Description

COMPOSITIONS FOR EXTERNAL USE CONTAINING

MINOXIDIL FOR HAIR GROWTH WHICH HAVE AN

IMPROVED SKIN PERMEABILITY

Technical Field

[1] The present invention relates to a composition for external use containing minoxidil for hair growth, more particularly a composition for external use containing minoxidil for hair growth that has so excellent skin permeability that the effective ingredient minoxidil is delivered effectively to target skin tissues. Background Art

[2] Minoxidil was approved by FDA (USA), as a hypertension treatment agent for oral administration in 1979. Later during the clinical tests for the treatment of hypertension, minoxidil was confirmed to cause hypertrichosis as a side effect. Since then, minoxidil has been used as an agent for hair growth. A drug containing Minoxidil by 2% was approved by FDA (USA) as a prescribed drug in 1988, as a medicine in 1996 and a drug containing minoxidil by 5% was approved by FDA as a medicine in 1997 (fraprance journal, 233-37(2000)).

[3] Minoxidil liquid, in which aqueous solvents such as propyleneglycol that has high solubility for minoxidil, ethanol and water are mixed, has been used as a general minoxidil solution preparation. However, this formulation does not have affinity with sebum, the oil component surrounding pilar cyst on skin, suggesting low skin permeability.

[4] To overcome the problem of low skin permeability, European Patent No. 3156488

(1942.1.4) describes the use of such a nonaqueous solvent as silicon oil that is able to dissolve sebum and Japanese Patent Publication No. 0262818A (1990.3.2) describes the use of such a nonaqueous solvent as glycerin fatty acid ester. Japanese Patent Publication No. 62-230710 (1987.10.9) describes the use of such a nonaqueous solvent as fatty acid alcohol and fatty acid alkylester. These solvents seemed to have better effect on skin absorption than water-soluble solvents but the effect was not satisfactory. Korean Patent No. 0352088 (2002.09.12) describes that skin absorption is improved by using lipophilic oil components castor oil (product name: Cremophor), poly oxy ethylene stearate ester (product name: Myrj), and reactant of trans -es- terification of natural vegetable oil triglyceride and polyalkylene polyol (product name : Labrafil M). However, these compositions also have a problem of feeling something sticky and foreign body sensation owing to their oily, high molecular substances when they are applied.

[5] Thus, the present inventors have studied to develop a composition for external use containing minoxidil for hair growth that has improved skin permeability to bring satisfactory skin absorption effect. As a result, the present inventors completed this invention by confirming that the composition for external use containing a co- surfactant and a surfactant selected from the group consisting of polysorbate-20 or polysorbate-80 can be fast absorbed through skin by contacting moisture on skin when it is applied on the skin. Disclosure of Invention Technical Problem

[6] It is an object of the present invention to provide a composition for external use containing minoxidil for hair growth that has excellent skin permeability. Technical Solution

[7] The above object of the present invention can be achieved by the following embodiments of the present invention.

[8] The present invention is described in detail hereinafter.

[9] To achieve the above object, the present invention provides a composition for external use containing minoxidil for hair growth comprising:

[10] 1 - 7 w/v% of one or more active ingredients selected from the group consisting of minoxidil, its derivatives and its salts;

[11] 30 - 90 w/v% of one or more co- surfactants selected from the group consisting of glycerin, propyleneglycol and ethanol; and

[12] 2 - 30 w/v% of one or more surfactants selected from the group consisting of polysorbate-20 and polysorbate-80.

[13] The composition of the present invention has optimal skin permeability so that the active ingredient can be delivered effectively to the target skin tissues when it is applied on the skin.

[14] Hereinafter, the kinds and characteristics of components of the composition of the invention are described in detail.

[15] (l) Active ingredient

[16] The active ingredient for the composition of the present invention includes minoxidil, its derivatives and its salts. The content of the active ingredient in the composition of the present invention is preferably 1-7 w/v% based on the total weight of the composition, and more preferably 2-5 w/v%. If the content of the active ingredient is less than 1 w/v%, its pharmaceutical effect will be in doubt. If the content of the active ingredient is more than 7 w/v%, solubility will be so low that crystals are educed and side effects such as hair growing on the non-target area can be brought.

[17] (2) Co-surfactant

[18] The co-surfactant used for the composition of the present invention is a solvent that has both hydrophilicity and lipophilicity, which favors solution of the active ingredient and maintaining the composition regularly. The co-surfactant to meet the above object is exemplified by glycerin, propyleneglycol, and ethanol, and particularly glycerin or ethanol is more preferred. These compounds can be used independently or as a mixture of the two or more. The content of the co-surfactant in the total weight of the composition of the invention may be preferably 30-90 w/v% and more preferably 50-80 w/v%. If the content of the co-surfactant is less than 30 w/v%, it appears to have a problem with a solubility of major components. If the content is more than 90 w/v%, also solubility will be a problem.

