Asthma is one of the most common respiratory diseases that can be efficiently managed through combined treatment of fluticasone propionate (FP) and salmeterol xinafoate (SX). In this study, we challenged the use of both spray drying and mixing techniques in sequential combination of lactose or mannitol with FP and SX as two steps in development of inhalable powder formulation of the drugs. Leucine was used as a dispersibility enhancer. The formulations were optimized using the Design-Expert software. The effects of three independent variables namely the type of carrier, percentage of spray-dried carrier and the amount of leucine were investigated on in vitro deposition. The results showed that the maximum fine particle fraction (FPF) and the minimum particle size was belonged to formulation in which the percentage of leucine was 20% with respect to the total solid content and 50% of mannitol was used during spray drying, while the remaining 50% of it was applied in the physical mixing process. This study showed that not only the choice of carrier and additives for every drug combination, but also an optimized ratios of them during both spray drying and physical mixing can be crucial in developing suitable inhalable dry powder formulations. (C) 2016 The Society of Powder Technology Japan. Published by Elsevier B.V. and The Society of Powder Technology Japan. All rights reserved.