CN1327835C - 水飞蓟素口腔崩解片及其制备方法 - Google Patents
水飞蓟素口腔崩解片及其制备方法 Download PDFInfo
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- CN1327835C CN1327835C CNB2004100627438A CN200410062743A CN1327835C CN 1327835 C CN1327835 C CN 1327835C CN B2004100627438 A CNB2004100627438 A CN B2004100627438A CN 200410062743 A CN200410062743 A CN 200410062743A CN 1327835 C CN1327835 C CN 1327835C
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- silymarin
- disintegration tablet
- tablet
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- hepedestal
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Abstract
本发明涉及一种水飞蓟素口腔崩解片及其制备工艺，以水飞蓟素为原料，填充剂、崩解剂、矫味剂、助流剂、润滑剂等为辅料，根据不同情况可使用粘合剂，也可酌情加入适量泡腾剂，其特征在于以丙烯酸树脂类作为包衣材料，水飞蓟素经粉末包衣制得水飞蓟素粉末包衣颗粒，再与其它组分混匀、压片，得到崩解片。本发明的口腔崩解片脆碎度良好，崩解迅速，口感好，无砂砾感，不需要特殊的生产条件；具有生产成本低，携带、储藏、运输和服用方便等特点；特别适用于吞咽困难的患者或在无水条件下服用，改善患者的依从性，提高药物的疗效。
Description
[技术领域]本发明涉及一种具有明显的保护和稳定肝细胞的作用，用于治疗急慢性肝炎、肝硬化、肝中毒等病症的水飞蓟素制剂，尤其涉及一种具有速释作用的水飞蓟素口腔崩解片制剂。
[背景技术]水飞蓟素是由菊科药用植物水飞蓟种籽经科学方法精制而成的黄酮类化合物，为淡黄色或结晶性粉末。味微苦而甜，无臭，易溶于丙酮、乙酸乙酯、乙醇及甲醇，难溶于氯仿，不溶于水，其主要成分为水飞蓟宾、异水飞蓟宾、水飞蓟亭、飞水蓟宁等。具有保肝、抗辐射及降血脂等作用。应用范围由预防、治疗急慢性肝炎扩展到抗衰老、防治动脉粥样硬化等方面。
水飞蓟素经过近30年的临床检验，证明该药的确切疗效和极低的毒性。归纳该药的主要作用特点有以下几点：
1抗自由基活性 水飞蓟素对于由CCl4、半乳糖胺、醇类和其它肝毒素(如Amanita phalleodes)造成的肝损害有保护作用。
2抗脂质过氧化作用 水飞蓟素和水飞蓟宾为抗氧自由基活性物质。其抗脂质过氧化的作用已经被实验证实。水飞蓟自己本身能作为自由基清除剂，特别是对由细胞色素P45201E1代谢激活所生成的乙氧基自由基有较强的清除作用。通过灭活这些自由基，水飞蓟素阻碍这些自由基与不饱和脂肪酸的作用。水飞蓟素能使肝中总谷胱甘肽增加32％。
3抗脂氧酶作用 实验表明水飞蓟素在体内有较强的抗炎作用，正是由于水飞蓟素的抗自由基作用，使其能抑制环氧酶和脂氧酶，并预示水飞蓟素除保肝作用外，还可作为抗炎药物使用。有研究结果表明水飞蓟宾同槲皮素一样，具有抑制脑血管内5-脂氧酶合成和释放LT的作用，这揭示水飞蓟宾对脑缺血具有保护作用。
