CN105188675A - 经修饰多西他赛脂质体制剂 - Google Patents
经修饰多西他赛脂质体制剂 Download PDFInfo
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- CN105188675A CN105188675A CN201480026436.6A CN201480026436A CN105188675A CN 105188675 A CN105188675 A CN 105188675A CN 201480026436 A CN201480026436 A CN 201480026436A CN 105188675 A CN105188675 A CN 105188675A
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- Prior art keywords
- liposome
- lipid
- cholesterol
- peg
- taxane
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Abstract
本发明提供了用于治疗癌症的组合物。所述组合物包含含有磷脂酰胆碱脂、甾醇、PEG-脂质和紫杉烷的脂质体。所述PEG-脂质构成所述脂质体中脂质的约2至约8mol%。所述紫杉烷是在2′-O-位用杂环基-(C2-5烷酸)酯化的多西他赛。还公开了用于制备紫杉烷脂质体的方法和采用紫杉烷脂质体治疗癌症的方法。
Description
相关申请的交叉引用
本申请要求于2013年3月13日提交的美国临时申请序列号61/779,902的优先权,该申请的全部内容通过引用并入本申请。
关于联邦政府资助的研究和开发下作出的发明的权利声明
不适用。
序列表、表格或计算机程序列表光盘附件的引用
不适用。
发明背景
(多西他赛)和(紫杉醇)是市场上最为广泛处方的抗癌药物,并与许多药理学和毒理学关切相关,其包括高度可变(多西他赛)和非线性(紫杉醇)药代动力学、与制剂媒介物(CremophorEL,吐温80)相关的严重超敏反应以及剂量限制性骨髓抑制和神经毒性。在的情况下,药代动力学的高度可变性引起毒性和有效性的显著可变性,以及与系统性暴露至非结合药物相关的血液学毒性。此外,由于紫杉烷的治疗活性随着肿瘤细胞药物暴露持续时间增加,市售紫杉烷制剂的剂量限制性毒性大幅度限制其治疗潜力。由于例如癌细胞蛋白转运泵上调原因的抗药性进一步使基于紫杉烷的治疗复杂化。由此,存在对于具有减小的毒性和改善的功效的紫杉烷基化学疗法的需求。本发明解决这些和其它需求。
发明简述
在第一方面中,本发明提供了用于治疗癌症的组合物。所述组合物包含含有磷脂酰胆碱脂、甾醇、聚(乙二醇)-磷脂缀合物(PEG-脂质)和紫杉烷或其药学上可接受的盐的脂质体。所述紫杉烷是在2′-O-位用杂环基-(C2-5烷酸)酯化的多西他赛,且所述PEG-脂质构成所述脂质体中总脂质的2-8mol%。
在第二方面中,本发明提供了用于制备紫杉烷脂质体的方法。所述方法包括:a)形成具有包含磷脂酰胆碱脂和甾醇的脂质双层的第一脂质体,其中所述脂质双层包封包含水溶液的内部隔室;b)用紫杉烷或其药学上可接受的盐装载所述第一脂质体,以形成经装载脂质体,其中所述紫杉烷是在2′-O-位用杂环基-(C2-5烷酸)酯化的多西他赛;以及c)在足以允许将PEG-脂质嵌入所述脂质双层的条件下形成包含经装载脂质体和PEG-脂质的混合物。
在第三方面中,本发明提供了用于治疗癌症的方法。所述方法包括给药至有此需求的受试者本发明紫杉烷脂质体。
附图简述
图1显示了给药TD-1、TD-1脂质体和PEG化TD-1脂质体至具有PC3移植瘤的小鼠后TD-1(A)和多西他赛(B)从血浆的清除。
图2显示了给药PEG化TD-1脂质体至具有A549移植瘤的小鼠后TD-1从血浆的清除。数据表示为三只小鼠的均值±标准误差或表示为均值或单一值(若少于三只小鼠)。
图3显示了给药TD-1、TD-1脂质体和PEG化TD-1脂质体至具有PC3移植瘤的小鼠后TD-1(A)和多西他赛(B)在肿瘤中的水平。数据表示为三只小鼠的均值±标准误差。
图4显示了给药PEG化TD-1脂质体和多西他赛至具有A549人NSCLC移植瘤的小鼠后TD-1(A)和多西他赛(B)在肿瘤中的水平。数据表示为三只小鼠的均值±标准误差或表示为均值或单一值(若少于三只小鼠)。
图5显示了给药40mg/kg(A)和144mg/kg(B)PEG化TD-1脂质体至具有A549人NSCLC移植瘤的小鼠后TD-1在组织中的水平。数据表示为三只小鼠的均值±标准误差或表示为均值或单一值(若少于三只小鼠)。
图6显示了给药40mg/kg(A)和144mg/kg(B)PEG化TD-1脂质体至具有A549人NSCLC移植瘤的小鼠后多西他赛在组织中的水平。数据表示为三只小鼠的均值±标准误差或表示为均值或单一值(若少于三只小鼠)。
图7(A)显示了PEG化TD-1脂质体和多西他赛在无胸腺裸鼠中抗人A253(头&颈)移植瘤的抗肿瘤作用。数据表示为均值±标准误差(n=5-10)。在处理后第31天,PEG化TD-1脂质体(90mg/kg)治疗小鼠相比于生理盐水(对照)或多西他赛(30mg/kg)治疗小鼠具有显著更小的肿瘤,*,p<0.05,单向ANOVA后进行Newman-Keuls事后检验。图7(B)显示了采用PEG化TD-1脂质体、多西他赛或生理盐水治疗的具有(头&颈)移植瘤的无胸腺裸鼠的Kaplan-Meier存活曲线。PEG化TD-1脂质体(90mg/kg)相比于多西他赛和对照显著增加存活,*,p<0.05,Mantel-Cox,时序检验。各组由10只具有肿瘤的雌性小鼠开始。
图8(A)显示了PEG化TD-1脂质体和多西他赛在无胸腺裸鼠中抗人A549NSCLC移植瘤的抗肿瘤作用。数据表示为均值±标准误差(n=5-10)。PEG化TD-1脂质体(90mg/kg)相比于对照或多西他赛(10、20和30mg/kg)在治疗后第70天显著抑制肿瘤生长,*,p<0.05,ANOVA后进行Neuman-Keuls事后检验。图8(B)显示了采用PEG化TD-1脂质体、多西他赛或生理盐水治疗的具有A549NSCLC移植瘤的小鼠的Kaplan-Meier存活曲线。各组由10只具有肿瘤的雌性小鼠开始。
图9(A)显示了PEG化TD-1脂质体和多西他赛在裸鼠中抗人A549NSCLC移植瘤的抗肿瘤作用。在0天和21天给药试验品。给药PEG化TD-1脂质体(60&90mg/kg)和多西他赛(18&27mg/kg)导致初始治疗37天后相比于生理盐水的显著更小肿瘤,*,p<0.05。采用PEG化TD-1脂质体(60&90mg/kg)治疗导致相比于可比较耐受剂量下的多西他赛(18&27mg/kg)在治疗后第37和56天显著更小的肿瘤,#,p<0.05。单向ANOVA后进行Newman-Keuls事后检验。数据表示为5-10只小鼠的均值±标准误差。图9(B)显示了采用PEG化TD-1脂质体、多西他赛或生理盐水治疗的具有A549NSCLC移植瘤的无胸腺裸鼠的Kaplan-Meier存活曲线。所有剂量水平的PEG化TD-1脂质体和多西他赛相比于生理盐水均显著增加存活,p<0.05,Mantel-Cox,时序检验。各组由10只具有肿瘤的雌性小鼠开始。
图10(A)显示了TD-1脂质体、PEG化TD-1脂质体和多西他赛在无胸腺裸鼠中抗人PC3(前列腺)移植瘤的抗肿瘤作用。所有治疗组在单一静脉给药后第36天相比于生理盐水呈现出显著更小的肿瘤。采用PEG化TD-1脂质体以19mg/kg治疗导致相比于等毒剂量的多西他赛(9mg/kg)和TD-1脂质体(30mg/kg)显著更小的肿瘤,*,p<0.05。PEG化TD-1脂质体(38mg/kg)导致相比于可比较耐受剂量下的多西他赛(18mg/kg)在治疗后第79天更小的肿瘤,#,p<0.05。单向ANOVA后进行Newman-Keuls事后检验。数据表示为3-6只小鼠的均值。图10(B)显示了采用TD-1脂质体、PEG化TD-1脂质体、多西他赛或生理盐水治疗的具有人PC3(前列腺)移植瘤的无胸腺裸鼠的Kaplan-Meier存活曲线。18和27mg/kg下的多西他赛治疗以及所有治疗剂量的TD-1脂质体和PEG化TD-1脂质体相比于生理盐水均显著更多增加存活,p<0.05,Mantel-Cox,时序检验。各组由5-6只具有肿瘤的雄性小鼠开始。
图11(A)显示了PEG化TD-1脂质体和多西他赛在无胸腺裸鼠中抗MDA-MB-435/PTK7(人乳腺)移植瘤的抗肿瘤作用。单一静脉给药试验品后显示了经时中位肿瘤体积(mm3)。数据表示为4-8只小鼠的中值。图11(B)显示了采用单一给药多西他赛、PEG化TD-1脂质体或生理盐水治疗的具有MDA-MB-435/PTK7(人乳腺)移植瘤的无胸腺裸鼠的Kaplan-Meier存活曲线。各组由8只具有肿瘤的雌性小鼠开始。
图12(A)显示了PEG化TD-1脂质体和多西他赛在无胸腺裸鼠中抗HT1080/PTK7人纤维肉瘤移植瘤的抗肿瘤作用。单一静脉给药多西他赛、PEG化TD-1脂质体或生理盐水后显示了经时中位肿瘤体积(mm3)。采用PEG化TD-1脂质体(30、60&90mg/kg)和多西他赛(27mg/kg)治疗在治疗后第14天引起了相比于生理盐水显著更小的肿瘤,*,p<0.05。给药PEG化TD-1脂质体(60&90mg/kg)导致相比于相应等毒剂量下的多西他赛(18&27mg/kg)在治疗后第21天显著更小的肿瘤,**,p<0.05。给药PEG化TD-1脂质体(90mg/kg)导致相比于可比较耐受剂量下的多西他赛(27mg/kg)在治疗后第30天显著更小的肿瘤,#,p<0.05。单向ANOVA后进行Newman-Keuls事后检验。数据表示为5-10只小鼠的均值±标准误差。图12(B)显示了采用多西他赛、PEG化TD-1脂质体或生理盐水治疗的具有HT1080/PTK7人纤维肉瘤移植瘤的无胸腺裸鼠的Kaplan-Meier存活曲线。所有剂量水平的PEG化TD-1脂质体相比于生理盐水显著增加存活,*,p<0.05,且90mg/kgPEG化TD-1脂质体相比于多西他赛(所有剂量水平)显著增加存活,#,p<0.05,Mantel-Cox,时序检验。各组由10只具有肿瘤的雌性小鼠开始。
图13(A)PEG化TD-1脂质体和多西他赛在无胸腺裸鼠中抗A431人表皮样移植瘤的抗肿瘤作用。单一静脉给药PEG化TD-1脂质体、多西他赛或生理盐水后显示了经时中位肿瘤体积(mm3)。所有剂量水平的PEG化TD-1脂质体和多西他赛导致治疗后第7天相比于生理盐水显著更小的肿瘤。PEG化TD-1脂质体(60m/kg)导致相比于采用20或30mg/kg多西他赛治疗显著更小的肿瘤,*,p<0.05。在给药后第17天,采用PEG化TD-1脂质体(60和90mg/kg)治疗组呈现出相比于多西他赛(20mg/kg)显著更小的肿瘤,#,p<0.05。单向ANOVA后进行Newman-Keuls事后检验。数据表示为4-8只小鼠的均值±标准误差。图13(B)Kaplan-Meier存活曲线显示了采用PEG化TD-1脂质体、多西他赛或生理盐水治疗的具有A431人(表皮样)移植瘤的无胸腺裸鼠的存活百分数。所有剂量水平的PEG化TD-1脂质体相比于生理盐水和多西他赛(20和30mg/kg)显著增加存活,p<0.05,Mantel-Cox,时序检验。各组由8只具有肿瘤的雌性小鼠开始。
图14(A)、14(B)和14(C)提供了经评估组合物表以开发请求保护的组合物和方法。说明栏中提供的比率是用于制备第一脂质体(在如本文中所述装载紫杉烷之前并在加入PEG-脂质之前)的初始比率。组装最终组合物后,PC(磷脂酰胆碱脂)、Chol(胆固醇)和DSPE-PEG2000的百分数以mol%提供。
发明详述
I.概述
本发明提供了新型紫杉烷脂质体,以及用于将紫杉烷包封入脂质体并随后将聚(乙二醇)-功能化脂质并入所述脂质体的多步骤、一锅法。通过本发明所述方法制备的紫杉烷脂质体证实了数种优势,包括货架稳定性、体内循环时间和体内功效的增加。所述紫杉烷脂质体有用于治疗如本发明所述癌症。
II.定义
如本文中使用的,术语“脂质体”涵盖由脂质双层包封的任何隔室。术语脂质体包括单层脂质体,其由单一的脂质双层构成,且直径通常在约20至约400nm范围内。脂质体也可以是多层的,其直径通常在1至10μm范围内。在一些实施方式中,脂质体可包括多层脂质体(MLV;尺寸约1μm至约10μm)、大单层脂质体(LUV;尺寸从几百纳米至约10μm)和小单层脂质体(SUV;尺寸约20nm至约200nm)。
如本文中使用的,术语“磷脂酰胆碱脂”是指具有胆碱头基的二酰基甘油化磷脂(即,1,2-二酰基-sn-甘油-3-磷酸胆碱)。磷脂酰胆碱脂中的酰基通常来源于具有6-24个碳原子的脂肪酸。磷脂酰胆碱脂可包括合成及天然来源的1,2-二酰基-sn-甘油-3-磷酸胆碱。
如本文中使用的,术语“甾醇”是指包含至少一个羟基的甾族化合物。甾族化合物的特征在于存在稠合、四环甾烷环系。甾醇包括但不限于,胆固醇(即,2,15-二甲基-14-(1,5-二甲基己基)四环[8.7.0.02,7.011,15]二十七-7-烯-5-醇;化学文摘服务登记号57-88-5)。
