CN104434971A - 一种用于治疗急性早幼粒细胞白血病的复方制剂、及其药物组合物、应用和制备方法 - Google Patents
一种用于治疗急性早幼粒细胞白血病的复方制剂、及其药物组合物、应用和制备方法 Download PDFInfo
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Abstract
本发明提供一种用于治疗急性早幼粒细胞白血病的复方制剂、及其药物组合物、应用和制备方法,其复方制剂的原料按重量份计,包括:维甲酸5.25-30份,雄黄12.5-50份。本发明提供的用于治疗急性早幼粒细胞白血病的复方制剂,其中,雄黄作为我国传统的中药,其不仅具有与三氧化二砷同等的疗效,而且可口服给药,价格便宜,毒性更低,非常适合与维甲酸配伍研发复方制剂。
Description
技术领域
本发明涉及医药领域,尤其涉及一种用于治疗急性早幼粒细胞白血病的复方制剂、及其药物组合物、应用和制备方法。
背景技术
急性早幼粒细胞白血病(acute promyelocyt ic leukemia,以下简称:APL)作为急性髓系白血病(acute myeloid leukemia,以下简称:AML)中的一个特殊亚型,约占成人AML的10%-15%。近十余年,由于全反式维甲酸和三氧化二砷的发现和应用,采用双诱导治疗能够使初发APL的初期诱导缓解率达到90%以上,且不易诱发弥散性血管内凝血(DIC),大大减少了因出血而导致的死亡。目前临床上主要采用维甲酸口服,联合三氧化二砷静脉滴注进行双诱导治疗,但三氧化二砷需要静脉给药,毒性相对较大,且价格昂贵。
发明内容
本发明的目的在于解决上述现有技术存在的缺陷,提供一种能够口服、毒性相对较小,且价格便宜的用于治疗急性早幼粒细胞白血病的双诱导复方制剂。
为实现上述目的,本发明采用以下技术方案:
一种用于治疗急性早幼粒细胞白血病的复方制剂,其原料按重量份计,包括:维甲酸5.25-30份,雄黄12.5-50份。
优选地,所述维甲酸为10.5-30份,雄黄为12.5-50份。
进一步地,所述制剂为饮品、胶囊剂、片剂、颗粒剂或丸剂。
一种用于治疗急性早幼粒细胞白血病的药物组合物,其中含有治疗有效量的权利要求1复方制剂和药学上可接受的载体。
一种维甲酸联合雄黄在制备治疗急性早幼粒细胞白血病的药物中的应 用。
一种用于治疗急性早幼粒细胞白血病的复方制剂的制备方法,按所述配方中配比称取各种原料,将其研成细粉,加适量蜜糖揉成药丸,每丸重6g。
维甲酸,又称维A酸,为体内维生素A的代谢中间产物,维甲酸在对机体生长、发育、免疫、抑制多种肿瘤细胞的增殖及诱导分化具有很强的调节功能,起着至关重要的作用,是机体正常的生长发育以及在各种生理活动中的重要的因素。维甲酸的治疗效应不同于细胞毒药物,它不是通过细胞的毒杀作用杀灭肿瘤细胞,而是通过诱导肿瘤细胞的分化及凋亡而达到控制或治愈肿瘤的目的,是目前肿瘤治疗中常用的分化诱导剂,而且研究证明维甲酸与细胞毒药物联合应用还可发挥较好的协同治疗作用。
雄黄是砷硫化物矿物之一,含As70.1%。单斜晶系,单晶体呈细小的柱状、针状;通常为致密粒状或土状块体。桔红色,条痕呈浅桔红色。金刚光泽,断口为树脂光泽。硬度1.5~2,密度3.5~3.6g/cm3。性脆,熔点低。用炭火加热,会冒出有大蒜臭味的白烟。置于阳光下曝晒,会变为黄色的雌黄(As2S3)和砷华,不溶于水和盐酸,可溶于硝酸,溶液呈黄色。雄黄主要产于低温热液矿床中,常与雌黄、辉锑矿、辰砂共生。我国著名古代医学典籍《神农本草经》、《(本草纲目》中均有记载。其味辛苦、性温,归肝经、大肠经,具有解毒杀虫、燥湿祛痰、截疟等作用,古时多作为外用药治疗痈疮肿毒、虫蛇咬伤、疥癣秃疮、虫积腹痛等。现代医学发现As4S4雄黄除具有镇痛、抗炎、杀菌等药理作用外,还可以显著抑制肿瘤细胞增殖、诱导肿瘤细胞分化和凋亡,发挥突出的肿瘤杀伤作用。
本发明提供的用于治疗急性早幼粒细胞白血病的复方制剂,其中,雄黄作为我国传统的中药,其不仅具有与三氧化二砷同等的疗效,而且可口服给药,价格便宜,毒性更低,非常适合与维甲酸配伍研发复方制剂。
