CN105142637A - 用于预防或治疗干眼症的含瑞巴派特或其前药的口服药物组合物 - Google Patents
用于预防或治疗干眼症的含瑞巴派特或其前药的口服药物组合物 Download PDFInfo
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- CN105142637A CN105142637A CN201480022068.8A CN201480022068A CN105142637A CN 105142637 A CN105142637 A CN 105142637A CN 201480022068 A CN201480022068 A CN 201480022068A CN 105142637 A CN105142637 A CN 105142637A
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Abstract
本发明公开了一种用于预防或治疗干眼症的口服药物组合物，所述口服药物组合物包含瑞巴派特或其前药、或其可药用盐作为有效成分。所述化合物可经由口服途径治疗干眼症，并且因此与传统滴眼液相比使用起来更为安全和方便。
Description
技术领域
本发明涉及一种用于预防或治疗干眼症的口服药物组合物，该组合物包含瑞巴派特(Rebampide)或其前药。
背景技术
干眼症是一种临床特征为泪液缺乏的症状，由泪腺炎和角膜去神经化或是因睑板腺功能障碍或眼睑病变所导致的泪液过度蒸发所引起。此外，据报道T细胞介导的炎性反应也是干眼症的病因之一(EyeContactLens，29(1Suppl):S96-100，2003；和Opthalmologe，103:9-17，2006)。
干眼症的症状包括灼热、异物感、瘙痒、红肿、甚至严重的视力障碍等。干眼症被认为是停经后妇女的一种常见老化症状。然而。在如今广泛使用电视、电脑、隐形眼镜的生活环境下，干眼症在一般男女中也很常见。此外，干眼症的发病年龄呈逐渐下降的趋势(Gynecol.Endocrinol.，20:289-98，2005；和Surv.Opthalmol.，50:253-62，2005)。
干眼症的治疗方法包括用于补充泪液的人工泪液滴剂、用于抑制炎性反应的类固醇类抗炎滴眼液、治疗性隐形眼镜(TCL)、用以抑制因泪液漏出导致人工泪液或其替代物在眼睛上滞留的外科泪点栓塞术等等(J.KoreanOpthalmol.Soc.，46:1774-1779，2005)。然而，人工泪液制剂存在因其治疗效果短暂而需每天使用多次的缺点，并且对于角膜损伤并无任何保护功能；另一方面，类固醇制剂的长期用药可能会引起诸如青光眼等致命的副作用。此外，治疗性隐形眼睛不便于佩戴，还可能导致细菌感染。而泪点栓塞术则具有诸如因外科手术而引起的心理抗拒感等缺点，且如果产生不良副作用，会难以恢复到先前的健康状态。总而言之，上述各种常规治疗方式仅用于症状治疗，并非专注于治疗或解决干眼症状的根本原因。
2006年，由美国Allergan公司开发了一种用于治疗干眼症的采用环孢菌素免疫调节剂的滴眼液(也称为)。据报道，Restasis滴眼液能抑制与干燥性角膜结膜炎相关的免疫细胞的产生和活化并增加泪液分泌水平(Opthalmology，107:967-74，2000；和Opthalmology，107:631-9，2000)。然而，该制剂藉由抗炎作用产生其药效，因此需进行数月反覆用药才足以达到满意的疗效。另外，其施用伴随有相当高频率的典型副作用发生率(17％)，所述典型副作用如灼热感(Opthalmology，107:631-9，2000；和ThomsonPharma)。
因此，仍有必要开发一种治疗剂，其不仅是可缓解症的症状治疗剂，并且能够治疗干眼症状的根本原因，同时还能通过不良副作用的低发生率保证药物的安全性。
