CN113546054A - 包含依鲁替尼的组合物 - Google Patents
包含依鲁替尼的组合物 Download PDFInfo
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- CN113546054A CN113546054A CN202110822502.2A CN202110822502A CN113546054A CN 113546054 A CN113546054 A CN 113546054A CN 202110822502 A CN202110822502 A CN 202110822502A CN 113546054 A CN113546054 A CN 113546054A
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- Prior art keywords
- ibrutinib
- sodium
- composition
- another embodiment
- pharmaceutical composition
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- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title claims abstract description 131
- 229960001507 ibrutinib Drugs 0.000 title claims abstract description 131
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 100
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 76
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 57
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 24
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Abstract
本文讨论了包含依鲁替尼的药物组合物及其制备方法。所述组合物可用于治疗多种病症,包括但不限于B细胞增殖性疾病,诸如非霍奇金淋巴瘤(弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤或伯基特淋巴瘤)、瓦尔登斯特伦巨球蛋白血症、浆细胞骨髓瘤、慢性淋巴细胞性白血病、淋巴瘤或白血病。这些组合物被设计成用于口服给药。所述组合物容纳于胶囊诸如标准胶囊或喷洒胶囊,或呈液体制剂诸如悬浮液形式。在一个实施方案中,所述药物组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。在另一个实施方案中,所述药物组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、柠檬酸一水合物、磷酸氢二钠、三氯蔗糖、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠、浓盐酸、氢氧化钠和水。
Description
技术领域
本发明涉及包含依鲁替尼的组合物及其使用方法。
背景技术
靶向治疗涉及鉴定癌细胞和正常细胞之间的特异性差异。这些差异用于创建靶向治疗以攻击癌细胞而不损害正常细胞,从而导致较少的副作用。差异存在于各种靶向治疗之间但全部均干扰癌细胞生长、分裂、修复和/或与其它细胞通信的能力。
依鲁替尼为靶向B细胞恶性肿瘤的抗癌药物。依鲁替尼阻断刺激恶性B细胞不受控制地生长和分裂的信号。其于2013年11月被US FDA批准用于治疗套细胞淋巴瘤,并于2014年2月被批准用于治疗慢性淋巴细胞性白血病。其为经由共价键合到BTK活性位点中的半胱氨酸残基Cys-481的酶,布鲁顿氏酪氨酸激酶(BTK)的经口服给药的选择性共价抑制剂(IC50=0.46nM)。BTK为B细胞抗原受体(BCR)和细胞因子受体通路的信号分子。BCR通路在多种B细胞恶性肿瘤中,包括MCL和B细胞CLL中被涉及。依鲁替尼在美国以口服胶囊形式出售(ImbruvicaTM)。
本领域需要包含依鲁替尼的另选的制剂。
发明内容
在一个方面,提供药物组合物,所述药物组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。在一个实施方案中,所述组合物包含约40至约45重量%的依鲁替尼。
在一个方面,提供药物组合物,所述药物组合物包含(i)约40至约45重量%的依鲁替尼;(ii)约44至约47重量%的微晶纤维素;(iii)约6至约8重量%的交联羧甲基纤维素钠;(iv)约1至约5重量%的月桂基硫酸钠;和(v)约0.2至约0.3重量%的硬脂酸镁。
在另一个方面,提供药物组合物,所述药物组合物包含(i)约140mg的依鲁替尼;(ii)约151mg的微晶纤维素;(iii)约23mg的交联羧甲基纤维素钠;(iv)约14mg的月桂基硫酸钠;和(v)约1.6mg的硬脂酸镁。
在另一个方面,提供药物组合物,所述药物组合物包含(i)约50mg的依鲁替尼;(ii)约54mg的微晶纤维素;(iii)约8mg的交联羧甲基纤维素钠;(iv)约5mg的月桂基硫酸钠;和(v)约0.6mg的硬脂酸镁。
在另一个方面,提供胶囊和小袋,其包含本文所述的药物组合物中的至少一种。在某些实施方案中,胶囊为标准或喷洒胶囊。
在另一个方面,提供药物组合物,所述药物组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、柠檬酸一水合物、磷酸氢二钠、三氯蔗糖、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠、浓盐酸、氢氧化钠和水。
在另一个方面,提供药物组合物,所述药物组合物包含(i)约70mg/mL的依鲁替尼;(ii)约13mg的微晶纤维素和羧甲基纤维素钠的组合;(iii)约2.5mg/mL的羟丙基甲基纤维素;(iv)约1.5mg/mL的柠檬酸一水合物;(v)约1.4mg/mL的磷酸氢二钠;(vi)约1mg/mL的三氯蔗糖;(vii)约1mg/mL的对羟基苯甲酸甲酯钠;和(viii)约0.6mg/mL的对羟基苯甲酸乙酯钠。
在其它方面,提供药物组合物,所述药物组合物包含(i)约40mg/mL的依鲁替尼;(ii)约14mg的微晶纤维素和羧甲基纤维素钠的组合;(iii)约1mg/mL的羟丙基甲基纤维素;(iv)约1.5mg/mL的柠檬酸一水合物;(v)约1.4mg/mL的磷酸氢二钠;(vi)约0.5mg/mL的三氯蔗糖;(vii)约1.4mg/mL的对羟基苯甲酸甲酯钠;和(viii)约0.6mg/mL的对羟基苯甲酸乙酯钠。
在另一个方面,提供用于治疗B细胞增殖性疾病的方法,所述方法包括将至少一种本文所述的药物组合物施用给对其有需要的受治疗者的步骤。在某些实施方案中,所述B细胞增殖性疾病为非霍奇金淋巴瘤、瓦尔登斯特伦巨球蛋白血症、浆细胞骨髓瘤、或慢性淋巴细胞性白血病。
在另一个方面,提供用于治疗淋巴瘤的方法,所述方法包括将至少一种本文所述的组合物施用给对其有需要的受治疗者。
在另一个方面,提供用于治疗白血病的方法,所述方法包括将至少一种本文所述的组合物施用给对其有需要的受治疗者。
在另一个方面,提供用于治疗已经接受对套细胞淋巴瘤的至少一种在先治疗的受治疗者中的套细胞淋巴瘤的方法,所述方法包括每天一次将至少一种本文所述的组合物施用给受治疗者。
在另一个方面,本文的治疗方法涉及使用喷洒胶囊,所述喷洒胶囊打开以有助于将胶囊的内容物喷洒到食物或饮料中。在一个实施方案中,所述饮料为水。在另一个实施方案中,所述食物为软食物。胶囊内容物还可在投入合适的载体诸如水、牛奶、或其它常见饮料中之后,经由饲管给药。请注意,悬浮制剂也可经由饲管给药。
在另一个方面,提供用于制备本文所述的组合物的方法,所述方法包括:(a)将微晶纤维素、第一部分月桂基硫酸钠和第一部分交联羧甲基纤维素钠共混;(b)将步骤(a)的产物与第一部分的依鲁替尼共混;(c)将步骤(b)的产物与第二部分的依鲁替尼共混;(d)将步骤(c)的产物与第一部分的硬脂酸镁共混;(e)辊压步骤(d)的产物;(f)研磨步骤(e)中制得的带状物;(g)将步骤(e)中制得的颗粒与第二部分的月桂基硫酸钠和交联羧甲基纤维素钠共混;以及(h)将步骤(g)的产物与第二部分的硬脂酸镁共混。在一个实施方案中,所述方法还包括(i)向胶囊添加步骤(h)的产物。
