CN1515257A - 帕罗西汀控释组合物 - Google Patents

帕罗西汀控释组合物 Download PDF

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CN1515257A
CN1515257A CNA031490468A CN03149046A CN1515257A CN 1515257 A CN1515257 A CN 1515257A CN A031490468 A CNA031490468 A CN A031490468A CN 03149046 A CN03149046 A CN 03149046A CN 1515257 A CN1515257 A CN 1515257A
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G��S���հ��ɵ�
G·S·勒安纳德
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D·P·艾德勒尔
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Abstract

含有经选择的5－羟色胺再吸收抑制剂(SSRI)如帕罗西汀的控释和延时释放制剂。

Description

帕罗西汀控释组合物
技术领域
本发明涉及含有帕罗西汀或其药学上适用盐的制剂，以及它在治疗和/或预防某些疾病中的应用。
背景技术
美国专利No.4,007,196特别叙述了通常称为帕罗西汀的化合物。该化合物是选择性的5-羟色胺再吸收抑制剂(SSRI)，目前在世界范围内作为治疗和/或预防抑郁症销售。
目前唯一销售的帕罗西汀盐酸盐制剂是吞服片剂。
发明内容
现已令人惊奇地发现，含有帕罗西汀的控释(controlled release)和延时释放(delayed release)制剂可以意想不到地减少由于吞服片剂产生的副作用。
因此，本发明提供了含有帕罗西汀或其药学上适用盐的控释和延时释放制剂。
另一方面，本发明提供了含有SSRI的控释和延时释放制剂。除了帕罗西汀以外，SSRI的实例包括氟西汀(美国专利No.4,314,081)、氟伏沙明(美国专利No.4,085,225)和舍曲林(美国专利No.4,536,518)。
所谓控释制剂是指与即时释放(immediate release)制剂(如常用的吞服片或胶囊)相比，其中活性物质从该剂型的释放变得更慢的一种制剂技术。
所谓延时释放制剂是指与通常即时释放制剂相比，其中活性物质从该剂型释放发生在更迟时间的一种制剂技术。从延时释放制剂中接着发生的活性物质的释放也可以按以上所述进行控制。
适合于含有帕罗西汀和其他5-羟色胺再吸收抑制剂(SSRI)的控释制剂的实例已在下述文献中叙述：
Sustained Release Medications，Chemical Technology ReviewNo.177，由J.C.Johnson编著，Noyes Data Corporation 1980。
Controlled Drug Delivery， Fundamentals and Applications，第2版，由J.R.Robinson，V.H.L.Lee编著，Mercel Dekkes Inc.纽约1987。
适合于含有帕罗西汀和其他5-羟色胺再吸收抑制剂(SSRI)的延时释放制剂的实例已在下述文献中叙述：
Remington’s Pharmaceutical Scierces第16版，Mack PublishingCompany 1980，由A.Osol编著。
所述控释制剂最好配制成使活性物质(如帕罗西汀)占优势地在其通过胃和小肠时进行释放，而延时释放制剂最好配制成避免在胃中释放活性物质(如帕罗西汀)，并且使活性物质(如帕罗西汀)占优势地在其通过小肠时进行释放。
所述制剂最好配制成使活性物质主要在服用后11/2～3小时释放。
合适的小肠是十二指肠，回肠或空肠(jejunem)。
从本发明制剂获益最大的是已知口服吞服片引起恶心的患者。
优选的制剂主要是肠溶衣片剂或胶囊剂、蜡或聚合物包衣片剂或胶囊剂或定时释放(time-release)基质，或它们的合并物。
尤其优选的制剂已在美国专利No.5,102,666中叙述。
因此本发明的一个具体的内容是提供一聚合的控释组合物，该组合物含有在选自SSRI如帕罗西汀的活性剂存在下通过下述(1)和(2)相互作用而形成的反应复合物：(1)聚卡波非钙(Calcium Polycarbophil)成分，它是水可膨胀但不可溶解的纤维状交联的羧基官能的聚合物，该聚合物含有(a)其中至少约80％含有至少一个羧基官能度的许多重复的单元，以及(b)约0.05～1.5％交联剂，其中实质上没有聚合链烯基聚醚，所述百分比分别是以未聚合的重复单元和交联剂的重量为基准，(2)水。存在的聚卡波非钙的量约占0.1～99％(按重量计)，例如占约10％。存在的活性剂的量约占0.0001～65％(按重量计)，例如占约5～20％。存在的水的量约占5～200％(按重量计)，例如约占5～10％。上述相互作用是在pH约3～10，例如6～7下进行的。聚卡波非钙原本以含有约5～25％钙的钙盐的形式存在。
