Hair-growing composition containing prostaglandin I 2 derivatives

Abstract: A composition for stimulating hair growth is described. The composition comprises as an effective ingredient a 5,6,7-trinor-4 ,8-inter-m-phenylene prostaglandin I₂ derivative of the formula (I) below or a pharmaceutically acceptable salt thereof: (wherein R¹ represents hydrogen, carboxylic group or a functional derivative thereof, -CH₂OH or a pharmaceutically acceptable cation; A represents (i) -(CH₂) n -, (ii) -(CH₂) m -CH=CH-(CH₂) p -, (iii) -(CH₂) m -C≡C-(CH₂) p - or (iv) -CH₂-O-CH₂- (wherein n represents an integer of 0 - 3, m and p, the same or different, represent 0 or 1); R² represents (i) C₅ - C₁₀ straight or branched alkyl group, (ii) -C t H 2t -OR³ (wherein t represents an integer of 1 - 5, R³ represents C₁ - C₅ straight or branched alkyl group or phenyl group), (iii) -C t H 2t -CH=C(R⁴)(R⁵) (wherein t represents the same meaning as mentioned above, R⁴ and R⁵, the same or different, represent hydrogen, methyl, ethyl, propyl or butyl group), or (iv) -C t H 2t -C≡C-R⁶ (wherein t represents the same meaning as mentioned above, R⁶ represents hydrogen, methyl or ethyl group, and -C t H 2t in (ii), (iii) and (iv) represent straight or branched alkylene group); wherein said compound of the formula (I) may be d-, l- or dl-form.

Description: BACKGROUND OF THE INVENTION I. Field of the Invention This invention relates to a composition for stimulating growth of hair. II. Description of the Related Art Prostaglandin I 2 (PGI 2 , prostacyclin) is a substance known to have strong platelet-aggregation inhibition activity and vasodilating activity. However, since PGI 2 has an unstable exoenol structure, it is extremely unstable even in neutral aqueous solution and is easily converted to 6-oxo-PGF1α which has substantially no activities. The instability of PGI 2 is a great problem in using this compound as a pharmaceutical. Furthermore, PGI 2 is unstable in the body and its duration of pharmacological activity is short. To eliminate these drawbacks of PGI 2 , PGI 2 derivatives in which the characteristic exoenol ether moiety of PGI 2 is converted to inter-m-phenylene have been proposed in, for example, Japanese Laid-open Patent Application (Kokai) Nos. 57-32277, 57-144276 and 58-124778. Derwent Publications AN-86-295722 and patent JP-A-61 218 510 disclose hair cosmetic compositions comprising PGE 1 and/or PGI 2 as effective ingredients against alopecia. However, there is no disclosure or suggestion in these and other published references that these PGI 2 derivatives have activities to stimulate hair growth and so the usefulness for the treatment of alopecia. SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a composition for stimulating or promoting hair growth of an animal including human. Another object of the present invention is to provide a new use of the known PGI 2 derivatives. The present inventors intensively studied to find that the PGI 2 derivatives have activities to stimulate or promote hair growth of animals including human, thereby completing the present invention. That is, the present invention provides a hair-growing composition comprising a 5,6,7-trinor-4,8-inter-m-phenylene prostaglandin I 2 derivative of the formula (I) below or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable vehicle in an amount effective for stimulating growth of hair: (wherein R 1 represents hydrogen, carboxylic group or a functional derivative thereof, -CH 2 OH or a pharmaceutically acceptable cation; A represents (i) -(CH 2 ) n -, (ii) -(CH 2 ) m -CH=CH-(CH 2 ) p -, (iii) -(CH 2 ) m -C≡C-(CH 2 ) p - or (iv) -CH 2 -O-CH 2 - (wherein n represents an integer of 0 - 3, m and p, the same or different, represent 0 or 1); R 2 represents (i) C 5 - C 10 straight or branched alkyl group, (ii) -C t H 2t -OR 3 (wherein t represents an integer of 1 - 5, R 3 represents C 1 - C 5 straight or branched alkyl group or phenyl group), (iii) -C t H 2t -CH=C(R 4 )(R 5 ) (wherein t represents the same meaning as mentioned above, R 4 and R 5 , the same or different, represent hydrogen, methyl, ethyl, propyl or butyl group), or (iv) -C t H 2t -C≡C-R 6 (wherein t represents the same meaning as mentioned above, R 6 represents hydrogen, methyl or ethyl group, and -C t H 2t in (ii), (iii) and (iv) represent straight or branched alkylene group); wherein said compound of the formula (I) may be d-, l- or dl-form. The present invention also provides a use of a 5,6,7-trinor-4,8-inter-m-phenylene prostaglandin I 2 derivative of the above-described formula (I) or a pharmaceutically acceptable salt thereof as a hair-growing agent. The hair-growing composition exhibits high activity to stimulate or promote hair growth in animals including human when orally or parenterally administered. