CN102014906A - 治疗具有慢性炎症的阴道感染的组合物 - Google Patents
治疗具有慢性炎症的阴道感染的组合物 Download PDFInfo
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Abstract
本发明涉及包含苯并呋喃化合物和苯并菲啶生物碱的组合物,其具有抗炎、抗细菌和抗真菌活性,用于治疗阴道感染和产生的炎性状态。
Description
概述
本发明涉及包含苯并呋喃化合物和苯并菲啶生物碱的组合物,其具有抗炎、抗细菌和抗真菌活性,用于治疗阴道感染和产生的炎性状态。
现有技术
阴道炎通常在最初是无症状的,但是随着时间的推移会发展为可能危险的感染。外阴感染,无论是病毒、细菌、真菌还是原生动物起源(疱疹、毛滴虫病、念珠菌病)引起外阴瘙痒、螫伤、刺激和损伤,随后是外排尿困难和外阴交媾困难。阴道炎可以导致一系列严重的事件,复发感染,例如对其它器官和器具(apparatus)的毒性。这种现象在很多发展中国家尤为重要,在那里这些事件使患者感染HIV或其它性传播疾病的危险增加。
毛滴虫病表现出的症状是例如微黄、脓性渗出物和外阴刺激,阴道和外阴上皮的炎症,以及宫颈的瘀点性损伤。分泌物的pH大于5,从而促进毛滴虫病(Trichomonas)的发展。念珠菌病具有严重的外阴瘙痒,伴有红斑和水肿,并且分泌物是恶臭的气味,如在细菌性阴道炎的情况中一样。这些障碍是以高剂量口服施用抗生素和抗真菌药治疗的,或者用用于局部治疗的凝胶剂。这些治疗通常需要很长时间并且可能具有副作用。
从博落回(Macleaya cordata)、小果博落回(Macleaya microcarpa)、血根草(Sanguinaria canadensis)和白屈菜(Chelidonia majus)中分离的苯并菲啶生物碱对直接涉及阴道感染的菌株(例如阴道毛滴虫(Trichomonas vaginalis)、大肠杆菌(Escherichia coli)、绿脓杆菌(Pseudomonas aeruginosa)等)特别具有活性。
根据本发明,苯并呋喃化合物具有下式:
其中R可以是氢或者具有2至6个碳原子的直链或支链烷基,或者被胺、硝基取代的烷基链;R优选是氢或C1-C3烷基。
所述的苯并呋喃化合物是已知的并且可以通过常规方法制备,例如通过将被适当取代的苯酚和2-苯氧基-2’,4’-二甲氧基苯乙酮在Chimie Therapeutique 1973,8,398中报道的条件下反应,然后在多磷酸的存在下在二甲苯中环化并且将甲氧基和羟基水解而制备。本发明组合物中所用的苯并呋喃化合物具有结构式I并且具有强大的抗细菌和抗真菌作用以对抗念珠菌属的多种菌株。
发明详述
本发明涉及组合物,该组合物包含:
a)苯并菲啶生物碱;和
b)苯并呋喃化合物;
并且可能包含
c)花椒(Zanthoxylum bungeanum)或狭叶松果菊(Echinacea angustifolia)的提取物;
其具有抗炎、抗细菌和抗真菌活性,用于治疗阴道感染和产生的炎性状态,特别是与炎性问题有关的多种起源的阴道炎。
更特别的是,本发明涉及制剂,该制剂包含:
a)苯并菲啶生物碱,选自血根碱和/或白屈菜赤碱和/或其衍生物;和
b)如上文指定的苯并呋喃化合物;
并且可能包含
c)花椒或狭叶松果菊的提取物。
已经令人惊奇地发现本发明的组合物具有抗细菌、抗真菌和抗酶活性,大于分别施用多种组分的总和获得的抗细菌、抗真菌和抗酶活性。所述作用可能归因于所述的联合中多种组分之间发生的协同作用机制。本发明的组合物迅速消除这些感染,消除存在的腐生物并且减轻炎症、瘙痒和降低阴道pH。
根据本发明,组合物将包含在下列区间内的多种组分(每单位剂量以重量计):
a)苯并菲啶生物碱:从0.15mg至15mg;和
b)苯并呋喃化合物:从0.2至25mg;
并且可能包含
c)花椒或狭叶松果菊的提取物:从0.1至10mg。
根据特别优选的方面,所述组合物将包含在下列区间内的多种组分(每单位剂量以重量计):
a)苯并菲啶生物碱:从0.4至10mg;和
b)苯并呋喃化合物:从0.4至10mg;
并且可能包含
c)花椒或狭叶松果菊的提取物:从0.2至5mg。
苯并菲啶生物碱血根碱和白屈菜赤碱可以以游离或成盐形式存在,例如以基本上纯的形式或者以血根草(Sanguinaria canadensis)、博落回(Macleaya cordata)、小果博落回(Macleaya macrocarpa)或白屈菜(Chelidonia majus)的提取物形式存在。根据优选的方面,苯并菲啶生物碱将以与淡黄霉酸成盐的形式存在。所述盐通过将生物碱的硫酸酯或氯化物与淡黄霉酸的钠或钾盐反应并且随后环化而制备,该盐已经证明对于本发明的目的特别有效。特别的是,血根碱是强大的抗血管生成因子,其有助于减轻炎症(Jong-Pil Eun 2004)。在体内,血根碱抑制鸡胚胎中基质胶和尿囊绒膜中毛细管的形成(Jong-Pil Eun 2004)。
所述苯并菲啶生物碱不仅具有相当的抗细菌、抗真菌和抗毛滴虫活性,还具有相当的抗巨细胞病毒和乳头瘤病毒的活性。因此,这些生物碱、血根碱、白屈菜赤碱和白屈菜碱的原型,也具有镇痛作用,在治疗不同病因学的阴道炎中非常有用。这些化合物互相协同作用以减轻炎症,从而减轻症状,并且抑制障碍。
