CN108834401A - 包含消旋卡多曲的药物组合物及其制备方法 - Google Patents
包含消旋卡多曲的药物组合物及其制备方法 Download PDFInfo
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- CN108834401A CN108834401A CN201880000987.3A CN201880000987A CN108834401A CN 108834401 A CN108834401 A CN 108834401A CN 201880000987 A CN201880000987 A CN 201880000987A CN 108834401 A CN108834401 A CN 108834401A
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- racecadotril
- sugar
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- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
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Abstract
本发明涉及一种包含消旋卡多曲的药物组合物及其制备方法。本发明涉及一种包含消旋卡多曲和共晶糖的药物组合物及其制备方法。
Description
技术领域
本发明涉及包含消旋卡多曲(Racecadotril)和共晶糖(co-crystallized sugar)的药物组合物、及其制备方法。
背景技术
消旋卡多曲(公开自欧洲专利EP038758Bl)是止泻药,作为脑啡肽酶抑制剂,其通过减少水和电解质分泌到肠中而起作用。化学上,消旋卡多曲是具有以下化学结构的(RS)-N-[3(乙酰硫基)-2-苄基丙酰基]甘氨酸苄酯((RS)-Benzyl N-[3-(acetylthio)-2-benzylpropanoyl]glycinate)。
市售有和的分散片和散剂(sachet)剂型。消旋卡多曲为疏水物质,其表示在混悬剂(suspension)剂型的制备中存在困难。因此,它被配制成散剂和分散片剂型。
EP1294372公开了一种干粉组合物,其包含包衣颗粒,包衣颗粒包含消旋卡多曲和药学上可接受的载体。
EP2749270公开了一种包含消旋卡多曲的分散片,其味道被掩盖,其中在不混合任何赋形剂的情况下通过湿法制粒方法用丙烯酸类聚合物或纤维素聚合物包衣来掩盖味道。
在现有的剂型中,药物消旋卡多曲被包衣,虽然就良好的适口性、对水解或其它环境条件的敏感性和产品外观而言,并不需要相同的剂型。具体地,消旋卡多曲与甜味剂混合时不需要任何包衣以显示良好的适口性。另外,药物对水解或任何其他体内降解过程或环境条件如湿度和温度不敏感。同样,也不需要任何包衣来改善产品外观。
另外,可用剂型和公开内容中公开的包衣制剂具有额外的工艺要求和限制。通常,包衣工艺价格昂贵,并且包含制造诸如散剂的简单剂型的额外步骤。此外,由于消旋卡多曲的疏水性,包衣工艺和赋形剂的选择也较为困难。
另外,通常包衣必须足够稳定且坚固以经受住制剂处理,并且必须遵循制剂上压印字符的精细轮廓。包衣剂型导致各种缺陷,如短暂粘结(picking)和粘连(当包衣使一块制剂脱离片芯时)、桥接(包衣填充制剂上的字母或商标)、侵蚀、结对(其中两个或更多组元因包衣而相互粘结)、剥离和起霜(包衣脱落)、起泡(溶剂由包衣制剂中快速蒸发)或桔皮(包衣纹理类似于桔子表面)。包衣工艺的制造障碍及其在配方的保质期内的效果意味着避免包衣工艺,除非绝对必要。
因此,需要简单的方法来制备消旋卡多曲的散剂剂型。该工艺还应易于开发,且不应涉及不必要和复杂的包衣工艺。
发明内容
为了实现前述和其他目的和需要,本发明提供了包含消旋卡多曲和共晶糖的药物组合物及其制备方法。
在一个实施方案中,本发明提供了包含消旋卡多曲、共晶糖和药学上可接受的惰性赋形剂的药物组合物,其中,消旋卡多曲和共晶糖的比例为约1:10~约1:150。
在另一实施方案中,本发明提供了药物组合物,其包含:
约0.5%~2%w/w的消旋卡多曲;
约40%~99%w/w的共晶糖;
约0.1%~5%w/w的崩解剂;
约0.05%~2%w/w的助流剂。
在又一实施方案中,本发明提供了制备包含消旋卡多曲的药物组合物的方法,该方法包括以下步骤:
(a)将消旋卡多曲、部分共晶糖和药学上可接受的惰性赋形剂过筛以形成混合物;
(b)在聚乙烯吡咯烷酮中加入溶剂以形成溶液或混悬液;
(c)将步骤(a)中形成的混合物用步骤(b)中形成的溶液或混悬液造粒以形成颗粒;
(d)干燥步骤(c)中形成的颗粒;
(e)将另一部分共晶糖与二氧化硅共混以形成中间共混物;
(f)将步骤(d)中形成的干燥的颗粒与步骤(e)中形成的中间共混物混合以形成最终共混物;
(g)将步骤(f)中形成的最终共混物填充到适当尺寸的散剂袋中。
附图说明
参照附图的详细描述和权利要求,本发明的优势和特征将变得更好理解,其中:
参照本发明的示例性实施方案,图1显示了制备包含消旋卡多曲的药物组合物的工艺流程。
具体实施方式
出于说明性目的,本发明详细描述的示例性实施方案在结构和设计方面存在许多变化。然而,应该强调的是,本发明不限于如所示和所述的包含消旋卡多曲的药物组合物及其制备方法。各种省略和等同替换应当被理解为在建议或提供权宜之计的情况下做出的,旨在不脱离本发明的权利要求的精神或范围内,覆盖本申请或实施。文中的措辞和术语也应当被理解为为了描述的目的而使用,而不应当被认为是限制性的。
本文中术语“包括”,“包含”或“具有”及其变体的使用旨在涵盖其后列出的项目及其等同物以及附加项目。此外,这里的术语“一”和“一个”不表示数量的限制,而是表示存在至少一个所引用的项目。
本发明提供药物组合物(下文称为“组合物”),其包含消旋卡多曲、共晶糖和药学上可接受的惰性赋形剂。本发明的组合物易于制备,并且不涉及任何复杂的步骤如包衣。本发明特别涉及以散剂剂型的药物组合物,其中消旋卡多曲与共晶糖的比例为约1:10~约1:150。
在本发明的一个方面,药物组合物是固体口服剂型的形式。固体剂型可以是片剂、胶囊剂、丸剂、散剂、锭剂(lozenge)、颗粒剂、和粉剂等。优选地,药物组合物是散剂的形式。
本文所用的术语消旋卡多曲包括游离碱及其药学上可接受的盐、对映异构体和多晶型。
本文中所用的共晶糖包括通过共结晶技术制备的任何糖。该技术涉及通过在冷却的情况下搅拌的过饱和糖溶液和第二种成分的自发结晶。该过程产生团聚的海绵状结构,极大提高了表面积。第二种成分为结构基质中的组成部分。
共晶糖包括葡萄糖、果糖、异麦芽酮糖醇、赤藓糖醇、氢化异麦芽酮糖、氢化淀粉水解物、乳糖醇、麦芽糖醇、甘露糖醇、聚葡萄糖、山梨糖醇、蔗糖、海藻糖、和木糖醇等。
一种优选的共晶糖为共晶蔗糖。市售等级的共晶糖可用于实施本发明的目的。
在本发明的一个方面,本发明的组合物包含消旋卡多曲与共晶糖的比例为约1:10~约1:150。具体地,消旋卡多曲与共晶糖的比例为1:10或1:20或1:25或1:50或1:75或1:85或1:87.5或1:90或1:91或1:92或1:93或1:94或1:95或1:96或1:97或1:98或1:99或1:100或1:105或1:110或1:120或1:125或1:150或1:180或1:198等。
术语“药学上可接受的惰性赋形剂”是指药物组合物的除活性成分之外的任何组分,并且由管理机构批准或通常被认为对人或动物使用是安全的。
药学上可接受的惰性赋形剂的实例包括但不限于稀释剂、粘结剂、甜味剂、崩解剂、溶剂、润滑剂、助流剂和调香剂(flavorant)。也可以使用多种赋形剂的组合。所用赋形剂的量取决于活性剂的用量。一种赋形剂也可以实现多种功能。
稀释剂包括但不限于糖粉(confectioner's sugar)、可压缩糖、葡萄糖结合剂(dextrate)、糊精、葡萄糖、果糖、乳糖醇、甘露糖醇、蔗糖、淀粉、乳糖、木糖醇、山梨糖醇、滑石、微晶纤维素、碳酸钙、二元或三元磷酸钙(calcium phosphate dibasic or tribasic)、硫酸钙和本领域普通技术人员已知的其他材料及其混合物。本发明中使用的共晶糖用作稀释剂。
