JP6244101B2 - Minoxidil-containing external composition - Google Patents

Description

  The present invention relates to an external composition containing minoxidil, which is used as a pharmaceutical external preparation, a quasi-drug, or a cosmetic.

Minoxidil (6- (1-piperidinyl) 2,4-pyrimidine-3-oxide) is widely used as an alopecia ameliorating agent because it provides excellent hair growth and nourishing effects for external use.
However, minoxidil has poor solubility in water and ethanol, and crystals tend to precipitate particularly when stored at low temperatures. Moreover, the liquid agent containing minoxidil is colored with time and the commercial value is lowered.

Here, Patent Document 1 proposes blending a large amount of polyhydric alcohol in order to improve the solubility of minoxidil, but when blending a large amount of polyhydric alcohol, the scalp remains sticky, There are problems in use such as hair stickiness and does not dry forever.
Patent Document 2 proposes to suppress the precipitation of minoxidil crystal by adjusting the pH of the composition to 5.5 to 6.5 while blending 8 to 30% by weight of polyhydric alcohol. . However, the method of Patent Document 2 cannot suppress the coloring of the minoxidil-containing liquid agent.

  As an attempt to suppress the coloration of the minoxidil-containing liquid over time, Patent Document 3 teaches that an amino acid is blended with the minoxidil-containing liquid, and Patent Document 4 blends an antioxidant with the minoxidil-containing liquid, and It teaches that the pH is adjusted to 5.5 to 7.0, and Patent Document 5 discloses that dibutylhydroxytoluene or dibutylhydroxyanisole is added to the minoxidil-containing liquid and the pH is adjusted to 5.7 to 6.4. Teaching. However, the methods described in these documents cannot sufficiently suppress coloring of the minoxidil-containing liquid agent practically.

Special table 2002-512192 WO2001 / 76541 WO99 / 27966 JP 2001-288090 A JP 2002-308740 A

  An object of the present invention is to provide an external composition containing minoxidil, in which the crystal precipitation of minoxidil and coloring over time are suppressed, and the composition has excellent usability.

  The present inventor conducted researches to solve the above-mentioned problems, and in an external composition containing 3 to 10% by weight of minoxidil, propylene was added so that the weight ratio of minoxidil: propylene glycol was 1: 3 to 1: 9. By blending glycol and adjusting the pH of the composition to 6.5-7.5, crystal precipitation of minoxidil is suppressed, it is difficult to color even when exposed to heat and light, and stickiness is further suppressed. It was found to be a composition.

This invention is completed based on the said knowledge, and provides the following external compositions.
Item 1. A composition for external use containing 3 to 10% by weight of minoxidil, containing propylene glycol such that the weight ratio of minoxidil: propylene glycol is 1: 3 to 1: 9, and the pH of the composition is 6.5 to 7.5 object.
Item 2. Furthermore, the external composition of claim | item 1 containing water.
Item 3. Item 3. The external composition according to Item 2, wherein the water content is 5 to 30% by weight based on the total amount of the composition.
Item 4. Furthermore, the external composition in any one of claim | item 1 -3 containing a lower alcohol.
Item 5. Item 5. The external composition according to Item 4, wherein the content of the lower alcohol is 30 to 80% by weight based on the total amount of the composition.
Item 6. Item 6. The composition for external use according to any one of Items 1 to 5, which is used for hair growth, hair restoration, or hair growth.
Item 7. The external composition according to any one of Items 1 to 5 is accommodated in a container in which part or all of the surface in contact with the external composition is composed of at least one material selected from the group consisting of polyolefin and glass. Containerized external composition.

The composition for external use of the present invention contains propylene glycol so that the weight ratio of minoxidil: propylene glycol is 1: 3 to 1: 9 while containing a relatively high concentration of minoxidil of 3 to 10% by weight, and the pH is By being 6.5 to 7.5, crystal precipitation of minoxidil and coloring over time are suppressed, and the material has a good feeling of use with less stickiness.
Minoxidil is particularly likely to crystallize at low temperatures, but the composition for external use of the present invention also suppresses crystal precipitation during low-temperature storage. Therefore, it can withstand distribution to cold regions and storage in winter. Further, since coloring at high temperatures or exposure to light is suppressed, the light-shielding container does not necessarily have to be filled. Accordingly, it is a minoxidil-containing preparation with extremely high commercial value.

