CN103068364B - 不含防腐剂的比马前列素和噻吗洛尔溶液 - Google Patents

不含防腐剂的比马前列素和噻吗洛尔溶液 Download PDF

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CN103068364B
CN103068364B CN201180040407.1A CN201180040407A CN103068364B CN 103068364 B CN103068364 B CN 103068364B CN 201180040407 A CN201180040407 A CN 201180040407A CN 103068364 B CN103068364 B CN 103068364B
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timolol
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S·利基勒桑
A·P·帕拉沙
C·P·普贾瑞
W·F·凯利
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Abstract

本发明是针对用于降低眼内压和治疗青光眼的不含防腐剂的比马前列素和噻吗洛尔溶液。

Description

不含防腐剂的比马前列素和噻吗洛尔溶液
发明人：Sukhon Likitlersuang、Ajay Parashar、Chetan P.Pujara以及William F.Kelly
相关申请的交叉引用
本申请要求在2010年7月29日提交的美国临时专利申请序列No.61/368,685的权益，此专利申请的全部内容以引用的方式并入本文。
发明领域
本申请是针对不含防腐剂的比马前列素和噻吗洛尔制剂。
发明背景
比马前列素是一种前列酰胺，是具有强有力的降眼压活性的前列腺素F2α(PGF2α)的合成类似物。比马前列素通过增加经过小梁网和葡萄膜巩膜途径的房水流出而降低青光眼或高眼压症患者的眼内压(IOP)。噻吗洛尔是一种非选择性β肾上腺素能受体阻断剂，并且通过阻断睫状体上皮上的β受体而减少房水的产生来起作用。
已经显示含防腐剂的滴眼剂的使用与眼表疾病的发展和恶化有牵连。开角型青光眼和高眼压症的管理需要使用含有防腐剂的滴眼剂进行长期治疗。眼表疾病的症状和体征，如眼表破坏(breakdown)、刺激、烧灼感、异物感、干燥、泪液不足等在大比例的开角型青光眼和高眼压症患者中是普遍的。
与使用苯扎氯铵进行保存的滴眼剂相比，不含防腐剂的滴眼剂引起患者的显著较少的眼部刺激症状和体征，如疼痛或不适、异物感、刺痛或烧灼感，以及眼干感。
经历对苯扎氯铵的超敏反应的患者不能使用含有苯扎氯铵的商用比马前列素产品，即使所述产品仅用0.005%w/v的苯扎氯铵进行保存。苯扎氯铵还可以被软性隐形眼镜吸收，因此建议配戴软性隐形眼镜的患者在施用之前先卸下眼镜，并且在将它们重新放入之前等待至少15分钟。
发明概述
本发明是针对不含苯扎氯铵或任何其它防腐剂的比马前列素和噻吗洛尔溶液，所述溶液从安全性和耐受性观点来看将是优越的，同时维持和/或改进其降低IOP的功效，并且可供对苯扎氯铵超敏的患者使用，并且方便于佩戴软性隐形眼镜的患者。
不含防腐剂的比马前列素和噻吗洛尔眼用溶液是一种透明至微黄色的、等渗、无菌溶液。所述药物产品含有比马前列素和噻吗洛尔作为活性成分。非活性成分是张度剂和缓冲剂，以及净化水。可以包括合适的缓冲剂(如磷酸氢二钠七水合物和柠檬酸一水合物)以及合适的张度剂(如氯化钠)。所述溶液是水性溶液，其pH值范围在约7至约8之内，并且优选为约7.3。可以包括合适的缓冲剂，如磷酸氢二钠七水合物、柠檬酸一水合物。优选地，所述张度剂如氯化钠将以提供至少约200mOsm/kg、优选约280至约370mOsm/kg的最终渗透值的量来采用。
本发明总体上是根据美国专利申请序列No.10/153,043的教义而做出的，此专利申请的全部内容以引用的方式并入本文。
本发明的一些实施方案包括以下各项：
1)一种用于降低人类患者的眼内压的不含防腐剂的比马前列素和噻吗洛尔组合物，其包括以下制剂：约0.03％w/v的比马前列素；约0.5％的噻吗洛尔；约0.268％w/v的磷酸氢二钠七水合物；约0.014％的柠檬酸一水合物；约0.68％的氯化钠、水、盐酸、氢氧化钠，并且其pH值为约7.3。
2)如段落1所述的用于降低人类患者的眼内压的不含防腐剂的比马前列素和噻吗洛尔溶液，其包括以下制剂：0.03％w/v的比马前列素；0.5％的噻吗洛尔；约0.268％w/v的磷酸氢二钠七水合物；0.014％的柠檬酸一水合物；约0.68％的氯化钠、盐酸、水、氢氧化钠，并且其pH值为约7.3。
3)如段落1至2所述的不含防腐剂的比马前列素和噻吗洛尔溶液，其中所述噻吗洛尔是0.68%w/v的马来酸噻吗洛尔。
4)一种如表1中所述的组合物。
5)如段落1至4所述的比马前列素和噻吗洛尔溶液，其中所述溶液对治疗青光眼有用。
6)如段落1至4所述的比马前列素和噻吗洛尔组合物，其中所述组合物是溶液，其中所述溶液以单位剂量试剂盒形式被包含。
7)如段落1至6中任一项所述的比马前列素和噻吗洛尔组合物，其中所述组合物每天施加于每只眼一次。
8)如段落1至6中任一项所述的比马前列素和噻吗洛尔组合物，其中所述组合物每天施加于每只眼两次。
9)如段落1至4所述的比马前列素和噻吗洛尔组合物，其中所述组合物与使用苯扎氯铵或另一种防腐剂进行保存的比马前列素和噻吗洛尔相比，具有较大的功效，同时副作用较少。
10)如段落1所述的组合物，其中所述组合物可以是溶液、乳液、分散液、混悬液、反相乳液以及微乳液。
11)如段落1所述的组合物，其中所述组合物被包含在单位剂量瓶中。
12)如段落1所述的组合物，其中所述组合物被包含在多剂量瓶中，所述瓶具有抗防腐剂特性，如嵌入在其配药尖端的金属离子。
13)如段落12所述的组合物，其中所述金属离子是银离子。
发明详述
本发明的不含防腐剂的比马前列素和噻吗洛尔眼用制剂显示在表1中。
表1：根据本发明的不含防腐剂的比马前列素和噻吗洛尔眼用溶液的实例：
成分 单位 级别 量
比马前列素 %w/v N/A 0.03
马来酸噻吗洛尔 %w/v USP/Ph Eur 0.68
磷酸氢二钠七水合物 %w/v USP 0.268
柠檬酸一水合物 %w/v USP/Ph Eur 0.014
氯化钠 %w/v USP/Ph Eur 0.68
盐酸 %w/v USP/Ph Eur pH7.3
氢氧化钠 %w/v USP/Ph Eur pH7.3
净化水/WFI Q.S. USP/Ph Eur QS
本发明是针对不含苯扎氯铵作为防腐剂的比马前列素和噻吗洛尔制剂，并且可以按照单位剂型来销售。因为去除了苯扎氯铵，本发明产生相同的或更大的功效，而没有与防腐剂苯扎氯铵相关联的不良副作用，如充血，这将改进所述产品每剂量单位降低IOP的功效，具有优良的患者依从性和较少的副作用。使用本发明的不含防腐剂的组合物可以避免的其它副作用包括：眼睑炎、角膜糜烂、凹陷(depression)、溢泪、眼分泌物、眼干、眼刺激、眼痛、眼睑水肿、眼睑红斑、眼睑瘙痒、异物感、头痛、高血压、口干、嗜睡、浅层点状角膜炎以及视觉障碍。

