CN1233476A - 治疗急性白血病的药物及其制备方法 - Google Patents

治疗急性白血病的药物及其制备方法 Download PDF

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CN1233476A
CN1233476A CN98101635A CN98101635A CN1233476A CN 1233476 A CN1233476 A CN 1233476A CN 98101635 A CN98101635 A CN 98101635A CN 98101635 A CN98101635 A CN 98101635A CN 1233476 A CN1233476 A CN 1233476A
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陆道培
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Abstract

本发明涉及一种治疗白血病的药物及其制备方法。该药物是由纯化的四硫化四砷(AS4S4)结晶与柏子仁浆按一定的比例制成的药剂。生产这种药物的方法是依去砷、脱酸、干燥等几个重要的步骤,并在这些步骤中逐以pH值的核定标准为标准近而获得纯化的AS粉,之后,再将柏子仁浆状物与纯化的AS粉调和一处制成药剂。

Description

治疗急性白血病的药物及其制备方法
本发明涉及一种治疗人体造血系统的恶性增生性病变的药物及其制做这种药物的方法，具体地说是一种治疗急性白血病的药物及其制备方法。
白血病是指因人体内白细胞异常增生并浸润全身各组织，在血液中有幼稚白细胞出现而形成的恶性肿瘤疾病。按细胞学分类有三种表现形式即粒细胞性、淋巴细胞性、单核细胞性的恶性肿瘤；若按病程的急缓程度和白细胞成熟的程度又可分为急性白血病和慢性白血病，诊其临床表现多为贫血、出血、发热、盗汗并伴有淋巴结肿大，肝、脾肿大等症状。传统的临床治疗则是在化验确诊不同的类型肿瘤后或施以抗肿瘤药物、糖类皮质激素、中草药等药物的治疗，或以放射疗法、免疫疗法治疗或者以药、疗法混合治疗。但是，患者存活期的长短并非以上述诸种治疗手段为绝对的保证，尤其是早幼粒细胞白血病(APL)也就是急性白血病，它的发病甚为凶险，迅速死亡率也最高，对此病的攻关也自然而然的成为了医务科研人员义不容辞的首选任务。
本发明的目的在于提供一种治疗急性白血病的药物，籍以此药物实现对早幼粒细胞白血病患者的治疗。
本发明的再一目的是提供一种制备上述药物的方法，并以此方法作为生产成药的标准。
本发明上述的两个目的是这样实现的：
一种治疗急性白血病的药物，该药物是由纯化的硫化砷结晶体AS4S4(AS)和柏子仁浆状物按1∶0.5-50的比例制成的药剂。
一种用于治疗急性白血病药物的制备方法，该方法是：
(a)取硫化砷结晶体(AS)置大乳钵中加水后以研磨棒压碎研磨，得含油腻状酸溶性不纯物的液体；
(b)以稀盐酸反复调制大乳钵中的酸溶性不纯物的液体，得PH值为4-4.5的混悬物；
(c)将(b)中的混悬物置专用器皿(如大烧杯等)内搅拌再入磁力搅拌器中不断地、充分地搅拌；
(d)重复(c)中的过程至二十四小时且倾去上清液并终以测得上清液不含砷质为标准后得沉淀物；
(e)将(d)中所得沉淀物再入搅拌器同时加入蒸溜水反复充分洗涤，去酸质得PH值为6-7的混合液；
(f)将由(e)所得的混合液入离心机分离去液体后得纯化AS沉淀物；
(g)将(f)所得的纯化AS沉淀物置真空低湿环境中干燥得纯化AS粉；
(h)取适量事先破碎研压过的浆状柏子仁与由(g)所得的纯化AS粉在非高温条件下按比例混匀、研压、同调一处装入胶囊。
在上述方案中，所使用的硫化砷AS4S4是源于雄黄纯化了的结晶体。雄黄是由于地壳低温热液作用或火山喷气所形成的一种矿物质。在我国中医史上用雄黄作药的记载已有近二千年的历史。它性属温，味苦辛，外用可治疥癣恶疮、蛇虫咬伤等症，内服微量则可治惊痫、疮毒等症。柏子仁也是一味中药，它性平，味甘辛且以其润燥、养心、安神的功能可内服治疗惊悸、不寐、便秘等症。将纯化的AS4S4与佐剂柏子仁合为一处作为主治急性白血病的药物迄今为止国内外倘无报道。这是由于一是单独用纯化的AS4S4治疗恶性肿瘤的药用范围前人无更深入的研究和理论上的探索，二是由于硫化砷AS4S4源于自然矿物质雄黄，而雄黄矿又常与雌黄、辉锑矿等共生，其矿内杂质很多，尤其是在矿内更存在诸如AS2O3、(CaMg)3(ASO3)、(CaMg)(ASO4)2等有毒的物质，而传统处理雄黄的方法是不足以尽除矿物中的砒霜(AS2O3)等有害物质的。另外，择选上品雄黄的概念和制备方法不标准也是传统上使用雄黄的一大缺憾，它包括经水洗、酸(碱)洗的PH终值标准、纯化AS结晶体沉淀物的干燥程度。如此等等都大大增加了提纯AS4S4结晶体的程度。而在实现本发明的药物和制备这一药物的方案中，格外强调的是采用纯化的AS4S4结晶体作为主药，它的独立存在和使用直接关系到治疗急性白血病的效果，因为分子排列结构的特点在AS4S4呈结晶体后其它物质进入它的可能性被排除了。它的药理作用是直接针对早幼粒细胞的。柏子仁浆作为配药，实际上它亦是佐剂，它的作用是促进AS4S4结晶体的溶解度使其发挥最大的药力。反复酸(碱)洗是为了去除所选AS4S4中的酸溶性不纯物乃至PH值到4-4.5后再用蒸溜水反复洗涤沉淀物使它的PH值达到6-7，最后得到的纯化AS4S4结晶体又必须是在真空或低温真空环境中干燥处理后获得的。
