JP6880871B2 - Aerosol agent - Google Patents

Description

The present invention relates to a time-stable aerosol agent containing minoxidil. More specifically, the present invention relates to a minoxidil-containing aerosol agent that does not form a precipitate when stored at a low temperature.

Minoxidil has a chemical name of 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxide and is known to be applied as a hair restorer (Patent Document 1), and has excellent hair growth and hair growth effects. There are many reports as a drug to exert.

Liquid agents and lotions are mainly known as forms for applying minoxidil to the scalp. Minoxidil is known to cause a phenomenon in which crystals are precipitated when stored in a solution at a low temperature for a long time, and techniques for suppressing crystal precipitation (Patent Documents 2 to 4) have been reported.
On the other hand, an aerosol agent is also known as another form. It is a dosage form that has the characteristics that a cooling sensation can be obtained by vaporizing the propellant and that the storage stability of the components is excellent due to the excellent light-shielding property. A technique relating to an aerosol agent that ensures that minoxidil reaches the scalp by making it have a specific jetting property is disclosed (Patent Document 5).

U.S. Pat. No. 4,139,619 Japanese Patent No. 5527787 Japanese Patent No. 5561264 Japanese Unexamined Patent Publication No. 2014-21409 Japanese Unexamined Patent Publication No. 11-12136

In order to provide a minoxidil-containing aerosol agent that does not cause crystal precipitation even at a low temperature, the present inventors prepare a minoxidil-containing liquid agent that does not cause crystal precipitation at a low temperature, use this as a stock solution, and add a propellant to the aerosol agent. I tried to manufacture it. More specifically, when minoxidil was mixed with a stock solution containing phosphoric acid, citric acid, or lactic acid and a propellant to produce an aerosol agent, surprisingly, precipitates were formed in the aerosol agent during low temperature storage. It turns out that there are cases.

Therefore, it is an object of the present invention to provide an aerosol agent containing minoxidil in which crystals do not precipitate when stored at a low temperature.

As a result of diligent studies to solve the above problems, the present inventors unexpectedly blended two or more kinds of acids selected from the group consisting of citric acid, phosphoric acid, and lactic acid in the undiluted solution. It has been found that an aerosol agent using dimethyl ether as a propellant does not precipitate crystals when stored at a low temperature and can contain minoxidyl in a dissolved state, and has completed the present invention.

That is, the present invention
(1) (a) A stock solution containing minoxidil and two or more acids selected from the group consisting of phosphoric acid, citric acid, and lactic acid, and (b) an aerosol agent consisting of a propellant containing dimethyl ether.
(2) The aerosol agent according to (1), wherein the content of minoxidil in the stock solution is 5 w / v% or more.
Is.

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide an aerosol agent containing minoxidil in a dissolved state in which crystals do not precipitate during storage at a low temperature. In addition, it became an aerosol agent having excellent compatibility between the undiluted solution and the propellant.

The aerosol agent of the present invention is composed of (a) minoxidil, a stock solution containing two or more acids selected from the group consisting of phosphoric acid, citric acid, and lactic acid, and (b) a propellant containing dimethyl ether. To. The aerosol agent of the present invention is an aerosol agent containing minoxidil in a dissolved state without crystals precipitating during storage at a low temperature.
The undiluted solution constituting the aerosol agent of the present invention contains minoxidil and two or more kinds of acids selected from the group consisting of phosphoric acid, citric acid, and lactic acid as essential components, and if necessary, alcohols, water, and other general solutions. Various active ingredients and auxiliary ingredients used in external preparations can be blended.

As the minoxidil in the undiluted solution of the present invention, those of the quality usually used for pharmaceutical products can be appropriately used. As the content of minoxidil in the undiluted solution increases, the problem of precipitation at low temperature increases. Therefore, the higher the concentration of minoxidil, the greater the significance of carrying out the present invention. Specifically, the concentration of minoxidil in the stock solution is preferably 3 w / v% or more, more preferably 5 w / v% or more. The upper limit is preferably 10 w / v%.