此外，尤其优选的制剂在美国专利No.5,422,123中已有叙述。
因此，本发明又一具体方面是提供活性物质是SSRI(如帕罗西汀)的控释系统，它包括(a)含有有效剂量的活性物质并具有确定几何形状的沉积片芯(deposit-core)，以及(b)应用于所述沉积片芯的承载座(support-platform)，其中所述沉积片芯至少含有活性物质，以及至少一个选自以下一组的成分(1)一种与水或含水液体接触即膨胀的聚合材料和一种可凝胶的聚合材料，其中该可膨胀的聚合材料与该可凝胶的聚合材料的比例为1∶9～9∶1，以及(2)具有膨胀和凝胶性质的单一聚合材料，其中承载座为一弹性载体，它应用于所述沉积片芯，结果它部分地覆盖该沉积片芯的表面，并且由于沉积片芯的水合作用随之变化，在含水液体中慢慢地可溶和/或可凝胶。所述承载座可以包括聚合物如羟丙基甲基纤维素、增塑剂如甘油酯、粘合剂如聚乙烯吡咯烷酮、亲水剂如乳糖和硅胶、和/或疏水剂如硬脂酸镁和甘油酯类。聚合物可以占承载座重量30～90％，例如占约35～40％。增塑剂至少可以占承载座重量2％，例如占约15～20％。粘合剂，亲水剂和疏水剂通常约占承载座重量50％，例如占约40～50％。
适用于本发明的帕罗西汀为游离碱或其药学上适用的盐的形式。帕罗西汀为盐酸盐半水合物形式更为合适。
帕罗西汀盐酸盐半水合物可以按照美国专利No.4,721,723中一般概述的方法进行制备。
控释和延时释放剂型的帕罗西汀可用于治疗和预防下述疾病：
酒精中毒
焦虑
抑郁症
强迫观念与行为的疾病
惊恐症
慢性疼痛
肥胖
老年性痴呆
偏头痛
食欲过盛
厌食
社交恐怖症
经前期综合症
青春期抑郁症
拔毛发癖
精神抑郁症
药物滥用
上述疾病后面统称为“疾病”。
本发明提供了治疗和/或预防所述疾病的方法，该方法是给需要的患者服用治疗有效剂量和/或预防剂量的含有帕罗西汀或其药学上适用盐的控释和延时释放制剂。
本发明还提供了应用含有帕罗西汀或其药学上适用盐的控释和延时释放制剂制备治疗和/或预防上述疾病的药物。
本发明也提供了用于治疗和/或预防所述疾病的药用组合物，该组合物包括含有帕罗西汀或其药学上适用盐的控释和延时释放制剂。
具体实施方式
下面的实施例详叙本发明
实施例1(亲水基质)
内颗粒                                    ％w/w
帕罗西汀盐酸盐                            11.45
Methocel E5                               1.25
乳糖                                      12.3
外颗粒
Methocel K 100LV                          30.0
乳糖                                      44.0
硬脂酸镁                                  1.0
总计                                      100.0
实施例2(亲水基质)
内颗粒                                    ％w/w
帕罗西汀盐酸盐                            11.45
Methocel E5                               1.25
乳糖                                      12.3
外颗粒
Methocel K 100LV                          27.5
Methocel K 4M                             7.5
乳糖                                      39.0
硬脂酸镁                                1.0
总计                                    100.0
实施例3(在直接释放片芯上pH敏感的包衣)
片芯                                    ％w/w
帕罗西汀盐酸盐                          11.45
乳糖                                    64.05
微晶纤维素                              20.0
淀粉羟基乙酸钠                          4.0
硬脂酸镁                                0.5
总计                                    100.0
片剂包衣(应用片芯重量的约6～10％)       ％w/w
羟丙基甲基纤维素                        90.0
三乙酸甘油酯                            10.0
实施例4(在即时释放片芯上有pH敏感的包衣)
片芯  同实施例3
