CN117377463A - 包含1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1h-吡咯-3-基)-n-甲基甲胺的注射用新配制物 - Google Patents
包含1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1h-吡咯-3-基)-n-甲基甲胺的注射用新配制物 Download PDFInfo
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- CN117377463A CN117377463A CN202280036641.5A CN202280036641A CN117377463A CN 117377463 A CN117377463 A CN 117377463A CN 202280036641 A CN202280036641 A CN 202280036641A CN 117377463 A CN117377463 A CN 117377463A
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明涉及一种包含1‑(5‑(2,4‑二氟苯基)‑1‑((3‑氟苯基)磺酰基)‑4‑甲氧基‑1H‑吡咯‑3‑基)‑N‑甲基甲胺或其药学上可接受的盐的注射用配制物。
Description
技术领域
相关申请的交叉引用
本申请要求在韩国知识产权局于2021年5月26日提交的韩国专利申请号10-2021-0067636和于2022年5月26日提交的韩国专利申请号10-2022-0064451的权益,这些申请的全部公开内容通过引用并入本文。
本发明涉及一种包含1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1H-吡咯-3-基)-N-甲基甲胺的注射用新配制物。
背景技术
已知即使在含有相同活性成分的配制物的情况下,活性成分的药学上重要的性质,诸如溶解度、溶解特征和生物可用性可根据配制物中所含有的另外组分而不同。因此,随着新化合物的开发,开发配制物中含有的可使所开发化合物的药理学效应最大化的组分也非常重要。
同时,1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1H-吡咯-3-基)-N-甲基甲胺是韩国专利注册号10-1613245中所描述的物质,其为具有优异抗溃疡活性(即,质子泵抑制活性等)、抗幽门螺杆菌(H.pylori)活性和GPCR抑制活性的物质,并因此适用于预防和治疗肠胃溃疡、胃炎、反流性食道炎或由幽门螺杆菌引起的肠胃损伤。
然而,以上物质或其盐酸盐表现出稳定性差的问题,例如在中性pH环境中水溶性较低,并且在具有良好溶解度的酸性环境(2.17mg/ml,pH 6.8)中酸分解产物增加,由此,通过在水溶液中溶解和稳定来配制注射用配制物存在很大困难。因此,为了开发可实现溶解度与稳定性之间的平衡的注射用配制物,不断需要研究适当pH的调整和除活性药物成分以外的成分的组合。
因此,本发明人已尝试通过改善1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1H-吡咯-3-基)-N-甲基甲胺的溶解度和稳定性来配制注射用配制物,并由此确认,当在特定pH范围内含有特定等渗剂时,可解决上述问题,从而完成本发明。
发明内容
[技术问题]
本发明的目的是提供一种注射用新配制物,该注射用新配制物包含具有高溶解度和优异稳定性的1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1H-吡咯-3-基)-N-甲基甲胺或其药学上可接受的盐。
[技术方案]
根据本发明的实施方式,提供一种注射用配制物,该注射用配制物包含:由以下化学式1表示的化合物或其药学上可接受的盐;环糊精;和等渗剂,其中注射用配制物具有4.0至6.0的pH:
[化学式1]
由化学式1表示的化合物的化学名称为1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1H-吡咯-3-基)-N-甲基甲胺,其为韩国专利注册号10-1613245中描述的物质。
