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Transdermal Delivery of Metformin Utilizing Ionic Liquid Technology: Insight Into the Relationship Between Counterion Structures and Properties

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Abstract

Purpose

The purpose of the present study was to explore the feasibility of transdermal delivery of metformin, a commonly used oral antidiabetic drug, by ionic liquid (IL) technology.

Methods

Metformin hydrochloride (MetHCl) was first transformed into three kinds of ILs with different counterions. The physicochemical properties of the obtained ILs were characterized in depth. The simulation of stable configuration and calculation of interaction energies were conducted based on density functional theory (DFT). Skin-PAMPA was used to evaluate the intrinsic transdermal permeation properties. The cytotoxicity assay of these ILs was conducted using HaCaT cells to evaluate the toxicity to skin. These metformin ILs were then formulated into transdermal patch, and the transdermal potential was further evaluated using in vitro dissolution test and skin permeation assay. Finally, the pharmacokinetic profiles of these metformin IL-containing patches were determined.

Results

Among all the three Met ILs, metformin dihexyl sulfosuccinate (MetDH) with proper overall physiochemical and biological properties demonstrated the highest relative bioavailability. Metformin docusate (MetD) with the highest lipophilicity and intrinsic transdermal permeability exhibited the most significant sustained release profile in vivo. Both MetDH and MetD were the promising candidates for further clinical investigations.

Conclusions

Overall, the properties of ILs were closely related to the structures of counterion. IL technology provided the opportunities to finely tune the solid-state and biological properties of Metformin and facilitated the successful delivery by transdermal route.

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Funding

This work was sponsored by Natural Science Foundation of Shanghai (No. 20ZR1413600), the National Natural Science Foundation of China (No. 21576080) and Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission).

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Authors and Affiliations

  1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China

    Minghuang Hong & Guo-Bin Ren

  2. Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, Shanghai, 200237, China

    Minghuang Hong, Qinglin Wang, Kai Wang, Jinghui Li, Ming-Hui Qi & Guo-Bin Ren

  3. Laboratory of Pharmaceutical Crystal Engineering & Technology, No. 130 Meilong Road, Shanghai, 200237, China

    Minghuang Hong, Qinglin Wang, Kai Wang, Jinghui Li, Ming-Hui Qi & Guo-Bin Ren

  4. Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, East China University of Science and Technology, No. 130 Meilong Road, 200237, Shanghai, China

    Minghuang Hong, Qinglin Wang, Kai Wang, Jinghui Li, Ming-Hui Qi & Guo-Bin Ren

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  1. Minghuang Hong
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  2. Qinglin Wang
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Contributions

Minghuang Hong: conceptualization, supervision, funding acquisition, methodology, investigation, writing-review & editing. Qinglin Wang: investigation, software, formal analysis, writing-original draft. Kai Wang: investigation, formal analysis, writing-original draft. Jinghui Li: investigation, validation. Ming-Hui Qi: Resources. Guo-Bin Ren: supervision, funding acquisition, project administration.

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Correspondence to Minghuang Hong or Guo-Bin Ren.

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Hong, M., Wang, Q., Wang, K. et al. Transdermal Delivery of Metformin Utilizing Ionic Liquid Technology: Insight Into the Relationship Between Counterion Structures and Properties. Pharm Res 39, 2459–2474 (2022). https://doi.org/10.1007/s11095-022-03394-9

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