Development and validation of an in vitro permeation test method for rectal mesalamine suppositories.

For locally-acting rectal drug products, an assessment of bioequivalence has traditionally necessitated an in vivo comparative clinical endpoint bioequivalence study. By contrast, for locally-acting dermal drug products, an in vitro permeation test (IVPT) using excised skin has become a useful tool to evaluate and compare topical bioavailability as a component of bioequivalence approaches for products applied to the skin. However, whether an IVPT study using excised mucosal tissue could be used in a similar manner to efficiently evaluate the rate and extent of local bioavailability for transmucosal drug products (e.g., rectal drug products) was unknown. To explore this, the present research thoroughly investigated the key considerations such as mucosal tissue handling procedures, study duration, individual animal donor tissue variation as well as method validation strategies for IVPT studies with locally-acting rectal drug products, using mesalamine rectal suppositories as model transmucosal drug products. A reproducible and discriminatory IVPT method using excised porcine rectal tissues mounted in a vertical diffusion cell (VDC) was successfully developed and IVPT method validation strategies were investigated. The established IVPT method was capable of detecting differences in drug permeation resulting from differences in strength, dose duration, and dosage form (suppository vs. solution) under the conditions evaluated. A comparative IVPT study was conducted to characterize the rate and extent of drug permeation behavior for the marketed reference listed drug (RLD) product and laboratory-made (LM) mesalamine rectal suppositories using excised porcine rectal tissues from multiple donors. The results of our research demonstrated the feasibility of utilizing IVPT studies with mucosal tissues to evaluate the in vitro performance of locally-acting rectal semisolid drug products. Data from such studies are in vitro surrogates that are expected to enhance our understanding of local drug bioavailability from these drug products and may contribute to an overall assessment of bioequivalence in the future.