Exploring the influence of drug-excipient interaction on batch-to-batch variabilityin Seretide

Abstract

Seretide® is a dry powder inhaler (DPI) that contains two drugs, fluticasone propionate (FP) and salmeterol xinafoate (SX). Batch-to-batch variability in vivo is known to exist amongst DPIs, although the exact cause is unknown. The lactose excipient in Seretide contains fines and is more soluble than FP (which is practically insoluble in water). The interaction between lactose fines and the drugs can vary. It has been suggested that it may influence deposition profiles in the lung, wettability, and dissolution. Such variability between batches, and upon storage, would lead to changes in pharmacokinetics (PK) and thus variability in product performance. In this study, the characteristics of lactose-drug interactions and their influence on aerosol performance and dissolution rate of FP in two different batches of Seretide \were investigated to establish the cause of batch-to-batch variability and the impact of storage. Two batches were placed at room temperature as well as stability cabinets of 30°C/65% RH and 40°C/75% RH for 1, 3 and 6 months. Drug and excipient deposition were evaluated using an Apparatus E impactor followed by detection and quantitation with high-performance liquid chromatography and liquid chromatography-mass spectrometry. Scanning electron microscopy and Raman microscopy were used to study agglomeration and morphology. The results showed changes in lactose/FP ratio over time and on accelerated storage conditions. A Franz cell dissolution was carried out to investigate dissolution and the potential impact on PK. The data collected were analysed to determine the impact of lactose-drug interaction on batch-to-batch variability in drug delivery under different storage conditions. Future work will be required to further define the relationship between lactose/FP ratio and PK.