CN1635884A - 包含外消旋卡朵曲的干粉制剂 - Google Patents
包含外消旋卡朵曲的干粉制剂 Download PDFInfo
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- CN1635884A CN1635884A CNA018131867A CN01813186A CN1635884A CN 1635884 A CN1635884 A CN 1635884A CN A018131867 A CNA018131867 A CN A018131867A CN 01813186 A CN01813186 A CN 01813186A CN 1635884 A CN1635884 A CN 1635884A
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- racecadotril
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- 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
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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
- A61K31/21—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
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- Pharmacology & Pharmacy (AREA)
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- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
化合物外消旋卡朵曲的干粉颗粒制剂及其在治疗腹泻中的应用。
Description
本发明涉及化合物外消旋卡朵曲(racecadotril)的新制剂,及其在治疗腹泻,特别是治疗儿科患者中的应用。
外消旋卡朵曲是外消旋形式的式(I)化合物。
该化合物一般性地以及具体地公开于EP 038758 B1(US 4513009的同族专利)中,并且据述特别具有抑制脑啡肽酶和抗腹泻活性。这些专利指出该化合物可通过口服、非胃肠道或直肠途径对人给药,但是没有详细描述所要求保护的化合物的具体制剂。此外,提供了表明该化合物的生物活性的很多试验结果,但是在所有情况下,都仅仅涉及化合物的静脉内给药制剂。
为了寻找适于对患者给药的制剂,很重要的是,保证制剂是患者最易接受的形式,例如在剂型的性质和外观,以及易于摄取方面是患者最易接受的形式。这些特征在提供有助于保证患者配合所需给药方案的制剂方面很重要。当考虑针对儿科患者(也就是说年龄在14岁或14岁以下的儿童)的剂型时,这样的剂型在保证患者配合方面特别关键。例如,儿童可能经常发现难以吞咽片剂或胶囊制剂,结果液体或悬浮制剂通常是更理想的,并经常认为是儿科患者的制剂选择。
就本发明而言,在很多国家,对于成人使用,化合物外消旋卡朵曲是以填充有干粉制剂的胶囊形式市售(并作为TIORFAN-Societe Civile deRecherche Bioprojet的商标销售),但是迄今为止,由于将该化合物制成制剂时的固有困难没有提供合适的儿科剂型(例如液体或悬浮制剂)。特别是,该化合物疏水性较强,即排斥水,这样其不易于配制成适于儿科使用的悬浮制剂。如上所述,片剂和胶囊不是儿童的优选剂型,尤其是对于年龄更小的儿童,液体/悬浮液剂型一般是更容易接受的剂型。
为了克服提供合适的儿科剂型这个问题,本申请人已经发现,可将外消旋卡朵曲配制成干粉形式,该干粉形式可对患者直接给药,或者加到例如食品中然后再由患者摄取。
因此,在第一个方面,本发明提供了适于口服使用的干粉药物组合物,其中包含外消旋卡朵曲和可药用载体。
适当地,本发明干粉组合物包含外消旋卡朵曲的颗粒。可通过如下文实施例中描述的标准制粒技术制备具有所需粒径的外消旋卡朵曲的颗粒。一般情况下,制备外消旋卡朵曲的颗粒,用包衣材料包衣以有助于遮蔽该组合物的味道,然后与甜味剂/调味剂混合以提供最终的组合物。
适当地,外消旋卡朵曲的颗粒包含外消旋卡朵曲以及有助于遮蔽最终的组合物的味道的甜味剂。合适的甜味剂包括例如天冬甜素和蔗糖,优选蔗糖。然后将外消旋卡朵曲与蔗糖的颗粒包衣以进一步帮助遮蔽最终的产品的味道。可使用标准技术对颗粒进行膜包衣。合适的包衣包括例如羟丙基纤维素、丙烯酸酯和/或异丁烯酸酯共聚物、树脂等。包衣优选是丙烯酸酯或异丁烯酸酯聚合物,最优选是EUDRAGIT NE 3OD。然后可任选将外消旋卡朵曲的包衣颗粒与用于改善粉末流动性的润滑剂,以及用于改善适口性的味道遮蔽剂或甜味剂混合,以制得最终的组合物。
对于本领域技术人员来说,合适的润滑剂是显而易见的,并包括例如长链脂肪酸如硬脂酸及其盐,特别是第II组金属盐例如镁盐或钙盐,或无水胶态二氧化硅。可使用单一的润滑剂或润滑剂的组合来实现所需的流动特性。在本发明中,单一的稀释剂是优选的,无水胶态二氧化硅是最优选的。
对于本领域技术人员来说,合适的甜味剂或调味剂同样是显而易见的,并包括例如蔗糖或天冬甜素作为甜味剂,和标准水果类调味剂。
一般需要将颗粒研磨并过筛以获得合适的粒径分数。特别是,0.630-1.58的粒径是优选的,最优选的是将颗粒研磨并过筛以获得接近1.01mm的分数粒径。
本发明干粉制剂优选以单位剂量制剂提供给患者。适当地,单位剂量包含1-50mg外消旋卡朵曲,更适当地5-30mg外消旋卡朵曲。单位剂量优选包含6、10、18或30mg外消旋卡朵曲。在本发明优选的方面中,在小袋中提供单位剂量的干粉组合物。各个小袋保证组合物在使用之前保持干燥形式,并提供从中配送粉末的方便形式。
