CN1634584A - 一种含抗代谢类药物的抗癌药物组合物 - Google Patents
一种含抗代谢类药物的抗癌药物组合物 Download PDFInfo
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- CN1634584A CN1634584A CN 200410036099 CN200410036099A CN1634584A CN 1634584 A CN1634584 A CN 1634584A CN 200410036099 CN200410036099 CN 200410036099 CN 200410036099 A CN200410036099 A CN 200410036099A CN 1634584 A CN1634584 A CN 1634584A
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Abstract
一种抗癌药物组合物，属于药物技术领域。包括药用辅料和抗代谢类药物。其中抗代谢类药物可有效地破坏肿瘤细胞内的DNA和/或蛋白质合成及修复功能，从而抑制肿瘤细胞的生长，而药用辅料主要为生物可容性可降解吸收的高分子多聚物，在其降解吸收的过程中能将抗代谢类药物缓慢释放于肿瘤局部，因此在明显降低其全身毒性反应的同时还可于肿瘤局部维持有效药物浓度。肿瘤局部放置该组合物还能选择性地提高肿瘤局部的药物浓度，增强化疗药物及放射治疗等非手术疗法的治疗效果。
Description
(一)技术领域
本发明涉及一种抗癌药物组合物，属于药物技术领域。
(二)背景技术
实体肿瘤的治疗主要包括手术、放疗及化疗等方法。在所用的各种化疗药物中，抗代谢类药物的作用效果较为明显，已广泛应用于多种恶性肿瘤。然而，进一步研究发现，实体肿瘤过度膨胀性增生，其间质压力、组织弹性压力、流体压力及间质的粘稠度均较其周围正常组织为高，因此，常规化疗，难于肿瘤局部形成有效药物浓度(参见孔庆忠等“瘤内放置顺铂加系统卡莫司汀治疗大鼠脑肿瘤”《外科肿瘤杂志》69期76-82页(1998年)(KongQ et al.，J Surg Oncol.1998 Oct；69(2)：76-82)，单纯提高给药剂量又受到全身反应的限制。因此，本发明的一个具体的主题是抗癌药物组合物，所述抗癌药物组合物含抗代谢类药物。
(三)发明内容
本发明针对现有技术的不足，提供一种抗癌药物组合物。
本发明抗癌药物组合物包括抗代谢类药物和药用辅料，其中抗代谢药物选自脱氧氟尿苷(Doxifloridine，氟铁龙)、5-脱氧氟尿苷、氟脲苷(flurdine)、丙硫氧嘧啶、丁基氟尿嘧啶、5-氟嘧啶醇、磺巯嘌呤钠、巯咪嘌呤、6-巯基嘌呤、6-氨基嘌呤盐酸盐、甘氨硫嘌呤、硫乌嘌呤、溶癌呤、硫酸肼、卫康醇、亚丝醌、芬可洛宁、异优散酮、抑素、氯屈磷酸、氯屈磷酸二钠、环亮氨酸、地查枸林、甲黄酸地查枸林、白瑞夸尔、奥昔嘌醇、澳马利特、溴巴酸(钠)、百利德定、溴脲苷、氟脲己胺、10-乙基去氮氨蝶呤(氨基扑发宁)、氟甲氨蝶呤、二氧甲氨蝶呤、5，10-双去氮四氢叶酸、甲满蝶呤、丁巯嘌呤、丁克他酰胺、胱氮杂乌苷、卡莫氟(Carmofur)、尿嘧啶替加氟、戊稀吲哚、硫若星、优福定(Tegafur-Uracil，UFT)、甲氧檗因、甲酰溶肉瘤素、氨(基)蝶呤(aminopterin)、氨蝶呤钠(AminopterinSodium)、8-氮鸟嘌呤(8-azaguanine)、二甲胺腺苷、(硝基)咪唑硫嘌呤(azathioprine)、尿嘧啶、巯甲脲嘧啶、重氮丝氨酸(azaserine)、雷替曲塞(Raltitrexed)、雷替曲占、盐酸洛拉曲克、槐定碱、甲酰四氢叶酸、甲基四氢高叶酸、唑来磷酸、替莫唑胺、比卡鲁胺、门冬酰胺酶(L-Asparaginase，左旋门冬酰胺)、左亚叶酸钙、亚叶酸钙(CalciumLevofolinate、甲酰四氢叶酸钙)、坤来斯巴、三嗪苯酰胺、曲麦克特、曲马多、氯巴比酸、5-重氮脲嘧啶、吡拉西坦、托泊替康、盐酸拓扑替康、环胞苷(cyclotidine，Cyclocytidine]、羟基胍、5-氟尿嘧啶核苷、5-氟尿嘧啶脱氧核苷又称氟脲嘧啶脱氧核苷(floxuridine)、甘油柑碱、阿垒可散、异恶唑醋酸