JP2004518701A - Novel compositions of potassium channel openers and protein kinase C inhibitors and uses thereof - Google Patents
Novel compositions of potassium channel openers and protein kinase C inhibitors and uses thereof Download PDFInfo
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- JP2004518701A JP2004518701A JP2002562427A JP2002562427A JP2004518701A JP 2004518701 A JP2004518701 A JP 2004518701A JP 2002562427 A JP2002562427 A JP 2002562427A JP 2002562427 A JP2002562427 A JP 2002562427A JP 2004518701 A JP2004518701 A JP 2004518701A
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- MOJZMWJRUKIQGL-FWCKPOPSSA-N Procyanidin C2 Natural products O[C@@H]1[C@@H](c2cc(O)c(O)cc2)Oc2c([C@H]3[C@H](O)[C@@H](c4cc(O)c(O)cc4)Oc4c3c(O)cc(O)c4)c(O)cc(O)c2[C@@H]1c1c(O)cc(O)c2c1O[C@@H]([C@H](O)C2)c1cc(O)c(O)cc1 MOJZMWJRUKIQGL-FWCKPOPSSA-N 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003571 Vitamin B5 Natural products 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 102000001307 androgen receptors Human genes 0.000 description 1
- 108010080146 androgen receptors Proteins 0.000 description 1
- NUZWLKWWNNJHPT-UHFFFAOYSA-N anthralin Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
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- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
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- 230000003778 catagen phase Effects 0.000 description 1
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- 230000009918 complex formation Effects 0.000 description 1
- 239000008408 compound extracted from plant Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000001120 cytoprotective effect Effects 0.000 description 1
- 230000035617 depilation Effects 0.000 description 1
- 229960001673 diethyltoluamide Drugs 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- 229960002311 dithranol Drugs 0.000 description 1
- 229960000878 docusate sodium Drugs 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- 210000001061 forehead Anatomy 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000031774 hair cycle Effects 0.000 description 1
- 229940124563 hair growth stimulant Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
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- 239000000178 monomer Substances 0.000 description 1
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- 229940101267 panthenol Drugs 0.000 description 1
- 235000020957 pantothenol Nutrition 0.000 description 1
- 239000011619 pantothenol Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000003658 preventing hair loss Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- MOJZMWJRUKIQGL-XILRTYJMSA-N procyanidin C1 Chemical compound C1([C@@H]2[C@H](O)[C@H](C3=C(O)C=C(O)C=C3O2)C2=C3O[C@@H]([C@H](O)[C@H](C3=C(O)C=C2O)C=2C(O)=CC(O)=C3C[C@H]([C@H](OC3=2)C=2C=C(O)C(O)=CC=2)O)C=2C=C(O)C(O)=CC=2)=CC=C(O)C(O)=C1 MOJZMWJRUKIQGL-XILRTYJMSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000001297 telogen effluvium Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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- 230000007704 transition Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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- 235000009492 vitamin B5 Nutrition 0.000 description 1
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Classifications
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4953—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom containing pyrimidine ring derivatives, e.g. minoxidil
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- A—HUMAN NECESSITIES
