Enhancing the bioavailability of ABT-963 using solid dispersion containing Pluronic F-68.
Solid dispersions using Pluronic F-68 as a carrier were studied for improving the dissolution and bioavailability of ABT-963, a poorly water-soluble compound. The solid dispersions were prepared either by evaporation of the ethanol solutions containing ABT-963 and Pluronic, or by cooling the hot melt of the drug in the carrier. The dispersions were characterized using differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, elemental mapping, and by constructing the melting point phase diagram. In vitro dissolution and in vivo oral bioavailability in fasted dogs were compared for the solid dispersion and a conventional IR capsule formulation. Results showed that, at a composition of approximately 7.5%, ABT-963 formed a eutectic mixture with Pluronic F-68. Both the drug and the polymer were crystalline in the solid dispersion with a wide range of composition of each component. The solid dispersion substantially increased the in vitro dissolution rate of ABT-963. Dosing of the dispersion to fasted dogs resulted in a significant increase of oral bioavailability compared with the conventional IR capsule formulation. These results show that solid dispersion is a promising approach for developing ABT-963 drug products.
Chen
Y
Y
Abbott Laboratories, Global Pharmaceutical R&D, 1401 Sheridan Road, North Chicago, IL 60064, USA. yisheng.1.chen@abbott.com
Zhang
G G Z
GG
Neilly
J
J
Marsh
K
K
Mawhinney
D
D
Sanzgiri
Y D
YD
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D001682:Biological Availability; D002152:Calorimetry, Differential Scanning / Q000379:methods; D002214:Capsules; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005502:Food; D008422:Materials Testing / Q000379:methods; D020442:Poloxamer / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility / Q000187:drug effects; D013450:Sulfones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014961:X-Ray Diffraction / Q000379:methods
C495029:2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-(4-methanesulfonylphenyl)-2H-pyridazin-3-one; D002214:Capsules; D016861:Cyclooxygenase Inhibitors; D004337:Drug Carriers; D011724:Pyridazines; D013450:Sulfones; D020442:Poloxamer