CN102548536A - 奥洛他定组合物及其用途 - Google Patents
奥洛他定组合物及其用途 Download PDFInfo
- Publication number
- CN102548536A CN102548536A CN2010800434937A CN201080043493A CN102548536A CN 102548536 A CN102548536 A CN 102548536A CN 2010800434937 A CN2010800434937 A CN 2010800434937A CN 201080043493 A CN201080043493 A CN 201080043493A CN 102548536 A CN102548536 A CN 102548536A
- Authority
- CN
- China
- Prior art keywords
- liquid composite
- alkyl
- olopatadine
- amino
- pde4 inhibitor
- 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.)
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- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 title claims abstract description 79
- 229960004114 olopatadine Drugs 0.000 title claims abstract description 77
- 239000000203 mixture Substances 0.000 title claims abstract description 53
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims abstract description 34
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims abstract description 34
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000002131 composite material Substances 0.000 claims description 44
- 239000007788 liquid Substances 0.000 claims description 44
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 16
- -1 acyl group alkyl Chemical group 0.000 claims description 15
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 230000036783 anaphylactic response Effects 0.000 claims description 12
- 208000003455 anaphylaxis Diseases 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims description 8
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 235000001014 amino acid Nutrition 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 claims description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims description 2
- 125000005157 alkyl carboxy group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-N anhydrous cyanic acid Natural products OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 claims description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