如本文中使用的,术语“PEG-脂质”是指共价结合疏水或两亲性脂质部分的聚(乙二醇)聚合物。所述脂质部分可包括脂肪、蜡、类固醇、脂溶性维生素、甘油单酯、甘油二酯、磷脂和鞘脂。优选的PEG-脂质包括二酰基-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)]和N-酰基-鞘氨醇-1-{琥珀酰[甲氧基(聚乙二醇)]}。PEG-脂质中PEG的分子量通常为约500至约5000道尔顿(Da;g/mol)。PEG-脂质中的PEG可具有直链或支链结构。
如本文中使用的,术语“紫杉烷”是指具有相似于双萜天然产物的结构骨架的化合物,其还称作紫杉烷类,首先分离自紫杉树(Taxus属)。紫杉烷类的通常特征在于稠合6/8/6三环碳骨架,且所述组包括天然产物和合成衍生物。紫杉烷的实例包括但不限于,紫杉醇、多西他赛和卡巴他赛。本发明的某些紫杉烷在从三环紫杉烷核心延伸的3-苯基丙酸酯侧链的2′羟基处包括酯部分。
如本文中使用的,术语“杂环基”是指具有3至12个环成员和1至4个杂原子N、O和S的饱和或不饱和环系。杂原子还可被氧化,其例如但不限于-S(O)-和-S(O)2-。杂环基可包括任意环原子数目,例如,3至6个、4至6个、5至6个、3至8个、4至8个、5至8个、6至8个、3至9个、3至10个、3至11个或3至12个环成员。杂环基中可包括任意适当数目的杂原子,例如1个、2个、3个或4个,或1至2个,1至3个,1至4个,2至3个,2至4个或3至4个。杂环基包括但不限于,4-甲基哌嗪基、吗啉基和哌啶基。
如本文中使用的,术语“烷酸”是指含有2-5个碳原子的羧酸。烷酸可为直链或支链的。烷酸的实例包括但不限于,醋酸、丙酸和丁酸。
如本文中使用的,术语“摩尔百分数”和“mol%”是指脂质体给定脂质组分的摩尔数除以所有脂质组分的总摩尔数。除非明确规定,否则当计算脂质体脂质组分的摩尔%时,不包含活性剂、稀释剂或其它组分的量。
如本文中使用的,术语“装载”是指在脂质体中产生紫杉烷积聚。所述紫杉烷可被包封在脂质体的水室内,或其可被嵌入脂质双层中。脂质体可被被动装载,其中在脂质体制备期间将紫杉烷包含在所用溶液中。或者,脂质体可被远程装载,通过建立横跨脂质体双层的化学梯度(例如,pH或离子梯度),导致紫杉烷从水性外部迁移至脂质体内部。
如本文中使用的,术语“嵌入”是指将脂质成分植入脂质体双层中。通常,两亲性脂质例如PEG-脂质由于两亲性脂质疏水部分和双层疏水内部之间的范德华相互作用而从溶液转移至双层。
如本文中使用的,术语“组合物”是指包含指定量的指定成分的产品,以及直接或间接导致指定量的指定成分组分的任意产品。本发明的药物组合物通常包含如本文中所述的紫杉烷脂质体以及药学上可接受的载体、稀释剂或赋形剂。“药学上可接受的”是指所述载体、稀释剂或赋形剂必需与制剂的其它成分相容并对其接受者无害。
如本文中使用的,术语“癌症”是指包括人类癌症和肿瘤、肉瘤、腺癌、淋巴瘤、白血病以及实体和淋巴癌症的病症。不同癌症类型的实例包括但不限于,肺癌(例如,非小细胞肺癌或NSCLC)、卵巢癌、前列腺癌、结肠直肠癌、肝脏癌(即,肝癌)、肾癌(即,肾细胞癌)、膀胱癌、乳腺癌、甲状腺癌、胸膜癌、胰腺癌、子宫癌、宫颈癌、睾丸癌、肛门癌、胰腺癌、胆管癌、胃肠道类癌、食管癌、胆囊癌、附件癌、小肠癌、胃(胃部)癌、中枢神经系统癌、皮肤癌、绒毛膜癌、头颈癌、血癌、骨原性肉瘤、纤维肉瘤、成神经细胞瘤、胶质瘤、黑素瘤、B细胞淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、小细胞淋巴瘤、大细胞淋巴瘤、单核细胞性白血病、骨髓性白血病、急性淋巴细胞白血病、急性髓细胞白血病和多发性骨髓瘤。
如本文中使用的,术语“治疗”(treat、treating和treatment)是指癌症或癌症症状治疗或改善中的任何成功标记,其包括任何客观或主观参数例如症状的减轻;缓解;减少或使得癌症或癌症症状对于患者而言更加可容忍。症状的治疗或改善可基于任何客观或主观参数,包括例如,体格检查或临床试验的结果。
如本文中使用的,术语“给药”(administer、administered或administering)是指给药本发明脂质体组合物的方法。本发明脂质体组合物可以各种方式给药,包括肠胃外、静脉内、皮内、肌内或腹腔内。所述脂质体组合物还可作为组合物或制剂的一部分给药。
如本文中使用的,术语“受试者“是指处于其生命任何阶段的任何哺乳动物。
如本文中使用的,当用于修饰特定值时,术语“约”指示围绕数值的邻近范围。若“X”是数值,例如“约X”将指示自0.9X至1.1X的值,且更优选地,自0.95X至1.05X的值。任意提及“约X”特别指示至少以下值:X、0.9X、0.91X、0.92X、0.93X、0.94X、0.95X、0.96X、0.97X、0.98X、0.99X、1.01X、1.02X、1.03X、1.04X、1.05X、1.06X、1.07X、1.08X、1.09X和1.1X。
III.本发明实施方式
在第一方面中,本发明提供了用于治疗癌症的组合物。所述组合物包含含有磷脂酰胆碱脂、甾醇、PEG-脂质和紫杉烷或其药学上可接受的盐的脂质体。所述紫杉烷用杂环基-(C2-5烷酸)酯化,且所述PEG-脂质构成所述脂质体中总脂质的2-8mol%。
紫杉烷
在一些实施方式中,所述紫杉烷是根据式I的化合物,或其药学上可接受的盐。
对于式I化合物,R1选自苯基和叔丁氧基;R2选自H、乙酰基和甲基;R3选自H、4-(4-甲基哌嗪-1-基)-丁酰基和甲基;且R4选自H和杂环基-C2-5烷酰基。R3和R4中至少一个不是H。
式I化合物用作用于治疗包括乳腺癌、卵巢癌和肺癌的各种癌症的化疗剂。式I包括紫杉醇衍生物,其中R1是苯基。紫杉醇自身可通过各种方法获得,所述方法包括化学全合成以及使用10-脱乙酰基巴卡亭III(10-DAB;下式II)的半合成方法。10-DAB可分离自太平洋和欧洲紫杉树(分别为Taxusbrevifolia和Taxusbaccata)并可用作用于根据已知方法制备紫杉醇和其它紫杉烷的起始原料,所述其它紫杉烷包括但不限于多西他赛(即,R1=叔丁氧基;R2、R3、R4=H)和卡巴他赛。除了经由全合成制备紫杉烷外,本发明还考虑使用经由半合成方法制备紫杉烷。
如上所述,紫杉烷(包括紫杉醇和多西他赛)用于癌症治疗的用途可受限于由于不充分溶解性的低生物利用度,以及高毒性。已经使用各种策略弥补这些缺陷。例如,可使用具有不同极性的部分在三环核心的C7和C10官能团处或在C13侧链的C2′羟基处对紫杉烷骨架进行衍生化以改变紫杉烷基药物的生物利用度(参见例如,美国专利号6,482,850;美国专利号6,541,508;美国专利号5,608,087;和美国专利号5,824,701)。
将紫杉烷并入脂质体中可改善紫杉烷的生物利用度并减小其毒性。在本发明中,用弱碱部分修饰紫杉烷骨架可促进紫杉烷(否则其水难溶性)主动装载于脂质体的水性内室中。通常,所述弱碱部分可包括可电离氨基,例如N-甲基-哌嗪基、吗啉基、哌啶基、双-哌啶基或二甲基氨基。在一些实施方式中,所述弱碱部分是N-甲基-哌嗪基。
可在对于预期治疗活性而言不是必需的区域对紫杉烷进行衍生化以使衍生物的活性与该游离药物实质上相同。例如,在一些方面中,弱碱衍生物包括在巴卡亭骨架7-OH基团处衍生化的紫杉烷多西他赛。在一些实施方式中,提供在对于多西他赛活性而言必需的2'-OH基团处衍生化的多西他赛衍生物。
因此,本发明的一些实施方式提供了包含紫杉烷或其药学上可接受的盐的脂质体,其中所述紫杉烷是在2′-O-位用杂环基-(C2-5烷酸)酯化的多西他赛(即,所述紫杉烷是式I化合物,其中R1是叔丁氧基;R2是H;R3是H;且R4是杂环基-C2-5烷酰基)。在一些实施方式中,所述杂环基-(C2-5烷酸)选自5-(4-甲基哌嗪-1-基)-戊酸、4-(4-甲基哌嗪-1-基)-丁酸、3-(4-甲基哌嗪-1-基)-丙酸、2-(4-甲基哌嗪-1-基)-乙酸、5-吗啉代-戊酸、4-吗啉代-丁酸、3-吗啉代-丙酸、2-吗啉代-乙酸、5-(哌啶-1-基)戊酸、4-(哌啶-1-基)丁酸、3-(哌啶-1-基)丙酸和2-(哌啶-1-基)乙酸。在一些实施方式中,所述杂环基-(C2-5烷酸)是4-(4-甲基哌嗪-1-基)-丁酸。
脂质体
本发明脂质体可含有任何合适的脂质,包括阳离子脂质、两性离子脂质、中性脂质或如上所述的阴离子脂质。合适的脂质可包括脂肪、蜡、类固醇、胆固醇、脂溶性维生素、甘油单酯、甘油二酯、磷脂、鞘脂、糖脂、阳离子或阴离子脂质、衍生脂质等。
通常,本发明脂质体含有至少一种磷脂酰胆碱脂(PC)。合适的磷脂酰胆碱脂包括饱和PC和不饱和PC。
饱和PC的实例包括1,2-二月桂酰-sn-甘油-3-磷酸胆碱(DLPC)、1,2-二肉豆蔻酰-sn-甘油-3-磷酸胆碱(二肉豆蔻酰磷脂酰胆碱;DMPC)、1,2-二硬脂酰-sn-甘油-3-磷酸胆碱(二硬脂酰磷脂酰胆碱;DSPC)、1,2-二油酰-sn-甘油-3-磷酸胆碱(DOPC)、1,2-二棕榈酰-sn-甘油-3-磷酸胆碱(二棕榈酰磷脂酰胆碱;DPPC)、1-肉豆蔻酰-2-棕榈酰-sn-甘油-3-磷酸胆碱(MPPC)、1-棕榈酰-2-肉豆蔻酰-sn-甘油-3-磷酸胆碱(PMPC)、1-肉豆蔻酰-2-硬脂酰-sn-甘油-3-磷酸胆碱(MSPC)、1-棕榈酰-2-硬脂酰-sn-甘油-3-磷酸胆碱(PSPC)、1-硬脂酰-2-棕榈酰-sn-甘油-3-磷酸胆碱(SPPC)和1-硬脂酰-2-肉豆蔻酰-sn-甘油-3-磷酸胆碱(SMPC)。
不饱和PC的实例包括但不限于,1,2-二肉豆蔻油酰-sn-甘油-3-磷酸胆碱、1,2-二肉豆蔻反油酰(elaidoyl)-sn-甘油-3-磷酸胆碱、1,2-二棕榈油酰-sn-甘油-3-磷酸胆碱、1,2-二棕榈反油酰-sn-甘油-3-磷酸胆碱、1,2-二油酰-sn-甘油-3-磷酸胆碱(DOPC)、1,2-二反油酰-sn-甘油-3-磷酸胆碱、1,2-dipetroselenoyl-sn-甘油-3-磷酸胆碱、1,2-二亚油酰-sn-甘油-3-磷酸胆碱、1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱(棕榈酰油酰磷脂酰胆碱;POPC)、1-棕榈酰-2-亚油酰-sn-甘油-3-磷酸胆碱、1-硬脂酰-2-油酰-sn-甘油-3-磷酸胆碱(SOPC)、1-硬脂酰-2-亚油酰-sn-甘油-3-磷酸胆碱、1-油酰-2-肉豆蔻酰-sn-甘油-3-磷酸胆碱(OMPC)、1-油酰-2-棕榈酰-sn-甘油-3-磷酸胆碱(OPPC)和1-油酰-2-硬脂酰-sn-甘油-3-磷酸胆碱(OSPC)。
脂质提取物,例如卵PC、心提取物、脑提取物、肝提取物、大豆PC和氢化大豆PC(HSPC)也可用于本发明中。
在一些实施方式中,本文中提供的组合物将基本上由PC/胆固醇混合物组成(具有如下所述的加入的紫杉烷和PEG-脂质)。在一些实施方式中,所述脂质体组合物将基本上由磷脂酰胆碱脂或磷脂酰胆碱脂混合物与胆固醇、PEG-脂质和紫杉烷组成。又在其它实施方式中,所述脂质体组合物将基本上由单一类型的磷脂酰胆碱脂与胆固醇、PEG-脂质和紫杉烷组成。在一些实施方式中,当使用单一类型的磷脂酰胆碱脂时,其选自DOPC、DSPC、HSPC、DPPC、POPC和SOPC。
在一些实施方式中,磷脂酰胆碱脂选自由以下构成的组:DPPC、DSPC、HSPC及其混合物。在一些实施方式中,本发明组合物包含含有50-65mol%磷脂酰胆碱脂或磷脂酰胆碱脂混合物或者45-70mol%磷脂酰胆碱脂或磷脂酰胆碱脂混合物的脂质体。所述脂质体可含有例如,50、51、52、53、54、55、56、57、58、59、60、61、62、63、64或65mol%磷脂酰胆碱。在一些实施方式中,所述脂质体含有约55mol%磷脂酰胆碱。在一些实施方式中,所述脂质体含有约53mol%磷脂酰胆碱。
通常以少量或少于磷脂酰胆碱脂的量使用的其它合适的磷脂包括磷脂酸(PA),磷脂酰乙醇胺(PE),磷脂酰甘油(PG),磷脂酰丝氨酸(PS)和磷脂酰肌醇(PI)。磷脂的实例包括但不限于,二肉豆蔻酰磷脂酰甘油(DMPG)、二硬脂酰磷脂酰甘油(DSPG)、二油酰磷脂酰甘油(DOPG)、二棕榈酰磷脂酰甘油(DPPG)、二肉豆蔻酰磷脂酰丝氨酸(DMPS)、二硬脂酰磷脂酰丝氨酸(DSPS)、二油酰磷脂酰丝氨酸(DOPS)、二棕榈酰磷脂酰丝氨酸(DPPS)、二油酰磷脂酰乙醇胺(DOPE)、棕榈酰油酰磷脂酰胆碱(POPC)、棕榈酰油酰磷脂酰乙醇胺(POPE)、二棕榈酰磷脂酰乙醇胺(DPPE)、二肉豆蔻酰磷酸乙醇胺(DMPE)、二硬脂酰磷脂酰乙醇胺(DSPE)、16-O-单甲基PE、16-O-二甲基PE、18-1-反式PE、1-硬脂酰-2-油酰基-磷脂酰乙醇胺(SOPE)、二反油酰基(didaidoyl)磷酸乙醇胺(反式DOPE)和心磷脂。
在一些实施方式中,磷脂可包含用于进一步衍生化的反应性官能团。此反应性脂质的实例包括但不限于,二油酰磷脂酰乙醇胺-4-(N-马来酰亚胺基甲基)-环己烷-1-羧酸酯(DOPE-mal)和二棕榈酰磷脂酰乙醇胺-N-琥珀酰基(琥珀酰-PE)。
本发明脂质体可含有类固醇,其特征在于存在稠合、四环甾烷环系。类固醇的实例包括但不限于,胆酸、黄体酮、可的松、醛固酮、睾酮、脱氢表雄酮和诸如雌二醇和胆固醇的甾醇。也可考虑将合成类固醇及其衍生物用于本发明中。
