CN106902117A - 一种预防或治疗脉络膜新生血管形成的药物 - Google Patents
一种预防或治疗脉络膜新生血管形成的药物 Download PDFInfo
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- CN106902117A CN106902117A CN201611187205.0A CN201611187205A CN106902117A CN 106902117 A CN106902117 A CN 106902117A CN 201611187205 A CN201611187205 A CN 201611187205A CN 106902117 A CN106902117 A CN 106902117A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种预防或治疗脉络膜新生血管形成的药物，该药物包括活性成分，所述活性成分为尼达尼布及其盐或溶剂合物中的一种或几种的组合。本发明所述尼达尼布及其盐或溶剂合物能够预防或治疗脉络膜新生血管形成，发现当口服使用剂量为1.26~32毫克/人/次时，对预防或治疗脉络膜新生血管形成具有显著的疗效。
Description
技术领域
本发明涉及一种预防或治疗脉络膜新生血管形成的药物。
背景技术
脉络膜新生血管是指来自脉络膜毛细血管的增殖血管，通过Bruch膜的裂口而扩展，在Bruch膜与视网膜色素上皮之间、或神经视网膜与视网膜色素上皮之间、或位于视网膜色素上皮与脉络膜之间增殖形成，许多累及RPE-Bruch膜-脉络膜毛细血管复合体的疾病均可导致CNV的形成，又称视网膜下新生血管。多见于黄斑部，因而损害中心视力。本病已成为致盲的主要原因之一。常见于成人眼，特别是60岁以上者。许多疾病过程都可影响视网膜色素上皮-Bruch膜-脉络膜毛细血管，因而常伴有视网膜下新生血管。例如年龄相关性黄斑变性，也称老年黄斑变性（AMD）。
血管内皮生长因子受体（VEGF）是经典的血管生成信号通路，可用于治疗多种实体瘤和湿性年龄相关性黄斑变性（AMD），FDA已经批准的针对VEGF单抗或融合蛋白有贝伐珠单抗(Avastin)、雷珠单抗(Lucentis)、阿柏西普(Eylea)、雷莫芦单抗(Cyramza)，我国自主研发的康柏西普（商品名：朗沐）已于2013年上市。但针对VEGF、PDGF、FGF三种血管生成受体的药物用于治疗眼睛病症还没有产品上市，并且这些药物都是眼内注射剂，患者顺应性查差，因此仍然需要寻找更好的药物来治疗眼病诸如AMD，且能提高患者顺应性。
尼达尼布，即3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧基羰基-2-二氢吲哚酮，分子式C31H33N5O4，化合物结构见式为：
尼达尼布是一种新型的血管生成抑制剂，可同时作用于血管生成过程中涉及的3种关键受体家族：血管内皮生长因子受体（VEGFR）、血小板源性生长因子受体（PDGFR）以及成纤维细胞生长因子受体（FGFR）。尼达尼布已被FDA和EMA批准上市，用于治疗特发性肺纤维化（IPF），也被EMA批准联合多西他赛在一线化疗之后应用于组织学诊断为腺癌的、局部晚期或转移性或局部复发性非小细胞肺癌（NSCLC）成年患者。但未发现关于尼达尼布在预防或治疗脉络膜新生血管形成方面的报道。
发明内容
本发明所要解决的技术问题是提供一种预防或治疗脉络膜新生血管形成等眼部疾病的药物，其对脉络膜新生血管形成具有显著的预防或治疗作用。
为解决以上技术问题，本发明采取如下技术方案：
