Palmitoylethanolamide (CAS：544 - 31 - 0) Anti - Inflammatory Activity by Pegylated Prodrugs

   Synthesized prodrugs of palmitoylethanolamide (PEA) were studied for their skin accumulation, pharmacological activities, in vitro chemical stability, and in silico enzymatic hydrolysis. Prodrugs proved to be able to delay and prolong the pharmacological activity of PEA by modification of its skin accumulation profile .Pharmacokinetic improvements were particularly evident when specific structural requirements, such as flexibility and reduced molecular weight, were respected. Some of the synthesized prodrugs prolonged the pharmacological effects 5 days following topical administration, while a formulation composed by PEA and two pegylated prodrugs showed both rapid onset and longlasting activity, suggesting the potential use of polyethylene glycol prodrugs of PEA as a suitable candidate for the treatment of skin inflammatory diseases（Figure 1）.

In this work, a prodrug approach for topical delivery of PEA as anti-inflammatory drug was investigated. The chemical combination of the parent drug with specific polyethylene glycol moieties, using the proper spacer, proved to be a viable approach to increase skin accumulation and overcome pharmacokinetic limitations to the use of topical PEA. Therefore, a combination of the parent drug and the most active prodrugs led to a retarding topical formulation, characterized by rapid onset of action and long duration. Collectively these results suggest the use of polyethylene glycol prodrugs of PEA as suitable candidates for the treatment of skin inflammatory diseases. Moreover, considering the role of lipids as prodrug carriers, and the well-described use of lipid−PEG conjugates for the design drug delivery systems, results obtained pave the way for the use of PEA and its derivatives as components of codrugs and particles for sustained and/or targeted delivery.

(REFERENCES: DOI:10.1021/acs.molpharmaceut. 5b00397 Mol. Pharmaceutics 2015, 12, 3369−3379)