CN115381960A - 水性肠溶包衣组合物 - Google Patents
水性肠溶包衣组合物 Download PDFInfo
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- CN115381960A CN115381960A CN202211017772.7A CN202211017772A CN115381960A CN 115381960 A CN115381960 A CN 115381960A CN 202211017772 A CN202211017772 A CN 202211017772A CN 115381960 A CN115381960 A CN 115381960A
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- Prior art keywords
- enteric coating
- coating composition
- aqueous enteric
- composition according
- mixtures
- Prior art date
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 16
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Abstract
本发明是水性肠溶包衣组合物。本发明涉及包含羟丙基甲基纤维素乙酸琥珀酸酯和碱性氨基酸的水性肠溶包衣组合物。
Description
本申请是国际申请日为2016年4月27日、申请号为“201680027470.4”、发明名称为“水性肠溶包衣组合物”的发明专利申请的分案申请。
交叉相关申请数据
本申请要求2015年5月12日提交的美国临时申请第62/160,203号的优先权，其内容通过引用整体并入本文。
发明领域
本发明涉及具有改进的加工性能的水性肠溶包衣组合物。
发明背景
肠溶包衣在各种用于口服递送宽范围的药物和营养物质的片剂或丸剂中使用。肠溶包衣通常用于保护递送的药物或营养物质免受胃的酸性pH。大多数肠溶包衣包含羟丙基甲基纤维素邻苯二甲酸酯、纤维素乙酸邻苯二甲酸酯、羧甲基乙基纤维素、甲基丙烯酸甲酯-甲基丙烯酸酯共聚物、甲基丙烯酸酯-丙烯酸乙酯共聚物、甲基丙烯酸酯-丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素乙酸琥珀酸酯、聚乙酸邻苯二甲酸乙烯酯和虫胶中的一种或多种。
一种具体的肠溶包衣组合物基于以Shin-Etsu AQOAT®得自Shin-Etsu ChemicalCo.，Ltd.(日本)的羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)。然而，使用HPMCAS的现有包衣方法有一些加工困难。在喷雾装置中喷嘴堵塞方面存在明显问题。一个解决方案是将包衣液冷却至低于10℃的温度并将聚合物浓度降低到小于7%。其他解决方案包括将HPMCAS悬浮在氨中或将其溶解在溶剂如乙醇或丙酮中。使用氨或溶剂可能难以对付大规模的商业用途，因为存在稳定性问题和潜在的环境和安全问题。其他选择是使用特殊的双喷嘴或使用粉末喷嘴。这些选择需要在喷雾技术中大量资金投资。
发明概述
本发明的目的是用水性肠溶包衣组合物克服上述问题和困难，该水性肠溶包衣组合物在喷嘴中不引起堵塞，避免使用氨或溶剂并且不需要昂贵的喷嘴或喷雾技术。
所述水性肠溶包衣组合物包含羟丙基甲基纤维素乙酸琥珀酸酯和碱性氨基酸。在一个实施方案中，所述水性肠溶包衣组合物包含5至20%的羟丙基甲基纤维素乙酸琥珀酸酯、0.05至1.0%的L-精氨酸或L-组氨酸、0.5至10%的增塑剂、0.1至10%的抗粘连剂、0.05至0.5%的表面活性剂和65至95%的水。
发明实施方案的详述
现在将在本文提供的描述和方法方面更详细地描述本发明的前述和其他方面。应当理解，本发明可以不同的形式实施，并且不应被解释为限于本文所阐述的实施方案。相反，提供这些实施方案使得本公开将是彻底和完整的，并且将向本领域技术人员充分地告知本发明的范围。
