CN1096279C - 含有酸性不溶或难溶活性物质的碱金属盐或赖氨酸盐的起泡混合物 - Google Patents
含有酸性不溶或难溶活性物质的碱金属盐或赖氨酸盐的起泡混合物 Download PDFInfo
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- A—HUMAN NECESSITIES
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Abstract
该起泡混合物含有可溶碱金属盐或赖氨酸盐形式的至少一种酸性不溶或难溶药物活性物质，它与碱性组分呈密切混合状态并优选包裹起泡体系碱性组份的颗粒，例如用碳酸氢钠和/或碳酸钠包裹。两种组份也可借助于粘合剂细粉化成为颗粒。特别是该起泡混合物每100份活性物质含有至少0.5，优选1至3份表面活性剂，特别是磺基琥珀酸二辛酯，和/或至少1，优选3至5份粘合剂或悬浮剂，特别是聚乙烯吡咯烷酮。起泡体系的酸性组分是表面钝化的。
Description
本发明涉及含有可溶碱金属盐或赖氨酸盐(Lysinate)形式的至少一种酸性不溶或难溶药物活性物质的起泡混合物。这些药物活性物质例如是乙酸或丙酸的有机衍生物，例如异丁苯丙酸、甲氧萘丙酸、二氯伐草克、仲丁巴比妥、苯巴比妥、先锋唑啉、泛影酸盐(酯)、利尿酸盐(酯)、氟联苯丙酸、乙酰磺胺或赫它西林。
该酸性活性物质一般不能作成细分散或胶体状，因此乐意在溶液中作为其钾盐(例如赫它西林)或赖氨酸盐(例如异丁苯丙酸)，或作为其钠盐(也可以为异丁苯丙酸，及一般其它活性物质)服用。
与纯酸相反，这些活性物质的碱金属盐一般是易水溶性的，但常常有一种苦味，而且在酸溶液中沉淀成块和/或形成泡沫；在用固体药剂时，由胃酸也引起这种现象。所以，这些活性物质容易引起胃壁刺激。
为了避免这些缺点，EP-A1-369228已经提出，将100重量份水溶性异丁苯丙酸盐与200至1000重量份载体、30至80重量份稳定剂(例如聚乙烯吡咯烷酮，“PVP”)和10至100重量份碱金属碳酸盐造粒，并将得到的颗粒与100至400重量份酸组分混合。目的是在将起泡药片溶解进溶液后得到钠盐。这可以通过以下措施实现，即在选定组成时使PH值总是保持大于6。然而，这种溶液的味道不太舒适；例如二氯伐草克钠甚至是苦的。此外，为了防止在起泡起间活性物质沉淀成为酸，必须使用超常数量的PVP。
因此，本发明的目的在于，提供开头所述类型的起泡混合物，该混合物可在酸性溶液或胃酸作用下产生滞后的、但总是细分散或者甚至是胶体状的活性物质沉淀。其中PH值应调节到4至5.5，这时的起泡溶液或悬浮液会好喝得多。
本发明第一次意外地达到了该目的，其解决方案是不仅对可溶性活性物质而且也对起泡体系的酸性成分进行表面钝化。优选用碱金属盐或赖氨酸盐包封起泡体系的碱性成分颗粒，例如用碳酸氢钠和/或碳酸钠，特别是再用另一种碱金属碳酸盐包覆。有利的是使活性物质层也含有(以100重量份活性物质计)至少0.5，优选1至3重量份表面活性剂，尤其是二十二烷酸(Docusat)钠或十二烷基硫酸钠。为了寻找所提任务的解决方案而从众多的配方可能性中选择极少量(甚至有时根本没有)稳定剂量与表面钝化组分的结构，这对于技术人员来讲不是轻而易举的，可能需要大量的思考步骤。
理论上虽然可以得到微米级的各种酸。但本发明的沉淀要比可能得到的微粉状活性物质细得多。在起泡药片或起泡混合物溶解时，由于紧紧连在一个碳酸氢钠或一个碳酸钠粒子上，活性酸的碱金属盐或赖氨酸盐首先溶解；它仍随后在饮用溶液中通过起泡体系的酸成分例如在5秒钟内有时甚至形成胶体状的沉淀，但无论如何是细分散的。这些细分散的颗粒可在较长时间内悬浮，因而形成好喝的液体。
所述的分散或者甚至是胶体状的酸对胃壁不再起刺激作用，此外，起泡体系的缓冲作用也保护胃壁。
本发明的活性物质大多数不是应当被胃的酸液吸收的物质，而且应当被肠的碱液吸收的物质。由于活性物质在溶液中的细分散形式，从胃中通过仅需约15至20分钟，所以在进入幽门和肠时，由于细分散成几乎是胶体状的活性物质的酸颗粒有很高的表面积，可以立即发生吸收。
然而，为了可以达到这种效果，使活性物质碱金属盐或赖氨酸盐在起泡药片溶解时短时间进入溶液，并在形成PH值为4至5.5的酸性溶液时才(滞后地)使活性物质沉淀成酸，必须使活性物质碱金属盐或赖氨酸盐非常紧密地结合在碱金属碳酸盐例如碳酸氢钠或碳酸钠上，以便在溶解的瞬间在颗粒周围形成一种碱性保护来延缓沉淀。仅将活性物质的盐与一种起泡碱混合则没有这种功能，因为这时在溶解的瞬间立即会与酸如柠檬酸相接触。
因此，有利的是向混合物中再加入药物及毒性方面都没有怀疑的表面活性剂例如二十二烷酸(Docusat)钠或十二烷基硫酸钠(深色或软膏状的、难加工的表面活性剂除外)，优选与粘合剂(例如糊精或聚乙烯吡咯烷酮，或水解胶体例如麦芽糊精)结合使用。由此大大改进了活性物质酸在液体中的悬浮性能。但当使用大量粘合剂时可能引起不希望有的起泡，会延迟起泡药片的溶解。该作用也与是否用水或醇溶液处理有关。
