title: Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral absorption of the poorly soluble weak base itraconazole.
abstract: The release of poorly soluble drugs from mesoporous silicates is often associated with the generation of supersaturation, which implies the risk of drug precipitation and reduced availability for absorption. The aim of this study was to enhance the in vivo performance of an ordered mesoporous silicate (SBA-15) by combining it with the precipitation inhibitors hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS). The poorly soluble weak base itraconazole was used as a model compound. Formulations were prepared by physically blending itraconazole-loaded SBA-15 with the precipitation inhibitors. In vitro release experiments implementing a transfer from simulated gastric fluid to simulated intestinal fluid were used to evaluate the pharmaceutical performance. Subsequently, the formulations were evaluated in vivo in rats. When high enough amounts of HPMC were co-administered with itraconazole-loaded SBA-15 (itraconazole:SBA-15:HPMC 1:4:6), the extent of absorption was increased by more than 60% when compared to SBA-15 without precipitation inhibitors (AUC 14,937+/-1617 versus 8987+/-2726nMh). HPMCAS was found ineffective in enhancing the in vivo performance of SBA-15 due to its insolubility in the stomach. The results of this study demonstrate that the pharmaceutical performance of SBA-15 is enhanced through addition of an appropriate precipitation inhibitor.
authors.affiliation: Laboratory for Pharmacotechnology and Biopharmacy, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Michiel
authors.initials: M
authors.lastname: Van Speybroeck
authors.forename: Raf
authors.initials: R
authors.lastname: Mols
authors.forename: Randy
authors.initials: R
authors.lastname: Mellaerts
authors.forename: Thao Do
authors.initials: TD
authors.lastname: Thi
authors.forename: Johan A
authors.initials: JA
authors.lastname: Martens
authors.forename: Jan
authors.initials: J
authors.lastname: Van Humbeeck
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.forename: Guy
authors.initials: G
authors.lastname: Van den Mooter
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000284:Administration, Oral; D000327:Adsorption; D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics*; D002152:Calorimetry, Differential Scanning; D002853:Chromatography, Liquid; D017964:Itraconazole / Q000493:pharmacokinetics*; D008297:Male; D013058:Mass Spectrometry; D051381:Rats; D017208:Rats, Wistar; D012822:Silicon Dioxide; D012995:Solubility
chemical_list: D000935:Antifungal Agents; D017964:Itraconazole; D012822:Silicon Dioxide