WO2013161978A1 - 育毛剤 - Google Patents

育毛剤 Download PDF

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Publication number
WO2013161978A1
WO2013161978A1 PCT/JP2013/062332 JP2013062332W WO2013161978A1 WO 2013161978 A1 WO2013161978 A1 WO 2013161978A1 JP 2013062332 W JP2013062332 W JP 2013062332W WO 2013161978 A1 WO2013161978 A1 WO 2013161978A1
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WO
WIPO (PCT)
Prior art keywords
group
hair
formula
carbon atoms
linear
Prior art date
Application number
PCT/JP2013/062332
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English (en)
French (fr)
Japanese (ja)
Inventor
室伏　きみ子
俊郎 諸星
茂行 今村
達郎 藤原
良彦 野方
Original Assignee
Ｓａｎｓｈｏ株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ｓａｎｓｈｏ株式会社 filed Critical Ｓａｎｓｈｏ株式会社
Priority to KR1020147032100A priority Critical patent/KR102165591B1/ko
Priority to SG11201406911RA priority patent/SG11201406911RA/en
Priority to CN201380022119.2A priority patent/CN104254317B/zh
Priority to JP2014512699A priority patent/JP6074411B2/ja
Publication of WO2013161978A1 publication Critical patent/WO2013161978A1/ja
Priority to HK15105548.9A priority patent/HK1204935A1/xx

