CN112353795A - 奥利司他及其组合物的抗疟疾用途 - Google Patents
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Abstract
本发明一方面提供了一种奥利司他在制备抗疟疾的药物中的作用，体外试验结果显示，奥利司他对恶性疟原虫以外的三种疟原虫的杀灭活性显著高于其对恶性疟原虫的杀灭活性。本发明另一方面提供了一种含有奥利司他与青蒿素类抗疟药的组合物及其用途，体外试验结果显示，奥利司他与青蒿素类抗疟药能对恶性疟原虫等疟原虫产生协同的杀灭作用。
Description
技术领域
本发明属于医药技术领域，具体涉及奥利司他及其组合物的抗疟疾用途。
背景技术
奥利司他是一种胰腺脂肪酶抑制剂类抗肥胖药物，近年来越来越多的研究披露了奥利司他在肥胖症以外的潜在用途。Yoo E等人在The Antimalarial Natural ProductSalinipostin A Identifies Essentialα/βSerine Hydrolases Involved in LipidMetabolism in P.falciparum Parasites.一文(出处：Cell Chem Biol.2020Feb 20；27(2):143-157)中指出，奥利司他对恶性疟原虫(Plasmodium falciparum)的单酰甘油脂肪酶样蛋白(PfMAGLLP)的抑制作用与Salinipostin A相当，但其对恶性疟原虫的杀灭作用却不及后者(EC50分别为280nM与50nM)，因此奥利司他的抗疟活性有待进一步提高。此外，根据Yoo E等人所披露的信息，奥利司他的抗恶性疟原虫作用主要源自于其对与脂肪酶类似的PfMAGLLP的抑制作用。虽然现有技术中披露了位于其他寄生虫中的脂肪酶，但其与奥利司他已知的作用靶点(胰腺脂肪酶及PfMAGLLP)的基因学特征存在显著差异，因此无法确定奥利司他对其他寄生虫的脂肪酶有同等的抑制作用，而且现有技术中也未给出奥利司他对其他疟原虫的杀灭作用高于其对恶性疟原虫的杀灭作用的技术启示。
Ting-Chao Chou等人在Theoretical basis,experimental design,andcomputerized simulation of synergism and antagonism in drug combinationstudies一文(出处：Pharmacol Rev.2006Sep；58(3):621-81)中指出，针对多靶点与单一靶点的联合用药的协同作用能带来诸多治疗效益，而联合用药是否产生协同或拮抗作用具有高度的不可预测性。而现有技术中暂无奥利司他联合其他药物产生协同的抗疟疾作用的技术启示。
发明内容
本发明的目的之一在于提供一种奥利司他在制备抗疟疾的药物中的用途。
为了实现这一目的，本发明提供了一种奥利司他在制备抗疟疾的药物中的作用，其特征在于，所述疟疾是由恶性疟原虫以外的至少一种疟原虫所致的。
一方面优选的，本发明所述的疟原虫是选自间日疟原虫、卵形疟原虫与三日疟原虫中的至少一种。
另一方面优选的，本发明所述的药物可制成口服固体制剂；进一步优选的，所述的口服固体制剂是选自片剂、颗粒剂与胶囊剂中的一种。
本发明的另一个目的是提供一种含有奥利司他与第二治疗剂组合物及其用途，所述组合物能对疟原虫协同的杀灭作用。
为了实现这一目的，本发明一方面提供了一种含有奥利司他与第二治疗剂的组合物，其特征在于，所述的第二治疗剂是选自青蒿素、蒿甲醚、青蒿琥酯与双氢青蒿素中的一种。
另一方面优选的，本发明所述的组合物中奥利司他与第二治疗剂的摩尔比在(0.01～100):1之间。
另一方面优选的，本发明所述的组合物可制成口服固体制剂；进一步优选的，本发明所述的口服固体制剂是选自片剂、胶囊剂与颗粒剂中的一种。
本发明另一方面提供了一种含有奥利司他与如前所述的第二治疗剂的组合物在制备用于抗疟疾的药物中的用途。
一方面优选的，本发明所述的疟原虫是选自恶性疟原虫、间日疟原虫、卵形疟原虫与三日疟原虫中的至少一种。
体外试验显示，奥利司他对间日疟原虫、卵形疟原虫与三日疟原虫的杀灭作用显著优于其对恶性疟原虫的杀灭作用，而且奥利司他与青蒿素类抗疟药能对上述疟原虫产生协同的杀灭作用。
具体实施方式
试验例1奥利司他及其与第二治疗剂合用时对疟原虫复制的抑制作用
采用Yoo E等人在The Antimalarial Natural Product Salinipostin AIdentifies Essentialα/βSerine Hydrolases Involved in Lipid Metabolism inP.falciparum Parasites.一文(出处：Cell Chem Biol.2020Feb 20；27(2):143-157)中披露的方法考察以下受试物处理后不同疟原虫的细胞存活率(CS)。
