CN1466451B - 不受离子强度影响的持续释放的医药制剂 - Google Patents

不受离子强度影响的持续释放的医药制剂 Download PDF

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CN1466451B
CN1466451B CN01816515XA CN01816515A CN1466451B CN 1466451 B CN1466451 B CN 1466451B CN 01816515X A CN01816515X A CN 01816515XA CN 01816515 A CN01816515 A CN 01816515A CN 1466451 B CN1466451 B CN 1466451B
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H·R·M·格里森
H·W·弗里齐林科
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Abstract

本发明涉及一种视需要经包衣的医药亲水性凝胶生成性基体制剂，其包含一或多种活性物质，以及当暴露于胃肠道消化液时可延长所述一或多种活性物质的释放，其特征在于，所述释放实质上不受离子强度影响的。本发明进一步涉及一种制备这种制剂的方法，该制剂可服用活性物质用于治疗多种病症。

Description

不受离子强度影响的持续释放的医药制剂
本发明涉及一种实质上具有延长释放表现的医药制剂，该释放表现与溶解介质例如胃肠道消化液的离子强度无关。所述延长释放可达至十六小时的时段。该剂型组合一或多种活性物质和亲水聚合物载剂的混合物，结果导致一种凝胶生成性基体制剂。
亲水性凝胶生成性基体制剂为众所周知控制活性物质溶解表现的剂型。活性物质的释放机质始于剂型表面水合而形成凝胶结构。同时制剂表面活性物质溶解于溶解介质。在固定相，溶解介质连续渗透凝胶结构而使凝胶胀大。活性物质溶解于溶解介质并被转运至凝胶外层。同时出现凝胶外层的溶蚀。最后由于制剂中的活性物质的浓度梯度降低和溶解介质的渗入致使释放程度的消减。这种机质属于先前技术例如ManfordRobinson，产业制药理论与实务第二版第十四章：[持续作用剂型](TheTheory and Practice of industrial Pharmacy，2nd edition，Chapter 14：“Sustained Action Dosage Forms”)。
用于前述制剂的亲水聚合物大部分为多醣类载剂如纤维素衍生物，羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、羧甲基纤维素钠(NaCMC)或这些纤维素衍生物的组合。
这些类型的制剂在大量专利案及专利申请案例如US 4,871,548及EP-A-0923934中有描述。
US 4,871,548揭示一种控制的释放剂型，其包含活性化合物以及至少一种低粘度纤维素醚与一种高粘度纤维素醚的混合物。EP-A-0923934揭示头孢克洛(cefaclor)及头孢氨苄(cephalexin)的改性释放基体制剂，其包含5-35％不同等级亲水聚合物的混合物，其中亲水聚合物包含约0.1％至约20％重量比中等粘度羟丙基甲基纤维素及约0.1至约20％低粘度羟丙基纤维素。
虽然前述制剂通常被描述为持续释放制剂，但这种持续释放仅出现于盐浓度、离子强度在溶解介质中低的时候。前述制剂的活性物质释放速率实质上取决于离子强度。高离子强度甚至可能导致所谓的剂量倾泻效应。这种情况下，活性物质总量在极短时间内释放，可能导致非期望的且甚至危险的高水平活性物质血浓度。高离子强度常直接出现在餐后。由于病人常在餐后服药，因而受离子强度影响的制剂具有高度风险，其非期望地快速释放活性物质而非所期望的持续释放。
WO 98/47491描述一种持续释放制剂，其中活性物质的释放控制是基于两种所谓的具有相反湿润特性的[智慧型]聚合物的组合，一种聚合物显示强力疏水性倾向，而另一种聚合物显示强力亲水性倾向。这种制剂只有经肠包衣才能防止剂量倾泻效应。
本发明的目的是提供一种实质上不取决于溶解介质离子浓度的持续释放制剂，该溶解介质通常为胃肠道消化液，即使当制剂未经包衣时亦如此。显然对于此领域技术人员，制剂应该也符合本领域正常的物理及医药要求，例如制片时粉末的良好流动性、压缩片的耐轧碎强度至少30牛顿(N)、易碎性在压缩力10至40千牛顿之间时低于1％、含量均匀性和足够的稳定性。进一步要求制剂可使用一般配方程序及设备制备，因而无需大量投资成本。
根据本发明经由一种医药亲水性凝胶生成性基体制剂可实现此项目标，该制剂当暴露于胃肠道消化液时可长期释放一或多种活性物质，其特征在于，所述释放实质上不受离子强度影响.