片剂包衣(应用片芯重量的约6～10％)       ％w/w
邻苯二甲酸乙酸纤维素                    90.0
邻苯二甲酸二乙酯                        10.0
实施例5(在即时释放片芯上控释包衣)
片芯  同实施例3
片剂包衣(应用片芯重量的约5～12％)       ％w/w
Eudragit RS 100                         86.0
邻苯二甲酸二丁酯                        10.0
滑                                      4.0
FD & C Yellow  No.6                     0.01
实施例6(在控释片芯上有pH敏感的包衣)
片芯  同实施例3
片剂包衣同实施例3
实施例7(微囊控释包衣微球)
小丸                                   ％w/w(约)
丸模                                   30
帕罗西汀盐酸盐                         40
明胶                                   8
乳糖                                     20
滑石                                     2
包衣                                     ％w/w
单硬脂酸甘油酯                           36.6
二硬脂酸甘油酯                           53.4
白蜡                                     10.0
实施例8(控释双层片剂)
有效层
成分                      mg/片         作用
帕罗西汀盐酸盐            22.89*       活性成分
Methocel K4M              15.00         水凝胶聚合物
乳糖一水合物              62.0          亲水剂
聚乙烯吡咯烷酮            3.0           粘合剂
硬脂酸镁                  1.0           疏水剂
Syloid 244                1.0           亲水剂
承载座
成分                      mg/片         作用
Compritol 888             15.04         增塑剂
乳糖一水合物              29.32         亲水剂
聚乙烯吡咯烷酮            4.0           粘合剂
硬脂酸镁                  1.52          疏水剂
Methocel E5               29.32         水凝胶聚合物
氧化铁                    0.08          着色剂
总片重                    l84.89mg
* 相当于20mg帕罗西汀游离碱。
每层的粉末混合物用高强力混合机/制粒机进行湿法制颗粒并在流化床干燥器中干燥。在Maresty三重压片机上压制双层片。实施例9(肠溶包衣的聚卡波非钙制剂)
片芯
成分                  mg/片             作用
帕罗西汀盐酸盐        22.89*           活性成分
聚卡波非钙            20.00             基质
乳糖(无水)            146.11            亲水剂/稀释剂
聚乙烯吡咯烷酮        10.0              粘合剂
硬脂酸镁              1.0               疏水剂/润滑剂
水**                   0.024            制粒液体
肠溶包衣
成分                    mg/片            作用
Eudragit                22.19            聚合物
滑石                    1.53             润滑剂
柠檬酸三乙酯            1.00             增塑剂
水**                   24.6             稀释剂
薄膜包衣
Opadry pink             10.5             薄膜包衣
水**                   94.5             稀释剂
抛光包衣
Opadry clear            0.750
水**                   29.3             稀释剂
*相当于20mg帕罗西汀游离碱