粘结剂包括但不限于:淀粉如马铃薯淀粉、小麦淀粉、玉米淀粉;微晶纤维素;纤维素如羟丙基纤维素、羟乙基纤维素、羟丙基甲基纤维素(HPMC)、乙基纤维素、羧甲基纤维素钠;天然树胶如阿拉伯树胶(acacia)、海藻酸、瓜尔豆胶;液体葡萄糖、糊精、聚维酮、糖浆、聚环氧乙烷、聚乙烯吡咯烷酮、聚-N-乙烯基酰胺、聚乙二醇、明胶、聚丙二醇、黄芪胶和本领域普通技术人员已知的其它材料及其混合物。
甜味剂包括但不限于阿斯巴甜、糖精钠、甘草酸二钾、甜叶菊、奇异果甜蛋白(thaumatin)、乙酰磺胺酸钾(acesulfame K)、三氯蔗糖和本领域普通技术人员已知的其它材料及其混合物。
崩解剂包括但不限于淀粉、交联羧甲基纤维素钠、聚乙烯吡咯烷酮、羟基乙酸淀粉钠和本领域普通技术人员已知的其他材料及其混合物。崩解剂优选为聚乙烯吡咯烷酮。
溶剂包括但不限于纯化水、丙酮、乙醇、异丙醇二氯甲烷,和本领域普通技术人员已知的其他材料及其混合物。
润滑剂可选自但不限于本领域常规已知的物质,如镁、铝、钙或锌的硬脂酸盐、聚乙二醇、甘油二十二烷酸酯、矿物油、硬脂酰富马酸钠、硬脂酸、氢化植物油、滑石和本领域普通技术人员已知的其他材料及其混合物。
助流剂包括但不限于二氧化硅、三硅酸镁、粉状纤维素、淀粉、滑石和三元磷酸钙、硅酸钙、硅酸镁、胶体二氧化硅、硅水凝胶(silicon hydrogel)和本领域普通技术人员已知的其它材料及其混合物。助流剂优选为胶体二氧化硅。
调香剂包括天然和人造香料。这些香料包括但不限于合成香料油、调味芳香料,和/或来源于植物、叶子、花、果实等的油、油性树脂和提取物,以及本领域普通技术人员已知的其他材料及其混合物。典型的香料油包括:留兰香油、肉桂油、胡椒薄荷油、丁香油、月桂油、百里香油、雪松叶油、肉豆蔻油、鼠尾草油和苦杏仁油。人造的、天然的或合成的果味香料也是有用的,如香草、巧克力、咖啡、可可和柑橘油,包括柠檬、橘子、葡萄、酸橙和葡萄柚,以及果味精华,包括苹果、梨、桃、草莓、覆盆子、樱桃、李子、菠萝、和杏等等。这些调味剂(Flavoring)可以单独使用或混合使用。常用的香料还包括薄荷,例如胡椒薄荷(peppermint)、人造香草、肉桂衍生物和各种果味香料,可单独使用或混合使用。还可以使用诸如醛和酯的调味剂,包括乙酸肉桂酯、肉桂醛、柠檬醛、二乙基乙缩醛、乙酸二氢香芹酯、甲酸丁香酚酯、对甲基苯甲醚等。
本发明还涉及药物组合物,其包含:
约0.5%~2%w/w的消旋卡多曲;
约40%~99%w/w的共晶糖;
约0.1%~5%w/w的崩解剂;
约0.05%~2%w/w的助流剂。
本发明还涉及制备包含消旋卡多曲的药物组合物的方法。可以采用制备组合物的常规方法,如湿法制粒、干法制粒和直接压缩。
在实施方案中,本发明涉及制备包含消旋卡多曲的药物组合物的方法,该方法包括以下步骤:
(a)将消旋卡多曲、部分共晶糖和药学上可接受的惰性赋形剂过筛以形成混合物;
(b)在聚乙烯吡咯烷酮中加入溶剂以形成溶液或混悬液;
(c)将步骤(a)中形成的混合物用步骤(b)中形成的溶液或混悬液造粒以形成颗粒;
(d)干燥步骤(c)中形成的颗粒;
(e)将另一部分共晶糖与二氧化硅共混以形成中间共混物;
(f)将步骤(d)中形成的干燥的颗粒与步骤(e)中形成的中间共混物混合以形成最终共混物;
(g)将步骤(f)中形成的最终共混物填充到适当尺寸的散剂袋中。
赋形剂的混合可以在用于混合粉末的常规装置中进行,例如静态(被动式)混合器、流化床、扩散混合器、双锥扩散混合器、单锥混合器、双锥混合器、管式混合器、立方混合器、行星式混合器、Y型、V型混合器、或低剪切或高剪切混合器。
造粒操作可以使用例如流化床造粒机、搅拌造粒机、或双轴造粒机等设备进行。
通常,成粒的混合物优选在步骤(c)中以任何药学上可接受的方式造粒后干燥。例如,颗粒的干燥可以以下列方式之一进行:盘架、流化床、和微波辅助/真空/气提(gasstripping)(一锅法)。
造粒可通过适当的水性或非水性溶剂进行。
根据本发明,药物组合物提供了不必包衣消旋卡多曲药物的进一步优点。如上所述,不需要包衣消旋卡多曲以实现良好的适口性、对水解或其他环境条件的敏感性和产品外观。因此,本发明的方法避免了包衣工艺,从而避免了额外的包衣工艺。
