CN113491674A - 一种用于含有稳定性差和含量低的脂溶性维生素预混粉的制备方法 - Google Patents
一种用于含有稳定性差和含量低的脂溶性维生素预混粉的制备方法 Download PDFInfo
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Abstract
本发明涉及维生素，具体本发明公开了一种脂溶性维生素预混粉的制备工艺。一种脂溶性维生素预混粉的制备方法，其特征在于：将脂溶性维生素1份，脂肪酸10~100份，两者溶解混合均匀，利用热熔喷雾制粒机制备含维生素粉体，通过调整喷雾参数控制粉体粒度为10‑140μm；用隔湿膜材流化床包衣；得到的预混粉的粒径在20~150μm，水分含量小于1.0%。本发明可以有效改善脂溶性维生素的不稳定性和制剂中脂溶性维生素成分的含量均匀度。方法中的硬脂酸可溶于pH6.8以上的溶液，隔湿膜材包衣层为水溶性在接触胃液时会溶解，两者共同作用可保证脂溶性维生素的释放吸收，药物生物利用度高。
Description
技术领域
本发明涉及维生素，具体本发明公开了一种脂溶性维生素预混粉的制备工艺。
背景技术
脂溶性维生素类药物普遍具有性质不稳定，易被氧化、液体状态不便于运输和保存等缺点；制剂中剂量较低，制剂含量均匀度不易于保证。例如维生素D3成分在诸多含钙类制剂中含量范围为90％-120％，只有几微克，单制剂含量均匀度很难保障。在以前技术中，虽然也有将诸如维生素D3制备成粉体来克服上述不稳定性和含量均匀度较低的技术手段(帝斯曼公司维生素D3粉)，但其组分和制备技术均较为复杂，并且所制粉体粒度较大(大于180um)。
维生素D3结构式
维生素D类降解途径
发明内容
本发明的目的在于克服上述现有技术的不足，提供一种组分和制备工艺更为简单的脂溶性维生素预混粉的方法。
技术方案
一种脂溶性维生素预混粉的制备方法，其特征在于：按重量份计，将脂溶性维生素1份，脂肪酸10～100份，两者溶解混合均匀，利用热熔喷雾制粒机制备含维生素粉体，通过调整喷雾参数控制粉体粒度为10-140μm；用隔湿膜材流化床包衣；得到的预混粉的粒径在20～150μm，水分含量小于1.0％。
所述的脂肪酸为硬脂酸或硬脂酸与棕榈酸的混合物，其中硬脂酸与棕榈酸重量比为1:4—4:1。
所述的脂溶性维生素包括：维生素D类、维生素A类、维生素E类、维生素K或上述任意两种以上的维生素组合的混合物。
所述的包衣材料为欧巴代Ⅱ 85G60991。
所制得预混粉进一步加工制备为干混悬剂、颗粒剂、片剂或咀嚼片。尤其在含钙类固体制剂中应用。
硬脂酸在pH6.8以上的溶液和接触肠液时也会分散或溶解，不会影响脂溶性维生素的口服生物利用度。
有益效果
1、本发明关键定在于脂溶性维生素与脂肪酸控制特定比例，如1:10～100(重量比)，根据实施例与对比例比较获知，就考察含量均匀度、稳定性和释放而言，脂溶性维生素与脂肪酸的比例与产品中含量均匀度的风险程度和产品的稳定性相关。在脂溶性维生素：脂肪酸比例高于1:10(如1:5)时，脂肪酸不能将脂溶性维生素更好的包裹，产品稳定性较差；在脂溶性维生素：脂肪酸比例低于1:100(如1:199)时，由于一般情况下在制剂产品中脂溶性维生素占比较低(小于1％)，为了达到相同的脂溶性维生素规格剂量，需要添加更多的维生素预混粉，其释放也存在风险。而本发明选定的比例保证了脂溶性维生素被隔绝空气及水分，稳定性良好；且通过控制粉体粒径，可以使此含脂溶性维生素预混粉使用时，制剂中维生素含量均匀度良好，与参比试剂在含量均匀度，稳定性，释放曲线都是符合一致性评价要求。该本发明制得的预混粉具有较小的粒度分布20um-150um，良好的稳定性。该技术可广泛应用于含脂溶性维生素的固体制剂的制备。
2、本发明可以有效改善脂溶性维生素的不稳定性和制剂中脂溶性维生素成分的含量均匀度。方法中的硬脂酸可溶于pH6.8以上的溶液，隔湿膜材包衣层为水溶性在接触胃液时会溶解，两者共同作用可保证脂溶性维生素的释放吸收，药物生物利用度高。
具体实施方式
下述实施例用于进一步阐述权利要求的实施方式，不限制本发明。
实施例1：含维生素D3成分预混粉的制备(维生素D31份，硬脂酸10份)维生素D3预混粉的成分为：维生素D3 25g，硬脂酸250g，欧巴代85F120028-CN包衣粉，适量。
维生素D3预混粉的制备方法：
(1)将处方量的硬脂酸和维生素D3，加热至85℃熔融，将熔融后物料利用热熔喷雾制粒机喷雾冷却制粒，雾化压力0.25MPa，进风温度-10℃，进液转速35rpm。收集冷却后粉体。
(2)将步骤(1)所得的粉体用85F120028-CN包衣粉流化床底喷喷包衣，进风温度35～50℃，风量0.9～1.5m3/min·kg，雾化压力0.35MPa。收集包衣后粉体。
(3)将步骤(2)包衣后粉体测试粒度。
实施例2：维生素D3和维生素E预混粉的制备(维生素D31份，维生素E 0.055份，硬脂酸89.5份)
