CN1416353A - 抗感染活性成分组合以及它们用于局部治疗脚趾甲和手指甲真菌感染的应用 - Google Patents
抗感染活性成分组合以及它们用于局部治疗脚趾甲和手指甲真菌感染的应用 Download PDFInfo
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- CN1416353A CN1416353A CN01806207A CN01806207A CN1416353A CN 1416353 A CN1416353 A CN 1416353A CN 01806207 A CN01806207 A CN 01806207A CN 01806207 A CN01806207 A CN 01806207A CN 1416353 A CN1416353 A CN 1416353A
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Abstract
本发明涉及一种含有活性成分组合的制剂，所述组合包含局部抗真菌剂、系统抗真菌剂和生理学上安全的漆基质。本发明的制剂适于治疗甲真菌病。本发明优选使用不溶于水的漆制剂和至少一种来自伊曲康唑、特比萘芬和氟康唑或它们的盐的系统抗真菌剂与至少一种来自环吡酮胺、6－(2，4，4－三甲基戊基)－1－羟基－4－甲基－2(1H)－吡啶酮、阿莫罗芬和布特萘芬或它们的盐的局部抗真菌剂的组合。
Description
脚趾甲和手指甲真菌感染(甲真菌病)盛行于世。这种慢性病理实体不趋于自愈，且在高度发达的工业化国家中显得日益重要。甲真菌病是最普遍的指甲疾病，所占的比例高达40％。现有技术中记载的甲真菌病的流行率为2.8％-8.4％。目前指甲真菌病大约占所有皮真菌病的30％。疫学研究表明20％-30％脚癣患者还患有甲真菌病。
许多患者感到其社交受至限制，特别是当甲真菌病位于明显可见的手指甲处的时候。此外，这种病理事件导致触感、运动性和手工能力可能受到限制。治疗的需要还源于以下事实：作为感染源，甲真菌病导致这种疾病从指甲扩散到游离的皮肤。此外，它们还有感染逐渐增多的人口的风险。
20世纪90年代早期以来，已研制出大量的用于治疗甲真菌病的新治疗方法。一方面，它们是新的系统活性抗真菌剂；如伊曲康唑，参见美国专利4,267,179；(E)-N-(6，6-二甲基-2-庚烯-4-炔基)-N-甲基-1-萘-甲基胺，它还称为特比萘芬；和α-(2，4-二氟苯基)-α-(1H-1，2，4-三唑-1-基甲基)-1H-1，2，4-三唑-1-乙醇，它还称为氟康唑；以及局部使用的漆制剂，它使甲真菌病的治疗更有希望。
经验表明系统治疗有时可能导致严重、不期望的药物副作用，并在某些情况下可能危及生命，因为活性成分必须通过血液循环到达感染部位。
副作用和与其它药物的相互作用是不可避免的，尤其是在许多患多种病的年老患者身上。系统抗真菌药还具有其它不期望的伴随效果，如可以治疗的病原体范围中的裂隙，或在某些情况下的不安全的吸收。
最近进行的多项研究采用含抗真菌剂的漆制剂与系统伊曲康唑或特比萘芬组合治疗显著的甲真菌病患者。结果表明，对于严重甲真菌病的治疗，局部漆制剂与伊曲康唑或特比萘芬的系统活性的组合明显优于伊曲康唑和特比萘芬的单一治疗。迄今的结果表明，采用局部活性的含抗真菌剂的漆制剂和系统活性的抗真菌剂的组合治疗可以可观地降低甲真菌病系统治疗的不成功率。
在甲真菌病的治疗中采用局部活性抗真菌剂和系统活性抗真菌剂的组合治疗的缺点是即使采用这种治疗策略的患者仍存在所有可能与这种治疗相关的副作用系统的压力。这种治疗的另一个重要的缺点是少量的系统活性抗真菌剂到达脚趾甲或手指甲。此外，目前仅可能采用非常复杂和剧烈的方法将系统活性抗真菌剂如伊曲康唑以治疗有效浓度局部应用于脚趾甲或手指甲(参见WO 96/19186)。
