CN106692096B - 一种复合维生素缓释片胶囊 - Google Patents
一种复合维生素缓释片胶囊 Download PDFInfo
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- CN106692096B CN106692096B CN201611234278.0A CN201611234278A CN106692096B CN 106692096 B CN106692096 B CN 106692096B CN 201611234278 A CN201611234278 A CN 201611234278A CN 106692096 B CN106692096 B CN 106692096B
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Abstract
本发明涉及制剂技术领域,特别涉及一种复合维生素缓释片胶囊。该复合维生素缓释片胶囊内的复合维生素缓释片由B族维生素缓释片、维生素C缓释片和微量维生素片组成。释放度实验、中试实验和稳定性试验结果,表明此组合方案的水溶性、脂溶性复合维生素缓释片制备工艺、缓释效果和稳定性良好;本发明制备的维生素缓释片胶囊服用方便,顺应性好,缓释效果良好;制备工艺,方便快捷,稳定性良好,载药量高;片剂填充胶囊设计,小巧新颖,便于携带,利于工业化生产。
Description
技术领域
本发明涉及制剂技术领域,特别涉及一种复合维生素缓释片胶囊。
背景技术
维生素是一类在日常饮食中必需的、少量即可满足机体需要的营养物质。尽管维生素分子小、数量甚微,但对机体至关重要,一般分为脂溶性维生素和水溶性维生素。脂溶性维生素包括维生素A、D、E、K及其衍生物,是维持机体正常生长、发育、代谢和机体生理功能所必需的物质。
维生素A又称为视黄醇,只存在动物性食品中,具有维持视觉、生殖、细胞生长发育等生理功能,但过量会引起肝脏毒性作用,视力下降、孕妇产畸形胎儿。维生素E又称为生育酚,具有抗氧化、抗衰老、保护血管、促进生育的作用。维生素D为固醇类衍生物,能够促进钙在骨骼沉积,具抗佝偻病作用。如果缺乏或者摄入过量,就会引起代谢失衡,严重时会产生缺乏症疾病,甚至致人死亡。水溶性维生素包括B族维生素及维生素C等。维生素C又名抗坏血酸,是一种水溶性维生素,化学性质不稳定,在光、热、氧、碱性和金属离子环境下易氧化降解。维生素C具有增强机体免疫力,改善心功能,降血脂,抗血栓,抗癌等药理作用。口服的维生素C通常在口腔黏膜和胃有少量吸收,主要在小肠上方(十二指肠和空肠上部)被吸收。其吸收过程是一个主动运输的过程,吸收能力与载体的数量有关。当摄取量在30-180mg时,吸收率可达70%-90%;然而当摄取量为1500mg时,吸收率降到50%;当摄取量达到6000mg时,吸收率则只有16%。故当临床上需要大剂量服用维生素C时,需要每日给药3-4次,频繁且大剂量的给药会导致患者顺应性差、易出现漏服现象,而且瞬时较大剂量的服用会导致大量维生素C无法被吸收,不但达不到最佳治疗效果,而且还会造成维生素C很大的浪费。B族维生素是水溶性维生素中重要的一类,其中多种是酶的辅基和酶的组成部分。当人体内缺乏B族维生素时,便可导致多种疾病的产生,而人体自身又无法合成这些化合物,必须通过食物链或服用复合维生素制剂给予补充。随着人们对生活品质要求的提高,复合维生素制剂及高档营养品的出现,对食物中或药物中B族维生素的产生了广泛关注。维生素B1(VB1)、维生素B2(VB2)是人们生活中必需的营养要素,是一些具有调节和控制新陈代谢过程作用的生物活性物质。VB1与糖代谢有密切关系,缺乏时会使血、尿和神经组织中丙酮酸含量升高和得脚气病。VB2的生理功能是作为辅酶,参与氧化作用,缺乏时会使皮肤、眼睛与神经系统损伤。维生素B3(烟酸)过量会引起高血糖、肝脏毒性作用。
