CN1106841C - 治疗皮肤病的组合物 - Google Patents

治疗皮肤病的组合物 Download PDF

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Publication number
CN1106841C
CN1106841C CN95195041A CN95195041A CN1106841C CN 1106841 C CN1106841 C CN 1106841C CN 95195041 A CN95195041 A CN 95195041A CN 95195041 A CN95195041 A CN 95195041A CN 1106841 C CN1106841 C CN 1106841C
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acne
treatment
compositions
cholesterol
inhibitor
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CN1158567A (zh
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N·萨维昂
S·布伦纳
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RAMOT UNIV AUTHORITY FOR APPLIED RESEARCH AND INDUSTRIAL DEVELOPMENT Ltd
Ramot at Tel Aviv University Ltd
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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K8/4973—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
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • 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
    • A61P17/08—Antiseborrheics
    • 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
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q5/00—Preparations for care of the hair
    • A61Q5/006—Antidandruff preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Abstract

本发明涉及一种胆固醇合成抑制剂，可以用于治疗、缓和或预防皮肤病。

Description

治疗皮肤病的组合物
发明领域
本发明涉及应用于皮肤表面以改善皮肤状况的组合物领域。本发明提供了用于改善各种皮肤状况特别是痤疮的方法和组合物。
发明背景
痤疮是一种毛囊皮脂腺滤泡的慢性炎症，尤其是在面部和颈部，并且绝大多数发生在约14-19岁的青春期。痤疮与皮脂分泌物增加，滤泡管下动脉圆锥角化过度，微生物移生的增加和炎症有关(Strauss，J.S.，J.Dermatol.Treat.(皮肤病治疗杂志)， 1：3-6(1989))。人们已经提出了多种治疗痤疮和其它皮脂腺炎症的方法，从具体饮食，防止皮肤与已知导致痤疮(acneignic)的制剂(如低级化妆品)接触，到含有孕酮或雌激素及其它激素制剂的使用，但它们中的大多数还未被证明是有效的。此外，人们还建议在表面和全身使用防腐剂，抗菌剂和广谱抗菌化合物。
迄今为止，所有使用的抗痤疮制剂在抑制皮脂腺中微生物种群的发展，角化和粉刺的形成方面都是有效的。然而，迄今为止所用的抗痤疮制剂中仅有少数几个对降低皮脂分泌率有效(Gollnick，H.，J.Dermatol.Treat.(皮肤病治疗杂志)， 1：S23-S28(1990))，还没有任何制剂被用于控制毛囊皮脂腺单元中脂质的生物合成。
通过甲羟戊酸酯途径可以合成类异戊二烯基团如胆固醇，角鲨烯和胆固醇酯(Goldstein，J.L.，Brown，M.S.，Nature(自然)， 34B，425(1990))，其中终产物是胆固醇。调节甲羟戊酸酯制备的关键酶，即上述类异戊二烯基团的前体是3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶。这种酶抑制剂抑制了胆固醇的合成，并因此被用作治疗动脉硬化，高血脂以及相关疾病的抗高胆固醇血药物。这种抑制剂的实例有洛伐他汀(MerckIndex 5460，U.S.4,231,938)。含有HMG-CoA还原酶抑制剂的药物组合物可通过口服或非肠道给药的方式用于患有动脉硬化或高血脂病人。
发明概述
我们惊喜地发现，根据本发明通过表面使用胆固醇合成的抑制剂可以治疗痤疮。因此，本发明的用途是用胆固醇合成的抑制剂治疗多种皮肤病。
本发明提供了用于皮肤表面并含有载体和作为活性成份的有效量的胆固醇合成抑制剂的组合物。
本发明组合物可以是药物组合物或化妆品组合物。
本发明药物组合物可用于多种适应症，包括普通痤疮，牛皮癣，头皮的溢脂性皮炎和溢脂性皮炎。
本发明进一步涉及胆固醇合成抑制剂如HMG-CoA还原酶抑制剂在治疗，缓和或预防皮肤病的表面药物组合物的制备方面的应用。
本发明还提供了改善皮肤状况的方法，包括在皮肤表面使用含有载体和作为活性成份的有效量的胆固醇合成抑制剂的组合物。本方法的具体应用是治疗，缓和或预防痤疮。
术语“有效量”应该被理解为达到所需治疗或预防效果所需的活性成份的平均量。例如，在本发明药物组合物中胆固醇合成抑制剂的有效量是指在治疗方案下该药物组合物的使用范围足以达到改善皮肤状况的用量。
用于本发明的胆固醇合成抑制剂是抑制终产物如胆固醇或甲羟戊酸酯方法之各步中任何中间体产生的各种制剂，其中胆固醇由前体乙酰CoA和乙酰乙酰CoA产生的。该抑制剂可以是各步中抑制酶的抑制剂，或作为隔离中间体的的制剂，这两种制剂都减少该方法所产生的胆固醇的量。
本发明优选的胆固醇合成抑制剂是HMG-CoA还原酶抑制剂如洛伐他汀。
洛伐他汀的浓度优选约0.2-10％，最优选约2％。
该胆固醇合成抑制剂可以与多种其它制剂如抗微生物剂，例如抗菌素，以治疗或预防二次感染，去皮剂，单独或含间苯二酚的retin-A等一起用于皮肤。
本发明组合物的载体可以是任何药物或化妆品可用的载体，例如，乙醇，明胶，脂质体剂型，软膏，油膏等。
实施例：I.组合物的制备
研磨洛伐他汀胶囊(MevacorTM，Merck，U.S.A.)，通过用95％乙醇萃取将活性成份从赋形剂中分离并过滤，得到2％洛伐他汀的乙醇溶液。II.临床试验
分别在两个临床试验中测试上述制剂的效率。A.试验1
将如上所述制备药物组合物每天两次表面用于患有普通痤疮的两个人的面部，共12周。试验开始前30天患者需要中断所有其它表面和全身抗痤疮治疗，进行治疗前7天中断一切面部化妆。
在治疗开始之前和开始治疗后4，8和12周通过记录全部痤疮损伤部位，包括红肿的痤疮部位(丘疹和脓疱)和未红肿的痤疮部位(白和黑粉刺)来测定痤疮状况。
两个患者的所有上述痤疮都得到明显改善，而且，在12周的治疗期结束时损伤的数量减少了一半多。可能是由于乙醇的原因，试验对轻度干燥的皮肤没有明显副作用。B.试验2
两男两女4名患者，年龄在16-25岁，患有轻微到中度痤疮，用上述制剂治疗。所有药物和化妆品停用14天，然后要求每名患者使用上述制剂，每天两次，使用8星期。治疗期间禁止采用任何其它形式的治疗和化妆。在治疗前和治疗后4和8周记录痤疮部位(丘疹，脓疱，白和黑粉刺)的数量，结果示于下列表1。表1的结果说明，所有类型的损伤部位数量的减少证明4名患者的情况全部得到改善。
                        表1
         治疗前和治疗期间痤疮损伤部位的数量
    患者     损伤   治疗前 治疗后1个月 治疗后2个月
    1     丘疹脓疱白和黑粉刺     101118     7310     327
    2     丘疹脓疱白和黑粉刺     171718     151515     2106
    3     丘疹脓疱白和黑粉刺     71222     2714     -47
    4     丘疹脓疱白和黑粉刺     201615     18910     555
    平均     丘疹脓疱白和黑粉刺     131418     10812     256