通常,所述脂质体含有至少一种甾醇。在一些实施方式中,所述甾醇是胆固醇(即,2,15-二甲基-14-(1,5-二甲基己基)四环[8.7.0.02,7.011,15]二十七-7-烯-5-醇)。在一些实施方式中,脂质体可含有约30-50mol%胆固醇或约30-45mol%胆固醇。所述脂质体可含有,例如,30、31、32、33、34、35、36、37、38、39、40、41、42、43、44或45mol%胆固醇。在一些实施方式中,所述脂质体含有30-40mol%胆固醇。在一些实施方式中,所述脂质体含有40-45mol%胆固醇。在一些实施方式中,所述脂质体含有45mol%胆固醇。在一些实施方式中,所述脂质体含有44mol%胆固醇。
本发明脂质体可包含任何适当的聚(乙二醇)-脂质衍生物(PEG-脂质)。在一些实施方式中,所述PEG-脂质为二酰基-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)]。所述PEG-脂质中聚(乙二醇)的分子量范围通常为约500Da至约5000Da。所述聚(乙二醇)可具有例如,750Da、1000Da、2000Da或5000Da的分子量。在一些实施方式中,所述PEG-脂质选自二硬脂酰-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)-2000](DSPE-PEG-2000)和二硬脂酰-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)-5000](DSPE-PEG-5000)。在一些实施方式中,所述PEG-脂质为DSPE-PEG-2000。
通常,本发明组合物包括含有2-8mol%所述PEG-脂质的脂质体。所述脂质体可含有例如,2、3、4、5、6、7或8mol%PEG-脂质。在一些实施方式中,所述脂质体含有2-6mol%PEG-脂质。在一些实施方式中,所述脂质体含有3mol%PEG-脂质。在一些实施方式中,所述脂质体含有3mol%DSPE-PEG-2000。
本发明脂质体还可包含一些量的阳离子脂质–其量通常低于磷脂酰胆碱脂的量。阳离子脂质包含在生理条件下带正电荷的官能团。阳离子脂质包括但不限于,N,N-二油基-N,N-二甲基氯化铵(DODAC)、N,N-二硬脂酰-N,N-二甲基溴化铵(DDAB)、N-(1-2,3-二油酰氧基)丙基)-N,N,N-三甲基氯化铵(DOTAP)、N-(1-(2,3-二油酰氧基)丙基)-N,N,N-三甲基氯化铵(DOTMA)、N-[1-(2,3-双十四烷基氧基)丙基]-N,N-二甲基-N-羟乙基溴化铵(DMRIE)、N-[1-(2,3二油酰氧基)丙基]-N,N-二甲基-N-羟基乙基溴化铵(DORIE)、3β-[N-(N',N'-二甲基氨基乙烷)氨基甲酰基]胆固醇(DC-Chol)、双甲基双十八烷基铵(DDAB)和N,N-二甲基-2,3-二油酰氧基)丙胺(DODMA)。
在本发明的一些实施方式中,所述脂质体包含约50mol%至约70mol%DSPC和约25mol%至约45mol%胆固醇。在一些实施方式中,所述脂质体包含约53mol%DSPC、约44mol%胆固醇和约3mol%DSPE-PEG-2000。在一些实施方式中,所述脂质体包含约66mol%DSPC、约30mol%胆固醇和约4mol%DSPE-PEG-2000。
诊断剂
本发明脂质体还可以包含诊断剂。本发明中使用的诊断剂可包括本领域已知的任何诊断剂,例如以下参考文献所提供的:Armstrong等人,DiagnosticImaging,第5版,BlackwellPublishing(2004);Torchilin,V.P.编,TargetedDeliveryofImagingAgents,CRCPress(1995);Vallabhajosula,S.,MolecularImaging:RadiopharmaceuticalsforPETandSPECT,Springer(2009)。诊断剂可通过多种方式检测,包括提供和/或增强可检测信号的试剂,该信号包括但不限于,γ-发射、放射性、回声、光学、荧光、吸收、磁性或断层扫描信号。用于成像诊断剂的技术可包括但不限于,单光子发射计算体层摄影术(SPECT)、磁共振成像(MRI)、光学成像、正电子发射断层摄影术(PET)、计算机断层摄影术(CT)、X-射线成像、γ射线成像等。所述诊断剂可通过各种方式与治疗性脂质体相联,包括例如嵌入或包囊入所述脂质体。
在一些实施方式中,诊断剂可包括螯合剂,该螯合剂结合至金属离子以用于多种诊断成像技术。示例性螯合剂包括但不限于乙二胺四乙酸(EDTA)、[4-(1,4,8,11-四氮杂环十四烷-1-基)甲基]苯甲酸(CPTA)、环己烷二胺四乙酸(CDTA)、乙二醇双(2-氨基乙基醚)四乙酸(EGTA)、二乙烯三胺五乙酸(DTPA)、柠檬酸、羟基乙基乙二胺三乙酸(HEDTA)、亚氨基二乙酸(IDA)、三亚乙基四胺六乙酸(TTHA)、1,4,7,10-四氮杂环十二烷-1,4,7,10-四(亚甲基膦酸)(DOTP)、1,4,8,11-四氮杂环十二烷-1,4,8,11-四乙酸(TETA)、1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)及其衍生物。
放射性同位素可掺入本文中所述的一些诊断剂中,且可包括发射γ射线、正电子、β和α颗粒和X-射线的放射性核素。合适的放射性核素包括但不限于225Ac、72As、211At、11B、128Ba、212Bi、75Br、77Br、14C、109Cd、62Cu、64Cu、67Cu、18F、67Ga、68Ga、3H、123I、125I、130I、131I、111In、177Lu、13N、15O、32P、33P、212Pb、103Pd、186Re、188Re、47Sc、153Sm、89Sr、99mTc、88Y和90Y。在某些实施方式中,放射性试剂可包括111In-DTPA、99mTc(CO)3-DTPA、99mTc(CO)3-ENPy2、62/64/67Cu-TETA、99mTc(CO)3-IDA、和99mTc(CO)3三胺(环状或线状)。在其它实施方式中,所述试剂可包括DOTA及其具有111In、177Lu、153Sm、88/90Y、62/64/67Cu、或6w/68Ga的多种类似物。在一些实施方式中,所述脂质体可被放射标记,例如,通过掺入连接至螯合剂的脂质,如DTPA-脂质,如以下参考文献提供的:Phillips等人,WileyInterdisciplinaryReviews:NanomedicineandNanobiotechnology,1(1):69-83(2008);Torchilin,V.P.&Weissig,V.编,Liposomes第2版:OxfordUniv.Press(2003);Elbayoumi,T.A.&Torchilin,V.P.,Eur.J.Nucl.Med.Mol.Imaging33:1196–1205(2006);Mougin-Degraef,M.等人,Int’lJ.Pharmaceutics344:110-117(2007)。
在其它实施方式中,所述诊断剂可包括光学试剂如荧光剂、磷光试剂、化学发光试剂等。多种试剂(例如染料、探针、标记或指示剂)是本领域已知的并可在本发明中使用(参见例如,Invitrogen,TheHandbook—AGuidetoFluorescentProbesandLabelingTechnologies,第10版(2005))。荧光剂可包括多种有机和/或无机小分子或多种荧光蛋白质及其衍生物。例如,荧光剂可包括但不限于花青、酞菁、卟啉、靛青、罗丹明、吩恶嗪、苯基呫吨、吩噻嗪、吩硒嗪、荧光素、苯并卟啉、方酸菁、二吡咯并嘧啶酮、并四苯(tetracenes)、喹啉、吡嗪、咕啉、克酮酸(croconiums)、吖啶酮、菲啶、罗丹明、吖啶、蒽醌、chalcogenopyrylium类似物、二氢卟酚、萘酞菁、甲川染料(methinedyes)、吲哚鎓染料(indoleniumdyes)、偶氮化合物、甘菊蓝、氮杂甘菊蓝、三苯基甲烷染料、吲哚、苯并吲哚、吲哚碳菁、苯并吲哚碳菁,和具有4,4-二氟-4-硼-3a,4a-二氮杂-s-二环戊二烯并苯的通用结构的BODIPYTM衍生物,和/或任意这些的缀合物和/或衍生物。可使用的其它试剂包括但不限于,例如,荧光素、荧光素-多天冬氨酸缀合物、荧光素-多谷氨酸缀合物、荧光素-多精氨酸缀合物、靛青绿、靛青-十二天冬氨酸缀合物、靛青-多天冬氨酸缀合物、异舒泛蓝、吲哚二磺酸盐(indoledisulfonates)、苯并吲哚二磺酸盐、二(乙基羧基甲基)靛青、二(戊基羧基甲基)靛青、多羟基吲哚磺酸盐、多羟基苯并吲哚磺酸盐、刚性杂原子吲哚磺酸盐、靛青双丙酸、靛青双己酸、3,6-二氰基-2,5-[(N,N,’,N’-四(羧基甲基)氨基]吡嗪、3,6-[(N,N,’,N’-四(2-羟基乙基)氨基]吡嗪-2,5-二羧酸、3,6-二(N-氮杂环丁烷子基(azatedino))吡嗪-2,5-二羧酸、3,6-二(N-吗啉代)吡嗪-2,5-二羧酸、3,6-二(N-哌嗪子基)吡嗪-2,5-二羧酸、3,6-二(N-硫吗啉代)吡嗪-2,5-二羧酸、3,6-二(N-硫吗啉代)吡嗪-2,5-二羧酸S-氧化物、2,5-二氰基-3,6-二(N-硫吗啉代)吡嗪S,S-二氧化物、吲哚碳菁四磺酸盐(indocarbocyaninetetrasulfonate)、氯吲哚碳菁,和3,6-二氨基吡嗪-2,5-二羧酸。
本领域技术人员将理解使用的具体光学试剂可取决于用于激发的波长、皮肤组织下面的深度,和本领域通常众所周知的其它因素。例如,光学试剂的最佳的吸收或激发最大量可根据使用的试剂而改变,但通常,本发明的光学试剂将吸收以下光或被以下光激发:电磁波谱的紫外(UV)、可见或红外(IR)范围的光。对于成像,在近红外吸收和发射的染料(约700-900nm,例如,靛青)是优选的。对于使用内窥镜方法的局部可视化,在可见范围吸收的任何染料是合适的。
在一些实施方式中,本发明方法中使用的非电离辐射的波长范围可为约350nm至约1200nm。在一个示例性实施方式中,该荧光剂可被波长在电磁波谱的可见部分的蓝色范围的光激发(约430nm至约500nm)且以在电磁波谱的可见部分的绿色范围的波长(约520nm至约565nm)发射。例如,荧光素染料可被波长约488nm的光激发且具有约520nm的发射波长。作为另一实例,3,6-二氨基吡嗪-2,5-二羧酸可被波长约470nm的光激发且在波长约532nm发荧光。在另一实施方式中,光学试剂的激发和发射波长可落在电磁波谱的近红外范围。例如,靛青染料,如靛青绿,可被波长约780nm的光激发且具有约830nm发射波长。
又在其它实施方式中,所述诊断剂可包括但不限于本领域通常已知的磁共振(MR)和X-射线造影剂,包括,例如,基于碘的X-射线造影剂、超顺磁氧化铁(SPIO)、钆或锰的复合物等(参见,例如,Armstrong等人,DiagnosticImaging,第5版,BlackwellPublishing(2004))。在一些实施方式中,诊断剂可包括磁共振(MR)显像剂。示例性磁共振试剂包括但不限于顺磁剂、超顺磁剂等。示例性顺磁剂可包括但不限于钆喷酸、钆特酸、钆双胺、钆、钆特醇、锰福地吡、钆弗塞胺、柠檬酸铁铵、钆贝酸、钆布醇或钆塞酸。超顺磁剂可包括但不限于超顺磁氧化铁以及氧化铁和氧化亚铁复合物(Ferristene)。在某些实施方式中,所述诊断剂可包括X-射线造影剂,例如,在以下参考文献中提供的:H.SThomsen、R.N.Mulle和R.F.Mattrey编,TrendsinContrastMedia,(Berlin:Springer-Verlag,1999);P.Dawson、D.Cosgrove和R.Grainger编,TextbookofContrastMedia(ISISMedicalMedia1999);Torchilin,V.P.,Curr.Pharm.Biotech.1:183-215(2000);Bogdanov,A.A.等人,Adv.DrugDel.Rev.37:279-293(1999);Sachse,A.等人,InvestigativeRadiology32(1):44-50(1997)。X-射线造影剂的实例包括但不限于,碘帕醇、碘美普尔、碘海醇、碘喷托、碘普胺、碘西胺、碘佛醇、碘曲仑、碘酞硫、碘克沙醇、碘西醇、碘葡糖酰胺、碘葡苯胺、iogulamide、碘沙考、碘昔兰、碘帕醇、甲泛葡胺、碘比醇和碘美醇。在某些实施方式中,所述X-射线造影剂可包括碘帕醇、碘美普尔、碘普胺、碘海醇、碘喷托、碘佛醇、碘比醇、碘克沙醇、碘曲仑和碘美醇。
靶向剂
在一些情况下,脂质体在靶点部位累积可能是由于某些组织如癌组织的渗透性和保留特性的增强。以此方式累积可能部分由于脂质体的大小,并且可能并不需要特殊的靶向功能。在其他情况下,本发明脂质体还可包含靶向剂。通常,本发明靶向剂可以与任何感兴趣的靶点相关联,如与器官、组织、细胞、细胞外基质、细胞内或区域相关联。在某些实施方式中,靶点可以与特定的疾病状态例如癌性病症相关联。在一些实施方式中,靶向组分可仅对一个靶点例如受体具有特异性。合适的靶点可包括但不限于核酸,例如DNA、RNA或其修饰的衍生物。合适的靶点还可包括但不限于蛋白质,例如胞外蛋白、受体、细胞表面受体、肿瘤标志物、跨膜蛋白、酶或抗体。合适的靶点可包括碳水化合物,例如可以是存在于细胞表面上的单糖、二糖或多糖。
