Purpose. Demonstrate the applicability of a novel particle-based technology for the development of suspensions of small polar drugs and biomolecules in hydrofluoroalkane (HFA) propellants for pressurized metered-dose inhalers (pMDIs). Materials and Methods. Emulsification diffusion was used to prepare core-shell particles. The shell consisted of oligo(lactide) grafts attached onto a short chitosan backbone. The active drug was arrested within the particle core. Colloidal Probe Microscopy (CPM) was used to determine the cohesive forces between particles in a model HFA propellant. The aerosol characteristics of the formulations were determined using an Anderson Cascade Impactor (ACI). Cytotoxicity studies were performed on lung epithelial and alveolar type II cells. Results. CPM results indicate that particle cohesive forces in liquid HFA are significantly screened in the presence of the polymeric shell and correlate well with the physical stability of suspensions in propellant HFA. The proposed formulation showed little or no cytotoxic effects on both Calu-3 and A549 cells. Conclusions. Core-shell particles with a shell containing the lactide moiety as the HFA-phile showed excellent dispersion stability and aerosol characteristics in HFA-based pMDIs. This is a general strategy that can be used for developing novel suspension pMDIs of both small polar drugs and large therapeutic molecules.
Bibliographical noteFunding Information:
L.W. acknowledges Wayne State University (WSU) for a Ph.D. assistantship. The authors would also like to acknowledge Solvay Fluor und Derivate GmbH & Co., Hannover—Germany, for the propellant HFAs; West Pharmaceuticals and 3M, for the glass vials and metering valves, respectively; Dr. Verani_s group (Department of Chemistry at WSU), Dr. Oupicky_s group (College of Pharmacy at WSU), and Dr. Sujatha Kannan_s group (Med School at WSU) for providing access to the FTIR, GPC and plate reader, and the A549 cell line, respectively; and financial support from the Office of the VP for Research at Wayne State University, through a Nano@Wayne grant, and from the National Science Foundation through an NSF-CBET grant no. 0553537.
- Colloidal probe microscopy
- Pressurized metered-dose inhaler
- Pulmonary drug delivery
- Salbutamol sulfate