Claims (3)

1、洛伐他汀在制备治疗痤疮的药物组合物中的用途。
2、根据权利要求1的用途，其中在药物组合物中的洛伐他汀的浓度为0.2-10％。
3、根据权利要求1的用途，其中在药物组合物中的洛伐他汀的浓度为2％。
CN95195041A 1994-09-13 1995-09-13 治疗皮肤病的组合物 Expired - Fee Related CN1106841C (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IL11094394A IL110943A (en) 1994-09-13 1994-09-13 Compositions comprising an inhibitor of cholesterol synthesis for the treatment of skin disorders
IL110943 1994-09-13

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CN1158567A CN1158567A (zh) 1997-09-03
CN1106841C true CN1106841C (zh) 2003-04-30

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US (1) US6126947A (zh)
EP (1) EP0793489B9 (zh)
JP (1) JP4128616B2 (zh)
KR (1) KR970705990A (zh)
CN (1) CN1106841C (zh)
AT (1) ATE321548T1 (zh)
AU (1) AU694274B2 (zh)
BR (1) BR9509006A (zh)
CA (1) CA2199844C (zh)
DE (1) DE69534908T2 (zh)
IL (1) IL110943A (zh)
MX (1) MXPA97001884A (zh)
RU (1) RU2159611C2 (zh)
WO (1) WO1996008248A1 (zh)

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EP0793489B1 (en) 2006-03-29
JP4128616B2 (ja) 2008-07-30
DE69534908D1 (de) 2006-05-18
CA2199844A1 (en) 1996-03-21
KR970705990A (ko) 1997-11-03
ATE321548T1 (de) 2006-04-15
EP0793489B9 (en) 2006-08-30
DE69534908T2 (de) 2007-01-25
US6126947A (en) 2000-10-03
MXPA97001884A (es) 2004-04-16
IL110943A (en) 1997-02-18
AU694274B2 (en) 1998-07-16
WO1996008248A1 (en) 1996-03-21
RU2159611C2 (ru) 2000-11-27
EP0793489A1 (en) 1997-09-10
EP0793489A4 (en) 2001-12-19
BR9509006A (pt) 1998-06-23
IL110943A0 (en) 1994-11-28
AU3717395A (en) 1996-03-29
CA2199844C (en) 2007-04-10
CN1158567A (zh) 1997-09-03
JPH10505838A (ja) 1998-06-09

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