专利CN104258407A以原淀粉制备缓释型维生素E衍生物,具有很好的产业价值,由于其在小肠吸收,缓释并未能有效的提高其稳定性。专利CN101002789A中提到维生素A、维生素D和维生素E在一起的可以增强主药的药效的作用效果。专利1939301A提供了维生素A烟酸酯缓释制剂的方法,通过包衣微丸,制备微丸片的方法。但是以上微量脂溶性的维生素制剂均未提供一些稳定性的实验,而且制剂工艺操作繁琐。
专利CN102038691A公开了一种复合维生素制剂,包括维生素B1、维生素B2、维生素B3、维生素B5、维生素B6、维生素B9、维生素B12、维生素C、维生素A、维生素D2、维生素E和氨基酸,通过制备缓释微丸,填装胶囊来达到缓释的效果。专利CN105434402A通过制备B族维生素和维生素C的微囊,选用磷脂作为助剂,达到制备一种优化释放的缓释胶囊,提高了原料的部位定性质,增加产品的润湿性和水分散性。专利CN103877115B、CN105410943A公开了维生素B1、维生素B2、维生素B3、维生素B5、维生素B6、维生素B7、维生素B9、维生素A、维生素E、维生素K和维生素C的组合物。专利CN102150748A公开了一种B族维生素的晶体胶囊的方法,来达到缓释的效果。专利CN204671589U涉及一种缓释B族维生素的软胶囊的结构设计,保证了其结构的稳定性。专利105560201A提供了缓释维生素的滴丸制备工艺,但是其含有多种维生素的复合体系,未对其每个维生素进行考察其稳定性和释放度。
专利CN103478732通过骨架材料控释制备骨架型缓释维生素功能食品(维生素B1、维生素B2、维生素B3、维生素B5、维生素B6、维生素B7、维生素B9、维生素B12、维生素A、维生素D、维生素E、维生素K和维生素C),骨架材料主要为HPMC和胶块糖。此类专利虽保证了维生素的整体摄取和用量,但是并未能够考察到稳定性和各个维生素之间的相互作用以及糖的用量等问题。专利CN101756916A制备了维生素B6的缓释层与维生素B9和维生素B12的速释层,用以减轻晨吐症状的发生,但此专利缺乏对稳定性的考察、药物的释放度性质和药物的相互作用的考察。但是以上方法均没有提供一种比较好的稳定的B族维生素缓释制剂,也没有能够改善维生素之间的稳定性问题。
专利CN1533767A先将维生素C及金属螯合剂等辅料混合后,采用粉末层积的方式以20%虫胶乙醇溶液为粘合剂将维生素C层积至空白丸芯上,制备维生素C载药微丸,再在上述微丸基础上进行缓释包衣制备维生素C缓释微丸,最后填装胶囊。其缺点在于:(1)在处方中使用了金属螯合剂,增加了处方的复杂性;(2)在制备维生素C微丸的过程中使用了乙醇,由于乙醇的易燃易爆,对生产环境有更高的要求;(3)由于使用了空白丸芯,所以单位体积下维生素C的载药量较少,维生素C微丸中维生素C的含量及含量均匀度均难以控制;(4)制备工艺复杂,需长时间干燥,制备周期较长。专利CN1582922A将维生素C、金属螯合剂及抗氧剂溶解于水中,采用液相层积的方式将维生素C喷于空白丸芯上,制备维生素C载药微丸。其缺点在于:(1)在处方中含有金属螯合剂,此外还包括致孔剂和消泡剂,增加了处方的复杂性和生产成本;(2)在制备维生素C缓释微丸时,将维生素C全部溶解于水中极大的降低了维生素C的稳定性,虽然在此溶液中加入了金属螯合剂及抗氧剂,但是由于液相层积方式制备微丸所耗用时间过长,维生素C极易降解。(3)由于使用了空白丸芯,一方面使单位体积下维生素C的载药量较少,不利于胶囊填充,另一方面导致维生素C微丸中维生素C的含量及含量均匀度均难以控制。专利CN102908319A使用粘合剂水溶液对维生素C和素丸辅料混合均匀的素丸粉进行制粒,然后用余量的素丸粉料和粘合液对该颗粒进行粉末层积制成素丸,最后对素丸进行缓释包衣制成维生素C缓释微丸。其缺点在于:制备过程主要为湿法制粒,需进行多次粉末层积,进行多次干燥,并对干燥后水分控制有严格要求,操作较为繁琐。
