Pharmacokinetic Evaluation of Thermosensitive Sustained Release Formulations Developed for Subcutaneous Delivery of...

Injectable, thermosensitive hydrogels, constructed from cross-linked polymers, can offset the limitations of other sustained release delivery systems, overcome constrains of available therapies, and improve patient compliance to chronic therapy. The goal of this project was to identify and evaluate such sustained release, in situ formulations that can help achieve prolonged exposure of protein therapeutics with a short systemic half-life. Natural polymers were used to develop injectable, thermosensitive in situ hydrogels and single-chain variable fragment (scFv) of trastuzumab was used as the model protein with a short half-life. The three polymer combinations tested were: (1) Chitosan and β-glycerophosphate, (2) Chitosan, β-glycerophosphate, and Hyaluronic Acid, and (3) Hyaluronic Acid and Dextran. In vitro drug release experiments were conducted, using different combinations of various polymer concentrations and different drug loading amounts, to identify optimal combinations with prolonged and controlled drug release while exhibiting minimal burst release effect. Select formulations were injected subcutaneously in normal mice to evaluate the pharmacokinetics of scFv for 14 days and identify drug release kinetics in vivo. A two-compartment PK model was also established to quantitatively characterize the release kinetics and disposition of scFv following in vivo administration of the hydrogels. The scFv was undetectable in plasma after 4 and 24 hours following intravenous and subcutaneous administration, respectively. However, all three hydrogel systems were found to provide controlled release of scFv in vivo and maintain detectable concentrations of scFv for at least 14 days. The results suggested that subcutaneous injection of thermosensitive in situ hydrogels may be used to achieve sustained exposure of protein therapeutics which have a very short half-life and thus require frequent administration.