CN103458880A - 口服给药的单位剂型 - Google Patents
口服给药的单位剂型 Download PDFInfo
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- CN103458880A CN103458880A CN2012800173194A CN201280017319A CN103458880A CN 103458880 A CN103458880 A CN 103458880A CN 2012800173194 A CN2012800173194 A CN 2012800173194A CN 201280017319 A CN201280017319 A CN 201280017319A CN 103458880 A CN103458880 A CN 103458880A
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- Prior art keywords
- alkyl
- assorted
- coating
- anoxia
- aryl
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Abstract
TH-302和适合用于口服给药的其他缺氧激活前药的制剂和单位剂型用于治疗癌症。
Description
相关申请的引用
本申请根据35U.S.C.119(e)要求于2011年4月15日提交的美国临时申请号61/475,844的优先权,其全部内容以引用方式结合于本文。
技术领域
本发明涉及用于口服给予以治疗癌症的缺氧激活前药的药物制剂和单位剂型以及通过给予这样的制剂和单位剂型来治疗癌症的方法。因而本发明还涉及医学和药理学领域。
背景技术
TH-302是一种临床测试用于治疗癌症的缺氧激活前药,其作为静脉内(IV)输注给药并且显示出优异的临床活性。TH-302是一种异磷酰胺氮芥(IPM)与以下结构(TH-302向Br-IPM的转化在缺氧条件下发生)的溴化形式(Br-IPM)的硝基咪唑连接的前药:
在PCT公开第WO2007/002931号、第WO2008/083101号、第WO2010/048330号、第WO2012/006032号和第WO2012/009288号;以及PCT专利申请第PCT/US2012/031677号中描述了TH-302的合成方法和用途,其中的每一篇均结合于本文作为参考。
对于TH-302和其他缺氧激活前药的口服制剂存在需要;本发明满足了这种需要。
发明内容
在一方面,本发明提供了一种口服剂型,优选修饰释放制剂,包含TH-302或式I(见下文)的其他缺氧激活前药或基本上由TH-302或式I(见下文)的其他缺氧激活前药组成,以及可选地一种或多种可药用赋形剂。如在本文中使用的,赋形剂适用于向人类癌症患者给药。在一些实施方式中,该剂型为固体剂型,其在一些实施方式这作为单位剂型提供,例如片剂或胶囊。在其他实施方式中,该剂型为液体剂型。
尽管口服剂型提供了诸如较低的住院治疗成本和容易给药的优点,但诸如TH-302的抗癌剂由于其毒性、尺寸、和/或通常具有较差的口服生物利用度而通常通过IV输注给药。TH-302是一种前药,并且其毒性被充分掩蔽直至其含有的毒素无法掩蔽(unmask),例如在缺氧条件下。而且,如通过本文中披露的研究所证明的,TH-302具有出人意料地高的生物利用度。因此,本发明提供的TH-302的口服制剂提供了超越用于IV输注的液体制剂的某些优点。考虑到TH-302的半衰期,本发明提供的TH-302的修饰释放的口服制剂还具有治疗有益的应用。因此,如本文中所提供的其他缺氧激活前药的口服制剂也是治疗有益的。
在不同的实施方式中,本发明的制剂和单位剂型中存在的缺氧激活前药为式I的化合物:
其中Y2为O、S、NR6、NCOR6或NSO2R6,其中R6为C1-C6烷基、C1-C6杂烷基、芳基、或杂芳基;R3和R4独立地选自2-卤代烷基、2-烷基磺酰氧基烷基、2-杂烷基磺酰氧基烷基、2-芳基磺酰氧基烷基、和2-杂烷基磺酰氧基烷基;R1具有式L-Z3;L为C(Z1)2;每个Z1独立地为氢、卤素、C1-C6烷基、C1-C6杂烷基、芳基、杂芳基、C3-C8环烷基、杂环基、C1-C6酰基、C1-C6杂酰基、芳酰基、或杂芳酰基;或L为:
Z3为具有选自下式的生物还原基团:
其中每个X1独立地为N或CR8;X2为NR7、S、或O;每个R7独立地为C1-C6烷基、C1-C6杂烷基、C3-C8环烷基、杂环基、芳基或杂芳基;且R8独立地为氢、卤素、氰基、CHF2、CF3、CO2H、氨基、C1-C6烷基、C1-C6杂烷基、C1-C6环烷基、C1-C6烷氧基、C1-C6烷基氨基、C1-C6二烷基氨基、芳基、CON(R7)2、C1-C6酰基、C1-C6杂酰基、芳酰基或杂芳酰基;或其可药用盐。在不同的实施方式中,本发明口服剂型和的方法中使用的化合物为选自由TH-281、TH-302和TH-308(结构如下文所示)组成的组中的式I化合物。
在一种实施方式中,该缺氧激活前药为TH-302。
在另一种实施方式中,该口服剂型为立即释放剂型,包括但不限于包含TH-302或式I的另外缺氧激活前药的片剂或胶囊剂型。
在另一种实施方式中,该口服剂型为修饰释放制剂。在一种实施方式中,该修饰释放制剂为片剂或胶囊剂。在一种实施方式中,该修饰释放制剂包含微粒或纳米颗粒或基本上由微粒或纳米颗粒组成,该微粒或那纳米颗粒包含TH-302或式I的另外缺氧激活前药或基本上由TH-302或式I的另外缺氧激活前药组成。在一种实施方式中,该修饰释放制剂包含受控释放基质或基本上由受控释放基质组成。在一种实施方式中,该修饰释放制剂包含核,该核包含TH-302或式I的另外缺氧激活前药或基本上由TH-302或式I的另外缺氧激活前药组成。在一种实施方式中,该修饰释放制剂进一步包含包衣。在一种实施方式中,该包衣为控释包衣。在一种实施方式中,该包衣为水分屏障包衣。在一种实施方式中,该修饰释放制剂进一步包含以下一种或多种或基本上由以下的一种或多种组成的添加剂:促进水渗透进制剂的添加剂(即,含有这样的制剂的单位剂型)、粘结剂、稀释剂、助流剂、润滑剂、增塑剂、增溶剂和/或溶胀增强剂。在一种实施方式中,该修饰释放制剂具有释放TH-302或式I的另外缺氧激活前药的脉冲释放曲线。
在另一方面,本发明提供了治疗癌症的方法,包括向对这样的治疗有需要的患者给予治疗有效量的本文中提供的制剂或单位剂型。这样的方法包括单药治疗或包括TH-302或式I的另外缺氧激活前药的组合治疗。在不同的实施方式中,该方法类似于PCT公开第WO2007/002931号、第WO2008/083101号、第WO2010/048330号、第WO2012/006032号和第WO2012/009288号;以及PCT专利申请第PCT/US2012/031677号中描述的那些方法,其中的每一篇均以引用方式结合于本文作为参考,除非如本文中所述,使用适合等价剂量的TH-302或式I的另外缺氧激活前药代替其中所述的IV给药剂量的TH-302。
附图说明
图1图示出了在单独IV或口服(PO)给药TH-302之后Sprague-Dawley大鼠中TH-302随时间变化的血浆浓度数据,其中在IV给药之后的值代表每一剂量水平三只大鼠的平均(±S.D.)浓度,而在PO给药之后的值为不同组动物的组合值并且代表在每一时间点三只大鼠的平均(±S.D.)浓度。
具体实施方式
仅为了便于阅读而讲本详细描述分为若干部分,在一个部分中披露的内容可应用于任何其他部分的披露内容或与任何其他部分的披露内容相关。
定义
所有的数字指定,例如pH、温度、时间、浓度和重量且包括它们的范围均为近似值,通常可在(+)或(-)增加0.1、1.0、10.0或100.0范围内适当变化。应当理解,尽管并不总是明确指出,但所有的数字之前均冠有术语“约”。
如本说明书和权利要求书中使用的,除非上下文中明确指出,否则单数形式“一个”、“一种”和“该”包括复数对象。
以下列出了与式I有关的某些术语。
“酰基”是指–CO-烷基,其中烷基如本文中所定义。
“芳酰基”是指-CO-芳基,其中芳基如本文中所定义。
“烷氧基”是指–O-烷基,其中烷基如本文中所定义。
“烯基”是指具有在字首指示氮原子数且含有至少一个双键但不超过三个双键的线性单价烃基或支链单价烃基。例如,(C2-C6)烯基包括,乙烯基、丙烯基、1,3-丁二烯基等。烯基可以可选地被取代基取代,包括例如氘(“D”)、羟基、氨基、单或二(C1-C6)烷基氨基、卤素、C2-C6烯基醚、氰基、硝基、乙炔基、C1-C6烷氧基、C1-C6烷硫基、-COOH、-CONH2、单-或二(C1-C6)烷基碳酰氨基、-SO2NH2、-OSO2-(C1-C6)烷基、单或二(C1-C6)烷基磺酰氨基、芳基、杂芳基、烷基或杂烷基磺酰氧基,以及芳基或杂芳基磺酰氧基。
“烷基”具有字首所指的碳原子数的直链饱和一价烃基或支链饱和一价烃基。(C1-C6)烷基可以可选地被取代基取代,所述取代基包括例如,氘(“D”)、羟基、氨基、单或二(C1-C6)烷基氨基、卤素、C2-C6烯基醚、氰基、硝基、乙烯基、乙炔基、C1-C6烷氧基、C1-C6烷硫基、-COOH、-CONH2、单-或二(C1-C6)烷基碳酰氨基、-SO2NH2、-OSO2-(C1-C6)烷基、单或二(C1-C6)烷基磺酰氨基、芳基、杂芳基、烷基磺酰氧基,、杂烷基磺酰氧基、芳基磺酰氧基或杂芳基磺酰氧基。
字首(C1-Cqq)、C1-qq和C1-Cqq,其中qq为2-20的整数,具有相同的含义。例如,(C1-C6)烷基、C1-6烷基、或C1-C6烷基包括甲基、乙基、正丙基、2-丙基、正丁基、2-丁基、叔丁基、戊基等。对于本文中的每一定义(例如,烷基、烯基、烷氧基等),当不包括字首以指明烷基部分中主链碳原子数时,该基团或其部分具有六个或更少的主链碳原子。
“烷基氨基”或单-烷基氨基是指–NH-烷基,其中烷基如本文中所定义。
