Aerosol

Abstract

In an aerosol preparation containing minoxidil and hyaluronic acid or a salt thereof, the analysis over time... To provide an aerosol agent that suppresses discharge. [Solution] (a) minoxidil, (b) hyaluronic acid or a salt thereof, and (c) polyhydric alcohols (d) an aerosol agent comprising a stock solution and a propellant.

Description

Technical Field

[0001] The present invention relates to an aerosol preparation containing minoxidil.

Background Art

[0002] Minoxidil has the chemical name 6-(1-piperidinyl)-2,4-pyrimidinediamine-3 -oxide and is known to be applicable as a hair growth agent (Patent Document 1), and there are many reports as a drug that exhibits excellent hair growth and hair growth effects. And, in order to provide a topical solution containing minoxidil, since minoxidil is insoluble in water, a solvent having the property of dissolving minoxidil, for example, alcohol, must be blended. However, when applying a topical solution containing minoxidil to the head, there is concern about the drying of the scalp after the alcohol has evaporated, so it is conceivable that scalp troubles can be reduced by blending a humectant. Here, hyaluronic acid has excellent water retention ability and is known to form a viscous gel even in a dilute solution (Non-Patent Document 1). Also, in order to exhibit the effect as a humectant, a minoxidil preparation containing a relatively high concentration of hyaluronic acid is known (Patent Document 2), and Patent Document 3 also discloses a minoxidil preparation containing hyaluronic acid. <00000{\*}

[0004]

[0005] In addition, as a form of applying minoxidil to the scalp, mainly solutions and lotions are known. On the other hand, as another form, aerosol preparations are also known. Aerosol preparations are a dosage form characterized by obtaining a cooling sensation by the vaporization of the propellant and having excellent storage stability of the components due to excellent light shielding properties. By achieving a specific spraying property, minoxidil can be surely applied to the scalp.

[0006] ​Technology relating to aerosol agents that reach their target has been disclosed (Patent Document 4).

[0005] However, aerosols containing minoxidil and hyaluronic acid are known to be do not have. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] U.S. Patent No. 4139619 [Patent Document 2] Japanese Patent Publication No. 7-48230 [Patent Document 3] Japanese Patent Publication No. 2009-108038 [Patent Document 4] Japanese Patent Application Publication No. 11-12136 [Non-patent literature]

[0007] [Non-Patent Document 1] Okuyama et al., 1982, Fragrance Journal, No. 56, 39-42. [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] Based on the above background, a minoxidil preparation containing hyaluronic acid or its salt is being developed as an aerosol. We found that this presents a problem in that precipitates are generated over time. In an aerosol containing xidyl and hyaluronic acid or a salt thereof, precipitation over time is... The objective is to provide an aerosol agent that suppresses this process. [Means for solving the problem]

[0009] The inventors of this invention diligently studied to solve the above problem and, surprisingly, discovered that polyvalent alcohol By incorporating a call, it has been found that precipitation over time can be suppressed in an aerosol agent containing minoxidil and hyaluronic acid or a salt thereof, leading to the completion of the present invention. .

[0010] That is, the present invention relates to: (1) A stock solution containing (a) minoxidil, (b) hyaluronic acid or a salt thereof, and (c) a polyhydric alcohol, and an aerosol agent comprising (d) an aerosol propellant. (2) The aerosol agent according to (1), wherein the stock solution contains (e) a lower alcohol. (3) The aerosol agent according to (1) or (2), wherein the aerosol propellant contains dimethyl ether. (4) The aerosol agent according to any one of (1) to (3), wherein the hyaluronic acid or a salt thereof is sodium hyaluronate. (5) The aerosol agent according to any one of (1) to (4), wherein the polyhydric alcohol is at least one selected from the group consisting of 1,3 - butylene glycol, propylene glycol, and glycerin. (6) The aerosol agent according to any one of (2) to (5), wherein the lower alcohol is ethanol or isopropanol. (7) The aerosol agent according to any one of (1) to (6), wherein the content of dimethyl ether is 0.25 parts by volume or more with respect to 1 part by volume of the stock solution. (7) The aerosol agent according to any one of (1) to (6), wherein the content of dimethyl ether is 0.25 parts by volume or more with respect to 1 part by volume of the stock solution. (7) The aerosol agent according to any one of (1) to (6), wherein the content of dimethyl ether is 0.25 parts by volume or more with respect to 1 part by volume of the stock solution. (7) The aerosol agent according to any one of (1) to (6), wherein the content of dimethyl ether is 0.25 parts by volume or more with respect to 1 part by volume of the stock solution. (7) The aerosol agent according to any one of (1) to (6), wherein the content of dimethyl ether is 0.25 parts by volume or more with respect to 1 part by volume of the stock solution. (7) The aerosol agent according to any one of (1) to (6), wherein the content of dimethyl ether is 0.25 parts by volume or more with respect to 1 part by volume of the stock solution. (7) The aerosol agent according to any one of (1) to (6), wherein the content of dimethyl ether is 0.25 parts by volume or more with respect to 1 part by volume of the stock solution. That's it.

