Bilayered transmucosal drug delivery system of pravastatin sodium: Statistical optimization, in vitro, ex vivo, in vivo and stability assessment

Abstract

The objective of the present study was to develop a mucoadhesive sustained release bilayered buccal patch of pravastatin sodium using Eudragit S100 as the base matrix so as to surmount hepatic first pass metabolism and gastric instability of the drug. A 32 full factorial design was employed to study the effect of independent variables viz. levels of HPMC K4M and carbopol 934P on % cumulative drug release, mucoadhesion time and mucoadhesive force. Amount of carbopol 934P and HPMC K4M significantly influenced characteristics like swelling index, in vitro mucoadhesive force, drug release, and mucoadhesion time. In vitro evaluation revealed that formulations exhibited satisfactory technological parameters. The mechanism of drug release was found to be non-Fickian diffusion. Different permeation enhancers were investigated to improve the permeation of drug from the optimized patches (F9) across the buccal mucosa. Formulation [F9 (P3)] containing 4% (v/v) dimethyl sulfoxide exhibited desirable permeation of drug. Histopathological studies performed using goat buccal mucosa revealed no mucosal damage. Bioavailability studies in rabbits demonstrated that [F9 (P3)] significantly higher Cmax (67.34 ± 3.58 ng/ml) and AUC0-∞ (350.27 ± 9.59 ng/ml×h) (p < 0.05) of pravastatin sodium from optimized patch than IR tablet (Cmax 58.73 ± 4.63 ng/ml and AUC0-∞ 133.80 ± 8.25 ng/ml×h). Formulation [F9 (P3)] showed sustained drug plasma concentration over a period of 10 h which was significantly longer than oral tablet (p < 0.05). Stability studies as per ICH guidelines established physical stability of the patch and chemical stability drug. The present study established potential of the optimized mucoadhesive buccal patches to circumvent the hepatic first-pass metabolism, gastric instability and to improve bioavailability of pravastatin sodium.