CN1145586A - 含药物/聚合物复合物的味掩蔽组合物 - Google Patents
含药物/聚合物复合物的味掩蔽组合物 Download PDFInfo
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- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
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Abstract
一种可咀嚼的味掩蔽制剂，含有一种至少具有一种任选以盐形式存在的碱性基团或原子的治疗剂(或药物)，其与含至少一个酸性基团的聚合物反应以形成复合物。
Description
本发明涉及治疗剂/聚合物基质复合物，这种复合物具有改善的味觉特性。
很多治疗活性物质，当患者口服时，有不良的味觉或导致麻木。
已知有很多治疗剂/聚合物组合物，但其治疗剂是以聚合物包衣。这种产品存在的问题是，当患者口服给药，尤其是咀嚼时易破裂，因此使得治疗剂直接与口腔接触，这样治疗剂的味道和/或致麻木感不再能有效地被掩蔽。
甲基丙烯酸和甲基丙烯酸甲酯共聚物的进一步的问题是，当与治疗剂复合后，所形成的产物倾向于是一种胶状物。
一种具体的药物，茶苯海明，用于治疗与晕动病有关的病症。茶苯海明味麻。
茶苯海明的一个优选的制剂是咀嚼胶剂或咀嚼片剂型，这样意味着使用聚合物，例如基于甲基丙烯酸和甲基丙烯酸甲酯的阴离子型共聚物(例如Eudragit)的常规包衣工艺，不再能有效地用于掩蔽味麻木感，因为常规的聚合物包衣的茶苯海明复合物，当患者咀嚼时被破坏了。
另一种药物，帕罗西汀，用于治疗抑郁症，恐慌障碍和强迫观念与行为障碍。帕罗西汀有不良的苦味。
本发明提供具有优良的味觉掩蔽特性的治疗剂/聚合物复合物，可以制成粉末，更易与其它赋形剂调配以形成常规制剂。
因此，本发明提供一种可咀嚼的味掩蔽制剂，含有一种具有至少一种任选以盐形式存在的碱性基团或原子的治疗剂(或药物)，其与含至少一种酸性基团的聚合物反应以形成复合物。
优选的治疗剂是茶苯海明或帕罗西汀。
术语“碱性基团或原子”可以理解为指的是一种能够提供电子的基团，这些基团包括任选取代的氨基基团或任选取代的硫基团。
治疗剂合适的盐包括可被接受适合于药用的酸加成盐，例如帕罗西汀的盐酸盐半水合物。
应该意识到在药物包括两种活性组分即以盐的形式存在的一种碱性组分和一种酸性组分，例如茶苯海明作为苯海拉明的8-氯茶碱盐时，那么术语“治疗剂”以盐的形式存在时应扩展到这两种组分。
合适的聚合物包括聚甲基丙烯酸酯，例如Eudragit L和S，其为甲基丙烯酸和甲基丙烯酸甲酯的共聚物，平均分子量约为135,000。
术语“酸性基团”可以理解为指的是一种可以接受电子的基团，例如羧酸基团。
治疗剂(包括它的盐)与聚合物的复合物可以有不同的重量比。对于帕罗西汀和茶苯海明，复合物优选治疗剂与聚合物重量比为1∶0.8到1∶1.5，优选重量比为1∶1。
治疗剂(包括它的盐)和聚合物的复合物的制备可合适地按下法进行：将聚合物和治疗剂(包括它的盐)溶于适当的溶剂，例如异丙醇，乙醇或乙醚，任选在升高的温度例如40℃下，然后例如加入沉淀剂例如正己烷或蒸发溶剂，用合适的溶剂如丙酮研磨残留物，对所得沉淀的复合物进行适当的过滤和干燥。
另外，也可按下法，制备这些复合物，在环境温度或升温到例如25℃到60℃，优选50℃到60℃时，在水中混悬和混合治疗剂(包括它的盐)和聚合物5到24小时。所得复合物适当过滤和干燥。
治疗剂(包括它的盐)和聚合物的复合物可使用本领域公知的一般技术或者在实施例中所描述的或类似的方法，配制成常规的可以咀嚼的制剂形式例如咀嚼片，糖果剂(candies)，咀嚼胶剂或软咀嚼胶囊。
优选的茶苯海明/聚合物复合物可以为咀嚼胶剂或咀嚼片，帕罗西汀/聚合物复合物可以为咀嚼片或咀嚼胶剂。
下面的实施例用于说明本发明。实施例1：
茶苯海明和甲基丙烯酸与甲基丙烯酸甲酯共聚物的复合物(CDC 〕可按下法得到：在100ml异丙醇中分步溶解10g共聚物(Eudragit L)和10g茶苯海明，加热到40℃溶解，然后加入200ml正己烷沉淀出所得产物，过滤，干燥。
168克CDC给出下面的分析结果。
外观 ：白色粉末
味麻 ：无
茶苯海明(HPLC测定) ：45.78mg/100ml CDC实施例2：
茶苯海明和甲基丙烯酸与甲基丙烯酸甲酯之共聚物的复合物(CDC 〕按下法获得将1.5kg茶苯海明和1.5kg共聚物(Eudragit L)加入到22.5升水中，室温(约20℃)搅拌5小时，加热到50℃，50℃搅拌4小时，冷到室温，室温搅拌2小时，过滤，干燥。
2.81kg CDC给出了下面的分析结果：
外观 ：白色粉末
味麻 ：无
茶苯海明(HPLC测定) ：46.27mg/100mg CDC
湿度 ：0.54％咀嚼片实施例3-5
下列成分被颗粒化，以常规方法混匀，制成片剂150mg(实施例3)，300mg
(实施例4)和600mg每片(实施例5)。
实施例序号
