Aerosol

Abstract

To provide an aerosol agent containing minoxidil and hyaluronic acid or a salt thereof, which suppresses deposition over time.SOLUTION: An aerosol agent consists of: stock solution containing (a) minoxidil, (b) hyaluronic acid or a salt thereof and (c) polyhydric alcohol; and (d) propellant.SELECTED DRAWING: None

Description

Technical Field

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

Background Art

[0002] Minoxidil is chemically named 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 an agent that exhibits an excellent hair growth and hair follicle activation effect. And, in order to provide a minoxidil-containing topical solution, since minoxidil does not dissolve in water, it is essential to blend a solvent having the property of dissolving minoxidil, such as alcohol. However, when applying a minoxidil-containing topical solution to the head, since there is concern about the dryness of the scalp after alcohol volatilizes, it is conceivable that scalp troubles can be reduced by blending a humectant.

[0003] 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). Further, 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 a minoxidil preparation containing hyaluronic acid is also disclosed in Patent Document 3.

[0004] In addition, as a form of applying minoxidil to the scalp, mainly topical solutions and lotions are known. On the other hand, as another form, aerosol preparations are also known. An aerosol preparation is a dosage form having characteristics such as obtaining a cooling sensation by vaporization of an aerosol agent and having excellent storage stability of components due to excellent light shielding properties. A technique related to an aerosol preparation that surely reaches minoxidil to the scalp by making a specific spraying property has been disclosed (Patent Document 4).

[0005] However, an aerosol preparation containing minoxidil and hyaluronic acid is not known.

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 project] [Problems that the invention aims to solve]

[0008] Against the above background, we have found that when minoxidil preparations containing hyaluronic acid or a salt thereof are made into aerosol formulations, a problem arises in that precipitates occur over time. The object of the present invention is to provide an aerosol formulation containing minoxidil and hyaluronic acid or a salt thereof that suppresses precipitation over time. [Means for solving the problem]

[0009] The inventors of the present invention conducted extensive research to solve the above problems and, surprisingly, discovered that by incorporating a polyhydric alcohol, it is possible to suppress precipitation over time in aerosol formulations containing minoxidil and hyaluronic acid or its salts, thus completing the present invention.

[0010] In other words, the present invention is (1) an aerosol comprising (a) minoxidil, (b) hyaluronic acid or a salt thereof, and (c) a polyhydric alcohol stock solution, and (d) a propellant. (2) The aerosol agent described in (1) whose undiluted solution contains (e) a lower alcohol, (3) an aerosol agent according to (1) or (2) that contains dimethyl ether as a propellant, (4) an aerosol agent according to any of (1) to (3) wherein 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 of (2) to (5), wherein the lower alcohol is ethanol or isopropanol. (7) The aerosol agent according to any of (1) to (6), wherein the dimethyl ether content is 0.25 parts by volume or more per 1 part by volume of the undiluted solution. That is the case. [Effects of the Invention]

[0011] The present invention makes it possible to provide a minoxidil-containing aerosol formulation that does not precipitate over time. Furthermore, the present invention makes it possible to provide an aerosol formulation in which dripping is suppressed. [Brief explanation of the drawing]

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

[0013] The minoxidil in the stock solution of the present invention can be of a quality commonly used in pharmaceuticals. The minoxidil content in the stock solution is not particularly limited, but from the viewpoint of being able to expect sufficient hair growth effects, 1 w / v% or more is preferred, 1 to 10 w / v% is more preferred, and 1 to 5 w / v% is even more preferred.

[0014] The hyaluronic acid in the stock solution of the present invention is a kind of linear glycosaminoglycan. Examples of salts of hyaluronic acid include sodium salt, potassium salt, ammonium salt, zinc salt, etc., and preferably, it is sodium salt. The content of hyaluronic acid or its salt is preferably 0.001 - 0.01 w / v% in the stock solution, more preferably 0.001 - 0.075 w / v%, and even more preferably 0.001 - 0.005 w / v%. The molecular weight of hyaluronic acid is not particularly limited, but those with an average molecular weight of 500,000 - 5,000,000 are preferred, and those with an average molecular weight of 500,000 - 2,000,000 are more preferred from the aspect of ease of handling during formulation preparation, such as swelling property (ease of dissolution) in an aqueous solution. Also, the hyaluronic acid or its salt used can be appropriately selected from those of the quality usually used in pharmaceuticals.

