CN112603899A - 瑞巴派特肠溶片及其制备方法 - Google Patents
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Abstract
本发明公开了一种瑞巴派特肠溶片，包含瑞巴派特、至少包含一种强碱弱酸盐和一种肠溶材料。本发明的肠溶片显著性提高了在肠道吸收部位的主药溶出度，且生产工艺稳健，质量可控。因此，本发明可以确保优异的溶解度以相应地提高生物利用度，提高治疗胃溃疡疗效。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种的瑞巴派特肠溶片及其制备方法。
背景技术
瑞巴派特为pH依赖性化合物。微溶于N，N-二甲基甲酰胺，极不溶于甲醇或乙醇(99.5)，几乎不溶于水。瑞巴派特有一定吸湿性的。瑞巴派特的固态非常稳定，而其溶液对光敏感。
瑞巴派特主要用于治疗胃溃疡，急性胃炎、慢性胃炎的急性加重期胃粘膜病变(糜烂、出血、充血、水肿)的改善。幽门螺旋杆菌感染及胃酸过量分泌为消化性溃疡的主要病因，因此，其治疗以抑制胃酸分泌和抗幽门螺旋杆菌感染为主。消化性溃疡以胃溃疡和十二指肠溃疡常见，其患者的主要表现为节律性腹痛，可伴有恶心、呕吐、食欲降低等症状，可影响患者正常工作和生活，降低生活质量。抗生素与质子泵抑制药联合治疗是消化性溃疡目前常用治疗方法，但临床实践中部分患者的治疗效果差，治疗后可出现复发和迁延不愈。瑞巴派特可刺激胃黏膜内源性前列腺素E2合成从而导致胃黏液糖蛋白复合物增加以及表皮生长因子增加,并可通过作用于损伤处黏膜上皮细胞促使其大量增殖，抑制幽门螺旋杆菌感染引起的中性粒细胞激活，从而增强胃黏膜防御功能。
瑞巴派特为BCSⅣ类药物，极低溶解性和极低渗透性不利于药物体内溶解吸收。pH高依赖型，在酸性条件下不溶，随着pH增加溶解度增大。可知，空腹在胃中崩散后几乎不溶解，呈分子态，但渗透性好；肠道中溶解增加，离子态，渗透性较差。综上，瑞巴派特生物利用度低。
由药代动力学数据可知，瑞巴派特片在口服给药后，主要吸收部位为小肠上端，具体讲是胃和十二指肠部位，pH约为5.0-6.8，因此在此部位的溶解度直接影响瑞巴派特吸收渗透。
目前现有技术研究片剂组合物方法主要有：
专利CN109078186A公开一种瑞巴派特的每日一次口服剂型，属于胃漂浮制剂，主要辅料有热塑性聚合物和塑化剂，并使用热熔挤出机制备。该制剂采用大量热塑性聚合物，且使用热熔挤出工艺，使溶解性差的瑞巴派特层层包裹，严重阻滞药物释放，其制备工艺复杂，对辅料、生产工艺要求严格，以避免瑞巴派特团聚或者包裹而难以释放的问题，上述环节中系列问题导致生产成本高昂而难以实现工业化生产。
发明内容
发明目的：本发明的目的是提供一种在吸收部位小肠上端溶解性和渗透性俱佳的瑞巴派特肠溶片，本发明的另一个目的是提供上述肠溶片的制备方法。
技术方案：本发明所述的一种瑞巴派特肠溶片，至少包含一种强碱弱酸盐和至少一种肠溶材料。
本发明所述的瑞巴派特肠溶片，包括片芯、隔离层和肠溶衣层，各组分以重量计包括：
(a)片芯
在一些实施方案中，所述瑞巴派特的含量优选为57.14％。
在一些实施方案中，所述强碱弱酸无机盐选自碳酸钠、碳酸氢钠、碳酸氢钙、碳酸钙、磷酸钙、碳酸镁、碳酸钾、碳酸氢钾、磷酸氢钙无机盐中的一种，特别优选为碳酸钙、碳酸钠。优选地，碳酸钙或碳酸钠含量1％—20％，特别优选为1％至10％的重量。