瑞巴派特，2-(4-氯苯甲酰基-氨基)-3-[2(1H)-喹诺酮-4-基]-丙酸以化学式1表示，已知是一种有用的胃溃疡治疗剂。此外，瑞巴派特能增加眼睛上的杯状细胞密度、增加泪液的分泌，并且已知是治疗干眼症的试剂(JP-A-2009-301866)。
<化学式1>
关于干眼症的治疗，美国公布No.2007-0287729公开了一种包含中性或弱酸性瑞巴派特的眼科用品，更具体地讲是一种结晶瑞巴派特的水性悬浮液，其包含选自水溶性聚合物和表面活化剂的化合物中的至少一种、酸性水溶液和含水溶性瑞巴派特盐的水溶液。此外，KR公布No.10-2011-0027786描述了一种含瑞巴派特、氨基糖和缓冲剂，但不含无机阳离子的眼科药物组合物。
然而，由于上述组合物为用于治疗干眼症的滴眼液形式，其易于局部刺激眼粘膜、难于以固定剂量施用、保存期限短并且依从性差，从而导致显著较低的治疗效果。
发明内容
技术问题
本发明的目的在于提供一种包含瑞巴派特的药物组合物，其可通过口服途径而非经眼途径来预防或治疗干眼症。
技术解决方案
根据其一方面，本发明提供了一种用于预防或治疗干眼症状的口服药物组合物，该组合物包含瑞巴派特或其前药、或其可药用盐作为有效成分。
有益效果
如本文所述，瑞巴派特或其前药、或其可药用盐可经由口服途径治疗干眼症，并且因此与传统滴眼液相比使用起来更为安全和方便。
附图说明
图1至图5是示出根据本发明(实例1至实例28)施用口服组合物10天后干眼症小鼠模型的泪液产生量的图。在这些图中，“正常组”是指未引起干眼症的小鼠，而“对照组”是指仅施用赋形剂的干眼症小鼠模型。此外，符号“#”表示对于正常组p<0.05，而符号“*”表示对于对照组p<0.05(t测试)。
图6至图10是示出根据本发明(实例1至实例28)施用口服组合物10天后干眼症小鼠模型的角膜平滑度的图。在这些图中，“正常组”是指未引起干眼症的小鼠，而“对照组”是指仅施用赋形剂的干眼症小鼠模型。此外，符号“#”表示对于正常组p<0.05，而符号“*”表示对于对照组p<0.05(t测试)。
图11至图15是示出根据本发明(实例1至实例28)施用口服组合物10天后干眼症小鼠模型的角膜渗透性的图。在这些图中，“正常组”是指未引起干眼症的小鼠，而“对照组”是指仅施用赋形剂的干眼症小鼠模型。此外，符号“#”表示对于正常组p<0.05，而符号“*”表示对于对照组p<0.05。
具体实施方式
根据其一方面，本发明提供了一种用于预防或治疗干眼症的口服药物组合物，该组合物包含瑞巴派特或其前药、或其可药用盐作为有效成分。瑞巴派特以化学式1表示，已知是胃溃疡或干眼症的治疗剂：
[化学式1]
具体地讲，对于干眼症，瑞巴派特仅以滴眼液的形式使用，这种形式被认为是最有效的，因为这样该制剂可将药物和其他水分直接递送到眼睛上。
然而，本发明提出了一些特别的发现：即使经由口服施用，瑞巴派特也会刺激结膜上的粘液分泌，并防止眼表损伤，从而表现出对干眼症的优异治疗效果。通常，滴眼液与口服施用的试剂尽管含有相同的药物，但因它们的作用机制不同而无法呈现相同的治疗效果。具体地讲，考虑到口服试剂在通过身体内多个器官的过程中易于发生降解并且需耗费大量时间才能到达目标部位，因此无法保证口服试剂具有与滴眼液相当的效果。即便如此，本发明发现，经由口服途径施用的瑞巴派特仍表现出对干眼症的治疗效果。因此，对于可能具有引起不适、难于以固定剂量施用、依从性低、保存期限短等问题的滴眼液而言，本发明的用于口服施用的试剂可替代其进行施用。
本发明的组合物可包含瑞巴派特前药或其可药用盐来代替瑞巴派特。
瑞巴派特前药是指可在体内降解为瑞巴派特的化合物，具体地讲是指一种具有在体内吸收后可容易地从该化合物上分离的基团的化合物。该前药用于提高体内吸收率和/或增强溶解性。
该前药的优选实施例可包括具有下列化学式2至7的化合物：
[化学式2]
具有化学式2的化合物为(2-吗啉代乙基2-(4-氯苯甲酰)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯，可与“瑞巴派特前药I”互换使用。瑞巴派特前药I可通过使瑞巴派特与4-(2-羟乙基)吗啉反应而制备。