由化学式1表示的化合物是本发明的注射用配制物的表现出药理学效应的活性成分,该化合物为具有优异抗溃疡活性(即,质子泵抑制活性等)、抗幽门螺杆菌(H.pylori)活性和GPCR抑制作用的物质,并因此适用于预防和治疗肠胃溃疡、胃炎、反流性食道炎或由幽门螺杆菌引起的肠胃损伤。
此外,作为本发明的注射用配制物的表现出药理学效应的活性成分,不仅可使用由化学式1表示的化合物,而且也可使用其药学上可接受的盐。作为盐,可不受限制地使用本领域中常用的盐,诸如由药学上可接受的游离酸形成的酸加成盐。如本文所用,术语“药学上可接受的盐”是指由化学式1表示的化合物的任何有机或无机加成盐,其浓度对于患者而言相对无毒和无害且能有效活化,并且其副作用不降低以上化合物的有益功效。
由化学式1表示的化合物或其药学上可接受的盐可使用无机酸或有机酸通过常规方法获得药学上可接受的盐。例如,药学上可接受的盐可通过以下方式制备:将由化学式1表示的化合物溶解于可与水混溶的有机溶剂(例如丙酮、甲醇、乙醇或乙腈)中,然后加入有机酸或无机酸,并过滤和干燥沉淀的晶体。替代性地,该药学上可接受的盐可通过以下方式制备:使溶剂或来自酸加成的反应混合物的过量的酸经受减压并然后干燥残余物,或通过加入不同的有机溶剂并然后过滤所沉淀的盐。此时,优选的盐可包括源自以下各项的盐:盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乙醇酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二酸、反丁烯二酸、苹果酸、杏仁酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、顺丁烯二酸、羟基顺丁烯二酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸或甲苯磺酸等。
由化学式1表示的化合物或其药学上可接受的盐具有低水溶度,因此需要过量增溶剂和有机溶剂以便制备成用于注射组合物(诸如可注射药物组合物)的配制物。然而,过量增溶剂等在给予到患者时可引起过敏反应。因此,在本发明中,使用环糊精和等渗剂代替使用在注射用配制物中通常使用的增溶剂,并且调节pH,从而获得具有由化学式1表示的化合物的优异溶解度和稳定性的注射用配制物。
为根据本发明的注射用配制物中使用的组分的环糊精为其中6至12个葡萄糖分子为α-1,4-糖苷键的环状寡醣,并且在本发明中用作稳定剂。优选地,环糊精为β-环糊精或γ-环糊精,更优选地为β-环糊精。更优选地,β-环糊精为(2-羟丙基)-β-环糊精或磺基丁醚-β-环糊精,其英文缩写分别为“HP-β-CD”和“SBE-β-CD”。
在注射用配制物中常用的稳定剂中,环糊精适合于使由化学式1表示的化合物或其药学上可接受的盐稳定。
优选地,相对于1重量份的由化学式1表示的化合物或其药学上可接受的盐,环糊精以3.0至25.0重量份的量使用。当含量小于3.0重量份时,其不足以使由化学式1表示的化合物稳定,这可引起注射用配制物的复水困难或在长期储存期间总相关物质增加的问题。此外,当含量大于25.0重量份时,所用稳定剂的量过大,并因此注射用配制物的黏度变得较高,或当向患者给予时存在引起过敏反应的风险。
更优选地,相对于1重量份的由化学式1表示的化合物或其药学上可接受的盐,环糊精的含量为3.5重量份或更大、4.0重量份或更大或4.5重量份或更大;且20.0重量份或更小、19.0重量份或更小、18.0重量份或更小、17.0重量份或更小、16.0重量份或更小、15.0重量份或更小、14.0重量份或更小、13.0重量份或更小、12.0重量份或更小、11.0重量份或更小;或10.0重量份或更小。
同时,根据本发明的注射用配制物中使用的“等渗剂”为添加剂,其添加以使得注射用配制物的渗透压类似于身体内渗透压。因为注射用配制物在无单独稀释过程的情况下直接给予到身体中,其应在与身体相同的渗透压下制造以便在给予到身体内时减少副作用。优选地,等渗剂可为氯化钠(NaCl)、D-甘露糖醇、右旋糖、甘油或氯化钾(KCl),更优选为氯化钠(NaCl)、右旋糖、甘油或氯化钾(KCl),最优选为氯化钠(NaCl)、右旋糖或氯化钾(KCl)。