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS As described above, the effective ingredient having hair-growing activity in the composition according to the present invention is represented by the above-described formula (I). The functional derivative of carboxylic group for R 1 means the derivative of identical function, such as carboxylic esters. The pharmaceutically acceptable cation for R 1 may be an alkaline metal or an alkaline earth metal such as sodium, potassium or calcium. The compound represented by the formula (I) may be optically active d-form (d-optical isomer) or l-form (l-optical isomer) or may be racemate body (dl-form). Among the PGI 2 derivatives represented by the formula (I), preferred are those represented by the formula (II): (wherein R 7 represents methyl or ethyl, a pharmaceutically acceptable alkaline metal or alkaline earth metal, or an amine or basic amino acid; A represents (i) -(CH 2 ) n' -, (ii) -(CH 2 ) m -CH=CH-(CH 2 ) p -, (iii) -(CH 2 ) m -C≡C-(CH 2 ) p - or (iv) -CH 2 -O-CH 2 - (wherein n' represents an integer of 1 - 3, m and p represent the same meanings as in formula (I)); R 2' represents (i) C 5 - C 7 straight or branched alkyl group, (ii) -C t ,H 2t ,-OR 3' (wherein t' represents an integer of 1 - 3, R 3' represents C 2 - C 4 straight or branched alkyl group or phenyl group, (iii) -C t ,H 2t ,-CH=C(R 4 )(R 5 ) (wherein t' represents the same meaning as mentioned above, R 4 and R 5 represent the same meanings as in formula (I)), or (iv) -C t' H 2t' -C≡C-R 6 (wherein t' represents the same meaning as mentioned above, R 6 represents the same meaning as in formula (I), and -C t' H 2t' in (ii), (iii) and (iv) represent straight or branched alkylene group); wherein said compound of the formula (II) may be d-, l-or dl-form. In the formula (II), the pharmaceutically acceptable alkaline metal or alkaline earth metal for R 7 may preferably be sodium, potassium or calcium. The amine and the basic amino acid for R 7 may preferably be one selected from the group consisting of monomethylamine, dimethylamine, trimethylamine, methylpyperidine, monoethanolamine, diethanolamine, triethanolamine and lysine. As mentioned above, the PGI 2 derivatives represented by the formula (I) per se are known and the production processes thereof are described in, for example, U.S. Patent No. 4,474,802. The compounds represented by the formula (I) exhibit hair-growing activities when administered orally or parenterally. The compounds represented by the formula (I) may usually be administered in a dose of 0.01 - 100 mg/body and 1 - 3 times a day (i.e., 0.01 - 300 mg/body/day). Although the compounds represented by the formula (I) alone can be administered, they can also be administered together with a pharmaceutically acceptable vehicle. For oral administration, the active compound may be formulated with a pharmaceutically acceptable vehicle to form a solid composition. Preferred examples of the pharmaceutically acceptable vehicle used for this purpose include starches, lactose, sucrose, glucose, mannitol, calcium carbonate, calcium sulfate and the like. The composition may also contain a binding agent such as starch, dextrin, gum arbicae, tragacanth, methyl cellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol or the like; a disintegrator such as starch, polyvinylpyrrolidone, crystalline cellulose or the like; a lubricant such as magnesium stearate, talc or the like; a coloring agent; and a perfume. The formulation for oral administration may be in the form of tablets, sugar-coated tablets, powder, granules, troches, capsules, balls and syrups. For parenteral administration, the composition may be formulated into an aqueous sterilized solution for injection (subcutaneous, intravenous, intramuscular, intraperitoneal or the like). The solution may contain other solutes such as sodium chloride or glucose in an amount sufficient to make the solution isotonic. The concentration of the active ingredient in the composition for oral or parenteral administration is not restricted and may usually be 0.1 ng/ml to 500 µg/ml. Since the compound of the formula (I) has a stable chemical structure, there is no difficulty in formulating the compound. Thus, in addition to the above-described formulations for oral administration and for injection, the compound may easily be formulated in the form of an absorption-promoting agent, a topical formulation such as ointment, and in the form of a suppository. The present invention will now be described by way of examples thereof. It should be noted that the examples are presented for the illustration purpose only and should not be interpreted in any restrictive way. Example The compound having a structure shown in Table 1 (beraprost) was tested for its hair-growing activity using