Advantages of the Invention

[0011] According to the present invention, it has become possible to provide a minoxidil - containing aerosol agent that does not cause precipitation over time in the preparation. Also, according to the present invention, it has become possible to provide an aerosol agent with suppressed liquid dripping. According to the present invention, it has become possible to provide a minoxidil - containing aerosol agent that does not cause precipitation over time in the preparation. Also, according to the present invention, it has become possible to provide an aerosol agent with suppressed liquid dripping. According to the present invention, it has become possible to provide a minoxidil - containing aerosol agent that does not cause precipitation over time in the preparation. Also, according to the present invention, it has become possible to provide an aerosol agent with suppressed liquid dripping.

Brief Description of the Drawings

[0012] [Figure 1] This diagram shows the evaluation criteria for Test Example 3. [Modes for carrying out the invention]

[0013] The minoxidil used in the stock solution of this invention is of a quality commonly used in pharmaceuticals, as appropriate. It is possible. The amount of minoxidil in the undiluted solution is not particularly limited, but sufficient hair growth effect can be achieved. From the perspective of expected efficacy, 1 w / v% or more is preferable, and 1 to 10 w / v% is more preferable. A percentage of 1-5 w / v% is even more preferable.

[0014] Hyaluronic acid in the stock solution of the present invention is a type of linear glycosaminoglycan, and Examples of luronic acid salts include sodium salt, potassium salt, ammonium salt, and zinc salt. The following are listed, preferably sodium salts. The content of hyaluronic acid or its salt is as follows: A concentration of 0.001 to 0.01 w / v% is preferred, and more preferably 0.001 to 0.075 w / v%. The molecular weight of hyaluronic acid is / v%, more preferably 0.001-0.005 w / v%. While not particularly limited, those with an average molecular weight of 500,000 to 5,000,000 are preferred for formulation preparation. In terms of ease of handling, for example, swelling in aqueous solution (ease of absorption), the price ranges from 500,000 to 200,000. A value of 0 is more preferable. Also, the hyaluronic acid or salt thereof used is usually a pharmaceutical product. Materials of appropriate quality can be used as needed.

[0015] Examples of polyhydric alcohols in the stock solution of the present invention include 1,3-butylene glycol and dipropyl alcohol. Examples include pyrene glycol, propylene glycol, glycerin, etc., and these can be used individually or Two or more types may be combined. Of the polyhydric alcohols, 1,3-butyrate is preferred. The substance is glycol, glycerin, and more preferably 1,3-butylene glycol. Furthermore, the polyhydric alcohol content is preferably 2-30 w / v% in the undiluted solution, and more preferably The w / v concentration is 5-15%, and more preferably 5-10%.

[0016] The stock solution of the present invention contains, from the viewpoint of improving the solubility of minoxidil in the stock solution, typically lower grades It is good if it contains alcohol. As for lower alcohols, those with 1 to 5 carbon atoms are preferable, for example Ethanol or isopropanol may be used in combination. Of these, preferably ethanol and isopropanol, and more comfortably, ethanol. Yes. The lower alcohol content is preferably 20 w / v% or more in the undiluted solution, and more preferably It is 30 w / v% or more, more preferably 35 w / v% or more, and particularly preferably 50 The w / v% is 1% or higher. The upper limit is preferably 80 w / v%. The lower alcohol content is as follows: Medium 20~80w / v%, 30~80w / v%, 35~80w / v%, 50~80w / v% That's fine.

