CN112972400A - 可快速崩解的米诺膦酸颗粒及制备方法 - Google Patents
可快速崩解的米诺膦酸颗粒及制备方法 Download PDFInfo
- Publication number
- CN112972400A CN112972400A CN202110256121.2A CN202110256121A CN112972400A CN 112972400 A CN112972400 A CN 112972400A CN 202110256121 A CN202110256121 A CN 202110256121A CN 112972400 A CN112972400 A CN 112972400A
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- Prior art keywords
- minodronic acid
- agent
- minodronate
- granules
- rapidly
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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Abstract
本发明涉及一种可快速崩解的米诺膦酸颗粒，包括如下重量百分比的原料：米诺膦酸0.5％‑1.5％、辅助中药单体10‑25％、填充剂50％‑70％、崩解剂5％‑10％、润滑剂0.1％‑1.5％、混悬剂0.4‑0.8％以及余量的润湿剂。本发明的颗粒作为片剂制备工艺的中间体，在制备溶出度高，含量均匀度高的片剂中起着至关重要的作用。本发明制备方法将米诺膦酸制备成混悬液喷洒在辅料中，可提高含量均匀度，同时所制备的米诺膦酸颗粒均匀，休止角小，颗粒流动性好，为后期制备含量均匀度高的片剂提供基础。
Description
技术领域
本发明涉及一种可快速崩解的米诺膦酸颗粒及制备方法，属于医药技术领域。
背景技术
骨质疏松症是一种内分泌、营养、免疫、遗传等多种复合因素引起的代谢性疾病，其主要特征是骨质在代谢进程中，骨组织微观结构变化，表现为骨矿含量减少和骨骼脆性的增加，随骨密度的下降，易导致全身性骨骼疾病，造成骨骼持续疼痛，腰背畸形和脊柱变形，此外可引起椎骨及桡骨远端骨折，被称为吞噬老年人健康的隐形流病。
米诺膦酸水合物2009年4月首次获准上市，商品名分别为
(小野药品)和
(Astel las制药)。英文名minodronic acid，化学名称为1-羟基-2-[咪唑并(1,2-a)吡啶-3-基]亚乙基)双膦酸一水合物，分子量为340.16，分子式为C9H12N2O7P2·H2O。米诺膦酸为一种新型杂环双膦酸类化合物，用于治疗骨质疏松症以及由骨质疏松症和恶性肿瘤引起的高血症，其抑制骨吸收活性分别是阿仑膦酸和帕米膦酸的10倍和100倍。与以往药物相比，具有更好的疗效，且不良反应更少见的优势。
米诺膦酸原研药的处方组成包括乳糖、玉米淀粉、羟丙基纤维素、硬脂酸镁、羟丙基甲基纤维素、滑石粉、聚乙二醇6000、二氧化钛，米诺膦酸原研药的处方成分是较常用的药用辅料，在溶出过程中易形成椎体效应，选择溶解性好的辅料以及合适的崩解剂，可提高崩解速度，改善溶出。
专利CN201510596342.9公开了一种含有米诺膦酸的制剂及其制备，包括米诺膦酸与分散载体的微粉化颗粒、微晶纤维素和水溶性聚合物粘合剂。该发明制备米诺膦酸需将米诺膦酸及辅料微粉化至1-12μm，分散载体为聚乙二醇，黏度大，在压片步骤中因辅料黏度增大导致黏冲使得制备工艺难度大。