[0015] Examples of the polyhydric alcohol in the stock solution of the present invention include 1,3 - butylene glycol, dipropylene glycol, propylene glycol, glycerin, etc., and one or a combination of two or more of these may be used. Among the above - mentioned polyhydric alcohols, preferably, 1,3 - butylene glycol and glycerin, and more preferably, 1,3 - butylene glycol. Also, the content of the polyhydric alcohol is preferably 2 - 30 w / v% in the stock solution, more preferably 5 - 15 w / v%, and even more preferably 5 - 10 w / v%.

[0016] From the perspective of improving the solubility of minoxidil in the stock solution, the stock solution of the present invention usually preferably contains a lower alcohol. As the lower alcohol, those having 1 - 5 carbon atoms are preferred, and for example, ethanol and isopropanol can be used in combination. Among the above - mentioned lower alcohols, preferably ethanol and isopropanol, and more preferably ethanol. The content of the lower alcohol is preferably 20 w / v% or more in the stock solution, more preferably 30 w / v% or more, even more preferably 35 w / v% or more, and particularly preferably 50 w / v% or more. The upper limit is preferably 80 w / v%. The content of the lower alcohol can be 20 - 80 w / v%, 30 - 80 w / v%, 35 - 80 w / v%, or 50 - 80 w / v% in the stock solution.

[0017] As the propellant constituting the present invention, it is preferable to contain dimethyl ether. This is because it has excellent compatibility with the stock solution, and also has good stability and feel in use. Therefore, a propellant containing dimethyl ether at a high content (for example, 90% or more, 95%, 98% or more, 99% or more, or 99.5% or more in the propellant) is more preferable. Together with dimethyl ether, a small amount of a propellant such as liquefied petroleum gas or compressed gas can be used. Examples of the liquefied petroleum gas include propane, normal butane, and isobutane, and examples of the compressed gas include carbon dioxide gas, nitrogen, and nitrous oxide.

[0018] The blending ratio of the stock solution and the propellant is preferably 0.25 to less than 1 part by volume of the propellant with respect to 1 part by volume of the stock solution, more preferably 0.25 to 0.7 part by volume, and even more preferably 0.25 to 0.5 part by volume. This is because if the propellant is less than 0.25 part by volume, it becomes difficult to spread uniformly when spraying. Also, when the propellant contains dimethyl ether, the blending ratio of the stock solution and dimethyl ether is preferably 0.25 to less than 1 part by volume of dimethyl ether with respect to 1 part by volume of the stock solution, more preferably 0.25 to 0.7 part by volume, and even more preferably 0.25 to 0.5 part by volume. If dimethyl ether is less than 0.25 part by volume, the cooling sensation cannot be obtained, and if it is 1 part by volume or more, the odor of the propellant during use becomes strong and the good feel in use is impaired.

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

[0020] In addition to the above-described components, the aerosol agent of the present invention can contain necessary active ingredients and auxiliary components within a range that does not impair the effects of the present invention. Examples of the medicinal components that are preferably added and blended in the aerosol agent of the present invention include components selected from the group consisting of menthol, tocopherol acetate, pantothenyl ethyl ether, hinokitiol, pyridoxine hydrochloride, glycyrrhetinic acid, diphenhydramine hydrochloride, and panthenol.

[0021] There are no particular restrictions on the amount of these selected ingredients added, and they can be determined experimentally while considering factors such as the feel of use, the stability of minoxidil, and the composition of the solvent system.

