CN107496426A - 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 - Google Patents
含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 Download PDFInfo
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Abstract
本申请涉及含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物。本发明涉及含有以往作为慢性髓性白血病的治疗剂使用的伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的药物组合物及利用上述组合物来治疗血管渗透性疾病的方法。本发明的用于治疗或预防血管渗透性疾病的药物组合物含有以往作为慢性髓性白血病的治疗剂使用的伊马替尼作为有效成分，提供了伊马替尼的新用途的同时，能够有效地治疗或预防血管渗透性疾病，因此，能够广泛应用于新的血管渗透性疾病的治疗剂的开发。
Description
本申请是申请日为2013年6月10日的申请号为201380032289.9(PCT申请号：PCT/KR2013/005068)、发明名称为“含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物”的分案申请。
技术领域
本发明涉及含有伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物，更具体地，本发明涉及含有以往作为慢性髓性白血病的治疗剂使用的伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的药物组合物及利用上述组合物来治疗血管渗透性疾病的方法。
背景技术
血管是构成人体的所有细胞的生存及正常功能的维持所必需的器官，特别是，构成血管的最内侧的血管内皮细胞由单层构成，形成用于调节血液内的蛋白质、流体及电解质渗漏到周边组织的细胞性屏障。这种血管内皮细胞之间的间隔在正常血管中很窄而血管的渗透性低，但当血管中浸润炎症细胞或因血管损伤导致低氧状态时，各种细胞因子及血管内皮细胞生长因子(vascular endothelial growth factor，VEGF)之类的生长因子的分泌会显著地增加。特别是，VEGF促进血管内皮细胞的增殖、生存及移动，以促进新生血管的生成，同时使血管内皮细胞间的间隔变得不稳定，以显著地提升血管渗透性。因此，通过VEGF过表达而形成的血管具有体液朝向周边组织的渗漏增加的特征。
过度的血管渗透性的增加会成为多种疾病的原因，特别是，视网膜(retina)或脉络膜(choroid)中的过度的血管渗透性增加会促进出血和黄斑水肿(macular edema)，从而作用为致命性的失明的最为常见的原因。作为具有这种发病机理的代表性的疾病有糖尿病性视网膜症(diabetic retinopathy，DR)、糖尿病性黄斑水肿(diabetic macular edema，DME)、老年性黄斑变性(age-related macular degeneration，AMD)、脉络膜新生血管(choroidal neovascularization)、早产儿视网膜病变(ROP：retinopathy ofprematurity)等。黄斑水肿在糖尿病患者中的轻微的糖尿病性视网膜症中以2～6％的频度、在中度糖尿病性视网膜症中以20～63％的频度及在严重的糖尿病性视网膜症中以70％以上的频度发生，一旦在黄斑部位上发生水肿，其中约50％的患者上会出现视力下降。为了预防这种基于糖尿病的严重的视力下降及损失，尝试有通过减少毛细管泄漏来治疗及抑制黄斑水肿的方法，报告了在抑制了用于增加血管渗透性的VEGF的活性的情况下，显示出抑制血管水肿的效果。这种抑制VEGF的活性的方法有：通过使用与VEGF直接结合的抗体(贝伐单抗(Bevacizumab)、兰尼单抗(Ranibizumab)等)来抑制VEGF受体的活性以减少血管渗透性的方法，通过使用用于诱导血管内皮细胞的紧密结合(tight juction)分子的向细胞内的内吞(endocytosis)的PKC(蛋白激酶C(protein kinase C))的抑制剂(鲁伯斯塔(ruboxistaurin)等)来抑制黄斑水肿的方法，同时抑制用于参与VEGF和VEGF受体的信号传递途径并增加视网膜血管渗透性的Src(可溶性酪氨酸激酶(soluble tyrosine kinase))和VEGF受体的方法等。但是，目前为止的大部分的关于血管新生及血管渗透性调节的研究仍局限于VEGF或VEGF受体，大部分集中于上述基因的抑制剂的开发，因此，关于血管新生及血管渗透性调节的研究处于欠缺的状况。
