CN105555271A - 含有聚乙二醇的组合物 - Google Patents
含有聚乙二醇的组合物 Download PDFInfo
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- CN105555271A CN105555271A CN201480051151.8A CN201480051151A CN105555271A CN 105555271 A CN105555271 A CN 105555271A CN 201480051151 A CN201480051151 A CN 201480051151A CN 105555271 A CN105555271 A CN 105555271A
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- polyethylene glycol
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Abstract
本发明涉及含有式(1)表示的化合物或其盐及聚乙二醇的药物组合物。
Description
技术领域
本发明涉及含有式(1)表示的化合物或其盐及聚乙二醇的药物组合物、以及将式(1)表示的化合物或其盐稳定化的方法。
[式(1)中,
R1表示氢原子、卤素原子、羟基、C1-6烷基、被1个或多个卤素原子取代的C1-6烷基、C1-6烷氧基或被1个或多个卤素原子取代的C1-6烷氧基;
R2表示氢原子、C1-6烷基、C1-6烷基羰基或被1个或多个羟基取代的C1-6烷基羰基]
背景技术
专利文献1中记载了以下内容:式(1)表示的化合物,在使用了VEGF诱发HUVEC增殖反应评价体系的试验体系中显示细胞增殖抑制作用,在使用了小鼠荷瘤模型的试验体系中显示肿瘤增殖抑制作用,在使用了大鼠佐剂性关节炎(ADJUVANTARTHRITIS)模型的试验体系中显示足部浮肿抑制作用,在使用了大鼠脉络膜血管新生模型的试验体系中显示脉络膜血管新生抑制作用。专利文献1中还记载了:由于具有上述药理作用,所以式(1)表示的化合物作为药物是有用的,尤其是作为癌、类风湿性关节炎、老年性黄斑变性、糖尿病性视网膜病、糖尿病性黄斑水肿等疾病的预防或治疗剂而受到期待。
另外,专利文献2中记载了作为式(1)表示的化合物之一的2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺的苯磺酸盐、其晶体、其多晶型物(crystalpolymorphism)及它们的制造方法。专利文献2中还记载了:2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺的苯磺酸盐的保存稳定性优异,即使反复进行口服给药,也未在胃中发现矿物沉淀。
另一方面,专利文献3~5中公开了含有作为受体酪氨酸激酶抑制化合物的N-[4-(3-氨基-1H-吲唑-4-基)苯基]-N’-(2-氟-5-甲基苯基)脲及聚乙二醇的眼科用组合物。
另外,专利文献6中公开了含有雷帕霉素及聚乙二醇的眼科用组合物。
然而,专利文献1~6中并未记载含有式(1)表示的化合物或其盐及聚乙二醇的药物组合物,另外,对于聚乙二醇可提高药物组合物中的药理活性化合物的稳定性的内容也没有任何记载。
专利文献1:美国专利申请公开第2007/0149574号说明书
专利文献2:美国专利申请公开第2012/0116088号说明书
专利文献3:国际公开WO2007/076358号小册子
专利文献4:国际公开WO2009/014510号小册子
专利文献5:国际公开WO2010/101971号小册子
专利文献6:美国专利第8367097号说明书
发明内容
本申请发明人在开发含有上述式(1)表示的化合物或其盐(以下也称为“本化合物”)的药物组合物的过程中发现,在溶解有本化合物的药物组合物中,本化合物的稳定性显著降低。
本发明的课题在于提供一种药物组合物,所述药物组合物为含有本化合物的药物组合物,药物组合物中的本化合物稳定,而且药物组合物具有持续释放出本化合物的性质。
为了解决上述课题,本申请发明人对溶解本化合物的溶剂(例如,聚乙二醇、二甲基亚砜、N-甲基吡咯烷酮、N,N-二甲基乙酰胺)进行了深入研究,结果发现,在使用了聚乙二醇时,即使在药物组合物中长期保存本化合物,本化合物也具有高的残存率,从而完成了本发明。
即,本发明涉及以下方案。
(1)一种药物组合物,其含有上述式(1)表示的化合物或其盐及聚乙二醇。
(2)如上述(1)所述的药物组合物,其中,上述式(1)中,
R1表示C1-6烷氧基或被1个或多个卤素原子取代的C1-6烷氧基;
R2表示C1-6烷基羰基或被1个或多个羟基取代的C1-6烷基羰基。
(3)如上述(1)所述的药物组合物,其中,上述式(1)中,
R1表示被1个或多个卤素原子取代的C1-6烷氧基;
R2表示被1个或多个羟基取代的C1-6烷基羰基。
(4)如上述(1)所述的药物组合物,其中,上述式(1)表示的化合物为2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺。
(5)如上述(1)~(4)中任一项所述的药物组合物,其中,聚乙二醇的平均分子量在100~2000的范围内。
(6)如上述(1)~(4)中任一项所述的药物组合物,其中,聚乙二醇的平均分子量在200~600的范围内。
(7)如上述(1)~(4)中任一项所述的药物组合物,其中,聚乙二醇为PEG400。
(8)如上述(1)~(7)中任一项所述的药物组合物,其中,在所述药物组合物中,聚乙二醇的含量为70~99.99%(w/w)。
