CN1384739A - 缓释的口服药物形式 - Google Patents
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Abstract
本发明涉及具有至少部分延迟作用的口服药物形式。在所述药物形式中含有的药物活性试剂曲马朵至少部分是水溶解度≤100mg/ml的、就地形成的化合物形式。本发明还涉及制备本发明药物形式的方法。
Description
本发明涉及至少部分缓释(sustained-release)的口服药物形式,其中药物活性物质曲马朵(tramadol)至少部分以就地形成的化合物形式存在,其水溶解度≤100mg/ml,并涉及其制备方法。
对于很多药物活性物质特别是镇痛药来说,以缓释制剂的形式给药代表了治疗的改进。即使对于在有机体中半衰期较短,迟延作用使其能够提供作用时间长的制剂,且以更稳定的血液浓度来避免副作用并改进患者对指定药量的顺从性。
例如,通过埋植在缓释骨架中或通过使用缓释膜包衣,可以延迟药物活性物质。借助于膜包衣对非常易溶于水的活性物质(例如,曲马朵盐酸盐,一种控制强烈至非常强烈的疼痛的镇痛药)的延迟作用时常是昂贵的,这是因为这样的活性物质的膜包衣常常构成不适当的扩散屏障或在保存期间这些膜包衣的渗透性起变化(P.B.O′Donnell,J.W.McGinity,“由在药剂的含水聚合物包衣中的含水聚合物分散液制备的聚合物膜的机械性能”,Drugs and the Pharmaceutical Science,vol.79,J.W.McGinity编辑,Marcel Decker,New York,Basle,Hong Kong 1997)。
因此,制备带有由施用含水分散液形成的缓释包衣膜的制剂需要高成本的包衣过程,该过程中进行多层膜或耗时的淬硬处理过程,如下列文献所述:US-PS5645858、US-PS5580578、US-PS5681585或US-PS5472712、K.Bauer,“包衣的药物剂型”,Medpharm ScientificPulishers,Stuttgart 1998、B.Sutter,“论文集”(Thesis),University of Düsseldorf,1987或F.N.Christensen,Procceed.Intern.Symp.Contr.Rel.Bioact.Mater.17,124,1990。
延迟药物活性物质还可能通过降低它们的溶解度来实现,例如,通过形成溶解度小的盐(H.Sucker,PharmazeutischeTechnologie(药学技术),Georg Thieme Verlag,Stuttgart,NewYork 1991)。但是,在一些情况下,此类溶解度小的盐的药用,需要非常昂贵的方法来制备这些盐。
因此,本发明的目的是提供没有现有技术中缺点的药物形式。
令人惊奇的是,现在发现可以通过制备至少部分缓释的曲马朵的口服药物形式来达到此目的,在该形式中活性物质的缓释部分以曲马朵与另一活性物质和/或辅剂的就地形成的化合物的形式存在,其水溶解度≤100mg/ml。
就地形成的该化合物的水溶解度优选≤50mg/ml,特别优选≤30mg/ml,尤其特别优选≤10mg/ml。
为了制备该就地形成的化合物,活性物质曲马朵,优选以水溶性盐并特别优选以曲马朵盐酸盐的形式,与另一种酸性药物活性物质或辅剂的水溶性可药用盐反应,与曲马朵形成化合物,其水溶解度≤100mg/ml,优选≤50mg/ml,特别优选≤30mg/ml,尤其特别优选≤10mg/ml。这些化合物被归类为水溶性小的化合物。
在本发明中,就地形成是指曲马朵或其水溶性盐与另一种酸性药物活性物质或辅剂或其水溶性盐混合,优选在本发明药物形式的制备期间,湿润几次,并非必需地在一些其它能量输入下挤出或配制。
