CN101716180B - 一种组合补充锌、钙药物及其制备方法 - Google Patents
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Abstract
发明一种组合补充锌、钙药物及其制法,药物成分定部位释放。制法的步骤是:取葡萄糖酸锌,维生素D,加入药用淀粉、微晶纤维素,混合,加入粉碎好的微粉硅胶混合均匀,分装成肠溶胶囊;将水溶性醋酸钙、药用淀粉、微晶纤维素、混合,加入粉碎好的微粉硅胶混合均匀,分装成清真胶囊。本药物和制法保证维生素D在酸性环境下不被破坏;避免了葡萄糖酸锌对胃部的直接刺激;阻断了维生素E与氧的直接接触。患者同时服用两种胶囊后,维生素E和醋酸钙的有效成分会在胃内迅速崩解、吸收;维生素D和葡萄糖酸锌会在肠内崩解、吸收,具有药物起效、生物利用度高、副作用小等特点,特别适用于儿童、孕妇、成年和老年人长期补充服用。
Description
技术领域:
本发明涉及一种药物及其制备方法,特别是一种组合补充锌、钙药物及其制备方法。
背景技术:
目前,我国国民钙摄入存在两方面问题。一是就总体而言,国民钙摄入量确实偏低。中国营养学会公布的每天钙摄入推荐量为800毫克,青少年及孕妇钙摄入推荐量为1200-1500毫克,但目前国民每天钙摄入量为400毫克左右。二是国民钙摄入量因地区间的差异很大,并非人人缺钙。牧区人群以及豆制品摄入量较高地区人群的钙摄入充足,蛋奶摄入较多的城市人群及沿海食用鱼类较多的人群钙摄入量也比较充足,而内地部分地区尤其是北方农村以米面菜为主食的人群钙摄入量偏低。
一般人饮食中,很容易缺锌,每天的锌摄取量平均在8-12毫克之间,男性比女性稍高。每天的锌摄取量合并食物及补充剂,最好能介于15-25毫克。如果担心食物中的锌含量不足,每天所需摄取锌的补充剂只要有10-15毫克就够了。锌存在于众多的酶系中,如碳酸酐酶,呼吸酶,乳酸脱氢酶,超氧化物歧化酶。碱性磷酸酶,脱氧核糖核酸和核糖核酸聚合酶等,为核酸,蛋白质,碳水化合物的合成和维生素A的利用所必需。锌具有促进生长发育,改善味觉的作用。锌缺乏时出现味觉,嗅觉差,厌食,生长与智力发育低于 正常。
现阶段补锌补钙的药物,品种繁多,功效各异,既有生物活性制剂,也有无机钙锌盐等,但现有的药物有的毒副作用大,有的不能被身体吸收,不适合长期使用,甚至一些无机盐类在体内无法代谢,滞留体内,引发一些病症,这些都不符合补锌补钙用药的特点,未能使药效充分发挥出来。
发明内容:
本发明的目的是发明一种适合长期使用、能被身体吸收、能使药效充分发挥的组合补充锌、钙药物及其制备方法。
本发明组合补充锌、钙药物,其特征在于药物成分定部位释放。
本发明组合补充锌、钙药物的制备方法,其主要步骤是:
(1)取葡萄糖酸锌,维生素D,加入药用淀粉、微晶纤维素,混合,制成软材,16-20目筛制粒,在50℃以下干燥,将微粉硅胶与上述颗粒混合均匀,分装成肠溶胶囊;
(2)将水溶性醋酸钙超微粉碎备用;
(3)将药用淀粉、微晶纤维素、混合备用;
(4)将(2)和(3)的细粉混合,制成软材,16-20目筛制粒,在低温下干燥,加入微粉硅胶混合均匀,分装成清真胶囊。
在分装清真胶囊前还可以加入维生素E。其步骤是:将维生素E加入到β环糊精中,两相配方摩尔比为0.5-1.5∶0.75-1.25,包合时间为10-40min,溶剂为45-75%乙醇,包合物低温干燥制成细粉,与上述(2)和(3)的细粉混合,制成软材,16-20目筛制粒,在低温下干燥,加入微粉硅胶混合均匀,分装成清真胶囊。