在一些实施方案中，所述隔离层包含羟丙甲纤维素和滑石粉。
在一些实施方案中，所述肠溶衣层包含丙烯酸树脂肠溶材料和柠檬酸三乙酯。
在一些实施方案中，所述丙烯酸树脂肠溶材料选自聚乙烯醇乙酸苯二甲酸酯、邻苯二甲酸乙酸纤维素、1,2,4-苯三甲酸乙酸纤维素、邻苯二甲酸羟丙基甲基纤维素、1,2,4-苯三甲酸羟丙基甲基纤维素、琥珀酸乙酸纤维素、醋酸羟丙甲纤维素琥珀酸酯、醋酸羟丙基甲基纤维素酞酸酯、甲基丙烯酸-丙烯酸乙酯共聚物、甲基乙烯基醚-马来酸酐共聚物、甲基丙烯酸-丙烯酸乙酯共聚物水分散体、甲基丙烯酸-甲基丙烯酸甲酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯共聚物、聚乙酸乙烯酯、乙基纤维素、聚醋酸乙烯酯与聚乙烯吡咯烷酮K30混合物，优选醋酸羟丙甲纤维素琥珀酸酯、甲基丙烯酸-甲基丙烯酸甲酯共聚物、甲基丙烯酸-丙烯酸乙酯共聚物、邻苯二甲酸羟丙基甲基纤维素。
肠溶性包衣材料甲基丙烯酸-丙烯酸乙酯共聚物水分散体，优选地，甲基丙烯酸-丙烯酸乙酯共聚物水分散体包衣增重为1％至5％，特别优选增重为2％至4％，最优选增重为2.5％至3.5％。
本发明所述的瑞巴派特肠溶片的制备方法，包括以下步骤：
(1)瑞巴派特分散于pH6.8缓冲液体系中备用；
(2)将碳酸钙和部分羟丙基甲基纤维素完全分散溶解在步骤⑴所处理的瑞巴派特溶液中；
(3)将步骤(2)溶液喷雾干燥；
(4)将步骤(3)得到的干燥颗粒与微晶纤维素释放制粒，干燥后，加硬脂酸镁总混，压片，片剂硬度为9kg/cm2～12kg/cm2；
(5)将步骤(4)得到的素片，先包隔离层后包肠溶衣。
在一些实施方案中，步骤(1)中瑞巴派特溶解于pH6.8的磷酸盐缓冲液中备用。
在一些实施方案中，，步骤(3)中喷雾干燥以4-6ml/min的流速进行，注入口的温度为100-200℃，排出口的温度为40-100℃。
在一些实施方案中，制备得到的瑞巴派特肠溶片的片剂硬度为5kg/cm2～7kg/cm2。优选片剂硬度范围为8kg/cm2～12kg/cm2。
本发明所述的瑞巴派特肠溶片剂，通过体外释放度试验，在pH5.0、pH5.5、pH6.0、pH6.8四种缓冲液中溶出行为稳定可控，末点溶出完全，有助于提高体内生物利用度。使用喷雾制粒工艺，制备颗粒流动性好，原料无团聚，粒度分布窄，可压性良好，溶出行为稳定，含量均匀度批间差异小。
本发明所述的一种瑞巴派特肠溶片剂的优势在于以碳酸钙为pH调节剂，提高于瑞巴派特微环境下的pH，增加了瑞巴派特的溶解度和释放度。
有益效果：本发明所述的一种瑞巴派特肠溶片剂的优点在于瑞巴派特粒径细，静电强，使用喷雾造法后，制备颗粒流动性好，原料无团聚，粒度分布窄，可压性良好，溶出行为稳定，含量均匀度批间差异小。本发明所述的瑞巴派特肠溶片剂的制备方法易于操作，稳定性高，含量均匀度和累计释放度批间差异小，生产成本低，适合大规模工业化生产。
附图说明
图1为本发明所述原料药瑞巴派特在9种不同pH介质中24h的药物-饱和溶解度；
图2为本发明所述瑞巴派特肠溶片(实施例3)在5种不同pH介质中的药物释放曲线；
图3为本发明包含0％重量的碳酸钙肠溶片(实施例2)在4种不同pH介质中的药物释放曲线的药物释放曲线；