双氯芬酸(diclofenac)、萘普生、乙酰水杨酸、水杨酸、苯甲酸、糖精、环己烷氨基磺酸或乙酰舒泛的钠盐,优选用作制备就地形成的曲马朵化合物的所述另一酸性药物活性物质和/或生物相容性辅剂的水溶性盐。
本发明的缓释的口服药物形式可以以任何摩尔比含有曲马朵组分和另一药物活性物质和/或辅剂。
在本发明药物形式的一个优选实施方案中,曲马朵组分是过量的,并以两种或多种不同速度释放。这意味着由就地形成的化合物中延迟释放曲马朵的同时,部分活性组分以起始剂量快速释放。
在本发明药物形式的另一种优选实施方案中,曲马朵组分及另一酸性药物活性物质或辅剂以克分子数相等的量作为溶解性小的就地形成化合物。因此,尽管它们的原始水溶解度可能不同,这两种活性物质或者活性物质/辅剂以相同的速度进行延迟释放。
在本发明药物形式的一个特别优选的实施方案中,曲马朵盐酸盐和双氯芬酸钠就地反应得到溶解度非常小的化合物,其水溶解度≤0.3mg/ml。在本发明的这些药物形式中,曲马朵与双氯芬酸的比例优选0.5∶1至4∶1,并特别优选1∶1至2∶1。对于与双氯芬酸的就地反应,曲马朵优选过量使用,以便在这些药物形式中,曲马朵的起始剂量快速释放,而曲马朵和双氯芬酸以相同的速度进行延迟释放。通过含此活性物质的联合药物形式以起始剂量立即释放,可以迅速减轻疼痛。然后,由该缓释形式中这些活性物质的缓释使镇痛作用维持较长的时间。
本发明的其它优选缓释药物形式含有由等克分子数的活性物质曲马朵和双氯芬酸就地形成的化合物,使各活性物质的总量以相同的速度延迟释放。
本发明的曲马朵的至少部分缓释的口服药物形式优选是多颗粒的制剂,特别优选颗粒剂、微粒、微片或小丸(pellet)的形式,并特别优选小丸的形式,非必需地填充到胶囊中。这些小药丸优选通过挤出和球粒化制备,并优选直径为0.1至3mm。
本发明的药物形式还可以配制为包衣的片剂或普通片剂,优选快速崩解片。这些片剂可以由压制的小丸组成,特别优选是快速崩解型的。
本发明药物形式的一个特别的优点是,通过就地形成曲马朵和另一种活性物质和/或辅剂的化合物(其水溶解度≤100mg/ml),在药物形式的制备过程中,曲马朵已经是延迟形式,而不用缓释骨架和/或缓释包衣。
本发明的药物形式优选具有至少一种肠溶包衣,其溶解依赖于pH。由于此包衣的作用,所述剂型通过胃而不溶解,且活性物质(一种或多种)和/或辅剂(一种或多种)只在肠道进行控释。该肠溶包衣可以由水溶液或分散液和/或有机溶液进行涂覆。它优选在pH为5至7时溶解。
肠溶包衣优选由以下物质组成:虫胶、聚甲基丙烯酸/丙烯酸乙酯或甲基丙烯酸/丙烯酸甲酯/甲基丙烯酸甲酯共聚物、甲基丙烯酸/甲基丙烯酸甲酯共聚物、琥珀酸乙酸羟丙甲基纤维素、邻苯二甲酸乙酸纤维素、聚乙酸-邻苯二甲酸乙烯酯、邻苯二甲酸羟丙甲基纤维素和/或苯三酸乙酸纤维素。
在就地形成的延迟作用之外,可以通过多种本领域技术人员已知的方法,就势进一步修饰活性物质曲马朵和非必需的其它活性物质的释放。
优选,借助于缓释包衣完成进一步的延迟作用。适宜的缓释包衣包括水不溶性蜡或聚合物,例如,丙烯酸树脂,优选聚(甲基)丙烯酸酯,或者水不溶性纤维素,优选乙基纤维素。这些物质是本领域已知的,例如,Bauer,Lehmann,Osterwald,Rothgang,“UberzogeneArzneiformen”(“包衣的药物剂型”),WissenschaftlicheVerlagsgesellschaft mbH Stuttgart,1988,p.69以后,通过引用将其引入本文并因此形成本公开的一部分。
为了调整活性物质的释放速度,除水不溶性聚合物外,该缓释包衣可以非必需地含有最多为30%重量的非延迟性物质,优选水溶性聚合物,如聚乙烯吡咯烷酮,或水溶性纤维素,优选羟丙甲基纤维素或羟丙基纤维素,及/或亲水性成孔试剂如蔗糖、氯化钠或甘露醇,及/或已知的增塑剂。