在另一个方面,提供制备本文所述的组合物的方法,所述方法包括:(a)将水、微晶纤维素、交联羧甲基纤维素钠混合;(b)将水与羟丙基甲基纤维素混合;(c)将步骤(b)的产物与依鲁替尼混合;(d)将步骤(a)和(c)的产物混合;(e)将步骤(d)的产物与三氯蔗糖混合;(f)将步骤(e)的产物与对羟基苯甲酸甲酯钠和对羟基苯甲酸乙酯钠混合;(g)将步骤(f)的产物与一水合柠檬酸混合;以及(h)将步骤(g)的产物与无水磷酸氢二钠混合。在一个实施方案中,所述方法还包括(i)将步骤(h)的产物的pH调节成pH为约6。在另一个实施方案中,所述方法还包括向步骤(h)或(i)的产物添加水。在另一个方面,所述方法还包括将组合物加入小瓶中。
本发明的其它方面和优点还描述于其优选的实施方案的以下详细说明中。
附图说明
当结合附图阅读时进一步理解本申请。出于说明主题的目的,在附图中示出了所述主题的示例性实施方案;然而目前公开的主题不限于本发明所公开的具体组成、方法、装置和体系。另外,附图未必按比例绘制。
图1提供了用于制备包含依鲁替尼的胶囊的工艺流程图。
图2提供了用于制备包含依鲁替尼的液体制剂的工艺流程图。
图3提供了用于大规模制备包含依鲁替尼的液体制剂的工艺流程图。
具体实施方式
结合对构成本公开一部分的所附的附图和实施例的下列详细说明,可以更容易地理解本发明。应当理解,本发明不限于本文所描述和/或示出的具体产品、方法、条件或参数,并且本文所用术语仅用于以举例方式描述具体实施方案,并不旨在限制受权利要求书保护的本发明。相似地,除非另外说明,否则关于可能的机制或作用模式或改善原因的任何描述仅旨在出于示例性目的,并且本文的发明不受任何此类建议的机制或作用模式或改善原因的正确或错误的约束。在本文中,应当认识到,说明涉及制备和使用本文所述的组合物的特征结构和方法。
在本公开中,除非上下文相反地明确指出,否则单数“一个”、“一种”和“该”包括复数含义,对具体数值的引用至少包括该具体数值。因此,例如当提及“一种材料”时,是指至少一种此类材料,以及本领域的技术人员已知的该材料的等同物,等等。
当使用描述语“约”或“基本上”将值表示为近似值时,应当理解,该具体值构成了另一个实施方案。一般来讲,术语“约”或“基本上”的使用指示可根据本发明所公开的主题要获得的所需特性变化并且将在使用其的具体上下文中基于其功能进行解释的近似值。本领域的技术人员将能够按常规对其进行解释。在一些情况下,用于具体值的有效数字的数目可以是一种确定词“约”或“基本上”的程度的非限制性方法。在其它情况下,用于一系列值的梯度可用于针对每个值确定术语“约”或“基本上”的预期范围。在存在的情况下,所有范围均包括端点值并且是可组合的。也就是说,在提到以范围形式表述的值时,包括该范围内的每个值。
当提供一个列表时,除非另行指出,否则应当理解,该列表中的每个单独元素和该列表的每种组合将被视为单独的实施方案。例如,以“A、B或C”提供的实施方案列表将被视为包括实施方案“A”、“B”、“C”、“A或B”、“A或C”、“B或C”、或“A、B或C”。
应当理解,为清楚起见,本发明的某些特征在单独实施方案的上下文中进行阐述,但也可以组合形式提供在单个实施方案中。也就是说,除非明显不相容或被排除在外,否则每个单独实施方案被认为可与任何其它实施方案组合,并且这种组合被视为另一个实施方案。相反地,为简明起见,本发明的各种特征在单个实施方案的上下文中进行阐述,也可单独地或以任何子组合形式提供。还应当注意,权利要求书可制定为排除任何任选的元素。同样地,这一声明旨在当结合权利要求元素的表述“单独地”、“唯一地”等使用此类专用术语时,或使用“负”限制时充当先行基础。最终,当实施方案可描述为一系列步骤的一部分或更普遍的结构的一部分时,每个所述步骤本身也可视为一个独立的实施方案。
如本文所用,术语“受治疗者”是指需要依鲁替尼治疗病症的动物。在一个实施方案中,受治疗者为人。在另一个实施方案中,受治疗者为成人,包括青少年、成年人、老年人或儿童,包括少年。
如本文所用,术语“经纯化的”优选是指包含少于约1%杂质的依鲁替尼。在一个实施方案中,依鲁替尼包含少于约0.5%杂质。在另一个实施方案中,依鲁替尼包含少于约0.1%杂质。在另一个实施方案中,依鲁替尼为约100%纯。
如本文所用,术语颗粒内和颗粒外在制剂领域中是已知的。在颗粒形成之前,添加制剂组分的颗粒内形式。类似地,在压缩之前,将制剂组分的颗粒外形式加入制剂的颗粒中。简单地说,颗粒外部分将组合物分解成颗粒,并且颗粒内部分将颗粒崩解以释放依鲁替尼、其盐、前药或代谢物。
本文所用的缩写包括CCS(交联羧甲基纤维素钠)、MCC(微晶纤维素)、SLS(月桂基硫酸钠)、HPMC(羟丙基甲基纤维素;羟丙甲纤维素)、DSC(差示扫描量热计)、BHT(丁基化羟基甲苯)、BHA(丁基化羟基苯甲醚)、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠、CLL(慢性淋巴细胞白血病)和SLL(小淋巴细胞淋巴瘤)。
A.依鲁替尼形式
本文所述的组合物包含依鲁替尼(Imbruvica)作为活性剂。依鲁替尼如美国专利7,514,444、8,003,309、8,697,711、8,735,403、8,957,079和8,754,091中所述并可如其中所示制备,所述专利文献以引用方式并入本文。如本领域所已知的,依鲁替尼为1-[(3R)-3-[4-氨基-3-(4-苯氧苯基)-1H-吡唑并[3,4d]嘧啶-1-基]-1-哌啶基]-2-丙烯-1-酮并具有以下结构。依鲁替尼具有约149℃至约158℃的熔点范围,在pH为7下约4的分配系数,约3.7的离解常数,和在约156℃下起始的DSC熔点。
本文所用的依鲁替尼可包括其它形式,包括其代谢物,前提条件是依鲁替尼形式是稳定且非毒性的。依鲁替尼形式还可具有基础依鲁替尼分子的一些或与所述基础依鲁替尼分子相同的活性。在一个实施方案中,依鲁替尼的活性代谢物具有以下结构。
用于本文的依鲁替尼形式可包括依鲁替尼、前药和盐的互变异构形式。在一个实施方案中,依鲁替尼可衍生自药学上或生理上可接受的酸、碱、碱金属和碱土金属。生理上可接受的酸包括来自无机酸和有机酸的那些。无机酸在本领域中是已知的并且包括但不限于盐酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸。有机酸在本领域中也是已知的,并且包括但不限于乳酸、甲酸、乙酸、富马酸、柠檬酸、丙酸、草酸、琥珀酸、乙醇酸、葡萄糖醛酸、马来酸、糠酸、谷氨酸、苯甲酸、邻氨基苯甲酸、水杨酸、酒石酸、丙二酸、苹果酸、苯乙酸、扁桃酸、扑酸、甲磺酸、乙磺酸、泛酸、苯磺酸、甲苯磺酸、硬脂酸、磺胺酸、海藻酸和半乳糖醛酸。无机碱在本领域中也是已知的,并且包括但不限于铝、钙、锂、镁、钾、钠和锌的硫酸盐或磷酸盐。类似地,有机碱在本领域中也是已知的,并且包括但不限于N,N-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺和普鲁卡因。碱金属和碱土金属盐可包括但不限于呈酯和氨基甲酸酯形式的钠、钾、钙和镁盐。
还可以想到依鲁替尼的前药并且包括但不限于酯、氨基甲酸酯、硫酸盐、醚、肟、碳酸盐等等。当以此类形式给药时,前药形式在体内转换成活性部分。参见,Testa,“ProdrugsRevisited:The“AdHoc”Approach as a Complement to Ligand Design”,MedicinalResearch Reviews,16(3):233-241,编辑,John Wiley&Sons(1996),其以引用的方式并入本文。
依鲁替尼的“代谢物”也可如本文所述利用。如本领域所已知的,代谢物为当化合物代谢时形成的依鲁替尼的化合物,如“The Pharmacological Basis of Therapeutics”,第9版,McGraw-Hill(1996)中所述的,其以引用的方式并入。
B.固体制剂
依鲁替尼可以固体制剂形式配制用于给药于受治疗者。固体制剂为基本上干燥的,即,不含液体。在一个实施方案中,固体制剂为约90%或更多的干燥的。
在一个实施方案中,本文所述的药物组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。如上所述,该组合物中包含的依鲁替尼可以为基础分子、盐、前药、或其代谢物。
所述组合物包含约40至约45重量%的依鲁替尼、其盐、前药或代谢物。在一个实施方案中,所述组合物包含约41至约44重量%的依鲁替尼、其盐、前药或代谢物。在另一个实施方案中,所述组合物包含约42至约43重量%的依鲁替尼、其盐、前药或代谢物。在另一个实施方案中,所述组合物包含约42或约43重量%的依鲁替尼、其盐、前药或代谢物。在另一个实施方案中,所述组合物包含约50至约140mg的依鲁替尼、其盐、前药或代谢物。在另一个实施方案中,所述组合物包含约50mg的依鲁替尼、其盐、前药或代谢物。
本文所述的液体组合物中可包含一种或多种悬浮剂。在一个实施方案中,本文所述的组合物中还可包含微晶纤维素。在另一个实施方案中,所述组合物包含约44至约47重量%的微晶纤维素。在另一个实施方案中,所述组合物包含约45至约46重量%的微晶纤维素。
