CN111201019A - 口服苯达莫司汀制剂 - Google Patents
口服苯达莫司汀制剂 Download PDFInfo
- Publication number
- CN111201019A CN111201019A CN201880063904.5A CN201880063904A CN111201019A CN 111201019 A CN111201019 A CN 111201019A CN 201880063904 A CN201880063904 A CN 201880063904A CN 111201019 A CN111201019 A CN 111201019A
- Authority
- CN
- China
- Prior art keywords
- cyclodextrin
- composition
- bendamustine
- alkyl
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Abstract
本发明涉及口服药物组合物,其包含苯达莫司汀与修饰的环糊精例如甲基‑β‑环糊精或羟丙基‑β‑环糊精的组合。令人惊奇地发现,在本发明的上下文中,这种组合物显示出显著改善的口服生物利用度,这使得它们特别有利于口服治疗应用,例如用于治疗癌症。
Description
本发明涉及口服药物组合物,其包含苯达莫司汀与修饰的环糊精,例如甲基-β-环糊精或羟丙基-β-环糊精的组合。令人惊奇地发现,在本发明的上下文中,这种组合物显示出显著改善的口服生物利用度,这使得它们特别有利于口服治疗应用,例如用于治疗癌症。
盐酸苯达莫司汀[即4-(5-(双-(2-氯-乙基)-氨基)-1-甲基-1H-苯并咪唑-2-基)-丁酸盐酸盐]首次由Ozegowski等人在1963合成,并且在上世纪60年代由前德意志民主共和国(GDR)的Jenapharm开发为抗癌药(Ozegowski W等人,J Prakt Chem,1963,20,178-186;Ozegowski W等人,Zentralbl Pharm,1971,110,1013-1019)。苯达莫司汀合并了氮芥基团的烷化活性和苯并咪唑骨架的抗代谢物特性。它具有二-(氯乙基)-胺基团,该基团能够使得DNA链交联烷基化。
盐酸苯达莫司汀(C16H21N3Cl2O2·HCl;MW:394.7Da)
苯达莫司汀的氮芥基团易于化学水解,特别是在中性或碱性pH值下,由此导致形成基本上无活性的单-和5-(双-(2-羟基乙基)-氨基)-取代的苯达莫司汀衍生物(参见流程1)。在酸性pH下可以防止或减少水解分解,因为氮原子的质子化导致苯达莫司汀亲核性下降,因此形成氮丙啶鎓离子的倾向显着降低。在高浓度氯化物存在下,水解速率也下降(Maas B等人,Pharmazie,1994,49(10),775-777)。
流程1:苯达莫司汀的I期代谢(CYP1A2)和化学水解。
除在向患者施用药物期间已经开始的氮芥基团化学水解外,苯达莫司汀还在血浆中形成I期和II代谢物,如文献中所述(Darwish M等人,Cancer Chemother Pharmacol,2015,75,1143-1154)。特别是CYP1A2被认为与两种已知的活性I期代谢物N-去甲基-苯达莫司汀和γ-羟基苯达莫司汀(M3代谢物)的形成有关(参见流程1)(Teichert J等人,CancerChemother Pharmacol,2007,59(6),759-770)。关于II期代谢物,先前将N-乙酰基-L-半胱氨酸结合物的胆汁排泄描述为苯达莫司汀的消除机制(Teichert J等人,Drug MetabDispos,2005,33(7),984-992;Teichert J等人,Drug Metab Dispos,2009,37(2),292-301)。
苯达莫司汀的第一次临床试验于1965年进行,用于治疗肿瘤学中的几种适应症,尤其是血液系统恶性肿瘤、乳腺癌、肺癌和卵巢癌。Jenapharm于1971年在前东德注册了一种名为Cytostasan的注射用粉末制剂。德国统一后,该产品自1991年以来一直以其目前的制剂销售,主要以商品名RibomustinTM销售,并因此在欧洲注册。注射用盐酸苯达莫司汀粉末自2008年以来以商品名TreandaTM在美国上市,由Teva注册(Werner W等人,Onkologie,2013,36(增刊1),2-10)。已发布的信息表明,Eagle Pharmaceuticals,Inc.于2013年开发了一种不同的“快速和方便”制剂。新的静脉注射制剂现在可以以用丙二醇、聚乙二醇400和硫代甘油配制的100mg/4mL非水溶液的形式得到。
苯达莫司汀在德国被批准用于治疗慢性淋巴细胞白血病(CLL)、惰性非霍奇金淋巴瘤(惰性NHL)和多发性骨髓瘤(MM)(LevactTM)并在美国被批准用于专利CLL和惰性NHL(TreandaTM)。大部分治疗方案采用将苯达莫司汀与另外的细胞生长抑制药物联用,通常与利妥昔单抗联用。有关苯达莫司汀的临床研究在过去几年中得到了加强。然而,大多数以苯达莫司汀作为单一药物的试验,例如,用于治疗胆管癌、软组织肉瘤、生殖细胞癌、小细胞肺癌、预先治疗过的转移或晚期乳腺癌,一方面显示出良好的耐受性,但另一方面又显示出有限的有益性。有关苯达莫司汀在联合疗法中的研究,例如与甲氨蝶呤和5-氟尿嘧啶联合用于治疗转移性乳腺癌或苯达莫司汀与卡铂联合用于治疗小细胞肺癌的研究,报道了与各自的标准治疗方案相当的功效。由于副作用温和并且与其他烷化药物的交叉耐药性降低,苯达莫司汀被认为是治疗临床情况差的患者或作为二线疗法的有意义的药物。
迄今为止,市场上仅有苯达莫司汀的静脉内制剂而无口服制剂,尽管苯达莫司汀本身具有约56%的口服生物利用度(Preiss R等人,Pharmazie,1985,40(11),782-784)。例如,在WO 2011/103150中描述了如何将苯达莫司汀施用于患者的方法。在例如WO 2010/036702、WO 2010/097700、WO 2012/127277和CN-A-101606934中描述了其他胃肠外苯达莫司汀制剂。
尽管有一些有关苯达莫司汀口服制剂的专利申请和科学出版物(WO 2010/063476;WO 2010/063493;WO 2010/126676;Gidwani B等人,Drug Dev Ind Pharm,2015,41(12),1978-1988;Gidwani B等人,Pharm Dev Technol,2016,21(2),161-171),但是所提到的该产品的制剂无一在市场上销售。
因此,对于新的和/或改进的苯达莫司汀口服制剂、特别是满足如下列出的标准的苯达莫司汀口服制剂仍然存在强烈和持续的需求。
本发明人对理想的口服制剂设定的标准如下(另外参见图1):
-母体药物的目标口服生物利用度为75-90%
-代谢物的目标生物利用度为120-140%
-口服施用后母体药物和代谢物的半衰期值与静脉内施用后的半衰期值非常接近
-口服施用后代谢物的外观与静脉内施用后的代谢物外观非常接近
-母体药物口服施用后的Cmax达到静脉内施用后的Cmax的80%
-在母体药物的Cmax和AUC方面与静脉内(IV)制剂相当
-代谢物的制剂在口服与IV之间有合理的可比性
-如果生物利用度(F)>80%,允许每日1次给药
-如果生物利用度>50%但<80%,允许每日2次给药(BID)
本发明解决了上述需求。因此,本发明的一个目的在于提供新的和/或改进的苯达莫司汀口服制剂,特别是满足上述列出的标准的口服苯达莫司汀制剂。
令人惊奇地发现,在本发明的上下文中,含有特定修饰的环糊精例如甲基-β-环糊精的苯达莫司汀口服制剂表现出显著改善的口服生物利用度,这使得这些制剂对于通过口服施用的治疗应用是非常有利的,包括癌症的治疗。
因此,本发明提供了用作药物的组合物,其中该组合物包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中该组合物通过口服施用,且其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
因此,本发明提供了用于疗法的组合物,其中该组合物包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中该组合物通过口服施用,且其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
换句话说,本发明提供了用于口服施用的药物组合物,其中该药物组合物包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
本发明还提供了口服药物组合物,其包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
本发明还提供了口服药物制剂,其包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
本发明还提供了被配制用于(或适合于)口服施用的药物组合物,其中该药物组合物包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,且其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
此外,本发明还涉及苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合在制备用于口服施用的药物中的用途,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
本发明还涉及苯达莫司汀或其药学上可接受的盐或溶剂化物和修饰的环糊精在制备药物中的用途,所述药物被配制用于(或适合于)口服施用,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
本发明还涉及苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合在制备用于治疗疾病或障碍的口服药物(或口服药物组合物)中的用途,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
本发明还提供了在有需要的个体/患者(例如人)中治疗疾病或障碍(例如癌症)的方法,该方法包括对所述个体/患者口服施用包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合的药物组合物,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。具体地讲,该方法包括口服施用治疗有效量的所述药物组合物。所治疗的疾病或障碍的实例在下文中进一步描述。
此外,本发明还提供了增强苯达莫司汀或其药学上可接受的盐或溶剂化物的口服生物利用度的方法,该方法包括对有此需要的个体/患者(例如人)口服施用包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合的药物组合物,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
本发明还涉及向有需要的个体/患者(例如人)递送苯达莫司汀或其药学上可接受的盐或溶剂化物的方法,该方法包括对所述个体/患者口服施用包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合的药物组合物,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。该方法特别包括口服施用治疗有效量的所述药物组合物。
本发明的组合物(或药物组合物、制剂或药物)可用于治疗各种疾病或障碍,尤其包括癌症(Darwish M等人,Cancer Chemother Pharmacol,2015,75(6),1143-1154;MundtM等人,Beilage zu Onkologie,Band 24,Heft 3,Juni 2001(doi:10.1159/000055100);Cheson BD等人,J Clin Oncol,2009,27(9),1492-1501),以及非癌性疾病/障碍(Faivre G等人,Neurology,2014,82(增刊10),P7.261(2014年5月1日,Poster Session VII Neuro-oncology:Primary CNS Lymphoma and Other Hematologic Malignancies),http://www.neurology.org/content/82/10_Supplement/P7.261)。例如,已经证实苯达莫司汀在使用人体B细胞的研究中诱导可抑制炎症的白细胞介素-10产生,因此发现其可发挥抗炎活性(参见,例如Lu L等人,Int Immunopharmacol,2016,39,273-279);本发明的组合物(或药物组合物、制剂或药物)因此被认为在治疗自身免疫疾病/障碍,例如系统性红斑狼疮中有效。