、氨格鲁米特(乙苯胺哌啶酮，氨基导眠能，氨格鲁米特)、氨萘非特、氯胞苷、阿他美坦、氮杂胞苷(Azacitidine，5-氮杂胞苷，阿托胞苷，氮胞苷)、抗瘤氨酸(异芳芥，异位溶肉瘤素)、脱氧氮杂胞苷、右雷佐生[Dexrazoxane]、克雷斯托、克尼斯他酸、克拉利平、克拉利宾、加洛他滨[Galocitabine]、吉西他滨[Gemcitabine]、伊巴他滨[Ibacitabine]、依诺他滨[Enocitabine]、安西他滨[Ancitabine]、地西他滨[Decitabine]、氟西他滨(Flurocitabine)、卡培他滨(Capecitabine)、依诺他滨、咪唑他滨、克兰非鲁、卡拉酰胺、卡唑酰胺、卡巴萘醌、偶氮苯溴丙胺、姜黄素、姜黄素二酮、酮曲沙、三甲曲沙、斯泼古宁、去氧斯泼古宁、萘脲磷酸胺、氯化地特卡里、磷酸氟达那苷、氟苄噻酮、藤黄酸、戈舍瑞林、氮枸岭、海尼白瑞宁、肌苷二醛、氯苯氨啶、二溴甘露醇(Dibromomannitol，Mitobronitol)、二溴卫矛醇(Mitolactol)、柯替波斯地、益若蓝精、多潘(Chlorethylaminouracil，Dopan)、美洛格瑞、丙米腙、迷托醌、米托坦、法扎拉滨(Fazarabine)、氟达拉滨(fludarabine)、克拉屈滨(cladribine)，戊糖苷(pentostatin)、苯来宁、苯来美特、磷嘧阿泽胺、匹毛尼唑、聚烯瑞尼酸、蝶酰天冬氨酸、蝶酰三谷氨酸、嘌米舌泊、利波腺苷、双曲秦、裂裥多糖、溴茴丙烯酸钠、氨偶氮苄、曲丁磺酯、三乙密胺、三亚胺醌、曲西瑞宾、磷酸曲西瑞宾、雷藤素甲、曲普瑞林、九布洛唑、优福定、维他命B-17、威麦宁、z-氮杂腺苷、扎西胞苷、依匹哌啶[Epipropidine]、阿莫诺期、阿多来新(Adozelesin)、阿克罗宁(Acronine)、阿拉诺新(Alanosine)、阿美蒽醌(Ametantrone)、阿那曲唑、阿那西戎、阿那昔酮(Anaxirone)、阿斯吲醒、阿西维辛(Acivicin)、阿替韦啶[Atevirdine]、艾多昔芬(idoxifene)、癌可萘、昂究吉宁、个鲁达卜辛、抗瘤酮、抗瘤酮A-10、阿沙芳、芦笋精、芥吲酸、白瑞夸尔(钠)、(盐酸)必桑郡、格拉司琼、托烷司琼、氮烯咪胺、恩丹西酮、胸腺素、曲马多、甲磺酸伊马替尼、双氯芬酸、沙利度胺、托氟杀星、托瑞米芬、安溴索、高乌甲素、耐普等因、胸腺肽、氟他胺、乙亚胺、胺苯、氧化新喹、N-甲基甲酰胺、牢可达唑、蒽甲硫脲、奥昔舒仑、氧化石蒜碱、泊芬撒尔、泊泽尼普定、戊必罗尔、螺氯丙醇、原白头翁素、佳代胞、雷替尼卜定、生索拉德、素道霉素、茄软酯碱、亚胺醌、斯替苯嘧啶、泰莫佐罗、台多西隆、硫奥里发新、硝氨丫啶或安丫啶中的一种或多种。优选6-巯基嘌呤、脱氧氟尿苷、氟脲苷、卡莫氟、加洛他滨、伊巴他滨、依诺他滨、安西他滨、地西他滨、氟西他滨、依诺他滨、咪唑他滨、迷托醌、米托坦、5-氟尿嘧啶核苷、卡培他滨、吉西他滨、氟达拉滨、克拉屈滨或戊糖苷。
上述抗代谢类药物在组合物中的含量为0.01％-99.99％，以1％-50％为佳，以5％-30％为最佳，以上均为重量百分比。
药用辅料包括下列之一或其组合：
(1)生物相容性多聚物，包括生物可降解的或生物不可降解的多聚物及其混合物或共聚物，(2)水溶性低分子化合物，或/和(3)用于实现针剂和缓释剂等药物剂型的合适的添加剂及赋型剂。
上述生物可降解的多聚物包括天然的和/或合成的多聚物。合成的多聚物如，但不限于，聚酐类、聚羟基酸、聚酯(polyesters)、聚酰胺(polyamides)、聚原酸酯(polyorthoesters)、聚磷腈(polyphosphazenes)、对羧苯基丙烷(p-CPP)、葵二酸(sebacicacid)、聚苯丙生(对羧苯基丙烷与葵二酸的共聚物)等；天然的多聚物如，但不限于，蛋白质及多糖，包括透明质酸、胶原蛋白、明胶、白蛋白等。
上述聚酐类可选用，但不限于，芳香聚酐、脂肪族聚酐；其中芳香聚酐降解较慢，熔点高，有机溶剂中溶解度低，然而，芳香聚酐与脂肪族聚酐的共聚物却较为理想(美国专利4757128)。其中的代表物是聚苯丙生(对羧苯基丙烷(p-CPP)与葵二酸(SA)的共聚物)，而对羧苯基丙烷为芳香聚酐，葵二酸则是一个芳香二酸与一个脂肪二酸的共聚物。可选用的其它芳香或脂肪族聚酐的共聚物在其它美国专利中已有详细描述(US 4857311；4888176；4789724)。