Claims (7)

1.一种用于降低患者的眼内压的不含防腐剂的比马前列素和噻吗洛尔组合物，其由以下组成：0.03％w/v的比马前列素；0.5％的噻吗洛尔；0.268％w/v的磷酸氢二钠七水合物；0.014％的柠檬酸一水合物；0.68％的氯化钠；水；并且所述组合物的pH值为7.3。
2.如权利要求1所述的用于降低患者的眼内压的不含防腐剂的比马前列素和噻吗洛尔组合物，其中所述噻吗洛尔是0.68％w/v的马来酸噻吗洛尔。
3.如权利要求1所述的用于降低患者的眼内压的不含防腐剂的比马前列素和噻吗洛尔组合物，其中所述组合物是溶液并且对治疗青光眼有用。
4.如权利要求1所述的用于降低患者的眼内压的不含防腐剂的比马前列素和噻吗洛尔组合物，其中所述组合物以单位剂量试剂盒的形式被包含。
5.如权利要求1所述的用于降低患者的眼内压的不含防腐剂的比马前列素和噻吗洛尔组合物，其中所述组合物与使用苯扎氯铵进行保存的比马前列素和噻吗洛尔相比，具有较高的功效，同时副作用较少。
6.如权利要求1所述的用于降低患者的眼内压的不含防腐剂的比马前列素和噻吗洛尔组合物，其中所述组合物是包含在单位剂量瓶中的溶液。
7.一种组合物，其具有以下配方：0.03％w/v比马前列素、0.68％w/v马来酸噻吗洛尔、0.268％w/v磷酸氢二钠七水合物、0.014％w/v柠檬酸一水合物、0.68％w/v氯化钠、盐酸、氢氧化钠，和净化水；其中组合物的pH值为7.3。
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