CN85107562B - 改进一种蒽环糖苷化合物在一种注射溶液中的溶解性的方法 - Google Patents
改进一种蒽环糖苷化合物在一种注射溶液中的溶解性的方法 Download PDFInfo
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- CN85107562B CN85107562B CN85107562A CN85107562A CN85107562B CN 85107562 B CN85107562 B CN 85107562B CN 85107562 A CN85107562 A CN 85107562A CN 85107562 A CN85107562 A CN 85107562A CN 85107562 B CN85107562 B CN 85107562B
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Abstract
改进一种蒽环糖苷或其可供药用的盐在一种可注射溶液中的溶解性的方法。该方法包括将该蒽环糖苷与一种辅助加溶剂配制在一起。
Description
本发明涉及改进一种蒽环糖苷在一种注射溶液中的溶解性的方法,这种注射溶液是将含有一种蒽环糖苷或其药物上可接受的盐作为活性药用物质的稳定、迅速溶解的冷冻干燥制剂重新加水复制而得到的。
上述冻干制剂的特征在于,除含有活性药物外,还含一种辅助加溶剂它在冷冻干燥块加水复制时能增进其溶解度,尤其是用生理食盐液复制时。
目前已经知道用生理食盐溶液(而不是用无菌水)来复制是比较好的,以期得到等渗的复制注射溶液,即溶液具有比血液更为适合的张力。
也知道某些含蒽环糖苷的制剂在加水复制时,特别用生理食盐溶液时,常常会碰到溶解度的问题,因为冻干块溶解得总是有点慢,完全溶解则需要持续的摇动。
考虑到蒽环糖苷族药物的已认识到的毒性,溶解问题就特别主要。现在已经发现在冷冻干燥的含蒽环糖苷制剂中适宜的共增溶解剂的存在能大幅度地提高药物的溶解度,所以在加水复制时,用生理食盐液,或者也可以用无菌水,在几秒钟内即可毫无困难地达到完全溶解。
在本发明的药物组合物中的蒽环糖苷活性药用物质是羟基道诺红菌素(译者注:即亚德里亚霉素)、4′-表-羟基道诺红菌素(即表红菌素)、4′-去氧羟基道诺红菌素(即伊索红菌素)、道诺红菌素或4-去甲氧基道诺红菌素(即伊达红菌素)。
在本发明制剂中用作溶解度增强剂的辅助加溶剂选自带有羟基-,巯基-,或氨基苯甲酸的化合物,例如对-羟基,或邻-羟基或对-氨基苯甲酸,及它们的碱金属盐,例如钠或钾盐,或它们的C1-C4烷基酯,例如,甲基-,乙基-,丙基-或丁基酯,环囟代甲基取代酚,例如3-甲基-4-氯酚或3,5-二甲基-4-氯酚;氨基酸,特别是中性氨基酸,例如中性脂肪氨基酸诸如:甘氨酸、丙氨酸、亮氨酸等等,中性硫代脂肪氨基酸诸如半胱氨酸或蛋氨酸,中性芳香氨基酸诸如苯丙氨酸或酪氨酸,或中性杂环氨基酸诸如脯氨酸或羟脯氨酸;或上述化合物中的两个或多个的组合物。