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- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/74—Biological properties of particular ingredients
- A61K2800/78—Enzyme modulators, e.g. Enzyme agonists
- A61K2800/782—Enzyme inhibitors; Enzyme antagonists
Landscapes
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- Dermatology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本発明は、カリウムチャネル開口薬およびプロテインキナーゼＣ阻害薬の新規な組成物、それらの組成物の製法、ならびにそれらの組成物を使用して毛髪成長を誘発および／または刺激し、および／または脱毛を低減する方法に関する。本発明は１以上のカリウムチャネル開口薬を含む第１の組成物および１以上のプロテインキナーゼＣ阻害薬を含む第２の組成物にも関し、該第１および第２の組成物は毛髪成長を誘発および／または刺激し、および／または抜毛を低減するために組み合せて用いられる。The present invention provides novel compositions of potassium channel openers and protein kinase C inhibitors, methods of making those compositions, and the use of these compositions to induce and / or stimulate hair growth and / or hair loss And a method for reducing the The present invention also relates to a first composition comprising one or more potassium channel openers and a second composition comprising one or more protein kinase C inhibitors, wherein the first and second compositions enhance hair growth. Used in combination to induce and / or stimulate and / or reduce hair loss.
Description
【技術分野】
【０００１】
本発明は、カリウムチャネル開口薬およびプロテインキナーゼＣ阻害薬の新規な組成物、それらの組成物の製法、ならびにそれらの組成物を使用して毛髪成長を誘発および／または刺激し、および／または脱毛を低減する方法に関する。本発明は１以上のカリウムチャネル開口薬を含む第１の組成物および１以上のプロテインキナーゼＣ阻害薬を含む第２の組成物にも関し、該第１および第２の組成物は毛髪成長を誘発および／または刺激し、および／または抜毛を低減するために組み合せて用いられる。
【背景技術】
【０００２】
いくつかのカリウムチャネル開口薬（ＰＣＯ）は、カリウムチャネルアゴニストとも呼ばれ、男性ホルモン性脱毛症の動物およびヒトの双方において毛髪成長を促進することが示されている。そのようなＰＣＯの例は、ピナシジル、Ｎ−シアノ−Ｎ−ｔｅｒｔペンチル−Ｎ’−３−ピリジニルグアジニンであるピナシジルアナログＰ−１０７５、ジアゾオキシド、クロマキリンおよびミノキシジルである。［ブール・エイイー（ＢｕｈｌＡＥ），コンラッド・エスジェイ（ＣｏｎｒａｄＳＪ），ワルドン・ディージェイ（ＷａｌｄｏｎＤＪ）およびブルンデン・エムエヌ（ＢｒｕｎｄｅｎＭＮ）．「Ｐｏｔａｓｓｉｕｍｃｈａｎｎｅｌｃｏｎｄｕｃｔａｎｃｅａｓａｃｏｎｔｒｏｌｍｅｃｈａｎｉｓｍｉｎｈａｉｒｆｏｌｌｉｃｌｅｓ、ジャーナル・オブ・インベスティゲイティブ・ダーマトロジー（ＪＩｎｖｅｓｔＤｅｒｍａｔｏｌ）」、１９９３年、第１０１巻（補遺１）：ｐｐ．１４８Ｓ−１５２Ｓ］；および［ハーモン・シイエス（ＨａｒｍｏｎＣＳ），ルッツ・ディー（ＬｕｔｚＤ），デュコート・ジェイ（ＤｕｃｏｔｅＪ）．「ＰｏｔａｓｓｉｕｍｃｈａｎｎｅｌｏｐｅｎｅｒｓｓｔｉｍｕｌａｔｅｓＤＮＡｓｙｎｔｈｅｓｉｓｉｎｍｏｕｓｅｅｐｉｄｅｒｍａｌｋｅｒａｔｉｎｏｃｙｔｅａｎｄｗｈｏｌｅｈａｉｒｆｏｌｌｉｃｌｅｃｕｌｔｕｒｅｓ、スキン・ファーマコロジー（ＳｋｉｎＰｈａｒｍａｃｏｌ）」、１９９３年、第６巻、ｐ．１７０−１７８］を参照せよ。これらのＰＣＯは、それらが毛細血管の平滑筋細胞を弛緩させる血管効果も有する。この特性は毛包への血液供給を増大することによって毛髪成長を刺激するという可能性のある機序として暗示されてきたが、毛髪成長刺激剤ミノキシジルについて他の機序も示唆されている。
【０００３】
このような機序は、リシルヒドロキシラーゼの阻害［ムラード・エス（ＭｕｒａｄＳ），ピネル・エスアール（ＰｉｎｅｌｌＳＲ）．「Ｓｕｐｐｒｅｓｓｉｏｎｏｆｆｉｂｒｏｂｌａｓｔｐｒｏｌｉｆｅｒａｔｉｏｎａｎｄｌｙｓｙｌｈｙｄｒｏｘｙｌａｓｅａｃｔｉｖｉｔｙｂｙｍｉｎｏｘｉｄｉｌ、ジャーナル・オブ・バイオロジカル・ケミストリー（ＪＢｉｏｌＣｈｅｍ）」、１９８７年、第２６２巻、ｐ．１１９７３−７８］、ケラチノサイトの刺激［ハーモン・シイエス（ＨａｒｍｏｎＣＳ），ルッツ・ディー（ＬｕｔｚＤ），デュコート・ジェイ（ＤｕｃｏｔｅＪ）．「ＰｏｔａｓｓｉｕｍｃｈａｎｎｅｌｏｐｅｎｅｒｓｓｔｉｍｕｌａｔｅＤＮＡｓｙｎｔｈｅｓｉｓｉｎｍｏｕｓｅｅｐｉｄｅｒｍａｌｋｅｒａｔｉｎｏｃｙｔｅａｎｄｗｈｏｌｅｈａｉｒｆｏｌｌｉｃｌｅｃｕｌｔｕｒｅｓ、スキン・ファーマコロジー（ＳｋｉｎＰｈａｒｍａｃｏｌ）」、１９９３年、第６巻、ｐ．１７０−１７８］；および［ボイェラ・エヌ（ＢｏｙｅｒａＮ），ゲイリー・アイ（ＧａｌｅｙＩ），バーナード・ビイエイ（ＢｅｒｎａｒｄＢＡ）．「Ｂｉｐｈａｓｉｃｅｆｆｅｃｔｓｏｆｍｉｎｏｘｉｄｉｌｏｎｔｈｅｐｒｏｌｉｆｅｒａｔｉｏｎａｎｄｄｉｆｆｅｒｅｎｔｉａｔｉｏｎｏｆｎｏｒｍａｌｈｕｍａｎｋｅｒａｔｉｎｏｃｙｔｅｓ、スキン・ファーマコロジー（ＳｋｉｎＰｈａｒｍａｃｏｌ）」、１９９７年、第１０巻、ｐ．２０６−２２０］、種々の成長因子の刺激［ラハガー・エス（ＬａｃｈｇａｒＳ），シャルベロン・エム（ＣｈａｒｖｅｒｏｎＭ），ガル・ワイ（ＧａｌｌＹ），ボナフェ・ジェイエル（ＢｏｎａｆｅＪＬ）．「Ｍｉｎｏｘｉｄｉｌｕｐｒｅｇｕｌａｔｅｓｔｈｅｅｘｐｒｅｓｓｉｏｎｏｆｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒｉｎｈｕｍａｎｈａｉｒｄｅｒｍａｌｐａｐｉｌｌａｃｅｌｌｓ、ブリティッシュ・ジャーナル・オブ・ダーマトロジー（ＢｒＪＤｅｒｍａｔｏｌ）」、１９９８年、第１３８巻、ｐ．４０７−４１１］；および［ヤマザキ・エム（ＹａｍａｚａｋｉＭ），ツボイ・アール（ＴｓｕｂｏｉＲ），リー・ワイアール（ＬｅｅＹＲ），イシド・ケイ（ＩｓｈｉｄｏＫ），ミツイ・エス（ＭｉｔｓｕｉＳ），オガワ・エイチ（ＯｇａｗａＨ）．「Ｈａｉｒｃｙｃｌｅ―ｄｅｐｅｎｄｅｎｔｅｘｐｒｅｓｓｉｏｎｏｆｈｅｐａｔｏｃｙｔｅｇｒｏｗｔｈｆａｃｔｏｒ（ＨＧＦ）ａｃｔｉｖａｔｏｒ，ｏｔｈｅｒｐｒｏｔｅｉｎａｓｅｓ，ａｎｄｐｒｏｔｅｉｎａｓｅｉｎｈｉｂｉｔｏｒｓｃｏｒｒｅｌａｔｅｓｗｉｔｈｔｈｅｅｘｐｒｅｓｓｉｏｎｏｆＨＧＦｉｎｒａｔｈａｉｒｆｏｌｌｉｃｌｅｓ．ジャーナル・オブ・インベスティゲイティブ・ダーマトロジー・シンポジウム・プロシーディングス（ＪＩｎｖｅｓｔＤｅｒｍａｔｏｌＳｙｍｐＰｒｏｃ）」、１９９９年、第４巻、ｐ．３１２−３１５）］、低下したコラーゲン合成［ラハガー・エス（ＬａｃｈｇａｒＳ），シャルベロン・エム（ＣｈａｒｖｅｒｏｎＭ），ブハディウィ、エボ・ワイ（Ｂｏｕｈａｄｄｉｏｕｉ，ＥｖｅｕｘＹ），ガル・ワイ（ＧａｌｌＹ），ボナフェ（Ｂｏｎａｆｅ）．「ＩｎｈｉｂｉｔｏｒｙｅｆｆｅｃｔｓｏｆｂＦＧＦ，ＶＥＧＦａｎｄｍｉｎｏｘｉｄｉｌｏｎｃｏｌｌａｇｅｎｓｙｎｔｈｅｓｉｓｂｙｃｕｌｔｕｒｅｄｈａｉｒｄｅｒｍａｌｐａｐｉｌｌａｃｅｌｌｓ．アーカイブ・オブ・ダーマトロジー・リサーチ（ＡｒｃｈＤｅｒｍａｔｏｌＲｅｓ）」１９９６年；第２８８巻：ｐ．４６９−４７３］、および細胞保護プロスタグランジンＰＧＨＳ−１［ミシェレット・ジェイエフ（ＭｉｃｈｅｌｅｔＪＦ），コモ・エス（ＣｏｍｍｏＳ），ビローニ・エヌ（ＢｉｌｌｏｎｉＮ），マーエ・ワイエフ（ＭａｈｅＹＦ）．「ＢｅｒｎａｒｄＢＡ．Ａｃｔｉｖａｔｉｏｎｏｆｃｙｔｏｐｒｏｔｅｃｔｉｖｅｐｒｏｓｔａｇｌａｎｄｉｎｓｙｎｔｈａｓｅ―１ｂｙｍｉｎｏｘｉｄｉｌａｓａｐｏｓｓｉｂｌｅｅｘｐｌａｎａｔｉｏｎｆｏｒｉｔｓｈａｉｒｇｒｏｗｔｈ―ｓｔｉｍｕｌａｔｉｎｇｅｆｆｅｃｔ．ジャーナル・オブ・インベスティゲイティブ・ダーマトロジー（ＪＩｎｖｅｓｔＤｅｒｍａｔｏｌ）」、１９９７年、第１０８巻、ｐ．２０５−２０９］による抗線維症効果である。