(9)如上述(1)~(8)中任一项所述的药物组合物,其中,上述式(1)表示的化合物或其盐的含量为0.01~20%(w/v)。
(10)如上述(1)~(9)中任一项所述的药物组合物,其用于预防或治疗眼部疾病。
(11)如上述(10)所述的药物组合物,其中,眼部疾病为老年性黄斑变性、糖尿病性视网膜病、早产儿视网膜病、视网膜静脉阻塞、视网膜动脉阻塞、息肉状脉络膜血管病变、视网膜血管瘤样增生、近视性脉络膜新生血管、糖尿病性黄斑水肿、眼肿瘤、放射性视网膜病变(radiationretinopathy)、虹膜红变(irisrubeosis)、新生血管性青光眼或增生性玻璃体视网膜病变(PVR)。
(12)如上述(10)或(11)所述的药物组合物,其用于玻璃体内给予。
(13)如上述(12)所述的药物组合物,所述药物组合物每1次给予1~100μL。
(14)如上述(12)或(13)所述的药物组合物,所述药物组合物以1周1次~3年1次的间隔给予。
(15)一种将上述式(1)表示的化合物或其盐稳定化的方法,所述方法是通过将上述式(1)表示的化合物或其盐溶解在聚乙二醇中而进行的。
(16)如上述(15)所述的方法,其中,上述式(1)表示的化合物为2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺。
本发明还涉及以下方案。
(17)如上述(15)所述的方法,其中,上述式(1)中,
R1表示C1-6烷氧基或被1个或多个卤素原子取代的C1-6烷氧基;
R2表示C1-6烷基羰基或被1个或多个羟基取代的C1-6烷基羰基。
(18)如上述(15)所述的药物组合物,其中,上述式(1)中,
R1表示被1个或多个卤素原子取代的C1-6烷氧基;
R2表示被1个或多个羟基取代的C1-6烷基羰基。
(19)如上述(1)~(16)中任一项所述的药物组合物,所述药物组合物用于长期保存。
(20)如上述(1)~(16)中任一项所述的药物组合物,所述药物组合物用于持续释放。
需要说明的是,对于上述(1)~(20)的各构成,可任意选择两个以上进行组合。
通过本发明,可提供一种使药物组合物中的本化合物长期保持稳定的药物组合物。另外,本发明的药物组合物具有持续释放出本化合物的性质,对脉络膜视网膜血管通透性增高模型长期有效,因此,其作为老年性黄斑变性、糖尿病性视网膜病、早产儿视网膜病、视网膜静脉阻塞、视网膜动脉阻塞、息肉状脉络膜血管病变、视网膜血管瘤样增生、近视性脉络膜新生血管、糖尿病性黄斑水肿、眼肿瘤、放射性视网膜病变(radiationretinopathy)、虹膜红变、新生血管性青光眼、增生性玻璃体视网膜病变(PVR)等的预防或治疗剂是有用的。进而,本发明的药物组合物作为药品具有充分的安全性。
具体实施方式
以下,对本发明进行详细说明。
本发明的药物组合物含有上述式(1)表示的化合物或其盐(本化合物)。
“卤素原子”表示氟、氯、溴或碘。
“C1-6烷基”表示碳原子数为1~6个的直链或支链烷基,优选碳原子数为1~4个的直链或支链烷基。作为具体例,可举出甲基、乙基、正丙基、正丁基、正戊基、正己基、异丙基、异丁基、仲丁基、叔丁基、异戊基等。
“C1-6烷氧基”表示羟基的氢原子被上述C1-6烷基取代而成的基团。作为具体例,可举出甲氧基、乙氧基、正丙氧基、正丁氧基、正戊氧基、正己氧基、异丙氧基、异丁氧基、仲丁氧基、叔丁氧基、异戊氧基等。
“C1-6烷基羰基”表示甲酰基的氢原子被上述C1-6烷基取代而成的基团。作为具体例,可举出甲基羰基(乙酰基)、乙基羰基、正丙基羰基、正丁基羰基、正戊基羰基、正己基羰基、异丙基羰基、异丁基羰基、仲丁基羰基、叔丁基羰基、异戊基羰基等。
本发明中所述的“被1个或多个卤素原子取代”,是表示上述C1-6烷基被个数为1个以上、可取代数以下的卤素原子取代。各个卤素原子可以相同也可以不同,卤素原子的个数优选为2个或3个,特别优选为3个。
本发明中所述的“被1个或多个羟基取代”,是表示上述C1-6烷基被个数为1个以上、可取代数以下的羟基取代。羟基的个数优选为1个或2个,特别优选为1个。
另外,本发明中的本化合物还包括酯、酰胺等衍生物。作为酯的具体例,可例举本化合物中的羟基与乙酸、丙酸、异丙酸、丁酸、异丁酸、特戊酸等羧酸缩合而成的酯。作为酰胺的具体例,可例举本化合物中的氨基与乙酸、丙酸、异丙酸、丁酸、异丁酸、特戊酸等羧酸缩合而成的酰胺。
另外,本化合物可以为水合物或溶剂化物的形态。
当本化合物存在几何异构体、互变异构体或光学异构体时,这些异构体也包括在本发明的范围之内。
进而,当本化合物存在多晶型时,多晶型物也包括在本发明的范围之内。
(a)作为式(1)表示的化合物的优选例,可举出式(1)中各基团为下述所示的基团的化合物或其盐。
(a1)R1表示C1-6烷氧基或被1个或多个卤素原子取代的C1-6烷氧基;及/或
(a2)R2表示C1-6烷基羰基或被1个或多个羟基取代的C1-6烷基羰基。
即,式(1)表示的化合物中,可举出由选自上述(a1)及(a2)中的1项或2项以上的各组合形成的化合物或其盐作为优选例。
(b)作为式(1)表示的化合物的更优选的例子,可举出式(1)中各基团为下述所示的基团的化合物或其盐。
(b1)R1表示被1个或多个卤素原子取代的C1-6烷氧基;及/或
(b2)R2表示被1个或多个羟基取代的C1-6烷基羰基。
即,式(1)表示的化合物中,可举出由选自上述(b1)及(b2)中的1项或2项以上的各组合形成的化合物或其盐作为优选例。另外,所选择的条件也可与(a)的条件组合。
(c)作为式(1)表示的化合物的最优选的例子,可举出式(2)表示的化合物(2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺)或其盐。
