CN114080227B - 包含o-环植物鞘氨醇-1-磷酸酯的用于预防或治疗帕金森氏病的组合物 - Google Patents
包含o-环植物鞘氨醇-1-磷酸酯的用于预防或治疗帕金森氏病的组合物 Download PDFInfo
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Abstract
本发明提供一种用于预防或治疗帕金森氏病的组合物，所述组合物包含O‑环植物鞘氨醇‑1‑磷酸酯。根据本发明的组合物可以防止多巴胺能SH‑SY5Y神经细胞的死亡并且增加多巴胺形成所需的酶酪氨酸羟化酶的表达，由此发现在预防或治疗帕金森氏病中的有利应用。
Description
技术领域
本公开涉及一种用于预防或治疗帕金森氏病的组合物，所述组合物包含O-环植物鞘氨醇-1-磷酸酯。具体地，本公开涉及一种包含O-环植物鞘氨醇-1-磷酸酯的组合物，所述组合物可以抑制多巴胺能神经细胞的死亡并增加酪氨酸羟化酶的表达，从而预防或治疗帕金森氏病。
背景技术
帕金森氏病(PD)是一种由缺乏称为多巴胺的神经递质引起的疾病。多巴胺的缺乏由中脑的黑质区域中多巴胺能神经细胞的渐进性和选择性丧失引起。帕金森氏病导致手臂、腿部和面部的震颤或瘫痪，僵硬，由于运动迟缓和姿势不稳引起的运动障碍。
帕金森氏病的病因非常多样。所有患者的约5％由遗传因素引起，并且外界环境因素(如炎症和氧化应激)起重要作用。帕金森氏病由多巴胺能神经细胞中α-突触核蛋白的异常聚集引起。氧化应激进一步促进了这些蛋白质的聚集。到目前为止，帕金森氏病的治疗已经通过补充多巴胺神经递质来实现，但这并没有为帕金森氏病提供根本治疗。对于帕金森氏病的根本治疗，需要抑制参与多巴胺产生的神经细胞的死亡，并促进多巴胺的产生。对于帕金森氏病的根本治疗，关于直接靶向疾病修饰基因的小分子治疗药物、基因疗法、单克隆抗体、靶向相关适应症的免疫疗法以及生物制剂(如干细胞和诱导的多能干细胞)的研究正在进行中。最近，在临床实践中已经尝试了使用干细胞的PD治疗。
O-环植物鞘氨醇-1-磷酸酯(O-cyclic phytosphingosine-1-phosphate)是由以下化学式I表示的化合物，其在韩国专利第10-1340556号中公开为可用于防止脱发或促进毛发生长。
然而，到目前为止，还没有文献报道表明在帕金森氏病的细胞模型中，O-环植物鞘氨醇-1-磷酸酯可以抑制作为多巴胺能神经细胞的SH-SY5Y神经细胞的死亡并且增加多巴胺形成所需的酶酪氨酸羟化酶的表达。
发明内容
技术问题
本发明人进行了深入研究以开发用于帕金森氏病的有效治疗剂，结果发现，O-环植物鞘氨醇-1-磷酸酯抑制作为多巴胺能神经细胞的SH-SY5Y神经细胞的死亡并且增加多巴胺形成所需的酶酪氨酸羟化酶的表达，并完成了本发明。
因此，本公开的目的是提供一种包含O-环植物鞘氨醇-1-磷酸酯的用于预防或治疗帕金森氏病的组合物。
技术方案
本公开的一个实施例涉及一种用于预防或治疗帕金森氏病的药物组合物，其包含由以下化学式I表示的化合物或其药学上可接受的盐：
如本文所用，药学上可接受的盐包括无毒的无机和有机酸盐两者，例如盐酸盐、硫酸盐、硝酸盐、磷酸盐、乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、二磷酸盐、乙磺酸盐、富马酸盐、谷氨酸盐、苹果酸盐、乳酸盐、甲磺酸盐、琥珀酸盐、酒石酸盐、苦味酸盐、甲苯磺酸盐等，并且具体地可以是盐酸盐。
由化学式I表示的化合物或其药学上可接受的盐可以商业获得，或者可以通过本领域已知的方法容易地制备(参见韩国专利第10-1340556号)。
由本公开的化学式I表示的化合物或其药学上可接受的盐被证明抑制由分别用鱼藤酮和MPP+处理诱导的帕金森氏病细胞模型中在作为多巴胺能神经细胞的SH-SY5Y神经细胞中的神经细胞死亡并且增加神经细胞中多巴胺形成所需的酶酪氨酸羟化酶的表达(实例2至4，图2至4)。因此，由本公开的化学式I表示的化合物或其药学上可接受的盐可以有效地用于预防或治疗帕金森氏病的药物组合物中。
