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CN1303992C - 用于局部治疗口咽腔疾病的基于双氯芬酸的组合物 - Google Patents

用于局部治疗口咽腔疾病的基于双氯芬酸的组合物 Download PDF

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CN1303992C
CN1303992C CNB038105764A CN03810576A CN1303992C CN 1303992 C CN1303992 C CN 1303992C CN B038105764 A CNB038105764 A CN B038105764A CN 03810576 A CN03810576 A CN 03810576A CN 1303992 C CN1303992 C CN 1303992C
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diclofenac
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topical treatment
oropharyngeal cavity
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CN1652763A (zh
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M·平扎
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Angelini Acraf SpA
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Aziende Chimiche Riunite Angelini Francesco ACRAF SpA
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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics

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Abstract

本发明涉及用于局部治疗口咽腔疾病的组合物，其包含双氯芬酸与氨丁三醇的盐的水溶液，其中所述盐的量为0.1%至0.2%(w/w)且将pH调为7至8。

Description

用于局部治疗口咽腔疾病的基于双氯芬酸的组合物
本发明涉及用于局部治疗口咽腔疾病的基于双氯芬酸的组合物。
已知双氯芬酸[2-(2，6-二氯苯胺基)苯乙酸]是一种广泛使用的药物产品，具有抗炎、解热和镇痛性质。它主要以原形或以其与无机或有机碱的盐形式全身施用。
但是，它的盐几乎不溶于水。
专利US-4 407 824的实施例2描述了双氯芬酸与氨丁三醇[三(羟甲基)甲胺]的盐的制备，但没有详细说明其在水中的溶解度，并且未给出任何含有上述盐的药物形式的实例。
在EP-A-0 521 393中也确认了双氯芬酸盐不溶于水的问题，其建议用胆碱盐解决所述问题。据描述，该盐是可令人惊讶地溶于水且还特别适于制备漱口剂的化合物。
但是，胆碱盐具有胆碱的典型缺点，即众所周知的其令人不愉快的气味和味道。
对于需要与粘膜保持接触较长时间以发挥其治疗作用、用于局部治疗口咽腔疾病的组合物，例如漱口剂和口腔喷雾剂，这些缺点特别不利。
即使加入大量能掩盖其味道的成分[0.5％(w/w)的乙酰舒泛和35％(w/w)的山梨醇]，用于局部治疗口咽腔疾病的基于双氯芬酸与胆碱的盐的组合物仍然口味较差。
因此，仍然非常需要用于局部治疗口咽腔疾病、具有令人愉快或者至少是中性味道的基于双氯芬酸的组合物。
尽管A.Fini等人已经报道说认为氨丁三醇盐在水中的溶解度为0.167g/100ml(European J.Pharm.Sci. 4，231，1996)，但本发明人所进行的试验已证明：即使在化学计算量(分别为0.029至0.058g)的氨丁三醇存在下，量为0.071至0.142g的双氯芬酸也不能溶于100ml水(对比实施例1和2)。
令人惊讶的是，现已发现：如果将它们的pH调至7-8，则含有0.071至0.142g双氯芬酸与化学计算量(分别为0.029至0.058g)氨丁三醇的上述组合物在100ml水中变得澄明且长时间保持澄明(实施例1和2)。
同样令人惊讶的是，已发现：这些溶液的口味良好，并且也可非常容易地用中等量的标准矫味剂和甜味剂来改善口味。
因此，本发明的一项主题是用于局部治疗口咽腔疾病的组合物，其特征在于：其包含双氯芬酸与氨丁三醇的盐的水溶液，其中所述盐的量为0.1％至0.2％(w/w)且将pH调为7至8。
在本发明的组合物中，双氯芬酸与氨丁三醇的盐的优选浓度为0.1％(w/w)。
有利地，上述漱口剂包含其它标准成分，例如乙醇、多羟基醇、络合剂、防腐剂、湿润剂、甜味剂、矫味剂、着色剂等。
这些成分的典型例子有：
多羟基醇：甘油、丙二醇和聚乙二醇；
络合剂：依地酸钠；
防腐剂：对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、苯甲酸钠；
湿润剂：甘油聚乙二醇蓖麻醇酸酯(glyceryl polyethylene glycolricinoleate)；
甜味剂：糖精钠、山梨醇、乙酰舒泛和木糖醇；
胶凝剂：聚乙二醇和聚丙二醇嵌段共聚物，例如PoloxamerTM 407；
矫味剂：薄荷矫味剂、天然什锦果味矫味剂和石榴汁矫味剂；
着色剂：喹啉黄E104和专利蓝E131。
用本发明的组合物进行治疗可受益的口咽腔疾病的典型例子有：由放射治疗和化学治疗引起的龈炎、舌炎、口炎、口疮、牙周病、牙周炎、喉炎、咽炎和粘膜炎。另外，本发明的组合物可用于治疗牙外科手术和/或普通外科手术的后遗效应。
本发明组合物的优选剂型是漱口剂和口腔喷雾剂。
根据药物化学工作者已知的技术可容易地制备这些剂型，包括如混合、溶解、灭菌等步骤。
以下实施例用于举例说明本发明，但不限制本发明。
                      实施例1
                      漱口剂A
100g漱口剂A含有：
双氯芬酸与氨丁三醇的盐*              0.104g
木糖醇                               10.000g
PoloxamerTM407                      0.500g
苯甲酸钠                             0.500g
天然薄荷矫味剂                       0.500ml
E 131水溶液(1mg/ml)                  0.200ml
pH 7.8的磷酸盐缓冲液**适量至         100g
pH                                   7.6
*等于0.074g 双氯芬酸
**1升在纯化水中的溶液含有：无水磷酸氢二钠(5.803g)、无水磷酸二氢钾(3.522g)和1N氢氧化钠(18.70ml)。
                        实施例2
                        漱口剂B
除以下区别外，100g漱口剂B具有与漱口剂A相同的组成：
-其还含有天然什锦果味矫味剂(0.04ml)和天然石榴汁矫味剂(0.02ml)，和
-其含有0.25mlE 124水溶液(10mg/ml)，用于代替0.2ml E 131水溶液(1mg/ml)。
                       对比实施例1
                       漱口剂C
制备除含有纯化水代替pH 7.8的磷酸盐缓冲液之外与漱口剂A组成相同的漱口剂。
                       对比实施例2
                       漱口剂D
制备除含有纯化水代替pH 7.8的磷酸盐缓冲液之外与漱口剂B组成相同的漱口剂。
                       稳定性
发现漱口剂A和B稳定。
相反，漱口剂C和D尤其是在冷的条件下在一段时间中释放双氯芬酸沉淀。
对于所含有的双氯芬酸与氨丁三醇的盐的量低于(以上所引用的)Fini等人报道的溶解度限度的漱口剂，该现象是完全出乎意料的。

