CN1968681A - 用于局部给药治疗牛皮癣的加压泡沫组合物 - Google Patents
用于局部给药治疗牛皮癣的加压泡沫组合物 Download PDFInfo
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- CN1968681A CN1968681A CNA2005800199993A CN200580019999A CN1968681A CN 1968681 A CN1968681 A CN 1968681A CN A2005800199993 A CNA2005800199993 A CN A2005800199993A CN 200580019999 A CN200580019999 A CN 200580019999A CN 1968681 A CN1968681 A CN 1968681A
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Abstract
本发明的目的是治疗牛皮癣用的局部涂敷用稳定的泡沫药物组合物,该组合物含有亲水相、至少一个疏水相、表面活性剂和作为活性成分的维生素D类似物和皮质类固醇,以及至少一种气体推进剂。
Description
本发明涉及用于治疗牛皮癣的局部涂敷组合物。
牛皮癣是一种皮肤的慢性炎症,涉及到大约5%的法国居民。这种疾病的症状表现为覆盖着白色皮屑的红斑,皮屑从皮肤上脱落,就是鳞屑。牛皮癣的斑经常位于肘部、头皮和膝盖处,但也可达到身体的其它部位,比如面部、手部、足部和粘膜上。牛皮癣的本质既非接触传染的,亦非变态反应的,但可通过遗传传播,对该疾病的进展表现出敏感的形式。在任何年纪都可能罹患牛皮癣,但最多出现在10~30岁的人群中。这是一种慢性病,其进展是难以预料的:复发期接着暂缓期。如果说这种疾病还不容易危及人的生命,可是反过来它对生活质量会有很大的影响。鉴于其难看的外貌及其慢性的进程,这种疾病经常使人感到自惭形秽、精神痛苦以及日益增长的压抑。患有牛皮癣的人经常具有交往上的困难,特别是当其病变的部位曝露在他人面前时:对于在面部、头皮和手上患有牛皮癣时就是这样。心理上的创伤(伤感、情感的断裂)或身体上的打击(偶发事件、手术介入等)经常是首次发病和复发的根源。
牛皮癣被分为两类:
-I型牛皮癣,发病是儿童和年轻的成人,具有家族的既往史,进展很重,
-II型牛皮癣,是在40岁以后发病的牛皮癣,没有家族的既往史,进展比较轻。
对于牛皮癣,某些病人只在身体的特定区域患有红斑,而另外一些病人则在整个的身体上都患有牛皮癣。同样,有许多类型的症状,构成很不同的牛皮癣。
在先有技术中,一般在治疗牛皮癣时都使用皮质类固醇。皮质类固醇的作用机理有赖于其对炎性过程的抑制(Lange K等人,SkinPharmacol Appl.Skin Physiol.13(2):93-103(2000))。
文献US 4,610,978叙述了使用维生素D或维生素D类似物,必要时同时使用皮质类固醇来治疗牛皮癣的方法。当前已知在治疗牛皮癣时要联合使用活性药物,特别是联合使用皮质类固醇和维生素D或维生素D类似物。实际上,由于联合治疗能够降低给药的活性成分的剂量,因此就降低了这些活性成分的副作用,所以这样做是有利的。
文献WO 00/64450叙述了为了治疗牛皮癣,使用了含有至少一种维生素D类似物和至少一种皮质类固醇的皮用药物组合物。这样的组合物具有洗剂或乳脂的形式。
文献WO 02/34235叙述了为了治疗牛皮癣,使用了含有至少一种维生素D类似物、至少一种皮质类固醇和增粘赋形剂的皮肤涂敷用凝胶药物组合物。
但是,这些先有技术的文献中迄今都没有谈到呈加压含水泡沫状,同时含有维生素D和皮质类固醇的用于治疗牛皮癣的组合物。
实际上,对于先有技术的专业人员,将维生素D类似物与皮质类固醇以泡沫的形式进行组合是显而易见的。
因此,本发明的目的是用来治疗牛皮癣的局部涂敷用稳定的加压含水泡沫药物组合物,该组合物含有一个亲水相、至少一个疏水相、表面活性剂和作为活性成分而联合使用的维生素D类似物比如骨化三醇和皮质类固醇比如丙酸氯倍他索和至少一种气体推进剂(gazpropulseur)。所谓“加压的”指的是含有至少一种气体推进剂的组合物。此泡沫药物组合物可任选含有助表面活性剂、溶剂和有机助溶剂和凝胶化剂。
按照本发明的泡沫药物组合物所具有的优点是很多的。实际上,由于泡沫容易涂布,特别是涂布在头皮上,致使能够改善病人的举止(observance)。
在本申请书中,所谓“用于局部涂敷的组合物”,表示用来涂布在身体各部分,比如头皮、粘膜、肘部、膝盖、手、脚或面部等的组合物。
