Design, development and evaluation of controlled release multiple unit pellets for potential delivery of antiulcerants

AIM AND OBJECTIVES: The main aim of the present study was to formulate and evaluate enteric coated, controlled release multiple unit pellets of Esomprazole magnesium and Rabeprazole sodium using natural and synthetic polymers. OBJECTIVES: 1. To formulate Esomeprazole magnesium and Rabeprazole Sodium Controlled release Multiple Unit Pellets using various concentrations of Hydroxy Propyl Methyl Cellulose K15, Hydroxy Propyl Methyl Cellulose K100, Ethyl Cellulose, and Xanthan gum by Extrusion Spheronization process. 2. To evaluate the pre - compression parameters like drug excipient interaction study, bulk density, tapped density, compressibility index and angle of repose. 3. To evaluate various post compression evaluation parameters like friability, drug content and in vitro dissolution studies and Scanning Electron Microscopy (SEM) study. 4. To formulate gastric protection for the prepared multiple unit pellets using Hydroxy Propyl Methyl Cellulose Phthalate as enteric polymer. 6. To determine the mechanism and kinetics of drug release. 7. To conduct stability studies on optimized formulation as per ICH guidelines. SUMMARY: In the modern era of Pharmaceutical research much attention has been focussed on patient’s health in terms of therapeutic efficacy and safety. Modified Dosage Form (MRDF) has always been more effective therapeutic alternative to conventional or immediate release. The term modified release drug product is used to describe product that alter the timing and /or the rate of release of the drug substances. There are two types of MRDF .i) Delayed release ii) Extended release. The terms Controlled release (CR), Sustained release (SR) Prolong release (PR) has been used synonymously with extended release dosage forms. Controlled release drug delivery is one which delivers the drug at a predetermined rate for locally (or) systemically for a specified period of time. Controlled release drug delivery system aim to maintain plasma concentration of drugs within the therapeutic window for a longer period of time. Delayed release products are formulated with acid resistance (or) enteric coating protects acid labile drug substance from the gastric environment (or) to prevent adverse events such as irritation. A peptic ulcer is an open sore on the lining of the stomach or duodenum. Gastric and duodenal ulcer is produced by an imbalance between mucosal defences particularly gastric acid and pepsin. In addition, H.pylori infection is a major factor in the pathogenic of peptic ulcer. Proton pump inhibitors (PPI) rank among the top 10 prescribed classes of drugs and are commonly used to treat acid reflux, indigestion and peptic ulcers. PPIs are among the most widely sold drugs in the world and the first one in antiulcer medicine is omeprazole(WHO model list of essential medicines). Among seven available PPI drugs Esomeprazole magnesium and Rabeprazole sodium are classical examples of proton pump inhibitors and are approved by FDA for the treatment of GERD, Peptic ulcer and maintains of erosive esophagites. These drugs will degrading in acidic environment of stomach and will lead to therapeutic in efficacy so it is necessary to bypass the acidic pH of the stomach which can be achieved by formulating delayed release dosage forms by using different enteric polymers. The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly and then maintain the desired drug concentration. Many marketed Esomeprazole and Rabeprazole tablets/pellets are available as enteric coated formulation only. The main aim of the present study was to develop and evaluate enteric coated, controlled release tablets of Esomeprazole magnesium and Rabeprazole sodium using natural and synthetic polymers gives better and more uniform drug absorption and greater bioavailability. To design the multiple unit pellets, we have developed two different spheroid unit of uniform drug content with varying in polymer concentration to achieve rate controlled drug release as per our specification. The first group spheroid unit which contain only drug with spheroidizing polymers was prepared to achieve the minimum effective concentration. The second group of spheroid unit was prepared by using the controlled release polymers HPMC K100, HPMC K15, Ethyl cellulose and Xanthan gum. Among the four polymers HPMC K100 the drug Polymer ratio 1:1.5 shows good controlled release characters in Esomeprazole magnesium and HPMC K 15 the drug and polymer ratio 1:2 shows good controlled release profile in Rabeprazole sodium. The MUPS were prepared by Extrusion -Spheronization a promising pelletization technique. In this process the pellets were prepared by mixing the drug with excipient along with binder solution the resultant mass was extruded through extruder followed by spheronizer and finally dried. The possible interactions between drugs and distinct polymers were investigated via FT-IR Studies. Results proved that Rabeprazole sodium and Esomeprazole magnesium was found to be compatible with excipient as no disappearance of the peaks or shift of the peaks indicating that the drugs are compatible with ingredients. The micromeritics evaluation like Bulk density, Tapped density, Angle of repose, Carr’s index and Hauser’s ratio of the prepared pellets shows good flow property. The post formulation parameters like friability, drug content were carried out and found to be within acceptable limit. SEM study shows the surface morphology of the optimized formulations E2 and R6 the pellets was compact, continuous and was porous in nature, demonstrated the spherical nature of the pellets. Based on in vitro dissolution profile the enteric coated, controlled release multiple unit pellets of Esomeprazole magnesium and Rabeprazole sodium was developed using HPMCK100 in the ratio 1:1.5 ( drug :polymer) and HPMC K15 in the ratio 1:1.5 ( drug :polymer) respectively as controlled release polymer and Hypromellose phthalate HP55 as enteric coated polymer. The optimized formulations E2 (Esomeprazole) and R6 (Rabeprazole) had better resistant to 0.1N HCl and better cumulative percent drug release as compared to other formulation. After 12 hours E2 shows 97.88% and R6 shows 97.59 % cumulative percent drug release as compared to other formulation. So E2 (Esomeprazole) R6 (Rabeprazole) was selected as optimized formulation from the trail batches. The in vivo pharmacokinetic plasma concentration and time curve parameters shows that less plasma concentration fluctuation, lower Cmax, prolonged tmax and MRT of formulated MUPS than that of marketed enteric coated formulations. Stability study revealed there was no significant change in in vitro release profile. All the parameters were within limit after 90 days. CONCLUSION: From the above research finding it can be concluded that controlled release of Esomeprazole Magnesium and Rabeprazole Sodium Multiple Unit Pellets could be developed by using HPMC K100 the drug Polymer ratio 1:1.5 and HPMC K 15 the drug and polymer ratio 1:2 prepared by Extrusion -Spheronization to achieve better bioavailability and extended drug release. Further, the first group spheroid unit could maintain the minimum effective concentration and the second group spheroid unit could release the medicament in control release manner. Hence the prepared Multiple Unit Pellets could achieve both enteric coating and controlled release approach for the potential delivery of Antiulcerants