Improvement of Topical Palmitoylethanolamide Anti-Inflammatory Activity by Pegylated Prodrugs.
A small library of polyethylene glycol esters of palmitoylethanolamide (PEA) was synthesized with the aim of improving the pharmacokinetic profile of the parent drug after topical administration. Synthesized prodrugs 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 long-lasting activity, suggesting the potential use of polyethylene glycol prodrugs of PEA as a suitable candidate for the treatment of skin inflammatory diseases.
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Diana
D
Tronino
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Roberto
R
Russo
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Carmine
C
Ostacolo
Department of Pharmaceutical Sciences "Pietro Pratesi", University of Milan , Via Mangiagalli 25, 20133 Milan, Italy.
Angelica
A
Mazzolari
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Carmen
C
De Caro
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Carmen
C
Avagliano
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Sonia
S
Laneri
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Giovanna
G
La Rana
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Antonia
A
Sacchi
Epitech Group s.r.l. , Via Egadi 7, 20144 Milan, Italy.
Francesco
F
Della Valle
Department of Pharmaceutical Sciences "Pietro Pratesi", University of Milan , Via Mangiagalli 25, 20133 Milan, Italy.
Giulio
G
Vistoli
Department of Pharmacy, University of Naples Federico II , Via D. Montesano 49, 80131 Naples, Italy.
Antonio
A
Calignano
D000279:Administration, Cutaneous; D000287:Administration, Topical; D000577:Amides; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D003879:Dermatologic Agents / Q000737:chemistry / Q000494:pharmacology*; D004355:Drug Stability; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology*; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010169:Palmitic Acids / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D012869:Skin Absorption / Q000187:drug effects*
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003879:Dermatologic Agents; D004983:Ethanolamines; D010169:Palmitic Acids; D011355:Prodrugs; D011092:Polyethylene Glycols; C005958:palmidrol
N-palmitoylethanolamide; anti-inflammatory effects; antihyperalgesic effects; pegylated prodrugs; topical delivery