Breath-activated nanomedicine: Ambrisentan-loaded chitosomes for pulmonary arterial hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening condition that detrimentally affects patient's quality of life. PAH is commonly managed by oral endothelin receptor antagonists like ambrisentan (AMB). However, due to untargeted delivery, AMB oral administration is associated with peripheral oedema among other systemic side effects. Hence, our study aimed to develop an inhalable nano-in-micro dry powder of AMB to achieve targeted pulmonary delivery and minimize systemic exposure. AMB was encapsulated in liposomes and subsequently coated with chitosan to preserve liposomal integrity during drying process. The developed AMB-loaded chitosan-coated liposomes (Ambri-Chitosomes) were incorporated into lactose-leucine based microspheres via nano spray drying to produce inhalable dry powders. The formulations were evaluated for particle size, drug encapsulation, morphology, Fourier-transform infrared spectroscopy, dynamic scanning calorimetry, aerodynamic performance, in vitro release, cytotoxicity, and in vivo pharmacokinetics. Chitosan coating was found to be crucial to liposomal stability, preventing fusion during drying and reconstitution. The optimized Ambri-Chitosomes exhibited uniform particle size (∼190 nm upon reconstitution), suitable mass mean aerodynamic diameter (∼1.9 µm) and favorable dispersibility. In vitro release showed sustained drug release over 48 h, while cytotoxicity confirmed the biocompatibility of the formulation on A549 cells. Pharmacokinetic analysis in rats demonstrated significantly higher pulmonary drug accumulation and retention with inhaled Ambri-Chitosomes compared to oral AMB, alongside interestingly reduced systemic exposure. These results indicate that Ambri-Chitosomes can serve as a safe and effective inhalable delivery system for targeted PAH therapy.