当临床上或者生活中大剂量服用复合维生素片的时候,患者的依从性较差,经常出现漏服现象。如何研制一种稳定的、长期缓释的、具有独特的释放动力学的复合维生素缓释片一直备受人们关注。而且在复合维生素的整体输送系统上,不同维生素之间的组合设计和维生素的释放动力学设计急需一种新的制剂设计策略。
发明内容
有鉴于此,本发明提供了一种复合维生素缓释片胶囊。该复合维生素缓释片胶囊为新型释放动力学组合的复合维生素缓释片组合物。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种复合维生素缓释片胶囊,胶囊内的复合维生素缓释片由B族维生素缓释片、维生素C缓释片和微量维生素片组成;B族维生素缓释片包括B族维生素、缓释骨架材料和润滑剂,B族维生素选自VB1、VB2、VB3、VB5、VB6、VB7、VB12中的一种或几种。
本发明提供了一种新型释放动力学组合的缓释片剂组合物,包括B族维生素缓释片、维生素C缓释片和微量维生素片3个片,然后填充胶囊。释放度实验、中试实验和稳定性试验结果,表明此组合方案的水溶性、脂溶性复合维生素缓释片缓释效果和稳定性良好。
本研究在复合维生素的稳定性研究上,通过不同维生素的组合研究发现B族维生素之间有明显的相互作用,尤其是维生素B9的稳定性,需要将其与B族维生素其他维生素分开。试验结果显示本发明中组合对VB9的稳定性可较好的维持作用。
试验表明,B族维生素缓释片和维生素C缓释片有显著的缓释效果,其中复合VB缓释片中,VB2呈零级释放,VB1、VB3、VB5和VB6呈一级释放,VB7呈Higchi释放;VC缓释片呈一级释放。
作为优选,每180mg B族维生素缓释片中,各组分用量为:VB1 0~4.8mg,VB2 0~4.8mg,VB3 0~40.0mg,VB5 0~12.0mg,VB6 0~4.8mg,VB7 10~45.0mg,VB12 0~4.8mg。
作为优选,维生素C缓释片包括维生素C、缓释骨架材料、抗氧剂、助流剂和润滑剂。
作为优选,每180mg维生素C缓释片中,维生素C的用量为1~150mg。
优选地,每180mg维生素C缓释片中,维生素C的用量为50~150mg。
作为优选,微量维生素片包括微量维生素、填充剂、崩解剂、助流剂和润滑剂。
作为优选,微量维生素选自VB7、VB12、VB9(叶酸)、维生素A、维生素D3、天然维生素E醋酸酯中的一种或几种。
作为优选,每180mg微量维生素片中,微量维生素各组分量为:VB70.1~0.9mg,VB120.001~0.0048mg,叶酸0.1~1.0mg,维生素A 0.1~1.0mg,维生素D3 1~10mg,天然维生素E醋酸酯10~40mg。
作为优选,B族维生素缓释片中缓释骨架材料选自羟丙甲基纤维素、黄原胶、海藻酸钠、卡波姆、羧甲基纤维素钠、阿卡伯胶、黄原胶或卡拉胶中的一种或几种。
作为优选,B族维生素缓释片中缓释骨架材料的质量百分含量为30%~60%。
作为优选,羟丙甲基纤维素为K100LV、K4M、K15M或K100M。
优选地,B族维生素缓释片中缓释骨架材料的质量百分含量为40%~50%。
优选地,B族维生素缓释片中缓释骨架材料为羟丙甲基纤维素K4M和羧甲基纤维素钠,羟丙甲基纤维素K4M与羧甲基纤维素钠的质量比为(1:1)~(10:1)。
更优选地,羟丙甲基纤维素K4M与羧甲基纤维素钠的质量比为(4.3:1)~(9.5:1)。
优选地,B族维生素缓释片中缓释骨架材料为羟丙甲基纤维素K4M和卡波姆,羟丙甲基纤维素K4M与卡波姆的质量比为(1:1)~(10:1)。
更优选地,羟丙甲基纤维素K4M与卡波姆的质量比为(4.3:1)~(9.5:1)。
润滑剂选自硬脂酸镁、聚乙二醇或滑石粉中的一种或几种,B族维生素缓释片中润滑剂的质量百分含量为0.001%~1%。
