CN101137383B - 增强型比马前列素眼用溶液 - Google Patents

增强型比马前列素眼用溶液 Download PDF

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CN101137383B
CN101137383B CN2006800075548A CN200680007554A CN101137383B CN 101137383 B CN101137383 B CN 101137383B CN 2006800075548 A CN2006800075548 A CN 2006800075548A CN 200680007554 A CN200680007554 A CN 200680007554A CN 101137383 B CN101137383 B CN 101137383B
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bimatoprost
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edta
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bak
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张金明
J·N·张
R·M·希夫曼
R·S·乔丹
J-E·张-林
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Abstract

本文公开了一种组合物，包括以重量百分比计0.005％至0.02％的比马前列素和100ppm至250ppm的苯扎氯胺，其中所述组合物是按配方配制的用于眼用给药的水成液。此外本文也公开了一种可用于治疗青光眼或相关的高眼压症的方法。

Description

增强型比马前列素眼用溶液
技术领域
本发明涉及到包括比马前列素的药物组合物。
背景技术
相关技术说明
比马前列素，如下所示，为一种市售的用于治疗青光眼和高眼压症的前列腺酰胺(prostamide)。
Figure S2006800075548D00011
化学式I
苯扎氯胺(BAK)为一种防腐剂，用于很多市售眼用产品来防止在多次使用产品中的微生物污染。市售滴眼剂(Bimatoprost，Allergan，Irc.，Irvine，CA)含有0.03％比马前列素和0.005％BAK。尽管现在没有其它市售的用于治疗青光眼的比马前列素，但是有几种市售的含有BAK作为防腐剂的前列腺素类似物。这些前列腺素类似物包括拉坦前列素(Xalatan)、曲伏前列素(Travatan)和异丙基乌诺前列酮(Rescula)，这些前列腺素需要相当多的150至200ppm的BAK，，来达到美国和欧洲的抗菌效果测试的要求。
美国专利No.6,596,765 B2公开了一种组合物，含有0.005％或0.0005％的拉坦前列素和0.2mg/mL的BAK。
美国专利No.6,646,001 B2公开了组合物，含有0.03％的比马前列素和0.01％的BAK或“0.01％+5％过量”的BAK。
附图说明
图1为一幅给出了在几种制剂的局部给药后，比马前列素母酸的房水浓度的图。
图2为一幅给出了在几种不同制剂中，比马前列素的膜渗透性的图。
发明内容
本文公开了一种组合物，包括以重量百分比计0.005％至0.02％的比马前列素和100ppm至250ppm的苯扎氯胺，其中所述组合物是按配方配制的用于眼部给药的水成液。
此外本文也公开了一种可用于治疗青光眼或相关的高眼压症的方法。
配制出了一种按配方配制用于眼用给药的水成液，使得它可以被局部给药至眼部。应尽可能地使被给药者感到舒适，但是有时出于配方的考虑(如药物稳定性)可能无法达到最佳的舒适感。
在某些组合物中比马前列素的浓度为0.01％至0.02％。在另一些组合物中比马前列素的浓度为0.015％至0.02％。
在某些组合物中BAK的浓度为150ppm至200ppm。在另一些组合物中BAK的浓度为150ppm至200ppm。在另一些组合物中BAK的浓度为150ppm至250ppm。
在眼用组合物中，可以使用一种螯合剂来增强防腐剂效果。适宜的螯合剂在本领域中是已知，并非为了限制，乙二胺四乙酸盐(EDTA)为可用的螯合剂。
在某些组合物中EDTA的浓度为至少0.001％。在另一些组合物中EDTA的浓度为至少0.01％。在另一些组合物中EDTA的浓度为0.15％或更少。在另一些组合物中EDTA的浓度为0.1％或更少。在另一些组合物中EDTA的浓度为0.05％或更少。
某些组合物包含150至250ppm的BAK和有效量的EDTA。
如本领域中已知的，经常使用缓冲液将pH值调整到一个所需的适于眼用的范围。通常需要6-8左右的pH值，而且在某些组合物中需要7.4的pH值。已知许多包括无机酸盐的缓冲液，如磷酸盐，硼酸盐和硫酸盐。
另外一种在眼用组合物中常用的赋形剂为粘度增强剂或增稠剂。使用增稠剂可出于各种原因，包括从改良制剂形式以方便给药，到增加与眼球接触以提高生物利用度。粘度增强剂可以包括含亲水基团的聚合物，亲水基团如单糖、多糖、环氧乙烷基团、羟基基团、羧酸或其他带电官能团。并非为了限制本发明的范围，一些有用的粘度增强剂的实例为羧甲基纤维素钠、羟丙基甲基纤维素、聚维酮、聚乙烯醇和聚乙二醇。
在眼用溶液中，经常使用张度剂将制剂的组成调整到所需的等渗范围。张度剂是本领域熟知的，一些实例包括丙三醇、甘露醇、山梨糖醇、氯化钠和其它电解质。
一种组合物的pH值为7.4，且基本由0.015％比马前列素、200ppm苯扎氯胺、0至0.03％的EDTA、磷酸盐缓冲液、NaCl和水组成。
另一种组合物的pH值为7.4，且包括0.02％比马前列素、200ppm苯扎氯胺、0至0.03％的EDTA、磷酸盐缓冲液、NaCl和水。
另一种组合物的pH值为7.4，且由0.01％比马前列素、200ppm苯扎氯胺、0至0.03％的EDTA、磷酸盐缓冲液、NaCl和水组成。
在下面的实例中描述了制造和使用本发明组合物的最好方式。这些实例只是为如何制造和使用本发明组合物提供了方向和指导，并不意在以任何方式限制本发明的范围。
一个实施方案包括0.01％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水，其中pH值为7.3。
另一个实施方案包括0.015％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水，其中pH值为7.3。
另一个实施方案包括0.015％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠、0.03％EDTA和水，其中pH值为7.3。
另一个实施方案包括0.02％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水，其中pH值为7.3。