**在操作中除去。
用高强力混合机/制粒机将片芯成分用湿法制颗粒，并在流化床干燥器中干燥。然后加入硬脂酸镁，将混合物在低切力混合机中混合。然后将混合物用B型旋转式压片机压片。用Accela cota进行包衣。
实施例10(控释双层片剂)
活性层
成分                      mg/片         作用
帕罗西汀盐酸盐            22.89*       活性成分
Methocel K4M              20.00         水凝胶聚合物
乳糖一水合物              60.0          亲水剂
聚乙烯吡咯烷酮            5.0           粘合剂
硬脂酸镁                  1.0           疏水剂
Syloid 244                1.0           亲水剂
承载座
成分                      mg/片         作用
Compritol 888             14.72         增塑剂
乳糖一水合物              30.60         亲水剂
聚乙烯吡咯烷酮            2.80          粘合剂
硬脂酸镁                  0.80          疏水剂
Methocel E5               30.60         水凝胶聚合物
Syloid 244                0.40          亲水剂
氧化铁                    0.08          着色剂
总片重                    189.89mg
*相当于20mg帕罗西汀游离碱
制法用实施例8
实施例11(控释双层片剂)
活性层
成分                      mg/片        作用
帕罗西汀盐酸盐            22.89*      活性成分
Methocel K4M              15.00        水凝胶聚合物
乳糖一水合物              63.31        亲水剂
聚乙烯吡咯烷酮            2.0          粘合剂
硬脂酸镁                  1.0          疏水剂
Syloid 244                0.40         亲水剂
承载座  同实施例10
总片重          184.60mg
*相当于20mg帕罗西汀游离碱
制法同实施例8。
实施例12(肠溶包衣控释双层片剂)
活性层
成分                      mg/片        作用
帕罗西汀盐酸盐            28.61*      活性成分
Methocel K4M              18.75        水凝胶聚合物
乳糖一水合物              79.14        亲水剂
聚乙烯吡咯烷酮            2.50         粘合剂
硬脂酸镁                  1.25         疏水剂
Syloid 244                0.50         亲水剂
承载座
成分                      mg/片        作用
Compritol 888             15.04        增塑剂
乳糖一水合物              30.50        亲水剂
聚乙烯吡咯烷酮            4.00         粘合剂
硬脂酸镁                  0.80         疏水剂
Methocel E5               29.32        水凝胶聚合物
Syloid 244                0.32         亲水剂
氧化铁                0.02           着色剂
肠溶包衣
成分                  mg/片          作用
Eudragit              13.27          聚合物
滑石                  3.31           润滑剂
柠檬酸三乙酯          1.33           增塑剂
水**                 36.25          稀释剂
总片重                228.66mg
*相当于25mg帕罗西汀游离碱
**在操作中除去。
制法同实施例9。
实施例13
胃肠忍耐性研究
本研究的试验设计概述如下
受试者：           正常的健康志愿者
设计  ：           平行对照组、安慰剂对照、双盲试验
治疗分组：         (a)安慰剂，(b)即时释放帕罗西汀，
                   (c)实施例8制剂，(d)具有肠溶包衣的
                   实施例8制剂