上述聚羟基酸可选用，但不限于，聚乳酸(PLA)、聚乙醇酸(PGA)、聚乳酸(PLA)与聚乙醇酸的混合物、乙醇酸和羟基羧酸的共聚物(PLGA)；当PLA和PLGA混合时，其含量重量百分比分别为0.1-99.9％和99.9-0.1％。聚乳酸的分子量可为，但不限于，5000-100,000，但以10,000-50000为优选，以10,000-20000为最优选；聚乙醇酸的分子量可为，但不限于，5000-100,000，但以10,000-50000为优选，以10,000-20000为最优选；以上聚羟基酸可单选或多选。当单选时，以聚乳酸(PLA)或羟基羧酸和乙醇酸的共聚物(PLGA)为优选，共聚物的分子量可为，但不限于，1000-100,000，但以10,000-50000为优选；以10,000-20000为最优选；当多选时，以高分子多聚物或不同高分子多聚物组成的复合多聚物或共聚物为优选，以含不同分子量聚乳酸或葵二酸的复合多聚物或共聚物为最优选，如，但不限于，分子量为5000到10000的聚乳酸与分子量为20000到50000的聚乳酸混合、分子量为10000到20000的聚乳酸与分子量为30000到80000的PLGA混合、分子量为5000到10000的聚乳酸与葵二酸混合、分子量为30000到80000的PLGA与葵二酸混合。
上述生物不可降解的多聚物包括，但不限于：有机硅聚合物、乙烯乙酸乙烯酯共聚物(Ethelene-vinyl acetate copolymer，EVAc)、聚丙烯腈(polyacrylonitriles)，聚氨基甲酸酯(polyurethanes)及聚磷腈(polyphosphazenes)等。组合物可通过直接扩散的方式将有效成分释放出来。
为调节药物释放速度或改变本发明抗癌药物组合物的其它特性，可以改变聚合物的单体成分或分子量、添加或调节药用辅料的组成及配比，添加水溶性低分子化合物，如，但不限于，各种糖和盐等。其中糖可为，但不限于，木糖醇、低聚糖及甲壳素等，其中盐可为但不限于，钾盐和钠盐等。
本发明抗癌药物组合物所用的药用辅料可为上述药用辅料中的任何一种或多种物质，但以水溶性高分子聚合物为主选，在各种高分子聚合物中，以聚乳酸、葵二酸、含聚乳酸或葵二酸的高分子多聚物的混合物或共聚物为首选，混合物和共聚物可选自，但不限于，PLGA、乙醇酸和羟基羧酸的混合物、葵二酸与芳香聚酐或脂肪族聚酐的混合物或共聚物。乙醇酸和羟基羧酸的共混比例是10/90-90/10(重量)，最好是25/75-75/25(重量)。共混的方法是任意的。乙醇酸和羟基羧酸共聚时的含量分别为重量百分比10-90％和90-10％。芳香聚酐的代表物是对羧苯基丙烷(p-CPP)，对羧苯基丙烷(p-CPP)与葵二酸共聚时的含量分别为重量百分比10-60％和20-90％，共混重量比是10-40∶50-90，最好是重量比15-30∶65-85。
药用辅料在《药用辅料大全》(第123页，四川科学技术出版社1993年出版，罗明生和高天惠主编)中已有详细描述。另外，中国专利(申请号96115937.5；91109723.6；9710703.3；01803562.0)及美国发明专利(专利号5,651,986)也列举了某些药用辅料。包括充填剂、增溶剂、吸收促进剂、成膜剂、胶凝剂、制(或致)孔剂、赋型剂或阻止剂。以上药用辅料有的具有多重作用，因此有的同种物质被列为不同的类别。本发明抗实体肿瘤组合物可选用的支持物可为上述药用辅料中的任何一种或多种物质，并不完全根据其分类或定义来限制组合物的技术特征。
抗癌药物组合物的有效成分抗代谢类药物可均匀地包装于整个药用辅料中，也可包装于载体支持物中心或其表面；可通过直接扩散或经多聚物降解的方式或如此两种方式将有效成分释放。除此之外，抗癌药物组合物的有效成分抗代谢类药物也可均匀地包装于脂质体中，或以现有技术方法制成微球。
本发明的特点在于所用的药用辅料除高分子聚合物外，还含有上述任意一种或多种其它药用辅料。添加的药用辅料统称为添加剂。添加剂可根据其功能分为充填剂、致孔剂、赋型剂、分散剂、等渗剂、保存剂、阻止剂、增溶剂、吸收促进剂、成膜剂、胶凝剂等。
