Pfizer Inc., Center for Discovery and Development Sciences, Groton, Connecticut 06340, United States.
Mol Pharm. 2012 Dec 3;9(12):3526-34. doi: 10.1021/mp3003607. Epub 2012 Oct 30.
Reducing the absorption difference between fed and fasted states is an important goal in the development of pharmaceutical dosage forms. The goal of this work was to develop and characterize a solid nanocrystalline dispersion (SNCD) to improve the oral absorption of ziprasidone in the fasted state, thereby reducing the food effect observed for the commercial formulation. A solution of ziprasidone hydrochloride and the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS) was spray-dried to form a solid amorphous spray-dried dispersion (SDD), which was then exposed to a controlled temperature and relative humidity (RH) to yield the ziprasidone SNCD. The SNCD was characterized using powder X-ray diffraction, thermal analysis, microscopy, and in vitro dissolution testing. These tools indicate the SNCD consists of a high-energy crystalline form of ziprasidone in domains approximately 100 nm in diameter but with crystal grain sizes on the order of 20 nm. The SNCD was dosed orally in capsules to beagle dogs. Pharmacokinetic studies showed complete fasted-state absorption of ziprasidone, achieving the desired improvement in the fed/fasted ratio.
减少进食和禁食状态下的吸收差异是药物剂型开发的一个重要目标。本工作的目的是开发和表征固体纳米结晶分散体（SNCD），以提高 ziprasidone 在禁食状态下的口服吸收，从而减少商业制剂观察到的食物效应。盐酸 ziprasidone 和聚合物羟丙基甲基纤维素醋酸琥珀酸酯（HPMCAS）的溶液经喷雾干燥形成固体无定形喷雾干燥分散体（SDD），然后在受控温度和相对湿度（RH）下暴露于 SDD 以生成 ziprasidone SNCD。使用粉末 X 射线衍射、热分析、显微镜和体外溶解试验对 SNCD 进行了表征。这些工具表明，SNCD 由约 100nm 直径的高能量结晶形式的 ziprasidone 组成，但晶体粒度在 20nm 左右。SNCD 以胶囊形式口服给予比格犬。药代动力学研究表明 ziprasidone 完全在禁食状态下吸收，实现了改善进食/禁食比的预期效果。
