(48b) Core-Shell Nanoparticles: Novel Formulations for the Systemic Delivery of Biomolecules to and Trough the Lungs

Drug delivery technologies that allow for the administration of biomolecules such as proteins and peptides by non-parenteral routes, including oral, nasal, transdermal, and pulmonary delivery, have drawn increasing interest in the past few years. The pulmonary route has several advantages including the large surface area of the lungs, and the relatively high absorption efficiency of biomolecules at this site. Pressurized metered dose inhalers (pMDIs) are the cheapest aerosol therapy devices available. The development of novel pMDI-based formulations has been challenged, however, by the replacement of CFCs with the more environmentally friendly hydrofluoroalkanes (HFAs). Previous formulations are not compatible due to the significantly different properties between these two classes of fluids. Several alternative propellant-based formulations have been recently proposed to overcome some of difficulties in reformulating HFA-based pMDIs. Unlike small molecular-weight drugs that have been successfully delivered through pMDIs, there are no commercially available propellant-based formulations for the delivery of biomolecules. These difficulties are limiting the applicability of such inexpensive drug delivery vehicles, the pMDIs, for the treatment of a broad range of diseases and alternative routes for vaccination.

In this work a novel dispersion-based formulation is proposed for the systemic delivery of hydrophilic drugs, including biomolecules, to and through the lungs. A low energy, single-step method was developed to prepare particles with a core composed of small polar solutes and/or biomolecules, and with a biodegradable shell. The chemistry of the outer layer of the shell needs be tuned to interact favorably with the dipole of semi-fluorinated alkanes, thus enhancing dispersion stability, while the inner layer of the shell interacts with the polar solute. Biodegradable copolymers were synthesized to accomplish those tasks. The cohesion between core-shell particles in 2H, 3H-perfluoropentane (HPFP), a mimic solvent for HFAs, was quantitatively investigated using colloidal probe microscopy (CPM). The results are compared with those of the ‘naked' particles, and correlated with visual stability studies in both HPFP and HFA134a and HFA227. The results shown here are also expected to be of great importance to dry powder inhaler (DPI) formulations, where the properties of the surface of the particles need to be tuned to control the drug delivery efficiency. Such systems can be potentially used in vaccine delivery, and in the treatment of medically relevant diseases including cancer and diabetes.

Keywords: core-shell nanoparticles; HFA; HFA134a; HFA227; biomolecules; pressurized metered-dose inhalers (pMDI); dry powder inhalers (DPI); colloidal probe microscopy; adhesion force; pulmonary drug delivery, atomic force microscopy.