【摘要】：目的研究鹽酸甜菜堿泡騰片的處方、工藝和制備方法,建立初步質(zhì)量評(píng)價(jià)方法并考察其質(zhì)量,觀察鹽酸甜菜堿泡騰片對(duì)中樞神經(jīng)系統(tǒng)的藥理作用及急性毒性反應(yīng),為鹽酸甜菜堿泡騰片的研究開發(fā)提供實(shí)驗(yàn)依據(jù)。方法1鹽酸甜菜堿泡騰片的制備與質(zhì)量評(píng)價(jià)固定處方中鹽酸甜菜堿的用量,通過(guò)綜合考察制劑的崩解時(shí)限、硬度、脆碎度、外觀等因素,初步篩選出泡騰劑、填充劑、潤(rùn)滑劑、粘合劑的種類及用量。采用正交設(shè)計(jì)方法進(jìn)行處方優(yōu)化,確定工藝操作簡(jiǎn)單、制劑質(zhì)量穩(wěn)定的最佳處方。按中國(guó)藥典2010版二部附錄IA,對(duì)制劑質(zhì)量進(jìn)行評(píng)價(jià),初步建立鹽酸甜菜堿泡騰片的質(zhì)量標(biāo)準(zhǔn)。2鹽酸甜菜堿泡騰片的神經(jīng)藥理作用與急性毒性研究2.1鎮(zhèn)靜催眠實(shí)驗(yàn)①取小鼠隨機(jī)分為空白對(duì)照組(NS)、地西泮組(2.0mg·kg-1)、甜菜堿低、中、高劑量組(0.29g·kg-1、0.58g·kg-1、1.16g·kg-1),觀察記錄灌胃給藥后不同時(shí)間小鼠的自主活動(dòng);②分組同“①”,灌胃給藥30min后,腹腔注射催眠閾下劑量的戊巴比妥鈉(25mg·kg-1),觀察小鼠翻正反射消失情況。③分組同“①”,灌胃給藥30min后,腹腔注射催眠劑量的戊巴比妥鈉(40mg·kg-1),觀察各組小鼠的催眠潛伏期及睡眠時(shí)間。2.2抗驚厥實(shí)驗(yàn)取小鼠隨機(jī)分為對(duì)照組(NS)、戊巴比妥鈉組(25mg·kg-1)、甜菜堿低、中、高劑量組(0.29g·kg-1、0.58g·kg-1、1.16g·kg-1),灌胃給藥30min后,腹腔注射尼可剎米150mg·kg-1,記錄各組小鼠驚厥和死亡情況,計(jì)算驚厥潛伏期和死亡率。2.3鎮(zhèn)痛實(shí)驗(yàn)①光輻射熱甩尾法:篩選出在正常痛閾中的50只昆明小鼠,隨機(jī)分5組,分別為甜菜堿低劑量組(0.29g·kg-1)、甜菜堿中劑量組(0.58g·kg-1)、甜菜堿高劑量組(1.16g·kg-1)、陽(yáng)性對(duì)照組(乙酰水楊酸溶液400mg·kg-1)、空白對(duì)照組(NS),給藥30min、60 min后用輻射熱測(cè)痛儀測(cè)其痛閾值,計(jì)算痛閾提高百分率(%)。②用上述相同的分組方法,灌胃給藥30min后,每組小鼠腹腔注射(ip)0.6%醋酸溶液,劑量為0.1ml·10g-1,記錄10min內(nèi)各組出現(xiàn)扭體反應(yīng)的鼠數(shù)及小鼠的扭體次數(shù),計(jì)算鎮(zhèn)痛百分率和抑制扭體反應(yīng)百分率。2.4急性毒性實(shí)驗(yàn)以能夠灌的最大濃度和最大容量給小鼠灌胃鹽酸甜菜堿泡騰片懸液,觀察小鼠灌胃鹽酸甜菜堿泡騰片的最大耐受量。結(jié)果1鹽酸泡騰片的制備最佳工藝和含量測(cè)定的結(jié)果①根據(jù)實(shí)驗(yàn)結(jié)果顯示:運(yùn)用非水制粒法制備鹽酸甜菜堿泡騰片最佳,最優(yōu)的處方為:鹽酸甜菜堿(10%)、酒石酸(22%)、碳酸氫鈉(28%)、乳糖(17.5%)、甘露醇(17.5%)、氯化鈉(2%)、聚乙二醇6000(3%)、2%的聚乙烯吡咯烷酮無(wú)水乙醇液適量,對(duì)制得的鹽酸甜菜堿泡騰片進(jìn)行質(zhì)量檢查,崩解時(shí)限、重量差異、脆碎度均符合中國(guó)藥典規(guī)定。②對(duì)制得的鹽酸甜菜堿泡騰片進(jìn)行質(zhì)量檢查,崩解時(shí)限、重量差異、脆碎度均符合中國(guó)藥典規(guī)定。加速試驗(yàn)預(yù)計(jì)產(chǎn)品有效期為2年。