CN1101679C - 高脂溶性喜树碱衍生物的药物制剂 - Google Patents

高脂溶性喜树碱衍生物的药物制剂 Download PDF

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CN1101679C
CN1101679C CN96194482A CN96194482A CN1101679C CN 1101679 C CN1101679 C CN 1101679C CN 96194482 A CN96194482 A CN 96194482A CN 96194482 A CN96194482 A CN 96194482A CN 1101679 C CN1101679 C CN 1101679C
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F·H·豪谢尔
D·莫拉里
K·哈里达斯
D·G·雷迪
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Abstract

一种水溶性小于5mg/ml的喜树碱或脂溶性喜树碱衍生物的药物制剂，它是一种pH为2到6的N-甲基吡咯烷-2-酮溶液或悬浮液。

Description

高脂溶性喜树碱衍生物的药物制剂
本发明涉及可用的新型非显而易见的喜树碱衍生物制剂，本发明对水溶性不好(＜5ug/ml)喜树碱衍生物的配制具有特殊用途。
为了本发明的目的，把水溶性不好且高脂溶性的喜树碱衍生物(为了本发明的目的称作“HLCD”)可替代性地定义为任何未取代的或任何A-环和/或B-环取代的喜树碱，该喜树碱具有低于5μg/ml(＜5ug/ml)的水溶性。也为了本发明的目的，术语“高脂溶性”和“水溶性不好”可替代性用来描述喜树碱衍生物的基本生物利用度和化学特性。
使用HPLC和NMR技术，研究者已经证实了喜树碱和许多喜树碱的衍生物进行一种碱性并依赖于pH的E-环内酯的水解。慢反应的动力学可以使人们估计该药物的内酯和非内酯形式是否能稳定拓朴异构酶I-裂解DNA络合物。研究表明只有药物的闭合内酯结构能够帮助稳定可裂解的络合物。这种观察给在固体肿瘤模型上所看到的高度药物活性提供了解释。肿瘤细胞，特别是普遍存在于固体瘤中的含氧量低的细胞，具有比正常细胞相对较低的细胞外pH水平。在pH低于7.0时，喜树碱的内酯E-环结构占主导。
因为上述因素，把内酯结构的喜树碱及其衍生物配制成制剂是很困难的。这些化合物在水溶液中的低溶解度阻止了有效剂量的给药。由于在碱性制剂中打开了内酯环实际上降低了该化合物的抗肿瘤功效，所以这也妨碍了它们的应用。
现有技术教导各种有机溶剂可用于喜树碱制剂。这些现有技术与本申请所附的说明书陈述的信息一致。这类溶剂包括类脂为主的油如棉花籽油、花生油、IL-20等，以及有机溶剂如N，N-二甲基乙酰胺(DMA)、二甲基异山梨醇(DMI)等。该化合物在类脂为主的溶剂中的溶解度一般低于1mg/ml，而在特定有机溶剂中溶解度能够增加到大约6.7mg/ml。
本发明的制剂包括作为主要溶剂的化合物N-甲基吡咯烷-2-酮，也称作N-甲基吡咯烷酮，或简称为NMP。高脂溶性、低水溶性喜树碱衍生物在NMP中溶解度被增加到了15.0至20.0mg/ml之间，它能够在制成制剂之前被制备成更浓的溶液。由本发明所达到的较高药物浓度对配制口服和胃肠外制剂具有更大的用途。
本发明优选的制剂包括：(a)HLCD；(b)NMP；(c)聚乙二醇(PEG)或丙二醇；(d)一种酸；(e)一种非离子型表面活性剂；和(f)一种低分子量的醇。此外，一些制剂还包括(g)一种重油如环氧化的蓖麻油；(h)甘油；和(i)牛黄胆酸或其药物可接受的盐，或者一种类似的肠道吸收促进剂。
由于化合物在NMP中出人意料的高溶解度，本发明的溶液和制剂能够包括高浓度的有效成分。这使得只需较低溶剂容量的运送就能够给患者输送相同量的有效成分，反过来，导致了毒性和高龄患者耐受性危险的降低。
本发明制剂适合于各种类型包括胃肠外、皮下和口服的运送。以下优选实施例的描述给出了口服和胃肠外制剂的特殊实施例。优选实施例的描述
下文所述的优选实施例不是为了全包括或不是为把本发明限定到所公开的具体内容。然而，现已选择它们并对其进行描述来解释本发明的原理，和它们的用途和最好能使本领域的其它技术人员按照它的教导实际操作。本发明的药物制剂包括溶解或悬浮于N-甲基吡咯烷-2-酮(NMP)中的药物有效量的高脂溶性喜树碱衍生物(HLCD)作为基本成分。多数HLCDs在NMP中的溶解度在15.0至20.0mg/ml。在配置溶液中，在加入其它赋型剂或稀释剂之前需要使用足够的NMP来完全溶解HLCD。配置溶液的大致比率是每重量份HLCD用25重量份到1,000重量份的NMP，优选每重量份的HLCD用50到500重量份NMP，最优选每重量份的HLCD用100到300重量份NMP。在最优选的实例中，这将得到浓度大约1mg/ml到大约40mg/ml的NEAT原溶液。
一般用于口服制剂的悬浮液可以包括显著高的浓度，如高达每毫升NEAT制剂含400mg。
在如下概括的优选的制剂中，也可以包括其它药物可接受的稀释剂和赋型剂。一般HLCD药物制剂包括每毫升溶液1.0到40.0毫克HLCD或每毫升悬浮液1.0到400毫克HLCD。
药物可接受的赋型剂和稀释剂优选选自于下列组中，但应牢记制剂的具体特性取决于所要求的运送方法。
包括在该制剂的药物可接受的一种赋型剂是一种药物可接受的酸，这些酸包括把制剂的pH降低到2.0-6.0(最优选在3.0-5.0)以保持HLCD的活性内酯构型的酸。优选的酸可选自于许多药物可接受的无机酸或有机酸中的任何一种，这些酸包括盐酸、抗坏血酸、柠檬酸、葡糖酸、富马酸、马来酸等。这些酸优选以每重量份HLCD的10到5,000重量份，最优选每重量份HLCD的100到2,500重量份的比率使用。柠檬酸是最优选的酸。
其它赋型剂将包括聚乙二醇(PEG)或丙二醇和一种费离子型表面活性剂。优选的PEG分子量为300到400，对胃肠外给药制剂最优选300和对口服制剂最优选400。PEG是以每重量份HLCD含100到10,000重量份PEG的比率包括在该制剂中。
