CN115551476A - 用于线粒体靶向抗氧化剂的不同组合物的聚合物基质 - Google Patents
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Abstract
包含SkQ型线粒体靶向抗氧化剂和聚丙烯酸化合物、琼脂糖、琼脂或透明质酸聚合物的组合物,其可用于制备具有良好稳定性的药物、医学和美容化妆品组合物。此类组合物还可以有用地包含乳酸。
Description
相关申请的交叉引用
本申请要求于2019年12月10日提交的美国临时专利申请No.62/945,939的权益,其内容通过引用并入本文。
发明概述
本发明涉及药剂学、医学和美容化妆品学。本发明描述了几种稳定的组合物,其包含线粒体靶向抗氧化剂、聚合物基质和任选的另外的组分。
发明背景
SkQ型线粒体靶向抗氧化剂(SkQ,参见通式1)在包含药物或美容化妆品组合物中常见的许多成分的组合物中是不稳定的。这使得SkQ与药物和\或美容化妆品的许多典型成分不相容(考虑到某些合理储存期限所需的稳定性)。
发明描述
本发明提供了几种相当稳定的组合物,其包含SkQ型线粒体靶向抗氧化剂,其中SkQ型线粒体靶向抗氧化剂具有通式1:
其中:
A为具有如下结构的醌抗氧化剂:
和/或其还原(醌醇)形式,其中:
m为1-3的整数;
Y为低级烷基或低级烷氧基;
L为连接基,其包含可以任选被一个或多个取代基取代并且任选包含一个或多个双键或三键的直链或支链烃链;并且
n为1-40的整数;
B为包含SkZ的靶向基团,其中Sk为亲脂性阳离子;并且Z为药理学上可接受的阴离子。
SkQ1为SkQ型化合物(SkQ)的非限制性实例。SkQ1的式(氧化形式)为:
SkQ1以溴化物或氯化物的形式用于以下试验中。
在我们的试验中,我们证明了药物和美容化妆品的许多常见组分与SkQ不相容,因为这些组分使SkQ不稳定,从而使相应组合物的储存时间短。然而,我们已经发现,当与组合物中的线粒体靶向抗氧化剂组合时,以下聚合物和其它组分不会使SkQ显著不稳定(参见表1):
表1.
在我们的试验中,几种组合物提供了高SkQ1稳定性(参见试验实施例1)。组合物如下:
组合物1:
丙二醇3%
戊二醇5%
聚丙烯酸钠0.9%
乙基己基甘油0.3%
乳酸0.2%
SkQ1-不同浓度,例如6ug/mL
水-至100%
稳定性研究在试验实施例1中显示。
组合物2:
异戊二醇5%
Aquaxyl(木糖醇葡糖苷和无水木糖醇和木糖醇)-3%
丙二醇3%
聚丙烯酸钠0.9%
乙基己基甘油0.3%
乳酸0.2%
SkQ1-不同浓度,例如6ug/mL
水-至100%
试验实施例1.作为SkQ的适合的聚合物基质的聚丙烯酸化合物
(A)基于卡波姆640和641的美容化妆品制剂的稳定性研究
样品制备:1V样品+1V NaBr 0.5M,用振荡器在70C混合15分钟,+9V乙醇96%,每次1V,离心。向500mcl上层添加500mcl在水中的0.1M磷酸,离心,并且转入小瓶。最终稀释22倍。
注射体积:100μL,在260nm检测。
+60℃温育后的分析结果
组合物03和05显示显著降解(具有双相动力学)。
仅对于组合物C088-060819-05-60观察到一定的稳定性,条件是初始浓度不超过10微克。
0号塑料包装的新组合物的稳定性研究
样品制备方法:将200mg测试聚丙烯酸化合物组合物(精确重量)放入Eppendorf试管,加入2个体积的水(约400μL),并且加热30分钟(在热振荡器上,70C)。加入1个体积的在水中的NaBr 1M(约200μL),加热,同时再混合30分钟(在热振荡器上,70C)。加入2个体积的96%乙醇(约400μL),涡旋混合,并且离心。选择900μL上清液,并且加入300μL磷酸的乙醇溶液,混合,并且离心。
最终稀释比:8倍。
注射体积为100μL。
测试聚丙烯酸化合物组合物:
在+60℃进行加速稳定性研究。如上所述制备样品,并且通过HPLC方法分析SkQ1浓度(注射体积100uL,在260nm检测)。
分析结果:
动力学常数外推至实际储存条件
结论:聚丙烯酸化合物组合物中的SkQ1显示出可接受的稳定性。
(B)在甘油存在下基于卡波姆的凝胶980(10uM和50mM SkQ1浓度)的稳定性研究