另一个实施方案基本由0.01％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水组成，其中pH值为7.3。
另一个实施方案基本由0.015％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水组成，其中pH值为7.3。
另一个实施方案基本由0.015％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠、0.03％EDTA和水组成，其中pH值为7.3。
另一个实施方案基本由0.02％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水组成，其中pH值为7.3。
另一个实施方案由0.01％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水组成，其中pH值为7.3。
另一个实施方案由0.015％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水组成，其中pH值为7.3。
另一个实施方案由0.015％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠、0.03％EDTA和水组成，其中pH值为7.3。
另一个实施方案由0.02％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠和水组成，其中pH值为7.3。
另一个实施方案包括0.0125％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠、足够将pH值调整至7.3的氢化钠和/或盐酸和水。
另一个实施方案基本由0.0125％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠、足够将pH值调整至7.3的氢化钠和/或盐酸和水组成。
另一个实施方案由0.0125％的比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠、足够将pH值调整至7.3的氢化钠和/或盐酸和水组成。
实施例1
用本领域熟知的常规方法来制备制剂，这些制剂含有0.268％七水磷酸氢二钠、0.014％柠檬酸、0.83％氯化钠，在qs(质量安全)水中将pH调整至7.3，且比马前列素、BAK和EDTA的量列于下表1中。
表1
制剂
1.0.03％比马前列素(50ppm BAK)对照
2.0.03％比马前列素-200ppm BAK
3.0.03％比马前列素-0.015％TPGS(无防腐剂)
4.0.03％比马前列素-0.2％TPGS(无防腐剂)
5.0.03％比马前列素-0.4％TPGS(无防腐剂)
6.0.03％比马前列素-1.0％TPGS(无防腐剂)
实施例2
在体内进行研究来测定苯扎氯胺(BAK)和d-α维生素E琥珀酸聚乙二醇1000酯(TPGS)对于比马前列素的眼部吸收的影响。在该体内实验中，对十八只雌兔的两眼各加一滴28μL眼药水，并且收集用药后60分钟时的房水样品(每种制剂分配n＝3只动物6只眼睛)。两只兔子(4只眼睛)未被处理以作为未用药的生物分析对照。用液相色谱串联质谱(LC-MS/MS)法分析从房水和体外样品中提取的比马前列素及其母体羧酸，定量范围为0.25-60ng/mL。
由于比马前列素在兔眼中的广泛代谢，其母酸被用作代替品来测定比马前列素的眼部吸收。图1和下表2总结了用6种不同的比马前列素制剂单次给药后兔房水中的酸浓度。
表2
制剂     房水a(ng/mL)
1.0.03％比马前列素(50ppm BAK)对照     51.0±9.4
2.0.03％比马前列素-200ppm BAK     87.2±19.0*
3.0.03％比马前列素-0.015％TPGS(无防腐剂)     26.1±3.3*
4.0.03％比马前列素-0.2％TPGS(无防腐剂)     22.9±3.2*
5.0.03％比马前列素-0.4％TPGS(无防腐剂)     19.3±5.6*
6.0.03％比马前列素-1.0％TPGS(无防腐剂)     15.4±3.3*
a平均值±SD。每个制剂，N＝3只兔子(6只眼睛)
*与0.03％比马前列素相比的统计学差异(p＜0.05)
与比马前列素对照相比，含有0.015％、0.2％、0.4％和1.0％TPGS的测试制剂使得房水羧酸浓度分别降低了52％、59％、62％和72％。相反，与比马前列素(50ppm BAK)相比，含200ppm BAK的0.03％比马前列素会导致房水AGN 191522浓度提高57％。
并非以任何方式或理论限制本发明，与比马前列素对照相比，含有TPGS的制剂会导致比马前列素渗透性的下降。相比而言，含较高BAK含量的制剂会导致较高的渗透性。
实施例3
用本领域熟知的常规方法来制备制剂，这些制剂含有0.268％七水磷酸氢二钠、0.014％柠檬酸、0.83％氯化钠，在qs(质量安全)水中将pH调整至7.3，且比马前列素、BAK和EDTA的量列于下面表3中。
表3
 制剂
 A.0.03％比马前列素(50ppm BAK)-对照
 B.0.015％比马前列素(50ppm BAK)
 C.0.015％比马前列素(50ppm BAK)0.03％EDTA
 D.0.015％比马前列素(200ppm BAK)
 E.0.015％比马前列素(200ppm BAK)0.03％EDTA
 F.0.015％比马前列素(50ppm BAK)0.015％EDTA
 G.0.015％比马前列素(200ppm BAK)0.015％EDTA
 H.0.015％比马前列素(125ppm BAK)
 I.0.015％比马前列素(125ppm BAK)0.03％EDTA
 J.0.015％比马前列素(125ppm BAK)0.015％EDTA
 K.0.015％比马前列素(150ppm BAK)
 L.0.015％比马前列素(150ppm BAK)0.1％EDTA
 M.0.015％比马前列素
 N.0.03％比马前列素
实施例4
苯扎氯胺(BAK)和乙二胺四乙酸(EDTA)对于比马前列素穿过兔角膜上皮细胞层(RCECL)原代培养系时的渗透性的影响。角膜上皮细胞采集自新西兰白兔，并在TranswellTM filters上培养至汇合(5天)。对于转运实验，细胞首先在37℃下用转运缓冲液平衡1小时。然后将含有0.015％或0.03％比马前列素和各个浓度BAK和EDTA的剂量溶液加到TranswellTM的顶区室(两个培养系；每个培养系n＝3-4)，且细胞在37℃下孵育。为测试从顶部到基底外侧的(AB)转运，在给药后30、60、90和120分钟时，分别从基底外侧室取出200μL样品。用液相色谱串联质谱(LC-MS/MS)来分析样品，定量范围为1-600ng/mL。
结果在图2中示出。
实施例5
每天一次，给一个患有青光眼的人的眼睛局部给药一滴制剂J。几小时后，观察到与制剂A相比，制剂J使眼内压下降更多，眼内充血更少。只要治疗一直持续，就可以一直保持较低的眼内压。

