CN1200673C - 抗真菌指甲油组合物 - Google Patents
抗真菌指甲油组合物 Download PDFInfo
- Publication number
- CN1200673C CN1200673C CNB018145744A CN01814574A CN1200673C CN 1200673 C CN1200673 C CN 1200673C CN B018145744 A CNB018145744 A CN B018145744A CN 01814574 A CN01814574 A CN 01814574A CN 1200673 C CN1200673 C CN 1200673C
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- chitosan
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- Expired - Lifetime
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Abstract
本发明涉及一种组合物及其用作指甲油的用途，其中该组合物含有：a)至少一种抗真菌剂，和b)至少一种成膜剂，其中组分b)是选自羟烷基脱乙酰壳多糖和羧烷基脱乙酰壳多糖的脱乙酰壳多糖衍生物。本发明还涉及选自羟烷基脱乙酰壳多糖和羧烷基脱乙酰壳多糖的水溶性成膜剂在指甲油中用作添加剂的用途。
Description
本发明涉及一种组合物及其用作指甲油的用途，其中该组合物含有至少一种抗真菌剂和至少一种成膜剂。本发明还涉及水溶性成膜剂在指甲油中用作添加剂的用途。
指甲和指甲连接部位的真菌病(甲癣)是一种常见病，并且在许多情况下不能完全治愈。甲癣常常是由皮真菌引起的，但也会由酵母菌和念珠菌引起。其中包括甲板被皮真菌感染，以及指甲被包括酵母菌或霉菌在内的各种真菌感染。导致指甲感染最常见的皮真菌是深红色发癣菌、须发癣菌和絮状表皮癣菌。
循环障碍、多汗、戴橡胶手套或用橡胶鞋垫、修指甲损伤以及频繁与水和皂类接触均会促使甲癣生长。易感职业人群包括运动员和医药领域工作人员。
治疗甲癣的可行方式包括口服应用抗真菌剂的系统治疗、对感染的指甲进行手术或化学处理以及将抗真菌剂局部涂敷在指甲上对指甲进行局部治疗。局部治疗比其它方式更有利，因其无侵害性，副作用少，并且可局部作用于指甲。
现有技术中提出了多种用于局部应用活性成分的组合物。例如，WO00/15202中公开了局部用于指甲的产品，其可用于治疗甲癣。该产品中不含水，含有一种或多种活性成分、作为载体的乳酸、酒石酸或柠檬酸的C1-C4烷基酯以及任选的生理可接受的辅剂。优选的局部给药形式是溶液剂，但也可以是酊剂、乳剂、凝胶、膏霜和糊剂。
近来提出的另一种局部给药方式是在指甲油中加入抗真菌剂，然后将其涂敷在指甲和指甲连接处。在早期的组合物中，出现的问题在于其难于有效地治疗严重的甲癣，这可能是由于指甲油干化并形成固体组合物后活性成分的生物利用度不足引起的。
最近，有人提出了试图解决上述问题的指甲油。例如，WO99/39680公开了一种抗真菌指甲油。该指甲油适用于治疗甲癣，并且含有有效量的环吡酮及其可药用盐。该指甲油的特征在于其中采用水不溶性成膜聚合物形成硬的、透明的防水膜以保护被治疗的指甲。类似的，在EP-A-226984中描述了一种抗真菌指甲油，其中含有1-羟基-2-吡啶酮例如环吡酮胺、水不溶性成膜剂和生理可接受的溶剂，以及常用于化妆品的添加剂。