优选表面活性剂是一种以聚山梨醇为主的化合物，最优选聚山梨醇-80(PSB-80)。该表面活性剂是以每重量份HLCD含100到10,000重量份PSB的比率包括在制剂中。最优选的比率是每重量份HLCD含250和6500重量份的PSB。
胃肠外制剂任选包括一定量的低级醇，最优选乙醇和/或苯甲醇，和一种以类脂为主的赋型剂，优选蓖麻油，最优选一种环氧化蓖麻油如Cremaphor-80。
低级醇是以每重量份的HLCD含0到5,000重量份所用的每种醇的用量掺入该制剂中的，醇的最大含量是每重量份的HLCD含10,000重量份的醇。
类脂为主的赋形剂是以每重量份的HLCD含0到10,000重量份的量掺入到该制剂中。
口服制剂将包括上述组分并任选包括一定量的甘油。优选甘油的比例是每重量份的HLCD含0到5重量份的甘油，最优选每重量份的HLCD含0.5到2.5重量份的甘油。
口服制剂还可以每重量份的HLCD含1到10重量份的量包括一种便于肠道吸收的化合物，最优选为一种胆酸如牛磺胆酸或其盐。最好配制成口服制剂并将口服制剂掺入一种药物可接受的载体如软或硬明胶胶囊，与其一起来方便吞咽。
下表1列出了一种适合于对患者胃肠外给药的典型的药物可接受的HLCD/NMP制剂。
              表1
    胃肠外给药的HLCD制剂中组分的份数
    组分     重量份
    HLCD     1(1-40mg/ml)
    乙醇     0-5,000
    苯甲醇     0-5,000
    酸     100-5,000
    PEG 400     100-5,000
    NMP     25-10,000
    Cremaphor-EL     100-10,000
    甘油     0-2.5
    牛磺胆酸     0-10
    聚山梨醇80(吐温-80)     100-10,000
胃肠外制剂一般是在对患者给药之前用一种常规的运送溶液如5％葡萄糖USP、乳酸化的格林溶液或生理盐水稀释。
表2列出了优选的HLCD/NMP的口服制剂。
                 表2
           HLCD口服制剂中组分的份数
    组分     重量份
    HLCD     1(1-400mg/ml)
    NMP     25-1,000
    柠檬酸     100-5,000
    乙醇     100-5,000
    聚山梨醇80(吐温-80)     100-10,000
    PEG-400     100-10,000
    甘油     1.5-2.5
  牛磺胆酸     1-10
优选把口服制剂悬浮于适当的用于口服运送的载体，一般是明胶胶囊中。
在上述制剂中优选用作活性组分的HLCD包括喜树碱(CPT)及其衍生物，它们只有在每毫升水中小于5毫克的溶解度。CPT的衍生物包括在这样一组中，即在分子的下列一个或多个位置有取代基：(a)7-取代；(b)9-取代；(c)10-取代和(d)11-取代；或者是上述任何一种组合的二或三取代的CPT衍生物，它们在水中的溶解度5ug/ml。归于HLCD类型的最优选的CPT衍生物是10，11-亚甲基二氧基喜树碱、 10，11-亚乙基二氧基喜树碱、7-乙基喜树碱、7-乙基-10-羟基喜树碱、9-甲基喜树碱、9-氯-10，11-亚甲基二氧基喜树碱，9-氯代喜树碱、10-羟基喜树碱、9，10-二氯代喜树碱、10-溴代喜树碱、10-氯代喜树碱、9-氟代喜树碱、10-甲基喜树碱、10-氟代喜树碱、9-甲氧基喜树碱、9-氯代-7-乙基CPT、和11-氟代喜树碱。其它HLCD也将适合于最优选活性化合物的类型并且用最少的实验法就能实现将它们包括在这些制剂中。
以下特殊的实施例详细说明了组成本发明的最优选的制剂。这些制剂是用来详细说明制备该制剂的最佳模式而不是对本发明作任何的限定。实施例1和2CPT和7-乙基CPT在NMP中的溶解度(1)在50摄氏温度，一只干净的试管中，把CPT(14mg)和NMP(1ml)的混合物超声处理30分钟。该溶液变得澄清并甚至在室温下72小时后没有沉淀或絮状物出现。(2)在50摄氏温度，一只干净的试管中，把7-乙基CPT(11.5mg)和NMP(0.5ml)的混合物超声处理30分钟。该溶液变得澄清并甚至在室温下一周后没有沉淀或絮状物出现。实施例1和2下列NMP制剂的制备制剂#1
    乙醇     6.4ml
    柠檬酸     1.0g
    PEG 300     50g
    NMP     10.7ml
    TWEEN 80     10g
按上述顺序混合上述组分。首先在50摄氏温度用30分钟的超声处理把柠檬酸溶于乙醇中。制剂#2
    乙醇     20.3ml
    苯甲醇     3.44ml
    柠檬酸     4.0g
    PEG 300     40g
    NMP     8.55ml
    TWEEN 80     8.0g
按上述顺序混合上述组分。首先在50摄氏温度用30分钟的超声处理把柠檬酸溶于乙醇中。实施例3：在制剂#1中CPT的溶解度
按照1ml制剂中0.3、0.4和0.5mg的CPT的浓度制备在上述制剂#1中CPT的溶液。在50摄氏温度把该混合物超声处理60分钟。没有出现絮状物、悬浮物和沉淀。用0.2微米的滤头过滤该混合物。用0.9％氯化钠溶液稀释该混合物并观察廷德尔作用的外观，在下表中给出了结果：
表1：用0.9％NaCl溶液稀释的制剂#1的0.3mg/ml CPT
  稀释     0   15分钟   30分钟   45分钟   60分钟   90分钟   120分钟   1天
  1∶1   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶2   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶5   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶10   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶100   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