图4为本发明包含10％重量的碳酸钙肠溶片在4种不同pH介质中的药物释放曲线的药物释放曲线；
图5本发明包含0％、5％、10％重量的碳酸钙肠溶片在pH6.0介质中的药物释放曲线的药物释放曲线。
具体实施方式
为进一步了解本发明的内容，结合附图及实施例对本发明作详细描述。
实施例中各组分来源：瑞巴派特(苏州正济有限公司，纯度：99.4％)；微晶纤维素(型号101，安徽山河辅料有限公司)；碳酸钙(斯百全化学(上海)有限公司)；碳酸钠(湖南新绿方药业有限公司)；羟丙基纤维素(亚什兰化工(南京)有限公司)；硬脂酸镁(湖州展望药业有限公司)，胃溶型薄膜包衣粉(安徽山河药用辅料股份有限公司)；肠溶型薄膜包衣粉(安徽山河药用辅料股份有限公司)。
实施例1
瑞巴派特肠溶片剂制备工艺
(1)瑞巴派特溶解于pH6.8的磷酸盐缓冲液中备用；
(2)将碳酸钙和部分羟丙基甲基纤维素完全分散溶解在步骤⑴所处理的瑞巴派特溶液中；
(3)将步骤(2)溶液喷雾干燥，以6ml/min的流速进行，注入口的温度为180℃，排出口的温度为70℃；
(4)将步骤⑶得到的干燥颗粒与微晶纤维素释放制粒，烘箱60℃干燥后，加硬脂酸镁总混5min，压片，片剂硬度为9kg/cm2～12kg/cm2；
(5)将步骤(4)得到的素片，先包隔离层后包肠溶衣。
下列实施例2-4瑞巴派特肠溶片(按照实施例1的方法制备得到)，碳酸钙作为pH调节剂，其提供在随着碳酸钙用量增加，稀释剂微晶纤维素的用量递减，在pH≥5时有较快的释放特性。
实施例2
实施例3
实施例4
下列实施例5-6瑞巴派特肠溶片(按照实施例1的方法制备得到)，碳酸钠作为pH调节剂，其提供在随着碳酸钠用量增加，稀释剂微晶纤维素的用量递减，在pH≥5时有较快的释放特性。
实施例5
一种瑞巴派特肠溶片的优化处方组成
实施例6
一种瑞巴派特肠溶片的优化处方组成
实施例7-18(按照实施例1的方法制备得到)，具体组分与实施例3相同，加入比例不同。
实施例7-18的瑞巴派特肠溶片分别在pH5.0磷酸缓冲液、pH5.5磷酸缓冲液、pH6.0磷酸缓冲液、pH6.8磷酸缓冲液五种介质中进行释放，在40min时的累计溶出度％如下：
实施例19-21(按照实施例1的方法制备得到)，和实施例3的区别仅在于加入强碱弱酸无机盐的种类不同。分别在pH5.0磷酸缓冲液、pH5.5磷酸缓冲液、pH6.0磷酸缓冲液、pH6.8磷酸缓冲液四种介质中进行释放，在40min时的累计溶出度％如下：
实施例22-27(按照实施例1的方法制备得到)，和实施例3的区别仅在于加入肠溶衣层材料的种类不同。分别在pH5.0磷酸缓冲液、pH5.5磷酸缓冲液、pH6.0磷酸缓冲液、pH6.8磷酸缓冲液四种介质中进行释放，在40min时的累计溶出度％如下：
瑞巴派特肠溶片剂释放曲线测定方法
按中华人民共和国药典2015版附录XD释放度测定法第一法有关规定，以pH1.28盐酸溶液、pH5.0磷酸盐缓冲液、pH5.5磷酸盐缓冲液、pH6.0磷酸盐缓冲液、pH6.8磷酸盐缓冲液为释放介质，转速50r/min，温度为(37.5±0.5)℃，分别于5min、10min、15min、30min、45min、60min、90min、120min取样。
根据已确定的高效液相分析方法，计算不同时间的释放率。释放曲线如1～5图所示，结果表明，优化的瑞巴派特肠溶片剂具有在胃内不释放、肠溶释放特征，在生理pH5.0-pH6.8范围内快速释放，且释放完全。