In the stock solution of the present invention, it is essential to mix two or more kinds of acids selected from the group consisting of phosphoric acid, citric acid and lactic acid. When an aerosol agent is produced using only one of these acids, crystals are precipitated during storage at a low temperature, and minoxidil cannot be contained in a dissolved state. The blending ratio of phosphoric acid and citric acid in the stock solution of the present invention is preferably 0.3 to 5 parts by mass, more preferably 0.5 to 2 parts by mass with respect to 1 part by mass of phosphoric acid. The total amount of phosphoric acid and citric acid is preferably 0.1 to 2.0 w / v%, more preferably 0.3 to 1.2 w / v%, still more preferably 0.5 to 1.0 w / v%. .. The blending ratio of phosphoric acid and lactic acid is preferably 0.3 to 5 parts by mass, more preferably 0.5 to 2 parts by mass, based on 1 part by mass of phosphoric acid. The total amount of phosphoric acid and lactic acid is preferably 0.1 to 2.0 w / v%, more preferably 0.3 to 1.2 w / v%, and even more preferably 0.5 to 1.0 w / v%. The mixing ratio of citric acid and lactic acid is preferably 0.3 to 5 parts by mass, more preferably 0.5 to 2 parts by mass, based on 1 part by mass of citric acid. The total amount of citric acid and lactic acid is preferably 0.1 to 2.0 w / v%, more preferably 0.3 to 1.2 w / v%, and even more preferably 0.5 to 1.0 w / v%.

The pH of the undiluted solution is preferably adjusted to the range of 4.0 to 8.0 from the viewpoints of stability of minoxidil, irritation to the skin during use, drug permeability, feeling of use and the like. A range of .0 to 7.0 is more preferred.

The stock solution of the present invention preferably contains a mixture of alcohols and water from the viewpoint of usability, solubility of minoxidil and stability. The blending amount of alcohols is preferably 30 to 80 w / v% of the total stock solution. As the alcohols, lower alcohols and polyhydric alcohols can be used alone or in combination. As the lower alcohol, those having 1 to 5 carbon atoms are preferable, and for example, ethanol and isopropanol are preferable, and these can be used in combination. The blending amount of the lower alcohol is preferably 30 w / v% or more, more preferably 40 w / v% or more of the whole stock solution. Examples of the polyhydric alcohol include 1,3-butylene glycol, dipropylene glycol, propylene glycol, glycerin and the like, and these can be used alone or in combination of two or more. The blending amount of the polyhydric alcohol is preferably 30 w / v% or less of the total stock solution. The amount of water blended in the undiluted solution of the present invention is not particularly limited, but is preferably 10 to 50 w / v%, more preferably 10 to 30 w / v%, and 10 w / v% or more and 20 w with respect to the entire undiluted solution. Less than / v% is more preferred. The water content can be calculated from the amount of mixed water and the amount of water in the mixed components, but it can also be measured by, for example, a Karl Fischer titer.

In addition to the above-mentioned components, various active ingredients and auxiliary components used in general external preparations can be added to the stock solution containing minoxidil of the present invention as long as the effects of the present invention are not impaired. For example, hydrochloric acid, hair-growth component (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, ascorbic acid, etc.), vasodilator (carpronium chloride, benzyl nicotinate, assembly extract, otane carrot extract, chixetsu carrot tincture, etc. Togarashi tinki, etc.), antihistamines (isotipendyl hydrochloride, diphenhydramine hydrochloride, etc.), anti-inflammatory agents (guaizulene, glycyrrhetinic acid, etc.), keratolytic agents (urea, salicylic acid, etc.), bactericides (chlorhexidine gluconate, isopropylmethylphenol, quaternary grade 4) Ammonium salt, pyrocton olamine, hinokithiol, etc.), moisturizer (hyaluronic acid or its salt, chondroitin sulfate, etc.), various animals and plants (ichii, buttonpi, kanzo, otogirisou, tsuko, biwa, kawarayomogi, confrey, ascorbic acid, saffron, etc. Extracts of sanshishi, rosemary, sage, mokko, seimokko, hops, placenta, sawtooth palm, pumpkin seed, etc., vitamins (tocopherol acetate, pantothenyl ethyl ether, pantenol, pyridoxin hydrochloride, retinol acetate, ascorbic acid, thiamine nitrate , Cyanocobalamine, biotin, etc.), Antioxidants (dibutylhydroxytoluene, sodium pyrosulfate, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.), solubilizers (diisopropyl adipate, isopropyl myristate, various vegetable oils, various animal oils) , Alkyl glyceryl ether, hydrochloric acid, etc.), Metabolism activator, gelling agent (water-soluble polymer, etc.), adhesive, fragrance, cooling agent (menthol, peppermint oil, camphor, etc.), dye, etc. Ingredients can be blended.