可以根据本发明治疗的癌症优选为血癌。所述血癌例如可以选自淋巴瘤、霍奇金淋巴瘤、结节硬化型霍奇金淋巴瘤、混合细胞型霍奇金淋巴瘤、富含淋巴细胞的霍奇金淋巴瘤、淋巴细胞耗竭型霍奇金淋巴瘤、结节性淋巴细胞优势型霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性非霍奇金淋巴瘤、弥漫性非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤、套细胞淋巴瘤、外周T-细胞淋巴瘤、皮肤T-细胞淋巴瘤、蕈样真菌病、Sézary病、T区淋巴瘤、淋巴上皮样淋巴瘤、伦纳特淋巴瘤、淋巴肉瘤、恶性免疫增殖性疾病、瓦尔登斯特伦巨球蛋白血症、α-重链病、γ-重链病、富兰克林病、免疫增殖性小肠病、地中海淋巴瘤、多发性骨髓瘤、卡勒病、骨髓瘤病、白血病、浆细胞白血病、淋巴细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、亚急性淋巴细胞白血病、幼淋巴细胞白血病、毛细胞白血病、白血病性网状内皮组织增殖、成人T细胞白血病、骨髓性白血病、急性骨髓性白血病、慢性骨髓性白血病、亚急性骨髓性白血病、髓样肉瘤、绿色瘤、粒细胞肉瘤、急性早幼粒细胞白血病、急性粒-单核细胞白血病、慢性BCR-ABL阴性骨髓增生病、真性红细胞增多症、原发性血小板增多症、特发性骨髓纤维化、单核细胞白血病、急性红细胞增多症、红白血病、急性红细胞性骨髓增生症、Di Guglielmo病、慢性红细胞增多症、Heilmeyer-病、急性巨核细胞白血病、肥大细胞白血病、急性全骨髓增生症、急性骨髓纤维化和Letterer-Siwe病。特别优选所治疗的癌症是选自下列的血癌:慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性非霍奇金淋巴瘤、惰性B细胞非霍奇金淋巴瘤、套细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症和多发性骨髓瘤。
此外,根据本发明治疗的血癌包括以上提到的具体血癌的任意一种(例如慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性非霍奇金淋巴瘤、惰性B细胞非霍奇金淋巴瘤、套细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症或多发性骨髓瘤),其可以为复发性或难治性血癌(例如对烷化剂不敏感的血癌),优选利妥昔单抗难治性血癌。
可根据本发明治疗的癌症也可以是实体癌症。具体地讲,待治疗的癌症可以选自乳腺癌(例如转移性乳腺癌,特别是预先治疗过的转移性或晚期乳腺癌)、肺癌(特别是小细胞肺癌)、卵巢癌、结肠直肠癌、结肠癌、胰腺癌、膀胱癌、前列腺癌、头部和/或颈部癌症和软组织肉瘤。
如上所述,本发明的组合物(或药物组合物)还可以用于治疗非癌症的疾病或障碍。例如,按照本发明治疗的疾病或障碍还可以是自身免疫疾病/障碍,例如类风湿性关节炎、多发性硬化(例如复发缓解型多发性硬化症、原发进展型多发性硬化症、继发进展型多发性硬化症、临床孤立综合征、视神经脊髓炎、巴洛同心硬化症、Schilder’s弥漫性硬化症或Marburg多发性硬化症)或红斑狼疮(例如系统性红斑狼疮、急性皮肤红斑狼疮、亚急性皮肤红斑狼疮、盘状红斑狼疮、冻疮样红斑狼疮、红斑狼疮-扁平苔藓重叠综合征、红斑狼疮性脂膜炎、肿胀性红斑狼疮、疣状红斑狼疮、皮肤狼疮粘蛋白病、药物诱发的红斑狼疮或新生儿红斑狼疮;特别是系统性红斑狼疮)。按照本发明治疗的疾病或障碍还可以是神经变性疾病/障碍,例如帕金森病、阿尔茨海默病或亨廷顿病。此外,本发明的组合物(或药物组合物)还可以用于免疫调节疗法,即作为免疫调节治疗剂。
本发明还通过所附说明性附图进行描述,所述附图示出:
图1:口服与静脉内(IV)施用对比的药代动力学特性和参数。
图2:NOD/Scid小鼠中伯基特癌细胞异种移植物模型中的肿瘤体积:疾病=对照;Pc=苯达莫司汀i.v.(25mg/kg);T1=苯达莫司汀-Me-β-CD制剂口服(30mg/kg);T2=苯达莫司汀-2-HP-β-CD制剂口服(30mg/kg);T3=苯达莫司汀水溶液口服。参见实施例9。
图3:NOD/Scid小鼠中伯基特癌细胞异种移植物模型中的体重:疾病=对照;Pc=苯达莫司汀i.v.(25mg/kg);T1=苯达莫司汀-Me-β-CD制剂口服(30mg/kg);T2=苯达莫司汀-2-HP-β-CD制剂口服(30mg/kg);T3=苯达莫司汀水溶液口服。参见实施例9。
图4:雄性SD大鼠中分别含有2-羟丙基-β-环糊精(2HPCD)、随机化甲基-β-环糊精(rMeCD)和聚合的表氯醇-β-环糊精(表氯CDp;参比)的苯达莫司汀制剂的血浆浓度与时间曲线。参见实施例11。
下文详细描述适用于如上文所述和定义的本发明的所有方面和实施方案。
如上所述,本发明提供的组合物(或药物组合物或制剂)包含苯达莫司汀或其药学上可接受的盐或溶剂化物。优选地,它包含盐酸苯达莫司汀。更优选地,它包含一水合盐酸苯达莫司汀。苯达莫司汀、盐酸苯达莫司汀和一水合盐酸苯达莫司汀是本领域已知的并且已经分别描述在例如Chemical Abstracts Services(CAS)登记号、特别是CAS编号16506-27-7、3543-75-7和1374784-02-7中。
本发明提供的组合物(或药物组合物/制剂)还包含修饰的环糊精,其选自α-环糊精、β-环糊精和γ-环糊精,其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。因此,修饰的环糊精可以是被一个或多个独立地选自C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基和-CO(C1-4烷基)的基团取代的α-、β-或γ-环糊精。
α-环糊精(α-CD)、β-环糊精(β-CD)和γ-环糊精(γ-CD)由六个(在α-CD的情况下)、七个(在β-CD的情况下)和八个(在γ-CD的情况下)α-D-葡萄糖单体单元(也可以称为脱水葡萄糖单元)组成,它们分别通过α-1,4-糖苷键连接形成环状寡糖。在用于本发明的修饰的环糊精中,α-CD、β-CD或γ-CD的葡萄糖单元的2、3和/或6位中的一个或多个游离羟基被取代。取决于环糊精中有多少个羟基(以及多少个葡萄糖单元)被以这种方式取代,可以获得具有不同取代度的修饰的环糊精。可以确定总取代度(TDS),其表示每个环糊精分子的取代基的平均数,例如如下列文献中所述:Challa R等人,AAPS PharmSciTech,2005,6(2),E329-E357;Choisnard L等人,Biomacromolecules,2011,12(8),3031-3038;或Yuan C等人,Journal of Investigative Medicine,2014,62(增刊8),S107。在β-环糊精的情况中,总取代度(TDS)也称作MS7值(Roquette,“Betacyclodextrins&hydroxypropylBetacyclodextrins”,制造商宣传手册,2006)。
优选地,用于本发明的修饰的环糊精是修饰的β-环糊精,即被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代的β-环糊精。修饰的β-环糊精例如可以具有约2至约16、特别是约3至约14(例如约3、约4、约5、约6、约7、约8、约9、约10、约11、约12、约13或约14)的总取代度(TDS或MS7值)。
修饰的环糊精上(例如修饰的β-环糊精上)的取代基选自C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)及其任意组合。优选地,所述取代基选自甲基、羟基乙基(例如1-羟基乙基或2-羟基乙基;特别是2-羟基乙基)、羟基丙基(例如1-羟基丙基、2-羟基丙基、3-羟基丙基、1-羟基-1-甲基乙基或2-羟基-1-甲基乙基;特别是2-羟基丙基或3-羟基丙基;更优选2-羟基丙基)、二羟基丙基(例如1,1-二羟基丙基、2,2-二羟基丙基、3,3-二羟基丙基、1,2-二羟基丙基、1,3-二羟基丙基、2,3-二羟基丙基、2,2-二羟基-1-甲基乙基、1,2-二羟基-1-甲基乙基或1-(羟基甲基)-2-羟基乙基;例如2,3-二羟基丙基)、羟基丁基(例如1-羟基丁基、2-羟基丁基、3-羟基丁基或4-羟基丁基;例如2-羟基丁基)、乙酰基(即-C(=O)-CH3)及其任意组合。
因此,特别优选修饰的环糊精是β-环糊精,其被甲基、羟基乙基、羟基丙基、二羟基丙基、羟基丁基、乙酰基或其任意组合取代。因此,特别优选修饰的环糊精选自甲基-β-环糊精、羟丙基-β-环糊精(例如(2-羟基丙基)-β-CD)、羟基乙基-β-环糊精(例如(2-羟基乙基)-β-CD)、二羟丙基-β-环糊精(例如(2,3-二羟基丙基)-β-CD)、羟基丁基-β-环糊精(例如(2-羟基丁基)-β-CD)、乙酰基-β-环糊精和被至少两个不同基团取代的β-环糊精,所述基团选自甲基、羟基乙基、羟基丙基、二羟基丙基、羟基丁基和乙酰基(例如被甲基和乙酰基取代的β-环糊精,例如七(3-O-乙酰基-2,6-二-O-甲基)-β-环糊精)。
甚至更优选地,修饰的环糊精是甲基-β-环糊精或羟丙基-β-环糊精。甲基-β-环糊精可以为,例如2-O-甲基-β-环糊精、3-O-甲基-β-环糊精、6-O-甲基-β-环糊精、2,3-二-O-甲基-β-环糊精、2,6-二-O-甲基-β-环糊精、3,6-二-O-甲基-β-环糊精、2,3,6-三-O-甲基-β-环糊精或随机甲基-β-环糊精(即随机甲基化β-环糊精);优选随机甲基-β-环糊精、七(2,6-二-O-甲基)-β-环糊精或七(2,3,6-三-O-甲基)-β-环糊精,且更优选随机甲基-β-环糊精或七(2,6-二-O-甲基)-β-环糊精。相应的示例性随机甲基-β-环糊精例如可以具有约1310Da的分子量,和/或每个β-环糊精脱水葡萄糖单元可以包含平均约1.6至约2.0个甲基基团。羟丙基-β-环糊精可以为,例如2-O-(2-羟基丙基)-β-环糊精、3-O-(2-羟基丙基)-β-环糊精、6-O-(2-羟基丙基)-β-环糊精、2,3-二-O-(2-羟基丙基)-β-环糊精、2,6-二-O-(2-羟基丙基)-β-环糊精、3,6-二-O-(2-羟基丙基)-β-环糊精、2,3,6-三-O-(2-羟基丙基)-β-环糊精或随机羟丙基-β-环糊精,且优选随机羟丙基-β-环糊精(特别是MS7值为约4至约6、例如约4.5或约5.6的随机羟丙基-β-环糊精)。相应的示例性随机羟丙基-β-环糊精例如可以具有约1540Da的分子量。最优选地,修饰的环糊精是甲基-β-环糊精(特别是随机甲基-β-环糊精或七(2,6-二-O-甲基)-β-环糊精)。
本发明的组合物(或药物组合物)可以含有一种单一类型的修饰的环糊精(例如仅甲基-β-环糊精),或者可以含有两种或多种不同类型的修饰的环糊精的混合物(例如甲基-β-环糊精和羟丙基-β-环糊精的混合物,其可以以约1:10至约10:1的摩尔比、特别是约1:1的摩尔比存在于组合物中)。优选该组合物包含单一类型的修饰的环糊精(优选为甲基-β-环糊精)。
