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United States Patent (19) 11 Patent Number: 4,874,791 Adachi et al. (45) Date of Patent: Oct. 17, 1989

(54. STIMULATION OF HAIR GROWTH WITH ALPHATC CARBOXYTLIC ACDS FOREIGN PATENT DOCUMENTS 75 Inventors: Kuniaki Adachi, Odawara; Hideo 2477871 9/1981 France . Tamai, Kanagawa; Masanao Sadai, 1469988 4/1977 United Kingdom...... A61 K/31/125 Hiratsuka, all of Japan OTHER PUBLICATIONS 73) Assignee: Lion Corporation, Tokyo, Japan Chemical Abstracts, vol. 10G, (1987), #201540g; Oono et al. 21 Appl. No.: 923,902 Chemical Abstracts, vol. 102, (1985), #137579g; Adachi 22 Filed: Oct. 28, 1986 et al. Chemical Abstracts; vol. 84, (1976), #35202d, Menyailo Related U.S. Application Data et al. 63 Continuation of Ser. No. 724,354, Apr. 18, 1985, aban Vol. 3, No. 152(C-67), Dec. 14, 1979, and JP-A-54 129 doned, which is a continuation of Ser. No. 518,447, Jul. 135, Jun. 10, 1979. 29, 1983, abandoned. Primary Examiner-Douglas W. Robinson 30 Foreign Application Priority Data Assistant Examiner-Joseph A. Lipovsky Aug. 10, 1982 JP Japan ...... 57-137909 Attorney, Agent, or Firm-Bacon & Thomas 511 Int. Cl."...... A61K 31/20 57 ABSTRACT 52 U.S. Cl...... 514/558; 514/880 A hair-growing agent which exhibits a strong hair 58) Field of Search ...... 514/557, 558,560 growing effect. The hair-growing agent according to (56) References Cited the present invention contains as an effective ingredient U.S. PATENT DOCUMENTS an aliphatic carboxylic acid having an odd number of carbon atoms or a derivative thereof. 4,139,619, 2/1979 Chidsey, III ...... 424/45 4,263,313 4/1981 Eckett et al...... 514/558 4,745,103 5/1988 Oono et al...... 514/558 10 Claims, No Drawings 4,874,791 1. 2 The aliphatic carboxylic acid to be used for the hair STMULATION OF HAR GROWTH WITH growing agent according to the present invention may ALPHATIC CARBOXYTLCACDS be a saturated or unsaturated aliphatic carboxylic acid provided it has an odd number of carbon atoms. The This case is a continuation of Ser. No. 724,354 filed 5 unsaturated aliphatic carboxylic acid may contain a 4/18/85, now abandoned, which is in turn a continua plurality of double bonds. The aliphatic carboxylic acid tion of Ser. No. 518,447 filed 7/29/83, now abandoned. may be a lower aliphatic carboxylic acid such as propi BACKGROUND OF THE INVENTION onic acid (having 3 carbon atoms) or valeric acid (hav I. Field of the Invention 10 ing 5 carbon atoms), or a higher aliphatic carboxylic The present invention relates to a hair-growing agent. acid such as tricosanoic acid (having 23 carbon atoms) II. Description of the Prior Art or pentacosanoic acid (having 25 carbon atoms). Pre Hair-growing agents containing various agents exhib ferred aliphatic carboxylic acids having an odd number iting pharmaceutical properties are known. Such phar of carbon atoms may include propionic acid, Valeric maceutical agents may include, for example, a vitamin 15 acid, heptanoic acid, nonanoic acid, undecanoic acid, such as vitamin E, an amino acid such as serine or me tridecanoic acid, pentadecanoic acid, heptadecanoic thionine, a vasodilator such as acetylcholine derivative, acid, nonadecanoic acid, heneicosanoic acid, tricosa an anti-inflammatory agent such as lithospermum root noic acid and pentacosanoic acid. extract, a female such as estradiol, a skin For the hair-growing agent according to the present function stimulant such as cepharanthine, a melanine synthesis catalyst such as copper pantothenate, a kera invention, any derivative of an aliphatic carboxylic acid tolytic such as salicylic acid, or the like. These agents having an odd number of carbon atoms are enumerated may assist in the prevention and cure of allopecia. hereinabove may be used an an effective ingredient. There are known cases where an aliphatic carboxylic However, needless to say, any compound which may acid or a derivative thereof such as natural vegetable 25 adversely affect the human body cannot be used. Pre oil, e.g., olive oil and castor oil, or is con ferred derivatives include the following. tained in a hair cosmetic such as a hair tonic or the like (A) a represented by the general for to improve performance of the product. Aliphatic car mula (I) or (II): boxylic acids constituting various naturally occurring , such as vegetable oils and animal