COMPOSITION FOR TOPICAL APPLICATION FOR PREVENTING HAIR LOSS AND STIMULATING HAIR GROWTH

Abstract

The present invention relates to a composition for topical application for preventing hair loss and stimulating hair growth having a 5α-reductase suppressant and minoxidil. The composition for topical application for preventing hair loss and stimulating hair growth according to the present invention provides equal or superior hair loss prevention and hair growth stimulation effects while using a much smaller dosage than conventional compositions which use oral 5α-reductase inhibitors and minoxidil alone or together.

Claims

1-9. (canceled)

10. A composition for a topical application for stimulating hair growth, the composition comprising finasteride or a pharmaceutically acceptable salt thereof, and minoxidil or a pharmaceutically acceptable salt thereof, and wherein the finasteride or a pharmaceutically acceptable salt thereof contained in the topical application is transdermally administered at a daily dose of 0.001 mg to 0.12 mg.

11. The composition of claim 10, wherein the finasteride or a pharmaceutically acceptable salt thereof contained in the topical application is transdermally administered at a daily dose of 0.005 mg to 0.05 mg.

12. The composition of claim 11, wherein the finasteride or a pharmaceutically acceptable salt thereof contained in the topical application is transdermally administered at a daily dose of 0.005 mg to 0.025 mg.

13. The composition of claim 10, wherein the minoxidil or a pharmaceutically acceptable salt thereof contained in the topical application is transdermally administered at a daily dose of 0.008 g to 0.12 g.

14. The composition of claim 10, wherein the finasteride or a pharmaceutically acceptable salt thereof is present in an amount of 0.1 mg to 5 mg per 100 ml of the composition.

15. The composition of claim 10, further comprising alfatradiol.

16. The composition of claim 10, further comprising a solvent containing a lower monoalcohol having 1 to 4 carbon atoms, a polyhydric alcohol, and water.

17. The composition of claim 10, wherein the composition for topical application has a formulation selected from the group consisting of hair tonic, scalp treatment, hair cream, general ointment, cosmetic water, powder, essence, pack, hair dye, shampoo, conditioner, lotion, gel, patch, and spray type.

Description

BEST MODE

[0018] Hereinafter, the present invention will be described in detail.

[0019] The present invention relates to a composition for topical application for preventing hair loss and stimulating hair growth, comprising a 5α-reductase inhibitor, and minoxidil or a pharmaceutically acceptable salt thereof.

[0020] The daily dose of the 5α-reductase inhibitor contained in the topical application for preventing hair loss and stimulating hair growth and transdermally administered is 0.8 μg to 0.12 mg, which is about less than one quarter that of oral dutasteride (0.5 mg), a current commercially available 5α-reductase inhibitor (the daily dose of commercially available oral finasteride is 1 mg).

[0021] More preferably, the daily dose of the 5α-reductase inhibitor is 0.8 μg to 0.05 mg, and most preferably, the daily dose of the 5α-reductase inhibitor is 0.001 mg to 0.025 mg.

[0022] If the daily dose of the 5α-reductase inhibitor is less than 0.8 μg, the onset of the effect is insignificant, whereas, if it exceeds 0.12 mg, side effects such as hyposexuality, ejaculation decrease, etc. may occur.

[0023] The daily dose of minoxidil or a pharmaceutically acceptable salt thereof contained in the topical application for preventing hair loss and stimulating hair growth and transdermally administered is 0.008 g to 0.12 g. If the daily dose is less than 0.008 g, the desired effect cannot be obtained, whereas if it exceeds 0.12 g, side effects such as increased cardiac output, increased left ventricular end-diastolic volume, etc. may occur.

[0024] If the 5α-reductase inhibitor is finasteride or a. pharmaceutically acceptable salt thereof, the daily dose may preferably be 0.001 mg to 0.12 mg, more preferably 0.005 mg to 0.05 mg, and most preferably 0.005 mg to 0.025 mg. If the dose of finasteride or a pharmaceutically acceptable salt thereof is out of the range, the effect is insufficient or side effects may occur.

