In vitro-in vivo correlation in the effect of cyclodextrin on oral absorption of poorly soluble drugs.

In this study the concentration effect of 2-Hydroxypropyl-beta-cyclodextrin (HP-ßCyD) on oral drug absorption of the BCS class II drugs Danazol (DNZ) and Albendazole (ABZ) was evaluated. In vitro permeation of solutions and suspension systems was compared with their in vivo intestinal absorption in rats and their in vitro-in vivo correlation assessed. In solutions excess amounts of HP-ßCyD decreased both in vitro permeation and in vivo absorption due to the decrease in free drug concentration, as expected. However, in suspension systems the contribution of HP-ßCyD by drug complexation was found to be altered by further rate limiting steps for membrane permeation and intestinal absorption of each drug. In vitro permeation of DNZ was rate-limited by the diffusion into the unstirred water layer (UWL), while that of ABZ was rate-limited by the permeation across the lipid membrane. For the in vivo intestinal absorption, both drugs were rate-limited by the dissolution rate from undissolved drug. These differences in the rate-limiting process were considered to cause discrepancies in the result of in vitro and in vivo assays. In conclusion, it is quite important to understand the rate limiting process of oral absorption of the target drug for designing oral liquid formulations containing cyclodextrins.

Harmonizing solubility measurement to lower inter-laboratory variance - progress of consortium of biopharmaceutical tools (CoBiTo) in Japan.

The purpose of the present study was to harmonize the protocol of equilibrium solubility measurements for poorly water-soluble drugs to lower inter-laboratory variance. The "mandatory" and "recommended" procedures for the shake-flask method were harmonized based on the knowledge and experiences of each company and information from the literature. The solubility of model drugs was measured by the harmonized protocol (HP) and the non-harmonized proprietary protocol of each company (nonHP). Albendazole, griseofulvin, dipyridamole, and glibenclamide were used as model drugs. When using the nonHP, the solubility values showed large inter-laboratory variance. In contrast, inter-laboratory variance was markedly reduced when using the HP.

Application of an In Vitro Dissolution/Permeation System to Early Screening of Oral Formulations of Poorly Soluble, Weakly Basic Drugs Containing an Acidic pH-Modifier.

This study aimed to evaluate the usefulness of the dissolution/permeation system (D/P system) as an in vitro tool for early screening of oral formulations of weakly basic drugs containing an acidic pH-modifier. Dipyridamole, having a prominent pH-dependent solubility, was used as a model drug, and various granules containing different amounts of fumaric acid were prepared. Prepared granules were administered orally to hypochlorhydria model rats. It was confirmed that fumaric acid improved the absorption of dipyridamole depending on its amount in the granules. Separately, dissolution and permeation of dipyridamole were observed in vitro in the D/P system. When using a medium with a low buffer capacity which mimicked the human intestinal fluid, rank order of the permeated amount of dipyridamole from various granules in the D/P system did not correlate with its absorption in hypochlorhydric rats. In contrast, when applying a medium with high buffer capacity, the permeated amount in the D/P system well reflected the effects of fumaric acid on the in vivo absorption of dipyridamole. In conclusion, by setting appropriate experimental protocols according to the properties of test compounds and formulations, D/P system can be a potent in vitro tool to predict in vivo performance of oral formulations.