【０００４】
２，４−ジアミノ−６−ピペリジニルピリミジン−３−オキシドであるミノキシジルは、ロニテンＲ（ＬｏｎｉｔｅｎＲ）およびロゲインＲ（ＲｏｇａｉｎｅＲ）の有効成分であり、それらは、それぞれ高血圧症治療薬および男性ホルモン性脱毛症（男性型および女性型禿頭症）の治療薬および予防薬として、ファルマシアから販売されている。ミノキシジルの調製および抗高血圧症使用は米国特許第３，４６１，４６１号に記載されている。毛髪を成長させ、男性型および女性型禿頭症の治療用の当該化合物の使用のための方法および局所製剤は、米国特許第４，１３９，６１９および４，５９６，８１２号に記載され特許請求されている。
【０００５】
近年、いくつかの選択的プロテインキナーゼＣ阻害薬が毛髪成長を促進することが示された。［タカハシ・ティー（ＴａｋａｈａｓｈｉＴ），カミムラ・エイ（ＫａｍｉｎｕｒａＡ），ヨコオ・ワイ（ＹｏｋｏｏＹ）．「ＳｅｖｅｒａｌｓｅｌｅｃｔｉｖｅｐｒｏｔｅｉｎｋｉｎａｓｅＣｉｎｈｉｂｉｔｏｒｓｉｎｃｌｕｄｉｎｇｐｒｏｃｙａｎｉｄｉｎｅｓｐｒｏｍｏｔｅｈａｉｒｇｒｏｗｔｈ、スキン・ファーマコロジー・アンド・アプライド・スキン・フィジオロジー（ＳｋｉｎＰｈａｒｍａｃｏｌＡｐｐｌＳｋｉｎＰｈｙｓｉｏｌ）」、２０００年、第１３巻、ｐ．１３３−１４２］および［ハーモン、チャールズ・エス（Ｈａｒｍｏｎ，ＣｈａｒｌｅｓＳ．），ネバン、トーマス・ディー（Ｎｅｖｉｎｓ，ＴｈｏｍａｓＤ）．「Ｂｉｓｉｎｄｏｌｙｌｍａｌｅｍｉｄｅｐｒｏｔｅｉｎｋｉｎａｓｅ―ＣｉｎｈｉｂｉｔｏｒｓｄｅｌａｙｔｈｅｄｅｃｌｉｎｅｉｎＤＮＡｓｙｎｔｈｅｓｉｓｉｎｍｏｕｓｅｈａｉｒｆｏｌｌｉｃｌｅｏｒｇａｎｃｕｌｔｕｒｅｓ、スキン・ファーマコロジー（ＳｋｉｎＰｈａｒｍａｃｏｌ．）」、１９９７年、第１０（２）巻、ｐ．７１−７８］を参照せよ。とりわけ、カルホスチンＣ、プロシアニジンＣ１、ヘキサデシルホスホコリン、塩化パルミトイル−ＤＬ−カルニチン、硫酸ポリミキシンＢ、およびプロシアニジンＢ２が見出された。それらの分子は全て、顕著なイン・ビボ成長期導入を示し、カリウムチャネル作動とは関連しなかった。植物から抽出したフェノール化合物を毛髪成長の可能性につき調査し、プロアントシアニジンが成長期を誘発することが分った。プロアントシアニジンは、カテキン、エピカテキン、ガロカテキン、エピガロカテキン、アフィゼレチンおよびエピアフゼレチンのごときフラバン−３−オール単位のポリマーまたはオリゴマーであり、それらの分子は時に没食子酸を含んでいる。［ポーター・エルジェイ（ＰｏｒｔｅｒＬＪ）．「Ｆｌａｖａｎｓａｎｄｐｒｏａｎｔｈｏｃｙａｎｉｄｉｎｓ．ＩｎＴｈｅＦｌａｖｏｎｏｉｄｓ：アドバンス・イン・リサーチ・サイエンス・シンス１９８６（ＡｄｖａｎｃｅｓｉｎＲｅｓｅａｒｃｈＳｉｎｃｅ１９８６），ハルボルン・ジェイビイ（ＨａｒｂｏｒｎｅＪＢ）編，ｐ．２３−５５」チャップマン（Ｃｈａｐｍａｎ）およびホール（Ｈａｌｌ），ロンドン１９９４年］、および［タカハシ・ティー（ＴａｋａｈａｓｈｉＴ），カミムラ・エイ（ＫａｍｉｍｕｒａＡ），シライ・エイ（ＳｈｉｒａｉＡ），ヨコオ・ワイ（ＹｏｋｏｏＹ）．「ＳｅｖｅｒａｌｓｅｌｅｃｔｉｖｅｐｒｏｔｅｉｎｋｉｎａｓｅＣｉｎｈｉｂｉｔｏｒｓｉｎｃｌｕｄｉｎｇｐｒｏｃｙａｎｉｄｉｎｓｐｒｏｍｏｔｅｈａｉｒｇｒｏｗｔｈ、スキン・ファーマコロジー・アンド・アプライド・スキン・フィジオロジー（ＳｋｉｎＰｈａｒｍａｃｏｌＡｐｐｌＳｋｉｎＰｈｙｓｉｏｌ）」、２０００年、第１３巻、ｐ．１３３−１４２］を参照せよ。
【０００６】
プロシアニジンＢ１、Ｂ２およびＢ３のごときエピカテキン二量体ならびにこのカテキンの三量体Ｃ１は、Ｃ３Ｈマウスにおいて毛髪ケラチノサイトの刺激、および毛髪成長刺激を示したが、単量体は示さなかった。［タカハシ・ティー（ＴａｋａｈａｓｈｉＴ），カミヤ・ティー（ＫａｍｉｙａＴ），ハセガワ・エイ（ＨａｓｅｇａｗａＡ），ヨコオ・ワイ（ＹｏｋｏｏＹ）．「Ｐｒｏｃｙａｎｉｄｉｎｏｌｉｇｏｍｅｒｓｓｅｌｅｃｔｉｖｅｌｙａｎｄｉｎｔｅｎｓｉｖｅｌｙｐｒｏｍｏｔｅｐｒｏｌｉｆｅｒａｔｉｏｎｏｆｍｏｕｓｅｈａｉｒｅｐｉｔｈｅｌｉａｌｃｅｌｌｓｉｎｖｉｔｒｏａｎｄａｃｔｉｖａｔｅｈａｉｒｆｏｌｌｉｃｌｅｇｒｏｗｔｈｉｎｖｉｖｏ．、ジャーナル・オブ・インベスティゲーティブ・ダーマトロジー（ＪＩｎｖｅｓｔＤｅｒｍａｔｏｌ）」、１９９９年；第１１２巻：ｐ．３１０−３１６］を参照せよ。
【０００７】
毛髪成長促進剤としてのプロアントシアニジンの使用は国際公開第９６／００５６１号に開示されている。
カリウムチャネル開口薬およびいくつかの他の毛髪促進剤、例えば、ミノキシジルと５−アルファリダクターゼ阻害薬フィナステリド（米国特許第５，５７８，５９９号）、およびミノキシジルとアンドロゲン受容体ＲＵ５８８４１（米国特許第５，４１１，９８１号）を含むコンビネーション製品が開示されている。
いずれにせよ、１以上のカリウムチャネル開口薬と１以上のプロテインキナーゼＣ阻害薬とを組み合せることはどこにも開示されていない。
別々の作用機序で特徴付けられる１以上のカリウムチャネル開口薬と１以上のプロテインキナーゼＣ阻害薬とを製剤中で組み合せることによって、製剤中で２つの化合物タイプのうちの１のみを有することと比較して、毛髪成長刺激が増大する。これら２つの化合物タイプを混合し、脱毛治療用局所製剤中で組み合せ得る。本発明はこれらおよび他の重要な目的に向けられる。この書類に引用され、記載された各特許、特許出願および特許公開の開示は、出典明示して、その全体が本明細書に含まれるものとみなされる。
【０００８】
【発明の開示】
【発明が解決しようとする課題】
【０００９】
発明の概要
本発明は、１以上のカリウムチャネル開口薬および１以上のプロテインキナーゼＣ阻害薬の第１の新規な組成物に向けられる。詳しくは、一つの具体例において、ミノキシジルおよびプロシアニジンＢ２を含む組成物を提供する。
本発明の他の具体例は他のカリウムチャネル開口薬および他のプロテインキナーゼＣ阻害薬のコンビネーションを含む第１の組成物に関する。
【００１０】
本発明のさらなる具体例は１以上のカリウムチャネル開口薬を含む第２の組成物および１以上のプロテインキナーゼＣ阻害薬を含む第３の組成物に関し、該第１および第２の組成物は毛髪成長を誘発および／または刺激し、および／または抜毛を低減するために組み合せて用いられる。
【００１１】
患者のある領域の抜毛を治療および／または予防する方法であって、本明細書に記載する組成物を該領域に局所投与することを特徴とする方法も本発明によって提供される。
本発明のこれらのまたは他の局面は本開示および特許請求の範囲からより明確になるであろう。
【課題を解決するための手段】
【００１２】
発明の詳細な説明
本発明は、ひとつには、１以上のカリウムチャネル開口薬および１以上のプロテインキナーゼＣ阻害薬の新規な第１の組成物、該組成物の製造方法、および該組成物を用いて毛髪成長を誘発および／または刺激し、および／または抜毛を低減する方法に向けられる。本発明は１以上のカリウムチャネル開口薬を含む第２の組成物および１以上のプロテインキナーゼＣ阻害薬を含む第３の組成物にも関し、該第２および第３の組成物は毛髪成長を誘発および／または刺激し、および／または抜毛を低減するために組み合せて用いられる。
【００１３】