药用辅料还可为流质，如，但不限于芝麻油、混悬液、蒸馏水、生理冲液、以及半固态物质，如(但不限于)果冻、糊剂、软膏等，上述药用辅料适用于含或不含添加剂的组合物。
本发明抗癌药物组合物可制成多种剂型。如，但不限于，针剂、混悬液、软膏、胶囊及缓释剂等；呈各种形状，如，但不限于，颗粒样、片状、球形、块状、针状、棒状及膜状。在各种剂型中，以体内缓慢释放剂为主。上述剂型和形状适用于含或不含添加剂的组合物。
本发明抗癌药物组合物可使常规化疗、免疫治疗、高热治疗、光化学治疗、电疗、生物治疗、激素治疗、磁疗、超声治疗、放疗及基因治疗等方法的作用效果加强。因此在局部缓慢释放的同时可与上述非手术疗法合用，从而使其抗癌效果进一步加强。
给药途径
本发明抗癌药物组合物可经各种途径应用，如静脉、动脉、皮下、肌肉、皮内、腔内、瘤内、瘤周等。给药途径取决于多种因素，为于肿瘤所在部位获有效浓度，药物可经其它多种途径给予，如选择性地动脉灌注，腔内灌注(intracavitary)，腹腔(intraperitoneal)或胸腔(intrapleural)及椎管内给药。在多种途径中，以局部给药，如以选择性动脉、瘤内、瘤周注射为主，以瘤内、瘤周或瘤腔缓慢释放的形式为优选，如可选用可种缓释泵及缓释胶囊或体内缓释植入剂。
给药剂量
抗癌药物的用量取决于很多因素，如，但不限于，肿瘤体积、病人体重、给药方式、病情进展情况及治疗反应。但常用的有效剂量为0.01-80毫克/公斤体重，以1-50毫克/公斤体重为理想，以2-10毫克/公斤体重为最理想。在抗代谢类药物组合物中所占的比例因具体情况而定，可从0.01％-99.99％，以1％-80％为佳，以2％-50％为最佳。以上均为重量百分比。
本发明抗癌药物组合物可以用于制备治疗人的各种实体肿瘤，包括起源于大脑、中枢神经系统、肾脏、肝、胆囊、头颈部、口腔、甲状腺、皮肤、黏膜、腺体、血管、骨组织、淋巴结、肺脏、食管、胃、乳腺、胰腺、眼睛、鼻咽部、子宫、卵巢、子宫内膜、子宫颈、前列腺、膀胱、结肠、直肠的原发或转移的癌或肉瘤或癌肉瘤的药物。
本发明抗癌药物组合物也可以用于治疗宠物及动物的各种实体肿瘤，当用于治疗宠物及动物的各种实体肿瘤时，本发明抗癌药物组合物的有效成份最好选用种属特异性的物质。
本发明抗癌药物组合物中还可加入其它药用成分，如，但不限于，抗菌素、止疼药、抗凝药、止血药等。以上药用成分可单选或多选，可加入到含或不含添加剂的组合物，其含量因具体需要而定。
本发明抗癌药物组合物可通过以下方式应用。
将上述有效成分抗代谢类药物包装于药用辅料中，然后局部应用。该组合物可经各种途径给药，以局部给药，如选择性动脉注射和直接瘤体内注射为佳，其中又以局部缓慢释放为最佳。当局部应用时，本发明抗癌药物组合物可直接置于原发或转移的实体肿瘤周围或瘤体内，也可直接置于原发或转移的实体肿瘤全部或部分切除后所形成的腔内。
本发明抗癌药物组合物主要成份以生物可容性物质为支持物，故不引起异物反应。支持物体内放置后可降解吸收，故不再手术取出。因在肿瘤局部释放所含药物，从而选择性地提高并延长局部药物浓度，同时可降低由常规途径给药所造成的全身毒性反应。
抗癌药物组合物可制成各种形状，其中有效成份抗代谢类药物的含量因不同需要而定。可从0.1％-99.9％，以1％-50％为佳，以5％-30％为最佳。该抗癌药物组合物可制成各种剂型，如，但不限于，针剂、混悬液、软膏、胶囊、及植入缓释剂等；呈各种形状，如，但不限于，颗粒样、片状、球形、块状、针状、棒状及膜样；可经各种途径给药，以动脉途径为佳，肿瘤体内直接放置为最佳。本发明的最佳剂型为生物可容性、可降解吸收的植入缓释剂，可因不同临床需要而制成各种形状。其主要成份的包装方法和步骤在美国专利中(US5651986)已有详细描述，包括若干种制备缓释制剂的方法：如，但不限于，(i)把载体支持物粉末与药物混合然后压制成植入剂，即所谓的混合法；(ii)把载体支持物熔化，与待包装的药物相混合，然后固体冷却，即所谓的熔融法；(iii)把载体支持物溶解于溶剂中，把待包装的药物溶解或分散于聚合物溶液中，然后蒸发溶剂，乾燥，即所谓的溶解法。其中溶解法可用以微球的制造，其方法是任意的，抗实体肿瘤组合物也可包装脂质体中。