在某些实施方式中,靶向剂可以包括靶向配体(例如含RGD肽)、靶向配体的小分子模拟物(例如肽模拟物的配体)或特定靶点的特异性抗体或抗体片段。在一些实施方式中,靶向剂可进一步包括叶酸衍生物、B-12衍生物、整联蛋白RGD肽、NGR衍生物、结合到促生长素抑制素受体的生长抑素衍生物或肽,例如,奥曲肽和octreotate,等等。本发明靶向剂还可包括适体。适体可以设计成与感兴趣靶点相关联或相结合。适体可包括,例如,DNA、RNA和/或肽,和现有技术公知的某些适体(参见,例如,Klussman,S.编,TheAptamerHandbook,Wiley-VCH(2006);Nissenbaum,E.T.,TrendsinBiotech.26(8):442-449(2008))。
用于制备紫杉烷脂质体的方法
在第二方面中,本发明提供了用于制备紫杉烷脂质体的方法。可使用本领域技术人员已知的多种技术制备脂质体并用紫杉烷进行装载。脂质囊泡的制备可通过例如用水或水性缓冲液水化经干燥的脂膜(经由在适当容器中蒸发脂质和有机溶剂的混合物进行制备)。脂膜水化通常形成多层脂质体(MLV)混悬液。或者,MLV的形成可通过用水或水性缓冲液稀释脂质在适当溶剂(例如C1-4烷醇)中的溶液。单层脂质体可经由超声或挤出通过具有定义孔径的薄膜而形成自MLV。紫杉烷包封的进行可通过将药物包含在用于MLV形成期间的薄膜水化或脂质稀释的水溶液中。还可使用“远程装载”技术将紫杉烷包封在预先形成的囊泡中。远程装载包括在泡膜任意一侧建立pH或离子梯度,其驱使紫杉烷从外部溶液进入囊泡内部。
因此,本发明的一些实施方式提供了用于制备紫杉烷脂质体的方法,其包括:a)形成具有包含磷脂酰胆碱脂和甾醇的脂质双层的第一脂质体,其中所述脂质双层包封包含水溶液的内部;b)用紫杉烷或其药学上可接受的盐装载所述第一脂质体,以形成经装载脂质体,其中所述紫杉烷是在2′-O-位用杂环基-(C2-5烷酰基)基团酯化的多西他赛;以及c)将所述PEG-脂质并入所述脂质双层中。
本发明方法中使用的紫杉烷和脂质通常如上所述。然而,紫杉烷脂质体的路线将部分取决于特定紫杉烷和脂质的特性以及所使使用的用量和组合。例如,紫杉烷可在脂质体制备的不同阶段包封入囊泡。在一些实施方式中,形成第一脂质体以使脂质双层包含DSPC和胆固醇,且DSPC:胆固醇比率为约55:45(mol:mol)。在一些实施方式中,形成第一脂质体以使脂质双层包含DSPC和胆固醇,且DSPC:胆固醇比率为约70:30(mol:mol)。在一些实施方式中,第一脂质体内部包含水性硫酸铵缓冲液。装载第一脂质体可包括在足以允许紫杉烷在第一脂质体内部隔室中积聚的条件下形成包含第一脂质体和紫杉烷或其药学上可接受的盐的水溶液。
装载条件通常包括在第一脂质体内部中相比于外部水溶液中更高的硫酸铵浓度。在一些实施方式中,装载步骤在高于脂质体中一种或多种脂质成分的凝胶-流体相变温度(Tm)的温度下进行。所述装载可在例如约50、约55、约60、约65或约70℃下进行。在一些实施方式中,装载步骤在约50℃至约70℃的温度下进行。可使用任何适当量的紫杉烷进行装载。通常,以使脂质体中磷脂酰胆碱和甾醇的总重量与紫杉烷重量的比率为约1:0.01至约1:1的量使用紫杉烷。磷脂酰胆碱/甾醇的组合与紫杉烷重量的比率可为例如,约1:0.01,约1:0.05,约1:0.10,约1:0.15,约1:0.20,约1:0.25,约1:0.30,约1:0.35,约1:0.40,约1:0.45,约1:0.50,约1:0.55,约1:0.60,约1:0.65,约1:0.70,约1:0.75,约1:0.80,约1:0.85,约1:0.90,约1:0.95,或约1:1。在一些实施方式中,进行装载步骤以使磷脂酰胆碱和甾醇的总重量与紫杉烷重量的比率为约1:0.01至约1:1。在一些实施方式中,磷脂酰胆碱和甾醇的总重量与紫杉烷重量的比率为约1:0.05至约1:0.5。在一些实施方式中,磷脂酰胆碱和甾醇的总重量与紫杉烷重量的比率为约1:0.2。可以足以允许紫杉烷在脂质体内部中以期望水平积聚的任何时间量进行所述装载步骤。
PEG-脂质也可在脂质体制备的不同阶段并入脂质囊泡中。例如,可在用紫杉烷装载之前制备包含PEG-脂质的MLV。或者,可在用紫杉烷装载囊泡后将PEG-脂质嵌入脂质双层中。可在挤出SUV前将PEG-脂质嵌入MLV中,或可将PEG-脂质嵌入预先形成的SUV中。
因此,本发明的一些实施方式提供了用于制备紫杉烷脂质体的方法,其中所述方法包括:a)形成具有包含磷脂酰胆碱脂和甾醇的脂质双层的第一脂质体,其中所述脂质双层包封包含水溶液的内部隔室;b)用紫杉烷或其药学上可接受的盐装载所述第一脂质体,以形成经装载脂质体,其中所述紫杉烷是在2′-O-位用杂环基-(C2-5烷酰基)基团酯化的多西他赛;以及c)在足以允许将PEG-脂质嵌入所述脂质双层的条件下形成包含经装载脂质体和聚(乙二醇)-磷脂缀合物(PEG-脂质)的混合物。
在一些实施方式中,所述PEG-脂质的嵌入在约35-70℃的温度下进行。装载可在例如约35、约40、约45、约50、约55、约60、约65或约70℃下进行。在一些实施方式中,在约50℃至约55℃的温度下进行PEG-脂质的嵌入。可使用任何适当量的PEG-脂质进行嵌入。通常,以使磷脂酰胆碱和甾醇总摩尔数与PEG-脂质摩尔数的比率为约1000:1至约20:1的量使用PEG-脂质。磷脂酰胆碱/甾醇的组合与PEG脂质的摩尔比率可为例如,约1000:1,约950:1,约900:1,约850:1,约800:1,约750:1,约700:1,约650:1,约600:1,约550:1,约500:1,约450:1,约400:1,约350:1,约300:1,约250:1,约200:1,约150:1,约100:1,约50:1或约20:1。在一些实施方式中,进行装载步骤以使磷脂酰胆碱和甾醇的组合与PEG-脂质的比率为约1000:1至约20:1(mol:mol)。在一些实施方式中,磷脂酰胆碱和甾醇的组合与PEG-脂质的比率为约100:1至约20:1(mol:mol)。在一些实施方式中,磷脂酰胆碱和甾醇的组合与PEG-脂质的比率为约35:1(mol:mol)至约25:1(mol:mol)。在一些实施方式中,磷脂酰胆碱和甾醇的组合与PEG-脂质的比率为约33:1(mol:mol)。在一些实施方式中,磷脂酰胆碱和甾醇的组合与PEG-脂质的比率为约27:1(mol:mol)。
本发明方法中可包括本领域技术人员已知的多种附加制备技术。可通过包括透析、排阻色谱、渗滤和超滤的技术将脂质体更换入各种缓冲液中。缓冲液更换可用于从组合物中除去未包封的紫杉烷以及其它不想要的可溶性物质。经由冻干可从脂质体除去水性缓冲液和某些有机溶剂。在一些实施方式中,本发明方法包括将紫杉烷脂质体从步骤c)中的混合物更换至实质上不含未包封紫杉烷以及未嵌入PEG-脂质的水溶液。在一些实施方式中,所述方法包括冻干所述紫杉烷脂质体。
治疗癌症的方法
在另一方面中,本发明提供了治疗癌症的方法。所述方法包括给药至有此需求的受试者包含如上所述的紫杉烷脂质体的组合物。在用于治疗癌症的治疗用途中,可给药本发明脂质体组合物以使紫杉烷的初始剂量范围为约每天0.001mg/kg至约1000mg/kg。可使用约0.01-500mg/kg、或约0.1-200mg/kg、或约1-100mg/kg、或约10-50mg/kg、或约10mg/kg、或约5mg/kg、或约2.5mg/kg、或约1mg/kg的日剂量。
剂量可根据患者需求、所治疗癌症类型和严重度以及使用的脂质体组合物而不同。例如,可考虑特定患者中诊断的癌症类型和阶段经验性地确定剂量。给药至患者的剂量应足以在患者中产生经时有益治疗响应。还将通过在特定患者中伴随给药特定脂质体组合物的任何不良副作用的存在、性质和程度而确定剂量大小。确定针对特定状况的合适剂量是在执业医师的技能范围内。通常,采用小于脂质体组合物最佳剂量的较小剂量开始治疗。此后,通过小的增量增加剂量直至实现环境下的最佳效应。若需要,为方便起见,可将总日剂量划分并在一天当中将其按份给药。
本文中所述方法特别适用于实体瘤癌症(实体瘤),其为器官和组织的癌症(不同于恶性血液肿瘤),并最理想适用于上皮性癌。实体瘤癌症的实例包括膀胱癌、乳腺癌、宫颈癌、结肠直肠癌(CRC)、食管癌、胃癌、头颈癌、肝细胞癌、肺癌、黑素瘤、神经内分泌癌、卵巢癌、胰腺癌、前列腺癌和肾癌。在一组实施方式中,适于根据本发明方法治疗的实体瘤癌症选自CRC、乳腺癌和前列腺癌。在另一组实施方式中,本发明方法适用于治疗恶性血液肿瘤,包括例如多发性骨髓瘤、T细胞淋巴瘤、B细胞淋巴瘤、霍奇金病、非霍奇金淋巴瘤、急性髓性白血病和慢性髓性白血病。
所述组合物在本发明方法中可单独给药,或与其它治疗剂组合给药。另外的治疗剂可为抗癌剂或细胞毒素剂,其包括但不限于安维汀、多柔比星、顺铂、奥沙利铂、卡铂、5-氟尿嘧啶、吉西他滨或其它紫杉烷。另外的抗癌剂可包括但不限于20-环氧-1,25-二羟基维生素D3,4-甘薯苦醇、5-乙炔基尿嘧啶、9-二氢紫杉醇、阿比特龙、阿西维辛、阿柔比星、盐酸阿考达唑、阿克罗宁、酰基富烯(acylfulvene)、腺环戊醇、阿多来新、阿地白介素、all-tk拮抗剂、六甲蜜胺、氨莫司汀、安波霉素、醋酸阿美蒽醌、amidox、氨磷汀、氨鲁米特、氨基乙酰丙酸、氨柔比星、安吖啶、阿那格雷、阿那曲唑、穿心莲内酯、血管发生抑制剂、拮抗剂D、拮抗剂G、安雷利克斯、安曲霉素、抗背侧化形态形成蛋白-1(anti-dorsalizingmorphogeneticprotein-1)、抗雌激素药、抗瘤酮、反义寡核苷酸、阿非迪霉素甘氨酸盐、凋亡基因调节剂、凋亡调节剂、脱嘌呤核酸、ARA-CDP-DL-PTBA、精氨酸脱氨基酶、门冬酰胺酶、曲林菌素、asulacrine、阿他美坦、阿莫司汀、海洋环肽1、海洋环肽2、海洋环肽3、阿扎胞苷、阿扎司琼、阿扎毒素、重氮酪氨酸、阿扎替派、阿佐霉素、浆果赤霉素III衍生物、balanol、巴马司他、苯并二氢卟酚、苯佐替派、苯甲酰基十字孢碱、β内酰胺衍生物、β-alethine、β克林霉素B、桦木酸、BFGF抑制剂、比卡鲁胺、比生群、盐酸比生群、双吖丙啶基精胺、双奈法德、二甲磺酸双奈法德、bistrateneA、比折来新、博来霉素、硫酸博来霉素、BRC/ABL拮抗剂、breflate、布喹那钠、溴匹立明、布多替钛、白消安、丁硫氨酸亚矾胺、放线菌素C、卡泊三醇、卡弗他丁C、卡普睾酮、喜树碱衍生物、金丝雀痘IL-2(canarypoxIL-2)、卡培他滨、卡醋胺、卡贝替姆、卡铂、甲酰胺-氨基-三唑、羧基酰胺基三唑、carestM3、卡莫司汀、cam700、软骨衍生的抑制剂(cartilagederivedinhibitor)、盐酸卡柔比星、卡折来新、酪蛋白激酶抑制剂、澳粟精胺、杀菌肽B、西地芬戈、西曲瑞克、苯丁酸氮芥、绿素类、氯喹喔啉磺酰胺、西卡前列素、西罗霉素、顺铂、顺-卟啉、克拉屈滨、氯米芬类似物、克霉唑、collismycinA、collismycinB、考布他汀A4、考布他汀类似物、conagenin、crambescidin816、克立那托、甲磺酸克立那托、念珠藻素8、念珠藻素A衍生物、curacinA、环戊蒽醌、环磷酰胺、cycloplatam、cypemycin、阿糖胞苷、阿糖胞苷烷磷酯(cytarabineocfosfate)、溶细胞因子、cytostatin、达卡巴嗪、达昔单抗、放线菌素D、盐酸柔红霉素、地西他滨、dehydrodidemninB、地洛瑞林、右异环磷酰胺、右奥马铂、右雷佐生、右维拉帕米、地扎呱宁、甲磺酸地扎呱宁、地吖醌、代代宁B、didox、二乙基去甲精胺、二氢-5-氮胞苷、dioxamycin、二苯基螺莫司汀、多西他赛、二十二烷醇、多拉司琼、去氧氟尿苷、多柔比星、盐酸多柔比星、屈洛昔芬、柠檬酸屈洛昔芬、丙酸屈他雄酮、屈大麻酚、达佐霉素、duocarmycinSA、依布硒、依考莫司汀、依达曲沙、依地福新、依决洛单抗、依氟鸟氨酸、盐酸依氟鸟氨酸、榄香烯、依沙芦星、乙嘧替氟、恩洛铂、恩普氨酯、依匹哌啶、表柔比星、盐酸表柔比星、爱普列特、厄布洛唑、红细胞基因治疗载体体系、盐酸依索比星、雌莫司汀、雌莫司汀类似物、雌莫司汀磷酸钠、雌激素激动剂、雌激素拮抗剂、依他硝唑、依托泊苷、磷酸依托泊苷、氯苯乙嘧胺、依西美坦、法倔唑、盐酸法倔唑、法扎拉滨、芬维A胺、非格司亭、非那雄胺、夫拉平度、氟卓斯汀、氟尿苷、fluasterone、氟达拉滨、磷酸氟达拉滨、氟道诺霉素盐酸盐、氟尿嘧啶、fluorocitabine、福酚美克、福美坦、磷喹酮、福司曲星、福司曲星钠、福莫司汀、钆替沙林、硝酸镓、加洛他滨、加尼瑞克、明胶酶抑制剂、吉西他滨、盐酸吉西他滨、谷胱甘肽抑制剂、hepsulfam、heregulin、六亚甲基双乙酰胺、羟基脲、金丝桃素、伊班膦酸、伊达比星、盐酸伊达比星、吲哚昔酚、伊决孟酮、异环磷酰胺、ilmofosine、伊洛马司他、咪唑并吖啶酮、咪喹莫特、免疫刺激剂肽、胰岛素样生长因子-1受体抑制剂、干扰素激动剂、干扰素α-2A、干扰素α-2B、干扰素α-N1、干扰素α-N3、干扰素β-IA、干扰素γ-IB、干扰素、白介素、碘苄胍、碘阿霉素、异丙铂