所述组合物还包含交联羧甲基纤维素钠。所述交联羧甲基纤维素钠可以呈颗粒内或颗粒外形式。在一个实施方案中,所述组合物包含约6至约8重量%的交联羧甲基纤维素钠。在另一个实施方案中,所述组合物包含约7重量%的交联羧甲基纤维素钠。在另一个实施方案中,所述组合物包含约3至约5重量%的颗粒内交联羧甲基纤维素钠。在另一个实施方案中,所述组合物包含约4重量%的颗粒内交联羧甲基纤维素钠。在另一个实施方案中,所述组合物包含约2至约4重量%的颗粒外交联羧甲基纤维素钠。在另一个实施方案中,所述组合物包含约3重量%的交联羧甲基纤维素钠。在另一个实施方案中,所述组合物包含约13mg的颗粒内交联羧甲基纤维素钠和约9.9mg的颗粒外交联羧甲基纤维素钠。在另一个实施方案中,所述组合物包含约4.6mg的颗粒内交联羧甲基纤维素钠和约3.5mg的颗粒外交联羧甲基纤维素钠。
本文所述的组合物中还可包含月桂基硫酸钠。月桂基硫酸钠可以呈颗粒内或颗粒外形式。在一个实施方案中,所述组合物包含约1至约5重量%的月桂基硫酸钠。在另一个实施方案中,所述组合物包含约2至约4.5重量%的月桂基硫酸钠。在另一个实施方案中,所述组合物包含约3至约4重量%的月桂基硫酸钠。在另一个实施方案中,所述组合物包含约2.5至约3重量%的颗粒内月桂基硫酸钠。在另一个实施方案中,所述组合物包含约3重量%的颗粒内月桂基硫酸钠。在另一个实施方案中,所述组合物包含约1至约2重量%的颗粒外月桂基硫酸钠。在另一个实施方案中,所述组合物包含约1.4重量%的颗粒外月桂基硫酸钠。在另一个实施方案中,所述组合物包含约9.4mg的颗粒内月桂基硫酸钠和约4.6mg的颗粒外月桂基硫酸钠。在另一个实施方案中,所述组合物包含约3.3mg的颗粒内月桂基硫酸钠和约1.6mg的颗粒外月桂基硫酸钠。
本文所述的组合物还可包含硬脂酸镁。硬脂酸镁可以呈颗粒内或颗粒外形式。在一个实施方案中,所述组合物包含约0.4至约0.6重量%的硬脂酸镁。在另一个实施方案中,所述组合物包含约0.4至约0.5重量%的硬脂酸镁。在另一个实施方案中,所述组合物包含约0.45至约0.5重量%的硬脂酸镁。在另一个实施方案中,所述组合物包含约0.2至约0.3重量%的颗粒内硬脂酸镁。在另一个实施方案中,所述组合物包含约0.2至约0.3重量%的颗粒外硬脂酸镁。在另一个实施方案中,所述组合物包含约0.8mg的颗粒内硬脂酸镁和约0.8mg的颗粒外硬脂酸镁。在另一个实施方案中,所述组合物包含约0.3mg的颗粒内硬脂酸镁和约0.3mg的颗粒外硬脂酸镁。
在一个实施方案中,药物组合物在本文中描述并且包含颗粒内物质,所述颗粒内物质包括依鲁替尼、其盐、前药或代谢物、微晶纤维素、交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。
在另一个实施方案中,药物组合物包含颗粒外物质,所述颗粒外物质包括交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。
在另一个实施方案中,提供药物组合物并且包含:(i)约40至约45重量%的依鲁替尼;(ii)约44至约47重量%的微晶纤维素;(iii)约6至约8重量%的交联羧甲基纤维素钠;(iv)约1至约5重量%的月桂基硫酸钠;和(v)约0.2至约0.3重量%的硬脂酸镁。
在另一个实施方案中,提供药物组合物并且包含:(i)约140mg的依鲁替尼;(ii)约151mg的微晶纤维素;(iii)约23mg的交联羧甲基纤维素钠;(iv)约14mg的月桂基硫酸钠;和(v)约1.6mg的硬脂酸镁。
在另一个实施方案中,提供药物组合物并且包含:(i)约50mg的依鲁替尼;(ii)约54mg的微晶纤维素;(iii)约8mg的交联羧甲基纤维素钠;(iv)约5mg的月桂基硫酸钠;和(v)约0.6mg的硬脂酸镁。
在另一个实施方案中,提供药物组合物,所述药物组合物包含表1中的组分。
表1
本文所述的固体组合物包含具有最佳尺寸以允许组合物溶解的颗粒,例如所述颗粒小于或等于约10μ。所述组合物的颗粒的尺寸可通过使固体组合物通过不同尺寸的筛来测量。如果所述组合物的颗粒大于最佳尺寸并且如果所述组合物的颗粒不封装在胶囊中或溶解于一种或多种赋形剂中,则所述组合物的颗粒可经受进一步研磨和筛分步骤等,以减小粒度。依鲁替尼可任选在氮气下和施用于未微粉化依鲁替尼的常规微粉化技术,例如利用Trost或喷射磨来微粉化。然而,本文所述的组合物不限于由此制备依鲁替尼的方法。依鲁替尼可具有小于约10μm、小于约7μm、或小于约5μm的中值粒度。具体地,90%的颗粒小于或等于约10μm,并且50%的颗粒小于或等于约10μm,如由Malvern方法所测定的,其为本领域技术人员所容易理解的。
各种设备可用于进行制备固体组合物的制造过程,并且包括小尺寸、中尺寸和大尺寸的袋,不同尺寸的筛,和搅拌机。所述方法还可包括混合、挤出、熔融、压实和/或研磨组合物,其通常使用本领域技术人员选择的压实机和研磨机。研磨步骤可对不同尺寸的颗粒(即,大颗粒、粉末和细粉)来进行以获得更均匀的粒度。研磨可包括一个或多个分离、再循环和筛分步骤以获得期望的粒度。在一个实施方案中,所述组合物可通过基于组合物的总重量,将依鲁替尼与组合物的其它组分干混来制备。在另一个实施方案中,本文所述的组合物可通过基于组合物的总重量,将依鲁替尼与组合物的其它组分湿混来制备。干燥可使用由本领域技术人员选择的干燥仪器来进行。参见,例如,Lachman,“The Theory andPractice of Industrial Pharmacy”,第3版,(1986),其以引用的方式并入。
在一个实施方案中,本文所述的固体组合物通过以下方法制备:(a)将微晶纤维素、第一部分月桂基硫酸钠和第一部分交联羧甲基纤维素钠共混;(b)将步骤(a)的产物与第一部分的依鲁替尼共混;(c)将步骤(b)的产物与第二部分的依鲁替尼共混;(d)将步骤(c)的产物与第一部分的硬脂酸镁共混;(e)辊压步骤(d)的产物;(f)研磨步骤(e)中制得的带状物;(g)将步骤(f)中制得的颗粒与第二部分的月桂基硫酸钠和交联羧甲基纤维素钠共混;以及(h)将步骤(g)的产物与第二部分的硬脂酸镁共混。在另一个实施方案中,固体组合物如图1中所述制备。
然后,可将固体组合物形成为合适的给药单位以递送给患者,如通过本领域技术人员所确定的。合适的给药单位包括口服给药单位。在一个实施方案中,向胶囊添加组合物。在另一个实施方案中,胶囊用于儿科给药。在另一个实施方案中,胶囊用于由不能吞咽固体药物制剂的成人施用。在另一些实施方案中,胶囊为HPMC(羟丙甲纤维素)胶囊。在另一个实施方案中,胶囊为明胶胶囊。在另一个实施方案中,胶囊为硬明胶胶囊。在另一个实施方案中,胶囊为标准或喷洒胶囊。在另一个实施方案中,胶囊为瑞典橙胶囊。在另一个实施方案中,胶囊为0号胶囊。在另一个实施方案中,可打开喷洒胶囊并且将内容物加入可由受治疗者摄取的物质诸如食物或饮料中。所述食物可以为半固体或固体的,包括软食物。
在另一个实施方案中,包含依鲁替尼的胶囊为膜包衣的。合适的膜包衣将是本领域技术人员已知的。例如,膜包衣可以为聚合物诸如HPMC、乙基纤维素、聚乙烯醇、或它们的组合。
还可将固体组合物加入小袋中。如本文所用,术语“小袋”是指能够容纳本文所述的组合物的袋或箱。小袋的尺寸取决于待添加的组合物的量。在一个实施方案中,所述小袋为单剂量小袋。在另一个实施方案中,所述小袋包含大量本文所述的组合物。在后一情况下,患者、医师或护理者测量用于给药的组合物的适当剂量。在另一个实施方案中,所述小袋为纸/铝/聚乙烯层压体或聚酯/铝/聚乙烯层压体,两者可任选设置有阻隔涂层,诸如乙烯-乙酸乙烯酯、聚乙酸乙烯酯、聚硅氧烷或三聚氰胺等。在另一个实施方案中,可打开小袋并且将内容物加入可由受治疗者摄取的物质诸如食物或饮料中。所述饮料可包括但不限于水、牛奶或其它常用饮料。
固体组合物的液体制剂(以液体形式配制)可经由饲管给药于受治疗者。所述饲管可使用本领域的技术暂时或永久性附连到患者。根据需要,患者可以是清醒的、半清醒的、或熟睡的,如由主治医师所确定的。多种类型的饲管在本领域中是已知的并且可由主治医师选择。
C.液体制剂
依鲁替尼还可以液体制剂形式配制用于给药于受治疗者。液体包括但不限于悬浮液、糖浆和酏剂。这些给药单位容易使用本文所述的方法和本领域技术人员已知的那些来制备。当配制成悬浮液时,可发生颗粒沉降,从而需要使用本领域的技术将颗粒重新悬浮于悬浮液中。
本文所述的液体组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、柠檬酸一水合物、磷酸氢二钠、三氯蔗糖、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠、浓盐酸、氢氧化钠和水。
因此,所述液体组合物包含约30至约80mg/mL的依鲁替尼、其盐、前药或代谢物。在一些实施方案中,所述组合物包含约30至约50mg/mL的依鲁替尼、其盐、前药或代谢物。在另一个实施方案中,所述组合物包含约40mg/mL的依鲁替尼、其盐、前药或代谢物。在其它实施方案中,所述组合物包含约60至约80mg/mL至约70mg/mL的依鲁替尼、其盐、前药或代谢物。在另一个实施方案中,所述组合物包含约70mg/mL的依鲁替尼、其盐、前药或代谢物。
