CN115518056A - 橙花叔醇、橙花醇和香叶醇在抗菌方面的用途 - Google Patents
橙花叔醇、橙花醇和香叶醇在抗菌方面的用途 Download PDFInfo
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Abstract
本发明公开了橙花醇、香叶醇在制备抑制或杀灭耐药或不耐药细菌、真菌药物或试剂中的用途。本发明还公开了本发明公开了橙花叔醇在制备抑制或杀灭耐药或不耐药细菌、真菌药物或试剂中的用途。橙花叔醇、橙花醇和香叶醇对真菌、多种革兰氏阴性菌耐药菌和革兰氏阳性菌耐药菌具有抗菌活性，有望开发成为临床上抗菌、特别是抗耐药菌的新型药物。
Description
技术领域
本发明属于天然药物技术领域，涉及橙花叔醇、橙花醇和香叶醇在抗菌方面的用途。
背景技术
青霉素与链霉素的发现，被誉为抗生素发展史上的重要里程碑，前者开创了抗生素时代，后者的发现，开启了大规模筛选抗生素的新时代。抗生素研发的蓬勃发展与应用使人类的平均寿命得到大幅延长，为人类健康做出重要贡献。随着科学技术的发展，半合成抗生素兴起，合成抗菌药应运而生，抗菌药物家族日渐壮大。目前发现的抗菌作用机制主要有抑制细菌细胞壁、蛋白质、核酸的合成，以及抑制细菌叶酸代谢、细胞膜功能等。随着抗生素的使用，随之而来的是各种耐药菌的出现，他们不再被原来的抗生素所抑制，给人类的健康带来巨大威胁。WHO列出了新型抗生素研发重点病原体清单：
1类重点(极为重要)：碳青霉烯类药物耐药鲍曼不动杆菌、碳青霉烯类药物耐药绿脓杆菌、碳青霉烯类药物耐药、产超广谱β-内酰胺酶(ESBL)肠杆菌科。
2类重点(十分重要)：万古霉素耐药屎肠球菌、甲氧西林耐药、万古霉素中介和耐药金黄色葡萄球菌、克拉霉素耐药幽门螺旋杆菌、氟喹诺酮类药物耐药弯曲菌属、氟喹诺酮类药物耐药沙门氏菌、头孢菌素耐药、氟喹诺酮类药物耐药淋病奈瑟菌。
3类重点(中等重要)：青霉素不敏感肺炎链球菌、氨苄西林耐药流感嗜血杆菌、氟喹诺酮类药物耐药志贺氏菌属。
为了解决抗生素耐药问题，我们需要寻找新的抑菌药物。
此外，近年来，随着免疫缺陷人数的增加，器官移植、气道或者消化道的有创检查广泛应用以及大量常规使用抗生素、糖皮质激素及免疫抑制剂应用，侵袭性真菌感染患者明显增多。但目前抗真菌药物较为缺乏，寻找抗真菌的药物具有重要意义。
发明内容
本发明首次发现橙花叔醇、橙花醇和香叶醇对真菌、多种革兰氏阴性菌耐药菌和革兰氏阳性耐药菌具有抗菌活性，有望开发成为临床上抗菌、特别是抗耐药菌的新型药物。
橙花醇的结构如式Ⅰ所示：
香叶醇的结构如式Ⅱ所示：
橙花醇和香叶醇互为顺反异构体。
橙花叔醇的结构如式Ⅲ所示：
本发明的目的之一是提供橙花醇和香叶醇在抗菌方面的新用途。
橙花醇、香叶醇在制备抑制或杀灭耐药或不耐药细菌、真菌药物或试剂中的用途。
所述的耐药细菌为产超广谱β-内酰胺酶的大肠埃希菌、耐碳青霉烯类鲍曼不动杆菌、耐碳青霉烯类肺炎克雷氏菌、耐万古霉素屎肠球菌、耐甲氧西林金黄色葡萄球菌、耐碳青霉烯类铜绿假单胞菌；所述的不耐药细菌为大肠埃希菌、鲍曼不动杆菌、肺炎克雷氏菌、屎肠球菌、金黄色葡萄球菌、铜绿假单胞菌；所述的真菌为新生隐球菌。
本发明的目的之二提供一种用于抗菌的药物组合物，所述的药物组合物是以橙花醇或其衍生物、香叶醇或其衍生物中的至少一种为主要有效成分或有效成分，与药物可接受的载体，制成适合药用的制剂。
药物组合物中，橙花醇或其衍生物、香叶醇或其衍生物中的至少一种在药物组合物中的重量比为0.1～99.9％，药物可接受的载体在药物组合物中的重量比为0.1～99.9％。
本发明所述的药物组合物以制剂形式存在，每剂中含有的橙花醇或其衍生物、香叶醇或其衍生物中的至少一种的有效量为0.1～1000mg，每剂指的是每一制剂单位，如片剂的每片，胶囊的每粒，也可指每次服用剂量，如每次服用100mg。
本发明的目的之三是提供橙花叔醇在抗菌方面的新用途。
