Development and In Vivo Evaluation of Sustained Release Microparticles Loaded with Levothyroxine for Hypothyroidism Treatment.

Hypothyroidism is a chronic condition combated by a daily oral supplementation of levothyroxine. In addition to the need for frequent dosing, oral administration may result in variable absorption of the drug leading to a failure in achieving normal thyroid function. Therefore, the development of a long-acting injectable system capable of delivering the drug is necessary. This work was aimed at developing sustained release microparticles loaded with levothyroxine. The microparticles were produced through the emulsification-solvent evaporation method using 2 grades of biocompatible and biodegradable polyesters: poly(ᴅ,ʟ-lactide-co-glycolide) (PLGA) and poly(ᴅ,ʟ-lactide) (PLA). Both polymers produced microparticles with very similar sizes (1.9 µm) and zeta potential values (around -22.0 mV). However, PLA microparticles had a significantly higher drug loading (6.1% vs. 4.4%, respectively) and encapsulation efficiency (36.8%, vs. 26.1%, respectively) when compared to PLGA counterparts. While both types of microparticles displayed a biphasic release pattern in vitro, a slower rate of release was observed with PLA microparticles. Moreover, a similar biphasic release pattern was found in vivo, with an initial phase of rapid release followed by a slower phase in the subsequent 10 days. These results indicate the possibility of developing levothyroxine loaded polyester microparticles as a potential long-acting thyroid hormone replacement therapy.

Optimizing formulation parameters for the development of carvedilol injectable in situ 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.