[0025] If the 5α-reductase inhibitor is dutasteride or pharmaceutically acceptable salt thereof, the daily dose may preferably be 0.8 μg to 0.06 mg, more preferably 0.0016 mg to 0.025 mg, and most preferably 0.0016 mg to 0.012 mg. If the dose of dutasteride or a pharmaceutically acceptable salt thereof is out of the range, the effect is insufficient or side effects may occur.

[0026] The 5α-reductase inhibitor has side effects such as hyposexuality, impotence, ejaculation disorder, etc., and the FDA has recently amended its approval regarding the duration of these side effects even after discontinuation of use and recommended attention to medical professionals and patients.

[0027] Therefore, it is required to reduce the dose of the 5α-reductase inhibitor so as to reduce these side effects. Therefore, extensive research aimed at allowing the 5 α-reductase inhibitor to reach an accurate target by oral administration has been actively conducted. Meanwhile, an attempt to transdermally administer finasteride, a 5α-reductase inhibitor, has also been made, but no significant effect was obtained.

[0028] The composition for topical application of the present invention, in which the 5α-reductase inhibitor and minoxidil are dissolved in solvent, is transdermally applied to a target such that the 5α-reductase inhibitor is very effectively delivered to the target by syniergistic effect, thus (1)providing almost 100% effect to hair loss patients, and (2) providing very rapid and excellent effects even though the amount of the 5α-reductase inhibitor used is less than one s quarter that of the conventional prescription.

[0029] It is considered that the above significant effect results from the transdermal delivery efficiency of the 5α-reductase inhibitor that is significantly improved by vasodilation effect of minoxidil.

[0030] The 5a-reductase (reduced nicotinamide adenine dinucleotide phosphate:Δ4-3-ketosteroid 5α-oxidoreductase) is present in type I and type II isozymes and stimulates the reductive conversion of testosterone into 5α-dihydrotestosterone. Testosterone mainly plays a role in determining the morphology of the male internal genitalia, and dihydrotestosterone is required for development of the external genitalia.

[0031] The type I 5α-reductase is mainly distributed around sebaceous glands and the type II 5α-reductase is found in the dermal papillae, which are crucial for follicle growth, and in the outer root sheath of follicles. Dihydrotestosterone (DHT) produced by the 5α-reductase binds to receptors of follicular cells, and the DHT-receptor complex enters cell nucleus so that the DNA induces the synthesis of various protein regulators that influence the proliferation and differentiation of follicular cells. These various regulators formed by DHT stimulate the proliferation of hair matrix cells to accelerate the growth period (growth stage 1-growth stage 5) to relatively shorten the differentiation period (growth stage 6-regression stage) of follicular cells, thus increasing hair loss and inhibiting hair growth.

[0032] It is preferable that the 5α-reductase inhibitor is finasteride, dutasteride, or a pharmaceutically acceptable salt thereof.

[0033] The finasteride inhibits only the type I isozyme 5α-reductase, which is an enzyme that converts testosterone into dihydrotestosterone (DHT), and the dutasteride inhibits both the type I and type II isozymes of 5α-reductase to strongly maintain testosterone, thus inhibiting hair loss.

[0034] The structure of finasteride is represented by the following formula 1.

##STR00001##

[0035] The structure of dutasteride is represented by the following formula 2.

##STR00002##

[0036] The minoxidil, a lipophilic ingredient, is the only topical application approved by the FDA as a hair restorer and treatment agent for female pattern hair loss that has an excellent ability to penetrate into hair roots and serves to supply nutrients useful for hair growth by improving blood flow around the follicles of the scalp.

[0037] The structure of minoxidil is represented by the following formula 3.

##STR00003##

[0038] The composition for topical application for preventing hair loss and stimulating hair growth may be prepared, comprising finasteride or a pharmaceutically acceptable salt thereof in an amount of 0.1 mg to 5 mg, more preferably 0.1 mg to 2 mg with respect to 100 ml of the composition for topical application. Also, it may be prepared, comprising minoxidil or a pharmaceutically acceptable salt thereof in an amount of 0.5 g to 5 g respect to 100 ml of the composition for topical application.

