Composition for external use comprising minoxidil

Abstract

The present invention provides a composition for external use comprising minoxidil and propylene glycol monocaprylate. The composition for external use of the present invention not only improves the solubility of minoxidil but also maintains a transparent appearance with minimal coloration, while enhancing the skin permeability of minoxidil to significantly increase dermal absorption. Accordingly, the composition can be effectively used as a topical composition for promoting hair growth in the pharmaceutical and medical fields.

Description

Topical composition containing minoxidil

[0001] This application claims priority to Korean Patent Application No. 10-2024-0084800, filed June 27, 2024, the entire disclosure of which is incorporated herein by reference. The present invention relates to topical compositions, and more particularly, to topical compositions comprising minoxidil.

[0002] Minoxidil was approved by the U.S. Food and Drug Administration in 1979 as an oral antihypertensive drug, but its use was changed to a hair growth drug after hair growth side effects were accidentally discovered during use.

[0003] Currently, minoxidil's hair growth and hair growth effects have been proven, and it has been developed into a topical formulation for use in the treatment of male pattern baldness. However, minoxidil has a very low solubility in water of 0.2%, making it difficult to formulate and maintain stability at concentrations of 2%, 3%, and 5%, which are typical concentrations for topical hair loss treatments. Furthermore, minoxidil particles precipitate at concentrations exceeding 0.2% in aqueous solutions, and it is difficult to maintain dispersion stability in formulations such as emulsions.

[0004] Additionally, minoxidil has a tendency to discolor over time when stored in solution form. The mechanism of minoxidil solution discoloration has not yet been clearly elucidated, but light is believed to be involved. Minoxidil discoloration does not affect other quality characteristics, such as content or pH, and thus has no significant impact on efficacy. However, it does reduce product value.

[0005] Therefore, there is an urgent need to develop a liquid formulation containing minoxidil that can be stably present in solution at concentrations used as topical hair loss treatment agents while minimizing pigmentation.

[0006] The problem to be solved by the present invention is to provide a stable external application composition with improved solubility and skin permeability of minoxidil.

[0007] The problems to be solved by the present invention are not limited to the problems mentioned above, and other technical problems not mentioned can be clearly understood by a person having ordinary skill in the technical field to which the present invention belongs from the description below.

[0008] In order to solve the above problem, according to one aspect of the present invention, an external composition comprising minoxidil and propylene glycol monocaprylate is provided.

[0009] In one embodiment, the minoxidil may be included at 1 to 6% (w / v).

[0010] In one embodiment, the propylene glycol monocaprylate may be included in an amount of more than 0% (w / v) and less than 70% (w / v) or 0.1 to 10% (w / v) of the total amount of the external preparation composition.

[0011] In one embodiment, the external composition may be in any one formulation selected from a solution, suspension, emulsion, paste, gel, cream, essence, lotion, emulsion, oil, wax, spray, pack, ampoule, shampoo, hair toner, hair tonic, foam, and skin ointment.

[0012] In one embodiment, the topical composition may further comprise at least one selected from the group consisting of L-menthol, pyridoxine, a preservative, and a polyhydric alcohol.

[0013] In one embodiment, the topical composition may include alcohol as a solvent, and the alcohol may be included in an amount of 10 to 80% (v / v).

[0014] In one embodiment, the topical composition may have a pH of 5.0 to 7.0.

[0015] According to the present invention, it has been found that an external composition comprising minoxidil and propylene glycol monocaprylate not only improves the solubility of minoxidil, but also maintains the transparent appearance of the external composition, minimizes discoloration, and improves the skin permeability of minoxidil, thereby significantly increasing skin absorption.

[0016] Therefore, the topical composition comprising minoxidil and propylene glycol monocaprylate of the present invention can be usefully used as a topical composition for hair growth in the medical and pharmaceutical fields.

[0017] The effects of the present invention are not limited to the effects described above, and should be understood to include all effects that can be inferred from the composition of the invention described in the description or claims of the present invention.

[0018] Figure 1 is a graph showing the cumulative skin penetration of minoxidil measured over 24 hours using Franz Cell for full thickness human skin.

[0019] Figure 2 shows the results of measuring skin permeability for 24 hours for formulations with different concentrations of propylene glycol monocaprylate (Capryol 90).

[0020] Figure 3 shows the results of measuring the residual amount in the skin after 24 hours for preparations with different concentrations of propylene glycol monocaprylate (Capryol 90) (epidermis, dermis, receptor).

[0021] [Revised 04.08.2025 according to Rule 91] Figure 4 shows the results of measuring skin permeability for 24 hours for formulations with different concentrations of propylene glycol monocaprylate (Capryol 90). Figure 5 shows the results of confirming the color change over time of a commercially available minoxidil 5% complex formulation from Company H and Example 2. Figure 6 shows the results of showing the properties of the formulations of Comparative Example 11 and Examples 4 to 11.