4抗谷胱甘肽排空作用 水飞蓟素不同于其它抗氧化的黄酮类似物，它可以增加肝和其它组织中谷胱甘肽水平。已发现服用水飞蓟素后，在肝、肠、胃等消化器官中，谷胱甘肽增加，说明水飞蓟素能增加氨基酸的内脏通透性，这使谷胱甘肽合成增加，并且抑制由胆汁释放谷胱甘肽。在非消化器如肺、脾、肾等器官，水飞蓟素不能影响其水平变化，在肾中其谷胱甘肽水平稍有降低，这说明肾在体内是一个血浆谷胱甘肽降解的主要部位。水飞蓟素使谷胱甘肽在消化器官内增加，可以保护上述组织免受异生物质的损害，起到解毒作用。
5抗肿瘤作用 各种活性氧能氧化鸟嘌呤形成8-羟基鸟嘌呤，造成DNA损伤，进而引起肿瘤，应用抗氧化剂，特别是自由基清除剂可以防止这一过程的发生。
水飞蓟素作为一个有效的抗自由基物质也显示了预防和治疗恶性肿瘤的作用。表明水飞蓟素的保肝作用机制可能与其抑制TNF的产生和活性有关。
6降血脂作用 动脉粥样硬化(atherosclerosis)是心、脑血管病的重要病理基础，血浆脂质代谢紊乱是动脉粥样硬化形成的重要危险因素。大量临床试验证明，血浆甘油三酯(TC)和低密度脂蛋白-胆固醇(LDL-C)水平升高或高密度脂蛋白-胆固醇(HDL-C)水平下降，都会使冠心病的危险性增加，与此相反，降低血浆TC和LDL-C水平或升高HDL-C水平，可延缓动脉粥样硬化病变的进展，减少冠心病的危险性。极低密度脂蛋白(VLDL)和TC可能不是独立的危险因素，但是它们与心血管病的死亡率也有明显联系，所以，调整和控制血脂水平是降低动脉粥样硬化发病率和死亡率的重要手段之一。水飞蓟素体外实验具有抑制3-羟基-3-甲基戊二酰辅酶A的作用。Krecman等人研究水飞蓟素对高胆固醇饮食小鼠引起血胆固醇过多症的抑制并以丙丁酚作对照药。其结果表明：水飞蓟素和丙丁酚对总胆固醇和VLDL-C和LDL-C及亚型HDLa和HDLb都有显著升高作用，但丙丁酚只有降低作用。
水飞蓟素由于其难溶性，导致其生物利用度较低。目前水飞蓟素制剂的剂型主要有普通片、分散片、硬胶囊、软胶囊、液体胶囊和滴丸等剂型。尚未发现有水飞蓟素的口腔崩解片制剂或有关文献。将水飞蓟素制成口腔崩解片，有利于提高水飞蓟素的生物利用度，进而提高其疗效。
[发明内容]本发明的目的在于改进现有的水飞蓟素在口服剂型方面的的不足，向广大患者和医务工作者提供一种服用方便、吸收起效快、生物利用度高的水飞蓟素口腔崩解片制剂。本发明涉及服用时不必饮水、在口腔中仅需几十秒即可迅速崩解或溶解、随唾液下咽即可完成服药的水飞蓟素口腔崩解片及其制备方法。
一、处方
本发明所述及的水飞蓟素口腔崩解片，包括原料药物水飞蓟素，共需要以下9类原、辅材料，其中：不作包衣处理时，则不使用包衣材料，泡腾剂为酌情可选用辅料，也可不用。
对于不作包衣处理时，处方组成：水飞蓟素(5-50)％，粘合剂(0-5)％，填充剂(10-80)％，崩解剂(2-35)％，矫味剂(1-40)％，泡腾剂(0-30)％，助流剂(0.01-5)％，润滑剂(0.3-3)％。
进行包衣处理时，本发明的水飞蓟素口腔崩解片，通过水飞蓟素粉末包衣制得水飞蓟素粉末包衣颗粒，再与其它组分混匀、压片，得到崩解片，即所述的水飞蓟素口腔崩解片，由水飞蓟素、填充剂、崩解剂、矫味剂、助流剂、润滑剂、包衣材料、任选存在的粘合剂、任选存在的泡腾剂组成，其中，以重量百分含量计算，水飞蓟素5％～50％，填充剂10％～80％，崩解剂2％～35％，矫味剂1％～40％，助流剂0.01％～5％，润滑剂0.3％～3％，粘合剂0～5％，泡腾剂0～30％，包衣材料不超过40％，其特征在于：所述的包衣材料为丙烯酸树脂类，水飞蓟素通过粉末包衣制得水飞蓟素粉末包衣颗粒，再与其它组分混匀、压片制得崩解片。
