Calcium Phosphate Particles as Pulmonary Delivery System for Interferon-α in Mice
Systemically administered interferons are rapidly cleared from the circulation thus requiring frequent dosing to maintain the therapeutic levels of circulating interferon. This is particularly problematic for their use in the treatment of chronic diseases. The purpose of this study was to evaluate the potential of proprietary calcium phosphate (CaP) particles to deliver biologically active interferon alpha (IFNα) via the lungs into systemic circulation. Recombinant human IFNα-2a was formulated with proprietary CaP particles. In vitro biological activity of IFNα was assessed for its potential to activate IFN-induced cellular pathways in HEK-Blu-IFN α/β cell cultures. Antiviral activity was evaluated against vesicular stomatitis virus (VSV) infection of HeLa cells. Male BALB/c mice were used to evaluate the absorption of IFNα from CaP-IFNα across the lungs following intratracheal (IT) instillation. Serum IFNα concentrations up to 9 h post-treatment were determined. Data were analyzed to obtain pharmacokinetic (PK) parameters. Data from these studies indicated that IFNα formulated with CaP retains its biological activity, and it is transported into circulation in a dose-dependent manner. PK analysis showed larger than two-fold area under the serum concentration-time curve (AUC) for CaP-IFNα compared to non-formulated IFNα administered IT. The IFNα formulated with CaP had two-fold longer half-life (t1/2) and mean residence time (MRT) relative to IFNα alone administered by injection. Clearance of CaP-IFNα was slower than IFNα administered IM or IT. Relative bioavailability of CaP-IFNα was 1.3-fold of IFNα injection and twofold of IFNα administered IT. Furthermore, inhalation of aerosolized CaP did not indicate any lung toxicity in animals.