“炔基”是指具有字首中指明的碳原子数并且含有至少一个三键但不超过两个三键的直链一价烃基或支链一价烃基。例如,(C2-C6)炔基包括,乙炔基、丙炔基等。炔基可以可选地被取代基取代,所述取代基包括例如,氘(“D”)、羟基、氨基、单或二(C1-C6)烷基氨基、卤素、C2-C6烯基醚、氰基,、硝基、乙烯基、C1-C6烷氧基、C1-C6烷硫基、-COOH、-CONH2、单-或二(C1-C6)烷基碳酰氨基、-SO2NH2、-OSO2-(C1-C6)烷基、单或二(C1-C6)烷基磺酰氨基,、芳基、杂芳基,、烷基或杂烷基磺酰氧基,和芳基或杂芳基磺酰氧基。
“芳基”是指6至10个环原子的一价单环或二环芳香烃基,其独立地被选自以下的一至八个取代基取代,例如被一个、两个、三个、四个或五个取代基取代:氘(“D”)、烷基、环烷基、环烷基烷基、卤素、硝基、氰基、羟基、烷氧基、氨基、酰基氨基、单-烷基氨基、二-烷基氨基、卤代烷基、卤代烷氧基、杂烷基、COR(其中R为氢、烷基、环烷基、环烷基-烷基、苯基或苯基烷基)、-(CR′R″)n-COOR(其中n为0至5的整数,R′和R″独立地为氢或烷基,并且R为氢、烷、环烷基、环烷基烷、苯基或苯基烷基)或-(CR′R″)n-CONRxRy(其中n为0至5的整数,R′和R″独立地为氢或烷基,并且Rx和Ry独立地选自氢、烷基、环烷基、环烷基烷基、苯基或苯基烷基)。在一种实施方式中,Rx和Ry一起为环烷基或杂环基。更具体地,术语芳基包括但不限于,苯基、联苯基、1-萘基和2-萘基,以及它们的取代形式。
“环烷基”是指三至七个环碳的一价环烃基。环烷基可具有一个或多个双肩并且可以可选地被选自以下的一个、两个、三个或四个取代基取代:烷基、可选地取代的苯基或-C(O)Rz(其中Rz为氢、烷基、卤代烷基、氨基、单-烷基氨基、二-烷基氨基、羟基、烷氧基、或可选地取代的苯基)。更具体地,术语环烷基包括,例如,环丙基、环己基、环己烯基、苯基环己基、4-羧基环己基、2-碳酰氨基环己烯基、2-二甲基氨基羰基-环己基等。
“二烷基氨基”或二-烷基氨基是指–N(烷基)2,其中烷基如本文中所定义。
“杂烷基”是指如本文中定义的具有一个、两个或三个独立地选自氰基、-ORw、-NRxRy和-S(O)pRz(其中p为0至2的整数)的取代基的烷基基团,应理解为杂烷基基团的连接点通过该杂烷基基团的碳原子。Rw为氢、烷基、环烷基、环烷基-烷基、芳基、芳烷基、烷氧基羰基、芳氧基羰基、碳酰氨基、或单-或二-烷基氨基甲酰基。Rx为氢、烷基、环烷基、环烷基-烷基、芳基或芳烷基。Ry为氢、烷基、环烷基、环烷基-烷基、芳基、芳烷基、烷氧基羰基、芳氧基羰基、碳酰氨基、单-或二-烷基氨甲酰基或烷基磺酰基。Rz为氢(条件是p为0)、烷基、环烷基、环烷基-烷基、芳基、芳烷基、氨基、单-烷基氨基、二-烷基氨基或羟基烷基。代表性实例包括,例如,2-羟乙基、2,3-二羟基丙基、2-甲氧基乙基、苄氧基甲基、2-氰基乙基和2-甲基磺酰基-乙基。对于上述的每一个,Rw、Rx、Ry和Rz可进一步被氨基、卤素、氟、烷基氨基、二烷基氨基、OH或烷氧基取代。另外,指明碳原子数的字首(例如C1-C10)是指杂烷基基团除氰基、-ORw、-NRxRy或-S(O)pRz部分之外的部分中的碳原子总数。在一种实施方式中,Rx和Ry一起为环烷基或杂环基。
“杂芳基”是指具有至少一个芳香环且含有一个、两个或三个选自N、O或S而其他环原子为碳的环杂原子的5至12个环原子的一价单环、二环或三环基团,应理解为杂芳基基团的连接点位于芳香环上。杂芳基环可选地被一至八个取代基独立地取代,优选被一个、两个、三个或四个取代基取代,所述取代基选自烷基、环烷基、环烷基-烷基、卤素、硝基、氰基、羟基、烷氧基、氨基、酰基氨基、单-烷基氨基、二-烷基氨基、卤代烷基、卤代烷氧基、杂烷基、-COR(其中R为氢、烷基、苯基或苯基烷基、-(CR′R″)n-COOR(其中n为0至5的整数,R′和R″独立地为氢或烷基,且R为氢、烷基、环烷基、环烷基-烷基、苯基或苯基烷基)、或-(CR′R″)n-CONRxRy(其中n为0至5的整数,R′和R″独立地为氢或烷基,且Rx和Ry彼此独立地为氢、烷基、环烷基、环烷基-烷基、苯基或苯基烷基)。在一种实施方式中,Rx和Ry一起为环烷基或杂环基。更具体地,术语杂芳基包括但不限于,吡啶基、呋喃基、噻吩基、噻唑基、异噻唑基、三唑基、咪唑基、异噁唑基、吡咯基、吡唑基、哒嗪基、嘧啶基、苯并呋喃基、四氢呋喃基、异苯并呋喃基、苯并噻唑基、苯并异噻唑基、苯并三唑基、吲哚基、异吲哚基、苯并噁唑基、喹啉基、四氢喹啉基、异喹啉基、苯并咪唑基、苯并异唑基(benzisoxazolyl)、苯并噻吩基、吲唑基、吡咯并嘧啶基(pyrrolopyrymidinyl)、中氮茚基(indolizinyl)、吡唑并吡啶基、三唑并吡啶基、吡唑并嘧啶基、三唑并嘧啶基、吡咯并三嗪基、吡唑并三嗪基、三唑并三嗪基、吡唑并四嗪基(pyrazolotetrazinyl)、hexaaza-茚基和heptaaza-茚基以及它们的衍生物。除非另外说明,环中杂原子的安排可以是可通过构成环原子的键合特性形成的任意安排。
“杂环基”或“环杂烷基”是指3至8个环原子的饱和或不饱和非芳香环基团,其中一至四个环原子为杂原子选自O、NR(其中R为氢、烷基、环烷基、环烷基烷基,、苯基或苯基烷基)、P(=O)ORw或S(O)p(其中p为0至2的整数)的杂原子,其余的碳原子为C,其中一个或两个C原子可以可选地被羰基代替。杂环基环可以可选地被选自以下的一个、两个、三个或四个取代基独立地取代:烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、卤素、硝基、氰基、羟基、烷氧基、氨基、单-烷基氨基、二-烷基氨基、卤代烷基、卤代烷氧基、-COR(其中R为氢、烷基、环烷基、环烷基烷基、苯基或苯基烷基)、-(CR′R″)n-COOR(n为0至5的整数,R′和R″独立地为氢或烷基,且R为氢、烷基、环烷基、环烷基烷基、苯基或苯基烷基)或-(CR′R″)n-CONRxRy(其中n为0至5的整数,R′和R″独立地为氢或烷基,Rx和Ry彼此独立地为氢、烷基、环烷基、环烷基烷基、苯基或苯基烷基)。更具体地,术语杂环基包括,但不限于四氢吡喃基、N-甲基哌啶-3-基、N-甲基吡咯烷-3-基、2-吡咯烷酮-1-基、吡咯烷基、哌啶基、吗啉基、四氢呋喃基、四氢噻吩基、1,1-二氧-六氢-1Δ6-噻喃-4-基、四氢咪唑并[4,5-c]吡啶基、咪唑啉基、哌嗪基和哌啶-2-基以及它们的衍生物。碳原子的字首指示(例如C3-C10)是指除杂原子外,环杂烷基或杂环基基团的部分中碳原子的总数。
“杂酰基”是指-CO-杂烷基,其中杂烷基如本文中所定义。
“杂芳酰基”是指-CO-杂芳基,其中杂芳基如本文中所定义。
“Rsul磺酰氧基”是指Rsul-S(=O)2–O-并且包括烷基磺酰氧基、杂烷基磺酰氧基、环烷基磺酰氧基、杂环基磺酰氧基、芳基磺酰氧基和杂芳基磺酰氧基,其中Rsul分别为烷基、杂烷基、环烷基、杂环基、芳基和杂芳基,并且其中烷基、杂烷基、环烷基、杂环基、芳基和杂芳基如本文中所定义。烷基磺酰氧基的实例包括Me-S(=O)2-O-、Et-S(=O)2-O-、CF3-S(=O)2-O-等,而芳基磺酰氧基的实例包括:
其中Rar为H、甲基或溴。
“取代基”是指在上述每一基团的定义中具体描述的取代基,选自:氘、-卤素、-OR′、-NR′R″、-SR′、-SiR′R″R′″、-OC(O)R′、-C(O)R′、-CO2R′、-CONR′R″、-OC(O)NR′R″、-NR″C(O)R′、-NR′-C(O)NR″R′″、-NR″C(O)2R′、-NH-C(NH2)=NH、-NR′C(NH)=NH、-NH-C(NH2)=NR′、-S(O)R′、-S(O)2R′、-S(O)2NR′R″、-NR′S(O)2R″、-CN、-NO2、-R′、-N3、全氟(C1-C4)烷氧基、和全氟(C1-C4)烷基,数值范围从零至基团自由价(open valences)的总数;并且其中R′、R″和R′″独立地选自氢、C1-8烷基、C3-6环烷基、C2-8烯基、C2-8炔基、不饱和芳基和杂芳基、(不饱和芳基)-C1-4烷基、和不饱和芳氧基-C1-4烷基、被1-3个卤素取代的芳基、不饱和C1-8烷基、C1-8烷氧基或C1-8硫代烷氧基、或不饱和芳基-C1-4烷基。当R′和R″连接至同一氮原子时,它们与氮原子组合形成3-、4-、5-、6-或7-元环。例如,-NR′R″意指包括1-吡咯烷基和4-吗啉基。其他适合的取代基包括通过1-4个碳原子烷基醚连接于环原子的上述芳基取代基中的每一个。芳基或杂芳基环的相邻原子上的取代基中的两个可以可选地用式-T2-C(O)-(CH2)q-U3-的取代基代替,其中T2和U3独立地为–NH-、-O-、-CH2-或单键,并且q为0至2的整数。可替代地,芳基或杂芳基环的相邻原子上的取代基中的两个可以可选地用式-A-(CH2)r-B-的取代基代替,其中A和B独立地为-CH2-、-O-、-NH-、-S-、-S(O)-、-S(O)2-、-S(O)2NR′-或单键,并且r为1至3的整数。如此形成的新环的单键之一可以可选地被双键代替。可替代地,芳基或杂芳基环的相邻原子上的取代基中的两个可以可选地用式-(CH2)s-X5-(CH2)t-的取代基代替,其中s和t独立地为0至3的整数,并且X5为-O-、-NR′-、-S-、-S(O)-、-S(O)2-或-S(O)2NR′-。-NR′-和-S(O)2NR′-中的取代基R′选自氢或未取代的C1-6烷基。
本发明中使用的某些化合物具有不对称碳原子(光学中心)或双键;意在将外消旋化合物、非对映体、几何异构体、区域异构体(例如分离的对映体)均包括在本发明的范围内。本发明的化合物也可以在构成这样的化合物的一个或多个原子处含有非天然比例的原子同位素。例如,该化合物可用放射性同位素放射性标记,例如但不限于氚(3H)、碘-125(125I)、或碳-14(14C)。意在将本发明化合物的所同位素变体均包括在本发明的范围内,不论其是否具有放射活性。
以下定义本发明涉及的其他术语。
向患者“给药”或“药物的给予”(以及该短语的语法上等同替代)是指直接给药,可以通过医学专业人士向患者给药或者可以自己给药,和/或间接给药,可以通过处方开药期作用。例如,医生指示的患者自己给药药物和/或向患者提供药物的处方均为向患者给药。
