CN102458362A - 外用类维生素a溶液 - Google Patents
外用类维生素a溶液 Download PDFInfo
- Publication number
- CN102458362A CN102458362A CN2010800288894A CN201080028889A CN102458362A CN 102458362 A CN102458362 A CN 102458362A CN 2010800288894 A CN2010800288894 A CN 2010800288894A CN 201080028889 A CN201080028889 A CN 201080028889A CN 102458362 A CN102458362 A CN 102458362A
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- China
- Prior art keywords
- compositions
- pharmaceutically acceptable
- biostearin
- isotretinoin
- carrier
- Prior art date
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Abstract
本发明涉及包含类维生素A或其药学上可接受的盐的外用溶液,以及其制备工艺。
Description
发明领域
本发明涉及包含类维生素A或其药学上可接受的盐的外用溶液,以及其制备工艺。
发明背景
痤疮是一种皮肤病,其中,皮肤的毛囊皮脂结构发炎,导致形成粉刺、脓疱和囊肿。普遍认为,当毛囊皮脂结构角化过度完全或部分阻塞该结构的开口,导致充满皮脂、角质和痤疮丙酸杆菌(Propionibacterium aches(“P.acnes”))的粉刺,于是形成痤疮。通常将这些病损认定为痤疮。痤疮丙酸杆菌天然存在于正常皮肤,但尤见于并特征性地存在于痤疮病损。据信,毛囊皮脂结构内痤疮丙酸杆菌的代谢副产物和废物造成或促成了痤疮炎症。
痤疮的严重程度可从轻度到极其严重不等。轻度(浅表)痤疮患者只出现一些非炎症性黑头或中等数量的中度应激的小疱,多发于面部。黑头看上去为位于正常颜色皮肤的小肿起处中心的小黑点。面疱略有不适,中心为白色,周围小片皮肤呈红色。另一方面,严重(深度或囊肿性)痤疮呈现大量大形、红斑、疼痛的脓疱(囊肿),有时甚至在皮下彼此相连成巨大的渗出性脓肿。
根据严重程度和主要表现,可称为寻常性痤疮、黑头/白头痤疮(acnecomedonica)、粉刺型痤疮(acne papulo pustulosa),聚合性痤疮等等。并且,根据病理学和治疗差异,痤疮可分为两类,炎性痤疮和非炎性痤疮。
已有多种形式的传统痤疮治疗。有时采用口服药,包括抗生素,如四环素、米诺环素、强力霉素和红霉素,有时用外用去角质剂,例如水杨酸。去角质剂被认为能促进打开阻塞的毛囊皮脂结构,由此减轻易导致炎症的状况。过氧化苯甲酰,一种抗微生物剂,仍是常用且有效的疗法之一。外用抗生素,例如有效抗痤疮丙酸杆菌的克林霉素,已被用来避免形成痤疮丙酸杆菌的代谢副产物。