oils, are in 30 almost all cases aliphatic carboxylic acids having an fHocoR, (I) even number of carbon atoms, whether they are satu (HOH) rated aliphatic carboxylic acids such as stearic acid and CH2(OH) or unsaturated aliphatic carboxylic acids such as oleic acid and linoleic acid. There are no known 35 CH2(CH) (II) cases where an aliphatic carboxylic acid having an odd CHOCOR1 number of carbon atoms or a derivative thereof is used in a hair cosmetic. th.OH) Conventional hair-growing agents are claimed to be effective in preventing or improving dandruff, itchiness where R1 is a straight-chain aliphatic group having an and hair loss as well as in accelerating hair generation even number of carbon atoms. and growth. However, it seems that a satisfactory effect (B) a represented by the general formula has not yet been obtained. (III) or (IV): SUMMARY OF THE INVENTION 45 Therefore, the object of the present invention is to HocOR: (III) provide a hair-growing agent exhibiting a strong hair CHOCOR3 growing effect. The object can be accomplished by providing a hair th.OH) growing agent comprising as an effective ingredient an 50 CHOCOR2 (IV) aliphatic carboxylic acid having an odd number of car bon atoms or a derivative thereof. HOH) The hair-growing agent according to the present CHOCOR3 invention provides a strong hair-growing effect. 55 DETAILED DESCRIPTION OF THE where at least one of R2 and R3 is a straight-chain ali PREFERRED EMBODIMENTS phatic group having an even number of carbon atoms. It should be noted here that the effect to be accomplished Alopecia may arise from various causes. In each case, by the present invention can be achieved if either R2 or individual hairs cannot complete their normal hair cycle R3 represents an aliphatic group having an even number to reach the telogen state. In order to decrease baldness and accelerate hair generation, it is necessary to bring of carbon atoms while the other represents a hydrogen the hair follicles from the telogen state into the normal or an aliphatic group having an odd number of carbon anagen state. As a result of extensive research into the atoms or another organic group which does not ad conversion of hair from the telogen state into the ana versely affect the human body. However, a diglyceride gen state, it has been found that an aliphatic carboxylic 65 of an aliphatic carboxylic acid having an odd number of acid having an odd number of carbon atoms and a deriv carbon atoms is particularly preferred. ative thereof exhibit a remarkable hair-growing effect. (C) a represented by the general formula The present invention is based on this finding. (V): 4,874,791

CHOCOR4 (V) Ricocort (X) HOCOR: COR18 CH2OCOR6 where at least one of R16, R17 and R18 are straight-chain where at least one of R4, R5 and Ró is a straight-chain aliphatic group having an even number of carbon aliphatic group having an even number of carbon atoms. It is to be noted that where at least one of R16, atoms. It should be noted here that, where at least one R17 and R18 is an organic group with an even number of of R4, R5 and R5 is a aliphatic group having an even 10 carbon atoms, the present invention can achieve the number of carbon atoms, the effect sought by the pres desired effect, and also that the others may each be any ent invention can be achieved even if the others are in organic group exerting no adverse influence on the each case hydrogen or an aliphatic group having an odd human body. However, it is particularly preferred that number of carbon atoms or another organic group all three be independently a straight-chain aliphatic which does not adversely affect the human body. How 15 ever, a triglyceride of an aliphatic carboxylic acid hav group having an even number of carbon atoms. ing an odd number of carbon atoms is particularly pre (I) a dibasic carboxylic acid represented by the gen ferred. eral formula (XI) or a salt thereof; (D) an aliphatic carboxylic acid salt represented by the general formula (VI): 20 HOOCR19COOH (XI) (R7COO)M (VI) where R19 is a straight-chain aliphatic group having an odd number of carbon atoms. where R7 is a straight-chain aliphatic group having an (J) a sterol ester represented by the general formula even number of carbon atoms, Mis a metal atom, and n 25 (XII): is an integer corresponding the valence