所谓“亲水相”,指的是主要由水组成的相。
疏水相在下文中也称为疏水溶剂,可以是但并不限于植物油、动物油、在环境温度下是液体或固体的矿物油、硅油、合成油或它们的混合物。疏水相对活性成分起着溶剂的作用。
另外,活性成分可溶解于不同于疏水相的各种有机溶剂中。此溶剂可来源于二元醇比如丙二醇、脂肪酸酯比如具有C12~C15烷基链的苯甲酸烷基酯、具有中等链或长链的醇、脂肪醇、芳香族或烷基化的吡咯烷酮、环酮、环醚、具有线形、分支或环状链的烷烃。
作为凝胶化剂,可以举出多糖和衍生物比如藻酸盐、壳多糖、淀粉和衍生物、天然胶和衍生物比如黄原胶、粘土、合成聚合物比如纤维素衍生物、聚乙烯基吡咯烷酮和衍生物、羧基乙烯基聚合物、丙烯酸类共聚物比如丙烯酸酯/烷基丙烯酸酯共聚物、聚丙烯酰胺、Pemulen等。
作为植物油的例子,可以举出大豆油、棉籽油、甜杏仁油、棕榈油、芝麻油、葵花子油。作为动物油的例子,可以举出羊毛脂、角鲨烯、鱼油、貂油。作为矿物油的例子,可以举出各种粘度的石蜡油,比如Esso公司销售的Primol 352、Marcol 82、Marcol 152。作为合成油的例子,可以举出酯类比如法国Cognis公司以商品名Cetiol SN销售的异壬酸鲸蜡酯、棕榈酸异丙酯、棕榈酸辛酯、异硬脂酸衍生物、二辛酸/二己酸新戊二醇酯、加氢甘油、ISF公司以商品名Ceraphyl 230销售的己二酸二异丙酯、Croda公司以商品名Crodamol IPP销售的棕榈酸异丙酯、Stearinerie Dubois公司以商品名Dub Inin销售的异壬酸异壬酯、Huls/Lambert Riviere公司以商品名Miglyol 812销售的辛酸/己酸三甘油酯。作为硅油的例子,可以举出非挥发性硅油,比如聚烷基硅氧烷、聚芳基硅氧烷、Dow Corning公司以商品名Dow CorningFluid 20cSt销售的二甲基硅氧烷。
相对于该组合物的总重量,此疏水溶剂的浓度为20~75wt%,优选为20~50wt%。
凝胶化剂的浓度为0.1~5.0wt%。
作为维生素D类似物的例子,可以举出骨化三醇、他卡西妥、钙泊三醇和在专利WO 00/64450中所举出的各种维生素D类似物。维生素D类似物优选是骨化三醇。
作为皮质类固醇的例子,可以举出氯倍他索及其酯,比如17-丙酸氯倍他索(在下文中也称为氯倍他索丙酸酯)、倍他米松及其酯、氟轻松、氢化可的松和在专利WO 00/64450中所举出的各种其它皮质类固醇。皮质类固醇优选是丙酸氯倍他索。
表面活性剂可以是非离子型、两性离子型、阴离子型或阳离子型表面活性剂,或者是这些表面活性剂的混合物。
非离子型表面活性剂可选自乙氧基化缩水山梨糖醇硬脂酸酯、乙氧基化缩水山梨糖醇棕榈酸酯、乙氧基化缩水山梨糖醇油酸酯、壬基酚乙氧基化合物、脂肪醇乙氧基化合物、聚氧乙烯月桂基醚、聚氧乙烯鲸蜡基醚、蔗糖酯、聚乙二醇化的酯类或它们的混合物。
两性离子表面活性剂可以是椰油酰胺基烷基胺,特别是椰油酰胺基丙胺和/或椰油酰胺基丙胺氧化物。
阳离子型表面活性剂可以是甜菜碱。
阴离子型表面活性剂可以是月桂基硫酸钠。
表面活性剂优选是非离子型的。
助表面活性剂选自HLB值在6~10,优选为6~8的助表面活性剂。
本发明还涉及含有至少一种气体推进剂的组合物。此种气体推进剂可以是先有技术中专业人员公知的气体,比如烃类、CFC、HFC、氮气、二氧化碳、空气或它们的混合物。这种气体的例子是丙烷、丁烷、异丁烷、二氯二氟甲烷、二氯四氟乙烷、八氟环丁烷、二甲基醚或它们的混合物。按照本发明的一个优选形式,该气体推进剂呈液化的形式,其浓度为组合物总重量的5~30wt%。
本发明的目标组合物还可以含有软化剂(émollient)、一种或几种吸收促进剂、适当的缓冲物质、防腐剂和/或抗氧剂。
作为软化剂的例子,可以举出甘油、泛醇或山梨醇。
作为缓冲物质的例子,可以举出成对的醋酸/醋酸钠、柠檬酸/柠檬酸钠、磷酸/磷酸钠或柠檬酸酐/柠檬酸钾。
抗氧剂可以是4-氨基水杨酸、5-氨基水杨酸、丁基羟基甲苯、丁基羟基苯甲醚、没食子酸丙酯、过氧化歧化酶、泛醇、α-维生素E和衍生物或某些金属螯合物。在本发明的组合物中优选使用的抗氧剂是D,L-α-维生素E、丁基羟基苯甲醚和丁基羟基甲苯。
可任选将活性成分包裹在药物输送系统的胶囊中,以增加其稳定性。药物输送剂的例子是脂类载体、环化糊精、直接或逆向微胶束。
按照本发明的一个优选实施模式,相对于组合物总重量,表面活性剂的含量为0.1~15wt%,优选为0.1~10wt%,更优选为0.2~5wt%。
相对于该组合物的总重量,维生素D类似物的含量为0.0001~1wt%,优选为0.0001~0.1,更优选为0.0001~0.025wt%。