在本发明的描述中使用的术语在本文中仅用于描述具体实施方案的目的而不意在限制本发明。如在本发明的实施方案和所附权利要求书的描述中使用的单数形式“一个/种”和“该”也旨在包括复数形式，除非上下文另有明确指出。此外，如本文所用的“和/或”是指并包括一个或多个相关列出项目的任何和所有可能组合。此外，当提到诸如化合物的量、剂量、时间、温度等的可测量值时，本文所用的术语“约”意在包括指定量的20%、10%、5%、1%、0.5%或甚至0.1%的变化。
将进一步理解，当在说明书中使用时，术语“包括(comprises)”和/或“包括(comprising)”是指存在所阐述的特征、整数、步骤、操作、要素和/或组分，但不排除存在或添加一个或多个其他特征、整数、步骤、操作、要素、组分和/或其集合。除非另有定义，在说明书中使用的所有术语(包括技术和科学术语)具有与本发明所属领域的普通技术人员通常理解相同的含义。
如用于本发明的方法的术语“基本上由……组成”(和语法变体)是指方法或组合物可以包含附加的步骤，只要附加的步骤或组分不会实质上改变本发明的基本和新的特征。
术语“由……组成”排除了未在权利要求中指定的任何附加的步骤。
除非上下文另有指示，否则明确的意图是可以任何组合使用本文所述的本发明的各种特征。
此外，本发明还考虑在本发明的一些实施方案中，可以排除或省略本文所阐述的任何特征或特征组合。
本文提到的所有专利、专利申请和出版物通过引用整体并入。在术语冲突的情况下，以本说明书为准。
本领域普通技术人员可以理解，本文所述的参数可以根据工艺和/或配方以及最终产品的期望性质非常大地变化。
本发明涉及包含羟丙基甲基纤维素乙酸琥珀酸酯(HPMCAS)、碱性氨基酸和添加剂(如增塑剂、表面活性剂、抗粘连剂等)的新型水性肠溶包衣组合物。
在一个实施方案中，HPMCAS是可得自Shin-Etsu Chemical Co.，Ltd. (日本)的Shin-Etsu AQOAT®。任选地，可以包括其他肠溶包衣材料。示例性的其他材料包括羟丙基甲基纤维素邻苯二甲酸酯、纤维素乙酸邻苯二甲酸酯、羧甲基乙基纤维素、甲基丙烯酸甲酯-甲基丙烯酸酯共聚物、甲基丙烯酸酯-丙烯酸乙酯共聚物、甲基丙烯酸酯-丙烯酸甲酯-甲基丙烯酸甲酯共聚物、羟丙基甲基纤维素乙酸琥珀酸酯、聚乙酸邻苯二甲酸乙烯酯和虫胶。常常包括这样的材料以使得整个肠溶包衣基于不同的pH值以不同的速率溶解。组合物中HPMCAS的量可以为组合物的约5至约20重量%。
合适的碱性氨基酸包括L-精氨酸、L-组氨酸和L-赖氨酸中的一种或多种。组合物中碱性氨基酸的量可以为组合物的约0.05%至约1.0%重量。
添加增塑剂以有助于组合物的熔融特性。可用于本发明的示例性的增塑剂是柠檬酸三乙酯(TEC)、三醋精、柠檬酸三丁酯、乙酰柠檬酸三乙酯(ATEC)、乙酰柠檬酸三丁酯(ATBC)、邻苯二甲酸二丁酯、癸二酸二丁酯(DBS)、邻苯二甲酸二乙酯、乙烯基吡咯烷酮二醇三乙酸酯、聚乙二醇、聚氧乙烯脱水山梨糖醇单月桂酸酯、丙二醇、碳酸亚丙酯或蓖麻油；及其组合或混合物。组合物中增塑剂的量可以为组合物的约0.5至约10重量%。
添加表面活性剂以改进包衣材料的表面特性，且包括Pluronics®(环氧乙烷和环氧丙烷的嵌段共聚物)、卵磷脂、Aerosol OT®(二辛基磺基琥珀酸钠)、月桂基硫酸钠、Polyoxyl 40™氢化蓖麻油、聚氧乙烯脱水山梨糖醇脂肪酸酯(即聚山梨醇酯如Tween®，例如Tween 20、60和80)、脱水山梨糖醇脂肪酸酯(即脱水山梨糖醇单月桂酸酯、单油酸酯、单棕榈酸酯、单硬脂酸酯等，例如Span®或Arlacel®、Emsorb®、Capmul®或Sorbester®)、Triton X-200、聚乙二醇类、单硬脂酸甘油酯、Vitamin E-TPGS®(d-α-生育酚聚乙二醇1000琥珀酸酯)、蔗糖脂肪酸酯(如蔗糖硬脂酸酯、蔗糖油酸酯、蔗糖棕榈酸酯、蔗糖月桂酸酯和蔗糖乙酸丁酸酯)及其组合和混合物。优选的表面活性剂是Vitamin E-TPGS®、月桂基硫酸钠、蔗糖脂肪酸酯、卵磷脂和Pluronic系列。组合物中表面活性剂的量可以为组合物的约0.05至约0.5%重量。
可以包括抗粘连剂或加工润滑剂。示例性的试剂和润滑剂包括硬脂醇、硬脂酸、单硬脂酸甘油酯(GMS)、滑石、硬脂酸镁、二氧化硅、无定形硅酸和气相法二氧化硅；及其组合或混合物。抗粘连剂或加工润滑剂的量可以为组合物的约0.1%至约10%重量。