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • the present invention relates to a hair restorer containing cyclic phosphatidic acid or carbacyclic phosphatidic acid as an active ingredient.
  • Alopecia can be congenital or acquired, and many studies have been conducted on its cause and mechanism of alopecia. However, although there are many hair nourishing and hair restorers on the market today, there are many unclear points.
  • medicinal ingredients include vasodilators such as assembly extract, vitamin E acetate, stimulants such as pepper tincture, pantothenic acid, biotin and the like. Vitamins, hormonal agents, anti-inflammatory agents, bactericides, and the like are used. It is also known that lysophosphatidic acid or phosphatidic acid derivatives have a hair-growing action (Patent Documents 1 and 2). In addition, a hair nurturing agent containing a hyaluronic acid synthesis promoting component is known (Patent Document 3).
  • This invention makes it the subject which should solve the problem in the above-mentioned prior art, and to provide the hair restorer which shows the outstanding hair restoration and hair growth effect.
  • the present inventors have found that cyclic phosphatidic acid and its derivatives show an excellent hair nourishing / hair growth effect, and have completed the present invention.
  • the hair restorer which contains the compound shown by following formula (1) as an active ingredient is provided.
  • R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms.
  • An alkynyl group, and these groups may contain a cycloalkane ring or an aromatic ring, and X and Y each independently represent an oxygen atom or a methylene group; M is a hydrogen atom or an alkali metal atom.
  • X and Y are oxygen atoms.
  • one of X and Y is an oxygen atom, and the other is a methylene group.
  • the compound represented by the formula (1) is a compound having an acyl group composed of a fatty acid derived from soybean lecithin.
  • a hair growth method comprising administering a compound represented by the above formula (1) to a subject.
  • FIG. 1 shows changes in hair growth scores of the control group and the NcPA administration group.
  • FIG. 2 shows the hair growth state on the 25th day after administration of the control group.
  • FIG. 3 shows the hair growth state on the 25th day of administration in the NcPA administration group.
  • the hair restorer of the present invention can be used for the treatment of androgenetic alopecia, and contains cyclic phosphatidic acid, carbacyclic phosphatidic acid or a salt thereof as an active ingredient.
  • the cyclic phosphatidic acid or the carbcyclic phosphatidic acid or a salt thereof is not particularly limited as long as it exhibits the effects of the present invention, but preferably a compound represented by the following formula (I) can be used.
  • R is a linear or branched alkyl group having 1 to 30 carbon atoms, a linear or branched alkenyl group having 2 to 30 carbon atoms, or a linear or branched group having 2 to 30 carbon atoms.
  • An alkynyl group, and these groups may contain a cycloalkane ring or an aromatic ring, and X and Y each independently represent an oxygen atom or a methylene group; M is a hydrogen atom or an alkali metal atom.
  • specific examples of the linear or branched alkyl group having 1 to 30 carbon atoms represented by the substituent R include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
  • linear or branched alkenyl group having 2 to 30 carbon atoms represented by the substituent R include an allyl group, a butenyl group, an octenyl group, a decenyl group, a dodecadienyl group, a hexadecatrienyl group, and the like.
  • linear or branched alkynyl group having 2 to 30 carbon atoms represented by the substituent R include, for example, 8-decynyl group, 8-undecynyl group, 8-dodecynyl group, 8-tridecynyl group, and 8-tetradecynyl group.
  • cycloalkane ring that can be contained in the alkyl group, alkenyl group, or alkynyl group
  • a cyclopropane ring a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, and a cyclooctane ring.
  • the cycloalkane ring may contain one or more heteroatoms, and examples thereof include an oxirane ring, an oxetane ring, a tetrahydrofuran ring, and an N-methylprolysine ring.
  • aromatic ring that can be contained in the alkyl group, alkenyl group, or alkynyl group include a benzene ring, a naphthalene ring, a pyridine ring, a furan ring, and a thiophene ring.
  • substituent R is an alkyl group substituted by a cycloalkane ring
  • substituent R is an alkyl group substituted by a cycloalkane ring
  • specific examples in the case where the substituent R is an alkyl group substituted by a cycloalkane ring include a cyclopropylmethyl group, a cyclohexylethyl group, an 8,9-methanopentadecyl group, and the like.
  • substituent R is an alkyl group substituted by an aromatic ring
  • substituent R is an alkyl group substituted by an aromatic ring
  • R is preferably a linear or branched alkyl group having 9 to 17 carbon atoms, a linear or branched alkenyl group having 9 to 17 carbon atoms, or a linear or branched alkynyl group having 9 to 17 carbon atoms. It is a group. R is more preferably a linear or branched alkyl group having 9, 11, 13, 15 or 17 carbon atoms, or a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms. is there. R is particularly preferably a linear or branched alkenyl group having 9, 11, 13, 15 or 17 carbon atoms.
  • X and Y in the compound represented by the formula (1) each independently represents an oxygen atom (—O—) or a methylene group (—CH 2 —), but X and Y do not simultaneously become a methylene group. . That is, there are the following three combinations of X and Y. (1) X is an oxygen atom and Y is an oxygen atom. (2) X is an oxygen atom and Y is a methylene group. (3) X is a methylene group and Y is an oxygen atom.