本发明的目的在于提供了一种不具有已知的与所述的甲真菌病的局部/系统组合治疗有关的缺点的配方。
系统抗真菌剂如伊曲康唑仅在破坏指甲角蛋白中的硫桥并通过加入尿素之后才以充足的局部应用浓度渗透进入指甲(WO 96/19186)，与上述的技术偏见相反的是，已意外地发现漆基质中局部活性抗真菌剂与系统活性抗真菌剂的组合能够在局部应用后以治疗学有效浓度渗透进入并通过指甲。而不具有上述措施和所述添加。相比之下，用系统活性的抗真菌治疗的患者仅表现出脚趾甲或手指甲处的较低抗真菌剂浓度。
因此，本发明涉及包含在生理学上可接受的漆基质中的局部和系统抗真菌活性成分的组合的药剂。
本发明具体涉及一种包含以下的药剂：不溶于水的成膜剂，至少一种来自伊曲康唑、特比萘芬和氟康唑和/或伊曲康唑、特比萘芬和氟康唑的生理学耐受盐的系统抗真菌剂，和至少一种来自环吡酮胺、6-(2，4，4-三甲基戊基)-1-羟基-4-甲基-2(1H)-吡啶酮、阿莫罗芬和布特萘芬和/或环吡酮胺、6-(2，4，4-三甲基戊基)-1-羟基-4-甲基-2(1H)-吡啶酮、阿莫罗芬和布特萘芬的生理学耐受盐的局部抗真菌剂，或者一种以上上述抗真菌剂或其盐的混合物。
优选的药剂包括环吡酮胺(还称为6-环己基-1-羟基-4-甲基-2(1H)-吡啶酮)和伊曲康唑，或盐酸布特萘芬和氟康唑，或环吡酮胺和氟康唑，或盐酸阿莫罗芬和盐酸特比萘芬，作为抗真菌剂。
上述的局部或系统抗真菌剂可以自由形式或作为生理学耐受盐使用。如果有机碱用于此盐，则所用的碱包括低挥发性碱，如低分子量链烷醇胺如乙醇胺、二乙醇胺、N-乙基乙醇胺、N-甲基二乙醇胺、三乙醇胺、二乙基氨基乙醇、2-氨基-2-甲基-正丙醇、二甲基氨基丙醇、2-氨基-2-甲基丙二醇和三异丙醇胺。例如，可以提及的进一步的低挥发性碱为乙二胺、六亚甲基二胺、吗啉、哌啶、哌嗪、环己基胺、三丁基胺、十二烷基胺、N，N-二甲基十二烷基胺、硬脂酰胺、油胺、苄基胺、二苄基胺、N-乙基苄基胺、二甲基硬脂酰胺、N-甲基吗啉、N-甲基哌嗪、4-甲基环己基胺和N-羟基乙基吗啉。还可以使用氢氧化季铵盐，如三甲基苄基氢氧化铵、四甲基氢氧化铵或四乙基氢氧化铵，以及胍及其衍生物，特别是它的烷基化产物。但是，还可以使用诸如以下物质作为成盐剂：低分子量烷基胺，如甲基胺、乙基胺或三乙基胺。对根据本发明的化合物，还可以使用适宜的无机阳离子盐，如碱金属盐，例如钠、钾或铵盐，特别是盐酸盐；碱土金属盐，如镁或钙盐；以及带双电荷至带四电荷的阳离子的盐，如锌、铝或锆盐。
本发明还涉及在生理学上可接受的漆基质中的局部和系统抗真菌剂活性成分组合用于生产预防和治疗脚趾甲和手指甲真菌感染的药剂的应用。
本发明还涉及不溶于水的成膜剂，至少一种来自伊曲康唑、特比萘芬和氟康唑和/或伊曲康唑、特比萘芬和氟康唑的生理学耐受盐的系统抗真菌剂，和至少一种来自环吡酮胺、6-(2，4，4-三甲基戊基)-1-羟基-4-甲基-2(1H)-吡啶酮、阿莫罗芬、布特萘芬和/或环吡酮胺、6-(2，4，4-三甲基戊基)-1-羟基-4-甲基-2(1H)-吡啶酮、阿莫罗芬和布特萘芬的生理学耐受盐的局部抗真菌剂，或者一种以上上述抗真菌剂或其盐的混合物，用于生产预防和治疗脚趾甲和手指甲真菌感染的局部药剂的应用。
本发明漆制剂中局部和系统活性成分的含量取决于每种活性成分的结构，并因而取决于其从漆膜中的释放、其在指甲中的渗透特性和其抗真菌性能。
在本发明的治疗甲真菌病的药剂中，局部活性成分一般以0.25-20wt％，优选2-15wt％的量存在，所述的药剂作为指甲漆，即含溶剂的使用形式。“系统”活性成分的含量一般为0.05-10wt％，优选0.1-5wt％。
除了溶于溶剂或溶剂混合物中的活性成分作为必需成分以外，本发明的指甲漆还包含一种或多种在制剂干燥以后在指甲上形成不溶于水的膜的成膜剂。