整个组合物可以包括约65至约95重量%的水作为分散剂以提供水性形式的组合物。
其他添加剂可包括吸收促进剂、溶解改性剂、着色助剂、调味剂和稳定剂(例如磷酸氢二钠)。
水性肠溶包衣组合物可以用于片剂、丸剂、颗粒剂、硬和软胶囊上以递送药物和营养物质。
如本文所用的“药物”定义为旨在用于医学诊断、治愈、治疗或预防疾病的任何化学物质，例如非处方药(OTC)和处方药(POM)。示例性的活性药物组分在美国专利第6,723,358号第9栏第25行至第13栏第25行中列出，其公开内容通过引用整体并入本文。
如本文所用的“营养物质”补充物包括可提供健康和医用益处(包括预防和治疗疾病)的任何营养物。实例包括但不限于维生素、矿物质、益生菌、酶、草本植物和其他植物提取物、氨基酸、浓缩物、代谢物、成分(constituents)等。
示例性的维生素和矿物质包括但不限于维生素A(例如以棕榈酸酯或β-胡萝卜素形式)、B-复合物(例如B-1、B-2、B-6和B-12)、C、D、E和K；烟酸；酸型维生素如泛酸和叶酸；生物素；矿物质如铁、钙、镁、碘、铜、磷、锌、锰、钾、铬、钴、钼、硒、镍、锡、硅、钒和硼；营养补充物如氟和氯；等。各种草本植物和草本药物可用作营养补充物。草本植物通常选自具有各种药用或膳食补充性质的那些。草本植物通常是可药用或用于调味品的芳香植物或植物部分。实例包括银杏、积雪草、紫锥菊、圣约翰草、人参、缬草等。合适的草本植物可以单独或以各种混合物形式用于本文所述的填充物中。
本发明将通过以下非限制性实施例进一步说明。
实施例
实施例1
通过将3g L-组氨酸溶解在100ml水中制备L-组氨酸的储备溶液。溶液的pH为7.47。制备和评价以下制剂：
常规制剂(无氨基酸)
| HPMCAS(AS-MF) | 7(重量%) |
| TEC(柠檬酸三乙酯) | 2.1 |
| 滑石 | 2.1 |
| SLS(月桂基硫酸钠) | 0.2 |
| 水 | 至100(最终重量600g) |
将SLS溶解在水中。然后将HPMCAS分散在相同量的水中。将滑石在单独的容器中分散并如前所述通过高剪切均化器，然后加入到上述分散体中并再混合30分钟。然后将TEC加入到上述分散体中并混合30分钟。
制剂
| HPMCAS(AS-MF) | 10(重量%) |
| L-组氨酸 | 0.03 |
| TEC(柠檬酸三乙酯) | 3.0 |
| 滑石 | 2.5 |
| SLS(月桂基硫酸钠) | 0.3 |
| 水 | 至100(最终重量600g) |
将SLS溶解在水中。然后将HPMCAS分散在相同量的水中。将L-组氨酸溶液缓慢加入上述分散体中以提高pH(目标为5.6至5.8)。在加入100ml后，测定pH为5.3。将滑石在单独的容器中分散并如前所述通过高剪切均化器，然后加入到上述分散体中并再混合30分钟。然后将TEC加入到上述分散体中并混合30分钟。
结果：
凝结行为
将包衣分散体通过60目筛。常规制剂在室温下显示出凝结，并且在筛网上留下相当大量的聚集物质。实施例1的制剂没有显示凝结，在筛网上的残留物质最少。
还使用以下进行包衣实验：
设备：台顶式侧面通气盘式包衣机(Glatt GMPC-I，批量：500g)
芯片剂：安慰剂片剂(主要由乳糖和玉米淀粉制备)
对于常规制剂，由于在室温下凝结，不能进行包衣。使用制剂A，包衣运行良好，无喷嘴堵塞。
实施例2
使用另一种氨基酸L-精氨酸作为稳定剂。将10g L-精氨酸溶解在100mL水中作为储备溶液。
制剂
| HPMCAS(AS-MF) | 10(重量%) |
| L-精氨酸 | 0.33 |
| TEC | 2.5 |
| 滑石 | 3.0 |
| SLS | 0.3 |
| 水 | 至100(最终重量600g) |
将SLS溶解在所需量的水中。然后加入HPMCAS并混合60分钟。将滑石在具有高剪切均化器的单独的容器中分散，然后加入到上述分散体中并混合30分钟。最后将TEC加入到上述分散体中并再混合60分钟。分散体的pH为5.08。
结果：
凝结行为
没有观察到凝结。
包衣实验(与实施例1相同)
包衣进行顺利，没有任何喷嘴堵塞。进行包衣至13%的重量增加。
耐胃液试验(Gastric resistance test)
使用崩解试验机将六片片剂浸入USP模拟胃液(pH 1.2，不含胃蛋白酶)中持续1小时。所有片剂均完好无损，胃液的平均吸收(试验后片剂重量增加)仅为4.2%。