根据本发明所涉及的药物及其制备这种药物的方法，比较已知用于临床治疗急性白血病的药物和生产这些药物的方法，本发明的贡献在于：
一是强调单独使用纯化的AS4S4结晶体作为治疗急性白血病的主药和与之配伍的佐剂柏子仁，它们的药理作用是创新的、有效的；
二是强调了纯化AS4S4(或上品雄黄)结晶体的过程。这一过程的几个阶段分别是标准化制备药物必须遵循的准则，即PH值标准、非高温条件下混合药物的标准。
下面结合实施例和附图对本发明涉及的治疗急性白血病的药物及该药物的制备方法再作详细说明。
图1是关于本发明涉及的药物之制备方法流程图。
一种治疗急性白血病的药物，它是由纯化的硫化砷结晶体AS4S4(AS)和柏子仁浆状物按1∶0.5-50的比例制成的药剂。上述的纯化硫化砷结晶体(AS)可以是源于雄黄的四硫化四砷纯化结晶体，且它可以与柏子仁浆按1∶0.5-50的比例制成药剂。
一种用于治疗急性白血病药物的制备方法，它是：
(a)取硫化砷结晶体(AS)置大乳钵中加水后以研磨棒压碎研磨，得含油腻状酸溶性不纯物的液体；
(b)以稀盐酸反复调制大乳钵中的酸溶性不纯物的液体，得PH值为4-4.5的混悬物；
(c)将(b)中的混悬物置专用器皿(如大烧杯等)内搅拌再入磁力搅拌器中不断地、充分地搅拌；
(d)重复(c)中的过程至二十四小时且倾去上清液并终以测得上清液不含砷质为标准后得沉淀物；
(e)将(d)中所得沉淀物再入搅拌器同时加入蒸溜水反复充分洗涤去酸质得PH值为6-7的混合液；
(f)将由(e)所得的混合液入离心机分离去液体后得纯化AS沉淀物；
(g)由(f)所得纯化AS沉淀物置真空低湿环境中干燥得纯化AS粉；
(h)取适量事先破碎研压过的浆状柏子仁与由(g)所得的纯化AS粉在非高温条件下按比例混匀、研压同调一处装入胶囊。
另外，由(g)所得的纯化AS粉亦可与柏子仁浆混合后经蒸溜再得提取液。为证实上述药物的临床效果，迄今已有四十八例早幼粒细胞性白血病(APL)患者照此方用药。由于这四十八例患者皆有典型APL的形态学特征，在用药后与未经本方治疗的其他APL患者比较，他们皆处于持续完全缓解中，除此之外的APL患者其细胞遗传学检查可发现APL的特征性改变，即t(15∶17)，分子生物学PCR(多聚酶链反应)RARa/PMLmPNA呈阳性。诊断慢性髓性白血病均按公认的标准确定其诊断。在上述四十八例皆处于持续完全缓解的APL患者中无一复发。按Kaplan-Maier统计方法的寿命预测的无病存活率达100％(实际情况可能较此略低)。此四十八例APL患者中未经任何治疗的初治病例，复发或对其它药物耐药者有十例，其中八例只经一个疗程的AS后就完全缓解。另二例分别经过应用二和三个疗程后就完全缓解。四十八例APL中有三十八例为已经化疗而血液完全缓解者。但这些患者迄今非但全部持续缓解，而且检测发现有异常细胞遗传学改变与PCR检测阳性的九例患者皆已转为持续阴性。AS的副作用远较其它抗肿瘤药物为轻。少数病人有食欲下降、轻度腹泻、可逆性的暂时转氨酶(AST)上升、皮肤搔痒或眼睑浮肿现象。白细胞下降仅发生于34％病例，而且一般进程慢，程度轻。治疗APL的四十八例中仅有一例发生血小板减少，但并无出血现象。无服用AS的死亡病例。在实践中将AS与柏子仁混合的制剂用于治疗恶性淋巴瘤亦有效。本发明的另一目的即制备治疗急性白血病药物的方法可以以制备的流程图描述之，由图中可看到在水研磨→用酸(碱)性溶液反复调制→去砷→用蒸溜水反复洗涤→脱酸(碱)→干燥的过程中PH值的标准极为重要，整个制备过程必须严格按照此方法进行。
结合实施例，需要指出的是在我国药典中所称雄黄中所含不得少于90％的硫化砷的分子式是AS2S2，但实际上应写作AS4S4或AsS或简称AS。按上述方法制备的药物若装入胶囊则每粒所含的总重量为0.5克，临床使用剂量一般为一日四粒胶囊，且2-3周为一疗程。另外，在获得上述纯化AS4S4结晶后，还可将它溶于若干溶液中做成注射剂。获得AS4S4注射剂的方法还包括调节溶液的酸碱度，添加助溶剂、以柏子仁浆混合的蒸溜提取法以及联接某些无活性的化学集团如-SH基以增加其溶解度的制备方法。

