Date Published: February 13, 2020
Publisher: Springer International Publishing
Author(s): Robert Price, Jagdeep Shur, William Ganley, Gonçalo Farias, Nikoletta Fotaki, Denise S. Conti, Renishkumar Delvadia, Mohammad Absar, Bhawana Saluja, Sau Lee.
The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) and a range of dry powder inhaler (DPI) formulations containing inhaled corticosteroids were tested. The uniform distribution of the validated ISM dose considerably reduced drug loading effects on the dissolution profiles for both MDI and DPI formulations. The improvement in the robustness and discriminatory capability of the technique enabled characterization of dissolution rate differences between inhaler platforms and between different DPI product strengths containing fluticasone propionate. A good correlation between in vivo mean absorption time and in vitro dissolution half-life was found for a range of the inhaled corticosteroids. The ADC system and the reproducible in vitro POD dissolution measurements provided a quantitative-based approach for measuring the relationship between the influence of device and the dispersion characteristics on the aerosol dissolution of low solubility compounds. The in vitro dissolution method could potentially be applied as a dissolution methodology for compendial, quality control release testing, and during development of both branded orally inhaled drug products and their generic counterparts.
For a locally acting inhaled drug product to elicit a pharmacological effect, the therapeutic dose must first reach the mucosal surface, lining the respiratory tract. Upon reaching the respiratory mucosa, the fate of the inhaled drug substance is not well understood. However, it is believed that the critical determinants that affect the local drug concentration at the sites of action, as well as the rate and extent of drug absorption through the lung, are the deposition pattern (i.e., the distribution of the respirable dose among mouth–throat regions, conducting and peripheral airways), the molecular properties of the active pharmaceutical ingredient (API) and the need for the drug to be in solution, that is, the in vivo dissolution kinetics (1).
Upon initially validating the dose collection efficiency of the ADC system, the apparatus was used to investigate loaded dose effects (approximately 50–500 μg) on the dissolution release profiles of both 250 μg FP DPI and 125 μg FP MDI. The system was also used to study the relationship between mean absorption time and dissolution kinetics of a series of low solubility inhaled corticosteroids. Finally, the dissolution characteristics of FP from the three different product strengths of FP MDI, FP DPI, and S/FP DPI products were compared.
In this study, we have designed and engineered a novel dose collection system for in vitro dissolution testing of orally inhaled drug products that uniformly distributed the whole impactor stage mass (ISM) onto a single membrane surface. The validated dose collection method was utilized to demonstrate that dissolution profiles of both commercial MDI and DPI products were independent of loaded dose over a wide range of concentrations of drug loading. The independence of the dissolution rate measurements with loaded mass allowed quantitative comparisons to be made between formulation characteristics and dissolution behavior. The increase in robustness and the discriminatory capability of the dissolution method developed in this work may enable quantitative-based comparisons of orally inhaled drug products (inter- and intra-batches) and may aid in the development of a standardized dissolution method for compendial testing of orally inhaled drug products.