可选的痤疮疗法之一是类维生素A,它们曾被广泛用于治疗众多皮肤病,其中包括痤疮和皮脂溢出症。1982年首次采用口服13-顺式视黄酸(异维A酸)治疗严重痤疮时,堪称一次革新,至今仍是严重痤疮的唯一疗法。口服异维A酸之所以对痤疮如此有效是因为它是唯一作用于所有主要病因的疗法,尤其是例如,通过抑制脂质的合成显著减少皮脂产生,缩小患者的皮脂腺。因此,口服异维A酸在最近十年被作为痤疮的金标准,能够持续缓解约80%严重痤疮患者。
已知类维生素A可能引起严重的副作用,尤其是全身性使用时,例如会引起生育缺陷;精神健康问题,包括自杀危险;脑压升高失控,可能导致永久性失明等;肝、胰、肠和食道损伤;可能造成骨骼和肌肉问题;血液内胆固醇和其他脂肪水平升高;等等。然而,类维生素A制剂外用就副作用风险来说肯定是一大进步,因为外用时,药物由给药位点到作用位点的路经显著缩短,因此减少了全身性吸收;所以,外用疗法优于口服类维生素A疗法。
已可购买到大量的类维生素A制剂,形式有霜剂、凝胶、洗液、膏剂和溶液。但据报道,已有的外用剂型会造成皮肤刺激(皮炎),表现为红斑、皮屑、蜕皮、干燥、瘙痒和类似日晒性灼伤的不适。这一问题可参考美国专利4,888,342。外用类维生素A的其它副作用据报道有诸如瘙痒、刺痛或灼痛。还会发生鲜见的水肿和皮肤起泡或开裂。个别接受维A酸治疗的患者还会发生暂时性色素减少或色素沉积。暂时性色素减少见于非白种人。
类维生素A不溶于水,至多是微溶于水,但易溶于例如乙醇。所以含类维生素A的制剂用含醇载体系统来施用最有效,但含醇载体系统本身就会造成灼热的不适感。当同一片皮肤先行或同时接受视黄酸处理时,这种不适会加剧。大多数市售外用类维生素A制剂,例如ISOTREX凝胶,ISOTREXIN凝胶,DIFFERIN(阿达帕林)溶液和RETIN-A(维A酸)溶液,SOLAGE(对甲氧酚和维A酸)溶液含有据报道对皮肤有刺激的醇。
WO 90/14833公开了一种皮肤外用水性组合物,包含类维生素A和乙醇以及表面活性剂。该组合物包含0.1-20wt%助溶剂(乙醇)和表面活性剂。
大多数现有技术用另外的药剂来减轻含抗痤疮剂制剂引起的皮肤刺激。这些另外的药剂增加了不必要的制剂负担。
美国专利5,252,604在视黄酸外用组合物中使用生育酚例如α-生育酚来克服外用视黄酸引起视黄酸所致皮炎的问题,因为生育酚具有清除自由基的抗氧化剂特性。
美国专利4,593,046公开了一种用芦荟减轻过氧化苯甲酰所致皮肤刺激的方法,芦荟帮助减轻用过氧化苯甲酰治疗皮肤病变所致的特定不良反应。
美国专利6,277,881公开了姜黄提取物在含羟基酸和/或类维生素A的组合物中作为抗刺激/抗刺痛剂的用途。
美国专利5,643,584公开了一种类维生素A水性凝胶组合物,包含有效量的类维生素A微化颗粒,增强类维生素A透皮渗透的表面活性剂,防腐剂和胶凝剂。该发明还包含聚乙烯吡咯烷酮来抑制微化类维生素A的晶体生长。
霜剂被认为较易为患者所接受,但它们也有缺点,例如,与含有等量视黄酸的含醇组合物相比,临床效果较差。还没有临床非常有效的不含醇且不含脂肪的水性视黄酸制剂,这是因为活性成分不溶解,因而无法提供所需疗效。
因此,需要一种含类维生素A的组合物,其化学性质和物理性质稳定,不含醇,不含表面活性剂,但能够瞬间提供溶解的类维生素A,并且在临床上与现有技术中的组合物一样有效,但几乎没有或没有皮肤刺激。
本发明概述
本发明总体来说的内容之一提供了一种溶液形式的外用组合物。所述溶液包含:(i)治疗有效量的类维生素A或其药学上可接受的盐;(ii)药学上可接受的载体;以及(iii)一种或多种药学上可接受的赋形剂,所述组合物不含醇。所述外用组合物于40℃和75%RH,以及于25℃和60%RH储存期间保持稳定。