取决于等渗剂是电解质还是非电解质,等渗剂可在达到所需的注射用配制物的容量渗透摩尔浓度(osmolarity)所需的含量方面不同。因此,优选含有等渗剂以使得取决于特定物质的类型,根据本发明的注射用配制物的容量渗透摩尔浓度可为100至700mOsmol/L。更优选地,注射用配制物的容量渗透摩尔浓度可为150至650mOsmol/L、150至450mOsmol/L、250至450mOsmol/L或270至420mOsmol/L。
优选地,根据本发明的注射用配制物的pH为5.0至6.0。优选地,由于本发明的液体药物组合物本身的化学性质,本发明的注射用配制物可具有以上pH范围,并因此注射用配制物可不含有用于调节pH的额外的pH调节剂。这里,pH调节剂为通过加入该试剂来调节溶液pH以由此提高水溶性差或不溶性化合物的溶解度的物质,并且使用药学上可接受的酸或碱试剂。pH调节剂的实例可包括以下各项中的任一种或多种:盐酸、磷酸、氢氧化钠、氢氧化钾、磷酸一氢钾、磷酸二氢钾、磷酸一氢钠、磷酸二氢钠、碳酸钠、碳酸钾和三乙醇胺。
优选地,注射用配制物进一步包括冷冻干燥助剂。一般而言,注射用配制物批量生产,然后冷冻并在减压下储存和分布,这可增强活性成分的稳定性且改善长期储存稳定性。因此,在冷冻干燥过程期间必须保持活性物质的稳定性,因此在本发明中,可进一步包括冷冻干燥助剂。优选地,冷冻干燥助剂为D-甘露糖醇、蔗糖、山梨糖醇或海藻糖,更优选地,冷冻干燥助剂为D-甘露糖醇。
优选地,相对于1重量份的由化学式1表示的化合物或其药学上可接受的盐,冷冻干燥助剂以3.0至25.0重量份的量使用。当含量小于3.0重量份时,其不足以使由化学式1表示的化合物稳定,这可引起注射用配制物的复水困难或在长期储存期间相关物质增加的问题。此外,当含量大于25.0重量份时,冷冻干燥助剂的量过大,并因此注射用配制物的黏度变得较高,或当向患者给予时存在引起过敏反应的风险。
更优选地,相对于1重量份的由化学式1表示的化合物或其药学上可接受的盐,冷冻干燥助剂的含量为3.5重量份或更大、4.0重量份或更大或4.5重量份或更大;且20.0重量份或更小、15.0重量份或更小、13.0重量份或更小、10.0重量份或更小、9.0重量份或更小、8.0重量份或更小、7.0重量份或更小或6.0重量份或更小。
优选地,相对于1重量份的环糊精,冷冻干燥助剂以0.5至5.0重量份的量使用。更优选地,相对于1重量份的环糊精,冷冻干燥助剂的含量为0.6重量份或更大、0.7重量份或更大或0.8重量份或更大;且4.5重量份或更小、4.0重量份或更小、3.5重量份或更小、3.0重量份或更小、2.5重量份或更小、2.3重量份或更小、2.0重量份或更小、1.9重量份或更小、1.8重量份或更小、1.7重量份或更小;1.6重量份或更小、1.5重量份或更小、1.4重量份或更小、1.3重量份或更小或1.2重量份或更小。
优选地,注射用配制物可包括本领域中常用的溶剂以便制备液体形式的药物组合物。举例而言,注射用配制物的溶剂可为蒸馏水、注射用水、乙酸盐缓冲液或生理盐水。
优选地,由化学式1表示的化合物或其药学上可接受的盐以1至8mg/mL的量包含于注射用配制物中。即,由化学式1表示的化合物或其药学上可接受的盐的含量可定义为通过使由化学式1表示的化合物或其药学上可接受的盐的含量(mg)除以注射用配制物的总体积(mL)获得的值。
更优选地,由化学式1表示的化合物或其药学上可接受的盐以2mg/mL或更大、3mg/mL或更大、或4mg/mL或更大或5mg/mL或更大;且7mg/mL或更小、6mg/mL或更小或5.5mg/mL或更小的量包含在注射用配制物中。
此外,必要时,根据本发明的注射用配制物可进一步包括防腐剂、抗氧化剂等。防腐剂和抗氧化剂不受特别限制,只要它们在本发明所属技术领域中常用即可。
此外,根据本发明的注射用配制物可通过将不包括溶剂的上述成分与溶剂混合来制备。在该过程中,可根据需要调节各组分加入到溶剂中的顺序,或可将所有组分在加入到溶剂中之前混合并加入到溶剂中。然而,这种制备方法不受限制,并且可根据本领域中已知的方法修改注射用配制物的制备。
必要时可对所制备的注射用配制物进行灭菌和/或过滤,并且可将其进行冷冻干燥以便储存和分布。
[有益效果]