因此，有利的是使混合物每100重量份活性物质至少含有1，优选3至5，但最高20重量份粘合剂或悬浮剂，尤其是聚乙烯吡咯烷酮。与开头所述EP-A1相反，这里仅少量粘合剂是必需的，因为在起泡药片溶解时已由碱金属盐或赖氨酸盐形成活性物质酸，并细分散地分布在溶液中。因此，为了在溶解时实现酸粒子更好的润湿，也就选加入一种表面活性剂。
活性物质的结合可以各种方式实现：
1.溶解碱金属或赖氨酸盐，用碳酸氢钠吸收该溶液，随后干燥；活性物质在碳酸氢钠晶体表面再次结晶出来。
2.将细粉末状活性物质与碳酸氢钠混合；两者与一种粘合剂例如糊精附聚。由于粘合剂是延缓可溶性的，由此可实现活性物质盐在碳酸氢钠或碳酸钠上的结合。因此，活性物质先作为盐进入溶液，并在时间上滞后地在与起泡体系的酸成分作用和反应后才细分散或胶体地作为酸而沉淀。
例1
使25份二氯伐草克钠与10份丙二醇和40份山梨醇以及1份聚乙烯吡咯烷酮K30和0.5份表面活性物质特别是二十二烷酸(Docusat)钠一起溶入40份乙醇和15份水中。加入表面活性剂的好处是使颗粒在加酸沉淀阶段立即湿润，从而可以更好地防止结块。将该溶液浇在350份碳酸氢钠上并使其良好分布；随后添加100份碳酸钠，碳酸钠先吸水，随后才进入溶液，以改善碱性保护。然后在真空下干燥该物料，并筛至例如0.1至0.5mm的所需粒度。接着将颗粒混入一种由一种固体可食用有机的表面钝化的酸组成的酸性起泡基料，并且需要时压制成药片。
表面钝化可以公知方式例如按EP-B1-272312或WO93/00886所述进行。但也可以在钝化时回避酸和碳酸盐之间的反应，使酸晶体如柠檬酸的表面由一种柠檬酸钠溶液涂覆或覆盖，并在该层上再涂一层碳酸氢钠和/或碳酸钠溶液。特别有利的是在一个真空混合锅中进行这种涂覆，得到最好的保护。
例2
将25份二氯伐草克钠与350份碳酸氢钠混合并与下列溶液一起造粒：15份糊精、1份PVP和0.5份表面活性物质被溶入20份乙醇和20份水中。接着干燥产物，按需要筛成0.1至0.5mm，随后如例1那样处理。
例3：
将1重量份二十二烷酸(Docusat)钠、2重量份PVP和100重量份甲氧萘丙酸钠溶入400重量份73％的醇中。在一台真空混合器中将700重量份碳酸氢钠搅拌加热到50℃；用真空吸入溶液，并搅拌使之均匀分布，将150重量份碳酸钠涂覆在湿颗粒上。随后在真空下搅拌干燥该颗粒，并筛至0.25mm。
制备由碳酸氢钠进行表面钝化的酸颗粒：
将1400重量份晶体和200重量份粉末状柠檬酸在一台真空混合器中搅拌加热到60℃，并用6重量份水润湿。接着加入200重量份碳酸氢钠并使之在柠檬酸表面上反应，随后添加50重量份碳酸钠。借助于真空搅拌干燥产物。
使甲氧萘丙酸与酸颗粒相互混合，并掺入甜料、香料及填料。混合均匀并将颗粒压制成药片，每片重3.2g。
将起泡药片放入水中时，药片约80秒内溶解，其中甲氧萘丙酸在溶液中分布成细的悬浮体，溶液的PH值为4至4.5。
Claims (9)
1.一种含有下列成分的起泡制剂：
i)可溶碱金属盐或赖氨酸盐形式的至少一种酸性不溶或难溶药物活性物质，和
ii)由一种固体可食用有机酸的酸性组分和一种由至少一种碱金属的碳酸盐或碳酸氢盐组成的碱性组分组成的起泡体系，其中
所述酸性组分被所述碱性组分的一部分包覆，
所述活性物质与所述碱性组分的另一部分结合，并且
所述结合后的活性物质与所述包覆后的酸性组分以混合物的形式存在。
2.按照权利要求1的制剂，其中所述活性物质包裹着所述碱性组分的颗粒，然后该颗粒进一步被碱金属碳酸盐包覆。
3.按照权利要求2的制剂，其中所述活性物质与一种粘合剂相混合存在。
4.按照权利要求3的制剂，其中每100重量份活性物质含有约3至5重量份粘合剂。
5.按照权利要求2的制剂，其中所述活性物质与一种表面活性剂相混合存在。
6.按照权利要求5的制剂，其中每100重量份活性物质至少含有0.5重量份表面活性剂。
7.按照权利要求6的制剂，其中每100重量份活性物质至少含有约1至3重量份表面活性剂。
8.按照权利要求5的制剂，该制剂溶解于口服水溶液中，其中所述活性物质作为可溶碱金属盐或赖氨酸盐的酸而沉淀出，并且以细分散的形式存在于所述水溶液中。
9.按照权利要求1的制剂，其中在所述制剂溶解于口服水溶液中之后，该水溶液的pH为4至5.5。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH265293 | 1993-09-07 | ||
| CH2652/93 | 1993-09-07 |
Publications (2)
| Publication Number | Publication Date |
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| CN1107366A CN1107366A (zh) | 1995-08-30 |
| CN1096279C true CN1096279C (zh) | 2002-12-18 |