of M. Repre sentatives may be R7COONa, R7COOK and R7COOLi. (E) an ester represented by the general formula (VII): (XII) R3COOR9 (VIII) 30 where R8 is a straight-chain aliphatic group having an even number of carbon atoms, R9 is a residue of a pri mary or secondary alcohol, an amine residue, a poly oxyethylene residue, a sorbitan residue or a sucrose 35 R20COO residue. A representative primary alcohol may be meth anol and ethanol and a representative amine residue is mono-, di- and tri-ethanolamine. where R20 is a straight-chain aliphatic group having an (F) a primary amide represented by the general for even number of carbon atoms. mula (VIII): 40 (K) a represented by the general for mula (XIII): R10CONR11R12 (VIII) where R10 is a straight-chain aliphatic group having an CH2OCOR21 (XIII) even number of carbon atoms, and R11 and R12 are 45 (HOCOR: independently a hydrogen atom or an organic group CH-O O having no adverse effect on the human body. N / (G) a secondary amide represented by the general P formula (IX): 50 / Y Rico COR: (IX) where at least one of R21 and R22 is an straight-chain R15 aliphatic group having an even number of carbon atoms, and the other may be a hydrogen or an organic where at least one of R13 and R14 is a straight-chain 55 group having no adverse effect on the human body. aliphatic group having an even number of carbon However, it is preferred that both of R21 and R22 are atoms, and R15 may be a hydrogen atom or any organic independently a straight-chain aliphatic group having group which does not adversely affect the human body. an even number of carbon atoms. X is a choline residue, It should be noted here that where at least one of R13 an ethanolamine residue, a serine residue or an inositol and R14 is an aliphatic group having an even number of 60 residue. When X is a choline residue, it represents a carbon atoms the effect of the present invention can be achieved, and that the other may be any organic group phosphatidyl choline. When X is a ethanolamine resi which does not adversely affect the human body al due, it represents a phosphatidyl ethanolamine. When X though it is particularly preferred that both be a is a serine residue, it represents a phosphatidyl serine. straight-chain aliphatic group having an even number of 65 When X is a inositol residue, it represents a phosphati carbon atoms. dyl inositol. (H) a tertiary amide represented by the general for (L) a phosphatidic acid represented by the general mula (X): formula (XIV): 4,874,791 6 centrations of the test substances were 0.3, 3.0 and 10.0% by weight, respectively. As a control, ethanol HOCOR: (XIV) containing no test substance was also tested. HOCOR: The test animals were groups of 6 to 8 male rabbits of CH-O O New Zealand White species each weighing about 2.5 kg N / from whose backs hair was removed. Rabbits in the 4'S telogen state alone were used. The test specimen was of Yo applied in the amount of 0.2 ml twice per week for 30 to 60 days to the area of the rabbits' backs from which the where at least one of R23 and R24 is an straight-chain 10 aliphatic group having an even number of carbon hair had been removed. The test was conducted by atoms, and the other is a hydrogen or an organic group observing the number of days required for the conver having no adverse effect on the human body. However, sion of hair from the telogen state into the anagen state. it is preferred that both of R23 and R24 are indepen The results are shown in Table 1 below. In the Table, dently a straight-chain aliphatic group having an even 15 "shortened days' means the number of days by which number of carbon atoms. the conversion of the telogen state into anagen state is (M) a represented by the general for shortened, compared with the control in which ethanol mula (XV): containing no test substance was applied. For example, when the number of shortened days is 10, it means that the conversion of telogen state into anagen state oc curred 10 days earlier than the control experiment. OH NH TABLE 1. Concen tration Hair-growing effect - 25 (% by Shortened Overal where R25 is a straight-chain aliphatic group having an Test substance weight) days evaluation even number of carbon atoms, and X is a sugar residue, Propionic acid 0.3 10 Effective a phosphate residue or an amine base residue such as