为了进一步延迟就地形成的溶解性小的曲马朵化合物的释放,本发明的药物形式可以优选还含有存在于缓释骨架(sustained-release matrix)中的所述化合物,优选以均匀分配的形式。
可以使用的骨架物质是本领域技术人员已知的生理相容的、亲水物质。所用亲水骨架物质优选聚合物,并特别优选纤维素醚、纤维素酯和/或丙烯酸类树脂。所用骨架物质尤其特别优选乙基纤维素、羟丙甲基纤维素、羟丙基纤维素、羟甲基纤维素、聚(甲基)丙烯酸和/或其衍生物,如其盐、酰胺或酯。
其它优选的骨架物质是疏水物质,如疏水性聚合物、蜡、脂肪、长链脂肪酸、脂肪醇或相应的酯或醚,或它们的混合物。所用疏水物质特别优选C12-C30脂肪酸单-或二甘油酯和/或C12-C30脂肪醇和/或蜡,或其混合物。
所用缓释骨架物质还可以是所述亲水和疏水物质的混合物。活性物质的释放优选调节为本发明的药物形式至多每天给药两次,并特别优选每天只给药一次。根据对镇痛药作用的知识,本领域技术人员知道为了达到所需作用应使用的剂量。
修饰本发明药物形式中活性物质曲马朵和非必需的其它活性物质释放性的另一种可能的方式,是通过改变它们的表面积和/或通过使用亲水性辅剂。增大表面积(例如,通过使用较小的小丸),目的是增加这些活性物质的释放速度。在小丸芯中增加亲水性辅剂如乳糖用量的结果,是增加了活性物质(一种或多种)的释放速度。
本发明的药物形式优选适于控制疼痛或适用于治疗尿失禁、咳嗽、炎性和/或变应性反应、抑郁、药物滥用和/或酗酒、胃炎、腹泻、心血管病、呼吸***疾病、精神病或癫痫。
本发明还提供了本发明的至少部分缓释的口服药物形式的制备方法,其中将曲马朵或其盐、另一种酸性药物活性物质或者辅剂或其水溶性盐,以及非必需的其它辅剂混合,润湿几次并在能量输入下配制。
该混合物优选每次用含水介质,特别优选用水或粘合剂水溶液润湿。能量输入优选以压力和/或热的形式。
本发明方法的一个优选实施方案中,将该混合物润湿和制粒几次,至少挤出一次,然后非必需地转变为最终制剂。
每次润湿和制粒步骤后,优选将此混合物挤出和/或干燥。
所有这些润湿、制粒、挤出和/或干燥步骤后,优选使混合物成为小丸,非必需地与其它辅剂混合,然后压制为片剂。优选通过挤出制成小丸。
在本发明方法的一个特别优选的实施方案中,将盐的湿润的混合物制粒、挤出、湿润并再次制粒、挤出,然后使其变成小丸。在另一个特别优选的方法中,将湿润的混合物制粒、干燥、湿润,并再次制粒、挤出,然后使其变成小丸。
在压制前,小丸优选进行肠溶包衣。
在本发明方法的一个特别优选的实施方案中,用曲马朵盐酸盐双氯芬酸钠制备就地形成的化合物。
如果将本发明的药物形式转变为最终制剂,则可以通过本领域技术人员已知的多种方法进行。
根据实施方案,本发明的药物形式还可以含有本领域技术人员已知的常规辅剂和添加剂作为附加组分。如果本发明的药物形式要带有包衣,可以通过常规方法来完成,例如,通过包衣锅方法,通过溶液、分散液或混悬液的喷雾,通过热融方法或通过粉末覆着方法。
令人惊奇的是,本发明药物形式的特征是活性物质曲马朵和非必需的其它活性物质从本发明药物形式中的释放不受常规标准范围内释放条件改变的影响,例如,缓冲剂的离子浓度、表面活性物质的存在、不同类型缓冲剂的使用和/或不同机械应力的应用。即使在达40℃的较高温度下长期保存后,活性物质(一种或多种)从本发明药物形式中的释放速度仍保持不变。保存时所得药物形式给出的释放曲线是稳定的。
从本发明的至少部分缓释的口服药物形式中,活性物质的释放遵循只能通过昂贵的骨架***达到的动力学。令人惊奇的是,发现药物活性物质的释放可以在不用常规缓释***的前提下得以延迟,于是可通过改变该药物形式的大小并掺入溶解性辅剂来调整释放曲线,同时维持两种活性物质的普通释放速度。令人惊奇的是,尽管粒径非常小(平均≤5μm),由就地制备的溶解性小的曲马朵/双氯芬酸化合物中两种活性物质的释放,与相同药物形式(虽然实际粒度较大,约20-100μm)中分别制备的曲马朵和双氯芬酸盐的释放,以完全相同的延迟性发生。