[0017] The propellant constituting the present invention preferably contains dimethyl ether. This is because it has excellent compatibility with [the other substance], and also offers good stability and usability. Therefore, And, dimethyl ether is present in high concentrations (for example, in the propellant, 90% or more, 95%, 98% or more, A propellant containing 99% or more, or 99.5% or more, is more preferable, and dimethyl ether and Additionally, small amounts of propellants such as liquefied petroleum gas or compressed gas can be used. Examples include propane, n-butane, and isobutane; compressed gases include carbon dioxide and nitrogen. Examples include nitrous oxide.

[0018] The mixing ratio of the concentrate to the propellant is 0.25 to less than 1 volume of propellant per 1 volume of concentrate. Preferably, more preferably 0.25 to 0.7 volume parts, and even more preferably 0.25 to 0.5 This is the volume section. If the propellant is less than 0.25 volume sections, it will be difficult to spread evenly during spraying. This is because... Also, if the propellant contains dimethyl ether, the undiluted solution and the dimethyl ether mixture... The preferred ratio is 0.25 to less than 1 part by volume of dimethyl ether per 1 part by volume of the stock solution. Preferably, the volume is 0.25 to 0.7 parts, and more preferably 0.25 to 0.5 parts. If the amount of dimethyl ether is less than 0.25 parts by volume, the cooling sensation will not be obtained, and if it is 1 part by volume or more... The propellant has a strong odor during use, which detracts from the overall user experience.

[0019] The pH of the stock solution of the present invention is preferably 5 to 9 from the viewpoint of minoxidil solubility. Preferably, it is 6 to 9, and even more preferably, 7 to 8.5.

[0020] In addition to the above-mentioned components, the aerosol agent of the present invention contains, to the extent that it does not impair the effects of the present invention, Necessary active ingredients and auxiliary ingredients can be added. These can be added to and incorporated into the aerosol agent of the present invention. Preferred medicinal ingredients include menthol, tocopherol acetate, and pantothenic acid. Tenyl ethyl ether, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, dihydrochloride Examples include components selected from the group consisting of phenhydramine and panthenol.

[0021] There are no particular restrictions on the amount of these selected ingredients added, depending on the user experience, the stability of minoxidil, or It can be determined experimentally while considering the solvent system composition, etc.

[0022] In the aerosol agent of the present invention, in addition to the above-mentioned components, to the extent that the effects of the present invention are not impaired, Therefore, various active ingredients and auxiliary ingredients commonly used in topical preparations can be incorporated. For example Excipients, hair growth ingredients (6-benzylaminopurine, adenosine, glyceryl pentadecanoate) Lido, He Shou Bird, etc.), vasodilators (carpronium chloride, benzyl nicotinate, Swertia japonica extract) Extract, Panax ginseng extract, Panax ginseng tincture, Capsicum tincture, etc.), anti-histamine Vitamins (such as isotipendyl hydrochloride), anti-inflammatory agents (such as guaiazulene), keratolytic agents (urea) (e.g., salicylic acid), disinfectants (chlorhexidine gluconate, isopropylmethylphenol) (L, quaternary ammonium salts, piroctone olamine, etc.), humectants (hyaluronic acid or its salts) , chondroitin sulfate, etc.), various plants and animals (yew, peony root, licorice, St. John's wort, Aconite, loquat, wormwood, comfrey, angelica tree, saffron, gardenia, rosemary Sage, Banksia japonica, Japanese Banksia japonica, hops, placenta, saw palmetto, pumpkin fruit Extracts of (such as citric acid), vitamins (retinyl acetate, ascorbic acid, thiamine nitrate, shea butter extract, etc.), Nocobalamin, biotin, etc.), amino acids (glycine, alanine, aspartic acid, argy Nin) Antioxidants (Dibutylhydroxytoluene, Sodium pyrosulfite, Tocopherol) , sodium edetate, ascorbic acid, isopropyl gallate, etc.), solubilizer (Aji Diisopropyl pitate, isopropyl myristate, various vegetable oils, various animal oils, alkyl Glyceryl ethers, hydrocarbons, etc.), metabolic activators, gelling agents (water-soluble polymers, etc.), wetting agents Agent (hydroxypropyl chitosan solution), viscous agent, thickening agent, adhesive, tack enhancer. Agents (polyvinyl alcohol, povidone, acrylic resin alkanolamine solution), fragrance, It can contain commonly used ingredients such as cooling agents (peppermint oil, camphor, etc.) and dyes. .