本发明的药物组合物中含有的式(1)表示的化合物或其盐可按照美国专利申请公开第2007/0149574号说明书中记载的方法等本技术领域中的通常方法进行制造。
即使在本发明的药物组合物中使用下述酪氨酸激酶抑制剂来代替式(1)表示的化合物,也能够得到本发明的效果,所述酪氨酸激酶抑制剂选自由他菲替尼(Tafetinib)、SIM-817378、ACTB-1003、西奥罗尼(Chiauranib)、CT-53608、肉桂(Cinnamon)、chim4G8-SDIE、CEP-5214、IMC-1C11、CEP-7055、3-[5-[2-[N-(2-甲氧基乙基)-N-甲基氨基]乙氧基]-1H-吲哚-2-基]喹啉-2(1H)-酮、hF4-3C5、ZK-CDK、IMC-EB10、LS-104、CYC-116、OSI-930、PF-337210、JNJ-26483327、SSR-106462、R-1530、PRS-050、TG-02、SC-71710、SB-1578、AMG-191、AMG-820、索凡替尼(Sulfatinib)、德立替尼盐酸盐(Lucitanibhydrochloride)、JNJ-28312141、依洛赛替(Ilorasertib)、PLX-5622、ARRY-382、TAS-115、Tanibirumab、海那替尼(Henatinib)、LY-2457546、PLX-7486、FPA-008、NVP-AEE-788、cgi-1842、RAF-265、MK-2461、SG-00529、Rebastinib、Golvatinib、Roniciclib、BVT-II、X-82、XV-615、KD-020、来他替尼(Lestaurtinib)、飞燕草素(Delphinidin)、司马沙尼(Semaxanib)、瓦他拉尼(Vatalanib)、OSI-632、替拉替尼(Telatinib)、培化阿珠单抗(Alacizumabpegol)、ATN-224、Tivozanib、XL-999、Icrucumab、Foretinib、Crenolanibbesylate、R-406、布立尼布(Brivanib)、Pegdinetanib、TG-100572、Olaratumab、福他替尼二钠(Fostamatinibdisodium)、BMS-690514、AT-9283、MGCD-265、奎扎替尼(Quizartinib)、ENMD-981693、法米替尼(Famitinib)、厄洛替尼(Anlotinib)、Tovetumab、PLX-3397、呋喹替尼(Fruquintinib)、(-)-表没食子儿茶素((-)-Epigallocatechin)、米哚妥林(Midostaurin)、NSC-706456、Orantinib、西地尼布(Cediranib)、多韦替尼(Dovitinib)、XL-647、莫特塞尼(Motesanib)、利尼伐尼(Linifanib)、Brivanib、西地尼布(Cediranib)、阿帕替尼(Apatinib)、Fedratinib、帕克替尼(Pacritinib)、Ramucirumab、尼达尼布(Intedanib)、马赛替尼(Masitinib)、榄香烯(Elemene)、二氢青蒿素(Dihydroartemisinin)、WS-1442、伊曲康唑(Itraconazole)、来氟米特(Leflunomide)、二氢青蒿素(Dihydroartemisinin)、伊马替尼(Imatinib)、索拉非尼(Sorafenib)、舒尼替尼(Sunitinib)、达沙替尼(Dasatinib)、帕唑帕尼(Pazopanib)、凡德他尼(Vandetanib)、阿西替尼(Axitinib)、瑞格非尼(Regorafenib)、卡博替尼(Cabozantinib)及普纳替尼(Ponatinib)组成的组。即,本发明可提供一种使药物组合物中的上述酪氨酸激酶抑制剂长期保持稳定的药物组合物。进而,该药物组合物具有持续释放出酪氨酸激酶抑制剂的性质,其对脉络膜视网膜血管通透性增高模型长期有效,作为老年性黄斑变性、糖尿病性视网膜病、早产儿视网膜病、视网膜静脉阻塞、视网膜动脉阻塞、息肉状脉络膜血管病变、视网膜血管瘤样增生、近视性脉络膜新生血管、糖尿病性黄斑水肿、眼肿瘤、放射性视网膜病变(radiationretinopathy)、虹膜红变、新生血管性青光眼、增生性玻璃体视网膜病变(PVR)等的预防或治疗剂是有用的。进而,该药物组合物作为药品具有充分的安全性。
本发明的药物组合物中,式(1)表示的化合物的盐只要是药物中容许的盐即可,没有特别限制,作为盐,可举出与无机酸形成的盐、与有机酸形成的盐、季铵盐、与卤素离子形成的盐、与碱金属形成的盐、与碱土金属形成的盐、金属盐、与有机胺形成的盐等。作为与无机酸形成的盐,可举出与盐酸、氢溴酸、氢碘酸、硝酸、硫酸、磷酸等形成的盐。作为与有机酸形成的盐,可举出与乙酸、草酸、富马酸、马来酸、琥珀酸、苹果酸、柠檬酸、酒石酸、己二酸、葡糖酸、葡庚糖酸、葡糖醛酸、对苯二甲酸、甲磺酸、丙氨酸、乳酸、马尿酸、1,2-乙二磺酸、羟乙基磺酸、乳糖酸、油酸、没食子酸、帕莫酸、多聚半乳糖醛酸(polygalacturonicacid)、硬脂酸、单宁酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、硫酸月桂酯、硫酸甲酯、萘磺酸、磺基水杨酸等形成的盐。作为季铵盐,可举出与溴甲烷、碘甲烷等形成的盐。作为与卤素离子形成的盐,可举出与氯化物离子、溴化物离子、碘化物离子等形成的盐,作为与碱金属形成的盐,可举出与锂、钠、钾等形成的盐,作为与碱土金属形成的盐,可举出与钙、镁等形成的盐,作为金属盐,可举出与铁、锌等形成的盐。作为与有机胺形成的盐,可举出与三乙烯二胺(triethylenediamine)、2-氨基乙醇、2,2-亚氨基双(乙醇)、1-脱氧-1-(甲氨基)-2-D-山梨糖醇、2-氨基-2-(羟基甲基)-1,3-丙二醇、普鲁卡因、N,N-双(苯基甲基)-1,2-乙二胺等形成的盐。