通常制2000粒肠溶胶囊,要按Zn2+8-15g计称取固体葡萄糖酸 锌,按D360000-400000IU计称取固体维生素D,加入药用淀粉、微晶纤维素、羧甲基淀粉钠或是其它适宜辅料,混合,制成软材,过筛制粒,在50℃以下干燥,加入润滑剂与干燥好的颗粒混合均匀分装即成。
通常制4000粒清真胶囊,要按Ca2+150-1000g计称取水溶性醋酸钙,加入药用淀粉、微晶纤维素、羧甲基淀粉钠、微粉硅胶制成。加入维生素E时要按维生素E100%计75g折合固体维生素E。
根据处方中各成份的理化性质不同和药物吸收的特点,对维生素D和葡萄糖酸锌混合制粒,装入肠溶胶囊,保证维生素D在酸性环境下不会被破坏;葡萄糖酸锌对胃部直接刺激也会避免。维生素E与β环糊精包裹工艺制备,阻断了维生素E与氧的直接接触,且在胃内崩解吸收,进一步提高了本品的生物利用度。
所制的药物根据不同人群采用不同的配方,第一、儿童补钙加维生素D可以增加有机钙的吸收,减少有机钙的服用量,降低钙质在体内的非药理残留,处方中增加适量锌改善儿童味觉和嗅觉,增加食欲,促进身体生长与智力发育。第二、孕妇补钙相对其它人群钙元素的含量较大且辅助维生素D,可以增加钙质的吸收,严格控制应用原料重金属和有害物质的检测,制剂工艺要求锌和维生素D固定部位释放,合理避免了药物的不良反应,有利于在体内吸收,处方中增加适量锌改善孕妇味觉和嗅觉,增加食欲,促进孕儿的身体生长与智力发育。第三、根据成人在生育期及40岁以后钙质大量流失的特点,尤其女性性激素同时下降明显的特点,钙质加维生素D可以增加有机钙的吸收,促进骨质形成,维持神经传导、肌肉收缩、毛细血管正常渗透压,保持血液酸碱平衡,参与酶的合成和代谢。补 充适量的维生素E和增加锌含量可以提高服用人群的激素水平,增加食欲,减少或消除由于钙质流失和激素水平降低出现的不良症状,降低细胞老化,增加皮肤弹性。保持红细胞的完整性,促进细胞合成,抗污染,促进机体新陈代谢。
根据临床的实际需求和新技术的支撑,可任意调配辅料的种类和用量,也可以探讨将上述产品制成其它适宜剂型,如片剂、丸剂、颗粒剂等。按需要将两种成品胶囊按服用剂量形成伴侣分包装即得上市产品。
本发明的质量考察
1、外观:清真胶囊和肠溶胶囊外观整洁,无粘结、变形或破裂等现象,无异臭。两种胶囊剂的内容物干燥、松紧适度、混合均匀,经检查均符合规定。
2、水分:两种胶囊剂内容物的水分,除另有规定外,不得超过9.0%,经检查均符合规定。
3、装量差异:取清真胶囊和肠溶胶囊各20粒,分别精密称定重量,倾出内容物(不得损失囊壳),硬胶囊剂囊壳用小刷或其他适宜的用具拭净,再分别精密称定囊壳重量,求出每粒胶囊内容物的装量与20粒的平均装量。每粒装量与平均装量相比较,超出装量差异限度的不得多于2粒,并不得有一粒超出限度一倍,经检查均符合规定。
4、崩解度与溶出度:清真胶囊,取供试品6粒检查。硬胶囊剂应在30分钟内全部崩解并通过筛网(囊壳碎片除外),结果见表1。肠溶胶囊剂,取供试品6粒检查。先在盐酸溶液(9→1000)中检查2小时,每粒的囊壳均不得有裂缝或崩解现象;再在磷酸盐缓冲液 (pH6.8)中进行检查,1小时内应全部崩解并通过筛网(囊壳碎片除外),结果见表1。
1 | 2 | 3 | 4 | 5 | 6 | 平均值 | |
清真胶囊(分) | 22 | 25 | 23 | 21 | 25 | 28 | 24 |
肠溶胶囊(分) | 45 | 48 | 46 | 44 | 48 | 51 | 47 |
5、稳定性考查:根据实验确定的工艺,制备3批产品(每批1万粒),采用铝塑泡罩包装,室温条件下放置,分别于第0,1,3,6,12月定期取样检测,经多方面考核,在考察期内,采用本工艺生产的成品均符合质量标准的要求、证明此工艺切实可行。
