Purpose: Metoprolol succinate (MS), β1- selective adrenergic receptor blocking agent used in the management of hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction, is a BCS Class 1 drug with a relatively short half-life about 4-6hrs which results in multiple doses. It is mainly absorbed from the upper parts of GIT. One of the most feasible approach for achieving a sustained drug delivery profile is floating drug delivery system (FDDS), which prolongs the gastric residence time and thus increasing the overall bioavailability.
Methods: Non effervescent (NE), effervescent (E), immediate release (IR) mini tablets were prepared and filled into capsule shell. Non effervescent gastric floating (NE) matrix mini tablets of 35 mg MS were prepared using a low density polymer glyceryl behenate. Both direct compression and melt granulation techniques were used for preparation of NF tablets. Effervescent gastric floating (E) matrix tablets with 35mg MS were formulated with polymers such as HPMC K 15M, HPME K4M, PEO 303 WSR, and sodium bicarbonate as a floating agent. Immediate release (IR) mini tablets with 30mg MS were prepared by direct compression technique. All the prepared individual tablets were evulated for various tabletting parameters like drug content, thickness, hardness. UV analytical methods were used for the estimation of metoprolol succinate. pH 6.6 phosphate buffer was used as dissolution media and in vitro studies were carried and optimised formulations were selected for further study. A drug delivery system, in the form of capsule (CAP) containing 100mg MS was prepared using one NE, one E and one IR mini tablet and was further studied for various properties. With necessary ethical clearance In vivo behavior and pharmacokinetic parameters were estimated. Stability studies were performed according to ICH guidelines.
Results: All the prepared mini tablets were evaluated for various tabletting parameters followed by in vitro dissolution studies. From the in vitro dissolution results it was observed that desired drug release was achieved from the NE mini tablets prepared by both direct compression and melt granulation at the same polymer concentration. However less amount of channeling agent was adequate to release 100% of the drug from the tablets prepared by direct compression, when compared to the tablets prepared by melt granulation, for a period of 12 hours. PEO 303 WSR was found to be a promising agent in formulation of effervescent gastric floating mini tablets (E). As the polymer concentration increased the drug release was retarded. Formulations with drug release of 96.20% and 97.39 percent respectively in 12 hours were selected as optimized formulations. For IR mini tablets, formulations which released drug in 30 minutes were selected and optimized.In vitro dissolution studies were performed on drug delivery system CAP which contained three mini tablets. Prepared system showed 99.40% drug release in 12 hours. Drug release kinetics followed zero order kinetics (K0 = 6.643) and non Fickian diffusion (n=0.597).
From the pharmacokinetic data it was observed that higher AUC-24 values were observed for metoprolol succinate capsule compared to commercial extended release oral tablet. Results of the studies on stability showed that formulation CAP was stable and did not show any change in all the required characteristics such as average weight, drug content, floating lag time, and drug release profile. Thus from the stability studies conducted as per ICH guidelines it could be concluded that the optimized formulation CAP, i.e. capsule, is stable.
Conclusion: 1. Applicability of glyceryl behanate for the preparation of non effervescent gastric floating matrix tablets of metoprolol succinate was studied. For the first time
2. Applicability of HPMC K 4 M, K 15 M, PEO 303 WSR in the preparation of effervescent gastric floating matrix tablets of were studied.
3. Capsule containing combination of mini tablets of E, NE, IR was prepared. Prepared CAP could sustain and prolong drug release of metoprolol succinate for 12 hours and thus enhance the bioavailability.