Comparative Human in-vivo Study And The Impact Of The Dissolution Rate On Bioequivalence

By Sven Stegemann, Sudershan Vishwanath, Ravi Kumar, Dominique Cade, Missy Lowery, Keith Hutchison, Michael Morgen, Aaron Goodwin and Chang Lee

Rapid and consistent in-vivo drug dissolution is critical for drug absorption. In-vitro dissolutions tests are used to predict in-vivo disintegration and dissolution properties of drug products. The in-vitro disintegration and dissolution times of tablets and capsules can vary significantly based on their composition and processing. Though small differences in-vitro dissolution are not expected to result in significant in-vivo performance differences, the slight in-vitro dissolution delay observed by over-encapsulation for double blind clinical trials, as well as switching from gelatin to HPMC capsules often raises concerns on the potential impact on in-vivo bioavailability. While it is accepted that the in-vitro dissolution delay of about 5 minutes caused by over-encapsulation with gelatin capsules of immediate release (IR) tablets or powder formulation does not lead to non-bioequivalence, no data on bioequivalence exist for over-encapsulation with an HPMC capsule having a dissolution lag time of around 10 minutes. To assess the potential impact, a comparative investigation was performed using in-vitro dissolution, PK simulation and human bioequivalence comparing an IR fixed dose combination compressed caplet containing three different rapidly-absorbed drugs over-encapsulated with gelatin capsules and the same caplet over-encapsulated with HPMC capsules made by a thermo-gelation process.