CN101829061A - 一种紫杉醇纳米颗粒组合物及其制备方法 - Google Patents
一种紫杉醇纳米颗粒组合物及其制备方法 Download PDFInfo
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- CN101829061A CN101829061A CN 201010177980 CN201010177980A CN101829061A CN 101829061 A CN101829061 A CN 101829061A CN 201010177980 CN201010177980 CN 201010177980 CN 201010177980 A CN201010177980 A CN 201010177980A CN 101829061 A CN101829061 A CN 101829061A
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Abstract
一种紫杉醇纳米颗粒组合物及其制备方法，属于紫杉醇制剂技术领域。本发明涉及包括紫杉醇纳米颗粒组合物及纳米混悬液，以表面稳定剂为载体，制备了高载药量的紫杉醇纳米颗粒组合物和纳米混悬液，所述组合物具有小于1000nm的有效平均粒径；混悬液经过冷冻干燥或喷雾干燥的方法即可获得紫杉醇纳米颗粒制剂，可用于静脉注射或口服。本发明方法可靠，操作简便，所需能耗很低，且避免了有机溶剂的干扰，所制得的紫杉醇纳米颗粒组合物具有更高的生物活性，可以充分发挥紫杉醇的治疗效果。
Description
技术领域
本发明涉及紫杉醇纳米颗粒或纳米混悬液的制备方法，所述纳米颗粒组合物含有紫杉醇和优选至少一种表面稳定剂，具有1000nm以下有效平均粒径，本发明也包括制备纳米颗粒组合物的方法。属于紫杉醇制剂技术领域。
背景技术
紫杉醇(Paclitaxel，商品名Taxol)是从红豆杉属植物中提取分离出来的具有抗癌活性的四环二萜类化合物，其分子式为C47H51NO14，分子量为853.9。1992年12月29日，美国食品和药物管理局(FDA)批准紫杉醇(商品名泰素)新药上市，用于其他抗癌药无效的卵巢癌的治疗，1994年该药又批准用于治疗晚期乳腺癌。1995年半合成紫杉烷一多烯紫杉醇(泰索帝)被批准在墨西哥上市。至今已有英国、法国、日本、意大利、加拿大、德国等40多个国家批准将紫杉醇用于临床治疗。目前紫杉醇除了在临床上主治乳腺癌、卵巢癌、非小细胞肺癌(NSCLC)、卡波络氏肉瘤等多种恶性肿瘤和实体瘤以外，其临床适应证还扩大到子宫癌、肺癌、食管癌、前列腺癌及直肠癌等十几种癌症，被认为是迄今人类发现的最有效的抗癌药物，因此在业界有“抗肿瘤之王”的美誉。
紫杉醇作为抗癌药的主要剂型为注射剂与静脉输液。由于传统的紫杉醇类注射剂在使用中需要聚氧乙烯蓖麻油作为溶剂才能进行注射，而为了预防溶剂带来的过敏反应，患者需要在化疗前进行预防用药，使用抗阻胺及地塞米松等药物；为了增加其对卵巢癌的疗效，减轻其不良反应，美国阿博利斯生命科学(American Bioscience)公司开发了白蛋白结合紫杉醇纳米粒注射混悬液(paclitaxel，Abraxane)，已获得美国FDA批准上市，适用于治疗联合化疗失败的转移性乳腺癌或辅助化疗6个月内复发的乳腺癌。临床研究的数据表明：接受该品治疗的患者疗效是含聚氧乙烯蓖麻油溶媒紫杉醇制剂的2倍，可定向释放至肿瘤细胞，提高药物的疗效。化疗前不使用抗组胺药物，所有病人均在30min内完成静脉滴注，最大耐受剂量为300mg/m2，每3周给药一次。在静滴过程中未出现过敏反应，血液系统不良反应轻且无累积性。Abraxane注射用紫杉醇(白蛋白结合型)利用创新的纳米微粒白蛋白结合技术，使紫杉醇直达肿瘤间质。该技术将紫杉醇和白蛋白(天然的蛋白质)结合在一起，这样就无需在药物中使用聚氧乙烯蓖麻油溶媒了。Abraxane注射用紫杉醇(白蛋白结合型)是一种新型的化疗药物。通过利用肿瘤摄取营养的生物机制，纳米微粒白蛋白结合技术平台将更多药物送达肿瘤部位。所以，对于转移性乳腺癌患者而言，Abraxane注射用紫杉醇(白蛋白结合型)是一种既高效又方便的选择。
白蛋白纳米紫杉醇与传统紫杉醇注射剂相比具有极大优势，那就是无需使用环氧乙烯蓖麻油，大大地降低了其毒副作用。然而，它也有一些缺点：
(1)生产过程中需要使用毒性较大的有机溶剂二氯甲烷，虽然二氯甲烷沸点低易挥发，但药物中难免总有残留，从而造成药品的毒性增加；
