CN115531433B - 酮康唑、余甘子组合物及其抗真菌用途 - Google Patents
酮康唑、余甘子组合物及其抗真菌用途 Download PDFInfo
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- CN115531433B CN115531433B CN202211480648.4A CN202211480648A CN115531433B CN 115531433 B CN115531433 B CN 115531433B CN 202211480648 A CN202211480648 A CN 202211480648A CN 115531433 B CN115531433 B CN 115531433B
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- ketoconazole
- phyllanthus emblica
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Abstract
本发明属于抗真菌治疗技术领域，本发明提供了酮康唑、余甘子组合物及其抗真菌用途，所述组合物包括咪唑类抗真菌药和余甘子提取物，所述药物组合物中，咪唑类抗真菌药、余甘子提取物的质量比为（1~10）:（25~500）。本发明提供的抗菌药物组合物能够有效的降低酮康唑的MIC值，对疣状毛癣菌具有抑制作用。
Description
技术领域
本发明属于抗真菌治疗技术领域，尤其涉及酮康唑、余甘子组合物及其抗真菌用途。
背景技术
真菌感染主要分为三类:浅部真菌感染、深部真菌感染和条件性真菌感染。深部真菌感染是指真菌侵犯体内各个脏器时引起的疾病感染，危害较大，但较少见；条件性真菌感染只在免疫力低下、器官移植、接受化疗的癌症患者中比较常见。浅部真菌感染在我国属于最常见的皮肤病感染病种之一，其分布广泛，虽然不至于导致生命危险，但是较难治愈。
疣状毛癣菌属不全菌纲-丝孢目-从梗孢科-毛癣菊属，是一种亲动物性皮肤癣真菌，具有较强的传染性，能引起头部、脸部、身体多部位皮肤感染。近年来,国内外关于疣状毛癬菌引起人畜共患皮肤癬菌病的报道逐渐增多。
由于近些年能治疗真菌的抗生素的滥用，尤其是免疫力低下患者机会性真菌感染的发病率不断上升，使真菌感染的治疗面临严峻的挑战。虽然不断有新的抗真菌药物问世，为抗真菌治疗提供了新的契机，但同时有关药物治疗的耐药报道也逐渐增加。因此需要发展新的抗真菌治疗方法。
目前，临床上通常采用酮康唑等抗菌药物治疗疣状毛癣菌过度增殖引起的相关皮肤疾病。其中，应用较广的酮康唑既能外用，又能内服，但是，酮康唑用于全身给药时，副作用很多，而且还可致肝毒性，这就限制了它的临床应用。酮康唑单独用于抑菌时，用药量较大，会产生较大的毒副作用，长期使用，又易使病菌产生耐药性。
因此，目前现有技术中存在的问题是：
(1) 现有技术中存在的抗真菌药物组合匮乏，近年来少有新的抗真菌药物及组合制剂问世，导致了抗真菌药物储备不足的现状。
(2)现有抗真菌药物毒副作用较大，且毒副作用大多为剂量依赖性。现有抗真菌药物的毒副作用主要包括：局部反应，如刺激痛、灼烧痛、红肿、瘙痒及过敏反应；全身反应，如发热、消化道症状、神经症状、贫血等，极大地限制了传统抗真菌药物的使用。
（3）传统药物的持续使用导致真菌耐药现象严重。通常情况下，真菌对一线抗真菌药物，如唑类耐药逐渐增多，部分真菌甚至出现了对杀菌性药物的耐药。
（4）增大药物剂量。增大药物剂量可在一定程度上加强药物的作用效果，而此时药物剂量依赖的毒副作用也会随之增加，为治疗过程带来隐患。同时部分药物溶解性较差，无法通过增加药物剂量来产生更高的作用效果。
（5）新型抗真菌药物的研发。研发新型药物难度非常大，首先需明确新型药物的作用靶点及相关机制，这是非常复杂的；此外，新型药物研发后上市需经过体外实验、动物实验、人体实验等复杂的流程，结合商业价值及审批流程，其过程非常漫长。
若通过增大药物剂量加强药物的作用效果，此时药物剂量依赖的毒副作用也会随之增加，为治疗过程带来隐患。同时部分药物溶解性较差，无法通过增加药物剂量来产生更高的作用效果。所以寻找高效、安全、温和、平价的新型抗菌药物成为当今药物研发的热点之一。
发明内容