[0022] The present invention provides an external composition comprising minoxidil and propylene glycol monocaprylate.

[0023] The topical composition of the present invention is a topical composition that exists in a formulation that can be used as an external agent within the concentration range of minoxidil used in general hair loss treatments. Furthermore, according to the composition of the topical composition of the present invention, compared to existing commercial products that are prone to discoloration over time during storage, the topical composition of the present invention is a formulation that significantly mitigates discoloration during storage.

[0024] In the structure of the skin, hair follicles are distributed in the dermis and the subcutaneous fat layer below it. Since minoxidil must penetrate the hair follicles to exhibit its hair growth effect, penetration below the epidermis is crucial for achieving minoxidil's hair growth effect. The topical composition of the present invention was confirmed to contain propylene glycol monocaprylate, allowing minoxidil to reach and penetrate the dermis. This skin penetration effect was confirmed to be significantly improved compared to commercially available products.

[0025] In the topical composition of the present invention, minoxidil may be included in a concentration capable of exhibiting a hair growth (hair growth) effect. For example, it may be included in a concentration of 1 to 6% (w / v), 2 to 5% (w / v), 2% (w / v), 3% (w / v), 5% (w / v), etc., but is not limited thereto.

[0026] In one embodiment, the propylene glycol monocaprylate may be included in an amount of more than 0% (w / v) and less than 70% (w / v) based on the total amount of the external preparation composition, and preferably may be included in an amount of 0.1 to 50% (w / v), 0.1 to 30% (w / v), 0.1 to 20% (w / v), 0.1 to 15% (w / v), 0.1 to 10% (w / v), 0.1 to 7% (w / v), or 1 to 6% (w / v).

[0027] In one embodiment, the external composition may be in any one of the following dosage forms: a solution, a suspension, an emulsion, a paste, a gel, a cream, an essence, a lotion, an emulsion, an oil, a wax, a spray, a pack, an ampoule, a shampoo, a hair toner, a hair tonic, a foam, and an ointment for external use. Preferably, the external composition may be a solution, and it is preferable that the external composition exists as a solution in terms of skin absorption of the active ingredient (minoxidil) and the expression of effects (hair growth, hair growth) at the target site of activity (hair follicles). In addition, there is an advantage in terms of stability of the formulation, and it is also advantageous in terms of user convenience.

[0028] In one embodiment, the topical composition may include at least one selected from the group consisting of L-menthol, pyridoxine, a preservative, and a polyhydric alcohol.

[0029] The above L-menthol induces angiogenesis to alleviate hair loss, relieve itching, and reduce scalp heat, and can be included in the external application composition of the present invention at 0.01 to 2% (w / v).

[0030] The above pyridoxine is involved in protein metabolism, thereby supplying keratin and melanin to hair follicles, promoting hair growth and regeneration, and inhibiting sebum secretion. It can be included in the topical composition of the present invention at 0.001 to 2% (w / v).

[0031] The above preservative reduces oxidative stress on hair follicles through its antioxidant effect, thereby preventing hair loss and promoting hair regeneration. For example, the preservative may be tocopherol, sesame oil, gossypol, phospholipids, phenolic compounds, quinones, amines, organic acids, alcohols, inorganic acids, inorganic salts, sulfur compounds, or a combination thereof, but is not limited to a known preservative commonly used in the manufacture of external skin compositions. Tocopherol is preferably used, and may be included in the external skin composition of the present invention at 0.001 to 2% (w / v).

[0032] The above polyhydric alcohol may be at least one selected from the group consisting of propanediol, methylpropanediol, 1,3-butylene glycol, propylene glycol, glycerin, 1,2-hexanediol, 1,2-pentanediol, D-panthenol, dipropylene glycol, sorbitol, polyethylene glycol, diglycerin, or a mixture of two or more thereof, but is not particularly limited as long as it is a polyhydric alcohol that can be typically used in the manufacture of a skin external preparation composition. In the external preparation composition of the present invention, it may be included in an amount of 0 to 50% (w / v).

[0033] In one embodiment, the topical composition may include alcohol as a solvent. Examples of alcohols that may be used include, but are not limited to, methanol, ethanol, and propanol. The alcohol may be included in an amount of 10 to 80% (v / v).

[0034] In one embodiment, the topical composition may have a pH of 5.0 to 7.0. The desired pH may be adjusted using a pH adjusting agent commonly used during formulation.

[0035] The external preparation composition of the present invention can be manufactured by adding the included components to a solvent, adjusting the pH to the desired pH with a pH adjuster, and then adjusting the final volume of the preparation to water (purified water) and stirring.

[0036]

[0037] Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are intended to illustrate the present invention and are not intended to limit the scope of the present invention.