通过以下非限制性实施例进一步说明本发明的包含消旋卡多曲的药物组合物的描述。然而,本领域技术人员将认识到,具体实施例旨在说明而非限制本发明的范围。
实施例
实施例1:根据本发明的药物组合物
表1:包含消旋卡多曲的药物组合物
加工工艺:
1.药物颗粒的制备:
在适当的研磨机中研磨共晶蔗糖。并在适当的过筛机中,将共晶蔗糖与中间加入的消旋卡多曲和胶体二氧化硅过筛。将过筛后的物质加入到混合器中并混合。
将纯化水加入聚乙烯吡咯烷酮中以形成混悬液。在适当的造粒机中,将粘结剂混悬液加入到干混合物中。在适当的干燥器中干燥湿物质。筛分并研磨干燥的颗粒。将干燥的颗粒转移到适当的共混机中并充分混合。
2.散装颗粒(bulk granule)的制备:
将另一部分共晶蔗糖在适当的研磨机中研磨。筛分消旋卡多曲和研磨过的共晶蔗糖。过筛物料适当共混。将共混的药物颗粒材料转移到含有中间共混物的共混机中并适当混合。将上述步骤中的共混材料再次筛分并适当混合。
3.装袋:
将消旋卡多曲的散装颗粒装入适当的散剂袋中。
包装细节如下所示:
表2包含消旋卡多曲的药物组合物的包装细节。
Claims (13)
1.一种药物组合物,其包含消旋卡多曲、共晶糖和药学上可接受的惰性赋形剂,其中,所述消旋卡多曲与所述共晶糖的比例为约1:10~约1:150。
2.根据权利要求1所述的药物组合物,其中所述组合物是未经包衣的。
3.根据权利要求1所述的药物组合物,其中所述药学上可接受的惰性赋形剂包括稀释剂、粘结剂、甜味剂、崩解剂、溶剂、润滑剂、助流剂和调香剂。
4.根据权利要求1所述的药物组合物,其中所述共晶糖为共晶蔗糖。
5.一种药物组合物,其包含:
约0.5%~2%w/w的消旋卡多曲;
约40%~99%w/w的共晶糖;
约0.1%~5%w/w的崩解剂;
约0.05%~2%w/w的助流剂。
6.根据权利要求5所述的药物组合物,其中所述组合物为固体剂型。
7.根据权利要求5所述的药物组合物,其中所述组合物为散剂的形式。
8.根据权利要求5所述的药物组合物,其中所述共晶糖为共晶蔗糖。
9.根据权利要求5所述的药物组合物,其中所述崩解剂为聚乙烯吡咯烷酮。
10.根据权利要求5所述的药物组合物,其中所述助流剂为胶体二氧化硅。
11.一种制备包含消旋卡多曲的药物组合物的方法,所述方法包含以下步骤:
(a)将消旋卡多曲、部分共晶糖和药学上可接受的惰性赋形剂过筛以形成混合物;
(b)在聚乙烯吡咯烷酮中加入溶剂以形成溶液或混悬液;
(c)将步骤(a)中形成的混合物用步骤(b)中形成的溶液或混悬液造粒以形成颗粒;
(d)干燥步骤(c)中形成的颗粒;
(e)将另一部分共晶糖与二氧化硅共混以形成中间共混物;
(f)将步骤(d)中形成的干燥的颗粒与步骤(e)中形成的中间共混物混合以形成最终共混物;
(g)将步骤(f)中形成的最终共混物填充到适当尺寸的散剂袋中。
12.根据权利要求11所述的方法,其中所述造粒方法为水性造粒。
13.根据权利要求11所述的方法,其中所述造粒方法为非水性造粒。
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EP3592333A4 (en) | 2020-08-19 |
MX2018014260A (es) | 2019-04-29 |
EP3592333C0 (en) | 2024-04-03 |
EP3592333B1 (en) | 2024-04-03 |
EP3592333A1 (en) | 2020-01-15 |
RU2018131133A3 (zh) | 2021-01-22 |
WO2018163195A1 (en) | 2018-09-13 |
US20200061014A1 (en) | 2020-02-27 |
RU2018131133A (ru) | 2021-01-22 |
BR112018069973A2 (pt) | 2019-09-17 |
RU2749949C2 (ru) | 2021-06-21 |
KR20180129807A (ko) | 2018-12-05 |
KR102195776B1 (ko) | 2020-12-29 |
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