由于从本发明药物形式中活性物质曲马朵和非必需的其它活性物质的释放,可以不用附加的缓释***就能得以延迟,故此所述药物形式可以以较短的时间和较低的成本制备,该制备具有优异的再现性。
曲马朵和另一种相应的酸性药物活性物质或者辅剂的化合物的溶解度检测如下:
将由本发明方法制备的、不带有缓释包衣的、含有曲马朵(即(1RS,2RS)-2-[(二甲基氨基)甲基]-1-(3-甲氧基苯基)环己烷醇)和适当的酸性药物活性物质或辅剂的被测小丸,置于25℃的去离子水中,加入量(相当于每5ml去离子水中约25mg的小丸)使在此温度下形成饱和溶液,摇动24小时(Vibrax,25℃下浴震动器设置=1200)后仍是饱和的。
在初步实验中,用曲马朵和适当的酸性药物活性物质或辅剂的分别制备的盐,估测相应的饱和溶解度范围。
饱和溶液稳定后,用吸量管移出上清液并以3500rpm离心5分钟。
将部分所得清澈上清液转移至HPLC样品瓶中,以曲马朵盐酸盐为标准测定曲马朵和适当酸性药物活性物质或辅剂的化合物的浓度。
实施例制剂的释放特性测定如下:
如欧洲药典所述,在37℃(±0.5℃)的温度下及在100min-1或50min-1转速下,这些制剂或者在纺丝笼(spinning cage)仪器(实施例1至6)或者在桨式搅拌器(实施例7)中测试。在900ml不含酶的人工肠液(pH7.2)中,在实施例1中,检测制剂10小时,在实施例6中检测5小时,而在实施例5中检测4小时。在实施例2至4和7中,将制剂先在600ml不含酶的人工胃液(pH1.2)中检测2小时,然后在900ml不含酶的人工肠液(pH7.2)中再检测8小时。
通过HPLC测定任何指定时间内活性物质的释放量。对于每种情况,所示的数值和曲线是3个样品的平均。
下面借助于实施例说明本发明。这些说明只是举例而已,并非要限制本发明的范围。
实施例:
实施例1:
在Kenwood Chef混合器中,将125g的曲马朵盐酸盐、125g的双氯芬酸钠和250g的微晶纤维素(Avicel PH101,FMC)均匀混合10分钟,然后用足够润湿量的水制粒。再将颗粒的粘结粗料在Nica挤出机(E140型)用1.0mm挤出模具挤出。虽然棒状挤出物起初仍极粘,但是在此挤出过程中它们变成非常干燥的挤出物,其可塑性不能满足随后的小丸化的要求。将该挤出物再次湿润并制粒。将所得颗粒在Nica挤出机中再次挤出,再将潮湿的挤出物在Nica球化器(S450型)中转变为粒度均匀的小丸。将这些小丸在约50℃下在干燥箱中干燥,并分为筛分粒级,≥90%的小丸在所需的800-1250μm的筛分粒级范围内。小丸的组成:曲马朵盐酸盐 50mg双氯芬酸钠 50mg微晶纤维素(Avicel PH101,FMC) 100mg
200mg
通过上述方法检测,对于上述制备的小丸,发现从该就地形成的化合物中活性物质曲马朵的水溶解度是0.36mg/ml。
通过上述方法检测,释放特性如下:
时间(分钟) | 从200mg小丸中的释放量(mg)曲马朵 双氯芬酸 |
30120300600 | 10 718 1526 2435 33 |
实施例2:
将200g的曲马朵盐酸盐、100g的双氯芬酸钠、22g的琥珀酸粉末和332g的微晶纤维素(Avicel PH101,FMC)在Kenwood Chef混合器中均匀混合10分钟,并类似于实施例1加工为小丸。小丸的组成:曲马朵盐酸盐 100mg双氯芬酸钠 50mg琥珀酸粉末 11mg微晶纤维素(Avicel PH101,FMC) 166mg
327mg
