title: Development and evaluation of optimized sucrose ester stabilized oleanolic acid nanosuspensions prepared by wet ball milling with design of experiments.
abstract: The aim of this study was to develop optimized sucrose ester (SE) stabilized oleanolic acid (OA) nanosuspensions (NS) for enhanced delivery via wet ball milling by design of experiments (DOE). In this study, SEOA NS batches were prepared by wet ball milling method. Mean particle sizes and polydispersity indices were determined using a nanosizer. The percent encapsulation efficiency, saturation solubility and in vitro dissolution rate were obtained with analyses using HPLC. Preparation methods were optimized by DOE using the Minitab software. The in vitro bioefficacy was obtained by methyl thiazolyl tetrazolium (MTT) measurements in A549 human non small cell lung cancer cell line. The in vivo pharmacokinetics profile was determined using LC-electrospray ionization (ESI)-MS/MS. The study produced spherical SEOA NS particles (ca. 100 nm in diameter) which were found to be able to increase OA saturation solubility considerably. Optimized SEOA-GBD NS (milled at 600 rpm for 3 h, sucrose monolaurate (SEL) : sucrose monopalmitate (SEP) at 9 : 1, w/w; SE : OA at 1 : 1, w/w) was found to be physically stable over 14 d at 4°C. The NS showed much higher dissolution rate, cytotoxicity and bioavailability when compared with the free drug. Thus, the prepared OA as SE stabilized NS particles by wet ball milling enhanced the saturation solubility, in vitro dissolution rate, bioefficacy and in vivo bioavailability of OA. The use of sugar esters may also be potentially applied to other hydrophobic drugs.
authors.affiliation: Department of Pharmacy, National University of Singapore.
authors.forename: Wenji
authors.initials: W
authors.lastname: Li
authors.forename: Ka-yun
authors.initials: KY
authors.lastname: Ng
authors.forename: Paul Wan Sia
authors.initials: PW
authors.lastname: Heng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D004355:Drug Stability; D004952:Esters; D005612:Freeze Drying; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission; D049329:Nanostructures / Q000737:chemistry*; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D010316:Particle Size; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013395:Sucrose / Q000031:analogs & derivatives* / Q000737:chemistry; D013499:Surface Properties
chemical_list: D004337:Drug Carriers; D004952:Esters; C018152:sucrose monolaurate; C041567:sucrose monopalmitate; D013395:Sucrose; D009828:Oleanolic Acid