title: A solid-state approach to enable early development compounds: selection and animal bioavailability studies of an itraconazole amorphous solid dispersion.
abstract: A solid-state approach to enable compounds in preclinical development is used by identifying an amorphous solid dispersion in a simple formulation to increase bioavailability. Itraconazole (ITZ) was chosen as a model crystalline compound displaying poor aqueous solubility and low bioavailability. Solid dispersions were prepared with different polymers (PVP K-12, K29/32, K90; PVP VA S-630; HPMC-P 55; and HPMC-AS HG) at varied concentrations (1:5, 1:2, 2:1, 5:1 by weight) using two preparation methods (evaporation and freeze drying). Physical characterization and stability data were collected to examine recommended storage, handling, and manufacturing conditions. Based on generated data, a 1:2 (w/w) ITZ/HPMC-P dispersion was selected for further characterization, testing, and scale-up. Thermal data and computational analysis suggest that it is a possible solid nanosuspension. The dispersion was successfully scaled using spray drying, with the materials exhibiting similar physical properties as the screening samples. A simple formulation of 1:2 (w/w) ITZ/HPMC-P dispersion in a capsule was compared to crystalline ITZ in a capsule in a dog bioavailability study, with the dispersion being significantly more bioavailable. This study demonstrated the utility of using an amorphous solid form with desirable physical properties to significantly improve bioavailability and provides a viable strategy for evaluating early drug candidates.
authors.affiliation: SSCI, division of Aptuit, Inc., West Lafayette, Indiana, USA. david.engers@aptuit.com
authors.forename: David
authors.initials: D
authors.lastname: Engers
authors.forename: Jing
authors.initials: J
authors.lastname: Teng
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jimenez-Novoa
authors.forename: Philip
authors.initials: P
authors.lastname: Gent
authors.forename: Stuart
authors.initials: S
authors.lastname: Hossack
authors.forename: Cheryl
authors.initials: C
authors.lastname: Campbell
authors.forename: John
authors.initials: J
authors.lastname: Thomson
authors.forename: Igor
authors.initials: I
authors.lastname: Ivanisevic
authors.forename: Alison
authors.initials: A
authors.lastname: Templeton
authors.forename: Stephen
authors.initials: S
authors.lastname: Byrn
authors.forename: Ann
authors.initials: A
authors.lastname: Newman
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D003460:Crystallization; D004285:Dogs; D004355:Drug Stability; D017964:Itraconazole / Q000737:chemistry* / Q000493:pharmacokinetics*; D033362:Powder Diffraction; D012995:Solubility; D014961:X-Ray Diffraction
chemical_list: D000890:Anti-Infective Agents; D017964:Itraconazole