本发明抗癌药物组合物制备技术的特点在于将一种或多种抗代谢类药物包装于药用辅料中，按照比例将有效成份和药用辅料溶解，待充份混匀之后乾燥。待乾燥后立即成形并消毒分装。局部放置，不仅能够克服全身给药带来的毒性反应，而且解决了肿瘤局部药物浓度过低以及细胞对药物的敏感性问题。
试验一、抗代谢类药物的体内抑瘤作用。
以小白鼠为试验对象，将2×105个肿瘤细胞皮下注射于其季肋部，待肿瘤生长7天后将其分为以下10组(见表1)。第一组为对照，第2到10组为治疗组，其中，第2到4组为卡莫氟，第5到7组为吉西他滨，第8到10组为克拉屈滨。药物分别经腹腔注射(ip)、瘤内注射(it)和瘤内放置(itp)。剂量均为5mg/kg。治疗后第10天测量肿瘤体积大小，比较治疗效果(见表1)。
表1
| 试验组(n) | 所受治疗 | 肿瘤体积(cm3) | P值 |
| 1(6) | 对照 | 38.5±12.3 | |
| 2(6) | 卡莫氟(ip) | 22±6.3 | ＜0.05 |
| 3(6) | 卡莫氟(it) | 12±5.5 | ＜0.01 |
| 4(6) | 卡莫氟(itp) | 6±3.6 | ＜0.01 |
| 5(6) | 吉西他滨(ip) | 26±6 | ＜0.01 |
| 6(6) | 吉西他滨(it) | 20±3.6 | ＜0.01 |
| 7(6) | 吉西他滨(itp) | 10±2.6 | ＜0.001 |
| 8(6) | 克拉屈滨(ip) | 26±5.6 | ＜0.001 |
| 9(6) | 克拉屈滨(it) | 16±3.6 | ＜0.001 |
| 10(6) | 克拉屈滨(itp) | 8±0.6 | ＜0.001 |
试验二、抗代谢类药物的体内抑瘤作用。
以大白鼠为试验对象，将2×105个肿瘤细胞皮下注射于其季肋部，待肿瘤生长14天后将其分为以下10组(见表2)。第一组为对照，第2到10组为治疗组，其中，第2到4组为雷替曲塞，第5到7组为6-巯基嘌呤，第8到10组为雷替曲占。药物分别经腹腔注射(ip)、瘤内注射(it)和瘤内放置(itp)。剂量均为5mg/kg。治疗后第10天测量肿瘤体积大小，比较治疗效果(见表2)。
表2
| 试验组(n) | 所受治疗 | 肿瘤体积(cm3) | P值 |
| 1(6) | 对照 | 88±12 | |
| 2(6) | 雷替曲塞(ip) | 48±5.3 | ＜0.05 |
| 3(6) | 雷替曲塞(it) | 58±7.3 | ＜0.01 |
| 4(6) | 雷替曲塞(itp) | 56±6.4 | ＜0.01 |
| 5(6) | 6-巯基嘌呤(ip) | 48±4.0 | ＜0.01 |
| 6(6) | 6-巯基嘌呤(it) | 44±3.5 | ＜0.01 |
| 7(6) | 6-巯基嘌呤(itp) | 33±3.3 | ＜0.001 |
| 8(6) | 雷替曲占(ip) | 32±3.6 | ＜0.001 |
| 9(6) | 雷替曲占(it) | 24±2.6 | ＜0.001 |
| 10(6) | 雷替曲占(itp) | 18±1.6 | ＜0.001 |
注解：BD：苯并咪唑；其BD为聚(ADP-核糖)聚合酶抑制剂，而6-巯基嘌呤、脱氧氟尿苷、氟脲苷、巯嘌呤均为抗代谢类药物。
试验一和二的结果表明，所用各种抗代谢类药物在该浓度时对肿瘤细胞生长均有明显的抑制作用，但以局部用药效果较为明显，其中局部放置最为明显。局部放置不仅能够有效地抑制肿瘤生长，而且能够显著降低药物的全身毒性反应。
本发明加工成抗癌药物组合物的的制备方法如下：
1.将称重的药用辅料放入容器中，加一定量的有机溶剂溶解均匀，有机溶剂的量不严格限定，以充分溶解为宜。
2.加入称重之抗癌有效成份重新摇匀。抗癌有效成份与药用辅料的用量比例因具体要求而定。
3.去除有机溶剂。真空干燥或低温干燥法均可。
4.将干燥后的固体组合物根据需要制成各种形状。
5.分装后射线灭菌(射线剂量因体积而异)备用。也可用其它方法灭菌。
总之，含有以上有效成分的抗癌药物组合物可制成任意剂型或形状，抗癌复合物的有效成分为任意一种(或多种)抗代谢类药物，但以缓慢释放剂为优选。
(四)具体实施方式
下面结合实施例对本发明做进一步说明，但不限于此。
实施例1.
