(439d) Developing Novel Inhalation Formulations: a Microscopic Approach

Aerosol inhalation therapy offers several advantages over oral and parenteral approaches for the systemic delivery of drugs to and through the lungs. Pressurized metered-dose inhalers (pMDIs) are the cheapest aerosol therapy devices available. Approximately 50% of currently marketed pMDIs consist of dispersion-type formulations; i.e., micronized drugs dispersed in the propellant. Most drug particles, however, cannot be suspended directly in hydrofluoroalkanes (HFAs), the propellants in pMDIs, due to strong cohesive forces. They generally require some type of excipient that can adsorb onto the drug particle, thus modifying their surface properties. The systemic delivery of therapeutic drugs can also be accomplished using dry powder inhalers (DPIs). DPIs involve the application of an inspirational energy to a blend of drug and carrier particles. The efficacy of DPIs is governed by the interaction between drug and carrier particles. Future advances in inhalation therapy, therefore, will require a fundamental understanding of particle-particle interactions. Colloidal probe microscopy (CPM) is a powerful approach that can be used to quantitatively determine the forces between drug particles, or particles with surfaces. The effect of surface chemistry, morphology, (and in the case of pMDIs) solvent environment and excipients on colloidal stability can be addressed using CPM.

In this work, we show how we employ CPM to address issues relevant to both DPI and pMDI formulations. A series of biocompatible and biodegradable amphiphiles was designed to stabilize dispersion-based formulation of a drug compound (salbutamol) in HFA propellants. Drug-drug interaction with or without surfactants in 2H, 3H-perfluoropentane (HPFP), a mimic solvent for HFAs, is quantitatively investigated by CPM. However, the interactions are generally measured using drug crystals (probes) of irregular shape. Thus, comparison of different excipients and formulation conditions are generally hard if not impossible to be made. In order to address this limitation, a low energy, single-step method for making smooth spherical particles of hydrophilic solutes (without the help of excipients) was developed. The same method can be used to make core-shell particles. This approach allows for modification of the surface properties of the particles, and thus the ability to tune particle-particle (DPIs and pMDIs) and particle-solvent (pMDIs) interactions. Using this technique, bare and polymer-coated salbutamol sulfate spheres have been made. Microspheres were attached to AFM tips, and particle cohesion measured by CPM in air (at controlled relative humidity), and also in HPFP.

Keywords: inhalation formulation; HFA; HFA134a; HFA227; salbutamol; pressurized metered-dose inhalers (pMDI); dry powder inhalers (DPI); colloidal probe microscopy; adhesion force; pulmonary drug delivery, atomic force microscopy; surfactants.