在流化床中以空气入口温度40℃,用虫胶水溶液给500g的分级小丸提供肠溶包衣,基于小丸的重量,虫胶的使用量为5%重量。500g小丸的膜包衣虫胶水溶液ASL 125 125g(20%固体物质,Marchand & Cie)枸橼酸三乙酯 1.25g水 136.25g
如上所述检测,释放特性如下:
时间(分钟) | 从344mg小丸中的释放量(mg)曲马朵 双氯芬酸 |
120240480600 | 0 061 1076 2584 28 |
实施例3:
将1.25kg的曲马朵盐酸盐、1.25kg的双氯芬酸钠、1.0kg的乳糖一水合物、0.75kg的微晶纤维素(Avicel PH101,FMC)和0.75kg的胶体微晶纤维素(Avicel RC 591,FMC)在Diosna(P25型)中混合并制粒。类似于实施例1制备小丸,其中有如下变化。粘结的湿润颗粒在制粒后不挤出,而是直接散布到用箔密封的金属盘中,并在干燥箱中在50至70℃下加热20分钟,这样避免了水分的丧失。再将这些颗粒湿润并制粒。将其在Nica挤出机(E140型)中用0.8mm挤出模具挤出。在Nica球化器(S450型)中将挤出物小丸化。这些小丸在干燥箱内干燥后,将它们分级,≥90%的小丸在所需的0.63至1.0mm的筛分粒级范围内。小丸的组成:曲马朵盐酸盐 75mg双氯芬酸钠 75mg乳糖一水合物 60mg微晶纤维素(Avicel PH101,FMC) 45mg胶体微晶纤维素(Avicel RC 591,FMC) 45mg
300mg
然后,将5kg的小丸在Hüttlin球包衣机中,以40℃的空气入口温度,用基于小丸总重量的21%的Eudragit L-55从下列组成的水分散液中包衣:5kg小丸的膜包衣:Eudragit L30D-55(Rhm,1∶1的聚甲基丙烯酸 3500g/丙烯酸乙酯共聚物的30%水分散液)Eudragit NE30D(Rhm,聚丙烯酸乙酯/甲基丙 315g烯酸甲酯共聚物的30%水分散液)枸橼酸三乙酯 175g微粉化的滑石 262.5g水 3657.5g胶囊的组成:
用带有2个颗粒调剂台的Zanasi E6胶囊填充机,将400mg的包衣小丸及46mg曲马朵初始剂量小丸(相当于25mg的曲马朵盐酸盐、10.5mg的Avicel PH105和10.5mg的I-HPC LH31),填充到0号硬明胶胶囊中。
按照上述方法检测,释放特性如下:
时间(分钟) | 从每个胶囊中的释放量(mg)曲马朵(剂量100mg) 双氯芬酸(剂量75mg) |
30120240480600 | 25 028 056 2979 5085 56 |
实施例4:
将1.5kg的曲马朵盐酸盐、1.0kg双氯芬酸钠、1.0kg乳糖一水合物、0.75kg的微晶纤维素(Avicel PH101,FMC)和0.75kg的胶体微晶纤维素(Avicel RC 591,FMC)在Diosna(P25型)中混合并制粒。类似于实施例3制备小丸,其中有如下变化。在混合器中,在第一次制粒后,通过将夹套在70℃下加热30分钟,直接进行双氯芬酸钠与曲马朵盐酸盐的反应,在若干短暂的时间内开动搅拌器叶片。此反应后,不用倒出,直接进行第二次制粒。小丸的组成:曲马朵盐酸盐 75mg双氯芬酸钠 50mg乳糖一水合物 50mg微晶纤维素(Avicel PH101,FMC) 37.5mg胶体微晶纤维素(Avicel RC 591,FMC) 37.5mg
250mg
然后,将5kg的小丸在Hüttlin球包衣机中,以40℃的空气入口温度,用基于小丸总重量的22%的Eudragit L-55从下列组成的水分散液中进行包衣:5kg小丸的膜包衣:Eudragit L30D-55(Rhm,1∶1的聚甲基丙 3667g烯酸/丙烯酸乙酯共聚物的30%水分散液)枸橼酸三乙酯 220g微粉化的滑 550g水 4913.5g胶囊的组成:
用带有2个颗粒调剂台的Zanasi E6胶囊填充机,将348mg的包衣小丸及46mg曲马朵初始剂量小丸(相当于25mg的曲马朵盐酸盐、10.5mg的Avicel PH105和10.5mg的I-HPC LH31),填充到0号硬明胶胶囊中。
按照上述方法检测,释放特性如下:
时间(分钟) | 从每个胶囊中的释放量(mg)曲马朵(剂量100mg) 双氯芬酸(剂量50mg) |
30120240480600 | 27 032 078 2494 4099 45 |
实施例5:
将100g曲马朵盐酸盐、69g糖精钠和169g微晶纤维素(Avicel PH101,FMC)在Kenwood Chef混合器中均匀混合10分钟,然后类似于
实施例1加工为小丸。小丸的组成:曲马朵盐酸盐 100mg糖精钠 69mg微晶纤维素(Avicel PH101,FMC) 169mg
338mg
如上所述进行测定,释放特性如下:
时间(分钟) | 曲马朵的释放百分率 |
30 | 84 |
120 | 100 |
240 | 104 |
实施例6:
将100g曲马朵盐酸盐、84g萘普生钠和184g微晶纤维素(AvicelPH101,FMC)在Kenwood Chef混合器中均匀混合10分钟,然后类似于实施例1加工为小丸。小丸的组成:曲马朵盐酸盐 100mg萘普生钠 84mg微晶纤维素(Avicel PH101,FMC) 184mg
368mg
如上所述进行检测,释放特性如下:
时间(分钟) | 释放百分率曲马朵 萘普生 | |
30 | 72 | 55 |
120 | 91 | 88 |
240 | 101 | 100 |
300 | 102 | 102 |
实施例7:
将1.5kg曲马朵盐酸盐、1.0kg双氯芬酸钠、1.0kg乳糖一水合物、0.75kg微晶纤维素(Avicel PH101,FMC)和0.75kg胶体微晶纤维素(Avicel RC 591,FMC)在Diosna(P25型)中均匀混合10分钟,并类似于实施例3加工为小丸。小丸的组成:曲马朵盐酸盐 75mg双氯芬酸钠 50mg乳糖一水合物 50mg微晶纤维素(Avicel PH101,FMC) 37.5mg胶体微晶纤维素(Avicel RC 591,FMC) 37.5mg
250mg
然后,将5kg的小丸在Hüttlin球化包衣机中,以40℃的空气入口温度,用基于小丸总重量的21%的Eudragit L-55从组成如下的水分散液中进行包衣:5kg小丸的膜包衣:Eudragit L30D-55(Rhm,1∶1的聚甲基丙烯酸 3500g/丙烯酸乙酯共聚物的30%水分散液)Eudragit FS 30D(Rhm,聚甲基丙烯酸/丙烯酸 350g甲酯/甲基丙烯酸甲酯共聚物的30%水分散液)枸橼酸三乙酯 210g甘油单硬脂酸酯(Cutina GMS,Henkel) 92.4g水 3134.6g
将322.5mg的小丸(相当于剂量75mg的曲马朵盐酸盐和50mg的双氯芬酸钠)按照顺序先与22.5mg交联聚乙烯吡咯烷酮(Kollidon CL,BASF)混合,然后与205.6mg的Cellatose(Meggle)、25mg曲马朵盐酸盐和1.4mg硬脂酸镁混合,并压制为7×14mm的刻痕长椭圆形片剂,重577mg。在水性介质中,这些片剂崩解为单个的小丸。
如上所述进行测定,释放特性如下:
时间(分钟) | 从每片中的释放量(mg)曲马朵(剂量100mg) 双氯芬酸(剂量50mg) |
30120240360420600 | 25 025 065 2277 3181 3591 42 |
Claims (29)
1.曲马朵的至少部分缓释的口服药物形式,其特征在于药物活性物质的缓释部分以曲马朵与另一种酸性的药物活性物质和/或辅剂就地形成的、水溶解度≤100mg/ml的化合物的形式存在。
