Probing Subtle Variabilities in Seretide/Advair Batches by Evaluation of Drug-Lactose Aerosol Interaction
Larissa Gomes dos Reis 1, Michele Pozzoli1 Paul M Young1,2, Robert Johnson2
1Woolcock Institute of Medical Research, University of Sydney, 431 Glebe Point Road, Sydney, NSW 2037, Australia
2Oz-UK Ltd, Unit 15, Lansdowne Court, Bumpers Way Chippenham Wiltshire, SN14 6RZ, UK
Summary
A sensitive high-pressure liquid chromatography (HPLC) and HPLC/mass spectrometry (MS) method was developed to determine the aerosol properties of fluticasone propionate (FP) and salmeterol xinafoate (SX) active ingredients and excipient (lactose (LAC)) from two batches (lots) of Advair/Seretide (500/50 mg). The aerosol properties of all components were evaluated using cascade impaction by Next Generation Impactor (NGI). Both lots had similar deposition profiles and fine particle fractions. Statistical analysis of conventional aerosol parameters indicated no significant differences between lots when evaluating the aerosol performance of FP, SX or LAC. However, analysis of the LAC/FP ratio as a function of aerodynamic diameter (Dae) indicated differences in the LAC/FP ratio, as a function of both aerodynamic diameter and lot number. For example, on Stage 3 of the NGI (Dae 4.46 µm) the ratio of LAC/FP was approximately 1:1, indicating that there is approximately one LAC particle to every FP particle. Importantly, significant differences in this ratio were observed. Electron microscopy was conducted to evaluate morphology of the particles captured on NGI collection cups 2, 3 and 5. Particles appeared as loose agglomerates, presumable as LAC/FP mixtures. While conventional aerosol analysis showed no significant difference the LAC/FP ratio appears to be an important tool for batch-to-batch differentiation of multi-component DPIs, such as Seretide/Advair. This variation in LAC/FP ratio may drive variations in drug wettability, dissolution and ultimately pharmacokinetics (PK).