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- 239000004094 surface-active agent Substances 0.000 description 7
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
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- 229920002125 Sokalan® Polymers 0.000 description 3
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
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- URLVCROWVOSNPT-XOTOMLERSA-N (2s)-4-[(13r)-13-hydroxy-13-[(2r,5r)-5-[(2r,5r)-5-[(1r)-1-hydroxyundecyl]oxolan-2-yl]oxolan-2-yl]tridecyl]-2-methyl-2h-furan-5-one Chemical compound O1[C@@H]([C@H](O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 URLVCROWVOSNPT-XOTOMLERSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 2
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
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- 229910019142 PO4 Inorganic materials 0.000 description 2
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Abstract
Description
相关申请的交叉参考
本申请要求于2009年10月1日提交的在35 U.S.C.§119下的美国临时专利申请号61/247,618的优先权,将其全部内容并入本文作为参考。
发明领域
本发明涉及用于治疗过敏性和炎性疾病的奥洛他定制剂。更特别地,本发明涉及奥洛他定制剂以及它们在治疗和/或预防眼、耳、皮肤和鼻的过敏性或炎性障碍中的用途。
发明背景
如美国专利号4,871,865和4,923,892(均为Burroughs Wellcome Co.(“the Burroughs Wellcome专利”)所有)中所教导的,多塞平的某些羧酸衍生物(包括奥洛他定(化学名:Z-11-(3-二甲基氨基亚丙基)-6,11-二氢二苯并[b,e]氧杂环庚三烯-2-乙酸))具有抗组胺和止喘活性。这两个专利把多塞平的羧酸衍生物归为肥大细胞稳定剂,具有抗组胺作用,因为它们被认为抑制自体有效物质(即组胺5-羟色胺等)从肥大细胞中释放并且直接抑制组胺对靶组织的作用。Burroughs Wellcome Patents教导了包含多塞平的羧酸衍生物的多种药物制剂,包括鼻喷雾剂和眼用制剂。参见,例如’865专利的第7栏,第7-26行以及实施例8(H)和8(I)。
美国专利号5,116,863(为Kyowa Hakko Kogyo Co.Ltd.(“the Kyowa专利”)所有)教导了多塞平的乙酸衍生物,特别是奥洛他定,具有抗过敏性和抗炎性活性。对于多塞平的乙酸衍生物,Kyowa专利教导的药物形式包括宽范围的可接受的载体;但是,仅提及了口服和注射施用形式。
美国专利号5,641,805(为Alcon Laboratories Inc.和Kyowa HakkoKogyo Co.Ltd.所有)教导了包含奥洛他定的局部眼用制剂,其用于治疗过敏性眼病。根据’805专利,局部制剂可以是溶液剂、混悬剂或凝胶剂。制剂包含奥洛他定、等渗剂,和“如果需要的话,还包含防腐剂、缓冲剂、稳定剂、粘稠介质等”。参见第6栏,第30-43行。“聚乙烯醇、聚乙烯吡咯烷酮、聚丙烯酸等”被提及作为粘稠介质。参见第6栏,第55-57行。
磷酸二酯酶IV型(PDE4或PDE-IV)是炎性白细胞(例如肥大细胞、嗜中性粒细胞、单核细胞和T-淋巴细胞)中发现的主要的环核苷酸水解酶。已知PDE4抑制剂化合物可用作抗炎剂和抗过敏剂。
通常,在药物组合物中,更希望活性成分在溶液中,而非在混悬液中。例如,溶液剂更易于制备,更易于处理,提供了更好的渗透至作用靶点,并且提供了更好的剂量一致性。
同时包含奥洛他定和PDE4抑制剂化合物的制剂是希望的,因为该组合满足了过敏反应的早期和晚期。此外,包含增加奥洛他定溶解度的化合物的制剂是希望的,因为这确保奥洛他定在希望的贮存期限内不沉淀,并且使得溶解的奥洛他定的浓度增加。
