CN1181738C - 治疗用抗真菌性甲病制剂 - Google Patents

治疗用抗真菌性甲病制剂 Download PDF

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CN1181738C
CN1181738C CNB998147346A CN99814734A CN1181738C CN 1181738 C CN1181738 C CN 1181738C CN B998147346 A CNB998147346 A CN B998147346A CN 99814734 A CN99814734 A CN 99814734A CN 1181738 C CN1181738 C CN 1181738C
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S·F·里维斯
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Abstract

用于治疗指(趾)甲真菌感染或甲癣病的治疗溶液和应用方法，包括：在无水聚乙二醇溶液中把抗真菌剂和DMSO相混合，还包括另一种抗炎剂。DMSO作为转运载体，从而活性抗真菌试剂例如咪康唑和抗炎化合物例如布洛芬能够被直接转运到指(趾)甲下方真菌感染区域。把DMSO、咪康唑和布洛芬溶解于聚乙二醇粘性溶液中，这样合并后成分能够以超穿透方式直接施加于被感染的指(趾)甲。所述治疗溶液配制如下：加热状态下，把咪康唑溶解到聚乙二醇中；再在加热下把把布洛芬溶解到DMSO中形成第二种溶液，然后把这两种溶液混合形成治疗溶液。把所得溶液重复应用于甲癣病原感染的指(趾)甲区域，持续4-6周，在不增加全身用药的条件下，其令人满意的结果率高达85-90%。该治疗溶液的太多数方案可期望成为非处方药。