本发明的目的是提供尼达尼布及其盐或溶剂合物在制备预防或治疗脉络膜新生血管形成的药物中的应用。
本发明的另一个目的是提供一种预防或治疗脉络膜新生血管形成的药物，所述药物包括活性成分，所述活性成分为尼达尼布及其盐或溶剂合物中的一种或几种的组合。
需要说明的是，溶剂合物为其中溶剂分子形成固态的化学计量复合物且包括但不限于乙醇和甲醇的化合物或其盐。溶剂合物包括水合物，水合物为特定形式的溶剂合物，其中溶剂分子为水。本发明的化合物或其盐的水合物为所述化合物或盐与水的化学计量组合物，诸如半水合物、单水合物或二水合物。
盐优选为根据本发明的化合物的药学上可接受的盐。合适的药学上可接受的盐包括无机酸和有机酸的盐，包括盐酸、硫酸、磷酸、氢溴酸、甲烷磺酸、三氟甲烷磺酸、苯磺酸、对甲苯磺酸、1-萘磺酸、2-萘磺酸、乙酸、三氟乙酸、苹果酸、酒石酸、柠檬酸、乳酸、乙二酸、琥珀酸、富马酸、马来酸、苯甲酸、水杨酸、苯基乙酸和扁桃酸。另外，药学上可接受的盐包括无机碱的盐，诸如含有碱阳离子(例如Li+、Na+或K+)、碱土阳离子（例如Mg2+、Ca2+或Ba2+）、铵阳离子的盐；以及有机碱的酸式盐，包括脂肪族和芳香族被取代铵和季铵阳离子，诸如来自三乙胺、N,N-二乙胺、N,N-二环己胺、赖氨酸、吡啶、N,N-二甲基氨基吡啶（DMAP）、1,4-二氮杂双环[2.2.2]辛烷（DABCO）、1,5-二氮杂双环[4,3,0]壬-5-烯（DBN）和1,8-二氮杂双环[5.4.0]十一碳-7-烯（DBU）的质子化或全烷基化的盐。
优选地，所述活性成分为乙磺酸尼达尼布。
优选地，所述药物为口服制剂。
更优选地，所述药物的剂型为片剂、胶囊剂、颗粒剂、散剂或口服液体制剂。
更优选地，所述药物包括一个或多个单位的单位制剂，每个单位制剂含有的活性成分的重量为活性成分的有效治疗剂量的n倍，其中，n为0.1~10之间的数。
所述n为0.1~1之间的数。更优选n为1。
根据本发明，当药物为片剂时，所述一个单位制剂指一片；当药物胶囊剂时，所述一个单位制剂指一粒胶囊；当药物为颗粒剂或散剂时，所述一个单位制剂指一袋装用量；当药物为口服液体制剂时，所述一个单位制剂指一瓶装用量。
所述活性成分的有效治疗剂量为1.26~32毫克/人/次，优选地，所述的活性成分的有效治疗剂量为2~10毫克/人/次。更优选地，所述的活性成分的有效治疗剂量为3~6.3毫克/人/次。
上述药物剂型可以采用本领域技术人员所周知的方法进行制备。
所述药物还包括药学上可接受的辅料。
优选地，所述的辅料为选自赋形剂、粘合剂、助流剂、润滑剂、崩解剂、着色剂、矫味矫嗅剂、乳化剂、表面活性剂、助溶剂、混悬化剂、等渗剂、缓冲剂、防腐剂、抗氧化剂、稳定剂、吸收促进剂中的任一种或几种。
优选的赋形剂是：乳糖、蔗糖、葡萄糖、玉米淀粉、甘露醇、山梨糖醇、淀粉、α淀粉、糊精、微晶纤维素、轻质硅酸酐、硅酸铝、硅酸钙、硅酸铝酸镁、磷酸氢钙等。
优选的粘合剂是：聚乙烯醇、甲基纤维素、乙基纤维素、阿拉伯胶、黄耆胶、明胶、虫胶、羟丙基纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯基吡咯烷酮、聚乙二醇等。
优选的助流剂是：胶态二氧化硅。
优选的润滑剂是：硬脂酸镁、聚乙二醇、硬脂酸钙、富马酸十八酯钠、滑石粉、聚乙二醇。
优选的崩解剂是：微晶纤维素、琼脂、明胶、碳酸钙、碳酸氢钠、柠檬酸钙、糊精、果胶、低取代羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、交联羧甲基纤维素钠、羧甲基淀粉、羧甲基淀粉钠等。
优选的着色剂是：三氧化二铁、黄色三氧化二铁、胭脂红、焦糖、β-胡萝卜素、氧化钛、滑石粉、磷酸核黄素钠等。