[0022] In addition to the components described above, the aerosol formulation of the present invention may contain various active ingredients and auxiliary ingredients commonly used in topical preparations, as long as they do not impair the effects of the present invention. For example, excipients, hair growth ingredients (6-benzylaminopurine, adenosine, pentadecanoic acid glyceride, He Shou Wu, etc.), vasodilators (carpronium chloride, benzyl nicotinate, Swertia japonica extract, Panax ginseng extract, Panax ginseng tincture, Capsicum tincture, etc.), antihistamines (isotipendyl hydrochloride, etc.), anti-inflammatory agents (guaiazulene, etc.), keratolytic agents (urea, salicylic acid, etc.), and antiseptics (gluconic acid Chlorhexidine, isopropylmethylphenol, 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, Artemisia capillaris, comfrey, Angelica keiskei, saffron, gardenia, rosemary, sage, Banksia japonica, Western Banksia japonica, hops, placenta, saw palmetto, pumpkin) Ingredients commonly used in this product may include extracts of seeds, vitamins (retinol acetate, ascorbic acid, thiamine nitrate, cyanocobalamin, biotin, etc.), amino acids (glycine, alanine, aspartic acid, arginine), antioxidants (dibutylhydroxytoluene, sodium pyrosulfite, tocopherol, sodium edetate, ascorbic acid, isopropyl gallate, etc.), solubilizers (diisopropyl adipate, isopropyl myristate, various vegetable oils, various animal oils, alkyl glyceryl ethers, hydrocarbons, etc.), metabolic activators, gelling agents (water-soluble polymers, etc.), humectants (hydroxypropyl chitosan solution), viscosities, adhesives, and tack enhancers (polyvinyl alcohol, povidone, acrylic resin alkanolamine solution), fragrances, cooling agents (peppermint oil, camphor, etc.), dyes, and other similar ingredients.

[0023] The container for filling the aerosol agent of the present invention must have pressure resistance to withstand the internal pressure of the aerosol and airtightness to prevent leakage of the contents. As long as the pressure resistance performance stipulated by regulations (not deforming at 1.3 MPa and not breaking at 1.5 MPa) is maintained, the material may be any of aluminum, glass, tinplate, or synthetic resin. When using tinplate or aluminum containers, a resin surface coating can be applied to prevent corrosion, but aluminum containers are preferred from the viewpoint of versatility. In addition to being a pressure-resistant container, the container used for the aerosol agent of the present invention is equipped with valves, buttons, spouts, caps, etc., in the same way as known aerosol containers.

[0024] The aerosol agent of the present invention is prepared by conventional methods, by including each of the above-mentioned components. For example, the components are mixed and dissolved in a solution to form a stock solution, and the stock solution and propellant are filled into a container to manufacture the product. [Examples]

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

[0026] The stock solution was prepared as shown below and filled into a container with the propellant. 95% ethanol was used. For sodium hyaluronate, Kewpie Corporation's Hyaluronsan HA-QA was used. For purified sodium hyaluronate, Kewpie Corporation's Hyaluronsan HA-AML was used.

[0027] (Example 1) Minoxidil 1g, sodium hyaluronate 0.005g, 1,3-butylene glycol 10g, purified water 15.0g, an appropriate amount of citric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

[0028] (Example 2) Minoxidil 1g, sodium hyaluronate 0.005g, prole glycol 10g, purified water 15.3g, an appropriate amount of citric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

[0029] (Example 3) Minoxidil 1g, sodium hyaluronate 0.005g, glycerin 10g, purified water 15.3g, an appropriate amount of citric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

[0030] (Example 4) Minoxidil 1g, sodium hyaluronate 0.005g, 1,3-butylene glycol 10g, purified water 15.3g, an appropriate amount of phosphoric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

[0031] (Example 5) Minoxidil 1g, sodium hyaluronate 0.005g, 1,3-butylene glycol 10g, purified water 15.3g, an appropriate amount of tartaric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

[0032] (Example 6) Minoxidil 1g, sodium hyaluronate 0.005g, propylene glycol 10g, purified water 15.3g, tartaric acid appropriate amount, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

[0033] (Comparative Example 1) Minoxidil 1g, sodium hyaluronate 0.005g, purified water 15.0g, an appropriate amount of citric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to dissolve and obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

[0034] (Example 7) Minoxidil 1g, purified sodium hyaluronate 0.005g, 1,3-butylene glycol 5g, purified water 15.3g, an appropriate amount of citric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

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

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

[0037] (Example 10) Minoxidil 1g, purified sodium hyaluronate 0.005g, 1,3-butylene glycol 10g, purified water 15.3g, an appropriate amount of citric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution and dimethyl ether were mixed in a volume ratio of 1:1 and filled into an aluminum aerosol container to a total volume of 45mL.

