Optimizing formulation parameters for the development of carvedilol injectable <i>in situ</i> forming depots

In situ forming depots (ISFDs) represent attractive alternatives to the conventional sustained drug delivery systems. Carvedilol, a short half-life drug used on a daily basis to manage chronic conditions, could benefit from this technology. The aim of this work was to develop, for the first time, a new injectable long-acting carvedilol-ISFD. Accordingly, 4 different grades of polyesters with varying properties as i) lactide-to glycolide ratio (polylactide-co-glycolide (PLGA) vs. polylactide (PLA)), and ii) end functionality (acid- vs. ester-capped) were utilized for the preparation of ISFD formulations. In addition, 4 different organic solvents with varying properties (i.e. N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), ethyl acetate, and benzyl benzoate) were also investigated. It was found that NMP and DMSO were more suitable for the formation of depots. Furthermore, all ISFD formulations demonstrated excellent encapsulation efficiency (i.e. 96–98%). Interestingly, both PLGA-based ISFDs (acid-capped and ester-capped) exhibited similar release behaviors and were able to extend carvedilol release over 30 days. On the other hand, acid-capped and ester-capped PLA-based ISFDs exhibited slower release over the 30 days with an average release of only 36% and 60%, respectively. In conclusion, the developed carvedilol-ISFDs resulted in a tunable extended-release behavior, simply by choosing the appropriate grade of polymer. These results open the door toward a novel injectable carvedilol-ISFD formulation.</p