Valeric acid 0.3 12 Effective choline or ethanolamine. Heptanoic acid 0.3 2 Effective 30 Nonanoic acid 0.3 14 Effective The hair-growing agent according to the present Hendecanoic acid 0.3 18 Effective invention may be used in a conventional manner in a Tridecanoic acid 0.3 20 Effective variety of forms such as a hair-growing agent for an Pentadecanoic acid 0.3 22 Effective endermic liniment, a hair-growing agent for internal Heptadecanoic acid 0.3 22 Effective use, a hair-growing agent to be taken by injection, a hair Nonadecanoic acid 0.3 6 Effective 35 Heneicosanoic acid 0.3 12 Effective tonic, hair lotion, hair cream, hair shampoo, hair rinse Tricosanoic acid 0.3 12 Effective or the like. Pentacosanoic acid 0.3 12 Effective In addition to the above-mentioned effective ingredi Butyric acid 0.3 2 Ineffective ents, the hair-growing agent according to the present Caproic acid 0.3 Ineffective invention may usually contain a cosmetically or phar 0.3 3 Ineffective 0.3 3 Ineffective maceutically acceptable carrier. Such a carrier is not 0.3 1. Ineffective described in detail here since it is well known in this 0.3 O Ineffective field. Examples of such a carrier include water; ethanol; Palmitic acid 0.3 O Ineffective a polyol such as ethylene glycol, propylene glycol, Stearic acid 0.3 0 Ineffective 1,3-butylene glycol, glycerine or sorbitol; a siloxane Arachic acid 0.3 O Ineffective such as dimethyl polysiloxane, phenyl polysiloxane or 45 Behemic acid 0.3 O Ineffective 0.3 O Ineffective polyoxyalkylene polysiloxane, and animal or vegetable Tripropionin 3.0 10 Effective oil such as sperm oil or jojoba oil; liquid paraffin; vase Tripentanoin 3.0 16 Effective line; paraffin wax, squalane; and an olefin oligomer. Triheptanoin 3.0 20 Effective The hair-growing agent according to the present Trinonanoin 3.0 22 Effective invention may also contain an effective ingredient that 50 Remarkably Trihendecanoin 3.0 26 effective is conventionally used. Such an effective ingredient Remarkably may include, for example, a vitamin such as vitamin E, Tritridecanoin 3.0 28 effective a hormone such as estradiol, a vasodilator such as an Remarkably acetylcholine derivative, an amino acid such as serine or Tripentadecanoin 3.0 30 effective methionine, an anti-inflammatory agent such as lithos 55 Remarkably Triheptadecanoin 3.0 30 effective permum root extract, a skin function stimulant such as Trinonadecanoin 3.0 22 Effective cepharanthine, or a keratolytic such as salicyclic acid. Triheneicosanoin 3.0 18 Effective Tritricosanoin 3.0 16 Effective TEST 1: ANIMA STUDY FOR EVALUATING Tributyrin 3.0 2 Ineffective EFFECTIVENESS Tricaprone 3.0 2 Ineffective Tricaprin 3.0 4. Ineffective Aliphatic carboxylic acids having an odd number of Tricaprylin 3.0 2. Ineffective carbon atoms and derivatives thereof were tested for Trilaurin 3.0 O Ineffective their hair growing effects. 3.0 O Ineffective The tested substances were linear saturated aliphatic Tristearin 3.0 O Ineffective carboxylic acids having carbon atoms in variously odd 65 Triarachin 3.0 O Ineffective and even numbers, a of the aliphatic car Tribehen 3.0 0 Ineffective boxylic acids. Test specimens were prepared by dis Triliignocerin 3.0 O Ineffective solving each test substance to be tested in ethanol. Con 4,874,791 7 It can be seen from Table 1 that the aliphatic carbox ylic acids having an odd number of carbon atoms and EXAMPLE 2 the thereof have significant hair-growing Hair-Growing Composition for Endermic Liniment effects whereas the aliphatic carboxylic acids having even-numbered carbon chains as long as the former and 5 the glycerides thereof have no hair-growing effect. Ingredient Amount 85% ethanol 97.5 TEST 2: HUMAN STUDY FOR EVALUATING n-nonanoic acid 0.5 Olive oil 1.0 EFFECTIVENESS a-tocopherol 0.5 A hair-growing composition comprising 10.0% by 10 Perfume 0.5 weight of n-trihendecanoin, 1.0% by weight of castor oil, 0.5% by weight of pyrrolidone carboxylic acid, 0.5% by weight of a perfume and 88% by weight of EXAMPLE 3 80% ethanol was prepared. This composition was then used by patients (totaling 25 patients) suffering from Hair-Growing Composition for Endermic Liniment various types of allopecia over a period of 3 to 6 months. The effects were evaluated according to subjective Ingredient Amount observation by the patients themselves. The results are 90% ethanol 92.5 n-tritridecanoin 5.0 shown in Table 2 below. 