尽管这些常用的指甲油适用于预防和治疗指甲和指甲连接处的真菌病，其仍在皮肤病学和美学方面存在某些缺点。例如，在涂敷指甲油特别是涂敷在甲周部位上时会引起灼痛。为除去指甲油，不得不采用有机溶剂，其会对与其接触的邻近皮肤产生不利影响。因此，这些指甲油不适用于皮肤敏感的患者。此外，指甲油会形成有光泽的、粘的和发亮的涂层，这并不是所有真菌病患者都愿意接受的。由于其亮泽特性，市售的抗真菌指甲油还易于开裂。此外，由于其组分的特性，常规的指甲油制剂不能令水分和空气渗透。这会导致封闭的药物治疗，这在治疗真菌病时是不利的。
因此，本发明的目的是提供一种指甲油组合物，其可克服上述缺点，易于配制、制备和贮存，并可提供良好的抗真菌效果。
该目的是通过如下组合物达到的，该组合物中含有：
a)至少一种抗真菌剂，和
b)至少一种水溶性成膜剂。
此外，本发明还涉及所述组合物用作指甲油的用途。
本发明还涉及水溶性成膜剂在指甲油中用作添加剂的用途。
本发明的组合物包含作为组分a)的至少一种抗真菌剂，其可选自各种已知的合成或天然来源的抗真菌剂。该活性成分可以为游离形式，例如为游离酸或游离碱的形式，或为其盐的形式。其实例包括：
-1-羟基-2-吡啶酮化合物及其盐，例如，环吡酮、利洛吡司、吡罗克酮、环吡酮胺和US-A-4957730中所公开的1-羟基-2-吡啶酮化合物；
-咪唑衍生物及其盐，例如，克霉唑、益康唑、异康唑、酮康唑、咪康唑、噻康唑、联苯苄唑、芬替康唑和奥昔康唑；
-多烯衍生物及其盐，例如制霉菌素、那他霉素和两性霉素；
-烯丙基胺衍生物及其盐，例如萘替芬和特比萘芬；
-三唑衍生物及其盐，例如氟康唑、伊曲康唑、特康唑、伏立康唑(voriconazole)；
-吗啉衍生物及其盐，例如阿莫罗芬和US-A-5120530中所公开的吗啉化合物。
-灰黄霉素及相关化合物，例如灰黄霉素；
-酸性化合物，例如十一碳烯酸及其盐，特别是十一碳烯酸锌盐和钙盐；
-托萘酯及其盐；以及
-氟胞嘧啶及其盐。
抗真菌剂优选选自1-羟基-2-吡啶酮化合物及其盐。
抗真菌剂也可选自天然来源，特别是植物提取物。这类提取物的实例包括茶树油(Melaleuca alternifolia)、熏衣草油(Lavandula officinalischaix)和楝树叶提取物(Azadirachat indica)。
抗真菌剂可单用或与其它抗真菌剂联用。具体地说，如果抗真菌剂是天然来源的，优选以联用的形式应用。优选的混合物是共用的茶树油、熏衣草油和楝树叶提取物。
抗真菌剂(组分a))的用量根据其结构和抗菌活性、从涂层中释放的速率、在指甲中的扩散特性和渗透特性而有所不同。在本发明的组合物中，通常可以采用有效量(即有效杀灭感染性微生物的用量)的抗真菌剂，所述有效量一般可比平均抑菌浓度(MIC)高几倍、几十倍甚至上百倍。因此，优选组分a)的含量占组合物总重量的0.1-15％(重量)，更优选为0.3-15％(重量)，首选0.5-10％(重量)。
本发明的组合物中还可含有作为组分b)的至少一种水溶性成膜剂。水溶性成膜剂可选自本领域已知的各种水溶性成膜剂。成膜剂的定义(参见DIN 55945(12/1998))是指成膜(即薄的涂层或外层)所必需的粘合剂组分。
本文中的术语“水溶性的”是指成膜剂可与水充分相容，从而在20℃下，1份成膜剂可溶于100份或100份以下、优选50份或50份以下、更优选30份或30份以下、最优选10份或10份以下的水中。
由于水溶性成膜剂的存在，可以使用各种溶剂，因此可以确保药物易于涂敷，并且简化制剂的贮存。由于成膜剂可与各种溶剂共用，因此可对配方进行选择，从而使得本发明的指甲油组合物不会产生灼痛，无需采用有机溶剂即可轻易去除并且可在甲周部位上涂用(在甲周部位，由于存在菌丝而有利于真菌的增殖)。因此本发明的组合物适于用作指甲油，甚至适用于那些因敏感性皮肤而会对某些有机溶剂产生不利反应的患者。此外，用于本发明组合物的水溶性成膜剂可形成无光泽、不粘着和可塑性很高的涂层，该涂层具有大多数真菌病患者所喜爱的无光泽和天然的外观。更有利的是，当所请求保护的组合物用作指甲油时，可渗透水分和空气，因此是治疗真菌病的有效手段。
