KR100878198B1 - Gel composition comprising minoxidil - Google Patents

Abstract

A gel composition is provided to allow a stable gel phase to be maintained with dissolving a higher concentration of minoxidil and to reduce the irritation of the skin. A gel composition comprises an effective amount of minoxidil; a thickening agent; and an aqueous solvent containing glycerin, wherein the content of glycerin 12-28 wt% based on the total gel composition, and the gel composition has a pH of 7.5-9.0. Preferably the content of minoxidil is 1-10 wt%, the content of the thickening agent is 0.1-2 wt%, and the content of the aqueous solvent containing glycerin is 89-98 wt%.

Description

Gel composition containing minoxidil {GEL COMPOSITION COMPRISING MINOXIDIL}

The present invention relates to a gel composition comprising minoxidil. More specifically, the present invention relates to a gel composition capable of maintaining a stable gel phase while dissolving a high concentration of minoxidil.

Minoxidil, ie 2,4-diamino-6-piperidinylpyrimidine-3-oxide, is an active ingredient that is widely used for the treatment or prevention of hypertension or androgenetic alopecia. In particular, methods for using minoxidil and topical formulations for growing hair and treating male or female baldness are disclosed in US Pat. Nos. 4,139,619 and 4,596,812 and the like.

The topical formulations comprising minoxidil can take various forms, including liquids, gels or suspensions.

However, when a topical preparation in the form of a suspension in which the active ingredient minoxidil is not dissolved in the medium but only suspended is used, the absorption of the active ingredient is not properly achieved in the body and the therapeutic effect cannot be properly expressed. In addition, even in the case of a topical preparation in liquid form, since it is difficult to stay at the application site for a sufficient time, the active ingredient minoxidil is not absorbed in a sufficient amount and the bioavailability is low, thereby fully expressing the therapeutic effect of the minoxidil. none.

In contrast, in the case of a gelled topical preparation, since it can stay at the application site such as the scalp for a sufficient time, the absorption rate and bioavailability of the minoxidil can be further improved, and the improved treatment effect for alopecia and the like is exhibited. Can be.

Accordingly, various attempts have been made to provide a topical formulation comprising minoxidil in the form of a gel.

For example, US Pat. No. 5,225,189 discloses water, carbomer thickeners, pharmaceutically acceptable glycols (e.g., propylene glycol), ethanol or isopropanol, and water or alcohols with minoxidil as an active ingredient. A gel composition comprising an amine soluble in is disclosed. In such gel compositions, minoxidil is solubilized using glycols such as propylene glycol, and the topical preparations are made to have a gel form using the carbomer thickener.

International Publication No. WO 02/11698 also includes noncarbomer thickeners and pharmaceutically acceptable solvents (eg, glycols such as propylene glycol and alcohols such as ethanol) together with minoxidil as active ingredient. A composition in the form of a gel is disclosed. In such a composition, a minoxidil is solubilized using a solvent such as glycol such as propylene glycol, and the composition is provided in a gel form using the noncarbomer thickener.

By the way, in the conventional gel-type topical preparation mentioned above, although minoxidil is solubilized to some extent using solvents, such as propylene glycol, there exists a limit to solubilizing minoxidil using such propylene glycol. Therefore, the conventional gel-type topical preparations are difficult to maintain a stable gel phase while dissolving the minoxidil at a high concentration of, for example, 3 wt% or more, and thus may not exhibit a sufficient therapeutic effect against alopecia and the like.

In addition, the propylene glycol is a solvent showing a relatively large irritation to the skin, the conventional gel-type topical formulation using the same may cause side effects when applied to the scalp for the treatment of alopecia and the like.

Accordingly, the present invention is to provide a gel composition that can maintain a stable gel phase while dissolving a higher concentration of minoxidil, and can reduce skin irritation.

The present invention provides a gel composition comprising an effective amount of minoxidil, a thickener, and a water soluble solvent containing glycerin.

Hereinafter, the pharmaceutical composition and the preparation method thereof according to an embodiment of the present invention will be described in detail.

According to one embodiment of the invention, there is provided a gel composition comprising an effective amount of minoxidil, a thickening agent, and a water soluble solvent containing glycerin.

As a result of the experiments of the present inventors, with glycerin, higher concentrations, for example, 3 to 5% by weight or more of minoxidil can be dissolved in the solvent, and in particular, a thickening agent for providing a composition in the form of a gel is mixed. Even though it has been found that minoxidil dissolved in the aqueous solvent can stably maintain the dissolved transparent gel state without generating white precipitate. Therefore, according to one embodiment of the present invention, a gel composition of minoxidil can be provided that can maintain a stable gel phase while dissolving a higher concentration of minoxidil.