(2)因二氯甲烷属于致癌物质，生产流程中二氯甲烷的挥发造成环境污染；
(3)生产工艺复杂，成本高。
因此，在本领域里需要这样的紫杉醇纳米制剂，能克服白蛋白纳米紫杉醇的缺点，并且与传统的紫杉醇注射液比较，具有以下优势：1、提高药物溶解度和溶出速率；2、使黏膜组织有良好的粘附性；3、载药量高，可降低给药体积，增加生物安全性；4、能提高药物制剂的稳定性；5、可实现靶向给药；6、工艺简单，适用于大规模生产。
发明内容
本发明的目的在于提供一种紫杉醇纳米颗粒组合物以及纳米混悬液。该组合物包含紫杉醇和至少一种与紫杉醇原料表面结合的表面稳定剂。本发明使用的表面稳定剂不与紫杉醇或其自身发生化学反应，表面稳定剂的各个分子基本上不含分子间交联。紫杉醇纳米粒子具有小于1000nm的有效平均粒径。
本发明的另一目的提供含有本发明紫杉醇纳米颗粒组合物的药物组合物。该药物组合物优选含有紫杉醇、至少一种表面稳定剂，和一种或多种无毒生理可接受的载体、助剂或赋形剂，可以将组合物配制成用于胃肠外注射(例如静脉内、肌内或皮下)的剂型，口服给药的固体、液体剂型，或气雾剂，肺部给药剂型、经鼻给药剂型、直肠给药剂型、眼给药剂型、鞘内注射给药剂型、局部给药剂型(粉剂、膏剂或滴剂)、颊给药剂型、池内给药剂型、腹膜内给药剂型等。
本发明提供的紫杉醇纳米颗粒组合物或纳米混悬液，较之传统形式的紫杉醇注射剂，所述组合物具有良好的粘膜组织粘附力，稳定性，载药量高以及生物利用度高的优点。
本发明还公开了制备紫杉醇纳米颗粒组合物的方法。这样的方法包括将紫杉醇原料和至少一种表面稳定剂在足以提供纳米级紫杉醇组合物的条件下接触一定时间。该一种或多种表面稳定剂可以在紫杉醇的尺寸减小以前、减小过程中或减小以后与紫杉醇接触。
本发明的技术方案：一种紫杉醇纳米颗粒组合物，含有以下组分：
(a)具有小于1000nm的有效平均粒径的紫杉醇纳米颗粒；
和(b)至少一种表面稳定剂。
所述一种紫杉醇纳米颗粒组合物，还含有以下组分：
(a)具有小于1000nm的有效平均粒径的紫杉醇纳米颗粒；
(b)至少一种表面稳定剂；
和(c)一种或多种附加剂：药用赋形剂、载体、缓冲液、盐、多元醇、渗透压调节剂、抗冻剂或其组合。
所述一种紫杉醇纳米颗粒组合物，还含有以下组分：
(a)具有小于1000nm的有效平均粒径的紫杉醇纳米颗粒；
(b)至少一种表面稳定剂；
(c)一种或多种附加剂：药用赋形剂、载体、缓冲液、盐、多元醇、渗透压调节剂、抗冻剂或其组合；
(d)还含有至少一种非紫杉醇活性剂。
所述紫杉醇纳米颗粒组合物，其中：
(a)紫杉醇以下述重量存在于组合物中：99.8％-0.001％；
(b)至少一种表面稳定剂以下述重量存在于组合物中：0.2％-99.999％。
所述紫杉醇纳米颗粒组合物，其中所述表面稳定剂选自非离子表面稳定剂、阴离子表面稳定剂、阳离子表面稳定剂或两性离子表面稳定剂。
所述紫杉醇纳米颗粒组合物，其中至少一种表面稳定剂选自泊洛沙姆、泰洛沙泊、吐温-80、月桂醇硫酸钠、鲸蜡醇硫酸钠、硬脂醇硫酸钠、聚维酮、卵磷脂、阿拉伯胶、明胶、聚乙烯醇、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羟乙基纤维素、胆酸、脱氧胆酸、聚乙烯吡咯烷酮、卡波普、油酸钾、油酸钠、油酸三乙醇胺、蔗糖酯、羧甲基纤维素、聚乙二醇、海藻糖、季铵化物、苯扎氯铵、丙烯酰胺、有机胺皂、碱土金属皂、脂肪族磺酸化物、烷基芳基磺酸化物、十二烷基磺酸钠、多库酯钠、十二烷基苯磺酸钠、二辛基琥珀酸磺酸钠、丁二酸二辛基磺酸钠、二己基琥珀酸磺酸钠、甘胆酸钠、牛磺酸胆酸钠、单硬脂酸甘油酯、单硬脂酸丙二酯、二硬脂酸乙二酯、蔗糖脂肪酸酯、脂肪酸山梨坦、聚山梨酯、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、聚氧乙烯月桂酸酯、聚氧乙酸单油酸酯、聚氧乙烯烷基酚、聚氧乙烯壬烷基酚醚、阿特拉斯、聚甲基丙烯酸甲酯三甲基溴化铵、聚乙烯基吡咯烷酮-2-二甲基氨基乙基甲基丙烯酸酯二甲基硫酸酯、溴化十六烷基三甲铵。
所述紫杉醇纳米颗粒组合物，其中紫杉醇存在于组合物中的量为30％-90％。
所述紫杉醇纳米颗粒组合物，其中所述非紫杉醇活性剂选自氨基酸，葡萄糖，生理盐水，神经营养剂，蛋白，肽，核苷酸，抗肥胖药物，营养品，膳食补充剂，中枢神经系统刺激剂，类胡萝卜素，抗组胺药，皮质类固醇药物，弹性蛋白酶抑制剂，抗真菌剂，抗肿瘤剂，烷基黄嘌呤，肿瘤治疗剂，抗呕吐剂，抗过敏药物，抗癫痫药，镇痛剂，阿片类物质，退热药，心血管治疗剂，抗炎剂，驱肠虫剂，抗心律失常剂，抗生素，抗糖尿病剂，抗组胺剂，抗高血压剂，抗毒覃碱剂，免疫抑制剂，血液制品，H2受体阻断剂，利尿药，抗脱发药物。
