Abstract
Background: Inhaled drug particles dissolve in the respiratory tract lining fluid (RTLF) to get absorbed and show therapeutic effects. The RTLF is a thin fluid that covers the surface of the respiratory system from nasal airways to alveolar region. Composition and thickness of the RTLF varies along the respiratory tract. Moreover, the RTLF is non-stationary because of pulmonary ventilation and mucociliary clearance (MCC). In the upper respiratory tract, the RTLF moves towards oropharynx at a constant speed referred as MCC. Therefore, we hypothesize that composition, volume and movement of the RTLF impact on dissolution and absorption of inhaled drug particles in the lungs.
Purpose: The research work reported in this thesis basically aimed to investigate the impact of composition, volume and movement of simulated RTLF on in vitro dissolution permeation of an inhalable model drug, triamcinolone acetonide (TAA). Moreover, it aimed to explore mathematical relationships between simulated RTLF components with their attributes.
Methods: Components such as polyethylene oxide (non-protein mucus simulant), Curosurf® (commercial lung surfactant), albumin (protein), L-ascorbic acid and phosphate buffered saline (PBS) were used to prepare simulated RTLFs to investigate the impact of composition. Using these simulated RTLFs, in vitro dissolution permeation studies were conducted in small volume custom-made dissolution apparatus that was updated to include the movement of fluid. For the first-time such fluid movement has been included in a small volume dissolution apparatus. In addition, in vitro dissolution-permeation experiments were carried out using different volumes of fluid and by introducing variation in the movement of fluid to investigate the impact of volume and movement respectively. Furthermore, simulated RTLFs were prepared using proteins such as albumin, transferrin and IgG along with polyethylene oxide and PBS to investigate the impact of protein type and content. Finally, univariate and multivariate regression models were established between simulated RTLF components and attributes such as surface tension, viscosity and in vitro dissolution-permeation of TAA.
Results: Simulated RTLF components such as polyethylene oxide and Curosurf® decreased in vitro dissolution-permeation of TAA. The volume and movement of fluid had no impact on dissolution-permeation of TAA. Inclusion of transferrin in the simulated RTLF resulted in higher dissolution-permeation of TAA in comparison to IgG. Dissolution-permeation of TAA for simulated RTLFs containing protein combination was in the order; (albumin + transferrin) > albumin and (albumin + transferrin) > (albumin + transferrin + IgG). Univariate regression model established between in vitro dissolution-permeation of TAA and polyethylene oxide was fit for the data. Multivariate regression model for in vitro dissolution permeation of TAA fitted the data and suggested that dissolution-permeation depended only upon polyethylene oxide.
Conclusions: Regional variation in composition of RTLF like mucus and surfactant may affect dissolution and absorption of drugs in the lungs. However, volume (thickness) and movement (speed or MCC) of RTLF may not have similar effect. Variation in protein composition of the RTLF may impact on dissolution and absorption of inhaled drug particles. Regression analysis shows that dissolution and absorption of inhaled drug particles mainly depend upon mucus component (polyethylene oxide) of simulated RTLF.