如上所述,本发明提供的组合物(或药物组合物)包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合。具体地讲,它包含所述修饰的环糊精和所述苯达莫司汀或其药学上可接受的盐或溶剂化物的包合配合物。苯达莫司汀(或其药学上可接受的盐或溶剂化物)和修饰的环糊精的包合配合物可以使用本领域已知用于形成环糊精包合配合物的方法制备,包括,例如捏合、物理混合、共蒸发、冷冻干燥或喷雾干燥。可以用于形成本发明的修饰的环糊精和苯达莫司汀的包合配合物的这类技术进一步描述在文献中,例如:Del Valle EMM,Process biochemistry,2004,39(9),1033-1046;Nasir A等人,IntRes J Pharm,2012,3(4),44-50;Loftsson T等人,J Pharm Sci,1996,85,1017-1025;Roquette,“Betacyclodextrins&hydroxypropyl Betacyclodextrins”,制造商宣传手册,2006;Gidwani B等人,Drug Dev Ind Pharm,2015,41(12),1978-1988;Blanco J等人,Drug development and industrial pharmacy,1991,17(7),943-957;或Junco S等人,Journal of inclusion phenomena and macrocyclic chemistry,2002,44(1-4),117-121。本发明组合物(或药物组合物)中包含的修饰的环糊精和苯达莫司汀(或其药学上可接受的盐或溶剂化物)的包合配合物由此可以例如通过捏合、物理混合、共蒸发、冷冻干燥或喷雾干燥修饰的环糊精和苯达莫司汀(或其药学上可接受的盐或溶剂化物)得到(即可通过上述方法得到)。优选地,通过捏合修饰的环糊精和苯达莫司汀(或其药学上可接受的盐或溶剂化物)得到/可得到所述包合配合物。
苯达莫司汀(或其药学上可接受的盐或溶剂化物)和修饰的环糊精优选以摩尔比约为1:10至约1:0.5(例如摩尔比约为1:0.5、约1:0.6、约1:0.8、约1:1、约1:1.5、约1:2或约1:3),更优选摩尔比约为1:10至约1:1,甚至更优选摩尔比约为1:10至约1:1.5,甚至更优选摩尔比约为1:10至约1:2,且仍然更优选摩尔比约为1:10至约1:3包含在本发明的组合物(或药物组合物)中。
本发明的范围涵盖本文提供的化合物、特别是苯达莫司汀的所有药学上可接受的盐形式,其可以通过例如用无机或有机酸质子化带有易于质子化的孤对电子的原子例如氨基基团而形成,或者是酸基团例如羧酸基团与生理学上可接受的阳离子的盐的形式。示例性的碱加成盐包括,例如:碱金属盐,例如钠盐或钾盐;碱土金属盐,例如钙或镁盐;锌盐;铵盐;脂族胺盐,例如三甲胺、三乙胺、二环己基胺、乙醇胺、二乙醇胺、三乙醇胺、普鲁卡因盐、葡甲胺盐、乙二胺盐或胆碱盐;芳烷基胺盐,如N,N-二苄基乙二胺盐、苄星盐、苯乙苄胺盐;杂环芳香胺盐,如吡啶盐、甲基吡啶盐、喹啉盐或异喹啉盐;季铵盐,如四甲基铵盐、四乙基铵盐、苄基三甲铵盐、苄基三乙铵盐、苄基三丁基铵盐、甲基三辛基铵盐或四丁基铵盐;和碱性氨基酸盐,例如精氨酸盐、赖氨酸盐或组氨酸盐。示例性的酸加成盐包括,例如:无机酸盐,例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐(例如硫酸盐或硫酸氢盐)、硝酸盐、磷酸盐(例如磷酸盐、磷酸氢盐或磷酸二氢盐)、碳酸盐、碳酸氢盐、高氯酸盐、硼酸盐或硫氰酸盐;或有机酸盐,例如乙酸盐、丙酸盐、丁酸盐、戊酸盐、己酸盐、庚酸盐、辛酸盐、环戊烷丙酸盐、癸酸盐、十一酸盐、油酸盐、硬脂酸盐、乳酸盐、马来酸盐、草酸盐、富马酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、琥珀酸盐、己二酸盐、葡糖酸盐、乙醇酸盐、烟酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐、双羟萘酸盐(恩波酸盐)、樟脑酸盐、葡庚酸盐或新戊酸盐;磺酸盐,如甲烷磺酸盐(甲磺酸盐)、乙烷磺酸盐(乙磺酸盐)、2-羟基乙磺酸盐(羟乙基磺酸盐)、苯磺酸盐(苯磺酸盐)、对甲苯磺酸盐(甲苯磺酸盐)、2-萘磺酸盐(萘磺酸盐)、3-苯基磺酸盐或樟脑磺素盐酸盐;甘油磷酸盐;和酸性氨基酸盐,例如天冬氨酸盐或谷氨酸盐。苯达莫司汀的药学上可接受的盐的优选实例特别包括盐酸盐、氢溴酸盐、甲磺酸盐、硫酸盐、酒石酸盐、富马酸盐、乙酸盐、柠檬酸盐或磷酸盐。苯达莫司汀的特别优选的药学上可接受的盐是盐酸盐。
此外,本发明的范围涵盖本文提供的化合物、特别是苯达莫司汀的任意溶剂化形式,包括,例如,与水的溶剂化物(即,水合物的形式)或与有机溶剂例如甲醇、乙醇或乙腈的溶剂化物(即,甲醇化物、乙醇化物或乙腈化物的形式),或任意结晶形式(即为任意的多晶型物)或无定形形式。应当理解,这类溶剂化物还包括相应化合物的药学上可接受的盐的溶剂化物(例如盐酸苯达莫司汀的水合物,特别是一水合盐酸苯达莫司汀)。
如上所述,用于本发明的苯达莫司汀可以为任意结晶形式(多晶型物)或无定形形式。苯达莫司汀(特别是盐酸苯达莫司汀)的各种多晶型物以及无定形苯达莫司汀已经描述在文献中,例如WO 2010/144675、WO 2009/120386、US 8,445,524或CN-A-102351799。本发明可以使用苯达莫司汀的这些形式的任意一种。
例如,本发明的组合物(或药物组合物或制剂)可以包含:
(i)结晶盐酸苯达莫司汀,其特征在于具有包含在3.3、11.1、12.0、16.0和16.6度2-θ的峰的X-射线粉末衍射(XRPD)图案;或
(ii)结晶盐酸苯达莫司汀,其特征在于具有包含在14.1、22.0、22.9、24.9和25.1度2-θ的峰的XRPD图案;或
(iii)结晶盐酸苯达莫司汀,其特征在于具有包含在14.1、16.8、17.5、18.5、22.0、22.9、24.9、25.1和28.3度2-θ的峰的XRPD图案;或
(iv)结晶盐酸苯达莫司汀,其特征在于具有包含在26.1、27.9和28.1度2-θ的峰的XRPD图案;或
(v)结晶盐酸苯达莫司汀,其特征在于具有包含在10.6、15.6、19.8、26.1、27.9和28.1度2-θ的峰的XRPD图案;或
(vi)结晶盐酸苯达莫司汀,其特征在于具有包含在10.8、15.5、20.5和23.6度2-θ的峰的XRPD图案;或
(vii)结晶盐酸苯达莫司汀,其特征在于具有包含在10.3、10.8、15.5、19.6、20.5、20.7、21.2、23.6、25.8和27.6度2-θ的峰的XRPD图案;或
(viii)结晶盐酸苯达莫司汀,其特征在于具有包含在8.3、16.8和18.5度2-θ的峰的XRPD图案;或
(ix)结晶盐酸苯达莫司汀,其特征在于具有包含在8.3、14.0、16.8和18.5度2-θ的峰的XRPD图案;或
(x)结晶盐酸苯达莫司汀,其特征在于具有包含在8.3、14.0、16.8、18.5、22.0、22.9、25.1和28.3度2-θ的峰的XRPD图案;或
(xi)结晶盐酸苯达莫司汀,其特征在于具有包含在10.6、15.0、18.7、20.0、22.9和26.5度2-θ的峰的XRPD图案;或
(xii)结晶盐酸苯达莫司汀,其特征在于具有包含在7.4、10.6、13.6、15.0、17.4、18.7、20.0、20.3、22.0、22.9、24.3和26.5度2-θ的峰的XRPD图案;或
(xiii)盐酸苯达莫司汀形式1(如WO 2009/120386中所述);或
(xiv)盐酸苯达莫司汀形式3(如WO 2009/120386中所述);或
(xv)盐酸苯达莫司汀形式4(如WO 2009/120386中所述);或
(xvi)上述项目(i)-(xv)中列出的晶型的任意两种或多种的混合物。
应当理解,上述项目(i)-(xii)中提到的XRPD峰各自具有所示的数值±0.2度2-θ,优选±0.1度2-θ且甚至更优选具有所示的确切数值。例如,可以使用WO 2010/144675、WO2009/120386、US 8,445,524或CN-A-102351799中所述的方法制备上述盐酸苯达莫司汀的晶型。
本发明还包括前药的应用,特别是苯达莫司汀的药学上可接受的前药(其可用于代替苯达莫司汀)的应用。前药是药学活性母体化合物的衍生物,其具有可化学或代谢裂解的基团,并通过溶剂分解或在生理条件下转化成相应的药学活性母体化合物。前药包括酸衍生物,例如通过母体酸性化合物与适合的醇反应制备的酯或通过母体酸性化合物与适合的胺反应制备的酰胺。如果用于本发明的化合物具有羧基(例如苯达莫司汀),则前药的实例是通过使羧基与适合的醇反应制备的酯衍生物或通过使羧基与适合的胺反应制备的酰胺衍生物。可用作前药的相应的示例性酯衍生物(例如苯达莫司汀的酯衍生物)尤其包括甲酯、乙酯、正丙酯、异丙酯、正丁酯、异丁酯、叔丁酯、吗啉代乙酯或α-乙酰氧基乙酯。如果用于本发明的化合物具有羟基,则前药的实例是通过使羟基与适合的酰卤或适合的酸酐反应制备的酰氧基衍生物。如果用于本发明的化合物具有氨基,则前药的实例是通过使氨基与适合的酰卤或适合的混合酸酐反应制备的酰胺衍生物。可用作前药的相应示例性酰胺衍生物是-NHC(=O)-(CH2)2OCH3或-NHC(=O)-CH(NH2)CH3。因此,也可以使用其中苯达莫司汀的羧基是酯的形式或酰胺形式的苯达莫司汀的前药,特别是酯的形式(例如苯达莫司汀的甲酯、乙酯、正丙酯、异丙酯、正丁酯、异丁酯、叔丁酯、吗啉代乙酯或α-乙酰氧基乙酯)。苯达莫司汀的这类前药的相应实例、例如苯达莫司汀甲酯、苯达莫司汀乙酯、苯达莫司汀丙酯、苯达莫司汀异丙酯、苯达莫司汀丁酯、苯达莫司汀吗啉代乙酯、苯达莫司汀哌啶-1-基乙酯、苯达莫司汀吡咯烷-1-基乙酯或苯达莫司汀甲基哌嗪-1-基乙酯进一步描述在文献中,例如EP-A-2656843中。本发明还涵盖如本文所述和定义的组合物,其包含苯达莫司汀的上述前药的任意一种或EP-A-2656843中公开的替代苯达莫司汀的化合物的任意一种。
根据本发明提供的组合物优选是药物组合物。药物组合物可以通过本领域已知的技术配制,特别包括“Remington:The Science and Practice of Pharmacy”,Pharmaceutical Press,第22版中描述的技术。配制本发明的药物组合物用于口服施用。它们任选地包含一种或多种药学上可接受的赋形剂,例如载体、填充剂、崩解剂、润滑剂、粘合剂、着色剂、色素、稳定剂、防腐剂、抗氧化剂、甜味剂和/或矫味剂。特别地,药物组合物可含有一种或多种药学上可接受的赋形剂,例如非还原糖、微晶纤维素、柠檬酸钠、碳酸钙、磷酸氢钙或甘氨酸;崩解剂,例如淀粉(例如玉米、马铃薯或木薯淀粉)、淀粉羟乙酸钠、交联羧甲基纤维素钠或复合硅酸盐;造粒粘合剂,例如聚乙烯吡咯烷酮、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、蔗糖或阿拉伯胶;润滑剂,例如硬脂酸镁、硬脂酸、甘油二十二烷酸酯或滑石粉;和/或增强剂,例如N-[8-(2-羟基苯甲酰基)氨基]辛酸钠(“SNAC”)。
本发明的组合物(或药物组合物)用于口服施用,即旨在通过口服施用,特别是通过口服摄入或吞咽。
本发明的组合物(或药物组合物)可以以适合于口服施用的任何形式提供,特别是以任何药物剂型提供,包括固体组合物的形式或液体组合物的形式。用于口服施用的剂型包括例如丸剂、片剂(例如咀嚼片或泡腾片剂)、小片、胶囊剂、锭剂、药片、弹丸剂、阴道栓、溶液剂、乳剂、混悬剂、糖浆剂、酏剂、散剂、颗粒剂、薄膜剂、含药口香糖和多颗粒剂型。
优选的是,本发明的组合物(或药物组合物)是固体组合物,特别是它以固体口服剂型的形式提供。固体口服剂型的优选实例包括丸剂、片剂、小片、胶囊(例如明胶胶囊剂、HPMC胶囊[例如Plus HPMC胶囊,例如可获自Capsugel的那些]或PVP胶囊)、锭剂、药片、弹丸剂、散剂、颗粒或薄膜。固体组合物(或固体口服剂型,包括任何上述示例性固体口服剂型)并非特别限制其含水量,只要其为固体形式即可。例如,固体组合物(或固体口服剂型)可含有少于约15%(w/w)的水、优选少于约10%(w/w)的水、更优选少于约5%(w/w)的水。具有低含水量的这种固体组合物(或固体口服剂型)是有利的,因为它们提供改善的贮存稳定性并因此能够延长储存期。
固体口服剂型,优选丸剂、片剂、小片、胶囊剂、锭剂、药片、弹丸剂、散剂、颗粒剂或薄膜,还可具有肠溶包衣。这种包衣在本领域中是已知的并且不受特别的限制。例如,肠溶包衣可以由选自如下的材料制成:丙烯酸甲酯-甲基丙烯酸共聚物、丙烯酸乙酯-甲基丙烯酸共聚物、甲基丙烯酸甲酯-甲基丙烯酸共聚物、乙酸邻苯二甲酸纤维素、乙酸琥珀酸纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、聚乙酸乙烯邻苯二甲酸酯、虫胶、乙酸偏苯三酸纤维素、羧甲基纤维素、藻酸钠、玉米醇溶蛋白、直链淀粉、淀粉和糊精。关于这些包衣以及其他适宜肠溶包衣的更多细节可以在文献中找到,例如:Wen H等人,Oral controlled release formualtion design and drugdelivery:theory to practice,John Wiley&Sons,2011;Aulton M等人,Pharmaceuticalcoating technology,Taylor&Francis,1995;或Hussan SD等人,IOSR Journal ofPharmacy,2012,2(6),5-11。