[0039] Moreover, the composition for topical application preventing hair loss and stimulating hair growth may be prepared, comprising dutasteride or a pharmaceutically acceptable salt thereof in an amount of 0.05 mg to 2.5 mg, preferably 0.1 mg to 1.0 mg with respect to 100 ml of the composition for topical application.sub.— Also, it may be prepared, comprising minoxidil in an amount of 0.5 g to 5 g respect to 100 ml of the composition for topical application.

[0040] It is preferable that the composition for topical s application prepared in the above manner is applied in an amount of 100 ml once or twice a day or once every two days for 45 to 60 days.

[0041] The finasteride, dutasteride, and minoxidil of the present invention may be used in the form of pharmaceutically acceptable salts, and acid addition salts formed with pharmaceutically acceptable free acids are useful as such salts. Acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid, or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylate, phenyl-substituted alkanoate, hydroxy alkanoate and, alkandioate, aromatic acids, and aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maliate, butin-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, citrate, lactate, p-hydroxybutyrate, glycolate, malate, tartrate, methane sulfonate, propane sulfonate, naphthalene-l-sulfonate, naphthalene-2-sulfonate, or mandelate, but not limited thereto.

[0042] The composition for topical application for preventing hair loss and stimulating hair growth for women may further comprise estradiol, preferably alfatradiol (17α-estradiol).

[0043] The alfatradiol, which is an estrogen derivative, may prevent testosterone from being converted into dihydrotestosterone and stimulate the proliferation of follicle cells. Particularly, the alfatradiol can be effectively used for the treatment of female hair loss patients.

[0044] Any solvents, which are typically used in the art, may be used as the solvent of the composition for topical application for preventing hair loss and stimulating hair growth, and the solvent may comprise at least one selected from group consisting of: water; a lower mono-alcohol having 1 to 4 carbon atoms including methanol, ethanol, isopropyl alcohol, and butanol; a polyhydric alcohol including ethylene glycol, propylene glycol, 1,3-butylene glycol; glycerin; and mixtures thereof.

[0045] Particularly, it is preferable that the solvent comprises a lower mono-alcohol having 1 to 4 carbon atoms, a polyhydric alcohol, and water for effective drug delivery.

[0046] In the foregoing, the lower mono-alcohol having 1 to 4 carbon atoms may preferably include, but not limited to, ethanol, and the polyhydric alcohol may preferably include, but not limited to, propylene glycol.

[0047] When the solvent comprises a lower mono-alcohol having 1 to 4 carbon atoms, a polyhydric alcohol, and water, it is preferable to contain 10 to 60 vol % lower :ono- alcohol having 1 to 4 carbon atoms, 3 to 20 vol % polyhydric alcohol, and the remainder water, more preferably 30 to 50 vol % lower mono-alcohol having 1 to 4 carbon atoms, 5 to 15 vol % polyhydric alcohol, and the remainder water with respect to the total volume of the solvent.

[0048] When the solvent has the above composition ratio, the efficiency of transdermal drug delivery is significantly increased.

[0049] The composition for topical application for preventing hair loss and stimulating hair growth of the present invention may be prepared in any dosage forms such as liquid or gel type, which can be applied to the scalp. However, the composition may preferably be prepared in a dosage form selected from the group consisting of hair tonic, scalp treatment, hair cream, general ointment, cosmetic water, powder, essence, pack, hair dye, shampoo, conditioner, lotion, gel, patch, and spray type, more preferably a spray type or gel type.

[0050] If the amount of the ingredients such as finasteride, dutasteride, and minoxidil used increases, systemic absorption increases, and thus the possibility of occurrence of side effects may increase. The amount of finasteride, dutasteride, or minoxidil used in the present invention is much smaller than that of the conventional hair growth stimulating-agents, and the present invention can minimize side effects by selective administration through topical absorption and provide excellent effects of preventing hair loss and stimulating hair growth.

