CN114681398A - 一种枸橼酸莫沙必利糖浆剂及其制备方法 - Google Patents
一种枸橼酸莫沙必利糖浆剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种含有枸橼酸莫沙必利的糖浆剂，属于医药制剂领域，本发明糖浆剂含有枸橼酸莫沙必利、矫味剂、β‑环糊精、稳定剂、芳香剂、抑菌剂以及纯化水组成，制备方法为：先将β‑环糊精溶于水中，搅拌溶解，再加入枸橼酸莫沙必利，搅拌溶解，得溶液I，备用；将稳定剂、抑菌剂、芳香剂溶于水中，再加入矫味剂，得溶液II备用；将溶液I、溶液II混合，即得。本发明制备的糖浆剂，稳定性提高，儿童服用方便、安全的特点。制备工艺简单，适于工业生产，便于市场推广。
Description
技术领域
本发明涉及一种枸橼酸莫沙必利糖浆及其制备方法，属于医药制剂领域
技术背景
本品为选择性5-羟色胺4(5-HT4)受体激动剂，通过兴奋胃肠道胆碱能中间神经元及肌间神经丛的5-HT4受体，促进乙酰胆碱的释放，从而增强胃肠道的运动，改善功能性消化不良病人的胃肠道症状，不影响胃酸的分泌。本品与大脑突触膜上的多巴胺D2、5-HT1、5-HT2受体无亲和力，因而没有这些受体阻滞所引起的锥体外系的副作用。
枸橼酸莫沙必利临床选择的剂型有片剂，口服溶液等，由于枸橼酸莫沙必利水溶性较差，故在片剂等固体制剂中药物难以溶出，使药物达不到应有的治疗作用。而糖浆、口服溶液等液体制剂则生物利用度高，并且特别适于儿童和吞咽困难病人使用。
中国专利CN101273973B公开了一种用粉末直接压片制备的含有枸橼酸莫沙必利的药物组合物及其制备方法
目前国内已有的枸橼酸莫沙必利制剂主要为片剂和口服溶液制剂，本发明提供一种可增加患者适应性的糖浆剂，已达到广大患者的服用需求。
发明内容
本发明的目的在于提供一种优质，口服用枸橼酸莫沙必利糖浆剂，克服现有技术存在的不足，制剂降解杂质得到很好的改善，稳定性大大提高，儿童服用更安全的枸橼酸莫沙必利糖浆制剂及其制备方法。
本发明的目的是通过如下技术方案来完成的，一种枸橼酸莫沙必利的糖浆制剂，所述枸橼酸莫沙必利含有枸橼酸莫沙必利、矫味剂、β-环糊精、稳定剂、芳香剂、抑菌剂以及纯化水。
所述的β-环糊精为水溶性β-环糊精，所述的水溶性β环糊精为羟丙基-β-环糊精、磺丁基-β-环糊精、2,6-二甲氧基-β-环糊精、羟乙基-β-环糊精中的一种或多种；优选地，所述的水溶性β环糊精为羟丙基-β-环糊精。
所述的矫味剂为葡糖糖、麦芽糖、蔗糖中的一种或多种。
所述的稳定剂为甘油、海藻酸钠、预胶化淀粉、聚维酮、羧甲基纤维素钠、羟丙基纤维素、枸橼酸钠、羟丙甲纤维素中的一种或多种。
所述的芳香剂为柠檬香精、甜橙香精、水蜜桃香精、覆盆子香精中的一种或多种。
所述的抑菌剂是苯甲酸、苯甲酸钠、羟苯甲酯、羟苯乙酯、山梨酸钾中的一种或几种；
所述的枸橼酸莫沙必利糖浆剂，以重量比计算，
所述的稳定剂为甘油、海藻酸钠，进一步地优选为，二者的用量比为1:1。
所述的抑菌剂是苯甲酸钠。
本发明的第二个目的在于，提供一种制备枸橼酸莫沙必利糖浆剂的制备方法，所述枸橼酸莫沙必利糖浆剂的制备方法包括以下步骤：
步骤1)：先将β-环糊精溶于水中，搅拌溶解，再加入枸橼酸莫沙必利，搅拌溶解，得溶液I，备用；
步骤2)：将稳定剂、抑菌剂、芳香剂溶于水中，再加入矫味剂，得溶液II备用；
步骤3)：将溶液I、溶液II混合，即得。
进一步地，为达本发明的目的，发明人通过大量试验，筛选处方组成及用量，优化工艺操作和工艺参数，最终得到了解决本发明技术问题的技术方案。
一种如上述的枸橼酸莫沙必利糖浆制剂的制备方法，所述的制备方法包括如下步骤：
(1)水溶性β环糊精用适量的水溶解；
(2)将枸橼酸莫沙必利溶解在步骤(1)溶液中
(3)芳香剂、稳定剂、抑菌剂用适量的水溶解，再加入蔗糖使溶解；
(4)将步骤(2)和步骤(3)两溶液混合，使溶液澄清，搅拌均匀并补加水至全量
本发明优选的方案是：所述的步骤中：
步骤(1)中，羟丙基-β-环糊精在搅拌下加入80℃以上注射用水，搅拌使其溶解；