作为优选,维生素C缓释片中缓释骨架材料选自羟丙甲基纤维素、海藻酸钠、卡波姆、羧甲基纤维素钠、卡拉胶、黄原胶或阿拉伯胶中的一种或几种;
优选地,维生素C缓释片中缓释骨架材料的质量百分含量为30%~60%。
更优选地,维生素C缓释片中缓释骨架材料的质量百分含量为30%~50%。
作为优选,羟丙甲基纤维素为K100LV、K4M、K15M或K100M。
优选地,羟丙甲基纤维素为羟丙甲基纤维素K100M和羧甲基纤维素钠,或者为羟丙甲基纤维素K100M和卡波姆。
作为优选,抗氧剂选自硫脲、硫代苏糖醇、亚硫酸钠、硫酸氢钠、柠檬酸、酒石酸、苹果酸或硼酸中的一种或几种。
作为优选,维生素C缓释片中抗氧剂的质量百分含量为0.1%~2%,优选0.5%~1.5%。
作为优选,助流剂为胶态二氧化硅和/或二氧化硅。
作为优选,维生素C缓释片中助流剂的质量百分含量为0.1%~2%,优选0.1%~1%。
作为优选,润滑剂选自硬脂酸镁、聚乙二醇或滑石粉中的一种或几种。
作为优选,维生素C缓释片中润滑剂的质量百分含量为0.1%~2%。
优选地,维生素C缓释片中润滑剂的质量百分含量为0.1%~1%。
作为优选,微量维生素片中填充剂为乳糖、微晶纤维素、淀粉、甘露醇、磷酸钙或者硫酸钙中的一种或几种。
优选地,填充剂为乳糖和微晶纤维素。
作为优选,微量维生素片中填充剂的质量百分含量为10%~60%。
优选地,微量维生素片中填充剂的质量百分含量为20%~50%。
崩解剂为干淀粉、羧甲淀粉钠、交联羧甲基纤维素钠、交联聚维酮或低取代羟丙甲基纤维素中的一种或几种。
优选地,崩解剂为羧甲淀粉钠。
作为优选,微量维生素片中崩解剂的质量百分含量为1%~20%。
优选地,微量维生素片中崩解剂的质量百分含量为1%~15%。
作为优选,助流剂为微粉硅胶和/或SiO2。
作为优选,微量维生素片中助流剂的质量百分含量为0.001%~1%。
作为优选,微量维生素片中润滑剂选自硬脂酸镁、聚乙二醇或滑石粉中的一种或几种。
作为优选,微量维生素片中润滑剂的质量百分含量为0.001%~1%。
作为优选,胶囊为0#~5#填充胶囊。
优选地,胶囊为0#~3#填充胶囊。
在本发明提供的实施例中,B族维生素缓释片、维生素C缓释片和微量维生素片3个片剂均通过粉末直压和薄膜包衣的制剂方法制备。制备的具体工艺:将各原辅料过60~100目筛网后混合均匀,备用;然后加入处方量的润滑剂,混合均匀,压片;最后缓释片外层包防潮保护衣。
作为优选,B族维生素缓释片还包括包衣材料;维生素C缓释片还包括包衣材料;微量维生素片还包括包衣材料。
包衣粉:羟丙基甲基纤维素、二氧化钛、胭脂红铝色淀、日落黄铝色淀、滑石粉、聚多糖、三乙酸甘油酯和柠檬黄铝色淀等不同种组合;B族维生素缓释片包黄色薄膜衣。
本发明提供了一种复合维生素缓释片胶囊。该复合维生素缓释片胶囊内的复合维生素缓释片由B族维生素缓释片、维生素C缓释片和微量维生素片组成。本发明至少具有如下优势之一:
1、本发明提供了一种新型释放动力学组合的缓释片剂组合物,包括B族维生素缓释片、维生素C缓释片和微量维生素片3个片,然后填充胶囊。释放度实验、中试实验和稳定性试验结果,表明此组合方案的水溶性、脂溶性复合维生素缓释片制备工艺、缓释效果和稳定性良好;
2、本发明制备的维生素缓释片胶囊服用方便,顺应性好,缓释效果良好;
3、本发明制备的维生素缓释片制备工艺,方便快捷,稳定性良好,载药量高;片剂填充胶囊设计,小巧新颖,便于携带,利于工业化生产。
附图说明
图1示实施例1中B族维生素缓释片释放曲线;
图2示实施例2中B族维生素缓释片释放曲线;
图3示对比例1中B族维生素缓释片释放曲线;
图4示对比例1中B族维生素缓释片中VB9稳定性;
图5示对比例1中B族维生素缓释片中其他VB的稳定性;
图6示实施例3中维生素C缓释片释放曲线;
图7示实施例3中维生素C缓释片加速实验样品释放曲线;
图8示实施例4中维生素C缓释片释放曲线;
图9示实施例5中微量维生素片中VB9稳定性;