本发明的实施方式可包含一项或多项以下特征。例如,类维生素A的浓度为每体积组合物中按重量计约0.001%-1.5%。类维生素A可以是他扎罗汀,视黄酸,维A酸,异维A酸,阿达帕林,蓓萨罗丁,阿维A酸(alitretinoin),维生素A,视黄醇,视黄醛,棕榈酸视黄脂,乙酸视黄脂,5-(2-(4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)噻吩-2-羧酸乙酯,6-(2-4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)-3-吡啶基甲醇,2-(2-(4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)-5-吡啶甲醛。例如,类维生素A是异维A酸。
所述载体可以是亲脂性的,可以包括脂肪酸酯、脂肪酸、脂肪醇或植物油之一或若干。所述药学上可接受的赋形剂可包括色素、芳香剂、气味修正剂、粘度调节剂、推进剂、螯合剂、助溶赋形剂、渗透增强剂、防腐剂、抗氧化剂、稳定剂、清洁剂、增湿剂、保湿剂、润肤剂、收敛剂、去角质剂、增湿剂、防晒剂中一种或多种及其混合物,所述混合物可包含其它可选组分,所述可选组分溶于所述药学上可接受的载体或与之互溶。
所述外用组合物还可包含其它活性成分。所述其它活性成分选自抗生素、灭菌药物、抑菌药物、抗感染药和消炎药。
总体来说的另一内容中,本发明提供了一种治疗痤疮或其它皮肤病的方法。所述方法包括施用外用溶液,所述外用溶液包含:(i)治疗有效量的类维生素A或其药学上可接受的盐;(ii)药学上可接受的载体;和(iii)一种或多种药学上可接受的赋形剂,所述组合物不含醇。
总体来说的再一内容中,本发明提供了一种溶液形式的外用组合物,所述外用组合物包含类维生素A或其药学上可接受的盐,药学上可接受的载体,以及一种或多种药学上可接受的赋形剂,所述组合物基本如本说明书所述。
本发明详述
本发明涉及一种不含醇的溶液形式的外用组合物,其包含:
(i)治疗有效量的类维生素A或其药学上可接受的盐;
(ii)药学上可接受的载体;和
(iii)一种或多种药学上可接受的赋形剂,
所述组合物不含醇。
某活性物质的“治疗有效量”在此表示药物活性物质的量足以在使用区域产生正效应。因此,这样的量足以改变接受治疗的皮肤的病变、状况或外观,但就避免副作用而言则足够低,在医药或皮肤科认为合理的范围内。治疗有效量的药理学活性物质在一段时间内反复施用能够显著缓解症状。药理学活性物质的有效量根据所治疗的一种或多种具体病况、病况严重程度、疗程长短、所用组合物的具体组分等而不同。
本发明所用的类维生素A包括所有天然及合成类维生素A。本发明组合物所用类维生素A的非限定性实施例包括:他扎罗汀、视黄酸、维A酸、异维A酸、阿达帕林、蓓萨罗丁、阿维A酸、维生素A、视黄醇、视黄醛、棕榈酸视黄脂、乙酸视黄脂、5-(2-(4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)噻吩-2-羧酸乙酯、6-(2-4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)-3-吡啶基甲醇、2-(2-(4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)-5-吡啶甲醛,各自的盐、衍生物,以及它们的组合。他扎罗汀,阿达帕林,维A酸和异维A酸,以及它们的盐或衍生物尤其为本发明所优选。最为优选的实施方式中,类维生素A是异维A酸或其盐或衍生物。类维生素A的药学上可接受的盐、酯或衍生物指具有所需药理学学活性并且在生物学或其它方面没有不良特性的那些。