所述紫杉醇纳米颗粒组合物，其中紫杉醇结晶性颗粒的有效平均粒径为50nm-1000nm。
所述的紫杉醇纳米颗粒组合物的制备方法，以镐珠，高交联度聚苯乙烯聚合物树脂或玻璃粒子为研磨介质，采用湿研磨法制备紫杉醇纳米颗粒组合物。
1、紫杉醇原料
紫杉醇(paclitaxel)是从红豆杉科红豆杉属(Taxus)植物的树皮中提取得到的二萜类化合物。是目前所了解的惟一一种可以促进微管聚合和稳定已聚合微管的药物。同位素示踪表明，紫杉醇只结合到聚合的微管上，不与未聚合的微管蛋白二聚体反应。细胞接触紫杉醇后会在细胞内积累大量的微管，这些微管的积累干扰了细胞的各种功能，特别是使细胞分裂停止于有丝分裂期，阻断了细胞的正常分裂。紫杉醇并用络铂类药物已成为卵巢癌一线治疗的一种新的标准疗法。作用晚期乳腺癌二线治疗是紫杉醇获得的第一个适应症。紫杉醇加目前标准化疗药物治疗早期乳腺癌作用显著，用于Her-2过度表达转移性乳腺癌一线药物和转移性乳腺癌的二线治疗。除上述已显临床特点并经确认获准适应证之外，紫杉醇现也在进行着其单用和合用其它抗肿瘤药物治疗乳腺癌、非小细胞肺癌、小细胞肺癌、食管癌、膀胱癌、头颈部肿瘤、子宫颈癌和胃癌等癌症。
2、表面活性剂
在本发明中可使用一种以上表面稳定剂的组合。优选的表面稳定剂包括但不限于羟丙基甲基纤维素、羟丙基纤维素，聚乙烯吡咯烷酮、乙烯基吡咯烷酮与醋酸乙烯酯的无规共聚物、十二烷基硫酸钠、磺基琥珀酸二辛酯或其组合。
可用于本发明的其他表面稳定剂包括非离子型、阳离子型、阴离子型和两性离子型表面活性剂。
表面稳定剂的代表性实例还包括十二烷基硫酸钠、磺基琥珀酸二辛酯、酪蛋白、葡聚糖、胆固醇、西黄著胶、硬脂酸、硬脂酸钙、十六醇十八醇混合物、聚乙二醇单鲸蜡基醚乳化蜡、脱水山梨醇酯、聚氧化乙烯烷基醚、聚氧化乙烯蓖麻油衍生物、聚氧化乙烯脱水山梨醇脂肪酸酯；聚氧化乙烯硬脂酸酯、邻苯二甲酸羟丙基甲基纤维素、非晶纤维素、硅酸铝镁、三乙醇胺、胆酸钠、脱氧胆酸钠、生物聚合物、多糖化合物、纤维素、藻酸盐。
3、其它药物赋形剂
本发明的紫杉醇纳米颗粒组合物还可以含有一种或多种粘合剂、填充剂、润滑剂、悬浮剂、甜味剂、风味剂、防腐剂、缓冲剂、润湿剂、崩解剂、泡腾剂和其它赋形剂。这些赋形剂是本领域已知的。
填充剂包括乳糖、淀粉；粘合剂包括聚乙烯吡咯烷酮、微晶纤维素；润滑剂包括硬脂酸、硬脂酸镁、硬脂酸钙；甜味剂包括蔗糖、木糖醇、糖精钠；防腐剂包括山梨酸钾、对羟基苯甲酸甲酯，对羟基苯甲酸丙酯，苯甲酸及其盐，对羟基苯甲酸的其它酯，例如对羟基苯甲酸丁酯，醇例如乙醇或苯甲醇，酚类化合物如苯酚，以及季铵化合物如苯扎氯铵；稀释剂包括可药用的惰性填料，例如微晶纤维素、乳糖、磷酸氢钙、甘露醇，淀粉，山梨醇，蔗糖和葡萄糖等糖类和/或上述任何物质的混合物；崩解剂包括轻度交联的聚乙烯吡咯烷酮，谷物淀粉，马铃薯淀粉，玉米淀粉及改性淀粉，交联的羧甲基纤维素钠，交联的聚乙烯吡咯烷酮；泡腾剂如有机酸与碳酸盐或碳酸氢盐。合成有机酸包括柠檬酸、酒石酸、苹果酸、富马酸、己二酸、丁二酸和藻酸以及酸酐和酸式盐。合适的碳酸盐和碳酸氢盐包括例如碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸镁、甘氨酸碳酸钠、L-赖氨酸碳酸盐和精氨酸碳酸盐。
除上述所需辅料外，如需制成固体制剂，要将通过研磨、湿研磨、高压匀质法、乳化法、微乳法或其组合制备的紫杉醇纳米混悬液应用冻干保护剂葡萄糖、乳糖、甘露醇、蔗糖、海藻糖低温冷冻干燥或喷雾干燥，提高稳定性。冻干保护剂可以是其中一种或任何组合。
4、紫杉醇纳米颗粒组合物或纳米混悬液和表面稳定剂浓度
紫杉醇纯度可以为99.8％-0.001％、99.5％-0.01％、99％-0.05％、95％-0.1％或90％-0.5％，基于不包括其他附加剂的紫杉醇与至少一种表面稳定剂的总组合重量计。
至少一种表面稳定剂的重量0.2％-99.999％、0.5％-99.99％、1％-99.95％，5％-99.9％或10％-99.5％，基于不包括其他附加剂的紫杉醇与至少一种表面稳定剂的总组合重量计。
5、制备紫杉醇纳米颗粒组合物和纳米混悬液方法
5.1湿磨法