上記のように、ミノキシジルの調製および抗高血圧症使用は米国特許第３，４６１，４６１号に記載され、毛髪を成長させ、男性ホルモン性脱毛症を治療するための該化合物の使用に関する局所製剤および方法は米国特許第４，１３９，６１９および４，５９６，８１２号に記載され特許請求されている。これら３つの特許の開示は、出典明示してその全体が本明細書に含まれるものとみなされる。
上記のように、脱毛症を治療するためのプロテインキナーゼＣ阻害薬の使用は解説された［タカハシら、１９９９年および２０００年］に開示されている。
【００１４】
本発明の組成物は様々な形態をとることができ、例えば、直接的局所適用または噴霧による局所適用のためのゲル化または非ゲル化形態の半固型を含む広範囲の粘度を有する水剤、乳剤、懸濁剤またはそれらの混合物、局所適用のための種々の貼付剤の形態を包含する。
本発明の組成物中の１以上のカリウムチャネル開口薬および１以上のプロテインキナーゼＣ阻害薬の各々の濃度は、各化合物および用いる医薬製剤の特異性に依存して広い範囲で変化することができる。有用な濃度は、カリウムチャネル開口薬がミノキシジルのとき約０．５％（ｗ／ｗ）から約１０％（ｗ／ｗ）まで、プロテインキナーゼＣ阻害薬がプロシアニジンＢ２のとき約０．１％（ｗ／ｗ）から約１０％（ｗ／ｗ）までである。
【００１５】
広範囲にわたる溶媒を本発明の組成物に用いることができる。好ましくは、溶媒は極性溶媒である。これらのなかでも、極性プロトン性溶媒が好ましい。好ましくは、溶媒は水またはヒドロキシ化合物、すなわち、少なくとも１のヒドロキシ（ＯＨ）基を含有する化合物である。ヒドロキシ化合物のなかでもアルコール（すなわち、１のヒドロキシ基を含有する化合物）またはポリオール（すなわち、２以上のヒドロキシ基を含有する化合物）またはアルコールおよび／もしくはポリオールの混合物が好ましい。代表的なアルコールは、例えば、エタノール、プロパノールおよびブタノールを含む。本明細書中の「エタノール」への言及は、無水アルコールならびに「アルコールＵＳＰ」および９５％エタノールの全変性形態を含む。本明細書で用いるとき、「プロパノール」なる用語は全ての異性体をいい、ｎ−プロパノールおよびイソプロパノールを含み、ならびに「ブタノール」なる用語は全ての異性体をいい、例えば、ｎ−ブタノール、イソ−ブタノールおよびｓｅｃ−ブタノールを包含する。これらのアルコールのなかでも、エタノールおよびプロパノールが好ましく、エタノールがより好ましい。代表的なポリオールは、例えば、プロピレングリコール、ジプロピレングリコール、ヘキシレングリコール、１，３−ブチレングリコール、ポリエチレングリコール２００（ＰＥＧ−２００）およびポリエチレングリコール４００（ＰＥＧ−４００）のごとき液状ポリエチレングリコール、ならびにグリセロール（最後のものは、ときに、グリセリンともいう）を包含する。これらのポリオールのなかでも、プロピレングリコールが好ましい。
特に好ましい具体例において、用いる溶媒は、水、アルコールおよびポリオールの混合物である。
【００１６】
本発明の組成物は、抜毛の予防または治療のために患者のある領域に局所投与することができる。したがって、当業者にとって明らかなように、一旦本発明の開示による教示に手にすれば、当該組成物は所望により、例えば、ｐＨ調節剤、抗酸化剤を含む化学安定剤、ビタミンＢ５／パンテノール、パントテン酸カルシウムまたは他のパンテノール誘導体のごときヘアーコンディショナー、着色剤、芳香剤、芳香性改質剤、ビタミンＥのごとき他のビタミン、アゾン（ａｚｏｎ）およびＤＥＥＴのごとき浸透性改質剤、クレモホアＲ（（ＣｒｅｍｏｐｈｏｒＲ）；ＢＡＳＦ）のごとき界面活性剤、脂肪酸または脂肪酸エステルのごとき皮膚すなわち頭皮へのコスメチック剤、ヘンナのごときハーブエキス、他の粘度上昇剤すなわち増粘剤、オイル、乳化剤、湿潤剤、サンスクリーンおよび抗刺激剤のごときさらなる医薬上許容される添加物および成分を含むことができる。広汎な方法を用いて、本発明の組成物を調製することができる。概して、当該組成物は、本明細書に記載されるごとく、医薬上優れた組成物を好ましく提供するのに十分な温度および時間で、該組成物の成分を一緒に合わせることによって調製することができる。「一緒に合わせる」なる用語は、本明細書で用いるとき、該組成物の全成分を組み合せてほぼ同時に一緒に混合することができることを意味する。特定の好ましい具体例において、「一緒に合わせる」なる用語は、様々な成分を１以上の優先順位をつけて組み合せて所望の生成物を得ることができることを意味する。
【００１７】
本発明の組成物は、患者の抜毛すなわち脱毛した領域を治療および／または予防するために有利に用いることができる。一般的には、当該方法は、本明細書に記載したごとく、当該領域に組成物を局所投与することを特徴とする。毛髪の寿命は、ピラーサイクル（ｐｉｌａｒｃｙｃｌｅ）と呼ばれる周期に支配され、その間、毛髪は成長し（成長期）、退行し（退行期）、次いで抜け落ち（休止期）、その後、同じ毛包から現われる新たな毛髪と置き換わり、周期が繰り返される。この定常的再生プロセスは加齢にしたがい自然に変化する。毛周期は短くなり、毛が細く短くなる。このプロセスが加速されるか妨害されると抜毛になる。すなわち、成長期が短くなり、休止期への毛髪の移行が早くなって、毛髪が大量に抜け落ちる。成長周期がどんどん短くなれば、細く短い毛が増加し、それはゆっくりと産毛に変るであろう。この現象は進行性薄毛症を引き起こし、最終的に禿頭症に行き付くであろう。
【００１８】
皮膚科医は多くの異なるタイプの抜毛を認識しており、最も一般的なものは断然（男性または女性型禿頭症としても知られる）男性ホルモン性脱毛症であり、人類は老化とともに頭髪を失っていく。このタイプの抜毛は男性により一般的であるが、女性にも起る。この男性型脱毛症は、上記のごとく進行性薄毛症で特徴付けられるか、または前頭部抜毛、中央前部脱毛、両側頭部後退、および／または頭頂部脱毛のごときびらん性薄毛のほとんどない抜毛によって特徴付けられるであろう。女性では、男性ホルモン性脱毛症は一般に頭頂部のびらん性薄毛で特徴付けられるが、額生え際の生え残りはない。休止期脱毛症のごとき、円形脱毛症、成長期抜毛、およびびまん性脱毛症は、他の抜毛の代表であり、それらは男性ホルモン性脱毛症とは区別される。これらの他の抜毛の形態も本発明の組成物で治療することができる。
【００１９】
本発明はさらに以下の実施例を記載する。これらの実施例は単に例示の目的であって、付随する特許請求の範囲を制限するものと理解されるべきではない。
反する明示の記述がない場合、本明細書で用いるとき、「含む（ｃｏｍｐｒｉｓｉｎｇ）」、「包含する（ｉｎｃｌｕｄｉｎｇ）」、「有する（ｈａｖｉｎｇ）」、「持つ（ｗｉｔｈ）」および同様の用語のような表現は挙げられた要素に排他的に制限するものと理解されるべきではなく、さらなる要素の存在も同様に許容するものと理解されるべきであり、統合、細分または集合形態でいずれの要素もカバーし、ならびに言明された整数もしくはステップまたは整数もしくはステップの群を包含することを暗示するがいずれの他の整数もしくはステップまたは整数もしくはステップの群を排除することは暗示しないものと理解されるべきである。
【００２０】
本発明による組成物は、カリウムチャネル開口薬のみまたはプロテインキナーゼＣ阻害薬のみのいずれかを含む組成物よりも高い毛髪成長効果を有するので、同一の効果を得るために、カリウムチャネル開口薬のみまたはプロテインキナーゼＣ阻害薬のみのいずれかを含む組成物を投与していたときよりもより低い頻度で本発明の組成物を投与すればよい。それゆえ、本発明の組成物の有用な投与は、１日一回またはそれよりも低い頻度で投与することを含む。
【００２１】
最小限相加効果（ａｔｌｅａｓｔａｄｄｉｔｉｖｅｅｆｆｅｃｔ）
好ましくは、本発明による組成物の使用は、排他的ではなく、カリウムチャネル開口薬およびプロテインキナーゼＣ阻害薬のそれぞれの個別使用に対して最小限相加的な効果を付与する。そのような相加効果は全く自明ではない。
一緒に投与される薬物の効果の低下を招く薬物相互作用についての多くの実例がある。そのような相互作用はそのような調剤中に起きる。しかし、より普通には、該相互作用は吸収の間、特定の受容体への結合の間および／または代謝の間に起る。調剤誘発相互作用の実例は、フッ素塩と歯磨き粉のカルシウムとの間の反応による初期のフッ素歯磨き粉由来の小さいかまたは無視できるフッ素効果である。吸収の間の阻害の実例は、例えばミルク中の様々な抗菌剤とカルシウムとの間のコンプレックス形成である。相互作用のための受容体レベルに対する効果の低下は典型的には伝達物質であるアセチルコリンとアトロピンとの間で見られる。
