Minghuang Hong1,2,3,4, Qinglin Wang5,6,7, Kai Wang5,6,7, Jinghui Li5,6,7, Ming-Hui Qi5,6,7, Guo-Bin Ren8,9,10,11. 1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China. mhhong@ecust.edu.cn. 2. Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, Shanghai, 200237, China. mhhong@ecust.edu.cn. 3. Laboratory of Pharmaceutical Crystal Engineering & Technology, No. 130 Meilong Road, Shanghai, 200237, China. mhhong@ecust.edu.cn. 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. mhhong@ecust.edu.cn. 5. Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, Shanghai, 200237, China. 6. Laboratory of Pharmaceutical Crystal Engineering & Technology, No. 130 Meilong Road, Shanghai, 200237, China. 7. Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, East China University of Science and Technology, No. 130 Meilong Road, 200237, Shanghai, China. 8. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China. rgb@ecust.edu.cn. 9. Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, Shanghai, 200237, China. rgb@ecust.edu.cn. 10. Laboratory of Pharmaceutical Crystal Engineering & Technology, No. 130 Meilong Road, Shanghai, 200237, China. rgb@ecust.edu.cn. 11. Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, East China University of Science and Technology, No. 130 Meilong Road, 200237, Shanghai, China. rgb@ecust.edu.cn.
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.
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.
Authors: Garry G Graham; Jeroen Punt; Manit Arora; Richard O Day; Matthew P Doogue; Janna K Duong; Timothy J Furlong; Jerry R Greenfield; Louise C Greenup; Carl M Kirkpatrick; John E Ray; Peter Timmins; Kenneth M Williams Journal: Clin Pharmacokinet Date: 2011-02 Impact factor: 6.447
Authors: Kristiina M Huttunen; Anne Mannila; Krista Laine; Eeva Kemppainen; Jukka Leppänen; Jouko Vepsäläinen; Tomi Järvinen; Jarkko Rautio Journal: J Med Chem Date: 2009-07-23 Impact factor: 7.446