title: In vitro and in vivo evaluation of an in situ gel forming system for the delivery of PEGylated octreotide.
abstract: The objective of this study was to develop a controlled delivery system for PEGylated octreotide using a Poloxamer based in situ gel forming polymer. PEGylated octreotide kept its full biological activity and higher serum half-life compared to the original octreotide. The designed drug delivery system contained low concentration of Poloxamer 407 (P407) (<0.16%) with polyvinyl alcohol (PVA) as a polymeric additive. Rheological measurements of gel vehicle formulations indicated that the in situ gel forming system with optimum sol-gel transition temperature of 28.7°C could be formed using a combination of P407 and PVA at ratio of 15-10% (w/v). The effect of formulation additives such as buffering agents on rheological behavior demonstrated that sodium bicarbonate and lactic acid have opposite effect on sol-gel transition temperature of the system. Using buffering agents, it was possible to shift the sol-gel transition to lower or higher temperatures. The in vitro release profiles of octreotide and PEGylated octreotide from the selected P407/PVA formulations were measured using a membrane-less device. PEGylated octreotide showed slower release rate from the gel system with different release kinetic compared to octreotide. In animal studies, a sustained release rate was achieved with both PEGylated and non-PEGylated octreotide, but longer delivery was observed for PEGylated octreotide. Tissue histopathological studies confirmed the biocompatibility of the delivery system for PEGylated octreotide, supporting the suitability of P407/PVA mixture as an injectable drug delivery system. The total effects of increasing PEGylated peptide half-life and prolonged release from thermoresponsive gel system offer the potential for sustained delivery of PEGylated octreotide.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran.
authors.forename: Laleh
authors.initials: L
authors.lastname: Erfani Jabarian
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Rouini
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Atyabi
authors.forename: Alireza
authors.initials: A
authors.lastname: Foroumadi
authors.forename: Seyed Mahdi
authors.initials: SM
authors.lastname: Nassiri
authors.forename: Rassoul
authors.initials: R
authors.lastname: Dinarvand
mesh_terms: D000818:Animals; D002452:Cell Count; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004804:Eosinophils / Q000187:drug effects; D005782:Gels; D007279:Injections, Subcutaneous; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D015282:Octreotide / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D020442:Poloxamer / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011142:Polyvinyl Alcohol / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012212:Rheology
chemical_list: D003692:Delayed-Action Preparations; D005782:Gels; D020442:Poloxamer; D011092:Polyethylene Glycols; D011142:Polyvinyl Alcohol; D015282:Octreotide