讨论
(1)维生素D和葡萄糖酸锌混合制粒,因为有效成分不怕水且混合稳定,所以制成肠溶胶囊。
(2)维生素D的理化性质呈中性和碱性,在溶液中耐热,不易被氧化;但在酸性环境下会逐渐破坏;考虑到胃液对其直接的破坏,做成肠溶胶囊解决了原药物的有效吸收和利用。
(3)葡萄糖酸锌对胃部直接刺激,容易产生胃部不适,恶心或呕吐等消化道刺激症状,本身理化性质比较稳定,所以与维生素D混合制成肠溶胶囊。
(4)维生素E对热及酸稳定,对碱不稳定,对氧十分敏感,所以维生素E用β环糊精包裹工艺制备,阻断了维生素E与氧的直接接触,且在胃内崩解吸收,进一步提高了本品的生物利用度。
本发明的优点是:
本发明组合补充锌、钙药物根据不同的人群用药特点制定不同的产品配方:儿童补钙加维生素D和锌元素符合身体生长与智力发 育;孕妇补钙和锌量大且同时辅助维生素D,严控重金属和有害物质的检测,在保证患者用药安全的前提下,不断提高药物的生物利用度,从而减少了原料的用量,减轻了肝脏的负担;根据成人在40岁以后钙质大量流失的特点,尤其女性性激素同时下降明显的现象,补充适量的维生素E和增加锌含量可以提高服用人群的激素水平,增加食欲,减少或消除由于钙质流失和激素水平降低出现的不良症状,降低细胞老化,促进细胞合成,保持红细胞的完整性,增加皮肤弹性。本发明的药物适用于治疗儿童、孕妇、成人或老年人缺钙缺锌和激素分泌不足引起的骨质疏松、骨质增生、骨痛、肌肉痉挛,更年期综合症、小儿佝偻、生长发育迟缓,营养不良,厌食症,复发性口腔溃疡,皮肤痤疮等症。
本发明的方法保证维生素D在酸性环境下不被破坏;避免了葡萄糖酸锌对胃部的直接刺激;阻断了维生素E与氧的直接接触。依托强寿药业公司新药科研力量与符合GMP要求先进的生产设备,在保证原药有效成分不变的同时,合理制得肠溶胶囊和清真胶囊,患者同时服用后,维生素E和醋酸钙的有效成分会在胃内迅速崩解、吸收;维生素D和葡萄糖酸锌会在肠内崩解、吸收,具有药物起效、生物利用度高、副作用小等特点,特别适用于儿童、孕妇、成年和老年人长期补充锌、钙服用。
具体实施方式:
实施例1
本发明药物儿童配方制备方法的主要步骤是:
(1)按Zn2+计10g称取固体葡萄糖酸锌和按D3计称取200000IU固体维生素D,药用淀粉365g、微晶纤维素10g、微粉硅胶10g。先将葡萄糖酸锌与维生素D混合得1号混合粉,再将药用淀粉、微晶纤维素混合,得2号混合粉,然后将1号2号混合粉按等量递增法混合,加入10g微粉硅胶混合均匀,用肠溶胶囊分装成2000粒;
(2)按Ca2+计200g称取超微粉碎好的水溶性醋酸钙备用;
(3)将药用淀粉50g、微晶纤维素10g、混合、备用;
(4)将(2)和(3)混合,加入微粉硅胶20g混合均匀,用清真胶囊分装成4000粒;
(5)将肠溶胶囊、清真胶囊按伴侣搭配包装即得。
实施例2
本发明药物孕妇配方制备方法的主要步骤是:
(1)按Zn2+计15g称取固体葡萄糖酸锌和按D3计称取400000IU固体维生素D,药用淀粉330g、微晶纤维素10g、微粉硅胶10g。先将葡萄糖酸锌与维生素D混合均匀得1号混合粉,再将药用淀粉与微晶纤维混合均匀得2号粉,然后将1号2号混合粉按等量递增法混合,加入微粉硅胶10g混合均匀,用肠溶胶囊分装成2000粒;
(2)按Ca2+计300g称取超微粉碎的水溶性醋酸钙备用;
(3)将药用淀粉55g、微晶纤维素15g、混合粉碎备用;
(4)将(2)和(3)混合,加入微粉硅胶20g混合均匀,用清真胶囊分装成4000粒;