如上文所描述,根据本发明的含有1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1H-吡咯-3-基)-N-甲基甲胺或其药学上可接受的盐的注射用配制物满足特定pH范围并且包括等渗剂,由此该注射用配制物具有高的溶解度并且能表现出优异的稳定性,因此可用作适用于预防和治疗肠胃溃疡、胃炎、反流性食道炎或由幽门螺杆菌引起的肠胃损伤的注射用配制物。
具体实施方式
在下文中,给出了优选实施例以便帮助容易理解本发明,但以下实施例仅用于说明性目的,且本发明的范围不限于此。
实施例1
使用40mg的由化学式1表示的化合物的盐酸盐(在下文中称为“API”),通过用表1中所示的组成调节pH来分别制备溶液。
之后,将各制备溶液填充到小瓶中,且在苛刻条件(60℃,80%RH)下以液体形式储存于腔室中4周,并然后评估稳定性。结果在下表2中示出。对于稳定性评估,通过HPLC分析液体溶液的相关物质的含量,并测量所检测到的相关物质的总量。
[表1]
[表2]
如表2中所示,确认当在苛刻条件下以液体溶液状态储存4周时,pH为4.0至6.0的#1-2至#1-4的组合物具有相对而言总相关物质的产量不会显著增加的稳定性。
实施例2
在实施例1中,通过选择pH 6.0来进行以下实验,在该pH下总相关物质的产量最低。
如下表3中所示,样品是在不同浓度的API下制备,确认了性质根据浓度的褐变模式。视觉评估所制备溶液中的各溶液,并且结果在下表4中示出。
[表3]
#1-4 | #2 | |
API | 40mg | 40mg |
HP-β-CD | 200mg | 200mg |
D-甘露糖醇 | 200mg | 200mg |
注射用水 | 4mL | 10mL |
pH | 6.0 | 6.0 |
[表4]
如表4中所示,确认具有低浓度的#2的性质即使在苛刻条件下储存4周时也不会发生改变。
实施例3
通过选择在实施例2中性质稳定的浓度(4mg/mL)进行以下实验。
如下表5中所示,通过改变各等渗剂的量以使得溶液的渗透压为380mOsmol/L(或类似于身体内渗透压)来制备样品溶液。将所制备溶液在苛刻条件(60℃,80% RH)下储存于腔室中4周,并通过与实施例1中相同的方法评估性质和稳定性。结果在下表6中示出。
[表5]
[表6]
如上表6中所示,确认所有添加了等渗剂的溶液即使在苛刻条件下储存4周的后性质也不会发生改变。而且特别是,确认#3-1至#3-4的组合物表现出与比较组#2相比更为稳定的总相关物质产量水平。
参考实施例1
在实施例3中显示为相对稳定的等渗剂中,选择NaCl并进行以下实验。
如下表7中所示,在不添加pH调节剂的情况下或通过改变类型来制备各溶液。将所制备溶液在苛刻条件(60℃,80% RH)下储存于腔室中4周,并通过与实施例1中相同的方法评估性质和稳定性。结果在下表6中示出。
[表7]
[表8]
如表8中所示,确认不含pH调节剂的#4-1具有优异的稳定性,因为相关物质的总量小于含有pH调节剂的#3-1或#4-2的相关物质的总量。
参考实施例2
选择实施例3和参考实施例1中确认的两个实验组(具有/不具有HCl/NaOH pH调节剂),并进行以液体组合物状态长期储存的实验。各实验组的组成在下表9中示出。
将各制备溶液在加速条件(40℃,75% RH)下储存于腔室中6个月,并通过与实施例1中相同的方法评估性质和稳定性。结果在下表10中示出。
[表9]
[表10]
如表10中所示,确认尽管不含pH调节剂的#4-1以液态储存了很长一段时间,但性质也没有发生变化且几乎没有总相关物质的产量,由此具有优异的稳定性。
Claims (11)
1.一种注射用配制物,其包含由以下化学式1表示的化合物或其药学上可接受的盐;环糊精;和等渗剂,
其中,所述注射用配制物的pH为4.0至6.0:
[化学式1]
2.根据权利要求1所述的注射用配制物,其中
所述环糊精是(2-羟丙基)-β-环糊精或磺基丁醚-β-环糊精。
3.根据权利要求1所述的注射用配制物,其中
相对于1重量份的所述由化学式1表示的化合物或其药学上可接受的盐,所述环糊精的含量为4.5至15.0重量份。
4.根据权利要求1所述的注射用配制物,其中
所述等渗剂为氯化钠(NaCl)、D-甘露糖醇、右旋糖、甘油或氯化钾(KCl)。
5.根据权利要求1所述的注射用配制物,其中
所述注射用配制物的容量渗透摩尔浓度为100至700mOsmol/L。
6.根据权利要求1所述的注射用配制物,其中