  • M in the cyclic phosphatidic acid derivative represented by the formula (I) is a hydrogen atom or an alkali metal atom.
  • alkali metal atom examples include lithium, sodium, potassium and the like, and sodium is particularly preferable.
  • Specific examples of the compound represented by the formula (1) used in the present invention include, as a 1-position acyl group, R is a stearoyl group having 17 carbon atoms, an oleoyl group, a linoleoyl group, a linolenoyl group, and R is the number of carbon atoms. 15 palmitoyl groups, palmitooleoyl groups, or cyclic phosphatidic acid derivatives having two or more of these fatty acids and having mixed fatty acid residues are preferred. Especially, the cyclic phosphatidic acid derivative which has an acyl group which consists of a fatty acid derived from soybean lecithin is especially preferable.
  • the compounds of formula (I) may have isomers such as positional isomers, geometric isomers, tautomers, or optical isomers depending on the type of substituent, but all possible Isomers and mixtures containing two or more of these isomers in any ratio are also within the scope of the present invention.
  • the compound of formula (I) may exist in the form of an adduct (hydrate or solvate) with water or various solvents, and these adducts are also within the scope of the present invention. is there. Furthermore, any crystalline form of the compound of formula (I) and salts thereof is within the scope of the invention.
  • compounds in which X and Y are oxygen atoms include, for example, JP-A-5-230088, JP-A-7-149772, JP-A-7-258278, and JP-A-9. It can be chemically synthesized according to the method described in Japanese Patent No. 25235.
  • a compound in which X and Y are oxygen atoms is synthesized by allowing phospholipase D to act on lyso-type phospholipid according to the method described in Japanese Patent Application Laid-Open No. 2001-178489. You can also
  • the lyso-type phospholipid used here is not particularly limited as long as it is a lyso-type phospholipid capable of acting on phospholipase D. Many types of lyso-type phospholipids are known, those having different fatty acid types, and molecular types having ether or vinyl ether bonds are known, and these are available as commercial products.
  • phospholipase D those derived from higher plants such as cabbage and peanuts and those derived from microorganisms such as Streptomyces uschromofuscus and Actinomadula sp. Are available as commercially available reagents, but are extremely selected by the enzyme derived from Actinomadula sp. No.362.
  • cyclic phosphatidic acid is synthesized (Japanese Patent Laid-Open No. 11-367032).
  • the reaction between lyso-type phospholipid and phospholipase D is not particularly limited as long as the enzyme is capable of expressing the activity. For example, it is heated from room temperature in an acetate buffer solution (pH of about 5 to 6) containing calcium chloride. (Preferably at about 37 ° C.) for about 1 to 5 hours.
  • the produced cyclic phosphatidic acid derivative can be purified by extraction, column chromatography, thin layer chromatography (TLC) or the like according to a conventional method
  • a compound in which X is an oxygen atom and Y is a methylene group can be obtained by a method described in the literature (Kobayashi, S., et al., TetrahedronroLetters 34, 4047-4050 (1993)). ) And can be synthesized by the method described in International Publication WO2002 / 094286. An example of a specific synthesis route is shown below.
  • a compound in which X is a methylene group and Y is an oxygen atom is synthesized by the method described in JP-A No. 2004-010582 or WO 03/104246. can do.
  • the dosage form of the hair restorer of the present invention is not particularly limited as long as it is a dosage form that can be compounded with the compound represented by the following formula (1) and can be applied to the outer skin.
  • a suitable cosmetic base Alternatively, it can be blended with a pharmaceutical base and used as a liquid, emulsion, semi-solid or solid hair restorer.
  • it may be included in microcapsules or liposomes.
  • the form of the hair restorer of the present invention is arbitrary, and examples thereof include hair liquid, hair tonic, hair lotion, ointment, hair cream, mousse, gel, shampoo, rinse, etc., each of which is used as a suitable base for the present invention.
  • the cyclic phosphatidic acid derivative obtained can be added and can be produced by a conventional method.
  • the content of the cyclic phosphatidic acid derivative in the hair restorer of the present invention varies depending on the type of the cyclic phosphatidic acid derivative, but is usually 0.01 to 5.0% by weight, preferably 0.01 to 3.0% by weight, more. Preferably, it is 0.1 to 1.0% by weight.
  • Suitable bases for liquid dosage forms include those commonly used for hair restorers, such as purified water, ethyl alcohol, and polyhydric alcohols, and additives may be added as necessary.
  • the polyhydric alcohol include glycerol, 1,3-butylene glycol, propylene glycol and the like.
  • Additives include surfactants, vitamins, anti-inflammatory agents, bactericides, hormonal agents, herbal extracts, tinctures, refreshing agents, moisturizers, keratolytic agents, antioxidants, sequestering agents, fragrances, etc. It is done.
  • the surfactant is not particularly limited, and nonionic, anionic, cationic and amphoteric surfactants can be appropriately used.
  • vitamins examples include benzyl nicotinate, nicotinamide, D-pantothenyl alcohol, pantothenyl ethyl ether, biotin, pyridoxine hydrochloride, riboflavin and the like.
  • Anti-inflammatory agents include dipotassium glycyrrhizinate, ⁇ -glycyrrhetinic acid, allantoin, diphenhydramine hydrochloride, guaiazulene, 1-menthol and the like.
