Research On The Preparation Of Simvastatin And Sustained-release Nicotinic Acid Capsules

Abnormal lipid metabolism is a risk factor in atherosclerosis and coronary heart diseases. Lipid regulators reduce blood lipids by controlling lipid metabolism. Simvastatin and Nicotinic acid are both the first-line Lipid-regulators. Nicotinic acid, one of the vitamin B group, is firstly used to prevent and cure aniacinosis under low dose and later also used to lower blood lipid under large dose. Nicotinic acid is a commonly used antidyslipidemia agent that effectively decreases the plasma levels Of total cholesterol, triglycerides(TG), LDL cholesterol(LDL-C), and LP(a), and increases HDL cholesterol(HDL-C),moreover, it’s the only agent that can availably decreases LP(a).The considerable adverse effects of rapid-release Nicotinic acid preparation, especially flush and hepatotoxicity, resulted in the emergence of the sustained-release Nicotinic acid formulation, which greatly relieve adverse reactions and afford a better choice with effectiveness and safety for hyperlipidemia as well as its combined treatment. Simvastatin, an HMG-CoA reductase inhibitors, is proved by clinical trials to be an able agent which can lower plasma level of total cholesterol, LDL cholesterol(LDL-C), VLDL cholesterol(VLDL-C) and triglycerides(TG), while its effect on increasing HDL-C is moderate. With its advantages of significantly lipid-lowering effect, safety, few adverse actions, Simvastatin has become one of the first-line agent for the treatment of hyperlipidemia. When Nicotinic acid and Simvastatin were combined, they not only can enhance their reducing effect on hyperlipidemia but also decrease the frequency of drug use, as well as their alleviating hypercholesterolemia effect is more efficient than just taking drug alone. This project is supposed to make Nicotinic acid and simvastatin into a day fixed-dosage preparation, in which Nicotinic acid is processed into sustained-release granules while simvastatin is processed into normal-release granules.After resorted to relevant references and completed necessary pre-tests, we studied and decided the preparation process of Nicotinic acid sustained-release granules by extrusion and airflow-coating method, as well as the preparation process of Simvastatin granules by extrusion method. Then we selected the proper method to fill capsules with both the granules according respective specification.Then we made the Simvastatin and sustained-release Nicotinic acid capsules according the selected process, and analyzed the key quality items as well as the imported tablets. The results were as follows:the release curves of Nicotinic acid in4different disperse mediums:water,0.1mol/L HCL solution, pH6.8phosphate solution and pH4.0acetate solution resembled those of the imported tablets with the similarity factors f2numbered in turn:85,72,58,64. The same case also took place when the dissolution curves of Simvastatin of the capsules were compared in4different disperse mediums:0.1mol/L HCL solution, pH6.8phosphate solution, pH4.0acetate solution and water, the similarity factors f2numbering in turn:56,62,58,57. Additionally, other key items includes the contents of both active substances, the content uniformity and impurities of simvastatin could all met the need of quality standard.Next we researched the stability of the product exposed to the severe conditions as follows:high temperature (40℃or60℃), high humidity (25℃,rh92.5%) and strong light(45001x) for5and10days. After the exposure we examined the key items such as the characteristics of the granules, the contents of both active substances, the release of Nicotinic acid, the dissolution and impurities of simvastatin as well as the weigh increase of the whole capsule. The analytical reports showed that impurities of simvastatin increased obviously under60℃condition, certain moisture absorption were found under high humidity. Other items didn’t change compared with the original product. The results suggested the stability of the product was quite available, however, the product should be sealed well from moisture and put at cold and dry place, away from high temperature environment.In the end, we carried out the research on pharmacokinetics of both self-made capsules and reference imported tablets, and the pharmacokinetic parameters were as follows:Nicotinamide:Cmax (15.771±6.033) and (13.183±3.209)mg/l; Tmax(22±9.165) and (22±9.165)h;T1/2(5.305±1.653) and (6.499±5.085)h;AUC0�'48(429.694±1.118.947) and (359.106±101.332)h-mg/l, the relative bioavailability of the preparation was (120.0±12.7)%, Simvastatin:Cmax (8.558±0.614) and (8.230±0.773)μg/l; Tmax(2.667±0.289) and (2.5±0)h;T1/2(1.404±0.071) and (1.968±0.867)h;AUC0�'48(42.719±3.599) and (39.832±4.341)h·μg/l, the relative bioavailability of the preparation was (107.5±6.3)%. There was no statistical difference between the two formulations on AUC0�'48、Cmax and Tmax.Above all, we could draw the conclusion as follows:the preparation process of the Simvastatin and sustained-release Nicotinic acid capsules through filling respectively with the sustained-release Nicotinic acid granules made by extrusion and air-coating method and the Simvastatin granules made by extrusion method is practical and effective. The quality analysis showed the release of Nicotinic acid and the dissolution of Simvastatin of the capsules in vitro were similar to the imported reference. All other key items could also meet the need of quality standard. The research on the stability of the product exposed to the severe conditions proved the self-made product was quite stable under high temperature (40℃), high humidity (25℃,rh75%) and strong light(45001x) for10days. The pharmacokinetic parameters from the research on pharmacokinetics of both self-made capsules and reference proved the two formulations were bioequivalent.