Development and Optimization of Osmotically Controlled Oral Drug Delivery Systems for Highly and Poorly Water Soluble Drugs

INTRODUCTION: Controlled release drug delivery systems (CRDDS) offer many advantages over conventional dosage forms like improved patient compliance and convenience and reduced adverse effects. A constant therapeutic plasma concentration of the drug within the therapeutic index of the drug over extended periods was maintained in CRDDS. In conventional oral dosage forms, the resulting pattern of concentration of drug in plasma widely varies and this may cause unpredictable and undesired clinical effects. Variations of the blood concentration above the MSC may result in adverse effects. With CR products drug entry with a precise extent, rate, or timing into the blood can be programmed or achieved. Release of the drugs from all other conventional dosage forms except intravenous dosage forms follows first-order kinetics. This results in irregular high and low concentrations and only a brief optimal therapeutic level. But the controlled release systems release the drug at a constant rate (zero order) for a definite time period. This results in consistent concentration of drug in tissue and plasma. In order to maintain blood concentrations within the therapeutic index, frequent dosing will be done for drugs with short half life. Frequency of dosing and patient compliance is inversely related. CR products have the potential to improve patient compliance by reducing the number of daily doses. AIMS OF THE STUDY: For a successful drug therapy the concentration of the drug in the plasma should be maintained constant within the therapeutic index (TI) throughout the treatment period. It avoids the fluctuations in plasma concentration of drug and improves the patient compliance. Diseases which need a longer duration of treatment (sometimes a life time) require more careful medications and drug delivery systems for the better patient compliance and comfort. Controlled release drug delivery systems, release the drug at a controlled and constant manner within the therapeutic index throughout the treatment period. Osmotic pumps are such a device which can strictly maintain a controlled release of the drug in the blood plasma within the therapeutic index up to the desired time period. OBJECTIVES OF THE STUDY: 1. To develop and evaluate an OCODDS (Push pull osmotic tablets) of highly and poorly water soluble drugs. 2. To study and optimize core as well as membrane parameters affecting the release profile using design of experiments (DoE). 3. To compare and conclude the effect of different parameters of the formulation on the release profile/pattern of the selected drugs from the device using different statistical tools. 4. To optimize the push pull osmotic tablet formulation of all the four selected drugs using numerical optimization and desirability techniques. 5. To study the factor influence on the desirability function of highly and poorly soluble drugs. 6. To conduct the stability studies of the selected optimized formulations as per ICH guidelines. 7. To conduct an in vivo animal studies for the selected optimized formulation of all the four drugs. MATERIALS AND METHODS: Study Design: Parallel design. Sample size: 6 healthy rabbits (New Zealand, White) of either sex weighing 3.0 -3.5 kg). Study treatments: Reference (R) – Marketed XR formulation (12mg), Test (T) - Optimized formulation of push pull osmotic tablets of Ropinirole HCl (12mg). Introduction: Ropinirole HCl an orally administered non-ergoline dopamine agonist used for the treatment of Idiopathic Parkinson’s disease. Dose: A single oral dose of either (R) – Marketed XR formulation (12mg) or test treatment (T) Ropinirole HCl push pull OT (12mg), along with water. Dietary Plan: Food was withdrawn from the rats 12 hr before drug administration. Until 24 hr post dosing food was not given to the animals. All rats have access to water during the study period. Sampling Schedules: At defined time intervals blood samples will be collected from marginal ear vein. Bio analytical Method: Ropinirole HCl will be estimated in plasma using a validated analytical method. Pharmacokinetic Parameters: tmax, Cmax, AUC0-t, AUC0-α, kel and t1/2 will be determined from the plasma concentration data of Ropinirole HCl. Ethical: Considerations The study will be carried out as per the ICH- Guidelines. SUMMARY AND CONCLUSION: In this research work, once daily push pull osmotic tablets of two highly soluble drugs (Ropinirole HCl and Ivabradine Hcl) and two poorly soluble drugs (Nisoldipine and Carvedilol phosphate) were developed,optimized and different factors affecting the release profile were extensively studied. The concept of QbD was applied and the design space was successfully obtained with the help of design expert soft ware. Different statistical tools like ANOVA, regression analysis were used for the study. Analytical method was developed in pH 6.8 phosphate buffer for all the selected drugs. The drugs exhibited greater linearity at the selected ranges. Regression equations and R2 were created and studied for all the drugs in both the solvents. Pre formulation studies of the selected drugs like, organoleptic properties, solubility, flow property, particle size determination and drug–excipients interaction study were performed and reported. The amount of the drug to incorporated in to the push pull osmotic tablets of the selected drugs were calculated with the help of the available labeled claim of the XR products and Robinson – eriksen equation. An extensive literature survey was performed and the various vital factors affecting the drug release profile from the push pull OT were identified. Formulation development, factor influence study and optimization of the formulations were done with the help of design expert software. A fractional factorial design (2 8-4 with Resolution IV) with 4 centre points were selected for the study. Push pull OTs of the selected drugs were formulated and both blend as well as whole tablet evaluations were performed. All the tests were within specified limits of the pharmacopoeia. In vitro dissolution study of all the trials of the selected drugs were carried out in triplicate. The selected responses like PCUR at 24 hrs, lag time and R2 were reported for each trial. The responses were analyzed with the help of design expert software and different significant factors affecting the selected responses were identified. The factor influences were extensively studied and reported with the help of different plots like half normal plot, normal plots, Pareto charts, contour plots, RS plots and cube plots. ANOVA analysis was also performed for the identification significant factors. From the regression analysis the coefficients of significant factors were determined. Polynomial equations representing the responses were framed after eliminating the non significant factors. Optimization of the push pull OTs of the selected drugs was done with the help of numerical optimization and desirability function. A better identification of design space was done with the help of desirability contour plots and RS plots. Check point batches of all the four selected drugs were formulated and evaluated for the design model validity. Stability studies on the optimized push pull OT formulations of all the selected drugs were performed to assess their stabilityover time. The ICH guidelines were strictly followed during the stability study. None of the formulations showed any significant changes in any of the parameters evaluated. An In vivo animal study of the optimized formulations of all the selected drugs was performed to assess the in vivo performance of the dosage form. Pharmacokinetic parameters like tmax,Cmax, AUC0-t,AUC 0-∞,Kel, t½ were determined and compared with the available marketed products of the selected drugs. So it can be concluded that in this research work, stable optimized formulations of push pull OTs of highly and poorly soluble drugs were successfully formulated and extensively studied the significant factors affecting the release pattern of the drug from the system with the help of design of experiments