本发明干粉可由患者直接摄取,即直接摄取到患者的口中,或患者撒到食品中然后摄取。此外,即使由于外消旋卡朵曲的疏水性颗粒不形成悬浮液,也可以在给药前将粉末加到少量干净的水中,确保将水和颗粒一起剧烈搅拌,然后在颗粒沉降到瓶底之前提供给患者。
如上所述,本发明组合物特别有利于对儿科患者给药,因为目前已知的唯一制剂是胶囊,胶囊对于给儿童、特别是幼小儿童施用不是优选的。通过直接摄取到患者口中或者例如撒到食品上,本发明适口粉末组合物更易被接受且有效得多。
下面的实施例是为了举例说明本发明,而不是限制本发明的范围。
实施例
1.制备用于随后填充到小袋中的250kg批量的外消旋卡朵曲干粉制剂。
组分 | 百分比(%) | 量(kg) |
外消旋卡朵曲 | 1.00 | 2.50 |
蔗糖Eudragit NE 3OD*(干重)杏调味剂胶态二氧化硅 | 96.650.152.000.20 | 241.6250.3755.0000.500 |
纯化水 | 1.250 |
*对于250kg批量,等于1.250kg溶液
在Fielder型制粒机中将外消旋卡朵曲与10%蔗糖在一起混合10分钟。
将Eudragit溶解在纯化水中,并混合以获得均匀的分散液,然后加到外消旋卡朵曲/蔗糖混合物中以形成颗粒。然后将所形成的颗粒在气流化床干燥器(例如Franco Moran或Aeromatic型干燥器)中以45-55℃的干燥温度干燥,直至获得水分含量小于1%的颗粒。然后将干燥的颗粒与剩余的蔗糖、胶态二氧化硅和调味剂在混合器(例如Robotianer转化型混合器)中混合,然后在装配有孔径为1.01mm的筛网的Frewitt型摇摆式制粒机中制备具有一定粒径的颗粒。然后将所得粒径的混合物在Robotianer转化型混合器中再混合直至均匀。
将含有1%活性组分的最终颗粒包装在小袋中,其中是通过以0.6g-3.0g最终颗粒/小袋的量填充小袋获得6-30mg外消旋卡朵曲的剂量强度。
Claims (11)
1.适于口服使用的干粉药物细合物,其中包含外消旋卡朵曲与可药用载体。
2.权利要求1的干粉药物组合物,其中所述组合物包含颗粒形式的外消旋卡朵曲。
3.权利要求2的干粉药物组合物,其中所述外消旋卡朵曲颗粒是用包衣剂包衣的。
4.权利要求3的干粉组合物,其中所述颗粒包衣剂是丙烯酸酯或异丁烯酸酯聚合物。
5.权利要求4的干粉药物组合物,其中所述颗粒包衣剂是EUDRAGIT NE3OD。
6.权利要求1-5任一项的干粉药物组合物,其中所述组合物包含1-50mg外消旋卡朵曲的单位剂量。
7.权利要求6的药物组合物,其中所述组合物包含5-30mg外消旋卡朵曲的单位剂量。
8.权利要求7的药物组合物,其中所述组合物包含6、10、18或30mg外消旋卡朵曲。
9.权利要求1-8任一项的干粉药物组合物,其中所述组合物包含在小袋形式中。
10.用于治疗的权利要求1-9任一项的包含外消旋卡朵曲的干粉药物细合物
11.治疗包括人在内的哺乳动物腹泻的方法,包括施用权利要求1-9任一项的组合物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP00401799.2 | 2000-06-23 | ||
EP00401799 | 2000-06-23 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN2011100456773A Division CN102151247A (zh) | 2000-06-23 | 2001-06-22 | 包含外消旋卡朵曲的干粉制剂 |
Publications (1)
Publication Number | Publication Date |
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CN1635884A true CN1635884A (zh) | 2005-07-06 |
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Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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CNA018131867A Pending CN1635884A (zh) | 2000-06-23 | 2001-06-22 | 包含外消旋卡朵曲的干粉制剂 |
CN2011100456773A Pending CN102151247A (zh) | 2000-06-23 | 2001-06-22 | 包含外消旋卡朵曲的干粉制剂 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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CN2011100456773A Pending CN102151247A (zh) | 2000-06-23 | 2001-06-22 | 包含外消旋卡朵曲的干粉制剂 |
Country Status (13)
Country | Link |
---|---|
US (1) | US6919093B2 (zh) |
EP (1) | EP1294372B1 (zh) |
CN (2) | CN1635884A (zh) |
AT (1) | ATE301999T1 (zh) |
AU (1) | AU2001289606A1 (zh) |
BG (1) | BG66212B1 (zh) |
CA (1) | CA2415957C (zh) |
CZ (1) | CZ299591B6 (zh) |
DE (1) | DE60112756T2 (zh) |
DK (1) | DK1294372T3 (zh) |
ES (1) | ES2247163T3 (zh) |
SK (1) | SK287819B6 (zh) |
