CN102698256B - 治疗肿瘤的药物组合物及其制备方法 - Google Patents
治疗肿瘤的药物组合物及其制备方法 Download PDFInfo
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- CN102698256B CN102698256B CN 201210202560 CN201210202560A CN102698256B CN 102698256 B CN102698256 B CN 102698256B CN 201210202560 CN201210202560 CN 201210202560 CN 201210202560 A CN201210202560 A CN 201210202560A CN 102698256 B CN102698256 B CN 102698256B
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Abstract
本发明公开了一种治疗肿瘤的药物组合物，该药物由豹蛙酶、甘露聚糖肽及辅料制备而成，所述药物既能提高机体的免疫功能，又能直接抑杀肿瘤细胞，效果明显，为肿瘤患者带来了福音。
Description
发明领域
本发明涉及一种治疗肿瘤的药物组合物及其制备方法，属于药品技术的领域。
技术背景
一直以来，肿瘤都被视为是“不治之症”，尤其晚期肿瘤，人们更是谈其色变。形成此观念的原因是多方面的。首先是由于晚期肿瘤患者机体免疫力低下，快速增殖的肿瘤细胞在消耗大量营养后，会加剧肿瘤患者免疫功能下降的速度，形成恶性循环，导致患者出现高热、乏力、厌食、进行性消瘦等多种症状，以至卧床不起。
近年来，肺癌、原发性肝癌、结直肠癌、妇科恶性肿瘤等的发病率逐年上升，已成为严重危害人类健康的最常见的恶性肿瘤，给我们的社会、经济、生活带来诸多不变。1996年以来，全球每年新确诊的肿瘤病人都在1000万以上，死亡700多万，到1999年底全球肿瘤病人总数已逾4000万。到2000年，依据卫生部信息中心数据，城市恶性肿瘤死亡率较大幅度上升，比十年前增幅为30.24%。从年龄上来看，目前肿瘤病人的总体增加趋势和肿瘤发病者呈年轻化趋势。但由于治疗肿瘤的费用非常昂贵，且病死率很高，许多欠发达国家和地区的患者会放弃治疗，故全球肿瘤患者的实际数量要大于以上数字。
抗肿瘤主要采用手术治疗、冷冻治疗、放疗、药物等方法。手术治疗，通过完整的清除肿瘤组织，达到治愈的目的，但存在高风险、高复发的危险，并且有的肿瘤不能进行手术治疗，例如中晚期肺癌、淋巴细胞癌症等。手术治疗有一定局限性。虽然放化疗初期有效率高，但大部分病人副反应严重、容易出现复发，同时需要药物治疗，因此，采用药物治疗为最常见的治疗方法。抗肿瘤药物市场近年来呈逐年增长的势头，临床上对于新型肿瘤治疗药的需求量急剧上升。抗肿瘤药的平均增长率高于12%，大大高于其他大类药物年平均8%的增长率，由于肿瘤病人逐年增加，加之癌症不是一种疾病，且多数抗肿瘤药物毒副作用较大，因此在临床上须联用多种药物综合治疗。
发明内容
本发明所要解决的技术问题在于提供一种治疗肿瘤的药物组合物，本发明所要解决的另一技术问题在于提供一种治疗肿瘤的药物组合物的制备方法。
为解决以上技术问题，本发明采用以下技术方案：
一种治疗肿瘤的药物组合物，所述组合物按照重量组分计算，由豹蛙酶5-15、甘露聚糖肽5-20及辅料制备而成。
优选的，所述治疗肿瘤的药物组合物，所述组合物按照重量组分计算，由豹蛙酶5-10、甘露聚糖肽5-10及辅料制备而成。
更优选的，所述治疗肿瘤的药物组合物，所述组合物按照重量组分计算，由豹蛙酶10、甘露聚糖肽10及辅料制备而成。
本发明所述治疗肿瘤的药物组合物通过以下方法制备而成：将豹蛙酶和甘露聚糖肽按照确定的比例混合均匀，然后按照常规方法制备成常规制剂。