“癌症”是指潜在地不受限生长的恶性实体瘤,以及可起源于骨髓中的癌性干细胞的各种血癌,其能够通过侵入局部性蔓延和通过转移全身性蔓延。癌症的实例包括,但不限于肾上腺癌、骨癌、脑癌、乳腺癌、支气管癌、结肠和/或直肠癌、胆囊癌、胃肠道癌、头颈癌、肾癌、喉癌、肝癌、肺癌、神经组织癌、胰腺癌、前列腺癌、甲状旁腺癌、皮肤癌、胃癌、和甲状腺癌。癌症的其他实例包括腺癌、腺瘤、基底细胞癌、宫颈非典型增生(cervical dysplasia)和原位癌、Ewing′s肉瘤、表皮样癌、巨细胞瘤、多形神经胶母细胞瘤、毛样细胞瘤、肠内神经节瘤、增生性角膜神经瘤、岛细胞癌、卡波西肉瘤、平滑肌瘤、白血病、淋巴瘤、恶性类癌瘤、恶性高血钙症、恶性体质瘤、骨髓瘤、恶性皮肤癌、粘膜神经瘤、脊髓发育不良综合征、骨髓瘤、蕈状霉菌病、成神经细胞瘤、骨肉瘤、成骨性和其他肉瘤、卵巢肿瘤、嗜铬细胞瘤、真性红细胞增多症、原发性脑瘤、小细胞肺癌、溃疡型和乳头型鳞状细胞癌、精原细胞瘤、软组织肉瘤、视网膜母细胞瘤、横纹肌肉瘤、肾细胞瘤或肾细胞癌、和肾母细胞瘤(Wilm′s tumor)。癌症的实例还包括星形细胞瘤、胃肠道间质瘤(GIST)、神经胶质瘤或成胶质细胞瘤,、肾细胞癌(RCC)、肝细胞癌(HCC)和胰腺神经内分泌癌。血癌的实例包括但不限于,急性髓性白血病(AML)、急性淋巴细胞白血病(ALL)、慢性髓性白血病(CML)、慢性淋巴细胞白血病(CLL)、慢性粒单核细胞白血病(CMML)、骨髓增生异常综合征(MDS)、骨髓纤维化(MF)、多发性骨髓瘤(MM)、未定性的单克隆免疫球蛋白病(MGUS)、滤泡型淋巴瘤、套细胞淋巴瘤(MCL)、弥漫性大B细胞淋巴瘤(DLCBL)、伯基特淋巴瘤、肝脾T细胞淋巴瘤、母细胞性NK细胞淋巴瘤、皮肤T细胞淋巴瘤(CTCL)、间变性大细胞淋巴瘤和霍奇金淋巴瘤。
如本文中使用的,术语“包含”意指必须包括所述元素或者可以可选地包括其他元素。“由...组成”意指任一所述元素均必须包括在内,不包括实质上影响所列元素的基本性质和新性质的元素,并且可选地包括其他元素。“由...组成”意指除所列元素之外是全部元素。由这些术语中的每一个所定义的实施方式包括在本发明的范围内。
“联合治疗(或组合疗法)”或“组合治疗”是指在治疗中使用两种或更多种药物,即,一起使用如本文中所述的缺氧激活前药和一种或多种其他抗癌药物来治疗癌症。“联合”给药是指以最患者中显示药理学有效的任意方式同时给予两种或更多种药剂(例如,缺氧激活前药和抑制剂,以及可选地一种或多种抗癌药剂以用于治疗癌症)。因此,联合给药不需要使用单一的药物组合物、相同的剂型或相同给药途径来给予两种药剂或在精确的同一时间给予两种药剂。
“控释包衣”或“受控释放包衣”是指能够例如包括至少一种pH非依赖性或pH依赖性(例如肠溶衣型或反肠溶衣型)聚合物、可溶性或不可溶性聚合物、液体或液态材料、或它们的组合的功能性包衣,当将其施加于制剂时能够减慢(例如当施加于立即释放制剂或正常释放基质制剂时)、进一步减慢(例如当施加于受控释放基质制剂)、或改变TH-302或式I的另外缺氧激活前药的释放速率。
“控释基质”或“受控释放基质”是指其中TH-302或式I的另外缺氧激活前药包括在基质中的制剂,其中该基质可以是不可溶的、少量可溶的、可溶的或部分可溶的。不可溶型受控释放基质制剂也被称为不可溶聚合物基质、可溶胀基质或液体基质,这取决于构成该基质的组分。可溶型受控释放基质制剂也被称为亲水胶质基质或贮器系统。本发明的受控释放基质是指包含不可溶基质、可溶性基质或不可溶和可溶性基质的组合的制剂,其中释放速率比未包衣的非基质、立即释放制剂、或未包衣的正常释放基质制剂要慢。受控释放基质制剂可涂覆有控释包衣以进一步减慢TH-302或式I的另外缺氧激活前药从受控释放基质制剂的释放。这样的包衣受控释放基质制剂能够显示出TH-302或式I的另外缺氧激活前药的改进释放、受控释放、持续释放、延缓释放、延长释放、延迟释放或它们的组合。
“核”是指被壁、膜或包衣包围的结构。该壁、膜或包衣可以是功能化或非功能化包衣。
“酏剂”是指液体制剂,包括但不限于糖浆剂、甘油、或添加醇,例如用于掩蔽活性剂的令人不快的味道。
“增强吸收制剂”是指表现出增强的TH-302或式I的另外缺氧激活前药的吸收的制剂,以使得当暴露于类似条件时,与不含有提供增强的吸收的赋形剂的具有相同或更高量的TH-302或式I的另外缺氧激活前药的立即释放制剂相比,其可减慢TH-302或式I的另外缺氧激活前药的较高释放和/或较多吸收。例如,单不限于,与相应的立即释放形式相比,在增强吸收制剂中用较少的TH-302或式I的另外缺氧激活前药能够达到相同的治疗效果。
“肠溶包衣”是指控制在消化系统中该口服制剂的内容物被吸收的位置的施加于口服制剂的屏障。例如,肠溶包衣防止在内容物到达小肠之前被吸收。
“肠溶聚合物”是指在酸性胃pH中呈现稳定表面但在酸性较弱(相对更偏碱性)pH中分解的聚合物。例如,这样的聚合物在酸性胃液(pH~3)中不可溶、或仅部分可溶,而在小肠中存在的碱性(pH7-9)环境中可溶。肠溶聚合物适合用于水分屏障和/或肠溶包衣。
“赋形剂”是指与制剂的活性剂或药物一起使用的无药理学活性的可药用物质。赋形剂也被用作含有非常大量活性成分的原料药制剂,以使得方便和精确获得单位剂型中的剂量。除了其在单位剂型中的应用,赋形剂也可用于制造过程以辅助所涉及的活性物质的处理。根据给药途径和药物治疗的形式,可以使用不同的赋形剂。赋形剂的实例包括,但不限于以下的一种或多种:添加剂、消泡剂、粘结剂、化学稳定剂、着色剂、稀释剂、崩解剂、乳化剂、填料、矫味剂、助流剂、润滑剂、pH调节剂、增塑剂、助溶剂、溶胀增强剂、滚圆助剂(spheronization aid)、溶解增强剂和悬浮剂。
“延长或持续释放制剂”是指相对于立即释放制剂表现出延长的或持续释放TH-302或式I的另外缺氧激活前药以使得,例如但不限于,当每天给予一次或两次时,该制剂缓慢地释放TH-302或式I的另外缺氧激活前药,从而使TH-302或式I的另外缺氧激活前药的血浆浓度保持在治疗水平持续一段较长时间。
“缺氧激活前药”是指在常氧条件下比在低氧或缺氧条件下的活性低或无活性的药物。缺氧激活前药包括例如通过各种还原剂和还原酶激活的药物,包括但不限于单电子转移酶(例如细胞色素P450还原酶)和二电子转移(或氢化物转移)酶(参见美国专利申请公开第2005/0256191号、第2007/0032455号、和第2009/0136521号,以及PCT公开第2000/064864号、第2004/087075号、和第2007/002931号,其中的每一篇均以引用方式结合于本文)。在本发明的口服制剂和方法中使用缺氧激活前药包括式I的化合物,包括但不限于其中Z3(如式中所定义的)为2-硝基咪唑部分的化合物,以及通过HDR系统诱导DNA损伤修复的其他缺氧激活前药。在本发明方法中使用的特定缺氧激活前药的实例包括但不限于TH-281、TH-302和TH-308。PCT公开第2007/002931号、第2008/083101号、第2010/048330号、第2012/006032号和第WO2012/009288,以及以及PCT专利申请第PCT/US2012/031677号中描述了合成、配制和使用TH-302和其他式I化合物的方法,其中每一篇均一引用方式结合于本文。
“过度增殖性疾病”是指特征为细胞过度增殖的疾病(例如细胞增殖的速率异常增加或量增加)。癌症是一种过度增殖性疾病。过度增殖性疾病的实例除了癌症还包括,单不限于,过敏性血管炎和肉芽肿病(Churg-Strauss病)、石棉沉着病、哮喘、萎缩性胃炎、良性前列腺增生、大疱性类疱疮(bullous pemphigoid)、乳糜泻、慢性支气管炎和慢性气道阻塞性疾病、慢性鼻窦炎、克罗恩病、脱髓鞘神经病、皮肌炎、湿疹包括异位性皮炎,咽鼓管病、巨细胞动脉炎、移植排斥、过敏性肺炎、过敏性血管炎(过敏性紫癜)、刺激性皮炎、炎性溶血性贫血、炎性嗜中性白细胞减少、炎性肠病、川崎病(Kawasaki′s disease)、多发性硬化症、心肌炎、肌肉炎、鼻息肉、鼻泪管阻塞病、新生血管、胰腺疾病、寻常天疱疮、原发性肾小球肾炎、牛皮癣、牙周病、多囊性肾病、结节性多动脉炎、多血管炎重叠综合征、原发性硬化性胆管炎、类风湿性关节炎、血清病、外科手术粘连、狭窄或再狭窄、巩膜炎、硬皮病、胆管狭窄、十二指肠、小肠和结肠的狭窄、硅肺病和其他形式的尘肺病、I型糖尿病、溃疡性结肠炎、溃疡性直肠炎、与结缔组织有关的血管病、与补体系统先天缺陷有关的血管病、与中枢神经系统有关的血管病、以及Wegener′s肉芽肿病。
“立即释放制剂”是指药物基本无任何延迟地从其释放且基本上一次释放的制剂。
“微粒”或“纳米颗粒”是指单独颗粒形式的药物制剂,并且可与诸如“微球”、“球形颗粒”、“微囊”、“颗粒”、“多颗粒”、“颗粒”、“球体”、“微珠”和“小球”这样的术语互换使用,但是对于本领域技术人员而言,纳米颗粒通常比微粒小约10倍或约1000倍。
“修饰释放制剂”是指具有立即释放或未包衣常规基质制剂不能赋予的达到治疗目的或方便目的的时程和/或位置的药物释放特性的制剂。参见,例如美国专利第6,245,357号和第7,968,120号,其中每一篇以引用方式结合于本文作为参考。活性药剂从修饰释放制剂释放的速率受到制剂特性和/或制剂特性与生理或环境条件组合的控制,而不单独受到生理或环境条件的控制。相对于立即释放或未包衣的常规基质制剂,由于药物快速吸收到体内,其在最大和最小血浆浓度(Cmax和Cmin)之间通常产生较大差异,活性药剂从修饰释放制剂的释放速率产生较小的差异。在立即释放或未包衣的常规基质制剂中,药物内容物在较短时间内被释放到胃肠道中,并且在给药后短时间内达到血浆药物水平峰值。立即释放或未包衣的常规基质制剂的设计通常是基于获得可能的最快药物释放速率。修饰释放制剂包括比立即释放制剂慢得多的释放药物(或剂量形式中的部分药物)的那些制剂。
“水分屏障”是指在体内或在相似条件下通过制剂阻止或阻碍水分吸收的屏障。在不同的实施方式中,该水分屏障由肠溶和/或丙烯酸树脂组成,并且可以可选地包括增塑剂和/或渗透增强剂。
“单药治疗”或“单一药剂治疗”是指利用单一药物来治疗疾病,即利用缺氧激活前药如TH-302或式I的另外缺氧激活前药作为唯一的化学药剂来治疗癌症。对于出于直接治疗疾病之外的目的,单药治疗可以给予缓和剂和/或维生素和/或其他药剂。接受单药治疗的患者也可以接受辐照治疗和/或外科手术。
