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. 2021 May 30;13(6):816.
doi: 10.3390/pharmaceutics13060816.

Exenatide Microspheres for Monthly Controlled-Release Aided by Magnesium Hydroxide

Yuxuan Ge  1 , Zhenhua Hu  1 , Jili Chen  1 , Yujie Qin  2 , Fei Wu  1 , Tuo Jin  1   2   3
Affiliations

Exenatide Microspheres for Monthly Controlled-Release Aided by Magnesium Hydroxide

Yuxuan Ge et al. Pharmaceutics. .

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.

Keywords: PLGA; controlled-release; exenatide; magnesium hydroxide; microsphere.

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Conflict of interest statement

The authors declare no conflict of interest. Yujie Qin is from BioDosage Tech, Ltd.; Tuo Jin is from BioDosage Tech, Ltd. and BioPharm Solutions, Inc., BioDosage Tech, Ltd provided the instrument of microsphere production and BioPharm Solutions, Inc. was involved in the interpretation of data.

Figures

Figure 1
Figure 1
Schematic description of the PLGA microsphere preparation process and the mechanism of Mg(OH)2 as a dual-functional excipient.
Figure 2
Figure 2
SEM images of microspheres produced by the present extruding–settling method, microspheres by W/O/W double emulsion and BydureonTM.
Figure 3
Figure 3
Cumulative exenatide release profile of microsphere formulations (means ± SD, n = 3). 1: MS 0% Mg(OH)2, 2: MS 6% Mg(OH)2, 3: MS 8% Mg(OH)2, 4: MS 11% Mg(OH)2, 5: BydureonTM (1/5 vs. 2–4, p < 0.05; 2 vs. 3/4, p < 0.05).
Figure 4
Figure 4
SEM images of microspheres under incubation of different times.
Figure 5
Figure 5
pH curves of release medium during the incubation (means ± SD, n = 3). 1: MS 0% Mg(OH)2, 2: MS 6% Mg(OH)2, 3: MS 8% Mg(OH)2, 4: MS 11% Mg(OH)2 (1 vs. 2–4, p < 0.05).
Figure 6
Figure 6
Mn (A) and Mw (B) of PLGA in microspheres under incubation of different times analyzed by GPC (means ± SD, n = 3). 1: MS 0% Mg(OH)2, 2: MS 6% Mg(OH)2, 3: MS 8% Mg(OH)2, 4: MS 11% Mg(OH)2 (1 vs. 2–4, p < 0.05).
Figure 7
Figure 7
Plasma concentrations of exenatide released from the microspheres of the present study and commercial product BydureonTM in rhesus monkeys (means ± SD, n = 5) (p < 0.05).
Figure 8
Figure 8
Plasma concentrations of exenatide released from the microspheres of the present study and commercial product BydureonTM in rhesus monkeys (means ± SD, n = 5). 1: PBS, 2: Bydureon at 125 µg/kg, 3: Bydureon at 250 µg/kg, 4: Bydureon at 500 µg/kg, 5: Present MS at 125 µg/kg, 6: Present MS at 250 µg/kg, 7: Present MS at 500 µg/kg (1 vs. 2–7, p < 0.05; 2 vs. 5, p < 0.05; 3 vs. 6, p < 0.05; 4 vs. 7, p < 0.05).
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