title: Osmotic pressure driven protein release from viscous liquid, hydrophobic polymers based on 5-ethylene ketal ε-caprolactone: potential and mechanism.
abstract: In this study, the potential of low molecular weight, viscous liquid polymers based on 5-ethylene ketal ε-caprolactone for localized delivery of proteins via an osmotic pressure release mechanism was investigated. Furthermore, the osmotic release mechanism from viscous liquid polymers was elucidated. 5-Ethylene ketal ε-caprolactone was homopolymerized or copolymerized with D,L-lactide (DLLA) by ring-opening polymerization. Polymer hydrophobicity was adjusted by choice of initiator; hydrophobic polymers were prepared by initiating with octan-1-ol, while more hydrophilic polymers were prepared by initiating with 350 g/mol methoxy poly(ethylene glycol) (PEG). Particles consisting of bovine serum albumin (BSA) as a model protein drug were co-lyophilized with trehalose at 50:50 and 10:90 (w/w) ratios and were mixed into the polymers at 1% and/or 5% (w/w) particle loading. The release and mechanism of release of BSA from the polymers were assessed in vitro. BSA was released in a sustained manner, with a near zero-order release profile and with minimal burst effect for 5-80 days depending on the polymer's hydrophilicity; the release was faster from the PEG initiated polymers than from the octan-1-ol initiated polymers. Increasing the particle loading from 1% to 5% (w/w) resulted in a more noticeable burst effect, but did not significantly increase the mass fraction release rate. This release behavior was determined to proceed as follows. Release from the polymer was triggered by the water activity gradient between the surrounding aqueous medium and the saturated solution, which forms when water is absorbed from the surrounding medium to dissolve a given particle. The generated pressure initiates swelling around the particle/polymer interface and creates a superhydrated polymer region through which the solute is transported by convection, at a rate determined by the osmotic pressure generated.
authors.affiliation: Department of Chemical Engineering, Queen's University, Kingston, ON, Canada.
authors.forename: Iyabo Oladunni
authors.initials: IO
authors.lastname: Babasola
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Brian G
authors.initials: BG
authors.lastname: Amsden
mesh_terms: D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying; D057927:Hydrophobic and Hydrophilic Interactions; D008970:Molecular Weight; D009997:Osmotic Pressure; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D058105:Polymerization; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000737:chemistry; D014199:Trehalose / Q000737:chemistry; D014783:Viscosity; D014867:Water / Q000737:chemistry
chemical_list: D003692:Delayed-Action Preparations; D005079:Excipients; D011091:Polyesters; C576040:poly(5-ethylene ketal epsilon-caprolactone-co-lactide); D014867:Water; D012710:Serum Albumin, Bovine; D011092:Polyethylene Glycols; D014199:Trehalose
keywords: Biodegradable polymer; Liquid injectable polymer; Osmotic pressure; Protein delivery; Release mechanism; Sustained release