Characterization of Dissolution-Permeation System using Hollow Fiber Membrane Module and Utility to Predict in Vivo Drug Permeation Across BCS Classes

Abstract

A dissolution-permeation system has potential to provide insight into the kinetic contributions of dissolution and permeation to overall drug absorption. The goals of the study were to characterize a dissolution-hollow fiber membrane (D-HFM) system and compare its resulting in vitro drug permeation constants (K_p^') to in vivo clinical permeation constants (k_p), for four drugs in various Biopharmaceutics Classification System (BCS) classes. Model predictions for D-HFM were made based on derived mixing tank (MT) and complete radial (CRM) flow models and independent measurement of membrane permeability. Experimental D-HFM studies included donor flow rate and donor volume sensitivity studies, and drug permeation profile studies. Additionally, for the four drugs, K_p^'from D-HFM system was compared to (k_p) from literature, as well as K_p^' values from side-by-side diffusion cell and dissolution/Caco-2 system. Results show progressive D-HFM system development as a dissolution-permeation tool. Results indicated that D-HFM models using MT or CRM provided close agreement between predicted and observed drug permeation profiles. Drug permeation in D-HFM system was volume dependent, as predicted. Favorably, more drug permeated through the D-HFM system (10-20% in 60 min) compared to side-by-side diffusion cell (1%) and dissolution/Caco-2 system (0.1%). K_p^' from D-HFM system was also closer to in vivo k_p; the two other in vitro models showed lower K_p^'. Overall, studies reflect that HFM module has potential to incorporate drug permeation into the in vitro assessment of in vivo tablet and capsule performance.

Keywords: Absorption; Biopharmaceutics classification system; Caco-2; Dissolution; Permeation; Pharmacokinetics.