title: In Vivo Formation of Cubic Phase in Situ after Oral Administration of Cubic Phase Precursor Formulation Provides Long Duration Gastric Retention and Absorption for Poorly Water-Soluble Drugs.
abstract: Lipid-based liquid crystalline systems based on the combination of digestible and nondigestible lipids have been proposed as potential sustained release delivery systems for oral delivery of poorly water-soluble drugs. The potential for cubic phase liquid crystal formation to induce dramatically extended gastric retention in vivo has been shown previously to strongly influence the resulting pharmacokinetics of incorporated drug. In vitro studies showing the in situ formation of cubic phase from a disordered precursor comprising a mixture of digestible and nondigestible lipids under enzymatic digestion have also recently been reported. Combining both concepts, here we show the potential for such systems to form in vivo, increasing gastric retention, and providing a sustained release effect for a model poorly water-soluble drug cinnarizine. A mixture of phytantriol and tributyrin at an 85:15 mass ratio, shown previously to form cubic phase under the influence of digestion, induced a similar pharmacokinetic profile to that in the absence of tributyrin, but completely different from tributyrin alone. The gastric retention of the formulation, assessed using micro-X-ray CT imaging, was also consistent with the pharmacokinetic behavior, where phytantriol alone and with 15% tributyrin was greater than that of tributyrin in the absence of phytantriol. Thus, the concept of precursor lipid systems that form cubic phase in situ during digestion in vivo has been demonstrated and opens new opportunities for sustained release of poorly water-soluble drugs.
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pham
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Hong
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Montagnat
authors.affiliation: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Tri-Hung
authors.initials: TH
authors.lastname: Nguyen
authors.affiliation: Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.|ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Boyd
mesh_terms: D000284:Administration, Oral; D002936:Cinnarizine / Q000737:chemistry; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D005233:Fatty Alcohols / Q000737:chemistry; D050866:Liquid Crystals / Q000737:chemistry; D012995:Solubility; D014280:Triglycerides / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005233:Fatty Alcohols; D014280:Triglycerides; D014867:Water; D002936:Cinnarizine; C508873:3,7,11,15-tetramethyl-1,2,3-hexadecanetriol; C005830:tributyrin
keywords: cubic phase; gastric retention; micro-X-ray CT imaging; oral drug delivery; pharmacokinetics