、伊立替康、盐酸伊立替康、伊罗普拉、伊索拉定、isobengazole、isohomohalicondrinB、伊他司琼、jasplakinolide、kahalalideF、lamellarin-Ntriacetate、兰瑞肽、醋酸兰瑞肽、leinamycin、来格司亭、硫酸蘑菇多糖、leptolstatin、来曲唑、白血病抑制因子、白细胞α干扰素、醋酸亮丙瑞林、亮丙瑞林/雌激素/孕酮、亮丙瑞林、左旋咪唑、利阿唑、盐酸利阿唑、线性多胺类似物、亲脂二糖肽、亲脂铂化合物、lissoclinamide7、洛铂、胍乙基磷酸丝氨酸、洛美曲索、洛美曲索钠、洛莫司汀、氯尼达明、洛索蒽醌、盐酸洛索蒽醌、洛伐他汀、洛索立宾、勒托替康、lutetiumtexaphyrin、lysofylline、裂解肽、美坦新、mannostatinA、马立马司他、马索罗酚、maspin、基质溶解因子抑制剂、基质金属蛋白酶抑制剂、美登素、氮芥盐酸盐、乙酸甲地孕酮、醋酸美仑孕酮、美法仑、美诺立尔、merbarone、疏基嘌呤、美替瑞林、蛋氨酸酶、甲氨蝶呤、甲氨蝶呤钠、甲氧氯普胺、氯苯氨啶、美妥替哌、微藻蛋白激酶C抑制剂、MIF抑制剂、米非司酮、米替福新、米立司亭、错配双链RNA、米丁度胺、米托卡星、丝裂红素、米托洁林、米托胍腙、二溴卫矛醇、米托马星、丝裂霉素、丝裂霉素类似物、米托萘胺、米托司培、米托坦、迈托毒素成纤维细胞生长因子-皂草素、米托蒽醌、盐酸米托蒽醌、莫法罗汀、莫拉司亭、单克隆抗体、人绒毛膜促性腺激素、单磷酰脂质a/分支杆菌细胞壁SK、莫哌达醇、多重抗药性基因抑制剂、基于多重肿瘤抑制因子1的治疗、芥子抗癌剂、印度洋海绵(mycaperoxide)B、分枝杆菌细胞壁提取物、麦考酚酸、myriaporone、正乙酰基地那林、那法瑞林、nagrestip、纳洛酮/喷他佐辛、napavin、萘萜二醇、那托司亭、奈达铂、奈莫柔比星、奈立膦酸、中性肽链内切酶、尼鲁米特、nisamycin、一氧化氮调节剂、硝基氧抗氧化剂(nitroxideantioxidant)、nitrullyn、诺考达唑、诺拉霉素、n-取代的苯甲酰胺、06-苄基鸟嘌呤、奥曲肽、okicenone、寡核苷酸、奥那司酮、昂丹司琼、oracin、口腔细胞因子诱导剂、奥马铂、奥沙特隆、奥沙利铂、oxaunomycin、奥昔舒仑、紫杉醇、紫杉醇类似物、紫杉醇衍生物、palauamine、棕榈酰基根霉素、帕米磷酸、人参炔三醇、帕诺米芬、parabactin、帕折普汀、培门冬酶、培得星、培利霉素、戊氮芥、戊聚硫钠、喷司他丁、pentrozole、硫酸培洛霉素、全氟溴烷、培磷酰胺、紫苏醇、phenazinomycin、乙酸苯酯、磷酸酶抑制剂、溶链菌素、盐酸毛果云香碱、哌泊溴烷、哌泊舒凡、吡柔比星、吡曲克辛、盐酸吡罗蒽醌、placetinA、placetinB、纤溶酶原激活物抑制剂、铂络合物、铂化合物、铂-三胺络合物、普卡霉素、普洛美坦、卟吩姆钠、泊非霉素、泼尼莫司汀、盐酸丙卡巴肼、丙基双吖啶酮、前列腺素J2、前列腺癌抗雄激素、蛋白酶体抑制剂、基于蛋白质A的免疫调节剂、蛋白质激酶C抑制剂、蛋白质酪氨酸磷酸酶抑制剂、嘌呤核苷磷酸化酶抑制剂、嘌呤霉素、嘌呤霉素盐酸盐、红紫素、吡唑呋喃菌素、吡唑并吖啶、吡哆醛化血红蛋白聚氧乙烯缀合物、RAF拮抗剂、雷替曲塞、雷莫司琼、RAS法呢基蛋白质转移酶抑制剂、RAS抑制剂、RAS-GAP抑制剂、脱甲基瑞替普汀、铼RE186依替膦酸盐、根霉素、利波腺苷、核酶、RII维甲酰胺(retinamide)、RNAi、罗谷亚胺、罗希吐碱、罗莫肽、罗喹美克、rubiginoneB1、ruboxyl、沙芬戈、盐酸沙芬戈、saintopin、sarcnu、sarcophytolA、沙格司亭、SDI1模拟物、司莫司汀、老化衍生的抑制剂1、正义寡核苷酸、信号转导抑制剂、信号转导调节剂、辛曲秦、单链抗原结合蛋白质、sizofuran、索布佐生、硼卡钠、苯基乙酸钠、solverol、生长调节素结合蛋白质、索纳明、磷乙酰天冬氨酸钠、膦门冬酸、司帕霉素、spicamycinD、盐酸螺旋锗、螺莫司汀、螺铂、脾脏五肽、海绵抑制素1、角鲨胺、干细胞抑制剂、干细胞分裂抑制剂、stipiamide、链黑菌素、链佐星、基质分解素抑制剂、sulfinosine、磺氯苯脲、强效血管活性肠肽拮抗剂、suradista、苏拉明、苦马豆碱、合成糖胺聚糖、他利霉素、他莫司汀、他莫昔芬甲碘化物、牛磺莫司汀、他扎罗汀、替可加兰钠、替加氟、tellurapyrylium、端粒酶抑制剂、替洛蒽醌盐酸盐、替莫泊芬、替莫唑胺、替尼泊苷、替罗昔隆、睾内酪、四氯十氧化物、tetrazomine、thaliblastine、沙利度胺、硫咪嘌呤、噻可拉林、硫鸟嘌呤、塞替派、血小板生成素、血小板生成素模拟物、胸腺法新、胸腺喷丁受体激动剂、胸腺曲南、甲状腺刺激激素、噻唑羧胺核苷、本紫红素乙酯锡、替拉扎明、二氯环戊二烯钛、盐酸拓扑替康、topsentin、托瑞米芬、柠檬酸托瑞米芬、全能干细胞因子、翻译抑制剂、醋酸曲托龙、维甲酸、三乙酰基尿苷、曲西立滨、磷酸曲西立滨、三甲曲沙、葡萄糖醛酸三甲曲沙、曲普瑞林、托烷司琼、盐酸妥布氯唑、妥罗雄脲、酪氨酸激酶抑制剂、酪氨酸磷酸化抑制剂、UBC抑制剂、乌苯美司、尿嘧啶芥子、乌瑞替派、泌尿生殖窦衍生的生长抑制因子、尿激酶受体拮抗剂、伐普肽、variolinB、维拉雷琐、藜芦明、verdins、维替泊芬、硫酸长春碱、硫酸长春新碱、长春地辛、硫酸长春地辛、硫酸长春匹定、硫酸长春甘酯、硫酸长春罗新、长春瑞滨、酒石酸长春瑞滨、硫酸长春罗定、vinxaltine、硫酸长春利定、vitaxin、伏氯唑、扎诺特隆、折尼铂、亚苄维C(zilascorb)、净司他丁、净司他丁斯酯,或盐酸佐柔比星。
IV.实施例
实施例1.紫杉烷脂质体的制备
缓冲液和试剂制备
300mM蔗糖透析液制备。称重102.69g蔗糖并将其加至1L容量瓶。将烧瓶装满3/4去离子(DI)水并通过震摇混合直至固体溶解。在室温下加入去离子水以实现蔗糖的期望浓度并通过多次翻转封盖烧瓶进行混合。真空下将溶液过滤通过0.2μm47mm尼龙膜并在2-5℃下贮存。
350mM硫酸铵缓冲溶液制备。称重23.13g硫酸铵并将其加至A级500mL容量瓶。将烧瓶装满3/4去离子水并通过震摇混合直至固体溶解。在室温下加入去离子水以实现硫酸铵的期望浓度并通过多次翻转封盖烧瓶进行混合。真空下将溶液过滤通过0.2μm47mm尼龙膜并在2-5℃下贮存。
350mM硫酸铵/100mM蔗糖缓冲溶液制备。称重34.24g蔗糖和46.24g硫酸铵并将其加至1LA级容量瓶。将烧瓶装满3/4去离子水并通过震摇混合直至固体溶解。在室温下加入去离子水以实现溶液的期望浓度并通过多次翻转封盖烧瓶进行混合。真空下将溶液过滤通过0.2μm47mm尼龙膜并在2-5℃下贮存。
脂质溶解。在洁净玻璃称量漏斗中称重DSPC(1.785g)和胆固醇(0.715g)。将所述物质装入洁净1L圆底烧瓶中。使用A型容量吸管在室温下加入15mL乙醇。将所述圆底烧瓶连接至60℃下的旋转蒸发仪水浴。在水浴中无真空下在150RPM和60℃下旋转烧瓶直至所有物质完全溶解(约30分钟)。溶解后在60℃温度下保持脂质溶液。在A型刻度量筒中测量85mL硫酸铵/蔗糖,用封口膜封盖并使用水浴加热至60℃。
脂质体制备
从旋转蒸发仪移除该1L圆底烧瓶。在大力涡旋下将经加热的85mL硫酸铵/蔗糖泻入烧瓶中。在旋转蒸发仪上60℃水浴下旋转烧瓶中的混合物30分钟。然后移除烧瓶并立即开始挤出。
挤出。通过用乙醇冲洗三次并采用UHP氮气干燥准备四个玻璃血清瓶和塞子。将瓶封盖直至加入样品。用加至挤出机过滤基底的一个排水阀盘和两个0.2μm核孔膜组装100mL挤出机。通过完全通过100mL加热至70℃的去离子水净化挤出机。将脂质体溶液由1L烧瓶泻入加热至70℃的挤出机。将脂质体挤出并通入250mL玻璃烧杯。用双重100nm薄膜替代200-nm薄膜并将系统清洗入洁净250mL烧杯。使用洁净烧杯重复挤出10次。在洁净血清瓶中收集最终脂质体样品,加盖、密封并冷却至室温。2-5℃下贮存脂质体。
渗滤。用加热至95℃的1L0.1NNaOH以100ml/min的流速和3Psi的跨膜压清洗光谱KrossFlo单位渗滤装置。洗出500mL后反转流向,并另外持续流动500mL。充满和置换样品池至少三次,并在冲洗前将系统净化干燥。通过异丙醇擦拭来清洁来自管道外部的灰尘和碎片。将无菌0.1μm25mmPVDF注射器式滤器插入GL45介质瓶盖用于空气进气过滤。在室温下用1L去离子水以100mL/min和3Psi跨膜压冲洗系统。用去离子水充满和置换样品池至少三次。在室温下用300mM蔗糖净化系统之前将系统净化干燥。排空样品池并用乙醇冲洗三次、用去离子水冲洗三次(每次冲洗约10mL)。室温下将经挤出脂质体样品加至样品池。
使用500kDa截断mPES中空纤维模块开始渗滤,泵速为100.0±1.0mL/min、TMP为3.0±1.0Psi、Pp为-0.3≤0.0Psi且Pf为5.0±1.0Psi。持续渗滤直至滤液体积达到保留物体积的约30倍。从池中移除样品并泻入洁净血清瓶。将样品过滤通过0.2μm25mm注射器式滤器进入洁净血清瓶。然后将样品过滤通过0.1μm25mm无菌无机注射器式滤器进入洁净血清瓶,弃掉前三滴洗脱液。将样品封盖、密封并在2-5℃下贮存。挤出后,表征样品的以下项:粒径、pH、脂质浓度和铵浓度。
2′O-4-(4-甲基哌嗪-1-基)-丁酰基-多西他赛(TD-1)的远程装载以及
DSPE-PEG-2000的嵌入
远程装载步骤。将多西他赛衍生物TD-1(386mg,如WO2009/141738A2中所述制备)称入配有两个橡胶塞、一个控温热电偶适配器和一个搅拌棒的500mL3颈圆底烧瓶中。将TD-1溶于190mL10mM醋酸盐缓冲的蔗糖溶液(pH5.5)中,并使用氢氧化钠水溶液调节溶液pH至5.5-5.6。使用加热罩伴随温和搅拌将溶液加热至65℃。
向第二个500mL圆底烧瓶中加入脂质体硫酸铵样品(1.932g总脂质)。采用醋酸盐缓冲的蔗糖稀释该脂质体至196mL最终体积并调节pH至5.5。使用热电偶控制加热罩将混合物加热至65℃并倾入TD-1溶液中。持续加热15分钟,然后将温度降至55℃。收集脂质体样品用于尺寸和pH分析。
嵌入DSPE-PEG-2000。将DSPE-PEG-2000(290mg)溶于8mL醋酸盐缓冲的蔗糖中并加至经加热的脂质体溶液。55℃下维持该混合物30分钟。移除加热罩并将混合物冷却至环境温度。收集脂质体样品用于尺寸和pH分析。
渗滤。如上所述用20mM醋酸盐/300mM蔗糖缓冲液平衡渗滤装置。将250mL脂质体混合物加至池中并经由超滤浓缩至约50mL的总体积。加入剩下的脂质体混合物并将其浓缩至50mL。经至少15体积的20mM醋酸盐/300mM蔗糖(pH5.50)渗滤超滤液。将脂质体浓缩至60mL并采样用于尺寸和pH分析。定量分析样品的TD-1、多西他赛、DSPC、胆固醇、DSPE-PEG-2000和lyso-DSPC。将最终脂质体制品贮存在5℃下的具有丁基胶塞和卷曲密封的洁净血清瓶中。
在不同条件下贮存根据以上方法制备的脂质体制品并分析其如表1中汇总的粒径和药物释放。将脂质体与非PEG化样品进行对比。如通过贮存时观测的从脂质体泄露的药物水平所评估的,脂质体的PEG化导致脂质体完整性的出乎意料的收益。相对于非PEG化脂质体,冷冻时TD-1从PEG化脂质体的泄露减小了将近一个数量级。令人惊奇地,5℃下贮存时TD-1从PEG化脂质体的泄露减小了超过了22倍。
表1.不同贮存条件下的PEG化和非PEG化脂质体
实施例2.PEG-脂质嵌入紫杉烷脂质体组合物的控制
已发现载药后以热嵌入步骤的形式并入DSPE-PEG(2000)是最佳确立的。发现细心控制DSPE-PEG(2000)嵌入的温度和时间提供了充分的PEG化,表3中给出了不同批次(lots)的细节。在所有情况下,通过伴随控制所有进入原料来通过0.2微米滤器过滤,以进行PEG化TD-1脂质体的热嵌入。
如上所述制备空脂质体用于装载TD-1并嵌入PEG以形成最终的PEG化TD-1脂质体。下表比较了各批次生成物质的各种参数以及使用的PEG嵌入条件。
表2.将TD-1载入脂质体的条件
表3.DSPE-PEG(2000)热嵌入参数
表4.使用不同嵌入参数制备的TD-1脂质体的分析
上述7个批次工艺参数中的主要、显著差异发生在将DSPE-PEG(2000)并入载药脂质体期间。如表3和表4中所示,PEG化取决于嵌入所使用的温度和时间。较低温度(例如,50℃)或较短时间(例如,30分钟维持时间)导致药物产品中较少的DSPE-PEG(2000)(例如,批次2具有28.2%PEG并入且批次3具有45.3%PEG并入),而高温(例如,62℃)在牺牲药物包封(45.8%)的情况下提供了较高的PEG并入(80.5%),其导致药物产品中较低的药物脂质比。显示加热至55℃60分钟同时提供了载药和PEG并入的良好收率(对于表中所述的最后4个批次分别为65-87%和68-90%)。
实施例3.紫杉烷衍生物脂质体的生物分布,比较结果
已在患瘤小鼠中完成了比较PEG化TD-1脂质体和多西他赛的两项药代动力学和组织分布研究。