所述pH为5.0至6.0。
7.根据权利要求1所述的注射用配制物,其中
所述注射用配制物不包含pH调节剂。
8.根据权利要求1所述的注射用配制物,其中
所述注射用配制物进一步包含冷冻干燥助剂,并且
所述冷冻干燥助剂为D-甘露糖醇、蔗糖、山梨糖醇或海藻糖。
9.根据权利要求8所述的注射用配制物,其中
相对于1重量份的所述由化学式1表示的化合物或其药学上可接受的盐,所述冷冻干燥助剂的含量为3.0至25.0重量份。
10.根据权利要求1所述的注射用配制物,其中
所述注射用配制物的溶剂为蒸馏水、注射用水、乙酸盐缓冲液或生理盐水。
11.根据权利要求1所述的注射用配制物,其中
所述由化学式1表示的化合物或其药学上可接受的盐以1至8mg/mL的量包含于所述注射用配制物中。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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KR10-2021-0067636 | 2021-05-26 | ||
KR20210067636 | 2021-05-26 | ||
PCT/KR2022/007479 WO2022250469A1 (ko) | 2021-05-26 | 2022-05-26 | 1-(5-(2,4-다이플루오로페닐)-1-((3-플루오로페닐)술포닐)-4-메톡시-1h-피롤-3-일)-n-메틸메탄아민을 포함하는 신규한 주사용 제제 |
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Publication Number | Publication Date |
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CN117377463A true CN117377463A (zh) | 2024-01-09 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN202280036641.5A Pending CN117377463A (zh) | 2021-05-26 | 2022-05-26 | 包含1-(5-(2,4-二氟苯基)-1-((3-氟苯基)磺酰基)-4-甲氧基-1h-吡咯-3-基)-n-甲基甲胺的注射用新配制物 |
Country Status (4)
Country | Link |
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EP (1) | EP4356900A1 (zh) |
KR (1) | KR20220159916A (zh) |
CN (1) | CN117377463A (zh) |
TW (1) | TW202304426A (zh) |
-
2022
- 2022-05-25 TW TW111119456A patent/TW202304426A/zh unknown
- 2022-05-26 EP EP22811660.4A patent/EP4356900A1/en active Pending
- 2022-05-26 CN CN202280036641.5A patent/CN117377463A/zh active Pending
- 2022-05-26 KR KR1020220064451A patent/KR20220159916A/ko unknown
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Publication number | Publication date |
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KR20220159916A (ko) | 2022-12-05 |
EP4356900A1 (en) | 2024-04-24 |
TW202304426A (zh) | 2023-02-01 |
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