所述常规制剂是指任何可药用的剂型，这些剂型选自：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、糖浆剂、滴丸、口含剂、颗粒剂、丸剂、散剂、膏剂、丹剂、混悬剂、溶液剂、注射制剂、冻干粉针、大容量注射液、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂。
本发明优选的制剂形式是注射液、注射用冻干粉针、大输液、硬胶囊、软胶囊剂、片剂、颗粒剂、口服制剂和丸剂。
本发明的药物组合物，在制备成药物制剂时，根据需要可以加入一些药物可接受的辅料，可以采用制剂学常规技术制备该药物制剂，如将药物活性物质与药物可接受的辅料混合。所述药物可接受的的辅料选自：甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、氮酮、EDTA二钠、EDTA钙钠，一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、土温60-80、司班-80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、表面活性剂、聚乙二醇、环糊精、β－环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、羟丙基甲基纤维素、羟丙基纤维素、淀粉、硬脂酸镁、低取代羟丙基纤维素、微晶纤维素、
薄荷脑、豆油、乙基纤维素、玉米油、炼蜜等。
本发明的药物制剂在使用时根据病人的情况确定用法用量。
本发明的药物组合物，在制成药剂时，单位剂量的药剂可含有本发明的药物活性物质0.1-1000mg，其余为药学上可接受的辅料。药学上可接受的辅料以重量计可以是制剂总重量的0.1-99.9%。
本发明选用豹蛙酶和甘露聚糖肽组方，制成治疗肿瘤的药物组合物。豹蛙酶（ranpimase,商品名为Onconase），它是从北方豹蛙（Ranapipiens）卵或早期胚胎中提取的一种核糖核酸酶，由104个氨基酸残基组成，相对分子质量为11835，等电点为9.7，是已知的胰核糖核酸酶超家族成员中最小的单结构域蛋白。Onconase可以抑制多种肿瘤的生长，其虽然是蛋白质药物，但免疫原性很低，在临床上可以应用多个疗程，它的副反应不大，且具有抗多重耐药性的能力。甘露聚糖肽，别名多抗甲素、A型链球菌甘露聚糖、多康甲、α-甘露聚糖肽，属免疫增强剂，对人的淋巴细胞有直接激活作用，能促进胸腺淋巴细胞分化与增殖，促进机体抗肿瘤免疫功能，能激活吞噬细胞，使白细胞生成增加，促进补体生成，促进白细胞介素-1的生成，能提高骨髓造血功能。
本发明选用豹蛙酶和甘露聚糖肽进行组方制成抗癌药物，对于抑制肿瘤有显著的效果。本申请人在研究中发现，以上药物组方有协同增效的效果，制成的药物疗效优于豹蛙酶注射液，且本发明所述药物除了能抑制肿瘤细胞的生长，其增强机体免疫力的作用也非常明显。
申请人对本发明药物进行了药效学实验研究，实验结果如下：
实验例1：抗肿瘤作用研究
1实验材料：
1.1药物：
本发明注射液1：取豹蛙酶5mg和甘露聚糖肽5mg混合，加入注射用水至100ml，制成注射液；
本发明注射液2：取豹蛙酶10mg和甘露聚糖肽10mg混合，加入注射用水至100ml，制成注射液；
本发明注射液3：取豹蛙酶15mg和甘露聚糖肽20mg混合，加入注射用水至100ml，制成注射液；
对照药物：豹蛙酶注射液，采用常规制法制得的注射液，规格为10ml:1mg；
1.2瘤株：小鼠肉瘤S180、H22。动物：昆明种小鼠，18-24g。
2方法与结果：对动物移植性肿瘤的抑制作用：①对小鼠S180的抑制作用：取传代接种7~10d的瘤源动物，无菌条件下抽取腹水瘤液，每鼠右腋皮下接种1×106瘤细胞，24h后随机分组并开始给本发明药物及对照药物，每天腹腔注射1次，连续9~11d。生理盐水组腹腔注射灭菌生理盐水。停药次日处死小鼠，称体重并剥离皮下瘤块，称瘤重，计算抑瘤率，结果见表1。可见本发明注射液有明显抑制S180生长作用，并呈良好量效关系。②对小鼠H22的抑制作用：方法同上，每鼠接种1×106H22细胞，结果见表2。