长期释放定义为剂型里的活性物质以45分钟时间或以上的(逐步)释放。此段时间通常始于剂型的服用，或始于体外溶解试验的开始(剂型接触溶解介质的瞬间)。
实质上不受离子强度影响的术语表示当离子强度(I)于0.05至0.45摩尔/升之间变化时，活性物质的释放速率侧绘图不会显著改变(根据一般章节711：以USP24物理试验及测定(±标记含量))。离子强度(I)定义为I＝1/2∑czi 2，其中c为不同离子在溶液中的浓度，Zi为其各别电荷数(化学及物理手术71版(Handbook of Chemistry and Physics 71stedition)，David R.Lide编辑，2-18页，波士顿，CRC出版公司，1990-1991)。
虽然包衣对于实现不受离子强度影响并非是必要的，但制剂可视需要包覆包衣材料以实现另一项预定效果，例如掩盖味觉或着色。合适的包衣材料为本领域所已知的，例如HPMC、丙烯酸树脂、乙基纤维素(参考Graham Cole编辑，医药包衣技术(Pharmaceutical coatingTechnology)，Taylor & Francis Ltd.1995)。
亲水凝胶生成性基体具有片剂剂型或多微粒剂型，优选含有至少两种亲水高粘度纤维素醚的混合物。虽然存在有疏水纤维素醚如乙基纤维素，通常对本配方的释放性质无不良影响，但优选不存在有实质量的这种疏水纤维素醚。实质量的疏水纤维素醚表示该量超过凝胶生成性聚合物总重量的20％。
纤维素醚为本领域众所周知，可以医药级别取得，并且不同平均分子量的纤维素醚其溶液的粘度不同。用于本专利申请目的的亲水聚合物的特征为在2％w/w水溶液中其粘度分成低粘度(低于约1000毫帕斯卡(mPas))、为中粘度(约1000至约10,000mPas)及高粘度(大于约10,000mPas)。
可用于本发明的亲水性羟丙基甲基纤维素聚合物(HPMC’s)可以不同粘度等级以商标名得自陶氏化学公司(Dow Chemical Co.)，以及以商标名得自新越化学公司(Shin Etsu)。
低粘度聚合物例如为MethocelMethocelMethocelMethocel及Methocel
Figure G01816515XD00037
其2％水溶液于25℃分别具有粘度5、15、50、100及50mPas。
中粘度HPMC’s例如为Methocel
Figure G01816515XD00038
及Methocel K4M，其2％水溶液于25℃的粘度为4000mPas。
高粘度HPMC’s例如为Methocel及Methocel其2％水溶液于25℃的粘度分别为15,000及100,000mPas。
可用于本发明的亲水羟乙基纤维素聚合物(HEC’s)可以不同粘度等级以商标名得自AQUALON公司，以及以商标名得自Amerchol公司。
低粘度聚合物例如为Natrosol
Figure G01816515XD00041
及Natrosol其2％水溶液于25℃的粘度分别为10mPas及20mPas。
中粘度聚合物例如为Natrosol及Natrosol其2％水溶液于25℃的粘度分别为200mPas及1500mPas。
高粘度聚合物例如为Natrosol及Natrosol
Figure G01816515XD00046
其2％水溶液于25℃的粘度分别为4000mPas及90000mPas。
本发明的优选实施例中，制剂包含高或中粘度羟丙基甲基纤维素(HPMC)与高或中粘度羟乙基纤维素(HEC)的混合物。高或中粘度HPMC与高或中粘度HEC的比为1/0.85至1/1.2，优选为1/0.9至1/1.1，更优选为1/0.95至1/1.05及最优选为1/1。制剂可视需要包含一种低粘度HPMC。该种情况下，高或中粘度HPMC与低粘度HPMC的比为1/0.01至1/0.2并优选1/0.01至1/0.1，及更优选为1/0.02至1/0.05。