【００２２】
局所投与されたミノキシジルと他の局所薬物との間のいくつかの相互作用が同定されている。フィドラー（Ｆｉｅｄｌｅｒ）らによる一つの研究（１９９０年）において、乾癬の治療に用いられるが円形脱毛症の治療にも用いられるアントラリンと一緒にミノキシジルを用いたとき、何人かの患者についてミノキシジルの強く増大した吸収が観察された。フェリー（Ｆｅｒｒｙ）およびフィドラー（Ｆｉｅｄｌｅｒ）による別の研究（１９９０年）において、ミノキシジルの吸収が減少することが、コーチゾン軟膏ベタメタゾンを併用して使用したときに観察された。フェリー（Ｆｅｒｒｙ）らによるさらに別の研究において、２％ミノキシジル溶液をビタミンＡを含む皮膚製剤と局所的に共投与したとき、ミノキシジルの吸収が増大したことが示された。
【００２３】
ミノキシジルが毛包に作用している時間がミノキシジルの毛髪刺激効果を左右する。ミノキシジルが皮膚からあまりにも早く消滅すると、その効果は低下する。例えばｐＨ変化により、吸収が低下すると、毛包へのミノキシジルへの効果も低下する。
ミノキシジルはカリウムチャネル開口薬である。特定の他のカリウムチャネル開口薬も毛髪成長刺激効果を有する。かくして、ミノキシジルを同じ態様の作用を有する物質と組み合せたら、ミノキシジルのみの使用で、この効果の上限に達してしまっているので、さらなる効果は期待できないであろう。しかしながら、ミノキシジルを他の態様の作用を有する物質と組み合せれば、最小限相加効果を達成するのは可能であろう。この他の物質は製剤中でミノキシジルを阻害もせず、吸収、受容体結合および代謝に関してミノキシジルを妨害もしないものであるべきである。換言すれば、カリウムチャネル開口薬とプロテインキナーゼＣ阻害薬との複合使用による最小限累積効果を好ましく達成するために必要な条件を満たすことを確保するために非自明かつ進歩性のある方法が行われた。
【実施例１】
【００２４】
溶液１の調製
５００ｍｇのミノキシジル、２００ｍｇのプロシアニジンＢ２、５．０ｇのプロピレングリコール、３．０ｍｌのエタノールに精製水を加えて１０ｍｌにして、室温にて混合した。この混合物を透明赤茶色溶液が得られるまで攪拌した。
【実施例２】
【００２５】
溶液２の調製
０．３％（ｗ／ｗ）のプロシアニジンＢ２、２．０％（ｗ／ｗ）のミノキシジル、７０％（ｗ／ｗ）のエタノール、１０％（ｗ／ｗ）の１，３−ブチレングリコールおよび１８％（ｗ／ｗ）の精製水を混合することによって１００ｍｌのバッチを得、それを室温にて混合、攪拌して透明赤茶色溶液を得た。
【実施例３】
【００２６】
代替溶液の調製
溶液１および溶液２の代替物として、実質的に実施例１および２に準じて溶液が製造され、ここに、代わりの溶媒は上記の適当な溶媒のリストから選択される。
【実施例４】
【００２７】
代替的具体例の調製
実施例１、２または３に準じた溶液の代替物として、１以上のカリウムチャネル開口薬を含む第２の組成物および１以上のプロテインキナーゼＣ阻害薬を含む第３の組成物を製造することができ、該第１および第２の組成物は組み合せて、毛髪成長を誘発および／または刺激し、および／または抜毛を低減するために用いられる。該第２および第３の組成物は実質的に実施例１、２または３に準じて製造される。
該第２および第３の組成物は、多くの異なった投薬プログラムで、例えば、併用または互いに無関係に投与することができる。例えば、患者は、朝に各組成物から１の用量を、晩に各組成物から１の用量を投与することができる。あるいは、患者は、朝に第２の組成物から１の用量を、晩に第３の組成物から１の用量を投与することができる。また、第２および第３の組成物の各々につき、一日あたり異なる数の用量のごときく、他の投薬プログラムも企図できる。最も適した投与プログラムは実際の治療状況に依存する。
【実施例５】
【００２８】
ミノキシジルの分析
ミノキシジルの定量測定は、カラム（シンメトリーＴＭ（ＳｙｍｍｅｔｒｙＴＭ））、Ｃ１８、３．５μｍ、１００Å、１５０×４．６ｍｍおよび、ペルクロロ酢酸でｐＨ３．０に調節した３ｇ／ｌのドクサートナトリウム（ｄｏｃｕｓａｔｅｓｏｄｉｕｍ）入りの水／メタノール／氷状酸（ｇｌａｃｉａｌａｃｉｄ）（３０：７０：１）移動相を用いるＨＰＬＣ法で行った。フローは１．０ｍｌ／分のインジェクション量２０μｌであり、検出はＵＶ検出器を用いて２５４ｎｍで行った。
１．０ｍｌの試料をエタノールで１００ｍｌに希釈し、この混合物のアリコートを移動相で１：５０に希釈した。標準溶液は１０μｇ／ｍｌのミノキシジルを含有した。試料および標準溶液をインジェクションし、ミノキシジルの含有量をピーク反応に基づき算出した。
【実施例６】
【００２９】
プロシアニジンＢ２の分析
プロシアニジンＢ２の定性測定は、カラム（シンメトリーＴＭ（ＳｙｍｍｅｔｒｙＴＭ））、Ｃ１８、３．５μｍ、１００Å、１５０×４．６ｍｍおよび水／メタノール／氷状酸（ｇｌａｃｉａｌａｃｉｄ）（９３：５：２）移動相を用いるＨＰＬＣ法で行った。フローは１．０ｍｌ／分のインジェクション量１０μｌであり、検出はＵＶ検出器を用いて２８０ｎｍで行った。
０．５ｍｌの試料を移動相で２５ｍｌに希釈した。標準溶液は５０μｇ／ｍｌのプロシアニジンＢ２を含有した。試料および標準溶液をインジェクションし、プロシアニジンＢ２の含有量をピーク反応に基づき算出した。
【実施例７】
【００３０】
溶液１および溶液２の安定性を以下の表１および表２にそれぞれ開示する。
【００３１】
【表１】
【表２】
上記の結果は、安定な生成物が得られたことを示す。
【００３４】
サルでの研究
ベニガオザルを用いて、毛髪成長に対する当該物質の効果を試験した。この種族は２年齢からすでに前頭部領域に一般的な男性ホルモン性脱毛症を示し、局所ミノキシジルおよび経口フィナステリドの双方に対して毛髪成長で反応することが示されている。マウスとは対照的に、ベニガオザルは、ホルモン性および非ホルモン性の毛髪成長促進物質の双方に対して反応する、この治療分野における最も普遍的なモデル動物である。
【００３５】
１インチ角の四角の四隅に点を刺青して、試験領域をマークした。基準線として、試験領域を剃毛し、４ヶ月間、一月ごとに試験領域を剃毛して毛の重量を測定する。毛重量は毛髪成長の目安である。各群少なくとも５匹を含む３群でサルを研究した。３群で試験した製品は、（ａ）５％局所ミノキシジル、（ｂ）１％局所プロシアニジンＢ２、（ｃ）実施例１の溶液１と同様にして製造した５％ミノキシジルと１％プロシアニジンＢ２との混合物である。
【００３６】
本明細書に記載されたものに加えて、本発明の様々な変形は前記説明により当業者に明らかであろう。そのような変形も付随する特許請求の範囲に入ることを意図する。【Technical field】
[0001]
The present invention provides novel compositions of potassium channel openers and protein kinase C inhibitors, methods of making those compositions, and the use of these compositions to induce and / or stimulate hair growth and / or hair loss To a method for reducing The present invention also relates to a first composition comprising one or more potassium channel openers and a second composition comprising one or more protein kinase C inhibitors, wherein the first and second compositions enhance hair growth. Used in combination to induce and / or stimulate and / or reduce hair loss.
