• Assessment of Bioequivalence in Nasal Sprays Containing Suspension Formulations

      Jin, Feiyan; Dalby, Richard N. (2010)
      FDA's draft guidance "Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (2003)" recommends that the bioequivalence (BE) of nasal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.
    • Development of a Novel Color Based Method for Assessing Deposition Patterns of Nasal Sprays and Nebulized Aerosols

      Kundoor, Vipra; Dalby, Richard N. (2010)
      Aqueous nasal sprays are widely used to treat patients with local diseases such as allergic rhinitis. Several nasally administered corticosteroid products are nearing patent expiration and are candidates for generic copies, which is driving interest in how bioequivalence will be established - possibly using clinical and scintigraphic methods, but these methods each have specific limitations, as does the existing practice of measuring spray pattern and plume geometry which have proven difficult to correlate with nasal deposition. To overcome these limitations this thesis focused on designing a simple and inexpensive method that allows simulation of nasal anatomy and airflow, and is able to visualize and quantify deposition patterns of nasal sprays. Initially, we used the method to compare deposition patterns of different nasal sprays and different nasal drug delivery devices. Results showed that lower viscosity formulations provided greater coverage than the higher viscosity formulation and the nebulizer covered a greater surface area than the spray pump we evaluated. We also systematically investigated the effect of various formulation and patient related factors, and inspiratory flow rate on nasal deposition pattern and the results obtained showed that inspiratory flow rate did not have a significant effect whereas formulation and patient related factors had a significant effect on deposition pattern. Since bioequivalence of nasal sprays is carried out using in vitro studies, we compared the method to laser based systems which are used to measure spray pattern and plume geometry and we found that both the methods yielded similar results. We also evaluated the use of the method on cascade impactor stages (to detect droplet deposition) and on model faces fitted with facemasks (to quantify unintended facial and ocular droplet deposition associated with nebulizer use). It revealed that impactor temperature does have an effect on the size of nebulized droplets and facemask design had a significant effect on unintended facial and ocular deposition of nebulized droplets. This thesis demonstrates that this approach can be used as an alternative tool to justifiably establish in vitro bioequivalence of nasally administered, locally acting drug solutions and also provide a scientific rationale for justifying patient instructions for use.