橙花叔醇在制备抑制或杀灭耐药或不耐药细菌、真菌药物或试剂中的用途。
所述的耐药细菌为耐万古霉素屎肠球菌、耐甲氧西林金黄色葡萄球菌、耐碳青霉烯类铜绿假单胞菌；所述的不耐药细菌为屎肠球菌、金黄色葡萄球菌、铜绿假单胞菌；所述的真菌为新生隐球菌。
本发明的目之四的提供一种用于抗菌的药物组合物，所述的药物组合物是以橙花叔醇或其衍生物为主要有效成分或有效成分，与药物可接受的载体，制成适合药用的制剂。
药物组合物中，橙花叔醇或其衍生物在药物组合物中的重量比为0.1～99.9％，药物可接受的载体在药物组合物中的重量比为0.1～99.9％。
本发明所述的药物组合物以制剂形式存在，每剂中含有的橙花叔醇或其衍生物的有效量为0.1～1000mg，每剂指的是每一制剂单位，如片剂的每片，胶囊的每粒，也可指每次服用剂量，如每次服用100mg。
所述的制剂为片剂、胶囊剂、扁囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、粉针剂、栓剂、霜剂、滴剂或贴剂、溶液剂、混悬液、乳液、喷雾剂、气雾剂等。其中，所述的片剂为糖衣片剂、薄膜衣片剂、肠溶衣片剂或缓释片剂；所述的胶囊剂为硬胶囊剂、软胶囊剂、缓释胶囊剂；所述的粉针剂为冻干粉针剂。
所述的药物组合物在制备成粉针剂、片剂、散剂、胶囊剂、扁囊剂、栓剂和膏剂形式的固体或半固体药物制剂时，可使用固体载体。可使用的固体载体选自稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质，或可为包封物质。在粉状制剂中，在载体中含有5～70％的微粒化活性成分。适宜的固体载体包括碳酸镁、硬脂酸镁、滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低沸点蜡、可可脂等。由于它们易于给药，片剂，粉剂、扁囊剂和胶囊等代表最有利的口服固体制剂。
液体制剂包括溶液剂、混悬液和乳液。例如，非胃肠道给药的注射制剂可为水或水-丙二醇溶液形式，调节液体制剂等渗度、pH等使适于活体的生理条件。液体制剂还可制成在聚乙二醇、水溶液中的溶液形式。可通过将活性成分溶解在水中，再加入适量的着色剂、调味剂、稳定剂和增稠剂，来制备口服水溶液。可将微粒化的活性成分分散在粘性物质如天然和合成胶、甲基纤维素、羧甲基纤维素钠和其它已知悬浮剂中制备适于口服的水悬液。
为了易于给药及剂量均一，将上述药物制剂配制成剂量单位形式是特别有利的。制剂的剂量单位形式指适于作为单一剂量的物理分离单位，每个单位含有产生所期望的治疗效果的计算好的预定量的活性成分。这种剂量单位形式可为包装形式，如片剂、胶囊或装在小管或小瓶中的粉剂，或装在管或瓶中的软膏、凝胶或霜剂。
虽然剂量单位形式中所含活性成分的量可以变化，但一般根据所选择活性成分的效力，调节在1～1000mg范围内。
本领域技术人员可按常规方法确定适于某种情况的优选剂量。一般，开始治疗的量低于活性成分的最佳剂量，然后逐渐增加给药剂量，直到达到最佳治疗效果。为治疗需要，总的日剂量可一次给药或分数次给药。
具体实施方式
以下所列实施例是为帮助本领域技术人员更好地理解本发明，但不以任何方式限制本发明。
实施例1
橙花叔醇、橙花醇和香叶醇对细菌和真菌的最低抑菌浓度测定
6种细菌：产超广谱β-内酰胺酶的大肠埃希菌(ESBLS)，耐碳青霉烯类鲍曼不动杆菌(CRAB)，耐碳青霉烯类铜绿假单胞菌(CRPA)，耐甲氧西林金黄色葡萄球菌(MRSA)，耐万古霉素屎肠球菌(VRE)，耐碳青霉烯类肺炎克雷氏菌(CRE)。
1种真菌：新生隐球菌(Cryptococcus neoformans ATCC208821)。
操作步骤：在96孔板中，用二倍稀释法测定橙花叔醇、橙花醇和香叶醇最低抑菌浓度(MIC)，细菌培养基为MH培养基，真菌使用SDB培养基。培养体积为每孔100μL，细菌起始浓度为5×105CFU/L，加药组第一孔药物浓度为50μL/mL。以相应100μL培养基作为空白对照(细菌为MH培养基，真菌为SDB培养基)。37℃培养16小时，观察孔是否清澈，做好标记，并用酶标仪测定600nm处的吸光值。通过观察对比加药组与空白对照组澄清孔，计算橙花叔醇、橙花醇和香叶醇对七种菌的最低抑菌浓度(MIC)，测定结果如表1所示。
