| Cardiovascular and cerebrovascular diseases are among the three most serious deseases that are threatening human lives. The incidence of the diseases increases continueously along with the coming of the ageing era. Angina pectoris is the most common symptom of the cardiovascular and cerebrovascula diseases. Sublingual administration of glyceryl trinitrate for the acute angina is the general treatment and anti-anginal drugs should be used subsequently to prevent the recrudescence. Current medical therapies for treating angina include agents that increase coronary arterial blood flow (such as nitrates) and agents that decrease myocardial work (such as beta-adrenergic blockers and calcium-channel antagonists). These agents can relieve the symptom by reducing the heart rate and the blood pressure of the patient, weaken cordis pumping function and myocardial contractility, or decrease myocardial oxygen consumption. Because of most of the angina patients acompanied by congestive heart failure, chronic disease in lung or diabetes, these agents cause severe damage to the weak heart. Fatigue, headache, extremity cool, edema and impotence are the common side effects and these side effects cause badly negative impact on the life quality of the patients. Therefore, it is important to develop high-effective and low-toxicity medicine to treat the ischemic heart disease. Since angina can be considered as a sort of metabolic disease, metabolic modulators have become a novel approach for developping new drug to treat ischemic heart disease.Ranolazine hydrochloride which represents a new class of anti-anginal drugs, is called partially fatty acid oxidation (pFOX) inhibitors. Ranolazine produces anti-anginal effects by shifting the heart's metabolism and reducing oxygen required. According to this novel mechanism, ranolazine can treat angina without reducing blood pressure and heart rate. Clinical trials results indicated that ranolazine is an effective anti-anginal agent. It is safety and can be well toleranced. But the effective time of ranolazine is very short, the antianginal and antiischemic activities ofranolazine can't maintain throughout the dosing interval. Ranolazine produced antianginal effects only under the dose higher than 240mg, and the peak plasma concentration should be higher than 550ng/mL. As an anti-anginal drug, immediate-release ranolazine formulation is not practicality. To produce a marked antianginal and antiischemic effects of the ranolazine throughout the dosing interval, the plasma levels of ranolazine must be maintained over 550ng base/mL according to the Clinical trials results. Therefore, a ranolazine hydrochloride sustained release formulation of twice daily administration was developed .Firstly, a HPLC method was established to determine the content of RH and to study the stability characteristic of the RH sustained release tablets. Ultraviolet spectrophotometry (UV) was developed to assay drug release characteristic in vitro. The equilibrium solubility value of ranolazine base(R) at 37°C in distilled water, O.lmol/LHCl, pH5.8 phosphate buffer(PB) and pH6.8 PB was 0.35, 54.45, 2.73, 0.79mg/ml, respectively. The equilibrium solubility values of ranolazine hydrochloride (RH) at 37°C in distilled water, O.lmol/LHCl, pH5.8PB and pH6.8 PB were all higher than lg/ml. It can be concluded that the solubility of ranolazine base (R) decreased while pH increased, and the solubility of ranolazine hydrochloride (RH) was independent with pH.Secondly, single factor experiments were performed and the release rate in vitro was used as evaluation index. The viscosities & dosages of matrix material HPMC;the species & dosages of EC, Eudragit and Carbopol;the species & dosage of adhesive;different granulating method;different tablet shape, weight and hardness;defferent dissolution medium and stirring rate were evaluated, respectively. The release rate of RH SR tablets decreased as the content of HPMC increased. The viscosity of HPMC had unconspicuous influence on the release rate of RH SR tablets. When the hydrophobic material such as EC and Eudragit were used in matrix, the release rate of RH SR tablets decreased greatly. The release rates of RH sustained release tablets were decreased greater when the more hydrophobic material were used. When hydrophilic material such as Carbopol was used in the formulation, the release rate of RH SR tablets was fast at the first stage, then became slower at the last stage.Because the viscosity of Carbopol increased while pH increased, Carbopol was not suitable using as the matrix material of RH SR tablets. The alcohol concent in adhesives, granulating method, tablet shape, weight and hardness had influence on the release rate of RH SR tablets markedly, while dissolution medium and stirring rate had unconspicuous influence on the release rate of RH SR tablets.Based on the studies of single factor experimentations, optimal formulation and technics were selected by orthogonal design test. When using HPMC, EC and Eudragit as multi-matrix, RH SR tablets of twice daily administration had significantly sustained- release characteristics in vitro. The release behavior of the RH SR tablets followed the Higuchi equation. The rationality and stability of the formulation and technics of RH SR tablets were validated by the release determination of 3 batches of RH SR tablets. Stability experiments results indicated that RH SR tablets were stable to light, high temperature, while the moisture absorption character in high humidity was observed. These results indicated that RH SR tablets were instable to high humidity, so the RH SR tablets must be stored in airproof containers. The stability experiments results of RH SR tablets indicated that RH SR tablets were stable at 40°C,RH75% and 25°C,RH60% for six month. The experiments results of selecting the coating material of RH SR tablets showed that coating had no effect on the release characteristics of RH SR tablets.Finally, a LC-MS method was established to determine the RH content in plasma sample. The immediate-release (IR) tablets were used as standard samples, the single dose and multi-dose of pharmacokinetics and bioavailabilities of RH SR tablets in dogs were studied. Results show that the RH concentration in plasma sample determined using LC-MS method were not influnced by inner substance of plasm. The recovery ratio of RH in plasma was higher than 92.6%, and the RSD of precision in the intra-day and inter-day experiments were lower than 13.6%. The minimal detectable concentration in plasma was 46ng/ml. The related coefficient of standard curve in plasma was higher than 0.99. The results of serviceable test and frozen-melt test showed that the LC-MS experiment methods were accorded with the demand of analysis for biologic sample. The plasma concentration-time data of RH in dogs afteroral administration single dose of RH IR tablets(333mgX 1) and SR tablets (500mgX 1) were according with a two-compartment model by a 3p97 program. The kaof RH IR (333mg) andSR (500mg) tablets were 2.06±0.72h and 0.96±0.41h respectively. The CmaxWere 11.51±3.20|ag/ml and 14.05±3.50fxg/ml respectively. The Tmax were 1.0±0.3h and 1.5±0.5h respectively. The tm were 11.10±1.52h and 10.06±1.39h respectively. The AUCo-T were 31.18±7.17ug.h/ml and 39.85±11.62ug.h/ml respectively. The bioavailability of RH SR tablets was 84.4% comparing to IR tablets. The RH SR tablets had a good in vtro-in vivo correlation (r=0.9663 ) . The Cmax of RH in dogs after oral administration multi-dose of RH IR and SR tablets were 6.52±1.23ng/ml and 6.86±1.22ug/ml respectively. The Cmin were 0.60±0.23ug/ml and 0.59±0.47ng/ml respectively. The Tmax were 0.79±0.33h and 2.10±0.8h respectively. The AUCSS were 22.4±3.62ug.h/ml and 32.66±7.96ug.h/ml respectively. The DF of RH IR tablets and RH SR tablets were 2.09±0.42 and 2.36±0.34 respectively. The results indicated that there was a well linearity character between the absorption stage in vivo and the release in vitro. The study of multi-dose of RH IR and SR tablets showed that the DF of RH SR tablets was same as that of immediate-release tablets. |
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