Claims (16)

1.一种组合物，包括以重量百分比计0.005％至0.02％的比马前列素和100ppm至250ppm的苯扎氯胺，其中所述组合物是按配方配制的用于眼用给药的一种水成液。
2.权利要求1的组合物，进一步包括EDTA。
3.权利要求2的组合物，其中苯扎氯胺的浓度为150ppm至200ppm。
4.权利要求1的组合物，其中比马前列素的浓度为0.01％至0.02％。
5.权利要求4的组合物，其中比马前列素的浓度为0.015％至0.02％。
6.权利要求5的组合物，其中苯扎氯胺的浓度为150ppm至200ppm。
7.权利要求6的组合物，其中苯扎氯胺的浓度为200ppm。
8.权利要求5的组合物，进一步包括EDTA。
9.权利要求8的组合物，pH值为7.4，其包括0.015％比马前列素、200ppm苯扎氯胺、0至0.03％的EDTA、磷酸盐缓冲液和NaCl。
10.权利要求9的组合物，pH值为7.4，所述组合物由0.015％比马前列素、200ppm苯扎氯胺、0至0.03％的EDTA、磷酸盐缓冲液、NaCl和水组成。
11.一种组合物，包括以重量百分比计0.005％至0.02％比马前列素和100ppm至250ppm苯扎氯胺，在制备用于治疗青光眼或高眼内压症的药剂中的用途。
12.权利要求2的组合物，包括0.001％至0.15％的EDTA。
13.权利要求12的组合物，包括0.01％至0.1％的EDTA。
14.权利要求13的组合物，包括0.01％至0.05％的EDTA。
15.权利要求2的组合物，包括150ppm至250ppm BAK。
16.权利要求4的组合物，包括0.0125％比马前列素、0.02％苯扎氯胺、0.268％七水磷酸氢二钠、0.014％一水柠檬酸、0.81％氯化钠、足够将pH值调整至7.3的氢化钠和/或盐酸和水。
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US20110124737A1 (en) 2011-05-26
HK1104211A1 (en) 2008-01-11
CA2585691A1 (en) 2006-09-28
JP5899267B2 (ja) 2016-04-06
ZA200707246B (en) 2008-09-25
JP2008511539A (ja) 2008-04-17
JP2011148827A (ja) 2011-08-04
PL1753434T5 (pl) 2018-05-30
TWI399207B (zh) 2013-06-21

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