对于适用于本发明的成膜剂，一般可采用水溶性的合成或天然来源的大分子化合物或经功能基改性使其具有水溶性的化合物。优选采用天然聚合物的水溶性衍生物，或天然聚合物的衍生物。特别优选脱乙酰壳多糖的水溶性衍生物，脱乙酰壳多糖是壳多糖的脱酰产物，壳多糖本身是不溶于水的。壳多糖是一种天然物质，它构成例如甲壳纲动物和许多昆虫的外壳。
特别适用的是羟烷基脱乙酰壳多糖和羧烷基脱乙酰壳多糖。羟烷基脱乙酰壳多糖包括经含1-3个羟基的C1-6烷基改性的脱乙酰壳多糖。其实例可以提及羟丙基脱乙酰壳多糖。羧烷基脱乙酰壳多糖包括经含1-3个羧基的C1-6烷基改性的脱乙酰壳多糖。其实例可以提及羧甲基脱乙酰壳多糖。
可采用任何用量的水溶性成膜剂(组分b))，只要所请求保护的组合物可成膜即可。组分b)的用量一般占组合物总重量的0.1-10％(重量)，更优选为0.3-8％(重量)，最优选为0.5-5％(重量)。
本发明的组合物通常还含有作为组分c)的至少一种生理可接受的溶剂。该溶剂一般是含水溶剂，以避免指甲和相邻皮肤频繁和反复地与侵害性有机溶剂接触。因此，生理可接受的溶剂包括水，以及水与助溶剂的混合物。
本发明组合物中的可与水共用的助溶剂并非特别关键，但可选自本领域已知的常规的生理学上安全的有机溶剂。助溶剂一般是亲水性溶剂，并且优选选自醇类。
适用的醇是含1-3个羟基和2-6个碳原子的支链或直链醇，其中羟基可部分转化成醚。特别适用的醇是乙醇、1-丙醇、2-丙醇(异丙醇)。其中特别适用的是乙醇或异丙醇。本发明的组合物中，可与水共用的助溶剂的总量优选能令其充分挥发，使指甲油具有适宜的干化时间。通常的干化时间(即触感干燥所需的时间)应少于约5分钟，优选少于约2分钟。
当水与一种或多种助溶剂共用时，要求各溶剂彼此相容并可形成透明溶液，形成的溶液贮存稳定，不会随时间变化而出现相分离。此外，用于本发明的溶剂体系应不仅能提供均匀的蒸发速率和良好的稳定性，而且还应能提供良好的流动粘度特性，以使指甲油易于涂敷。
所述的至少一种生理可接受的溶剂(组分c))通常以能够达到上述特性的适宜用量应用。优选本发明组合物中组分c)的含量占组合物总重量的40-99.8％(重量)，更优选为60-99％(重量)，最优选80-95％(重量)。组分c)中的含水量一般占组分c)的5-60％(重量)，优选10-40％(重量)，以达到所需特性。因此，为达到上述特性，与水共用的助溶剂的量一般占组分c)重量的20-95％(重量)，优选60-90％(重量)。
除抗真菌剂之外，本发明的组合物中还可含有其它活性成分，例如抗生素、抗炎剂、杀菌剂和/或局部麻醉剂。
适用于本发明组合物的抗生素的实例中可列举的包括：阿莫西林、氨苄西林、苄青霉素、头孢克洛、头孢羟氨苄、头孢氨苄、氯霉素、环丙沙星、克拉维酸、克林霉素、多西环素、依诺沙星、氟氯西林、卡那霉素、林可霉素、米诺环素、萘夫西林、萘啶酸、新霉素、诺氟沙星、氧氟沙星、苯唑西林、苯氧甲基青霉素、四环素以及甲氯环素磺基水杨酸盐。
这些抗生素可分别根据其在本领域中的常规用量应用。抗生素的用量一般为0.1-10％(重量)。
可用于本发明组合物的抗炎剂包括甾族和非甾族抗炎剂。