出乎意外地发现具有前述组成的制剂可用于制备片剂，该片剂的释放速率是与胃肠道消化液正常范围的离子强度无关。所述正常范围为0.17至0.35摩尔/升。
除了不受离子强度影响外，制剂的释放控制原理也实质上不受pH＝1.3至pH＝7.4范围的pH影响。这表示活性物质的释放速率不受pH影响，在那种情况下活性物质的释放不受活性物质溶解度所限，换言之就给定时间点的释放值差异(以％表示)在1.3至7.4的整个pH范围内是低于标记请求的20％(参考溶解规格章节(1080-81页)，FIP固体口服制品溶解试验指南(FID Guidelines for Dissolution Testing of SolidOral Products)(终稿本，1995年)，药物资讯期刊1996年(DrugInformation Journal 1996)，30期，1071-84页)。
由于具有作为持续释放制剂的最理想性质，故根据本发明的制剂可用于治疗一系列需要用持续释放性质的疾病。可调配于持续释放制剂的活性物质为用于治疗下列病症的活性物质：中枢神经系统病症，包括精神分裂症，发作型阵发性焦虑(EPA)病症例如强迫观念与行为障碍(OCD)，创伤后精神紧张性障碍(PTSD)，恐怖症及惊恐性障碍，重性抑郁症，双相性精神障碍，帕金森病，泛化性焦虑症，孤独症，谵妄，多发性硬化，阿尔兹海默氏病/痴呆及其它神经变化疾病，重度精神发育迟缓与运动障碍，例如亨廷顿舞蹈病或图雷特综合征，厌食，贪食，中风，瘾/依赖/癖，睡眠障碍，癫痫，偏头痛；注意涣散/多动症(ADHD)；心血管病包括心力衰竭，心绞痛，心律不齐，心肌梗塞，心脏肥大，低血压，高血压例如原发性高血压、肾性高血压或肺动脉高血压，血栓，动脉硬化，脑血管痉挛，蜘蛛膜下腔出血，脑缺血，脑梗塞，外周血管病，雷诺病，肾脏病例如肾脏衰竭；血脂代谢异常；肥胖；呕吐；胃肠道障碍包括过敏性肠综合征(IBS)，炎性肠病(IBD)，胃食道反流病(GERD)，蠕动障碍以及胃排空延迟病症例如术后或糖尿病性胃轻瘫，及糖尿病，溃疡如胃溃疡；腹泻；其它疾病包括妇科疾病；骨质疏松炎症；感染如细菌性、真菌性、原虫性及病毒性感染特别是由HIV-1或HIV-2引起的感染；疼痛；癌症；化学治疗诱发的损伤；肿瘤侵袭；免疫障碍；尿潴留；哮喘；过敏；关节炎；良性前列腺肥大；内毒素性休克；脓毒病；糖尿病并发症。
优选配方的活性物质为可用于治疗中枢神经系统病症的活性物质如氟伏沙明(fluvoxamine)(5-甲氧基-1-[4-(三氟-甲基)苯基]-1-戊酮O-(2-氨基乙基)肟)或氟辛克生(flesinoxan)((+)-苯甲酰胺，N-[2-[4-[(2R)-2，3-二氢-2-(羟基甲基)-1，4-苯并二噁烯-5-基]-1-哌嗪基]乙基]-4-氟)；治疗心血管病症的活性物质例如替地沙米(tedisamil)(N，N’-二环丙基甲基-9，9-四亚甲基-3，7-二氮二环[3.3.1]-壬烷)或普萘洛尔(propanolol)；或用于治疗妇科病症的活性物质例如激素补充治疗例如地屈孕酮(dydrogesterone)、雌二醇(estradiol)或结合型雌激素.本发明特别可用于活性物质氟辛克生，优选其单氢氯化物((+)-苯甲酰胺，N-[2-[4-[(2R)2，3-二氢-2-(羟基甲基)-1，4-苯并二噁烯-5-基]-1-哌嗪基]乙基]4-氟-单氢氯化物)在EP0138280和EP307061中有描述，对于替地沙米，优选其倍半反丁烯二酸盐(N，N’-二环丙基甲基-9，9-四亚甲基-3，7-二氮杂双环[3.3.1]壬烷1.5氢反丁烯二酸盐)的制剂，这种化合物术于EP0550383中有描述.