剂量：             30mg每天一次，连续3天
受试者数目：       可评价的452例(随机选取488名，可试验
                   的485名)
进行该项试验以比较恶心、呕吐和腹泻的发病率，严重程度和持续的时间(理论上讲，因为已知帕罗西汀对胃肠道是促运动的，如果控释制剂减慢了对帕罗西汀的吸收，那么可能会增加发病率)。
每次早晨给药时和最后一次给药后24小时评定不良反应(AE)的情况。研究者和受试者用日记卡详细记录，将不良反应严重程度进行分类，以便尽可能使交叉的所有6个中心点标准化。
485名可试验的受试者中，18名(3.7％)被停止服药，其中17名是因为不良的反应。在退出试验的当天，有恶心/呕吐的受试者(b)组比(c)组和(d)组更为普遍。
恶心/呕吐和腹泻的发病率见下表
                  (b)       (c)       (d)       安慰剂
恶心的发病率      59％      49％      39％      13％
腹泻的发病率      15％      21％      20％      7％
对于以上述剂量连续3天给药的志愿者，(b)组和安慰剂组恶心的发病率与预计的分别为约25％和5％的比例相比约有增加。恶心总的发病率(c)组和(d)组均低于(b)组。恶心的严重程度也降低了，如下表所示。
恶心严重程度    (b)          (c)         (d)         安慰剂
无              50(41％)     63(52％)    74(61％)    104(87％)
轻微            45(37％)     40(33％)    30(25％)    16(13％)
中等            21(17％)     17(14％)    15(12％)    0(0％)
严重            6(5％)       1(1％)      3(2％)      0(0％)
腹泻的严重程度见下表
腹泻严重程度    (b)          (c)         (d)         安慰剂
无              104(85％)    95(79％)    97(80％)    112(93％)
轻微            16(13％)     16(13％)    16(13％)    8(7％)
中等            1(1％)       8(7％)      9(7％)      0(0％)
严重            1(1％)       2(2％)      0(0％)      0(0％)
总之，与(b)组相比，看来(c)组恶心发病率和由于不良反应退出试验的比例均有下降的趋势，但是用统计学中心差显著性处理(statisticallysignificant treatment-by-centre difference)，结果的分析是复杂的。(d)组显示出减半的退出试验比例，并且恶心发病率降低20％(按比例降低33％)。此外，在(c)组和(d)组中报告恶心症状的受试者，其恶心的严重程度也有下降。相对于(b)组，(c)组和(d)组腹泻的发病率都有增加，但是这仅限于增加报告有中等程度腹泻的受试者人数，而严重腹泻者的人数并未增加。

Claims (7)

1.适于或用于口服的、含有选择性的5-羟色胺再吸收抑制剂的控释和延时释放制剂。
2.权利要求1所述的制剂，其中选择性的5-羟色胺再吸收抑制剂为帕罗西汀或其药学上适用的盐。
3.权利要求1或2所述的制剂，它包括肠溶包衣片剂或胶囊剂、蜡或聚合物包衣的片剂或胶囊剂或定时释放基质，或它们的组合。
4.上述任一项权利要求所述的制剂，它是一聚合的控释组合物，该组合物含有在选自选择性的5-羟色胺再吸收抑制剂的活性剂存在下通过下述(1)和(2)相互作用而形成的反应复合物：(1)聚卡波非钙，它是水可膨胀但不可溶解的、纤维状交联的羧基官能的聚合物，该聚合物含有(a)其中至少约80％含有至少一个羧基官能度的许多重复的单元，以及(b)约0.05～1.5％的交联剂，其中实质上没有聚合链烯基聚醚，所述百分比分别是以未聚合的重复单元和交联剂的重量为基准，(2)水。
5.权利要求1～3中任何一项所述的制剂，该制剂是活性物质为选择性的5-羟色胺再吸收抑制剂的控释系统，它包括(a)含有有效剂量的活性物质并具有确定几何形状的沉积片芯，以及(b)应用于所述沉积片芯的承载座，其中所述沉积片芯至少含有活性物质，以及至少一个选自以下一组的成分：(1)一种与水或含水液体接触即膨胀的聚合材料和一种可凝胶的聚合材料，其中该可膨胀的聚合材料与该可凝胶的聚合材料的比例为1∶9～9∶1，以及(2)具有膨胀和凝胶性质的单一的聚合材料，并且其中承载座为一弹性载体，它应用于所述沉积片芯，结果它部分地覆盖该沉积片心的表面，并且由于沉积片芯的水合作用随之变化，在含水液体中慢慢地可溶和/或慢慢地可凝胶。
6.权利要求1～5中任何一项所述的控释和延时释放制剂在制备治疗和/或预防酒精中毒、焦虑、抑郁症、强迫观念与行为的疾病、惊恐症、慢性疼痛、肥胖、老年性痴呆、偏头痛、食欲过盛、厌食、社交恐怖症、经前期综合症、青春期抑郁症、拔毛发癖、精神抑郁症或药物滥用的药物中的应用。