In addition, the gel composition can be solubilized minoxidil using propylene glycol having a relatively low skin irritation and glycerin with a low skin irritation enough to be used in cosmetics, thereby greatly reducing the skin irritation and its side effects caused by the gel composition. Can be. In addition, the gel composition can stay in the application site such as the scalp for a sufficient time, and can sufficiently increase the absorption rate and bioavailability of the minoxidil, as compared to topical preparations in liquid form.

Therefore, by using such a gel composition, by maintaining a higher concentration of minoxidil at the application site such as the scalp for a sufficient time, it is possible to greatly increase the absorption rate and bioavailability of the minoxidil, and to increase the therapeutic effect such as alopecia using it. have. In addition, the gel composition can also be used to lower skin irritation or side effects due to the solvent.

On the other hand, the gel composition may include the minoxidil of the active ingredient in an amount of 1 to 10g per 100g, preferably 3 to 7g, most preferably in an amount of 5g. As such, the gel composition may be preferably used for the treatment or prevention of alopecia and the like.

In addition, in the gel composition, the thickener may preferably include a carbomer thickener. Such carbomer thickeners include commercially available Carbopol 940 and the like. The thickener is to impart some viscosity so that the composition can take the form of a gel, and the carbomer thickener can be used to allow the composition to maintain a more stable gel phase.

In addition, the gel composition preferably contains 1 to 10% by weight of the minoxidil, 0.1 to 2% by weight of the thickener, and 89 to 98% by weight of the aqueous solvent containing the glycerin, in particular, It is preferred to include glycerin in an amount of 10 to 30% by weight based on the total gel composition. More preferably, the gel composition may include the glycerin in an amount of 12 to 24% by weight.

As the gel composition comprises in each of these constituents, particularly the aqueous solvent containing minoxidil and glycerin in this content range, the gel composition is stable in dissolving higher concentrations of minoxidil in the aqueous solvent. You can keep it. If it is out of the content range of each of these components, in particular, the content of the glycerin is too high or low, it is difficult to dissolve a high concentration of minoxidil and the gel composition is difficult to maintain a stable gel phase white Problems such as causing precipitation may occur.

In addition, in the gel composition, the glycerin-containing water-soluble solvent may contain water together with the glycerin, and may further include an alcohol solvent, for example, ethanol. In this case, the water and the alcohol solvent may be included in a weight ratio of water: alcohol solvent (for example, ethanol) = 1: 2 to 1: 4, preferably in a weight ratio of 1: 2.5 to 1: 3.75. Can be.

As the aqueous solvent contains water and an alcoholic solvent in this weight ratio together with glycerin, the minoxidil can be dissolved at a higher concentration and the gel composition can be maintained on a stable gel. If the weight ratio of water and ethanol becomes too small or too large, problems such as difficulty in dissolving high concentrations of minoxidil or providing thick dough mass with a carbomer thickener occur, such that the gel composition maintains a desirable gel phase. It can be difficult to do.

In addition, the gel composition is preferably provided in a state of pH 7.5 to 9.0, for this purpose, may further comprise an amine pH adjuster, for example, triethanolamine.

As a result of the experiments of the present inventors, when the gel composition exhibits such a weakly basic pH, while dissolving a high concentration of minoxidil, it can be formed and maintained in a more stable gel form, and can stay for a sufficient time at an application site such as the scalp. It was found to exhibit an appropriate viscosity (for example, 8000-14000 cP). Therefore, such a gel composition can be used more effectively for the treatment of alopecia and the like.

As described above, the gel composition according to one embodiment of the invention can maintain a stable gel phase while dissolving a higher concentration of minoxidil without skin irritation. Therefore, such a gel composition can maintain a higher concentration of minoxidil at the application site, for example, the scalp for a sufficient time, thereby further improving the absorption and bioavailability of minoxidil, and thus, alopecia using minoxidil and the like. Can increase the therapeutic effect.

The above-mentioned gel composition can be prepared as follows according to the conventional method of preparing a gel composition.

First, the thickener is mixed with an alcohol solvent or the like to dissolve the thickener and stirred for about 10 to 20 minutes to form a thickener solution.

Then, glycerin and a solvent (for example, water and an alcohol solvent) are mixed and stirred for about 10 to 20 minutes, and then, minoxidil, which is an active ingredient, is added to this solution, stirred for about 30 to 50 minutes, and dissolved in the minoxidil solution. Make At this time, a higher concentration of minoxidil may be dissolved due to the action of the glycerin.

