Inhalable Single Crystalline Particles Containing Two Low-Dose Active Ingredients

Michiko Kumon (1), PHILIP CHI LIP KWOK (1), Handoko Adi (1), Desmond Heng (2), Hak-Kim Chan (1)

(1) Advanced Drug Delivery Group, Faculty of Pharmacy, Building A15, The University of Sydney, NSW 2006, Australia, (2) Crystallization and Particle Science Group, Institute of Chemical and Engineering Sciences (ICES), Agency for Science, Technology and Research (A*STAR), 1 Pesek Road, Jurong Island, Singapore 627833

     Abstract Number: 345
     Last modified: May 9, 2010

Abstract
Objectives: To formulate and test the aerosol performance of inhalable crystalline particles containing two low-dose active ingredients without blending with carriers.
Materials and Methods: Two formulations comprising an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and mannitol as a crystalline excipient were studied: budesonide / formoterol fumarate dihydrate / mannitol (B/F/M) and fluticasone propionate / salmeterol xinafoate / mannitol (F/S/M). The ICS, LABA, and mannitol were dissolved in a water / ethanol mixture and spray dried to obtain ternary powders. The particles were sized by laser diffraction and cut open by focused-ion beam milling for internal structure observation. Surface morphology and elemental composition were examined by scanning electron microscopy and X-ray photoelectron spectroscopy, respectively. Crystallinity of the powders was determined by X-ray diffraction and differential scanning calorimetry. Aerosol performance of the powders dispersed from an Aerolizer® was measured using a Next Generation Impactor (n =3) at 60 and 100 L/min, followed by chemical assay of the drugs using high performance liquid chromatography.
Results and Discussion: The ternary particles (volume median diameters = 2 micro-metres) were spherical and partially hollow, with drug-enriched surfaces. Both formulations contained alpha-mannitol, and the ICSs were crystalline. The content of each drug component in the powder was found to conform to the theoretical dose. The ternary powders generated high fine particle fractions (> 50% of the loaded dose), with concomitant drug deposition on the impactor stages. The aerosol performance of B/F/M was maintained after storage over silica gel at 22 °C for 11 weeks.
Conclusions: Co-spray dried particles of ICS/LABA/M were largely crystalline, stable, and showed excellent aerosol performance. They may provide an attractive alternative approach to develop combination products without lactose blends.