受试物①：奥利司他(OsT)；
受试物②：表1所示的各种第二治疗剂，记为化合物X。
受试物③：奥利司他与受试物②以特定的摩尔比(R)形成的混合物，记为MIX(OsT-X)，X的定义见表1。
表1化合物X的编号与定义
| 编号(化合物X) | 通用名 |
| 化合物1 | 青蒿素 |
| 化合物2 | 蒿甲醚 |
| 化合物3 | 青蒿琥酯 |
| 化合物4 | 双氢青蒿素 |
采用下式计算不同浓度下的受试物①～③(其中，受试物③的浓度均依其中的奥利司他计)对各种疟原虫复制的抑制率(IR)。
IR＝1-CS
采用IR值对各受试物浓度(nM)的对数(log(c))进行线性回归，根据线性回归方程(r2≥0.96)的斜率与截距计算产生fa抑制率时的各受试物的浓度(ICfa，nM)。
采用下式计算混合物的联合用药指数(CI)
CI＝a/A+a/(R×B)
其中，a为受试物③依奥利司他计的ICfa，A、B分别为奥利司他与化合物X的ICfa。
CI<1时，提示有协同作用，CI值越小，协同作用越强。
结果如表2～表5所示。
表2.各受试物对恶性疟原虫的杀灭作用
| 受试物 | log(R) | C<sub>max</sub> | IR<sub>max</sub> | 斜率 | 截距 | fa | a、A或B | CI |
| MIX(OsT-1) | -1.7 | 0.060 | 91.94％ | 1.466 | 2.720 | 99.52％ | 0.067 | 0.331 |
| MIX(OsT-1) | 1.1 | 50.000 | 93.30％ | 1.380 | -1.417 | 99.52％ | 55.868 | 0.554 |
| MIX(OsT-2) | -0.3 | 0.400 | 95.37％ | 1.427 | 1.488 | 99.52％ | 0.451 | 0.123 |
| MIX(OsT-2) | 0.6 | 10.000 | 90.89％ | 0.508 | 0.361 | 99.52％ | 17.719 | 0.640 |
| MIX(OsT-3) | -0.8 | 0.700 | 99.33％ | 0.745 | 1.098 | 99.52％ | 0.727 | 0.307 |
| MIX(OsT-3) | 0.4 | 5.000 | 92.78％ | 0.720 | 0.414 | 99.52％ | 6.416 | 0.183 |
| MIX(OsT-4) | -1.9 | 0.008 | 90.92％ | 1.451 | 3.916 | 99.52％ | 0.010 | 0.482 |
| MIX(OsT-4) | 1 | 3.000 | 95.22％ | 1.199 | 0.357 | 99.52％ | 3.409 | 0.220 |
| 化合物1 | 9.000 | 96.16％ | 1.249 | -0.259 | 99.52％ | 10.099 | ||
| 化合物2 | 7.000 | 99.52％ | 1.393 | -0.213 | 99.52％ | 7.372 | ||
| 化合物3 | 10.000 | 96.06％ | 0.586 | 0.305 | 99.52％ | 15.039 | ||
| 化合物4 | 1.000 | 96.61％ | 0.830 | 0.826 | 99.52％ | 1.601 | ||
| OsT | 500.000 | 97.57％ | 1.434 | -2.861 | 99.52％ | 489.325 |
表3.各受试物对间日疟原虫的杀灭作用
表4.各受试物对卵形疟原虫的杀灭作用
| 受试物 | log(R) | C<sub>max</sub> | IR<sub>max</sub> | 斜率 | 截距 | fa | a、A或B | CI |
| MIX(OsT-1) | -0.9 | 0.400 | 97.48％ | 1.140 | 1.444 | 99.77％ | 0.406 | 0.219 |
| MIX(OsT-1) | -0.3 | 3.000 | 94.80％ | 0.597 | 0.665 | 99.77％ | 3.605 | 0.672 |
| MIX(OsT-2) | -2 | 0.010 | 94.07％ | 1.023 | 2.984 | 99.77％ | 0.011 | 0.101 |
