• 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      FDA's draft guidance "Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (2003)" recommends that the bioequivalence (BE) of nasal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.
    • In Vitro Dissolution, Supersaturation, and Permeation to Predict In Vivo Oral Drug Absorption

      Adhikari, Asmita; Polli, James E. (2022)
      Most new drug candidates are poorly water soluble, and as such have limited absorption and bioavailability. The current research focuses on two major aspects of oral drug absorption research (i) characterization of spray dried dispersions (SDDs) of a poorly soluble drug to elucidate the factors that impact overall formulation performance and absorption, and (ii) development and utilization of an in vitro dissolution-permeation model to predict in vivo human absorption and performance of various drugs representing different Biopharmaceutic Classification System (BCS) classes. The first aim was to characterize itraconazole (ITZ) SDDs from three grades (L, M and, H) of hydroxypropyl methylcellulose acetate succinate (HPMCAS) polymer based on supersaturation kinetics and molecular interactions that contributed to the overall SDD performance and drug absorption. A combination of in vitro and solution state drug-polymer interaction studies was used. Results indicated that a high supersaturating concentration, and rate and extent of supersaturation caused the largest increase in absorption. We concluded that such stronger hydrophobic interactions between drug and polymer were relative detriment to ITZ absorption for ITZ and HPMCAS SDDs. Conventional dissolution testing has been modified in terms of in vitro design and medium composition. Biorelevant media closely simulate the composition of human gastrointestinal fluids but are challenging to prepare and contain multiple components. The second aim was to assess the similarity of dissolution profiles from biorelevant media. Results indicated favorable interday repeatability, interanalyst repeatability, and interlaboratory reproducibility suggesting this approach could be incorporated into clinically relevant dissolution models. An in vitro model that can capture the dynamic interplay between dissolution and permeation is sought for poorly soluble drugs, with potential to guide the drug development process and product life cycle management. The third aim was to characterize and utilize a dissolution-hollow fiber membrane (D-HFM) system to correlate in vitro and in vivo parameters for several BCS classes drugs. Model predictions and experimental D-HFM system studies were performed using drug solutions and drug products. Results indicated close agreement between predicted and observed drug permeation profiles, and between the D-HFM system derived in vitro and in vivo permeation constants and absorption profiles.