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| CN94113873A Expired - Fee Related CN1096279C (zh) | 1993-09-07 | 1994-09-07 | 含有酸性不溶或难溶活性物质的碱金属盐或赖氨酸盐的起泡混合物 |
Country Status (9)
| Country | Link |
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| US (1) | US5593693A (zh) |
| EP (2) | EP0642784B1 (zh) |
| JP (1) | JPH07223937A (zh) |
| CN (1) | CN1096279C (zh) |
| AT (2) | ATE219762T1 (zh) |
| CA (1) | CA2131515C (zh) |
| DE (3) | DE59410143D1 (zh) |
| DK (1) | DK0642784T3 (zh) |
| ES (1) | ES2133454T3 (zh) |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1283029B1 (it) * | 1996-05-17 | 1998-04-03 | Resa Farma | Composizioni farmaceutiche a base di diclofenac |
| US7687542B2 (en) | 1996-05-17 | 2010-03-30 | Kowa Pharmaeuticals America, Inc. | Rapidly bioavailable tablet and capsule formulations of diclofenac |
| US6974595B1 (en) | 1996-05-17 | 2005-12-13 | Proethic Pharmaceuticals, Inc. | Pharmaceutical compositions based on Diclofenae |
| EP0962443B1 (de) * | 1998-06-03 | 2003-04-23 | Dr. Gergely & Co. | Mit Alkali- bzw. Erdalkali-Ionen dotierte Zitronensäure |
| US6121215A (en) * | 1999-08-27 | 2000-09-19 | Phyzz, Inc. | Foaming effervescent bath product |
| DE59905198D1 (de) * | 1999-09-09 | 2003-05-28 | Gergely Dr & Co | Brausegranulat mit verzögerter Brausewirkung |
| US6432450B1 (en) | 1999-09-09 | 2002-08-13 | Gerhard Gergely | Effervescent granules with delayed effervescent effect |
| FR2811531A1 (fr) * | 2000-07-12 | 2002-01-18 | Bionatec | Produit pour le maintien d'objets decoratifs, procede de fabrication et d'utilisation dudit produit |
| EA200401244A1 (ru) * | 2002-03-25 | 2005-02-24 | Вашингтон Юниверсити | Химерная поджелудочная железа |
| WO2004050068A1 (en) * | 2002-11-29 | 2004-06-17 | Janssen Pharmaceutica N.V. | Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base |
| WO2005115345A1 (en) * | 2004-05-28 | 2005-12-08 | Imaginot Pty Ltd | Oral therapeutic compound delivery system |
| US8216610B2 (en) * | 2004-05-28 | 2012-07-10 | Imaginot Pty Ltd. | Oral paracetamol formulations |
| JO3352B1 (ar) | 2005-06-17 | 2019-03-13 | Apr Applied Pharma Res Sa | صيغ دايكلوفيناك وطرق استخدامه |
