title: Experimental design in formulation of diazepam nanoemulsions: physicochemical and pharmacokinetic performances.
abstract: With the aid of experimental design, we developed and characterized nanoemulsions for parenteral drug delivery. Formulations containing a mixture of medium-chain triglycerides and soybean oil as oil phase, lecithin (soybean/egg) and polysorbate 80 as emulsifiers, and 0.1 M phosphate buffer solution (pH 8) as aqueous phase were prepared by cold high-pressure homogenization. To study the effects of the oil content, lecithin type, and the presence of diazepam as a model drug and their interactions on physicochemical characteristics of nanoemulsions, a three factor two-level full factorial design was applied. The nanoemulsions were evaluated concerning droplet size and size distribution, surface charge, viscosity, morphology, drug-excipient interactions, and physical stability. The characterization revealed the small spherical droplets in the range 195 -220 nm with polydispersity index below 0.15 and zeta potential between -30 and - 60 mV. Interactions among the investigated factors, rather than factors alone, were shown to more profoundly affect nanoemulsion characteristics. In vivo pharmacokinetic study of selected diazepam nanoemulsions with different oil content (20%, 30%, and 40%, w/w) demonstrated fast and intense initial distribution into rat brain of diazepam from nanoemulsions with 20% and 30% (w/w) oil content, suggesting their applicability in urgent situations.
authors.affiliation: Department of Pharmaceutical Technology and Cosmetology, Faculty of Pharmacy, University of Belgrade, Belgrade, 11221, Serbia.
authors.forename: Sanela M
authors.initials: SM
authors.lastname: Đorđević
authors.forename: Tamara S
authors.initials: TS
authors.lastname: Radulović
authors.forename: Nebojša D
authors.initials: ND
authors.lastname: Cekić
authors.forename: Danijela V
authors.initials: DV
authors.lastname: Ranđelović
authors.forename: Miroslav M
authors.initials: MM
authors.lastname: Savić
authors.forename: Danina R
authors.initials: DR
authors.lastname: Krajišnik
authors.forename: Jela R
authors.initials: JR
authors.lastname: Milić
authors.forename: Snežana D
authors.initials: SD
authors.lastname: Savić
mesh_terms: D000759:Adjuvants, Anesthesia / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003975:Diazepam / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D045703:Emulsifying Agents / Q000737:chemistry; D004655:Emulsions / Q000737:chemistry*; D054709:Lecithins / Q000737:chemistry; D008297:Male; D014677:Pharmaceutical Vehicles / Q000737:chemistry*; D011136:Polysorbates / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013024:Soybean Oil / Q000737:chemistry; D014280:Triglycerides / Q000737:chemistry
chemical_list: D000759:Adjuvants, Anesthesia; D045703:Emulsifying Agents; D004655:Emulsions; D054709:Lecithins; D014677:Pharmaceutical Vehicles; D011136:Polysorbates; D014280:Triglycerides; D013024:Soybean Oil; D003975:Diazepam
keywords: FTIR; atomic force microscopy; diazepam; drug-excipient interaction; full factorial design; nanoemulsion; particle size; pharmacokinetics; stability