优选的矫味剂是：可可粉、薄荷醇、薄荷油、冰片、桂皮粉等。
优选的乳化剂或表面活性剂是：十八烷基三乙醇胺、十二烷基硫酸钠、十二烷基硫酸钠、十二烷基硫酸钠氨基丙酸、卵磷脂、甘油单硬脂酸、蔗糖脂肪酸酯、甘油脂肪、酸酯等。
优选的助溶剂是：聚乙二醇、丙二醇、安息香酸苄酯、乙醇、胆固醇、三乙醇胺、碳酸钠、柠檬酸钠、吐温80、烟酰胺等。
优选的混悬剂是：聚乙烯醇、聚乙烯吡咯烷酮、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等亲水性高分子。
优选的等渗剂是：葡萄糖、氯化钠、甘露醇、山梨糖醇等。
优选的缓冲剂是：磷酸盐、醋酸盐、碳酸盐、柠檬酸盐等缓冲液。
优选的防腐剂是：对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、氯丁醇、苄醇、苯乙醇、脱氢乙酸、山梨酸等。
优选的抗氧化剂是：亚硫酸盐、抗坏血酸、α-生育酚等。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明所述尼达尼布及其盐或溶剂合物能够预防或治疗脉络膜新生血管形成，发现当口服使用剂量为1.26~32毫克/人/次时，对预防或治疗脉络膜新生血管形成具有显著的疗效。
具体实施方式
下面结合具体的实施例对本发明做进一步详细的说明，但不限于这些实施例。
实施例
乙磺酸尼达尼布灌胃23天对大鼠脉络膜新生血管的抑制作用
BN大鼠 20只，雌雄各半，试验动物双眼于零天（D0）进行眼底激光光凝以诱导脉络膜新生血管（CNV）形成。激光光凝后 8 天（D8），选择眼底激光光斑的荧光渗漏平均分相近的动物，将其随机分组，每组 4 只，雌雄各半。
模型组（组1）动物不作处理，阳性对照组（组2）动物单次玻璃体腔注射康柏西普，供试品低剂量组（组3）给予供试品剂量为8 mg/kg、供试品中剂量组（组4）给予供试品剂量为40 mg/kg、供试品高剂量组（组5）给予供试品剂量为200 mg/kg，试验动物灌胃给药，每日给药2次，连续给药23天。
给药前（D7）、给药后 6、 16、 23 天（D14、 D24、 D31）对各组动物进行眼底照相和眼底血管荧光造影（FFA）检测，依据激光光斑荧光渗漏情况对大鼠 CNV 进行评级和比较分析。 D0~D31 期间每天对动物进行一般临床观察， D0、 D7、 D14、 D24、D31 对动物进行称重和一般眼科检查。
结果：
1）一般临床观察：实验期间（D0-D31），模型组，阳性对照组，灌胃低剂量组和灌胃中剂量组动物均未见异常临床表现。灌胃高剂量组 2/4 雄性动物于 D26 开始观察到生殖器外翻、睾丸肿胀， 1/4 雌性动于 D28 开始观察到弓背、苍白，并持续至实验结束。
2）体重：D0、 D7、 D14、 D24 和 D31，同期各组间体重差异均无统计学意义（p>0.05），除灌胃高剂量组动物的体重均值自 D14 开始逐渐下降外，其余各组动物的体重均值均逐渐升高。
3）一般眼科检查：D0 时，所有动物双眼眼前节及眼底均未见异常。 D7 时，各组动物双眼眼底均可见激光光斑，光斑附近伴或不伴出血，模型组、阳性对照组和灌胃低、中、高剂量组动物光斑附近可见出血的比例分别为： 2/8、 1/8、1/8、 0/8、 0/8 眼，眼底出血的总发生率为 10%（4/40）。随观察时间的延长，动物眼底出血均恢复。至 D24 时，各组动物眼底光斑附近可见出血的比例均已为 0。
除以上外，各组动物一般眼科检查均未见其它异常。
