CN101854913A - 含有缬沙坦的液体组合物 - Google Patents

含有缬沙坦的液体组合物 Download PDF

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CN101854913A
CN101854913A CN200880115379A CN200880115379A CN101854913A CN 101854913 A CN101854913 A CN 101854913A CN 200880115379 A CN200880115379 A CN 200880115379A CN 200880115379 A CN200880115379 A CN 200880115379A CN 101854913 A CN101854913 A CN 101854913A
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liquid oral
valsartan
oral medicine
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G·哈拉希米沃
W·塔拉蒙帝
R·F·瓦格纳
J·L·杰林斯基
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Novartis AG
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Abstract

本发明提供适用于口服施用的含有缬沙坦水溶液的组合物，优选用于儿童和老年人群。本发明还提供制备这种组合物的方法和稳定这种组合物的方法。

Description

含有缬沙坦的液体组合物
本发明涉及用于治疗由血管紧张素II介导的病症和情况的适合于口服施用的药物组合物，其包含缬沙坦或其可药用盐，本发明还涉及通过口服施用这种缬沙坦的药物组合物来治疗由血管紧张素II介导的病症和情况的方法。
本文提到的所有专利、专利申请和其它出版物的全文均被明确引入本文作为参考。若本说明书的内容与所引入的参考材料出现冲突，则以本说明书为准。
本发明涉及用于治疗由血管紧张素II介导的病症和情况的组合物，所述组合物包含缬沙坦的溶液。缬沙坦的化学名为(S)-N-戊酰基-N-{[2′-(1H-四唑-5-基)联苯-4-基]甲基}缬氨酸，适用于本发明的缬沙坦可商购获得或者可根据已知的方法制备。例如，美国专利US 5,399,578描述了缬沙坦的制备方法，本发明引入其全文作为参考。缬沙坦可以以其游离形式或任何适当的盐形式用于本发明。
本发明的范围内还包括缬沙坦的盐、酯、酰胺、前药、活性代谢物、类似物等，特别是缬沙坦的钙盐。美国专利申请US 2003/0207930中公开了缬沙坦的钙盐的详细描述及其制备方法，本文引入其全文作为参考。
本发明还涉及治疗由血管紧张素II介导的疾病或情况的方法，包括施用有效量的本发明的组合物，即含有缬沙坦的液体口服制剂。
如美国专利US 5,399,578中所述，通过向需要治疗的个体施用治疗有效量的本发明的药物组合物，可以用包括缬沙坦在内的一类化合物来治疗高血压、充血性心力衰竭、心绞痛、心肌梗塞、动脉粥样硬化、糖尿病性肾病、糖尿病性心肌病、肾功能不全、外周血管疾病、中风、左心室肥大、认知障碍、头痛或慢性心力衰竭。
有些人、特别是儿童和老年人在吞咽固体口服制剂时有困难。而且，儿童和老年人群要求mg/kg给药具有灵活性。因此期望提供稳定持久的含有缬沙坦的液体口服制剂用于在难以吞咽固体口服制剂的个体中治疗上述情况。
现已惊人地发现，可制备货架稳定的含有缬沙坦的液体口服制剂。缬沙坦药物在水中相对不溶，而且在水中还发生降解，因此能够制备货架稳定的制剂是出人意料的。含有缬沙坦的液体口服制剂优选是缬沙坦溶液剂。缬沙坦的浓度为约1mg/ml至约5mg/ml，优选约3mg/ml。本发明的制剂还可含有湿润剂，例如聚山梨醇酯80、泊洛沙姆类，包括泊洛沙姆188、聚氧乙烯蓖麻油和聚氧乙烯氢化蓖麻油以及聚氧乙烯(40)硬脂酸酯。泊洛沙姆188的结构为HO(CH2CH2O)a(CH(CH3)CH2OH)b(CH2CH2O)cH，其中a是75，b是30，c是75，平均分子量约8350。湿润剂的量通常为约0.1％至约5％，或者约0.2％至约1％，或者约0.5％。
制剂的pH可为约4.5至7.0、优选约5.5至约6.5，更优选约5.5至约6.0或约5.7至约6.2、最优选约5.9。合适的缓冲剂包括例如碱金属柠檬酸盐缓冲剂例如碱金属柠檬酸盐与柠檬酸、碱金属醋酸盐缓冲剂例如醋酸钠与醋酸、碱金属琥珀酸盐缓冲剂例如琥珀酸钠与琥珀酸，以及它们的混合物。优选的缓冲剂包括柠檬酸和柠檬酸钠。
制剂通常含有消泡剂，例如聚二甲基硅氧烷，其通常以乳剂形式例如30％乳剂形式加入。这种30％乳剂的加入量可以使在最终制剂中其浓度为约0.1％至约0.25％。可使用甜味剂例如甘露醇、三氯蔗糖、糖精、糖精钠、阿斯帕坦、三氯蔗糖、乙酰磺胺酸钾、葡萄糖、果糖、乳糖醇、麦芽糖醇、麦芽糖、山梨糖醇、蔗糖和木糖醇。还可加入矫味剂以改善顺应性。
适用于口服溶液剂的防腐剂对于本领域技术人员是已知的，其包括例如苯甲酸、山梨酸(及其盐)、尼泊金酯类(丁酯、乙酯、甲酯、丙酯)、苯甲酸钠和丙酸钠。如上所述的防腐剂或其混合物的存在量可以是约0.01％至约0.5％、或者约0.02％至约0.25％、或者约0.1％至约0.2％。在一个实施方案中，制剂含有约0.02％的尼泊金丙酯和约0.18％的尼泊金甲酯。其它实施方案中，制剂含有0.03％的尼泊金丙酯和0.12％的尼泊甲酯、含有0.148％的尼泊金甲酯和0.016％的尼泊金丙酯、含有0.16％的尼泊金甲酯和0.2％的山梨酸钾。
本发明的溶液剂可以在常规液体制剂设备中制备。在一个实施方案中，本发明溶液剂的制备工艺包括将水、药物混合，然后加入缓冲剂成分、甜味剂和矫味剂并混合。或者将防腐剂、甜味剂、矫味剂和缓冲剂成分溶于水。另外将尼泊金甲酯和缬沙坦药物在加热下溶于丙二醇形成溶液。然后将该丙二醇溶液与水溶液部分混合，制备终溶液剂。缓冲剂成分可以进行调节以达到期望的溶液pH。溶液pH为约4.5至7.0之间时溶液剂中的药物最为稳定。
以下的实施例举例说明但不限制本发明的范围。这些实施例只是建议实施本发明的方法。
实施例
实施例1：制剂
表1
表1代文口服溶液剂的组成
Figure GPA00001136248100041
将泊洛沙姆188、防腐剂、甜味剂、矫味剂、缓冲剂成分溶于水，然后加入缬沙坦药物，加热至90℃，形成溶液。根据以上所述使用以下成分制备以下制剂：
表2代文口服溶液剂的组成
Figure GPA00001136248100051
pH 5.9
表3代文口服溶液剂的组成
Figure GPA00001136248100061
表4代文口服溶液剂的组成
Figure GPA00001136248100071
pH 6
表5代文口服溶液剂的组成
Figure GPA00001136248100081
pH 6
表6代文口服溶液剂的组成
Figure GPA00001136248100091
pH 5.5
表7代文口服溶液剂的组成
Figure GPA00001136248100101
pH 5.0
表8代文口服溶液剂的组成
Figure GPA00001136248100111
pH 5.7
表9代文口服溶液剂的组成
Figure GPA00001136248100121
pH 5.7
表10代文口服溶液剂的组成
Figure GPA00001136248100131
pH 4.7
表11代文口服溶液剂的组成
Figure GPA00001136248100141
pH 5.7
表12代文口服溶液剂的组成
pH 6.5
应该理解，尽管结合详细描述对本发明进行了描述，但以上描述旨在举例说明本发明而无意限制本发明的范围。本发明的范围由所附的权利要求书定义。其它方面、优点和修改都在权利要求书的范围内。