It is essential to use dimethyl ether as the propellant constituting the present invention. This is because the compatibility with the undiluted solution is excellent, and the stability and usability are also good. The mixing ratio of the undiluted solution and dimethyl ether is preferably 0.25 to 1 part by volume of dimethyl ether with respect to 1 part by volume of the undiluted solution. This is because if it is less than 0.25 parts by volume, a cold feeling cannot be obtained, and if it exceeds 1 part by volume, the propellant odor during use is strong and a good feeling of use is impaired. Further, other propellants such as compressed gas can be used together with dimethyl ether as long as the stability and usability are not impaired. Examples of the compressed gas include carbon dioxide gas, nitrogen, nitrous oxide and the like.

The container filled with the aerosol agent of the present invention is required to have a pressure resistance to withstand the internal pressure of the aerosol and an airtightness to prevent the contents from leaking. The material may be aluminum, glass, tinplate, or synthetic resin as long as the pressure resistance performance specified by law (not deformed at 1.3 MPa and not destroyed at 1.5 MPa) is maintained. When a tin container or an aluminum container is used, the surface can be coated with a resin to prevent corrosion, but the aluminum container is preferable from the viewpoint of versatility. Further, the container used for the aerosol agent of the present invention is provided with a valve, a button, a spout, a cap and the like in addition to a pressure-resistant container in the same manner as a known aerosol container.

The aerosol agent of the present invention is prepared by containing each of the above components according to a conventional method.

Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples, but the present invention is not limited to these Examples and the like.

The following stock solutions 1 to 5 were prepared. As ethanol, 95% ethanol was used.

* Undiluted solution 1
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, citric acid 0.45 g, phosphoric acid 0.38 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.1. The content of water in the undiluted solution was 17 g / 100 mL.

* Undiluted solution 2
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, citric acid 0.55 g, phosphoric acid 0.34 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.1. The content of water in the undiluted solution was 17 g / 100 mL.

* Undiluted solution 3
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, phosphoric acid 0.4 g, lactic acid 0.4 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.1. The content of water in the undiluted solution was 17 g / 100 mL.

* Undiluted solution 4
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, citric acid 0.45 g, lactic acid 0.5 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.0. The content of water in the undiluted solution was 16 g / 100 mL.

* Undiluted solution 5
Minoxidil 5 g, 1,3-butylene glycol 12 g, ethanol 60 g, citric acid 0.45 g, lactic acid 0.5 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.0. The content of water in the undiluted solution was 14 g / 100 mL.

* Undiluted solution 6
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, phosphoric acid 0.38 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.5. The content of water in the undiluted solution was 17 g / 100 mL.

* Undiluted solution 7
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, citric acid 0.45 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.5. The content of water in the undiluted solution was 17 g / 100 mL.

* Undiluted solution 8
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, phosphoric acid 1.02 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.0. The content of water in the undiluted solution was 17 g / 100 mL.

* Undiluted solution 9
Minoxidil 5 g, 1,3-butylene glycol 10 g, ethanol 60 g, lactic acid 0.5 g, purified water to make a total volume of 100 mL, and the mixture was stirred and dissolved to obtain a stock solution having a pH of 6.4. The content of water in the undiluted solution was 17 g / 100 mL.

The formulations of undiluted solutions 1 to 9 are shown in Table 1 (note that the unit in the table is g / 100 mL).

<Test Example 1: Low temperature stability test of stock solution>
The stock solutions 1 to 9 were each filled in a transparent container, and the presence or absence of crystal precipitation after storage at 5 ° C. for 9 days was visually evaluated. As a result, no crystal precipitation occurred.

(Example 1)
26.7 mL of the stock solution 1 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 13.3 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and the propellant dimethyl ether becomes 1 / 0.5. Got

(Example 2)
32.0 mL of the stock solution 1 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 8.0 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and dimethyl ether, which is the propellant, is 1 / 0.25, and the aerosol agent is added. Obtained.