Hereinafter, the present invention will be described in detail.
The composition for external use of the present invention contains about 3 to 10% by weight of minoxidil, contains propylene glycol so that the weight ratio of minoxidil: propylene glycol is about 1: 3 to 1: 9, and has a pH of about 6.5. -7.5 composition.

Minoxidil Minoxidil is commercially available and can be purchased from, for example, Tokyo Chemical Industry Co., Ltd.
The content of minoxidil is about 3% by weight or more, preferably about 4% by weight or more, more preferably about 5% by weight or more based on the total amount of the composition. In general, a composition containing minoxidil within this range has poor solubility of minoxidil and is likely to be colored over time, so this range is a preferred subject of the present invention.
The content of minoxidil is about 10% by weight or less, preferably about 9% by weight or less, more preferably about 7% by weight or less based on the total amount of the composition. Within this range, minoxidil crystal precipitation and coloration of the composition over time are suppressed.
The content of minoxidil is about 3 to 10% by weight, about 3 to 9% by weight, about 3 to 7% by weight, about 4 to 10% by weight, about 4 to 9% by weight, based on the total amount of the composition, Examples include about 4 to 7% by weight, about 5 to 10% by weight, about 5 to 9% by weight, and about 5 to 7% by weight.

Propylene glycol The content of propylene glycol is about 3 parts by weight or more, preferably about 3.5 parts by weight or more, and more preferably about 4 parts by weight or more with respect to 1 part by weight of minoxidil. Within this range, minoxidil crystal precipitation and coloration of the composition over time are sufficiently suppressed.
Further, the content of propylene glycol is about 9 parts by weight or less, preferably about 8 parts by weight or less, more preferably about 7 parts by weight or less with respect to 1 part by weight of minoxidil. If it is this range, it will become a composition with a favorable usability | use_condition.
The content of propylene glycol is about 3 to 9 parts by weight, about 3 to 8 parts by weight, about 3 to 7 parts by weight, about 3.5 to 9 parts by weight, and about 3 parts by weight with respect to 1 part by weight of minoxidil. 5-8 weight part, about 3.5-7 weight part, 4-9 weight part, about 4-8 weight part, about 4-7 weight part is mentioned.

Base or Carrier The composition for external use of the present invention can contain a pharmaceutically or physiologically acceptable base or carrier for pharmaceutical external preparations, quasi drugs, and cosmetics.
Such bases or carriers include liquid paraffin, squalane, petrolatum, gelled hydrocarbons (such as plastibase), ozokerite, α-olefin oligomers, and hydrocarbons such as light liquid paraffin; methyl polysiloxane, highly polymerized methyl Polysiloxane, cyclic silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branch Silicone oils such as silicones, polyglycerin-modified branched silicones, acrylic silicones, phenyl-modified silicones, and silicone resins; coconut oil, olive oil, rice bran oil, shea butter Oils and fats; waxes such as jojoba oil, miw wax, candelilla wax, and lanolin; higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, and cholesterol; Cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose; polyvinyl pyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, palmitate Cetyl acid, isononyl isononanoate, and tetra-2-ethylhexa Esters such as pentaerythritol acid; polysaccharides such as dextrin and maltodextrin; vinyl polymers such as carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer; methanol, ethanol, propanol, isopropyl alcohol, butanol , Lower (1 to 4 carbon) alcohols such as isobutyl alcohol, sec-butyl alcohol, test-butyl alcohol, etc .; and ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol Monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol Glycol ethers such as monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, and dipropylene glycol monopropyl ether; glycerin, diglycerin, polyglycerin, polyethylene glycol, butylene glycol, dipropylene glycol, polypropylene glycol , Polyols such as sorbitol, mannitol, trehalose, erythritol, xylitol; water and the like.

  A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

It is preferable that the composition of this invention contains 1 or more types chosen from the group which consists of water and a lower alcohol (especially ethanol) as a base or a support | carrier. In general, since minoxidil is difficult to dissolve in water or lower alcohol, a composition containing these is a suitable subject of the present invention.
The content of one or more selected from the group consisting of water and lower alcohols is preferably about 5% by weight or more, more preferably about 10% by weight or more, and more preferably about 15% by weight relative to the total amount of the composition. Even more preferred is weight percent or more. If it is this range, a formulation with a favorable feeling of use will be obtained.
In addition, the content when containing at least one selected from the group consisting of water and lower alcohol is preferably about 90% by weight or less, more preferably about 80% by weight or less, based on the total amount of the composition, Even more preferred is about 70% or less by weight. If it is this range, the solubility of minoxidil will become favorable.
The content of one or more selected from the group consisting of water and lower alcohol is about 5 to 90% by weight, about 5 to 80% by weight, about 5 to 70% by weight, about 5% by weight, based on the total amount of the composition. 10-90 wt%, about 10-80 wt%, about 10-70 wt%, about 15-90 wt%, about 15-80 wt%, about 15-70 wt%.