相对于该组合物的总重量,皮质类固醇的含量为0.001~1wt%,优选为0.001~0.2wt%,更优选为0.005~0.1wt%。
相对于该组合物的总重量,气体推进剂的含量为3~30wt%,优选为3~10wt%。
相对于该组合物的总重量,疏水相的量为20~75wt%,优选为20~50wt%。
本发明的另一个目的是含有如上所定义组合物的气雾喷射器(bombe aérosol)。
本发明还涉及在气雾剂中如上所定义的泡沫药物组合物的制备方法。
作为本发明目的的泡沫组合物的制备方法,其特征在于,该方法包括如下步骤:
(a)将活性成分分别溶解于适当的溶剂中;
(b)如果需要,将疏水相加热到50~70℃;
(c)在搅拌下将溶解的活性成分加入到疏水相中;
(d)慢慢地将预先加热到同样温度下(如果需要)的含有表面活性剂的水相加入到疏水相中;
(e)用Ultra-Turrax搅拌器将全部反应物均匀化,并冷却到环境温度;
(f)然后将该混合物置入气溶胶中,封闭气溶胶容器,在容器中压入必需量的推进剂(占组合物质量的大约10%)。
本发明的另一个目的是维生素D类似物与皮质类固醇的混合物在制造治疗牛皮癣的局部涂敷用泡沫药物组合物方面的应用。
按照如上所述的制备模式制备如下的实施例。
实施例1
成分 | 含量(wt%) |
Mygliol 812 | 50.0 |
水 | 31.5 |
丙二醇 | 5.0 |
蔗糖酯 | 3.0 |
抗氧剂 | 0.04 |
防腐剂 | 0.5 |
骨化三醇 | 0.0003 |
丙酸氯倍他索 | 0.05 |
丙烷/异丁烷 | 10 |
实施例2
成分 | 含量(wt%) |
Mygliol 812 | 47.0 |
水 | 29.0 |
丙二醇 | 10.0 |
乙氧基化缩水山梨糖醇酯 | 3.4 |
缩水山梨糖醇酯 | 0.1 |
抗氧剂 | 0.04 |
防腐剂 | 0.46 |
骨化三醇 | 0.0003 |
丙酸氯倍他索 | 0.05 |
丙烷/异丁烷 | 10.0 |
实施例3
成分 | 含量(wt%) |
Mygliol 812 | 50.0 |
水 | 31.5 |
丙二醇 | 5.0 |
蔗糖酯 | 3.0 |
抗氧剂 | 0.04 |
防腐剂 | 0.5 |
骨化三醇 | 0.005 |
倍他米松二丙酸酯 | 0.05 |
丙烷/异丁烷 | 10.0 |
实施例4
成分 | 含量(wt%) |
Mygliol 812 | 50.0 |
水 | 31.0 |
丙二醇 | 5.0 |
蔗糖酯 | 3.0 |
羟甲基纤维素 | 0.5 |
抗氧剂 | 0.04 |
防腐剂 | 0.5 |
骨化三醇 | 0.0003 |
丙酸氯倍他索 | 0.05 |
丙烷/异丁烷 | 10.0 |
Claims (26)
1.用来治疗牛皮癣的局部涂敷用加压含水泡沫药物组合物,该组合物含有亲水相、至少一个疏水相、表面活性剂和维生素D类似物与皮质类固醇的组合,以及至少一种气体推进剂。
2.按照权利要求1的组合物,其特征在于,该组合物还含有助表面活性剂。
3.按照权利要求1和2的组合物,其特征在于,该组合物含有有机溶剂。
4.按照权利要求1~3中任何一项的组合物,其特征在于,该组合物还含有凝胶化剂。
5.按照权利要求1~4中任何一项的组合物,其特征在于,维生素D类似物选自骨化三醇、钙泊三醇和他卡西妥。
6.按照权利要求5的组合物,其特征在于,维生素D类似物是骨化三醇。
7.按照权利要求1~6中任何一项的组合物,其特征在于,皮质类固醇选自丙酸氯倍他索、倍他米松及其酯、氟轻松和氢化可的松。
8.按照权利要求7的组合物,其特征在于,皮质类固醇是丙酸氯倍他索。
9.按照权利要求1~8中任何一项的组合物,其特征在于,该表面活性剂是非离子型、阴离子型、两性离子型或阳离子型表面活性剂。
10.按照权利要求9的组合物,其特征在于,该非离子型表面活性剂选自乙氧基化缩水山梨糖醇硬脂酸酯、乙氧基化缩水山梨糖醇棕榈酸酯、乙氧基化缩水山梨糖醇油酸酯、乙氧基化壬基酚、乙氧基化脂肪醇、聚氧乙烯月桂基醚、聚氧乙烯鲸蜡基醚、蔗糖酯、或它们的混合物。
11.按照权利要求9的组合物,其特征在于,该两性离子型表面活性剂选自椰油酰胺基烷基胺,以及特别是椰油酰胺基丙胺和/或椰油酰胺基丙胺氧化物。
12.按照权利要求9的组合物,其特征在于,该阳离子型表面活性剂是甜菜碱。
13.按照权利要求4~12中任何一项的组合物,其特征在于,该凝胶化剂选自多糖和衍生物比如藻酸盐、壳多糖、淀粉和其衍生物、天然胶和其衍生物比如黄原胶、粘土、合成聚合物比如纤维素衍生物、聚乙烯基吡咯烷酮和其衍生物、羧基乙烯基聚合物、丙烯酸类共聚物比如丙烯酸酯/烷基丙烯酸酯共聚物、聚丙烯酰胺、Pemulen。
