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Stable Suspensions of Protein and Poorly Water Soluble Drug Particles for High Dosages with Pressurized Metered Dose Inhalers

Joshua D. Engstrom1, Jasmine Tam2, Maria Andrea Miller2, Robert O. Williams III3, and Keith P. Johnston4. (1) Engineering Technology, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903, (2) Chemical Engineering, The University of Texas at Austin, 1 University Station C0400, Austin, TX 78712, (3) College of Pharmacy, The University of Texas at Austin, 1 University Station, Austin, TX 78712, (4) Department of Chemical Engineering, The University of Texas at Austin, 1 University Station C0400, Austin, TX 78712

A novel concept is presented for the formation of concentrated (up to 50 mg/mL), stable suspensions composed of low density flocs of anisotropic drug particles in hydrofluoroalkane (HFA) propellants without surfactants to achieve high fine particle fractions in pulmonary delivery with a pressurized meter dose inhaler (pMDI). Bovine serum albumin (BSA) and itraconazole (Itz) particles were prepared by thin film freezing (TFF). BSA (0.5% w/v) was dissolved in 10 mM potassium phosphate buffer (pH 7.4). The protein solution was passed though a stainless steel needle and dripped onto a rotating stainless steel drum, which was filled with dry ice to maintain a surface temperature of 223K. On impact, the droplets deformed into thin films and froze. The frozen films were collected and lyophilized to yield a dry powder. Itz particles were made using the same method, where the feed solution consisted of Itz (0.4% w/v) dissolved in 1,4 dioxane. The particles were analyzed with static and dynamic light scattering and scanning electron microscopy (SEM). Aerodynamic properties of the aerosolized particles were determined by an Andersen Cascade Impactor. Anisotropic BSA and Itz particles, in the shape of rods or thin plates, formed highly open, space-filling flocs in HFA, and were stable against settling for one year at drug concentrations up to 50 mg/mL. In contrast, spherical particles produced by milling formed dense aggregates that settled within 60 seconds in HFA. The atomized HFA droplets were shown to break apart and template the highly open flocs. Upon evaporation of HFA, capillary forces shrink the templated flocs to produce porous particles with optimal mass median aerodynamic diameters (MMAD) for deep lung delivery. The pMDI suspensions composed of anisotropic particles produced aerosol particles with MMADs between 3-4 ým, high fine particle fractions (47-56%), and a delivered dose up to 3.7 mg/actuation. The concept of forming open flocs composed of anisotropic particles, that are stable against settling without surfactants, and templating the flocs during pMDI actuation to achieve optimal aerodynamic diameters and high fine particle fractions is of practical interest for wide classes of low and high molecular weight pharmaceuticals.