[Background Art]
[0002]
Some potassium channel openers (PCOs), also called potassium channel agonists, have been shown to promote hair growth in both androgenetic alopecia animals and humans. Examples of such PCOs are pinacidil, the pinacidil analog P-1075 which is N-cyano-N-tertpentyl-N'-3-pyridinyl guandinine, diazooxide, chromakilin and minoxidil. [BuhlAE, Conrad SJ, Waldon DJ and Brunden MN. “Potassiumchannel conductasacontrolmechanisminhairfollicles, Journal of Investigative Dermatology (JInvestDermatol)”, Vol. 101 (Supplement 1): 1993. 148S-152S]; and [Harmon CS, Lutz D, Ducotte J. "Potasiumchannelopeners stimulatesDNAsynthesisminimouseepidermalkeratinocyteandholeholairfolliclecules, Skin Pharmacology", Skin Pharmacol, 1993, Vol. 6, p. 170-178]. These PCOs also have a vascular effect as they relax capillary smooth muscle cells. While this property has been implicated as a possible mechanism of stimulating hair growth by increasing the blood supply to the hair follicle, other mechanisms have been suggested for the hair growth stimulant minoxidil.
[0003]
Such a mechanism is based on the inhibition of lysyl hydroxylase [Murad S, Pinell SR. "Suppressionofibroblastproliferationandlysylhydroxylaseactivitybyminoxidir, Journal of Biological Chemistry (JBiolChem)", 1987, Vol. 262, p. 11973-78], stimulation of keratinocytes [Harmon CS, Hartz CS, Lutz D, Ducotte J. "PotasiumchannelopenersstimulateDNAsynthesisminimouseepidermalkeratinocyteandholeholairfolliclecules, Skin Pharmacology (Skin Pharmacol), 1993, Vol. 6, p. 170-178]; and [Boyera N, Gary I, Bernard BA. "Biphaseeffectsminoxidilontheproliferationanddifferentiationofnormalmalhumankeratinocytes, Skin Pharmacology (Skin Pharmacol)", 1997, Vol. 10, p. 206-220], stimulation of various growth factors [Lachgar S, Charveron M, Gall Y, Bonafee JL. "Minoxidilupregulatestheexpressionofvasionofendicularialthrowthfactorinhumanhairdermalpalpillarcells, British Journal of Dermatology (BrJ Dermatol)," Vol. 1, p. 38, 1998. 407-411]; and [YamazakiM, Tsuboi R, Lee Wyre, LeeYR, IsidoK, MitsuiS, OgawaH. "Haircycle-dependentexpressionofhepatocytegrowthfactor (HGF) activator, otherproteinases, andproteinaseinhibitorscorrelateswiththeexpressionofHGFinrathairfollicles. Journal of Investing Institute Gay Restorative, Damato Biology Symposium Proceedings (JInvestDermatolSympProc)", 1999, Vol. 4, p. 312-315)], reduced collagen synthesis [Lachgar S, Charveron M, Bhadiwi, Evo WY (Bouaddioui, Eveux Y), Gall Y, Bonafee. "InhibitoryeffectsofbFGF, VEGFandminoxidironcollengensynthesisbyculturedhairdermalpalpillarcells. Archive of Dermatology Research (ArchDermatolRes)", 1996, 28:28; 469-473], and the cytoprotective prostaglandin PGHS-1 [Michelet JF, ComoS, BilloniN, MaheYF]. "BernardBA.Activationofcytoprotectiveprostaglandinsynthase-1 byminoxidilasaspossibleexpansionforitshairgrowth-sti-muting-effects-germ-in-the-move. 205-209].
[0004]
Minoxidil, which is 2,4-diamino-6-piperidinylpyrimidine-3-oxide, is lonitene R (Loniten R ) And Rogaine R (Rogaine R ), Which are sold by Pharmacia as a therapeutic agent for hypertension and a therapeutic agent and prophylactic agent for androgenetic alopecia (male and female baldness), respectively. The preparation of minoxidil and its use for antihypertensive use is described in U.S. Pat. No. 3,461,461. Methods and topical formulations for the use of such compounds for growing hair and treating male and female baldness are described and claimed in US Pat. Nos. 4,139,619 and 4,596,812. ing.
[0005]
Recently, several selective protein kinase C inhibitors have been shown to promote hair growth. [Takahashi T, Kamimura A, Yokoo Y. "SeveralselectiveproteinkinaseCinhibitors Included procyanidinespromotehairgrowth, Skin Pharmacology and Applied Skin Physiology (Skin PharmacolApplSkinPl.13, Year 2000, Volume 13). 133-142] and [Harmon, Charles S., Nevan, Thomas D.]. "Bisindollmalemideproteinkinase-CinhibitorsdelaythedeclineinDNAsynthesismouseairairfollicleorgancules, Skin Pharmacology (Skin Pharmacol.), 1997, p.2, p.2 (1997). 71-78]. Among others, calphostin C, procyanidin C1, hexadecylphosphocholine, palmitoyl chloride-DL-carnitine, polymyxin B sulfate, and procyanidin B2 were found. All of these molecules showed significant in vivo anagen induction and were not associated with potassium channel activation. Phenolic compounds extracted from plants were examined for potential hair growth and found that proanthocyanidins induced the anagen. Proanthocyanidins are polymers or oligomers of flavan-3-ol units, such as catechin, epicatechin, gallocatechin, epigallocatechin, affizeletin, and epiafuzeletin, whose molecules sometimes contain gallic acid. [Porter LJ. "Flavansandproanthocyanidins. InThe Flavonoids: Advances in Research Sciences 1986, eds., Harbin JB, Ed., Harbourne JB, Hall 23, and Hapman, 1973. Takahashi T (Takahashi T), Kamimura A (Kamimura A), Shirai A (Shira A), Yokoo W (Yokoo Y). "SeveralselectiveproteinkinaseCinhibitors Included procyanidinspromotehairgrowth, Skin Pharmacology and Applied Skin Physiology (Skin PharmacolApplSkinPhil., Vol. 13, 2000). 133-142].
[0006]
Epicatechin dimers such as procyanidins B1, B2 and B3 and the catechin trimer C1 showed stimulation of hair keratinocytes and hair growth in C3H mice, but no monomer. [Takahashi T (Takahashi T), Kamiya T (Kamiya T), Hasegawa A (Hasegawa A), Yokoo W (Yokoo Y). "Procyanidinoligomersselectivelyandintensivepromoteproliferationofmousehaileipithelicellialcellsinvitroandactivate.ht.J.p.t. 310-316].
[0007]
The use of proanthocyanidins as hair growth promoters is disclosed in WO 96/00561.
Potassium channel openers and some other hair promoting agents such as minoxidil and the 5-alpha reductase inhibitor finasteride (US Pat. No. 5,578,599), and minoxidil and the androgen receptor RU588841 (US Pat. No. 411,981).
In any case, there is no disclosure of combining one or more potassium channel openers with one or more protein kinase C inhibitors.
Having only one of the two compound types in the formulation by combining in the formulation one or more potassium channel openers and one or more protein kinase C inhibitors characterized by separate mechanisms of action Stimulus for hair growth is increased. These two compound types can be mixed and combined in a topical formulation for the treatment of hair loss. The present invention is directed to these and other important objects. The disclosure of each patent, patent application, and patent publication cited and described in this document is hereby incorporated by reference in its entirety.
[0008]
DISCLOSURE OF THE INVENTION
[Problems to be solved by the invention]
[0009]
Summary of the Invention
The present invention is directed to a first novel composition of one or more potassium channel openers and one or more protein kinase C inhibitors. In particular, in one embodiment, there is provided a composition comprising minoxidil and procyanidin B2.
Another embodiment of the present invention relates to a first composition comprising a combination of another potassium channel opener and another protein kinase C inhibitor.
[0010]
A further embodiment of the present invention relates to a second composition comprising one or more potassium channel openers and a third composition comprising one or more protein kinase C inhibitors, wherein said first and second compositions comprise hair. Used in combination to induce and / or stimulate growth and / or reduce hair loss.
[0011]
Also provided by the invention is a method of treating and / or preventing hair loss in an area of a patient, the method comprising topically administering a composition described herein to the area.
These and other aspects of the present invention will become more apparent from the present disclosure and the appended claims.
[Means for Solving the Problems]
[0012]
Detailed description of the invention
The present invention provides, in part, a novel first composition of one or more potassium channel openers and one or more protein kinase C inhibitors, a method of making the composition, and hair growth using the composition. It is directed to methods for inducing and / or stimulating and / or reducing hair loss. The present invention also relates to a second composition comprising one or more potassium channel openers and a third composition comprising one or more protein kinase C inhibitors, wherein the second and third compositions enhance hair growth. Used in combination to induce and / or stimulate and / or reduce hair loss.
