CN1052878C - 缓冲的烷基胆碱磷水溶液及其制备方法、药物和用途 - Google Patents

缓冲的烷基胆碱磷水溶液及其制备方法、药物和用途 Download PDF

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CN1052878C
CN1052878C CN93119330A CN93119330A CN1052878C CN 1052878 C CN1052878 C CN 1052878C CN 93119330 A CN93119330 A CN 93119330A CN 93119330 A CN93119330 A CN 93119330A CN 1052878 C CN1052878 C CN 1052878C
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J·恩格尔
E·沃尔夫-霍伊斯
H·奥斯
B·威彻特
D·索尔比尔
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Abstract

通过调节pH范围在4pH和6pH之间，无需防腐剂和抗氧剂等保护试剂，可以制备一种具有可稳定贮存性质的在甘油烷基醚里的烷基胆碱磷酸溶液。

Description

缓冲的烷基胆碱磷酸水溶液及其制备方法、药物和用途
烷基磷酸类化合物是已知的具有抗肿瘤作用的物质。德国已公开专利3343530.8公开了这些化合物的抗肿瘤作用和初步表征。水或生理上可接受的有机溶剂如甘油烷基醚用作这些活性物质的溶剂。
例如，已经发现，活性物质和至少一种有2-12碳原子，可以与甘油中任一一级或二级羟基成醚形式存在的烷基的甘油烷基醚一起使用，适宜于典型应用。这种类型的甘油烷基醚提高或改进烷基磷酸化合物的作用。这里，优选单独使用或混和使用3-9碳原子烷基的甘油烷基醚。因而含有下列物质的药物呈现了特别适宜的药效：
a)具有通式I的一种或几种烷基磷酸化合物
Figure C9311933000041
R表示有12-20碳原子的烷基，它可以含有或不含有双键或叁键；
b)具有通式II的甘油烷基醚
Figure C9311933000051
其中，基团R1和R2中的一个表示含有2至12碳原子的烷基，另一个表示氢原子，另外还可以含有或不含有传统添加剂和稀释剂。
例如，有可能考虑水和甘油烷基醚混合物的混合物，甘油烷基醚混合物是甘油壬基或辛基醚、甘油己基或戊基醚和甘油丙基或乙基醚的混合物。例如用于典型应用的适宜配置是每ml甘油烷基醚或相应的甘油烷基醚和水的混合物中含有1-100mg烷基磷酸化合物。
这种类型的混合物此处被称做串级混和物(cascade)。
例如优选甘油烷基——水混和物，如含有甘油壬基醚、甘油己基醚、甘油丙基醚。这种混和物最好含有3种提及的甘油醚，即一种低级甘油醚(丙基)、一种中级甘油醚(己基)、一种高级甘油醚(壬基)，低级醚的重量总量约与另外两种甘油醚重量和相同。水量约与低级醚的量相同，相当于所有甘油醚总量的一半。
这种类型的甘油醚/水混合物的例子列于下表：
            水    甘油丙基醚  甘油已基醚  甘油壬基醚重量份数    2    ∶    2    ∶    1    ∶    1水    甘油乙基醚  甘油戊基醚  甘油辛基醚重量份数    2    ∶    2    ∶    1    ∶    1
除了水以外，也可以使用典型药物可用的所有溶剂。
对烷基磷酸化合物十六烷基胆碱磷酸，一种特定的适宜载体混合物由约4份重量的水、4份重量的甘油丙基醚和各2份重量的甘油己基醚和甘油壬基醚组成的混合物组成。
因为微生物负载试验表明这些溶液具有最佳抗菌性，这种类型的溶液不需加入防腐剂。
例如，6％的十六烷基胆碱磷酸溶液的组成如下：
十六烷基胆碱磷酸           0.600g
甘油-1-正丙基醚            3.145g
甘油-1-正己基醚            1.570g
甘油-1-正壬基醚            1.570g
水                         3.145g
                           10.030g＝10ml
遣憾地发现在稳定贮存期间氧化反应使溶液里形成过氧化物，氧化物后来导致酸并且由于进一步分解而使pH值降低。pH值在规格里设定在4～6。
6％十六烷基胆碱磷酸串级溶液(未处理)的pH值和过氧数。
              -4℃    +2℃    RT      31℃   41℃初始检测pH值                          5.6过氧化物数                    0.43个月pH值          5.0     5.0     4.0     3.6    3.3过氧化物数    0.81    0.95    0.91    3.6    6.06个月pH值          7.4     6.0     3.8     3.5    3.1过氧化物数    0.55    0.18    1.9     4.9    7.8
为了控制过氧化物的形成，十六烷基胆碱磷酸串级溶液用氮气充气，并且注入到10ml的瓶子里后用氮气盖封。也试图添加抗氧剂以防止过氧化物的形成。
6％的十六烷基胆碱磷酸串级溶液(用氮气充气后)的pH值和过氧数
              -4℃   +2℃    RT      31℃   41℃初始检测pH值                         4.6过氧化物数                   0.03个月pH值          4.6    5.0     4.2     3.9     3.6过氧化物数    0.1    0.11    0.97    0.94    5.16个月pH值          4.5    4.4     4.1     3.9     3.5过氧化物数    0.0    0.0     1.73    1.1     4.6
RT＝室温
可以看出，在这种情况下，pH值也降低，和过氧化物含量也升高。
正象下表所显示的那样，加入抗氧剂并没有导致任何改进。
加入抗氧剂的十六烷基胆碱磷酸串级溶液的pH值
加入0.1％的亚硫酸氢钠-4℃   +2℃   RT     31℃   41℃初始pH值                     3.83个月后pH值    3.8    3.7    3.3    3.1    2.8加入0.01％棕榈酸(抗坏血酸)酯和0.05％α-维生素E-4℃   +2℃   RT     31℃   41℃初始pH值                     3.83个月后pH值    3.8    3.7    3.3    3.1    2.8
实验证明传统的配置不具贮存稳定性。
使用传统试剂抑制过氧化物形成，如用N2充气以除去溶液中的氧气和加入抗氧剂，不能形成可稳定贮存的溶液。
在一个实验中，除了加入抗氧剂亚硫酸氢钠，还加入了柠檬酸缓冲体系，发现pH值可以保持在规定之内。
加有0.1％亚硫酸氢钠和柠檬酸缓冲体系(在水相里0.1摩尔)的milte fosine串级溶液的pH值
               -4℃   +2℃   RT     31℃   41℃初始pH值                     5.63个月后pH值    5.6    5.6    5.3    5.1    5.2
由于亚硫酸氢钠做为抗氧剂没有起到积极作用，制备了一种只含有柠檬酸缓冲溶液的milte fosine串级溶液。
令人惊奇地发现，缓冲溶液的加入能够抑制过氧化物的形成和由此引起的pH值的降低。
加有柠檬酸缓冲液的十六烷基胆碱磷酸串级溶液
              -4℃    +2℃    RT      31℃    41℃pH值                          5.8过氧化物数                    0.583个月pH值          5.8     5.8     5.8     5.8     5.7过氧化物数    0.33    0.29    0.41    0.51    0.586个月pH值          5.8     5.8     5.8     5.7     5.6过氧化物数    0.02    0.39    0.11    0.36    0.5412个月pH值          5.8     5.8     5.7     5.6     5.3过氧化物数    0.06    0.04    0.18    0.11    0.4
10ml加有缓冲液的6％的十六烷基胆碱磷酸串级溶液组成如下：
十六烷基胆碱磷酸               0.6000g
D.L--甘油-1-正丙基醚           3.1600g
D.L--甘油-1-正己基醚           1.5800g
D.L--甘油-1-正壬基醚           1.5800g
无水柠檬酸                     0.0484g
氢氧化钠                       0.0227g
净化水                         3.0889g
                               10.0800g＝10ml
下列混合物是其它适宜的缓冲溶液混合物：
磷酸氢二钠/柠檬酸，
琥珀酸/氢氧化钠，
磷酸二氢钾/磷酸氢二钠
马来酸氢钠/氢氧化钠，
三-马来酸盐/氢氧化钠，
磷酸二氢钾/氧氧化钠的混合物。
最优选pH值为5.3的柠檬酸和氢氧化钠的混合物。实施例1
适于典型应用的加入缓冲溶液的6％(W/V)十六烷基胆碱磷酸。
十六烷基胆碱磷酸溶解于被称做为串级湿剂(cascake)的缓冲溶剂中，制得十六烷基胆碱磷酸溶液。
使6.27kg DL-甘油-1-甲基醚、3.135kg DL-甘油-1-正戊基醚和3.135kg DL-甘油-1-正辛基醚混合，1.19kg十六烷基胆碱磷酸溶解于这种混合物中。
pH为5.3的柠檬酸缓冲溶液的制备
0.0965kg无水柠檬酸溶于5.8kg的净化水中，0.047kg NaOH溶于0.3kg净化水中。现将氢氧化钠溶液加入到柠檬酸溶液中至pH值达5.3。然后加水加到共6.27kg。柠檬酸缓冲液6.27kg和十六烷基胆碱磷酸溶于醚混合物的溶液13.73kg混合在一起。用氮气充气得到均一的溶液。溶液用孔径为0.2μm的过滤膜过滤，以10ml为一剂量注入棕色滴瓶中并用吸移管和保护盖封口。