[化学式3]
具有化学式3的化合物为(2-吗啉乙氧基)-2-氧代乙基2-(4-氯苯甲酰)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯，可与“瑞巴派特前药II”互换使用。瑞巴派特前药II可通过使瑞巴派特与溴化4-(2-(2-溴乙酰氧基)乙基)吗啉-4-鎓反应而制备。
[化学式4]
具有化学式4的化合物为((2-吗啉乙氧基)羰氧基)甲基2-(4-氯苯甲酰)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯，可与“瑞巴派特前药III”互换使用。瑞巴派特前药III可通过使瑞巴派特与溴化4-(2-(3-氯代丙酰氧基)乙基)吗啉-4-鎓反应而制备。
[化学式5]
具有化学式5的化合物为2-吗啉代乙基2-(2-(4-氯苯甲酰)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酰氧基)-丁酸酯，可与“瑞巴派特前药IV”互换使用。瑞巴派特前药IV可通过使瑞巴派特与4-(2-(2-溴代丁酰氧基)乙基)吗啉-4-鎓反应而制备。
[化学式6]
具有化学式6的化合物为(2-(4-甲基哌嗪-1-基)-2-氧代乙基2-(4-氯苯甲酰)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯，可与“瑞巴派特前药V”互换使用。瑞巴派特前药V可通过使瑞巴派特与1-(2-溴乙酰基)-4-甲基哌嗪-1-鎓反应而制备。
[化学式7]
具有化学式7的化合物为1-(4-甲基哌嗪-1-基)-1-氧代丁-2-基2-(4-氯苯甲酰)-3-(2-氧代-1,2-二氢喹啉-4-基)丙酸酯，可与“瑞巴派特前药VI”互换使用。瑞巴派特前药VI可通过使瑞巴派特与溴化1-(2-溴丁酰基)-4-甲基哌嗪-1-鎓反应而制备。
根据本发明的实验例，与瑞巴派特相比，上述前药对干眼症具有更佳的治疗效果(参见图1至图15)。
可用于本发明组合物的瑞巴派特前药的可药用盐是指用酸制成的酸加成盐。酸的例子包括但不限于盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸、酒石酸、甲酸、柠檬酸、醋酸、三氯醋酸、三氟醋酸、葡萄糖酸、苯甲酸、乳酸、草酸、富马酸、丙二酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸。盐的优选例子包括用硫酸、丙二酸或草酸形成的酸加成盐。
根据本发明的实验例，与瑞巴派特相比，上述前药对干眼症具有更佳的治疗效果(参见图1至图15)。
在本发明的组合物中，基于组合物的总量计，瑞巴派特或其前药、或其可药用盐可以1重量％至50重量％的量使用。
此外，本发明的药物组合物还可包含可药用载体或添加剂。
如本文所用，“可药用”一词是指在对人施用后具有生理相容性并且不会引起肠胃失调、诸如头晕的过敏反应或类似反应。添加剂可为赋形剂、崩解剂、粘结剂、润滑剂、悬浮剂、稳定剂等等中的任一种。赋形剂的例子包括乳糖、甘露醇、益寿糖、微晶纤维素、硅化微晶纤维素、粉状纤维素等等。崩解剂的例子包括低取代羟丙基纤维素、交聚维酮、羧基乙酸淀粉钠、交联羧甲基纤维素钠、淀粉等等。粘结剂的例子包括羟丙基纤维素、羟丙甲纤维素、聚维酮、共聚维酮、预胶凝淀粉等等。润滑剂的例子包括硬脂酸、硬脂酸镁、富马酰硬脂酸钠等等；润湿剂的例子包括聚氧乙烯山梨糖醇酐脂肪酸酯、泊洛沙姆、聚氧乙烯蓖麻油衍生物等等。悬浮剂的例子包括羟丙甲纤维素、羟丙基纤维素、聚维酮、共聚维酮、羧甲基纤维素钠、甲基纤维素等等。稳定剂的例子包括柠檬酸、富马酸、琥珀酸等等。另外，本发明的药物组合物还可包括阻凝剂、增味剂、乳化剂、防腐剂等等中的任一种。
此外，本发明的药物组合物可通过本领域已知的方法制备，以便在对哺乳动物施用后提供一种速释、缓释或迟释的有效成分。该药物制剂可以是粉末、颗粒、片剂、悬浮剂、乳剂、糖浆、气雾剂或者软胶囊或硬胶囊的形式。