本发明组合物中类维生素A组分的浓度为每体积组合物中按重量计约0.001%至约1.5%,优选约0.01%至约0.5%。
组合物配制过程中,各种常规无毒、无刺激和皮肤学上可接受的基底或载体,如果类维生素A能溶于其中且保持稳定,都是可用的。
本发明组合物所用载体包括亲脂性载体,选自脂肪酸酯、脂肪酸、脂肪醇或植物油。
脂肪酸酯包括多元醇的中链脂肪酸酯。多元醇的中链脂肪酸酯选自甘油、丙二醇、聚甘油和聚乙二醇与中链脂肪酸的酯和混合酯。多元醇的中链脂肪酸酯优选中链甘油三酯或丙二醇单酯或二酯。
中链甘油三酯是甘油的中链(C6-C12)脂肪酸酯。中链脂肪酸的例子包括己酸、辛酸、癸酸和月桂酸。市售中链甘油三酯的例子包括:0和M5,810、812、818和829;350、355和810D,LabrafacTMlipophile WL 1349,CrodamolTM GTCC。中链甘油三酯有很高的抗氧化稳定性。
丙二醇单酯或二酯包括丙二醇单月桂酸酯、丙二醇单豆蔻酸酯、丙二醇二辛酸酯/二癸酸酯。市售丙二醇二辛酸酯或二癸酸酯的例子包括840,200P,LabrafacTM PG,1526,PG-810,M-20。
脂肪酸酯的例子还包括CapryolTM PGMC,CapryolTM 90,LauroglyocolTMFCC,LauroglycolTM 90,HP。
脂肪酸的具体例子包括C6-C20饱和或单不饱和或二不饱和酸,例如油酸、亚油酸、辛酸或己酸。
本发明组合物所用脂肪醇的具体例子包括C6-C20饱和或单不饱和或二不饱和醇,例如油醇、辛醇或癸醇。
本发明组合物所用植物油的具体例子包括核仁油、杏仁油、花生油、橄榄油、大豆油、红花油、棕榈油、芝麻油、菜籽油或玉米油或它们的混合物。更好的是,本发明组合物所用植物油是橄榄油或大豆油。
优选的是,本发明组合物所用载体选自脂肪酸酯或植物油或它们的混合物。
并且,本发明组合物所用载体具有特征性的酸价、羟价、碘价、过氧化物值和皂化值。
“酸价”可定义为中和1g样品所需氢氧化钾(KOH)的毫克(mg)数。已发现,酸价越低,组合物稳定性越高。组合物中所用载体的酸价应低于1,低于0.5为佳,低于0.2更好。
“羟价”反映有机物中的羟基(一价OH)量。已发现,越低羟价,组合物稳定性越高。组合物中所用载体的羟价应低于100,低于50为佳,低于10更好。
“碘价”反映脂肪和油脂的不饱和度,每克样品所吸收的表示为厘克碘(%吸收碘)。已发现,碘价越低,组合物稳定性越高。组合物中所用载体的碘价应低于10,低于5为佳,低于1更好。
“过氧化物值”通过测定物质中的过氧化物含量反映物质中脂肪或油脂的氧化程度。过氧化物是脂类氧化过程中形成的中间体化合物,它们会进一步反应形成导致酸败味的化合物。已发现,过氧化物值越低,组合物稳定性越高。组合物中所用载体的过氧化物值应低于10,低于6为佳,低于1更好。
“皂化值”指皂化一定量物质所需的碱量。它通常表示为皂化1克底物所需氢氧化钾(KOH)或氢氧化钠(NaOH)的毫克数。已发现,皂化值越高,组合物稳定性越高。组合物中所用载体的皂化值应高于200,高于250为佳,高于300更好。