甾族抗炎剂的实例包括：21-乙酰氧基孕烯醇酮、阿氯米松或其二丙酸盐、阿尔孕酮、安西奈德、倍氯米松或其二丙酸盐、倍他米松及其盐，包括例如苯甲酸倍他米松、二丙酸倍他米松、倍他米松磷酸酯钠、倍他米松磷酸酯醋酸酯钠以及戊酸倍他米松；氯倍他索或其丙酸盐、氯可托龙新戊酸酯、氢化可的松及其盐，包括例如醋酸氢化可的松、丁酸氢化可的松、环戊丙酸氢化可的松、磷酸氢化可的松、氢化可的松磷酸钠、氢化可的松琥珀酸钠、叔丁醋酸氢化可的松和戊酸氢化可的松；醋酸可的松、地奈德、去羟米松、地塞米松及其盐，例如醋酸地塞米松和地塞米松磷酸钠；二醋酸二氟拉松、醋酸氟氢可的松、氟尼缩松、氟轻松、醋酸氟轻松、氟米龙、氟氢缩松、哈西奈德、甲羟松、甲泼尼龙及其盐，例如醋酸甲泼尼龙和甲泼尼龙琥珀酸钠；糠酸莫米松、乙酸帕拉米松、泼尼松龙及其盐，例如醋酸泼尼松龙、二乙胺醋泼尼松龙、泼尼松龙磷酸钠、泼尼松龙琥珀酸钠、泼尼松龙叔丁乙酯、泼尼松龙特戊酸酯；泼尼松、曲安西龙及其衍生物，例如曲安奈德、苯曲安奈德、二醋酸曲安西龙、己曲安奈德。
非甾族抗炎剂的实例包括：乙酰水杨酸、吲哚美辛、舒洛芬、保泰松、舒林酸、布洛芬、萘普生、酮洛芬、氟比洛芬、吡罗昔康和双氯芬酸。
这些抗炎剂可分别根据其在本领域中的常规用量应用。这些抗炎剂的用量一般为0.1-5％(重量)。
适用于本发明组合物中的杀菌剂包括：洁而灭、苄索氯铵、西曲溴铵、洗必太、克菌定、三氯卡班、三氯生、水杨酸、苯甲酸以及它们的盐、对羟基苯甲酸及其酯。
这些杀菌剂可分别根据其在本领域中的常规用量应用。这些杀菌剂的用量一般为0.01-5％(重量)。
适用于本发明组合物中的局部麻醉剂的实例包括：苯佐卡因、氨苯丁酯及其苦味酸盐、盐酸哌罗卡因、盐酸奥布卡因、盐酸丁卡因、盐酸利多卡因、盐酸辛可卡因、奥昔卡因、盐酸丙哌卡因、盐酸布比卡因、盐酸甲哌卡因、盐酸达克罗宁、盐酸福莫卡因、盐酸奎尼卡因、聚乙二醇单十二醚和苄醇。
这些局部麻醉剂可分别根据其在本领域中的常规用量应用。这些局部麻醉剂的用量一般为0.3-10％(重量)。
此外，本发明的组合物中还可含有其它常用于化妆用或药用指甲油中的添加剂，特别是渗透促进剂。渗透促进剂包括本领域已知的各种可促进药物活性化合物渗透通过皮肤或指甲的化合物。换言之，渗透促进剂可促进药品的深度扩散。适宜的渗透促进剂包括：乙酸乙酯、二甲基亚砜(DMSO)、二甲基乙酰胺以及在WO99/39680中公开的那些渗透促进剂。特别优选乙酸乙酯。
渗透促进剂的用量可占组合物总重量的0-10％(重量)，优选0.1-8％(重量)，最优选1-5％(重量)。
本发明的组合物中还可含有作为另一类辅剂的鲸蜡-硬脂醇。业已发现，鲸蜡-硬脂醇的存在可有效地防止抗真菌剂的可能的结晶现象。出于美观的考虑不希望出现抗真菌剂结晶现象，因为其会在指甲油中形成白色污迹。更重要的是，如果抗真菌剂析出结晶，抗真菌剂的生物利用度会急剧降低。
优选鲸蜡-硬脂醇的用量占组合物总重量的0-5％(重量)，更优选为0.1-3％(重量)，最优选为0.5-1.5％(重量)。
其它常用于化妆用或药用指甲油中的常规添加剂包括：沉降抑制剂、螯合剂、抗氧化剂、硅酸盐、芳香物质、润湿剂、羊毛脂衍生物、光稳定剂和抗菌物质。
可采用常用于指甲油领域的典型工序制备本发明的组合物。具体地说，可通过常规混合技术，将至少一种抗真菌剂和至少一种水溶性成膜剂与溶剂或溶剂混合物以及其它液体组分同时或分别进行接触混合。对各组分的加入顺序没有特殊要求。优选进行搅拌以确保各成分的完全溶解。如果有固体形式的组分，特别优选向液体组分中逐渐加入该组分以防止结块。
将本发明的组合物以薄膜的形式涂敷在指甲上，以预防和/或治疗甲癣和其它指甲真菌病。一般需要根据感染的严重程度、活性成分的含量和患者指甲的状况，在数周或数月的时间内反复涂敷指甲油。也可预防性地反复涂敷该指甲油，以预防甲癣和其它指甲真菌病。抗真菌剂可以很好地渗入指甲层和皮肤中，并且不易被除去。因此，抗真菌指甲油无需十分频繁地使用。所用的指甲油中一般含有足量的可扩散到指甲和皮肤内的活性成分，从而每日仅需重复涂敷抗真菌剂一次或两次以确保其功效。