发明概述
本发明提供了包含奥洛他定和本文提供的式I的PDE4抑制剂化合物的药用水溶液组合物。本发明还提供了治疗眼、耳、皮肤和鼻过敏性和炎性病症的方法。一方面,溶液组合物中奥洛他定的浓度为至少0.17%w/v,并且式I的PDE4抑制剂化合物的浓度为至少0.05%w/v。
本发明特别优选的实施方案将从下列某些优选的实施方案和权利要求的更详细的描述中变得显而易见。
附图简述
图1是显示奥洛他定游离碱溶解度和PDE4抑制剂浓度(%w/v)的图。
图2是显示奥洛他定游离碱溶解度和PDE4抑制剂浓度(毫摩尔)的图。
发明详述
本文特别通过实例的方式显示,并且仅为了本发明优选的实施方案的说明性讨论的目的,并且为提供被认为最有用且最易理解地描述本发明多个实施方案的原则和概念方面而存在。在这方面,没有尝试比基本理解本发明所需的更详细地显示本发明的结构细节,附图和/或实施例的描述对于本领域技术人员如何在实践中体现本发明的数种形式是显而易见的。
除非另外说明,本文所用的术语“一个”和“一种”表示“一个(种)”、“至少一个(种)”或“一个(种)或多个(种)”。除非上下文另外要求,本文所用的单数术语应当包括复数,并且复数术语应当包括单数。
除非另外说明,本文提供的所有组分的量是以%(w/v)基础表示的,并且所有涉及奥洛他定的是奥洛他定游离碱。
在某些实施方案中,本发明提供了包含治疗有效量的奥洛他定和式I的PDE4抑制剂化合物的溶液组合物,所述的式I的PDE4抑制剂化合物使奥洛他定的水溶解度增加了约0.2-0.6%。
术语“治疗有效量”表示确定在哺乳动物中产生治疗效应的本发明的溶液组合物(奥洛他定或式I的PDE4抑制剂化合物)的量。该治疗有效量易于由本领域技术人员并且使用本文描述的方法来确定。
本文所用的术语“药用水溶液组合物”和“溶液组合物”表示当适当施用于患者时能诱导希望的治疗作用(例如降低、预防和/或消除过敏或过敏症状或炎症)的包含奥洛他定或其可药用盐、式I的PDE4抑制剂化合物或其可药用盐以及本文描述的可药用载体(例如眼用或鼻用或耳用载体,或适合于递送至皮肤的载体)、赋形剂或稀释剂的组合物。本文所用的术语“药用水溶液组合物”和“溶液组合物”包括其中奥洛他定(或其可药用盐)和式I的PDE4抑制剂化合物(或其可药用盐)是在溶液中的组合物,并且其中取决于组合物中存在或不存在任何赋形剂,所有组合物是溶液剂、混悬剂或半固体(例如乳膏剂、凝胶剂或乳剂)。
本文所用的术语“可药用眼用或鼻用或耳用载体”表示最多引起、很小至没有眼、耳或鼻刺激,提供适合的防腐(如果需要)并且以均匀剂量递送奥洛他定和式I化合物的那些载体。
本文所用的术语“患者”包括人和动物个体。
在一个实施方案中,本发明的溶液组合物包含具有式I结构的PDE4抑制剂化合物:
在某些实施方案中:
R1和R2独立地选自-(CH2)sG1G2G3、酰基、酰基烷基、羧基烷基、氰基烷基、烷氧基、烷氧基烷基、酰氨基烷基、氨基、烷基、烷基烷氧基、氨基烷基、链烯基、炔基、羧基、羧基烷基、醚、杂烷基、卤代烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳烷基、芳基、胍、杂芳基、杂芳烷基和羟基烷基,任何上述基团可以任选被取代;
s是1-8;
G1选自烷氧基、氨基、酰氨基、羰基、羟基、醚、氨基酸和不存在;
G2选自烷基、烷氧基、氨基、芳基、卤素、卤代烷基、杂环烷基、杂芳基、羧基烷基氨基、胍、氨基酸和不存在,任何上述基团可以任选被取代;
G3选自烷基、烷氧基、氨基、羟基、醚、羧基、异羟肟酸、氨基酸、膦酸酯、磷酰胺和不存在,任何上述基团可以任选被取代;
R5选自-(CR8R9)mW(CR10R11)n-和-(CR12R13)p-;
W选自O、N(R7)、C(O)N(R7)和SOq;
m、n和q独立地是0、1或2;
p是1或2;
R6选自羧基、烷基羧基、酰氨基、芳基、杂芳基、环烷基、杂环烷基、烷基、杂烷基、酰基和异羟肟酸,任何上述基团可以任选被取代;
R7和R14独立地选自氢、卤素、羟基、低级烷基、羟基烷基、卤代烷基和氨基烷基;
R8、R9、R10、R11、R12和R13独立地选自氢和任选取代的低级烷基;
并且R19选自氢、卤素、低级烷基和卤代烷基;以及
可药用载体或赋形剂。
在一个实施方案中,式I的PDE4抑制剂化合物是(4-(3,5-二氯吡啶-4-基氨基)-7-甲氧基-8-(6-(4-甲基哌嗪-1-基)己基氧基)喹啉-2(1H)-酮):
在另一个实施方案中,式I化合物是(4-(3,5-二氯吡啶-4-基氢基)-7-甲氧基-8-(6-吗啉代己基氧基)喹啉-2(1H)-酮):