[0051] Moreover, while the treatment failure rate of conventional oral administration forms is high due to irregular administration, the method of applying the composition of the present invention in a spray type stimulates the effects of decreasing the risk of side effects, increasing the hair thickness, and reducing the hair loss in a short period of time, and is easy to facilitate the application, which in turn increases the compliance of patients, thus increasing he treatment success rate.

[0052] The composition for topical application for preventing hair loss and stimulating hair growth, containing finasteride and minoxidil, is mainly for men, and a composition for topical application containing finasteride and minoxidil of low concentration is also available for non-childbearing women.

[0053] The composition for topical application for preventing hair loss and stimulating hair growth, containing dutasteride and minoxidil, is available for men or non-childbearing women.

[0054] Moreover, the composition for topical application may further comprise an excipient typically used in the art, preferably a pharmaceutically acceptable excipient selected from the group consisting of a pH adjusting agent, solubilizing agent, and a combination thereof within the range that the object and effect of the present invention are not impaired.

[0055] The pH adjusting agent may he selected from the group consisting of citric acid, malic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, and a combination thereof, but not limited thereto.

[0056] The solubilizing agent may be selected from the group consisting of diethylene glycol monoethyl ether, benzyl alcohol, glycerin, octoxynol, propylene glycol, propylene carbonate, polyethylene glycol, and a mixture thereof, but not limited thereto.

MODE FOR INVENTION

[0057] Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. However, it should be understood that the following Examples and Test Examples are provided only for illustrating the present invention in more detail, and the scope of the present invention is not limited by the following Examples and Test Examples.

EXAMPLES 1 to 6

Preparation of Composition for Topical Application for Preventing Hair Loss and Stimulating Hair Growth

[0058] After mixing ethanol, propylene glycol, and water at a volume ratio of 4:1:5, finasteride or dutasteride and minoxidil in amounts shown in Table 1 were dissolved in the mixed solution, thus preparing each 100 ml of a composition for topical application for preventing hair loss and stimulating hair growth in Examples 1 to 6.

TABLE-US-00001 TABLE 1 Ingredient Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Finasteride .sup. 1 mg .sup. 1 mg .sup. 2 mg .sup. 2 mg —  —  (0.001%) (0.001%) (0.002%) (0.002%) Dutasteride —  —  —  —  0.2 mg 0.5 mg (0.0002%) (0.0005%) Minoxidil 5 g 2 g 2 g 5 g 2 g 2 g    (5%)    (2%)    (2%)    (5%)    (2%)    (2%) Note: % concentration in the present invention represents w/v % concentration.

COMPARATIVE EXAMPLES 1 to 3

[0059] In Comparative Examples 1 to 3, commercially available finasteride oral medication, dutasteride oral medications, and minoxidil topical applications were purchased to prepare compositions comprising the oral medication and the topical medication together or a topical application alone using the following ingredients shown in the following Table 2.

TABLE-US-00002 TABLE 2 Comparative Comparative Comparative Ingredient Example 1 Example 2 Example 3 Finasteride oral 1 mg — medication Dutasteride oral — 0.5 medication (mg) Minoxidil topical 5% 5% 5% application (%)

TEST EXAMPLE 1

Clinical Trials on Effects of Preventing Hair Loss and Stimulating Hair Growth

[0060] (1) Evaluation of Changes in Hair Thickness and Number

[0061] Each 100 ml of the compositions for topical application of Examples 1. to 6 was placed in a spray container and sprayed onto hair loss areas of alopecia patients twice a day (morning and evening), and then the effect was evaluated. Each 100 ml of the composition for topical application of Examples 1 to 6 was used for about 45 to 60 days, and the compositions were prepared by the same method as mentioned above upon completion of use. For the prescription of Comparative Examples 1 and 2, the oral medication was administered to alopecia patients once a day, and the minoxidil topical application was applied to hair loss areas and expected hair loss areas twice a day, and then the effect was evaluated. For the prescription of Comparative Example 3, only the minoxidil topical application was applied onto hair loss areas and expected hair loss areas of alopecia patients twice a day, and then the effect was evaluated.