[0038]

[0039] Test Example 1: Evaluation of properties and solubility

[0040] Ethanol, purified water, solubilizer, and minoxidil were mixed in a weight ratio of 5:3:2:1.2, and the pH was adjusted to 6.0 with phosphoric acid. Minoxidil was added until supersaturated and stirred overnight. After incubation at room temperature for 2 hours, the appearance was recorded, and the filtrate was filtered through a 0.2 μm syringe filter. The amount of minoxidil present in the filtrate was analyzed by HPLC. Table 1 below shows the appearance and solubility comparison results according to the type of propylene glycol monocaprylate.

[0041] Solubility in mg / mL of group solubilizer ingredients - Control (only water and ethanol, pH adjuster) X (turbid) 64.13 Ester compounds of fatty acid alcohols Propylene glycol monocaprylate O (colorless and transparent) 74.64 Propylene glycol monolaurate X (layer separation) 58.27 Propylene glycol dicaprylated / dicaprylate X (layer separation) 56.28 Nitrogen-containing 5-membered lactam organic compounds N-methyl-2-pyrrolidone O (colorless and transparent) 73.66 N-dodecyl-2-pyrrolidone O (colorless and transparent) 65.84 Ether alcohols Diethylene glycol monoethyl ether O (colorless and transparent) 71.26 Glyceryl monoester Glyceryl monooleate X (turbid) 63.73 Glyceryl triester Caprylic / capric triglyceride X (Layer separation) 58.59 Fatty acid and polyalkylene glycol ester Caprylocapriol polyoxylglyceride O (colorless transparent) 70.99 Oleyl polyoxylglyceride X (turbid) 61.84 Polyoxyethylene fatty ether Polyoxyl 2 oleyl ether O (colorless transparent) 59.57 Polyoxyethylene polyoxypropylene copolymer Poloxamer 124 O (colorless transparent) 65.67 Alkoxylated derivative of natural oil Polyoxyl-35 castor oil O (colorless transparent) 68.87 Alkoxylated sugar derivative Polysorbate 20 O (colorless transparent) 68.05 Fatty acid ester of alcohol Isopropyl myristate X (Layer separation) 57.95

[0042] In the above results, propylene glycol monocaprylate dissolved in a colorless and transparent form was formulated as in Example 1 and Comparative Examples 1 to 6.

[0043]

[0044] Comparative Example 1

[0045] 50 g of ethanol, 2 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, and 5 g of minoxidil were added, the pH was adjusted to 6.0 with phosphoric acid, and the final volume was made to 100 mL with purified water, followed by stirring for 1 hour.

[0046]

[0047] Example 1

[0048] 50 g of ethanol, 2 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 20 g of propylene glycol monocaprylate, and 5 g of minoxidil were added, the pH was adjusted to 6.0 with phosphoric acid, and the final volume was made to 100 mL with purified water, followed by stirring for 1 hour.

[0049]

[0050] Comparative Example 2

[0051] 50 g of ethanol, 2 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 20 g of N-methyl-2-pyrrolidone, and 5 g of minoxidil were added, the pH was adjusted to 6.0 with phosphoric acid, and the final volume was made to 100 mL with purified water, followed by stirring for 1 hour.

[0052]

[0053] Comparative Example 3

[0054] 50 g of ethanol, 2 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 20 g of diethylene glycol monoethyl ether, and 5 g of minoxidil were added, the pH was adjusted to 6.0 with phosphoric acid, and the final volume was made to 100 mL with purified water, followed by stirring for 1 hour.

[0055]

[0056] Comparative Example 4

[0057] Ethanol 50 g, butylhydroxytoluene 2 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, tocopherol acetate 0.08 g, caprylocapriol polyoxylglyceride 20 g, and minoxidil 5 g were added, pH was adjusted to 6.0 with phosphoric acid, and the final volume was made to 100 mL with purified water and stirred for 1 hour to prepare.

[0058]

[0059] Comparative Example 5

[0060] 50 g of ethanol, 2 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 20 g of polysorbate 20, and 5 g of minoxidil were added, the pH was adjusted to 6.0 with phosphoric acid, and the final volume was made to 100 mL with purified water, followed by stirring for 1 hour.

[0061]

[0062] Comparative Example 6

[0063] 50 g of ethanol, 2 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 20 g of polyoxyl-35 castor oil, and 5 g of minoxidil were added, the pH was adjusted to 6.0 with phosphoric acid, and the final volume was made to 100 mL with purified water, followed by stirring for 1 hour.

[0064]

[0065] The components of Example 1 and Comparative Examples 1 to 6 are summarized in Table 2 below.

