Production and characterization of pressurized metered dose inhalers (pMDI) carrying mometasone microparticles

CESCHAN, NAZARETH ELIANA; BALBUENA, FLORENCIA; CABRERA, FERNANDA; RAMIREZ RIGO, MARÍA VERÓNICA

Rosario

Congreso; 7ma Edición de la Reunión Internacional de Ciencias Farmacéuticas; 2023

Universidad Nacional de Rosario

Pressurized metered-dose inhalers (pMDIs) are a well-known technology useful for inhalatory administration in all patients, particularly in pediatrics. In most cases, pMDIs are formulated as suspensions of drugs and excipients in propellants. In those, particle agglomeration leads to dose variability, low airway deposition efficiency and a high drug retention in the oropharynx, which is then swallowed. To solve this problem, stabilizing excipients are used, but such excipients make formulation complex and also, if used in high concentration, deteriorate aerodynamic performance. Alternatively, the development of products based on engineered particles with controlled physical properties has been proposed. The aim of this work is to produce and study the stability and aerosolization behavior of excipient-free pMDIs, carrying spray dried (SD) or micronized (Mic) microparticles of mometasona (M, corticosteroid used in antiasthmatic treatments). Particle size and morphology were analyzed by laser diffraction and SEM. For pMDIs production, particles were accurately weighted in aluminum canisters (to achieve the same dose than commercial products per actuation) and crimped with a metered valve using a manual crimper. Filling burette was filled with the propellant 1,1,1,2-tetrafluoroethane. Different propellant pressures (with or without the addition of an inert gas) were tested. Adequacy of metered valve to filling burette was study to open the valve during filling. Aerodynamic performance of pMDIs carrying M was assessed in a cascade impactor. Microparticle stability was preliminary assessed dispersing the particles in saline solution and measuring particle size at predefined time intervals. Volumetric mean diameter (VMD) was 4.7micrometers for SD particles which had rounded rough surfaces. Mic particles displayed plate-like elongated shape with smooth surface and VMD of 4.0micrometers. Propellant pressures of 50-90psi were not enough to fill canisters completely and an inert gas was required to increase pressure up to 125-150psi and fill recipients. The mechanical pressure of the filling burette base was optimized to completely open the metering valve during propellant feeding. According to in vitro aerosolization studies, around 47% of the SD M dose would access deep lung regions while oropharynx loss was ca. 13 %. Mass median aerodynamic diameter (MMAD) was around 3.3micrometers. Around 50% of M dose, with a 2.7micrometers MMAD and 16% oropharynx loss, would reach the deep lung for Mic particles. In both cases, aerodynamic particle size distribution was narrow (GSD value lower than 3). Mic and SD M demonstrated to be stable in saline solution as particle size did not importantly change over time. In conclusion, stable pMDIs with adequate aerodynamic performance were produced using a propellant filling process. Both engineered M particles (Mic and SD) were useful for excipient free-pMDI formulation with 1,1,1,2-tetrafluoroethane.