[0062] The alopecia patients were selected according to the selection and exclusion criteria shown in the following Table 3, and when the patients first visited the hospital, their hair conditions were diagnosed, hair loss areas were marked and recorded, and black dots were tattooed on the most serious area so that the same area could be measured every time. Moreover, the number of hairs per unit area (hair number/cm.sup.2) the hair thickness (μm) were measured using a simple hand-held phototrichogram (Folliscope, Lead M Co, Seoul, Korea). Hair loss area around the marked area was photographed using a 30 magnification lens, and then the number of terminal hairs per unit area was calculated. The thickness of hair, determined as the average thickness of 5 hairs around the marked area by measuring with 200 magnification lens

[0063] The change in the number of hairs (hair number /cm.sup.2) and the change in the hair thickness (μm) in the alopecia patients were measured before administration and at a certain time after administration and shown in the following Tables 4, 5, and 7, and then the significance of these data was evaluated by T-TEST (including F-TEST). The results of T-TEST (including F-TEST) evaluation are shown in the Tables 6 and 8.

TABLE-US-00003 TABLE 3 Alopecia (1) Male or female patients of 18 to 60 years old diagnosed as patient androgenetic alopecia; (2) Androgenetic alopecia patients with selection basic type diagnosed as M2 disorder, C2 disorder or U1 criteria disorder and specific type diagnosed as V1 disorder or F1 disorder by Basic and specific (BASP) classification; (3) Patients who will not use any special hair product or undergo any hair care and treatment during the study period; (4) Patients who will maintain the same hair style during the study period; and (5) Male patients who are experiencing rapid hair loss recently Alopecia (1) People with serious acute kidney or heart disease, or other patient chronic diseases (hypertension, diabetes, etc.)that may affect exclusion the test results in the past six months; (2) People with criteria psychiatric diseases; (3) People with infectious skin diseases; (4) People who had surgical treatments for hair loss such as hair transplants, scalp reduction, etc.; (5) People who have used oral medication Finasteride or oral medication Dutasteride in the past 12 months; (5) People who have applicated any topical hair restorer, hair tonic, or hair growth promoter in the last six months; (7) People who are expected to have difficulties in application of test substance due to severe seborrheic dermatitis, scalp psoriasis, scalp infection, etc; (8) Patient with other hair loss diseases such as alopecia areata, telogen alopecia, cicatricial alopecia, etc. other than androgenetic alopecia; and (9) People who are expected to have difficulties to perform the test according to the opinion of the test director, other than the above items.

TABLE-US-00004 TABLE 4 Composition ratio Measuring time 2 weeks 4 weeks 6 weeks 7 weeks 8 weeks Example 1 Finasteride 1 Increased 23 0.001% + number of hairs Minoxidil Increased hair 0.012 5% thickness (μm) Example 2 Finasteride 1 Increased 29 0.001% + number of hairs Minoxidil Increased hair 0.002 2% thickness (μm) 2 Increased 26 number of hairs Increased hair 0.012 thickness (μm) 3 Increased 19 number of hairs Increased hair 0.009 thickness (μm) 4 Increased 13 16 number of hairs Increased hair 0.028 0.03 thickness (μm) 5 Increased 4 9 number of hairs Increased hair 0.006 0.012 thickness (μm) 6 Increased 3 8 number of hairs Increased hair 0.003 0.004 thickness (μm) 7 Increased 1 9 number of hairs Increased hair 0.004 0.006 thickness (μm) 8 Increased 3 8 number of hairs Increased hair 0.003 0.004 thickness (μm) 9 Increased −5 6 number of hairs Increased hair 0.004 0.007 thickness (μm) 10 Increased 3 10 number of hairs Increased hair 0.003 0.011 thickness (μm) 11 Increased 11 19 number of hairs Increased hair 0.005 0.01 thickness (μm) Example 3 Finasteride 1 Increased 24 0.002% + number of hairs Minoxidil Increased hair 0.012 2% thickness (μm) 2 Increased 35 number of hairs Increased hair 0.021 thickness (μm) Comparative Finasteride 1 Increased −39 example 1 1 mg + number of hairs Minoxidil Increased hair −0.007 5% thickness (μm) 2 Increased 3 number of hairs Increased hair 0.001 thickness (μm) 3 Increased 4 number of hairs Increased hair 0.002 thickness (μm)

