title: Pluronic-Functionalized Silica-Lipid Hybrid Microparticles: Improving the Oral Delivery of Poorly Water-Soluble Weak Bases.
abstract: A Pluronic-functionalized silica-lipid hybrid (Plu-SLH) microparticle system for the oral delivery of poorly water-soluble, weak base drugs is reported for the first time. A highly effective Plu-SLH microparticle system was composed of Labrasol as the lipid phase, Pluronic F127 as the polymeric precipitation inhibitor (PPI), and silica nanoparticles as the solid carrier. For the model drug cinnarizine (CIN), the Plu-SLH delivery system was shown to offer significant biopharmaceutical advantages in comparison with unformulated drug and drug in the silica-lipid hybrid (SLH) system. In vitro two-phase dissolution studies illustrated significantly reduced pH provoked CIN precipitation and an 8- to 14-fold improvement in the extent of dissolution in intestinal conditions. In addition, under simulated intestinal digesting conditions, the Plu-SLH provided approximately three times more drug solubilization than the SLH. Oral administration in rats resulted in superior bioavailability for Plu-SLH microparticles, i.e., 1.6- and 2.1-fold greater than the SLH and the unformulated CIN, respectively. A physical mixture of Pluronic and SLH (Plu&SLH), having the same composition as Plu-SLH, was also evaluated, but showed no significant increase in CIN absorption when compared to unmodified CIN or SLH. This work represents the first study where different methods of incorporating PPI to formulate solid-state lipid-based formulations were compared for the impact on the biopharmaceutical performance. The data suggest that the novel physicochemical properties and structure of the fabricated Plu-SLH microparticle delivery system play an important role in facilitating the synergistic advantage of Labrasol and Pluronic F127 in preventing drug precipitation, and the Plu-SLH provides efficient oral delivery of poorly water-soluble weak bases.
authors.affiliation: School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia , City East Campus, Adelaide, South Australia 5000, Australia.
authors.forename: Shasha
authors.initials: S
authors.lastname: Rao
authors.affiliation: Ian Wark Research Institute, University of South Australia , Mawson Lakes Campus, Mawson Lakes, South Australia 5095, Australia.
authors.forename: Katharina
authors.initials: K
authors.lastname: Richter
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University , Parkville Campus, Parkville, Victoria 3052, Australia.
authors.forename: Tri-Hung
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University , Parkville Campus, Parkville, Victoria 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville Campus, Parkville, Victoria 3052, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Boyd
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University , Parkville Campus, Parkville, Victoria 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville Campus, Parkville, Victoria 3052, Australia.
authors.forename: Christopher J H
authors.initials: CJ
authors.lastname: Porter
authors.affiliation: Ian Wark Research Institute, University of South Australia , Mawson Lakes Campus, Mawson Lakes, South Australia 5095, Australia.
authors.forename: Angel
authors.initials: A
authors.lastname: Tan
authors.affiliation: School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia , City East Campus, Adelaide, South Australia 5000, Australia.
authors.forename: Clive A
authors.initials: CA
authors.lastname: Prestidge
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D008055:Lipids / Q000737:chemistry*; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D020442:Poloxamer / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012822:Silicon Dioxide / Q000737:chemistry*; D012995:Solubility; D014867:Water / Q000737:chemistry*
chemical_list: D004337:Drug Carriers; D008055:Lipids; D014867:Water; D020442:Poloxamer; D012822:Silicon Dioxide
keywords: Pluronic; drug precipitation; oral bioavailability improvement; poorly water-soluble drug; silica−lipid hybrid; weak bases