这些化合物和其它式I的PDE4抑制剂化合物是PDEIV抑制剂,并且在2007年7月6日提交的共同未决美国申请号11/774,053和2009年8月19日提交的美国申请号12/544,185中有详细描述,将其全部内容并入本文作为参考。
奥洛他定是通过美国专利号5,116,863中公开的方法可以获得的已知化合物,在本说明书中将其全部内容并入本文作为参考。
通常,奥洛他定将以可药用盐形式加入。奥洛他定的可药用盐的实例包括无机酸盐,例如盐酸盐、氢溴酸盐、硫酸盐和磷酸盐;有机酸盐,例如乙酸盐、马来酸盐、富马酸盐、酒石酸盐和柠檬酸盐;碱金属盐,例如钠盐和钾盐;碱土金属盐,例如镁盐和钙盐;金属盐,例如铝盐和锌盐;和有机胺加成盐,例如三乙胺加成盐(也称为氨基丁三醇(tromethamine))、吗啉加成盐和哌啶加成盐。用于本发明的溶液组合物的最优选的奥洛他定形式是(Z)-11-(3-二甲基氨基亚丙基)-6,11-二氢二苯并-[b,e]氧杂环庚三烯-2-乙酸的盐酸盐。当奥洛他定以其盐形式加入至本发明的组合物中时,0.222%的奥洛他定盐酸盐等同于0.2%的奥洛他定游离碱,0.443%的奥洛他定盐酸盐等同于0.4%的奥洛他定游离碱,并且0.665%的奥洛他定盐酸盐等同于0.6%的奥洛他定游离碱。除非另外说明,当提及奥洛他定的浓度时指的是奥洛他定游离碱的浓度。
意外发现,式I的PDE4抑制剂化合物增加奥洛他定的溶解度。因此,无需任何其它溶解度增强组分即可制备本发明的水溶液组合物。
根据本发明施用的组合物还可以包含多种其它成分,包括但不限于表面活性剂、张力剂、缓冲剂、防腐剂和粘度构建剂。
适合的缓冲体系(例如磷酸钠、乙酸钠、柠檬酸钠、硼酸钠或硼酸)可以加入至组合物中,以防止在贮存条件下pH漂移。具体的浓度将取决于所用的试剂而不同。然而,优选选择缓冲液以维持目标pH范围为pH6.0-7.5。
在某些实施方案中,本发明的溶液组合物中奥洛他定的浓度为至少0.05%w/v。例如,奥洛他定的浓度可以为约0.05%、0.075%、0.10%、0.15%、0.20%、0.25%、0.30%、0.35%、0.40%、0.45%、0.50%、0.55%或0.60%w/v或更高。在某些实施方案中,本发明的溶液组合物是包含至少0.05%w/v奥洛他定的溶液制剂。在某些实施方案中,本发明的溶液制剂包含0.17-0.62%w/v奥洛他定。在某些实施方案中,旨在用于眼的溶液制剂包含0.17-0.25%奥洛他定并且优选0.18-0.22%w/v奥洛他定。在某些实施方案中,旨在用于鼻的溶液制剂包含0.38-0.62%w/v奥洛他定。
在某些实施方案中,本发明的溶液组合物中的式I的PDE4抑制剂化合物的浓度为至少0.05%w/v。例如,式I的PDE4抑制剂化合物的浓度可以为约0.05%、0.10%、0.15%、0.20%、0.25%、0.30%、0.35%、0.40%、0.45%、0.50%、0.55%或0.60%w/v或更高。
在某些实施方案中,本发明的溶液组合物可用于治疗过敏性或炎性障碍,包括眼、鼻、皮肤和耳的过敏性或炎性障碍。
在某些实施方案中,眼用制剂施用于需要的患者的眼以治疗眼部障碍。本文所用的术语“眼部障碍”包括眼的过敏性和/或炎性病症,例如眼过敏性障碍,包括过敏性结膜炎、春季结膜炎、春季角膜结膜炎和巨乳头状结膜炎、干眼、青光眼、角膜新血管生成、视神经炎、舍格伦综合征、视网膜神经节退化、眼局部缺血、视网膜炎、视网膜病变、眼色素层炎、眼畏光,以及与眼组织急性损伤相关的炎症和疼痛。特别地,化合物可以用于治疗青光眼性视网膜病变和/或糖尿病性视网膜病变。化合物还可以用于治疗眼科手术的术后炎症或疼痛,所述的眼科手术例如白内障手术和屈光(refractive)手术。在某些实施方案中,本发明化合物用于治疗过敏性眼病,所述的过敏性眼病选自过敏性结膜炎;春季结膜炎;春季角膜结膜炎;和巨乳头状结膜炎,过敏性结膜炎。
在一个实施方案中,本发明的溶液组合物是用于递送至眼睛的眼用制剂,例如局部眼用制剂。该溶液组合物可以包含可眼用防腐剂、表面活性剂、粘度增强剂、渗透增强剂、缓冲剂、张力剂和水,以形成水性、无菌眼用溶液剂、混悬剂或乳剂。还可以使用胶凝剂,包括但不限于胶凝糖和黄原胶。为了制备无菌眼用软膏制剂,将奥洛他定和式I的PDE4抑制剂化合物与防腐剂在适合的介质中混合。根据公开的类似眼用制剂的配方,无菌眼用凝胶制剂可以通过将奥洛他定和式I的PDE4抑制剂化合物悬浮于亲水基质中制备,所述的亲水基质是由例如-974、-940(BF Goodrich,Charlotte,NC)等的组合制备的,可以掺入防腐剂和张力剂。
本发明的溶液组合物可以局部施用于眼,例如治疗过敏性结膜炎和/或眼炎症。通常,用于上述目的的剂量将不同,但是以减轻或消除过敏性结膜炎和/或眼炎症的有效量施用。通常,1-2滴该组合物每天施用1次或多次。例如,组合物可以每天施用2至3次或如眼护理提供者所示的。