上述所述的崩解片，其中：
粘合剂包括但不仅限于淀粉、预胶化淀粉、糊精、麦芽糖糊精、蔗糖、阿拉伯胶、甲基纤维素、羧甲基纤维素、乙基纤维素、聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮(PVP)、海藻酸及海藻酸盐、黄原胶和羟丙基甲基纤维素(HPMC)，可单独使用，也可组合使用。
填充剂包括但不仅限于甘露醇(粒状或粉状)、木糖醇、山梨醇、麦芽糖、微晶纤维素、聚合糖(EMDEX)、葡萄糖、乳糖、蔗糖、糊精和淀粉等，可以单独使用，也可以组合应用，用量通常为(10-80)％。
崩解剂包括但不仅限于交联聚乙烯吡咯烷酮(PVPP)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基甲基纤维素(L-HPC)、交联羧甲基纤维素钠(CCNa)和大豆多糖(EMCOSOY)等，可单独使用，也可组合使用。
矫味剂包括但不仅限于甘露醇、木糖醇、甜菊甙、乳糖、果糖、蔗糖、蛋白糖、麦芽糖醇、甘草甜素、环己氨基磺酸钠、明胶、阿斯巴甜、香蕉香精、菠萝香精、香兰素、香橙香精、桔子香精、薄荷香精、人参香精、草莓香精、枸橼酸、柠檬酸等，可单独使用，也可组合使用。
助流剂 包括但不仅限于微粉硅胶、滑石粉、Cab-O-sil、Arosil、水合硅铝酸钠等，可单独使用，也可组合使用。
润滑剂 包括但不仅限于硬脂酸镁、硬脂酸钙、硬脂酸锌、单硬脂酸甘油脂、聚乙二醇、氢化植物油、硬脂富马酸钠、聚氧乙烯单硬脂酸酯、单月桂蔗糖酸酯、月桂醇硫酸钠、月桂醇硫酸妹、十二烷基硫酸镁和滑石粉等，可单独使用，也可组合使用。
泡腾剂 包括但不仅限于苹果酸、柠檬酸或枸橼酸与碳酸氢钠或碳酸钠的混合物。
丙烯酸树脂类，为国产丙烯酸树脂I、II、III或IV，或者Eudragit系列，例如EudragitE100。
二、制备方法
本发明所述及的水飞蓟素口腔崩解片，其制备方法为直接压片法，具有制备常规片剂的生产厂家均可采用。
水飞蓟素味微苦而甜，本发明可采用二种不同方法进行矫味或掩味：①采用矫味剂直接矫味；②预先将水飞蓟素进行粉末包衣以掩味。
具体制备方法如下：
第一步水飞蓟素的预处理方法：
①直接矫味法——本法对水飞蓟素原料进行制粒或不作处理，直接进入第二步；
②粉末包衣掩味——取所选定的包衣材料，用与之相适应的溶媒溶解并稀释至适当浓度备用，再取水飞蓟素置于沸腾床中使沸腾，然后以适当速度喷入上述溶液进行粉末包衣，得水飞蓟素粉末包衣颗粒，干燥后过筛备用；
第二步将矫味剂与水飞蓟素或经第一步掩味处理后的原料颗粒按量称取，并混合均匀备用；
第三步将填充剂、崩解剂、泡腾剂、助流剂按量称取并混合均匀，再与经第二步所得之物料混合使均匀，加入润滑剂混匀备用；
第四步所得物料经中间体检测，确定片重后，送入压片机压片即得。
粉末包衣制备水飞蓟素口腔崩解片的具体制备方法如下：
第一步取所选定的包衣材料，用与之相适应的溶媒溶解并稀释至适当浓度备用；
第二步再取水飞蓟素置于沸腾床中使沸腾，然后以适当速度喷入上述溶液进行粉末包衣，得水飞蓟素粉末包衣颗粒，干燥后过筛备用；
第三步将填充剂、崩解剂、泡腾剂、助流剂、矫味剂按量称取并混合均匀，再与经第二步所得之物料混合使均匀，加入润滑剂混匀备用；
第四步所得物料经中间体检测，确定片重后，送入压片机压片即得。