WO (1) | WO2001097801A2 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101103960B (zh) * | 2006-07-14 | 2010-12-08 | 海南盛科生命科学研究院 | 一种含有消旋卡多曲的干混悬剂及其制备方法 |
CN102166197A (zh) * | 2011-04-25 | 2011-08-31 | 四川百利药业有限责任公司 | 消旋卡多曲颗粒及其生产工艺 |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2900823B1 (fr) * | 2006-05-15 | 2009-02-13 | Bioprojet Soc Civ Ile | Nouvelle forme d'administration du racecadotril. |
EP2462922A1 (en) | 2010-12-10 | 2012-06-13 | Bioprojet | New form of administration of enkephalinase inhibitor |
JP6246720B2 (ja) * | 2011-10-18 | 2017-12-13 | パーデュー、ファーマ、リミテッド、パートナーシップ | アクリルポリマー製剤 |
AU2013282413B2 (en) | 2012-06-28 | 2018-04-19 | Mcneil-Ppc, Inc. | Racecadotril lipid compositions |
US9114171B2 (en) * | 2012-06-28 | 2015-08-25 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
SG11201408565VA (en) | 2012-06-28 | 2015-02-27 | Mcneil Ppc Inc | Racecadotril liquid compositions |
US9801819B2 (en) | 2012-06-28 | 2017-10-31 | Johnson & Johnson Consumer Inc. | Racecadotril compositions |
TR201801726T4 (tr) * | 2012-12-26 | 2018-03-21 | Ilko Ilac Sanayi Veticaret A S | Rasekadotri̇l ve farmasöti̇k bi̇leşi̇mleri̇. |
EP2918268A1 (en) | 2014-03-10 | 2015-09-16 | Galenicum Health S.L. | Pharmaceutical compositions comprising an active agent |
EP2949318A1 (en) * | 2014-05-26 | 2015-12-02 | Galenicum Health S.L. | Pharmaceutical compositions comprising racecadotril |
MA40859A (fr) | 2014-10-29 | 2017-09-05 | Johnson & Johnson Consumer Inc | Particules de cadotril |
EP3558272A1 (en) | 2016-12-23 | 2019-10-30 | Hermes Arzneimittel GmbH | Oral pharmaceutical composition with improved taste-masking properties |
WO2018163195A1 (en) | 2017-03-06 | 2018-09-13 | Athena Drug Delivery Solutions Pvt Ltd. | A pharmaceutical composition comprising racecadotril and process for preparing the same |
CN109589310A (zh) * | 2017-10-01 | 2019-04-09 | 北京万全德众医药生物技术有限公司 | 消旋卡多曲干混悬剂及其制备方法 |
GB2586201B (en) * | 2019-05-14 | 2023-05-24 | Orbit Pharmaceuticals | A stable powder formulation of racecadotril |
EP4056171A1 (en) | 2021-03-12 | 2022-09-14 | Athena Pharmaceutiques SAS | Taste masked racecadotril tablet composition and process for preparation thereof |
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FR2480747A1 (fr) * | 1980-04-17 | 1981-10-23 | Roques Bernard | Derives d'acides amines et leur application therapeutique |
ZA919510B (en) * | 1990-12-05 | 1992-10-28 | Smithkline Beecham Corp | Pharmaceutical compositions |
GR1002332B (el) * | 1992-05-21 | 1996-05-16 | Mcneil-Ppc Inc. | Νεες φαρμακευτικες συνθεσεις που περιεχουν σιμεθεικονη. |
US5914132A (en) * | 1993-02-26 | 1999-06-22 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