局部眼用产品还可以以多剂量形式包装。因此,需要防腐剂以防止使用过程中微生物污染。适合的防腐剂包括:苯扎氯铵、苯度溴铵、三氯叔丁醇、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、苯基乙基醇、依地酸二钠、山梨酸、聚季铵盐-1或本领域技术人员已知的其它试剂。这些防腐剂典型地以0.001至5.0%w/v的水平使用。本发明的单位剂量组合物是无菌的,但典型地没有防腐。因此,这类组合物通常不含防腐剂。还可以提供不含防腐剂并且包装在单位剂量形式中的本发明的眼用组合物。
本发明的组合物任选包含一种或多种赋形剂。预期局部应用于眼或鼻的溶液组合物(例如溶液剂或喷雾剂)中通常所用的赋形剂包括但不限于张力剂、防腐剂、螯合剂、缓冲剂、表面活性剂和抗氧化剂。适合的张力调节剂包括甘露醇、氯化钠、甘油、山梨醇等。适合的防腐剂包括对羟基苯甲酸酯、苯扎氯铵、苯度溴铵、聚季铵盐-1等。适合的螯合剂包括依地酸钠等。适合的缓冲剂包括磷酸盐、硼酸盐、柠檬酸盐、乙酸盐、氨基丁三醇等。适合的表面活性剂包括离子和非离子型表面活性剂,尽管优选非离子型表面活性剂,例如聚山梨酯、聚乙氧基化蓖麻油衍生物、聚乙氧基化脂肪酸、聚乙氧基化醇、聚氧乙烯-聚氧丙烯嵌段共聚物和氧乙烯化叔辛基酚醛聚合物(泰洛沙泊)。适合的抗氧化剂包括亚硫酸盐类、硫代硫酸盐、抗坏血酸盐、BHA、BHT、生育酚类等。本发明的组合物任选包含另外的活性剂。本发明的组合物可以包含一种或多种非离子、阴离子或阳离子聚合物作为润滑剂或粘度剂,包括但不限于羟丙基甲基纤维素(HPMCs)、甲基纤维素、羧甲基纤维素(CMCs)、聚乙二醇(PEGs)、泊洛沙姆、聚丙二醇、黄原胶、瓜尔胶、卡波姆、聚乙烯醇(PVAs)、聚乙烯吡咯烷酮(PVPs)、海藻酸和盐、胶凝糖、角叉菜胶和壳聚糖。
可以使用多种张力剂以调节组合物的张力,对于眼用组合物优选调节至天然泪液的张力。例如,可以将氯化钠、氯化钾、氯化镁、氯化钙、右旋糖、甘露醇、山梨醇、丙二醇或甘油加入至组合物中,以接近生理张力。张力剂的量将取决于加入的的特别试剂而不同。然而,通常组合物具有张力剂的量足以引起最终组合物具有可眼用的重量克分子渗透浓度(通常约150-450mOsm,优选250-350mOsm)。
在某些实施方案中,本发明的组合物具有约3.0至约8.5的pH。在一个实施方案中,本发明的眼用组合物具有4.0-8.0的pH,优选5.0-7.5的pH,并且最优选6.0-7.4的pH。预期用于鼻的本发明的组合物优选具有3.0-8.0的pH,最优选5.0-7.5的pH。
在某些实施方案中,本发明的溶液组合物可以配制成鼻用,并且可以用于治疗鼻障碍。因此,在某些实施方案中,本发明提供了治疗鼻障碍的方法,该方法包含将本发明的溶液组合物施用于需要的患者的鼻。本文所用的术语“鼻障碍”包括鼻的过敏性和/或炎性病症。
在进一步的实施方案中,本发明的鼻用溶液组合物配制成提供治疗有效的鼻内浓度。例如,本发明的鼻用溶液组合物可以具有约0.1-1000nM或1-100nM的鼻内浓度。根据熟练的临床医生的常规判断,鼻内组合物是以每天1至4次递送至鼻粘膜。制剂的pH范围应当为3至8或优选5至7.5。根据装置设计、它的药物释放特性以及根据熟练的临床医生的判断,通过鼻内插入或植入装置或溶液药物-递送-海绵(Pharmacia& Upjohn,Kalamazoo,MI)在鼻粘膜上直接局部施用可以以1-2μL/小时(例如0.0001-10mg/天)递送奥洛他定和式I的PDE4抑制剂化合物达数周。
然而准确的给药方案由临床医生判断,产生的溶液优选鼻内施用,如本文描述的每天1至4次,或如临床医生所示的。
可鼻用载体表示最多引起很小至没有鼻刺激,提供适合的防腐(如果需要)并且以均匀剂量递送本发明的溶液组合物的那些载体。对于鼻递送,本发明的溶液组合物可以与可鼻用防腐剂、共溶剂、表面活性剂、粘度增强剂、渗透增强剂、缓冲剂、张力剂和水混合,以形成水性、无菌混悬剂、溶液剂、乳剂或粘稠、半粘稠或半固体凝胶剂。鼻用溶液制剂可以通过将试剂溶于生理可接受的等渗水性缓冲液中而制备。此外,鼻用溶液剂可以包含可鼻用表面活性剂。例如可以在本发明的组合物中加入粘度构建化合物(例如羟甲基纤维素、羟乙基纤维素、甲基纤维素或卡波姆),以改善化合物的保留(retention)。
为了制备无菌鼻用软膏制剂,本发明的溶液组合物可以在适合的介质中包含防腐剂。根据本领域其它适合的鼻用制剂的已知方法,无菌鼻用凝胶制剂可以通过将奥洛他定和/或式I的PDE4抑制剂化合物悬浮于亲水基质中而制备,所述的基质由例如-974、-940(BFGoodrich,Charlotte,NC)等制备的。例如(Alcon Laboratories,Inc.,Fort Worth,TX)可以用于鼻内注射。本发明的其它组合物可以包含渗透增强物质,例如(聚氧乙烯蓖麻油)和80(聚氧乙烯脱水山梨醇单月桂酸酯)。