图10示维生素组合物的外观形态结构图。
具体实施方式
本发明公开了一种复合维生素缓释片胶囊,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
术语解释:
如本文所用,术语“复合维生素缓释骨架片”、“复合维生素缓释凝胶骨架片”、“复合维生素缓释片”可互换使用,是利用复合维生素和凝胶骨架混合压片成为凝胶骨架制剂,遇到水形成一定的凝胶形态,控制药物释放的机理形成的一种缓控释制剂。
如本文所用,术语“VB”是指第B族复合维生素。
如本文所用,术语“VC”是指维生素C。
如本文所用,术语“VADE”是指复合维生素A、复合维生素D、复合维生素E。
各B族维生素简写如下:
硝酸硫胺素: | VB1 | 盐酸吡哆醇: | VB6 |
核黄素: | VB2 | 生物素: | VB7 |
烟酰胺: | VB3 | 叶酸: | VB9 |
泛酸钙: | VB5 | 钴胺素: | VB12 |
在以下实施例中,维生素A为维生素A粉(325000IU),维生素D3为维生素D3粉(100000IU/g,2.5‰),天然维生素E醋酸酯为天然维生素E醋酸酯粉(50%)。
本发明提供的复合维生素缓释片胶囊中所用原料或辅料均可由市场购得。
下面结合实施例,进一步阐述本发明:
实施例1 B族维生素缓释片的制备
(1)B族维生素缓释片的配方如下:
表1 B族维生素缓释片的配方
成分 | 每片用量/mg | 百分比/% |
硝酸硫胺素VB1 | 2.40 | 1.33 |
核黄素VB2 | 2.40 | 1.33 |
烟酰胺VB3 | 20.00 | 11.11 |
泛酸钙VB5 | 6.00 | 3.33 |
盐酸吡哆醇VB6 | 2.40 | 1.33 |
生物素(2%)VB7 | 45.00 | 25.00 |
钴胺素(0.1%)VB12 | 3.20 | 1.77 |
羟丙甲基纤维素K4M | 87.40 | 48.60 |
羧甲基纤维素钠 | 9.40 | 5.00 |
硬脂酸镁MS | 1.80 | 1.00 |
总量 | 180.00 | 100 |
(2)制备方法:将各原辅料混合均匀,备用。最后加入处方量的硬脂酸镁,混合均匀,压片。具体为:
先将VB1、VB2、VB5、VB6和VB12手动混合均匀(物料①);将物料①和VB3、VB7混合均匀(物料②);物料②与HPMC(K4M SR/K15M SR)、CMCNa用三维混合机混合均匀,最后加入硬脂酸镁混合。
压片参数:直径6mm,片重175-185mg。
(3)释放度测定方法:
色谱条件:色谱柱为Agilent ZORBAX Plus C18色谱柱2.1×100mm,3.5μm);柱温:25℃;流动相为10mM甲酸铵-乙腈;流速:0.20mL/min;进样量:1μL;
质谱条件:干燥气温度和流速为300℃和8L/min;鞘气温度和流速为350℃和8L/min;雾化气压力为35psi;毛细管电压为3500V;喷嘴电压为500V;△EMV为200eV;检测离子如下表所示:
表2 B族维生素缓释片的检测结果
VB | m/z | T(min) |
VB1 | 265.1>122 | 1.18 |
VB2 | 377.1>243 | 3.71 |
VB3 | 123.1>80.1 | 1.4 |
VB5 | 220.1>90 | 1.8 |
VB6 | 170.1>152 | 1.34 |
VB7 | 245.1>227 | 4.70 |
VB12 | 678.3>147 | / |
释放度测定装置:中国药典桨法;
溶出条件:介质为1000mL去离子水,转速100rpm,温度37℃;
取样测定:在0.5、1、2、4、6、8、10和12h取样5mL,并补液5mL,稀释10倍作为溶出样品,用LC-MS/MS测定。释放度结果如图1。