附图说明:
图1为非药物处理APL模型组小鼠骨髓单个核细胞CD33表达白光图和荧光图;
图2为给药组一的小鼠骨髓单个核细胞CD33表达白光图和荧光图;
图3为给药组二的小鼠骨髓单个核细胞CD33表达白光图和荧光图;
图4为给药组三的小鼠骨髓单个核细胞CD33表达白光图和荧光图;
图5为给药组四的小鼠骨髓单个核细胞CD33表达白光图和荧光图。
图6为给药组五的小鼠骨髓单个核细胞CD33表达白光图和荧光图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚,下面将结合本发明中的附图,对本发明中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1:
维甲酸5.25份,雄黄12.5份,将上述原料制成颗粒剂,按照每人每天维甲酸5.25mg,雄黄12.5mg服用,具有明显的疗效。
实施例2:
维甲酸5.25份,雄黄25份,将上述原料制成颗粒剂,按照每人每天维甲酸5.25mg,雄黄25mg服用,具有明显的疗效。
实施例3:
维甲酸5.25份,雄黄50份,将上述原料制成颗粒剂,按照每人每天维甲酸5.25mg,雄黄50mg服用,具有明显的疗效。
实施例4:
维甲酸10.5份,雄黄12.5份,将上述原料制成颗粒剂,按照每人每天维甲酸10.5mg,雄黄12.5mg服用,具有明显的疗效。
实施例5:
维甲酸10.5份,雄黄25份,将上述原料制成颗粒剂,按照每人每天维甲酸10.5mg,雄黄25mg服用,具有明显的疗效。
实施例6:
维甲酸10.5份,雄黄50份,将上述原料制成颗粒剂,按照每人每天维甲酸10.5mg,雄黄50mg服用,具有明显的疗效。
实施例7:
维甲酸15.75份,雄黄12.5份,将上述原料制成颗粒剂,按照每人每天维甲酸15.75mg,雄黄12.5mg服用,具有明显的疗效。
实施例8:
维甲酸15.75份,雄黄25份,将上述原料制成颗粒剂,按照每人每天维甲酸15.75mg,雄黄25mg服用,具有明显的疗效。
实施例9:
维甲酸15.75份,雄黄50份,将上述原料制成颗粒剂,按照每人每天维甲酸15.75mg,雄黄50mg服用,具有明显的疗效。
实施例10:
维甲酸23.25份,雄黄12.5份,将上述原料制成颗粒剂,按照每人每天维甲酸23.25mg,雄黄12.5mg服用,具有明显的疗效。
实施例11:
维甲酸23.25份,雄黄25份,将上述原料制成颗粒剂,按照每人每天维甲酸23.25mg,雄黄25mg服用,具有明显的疗效。
实施例12:
维甲酸23.25份,雄黄50份,将上述原料制成颗粒剂,按照每人每天维甲酸23.25mg,雄黄50mg服用,具有明显的疗效。
实施例13:
维甲酸30份,雄黄12.5份,将上述原料制成颗粒剂,按照每人每天维甲酸30mg,雄黄12.5mg服用,具有明显的疗效。
实施例14:
维甲酸30份,雄黄25份,将上述原料制成颗粒剂,按照每人每天维甲酸30mg,雄黄25mg服用,具有明显的疗效。
实施例15:
维甲酸30份,雄黄50份,将上述原料制成颗粒剂,按照每人每天维甲酸30mg,雄黄50mg服用,具有明显的疗效。
国内外目前尚无此口服的双诱导复方制剂。因此,确定维甲酸与雄黄的最佳配比比例和剂量,研发维甲酸/雄黄双诱导复方制剂尤为重要。
实验例:
1、急性早幼粒细胞白血病严重联合免疫缺陷(severe combined immune deficency,以下简称:SCID)小鼠模型的建立
①急性早幼粒细胞白血病细胞株NB4的体外培养:
将NB4细胞以5×105个/mL的浓度接种于含10%灭活新生牛血清、100KU/L青霉素、100mg/L链霉素的RPMI1640培养液,于37℃、饱和湿度条件下、在体积分数为5%的CO2培养箱培养,每隔36-48小时换液传代一次,传代比例为1:2。取对数生长期细胞进行后续试验。
②急性早幼粒细胞白血病SCID小鼠动物模型的建立:
(I)SCID小鼠:3-5周龄,20只(雌雄不限),小鼠在层流架内带盖鼠盒中饲养(符合SPF标准),室内空气经中效过滤,饮用水为加少量食盐的灭菌双蒸水标准颗粒饲料加维生素C、鸡蛋、垫料及一切与鼠接触物品均灭菌处理。随机分为A、B两组,每组10只,A组为模型组,B组为正常对照。
(II)配制NB4细胞接种液:取对数生长期的NB4细胞,1000rpm,离心5min,弃上清,PBS(phosphate buffer saline,磷酸缓冲盐溶液)洗涤3次,充分去除胎牛血清。细胞计数板计算细胞密度,PBS液调整细胞悬液密度。在超净工作台密封瓶口,75%酒精消毒瓶身,经递物窗送入SPF室。A组给予腹腔注射NB4细胞3×106个/只(200μL),B组腹腔注射等量生理盐水。
③急性早幼粒细胞白血病SCID小鼠动物模型的鉴定:
接种前和接种1、2、3、4周后以及病程后期,分别进行:
(I)形态学观察:取鼠尾静脉血(剪尾采血或眼球取血)分别进行白细胞计数和涂片镜检(表1):
表1SCID小鼠接种NB4细胞后外周血情况
(II)病理学检测:
腹腔接种NB4细胞,可见少量腹水。组织切片结果显示在肝、脾、肺、肌组织内有瘤细胞浸润,以肝组织最明显,瘤组织主要为淋巴细胞样肿瘤。
(III)小鼠骨髓单个核细胞CD33阳性率检测:
提取模型组小鼠的骨髓单个核细胞,细胞涂片后行免疫组织化学法检测CD33阳性细胞率。实验结果发现CD33在小鼠骨髓单个核细胞中呈强阳性表达(即阳性着色细胞占细胞总数大于50%)。
(IV)发病情况:
10只模型组小鼠腹腔接种NB4细胞33天后均在腹腔形成肿块。发病小鼠晚期有不同程度的消瘦,动物皮毛起皱,步态不稳,萎靡不动,侧偏或转圈。腹腔接种小鼠发病情况如表2,生存时间见表3。
表2NB4细胞移植SCID小鼠发病情况
表3实验各组SCID小鼠生存时间
2、均匀设计进行维甲酸与雄黄组方分析,确定两药最佳配比比例及剂量。
剂型、给药方式:维甲酸与雄黄组成的复方制剂采用灌胃给药,每天6点、14点、22点给药,给药时间为第5-8周,即模型成功后持续4周,给药量见表4。
利用均匀设计表来安排实验步骤:该实验选取维甲酸与雄黄给药量两个因素。维甲酸根据人体每日给药安全范围,设5个水平(mg/d):5.25、 10.5、15.75、23.25、30。雄黄给药量根据人体每日给药安全范围,设3个水平(mg/d):个体化给药半量(12.5)、个体化给药量(25)和个体化给药二倍量(50)。共需要安排15次试验,根据因素和水平,选用均匀设计表,进行该试验。
表4均匀设计试验方案
实验观测结果为外周血白细胞计数及分类,结果采用回归分析或逐步回归分析,获得维甲酸与雄黄的最佳配比比例和剂量。接下来的实验选用维甲酸和雄黄的最佳剂量和最佳比例。
3、实验指标检测:形态学观察、病理学检测和染色体核型分析等多个方面,判断两药的相互作用关系(协同、相加、无关或拮抗)。
①取鼠尾静脉血(剪尾采血或眼球取血)分别进行白细胞计数和涂片镜检:吉姆萨染色油镜下观察细胞形态,每片计数200个细胞。按早幼粒、中幼粒、晚幼粒杆状核及分叶核细胞分类计数计算早幼粒细胞的比例,经试验观测,从第三周开始,非药物处理模型组小鼠鼠尾静脉血中白细胞数 目显著增加,并且可以检测出大量NB4细胞。不同维甲酸/雄黄配比比例的药物处理模型组小鼠白细胞数较非给药组均有所降低,尤以维甲酸23.25mg/d+雄黄25mg、维甲酸30mg/d+雄黄12.5mg和维甲酸10.5mg/d+雄黄50mg三组白细胞数最低,接近正常对照组SCID小鼠。
②经试验观测可见非药物处理模型组小鼠体内有大量腹水。取发病/濒死小鼠肝、脾、肾、肺、肌肉及肿瘤实体以10%甲醛固定48小时以上,常规石蜡切片,HE染色、镜检。组织切片显示在肝、脾、肺、肌组织内有瘤细胞浸润,瘤组织为淋巴细胞样肿瘤。不同维甲酸/雄黄配比比例的药物处理模型组小鼠腹水及组织肿瘤细胞浸润均不及非给药组明显。其中,维甲酸15.75mg/d+雄黄25mg、维甲酸23.25mg/d+雄黄25mg、维甲酸30mg/d+雄黄12.5mg和维甲酸10.5mg/d+雄黄50mg四组小鼠模型体内未见腹水形成,组织切片也未见明显肿瘤细胞浸润。