本发明的组合物可以以鼻用喷雾剂的形式鼻内施用,如本领域技术人员已知的。
鼻递送可以通过将奥洛他定和式I的PDE4抑制剂化合物掺入生物粘附颗粒载体(<200μm)(例如包括纤维素、聚丙烯酸酯或聚卡波非那些)中并且结合适合的吸收增强剂(例如磷脂或酰基肉毒碱)而实现。适合的体系包括DanBiosyst and Scios开发的那些。制剂可以应用由公司(例如Valois或Pfeiffer)可获得的简单鼻用喷雾装置来施用。
在某些实施方案中,配制包含奥洛他定和式I的PDE4抑制剂化合物的溶液,用于递送至皮肤。特别是预期施用于皮肤的组合物可以是溶液剂、混悬剂或半固体。但是,所述剂型中存在的奥洛他定(或其可药用盐)和PDE4抑制剂化合物(或其可药用盐)应当是所有分子溶解为溶液。剂型中存在的赋形剂可以是固体,例如如混悬剂或半固体或如乳膏剂。取决于皮肤病产品的需求,所述的组合物的粘度可以在1至100,000cps或更高内变化。
在进一步的实施方案中,配制包含奥洛他定和式I的PDE4抑制剂化合物的耳用组合物,以提供药理学有效的耳内浓度。根据熟练的临床医生的常规判断,局部耳用组合物可以每天一至四次或更多次递送至耳。制剂的pH范围应当为4.0至9.0或4.5至7.4。根据装置设计、它的药物释放特性以及根据熟练的临床医生的判断,通过耳内插入或植入装置或溶液药物-递送-海绵(Pharmacia & Upjohn,Kalamazoo,MI)在耳神经(听觉和前庭)或耳神经头上直接局部施用可以以1-2μL/小时(例如0.0001-10mg/天)递送本发明的溶液组合物达数周。
对于耳递送,本发明的溶液组合物可以与可耳用防腐剂、共溶剂、表面活性剂、粘度增强剂、渗透增强剂、缓冲剂、张力剂或水混合,以形成水性、无菌混悬剂、溶液剂或粘稠、半粘稠或半固体凝胶剂。
本发明的溶液组合物可以直接递送至耳(例如:局部耳用滴剂或软膏剂;耳内或邻近耳植入的缓慢释放装置)。局部施用包括耳肌内、鼓室内腔和耳蜗内注射施用途经。而且,在熟练的临床医生的正确判断和提醒下,本发明的溶液组合物可以施用于内耳,通过在靠近中耳/内耳的窗膜或邻近结构处放置用本发明的溶液组合物浸泡的明胶泡沫或类似的吸附和粘附产品。
本发明的组合物优选包装在不透明的塑料容器中。对于眼用产品,优选的容器是低密度聚乙烯容器,其是用环氧乙烷代替γ辐射来灭菌的。对于鼻用产品,优选的容器是装有鼻喷雾泵的高密度聚乙烯容器。
就它们提供示例性方法或补充本文公开的那些的其它细节而言,本文引用的参考明确地并入作为参考。
除非上下文另外要求,本文所用的单数术语应当包括复数,并且复数术语应当包括单数。
实施例
下列实施例,包括进行的试验和获得的结果,是仅用于说明目的,而不能认为是限制本发明。
实施例1
奥洛他定-PDE4抑制剂溶解度研究
下列试验用于测定式I化合物对奥洛他定的水溶解度的作用。
制备含表1所示组合物的制剂,用于如下奥洛他定溶解度试验:制备包含表2所示的0%、0.1%、0.3%或1%的化合物1(4-(3,5-二氯吡啶-4-基氨基)-7-甲氧基-8-(6-(4-甲基哌嗪-1-基)己基氧基)喹啉-2(1H)-酮)或化合物2(4-(3,5-二氯吡啶-4-基氨基)-7-甲氧基-8-(6-吗啉代己基氧基)喹啉-2(1H)-酮)以及至少1%奥洛他定盐酸盐的10毫升制剂样品,并且调至目标pH。化合物2不在pH 7.4下进行试验,因为它在该pH下溶解不充分。将样品在振荡器上混合,并且混合1和6天后将pH再调至目标pH。在第7天,将样品通过Acrodisc 25mm GXF/GHP 0.2微米过滤器过滤。收集第一份3毫升滤液,用于最终pH测量,并且将下一份3毫升滤液装入两个1.5mLHPLC小瓶中,用于奥洛他定分析(游离碱),如下面所示。由于分析方法不可获得,不分析样品A至H中的化合物1。对于奥洛他定分析,将一式两份化合物1/奥洛他定样品小心注入HPLC中。分析样品I、J和K中的化合物2和奥洛他定。单个化合物2/奥洛他定样品用50/50乙腈/水以1/10稀释并且注入UPLC中。
表1.用于奥洛他定-PDE4抑制剂溶解度研究的通用制剂
成分 | 目标浓度 |
奥洛他定盐酸盐 | >1%(即饱和的) |
化合物1或化合物2 | 0%、0.1%、0.3%或1% |
氢氧化钠和/或盐酸 | 适量至pH 5.2或7.4 |
聚季铵盐-1 | 0.001% |
硼酸 | 0.6% |
甘露醇 | 0.3% |
氯化钠 | 0.5% |
纯水 | 适量至100% |
过滤样品的最终pH是用Orion 525A+pH计测量的,使用RossSemimicro组合pH电极和自动温度探针。
化合物1和奥洛他定HPLC分析是用下列条件进行的:
仪器:装有Empower软件的Waters 2695分离模块和Waters 2487可变波长紫外-可见光检测器