Claims (7)

1.一种或几种通式I的烷基胆碱磷酸和通式II的甘油烷基醚在水中的溶液：
式中，R表示有12-20个碳原子的烷基，它可以含有或不含有双键或叁键；
Figure C9311933000022
式中，基团R1和R2中的一个表示含有2-12个碳原子的烷基，另一个表示氢原子；
其特征在于，该溶液还包含缓冲溶液，使溶液的pH值介于4和6之间。
2.权利要求1的溶液，其特征在于，柠檬酸和氢氧化钠的水溶液用做缓冲溶液。
3.制备权利要求1或2的溶液的方法，其特征在于，将一种或几种通式I的烷基胆碱磷酸与通式II的甘油烷基醚的混合物溶解于水中，并加入缓冲溶液使pH值达到4pH至6pH。
4.权利要求3的方法，其特征在于，柠檬酸和氢氧化钠的溶液用作缓冲溶液。
5.一种治疗肿瘤的药物，其特征在于，它含有权利要求1或2的溶液，以及可有可无的其它常规的添加剂和稀释剂。
6.pH值介于4和6之间的缓冲溶液用于抑制溶液中过氧化物形成和改进溶液的贮存稳定性的用途，所述溶液是一种或几种通式I的烷基胆碱磷酸和通式II的甘油烷基醚在水中的溶液：
式中，R表示有12-20个碳原子的烷基，它可以含有或不含有双键或叁键；
Figure C9311933000032
式中，基团R1和R2中的一个表示含有2-12个碳原子的烷基，另一个表示氢原子。
7.权利要求6的用途，其特征在于，柠檬酸和氢氧化钠的水溶液用作缓冲溶液。
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CA2109053C (en) 2004-02-10
CN1090174A (zh) 1994-08-03
ES2086168T3 (es) 1996-06-16
UA27099C2 (uk) 2000-02-28
DE59302251D1 (de) 1996-05-23
SG48779A1 (en) 1998-05-18

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