The Pre-clinical Study Of Ranolazine Extended-release Tablets

Angina pectoris is a common type of coranry heart disease triggered by coronary atheroscle. Angina pectoris coranry heart disease is the clinical synchrome with symptom of sternum pain or precordialgia triggered by coronary drastic ischemia and temperory myocardial ischemia. The treatment mechanism is to alleviate the symptoms:improve myocardial blood supply, reduce myocardial oxygen consumption. The representative drugs are nitric acid ester, calcium antagonist and (3 blocking agents.Ranolazine is a new type of anti-angina pectoris agent. Abroad researches demonstrate ranolazine, as an inhibitor of fatty acid oxidation, can optimize myocardial energy supply by inhibiting theβ-oxidation of fatty acid and futher activating pyruvate dehydrogenase. These functions can result in the oxidation of glucose and enhance the oxygen utilization. Ranolazine can maintain the coupling of glucose oxidation-zymolysis during the period ischemia, which can reduce the toxicity to the tissue. Differ from the nitric acid ester, calcium antagonist and (3 blocking agents, ranolazine does not affect heart rate and biood pressure. According to the clinical research result, ranolazine can enhance the energy resorement and stamina of patients and improve their life quality.Ranolazine extended-release tablet is developed by CV Therapeutics Company, USA. The extended-release tablet has been approved by FDA on 27, Jan,2006 and have been on the market with dose of 500mg/tablet and its product name is RanexaTM. Ranolazine is mainly utilized to treat chronic angina pectoris.This project aims at optimizing preparation screening method and production techniques of ranolazine extended-release tablet. The new preparation has identical or similar drug-release profile and phannacokinetics with the original dose. The analytical method is estabilished to determine the content and stability. The analytical method is estabilished to determine the release rate and concentration of ranolazine in dissolution solvent. The drug release characteristic is also studied for the sustainable preparation. Analytical method is also established to quantisized ranolazine in plasma samples to determine the pharmacokinetics of preparation in Beagle dogs.This theis includes four parts:1. The study of determination methodA simple and sensitive HPLC-UV method was established to determine the ranolazine in extended-release tablet, and ultraviolet spectrophotometry was applied to determine the dissolution rate of Ranolazine. Method validation demonstrated that the established method was simple, and the precision and accuracy could satisfy the study requirement. The preparation content, dissolution rate and stability was also determined.2. Preparation of Ranolazine extended-release tabletRanolazine resolution rate could differ from PH, so the preparation should pay extra attention to the PH of supplement. In our preparation, we applied the PH dependent antagonist and apply lactose and microcrystalline cellulose modifier. We added sodium hydroxide and Eudragit NE30D as adhesives. Preparation screening process should consider tablet weight difference, preparation, liquidity, and pressure tolerance. Besides, preparation screening evaluated drug release rate to establish drug release curve and finally detennined the comparability of original dose with optimized dose on animal study.The validated method was feasible and drug release rate in the result abide by the requirement of extended-release tablet.3. Quality standard and preliminary stability studyIt was of great importance to actively control the quality of extended-release tablet in the manufacturing process. We established feasible quality control method for self-produced preparation including distinguishment, content determination, and drug release test. Preperation stability was also studied for expiration date.4. Pharmacokinetic study in Beagle dogAnalytical method was established to determine the Ranolazine concentration in Beagle dog plasma samples. The experiment was two round crossover study. The original formulation was the reference and self-produced fonnulation was the test. The study was to evaluate the pharmacokinetics of self-produced fonnulation. The result showed that:Cmax、Tmax、t1/2、MRT、AUC0-t、AUC0-∞of Ranolazine in plasma had no statistical significance between reference and test, The relative bioavailability of the test formulation was 90.9% by mean AUC0-t, indicating that self-produced formulation had similar drug release profile with the reference formulation.