Assessing Supersaturation and Its Impact on In Vivo Bioavailability of a Low-Solubility Compound ABT-072 With a Dual pH, Two-Phase Dissolution Method.

ABT-072 is a candidate drug evaluated for treatment of hepatitis C virus. It is an acidic compound with extremely low intrinsic aqueous solubility. An in vitro dissolution-partition system, referred as biphasic test method, was used to characterize ABT-072 prototype formulations. This test used 2 aqueous dissolution media of pH 2 and 6.5 in a sequential manner to simulate the transition of drug in gastrointestinal tract. The biphasic test used in this work effectively differentiated various ABT-072 formulations derived from conventional and enabling technologies. In vitro profiles of these formulations indicate a complex interplay among the 3 competitive kinetic processes including dissolution, precipitation, and partition in the aqueous media. The relative amount of drug partitioned into the organic phase (i.e., octanol) from different formulations was found to be directly related to their in vivo exposures observed in both dogs and human subjects, respectively. An in vitro-in vivo relationship was obtained between ABT-072 concentrations in octanol at t = 2 h from these formulations and the relative bioavailabilities in dogs and human subjects. This work revealed the significance of polymeric precipitation inhibition by sustaining a supersaturated state of ABT-072 and its impact on in vivo exposure in human subjects.

Formulation and characterization of bupivacaine lipospheres.

Bupivacaine lipospheres were prepared as a parenteral sustained-release system for post-operative pain management. Bupivacaine free base was incorporated into micron-sized triglyceride solid particles coated with phospholipids, which were formed via a hot emulsification and cold resolidification process. The bupivacaine liposphere dispersions were characterized with respect to drug loading, particle-size distribution, and morphology. Gelation of the fluid liposphere dispersions was observed at different time intervals upon storage. The type of phospholipids used in the formulation was found to have a major impact on the gelation of the dispersion. The use of synthetic phospholipids instead of the natural phospholipids in the formulation yielded bupivacaine liposphere dispersions exhibiting prolonged gelation time. The addition of a hydrophilic cellulosic polymer can further improve the physical stability of the dispersion.