实施例3
然后用以下制剂将HPMCAS的负载量增加至12%：
制剂
| HPMCAS(AS-MF) | 12(重量%) |
| L-精氨酸 | 0.33 |
| TEC | 3.6 |
| 滑石 | 3.6 |
| SLS | 0.12 |
| 水 | 至100(最终重量600g) |
制备程序与实施例2相同。
结果：
凝结行为
没有观察到凝结。
包衣实验(与实施例1相同)
包衣顺利进行，没有任何喷嘴堵塞。进行包衣至14%的重量增加。
耐胃液试验及其稳定性
试验方法与实施例2相同。所有片剂均完好无损，胃液的平均吸收(试验后片剂重量增加)仅为4.0%。将片剂在40℃/75%RH(封闭瓶)下进行加速稳定性试验。4周后胃液吸收仅为2.9%。
已经描述了本发明的某些实施方案，应当理解，由所附权利要求限定的本发明不受上述描述中阐述的特定细节的限制，原因是在不偏离如下文所要求保护的其精神或范围的情况下可能有许多明显变化。
实施例4
添加着色剂(氧化钛)：
制剂
| HPMCAS(AS-MF) | 12(重量%) |
| L-精氨酸 | 0.33 |
| TEC | 3.6 |
| 滑石 | 3.6 |
| SLS | 0.25 |
| 二氧化钛 | 0.5 |
| 水 | 至100(最终重量600g) |
制备程序与实施例2相同。
结果：
凝结行为
没有观察到凝结。
包衣实验(与实施例1相同)
包衣顺利进行，没有任何喷嘴堵塞。进行包衣至14%的重量增加。
实施例5
添加另一种着色剂(氧化铁)：
| HPMCAS(AS-MF) | 12(重量%) |
| L-精氨酸 | 0.33 |
| TEC | 3.6 |
| 滑石 | 3.6 |
| SLS | 0.25 |
| 氧化铁 | 0.5 |
| 水 | 至100(最终重量600g) |
制备方法与实施例2相同。
结果：
凝结行为
没有观察到凝结。
包衣实验(与实施例1相同)
包衣顺利进行，没有任何喷嘴堵塞。进行包衣至14%的重量增加。
实施例6
使用二氧化硅作为抗粘连剂：
| HPMCAS(AS-MF) | 12(重量%) |
| L-精氨酸 | 0.33 |
| TEC | 3.6 |
| 二氧化硅(Aerosil® R972) | 0.5 |
| SLS | 0.25 |
制备程序与实施例2相同。
结果：
凝结行为
没有观察到凝结。
包衣实验(与实施例1相同)
包衣顺利进行，没有任何喷嘴堵塞。进行包衣至14%的重量增加。
实施例7。
丸剂包衣的实施例。
制剂与实施例3相同。芯丸粒是纤维素珠粒。
| 机器 | MIDI-GLATT Wurster包衣 |
| 装料 | 180 g (Celphere CP-507) |
| 入口温度 | 42-43℃ |
| 产品温度 | 33-35℃ |
| 空气流量 | 0.8 m<sup>3</sup>/min |
| 喷雾进料速率 | 3.3 g/min |
| 雾化压力 | 100 kPa |
| 喷嘴 | 0.5 mm |
| 分隔高度 | 20 mm |
| 保留筛网 | 100目 |
结果：
凝结行为
没有观察到凝结。
包衣实验(与实施例1相同)
包衣顺利进行，没有任何喷嘴堵塞。进行包衣至30%的重量增加。
已经描述了本发明的某些实施方案，应当理解，由所附权利要求限定的本发明不受上述描述中阐述的特定细节的限制，原因是在不偏离如下文所要求保护的其精神或范围的情况下可能有许多明显变化。
Claims (11)
1.一种水性肠溶包衣组合物，其包含：
a) 羟丙基甲基纤维素乙酸琥珀酸酯；和
b) 碱性氨基酸。
2.根据权利要求1的水性肠溶包衣组合物，其还包含增塑剂、表面活性剂和抗粘连剂。
3.根据权利要求1或2的水性肠溶包衣组合物，其中所述碱性氨基酸选自L-精氨酸、L-组氨酸和L-赖氨酸。
4.根据权利要求2的水性肠溶包衣组合物，其中所述增塑剂包括柠檬酸三乙酯(TEC)、三醋精、柠檬酸三丁酯、乙酰柠檬酸三乙酯(ATEC)、乙酰柠檬酸三丁酯(ATBC)、邻苯二甲酸二丁酯、癸二酸二丁酯(DBS)、邻苯二甲酸二乙酯、乙烯基吡咯烷酮二醇三乙酸酯、聚乙二醇、聚氧乙烯脱水山梨糖醇单月桂酸酯、丙二醇、碳酸亚丙酯、蓖麻油及其组合或混合物。
5.根据权利要求2的水性肠溶包衣组合物，其中所述表面活性剂选自月桂基硫酸钠、蔗糖脂肪酸酯、卵磷脂和d-α-生育酚聚乙二醇及其组合和混合物。