“患者”或“受试者”是指哺乳动物,尤其是人,并且因此包括兽医学和研究感兴趣的动物,例如患有癌症或其他过度增殖性疾病的类人猿、牛、马、狗、猫和啮齿动物。
“渗透增强剂”是指亲水物质,当作为制剂包衣的一部分施加时,其使得水进入制剂中而不会使包衣受到实质性物理破坏。
“可药用的”是指安全、无毒并且适合用于向患者给药的物质。
“可药用盐”是指衍生自本领域公知的各种有机或无机反离子的可药用盐,举例而言,包括钠、钾、钙、镁、铵和四烷基铵盐,当分子含有碱性官能团时,包括有机或无机酸的盐,例如盐酸盐、氢溴酸盐、酒石酸盐、家磺酸盐、乙酸盐、马来酸盐和草酸盐。适合的盐包括在P.Heinrich Stahl,Camille G.Wermuth(Eds.),Handbook ofPharmaceutical Salts Properties,Selection,and Use;2002中描述的那些,其以引用方式结合于本文。
“增塑剂”是指能够使聚合物或粘结剂塑化或软化的化合物。增塑剂能够扩大其中包括增塑剂的聚合物的平均分子量,从而降低玻璃化转变温度或软化点。增塑剂还能够降低聚合物的粘度。制剂中可包括增塑剂以改变制剂的(一层或多层)包衣或核中使用的聚合物的性质和特性,以便于在该制剂的(一层或多层)包衣和/或核的制造过程中进行处理。在(一层或多层)包衣和/或核的制造过程中,增塑剂能够降低聚合物或粘结剂的熔融温度或玻璃化转变温度(软化点温度)。一旦制成该(一层或多层)包衣和/或核,某些增塑剂能够起到增加该制剂的(一层或多层)包衣和/或核在使用环境中的亲水性的作用。在(一层或多层)包衣和/或核的制造过程中,增塑剂能够降低聚合物或粘结剂的熔融温度或玻璃化转变温度(软化点温度)。
“固体制剂”是指既不是液体也不是气体的制剂。固体制剂包括,但不限于片剂、粉剂、颗粒剂(例如微粒和纳米颗粒)、胶囊剂、基质形式、栓剂、囊剂、锭剂、贴片、和锭剂(lozenge)。胶囊形式的固体制剂在胶囊中含有固体组合物,该胶囊可由明胶或其他包封材料制成。液体制剂包括,但不限于液体混悬剂、溶剂和酏剂。
“溶胀增强剂”是指快速溶胀以使得固体制剂(例如片剂)的尺寸增加的赋形剂。在较低浓度的情况下,这些赋形剂可被用作超级崩解剂;然而,在较高浓度的情况下,例如在浓度高于约5%w/w时,这些赋形剂起到溶胀增强剂的作用并且使基质制剂的尺寸增加。
TH302或TH-302是指下式的化合物:
并包括其可药用盐。
TH281或TH-281是指下式的化合物:
并包括其可药用盐。
TH308或TH-308是指下式的化合物:
并包括其可药用盐。
“治疗有效量”是指当向患有癌症或其他过度增殖性疾病的患者给予时预期具有治疗作用的药物或药剂的量,例如缓解、改善、减轻或消除患者中癌症或其他过度增殖性疾病的一种或多种临床表现。治疗有效剂量不一定在一次给药时达到,而是可以在一系列给药后达到。通常,癌症药物以重复系列剂量给药,而在某些情况下,每一个系列可以被称为一个治疗“循环”。因此,可以在一次或多次给药中达到治疗有效量。
对疾病或患者的“治疗”或“处理”是指采取步骤以获得益处或期望的结果,包括临床结果。对于本发明的目的,益处或期望的结果包括但不先于缓解或改善癌症(或其他过度增殖性疾病)的一种或多种症状,包括有条件的存活和减小肿瘤载荷和体积;减小疾病的程度;延迟或延缓疾病发展;改善、减轻或稳定疾病状态;或其他有益结果。
TH-302和其他缺氧激活前药的口服制剂
当向雄性Sprague-Dawley大鼠给予单一口服剂量的生理盐水中的100mg/kgTH-302时,TH-302被迅速吸收,并且在第一(0.25小时)采样时间点达到平均峰值血浆浓度(15.8μg/mL)。相应的平均浓度曲线下面积(AUC)和半衰期为13.1μg-h/mL和1.6小时。在静脉内(IV)输注给予相同量(100mg/kg)之后30分钟,在输注结束时的平均峰值血浆浓度为30.9μg/mL,平均AUC和半衰期分别为17.1μg-h/mL和0.27小时。基于这两项测试,确定了TH-302的绝对生物利用度约为77%,这表明TH-302适合用于口服给药。
在本发明之前,TH-302就已经以约100mg/m2(其中“m2”是指待治疗患者的体表面积)至约700mg/m2的剂量被静脉内(IV)给予人类,例如240mg/m2或340mg/m2,或575mg/m2。通常,这样的剂量经常以每周一次的剂量方案给药。也已经以约450mg/m2,每周5天的剂量向例如白血病患者给药。出于依从性的原因,本发明的立即释放制剂的最佳口服剂量为每日一次(QD)、每日两次(BID)或每日三次(TID)给药,并且在许多设置中采用每日持续给药。利用这样的每日持续给药,口服每日剂量通常在每周剂量的约四分之一至约一半的范围内,即,约每周剂量的三分之一。考虑到从本文中所描述的基于大鼠的测试中能够预测到的在人类中少于100%的口服生物利用度(例如在人类中约70%-约80%的口服生物利用度),预期口服日剂量为例如约50mg/m2–约900mg/m2,约100mg/m2–约800mg/m2,约200mg/m2–约700mg/m2,约50mg/m2–约200mg/m2或约700mg/m2–约900mg/m2,这取决于待治疗的癌症的性质和是否共同给予另外的化疗剂(通常,相对于TH-302单药治疗,在联合治疗中会使用较低剂量的TH-302)。在一个示例性实例中,口服日剂量为约150mg/m2。
考虑到通常成人体表面积(BSA)为约1.73m2,本发明的口服剂型的通常日剂量范围为约100mg-约1600mg,约200mg-约1500mg,约300mg-约1400mg,约100mg-约200mg或约1200mg-约1600mg。
在一种实施方式中,口服剂型的日剂量,尤其是TH-302的日剂量为约520mg-约590mg,例如500mg,550mg或600mg。在一种实施方式中,口服剂型的日剂量为约735mg-约840mg,例如700mg,750mg,800mg或850mg。这样的日剂量尤其适合用于每周一次给药。较低的量,例如这些量的五分之一(1/5)或七分之一(1/7)适合用于每日给予缺氧激活前药。这样的较低每日量包括100mg-170mg的量。
然而,如从本文披露内容中可看出的,本发明提供了用于口服给予TH-302或另外的缺氧激活前药治疗的各种制剂和单位剂型以及剂量方案。提供了修饰释放制剂,包括但不限于持续释放制剂和脉冲释放制剂,例如允许作为等价于立即释放制剂的任意BID或TID给药的QD给药。类似地,提供了除了持续每日给药之外的剂量方案,并且包括例如每日×5天和每日×3天给药(例如治疗每周或三周,之后一周中断治疗)以及每周给药一次。
尽管口服给药提供了诸如较低的住院治疗费用和较容易给药的优点,但抗癌剂(例如TH-302)由于其毒性、尺寸以及通常具有较差的生物利用度而通常通过IV输注给药。TH-302和式I的其他化合物为前药,并且它们的毒性被充分掩蔽,例如在缺氧条件下。而且,如通过本文中披露的研究所证明的,TH-302和式I的其他化合物具有出人意料地高的生物利用度。因此,本发明提供的TH-302和式I的其他化合物的口服制剂提供了超越适合用于IV输注的液体制剂的某些优点。考虑到TH-302和式I的其他化合物的半衰期,本发明提供的TH-302的修饰释放的口服制剂具有治疗有益的应用。
在一方面,本发明提供了包含TH-302或式I的另外缺氧激活前药以及可选地赋形剂或由TH-302或式I的另外缺氧激活前药以及可选地赋形剂组成的口服剂型。如本文中使用的,该赋形剂适用于向癌症患者给药,通常为人类患者,但本发明的制剂和剂型也可用于兽医学应用。在某些实施方式中,提供了除TH-302之外的式I的缺氧激活的药物的口服制剂。这些实施方式能够被看作是本文中具体描述的TH-302制剂,其中用式I的其他缺氧激活前药代替TH-302。在一种实施方式中,该口服剂型为固体剂型。
在一种实施方式中,该口服剂型为立即释放剂型。这样的实施方式包括,但不限于,包含TH-302或另外的缺氧激活前药或基本上由TH-302或另外的缺氧激活前药组成的明胶胶囊或片剂制剂。
在一种实施方式中,该口服制剂为修饰释放制剂。在一种实施方式中,该修饰释放制剂为片剂。在一种实施方式中,该修饰释放制剂包含微粒或纳米颗粒,该微粒或纳米颗粒包含TH-302或另外的缺氧激活前药或基本上由TH-302或另外的缺氧激活前药组成。在一种实施方式中,该修饰释放制剂包含控释基质。在一种实施方式中,该修饰释放制剂包含核,该核包含TH-302或另外的缺氧激活前药或基本上由TH-302或另外的缺氧激活前药组成。在一种实施方式中,该修饰释放制剂包括立即释放组分。在一种实施方式中,该修饰释放制剂进一步包含包衣。在一种实施方式中,该包衣为控释包衣。在一种实施方式中,该包衣为水分屏障包衣。在一种实施方式中,该修饰释放制剂进一步包含选自由以下添加剂组成的组中的添加剂:促进水渗透进制剂的添加剂、粘结剂、稀释剂、助流剂、润滑剂、增塑剂、增溶剂和/或溶胀增强剂。在一种实施方式中,该修饰释放制剂具有释放TH-302或式I的另外缺氧激活前药的脉冲释放曲线。
立即释放制剂
在一种实施方式中,本发明的制剂为包含TH-302或式I的另外缺氧激活前药或基本上由TH-302或式I的另外缺氧激活前药组成的立即释放制剂。在一种实施方式中,该立即释放制剂为未包衣的常规基质制剂。在一种实施方式中,该立即释放制剂为包含TH-302或式I的另外缺氧激活前药的明胶胶囊或片剂。在不同的实施方式中,明胶胶囊中包含的TH-302或其他缺氧激活前药为粉末、颗粒状物质、或基本上为球形微粒。本发明的明胶胶囊能够通过采用报道用于制备不同类型的烷化剂异环磷酰胺的明胶胶囊的方法来制造。参见Manegold等人,Ann Oncol.1996;7(6):637-9,其以引用方式结合于本文作为参考。立即释放制剂通常提供较快的药物释放速率和/或较高的Cmax。制造其他立即释放制剂的各种方法(根据本文披露内容,能够用于制造本发明的制剂)是本领域技术人员公知的,并且能够被用于或适用于制造本发明的制剂和剂型。
修饰释放制剂