表1.橙花叔醇、橙花醇和香叶醇对细菌和真菌的最低抑菌浓度测定(μL/mL)
| 橙花叔醇 | 橙花醇 | 香叶醇 | |
| 产超广谱β-内酰胺酶的大肠埃希菌 | - | ＜0.25 | ＜0.25 |
| 耐碳青霉烯类鲍曼不动杆菌 | - | 1 | ＜0.25 |
| 耐碳青霉烯类肺炎克雷氏菌 | - | ＜0.25 | ＜0.25 |
| 耐万古霉素屎肠球菌 | ＜0.25 | ＜0.25 | ＜0.25 |
| 耐甲氧西林金黄色葡萄球菌 | ＜0.25 | ＜0.25 | ＜0.25 |
| 耐碳青霉烯类铜绿假单胞菌 | ＜0.25 | ＜0.25 | ＜0.25 |
| 新生隐球菌 | ＜0.25 | ＜0.25 | ＜0.25 |
本发明实施例中使用的各细菌、真菌，仅是为了举例说明“橙花叔醇对耐甲氧西林金黄色葡萄球菌、耐万古霉素屎肠球菌、耐碳青霉烯类铜绿假单胞菌、新生隐球菌有抑制或杀灭作用；紫苏醇对耐碳青霉烯类铜绿假单胞菌有抑制或杀灭作用”、“橙花醇和香叶醇对产超广谱β-内酰胺酶的大肠埃希菌、耐碳青霉烯类鲍曼不动杆菌、耐甲氧西林金黄色葡萄球菌、耐万古霉素屎肠球菌、耐碳青霉烯类肺炎克雷氏菌、耐碳青霉烯类铜绿假单胞菌、新生隐球菌有抑制或杀灭作用”，但使用的各细菌、真菌并不局限于该来源。本领域技术人员应该清楚，只要使用具有相应细菌、真菌的且鉴定为产超广谱β-内酰胺酶的大肠埃希菌、耐碳青霉烯类鲍曼不动杆菌、耐碳青霉烯类铜绿假单胞菌、耐甲氧西林金黄色葡萄球菌、耐万古霉素屎肠球菌、耐碳青霉烯类肺炎克雷氏菌、新生隐球菌，均适用于本发明。
Claims (10)
1.橙花醇、香叶醇在制备抑制或杀灭耐药或不耐药细菌、真菌药物或试剂中的用途。
2.根据权利要求1所述的用途，其特征在于：所述的耐药细菌为产超广谱β-内酰胺酶的大肠埃希菌、耐碳青霉烯类鲍曼不动杆菌、耐碳青霉烯类肺炎克雷氏菌、耐万古霉素屎肠球菌、耐甲氧西林金黄色葡萄球菌、耐碳青霉烯类铜绿假单胞菌；所述的不耐药细菌为大肠埃希菌、鲍曼不动杆菌、肺炎克雷氏菌、屎肠球菌、金黄色葡萄球菌、铜绿假单胞菌。
3.根据权利要求1所述的用途，其特征在于：所述的真菌为新生隐球菌。
4.一种用于抗菌的药物组合物，其特征在于：所述的药物组合物是以橙花醇或其衍生物、香叶醇或其衍生物中的至少一种为主要有效成分或有效成分，与药物可接受的载体，制成适合药用的制剂。
5.根据权利要求4所述的用于抗菌的药物组合物，其特征在于：所述的制剂为片剂、胶囊剂、扁囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、粉针剂、栓剂、霜剂、滴剂或贴剂、溶液剂、混悬液、乳液、喷雾剂、气雾剂。
6.橙花叔醇在制备抑制或杀灭耐药或不耐药细菌、真菌药物或试剂中的用途。
7.根据权利要求6所述的用途，其特征在于：所述的耐药细菌为耐万古霉素屎肠球菌、耐甲氧西林金黄色葡萄球菌、耐碳青霉烯类铜绿假单胞菌；所述的不耐药细菌为屎肠球菌、金黄色葡萄球菌、铜绿假单胞菌。
8.根据权利要求6所述的用途，其特征在于：所述的真菌为新生隐球菌。
9.一种用于抗菌的药物组合物，所述的药物组合物是以橙花叔醇或其衍生物为主要有效成分或有效成分，与药物可接受的载体，制成适合药用的制剂。
10.根据权利要求9所述的用于抗菌的药物组合物，其特征在于：所述的制剂为片剂、胶囊剂、扁囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、粉针剂、栓剂、霜剂、滴剂或贴剂、溶液剂、混悬液、乳液、喷雾剂、气雾剂。
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