Development and Optimization of Atorvastatin Calcium-Cyclodextrin Inclusion Complexed Orally-Disintegrating Tablets with Enhanced Pharmacokinetic and Pharmaco-dynamic Profile

Abstract

The content of the investigation was to study the influence of hydroxy propyl-b-cyclodextrin (HPβCD) complexed oral disintegrating tablets (ODTs) on enhancement of solubility, dissolution rate, pharmacodynamic activity and bioavailability of atorvastatin calcium (AT) by central composite design. Based on preliminary phase solubility studies, solubility was linearly increased and followed AL-type profile. Solid complexes were prepared by physical mixing, kneading, freeze and spray drying methods. Spray-dried product showed higher solubility and dissolution rate than other complexes. Amount of drug (X1), amount of HPβCD (X2) and amount of supradisintegrant (X3) as independent and solubility (Y1), disintegration time (Y2) and percent drug release in 15 min (Q15, Y3) as dependent responses. Drug- HPβCD complex formation was confirmed by FTIR, DSC and XRD. AT-HPβCD ODTs were developed and evaluated for physico-chemical properties, stability and dissolution rate. Further, in vivo pharmacokinetic and pharmacodynamic studies were performed in rat model. The statistically optimized formulation showed 0.817 ± 0.06 mg/ml of solubility, 54 ± 2 sec of DT and 69 ± 2.4 % of Q15. The physical stability was studied for 6 months. No significant changes were detected in dissolution profile and drug content of tablets after 6 months during the stability studies. The in vivo studies of spray dried complexed tablets compared to AT in rats revealed that 3.3-folds improvement in oral bioavailability and there was significant reduction (p<0.01) in cholesterol and triglyceride levels and significant improvement (p<0.01) in HDL level. The results conclusively demonstrated that the AT-HPbCD-ODT could be prepared with improved solubility and hypolipidemic activity by using central composite design.