3.2.2. Cumulative AUC Results of cumulative area under the curve (AUC) for the active moiety were calculated by the trapezoidal method (1), are shown in Table 2: AUC(t1−t2)=[(C1+C2)2]×(t2− t1). (1) Table
2 AUC for Risperidone PLGA microspheres. In (1) “t” represents time in hours while “C” denotes serum concentration of Risperidone (ng/mL). Results from AUC calculations indicate that the cumulative AUC values through 15 days for Formulations A and B were remarkably similar (1110 and 1159ng×mL/day, respectively). Both formulations, administered at 20mg/kg dose, were prepared using the fast degrading 50:50 PLGA copolymer had a small particle size and high loading but a difference Inhibitors,research,lifescience,medical of ~ 10kDa in molecular weight. In vivo, they exhibited similar burst levels Inhibitors,research,lifescience,medical followed by a brief trough with noticeable levels through 15 days. Though the formulations exhibited a high initial burst, more than 98% of the cumulative AUC was contributed by drug encapsulated in the polymer matrix with initial burst amounting to a mere 1.4–1.8% of the total profile. Cumulative AUC levels for Formulations C and D, dosed at 40mg/kg, are presented in Table 2. Values of 1821 and 1522ng×mL/day were obtained for Formulations C and D, respectively. As expected,
values are higher than those observed with Formulations A and B. With Formulation C, initial burst Inhibitors,research,lifescience,medical contributed nearly 2% to the cumulative AUC whereas, with Formulation D, the value was smaller (1%). Once again, these data suggest that most of the in vivo activity was due to drug incorporated in the polymer matrix Inhibitors,research,lifescience,medical that was available for release in a sustained fashion. In contrast, the marketed formulation does not exhibit initial burst and supplementation with oral
therapy is needed to achieve pharmacologically effective levels of the drug , suggesting that drug encapsulated in Inhibitors,research,lifescience,medical the polymer matrix was solely responsible for in vivo activity. The following observations were noted upon analyzing the cumulative AUC values of Formulations A–D. The contribution of initial burst towards the total AUC for all formulations was minor (equal to or less than 2%). Risperidone encapsulated in the PLGA polymer was responsible for over 98% of the cumulative AUC in vivo. The cumulative AUC obtained with Formulations C and D was nearly 1.5–1.7 times greater than that observed with Formulations A and B. These Anacetrapib results suggest that proper choice of a copolymer and molecular weight will enable customization of drug release profiles from microsphere dosage forms of Risperidone. 3.2.3. Selection of Dosing Regimen The objective of the current study was to develop and evaluate PLGA microspheres of Risperidone that offered initial and maintenance levels of the drug for extended intervals. To predict the in vivo profile of Risperidone PLGA microspheres for a prolonged duration, plasma levels through 4 doses for all four formulations were simulated using the superposition principle.