Thiolated Polymer Conjugation with Peptide Drug: Formulation, Design and In Vivo Pharmacokinetic Characterization
Gul Shahnaz
Department of Pharmaceutical Technology
Institute of Pharmacy
University of Innsbruck
Austria
Abstract:
The aim of this study is to evaluate the contribution of a thiolated polymer for improving the therapeutic efficacy of the Leu-Enkephalin Analog [D-Ala2, Leu5, Cys6]-enkephalin (DALCE), as representative of low molecular weight peptides that are rapidly cleared showing short plasma half life. DALCE was conjugated with a novel thiolated carboxymethyl dextran (CMD-Cys) via disulfide bond formation with the polymer. The resulting CMD-Cys-DALCE conjugates displayed 24.3± 7.9 % of DALCE (mean ± S.D.; n=3). The conjugation of DALCE with CMD-Cys was also characterized by using FTIR-ATR spectroscopy. In vitro release studies of conjugate CMD-Cys-DALCE in the presence of 200 μM/L, 400 μM/L, and 600 μM/L reduced glutathione (GSH) showed a sustained drug release over a time period of 8, 5.5 and 8h, respectively. For in vivo pharmacokinetic study, DALCE and CMD-Cys-DALCE were administered intravenously to male Sprague-Dawley rats at a dose of 1mg/kg.The AUC0-∞ (ng.min/ml) was estimated to be 156759 ± 924 and 12817 ± 495 of CMD-Cys-DALCE and DALCE, respectively. The MRT (min) was determined to be 90 ± 8 and 17.4 ± 3.2 of CMD-Cys-DALCE and DALCE, respectively. CMD-Cys-DALCE had a 7-fold increase in elimination half-life (p < 0.01), 2-fold decrease in volume of distribution (p < 0.01), and a 12-fold decrease in plasma clearance rate (p < 0.01) as compared to DALCE. In these findings, CMD-Cys-DALCE seems to act as prodrug by improving half life and decrease in plasma clearance, anticipated that thiolated polymer will be promising for future peptides drug development paradigms.