表1对小鼠S180的抑制作用
从表1可知，本发明药物组与生理盐水组相比，有非常显著性差异，P<0.01，说明本发明药物对小鼠S180有抑制的作用；本发明药物组与对照药物组相比有显著统计学意义，P<0.05，说明本发明药物对小鼠S180的抑制作用优于对照药物，本发明药物组中，豹蛙酶10mg、甘露聚糖肽10mg的剂量配比效果最优。
表2对小鼠H22的抑制作用
从表2可知，本发明药物组与生理盐水组相比，有非常显著性差异，P<0.01，说明本发明药物对小鼠H22有抑制的作用；本发明药物组与对照药物组相比有显著统计学意义，P<0.05，说明本发明药物对小鼠H22的抑制作用优于对照药物，本发明药物组中，豹蛙酶10mg、甘露聚糖肽10mg的剂量配比效果最优。
3结论：根据以上实验结果，可见本发明药物对小鼠S180和小鼠H22具有明显的抑制作用，其作用优于对照药物。
实验例2：对淋巴细胞亚群的影响
1实验材料：
1.1动物：4~5周龄SD大鼠，体重（112.7±15.7）g,雌雄兼用。
1.2瘤株：大肠癌细胞（L0V0株）。
1.3药物：
本发明注射液1：取豹蛙酶5mg和甘露聚糖肽5mg混合，加入注射用水至100ml，制成注射液；
本发明注射液2：取豹蛙酶10mg和甘露聚糖肽10mg混合，加入注射用水至100ml，制成注射液；
本发明注射液3：取豹蛙酶15mg和甘露聚糖肽20mg混合，加入注射用水至100ml，制成注射液；
对照药物：豹蛙酶注射液，采用常规制法制得的注射液，规格为10ml:1mg；
2方法与结果：SD大鼠腹腔常规接种大肠癌L0V0细胞悬液0.2ml约1×106瘤细胞，一周后随机分为5组，每组10只，静脉给本发明药物及对照药物，生理盐水组腹腔注射灭菌生理盐水，每天一次，连续一周。停药后次日采外周血并处死大鼠，取10ul腹水加生理盐水1.99ml稀释，计数并计算每升腹水中所含肿瘤细胞数及每高倍视野核分裂数，并求出肿瘤细胞生长抑制率及每高倍视野核分裂抑制率，用流式细胞仪测定外周血中CD3+、CD4+、CD8+，计算CD4+/CD8+比值。
细胞生长抑制率%=（1-实验组平均瘤细胞数/对照组品均瘤细胞数）×100%
核分裂抑制率%=(1-实验组平均核分裂数/对照组平均核分裂数)×100%
表3对T淋巴细胞亚群的影响（x±s）
从表3可知，本发明药物组与生理盐水组相比，T淋巴细胞亚群CD3+、CD4+、CD4+/CD8+均高于生理盐水组，CD8+均低于生理盐水组，两者比较差异有极显著性，P＜0.01；本发明药物组与对照药物组相比，T淋巴细胞亚群CD3+、CD4+、CD4+/CD8+均高于对照药物组，CD8+均低于对照药物组，差异有显著性，P＜0.05；说明本发明药物增强机体免疫功能的作用优于对照药物，本发明药物组中，豹蛙酶10mg、甘露聚糖肽10mg的剂量配比效果最优。
3结论：T淋巴细胞浸润程度直接反映机体抗肿瘤的状态。根据以上实验结果，可见本发明药物具有明显的增强机体免疫功能的作用，且其作用优于对照药物。
与现有技术相比，本发明选用豹蛙酶和甘露聚糖肽组方，有协同增效的效果，制成的药物既能提高机体的免疫功能，又能直接抑杀肿瘤细胞，效果显著，达到了发明目的。
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
具体实施方式
实施例1
组方：豹蛙酶10mg、甘露聚糖肽10mg
所述注射剂的制备工艺为：取上述豹蛙酶、甘露聚糖肽混合，加入注射用水至1000ml，用0.45μm的微孔滤膜过滤，搅拌20分钟使混合均匀，灌封、灭菌即得注射制剂。
用法用量：静脉注射或静脉滴注，一次10-50ml，一日1次。
实施例2
组方：豹蛙酶5mg、甘露聚糖肽5mg
