title: Processing factors in development of solid solution formulation of itraconazole for enhancement of drug dissolution and bioavailability.
abstract: This study investigated solid solutions of itraconazole, a water insoluble antifungal, for improved dissolution and improved bioavailability. Influence of processing factors on drug and carrier properties in solid solution and subsequently on drug dissolution behavior was also studied. An optimized solid solution formulation was compared with marketed product in healthy human subjects under fasted and fed conditions for bioequivalency. Polyethylene glycol (PEG) and drug were made into a solid solution at 120 degrees C. The cooled, solid solution was then ground into granules of different sizes. Solid solutions of lower drug concentration dissolved at a faster rate, and drug dissolution improved considerably with increasing molecular weight of PEG. Initial treatment of itraconazole with the wetting agent/cosolvent glycerol prior to making itraconazole into a solid solution improved drug dissolution, and also reduced the PEG amount required to dissolve drug to form solid solution. Addition of a polymer such as HPMC to the solid solution eliminated precipitation of drug following dissolution. As the granule size of the solid solution was reduced, precipitation of drug during dissolution became prominent. Equivalence of two formulations could not be shown for pharmacokinetic parameters C(max) and AUC, under both fasting and fed conditions.
authors.affiliation: GlaxoSmithKline Pharmaceuticals, 709, Swedeland Road, King of Prussia, PA 19406, USA. shiva_g_kapsi@gsk.com
authors.forename: S G
authors.initials: SG
authors.lastname: Kapsi
authors.forename: J W
authors.initials: JW
authors.lastname: Ayres
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning; D018592:Cross-Over Studies; D004339:Drug Compounding; D005079:Excipients; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D007785:Lactose / Q000031:analogs & derivatives*; D008747:Methylcellulose / Q000031:analogs & derivatives*; D010078:Oxazines; D010316:Particle Size; D019999:Pharmaceutical Solutions; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols; D012995:Solubility
chemical_list: D000935:Antifungal Agents; D005079:Excipients; D010078:Oxazines; D019999:Pharmaceutical Solutions; D014677:Pharmaceutical Vehicles; D017964:Itraconazole; D011092:Polyethylene Glycols; D008747:Methylcellulose; C071191:MK 458; D007785:Lactose; D005990:Glycerol