[有益效果]片剂是一种传统剂型，因其质量稳定、剂量准确、服用、携带方便、机械化程度高、生产成本低而成为目前最常用的剂型之一，但因片剂加压成型，崩解较慢、生物利用度较低，且部分患者吞服较为困难，因而片剂的推广使用在一定程度上受到限制。为此口服固体速释制剂成为近年新药研发的一个热点，特别是口腔崩解片，因其服用方便、起效快、生物利用度高、口感好而成为片剂开发的重点。
口腔崩解片是指不需用水或只需少量水，无需咀嚼，片剂置于舌面，遇唾液迅速解或崩后，借吞咽动力，药物即可入胃起效的片剂。口腔崩解片的特点是吸收快、生物利用度高，肠道残留少，副作用低，避免肝脏首过效应等。
据《口腔崩解片的剂型特点和质量控制会议纪要》的要求，口腔崩解片比滴丸和普通片的崩解速度有本质的飞跃，口腔崩解片的崩解一般在30秒以内，最多不超过1分钟。而滴丸剂中国药典规定的溶散时限为30分钟内，普通片剂中国药典规定的崩解时限为5分钟左右全部溶散。
[具体实施例]为了更好的说明本发明所述水飞蓟素口腔崩解片的制备方法，结合直接矫味法和粉末包衣掩味法分别举一个实施例如下：
实施例一直接矫味法
一.处方
1.原料——水飞蓟素(80％)96.3g；
2.粘合剂——聚乙烯吡咯烷酮K-30 4.8g；
3.填充剂——甘露醇326.1g；
4.矫味剂——阿斯巴甜4.8g；
5.崩解剂——交联聚乙烯吡咯烷酮14.4g；
L-HPC 24.0g；
6.助流剂——微粉硅胶4.8g；
7.润滑剂——硬脂富马酸钠4.8g。
总重480g，共制成2000片，240mg/片。
二.制备方法
1)取水飞蓟素原料粉碎，用聚乙烯吡咯烷酮K-30制粒，过26目筛，备用；
2)将微粉硅胶和阿斯巴甜，分别过40目筛，混合均匀，再加入已制粒的水飞蓟素颗粒，混合均匀，备用；
3)取甘露醇、L-HPC和交联聚乙烯吡咯烷酮分别过40目筛，混合均匀，再将经矫味的原料加入并混合均匀，最后加入硬脂富马酸钠并混合均匀；
4)中间体含量检测，确定片重后，送入压片机压片即得。
实施例二粉末包衣掩味法
一.处方
1.原料——水飞蓟素(80％)96.3g；
2.包衣材料——EudragitE100 15.0g；
3.填充剂——甘露醇312.7g；
4.矫味剂——阿斯巴甜2.0g；
人参香精3.0g；
5.崩解剂——交联聚乙烯吡咯烷酮15.0g；
L-HPC 25.0g；
6.助流剂——微粉硅胶7.0g；
7.润滑剂——硬脂富马酸钠4.0g。
总重480g，共制成2000片，240mg/片。
二.制备方法
1)取EudragitE100用95％以上的药用工业乙醇溶解并稀释至一定浓度备用；
2)取水飞蓟素置于沸腾床中沸腾，按一定速度喷入上述溶液进行粉末包衣，制得水飞蓟素粉末包衣颗粒，干燥后备用；
3)将甘露醇、微粉硅胶、PVPP、L-HPC、阿斯巴甜、硬脂富马酸钠和人参香精混合均匀，再和过筛后的包衣颗粒混匀备用；
4)中间体含量检测，确定片重后，送入压片机压片即得。
上述实施例的崩解时限和片子硬度数值如下：
| 实施例 | 崩解时限(秒) | 片子硬度(牛顿) |
| 12 | 13-3214-35 | 15-2716-29 |
Claims (8)
1.一种具有治疗或预防急或慢性肝炎、迁延性肝炎或降血脂功效的水飞蓟素口腔崩解片，由水飞蓟素、填充剂、崩解剂、矫味剂、助流剂、润滑剂、包衣材料、任选存在的粘合剂、任选存在的泡腾剂组成，其中，以重量百分含量计算，水飞蓟素5％～50％，填充剂10％～80％，崩解剂2％～35％，矫味剂1％～40％，助流剂0.01％～5％，润滑剂0.3％～3％，粘合剂0～5％，泡腾剂0～30％，包衣材料不超过40％，其特征在于：所述的包衣材料为丙烯酸树脂类，水飞蓟素通过粉末包衣制得水飞蓟素粉末包衣颗粒，再与其它组分混匀、压片制得崩解片。