本发明旨在解决现有技术中存在的技术问题，因此，本发明提出一种酮康唑、余甘子组合物及其抗真菌用途，本发明发现酮康唑与余甘子提取物具协同效果，并能够显著抑制真菌的生长，同时能够有效降低酮康唑的用量，弥补了当前抗真菌治疗过程中的不足，降低了化药酮康唑的毒副作用，最终为设计广谱、微量、高效、低毒、平价的新型药物组合提供思路和依据，能够缓解目前真菌感染频发且药物毒性大，耐药问题难以控制的严峻形势。
在得到本发明技术方案之前，发明人从余甘子、诃子、甘松、千里光、虎耳草、多刺绿绒蒿、渣驯、雪莲花、天麻、软紫草、白花龙胆、麻花艽、乌贝等上百种藏药中选择了余甘子、诃子、甘松、千里光、虎耳草、多刺绿绒蒿、渣驯这几种藏药组分与酮康唑配伍，验证其组合对疣状毛癣菌的协同抑菌效果，结果发现，只有酮康唑、余甘子组合对疣状毛癣菌有协同抑菌效果。
本发明的目的是这样实现的：
一种联合抗菌药物组合物，包括咪唑类抗真菌药和余甘子提取物，所述药物组合物中，咪唑类抗真菌药、余甘子提取物的质量比为（1~10）:（25~500）。
余甘子系藏族习用药材。为大戟科油柑属植物余甘子Phyllanthus emblica L.的干燥成熟果实。冬季至次春果实成熟时采收，除去杂质，干燥。根据世界各国传统药物体系中余甘子的临床药用资料，全世界有近20个国家或民族在自己的传统药物体系中使用余甘子，作为一味重要的传统草药，余甘子已被载入《中国药典》。根据现代研究，余甘子的化学成分主要为含单宁成分，具体为柯子酸、柯黎勒酸、鞣云实素、原柯子酸、柯子裂酸、没食子酸等，另外还有Vc、有机酸、黄酮类成分，具有抗微生物感染、抗氧化、抗肿瘤、降血脂和血糖、降压、补益等多种生物活性，且无明显的毒副作用，在临床上已有多种应用。
进一步地，所述药物组合物中，咪唑类抗真菌药、余甘子提取物的质量比为（3~8）:（50~500）。
进一步地，所述药物组合物中，咪唑类抗真菌药、余甘子提取物的质量比为（3.2~6.4）:（57~350）。
当质量比或者其它值或参数以范围、优选范围、或一系列上限优选值和下限优选值限定的范围表示时，这应当被理解为具体公开了由任何范围上限或优选值与任何范围下限或优选值的任一配对所形成的所有范围，而不论该范围是否单独公开了。例如，当公开了范围“1至5”时，所描述的范围应被解释为包括范围“1至4”、“1至3”、“1至2”、“1至2和4至5”、“1至3和5”等。当数值范围在本文中被描述时，除非另外说明，否则该范围意图包括其端值和在该范围内的所有整数和分数。
说明书和权利要求书中的近似用语用来修饰数量，表示本发明并不限定于该具体数量，还包括与该数量接近的可接受的而不会导致相关基本功能的改变的修正的部分。在本申请说明书和权利要求书中，范围限定可以组合和/或互换，如果没有另外说明这些范围包括其间所含有的所有子范围。
进一步地，所述咪唑类抗真菌药选自酮康唑、氟康唑、伏立康唑、泊沙康唑中的一种，进一步为酮康唑。
进一步地，所述余甘子提取物为水提物或醇提物，所述醇提物为乙醇提取物。本发明中，所述乙醇提取物中的醇为无水乙醇。
本发明提取方法可以采用常规植物提取方法，例如可以选择但不限于加热提取、渗滤提取、超声提取、微波提取、浸渍提取、超临界提取、索式提取等等。进一步地，在本发明的具体实施方式中，所述提取方法为索式提取。
在提取以后，还包括其他的常规制备步骤，例如过滤、浓缩、离心、干燥、蒸发等等。
为尽可能提取余甘子中的生物活性成分，可对余甘子进行粉碎处理。
进一步地，所述联合抗菌药物组合物用于对抗疣状毛癣菌引起的感染。
提供一种前述组合物在制备抑制和/或预防真菌产品中的用途。
本发明产品包括但不限于食品、药品、保健品、消毒剂、卫生用品等。
进一地，所述真菌为疣状毛癣菌。
进一步地，所述产品还包括还包含药学上可接受的辅料或辅助性成分。
本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质，包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。