[0023] The container for filling the aerosol agent of the present invention has pressure resistance to withstand the internal pressure of the aerosol and the contents It must have airtightness to prevent leakage. It must also meet the pressure resistance performance (1.3M) stipulated by law. If the material does not deform at Pa and does not break at 1.5 MPa, then the material is aluminum. It may be made of aluminum, glass, tin, or synthetic resin. Tin container, aluminum When using a container, a resin surface coating can be applied to prevent corrosion. From the viewpoint of versatility, aluminum containers are preferred. Also, the aerosol agent of the present invention The container, in addition to being a pressure-resistant vessel, includes valves, buttons, spouts, caps, etc., as is common with aerosol containers. It is equipped with the same features as the vessel.

[0024] The aerosol agent of the present invention is prepared by a conventional method, containing the above-mentioned components. For example, the stock solution is prepared by mixing and dissolving each component in a solution, and the stock solution and propellant are then filled into a container. It can be filled and manufactured. [Examples]

[0025] The present invention will be described in more detail below with reference to examples, comparative examples, and test examples. The invention is not limited in any way by these embodiments, etc.

[0026] The stock solution was prepared as shown below and filled into a container together with the propellant. Note that ethanol is 95% ethanol was used. Sodium hyaluronate is from Kewpie Corporation. We used Ronsan HA-QA. The purified sodium hyaluronate was from Kewpie Corporation's Hyaluronic Acid. Longsan HA-AML was used.

[0027] (Example 1) Minoxidil 1g, Sodium hyaluronate 0.005g, 1,3-Butylene glyco Mix 10g of ethanol, 15.0g of purified water, an appropriate amount of citric acid, and ethanol to make a total volume of 100mL, then stir. Dissolve to obtain a stock solution with pH 8. The stock solution:dimethyl ether volume ratio was 1:0.5, total volume 45 The solution was filled into aluminum aerosol containers to a total volume of mL.

[0028] (Example 2) Minoxidil 1g, Sodium Hyaluronate 0.005g, Prolene Glycol 10g Add 15.3g of purified water, an appropriate amount of citric acid, and ethanol to make a total volume of 100mL, and stir to dissolve. A stock solution with a pH of 8 was obtained. The stock solution to dimethyl ether was adjusted to a volume ratio of 1:0.5, and the total volume was 45 mL. It was then filled into aluminum aerosol containers.

[0029] (Example 3) Minoxidil 1g, Sodium hyaluronate 0.005g, Glycerin 10g, Purified water Dissolve 15.3g of the substance in ethanol, add an appropriate amount of citric acid, and mix until the total volume is 100mL, then stir to reach a pH of 8. The stock solution was obtained. The volume ratio of stock solution to dimethyl ether was 1:0.5, and the total volume was 45 mL. It was filled into aluminum aerosol containers.

[0030] (Example 4) Minoxidil 1g, Sodium hyaluronate 0.005g, 1,3-Butylene glyco Mix 10g of phosphoric acid, 15.3g of purified water, an appropriate amount of phosphoric acid, and ethanol to make a total volume of 100mL, and stir until dissolved. Dissolve to obtain a stock solution with pH 8. The stock solution to dimethyl ether volume ratio was 1:0.5, and the total volume was 45 ml. The contents were filled into aluminum aerosol containers to the desired volume (L).

[0031] (Example 5) Minoxidil 1g, Sodium hyaluronate 0.005g, 1,3-Butylene glyco Mix 10g of tartaric acid, 15.3g of purified water, an appropriate amount of tartaric acid, and ethanol to make a total volume of 100mL, then stir until dissolved. Dissolve to obtain a stock solution with pH 8. The stock solution to dimethyl ether volume ratio was 1:0.5, and the total volume was 45 ml. The contents were filled into aluminum aerosol containers to the desired volume (L).