| EP3263117A1 (en) * | 2005-11-28 | 2018-01-03 | Imaginot Pty Ltd. | Oral therapeutic compound delivery system |
| US7939561B2 (en) | 2006-02-07 | 2011-05-10 | Apr Applied Pharma Research S.A. | Blister packaging for acute pain regimens |
| US7700125B2 (en) | 2006-02-07 | 2010-04-20 | Kowa Pharmaceuticals America, Inc. | Moisture resistant container systems for rapidly bioavailable dosage forms |
| PL2037758T3 (pl) | 2006-07-12 | 2019-04-30 | Purac Biochem Bv | Cząstki klasy spożywczej powlekane częściowo zobojętnionym kwasem |
| WO2013052019A1 (en) * | 2011-08-19 | 2013-04-11 | Mahmut Bilgic | Production method for effervescent formulations comprising diclofenac |
| WO2013109222A1 (en) * | 2012-01-18 | 2013-07-25 | Mahmut Bilgic | Formulations comprising diclofenac as the active agent |
| EP3037387A1 (en) * | 2014-12-22 | 2016-06-29 | Solvay SA | Alkali metal bicarbonate particles with exceptional flowability |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0369228A1 (de) * | 1988-11-12 | 1990-05-23 | Bayer Ag | Ibuprofen-Brausezubereitungen |
| WO1993000886A1 (de) * | 1991-07-01 | 1993-01-21 | Gerhard Gergely | Reaktionsdotierte brausesysteme |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3165572D1 (en) * | 1981-10-06 | 1984-09-20 | Gergely Gerhard | Process for manufacturing effervescent granules which may be transformed, when required, into effervescent tablets |
| US4678661A (en) * | 1983-09-28 | 1987-07-07 | Gerhard Gergely | Effervescent composition and method of making same |
| SE462014B (sv) * | 1983-09-28 | 1990-04-30 | Gerhard Gergely | Brusgranulat och foerfarande foer dess framstaellning |
| DE3440288C2 (de) * | 1984-11-05 | 1987-03-12 | Gergely, Gerhard, Dr.-Ing., Wien | Pharmazeutische Zubereitung mit einem Gehalt an Ibuprofen sowie Verfahren zu ihrer Herstellung |
| DE3627475A1 (de) * | 1986-06-26 | 1988-01-14 | Gergely Gerhard | Verfahren zum herstellen eines brausegranulates, danach hergestelltes brausegranulat sowie dessen verwendung |
| US5064656A (en) * | 1989-11-14 | 1991-11-12 | Dr. Gergely & Co. | Uncoated pharmaceutical reaction tablet |