虽然本发明的组合物优选是如上所述的固体组合物,但本发明的组合物也可以是液体组合物。在这种情况下,使用含有少于约15%(w/w)的水、优选少于约10%(w/w)的水、更优选少于约5%(w/w)的水的液体组合物是有利的。
此外,尽管不是优选的,本发明的组合物还可以是水性液体组合物(例如水溶液)。在这种情况下,组合物应优选在施用于个体/患者之前不久制备,并且应避免长时间存放。
通常,医生将确定最适合于每个个体的实际剂量。任何特定个体的具体剂量水平和给药频率可以变化,并且取决于包括接受治疗的个体的年龄、体重、一般健康状况、性别、饮食和具体病症的严重性在内的多种因素。
口服施用于人类个体(例如约70kg体重的人)的推荐、但非限制性的本发明组合物的剂量在每单位剂量中包含约10mg至约1g,优选约20mg至约800mg,更优选约30mg至约600mg,甚至更优选约50mg至约500mg(例如约50mg、约75mg、约100mg、约150mg、约180mg、约200mg、约250mg、约300mg、约350mg、约400mg、约450mg或约500mg)活性成分(即苯达莫司汀或其药学上可接受的盐或溶剂化物)。该单位剂量可以每3或4周施用例如1-5次。特别地,本发明的组合物可以以约50mg至约500mg(例如约50mg、约75mg、约100mg、约150mg、约180mg、约200mg、约250mg、约300mg、约350mg、约400mg、约450mg或约500mg)的单位剂量口服施用于人类个体,其中所述单位剂量以如下方式施用:(i)每隔21天在第1天和第2天施用;或(ii)每隔21天在第1-5天施用;或(iii)每隔28天在第1天和第2天施用;或(iv)每隔28天在第1天和第15天施用;或(v)每隔28天在第1-5天施用。应当理解,本段落中指定的剂量是指相当于非盐形式的苯达莫司汀的指示质量的苯达莫司汀或其药学上可接受的盐或溶剂化物(例如一水合盐酸苯达莫司汀)的量。进一步应当理解,可能需要根据患者/个体的年龄和体重以及待治疗的病症的严重性的不同对剂量进行常规的改变。精确剂量最终应由主治医生决定。
本发明的组合物(或药物组合物)可以包含苯达莫司汀或其药学上可接受的盐或溶剂化物作为唯一药物活性成分。可以在单一疗法中施用相应的组合物,例如,不伴随施用任何另外的治疗剂或不伴随施用任何另外的针对使用苯达莫司汀或其药学上可接受的盐或溶剂化物治疗的相同疾病的治疗剂。
然而,本发明的包含苯达莫司汀或其药学上可接受的盐或溶剂化物的组合物(或药物组合物)还可以与一种或多种另外的治疗剂联合施用。如果苯达莫司汀(或其药学上可接受的盐或溶剂化物)与针对相同疾病或病症的第二种治疗剂联合使用,则每种化合物的剂量可以不同于单独使用相应化合物时的剂量,特别是可以使用每种化合物的更低剂量。苯达莫司汀(或其药学上可接受的盐或溶剂化物)与一种或多种另外的治疗剂的组合可以包括同时/伴随施用苯达莫司汀(或其药学上可接受的盐或溶剂化物)和另外的治疗剂,它们可以在单一药物制剂中,也可以在单独的药物制剂中,或者依次/单独施用苯达莫司汀(或其药学上可接受的盐或溶剂化物)和另外的治疗剂。如果施用是依次进行的,则可以首先施用苯达莫司汀(或其药学上可接受的盐或溶剂化物),也可以首先施用一种或多种另外的治疗剂。如果施用是同时进行的,则可以将一种或多种另外的治疗剂与苯达莫司汀(或其药学上可接受的盐或溶剂化物)包含在同一药物制剂中,或将它们在一种或多种不同的(单独的)药物制剂中施用。
如果将本发明的组合物用于治疗癌症,则优选与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联合施用的一种或多种其他治疗剂是抗癌药物(即抗癌剂)。与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联合施用的抗癌药物可以例如选自:肿瘤血管生成抑制剂(例如蛋白酶抑制剂、表皮生长因子受体激酶抑制剂或血管内皮生长因子受体激酶抑制剂);细胞毒性药物(例如抗代谢物,例如嘌呤和嘧啶类似物抗代谢物);抗有丝分裂剂(例如微管稳定药物或抗有丝分裂生物碱);铂配合物;抗肿瘤抗生素;烷化剂(例如氮芥或亚硝基脲);内分泌药(例如肾上腺皮质激素、雄激素、抗雄激素、雌激素、抗雌激素、芳香酶抑制剂、促性腺素释放激素激动剂或生长抑素类似物);或靶向过表达和/或以其他方式参与肿瘤细胞中失调(或错误调节)的特定代谢途径的酶或受体的化合物(例如ATP和GTP磷酸二酯酶抑制剂、组蛋白脱乙酰基酶抑制剂、蛋白激酶抑制剂(例如丝氨酸、苏氨酸和酪氨酸激酶抑制剂,例如Abelson蛋白酪氨酸激酶抑制剂)和各种生长因子、它们的受体和相应的激酶抑制剂(例如表皮生长因子受体激酶抑制剂、血管内皮生长因子受体激酶抑制剂、成纤维细胞生长因子抑制剂、胰岛素样生长因子受体抑制剂和血小板衍生生长因子受体激酶抑制剂));蛋氨酸、氨基肽酶抑制剂、蛋白酶体抑制剂、环加氧酶抑制剂(例如环加氧酶-1或环加氧酶-2抑制剂)、拓扑异构酶抑制剂(例如拓扑异构酶I抑制剂或拓扑异构酶II抑制剂)、聚ADP核糖聚合酶抑制剂(PARP抑制剂)和表皮生长因子受体(EGFR)抑制剂/拮抗剂。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的烷化剂可以为例如氮芥(例如环磷酰胺、氮芥、乌拉莫司汀、美法仑、苯丁酸氮芥、异环磷酰胺或曲磷胺)、亚硝基脲(例如卡莫司汀、链脲佐菌素、福莫司汀、洛莫司汀、尼莫司汀、泼尼莫司汀、雷莫司汀或司莫司汀)、烷基磺酸酯(例如白消安、甘露舒凡或曲奥舒凡)、氮丙啶(例如六甲三聚氰胺(六甲蜜胺)、三乙烯三聚氰胺、ThioTEPA(N,N'N'-三亚乙基硫代磷酰胺)、卡波醌或三亚胺醌)、肼(例如丙卡巴肼)、三氮烯(例如达卡巴嗪)或咪唑并四嗪(例如替莫唑胺)。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的铂配合物可以为例如顺铂、卡铂、奈达铂、奥沙利铂、沙铂或四硝酸三铂(triplatintetranitrate)。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的细胞毒药物可以为例如抗代谢物,包括叶酸类似物抗代谢物(例如氨基蝶呤、甲氨蝶呤、培美曲塞或雷替曲塞)、嘌呤类似物抗代谢物(例如克拉屈滨、氯法拉滨、氟达拉滨、6-巯嘌呤(包括其前药形式硫唑嘌呤)、喷司他丁或6-硫鸟嘌呤)和嘧啶类似物抗代谢物(例如阿糖胞苷、地西他滨、5-氟尿嘧啶(包括其前药形式的卡培他滨和替加氟)、氟尿苷、吉西他滨、依诺他滨或沙帕他滨)。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的抗有丝分裂剂可以为例如紫杉烷(例如多西他赛、拉罗他赛、奥他赛、紫杉醇/泰素、替司他赛或nab-paclitaxel(例如))、长春花生物碱(例如长春碱、长春新碱、长春氟宁、长春地辛或长春瑞滨)、埃博霉素(例如埃博霉素A、埃博霉素B、埃博霉素C、埃博霉素D、埃博霉素E或埃博霉素F)或埃博霉素B类似物(例如伊沙匹隆/氮杂埃博霉素B)。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的抗肿瘤抗生素可以为例如蒽环类(例如阿克拉霉素、柔红霉素、阿霉素、表柔比星、伊达比星、氨柔比星、吡柔比星、白藜芦醇或红霉素)、蒽二酮(例如米托蒽醌或匹克生琼)或从链霉菌属(Streptomyces)分离的抗肿瘤抗生素(例如放线菌素(包括放线菌素D)、博来霉素、丝裂霉素(包括丝裂霉素C)或普卡霉素)。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的酪氨酸激酶抑制剂可以为例如阿昔替尼、波舒替尼、西地尼布、达沙替尼、厄洛替尼、吉非替尼、伊马替尼、拉帕替尼、来妥替尼、尼洛替尼、司马尼布、索拉非尼、舒尼替尼、阿西替尼、尼达尼布、普纳替尼或凡他尼布。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的拓扑异构酶抑制剂可以为拓扑异构酶I抑制剂(例如伊立替康、托泊替康、喜树碱、贝洛替康、芦比替康或片螺素D)或拓扑异构酶II抑制剂(例如安吖啶、依托泊苷、磷酸依托泊苷、替尼泊苷或多柔比星)。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的PARP抑制剂可以为例如BMN-673、奥拉帕利、瑞卡帕布(rucaparib)、维利帕尼(veliparib)、CEP9722、MK 4827、BGB-290或3-氨基苯甲酰胺。
可以作为抗癌药与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的EGFR抑制剂/拮抗剂可以为例如吉非替尼、厄洛替尼、拉帕替尼、阿法替尼、奈拉替尼、奥希替尼、ABT 414、达克替尼、AV-412、PD 153035、凡他尼布、PKI-166、培利替尼、卡纽替尼、埃克替尼、波齐替尼、BMS-690514、CUDC-101、AP26113、XL647、西妥昔单抗、帕木单抗、扎芦木单抗、尼妥珠单抗或马妥珠单抗。
其他抗癌药也可以与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用。所述抗癌药可以包含生物或化学分子,如TNF相关凋亡诱导配体(TRAIL)、他莫昔芬、安吖啶、贝沙罗汀、雌莫司汀、伊罗夫文、曲贝替定、西妥昔单抗、帕木单抗、托西莫单抗、阿仑珠单抗、贝伐珠单抗、依屈洛单抗、吉妥珠单抗、阿伏西地、塞利西利、氨基乙酰丙酸、氨基乙酰丙酸甲酯、乙法昔罗、卟菲尔钠、他拉泊芬、替莫泊芬、维替泊芬、阿利维A酸、维A酸、阿那格雷、三氧化二砷、阿曲生坦、硼替佐米、卡莫氟、塞来昔布、秋水仙胺、伊来司莫、依沙芦星、依托格鲁、氯尼达明、硫蒽酮、马索罗酚、二溴甘露醇、米托胍腙、米托坦、奥利默森、高三尖杉酯(omacetaxine)、sitimagene、ceradenovec、替加氟、睾内酯、噻唑呋林、替匹法尼、伏林司他、iniparib或库潘尼西(copanlisib)。
生物药物,例如针对癌症或肿瘤标志物/参与增殖性疾病的因子/细胞因子的抗体、抗体片段、抗体构建体(例如,单链构建体)和/或修饰的抗体(如CDR-移植抗体、人源化抗体、“全人源化”抗体、抗体-药物缀合物等),也可以与本发明的苯达莫司汀(或其药学上可接受的盐或溶剂化物)一起用于共同治疗方法中。此类生物分子的实例是抗-HER2抗体(例如曲妥珠单抗)、抗-CD20抗体(例如利妥昔单抗、奥瑞珠单抗、奥法木单抗、阿托珠单抗或替伊莫单抗)、抗-CD19/CD3构建体、trastuzumab emtansin、brentuximab vedotin或抗-TNF抗体。
可以与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的抗癌药物也可以是免疫肿瘤学治疗剂(例如靶向CTLA-4、PD-1/PD-L1、TIM3、LAG3、OX4、CSF1R、IDO或CD40中的任一个的抗体(例如单克隆抗体或多克隆抗体)、抗体片段、抗体构建体(例如单链构建体)或修饰的抗体(例如CDR-移植抗体、人源化抗体或“完全人源化”抗体)。这类免疫肿瘤学治疗剂包括例如抗-CTLA-4抗体(特别是拮抗性或途径阻断性抗-CTLA-4抗体;例如伊匹木单抗或曲美木单抗)、抗-PD-1抗体(特别是拮抗性或途径阻断性抗-PD-1抗体;例如纳武单抗(nivolumab)(BMS-936558)、帕姆单抗(pembrolizumab)(MK-3475)、pidilizumab(CT-011)、AMP-224或APE02058)、抗-PD-L1抗体(特别是途径阻断性抗PD-L1抗体;例如BMS-936559、MEDI4736、MPDL3280A(RG7446)、MDX-1105或MEDI6469)、抗-TIM3抗体(特别是途径阻断性抗-TIM3抗体)、抗-LAG3抗体(特别是拮抗性或途径阻断性抗-LAG3抗体;例如BMS-986016、IMP701或IMP731)、抗-OX4抗体(特别是激动性抗OX4抗体;例如MEDI0562)、抗-CSF1R抗体(特别是途径阻断性抗-CSF1R抗体;例如IMC-CS4或RG7155)、抗-IDO抗体(特别是途径阻断性抗IDO抗体)或抗-CD40抗体(特别是激动性抗-CD40抗体;例如CP 870,893或ChiLob 7/4)。可以与苯达莫司汀(或其药学上可接受的盐或溶剂化物)联用的其他免疫肿瘤学治疗剂是本领域已知的并且描述在如下文献中,例如:Kyi C等人,FEBS Lett,2014,588(2),368-376;Intlekofer AM等人,J Leukoc Biol,2013,94(1),25-39;Callahan MK等人,J Leukoc Biol,2013,94(1),41-53;Ngiow SF等人,Cancer Res,2011,71(21),6567-6571;或Blattman JN等人,Science,2004,305(5681),200-205。