  • bactericides include trichlorohydroxydiphenyl ether, hinokitiol, triclosan, chlorhexidine gluconate, phenoxyethanol, resorcin, isopropylmethylphenol, azulene, salicylic acid, zinc pyrithione, benzalkonium chloride, photosensitizer 301, mononitroguaiacol sodium, etc. .
  • hormone agents include ethinyl estradiol, estrone, estradiol and the like.
  • Herbal extracts include assembly extract, garlic extract, carrot extract, aloe extract, kina extract and the like.
  • Examples of the tincture include chili tincture, ginger tincture, cantharis tincture and the like.
  • Examples of the refreshing agent include chili pepper tincture, 1-menthol and camphor.
  • humectant examples include L-pyrrolidone carboxylic acid, sodium hyaluronate, chondroitin sulfate, cordyceps extract, saffron extract and the like.
  • antioxidant examples include butylhydroxyanisole, isopropyl gallate, propyl gallate, erythorbic acid and the like.
  • sequestering agent examples include ethylenediaminetetraacetate or a salt thereof.
  • fragrances examples include natural fragrances such as orange oil, lemon oil, bergamot oil, lime oil, lemongrass oil, and lavender oil, and synthetic fragrances such as menthol, rose oxide, linalool, citral, and linalyl acetate.
  • a combustible gas, an incombustible gas, or the like can be used.
  • the combustible gas include LPG (liquefied petroleum gas) and dimethyl ether
  • examples of the non-combustible gas include nitrogen gas and carbon dioxide gas.
  • Semi-solid or solid dosage form bases include petrolatum, solid paraffin, vegetable oil, mineral oil, lanolin, wax, macrogol, etc. If necessary, the aforementioned additives, emulsifiers such as lecithin, ethyl alcohol A lower alcohol such as isopropyl alcohol may be added.
  • the dose of the hair restorer of the present invention varies depending on the subject's symptoms, administration method, etc., but is 0.1 to 250 mg, preferably 1 to 100 mg as the compound represented by the formula (1) at a time per adult. Is administered transdermally once to several times a day.
  • NcPA Native cPA
  • soybean phospholipid lecithin content: 70%
  • 1 M acetate buffer pH 6.5
  • Streptomyces phospholipase A2 100 ml
  • the reaction solution was adjusted to pH 2.5 to inactivate the enzyme, and then 100 ml of chloroform and 50 ml of methanol were added and mixed with sufficient stirring to extract lipid components.
  • the chloroform layer was collected and dried under reduced pressure on a rotary evaporator. 100 ml of acetone was added to the solid content to precipitate phospholipids and remove free fatty acids. Dissolve 5 g of the precipitate in 40 ml of chloroform, add 10 ml of 1M acetate buffer (pH 5.5), add 1500 units of phospholipase D derived from the genus Actinomadura, and perform the reaction with stirring at 40 ° C. for 18 hours. It was. 20 ml of 3M sodium chloride and 20 ml of 0.1M EDTA solution were added to the reaction solution and stirred at 40 ° C. for 1 hour.
  • the above cyclic phosphatidic acid sodium salt 500 mg was dissolved in 5 ml of chloroform containing 10% methanol, applied to a silica gel column, developed with the same solvent, further developed with chloroform containing 20% methanol, and fractionated into 10 ml fractions. Fractions containing cyclic phosphatidic acid sodium salt were confirmed and collected by the above TLC method, and dried under reduced pressure using a rotary evaporator to obtain 320 mg of cyclic phosphatidic acid sodium salt powder. The purity of the cyclic phosphatidic acid sodium salt of this sample was 95%.
  • the fatty acid composition of the high purity cyclic sodium phosphatidic acid obtained above was analyzed by gas chromatogram method.
  • the sample was dissolved in hydrochloric acid methanol so as to be 20 mg / ml, and heated at 65 ° C. for 30 minutes. After returning to room temperature, the water of the master beam and then the hexane of the master beam were added and mixed thoroughly with stirring. Centrifugation was performed at 3000 rpm for 5 minutes, and 2 ⁇ l of the hexane layer was injected into the capillary column to analyze the constituent fatty acids. The analysis is as follows. Fatty acid content (%) Palmitic acid 23.9 Stearic acid 5.4 Oleic acid 8.6 Linoleic acid 53.4 Linolenic acid 4.9 Other fatty acids 3.8
  • Test Example 1 Using the NcPA produced in Production Example 1, a hair growth effect test in mice was performed.
  • the administration route was transdermal administration.
  • a sample to be administered (control or test substance) was administered to the back skin of a mouse using a micropipette, and lightly smeared with a finger (control group: 10 animals; and 10 NcPA administration groups).
  • the administration liquid volume was 100 ⁇ l / site.
  • the administration frequency was once a day.
  • the administration period was 24 days, with the first day of administration being 1 day of administration.
  • the naked eye observation of the shaved part was based on the criteria shown in the following Table 1 on the day of grouping (1 day of administration), 5th, 7th, 10th, 13th, 16, 19, 22 and 25th. The score was scored and the average value ⁇ standard deviation was calculated for each group. In addition, a photograph was taken for each group on the score observation day. Photographing and score observation were performed before administration.
  • Results Table 2 and FIG. 1 show the results of the hair growth state score observation. The results of mouse photography are shown in FIGS.
  • the NcPA administration group in which 1100 ⁇ l / site / day of NcPA was administered transdermally for 24 days showed a higher tendency (P ⁇ 0.1) on the 19th and 25th administration than the control group. ) was observed, and the hair growth promoting action of NcPA was confirmed.

