title: Improved oral absorption of exenatide using an original nanoencapsulation and microencapsulation approach.
abstract: Oral delivery is the most convenient and favorable route for chronic administration of peptides and proteins to patients. However, many obstacles are faced when developing such a delivery route. Nanoparticles (NPs) are among the leading innovative solutions for delivery of these drugs. Exenatide is a peptidic drug administered subcutaneously (SC) twice a day chronically as an add-on therapy for the worldwide pandemic disease, diabetes. Many attempts to develop oral nanocarriers for this drug have been unsuccessful due to the inability to retain this hydrophilic macromolecule under sink conditions or to find a suitable cross-linker which does not harm the chemical integrity of the peptide. In this study, we report about an original oral delivery solution based on a mixture of albumin and dextran NPs cross-linked using sodium trimetaphosphate (STMP). Moreover, we suggest a second defense line of gastro-resistant microparticles (MPs) composed of an appropriate ratio of Eudragit® L100-55 (Eudragit L) and hydroxypropylmethylcellulose (HPMC), for additional protection to these NPs presumably allowing them to be absorbed in the intestine intact. Our results demonstrate that such a system indeed improves the relative oral bioavailability of exenatide to a level of about 77% compared to subcutaneous injection due to the presence of dextran in the coating wall of the NPs which apparently promotes the lymphatic uptake in the enterocytes. This technology may be a milestone on the way to deliver other peptides and proteins orally.
authors.affiliation: The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, 9112102, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Soudry-Kochavi
authors.affiliation: The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, 9112102, Israel.
authors.forename: Natalya
authors.initials: N
authors.lastname: Naraykin
authors.affiliation: The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, 9112102, Israel.
authors.forename: Taher
authors.initials: T
authors.lastname: Nassar
authors.affiliation: The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, 9112102, Israel. Electronic address: simonb@ekmd.huji.ac.il.
authors.forename: Simon
authors.initials: S
authors.lastname: Benita
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D003911:Dextrans / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004339:Drug Compounding; D065546:Drug Liberation; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D065347:Hypromellose Derivatives / Q000737:chemistry; D007408:Intestinal Absorption; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011109:Polymethacrylic Acids / Q000737:chemistry; D011122:Polyphosphates / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000737:chemistry; D014688:Venoms / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D003911:Dextrans; D004337:Drug Carriers; D007004:Hypoglycemic Agents; D010455:Peptides; D011109:Polymethacrylic Acids; D011122:Polyphosphates; D014688:Venoms; C038300:methylmethacrylate-methacrylic acid copolymer; D012710:Serum Albumin, Bovine; D065347:Hypromellose Derivatives; D000077270:Exenatide; C009293:trimetaphosphoric acid
keywords: Albumin; Bioavailability; Dextran; Exenatide; Microparticle; Nanoparticle; Oral