具有上文描述的苯并呋喃结构的化合物可以以本身存在或者以包含它们的提取物的形式存在,例如秘鲁拉坦尼(Krameria triandra)、Eupomatia laurina和胡椒物种(Piper sp)的提取物。已经证明特别有效的从秘鲁拉坦尼分离的化合物是Eupomatenoid 6和新木脂素2-(2,4-二羟基苯基)-5-(E)-丙烯基-苯并呋喃,已经证明其对革兰氏阳性细菌、真菌和厌氧细菌的多种菌株具有抗细菌和抗真菌活性。
根据特别优选的方面,所述组合物还包含花椒或狭叶松果菊的提取物以帮助消除存在的瘙痒和/或疼痛。此作用归因于异丁基酰胺的存在,所述的异丁基酰胺与大麻素CB2和CB1受体结合。本发明的制剂可以根据众所周知的常规方法和适合的赋形剂一起制备,所述的方法例如在“Remington’s Pharmaceutical Handbook(雷明顿药物手册)”,Mack Publishing Co.,N.Y.,USA中描述的那些。
本发明的组合物将方便地与其它可相容的赋形剂配制成水/油乳剂,用于肛门生殖器区的外部治疗;对于内部治疗,将化合物悬浮于软明胶胶囊剂的油中,其在引入阴道口后易于崩解。
本发明的制剂的实例包括乳膏剂、软膏剂、散剂、洗剂等,阴道栓剂或相当的制剂,包括在内部体温下溶解的胶囊剂。
下面列出的实施例用于说明本发明而不限制其范围。
实施例1-苯并呋喃化合物的制备
阶段A.2-苯氧基-2’,4’-二甲氧基苯乙酮(a)的制备
将2-溴-2’,4’-二甲氧基苯乙酮(5g,19.1mmol)的25mL 2-丁酮溶液加入至苯酚(1.8g,19.1mmol)、K2CO3(2.6g,19.1mmol)和KI(41.5mg,0.25mmol)在20.0mL相同溶剂中的悬浮液中。然后将溶液回流20小时。将混合物过滤并且将溶剂真空除去。将获得的残留物溶于EtOAc中并且用10%的NaOH水溶液洗涤,然后用水洗涤。将有机萃取物经Na2SO4干燥,过滤并且真空蒸发。最后,将粗残留物用Et2O洗涤并且低压干燥,得到4.4g(产率:84%)标题化合物。
阶段B.2-(2’,4’-二甲氧基苯基)苯并呋喃(b)的制备
将12g多磷酸加入至阶段A获得的化合物(4.4g,16.2mmol)的130.0mL二甲苯溶液中。将混合物回流2小时,然后在环境温度下冷却。然后将溶液轻轻倒出并且低压蒸发。将产生的残留物(3.7g,产率:90%)用于下一阶段而无需进一步纯化。
阶段C.2-(2’,4’-二羟基苯基)苯并呋喃(1)的制备
将阶段B制备的化合物(3.7g,14.5mmol)和盐酸吡啶(11.1g,96.4mmol)的混合物加热至225℃达45分钟。将形成的红色产物倾倒入10%HCl中。将混合物用EtOAc反复洗涤;将合并的有机层经Na2SO4干燥并且蒸发。将残留物通过柱色谱(己烷/EtOAc=7∶3)纯化以提供。从苯中结晶后以41%的产率(1.36g)获得最终化合物。
制剂实施例1
插入阴道口的软明胶胶囊剂的油状混悬液
博落回的亲脂提取物(75%) 10mg
2,4-二羟基苯基-3-苯并呋喃 10mg
大豆卵磷脂 60mg
蜂蜡 50mg
植物油适量至 800mg
制剂实施例2
乳膏剂(水包油乳剂)
秘鲁拉坦尼的提取物 0.4g
博落回生物碱级分 0.4g
花椒的亲脂提取物 0.2g
丙二醇 10.00g
肉豆蔻酸异丙酯 5.00g
鲸蜡醇 5.00g
聚山梨酯80 3.00g
卡波姆 0.40g
对羟基苯甲酸甲酯 0.10g
对羟基苯甲酸丙酯 0.05g
纯化水适量至 100g
制剂实施例3
阴道栓剂
2,4-二羟基苯基-3-苯并呋喃 10mg
博落回属(Macleaya)生物碱级分 3mg
脂肪酸甘油酯适量至 2.0g
Claims (11)
2.权利要求1的组合物,其包含:
a)苯并菲啶生物碱,选自血根碱、白屈菜赤碱或白屈菜碱或其衍生物;和
b)如上文指定的苯并呋喃化合物;
并且可能包含
c)花椒或狭叶松果菊的提取物。
3.权利要求1和2的组合物,其中多种组分在下列区间内存在(每单位剂量以重量计):
a)苯并菲啶生物碱:从0.15mg至15mg;和
b)苯并呋喃化合物:从0.2至25mg;
并且可能包含
c)花椒或狭叶松果菊的提取物:从0.1至10mg。
4.权利要求3的组合物,其中多种组分在下列区间内存在(每单位剂量以重量计):
a)苯并菲啶生物碱:从0.4至10mg;和/或
b)苯并呋喃化合物:从0.4至10mg;
并且可能包含
c)花椒或狭叶松果菊的提取物:从0.2至5mg。
5.前述权利要求的组合物,其中苯并菲啶生物碱血根碱和白屈菜赤碱以游离或成盐形式存在,例如以基本上纯的形式或者以血根草、博落回、小果博落回或白屈菜的提取物形式存在。
6.权利要求5的组合物,其中苯并菲啶生物碱以与淡黄霉酸成盐的形式存在。
7.权利要求1-4的组合物,其中式1和2的苯并呋喃化合物以本身存在或者以包含它们的提取物的形式存在。
8.权利要求7的组合物,其中苯并呋喃化合物以秘鲁拉坦尼、Eupomatia laurina和胡椒物种的提取物形式存在。
9.权利要求1至8中任意一项的制剂,其是水/油乳剂、软明胶胶囊剂、阴道栓剂或相当的制剂、乳膏剂、软膏剂、散剂、洗剂等形式。