本文所述的液体组合物中可包含一种或多种悬浮剂。在一个实施方案中,所述液体组合物中还可包含微晶纤维素和羧甲基纤维素钠。在一些实施方案中,所述组合物包含约12至约15mg/mL的悬浮剂。在另一个实施方案中,所述组合物包含约13至约15mg/mL的悬浮剂。在其它实施方案中,所述组合物包含约12至约14mg/mL的悬浮剂。在另一个实施方案中,所述组合物包含约13mg/mL的悬浮剂。在另一个实施方案中,所述组合物包含约14mg/mL的悬浮剂。
所述组合物还可包含润湿剂中的一种或多种。在一个实施方案中,所述组合物包含羟丙基甲基纤维素。在一些实施方案中,所述组合物包含约0.5至约3mg/mL的润湿剂。在其它实施方案中,所述组合物包含约2至约3mg/mL的润湿剂。在另一个实施方案中,所述组合物包含约2.5mg/mL的润湿剂。在另一个实施方案中,所述组合物包含约0.5至约1.5mg/mL的润湿剂。在其它实施方案中,所述组合物包含约1mg/mL的润湿剂。
固体或液体组合物中可包含一种或多种缓冲剂。在一个实施方案中,缓冲剂为柠檬酸一水合物或磷酸氢二钠。在另一个实施方案中,所述组合物包含约2.5至约3.5mg/mL的缓冲剂。在一些实施方案中,所述组合物包含约1至约1.5mg/mL的第一缓冲剂。在其它实施方案中,所述组合物包含约0.5至约0.7mg/mL的缓冲剂。在另一个实施方案中,所述组合物包含约1.5mg/mL的第一缓冲剂和约1.5mg/mL的第二缓冲剂。在其它实施方案中,所述组合物包含约1.6mg/mL的第一缓冲剂和约1.4mg/mL的第二缓冲剂。在另一个实施方案中,所述组合物包含约1.5mg/mL或1.6mg/mL的柠檬酸一水合物。在另一个实施方案中,所述组合物包含约1.4mg/mL的磷酸氢二钠。
在本文所述的固体或液体组合物中还可包含甜味剂。在一个实施方案中,所述甜味剂为三氯蔗糖。在另一个实施方案中,所述组合物包含约0.1至约1.5mg/mL的甜味剂。在其它实施方案中,所述组合物包含0.5至约1.5mg/mL的甜味剂。在另一个实施方案中,所述组合物包含约1mg/mL的甜味剂。在另一个实施方案中,所述组合物包含约0.5mg/mL的甜味剂。
所述固体或液体组合物中还可包含一种或多种防腐剂。所述防腐剂在液体制剂中有利地提供最佳的微生物活性。在一个实施方案中,所述组合物保留尼泊金甲酯/尼泊金乙酯的最佳活性。在一个实施方案中,所述防腐剂为对羟基苯甲酸甲酯钠。在另一个实施方案中,所述防腐剂为对羟基苯甲酸乙酯钠。在另一个实施方案中,所述组合物包含约1.5至约2.5mg/mL的防腐剂。在其它实施方案中,所述组合物包含约1.5至约2mg/mL的防腐剂。在另一个实施方案中,所述组合物包含约0.5至约1.8mg/mL的第一防腐剂。在另一个实施方案中,所述组合物包含约1.0至约1.8mg/mL的第一防腐剂。在另一个实施方案中,所述组合物包含约1.25至约1.5mg/mL的第二防腐剂。在另一个实施方案中,所述组合物包含约1.1mg/mL的第一防腐剂和约0.6mg/mL的第二防腐剂。在其它实施方案中,所述组合物包含约1.4mg/mL的第一防腐剂和约0.7mg/mL的第二防腐剂。在另一个实施方案中,所述组合物包含约1mg/mL的对羟基苯甲酸甲酯钠。在另一个实施方案中,所述组合物包含约0.6mg/mL的对羟基苯甲酸乙酯钠。在另外的实施方案中,所述组合物包含约1.4mg/mL的对羟基苯甲酸甲酯钠。在另一个实施方案中,所述组合物包含约0.7mg/mL的对羟基苯甲酸乙酯钠。
如果溶液的pH需要调节,则可在所述组合物中包含pH调节剂。本领域技术人员将能够选择合适的pH调节剂来确保安全、稳定和受治疗者相容的组合物。在一个实施方案中,将组合物的pH值调节至约6。在另一个实施方案中,pH调节剂为酸或碱。在另一个实施方案中,pH调节剂为盐酸。在另一个实施方案中,pH调节剂为浓盐酸。在另一个实施方案中,pH调节剂为氢氧化钠。
最后,所述组合种可包含足量的稀释剂,诸如水,以确保约1mL的体积。在一个实施方案中,所述稀释剂为纯化水。包含较少量依鲁替尼的组合物可如本文所述通过使用稀释剂稀释包含更大量的依鲁替尼的组合物来制备。
在一个实施方案中,提供药物组合物并且包含:(i)约70mg/mL的依鲁替尼;(ii)约13mg的微晶纤维素和羧甲基纤维素钠;(iii)约2.5mg/mL的羟丙基甲基纤维素;(iv)约1.5mg/mL的柠檬酸一水合物;(v)约1.4mg/mL的磷酸氢二钠;(vi)约1mg/mL的三氯蔗糖;(vii)约1mg/mL的对羟基苯甲酸甲酯钠;和(viii)约0.6mg/mL的对羟基苯甲酸乙酯钠。
在另一个实施方案中,提供药物组合物并且包含表2的组分。
表2
组分 | 浓度(mg/mL) |
依鲁替尼,微粉化 | 70 |
MCC和CMC | 13 |
HPMC | 2.5 |
柠檬酸一水合物 | 1.513 |
磷酸氢二钠 | 1.38 |
三氯蔗糖 | 1 |
对羟基苯甲酸甲酯钠 | 1.145 |
对羟基苯甲酸乙酯钠 | 0.575 |
在其它实施方案中,提供药物组合物并且包含:(i)约40mg/mL的依鲁替尼;(ii)约14mg的微晶纤维素和羧甲基纤维素钠;(iii)约1mg/mL的羟丙基甲基纤维素;(iv)约1.6mg/mL的柠檬酸一水合物;(v)约1.4mg/mL的磷酸氢二钠;(vi)约0.5mg/mL的三氯蔗糖;(vii)约1.4mg/mL的对羟基苯甲酸甲酯钠;和(viii)约0.7mg/mL的对羟基苯甲酸乙酯钠。
在其它实施方案中,提供药物组合物并且包含表3的组分。
表3
组分 | 浓度(mg/mL) |
依鲁替尼,微粉化 | 40 |
MCC和CMC | 14 |
HPMC | 1 |
柠檬酸一水合物 | 1.602 |
磷酸氢二钠 | 1.38 |
三氯蔗糖 | 0.5 |
对羟基苯甲酸甲酯钠 | 1.3582 |
对羟基苯甲酸乙酯钠 | 0.6773 |
所述液体组合物可通过以下方法制备:(a)将水、微晶纤维素、交联羧甲基纤维素钠混合;(b)将水与羟丙基甲基纤维素混合;(c)将步骤(b)的产物与依鲁替尼混合;(d)将步骤(a)和(c)的产物混合;(e)将步骤(d)的产物与三氯蔗糖混合;(f)将步骤(e)的产物与对羟基苯甲酸甲酯钠和对羟基苯甲酸乙酯钠混合;(g)将步骤(f)的产物与一水合柠檬酸混合;以及(h)将步骤(g)的产物与无水磷酸氢二钠混合。所述方法还可包括(i)将步骤(h)的产物的pH调节成pH为约6。在一个实施方案中,步骤(i)使用盐酸或氢氧化钠进行。所述方法还包括向步骤(h)或(i)的产物添加水。还可设想可使用本领域已知的技术将步骤(a)的产物均化。
液体制剂然后可以作为本体单元储存或分配到独立地更小的小瓶中以由消费者存储或购买。本领域技术人员将容易地能够选择适用于本文的小瓶。在一个实施方案中,将所述液体组合物加入小瓶中。在另外的实施方案中,所述小瓶为玻璃。在另一个实施方案中,所述小瓶为透明的或琥珀色的。在另外的实施方案中,所述小瓶可以密封。在另一个实施方案中,所述小瓶用橡胶塞密封。在另外的实施方案中,所述小瓶用特氟隆涂覆的橡胶塞密封。所述塞子任选地包含可移除的,即可撕拉的铝盖。在另一个实施方案中,小瓶为10mL/20mm小瓶。在另外的实施方案中,小瓶为饮料瓶。
另外,在适宜的样品振摇以在给药前将颗粒重新悬浮之后,药物产品将以单剂量形式给药于每个受治疗者。此外,在药物产品给药后,将用适量水冲洗小瓶,并且小瓶的全部内容物将给药于受治疗者。出于上文提及的原因,即使沉降发生,也预计对递送剂量不具有影响。
D.附加组分
可将其它组分加入本文所述的组合物中,如由本领域技术人员所确定的。附加组分可以是惰性的并且不干扰所需的组合物组分的功能。因此,组合物可包括其它助剂、糖浆、酏剂、稀释剂、粘合剂、润滑剂、表面活性剂、造粒剂、崩解剂、润肤剂、金属螯合剂、pH调节剂、着色防腐剂、抗氧化剂、药剂、表面活性剂、填料、崩解剂或它们的组合。
防腐剂可包括抗坏血酸、BHT和BHA、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠或它们的组合。
甜味剂诸如天然或人造甜味剂、或它们的组合可包含在本文所述的组合物中。在一个实施方案中,天然甜味剂为三氯蔗糖,包括原糖、砂糖、红糖、糖粉和芸苔糖、果糖、蜂蜜、水果糖、高果糖玉米糖浆、玉米糖浆,糖醇如甘露糖醇、山梨醇、木糖醇、赤藓糖醇、氢化淀粉水解产物、乳糖醇或麦芽糖醇、osmalt、葡萄糖、转化糖、龙舌兰花蜜、葡萄糖、乳糖、麦芽糖、枫糖、椰枣糖、糖蜜、甜叶菊提取物、塔格糖、海藻糖或它们的任何组合。另一个实施方案,人造甜味剂为三氯蔗糖、阿斯巴甜、糖精、纽甜、糖精或乙酰磺胺酸钾。在另一个实施方案中,糖可以包含在组合物中。
粘合剂可包括但不限于纤维素、甲基纤维素、羟甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非晶纤维素、聚乙烯吡喀烷酮、聚乙烯吡咯烷酮(聚维酮,PVP)、明胶、阿拉伯胶和阿拉伯树胶、聚乙二醇、淀粉、糖诸如蔗糖、高岭土、葡萄糖和乳糖、胆固醇、黄蓍胶、硬脂酸、明胶、酪蛋白、卵磷脂(磷脂)、十八十六醇、鲸蜡醇、十六烷基酯蜡、糊精、葡聚糖、单油酸甘油酯、单硬脂酸甘油酯、甘油基棕榈酰硬脂酸酯、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物、聚氧乙烯硬脂酸酯、聚乙烯醇、明胶等。
