CN100564351C - 异波帕胺马来酸盐、其制备方法以及含有它的药物组合物 - Google Patents

异波帕胺马来酸盐、其制备方法以及含有它的药物组合物 Download PDF

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CN100564351C
CN100564351C CNB2005800030862A CN200580003086A CN100564351C CN 100564351 C CN100564351 C CN 100564351C CN B2005800030862 A CNB2005800030862 A CN B2005800030862A CN 200580003086 A CN200580003086 A CN 200580003086A CN 100564351 C CN100564351 C CN 100564351C
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ibopamine
pharmaceutical composition
weight
maleate
organic solvent
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CN1910139A (zh
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M·宾扎
C·玛杰里
N·卡佐尔拉
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Angelini Acraf SpA
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Aziende Chimiche Riunite Angelini Francesco ACRAF SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/08—Mydriatics or cycloplegics

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  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

异波帕胺马来酸盐(1∶1)、其制备方法以及含有它的药物组合物。

Description

异波帕胺马来酸盐、其制备方法以及含有它的药物组合物
本发明涉及异波帕胺马来酸盐(1∶1)、其制备方法以及含有它的眼用药物组合物。
US 4 218 470描述了作为药物的异波帕胺(麻黄宁3，4-O-二异丁酸酯)，其可用于全身性治疗心血管症状。
EP-A-0 205 606描述了异波帕胺及其可药用酸加成盐作为扩瞳剂的用途。在所述文献中，具体示例说明并测试的可药用酸加成盐是其盐酸盐。
EP-A-0 442 958描述了一种含有异波帕胺的可药用酸加成盐的眼用含水药物溶液剂，其中所述溶液剂被缓冲至pH 4.5，且每重量份所述异波帕胺盐含有0.1-0.5重量份羟丙基甲基-纤维素。同样，在此申请中，具体示例说明并测试的可药用酸加成盐也是盐酸盐。
目前发现马来酸盐显示出比盐酸盐更好的局部耐受性。
因此，本发明第一方面涉及异波帕胺马来酸盐(1∶1)。
该异波帕胺马来酸盐(1∶1)可以方便地通过已知技术制备得到，例如以1∶1的摩尔比例将溶解于适宜有机溶剂中的马来酸加入至同样溶解于适宜有机溶剂中的异波帕胺碱中。
所述加料优选在惰性气氛和室温下完成。
然后将由此形成的盐(异波帕胺马来酸盐1∶1)通过已知技术分离，包括使盐沉淀并过滤或者蒸发除去溶剂。
在一优选实施方案中，上述有机溶剂是丙酮，通过加入乙醚使该盐从丙酮溶液中沉淀析出。
因此，本发明第二方面涉及一种制备异波帕胺马来酸盐(1∶1)的方法，其特征在于包括以1∶1的摩尔比例将溶解于适宜有机溶剂中的马来酸加入至同样溶解于适宜有机溶剂中的异波帕胺碱中。
由于具有更好的局部耐受性，发现异波帕胺马来酸盐尤其适合用于诊断和治疗目的的眼科用途。
因此，本发明第三方面涉及一种眼用药物组合物，其特征在于含有异波帕胺马来酸盐(1∶1)与至少一种可药用溶媒。
可受益于使用本发明药物组合物进行治疗的病理状态的典型实例是眼压过低(ocular hypotonia)。
对于诊断目的而言，本发明的药物组合物可有利地用作扩瞳剂。
优选地，本发明的药物组合物可以为软膏剂或滴眼剂形式，同时也可以含有其它适合眼用的溶媒，例如乙二醇、PEG、羧甲基纤维素、甘露醇、山梨醇、泊洛沙姆、甲基纤维素、羟乙基纤维素、羟丙基纤维素等。
所述组合物还可以含有其它常规成分，例如：防腐剂、稳定剂、表面活性剂、缓冲剂、调节渗透压的盐、乳化剂等。
如果特殊诊断或治疗用途需要的话，本发明的药物组合物可以含有同时给药是有利的其它药理活性成分，例如透明质酸。
异波帕胺马来酸盐在本发明药物组合物中的用量可以根据各种已知因素在较大范围内变化，例如特定的诊断用途或待治疗疾病的特定类型、疾病的严重程度以及每日给药的次数。当然，本领域技术人员可以方便和按照惯例来确定最佳用量。
通常，异波帕胺在本发明药物组合物中的含量为0.01重量％至6重量％，更优选为0.1重量％至5重量％。
本发明药物组合物的剂型可以根据药剂师所熟知的技术制备，包括混和、溶解、灭菌等。
下面的实施例用于对本发明进行示例性说明，并不对其构成限制。
实施例1
异波帕胺马来酸盐的制备
步骤a)
将饱和碳酸钠溶液加入至异波帕胺盐酸盐(4g)的水(10ml)溶液中，直到不再形成沉淀。
沉淀用乙醚(50ml)萃取。分离有机相，用硫酸钠干燥并迅速通过布氏漏斗过滤。最后，在室温和减压下蒸发除去乙醚。
所得到的固体残余物由异波帕胺碱(3g)组成。
步骤b)
在惰性氛围下，向异波帕胺碱(1.78g；0.005mol)的丙酮(10ml)溶液中加入马来酸(674mg；0.005mol)的丙酮(5ml)溶液，不加热。
溶液搅拌放置于室温下(20分钟)。然后逐滴加入乙醚以形成乳光，继续搅拌直到沉淀完全(从乳光开始出现起30分钟)。
过滤收集固体后用乙醚洗涤。从而得到目标产物(1g)。
m.p.＝107-108℃
元素分析
C21H29N1O8     C       H       N
计算值         59.56   6.90    3.31
实测值         59.53   6.92    3.27
测试1
眼部耐受性
使用两份水溶液。
第一份含有2重量％的异波帕胺盐酸盐(相当于1.79重量％的异波帕胺)，缓冲至pH 7.0。
第二份含有2.46重量％的异波帕胺马来酸盐(相当于1.79重量％的异波帕胺)，缓冲至pH 7.0。
使用12只平均重量为2kg且平均年龄为10个月的雄性兔(NewZealand White)，分成两组，每组6只。第一组用0.1ml第一测试溶液治疗，每天3次，持续15天。第二组用0.1ml第二测试溶液治疗，每天3次，持续15天。
根据J.Draize等人，Pharmacol.Exp.Ther.，83，377-390(1944)评价耐受性。结果如下表1所示。
表1
Figure C20058000308600061