静脉给药PEG化TD-1脂质体导致系统暴露至多西他赛大于注射等量的多西他赛游离药物暴露量的10倍。静脉注射PEG化TD-1脂质体后TD-1和多西他赛均在PC3和A549肿瘤中蓄积。给药后TD-1和多西他赛浓度缓慢增加直至72小时并在整个观测期间(直至21天)保持在肿瘤中。相反,静脉注射多西他赛导致肿瘤中的起始高浓度,其经七天时间减小并在之后降至低于检测水平。
除了在肿瘤组织中蓄积外,给药PEG化TD-1脂质体后TD-1和多西他赛还在肝、脾和肾中蓄积。这些组织显示出与肿瘤相似的生物分布模式,具有缓慢的吸收以及稳定的长期停留时间。相反,游离多西他赛未在这些组织中收集并在注射24小时内降至低于检测水平。虽然多西他赛浓度在整个24小时中在肺组织中是可测的,但分析测试未能在骨骼肌组织中检测到多西他赛的存在。
高剂量PEG化TD-1脂质体(144mg/kg)下肿瘤中TD-1和多西他赛浓度的后期增加与在低剂量下或在其它组织中发现的行为不相一致,其可能为由于尺寸显著缩小的肿瘤中长期药物暴露的计算工件(calculationartifact)。
在非PEG化和PEG化脂质体中包封TD-1相比于未包封TD-1和多西他赛均增加了多西他赛系统暴露(AUC),同时产生较低的血浆峰浓度(Cmax)。
小鼠中的药代动力学研究证实了有关肿瘤内更高和更持久活性药物多西他赛暴露并具有更低血浓度峰值的益处。这提示了在人类患者中增强抗肿瘤活性而不增加毒性的可能性。
方法
设计。在各自皮下移植PC3细胞(人类前列腺癌)的雄性无胸腺裸鼠中研究血浆药代动力学和分布。一旦肿瘤达到100-300mm3体积,则将动物随机分入5组。如表5中所示给予各动物单一静脉剂量的多西他赛、未包封TD-1、非PEG化TD-1脂质体或PEG化TD-1脂质体。
表5.具有PC3移植瘤的裸鼠的剂量分配
a=试验品剂量表示为mg/kgTD-1
b=试验品剂量表示为mg/kg多西他赛等价物(TD-1/1.25换算因子)
在注射后5分钟以及1、4、24、48、72、120和168小时时各杀死三只动物。在各时间采集血样用于药代动力学分析。使用PhoenixWinNonLin软件通过非房室分析模型计算TD-1和多西他赛的药代动力学参数。
结果
如图A中所示,TD-1血浆浓度随时间降低。与任一种包封药物形式相比,未包封TD-1显示了低系统暴露(AUC)、快速清除以及大分布容量(表6)。
表6.给药TD-1、TD-1脂质体和PEG化TD-1脂质体至具有PC3移植瘤的裸鼠后的TD-1药代动力学
a=以多西他赛摩尔当量的形式给出所有剂量。
虽然脂质体制剂(TD-1脂质体和PEG化TD-1脂质体)的TD-1剂量较高,但剂量从11至30mg/kg的增加导致了包封TD-1系统暴露3600至4900倍的增加。此外,相比于未包封制剂,TD-1包封减缓了清除并限制了分布容量。这些数据表明TD-1脂质体形式长时间保留在血浆中。PEG化TD-1脂质体剂量从30增加至60mg/kg增加了Cmax和TD-1系统暴露,但未改变清除、终端半衰期或分布容量。
多西他赛血浆浓度随时间降低(图1B)。虽然在酸性或受保护条件(经包封)下稳定,但TD-1在中性pH和无保护条件下容易水解以形成多西他赛。未包封TD-1和多西他赛呈现相似的多西他赛浓度-时间曲线,48小时后浓度降至低于检测水平。给药经包封TD-1后,虽然多西他赛浓度也会降低,但降低速率相比于游离药物减缓。给药30和60mg/kg后分别直到给药后120和168小时仍出现多西他赛的可定量浓度。
作为游离药物,多西他赛和TD-1产生血浆多西他赛浓度,其相比于TD-1脂质体和PEG化TD-1脂质体具有相对小的系统暴露、快速清除以及大分布容量的药代动力学参数(表7)。
表7.给药TD-1、TD-1脂质体和PEG化TD-1脂质体至具有PC3移植瘤的裸鼠后的多西他赛药代动力学
a=以多西他赛摩尔当量的形式给出所有剂量。
多西他赛和未包封TD-1二者显示相似的血浆多西他赛浓度,其与TD-1转化为多西他赛相一致。通过PEG化TD-1脂质体提供的多西他赛的较慢清除、增加半衰期以及增加系统暴露表明经包封TD-1用作从脂质体持续释放并转化为多西他赛的贮库。
具有A549移植瘤的小鼠的药代动力学
在各自皮下移植A549细胞(人类非小细胞肺癌)的雌性无胸腺裸鼠中研究血浆药代动力学和分布。一旦肿瘤达到100-300mm3体积,则将动物随机分入4组。如表8中所示给予各动物单一静脉剂量的多西他赛或PEG化TD-1脂质体。
表8.具有A459移植瘤的裸鼠的剂量分配
a=试验品剂量表示为mg/kgTD-1
b=试验品剂量表示为mg/kg多西他赛等价物(TD-1/1.25换算因子)
在注射后1、4、24、72(3天)、168(7天)、216(9天)、336(14天)、432(18天)和504小时(21天)时各杀死三只动物。在各时间点采集血样用于药代动力学分析。使用PhoenixWinNonLin软件通过非房室分析模型计算TD-1和多西他赛的药代动力学参数。
如图2中所示,TD-1血浆浓度随时间降低。在40mg/kg剂量下,给药脂质体后经168小时TD-1浓度保持在定量限(0.025μg/mL)上;然而,给药144mg/kg剂量后,在脂质体给药后的整整三周观测期检测到TD-1。Cmax以及TD-1系统暴露(血浆AUC)随着PEG化TD-1脂质体剂量的增加而增加(表9)。
表9.给药PEG化TD-1脂质体至具有A549移植瘤的裸鼠后的TD-1药代动力学
静脉注射PEG化TD-1脂质体后,多西他赛血浆浓度经时缓慢降低并在给药40和144mg/kg剂量后分别保持在检测限以上三天和七天。相反,以游离药物形式给药的多西他赛仅在4小时中是可测的。PEG化TD-1脂质体(40mg/kg)呈现出与来源于给药多西他赛(50mg/kg)自身相似的Cmax多西他赛浓度,但从AUC来看暴露几乎大10倍(表10)。
表10.给药PEG化TD-1脂质体至具有A549移植瘤的裸鼠后的多西他赛药代动力学
*=不可计算
相比于以游离药物形式给药的多西他赛,来源于PEG化TD-1脂质体的多西他赛似乎受限于较小的分布容量。在给药后通过3天在血中测定,产生自PEG化TD-1脂质体的多西他赛血浆浓度约为TD-1的约1%。
具有PC3移植瘤的小鼠中的组织分布
除了上述血浆浓度和药代动力学计算以外,还评价了组织分布。获得自表5中所述各动物并在分析前冰冻的组织包括:肿瘤、肝、脾和肾。分析来自经多西他赛处理小鼠的组织的多西他赛水平。分析来自经TD-1、TD-1脂质体和PEG化TD-1脂质体处理小鼠的组织的多西他赛和TD-1水平。
对于脂质体制剂,PC3肿瘤中TD-1浓度初始增加,之后该浓度在168小时的观测时期内维持相当恒定(图3A)。相反,给药未包封TD-1后TD-1肿瘤浓度经约24小时下降并在剩余观测期间维持极低浓度。
给药TD-1脂质体和PEG化TD-1脂质体后肿瘤中多西他赛浓度经48至72小时缓慢增加并接着通过剩余观测期维持相对稳定(图3B)。给药未包封TD-1后多西他赛肿瘤浓度迅速增加并在观测期内持续增高。给药游离药物形式的多西他赛导致肿瘤中多西他赛高浓度的迅速开始。尽管以包封剂量的约2/3给药,但给药游离多西他赛导致相比于包封制剂更高的早期浓度并在注射后120和168小时时具有相似的浓度。
给药多西他赛、未包封TD-1、非PEG化TD-1脂质体和PEG化TD-1脂质体后,肝、脾和肾均包含多西他赛和TD-1(表11)。对于所有测试制剂而言,脾倾向于具有比肝和肾更高的多西他赛暴露(AUC)。相比于非PEG化TD-1脂质体,给药PEG化TD-1脂质体后肝、脾和肾具有较少的多西他赛暴露。该数据与PEG化脂质体较少被清除器官摄取相一致。
表11.用多西他赛、TD-1脂质体或PEG化TD-1脂质体处理后具有PC3移植瘤的裸鼠中多西他赛的组织分布
a=以多西他赛摩尔当量的形式给出所有剂量。
b=样品未分析。
具有A549移植瘤的小鼠中的组织分布
除了血浆浓度和药代动力学计算以外,还在给药PEG化TD-1脂质体(如表8中所示)后在具有A549人NSCLC肿瘤的小鼠中进行了组织分布评价。TD-1在A549肿瘤中长期蓄积(图4A)。在注射后最初24小时内TD-1浓度缓慢增加。在低剂量下,24小时后TD-1浓度趋于随时间下移。在高剂量下,在给药后约14天内维持浓度颇为稳定,然后趋于增加,但变化性也增加。通过21天观测期,TD-1浓度保持在最低定量限(2.0μg/g)以上。
类似于给药未包封TD-1,给药PEG化TD-1脂质体对于低剂量(40mg/kg)导致在前7天中A549肿瘤中多西他赛浓度的增加,而对于高剂量(144mg/kg)则导致在9天中A549肿瘤中多西他赛浓度的增加。初始峰值之后,多西他赛浓度轻微下降并接着在低剂量给药后21天观测期的余下部分保持稳定(图4B)。高剂量给药PEG化TD-1脂质体后,多西他赛浓度轻微下降并在给药后18和21天再次增加。相反,静脉注射多西他赛在注射后立即出现峰值并接着随时间降低,9天后降至低于定量水平(1.0μg/g)。
在可比剂量下,PEG化TD-1脂质体(40mg/kg)呈现出比给药多西他赛(50mg/kg)本身高3.9倍的多西他赛肿瘤暴露(AUC)(表12)
表12.给药多西他赛或PEG化TD-1脂质体至具有A549移植瘤的裸鼠后的组织中多西他赛水平
在肿瘤中,给药PEG化TD-1脂质体(表示为相对于给药未包封TD-1后的多西他赛百分数水平)后多西他赛水平在3至7天后增加,特别是在较低剂量下,其水平在21天后达到55%。该比率在其它组织中通常稳定且在肝和脾中范围约1-2%,在肾中直至3-5%。
TD-1在肝、脾、肾、肺和骨骼肌组织中的水平似乎分成两类(图5)。肝、脾和肾显示出类似于肿瘤的模式,通过前72小时缓慢吸收,通过剩下的3周时间浓度缓慢降低。肺和骨骼肌组织在注射后立即包含最高浓度,其分别在约72和24小时后降至接近检测水平的浓度。
约9天后,对于40mg/kg剂量的PEG化TD-1脂质体而言,骨骼肌组织中的TD-1浓度降至低于定量水平。以144mg/kg剂量给药PEG化TD-1脂质体后出现相似的TD-1吸收和分布模式。高剂量给药PEG化TD-1脂质体后,肺和骨骼肌组织在整个观测期保持可测的TD-1浓度,但浓度倾向于低于肿瘤、肝、脾和肾中发现的浓度,特别是在168至504小时之间的平台期。肝、肾、脾和肺的TD-1定量限为0.5μg/g,而骨骼肌的TD-1定量限为2.0μg/g。
对于TD-1,来源于PEG化TD-1脂质体的多西他赛的吸收和消除分成两类(图6)。40或144mg/kg剂量下的PEG化TD-1脂质体未在骨骼肌组织中产生可定量量的多西他赛。肝、肾、脾和肺的多西他赛定量限为0.5μg/g,而骨骼肌的多西他赛定量限为1.0μg/g。给药多西他赛(50mg/kg)仅分布至组织短暂时间。对于大部分组织(除了肿瘤以外),多西他赛浓度在24小时后降至低于定量限,而肿瘤中在216小时(9天中)保持可测的多西他赛水平。
实施例4.体内肿瘤模型,比较结果
已经完成了考察对抗植入免疫缺陷小鼠的各种肿瘤细胞系的活性以及比较PEG化TD-1脂质体和多西他赛活性的一系列研究。各研究具有广泛相似的设计。将肿瘤细胞系皮下植入裸(免疫缺陷)鼠侧腹并使其生长至固定大小。摒弃未生长肿瘤的小鼠。分配小鼠接受生理盐水(对照,包含在所有研究中)或多西他赛或PEG化TD-1脂质体并通过缓慢静脉推注给药指定治疗。在各种可能的情况下,在可能的情况下,以提供同等水平的毒性/耐受性选择剂量。TD-1的最高剂量通常受限于可给药体积。分析肿瘤体积以确定肿瘤生长延迟(TGD)和部分消退(partialregression)。若小鼠损失其20%初始体重或变为濒死或其肿瘤体积超过2500mm3或肿瘤溃烂则将其移除。若保留少于一半的初始鼠群,则该组不再作图,也不被包含在进一步的肿瘤分析中。然而,跟踪任何剩下的动物直至完成生前观测并将其包含在生存分析中。这些研究的可变特性汇总在表13中。
表13.免疫缺陷小鼠中体内抗肿瘤活性研究的可变特性汇总
a=PEG化TD-1脂质体剂量表示为多西他赛等价物(PEG化TD-1脂质体的剂量高1.25倍)。
b=肺A549疗效研究中的小鼠给予两次剂量,21天间隔;所有其它研究为单一剂量研究
c=前列腺PC3多西他赛(27mg/kg)剂量组具有5只小鼠。
d=前列腺PC3疗效研究包括3个附加组,其以与PEG化TD-1脂质体相同的剂量采用非PEG化TD-1治疗。
所有研究证实PEG化TD-1脂质体在这些移植瘤模型中用作活性抗肿瘤剂,并相比于可比较耐受剂量的多西他赛具有显著更高的抗肿瘤活性。
来自采用A253头&颈癌模型的研究数据证实,相比于生理盐水对照或多西他赛,以90mg/kg给药PEG化TD-1脂质体导致肿瘤体积的显著(p<0.05)减小,抑制肿瘤生长81%并增加肿瘤生长延迟17天(表14)。相比于对照或多西他赛具有显著的(p<0.05)生存增加。多西他赛未在小鼠中显著减小A253肿瘤体积或延长存活。PEG化TD-1脂质体出现抗肿瘤响应而未观测到毒性,所有动物耐受了给药后80天的观测期而无明显毒性(体重减轻),且在实验期间未观测到限定治疗相关性死亡。图7中描述了对肿瘤生长和存活的影响。
表14.采用PEG化TD-1脂质体或多西他赛治疗后具有A253移植瘤的小鼠中的疗效参数和存活
a=在治疗后第31天计算的肿瘤生长百分数抑制(TGI%)。