润滑剂可包括无水硅酸、滑石、硬脂酸、月桂基硫酸钠、硬脂酸镁和硬脂酰富马酸钠等。
造粒剂可包括但不限于二氧化硅、淀粉、碳酸钙、果胶、交聚维酮和交联聚维酮。
崩解试剂或崩解剂可包括但不限于淀粉、羧甲基纤维素、取代的羟丙基纤维素、碳酸氢钠、磷酸钙、柠檬酸钙、羧基乙酸淀粉钠、预胶凝淀粉或交聚维酮。
润肤剂可包括但不限于硬脂醇、貂油、鲸蜡醇、油醇、月桂酸异丙酯、聚乙二醇、橄榄油、凡士林、棕榈酸、油酸和肉豆蔻酸肉豆蔻酯。
表面活性剂可包括但不限于聚山梨酯、脱水山梨糖醇酯、泊洛沙姆或月桂基硫酸钠。
金属螯合剂可包括但不限于生理上可接受的螯合剂,其包括乙二酸、苹果酸或富马酸。
本文所述的呈干燥或液体形式的组合物具有约5.5至约6.5的pH。pH调节剂可用于将包含依鲁替尼的溶液的pH调节成约6。pH调节剂可包括但不限于柠檬酸、抗坏血酸、富马酸、苹果酸、盐酸、氢氧化钠、它们的盐或它们的组合。
E.组合物的稳定性
如本文所述的依鲁替尼组合物,无论呈固体形式或液体形式,在中性条件(即pH为约6至约8)下是稳定的。所述组合物在光照射下也是稳定的。在一个实施方案中,对于在不同温度和湿度下储存的样品而言,所述组合物在约1小时的时间段内是稳定的。如本文所用,术语稳定是指本文所述的组合物降解少于约3%。在一个实施方案中,所述组合物在约20℃/50%相对湿度至约45℃/75%相对湿度下是稳定的。在另一个实施方案中,本文所述的组合物在为或大于约25℃的温度下和为或大于约60%的相对湿度下,在大于1个月的时间段内降解少于约3%。
当与半固体或液体的药剂混合时,所述固体组合物也稳定至少约6小时。在一个实施方案中,所述固体组合物可悬浮于液体或半固体中并且在6小时后重新分散。在另一个实施方案中,悬浮在液体或半固体中的固体组合物稳定最多至约6小时。
稳定性可通过本领域中已知的多种方法来监控。在一个实施方案中,可观察胶囊和液体来检测任何物理方面或颜色变化。在一个实施方案中,胶囊颜色变化或胶囊的变型可指示胶囊的降解或恶化,从而影响安全性或功效。
本文所述的组合物可在减小的温度、室温或选定的温度下储存。在一个实施方案中,组合物储存在约0至约10℃的温度下。在另一个实施方案中,组合物储存在约2至约8℃的温度下。所述组合物可在不存在水、空气和水分的情况下储存。然而,除了大气条件,在室温下储存不影响组合物的总体稳定性。
F.使用所述组合物的方法
还提供将依鲁替尼递送到患者的方法,其中所述方法包括将本文所述的组合物给药于患者。因此,所述组合物可用于治疗或预防病症。在一些实施方案中,病症为列于美国专利8,497,277、8,476,284、8,703,780和8,754,090中的那些,所述专利文献以引用方式并入本文。
所述组合物可用于治疗具有本文所示任何病症中的一种或多种的受治疗者。所述组合物还可在预防方面是有用的,即所述组合物可给药于易受恶性肿瘤影响或以其它方式处于发展恶性肿瘤的风险的患者。所述组合物还可用于维持治疗,即给药于处于缓解期的患者。
在某些实施方案中,所述方法包括治疗一种或多种自身免疫性疾病。在一个实施方案中,自身免疫性疾病为炎症性肠病、关节炎、狼疮、类风湿性关节炎、牛皮癣关节炎、骨关节炎、斯提耳氏病、青少年关节炎、糖尿病、重症肌无力、桥本甲状腺炎、奥尔德甲状腺炎、格雷夫斯病、干燥综合征、多发性硬化症、急性播散性脑脊髓炎、艾迪生综合征、强直性脊柱炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、乳糜泻、古德帕斯特综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、赖特综合征、高羊动脉炎、颞动脉炎、温热自身免疫性溶血性贫血、韦格纳肉芽肿病、牛皮癣、全身脱发、白塞病、慢性疲劳、失眠症、子宫内膜异位症、间质性膀胱炎、神经肌肉瘤、硬皮病或外阴痛。
在其它实施方案中,所述方法包括治疗一种或多种异种免疫性疾病。在一个实施方案中,异种免疫性疾病为移植物抗宿主病、移植、输血、过敏性反应、过敏、I型超敏反应、过敏性结膜炎、过敏性鼻炎或特应性皮炎。
在某些实施方案中,所述方法包括治疗一种或多种炎症性疾病。在一个实施方案中,炎症性疾病为关节炎、哮喘、阑尾炎、睑炎炎、细支气管炎、支气管炎、滑囊炎、子宫颈炎、胆管炎、胆囊炎、结肠炎、结膜炎、膀胱炎、泪囊炎、皮炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维器炎、胃炎、胃肠炎、肝炎、化脓性荨麻疹、喉炎、乳腺炎、脑膜炎、脊髓炎心肌炎、肌炎、肾炎、卵巢炎、睾丸炎、骨炎、耳炎、胰腺炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、局限性肺炎、肺炎直肠炎、前列腺炎、肾盂肾炎、鼻炎、输卵管炎、鼻窦炎、口腔炎、滑膜炎、腱炎、扁桃体炎、葡萄膜炎、阴道炎、血管炎或外阴炎。
在其它实施方案中,所述方法包括治疗一种或多种癌症。在一个实施方案中,所述癌症为B细胞增殖性疾病。在另一个实施方案中,所述癌症为血液恶性肿瘤。在另一个实施方案中,癌症为B细胞淋巴细胞白血病、白血病、淋巴瘤、淋巴细胞增生性疾病、淋巴浆细胞性淋巴瘤、瓦尔登氏巨球蛋白血症、骨髓病、浆细胞骨髓瘤、浆细胞瘤、纵隔大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗液淋巴瘤、淋巴瘤样肉芽肿病、非霍奇金淋巴瘤CLL、SLL、高风险CLL、非CLL/SLL淋巴瘤、滤泡淋巴瘤、弥漫性大B细胞淋巴瘤、套细胞淋巴瘤、多发性骨髓瘤、边缘区淋巴瘤、非伯基特高级B细胞淋巴瘤、结外边缘区B细胞淋巴瘤、急性或慢性粒细胞性白血病、骨髓增生异常综合征、淋巴细胞白血病、复发性或难治性弥漫性大B细胞淋巴瘤、复发性或难治性套细胞淋巴瘤、复发性或难治性滤泡性淋巴瘤、复发性或难治性CLL、复发性或难治性SLL、复发或难治性多发性骨髓瘤、伯基特淋巴瘤、皮肤B细胞淋巴瘤、皮肤边缘区淋巴瘤、弥漫性混合小细胞淋巴瘤、弥漫性小切除细胞、结外滤泡小切割细胞、滤泡混合小切割和大细胞、滤泡大细胞、血管内淋巴瘤、大细胞免疫母细胞淋巴瘤、大细胞淋巴瘤、粘膜相关淋巴组织淋巴瘤、免疫细胞大细胞淋巴瘤、前体B淋巴细胞淋巴瘤、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤、淋巴结边缘区B细胞淋巴瘤、脾边缘区B细胞淋巴瘤、原发性纵隔B细胞淋巴瘤、毛细胞白血病和原发性中枢神经系统淋巴瘤。在另一个实施方案中,所述B细胞增殖性疾病为非霍奇金淋巴瘤、瓦尔登斯特伦巨球蛋白血症、浆细胞骨髓瘤、或慢性淋巴细胞性白血病。在另一个实施方案中,B细胞增殖性疾病为弥漫性大B细胞淋巴瘤、滤泡淋巴瘤、套细胞淋巴瘤和伯基特淋巴瘤。在另一个实施方案中,所述癌症为白血病。在另一个实施方案中,所述癌症为淋巴瘤。
在其它实施方案中,所述方法包括治疗血栓栓塞疾病。在一个实施方案中,血栓栓塞疾病为心肌梗塞、心绞痛、血管成形术后再闭塞、血管成形术后再狭窄、主动脉冠状动脉分流再闭塞、主动脉冠状动脉分流再狭窄、中风、短暂性缺血、外周动脉闭塞障碍、肺栓塞或深静脉血栓。
依鲁替尼的剂量要求可基于呈现的症状的严重性和正在治疗的特定受治疗者而有所不同。治疗可由少于依鲁替尼的最佳剂量的小剂量开始。此后,可增加剂量直至实现环境下的最佳效果。精确的剂量将由主治医师基于受治疗的个体受治疗者的体验来确定。在一个实施方案中,所述组合物以将提供有效结果但不引起任何不可接受的有害或危害性副作用的浓度给药。
如本文所用,术语“有效量”是指将缓解B细胞增殖性疾病的一种或多种症状的所给药的药剂或化合物的足够量。所述结果可减少和/或减轻疾病的病征、症状或成因。在某些实施方案中,有效量实现期望的药理作用或治疗改善而不具有过度不良副作用的量。
依鲁替尼的有效量可根据组合物的组分、递送的模式、正在治疗的病症的严重性、患者的年龄和重量、以及用于组合物中的任何其它活性成分而有所不同。还可调节给药方案以提供最佳的治疗反应。可每天递送数个分次剂量,例如以每天分次给药2至4次递送,或可递送单个剂量。然而,所述剂量可成比例减少或增加,如由治疗情况的紧急状态所指示的。在一个实施方案中,递送基于每天、每周或每月。在另一个实施方案中,递送基于每天递送。所述组合物可每天给药。在一些实施方案中,所述组合物可每隔一天给药。在一些实施方案中,所述组合物可以每天给药一次或多次。在一些实施方案中,所述组合物可以每天给药两次或更多次。在一些实施方案中,所述组合物可以每天给药三次或更多次。
所述剂量还可基于周期性递送减少或升高。主治医师还具有持续相同给药一个时间段的灵活性或可决定改变给药时间表。这可能是由于改善的病症,组合物的不利的但不致命的反应等。如果停止给药,则如果患者稳定或病症的改善已经实现,则可以继续重新给药。因此,给药的剂量、频率或它们的组合根据需要减少或增加。