将90mg分子量为10000的PLGA(羟基乙酸和乙醇酸的共聚物)放入容器中，加100毫升二氯甲烷，溶解混匀后，加入10mg吉西他滨，重新摇匀后真空干燥去除有机溶剂。将干燥后的固体组合物立即成形，分装后射线灭菌，得含重量百分比10％吉西他滨的抗癌药物组合物。该抗癌药物组合物在体外生理盐水中的释药时间为15-20天，在小鼠皮下的释药时间为30-40天左右。
实施例2.如实施例1所述，所不同的是抗代谢类药物为：
(a)1-50％脱氧氟尿苷、5-脱氧氟尿苷、氟脲苷、丙硫氧嘧啶、丁基氟尿嘧啶、双喃氟啶、5-氟嘧啶醇、磺巯嘌呤钠、巯咪嘌呤、6-巯基嘌呤、6-氨基嘌呤盐酸盐、甘氨硫嘌呤、硫乌嘌呤、溶癌呤、硫酸肼、卫康醇、亚丝醌、芬可洛宁、异优散酮、抑素、氯屈磷酸、氯屈磷酸二钠、环亮氨酸、地查枸林、甲黄酸地查枸林、白瑞夸尔、奥昔嘌醇、澳马利特、溴巴酸(钠)、百利德定、溴脲苷、氟脲己胺、10-乙基去氮氨蝶呤、氟甲氨蝶呤、二氧甲氨蝶呤、5，10-双去氮四氢叶酸、甲满蝶呤、丁巯嘌呤、丁克他酰胺、胱氮杂乌苷、卡莫氟、尿嘧啶替加氟、戊稀吲哚、硫若星、优福定、甲氧檗因、甲酰溶肉瘤素、氨(基)蝶呤、氨蝶呤钠、8-氮鸟嘌呤、二甲胺腺苷、(硝基)咪唑硫嘌呤、或尿嘧啶；或
(b)1-50％巯甲脲嘧啶、重氮丝氨酸、雷替曲塞、雷替曲占、盐酸洛拉曲克、槐定碱、甲酰四氢叶酸、甲基四氢高叶酸、唑来磷酸、替莫唑胺、比卡鲁胺、门冬酰胺酶、左亚叶酸钙、亚叶酸钙、坤来斯巴、三嗪苯酰胺、曲麦克特、曲马多、氯巴比酸、5-重氮脲嘧啶、吡拉西坦、托泊替康、盐酸拓扑替康、阿糖胞苷、环胞苷、羟基胍、5-氟尿嘧啶核苷、5-氟尿嘧啶脱氧核苷、氟脲嘧啶脱氧核苷、甘油柑碱、阿垒可散、异恶唑醋酸、氨格鲁米特、氨萘非特、氯胞苷、阿他美坦、氮杂胞苷、抗瘤氨酸、脱氧氮杂胞苷、右雷佐生、克雷斯托、克尼斯他酸、克拉利平、克拉利宾、加洛他滨、伊巴他滨、依诺他滨、安西他滨、地西他滨、氟西他滨、卡培他滨、依诺他滨或咪唑他滨；或
(c)1-50％克兰非鲁、卡拉酰胺、卡唑酰胺、卡巴萘醌、偶氮苯溴丙胺、姜黄素、姜黄素二酮、酮曲沙、三甲曲沙、斯泼古宁、去氧斯泼古宁、萘脲磷酸胺、氯化地特卡里、磷酸氟达那苷、氟苄噻酮、藤黄酸、戈舍瑞林、氮枸岭、海尼白瑞宁、肌苷二醛、氯苯氨啶、二溴甘露醇、二溴卫矛醇、柯替波斯地、益若蓝精、多潘、美洛格瑞、丙米腙、迷托醌、米托坦、法扎拉滨、氟达拉滨、克拉屈滨、戊糖苷、苯来宁、苯来美特、磷嘧阿泽胺、匹毛尼唑、聚烯瑞尼酸、蝶酰天冬氨酸、蝶酰三谷氨酸、嘌米舌泊、利波腺苷、双曲秦、裂裥多糖、溴茴丙烯酸钠、氨偶氮苄、曲丁磺酯、三乙密胺、三亚胺醌、曲西瑞宾、磷酸曲西瑞宾、雷藤素甲、曲普瑞林、九布洛唑、优福定、维他命B-17、威麦宁或z-氮杂腺苷或
(d)1-50％扎西胞苷、依匹哌啶、阿莫诺期、阿多来新、阿克罗宁、阿拉诺新、阿美蒽醌、阿那曲唑、阿那西戎、阿那昔酮、阿斯吲醒、阿西维辛、阿替韦啶、艾多昔芬、癌可萘、昂究吉宁、个鲁达卜辛、抗瘤酮、抗瘤酮A-10、阿沙芳、芦笋精、芥吲酸、白瑞夸尔(钠)、(盐酸)必桑郡、格拉司琼、托烷司琼、氮烯咪胺、恩丹西酮、胸腺素、曲马多、甲磺酸伊马替尼、双氯芬酸、沙利度胺、托氟杀星、托瑞米芬、安溴索、高乌甲素、耐普等因、胸腺肽、氟他胺、乙亚胺、胺苯、氧化新喹、N-甲基甲酰胺、牢可达唑、蒽甲硫脲、奥昔舒仑、氧化石蒜碱、泊芬撒尔、泊泽尼普定、戊必罗尔、螺氯丙醇、原白头翁素、佳代胞、雷替尼卜定、生索拉德、素道霉素、茄软酯碱、亚胺醌、斯替苯嘧啶、泰莫佐罗、台多西隆、硫奥里发新、硝氨丫啶或安丫啶。
以上均为重量百分比。
实施例3.
将80mg药用辅料乙烯乙酸乙烯酯共聚物(EVAc)放入容器中，加入100毫升二氯甲烷溶解混匀后，加入20mg雷替曲塞，重新摇匀后真空干燥去除有机溶剂。将干燥后的固体组合物立即成形，分装后射线灭菌，得含重量百分比20％雷替曲塞的抗癌药物组合物。该抗癌药物组合物在体外生理盐水中的释药时间为14-24天，在小鼠皮下的释药时间为20-35天左右。
实施例4.如实施例3所述，所不同的是抗代谢类药物为：
(a)5-30％6-巯基嘌呤、脱氧氟尿苷、氟脲苷、卡莫氟、加洛他滨、伊巴他滨、依诺他滨或安西他滨；或
(b)5-30％地西他滨、氟西他滨、依诺他滨、咪唑他滨、迷托醌、米托坦或5-氟尿嘧啶核苷；或
(c)5-30％雷替曲占、卡培他滨、吉西他滨、氟达拉滨、克拉屈滨或戊糖苷。
以上均为重量百分比。
实施例5.
