处方和粒径减少提高难溶于水的抗疟疾药物的生物利用度..docVIP

Formulation and Particle Size Reduction Improve Bioavailability of Poorly Water-Soluble Compounds with Antimalarial Activity Hongxing Wang, Qigui Li, Sean Reyes, Jing Zhang, Lisa Xie, VictorMelendez, Mark Hickman, andMichael P. Kozar Decoquinate癸氧喹酯 (DQ) is highly effective at killing malaria parasites in vitro; however, it is extremely insoluble in water. In this study, solid dispersion method was used for DQ formulation which created a suitable physical form of DQ in aqueous phase for particle manipulation（固体分散体的方法是：DQ为处方，使其可以在水相中分散溶解）. Among many polymers and surfactants tested, polyvinylpyrrolidone 10（聚乙烯吡咯烷酮10）, a polymer, and L-α-phosphatidylcholine（L-α-卵磷脂） or polysorbate【聚山梨醇酯（吐温）】, two surfactants, were chosen as DQ formulation components.The formulation particles were reduced to a mean size between 200 to 400 nm, which was stable in aqueous medium for at least three weeks（处方粒径平均200-400nm，在水相中至少稳定3周）. Pharmacokinetic (PK) studies showed that compared to DQ microparticle suspension（相比起微粒悬浮）, a nanoparticle formulation（纳米处方） orally dosed to mice showed a 14.47-fold increase in area under the curve (AUC) of DQ plasma concentration （小鼠口服后DQ血药浓度曲线下面积增加了14.17倍）and a 4.53-fold increase in AUC of DQ liver distribution（肝脏分配AUC增加了4.53倍）. WR 299666, a poorly water-soluble compound with antimalarial activity, was also tested and successfully made into nanoparticle formulation without undergoing solid dispersion procedure. We concluded that nanoparticles generated by using appropriate formulation components and sufficient particle size reduction significantly increased the bioavailability of DQ and could potentially turn this antimalarial agent to a therapeutic drug. 1. Introduction DQ has been marketed as a veterinary medicine for inhibiting the growth of coccidiosis（球虫病） in the digestive system of poultry for many years without any obvious adverse effects （DQ作为一种兽药，可以抑制家禽消化系统球虫病的发展而没有明显的副作用）[1]. This compound has been shown experimentally to have efficacy against