(5)将肠溶胶囊、清真胶囊按伴侣搭配包装即得。
实施例3
本发明药物成人配方制备方法的主要步骤是:
(1)按Zn2+计10g称取固体葡萄糖酸锌和按D3计称取200000IU固体维生素D,药用淀粉365g、微晶纤维素10g、微粉硅胶10g。先 将葡萄糖酸锌与维生素D混合得1号混合粉,再将药用淀粉、微晶纤维混全,得2号混合粉,然后将1号2号混合粉按等量递增法混合,加入10g微粉硅胶混合均匀,用肠溶胶囊分装成2000粒;
(2)按Ca2+计150g称取超微粉碎的水溶性醋酸钙备用;
(3)按维生素E100%计75g折合固体维生素E加入到β环糊精中,两相配方摩尔比为1∶1,包合时间为25min,溶剂为60%乙醇,包合物低温干燥备用;
(4)将药用淀粉40g、微晶纤维素10g、混合备用;
(5)将(2)、(3)、(4)混合,加入微粉硅胶20g混合均匀,用清真胶囊分装成4000粒;
(6)将肠溶胶囊、清真胶囊按伴侣搭配包装即得。
Claims (3)
1.一种组合补充锌、钙的药物,其特征在于药物成分定部位释放,该药物由以下步骤获得:
(1)按Zn2+计10g称取固体葡萄糖酸锌和按D3计称取200000IU固体维生素D,药用淀粉365g、微晶纤维素10g,微粉硅胶10g,先将葡萄糖酸锌与维生素D混合得1号混合粉,再将药用淀粉、微晶纤维素混合,得2号混合粉,然后将1号2号混合粉按等量递增法混合,加入10g微粉硅胶混合均匀,分装成2000粒肠溶胶囊;
(2)按Ca2+计200g称取超微粉碎好的水溶性醋酸钙备用;
(3)将药用淀粉50g、微晶纤维素10g、混合备用;
(4)将(2)和(3)混合,加入微粉硅胶20g混合均匀,分装成4000粒清真胶囊;
(5)将肠溶胶囊、清真胶囊按伴侣搭配包装即得。
2.一种组合补充锌、钙的药物,其特征在于药物成分定部位释放,该药物由以下步骤获得:
(1)按Zn2+计15g称取固体葡萄糖酸锌和按D3计称取400000IU固体维生素D,药用淀粉330g、微晶纤维素10g,微粉硅胶10g,先将葡萄糖酸锌与维生素D混合得1号混合粉,再将药用淀粉、微晶纤维素混合,得2号混合粉,然后将1号2号混合粉按等量递增法混合,加入10g微粉硅胶混合均匀,分装成2000粒肠溶胶囊;
(2)按Ca2+计300g称取超微粉碎好的水溶性醋酸钙备用;
(3)将药用淀粉55g、微晶纤维素15g、混合粉碎备用;
(4)将(2)和(3)混合,加入微粉硅胶20g混合均匀,分装成4000粒清真胶囊;
(5)将肠溶胶囊、清真胶囊按伴侣搭配包装即得。
3.一种组合补充锌、钙的药物,其特征在于药物成分定部位释放,该药物由以下步骤获得:
(1)按Zn2+计10g称取固体葡萄糖酸锌和按D3计称取200000IU固体维生素D,药用淀粉365g、微晶纤维素10g,微粉硅胶10g,先将葡萄糖酸锌与维生素D混合得1号混合粉,再将药用淀粉、微晶纤维素混合,得2号混合粉,然后将1号2号混合粉按等量递增法混合,加入10g微粉硅胶混合均匀,分装成2000粒肠溶胶囊;
(2)按Ca2+计150g称取超微粉碎好的水溶性醋酸钙备用;
(3)按维生素E100%计75g折合固体维生素E加入到β环糊精中,两相配方摩尔比为1∶1,包合时间为25min,溶剂为60%乙醇,包合物低温干燥备用;
(4)将药用淀粉40g、微晶纤维素10g、混合备用;
(5)将(2)、(3)、(4)混合,加入微粉硅胶20g混合均匀,分装成4000粒清真胶囊;
(6)将肠溶胶囊、清真胶囊按伴侣搭配包装即得。
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