Description

治疗用抗真菌性甲病制剂
                            技术领域
本发明总的涉及用布洛芬和二甲亚砜的组合作为转运机构把活性成分传递至被感染区域的治疗制剂。具体地说，本发明涉及合并应用布洛芬和二甲亚砜把抗真菌剂送至那些常规治疗化合物相对不容易到达的被感染区域的治疗制剂。
                            背景技术
许多微生物包括细菌、真菌和霉菌能够引起人体的外部感染。在人体体表或体内生存的许多微生物是有益的，但另一些微生物繁殖迅速，如果不加以治疗将形成感染。某些生物体例如微植物(microscopicplants)或真菌能够依靠皮肤生活，它们从死亡组织如毛发、指甲和外表皮中获得营养。如果体表生长的真菌生长失去控制，将会产生感染，并对活组织产生有害作用。另外，真菌感染性疾病是能够传染的，对于游泳池、体育馆、浴室和其它湿润和/或湿环境等公共区域来说，如果感染真菌的患者光顾这些公共区域，则经常出入这些公共区域的个体容易感染上各种真菌感染性疾病。
甲癣(Onychomycosis)是一类外部真菌，常被称之为“甲真菌”，甲癣病是致病性真菌和其它微生物引起的指(趾)甲和甲床感染，这种疾病虽然不是致死性的，但却能引起慢性不适和窘迫。该疾病攻击指(趾)甲，在其生长中心部位出现破裂、发黄和损形。对于急性患者，甲癣能引起指(趾)甲变厚，颜色发黄，从而容易受伤害，并导致指(趾)甲下方出血。
许多微生物例如皮肤真菌、酵母菌和霉菌都能够引起甲癣。然而，大部分甲癣病是由真菌引起的，其中所述真菌例如红色毛癣菌(Trichophyton rubrum)、须癣毛癣菌(Trichophyton mentagrophytes)、断发毛癣菌(Trichophyton tonsurans)和絮状表皮癣菌(Epidermophyton floccosum)。一旦微生物在皮下生长，难以用目前的非处方药进行根除，疾病复发使费用高昂，耗时长。
近年来，成人中甲癣患病率较高，部分原因可能是其具有传染性，并且一旦甲床中被感染，则缺乏能够迅速治疗该疾病的有效药物。目前的治疗包括长期(3-9月)应用局部杀真菌乳膏和/或溶液，并合并全身真菌治疗药物例如灰黄霉素、特比奈芬、伊曲康唑。有些全身治疗具有不良的副作用例如恶心、头痛、光敏感性、胃肠道不适、肝酶升高和不良的药物相互作用，根除方法是困难并麻烦。
还需注意到：全身真菌治疗是昂贵的。应用特比奈芬片剂(250mg)治疗费用将超过600.00美元，应用伊曲康唑的治疗费用为600.00-1200.00美元。相反，本发明考虑一种非全身治疗，其费用小于50.00美元。
快速治疗甲癣的困难部分原因在于不能把有效的抗真菌试剂送至病理活性区域，从而不能消灭所有致病真菌。如果不完全消灭致病真菌，疾病复发，从而必须再进行一轮合并的局部和/或全身治疗(其具有上述的全身作用)。由于皮肤甲壳不易被穿透，感染区域的治疗常常需要使皮肤变薄以便使抗真菌剂更好地穿透，这样一个事实使治疗复杂化。指(趾)甲作为保护性屏障，在其保护下，真菌能够不受干扰地生长，而且指(趾)甲甚至作为传播疾病的传输装置。目前用于治疗甲癣的局部抗真菌软膏和溶液不易穿透至甲床，因此在治疗后会留下一部分活真菌，引起疾病的复发。到目前为止，医药工业尚没有出现那些具有能够有效穿透硬肤甲壳并穿透至肤床用来快速和完全破坏真菌感染的必须化学性质的局部治疗剂。
因此，需要提供一种快速并完全穿透甲壳、置于甲床下面以及围绕指(趾)甲组织释放出能够杀死甲癣病病因的有效抗真菌剂的局部溶液。
                            发明的公开
本发明的目的是提供一种含有有效抗真菌剂的局部溶液，该溶液能够穿透硬皮肤壳以杀死甲癣病病因。
本发明另一个目的是提供制备穿透局部溶液的方法。
本发明还有一个目的是提供治疗方法用于在不用全身性药物条件下治疗甲癣病的方法。
总之，本发明提供一种组合物，所述组合物由抗真菌剂和由布洛芬和DMSO形成的组合的聚乙二醇非水溶液组成。其中由布洛芬和DMSO形成的组合用作转运载体，这样能够把活性抗真菌剂例如咪康唑能够直接送至指(趾)甲下方和周围的真菌感染区域。把咪康唑和布洛芬/DMSO组合溶解于聚乙二醇的粘溶液中，这样直接把所组合的成分用药于置于局部溶液中的被感染指(趾)甲。该治疗溶液制备如下：把咪康唑溶于一部分聚乙二醇中直至溶解，把布洛芬溶入DMSO中直至溶解，把这两种液体组合，加入余量的聚乙二醇直至达到需要的体积。把得到的溶液重复应用于甲癣感染指(趾)甲，时间长达12-16周，在不添加合并全身药的局部治疗条件下得到85％-90％的满意结果率。该优选溶液的多数类型可以非处方销售，比现有根治甲癣病的方法费用少得多。
通过阅读下面的描述，本发明的其它特征、目的和优点将变得更明显。
                  本发明的最佳实施方案
本领域技术人员熟知应用DMSO把化学物质传送至血液和组织。然而，迄今为止，合并应用布洛芬和DMSO来把抗真菌试剂穿过并到达指(趾)甲结构下还是未知技术。
