Applicability of non-halogenated methyl propionate to microencapsulation.

Applicability of methyl propionate to microencapsulation was evaluated with regard to volatility, capability of forming emulsions, and their quality. An emulsion-based technique was then developed to encapsulate progesterone into poly-d,l-lactide-co-glycolide microspheres. Their characteristics were compared with those prepared using ethyl acetate. Our results demonstrated that methyl propionate had greater evaporative tendency and less water miscibility than ethyl acetate did. The former allowed us to prepare good microspheres. Their average volume mean diameter was 68.3 ± 1.7 µm with a span index of 0.91 ± 0.13. Progesterone did not undergo polymorphic transition during microencapsulation, and its encapsulation efficiency ranged from 41.80 ± 1.83 to 85.64 ± 1.95%. Residual methyl propionate in various microspheres was found to be 0.97 ± 0.03 to 1.54 ± 0.07%. Such microsphere characteristics were quite similar to those prepared by the ethyl acetate-based microencapsulation process. Overall, our findings reflect that methyl propionate has a potential to become an invaluable solvent for microencapsulation.

Characterization of attributes and in vitro performance of exenatide-loaded PLGA long-acting release microspheres.

Bydureon® (Bdn) is a once-weekly injectable long-acting release (LAR) product for adults with type 2 diabetes based on PLGA microspheres encapsulating the glucagon like peptide (GLP-1) analog, exenatide. Despite its widespread use in type 2 diabetes treatment, little information has been published concerning the physical-chemical aspects and exenatide stability in this product. Here, we developed and validated methods to evaluate attributes and performance of Bdn such as particle size/size distribution and residual levels of moisture and organic solvent(s). The reverse engineering of the exenatide LAR was also performed to identify and quantify principal components in the product. Stability-indicating UPLC and LC-MS methods were applied to characterize exenatide degradation (such as oxidation, deamidation and acylation products) during in vitro release evaluation. The 55-µm volume-median Bdn microspheres slowly released the exenatidein vitroover two months with a very low initial burst release to avoid unwanted side effects. Residual organic solvent levels (methylene chloride, ethanol, heptane, and silicon oil) also met the USP criteria. Peptide acylation was the most prominent peptide reaction during both encapsulation and in vitro release, and the acylated peptide steadily increased during release relative to parent exenatide, becoming the most abundant peptide species extracted from the microspheres at later release stages. The presence of peptide impurities during the release period, which are not extractable in the polymer and likely insoluble in water, might be one potential cause for immunogenicity. Further evaluation will be needed to confirm this hypothesis. Release of peptide was minimal over the first 2 weeks before the microspheres steadily released peptide for more than 28 days. The rigorous technical approach discussed in this paper may provide critical information for both companies and the FDA for developing generic exenatide-PLGA formulations and other important PLGA microsphere products.