Claims (19)

1.含有水和缬沙坦的液体口服制剂，其中所述制剂的pH为约4.5至约7.0。
2.权利要求1的液体口服制剂，其还含有湿润剂。
3.权利要求2的液体口服制剂，其中所述湿润剂选自于聚山梨醇酯80、泊洛沙姆类、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、聚氧乙烯(40)硬脂酸酯、丙二醇及其混合物。
4.权利要求1的液体口服制剂，其中所述制剂的pH为约5.5至约6.2。
5.权利要求4的液体口服制剂，其中所述制剂的pH为约5.9。
6.权利要求1的液体口服制剂，其含有缓冲剂系统。
7.权利要求6的液体口服制剂，其中所述的缓冲剂系统选自于碱金属柠檬酸盐与柠檬酸、碱金属醋酸盐与醋酸、碱金属琥珀酸盐与琥珀酸及其混合物。
8.权利要求7的液体口服制剂，其还含有消泡剂。
9.权利要求7的液体口服制剂，其还含有防腐剂。
10.权利要求9的液体口服制剂，其中所述的防腐剂选自于苯甲酸、山梨酸、尼泊金丁酯、尼泊金乙酯、尼泊金甲酯、尼泊金丙酯、苯甲酸钠、丙酸钠及其混合物或其盐。
11.制备含有缬沙坦的液体口服溶液剂的方法，其包括：
将水、湿润剂、防腐剂、甜味剂、矫味剂和缓冲剂成分混合，
在加热下加入缬沙坦得到溶液剂。
12.权利要求11的方法，其中所述的液体口服溶液剂的pH为约5.5至7.0。
13.权利要求12的方法，其中所述缓冲剂系统成分是柠檬酸和柠檬酸钠。
14.权利要求13的方法，其中所述的液体口服溶液剂的pH为约5.9。
15.将缬沙坦水溶液降解程度降至最低的方法，其包括提供缬沙坦水溶液并将所述溶液的pH调节为约4.5至约7.0。
16.权利要求15的方法，其中将所述pH调节至约5.9。
17.治疗由血管紧张素II介导的病症或情况的方法，其包括向有需要的患者施用有效量的含有缬沙坦的液体口服制剂，其中所述制剂的pH为约4.5至7.0。
18.权利要求17的方法，其中所述患者属于儿童或老年人群。
19.权利要求17的方法，其中所述制剂的pH为约5.9。
CN200880115379A 2007-11-12 2008-11-10 含有缬沙坦的液体组合物 Pending CN101854913A (zh)

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