Subsequently, the minoxidil solution and the thickener solution are mixed and stirred for approximately 50 to 70 minutes, and the pH is adjusted by adding an amine pH adjuster such as triethanolamine and stirring for approximately 1 to 10 minutes.

Through this preparation method, the above-described gel composition can be prepared that maintains a stable gel phase while dissolving higher concentrations of minoxidil.

As described above, according to the present invention, a gel composition capable of maintaining a stable gel phase while dissolving higher concentrations of minoxidil can be provided. Such a gel composition may contain a higher concentration of minoxidil but still stay at the application site such as the scalp for a sufficient time, and thus may be more effectively applied to the treatment of alopecia and the like.

Hereinafter, the configuration and operation of the invention through the preferred embodiments of the invention will be described in more detail. However, the scope of the invention is not defined according to these embodiments, which are merely presented as an example.

Example 1 and Comparative Examples 1-4: Preparation of Gel Composition Comprising Minoxidil (Selection of Optimal Solvent)

According to the composition shown in Table 1, the active ingredient minoxidil and a thickener (Carbopol 940), an amine pH adjuster, ethanol, purified water and the addition solvent (glycerin of Example 1 and other solvents of Comparative Examples 1 to 4) is mixed To prepare a gel composition comprising minoxidil.

In this case, as the glycerin, a concentrated glycerin containing glycerin at a concentration of 98% or more was used, and triethanolamine was used as the amine pH adjusting agent.

For the mixing of each of these components, a propeller mixer (Azi mixer) of model name: IKA-RW20DZM.n was used, and the mixer was operated at 600 to 800 rpm.

The mixing method of each component and the specific manufacturing method of a gel composition are as follows.

First, the thickener was mixed with ethanol to dissolve the thickener and stirred for approximately 10 minutes to prepare a thickener solution. Then, the addition solvent, water and ethanol were mixed, stirred for about 10 minutes, minoxidil was added to the solution, and stirred for about 30 minutes to prepare a minoxidil solution. Thereafter, the minoxidil solution and the thickener solution were mixed and stirred for about 50 minutes, and an amine pH adjuster was added and stirred for about 2 minutes. As a result, gel compositions of Example 1 and Comparative Examples 1 to 4 were prepared.

TABLE 1

Ingredient Name Example 1 (g) Comparative Example 1 (g) Comparative Example 2 (g) Comparative Example 3 (g) Comparative Example 4 (g) Minoxidil 5.00 5.00 5.00 5.00 5.00 Thickener (Carbopol 940) 0.30 0.30 0.30 0.30 0.30 Amine pH Adjuster 0.30 0.30 0.30 0.30 0.30 ethanol 55.00 55.00 55.00 55.00 55.00 Purified water 21.40 21.40 21.40 21.40 21.40 Added solvent glycerin 18.00 Propylene glycol 18.00 Butylene glycol 18.00 Labrador M1944 CS 18.00 Cremophor ELP 18.00 Gross weight (g) 100.00 100.00 100.00 100.00 100.00

* In Table 1, "Labrafil M1944 CS" represents a trade name of "oleoyl macrogolglyceride" which is a kind of surfactant, "Cremophore ELP" of "peg-35 castor oil" used as a solubilizer It shows a brand name.

After preparing the gel composition of Example 1 and Comparative Examples 1 to 4, the occurrence of white precipitate was observed to determine whether the high concentration of minoxidil of 5% by weight was dissolved, the gel composition on a transparent gel is formed It was confirmed whether or not. The confirmation results are shown in Table 2 below.

TABLE 2

Experiment result Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Minoxidil dissolved or not O X (white precipitate occurs) X (white precipitate occurs) X (white precipitate occurs) X (white precipitate occurs) Whether to form a clear gel O (transparent gel formation) X (opaque) X (opaque) X (opaque) X (opaque)

Referring to Table 2, the gel composition of Example 1 is provided as a transparent and stable gel while completely dissolving a high concentration of minoxidil of 5% by weight, whereas the gel composition of Comparative Examples 1 to 4 is a high concentration of minoxidil It was found that it did not dissolve properly, resulting in white precipitates and not providing a clear gel.

Examples 2-6 and Comparative Examples 5-10: Preparation of Gel Composition Comprising Minoxidil (Control of pH)

According to the composition of Tables 3 and 4, a gel composition comprising minoxidil by mixing minoxidil and a thickener (Carbopol 940), a pH adjuster (alkali or acidifying agent), ethanol, purified water and glycerin (concentrated glycerin) as active ingredients Was prepared.