[19] (3) Surfactant

[20] The surfactant of the invention is used to maintain the composition as regular as possible by using lipophilic oil components, and may be a various types of surfactants including a pharmaceutically acceptable anionic, cationic, non-ionic or amphoteric surfactants. Particularly, polysorbate-20 and polysorbate-80 are preferred for the composition of the invention. The content of the surfactant in the total weight of the composition may be preferably 2-30 w/v%, more preferably 5-20 w/v%. If the content of the surfactant is less than 2 w/v%, it is very difficult to maintain the liquid composition stably. If the content is more than 30 w/v%, a subject might feel something sticky and foreign body sensation when it is applied.

[21] The composition of the present invention can additionally contains humectants, antioxidants, pH regulators, preserving agents, viscosity modifiers and purified water as long as the effect of the composition is not damaged. The humectant is exemplified by dexpanthenol, the preserving agent is exemplified by methylparaffin, the pH regulator is exemplified by citric acid and the viscosity modifier is exemplified by pytosterol, but not always limited thereto. Brief Description of the Drawings

[22] The application of the preferred embodiments of the present invention is best understood with reference to the accompanying drawings, wherein:

[23]

[24] Figure 1 is a graph illustrating the results of skin permeability tests with the composition for external use of the present invention and the control.

[25] Figure 2 is a graph of calibration over concentrations using the minoxidil standard.

Best Mode for Carrying Out the Invention

[26] Practical and presently preferred embodiments of the present invention are illustrative as shown in the following Examples.

[27] However, it will be appreciated that those skilled in the art, on consideration of this

disclosure, may make modifications and improvements within the spirit and scope of the present invention. [28]

[29] <Example 1>

[30] 100 ml of the composition for external use containing minoxidil for hair growth was prepared by mixing and dissolving the following components.

[31] Minoxidil 5.0 g

[32] Dexpanthenol 0.004 g

[33] Glycerin 24.5 g

[34] Polysorbate80 7.6 g

[35] Ethanol 44.2 g

[36] Methylparaben 0.09 g

[37] Pytosterol 0.0004 g

[38] Retinol palmitate 0.05 g

[39] Purified water 18.0 g [40]

[41] <Example 2>

[42] 100 ml of the composition for external use containing minoxidil was prepared by mixing and dissolving the following components in purified water.

[43] Minoxidil 5.0 g

[44] Dexpanthenol 0.004 g

[45] Glycerin 24.5 g

[46] Polysorbate20 7.6 g

[47] Ethanol 44.2 g

[48] Methylparaben 0.09 g

[49] Pytosterol 0.0004 g

[50] Retinol palmitate 0.05 g

[51] Purified water 18.0 g [52]

[53] <Example 3>

[54] 100 ml of the composition for external use containing minoxidil was prepared by mixing and dissolving the following components in purified water.

[55] Minoxidil 5.0 g

[56] Dexpanthenol 0.004 g

[57] Propyleneglycol 24.5 g

[58] Polysorbate80 7.6 g

[59] Ethanol 44.2 g

[60] Methylparaben 0.09 g

[61] Pytosterol 0.0004 g

[62] Purified water 18.0 g

[63]

[64] <Example 4>

[65] 100 ml of the composition for external use containing minoxidil was prepared by mixing and dissolving the following components in purified water.

[66] Minoxidil 5.0 g

[67] Dexpanthenol 0.004 g

[68] Propyleneglycol 24.5 g

[69] Polysorbate20 7.6 g

[70] Ethanol 44.2 g

[71 ] Methylparaben 0.09 g

[72] Pytosterol 0.0004 g

[73] Purified water 18.0 g [74]

[75] <Example 5>

[76] 100 ml of the composition for external use containing minoxidil was prepared by mixing and dissolving the following components in purified water.

[77] Minoxidil 5.0 g

[78] Dexpanthenol 0.004 g

[79] Glycerin 24.5 g

[80] Polysorbate80 7.6 g

[81] Ethanol 44.2 g

[82] Methylparaben 0.09 g

[83] Pytosterol 0.0004 g

[84] Retinol palmitate 0.05 g

[85] Citric acid 0.05 g

[86] Purified water 18.0 g [87]

[88] <Example 6>

[89] 100 ml of the composition for external use containing minoxidil was prepared by mixing and dissolving the following components in purified water.