1997年2月，本发明人把DMSO同数种治疗试剂合并应用，对人进行实验以确定治疗用抗真菌溶液的效能和治疗甲癣病的效能。结果是令人惊奇的，经12周治疗期，在不进行全身治疗的条件下，治疗结果令人满意的比例高达85-90％。另外，对于某些患者，用药两周就能观察到抗真菌结果。
在接下来的实验测试中，试验了各种成分浓度，并改变了组合技术，产生了具有用于治疗甲癣病所必须的穿透特性的局部治疗溶液。
DMSO(化学式为CH3(SO))是一种具有公知溶解特性的充满疑问的物质。现有技术中公开了DMSO在实验室研究中的一系列主要药理学作用，例如：膜转运、抗炎、镇痛、bactriosis、非特异性增强抗细菌剂作用、血管舒张、肌肉松驰和降低血浆胆固醇作用。然而人们尚不能准确地知道渗透增强的实际机理(某些研究表明：蒂状瓣循环和组胺释放是其原因)，DMSO能够用作进入到体内的低分子量非离子分子的载体物质。研究还表明：DMSO通过增加含水量来增加来增加角质层的通透性。
有一些研究表明：同低于或高于90％(体积比)浓度的DMSO溶液相比，90％(体积比)的溶液作为转运载体更有效些。然而，应用本发明实验所述的临床试验显示：应用40％DMSO溶液使抗真菌剂和抗炎剂具有良好的吸收，能够作为它们的良好载体。具体地说，对于抗真菌剂如咪康唑和克霉唑来说，组合应用聚乙二醇300MW(分子量)、布洛芬USP(美国药典标准)和DMSO(以40％体积应用，纯度为99％)能够作为它们有效的载体。
布洛芬USP[(Ch3)2ChCh2Ch(Ch3COOH)]还有一个商品名MotrinTM，其为白色结晶性粉末，略有气味，用作为抗炎剂已有一段时间。当把布洛芬同40％体积比的聚乙二醇溶液以4％体积比合并应用时，其把抗真菌剂传送到角质层下方真菌感染部位比不应用布洛芬时更快些。其确切原因是未知的，但这些研究显示：在某些类型的人组织中，布洛芬能够引起骨化形成。本领域已知的除布洛芬以外的抗炎剂也被怀疑能够增强抗真菌剂的效果。
聚乙二醇300是粘性的、基本上澄清的溶液，其用作本发明的无水基质。作为溶液基质，聚乙二醇是非常优秀的，因为其不会引起刺激，对人组织具有低毒性。其在大部分有机溶剂中是可溶的、澄清的和不污染的。另外，聚乙二醇300具有粘性，从而应用时能使本发明物质更好地存留于感染区域，例如指(趾)甲，因此提高感染区域的剂量体积。
尽管本发明可以应用数种类型的抗真菌剂，当有一种试剂咪康唑USP具有非常良好的杀甲癣作用。咪康唑USP(1-[2-(2，4-二氯苯基)-2-[2，4-二氯苯基]甲氧基]乙基-1h-咪唑单硝酸盐；其商品名也称为MonistatTM)是白色结晶性粉末，被用作抗真菌制剂的主要成分。本发明者发现：当在指(趾)甲渗透基质中应用时，4％的咪康唑溶液足以杀死甲癣中的真菌。其它能够有效地对抗致甲癣病真菌并适合用于本发明的抗真菌剂为：克霉唑、噻康唑、制霉菌素、特康唑、硝酸布康唑、恩尼环烯酸(Unecylenic acid)、碘氯羟喹、环吡酮胺、硝酸益康唑、甘油三乙酸酯、托萘酯、氟胞嘧啶和酮康唑。
实施本发明的优选溶液是这样一种溶液：在100ml量中含有4g布洛芬USP、40ml DMSO、4g咪康唑USP和100ml(加至足量)聚乙二醇300MW，NF液体。为了制备所述溶液，称取(推荐筛过的)4g咪康唑和温热的40ml聚乙二醇置于烧杯中，加热至45℃(40-50℃的温度范围就已经令人满意了，但45℃是最佳的)。应该应用电磁搅拌器使混合均匀，维持烧杯中温度为45℃直至所有成分混合完全。把该咪康唑缓慢地加入到聚乙二醇中，搅拌直至所有粉末完全溶解。量取40mlDMSO(99％纯)和4g布洛芬。搅拌下把布洛芬加入到DMSO中，使所有粉末溶解。在搅拌下把DMSO/布洛芬溶液加入到咪康唑/聚乙二醇溶液中。把足够的聚乙二醇加入到混合物中，使混合物总体积为100ml。搅拌该溶液15分钟，然后移开热源。所得溶液相对于聚乙二醇基质具有4％布洛芬、40％DMSO、4％咪康唑(体积比)。当溶液恢复至室温后，立即将其转移至容器瓶中。
为了保证本发明溶液的强度和稳定性，应该按照上述方法。例如咪康唑在某些液体中是不溶的，因此将其加入到温热的聚乙二醇中以有助于咪康唑更快地溶解。应用不同的混合步骤可能阻止成分的正常溶解，因此将使溶液变稀。并且，应该把布洛芬加入到DMSO中以加快溶解步骤。
为了杀死存在于指(趾)甲感染部位的致病微生物，需要以周期应用方案应用优选溶液。应该清洁并洗涤感染甲癣的指(趾)甲，并使其干燥。然后把溶液足量地应用至感染区域和所有指(趾)甲部位，包括表皮。让溶液在感染指(趾)甲区域(包括表皮)直接地自然风干。根据感染的严重程度，该应用步骤应该每天重复3次，持续12周。在许多治疗病人中，应用12周本发明物质能够达到85-90％令人满意的治疗效果。并且，能够应用该溶液对抗许多类型的致甲癣真菌，其可以作为非处方药(根据FDA制定的准则)。
本人已经以一种形式显示本人的发明，本领域技术人员显然明白其并不局限于此，能够在不偏离本发明的精神条件下，对本发明作出各种改变和修饰。例如，本发明告知把DMSO溶液和抗真菌剂和布洛芬合并应用，能够想像：抗真菌剂和抗炎剂混合于聚乙二醇中，其直接应用于被感染的指(趾)甲，然后把DMSO直接加入到上面。类似地，还能想出能够体现本发明的其它修改方式。

