CN117338739A - 一种6s-5-甲基四氢叶酸钙制剂及其制备方法 - Google Patents
一种6s-5-甲基四氢叶酸钙制剂及其制备方法 Download PDFInfo
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- CN117338739A CN117338739A CN202311327435.2A CN202311327435A CN117338739A CN 117338739 A CN117338739 A CN 117338739A CN 202311327435 A CN202311327435 A CN 202311327435A CN 117338739 A CN117338739 A CN 117338739A
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- methyltetrahydrofolate
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Abstract
本发明提供了一种6S‑5‑甲基四氢叶酸钙制剂及其制备方法,属于制药技术领域,包括以下组分:浓缩乳清蛋白、微晶纤维素、复配维生素、复配矿物质、填充剂、复配着色剂、甜菜碱、6S‑5‑甲基四氢叶酸钙、羟丙基甲基纤维素。该6S‑5‑甲基四氢叶酸钙固体分散体双层片制剂包括乳清蛋白速释层、固体分散体技术制备的复配维生素/矿物质与6S‑5‑甲基四氢叶酸钙缓释层,其中6S‑5‑甲基四氢叶酸钙粒径通过球磨技术控制在50~100μm。制粒工艺采用固体分散体技术,解决了脂溶性维生素生物利用度差、低含量组分均匀度差的问题,达到了延长释放效果、增加稳定性的目的,在同一片剂中实现了不同组分的速释和缓释效果,解决了普通制剂常见的均匀度差、生产成本高、服用顺应性差等问题。
Description
技术领域
本发明属于制药技术领域,特别涉及一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂及其制备方法。
背景技术
6S-5-甲基四氢叶酸钙作为叶酸的来源之一,为人体补充叶酸,提高体内叶酸水平。
叶酸缺乏可引起巨幼红细胞贫血,在妇女围孕期可导致胎儿神经管畸形、唇腭裂等出生缺陷。叶酸过量可掩盖维生素B12缺乏的早期表现,干扰锌吸收和抗惊厥药物的作用等。
低叶酸水平可能使尿嘧啶错误掺入DNA,使DNA链断裂增加,并导致DNA复制过程中错误发生率增加。叶酸缺乏引起5-甲基四氢叶酸水平下降,从而使S-腺苷甲硫氨酸(SAM)水平下降,最终导致DNA低甲基化。正常叶酸代谢水平对于正常胚胎生长和发育是必不可少的。
妇女围孕期(periconception)增补叶酸预防胎儿神经管畸形(neural tubedefects,NTDs)的效果已被公认,围孕期增补叶酸还有可能预防其他出生缺陷,如先天性心脏病。泌尿系统畸形、肢体短缩畸形、唇腭裂、先天性肥厚性幽门狭窄等。此外,叶酸是维持生物体正常生命过程的一类必需有机物,叶酸还具有预防肿瘤、巨幼红细胞贫血和心血管疾病等功能。
市售复合维生素矿物质产品,剂型通常为普通片剂和胶囊剂,存在脂溶性维生素(维生素A、维生素B2、维生素B5、维生素D、维生素E、维生素K)释放速率低且生物利用度差、低含量组分均匀度差等问题。其主要原因为普通固体制剂主要采用湿法制粒工艺生产,对有效成分的释放速率缺乏有效的控制,而不同成分之间的粒度差异、性状差异等导致的均匀度问题,通过简单的混合很难完全解决。
固体分散体技术在制剂工艺中得到应用,是因为有常规制粒技术无法比拟的优点:
(1)载体中药物以高度分散状态存在。
(2)亲水性载体可增加难溶性药物的溶解度和溶出速率,有助于提高药物的生物利用度;难溶性载体可延缓或控制药物释放;肠溶性载体可控制药物于小肠释放。
(3)利用载体的包载作用,可延缓药物的水解和氧化。
(4)载体可掩盖药物的不良气味和降低刺激性。
(5)实现液体药物固体化。
双层片之所以受人们青睐,是因为有许多普通片剂无法比拟的优点:
(1)可控制不同成分的释放速度。
(2)适用于不相容的组分。
(3)产品服用方便,避免服用多种产品时,发生忘服、漏服等现象。
(4)维持平稳有效的血浓度,确保恒定的药物疗效。
(5)服用一种产品,可补充多种营养成分。
(6)减少每日用药次数,提高病人的依从性。
(7)一些组分之间可发生协同作用,促进药物的吸收,增加生物利用度。
发明内容