在一种实施方式中,本发明的制剂为修饰释放制剂。在一种实施方式中,该修饰释放制剂为整体制剂(monolithic formulation)。如本文中所使用的,相对于多颗粒制剂,该整体制剂是指单个单位或片剂。在一种实施方式中,该修饰释放制剂为多颗粒制剂。美国专利第5,591,452号和第5,965,161号披露了修饰释放制剂的实例,并且能够根据本文披露内容对这样的实例进行修改以制备本发明的修饰释放制剂。在一种实施方式中,该修饰释放制剂是包衣的。在一种实施方式中,该包衣为功能性包衣。在一种实施方式中,该功能性包衣包括以下的一种或多种:聚合物包衣、水分屏障包衣、肠溶性包衣以及它们的混合物。在另一种实施方式中,该包衣为非功能性包衣。该非功能性包衣可以基本上不影响TH-302或式I的另外缺氧激活前药的释放,但可影响该制剂的其他性质,包括但不限于,增强该制剂或剂型的化学、生物学或生理学稳定性。
聚合受控释放包衣
在一种实施方式中,该功能性包衣为聚合物包衣。通常,在用于TH-302的聚合物包衣中避免使用含有反应性胺的聚合物。在一种实施方式中,该聚合物包衣为控释包衣。在一种实施方式中,该控释包衣包含丙烯酸聚合物。适合的丙烯酸聚合物包括但不限于丙烯酸和甲基丙烯酸共聚物、甲基丙烯酸氰乙基酯、甲基丙烯酸乙氧基乙基酯、甲基丙烯酸缩水甘油酯共聚物、甲基丙烯酸甲酯共聚物、聚(丙烯酸)、聚丙烯酰胺、聚(甲基丙烯酸)、聚(甲基丙烯酸甲酯)和聚(甲基丙烯酸酐)。
在一种实施方式中,丙烯酸聚合物为可聚合季铵化合物。这样的可聚合季铵化合物的非限制性实例包括丙烯酸和甲基丙烯酸的季铵化氨基烷基酯和氨基烷基酰胺,例如β-甲基丙烯酰-氧乙基-三甲基-铵甲磺酸酯、β-酰氧基-丙基-三甲基-氯化铵和三甲基氨基甲基-甲基丙烯酰胺甲磺酸酯。季铵也可以是杂环的一部分,如在甲基丙烯酰氧乙基甲基-吗啉氯化物或相应的哌啶鎓盐,或其可以通过含有杂原子的基团(例如聚乙二醇酯基团)的方式连接至丙烯酸基团或甲基丙烯酸基团。其他适合的可聚合季铵化合物包括但不限于季铵化乙烯基取代的氮杂环,例如甲基-乙烯基吡啶鎓盐、季铵化氨基羧酸的乙烯基酯、苯乙烯基三烷基铵盐等。其他的可聚合季铵化合物包括,但不限于丙烯酰基和甲基丙烯酰基-氧乙基三甲基-氯化铵、苄基二甲基铵乙基-甲基丙烯酸酯氯化物、二乙基甲基铵乙基-丙烯酸酯、N-三甲基铵丙基甲基丙烯酰胺氯化物和N-三甲基铵-2,2-二甲基丙基-1-甲基丙烯酸酯氯化物。
在一种实施方式中,聚合物控释包衣包含丙烯酸聚合物和可聚合季铵化合物或基本上由丙烯酸聚合物和可聚合季铵化合物组成。
在一种实施方式中,该控释包衣进一步包括其渗透率是pH依赖性的聚合物,例如从甲基丙烯酸和甲基丙烯酸甲酯合成的阴离子聚合物。在一些实施方式中,该聚合物在酸和纯水中是不溶性的和不渗水的,但在高于pH5.0-pH7.0下编程越来越可渗水的。这样的疏水酸性聚合物可包括基于二甲基氨基乙级甲基丙烯酸酯的阳离子聚合物。本发明中使用的该疏水酸性聚合物包衣可以包括基于聚(甲基)丙烯酸酯的天然聚合物或不溶于水和消化液但可渗水和可水溶胀的漆膜。
在一种实施方式中,该控释包衣包含用聚乙烯吡咯烷酮稳定化的聚乙烯醋酸酯和月桂基硫酸钠。可通过改变包衣中所包括的不同丙烯酸树脂搽剂的相对量来改变这样的包衣的溶解曲线。如本领域技术人员公知的,也可以通过改变可聚合的渗透性增强剂(例如季铵化合物)与中性(甲基)丙烯酸酯的摩尔比来改变所得包衣的渗透性质(并由此改变溶解曲线)。
能够用于控释包衣中的聚合物的其他实例包括一种或多种琼脂(包括例如琼脂和纤维素的可溶胀混合物,例如羧甲基纤维素);藻酸盐(例如,藻酸铵、藻酸钙、藻酸钠、藻酸钾,以及丙二醇藻酸盐)、羧基乙烯基聚合物、酪蛋白、纤维素(即,羧甲基纤维素钙、羧甲基纤维素、醋酸纤维素、醋酸邻苯二甲酸纤维素、醋酸三马来酸纤维素、纤维素基交联聚合物,其中交联度低以便于吸收水和聚合物即时的膨胀、丁酸纤维素、纤维素醚、丙酸纤维素、几丁质、胶原、马来酸酐和苯乙烯的共聚物、乙烯、丙烯、乙基纤维素、乙基羟基乙基纤维素、明胶、甘油脂肪酸酯、树胶(例如,阿拉伯胶、卡拉胶、洋槐豆胶、黄芪胶、角叉菜胶、瓜尔豆胶、黄原胶、硬葡聚糖以及它们的混合物和掺混物)、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、邻苯二甲酸羟丙基甲基纤维素、水凝胶(包括阴离子和阳离子水凝胶)以及凝胶形成材料、亲水聚合物、卵磷脂、麦芽糊精、甲基纤维素、甲基乙基纤维素、微晶纤维素、硝酸纤维素、果胶(例如摩尔重量为30-300kD)、包括摩尔重量范围为10-360kD的那些的PVP、聚丙烯酰胺、聚丙烯酸、聚酰胺、聚氧化乙烯(例如摩尔重量为100k至5000k)、聚(羟基烷基甲基丙烯酸酯)(例如摩尔重量为5-5000kD)、多糖(例如阿拉伯胶和海藻胶)、聚乙烯醋酸酯、聚乙烯醇(PVA,包括具有较低醋酸酯残基的PVA、支链淀粉、聚乙烯醋酸邻苯二甲酸酯、虫胶、羧甲基纤维素钠、淀粉(包括交联淀粉)、可溶胀亲水聚合物和玉米蛋白。其他聚合物包括海藻酸钠、羧甲基纤维素钠、羧甲基纤维素钙和羧甲基淀粉钠。
在不同的实施方式中,TH-302或式I的另外缺氧激活前药的制剂被聚合物涂覆,以促进在消化道中的黏膜粘附。能够用于黏膜粘附的聚合物的非限制性实例包括羧甲基纤维素、聚丙烯酸、明胶和其他天然或合成聚合物。
片剂
在一种实施方式中,TH-302或式I的另外缺氧激活前药的修饰释放制剂作为片剂以单位剂型提供。在一种实施方式中,片剂包含核和赋形剂,该核包含TH-302或式I的另外缺氧激活前药。当将核与赋形剂混合时,该核可以是立即释放制剂。在一种实施方式中,该核被控制TH-302或式I的另外缺氧激活前药的释放控释包衣所包围。在不同的实施方式中,水分屏障层包围该控释包衣。如果存在的话,该水分屏障包衣阻挡水分与TH-302或式I的另外缺氧激活前药接触。可选地,这种片剂可以进一步包含包围核、水分屏障包衣和/或控释包衣的一层或多层另外的功能性或非功能性包衣或基本上由包围核、水分屏障包衣和/或控释包衣的一层或多层另外的功能性或非功能性包衣组成。
延长释放片剂
在一种实施方式中,本发明提供的片剂为延长释放片剂。在一种实施方式中,该片剂包含核和一种或多种赋形剂,该核包含TH-302或式I的另外缺氧激活前药。在一种实施方式中,该核被控制TH-302或式I的另外缺氧激活前药的释放的控释包衣所包围。该片剂可以可选地包含包围核或控释包衣的一层或多层另外的功能性或非功能性包衣。
在一种实施方式中,延长释放片剂的核包含TH-302或式I的另外缺氧激活前药、粘结剂和润滑剂,并且可选地含有其他惰性赋形剂。根据本制剂可使用的各种粘结剂、润滑剂、助流剂和其他惰性赋形剂是本领域技术人员公知的,并且能够根据本文披露内容容易地选择。在相关文献中能够找到本领域技术人员公知的其他惰性赋形剂,例如Handbook of Pharmaceutical Excipients,第5版,Raymond C.Rowe等人编著,其结合于本文作为参考。在一些实施方式中,该延长释放制剂的核为未包衣的立即释放制剂或常规释放基质制剂。
根据本文披露内容使用的这些和其他片剂核可通过本领域技术人员公知的湿法或干法造粒、直接压制、挤出、滚圆、熔融造粒和旋转造粒工艺来制造。
包衣
在一种实施方式中,片剂核涂覆有延长释放的控释包衣。在一种实施方式中,该片剂核涂覆有水性控释包衣,其包含不具有任何官能团的中性酯共聚物的水性分散体。在一种实施方式中,该片剂进一步包含水分屏障。该控释包衣和水分屏障可在两个阶段施加。可将该控释包衣直接施加于片剂核的表面上并且主要起到控制TH-302或式I的另外缺氧激活前药的释放的作用。可将水分屏障直接施加于控释包衣的表面上,以防止或阻止片剂吸收水分。
延长释放控释包衣
在一种实施方式中,该片剂包含延长释放的(extended release,缓释)控释包衣。该延长释放的控释包衣为半透包衣,该半透包衣包含形成不溶于水且不透水的膜的聚合物,可选地水溶性聚合物,以及可选地增塑剂。用于延长释放的控释包衣的不溶于水且不透水的膜的聚合物的非限制性实例包括纤维素醚、纤维素酯和聚乙烯醇。用于延长释放的控释包衣的不溶于水且不透水的膜的聚合物的其他实例包括,但不限于羟丙基纤维素、羟丙基甲基纤维素和聚乙烯吡咯烷酮。
在某些实施方式中,该延长释放控释包衣进一步包含增塑剂。控释包衣中使用的增塑剂的非限制性实例包括但不限于,乙酰化甘油单酯、柠檬酸乙酰三丁基酯、柠檬酸乙酰三乙基酯,丁基邻苯二甲酰羟乙酸丁酯、邻苯二甲酸丁辛酯、蓖麻油、甘油二乙酸酯,邻苯二甲酸二苄酯、酒石酸二丁酯、邻苯二甲酸二丁酯、邻苯二甲酸二乙酯、邻苯二甲酸二乙基己基酯、邻苯二甲酸二正辛基酯、邻苯二甲酸二异辛基酯、邻苯二甲酸二异癸基酯、邻苯二甲酸二正十一烷基酯、邻苯二甲酸二正十三烷基酯、邻苯二甲酸二(十二烷基)酯、邻苯二甲酸二甲酯、壬二酸二辛酯、邻苯二甲酸二异壬酯、二-2-乙基己基己二酸酯、二-2-乙基己基癸二酸酯、二-2-乙基己基壬二酸酯、癸二酸二丁酯、草酸二乙酯、苹果酸二乙酯、富马酸二乙酯、琥珀酸二乙酯、丙二酸二乙酯、癸二酸二乙酯、环氧化妥儿油脂肪酸酯(epoxidized tallate)、邻苯二甲酸单乙二醇酯、甘油、甘油山梨醇、三醋酸甘油酯、甘油三酷酸酯、橄榄油、聚乙二醇、多元醇、丙二醇、菜籽油、芝麻油、三醋精、三丙酸甘油酯(tripropioin)、柠檬酸三乙酯、三-2-乙基己基偏苯三酸酯、和偏苯三酸三异辛基酯。
水分屏障包衣
在某些实施方式中,水分屏障与本发明的单位剂型的控释包衣直接接触。在不同的实施方式中,适合的屏障包含肠溶聚合物、渗透增强剂、以及可选的增塑剂。在某些实施方式中,该肠溶聚合物为丙烯酸聚合物。例如,但不限于,该丙烯酸聚合物可以为包含约1:1聚-甲基丙烯酸-甲基丙烯酸甲酯的甲基丙烯酸共聚物。
