ection in immune cells19 and inhibits direct infection of mucosal tissue.20,21 The half maximal effective concentration of UC781 is 83nM inMT2 cells.22 Unlike TFV, which requires intracellular phosphorylation prior to activity, UC781 can act extracellularly, thus inactivating virions directly. BMS-754807 BMS754807 Tenofovir and UC781 individually and in combination were investigated for their ability to inhibit HIV 1 infection under in vitro conditions.23 Testing of unformulated UC781 using TZM bl indicator cells demonstrated inhibitory activities against several HIV 1 X4 and R5 isolates with half maximal inhibitory concentrations ranging from about 5 to 10 nM. TFV was less potent in the same assays, with IC50 values ranging from about 2500 to 6700 nM.23 The combination of TFV and UC781 was also examined at a ratio of 347:1 TFV to UC781.
This combination led to an approximate 50% reduction in the IC50 of UC781 and a 61% reduction in the IC50 of TFV. On the basis of these data, it Vismodegib Hedgehog inhibitor was hypothesized that a combination of UC781 and TFV would be more potent than either agent alone. The development of a vaginal microbicide can be impacted by the formulation approach chosen. Gels were the initial dosage form created for topical microbicides, and remain a primary mode of delivery. Pharmaceutically, gel products are relatively simple to prepare and typically require a limited number of excipients. The initial goal of thework reported herein was development of gel product containing TFV and UC781.
In a previous detailed report, mixture design of experiments theory was used24 for the first time to establish the relationships between composition, properties, and performance of a vaginal gel by varying concentrations of the commonly used semisolid gelling agents HEC and Carbopol 974P. This work identified a 3.5mL gel composed of 3.0% HEC as optimal GDC-0879 in terms of rheological behavior as determined by predicted spreading of the gel. Herein, this work was extended to define compositions with higher resistance to flow, imparting bolus like properties compared with the 3.0% HEC gel. The idea behind a BG composition is that a higher resistance to flow would allow longer retention in the vaginal canal potentially increasing duration of drug activity. Another potential benefit of this type of gel is the ability to reduce the volume of gel applied. Flow resistant gels can be formulated by increasing the viscosity and yield stress of the gel.
A computational scoring function for gel spreading performance was defined, and used to formulate a gel with intermediate performance between that of the SG and BG. This gel is referred to as the intermediate spreading gel. In addition to rheological behavior, the in vitro drug release properties and in vitro tissue permeability of TFV and UC781 were used as response factors in the MDOE to identify the optimum compositions of the SG, ISG, and BG. In vitro permeability and safety studies and an in vivo pharmacokinetic study in rabbits dosed vaginally were performed to confirm the suitability of the SG, ISG, and BG prior to initiation of clinical evaluations. MATERIALS AND METHODS Materials Hydroxyethylcellulose was purchased from Hercules. Carbopol 974P NF was purchased from Lubrizol. TFV was obtained from Gilead Sciences. UC781 was prepared by cus