Systematic Evaluation of Excipient Effects on the Efficacy of Metered Dose Inhaler Products (U01)

There are a multitude of factors to be considered when developing a metered dose inhaler (MDI); drug-excipient interactions are one of them. Although much is known about these complex interactions at the empirical level, there is a lack of a systematic understanding of the effects of these interactions on the MDI product performance. More importantly, it is not well understood to what extent MDI product performance depends on the amount of co-solvents and surface active agents used in the formulation. Hence, a study that establishes this relationship would be very valuable, not only because it will provide a missing piece of scientific information in this area, but also because it will enhance the FDA's reviewing process under the quality by design (QbD) paradigm. Objectives The project will investigate the effect of excipient concentrations on the aerosolization performance of typical hydroflouroalkane (HFA)-based metered dose inhaler formulations and evaluate the sensitivity of the in vitro methods in detecting excipient concentration changes. Detailed Description The study will be divided into four phases. Phase 1: Selection of ideal drug candidates, representative drug particle sizes and design space of the study. Selection of ideal drug candidates: Selection of drug candidates should be based on their physicochemical properties, such that their results could be generalizable to other drugs. Additionally, the drug candidates should represent both solution and suspension MDIs. Selection of initial drug particle size to study suspension MDI: The drug candidates representing suspension MDIs, should be processed (micronized) to obtain two distinct particle size distributions that bracket the range of particle size distributions of the marketed formulations. Phase 2: Study the effect of addition of different amounts of co-solvent (ethanol) and surfactant (oleic acid) and propellant (HFA-134a) on MDI performance The effect of varying amounts of these three excipients on MDI performance should be evaluated. An appropriate experimental design (i.e. full/fraction factorial design, central composite design, or Box-Behnken design) should be selected to keep the number of experiments practically manageable without compromising the study power. The levels of excipients investigated in the study should be based on the inactive ingredient database (IID) safety limit. The study should include the scenarios where amounts of excipients are changed within as well as outside FDA's recommended Q2 acceptance limit of 5%. MDI performance should be tested using the Compendial tests (According to the methods described in USP and/or FDA's Guidance for Industry) and non-compendial tests including, but not limited to, dissolution and predictive total lung deposition using physical airway models. Phase 3: Study of other surfactants The knowledge and experience gained from the Phase 2 studies will be applied to evaluate other surfactants, such as povidone, lecithin NF, and sorbitan trioleate. Each surfactant should be evaluated at different levels; the levels defined based on individual IID safety limits and literature information. Phase 4: Mathematical modeling and overall recommendations Using the results obtained from this study, mathematical model(s) should be developed that can help predict the effect of change in excipient(s) amount on the in vitro performance of MDIs.