鉴于此，本案发明人对上述问题进行深入研究，遂有本案产生。
发明内容
本发明的目的在于提供一种适合大生产，含量均匀度高，可快速崩解的米诺膦酸颗粒。本发明的另一目的在于提供一种米诺膦酸颗粒制备方法，其具有工艺简单的优点。
为了达到上述目的，本发明采用这样的技术方案：
可快速崩解的米诺膦酸颗粒，包括如下重量百分比的原料：米诺膦酸0.5％-1.5％、辅助中药单体10-25％、填充剂50％-70％、崩解剂5％-10％、润滑剂0.1％-1.5％、混悬剂0.4-0.8％以及余量的润湿剂。
作为本发明的一种优选方式，所述米诺膦酸为D型一水合物晶型，粒径为100-120目。
作为本发明的一种优选方式，所述辅助中药单体为宝藿苷Ⅰ、龙胆根素、牡荆素、L-天冬氨酸螯合钙中的任意一种。
作为本发明的一种优选方式，所述填充剂为羧甲硫酸葡聚糖、粒化乳糖、箭根淀粉中的一种或几种。
作为本发明的一种优选方式，所述崩解剂为羧甲基木薯淀粉钠、膨润土、熔融制粒甘露醇中的一种或几种。
作为本发明的一种优选方式，所述润滑剂为甲壳胺、硬脂酸锌、硬脂马来酸钠中的一种或几种。
作为本发明的一种优选方式，所述混悬剂为卡拉胶、羟乙基田菁胶、丙烯酸树脂Ⅱ号中的一种或几种。
作为本发明的一种优选方式，所述润湿剂为水。
可快速崩解的米诺膦酸颗粒的制备方法，各原料以重量百分比计，包括如下步骤：
步骤a、取辅助中药单体10％-25％、填充剂50％-70％以及崩解剂4％-8％作为辅料，过100目筛，运用槽型混合机作为预混设备，混合15-25min；
步骤b、将米诺膦酸0.5％-1.5％、混悬剂0.4-0.8％用润湿剂溶解制备成混悬溶液，以雾化形式喷洒到持续混合的辅料中，喷射压力0.1-0.6MPa，喷射速度5-15mL·min-1；
步骤c、采用流化床制粒后，真空干燥2-4h，干燥温度40-60℃，干燥失重(LOD)小于3％；
步骤d、将整粒好的颗粒和崩解剂1％-5％、润滑剂0.1％-1.5％放入V型混合机中，混合10-15min，即得米诺膦酸颗粒。
作为本发明的一种优选方式，所述干燥时间为2.5-3.5h，所述干燥温度为45-55℃。
作为本发明的一种优选方式，所述崩解剂的添加方法为内外加法。
采用上述技术方案后，有以下有益效果：颗粒作为片剂制备工艺的中间体，在制备溶出度高，含量均匀度高的片剂中起着至关重要的作用。米诺膦酸片为低剂量固体制剂，本发明制备方法将米诺膦酸制备成混悬液喷洒在辅料中，可提高含量均匀度，同时所制备的米诺膦酸颗粒均匀，休止角小，颗粒流动性好，为后期制备含量均匀度高的片剂提供基础。新型药用辅料溶解度高，所制备的颗粒崩解速度快。辅助中药单体本质是化学成分，但其发源于中医药，中西药的复方剂有助于提高药物疗效，降低毒副作用，缩短用药周期。
现有实验研究不同粒径的主药对制剂的溶出度结果显示不同粒径主药对制剂溶出度无影响。因此只须在投料前将原辅料过100目筛即可。槽型混合机作为预混设备，运用等量递加原则进行混料，混合15-25min，可实现物料混合均匀，将米诺膦酸制成混悬剂，以雾状形式喷洒到物料中可实现原料药与辅料的充分混合，提高药物的含量均匀度。
具体实施方式
为了进一步解释本发明的技术方案，下面结合实施例进行详细阐述。
可快速崩解的米诺膦酸颗粒，包括如下重量百分比的原料：米诺膦酸0.5％-1.5％、辅助中药单体10-25％、填充剂50％-70％、崩解剂5％-10％、润滑剂0.1％-1.5％、混悬剂0.4-0.8％以及余量的润湿剂。