适于作为成膜剂的物质的实例基于硝酸纤维素或生理学上可接受的聚合物，如常规用于化妆品的物质，优选与硝酸纤维素混合。例如，可以提及聚乙酸乙烯酯和部分水解的聚乙酸乙烯酯，一方为乙酸乙烯酯而另一方为丙烯酸或巴豆酸或马来酸单烷基酯的共聚物，一方为乙酸乙烯酯而另一方为巴豆酸和新癸酸乙烯酯，或巴豆酸和丙酸乙烯酯的三元共聚物，甲基乙烯基醚和马来酸单烷基酯，尤其是马来酸一丁酯的共聚物，脂肪酸乙烯酯和丙烯酸或甲基丙烯酸的共聚物，N-乙烯吡咯烷酮、甲基丙烯酸和甲基丙烯酸烷基酯的共聚物，丙烯酸和甲基丙烯酸或丙烯酸烷基酯或甲基丙烯酸烷基酯的共聚物，聚乙酸乙烯酯和聚乙烯丁缩醛，烷基取代的聚-N-乙烯吡咯烷酮，和来自烯烃与马来酐的共聚物的烷基酯以及松香与丙烯酸的反应产物。酯中的烷基通常是短链且含有不超过四个的碳原子。
所用制剂优选包含以下不溶于水的成膜剂：丙烯酸乙酯/甲基丙烯酸甲酯/三甲基乙基氯化铵甲基丙烯酸酯的共聚物，丙烯酸和甲基丙烯酸酯与部分三甲基乙基氯化铵甲基丙烯酸酯的共聚物，甲基乙烯基醚和马来酸一丁酯的共聚物，聚乙烯丁缩醛和硝酸纤维素的聚合物，或甲基丙烯酸和丙烯酸乙酯的共聚物。
适宜的生理学可接受的溶剂为诸如以下的物质：用于化妆品的烃、卤代烃、醇、醚、酮和酯，尤其一元醇的乙酸酯如乙酸乙酯和丁酯，如果合适的话，与芳烃如甲苯和/或醇如乙醇或异丙醇混合。
已知溶剂的组合对漆或漆膜的干燥时间、扩散性和其它重要性质非常关键。此溶剂系统优选由低沸点物(＝沸点至高为100℃的溶剂)和中沸点物(＝沸点至高为150℃的溶剂)的混合物组成，如果合适的话，含有少部分高沸点物(＝沸点至高为200℃的溶剂)。
本发明的指甲漆还可以包含常规的化妆品添加剂，如基于邻苯二甲酸酯和樟脑的增塑剂，染料和染色色素，珠光剂，沉积抑制剂，磺胺树脂，硅酸盐，芳香剂，润湿剂如二辛基钠磺基琥珀酸酯、羊毛脂衍生物，光保护剂如2-羟基-4-甲氧基二苯酮，具有抗菌活性的物质，和具有溶角蛋白和/或角膜成形效果的物质如尿素、尿囊素、酶和水杨酸。
染色或着色指甲漆具有优点，例如本发明的制剂可以适合患者的美观感觉，且指甲上存在的变化不会直接被其它人看到。
用于生产不溶于水的指甲漆的方法由以下步骤组成：将溶解形式的生理学上可接受的漆基质与抗真菌剂混合，如果需要的话，进一步加工此制剂。
本发明的药剂中存在的抗真菌剂的量在每一种情况下一般占不挥发性成分的2-80wt％，优选10-60wt％，尤其20-40wt％；所述的不挥发性成分的量是成膜剂、任选存在的色素、增塑剂和其它不挥发性添加剂以及所用的有效抗真菌剂的总量。
采用本发明的漆制剂可以使甲真菌病的治疗完全痊愈-不发生系统副作用和药物相互作用。根据迄今的治疗经验，这是一种特别重要的发现。进一步的优点是采用本发明的药剂可观地缩短治疗时间。它具体表现在局部应用之后的相当高浓度的系统抗真菌剂。
本发明的药剂还适于预防甲真菌病，在这种情况下，足够大量的活性成分沉积在指甲上，从而在真菌污染的情况下不发生由真菌导致的指甲感染。用于预防的药剂包含少量的用于治疗的抗真菌剂。在用于预防甲真菌病的药剂中，活性成分的用量优选一般为0.25-4wt％，优选1-4wt％，所述药剂用作指甲漆，即含溶剂的使用形式。“系统”活性成分的含量一般为0.05-3wt％，优选0.1-1wt％。与系统单一治疗相比，需要较少量的物质形成适宜的活性成分的沉积。
本发明还涉及本发明的制剂在化妆品中的应用。
通过以下实施例详细解释本发明，但本发明不限于这些。除非另外指出，所述的数量都基于重量。
实施例1盐酸阿莫罗芬 5.0％盐酸特比萘芬 2.5％丙烯酸酯和甲基丙烯酸酯与部分三甲基乙基氯化铵甲基丙烯酸酯的共聚物(如EUDRAGIT RL 100) 20.0％豆蔻酸异丙酯 2.5％异丙醇 70.0％
实施例2盐酸布特萘芬 5.0％氟康唑 5.0％甲基乙烯基醚和马来酸一丁酯的共聚物 25.0％96％乙醇 65.0％
