Anti-inflammatory endocannabinoid-like molecule for topical and pulmonary administration: comparison between two different nano-delivery systems

Purpose Palmitoylethanolamide (PEA), an endogenous endocannabinoid-like molecule with important anti-inflammatory and immunomodulatory effects, appears particularly promising for the treatment of immune and / or inflammatory diseases (Alhouayek and Muccioli, 2014; Rankin and Fowler, 2020). However, until now, PEA has not yet been used as a drug due to its extremely low solubility in biological fluids and consequent poor bioavailability. The aim of this research was to compare two different delivery systems, such as classic solid lipid nanoparticles (SLNs) (Maretti et al., 2022) and the more innovative Nano-PEA, a new form of PEA, in terms of potential application for topical or inhaled administration. Nano-PEA is a nanoparticulate form of PEA developed in collaboration with PerFormS s.r.l., an innovative start-up of UniMoRe. Methods The two systems have been characterized from the morphological point of view through Scanning Electron Microscopy (SEM); size was detected by the use of the Photon Correlation Spectroscopy (PCS). In vitro studies of percutaneous absorption with Franz Cells were carried out to characterize the systems in view of a skin application. On the other hand, tests of respirability, density determination and angle of repose were conducted on freeze-dried nanosystems to investigate their possible application by inhalation using DPI device. In vitro skin permeation and respirability studies were performed by comparing the two systems with raw PEA. Results Both systems displayed a size of about 250 nm and an almost rounded shape. The results from skin permeation studies demonstrate an increase in the permeation rate over time in the case of Nano-PEA compared to PEA-loaded SLNs and raw PEA. By studying the potential of the two nanosystems for inhaled administration, it was observed good respirability parameters of the freeze-drying powder by using a w/w ratio of 1:2 between nanoparticle and cryoprotectants. An optimal emitted dose was achieved for both nanocarriers and in particular for PEA-loaded SLN. A higher respirable fraction was quantified in the case of Nano-PEA compared to PEA-loaded SLN. For this reason, Nano-PEA can be considered promising for the treatment of deeper airway diseases, while SLNs for the treatment of upper respiratory tract diseases, since a lower respirable fraction but a good emitted dose was found. Conclusions The application of suitable nanocarriers can overcome the disadvantages due to the negative chemical-physical characteristics of PEA, and, although these results are preliminary, they seem promising.