发明内容
本发明的发明人为了找到眼部疾病中的血管渗透性疾病的治疗物质而不断努力的结果，确认了以往作为慢性髓性白血病的治疗剂使用的伊马替尼(imatinib)或其药学上可接受的盐能够减少血管渗透性，从而可将伊马替尼或其药学上可接受的盐作为血管渗透性疾病的治疗剂使用，从而完成了本发明。
本发明的一个目的在于提供一种用于治疗或预防血管渗透性疾病的组合物，其中，含有伊马替尼或其药学上可接受的盐作为有效成分。
本发明的另一目的在于提供一种利用上述组合物来治疗血管渗透性疾病的方法。
本发明的用于治疗或预防血管渗透性疾病的药物组合物含有以往作为慢性髓性白血病的治疗剂使用的伊马替尼作为有效成分，提供了伊马替尼的新用途的同时，能够有效地治疗或预防血管渗透性疾病，因此，能够广泛应用于新的血管渗透性疾病的治疗剂的开发。
附图说明
图1是表示以诱导了作为血管渗透性增加疾病模型的糖尿病性视网膜症的大鼠为对象，确认了甲磺酸伊马替尼的治疗效果的结果的照片及图表，(A)是表示与甲磺酸伊马替尼的处理浓度对应的血管渗透性改善效果的照片，(B)是表示与甲磺酸伊马替尼的处理浓度对应的血管渗透性改善效果的图表。
具体实施方式
作为用于实现上述目的的一个实施方式，本发明提供一种含有伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的药物组合物。
本发明的发明人为了在眼部疾病中找到血管渗透性相关疾病的治疗物质而进行多种研究的过程中，注意到作为慢性髓性白血病的治疗剂使用的伊马替尼(imatinib)的新用途。根据目前所知的情况来说，上述伊马替尼对于血管渗透性相关疾病的治疗效果尚未被人所知，但是报告有其除了通常所知的慢性髓性白血病以外，对于类风湿性关节炎、病毒性肝炎等多种疾病显示出治疗效果，因此，预测出其对于上述血管渗透性相关疾病也会具有显示出一定水平的治疗效果的可能性。鉴于此，对通过注射STZ而诱导了作为血管渗透性增加疾病模型的糖尿病性视网膜症的大鼠，将伊马替尼进行给药，并确认其效果的结果，确认了通过注射STZ而显示出的血管渗透性随着伊马替尼的给药而显著地减少，从而证实了上述伊马替尼显示出治疗或预防糖尿病性视网膜症等血管渗透性疾病的效果。因此，本发明中提供的伊马替尼或其药学上可接受的盐能够作为用于预防或治疗血管渗透性相关疾病的药物组合物的有效成分而使用。
本发明的用语“伊马替尼(imatinib)”指的是化学上由4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-苯甲酰胺(4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-((4-pyridin-3-yl)pyrimi din-2-yl-amino)phenyl]-benzamide)表示的化合物。上述伊马替尼结合于由Bcr-Abl基因诱导表达的酪氨酸激酶的ATP结合部位，特异性地抑制酪氨酸激酶的活性，从而被认知为治疗慢性髓性白血病的治疗剂，作为其药学上可接受的盐的一种的甲磺酸伊马替尼以称为格列卫(GleevecTM，Novartis Pharmaceuticals，美国)的商品名进行有销售。并且，已知对于来自血小板的生长因子受体β(PDGF-β)、Akt(蛋白质激酶B)、细胞外调节激酶1和2(ERK1和ERK2)、c-kit等其它种类的酪氨酸激酶也显示出抑制效果。已知上述伊马替尼除了慢性髓性白血病以外，对于类风湿性关节炎(WO 03/063844)、病毒性肝炎(WO 2005/117885)等疾病的预防或治疗显示出效果，而对于血管渗透性疾病的效果则从未被所知。本发明的发明人首次确定了以往作为慢性髓性白血病的治疗剂所知的伊马替尼，其能够显著地减少由血管渗透性疾病而增加的血管渗透性。
本发明的用语“药学上可接受的盐”指的是在作为阳离子和阴离子通过静电引力结合的物质的盐中也能够在药剂学上使用的形态的盐，在本发明的目的上，上述药学上可接受的盐可被解释为是，适合于预计血管渗透性疾病的发病或上述疾病已发病的患者的治疗的伊马替尼的酸加成盐或碱加成盐。
