title: A self-microemulsifying drug delivery system to overcome intestinal resveratrol toxicity and presystemic metabolism.
abstract: A mixed lipid-mixed surfactant self-microemulsifying drug delivery system (SMEDDS) was developed to exploit the health benefits of resveratrol, a Biopharmaceutical Classification System Class 2 natural polyphenol, subject to extensive intestinal presystemic metabolism. SMEDDS with a mixed lipid phase (castor oil/Capmul MCM 1:1) and a mixed surfactant phase (Kolliphor EL/Kolliphor RH 40 1:1) was developed and evaluated for its self-emulsifying properties and in vitro dispersion. The impact of SMEDDS on the permeability properties of resveratrol and its metabolite fluxes through the rat intestine and Caco-2 cells was monitored. The inhibitory effect of selected SMEDDS components on the efflux transporters multidrug resistance-associated protein and P-gp as well as cytotoxicity was assessed on Caco-2 cells. The formulation allowed for high resveratrol loading (122.5 mg/g SMEDDS), excellent self-emulsifying properties, and very rapid release. When formulated in SMEDDS, resveratrol metabolite efflux significantly declined. The formulation (SMEDDS without incorporated resveratrol) and its individual components did not compromise in vitro cell vitality and integrity. Mixed lipid-mixed surfactant SMEDDS is a prospective formulation to improve resveratrol biopharmaceutical, pharmacokinetic, and toxicological properties, leading the way to resveratrol use not only as a supplement but also as a pharmacological drug.
authors.affiliation: Faculty of Pharmacy, Chair of Pharmaceutical Technology, University of Ljubljana, Slovenia.
authors.forename: Katarina Bolko
authors.initials: KB
authors.lastname: Seljak
authors.affiliation: Lek Pharmaceuticals d.d, Ljubljana, Slovenia.
authors.forename: Katja
authors.initials: K
authors.lastname: Berginc
authors.affiliation: Faculty of Pharmacy, Chair of Biopharmaceutics and Pharmacokinetics, University of Ljubljana, Slovenia.
authors.forename: Jurij
authors.initials: J
authors.lastname: Trontelj
authors.affiliation: Faculty of Pharmacy, Chair of Pharmaceutical Technology, University of Ljubljana, Slovenia.
authors.forename: Alenka
authors.initials: A
authors.lastname: Zvonar
authors.affiliation: Faculty of Pharmacy, Chair of Biopharmaceutics and Pharmacokinetics, University of Ljubljana, Slovenia.
authors.forename: Albin
authors.initials: A
authors.lastname: Kristl
authors.affiliation: Faculty of Pharmacy, Chair of Pharmaceutical Technology, University of Ljubljana, Slovenia. Electronic address: mirjana.gasperlin@ffa.uni-lj.si.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Gašperlin
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D002210:Caprylates / Q000737:chemistry*; D002368:Castor Oil / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers; D004655:Emulsions; D005989:Glycerides / Q000737:chemistry*; D006801:Humans; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D012995:Solubility; D013267:Stilbenes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013501:Surface-Active Agents / Q000737:chemistry*; D013678:Technology, Pharmaceutical / Q000379:methods; D014783:Viscosity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002210:Caprylates; D002368:Castor Oil; D004337:Drug Carriers; D004655:Emulsions; D005989:Glycerides; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000077185:Resveratrol; D013267:Stilbenes; D013501:Surface-Active Agents; C025343:monooctanoin
keywords: Caco-2 cells; dissolution; drug delivery systems; gastrointestinal; lipids; phase diagram; self-emulsifying; solubility; surfactants