[0066] Ingredient Comparative Example 1 Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6% Minoxidil 5555555 L-Menthol 0.30.30.30.30.30.30.3 Pyridoxine HCl 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Tocopherol Acetate 0.08 0.08 0.08 0.08 0.08 0.08 0.08 Solubilizer Propylene Glycol Monocaprylate-20-----N-Methyl-2-Pyrrolidone--20----Diethylene Glycol Monoethyl Ether---20---Caprylocapriol Polyoxylglyceride----20--Polysorbate 20-----20-Polyoxyl-35 Castor Oil------20 Ethanol 50 50 50 50 50 50 50 Butyl hydroxytoluene 22 22 22 2 Phosphoric acid Up to pH 6.0 Appropriate amount Up to pH 6.0 Appropriate amount Up to pH 6.0 Appropriate amount Up to pH 6.0 Appropriate amount Up to pH 6.0 Appropriate amount Up to pH 6.0 Appropriate amount Purified water Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount

[0067]

[0068] Test Example 2: Skin PAMPA (Parallel Artificial Permeability Assays)

[0069] 24 hours prior to the test, 0.2 mL of hydration solution was added to the upper well of the Skin PAMPA to hydrate it. After 24 hours, the hydration solution was removed, and 0.3 mL of pH 7.4 PBS solution was added, and 0.2 mL of the test solution (Example 1, Comparative Examples 1-6) was added to the bottom well. After a certain period of time, 0.2 mL of the receptor solution in the upper well was sampled and replenished with 0.2 mL of PBS solution. The amount of minoxidil in each sample was analyzed by HPLC to determine the cumulative permeation amount through the artificial membrane for 6 hours. The results are shown in Table 3 below.

[0070] Test group Comparative example 1 Example 1 Comparative example 2 Comparative example 3 Comparative example 4 Comparative example 5 Comparative example 6 Permeation amount (μg / cm) after 6 hours of artificial membrane (Skin PAMPA) 2 )590.23519.4418.7309.1247.7223.9456.3

[0071] As shown in Table 3 above, it was confirmed that the minoxidil permeation amount of the Example 1 solution was significantly higher than that of other comparative examples.

[0072]

[0073] Comparative Example 7

[0074] 60 g of ethanol, 0.1 g of butylated hydroxytoluene, 5 g of butylene glycol, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, and 5 g of minoxidil were added, and the pH was adjusted to 6.0 with phosphoric acid. The final volume was made to 100 mL with purified water, and stirred for 1 hour to prepare the solution.

[0075]

[0076] Example 2

[0077] 60 g of ethanol, 0.1 g of butylated hydroxytoluene, 5 g of butylene glycol, 2 g of propylene glycol monocaprylate, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, and 5 g of minoxidil were added, adjusted to pH 6.0 with phosphoric acid, and the final volume was made to 100 mL with purified water, followed by stirring for 1 hour.

[0078]

[0079] Comparative Example 8

[0080] 60 g of ethanol, 0.1 g of butylated hydroxytoluene, 5 g of butylene glycol, 2 g of N-dodecyl-2-pyrrolidone, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, and 5 g of minoxidil were added, adjusted to pH 6.0 with phosphoric acid, and the final volume was made up to 100 mL with purified water, followed by stirring for 1 hour.

[0081]

[0082] Comparative Example 9

[0083] 60 g of ethanol, 0.1 g of butylated hydroxytoluene, 5 g of butylene glycol, 2 g of polyoxyl 10 oleyl ether, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, and 5 g of minoxidil were added, adjusted to pH 6.0 with phosphoric acid, and the final volume was made up to 100 mL with purified water, followed by stirring for 1 hour.

[0084]

[0085] Comparative Example 10

[0086] 60 g of ethanol, 0.1 g of butylated hydroxytoluene, 5 g of butylene glycol, 2 g of diethylene glycol monoethyl ether, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, and 5 g of minoxidil were added, adjusted to pH 6.0 with phosphoric acid, and the final volume was made up to 100 mL with purified water, followed by stirring for 1 hour.

[0087]

[0088] The components of Example 2 and Comparative Examples 7 to 10 are summarized in Table 4 below.

[0089] Ingredient Comparative Example 7Example 2Comparative Example 8Comparative Example 9Comparative Example 10% Minoxidil 55555L-Menthol 0.30.30.30.30.3 Pyridoxine HCl 0.050.050.050.050.05 Tocopherol Acetate 0.080.080.080.080.080.08 Butylene Glycol 55555 Solubilizer Propylene Glycol Monocaprylate-2---N-Dodecyl-2-Pyrrolidone---2-Polyoxyl 10 Oleyl Ether---2-Diethylene Glycol Monoethyl Ether----2 Ethanol 6060606060 Butyl Hydroxytoluene 0.10.10.10.10.1 Phosphoric Acid Up to PH 6.0 Appropriate amount Up to PH 6.0 Appropriate amount Up to PH 6.0 Up to PH 6.0 Up to PH 6.0 Up to 100% of purified water Up to 100% Up to 100% Up to 100% Up to 100% Up to 100% Up to 100% Up to 100%

[0090]

[0091] Test Example 3: Evaluation of skin penetration and dermal residual amount for human full-thickness skin

[0092] In order to measure the skin penetration of three commercially available products (H Company 5% minoxidil complex, D Company 5% minoxidil complex, (Japan) T Company 5% minoxidil complex), Example 2, and Comparative Examples 7 to 10, the following procedure was performed using a Franz diffusion cell.