在本发明中，只要能够适合使用于预计血管渗透性疾病的发病或上述疾病已发病的患者的治疗，对于上述伊马替尼的药学上可接受的盐没有特别的限定，但是优选为是伊马替尼的金属盐、与有机碱的盐、与无机酸的盐、与有机酸的盐、与碱性或酸性氨基酸的盐等，更优选为是碱金属盐(钠盐、钾盐等)、碱土金属盐(钙盐、镁盐、钡盐等)、铝盐等金属盐；与三乙胺、吡啶、甲基吡啶、2，6-二甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、环己胺、二环己胺、N，N-二苄基乙二胺等有机碱的盐；与盐酸、氢溴酸、硝酸、硫酸、磷酸等无机酸的盐；与甲酸、乙酸、三氟乙酸、邻苯二甲酸、富马酸、草酸、酒石酸、马来酸、柠檬酸、琥珀酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸的盐；与精氨酸、赖氨酸、鸟氨酸等碱性氨基酸的盐；与天门冬氨酸、谷氨酸等酸性氨基酸的盐，最优选为是甲磺酸伊马替尼。
本发明的用语“血管渗透性疾病”指的是血管渗透性的正常调节崩溃引起的疾病，一般指的是血管发生变化而渗透性增加引起出血的疾病。只要能够通过本发明提供的药物组合物来治疗预计发病或已发病的疾病，对于上述血管渗透性疾病没有特别的限定，但是可以是脉络膜新生血管(choroidal neovascularization)、青光眼性视网膜色素变性(glaucoma retinitis pigmentosa)、早产儿视网膜病变(ROP：retinopathy ofprematurity)、增殖性糖尿病性视网膜症(proliferative diabetic retinopathy)、老年性黄斑变性(age-related macular degeneration)、青光眼、角膜营养不良症(cornealdystrophy)、视网膜劈裂症(retinoschises)、斯特格氏病(Stargardt's disease)、常染色体显性玻璃膜疣(autosomal dominant druzen)、贝斯特氏黄斑营养不良症(Best'smacular dystrophy)、非增殖性糖尿病性视网膜症(non-proliferative diabeticretinopathy)、黄斑囊样水肿(cystoid macular edema)、缺血性视网膜病变(ischemicretinopathy)、炎症诱导视网膜退行性疾病(inflammation-induced retinaldegenerative disease)、糖尿病性黄斑水肿(diabetic macular edema，DME)、与X染色体相关的青少年性视网膜劈裂症(X-linked juvenile retinoschisis)、莫拉蒂致拉分提那斯(Malattia Leventinese；ML)、多恩蜂窝状视网膜营养不良症(Doyne honeycombretinal dystrophy)、血管内皮细胞相关炎症疾病等。
本发明的用语“治疗”指的是为了改变所要治疗的个体或细胞的天然过程而临床上介入的所有行为，可在临床病理状态进行期间或为了预防其而执行。作为目标的治疗效果包括：预防疾病的发生或复发、缓解症状、阻碍伴随疾病的所有直接或间接的病理学结果、预防转移、减小疾病进行速度、减轻或暂时缓解疾病状态、病情好转或改善预后。
在本发明中，上述治疗优选地被解释为是利用伊马替尼或其药学上可接受的盐的血管渗透性疾病的治疗。
本发明的用语“预防”指的是向预计血管渗透性疾病发病的个体将本发明提供的包含伊马替尼或其药学上可接受的盐作为有效成分的药物组合物进行给药，从而抑制或延迟上述疾病的发病的所有行为。
根据本发明的一实施例，通过向大鼠将STZ进行给药来诱导作为血管渗透性相关疾病的糖尿病性视网膜症的发病，在向其将甲磺酸伊马替尼进行给药的结果，确认了血管渗透性显著地减少(图1)，从而可知伊马替尼或其药学上可接受的盐显示出血管渗透性相关疾病的治疗效果。