结果表明,各个B族维生素都呈现一个较好的缓释效果。选择实施例1的处方,进行释放度检测后,按照其平均释放度(见表2),应用零级释放、一级释放、Higuchi方程、Ritger-Peppas方程和Hixson-Crowell方程分别进行拟合,确定拟合方程,并计算各模型拟合方程的相关系数R值,确定缓释片体外释放的最佳拟合模型,根据拟合结果对释药机制进行初步研究和分析。结果表明:B族维生素缓释片有显著的缓释效果,其中复合VB缓释片中,VB2呈零级释放,VB1、VB3、VB5和VB6呈一级释放,VB7呈Higchi释放。
(4)维生素B缓释片加速稳定性实验
将维生素B缓释片在温度为40℃,湿度为75%的稳定性实验箱中进行加速稳定性实验考察,不同加速时间条件下,维生素B缓释片释放曲线的相似性f2值皆大于50,含量无明显差异。本发明中的维生素B缓释片稳定性良好。
实施例2 B族维生素缓释片的制备
(1)B族维生素缓释片的配方如下:
表3 B族维生素缓释片的配方
(2)制备方法:将各原辅料混合均匀,备用。最后加入处方量的硬脂酸镁,混合均匀,压片。具体为:
先将VB1、VB2、VB5和VB6手动混合均匀(物料①);将物料①和VB3混合均匀(物料②);物料②与HPMC(K4M SR/K15M SR)、CMCNa用三维混合机混合均匀,最后加入硬脂酸镁混合。
压片参数:直径6mm,片重175-185mg。
(3)释放度测定方法同实施例1,释放度结果如图2。
(4)维生素B缓释片加速稳定性实验
将维生素B缓释片在温度为40℃,湿度为75%的稳定性实验箱中进行加速稳定性实验考察,不同加速时间条件下,维生素B缓释片释放曲线的相似性f2值皆大于50,含量无明显差异。本发明中的维生素B缓释片稳定性良好。
对比例1 B族维生素缓释片
(1)B族维生素缓释片的配方如下:
表4 B族维生素缓释片的配方
(2)制备方法:将各原辅料混合均匀,备用。最后加入处方量的硬脂酸镁,混合均匀,压片。具体为:
先将VB1、VB2、VB5、VB6、VB9和VB12手动混合均匀(物料①);将物料①和VB3、VB7混合均匀(物料②);物料②与HPMC(K4M SR/K15M SR)、CMCNa用三维混合机混合均匀,最后加入硬脂酸镁混合。
压片参数:直径6mm,片重175-185mg。
(3)B族维生素释放度方法学:LC-MS/MS,同实施例1。
具体释放度实验结果见图3,结果表明VB缓释片中各个VB呈现缓释效果,但是VB9释放较低。
(4)稳定性检测
检测方法:VB缓释片中各个VB分别配制一定浓度的溶液分别混合在一起(混合液中VB1,2.40ng/mL;VB2,2.40ng/mL;VB3,20.00ng/mL;VB5,6.00ng/mL;VB6,2.40ng/mL;VB7,45.00ng/mL;VB9,0.40ng/mL;VB12,3.20ng/mL),在37℃的条件下考察不同维生素组合之间的稳定性。结果见图4、5。
试验结果:维生素缓释片的组合方案中的稳定性研究中,VB缓释片中各个VB分别配制处方量浓度的溶液分别混合在一起,在37℃的条件下考察不同维生素组合的稳定性。其中,以VB9为例,VB缓释片中其他的VB和辅料对VB9稳定性都有影响,其他B族维生素之间稳定性良好;VB9对其他成分几乎没有影响。因此,在本发明中需要将VB9与其它B族维生素分开制备片剂,以便提高VB9的稳定性。
实施例3 维生素C缓释片处方
(1)维生素C缓释片的配方如下:
表5 维生素C缓释片的配方
成分 | 每片用量/mg | 百分比/% |
VC(60目) | 100.0 | 55.6 |
HPMC(K100M) | 40.2 | 22.3 |
壳聚糖(CS) | 18.0 | 10.0 |
卡波姆 | 18.0 | 10.0 |
柠檬酸 | 2.0 | 1.1 |
微粉硅胶 | 0.9 | 0.5 |
硬脂酸镁 | 0.9 | 0.5 |
片重 | 180 | / |
