CN108524442B - 一种抗肿瘤药物的注射剂及其制备方法 - Google Patents
一种抗肿瘤药物的注射剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种抗肿瘤药物注射剂及其制备方法。该注射剂包含:活性成分、表面活性剂,聚乙二醇、抗氧剂和乙醇,所述的活性成分为微管蛋白抑制剂,具有(I)所示的结构式。本发明解决了该类化合物成药难的问题,并且具有易于工业化生产,质量可控,无需专用溶剂稀释即可使用,乙醇含量少,安全性好等优点。
Description
技术领域
本发明涉及一种抗肿瘤药物注射剂及其制备方法。
背景技术
中国专利申请CN106565686公开了具有(I)所示结构的微管蛋白抑制剂及其应用:
其中,n独立表示0~5的整数,条件是n≤5,A表示单取代或多取代的基团,所述基团选自H、C1~20烷基、C1~20烃基、C1~20酰氨基、C1~20酰氧基、C1~20烷酰基、C1~20烷氧羰基、C1~20烷氧基、C1~20烷氨基、C1~20烷羧氨基、芳酰基、芳烷酰基、羧基、氰基、卤素、羟基、硝基和甲基噻吩基。
此类化合物包括如表1所示的1~13:
表1
从结构上看,中国专利申请CN106565686公开的上述代表性化合物的结构相近,主要是在苯基上进行不同取代,化合物性质极为近似。例如,存在较多的氢键供体(6个及以上),分子内还存在大共轭体系,这种大共轭体系一方面形成很强的π-π堆叠,另一方面刚性平面构型对分子间氢键形成和强化非常有利。所以该系列化合物的一个明显特征是非常容易结晶,并且晶格能很高,熔点超过300℃。上述所说的氢键及π-π堆叠相互作用最终使得化合物的溶解性很差。例如,测定上述系列化合物在水中的溶解度都小于0.1μg/ml,在绝大多数的有机溶剂中室温时的溶解度都小于2mg/ml,在DMSO,DMF等良溶剂中室温下溶解度也只有100-200mg/ml。另外,测定在大豆油、葵花籽油、蓖麻油、橄榄油、油酸乙酯、中链甘油三酯等油脂中几乎不溶。
成盐是提高难溶性化合物在水中溶解度的一种常规方法。中国专利申请CN106565686公开的系列化合物结构中的咪唑环具有一定的碱性似乎能够与酸成盐,但由于共轭体系的电子分散效应,其成盐能力较弱,能够与三氟甲磺酸这种强酸形成相对稳定的盐,但是与柠檬酸、磷酸等中强酸形成的盐则不是很稳定,酸根容易游离导致药物析出。例如化合物2,成盐后的水溶性依然较低,只有大约0.4μg/ml的溶解度。通过研磨或者高压匀质的方法可以不需要溶剂溶解而将药物破碎至纳米级别的混悬液,从而实现加快药物溶出或者静脉注射给药。对于该系列化合物,试验中发现较高的晶格能使得最终很难获得粒径D90小于1000nm的混悬液,粒径偏大使得沉降较快,最终难以开发成制剂。乳剂也是解决难溶性药物给药的一种常用剂型,但因其在油脂类中不溶,乳剂的制备也难以实现。脂质体剂型实施起来也几乎不现实,因为需要用到大量的有机溶剂才可能溶解,很难实现工业化。尽管有文献(Yakushiji F,Tanaka H,Hayashi Y,et al.water-soluble prodrug ofantimicrotuble agent plinabulin:effective strat-egy with click chemistry[J].Chem Eur J,2011,17:12587-12590)报道通过前体药物或者链接化学技术来阻断分子间氢键或引入一些亲水基团能够使脱氢苯基阿夕斯丁及其类似物的溶解度提高,但这类技术是否可以实现工业化尚不清楚,合成过程中产物的分离纯化可能也是一大挑战。
综上,现有的难溶性药物成药技术如乳剂、脂质体、纳米晶体、成盐等都无法应用于中国专利申请CN106565686公开的系列化合物的药物制剂开发,急需找到一种可解决该类化合物可工业化生产的剂型、配方及制备方法。