本发明也涉及一种制备前述制剂的方法，其特征在于，
(1)一核芯，该芯是由包含一或多种活性物质的混合物以及至少两种亲水性高或中粘度纤维素醚混合物压制而成，其实质上不受离子强度影响实质上延长了活性物质的零级释放；以及
(2)该芯是视情况经包衣的。
组成分HPMC、HEC、活性物质、颜料掺合物及滑动剂(glidant)在适当的混合机中混合。粉末混合物在适当混合机中与混硬脂基反丁烯二酸钠混合。
活性物质可以预制粒剂形式添加至用于压缩的粉末混合物。另外制片用的粉末混合物可经由混合程序制造，随后为(湿或干)造粒处理。
组成分混合物使用商购设备(例如
Figure G01816515XD00061
R0)压缩成片，制片时使用流动调节剂例如氧化硅胶体及润滑剂例如滑石、硬脂基反丁烯二酸钠或硬脂酸镁。整体制剂的亲水纤维素含量为15％至99.5％，而活性物质含量是在0.1％至80％的范围。流动调节剂或润滑剂含量固定以提高粉末流动性和防止粉末沾粘至染色壁或冲压头。滑动剂用量为0.05％至5％及优选约0.2％。润滑剂用量为约0.05％至5％及优选约0.4％。由于商用因素，粉末混合物可使用0.1％至10％颜料掺合物着色。典型颜料掺合物为商购可得的例如
Figure G01816515XD00062
中的
此说明书中引述的全部公开文献，包括但非限于专利案及专利申请案，是以引述方式并入此处，如同每个单独的公开文献特别且单独地以完整的陈述结合引入参考。
下列实例仅供举例说明本发明的进一步细节，这些实例绝非意图局限本发明的范围。
实例1.不受离子强度影响的制剂的制备
实例1a.一般制备程序
首先将氧化硅胶体通过筛。所述筛优选具有网眼0.40毫米至0.595毫米。在适当混合机中将活性物质与亲水纤维素、氧化硅胶体、颜料掺合物以及若有所需与甘露糖醇混合。所述混合机优选为造粒机处于关闭位置的高剪混合机。将硬脂基反丁烯二酸钠过筛。所述筛优选具有网眼o.40毫米至5.95毫米。粉末混合物压缩成预定尺度的片剂。压缩设备优选为旋转机器例如Korsch及Courtoy设备。视需要地，片剂可使用水溶性纤维素或纤维素衍生物，例如乙基纤维素或基于丙烯酸酯的含水悬浮液或有机溶剂的包衣。包衣过程优选用穿孔转鼓(perforated drum)装置或基于流化床技术的设备进行。
表1.未包衣片剂(芯片)组成，以mg/片表示
材料   氟辛克生标记含量：2mg/片   乙酰米诺芬(Acetaminophen)标记含量：2.2mg/片   氟伏沙明顺丁烯二酸盐标记含量：100mg/片   替地沙米二盐酸盐标记含量：100mg/片   替地沙米倍半反丁烯二酸盐标记含量：150mg/片
  氟辛克生盐酸盐   2.18   n.a.   n.a.   n.a.   n.a.
  乙酰米诺芬   n.a.   2.19   n.a.   n.a.   n.a.
  氟伏沙明顺丁烯二酸盐   n.a.   n.a.   100.00   n.a.   n.a.
  替地沙米二盐酸盐   n.a.   n.a.   n.a.   124.4   n.a.