(2)制备方法:处方工艺为粉末直压。具体为:
处方中HPMC(K100M)、壳聚糖、卡波姆、柠檬酸均过100目筛后使用。
称取处方量的VC、CS、卡波姆、微粉硅胶于研钵中研磨混合5min,混合后再加入HPMC和柠檬酸研磨5min,最后加入硬脂酸镁研磨2min后在转速12.0rpm,压力“3”的条件下进行压片。
(3)HPLC法测定维生素C释放度:
色谱仪:Agilent 1260;色谱柱:Diamonsil C18(2)5u 250×4.6mm;
流动相:0.02mol/L磷酸二氢钾缓冲液(磷酸调pH 3.0):甲醇=95:5;
流速:1mL/min;柱温:25℃;进样量:20μL;检测波长:245nm;
释放度测定装置:中国药典2015年版第四部0931第二法(桨法);
溶出条件:溶出介质为1000mL水,转速100rpm,温度37℃;
取样点:在0.5、1、2、4、6、8、10和12h取样5mL,并同温同体积补液,样品溶液过0.45μm微孔滤膜,滤液用HPLC进行测定。
释放度结果如图6。
(4)维生素C缓释片加速稳定性实验
将维生素C缓释片在温度为40℃,湿度为75%的稳定性实验箱中进行加速稳定性实验考察,不同加速时间条件下,维生素C缓释片释放曲线的相似性f2值皆大于50,含量无明显差异。本发明中的维生素C缓释片稳定性良好。
表6维生素C缓释片加速样品含量测定
加速时间 | 含量/mg |
未加速 | 97.2 |
加速1个月 | 96.7 |
加速2个月 | 95.9 |
加速3个月 | 95.4 |
加速6个月 | 96.3 |
稳定性结果如图7。
实施列4 维生素C缓释片的制备
(1)维生素C缓释片的配方如下:
表7 维生素C缓释片的配方
成分 | 每片用量(mg) | 百分比(%) |
VC(60目) | 100.0 | 55.6 |
HPMC(K100M) | 39.3 | 21.8 |
壳聚糖 | 36.0 | 20.0 |
柠檬酸 | 2.0 | 1.1 |
硬脂酸镁 | 1.8 | 1.0 |
微粉硅胶 | 0.9 | 0.5 |
片重 | 180 | / |
(2)制备方法:处方工艺同实施例3。
(3)HPLC法测定维生素C释放度:同实施列3。
释放度结果如图8。
(4)维生素C缓释片加速稳定性实验
将维生素C缓释片在温度为40℃,湿度为75%的稳定性实验箱中进行加速稳定性实验考察,不同加速时间条件下,维生素C缓释片释放曲线的相似性f2值皆大于50,含量无明显差异。本发明中的维生素C缓释片稳定性良好。
表8 维生素C缓释片加速样品含量测定
加速时间 | 含量/mg |
未加速 | 96.0 |
加速1个月 | 94.4 |
加速2个月 | 95.9 |
加速3个月 | 98.5 |
加速6个月 | 95.4 |
实施例5 微量维生素缓释片的制备
(1)微量维生素缓释片的配方如下:
表9 微量维生素缓释片的配方
原辅料名称 | 含量(mg)/片 | 百分比/% |
维生素A粉(325000IU) | 4.6 | 2.56 |
叶酸(VB9) | 0.4 | 0.22 |
天然维生素E醋酸酯粉(50%) | 32.0 | 17.78 |
维生素D3粉(100000IU/g)(2.5‰) | 5.2 | 2.89 |
维生素B12(0.1%) | 3.2 | 1.78 |
生物素(2%) | 2.25 | 1.25 |
羧甲淀粉钠 | 9.0 | 5.00 |
乳糖(直压型) | 30.6 | 17.00 |
二氧化硅 | 1.8 | 1.00 |
硬脂酸镁 | 1.8 | 1.00 |
微晶纤维素(直压型,MCC) | 83.75 | 46.53 |
包衣粉 | 5.4 | 3.00 |
总量 | 180 | 100 |
(2)制备方法:
原辅料前处理:原辅料过60目筛;
混合均匀:将各原辅料过60目筛,混合均匀,备用。最后加入处方量的硬脂酸镁,混合均匀,压片。