本发明优选的成膜剂在与抗真菌剂共用时，具有意外的协同作用。该作用对于羟烷基脱乙酰壳多糖和羧烷基脱乙酰壳多糖特别明显。此外，当采用环吡酮或其盐作为抗真菌剂时，也明确存在该协同作用。
尽管在适宜的体系中测试时成膜剂本身没有抗真菌作用，但当与本发明的成膜剂共用时，抗真菌剂(优选环吡酮)本身的抗真菌作用会增强。
以下实施例用于说明本发明的组合物及其作为指甲油的应用。所有用量百分比均以重量百分比计。
实施例1
制备下述含8％环吡酮的指甲油组合物。
环吡酮 8g
乙醇95％ 73g
净化水 13g
乙酸乙酯 4g
羟丙基脱乙酰壳多糖 1g
鲸蜡-硬脂醇
1g
100g
采用带有搅拌器的适宜密封容器制备该制剂。向该容器中加入乙醇、去离子水和乙酸乙酯以形成混合物。然后加入鲸蜡-硬脂醇，待其溶解后，加入环吡酮。最后加入羟丙基脱乙酰壳多糖，搅拌所得混合物24小时或直至溶解。
所得的指甲油组合物即使经长期保存仍保持透明和均质的外观。此外，指甲油可形成无光泽、不粘着和可塑性的涂层，其可牢固地附着在指甲上。涂敷时，该可渗透水分和空气的指甲油不会令相邻的皮肤或甲周部位出现灼痛或产生刺激。
实施例2
制备下述含8％环吡酮胺的指甲油组合物。
环吡酮胺 8g
乙醇 57g
净化水 33g
羟丙基脱乙酰壳多糖 1g
鲸蜡-硬脂醇
1g
100g
按照实施例1中所述的方法制备该组合物，所得的指甲油具有实施例1中所提到的相同特性。
实施例3
制备下述含5％阿莫罗芬盐酸盐的指甲油组合物。
阿莫罗芬盐酸盐 5％
羟丙基脱乙酰壳多糖 1％
乙醇 70％
乙酸乙酯 4％
鲸蜡-硬脂醇 1％
净化水 加至 100％
按照实施例1中所述的方法制备该组合物，所得的指甲油具有实施例1中所提到的相同特性。
实施例4
制备下述含8％环吡酮的指甲油组合物。
环吡酮 8％
羧甲基脱乙酰壳多糖 1％
乙醇 60％
乙酸乙酯 2％
鲸蜡-硬脂醇 0.5％
净化水 加至 100％
按照实施例1中所述的方法制备该组合物，所得的指甲油具有实施例1中所提到的相同特性。
实施例5
制备下述含8％环吡酮和2％一水合盐酸利多卡因的指甲油组合物。
环吡酮 8％
一水合盐酸利多卡因 2％
羟丙基脱乙酰壳多糖 1％
乙醇 70％
乙酸乙酯 4％
鲸蜡-硬脂醇 1％
净化水 加至 100％
按照实施例1中所述的方法制备该组合物，所得的指甲油具有实施例1中所提到的相同特性。
实施例6
制备下述含8％环吡酮和1.46％甲氯环素5-磺基水杨酸盐的指甲油组合物。
环吡酮 8％
甲氯环素5-磺基水杨酸盐 1.46％
羟丙基脱乙酰壳多糖 1％
乙醇 70％
乙酸乙酯 4％
鲸蜡-硬脂醇 1％
净化水 加至 100％
按照实施例1中所述的方法制备该组合物，所得的指甲油具有实施例1中所提到的相同特性。
实施例7
制备下述含8％环吡酮、0.15％地塞米松磷酸二钠和0.5％硫酸新霉素的指甲油组合物。
环吡酮 8％
地塞米松磷酸二钠 0.15％
硫酸新霉素 0.5％
羟丙基脱乙酰壳多糖 1％
乙醇 70％
鲸蜡-硬脂醇 1％
异丙醇 5％
净化水 加至 100％
实施例8
制备下述含0.2％硝酸咪康唑的指甲油组合物。
硝酸咪康唑 0.2％
羟丙基脱乙酰壳多糖 1％
乙醇 73％
乙酸乙酯 4％
鲸蜡-硬脂醇 1％
净化水 加至 100％
按照实施例1中所述的方法制备该组合物，所得的指甲油具有实施例1中所提到的相同特性。
实施例9
渗透性研究