[0013]
As noted above, the preparation of minoxidil and the use of anti-hypertensives are described in U.S. Patent No. 3,461,461, which describes topical formulations and uses of the compounds to grow hair and treat androgenic alopecia. The method is described and claimed in U.S. Patent Nos. 4,139,619 and 4,596,812. The disclosures of these three patents are hereby incorporated by reference in their entirety.
As noted above, the use of protein kinase C inhibitors to treat alopecia is disclosed in [Takahashi et al., 1999 and 2000].
[0014]
The compositions of the present invention can take a variety of forms, including solutions in a wide range of viscosities, including semi-solid forms in gelled or non-gelled forms for direct topical application or topical application by spraying; Emulsions, suspensions or mixtures thereof, including various patches for topical application.
The concentration of each of the one or more potassium channel openers and one or more protein kinase C inhibitors in the compositions of the present invention can vary over a wide range depending on the specificity of each compound and the pharmaceutical formulation used. . Useful concentrations are from about 0.5% (w / w) to about 10% (w / w) when the potassium channel opener is minoxidil, and about 0.1% (w / w) when the protein kinase C inhibitor is procyanidin B2. w / w) to about 10% (w / w).
[0015]
A wide range of solvents can be used in the compositions of the present invention. Preferably, the solvent is a polar solvent. Of these, polar protic solvents are preferred. Preferably, the solvent is water or a hydroxy compound, ie, a compound containing at least one hydroxy (OH) group. Among the hydroxy compounds, alcohols (ie, compounds containing one hydroxy group) or polyols (ie, compounds containing two or more hydroxy groups) or mixtures of alcohols and / or polyols are preferred. Representative alcohols include, for example, ethanol, propanol, and butanol. Reference to "ethanol" herein includes anhydrous alcohol and "alcohol USP" and all denatured forms of 95% ethanol. As used herein, the term "propanol" refers to all isomers and includes n-propanol and isopropanol, and the term "butanol" refers to all isomers, e.g., n-butanol, iso- Butanol and sec-butanol. Among these alcohols, ethanol and propanol are preferred, and ethanol is more preferred. Representative polyols are liquid polyethylene glycols, such as, for example, propylene glycol, dipropylene glycol, hexylene glycol, 1,3-butylene glycol, polyethylene glycol 200 (PEG-200) and polyethylene glycol 400 (PEG-400), and Glycerol (the last being sometimes referred to as glycerin). Among these polyols, propylene glycol is preferred.
In a particularly preferred embodiment, the solvent used is a mixture of water, alcohol and polyol.
[0016]
The compositions of the present invention can be administered locally to an area of a patient for the prevention or treatment of hair loss. Thus, as will be apparent to those skilled in the art, once taught by the present disclosure, the composition can optionally include, for example, pH regulators, chemical stabilizers including antioxidants, vitamin B5 / panthenol. Conditioners, such as calcium pantothenate or other panthenol derivatives, coloring agents, fragrances, fragrance modifiers, other vitamins such as vitamin E, permeability modifiers such as azone and DEET, cremophor R ((Cremophor R Surfactants such as BASF), cosmetics for the skin or scalp such as fatty acids or fatty acid esters, herbal extracts such as henna, other viscosity-increasing agents or thickeners, oils, emulsifiers, wetting agents, sunscreens and Additional pharmaceutically acceptable additives and ingredients such as anti-irritants can be included. A wide variety of methods can be used to prepare the compositions of the present invention. In general, the compositions can be prepared by combining the components of the compositions together, as described herein, at a temperature and for a time sufficient to preferably provide a pharmaceutically superior composition. it can. The term "combined together" as used herein means that all the components of the composition can be combined and mixed together almost simultaneously. In certain preferred embodiments, the term "combined together" means that the various components can be combined in one or more priorities to give the desired product.
[0017]
The compositions of the present invention can be advantageously used to treat and / or prevent hair loss or depilation in a patient. Generally, the method is characterized by administering the composition locally to the area, as described herein. The life of the hair is governed by a cycle called the pillar cycle, during which the hair grows (anagen), regresses (catagen), then falls off (telogen), and then emerges from the same hair follicle. The hair is replaced and the cycle is repeated. This steady regeneration process changes spontaneously with aging. The hair cycle becomes shorter and the hair becomes thinner and shorter. Hair loss occurs when this process is accelerated or hindered. That is, the growth period is shortened, the transition of the hair to the rest period is accelerated, and a large amount of hair falls off. As the growth cycle becomes shorter and shorter, thin and short hairs will increase, which will slowly turn into hair growth. This phenomenon will cause progressive hirsutism and will eventually lead to baldness.
[0018]
Dermatologists are aware of many different types of hair removal, the most common being by far androgenetic alopecia (also known as male or female baldness), where humans lose their hair with aging To go. This type of hair removal is more common in men, but also occurs in women. This androgenetic alopecia is characterized by progressive hirsutism, as described above, or has little or no erosive hair loss, such as frontal hair loss, central frontal hair loss, bilateral head recession, and / or parietal hair loss Will be characterized by hair removal. In women, androgenic alopecia is generally characterized by erosive thinning hair on the top of the head, but no residual hairline on the forehead. Alopecia areata, alopecia areata, and diffuse alopecia, such as telogen effluvium, are representative of other hair loss and are distinguished from androgenic alopecia. These other forms of hair removal can also be treated with the compositions of the present invention.
[0019]
The invention is further described by the following examples. These examples are for illustrative purposes only and should not be understood as limiting the appended claims.
Unless expressly stated to the contrary, as used herein, such terms as “comprising,” “including,” “having,” “with,” and similar terms The expression should not be understood as limiting exclusively to the listed elements, but should be understood to allow for the presence of additional elements as well, and any elements in integrated, subdivided or aggregated form It is to be understood that covering and implying the stated integer or step or group of integers or steps but not excluding any other integer or step or group of integers or steps is implied. It is.
[0020]
The compositions according to the invention have a higher hair growth effect than compositions containing either only potassium channel openers or only protein kinase C inhibitors, so that to obtain the same effect, only potassium channel openers or The composition of the present invention may be administered less frequently than when a composition containing either protein kinase C inhibitor alone is administered. Therefore, useful administrations of the compositions of the present invention include administering once or less frequently.
[0021]
Minimal additive effect
Preferably, the use of the composition according to the invention is not exclusive and confers a minimal additive effect on the respective individual use of potassium channel openers and protein kinase C inhibitors. Such an additive effect is not at all obvious.
There are many instances of drug interactions leading to diminished efficacy of drugs co-administered. Such interactions occur during such preparations. However, more commonly, the interaction occurs during absorption, during binding to a particular receptor, and / or during metabolism. An example of a dispensing-induced interaction is the small or negligible fluorine effect from the initial fluorine toothpaste due to the reaction between the fluoride salt and the toothpaste calcium. Illustrative of inhibition during absorption is the complex formation between calcium and various antimicrobial agents in milk, for example. Reduced effects on receptor levels for interaction are typically seen between the mediators acetylcholine and atropine.
[0022]
Several interactions between locally administered minoxidil and other topical drugs have been identified. In one study by Fiedler et al. (1990), when using minoxidil together with anthralin, which is used to treat psoriasis but also used to treat alopecia areata, a strong increase in minoxidil in some patients Absorption was observed. In another study by Ferry and Fiedler (1990), reduced absorption of minoxidil was observed when used in combination with cortisone ointment betamethasone. Yet another study by Ferry et al. Showed that when a 2% minoxidil solution was topically co-administered with a skin formulation containing vitamin A, the absorption of minoxidil was increased.
[0023]
The time during which minoxidil acts on the hair follicles determines the hair stimulating effect of minoxidil. If minoxidil disappears from the skin too quickly, its effect is diminished. For example, when absorption is reduced due to a change in pH, the effect of minoxidil on hair follicles is also reduced.