2鹽酸甜菜堿泡騰片對(duì)小鼠中樞神經(jīng)系統(tǒng)作用和急性毒性研究結(jié)果①在研究鹽酸甜菜堿泡騰片的鎮(zhèn)靜作用時(shí)采用了小鼠的自主活動(dòng)實(shí)驗(yàn),實(shí)驗(yàn)結(jié)果表明:與空白對(duì)照組相比,地西泮在30min、60min后對(duì)小鼠的自由活動(dòng)均有明顯的抑制作用,鹽酸甜菜堿低劑量(0.29g·kg-1)和中劑量(0.58g·kg-1)組與空白對(duì)照組相比可以減少小鼠自主活動(dòng)的次數(shù),但是下降的趨勢(shì)沒(méi)有統(tǒng)計(jì)學(xué)意義,鹽酸甜菜堿高劑量組(1.16g·kg-1),在兩個(gè)時(shí)段后對(duì)小鼠的自主活動(dòng)有顯著性的抑制(P0.01)。②在對(duì)小鼠催眠實(shí)驗(yàn)的研究中,與空白對(duì)照組相比,陽(yáng)性對(duì)照組能顯著性地縮短小鼠的入睡時(shí)間,增加入睡的小鼠只數(shù);但在甜菜堿的三個(gè)濃度中,只有高濃度的甜菜堿能顯著性縮短小鼠的入睡時(shí)間和入睡率(P0.05);其余的兩個(gè)組有縮短小鼠的入睡時(shí)間增加入睡率的趨勢(shì),但都不具有統(tǒng)計(jì)學(xué)意義。③在注射戊巴比妥鈉后,與空白對(duì)照組相比較,陽(yáng)性對(duì)照組能顯著性縮短小鼠的催眠潛伏期,延長(zhǎng)睡眠時(shí)間;甜菜堿的三個(gè)劑量組也能明顯的延長(zhǎng)小鼠的睡眠時(shí)間,但只有高劑量組能明顯地縮短小鼠催眠潛伏期(P0.01)。④在注射尼可剎米致驚厥的實(shí)驗(yàn)中,與空白對(duì)照組比較,戊巴比妥鈉陽(yáng)性對(duì)照組能大幅度延長(zhǎng)小鼠的驚厥潛伏期,減少小鼠死亡率;甜菜堿中、高劑量組能明顯延長(zhǎng)小鼠驚厥潛伏期,降低小鼠的死亡率(P0.01)。⑤運(yùn)用甩尾法和扭體法研究甜菜堿對(duì)小鼠的鎮(zhèn)痛作用的實(shí)驗(yàn)結(jié)果表明:在甩尾法中,與對(duì)照組相比較,陽(yáng)性對(duì)照組在30min、60min后都延長(zhǎng)了小鼠的藥后痛閾,甜菜堿中只有高劑量時(shí)能延長(zhǎng)兩個(gè)時(shí)間點(diǎn)后的藥后痛閾(P0.05),其余的兩個(gè)劑量雖有延長(zhǎng)的趨勢(shì)但不具有統(tǒng)計(jì)學(xué)意義。在扭體法中,甜菜堿的低、中、高劑量均能降低小鼠的扭體反應(yīng)次數(shù),增加小鼠的鎮(zhèn)痛百分率,但只有高劑量的甜菜堿具有統(tǒng)計(jì)學(xué)意義,并且其鎮(zhèn)痛效果要高于陽(yáng)性對(duì)照組。證明甜菜堿泡騰片對(duì)小鼠有鎮(zhèn)痛作用。⑥在小鼠的急性毒性研究中,隨著甜菜堿所用劑量的升高,與對(duì)照組相比較,小鼠的死亡率也在逐漸升高。結(jié)論1運(yùn)用非水制粒法制備鹽酸甜菜堿泡騰片最佳,且最佳處方為:鹽酸甜菜堿(10%)、酒石酸(22%)、碳酸氫鈉(28%)、乳糖(17.5%)、甘露醇(17.5%)、氯化鈉(2%)、聚乙二醇6000(3%)、2%的聚乙烯吡咯烷酮無(wú)水乙醇液適量。2對(duì)制得的鹽酸甜菜堿泡騰片進(jìn)行質(zhì)量檢查,崩解時(shí)限、重量差異、脆碎度均符合中國(guó)藥典規(guī)定。加速試驗(yàn)預(yù)計(jì)產(chǎn)品有效期為2年。3鹽酸甜菜堿泡騰片有鎮(zhèn)靜、催眠、抗驚厥、鎮(zhèn)痛的藥理作用。4小鼠灌胃鹽酸甜菜堿泡騰片的最大耐受量為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.
【學(xué)位授予單位】：泰山醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R943;R96

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