[0064] Note: In the above table, each section without data represents that the number of hairs or the hair thickness was not measured at the corresponding time, and is the same in the following tablet

[0065] The data shown in Table 4 are to determine the rapid onset of the effect of the composition for topical application of the present invention. That is, the data in Table 4 shows that both the number of hairs and the hair thickness to significantly increase in almost all alopecia patients (nine patients administered with the compositions of the Example) 2 weeks to 4 weeks after the administration of the composition for topical application of the present invention. One patient showed decrease in the number of hairs after 4 weeks, but the number of hairs in this patient increased after 8 weeks.

[0066] Moreover, the data in Table 4 shows that both the number of hairs and hair thickness significantly increase in all alopecia patients (13 patients administered with the compositions of the Examples 1 to 3) 6 weeks to 8 weeks after the administration of the composition for topical application of the present invention.

[0067] As well known in the art, these effects of preventing hair loss prevention stimulating hair growth are very remarkable considering that these effects appear after at least 3 months in the conventional prescription (See the data in Comparative Example 1).

[0068] Specifically, according to the data in Table 4, the alopecia patients administered with the composition for topical application of Examples 1 to 3 of the present invention showed a significant increase in both the number of hairs and the hair thickness, compared to the patients treated with the conventional prescription of Comparative Example 1. That is, the alopecia patients administered with the composition for topical application of the present invention showed a more significant increase in both the number of hairs and the hair thickness after 2 weeks, and the effects increased gradually over time, resulting in a significant difference after 8 weeks compared to the alopecia patients treated with the prescription of Comparative Example 1.

[0069] The rapid onset of the effects of the above-described composition for topical application of the present invention suggests that the composition for topical application of the present invention can significantly improve the treatment compliance and satisfaction of patients. That is, in the case of the conventional prescription, the onset of the effects was very slow, and thus many patients abandoned the treatment. However, these problems can be significantly overcome by the use of the composition of the present invention.

[0070] Moreover, it can be said that the results of the clinical trials suggest the excellent effect of the composition for topical application of the present invention during exclusive use as well as the possibility of its use in combination with conventional oral medications.

[0071] That is, in the case of the conventional prescription, the effects of preventing hair loss and stimulating hair growth are not fully expressed until 3 months after the use, and thus the users' satisfaction is not high. This result reduces the treatment compliance of patients, leading the patients to abandon the treatment. However, in the case of the combination of the topical application of the present invention with the conventional oral medication, the effects of preventing hair loss and stimulating hair growth are rapidly expressed even at the beginning of treatment thanks to the characteristics of the composition for topical application of the present invention. Therefore, the treatment compliance and satisfaction of patients are significantly improved, and thus the possibility of abandoning the treatment is dramatically reduced.

TABLE-US-00005 TABLE 5 Comparative Comparative Example 1 Example 2 Example 3 Example 4 Example 1 Example 3 Drug administered finasteride finasteride finasteride finasteride finasteride 0.001% + 0.001% + 0.002% + 0.002% + 1 mg + minoxidil 5% minoxidil 2% minoxidil 2% minoxidil 5% minoxidil 5% Minoxidil 5% No. Measuring time 13 weeks 13 weeks 13 weeks 13 weeks 13 weeks 13 weeks 1 Increased number 15 29 32 16 −26 10 of hairs Increased hair 0.009 0.006 0.035 0.019 −0.015 0.005 thickness (μm) 2 Increased number 22 45 44 19 −3 9 of hairs Increased hair 0.006 0 0.016 0.017 0.012 0.001 thickness (μm) 3 Increased number 9 21 29 32 1 11 of hairs Increased hair 0.007 0.011 0.006 0.035 0.002 0.01 thickness (μm) 4 Increased number 9 6 39 35 9 13 of hairs Increased hair 0.015 0.009 0.019 0.021 0.005 0.005 thickness (μm) 5 Increased number 19 5 9 24 . −31 of hairs Increased hair 0.019 0.008 0.009 0.026 −0.016 thickness (μm) 6 Increased number 26 21 20 3 of hair Increased hair 0.021 0.019 0.024 −0.005 thickness (μm) 7 Increased number 19 32 −12 of hairs Increased hair 0.009 0.026 −0.012 thickness (μm) 8 Increased number 26 19 −11 of hairs Increased hair 0.021 0.019 −0.019 thickness (μm) 9 Increased number 20 −6 of hairs Increased hair 0.033 0.02 thickness (μm) 10 Increased number 21 −11 of hairs Increased hair 0.019 −0.016 thickness (μm) 11 Increased number 10 of hairs Increased hair 0.005 thickness (μm) 12 Increased number −1 of hairs Increased hair 0.001 thickness (μm) 13 Increased number 14 of hairs Increased hair 0.02 thickness (μm) 14 Increased number 10 of hairs Increased hair 0.002 thickness (μm) increased number 16.6667 21.2 27.375 23.8 −4.75 0.5714 of hairs, average increased hair 0.0128 0.0068 0.0168 0.0239 0.001 0.000071 thickness (μm), average