发明内容
本发明的目的是解决中国专利申请CN106565686公开的系列化合物难成药的问题。
具体地,本发明提供了一种抗肿瘤药物注射剂,包含活性成分、表面活性剂、聚乙二醇、抗氧剂、和乙醇,所述的活性成分具有(I)所示的结构式:
其中,n独立地为0~5的整数,A为单取代或多取代的基团,所述基团选自H、C1~20烷基、C1~20烃基、C1~20酰氨基、C1~20酰氧基、C1~20烷酰基、C1~20烷氧羰基、C1~20烷氧基、C1~20烷氨基、C1~20烷羧氨基、芳酰基、芳烷酰基、羧基、氰基、卤素、羟基、硝基和甲基噻吩基。
所述的注射剂无需专用稀释溶剂,直接使用临床常见的生理盐水或葡萄糖输液直接稀释配制,在室温具有较好的物理稳定性,能够满足滴注给药。
优选地,本发明的注射剂由以下组分构成:活性成分0.1%~2%(W/W),表面活性剂40%~70%(W/W),聚乙二醇30%~50%(W/W),抗氧剂0.01%~0.05%(W/W),和乙醇0.1%~3%(W/W)。
优选地,本发明的注射剂的活性成分为(3Z,6Z)-3-((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基)-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮,结构式为(II)
本发明的表面活性剂为可静脉注射给药的,如聚氧乙烯(35)蓖麻油,15-羟基硬脂酸聚乙二醇酯,吐温80,优选对本发明所述化合物具有更好增溶能力的聚氧乙烯(35)蓖麻油,15-羟基硬脂酸聚乙二醇酯。表面活性剂的作用是包载药物并使其能够稳定溶解于水相,表面活性剂包载药物的数量直接决定了其在水相中的稳定,故所述的活性成分与表面活性剂之间的数量关系是所述的表面活性剂的用量为抗肿瘤药物质量的30~200倍。
优选地,本发明的表面活性剂的HLB值为12~14。
优选地,本发明的表面活性剂选自聚氧乙烯(35)蓖麻油、15-羟基硬脂酸聚乙二醇酯中的一种或者两种。
所述的乙醇是指的是最终乙醇被除去后注射剂中乙醇的量,其残留限度不超过3%(W/W)。配液时所用的乙醇为95%乙醇及更高纯度的乙醇,如无水乙醇。从临床安全性和耐受性角度考虑,乙醇应尽可能的除去。乙醇的残留限度是基于安全和工艺经济性衡量后作出的评估,低于3%的乙醇残留限度时想进一步降低则需要付出更多的处理时间和消耗,而其对安全性的提高并则不比3%有显著变化。
乙醇在配方中的作用包括溶解一部分药物、降低配液时药液的黏度使后续除热原除菌、灌装操作能够进行。乙醇的用量可以根据配液时的溶解时间、配液时药液的黏度大小、除热原除菌过滤时的阻力等综合衡量,本发明中优选配液时的乙醇含量为40%~65%(W/W),在满足工艺操作要求的前提下配液时的乙醇含量越少越好。
由于表面活性剂黏度大,凝固点低,最终制剂除去乙醇后得到的浓溶液如果主要含表面活性剂和药物则在临床使用时可能面临以下几方面的问题:(1)注射器吸取药液时阻力非常大,极难吸取;(2)药液中表面活性剂水化溶解速度慢,需要采用含醇的专用溶剂稀释;(3)药液在冬天较低的温度下容易冻结影响使用。与本发明相比,不包括聚乙二醇的四元配方,即包含活性成分,表面活性剂、抗氧剂、和乙醇,其搅拌溶解时间、乙醇用量是本发明的2~4倍,且该配方最终除去乙醇后的制剂黏度较大、稀释操作比较困难,而本发明在药物的溶解度及溶解速度方面有显著提升。本发明创造性地添加了聚乙二醇,解决了上述问题。发明人进一步地对聚乙二醇进行了优化选择,发现低分子量的聚乙二醇,如PEG300、PEG400、PEG600等具有很强的氢键亲和力,它们的分子链中存在大量的氢键受体和供体,能够竞争性地与本发明所述的抗肿瘤药物分子结合,有效的降低药物分子间的氢键作用,从而起到加速抗肿瘤药物的溶解的作用。
优选地,本发明的聚乙二醇的分子量为200~1000。