(Example 3)
26.7 mL of the stock solution 2 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 13.3 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and the propellant dimethyl ether becomes 1 / 0.5, and the aerosol agent is added. Obtained.

(Example 4)
30.0 mL of the undiluted solution 3 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 15.0 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and dimethyl ether, which is the propellant, becomes 1 / 0.5, and the aerosol agent is added. Obtained.

(Example 5)
30.0 mL of the undiluted solution 4 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 15.0 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and dimethyl ether, which is the propellant, becomes 1 / 0.5, and the aerosol agent is added. Obtained.

(Example 6)
30.0 mL of the stock solution 5 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 15.0 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and dimethyl ether, which is the propellant, becomes 1 / 0.5, and the aerosol agent is added. Obtained.

(Comparative Example 1)
26.7 mL of the undiluted solution 6 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 13.3 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and the propellant dimethyl ether becomes 1 / 0.5, and the aerosol agent is added. Obtained.

(Comparative Example 2)
26.7 mL of the undiluted solution 7 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 13.3 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and the propellant dimethyl ether becomes 1 / 0.5, and the aerosol agent is added. Obtained.

(Comparative Example 3)
26.7 mL of the undiluted solution 8 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 13.3 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and the propellant dimethyl ether becomes 1 / 0.5, and the aerosol agent is added. Obtained.

(Comparative Example 4)
30.0 mL of the undiluted solution 9 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 15.0 mL of dimethyl ether is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and dimethyl ether, which is the propellant, becomes 1 / 0.5, and the aerosol agent is added. Obtained.

(Comparative Example 5)
26.7 mL of the stock solution 1 was filled in a transparent glass pressure resistant bottle. Next, an aerosol valve is attached to the transparent glass pressure-resistant bottle, and 13.3 mL of liquefied petroleum gas is filled in the transparent glass pressure-resistant bottle so that the volume ratio of the undiluted solution and the liquefied petroleum gas that is the propellant is 1 / 0.5. , Obtained an aerosol agent.

Table 2 shows the stock solutions and propellants of Examples 1 to 6 and Comparative Examples 1 to 5 (DME in the table is an abbreviation for dimethyl ether, and LPG is an abbreviation for liquefied petroleum gas).

<Test Example 2: Evaluation of compatibility and low temperature stability>
With respect to Examples 1 to 6 and Comparative Examples 1 to 5, the compatibility immediately after preparation and the presence or absence of crystal precipitation after storage at 5 ° C. for 9 days were evaluated. The compatibility immediately after preparation is indicated by ◯ when the undiluted solution and the propellant are mixed, and × when the undiluted solution and the propellant are separated. In the evaluation of low temperature stability, those in which crystals did not precipitate and remained mixed were marked with ◯, and those in which crystals were precipitated were marked with x. The results are shown in Table 3.

As is clear from Test Example 1, all of the stock solutions 6 to 9 using citric acid, phosphoric acid, or lactic acid alone did not have any problems such as crystal precipitation when stored at 5 ° C. for 9 days. However, when dimethyl ether was used as the propellant to prepare an aerosol agent, crystals were precipitated during storage at a low temperature (Comparative Examples 1 to 4). On the other hand, in Examples 1 to 6 of the present invention in which two or more acids selected from citric acid, phosphoric acid and lactic acid are used in combination in the undiluted solution, even if an aerosol agent using dimethyl ether as a propellant is prepared, it is stored at a low temperature. Occasionally no crystal precipitation occurred. Further, as shown in Comparative Example 5, when liquefied petroleum gas was used as the propellant, the stock solution and the propellant were separated immediately after the preparation and were not uniform. The result was that it was not suitable as a minoxidil-containing aerosol agent because it was not required to be measurable.

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide an aerosol agent containing minoxidil in a dissolved state in which crystals do not precipitate during storage at a low temperature.

Claims (2)

An aerosol agent consisting of (a) a stock solution containing minoxidil and two or more acids selected from the group consisting of phosphoric acid, citric acid, and lactic acid, and (b) a propellant containing dimethyl ether. The aerosol agent according to claim 1, wherein the content of minoxidil in the undiluted solution is 5 w / v% or more.