步骤(2)中，枸橼酸莫沙必利溶解在步骤(1)溶液中；
步骤(3)中，将甘油、苯甲酸钠、水蜜桃香精用适量的水溶解，加入蔗糖搅拌使溶解；
步骤(4)中，将步骤(2)、(3)在搅拌中缓慢混合在一起，使溶液澄清，搅拌均匀，并补加水至全量，过滤。
与现有技术相比，本发明的技术方案的优点在于：
(1)本发明糖浆剂含有枸橼酸莫沙必利、矫味剂、稳定剂、抑菌剂组成，通过优选地辅料组合，尤其是羟丙基-β-环糊精的优选，包含效果更好，可显著出去莫沙必利的苦涩口感。
(2)本发明的制备方法为：将水溶性β环糊精用适量的水溶解；再向枸橼酸莫沙必利溶于水溶液中搅拌溶解之后加入矫味剂、芳香剂、稳定剂、抑菌剂，搅拌溶解、均匀、过滤、灌装、包装。本发明制备的糖浆剂，稳定性提高，具有儿童服用方便、安全的特点。制备工艺简单，适于工业生产，便于市场推广。
附图说明：
图1：本发明实施例1在第0个月时的HPLC图
图2：本发明实施例1经过加速试验6个月之后，检测的HPLC图
图3：本发明实施例4在第0个月时的HPLC图
图4：本发明实施例4经过加速试验6个月之后，检测的HPLC图
图5：本发明对比实施例3在第0个月时的HPLC图
图6：本发明对比实施例3经过加速试验6个月之后，检测的HPLC图
具体实施方式
实施例1：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)：
具体制备工艺为：
步骤(1)中，羟丙基-β-环糊精在搅拌下加入80℃以上注射用水，搅拌使其溶解；
步骤(2)中，枸橼酸莫沙必利溶解在步骤(1)溶液中；
步骤(3)中，将甘油、苯甲酸钠、水蜜桃香精用适量的水溶解，加入蔗糖搅拌使溶解；
步骤(4)中，将步骤(2)、(3)在搅拌中缓慢混合在一起，使溶液澄清，搅拌均匀，并补加水至全量，测定pH值为5.0-6.0，过滤，即得。
实施例2：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)：
制备工艺同实施例1。
实施例3：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)
制备工艺同实施例1。
实施例4：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)：
制备工艺同实施例1。
对比实施例1：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)
制备工艺同实施例1。
对比实施例2：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)
制备工艺同实施例1。
对比实施例3：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)
制备工艺同实施例1。
对比实施例4：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)
制备工艺同实施例1。
对比实施例5：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)
制备工艺同实施例1。
对比实施例6：一种枸橼酸莫沙必利糖浆剂，以重量比计算，各成分含量如下(1000mL)
制法：
(1)枸橼酸莫沙必利溶解在的水中；
(2)将羟丙基-β-环糊精、甘油、苯甲酸钠加入适量的水中，搅拌使溶解，加入蔗糖搅拌使溶解；
(3)将步骤(1)在搅拌中缓慢加入步骤(2)中，使溶液澄清，再加入水蜜桃香精，搅拌均匀，并补加水至全量，循环过滤
验证实施例的技术效果：
1.口感度测试
无论在食品学还是药学领域，口感的评价方法均以人品尝为主，近年来虽有使用仪器进行口味评价的研究，但是限于技术问题，尚未能广泛应用。故口感评价研究依然采用以人品尝后对口感进行打分的方式，结合本发明提供的制剂为复方中药糖浆剂的特殊性，经查阅和参考文献后，本发明拟定了一套关于口感的评分标准系统，如表1所示：
