title: Enhanced oral delivery of celecoxib via the development of a supersaturable amorphous formulation utilising mesoporous silica and co-loaded HPMCAS.
abstract: Stabilization of amorphous formulations via mesoporous silica has gained considerable attention for oral delivery of poorly soluble drugs. The release of the drug from the silica is expected to generate supersaturation which is often associated with subsequent precipitation. The aim of the study was hence to develop a novel supersaturable amorphous formulation through the co-loading of a BCS class II drug Celecoxib (CXB) with a precipitation inhibitor hydroxypropyl methylcellulose acetate succinate (HPMCAS) onto the silica. The addition of HPMCAS did not hamper the adsorption but on the contrary promoted the complete solid state conversion of the drug as proved by DSC analysis. In an in vitro pH shift assay, the CXB-HPMCAS co-loaded silica achieved a 5-fold solubility increase over the crystalline CXB and over the CXB-loaded silica blended with HPMCAS which did not show any enhancement. The drug co-loaded silica was then suspended in an aqueous vehicle facilitating the dosing to animals. The CXB-HPMCAS co-loaded silica suspension achieved 15-fold solubility increase in vitro over the crystalline counterpart which translated in 1.35-fold Cmax increase in vivo after oral dosing in rats. This approach represents a novel formulation strategy to maximize in vivo exposure of poorly soluble drugs critical for discovery studies.
authors.affiliation: Pfizer-Neuroscience and Pain Research Unit, Granta Park, Cambridge CB21 6GS, United Kingdom. Electronic address: lainean@medimunne.com.
authors.forename: A-L
authors.initials: AL
authors.lastname: Lainé
authors.affiliation: Pfizer-Neuroscience and Pain Research Unit, Granta Park, Cambridge CB21 6GS, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Price
authors.affiliation: Pfizer-Neuroscience and Pain Research Unit, Granta Park, Cambridge CB21 6GS, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Davis
authors.affiliation: Pfizer-Neuroscience and Pain Research Unit, Granta Park, Cambridge CB21 6GS, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Roberts
authors.affiliation: Pfizer-Neuroscience and Pain Research Unit, Granta Park, Cambridge CB21 6GS, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Hudson
authors.affiliation: Pfizer, Discovery Park, Ramsgate Rd, Sandwich CT13 9ND, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Back
authors.affiliation: Pfizer-Neuroscience and Pain Research Unit, Granta Park, Cambridge CB21 6GS, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Bungay
authors.affiliation: Pfizer-Neuroscience and Pain Research Unit, Granta Park, Cambridge CB21 6GS, United Kingdom.
authors.forename: N
authors.initials: N
authors.lastname: Flanagan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D000068579:Celecoxib / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D004339:Drug Compounding / Q000379:methods*; D065546:Drug Liberation; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D051381:Rats; D012822:Silicon Dioxide / Q000737:chemistry*; D012995:Solubility
chemical_list: C048331:hydroxypropylmethylcellulose acetate succinate; D012822:Silicon Dioxide; D008747:Methylcellulose; D000068579:Celecoxib
keywords: Amorphous formulation; In vitro pH shift assay; Mesoporous material; Pharmacokinetic study