本发明的药物组合物中,式(1)表示的化合物或其盐的浓度只要是足以获得所期望的药效的浓度即可,没有特别限制,优选为0.01~20%(w/v)、更优选为0.1~15%(w/v)、进一步优选为0.5~12%(w/v)、更进一步优选为1~10%(w/v)、特别优选为1~8%(w/v)、最优选为1%(w/v)、1.5%(w/v)、2%(w/v)、2.5%(w/v)、3%(w/v)、3.5%(w/v)、4%(w/v)、5%(w/v)、6%(w/v)、7%(w/v)或8%(w/v)。
本发明的药物组合物中含有的聚乙二醇(PEG)是乙二醇聚合而成的聚醚,用化学式HO(CH2CH2O)nH表示,n为聚合数。聚乙二醇(PEG)可使用市售的聚乙二醇(PEG),也可使用按照本技术领域中的通常方法所制造的聚乙二醇(PEG)。
本发明的药物组合物中,聚乙二醇的平均分子量优选为100~2000、更优选为100~1000、进一步优选为100~800、还进一步优选为200~600、更进一步优选为400~600、特别优选为400及600、最优选为400。作为聚乙二醇的具体例,可举出PEG100、PEG200、PEG300、PEG400、PEG600、PEG800等。
本发明的药物组合物中,聚乙二醇的含量优选为70~99.99%(w/w)、更优选为80~99.9%(w/w)、进一步优选为90~99.5%(w/w)、特别优选为92~99.3%(w/w)、最优选为93~99%(w/w)。
本发明的药物组合物中,根据需要可使用添加剂,作为添加剂,可添加表面活性剂、缓冲剂、等渗剂、稳定剂、防腐剂、抗氧化剂、高分子量聚合物等。
可以在本发明的药物组合物中配合能够用作药品添加物的表面活性剂,例如阳离子表面活性剂、阴离子表面活性剂、非离子表面活性剂。作为阴离子表面活性剂的例子,可举出磷脂等,作为磷脂,可举出卵磷脂等。作为阳离子表面活性剂的例子,可举出烷基胺盐、烷基胺聚氧乙烯加成物、脂肪酸三乙醇胺单酯盐、酰基氨基乙基二乙基胺盐、脂肪酸多胺缩合物、烷基三甲基铵盐、二烷基二甲基铵盐、烷基二甲基苄基铵盐、烷基吡啶鎓盐、酰基氨基烷基型铵盐、酰基氨基烷基吡啶鎓盐、二酰氧基乙基铵盐、烷基咪唑啉、1-酰基氨基乙基-2-烷基咪唑啉、1-羟基乙基-2-烷基咪唑啉等。作为烷基二甲基苄基铵盐,可举出苯扎氯铵、西他氯铵等。作为非离子表面活性剂的例子,可举出聚氧乙烯脂肪酸酯、聚氧乙烯山梨糖醇酐脂肪酸酯、聚氧乙烯氢化蓖麻油、聚氧乙烯蓖麻油、聚氧乙烯聚氧丙烯二醇、蔗糖脂肪酸酯、维生素ETPGS等。
作为聚氧乙烯脂肪酸酯,可举出聚乙二醇(40)硬脂酸酯等。
作为聚氧乙烯山梨糖醇酐脂肪酸酯,可举出聚山梨醇酯80(polysorbate80)、聚山梨醇酯60(polysorbate60)、聚山梨醇酯40(polysorbate40)、聚氧乙烯山梨糖醇酐单月桂酸酯、聚氧乙烯山梨糖醇酐三油酸酯、聚山梨醇酯65(polysorbate65)等。
作为聚氧乙烯氢化蓖麻油,可使用氧化乙烯的聚合数不同的各种聚氧乙烯氢化蓖麻油,氧化乙烯的聚合数优选为10~100、更优选为20~80、特别优选为40~70、最优选为60。作为聚氧乙烯氢化蓖麻油的具体例,可举出聚氧乙烯(10)氢化蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(50)氢化蓖麻油、聚氧乙烯(60)氢化蓖麻油等。
作为聚氧乙烯蓖麻油,可使用氧化乙烯的聚合数不同的各种聚氧乙烯蓖麻油,氧化乙烯的聚合数优选为5~100、更优选为20~50、特别优选为30~40、最优选为35。作为聚氧乙烯蓖麻油的具体例,可举出聚氧乙烯(5)蓖麻油、聚氧乙烯(9)蓖麻油、聚氧乙烯(15)蓖麻油、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)蓖麻油等。
作为聚氧乙烯聚氧丙烯二醇,可举出聚氧乙烯(160)聚氧丙烯(30)二醇、聚氧乙烯(42)聚氧丙烯(67)二醇、聚氧乙烯(54)聚氧丙烯(39)二醇、聚氧乙烯(196)聚氧丙烯(67)二醇、聚氧乙烯(20)聚氧丙烯(20)二醇等。
作为蔗糖脂肪酸酯,可举出聚氧乙烯(40)硬脂酸酯等。
维生素ETPGS也称为生育酚聚乙二醇(1000)琥珀酸酯。
可以在本发明的药物组合物中配合能够用作药品添加物的缓冲剂。作为缓冲剂的例子,可举出磷酸或其盐、硼酸或其盐、柠檬酸或其盐、乙酸或其盐、碳酸或其盐、酒石酸或其盐、ε-氨基己酸、氨基丁三醇(trometamol)等。作为磷酸盐,可举出磷酸钠、磷酸二氢钠、磷酸氢二钠、磷酸钾、磷酸二氢钾、磷酸氢二钾等,作为硼酸盐,可举出硼砂、硼酸钠、硼酸钾等,作为柠檬酸盐,可举出柠檬酸钠、柠檬酸二钠等,作为乙酸盐,可举出乙酸钠、乙酸钾等,作为碳酸盐,可举出碳酸钠、碳酸氢钠等,作为酒石酸盐,可举出酒石酸钠、酒石酸钾等。
可以在本发明的药物组合物中适当配合能够用作药品添加物的等渗剂。作为等渗剂的例子,可举出离子性等渗剂、非离子性等渗剂等。作为离子性等渗剂,可举出氯化钠、氯化钾、氯化钙、氯化镁等,作为非离子性等渗剂,可举出甘油、丙二醇、山梨糖醇、甘露糖醇等。
可以在本发明的药物组合物中适当配合能够用作药品添加物的稳定剂。作为稳定剂的例子,可举出乙二胺四乙酸、乙二胺四乙酸钠、柠檬酸钠等。
可以在本发明的药物组合物中适当配合能够用作药品添加物的防腐剂。作为防腐剂的例子,可举出苯扎氯铵、苯扎溴铵、苄索氯铵、山梨酸、山梨酸钾、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯丁醇等。
