Box Behnken Design

Atorvastatin calcium is a HMG-CoA reductase inhibitor used in the treatment of hyperlipidaemia. It has oral bioavailability of less than 12%. It also undergoes high first pass metabolism. The objective of the present work was to formulate, optimize and in vivo evaluation of the potential novel proniosomal gel containing atorvastatin for transdermal delivery. On the basis of the preliminary trials a 3-factor, 3-level Box–Behnken design was employed to study the effect of Cholesterol, soya lecithin and Span 60 independent variable on dependent variables (particle size and % entrapment efficiency). Atorvastatin optimized proniosomal formulation F2 shown better particle size and % entrapment efficiency and also the drug release was 99.72% within 24h in slow and controlled manner when compared with control. The particle size and Zeta potential of the optimized atorvastatin proniosomal gel was found to be 65.72 and -10.5 respectively. Optimized batch of Proniosomes was used for the preparation of Atorvastatin - based proniosomal hydrogel by incorporating hydrated Proniosomes to Carbopol matrix to enhance the stability and viscosity of the system. The enhanced skin permeation for prolonged period of time, may lead to improved efficacy and better patient compliance. From in vivo studies the maximal concentrations (Cmax) of drug was significantly reduced while the areas under the plasma concentration–time curve (AUC) and t1/2 were evidently increased and extended. This study suggests that proniosomal gel of atorvastatin would be a promising alternative to improve the bioavailability problems of atorvastatin.

Compatibility study (based on microenvironmental pH and isothermal stress testing) of Febuxostat was carried out with selected excipients (Microcrystalline cellulose (MCC), Mannitol, Lactose, Hydroxypropyl-β-cyclodextrin (HP-β-CD), Polyethylene glycol(PEG) 6000, Polyvinyl pyrollidoneK30, Eudragit EPO, Sodium starch glycollate, Croscarmellose sodium (CCMC), Sodium lauryl sulphate, Magnesium stearate (MgS), Sodium steryl fumarate, Aerosil 200 and Purified talc) using FTIR and HPLC. Among them, Aerosil 200, MgS, Purified talc, Lactose and MCC were selected for the formulation of Febuxostat tablet. Three different polymers viz. PEG 6000, HP-b-CD and CCMC were selected as independent variables to enhance the dissolution rate by their complexation. Fifteen formulations obtained from Box Behnken design (BBD) (Minitab 16) were prepared through kneading method. Contour plot suggested CCMC (13.01mg) and HP-b-CD (65.45mg) excluding PEG 6000 for optimized formulation. Drug release profile of optimized formulation compared separately with formulation without filler, without polymer, physical mixture and a marketed product using similarity (fs) and dissimilarity (fd) factors showed similarity with marketed product. Similarly, similarity and dissimilarity factors for formulation without filler and optimized formulation was obtained within the range (fs= 82.34 and fd=5.42) indicating that the filler does not have any effect on the drug release. fs and fd for formulation without polymer and physical mixture lied outside the range suggesting the importance of the polymer complexation in the formulation. An accurate, simple, precise and robust reversed-phase liquid chromatographic method was developed for the estimation of Febuxostat. Furthermore, solid state characterization evaluated by FTIR showed that complexation between the polymers has occurred in the optimized formulation.