来自采用A549非小细胞肺癌(NSCLC)模型的研究数据证实,相比于生理盐水对照或多西他赛,以90mg/kg给药PEG化TD-1脂质体导致肿瘤体积的显著减小(p<0.05),抑制肿瘤生长89%(肿瘤生长抑制,TGI,%)并在40%动物中引起部分肿瘤消退(表15)。相反,给药多西他赛未在小鼠中显著减小A549肿瘤体积或延长存活。PEG化TD-1脂质体出现抗肿瘤响应而未观测到毒性。所有动物耐受给药后80天观测期而无明显毒性(体重减轻),且在实验期间未观测到限定治疗相关性死亡。图8中描述了对肿瘤生长和存活的影响。
表15.采用PEG化TD-1脂质体或多西他赛治疗后具有A549移植瘤的小鼠中的疗效参数和存活
采用相同NSCLC模型遵循21天间隔给予两次剂量获得了相似结果。以60或90mg/kg给药PEG化TD-1脂质体相比于以18或27mg/kg给药多西他赛或用生理盐水处理小鼠导致显著更小的肿瘤体积。虽然18和27mg/kg多西他赛也抑制肿瘤生长,但PEG化TD-1脂质体呈现出如通过TGD(肿瘤生长延迟)和部分肿瘤消退参数确定的更大抗肿瘤效应(表16)。PEG化TD-1脂质体相比于生理盐水在各评估剂量下增加存活,并且60和90mg/kg剂量水平相比于所有剂量的多西他赛均增加生存中值。图9中描述了对肿瘤生长的影响。
表16.采用多西他赛或PEG化TD-1脂质体治疗后具有A549移植瘤的小鼠中的疗效参数和存活
a经PEG化TD-1脂质体(90mg/kg)处理肿瘤未达到1cm3目标大小,并从TGD和TGD%排除。
来自采用PC3前列腺肿瘤模型的研究数据证实PEG化TD-1脂质体当以等毒剂量给予时具有大于多西他赛的抗肿瘤活性。相比于生理盐水处理小鼠,单一剂量的PEG化TD-1脂质体(19,38,or57mg/kg)导致肿瘤体积的显著(p<0.05)减小。虽然18和27mg/kg多西他赛也抑制肿瘤生长,但PEG化TD-1脂质体呈现出如通过TGD和部分肿瘤消退确定的更大抗肿瘤效应(表16)。PEG化TD-1脂质体在各评估剂量下显著(p<0.05)增加存活,且57mg/kgPEG化TD-1脂质体增加的存活显著(p<0.05)大于所有剂量的多西他赛。值得注意地,PEG化TD-1脂质体相比于非PEG化TD-1脂质体呈现出更大的肿瘤体积抑制。采用PEG化TD-1脂质体以19mg/kg处理导致相比于等毒剂量的多西他赛(9mg/kg)和TD-1脂质体(30mg/kg)显著更小的肿瘤,*,p<0.05。图10中描述了对肿瘤生长和存活的影响。
表17.采用多西他赛、TD-1脂质体或PEG化TD-1脂质体治疗后具有PC3移植瘤的小鼠中的疗效和存活参数
a经24mg/kgPEG化TD-1脂质体处理肿瘤未达到1cm3目标大小,并从TGD和TGD%排除。
来自采用MDA-MB-435/PTK7人乳腺抑制瘤的研究数据显示相比于生理盐水,给药单一剂量的PEG化TD-1脂质体(30、60或90mg/kg)导致更小的中位肿瘤体积。虽然18和27mg/kg多西他赛也抑制肿瘤生长,但PEG化TD-1脂质体呈现出如通过TGD、%TGI和部分肿瘤消退参数确定的更大抗肿瘤效应(表16)。PEG化TD-1脂质体在各评估剂量下增加存活,并且60和90mg/kgPEG化TD-1脂质体相比于所有剂量的多西他赛均增加存活。图11中描述了对肿瘤生长和存活的影响。
表18.采用多西他赛或PEG化TD-1脂质体治疗后具有MDA-MB-435/PTK7移植瘤的小鼠中的疗效参数和存活
当测试抗HT1080/PTK7人纤维肉瘤时,给药单一剂量的PEG化TD-1脂质体(30、60或90mg/kg)导致相比于生理盐水处理小鼠的肿瘤体积的显著(p<0.05)减小。虽然多西他赛(27mg/kg)也抑制肿瘤生长,但PEG化TD-1脂质体呈现出如通过TGI、TGD和部分肿瘤消退参数确定的更大抗肿瘤效应(表16)。PEG化TD-1脂质体在各评估剂量下显著(p<0.05)增加存活并且增加生存中值在生理盐水之上两至三倍。相反,多西他赛未显著增加存活。图12中描述了对肿瘤生长和存活的影响。
表19.采用多西他赛或PEG化TD-1脂质体治疗后具有HT1080/PTK7移植瘤的小鼠中的疗效参数和存活
a经多西他赛(9mg/kg)和PEG化TD-1脂质体(60mg/kg)处理肿瘤未达到1cm3目标大小,并从TGD和TGD%排除。
来自采用A431人表皮样移植瘤的研究数据显示给药单一剂量的PEG化TD-1脂质体(60或90mg/kg)导致相比于生理盐水处理动物的肿瘤体积显著(p<0.05)减小。虽然20和30mg/kg多西他赛也抑制肿瘤生长,但PEG化TD-1脂质体呈现出如通过TGD和部分肿瘤消退确定的更大抗肿瘤效应(表16)。各种PEG化TD-1脂质体处理(30、60或90mg/kg)增加的存活显著(p<0.05)高于生理盐水和所有剂量水平的多西他赛。图13中描述了对肿瘤生长和存活的影响。
表20.采用多西他赛或PEG化TD-1脂质体治疗后具有A431移植瘤的小鼠中的疗效参数和存活
a经多西他赛(30mg/kg)和PEG化TD-1脂质体(90mg/kg)处理肿瘤未达到1cm3目标大小,并从TGD和TGD%排除。
脂质组合物分析结果:
针对一系列脂质组合物评估了经由所述远程装载技术的TD-1(MP-3528)脂质体的制备。选择这些组合物以评估提供经包封TD-1、同时允许嵌入DSPE-PEG而无显著TD-1损失或水解的制剂的宽幅。用于制备这些制剂的方法学可概括如下:
1)包含经包封硫酸铵的囊泡的制备
a.将脂质溶于醇(EtOH)中,然后将其加至硫酸铵水溶液
b.挤出所得囊泡以获得明确定义的粒径
c.进行渗滤以除去未包封硫酸铵
2)将MP-3528远程装载入所述硫酸铵囊泡
3)将DSPE-PEG嵌入含有远程装载MP-3528的囊泡
4)针对组氨酸/生理盐水缓冲溶液渗滤
选择用于此研究的脂质包含各种特性,其包括:二烷基-甘油-磷脂酰胆碱链长的差异(C14-C18)、二烷基-甘油-磷脂酰胆碱脂肪酸中的不饱和、混合物中胆固醇摩尔%的变化以及DSPE-PEG中PEG的链长。
通过以下评判TD-1(MP-3528)脂质体制剂的成功制备:
1)如通过药物与总脂质比率测定的MP-3528包封。较高值表明高水平的远程装载入囊泡(数值低于0.1表明小于最佳远程装载或在DSPE-PEG嵌入步骤期间损失药物)
2)从制剂释放的MP-3528%(游离%),较高的游离%值提示药物保留不佳(>25%)
3)多西他赛%,低值表明成功制备而无前药的显著水解(>5%)
4)囊泡粒径作为处理期间囊泡完整性的指示(粒径大于120nm提示处理期间不可接受的改变)
5)远程装载MP-3528后的DSPE-PEG并入囊泡(<1摩尔%的低值指示并入不佳)
图14提供了所评估组合物的表。
结果:
所有包含约45%(摩尔)或更多胆固醇的所制备制剂均得到满足以上标准的组合物(实施例1、2、5、6、7、8、10)。不饱和、饱和PC(SOPC和POPC)的混合得到有关游离药物%的可接受结果(实施例11-13),以及包含带负电荷DSPG的制剂(实施例16)。
采用25%(摩尔)胆固醇水平研究的所有制剂得到不满足至少一项以上标准的组合物(实施例3、18和21)。通常,这些制剂存在药物并入不足(实施例18和21)或药物%是“游离的”(实施例3),且在一些情况下很少或未并入DSPE-PEG(实施例18和21)。
对于包含>C16的链长,以及两条链都是饱和或不饱和情况下的PC,中间胆固醇水平(35%摩尔)得到了可接受的组合物(实施例4、9、14)。在一些实施例中,POPC、SOPC、DPPC和DMPC未产生可接受的组合物(实施例15、17、19和20)。所述POPC和SOPC实施例(15和17)具有不可接受的“游离”药物水平而所述DPPC和DMPC实施例(19和20)未包含足够量的药物。
显示使用DSPE-PEG(2000)或DSPE-PEG(5000)是可接受的(对于DSPE-PEG(5000)–实施例8)。
虽然为了清楚和理解的目的,以上以示例和实施例的方式进行了相当详细地描述,但是本领域技术人员将会认识到可在所附权利要求的范围内实施某些改变和修饰。此外,本文中提供的各参考文献通过引用其整体并入,并达到如各参考文献通过引用单独并入的相同程度。
Claims (40)
1.一种用于制备紫杉烷脂质体的方法,所述方法包括:
a)形成具有包含磷脂酰胆碱脂和甾醇的脂质双层的第一脂质体,其中所述脂质双层包封包含水溶液的内部隔室;
b)用紫杉烷或其药学上可接受的盐装载所述第一脂质体,以形成经装载脂质体,其中所述紫杉烷是在2′-O-位用杂环基-(C2-5烷酰基)基团酯化的多西他赛;以及
c)在足以允许将PEG-脂质嵌入所述脂质双层的条件下形成包含经装载脂质体和聚(乙二醇)-磷脂缀合物(PEG-脂质)的混合物;
从而形成所述紫杉烷脂质体。
2.权利要求1所述方法,其中所述紫杉烷脂质体具有0.12至0.25的药物脂质比。
3.权利要求1所述方法,其中所述紫杉烷脂质体具有0.14至0.19的药物脂质比。
4.权利要求1或2所述方法,其中存在于所述紫杉烷脂质体中的甾醇是胆固醇,且其以相对于脂质量的约30%至45重量%的量存在。
5.权利要求1至3任一项所述方法,其中存在于所述紫杉烷脂质体中的甾醇是胆固醇,且其以相对于脂质量的约40%至45重量%的量存在。
6.权利要求1所述方法,其中所述第一脂质体由选自以下的脂质胆固醇组合而形成:DSPC/DSPE/胆固醇,45/10/45;DOPC/胆固醇,55/45;DOPC/胆固醇,65/35;HSPC/胆固醇,55/45;DSPC/胆固醇,55/45;DMPC/胆固醇,55/45;DSPC/胆固醇,65/35;DPPC/胆固醇,55/45;SOPC/胆固醇,55/45;POPC/胆固醇,55/45;HSPC/胆固醇,65/35;且其中所述PEG-脂质的嵌入导致PEG-脂质的量为脂质、胆固醇和PEG-脂质总量的约1.9%至约5.0重量%。
7.权利要求1所述方法,其中所述第一脂质体由选自以下的脂质胆固醇组合而形成:SOPC/胆固醇和POPC/胆固醇,其中胆固醇以约42-48mol%的量存在,且其中所述PEG-脂质的嵌入导致PEG-脂质的量为脂质、胆固醇和PEG-脂质总量的约1.9%至约5.0重量%。
8.权利要求1所述方法,其中所述第一脂质体由选自以下的脂质胆固醇组合而形成:DOPC/胆固醇、HSPC/胆固醇、DSPC/胆固醇和DPPC/胆固醇,其中胆固醇以约30-48mol%的量存在,且其中所述PEG-脂质的嵌入导致PEG-脂质的量为脂质、胆固醇和PEG-脂质总量的约1.9%至约5.0重量%。
9.权利要求1所述方法,其中所述杂环基-(C2-5烷酰基)基团选自由以下构成的组:5-(4-甲基哌嗪-1-基)-戊酰基、4-(4-甲基哌嗪-1-基)-丁酰基、3-(4-甲基哌嗪-1-基)-丙酰基、2-(4-甲基哌嗪-1-基)-乙酰基、5-吗啉代-戊酰基、4-吗啉代-丁酰基、3-吗啉代-丙酰基、2-吗啉代-乙酰基、5-(哌啶-1-基)戊酰基、4-(哌啶-1-基)丁酰基、3-(哌啶-1-基)丙酰基和2-(哌啶-1-基)-乙酰基。
10.权利要求1所述方法,其中所述杂环基-(C2-5烷酰基)基团为4-(4-甲基哌嗪-1-基)-丁酰基。
11.权利要求1所述方法,其中所述磷脂酰胆碱脂选自由以下构成的组:二棕榈酰磷脂酰胆碱(DPPC)、二硬脂酰磷脂酰胆碱(DSPC)、氢化大豆磷脂酰胆碱(HSPC)及其混合物;且其中所述甾醇是胆固醇。
12.权利要求11所述方法,其中所述脂质双层包含DSPC和胆固醇,且其中所述DSPC:胆固醇比率为约55:45(mol:mol)。
13.权利要求11所述方法,其中所述脂质双层包含DSPC和胆固醇,且其中所述DSPC:胆固醇比率为约70:30(mol:mol)。
14.权利要求1至13任一项所述方法,其中所述第一脂质体的内部隔室包含硫酸铵水溶液。
15.权利要求14所述方法,其中装载所述第一脂质体包括在足以允许在所述第一脂质体的内部隔室中蓄积紫杉烷的条件下形成包含所述第一脂质体和所述紫杉烷或其药学上可接受的盐的水溶液。
16.权利要求15所述方法,其中步骤b)在约50℃至约70℃的温度下进行。
17.权利要求15所述方法,其中进行步骤b)以使得所述磷脂酰胆碱和甾醇的总重量与紫杉烷重量的比率为约1:0.01至约1:1。
18.权利要求17所述方法,其中所述磷脂酰胆碱和甾醇的总重量与紫杉烷重量的比率为约1:0.2。
19.权利要求1所述方法,其中所述PEG-脂质为二酰基-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)]。
20.权利要求19所述方法,其中所述PEG-脂质选自由以下构成的组:二硬脂酰-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)-2000](DSPE-PEG2000)和二硬脂酰-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)-5000](DSPE-PEG5000)。
21.权利要求1所述方法,其中进行步骤c)以使得所述磷脂酰胆碱和甾醇的组合与所述PEG-脂质的比率为约1000:1(mol:mol)至约20:1(mol:mol)。
22.权利要求21所述方法,其中所述磷脂酰胆碱和甾醇的组合与所述PEG-脂质的比率为约35:1(mol:mol)至约25:1(mol:mol)。