Except according to the composition of Tables 3 and 4, the mixing method of each component and the specific manufacturing method of the gel composition were performed in the same manner as in Example 1 and Comparative Examples 1 to 4 described above.

TABLE 3

Ingredient Name Example 2 (g) Example 3 (g) Example 4 (g) Example 5 (g) Example 6 (g) Minoxidil 5.00 5.00 5.00 5.00 5.00 Thickener (Carbopol 940) 0.30 0.30 0.30 0.30 0.30 Glycerin (concentrated glycerin) 18.00 18.00 18.00 18.00 18.00 ethanol 55.00 55.00 55.00 55.00 55.00 Purified water 21.40 21.10 20.80 19.90 17.70 Alkalizing agent (triethanolamine) 0.30 0.60 0.90 1.80 4.00 Gross weight (g) 100.00 100.00 100.00 100.00 100.00 pH 7.95 8.25 8.35 8.82 9.02

TABLE 4

Ingredient Name Comparative Example 5 (g) Comparative Example 6 (g) Comparative Example 7 (g) Comparative Example 8 (g) Comparative Example 9 (g) Comparative Example 10 (g) Minoxidil 5.00 5.00 5.00 5.00 5.00 5.00 Thickener-Carbopol 940 0.30 0.30 0.30 0.30 0.30 0.30 Glycerin-Thickened Glycerin 18.00 18.00 18.00 18.00 18.00 18.00 ethanol 55.00 55.00 55.00 55.00 55.00 55.00 Purified water 21.40 21.40 21.40 21.67 21.65 21.60 Alkalizing agent 15.00 24.00 0.30 - - - Triethanolamine Triethanolamine NaOH - - - Acidifying agent - - - 0.025 0.05 0.10 - - - Citric acid Citric acid Citric acid Gross weight (g) 114.70 123.70 100.00 100.00 100.00 100.00 pH 9.66 9.83 12.97 7.02 6.89 6.46

After preparing the gel compositions of Examples 2 to 6 and Comparative Examples 5 to 10, the viscosity of each gel composition was measured, and it was confirmed whether the gel composition was formed in a transparent gel phase with an appropriate viscosity. The measurement results and confirmation results of the viscosity are shown in Tables 5 and 6.

TABLE 5

Experiment result Example 2 Example 3 Example 4 Example 5 Example 6 Viscosity (cP) 8850 8550 8850 8950 8650 Whether to form a clear gel 0 (transparent gel formation) 0 (transparent gel formation) 0 (transparent gel formation) 0 (transparent gel formation) 0 (transparent gel formation)

TABLE 6

Experiment result Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Viscosity (cP) 3500 2700 X (not measurable; formed in liquid rather than gel) X (not measurable; formed in liquid rather than gel) X (not measurable; formed in liquid rather than gel) X (not measurable; formed in liquid rather than gel) Whether to form a clear gel △ (formation of opaque gel) △ (formation of opaque gel) X (formed in liquid phase) X (formed in liquid phase) X (formed in liquid phase) X (formed in liquid phase)

Referring to Tables 5 and 6, the gel composition of Examples 2 to 6 is adjusted to pH 7.5 ~ 9.0, while dissolving a high concentration of minoxidil of 5% by weight, while staying in the application site such as scalp for a sufficient time. While the gel compositions of Comparative Examples 5-10 were formed in a substantially liquid phase, exhibiting too low a viscosity or poorly dissolving high concentrations of minoxidil, the gel composition of Comparative Examples 5 to 10 had a clear and stable gel phase. It was confirmed that it could not be provided.

Claims (9)

With an effective amount of minoxidil, With thickeners, Containing a solvent containing glycerin, The glycerin in an amount of 12 to 28% by weight based on the total gel composition, Gel composition having a pH of 7.5 to 9.0. The gel composition of claim 1, wherein the minoxidil is contained in an amount of 1 to 10% by weight. The gel composition of claim 1, wherein the thickener is a carbomer thickener. The method of claim 1, wherein 1 to 10% by weight of the minoxidil, 0.1 to 2% by weight of the thickener, Gel composition comprising 89 to 98% by weight of the aqueous solvent containing the glycerin. delete The gel composition of claim 1, wherein said water soluble medium contains glycerin, water and ethanol. The gel composition of claim 6, wherein the water and ethanol are included in a weight ratio of water: ethanol = 1: 2 to 1: 4. delete The gel composition of claim 1, further comprising an amine compound as a pH adjusting agent.