瑞巴派特或其前药、或其可药用盐的药物有效剂量取决于所治疗的受试者、疾病或症状的严重程度、施用率、处方医师的判断。该化合物可经由口服途径以约0.5mg/kg体重至100mg/kg体重的日剂量施用，并且优选以约0.5mg/kg体重至5mg/kg体重的日剂量施用。在某些情况下，实际日剂量可少于上述最低剂量，但在另外一些情况下，必须超过上述最高剂量，只要不产生毒性和副作用即可。在施用较高量的情况下，可取的是将其分为若干单独的剂量在一天内多次施用。
此外，本发明提供了一种用于为需要其的受试者预防或治疗干眼症的方法，该方法包括向受试者施用瑞巴派特或其前药、或其可药用盐。所述受试者为患有干眼症或具有患干眼症风险的受试者，诸如哺乳动物，优选为人。
此外，本发明提供了一种使用瑞巴派特或其前药、或其可药用盐制备用于预防或治疗干眼症的药物的方法。
可通过以下实例获得对本发明的更好理解，这些实例的示出仅处于示例性目的，不应视为对本发明的限制。
实例1至4：包含瑞巴派特的口服试剂的制备
将聚山梨醇酯80(Fluka)3.0g作为分散剂溶解于100mL纯化水中，以制备用于悬浮药物的载体。分别将1g、2g、4g和6g瑞巴派特(化学式1，HanseochemCo.Ltd.)加入其中，接着搅拌该混合物10分钟，制成悬浮液(实例1至4)。根据表1列出的剂量，对八周龄雄性C57BL/6小鼠干眼症模型每天施用该悬浮液(5mL/kg)两次。
实例5至10：包含瑞巴派特的口服试剂的制备
将柠檬酸(Sigma-Aldrich)0.1g作为稳定剂以及羟丙甲纤维素2910(Pharmacoat615，Shin-etsu)2g作为悬浮剂溶解于100mL纯化水中，以制备用于悬浮药物的载体。分别将1g瑞巴派特前药I至VI(化学式2至7，SamjinPharmaceuticalCo.Ltd)加入其中，接着搅拌该混合物10分钟，制成悬浮液(实例5至10)。根据表1列出的剂量，对八周龄雄性C57BL/6小鼠干眼症模型每天施用该悬浮液(5mL/kg)两次。
实例11至16：包含瑞巴派特前药丙二酸盐的口服试剂的制备
重复实例5至10的步骤，不同的是以基于每种前药相当于1g的量使用其丙二酸盐(SamjinPharmaceuticalCo.Ltd)代替瑞巴派特前药I至VI，制成悬浮液(实例11至16)。根据表1列出的剂量，对八周龄雄性C57BL/6小鼠干眼症模型每天施用该悬浮液(5mL/kg)两次。
实例17至22：包含瑞巴派特前药草酸盐的口服试剂的制备
重复实例5至10的步骤，不同的是以基于每种前药相当于1g的量使用其草酸盐(SamjinPharmaceuticalCo.Ltd)代替瑞巴派特前药I至VI，制成悬浮液(实例17至22)。根据表1列出的剂量，对八周龄雄性C57BL/6小鼠干眼症模型每天施用该悬浮液(5mL/kg)两次。
实例23至28：包含瑞巴派特前药硫酸盐的口服试剂的制备
重复实例5至9的步骤，不同的是以基于每种前药相当于1g的量使用其硫酸盐(SamjinPharmaceuticalCo.Ltd)代替瑞巴派特前药I至VI，制成悬浮液(实例23至28)。根据表1列出的剂量，对八周龄雄性C57BL/6小鼠干眼症模型每天施用该悬浮液(5mL/kg)两次。
[表1]
*上列剂量基于瑞巴派特前药计。
实验例1：使用干眼症动物模型进行药物有效性分析
<1-1>干眼症动物模型的构建
将八周龄雄性C57BL/6小鼠(CharlesRiverlaboratories)隔离一周，然后根据它们的平均体重和标准偏差，按照每组八只动物将它们分为若干组。
对于实验组(施用实例1至28)，通过皮下注射莨菪碱(2.5mg/mL，Sigma-Aldrich)10天并且每天暴露于通风环境(25-40％相对湿度)18小时，以引发干眼症。然后，分别为小鼠口服施用实例1至28，每天两次，共持续10天。
同时，对于正常组，不为正常小鼠施用任何药物或载体。而对于对照组，为患有干眼症的小鼠施用载体。