表2：用0.9％NaCl溶液稀释的制剂#1的0.4mg/ml CPT
  稀释     0   15分钟   30分钟   45分钟   60分钟   90分钟   120分钟   1天
  1∶1   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶2   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶5   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶10   清澈   清澈   ---   ---   ---   ---   ---   ---
  1∶100   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
表3：用0.9％NaCl溶液稀释的制剂#1的0.5mg/ml CPT
  稀释    0   15分钟   30分钟   45分钟   60分钟   90分钟   120分钟   1天
  1∶1   清澈   清澈   清澈   清澈   清澈   清澈   ---   ---
  1∶2   清澈   清澈   清澈   清澈   清澈   ---   ---   ---
  1∶5   清澈   清澈   清澈   清澈   ---   ---   ---   ---
  1∶10   清澈   清澈   ---   ---   ---   ---   ---   ---
  1∶100   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
实施例4：在制剂#1中7-乙基CPT的溶解度
按照1ml制剂中0.5、0.6、0.7和1.0mg的7-乙基CPT的浓度制备在上述制剂#1中CPT的溶液。在50摄氏温度把该混合物超声处理60分钟。没有出现絮状物、悬浮物和沉淀。用0.2微米的滤头过滤该混合物。用0.9％氯化钠溶液稀释该混合物并观察廷德尔作用的外观，在下表中给出了结果：
表4：用0.9％NaCl溶液稀释的制剂#1的0.5mg/ml 7-乙基CPT
  稀释     0   15分钟   30分钟   45分钟   60分钟   90分钟   120分钟   1天
  1∶1   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
    1∶2     清澈     清澈     清澈     清澈     清澈     清澈     清澈     清澈
    1∶5     清澈     清澈     清澈     清澈     清澈     清澈     清澈     清澈
    1∶10     清澈     清澈     清澈     清澈     清澈     清澈     清澈     清澈
    1∶100     清澈     清澈     清澈     清澈     清澈     清澈     清澈     清澈
表5：用0.9％NaCl溶液稀释的制剂#1的0.6mg/ml 7-乙基CPT
  稀释    0   15分钟   30分钟   45分钟   60分钟   90分钟   120分钟   1天
  1∶1   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶2   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶5   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶10   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶100   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
表6：用0.9％NaCl溶液稀释的制剂#1的0.7mg/ml 7-乙基CPT
  稀释    0   15分钟   30分钟   45分钟   60分钟   90分钟   120分钟   1天
  1∶1   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶2   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶5   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶10   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶100   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
表7：用0.9％NaCl溶液稀释的制剂#1的1.0mg/ml 7-乙基CPT
  稀释    0   15分钟   30分钟   45分钟   60分钟   90分钟   120分钟   1天
  1∶1   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈
  1∶2   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶5   清澈   清澈   清澈   清澈   清澈   清澈   清澈   ---
  1∶10   清澈   清澈   ---   ---   ---   ---   ---   ---
  1∶100   清澈   清澈   清澈   清澈   清澈   清澈   清澈   清澈