| MIX(OsT-2) | -0.5 | 0.400 | 99.77％ | 0.728 | 1.293 | 99.77％ | 0.393 | 0.135 |
| MIX(OsT-3) | -2 | 0.002 | 96.66％ | 1.486 | 5.044 | 99.77％ | 0.002 | 0.103 |
| MIX(OsT-3) | -1.9 | 0.006 | 92.23％ | 0.518 | 2.080 | 99.77％ | 0.008 | 0.351 |
| MIX(OsT-4) | -0.6 | 0.200 | 90.53％ | 1.149 | 1.601 | 99.77％ | 0.298 | 0.230 |
| MIX(OsT-4) | 1.7 | 8.000 | 94.27％ | 1.126 | -0.059 | 99.77％ | 8.691 | 0.620 |
| 化合物1 | 20.000 | 96.25％ | 0.899 | -0.104 | 99.77％ | 16.823 | ||
| 化合物2 | 10.000 | 99.14％ | 0.602 | 0.359 | 99.77％ | 11.491 | ||
| 化合物3 | 2.000 | 97.08％ | 1.283 | 0.658 | 99.77％ | 1.838 | ||
| 化合物4 | 5.000 | 90.64％ | 1.165 | 0.121 | 99.77％ | 5.657 | ||
| OsT | 10.000 | 96.37％ | 0.945 | -0.106 | 99.77％ | 14.749 |
表5.各受试物对三日疟原虫的杀灭作用
根据表2～表5中的数据计算而得的奥利司他对各种疟原虫的IC50如表6所示。
表6奥利司他对各种疟原虫的IC50(nM)
| 疟原虫 | IC<sub>50</sub>(nM) |
| 恶性疟原虫 | 220.696 |
| 间日疟原虫 | 18.694 |
| 卵形疟原虫 | 4.378 |
| 三日疟原虫 | 0.023 |
实施例1含有奥利司他或奥利司他与第二治疗剂的口服固体制剂的制备
处方
颗粒剂的制备工艺
取处方量的MIX(OsT-X)、磷酸氢钙、淀粉与糊精，混合均匀，过40目筛，用85％乙醇制成软材，过14目尼龙筛制湿颗粒，在60～65℃通风干燥，整粒，干粒加硬脂酸镁，混匀，分装成每5g的颗粒剂。
片剂的制备工艺
取处方量的MIX(OsT-X)、磷酸氢钙、淀粉与糊精，混合均匀，过40目筛，用85％乙醇制成软材，过14目尼龙筛制湿颗粒，在60～65℃通风干燥，整粒，干粒加硬脂酸镁，混匀，压片得每片重250mg的片剂。
胶囊的制备工艺
取处方量的MIX(OsT-X)、磷酸氢钙、淀粉与糊精，混合均匀，过40目筛，用85％乙醇制成软材，过14目尼龙筛制湿颗粒，在60～65℃通风干燥，整粒，干粒加硬脂酸镁，混匀，灌装胶囊，得每粒重250mg的胶囊。
Claims (10)
1.一种奥利司他在制备抗疟疾的药物中的作用，其特征在于，所述疟疾是由恶性疟原虫以外的至少一种疟原虫所致的。
2.根据权利要求1的用途，其特征在于，所述的疟原虫是选自间日疟原虫、卵形疟原虫与三日疟原虫中的至少一种。
3.根据权利要求1或2的用途，其特征在于，所述的药物可制成口服固体制剂。
4.根据权利要求3的用途，其特征在于，所述的口服固体制剂是选自片剂、颗粒剂与胶囊剂中的一种。
5.一种含有奥利司他与第二治疗剂的组合物，其特征在于，所述的第二治疗剂是选自青蒿素、蒿甲醚、青蒿琥酯与双氢青蒿素中的一种。
6.根据权利要求5的组合物，其特征在于，所述的组合物中奥利司他与第二治疗剂的摩尔比在(0.01～100):1之间。
7.根据权利要求5或6的组合物，其特征在于，所述的组合物可制成口服固体制剂。
8.根据权利要求7的组合物，本发明所述的口服固体制剂是选自片剂、胶囊剂与颗粒剂中的一种。
9.根据权利要求5或6的组合物在制备用于抗疟疾的药物中的用途。
10.根据权利要求9的用途，其特征在于，所述的疟原虫是选自恶性疟原虫、间日疟原虫、卵形疟原虫与三日疟原虫中的至少一种。
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| EP4574143A1 (en) * | 2023-12-21 | 2025-06-25 | Universität Regensburg | Inhibitors of plasmodia remodeling enzymes |
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