作为本发明的一种优选方式，所述米诺膦酸为D型一水合物晶型，粒径为100-120目。不同的药物晶型具有不同的机械性能和晶体形态学，导致松密度、流动性、可压性等粉体学性质不同，进而影响制剂工艺。与米诺膦酸相关的晶型专利有WO9400462A1，该专利报道了米诺膦酸的A、B、C、D和E五种晶型，其中A和B为米诺膦酸单钠盐的晶体形式，C为米诺膦酸的半水合物晶型，D和E为米诺膦酸一水合物的晶型，其中D晶型适宜工业化生产，为上市晶型。
作为本发明的一种优选方式，所述辅助中药单体为宝藿苷Ⅰ、龙胆根素、牡荆素、L-天冬氨酸螯合钙中的任意一种。
作为本发明的一种优选方式，所述填充剂为羧甲硫酸葡聚糖、粒化乳糖、箭根淀粉中的一种或几种。
作为本发明的一种优选方式，所述崩解剂为羧甲基木薯淀粉钠、膨润土、熔融制粒甘露醇中的一种或几种。
作为本发明的一种优选方式，所述润滑剂为甲壳胺、硬脂酸锌、硬脂马来酸钠中的一种或几种。
作为本发明的一种优选方式，所述混悬剂为卡拉胶、羟乙基田菁胶、丙烯酸树脂Ⅱ号中的一种或几种。
作为本发明的一种优选方式，所述润湿剂为水。
实施例1
可快速崩解的米诺膦酸颗粒的制备方法，为以下步骤：
(1)取宝藿苷Ⅰ10％、羧甲硫酸葡聚糖30％、粒化乳糖40％、羧甲基木薯淀粉钠8％，过100目筛运用槽型混合机作为预混设备形成辅料，混合20min。
(2)将米诺膦酸1％、卡拉胶0.4％用水溶解制备成混悬溶液，以雾化形式喷洒到持续混合的辅料中，喷射压力0.2MPa，喷射速度10mL·min-1。
(3)采用流化床制粒后，真空干燥3h，干燥温度60℃，干燥失重(LOD)小于3％。
(4)将整粒好的颗粒和羧甲基木薯淀粉钠2％、硬脂酸锌0.5％放入V型混合机中，混合10min，即得米诺膦酸颗粒。
实施例2
可快速崩解的米诺膦酸颗粒的制备方法，为以下步骤：
(1)取龙胆根素20％、箭根淀粉50％，粒化乳糖20％、膨润土4％，过100目筛运用槽型混合机作为预混设备形成辅料，混合15min。
(2)将米诺膦酸1％、丙烯酸树脂Ⅱ号0.5％用水溶解制备成混悬溶液，以雾化形式喷洒到持续混合的辅料中，喷射压力0.1MPa，喷射速度12mL·min-1。
(3)采用流化床制粒后，真空干燥2h，干燥温度50℃，干燥失重(LOD)小于3％，优选干燥时间2.5h，干燥温度45℃；
(4)将整粒好的颗粒和膨润土5％、甲壳胺1.5％放入V型混合机中，混合10-15min，即得米诺膦酸颗粒。
实施例3
可快速崩解的米诺膦酸颗粒的制备方法，为以下步骤：
(1)取牡荆素20％、羧甲硫酸葡聚糖10％、箭根淀粉50％、熔融制粒甘露醇6％，过100目筛运用槽型混合机作为预混设备形成辅料，混合15min。
(2)将米诺膦酸1％、羟乙基田菁胶0.5％用水溶解制备成混悬溶液，以雾化形式喷洒到持续混合的辅料中，喷射压力0.4MPa，喷射速度8mL·min-1。
(3)采用流化床制粒后，真空干燥2.5h，干燥温度50℃，干燥失重(LOD)小于3％，优选干燥时间2.5h，干燥温度45℃；
(4)将整粒好的颗粒和熔融制粒甘露醇1％、硬脂马来酸钠1％放入V型混合机中，混合15min，即得米诺膦酸颗粒。