柱:Phenomenex Ultracarb C8,5微米,150×4.6mm
流动相:
溶剂A=乙腈
溶剂B=含0.1%三乙胺的100毫摩尔磷酸钾,用NaOH/HCl调至pH 3.0
流速=1毫升/分钟
梯度:
检测:299nm紫外吸收
注入体积:20微升
奥洛他定保留时间:约6.2分钟
化合物2和奥洛他定UPLC分析是用下列条件进行的:
仪器:装有TUV检测器和Empower软件的Waters ACQUITY UPLC系统
柱:Acquity UPLC BEH Shield C18,1.7微米,100×2.1mm
流动相:
溶剂A=0.1%磷酸,用NaOH/HCl调至pH 3.0
溶剂B=乙腈
流速=0.3毫升/分钟
梯度:
检测:285nm紫外吸收
注入体积:3微升
AL-53817保留时间:约4.1分钟
奥洛他定保留时间:约4.5分钟
表2显示了样品中最终滤液pHs、奥洛他定和化合物2UPLC分析结果,以及目标化合物1浓度。
表2.奥洛他定-PDE4溶解度研究的结果
样品E至K的目标pH是5.2,并且悬浮液的pH读数在过滤前接近该数值。但是,过滤后溶液pH通常比悬浮液pH高约0.2pH单位。当测量悬浮液和溶液的pH时,通常观察到pH漂移。分析了A至H的一式两份样品,并且平均一式两份的数值。
毫摩尔(mM)浓度是通过将%w/v浓度除以分子量再乘以10000来计算的。
分子量如下:
奥洛他定(游离碱)=337.4克/摩尔;
化合物1=534.5克/摩尔;
化合物2=521.4克/摩尔。
将化合物1和2的浓度对产生的奥洛他定游离碱溶解度作图,以%w/v和毫摩尔(mM)浓度表示,并且将数据拟合成直线方程(图1和2)。
化合物1和化合物2以线性浓度依赖方式增加奥洛他定的水溶解度。溶解度增加比例约为2分子的化合物对1个奥洛他定分子。
应当理解的是,上述公开强调了本发明的某些特别的实施方案,对此所有的修饰或选择相当物在本发明的精神和范围内,如附加的权利要求中公开的。
Claims (15)
1.药用水溶液组合物,其包含:
治疗有效量的奥洛他定或其可药用盐作为在水相中的可溶形式,
式I的PDE4抑制剂化合物或其可药用盐,
其中:
R1和R2独立地选自-(CH2)sG1G2G3、酰基、酰基烷基、羧基烷基、氰基烷基、烷氧基、烷氧基烷基、酰氨基烷基、氨基、烷基、烷基烷氧基、氨基烷基、链烯基、炔基、羧基、羧基烷基、醚、杂烷基、卤代烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳烷基、芳基、胍、杂芳基、杂芳烷基和羟基烷基,任何上述基团可以任选被取代;
s是1-8;
G1选自烷氧基、氨基、酰氨基、羰基、羟基、醚、氨基酸和不存在;
G2选自烷基、烷氧基、氨基、芳基、卤素、卤代烷基、杂环烷基、杂芳基、羧基烷基氨基、胍、氨基酸和不存在,任何上述基团可以任选被取代;
G3选自烷基、烷氧基、氨基、羟基、醚、羧基、异羟肟酸、氨基酸、膦酸酯、磷酰胺和不存在,任何上述基团可以任选被取代;
R5选自-(CR8R9)mW(CR10R11)n-和-(CR12R13)p-;
W选自O、N(R7)、C(O)N(R7)和SOq;
m、n和q独立地是0、1或2;
p是1或2;
R6选自羧基、烷基羧基、酰氨基、芳基、杂芳基、环烷基、杂环烷基、烷基、杂烷基、酰基和异羟肟酸,任何上述基团可以任选被取代;
R7和R14独立地选自氢、卤素、羟基、低级烷基、羟基烷基、卤代烷基和氨基烷基;
R8、R9、R10、R11、R12和R13独立地选自氢和任选取代的低级烷基;
并且R19选自氢、卤素、低级烷基和卤代烷基;以及
可药用载体或赋形剂,
其中溶液组合物中奥洛他定的浓度为至少0.17%w/v。
2.权利要求1的溶液组合物,其中PDE4抑制剂化合物是(4-(3,5-二氯吡啶-4-基氨基)-7-甲氧基-8-(6-(4-甲基哌嗪-1-基)己基氧基)喹啉-2(1H)-酮或(4-(3,5-二氯吡啶-4-基氨基)-7-甲氧基-8-(6-吗啉代己基氧基)喹啉-2(1H)-酮)。
3.权利要求2的溶液组合物,其中PDE4抑制剂化合物是(4-(3,5-二氯吡啶-4-基氨基)-7-甲氧基-8-(6-(4-甲基哌嗪-1-基)己基氧基)喹啉-2(1H)-酮。
4.权利要求2的溶液组合物,其中PDE4抑制剂化合物是(4-(3,5-二氯吡啶-4-基氨基)-7-甲氧基-8-(6-吗啉代己基氧基)喹啉-2(1H)-酮)。
5.权利要求1的溶液组合物,其中奥洛他定的浓度为0.17-0.62%w/v。
6.权利要求5的溶液组合物,其中奥洛他定的浓度为0.17-0.25%w/v。
7.权利要求6的溶液组合物,其中奥洛他定的浓度为0.18-0.22%w/v。
8.权利要求1的溶液组合物,其中式I的PDE4抑制剂化合物的浓度为至少0.05%w/v。