In particular, when the external composition of the present invention contains water, the content of water is preferably about 5% by weight or more, more preferably about 10% by weight or more, and more preferably about 15% by weight or more based on the total amount of the composition. Is even more preferred. If it is this range, a formulation with a favorable feeling of use will be obtained.
In addition, when water is contained, the content of water is preferably about 30% by weight or less, more preferably about 25% by weight or less, and still more preferably about 20% by weight or less based on the total amount of the composition. If it is this range, the solubility of minoxidil will become favorable.
The water content is about 5-30% by weight, about 5-25% by weight, about 5-20% by weight, about 10-30% by weight, about 10-25% by weight, based on the total amount of the composition, Examples include about 10 to 20% by weight, about 15 to 30% by weight, about 15 to 25% by weight, and about 15 to 20% by weight.

In particular, when the composition for external use of the present invention contains a lower alcohol (particularly ethanol), the content thereof is preferably about 30% by weight or more, more preferably about 40% by weight or more based on the total amount of the composition. Preferably, about 50 wt% or more is even more preferred. If it is this range, a formulation with a favorable feeling of use will be obtained.
Further, when the composition for external use of the present invention contains a lower alcohol (particularly ethanol), the content thereof is preferably about 80% by weight or less, more preferably about 70% by weight or less based on the total amount of the composition, Even more preferred is about 60 wt% or less. If it is this range, the solubility of minoxidil will become favorable.
When the composition for external use of the present invention contains a lower alcohol (particularly ethanol), the content thereof is about 30 to 80% by weight, about 30 to 70% by weight, about 30 to 60% with respect to the total amount of the composition. Weight percent, about 40-80 wt%, about 40-70 wt%, about 40-60 wt%, about 50-80 wt%, about 50-70 wt%, about 50-60 wt%.

Additives The external composition of the present invention may contain pharmaceutically or physiologically acceptable additives for pharmaceutical external preparations, quasi-drugs, and cosmetics. Examples of such additives include antioxidants, surfactants, thickeners, preservatives, pH adjusters, stabilizers, irritation reducers, preservatives, colorants, fragrances, solubilizers, and the like. It is done.
An additive can be used individually by 1 type or in combination of 2 or more types.

Pharmacologically active ingredient / physiologically active ingredient The composition for external use of the present invention may contain a pharmacologically active ingredient or physiologically active ingredient for pharmaceutical external preparations, quasi drugs and cosmetics other than minoxidil. Such components include blood circulation promoting components, angiogenesis promoting factors, moisturizing components, anti-inflammatory components, antibacterial components, vitamins, peptides or derivatives thereof, amino acids or derivatives thereof, cell activation components, anti-aging components, keratin softening Alternatively, a keratolytic component, a whitening component, an astringent component, a vasodilator component, an antihistamine component, an antioxidant component, a metabolic activator, a refreshing agent and the like can be mentioned. Further, for example, hair growth ingredients other than minoxidil such as spiranolactone, assembly extract, capsaicinoid, keratin growth factor (KGF; FGF-7), glycyrrhizinate, glycyrrhetinic acid, carrot extract and the like can also be included.
A pharmacologically active ingredient or a physiologically active ingredient can be used individually by 1 type or in combination of 2 or more types.

Dosage Form The form of the composition for external use of the present invention is not particularly limited, and examples thereof include solutions, suspensions, emulsions, creams, gels, liniments, lotions, and aerosols. Moreover, when it contains the water which can melt | dissolve minoxidil, it can also be set as ointment. Among these, a liquid agent, a suspension agent, an emulsion, a lotion agent, and an aerosol agent are preferable, and a liquid agent, a lotion agent, and an aerosol agent are more preferable.
When an oily base and an aqueous base are included, such as creams, emulsions, and, in some cases, ointments, aerosols, etc., they may be W / O type or O / W type, but have a good feeling of use. In this respect, the O / W type is preferable.
The preparation can be produced by mixing each component according to or in accordance with the 16th revised Japanese Pharmacopoeia General Rules.