混合:维生素A粉、维生素D粉、维生素E粉、VB7、VB9和VB12预混;加入其他辅料;加入硬脂酸镁混合。
压片参数:直径6mm,片重175-185mg。
(3)稳定性检测
稳定性检测方法同实施例3。VB9稳定性结果见图9。
试验结果显示,微量维生素片中,VB9成分相对稳定,所以VB9适合加入微量维生素片中。
实施例6 复合维生素缓释片胶囊的制备
将实施例1制得的B族维生素缓释片、实施例3制得的维生素C缓释片和实施例5制得的微量维生素缓释片按图10填充入胶囊壳中,得到复合维生素缓释片胶囊。
实施例7 复合维生素缓释片胶囊的制备
将实施例2制得的B族维生素缓释片、实施例4制得的维生素C缓释片和实施例5制得的微量维生素缓释片按图10填充入胶囊壳中,得到复合维生素缓释片胶囊。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种复合维生素缓释片胶囊,其特征在于,胶囊内的复合维生素缓释片由B族维生素缓释片、维生素C缓释片和微量维生素片组成;所述B族维生素缓释片包括B族维生素、缓释骨架材料和润滑剂,所述B族维生素选自VB1、VB2、VB3、VB5、VB6、VB7或VB12中的一种或几种;所述微量维生素片包括微量维生素、填充剂、崩解剂、助流剂和润滑剂,所述微量维生素为VB9,或者VB7、VB12、维生素A、维生素D3、天然维生素E醋酸酯中的至少一种和VB9的组合。
2.根据权利要求1所述的复合维生素缓释片胶囊,其特征在于,每180mg B族维生素缓释片中,各组分用量为:VB1 0~4.8mg,VB2 0~4.8mg,VB3 0~40.0mg,VB5 0~12.0mg,VB6 0~4.8mg,VB7 10~45.0mg,VB120~4.8mg。
3.根据权利要求1或2所述的复合维生素缓释片胶囊,其特征在于,所述维生素C缓释片包括维生素C、缓释骨架材料、抗氧剂、助流剂和润滑剂。
4.根据权利要求3所述的复合维生素缓释片胶囊,其特征在于,每180mg维生素C缓释片中,维生素C的用量为1~150mg。
5.根据权利要求1所述的复合维生素缓释片胶囊,其特征在于,每180mg微量维生素片中,所述微量维生素各组分量为:VB7 0.1~0.9mg,VB12 0.001~0.0048mg,VB9 0.1~1.0mg,维生素A 0.1~1.0mg,维生素D3 1~10mg,天然维生素E醋酸酯10~40mg。
6.根据权利要求1所述的复合维生素缓释片胶囊,其特征在于,所述B族维生素缓释片中缓释骨架材料选自羟丙甲基纤维素、黄原胶、海藻酸钠、卡波姆、羧甲基纤维素钠、阿卡伯胶、黄原胶或卡拉胶中的一种或几种;所述B族维生素缓释片中缓释骨架材料的质量百分含量为30%~60%;
所述润滑剂选自硬脂酸镁、聚乙二醇或滑石粉中的一种或几种,所述B族维生素缓释片中润滑剂的质量百分含量为0.001%~1%。
7.根据权利要求3所述的复合维生素缓释片胶囊,其特征在于,维生素C缓释片中所述缓释骨架材料选自羟丙甲基纤维素、海藻酸钠、卡波姆、羧甲基纤维素钠、卡拉胶、黄原胶或阿拉伯胶中的一种或几种;
所述抗氧剂选自硫脲、硫代苏糖醇、亚硫酸钠、硫酸氢钠、柠檬酸、酒石酸、苹果酸或硼酸中的一种或几种;
所述助流剂为胶态二氧化硅和/或二氧化硅;
所述润滑剂选自硬脂酸镁、聚乙二醇或滑石粉中的一种或几种。
8.根据权利要求1所述的复合维生素缓释片胶囊,其特征在于,微量维生素片中所述填充剂为乳糖、微晶纤维素、淀粉、甘露醇、磷酸钙或者硫酸钙中的一种或几种;
所述崩解剂为干淀粉、羧甲淀粉钠、交联羧甲基纤维素钠、交联聚维酮或低取代羟丙甲基纤维素中的一种或几种;
所述助流剂为微粉硅胶和/或SiO2;
所述润滑剂选自硬脂酸镁、聚乙二醇或滑石粉中的一种或几种。
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