优选地,本发明的聚乙二醇选自聚乙二醇300、聚乙二醇400和聚乙二醇600中的一种或者两种以上。
优选地,本发明的注射剂中,表面活性剂∶抗肿瘤药物为30~200∶1(W/W)。
本发明的活性成分在溶解态时较容易被缓慢的氧化,尽管在制剂制备时可以充氮保护,但长期储存时仍有必要添加抗氧剂。
优选地,本发明所述的抗氧剂为脂溶性抗氧剂。
优选地,所述抗氧剂选自DL-α-生育酚,丁基羟基茴香醚、2,6-二叔丁基-4-甲基苯酚、棓丙酯中的一种或者两种以上。
本发明的注射剂可以在较低阻力下顺利用注射器吸取,不需要用专用溶剂稀释,可直接吸取注入生理盐水或葡萄糖输液袋中稀释配制成含药溶液进行滴注,且稀释配制过程溶解分散十分迅速,只需要摇晃混合10秒即可均匀。
本发明还提供了一种制备上述抗肿瘤药物注射剂的方法,包括步骤:
(1)将所述的活性成分、聚乙二醇、表面活性剂、抗氧剂和乙醇加入配液容器中搅拌溶解,获得药液1;
(2)用0.45μm滤膜对由步骤1获得的药液进行粗滤除杂,获得药液2;
(3)超滤或活性炭除去药液2的热原获得药液3;
(4)除菌过滤药液3,获得药液4;
(5)将药液4灌装于注射剂管制瓶,半压塞后进入冻干机或真空干燥设备,除去乙醇,获得权利要求1所述的注射剂。
本发明的方法中,抗肿瘤药物于室温(15-30℃)下在60-90min内即可搅拌溶解澄清,在加热40-60℃时其搅拌溶解澄清所需的时间更短。为了避免溶剂挥发和药物降解,优选室温下配液。
本发明的制备方法在药物溶解,及最终注射剂的使用方面均有显著的有益进步。
具体实施方式
以下将结合具体实施例来阐述本发明的技术方案,需强调的是,本发明包括但不限于以下实施例。
所有试剂均为商售试剂,分析纯,所用的辅料均为商售辅料,符合药用或注射用标准。
一、注射剂的制备方法
本发明注射剂的制备方法包括以下步骤:
(1)将所述的活性成分、聚乙二醇、表面活性剂、抗氧剂和乙醇加入配液容器中搅拌溶解,获得药液1;
(2)用0.45μm滤膜对由步骤1获得的药液进行粗滤除杂,获得药液2;
(3)超滤或活性炭除去药液2的热原获得药液3;
(4)除菌过滤药液3,获得药液4;
(5)将药液4灌装于注射剂管制瓶,半压塞后进入冻干机或真空干燥设备,除去乙醇,获得权利要求1所述的注射剂。
二、配方的优化选择
实施例1表面活性剂的对比
对比不同表面活性剂单一或联合使用时的增溶稳定效果:将活性成分(3Z,6Z)-3-((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基)-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮按下表中各组的配比溶于表面活性剂,另加入1ml的无水乙醇搅拌溶解后,再用纯化水稀释成2mg/ml,其结果评价如表2所示:
表2
上表的结果表明,单一使用聚氧乙烯35蓖麻油或者15-羟基硬脂酸聚乙二醇酯的效果优于混合使用。聚氧乙烯35蓖麻油和15-羟基硬脂酸聚乙二醇酯对本发明所述药物的增溶稳定能力相当。
实施例2不同分子量的聚乙二醇的对比
将活性成分(式Ⅱ)按照10-70mg/g的量加入聚乙二醇300、聚乙二醇400及聚乙二醇600等溶剂中,室温下搅拌4h,静置过夜后观察药物溶解情况及颜色,能保持无药物析出的浓度即为活性成分在相应分子量的聚乙二醇中的溶解度。结果如下:
表3
聚乙二醇分子量 | 药物溶解度(mg/ml) | 溶液颜色 | 凝固点 |
M=300 | 15 | 黄色 | -15~-8℃ |
M=400 | 20 | 橙黄色 | 4~8℃ |
M=600 | 30 | 红褐色 | 15~25℃ |
其中,凝固点引自《Handbook of pharmaceutical excipients》,Fouth Edtion。