9.权利要求1的溶液组合物,其中式I的PDE4抑制剂化合物的浓度为至少0.1%w/v。
10.权利要求1的溶液组合物,其具有pH范围为3.0至8.0。
11.权利要求10的溶液组合物,其中pH范围为5.0至7.5。
12.权利要求11的溶液组合物,其中pH范围为6.0至7.4。
13.权利要求1的溶液组合物,其中组合物配制用于递送至眼、鼻或皮肤。
14.权利要求13的溶液组合物,其中溶液组合物配制用于递送至皮肤,并且溶液组合物是粘稠的溶液剂或凝胶剂。
15.治疗眼、鼻或皮肤的过敏性或炎性病症的方法,该方法包括给需要的患者施用药用有效量的权利要求1的溶液组合物。
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- 2010-10-01 MX MX2012003693A patent/MX2012003693A/es not_active Application Discontinuation
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- 2010-10-01 BR BR112012007091A patent/BR112012007091A2/pt not_active IP Right Cessation
- 2010-10-01 US US12/896,056 patent/US20110082145A1/en not_active Abandoned
- 2010-10-01 CN CN2010800434937A patent/CN102548536A/zh active Pending
- 2010-10-01 RU RU2012117141/15A patent/RU2012117141A/ru not_active Application Discontinuation
- 2010-10-01 EP EP10762842A patent/EP2482798A1/en not_active Withdrawn
- 2010-10-01 AU AU2010300421A patent/AU2010300421B2/en not_active Ceased
- 2010-10-01 WO PCT/US2010/051062 patent/WO2011041640A1/en active Application Filing
- 2010-10-01 CA CA2773483A patent/CA2773483A1/en not_active Abandoned
- 2010-10-01 JP JP2012532346A patent/JP5721722B2/ja not_active Expired - Fee Related
-
2012
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2013
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CN103202833A (zh) * | 2012-12-25 | 2013-07-17 | 常州市亚邦医药研究所有限公司 | 一种奥洛他定或其盐的药用组合物及其制备方法 |
Also Published As
Publication number | Publication date |
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JP5721722B2 (ja) | 2015-05-20 |
JP2013506692A (ja) | 2013-02-28 |
US20140107121A1 (en) | 2014-04-17 |
EP2482798A1 (en) | 2012-08-08 |
AU2010300421B2 (en) | 2014-01-23 |
CA2773483A1 (en) | 2011-04-07 |
AU2010300421A1 (en) | 2012-04-12 |
RU2012117141A (ru) | 2013-11-10 |
KR20120091037A (ko) | 2012-08-17 |
CL2012000801A1 (es) | 2012-10-19 |
BR112012007091A2 (pt) | 2016-04-19 |
US20110082145A1 (en) | 2011-04-07 |
MX2012003693A (es) | 2012-04-19 |
WO2011041640A1 (en) | 2011-04-07 |
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