Effect of a lipoidic excipient on the absorption profile of compound UK 81252 in dogs after oral administration.

PURPOSE: Effect of caprylocaproyl macrogolglycerides (Labrasol), as a lipoidic excipient/vehicle in an oral capsule formulation, on pharmacokinetic disposition of a BCS Class 3 compound, UK-81252, was investigated in vivo in a canine model. METHODS: The control and lipoidic formulations were administrated to six Beagle dogs in a crossover, single dose design with a 2-week washout period in between treatments. The plasma concentration-time profile for the lipoidic formulation was compared to that of the control formulation (lactose-based oral capsule). RESULTS: Although the lipoidic formulation resulted in a markedly increased oral bioavailability (based on mean pharmacokinetic parameters, AUC(0-48 hr) and C(max) ), a double-peaking phenomenon was observed with this formulation. The most likely cause of this double-peak effect was the gastric emptying retardation attribute of the lipoidic vehicle/excipient. The initial peak (Tmax1) was due to the absorption enhancing properties of the lipoidic formulation and the second peak (Tmax2) was most likely the result of a shutdown in gastric emptying for a period of up to 2 hours (this value varied between dogs) after which the remaining Compound UK 81252 emptied from the stomach to generate the second peak. CONCLUSIONS: Caprylocaproyl macrogolglycerides enhanced the absorption of Compound UK 81252. After oral administration, the liquid-filled formulation consistently produced a double-peak phenomenon in the plasma profile. Labrasol was determined to be the most likely culprit for this double peaking phenomenon.

Effect of hydroxypropyl beta-cyclodextrin on drug solubility in water-propylene glycol mixtures.

Combined effects of cosolvency and inclusion complexation on drug solubility were studied using a model hydrophobic compound (carbamazepine) and a model hydrophilic compound (Compound S). Propylene glycol (PG) was used as the nonaqueous solvent, and deionized water was employed for the aqueous systems. Hydroxypropyl beta-cyclodextrin (HPbetaCD) was chosen as the complexing agent and studied at concentrations up to 28% (w/v). Complex formation constants (Kc) and solubility enhancement ratios were determined for the respective compounds in various water/PG vehicles. The data suggested that the inclusion of the compounds was most favorable when water alone was used as the vehicle. However, the combined approach of cosolvency and complexation resulted in a significant increase in the total apparent solubility of carbamazepine (the hydrophobic compound). The same was not observed with Compound S (the hydrophilic model), since PG weakened the interactions between the molecule and HPbetaCD, and thus, no synergistic or additive effects were observed with the combined approach of complexation and cosolvency.