实施例3环吡酮胺 8.0％伊曲康唑 0.5％豆蔻酸异丙酯 5.0％1，2-丙二醇 4.0％甲基乙烯基醚和马来酸一丁酯的共聚物 7.5％乙酸乙基酯 25.0％异丙醇 50.0％
实施例4环吡酮胺 7.5％氟康唑 5.0％甲基乙烯基醚和马来酸一丁酯的共聚物 15.0％乙酸乙酯 30.0％96％乙醇 42.5％
实施例5
通过HPLC测定法，在提取切下志愿者指甲时得到的未梢指甲物质之后，测定指甲中应用本发明制剂后的活性成分组合。
在进行6周每周2次治疗之后，发现的实施例3的制剂的值如下：伊曲康唑 800μg/g指甲环吡酮胺 140μg/g指甲
在进行3个月的每天100mg伊曲康唑的口服给药之后，现有技术中在未梢指甲平皿中的伊曲康唑浓度为100μg/g指甲。因此，采用本发明的药剂可以在短时间内在指甲中获得大约比通过系统治疗高8倍的伊曲康唑浓度
实施例6
在进行2周每周2次治疗之后，发现的实施例4的制剂的值如下：氟康唑 17μg/g指甲环吡酮胺 92μg/g指甲
Claims (10)
1.一种制剂，所述制剂包含局部和系统抗真菌活性成分与生理学上可接受的漆基质的组合。
2.如权利要求1所要求的制剂，所述制剂包含
不溶于水的成膜剂，
至少一种来自伊曲康唑、特比萘芬和氟康唑和/或伊曲康唑、特比萘芬和氟康唑的生理学耐受盐的系统抗真菌剂，
至少一种来自环吡酮胺、6-(2，4，4-三甲基戊基)-1-羟基-4-甲基-2(1H)-吡啶酮、阿莫罗芬和布特萘芬和/或环吡酮胺、6-(2，4，4-三甲基戊基)-1-羟基-4-甲基-2(1H)-吡啶酮、阿莫罗芬和布特萘芬的生理学耐受盐的局部抗真菌剂，或者一种以上上述抗真菌剂或它们的盐的混合物。
3.如权利要求1或2所要求的制剂，所述制剂包含如下抗真菌剂：
环吡酮胺和伊曲康唑，或
盐酸布特萘芬和氟康唑，或
环吡酮胺和氟康唑，或
盐酸阿莫罗芬和盐酸特比萘芬。
4.如权利要求1-3之一或多项所要求的制剂，所述制剂包含基于以下物质的成膜剂作为生理学上可接受的漆基质：硝酸纤维素，聚乙酸乙烯酯和部分水解的聚乙酸乙烯酯，一方为乙酸乙烯酯而另一方为丙烯酸或巴豆酸或马来酸单烷基酯的共聚物，一方为乙酸乙烯酯而另一方为巴豆酸和新癸酸乙烯酯，或巴豆酸和丙酸乙烯酯的三元共聚物，甲基乙烯基醚和马来酸单烷基酯，尤其是马来酸一丁酯的共聚物，脂肪酸乙烯酯和丙烯酸或甲基丙烯酸的共聚物，N-乙烯吡咯烷酮、甲基丙烯酸和甲基丙烯酸烷基酯的共聚物，丙烯酸和甲基丙烯酸或丙烯酸烷基酯或甲基丙烯酸烷基酯的共聚物，聚乙酸乙烯酯和聚乙烯丁缩醛，烷基取代的聚-N-乙烯吡咯烷酮，和来自烯烃与马来酐的共聚物的烷基酯以及松香与丙烯酸的反应产物；酯中的烷基通常是短链且含有不超过四个的碳原子。
5.如权利要求4所要求的制剂，所述制剂包含如下不溶于水的成膜剂：丙烯酸乙酯/甲基丙烯酸甲酯/三甲基乙基氯化铵甲基丙烯酸酯的共聚物，丙烯酸和甲基丙烯酸酯与部分三甲基乙基氯化铵甲基丙烯酸酯的共聚物，甲基乙烯基醚和马来酸一丁酯的共聚物，聚乙烯丁缩醛和硝酸纤维素的聚合物，或甲基丙烯酸和丙烯酸乙酯的共聚物。
6.如权利要求1-5之一或多项所要求的制剂，所述制剂包含含量为0.25-20wt％，优选2-15wt％的局部抗真菌剂，和含量为0.05-10wt％，优选0.1-5wt％的系统抗真菌剂。
7.一种生产权利要求1-6之一或多项所要求的药剂的方法，所述方法包括将溶解形式的生理学上可接受的漆基质与抗真菌剂混合，如果需要进一步加工此制剂。
8.在生理学上可接受的漆基质中的局部和系统抗真菌活性成分的组合用于生产如在权利要求1-6之一或多项中所要求的预防和治疗脚趾甲和手指甲真菌感染的药剂的应用。