依鲁替尼的给药量可根据疾病的严重性、受治疗者的重量、受治疗者的年龄等不同。在一个实施方案中,有效量为约0.1至约5000mg/天。在一个实施方案中,依鲁替尼的有效量为约1至约1500mg/天。在另一个实施方案中,依鲁替尼的有效量为约20至约450mg/天。在另外的实施方案中,依鲁替尼的有效量为约20至约420mg/天。在另一个实施方案中,依鲁替尼的有效量为约30至约300mg/天。在另外的实施方案中,依鲁替尼的有效量为约50至约200mg/天。在另一个实施方案中,依鲁替尼的有效量为约70至约140mg/天。
期望的剂量可以方便地以单剂量提供,或同时(或在短时间内)或以适当的间隔,例如两个、三个、四个或更多个亚剂量/天施用的分次剂量提供。
所述组合物可通过任何适当路径递送给受治疗者,如由主治医师所指导的。在一个实施方案中,所述组合物口服递送。
所述组合物还可与一种或多种第二药剂共给药。第二药剂可在本文所述的组合物之前、同时、或之后给药。在一些实施方案中,所述第二药剂包含化疗药、类固醇、免疫治疗药剂等。在另一个实施方案中,第二药剂为下列中的一种或多种:放线菌素、烷基化剂、阿维A酸、六甲蜜胺、阿扎伐林、阿那格雷、血管生成抑制剂、抗体、抗雄激素、抗雌激素、抗代谢药、蒽环类抗生素、三氧化二砷、门冬酰胺酶、B细胞受体通路抑制剂(CD79A抑制剂、CD79B抑制剂、CD19抑制剂、Lyn抑制剂、Syk抑制剂、PI3K抑制剂、Blnk抑制剂、PLCy抑制剂、PKCP抑制剂)、巴利昔单抗、贝沙罗汀、硼替佐米、钙调神经磷酸酶抑制剂、卡那霉素、塞来昔布、ceradenovec、秋水仙碱衍生物、细胞毒性抗生素、达替珠单抗、denileukin diftitox、DNA损伤剂、环氧化物、雌莫司汀、雌激素、乙烯亚胺、叶酸类似物、促性腺激素释放干扰素、生长因子、HDAC抑制剂、刺猬蛋白抑制剂、Hsp90抑制剂、组蛋白脱乙酰酶抑制剂、激素、激素类似物、激素拮抗剂、羟基脲、IAP抑制剂、伊布他珠单抗免疫刺激剂、免疫抑制剂、白细胞介素抑制剂、白细胞介素、伊立替康、Jakl/2抑制剂、罗丹明胺、马索波罗、米泊珠单抗、米特福星、米托胍、米托坦、单克隆抗体、mTOR抑制剂、甲基肼、氮芥、亚硝基脲、PI3K抑制剂、奥利默森、PARP抑制剂、培门冬酶、喷司他丁、PKC抑制剂、植物生物碱、铂化合物(卡铂、顺铂、奥沙利铂或沙铂)、鬼臼毒素衍生物、孕激素、蛋白酶体抑制剂、蛋白激酶抑制剂、蛋白酶抑制剂、嘌呤类似物、嘧啶类似物、放射免疫治疗剂、敏化剂、罗替曲松、西替加林、重氮呋喃、拓扑替康、维A酸、肿瘤坏死因子、TNF-α抑制剂、妥珠单抗、端粒酶抑制剂、替奈美丁、托西莫三胺、优特克单抗、长春花生物碱或伏立诺他胺。在另一个实施方案中,第二药剂包括阿霉素,更生霉素、博来霉素、长春碱、顺铂、阿西维辛、阿柔比星、盐酸阿考达唑、阿柔比星、阿多来新、阿地白介素、阿仑单抗、六甲蜜胺、安波霉素、乙酸异丙酯、氨鲁米特、安吖啶、阿那曲唑、氨茴霉素、天冬酰胺酶、曲林菌素、阿扎胞苷、阿扎替派、阿佐霉素、巴马司他、苯达莫司汀、贝伐单抗、苯佐替派、比卡鲁胺、盐酸必桑郡、双奈法德、比折来新、硫酸博莱霉素、布喹那钠、溴匹立明、白消安、放线菌素、卡普睾酮、卡醋胺、卡贝替姆、卡铂、卡莫司汀、盐酸卡米诺霉素、卡折来新、西地芬戈、西妥昔单抗、苯丁酸氮芥、西罗霉素、克拉屈滨、克立那托、克唑替尼、环磷酰胺、阿糖孢苷、达卡巴嗪、盐酸柔红霉素、地西他滨、右奥马铂、地扎胍宁、甲磺酸地扎呱宁、亚丝醌、阿霉素、盐酸阿霉素、屈洛昔芬、枸橼酸屈洛昔芬、屈他雄酮丙酸酯、达佐霉素、依达曲沙、盐酸依氟鸟氨酸、依沙芦星、恩洛铂、恩普氨酯、依匹哌啶、盐酸表柔比星、厄布洛唑、盐酸依索比星、雌莫司汀、雌莫司汀磷酸钠、依他硝唑、依托泊苷、磷酸依托泊苷、艾托卜宁、盐酸法屈唑、法扎拉滨、芬维A胺、氟尿苷、磷酸氟达拉滨、氟尿嘧啶、fluorocitabine、5-氟尿嘧啶、磷喹酮、福司曲星钠、吉西他滨、盐酸吉西他滨、吉姆单抗、羟基脲、盐酸伊达比星、异环磷酰胺、伊莫福新、白介素II、干扰素α-2a、干扰素α-2b、干扰素α-nl、干扰素α-n3、干扰素β-1a、干扰素γ-1b、异丙铂、盐酸伊立替康、醋酸兰瑞肽、来曲唑、醋酸亮丙瑞林、盐酸利阿唑、洛美曲索钠、环己亚硝脲、盐酸洛索蒽醌、马索罗酚、美登素、盐酸氮芥、醋酸甲地孕酮、醋酸美仑孕酮、美法仑、美诺立尔、巯嘌呤、甲氨蝶呤、甲氨蝶呤钠、氯苯氨啶、美妥替哌、米丁度胺、米托克星、丝裂红素、米托洁林、米托马星、丝裂霉素、米托司培、米托坦、盐酸米托蒽醌、霉酚酸、诺考达唑、诺加霉素、奥法木单抗、奥马铂、奥昔舒仑、紫杉醇、培门冬酶、培利霉素、戊氮芥、硫酸培洛霉素、培磷酰胺、哌泊溴烷、嗪消安、盐酸吡罗蒽醌、光神霉素、普洛美坦、卟吩姆钠、紫菜霉素、松龙苯芥、盐酸异丙胺酰苄肼、嘌呤霉素、盐酸嘌呤霉素、吡唑呋喃菌素、利波腺苷、利妥昔单抗、洛太米特、沙芬戈、盐酸沙芬戈、甲基环己亚硝脲、辛曲秦、磷乙酰天冬氨酸钠、稀疏霉素、盐酸螺旋锗、螺莫司汀、螺铂、链黑菌素、链脲菌素、磺氯苯脲、他利霉素、替可加兰钠、喃氟啶、盐酸替洛蒽醌、替莫泊芬、替莫唑胺、替尼泊苷、替罗昔隆、睾内脂、硫咪嘌呤、硫鸟嘌呤、噻替派、噻唑羧胺核苷、替拉扎明、枸橼酸托瑞米芬、乙酸曲托龙、磷酸曲西瑞宾、三甲曲沙、三甲曲沙葡糖醛酸脂、曲普瑞林、盐酸妥布氯唑、乌拉莫司丁、尿烷亚胺、伐普肽、维替泊芬、硫酸长春碱、硫酸醛基长春碱、去乙酰长春酰胺、
硫酸长春碱酰胺、硫酸长春匹定、硫酸长春甘酯、硫酸环氧长春碱、
酒石酸长春瑞滨、硫酸异长春碱、硫酸长春利定、伏氯唑、渥曼青霉素、折尼铂、净司他丁、盐酸佐柔比星。
G.包含组合物的试剂盒
还提供包含依鲁替尼和适用于给药于如上所述的哺乳动物受治疗者的任选载体的试剂盒或包装。在一个实施方案中,胶囊可包装在瓶、罩板包装、药丸盒等中。在另一个实施方案中,液体制剂可包装在任选地涂覆有可穿刺帽、安瓿、计滴器的瓶中或在盐水袋中。
包含本文所述的组合物的试剂盒或包装被设计成用于本文所述的方法中。试剂盒还可任选地包含对于施用组合物、适用于施用所述组合物的载体、一种或多种仪器(包括但不限于注射器、移液器、夹钳、量匙等)的说明。包含在试剂盒中的其它组分对本领域技术人员而言将是清楚的,同时考虑到期望的指示和递送方式。
提供下列实施例以示出本发明中所述的部分概念。尽管将每个实施例视为提供一个具体的单个的组合物实施方案,或制备和使用的方法,但所有的实施例均不视为限于本文所述的更普遍的实施方案。
在一些实施例中,已经努力确保所用数字(例如量、温度等)的准确性,但是应当考虑到一些实验误差和偏差。除非另外指明,温度以℃为单位,压力处于或近似大气压。
实施例
实施例1:包含依鲁替尼的固体组合物
制备包含依鲁替尼的固体组合物,其用于包含在胶囊中,如下所述。
A.140mg胶囊
在该方法中,颗粒内共混物通过在容器中将MCC(151.49mg;Avicel PH 101)、SLS(9.40mg;Kolliphor;微细)和CCS(13.10mg;Ac-di-sol)混合来制备。然后,可将其与依鲁替尼(70mg,微粉化的,Lonza,Nansha)混合。然后添加剩余的依鲁替尼(70mg)并且将组合物混合。然后,将硬脂酸镁(0.8mg;Non-Bovine#5712)加入该混合物中,并且将上述混合物共混以提供预辊压共混物。然后,将预辊压共混物辊压以形成带状物。然后将所述带状物研磨以提供包含颗粒的组合物。
然后所述颗粒与第二部分的SLS(4.6mg,Kolliphor,微细)和CCS(9.9mg,Ac-di-sol)共混。然后向共混物中添加第二部分的硬脂酸镁(0.8mg,Non-Bovine#5712)以提供润滑的共混物。然后将该润滑的共混物加入0号瑞典橙硬明胶胶囊中。
B.50mg依鲁替尼胶囊
在该方法中,颗粒内共混物通过将MCC(54.07mg;Avicel PH 101)、SLS(3.36mg;Kolliphor;微细)和CCS(4.68mg;Ac-di-sol)混合来制备。然后,可将这与依鲁替尼(25mg,微粉化的,Lonza,Nansha)混合。然后添加剩余的依鲁替尼(25mg)并且将组合物混合。然后,将硬脂酸镁(0.29mg;Non-Bovine#5712)加入该混合物中,并且将上述混合物共混以提供预辊压共混物。然后,将预辊压共混物辊压以形成带状物。然后将所述带状物研磨以提供包含颗粒的组合物。
然后所述颗粒与第二部分的SLS(1.64mg,Kolliphor,微细)和CCS(3.54mg,Ac-di-sol)共混。然后向共混物中添加硬脂酸镁(0.29mg,Non-Bovine#5712)以提供润滑的共混物。然后将该润滑的共混物(117.87mg)独立地加入0号瑞典橙硬明胶胶囊和瑞典橙喷洒胶囊中。
实施例2:包含依鲁替尼的液体悬浮液组合物
(i)70mg/mL依鲁替尼液体悬浮液