另外，本发明的药物组合物可进一步包含通常使用于药物组合物的制造的适合的载体、赋型剂或稀释剂。具体地，上述药物组合物可分别根据通常的方法以散剂、颗粒剂、片剂、胶囊剂、悬浊液、乳剂、糖浆、气雾剂等口服型剂型、外用剂、栓剂及灭菌注射溶液的形态进行剂型化而使用。在本发明中，上述药物组合物中可包括的载体、赋型剂及稀释剂可举出乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯橡胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油。在制剂化的情况下，通过使用通常使用的填充剂、增量剂、结合剂、湿润剂、崩解剂、表面活性剂等稀释剂或赋型剂进行调剂。用于口服给药的固体制剂中包含片剂、丸剂、散剂、颗粒剂、胶囊剂等，这种固体制剂是通过在伊马替尼或其药学上可接受的盐中混合至少一种以上的赋型剂，例如淀粉、碳酸钙(calciumcarbonate)、蔗糖(sucrose)或乳糖(lactose)、明胶等进行调剂。并且，除了单纯的赋型剂以外，还使用硬脂酸镁、滑石之类的润滑剂。用于口服的液状制剂有悬浊剂、内用液剂、乳剂、糖浆剂等，除了作为经常使用的单纯稀释剂的水、液体石蜡以外，还可包含多种赋型剂，例如湿润剂、甘味剂、芳香剂、保存剂等。用于非口服给药的制剂包括灭菌的水溶液、非水性溶剂、悬浊剂、乳剂、冻干制剂、栓剂。作为非水性溶剂、悬浊剂可使用丙二醇(propyleneglycol)、聚乙二醇、橄榄油等植物油、油酸乙酯等可注射的酯等。作为栓剂的基剂可使用威铁普首(witepsol)、聚乙二醇、吐温(tween)61、可可脂、月桂酸酯、甘油明胶等。
虽然本发明的一实施例的药物组合物中含有的上述伊马替尼或其药学上可接受的盐的含量没有特别的限定，但是以最终组合物总重量为基准，可以含有0.0001至50重量％的含量，更优选地含有0.01至10重量％的含量。
上述本发明的药物组合物可以按药剂学上有效的量进行给药，本发明的用语“药剂学上有效的量”指的是以可适用于医学治疗或预防的合理的受惠/危险比率足以治疗或预防疾病的量，可根据包括疾病的严重程度、药物的活性、患者的年龄、体重、健康、性别、患者对药物的敏感度、所使用的本发明组合物的给药时间、给药途径及排出比率、治疗时间、与所使用的本发明的组合物配合或同时使用的药物的要素及其它医学领域中公知的要素来决定有效用量水平。本发明的药物组合物可作为单独的治疗剂进行给药，或是与其它治疗剂并用地进行给药，可以与以往的治疗剂依次地或同时地进行给药。此外，可单次或多次地进行给药。重要的是，需要对上述要素均加以考虑，并且以无副作用的最少的量可取得最大效果的量进行给药。
本领域的技术人员可考虑使用目的、疾病的严重程度、患者的年龄、体重、性别、既往病历，或是作为有效成分使用的物质的种类等来决定本发明的药物组合物的给药量。例如，含有上述伊马替尼或其药学上可接受的盐的本发明的药物组合物，其优选地向包括人的哺乳动物一天给药1至20mg/kg，更优选地给药1至10mg/kg，本发明的组合物的给药频度没有特别的限定，但是可一天给药一次或是分用量给药多次。
作为用于实现上述目的的另一实施方式，本发明提供一种用于预防或治疗血管渗透性疾病的方法，其中，包括将包含上述伊马替尼或其药学上可接受的盐作为有效成分的药物组合物以药剂学上有效的量给药至有血管渗透性疾病的发病可能性或已发病的个体的步骤。
如上所述，本发明提供的伊马替尼或其药学上可接受的盐可作为用于预防或治疗血管渗透性疾病的药物组合物的有效成分来使用，因此，上述组合物可使用于血管渗透性疾病的预防或治疗。
本发明的用语“个体”指的是有上述血管渗透性疾病的发病可能性或已发病的包括人的所有动物，无任何限制。通过将本发明的组合物给药至个体，能够缓解或治疗血管渗透性疾病。
本发明的用语“缓解”指的是通过将本发明的组合物进行给药来使血管渗透性疾病好转或有利的所有行为。
本发明的用语“给药”指的是通过某种适当的方法向对象导入本发明的药物组合物，对于给药途径而言，只要能够到达目标组织，其可通过口服或非口服的多种途径进行给药。
在本发明的治疗血管渗透性疾病的方法中，对于上述药物组合物的给药途径而言，只要能够到达目标组织，其可通过任何的一般途径都能够进行给药。本发明的药物组合物对此没有特别的限定，但是可根据所目的而进行腹腔内给药、静脉内给药、肌内给药、皮下给药、皮内给药、口服给药、鼻内给药、肺内给药、直肠内给药。并且，上述组合物可通过可使活性物质移动至靶细胞的任何装置进行给药。
实施例
以下，通过实施例对本发明进行更加详细的说明。但是这些实施例仅是为了例示性地说明本发明，本发明的范围并不限定于这些实施例。
实施例1：动物模型中的甲磺酸伊马替尼的效果