将80mg聚苯丙生(对羧苯基丙烷(p-CPP)∶葵二酸(SA)共聚物)放入容器中，加入100毫升二氯甲烷溶解混匀后，加入20mg雷替曲塞，重新摇匀后真空干燥去除有机溶剂。将干燥后的固体组合物立即成形，分装后射线灭菌，得含重量百分比20％雷替曲塞的抗癌药物组合物。该抗癌药物组合物在体外生理盐水中的释药时间为15-25天，在小鼠皮下的释药时间为25-40天左右。
实施例6.如实施例5所述，所不同的是抗代谢类药物为：
(a)5-30％6-巯基嘌呤、脱氧氟尿苷、氟脲苷、卡莫氟、加洛他滨、伊巴他滨、依诺他滨或安西他滨；或
(b)5-30％地西他滨、氟西他滨、依诺他滨、咪唑他滨、迷托醌、米托坦或5-氟尿嘧啶核苷；或
(c)5-30％雷替曲占、卡培他滨、吉西他滨、氟达拉滨、克拉屈滨或戊糖苷。
以上均为重量百分比。
实施例7.如实施例1、3或5所述，所不同的是所用药用辅料为下列a)-d)之一：
a)分子量为5000-15000、10000-20000、25000-35000或30000-50000的聚乳酸(PLA)；
b)分子量为5000-15000、10000-20000、25000-35000或30000-50000的聚乙醇酸和羟基乙酸的共聚物(PLGA)；
c)乙烯乙酸乙烯酯共聚物(EVAc)；
d)对羧苯基丙烷(p-CPP)∶葵二酸(SA)共聚物(聚苯丙生)，p-CPP和SA的重量比为10∶90、20∶80、30∶70、40∶60、50∶50或60∶40。
如上所述，本发明抗癌药物组合物的制备方法可根据具体情况加以选择。抗癌药物组合物可用现有的方法制成各种剂型，因此，以上实施例仅用于说明，而并非局限本发明的应用。该组合物除单独应用外，还可与许多治疗措施联合应用：如与放射治疗、高热治疗、免疫治疗、光疗、电疗等联合应用。局部放置应用该组合物作为增效剂具有独特的优点及很高的临床应用价值。当该组合物与其它治疗措施联合应用时，该组合物可同时或先于其它治疗措施。
Claims (9)
1.一种抗癌药物组合物，其特征在于包括抗代谢类药物和药用辅料，所述抗代谢类药物选自脱氧氟尿苷、5-脱氧氟尿苷、氟脲苷、丙硫氧嘧啶、丁基氟尿嘧啶、双喃氟啶、5-氟嘧啶醇、磺巯嘌呤钠、巯咪嘌呤、6-巯基嘌呤、6-氨基嘌呤盐酸盐、甘氨硫嘌呤、硫乌嘌呤、溶癌呤、硫酸肼、卫康醇、亚丝醌、芬可洛宁、异优散酮、抑素、氯屈磷酸、氯屈磷酸二钠、环亮氨酸、地查枸林、甲黄酸地查枸林、白瑞夸尔、奥昔嘌醇、澳马利特、溴巴酸(钠)、百利德定、溴脲苷、氟脲己胺、10-乙基去氮氨蝶呤、氟甲氨蝶呤、二氧甲氨蝶呤、5，10-双去氮四氢叶酸、甲满蝶呤、丁巯嘌呤、丁克他酰胺、胱氮杂乌苷、卡莫氟、尿嘧啶替加氟、戊稀吲哚、硫若星、优福定、甲氧檗因、甲酰溶肉瘤素、氨(基)蝶呤、氨蝶呤钠、8-氮鸟嘌呤、二甲胺腺苷、(硝基)咪唑硫嘌呤、尿嘧啶、巯甲脲嘧啶、重氮丝氨酸、雷替曲塞、雷替曲占、盐酸洛拉曲克、槐定碱、甲酰四氢叶酸、甲基四氢高叶酸、唑来磷酸、替莫唑胺、比卡鲁胺、门冬酰胺酶、左亚叶酸钙、亚叶酸钙、坤来斯巴、三嗪苯酰胺、曲麦克特、曲马多、氯巴比酸、5-重氮脲嘧啶、吡拉西坦、托泊替康、盐酸拓扑替康、阿糖胞苷、环胞苷、羟基胍、5-氟尿嘧啶核苷、5-氟尿嘧啶脱氧核苷、氟脲嘧啶脱氧核苷、甘油柑碱、阿垒可散、异恶唑醋酸、氨格鲁米特、氨萘非特、氯胞苷、阿他美坦、氮杂胞苷、抗瘤氨酸、脱氧氮杂胞苷、右雷佐生、克雷斯托、克尼斯他酸、克拉利平、克拉利宾、加洛他滨、吉西他滨、伊巴他滨、依诺他滨、安西他滨、地西他滨、氟西他滨、卡培他滨、依诺他滨、咪唑他滨、克兰非鲁、卡拉酰胺、卡唑酰胺、卡巴萘醌、偶氮苯溴丙胺、姜黄素、姜黄素二酮、酮曲沙、三甲曲沙、斯泼古宁、去氧斯泼古宁、萘脲磷酸胺、氯化地特卡里、磷酸氟达那苷、氟苄噻酮、藤黄酸、戈舍瑞林、氮枸岭、海尼白瑞宁、肌苷二醛、氯苯氨啶、二溴甘露醇、二溴卫矛醇、柯替波斯地、益若蓝精、多潘、美洛格瑞、丙米腙、迷托醌、米托坦、法扎拉滨、氟达拉滨、克拉屈滨、戊糖苷、苯来宁、苯来美特、磷嘧阿泽胺、匹毛尼唑、聚烯瑞尼酸、蝶酰天冬氨酸、蝶酰三谷氨酸、嘌米舌泊、利波腺苷、双曲秦、裂裥多糖、溴茴丙烯酸钠、氨偶氮苄、曲丁磺酯、三乙密胺、三亚胺醌、曲西瑞宾、磷酸曲西瑞宾、雷藤素甲、曲普瑞林、九布洛唑、优福定、维他命B-17、威麦宁、z-氮杂腺苷、扎西胞苷、依匹哌啶、阿莫诺期、阿多来新、阿克罗宁、阿拉诺新、阿美蒽醌、阿那曲唑、阿那西戎、阿那昔酮、阿斯吲醒、阿西维辛、阿替韦啶、艾多昔芬、癌可萘、昂究吉宁、个鲁达卜辛、抗瘤酮、抗瘤酮A-10、阿沙芳、芦笋精、芥吲酸、白瑞夸尔(钠)、(盐酸)必桑郡、格拉司琼、托烷司琼、氮烯咪胺、恩丹西酮、胸腺素、曲马多、甲磺酸伊马替尼、双氯芬酸、沙利度胺、托氟杀星、托瑞米芬、安溴索、高乌甲素、耐普等因、胸腺肽、氟他胺、乙亚胺、胺苯、氧化新喹、N-甲基甲酰胺、牢可达唑、蒽甲硫脲、奥昔舒仑、氧化石蒜碱、泊芬撒尔、泊泽尼普定、戊必罗尔、螺氯丙醇、原白头翁素、佳代胞、雷替尼卜定、生索拉德、素道霉素、茄软酯碱、亚胺醌、斯替苯嘧啶、泰莫佐罗、台多西隆、硫奥里发新、硝氨丫啶或安丫啶中的一种或多种。
