Polyethylene glycol derivatives of palmitoylethanolamide and analogous acylethanolamides

Palmitoylethanolamide (PEA) belongs to a group of endogenous molecules known as acylethanolamides. PEA has a great pharmacological potential based on its anti-inflammatory and analgesic properties, although its use is somewhat limited by the high lipophilic nature of the molecule, thereby impairing its use, particularly by topical and injective routes. Here we report the synthesis, pharmacodynamic and pharmacokinetic characterization of a series of Polyethylene glycol conjugates (esters and carbonates) of PEA and its analogous acylethanolamides, that have improved chemical and physical properties, i.e., higher water solubility and good hydrophilic/lipophilic balance, resulting in (i) improved accumulation in tissues (particularly skin and mucosae), (ii) prolonged release, and (iii) increased bioavailability. In particular, here we report the improvement of PEA and analogous acylethanolamides levels in the tissues - particularly in the skin and mucosae - and their prolonged release due to the improved bioavailability of related conjugates. Pharmacological properties of polyethylene glycol conjugates of PEA have been tested in experimental models of inflammation and inflammation-sustained pain (carrageenan induced oedema and mechanical hyperalgesia), two models in which PEA and analogous acylethanolamides activity has been widely described. Our results demonstrate that conjugates are able to extend the time frame in which PEA and analogous acylethanolamides exert their pharmacological effects. These results clearly indicate that polyethylene glycol conjugates of PEA and analogous acylethanolamides could provide powerful pharmacological tools when a prolonged anti-inflammatory and analgesic action of such molecules is desired.