There are many challenges in predicting the fate of inhaled particles in the lung and to determine the influence of formulation and device factors on the efficacy and safety of orally inhaled drug products. In this proposal, we seek to develop a in vitro dissolution system, which can predict clinically related endpoints such as the rate and extent of drug absorption measured by pharmacokinetics. The major research objective is to develop a robust dissolution system which takes into account the composition and limited lung fluid available for dissolution, influence of local dosimetry differences between formulations and devices and how these factors influence dissolution and permeability of drugs for delivery to the respiratory tract. A greater understanding and IVIVC mathematical modeling of the relationship between the physico---chemical properties of drugs, local dissolution effects and permeability will provide the necessary science and tools to enable greater control of product safety, efficacy, potency, quality and functionality. The exploration into the relationship between dissolution, permeability and pharmacokinetics will enable the FDA to direct both branded and generic industries to define quality and functionality of orally inhaled drug products.
This project addresses one of the major hurdles in regulatory science of orally inhaled drug products (OIDPs). The ability to predict clinical based outcomes of therapeutic efficacy and safety of orally inhaled drugs requires an understanding of the site of deposition, local in vivo dissolution and drug permeability. To gain a better understanding of the relationship between device and formulation factors and how they impact dissolution, an in vitro dissolution model is required which simulates the limited lung fluid, its composition, mass of drug deposited per unit surface area and the concentration gradient required for passive diffusion of the solute. This study will show the use and merits of a bespoke in vitro dissolution system to measure the dissolution rates of a range of drugs, dry powder inhalers (DPIs), solution and suspension based pressurized metered dose inhaler (pMDIs). Results obtained from this study will be used to gain better understanding of the formulation factors that impact dissolution and thereby in vitro---in vivo relationships for orally inhaled drugs through the use of mathematical based modeling.