可以在本发明的药物组合物中适当配合能够用作药品添加物的抗氧化剂。作为抗氧化剂的例子,可举出抗坏血酸、生育酚、二丁基羟基甲苯、丁基羟基苯甲醚、异抗坏血酸钠、没食子酸丙酯、亚硫酸钠等。
可以在本发明的药物组合物中适当配合能够用作药品添加物的高分子量聚合物。作为高分子量聚合物的例子,可举出甲基纤维素、乙基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素、羟乙基甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、醋酸羟丙基甲基纤维素琥珀酸酯(hydroxypropylmethylcelluloseacetatesuccinate)、羟丙基甲基纤维素邻苯二甲酸酯、羧甲基乙基纤维素、邻苯二甲酸乙酸纤维素、聚乙烯吡咯烷酮、聚乙烯醇、羧基乙烯基聚合物、聚乙二醇等。
在本发明的药物组合物中配合添加剂时的添加剂的浓度可根据添加剂的种类等适当调整,作为其总量,优选为0.0001~20%(w/v)、更优选为0.001~10%(w/v)、进一步优选为0.01~8%(w/v)、特别优选为0.1~5%(w/v)、最优选为1~3%(w/v)。
可以在本发明的药物组合物中适当配合能够用作药品添加物的溶剂。作为溶剂的例子,可举出二甲基亚砜、N-甲基吡咯烷酮、N,N-二甲基乙酰胺、乙醇等。
在本发明的药物组合物中配合溶剂时的溶剂的浓度可根据溶剂的种类等适当调整,作为其总量,优选为0.1~30%(w/v)、更优选为1~20%(w/v)、进一步优选为1.5~15%(w/v)、特别优选为2~10%(w/v)、最优选为3~7%(w/v)。
本发明的药物组合物中,优选实质上仅含有式(1)表示的化合物或其盐及聚乙二醇的药物组合物。该情况下,式(1)表示的化合物或其盐的浓度优选为0.01~20%(w/v)、更优选为0.1~15%(w/v)、进一步优选为0.5~12%(w/v)、更进一步优选为1~10%(w/v)、特别优选为1~8%(w/v)、最优选为1%(w/v)、1.5%(w/v)、2%(w/v)、2.5%(w/v)、3%(w/v)、3.5%(w/v)、4%(w/v)、5%(w/v)、6%(w/v)、7%(w/v)或8%(w/v)。
本发明的药物组合物可口服给予也可非口服给予。对于本发明的药物组合物的剂型,只要是能够用作药品的剂型即可,没有特别限制。作为剂型,例如,如果是口服制剂,则可举出溶液剂、悬浮剂、片剂、胶囊剂、颗粒剂、散剂,如果是非口服制剂,则可举出注射剂、输液、滴鼻剂、滴耳剂、滴眼剂等。可优选举出眼科用注射剂、滴眼剂,可更优选举出眼科用注射剂,可最优选举出玻璃体内给予用注射剂。上述剂型可按照本技术领域中的通常方法进行制造。
本发明的药物组合物可根据其剂型而适当给予。例如在眼科用注射剂的情况下,可向玻璃体内、后巩膜附近、眼窝周围、巩膜与结膜之间给予。例如,在向玻璃体内给予眼科用注射剂时,只要是足以获得所期望的药效的量即可,对给予量没有特别限制,优选每1次给予1~100μL、更优选5~50μL、进一步优选10~30μL、最优选10μL、20μL或30μL。对于本化合物的给予量,优选0.001~30mg/eye、更优选0.01~10mg/eye、进一步优选0.1~5mg/eye、特别优选0.2~1.6mg/eye、最优选0.2mg/eye、0.3mg/eye、0.4mg/eye、0.5mg/eye、0.6mg/eye、0.7mg/eye、0.8mg/eye、1mg/eye、1.2mg/eye、1.4mg/eye或1.6mg/eye。
在向玻璃体内连续给予本发明的药物组合物时,只要足以获得所期望的药效即可,对给予间隔没有特别限制,优选以1周1次~3年1次的间隔进行给予,更优选以1周1次、2周1次、1个月1次、2个月1次、3个月1次、4个月1次、5个月1次、6个月1次、1年1次、2年1次或3年1次的间隔进行给予,最优选以2个月1次、3个月1次、4个月1次、5个月1次或6个月1次的间隔进行给予。另外,给予间隔可适当变更。
本发明的组合物作为药物是有用的,可用作老年性黄斑变性、糖尿病性视网膜病、早产儿视网膜病、视网膜静脉阻塞、视网膜动脉阻塞、息肉状脉络膜血管病变、视网膜血管瘤样增生、近视性脉络膜新生血管、糖尿病性黄斑水肿、眼肿瘤、放射性视网膜病变(radiationretinopathy)、虹膜红变、新生血管性青光眼、增生性玻璃体视网膜病变(PVR)等的预防或治疗剂。
以下,示出制剂例及试验结果,但它们是为了更好地理解本发明而示出的,并不限定本发明的范围。
制剂例
以下,示出使用了本化合物的代表性的制剂例。需要说明的是,在下述制剂例中各成分的配合量为100mL组合物中的含量。
制剂例1
本化合物0.01~20g
PEG400适量
制剂例2
本化合物0.01~20g
二甲基亚砜0.1~30g
PEG400适量
制剂例3
本化合物0.01~20g
聚山梨醇酯200.0001~20g
PEG400适量
制剂例4
本化合物0.01~20g
聚氧乙烯(60)氢化蓖麻油0.0001~20g
PEG400适量
制剂例5
本化合物0.01~20g
聚氧乙烯(35)蓖麻油0.0001~20g
PEG400适量
需要说明的是,可对上述制剂例1~5中的本化合物、聚乙二醇、添加剂、溶剂的种类、配合量进行适当调整而得到所期望的组合物。
1.稳定性评价试验(1)
研究了本发明的药物组合物的稳定性。
1-1.受试制剂的制备