粘合剂包含糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等；填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等；润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等；崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等；湿润剂包含十二烷基硫酸钠、水或醇等；抗氧剂包含亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等；抑菌剂包含0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇等；调节剂包含盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸二氢钠和磷酸氢二钠)等；乳化剂包含聚山梨酯-80、没酸山梨坦、普流罗尼克F-68，卵磷酯、豆磷脂等；增溶剂包含吐温-80、胆汁、甘油等。
所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然应属于本发明保护的范围。
本发明具有以下有益效果：
本发明开发出了一种协同性药物组合，该药物组合物包括抗真菌性的酮康唑以及协同性的余甘子提取物；本发明药物组合物的真菌抑制浓度系数FICI＝(药物组合物中提取物的MIC/提取物单独使用时的MIC)+(药物组合物中酮康唑药物的MIC/酮康唑药物单独使用时的MIC)≤0.5，具有协同作用，该药物组合物能够有效减少抗真菌药物酮康唑的最小抑菌浓度(MIC)，能够显著提高酮康唑的抗真菌效果，从而减少治疗过程中酮康唑的用量，进而减少其毒副作用，安全性具有保证，有效抑制疣状毛癣菌感染，扩大了现有抗疣状毛癣菌药物储备池，为抑制疣状毛癣菌药物提供了新选择。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
应当明确的是，下述实施例中所使用的实验方法如无特殊说明，均为常规方法，下述实施例中所使用的材料、试剂等，如无特殊说明，均可从商业途径得到。
酮康唑购自上海易恩化学技术有限公司（R015536）。
实施例1
1、培养基
皮肤癣菌（疣状毛癣菌）培养基使用沙氏固体培养基和RPMI-1640液体培养基（pH调至7.0），马拉色菌培养基使用Leeming-Nortman固体培养基和液态培养基，置于4℃储存备用。
2、实验菌株的准备
疣状毛癣菌菌株由四川省畜牧科学研究院兽医兽药研究所分离鉴定保存，马拉色菌来源于北京保藏生物科技有限公司（ATCC44344）。
取保存的疣状毛癣菌菌株接种于沙氏固体培养基上28℃培养7天活化，疣状毛癣菌接种于沙氏固体培养基上35℃培养7天活化，马拉色菌接种于Leeming-Nortman固体培养基35℃培养3~5天活化。
3、菌液的制备
用含有0.1%吐温-20的灭菌生理盐水（每100mL生理盐水中含有0.85g氯化钠）平板菌落，用无菌刮棒刮取菌落表面，吸取悬液至试管，置振荡器上振荡5min后，静置10min，抽取上层液体至4~5mL液体培养基中，调整菌悬液浓度为（1~3）×106CFU/mL，备用。将菌悬液用RPMI1640液体培养基稀释50倍，可进行接种进行药敏实验。
4、真菌药敏试验
药物储存液制备：100%二甲基亚矾(DMSO)溶解稀释酮康唑，并用含0.2%~0.5%DMSO的RPMI-1640进行稀释，获得浓度为1280μg/mL母液，无菌分装，-20℃存储备用。实验室保证DMSO的最终浓度不能超过1%。
藏药余甘子（入药部位：成熟果实）、甘松（入药部位：干燥根及根茎）、虎耳草（入药部位：全草）、诃子（入药部位：成熟果实）、多刺绿绒蒿（入药部位：成熟果实）、渣驯（成品购自药材市场，为从岩石缝中流出后凝结而成的一种岩石类药物）醇提取物按照如下方法分别制备：将藏药放至高速粉碎机中粉粹，称取100~150g藏药粉末，用滤纸包好后，放入索氏抽提器中，加入无水乙醇索氏提取5~6h，回收醇提取物，在水浴锅上浓缩并定容，即得乙醇提取物备用。
千里光水提取物制备：将千里光（入药部位：全草）至高速粉碎机中粉粹，将称取100~150g粉末，用滤纸包好后，放入索氏抽提器中，加入中性去离子水索氏提取6~8h，回收水提取物，在水浴锅上浓缩并定容，即得水提取物。
药敏板制备：采用M38-A2方案的棋盘式微量液基稀释法制备药敏板，单药药敏试验区，化药第一孔加培养基100μL，化药母液100μL，倍数稀释，最后一孔为对照组不加药液，各孔中DMSO含量均低于1%。藏药第一孔培养基加100μL，藏药提取物100μL，倍数稀释，最后一孔为对照组不加药液。
酮康唑组药物协同实验：