除了由化学式I表示的化合物或其药学上可接受的盐之外，根据本公开的药物组合物还可以包含用于帕金森氏病的另一种治疗剂。
根据本公开的药物组合物可以口服(例如，摄入或吸入)或肠胃外(例如，注射、透皮吸收、直肠施用)施用，并且注射可以是例如静脉注射、皮下注射、肌内注射或腹膜内注射。取决于施用途径，根据本公开的药物组合物可以配制成片剂、胶囊、颗粒、细粒剂(finesubtilae)、粉末、舌下片剂、栓剂、软膏、注射剂、乳剂、混悬剂、糖浆、喷雾剂等。优选地，药物组合物可以是片剂的形式。根据本公开的各种类型的药物组合物可以通过已知技术使用通常用于每种配制品的药学上可接受的载体来制备。药学上可接受的载体的例子包括赋形剂、粘合剂、崩解剂、润滑剂、防腐剂、抗氧化剂、等渗剂、缓冲剂、包衣剂、甜味剂、增溶剂、碱、分散剂、润湿剂、悬浮剂、稳定剂、着色剂等。
根据本公开的药物组合物的形式，本公开的药物组合物可以以按重量计为约0.001％至95％的量含有由化学式1表示的化合物或其药学上可接受的盐。
本公开的药物组合物的具体剂量可以根据哺乳动物的类型(包括被治疗的人)、体重、性别、疾病的严重程度、医生的判断等而变化。优选地，在口服施用的情况下，可以施用0.01mg至50mg活性成分/1kg体重，并且在肠胃外施用的情况下，可以施用0.01mg至10mg活性成分/1kg体重。根据疾病的严重程度、医生的判断等，总每日剂量可以一次或分成几个剂量施用。
本公开的一个实施例涉及一种用于预防或改善帕金森氏病的口服制剂，其包含由以下化学式I表示的化合物或其药学上可接受的盐：
根据本公开的口服制剂的类型没有特别限制，并且其可以是诸如粉末、颗粒、片剂、胶囊、悬浮剂、乳剂、糖浆的口服制剂形式，或者可以添加到诸如糖果、糕饼、口香糖、冰淇淋、面条、面包、饮料等的普通食品中。
根据本公开的口服制剂的形式，本公开的口服制剂可以使用填充剂、增量剂、粘合剂、润湿剂、崩解剂、甜味剂、芳香剂、防腐剂、表面活性剂、润滑剂、赋形剂等以常规方式来制备。
在口服制剂的制备中，由化学式I表示的化合物或其药学上可接受的盐的含量根据口服制剂的类型而变化，但为按重量计为约0.001％至10％，优选地按重量计为0.1％至5％。
本公开的一个实施例涉及一种用于预防或治疗帕金森氏病的方法，其包括向有需要的受试者施用有效量的由以下化学式I表示的化合物或其药学上可接受的盐：
本公开的一个实施例涉及由以下化学式I表示的化合物或其药学上可接受的盐用于预防或治疗帕金森氏病的用途：
有利作用
根据本公开的O-环植物鞘氨醇-1-磷酸酯或其药学上可接受的盐可以抑制由用鱼藤酮或MPP+治疗诱导的帕金森氏病细胞模型中的神经细胞死亡并且增加神经细胞中多巴胺形成所需的酶酪氨酸羟化酶的表达。因此，其可以有效地用于预防、治疗或改善帕金森氏病的组合物中。
附图说明
图1是示出cP1P药物浓度对SH-SY5Y人神经细胞系增殖的作用的图。
图2是示出cP1P药物抑制鱼藤酮处理的帕金森氏病细胞模型中的SH-SY5Y神经细胞死亡的功效的图。
图3是示出cP1P药物抑制MPP+处理的帕金森氏病细胞模型中的SH-SY5Y神经细胞死亡的功效的图。
图4示出了通过免疫组织化学方法(a)和蛋白质印迹方法(b)测量cP1P药物对SH-SY5Y神经细胞中酪氨酸羟化酶(TH)表达的作用的结果。
具体实施方式
在下文中，呈现实施例来帮助理解本发明。然而，提供以下实施例仅仅是为了更容易理解本发明，并且本发明不受以下实例限制。
实例1：cP1P药物对多巴胺能人神经细胞(SH-SY5Y)增殖的作用