Claims (11)

1.1∶1的异波帕胺马来酸盐。
2.眼用药物组合物，其特征在于它含有1∶1的异波帕胺马来酸盐与至少一种可药用溶媒。
3.根据权利要求2的药物组合物，特征在于其为软膏剂或滴眼剂形式。
4.根据权利要求2或3的药物组合物，其特征在于异波帕胺的用量为0.01重量％至6重量％。
5.根据权利要求2或3的药物组合物，其特征在于异波帕胺的用量为0.1重量％至5重量％。
6.制备1∶1的异波帕胺马来酸盐的方法，特征在于其包括以1∶1的摩尔比例将溶解于适宜有机溶剂中的马来酸加入至同样溶解于适宜有机溶剂中的异波帕胺碱中。
7.根据权利要求6的方法，其特征在于所述加料在惰性气氛下完成。
8.根据权利要求6或7的方法，其特征在于所述加料在室温下完成。
9.根据前述权利要求6-8中任一项的方法，其特征在于通过沉淀并过滤分离所形成的盐。
10.根据前述权利要求6-9中任一项的方法，其特征在于所述有机溶剂是丙酮。
11.根据权利要求10的方法，其特征在于通过加入乙醚使该盐从丙酮溶液中沉淀析出。
CNB2005800030862A 2004-01-30 2005-01-13 异波帕胺马来酸盐、其制备方法以及含有它的药物组合物 Expired - Fee Related CN100564351C (zh)

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US20240065999A1 (en) * 2020-11-09 2024-02-29 The Board Of Trustees Of The Leland Stanford Junior University Ophthalmic Formulation Containing a Dopaminergic Prodrug that may be Combined with One or More Agents

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US2400038A (en) * 1944-09-07 1946-05-07 Burroughs Wellcome Co Esters of secondary phenolic amines
IT1074038B (it) 1976-08-05 1985-04-17 Simes Esteri della epinina
IT1178800B (it) * 1984-12-27 1987-09-16 Simes Composizioni farmaceutiche e loro uso come midriatici
IT1231488B (it) 1988-11-09 1991-12-07 Zambon Spa Soluzione acquosa farmaceutica tamponata a ph 4,5 per uso oftalmico contenente ibopamina e idrossipropilmetilcellulosa
IT1247508B (it) * 1991-04-19 1994-12-17 Zambon Spa Composizioni farmaceutiche contenenti l'estere 4-(2 metilamminoetil)- 1,2- fenilenicodell`acido 2-metilpropanoico per il trattamento della neurootticopatia glaucomatosa

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.ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH.,Vol.36 No.(2a). 1986
Synthesis and chemical properties of Ibopamine and orrelated esters of N-substituted dopamines-Synthesis ofIbopamine metabolites
Synthesis and chemical properties of Ibopamine and orrelated esters of N-substituted dopamines-Synthesis ofIbopamine metabolites；. CASAGRANDE C等；.ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH.,Vol.36 No.(2a). 1986 *

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EA200601117A1 (ru) 2006-10-27
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DE602005026909D1 (de) 2011-04-28
CA2551411A1 (en) 2005-08-18
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WO2005075409A1 (en) 2005-08-18
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US20080242724A1 (en) 2008-10-02
EA009212B1 (ru) 2007-12-28
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EP1708988B1 (en) 2011-03-16
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BRPI0507153A (pt) 2007-07-31
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AU2005211453A1 (en) 2005-08-18
KR20060127940A (ko) 2006-12-13
US7667069B2 (en) 2010-02-23
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PL1708988T3 (pl) 2011-08-31
EP1708988A1 (en) 2006-10-11
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