表1糖浆剂口感评价评分表
| 口感级别 | 评判标准 | 评分 |
| 1 | 口感较差，感觉到明显的苦味或异味 | 1-2 |
| 2 | 口感一般，仅能感觉到微弱的苦味或异味 | 3-4 |
| 3 | 口感一般，完全感觉不到苦味和异味 | 5-6 |
| 4 | 口感较好，仅能感觉到微弱的苦味和异味 | 7-8 |
| 5 | 口感较好，完全感觉不到苦味和异味 | 9-10 |
口感的实验采用双盲法，由试服人员品尝，确定级别并按级别进行评分，满分为10分。因味觉灵敏度与年龄有关，幼儿对苦味很敏感，而老年人则较为迟钝，一般人在20岁时味蕾细胞总数达到最大，味觉相对灵敏。因此受试者年龄控制在20～25岁。本次试验的试服人员招募共110人(鲁南制药集团职工)，男女各半。其中空白对照组中不含有活性物质，其他同实施例1，实验前受试者应先用温水漱口，顺次品尝各溶液，每种溶液含于口中约10秒，吐出药液，马上选择苦味程度级别，然后用温水漱口，直至口中无前一种药液的味道。采用SPSS17.0对其进行相关的口感参数进行统计
表2各个实施例糖浆剂口感评价
注：**与对比实施例1相比，具有显著性差异
由表由表2的结果可知，在芳香剂的添加不是随意加入的，对用量和种类进行了严格的限制，在加入薄荷香精(对比实施例5)，虽然均为香精但是并不能达到同样的技术效果，口感度测试反而不好，在用量的问题上芳香剂的添加也不是越多越好。从表2可以看出，对比实施例1的不在本发明的比例中加入芳香剂，达不到本发明的技术效果加入不同。
2.稳定性试验测试：
对本发明实施例1-10的糖浆剂的稳定性进行测定，经过6个月的加速试验对其进行再次实验，条件为40℃±2℃，相对湿度75％±5％的条件，分别于0、3、6个月取样分析。主要观测其有关物质的含量等，结果见表3.
表3各个实施例糖浆剂稳定性评价
由表5可知，甘油与海藻酸钠混合物做稳定剂时本糖浆剂的稳定性良好。稳定性实验结果表明，本发明的枸橼酸莫沙必利糖浆加速、长期6个月，性状、含量均没有显著变化。在加速稳定性考察6个月中总有关物质不增加。
Claims (10)
1.一种枸橼酸莫沙必利糖浆剂，其特征在于，所述枸橼酸莫沙必利糖浆剂含有枸橼酸莫沙必利、矫味剂、β-环糊精、稳定剂、芳香剂、抑菌剂以及纯化水。
2.如权利要求1所述的枸橼酸莫沙必利糖浆剂，其特征在于，所述的β-环糊精为水溶性β-环糊精，优选地，所述的水溶性β环糊精为羟丙基-β-环糊精、磺丁基-β-环糊精、2,6-二甲氧基-β-环糊精、羟乙基-β-环糊精中的一种或多种；优选地，所述的β环糊精为羟丙基-β-环糊精。
3.如权利要求1所述的枸橼酸莫沙必利糖浆剂，其特征在于，所述的矫味剂为葡糖糖、麦芽糖、蔗糖中的一种或多种。
4.如权利要求1所述的枸橼酸莫沙必利糖浆剂，其特征在于，所述的稳定剂为甘油、海藻酸钠、预胶化淀粉、聚维酮、羧甲基纤维素钠、羟丙基纤维素、枸橼酸钠、羟丙甲纤维素中的一种或多种。
5.如权利要求1所述的枸橼酸莫沙必利糖浆剂，其特征在于，所述的芳香剂为柠檬香精、甜橙香精、水蜜桃香精、覆盆子香精中的一种或多种。
6.如权利要求1所述的枸橼酸莫沙必利糖浆剂，其特征在于，所述的抑菌剂是苯甲酸、苯甲酸钠、羟苯甲酯、羟苯乙酯、山梨酸钾中的一种或几种。
7.如权利要求1所述的枸橼酸莫沙必利糖浆剂，其特征在于，所述枸橼酸莫沙必利糖浆剂，以重量比计算：
8.如权利要求1所述的枸橼酸莫沙必利糖浆剂，其特征在于，所述的稳定剂为甘油、海藻酸钠的组合。
9.如权利要求1所述的枸橼酸莫沙必利糖浆剂，其特征在于，所述的抑菌剂是苯甲酸钠。
10.一种制备权利要求1-9所述的枸橼酸莫沙必利糖浆剂的方法，其特征在于，所述方法为：
步骤1)：先将β-环糊精溶于水中，搅拌溶解，再加入枸橼酸莫沙必利，搅拌溶解，得溶液I，备用；
步骤2)：将稳定剂、抑菌剂、芳香剂溶于水中，再加入矫味剂，得溶液II备用；
步骤3)：将溶液I、溶液II混合，即得。
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