TABLE-US-00006 TABLE 6 Data of Comparative Data of Comparative Type Example 1 Example 3 Data of number of hairs, TTEST Data of FTEST 0.130013191 0.166204493 Example 1 TTEST 0.01472931 0.011818468 Data of FTEST 0.894114552 0.458770619 Example 2 TTEST 0.046499133 0.012058313 Data of FTEST 0.475819066 0.69761868 Example 3 TTEST 0.001838518 0.000102744 Data of FTEST 0.051284979 0.048452534 Example 4 TTEST 0.000267943 0.000014812 Data of hair thickness, TTEST Data of FTEST 0.16297573 0.162697573 Example 1 TTEST 0.040829245 0.016450776 Data of FTEST 0.082456882 0.049214765 Example 2 TTEST 0.323896199 0.09803766 Data of FTEST 0.573873721 0.432576185 Example 3 TTEST 0.027277192 0.003679183 Data of FTEST 0.130017138 0.040734435 Example 4 TTEST 0.000342343 0.000004976 * If p < 0.05, it is determined to have significance.

[0072] As shown in Table 5, the composition for topical application of Examples 1 to 4 of the present invention showed a significant increase in both the number of hairs and the hair thickness (μm) 13 weeks after the administration in most cases, compared to the conventional prescription of Comparative Examples 1 and 3. Moreover, it was found from the results of evaluation by TTEST shown in Table 6 that all data of hair thickness have significance except for the data of Example 2.

[0073] The results of the clinical trials are very important in that the composition for topical application of Examples 1 to 4 of the present invention exhibited more significant effects of preventing hair loss and stimulating hair growth even with the use of finasteride in an amount much smaller than that of the conventional prescription.

[0074] That is, in the case of oral administration of finasteride (1 mg/day), side effects such as hyposexuality, impotence, ejaculation disorder, etc. have been reported. Based on this, it can be said that the composition for topical application of the present invention significantly reduces the dose of finasteride and, at the same time, provides much better effects, thus providing an innovative way to solve the conventional side effects.

TABLE-US-00007 TABLE 7 Drug administered Comparative Example 5 Example 6 Example 2 dutasteride dutasteride dutasteride 0.0002% + 0.0005% + 0.5 mg + minoxidil 2% minoxidil 2% minoxidil 5% No. Measuring time 4 weeks 8 weeks 4 weeks 8 weeks 4 weeks 8 Weeks 1 Increased 29 45 11 10 4 11 number of hairs Increased 0.019 0.018 0.301 −0.286 0.002 0.006 hair thickness (μm) 2 Increased 10 26 19 16 −16 5 number of hairs Increased −0.003 0.008 0.028 −0.001 −0.011 −0.003 hair thickness (μm) 3 Increased 10 17 3 19 1 8 number of hairs Increased 0.003 0.01 0.016 0.019 0.001 0.008 hair thickness (μm) 4 Increased 13 22 2 22 −1 6 number of hairs Increased 0.006 0.005 0.01 0.011 −0.022 −0.01 hair thickness (μm) 5 Increased 29 45 6 7 number of hairs Increased 0.014 0.013 0.003 0.535 hair thickness (μm) 6 Increased 6 21 number of hairs Increased −0.005 0.003 hair thickness (μm) 7 Increased 16 number of hairs Increased 0.408 hair thickness (μm) Increased 18.2 31 7.8333 15.8571 −3 7.5 number of hairs, average Increased 0.0078 0.0108 0.0588 0.0984 −0.0075 0.00025 hair thickness (μm), average