pH
The pH of the composition of the present invention is about 6.5 or higher, preferably about 6.6 or higher, more preferably about 6.7 or higher, and even more preferably about 6.8 or higher. If it is this range, coloring of the composition of Minoxidil with time will be sufficiently suppressed.
The pH of the composition of the present invention is about 7.5 or less, preferably about 7.3 or less, more preferably about 7.1 or less. If it is the said range, irritation | stimulation to the scalp by high pH can be avoided. In addition, since minoxidil is easily dissolved, the amount of propylene glycol used can be suppressed, and the composition has a good usability.
The pH range of the composition of the present invention is about 6.5 to 7.5, about 6.5 to 7.3, about 6.5 to 7.1, about 6.6 to 7.5, about 6. 6 to 7.3, about 6.6 to 7.1, about 6.7 to 7.5, about 6.7 to 7.3, about 6.7 to 7.1, about 6.8 to 7.5 About 6.8 to 7.3, about 6.8 to 7.1.

pH adjustment is possible with organic acids such as lactic acid, sodium lactate, citric acid, sodium citrate, malic acid, sodium malate, succinic acid, sodium succinate, tartaric acid, sodium tartrate; phosphoric acid, hydrochloric acid, sulfuric acid, etc. What is necessary is just to perform using pH adjusters, such as an inorganic acid. Moreover, what is necessary is just to use pH adjusters, such as organic bases, such as a triethanolamine, diisopropanolamine, and triisopropanolamine; inorganic bases, such as potassium hydroxide and sodium hydroxide, as needed.
A pH adjuster can be used individually by 1 type or in combination of 2 or more types.

Container The container for filling the composition for external use of the present invention is not particularly limited. What is necessary is just to be used as a pharmaceutical external preparation, a quasi-drug, and a container for cosmetics.
As such a container material, for example, a part or all, preferably all, of the contact surface with the composition for external use is polyolefin, acrylic acid resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethyl. Consists of at least one material selected from the group consisting of terpene, fluororesin, polyvinyl chloride, polyamide, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, aluminum, and glass Containers that are used.

  Among them, polyethylene (including high-density polyethylene, low-density polyethylene, ultra-low-density polyethylene, linear low-density polyethylene, ultra-high molecular weight polyethylene, etc.) in that the coloration with time of the composition can be more effectively suppressed. Polypropylene (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.) and polyolefin such as ethylene / propylene copolymer; glass is preferred, and polyethylene, polypropylene, and glass are more preferred.

Method of Use The method of using the composition for external use of the present invention varies depending on the condition of the hair to be used, the condition of the scalp, age, sex, etc., but for example, the following method may be used.
That is, several times a day (for example, about 1 to 5 times, preferably 1 to 3 times), an appropriate amount (for example, about 0.5 to 2 g, or 0.5 to 2 ml) is applied to the skin (for example, the scalp). That's fine. Moreover, what is necessary is just to apply a composition to skin (for example, scalp) so that the daily usage-amount of minoxidil may be about 1-1000 mg. The application method may be application or spraying according to the dosage form. The application period may be, for example, about 7 days or longer. Further, it may be applied until the hair-growth effect is sufficiently obtained, for example, within 6 months, at least within 4 months.
The composition for external use of the present invention can be used for hair growth, hair growth, or hair growth.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.

Evaluation of Crystal Precipitation / Coloring / Usage Feeling Each component was mixed and dissolved in accordance with the composition shown in Tables 1 to 5 below, and filled in a 50 ml container. In principle, the container material was glass, and when the influence of the container material was examined, a container made of glass, polyethylene, polypropylene, or polyethylene terephthalate was used.

  Evaluation of low temperature stability was performed by observing crystal precipitation visually after leaving each composition still at a 4 degreeC thermostat for about 2 months. The case where no precipitation of crystals was observed was marked with ◯, and the case where it was recognized was marked with x.

  Evaluation of thermal stability was performed by observing the degree of yellow coloring visually after each composition was allowed to stand for about 2 months in a 40 ° C. thermostat. When the coloring was not recognized,-, when the slight coloring was recognized, +, and whenever the coloring was recognized more strongly, the number of + was increased.

Evaluation of light stability was performed by irradiating 350 W / m ² for 72 hours at 30 ° C. or lower using SUNTESTER XLS + (Toyo Seiki Co., Ltd.) and visually observing the degree of yellow coloring. When the coloring was not recognized,-, when the slight coloring was recognized, +, and whenever the coloring was recognized more strongly, the number of + was increased.