3 4 5茶苯海明和甲基丙烯酸与甲基丙烯酸甲酯之共聚物的复合物(CDC)(g) 50 100 200预胶化淀粉(g) 12.5 25 50乳糖(g) 15 30 60糖精钠(g) 5 10 20薄荷干香精(g) 5 10 20山梨醇(g) 58.5 117 234甘草酸铵(g) 1.5 3 6硬脂酸镁(g) 2.5 5 10糖果剂实施例6茶苯海明和甲基丙烯酸与甲基丙烯酸甲酯之共聚物的复合物(CDC)(g) 100蔗糖(g) 1944液体葡萄糖(g) 1944薄荷香精(g) 12
按下法制备实施例6制剂加热蔗糖和溶于纯化水的葡萄糖液体，然后干燥所得的物质，在该物质中分散CDC和薄荷香精，最后的分散相被压制成每粒4g的糖果剂。咀嚼胶剂实施例7和8
实施例序号
7 8茶苯海明和甲基丙烯酸与甲基丙烯酸甲酯之共聚物的复合物(CDC)(g) 50 100胶基质(g) 495 495山梨糖(g) 637.5 587.5薄荷油(g) 10.7 10.7薄荷醇(g) 16.5 16.5天冬酰苯丙氨酸甲酯 7.6 7.6硬脂酸镁(g) 12.7 22.7
磨碎的胶基质与山梨醇(约为总量的40％)，薄荷醇(约为总量的90％)和天冬酰苯丙氨酸甲酯(约为总量的25％)混匀。混合物以纯化水湿润，揉制，颗粒化后在约40℃下干燥。干燥的颗粒与CDC，薄荷油，硬脂酸镁和剩余的山梨醇，薄荷醇和天冬酰苯丙氨酸甲酯混合，最终的混合物被压制成每粒1230mg的咀嚼胶剂，咀嚼胶剂可用常规的薄膜包衣工艺进行薄膜包衣。软咀嚼胶囊实施例9茶苯海明和甲基丙烯酸与甲基丙烯酸甲酯之共聚物的复合物(CDC)(g) 100明胶(g) 900甘油(g) 345糖精钠(g) 5橙香精(g) 50纯化水(g) 450
按下法制备实施例11的制剂：将明胶和甘油溶于加热到70℃的水中，冷却到50℃后，加入糖精钠，橙香精和CDC，得到的团块不断搅拌，采用传统的回旋成形工艺加工，得到每支1850mg的软咀嚼胶囊。实施例10
按下法制备帕罗西汀和甲基丙烯酸与甲基丙烯酸甲酯之共聚物的复合物(CPC)，将3g共聚物(Eudragit L)在150ml乙醇中的溶液与3g帕罗西汀碱在100ml乙醚中的溶液混合，室温搅拌12小时，真空蒸干溶剂，残留物以丙酮研磨，抽滤收集沉淀，用丙酮洗涤，干燥。
4.6g CPC给出下面的分析结果。
外观：白色粉末
苦味：无
熔点：215-230℃
帕罗西汀(HPLC测定)：42.50mg/100mg CPC
干燥失重：0.4％实施例11
按下法制备帕罗西汀和甲基丙烯酸与甲基丙烯酸甲酯之共聚物的复合物：将10g帕罗西汀盐酸盐半水合物，10g共聚物(Eudragit L)和2.3g碳酸氢钠加入到300ml水中，室温搅拌12小时，加热到60℃并在60℃搅拌12小时，冷到室温，抽滤收集沉淀，水洗，干燥。
18g CPC给出下面分析结果
外观 ：灰白色粉末
苦味 ：无
熔点 ：195-235℃
帕罗西汀(HPLC测定)：43.53mg/100mg CPC
湿度(K.F) ：6.3％咀嚼片实施例12，13和14
实施例序号
12 13 14帕罗西汀和甲基丙烯酸与甲基丙烯酸甲酯之共聚物的复合物(CPC)(g) 23 46 69预胶化淀粉(g) 5 10 15天冬酰苯丙氨酸甲酯 10 10 10草莓干香精(g) 50 50 50山梨醇(g) 409 381 353硬脂酸镁(g) 3 3 3
将CDC和预胶化淀粉混合，以纯化水湿润，揉制，颗粒化后在约40℃干燥。干燥的颗粒与山梨醇，乳糖，糖精钠，甘草酸铵，薄荷干香精和硬脂酸镁混合，最终的混合物被压制成150mg，300mg或600mg的片剂。生物等效研究
对12名健康的志愿者进行交叉单剂量研究表明，咀嚼片50mg(相当于100mg复合的茶苯海明)与吞咽非复合的茶苯海明产物的软胶囊剂(50mg)生物等效。
Claims (7)
1·一种可咀嚼的味掩蔽制剂，含有一种具有至少一种任选以盐形式存在的碱性基团或原子的治疗剂(或药物)，其与含至少一种酸性基团的聚合物反应以形成复合物。
2·根据权利要求1的可咀嚼的味掩蔽制剂，其中治疗剂为茶苯海明或帕罗西汀。
3·根据权利要求1的可咀嚼的味掩蔽制剂，其中治疗剂为帕罗西汀盐酸盐半水合物。
4·根据权利要求1-3中任一权项的可咀嚼的味掩蔽制剂，其中聚合物为聚甲基丙烯酸酯(Eudragit)。
5·根据权利要求1-4中任一权项的可咀嚼的味掩蔽制剂，其中治疗剂与药物的重量比为1∶0.8到1∶1.5。
6·根据权利要求1-5中任一权项的可咀嚼的味掩蔽制剂，其中治疗剂和聚合物的复合物可制成咀嚼片，糖果剂，咀嚼胶剂或软咀嚼胶囊。
7·根据权利要求6的可咀嚼的味掩蔽制剂，其中聚合物复合物为咀嚼胶剂或咀嚼片。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI93A002540 | 1993-12-03 | ||
