title: Improving oral bioavailability of metformin hydrochloride using water-in-oil microemulsions and analysis of phase behavior after dilution.
abstract: Microemulsions show significant promise for enhancing the oral bioavailability of biopharmaceutics classification system (BCS) class II drugs, but how about class III drugs remains unclear. Here we employed metformin hydrochloride (MET) as the model drug and prepared drug-loaded water-in-oil (W/O) microemulsions selecting different hydrophile-lipophile balance (HLB) surfactant systems, using HLB 8 as a cut-off. We examined the phase behaviors of microemulsions after dilution and attempted to correlate these behaviors to drug oral bioavailability. ME-A, including a lower content of surfactants (35%), underwent a transition of W/O emulsion and then became a stable O/W emulsion in a light milky appearance; ME-B, in contrast, introducing a higher content of surfactants (45%), still remained transparent or semitransparent upon dilution. Unexpectedly, ME-A showed significantly higher oral bioavailability, which can be reduced by blocking the lymphatic absorption pathway. Comparatively, the AUC of ME-B is lower, close to MET solution. Both microemulsions behaved similarly in intestinal perfusion test because of the dilution before perfusion, lacking of the important phase transition of W/O emulsion. These findings suggest that W/O microemulsions improve oral bioavailability of BCS class III drug by promoting lymphatic absorption. Analyzing the phase behavior of microemulsions after dilution may help predict the drug oral bioavailability and optimize formulations.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Song
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Ning
authors.initials: N
authors.lastname: Tian
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Meihong
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Xing
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Yalong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
authors.forename: Chuanbin
authors.initials: C
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China. Electronic address: lsshhy@mail.sysu.edu.cn.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Hu
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004655:Emulsions; D005026:Ethylene Glycols / Q000737:chemistry; D005989:Glycerides / Q000737:chemistry; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D006601:Hexoses / Q000737:chemistry; D007004:Hypoglycemic Agents / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008041:Linoleic Acids / Q000737:chemistry; D008297:Male; D008687:Metformin / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D009829:Oleic Acids / Q000737:chemistry; D009930:Organic Chemicals / Q000737:chemistry; D044367:Phase Transition; D011136:Polysorbates / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D004655:Emulsions; D005026:Ethylene Glycols; D005989:Glycerides; D006601:Hexoses; D007004:Hypoglycemic Agents; D008041:Linoleic Acids; D009829:Oleic Acids; D009930:Organic Chemicals; D011136:Polysorbates; D013501:Surface-Active Agents; C440220:Labrasol; D014867:Water; C018665:sorbitan monooleate; C000515:cremophor EL; D008687:Metformin; C010111:carbitol; C005953:monoolein; D005990:Glycerol
keywords: Lymphatic transport; Metformin hydrochloride; Oral bioavailability; Phase behaviors; W/O microemulsions