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The Modified Exenatide Microspheres: PLGA-PEG-PLGA Gel and Zinc-Exenatide Complex Synergistically Reduce Burst Release and Shorten Platform Stage

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Abstract

The existing exenatide microspheres have the problem of burst release in the early stage, and minimal release in the middle stage which makes it difficult to achieve effective blood drug concentration (platform period). In this study, the modified exenatide microspheres were constructed to address the aforementioned issues. Poly(D,L-lactic-co-glycolic acid) (PLGA) and triblock copolymer with sol-gel conversion characteristics (PLGA-PEG-PLGA gel) were introduced as carriers to prepare microspheres. The hot gel characteristics and hydrophilicity of PLGA-PEG-PLGA gel were utilized to decline the burst release and shorten the platform period. Simultaneously, zinc acetate and exenatide were combined to generate an insoluble complex to further reduce the burst release. Herein, we prepared three types of exenatide microspheres using the solvent evaporation method and investigated their characterization as well as in vitro and in vivo release. According to the experimental findings, the modified exenatide microspheres, i.e., PLGA-PEG-PLGA gel and PLGA co-loaded zinc-exenatide insoluble complex microspheres (Zn-EXT-Gel-MS), had smooth and rounded surfaces, with a particle size of 24.7 μm, and the encapsulation rate reached 89.43%. And it was released for 40 days in vitro, behaving better than the other two microspheres in terms of release behavior. When this product was administered subcutaneously to rats, it produced a comparatively constant plasma exenatide concentration that lasted for 24 days and superior bioavailability than the exenatide microspheres (EXT-MS). The creation of modified exenatide microspheres may serve as a heuristic method for other long-acting medications.

Graphical Abstract

Schematic diagram of the synthesis process and release curves of three types of exenatide microspheres in vitro and in vivo

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Acknowledgements

We are appreciative that this study had been funded by the Basic Research Project of Liaoning Provincial Department of Education in 2023 (Project Number: JYTZD2023143, Project Name: Preparation and Evaluation of the Modified exenatide Long-acting Sustained Release Microspheres). The authors are grateful to Shenyang Pharmaceutical University, Liaoning, China for providing the experimental platform and related instruments.

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  1. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, People’s Republic of China

    Wenjing Jiang, Xiangjun Gao, Qiuli Wang, Yang Chen, Dan Li, Xiaoyan Zhang & Xinggang Yang

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  1. Wenjing Jiang
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Contributions

Wenjing Jiang: conceptualization, data curation, investigation, methodology, validation, formal analysis, writing — original draft.

Xiangjun Gao: data curation, methodology, validation, formal analysis.

Qiuli Wang: formal analysis, investigation, validation.

Yang Chen: data curation, investigation, methodology.

Dan Li: investigation, writing — original draft.

Xiaoyan Zhang: methodology, writing—original draft.

Xinggang Yang: conceptualization, formal analysis, investigation, project administration, resources, supervision, writing — review and editing.

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Correspondence to Xinggang Yang.

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Jiang, W., Gao, X., Wang, Q. et al. The Modified Exenatide Microspheres: PLGA-PEG-PLGA Gel and Zinc-Exenatide Complex Synergistically Reduce Burst Release and Shorten Platform Stage. AAPS PharmSciTech 24, 251 (2023). https://doi.org/10.1208/s12249-023-02705-6

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