TABLE-US-00008 TABLE 8 Data of Comparative Type Example 2 (8 weeks) Data of number of hairs, TTEST Data of Example 5 FTEST 0.024723978 TTEST 0.014726095 Data of Example 6 FTEST 0.248152042 TTEST 0.02159579 Data of hair thickness, TTEST Data of Example 5 FTEST 0.685354662 TTEST 0.049411807 Data of Example 6 FTEST 0.000082551 TTEST 0.38806212 * If p < 0.05, it is determined to have significance.

[0075] As can be seen in Table 7, the compositions for topical application of Examples 5 to 6 of the present invention showed significant increases in the number of hairs and the hair thickness (μm) compared to the conventional prescription of Comparative Example 2. Moreover, it was found from these results of evaluation by TTEST shown in Table 8 that all data of hair thickness data have significance except for the data of Example 6.

[0076] The results of the clinical trials are very important in that the compositions for topical application of Examples 5 and 6 of the present invention exhibited more significant effects of preventing hair loss and stimulating hair growth even with the use of dutasteride in an amount much smaller than that of the conventional prescription.

[0077] That is, in the case of oral administration of dutasteride (0.5 mg/day), side effects such as hyposexuality, impotence, ejaculation disorder, etc. have been reported. Based on this, it can be said that the composition for topical application of the present invention significantly reduces the dose of dutasteride and, at the same time, provides much better effects, thus providing an innovative way to solve the conventional side effects.

[0078] Moreover, in the clinical trials, the changes in the number of hairs and hair thickness were measured 4 to 8 weeks after the administration, and the fact that composition for topical application of Examples 5 and 6 of the present invention exhibited more significant effects than the conventional prescription, indicating that the onset of the effects of the composition for topical application of the present invention is very rapid.

[0079] These results of the clinical trials indicate that the composition for topical application of the present invention can significantly improve the treatment compliance and satisfaction of patients due to the rapid effect.

[0080] That is, in the case of the conventional prescription, the onset of the effects was very low, and thus many patients abandoned the treatment. However, these problems can be significantly improved by the use of the composition of the present invention.

[0081] Moreover, as mentioned in Examples 1 to 4, it can be said that the results of the clinical trials suggest the excellent effect of the composition for topical application of the present invention during exclusive use as well as the possibility of its use in combination with conventional oral medications.

TEST EXAMPLE 2

Onset of Effects and Evaluation of Side Effects

[0082]

TABLE-US-00009 TABLE 9 Comp. Comp. Comp. Exam. Exam. Exam. Exam. Exam. Exam. Exam. Exam. Exam. 1 2 3 4 5 6 1 2 3 Number of 9 7 10 13 6 8 6 5 19 patients in test group Number of 0 0 0 0 0 0 1 0 3 patients who abandoned the treatment due to no effect Number of 0 0 0 0 0 0 0 1 0 patients who Abandoned the treatment due to side- effect Note: The above data were recorded after 32 weeks from the beginning of treatment.

[0083] As shown in Table 9, all of the hair loss patients administered with the composition for topical composition of Examples 1 to 6 of the present invention exhibited got the 100% effect, and there were no side effects except for two patients who experienced scalp pruritis temporarily.

[0084] On the contrary, in the case of Comparative Examples 1 to 3 of conventional prescription, 13% (4 patients) of the total patients (30 patients) of the test group abandoned the treatment due to no effect, and about 3.3% (1 patient) had side effects. These results of Comparative Examples 1 to 3 are considered to be consistent with the facts known about the side effects and the no effects.