Assessment of Bioequivalence in Nasal Sprays Containing Suspension Formulations

Abstract

FDA's draft guidance "Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (2003)" recommends that the bioequivalence (BE) of nasal suspension products should be established not only by a battery of in vitro tests but also clinical studies. However, locally acting solutions do not necessitate a clinical comparison. The different requirements for nasal solution and suspension formulations are based on the assumptions that in vitro studies are more sensitive indicators of drug delivery to nasal cavity than are clinical studies, and that the drug particle size distributions (PSDs) in suspension formulations may potentially affect the rate and extent of drug availability to nasal sites of action and to the systemic circulation. So the difficulty in establishing the BE of nasal spray suspension products through expensive clinical trials have become a long-standing challenge for the generic pharmaceutical industry and subsequently few generic nasal suspension products have been approved compared to the nasal solutions. Whether the sizes and shapes of primary drug particles in nasal suspensions influence drug absorption in local nasal passage was investigated in this project through 1) In vitro tests including viscosity measurement, spray weight testing, droplet size distribution characterization, spray pattern and plume geometry studies; 2) In vitro drug absorption studies such as drug uptake and transport in a human bronchial epithelium cell line Calu-3 cells, and dissolution tests in beakers and the USP apparatus II with a sensitive and robust LC/MS/MS assay method; 3) In vitro anti-inflammatory activity evaluation using necrosis factor κB reporter plasmids and nitrite measurement. Results showed that the sizes of primary drug particles in the small range with Dv50s of 2.13-3.35 µm did not influence the in vitro performances of nasal suspension formulations. Smaller particles (Dv50=1.58 µm) and spherical particles (Dv50=3.87 µm) exhibited slightly higher or lower dissolution rate differences which was nevertheless not reflected in the in vitro characterization tests, drug uptake, transport and in vitro efficacy studies. This project suggested that nasal suspension spray products containing primary drug particles with different sizes and shapes in the relevant range may not affect the drug absorption and in vivo BE studies may potentially be waived once the drug particle size and shape design space is defined.