Transdermal Delivery of Insulin Using Combination of Iontophoresis and Deep Eutectic Solvents as Chemical Penetration Enhancers: In Vitro and in Vivo Evaluations |
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| Institution: | 1. Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran;2. Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran;3. Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada;4. Department of Environmental Health Engineering, Faculty of Health and Research Center for Health Sciences, Hamadan University of Medical Sciences, Hamadan, Iran;1. Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455;2. Small Molecule Pharmaceutical Sciences, Genentech Inc., South San Francisco, CA 94080;3. Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455;1. School of Sciences, São Paulo State University, 17033-360, Bauru, Brazil;2. CQC/IMS, Chemistry Department, University of Coimbra, 3004-535, Coimbra, Portugal;3. Faculty of Pharmacy, University of Coimbra, 3000-548, Coimbra, Portugal;1. State Key Laboratory of Natural Medicines, Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana;3. Department of Pharmaceutical Chemistry, School of Pharmacy and Pharmaceutical Sciences, University for Development Studies, Tamale, Ghana;1. Drug Product Development (DPD), Global Product Development & Supply (GPS), Bristol Myers Squibb, 1 Squibb Drive, New Brunswick NJ 08903, United States;2. GEA Systems North America, 9165 Rumsey Rd Columbia MD 21045, United States |
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| Abstract: | A serious challenge in transdermal iontophoresis (IP) delivery of insulin (INS) is the low permeability of the drug across the skin. In this paper, we introduced deep eutectic solvent (DESs) as novel chemical penetration enhancers (CPEs) for transdermal IP of INS across rat skin, both in vitro and in vivo. Three different DESs based on choline chloride (ChCl), namely, ChCl/UR (ChCl and urea), ChCl/GLY (ChCl and glycerol), and ChCl/EG (ChCl and ethylene glycol) in the 1:2 molar ratios have been prepared. To evaluate the capability of studied DESs as CPEs for IP delivery of INS, the rat skin sample was treated with each DES. The effects of different experimental parameters (current density, formulation pH, INS concentration, NaCl concentration, and treatment time) on the in vitro transdermal iontophoretic delivery of INS were investigated. The in vitro permeation studies exhibited that INS was easily delivered employing ChCl/EG, and ChCl/GLY treatments, compared with ChCl/UR: the cumulative amount of permeated INS at the end of the experiment (Q24h) was found to be 131.0, 89.4, and 29.6 µg cm?2 in the presence of ChCl/EG, ChCl/GLY, and ChCl/UR, respectively. The differences in Q24h values of INS are due to the different capabilities of the studied DESs to treat the epidermis layer of skin. In vivo experiments revealed that the blood glucose level in diabetic rats could be decreased using ChCl/EG, and ChCl/GLY as novel CPEs in the IP delivery of INS. The presented work will open new doors towards searching for novel CPEs in the development of transdermal IP of INS. |
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