Prediction of pharmacokinetic studies outcome for locally acting nasal sprays by using different in vitro methods

Abstract

Demonstration of bioequivalence of locally acting nasal spray formulations is a challenging task and the regulatory agencies have different approach towards this goal. The pharmacokinetic bioequivalence studies are recognized as necessary for assessment of equivalent systemic exposure. We utilized three different in vitro methods for nasal spray evaluation and compared those results with the results of pharmacokinetic studies of different formulations of four intranasal corticosteroids, in order to evaluate their in vivo relevance. Two cell lines, RPMI 2650 and Calu-3, Transwell® polycarbonate membranes with different pore size and lipid-oil-lipid tri-layer membrane in the parallel artificial membrane permeability assay (PAMPA) system were used for this purpose. The in vitro results correlated with the results of pharmacokinetic studies and correctly predicted (non)equivalence of the nasal sprays, showing that in vitro methods are good indicator of the in vivo outcome. The Transwell® and PAMPA in vitro methods were additionally implemented for testing batch-to-batch variability of reference nasal spray formulations. The results from the Transwell® assay for the two poorly soluble corticosteroids are possibly over-discriminatory in showing differences between batches of reference nasal sprays. Overall, the three in vitro methods have potential to predict the results of bioequivalence testing of nasal spray products.

Keywords: Calu-3 cell line; Intranasal corticosteroids; Parallel artificial membrane permeability assay (PAMPA); Pharmacokinetic bioequivalence studies; RPMI 2650 cell line; Transwell® system.