该法需专门的介质碾磨机，系由碾磨室、碾磨杆和一个再循环室组成。碾磨室内装有碾磨介质、水、药物及相应的上述所述表面稳定剂。碾磨杆的高速剪切运动，使药物粒子之间及其与碾磨介质、碾磨室内壁发生猛烈碰撞，从而粉碎得到纳米级的药物粒子。得到的混合物通过滤网分离，使碾磨介质和大颗粒药物截留在碾磨室内，小粒子药物则进入再循环室。再循环室中药物粒径如达到要求则可直接取出，其余的进行新一轮碾磨。碾磨介质一般为玻璃粒子、氧化锆粉末或高交联度聚苯乙烯树脂。该法可在20～120min内将药物碾磨成粒径小于1000nm的粒子。具体步骤如下：
(1)将一种或两种以上表面稳定剂以上述所述的重量份溶解在蒸馏水中作为分散介质，得溶液A；
所加蒸馏水量控制在使紫杉醇与至少一种表面稳定剂的总组合物的质量含量为2.5％-10％。
(2)将紫杉醇以上述所述的重量份分散于步骤(1)制得的水相分散介质中，得混悬液B。
(3)将混悬液B加入到球磨机中，开始10min排气转速1500rpm，10min后研磨速度增加到3000-5000rpm，循环冷凝水4℃，锆珠50mL，用于湿磨的混悬液B的体积为锆珠体积的1.6-10倍，湿磨20-120分钟，得到紫杉醇纳米混悬液。
(4)如需制成固体制剂，经过低温冷冻或喷雾干燥处理后，将得到的颗粒通过加入附加剂以及口服或局部外用制剂的常规方法制备。
5.2高压匀质法
先将紫杉醇微粉化制成混悬液，然后在高压匀质机高压泵的作用下强行高速通过匀化阀的狭缝，制得纳米混悬剂。本法可一步完成，也可分两步完成，即经过两个串联的匀化阀，第一个匀化阀的压力降较大，主要起分散混悬剂的作用，第二个匀化阀的压力降低于第一个，以提高纳米混悬液的稳定性。本法除具备介质湿磨法的优点外，还适于制备注射用的无菌纳米混悬剂。但须预先将药物微粉化制成粒径不大于25μm的微粒。
5.3乳化法
乳化法是将紫杉醇溶解在无水乙醇溶剂中制成o/w型乳剂，乳滴内相中的药物成为纳米级粒子，再通过减压等方式使有机溶剂挥发，紫杉醇析出形成纳米混悬剂，通过超速离心分离得纳米级药物或进行浓缩。因此，通过控制乳滴的大小就可调节药物的粒径。有机溶剂一般选用乙酸乙酯、乙酸甲酯、无水乙醇、三氯甲烷、丙酮等。
5.4微乳法
微乳法是选用与水部分互溶的有机溶剂如乳酸丁酯、三乙酸甘油酯等作为内相制备乳剂，然后用水稀释，使内相的有机溶剂被水溶解而使药物析出，然后通过超速离心分离出药物的纳米粒子或浓缩得到纳米混悬剂。可通过控制乳滴的大小控制药物粒径；不需特殊的设备仪器；制备过程较简单，易批量制备。缺点是不适于既不溶于水、也不溶于有机溶剂的药物；须考虑有机溶剂的残留与安全性问题。
6、本发明的剂型
本发明紫杉醇纳米颗粒组合物可以经由任何常规途径对个体给药。包括但不限于口服、直肠给药、胃肠外给药(例如静脉内、肌内或皮下)，以固体、液体或气雾剂形式口服给药，经皮给药，经鼻给药，直肠给药，耳给药，眼部给药，肺部吸入给药，局部给药，颊给药，池内给药，腹膜内给药；静脉注射给药，鞘内注射给药。本文所用术语“个体”是指动物，优选哺乳动物，包括人类或非人类动物。术语患者和个体可以交替使用。
此外，本发明的紫杉醇纳米颗粒组合物或混悬液可以被配制成任何合适的剂型：注射液、分散剂、片剂、脂质体、凝胶剂、小药囊剂、溶液剂、膏剂、气雾剂、胶囊剂、霜剂及其混合物；缓释制剂、肺部靶向制剂、控释制剂、口服速溶制剂、冻干制剂、延迟释放制剂、延长释放制剂、透皮吸收制剂、脉冲释放制剂以及混合的速释和控释制剂。
适于胃肠外注射的紫杉醇纳米颗粒组合物可包含生理可接受的无菌水或非水溶液、分散体、悬浮液或乳剂，以及用于重新配制成无菌可注射溶液或分散体的无菌粉剂。合适的水和非水载体、稀释剂、溶剂或赋形剂的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、其他合适的混合物、植物油(例如橄榄油)和可注射的酯例如油酸乙酯。可通过例如以下手段来保持合适的流动性：使用包衣如卵磷脂，对于分散体保持所需粒径，以及使用表面活性剂。
紫杉醇纳米颗粒组合物还可以含有助剂例如防腐剂、润湿剂、乳化剂和分散剂。可通过各种抗菌剂和抗真菌剂例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等来防止微生物的生长。还有可能希望包括等渗剂、氯化钠等。注射药物剂型的延长吸收可通过使用延迟释放剂例如单硬脂酸铝和明胶来实现。