<1-2>泪液产生量的测量
施用药物十(10)天后，分析对照组和实验组的泪液产生量。泪液产生量是通过将酚红棉线置于小鼠眼睛的外眦部，保持一段时间，并使用ImageInside程序(2.32版)分析湿润面积(mm2)而测得的。测量结果示于图1至图5中。
如图1至图5所示，与对照组相比，瑞巴派特剂量为200mg/kg或更高时(实例3和4)，泪液产生量显著增加。此外，与对照组相比，瑞巴派特前药及其盐(实例5至28)也表现出泪液产生量的显著增加。
<1-3>角膜平滑度的分析
为分析角膜平滑度，在施用药物10天后对每只小鼠实施安乐死。然后，在体视变焦显微镜(Nikon)下观察每只小鼠的角膜表面，并基于角膜不规则性进行评分(四分制：0.5为正常，1为微度，1.5为轻度，3为中度，4为重度)。由两位专家评分，并将他们的分数求平均值。结果示于图6至图10中。
如图6至图10所示，与对照组相比，瑞巴派特剂量为200mg/kg或更高时(实例3和4)，角膜平滑度有显着改善。此外，与对照组相比，瑞巴派特前药及其盐(实例5至28)也表现出角膜平滑度的显著改善。
<1-4>角膜上皮细胞损伤
为评估角膜上皮细胞损伤程度，将在平衡盐溶液中包含1％荧光素钠盐(Sigma-Aldrich)作为荧光染料的5μL溶液滴在小鼠的结膜囊中。使用胶带将小鼠的眼睛闭合至少一小时。再用蒸馏水冲洗眼睛，除去多余的未渗透的荧光染料。然后，摘除眼球，分析其绿色荧光水平，并采集图像。使用ImageJ1.38x程序(http://rsb.info.nih.gov，NIH，Baltimore，USA)分析图像，计算绿色荧光强度。按如下标准对角膜上皮细胞损伤程度评分：3为正常，6为微度，9为轻度，12为中度，15为重度。
如图11至图15所示，与对照组相比，瑞巴派特剂量为200mg/kg或更高时(实例3和4)，荧光染料的角膜渗透性显著降低。此外，与对照组相比，瑞巴派特前药及其盐(实例5至28)也表现出荧光染料的角膜渗透性的显著降低。
Claims (12)
1.一种用于预防或治疗干眼症的口服药物组合物，所述口服药物组合物包含瑞巴派特或其前药、或其可药用盐作为有效成分。
2.根据权利要求1所述的口服药物组合物，其中所述前药选自具有化学式2至7的化合物：
[化学式2]
[化学式3]
[化学式4]
[化学式5]
[化学式6]
以及
[化学式7]
3.根据权利要求1所述的口服药物组合物，其中所述盐用选自以下酸的酸制成：盐酸、硫酸、硝酸、磷酸、氢溴酸、氢碘酸、酒石酸、甲酸、柠檬酸、醋酸、三氯醋酸、三氟醋酸、葡萄糖酸、苯甲酸、乳酸、草酸、富马酸、丙二酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸和萘磺酸。
4.根据权利要求1所述的口服药物组合物，其中所述盐用硫酸、丙二酸或草酸制成。
5.根据权利要求1所述的口服药物组合物，其中所述盐是具有化学式2至7的化合物中任一种的硫酸盐、丙二酸盐或草酸盐：
[化学式2]
[化学式3]
[化学式4]
[化学式5]
[化学式6]
以及
[化学式7]
6.根据权利要求1至权利要求5中任一项所述的口服药物组合物，其中基于所述组合物的总量计，瑞巴派特或其前药、或其可药用盐以1重量％至50重量％的量使用。
7.根据权利要求1所述的口服药物组合物，所述口服药物组合物还包含可药用载体或添加剂。
8.根据权利要求7所述的口服药物组合物，其中所述可药用添加剂选自赋形剂、崩解剂、粘结剂、润滑剂、润湿剂、悬浮剂、稳定剂、以及它们的混合物。
9.一种药物制剂，所述药物制剂由根据权利要求1所述的组合物制成。
10.根据权利要求9所述的药物制剂，所述药物制剂是粉末、颗粒、片剂、悬浮剂、乳剂、糖浆、气雾剂或者软胶囊或硬胶囊的形式。
11.一种用于为需要其的受试者预防或治疗干眼症的方法，所述方法包括向所述受试者施用瑞巴派特或其前药、或其可药用盐。
12.一种使用瑞巴派特或其前药、或其可药用盐制备用于预防或治疗干眼症的药物的方法。