Evaluation of the feeling of use was performed by 5 in-house male panelists applying 1 ml to the head with hair, and comprehensively judging stickiness, familiarity of the preparation with the skin, smell, and feel after application. It was. When 3 or more out of 5 judges that there is no problem in use, △ When 1 or 2 out of 5 judges that there is no problem in use △, it was judged that there is no problem in use When there was no panelist, it was set as x.
A result is combined with Tables 1-5 and shown. The unit of the content of each component in Tables 1 to 5 is% by weight.

表1が示すように、ミノキシジル1重量部に対して、プロピレングリコールの含有量が３重量部未満の場合、組成物のｐＨにかかわらず、結晶析出又は経時的な着色が認められた。

As shown in Table 1, when the propylene glycol content was less than 3 parts by weight relative to 1 part by weight of minoxidil, crystal precipitation or coloration with time was observed regardless of the pH of the composition.

表２が示すように、ミノキシジル1重量部に対して、プロピレングリコールの含有量が３重量部の場合、組成物のｐＨが６．５〜７．５の範囲で、低温での結晶析出及び経時的な着色の両方が抑制された。これに対して、組成物のｐＨが６．５未満の場合、熱により着色が認められ、ｐＨが７．５を超える場合、低温で結晶析出が認められた。

As shown in Table 2, when the content of propylene glycol is 3 parts by weight with respect to 1 part by weight of minoxidil, the pH of the composition is in the range of 6.5 to 7.5, and crystal precipitation and aging at low temperatures are performed. Both typical colors were suppressed. On the other hand, when the pH of the composition was less than 6.5, coloring was observed due to heat, and when the pH exceeded 7.5, crystal precipitation was observed at a low temperature.

表３が示すように、ミノキシジル1重量部に対して、プロピレングリコールの含有量が３〜９重量部の場合、結晶析出及び経時的な着色の両方が抑制され、使用感も良好であった。これに対して、プロピレングリコールの含有量が３重量部未満の場合は結晶析出が認められ、プロピレングリコールの含有量が9重量部を超える場合は使用感が悪かった。

As Table 3 shows, when the content of propylene glycol is 3 to 9 parts by weight with respect to 1 part by weight of minoxidil, both crystal precipitation and coloring over time are suppressed, and the usability is also good. On the other hand, when the content of propylene glycol was less than 3 parts by weight, crystal precipitation was observed, and when the content of propylene glycol exceeded 9 parts by weight, the usability was poor.

表４が示すように、プロピレングリコールに代えて、１，３−ブチレングリコールを用いることにより、結晶析出が認められるようになった。

As Table 4 shows, using 1,3-butylene glycol in place of propylene glycol, crystal precipitation was observed.

ＰＥＴ：ポリエチレンテレフタレート
ＰＥ ：ポリエチレン
ＰＰ ：ポリプロピレン
表５が示すように、着色の程度は容器材質の影響を受け、プラスティック容器の中では、ポリエチレン容器、又はポリプロピレン容器を使用した場合、着色が一層効果的に抑制され、ガラス容器を使用した場合は、着色がさらに一層効果的に抑制された。

PET: Polyethylene terephthalate PE: Polyethylene PP: Polypropylene As shown in Table 5, the degree of coloring is affected by the material of the container, and in a plastic container, coloring is more effective when a polyethylene container or a polypropylene container is used. When the glass container was used, the coloring was further effectively suppressed.

  Although the composition for external use of the present invention contains a relatively high concentration of minoxidil, crystal precipitation of minoxidil at a low temperature is suppressed, and coloring of the composition over time is also suppressed. Furthermore, the feeling of use is good and the product value is high.

Claims (3)

3 to 7 % by weight of minoxidil, propylene glycol is contained so that the weight ratio of minoxidil: propylene glycol is 1: 3 to 1: 9, water is contained in an amount of 5 to 30% by weight based on the total amount of the composition, The composition for external use which contains 30 to 80weight% of alcohol with respect to the whole quantity of a composition, and the pH of a composition is 6.5-7.5. The composition for external use according to claim 1 , which is used for hair growth, hair growth or hair growth. The external composition according to claim 1 or 2 is contained in a container in which a part or all of the surface in contact with the external composition is composed of at least one material selected from the group consisting of polyolefin and glass. External composition in a container.