[0038] (Example 11) Minoxidil 1g, purified sodium hyaluronate 0.01g, 1,3-butylene glycol 10g, purified water 15.3g, an appropriate amount of citric acid, and ethanol were mixed to make a total volume of 100mL, and stirred to obtain a stock solution with a pH of 8. The stock solution to dimethyl ether was mixed in a volume ratio of 1:0.5 and filled into an aluminum aerosol container to a total volume of 45mL.

[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> For Examples 1-11 and Comparative Example 1, after 7 days under 50°C conditions, a small hole was made in the aerosol container to release the propellant, and the recovered undiluted solution was visually observed. The evaluation criteria are as follows: Stock liquid properties ○: No precipitation was observed. ×: Precipitation was observed.

[0043] <Test Example 2: Dripping> For Examples 1-11 and Comparative Example 1, a spray button was attached to the tip of the aerosol container, and the tests were conducted in the following manner. An alcohol test sheet was placed on a flat plate at a 10° angle to the ground, and 0.2g of each sample was sprayed onto the alcohol test sheet from a distance of 5cm from the test sheet at a 90° angle to the plate (alcohol test sheet). The drip distance on the alcohol test sheet was measured 2 minutes after spraying. A ball tack tester (Tester Industry Co., Ltd.) was used to set up the alcohol test sheet. 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, a spray button was attached to the tip of the aerosol container, and the tests were conducted in the following manner. An alcohol test sheet was placed on a flat plate at a 10° angle to the ground, and 0.2g of each sample was sprayed onto the alcohol test sheet from a distance of 5cm from the test sheet at a 90° angle to the plate (alcohol test sheet). The spread of the spray on the alcohol test sheet (spray characteristics) was observed immediately after spraying. A ball tack tester (Tester Industry Co., Ltd.) was used to set up the alcohol test sheet. 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 no precipitation was observed in the formulations of Examples 1 to 11, which contained one of the polyhydric alcohols 1,3-butylene glycol, propylene glycol, or glycerin. Furthermore, while dripping occurred in Comparative Example 1, dripping was suppressed in the formulations of Examples 1 to 11, which contained one of the polyhydric alcohols 1,3-butylene glycol, propylene glycol, or glycerin. Furthermore, in Examples 1-8 and 11, where the ratio of the stock solution to dimethyl ether was adjusted to 1:0.5 and 1:0.6, it was confirmed that the spray characteristics were even better.

[0048] Furthermore, an example of the aerosol agent of the present invention is one which contains 0.1-10 w / v% minoxidil, 2-30 w / v% 1,3-butylene glycol, 20-80 w / v% ethanol, 0.001-0.02 w / v% sodium hyaluronate, and other active and auxiliary components such as 0.1-5 w / v% menthol, 0.001-1 w / v% tocopherol acetate, 0.1-10 w / v% pantothenyl ethyl ether, an appropriate amount of citric acid and / or phosphoric acid, 0.01-1 w / v% acrylic resin alkanolamine solution, 0.01-0.1 w / v% povidone, a trace amount of fragrance, and 10-20 w / v% water, with the remainder prepared with ethanol and filled into a container together with a propellant. These active and auxiliary components can be appropriately blended considering the feel of use, the stability of minoxidil, or the solvent system composition. Examples of these aerosol formulations are shown in Tables 4 and 5.

[0049] [Table 4]

[0050] [Table 5] [Industrial applicability]

[0051] The present invention makes it possible to provide an excellent aerosol formulation containing minoxidil and hyaluronic acid or a salt thereof, which does not precipitate over time and does not drip.

Claims

1. An aerosol preparation comprising (a) a stock solution containing minoxidil, (b) hyaluronic acid or a salt thereof, (c) a polyhydric alcohol selected from the group consisting of 1,3-butylene glycol, propylene glycol and glycerin, and (e) ethanol, and (d) a propellant, wherein the propellant contains dimethyl ether, the dimethyl ether is miscible with the stock solution, and the propellant content is 0.25 parts by volume to less than 1 part by volume per 1 part by volume of the stock solution.

2. The aerosol agent according to claim 1, wherein the hyaluronic acid or salt thereof is sodium hyaluronate.

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