向斯普拉-道来大鼠(Sprague Dawley rat，SD rat)的腹腔以200mg/kg的用量将STZ(链脲霉素(streptozotocin)，Sigma)进行给药(对照组)，或是在与STZ注射同时在动物模型的视网膜以50、100或250μg的用量处理了甲磺酸伊马替尼(Imatinib mesylate，Novatis.瑞士)(实验组)。将上述对照组作为对象，在一周后测定血糖水平的结果，显示出300mg/dL的血糖数值。
另外，将上述动物模型(对照组及实验组)饲养两周后，麻醉上述动物模型，将FITC标记葡聚糖(Fluorescein isothiocyanate-dextran)注射至上述动物模型的心脏(intracardiac FITC-Dextran iniection)，以使荧光物质沿着血液流动。30分钟后，将上述动物模型的视网膜摘出分离，执行平板安装(flat mounting)后，通过荧光显微镜观察了视网膜中存在的荧光物质的分布程度(图1)。图1是表示确认了对于作为血管渗透性增加疾病模型的糖尿病性视网膜症的诱导的甲磺酸伊马替尼的预防效果的照片及图表，图1的(A)是表示与甲磺酸伊马替尼的处理浓度对应的血管渗透性改善效果的照片，图1的(B)是表示与甲磺酸伊马替尼的处理浓度对应的血管渗透性疾病预防效果的图表。如图1所示，在注射STZ的动物模型(对照组)的视网膜中，视网膜血管的渗透性增加，荧光物质向血管周边组织泄漏，从而可以确认诱发了糖尿病性视网膜症，而在与上述STZ的注射同时处理了甲磺酸伊马替尼的情况下，荧光物质的泄漏程度显著地减少，从而可以确认能够预防或缓解所诱发的糖尿病性视网膜症的诱发。
由上述结果可知，甲磺酸伊马替尼能够治疗或预防血管渗透性增加的糖尿病性视网膜症。
Claims (6)
1.一种用于治疗或预防血管渗透性疾病的组合物，其中，包含伊马替尼或其药学上可接受的盐作为有效成分，所述伊马替尼为4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-苯甲酰胺。
2.根据权利要求1所述的组合物，其中，伊马替尼的药学上可接受的盐为甲磺酸伊马替尼。
3.根据权利要求1所述的组合物，其中，所述血管渗透性疾病选自脉络膜新生血管、青光眼性视网膜色素变性、早产儿视网膜病变即ROP、糖尿病性黄斑水肿即DME、老年性黄斑变性、青光眼、角膜营养不良症、视网膜劈裂症、斯特格氏病、常染色体显性玻璃膜疣、糖尿病性视网膜症、贝斯特氏黄斑营养不良症、黄斑囊样水肿、缺血性视网膜病变、炎症诱导视网膜退行性疾病、与X染色体相关的青少年性视网膜劈裂症、莫拉蒂致拉分提那斯即ML、多恩蜂窝状视网膜营养不良症及血管内皮细胞相关炎症疾病。
4.根据权利要求1所述的组合物，其中，进一步包含药学上可接受的载体、赋型剂或稀释剂。
5.根据权利要求1所述的组合物，其中，以组合物总重量为基准，所述伊马替尼或其药学上可接受的盐的含量为0.0001～50重量％。
6.一种预防或治疗血管渗透性疾病的方法，其中，包括将包含伊马替尼或其药学上可接受的盐作为有效成分的药物组合物以药剂学上有效的量给药至有血管渗透性疾病的发病可能性或已发病的个体的步骤，所述伊马替尼为4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯基]-苯甲酰胺。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2012-0065193 | 2012-06-18 | ||
| KR1020120065193A KR101386697B1 (ko) | 2012-06-18 | 2012-06-18 | 이매티닙 또는 이의 약학적으로 허용되는 염을 유효성분으로 포함하는 혈관 투과성 관련 질환의 치료 또는 예방용 조성물 |
| CN201380032289.9A CN104582704A (zh) | 2012-06-18 | 2013-06-10 | 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 |
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| CN201380032289.9A Pending CN104582704A (zh) | 2012-06-18 | 2013-06-10 | 含伊马替尼或其药学上可接受的盐作为有效成分的用于治疗或预防血管渗透性疾病的组合物 |