本发明组合物还可以包含一种或多种药学上可接受的赋形剂,例如抗氧化剂、防腐剂、色素、芳香剂、气味修正剂、粘度调节剂、推进剂、螯合剂、助溶赋形剂、渗透增强剂、稳定剂,业内熟知的各种赋形剂都可以。此外,组合物可包含润肤剂、保湿剂、收敛剂、去角质剂、增湿剂、清洁剂、防晒剂、及它们的混合物。组合物还可包含溶于本发明的亲脂性载体或与之互溶的各种药学上可接受的赋形剂,用于增强类维生素A组合物的物理和/或化学和/或微生物学稳定性。
制剂中使用适合的抗氧化剂往往有多种原因。各种抗氧化剂的主要功能之一是通过清除环境中的氧自由基来避免制剂氧化变质。有效的抗氧化剂还能够避免或减少微生物生长,由此避免载体腐坏。这两项活性都有利于制剂的整体稳定。
适合用于本发明的抗氧化剂包括丁基羟基茴香醚(BHA),二丁基羟基甲苯(BHT),乙氧喹啉,抗坏血酸棕榈酸酯,柠檬酸,硫醇,亚砜亚胺,金属螯合剂,脂肪酸,维生素,酚类,茋,脲酸,甘露糖,异黄酮,硒和没食子酸丙酯。
本发明组合物还可以包含防腐剂。外用组合物中防腐剂用于预防微生物(例如细菌、真菌、酵母菌)生长。较好的是,防腐剂应当能在较低浓度具有广谱抗微生物效力。此外,防腐剂在所需浓度应当无毒,与外用组合物中的其它成分相容,在制备和储存条件下稳定,并且被全球各地的管理机构所准用。本发明组合物可以包含一种以上防腐剂。当每种防腐剂分别针对不同微生物时,混合防腐剂有助于实现广谱抗微生物效果。
本发明组合物的适合防腐剂包季铵化合物,例如苯扎氯铵,苄索氯铵,溴棕三甲铵,地喹氯铵和西吡氯铵;汞剂,例如硝酸苯汞,乙酸苯汞和硫柳汞;醇剂,例如,氯丁醇,苯乙醇和卞醇;抗菌酯,例如,对羟基苯甲酸酯;以及其它抗微生物剂,例如氯己啶,氯甲酚,苯甲酸和多粘菌素。
润肤剂即皮肤软化剂。润肤剂的例子包括烃油,蜡或硅酮。收敛剂是令蛋白质沉淀、令皮肤皱缩的干燥剂。收敛剂的例子包括硫酸铝和碳酸钙。去角质剂软化、松化、促使表皮的鳞状细胞脱落。去角质剂的例子包括硫,雷琐辛和水杨酸。保湿剂用于皮肤保湿,包括甘油,丙二醇和三乙酸甘油。防晒剂可包括二氧化钛,氧化锌以及它们的混合物。
本发明组合物还可以包含其它活性成分,这包括其它类维生素A或其衍生物,抗生素、灭菌药物、抑菌药物、抗感染药和消炎药。
本发明所用抗生素的例子包括大环内酯,例如阿奇霉素,克拉霉素,林可霉是,林可霉素,红霉素,各自药学上可接受的盐等,以及它们的混合物。
大环内酯彼此结构、活性相似。所有大环内酯都易于吸收,主要表现抑菌活性,通过结合核糖体的50S亚基抑制细菌蛋白质合成。这类药物对好氧和厌氧革兰氏阳性球菌有效,但肠球菌例外,并且对革兰氏阴性厌氧菌有效,因此可用于本发明组合物。
灭菌药(即杀灭细菌)的例子包括青霉素、头孢菌素、万古霉素、氨基糖甙类、喹诺酮类和多粘菌素。
抑菌药(即抑制细菌生长)的例子包括但不限于:红霉素,四环素,氯霉素,林可霉素,克拉霉素,阿奇霉素和磺胺类。然而众所周知,有些灭菌药可能对某些微生物表现为抑菌性,反之,有些抑菌药可能对某些微生物表现为灭菌性。
适合的抗感染药可包括外用抗菌剂、抗酵母剂和抗真菌剂。
在痤疮治疗之外,本发明组合物还可以用于治疗多种皮肤病况,其中包括小脓疱疹,酒渣鼻,牛皮癣,异位性皮炎,二次皮肤感染,反应性皮肤病,以及它们的合并。可用外用组合物治疗的皮肤病还包括皮脂溢出症和皮肤病变。
