Improving solubility and oral bioavailability of a novel antimalarial prodrug: comparing spray-dried dispersions with self-emulsifying drug delivery systems.
Improving solubility and oral bioavailability of a novel antimalarial prodrug: comparing spray-dried dispersions with self-emulsifying drug delivery systems.
复制标题
DOI：
10.1080/10837450.2020.1725893
复制
发表时间：
2020-06
影响因子：
3.4
通讯作者：
Shankar G
中科院分区：
文献类型：
--
作者：
Potharaju S;Mutyam SK;Liu M;Green C;Frueh L;Nilsen A;Pou S;Winter R;Riscoe MK;Shankar G
为了改善新型抗疟药ELQ-331(ELQ-300的前药)的溶解度和口服生物利用度，开发了喷雾干燥分散体(SDD)和自乳化给药系统(SEDDS)。以聚乙烯己内酰胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物(Soluplus®)为载体，以Aerperl®300 Pharma为载体制备了喷雾干燥分散体，并用差示扫描量热法、粉末X射线衍射仪对其进行了表征。对于SEDDS，测定了其在油、表面活性剂和助表面活性剂中的溶解度，并绘制了三元相图以显示自乳化区域。对SEDDS的自发乳化和液滴大小分布进行了表征。非晶态ELQ-331SDD在禁食状态的模拟肠液中的溶解度提高到10倍，在SDDS中加入十二烷基硫酸钠后，其在~28.5X的溶解度进一步提高到非处方药物。SEDDS具有良好的自乳化特性，乳滴尺寸小，粒径分布窄。在大鼠体内进行了SDD和SEDDS制剂的口服药代动力学研究。在大鼠口服后不久，ELQ-331迅速转变为ELQ-300。SEDDS中ELQ-300的暴露水平(基于AUC)大约是SDD配方的1.4倍。像ELQ-331这样的难溶药物可以使用SDD或SEDDS来配方，以提高溶解度和口服生物利用度。
To improve the solubility and oral bioavailability of a novel antimalarial agent ELQ-331 (a prodrug of ELQ-300), spray-dried dispersions (SDD) and a self-emulsifying drug delivery system (SEDDS) were developed. Spray-dried dispersions were prepared with polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) polymer carrier and Aeroperl® 300 Pharma and characterized by differential scanning calorimetry, powder x-ray diffraction. For SEDDS, solubility in oils, surfactants, and co-surfactants was determined and ternary phase diagram was constructed to show self-emulsifying area. SEDDS were characterized for spontaneous emulsification and droplet size distribution. The amorphous ELQ-331 SDD improved the solubility to 10X in fasted-state simulated intestinal fluid and addition of sodium lauryl sulphate externally to SDDs further improved the solubility to ~28.5X vs non-formulated drug. SEDDS had good self-emulsifying characteristics with small emulsion droplet sizes and narrow particle distribution. Oral pharmacokinetic studies for SDD and SEDDS formulations were performed in rats. The ELQ-331 rapidly converted to ELQ-300 soon after oral administration in rats. Exposure levels of ELQ-300 were about 1.4-fold higher (based on AUC) in SEDDS than SDD formulations. Poorly soluble drugs like ELQ-331 can be formulated using SDD or SEDDS to improve solubility and oral bioavailability.