用于口服给药的固体剂型包括但不限于胶囊、片剂、丸剂、微粉剂和颗粒剂，在这样的固体剂型中，将活性剂与至少一种以下组分混合：(a)一种或多种惰性赋形剂(或载体)，例如柠檬酸钠或磷酸二钙；(b)填充剂或增量剂，例如糖、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(c)粘合剂，例如淀粉浆、甲基纤维素、羟丙基纤维素、乙基纤维素、羧甲基纤维素、聚维酮、聚乙二醇、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶；(d)增湿剂，例如甘油；(e)崩解剂，例如干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠；(f)溶解阻滞剂，例如石蜡，(g)吸收促进剂，例如季铵化合物；(h)润湿剂，例如十六醇和甘油单硬脂酸酯；(i)吸附剂，例如高岭土和膨润土；(j)润滑剂，例如滑石粉、硬脂酸钙、硬脂酸镁、月桂醇硫酸钠、月桂醇硫酸镁、固体聚乙二醇、十二烷基硫酸钠或其混合物；(k)稀释剂，例如淀粉、糖粉、糊精、乳糖、微晶纤维素、甘露醇、山梨醇。对于胶囊、片剂和丸剂，剂型中还可含有缓冲剂。
用于口服给药的液体纳米紫杉醇剂型包括可药用乳剂、溶液剂、悬浮液、糖浆剂。除了紫杉醇以外，液体剂型可含有本领域常用的惰性稀释剂，例如水或其他溶剂，增溶剂和乳化剂。乳化剂的实例有乙醇，异丙醇，碳酸乙酯，乙酸乙酯，苯甲醇，苯甲酸苄酯，丙二醇，1，3一丁二醇，二甲基甲酰胺，油例如棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油，甘油，四氢呋喃甲醇，聚乙二醇，脱水山梨醇的脂肪酸酯，或这些物质的混合物等。
除了惰性稀释剂以外，组合物还可以包含助剂例如润湿剂、乳化剂和悬浮剂，甜味剂、矫味剂和芳香剂。
7、紫杉醇纳米颗粒组合物有效剂量
本发明提供了在个体中以低于标准市售制剂的剂量在个体中达到治疗有效紫杉醇纳米颗粒或混悬液剂量。根据所选择的紫杉醇浓度，这可容许较小的给药体积或质量。这样的方法包括对个体口服施用有效量的紫杉醇纳米颗粒组合物。
其中优选的紫杉醇的治疗有效量选自标准紫杉醇注射剂的治疗有效量的1/8，1/6，1/5，1/4，1/3或1/2。
本文在药物剂量方面使用的“治疗有效量”是指这样的剂量，在需要这样的治疗的大量个体中施用药物，该剂量提供特定药理反应。需要强调的是。在特定情况下施用给特定个体的“治疗有效量”并不总是能够有效地治疗本文所述疾病，即使这样的剂量被本领域技术人员认为是“治疗有效量”。还应当理解，在特定情况下。药物剂量是作为口服剂量来测定的，或者是参照如在血液中测定的药物水平。
本领域技术人员应当理解，紫杉醇的有效量可凭经验确定，并且可以以纯的形式，或者如果存在的话，以可药用盐、酯或前药的形式采用。对于特定组合物和给药方法，可以改变本发明紫杉醇纳米颗粒组合物中紫杉醇的实际剂量水平以获得能够实现所需治疗反应的紫杉醇的量。因此，所选择的剂量水平取决于所需治疗作用、给药途径、施用的紫杉醇的效力、所需治疗持续时间以及其他因素。
剂量单位组合物可以含有这样量的次级多剂量，以用来构成日剂量。然而应该清楚，对于任何特定的患者，具体的剂量水平将取决于多种因素：要达到的细胞或生理反应的类型和程度；使用的具体药物或组合物的活性；使用的具体药物或组合物；患者的年龄、体重、一般健康状况、性别和饮食；给药时间、给药途径和药物的排泄速度；治疗的持续时间；与具体药剂联合或同时使用的药物；以及医学领域中众所周知的类似因素。
附图说明
图1纳米紫杉醇水分散液稳定性。
图2湿磨20min粒径统计图。
图3湿磨20min粒径分布图。
图4湿磨30min粒径统计图。
图5湿磨30min粒径分布图。
具体实施方式
实施例1
本实施例的目的是用各种表面稳定剂制备紫杉醇纳米颗粒组合物注射剂。
将2g紫杉醇与1.25g至少下列一种表面稳定剂混合：泰泊沙姆、泊洛沙姆188、吐温-80、羟丙基甲基纤维素、羟丙基纤维素、聚乙烯吡咯烷酮-K30、十二烷基硫酸钠、聚乙二醇400、脱氧胆酸钠、卵磷脂。
对于紫杉醇与表面稳定剂的每一组合，首先将1.25g表面稳定剂溶解在96.75g注射用水中，然后加入2g紫杉醇，超声分散均匀，在球磨机中加入50mL锆珠，在1500rpm转速下，循环冷凝水温度控制在4℃，边搅拌边加入紫杉醇和表面稳定剂混合溶液，脱气10min后，增加转速至4000rpm，总共湿磨30min，得到乳白色紫杉醇混悬液，其中0.75g泊洛沙姆188和0.5g吐温-80联合应用效果最好，平均粒径444.2nm，其中93.305％分布在330.9nm-591nm，载药量能达到60％。湿磨20min平均粒径为538nm，其中93.03％分布在417.3nm-663.8nm。