制备包含70mg/mL的依鲁替尼的液体组合物。具体地,将水(300mL)与CCS的组合物MCC(Avicel RC591;6.5g)混合并持续30分钟。然后使用均化器以最大速度(7500rpm)将该分散体均化30秒。使用磁力搅拌器将HPMC(29105mPas;1.25g)与水(120mL)混合直至均匀。然后将微粉化依鲁替尼(35g,Lonza Clinical)加入HPMC溶液中并混合120分钟。然后将MCC/CCS分散体与依鲁替尼混合物混合。将三氯蔗糖(0.5g)、对羟基苯甲酸甲酯钠(0.5725g)和对羟基苯甲酸乙酯钠(0.2875g)加入混合物中。在约10分钟搅拌之后,将柠檬酸一水合物(0.7565g)和胃肠外无水磷酸氢二钠(0.69g)加入该混合物中。将混合物搅拌约10分钟直至内容物增溶。测量混合物的pH并且发现为5.99,从而消除调节pH的需要。然后用纯化的水稀释混合物直至最终重量为510.5g。再次测量混合物并且发现为约6。
表2中提供了最终液体组合物中的每种组分的浓度。
(ii)40mg/mL依鲁替尼液体悬浮液
制备包含40mg/mL的依鲁替尼的液体组合物。具体地,将水(300mL)与CCS的组合物MCC(Avicel RC591;7g)混合并持续30分钟。然后使用均化器以最大速度(7500rpm)将该分散体均化30秒。使用磁力搅拌器将HPMC(29105mPas;0.5g)与水(120mL)混合直至均匀。然后将微粉化依鲁替尼(20g,Lonza Clinical)加入HPMC溶液中并混合120分钟。然后将MCC/CCS分散体与依鲁替尼混合物混合。将三氯蔗糖(0.25g)、对羟基苯甲酸甲酯钠(0.6791g)和对羟基苯甲酸乙酯钠(0.3387g)加入混合物中。在约10分钟搅拌之后,将柠檬酸一水合物(0.801g)和胃肠外无水磷酸氢二钠(0.69g)加入该混合物中。将混合物搅拌约10分钟直至内容物增溶。测量混合物的pH并且发现为约5.99,从而消除调节pH的需要。然后用纯化的水稀释混合物直至最终重量为507g。然后将混合物均化。再次测量pH并且发现为约6。
表3中提供了最终液体组合物中的每种组分的浓度。
实施例3:包含依鲁替尼的悬浮液的大规模制备,制备4L批次
将纯化的水(480g)加入容器中并且以约400rpm的搅拌速率加热至约83℃并且持续约60分钟。将HPMC(10.002g)缓慢加入容器中并且混合物以约7600rpm的速率搅拌约4分钟直至混合物均化。向该容器加入纯化水(480g)并且然后在室温下以约500rpm的速率将混合物搅拌约5分钟直至混合物增溶。将依鲁替尼(278.6g)加入混合物中,并且以600rpm将其搅拌约2h直至其均化。使用显微镜监测混合物的团聚物。
然后,将纯化水(2400g)加入第二容器中。以约500rpm的速率,在3分钟的时间段内将MCC(51.74g,Avicel)加入第二容器中,之后以约400rpm的速率搅拌约60分钟。然后在约4分钟的时间段内,使用约7600tr/min的搅拌速率,将该混合物均化。使用显微镜监测混合物的团聚物。
然后,将第一容器中的混合物加入第二容器中的混合物中,并且以约500rpm的速度将混合的内容物搅拌并持续约5分钟。然后,使用纯化水(200ml)冲洗第一容器,并且将其加入第二容器中。在中等搅拌条件下,将三氯蔗糖(4.0038g)、对羟基苯甲酸甲酯钠(4.5838g)和对羟基苯甲酸乙酯钠(2.300g)顺序添加到第二容器中并且将混合物搅拌约11分钟直至固体增溶。然后,将柠檬酸一水合物(6.052g)加入第二容器中并且将混合物搅拌约10分钟。然后添加无水硫酸氢二钠(5.521g)并且将混合物搅拌约10分钟直至内容物增溶。测量溶液的pH并且发现为约5.94,从而消除调节pH的需要。
然后使用纯化的水(4064g)稀释混合物直至最终重量为4084g。然后将混合物均化。再次测量pH并且发现为约5.98。然后在约75分钟的时间段内,以约500至约1300rpm的速度在恒定搅拌下移除混合物的等分试样(8ml)。将每个等分试样加入到琥珀色的玻璃小瓶(10ml)中,然后将Flurotec涂覆的橡胶注射塞(20mm)插入小瓶中,并且所述塞用铝制的撕拉盖(20mm)固定。参见图3。
实施例4:依鲁替尼制剂的稳定性研究
评价本文所述的固体组合物在3种液体中的稳定性。具体地,在室温下,将本文所述的4种喷洒胶囊的内容物(各自包含140mg的固体组合物)溶于水(100mL)、牛奶(100mL)和橙汁(100mL)中。在约6小时之后,牛奶和橙汁溶液的颜色保持不变,然而水溶液变成乳白色。
使用液相色谱发现三种依鲁替尼制剂是稳定的。具体地,在搅拌6小时之后,从这些制剂中回收具有微量杂质的大多数依鲁替尼活性剂。
实施例5:使用依鲁替尼制剂的饲管研究
使用本文所述的组合物对饲管进行可行性研究。具体地,制备两种制剂,每种制剂包含水(20mL)和4种本文所述的喷洒胶囊的内容物(总共为560mg的活性当量颗粒)。在使制剂通过尺寸为2.2mm和2.7mm ID饲管时,观察到所述制剂(包含水和组合物)由于重力并且不堵塞地通过管。
还发现在引入其它制剂之前,可重复使用所述管。具体地,通过使用注射器施加少量压力,将空气吹过管。然后可在没有任何中断的情况下使附加制剂通过管。应当理解,虽然本发明的描述中结合了其优选的具体实施方案,但上文中的描述和其后的实施例仅旨在阐述而非限制本发明的范围。本领域的技术人员将理解,可在不脱离本发明范围的前提下,进行多种更改并且用等同物进行取代,并且本发明的其它方面、优点和修改形式将对本发明所属领域的技术人员是显而易见的。除了本文所述的实施方案以外,本发明构想出并要求本文所引用的本发明的特征结合后得出的发明以及所引用的用于补充本发明特征的现有技术参考文献所得出的发明的权利。类似地,应当理解,所述的材料、特征或制品可与任何其它材料、特征或制品结合使用,并且此类结合也属于本发明的范围之内。
本文所引用或描述的每项专利、专利申请和专利公开中的公开内容,无论出于何种目的,均以引用方式全文并入本文。
本申请涉及以下实施方案:
1.一种药物组合物,所述药物组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。
2.根据实施方案1所述的药物组合物,所述药物组合物包含约40至约45重量%的依鲁替尼。
3.根据实施方案1或2所述的药物组合物,所述药物组合物包含约50至约140mg的依鲁替尼。
4.根据实施方案1至3中任一项所述的药物组合物,所述药物组合物包含约44至约47重量%的微晶纤维素。
5.根据实施方案1至4中任一项所述的药物组合物,所述药物组合物包含约6至约8重量%的交联羧甲基纤维素钠。
6.根据实施方案1至5中任一项所述的药物组合物,所述药物组合物包含约3至约5重量%的颗粒内交联羧甲基纤维素钠。
7.根据实施方案1至6中任一项所述的药物组合物,所述药物组合物包含约2至约4重量%的颗粒外交联羧甲基纤维素钠。
8.根据实施方案1至7中任一项所述的药物组合物,所述药物组合物包含约1至约5重量%的月桂基硫酸钠。
9.根据实施方案8所述的药物组合物,所述药物组合物包含约2.5至约3重量%的颗粒内月桂基硫酸钠。
10.根据实施方案8或9所述的药物组合物,所述药物组合物包含约1.2至约1.6重量%的颗粒外月桂基硫酸钠。
11.根据实施方案1至10中任一项所述的药物组合物,所述药物组合物包含约0.4至约0.6重量%的硬脂酸镁。
12.根据实施方案1至11中任一项所述的药物组合物,所述药物组合物包含约0.45至约0.5重量%的硬脂酸镁。
13.根据实施方案1至12中任一项所述的药物组合物,所述药物组合物包含约0.2至约0.3重量%的颗粒内硬脂酸镁。
14.根据实施方案1至13中任一项所述的药物组合物,所述药物组合物包含约0.2至约0.3重量%的颗粒外硬脂酸镁。
15.根据实施方案1所述的药物组合物,所述药物组合物包含颗粒内物质,所述颗粒内物质包括依鲁替尼、其盐、前药或代谢物、微晶纤维素、交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。
16.根据实施方案1或15所述的药物组合物,所述药物组合物包含颗粒外物质,所述颗粒外物质包括交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。
17.一种药物组合物,所述药物组合物包含:
(i)约40至约45重量%的依鲁替尼;
(ii)约44至约47重量%的微晶纤维素;
(iii)约6至约8重量%的交联羧甲基纤维素钠;
(iv)约1至约5重量%的月桂基硫酸钠;和
(v)约0.2至约0.3重量%的硬脂酸镁。
18.一种药物组合物,所述药物组合物包含:
(i)约140mg的依鲁替尼;
(ii)约151mg的微晶纤维素;
(iii)约23mg的交联羧甲基纤维素钠;
(iv)约14mg的月桂基硫酸钠;和
(v)约1.6mg的硬脂酸镁。
19.根据实施方案18所述的药物组合物,其中所述交联羧甲基纤维素钠包括约13mg的颗粒内交联羧甲基纤维素钠和约9.9mg的颗粒外交联羧甲基纤维素钠。
20.根据实施方案18所述的药物组合物,其中所述月桂基硫酸钠包括约9.4mg的颗粒内月桂基硫酸钠和约4.6mg的颗粒外月桂基硫酸钠。
21.根据实施方案18所述的药物组合物,其中所述硬脂酸镁包括约0.8mg的颗粒内硬脂酸镁和约0.8mg的颗粒外硬脂酸镁。