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  • Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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PCT/JP2013/062332 2012-04-27 2013-04-26 育毛剤 WO2013161978A1 (ja)

Priority Applications (5)

Application Number Priority Date Filing Date Title
KR1020147032100A KR102165591B1 (ko) 2012-04-27 2013-04-26 발모제
SG11201406911RA SG11201406911RA (en) 2012-04-27 2013-04-26 Hair-growing agent
CN201380022119.2A CN104254317B (zh) 2012-04-27 2013-04-26 生发剂
JP2014512699A JP6074411B2 (ja) 2012-04-27 2013-04-26 育毛剤
HK15105548.9A HK1204935A1 (en) 2012-04-27 2015-06-11 Hair growth agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2012102147 2012-04-27
JP2012-102147 2012-04-27

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WO2013161978A1 true WO2013161978A1 (ja) 2013-10-31

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PCT/JP2013/062332 WO2013161978A1 (ja) 2012-04-27 2013-04-26 育毛剤

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JP (1) JP6074411B2 (ko)
KR (1) KR102165591B1 (ko)
CN (1) CN104254317B (ko)
HK (1) HK1204935A1 (ko)
SG (1) SG11201406911RA (ko)
WO (1) WO2013161978A1 (ko)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021132297A1 (ja) * 2019-12-23 2021-07-01 大塚化学株式会社 カルバ環状ホスファチジン酸化合物

Citations (4)

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Publication number Priority date Publication date Assignee Title
JP2002363081A (ja) * 2001-06-06 2002-12-18 Nof Corp ヒアルロン酸産生能増強剤およびその用途
JP2003081778A (ja) * 2001-09-13 2003-03-19 Lion Corp 養育毛剤
JP2004010582A (ja) * 2002-06-11 2004-01-15 Gencom Co カルバ環状ホスファチジン酸誘導体
WO2011065480A1 (ja) * 2009-11-26 2011-06-03 国立大学法人お茶の水女子大学 神経細胞死抑制剤

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JPS5927809A (ja) * 1982-08-10 1984-02-14 Lion Corp 養毛剤
JPS6341363A (ja) 1986-08-07 1988-02-22 Minolta Camera Co Ltd フイニツシヤ付きソ−タ
CA2380640A1 (en) 1999-08-18 2001-02-22 Kyowa Hakko Kogyo Co., Ltd. Hair-growing agent
WO2008081580A1 (ja) * 2006-12-28 2008-07-10 Ochanomizu University 環状ホスファチジン酸誘導体を含む鎮痛剤
JP2008208058A (ja) * 2007-02-26 2008-09-11 Nof Corp フォーカルアドヒージョン形成促進剤および、その用途

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
JP2002363081A (ja) * 2001-06-06 2002-12-18 Nof Corp ヒアルロン酸産生能増強剤およびその用途
JP2003081778A (ja) * 2001-09-13 2003-03-19 Lion Corp 養育毛剤
JP2004010582A (ja) * 2002-06-11 2004-01-15 Gencom Co カルバ環状ホスファチジン酸誘導体
WO2011065480A1 (ja) * 2009-11-26 2011-06-03 国立大学法人お茶の水女子大学 神経細胞死抑制剤

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021132297A1 (ja) * 2019-12-23 2021-07-01 大塚化学株式会社 カルバ環状ホスファチジン酸化合物
US11958876B2 (en) 2019-12-23 2024-04-16 Otsuka Chemical Co., Ltd. Carbacyclic phosphatidic acid compound

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JPWO2013161978A1 (ja) 2015-12-24
CN104254317B (zh) 2018-01-30
KR102165591B1 (ko) 2020-10-14
KR20150006852A (ko) 2015-01-19
HK1204935A1 (en) 2015-12-11
JP6074411B2 (ja) 2017-02-01
SG11201406911RA (en) 2014-11-27
CN104254317A (zh) 2014-12-31

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