title: In vivo evaluation of an oral self-microemulsifying drug delivery system (SMEDDS) for leuprorelin.
abstract: The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) for the model peptide drug leuprorelin to prove a protective effect against luminal enzymatic metabolism. In order to incorporate leuprorelin into microemulsion droplets (o/w), the commercially available hydrophilic leuprolide acetate was modified by hydrophobic ion paring with sodium oleate. The obtained hydrophobic leuprolide oleate was dissolved in the SMEDDS formulation (30% (m/m) Cremophor EL, 30% (m/m) Capmul MCM, 10% (m/m) propylene glycol and 30% (m/m) Captex 355) in a concentration of 4 mg/g showing a mean droplet size of 50.1 nm when dispersed in a concentration of 1% (m/v) in phosphate buffer pH 6.8. The microemulsion was able to shield leuprolide oleate from enzymatic degradation by trypsin and α-chymotrypsin, so that after 120 min 52.9% and 58.4%, respectively, of leuprolide oleate were still intact. Leuprolide acetate dissolved in an aqueous control solution was completely metabolized by trypsin within 60 min and by α-chymotrypsin within 5 min. Moreover, an in vivo study in rats showed a 17.2-fold improved oral bioavailability of leuprolide oleate SMEDDS compared to a leuprolide acetate control solution. This is the first time, to our knowledge, that hydrophobic ion pairing is utilized in order to incorporate a peptide drug in SMEDDS and evidence of a protective effect of oil-in-water (o/w) microemulsion droplets against enzymatic degradation of a peptide drug was provided. According to these results, the system could be likely a novel platform technology to improve the oral bioavailability of peptide drugs.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, Innsbruck 6020, Austria.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hintzen
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, Innsbruck 6020, Austria.
authors.forename: Glen
authors.initials: G
authors.lastname: Perera
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, Innsbruck 6020, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hauptstein
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, Innsbruck 6020, Austria.
authors.forename: Christiane
authors.initials: C
authors.lastname: Müller
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, Innsbruck 6020, Austria.
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences, Leopold-Franzens-University Innsbruck, Innrain 80/82, Center for Chemistry and Biomedicine, Innsbruck 6020, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D002210:Caprylates / Q000737:chemistry; D016503:Drug Delivery Systems; D004655:Emulsions; D005300:Fertility Agents, Female / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D005989:Glycerides / Q000737:chemistry; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D016729:Leuprolide / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D019301:Oleic Acid / Q000737:chemistry; D019946:Propylene Glycol / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002210:Caprylates; D004655:Emulsions; D005300:Fertility Agents, Female; D005989:Glycerides; D014280:Triglycerides; D019301:Oleic Acid; C013173:osteum; C000515:cremophor EL; D019946:Propylene Glycol; D014357:Trypsin; D016729:Leuprolide; D005990:Glycerol; C025343:monooctanoin
keywords: Hydrophobic ion pairing; Leuprorelin; Protection against enzymatic degradation; Self-microemulsifying drug delivery system