根据米诺膦酸原研片的处方组成，按米诺膦酸1％、玉米淀粉25％、乳糖63.5％、低取代羟丙基纤维素10％、硬脂酸镁0.5％比例，与实施例一致的制备工艺制备米诺膦酸颗粒，操作步骤为(1)取米诺膦酸1％、玉米淀粉25％、乳糖63.5％、低取代羟丙基纤维素10％，过100目筛运用槽型混合机作为预混设备形成辅料，混合20min。(2)采用流化床制粒后，真空干燥3h，干燥温度60℃，干燥失重(LOD)小于3％。(3)将整粒好的颗粒和硬脂酸镁0.5％放入V型混合机中，混合10min，即得米诺膦酸原研药处方颗粒。称取合格的颗粒剂0.5g，共称6份，依次倒入崩解仪的吊篮中(0.425mm孔径)，测定颗粒全部通过筛网的时间，平行测定3次，测定的温度为37℃，求算平均值，比较崩解速度，结果见表1。
表1崩解速度考察结果
将实例1、2、3的可快速崩解的米诺膦酸颗粒压片，控制片剂硬度在50-70N。进行普通薄膜包衣。测定所得实例1、2、3米诺膦酸颗粒的休止角，片剂的含量均匀度及有关物质，见表2。按照溶出度测定方法，测定本发明实例1、2、3所制备的片剂，以500mL水为介质，浆法，转速为50转/分，考察5、10、15、30、45、60min的累积溶出度，见表3。
表2各实例的质量考察结果
表3累积溶出度考察
由以上实例验证，本发明一种可快速崩解的米诺膦酸颗粒含量均匀度好，流动性好，崩解快，溶出度高，适合工业化生产。
本发明的产品形式并非限于本案实施例，任何人对其进行类似思路的适当变化或修饰，皆应视为不脱离本发明的专利范畴。
Claims (10)
1.可快速崩解的米诺膦酸颗粒，其特征在于，包括如下重量百分比的原料：米诺膦酸0.5％-1.5％、辅助中药单体10-25％、填充剂50％-70％、崩解剂5％-10％、润滑剂0.1％-1.5％、混悬剂0.4-0.8％以及余量的润湿剂。
2.如权利要求1所述的可快速崩解的米诺膦酸颗粒，其特征在于，所述米诺膦酸为D型一水合物晶型，粒径为100-120目。
3.如权利要求1所述的可快速崩解的米诺膦酸颗粒，其特征在于，所述辅助中药单体为宝藿苷Ⅰ、龙胆根素、牡荆素、L-天冬氨酸螯合钙中的任意一种。
4.如权利要求1所述的可快速崩解的米诺膦酸颗粒，其特征在于，所述填充剂为羧甲硫酸葡聚糖、粒化乳糖、箭根淀粉中的一种或几种。
5.如权利要求1所述的可快速崩解的米诺膦酸颗粒，其特征在于，所述崩解剂为羧甲基木薯淀粉钠、膨润土、熔融制粒甘露醇中的一种或几种。
6.如权利要求1所述的可快速崩解的米诺膦酸颗粒，其特征在于，所述润滑剂为甲壳胺、硬脂酸锌、硬脂马来酸钠中的一种或几种。
7.如权利要求1所述的可快速崩解的米诺膦酸颗粒，其特征在于，所述混悬剂为卡拉胶、羟乙基田菁胶、丙烯酸树脂Ⅱ号中的一种或几种。
8.如权利要求1所述的可快速崩解的米诺膦酸颗粒，其特征在于，所述润湿剂为水。
9.可快速崩解的米诺膦酸颗粒的制备方法，其特征在于，各原料以重量百分比计，包括如下步骤：
步骤a、取辅助中药单体10％-25％、填充剂50％-70％以及崩解剂4％-8％作为辅料，过100目筛，运用槽型混合机作为预混设备，混合15-25min；
步骤b、将米诺膦酸0.5％-1.5％、混悬剂0.4-0.8％用润湿剂溶解制备成混悬溶液，以雾化形式喷洒到持续混合的辅料中，喷射压力0.1-0.6MPa，喷射速度5-15mL·min-1；
步骤c、采用流化床制粒后，真空干燥为2-4h，干燥温度为40-60℃，干燥失重(LOD)小于3％；
步骤d、将整粒好的颗粒和崩解剂1％-5％、润滑剂0.1％-1.5％放入V型混合机中，混合10-15min，即得米诺膦酸颗粒。
10.如权利要求9所述的可快速崩解的米诺膦酸颗粒的制备方法，其特征在于，所述干燥时间为2.5-3.5h，所述干燥温度为45-55℃。
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