Ann Newman - A Solid-state Approach to Enable Early Development Compunds: Selection and Animal Bioavailability Studies of an Itraconazole Amorphous Solid Dispersion

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        D. Engers, J. Teng, J. Jimenez-Novoa, P. Gent, S. Hossack, C.   Campbell, J. Thomson, I. Ivanisevic, A. Templeton, S. Byrn, A.   Newman. J Pharm. Sci. 2010,   99(9), 3901-3922


      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

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