Mannitol-leucine synergy in nanocrystal agglomerates for enhanced systemic delivery of inhaled ketoprofen: Pharmacokinetics and safety in ovalbumin-sensitized rats

Pulmonary administration offers a promising needle-free approach for systemic delivery of nonsteroidal anti-inflammatory drugs (NSAIDs), improving bioavailability and reducing required doses. While mannitol and leucine are widely used in inhalation formulations, their potential to enhance systemic drug delivery via the pulmonary route remains largely unexplored. This study utilizes the nanocrystal agglomerates (NCAs) approach to develop an inhalable NSAID formulation, with ketoprofen (KTP) as a model drug. Wet media milling and nano spray drying were employed for NCA fabrication, and the roles of mannitol and leucine were evaluated individually and in combination. Notably, their combination exhibited synergy, overcoming limitations observed with individual excipients. Mannitol-based sample (K1M) reduced aerosol performance by increasing the mass median aerodynamic diameter (MMAD) to 4.5 µm, whereas leucine-based sample (K1L) improved aerosolization but resulted in a low MMAD (<1 µm), suggesting a high tendency for exhalation. The combined mannitol-leucine formulation (K1ML) achieved optimal aerosol performance, balancing dispersibility and controlled deposition. K1ML also exhibited the fastest drug release (99 % in 5 min) and enhanced permeability across the alveolar barrier while maintaining biocompatibility. Pharmacokinetic analysis confirmed that inhaled K1ML provided superior bioavailability (AUC 73 µg·h/mL) compared to oral KTP nanosuspension (42 µg·h/mL) and raw KTP (9 µg·h/mL). Nonetheless, prolonged inhalation in asthmatic models (ovalbumin-sensitised rats) impaired pulmonary function, emphasizing the need for dose optimization. These findings demonstrate that the mannitol-leucine combination in NCAs enhances systemic NSAID delivery, optimizing both aerosol performance and bioavailability. Future studies should refine dosing strategies to ensure long-term safety and clinical feasibility.