Evaluation of preclinical formulations for a poorly water-soluble compound

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• 作者：Anna-Karin Granath^a ; Kalle Sigfridsson^b ; ^{carl-gustav.sigfridsson@astrazeneca.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：i.v ; Nanocrystals ; Nanosuspension ; High fat diet ; Oil formulation ; s.c. ; SEDDS
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：10 September 2016
• 年：2016
• 卷：511
• 期：1
• 页码：630-637
• 全文大小：552 K

文摘

One central aim of the present work was to find a robust oral formulation approach for Compound A, both to achieve reliable pharmacodynamic read outs but also for long time safety assessment studies. The compound has low aqueous solubility (0.4 μM at 37 °C), is highly lipophilic and has high Caco-2 permeability, i.e. a typical BCS II compound. A nanocrystal formulation, some oil approaches and a fat diet approach were evaluated in vivo in rats. The two latter strategies resulted in significantly higher in vivo exposures after oral administration compared to the nanocrystal approach. For simplicity, and due to the project development program, a food pellet formulation was selected. In addition, tentative data from a subcutaneous study in mice using nanocrystals of the compound are presented, showing extended profiles on the cost of C_max. Exposure data in monkeys after administration of nanocrystals both intravenously and per oral are presented. When switched from nanocrystals to an oil formulation, the observed oral exposure behavior was similar as observed in rats.