9.权利要求1-6中所述的不溶于水的成膜剂，至少一种来自伊曲康唑、特比萘芬和氟康唑和/或伊曲康唑、特比萘芬和氟康唑的生理学耐受盐的系统抗真菌剂，和至少一种来自环吡酮胺、6-(2，4，4-三甲基戊基)-1-羟基-4-甲基-2(1H)-吡啶酮、阿莫罗芬、布特萘芬和/或环吡酮胺、6-(2，4，4-三甲基戊基)-1-羟基-4-甲基-2(1H)-吡啶酮、阿莫罗芬和布特萘芬的生理学耐受盐的局部抗真菌剂，或者一种以上上述抗真菌剂或其盐的混合物，用于生产预防和治疗脚趾甲和手指甲真菌感染的药剂的应用。
10.权利要求1-6之一或多项所要求的制剂在化妆品中的应用。
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| PT983037E (pt) * | 1998-02-09 | 2003-09-30 | Macrochem Corp | Verniz para unhas antifungico |
| US6231875B1 (en) * | 1998-03-31 | 2001-05-15 | Johnson & Johnson Consumer Companies, Inc. | Acidified composition for topical treatment of nail and skin conditions |
-
2000
- 2000-03-09 DE DE10011081A patent/DE10011081A1/de not_active Withdrawn
-
2001
- 2001-02-28 JP JP2001564797A patent/JP4843176B2/ja not_active Expired - Lifetime
- 2001-02-28 RU RU2002126618/15A patent/RU2261701C2/ru active
- 2001-02-28 ES ES01919354T patent/ES2211792T3/es not_active Expired - Lifetime
- 2001-02-28 AU AU4648401A patent/AU4648401A/xx active Pending
- 2001-02-28 MX MXPA02008292A patent/MXPA02008292A/es active IP Right Grant
- 2001-02-28 SK SK1276-2002A patent/SK287076B6/sk not_active IP Right Cessation
- 2001-02-28 IL IL15151901A patent/IL151519A0/xx unknown
- 2001-02-28 CA CA002402267A patent/CA2402267C/en not_active Expired - Lifetime
- 2001-02-28 DK DK01919354T patent/DK1267932T3/da active
- 2001-02-28 CZ CZ20023001A patent/CZ298718B6/cs not_active IP Right Cessation
- 2001-02-28 PT PT01919354T patent/PT1267932E/pt unknown
- 2001-02-28 AT AT01919354T patent/ATE259660T1/de active
- 2001-02-28 PL PL359705A patent/PL200700B1/pl unknown
- 2001-02-28 RS YUP-647/02A patent/RS50450B/sr unknown
- 2001-02-28 CN CN018062075A patent/CN1216642C/zh not_active Expired - Lifetime