将实施例1中所述的含环吡酮的指甲油涂敷在3名成人志愿者的手指甲上，通过将涂敷后立即测出的右手(未清洗)数值与涂敷6小时后经清洗的左手数值相比来确定指甲上活性成分的浓度。所得的结果列于表1中。发现其对指甲具有良好的渗透性，因为在涂敷6小时后清洗指甲后仍有18-35％涂敷剂量的抗真菌剂存在于指甲中。由此表明，尽管成膜剂是水溶性的，本发明的组合物仍适于用作抗真菌指甲油。
实施例10
在标准平板上按照标准程序测定对人甲癣病原体的抑制作用。
将环吡酮(8％)本身、羟丙基脱乙酰壳多糖(1％)本身和这两种化合物(分别为8％和1％)联用对于30℃下在沙氏葡糖培养基上生长的须发癣菌的抗真菌作用进行比较，得到以下结果(各情况下的涂敷量为10、20和30μl)：
羟丙基脱乙酰壳多糖： 无抑制作用
环吡酮： 良好的抑制作用
环吡酮加羟丙基脱乙酰壳多糖：比环吡酮本身更好的抑制作用
表1
| 浓度值(μg/mg指甲) | |||||||||
| 被测者 | V01 | V02 | V03 | 平均值 | 比值 | ||||
| 手 | 左 | 右 | 左 | 右 | 左 | 右 | 左 | 右 | ％ |
| 手指拇指食指中指无名指小指 | 0.390.780.761.351.12 | 2.064.644.525.723.81 | 0.971.830.783.162.84 | 3.983.025.065.993.49 | 0.460.580.661.291.79 | 1.742.282.674.824.71 | 0.611.060.731.931.92 | 2.593.314.085.517.34 | 23.3932.0917.9635.0926.12 |
注：涂敷指甲油6小时后清洗左手
Claims (10)
1.一种指甲油组合物，其中含有：
a)至少一种抗真菌剂，和
b)至少一种水溶性成膜剂，
其中组分b)是选自羟烷基脱乙酰壳多糖和羧烷基脱乙酰壳多糖的脱乙酰壳多糖衍生物。
2.权利要求1的组合物，其中组分a)的含量为0.1-15％(重量)。
3.权利要求1的组合物，其中组分a)选自：1-羟基-2-吡啶酮化合物、咪唑衍生物、多烯衍生物、烯丙胺衍生物、三唑衍生物、吗啉衍生物、灰黄霉素类化合物、酸性化合物、托萘酯、氟胞嘧啶以及它们的盐。
4.权利要求1-3中任一权利要求的组合物，其中组分a)选自环吡酮或其盐、咪康唑或其盐、阿莫罗芬或其盐和特比萘芬或其盐。
5.权利要求1-3中任一权利要求的组合物，其中组分b)的含量为0.1-10％(重量)。
6.权利要求1-3中任一权利要求的组合物，其中组分b)是羟丙基脱乙酰壳多糖。
7.权利要求1-3中任一权利要求的组合物，其中还含有：
c)至少一种生理可接受的溶剂。
8.权利要求2的组合物，其中组分a)选自：1-羟基-2-吡啶酮化合物、咪唑衍生物、多烯衍生物、烯丙胺衍生物、三唑衍生物、吗啉衍生物、灰黄霉素类化合物、酸性化合物、托萘酯、氟胞嘧啶以及它们的盐。
9.权利要求4的组合物，其中含有：
c)至少一种生理可接受的溶剂。
10.权利要求5的组合物，其中含有：
c)至少一种生理可接受的溶剂。
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| US20240100004A9 (en) * | 2015-08-05 | 2024-03-28 | Cmpd Licensing, Llc | Topical compositions and methods of formulating same |
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