22.一种药物组合物,所述药物组合物包含:
(i)约50mg的依鲁替尼;
(ii)约54mg的微晶纤维素;
(iii)约8mg的交联羧甲基纤维素钠;
(iv)约5mg的月桂基硫酸钠;和
(v)约0.6mg的硬脂酸镁。
23.根据实施方案22所述的药物组合物,其中所述交联羧甲基纤维素钠包括约4.6mg的颗粒内交联羧甲基纤维素钠和约3.5mg的颗粒外交联羧甲基纤维素钠。
24.根据实施方案22所述的药物组合物,其中所述月桂基硫酸钠包括约3.3mg的颗粒内月桂基硫酸钠和约1.6mg的颗粒外月桂基硫酸钠。
25.根据实施方案22所述的药物组合物,其中所述硬脂酸镁包括约0.3mg的颗粒内硬脂酸镁和约0.3mg的颗粒外硬脂酸镁。
26.一种胶囊,所述胶囊包含根据实施方案1至25中任一项所述的药物组合物。
27.根据实施方案26所述的胶囊,所述胶囊为明胶胶囊。
28.根据实施方案26或27所述的胶囊,所述胶囊为硬明胶胶囊。
29.根据实施方案26至28中任一项所述的胶囊,所述胶囊为标准或喷洒胶囊。
30.根据实施方案26至29中任一项所述的胶囊,所述胶囊为瑞典橙胶囊。
31.根据实施方案26至30中任一项所述的胶囊,所述胶囊为0号胶囊。
32.一种药物组合物,所述药物组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、柠檬酸一水合物、磷酸氢二钠、三氯蔗糖、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠、浓盐酸、氢氧化钠和水。
33.根据实施方案32所述的药物组合物,所述药物组合物包含约30至约80mg/mL的依鲁替尼。
34.根据实施方案32或33所述的药物组合物,所述药物组合物包含约30至约50mg/mL的依鲁替尼。
35.根据实施方案32所述的药物组合物,所述药物组合物包含约60至约80mg/mL的依鲁替尼。
36.根据实施方案32至35中任一项所述的药物组合物,所述药物组合物包含约12至约15mg/mL的微晶纤维素和羧甲基纤维素钠。
37.根据实施方案32至36中任一项所述的药物组合物,所述药物组合物包含约13至约15mg/mL的微晶纤维素和羧甲基纤维素钠。
38.根据实施方案32至37中任一项所述的药物组合物,所述药物组合物包含约12至约14mg/mL的微晶纤维素和羧甲基纤维素钠。
39.根据实施方案32至38中任一项所述的药物组合物,所述药物组合物包含约0.5至约3mg/mL的羟丙基甲基纤维素。
40.根据实施方案32至39中任一项所述的药物组合物,所述药物组合物包含约2至约3mg/mL的羟丙基甲基纤维素。
41.根据实施方案32至40中任一项所述的药物组合物,所述药物组合物包含约0.5至约1.5mg/mL的羟丙基甲基纤维素。
42.根据实施方案32至41中任一项所述的药物组合物,所述药物组合物包含约1.4至约1.7mg/mL的柠檬酸一水合物。
43.根据实施方案32至42中任一项所述的药物组合物,所述药物组合物包含约1.4mg/mL的磷酸氢二钠。
44.根据实施方案32至43中任一项所述的药物组合物,所述药物组合物包含约0.5至约1.5mg/mL的三氯蔗糖。
45.根据实施方案32至44中任一项所述的药物组合物,所述药物组合物包含约1至约1.5mg/mL的对羟基苯甲酸甲酯钠。
46.根据实施方案32至45中任一项所述的药物组合物,所述药物组合物包含约0.5至约0.7mg/mL的对羟基苯甲酸乙酯钠。
47.根据实施方案32至46中任一项所述的药物组合物,所述药物组合物包含足量的浓盐酸以维持约6的pH。
48.根据实施方案32至47中任一项所述的药物组合物,所述药物组合物包含足量的氢氧化钠以维持约6的pH。
49.根据实施方案32至47中任一项所述的药物组合物,所述药物组合物包含足量的水以确保1mL的总体积。
50.根据实施方案32至49中任一项所述的药物组合物,所述药物组合物为液体悬浮液。
51.根据实施方案32所述的药物组合物,所述药物组合物包含:
(i)约70mg/mL的依鲁替尼;
(ii)约13mg/mL的微晶纤维素和羧甲基纤维素钠;
(iii)约2.5mg/mL的羟丙基甲基纤维素;
(iv)约1.5mg/mL的柠檬酸一水合物;
(v)约1.4mg/mL的磷酸氢二钠;
(vi)约1mg/mL的三氯蔗糖;
(vii)约1mg/mL的对羟基苯甲酸甲酯钠;和
(viii)约0.6mg/mL的对羟基苯甲酸乙酯钠。
52.根据实施方案32所述的药物组合物,所述药物组合物包含:
(i)约40mg/mL的依鲁替尼;
(ii)约14mg/mL的微晶纤维素和羧甲基纤维素钠;
(iii)约1mg/mL的羟丙基甲基纤维素;
(iv)约1.6mg/mL的柠檬酸一水合物;
(v)约1.4mg/mL的磷酸氢二钠;
(vi)约0.5mg/mL的三氯蔗糖;
(vii)约1.4mg/mL的对羟基苯甲酸甲酯钠;和
(viii)约0.7mg/mL的对羟基苯甲酸乙酯钠。
53.一种用于治疗B细胞增殖性疾病的方法,所述方法包括将根据实施方案1至52中任一项所述的药物组合物施用给对其有需要的受治疗者。
54.根据实施方案53所述的方法,其中所述B细胞增殖性疾病为非霍奇金淋巴瘤、瓦尔登斯特伦巨球蛋白血症、浆细胞骨髓瘤、或慢性淋巴细胞性白血病。
55.根据实施方案54所述的方法,其中所述非霍奇金淋巴瘤选自弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤和伯基特淋巴瘤。
56.根据实施方案53至55中任一项所述的方法,其中所述组合物为口服施用的。
57.一种用于治疗淋巴瘤的方法,所述方法包括将根据实施方案1至52中任一项所述的组合物施用给对其有需要的受治疗者。
58.一种用于治疗白血病的方法,所述方法包括将根据实施方案1至52中任一项所述的组合物施用给对其有需要的受治疗者。
59.一种用于治疗已经接受对套细胞淋巴瘤的至少一种在先治疗的受治疗者中的套细胞淋巴瘤的方法,所述方法包括每天一次将根据实施方案1至52中任一项所述的组合物施用给所述受治疗者。
60.根据实施方案53至59中任一项所述的方法,其中所述受治疗者为人。
61.根据实施方案53至60中任一项所述的方法,其中将所述组合物分散到食物中。
62.根据实施方案61所述的方法,其中所述食物为软食物。
63.根据实施方案61所述的方法,其中所述受治疗者为人类儿童。
64.一种用于制备根据实施方案1所述的组合物的方法,所述方法包括:
(a)将微晶纤维素、第一部分的月桂基硫酸钠和第一部分的交联羧甲基纤维素钠共混;
(b)将步骤(a)的产物与第一部分的依鲁替尼共混;
(c)将步骤(b)的产物与第二部分的依鲁替尼共混;
(d)将步骤(c)的产物与第一部分的硬脂酸镁共混;
(e)辊压步骤(d)的产物;
(f)研磨步骤(e)中制得的带状物;
(g)将步骤(f)中制得的颗粒与第二部分的月桂基硫酸钠和交联羧甲基纤维素钠共混;以及
(h)将步骤(g)的产物与第二部分的硬脂酸镁共混。
65.根据实施方案64所述的方法,所述方法还包括:
(i)向胶囊添加步骤(h)的产物。
66.一种用于制备根据实施方案32所述的组合物的方法,所述方法包括:
(a)将水、微晶纤维素、交联羧甲基纤维素钠混合;
(b)将水和羟丙基甲基纤维素混合;
(c)将步骤(b)的产物与依鲁替尼混合;
(d)将步骤(a)和(c)的产物混合;
(e)将步骤(d)的产物与三氯蔗糖混合;
(f)将步骤(e)的产物与对羟基苯甲酸甲酯钠和对羟基苯甲酸乙酯钠混合;
(g)将步骤(f)的产物与一水合柠檬酸混合;以及
(h)将步骤(g)的产物与无水磷酸氢二钠混合。
Claims (10)
1.一种药物组合物,所述药物组合物包含依鲁替尼、其盐、前药或代谢物、微晶纤维素、交联羧甲基纤维素钠、月桂基硫酸钠和硬脂酸镁。
2.根据权利要求1所述的药物组合物,所述药物组合物包含约40至约45重量%的依鲁替尼。
3.根据权利要求1或2所述的药物组合物,所述药物组合物包含约50至约140mg的依鲁替尼。
4.根据权利要求1至3中任一项所述的药物组合物,所述药物组合物包含约44至约47重量%的微晶纤维素。
5.根据权利要求1至4中任一项所述的药物组合物,所述药物组合物包含约6至约8重量%的交联羧甲基纤维素钠。
6.根据权利要求1至5中任一项所述的药物组合物,所述药物组合物包含约3至约5重量%的颗粒内交联羧甲基纤维素钠。
7.根据权利要求1至6中任一项所述的药物组合物,所述药物组合物包含约2至约4重量%的颗粒外交联羧甲基纤维素钠。
8.根据权利要求1至7中任一项所述的药物组合物,所述药物组合物包含约1至约5重量%的月桂基硫酸钠。
9.根据权利要求8所述的药物组合物,所述药物组合物包含约2.5至约3重量%的颗粒内月桂基硫酸钠。
10.根据权利要求8或9所述的药物组合物,所述药物组合物包含约1.2至约1.6重量%的颗粒外月桂基硫酸钠。
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