Claims (4)

1．一种治疗急性白血病的药物，其特征在于该药物是由
   纯化的硫化砷结晶体AS4S4(AS)和柏子仁浆
   状物按1∶0.5-50的比例制成的药剂。
2．根据权利要求1所述的治疗急性白血病的药物，其特
   征在于上述的纯化硫化砷结晶体(AS)可以是源于雄
   黄的四硫化四砷纯化结晶体，且它可以与柏子仁浆按
   1∶0.5-50的比例制成药剂。
3．一种用于治疗急性白血病药物的制备方法，其特征在于：
   (a)取硫化砷结晶体(AS)置大乳钵中加水后以研磨棒
   压碎研磨，得含油腻状酸溶性不纯物的液体；
   (b)以稀盐酸反复调制大乳钵中的酸溶性不纯物的液
   体，得PH值为4-4.5的混悬物；
   (c)将(b)中的混悬物置专用器皿(如大烧杯等)内搅拌
   再入磁力搅拌器中不断地、充分地搅拌；
   (d)重复(c)中的过程至二十四小时且倾去上清液并终
   以测得上清液不含砷质为标准后得沉淀物；
   (e)将(d)中所得沉淀物再入搅拌器同时加入蒸溜水反
   复充分洗涤去酸质得PH值为6-7的混合液；
   (f)将由(e)所得的混合液入离心机分离去液体后得纯
   化AS沉淀物；
   (g)由(f)所得纯化AS沉淀物置真空低温环境中干燥得
   纯化AS粉；
   (h)取适量事先破碎研压过的浆状柏子仁与由(g)所得
   的纯化AS粉在非高温条件下按比例混匀、研压同调一处
   装入胶囊。
4．根据权利要求3所述的用于治疗白血病药物的制备方法，
   其特征在于由(g)所得的纯化AS粉亦可与柏子仁浆混合
   后经蒸溜后得提取液。
CN98101635A 1998-04-24 1998-04-24 治疗急性白血病的药物及其制备方法 Pending CN1233476A (zh)