向0.10g上述式(2)表示的化合物(2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺,以下也称为化合物A;按照美国专利申请公开第2007/0149574号说明书记载的方法制备)中适量添加聚乙二醇400(NACALAITESQUE,INC.),使总量成为10mL,进行搅拌溶解,制备实施例1的制剂。
利用与实施例1的制备方法同样的方法,制备表1所示的实施例2~4的制剂。聚乙二醇使用NACALAITESQUE,INC.的产品。
1-2.试验方法
在3mL的小玻璃瓶(glassvial)(Wheaton)中填充0.4mL受试制剂,使用高效液相色谱(HPLC)对在40℃及60℃下分别保存3个月及4周后的2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺的含量进行定量,计算出其残存率(%)。
1-3.试验结果及考察
试验结果示于表1。
[表1]
由表1可知,实施例1~4的制剂于40℃保存3个月以及于60℃保存4周后,可维持高残存率。尤其是在使用了聚乙二醇400或聚乙二醇600的情况下,显示出高残存率。由以上结果确认了本发明的组合物具有优异的稳定性。
2.稳定性评价试验(2)
研究了本发明的药物组合物的稳定性。
2-1.受试制剂的制备
向0.6g及12g的化合物A中适量添加聚乙二醇400(日油株式会社),使总量成为240mL,进行搅拌溶解,制备实施例5及6的制剂。
2-2.试验方法
在3mL的小玻璃瓶(Wheaton)中填充2mL受试制剂,使用高效液相色谱(HPLC)对在25℃下分别保存3个月后的2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺的含量进行定量,计算出其残存率(%)。
2-3.试验结果及考察
试验结果示于表2。
[表2]
由表2可知,实施例5及6的制剂于25℃保存3个月后,维持了高残存率。由以上结果确认了本发明的组合物具有优异的稳定性。
3.稳定性评价试验(3)
研究了含有二甲基亚砜、非离子表面活性剂的本发明的组合物的稳定性。
3-1.受试制剂的制备
表3所示的实施例7是向0.75g化合物A中添加1.50g二甲基亚砜和32.11g聚乙二醇400并进行搅拌溶解而得的制剂。另外,利用与实施例1的制备方法同样的方法,制备表3所示的实施例8及9的制剂。聚乙二醇400使用日油株式会社的产品,二甲基亚砜使用NACALAITESQUE,INC.的产品,聚山梨醇酯20使用NikkoChemicalsCo.,Ltd.的产品,聚氧乙烯(35)蓖麻油使用BASF的产品。
3-2.试验方法
在2mL的小玻璃瓶(盐谷硝子株式会社)中填充0.4mL受试制剂,使用高效液相色谱(HPLC)对在60℃下保存4周后的2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺的含量进行定量,计算出其残存率(%)。
3-3.试验结果及考察
试验结果示于表3。
[表3]
由表3可知,实施例7~9的制剂于60℃保存4周后,维持了高残存率。由以上结果确认了本发明的组合物即使添加二甲基亚砜、非离子性表面活性剂也具有优异的稳定性。
4.动态试验
研究了向玻璃体内给予本发明的组合物后的动态。
4-1.受试制剂的制备
向100.5mg化合物A中添加1.8mL聚乙二醇400(NACALAITESQUE,INC.),进行搅拌,确认溶解后,适量添加聚乙二醇400从而使总量成为2.0mL,制备实施例10的制剂。
向50.4mg化合物A中,添加1.8mL聚乙二醇400(NACALAITESQUE,INC.),进行搅拌,确认溶解后,适量添加聚乙二醇400从而使总量成为2.0mL,制备实施例11的制剂。
向2.5g浓甘油(花王株式会社)、1.0g聚山梨醇酯80(三洋化成工业株式会社)、12g磷酸氢钠水合物(太平化学产业株式会社)、1.2g磷酸二氢钠(太平化学产业株式会社)、0.005g羟丙甲纤维素(hypromellose,信越化学工业株式会社)中添加注射用水(大冢制药株式会社)约400mL,进行搅拌溶解。进一步添加注射用水从而使总量成为500mL,将所得物作为悬浮液基剂。向75.3mg本化合物A中添加5.0mL悬浮液基剂,进行搅拌悬浮,制备比较例1的制剂。
4-2.试验方法
将受试制剂注入到日本大耳白兔的眼睛的玻璃体中。此时,注入的溶液相对于周围介质形成团。注入4、8、12或28周后,按照标准步骤将兔安乐死。
摘出眼球后,分离玻璃体,将其放入到已装有2个氧化锆珠(5mm)的50mL管(tube)(皮重已知)中。测定管的重量后,放入甲醇,利用ShakeMasterAuto将组织均化(1,100rpm、10分钟)。离心(3,000rpm、室温、10分钟)分离后,将上清液作为玻璃体基质试样。在使用前将制备的玻璃体基质试样在超低温冷柜中冷冻保存(设定温度:-80℃)。
提取玻璃体后,用生理盐水洗涤视网膜表面。采集视神经乳头附近的脉络膜视网膜,将其放入到装有0.5mL含有10mg/mL氟化钠的2%甲酸及2个氧化锆珠(3mm)的2mL管(皮重已知)中。测定装有脉络膜视网膜的管的重量。利用ShakeMasterAuto进行均化(1,100rpm、10分钟),然后添加0.5mL甲醇并进行搅拌。进行离心(11,000rpm、4℃、10分钟),将上清液作为脉络膜视网膜基质试样。在使用前将其在超低温冷柜中冷冻保存(设定温度:-80℃)。
使用内标,利用高效液相色谱/串联质谱仪(HPLC/MS/MS),确定玻璃体内及用氟化钠进行了抗分解处理后的脉络膜视网膜组织中的化合物A的含量。以在玻璃体部分包含玻璃体内观察到的团的状态进行分析。
需要说明的是,将在各时间点由各兔眼得到的化合物A的残存率或浓度分别相加,然后除以分析的眼睛的总数,从而计算出化合物A的平均残存率或浓度。该实验中,在各时间点示出2只兔的眼睛的平均值(在各时间点为3或4只眼)。