Claims (8)

1.用于局部治疗口咽腔疾病的组合物，其特征在于：其包含双氯芬酸与氨丁三醇的盐的水溶液，其中所述盐的量为0.1％至0.2％(w/w)且将pH调为7至8。
2.根据权利要求1的组合物，其特征在于：其含有0.1％(w/w)的双氯芬酸与氨丁三醇的盐。
3.根据权利要求1或2的组合物，其特征在于：其还包含选自糖精钠、山梨醇、乙酰舒泛和木糖醇的甜味剂。
4.根据权利要求1或2的组合物，其特征在于：其还包含选自苯甲酸钠、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯的防腐剂。
5.根据权利要求1或2的组合物，其特征在于：其还包含由聚乙二醇和聚丙二醇嵌段共聚物组成的胶凝剂。
6.根据权利要求1或2的组合物，其特征在于：其还包含可药用的矫味剂。
7.根据权利要求1或2的组合物，其特征在于：其还包含可药用的着色剂。
8.根据权利要求1或2的组合物，其特征在于：其用于治疗由放射治疗和化学治疗引起的龈炎、舌炎、口炎、口疮、牙周病、牙周炎、喉炎、咽炎、口腔粘膜炎，以及牙外科手术和/或普通外科手术的后遗效应。
CNB038105764A 2002-05-10 2003-04-16 用于局部治疗口咽腔疾病的基于双氯芬酸的组合物 Expired - Fee Related CN1303992C (zh)

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ITMI02A000986 2002-05-10
IT2002MI000986A ITMI20020986A1 (it) 2002-05-10 2002-05-10 Composizione a base di diclofenac per il trattamento topico di affezioni del cavo orofaringeo