在+60℃的稳定性曲线:
在基于卡波姆980的凝胶的组合物中在60C的SkQ1降解的动力学。
在实际储存条件下的平均速率的外推
结论:降解率略微取决于初始浓度,这表明不存在自催化降解机制。没有观察到所需的稳定性。
在下一个试验中,我们研究了升温下组合物中SkQ1的稳定性。与对照组合物一起,研究了以下组合物(代码MitoVitan-1-3):
异戊二醇5%
Aquaxyl(木糖醇葡糖苷和无水木糖醇和木糖醇)-3%
丙二醇3%
聚丙烯酸钠0.9%
乙基己基甘油0.3%
乳酸0.2%
SkQ1-6ug/mL
水加至100%
动力学常数外推至实际储存条件:
MitoVitan-1-3组合物在加速储存(在升温下)的模型试验中显示出可接受的稳定性。在+37C和室温的进一步试验显示,与计算的组合物相比,在该组合物中SkQ的稳定性更高。
来自上述试验的其它结论:
组合物C088-060819-03和C088-060819-04的稳定性的比较表明,添加乳酸稳定了SkQ1。这些试验还揭示出存在于C088-060819-05的组合物中的表面活性剂(乙基己基甘油)的预料不到的去稳定化作用,并且与不含乙基己基甘油的相同组合物(C088-060819-03)相比具有明显更差的稳定性。
基于我们的试验结果,我们可以得出结论,多种聚丙烯酸化合物与SkQ1良好相容,并且可以用作线粒体靶向抗氧化剂的美容化妆品和药物组合物的聚合物基质。同时,用卡波姆640、641和974显示了最佳相容性(SkQ1的稳定性)。预料不到的是,卡波姆980比上述产品差。
还揭示了戊二醇和甘油的稳定作用。
试验实施例2.作为SkQ的适合的天然聚合物基质的琼脂和琼脂糖
(А)基于琼脂糖和琼脂的组合物。在60C的稳定性研究
组合物:
琼脂(或琼脂糖)-5%,
乳酸(乳酸钠)-1%,
丙二醇-20%,
SkQ1-50微米,
水
样品制备(样品重量300-500mg):
在+60℃温度温育后,将300mg-500mg的组合物(精确重量)置于试管中。将收集的样品在热振荡器上在70℃熔化10分钟,并且加入约300-500μL体积的乙腈(体积等于精确重量)。将混合物充分混合,并且以14000rpm离心10分钟,然后将400μL上清液转入1.5mL试管中,加入600μL乙腈,混合,并且以14000rpm充分离心30分钟。最终,将400μL上清液转入色谱小瓶中,加入600μL水,并且将混合物充分混合。每个时间点取3个样品。
不同时间点的测量结果:
将动力学曲线的初始部分外推到实际储存条件:
结论:降解的初始阶段被浓度恒定的第二阶段替代。软膏很可能在2-8C储存时不具有需要的稳定性。对于这种类型的聚合物,由于所用聚合物的特征,在+60C储存期间获得的数据外推到显著更低的温度(25C、2-8C)可能是不完全正确的。有必要在更低温度进行长时间试验(参见下文)。
(B)基于琼脂糖的组合物。在+25℃储存
组合物:
琼脂(或琼脂糖)-5%,
乳酸(乳酸钠)-1%,
丙二醇-20%,
SkQ1-50微米,
水。
采样:每个点3个eppendorf管。25C,一个月1次。
样品制备(样品重量300-500mg):
试管包含300-500mg的组合物(精确重量)。在+25℃温育后,将样品在热振荡器上在70C熔化10分钟,并且加入约300-500μL体积的乙腈(体积等于精确重量)。将混合物充分混合,并且以14000rpm离心10分钟。将400μL上清液转入1.5mL试管中,加入600μL乙腈,混合,并且以14000rpm充分离心30分钟。将400μL上清液转入色谱小瓶,并且加入600μL水,随后混合。最终稀释12.5倍,HPLC注射体积为20μL,在260nm处检测。
选择样品的测量结果:
结论:未检测到25C的6个月期间的降解。
当用琼脂替代琼脂糖时,在25℃得到类似的结果。
(B)SkQ1在多活性美容化妆面膜中的稳定性研究
概述表:
所有面膜的样品制备:1V样品(约200mg)+1V 0.5M溴化钠,在混合的同时加热15分钟,取100μL所得溶液并且逐渐加入900μL 96%乙醇,每次加入乙醇后混合,离心。取500mL上清液,加入500mL在水中的磷酸,离心,转入小瓶中。最终稀释40倍,并且HPLC注射体积为100μL。在260nm检测。