玻璃体中的化合物A的残存率通过下述方式进行计算:测定化合物A的浓度后,将浓度值乘以玻璃体重量,然后除以化合物A的给予量。该测定值表示给予后采集组织时间时的包含团的玻璃体中的化合物A的残存量。
脉络膜视网膜中的浓度通过下述方式进行计算:计算出测定的化合物A的量后,用其除以分析中使用的脉络膜视网膜的量。该测定值表示由玻璃体组织送达至脉络膜视网膜的化合物A的浓度。
4-3.试验结果及考察
将在注入4周后、8周后、12周后及28周后的玻璃体内存在的化合物A的残存率(%)及注入4周后的脉络膜视网膜中的化合物A的浓度(μg/g)示于表4。
[表4]
由表4可知,与比较例1的制剂相比,实施例10及11的制剂显示出足够高的玻璃体内残存率及脉络膜视网膜浓度。由以上结果确认了本发明的组合物在向玻璃体内给予时具有优异的持续释放性。
5.药理试验
使用VEGF诱发兔视网膜血管通透性增高模型,评价化合物A的聚乙二醇400制剂的有用性。需要说明的是,已有通过在玻璃体内给予VEGF而使脉络膜视网膜的血管通透性增高的报道(InvestOphthalmolVisSci.2013;54(1):503-11.),VEGF已被广泛用于伴有视网膜/脉络膜血管异常的病症(例如,糖尿病性视网膜病、糖尿病性黄斑水肿、视网膜静脉阻塞、视网膜动脉阻塞、渗出型老年黄斑变性等)的制作。
5-1.受试制剂的制备
向1.5g本化合物A中添加12mL聚乙二醇400(日油株式会社),进行搅拌,确认溶解后,适量添加聚乙二醇400,使总量成为15mL。
5-2.试验方法
(药物给予方法)
对兔肌内给予5%氯胺酮注射液及2%赛拉嗪注射液的混合液(7:1)1mL/kg进行全身麻醉,向眼中滴加0.5%托品酰胺-0.5%盐酸苯福林滴眼液进行散瞳。然后,使用27G针,以不损伤晶状体以及视网膜的方式向玻璃体内注入5μL化合物A溶液(=0.5mg/eye)。需要说明的是,按照同样方式向基剂给予组的兔给予聚乙二醇400。
(VEGF诱发兔视网膜血管通透性增高模型制作方法)
给予药物2个月后,对兔肌内给予5%氯胺酮注射液及2%赛拉嗪注射液的混合液(7:1)1mL/kg进行全身麻醉,向眼中滴加0.5%托品酰胺-0.5%盐酸苯福林滴眼液进行散瞳。然后,使用27G针,以不损伤晶状体以及视网膜的方式向玻璃体内注入10μL的VEGF(50μg/mL)。需要说明的是,按照同样方式向正常组的兔给予PBS(磷酸缓冲液)以代替VEGF。
(评价方法)
给予VEGF2天后,向兔静脉内给予0.1mL/kg的10%荧光素(fluorescein)溶液。给予荧光素2小时后,利用荧光光度测定法测定玻璃体中的荧光素浓度,将其作为视网膜血管通透性的指标。
然后,按照式1,计算出所给予的药物对VEGF引起的视网膜血管通透性增高的抑制率(%)。将结果示于表5。需要说明的是,各组的例数为8,将其平均值用于计算抑制率。
[式1]视网膜血管通透性抑制率(%)=(AY-AZ)/(AY-AX)×100
AX:基剂(=聚乙二醇400)给予+PBS给予组的玻璃体中荧光素浓度
AY:基剂(=聚乙二醇400)给予+VEGF给予组的玻璃体中荧光素浓度
AZ:化合物A给予+VEGF给予组的玻璃体中荧光素浓度
[表5]
受试物质 | 抑制率(%) |
化合物0.5mg/eye | 95.3 |
由以上结果可以确认,化合物A的聚乙二醇400制剂即使在向玻璃体内给予2个月后也对VEGF诱发的视网膜血管通透性增高有优异的抑制效果。由此表明本发明的组合物对糖尿病性视网膜病、糖尿病性黄斑水肿、视网膜静脉阻塞、视网膜动脉阻塞、渗出型老年黄斑变性等与视网膜/脉络膜血管异常相关的眼后段疾病长期持续地具有显著的效果。
Claims (16)
1.一种药物组合物,其含有式(1)表示的化合物或其盐及聚乙二醇,
式中,
R1表示氢原子、卤素原子、羟基、C1-6烷基、被1个或多个卤素原子取代的C1-6烷基、C1-6烷氧基或被1个或多个卤素原子取代的C1-6烷氧基;
R2表示氢原子、C1-6烷基、C1-6烷基羰基或被1个或多个羟基取代的C1-6烷基羰基。
2.如权利要求1所述的药物组合物,其中,式(1)中,
R1表示C1-6烷氧基或被1个或多个卤素原子取代的C1-6烷氧基;
R2表示C1-6烷基羰基或被1个或多个羟基取代的C1-6烷基羰基。
3.如权利要求1所述的药物组合物,其中,式(1)中,
R1表示被1个或多个卤素原子取代的C1-6烷氧基;
R2表示被1个或多个羟基取代的C1-6烷基羰基。
4.如权利要求1所述的药物组合物,其中,式(1)表示的化合物为2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺。
5.如权利要求1~4中任一项所述的药物组合物,其中,聚乙二醇的平均分子量在100~2000的范围内。
6.如权利要求1~4中任一项所述的药物组合物,其中,聚乙二醇的平均分子量在200~600的范围内。
7.如权利要求1~4中任一项所述的药物组合物,其中,聚乙二醇为PEG400。
8.如权利要求1~7中任一项所述的药物组合物,其中,在所述药物组合物中,聚乙二醇的含量为70~99.99%(w/w)。
9.如权利要求1~8中任一项所述的药物组合物,其中,式(1)表示的化合物或其盐的含量为0.01~20%(w/v)。
10.如权利要求1~9中任一项所述的药物组合物,其用于预防或治疗眼部疾病。
11.如权利要求10所述的药物组合物,其中,眼部疾病为老年性黄斑变性、糖尿病性视网膜病、早产儿视网膜病、视网膜静脉阻塞、视网膜动脉阻塞、息肉状脉络膜血管病变、视网膜血管瘤样增生、近视性脉络膜新生血管、糖尿病性黄斑水肿、眼肿瘤、放射性视网膜病变(radiationretinopathy)、虹膜红变、新生血管性青光眼或增生性玻璃体视网膜病变(PVR)。