本发明组合物的施用可以是直接覆盖或铺展或喷涂在表皮组织上,尤其是表皮上。可将本发明组合物装入适合的包装部件,从而通过外用途径递送均一的、可重复的小量组合物。
以下将结合实施例来阐述本发明。然而,本领域技术人员懂得,此处所述的具体方法和结果仅仅是本发明的展示而非限定。
实施例
实施例1和2
过程:
1.持续搅拌中将丁基羟基茴香醚溶于亲脂性载体。
2.40℃-45℃持续搅拌中将异维A酸溶于步骤1所得溶液,形成澄清的溶液。
3.将步骤2所得溶液冷却至室温,将苯甲酸搅拌溶于其中,形成均匀的溶液。
实施例3和4
过程:
1.持续搅拌中将丁基羟基茴香醚溶于亲脂性载体。
2.40℃-45℃持续搅拌中将异维A酸溶于步骤1所得溶液,形成澄清溶液。
3.将步骤2的溶液冷却至室温。
实施例5
表1显示按照实施例1制备的0.1%w/v组合物的稳定性数据。
表1
实施例6
表2显示按照实施例1制备的0.05%w/v组合物的稳定性数据。
表2
实施例7
表3显示按照实施例3制备的0.1%w/v组合物的稳定性数据。
表3
实施例8
表4显示按照实施例3制备的0.05%w/v组合物的稳定性数据。
表4
实施例9
表5显示按照实施例4制备的0.05%w/v组合物的稳定性数据。
表5
实施例10
在雄性新西兰白兔中对按照实施例3制备的本发明0.1%w/v异维A酸外用溶液进行单剂量皮肤刺激试验。该试验与0.05%w/w异维A酸凝胶比较。
总共6只雄性新西兰白兔随机分成两组,每组3只。将不同测试制剂和安慰剂施于各个动物的右背-侧区域或左背-侧区域(随机定位)。同时给予三贴测试项,两只兔子给予异维A酸凝胶0.05%w/w,异维A酸外用溶液0.1%w/v,另一只雄兔给予异维A酸外用溶液的安慰剂。施用3分钟和1小时后,各揭去一贴异维A酸凝胶0.05%w/w,异维A酸外用溶液0.1%w/v和异维A酸外用溶液的安慰剂。第一组兔子在用药3分钟和1小时期间未见刺激迹象。给另外4只兔子施用一贴异维A酸凝胶0.05%w/w,异维A酸外用溶液0.1%w/v或异维A酸外用溶液的安慰剂,保持4小时。施用于前两只兔子的测试项和安慰剂的第三贴也保持4小时。检查各动物的红斑和水肿迹象,对用药期(4小时)后1小时、24小时、48小时和72小时的反应进行分级。此外,还检查了单贴保持3分钟和1小时的两只雄兔用药后5分钟后10分钟的红斑和水肿情况。异维A酸凝胶0.05%w/w和异维A酸外用溶液0.1%w/v用药3分钟和1小时后未见红斑和水肿迹象。单剂皮肤施用(用药4小时)异维A酸外用溶液0.1%w/v和异维A酸外用溶液0.1%w/v的安慰剂后14天未见红斑和水肿。皮肤施用(用药4小时)单剂异维A酸凝胶0.05%w/w后1小时出现红斑,24小时后发展为严重红斑,至72小时不愈。第5日起出现好转,至第14日痊愈。施用(用药4小时)单剂异维A酸凝胶0.05%w/w的另一只兔子用药后1小时出现非常轻微的红斑,24小时后发展为明显红斑,至72小时不愈。第5日起出现好转,至第8日痊愈。施用(用药4小时)单剂异维A酸凝胶0.05%w/w的两只兔子在用药后1小时出现红斑(非常轻微),72小时后痊愈。本发明异维A酸外用溶液0.1%w/v未见皮肤刺激可能性。
实施例11
在雄性新西兰白兔中对按照实施例1制备的本发明0.05%w/v和0.1%w/v异维A酸外用溶液进行28-天重复给药皮肤局部耐受性测试。