  替地沙米倍半反丁烯二酸盐 n.a. n.a. n.a. n.a. 240.0
  HPMC K4M   69.63   69.63   17.00   125.2   81.0
  HPMC E5   7.50   7.50   12.50   20.0   14.0
  HEC HX250PH   69.63   69.63   17.00   125.2   81.0
  甘露糖醇SD200   n.a.   n.a.   100.00   n.a.   n.a.
  氧化硅胶体   0.30   0.30   0.50   1.60   4.0
  颜料掺合物PB23015   0.15   0.15   n.a.   0.40   n.a.
  硬脂基反丁烯二酸钠   0.60   0.60   3.00   3.20   5.0
  片总重(mg)   150.00   150.00   250.00   400.00   425.00
n.a.：不适用
表2数种组合物性质
  片剂性质   氟辛克生标记含量：2mg/片   乙酰米诺芬标记含量：2.2mg/片   氟伏沙明顺丁烯二酸盐标记含量：100mg/片   替地沙米二盐酸盐标记含量：100mg/片   替地沙米倍半反丁烯二酸盐标记含量：150mg/片
  片剂尺度(毫米)   5.5×11.0毫米特殊形状   7.0毫米圆形   8.0毫米圆形   8.0×15.0毫米椭圆形   8.0×15.0毫米椭圆形
  片剂重量(mg)   150   150   275   400   425
  轧碎强度(N)   83   75   144   71   90
  易碎性(％)   未测定   未测定   未测定   0.4   0.05
  释放侧绘   表4   表4   表4   表4   表4
实例1b.数种制剂的释放性质
在USP装置II使用50rpm旋转的桨叶测量活性物质由亲水基体片剂的释放，片剂置于由磷酸氢二钠2水合物(2aq.)及柠檬酸1水合物制成的(分别标记为代码F、G、及H)分别为0.05摩尔浓度(M)、0.17M以及0.34M pH 6.8的USP溶解缓冲介质，或片剂置于半更换溶解介质，于试验的第一部分(90分钟)是由0.1M氯化氢水溶液制备，随后于试验的第二部分使用磷酸三钠12水合物调整为0.2MpH6.8。为了提高试验期间水溶液的离子强度，添加氯化钠至溶液。1升第二部分溶解介质含氯化钠剂量分别为0克(溶解介质A)、10克(溶解介质B)、15克(溶解介质C)、30克(溶解介质D1及D2)以及50克(溶解介质E1及E2)。在溶解介质B、C、D1及E1，氯化钠仅添加至试验的第二部分。在溶解介质D2及E2，75％氯化钠添加至试验的第一部分而25％添加至第二部分。活性物质的释放测量经历16小时时段，在前二小时以每一小时间隔抽样，之后的试验期以每两小时间隔抽样。样品于线上使用HPLC系统或紫外线光谱仪分析。由制剂释放不同活性化合物示于表4a-4c。
由表4a-4c列举的释放资料获得结论，活性物质由根据本发明的制剂释放，实质上是不受pH及离子强度影响，释放值差异小于20％。进一步获得结论，当离子强度在低pH(pH1.2)及较高pH(pH6.8)的情况于升高时，释放情形间实质上并无差异。
表3  溶解介质综览
Figure G01816515XD00091
表4a  数种未包衣片剂成分的释放作为时间的函数
表4b.数种未包衣片剂成分的释放作为时间的函数
Figure G01816515XD00093
表4c.替地沙米倍半反丁烯二酸盐未包衣片剂于单一溶解介质的释放作为时间的函数

Claims (7)

1.一种医药亲水性凝胶生成性基体制剂，包含一或多种活性物质，以及当暴露于胃肠道消化液时可延长所述一或多种活性物质的释放，其特征在于，该亲水性凝胶生成性基体包含高或中粘度羟丙基甲基纤维素HPMC及高或中粘度羟乙基纤维素HEC，其比例为HPMC/HEC＝1/0.85-1/1.2，以及视需要地包含一种低粘度HPMC，其比例为高或中粘度HPMC/低粘度HPMC＝1/0.01-1/0.2，且该释放实质上不受离子强度影响。
2.如权利要求1的制剂，其特征在于，该制剂是经包衣的。
3.如权利要求1或2的制剂，其特征在于，该活性物质为氟伏沙明或氟伏沙明的可药用盐或氟辛克生或氟辛克生的可药用盐。
4.如权利要求3的制剂，其特征在于，该活性物质是氟辛克生单氢氯化物(+)-苯甲酰胺，N-[2-[4-[(2R)-2，3-二氢-2-(羟基甲基)-1，4-苯并二噁烯-5-基]-1-哌嗪基]乙基]4-氟-单氢氯化物。
5.如权利要求1或2的制剂，其特征在于，该活性物质为替地沙米或替他沙米的可药用盐或普萘洛尔或普萘洛尔的可药用盐。
6.如权利要求5的制剂，其特征在于，该活性物质为替地沙米倍半反丁烯二酸盐N，N′-二环丙基甲基-9，9-四亚甲基-3，7-二氮杂双环[3.3.1]壬烷1.5氢反丁烯二酸盐。
7.一种制备如权利要求1至6之一的制剂的方法，其特征在于，
(1)一核芯，该芯是由包含一或多种活性物质、高或中粘度羟丙基甲基纤维素HPMC及高或中粘度羟乙基纤维素HEC，其比例为HPMC/HEC＝1/0.85-1/1.2，以及视需要地一种低粘度HPMC，其比例为高或中粘度HPMC/低粘度HPMC＝1/0.01-1/0.2，的混合物压制而成产生实质上不受离子强度影响并实质上延长了所述一种或多种活性物质的零级释放；以及
(2)该芯是视情况经包衣的。
CN01816515XA 2000-09-29 2001-09-28 不受离子强度影响的持续释放的医药制剂 Expired - Fee Related CN1466451B (zh)