制备工艺为：取上述豹蛙酶、甘露聚糖肽及甘油250ml、乳糖100g、甘露醇150g混合均匀，加注射用水至1000ml，调节药液PH值为7，过滤，灌装，冷冻干燥，即得冻干粉针。冻干工艺为：将灌装好的西林瓶半压塞后送入冻干机，缓慢冷冻至－15℃以下，抽真空至5-10Pa，控制加热升温速度不超过4℃/h进行升华，升华10个小时后，设定搁板温度为20℃进行第二次干燥，当制品温度和搁板温度接近时，恒定温度干燥0.5-1小时后全压塞。
用法用量：静脉注射或静脉滴注，一次0.5-5mg，一日1次。
实施例3
组方：豹蛙酶15mg、甘露聚糖肽20mg
制备工艺为：取上述豹蛙酶、甘露聚糖肽混合，同时加入氯化钠10Kg混合，加入注射用水至1000L，调节PH6，用0.22μm的微孔滤膜过滤，搅拌20分钟使混合均匀，分装、灭菌，即得大容量注射液。
用法用量：静脉注射或静脉滴注，一次500-1000ml，一日1次。
实施例4
组方：豹蛙酶10mg、甘露聚糖肽20mg
制备工艺为：取上述豹蛙酶、甘露聚糖肽混合，加入淀粉150g、滑石粉100g，混合，喷雾干燥，整粒，装入胶囊，制成2000粒，即得胶囊剂。
用法用量：口服，一日2次，一次1粒。
实施例5
组方：豹蛙酶10mg、甘露聚糖肽10mg
制备工艺为：取上述豹蛙酶、甘露聚糖肽及400g淀粉、100g微晶纤维素放入混合搅拌机中，混合30min，加入淀粉浆(10%)500g制成软才，经摇摆颗粒机过14目尼龙筛制粒，干燥，干颗粒与硬脂酸镁50g总混，整粒，压成2000片，包糖衣或薄膜衣，即得片剂。
用法用量：口服，一日2次，一次1片。
实施例6
组方：豹蛙酶10mg、甘露聚糖肽5mg
制备工艺为：取上述豹蛙酶、甘露聚糖肽混合，另取豆油300ml、吐温-80180ml、乙基纤维素200g混合均匀，将上述药粉加入到混合液中使分散均匀，制成1000丸，即得软胶囊剂。
用法用量：口服，一日1次，一次1粒。
实施例7
组方：豹蛙酶10mg、甘露聚糖肽20mg
制备工艺为：取上述豹蛙酶、甘露聚糖肽混合，另取蔗糖9000g溶于沸水中，与上述药粉混合均匀，制粒，干燥，即得颗粒剂。
用法用量：口服，一日2次，一次2-5g。
实施例8
组方：豹蛙酶15mg、甘露聚糖肽10mg
制备工艺为：取上述豹蛙酶、甘露聚糖肽混合，再加入单糖浆200g、苯甲酸钠1g，煮沸溶解，加水至1000ml，搅匀，滤过，灌封，即得口服液体制剂。
用法用量：口服，一日2次，一次5ml。
实施例9
组方：豹蛙酶15mg、甘露聚糖肽5mg
制备工艺为：取上述豹蛙酶、甘露聚糖肽混合，将聚乙二醇400200g熔融后加入以上药物粉末中混合均匀，滴入甲基硅油中中冷却，制成1000丸，即得滴丸剂。
用法用量：口服，一日1次，一次1粒。
Claims (6)
1.一种治疗肿瘤的药物组合物，其特征在于：所述药物组合物按照重量组分计算，由豹蛙酶5-15、甘露聚糖肽5-20及辅料制备而成。
2.根据权利要求1所述治疗肿瘤的药物组合物，其特征在于：所述组合物按照重量组分计算，由豹蛙酶5-10、甘露聚糖肽5-10及辅料制备而成。
3.根据权利要求1所述治疗肿瘤的药物组合物，其特征在于：所述治疗肿瘤的药物组合物按照重量组分计算，由豹蛙酶10、甘露聚糖肽10及辅料制备而成。
4.制备如权利要求1-3中任一项所述治疗肿瘤的药物组合物的方法，其特征在于：将豹蛙酶、甘露聚糖肽按照确定的比例混合均匀，然后按照常规方法制备成常规制剂。
5.根据权利要求4所述制备治疗肿瘤的药物组合物的方法，其特征在于：所述常规制剂选自：片剂、胶囊剂、口含剂、颗粒剂、丸剂、散剂、膏剂、丹剂、溶液剂、注射制剂、栓剂、霜剂、喷雾剂或贴剂。
6.根据权利要求5所述制备治疗肿瘤的药物组合物的方法，其特征在于：所述常规制剂是注射液、注射用冻干粉针、大输液、硬胶囊、软胶囊剂、片剂、颗粒剂或丸剂。
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