Claims (15)

1.能有效抑制致甲癣病微生物生长的局部用溶液，基本组成为：
a.用于杀死致甲癣病微生物的药理学试剂；b.布洛芬；c.溶解所述试剂和布洛芬的聚乙二醇基质；和d.同所述聚乙二醇基质混合的DMSO溶液。
2.权利要求1的局部用溶液，其中所述药理学试剂为抗真菌剂，选自：咪康唑、克霉唑、噻康唑、制霉菌素、特康唑、硝酸布康唑、恩尼环烯酸、碘氯羟喹、环吡酮胺、硝酸益康唑、甘油三乙酸酯、托萘酯、氟胞嘧啶和酮康唑。
3.权利要求1的局部用溶液，其中所述布洛芬浓度为4％体积。
4.权利要求2的局部用溶液，其中所述聚乙二醇的分子量为300。
5.权利要求1的局部用溶液，其中所述局部用溶液含有40％体积的DMSO。
6.权利要求1的局部用溶液，其中所述药理学试剂为所述溶液的1-30％体积。
7.权利要求1的局部用溶液，其中所述药理学试剂为咪康唑。
8.用于增强药学活性抗真菌物质的穿透性的药物组合物，基本组成为：
a.抗真菌剂，选自咪康唑、克霉唑、噻康唑、制霉菌素、特康唑、硝酸布康唑、恩尼环烯酸、碘氯羟喹、环吡酮胺、硝酸益康唑、甘油三乙酸酯、托萘酯、氟胞嘧啶和酮康唑；
b.布洛芬；
c.溶解所述试剂和所述布洛芬的聚乙二醇基质；和
d.同所述聚乙二醇基质混合的DMSO溶液。
9.用于增强治疗试剂穿透指/趾甲的药物组合物，基本组成为：
a.用于杀死所述致甲癣病微生物的抗真菌剂；
b.布洛芬；
c.溶解所述抗真菌剂和布洛芬的无水基质，其中所述无水基质含有聚乙二醇；和
d.同那些用于增强所述抗真菌剂穿透至所述指/趾甲的无水基质相混合的DMSO溶液。
10.用于增强药学活性物质穿透皮肤或穿透指/趾甲的组合物，基本组成为：
a.1-30％体积的抗真菌剂；
b.1-40％体积的布洛芬；
c.10-80％体积的溶解所述药剂和所述布洛芬的聚乙二醇；和
d.10-80％体积的混有所述聚乙二醇基质的DMSO溶液。
11.用于抑制致甲癣病微生物的治疗溶液的制备方法，其包括下列步骤：
a.加热并维持40ml聚乙二醇液体为45℃；
b.在搅拌下把4克咪康唑缓慢加入到所述热聚乙二醇中直至其在第一个容器中溶解；
c.在搅拌下把4g布洛芬加入到40ml 99％纯DMSO液体中直至其在第二个容器溶解；
d.把第一个容器同第二个容器中的溶液混合；和
e.往所述混合溶液中加入另外的聚乙二醇至所需体积。
12.权利要求11的方法，其中把所述咪康唑筛入所述热聚乙二醇基质。
13.权利要求11的方法，其中把所述布洛芬筛入所述热聚乙二醇基质。
14.权利要求11的方法，其中所述制备治疗溶液的方法还包括在所述冷却步骤后过滤所述混合溶液的步骤。
15.权利要求11的方法，其中所述搅拌咪康唑的步骤是在加入布洛芬之后。
CNB998147346A 1998-11-16 1999-11-15 治疗用抗真菌性甲病制剂 Expired - Fee Related CN1181738C (zh)

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US6159977A (en) 2000-12-12
DE69928278T2 (de) 2006-06-14
AU771851B2 (en) 2004-04-01
US6391879B1 (en) 2002-05-21
CA2351536C (en) 2007-08-07
EP1130964A4 (en) 2002-06-19
EP1130964A1 (en) 2001-09-12
JP2003535020A (ja) 2003-11-25
BR9915394A (pt) 2002-03-05
EP1130964B1 (en) 2005-11-09
IL143156A (en) 2005-11-20
CA2351536A1 (en) 2000-05-25
WO2000028821A1 (en) 2000-05-25
DE69928278D1 (de) 2005-12-15
AU1725700A (en) 2000-06-05
CN1359262A (zh) 2002-07-17
MXPA01004908A (es) 2003-03-10
IL143156A0 (en) 2002-04-21
ATE309032T1 (de) 2005-11-15

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