[0093] Human cadaver full-thickness skin (epidermis + dermis) was used. The Franz cell receptor was filled with PBS (phosphate buffer, pH 7.4), and the temperature was maintained at 32°C, while stirring at 600 rpm using a magnetic bar.

[0094] The skin was placed over the Franz cell receptor and firmly secured with a clamp. A dose equivalent to 5 mg of minoxidil was applied to the skin. For quantitative analysis of the permeated drug, approximately 1.5 mL was taken from the receptor chamber at regular intervals and quantified using HPLC. During sampling, the entire receptor media was removed and replaced with PBS solution. The results are shown in Figure 1.

[0095] After 24 hours, receptor chamber samples were taken, and the entire skin was soaked in 60°C water for 1-2 minutes to separate the epidermis and dermis. Each skin was separated, placed in 5 mL of methanol, and sonicated for 90 minutes to extract any residual minoxidil within the skin. This was then quantified using HPLC. The results are shown in Table 5 below.

[0096] Test group Skin residual amount after 24 hours (μg / cm) 2) Epidermis Dermis H Company Minoxidil 5% Complex 53.15105.48 D Company Minoxidil 5% Complex 70.81116.32 (Japan) T Company Minoxidil 5% Complex 135.6786.44 Comparative Example 7127.5489.29 Exemplary Example 232.62456.70 Comparative Example 84.1114.72 Comparative Example 9503.12120.53 Comparative Example 10216.9285.72

[0097] As shown in Fig. 1, Example 2, to which propylene glycol monocaprylate was applied, showed superior skin penetration compared to Comparative Examples 7 to 10 and three commercially available products.

[0098] In addition, as can be seen in Table 5 above, Example 2 was confirmed to be superior to Comparative Examples 7 to 10 and three commercially available products in terms of the amount of skin residue after 24 hours in terms of the amount transferred to the dermis compared to the epidermis.

[0099]

[0100] Test Example 4: Color Change over Time

[0101] The color change over time of the commercially available H Company minoxidil 5% complex and Example 2 was confirmed.

[0102] The two test groups were (1) stored under room temperature and natural light conditions for 7 months, (2) stored under harsh conditions (60℃, 80% relative humidity) for 2 weeks and then stored under room temperature and natural light conditions for 6.5 months, and (3) stored under harsh conditions (60℃, 80% relative humidity) for 4 weeks and then stored under room temperature and natural light conditions for 6 months. The results are shown in Table 6 below.

[0103] [Correction pursuant to Rule 91, 04.08.2025]

[0104] [Correction under Rule 91 04.08.2025] As shown in Table 6 and Figure 5 above, it was confirmed that the color change in Example 2 was significantly reduced compared to the commercial product.

[0105]

[0106] Example 3

[0107] Ethanol 60 g, butylated hydroxytoluene 0.1 g, butylene glycol 5 g, propylene glycol monocaprylate 3 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, tocopherol acetate 0.08 g, dexpanthenol 0.08 g, nicotinamide 0.8 g, and minoxidil 5 g were added, adjusted to pH 6.0 with phosphoric acid, made into 100 mL with purified water, and stirred for 1 hour to prepare.

[0108]

[0109] Test Example 5: Stability Test

[0110] Example 3 was stored under harsh storage conditions (60°C / RH 80%), and the content of each active ingredient was quantified using HPLC at 2, 4, and 6 weeks after storage. The results are shown in Table 7 below, and were compared by converting the initial value to 100%.

[0111] 60℃ / RH80% Minoxidil L-Menthol Pyridoxine HCl Tocopherol Acetate Relative Content % Initial 100.00 100.00 100.00 100.00 2 weeks 99.79 97.42 98.29 99.54 4 weeks 101.34 101.76 97.79 98.70 6 weeks 100.93 100.62 96.49 96.95

[0112] As can be confirmed in Table 7 above, it was confirmed that the content was stably maintained for 6 weeks under harsh conditions.

[0113]

[0114] Comparative Example 11

[0115] 50 g of ethanol, 0.08 g of tocopherol acetate, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.2 g of butylhydroxytoluene, and 5 g of minoxidil were added, the pH was adjusted to 6.0 with phosphoric acid, and the solution was made into 100 mL with purified water and stirred for 1 hour.

[0116]

[0117] Example 4

[0118] Propylene glycol monocaprylate 0.1 g, ethanol 50 g, tocopherol acetate 0.08 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, butylhydroxytoluene 0.2 g, minoxidil 5 g were added, the pH was adjusted to 6.0 with phosphoric acid, the volume was made to 100 mL with purified water, and the mixture was stirred for 1 hour to prepare.

