title: Nano-amorphous spray dried powder to improve oral bioavailability of itraconazole.
abstract: The objective of this study was to formulate nano-amorphous spray-dried powders of itraconazole to enhance its oral bioavailability. A combination approach of solvent-antisolvent precipitation followed by spray drying was used. DoE studies were utilized to understand the critical processing parameters: antisolvent-to-solvent ratio, drug concentration and stabilizer concentration. Particle size was the critical quality attribute. Spray drying of the nano-precipitated formulation was performed with several auxiliary excipients to obtain nano-sized amorphous powder formulations. PLM, DSC and PXRD were utilized to characterize the spray-dried powders. In vitro dissolution and in vivo bioavailability studies of the nano-amorphous powders were performed. The particle size of the nano-formulations was dependent on the drug concentration. The smallest size precipitates were obtained with low drug concentration. All high molecular weight auxiliary excipients and mannitol containing formulations were unstable and crystallized during spray drying. Formulations containing disaccharides were amorphous and non-aggregating. In vitro dissolution testing and in vivo studies showed the superior performance of nano-amorphous formulations compared to melt-quench amorphous and crystalline itraconazole formulations. This study shows superior oral bioavailability of nano-amorphous powders compared to macro-amorphous powders. The nano-amorphous formulation showed similar bioavailability to the nano-crystalline formulation but with a faster absorption profile.
authors.affiliation: University of Connecticut, School of Pharmacy, Storrs, CT 06269 USA.
authors.forename: Sumit
authors.initials: S
authors.lastname: Kumar
authors.affiliation: University of Connecticut, School of Pharmacy, Storrs, CT 06269 USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.affiliation: University of Connecticut, School of Pharmacy, Storrs, CT 06269 USA. Electronic address: d.burgess@uconn.edu.
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Burgess
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D011232:Chemical Precipitation; D003890:Desiccation; D004339:Drug Compounding / Q000295:instrumentation; D004867:Equipment Design; D017964:Itraconazole / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D010316:Particle Size; D011208:Powders; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D058888:14-alpha Demethylase Inhibitors; D011208:Powders; D017964:Itraconazole
keywords: Amorphous itraconazole; Antisolvent precipitation; DoE; Melt-quench; Nano-amorphous; Spray-drying