Minoxidil is a potassium channel opener. Certain other potassium channel openers also have a hair growth stimulating effect. Thus, if minoxidil is combined with a substance having the same mode of action, no further effect would be expected since the use of minoxidil alone has reached the upper limit of this effect. However, it would be possible to achieve a minimal additive effect if minoxidil is combined with a substance having other aspects of action. This other substance should not inhibit minoxidil in the formulation and should not interfere with minoxidil with respect to absorption, receptor binding and metabolism. In other words, non-obvious and inventive methods have been implemented to ensure that the combined use of potassium channel openers and protein kinase C inhibitors meets the conditions necessary to preferably achieve the minimal cumulative effect. I was
Embodiment 1
[0024]
Preparation of Solution 1
Purified water was added to 500 mg of minoxidil, 200 mg of procyanidin B2, 5.0 g of propylene glycol, and 3.0 ml of ethanol to make 10 ml, and mixed at room temperature. The mixture was stirred until a clear red-brown solution was obtained.
Embodiment 2
[0025]
Preparation of Solution 2
0.3% (w / w) procyanidin B2, 2.0% (w / w) minoxidil, 70% (w / w) ethanol, 10% (w / w) 1,3-butylene glycol and A 100 ml batch was obtained by mixing 18% (w / w) purified water, which was mixed and stirred at room temperature to give a clear red-brown solution.
Embodiment 3
[0026]
Preparation of alternative solutions
As an alternative to Solution 1 and Solution 2, solutions are prepared substantially according to Examples 1 and 2, wherein the alternative solvent is selected from the above list of suitable solvents.
Embodiment 4
[0027]
Preparation of alternative embodiments
Producing a second composition comprising one or more potassium channel openers and a third composition comprising one or more protein kinase C inhibitors as an alternative to the solution according to Example 1, 2 or 3 The first and second compositions can be used in combination to induce and / or stimulate hair growth and / or reduce hair loss. The second and third compositions are prepared substantially according to Example 1, 2 or 3.
The second and third compositions can be administered in many different dosing programs, for example, in combination or independently of one another. For example, a patient can administer one dose from each composition in the morning and one dose from each composition in the evening. Alternatively, the patient can administer one dose from the second composition in the morning and one dose from the third composition in the evening. Other dosing programs are also contemplated, such as different numbers of doses per day for each of the second and third compositions. The most suitable dosing program depends on the actual treatment situation.
Embodiment 5
[0028]
Analysis of minoxidil
Quantitative measurement of minoxidil is performed using a column (Symmetry TM (Symmetry TM )), C18, 3.5 μm, 100 °, 150 × 4.6 mm and water / methanol / glacialacid with 3 g / l docusatesodium adjusted to pH 3.0 with perchloroacetic acid (). 30: 70: 1) HPLC method using mobile phase. The flow was 1.0 μl / min with an injection volume of 20 μl, and detection was performed at 254 nm using a UV detector.
A 1.0 ml sample was diluted to 100 ml with ethanol and an aliquot of this mixture was diluted 1:50 with the mobile phase. The standard solution contained 10 μg / ml minoxidil. The sample and the standard solution were injected, and the content of minoxidil was calculated based on the peak reaction.
Embodiment 6
[0029]
Analysis of Procyanidin B2
The qualitative measurement of procyanidin B2 was performed using a column (Symmetry TM (Symmetry TM )), C18, 3.5 μm, 100 °, 150 × 4.6 mm and HPLC method using water / methanol / glacialacid (93: 5: 2) mobile phase. The flow was 1.0 μl / min with an injection volume of 10 μl, and detection was performed at 280 nm using a UV detector.
A 0.5 ml sample was diluted to 25 ml with the mobile phase. The standard solution contained 50 μg / ml procyanidin B2. The sample and the standard solution were injected, and the content of procyanidin B2 was calculated based on the peak reaction.
Embodiment 7
[0030]
The stability of Solution 1 and Solution 2 are disclosed in Tables 1 and 2 below, respectively.
[0031]
[Table 1]
[Table 2]
The above results indicate that a stable product was obtained.
[0034]
Research in monkeys
Macaca fascicularis was used to test the effect of the substance on hair growth. This race already shows general androgenic alopecia in the frontal region from the age of two and has been shown to respond to both topical minoxidil and oral finasteride in hair growth. In contrast to mice, macaques are the most ubiquitous model animals in this therapeutic field, responding to both hormonal and non-hormonal hair growth promoters.
[0035]
The test area was marked by tattooing dots at the four corners of a one inch square. As a reference line, the test area is shaved and the hair is weighed by shaving the test area monthly for 4 months. Hair weight is a measure of hair growth. Monkeys were studied in three groups, including at least five animals in each group. The products tested in group 3 were (a) 5% topical minoxidil, (b) 1% topical procyanidin B2, (c) 5% minoxidil and 1% procyanidin B2 prepared as in solution 1 of Example 1. It is a mixture.
[0036]
Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.
Claims (21)
インキナーゼＣ阻害薬を含む第１の組成物。A first composition comprising one or more potassium channel openers and one or more protein kinase C inhibitors.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0100374A SE0100374D0 (en) | 2001-02-07 | 2001-02-07 | Novel compositions of potassium channel openers and protein kinase c inhibitors and use thereof |
| PCT/SE2002/000105 WO2002062422A1 (en) | 2001-02-07 | 2002-01-23 | Novel compositions of potassium channel openers and protein kinase c inhibitors and use thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2004518701A true JP2004518701A (en) | 2004-06-24 |
Family
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| JP2002562427A Withdrawn JP2004518701A (en) | 2001-02-07 | 2002-01-23 | Novel compositions of potassium channel openers and protein kinase C inhibitors and uses thereof |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1357974A1 (en) |
| JP (1) | JP2004518701A (en) |
| SE (1) | SE0100374D0 (en) |
| WO (1) | WO2002062422A1 (en) |
Cited By (1)
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|---|---|---|---|---|
| JP2014221784A (en) * | 2008-09-27 | 2014-11-27 | ジャイナ ファーマシューティカルズ，インコーポレーテッド | Lipid based pharmaceutical preparations for oral and topical applications; compositions, methods, and uses thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070208087A1 (en) | 2001-11-02 | 2007-09-06 | Sanders Virginia J | Compounds, compositions and methods for the treatment of inflammatory diseases |
| SI1511710T1 (en) | 2002-05-31 | 2014-04-30 | Proteotech, Inc. | Compounds, compositions and methods for the treatment of amyloid diseases and synucleinopathies such as alzheimer s disease, type 2 diabetes, and parkinson s disease |
| CA2499549C (en) * | 2002-10-11 | 2012-01-24 | Proteotech, Inc. | Isolation, purification and synthesis of procyanidin b2 and uses thereof |
| EP1921076A1 (en) * | 2002-10-11 | 2008-05-14 | Proteotech Inc. | systhesis of procyanidin B2 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4596812A (en) * | 1976-05-24 | 1986-06-24 | The Upjohn Company | Methods and solutions for treating male pattern alopecia |
| ES2084175T3 (en) * | 1990-08-10 | 1996-05-01 | Upjohn Co | STIMULATION OF HAIR GROWTH WITH POTASSIUM CHANNEL ACTIVATORS AND 5-ALPHA-REDUCTASE INHIBITORS. |
| AU686691B2 (en) * | 1994-01-12 | 1998-02-12 | F. Hoffmann-La Roche Ag | Novel azepanes and homologs thereof |
| CA2194167C (en) * | 1994-06-30 | 2003-12-30 | Tomoya Takahashi | Hair-growing agent |
| TW339325B (en) * | 1995-07-05 | 1998-09-01 | Hoffmann La Roche | Novel azepane derivatives, process for the preparation thereof and pharmaceutical composition containing the same |
| KR100499190B1 (en) * | 1996-03-29 | 2006-04-17 | 교와 핫꼬 고교 가부시끼가이샤 | Hair restorer |
-
2001
- 2001-02-07 SE SE0100374A patent/SE0100374D0/en unknown
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2002
- 2002-01-23 WO PCT/SE2002/000105 patent/WO2002062422A1/en not_active Application Discontinuation
- 2002-01-23 EP EP02715944A patent/EP1357974A1/en not_active Withdrawn
- 2002-01-23 JP JP2002562427A patent/JP2004518701A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2014221784A (en) * | 2008-09-27 | 2014-11-27 | ジャイナ ファーマシューティカルズ，インコーポレーテッド | Lipid based pharmaceutical preparations for oral and topical applications; compositions, methods, and uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1357974A1 (en) | 2003-11-05 |
| WO2002062422A1 (en) | 2002-08-15 |
| SE0100374D0 (en) | 2001-02-07 |
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