7.制备权利要求1～5中任何一项所述制剂的方法，该方法包括按需要的比例混合各个成分。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103371982A (zh) * 2012-04-20 2013-10-30 王进京 盐酸帕罗西汀肠溶控释片新型处方组成及制备方法
CN103550182A (zh) * 2013-10-29 2014-02-05 吉林省东盟制药有限公司 一种肠溶缓释组合物

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6638948B1 (en) 1996-09-09 2003-10-28 Pentech Pharmaceuticals, Inc. Amorphous paroxetine composition
US5910319A (en) * 1997-05-29 1999-06-08 Eli Lilly And Company Fluoxetine enteric pellets and methods for their preparation and use
DE69704679T2 (de) 1997-06-10 2001-09-13 Synthon Bv 4-phenylpiperidin-derivate
US5955475A (en) * 1997-06-30 1999-09-21 Endo Pharmaceuticals Inc. Process for manufacturing paroxetine solid dispersions
ID23503A (id) 1997-07-01 2000-04-27 Pfizer Garam-garam sertralina dan bentuk-bentuk sediaan lepas-lambat dari sertralina
GB9808479D0 (en) * 1998-04-22 1998-06-17 Smithkline Beecham Plc Method of treatment
CH689805A8 (fr) * 1998-07-02 2000-02-29 Smithkline Beecham Plc Méthanesulfonate de paroxétine, procédé pour sa préparation et compositions pharmaceutiques le contenant.
US6139875A (en) * 1998-09-29 2000-10-31 Eastman Chemical Company Aqueous enteric coating composition and low gastric permeability enteric coating
AU3810100A (en) 1999-03-12 2000-10-04 Basf Aktiengesellschaft Stable pharmaceutical application form for paroxetin anhydrate
IE990406A1 (en) 1999-05-20 2000-12-27 Elan Corp Plc Multiparticulate controlled release selective serotonin reuptake inhibitor formulations.
ATE367153T1 (de) * 1999-05-20 2007-08-15 Elan Corp Plc Multipartikuläre arzneizusammensetzungen mit gesteuerter wirkstoffabgabe enthaltend selektive inhibitoren der serotoninwiederaufnahme
ES2159260B1 (es) * 1999-06-22 2002-05-01 Smithkline Beechan Plc Nueva composicion de metanosulfonato de paroxetina
WO2000078290A2 (en) * 1999-06-22 2000-12-28 Smithkline Beecham P.L.C. Pharmaceutical composition comprising a salt of paroxetine
ES2162560B1 (es) * 1999-06-25 2002-07-16 Rodriguez Concepcion Pena Uso de fluoxetina, paroxetina y otros isrs para la fabricacion de medicamentos con el fin de aumentar la capacidad de abstenerse de substancias o actividades que crean dependencia.