上述辅助加溶剂中有些在药物制剂中是已知用作保存剂/制菌剂的,但对它们在冻干制剂,如含蒽环糖苷的制剂加水复制时,能有溶解度增进的作用则并无所知。例如,K.P.弗洛拉等人(药物药理学杂志1980,32∶577)报道的冷冻干燥羟基道诺红菌素盐酸盐的配方中含4份对-羟-苯甲酸甲酯和1份对-羟-苯甲酸丙酯作为保存剂,但没有一点迹象提到上述保存剂对增进冷冻干燥制剂溶解度的可能作用。另外在弗洛拉等人的文章中也没有任何说明即在冷冻干燥过程时所用的溶液应是适宜于注射用的。事实上如所知,注射用溶液必须是无菌的,尤其,水溶液是将冻干制剂溶于注射用的无菌无热原水中得到的,而在弗洛拉的溶液中并没有这种结果。
按此,本发明提供一种改进选自羟基道诺红菌素、4′-表-羟基道诺红菌素、4′-去氧羟基道诺红菌素、道诺红菌素和4-去甲氧基道诺红菌素的一种蒽环糖苷或其可供药用的盐在一种可注射溶液中的溶解性的方法,该方法包括:将上述蒽环糖苷和一种辅助加溶剂配制在一起,该辅助加溶剂为羟基、巯基或氨基取代的苯甲酸,或其碱金属盐,或其C1-C4烷基酯或是一个环囟化甲基取代酚或一种氨基酸,或是上述化合物中两种或多种的组合物,对于每10份重量的蒽环糖苷,该辅助加溶剂的加入量为0.1~10份重量。
在本发明的制剂中,辅助加溶剂可以是前面指出中的任一种。优选的蒽环糖苷特别是羟基道诺红菌素或其可供药用的盐。
优选的辅助加溶剂或可选自包括对-羟-苯甲酸及其甲酯,对-氨基苯甲酸及其甲酯,邻-羟苯甲酸及其甲酯,3-甲基-4-氯酚和3,5-二甲基氯酚一类的化合物或是上述化合物的两种或多种的合并物。特别优选的共增溶解剂是对-羟苯甲酸甲酯。
本发明的组合物中蒽环糖苷药学上可接受的盐可以或是与无机酸的盐诸如,例子有盐酸,氢溴酸,硫酸或磷酸,或与有机酸的盐,例子有,醋酸、苯甲酸、马来酸、富马酸、琥珀酸、酒石酸、枸椽酸、草酸、二羟乙酸、甲基磺酸、乙基磺酸、苯磺酸,特别优选的盐是与盐酸成的盐。适宜于注射的溶液可以是,尤其是生理食盐溶液。
在本说明书中“药学的”,“药学上的”等名称意指可在人类或兽医范围内应用。名称“真空冷冻干燥”和“冻-干”的应用则无差别。
当本发明冷冻干燥配方中的主要成分是蒽环糖苷药物活性物质,和上面描述的共增溶解剂时,通常加一种适当量的惰性赋形剂作为另一种成分,它是,例如,乳糖,甘露醇,山梨醇和麦芽糖,最好是乳糖。
按此本发明一个特别优选的特色是提供改进羟基道诺红菌素在可注射溶液,特别是在生理食盐液中的溶解性的方法。该方法包括:将作为药用活性物质的盐酸道诺红菌素与作为辅助加溶剂的对羟基苯甲酸甲酯和作为惰性赋形剂的乳糖配制在一起;该蒽环糖苷与该辅助加溶剂之间的比例如上所述。
本发明制剂中活性药用物质和辅助加溶剂的优选比例是这样的,即按重量计10份药用活性物质加按重量计约0.5-2份的辅助加溶剂;在辅助加溶剂和活性药用物质之间的特别优选的重量比是1∶10。按本发明所用的方法冷冻干燥物的配方可含不同量的活性药用物质;典型的配方含,例如,5,10,20,25或50毫克蒽环糖苷。
如已经谈过的,在本发明冷冻干燥制剂中所存在的辅助加溶剂能大幅度地提高药物的溶解度,这样在加水复制时,即如用生理食盐溶液时,溶解时间可大大地减少,甚至可从2分钟(对不含溶解度增进剂的冷冻干燥配方的加水复制)减到10-30秒或更少。
按本发明方法所用的冷冻干燥配方可用通常的冷冻干燥技术的常规方式来制备,然而要采用在处理毒性物质象蒽环糖苷所要求的预防法。例如,共增溶解剂,蒽环糖苷和惰性赋形剂,在搅拌下相继溶解在适当量的去氧气注射用水中,然后再加水使达到所需的最后体积。所生成的溶液澄清并在无菌条件下过滤,并分装在所需容积的无菌容器(小瓶)内。溶液冷冻是在-40℃至-50℃约4到5小时,再干燥,即最后温度是40℃-50℃约6至7小时,待完成后小瓶按常用的过程在无菌情况下加封。