使用从ATCC购买的SH-SY5Y人神经细胞系作为神经细胞系来评价cP1P药物对多巴胺能人神经细胞增殖的作用。使用Dulbecco改良的Eagle培养基(Dulbeco's ModifiedEagle's Media)/高葡萄糖(含10％ FBS，0.5％ P/S)作为培养神经细胞的培养基，并且在5％ CO2培养箱中于37℃下培养神经细胞。
为了观察cP1P药物对多巴胺能人神经细胞增殖的作用，将SH-SY5Y细胞分别用浓度为10nM、100nM和1000nM的cP1P药物处理，并且培养48小时。根据制造商的方法进行MTT测定(分子探针)以测量细胞增殖率。
结果在图1中示出。
如图1所示，即使在10nM的低浓度cP1P药物下，也出现了对SH-SY5Y细胞增殖的作用。当cP1P药物浓度为100nM时，对神经细胞增殖的作用最大。
实例2：cP1P药物在鱼藤酮处理的帕金森氏病细胞模型中的作用
鱼藤酮是一种广泛用于细胞模型中以诱导帕金森氏病的物质。众所周知，当用鱼藤酮处理神经细胞时，线粒体功能被破坏，并且氧化应激被诱导，以导致神经细胞死亡。
将SH-SY5Y神经细胞培养基分别用浓度为100nM和1000nM的cP1P药物处理，并且培养24小时。然后，将鱼藤酮(Sigma)溶解在DMSO中，稀释至最终浓度为2μM，并且添加到SH-SY5Y神经细胞培养基中。将SH-SY5Y神经细胞培养额外的24小时。以与实例1相同的方式获得并培养SH-SY5Y神经细胞。
使用乳酸脱氢酶(LDH)检测试剂盒(BioVision)测量培养的SH-SY5Y神经细胞的坏死性细胞死亡。
为了进行比较，还测量了仅用DMSO而不用cP1P药物和鱼藤酮处理的对照组以及仅用稀释的鱼藤酮溶液而不用cP1P药物处理的对照组的坏死性细胞死亡。另外，测量了用浓度分别为100nM和1000nM的cP1P药物处理神经细胞的坏死性细胞死亡。
结果在图2中示出。
如图2所示，在仅用鱼藤酮处理的对照组中，神经细胞死亡的程度足够高到超过30％。然而，当cP1P药物首次处理时，神经细胞死亡被抑制到与不用鱼藤酮的DMSO处理相当的水平。
另外，如图2所示，与仅用DMSO处理的对照组相比，cP1P药物的处理降低了细胞死亡的程度。此结果似乎是因为用cP1P药物的处理增强了SH-SY5Y神经细胞的增殖。从这些结果可以看出，cP1P药物可用作帕金森氏病的治疗剂。
实例3：cP1P药物在MPP+处理的帕金森氏病细胞模型中的作用
为了通过用MPP+(1-甲基-4-苯基吡啶鎓碘化物，Sigma)诱导氧化应激来制备帕金森氏病细胞模型，将MPP+溶解在磷酸盐缓冲溶液中，稀释至3mM的最终浓度，并且添加到神经细胞培养基中。为了确认cP1P药物在MPP+环境中的功效，将SH-SY5Y细胞分别用浓度为10nM、100nM和1000nM的cP1P药物预处理1小时，然后通过用3mM MPP+处理24小时暴露于氧化应激。通过MTT测定确定cP1P药物对暴露于氧化应激24小时之后SH-SY5Y细胞的存活率的功效。
结果在图3中示出。
如图3所示，当用MPP+3mM处理SH-SY5Y细胞系时，神经细胞被杀死。然而，当用cP1P药物预处理细胞系时，神经细胞死亡显著减少。具体地，当cP1P药物以100nM的浓度处理时，神经细胞死亡显著减少。从这些结果可以看出，cP1P药物可用作帕金森氏病的治疗剂。
实例4：cP1P药物对神经细胞中多巴胺形成所需的酪氨酸羟化酶(TH)表达的作用
酪氨酸羟化酶(TH)是一种将氨基酸酪氨酸转化为多巴胺前体L-DOPA并且在神经细胞中多巴胺的形成方面起重要作用的酶。
为了确认cP1P药物对SH-SY5Y神经细胞中TH表达的功效，将SH-SY5Y神经细胞培养物分别用浓度为10nM和100nM的cP1P药物处理。在24小时后通过免疫组织化学和蛋白质印迹测定TH表达。
结果在图4中示出。
如图4所示，当cP1P药物以10nM和100nM的浓度处理时，TH酶的表达增加。这些结果表明，cP1P药物可以用作由多巴胺能神经细胞的死亡引起的帕金森氏病的治疗剂。
