(162i) Biocompatible Surfactants for Dispersion-Based Pressurized Metered-Dose Inhalers

Pressurized metered dose inhalers (pMDIs) are the most common vehicles for the delivery of drugs to the lungs, accounting for approximately 80 % of the total prescribed aerosols. However, the development of pMDI-based formulations has been confronted with several challenges since the replacement of CFCs with the more environmentally friendly hydrofluoroalkanes (HFAs). In spite of the fact that the operation of pMDIs with HFAs is similar to those containing CFCs, previous formulations are not compatible due to the significantly different physicochemical properties between these two classes of fluids. Importantly, the FDA approved surfactants commonly used in the CFC-based formulations have very limited solubility in 1,1,1,2-tetrafluoroethane (HFA134a) and (1,1,1,2,3,3,3-heptafluoropropane) HFA227. Surfactants are generally required excipients in pMDIs, with functions including dispersion stabilization and valve lubrication. Today's formulations incorporate co-solvents (alcohols) in order to enhance the solubility of the FDA approved amphiphiles. However, co-solvents may negatively impact the formulations, decreasing their chemical and/or physical stability.

In this work we present the results of the effect of biocompatible and biodegradable surfactants on the colloidal stability of drug crystals (salbutamol) in HFA propellants. A series of amphiphiles with high solubility in HFAs was designed and synthesized. Particle-particle interaction in the presence of surfactant is quantitatively investigated by colloidal probe microscopy (CPM). The effect of both molecular weight and hydrophilic-to-HFA-philic balance is discussed. It is shown that low concentrations of relatively low molecular weight surfactants can reduce particle cohesion to zero. The CPM results are compared with visual observations from the actual dispersions in HFA134a and HFA227. CPM and visual stability results with the new class of amphiphiles are contrasted/compared to those of a typical formulation containing ethanol and oleic acid. These studies are also relevant to solution based formulations since they surfactants also generally required excipients.

Keywords: hydrofluoroalkane; HFA134a; HFA227; salbutamol; pressurized metered-dose inhalers (pMDI); colloidal probe microscopy; adhesion force, drug delivery, atomic force microscopy; surfactants