本发明的组合物(或药物组合物)还可以与物理疗法联合施用,例如放疗。放疗可以在施用本发明组合物之前、之后或同时开始。例如,放疗可以在施用本发明的组合物后1-10分钟、1-10小时或24-72小时开始。然而,这些时间框架不应被解释为限制性的。将个体暴露于辐射,优选γ辐射,其中辐射可以以单剂量或多剂量提供,其在数小时、数天和/或数周内施用。可以根据标准放疗方案,使用标准剂量和方案进行伽马辐射。
本发明由此还涉及用于治疗癌症的如上文所述和定义的组合物(或药物组合物),其包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中将该组合物与一种或多种其他抗癌药联合施用和/或与放疗联合施用。
优选地,本发明的组合物(或药物组合物)与至少一种其他抗癌剂联合施用,所述其他抗癌剂选自依托泊苷、氟达拉滨、米托蒽醌、甲氨蝶呤、泼尼松、长春新碱和抗-CD20单克隆抗体。更优选地,其他抗癌剂是抗-CD20单克隆抗体,优选自利妥昔单抗、奥瑞珠单抗、奥法珠单抗、阿托珠单抗和替伊莫单抗(例如90Y-替伊莫单抗或111In-替伊莫单抗)。甚至更优选地,其他抗癌剂是利妥昔单抗或阿托珠单抗、特别是利妥昔单抗。因此,特别优选本发明的组合物(或药物组合物)与利妥昔单抗联合施用。本发明的组合物(或药物组合物)还可以与利妥昔单抗和一种或多种其他抗癌剂联合施用,包括任何上述示例性抗癌剂(例如copanlisib)。在另一个实施方案中,本发明的组合物(或药物组合物)与阿托珠单抗联合施用(特别是用于治疗滤泡性非霍奇金淋巴瘤)。
本发明的苯达莫司汀口服制剂还可以用于单一疗法,特别是癌症的单一疗法治疗(即,不施用任何其他抗癌药,直至终止用口服苯达莫司汀制剂治疗)。
此外,本发明的组合物(或药物组合物)——与一种或多种其他抗癌药组合(包括上述示例性抗癌药中的任何一种,例如抗-CD20单克隆抗体,特别是利妥昔单抗)或不与任何其他抗癌药组合——也可以与止吐药联合施用。所述止吐药可以选自例如阿洛司琼、阿扎司琼、贝美司琼、西兰司琼、氯氮平、达佐比利、多拉司琼、格拉司琼、来立司琼、甲氧氯普胺、米安色林、米氮平、奥氮平、昂丹司琼、帕洛诺司琼(例如单独的帕洛诺司琼或帕洛诺司琼与奈妥匹坦联合)、喹硫平、雷莫司琼、利卡司琼、托烷司琼、扎托司琼、氯氮平、赛庚啶、羟嗪、奥氮平、利培酮、齐拉西酮、屈大麻酚、大麻隆、四氢大麻酚、阿立必利、溴必利、氯丙嗪、氯波必利、多潘立酮、氟哌啶醇、羟嗪、伊托必利、甲氧氯普胺、美托哌丙嗪、丙氯拉嗪、硫乙拉嗪、曲美苄胺、赛克力嗪、茶苯海明、苯海拉明、羟嗪、美克洛嗪、异丙嗪、阿托品、苯海拉明、莨菪碱、东莨菪碱、阿瑞匹坦、卡索匹坦、依洛匹坦、福沙匹坦、马罗匹坦、奈妥匹坦、罗拉匹坦、维替匹坦、草酸铈、地塞米松、劳拉西泮、咪达唑仑、丙泊酚或其任意组合。优选地,所述止吐药为5-HT3拮抗剂(或“司琼”),例如阿洛司琼、阿扎司琼、贝美司琼、西兰司琼、氯氮平、达佐比利、多拉司琼、格拉司琼、来立司琼、甲氧氯普胺、米安色林、米氮平、奥氮平、昂丹司琼、帕洛诺司琼(任选与奈妥匹坦联合)、喹硫平、雷莫司琼、利卡司琼、托烷司琼或扎托司琼。特别优选的止吐药为帕洛诺司琼。
根据本发明的待治疗个体或患者可以是动物(例如非人类动物)。优选地,个体/患者是哺乳动物。更优选地,个体/患者是人(例如男性人类或女性人类)或非人类哺乳动物(例如豚鼠、仓鼠、大鼠、小鼠、兔、狗、猫、马、猴子、猿、绒猴、狒狒、大猩猩、黑猩猩、猩猩、长臂猿、绵羊、牛或猪)。最优选地,根据本发明的待治疗个体/患者是人。
本文使用的术语“治疗”等是指获得所需的药理学和/或生理学作用。该作用可以是预防性的(就完全或部分预防疾病或其症状而言)和/或是治疗性的(就部分或完全治愈或停止疾病或其症状和/或归因于该疾病的副作用而言)。本文所用的术语“治疗”包括对患者疾病的任何治疗,包括:(a)预防可能易患疾病/处于发生疾病风险中的患者的疾病;(b)抑制疾病,即阻止它的发展;或(c)缓解疾病,即使疾病消退。如本文所用,术语“治疗”疾病或疾病的“治疗”特别是指疾病进展的减缓或逆转。治疗疾病还包括治疗和/或减轻疾病症状。
术语“烃基”是指由碳原子和氢原子组成的基团。
术语“烷基”是指一价饱和无环(即非环状)烃基,其可以为直链或支链的。因此,“烷基”不含任何碳-碳双键或任何碳-碳三键。“C1-4烷基”表示具有1-4个碳原子的烷基。示例性的烷基为甲基、乙基、丙基(例如正丙基或异丙基)或丁基(例如正丁基、异丁基、仲丁基或叔丁基)。
除非另外明确指出或与上下文相矛盾,否则本文所用的术语“一种”、“一个”和“该”可与“一个或多个”和“至少一个”互换使用。因此,例如,包含“一种”赋形剂的组合物可以解释为是指包含“一种或多种”赋形剂的组合物。
如本文所用,术语“约”优选指所示数值的±10%,更优选所示数值的±5%,特别是所示的精确数值。如果术语“约”与范围的端点结合使用,则优选指从其所示数值的下端点-10%到其所示数值的上端点+10%的范围,更优选从下端点-5%到上端点+5%的范围,且甚至更优选由下端点和上端点的精确数值定义的范围。如果术语“约”与开放范围的端点结合使用,则优选指从下端点-10%或从上端点+10%开始的相应范围,更优选从下端点-5%或从上端点+5%开始的范围,甚至更优选由相应端点的精确数值定义的开放范围。
除非另有明确说明或与上下文相矛盾,否则本文所用的术语“包含”(或“含”、“含有”、“包括”或“具有”)具有“特别含有”的含义,即“除其他可选要素外,还含有......”。除此之外,该术语还包括“基本上由......组成”和“由......组成”的较窄含义。例如,术语“包含B和C的A”具有“A特别含有B和C”的含义,其中A可以包含其他可选要素(例如“A含有B、C和D”也包括在内),但该术语还包括“A基本上由B和C组成”的含义和“A由B和C组成”的含义(即A中不包含除B和C之外的其他成分)。
如本文所用,术语“任选的”、“任选地”和“可以”表示所指示的特征可以存在但也可以不存在。无论何时使用术语“可选的”、“任选地”或“可以”,本发明均具体涉及两种可能性,即,存在相应的特征,或者,相应的特征不存在。例如,如果组合物的一种成分被指示为“任选的”,则本发明具体涉及两种可能性,即相应的成分存在(包含在组合物中)或组合物中不存在相应的成分。
应当理解,本发明特别涉及本文所述特征和实施方案的每一种组合,包括一般和/或优选的特征/实施方案的任意组合。
在本说明书中,引用了许多文献,包括专利申请和科学文献。这些文献的公开内容在此通过引用整体并入作为参考,但并不认为其与本发明的可专利性相关。更具体地,所有参考文献均通过引用并入,其程度如同每个单独的文献被具体和单独地指出通过引用并入一样。
本说明书中对任何在先出版物(或由其得到的信息)的引用不是也不应被视为确认或承认或以任何形式暗示相应的在先出版物(或由其得到的信息)构成本发明涉及的技术领域的常规的一般知识的组成部分。
此外,本文还提供了用作药物的组合物(或相应地,用于疗法的药物组合物),其中该组合物包含苯达莫司汀或其药学上可接受的盐或溶剂化物(例如盐酸苯达莫司汀,特别是一水合盐酸苯达莫司汀)与磺丁基醚-β-环糊精(SBE-β-CD;例如)的组合,其中该组合物用于口服施用。相应的组合物可用于本文中关于本发明组合物所述的相同的治疗应用(包括例如癌症的治疗)。本发明组合物的一般和优选特征的描述同样适用于本段落中提供的组合物,不同之处在于后者含有SBE-β-CD代替修饰的环糊精。
本发明特别涉及如下项目:
1.用作药物的组合物,其中该组合物包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中该组合物用于口服施用,且其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
2.口服药物组合物,其包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
3.苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合在制备用于口服施用的药物中的用途,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
4.在有需要的个体中治疗疾病或障碍的方法,该方法包括对所述个体口服施用包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合的药物组合物,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
5.向有需要的个体递送苯达莫司汀或其药学上可接受的盐或溶剂化物的方法,该方法包括对所述个体口服施用包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合的药物组合物,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
6.用于项目1的用途的组合物或项目2的口服药物组合物或项目3的用途或项目4或5的方法,其中所述组合物包含盐酸苯达莫司汀。
7.用于项目1的用途的组合物或项目2的口服药物组合物或项目3的用途或项目4或5的方法,其中所述组合物包含一水合盐酸苯达莫司汀。
8.用于项目1、6或7任一项的用途的组合物或项目2、6或7任一项的口服药物组合物或项目3、6或7任一项的用途或项目4-7任一项的方法,其中修饰的环糊精是β-环糊精,其被甲基、羟基乙基、羟基丙基、二羟基丙基、羟基丁基、乙酰基或其任意组合取代。
9.用于项目1或6-8任一项的用途的组合物或项目2或6-8任一项的口服药物组合物或项目3或6-8任一项的用途或项目4-8任一项的方法,其中修饰的环糊精选自甲基-β-环糊精、羟丙基-β-环糊精、羟基乙基-β-环糊精、二羟丙基-β-环糊精、羟基丁基-β-环糊精、乙酰基-β-环糊精和被至少两个选自甲基、羟基乙基、羟基丙基、二羟基丙基、羟基丁基和乙酰基的不同基团取代的β-环糊精。
10.用于项目1或6-9任一项的用途的组合物或项目2或6-9任一项的口服药物组合物或项目3或6-9任一项的用途或项目4-9任一项的方法,其中修饰的环糊精是甲基-β-环糊精。
11.用于项目1或6-9任一项的用途的组合物或项目2或6-9任一项的口服药物组合物或项目3或6-9任一项的用途或项目4-9任一项的方法,其中修饰的β-环糊精是羟丙基-β-环糊精。
12.用于项目1或6-11任一项的用途的组合物或项目2或6-11任一项的口服药物组合物或项目3或6-11任一项的用途或项目4-11任一项的方法,其中所述组合物包含所述修饰的环糊精和所述苯达莫司汀或其药学上可接受的盐或溶剂化物的包合配合物。
13.用于项目12的用途的组合物或项目12的口服药物组合物或项目12的用途或项目12的方法,其中所述包合配合物可通过捏合、物理混合、共蒸发、冷冻干燥或喷雾干燥所述修饰的环糊精和所述苯达莫司汀或其药学上可接受的盐或溶剂化物得到。
14.用于项目1或6-13任一项的用途的组合物或项目2或6-13任一项的口服药物组合物或项目3或6-13任一项的用途或项目4-13任一项的方法,其中所述组合物包含所述苯达莫司汀或其药学上可接受的盐或溶剂化物和所述修饰的环糊精,两者的摩尔比约为1:10至约1:0.5。
15.用于项目1或6-14任一项的用途的组合物或项目2或6-14任一项的口服药物组合物或项目3或6-14任一项的用途或项目4-14任一项的方法,其中所述组合物以固体口服剂型的形式提供,优选丸剂、片剂、小片、胶囊剂、锭剂、药片、弹丸剂、散剂、颗粒或薄膜形式。
16.用于项目15的用途的组合物或项目15的口服药物组合物或项目15的用途或项目15的方法,其中所述固体口服剂型具有肠溶包衣。