在一种实施方式中,渗透增强剂包括但不限于,纤维素醚、羟丙基甲基纤维素和这些聚合物的蛋白质衍生的材料。在另一种实施方式中,该渗透增强剂为交联的聚乙烯吡咯烷酮、聚氧化乙烯、聚乙烯吡咯烷酮,以及水溶性葡聚糖、糖类和多糖类,例如支链淀粉、右旋糖苷、蔗糖、葡萄糖、乳糖、果糖、甘露醇、甘露糖、半乳糖、山梨醇等。渗透增强剂的其他非限制性实例包括碱金属盐,例如碳酸锂、氯化钾、硫酸钾、磷酸钾、乙酸钠、溴化钠、氯化钠、柠檬酸钠等。在一些实施方式中,渗透增强剂为成孔固体。成孔固体的实例包括但不限于,二醇、多元醇、多羟基醇、聚烷二醇、聚乙二醇、聚(a-w)烷基二醇等。本发明的制剂和单位剂型中可以使用的其他渗透增强剂包括淀粉、改性淀粉和淀粉衍生物、树胶,包括但不限于琼脂、直链淀粉、支链淀粉、海藻酸和其他藻酸盐、阿拉伯半乳聚糖(arabinogalactin)、生物合成树胶、角叉菜胶、κ-角叉菜胶、λ-角叉菜胶、膨润土、交联的聚乙烯吡咯烷酮、右旋糖苷、糊精、亚麻籽胶、瓜尔豆胶、阿拉伯胶、卡拉胶、离子交换树脂例如聚甲基丙烯酸酯钾、槐树豆胶、秋葵胶、果胶、温柏车前子(quince psyllium)、硬葡聚糖、黄芪胶、硅酸铝镁(veegum)和黄原胶。其他成孔固体包括用于在应用环境中制造多孔薄层的材料,例如缩醛聚合物、不对称孔聚合物、胶棉、胶体而氧化硅共聚物或具有降低的本体密度的互聚物,以及其他类似的材料、交联的烯烃共聚物、交联的链延长聚(氨酯)、亲水微孔均聚物、卤代聚(乙二烯)(halogenated poly(vinylidene))、微孔材料例如双酚、微孔聚氯乙烯、微孔聚酰胺、微孔变性腈纶共聚物、微孔苯乙烯-丙烯酸及其共聚物、微晶纤维素、由碳酸的线性聚酯组成的聚碳酸酯,其中碳酸脂基团在聚合物链中重新出现、多孔聚砜、聚氯醚、通过二羧酸或酸酐与亚烷基多元醇的酯化制备的聚酯、聚(亚烷基硫化物)、酚醛树脂、聚酯、聚氨酯、聚酰亚胺、聚(苯并咪唑)、再生蛋白、半固体交联的聚(乙烯吡咯烷酮)、二氧化硅,以及它们的任意组合。
根据本发明使用的这些和其他包衣可通过本领域技术人员从其他应用中得知的方法施加,包括但不限于喷涂包衣。喷涂包衣是利用本领域技术人员从其他应用中得知的片剂涂布器、流化床装置或其实适合的涂布装置实施的。
增强吸收片剂
在一种实施方式中,片剂为增强吸收片剂。在一种实施方式中,该增强吸收片剂包含核,该核包含TH-302或式I的另外缺氧激活前药,和一种或多种可药用赋形剂。在一种实施方式中,该核被控制TH-302或式I的另外缺氧激活前药的释放的增强吸收包衣所包围。在某些实施方式中,增强吸收包衣所由一层包衣构成。增强吸收片剂的优点包括相对某些其他类型的片剂或剂型而言组合物中所需药物的量较低,这能够使得减少副作用和/或减少制造成本。
增强吸收片剂的核包含TH-302或式I的另外缺氧激活前药、粘结剂和润滑剂,并且能够含有其他可药用赋形剂。在本制剂中可使用的各种粘结剂、润滑剂、助流剂和其他惰性赋形剂是本领域技术人员公知的。另外的惰性赋形剂是本领域技术人员从其他应用中可得知的,并且能够在相关文献中找到,例如上文所述的Handbook ofPharmaceutical Excipients。
增强吸收片剂能够进一步包含包衣。在一种实施方式中,该包衣为半渗透性包衣,其包含不溶于水且可渗水的成膜聚合物,以及可选地水溶性聚合物,并且进一步可选地包含增塑剂。在某些实施方式中,将水分屏障直接施加于控释涂层的表面上。在一些实施方式中,该水分屏障可包含肠溶聚合物(例如丙烯酸聚合物)、渗透增强剂以及可选地增塑剂或基本上由肠溶聚合物(例如丙烯酸聚合物)、渗透增强剂以及可选地增塑剂组成。用于本发明的延长释放片剂的各种肠溶聚合物、增塑剂、渗透增强剂、不溶于水且可渗水的成膜聚合物以及水溶性聚合物也可用于本发明的增强吸收片剂。
受控释放基质
在一种实施方式中,本发明提供的制剂为包含TH-302或式I的另外缺氧激活前药的受控释放基质。从该基质核的药物释放动力学至少部分地依赖于制剂中赋形剂的扩散和/或浸蚀性质。在这样的受控释放基质中使用的适合的赋形剂材料包括例如抗释放的或受控释放的材料,例如疏水性聚合物、亲水性聚合物、亲脂性材料以及它们的混合物。
疏水性或亲脂性组分的非限制性实例包括单硬脂酸甘油酯,单硬脂酸甘油酯和甘油单棕榈酸酯的混合物,甘油单油酸酯,单、二和三-甘油酯的混合物,甘油单月桂酸酯,石蜡,白蜡,长链羧酸或脂肪酸,长链羧酸酯,长链脂肪或羧酸醇,以及它们的混合物。在一些实施方式中,钙长链羧酸含有6至30个碳原子;在某些实施方式中,含有至少12个碳原子,而在其他实施方式只能够,含有12至22个碳原子。在一些实施方式中,该碳链是完全饱和且无分支的,而其他碳链含有一个或多个双键。在另一种实施方式中,该长链羧酸含有3-碳环或羟基。
饱和直链酸的非限制性实例包括但不限于,花生酸、山萮酸、己酸、辛酸、癸酸、月桂酸、褐煤酸、蜂花酸、肉豆蔻酸、正十二烷酸、正十六烷酸、正十四烷酸、软脂酸和硬脂酸。也可以使用不饱和单烯直链一元羧酸。其非限制性实例包括芥酸、顺二十碳-9-烯酸(鳕烯酸,gadoleic acid)和油酸。也可以使用单多烯直链一元羧酸。其非限制性实例包括花生四烯酸、二十二炔酸(behenolic acid)、亚油酸和亚麻酸。有用的分支酸包括,例如二乙酰基酒石酸。长链羧酸酯的非限制性实例包括单硬脂酸甘油酯,甘油单棕榈酸酯,单硬脂酸甘油酯和甘油单棕榈酸酯的混合物,单油酸甘油酯,甘油单棕榈酸酯、单硬脂酸甘油酯、单油酸甘油酯和单亚油酸甘油酯的混合物,单亚麻酸甘油酯,单顺二十碳-9-烯酸甘油酯,甘油单棕榈酸酯、单硬脂酸甘油酯、单油酸甘油酯、单亚油酸甘油酯、单亚麻酸甘油酯和单顺二十碳-9-烯酸甘油酯的混合物,乙酰化甘油酯例如蒸馏的乙酰化甘油单酯,丙二醇单酯、蒸馏的甘油单酯、硬脂酸基乳酸钠和二氧化硅的混合物,丙二醇单酯、蒸馏的甘油单酯、硬脂酸基乳酸钠和二氧化硅的混合物,d-α生育酚聚乙二醇1000琥珀酸酯,甘油单酯和甘油二酯例如Atmul甘油单酯和甘油二酯乳化液、硬脂酸基乳酸钙、乙氧基甘油单酯和甘油二酯的混合物,乳酸甘油单酯和甘油二酯、甘油和丙二醇的乳酸羧酸酯,长链羧酸的乳酰酯、长链羧酸的聚甘油酯、长链羧酸的丙二醇单酯和二酯,硬脂酸基乳酸钠,山梨聚糖单硬脂酸酯,山梨聚糖单油酸酯,长链羧酸的其他山梨聚糖酯,琥珀酰化甘油单酯,硬脂酰柠檬酸单甘油酯,硬脂酰庚酸酯,蜡的鲸蜡基酯,鲸蜡硬脂醉辛酸酯(cetearyl octanoate),C10-C30胆固醇/lavosterol酯,蔗糖长链羧酸酯,以及它们的混合物。
能够在受控释放基质制剂的某些实施方式中使用的亲水性聚合物的非限制性实例包括但不限于,丙烯酸衍生物例如聚丙烯酸、海藻酸、卡波姆、羧甲基纤维素或其他纤维素醚、羟丙基甲基纤维素、羟丙基纤维素、羟乙基纤维素、聚氧乙烯、羟甲基甲基丙烯酸聚合物、聚甲基丙烯酸酯聚合物例如甲基丙烯酸聚合物、羟乙基甲基丙烯酸聚合物、聚乙烯醇,和聚氧化乙烯或聚乙二醇。
在一种实施方式中,该受控释放基质制剂进一步包含一种或多种润滑剂、粘结剂或增塑剂。在一种实施方式中,该受控释放基质制剂进一步包含一种或多种润滑剂、增溶剂、溶胀增强剂、或用于使水能够渗透进制剂的核中的添加剂。
稀释剂的非限制性实例包括羟基磷酸钙(calcium hydroxyl-apatite)、磷酸钙、硫酸钙、纤维素、纤维素衍生物、糊精或其他多糖类、磷酸氢钙、干淀粉、脂肪酸盐例如硬脂酸镁、葡萄糖或其他单糖类、肌醇、高岭土、乳糖或蔗糖或其他二糖类、甘露醇、山梨醇和硫糖铝。
增溶剂能够起到增加TH-302或式I的另外缺氧激活前药的顺时溶解度的作用,并且能够选自亲水性表面活性剂、亲脂性表面活性剂或它们的混合物。表面活性剂可以是阴离子、非离子、阳离子和两性离子表面活性剂。
亲水非离子表面活性剂包括但不限于,多元醇与来自氢化植物油和d-α-生育酚聚乙二醇1000琥珀酸酯、甘油三酯的基团的至少一个成员的亲水性酯交换产物,以及植物油、聚乙二醇和山梨聚糖脂肪酸酯。
离子表面活性剂包括但不限于,酰基乳酸酯、烷基铵盐、单-和二-甘油酯的柠檬酸酯、肉碱脂肪酸酯盐、氨基酸的脂肪酸衍生物、脂肪酸盐、夫西地酸盐、氨基酸的甘油酯衍生物、卵磷脂和氢化卵磷脂、溶血卵磷脂和氢化溶血卵磷脂、溶血磷脂素及其衍生物、单-和二-甘油酯的单-和二-乙酰化酒石酸酯、寡肽、多肽、磷脂及其衍生物、烷基硫酸盐、多库酯钠、琥珀酰化的单-和二-甘油酯,以及它们的混合物。
亲脂性表面活性剂包括但不限于,乙酰化甘油脂肪酸酯,脂肪醇,甘油脂肪酸酯,多元醇与甘油酯、植物油、氢化植物油、脂肪酸和甾醇基团的至少一个成员的疏水性酯交换产物,单-和二-甘油酯的乳酸衍生物,低级醇脂肪酸酯,油溶性维生素/维生素衍生物,PEG山梨聚糖脂肪酸酯,PEG甘油脂肪酸酯,聚乙二醇化脂肪酸,聚氧乙烯-聚氧丙烯嵌段共聚物,聚丙二醇脂肪酸酯、聚乙二醇山梨聚糖脂肪酸酯,聚乙二醇化甾醇和甾醇衍生物,聚乙二醇烷基醚,山梨聚糖脂肪酸酯,甾醇和甾醇衍生物,糖酯,糖醚,以及它们的混合物。
在另一种实施方式中,增溶剂包括但不限于,甜菜碱、磺基琥珀酸二辛酯、甘油单油酸酯、亚油酸三甘酯、单硬脂酸甘油酯、L-羟丙基纤维素、羟乙基纤维素、羟丙基纤维素、月桂基聚乙二醇-32甘油酯、PEG-20-硬脂酸甘油酯、PEG-40氢化蓖麻油、PEG6玉米油、聚甘油基-10单二油酸酯、丙二醇油酸酯、丙二醇藻酸盐、丙二醇二碘苯腈辛酸酯、丙二醇辛酸酯/癸酸酯、PEG-20山梨聚糖单月桂醇酯、PEG-4月桂醚、聚氧乙烯-聚氧丙烯嵌段共聚物、聚乙二醇660羟基硬脂酸酯、聚乙二醇、月桂基硫酸钠、十二烷基硫酸钠、己烷磺酸钠、牛胆酸钠、去氧胆酸钠、硬脂酰基聚乙二醇甘油酯、蔗糖二硬脂酸酯、蔗糖单棕榈酸酯、d-α-生育酚聚乙二醇1000琥珀酸盐,以及它们的混合物。在另一种实施方式中,增溶剂包括但不限于,月桂基聚乙二醇-32甘油酯、硬脂酰基聚乙二醇甘油酯PEG-40氢化蓖麻油、PEG-20山梨聚糖、单月桂醇酯、PEG-4月桂醚、聚乙二醇、聚氧乙烯-聚氧丙烯嵌段共聚物、月桂基硫酸钠、十二烷基硫酸钠,以及它们的混合物。
溶胀增强剂的实例包括但不限于,藻酸盐、胶体硅酸镁-铝、玉米淀粉颗粒、交联的羧甲基纤维素钠或钙、纤维素纤维、交联的聚乙烯吡咯烷酮、交联的聚丙烯酸、交联的Amberlite树脂、低取代的羟丙基纤维素、微晶纤维素、土豆淀粉颗粒、预胶化淀粉、大米淀粉颗粒,羧甲基淀粉钠以及它们的混合物。
添加剂包括但不限于,亲水性聚合物例如聚乙二醇(PEG)和聚乙烯吡咯烷酮、糖例如D-山梨醇、木糖醇等,糖类例如无水麦芽糖、D-果糖、右旋糖苷(例如右旋糖苷40)、葡萄糖、蔗糖等,表面活性剂例如聚氧乙烯-氢化蓖麻油、聚氧乙烯-聚丙二醇、聚氧乙烯-山梨聚糖高分子脂肪酸酯等,盐例如氯化镁、氯化钠等,有机酸例如柠檬酸、酒石酸等,氨基酸例如β-丙氨酸、甘氨酸、赖氨酸盐酸盐等,以及氨基酸糖例如葡甲胺。