14.按照权利要求1~13中任何一项的组合物,其特征在于,该气体推进剂选自烃类、CFC、HFC、氮气、二氧化碳、空气或它们的混合物。
15.按照权利要求14的组合物,其特征在于,该气体推进剂选自丙烷、丁烷、异丁烷、二氯二氟甲烷、二氯四氟乙烷、八氟环丁烷、二甲基醚或它们的混合物。
16.按照权利要求1~15中任何一项的组合物,其特征在于,该气体推进剂以液化的形式存在。
17.按照权利要求1~16中任何一项的组合物,其特征在于,该组合物含有至少一种疏水溶剂。
18.按照权利要求17的组合物,其特征在于,该疏水溶剂选自矿物油、合成油、硅油、植物油、动物油或它们的混合物。
19.按照权利要求1~18中任何一项的组合物,其特征在于,相对于该组合物的总重量,该维生素D类似物的含量为0.0001~1wt%,优选为0.0001~0.1wt%,更优选为0.0001~0.025wt%。
20.按照权利要求1~19中任何一项的组合物,其特征在于,相对于该组合物的总重量,该皮质类固醇的含量为0.001~1wt%,优选为0.001~0.2wt%,更优选为0.005~0.1wt%。
21.按照权利要求1~20中任何一项的组合物,其特征在于,相对于该组合物的总重量,该表面活性剂的含量为0.1~10wt%,优选为0.2~5wt%。
22.按照权利要求1~16中任何一项的组合物,其特征在于,相对于该组合物的总重量,该气体推进剂的含量为3~30wt%,优选为3~10wt%。
23.按照权利要求17~18中任何一项的组合物,其特征在于,相对于该组合物的总重量,该疏水溶剂的含量为20~75wt%,优选为20~50wt%。
24.按照权利要求1~23中任何一项的组合物,其特征在于,该组合物还含有软化剂、缓冲物质、防腐剂和/或抗氧剂。
25.气雾喷射器,其特征在于其含有按照权利要求1~24中任何一项的组合物。
26.维生素D类似物和皮质类固醇混合物在制造用于治疗牛皮癣的局部涂敷用泡沫药物组合物方面的应用。
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FR0406613 | 2004-06-17 | ||
FR0406613A FR2871696B1 (fr) | 2004-06-17 | 2004-06-17 | Composition topique pour le traitement du psoriasis |
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CN1968681A true CN1968681A (zh) | 2007-05-23 |
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CNA2005800199993A Pending CN1968681A (zh) | 2004-06-17 | 2005-06-15 | 用于局部给药治疗牛皮癣的加压泡沫组合物 |
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US (1) | US20050281755A1 (zh) |
EP (1) | EP1778185A1 (zh) |
JP (1) | JP2008502663A (zh) |
KR (1) | KR20070024598A (zh) |
CN (1) | CN1968681A (zh) |
AU (1) | AU2005261571A1 (zh) |
BR (1) | BRPI0510840A (zh) |
CA (1) | CA2567687A1 (zh) |
FR (1) | FR2871696B1 (zh) |
MX (1) | MXPA06014409A (zh) |
RU (1) | RU2007101540A (zh) |
WO (1) | WO2006005844A1 (zh) |
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CN108289855A (zh) * | 2015-09-29 | 2018-07-17 | 盖尔德马研究及发展公司 | 含有丙酸氯倍他索的免冲洗化学泡沫、以及它们在治疗牛皮癣中的用途 |
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2004