维生素D3和维生素E预混粉的成分为：维生素D3 10g，维生素E 0.55g，硬脂酸895g，欧巴代Ⅱ 85G60991包衣粉，适量。
维生素D3和维生素E预混粉的制备方法：
(1)将处方量的硬脂酸和维生素D3和维生素E，加热至85℃熔融，将熔融后物料利用热熔喷雾制粒机喷雾冷却制粒，雾化压力0.4MPa，进风温度-10℃，进液转速25rpm。收集冷却后粉体。。
(2)将步骤(1)所得的粉体用欧巴代Ⅱ 85G60991包衣粉流化床底喷包衣，进风温度30～50℃，风量1.0～1.4m3/min·kg，雾化压力0.45MPa。
(3)将步骤(2)包衣后粉体测试粒度。
实施例3：含维生素D3成分预混粉的制备(维生素D31份，硬脂酸100份)
维生素D3预混粉的成分为：维生素D3 25g，硬脂酸2500g，欧巴代85F120028-CN包衣粉，适量。
制备工艺与实施例1维生素D3预混粉的制备方法一致。
对比例1：含维生素D3成分预混粉的制备(维生素D31份，硬脂酸199份)
维生素D3预混粉的成分为：维生素D3 25g，硬脂酸4975g，欧巴代85F120028-CN包衣粉，适量。
制备工艺与实施例1维生素D3预混粉的制备方法一致。
对比例2：含维生素D3成分预混粉的制备(维生素D31份，硬脂酸4份)
维生素D3预混粉的成分为：维生素D3 25g，硬脂酸100g，欧巴代85F120028-CN包衣粉，适量。
制备工艺与实施例1维生素D3预混粉的制备方法一致。
结果
1、粒度测试(实施例1)
| 粒度 | 维生素D<sub>3</sub>预混粉 | 维生素D<sub>3</sub>和维生素E预混粉 |
| D10(um) | 9.44 | 2.48 |
| D50(um) | 42.41 | 10.93 |
| D90(um) | 140.00 | 29.76 |
说明：上表可以看出通过不同的制备工艺所得预混粉粒度不同，可以获得权利保护要求粒度范围内的预混粉。
2、含脂溶性维生素的含量均匀度实验
使用实施例1制备的维生素D3和维生素E预混粉和使用市售的帝斯曼公司(DSMNutritional Products Ltd)生产的维生素D3粉使用相同的制备工艺制备小儿碳酸钙D3颗粒，测试含量均匀度及稳定性
说明：上表显示使用本发明工艺制得的预混粉可以大大提高制剂中有效成分的混合均匀度。与现有技术上市产品比较。
3、稳定性数据(测试维生素D3含量变化)
说明：上表显示使用本发明工艺制得的预混粉与现有技术产品比较，制剂中有效成分稳定性基本一致。
4、实施例与对比例的比对
脂溶性维生素与脂肪酸的比例与产品中含量均匀度的风险程度和产品的稳定性相关。在脂溶性维生素：脂肪酸比例高于1:10(如1:4)时，脂肪酸不能将脂溶性维生素更好的包裹，产品稳定性较差；在脂溶性维生素：脂肪酸比例低于1:100(如1:199)时，由于一般情况下在制剂产品中脂溶性维生素占比较低(小于1％)，为了达到相同的脂溶性维生素规格剂量，需要添加更多的维生素预混粉，其释放也存在风险。
(1)实施例1与对比例2的稳定性比对
利用相同的处方工艺，分别使用实施例1(含维生素D3成分预混粉)和对比例2(含维生素D3成分预混粉)制备制剂产品，比较其加速期间维生素D3的稳定性情况(测试样品加速期间维生素D3含量变化)。
结论：利用实施例1预混粉制备的样品获得较利用对比例2预混粉制备的样品更好的稳定性结果
(2)实施例3与对比例1的样品含量均匀度及活性成分释放的比对
利用相同的处方工艺，分别使用实施例3(含维生素D3成分预混粉)和对比例1(含维生素D3成分预混粉)制备制剂产品，比较两者的样品的含量均匀度及产品活性组分(维生素D3)释放情况
结论：样品3和样品4在产品活性组分含量均匀度水平方面基本一致。
结论：由样品3和样品4在同种介质的中活性成分的释放情况来看，样品3远优于样品4。在45min达到85％，符合溶出设计限度。脂溶性维生素：脂肪酸比例不得低于1:100。
Claims (5)
1.一种脂溶性维生素预混粉的制备方法，其特征在于：按重量份计，将脂溶性维生素1份，脂肪酸10~100份，两者溶解混合均匀，利用热熔喷雾制粒机制备含维生素粉体，通过调整喷雾参数控制粉体粒度为10-140μm；用隔湿膜材流化床包衣；得到的预混粉的粒径在20~150μm，水分含量小于1.0%。
2.权利要求1中所述的方法，其特征在于：所述的脂肪酸为硬脂酸或硬脂酸与棕榈酸的混合物，其中硬脂酸与棕榈酸重量比为1:4—4:1。
3.权利要求1所述的方法，其特征在于：所述的脂溶性维生素包括：维生素D类、维生素A类、维生素E类、维生素K或上述任意两种以上的维生素组合的混合物。
4.权利要求1所述的方法，其特征在于：所述的包衣材料为欧巴代Ⅱ85G60991。
5.权利要求1所述的方法，其特征在于所制得预混粉进一步加工制备为干混悬剂、颗粒剂、片剂或咀嚼片。
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