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EP (1) EP1503747B1 (zh)
JP (1) JP2005526120A (zh)
KR (1) KR20040111415A (zh)
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AR (1) AR039977A1 (zh)
AT (1) ATE333872T1 (zh)
AU (1) AU2003232480B2 (zh)
CA (1) CA2477773C (zh)
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GE (1) GEP20063822B (zh)
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ITMI20032523A1 (it) 2003-12-19 2005-06-20 Acraf Forma di dosaggio per uso orale comprendente un farmaco
ITMI20040235A1 (it) * 2004-02-13 2004-05-13 Therapicon Srl Preparazione farmaceutica per il cavo orale
CN101138544B (zh) * 2006-09-06 2010-09-29 上海医药工业研究院 双氯芬酸或其盐局部成膜凝胶组合物及其应用
CN104606126A (zh) 2006-10-17 2015-05-13 纽沃研究股份有限公司 双氯芬酸凝胶
US8618164B2 (en) 2009-03-31 2013-12-31 Nuvo Research Inc. Treatment of pain with topical diclofenac compounds
US8546450B1 (en) 2009-03-31 2013-10-01 Nuvo Research Inc. Treatment of pain with topical diclofenac compounds
US20120003162A1 (en) * 2010-06-30 2012-01-05 Mcneil-Ppc, Inc. Methods of Preparing Non-Alcohol Bioactive Esential Oil Mouth Rinses
KR101936192B1 (ko) 2010-12-29 2019-01-08 엘지전자 주식회사 공기조화기의 실외기
DE102011111944A1 (de) * 2011-08-29 2013-02-28 Richard A. Huthmacher Verwendung von Diclofenac zur Verhinderung und Behandlung grippaler Infekte sowie durch grippale Infekte bewirkter Krankheitssymtome
US20150374745A1 (en) * 2014-06-30 2015-12-31 Mitochondrial Substrate Invention Limited Nutrients solutions for enhancement of cognitive function
CN104546527A (zh) * 2014-12-29 2015-04-29 福建省闽东力捷迅药业有限公司 一种含七叶皂苷钠的漱口液及其制备方法

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US4407824A (en) * 1981-02-24 1983-10-04 Ciba-Geigy Corporation Pharmaceutical preparations for topical application which contain salts of alkanecarboxylic acids, novel carboxylic acid salts and the production thereof
EP0373103A1 (de) * 1988-11-10 1990-06-13 Ciba-Geigy Ag Flüssige orale Formulierung
US5852002A (en) * 1989-09-21 1998-12-22 Hyal Pharmaceutical Corporation Treatment of conditions and disease
WO1992000725A1 (en) * 1990-07-13 1992-01-23 Farcon Ag Liquid oral pharmaceutical compositions having anti-inflammatory activity
US5972906A (en) * 1991-07-03 1999-10-26 Hyal Pharmaceutical Corporation Treatment of mucous membrane disease, trauma or condition and for the relief of pain thereof
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EA200401090A1 (ru) 2005-02-24
CN1652763A (zh) 2005-08-10
PL371426A1 (en) 2005-06-13
EP1503747A1 (en) 2005-02-09
GEP20063822B (en) 2006-05-10
EP1503747B1 (en) 2006-07-26
CA2477773A1 (en) 2003-11-20
HK1071312A1 (zh) 2005-07-15
KR20040111415A (ko) 2004-12-31
AU2003232480A1 (en) 2003-11-11
WO2003094905A8 (en) 2004-04-01
ITMI20020986A1 (it) 2003-11-10
MXPA04010401A (es) 2005-02-17
PT1503747E (pt) 2006-11-30
US20050100597A1 (en) 2005-05-12
DK1503747T3 (da) 2006-11-27
DE60307086T2 (de) 2007-02-01
IL163871A (en) 2007-10-31
DE60307086D1 (de) 2006-09-07
JP2005526120A (ja) 2005-09-02
AU2003232480B2 (en) 2008-07-31
WO2003094905A1 (en) 2003-11-20
ITMI20020986A0 (it) 2002-05-10
IL163871A0 (en) 2005-12-18
UA79110C2 (en) 2007-05-25
EA006165B1 (ru) 2005-10-27
AR039977A1 (es) 2005-03-09
CA2477773C (en) 2011-01-18

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