③CD33是跨膜糖蛋白,属涎酸粘附家族,是人髓系细胞主要的表面抗原,主要分布于人髓性白血病细胞和浆细胞表面。NB4细胞的CD33阳性表达率可高达99%,且特异性较高,故可以CD33为特异性指标,检测SCID小鼠-AAPL模型中白血病细胞浸润能力和增殖能力:随机抽取发病小鼠骨髓细胞,经缓冲液洗2次,加入抗人CD33同时加入同种动物血清,4℃避光染色30分钟,荧光显微镜下观察,图1为非药物处理AML模型组小鼠骨髓单个核细胞CD33表达白光图和荧光图,如图1所示,实验结果显示,CD33在非药物处理模型组小鼠骨髓单个核细胞中呈强阳性表达(即阳性着色细胞占细胞总数大于50%);图2为给药组一的小鼠骨髓单个核细胞CD33表达白光图和荧光图,如图2所示,在维甲酸15.75mg/d+雄黄25mg的药物处理模型条件下,小鼠骨髓单个核细胞中呈弱阳性表达;图3为给药组二的小鼠骨髓单个核细胞CD33表达白光图和荧光图,如图3所示,在维甲酸30mg/d+雄黄12.5mg的药物处理模型条件下,小鼠骨髓单个核细胞中呈弱阳性表达;图4为给药组三的小鼠骨髓单个核细胞CD33表达白光图和荧光图,如图4所示,在维甲酸23.25mg/d+雄黄25mg的药物处理模型条件下,小鼠骨髓单个核细胞中则呈阴性表达;图5为给药组四的小鼠骨髓单个核细胞CD33表达白光图和荧光图,如图5所示,在维甲酸30mg/d+雄黄12.5mg的药物处理模型条件下,小鼠骨髓单个核细胞中则 呈阴性表达;图6为给药组四的小鼠骨髓单个核细胞CD33表达白光图和荧光图,如图6所示,在维甲酸10.5mg/d+雄黄50mg的药物处理模型条件下,小鼠骨髓单个核细胞中则呈阴性表达。
4、维甲酸/雄黄复方制剂的毒性反应实验。
急性毒性试验可通过由尾静脉(或腹腔)注射由注射用水稀释成不同浓度的药液,注射时间为4-5秒,观察有无不良反应(如惊厥、四肢瘫痪、步伐不稳、竖毛、呼吸抑制等)或死亡,经试验观测,各药物处理组均未见明显不良反应。
本发明提供一种用于治疗急性早幼粒细胞白血病的药物组合物,其中含有治疗有效量的用于治疗急性早幼粒细胞白血病的和药学上可接受的载体。
本发明还提供一种维甲酸联合雄黄在制备治疗急性早幼粒细胞白血病的药物中的应用。
最后应说明的是:以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的精神和范围。
Claims (6)
1.一种用于治疗急性早幼粒细胞白血病的复方制剂,其特征在于,其原料按重量份计,包括:维甲酸5.25-30份,雄黄12.5-50份。
2.根据权利要求1所述的复方制剂,其特征在于,所述维甲酸为10.5-30份,雄黄为12.5-50份。
3.根据权利要求1或2所述的复方制剂,其特征在于,所述制剂为饮品、胶囊剂、片剂、颗粒剂或丸剂。
4.一种用于治疗急性早幼粒细胞白血病的药物组合物,其特征在于,其中含有治疗有效量的权利要求1复方制剂和药学上可接受的载体。
5.一种维甲酸联合雄黄在制备治疗急性早幼粒细胞白血病的药物中的应用。
6.一种用于治疗急性早幼粒细胞白血病的复方制剂的制备方法,其特征在于,按所述配方中配比称取各种原料,将其研成细粉,加适量蜜糖揉成药丸,每丸重6g。
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CN1233476A (zh) * | 1998-04-24 | 1999-11-03 | 陆道培 | 治疗急性白血病的药物及其制备方法 |
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CN1233476A (zh) * | 1998-04-24 | 1999-11-03 | 陆道培 | 治疗急性白血病的药物及其制备方法 |
CN1299284A (zh) * | 1998-04-24 | 2001-06-13 | 陆道培 | 用于治疗恶性肿瘤的硫化砷化合物及其衍生物 |
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