[0119]

[0120] Example 5

[0121] Propylene glycol monocaprylate 10 g, ethanol 50 g, tocopherol acetate 0.08 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, butylhydroxytoluene 0.2 g, minoxidil 5 g were added, pH was adjusted to 6.0 with phosphoric acid, and then the solution was made into 100 mL with purified water and stirred for 1 hour.

[0122]

[0123] Example 6

[0124] Propylene glycol monocaprylate 20 g, ethanol 50 g, tocopherol acetate 0.08 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, butylhydroxytoluene 0.2 g, minoxidil 5 g were added, the pH was adjusted to 6.0 with phosphoric acid, the volume was made to 100 mL with purified water, and the mixture was stirred for 1 hour to prepare.

[0125]

[0126] Example 7

[0127] Propylene glycol monocaprylate 30 g, ethanol 50 g, tocopherol acetate 0.08 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, butylhydroxytoluene 0.2 g, minoxidil 5 g were added, the pH was adjusted to 6.0 with phosphoric acid, the volume was made to 100 mL with purified water, and the mixture was stirred for 1 hour to prepare.

[0128]

[0129] Example 8

[0130] Propylene glycol monocaprylate 40 g, ethanol 50 g, tocopherol acetate 0.08 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, butylhydroxytoluene 0.2 g, minoxidil 5 g were added, pH was adjusted to 6.0 with phosphoric acid, and then the solution was made into 100 mL with purified water and stirred for 1 hour.

[0131]

[0132] Example 9

[0133] Propylene glycol monocaprylate 50 g, ethanol 50 g, tocopherol acetate 0.08 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, butylhydroxytoluene 0.2 g, minoxidil 5 g were added, the pH was adjusted to 6.0 with phosphoric acid, the volume was made to 100 mL with purified water, and the mixture was stirred for 1 hour to prepare.

[0134]

[0135] Example 10

[0136] Propylene glycol monocaprylate 60 g, ethanol 50 g, tocopherol acetate 0.08 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, butylhydroxytoluene 0.2 g, minoxidil 5 g were added, the pH was adjusted to 6.0 with phosphoric acid, the volume was made to 100 mL with purified water, and the mixture was stirred for 1 hour to prepare.

[0137]

[0138] Example 11

[0139] Propylene glycol monocaprylate 70 g, ethanol 50 g, tocopherol acetate 0.08 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, butylhydroxytoluene 0.2 g, minoxidil 5 g were added, the pH was adjusted to 6.0 with phosphoric acid, the volume was made to 100 mL with purified water, and the mixture was stirred for 1 hour to prepare.

[0140]

[0141] Ingredient name Comparative example 11 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11% Minoxidil 555555555 L-menthol 0.30.30.30.30.30.30.30.30.3 Pyridoxine HCl 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Tocopherol acetate 0.08 0.08 0.08 0.08 0.08 0.08 0.08 0.08 Propylene glycol Monocaprylate 00.110 20 30 40 50 60 70 Butylhydroxytoluene 22 22 22 22 22 2 Ethanol 55 55 50 50 35 30 20 10 Phosphoric acid Up to PH 6.0 Appropriate amount Up to PH 6.0 Appropriate amount Up to PH 6.0 Appropriate amount Up to PH 6.0 Appropriate amount Up to PH 6.0 Appropriate amount Up to PH 6.0 Appropriate amount Up to PH 6.0 Appropriate amount Purified water Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount Up to 100% Appropriate amount

[0142]

[0143] Test Example 6: Comparison of the properties of the formulations

[0144] The properties of the formulations of Comparative Example 11 and Examples 4 to 11 are shown in Table 9 below.

[0145] [Correction pursuant to Rule 91, 04.08.2025]

[0146] [Correction under Rule 91 04.08.2025] As shown in Table 9 and Figure 6 above, when propylene glycol monocaprylate was added from 0% to 70% and formulated, precipitation occurred from 70%, and it was confirmed that the formulation was colorless and transparent in the range of 0% to 60%.

[0147]

[0148] Comparative Example 12

[0149] 60 g of ethanol, 0.1 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 0.08 g of dexpanthenol, 0.8 g of nicotinamide, and 5 g of minoxidil were added, adjusted to pH 6.3 with citric acid monohydrate, made into 100 mL with purified water, and stirred for 1 hour to prepare.

[0150]

[0151] Example 12

[0152] 60 g of ethanol, 0.1 g of propylene glycol monocaprylate, 0.1 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 0.08 g of dexpanthenol, 0.8 g of nicotinamide, and 5 g of minoxidil were added, adjusted to pH 6.3 with citric acid monohydrate, made into 100 mL with purified water, and stirred for 1 hour to prepare.

[0153]

[0154] Example 13

[0155] 60 g of ethanol, 1 g of propylene glycol monocaprylate, 0.1 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 0.08 g of dexpanthenol, 0.8 g of nicotinamide, and 5 g of minoxidil were added, adjusted to pH 6.3 with citric acid monohydrate, made into 100 mL with purified water, and stirred for 1 hour to prepare.