4）眼底照相和荧光造影：眼底照相可以客观的反应视网膜激光斑出血等情况。本实验中，对给药前（D7），给药后不同时间点（D14、D24、D31）眼底彩照进行阅图时发现的无效光斑（光斑处或附近有大片视网膜前/下出血者，或者视网膜前/下出血遮蔽了 FFA 影像的光斑）进行了剔除，剔除后各组动物 D7、 D14、 D21、 D28 的有效光斑数均无明显差异（ p>0.05）。荧光渗漏是评价 CNV 的重要指标，通过观察 FFA 图片中有效光斑的早期及晚期像，并通过晚期像是否有荧光渗漏和荧光渗漏情况我们对 CNV 进行了分级，评级标准为：0级（无荧光渗漏），1 级（轻度荧光渗漏）， 2 级（中度荧光渗漏）， 3 级（重度荧光渗漏），并计算和比较了各组大鼠各级光斑比率和光斑渗漏平均分。结果显示：
D7、 D14、 D21、 D28，模型组大鼠造影晚期未出现渗漏的光斑（0级光斑）比率分别为8.5%、 6.4%、 4.1%、 6.1%，出现轻度或中度或重度荧光渗漏的光斑（1级或2级或3级光斑）比率分别为 91.5%、 93.6%、 95.9%、 93.9%，其中重度渗漏光斑（3级光斑）的比率分别为6.4%、 12.8%、 42.7%、 34.9%，于D24达到最高，D31开始逐渐恢复；此外，光斑渗漏平均分分别为 1.4±0.4、 1.7±0.5、 2.2±0.4、 2.0±0.4；所得结果与文献报道的大鼠 CNV 生成情况和发展趋势基本一致，提示大鼠 CNV 模型诱导成功。
与同期模型组相比，各给药组大鼠 D7、 D14、 D24、 D31 的 0 级、 2 级光斑比率均无明显差异（ p >0.05）。
与同期模型组相比，各给药组大鼠 D14 的3级光斑比率和光斑渗漏平均分均有所下降， 1级光斑比率均有所升高，但差异均无统计学意义（p>0.05）；D24时，各给药组的3级光斑比率和光斑渗漏平均分均明显降低（p≤0.05），1 级光斑比率均升高（除阳性对照组、灌胃高剂量组有所升高外，其余给药组均显著升高）；D31 时，仅阳性对照组 3 级光斑比率的下降与模型组比较，无统计学意义（ p>0.05），其余各给药组的 3 级光斑比率和光斑渗漏平均分仍显著低于同期模型组（ p≤0.05），1 级光斑比率均升高。以上结果表明光凝 1周后给予阳性对照品或供试品进行干预，干预 6 天后大鼠的 CNV 均受到了一定程度的抑制，干预 16 天后对大鼠的 CNV 均具有明显的抑制作用，干预 23 天后阳性对照品对大鼠的 CNV 具有一定的抑制作用，其它供试品组有显著的抑制作用。
与同期阳性对照组相比，灌胃给药组 D14 的1级光斑率、3级光斑率及光斑渗漏平均分均无明显差异（p>0.05）；D24的3级光斑率均降低（其中，灌胃中剂量组显著下降， p≤0.05），光斑渗漏平均分均下降（p>0.05），1级光斑率均升高（其中，灌胃低、中剂量组显著上升， p≤0.05）； D31 的3级光斑率均降低（其中，灌胃低、中剂量组显著下降， p≤0.05），光斑渗漏平均分和1级光斑率均无明显差异（p>0.05）。提示康柏西普单次玻璃体腔注射对大鼠CNV的抑制作用在给药后16~23天可能弱于其它供试品组，尤其是低，中剂量（8、40 mg/kg）连续灌胃给药组。
灌胃三个剂量组间进行比较，高剂量组的 1 级光斑比率在 D24 较同期低、中剂量组明显下降（p≤0.05），在 D31 较同期中剂量明显下降（p≤0.05），除此之外， D7、D14、D24、 D31 时三组的各级光斑比率及光斑渗漏平均分均无明显差异（p>0.05）。
