盐酸甜菜碱泡腾片制备及部分药理作用研究

发布时间：2018-09-12 18:46

【摘要】：目的研究盐酸甜菜碱泡腾片的处方、工艺和制备方法,建立初步质量评价方法并考察其质量,观察盐酸甜菜碱泡腾片对中枢神经系统的药理作用及急性毒性反应,为盐酸甜菜碱泡腾片的研究开发提供实验依据。方法1盐酸甜菜碱泡腾片的制备与质量评价固定处方中盐酸甜菜碱的用量,通过综合考察制剂的崩解时限、硬度、脆碎度、外观等因素,初步筛选出泡腾剂、填充剂、润滑剂、粘合剂的种类及用量。采用正交设计方法进行处方优化,确定工艺操作简单、制剂质量稳定的最佳处方。按中国药典2010版二部附录IA,对制剂质量进行评价,初步建立盐酸甜菜碱泡腾片的质量标准。2盐酸甜菜碱泡腾片的神经药理作用与急性毒性研究2.1镇静催眠实验①取小鼠随机分为空白对照组(NS)、地西泮组(2.0mg·kg-1)、甜菜碱低、中、高剂量组(0.29g·kg-1、0.58g·kg-1、1.16g·kg-1),观察记录灌胃给药后不同时间小鼠的自主活动;②分组同“①”,灌胃给药30min后,腹腔注射催眠阈下剂量的戊巴比妥钠(25mg·kg-1),观察小鼠翻正反射消失情况。③分组同“①”,灌胃给药30min后,腹腔注射催眠剂量的戊巴比妥钠(40mg·kg-1),观察各组小鼠的催眠潜伏期及睡眠时间。2.2抗惊厥实验取小鼠随机分为对照组(NS)、戊巴比妥钠组(25mg·kg-1)、甜菜碱低、中、高剂量组(0.29g·kg-1、0.58g·kg-1、1.16g·kg-1),灌胃给药30min后,腹腔注射尼可刹米150mg·kg-1,记录各组小鼠惊厥和死亡情况,计算惊厥潜伏期和死亡率。2.3镇痛实验①光辐射热甩尾法:筛选出在正常痛阈中的50只昆明小鼠,随机分5组,分别为甜菜碱低剂量组(0.29g·kg-1)、甜菜碱中剂量组(0.58g·kg-1)、甜菜碱高剂量组(1.16g·kg-1)、阳性对照组(乙酰水杨酸溶液400mg·kg-1)、空白对照组(NS),给药30min、60 min后用辐射热测痛仪测其痛阈值,计算痛阈提高百分率(%)。②用上述相同的分组方法,灌胃给药30min后,每组小鼠腹腔注射(ip)0.6%醋酸溶液,剂量为0.1ml·10g-1,记录10min内各组出现扭体反应的鼠数及小鼠的扭体次数,计算镇痛百分率和抑制扭体反应百分率。2.4急性毒性实验以能够灌的最大浓度和最大容量给小鼠灌胃盐酸甜菜碱泡腾片悬液,观察小鼠灌胃盐酸甜菜碱泡腾片的最大耐受量。结果1盐酸泡腾片的制备最佳工艺和含量测定的结果①根据实验结果显示:运用非水制粒法制备盐酸甜菜碱泡腾片最佳,最优的处方为:盐酸甜菜碱(10%)、酒石酸(22%)、碳酸氢钠(28%)、乳糖(17.5%)、甘露醇(17.5%)、氯化钠(2%)、聚乙二醇6000(3%)、2%的聚乙烯吡咯烷酮无水乙醇液适量,对制得的盐酸甜菜碱泡腾片进行质量检查,崩解时限、重量差异、脆碎度均符合中国药典规定。②对制得的盐酸甜菜碱泡腾片进行质量检查,崩解时限、重量差异、脆碎度均符合中国药典规定。加速试验预计产品有效期为2年。2盐酸甜菜碱泡腾片对小鼠中枢神经系统作用和急性毒性研究结果①在研究盐酸甜菜碱泡腾片的镇静作用时采用了小鼠的自主活动实验,实验结果表明:与空白对照组相比,地西泮在30min、60min后对小鼠的自由活动均有明显的抑制作用,盐酸甜菜碱低剂量(0.29g·kg-1)和中剂量(0.58g·kg-1)组与空白对照组相比可以减少小鼠自主活动的次数,但是下降的趋势没有统计学意义,盐酸甜菜碱高剂量组(1.16g·kg-1),在两个时段后对小鼠的自主活动有显著性的抑制(P0.01)。②在对小鼠催眠实验的研究中,与空白对照组相比,阳性对照组能显著性地缩短小鼠的入睡时间,增加入睡的小鼠只数;但在甜菜碱的三个浓度中,只有高浓度的甜菜碱能显著性缩短小鼠的入睡时间和入睡率(P0.05);其余的两个组有缩短小鼠的入睡时间增加入睡率的趋势,但都不具有统计学意义。③在注射戊巴比妥钠后,与空白对照组相比较,阳性对照组能显著性缩短小鼠的催眠潜伏期,延长睡眠时间;甜菜碱的三个剂量组也能明显的延长小鼠的睡眠时间,但只有高剂量组能明显地缩短小鼠催眠潜伏期(P0.01)。④在注射尼可刹米致惊厥的实验中,与空白对照组比较,戊巴比妥钠阳性对照组能大幅度延长小鼠的惊厥潜伏期,减少小鼠死亡率;甜菜碱中、高剂量组能明显延长小鼠惊厥潜伏期,降低小鼠的死亡率(P0.01)。⑤运用甩尾法和扭体法研究甜菜碱对小鼠的镇痛作用的实验结果表明:在甩尾法中,与对照组相比较,阳性对照组在30min、60min后都延长了小鼠的药后痛阈,甜菜碱中只有高剂量时能延长两个时间点后的药后痛阈(P0.05),其余的两个剂量虽有延长的趋势但不具有统计学意义。在扭体法中,甜菜碱的低、中、高剂量均能降低小鼠的扭体反应次数,增加小鼠的镇痛百分率,但只有高剂量的甜菜碱具有统计学意义,并且其镇痛效果要高于阳性对照组。证明甜菜碱泡腾片对小鼠有镇痛作用。⑥在小鼠的急性毒性研究中,随着甜菜碱所用剂量的升高,与对照组相比较,小鼠的死亡率也在逐渐升高。结论1运用非水制粒法制备盐酸甜菜碱泡腾片最佳,且最佳处方为:盐酸甜菜碱(10%)、酒石酸(22%)、碳酸氢钠(28%)、乳糖(17.5%)、甘露醇(17.5%)、氯化钠(2%)、聚乙二醇6000(3%)、2%的聚乙烯吡咯烷酮无水乙醇液适量。2对制得的盐酸甜菜碱泡腾片进行质量检查,崩解时限、重量差异、脆碎度均符合中国药典规定。加速试验预计产品有效期为2年。3盐酸甜菜碱泡腾片有镇静、催眠、抗惊厥、镇痛的药理作用。4小鼠灌胃盐酸甜菜碱泡腾片的最大耐受量为1.05g/kg。