| IT1246350B (it) * | 1990-07-11 | 1994-11-17 | Eurand Int | Metodo per ottenere una rapida sospensione in acqua di farmaci insolubili |
| DE9300886U1 (de) * | 1993-01-22 | 1993-05-27 | Ebinger, Klaus, 5000 Köln | Stabförmige Magnetometer-Sonde |
-
1994
- 1994-09-05 DE DE59410143T patent/DE59410143D1/de not_active Expired - Lifetime
- 1994-09-05 DE DE9422239U patent/DE9422239U1/de not_active Expired - Lifetime
- 1994-09-05 EP EP94113877A patent/EP0642784B1/de not_active Expired - Lifetime
- 1994-09-05 AT AT98110087T patent/ATE219762T1/de active
- 1994-09-05 ES ES94113877T patent/ES2133454T3/es not_active Expired - Lifetime
- 1994-09-05 DE DE59408273T patent/DE59408273D1/de not_active Expired - Lifetime
- 1994-09-05 EP EP98110087A patent/EP0867426B1/de not_active Expired - Lifetime
- 1994-09-05 DK DK94113877T patent/DK0642784T3/da active
- 1994-09-05 AT AT94113877T patent/ATE180164T1/de active
- 1994-09-06 CA CA002131515A patent/CA2131515C/en not_active Expired - Lifetime
- 1994-09-07 JP JP6213623A patent/JPH07223937A/ja active Pending
- 1994-09-07 CN CN94113873A patent/CN1096279C/zh not_active Expired - Fee Related
- 1994-09-07 US US08/301,970 patent/US5593693A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0369228A1 (de) * | 1988-11-12 | 1990-05-23 | Bayer Ag | Ibuprofen-Brausezubereitungen |
| WO1993000886A1 (de) * | 1991-07-01 | 1993-01-21 | Gerhard Gergely | Reaktionsdotierte brausesysteme |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0867426B1 (de) | 2002-06-26 |
| ATE219762T1 (de) | 2002-07-15 |
| DE59408273D1 (de) | 1999-06-24 |
| DE9422239U1 (de) | 1999-05-06 |
| US5593693A (en) | 1997-01-14 |
| DK0642784T3 (da) | 1999-11-22 |
| EP0642784A1 (de) | 1995-03-15 |
| EP0642784B1 (de) | 1999-05-19 |
| CA2131515A1 (en) | 1995-03-08 |
| ES2133454T3 (es) | 1999-09-16 |
| JPH07223937A (ja) | 1995-08-22 |
| DE59410143D1 (de) | 2002-08-01 |
| ATE180164T1 (de) | 1999-06-15 |
| CA2131515C (en) | 2006-08-29 |
| EP0867426A2 (de) | 1998-09-30 |
| CN1107366A (zh) | 1995-08-30 |
| EP0867426A3 (en) | 1998-11-11 |
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