20 Olive oil 1.0 TABLE 2 Glycyrrhizin 1.0 Perfume 0.5 Results No. of Remarkably Ineffec Alopecia CaSS Effective Effective tive EXAMPLE 4 Alopecia 9 3 3 3 25 aredita Hair-Growing Composition for Endermic Liniment Alopecia praematura and 10 3 4. 3 praesenis Ingredient Amount Alopecia 3 0 2 1 90% ethanol 89.5 furfuracea 30 Ethyl n-tridecanoate 3.0 Alopecia 3 l O 2 Liquid paraffin 5.0 seborrheica Polyethylene glycol 2.0 Perfume 0.5 It can be seen from Table 2 that the hair-growing agent according to the present invention is effective for 35 various types of allopecia, particularly for male alopecia EXAMPLE 5 such as alopecia praematura and alopecia praesenilis as Shampoo Composition well as alopecia areata. TEST 3: HUMAN STUDY FOR EVALUATING Ingredient Amount SAFETY Lauryl ether sodium sulfate 5.0 a-olefin sodium sulfonate 10.0 Pieces of gauze of 1 cm in diameter were soaked with Lauryl sulfate triethanol amine 5.0 the hair-growing composition prepared for Test 2. As a n-tritridecanoin 3.0 control, pieces of gauze of 1 cm in diameter were Purified water 77.0 soaked with water. 45 Two pieces of each type of gauze (totaling 4 pieces) were attached to a closed patch by means of a fin cham EXAMPLE 6 ber to the antebrachial flexor side of 25 healthy females for 24 hours. The skin conditions were observed after 30 Hair Rinse Composition minutes and 24 hours of the removal of the gauze. The 50 result was that none of the women had any skin irrita Ingredient Annount tion. Stearyl trimethyl ammonium 1.5 The following indicates forms and compositions as chloride Distearyl dimethyl ammonium 0.5 examples of the hair-growing agents according to the 55 chloride present invention. In the following, the compositions Cetanol 1.5 are expressed in terms of % by weight, Polyoxyethylene stearyl 2.0 ether (P = 5) EXAMPLE 1. Liquid paraffin 1.0 Trihendecanoin 3.0 Hair-Growing Composition for Endermic Liniment 60 Purified water 90.5

Ingredient Amount EXAMPLE 7 80% ethanol 88 n-trihendecanoin 10.0 Hair Cream Composition Castor oil 1.0 65 Pyrrolidone carboxylic acid 0.5 Perfume 0.5 Ingredient Amount n-tripentadecanoin 10.0 4,874,791 9 10 -continued -continued Ingredient Amount Ingredient Amount Olive oil 5.0 Olive oil 99.5 Liquid paraffin 51.0 5 Beeswax 1.0 What is claimed is: Sorbitan sesquioleate 3.0 1. A method of stimulating growth of human hair on Purified water 30.0 a human head suffering from or susceptible to alopecia which comprises bringing active human hair follicles on 10 a human head from a telogen state into a normal anagen EXAMPLE 8 state by applying to said follicles a growth stimulating Hair Tonic Composition amount of an effective ingredient which is an aliphatic carboxylic acid which possesses an odd number of car bon atoms or derivative thereof and is selected from the Ingredient Amount 15 group consisting of n-hendecanoic acid, n-tridecanoic Ethyl n-nonanoate 3.0 acid, n-pentadecanoic acid, n-heptadecanoic acid, a Chillies tincture 0.5 of said acids, a metal salt of said acids and Hinokitiol 0.1 mixtures thereof. a-tocopherol 0.3 2. The method of claim 1 for treating males with Castor oil 10.0 20 alopecia. Ethanol 86.1 3. The method of claim 2, wherein the alopecia is alopecia areata. 4. The method of claim 2, wherein the alopecia is EXAMPLE 9 alopecia prematura and praesenilis. 25 5. The method of claim 2, wherein the alopecia is Hair-Growing Composition for Internal Use alopecia furfuracea. 6. The method of claim 2, wherein the alopecia is alopecia seborrheica. Ingredient Amount 7. The method of claim 2, wherein the effective ingre n-tripentadecanoin 68.0 30 dient is n-hendecanoic acid, a glyceride or metal salt Lactose 20.0 thereof. Corn starch 10.0 8. The method of claim 2, wherein the effective ingre Magnesium stearate 2.0 dient is n-tridecanoic acid, a glyceride or metal salt thereof. 35 9. The method of claim 2, wherein the effective ingre EXAMPLE 10 dient is n-pentadecanoic acid, a glyceride or metal salt Hair-Growing Composition to be taken by Injection thereof. 10. The method of claim 2, wherein the effective ingredient is n-heptadecanoic acid, a glyceride or metal Ingredient Amount 40 salt thereof. Tritridecanoin 0.5 sk k : k

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