10.以下物质在制备用于治疗阴道感染和产生的炎性状态的局部制剂中的用途:
a)苯并菲啶生物碱;和
b)苯并呋喃化合物;
并且可能包含
c)花椒或狭叶松果菊的提取物。
11.权利要求10的用途,其中阴道感染是与炎性问题有关的多种起源的阴道炎。
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ITMI20080751 ITMI20080751A1 (it) | 2008-04-24 | 2008-04-24 | Composizioni per il trattamento delle infezioni vaginali con infiammazione cronica |
ITMI2008A000751 | 2008-04-24 | ||
EP08425421.8 | 2008-06-12 | ||
EP08425421A EP2133079B1 (en) | 2008-06-12 | 2008-06-12 | Compositions for the treatment of vaginal infections with chronic inflammation |
PCT/EP2009/002516 WO2009129927A1 (en) | 2008-04-24 | 2009-04-06 | Compositions for the treatment of vaginal infections with chronic inflammation |
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CA (1) | CA2722211C (zh) |
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MX2012013339A (es) * | 2010-05-18 | 2013-01-24 | Indena Spa | Composiciones para el tratamiento de los transtornos ginecologicos. |
US20220280679A1 (en) * | 2021-03-08 | 2022-09-08 | Innovation Chemical and Enviromental Technologies, Inc. | Prophylactic Gel Compositions and Use as Barriers to Bacterial and Viral Colonization |
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US3944672A (en) * | 1972-12-13 | 1976-03-16 | Schering Corporation | Method for treating microbial infections |
AU548560B2 (en) * | 1980-05-20 | 1985-12-19 | Vipont Laboratories Inc. | Benzophenanthridine alkaloids as antimicrobial agents |
CH660456A5 (de) * | 1984-02-02 | 1987-04-30 | Bupharm Ag | Therapeutisches mittel zur bekaempfung von durch herpesviren verursachten infektionen. |
US5175000A (en) * | 1987-06-30 | 1992-12-29 | Vipont Pharmaceutical, Inc. | Free amine benzophenanthridine alkaloid compositions |
US5066483A (en) * | 1989-03-13 | 1991-11-19 | Vipont Pharmaceutical, Inc. | Oral rinse compositions |
DE69019517T2 (de) * | 1990-07-05 | 1995-12-14 | Indena Spa | Neolignanderivatkomplexen mit Phospolipiden, deren Verwendung und sie enthaltende pharmazeutische und kosmetische Zusammensetzungen. |
US6355684B1 (en) * | 1990-10-11 | 2002-03-12 | Meryl J. Squires | Antimicrobial treatment for herpes simplex virus and other infectious diseases |
