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Calcium Phosphate Particles as Pulmonary Delivery System for Interferon-α in Mice

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Abstract

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.

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Acknowledgments

This project, excluding the toxicity studies, was supported by Small Business Innovation Research Program Phase I (SBIR-I) Award Number R43AI078638 from the National Institute of Allergy and Infectious Diseases (NIAID) (T. Morcol: PI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or the National Institutes of Health (NIH). Toxicity studies were funded by BioSante Pharmaceuticals (currently ANI Pharmaceuticals). The authors would like to thank Dr. Patrick T. Curry, IIT Research Institute, for the helpful discussions on the pulmonary toxicity studies and data. We also thank PharmaDirections Inc. (Cary, NC) for their help with PK analyses, Lampire Biologics (Doylestown, PA) for performing animal studies, and Graham Wallace (Charles River Laboratories Preclinical Services, Montreal, Canada) for FTIR analysis and feedback in interpretation of data.

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Authors and Affiliations

  1. CaPtivate Pharmaceuticals LLC, Pennsylvania Biotechnology Center of Bucks County, 3805 Old Easton Road, Camp Hill, Pennsylvania, 17011, United States

    Tülin Morçöl

  2. US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fredrick, Maryland, USA

    Jessica M. Weidner

  3. Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, USA

    Anand Mehta

  4. Proventus Bio, Inc, Atlanta, Georgia, USA

    Stephen J.D. Bell

  5. Baruch S. Blumberg Institute and Hepatitis B Foundation, Doylestown, Pennsylvania, USA

    Timothy Block

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  1. Tülin Morçöl
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Correspondence to Tülin Morçöl.

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Conflict of Interest Statement

T. Morcol is the founder of CaPtivate Pharmaceuticals (a BioSante spin-off). T. Morcol and S.J.D. Bell are co-inventors of the CaP technology used in the study. J.M. Weidner, A. Mehta, S.J.D. Bell, or T. Block, or the institutions they are currently affiliated with have no known competing business interests in CaPtivate and vice versa.

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Morçöl, T., Weidner, J.M., Mehta, A. et al. Calcium Phosphate Particles as Pulmonary Delivery System for Interferon-α in Mice. AAPS PharmSciTech 19, 395–412 (2018). https://doi.org/10.1208/s12249-017-0847-5

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