干燥不开封的小瓶在40℃至少三个月内是完全稳定的。同样冻干制剂的加水复制,即用无菌生理食盐液,也是按常规方法进行的。这样例如,所用生理食盐溶液(0.9%氯化钠水溶液)的体积可随着冷冻干燥块中所含的活性成分的种类和数量而改变:可用体积为5毫升至25毫升的生理食盐液来复制5毫克至50毫克量的蒽环糖苷。
本发明的复制溶液的PH值可在约3到约6.5之间变化,这特别是与共增溶解剂的性质有关。
优选的一种复制溶剂是生理盐水。
由于蒽环糖苷活性药用物质的广为人所知的抗肿瘤活性,本发明的可注射溶液在治疗人类和动物肿瘤时是有用的。
能治疗的肿瘤例子有:如肉瘤,包括成骨和软组织肉瘤,癌,即乳腺,肝、膀胱、甲状腺,前列腺和子宫癌,淋巴瘤,包括何杰金和非何杰金氏淋巴瘤,成神经细胞瘤,维尔姆斯瘤,和白血病,包括急性成淋巴细胞白血病和急性成髓细胞白血病。
可以治疗的特殊肿瘤的例子是莫洛尼肉瘤病毒,肉瘤180腹水瘤,实体肉瘤180,大体移植性白血病,L1210白血病和淋巴细胞P388白血病。
本发明的可注射复制溶液的应用可按种种实用的剂量表快速静脉注射或输注。对羟基道诺红菌素适宜的剂量表是,例如每平方米身体表面积60至75毫克活性药用物质,一次快速输注,并在21天后重复;另一剂量表是30毫克/米每天静脉注射,连续3天,隔28天。
4′-表羟道诺红菌素和4′-去氧道诺红菌素的适宜剂量可以是,例如,各为75至90毫克/米2和25-35毫克/米2为单一输注量,在21天后再重复。
英达红菌素,即4-去甲氧道诺红菌素在治疗实体瘤时可每21天静脉用单一剂量13-15毫克/米2,当治疗白血病时优选的剂量表是,即静脉应用每天10-12毫克/米2连用3天,每隔15-21天重复给药;道诺红菌素可用相似的剂量。
下列例子阐明了但任何方面都不限制本发明。
实施例1
羟基道诺红菌素冷冻干燥配方是用下面程序制备的。在制剂中各种成分的相对比例如在下文所示(为每小瓶用量):
羟基道诺红菌素盐酸盐 10.00毫克
乳糖、H2O 52.63毫克(相当于50毫克无水乳糖)
对-羟苯甲酸甲酯 0.5毫克
注射用水 适量至 2.5毫升
对-羟苯甲酸甲酯,羟基道诺红菌素盐酸盐和乳糖依次在搅拌下溶于注射用水,通氮气泡使去氧(约用最终所需水体积的90%量)。再加去氧注射用水至最终体积。溶液经过一纤维玻璃预滤再过-0.45μ微孔膜使澄清,然后再在无菌条件下滤过一个0.22μ微孔膜;滤液直接收集在一无菌区。溶液按每2.5毫升的体积在无菌条件下自动分装入容量为8/10毫升的无菌Ⅲ型无色玻璃小瓶内。
溶液在温度-40℃至-45℃在小瓶内冷冻4至5小时。然后行真空冷冻干燥,最后阶段产物是在43-45℃温度干燥6到7小时。小瓶用无菌氯丁基橡皮塞加盖,并用无菌铝盖加封。
用类似的程序含20毫克活性药用物质的羟基道诺红菌素冷冻干燥配方的制备法是:
羟基道诺红菌素盐酸盐 20.00毫克
乳糖、H2O 105.26毫克
对-羟苯甲酸甲酯 2.00毫克
注射用水 适量至 3.00毫升
冷冻干燥是在容量为20/26毫升Ⅲ型玻璃小瓶内进行的。
再者用类似的程序,含50毫克活性药用物质的羟基道诺红菌素冷冻干燥配方的制备是:
羟基道诺红菌素盐酸盐 50.00毫克
乳糖、H2O 263.15毫克
对-羟苯甲酸甲酯 5.00毫克
注射用水 适量至 5.00毫升
冷冻干燥是在容量为50/57毫升Ⅲ型玻璃小瓶内进行。
羟基道诺红菌素的类似上述冷冻干燥配方,但分别含对-羟苯甲酸或对-氨基苯甲酸,或水杨酸,或3-甲基-4-氯酚或3,5-二甲基-4-氯酚或甘氨酸或半膀氨酸或苯丙氨酸或脯氨酸来代替对-羟基苯甲酸甲酯,亦都按类似程序制备的。特别是,例如,下述配方是冷冻干燥的:
10毫克配方
羟基道诺红菌素盐酸盐 10.00毫克
乳糖、H2O 52.63毫克
3-甲基-4-氯酚 1.00毫克
注射用水 适量至 2.50毫升
20毫克配方
羟基道诺红菌素盐酸盐 20.00毫克
乳糖、H2O 105.26毫克
对-羟苯甲酸 2.00毫克
注射用水 适量至 3.00毫升
完成这些配方的冷冻干燥是与在这个实例前面所报道的用于相同剂量羟基道诺红菌素的一样。
在上面有机下面实例中所指的各不同成分的量都是每小瓶的量。
实施例2
按在实例1中所描述的类似方式操作来制备含10,20和50毫克活性药用物质的4′-表-羟基道诺红菌素的冷冻干燥配方。在制剂中所用各成分的相对比例如下所示。
10毫克配方 20毫克配方 50毫克配方
4′-表-羟基道诺红菌
素盐酸盐 10.00毫克 20.00毫克 50.00毫克
乳糖、H2O 52.63毫克 105.26毫克 263.15毫克
对-羟苯甲酸甲酯 1.00毫克 2.00毫克 5.00毫克
注射用水 适量至2.5毫升 适量至3.00毫升 适量至5.00毫升
上述三种配方按实例1描述的方法分别在容量为8/10毫升,20/26毫升和50/57毫升的Ⅲ型玻璃小瓶中冷冻干燥。
相似的4′-表-羟基道诺红菌素的冷冻干燥配方也以类似的方法制备,但所含的共增溶解剂是选自对-羟苯甲酸,对氨基苯甲酸、水杨酸、3-甲基-4-氯酚,3,5-二甲基-4-氯酚,甘氨酸,半胱氨酸,苯丙氨酸和脯氨酸以代替对-羟苯甲酸甲酯。
实施例3
遵循在实例1中所描述的类似程序,制备含5和25毫克活性药用物质的4′-去氧羟基道诺红菌素的冷冻干燥配方。制剂中所用各成分的相对比例如下所示:
5毫克配方 25毫克配方
4′-去氧-羟基道诺红菌
素盐酸盐 5毫克 25毫克
乳糖、H2O 52.63毫克 263.15毫克
对-羟苯甲酸甲酯 0.5毫克 2.50毫克
注射用水 适量至2.00毫升 适量至 5.00毫升
这两种配方按照实例1的程序分别在容量为8/10毫升和50/57毫升的Ⅲ型玻璃小瓶内冷冻干燥。
也制备了类似的冷冻干燥配方,但含对-羟苯甲酸或对-氨基苯甲酸或水杨酸或3-甲基-4-氯酚或3,5-二甲基-4-氯酚或甘氨酸或半胱氨酸或苯丙氨酸或脯氨酸来代替对-羟苯甲酸甲酯。
实施例4
如实例1中所报道的类似方式进行,制备3含道诺红菌素(分别为20和50毫克活性药用物质)或4-去甲氧基道诺红菌素(分别为5和10毫克活性药用物质)的冷冻干燥配方。在不同配方中各成分的相对比例如下所报道。
20毫克配方 50毫克配方
道诺红菌素盐酸盐 20毫克 50.00毫克
甘露醇 100.00毫克 250.00毫克
对-羟苯甲酸甲酯 2.00毫克 5.00毫克
注射用水 适量至3.00毫升 适量至 7.5毫升
5毫克配方 10毫克配方
4-去甲氧基道诺红菌
