一种提高极难溶性新化合物生物利用度的处方开发及评价研究

发布时间：2019-03-14 19:01

【摘要】：目的:研究制剂新型乳化剂、助乳化剂、pH值等因素对难溶性药物的增溶效果,开发一种能够提高极难溶性抗肿瘤新化合物SIPI6908动物体内生物利用度的溶媒处方。方法:选择3个溶媒系统,以MS-275为阳性对照药,进行SIPI6908的处方研究试验,在进行ICR小鼠急毒试验和SD大鼠药代试验对比研究的基础上,发现处方为3%C_2H_5OH+10%HCl(pH 0.75)+20%Solutol HS15+40%PEG400+CH_3COONa(pH 4.0)的溶媒系统可有效提高SIPI6908的生物利用度。结果:该处方能将SIPI6908的溶解度从0.011增加至10 mg·mL~(-1);SD大鼠的生物利用度为(29.52±2.49)%,远大于早期开发的普通处方2.74%;空白溶媒处方无急毒性,且在该溶媒处方条件下ICR小鼠的LD_(50)(401.18 mg·kg~(-1))大于同等处方下阳性药MS-275的LD_(50)(304.82 mg·kg~(-1));同一溶媒处方条件下亦能达到阳性药MS-275的肿瘤抑制率。结论:研发新型溶媒处方,分析评价其安全性和有效性,为难溶性新化合物的研究提供了新思路。
[Abstract]:Aim: to study the solubilization effect of new emulsifier, co-emulsifier and pH value on insoluble drugs, and to develop a new solvent prescription which can improve the bioavailability of the new insoluble anti-tumor compound SIPI6908 in vivo. Methods: three solvent systems were selected to study the prescription of SIPI6908 with MS-275 as positive control drug. On the basis of comparative study of acute toxicity test in ICR mice and pharmacokinetic test in SD rats, It was found that the solvent system with prescription 3%C_2H_5OH 10%HCl (pH 0.75) 20%Solutol HS15 40%PEG400 CH_3COONa (pH 4.0) could effectively improve the bioavailability of SIPI6908. Results: this prescription could increase the solubility of SIPI6908 from 0.011 to (29.52 卤2.49)% in 10 mg 路mL ~ (- 1); SD rats, which was much higher than that of the general prescription developed in the early stage (2.74%). The LD_ (50) (401.18 mg kg~ _ (- 1) of ICR mice was higher than that of LD_ (50) of MS-275 (- 1);) (304.82 mg kg~ (- 1);) under the same prescription condition. Under the condition of the same solvent prescription, the tumor inhibition rate of the positive drug MS-275 could also be achieved. Conclusion: a new formulation of solvent is developed, and its safety and effectiveness are analyzed and evaluated, which provides a new idea for the study of new insoluble compounds.
【作者单位】：中国医药工业研究总院上海医药工业研究院;中国药科大学;
【基金】：上海市科技人才计划项目(15QB1404400)
【分类号】：R943

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