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  2. The elucidation of key factors for oral absorption enhancement of nanocrystal formulations: In vitro-in vivo correlation of nanocrystals

The elucidation of key factors for oral absorption enhancement of nanocrystal formulations: In vitro-in vivo correlation of nanocrystals

  • Eur J Pharm Biopharm. 2020 Jan;146:84-92. doi: 10.1016/j.ejpb.2019.12.002.
Masaaki Imono 1 Hiromasa Uchiyama 2 Shinpei Yoshida 3 Shiro Miyazaki 4 Naomi Tamura 3 Hidekazu Tsutsumimoto 4 Kazunori Kadota 2 Yuichi Tozuka 5
Affiliations

Affiliations

  • 1 Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan; Applied Chemistry and Analysis, Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan.
  • 2 Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
  • 3 Drug Metabolism & Pharmacokinetics, Research Laboratory for Development, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan.
  • 4 Department of Drug Safety & DMPK, Shionogi TechnoAdvance Research Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan.
  • 5 Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. Electronic address: ytozuka@gly.oups.ac.jp.
Abstract

Nanocrystal formulation is a well-established approach for improving oral absorption of poorly water-soluble drugs. However, it is difficult to predict the in vivo performance of nanocrystal formulations from in vitro dissolution studies. The object of the present study was to investigate the in vitro-in vivo correlation of nanocrystal formulations of different particle sizes. A microsuspension and three nanosuspensions with different particle sizes for model drugs, fenofibrate and megestrol acetate, were prepared. In the comparison between the microsuspension and the nanosuspension having the smallest particle sizes, drug permeation rates from the nanosuspension were about 3-fold higher in the dissolution-permeation study. On the other hand, the solubility enhancement effect due to nanocrystal formation was only up by 1.4-fold, suggesting that nanocrystal formulations dramatically improved not the solubility but the apparent permeability. The oral absorption rate in rats increased with particle size reduction. There were positive and very strong correlations (R2 > 0.95) between the in vitro permeation rate and in vivo maximum absorption rate. We concluded that the enhanced permeability rate due to nanocrystal formation is the main factor for improving oral absorption, and the in vitro dissolution-permeation study could be useful for predicting oral absorption enhancement of nanocrystal formulations.

Keywords

Dissolution-permeation study; Fenofibrate; Megestrol acetate; Nanocrystal; Oral absorption enhancement; Permeability.

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