综上所述，从以上各组动物 3 级光斑比率以及光斑渗漏平均分的结果来看，给予50 μg/眼的康柏西普单次玻璃体腔注射、乙磺酸尼达尼布连续灌胃（8、 40、200 mg/kg）后6~23 天，激光光凝诱导的大鼠 CNV 均可被抑制，抑制效果在给药后 16~23 天最为明显。三个剂量（8、40、200 mg/kg）的乙磺酸尼达尼布对大鼠CNV的抑制作用未见明显的剂量-反应关系。乙磺酸尼达尼布低，高剂量（8、200 mg/kg）连续灌胃给药与康柏西普（50 μg/眼）单次注射给药对大鼠 CNV 的抑制作用相近，乙磺酸尼达尼布中剂量（40 mg/kg）连续灌胃给药较康柏西普单次注射对大鼠 CNV的抑制作用可能略强。
本试验条件下，通过激光光凝成功诱导了大鼠脉络膜新生血管模型。乙磺酸尼达尼布连续灌胃给药（8、40、200 mg/kg， 2 次/天，连续23天）对大鼠脉络膜新生血管均具有明显的抑制作用，且抑制作用均与康柏西普（50 μg/眼）单次玻璃体腔注射相似，40 mg/kg的乙磺酸尼达尼布连续灌胃给药的效果可能略强。三个乙磺酸尼达尼布灌胃给药组间的剂量-反应关系不明显。乙磺酸尼达尼布（200 mg/kg）灌胃给药可见动物体重下降、雄性动物生殖器外翻和睾丸肿胀等全身毒性反应。
上述实验为动物实验，人和动物按体表面积折算的等效剂量比值（换算因子）为0.018；大鼠体重按0.2 Kg计算；人体重按70 Kg计算。
大鼠和人的有效治疗剂量换算符合下列公式：
大鼠剂量×大鼠体重=人剂量×人体重×换算因子
人剂量=大鼠剂量×大鼠体重/人体重×换算因子。
因此，在上述实验中，大鼠采用8 mg/kg/次、40 mg/kg/次、200 mg/kg/次的剂量，对应于人的剂量分别为：
人剂量=200 mg/Kg×0.2Kg/70Kg×0.018=32mg；
人剂量=40 mg/Kg×0.2Kg/70Kg×0.018=6.3mg；
人剂量=8 mg/Kg×0.2Kg/70Kg×0.018=1.26mg。
因此，乙磺酸尼达尼布用于人的有效治疗剂量范围为1.26~32毫克/人/次。
以上对本发明做了详尽的描述，其目的在于让熟悉此领域技术的人士能够了解本发明的内容并加以实施，并不能以此限制本发明的保护范围，凡根据本发明的精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围内。
Claims (10)
1.尼达尼布及其盐或溶剂合物在制备预防或治疗脉络膜新生血管形成的药物中的应用。
2.一种预防或治疗脉络膜新生血管形成的药物，所述药物包括活性成分，其特征在于：所述活性成分为尼达尼布及其盐或溶剂合物中的一种或几种的组合。
3.根据权利要求2所述的预防或治疗脉络膜新生血管形成的药物，其特征在于：所述活性成分为乙磺酸尼达尼布。
4.根据权利要求2所述的预防或治疗脉络膜新生血管形成的药物，其特征在于：所述药物为口服制剂。
5.根据权利要求4所述的预防或治疗脉络膜新生血管形成的药物，其特征在于：所述药物的剂型为片剂、胶囊剂、颗粒剂、散剂或口服液体制剂。
6.根据权利要求4所述的预防或治疗脉络膜新生血管形成的药物，其特征在于：所述药物包括一个或多个单位的单位制剂，每个单位制剂含有的活性成分的重量为活性成分的有效治疗剂量的n倍，其中，n为0.1~10之间的数。
7.根据权利要求6所述的预防或治疗脉络膜新生血管形成的药物，其特征在于：所述n为0.1~1之间的数。
8.根据权利要求6所述的预防或治疗脉络膜新生血管形成的药物，其特征在于：所述的活性成分的有效治疗剂量为1.26~32毫克/人/次。
9.根据权利要求8所述的预防或治疗脉络膜新生血管形成的药物，其特征在于：所述的活性成分的有效治疗剂量为2~10毫克/人/次。
10.根据权利要求9所述的预防或治疗脉络膜新生血管形成的药物，其特征在于：所述的活性成分的有效治疗剂量为3~6.3毫克/人/次。
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