将2g紫杉醇为相同的量，以不同的表面稳定剂组合的用量，以粒径为指标考察三种分散液在4℃的稳定性。样品1为0.9g泊洛沙姆188和0.6g吐温-80组合，样品2为0.25g泊洛沙姆188和0.5g吐温-80组合，样品3为0.75g泊洛沙姆188和0.5g吐温-80组合。实验结果表明微粒在水分散液中非常稳定，结果见图1。在该混悬液中加入1％甘露醇，在LABCONCO Freezone2.5冷冻干燥机上冷冻干燥48h，得到白色的疏松冻干粉，用蒸馏水分散后，药物溶液稳定性和再分散性好，平均粒径为486nm，载药量能达到50％。适用于静脉注射。纳米湿磨参数设置见表1。湿磨20min和30min粒径测定、统计图及粒径分布见图2、图3、图4和图5。湿磨20min和30min具体粒径统计数据见表2、表3。
表1 纳米湿磨参数
表2 湿磨20min粒径具体分布数据
| 粒径大小(nm) | 平均数(％) |
| 371.6 | 1.24 |
| 417.3 | 10.44 |
| 468.6 | 25.79 |
| 526.3 | 27.92 |
| 591 | 17.87 |
| 663.8 | 11.01 |
| 745.4 | 5.10 |
| 837.1 | 0.63 |
表3 湿磨30min粒径具体分布数据
| 粒径大小(nm) | 平均数(％) |
| 294.6 | 4.31 |
| 330.9 | 12.03 |
| 371.6 | 14.72 |
| 417.3 | 18.45 |
| 468.6 | 23.82 |
| 粒径大小(nm) | 平均数(％) |
| 526.3 | 17.66 |
| 591 | 6.63 |
| 663.8 | 1.86 |
| 745.4 | 0.52 |
实施例2
本实施例的目的是用各种表面稳定剂制备紫杉醇纳米颗粒组合物口服制剂
将2g羟甲基丙基纤维素和1g泊洛沙姆188溶解在92g注射用水中，配制成溶液，然后加入5g紫杉醇，将上述混合物溶液超声分散均匀，在球磨机中加入50mL锆珠，在1500rpm转速下，循环冷凝水温度控制在4℃，边搅拌边加入紫杉醇和表面稳定剂混合溶液，脱气10min后，增加转速至4000rpm，湿磨30min，得到乳白色紫杉醇混悬液，然后低温冷冻干燥得到白色固体颗粒，过80目筛，将得到的颗粒与适量淀粉混匀，加适量淀粉浆制成软材，用14目筛制粒后，置70℃-80℃干燥后于12目筛整粒，加入干淀粉及硬脂酸镁混匀后，压片即得。
Claims (10)
1.一种紫杉醇纳米颗粒组合物，其特征在于含有以下组分：
(a)具有小于1000nm的有效平均粒径的紫杉醇纳米颗粒；
和(b)至少一种表面稳定剂。
2.一种紫杉醇纳米颗粒组合物，其特征在于含有以下组分：
(a)具有小于1000nm的有效平均粒径的紫杉醇纳米颗粒；
(b)至少一种表面稳定剂；
和(c)一种或多种附加剂：药用赋形剂、载体、缓冲液、盐、多元醇、渗透压调节剂、抗冻剂或其组合。
3.一种紫杉醇纳米颗粒组合物，其特征在于含有以下组分：
(a)具有小于1000nm的有效平均粒径的紫杉醇纳米颗粒；
(b)至少一种表面稳定剂；
(c)一种或多种附加剂：药用赋形剂、载体、缓冲液、盐、多元醇、渗透压调节剂、抗冻剂或其组合；
(d)还含有至少一种非紫杉醇活性剂。
4.根据权利要求1-3中任一项的紫杉醇纳米颗粒组合物，其特征在于其中：
(a)紫杉醇以下述重量存在于组合物中：99.8％-0.001％；
(b)至少一种表面稳定剂以下述重量存在于组合物中：0.2％-99.999％。
5.根据权利要求1-3中任一项的紫杉醇纳米颗粒组合物，其特征在于其中所述表面稳定剂选自非离子表面稳定剂、阴离子表面稳定剂、阳离子表面稳定剂或两性离子表面稳定剂。
6.根据权利要求1-5中任一项的紫杉醇纳米颗粒组合物，其特征在于其中至少一种表面稳定剂选自泊洛沙姆、泰洛沙泊、吐温-80、月桂醇硫酸钠、鲸蜡醇硫酸钠、硬脂醇硫酸钠、聚维酮、卵磷脂、阿拉伯胶、明胶、聚乙烯醇、羟丙基纤维素、羟丙基甲基纤维素、甲基纤维素、羟乙基纤维素、胆酸、脱氧胆酸、聚乙烯吡咯烷酮、卡波普、油酸钾、油酸钠、油酸三乙醇胺、蔗糖酯、羧甲基纤维素、聚乙二醇、海藻糖、季铵化物、苯扎氯铵、丙烯酰胺、有机胺皂、碱土金属皂、脂肪族磺酸化物、烷基芳基磺酸化物、十二烷基磺酸钠、多库酯钠、十二烷基苯磺酸钠、二辛基琥珀酸磺酸钠、丁二酸二辛基磺酸钠、二己基琥珀酸磺酸钠、甘胆酸钠、牛磺酸胆酸钠、单硬脂酸甘油酯、单硬脂酸丙二酯、二硬脂酸乙二酯、蔗糖脂肪酸酯、脂肪酸山梨坦、聚山梨酯、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、聚氧乙烯月桂酸酯、聚氧乙酸单油酸酯、聚氧乙烯烷基酚、聚氧乙烯壬烷基酚醚、阿特拉斯、聚甲基丙烯酸甲酯三甲基溴化铵、聚乙烯基吡咯烷酮-2-二甲基氨基乙基甲基丙烯酸酯二甲基硫酸酯、溴化十六烷基三甲铵。