US5612330A (en) * | 1994-03-07 | 1997-03-18 | Warner-Lambert Company | Methods for inhibiting and controlling viral growth |
IT1284970B1 (it) * | 1996-10-17 | 1998-05-28 | Indena Spa | Formulazioni farmaceutiche e cosmetiche ad attivita' antimicrobica |
US6267996B1 (en) * | 1996-10-17 | 2001-07-31 | Indena S.P.A | Pharmaceutical and cosmetic formulations with antimicrobial activity |
US20030017207A1 (en) * | 2001-05-01 | 2003-01-23 | Lin Shun Y. | Compositions and methods for treating vulvovaginitis and vaginosis |
US20040023848A1 (en) * | 2002-02-27 | 2004-02-05 | Thomas Boehm | Compositions for the treatment, prevention, and diagnosis of gastrointestinal and other infections |
EP1882473A1 (en) * | 2006-07-28 | 2008-01-30 | Indena S.P.A. | Use of anthocyanosides to prepare formulations for the treatment of mucositis induced by antitumoral drugs |
-
2009
- 2009-04-06 JP JP2011505397A patent/JP5677936B2/ja not_active Expired - Fee Related
- 2009-04-06 US US12/988,897 patent/US20110104313A1/en not_active Abandoned
- 2009-04-06 AU AU2009240295A patent/AU2009240295B2/en not_active Ceased
- 2009-04-06 EP EP09735815A patent/EP2278971A1/en not_active Withdrawn
- 2009-04-06 CN CN2009801140228A patent/CN102014906A/zh active Pending
- 2009-04-06 KR KR1020107023537A patent/KR20100134686A/ko not_active Application Discontinuation
- 2009-04-06 RU RU2010143226/15A patent/RU2504379C2/ru active
- 2009-04-06 CA CA2722211A patent/CA2722211C/en active Active
- 2009-04-06 WO PCT/EP2009/002516 patent/WO2009129927A1/en active Application Filing
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2010
- 2010-10-21 IL IL208849A patent/IL208849A/en active IP Right Grant
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KR20100134686A (ko) | 2010-12-23 |
JP5677936B2 (ja) | 2015-02-25 |
WO2009129927A8 (en) | 2009-12-30 |
US20110104313A1 (en) | 2011-05-05 |
CA2722211C (en) | 2017-02-14 |
EP2278971A1 (en) | 2011-02-02 |
AU2009240295A1 (en) | 2009-10-29 |
AU2009240295B2 (en) | 2014-03-06 |
RU2504379C2 (ru) | 2014-01-20 |
RU2010143226A (ru) | 2012-05-27 |
WO2009129927A1 (en) | 2009-10-29 |
CA2722211A1 (en) | 2009-10-29 |
JP2011518793A (ja) | 2011-06-30 |
IL208849A0 (en) | 2011-01-31 |
IL208849A (en) | 2015-03-31 |
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