[0032] (Example 6) Minoxidil 1g, Sodium hyaluronate 0.005g, Propylene glycol 10 g, 15.3 g purified water, an appropriate amount of tartaric acid, and ethanol to make a total volume of 100 mL, then stir and dissolve. A stock solution with a pH of 8 was obtained. The stock solution to dimethyl ether was adjusted to a volume ratio of 1:0.5, and the total volume was 45 mL. It was then filled into aluminum aerosol containers.

[0033] (Comparative Example 1) Minoxidil 1g, Sodium hyaluronate 0.005g, Purified water 15.0g, Citric acid An appropriate amount of acid was added, and the total volume was reduced to 100 mL with ethanol. The mixture was stirred and dissolved to obtain a stock solution with a pH of 8. Stock solution: The dimethyl ether volume ratio is 1:0.5, and the total volume is 45 mL, using aluminum ether. It was filled into an azole container.

[0034] (Example 7) Minoxidil 1g, purified sodium hyaluronate 0.005g, 1,3-butyleneglycan Mix 5g of kohl, 15.3g of purified water, an appropriate amount of citric acid, and ethanol to make a total volume of 100mL, then stir. Dissolve by mixing to obtain a stock solution with pH 8. The volume ratio of stock solution to dimethyl ether was 1:0.5, and the total volume was 4 The solution was filled into aluminum aerosol containers to a volume of 5 mL.

[0035] (Example 8) Minoxidil 1g, purified sodium hyaluronate 0.005g, 1,3-butyleneglycan Mix 10g of kohl, 15.3g of purified water, an appropriate amount of citric acid, and ethanol to make a total volume of 100mL. The mixture was stirred and dissolved to obtain a stock solution with a pH of 8. The volume ratio of stock solution to dimethyl ether was 1:0.6, and the total volume was... The solution was filled into aluminum aerosol containers to a total volume of 45 mL.

[0036] (Example 9) Minoxidil 1g, purified sodium hyaluronate 0.005g, 1,3-butyleneglycan Mix 10g of kohl, 15.3g of purified water, an appropriate amount of citric acid, and ethanol to make a total volume of 100mL. The mixture was stirred and dissolved to obtain a stock solution with a pH of 8. The volume ratio of stock solution to dimethyl ether was 1:0.8, and the total volume was... The solution was filled into aluminum aerosol containers to a total volume of 45 mL.

[0037] (Example 10) Minoxidil 1g, purified sodium hyaluronate 0.005g, 1,3-butyleneglycan Mix 10g of kohl, 15.3g of purified water, an appropriate amount of citric acid, and ethanol to make a total volume of 100mL. The mixture was stirred and dissolved to obtain a stock solution with a pH of 8. The volume ratio of stock solution to dimethyl ether was 1:1, and the total volume was 45. The solution was filled into aluminum aerosol containers to a total volume of mL.

[0038] (Example 11) Minoxidil 1g, purified sodium hyaluronate 0.01g, 1,3-butylene glycoside Mix 10g of ethanol, 15.3g of purified water, an appropriate amount of citric acid, and ethanol to make a total volume of 100mL, then stir. Dissolve by mixing to obtain a stock solution with pH 8. The volume ratio of stock solution to dimethyl ether was 1:0.5, and the total volume was 4 The solution was filled into aluminum aerosol containers to a volume of 5 mL.

[0039] Table 1 shows the formulations for Examples 1-6 and Comparative Example 1, and Table 2 shows the formulations for Examples 7-11.

[0040] [Table 1]

[0041] [Table 2]

[0042] <Test Example 1: Confirmation of Precipitation> Regarding Examples 1 to 11 and Comparative Example 1, after 7 days under 50°C conditions, a small amount was found in the aerosol container. After drilling a hole and releasing the propellant, the recovered undiluted solution was visually inspected. The evaluation criteria are as follows: Stock liquid properties ○: No precipitation was observed. ×: Precipitation was observed.