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| GB201401005D0 (en) * | 2014-01-21 | 2014-03-05 | Ucl Business Plc | Inhibitor |
| KR101778004B1 (ko) | 2015-06-22 | 2017-09-15 | (주) 에빅스젠 | 이마티닙을 유효성분으로 포함하는 안구 건조 질환 예방 및 치료용 약학 조성물 |
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| CN1780627A (zh) * | 2003-04-29 | 2006-05-31 | 贝林格尔.英格海姆国际有限公司 | 用于治疗涉及细胞增殖、骨髓瘤细胞迁移或凋亡或者血管增殖疾病的联用药物 |
| CN1856469A (zh) * | 2003-07-23 | 2006-11-01 | 拜尔医药品股份有限公司 | 用于治疗和预防疾病和疾病症状的氟代ω－羧芳基二苯基脲 |
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| WO2010141427A1 (en) * | 2009-06-02 | 2010-12-09 | Novartis Ag | Treatment of ophthalmologic disorders mediated by albha-carbonic anhydrase isoforms |
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| CA2480809A1 (en) | 2002-04-11 | 2003-10-23 | Children's Medical Center Corporation | Methods for inhibiting vascular hyperpermeability |
| KR101501870B1 (ko) * | 2003-08-27 | 2015-03-12 | 옵쏘테크 코포레이션 | 안구의 혈관신생성 장애를 치료하기 위한 조합 치료법 |
| WO2006035204A2 (en) | 2004-09-27 | 2006-04-06 | Astrazeneca Ab | Combination comprising zd6474 and an imatinib |
| GB0421438D0 (en) * | 2004-09-27 | 2004-10-27 | Astrazeneca Ab | Combination therapy |
| TWI393565B (zh) | 2004-06-04 | 2013-04-21 | Bioniche Life Sciences Inc | 甲磺酸伊馬替尼治療肝病變及病毒感染的用途 |
| AU2005288736B2 (en) * | 2004-09-27 | 2008-08-14 | Astrazeneca Ab | Cancer combination therapy comprising AZD2171 and imatinib |
| DE602006012313D1 (de) * | 2005-06-03 | 2010-04-01 | Novartis Ag | Kombination aus pyrimidylaminobenzamid-verbindungen und imatinib zur behandlung oder verhinderung proliferativer erkrankungen |
| US20080003219A1 (en) * | 2005-09-26 | 2008-01-03 | Minu, L.L.C. | Delivery of an ocular agent |
| US20100143459A1 (en) | 2006-11-09 | 2010-06-10 | Abbott Gmbh & Co. Kg | Pharmaceutical dosage form for oral administration of tyrosine kinase inhibitor |
| SI2305263T1 (sl) | 2007-06-07 | 2012-10-30 | Novartis Ag | Stabilizirane amorfne oblike imatinib mezilata |