[Abstract]:OBJECTIVE To study the formulation, technology and preparation method of betaine hydrochloride effervescent tablets, establish a preliminary quality evaluation method and investigate its quality, observe the pharmacological effect and acute toxicity of betaine hydrochloride effervescent tablets on the central nervous system, and provide experimental basis for the research and development of betaine hydrochloride effervescent tablets. Preparation and quality evaluation of the fixed prescription of betaine hydrochloride dosage, through a comprehensive study of the preparation disintegration time, hardness, brittleness, appearance and other factors, preliminary screening effervescent agent, filler, lubricant, adhesives and dosage. The quality standard of betaine hydrochloride effervescent tablets was established preliminarily. 2. Neurological effects and acute toxicity of betaine hydrochloride effervescent tablets 2. 1 Sedative and hypnotic test. Mice were randomly divided into blank control group (NS), diazepam group (2.0mg Low, medium and high dose groups (0.29 g 65507 The hypnotic dose of sodium pentobarbital (40mg Fifty Kunming mice with normal pain threshold were randomly divided into 5 groups: low dose group of betaine (0.29g 6550 16g 6550 The number of mice with writhing reaction and the number of writhing times of mice in each group within 10 minutes were counted. The percentage of analgesia and the percentage of inhibition of writhing reaction were calculated. 2.4 Acute toxicity test was used to observe the maximum tolerance of mice by gastric administration of betaine hydrochloride effervescent tablets. The best preparation technology and content determination of acid effervescent tablets were as follows: (1) According to the experimental results, the preparation of Betaine Hydrochloride Effervescent Tablets by non-aqueous granulation method was the best. The optimal prescription was betaine hydrochloride (10%), tartaric acid (22%), sodium bicarbonate (28%), lactose (17.5%), mannitol (17.5%), sodium chloride (2%), polyethylene glycol (3%) and polyethylene pyrrole (2%). The quality of the prepared betaine hydrochloride effervescent tablets was inspected with proper amount of ketolane anhydrous ethanol solution. The disintegration time limit, weight difference and fragility of the tablets were in accordance with the provisions of the Chinese Pharmacopoeia. 2 The quality of the prepared betaine hydrochloride effervescent tablets was inspected with disintegration time limit, weight difference and fragility in accordance with the provisions of the Chinese Pharmacopoeia. Effect of betaine hydrochloride effervescent tablets on central nervous system and acute toxicity in mice Inhibitory effect of betaine hydrochloride low dose (0.29 g kg 1) and medium dose (0.58 g kg 1) group compared with the blank control group can reduce the number of spontaneous activities of mice, but the trend of decline was not statistically significant. High dose of betaine hydrochloride group (1.16 g kg 1) significantly inhibited the spontaneous activities of mice after two periods (P 0.01). (2) In the study of mouse hypnosis experiment, compared with the