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Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070099931A1 (en) * 2004-03-19 2007-05-03 Wyeth Pharmaceutical dosage forms and compositions
NZ551356A (en) 2004-05-11 2009-09-25 Emotional Brain Bv Pharmaceutical formulations and uses thereof in the treatment of female sexual dysfunction
US20060003003A1 (en) * 2004-06-28 2006-01-05 Bakker Johan A Oral sustained release formulation of tedisamil with gastric retention properties
CA2569919A1 (en) * 2004-06-28 2006-01-05 Solvay Pharmaceuticals B.V. Oral sustained release formulation of tedisamil with gastric retention properties
AR049936A1 (es) * 2004-06-28 2006-09-13 Solvay Pharm Bv Formulacion oral de liberacion sostenida de tedisamil con propiedades de retencion gastrica
JP2006143598A (ja) * 2004-11-16 2006-06-08 Nichi-Iko Pharmaceutical Co Ltd 経時的な変色を抑制した医薬組成物
RU2008108216A (ru) * 2005-09-09 2009-10-20 Вайет (Us) Фармацевтические дозированные формы и составы, содержащие лекозотан
EP1790343A1 (en) 2005-11-11 2007-05-30 Emotional Brain B.V. Pharmaceuticals formulations and uses thereof in the treatment of female sexual dysfunction
WO2008054693A2 (en) * 2006-10-30 2008-05-08 The Board Of Regents Of The University Of Texas System Uses of tetrahydrobiopterin and derivatives thereof
US8669258B2 (en) * 2006-10-30 2014-03-11 The Board Of Regents Of The University Of Texas System Treatment for gastroparesis using sepiapterin
EP1925307A1 (en) 2006-11-03 2008-05-28 Emotional Brain B.V. Use of 3-alpha-androstanediol in the treatment of sexual dysfunction
US7965077B2 (en) * 2008-05-08 2011-06-21 Everspin Technologies, Inc. Two-axis magnetic field sensor with multiple pinning directions
PL2395840T3 (pl) 2009-02-13 2020-09-07 Romark Laboratories, L.C. Preparaty farmaceutyczne nitazoksanidu o kontrolowanym uwalnianiu
WO2013157833A1 (ko) * 2012-04-18 2013-10-24 서울대학교산학협력단 베타-차단제를 유효성분으로 포함하는 비만, 비만으로 인한 대사성 질환 및 골감소증 예방, 개선 또는 치료용 조성물
KR102116495B1 (ko) * 2013-08-28 2020-06-03 삼성디스플레이 주식회사 축합환 화합물을 포함하는 유기 전계 발광 소자
AR101476A1 (es) 2014-08-07 2016-12-21 Acerta Pharma Bv Métodos para tratar cánceres, enfermedades inmunes y autoinmunes, y enfermedades inflamatorias en base a la tasa de ocupación de la tirosin quinasa de bruton (btk) y a la tasa de resíntesis de la tirosin quinasa de bruton (btk)
CN104352471A (zh) * 2014-11-21 2015-02-18 哈尔滨圣吉药业股份有限公司 一种马来酸氟伏沙明缓释片及其制备方法
US12016851B2 (en) * 2022-04-11 2024-06-25 Chiesi Farmaceutici S.P.A. Modified release pharmaceutical formulations comprising deferiprone

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1162263A (zh) * 1994-11-02 1997-10-15 詹森药业有限公司 西沙必利的缓释口服组合物