Claims (6)
1.由以下化学式I表示的化合物或其药学上可接受的盐在制备用于预防或治疗帕金森氏病的药物组合物中的用途：
2.根据权利要求1所述的用途，其中所述由化学式I表示的化合物或其药学上可接受的盐增加酪氨酸羟化酶的表达。
3.根据权利要求1所述的用途，其中所述药学上可接受的盐是盐酸盐。
4.由以下化学式I表示的化合物或其药学上可接受的盐在制备用于预防或改善帕金森氏病的口服制剂中的用途：
5.根据权利要求4所述的用途，其中所述由化学式I表示的化合物或其药学上可接受的盐增加酪氨酸羟化酶的表达。
6.根据权利要求4所述的用途，其中所述药学上可接受的盐是盐酸盐。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105246903A (zh) * | 2013-04-04 | 2016-01-13 | 匹托斯株式会社 | 新植物鞘氨醇-1-磷酸酯衍生物、其制造方法及包括其的脱毛预防治疗或育毛用组合物 |
| WO2017213341A1 (ko) * | 2016-06-08 | 2017-12-14 | 주식회사 피토스 | 피토스핑고신-1-포스페이트 또는 그 유도체를 포함하는 면역증강제 또는 치매 치료용 약학 조성물로서의 용도 |
| WO2018008864A1 (ko) * | 2016-07-06 | 2018-01-11 | 주식회사 피토스 | N-아세틸 피토스핑고신-1-포스페이트를 함유하는 주름개선 및 노화방지를 위한 화장품용 조성물 |
| KR20180032540A (ko) * | 2018-03-20 | 2018-03-30 | 주식회사 피토스 | 피토스핑고신-1-포스페이트 또는 그 유도체의 면역증강제 용도 |
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| KR101003532B1 (ko) * | 2008-08-06 | 2010-12-28 | (주)다미화학 | 탈모의 예방, 치료, 또는 육모용 조성물 |
| KR101214198B1 (ko) * | 2010-09-01 | 2012-12-21 | 서울대학교산학협력단 | 파이토스핑고신 유도체를 유효성분으로 함유하는 뇌질환 치료 또는 예방용 약학조성물 |
| KR101340556B1 (ko) | 2012-02-16 | 2013-12-11 | 주식회사 피토스 | 신규한 파이토스핑고신-1-포스페이트 유도체, 그 제조방법, 및 그것을 포함하는 탈모의 예방, 치료, 또는 육모용 조성물 |
| KR101514970B1 (ko) * | 2013-08-28 | 2015-04-24 | 주식회사 피토스 | 피토스핑고신-1-포스페이트 또는 그 유도체를 포함하는 아토피 또는 피부상처 치료 또는 예방용 조성물 |
| KR101900818B1 (ko) * | 2016-05-17 | 2018-09-20 | 주식회사 피토스 | 피토스핑고신-1-포스페이트 또는 그 유도체를 포함하는 줄기세포 성장 촉진용 조성물 및 이를 포함하는 줄기세포 배양배지용 조성물 |
| KR102218280B1 (ko) * | 2019-01-30 | 2021-02-22 | 주식회사 엑세쏘바이오파마 | P1p 유도체의 패혈증 치료제 용도 |
| KR102029090B1 (ko) * | 2019-07-11 | 2019-10-07 | 주식회사 엑세쏘바이오파마 | O-사이클릭 피토스핑고신-1-포스페이트를 포함하는 파킨슨병의 예방 또는 치료용 조성물 |