图1图解了原料药瑞巴派特在9种不同pH介质中的药物-溶解度曲线，瑞巴派特溶解度为pH依赖型，在酸性条件下不溶，随着pH增加溶解度增大。
图2图解了以占处方量5％的碳酸钙作为pH调节剂，所制瑞巴派特肠溶片(实施例3)在pH1.2盐酸溶液、pH5.0磷酸缓冲液、pH5.5磷酸缓冲液、pH6.0磷酸缓冲液、pH6.8磷酸缓冲液五种介质中释放曲线。
图3图解了分别占处方量的0％重量的碳酸钙，所制瑞巴派特肠溶片剂(实施例2)在四种磷酸缓冲液中的释放曲线。
图4图解了分别占处方量的10％重量的碳酸钙，所制瑞巴派特肠溶片剂(实施例4)在四种磷酸缓冲液中的释放曲线
图5图解了分别占处方量0％、5％、10％重量的碳酸钙所制瑞巴派特肠溶片剂在四种磷酸缓冲液中的释放曲线。
Claims (10)
1.一种瑞巴派特肠溶片，其特征在于，至少包含一种强碱弱酸盐和至少一种肠溶材料。
2.根据权利要求1所述的瑞巴派特肠溶片，其特征在于，包括片芯、隔离层和肠溶衣层，各组分以重量计包括：
(a)片芯
3.根据权利要求2所述的种瑞巴派特肠溶片，其特征在于，所述强碱弱酸无机盐选自碳酸钠、碳酸氢钠、碳酸氢钙、碳酸钙、磷酸钙、碳酸镁、碳酸钾、碳酸氢钾、磷酸氢钙无机盐中的一种。
4.根据权利要求2所述的瑞巴派特肠溶片，其特征在于，所述隔离层包含羟丙甲纤维素和滑石粉。
5.根据权利要求2所述的瑞巴派特肠溶片，其特征在于，所述肠溶衣层包含丙烯酸树脂肠溶材料和柠檬酸三乙酯。
6.根据权利要求5所述的瑞巴派特肠溶片，其特征在于，所述丙烯酸树脂肠溶材料选自聚乙烯醇乙酸苯二甲酸酯、邻苯二甲酸乙酸纤维素、1,2,4-苯三甲酸乙酸纤维素、邻苯二甲酸羟丙基甲基纤维素、1,2,4-苯三甲酸羟丙基甲基纤维素、琥珀酸乙酸纤维素、醋酸羟丙甲纤维素琥珀酸酯、醋酸羟丙基甲基纤维素酞酸酯、甲基丙烯酸-丙烯酸乙酯共聚物、甲基乙烯基醚-马来酸酐共聚物、甲基丙烯酸-丙烯酸乙酯共聚物水分散体、甲基丙烯酸-甲基丙烯酸甲酯共聚物、丙烯酸乙酯-甲基丙烯酸甲酯-甲基丙烯酸氯化三甲胺基乙酯共聚物、聚乙酸乙烯酯、乙基纤维素、聚醋酸乙烯酯与聚乙烯吡咯烷酮K30混合物。
7.一种权利要求1-6任一项权利要求所述的瑞巴派特肠溶片的制备方法，其特征在于，包括以下步骤：
(1)瑞巴派特分散于pH6.8缓冲液体系中备用；
(2)将碳酸钙和部分羟丙基甲基纤维素完全分散溶解在步骤⑴所处理的瑞巴派特溶液中；
(3)将步骤(2)溶液喷雾干燥；
(4)将步骤(3)得到的干燥颗粒与微晶纤维素释放制粒，干燥后，加硬脂酸镁总混，压片，片剂硬度为9kg/cm2～12kg/cm2；
(5)将步骤(4)得到的素片，先包隔离层后包肠溶衣。
8.根据权利要求7所述的制备方法，其特征在于，步骤(1)中瑞巴派特溶解于pH6.8的磷酸盐缓冲液中备用。
9.根据权利要求7所述的制备方法，其特征在于，步骤(3)中喷雾干燥以4-6ml/min的流速进行，注入口的温度为100-200℃，排出口的温度为40-100℃。
10.根据权利要求7所述的制备方法，其特征在于，制备得到的瑞巴派特肠溶片的片剂硬度为5kg/cm2～7kg/cm2。
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