总共9只雄性新西兰白兔。给每只兔子在测试部位施用不同测试项制剂和/或安慰剂,测试部位约为总体表面积的10%,或位于磨损皮肤或位于完整皮肤。施用500μl异维A酸外用溶液0.05%w/v或异维A酸外用溶液0.1%w/v或异维A酸外用溶液的安慰剂,连续施用28天。给所有兔子同时施用4贴测试项;异维A酸外用溶液0.05%w/v或异维A酸外用溶液0.1%w/v或异维A酸外用溶液的安慰剂。每天,用药4小时后的1至2小时检查所有兔子的红斑和水肿检查,并分级(表6)。红斑和水肿分0到4级,0级表示没有红斑也没有水肿,4级则表示严重红斑和严重水肿。
表6
全部动物在第29天被安乐死。采集各兔子的皮肤组织样本(用药部位),按标准方法进行处理。在接受评价的组织样本中均未见微观变化。在雄性新西兰白兔中,异维A酸外用溶液连续皮肤外用28天,未见皮肤刺激和/或蚀伤迹象。
虽然以上描述了本发明的几种具体实施方式,根据本发明的要旨在本发明范围内显然可以进行多种改变和组合。因此,本发明的范围仅由权利要求来限定。
Claims (12)
1.一种溶液形式的外用组合物,包含:
(i)治疗有效量的类维生素A或其药学上可接受的盐;
(ii)药学上可接受的载体;和
(iii)一种或多种药学上可接受的赋形剂,
所述组合物不含醇。
2.如权利要求1所述的组合物,所述类维生素A的浓度为每体积组合物中按重量计约为0.001%至1.5%。
3.如权利要求1所述的组合物,所述类维生素A包括他扎罗汀、视黄酸、维A酸、异维A酸、阿达帕林、蓓萨罗丁、阿维A酸、维生素A、视黄醇、视黄醛、棕榈酸视黄脂、乙酸视黄脂、5-(2-(4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)噻吩-2-羧酸乙酯、6-(2-4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)-3-吡啶基甲醇、2-(2-(4,4-二甲基-二氢苯并噻喃-6-基)乙炔基)-5-吡啶甲醛。
4.如权利要求1所述的组合物,所述类维生素A包含异维A酸。
5.如权利要求1所述的组合物,所述载体是亲脂性的。
6.如权利要求5所述的组合物,所述载体包含脂肪酸酯、脂肪酸、脂肪醇或植物油之一或若干。
7.如权利要求1所述的组合物,所述药学上可接受的赋形剂包含色素、芳香剂、气味修正剂、粘度调节剂、推进剂、螯合剂、助溶赋形剂、渗透增强剂、防腐剂、抗氧化剂、稳定剂、清洁剂、增湿剂、保湿剂、润肤剂、收敛剂、去角质剂、增湿剂、防晒剂及其混合物之一或若干,所述混合物可包含溶于所述药学上可接受的载体或与之互溶的其它可选组分。
8.如权利要求1所述的组合物,所述组合物包含其它活性成分。
9.如权利要求8所述的组合物,所述其它活性成分选自抗生素、灭菌药物、抑菌药物、抗感染药或消炎药。
10.如权利要求1所述的组合物,所述组合物于40℃和75%RH,于25℃和60%RH存储期间保持稳定。
11.一种治疗痤疮或其它皮肤病的方法,所述方法包括施用包含以下成分的外用溶液:
(i)治疗有效量的类维生素A或其药学上可接受的盐;
(ii)药学上可接受的载体;和
(iii)一种或多种药学上可接受的赋形剂,
所述组合物不含醇。
12.一种基本上如本申请所述的溶液形式的外用组合物,包含类维生素A或药学上可接受的盐,药学上可接受的载体,和一种或多种药学上可接受的赋形剂。
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