药物在聚乙二醇中的溶解呈现随分子量增加而升高的趋势,同时颜色也比药物固态时的颜色加深,颜色变化与药物浓度有关。溶解是溶剂与溶质分子间相互作用的过程,溶剂与溶质间亲和力高则容易溶解,聚乙二醇含有较多的O、H原子且分子量与本发明的药物分子量相当,故聚乙二醇比较容易与药物分子结合使之溶解。聚乙二醇300和聚乙二醇400凝固点更低,相对更适合制备及贮藏时保持药液呈液态,故优选。
实施例3制备不同配方的注射剂
用本发明的方法按照表4中所示的组分制备不同配方的注射剂,其中活性成分为(3Z,6Z)-3-((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基)-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮,结构式为:
表4
实施例4注射剂的检测
分别通过配液溶解时间、注射剂的黏度、注射剂用5%葡萄糖注射液稀释成2mg/ml时药液无肉眼可见析出物的稳定时间、在5%葡萄糖注射液中稀释分散时间(温和振摇混合稀释成2mg/ml)和注射剂吸取难度对实施例3的各组注射剂及其制备过程进行评价,结果如下表:
结果表明,聚乙二醇不仅能够减少配液溶解时所需的乙醇用量,可以加快药物溶解,还能使最终除醇的制剂具有更低的黏度,药液抽取操作时阻力更小,并且能够促进表面活性剂的水化在温和振摇下即可快速分散。
综上,本发明提供的剂型、配方和制备方法成功地克服了中国专利申请CN106565686所公开的这类化合物及其类似物的制剂开发难点。提供的配方及制备方法适合工业化生产,能够顺利的进行溶解,且所用的有机溶剂量适中。最终除去乙醇的注射剂具有更好的安全性,其黏度能满足正常的药液吸取,而且水化速度非常快。所述的注射剂无需专用稀释溶剂,可直接采用临床常见的生理盐水或葡萄糖输液直接稀释配制,在室温具有较好的物理稳定性,能够满足滴注给药。
Claims (1)
1.一种抗肿瘤药物注射剂,其特征在于,所述抗肿瘤药物注射剂由以下方法制备而得:
(1)将所述的活性成分、聚乙二醇、表面活性剂、抗氧剂和乙醇加入配液容器中搅拌溶解,获得药液1;
(2)用0.45μm滤膜对由步骤1获得的药液进行粗滤除杂,获得药液2;
(3)超滤或活性炭除去药液2的热原获得药液3;
(4)除菌过滤药液3,获得药液4;
(5)将药液4灌装于注射剂管制瓶,半压塞后进入冻干机或真空干燥设备,除去乙醇,获得所述的抗肿瘤药物注射剂;
所述药液中乙醇除去至含量小于3%(W/W);
其中,步骤(1)所述的活性成分为(3Z,6Z)-3-((E)-3-(5-叔丁基)-1H-咪唑基-4-基)亚甲基)-6-((E)-3-(3-氟苯基)-2-丙烯亚基)哌嗪-2,5-二酮,结构式为(II),聚乙二醇为聚乙二醇300或者聚乙二醇400,表面活性剂为聚氧乙烯35蓖麻油,抗氧剂为维生素E,乙醇为无水乙醇;
步骤(1)的原料配方选自以下任一种:
聚氧乙烯35蓖麻油100g,聚乙二醇300 100g,活性成分1.8g,无水乙醇158g,维生素E5.0g;
聚氧乙烯35蓖麻油100g,聚乙二醇300 100g,活性成分1.5g,无水乙醇158g,维生素E5.0g;
聚氧乙烯35蓖麻油100g,聚乙二醇300 67g,活性成分1.5g,无水乙醇132g,维生素E5.0g;
聚氧乙烯35蓖麻油100g,聚乙二醇300 150g,活性成分1.5g,无水乙醇197.5g,维生素E7.0g;
聚氧乙烯35蓖麻油100g,聚乙二醇300 100g,活性成分1.5g,无水乙醇316g,维生素E8.0g;
聚氧乙烯35蓖麻油100g,聚乙二醇300 75g,活性成分1.5g,无水乙醇197.5g,维生素E7.0g;或者
聚氧乙烯35蓖麻油100g,聚乙二醇400 100g,活性成分1.5g,无水乙醇158g,维生素E5.0g。
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