Recent efforts to develop novel suspension-based formulations in hydrofluoroalkane (HFA) propellants can be attributed, to a large extent, to the potential of inhalation formulations to serve as vehicles for the pulmonary delivery of systemically acting drugs, and the challenges in reformulating pressurized metered-dose inhalers (pMDIs) with HFAs. Such difficulties have prompted the research community not only to design amphiphiles that have enhanced solubility in cosolvent-free HFAs, but also to develop novel formulations altogether. Many of the advances related to novel dispersion formulations in HFAs are centered on controlling the morphology or the surface properties of the drugs to minimize the forces that impart physical instability to the system.

In this work we propose a novel methodology for engineering polar drug particles with enhanced physical stability and aerosol characteristics in HFA-based pMDIs. The approach consists in ‘trapping' HFA-philic moieties at the surface of the drug particles in a way that they can act as steric stabilizers. It differs from surfactant-stabilized dispersions in that no free amphiphile exist in solution, thus decreasing the potential toxicity of the formulation, and circumventing potential difficulties in optimizing the surfactant balance. Colloidal probe microscopy was used to quantitatively assess the ability of the trapped moieties in screening drug cohesive interactions. The general applicability of the methodology to polar compounds is shown for two drugs of interest in the treatment of asthma, namely salbutamol sulfate and terbutaline hemisulfate. The physical (bulk) stability of the dispersions in HFA134 and HFA227, and the performance of the corresponding aerosols were investigated. The results indicate that HFA-philes trapped at the particle surface can reduce cohesive forces between particles down to nearly zero, and that such results translate into dispersions with significantly improved physical stability, and aerosols with improved characteristics compared to those from existing commercial formulations.

Keywords: Pulmonary drug delivery; pressurized metered-dose inhalers; hydrofluoroalkanes; HFA-philes; colloidal probe microscopy; terbutaline hemisulfate; salbutamol sulfate.