title: Characterization of water-in-oil microemulsion for oral delivery of earthworm fibrinolytic enzyme.
abstract: Earthworm fibrinolytic enzyme (EFE-d, Mr 24177), a water-soluble protein, is clinically used for the management of cardiovascular diseases. However, this protein drug has a very low oral bioavailability because of its low oil/water partitioning, low membrane permeability and unstable nature in harsh gastric juice. This study explored the possibility of absorption and efficacy enhancement for EFE-d through the delivery of the water-in-oil (w/o) microemulsions. The w/o microemulsion consisting of Labrafac CC, Labrasol, Plurol Oleique CC 497 and saline (54/18/18/10, % w/w) was developed and characterized, including conductivity, viscosity, particle size and in vitro membrane permeability. The w/o microemulsion and the control solution of EFE-d were administered intraduodenally (or orally) to rats. The w/o microemulsion possessed a higher intestinal membrane permeability in vitro as well as a higher absorption and efficacy in vivo, when compared to control solution. The intraduodenal bioavailability of EFE-d for microemulsions was 208-fold higher than that of control solution and the absolute bioavailability was 17.55%. Meanwhile, there was no tissue damage of the intestinal mucosa found after oral multiple-dose administration of the EFE-d microemulsion to rats. These findings indicated that the w/o microemulsion may represent a safe and effective oral delivery system for hydrophilic bioactivity macromolecules.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
authors.forename: Mao-Bo
authors.initials: MB
authors.lastname: Cheng
authors.forename: Jian-Cheng
authors.initials: JC
authors.lastname: Wang
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Li
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Liu
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Chen
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002463:Cell Membrane Permeability; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004339:Drug Compounding; D004553:Electric Conductivity; D004655:Emulsions; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics; D005989:Glycerides; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects; D007441:Intubation, Gastrointestinal; D008297:Male; D009821:Oils / Q000737:chemistry*; D009829:Oleic Acids / Q000737:chemistry; D009835:Oligochaeta / Q000201:enzymology*; D009930:Organic Chemicals / Q000737:chemistry; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012697:Serine Endopeptidases / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics; D013501:Surface-Active Agents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods; D014783:Viscosity; D014867:Water / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D004655:Emulsions; D005343:Fibrinolytic Agents; D005989:Glycerides; D009821:Oils; D009829:Oleic Acids; D009930:Organic Chemicals; D013501:Surface-Active Agents; C440220:Labrasol; D014867:Water; D012697:Serine Endopeptidases