6.根据权利要求2的水性肠溶包衣组合物，其中所述抗粘连剂选自硬脂醇、硬脂酸、单硬脂酸甘油酯(GMS)、滑石、硬脂酸镁、二氧化硅、无定形硅酸和气相法二氧化硅及其组合或混合物。
7.一种药物组合物，其包含用权利要求1的水性肠溶包衣组合物包衣的片剂、丸剂、颗粒剂、硬胶囊或软胶囊以及药物或营养物质。
8.一种水性肠溶包衣组合物，其包含：
a) 5至20%的羟丙基甲基纤维素乙酸琥珀酸酯；
b) 0.05至1.0%的L-精氨酸、L-组氨酸或L-赖氨酸；
c) 0.5至10%的增塑剂；
d) 0.1至10%的抗粘连剂；
e) 0.05至0.5%的表面活性剂；和
f) 65至95%的水。
9.根据权利要求8的水性肠溶包衣组合物，其中所述表面活性剂选自月桂基硫酸钠、蔗糖脂肪酸酯、卵磷脂和d-α-生育酚聚乙二醇及其组合和混合物。
10.根据权利要求8的水性肠溶包衣组合物，其中所述抗粘连剂选自硬脂醇、硬脂酸、单硬脂酸甘油酯(GMS)、滑石、硬脂酸镁、二氧化硅、无定形硅酸和气相法二氧化硅及其组合或混合物。
11.一种药物组合物，其包含用权利要求8的水性肠溶包衣组合物包衣的片剂、丸剂、颗粒剂、硬胶囊或软胶囊以及药物或营养物质。
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2016
- 2016-04-19 US US15/132,627 patent/US20160331689A1/en not_active Abandoned
- 2016-04-27 CN CN202211017772.7A patent/CN115381960A/zh active Pending
- 2016-04-27 KR KR1020177032322A patent/KR102579495B1/ko active IP Right Grant
- 2016-04-27 EP EP16793160.9A patent/EP3294272B1/en active Active
- 2016-04-27 CN CN201680027470.4A patent/CN107847456A/zh active Pending
- 2016-04-27 WO PCT/US2016/029514 patent/WO2016182737A1/en active Application Filing
- 2016-04-27 JP JP2017559615A patent/JP6910962B2/ja active Active
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2020
- 2020-08-24 US US17/001,152 patent/US11833252B2/en active Active
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Also Published As
| Publication number | Publication date |
|---|---|
| WO2016182737A1 (en) | 2016-11-17 |
| KR102579495B1 (ko) | 2023-09-15 |
| EP3294272A1 (en) | 2018-03-21 |
| JP2018519272A (ja) | 2018-07-19 |
| EP3294272B1 (en) | 2022-11-16 |
| KR20180004149A (ko) | 2018-01-10 |
| CN107847456A (zh) | 2018-03-27 |
| US20200383925A1 (en) | 2020-12-10 |
| EP3294272A4 (en) | 2018-12-26 |
| US11833252B2 (en) | 2023-12-05 |
| US20160331689A1 (en) | 2016-11-17 |
| JP6910962B2 (ja) | 2021-07-28 |
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