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| CN114404379A (zh) * | 2022-01-29 | 2022-04-29 | 杭州沐源生物医药科技有限公司 | 一种瑞巴派特缓释片及其制备方法 |
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- 2014-04-17 JP JP2016508869A patent/JP6249194B2/ja active Active
- 2014-04-17 ES ES14785310T patent/ES2813649T3/es active Active
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112969464A (zh) * | 2018-10-23 | 2021-06-15 | 三进制药株式会社 | 用于预防或治疗干燥综合征的组合物 |
| CN114404379A (zh) * | 2022-01-29 | 2022-04-29 | 杭州沐源生物医药科技有限公司 | 一种瑞巴派特缓释片及其制备方法 |
| CN114404379B (zh) * | 2022-01-29 | 2024-01-26 | 杭州沐源生物医药科技有限公司 | 一种瑞巴派特缓释片及其制备方法 |
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| US11712414B2 (en) | 2023-08-01 |
| WO2014171748A1 (ko) | 2014-10-23 |
| AU2014254621A1 (en) | 2015-11-19 |
| BR112015026332B1 (pt) | 2022-05-03 |
| EP2987491A1 (en) | 2016-02-24 |
| RU2632107C2 (ru) | 2017-10-02 |
| TW201442710A (zh) | 2014-11-16 |
| AR096045A1 (es) | 2015-12-02 |
| AU2014254621B2 (en) | 2017-06-08 |
| KR20140125230A (ko) | 2014-10-28 |
| EP2987491A4 (en) | 2016-12-28 |
| SA114350449B1 (ar) | 2016-05-08 |
| ES2813649T3 (es) | 2021-03-24 |
| KR101692578B1 (ko) | 2017-01-03 |
| MX2015014672A (es) | 2016-02-19 |
| PH12015502406A1 (en) | 2016-02-22 |
| MY183526A (en) | 2021-02-24 |
| TWI535441B (zh) | 2016-06-01 |
| JP2016520566A (ja) | 2016-07-14 |
| RU2015146417A (ru) | 2017-05-24 |
| CA2909806A1 (en) | 2014-10-23 |
| EP2987491B1 (en) | 2020-06-03 |
| BR112015026332A2 (pt) | 2017-07-25 |
| US20160081922A1 (en) | 2016-03-24 |
| IL242143B (en) | 2021-03-25 |
| JP6249194B2 (ja) | 2017-12-20 |
| CN105142637B (zh) | 2021-08-17 |
| CA2909806C (en) | 2020-04-21 |
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