| KR101138840B1 (ko) | 2009-12-28 | 2012-05-10 | 주식회사 셀트리온화학연구소 | 이마티닙 다이클로로아세트산염 및 이를 포함하는 항암제 조성물 |
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- 2013-06-10 US US14/409,441 patent/US9511068B2/en active Active
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- 2013-06-10 CA CA2876926A patent/CA2876926C/en active Active
- 2013-06-10 CN CN201380032289.9A patent/CN104582704A/zh active Pending
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| CN1780627A (zh) * | 2003-04-29 | 2006-05-31 | 贝林格尔.英格海姆国际有限公司 | 用于治疗涉及细胞增殖、骨髓瘤细胞迁移或凋亡或者血管增殖疾病的联用药物 |
| CN1856469A (zh) * | 2003-07-23 | 2006-11-01 | 拜尔医药品股份有限公司 | 用于治疗和预防疾病和疾病症状的氟代ω－羧芳基二苯基脲 |
| CN101035536A (zh) * | 2004-10-08 | 2007-09-12 | 诺瓦提斯公司 | 有机化合物的组合 |
| CN101594851A (zh) * | 2006-11-09 | 2009-12-02 | 阿伯特有限及两合公司 | 用于口服给药的酪氨酸激酶抑制剂的药物剂型 |
| WO2010141427A1 (en) * | 2009-06-02 | 2010-12-09 | Novartis Ag | Treatment of ophthalmologic disorders mediated by albha-carbonic anhydrase isoforms |
Also Published As
| Publication number | Publication date |
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| BR112014032264A2 (pt) | 2017-06-27 |
| CN104582704A (zh) | 2015-04-29 |
| MX2014015785A (es) | 2015-06-10 |
| JP6030234B2 (ja) | 2016-11-24 |
| RU2014151382A (ru) | 2016-08-10 |
| EP2862573B1 (en) | 2018-03-07 |
| CA2876926C (en) | 2017-04-04 |
| KR101386697B1 (ko) | 2014-04-18 |
| RU2018128737A3 (zh) | 2019-03-14 |
| BR112014032264A8 (pt) | 2022-03-03 |
| US20150320750A1 (en) | 2015-11-12 |
| MX365021B (es) | 2019-05-20 |
| US9511068B2 (en) | 2016-12-06 |
| JP2015520226A (ja) | 2015-07-16 |
| EP2862573A1 (en) | 2015-04-22 |
| WO2013191401A1 (ko) | 2013-12-27 |
| RU2018128737A (ru) | 2019-03-14 |
| KR20130141998A (ko) | 2013-12-27 |
| EP2862573A4 (en) | 2016-01-27 |
| ES2668908T3 (es) | 2018-05-23 |
| CA2876926A1 (en) | 2013-12-27 |
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