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CN98101635A CN1233476A (zh) 1998-04-24 1998-04-24 治疗急性白血病的药物及其制备方法
AU81009/98A AU748795B2 (en) 1998-04-24 1998-07-06 Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies
NZ526746A NZ526746A (en) 1998-04-24 1998-07-06 Arsenious sulphide compounds other than As2O3 for treating hematological cancers such as leukemia or lymphoma
JP2000545542A JP2002512967A (ja) 1998-04-24 1998-07-06 悪性疾患治療のための硫化ヒ素化合物およびその誘導体
ES98930630T ES2242286T3 (es) 1998-04-24 1998-07-06 Compuestos de sulfuro de arsenico exentos de oxido de arsenico para el tratamiento de canceres hematologicos.
CNB988141310A CN1175823C (zh) 1998-04-24 1998-07-06 用于治疗恶性肿瘤的硫化砷化合物及其衍生物
US09/110,366 US6733792B1 (en) 1998-04-24 1998-07-06 Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies
IL13920898A IL139208A (en) 1998-04-24 1998-07-06 Pharmaceutical compositions containing arsenic sulfde derivatives
AT98930630T ATE292974T1 (de) 1998-04-24 1998-07-06 Arsentrioxidfreie arsensulfidverbindungen zur behandlung von hämatologischen tumoren
PCT/CN1998/000118 WO1999055344A1 (en) 1998-04-24 1998-07-06 Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies
IDW20002443A ID27299A (id) 1998-04-24 1998-07-06 Senyawa-senyawa arsen sulfida dan turunan-turunannya untuk mengobati maglinansis
DE69829782T DE69829782T2 (de) 1998-04-24 1998-07-06 Arsentrioxidfreie arsensulfidverbindungen zur behandlung von hämatologischen tumoren
TR2000/03117T TR200003117T2 (tr) 1998-04-24 1998-07-06 Hastalıkların tedavisi için arsenik sülfür bileşikleri ve bunların türevleri
EP05007964A EP1552841A1 (en) 1998-04-24 1998-07-06 Arsenic sulfide compounds and derivates thereof for the treatment of malignancies
EP98930630A EP1077709B1 (en) 1998-04-24 1998-07-06 Arsenic sulfide compounds free of arsenic oxide for the treatment of hematological cancers
PL98344410A PL344410A1 (en) 1998-04-24 1998-07-06 Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies
BR9815825-2A BR9815825A (pt) 1998-04-24 1998-07-06 Compostos de sulfeto de arsênico, respectivo processo de produção, composições farmacêuticas e métodos de tratamento e de manutenção em estágio de completa remissão de câncer hematológico
KR1020007011592A KR100610388B1 (ko) 1998-04-24 1998-07-06 악성질환의 치료를 위한 아스닉 설파이드 화합물과 그유도체
CA002328165A CA2328165A1 (en) 1998-04-24 1998-07-06 Arsenic sulfide compounds and derivatives thereof for the treatment of malignancies
NZ508240A NZ508240A (en) 1998-04-24 1998-07-06 Arsenic sulphide compounds, in particular arsenic disulphide (As4S4), for treating haematological cancers such as leukaemia or lymphoma
NO20005315A NO20005315L (no) 1998-04-24 2000-10-20 Arsenikksulfidforbindelser og derivater derav til behandlingen av maligniteter
HK01105198A HK1034466A1 (en) 1998-04-24 2001-07-24 Arsenic sulfide compounds free of arsenic oxide for the treatment of hematological cancers.
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