[90] Minoxidil 2.0 g

[91 ] Dexpanthenol 0.004 g

[92] Glycerin 24.5 g

[93] Polysorbate80 7.6 g

[94] Ethanol 44.2 g

[95] Methylparaben 0.09 g

[96] Pytosterol 0.0004 g

[97] Retinol palmitate 0.05 g

[98] Purified water 18.0 g

[99]

[100] <Example 7>

[101] 100 ml of the composition for external use containing minoxidil was prepared by mixing and dissolving the following components in purified water. [102] Minoxidil 2.0 g

[103] Dexpanthenol 0.004 g

[104] Glycerin 24.5 g

[105] Polysorbate80 7.6 g

[106] Ethanol 44.2 g

[107] Methylparaben 0.09 g

[108] Pytosterol 0.0004 g

[109] Rretinol palmitate 0.05 g

[110] Citric acid 0.05 g

[111] Purified water 18.0 g

[112]

[113] <Comparative Example 1> [Control drug: Rogaine (Pfizer)]

[114] 100 ml of the composition for external use containing minoxidil was prepared by mixing and dissolving the following components in purified water. [115] Minoxidil 5.0 g

[116] Ethanol 26.1 g

[117] Propylenegly col 52.8 g

[118] Purified water 18.0 g

[119]

[120] Experimental Example 1> In vitro skin permeability test using hairless mice

[121] To investigate skin permeability of the composition for external use of the invention, in vitro skin permeability test was performed using hairless mice. [122] The composition for external use of the invention prepared in example 1 was used as a test drug. The composition prepared in comparative example 1 was used as a control drug. All experiments were repeated twice. [123] Hairless mice (9 weeks, male, 25~30g) were anesthetized by ether, and skin tissues of the abdomen were cut off, which were used as a Franz cell (r=0.75 cm, vessel volume=5.5 ml) membrane and PBS (phosphate buffered saline : pH 7.2) was used as a vessel solution. [124] The experiment procedure is described in detail hereinafter. After applying 1 ml (50 mg) of minoxidil, the bottom of skin tissues were fully contacted with PBS in beaker,

followed by stirring at 600 rpm. Sampling was performed over the time (samples were taken at the time points of 0, 0.5, 1, 2, 4, 6, 9 and 24 hour) by 0.3 ml and the equal amount of PBS was supplemented every time. The samples were stored at 4 ⁰ C, and time dependent concentration curve was made by HPLC. The experimental group and the control group having equal content of minoxidil and the water bath were maintained at 37 ⁰ C and circulated.

[125] <Apparatus>

[126] ® HPLC 2690 (Waters, USA)

[127] © Franz-type diffusion cell (Korea)

[128] ® Shaking water bath

[129] <Analysis condition>

[130] - Mobile phase: Methanol, water and acetic acid were mixed at the ratio of

700:300:10. 3.0 g of Docusate sodium (Fluka co. 86139) was added thereto. PH was adjusted to 3.0 with perchloric acid, followed by filtering using 0.22 D filter and degas.

[131] - Detector: waters 996, Photodiode Array, 254 nm

[132] - Colum: Nova-Pak, C18 3.9 x 150 mm, 4D

[133] - Flow rate: 1.0 ml/min

[134] The standard minoxidil (Sigma M 1430) was dissolved in HPLC moving phase (1 mg/ml) and diluted serially to 100, 50, 25, 12.5, 6.25, 3.125, 1.563, and 0.78 D/ml, with which calibration curve was obtained.

[135] <Time dependent skin permeability concentration of 5% minoxidil tested with hairless mice>

[136] Sampling dilution ratios were calculated by measuring the minoxidil concentrations over the time according to the standard curve shown in Figure 2.

[137] Particularly, from the first 5.5 ml of PBS, 0.3 ml of sample was taken at the sampling hour 1 and 0.3 ml of PBS was supplemented thereto. So, HPLC value obtained therefrom was multiplied by 1.05. The HPLC value obtained from the sampling hour 2 was multiplied again by 1.05. This procedure was repeated to calculate the sampling dilution ratios.

[138] The results are shown in Table 1 and Figure 1.

[139] Table 1

[140] The abdomen skin tissue sections of the hairless mouse were divided into two groups (right and left) and the results were compared. As shown in Table 1 and Figure 1, it was confirmed that the composition of example 1 demonstrated 3 - 4 fold higher skin permeability from the sampling hour 6, compared with that of comparative example 1.

Industrial Applicability

[141] As explained hereinbefore, the composition for external use containing minoxidil for hair growth of the present invention has excellent skin permeability and thus the active ingredient of the composition, minoxidil, can reach the target skin tissues effectively when applied on the skin.

[142] [143] Those skilled in the art will appreciate that the conceptions and specific embodiments disclosed in the foregoing description may be readily utilized as a basis for modifying or designing other embodiments for carrying out the same purposes of the present invention. Those skilled in the art will also appreciate that such equivalent embodiments do not depart from the spirit and scope of the invention as set forth in the appended claims.