WO1997033571A1 (fr) * | 1996-03-14 | 1997-09-18 | Shionogi & Co., Ltd. | Preparation d'ecadotril a microdispersion et liberation rapides |
US6649186B1 (en) * | 1996-09-20 | 2003-11-18 | Ethypharm | Effervescent granules and methods for their preparation |
US6270804B1 (en) * | 1998-04-03 | 2001-08-07 | Biovail Technologies Ltd. | Sachet formulations |
GB0015490D0 (en) * | 2000-06-23 | 2000-08-16 | Smithkline Beecham Lab | Novel formulations |
-
2001
- 2001-06-22 CN CNA018131867A patent/CN1635884A/zh active Pending
- 2001-06-22 CN CN2011100456773A patent/CN102151247A/zh active Pending
- 2001-06-22 CA CA2415957A patent/CA2415957C/en not_active Expired - Lifetime
- 2001-06-22 AT AT01969310T patent/ATE301999T1/de active
- 2001-06-22 DE DE60112756T patent/DE60112756T2/de not_active Expired - Lifetime
- 2001-06-22 WO PCT/EP2001/007086 patent/WO2001097801A2/en active IP Right Grant
- 2001-06-22 AU AU2001289606A patent/AU2001289606A1/en not_active Abandoned
- 2001-06-22 CZ CZ20030185A patent/CZ299591B6/cs not_active IP Right Cessation
- 2001-06-22 ES ES01969310T patent/ES2247163T3/es not_active Expired - Lifetime
- 2001-06-22 DK DK01969310T patent/DK1294372T3/da active
- 2001-06-22 SK SK76-2003A patent/SK287819B6/sk not_active IP Right Cessation
- 2001-06-22 EP EP01969310A patent/EP1294372B1/en not_active Expired - Lifetime
-
2003
- 2003-01-13 US US10/347,332 patent/US6919093B2/en not_active Expired - Lifetime
- 2003-01-20 BG BG107481A patent/BG66212B1/bg unknown
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101103960B (zh) * | 2006-07-14 | 2010-12-08 | 海南盛科生命科学研究院 | 一种含有消旋卡多曲的干混悬剂及其制备方法 |
CN102166197A (zh) * | 2011-04-25 | 2011-08-31 | 四川百利药业有限责任公司 | 消旋卡多曲颗粒及其生产工艺 |
CN102166197B (zh) * | 2011-04-25 | 2012-09-05 | 四川百利药业有限责任公司 | 消旋卡多曲颗粒及其生产工艺 |
Also Published As
Publication number | Publication date |
---|---|
EP1294372A2 (en) | 2003-03-26 |
DE60112756T2 (de) | 2006-06-08 |
AU2001289606A1 (en) | 2002-01-02 |
ATE301999T1 (de) | 2005-09-15 |
SK287819B6 (sk) | 2011-11-04 |
EP1294372B1 (en) | 2005-08-17 |
BG66212B1 (bg) | 2012-05-31 |
CZ299591B6 (cs) | 2008-09-10 |
DK1294372T3 (da) | 2005-09-19 |
CN102151247A (zh) | 2011-08-17 |
CA2415957C (en) | 2010-08-10 |
WO2001097801A2 (en) | 2001-12-27 |
ES2247163T3 (es) | 2006-03-01 |
DE60112756D1 (de) | 2005-09-22 |
CZ2003185A3 (cs) | 2003-05-14 |
CA2415957A1 (en) | 2001-12-27 |
BG107481A (bg) | 2003-09-30 |
US20030166718A1 (en) | 2003-09-04 |
SK762003A3 (en) | 2003-07-01 |
WO2001097801A3 (en) | 2002-09-12 |
US6919093B2 (en) | 2005-07-19 |
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