23.权利要求21所述方法,其中所述磷脂酰胆碱和甾醇的组合与所述PEG-脂质的比率为约33:1(mol:mol)。
24.权利要求21所述方法,其中所述磷脂酰胆碱和甾醇的组合与所述PEG-脂质的比率为约27:1(mol:mol)。
25.权利要求1-24任一项所述方法,其中步骤c)在约35℃至约70℃的温度下进行。
26.权利要求25所述方法,其中步骤c)在约50℃至约55℃的温度下进行。
27.权利要求1所述方法,其进一步包括将所述紫杉烷脂质体由步骤c)中所述混合物交换至实质上无未包封紫杉烷和未嵌入PEG-脂质的水溶液。
28.权利要求1-27任一项所述方法,其进一步包括冻干所述紫杉烷脂质体。
29.根据权利要求1-28任一项所述方法制备的紫杉烷脂质体。
30.一种用于治疗癌症的方法,所述方法包括给药至有此需要的受试者根据权利要求1-28任一项所述方法制备的紫杉烷脂质体。
31.一种用于治疗癌症的包含脂质体的组合物,其中所述脂质体包含:
i)磷脂酰胆碱脂;
ii)甾醇;
iii)PEG-脂质;和
iv)紫杉烷或其药学上可接受的盐;
其中所述紫杉烷是在2′-O-位用杂环基-(C2-5烷酸)酯化的多西他赛;且
其中所述PEG-脂质构成所述脂质体中总脂质的2-8mol%。
32.权利要求31所述组合物,其中所述杂环基-(C2-5烷酸)选自由以下构成的组:5-(4-甲基哌嗪-1-基)-戊酸、4-(4-甲基哌嗪-1-基)-丁酸、3-(4-甲基哌嗪-1-基)-丙酸、2-(4-甲基哌嗪-1-基)-乙酸、5-吗啉代-戊酸、4-吗啉代-丁酸、3-吗啉代-丙酸、2-吗啉代-乙酸、5-(哌啶-1-基)戊酸、4-(哌啶-1-基)丁酸、3-(哌啶-1-基)丙酸和2-(哌啶-1-基)乙酸。
33.权利要求31所述组合物,其中所述杂环基-(C2-5烷酸)是4-(4-甲基哌嗪-1-基)-丁酸。
34.权利要求31所述组合物,其中所述磷脂酰胆碱脂选自由以下构成的组:二棕榈酰磷脂酰胆碱(DPPC)、二硬脂酰磷脂酰胆碱(DSPC)、氢化大豆磷脂酰胆碱(HSPC)及其混合物;且其中所述甾醇是胆固醇。
35.权利要求31所述组合物,其中所述PEG-脂质是二酰基-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)]。
36.权利要求31所述组合物,其中所述PEG-脂质选自由以下构成的组:二硬脂酰-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)-2000]和二硬脂酰-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)-5000]。
37.权利要求31所述组合物,其中所述脂质体包含约50mol%至约70mol%选自由DPPC和DSPC构成的组的磷脂酰胆碱脂和约25mol%至约45mol%胆固醇。
38.权利要求37所述组合物,其中所述脂质体包含约53mol%DSPC、约44mol%胆固醇和约3mol%所述PEG-脂质,其中所述PEG-脂质是二硬脂酰-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)-2000]。
39.权利要求37所述组合物,其中所述脂质体包含约66mol%DSPC、约30mol%胆固醇和约4mol%所述PEG-脂质,其中所述PEG-脂质是二硬脂酰-磷脂酰乙醇胺-N-[甲氧基(聚乙二醇)-2000]。
40.一种用于治疗癌症的方法,所述方法包括向有此需要的受试者给药根据权利要求31-39任一项制备的紫杉烷脂质体。
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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Publication number | Priority date | Publication date | Assignee | Title |
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JP6294456B2 (ja) * | 2013-03-13 | 2018-03-14 | マリンクロッド エルエルシー | 修飾されたドセタキセルリポソーム製剤 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102038641A (zh) * | 2009-10-26 | 2011-05-04 | 石药集团中奇制药技术(石家庄)有限公司 | 一种外层经亲水聚合物修饰的脂质体药物的制备方法 |
CN102105135A (zh) * | 2008-05-23 | 2011-06-22 | 英属哥伦比亚大学 | 用于脂质体纳米颗粒的修饰的药物 |
CN102188713A (zh) * | 2011-05-09 | 2011-09-21 | 中山大学 | 一种肝靶向药物组合物及其制备方法 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994005282A1 (en) | 1992-09-04 | 1994-03-17 | The Scripps Research Institute | Water soluble taxol derivatives |
US5824701A (en) | 1993-10-20 | 1998-10-20 | Enzon, Inc. | Taxane-based prodrugs |
US6107332A (en) | 1995-09-12 | 2000-08-22 | The Liposome Company, Inc. | Hydrolysis-promoting hydrophobic taxane derivatives |
TW520297B (en) * | 1996-10-11 | 2003-02-11 | Sequus Pharm Inc | Fusogenic liposome composition and method |
US6541508B2 (en) | 1999-09-13 | 2003-04-01 | Nobex Corporation | Taxane prodrugs |
CA2383259A1 (en) * | 2002-04-23 | 2003-10-23 | Celator Technologies Inc. | Synergistic compositions |
WO2004043363A2 (en) * | 2002-11-06 | 2004-05-27 | Azaya Therapeutics, Inc. | Protein-stabilized liposomal formulations of pharmaceutical agents |
US20070003607A1 (en) * | 2003-09-02 | 2007-01-04 | Vibhudutta Awasthi | Neutral liposome-encapsulated compounds and methods of making and using thereof |
JP2008515929A (ja) * | 2004-10-08 | 2008-05-15 | アルザ コーポレイション | 脂質連結部分を予備形成した脂質集合体にマイクロ波を使用して挿入する方法 |
BRPI0610026A2 (pt) * | 2005-04-22 | 2010-05-18 | Alza Corp | composição de imunolipossoma para direcionamento a um receptor celular her2 |
CN101485629B (zh) * | 2008-01-16 | 2013-01-23 | 沈阳药科大学 | 一种给药系统及其制备方法 |
US20120231066A1 (en) * | 2011-01-24 | 2012-09-13 | Henry John Smith | Multi-drug liposomes to treat tumors |
CN103338747A (zh) * | 2011-01-28 | 2013-10-02 | 皇家飞利浦电子股份有限公司 | 用于局部释放亲水性前药的载体 |
JP6294456B2 (ja) * | 2013-03-13 | 2018-03-14 | マリンクロッド エルエルシー | 修飾されたドセタキセルリポソーム製剤 |
-
2014
- 2014-03-13 JP JP2016502155A patent/JP6294456B2/ja not_active Expired - Fee Related
- 2014-03-13 CN CN201480026436.6A patent/CN105188675A/zh active Pending
- 2014-03-13 MX MX2015012201A patent/MX2015012201A/es unknown
- 2014-03-13 CA CA2903255A patent/CA2903255C/en not_active Expired - Fee Related
- 2014-03-13 WO PCT/US2014/026483 patent/WO2014160392A1/en active Application Filing
- 2014-03-13 BR BR112015022819A patent/BR112015022819A8/pt not_active IP Right Cessation
- 2014-03-13 US US14/208,324 patent/US20140271822A1/en not_active Abandoned
- 2014-03-13 EP EP14722857.1A patent/EP2968145A1/en not_active Withdrawn
-
2017
- 2017-09-15 JP JP2017177620A patent/JP2017214433A/ja active Pending
-
2018
- 2018-09-18 JP JP2018173770A patent/JP2019006815A/ja active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102105135A (zh) * | 2008-05-23 | 2011-06-22 | 英属哥伦比亚大学 | 用于脂质体纳米颗粒的修饰的药物 |
CN102038641A (zh) * | 2009-10-26 | 2011-05-04 | 石药集团中奇制药技术(石家庄)有限公司 | 一种外层经亲水聚合物修饰的脂质体药物的制备方法 |
CN102188713A (zh) * | 2011-05-09 | 2011-09-21 | 中山大学 | 一种肝靶向药物组合物及其制备方法 |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109310782A (zh) * | 2016-03-16 | 2019-02-05 | 梅里麦克制药股份有限公司 | 肝配蛋白受体A2(EphA2)靶向性的多西他赛生成纳米脂质体组合物 |
WO2019218857A1 (zh) * | 2018-05-18 | 2019-11-21 | 上海维洱生物医药科技有限公司 | 一种多西他赛棕榈酸酯脂质体及其制备方法 |
CN110496103A (zh) * | 2018-05-18 | 2019-11-26 | 上海维洱生物医药科技有限公司 | 一种多西他赛棕榈酸酯脂质体及其制备方法 |
CN110496103B (zh) * | 2018-05-18 | 2022-05-10 | 上海维洱生物医药科技有限公司 | 一种多西他赛棕榈酸酯脂质体及其制备方法 |
CN110571005A (zh) * | 2019-09-27 | 2019-12-13 | 广西科技大学 | 一种固定化金属离子-磁性脂质体及其制备方法和应用 |
CN110571005B (zh) * | 2019-09-27 | 2021-01-01 | 广西科技大学 | 一种固定化金属离子-磁性脂质体及其制备方法和应用 |
WO2021109944A1 (zh) * | 2019-12-03 | 2021-06-10 | 沈阳药科大学 | 卡巴他赛弱碱性衍生物及其制剂 |
CN114588279A (zh) * | 2022-03-31 | 2022-06-07 | 重庆医科大学附属第二医院 | 一种多功能纳米分子探针及其制备方法和其作为视网膜母细胞瘤诊疗制剂的应用 |
CN114588279B (zh) * | 2022-03-31 | 2023-10-20 | 重庆医科大学附属第二医院 | 一种多功能纳米分子探针及其制备方法和其作为视网膜母细胞瘤诊疗制剂的应用 |
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