在例如基质制剂中使用的崩解剂的非限制性实例包括,但不限于,海藻酸、交联羧甲基纤维素钠、交聚维酮、甲基丙烯酸DVB、交联PVP、微晶纤维素、波拉克林钾、预胶化淀粉、海藻酸钠、乙醇酸淀粉钠、淀粉等。在另一种实施方式中,崩解剂包括,但不限于,交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、酪蛋白甲醛、淀粉或淀粉衍生物例如乙醇酸淀粉钠或与淀粉的组合、可溶胀离子交换树脂(例如Amberlite IRP88),以及它们的混合物。
在另一种实施方式中,提供了可溶胀基质制剂,其中聚合物基质中包括TH-302或式I的另外缺氧激活前药,该聚合物基质是水可溶胀的而不仅仅是亲水的,并且其浸蚀速率比其溶胀速率要慢,并且基本上通过扩散释放TH-302或式I的另外缺氧激活前药。适合在可溶胀基质中使用的聚合物的非限制性实例包括纤维素聚合物及其衍生物,例如羧甲基纤维素、羟乙基纤维素、羟丙基纤维素和微晶纤维素、壳聚糖、交联聚丙烯酸及其衍生物、马来酸酐共聚物、多糖及其衍生物、聚氧化烯、聚乙二醇,、聚(乙烯基醇)、聚(乙烯基吡咯烷酮)、聚(乙撑亚胺)、聚氨酯水凝胶、淀粉和淀粉系聚合物、聚(2-乙基-2-噁唑啉)、黄原胶,以及它们的混合物。
制造受控释放基质的方法是本领域技术人员公知的,包括湿法造粒、干法造粒(例如流化(slugging)、辊筒压制)、直接压制、熔融造粒、熔融挤出和旋转造粒。受控释放基质中使用的受控释放颗粒能够被压制并置于胶囊中,其能够通过将TH-302或式I的另外缺氧激活前药与疏水性可熔组分和/或稀释剂混合来制备。也可以通过在产生聚集体(aglomerate)的混合条件下机械操作混合TH-302或式I的另外缺氧激活前药、疏水性可熔组分以及可选地释放组分,破碎该聚集体以产生具有所需释放性质的受控释放的种子,以及可选地加入更多的载体或稀释剂并重复混合步骤直至获得具有所需释放性质的受控释放种子来制备受控释放的基质,其中该释放组分包括水溶性可熔材料或颗粒状材料。也可将这些颗粒按尺寸分离(例如通过筛分)并压到基质中,或者甚至包封在胶囊中。
微粒
在一种实施方式中,TH-302或式I的另外缺氧激活前药的制剂为多颗粒系统,其含有多个含有TH-302或式I的另外缺氧激活前药的微粒,以及一种或多种可药用赋形剂。在摄取溶解于多个亚单位中之后该微粒可包含在胶囊中或被压到基质或片剂中,其中该亚单位或小丸具有制剂的期望的受控释放性质。该多颗粒或多个单位制剂可被一层或多层包衣包围。这样的包衣的实例包括但不限于,聚合物受控释放包衣、延迟释放包衣、肠溶包衣、立即释放包衣、味道掩蔽包衣、延长释放包衣和非功能性包衣。赋形剂包括但不限于,一种或多种消泡剂、粘结剂、化学稳定剂、着色剂、稀释剂、崩解及、乳化剂、填料、矫味剂、助流剂、润滑剂,pH调节剂、滚圆助剂、溶解度增强剂和悬浮剂。
溶解度增强剂可以是适合用于药物组合物中的任何表面活性剂,其可以是阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂或非离子表面活性剂。本文中提供的微粒可进一步通过涂覆控释涂层而被修饰。
可通过大量不同的程序来制备TH-302或式I的另外缺氧激活前药的微粒,例如喷雾干燥、基于造粒/制片工艺的流化床、滚圆工艺等,其是本领域技术人员公知的。
药物包衣的颗粒
在一种实施方式中,微粒制剂包含分层的微粒。这样的分层微粒可通过用TH-302或式I的另外缺氧激活前药以及可选地聚合物粘结剂涂覆颗粒或核(例如糖球)来制备。在不同的实施方式中,该颗粒或核含有TH-302或式I的另外缺氧激活前药或者是惰性的(剂量中不含有任何前药)。在某些实施方式中,该惰性核包括不溶于水的材料(例如纤维素球或二氧化硅)或由不溶于水的材料(例如纤维素球或二氧化硅)构成。在其他实施方式中,该惰性核包括水溶性材料(例如淀粉、盐或糖球)或由水溶性材料(例如淀粉、盐或糖球)构成。
纳米颗粒
在一种实施方式中,TH-302或式I的另外缺氧激活前药的制剂包含纳米颗粒。本文中使用的纳米颗粒为亚微粒(例如但不限于<1μm)颗粒,例如胶体颗粒。其包括其中药物被吸附溶解的纳米颗粒或纳米球,或者包括在整个颗粒或球体中,以及其中药物被限制在被壳样壁包围的水性或油性核中的纳米囊。
纳米颗粒可由一种或多种生物相容性或可生物降解的材料制成,例如聚合物,天然(例如,明胶、白蛋白)或合成(例如,多乳酸化合物、聚烷基氰丙烯酸酯)聚合物或固体脂质。在颗粒体内,药物(前药)通常通过扩散、溶胀、浸蚀或降解中的一种或多种从纳米颗粒释放。本发明中可以使用的纳米颗粒还包括那些具有从纳米颗粒受控和/或持续药物释放的纳米颗粒。利用本文中提供的信息和现有技术,本领域技术人员能够制备适合用于药物制剂的纳米颗粒。参见例如Bala等人,PLGA Nanoparticles In DrugDelivery:The State Of The Art,Crit.Rev.Ther.Drug Carrier Syst.2004,21:387–422;Vauthier等人,Poly(alkylcyanoacrylates)As Biodegradable Materials For BiomedicalApplications,Adv.Drug Deliv.Rev.2003,55:519–548;Couvreur等人,NanocapsuleTechnology:A Review,Crit.Rev.Ther.Drug Carrier Syst.,2002,19:99–134,每一篇均以引用方式结合于本文作为参考。
脉冲释放制剂
在一种实施方式中,本发明的制剂具有TH-302或式I的另外缺氧激活前药的脉冲释放。脉冲释放是指药物在一个或多个时间间隔释放,例如在最初快速释放时,时候药物缓慢释放或最初快速释放之后在一段时间内(通常为1至4小时)再次快速释放。参见例如美国专利第5,011,692号和第5,980,508号,其中每一篇均以引用方式结合于本文作为参考。例如但不限于,通过将未包衣的味道掩蔽的或肠溶包衣的微粒与延迟释放或持续释放的包衣微粒混合能够达到脉冲药物释放曲线或计时治疗曲线。例如但不限于,适合用于本发明的脉冲释放制剂的赋形剂包括胶原、去端肽胶原(atelocollagen)。
单位剂量制剂和治疗方法
在一种实施方式中,本发明提供了本文提供的TH-302或式I的另外缺氧激活前药的口服制剂的单位剂型。在不同的实施方式中,该单位剂型含有约25mg–约1000mg,约50mg–约900mg,约75mg–约700mg,约100mg–约600mg,约25mg–约100mg,或约700mg–约1000mg的TH-302或式I的另外缺氧激活前药。
含有约50mg,约75mg,约100mg,约150mg,约200mg或约250mg的被配制用于立即释放的TH-302或式I的另外缺氧激活前药的本发明的单位剂型是尤其有用的,因为这样的单位剂型能够方便地QD、BID或TID给药,并且根据BSA和给药频率,每次给药时可给予一个或多以一个这样的单位剂量。在不同的实施方式中,该单位剂型为明亮的颜色或具有醒目的图案或二者(例如具有黑色和黄色条纹的片剂或胶囊)以使得能够容易地辨认或减少与其他药物混淆的可能性。
在另一种实施方式中,本发明提供了治疗癌症的方法,该方法包括向对这样的治疗有需要的患者给予治疗有效量的本文提供的制剂。在一种实施方式中,TH-302或式I的另外缺氧激活前药作为唯一的抗癌记给予(单药治疗)。在一种实施方式中,TH-302或式I的另外缺氧激活前药与另外的抗癌剂抗癌治疗联合给药(联合治疗)。PCT公开第WO2007/002931号、第WO2008/083101号、第WO2010/048330号、第WO2012/006032号和第WO2012/009288号;以及PCT专利申请第PCT/US2012/031677号中披露了通过给予TH-302或式I的另外缺氧激活前药治疗癌症的方法、用于这样的治疗的前药的治疗有效量、给药频率和当与其他抗癌剂组合使用时的给药顺序以及适合用于共同给药的其他抗癌剂,其中的每一篇以引用方式结合于本文作为参考,并且根据本文披露内容能够应用于实施本发明能够的治疗方法。
在一种实施方式中,待治疗患者的癌症为转移癌或难治和/或对于一线、二线或三线治疗难治的复发的癌症。在另一种实施方式中,该治疗是一线、二线或三线治疗。如本文中使用的,短语“一线”、“二线”或“三线”治疗是指患者所接受的治疗。一线治疗方法为首先进行的治疗,而二线和三线治疗分别为在一线治疗或在二线治疗之后进行的治疗。因此,一线治疗是对于疾病或病症的首次治疗。在患有癌症的患者中,初期治疗可以是手术、化疗、放疗、或这些治疗的组合。一线治疗也被本领域技术人员称为初期治疗或初期处理。通常,患者由于对一线治疗未表现出阳性临床反应或仅仅表现出亚临床反应或一线治疗已经停止而接受随后的化疗方案。
在不同的实施方式中,待治疗的癌症选自由肛门癌、乳腺癌、食道癌、肺癌(小细胞肺癌和非小细胞肺癌)、黑素瘤、卵巢癌、胰腺癌、前列腺癌、肉瘤、软组织肉瘤、和任意实体瘤癌症组成的组。在各种其他实施方式中,待治疗的癌症选自血癌,其非限制性实例包括各种白血病。本发明也包括除了癌症之外的过度增殖性疾病的治疗。
通过以下实施例概括描述和详细描述本发明,其是示例性的而不是限制性的。
实施例
实施例1
本实施例证明了TH-302的出人意料高的口服生物利用度。使用基于高效液相色谱(HPLC)分析纯度为约96%的TH-302(1-甲基-2-硝基-1H-咪唑-5-基)N,N′-二(2-溴乙基)二氨基磷酸酯,m.w.=449)。向雄性Sprague-Dawley大鼠(n=3/时间点)给予单一口服剂量的100mg/kg TH-302(参见表1和图1)。TH-302被迅速地和良好地吸收,其在15分钟的第一取样时间点达到平均峰值血浆浓度并且绝对口服生物利用度为77.3%。相应的平均曲线下面积(AUC)和半衰期分别为13.1μg-h/mL和1.6小时。在IV输注给予相同剂量的100mg/kg30分钟(表2)之后,在输注结束时的平均峰值血浆浓度为30.9μg/mL,平均AUC和半衰期分别为17.1μg-h/mL和0.27小时。本实施例证明了TH-302和这样的其他药物适合用于作为口服制剂给药。
表1.大鼠中的TH-302药代动力学(平均值±标准差(S.D.))