- 2004-06-17 FR FR0406613A patent/FR2871696B1/fr not_active Expired - Fee Related
- 2004-10-15 US US10/965,195 patent/US20050281755A1/en not_active Abandoned
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2005
- 2005-06-15 MX MXPA06014409A patent/MXPA06014409A/es not_active Application Discontinuation
- 2005-06-15 KR KR1020067026292A patent/KR20070024598A/ko not_active Application Discontinuation
- 2005-06-15 JP JP2007515998A patent/JP2008502663A/ja not_active Withdrawn
- 2005-06-15 WO PCT/FR2005/001496 patent/WO2006005844A1/fr active Application Filing
- 2005-06-15 CA CA002567687A patent/CA2567687A1/fr not_active Abandoned
- 2005-06-15 CN CNA2005800199993A patent/CN1968681A/zh active Pending
- 2005-06-15 BR BRPI0510840-3A patent/BRPI0510840A/pt not_active Application Discontinuation
- 2005-06-15 AU AU2005261571A patent/AU2005261571A1/en not_active Abandoned
- 2005-06-15 EP EP05777132A patent/EP1778185A1/fr not_active Withdrawn
- 2005-06-15 RU RU2007101540/15A patent/RU2007101540A/ru unknown
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102438590A (zh) * | 2009-02-25 | 2012-05-02 | 施泰福研究澳大利亚有限公司 | 局部泡沫组合物 |
CN102438590B (zh) * | 2009-02-25 | 2013-07-10 | 施泰福研究澳大利亚有限公司 | 局部泡沫组合物 |
CN108289855A (zh) * | 2015-09-29 | 2018-07-17 | 盖尔德马研究及发展公司 | 含有丙酸氯倍他索的免冲洗化学泡沫、以及它们在治疗牛皮癣中的用途 |
CN108289855B (zh) * | 2015-09-29 | 2022-03-29 | 盖尔德马研究及发展公司 | 含有丙酸氯倍他索的免冲洗化学泡沫、以及它们在治疗牛皮癣中的用途 |
Also Published As
Publication number | Publication date |
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KR20070024598A (ko) | 2007-03-02 |
RU2007101540A (ru) | 2008-07-27 |
WO2006005844A1 (fr) | 2006-01-19 |
EP1778185A1 (fr) | 2007-05-02 |
MXPA06014409A (es) | 2007-02-19 |
BRPI0510840A (pt) | 2007-11-27 |
AU2005261571A1 (en) | 2006-01-19 |
FR2871696A1 (fr) | 2005-12-23 |
US20050281755A1 (en) | 2005-12-22 |
JP2008502663A (ja) | 2008-01-31 |
FR2871696B1 (fr) | 2006-11-10 |
CA2567687A1 (fr) | 2006-01-19 |
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