[0156]

[0157] Example 14

[0158] 60 g of ethanol, 2.5 g of propylene glycol monocaprylate, 0.1 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 0.08 g of dexpanthenol, 0.8 g of nicotinamide, and 5 g of minoxidil were added, adjusted to pH 6.3 with citric acid monohydrate, made into 100 mL with purified water, and stirred for 1 hour to prepare.

[0159]

[0160] Example 15

[0161] 60 g of ethanol, 5 g of propylene glycol monocaprylate, 0.1 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 0.08 g of dexpanthenol, 0.8 g of nicotinamide, and 5 g of minoxidil were added, adjusted to pH 6.3 with citric acid monohydrate, made into 100 mL with purified water, and stirred for 1 hour to prepare.

[0162]

[0163] Example 16

[0164] 60 g of ethanol, 7.5 g of propylene glycol monocaprylate, 0.1 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 0.08 g of dexpanthenol, 0.8 g of nicotinamide, and 5 g of minoxidil were added, adjusted to pH 6.3 with citric acid monohydrate, made into 100 mL with purified water, and stirred for 1 hour to prepare.

[0165]

[0166] Example 17

[0167] 60 g of ethanol, 10 g of propylene glycol monocaprylate, 0.1 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 0.08 g of dexpanthenol, 0.8 g of nicotinamide, and 5 g of minoxidil were added, adjusted to pH 6.3 with citric acid monohydrate, made into 100 mL with purified water, and stirred for 1 hour to prepare.

[0168]

[0169] Example 18

[0170] 60 g of ethanol, 15 g of propylene glycol monocaprylate, 0.1 g of butylhydroxytoluene, 0.3 g of L-menthol, 0.05 g of pyridoxine HCl, 0.08 g of tocopherol acetate, 0.08 g of dexpanthenol, 0.8 g of nicotinamide, and 5 g of minoxidil were added, and the pH was adjusted to 6.3 with citric acid monohydrate, and the solution was made into 100 mL with purified water and stirred for 1 hour.

[0171]

[0172] Example 19

[0173] Ethanol 60 g, propylene glycol monocaprylate 20 g, butylhydroxytoluene 0.1 g, L-menthol 0.3 g, pyridoxine HCl 0.05 g, tocopherol acetate 0.08 g, dexpanthenol 0.08 g, nicotinamide 0.8 g, and minoxidil 5 g were added, and the pH was adjusted to 6.3 with citric acid monohydrate, and the solution was made into 100 mL with purified water and stirred for 1 hour.

[0174]

[0175] Ingredient name Comparative example 12 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19% Minoxidil 555555555 L-menthol 0.30.30.30.30.30.30.30.30.3 Pyridoxine HCl 0.050.050.050.050.050.050.050.050.050.050.050.05 Tocopherol acetate 0.080.080.080.080.080.080.080.080.080.08 Propylene glycol Monocaprylate-0.112.557.5101520Butylhydroxytoluene0.10.10.10.10.10.10.10.10.10.1Dexpanthenol0.080.080.080.080.080.080.080.080.080.080.08Nicotinamide0.80.80.80.80.80.80.80.8Citric acid hydrateUp to pH 6.3Amount up to pH 6.3Amount up to pH 6.3Amount up to pH 6.3Amount up to pH 6.3Amount up to pH 6.3Amount up to pH 6.3Amount up to pH 6.3Amount up to pH 6.3 Ethanol 6060606060606060606060 Purified water Amount Amount Amount Amount Amount Amount Amount Amount Amount Amount Amount Amount

[0176]

[0177] Test Example 7: Measurement of Skin Permeability

[0178] For Comparative Example 12 and Examples 12 to 16, skin permeability was measured for 24 hours, and the results are shown in Table 11 and Figure 2 below.

[0179] Cumulative permeation (μg / cm) 2 )Example Comparative Example 12Example 12Example 13Example 14Example 15Example 16Propylene glycol monocaprylate concentration 0%0.1 %1%2.5%5%7.5%0 hours0.000.000.000.000.000.004 hours52.6668.5595.68113.45188.70150.038 hours126.76249.12287.73505.96652.78528.3312 hours220.44424.17500.34861.691044.08859.8824 hours341.24657.62729.411405.441570.441332.04

[0180]

[0181] Additionally, the residual amount in the skin after 24 hours is shown in Table 12 and Figure 3.

[0182] Test group epidermis (μg / cm) 2 )Dermis (μg / cm 2 ) receptor (μg / cm 2 )Example 16115.05177.341332.04Example 15106.49310.141570.44Example 1464.59157.321405.44Example 13145.30106.40729.41Example 12328.17111.26657.62Comparative Example 12283.5057.29341.24

[0183] As shown in Tables 11 and 12 and FIGS. 2 and 3, in the case of a formulation containing propylene glycol monocaprylate (capryol 90) in a concentration range of 0.1% to 7.5%, the amount of minoxidil permeated into the dermis and receptor increased compared to the case where propylene glycol monocaprylate (capryol 90) was not included (0%), and it was confirmed that there was an effect of improving skin permeation.