- 2001-02-28 AU AU2001246484A patent/AU2001246484B2/en not_active Expired
- 2001-02-28 ME MEP-288/08A patent/MEP28808A/xx unknown
- 2001-02-28 HU HU0300135A patent/HU228788B1/hu unknown
- 2001-02-28 ME MEP-2008-288A patent/ME00177B/me unknown
- 2001-02-28 WO PCT/EP2001/002236 patent/WO2001066145A1/de active IP Right Grant
- 2001-02-28 EP EP01919354A patent/EP1267932B1/de not_active Expired - Lifetime
- 2001-02-28 KR KR1020027011812A patent/KR100766738B1/ko active IP Right Grant
- 2001-02-28 NZ NZ521226A patent/NZ521226A/en not_active IP Right Cessation
- 2001-02-28 DE DE50101510T patent/DE50101510D1/de not_active Expired - Lifetime
- 2001-02-28 BR BRPI0108981A patent/BRPI0108981B8/pt not_active IP Right Cessation
- 2001-02-28 EE EEP200200482A patent/EE04994B1/xx unknown
- 2001-03-07 US US09/799,726 patent/US20010046478A1/en not_active Abandoned
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2002
- 2002-08-28 IL IL151519A patent/IL151519A/en active IP Right Grant
- 2002-09-05 HR HR20020731A patent/HRP20020731B1/xx not_active IP Right Cessation
- 2002-09-06 NO NO20024271A patent/NO330245B1/no not_active IP Right Cessation
- 2002-09-06 ZA ZA200207213A patent/ZA200207213B/en unknown
- 2002-12-16 US US10/319,626 patent/US20030086881A1/en not_active Abandoned
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2003
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319326A (zh) * | 2011-07-23 | 2012-01-18 | 李玮 | 一种治疗脚癣的浸药卫生纸 |
| CN104582734A (zh) * | 2012-05-02 | 2015-04-29 | 萨米·萨阿德 | 局部非水性药物配制剂 |
| CN106726750A (zh) * | 2016-12-09 | 2017-05-31 | 李晓光 | 一种环保抑菌护甲油及其制备方法 |
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