a复合数据,n=3/时间点
bn=2
AUC:从零至无穷大的总浓度时间曲线下面积;IV:静脉内;PO:口服
表2.在大鼠a中静脉内输注TH-302之后30分钟,TH-302的单一剂量药代动力学参数
an=3只大鼠/时间点
bn=2
以下实施例2提供了本发明的立即释放口服制剂。如本文中所使用的,“活性剂”是指TH-302或式I的其他化合物。
实施例2
将晶体形式的活性剂(约100mg-约500mg)装入明胶胶囊中以提供不同单位剂型的活性剂的立即释放制剂。可替代地,将含有约100mg-约500mg的活性剂以及乳糖、蔗糖或其他糖的微粒制剂装入明胶胶囊中,以提供不同单位剂型的活性剂的快速释放制剂。
以下实施例3-7提供了活性剂的修饰释放口服制剂。
实施例3
约500g的活性剂、分子量为约100,000的约600g聚(氧化乙烯)和平均分子量为约40,000的约50g聚乙烯吡咯烷酮加入到混合容器中,并将成分干混10分钟。然后缓慢加入约300g的无水乙醇并连续掺混10分钟以制备造粒混合物。将刚刚制得的造粒混合物通过20目筛,将其在25℃干燥约20小时,然后通过16目筛。接着,将该造粒混合物转移至混合物,并用约10g的硬脂酸镁润滑,以制造本发明的口服制剂。将该制剂中压力下压制成包含例如约100mg至约500mg活性剂的片剂。
实施例4
通过实施例3的以下程序制备本发明的口服制剂,以提供包含如下成分的单位剂型(i)约50mg至约500mg的活性剂;(ii)约10mg至约500mg的分子量为约100,000至约500,000的聚(烷撑氧化物)聚合物,例如聚(氧化乙烯)、聚(氧化丙烯)、聚(氧化异丙烯)和聚(氧化丁烯);或约10mg至约500mg的分子量为约7,500to325,000的聚合物,其选自碱金属羧甲基纤维素和碱土金属羧甲基纤维素;(iii)约0.5mg至约50mg的分子量为约5,000至约300,000的聚(乙烯基)聚合物,例如聚乙烯吡咯烷酮;乙烯基吡咯烷酮和一种或多种醋酸乙烯酯的共聚物、乙烯基氯化物、乙烯基氟化物、丁酸乙烯酯、月桂酸乙烯酯、和硬脂酸乙烯酯;以及(iv)约7.5mg的润滑剂,选自聚乙二醇、硬脂酸镁、硬脂酸钙、油酸钾、硬脂酸钠、硬脂酸和棕榈酸钠。本发明的其他口服制剂可以含有其他赋形剂,例如说色剂、压制助剂例如微晶纤维素等,以及粘结剂例如淀粉等。该制剂在1/8至3吨的力下被压制,以产生可口服给药的片剂。
实施例5
如下涂覆实施例3和4的片剂以提供本发明单位剂型。首先,制备涂覆溶液(其可以是亲水的或疏水的)。边搅拌边将分子量为约220,000且乙氧基含量为约50wt%的乙基纤维素(约154g)、约112g分子量为约80,000且摩尔取代为3的羟丙基纤维素、以及约15g聚氧乙烯(40)硬脂酸酯溶解于约3,700g无水乙醇。不搅拌将所得溶液静置3天,得到组成-1的涂覆溶液。
通过在稍微加热(根据需要加热至26℃)下边搅拌边将约160g乙酰基含量为约40wt%且分子量为约40,000的醋酸纤维素和约90g分子量为约8,400且氧化乙烯含量为约80wt%的氧化乙烯-氧化丙烯-氧化乙烯三嵌段共聚物溶解于约4,700g无水丙酮来制备其他类型的涂覆溶液。将所得混合物在室温下静置一天,得到组成-2的涂覆溶液。
接着,将活性剂片剂置于盘状涂布器中。在一股热空气中将涂布组合物喷涂在片剂上直至将具有所需厚度的包衣施加于片剂。在强制空气烘箱中在40℃干燥该包衣片剂24小时或在较低温度下干燥,这取决于所配制的活性剂的稳定性。
实施例6
如下制备能够在一段时间内缓慢释放活性剂的修饰释放微粒制剂。将微晶纤维素(约160g)、乳糖(约75g)、柠檬酸(约40g)和活性剂(约100g)混合并利用水中行星混合器中揉捏以形成湿的物质。使该湿的物质通过Nica E140挤出机以形成挤出物(直径为约1mm)。然后使该挤出物通过Nica成球机器以形成微粒,然后再托盘干燥烘箱或流化床干燥器中干燥该微粒以提供本发明的微粒制剂。如本文所述将这些微粒装填到硬壳(或涂覆的或分层的)药用胶囊中以提供本发明的其他口服制剂。
实施例7
在本实施例中,通过如下的两步过程涂覆如上所述制备的微粒。制备羟丙基甲基纤维素(约7.5wt%)和聚乙二醇(约2.5wt%)的水溶液并将其喷涂在微粒上以形成密封涂层。然后利用可商购的乙基纤维素(例如30wt%)与乙酰化甘油单酯(约9.5wt%)混合的水溶液用屏障涂层涂覆该密封涂覆的微粒。如本文所述将这些微粒装填到硬壳(或涂覆的或分层的)药用胶囊中以提供本发明的其他口服制剂。
以下实施例8描述了提供活性剂的脉冲释放的本发明的口服制剂。
实施例8
将约15mg of去端肽胶原和1mg活性剂在制片机上压缩模制(400kg/cm2)然后在其上再压缩模制35mg的去端肽胶原。由此制得含活性剂的胶原层和无活性剂的胶原层。上述程序重复三次以上,从而形成每一层的四个层。从而制得到厚度为约1.5mm,直径为约10mm且重量为约200mg的圆柱形小颗粒。单独地将约10g的382硅酮碱和约2滴辛酸亚锡迅速混合着一起。将混合物置于直径为15mm深度为5mm.的容器中。将上述分层的圆柱形小颗粒浸于所述混合物中,并且顶部(含活性剂的胶原层)保持与空气接触。通过将该混合物与浸于其中的小颗粒状室温下静置24小时使硅酮聚合物固化。之后从容器取出该制剂。活性剂从涂覆的药物制剂溶出,从而利用生理盐水在室温下确定所得的制剂,并在同样的时间间隔取样盐水以用于通过高效液相色谱来确定在单位时间内释放的活性剂的量。
可将如上文中举例说明的活性剂的微粒或含有立即释放核和可选地立即释放包衣那些微粒本实施例中所述包埋在去端肽胶原中,以制备本发明的脉冲释放口服制剂。
应该理解,尽管已经通过某些方面、实施方式和可选特征具体描述了本发明,但本领域技术人员能想到这些方面的修改、改进和变化、实施方式和可选的特征,并且应当认为这样的修改、改进和变化包括在本文披露内容的范围内。
本文中已经宽泛地和总体上描述了本发明。落在总体披露内容中的每一较窄的范围和下位的组也形成本发明的一部分。另外,当根据马库什组描述本发明的特征或方面时,本领域技术人员将认识到由此也是根据该马库什组的任意单个成员或成员的亚组描述本发明。
本文中提到的所有出版物、专利申请、专利和其他参考文献均表述为以其全部内容结合于本文作为参考,如同各自单独以引用方式在相同范围内结合于本文。在出现冲突的情况下,以本说明书(包括定义)为准。
Claims (19)
1.一种包含式I的缺氧激活前药的口服制剂:
其中
Y2为O、S、NR6、NCOR6、或NSO2R6
R6为C1-C6烷基、C1-C6杂烷基、芳基或杂芳基;
R3和R4独立地选自2-卤代烷基、2-烷基磺酰氧基烷基、2-杂烷基磺酰氧基烷基、2-芳基磺酰氧基烷基和2-杂烷基磺酰氧基烷基;
R1具有式L-Z3;
L为C(Z1)2;
每个Z1独立地为氢、卤素、C1-C6烷基、C1-C6杂烷基、芳基、杂芳基、C3-C8环烷基、杂环基、C1-C6酰基、C1-C6杂酰基、芳酰基或杂芳酰基;
或L为:
Z3为具有选自由以下组成的组中的式的生物还原基团:
每个X1独立地为N或CR8;
X2为NR7、S或O;
每个R7独立地为C1-C6烷基、C1-C6杂烷基、C3-C8环烷基、杂环基、芳基或杂芳基;
并且R8独立地为氢、卤素、氰基、CHF2、CF3、CO2H、氨基、C1-C6烷基、C1-C6杂烷基、C1-C6环烷基、C1-C6烷氧基、C1-C6烷基氨基、C1-C6二烷基氨基、芳基、CON(R7)2、C1-C6酰基、C1-C6杂酰基、芳酰基或杂芳酰基;
或其可药用盐;
其中,所述口服制剂为修饰释放制剂。
2.根据权利要求1所述的修饰释放制剂,其为片剂。
3.根据权利要求1所述的修饰释放制剂,其包含微粒。
4.根据权利要求1所述的修饰释放制剂,其包含受控释放基质。
5.根据权利要求1所述的修饰释放制剂,进一步包含核。
6.根据权利要求1所述的修饰释放制剂,进一步包含包衣。
7.根据权利要求6所述的修饰释放制剂,其中,所述包衣为受控释放包衣。
8.根据权利要求6所述的修饰释放制剂,其中,所述包衣为水分屏障包衣。
9.根据权利要求1所述的修饰释放制剂,其包含纳米颗粒。
10.根据权利要求1-9中任一项所述的修饰释放制剂,进一步包含添加剂、消泡剂、粘结剂、化学稳定剂、着色剂、稀释剂、崩解剂、乳化剂、填料、矫味剂、助流剂、润滑剂、pH调节剂、增塑剂、助溶剂、溶胀增强剂、滚圆助剂、溶解增强剂和悬浮剂中的一种或多种。
11.根据权利要求1-10中任一项所述的修饰释放制剂,其显示出所述缺氧激活前药的脉冲释放曲线。
12.一种口服、立即释放、微粒或纳米颗粒口服制剂,包含式I的缺氧激活前药:
其中
Y2为O、S、NR6、NCOR6或NSO2R6
R6为C1-C6烷基、C1-C6杂烷基、芳基或杂芳基;
R3和R4独立地选自2-卤代烷基、2-烷基磺酰氧基烷基、2-杂烷基磺酰氧基烷基、2-芳基磺酰氧基烷基和2-杂烷基磺酰氧基烷基;
R1具有式L-Z3;
L为C(Z1)2;
每个Z1独立地为氢、卤素、C1-C6烷基、C1-C6杂烷基、芳基、杂芳基、C3-C8环烷基、杂环基、C1-C6酰基、C1-C6杂酰基、芳酰基或杂芳酰基;
或L为:
Z3为具有选自下式的生物还原基团:
每个X1独立地为N或CR8;
X2为NR7、S或O;
每个R7独立地为C1-C6烷基、C1-C6杂烷基、C3-C8环烷基、杂环基、芳基或杂芳基;
并且R8独立地为氢、卤素、氰基、CHF2、CF3、CO2H、氨基、C1-C6烷基、C1-C6杂烷基、C1-C6环烷基、C1-C6烷氧基、C1-C6烷基氨基、C1-C6二烷基氨基、芳基、CON(R7)2、C1-C6酰基、C1-C6杂酰基、芳酰基或杂芳酰基;
或其可药用盐;
以及一种或多种可药用赋形剂。
13.包含权利要求12所述的立即释放制剂的明胶胶囊或片剂制剂。
14.根据权利要求1-13中任一项所述的口服制剂,其中,所述缺氧激活前药为TH-302。
15.权利要求1-14中任一项所述的口服制剂的单位剂量。
16.根据权利要求15所述的单位剂量,其包含约25mg–约1000mg的TH-302。
17.根据权利要求16所述的单位剂量,其包含约50mg–约500mg的TH-302。
18.根据权利要求17所述的单位剂量,其包含约75mg的TH-302。
19.一种治疗癌症的方法,包括向对这样的治疗有需要的患者给予治疗有效量的权利要求1-14中任一项所述的制剂或权利要求15-18中任一项所述的单位剂量。
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MX2013011655A (es) | 2013-11-01 |
JP2014510795A (ja) | 2014-05-01 |
IL228709A0 (en) | 2013-12-31 |
WO2012142520A3 (en) | 2013-01-03 |
EP2696858A2 (en) | 2014-02-19 |
EP2696858A4 (en) | 2014-09-03 |
CA2832203A1 (en) | 2012-10-18 |
US20140072624A1 (en) | 2014-03-13 |
BR112013025969A2 (pt) | 2016-12-20 |
WO2012142520A2 (en) | 2012-10-18 |
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