mixed solvent obtained by the step (bc), the step (c), the step (e), the step (f) or the step (g). Adding to the solution, mixing, adjusting the pH to 7.1-8.1 to prepare a uniformly mixed clear solution without separation,
Thus, 0.3-8 wt% minoxidil, 0.001-1 wt% eucalyptus oil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 10-40 wt% Water, 0.001-1 wt% l-menthol, 0.05-2.0 wt% dibutylhydroxytoluene, and 0.005-2 wt% citric acid,
the pH is adjusted to 7.1-8.1,
It has a clear state in which crystal precipitation during storage is suppressed and discoloration is suppressed,
The manufacturing method of the external preparation of Claim 16 characterized by the above-mentioned. (A) a step of preparing minoxidil, glycerin, absolute ethanol, and water,
(B) a step of mixing the glycerin, the absolute ethanol, and the water, thereby preparing a mixed solvent / solution mixed uniformly without separation;
(E) adding eucalyptus oil to the mixed solvent / liquid and mixing to prepare a clear liquid that is uniformly mixed without separation;
(Fg) Dibutylhydroxytoluene and l-menthol were added to the absolute ethanol and mixed to prepare a dibutylhydroxytoluene / menthol-containing ethanol solution,
after that,
A step of mixing the dibutylhydroxytoluene / menthol-containing ethanol solution with the mixed solvent / solution to prepare a clear solution uniformly mixed without separation;
(C) To the clear solution prepared by the step (fg),
Solid minoxidil is added to the mixed solvent / liquid and dissolved,
Thereby, a step of preparing a clear solution in which minoxidil is dissolved,
(H) An aqueous citric acid solution is prepared by dissolving citric acid in water;
Adding the citric acid aqueous solution to the solution prepared in the step (c) and mixing to prepare a clear solution,
Thus, 0.3-8 wt% minoxidil, 0.001-1 wt% eucalyptus oil, 12-30 wt% glycerin, 30-60 wt% absolute ethanol, 10-40 wt% Water, 0.001-1 wt% l-menthol, 0.05-2.0 wt% dibutylhydroxytoluene, and 0.005-2 wt% citric acid,
the pH is adjusted to 7.1-8.1,
The method for producing an external liquid preparation according to claim 16, which has a clear state in which crystal precipitation during storage is suppressed and discoloration is suppressed.   The manufacturing member which contacts the said minoxidil, the said eucalyptus oil, the said glycerin, the said absolute ethanol, the said water, the said l-menthol, the said dibutylhydroxytoluene, and the said citric acid does not contain a metal, or manufacture made from a ceramic It prepares using a member, The manufacturing method of the liquid for external use in any one of Claim 25 thru | or 27 characterized by the above-mentioned.   The method for producing an external liquid preparation according to any one of claims 16 to 28, wherein the preparation is performed in a state where the temperature of the glycerin, the absolute ethanol and the water is in the range of about 15 ° C to about 35 ° C. .   30. The method for producing an external liquid preparation according to any one of claims 16 to 29, wherein a polyhydric alcohol other than the glycerin is not contained.