7.根据权利要求1-6中任一项的紫杉醇纳米颗粒组合物，其特征在于其中紫杉醇存在于组合物中的量为30％-90％。
8.根据权利要求3所述的的紫杉醇纳米颗粒组合物，其特征在于其中所述非紫杉醇活性剂选自氨基酸，葡萄糖，生理盐水，神经营养剂，蛋白，肽，核苷酸，抗肥胖药物，营养品，膳食补充剂，中枢神经系统刺激剂，类胡萝卜素，抗组胺药，皮质类固醇药物，弹性蛋白酶抑制剂，抗真菌剂，抗肿瘤剂，烷基黄嘌呤，肿瘤治疗剂，抗呕吐剂，抗过敏药物，抗癫痫药，镇痛剂，阿片类物质，退热药，心血管治疗剂，抗炎剂，驱肠虫剂，抗心律失常剂，抗生素，抗糖尿病剂，抗组胺剂，抗高血压剂，抗毒覃碱剂，免疫抑制剂，血液制品，H2受体阻断剂，利尿药，抗脱发药物。
9.根据权利要求1-8中任一项的紫杉醇纳米颗粒组合物，其特征在于其中紫杉醇结晶性颗粒的有效平均粒径为50nm-1000nm。
10.权利要求1-3中任一项所述的紫杉醇纳米颗粒组合物的制备方法，其特征在于以镐珠，高交联度聚苯乙烯聚合物树脂或玻璃粒子为研磨介质，采用湿研磨法制备紫杉醇纳米颗粒组合物。
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Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103476801A (zh) * | 2011-02-02 | 2013-12-25 | 安大略省癌症研究所 | 用于药物递送的纤维素基纳米粒子 |
| CN103768046A (zh) * | 2014-02-21 | 2014-05-07 | 中国人民解放军军事医学科学院毒物药物研究所 | 一种注射用紫杉醇纳米晶体及其制备方法 |
| CN104434807A (zh) * | 2014-11-10 | 2015-03-25 | 上海交通大学 | 紫杉醇及其同系物固体分散体纳米粒及其制备方法 |
| US9018246B2 (en) | 2012-09-05 | 2015-04-28 | Lp Pharmaceutical (Xiamen) Co., Ltd. | Transmucosal administration of taxanes |
| CN105050585A (zh) * | 2013-03-04 | 2015-11-11 | Vtv治疗有限责任公司 | 稳定的葡萄糖激酶活化剂组合物 |
| CN105530919A (zh) * | 2013-06-28 | 2016-04-27 | 瑞沙恩医药公司 | 哌嗪化合物的纳米颗粒组合物和制剂 |
| WO2017049083A2 (en) * | 2015-09-16 | 2017-03-23 | Dfb Soria, Llc | Delivery of drug nanoparticles and methods of use thereof |
| WO2017176628A1 (en) * | 2016-04-04 | 2017-10-12 | Crititech, Inc. | Methods for solid tumor treatment |
| CN107303272A (zh) * | 2016-04-18 | 2017-10-31 | 北京大学 | 一种提高难溶性药物口服吸收的纳晶组合物 |
| CN107854430A (zh) * | 2017-11-20 | 2018-03-30 | 郭丽颖 | 一种紫杉醇口服纳米混悬剂及其制备方法 |
| US10398646B2 (en) | 2017-06-14 | 2019-09-03 | Crititech, Inc. | Methods for treating lung disorders |
| US10507195B2 (en) | 2015-06-04 | 2019-12-17 | Crititech, Inc. | Taxane particles and their use |
