Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence.

Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution-absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence.

The permeability of large molecular weight solutes following particle delivery to air-interfaced cells that model the respiratory mucosa.

The transepithelial transport rates of compounds after deposition as aerosolised particles onto respiratory cell layers and allowing dissolution in the cell surface secretions has not been reported in a comprehensive manner to date. Here, the twin-stage impinger (TSI) was used to deposit potentially respirable particles (aerodynamically <6.4 microm) of varying molecular weight dextrans labelled with fluorescein isothiocyanate (FITC-dex) onto Calu-3 cells, a model of the bronchial epithelium. The TSI functioned as a particle size segregator, with >96% of the deposited particles being geometrically <6.4 microm (as measured by microscopy) and the particles being deposited discretely with a uniform distribution. Cell layers tolerated particle deposition at an air flow of 60 L/min. A small reduction in transepithelial electrical resistance (TER) of <10% occurred initially, but the original TER was recovered within 10 min and there was no significant effect on apparent permeability (P(app)) of FITC-dex 4 over 4 h. Interleukin 8 (IL-8) secretion in the apical and basolateral directions over 24 h was not increased by exposure to the TSI and particle deposition. The rate of FITC-dex 4 (4 kDa) transport across the cell layer after deposition and dissolution of the particles in the cell surface secretions was approximately 20-fold higher (P<0.05) than if applied as a solution. The volume of cell surface secretions was estimated by tracer dilution (3.44+/-1.90 microl, mean+/-SEM) and this value was used to calculate the P(app) of compound once deposited as a particle. The Papp value was found to be similar to that obtained when the compound was applied in solution (P<0.05). Thus, the increased transport rate was attributable to the differences in donor chamber solute concentration rather than any change in the permeability of the cell layer itself. Following particle deposition, transport of FITC-dex with molecular weights between 4 and 70 kDa correlated well (r(2)=0.918) with reported in vivo canine pulmonary clearance after intratracheal instillation of dextrans of similar molecular weight. The use of the TSI and the Calu-3 cell line for the assessment of compound dissolution and transport rates after particle deposition may allow more realistic analyses to be made with respect to the in vivo situation.

Administration of an insulin powder to the lungs of cynomolgus monkeys using a Penn Century insufflator.

A powder formulation of live-attenuated measles vaccine is being developed for administration to the lungs. The safety and efficacy of the powder will be assessed by insufflation into cynomolgus monkeys. A Penn Century insufflator has been evaluated for powder dosing to the monkeys using an insulin formulation having similar physicochemical characteristics to the vaccine powder. Insulin pharmacokinetics were compared following dosing by powder insufflation, solution instillation into the trachea and subcutaneous injection. The insulin dosed to the lungs and trachea was more rapidly absorbed than that administered subcutaneously. Insulin bioavailability was greater from the inhaled powder than from the instilled solution. The findings confirm that the Penn Century device is suitable for vaccine powder dosing to the deep lung.