AR030557A1 (es) * 2000-04-14 2003-08-27 Jagotec Ag Una tableta en multicapa de liberacion controlada y metodo de tratamiento
US6482440B2 (en) * 2000-09-21 2002-11-19 Phase 2 Discovery, Inc. Long acting antidepressant microparticles
WO2003013480A1 (en) * 2001-08-06 2003-02-20 Dr. Reddy's Laboratories Ltd. Improved enteric formulation of fluoxetin
GB2392385A (en) * 2002-09-02 2004-03-03 Cipla Ltd Pharmaceutical preparations comprising a 5HT uptake inhibitor and a homopolymer or copolymer of N-vinyl pyrrolidone
JP5547865B2 (ja) 2003-10-29 2014-07-16 ワイス・エルエルシー アプリンドルおよびその誘導体を含む持続放出型医薬組成物
US20050209218A1 (en) * 2004-02-13 2005-09-22 Meyerson Laurence R Methods and compositions for the treatment of psychiatric conditions
WO2005107716A1 (en) * 2004-03-25 2005-11-17 Cadila Healthcare Limited Controlled release paroxetine-containing tablets based on a core and a coating
AU2006274565B2 (en) * 2005-08-02 2012-05-17 Lupin Limited Novel controlled release compositions of selective serotonin reuptake inhibitors
KR100591142B1 (ko) * 2005-11-04 2006-06-20 지엘팜텍 주식회사 파록세틴을 활성물질로 함유하는 장용성 서방형 정제
WO2007132344A2 (en) * 2006-05-09 2007-11-22 Aurobindo Pharma Limited Controlled release compositions of an antidepressant agent
KR100885029B1 (ko) 2007-02-07 2009-02-23 지엘팜텍 주식회사 경구투여용 서방성 삼중정제
WO2009006299A2 (en) * 2007-06-29 2009-01-08 Dr. Reddy's Laboratories Ltd. Multi-particulate systems
US8822498B2 (en) 2007-09-13 2014-09-02 Concert Pharmaceuticals, Inc. Synthesis of deuterated catechols and benzo[D][1,3]dioxoles and derivatives thereof
TW201010743A (en) 2008-09-05 2010-03-16 Otsuka Pharma Co Ltd Pharmaceutical solid preparation
MX2012002199A (es) * 2009-08-24 2012-03-16 Lundbeck & Co As H Nuevas composiciones de 1-[2-(2,4-dimetil-fenilsulfanil)-fenil]pip erazina.
WO2014009152A1 (en) * 2012-07-09 2014-01-16 Unilever N.V. A photoprotective personal care composition

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8626936D0 (en) * 1986-11-11 1986-12-10 Ferrosan As Treatment
MC2025A1 (fr) * 1988-04-20 1990-04-25 Asta Pharma Ag Medicament contenant de l'azelastine et capable de liberer celle-ci de facon controlee
IT1237904B (it) * 1989-12-14 1993-06-18 Ubaldo Conte Compresse a rilascio a velocita' controllata delle sostanze attive
JPH0436237A (ja) * 1990-06-01 1992-02-06 Taiho Yakuhin Kogyo Kk 抗腫瘍性複合製剤
WO1992003124A1 (en) * 1990-08-21 1992-03-05 Oramed, Inc. Controlled release formulations and method
AU658155B2 (en) * 1990-11-24 1995-04-06 Beecham Group Plc Use of paroxetine for the treatment of senile dementia, or anorexia
WO1992019241A1 (en) * 1991-05-07 1992-11-12 Dynagen, Inc. A controlled, sustained release delivery system for smoking cessation
JPH05139964A (ja) * 1991-11-14 1993-06-08 Takada Seiyaku Kk 塩酸メキシレチン腸溶性製剤
DE69429710T2 (de) * 1993-11-23 2002-08-08 Euro Celtique Sa Verfahren zur Herstellung einer Arzneizusammensetzung mit verzögerter Wirkstoffabgabe
IT1274241B (it) * 1993-12-03 1997-07-15 Smithkline Beecham Farma Complessi agente terapeutico/matrice polimerica dotati di migliorate caratteristiche di sapore e composizioni farmaceutiche che li contengono
CA2143070C (en) * 1994-02-22 2001-12-18 Pankaj Modi Oral controlled release liquid suspension pharmaceutical formulation
GB9422154D0 (en) * 1994-11-03 1994-12-21 Euro Celtique Sa Pharmaceutical compositions and method of producing the same
WO1996031197A1 (en) * 1995-04-03 1996-10-10 Abbott Laboratories Homogeneous mixtures of low temperature-melting drugs and additives for controlled release

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103371982A (zh) * 2012-04-20 2013-10-30 王进京 盐酸帕罗西汀肠溶控释片新型处方组成及制备方法
CN103550182A (zh) * 2013-10-29 2014-02-05 吉林省东盟制药有限公司 一种肠溶缓释组合物
CN103550182B (zh) * 2013-10-29 2015-04-08 吉林省东盟制药有限公司 一种肠溶缓释组合物

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