Inhalable spray-dried nano-in-microparticles encapsulating anandamide: a novel approach for the treatment of asthma.

Although β2-adrenoceptor agonists are widely established as effective therapeutics for asthma treatment, their use can be limited by systemic side effects and the potential for time-dependent desensitization. As a possible alternative, the endocannabinoid anandamide recently gathered attention due to its bronchodilatory effect. However, anandamide exhibits several unfavorable physicochemical properties, in particular strong sensitivity to temperature and light as well as poor aqueous solubility. To overcome these challenges, we developed an inhalable dry powder formulation composed of anandamide-loaded amphiphilic cyclodextrin nanoparticles, co-spray-dried with mannitol as stabilizing excipient. The resulting nano-in-microparticles exhibit a spherical, regular morphology, favorable size (1.24 ± 0.09µm) as well as aerodynamic properties suitable for targeted bronchial application (mass median aerodynamic diameter: 3.63 ± 0.03µm). Compared to pure mannitol particles, the novel carrier system encapsulates an almost three-fold higher drug load. Further physicochemical characterization proved the re-dispersibility and stability of the encapsulated nanocarriers after spray drying. Application onto primary human bronchial cells verified biocompatibility and time-dependent particle uptake of the formulation. pH-dependent intracellular release resulted in highly increased prostaglandin E2 secretion indicating a potential anti-asthmatic effect. In conclusion, the formulation unites drug protection with favorable aerosolization performance for targeted bronchial delivery. Overcoming the obstacle of anandamide degradation, the nano-in-microparticle system offers a novel approach for encapsulation of instable and sensitive drugs bearing great potential for the future treatment of lung diseases.