| US10555898B2 (en) | 2017-03-15 | 2020-02-11 | Dfb Soria, Llc | Topical therapy for the treatment of skin malignancies using nanoparticles of taxanes |
| CN111001495A (zh) * | 2019-08-13 | 2020-04-14 | 湖北远大生命科学与技术有限责任公司 | 一种制备选矿用调整剂的方法及其装置 |
| CN111317824A (zh) * | 2020-02-29 | 2020-06-23 | 复旦大学 | 一种载多肽药物的口服纳米制剂及其制备方法 |
| US11058639B2 (en) | 2017-10-03 | 2021-07-13 | Crititech, Inc. | Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer |
| US11497726B2 (en) | 2018-03-16 | 2022-11-15 | Dfb Soria, Ll. | Topical therapy for the treatment of cervical intraepithelial neoplasia (CIN) and cervical cancer using nanoparticles of taxanes |
| US11523983B2 (en) | 2017-06-09 | 2022-12-13 | Crititech, Inc. | Treatment of epithelial cysts by intracystic injection of antineoplastic particles |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030054042A1 (en) * | 2001-09-14 | 2003-03-20 | Elaine Liversidge | Stabilization of chemical compounds using nanoparticulate formulations |
| CN1463969A (zh) * | 2002-06-24 | 2003-12-31 | 成都思摩纳米技术有限公司 | 紫杉醇纳米微粒的制备方法 |
| CN1883266A (zh) * | 2006-07-05 | 2006-12-27 | 江苏省血吸虫病防治研究所 | 一种杀钉螺药物氯硝柳胺纳米悬浮剂及其制备方法 |
-
2010
- 2010-05-14 CN CN 201010177980 patent/CN101829061A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030054042A1 (en) * | 2001-09-14 | 2003-03-20 | Elaine Liversidge | Stabilization of chemical compounds using nanoparticulate formulations |
| CN1463969A (zh) * | 2002-06-24 | 2003-12-31 | 成都思摩纳米技术有限公司 | 紫杉醇纳米微粒的制备方法 |
| CN1883266A (zh) * | 2006-07-05 | 2006-12-27 | 江苏省血吸虫病防治研究所 | 一种杀钉螺药物氯硝柳胺纳米悬浮剂及其制备方法 |
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| CN103476801A (zh) * | 2011-02-02 | 2013-12-25 | 安大略省癌症研究所 | 用于药物递送的纤维素基纳米粒子 |
| US9018246B2 (en) | 2012-09-05 | 2015-04-28 | Lp Pharmaceutical (Xiamen) Co., Ltd. | Transmucosal administration of taxanes |
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