The importance of dissolution for orally inhaled drug products: pharmaceutical, regulatory, and clinical considerations.

Abstract

Almost all current orally inhaled drug products (OIDPs) are for the treatment of respiratory diseases, and many have been designed using molecular or formulation strategies to retain drug in the lungs. After deposition in the lungs, the rate at which aerosol particles release drug into the lung lining fluid is a determinant of local bioavailability for drugs with poor solubility. Slow dissolution provides an absorption rate-limiting mechanism for prolonging lung exposure to an inhaled drug and extending the duration of pharmacodynamic effects. Historically, the Inhalation Ad Hoc Advisory Panel of the United States (US) Pharmacopoeia (2008) considered that there was an absence of ‘compelling evidence that dissolution testing is kinetically important for currently approved inhaled drug products’; a conclusion supported in 2012 by an IPAC-RS Dissolution Working Group [1]. Paradoxically, there has since been an intensification of interest in dissolution testing for OIDPs, driven at least in part by the US Food and Drug Administration sponsorship of research in this area [2,3]. More recently, solubility has been proposed as a key attribute of the drug substance and dissolution as a key attribute of the drug product under the foundational principles of an inhaled biopharmaceuticals classification system (iBCS) [4]. This brings closer the prospect of dissolution being recognized formally as a critical quality attribute for certain classes of OIDP and that in vitro dissolution methods will be required to characterize OIDPs in a way that is biorelevant, predictive, and can be used with confidence by medicine developers and regulators. Developing a biorelevant dissolution assay for OIDPs is challenging in practice, requiring collection of a relevant aerosol fraction, a dissolution apparatus, and dissolution medium that replicate the key determinants of dissolution in the lungs and methods for data analysis and interpretation. This article summarizes briefly recent developments in dissolution testing with a focus on pharmaceutical, regulatory, and clinical relevance (Figure 1).