Xu Bo, Liu Han, Yang Guozhong, Zhang Suohui, Zhou Zequan, Gao Yunhua
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Beijing CAS Microneedle Technology Ltd., Beijing 102609, China.
Int J Pharm. 2025 Feb 10;670:125128. doi: 10.1016/j.ijpharm.2024.125128. Epub 2024 Dec 24.
The combination of microparticles (MPs) with dissolving microneedles (DMN) represents a promising transdermal approach for the sustained release of biomacromolecule drug. In this study, we developed a double-layered microparticles-dissolving microneedle (MPs-DMN) system, which strategically concentrates PLGA MPs at the tip of the microneedle to achieve sustained release of peptide drugs through transdermal delivery. We selected exenatide (EXT) as a model peptide drug and established HPLC-UV and UPLC-MS methods for the quantitative analysis of the drug content of MPs-DMN and drug concentrations in plasma. Ultrasonication was utilized in the first step of the double emulsion solvent evaporation method to produce PLGA microparticles, achieving a high drug loading efficiency of 22.76 ± 0.64 %, surpassing the commercial products. The EXT-loaded microparticles were then mixed with 10 % w/v sucrose solution to form the first layer of the microneedle, and the mixture of the base solution was added to form the double-layered dissolving microneedle. Microscopic analysis revealed that the MPs were predominantly concentrated in the upper 50 % of the microneedle body, resulting in an impressive drug delivery efficiency of 92.86 ± 1.62 %. The MPs-DMN patch demonstrated the capability to 238.20 ± 5.79 μg of EXT within a compact area of 0.75 cm, surpassing the capacities reported in existing research. The insertion and dissolution assessments exhibited rapid dissolution, maintaining the MPs as an effective drug reservoir within the skin. Pharmacokinetic assessments indicated that the long half-life (T) of 466.4 ± 12.2 h and high relative bioavailability of 89.71 % for MPs-DMN. Furthermore, pharmacodynamic studies indicated that the MPs-DMN effectively controlled blood glucose levels below 20 mmol/L in diabetic (db/db) mouse for two weeks. These promising findings suggest that the MPs-DMN system could serve as a viable transdermal delivery method for the prolonged administration of peptide drugs.
微粒（MPs）与溶蚀性微针（DMN）相结合是一种很有前景的用于生物大分子药物持续释放的经皮给药方法。在本研究中，我们开发了一种双层微粒 - 溶蚀性微针（MPs - DMN）系统，该系统巧妙地将聚乳酸 - 羟基乙酸共聚物（PLGA）微粒集中在微针尖端，以通过经皮给药实现肽类药物的持续释放。我们选择艾塞那肽（EXT）作为模型肽类药物，并建立了高效液相色谱 - 紫外检测法（HPLC - UV）和超高效液相色谱 - 质谱联用法（UPLC - MS），用于定量分析MPs - DMN的药物含量及血浆中的药物浓度。在复乳溶剂蒸发法的第一步中使用超声处理来制备PLGA微粒，实现了22.76±0.64%的高载药效率，超过了商业产品。然后将负载EXT的微粒与10% w/v的蔗糖溶液混合形成微针的第一层，再加入基础溶液混合物形成双层溶蚀性微针。显微镜分析显示，微粒主要集中在微针主体的上半部分，实现了92.86±1.62%的可观给药效率。MPs - DMN贴片在0.75平方厘米的紧凑区域内能够递送238.20±5.79微克的EXT，超过了现有研究报道的容量。插入和溶解评估显示溶解迅速，使微粒在皮肤内作为有效的药物储库。药代动力学评估表明，MPs - DMN的半衰期长（T）达466.4±12.2小时，相对生物利用度高，为89.71%。此外，药效学研究表明，MPs - DMN可在两周内有效将糖尿病（db/db）小鼠的血糖水平控制在20毫摩尔/升以下。这些有前景的发现表明，MPs - DMN系统可作为一种可行的经皮给药方法用于肽类药物的长期给药。
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