17.用于项目16的用途的组合物或项目16的口服药物组合物或项目16的用途或项目16的方法,其中所述肠溶包衣由选自如下的材料制成:丙烯酸甲酯-甲基丙烯酸共聚物、丙烯酸乙酯-甲基丙烯酸共聚物、甲基丙烯酸甲酯-甲基丙烯酸共聚物、乙酸邻苯二甲酸纤维素、乙酸琥珀酸纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、聚乙酸乙烯邻苯二甲酸酯、虫胶、乙酸偏苯三酸纤维素、羧甲基纤维素、藻酸钠、玉米醇溶蛋白、直链淀粉、淀粉和糊精。
18.用于治疗癌症的如项目1、2或6-17任一项中所定义的组合物,其中所述组合物通过口服施用。
19.项目3或6-17任一项的用途,其中所述药物用于治疗癌症。
20.项目4或6-17任一项的方法,其中所治疗的疾病或障碍是癌症。
21.用于项目18的用途的组合物或项目19的用途或项目20的方法,其中所述癌症是血癌。
22.用于项目21的用途的组合物或项目21的用途或项目21的方法,其中所述癌症是复发性或难治性血癌。
23.用于项目21的用途的组合物或项目21的用途或项目21的方法,其中所述癌症是利妥昔单抗难治性血癌。
24.用于项目21-23任一项的用途的组合物或项目21-23任一项的用途或项目21-23任一项的方法,其中所述血癌选自淋巴瘤、霍奇金淋巴瘤、结节硬化型霍奇金淋巴瘤、混合细胞型霍奇金淋巴瘤、富含淋巴细胞的霍奇金淋巴瘤、淋巴细胞耗竭型霍奇金淋巴瘤、结节性淋巴细胞优势型霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性非霍奇金淋巴瘤、弥漫性非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤、套细胞淋巴瘤、外周T-细胞淋巴瘤、皮肤T-细胞淋巴瘤、蕈样真菌病、Sézary病、T区淋巴瘤、淋巴上皮样淋巴瘤、伦纳特淋巴瘤、淋巴肉瘤、恶性免疫增殖性疾病、瓦尔登斯特伦巨球蛋白血症、α-重链病、γ-重链病、富兰克林病、免疫增殖性小肠病、地中海淋巴瘤、多发性骨髓瘤、卡勒病、骨髓瘤病、白血病、浆细胞白血病、淋巴细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、亚急性淋巴细胞白血病、幼淋巴细胞白血病、毛细胞白血病、白血病性网状内皮组织增殖、成人T细胞白血病、骨髓性白血病、急性骨髓性白血病、慢性骨髓性白血病、亚急性骨髓性白血病、髓样肉瘤、绿色瘤、粒细胞肉瘤、急性早幼粒细胞白血病、急性粒-单核细胞白血病、慢性BCR-ABL阴性骨髓增生病、真性红细胞增多症、原发性血小板增多症、特发性骨髓纤维化、单核细胞白血病、急性红细胞增多症、红白血病、急性红细胞性骨髓增生症、Di Guglielmo病、慢性红细胞增多症、Heilmeyer-病、急性巨核细胞白血病、肥大细胞白血病、急性全骨髓增生症、急性骨髓纤维化和Letterer-Siwe病。
25.用于项目21-23任一项的用途的组合物或项目21-23任一项的用途或项目21-23任一项的方法,其中所述血癌选自慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性非霍奇金淋巴瘤、惰性B细胞非霍奇金淋巴瘤、套细胞淋巴瘤、瓦尔登斯特伦巨球蛋白血症和多发性骨髓瘤。
26.用于项目18的用途的组合物或项目19的用途或项目20的方法,其中所述癌症是实体癌。
27.用于项目18或26的用途的组合物或项目19或26的用途或项目20或26的方法,其中所述癌症选自乳腺癌、肺癌、卵巢癌、结肠直肠癌、结肠癌、胰腺癌、膀胱癌、前列腺癌、头部和/或颈部癌症和软组织肉瘤。
28.项目1、2或6-17任一项中所定义的组合物,用于治疗自身免疫疾病/障碍、类风湿性关节炎、多发性硬化、红斑狼疮或神经变性疾病/障碍;或用于免疫调节疗法,其中所述组合物通过口服施用。
29.项目3或6-17任一项的用途,其中所述药物用于治疗自身免疫疾病/障碍、类风湿性关节炎、多发性硬化、红斑狼疮或神经变性疾病/障碍;或所述药物用于免疫调节疗法。
30.项目4或6-17任一项的方法,其中所治疗的疾病或障碍是自身免疫疾病/障碍、类风湿性关节炎、多发性硬化、红斑狼疮或神经变性疾病/障碍。
31.用于项目18或21-28任一项的用途的组合物或项目19、21-27或29任一项的用途或项目20-27或30任一项的方法,其中在单一疗法中施用所述组合物或药物。
32.用于项目18或21-27任一项的用途的组合物或项目19或21-27任一项的用途或项目20-27任一项的方法,其中将所述组合物或药物与其他抗癌药和/或放疗联合施用。
33.用于项目32的用途的组合物或项目32的用途或项目32的方法,其中所述其他抗癌药选自依托泊苷、氟达拉滨、米托蒽醌、甲氨蝶呤、泼尼松、长春新碱和抗-CD20单克隆抗体。
34.用于项目32的用途的组合物或项目32的用途或项目32的方法,其中所述其他抗癌药是抗-CD20单克隆抗体,优选选自利妥昔单抗、奥瑞珠单抗、奥法木单抗、阿托珠单抗和替伊莫单抗。
35.用于项目18或21-28任一项的用途的组合物或项目19、21-27或29任一项的用途或项目20-27或30任一项的方法,其中将所述组合物或药物与利妥昔单抗联合施用。
36.用于项目18或21-28任一项的用途的组合物或项目19、21-27或29任一项的用途或项目20-27或30任一项的方法,其中将所述组合物或药物与阿托珠单抗联合施用。
37.用于项目1、6-18、21-28或32-36任一项的用途的组合物或项目3、6-17、19、21-27、29或32-36任一项的用途或项目4-17、20-27、30或32-36任一项的方法,其中将所述组合物或药物与止吐药联合施用。
38.用于项目37的用途的组合物或项目37的用途或项目37的方法,其中所述止吐药选自阿洛司琼、阿扎司琼、贝美司琼、西兰司琼、氯氮平、达佐比利、多拉司琼、格拉司琼、来立司琼、甲氧氯普胺、米安色林、米氮平、奥氮平、昂丹司琼、帕洛诺司琼、喹硫平、雷莫司琼、利卡司琼、托烷司琼、扎托司琼、氯氮平、赛庚啶、羟嗪、奥氮平、利培酮、齐拉西酮、屈大麻酚、大麻隆、四氢大麻酚、阿立必利、溴必利、氯丙嗪、氯波必利、多潘立酮、氟哌啶醇、羟嗪、伊托必利、甲氧氯普胺、美托哌丙嗪、丙氯拉嗪、硫乙拉嗪、曲美苄胺、赛克力嗪、茶苯海明、苯海拉明、羟嗪、美克洛嗪、异丙嗪、阿托品、苯海拉明、莨菪碱、东莨菪碱、阿瑞匹坦、卡索匹坦、依洛匹坦、福沙匹坦、马罗匹坦、奈妥匹坦、罗拉匹坦、维替匹坦、草酸铈、地塞米松、劳拉西泮、咪达唑仑、丙泊酚及其组合。
39.用于项目1、6-18、21-28或31-38任一项的用途的组合物或项目3、6-17、19、21-27、29或31-38任一项的用途或项目4-17、20-27、30-38任一项的方法,其中将所述组合物或药物通过口服施用于人类个体。
40.用于项目1、6-18、21-28或31-39任一项的用途的组合物或项目3、6-17、19、21-27、29或31-39任一项的用途或项目4-17、20-27、30-39任一项的方法,其中以约10mg至约1g的单位剂量、优选约20mg至约800mg的单位剂量、更优选约30mg至约600mg的单位剂量、甚至更优选约50mg至约500mg的单位剂量口服施用所述组合物或药物。
41.用于项目40的用途的组合物或项目40的用途或项目40的方法,其中所述单位剂量每隔3或4周施用1-5次。
42.用于项目1、6-18、21-28或31-39任一项的用途的组合物或项目3、6-17、19、21-27、29或31-39任一项的用途或项目4-17、20-27、30-39任一项的方法,其中以约50mg至约500mg的单位剂量口服施用所述组合物或药物,且其中每隔21天在第1和第2天施用所述单位剂量。
43.用于项目1、6-18、21-28或31-39任一项的用途的组合物或项目3、6-17、19、21-27、29或31-39任一项的用途或项目4-17、20-27、30-39任一项的方法,其中以约50mg至约500mg的单位剂量口服施用所述组合物或药物,且其中每隔21天在第1-5天施用所述单位剂量。
44.用于项目1、6-18、21-28或31-39任一项的用途的组合物或项目3、6-17、19、21-27、29或31-39任一项的用途或项目4-17、20-27、30-39任一项的方法,其中以约50mg至约500mg的单位剂量口服施用所述组合物或药物,且其中每隔28天在第1和第2天施用所述单位剂量。
45.用于项目1、6-18、21-28或31-39任一项的用途的组合物或项目3、6-17、19、21-27、29或31-39任一项的用途或项目4-17、20-27、30-39任一项的方法,其中以约50mg至约500mg的单位剂量口服施用所述组合物或药物,且其中每隔28天在第1和第15天施用所述单位剂量。
46.用于项目1、6-18、21-28或31-39任一项的用途的组合物或项目3、6-17、19、21-27、29或31-39任一项的用途或项目4-17、20-27、30-39任一项的方法,其中以约50mg至约500mg的单位剂量口服施用所述组合物或药物,且其中每隔28天在第1-5天施用所述单位剂量。
47.用于项目40-46任一项的用途的组合物或项目40-46任一项的用途或项目40-46任一项的方法,其中单位剂量选自约50mg、约75mg、约100mg、约150mg、约180mg、约200mg、约250mg、约300mg、约350mg、约400mg、约450mg和约500mg。
现在通过参照下列实施例描述本发明,这些实施例仅是说明性的,不应解释为对本发明范围的限制。
实施例
不同制剂的体内PK研究
作为生物分析方法,用一种快速和可靠的方法同时测定存在于不同物种血浆中的苯达莫司汀及其主要代谢物γ-羟基苯达莫司汀(M3代谢物)(Srinivas NR等人,Drug Res(Stuttg),2016,66(7),351-356;Chandrashekar DV等人,Drug Res(Stuttg),2017,doi:10.1055/s-0043-108124)。
绝对生物利用度是指当通过非静脉内剂型(即口服)施用时,与通过静脉内施用的相同药物的生物利用度相比的生物利用度。它通过使用如下公式计算:
所有PK研究中测定的药代动力学参数如下所定义:
制剂的制备通过将盐酸苯达莫司汀和以1:2的摩尔比混合进行。制剂在给药当天通过将其溶解在足量的Milli-Q水中新鲜制备,并在5分钟内按照所需的给药体积施用于大鼠。在异氟烷麻醉下,在制剂施用后的预定时间点从每只动物收集大约0.2mL血样。
得到的结果如下表1中所示:
#i.v.数据来源于先前的实验
@i.v.数据来源于先前的实验
相应的γ-羟基苯达莫司汀代谢物(M3)与苯达莫司汀的AUC0->∞之比测定为0.09。
实施例2:使用β-环糊精的苯达莫司汀在SD大鼠中的口服生物利用度
制剂的制备通过将盐酸苯达莫司汀和β-环糊精以1:4的摩尔比混合进行。制剂在给药当天通过将其溶解在足量的Milli-Q水中新鲜制备,并在5分钟内按照所需的给药体积施用于大鼠。在异氟烷麻醉下,在制剂施用后的预定时间点从每只动物收集大约0.2mL血样。
得到的结果如下表2中所示:
#IV数据来源于先前的实验
@IV数据来源于先前的实验
表2(组-2):将苯达莫司汀-β-环糊精以9.0mg/kg(相当于苯达莫司汀碱)口服施用于雄性SD大鼠后苯达莫司汀的药代动力学参数
相应的γ-羟基苯达莫司汀代谢物(M3)与苯达莫司汀的AUC0->∞之比测定为0.05。
实施例3:使用α-环糊精的苯达莫司汀在SD大鼠中的口服生物利用度
制剂的制备通过将盐酸苯达莫司汀和α-环糊精以1:4.5的摩尔比混合进行。制剂在给药当天通过将其溶解在足量的Milli-Q水中新鲜制备,并在5分钟内按照所需的给药体积施用于大鼠。在异氟烷麻醉下,在制剂施用后的预定时间点从每只动物收集大约0.2mL血样。
得到的结果如下表3中所示:
#IV数据来源于先前的实验
@IV数据来源于先前的实验
表3:将苯达莫司汀-α-环糊精以9.0mg/kg(相当于苯达莫司汀碱)口服施用于雄性SD大鼠后苯达莫司汀的药代动力学参数
相应的γ-羟基苯达莫司汀代谢物(M3)与苯达莫司汀的AUC0->∞之比测定为0.16。
静脉施用后30分钟和60分钟相应的γ-羟基苯达莫司汀代谢物(M3)与苯达莫司汀的AUC0->∞之比分别测定为0.07和0.05。
实施例4:使用甲基-β-环糊精的苯达莫司汀在SD大鼠中的口服生物利用度
制剂的制备通过将盐酸苯达莫司汀和甲基-β-环糊精以1:1的摩尔比混合进行。制剂在给药当天通过将其溶解在足量的Milli-Q水中新鲜制备,并在5分钟内按照所需的给药体积施用于大鼠。在异氟烷麻醉下,在制剂施用后的预定时间点从每只动物收集大约0.2mL血样。
使用如下公式测定相对口服生物利用度:
得到的结果如下表4中所示:
*计算为适当剂量标准化的AUC0-∞(口服)和AUC0-∞(iv;1组)的商乘以100
表4:苯达莫司汀-甲基-β-环糊精制剂以15mg/kg口服施用于雄性SD大鼠后苯达莫司汀的药代动力学参数
M3代谢物的口服生物利用度与60分钟静脉输注时间相比为176%,与30分钟静脉输注时间相比为78%。
相应的γ-羟基苯达莫司汀代谢物(M3)与苯达莫司汀的AUC0->∞之比测定为0.05,其几乎等同地与静脉输注时间相对应。
实施例5:使用β-环糊精制剂的苯达莫司汀在Balb/c小鼠中的口服生物利用度
制剂的制备通过将盐酸苯达莫司汀和β-环糊精以1:1的摩尔比混合进行。制剂在给药当天通过将其溶解在足量的Milli-Q水中新鲜制备,并在5分钟内按照所需的给药体积施用于小鼠。进行稀疏采样(每个时间点n=3),并且给每只动物放血2次。在异氟烷麻醉下,在化合物施用后的下述时间点将血样(~200μL)采集在包含Na2.EDTA的试管中。
表5:对雄性Balb/c小鼠口服施用苯达莫司汀-β-环糊精制剂(相当于9mg/kg苯达莫司汀碱)后苯达莫司汀的药代动力学参数
实施例6:使用β-环糊精和SNAC制剂的苯达莫司汀在SD大鼠中的口服生物利用度
制剂的制备通过将盐酸苯达莫司汀、β-环糊精和N-[8-(2-羟基苯甲酰基)氨基]辛酸钠(SNAC)*以1:6:22的摩尔比混合进行。制剂在给药当天通过将其溶解在足量的Milli-Q水中新鲜制备,并在5分钟内按照所需的给药体积施用于大鼠。在异氟烷麻醉下,在制剂施用后的预定时间点从每只动物收集大约0.2mL血样。
*SNAC是口服生物利用度的增强剂(Castelli MC等人,The FASEB Journal,2008,22(2)增刊,795)。
得到的结果如下表6中所示:
表6:以9mg/kg(相当于苯达莫司汀碱)对雄性SD大鼠口服施用苯达莫司汀-β-环糊精-SNAC后苯达莫司汀的药代动力学参数
实施例7:苯达莫司汀的不同制剂及其代谢物M3在比哥犬中的PK研究的比较
在比哥犬中比较含有2-羟丙基-β-环糊精和β-环糊精的苯达莫司汀制剂的口服生物利用度和PK特性。
利用交叉设计,将含有使两种制剂均达到剂量为12mg/kg的量的盐酸苯达莫司汀的胶囊施用于比哥犬并且与60min IV输注施用进行比较。将胶囊制剂在2-8℃之间存放。在临给药前新鲜制备相应的IV制剂。
得到的结果如下表7中所示:
表7:两种苯达莫司汀制剂在狗中的PK数据对比表
对于2HP-β-CD制剂,相应的γ-羟基苯达莫司汀代谢物(M3)与苯达莫司汀的AUC0->∞之比测定为0.03,其几乎等同地与比值为0.08的IV输注时间60min相对应。
β-CD制剂的比值测定为0.26。
2HP-β-CD制剂与静脉内施用之间M3和苯达莫司汀的AUC比值接近表明苯达莫司汀的代谢在两种施用中是相同的。
苯达莫司汀制剂在水中的稳定性
实施例8:通过在水/乙醇中捏合得到的含有2-羟丙基-β-环糊精和甲基-β-环糊精的苯达莫司汀制剂的稳定性比较
2-羟丙基-β-环糊精制剂:将1.25mmol盐酸苯达莫司汀与1.25mmol 2HP-β-CD(MW=1540)混合,用等摩尔的EtOH/H2O混合物湿润并捏合约20分钟。然后在40℃浴温下真空蒸发澄清溶液,在高真空下进一步干燥,然后在真空干燥器中存放5天。
甲基-β-环糊精制剂:将1.25mmol盐酸苯达莫司汀与1.25mmol Me-β-CD(MW=1310)混合,用等摩尔的EtOH/H2O混合物湿润并捏合约20分钟。然后在40℃浴温下真空蒸发澄清溶液,在高真空下进一步干燥,然后在真空干燥器中存放5天。
将新鲜制备的苯达莫司汀制剂各10mg用HPLC测定,并且在3小时内测定苯达莫司汀的水解稳定性。
180分钟后,甲基-β-环糊精制剂存在89.40%的苯达莫司汀,而2-羟丙基-β-环糊精制剂为88.94%。在180分钟时间内,发现甲基-β-环糊精制剂和2-羟丙基-β-环糊精制剂对苯达莫司汀具有有利的和几乎等同的有效稳定作用。
苯达莫司汀制剂的效能研究
实施例9:使用苯达莫司汀的Me-β-CD和2-HP-β-CD制剂的B-细胞淋巴瘤异种移植物研究
给每组8只的雄性NOD/SCID小鼠注射Raji细胞,当肿瘤体积达到~150mm3时,小鼠分别用载体、苯达莫司汀静脉内注射、苯达莫司汀水溶液口服、苯达莫司汀-Me-β-CD制剂口服和苯达莫司汀-2HP-β-CD制剂治疗。所有组的治疗每周一次在第1天和第8天进行,持续2周。测量肿瘤体积和体重四周。研究在第30天终止。
两种口服制剂(即苯达莫司汀-2HP-β-CD口服和苯达莫司汀-Me-β-CD口服)的肿瘤体积在本研究时间期限内相同,并且明显抑制肿瘤生长,与苯达莫司汀静脉应用相比等同。与口服或静脉应用相比,苯达莫司汀水溶液的抑制作用较小(参见图2)。
值得注意的是,与静脉注射应用相比,口服苯达莫司汀制剂的体重变化较小(参见图3),这表明口服苯达莫司汀-Me-β-CD和口服苯达莫司汀-2HP-β-CD制剂具有更好的耐受性。
苯达莫司汀制剂的对比研究
实施例10:分别通过捏合和物理混合得到的含有2-羟丙基-β-环糊精或甲基-β-环糊精的苯达莫司汀制剂的比较
在PK研究中,分别评估了通过捏合(参见上述实施例8中所述的方法)和作为物理混合物制备的随机化甲基-β-环糊精和2-HP-β-环糊精之间的口服生物利用度(F)差异。
结果:对于两种环糊精,使用拟合方法的口服生物利用度均低于使用物理混合物的口服生物利用度。
甲基-β-环糊精-苯达莫司汀HCl之比1:1(M/M):捏合与物理混合物之比1:1(M/M):因子(捏合/物理混合物之比)=0.6
2-羟丙基-β-环糊精-苯达莫司汀HCl之比1:1(M/M):捏合与物理混合物之比1:1(M/M):因子(捏合/物理混合物之比)=0.8
实施例11:含有聚合的表氯醇-β-环糊精(参比)、2-羟丙基-β-环糊精和甲基-β-环糊精的苯达莫司汀制剂的比较
作为比较,在PK研究中测试了含有表氯醇-β-环糊精聚合比1:1(M/M)的苯达莫司汀制剂:绝对生物利用度为85%;相对生物利用度为214%,显著低于Gidwani B等人,DrugDev Ind Pharm,2015,41(12),1978-1988的出版物中所述的323%相对生物利用度值。Gidwani未给出表氯醇-β-环糊精制剂的绝对口服生物利用度,并且Gidwani的出版物中的药代动力学参数例如Cmax和AUC显著高于本实施例中的实验测量值,如下文所详述。
公布的苯达莫司汀水溶液的PK值(10mg/kg):Cmax=12.6μg/mL;AUC=13.2μg·h/mL
经实验确立的苯达莫司汀水溶液的PK值(15mg/kg):Cmax=2.6μg/mL;AUC=1.35μg·h/mL
公布的捏合的表氯醇-β-CD/苯达莫司汀制剂(1:1M/M)(10mg/kg)的PK值:Cmax=32.13μg/mL;AUC=42.64μg·h/mL
经实验确立的捏合的表氯醇-β-CD/苯达莫司汀制剂(1:1M/M)(15mg/kg)的PK值:Cmax=5.1μg/mL;AUC=2.9μg·h/mL
另外,测定的表氯醇-β-CD制剂的t1/2为25min,而公布的t1/2为74min。形成强烈对比的是,测定的2-HP-β-CD与苯达莫司汀的物理混合物3:1(M/M)制剂的t1/2为68min。
2-羟丙基-β-环糊精/苯达莫司汀HCl的制剂(3:1M/M)的绝对生物利用度为58%,而相对生物利用度测定为144%。
得到的结果如图4中所示。
含有随机化甲基-β-CD(rMeCD)和2-羟丙基-β-CD(2HPCD)的制剂的药代动力学在长时间暴露方面显示出优于静脉内给予的苯达莫司汀、甚至是聚合的表氯醇-β-CD(EpiCDp)的有利特性,清楚地表明了苯达莫司汀的稳定化作用。
对于2HP-β-CD制剂,相应的γ-羟基苯达莫司汀代谢物(M3)与苯达莫司汀的AUC0->∞之比测定为0.02,其几乎等同地与比值为0.01的30min IV输注时间相对应。
对于rMe-β-CD制剂,相应的γ-羟基苯达莫司汀代谢物(M3)与苯达莫司汀的AUC0->∞之比测定为0.027,其几乎等同地与比值为0.01的30min IV输注时间相对应。
实施例12:苯达莫司汀制剂的稳定性比较
比较以具有不同摩尔比例如1:0.5;1:0.7;1:0.9;1:1;1:1.5;1:2;1:5;1:7;1:10的物理混合物形式得到的苯达莫司汀/2-羟丙基-β-环糊精制剂的稳定性。作为一个例子,这里列出了一种典型方法,该方法也适用于确定的其他摩尔比:
通过将烧瓶充分摇动3小时,将0.5mmol苯达莫司汀HCl与1.5mmol 2-羟丙基-β-环糊精物理混合。通过HPLC测定10mg苯达莫司汀制剂,每30分钟一次,总共测定180分钟,以确定水解稳定性。180分钟后,存在97%的苯达莫司汀HCl。
将0.2mmol苯达莫司汀HCl与0.2mmol表氯醇-β-环糊精(参比)混合并且如上述实施例8中所述捏合。通过HPLC测定10mg苯达莫司汀制剂,每30分钟一次,总共测定180分钟,以确定水解稳定性。180分钟后,存在94%的苯达莫司汀HCl。
比较以具有不同摩尔比的物理混合物形式得到的苯达莫司汀/随机化甲基-β-环糊精制剂的水解稳定性。作为一个例子,这里列出了一种典型方法,该方法也适用于确定的其他摩尔比,例如1:0.5;1:0.7;1:0.9;1:1;1:1.5;1:2;1:3;1:5;1:10:
通过将烧瓶充分摇动3小时,将0.5mmol苯达莫司汀HCl与0.9mmol随机化甲基-β-环糊精物理混合。通过HPLC测定10mg苯达莫司汀制剂,每30分钟一次,总共测定180分钟,以确定水解稳定性。180分钟后,存在98%的苯达莫司汀HCl。
比较以具有不同摩尔比的物理混合物形式得到的苯达莫司汀与随机化甲基-β-环糊精和2-羟丙基-β-环糊精的混合物的制剂的水解稳定性。作为一个例子,这里列出了一种典型方法,该方法也适用于确定的其他摩尔比,例如1:0.5:0.5;1:0.7:1.3;1:0.9;1.1;1:1:2;1:1:3;1:1:5;1:2.6;1:3:7:
通过将烧瓶充分摇动3小时,将0.5mmol苯达莫司汀HCl与0.7mmol随机化甲基-β-环糊精和1.3mmol 2-羟丙基-β-环糊精物理混合。通过HPLC测定10mg苯达莫司汀制剂,每30分钟一次,总共测定180分钟,以确定水解稳定性。180分钟后,存在98.5%的苯达莫司汀HCl。
Claims (22)
1.用作药物的组合物,其中该组合物包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中该组合物用于口服施用,且其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
2.口服药物组合物,其包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
3.用于权利要求1的用途的组合物或权利要求2的口服药物组合物,其中所述组合物包含盐酸苯达莫司汀。
4.用于权利要求1的用途的组合物或权利要求2的口服药物组合物,其中所述组合物包含一水合盐酸苯达莫司汀。
5.用于权利要求1、3或4任一项的用途的组合物或权利要求2-4任一项的口服药物组合物,其中修饰的环糊精是被甲基、羟基乙基、羟基丙基、二羟基丙基、羟基丁基、乙酰基或其任意组合取代的β-环糊精。
6.用于权利要求1或3-5任一项的用途的组合物或权利要求2-5任一项的口服药物组合物,其中修饰的环糊精选自甲基-β-环糊精、羟丙基-β-环糊精、羟基乙基-β-环糊精、二羟丙基-β-环糊精、羟基丁基-β-环糊精、乙酰基-β-环糊精和被至少两个选自甲基、羟基乙基、羟基丙基、二羟基丙基、羟基丁基和乙酰基的不同基团取代的β-环糊精。
7.用于权利要求1或3-6任一项的用途的组合物或权利要求2-6任一项的口服药物组合物,其中修饰的环糊精是甲基-β-环糊精。
8.用于权利要求1或3-6任一项的用途的组合物或权利要求2-6任一项的口服药物组合物,其中修饰的β-环糊精是羟丙基-β-环糊精。
9.用于权利要求1或3-8任一项的用途的组合物或权利要求2-8任一项的口服药物组合物,其中所述组合物包含所述修饰的环糊精和所述苯达莫司汀或其药学上可接受的盐或溶剂化物的包合配合物,其中所述包合配合物可通过捏合、物理混合、共蒸发、冷冻干燥或喷雾干燥所述修饰的环糊精和所述苯达莫司汀或其药学上可接受的盐或溶剂化物得到。
10.用于权利要求1或3-9任一项的用途的组合物或权利要求2-9任一项的口服药物组合物,其中所述组合物包含所述苯达莫司汀或其药学上可接受的盐或溶剂化物和所述修饰的环糊精,两者的摩尔比约为1:10至约1:0.5。