[0043] <Test Example 2: Dripping> Regarding Examples 1 to 11 and Comparative Example 1, a spray button was attached to the tip of the aerosol container. The following method was used for the test: Alcohol test on a flat plate at a 10° angle to the ground. Place the paper and hold it at a 90° angle to the flat plate (alcohol test paper), 5 cm away from the test paper. 0.2g of each sample was sprayed onto alcohol test paper from a distance. The results were obtained 2 minutes after spraying. The drip distance on the alcohol test paper was measured. Note that the alcohol test paper was installed using a bolster. A tack tester (Tester Industry Co., Ltd.) was used. The evaluation criteria are as follows: Dripping ○: Average drip distance is 3cm or less ×: Average drip distance exceeds 3cm

[0044] <Test Example 3: Spray Characteristics> Similar to Test Example 2, for Examples 1-11 and Comparative Example 1, the spray was applied to the tip of the aerosol container. A button for the purpose was attached, and the test was conducted in the following manner: a flat plate positioned at a 10° angle to the ground. Place the alcohol test paper on top, and at a 90° angle to the flat plate (alcohol test paper) Spray 0.2g of each sample onto the alcohol test paper from a distance of 5cm from the test paper. The spread of the spray (spray characteristics) on the alcohol test paper was observed immediately after spraying. A ball tack tester (Tester Industry Co., Ltd.) was used to set up the alcohol test strips. . The evaluation criteria are as follows, and are specifically shown in Figure 1. Injection properties +++: Spreads evenly in a circular shape ++: Spreads in a generally circular pattern, but slight dispersion is observed. +: Spreads in a generally circular pattern, but scattering is observed.

[0045] The results of test examples 1-3 are shown in Table 3.

[0046] [Table 3]

[0047] As is clear from Table 3, precipitation was observed in Comparative Example 1, whereas with polyhydric alcohols... Contains one of the following: 1,3-butylene glycol, propylene glycol, or glycerin. No precipitation was observed in the formulations of Examples 1 to 11. Furthermore, while dripping occurred in Comparative Example 1, the polyhydric alcohol 1,3-butylene Examples 1-11 contain either glycol, propylene glycol, or glycerin. The formulation showed reduced dripping. Furthermore, in Examples 1-1, the ratio of the stock solution to dimethyl ether was adjusted to 1:0.5 and 1:0.6. In Examples 8 and 11, it was confirmed that the spray characteristics were superior.

[0048] Furthermore, as an aerosol agent of the present invention, for example, minoxidil 0.1-10 w / v%, ,3-Butylene glycol 2-30 w / v%, Ethanol 20-80 w / v%, Hyaluronic acid Sodium phosphate 0.001-0.02 w / v%, and other active and auxiliary ingredients such as menthol. Tall 0.1-5 w / v%, Tocopherol acetate 0.001-1 w / v%, Pan Tothenyl ethyl ether 0.1-10 w / v%, citric acid and / or phosphoric acid in appropriate amounts, acrylic acid Lyl resin alkanolamine solution 0.01-1 w / v%, povidone 0.01-0.1 w / v It contains %, a trace amount of fragrance, and 10-20 w / v% water, with the remainder adjusted with ethanol, and the propellant and These are also products that are filled into containers. These active ingredients and auxiliary ingredients affect the feel and minoxidil These aerosols can be formulated as appropriate, taking into consideration the stability of the solvent or the solvent system composition. Examples of drug prescriptions are shown in Tables 4 and 5.

[0049] [Table 4]

[0050] [Table 5] [Industrial applicability]

[0051] The present invention provides an aerosol containing minoxidil and hyaluronic acid or a salt thereof. Therefore, it is possible to provide an excellent formulation that does not cause precipitation over time and does not drip. It became Noh.

Claims

1. (a) minoxidil, (b) hyaluronic acid or a salt thereof, and (c) polyhydric alcohols are included. an aerosol agent comprising (d) a concentrated solution and a propellant.

2. The aerosol agent according to claim 1, wherein the undiluted solution contains (e) a lower alcohol.

3. The aerosol agent according to claim 1 or 2, wherein the propellant contains dimethyl ether.

4. The claim in any one of claims 1 to 3, wherein the hyaluronic acid or salt thereof is sodium hyaluronate. Aerosol spray.

5. The polyhydric alcohols are 1,3-butylene glycol, propylene glycol, and glycerin. The aerosol according to any one of claims 1 to 4, which is at least one selected from the group. Agent.

6. The lower alcohol is ethanol or isopropanol, according to any one of claims 2 to 5. Aerosol spray.

7. Claim 1, wherein the dimethyl ether content is 0.25 parts by volume or more per 1 part by volume of the undiluted solution. Aerosol agent as described in any of the above (6).

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