2.根据权利要求1所述的水飞蓟素口腔崩解片，其中：
所述的粘合剂选自淀粉、预胶化淀粉、糊精、麦芽糖糊精、蔗糖、阿拉伯胶、甲基纤维素、羧甲基纤维素、乙基纤维素、聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮、海藻酸或海藻酸盐、黄原胶、羟丙基甲基纤维素中的一种或多种；
所述的填充剂选自甘露醇、木糖醇、山梨醇、麦芽糖、微晶纤维素、聚合糖、葡萄糖、乳糖、蔗糖、糊精、淀粉中的一种或多种；
所述的崩解剂选自交联聚乙烯吡咯烷酮、羧甲基淀粉钠、低取代羟丙基甲基纤维素、交联羧甲基纤维素钠、大豆多糖中的一种或多种；
所述的矫味剂选自甘露醇、木糖醇、甜菊甙、乳糖、果糖、蔗糖、蛋白糖、麦芽糖醇、甘草甜素、环己氨基磺酸钠、明胶、阿斯巴甜、香蕉香精、菠萝香精、香兰素、香橙香精、桔子香精、薄荷香精、人参香精、草莓香精、枸橼酸、柠檬酸中的一种或多种；
所述的助流剂选自微粉硅胶、滑石粉、水合硅铝酸钠中的一种或多种；
所述的润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸锌、单硬脂酸甘油脂、聚乙二醇、氢化植物油、硬脂富马酸钠、聚氧乙烯单硬脂酸酯、单月桂蔗糖酸酯、月桂醇硫酸钠、月桂醇硫酸镁、十二烷基硫酸镁和滑石粉中的一种或多种；
所述的泡腾剂为苹果酸、柠檬酸或者枸橼酸与碳酸氢钠或者碳酸钠的混合物。
3.根据权利要求1或2所述的水飞蓟素口腔崩解片，其中所述的丙烯酸树脂类为国产丙烯酸树脂I、II、III或IV，或者Eudragit系列。
4.根据权利要求3所述的水飞蓟素口腔崩解片，其中所述的Eudragit系列为EudragitE100。
5.一种用于权利要求1所述的水飞蓟素口腔崩解片的制备方法，其特征在于由以下步骤组成：
第一步取所选定的包衣材料，用与之相适应的溶媒溶解并稀释至适当浓度备用；
第二步再取水飞蓟素置于沸腾床中使沸腾，然后以适当速度喷入上述溶液进行粉末包衣，得水飞蓟素粉末包衣颗粒，干燥后过筛备用；
第三步将填充剂、崩解剂、泡腾剂、助流剂、矫味剂按量称取并混合均匀，再与经第二步所得之物料混合使均匀，加入润滑剂混匀备用；
第四步所得物料经中间体检测，确定片重后，送入压片机压片即得。
6.根据权利要求5所述的方法，其中，所述的包衣材料为EudragitE100。
7.根据权利要求5所述的方法，其特征在于获得的片剂的硬度在10至45牛顿之间，崩解时间在1-60秒内。
8.根据权利要求5所述的方法，其特征在于其采用直接压片法。
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| CN1883456B (zh) * | 2005-06-20 | 2010-12-15 | 常州市第四制药厂有限公司 | 掩味药物颗粒及其制备方法和用途 |
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| CN102018700B (zh) * | 2009-09-22 | 2014-10-22 | 上海生物医药公共技术服务公司 | 含水飞蓟素的药物制剂及其制备方法 |
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