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Engineering Porous Drug Particles by Emulsification-Diffusion for Propellant-Driven Oral Inhalation Formulations

Libo Wu and Sandro R. P. da Rocha. Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48201

Aerosol inhalation has been traditionally used for the local delivery of therapeutics to the lungs. More recently, it has also been recognized as a potential route for the systemic delivery of both small molecules and large therapeutic biomolecules. Inhalation therapy is non-invasive, provides for fast drug uptake (second only to i.v.) and drugs delivered through the have good bioavailability. Pressurized metered dose inhalers (pMDIs) are the least expensive and most widely used oral inhalation devices. However, there are many challenges associated with the development of hydrofluoroalkane (HFA)-based dispersion pMDIs.

In this work we present a new, facile methodology for engineering porous drug particles with enhanced physical stability and aerosol characteristics in HFA-based pMDIs. The approach consists in preparing highly porous drug particles using a modified emulsification diffusion technique. The methodology allows for the control of the porosity and size of the particles (essential for controlling the aerosol characteristics), at very low concentrations of non-active excipients typically used in FDA-approved pMDIs. Results for the short-acting β2-adrenergic receptor agonists salbutamol sulfate (SS) and terbutaline hemisulfate (THS) are discussed. The physical stability and the aerosol characteristics of SS formulations are shown to be superior to the commercial formulation prepared with micronized crystals. This study is relevant in the development of formulations for the local and systemic delivery of small polar drugs to and through the lungs using the inexpensive and widely available pMDIs.

Keywords: pulmonary drug delivery; pressurized metered dose inhalers; porous particles, salbutamol sulfate; terbutaline hemisulfate.