Co-Spray-Dried Macitentan–Tadalafil with Leucine Microparticles for Inhalable Delivery in Pulmonary Arterial Hypertension

<b>Background/Objectives</b>: This study developed a macitentan (MAC)-tadalafil (TAD) dry powder inhalation preparation using suspension-based spray drying to enhance pulmonary delivery and reduce systemic exposure to oral combination therapy in patients with pulmonary arterial hypertension (PAH). <b>Methods</b>: MAC-TAD composite powders were prepared by physically mixing or spray-drying aqueous ethanol suspensions at various MAC:TAD ratios. The lead M2-T8 was co-spray-dried with 5, 25, or 50% (<i>w</i>/<i>w</i>) L-leucine. <b>Results</b>: Spray-dried formulations exhibited narrower and more uniform particle size distributions (Dv50 2-6 µm; Dv90~10 µm) and higher emitted dose values than the physical mixtures. In the M2-T8 spray-dried formulation, TAD exhibited an elevated fine particle dose (FPD) (3073.45 ± 1312.30 μg), demonstrating improved aerosolization relative to the physical mixture, even outperforming the TAD-higher M1-T9 formulation (2896.83 ± 531.38 μg), suggesting that favorable interparticle adhesive interactions were developed during co-drying. The incorporation of 25% L-leucine produced the greatest improvement in dispersibility, increasing the FPD by ~31% for MAC and 17% for TAD, whereas excessive L-leucine (50%) reduced the aerosol performance. Powder X-ray diffraction and differential scanning calorimetry confirmed the retention of the MAC and TAD crystallinities, with L-leucine remaining either amorphous or partially crystalline. <b>Conclusions</b>: Suspension-based spray drying yielded MAC-TAD composite formulations with improved uniformity and aerosol performance. The optimized 2:8 formulation containing 25% L-leucine demonstrated the most efficient pulmonary deposition, supporting its potential as an inhaled combination therapy for the treatment of PAH.