第一排第1~11孔每孔加酮康唑50μL，从左到右横向排布按倍数稀释。每列分别加藏药MIC的提取液50μL。再取一列作为对照。
5、接种和培养：
①向药敏板每孔各加入100μL 稀释好的相应终浓度的菌悬液(空白对照孔除外)。
②向试管中加入1mL稀释好的相应终浓度的菌悬液(空白对照孔除外)。
疣状毛癣菌于37℃恒温箱中培养5~7天，马拉色菌于37℃恒温箱中培养3~5天。每天观察生长情况，以阳性对照孔生长良好为准。
6、最低抑菌浓度(MIC值)的判定
按照CLSI M27-A3、CLSI M38-A2制定的标准进行结果判读。只有当生长对照生长良好且质控菌株最小抑菌浓度(minimal inhibitory concentrations，MIC)值在规定范围内时，方认为试验成功，可进行结果判读。所有试验均进行2次。同一菌株MIC值在2次试验不超过2个稀释度时认为相同。MIC判读标准均定为与生长对照相比生长明显抑制(80%)的最低药物浓度。
7、联合用药效果评价
联合用药效果评价方法参考文献“不同分数抑菌浓度解读标准评估抗真菌药物体外联合效应比较（吴伟伟，2016）”中的A标准：
采用分数抑菌浓度(fractional inhibitory concentration index，FICI)来判断两个药物A和B之间是协同、相加还是拮抗作用，即联合用药时药物的MIC值分别除以单独用药时药物MIC值的商之和，表示为:FICI =（MIC A联合/MIC A单独） +（MIC B联合/MIC B单独）。
如果FICI≤0.5为协同作用，0.5＜FICI≤4为无相互作用，FICI＞4为拮抗作用。
该方法为临床及实验室标准化协会(CLSI)公认有效方法，使用范围广而普遍，能够在短时间内快速实现对药物相互作用效果的检测，并可以通过对实验数据进一步分析得出可靠结论，结果稳定，可重复性高。
通过以上定义检测酮康唑和余甘子醇提取物的相互作用，结果如表1、表2-1、表2-2所示。
表1 单一药物的最小抑菌浓度（MIC）
表2-1 酮康唑、植物醇提取物组合后对疣状毛癣菌的FICI
表2-2 酮康唑、植物提取物组合后对马拉色菌的FICI
注：表2中， “-”表示与生长对照相比，菌落减少数是对照菌落数的80%以上，则生长明显抑制，“+”表示生长对照相比，菌落减少数是对照菌落数的80%以下，生长无明显抑制，“/”是指无FICI数值，因真菌生长后，就不再计算FICI数值。
表2-1中，FICI小于1且对疣状毛癣菌存在协同抑制的药物组合有：①酮康唑6.4μg/mL、余甘子0.0571mg/mL（酮康唑：余甘子提取物的质量比为6.4: 57.1）；
②酮康唑6.4μg/mL、余甘子0.1142mg/mL（酮康唑：余甘子提取物的质量比为6.4:114.2）；
③酮康唑4.8μg/mL、余甘子0.0571mg/mL（酮康唑：余甘子提取物的质量比为4.8:57.1）；
④酮康唑4.8μg/mL、余甘子0.1142mg/mL（酮康唑：余甘子提取物的质量比为4.8:114.2）；
⑤酮康唑4.8μg/mL、余甘子0.2283mg/mL（酮康唑：余甘子提取物的质量比为4.8:228.3）；
⑥酮康唑3.2μg/mL、余甘子0.3424mg/mL（酮康唑：余甘子提取物的质量比为3.2:342.4）。
其他浓度的酮康唑与余甘子、诃子、甘松、千里光、虎耳草、多刺绿绒蒿或渣驯组合后对于疣状毛癣菌的抑制并没有协同作用，只有药物组合①~⑥存在协同抗真菌作用，且余甘子与酮康唑组合后，能够明显降低酮康唑对疣状毛癣菌的抑菌浓度。
表2-2中，酮康唑与余甘子、诃子、甘松、千里光、虎耳草、多刺绿绒蒿、渣驯提取物中的任一种藏药提取物组合对马拉色菌的抑制有相加作用，但不存在协同抗菌作用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.一种联合抗菌药物组合物在制备抑制疣状毛癣菌产品中的用途，其特征在于，所述组合物包括咪唑类抗真菌药和余甘子提取物；所述药物组合物中，咪唑类抗真菌药、余甘子提取物的质量比为6.4: 114.2、4.8: 57.1、4.8: 114.2、4.8: 228.3或3.2: 342.4；所述咪唑类抗真菌药为酮康唑；所述余甘子提取物为水提物或醇提物，所述醇提物为乙醇提取物。
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