| ITMI932540A IT1274241B (it) | 1993-12-03 | 1993-12-03 | Complessi agente terapeutico/matrice polimerica dotati di migliorate caratteristiche di sapore e composizioni farmaceutiche che li contengono |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1145586A true CN1145586A (zh) | 1997-03-19 |
Family
ID=11367288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94194885A Pending CN1145586A (zh) | 1993-12-03 | 1994-11-24 | 含药物/聚合物复合物的味掩蔽组合物 |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0804168A1 (zh) |
| JP (1) | JPH09505818A (zh) |
| CN (1) | CN1145586A (zh) |
| AU (1) | AU693144B2 (zh) |
| CA (1) | CA2177721A1 (zh) |
| IT (1) | IT1274241B (zh) |
| NZ (1) | NZ277238A (zh) |
| WO (1) | WO1995015155A1 (zh) |
| ZA (1) | ZA949567B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100379407C (zh) * | 1997-12-19 | 2008-04-09 | 史密丝克莱恩比彻姆公司 | 生产咀嚼分散片的方法 |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU748804B2 (en) * | 1995-07-20 | 2002-06-13 | Smithkline Beecham Plc | Paroxetine controlled release compositions |
| GB9514842D0 (en) * | 1995-07-20 | 1995-09-20 | Smithkline Beecham Plc | Novel formulation |
| US6548084B2 (en) | 1995-07-20 | 2003-04-15 | Smithkline Beecham Plc | Controlled release compositions |
| CA2206592A1 (en) * | 1996-05-30 | 1997-11-30 | Shu-Zhong Wang | Method of producing amorphous paroxetine hydrochloride |
| US5965555A (en) * | 1996-06-07 | 1999-10-12 | Hoechst Aktiengesellschaft | Xanthine compounds having terminally animated alkynol side chains |
| DE19631084A1 (de) | 1996-08-01 | 1998-02-05 | Basf Ag | Verwendung von (Meth)acrylsäure-Copolymeren zur Erhöhung der Permeabilität der Schleimhaut |
| US6638948B1 (en) * | 1996-09-09 | 2003-10-28 | Pentech Pharmaceuticals, Inc. | Amorphous paroxetine composition |
| AU3108097A (en) | 1997-06-10 | 1998-12-30 | Synthon B.V. | 4-phenylpiperidine compounds |
| US5955475A (en) * | 1997-06-30 | 1999-09-21 | Endo Pharmaceuticals Inc. | Process for manufacturing paroxetine solid dispersions |
| IT1298732B1 (it) * | 1998-03-13 | 2000-02-02 | Recordati Chem Pharm | Composizioni farmaceutiche orali assumibili senza liquidi,contenenti complessi di inclusione |
| CH689805A8 (fr) * | 1998-07-02 | 2000-02-29 | Smithkline Beecham Plc | Méthanesulfonate de paroxétine, procédé pour sa préparation et compositions pharmaceutiques le contenant. |