CN1197387A (zh) * 1995-07-26 1998-10-28 杜拉梅德药品有限公司 共轭雌激素药物组合物及其应用方法

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4389393A (en) * 1982-03-26 1983-06-21 Forest Laboratories, Inc. Sustained release therapeutic compositions based on high molecular weight hydroxypropylmethylcellulose
FR2588188B1 (fr) 1985-10-04 1988-01-08 Delalande Sa Comprime de sel(s) hydrosoluble(s) de cinepazide a liberation programmee et son procede de preparation
US4786503A (en) * 1987-04-06 1988-11-22 Alza Corporation Dosage form comprising parallel lamine
US5387419A (en) * 1988-03-31 1995-02-07 The University Of Michigan System for controlled release of antiarrhythmic agents
US5009895A (en) * 1990-02-02 1991-04-23 Merck & Co., Inc. Sustained release with high and low viscosity HPMC
DE4139763A1 (de) * 1991-12-03 1993-06-09 Kali-Chemie Pharma Gmbh, 3000 Hannover, De Kristalline fumarsaure salze von 9,9-alkylen-3,7-diazabicyclononan-verbindungen und diese verbindungen enthaltende arzneimittel
ZA959221B (en) * 1994-11-02 1997-04-30 Janssen Pharmaceutica Nv Cisapride extended release
CA2216215A1 (en) 1997-04-05 1998-10-05 Isa Odidi Controlled release formulations using intelligent polymers having opposing wettability characteristics of hydrophobicity and hydrophilicity
DE69831335T3 (de) * 1997-06-06 2015-01-15 Depomed, Inc. Im magen verweilende orale dosierungsformen von wasserlöslichen arzneistoffen mit kontrollierter freisetzung
US5948440A (en) 1997-12-17 1999-09-07 Ranbaxy Laboratories Limited Modified release matrix formulation of cefaclor and cephalexin
US6099859A (en) * 1998-03-20 2000-08-08 Andrx Pharmaceuticals, Inc. Controlled release oral tablet having a unitary core
AU4426499A (en) * 1998-06-08 1999-12-30 Theravance, Inc. Novel potassium channel drugs and their uses
CN1406126A (zh) * 1998-10-01 2003-03-26 诺瓦提斯公司 新型缓释口服制剂
CO5140079A1 (es) 1998-10-14 2002-03-22 Novartis Ag Composicion farmaceutica de liberacion sostenida y metodo para liberar un agente farmaceuticamente activo de liberacion sostenida y metodo para liberar un agente far- maceuticamente activo
AU2002231175A1 (en) * 2000-12-27 2002-07-08 Focal, Inc. Controlled release of anti-arrhythmic agents from a biodegradable polyethylene oxide hydrogel for local application to the heart

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1162263A (zh) * 1994-11-02 1997-10-15 詹森药业有限公司 西沙必利的缓释口服组合物
CN1197387A (zh) * 1995-07-26 1998-10-28 杜拉梅德药品有限公司 共轭雌激素药物组合物及其应用方法

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