Claims (10)

1.一种含水溶性小于5μg/ml的喜树碱或脂溶性喜树碱衍生物的药物制剂，它是一种pH为2到6的N-甲基吡咯烷-2-酮溶液或悬浮液。
2.根据权利要求1的制剂，它还含有一种或多种药物可接受的赋形剂。
3.根据权利要求2的制剂，其中的赋形剂是聚乙二醇、环氧化蓖麻油、一种1到4个碳原子的脂族醇或苯甲醇。
4.根据权利要求3的制剂，其中的脂族醇是乙醇。
5.根据权利要求1、2、3或4的制剂，它还包括牛磺胆酸或其药物可接受的盐。
6.根据权利要求1、2、3或4的制剂，它还包括一种非离子型表面活性剂。
7.根据权利要求1、2、3或4的制剂，其中喜树碱或其衍生物的浓度从1.0mg/ml到其溶解度或悬浮度限度。
8.根据权利要求1、2、3或4的制剂，其中的喜树碱衍生物是7-乙基，7-乙基-10-羟基，10，11-亚甲二氧基，10，11-亚乙二氧基，9-甲基，9-氯-10，11-亚甲二氧基，9-氯代，10-羟基，9，10-二氯代，10-溴代，10-氯代，9-氟代，10-甲基，10-氟代，9-甲氧基，9-氯-7-乙基或11-氟代衍生物。
9.根据权利要求1的制剂，相对每重量份喜树碱或其衍生物，它以下列范围的份数含有下列组分，
a)25-1,000份N-甲基吡咯烷-2-酮，
b)100-5,000份一种药物可接受的酸，
c)0-10份牛磺胆酸或其药物可接受的一种盐，
d)0-2.5份甘油，
e)100-10,000份聚乙二醇，
f)100-5,000份一种含1到4个碳原子的脂族醇或苯甲醇，
g)100-10,000份非离子型表面活性剂，
h)0-10,000份环氧化蓖麻油。
10.一种用药物可接受的稀释剂稀释权利要求9的制剂形成的可运送的溶液，其中喜树碱或其衍生物的浓度是从0.001到1.0mg/ml。
CN96194482A 1995-06-05 1996-06-04 高脂溶性喜树碱衍生物的药物制剂 Expired - Lifetime CN1101679C (zh)

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