本发明的目的就是要提供一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂的制备方法,它能克服现有技术中存在的缺陷。本发明的目的是这样实现的,一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂,其特征在于:所述的6S-5-甲基四氢叶酸钙制剂包含乳清蛋白速释层、固体分散体技术制备的复配维生素/矿物质与6S-5-甲基四氢叶酸钙缓释层,其中6S-5-甲基四氢叶酸钙粒径控制在50~100μm,并包括以下质量百分比的组分:浓缩乳清蛋白:15%~40%,填充剂:1%~25%,复配维生素:1%~25%,复配矿物质:1%~25%,固体分散体载体:1%~25%,6S-5-甲基四氢叶酸钙:0.05%~3%,着色剂:0.05%~3%。
所述的6S-5-甲基四氢叶酸钙制剂包含乳清蛋白速释层、固体分散体技术制备的复配维生素/矿物质与6S-5-甲基四氢叶酸钙缓释层,其中6S-5-甲基四氢叶酸钙粒径通过球磨技术控制在50~100μm。
所述的固体分散体载体采用的是乳糖、麦芽糊精、微晶纤维素、玉米淀粉、预胶化淀粉中的一种或几种组合。
所述的羟丙基甲基纤维素为粘合剂。
所述的复配矿物质为焦磷酸铁、碳酸钙、氧化锌、亚硒酸钠中的一种或几种组合。
所述的着色剂采用羟丙基甲基纤维素、磷脂、高粱红、天然胡萝卜素中的一种或几种组合。
所述的复配维生素为dl-α-醋酸生育酚、烟酸、D-泛酸钙、醋酸视黄酯、氰钴胺、胆钙化醇、盐酸吡哆醇、盐酸硫胺素、核黄素、抗坏血酸中的一种或几种组合。
所述的6S-5-甲基四氢叶酸钙制剂以湿法制粒设备、固体分散体制备设备球磨机和双层压片设备制备。
本发明还提供一种6S-5-甲基四氢叶酸钙制剂的制备方法,其特征在于:包括以下步骤:
步骤一,根据配方进行称重配料,各组分的质量百分比如下:
浓缩乳清蛋白:15%~40%;
复配维生素:1%~25%;
复配矿物质:1%~25%;
填充剂:1%~25%;
6S-5-甲基四氢叶酸钙:0.05%~3%;
复配着色剂:0.05%~3%;
固体分散剂载体:1%~25%;
粘合剂:1%~5%;
甜菜碱:1%~15%;
步骤二:将羟丙基甲基纤维素制成浓度3%~10%的浆液,作为粘合剂备用;
步骤三:将浓缩乳清蛋白、填充剂投入湿法混合制粒锅内混合,加入粘合剂搅拌制粒,做成软材a:
步骤四:将所得软材a通过整粒机上制出湿粒a;
步骤五:将湿粒a投入流化床内进行干燥,得到干颗粒a;
步骤六:将复配维生素、复配矿物质、固体分散体载体、6S-5-甲基四氢叶酸钙投入球磨机内球磨2~12h,得到固体分散体;
步骤七:将干颗粒a、复配着色剂、甜菜碱一同投入总混机内,混合后得到总混颗粒a;
步骤八:将固体分散体、复配着色剂一同投入总混机内,混合后得到总混颗粒b;
步骤九:在双层压片机两个料斗中分别投入总混颗粒a和总混颗粒b,制备得到双层片。
本发明通过不断试验,优化配方和工艺,制粒工艺采用固体分散体技术,解决了脂溶性维生素生物利用度差、低含量组分均匀度差的问题,达到了延长释放效果、增加稳定性的目的,提供了连续批量化生产的可行性方案;成品采用双层片制备技术,在同一片剂中实现了不同组分的速释和缓释效果,解决了普通制剂常见的均匀度差、生产成本高、服用顺应性差等问题。本发明提供了一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂;提供了一种简便易行的制备方法;本方法操作性强,产能大,可行性好、制造成本较低。
具体实施方式
下面结合具体实施例对本发明作进行详细的说明。
实施例1:
本发明配方包括表1所示的组分:
表1
一种6S-5-甲基四氢叶酸钙制剂的制备方法包括以下步骤:
1、将配方中的羟丙基甲基纤维素制成浓度3%~10%的浆液;
2、根据配方称量配料,备用;
3、将浓缩乳清蛋白、填充剂投入湿法混合制粒锅内混合,加入羟丙基甲基纤维素浆液搅拌制粒,做成软材a:
4、将所得软材a通过整粒机上制出湿粒a;
5、将湿粒a投入流化床内,开启设备干燥得到干颗粒a;
6、将复配维生素、复配矿物质、填充剂、6S-5-甲基四氢叶酸钙投入湿法混合制粒锅内混合,加入粘合剂搅拌制粒,做成软材b:
7、将所得软材b在整粒机上制出湿粒b;
8、将湿粒b投入流化床内,开启设备干燥得到干颗粒b;
9、将干颗粒a、复配着色剂、甜菜碱一同投入总混机内,混合一定时间后得到总混颗粒a;
10、将干颗粒b、复配着色剂一同投入总混机内,混合一定时间后得到总混颗粒b;
11、在双层压片机两个料斗中分别投入总混颗粒a和总混颗粒b,制备双层片。
实施例2:
本发明配方包括表3所示的组分:
表2
一种6S-5-甲基四氢叶酸钙制剂的制备方法包括以下步骤:
步骤一,根据配方进行称量配料;
步骤二:将羟丙基甲基纤维素制成浓度3%~10%的浆液,作为粘合剂备用;
步骤三:将浓缩乳清蛋白、填充剂投入湿法混合制粒锅内混合,加入粘合剂搅拌制粒,做成软材a:
步骤四:将所得软材a通过整粒机上制出湿粒a;
步骤五:将湿粒a投入流化床内进行干燥,得到干颗粒a;