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- 2020-07-09 EP EP20836166.7A patent/EP3998071A4/en active Pending
- 2020-07-09 US US17/625,487 patent/US20220289777A1/en active Pending
- 2020-07-09 CN CN202080049861.2A patent/CN114080227B/zh active Active
- 2020-07-09 CA CA3145661A patent/CA3145661C/en active Active
- 2020-07-09 JP JP2022500946A patent/JP2022540455A/ja active Pending
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105246903A (zh) * | 2013-04-04 | 2016-01-13 | 匹托斯株式会社 | 新植物鞘氨醇-1-磷酸酯衍生物、其制造方法及包括其的脱毛预防治疗或育毛用组合物 |
| WO2017213341A1 (ko) * | 2016-06-08 | 2017-12-14 | 주식회사 피토스 | 피토스핑고신-1-포스페이트 또는 그 유도체를 포함하는 면역증강제 또는 치매 치료용 약학 조성물로서의 용도 |
| KR20170138705A (ko) * | 2016-06-08 | 2017-12-18 | 주식회사 피토스 | 피토스핑고신-1-포스페이트 또는 그 유도체의 치매 예방 또는 치료용 용도 |
| EP3501524A1 (en) * | 2016-06-08 | 2019-06-26 | Phytos Co., Ltd. | Use as immune enhancer or pharmaceutical composition for treatment of dementia, comprising phytosphingosine-1-phosphate or derivative thereof |
| WO2018008864A1 (ko) * | 2016-07-06 | 2018-01-11 | 주식회사 피토스 | N-아세틸 피토스핑고신-1-포스페이트를 함유하는 주름개선 및 노화방지를 위한 화장품용 조성물 |
| KR20180032540A (ko) * | 2018-03-20 | 2018-03-30 | 주식회사 피토스 | 피토스핑고신-1-포스페이트 또는 그 유도체의 면역증강제 용도 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2024015132A (ja) | 2024-02-01 |
| US20220289777A1 (en) | 2022-09-15 |
| CN114080227A (zh) | 2022-02-22 |
| EP3998071A4 (en) | 2023-08-02 |
| CA3145661A1 (en) | 2021-01-14 |
| EP3998071A1 (en) | 2022-05-18 |
| WO2021006663A1 (ko) | 2021-01-14 |
| CA3145661C (en) | 2023-11-07 |
| JP2022540455A (ja) | 2022-09-15 |
| KR102029090B1 (ko) | 2019-10-07 |
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