在+60℃的稳定性
降解曲线(SkQ1在60℃的降解动力学)
动力学常数外推至实际储存条件
结论:组合物2和3具有最好的稳定性。
另外的试验证实,当在+37C储存时,SkQ1在组合物C088-140219-02和C088-140219-03中的稳定性(检测到6个月无SkQ1降解迹象)。
还测试了如下组合物(具有接近中性的pH):
组合物C088-160419-07:
组合物С088-160419-08:
+60C的SkQ1稳定性的研究结果(SkQ1浓度以μg/mL表示):
预测的降解度:
研究了组合物C088-160419-07在+37C的稳定性:
样品制备:1V样品+1V 0.5M溴化钠,在混合的同时加热15分钟,+9V 96%乙醇,混合,离心。向500mL上层中添加500mL在水中的0.1M磷酸,离心,转入小瓶中。最终稀释22倍。HPLC样品体积为100μL,在260nm检测。
结果:
样品编号 | 储存37C,24小时 | C,μg/ml |
C088-160419-07-37-0 | 0 | 29.77 |
C088-160419-07-37-1 | 14 | 27.88 |
C088-160419-07-37-2 | 28 | 27.22 |
C088-160419-07-37-3 | 42 | 26.44 |
C088-160419-07-37-4 | 56 | 24.71 |
C088-160419-07-37-5 | 70 | 24.58 |
C088-160419-07-37-6 | 84 | 24.56 |
C088-160419-07-37-7 | 98 | 24.05 |
C088-160419-07-37-8 | 112 | 25.29 |
C088-160419-07-37-9 | 126 | 22.89 |
基于上述数据,预测了组合物在长期储存期间的以下稳定性:
结论:组合物稳定性是可接受的,特别是在2-8C储存。在分析25C的数据之后,结果可以改善。
此外,在我们的试验中,我们获得了显示SkQ1在包含聚乙烯醇或Aquaxyl的组合物中的可接受的稳定性的数据。
Claims (5)
2.权利要求1的组合物,其中线粒体靶向抗氧化剂为SkQ1。
3.权利要求2的组合物,其具有如下内容物:
异戊二醇 5%
Aquaxyl(木糖醇葡糖苷和无水木糖醇和木糖醇)-3%
丙二醇 3%
聚丙烯酸钠 0.9%
乙基己基甘油 0.3%
乳酸 0.2%
SkQ1-6ug/mL。
4.稳定药物或美容化妆品组合物中SkQ1的方法,通过将乳酸加入此类组合物中来进行。
5.包含乳酸的SkQ1的稳定的药物或美容化妆品组合物。
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PCT/US2020/064334 WO2021119330A1 (en) | 2019-12-10 | 2020-12-10 | Polymer matrixes for different compositions of mitochondrially targeted antioxidants |
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- 2020-12-10 EP EP20899678.5A patent/EP4072512A4/en active Pending
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WO2021119330A1 (en) | 2021-06-17 |
IL293737A (en) | 2022-08-01 |
EP4072512A1 (en) | 2022-10-19 |
US20230038070A1 (en) | 2023-02-09 |
CA3164227A1 (en) | 2021-06-17 |
JP2023506193A (ja) | 2023-02-15 |
EP4072512A4 (en) | 2024-01-10 |
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