11.用于权利要求1或3-10任一项的用途的组合物或权利要求2-10任一项的口服药物组合物,其中所述组合物以固体口服剂型的形式提供,优选丸剂、片剂、小片、胶囊剂、锭剂、药片、弹丸剂、散剂、颗粒或薄膜的形式;
且其中所述固体口服剂型任选地具有肠溶包衣,其中所述肠溶包衣优选由选自如下的材料制成:丙烯酸甲酯-甲基丙烯酸共聚物、丙烯酸乙酯-甲基丙烯酸共聚物、甲基丙烯酸甲酯-甲基丙烯酸共聚物、乙酸邻苯二甲酸纤维素、乙酸琥珀酸纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、乙酸琥珀酸羟丙基甲基纤维素、聚乙酸乙烯邻苯二甲酸酯、虫胶、乙酸偏苯三酸纤维素、羧甲基纤维素、藻酸钠、玉米醇溶蛋白、直链淀粉、淀粉和糊精。
12.用于治疗癌症的如权利要求1-11任一项中所定义的组合物,其中所述组合物通过口服施用。
13.用于权利要求12的用途的组合物,其中所述癌症是血癌,其优选选自淋巴瘤、霍奇金淋巴瘤、结节硬化型霍奇金淋巴瘤、混合细胞型霍奇金淋巴瘤、富含淋巴细胞的霍奇金淋巴瘤、淋巴细胞耗竭型霍奇金淋巴瘤、结节性淋巴细胞优势型霍奇金淋巴瘤、非霍奇金淋巴瘤、滤泡性非霍奇金淋巴瘤、弥漫性非霍奇金淋巴瘤、弥漫性大B细胞淋巴瘤、伯基特淋巴瘤、套细胞淋巴瘤、外周T-细胞淋巴瘤、皮肤T-细胞淋巴瘤、蕈样真菌病、Sézary病、T区淋巴瘤、淋巴上皮样淋巴瘤、伦纳特淋巴瘤、淋巴肉瘤、恶性免疫增殖性疾病、瓦尔登斯特伦巨球蛋白血症、α-重链病、γ-重链病、富兰克林病、免疫增殖性小肠病、地中海淋巴瘤、多发性骨髓瘤、卡勒病、骨髓瘤病、白血病、浆细胞白血病、淋巴细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、亚急性淋巴细胞白血病、幼淋巴细胞白血病、毛细胞白血病、白血病性网状内皮组织增殖、成人T细胞白血病、骨髓性白血病、急性骨髓性白血病、慢性骨髓性白血病、亚急性骨髓性白血病、髓样肉瘤、绿色瘤、粒细胞肉瘤、急性早幼粒细胞白血病、急性粒-单核细胞白血病、慢性BCR-ABL阴性骨髓增生病、真性红细胞增多症、原发性血小板增多症、特发性骨髓纤维化、单核细胞白血病、急性红细胞增多症、红白血病、急性红细胞性骨髓增生症、Di Guglielmo病、慢性红细胞增多症、Heilmeyer-病、急性巨核细胞白血病、肥大细胞白血病、急性全骨髓增生症、急性骨髓纤维化和Letterer-Siwe病。
14.用于权利要求12的用途的组合物,其中所述癌症是实体癌,其优选自乳腺癌、肺癌、卵巢癌、结肠直肠癌、结肠癌、胰腺癌、膀胱癌、前列腺癌、头部和/或颈部癌症和软组织肉瘤。
15.如权利要求1-11任一项中所定义的组合物,用于治疗自身免疫疾病/障碍、类风湿性关节炎、多发性硬化、红斑狼疮或神经变性疾病/障碍,或用于免疫调节疗法,其中所述组合物通过口服施用。
16.用于权利要求12-14任一项的用途的组合物,其中将所述组合物与其他抗癌药和/或放疗联合施用,
其中所述其他抗癌药优选自依托泊苷、氟达拉滨、米托蒽醌、甲氨蝶呤、泼尼松、长春新碱和抗-CD20单克隆抗体,且其中所述其他抗癌药更优选抗-CD20单克隆抗体,其选自利妥昔单抗、奥瑞珠单抗、奥法木单抗、阿托珠单抗和替伊莫单抗。
17.用于权利要求12-15任一项的用途的组合物,其中将该组合物与利妥昔单抗联合施用。
18.用于权利要求12-17任一项的用途的组合物,其中将该组合物与止吐药联合施用,其中所述止吐药优选选自阿洛司琼、阿扎司琼、贝美司琼、西兰司琼、氯氮平、达佐比利、多拉司琼、格拉司琼、来立司琼、甲氧氯普胺、米安色林、米氮平、奥氮平、昂丹司琼、帕洛诺司琼、喹硫平、雷莫司琼、利卡司琼、托烷司琼、扎托司琼、氯氮平、赛庚啶、羟嗪、奥氮平、利培酮、齐拉西酮、屈大麻酚、大麻隆、四氢大麻酚、阿立必利、溴必利、氯丙嗪、氯波必利、多潘立酮、氟哌啶醇、羟嗪、伊托必利、甲氧氯普胺、美托哌丙嗪、丙氯拉嗪、硫乙拉嗪、曲美苄胺、赛克力嗪、茶苯海明、苯海拉明、羟嗪、美克洛嗪、异丙嗪、阿托品、苯海拉明、莨菪碱、东莨菪碱、阿瑞匹坦、卡索匹坦、依洛匹坦、福沙匹坦、马罗匹坦、奈妥匹坦、罗拉匹坦、维替匹坦、草酸铈、地塞米松、劳拉西泮、咪达唑仑、丙泊酚及其组合。
19.用于权利要求1或3-17任一项的用途的组合物或权利要求2-11任一项的口服药物组合物,其中该组合物通过口服施用于人类个体。
20.苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合在制备用于口服施用的药物中的用途,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
21.在有需要的个体中治疗疾病或障碍的方法,该方法包括对所述个体口服施用包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合的药物组合物,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
22.向有需要的个体递送苯达莫司汀或其药学上可接受的盐或溶剂化物的方法,该方法包括对所述个体口服施用包含苯达莫司汀或其药学上可接受的盐或溶剂化物与修饰的环糊精的组合的药物组合物,其中所述修饰的环糊精选自α-环糊精、β-环糊精和γ-环糊精,且其中所述α-环糊精、所述β-环糊精或所述γ-环糊精被C1-4烷基、羟基-C1-4烷基、二羟基-C1-4烷基、-CO(C1-4烷基)或其任意组合取代。
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EP17194987.8 | 2017-10-05 | ||
EP17194987 | 2017-10-05 | ||
PCT/EP2018/077214 WO2019068904A1 (en) | 2017-10-05 | 2018-10-05 | ORAL ADMINISTRATION OF BENDAMUSTINE FORMULATIONS |
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CN201880063904.5A Pending CN111201019A (zh) | 2017-10-05 | 2018-10-05 | 口服苯达莫司汀制剂 |
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EP (1) | EP3691637A1 (zh) |
JP (1) | JP7267290B2 (zh) |
KR (2) | KR102450975B1 (zh) |
CN (1) | CN111201019A (zh) |
AU (1) | AU2018346395A1 (zh) |
BR (1) | BR112020006360A2 (zh) |
CA (1) | CA3078290A1 (zh) |
IL (1) | IL273644A (zh) |
MX (1) | MX2020003511A (zh) |
RU (1) | RU2020115024A (zh) |
SG (1) | SG11202003098WA (zh) |
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CN115379827A (zh) * | 2020-04-09 | 2022-11-22 | 比卡生物科技(广州)有限公司 | 苯达莫司汀组合物及其用途 |
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CN102164579A (zh) * | 2008-09-25 | 2011-08-24 | 赛福伦公司 | 苯达莫司汀的液体配制品 |
CN102421451A (zh) * | 2009-02-25 | 2012-04-18 | 休普拉特克药品有限公司 | 苯达莫司汀环多糖组合物 |
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AR072777A1 (es) | 2008-03-26 | 2010-09-22 | Cephalon Inc | Formas solidas de clorhidrato de bendamustina |
DK2367542T3 (da) | 2008-12-03 | 2014-03-10 | Astellas Deutschland Gmbh | Orale doseringsformer af bendamustin |
UA107186C2 (xx) | 2008-12-03 | 2014-12-10 | Тверді форми дозування бендамустину | |
MX2011011109A (es) | 2009-04-28 | 2011-11-18 | Cephalon Inc | Formulaciones orales de bendamustina. |
WO2010144675A1 (en) | 2009-06-10 | 2010-12-16 | Plus Chemicals Sa | Polymorphs of bendamustine hcl and processes for preparation thereof |
CN101606934B (zh) | 2009-07-27 | 2011-09-28 | 江苏奥赛康药业有限公司 | 盐酸苯达莫司汀组合物 |
WO2011103150A2 (en) | 2010-02-18 | 2011-08-25 | Cephalon, Inc. | Lyophilized preparations of bendamustine |
US8383663B2 (en) * | 2010-07-19 | 2013-02-26 | Supratek Pharma Inc. | Bendamustine anionic-catioinic cyclopolysaccharide compositions |
CN102351799B (zh) | 2011-10-24 | 2014-02-26 | 江苏奥赛康药业股份有限公司 | 一种盐酸苯达莫司汀晶型及其制备方法 |
PT2656843E (pt) | 2012-04-26 | 2015-04-14 | Helmut Schickaneder | Ésteres de bendamustina e compostos relacionados e a sua utilização médica |
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CN102164579A (zh) * | 2008-09-25 | 2011-08-24 | 赛福伦公司 | 苯达莫司汀的液体配制品 |
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MX2020003511A (es) | 2020-07-22 |
WO2019068904A1 (en) | 2019-04-11 |
RU2020115024A3 (zh) | 2022-03-17 |
KR20200066657A (ko) | 2020-06-10 |
KR20220138420A (ko) | 2022-10-12 |
ZA202002129B (en) | 2023-10-25 |
KR102450975B1 (ko) | 2022-10-07 |
BR112020006360A2 (pt) | 2020-09-24 |
EP3691637A1 (en) | 2020-08-12 |
IL273644A (en) | 2020-05-31 |
AU2018346395A1 (en) | 2020-04-30 |
JP7267290B2 (ja) | 2023-05-01 |
SG11202003098WA (en) | 2020-05-28 |
CA3078290A1 (en) | 2019-04-11 |
JP2020536126A (ja) | 2020-12-10 |
RU2020115024A (ru) | 2021-11-08 |
US20200246312A1 (en) | 2020-08-06 |
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