blank control group, the positive control group can significantly shorten the sleep time of mice, increase the number of mice to sleep; but in the three concentrations of betaine, only high concentration of betaine can significantly shorten the sleep time and sleep rate of mice (P 0.05); the other two groups have shortened the sleep time and sleep rate (P 0.05); After injection of pentobarbital sodium, the positive control group could significantly shorten the hypnotic latency and prolong the sleep time of mice, and the three doses of betaine could also significantly prolong the sleep time of mice, but only the high dose of betaine could prolong the sleep time of mice. The hypnotic latency of mice was significantly shortened in dose group (P 0.01). (4) In the convulsion induced by nicotinamide injection, compared with the blank control group, the pentobarbital sodium positive control group could significantly prolong the convulsion latency and reduce the mortality of mice; in betaine, the high dose group could significantly prolong the convulsion latency and reduce the death of mice. Mortality (P 0.01). _The analgesic effect of betaine on mice was studied by tail flick method and writhing method. The results showed that in tail flick method, compared with the control group, the positive control group prolonged the pain threshold of mice after 30 minutes and 60 minutes. Only high dose of betaine could prolong the pain threshold after two time points (P 0.05), the rest. In the writhing method, low, medium and high doses of betaine can reduce the writhing reaction times and increase the analgesic percentage of mice, but only high doses of betaine have statistical significance, and its analgesic effect is higher than that of the positive control group. _In the study of acute toxicity of betaine in mice, the mortality of mice increased gradually with the increase of the dosage of betaine compared with the control group. Conclusion 1 The best preparation of Betaine Hydrochloride Effervescent Tablets by non-aqueous granulation is the best, and the best prescription is: betaine hydrochloride (10%), tartaric acid (22%), sodium bicarbonate (28%), lactose. Sugar (17.5%), mannitol (17.5%), sodium chloride (2%), polyethylene glycol 6000 (3%) and 2% polyvinylpyrrolidone anhydrous ethanol were used to examine the quality of betaine hydrochloride effervescent tablets. The disintegration time, weight difference and fragility of the effervescent tablets were all in accordance with the Chinese Pharmacopoeia. Pharmacological effects of sedation, hypnosis, anticonvulsion and analgesia. 4 The maximum tolerance of betaine hydrochloride effervescent tablets in mice was 1.05g/kg.
【学位授予单位】：泰山医学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R943;R96

【参考文献】