On the usefulness of compendial setups and tiny-TIM system in evaluating the in vivo performance of oral drug products with various release profiles in the fasted state: Case example sodium salt of A6197

Abstract

We evaluated the usefulness of quality control dissolution data collected with compendial Apparatus I and II, biorelevant dissolution data collected with compendial apparatus IV, and bioaccessibility data collected with the non-compendial tiny-TIM system in screening modified release formulations during the development of BCS Class I compounds using a Boehringer Ingelheim model experimental compound, A6197. Four products were investigated: an immediate release tablet, an extended release tablet, modified release mini-tablets, and extended release pellets. Data with modified release products collected with the compendial apparatus were evaluated vs. the average intraluminal dissolution estimated after deconvoluting clinical data collected in healthy adults. Data collected with the tiny-TIM system were evaluated vs. the average AUC and C_max values estimated from the clinical data. Unlike with the quality control data collected with Apparatus I and II, data collected with Apparatus IV data and Level I biorelevant media adequately described the intraluminal dissolution process of the three modified release products. Data deviated less than 10% from the actual average deconvoluted intraluminal dissolution profiles, illustrating the usefulness of Apparatus IV biorelevant data in understanding the intraluminal dissolution process of BCS class I small molecules administered as modified release products in the fasted state. Total bioaccessibility data and maximum bioaccessibility data collected using the tiny-TIM and the immediate release tablet and the three modified release drug products correctly reproduced the ranking of A6197 AUC values (R² = 0.989) and C_max values (R² = 0.962), respectively, illustrating tiny-TIM as a useful system for formulation selection of BCS class I small molecules administered in the fasted state.

Keywords: Biorelevant dissolution; Dissolution apparatus I; Dissolution apparatus II; Dissolution apparatus IV; Immediate release; Modified release; Pharmaceutical bioaccessibility; Tiny-TIM system.