12.如权利要求10或11所述的药物组合物,其用于玻璃体内给予。
13.如权利要求12所述的药物组合物,所述药物组合物每1次给予1~100μL。
14.如权利要求12或13所述的药物组合物,所述药物组合物以1周1次~3年1次的间隔给予。
15.一种将式(1)表示的化合物或其盐稳定化的方法,所述方法是通过将式(1)表示的化合物或其盐溶解在聚乙二醇中而进行的。
16.如权利要求15所述的方法,其中,式(1)表示的化合物为2-[[[2-[(羟基乙酰基)氨基]-4-吡啶基]甲基]硫基]-N-[4-(三氟甲氧基)苯基]-3-吡啶甲酰胺。
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2014
- 2014-09-18 US US15/023,207 patent/US20160228420A1/en not_active Abandoned
- 2014-09-18 JP JP2014190339A patent/JP5856264B2/ja not_active Expired - Fee Related
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- 2014-09-18 CN CN201480051151.8A patent/CN105555271A/zh active Pending
- 2014-09-18 WO PCT/JP2014/074698 patent/WO2015041294A1/ja active Application Filing
- 2014-09-18 KR KR1020167008149A patent/KR20160060656A/ko not_active Application Discontinuation
- 2014-09-18 TW TW103132199A patent/TW201518291A/zh unknown
- 2014-09-18 MX MX2016003566A patent/MX2016003566A/es unknown
- 2014-09-18 EA EA201690621A patent/EA201690621A1/ru unknown
- 2014-09-18 MY MYPI2016000477A patent/MY163236A/en unknown
- 2014-09-18 SG SG11201602020QA patent/SG11201602020QA/en unknown
- 2014-09-18 AU AU2014322111A patent/AU2014322111A1/en not_active Abandoned
- 2014-09-18 EP EP14845745.0A patent/EP3047850A4/en active Pending
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2015
- 2015-12-10 JP JP2015240775A patent/JP2016094442A/ja active Pending
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2016
- 2016-03-09 PH PH12016500461A patent/PH12016500461A1/en unknown
- 2016-03-17 IL IL244648A patent/IL244648A0/en unknown
- 2016-07-21 HK HK16108793.4A patent/HK1220632A1/zh unknown
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US20160228420A1 (en) | 2016-08-11 |
CA2924628A1 (en) | 2015-03-26 |
JP2015083565A (ja) | 2015-04-30 |
HK1220632A1 (zh) | 2017-05-12 |
JP2016094442A (ja) | 2016-05-26 |
HK1221407A1 (zh) | 2017-06-02 |
WO2015041294A1 (ja) | 2015-03-26 |
SG11201602020QA (en) | 2016-04-28 |
IL244648A0 (en) | 2016-04-21 |
BR112016006153A2 (pt) | 2017-08-01 |
JP5856264B2 (ja) | 2016-02-09 |
AU2014322111A1 (en) | 2016-04-07 |
KR20160060656A (ko) | 2016-05-30 |
PH12016500461A1 (en) | 2016-05-16 |
EA201690621A1 (ru) | 2016-07-29 |
MX2016003566A (es) | 2016-06-02 |
TW201518291A (zh) | 2015-05-16 |
EP3047850A4 (en) | 2017-05-10 |
EP3047850A1 (en) | 2016-07-27 |
MY163236A (en) | 2017-08-30 |
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