male New Zealand white rabbits weighing 2 - 3 kg. In Table 1, the groups R 1 , R 2 and A in formula (I) are shown. R 1 : -COONa R 2 : -CH(CH 3 )-CH 2 -C≡C-CH 3 A: -(CH 2 ) 3 - Each group consisted of 3 - 4 rabbits. The hair on the back of each rabbit was shaved. The test compound was administered to each rabbit every day for two weeks and the length of the hair newly grown on the shaved back was measured. More particularly, for subcutaneous administration, the test compound was dissolved in physiological saline to a concentration of 400 µg/ml and 0.25 ml/kg body weight of the solution was administered to each rabbit at one time every day. For oral administration, the test compound was dissolved in distilled water to a concentration of 400 µg/ml and 0.25 ml/kg body weight of the solution was administered to each rabbit at one time every day. After the oral administration, the solution remaining in the oral administration tube was forced into the body with 3 ml of distilled water. As a control, 0.25 ml/kg body weight of physiological saline was subcutaneously administered. Five or more hairs were collected from five regions in the shaved back and the lengths of the hairs were measured. The results are shown in Table 2. As shown in Table 2, the test compound significantly increased the length of the newly grown hair when compared with the control group. Test Compound Administration Route Dose Length of Hair (mm) Control Subcutaneous 0.25ml/kg 2.38 ± 0.07 Beraprost Subcutaneous 0.1 mg/kg 4.54 ± 0.31 Oral 0.1 mg/kg 3.92 ± 0.24

Claims: Use as a hair growth promoting agent of a composition comprising a 5,6,7-trinor-4,8-inter-m-phenylene prostaglandin I 2 derivative of the formula (I) below or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier in an amount effective for stimulating growth of hair: (wherein R 1 represents hydrogen, carboxylic group or a functional derivative thereof, -CH 2 OH or a pharmaceutically acceptable cation; A represents (i) -(CH 2 ) n -, (ii) -(CH 2 ) m -CH=CH-(CH 2 ) p -, (iii) -(CH 2 ) m -C≡C-(CH 2 ) p - or (iv) -CH 2 -O-CH 2 - (wherein n represents an integer of 0 - 3, m and p, the same or different, represent 0 or 1); R 2 represents (i) C 5 - C 10 straight or branched alkyl group, (ii) -C t H 2t -OR 3 (wherein t represents an integer of 1 - 5, R 3 represents C 1 - C 5 straight or branched alkyl group or phenyl group), (iii) -C t H 2t -CH=C(R 4 )(R 5 ) (wherein t represents the same meaning as mentioned above, R 4 and R 5 , the same or different, represent hydrogen, methyl, ethyl, propyl or butyl group), or (iv) -C t H 2t -C≡C-R 6 (wherein t represents the same meaning as mentioned above, R 6 represents hydrogen, methyl or ethyl group, and -C t H 2t in (ii), (iii) and (iv) represent straight or branched alkylene group); wherein said compound of the formula (I) may be d-, l- or dl-form. Use according to claim 1, wherein said 5,6,7-trinor-4,8-inter-m-phenylene prostaglandin I 2 derivative is represented by the formula (II): (wherein R 7 represents methyl or ethyl, a pharmaceutically acceptable alkaline metal or alkaline earth metal, or an amine or basic amino acid; A represents (i) -(CH 2 ) n' -, (ii) -(CH 2 ) m -CH=CH-(CH 2 ) p -, (iii) -(CH 2 ) m -C≡C-(CH 2 ) p - or (iv) -CH 2 -O-CH 2 - (wherein n' represents an integer of 1 - 3, m and p represent the same meanings as in formula (I)); R 2' represents (i) C 5 - C 7 straight or branched alkyl group, (ii) -C t' H 2t' -OR 3' (wherein t' represents an integer of 1 - 3, R 3' represents C 2 - C 4 straight or branched alkyl group or phenyl group, (iii) -C t' H 2t' -CH=C(R 4 )(R 5 ) (wherein t' represents the same meaning as mentioned above, R 4 and R 5 represent the same meanings as in formula (I)), or (iv) -C t' H 2t' -C≡C-R 6 (wherein t' represents the same meaning as mentioned above, R 6 represents the same meaning as in formula (I), and -C t' H 2t' in (ii), (iii) and (iv) represent straight or branched alkylene group); wherein said compound of the formula (II) may be d-, l- or dl-form. Use according to claim 2, wherein said alkaline metal and alkaline earth metal for R 7 is selected from the group consisting of sodium, potassium and calcium, said amine and said basic amino acid for R 7 are selected from the group consisting of monomethylamine, dimethylamine, trimethylamine, methylpyperidine, monoethanolamine, diethanolamine, triethanolamine and lysine. Use according to claim 3, wherein said 5,6,7-trinor-4,8-inter-m-phenylene prostaglandin I 2 derivative is beraprost or a pharmaceutically acceptable salt thereof.

Inventors: ISOGAYA MASAFUMI, NISHIO SHINTARO, ISOGAYA, MASAFUMI, NISHIO, SHINTARO
Applicants: TORAY INDUSTRIES, TORAY INDUSTRIES, INC.
Application year: 1993
Main classification: A61K7
IPC codes: A61K31, A61Q7, A61K8, A61Q5, C07D307, A61P43