CN110944669A - 新的抗真菌组合物 - Google Patents
新的抗真菌组合物 Download PDFInfo
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- CN110944669A CN110944669A CN201880045113.XA CN201880045113A CN110944669A CN 110944669 A CN110944669 A CN 110944669A CN 201880045113 A CN201880045113 A CN 201880045113A CN 110944669 A CN110944669 A CN 110944669A
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Abstract
公开了用于设计局部用于治疗指甲真菌感染的组合物/制剂，其包含抗真菌化合物与角质溶解药和一种或多种阳离子聚合物，所述一种或多种阳离子聚合物具有对指甲角蛋白的粘附活性。所述组合物/制剂在角蛋白组织表面上形成物理屏障，其确保抗真菌化合物长期粘附于角蛋白表面，由此提供用于穿透的高浓度梯度和更大的效能。
Description
发明领域
本发明涉及用于局部治疗指甲真菌感染的组合物，该组合物包含法国百里香(Thymus vulgaris)精油、1，2-癸二醇、角质溶解药和对指甲和皮肤的角蛋白具有粘附活性的阳离子聚合物。
由法国百里香精油和1，2-癸二醇组成的组合表现出相当令人意外的协同抗真菌作用。
阳离子聚合物在角蛋白组织的表面上形成物理屏障，从而确保了抗真菌化合物对角蛋白表面的长期粘附，由此为穿透提供了高浓度梯度和更高的效能。
发明背景
甲癣是由皮肤癣菌真菌、酵母菌或霉菌导致的指甲感染。指甲真菌感染引起患者功能和美观上的问题，导致其个人和工作生活出现困难(Wollina U等人，Deutsch ArztblInt.2016 Jul 25；113(29-30)：509-18)。
甲癣在全世界范围内很普遍(Sang-Ha Kim等人，Osong Public Health ResPerspect 20156(6)，341e345)。在欧洲和美国，其流行病学发病率为4.3％，住院人群中的发病率更高，为8.9％。发病率随年龄增长而增加，并且在65岁以上人群中发病率最高。最常见的引起甲癣的病原体是红色毛癣菌(Trichophyton rubrum)，其为一种在约65％的病例中发现的皮肤癣菌真菌。在13.3％的病例中发现了霉菌，在21.1％的病例中发现了酵母菌。
近来，致病性酵母越来越多地被诊断为通常导致甲癣。例如，白色假丝酵母(Candida albicans)引起慢性念珠菌病，其涉及整个指甲器官。
非皮肤癣菌真菌也越来越多地被诊断为引起甲癣。例如，帚霉属物种(Scopulariopsis spp.)引起趾甲甲癣。
真菌感染可以在家庭成员之间传播，可以由一个配偶传播给另一方，也可以由父母传播给孩子。甲癣的诱发因素包括指甲外伤、高龄和血管疾病。
甲癣的治疗通常需要几个月的时间。复发可在感染根除后一年或一年以上发生，这很普遍，并且会影响所有成功治疗患者的一半以上。文献中引用的复发/再感染百分比为20-25％，复发率在6.5-53％之间。
考虑到其局限性作用，局部治疗是非常期望的，因为它引起最小的全身性不良反应并可以改善对治疗的依从性。
当前使用的局部治疗主要用于：(1)疾病的轻度或中度阶段；(2)与其他全身性药物联合使用；(3)预防复发；(4)患者非口服抗真菌治疗的良好候选者的病例中(Tosti A，Elewski BE.，Skin Appendage Disord.，2016年9月；2(1-2)：83-87.Epub 2016年9月14日；Faergemann J，Swanbeck G.，Mycoses，1989年10月；32(10)：536)。
为了有效，局部用药必须穿透并积聚在指甲中。然而，指甲的角质化结构表现出对抗真菌药渗透的高抵抗力(Fernandez-Flores A.等人，Rom J Morphol Embryol.2014；55(2)：235-56)。
包含百里香精油或麝香草酚即作为百里香油主要成分的萜烯的抗真菌和抗菌组合物公开于US 2009028119、US 8945596和US 20060073218中。百里香精油及其包含的萜烯的抗真菌活性也描述在Ramsewak RS等人，Phytother Res.2003 Apr；17(4)：376-9，FloresF.C.，Mycopathologia，2016年2月，第181卷，1，pp 9-15和Fontenelle RO.等人，Molecules.2011年7月29日；16(8)：6422-31中。
