Formulation and Development of Extended Release Dosage form of an Anticonvulsant Drug

INTRODUCTION: The ideal dosage regimen is that by which an acceptable therapeutic concentration of drug at the site(s) of action is attained immediately and is then maintained constant for the desired duration of the treatment. If the provided dose size and frequency of administration are correct, therapeutic steady state plasma concentration of a drug can be achieved promptly and maintained by the respective administration of conventional peroral dosage forms. However there are number of potential limitations associated with this. These limitations are: 1. The concentration of drug in the plasma and hence at the site(s) of action of the drug fluctuates over successive dosing intervals, even when the so-called ‘Steadystate condition’ is achieved. Hence it is not possible to maintain a therapeutic concentration of drug which remains constant at the site(s) of action for the duration of treatment. 2. The inevitable fluctuations of steady-state concentrations of drug in the plasma and hence at the site(s) of action can lead to a patient being over or under medicated. 3. For drugs with short biological half-lives frequent doses are required to maintain steady state plasma concentrations within the therapeutic range. For such drugs, the maintenance of therapeutic plasma concentrations is particularly susceptible to the consequence of forgotten doses and the overnight no-dose period. AIM: The aim of the work is to design and develop Extended Release (ER) tablets of an anticonvulsant drug and to carry out the in- vitro release study of the drug. OBJECTIVES: a) To carry out preformulation and physicochemical characterization of drug and excipients. b) To formulate extended release tablets of anticonvulsant drug. c) To optimize the ER formulations based on pre and post compression characterization. d) To carry out stability studies as per ICH guidelines. SUMMARY: In the study, anticonvulsant drug was selected for designing extended release matrix tablets. Pre-formulation studies were done with API. Compatibility was done before choosing the excipients for the study with physical observation and FTIR studies. The samples were charged in stability chambers at conditions 30°C/65%RH and 40°C/75%RH for 30 days. All the pre-formulation studies and compatibility studies were found to be satisfactory. So formulation trials were followed with the selected excipients. Blend for ER formulation was prepared by wet granulation method. Hypromellose K4M and Hypromellose K15M were used as release retarding polymers for optimizing the formula. Six trials were taken to optimize the release of API in ER form to be within specifications. F5 is the optimized formula with 11.66% concentration of HPMC K15M polymer which optimized the drug release profile as per predetermined specifications. A reproducibility trial F6 was performed to check the reproducibility of process of drug release as per F5. For the ER form, Other excipients include povidone as binder, Lactose monohydrate as diluent, colloidal silicon dioxide as glidant and Magnesium stearate as Lubricant. Instacoat yellow was used as ready mix. Post-Compression analysis of all formulations like Hardness, Weight variation, Friability and Assay were within the limits for all the formulations. In-vitro dissolution studies were performed by HPLC method revealed that the formulation F5 released the drug as per the specifications. Kinetic Model fitting was done by plotting graphs for Zero-Order kinetics, First-Order kinetics, Higuchi’s Kinetic model and Korsemeyer - Peppas kinetic model. The formulation selected was F5 which has shown the release rate of the drug by First order kinetics and follows matrix diffusion controlled mechanism. Accelerated stability studies are being performed. CONCLUSION: The aim of the study is to design and develop extended release matrix tablets of anticonvulsant drugs. Hypromellose, water swellable polymer was selected for the extended release of API. The formulation was optimized to obtain the release of API for a sustained period of 12 hours. In the initial trials, Hypromellose K4M of low viscosity grade was used, and then Hypromellose K15M of high viscosity grade was selected to check the feasibility of the polymer to sustain the release of API. With HPMC K4M the drug release was not controlled to the desired limit of 30-60% at 6th hour. So, a still high viscous polymer Hypromellose K15M was used in the formulations F-4 to F-6. The incorporation of the Polymer intragranularly at concentration 11.66% gave an optimum release profile within specifications. From graphs plotted for various Kinetic models, it can be concluded that the F5 follows First-order kinetics as the plots of that model had shown higher regression value. F5 formula extended the release and follows matrix diffusion controlled mechanism