Description
Clinical performance of orally inhaled drug products (OIDPs) depends not only on regional drug deposition in the lung but also on in vivo drug dissolution rate, thereby affecting local availability of the drug at sites of action in the lung as well as rate and extent of the drug absorption from the lung. An ideal dissolution method for inhalation products should take into account various biological and physicochemical factors including, but not limited to, scarce lung lining fluid available for drug dissolution, presence of endogenous lung surfactants, mass of drug deposited per unit surface area of lung and inter-particulate interactions of the depositing particles. Several attempts have been made to develop dissolution methods for characterization of OIDPs; however, none of the methods captures all the key factors described above and the methods developed have not been shown to be predictive of in vivo dissolution. In order to provide better prediction of drug dissolution within the lung, it is necessary to develop a dissolution method that accounts for relevant biological and physicochemical factors that impact drug dissolution in vivo. In 2011, OGD initiated a study titled Pharmacokinetics of Locally Acting Orally Inhaled Drug Products to evaluate the sensitivity of PK to differences in the aerodynamic particle size distribution (APSD) for three different formulations of an inhaled corticosteroid (fluticasone propionate, FP) dry powder inhaler (DPI). As differences in PK may result due to factors including, but not limited to, differences in dissolution rate of the formulations, it would be preferable to study the dissolution of the these formulations and incorporate this information to build a model to link regional lung deposition to PK. Objective The goal of this project is to develop an in vitro dissolution method for OIDPs which will be capable of predicting in vivo dissolution of drugs that are administered via the inhalation route. The 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. This investigation will constitute a significant step towards gaining a better understanding of relationship among OIDP formulations and local availability (efficacy) and pharmacokinetics (PK, safety). The outcome of the project will aid in development of a quality-by-design (QbD) tool that could be used for formulation development and optimization as well as product quality control. Detailed Description A predictive dissolution model will be developed to study the effect of formulation factors (API particle size, formulation composition, etc.) on dissolution of aerosolized drug particles. This investigation will consist of 3 phases: Phase 1: Development/ modification of existing dissolution methods for OIDPs, by accounting for mass of drug deposited per unit surface lung area, limited lung lining fluid and other factors that may impact drug dissolution in vivo. Phase 2: Selection of OIDPs for dissolution study. OIDPs should be selected to represent a range of physicochemical properties of the API (e.g., solubility, particle size, crystallanity, lipophilicity, adhesive/cohesive properties). The selected OIPDs should represent solution and suspension-based metered dose inhalers, and DPIs. OGDs research FP formulations will be provided for the study. Phase 3: Development of a mathematical model to describe a relationship between the in vitro dissolution data and PK.