1，2-癸二醇对导致皮肤真菌病和甲癣的微生物具有抗微生物活性，例如Tricophytum、表皮癣菌属和白色假丝酵母，其最低抑菌浓度极低(R.Pillai等人，Cosmetics Toiletries Journal，第123卷，pp.53-64，2008；N.Togashi等人，Molecules，第12卷，第2期，pp.139-148，2007；Schmaus G.等人，IFSCC Congress；Barcelona 2008)。
包含1，2-癸二醇的局部抗菌组合物描述在US 4294728和US 9511040中。
本发明的描述
目前已经发现如下的在单一制剂中的组合的用途：
1.特定抗微生物物质(对导致甲癣的酵母菌和霉菌具有活性)的组合
2.促进特定缔合抗微生物系统的经甲吸收的角质溶解系统
3.提供抗微生物和角质溶解与长期停留时间的粘附性阳离子聚合物在局部治疗甲癣中产生协同作用。
本发明的组合具体地包含：
a)由1，2-烷二醇、优选1，2-癸二醇和法国百里香精油组成的抗真菌药的协同作用组合；
b)促进特定抗微生物系统吸收和经甲渗透的至少一种角质溶解药；和
c)阳离子粘附性聚合物。
本发明的制剂在治疗主要导致甲癣的致病性酵母菌和致病性真菌中的有效性是出乎意料的，并且高于使用单独的抗真菌系统或单一角质溶解系统得到的有效性，这归因于三种化合物的协同作用和该制剂增加的停留时间。
根据本发明，选择携带正电荷的四元聚合物，从而中和负电荷(并因此减少表面静电)。优选的聚合物的实例包括聚季铵-7、山嵛基三甲基铵氯化物、山嵛基三甲基硫酸甲酯铵、西曲氯铵、硬脂氯化物、瓜尔羟丙将三甲基铵氯化物、羟丙基瓜尔羟丙基三甲基铵氯化物、二棕榈酰基乙基羟乙基硫酸甲酯铵、二氢化棕榈酰基乙基羟乙基硫酸甲酯铵、二硬脂酰基乙基羟乙基硫酸甲酯铵、二椰油基乙基羟乙基硫酸甲酯铵、羟乙基二甲基铵氯化物、椰油基二甲基铵羟丙基水解小麦蛋白、月桂基甲基葡萄糖醚-10羟丙基二甲基铵氯化物、硅酮季铵-17、硅酮季铵-22、三甲基甲硅烷氧基硅酸盐、C11-15 pareth-5、C11-15 pareth-9、苯基三甲基聚硅氧烷和季铵化蛋白质或蜂蜜。
尤其优选聚季铵-7，其为一种通过丙烯酰胺与二甲基二烯丙基铵氯化物聚合得到的阳离子聚合物。由于聚季铵-7与角蛋白的亲和力，所以聚季铵-7在各种化妆品(尤其是护发产品)中用作抗静电剂、成膜剂和固定剂，这归因于角蛋白和聚合物上带相反电荷的位点之间的静电相互作用。因此，聚合物继续粘附在角蛋白表面上，形成了持久的保护膜。
法国百里香精油特别适用于甲癣的局部治疗，因为它具有被证明的功效，耐药菌种出现的可能性低，和低比例的副作用。精油的主要成分是低分子量萜烯，它们很容易穿透指甲板，直到到达引起感染的真菌。麝香草酚是百里香精油中的主要萜烯，其为一种天然药物，可有效对抗引起皮肤和指甲真菌病的病原微生物。
本发明法国百里香精油和1，2-癸二醇的组合对真菌具有协同作用，其合并了角质溶解性和四元聚合物的成膜活性。
法国百里香精油在本发明的组合物中的存在浓度优选为0.1％-5％(w/w)，而1，2-癸二醇的存在浓度优选为0.1％-5％(w/w)。
粘附性阳离子聚合物、特别是聚季铵-7的浓度优选在0.1％-5％(w/w)。
角质溶解药的实例包括乳酸、乙醇酸、扁桃酸、水杨酸及其衍生物、乳糖酸及其衍生物、葡糖酸内酯及其衍生物、以及乳酸和尿素的混合物，优选乳酸和尿素的混合物，其浓度范围为30-50％(w/w)，尿素-乳酸的重量比为0.5∶1-1∶0.5。
该制剂还可以包含适合的载体或赋形剂，例如表面活性剂、溶剂、防腐剂、香料和pH调节剂。
本发明的组合物可以采取浆液、凝胶、油、水溶液、水-醇溶液或指甲油的形式。
本发明的组合物即使对其他抗真菌药具有抗性，也可用于局部治疗真菌甲癣。
本发明的组合物在指甲的角蛋白组织的表面上形成膜，该膜在表面上构成物理屏障，并确保抗真菌化合物对角蛋白表面的长期粘附，从而促进更好的穿透和出于意料的协同抗真菌作用。
在如下实施例中详细示例本发明。
实施例1-5制剂
实施例6：对真菌的最低抑菌浓度(MIC)的评价
评价了如下组合物对白色假丝酵母的MIC：
(0BIO4B010PON)，包含抗真菌成分(1，2-癸二醇和法国百里香精油)与尿素-乳酸角质溶解系统的组合物(实施例4)。
·(0BIO4B010PON/E)：仅包含尿素-乳酸角质溶解组合的组合物。
·(0BIO4B010PON/B)：仅包含1，2-癸二醇和尿素-乳酸角质溶解系统的组合物。
·(0BIO4B010PON/D)：仅包含法国百里香精油和尿素-乳酸角质溶解系统的组合物。
·安慰剂：不含抗真菌成分(1，2-癸二醇和法国百里香精油)且无尿素-乳酸角质溶解系统的组合物。
对于每种组合物，一式两份制备一组10个无菌试管。