[0184]

[0185] Test Example 8: Measurement of Skin Permeability

[0186] For Comparative Example 13 and Examples 20 to 23, skin permeability was measured for 24 hours, and the results are shown in Table 13 and Figure 4 below.

[0187]

[0188] Comparative Example 13

[0189] 50 g of ethanol, 5 g of minoxidil, and 5 g of butylene glycol were added, the pH was adjusted to 6.3 with citric acid hydrate, the solution was made into 100 mL with purified water, and stirred for 1 hour to prepare the solution.

[0190]

[0191] Example 20

[0192] 50 g of ethanol, 0.1 g of propylene glycol monocaprylate, 5 g of minoxidil, and 5 g of butylene glycol were added, the pH was adjusted to 6.3 with citric acid hydrate, the solution was made into 100 mL with purified water, and stirred for 1 hour to prepare the solution.

[0193]

[0194] Example 21

[0195] 50 g of ethanol, 1 g of propylene glycol monocaprylate, 5 g of minoxidil, and 5 g of butylene glycol were added, the pH was adjusted to 6.3 with citric acid hydrate, the solution was made into 100 mL with purified water, and stirred for 1 hour to prepare the solution.

[0196]

[0197] Example 22

[0198] 50 g of ethanol, 5 g of propylene glycol monocaprylate, 5 g of minoxidil, and 5 g of butylene glycol were added, the pH was adjusted to 6.3 with citric acid hydrate, the solution was made into 100 mL with purified water, and stirred for 1 hour to prepare the solution.

[0199]

[0200] Example 23

[0201] 50 g of ethanol, 10 g of propylene glycol monocaprylate, 5 g of minoxidil, and 5 g of butylene glycol were added, the pH was adjusted to 6.3 with citric acid monohydrate, the solution was made into 100 mL with purified water, and stirred for 1 hour to prepare the solution.

[0202]

[0203] Cumulative permeation (μg / cm) 2)Experimental group Comparative example 13Example 20Example 21Example 22Example 23Propylene glycol monocaprylate concentration0%0.1%1%5%10%0 hours0.000.000.000.000.003 hours0.670.660.150.380.176 hours1.562.230.992.442.5012 hours5.2710.2815.4228.8424.8518 hours9.2417.7337.1965.7153.5724 hours12.7823.4553.0495.6474.79

[0204] As shown in Table 13 and Fig. 4, except for the main ingredients and excipients other than minoxidil, formulations were prepared with butylene glycol, which helps solubilize minoxidil, solvents such as ethanol and water, pH adjuster citric acid hydrate, and propylene glycol monocaprylate (capryol 90) in a concentration range of 0.1% to 10%. When compared with the sample without propylene glycol monocaprylate (capryol 90) (Comparative Example 13), the permeation amount into the receptor increased in Examples 20 to 23 containing propylene glycol monocaprylate (capryol 90), confirming that propylene glycol monocaprylate (capryol 90) exhibits an effect of improving skin permeation of minoxidil. In addition, in connection with the previous experimental example 7, it was confirmed that the transmittance was highest at a concentration of propylene glycol monocaprylate (capryol 90) of around 5%.

[0205]

[0206] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single entity may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined manner.

[0207]

[0208] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. An external composition comprising minoxidil and propylene glycol monocaprylate.

2. An external application composition according to claim 1, wherein the minoxidil is contained in an amount of 1 to 6% (w / v).

3. A composition for external use, wherein the propylene glycol monocaprylate is contained in an amount of more than 0% (w / v) and less than 70% (w / v) of the total amount of the composition for external use.

4. A composition for external use, wherein the propylene glycol monocaprylate is contained in an amount of 0.1 to 10% (w / v) based on the total amount of the composition for external use.

5. An external composition according to claim 1, wherein the external composition is in any one of the following formulations: a solution, a suspension, an emulsion, a paste, a gel, a cream, an essence, a lotion, an emulsion, an oil, a wax, a spray, a pack, an ampoule, a shampoo, a hair toner, a hair tonic, a foam, and an external ointment for skin.

6. An external preparation composition according to claim 1, wherein the external preparation composition further comprises at least one selected from the group consisting of L-menthol, pyridoxine, a preservative, and a polyhydric alcohol.

7. An external preparation composition according to claim 1, wherein the external preparation composition contains alcohol as a solvent.

8. A composition for external use, wherein the alcohol is contained in an amount of 10 to 80% (v / v) in the 7th paragraph.

9. An external preparation composition according to claim 1, wherein the external preparation composition has a pH of 5.0 to 7.0.

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