素盐酸盐 5.00毫克 10.00毫克
乳糖、H2O 52.63毫克 105.26毫克
对-羟苯甲酸甲酯 0.5毫克 1.00毫克
注射用水 适量至2.00毫升 适量至 3.00毫升
含道诺红菌素配方的冷冻干燥是在Ⅰ型玻璃小瓶内进行的:对20毫克配方用容量为10/14毫升的小瓶,对50毫克配方用容量为50/57毫升的小瓶。冷冻干燥4-去甲氧基道诺红菌素配方是用Ⅲ型玻璃小瓶:5毫克配方用容量为8/10毫升小瓶,10毫克配方用20/26毫升的。
也制备了类似的冷冻干燥制剂,但含对-羟苯甲酸或对-氨基苯甲酸或水杨酸或3-甲基-4-氯酚或3,5-二甲基-4-氯酚或甘氨酸或半胱氨酸或苯丙氨酸或脯氨酸来代替对-羟苯甲酸甲酯。
实施例5
在前面例子中得到的各个冷冻干燥配方可用常规方法溶解在生理食盐液中复制。用来复制的生理食盐液的体积则依赖于在冷冻制剂中活性药用物质的品种和含量。这样,例如,含10毫克羟基道诺红菌素盐酸盐或10毫克4′-表-羟基道诺红菌素盐酸盐,以及含5毫克4′-去氧道诺红菌素盐酸盐或5毫克4-去甲氧基道诺红菌素盐酸盐的冷冻干燥制剂,可用5毫升生理食盐溶液来复制。
冷冻制剂含20毫克羟基道诺红菌素盐酸盐或20毫克4′-表-羟基道诺红菌素盐酸盐或10毫克4-去甲氧基道诺红菌素盐酸盐或20毫克道诺红菌素盐酸盐者可用10毫升生理食盐液来复制,而体积为25毫升的生理食盐溶液可用于复制含50毫克羟基道诺红菌素盐酸盐或50毫克4′-表-羟基道诺红菌素盐酸盐或50毫克道诺红菌素盐酸盐或25毫克的4′-去氧羟基道诺红菌素盐酸盐的冷冻干燥配方。
在所有例子中复制的时间都是极短的,约在5-20秒可见到完全溶解,总之不需要超过30秒钟。
Claims (9)
1、一种改进选自羟基道诺红菌素、4′-表-羟基道诺红菌素、4′-去氧羟基道诺红菌素、道诺红菌素和4-去甲氧基道诺红菌素的蒽环糖苷或其可供药用的盐在一种可注射溶液中的溶解性的方法,该方法包括:将该蒽环糖苷与一种辅助加溶剂配制在一起,该辅助加溶剂是羟基、巯基或氨基取代的苯甲酸或其碱金属盐或其C1-C4烷基酯,或是一种环囟化甲基取代酚或一种氨基酸,或是上述化合物中两种或多种的组合物,对于每10份重量的蒽环糖苷,该辅助加溶剂的加入量为0.1~10份重量。
2、根据权利要求1的方法,其中蒽环糖苷是羟基道诺红菌素或其可供药用的盐。
3、根据权利要求1或2的方法,其中蒽环糖苷的盐是盐酸盐。
4、根据上述任一项权利要求的方法,其中的辅助加溶剂选自对羟苯甲酸及其甲酯、对氨基苯甲酸及其甲酯、邻羟苯甲酸及其甲酯、3-甲基-4-氯苯酚和3,5-二甲基-4-氯苯酚,或是两种或多种上述化合物的组合物。
5、根据权利要求4的方法,其中的辅助加溶剂是对羟基苯甲酸甲酯。
6、根据任一前述权利要求的方法,其中在配制过程中还使用一种惰性赋形剂。
7、根据权利要求6的方法,其中惰性赋形剂是乳糖。
8、一种改进羟基道诺红菌素在一种可注射溶液中的溶解性的方法,该方法包括将羟基道诺红菌素盐酸盐与对羟基苯甲酸甲酯与乳糖配制在一起,对10份重量的羟基道诺红菌素盐酸盐,对羟基苯甲酸的加入量为0.1~10份重量。
9、根据权利要求1~8中任一项的方法,其中该可注射溶液为生理盐水。
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