| EP1161241B1 (de) | 1999-03-12 | 2005-12-07 | Aesica Pharmaceuticals Ltd. | Stabile pharmazeutische anwendungsform für paroxetin-anhydrat |
| US20040242497A1 (en) * | 2001-08-09 | 2004-12-02 | Barges Causeret Nathalie Claude Marianne | Composition comprising paroxetine and a pharmaceutically acceptable glycyrrhizinate salt |
| GB0119467D0 (en) * | 2001-08-09 | 2001-10-03 | Smithkline Beecham Plc | Novel compound |
| PT2802311T (pt) * | 2011-10-25 | 2019-03-19 | Expermed S A | Composição farmacêutica sublingual contendo um agente anti-histamínico e método para a sua preparação |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT83241B (pt) * | 1985-08-26 | 1988-07-01 | Searle & Co | Processo para a preparacao de composicoes de drogas de matriz polimerica, capazes de mascarar o sabor de um ingrediente activo, contendo um polimero tendo uma serie de grupos acido e ester carboxilicos |
-
1993
- 1993-12-03 IT ITMI932540A patent/IT1274241B/it active IP Right Grant
-
1994
- 1994-11-24 JP JP7515376A patent/JPH09505818A/ja active Pending
- 1994-11-24 CN CN94194885A patent/CN1145586A/zh active Pending
- 1994-11-24 NZ NZ277238A patent/NZ277238A/en unknown
- 1994-11-24 AU AU12198/95A patent/AU693144B2/en not_active Ceased
- 1994-11-24 WO PCT/EP1994/003903 patent/WO1995015155A1/en not_active Application Discontinuation
- 1994-11-24 CA CA002177721A patent/CA2177721A1/en not_active Abandoned
- 1994-11-24 EP EP95903281A patent/EP0804168A1/en not_active Withdrawn
- 1994-12-01 ZA ZA949567A patent/ZA949567B/xx unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100379407C (zh) * | 1997-12-19 | 2008-04-09 | 史密丝克莱恩比彻姆公司 | 生产咀嚼分散片的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH09505818A (ja) | 1997-06-10 |
| AU693144B2 (en) | 1998-06-25 |
| ZA949567B (en) | 1995-10-10 |
| ITMI932540A1 (it) | 1995-06-03 |
| EP0804168A1 (en) | 1997-11-05 |
| IT1274241B (it) | 1997-07-15 |
| ITMI932540A0 (it) | 1993-12-03 |
| NZ277238A (en) | 1998-04-27 |
| AU1219895A (en) | 1995-06-19 |
| WO1995015155A1 (en) | 1995-06-08 |
| CA2177721A1 (en) | 1995-06-08 |
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