步骤六:将复配维生素、复配矿物质、固体分散体载体、6S-5-甲基四氢叶酸钙投入球磨机内球磨2~12h,得到固体分散体;
步骤七:将干颗粒a、复配着色剂、甜菜碱一同投入总混机内,混合后得到总混颗粒a;
步骤八:将固体分散体、复配着色剂一同投入总混机内,混合后得到总混颗粒b;
步骤九:在双层压片机两个料斗中分别投入总混颗粒a和总混颗粒b,制备得到双层片。
对比各实施例的各组分溶出度,结果见表3和表4
表3
从数据上来看,每粒都符合30min溶出度大于85%的质量要求。
表4
从数据上来看,脂溶性成分核黄素在应用固体分散体制备技术的实施例2中,其释放度相对应用普通制粒工艺的实施例1有大幅度提升。
对比各实施例的各组分均匀度,结果见表5
数据上来看,采用双层片制备工艺,将粒度差异较大的浓缩乳清蛋白和复配维生素/矿物质分开制粒,同时采用球磨工艺制备固体分散体,提高了6S-5-甲基四氢叶酸钙在处方中的分散程度,对6S-5-甲基四氢叶酸钙的含量均匀度有极大的提升,对其余组分的均匀度也有小幅提升。
以上对本发明的具体实施例进行了描述。需要理解的是,本发明并不局限于上述特定实施方式,本领域技术人员可以在权利要求的范围内做出各种变形或修改,这并不影响本发明的实质内容。
Claims (8)
1.一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂,其特征在于:
由以下质量百分比的组分组成:
浓缩乳清蛋白:15%~40%;
复配维生素:1%~25%;
复配矿物质:1%~25%;
填充剂1%~25%;
6S-5-甲基四氢叶酸钙:0.05%~3%;
复配着色剂:0.05%~3%;
固体分散剂载体:1%~25%;
粘合剂:1%~5%;
甜菜碱:1~15%。
2.如权利要求1所述的一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂,其特征在于:所述的固体分散体载体采用的是乳糖、麦芽糊精、微晶纤维素、玉米淀粉、预胶化淀粉中的一种或几种组合。
3.如权利要求1所述的一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂,其特征在于:所述的填充剂为乳糖、麦芽糊精、玉米淀粉、预胶化淀粉中的一种或几种。
4.如权利要求1所述的一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂,其特征在于:粘合剂为羟丙基甲基纤维素。
5.如权利要求1所述的一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂,其特征在于:所述的复配矿物质为焦磷酸铁、碳酸钙、氧化锌、亚硒酸钠中的一种或几种组合。
6.如权利要求1所述的一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂,其特征在于:所述的复配着色剂为羟丙基甲基纤维素、磷脂、高粱红、天然胡萝卜素中的一种或几种组合。
7.如权利要求1所述的一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂,其特征在于:所述的复配维生素为dl-α-醋酸生育酚、烟酸、D-泛酸钙、醋酸视黄酯、氰钴胺、胆钙化醇、盐酸吡哆醇、盐酸硫胺素、核黄素、抗坏血酸中的一种或几种组合。
8.如权利要求1-7任一项所述的一种6S-5-甲基四氢叶酸钙固体分散体双层片制剂的制备方法,其特征在于:包括以下步骤:
步骤一,根据配方进行称重配料,各组分的质量百分比如下:
浓缩乳清蛋白:15%~40%;
复配维生素:1%~25%;
复配矿物质:1%~25%;
填充剂:1%~25%;
6S-5-甲基四氢叶酸钙:0.05%~3%;
复配着色剂:0.05%~3%;
固体分散剂载体:1%~25%;
粘合剂:1%~5%;
甜菜碱:1%~5%;
步骤二:将羟丙基甲基纤维素制成浓度3%~10%的浆液,作为粘合剂备用;
步骤三:将浓缩乳清蛋白、填充剂投入湿法混合制粒锅内混合,加入粘合剂搅拌制粒,做成软材a:
步骤四:将所得软材a通过整粒机上制出湿粒a;
步骤五:将湿粒a投入流化床内进行干燥,得到干颗粒a;
步骤六:将复配维生素、复配矿物质、固体分散体载体、6S-5-甲基四氢叶酸钙投入球磨机内球磨2~12h,得到固体分散体;
步骤七:将干颗粒a、复配着色剂、甜菜碱一同投入总混机内,混合后得到总混颗粒a;
步骤八:将固体分散体、复配着色剂一同投入总混机内,混合后得到总混颗粒b;
步骤九:在双层压片机两个料斗中分别投入总混颗粒a和总混颗粒b,制备得到双层片。
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