将标量体积的待测组合物溶液和TSB(胰蛋白胨大豆肉汤)体积添加到每个无菌试管中，直到总体积为达到9.90ml。混合后，向每组中加入包含107CFU/ml的特定微生物悬液的等分试样100μl。使用涡旋混合试管内容物，并将试管在37℃+1℃下温育24小时。
还为每种待测组合物制备了阴性对照，其由含有最高浓度的测试产品和培养基的无菌试管组成。
还制备了用于微生物的阳性对照，该阳性对照由无菌试管组成，该试管包含100μl的微生物悬浮液等分试样，其中含107CFU/ml和9.90ml的适当肉汤。
MIC通过评估导致培养基混浊的微生物生长来确定。
一对含有最低稀释度产品的试管代表了用于测试微生物的产品的MIC，其中没有检测到可见的微生物生长(溶液不混浊)。
根据在2个实验中获得的值评估MIC。
·(0BIO4B010PON)：包含抗真菌成分(1，2-癸二醇和法国百里香精油)与尿素-乳酸角质溶解系统的组合物，其提供MIC＞1<2％)，
·(0BIO4B010PON/E)：仅包含尿素-乳酸角质溶解组合的组合物，其提供MIC＞5％-<6％，
·(0BIO4B010PON/B)：仅包含1，2-癸二醇和尿素-乳酸角质溶解系统的组合物，其提供MIC＞3％-<4％，
·(0BIO4B010PON/D)：仅包含法国百里香精油和尿素-乳酸角质溶解系统的组合物，其提供MIC＞3％-<4％，
·安慰剂：其提供MIC＞50％。
结果表明，含有抗真菌系统1，2-癸二醇和法国百里香精油与尿素-乳酸角质溶解系统和聚季铵-7的组合物与单独的安慰剂系统以及单一抗真菌和角质溶解系统相比具有令人惊讶的效果。
还针对红色毛癣菌ATCC 28188和顶孢帚霉(Scopulariopsis acremonium)ATCC58636评估并证实了本发明的组合物(0BIO4B010PON)，这些真菌主要负责皮肤和指甲的真菌感染。对红色毛癣菌ATCC 28188的MIC＞0.5％-<1％，而对顶孢帚霉ATCC 58636的MIC＞1％-<2％。
结果表明高水平的广谱抗真菌活性。这证实了三种系统(抗微生物、角质溶解和聚合物)组合的创新协同作用活性。
通过体外SEM测试来验证以下发明的成膜活性，该体外SEM测试分析了用式(0BIO4B010PON)处理或未处理的指甲基质的表面。
实施例7：建立组合物在指甲表面上形成浅表粘附屏障的能力的体外试验：处理的指甲的扫描电子显微镜(SEM)分析
在未经处理的指甲(NT)涂有一层金，以拍摄显微照片；用双层本发明的组合物涂覆处理过的指甲(T)，并在室温下干燥1天或在50℃下炉干。然后将两个样品都涂上一层金，以拍摄显微照片。
结果如图1-3中所示：图1显示未处理的指甲，图2显示产品在50℃下干燥，且图3显示产品在室温下干燥。
对上述示例的指甲部分进行的微量分析表明下表中列出的原子组成百分比。
比较(处理之前和之后)表明，指甲的表面组成在处理之后显著改变。处理后，碳和钙的百分比增加，而硫和硅(指甲组合物的典型含量)的浓度下降。所示的显微照片表明指甲被产品覆盖，因为电子束穿透材料达约为1微米深度。因此可以得出结论，所施用产品的厚度约为1微米，并且发现的少量硫和硅(部分由电子显微镜检测到)是由于下面的指甲组成所致。
Claims (7)
1.用于治疗甲癣的化妆品或皮肤病学组合物或医疗装置，其包含：
a)由1，2-癸二醇和法国百里香精油组成的抗真菌药的协同作用组合；
b)至少一种角质溶解药；和
c)粘附性阳离子聚合物。
2.根据权利要求1的组合物，其中粘附性阳离子聚合物为聚季铵-7，其浓度为0.1％-5％(w/w)。
3.根据权利要求1或2的组合物，包含1，2-癸二醇，其浓度为0.1％-5％(w/w)。
4.根据上述权利要求的一项或多项的组合物，其包含法国百里香精油，其浓度为0.1％-5％(w/w)。
5.根据上述权利要求的一项或多项的组合物，其中角质溶解药由尿素和乳酸的混合物组成。
6.根据权利要求5的组合物，其中尿素和乳酸的混合物的浓度在30-50％，并且尿素-乳酸的重量比为0.5∶1-1∶0.5。
7.根据上述权利要求的一项或多项的组合物，其为浆液、凝胶、水溶液、水-醇溶液或指甲油的形式。
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| US11389496B2 (en) | 2022-07-19 |
| EP3651802A1 (en) | 2020-05-20 |
| IL271907A (en) | 2020-02-27 |
| CA3068796A1 (en) | 2019-01-17 |
| US20200129577A1 (en) | 2020-04-30 |
| WO2019012412A1 (en) | 2019-01-17 |
| IT201700078091A1 (it) | 2019-01-11 |
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