2.根据权利要求1所述之抗癌药物组合物，其特征在于抗代谢类药物在组合物中的重量百分比为1-50％。
3.根据权利要求1所述之抗癌药物组合物，其特征在于抗代谢类药物为5-30％ 6-巯基嘌呤、脱氧氟尿苷、氟脲苷、卡莫氟、加洛他滨、伊巴他滨、依诺他滨或安西他滨，均为重量百分比。
4.根据权利要求1所述之抗癌药物组合物，其特征在于抗代谢类药物为5-30％地西他滨、氟西他滨、依诺他滨、咪唑他滨、迷托醌、米托坦或5-氟尿嘧啶核苷，均为重量百分比。
5.根据权利要求1所述之抗癌药物组合物，其特征在于抗代谢类药物为5-30％雷替曲塞、雷替曲占、卡培他滨、吉西他滨、氟达拉滨、克拉屈滨或戊糖苷，均为重量百分比。
6.根据权利要求1所述之抗癌药物组合物，其特征在于药用辅料选自高分子多聚物及其混合物或共聚物。
7.根据权利要求1所述之抗癌药物组合物，其特征在于药用辅料选自聚乳酸、羟基乙酸和乙醇酸的共聚物、乙烯乙酸乙烯酯共聚物、对羧苯基丙烷/葵二酸共聚物及其混合物或共聚物。
8.根据权利要求1所述之抗癌组合物，其特征在于该抗癌组合物瘤内或瘤周放置。
9.权利要求1所述之抗癌药物组合物的应用，用于制备治疗起源于人及动物大脑、中枢神经系统、肾脏、肝、胆囊、头颈部、口腔、甲状腺、皮肤、粘膜、腺体、血管、骨组织、淋巴结、肺脏、食管、胃、乳腺、胰腺、眼睛、鼻咽部、子宫、卵巢、子宫内膜、子宫颈、前列腺、膀胱、结肠或直肠的原发或继发的癌、肉瘤或癌肉瘤的药物。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1304054C (zh) * | 2004-12-29 | 2007-03-14 | 山东蓝金生物工程有限公司 | 一种缓慢释放的抗癌药物组合物 |
| CN100464736C (zh) * | 2006-03-17 | 2009-03-04 | 山东蓝金生物工程有限公司 | 同载抗代谢药物及其增效剂的抗癌缓释注射剂 |
| CN101371820B (zh) * | 2006-01-23 | 2010-06-02 | 济南帅华医药科技有限公司 | 含氨甲喋呤增效剂的抗癌缓释剂 |
| CN101427994B (zh) * | 2006-03-17 | 2011-01-26 | 山东蓝金生物工程有限公司 | 一种含吉西他滨的抗癌药物缓释注射剂 |
| CN101433546B (zh) * | 2007-11-13 | 2011-03-30 | 上海医药工业研究院 | 一种卡培他滨口服缓控释制剂及其制备方法 |
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| US20020032488A1 (en) * | 1994-05-13 | 2002-03-14 | Brekke John H. | Device for regeneration of articular cartilage and other tissue |
| CN1089582C (zh) * | 1996-08-28 | 2002-08-28 | 孔庆忠 | 药物缓慢释放剂 |
| CN1524580A (zh) * | 2003-02-26 | 2004-09-01 | 天津市第一中心医院 | 卡氮芥缓释膜片及其制备方法 |
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| CN1304054C (zh) * | 2004-12-29 | 2007-03-14 | 山东蓝金生物工程有限公司 | 一种缓慢释放的抗癌药物组合物 |
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| CN100464736C (zh) * | 2006-03-17 | 2009-03-04 | 山东蓝金生物工程有限公司 | 同载抗代谢药物及其增效剂的抗癌缓释注射剂 |
| CN101427994B (zh) * | 2006-03-17 | 2011-01-26 | 山东蓝金生物工程有限公司 | 一种含吉西他滨的抗癌药物缓释注射剂 |
| CN101433546B (zh) * | 2007-11-13 | 2011-03-30 | 上海医药工业研究院 | 一种卡培他滨口服缓控释制剂及其制备方法 |
| CN103479586A (zh) * | 2008-05-15 | 2014-01-01 | 细胞基因公司 | 胞苷类似物的口服制剂和其使用方法 |
| WO2013071696A1 (zh) * | 2011-11-15 | 2013-05-23 | Zhang Shizhuang | 人体五种正常碱基在制备肿瘤药物中的应用 |
| CN103720693A (zh) * | 2011-11-15 | 2014-04-16 | 张始状 | 人体五种正常碱基在制备治疗肿瘤药物中的应用 |
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