Exenatide Microspheres for Monthly Controlled-Release Aided by Magnesium Hydroxide

Abstract

GLP-1 receptor agonists are a class of diabetes medicines offering self-regulating glycemic efficacy and may best be administrated in long-acting forms. Among GLP-1 receptor agonists, exenatide is the one requiring the least dose so that controlled-release poly(d,l-lactic-co-glycolic acid) (PLGA) microspheres may best achieve this purpose. Based on this consideration, the present study extended the injection interval of exenatide microspheres from one week of the current dosage form to four weeks by simply blending Mg(OH)2 powder within the matrix of PLGA microspheres. Mg(OH)2 served as the diffusion channel creator in the earlier stage of the controlled-release period and the decelerator of the self-catalyzed degradation of PLGA (by the formed lactic and glycolic acids) in the later stage due to its pH-responsive solubility. As a result, exenatide gradually diffused from the microspheres through Mg(OH)2-created diffusion channels before degradation of the PLGA matrix, followed by a mild release due to Mg(OH)2-buffered degradation of the polymer skeleton. In addition, an extruding–settling process comprising squeezing the PLGA solution through a porous glass membrane and sedimentation-aided solidification of the PLGA droplets was used to prepare the microspheres to ensure narrow size distribution and 95% encapsulation efficiency in an aqueous continuous phase. A pharmacokinetic study using rhesus monkey model confirmed the above formulation design by showing a steady blood concentration profile of exenatide with reduced CMAX and dosage form index. Mg(OH)2.