| Isosorbide-5-mononitrate(5-ISMN)is the main metabolite of isosorbide dinitrate. It is characterized by fast oral absorption, high absolute bioadvailability(near 100%), small difference of individuality and little toxicity. So it is one of most effective drugs of preventing and curing angina pectoris. But its common preparations are administrated several times in one day, and there are some fluctuation of plasma concentration. Zero-effect and drug tolerance happen frequently. Osmotic pump preparation is characterized by their distinct releasing mode and stable release velocity. We attempted to increase its curative effect, reduce its adverse effect, decrease the frequency of administration and avoid drug tolerance by the way of osmotic pump technique.we wish to provide a new preparation style for the clinical.The solubility of 5-ISMN in different solutions was determined. The solubility of 5-ISMN in water, artificial gastric juice and artificial intestinal juice, were 209.10mg/mL,245.59mg/mL,151.01mg/mL, respectively, which were in 50-300mg/mL, indicated that 5-ISMN was proper for osmotic pump tablet.In this paper, factors effecting drug release from the osmotic pump tablet were studied, including variety and amount of the osmotic pressure promoting agent, the release velocity blocking agent, and number, location and size of the release orifice, coating composition and coating thickness. The release property was evaluated by the factor of similarity (f2). The results indicated that the release velocity blocking agent should be used and the effect of osmotic pressure promoting agent was not obvious, but the osmotic pressure promoting agent should be added in the core of the table to keep integrity of the coating membrane. The release velocity blocking agent, coating composition and coating thickness had significant effect on the drug release. But the number, the location and the size of the release orifice in a certain range had little effect on drug release. In the paper, based on the investigation of factors analysis, homogeneous experiment designs were used to optimize the formulation. As a result, the osmotic pump tablets of 5-ISMN were prepared. They released drugs with constant speed in 18h, accumulative release were above 90%, and suitale to zero-order release kinetics. The factor of similarity between the releasing curve and designed releasing curve (releasing drugs with constant speed in 18h, moreover releasing drug completely at 18h) was larger than 60%.The results indicated that the drug release profiles of the optimal formulation had excellent zero-order release character in vitro (r=0.9952) from 0 to 18 hours. In addition, the results of stability experiments showed that this product was sensitive to temperature and humidity, but was stable under illumination.The release mechanism of the osmotic pump tables was investigated. The results indicated that the osmotic pressure was the main delivery force and the release rate from the tablet was insensitive to variations of the pH or rotation speeds of the paddle.Hardness of tablet core also had no obvious effect on the release behavior of controlled release isosorbide-5-mononitrate osmotic pump tablets.Because acetone was used in the coating film, it is necessary to establish a method to determine acetone in the film. The results showed that the content of acetone met the requirement.The method of detecting drug concentration in plasma was based on the reference and our own exploration. The two period cross-over design was used and the time-concentration curve of the test and reference tablets was plotted. AUC0-24, Tmax, Cmax, and t1/2 were(7254.68±1819.55) and (6787.58±769.28) ng-h/mL;(6.50±1.97) and (2.67±0.52)h,(631.85±194.94) and(1234.73±178.42) ng/mL, (4.52±1.14) and (2.16±0.75) h respectively. The relative bioavailability was(106.88±29.01)%.The correlation-ship of drug release behavior was studied according to W-N equation. The results indicated that the correlation-ship between vitro and vivo was good (r=0.9762).Using the sustained release tablet on market as the reference, the release in vitro of the osmotic pump tablets of 5-ISMN were studied. The result indicated that the osmotic pump tablets released drugs with constant speed in 18h, controlled releasing drugs in a longer time.3 batches of the osmotic pump tablets were prepared.The formulation craft was reproducible and stable. Through the factors of characteristics, identification, examination and content determination being studied, the qualities of the osmotic pump tablets of 5-ISMN were examined and the quality standard were regulated preliminarily. |
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