2.权利要求1所述的药物形式,其特征在于所述水溶解度≤50mg/ml,优选≤30mg/ml,并特别优选≤10mg/ml。
3.权利要求1或2所述的药物形式,其特征在于曲马朵以水溶性盐优选曲马朵盐酸盐的形式用来制备就地形成的化合物。
4.权利要求1至3的一项或多项所述的药物形式,其特征在于使用另一种酸性药物活性物质或辅剂的水溶性可药用盐来制备就地形成的化合物。
5.权利要求4所述的药物形式,其特征在于所用盐是双氯芬酸、萘普生、乙酰水杨酸、水杨酸、苯甲酸、糖精、环己烷氨基磺酸或乙酰舒泛的钠盐。
6.权利要求1至5的一项或多项所述的药物形式,其特征在于曲马朵组分过量存在。
7.权利要求6所述的药物形式,其特征在于曲马朵以两种或多种不同的速度释放。
8.权利要求1至5任一项所述的药物形式,其特征在于所述曲马朵和酸性药物活性物质或辅剂以等克分子数的量存在,成为就地形成的化合物。
9.权利要求8的药物形式,其特征在于曲马朵和所述酸性活性物质或辅剂以相同的速度释放。
10.权利要求4至9的一项或多项所述的药物形式,其特征在于曲马朵盐酸盐和双氯芬酸钠用作进行就地形成反应的活性物质。
11.权利要求1 0所述的药物形式,其特征在于曲马朵与双氯芬酸的摩尔比为0.5∶1至4∶1,并优选1∶1至2∶1。
12.权利要求10或11所述的药物形式,其特征在于至少部分曲马朵和至少部分双氯芬酸以相同的速度释放。
13.权利要求10所述的药物形式,其特征在于曲马朵和双氯芬酸以等克分子数的量、以就地形成的化合物的形式存在,且各活性物质的总量以相同的速度释放。
14.权利要求1至13一项或多项所述的药物形式,其特征在于它们是多颗粒制剂,优选是颗粒剂、微粒、微片或小丸的形式,并特别优选小丸的形式,非必需地填充到胶囊中。
15.权利要求1至13一项或多项所述的药物形式,其特征在于它们被制成包衣片剂或普通片剂,优选为快速崩解片剂。
16.权利要求15所述的药物形式,其特征在于所述片剂由被压制的小丸组成。
17.权利要求1至16一项或多项所述的药物形式,其特征在于它们具有至少一种肠溶包衣。
18.权利要求1至17一项或多项所述的药物形式,用于控制疼痛。
19.权利要求1至17一项或多项所述的药物形式,用于治疗尿失禁。
20.制备权利要求1至19任一项所述的至少部分缓释的口服药物形式的方法,其特征在于将曲马朵和酸性药物活性物质和/或辅剂或其水溶性盐,以及非必需的其它辅剂混合、润湿几次并在能量输入的条件下制剂。
21.权利要求20所述的方法,其特征在于所述混合物用含水介质,优选水或粘合剂水溶液润湿。
22.权利要求20或21所述的方法,其特征在于能量输入采用加压和/或加热的形式。
23.权利要求20至22任一项所述的方法,其特征在于将所述混合物润湿并制粒几次、挤出至少一次,然后非必需地转变为最终制剂。
24.权利要求20至22任一项所述的方法,其特征在于在所有这些润湿、制粒、挤出和/或干燥步骤后,将所述混合物非必需地与其它辅剂混合,然后制成小丸。
25.权利要求20至23任一项的方法,其特征在于将所述润湿的混合物制粒、挤出、润湿并再次制粒、挤出,然后制成小丸。
26.权利要求20至23任一项所述的方法,其特征在于将所述润湿的混合物制粒、干燥、润湿并再次制粒、挤出,然后制成小丸。
27.权利要求20至26所述的方法,其特征在于将所述小丸压制为片剂。
28.权利要求27所述的方法,其特征在于在压制前所述小丸具有至少一种肠溶包衣。
29.权利要求20至28的一项或多项所述的方法,其特征在于曲马朵盐是曲马朵盐酸盐,而其它活性物质是双氯芬酸钠。
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DE19940944A DE19940944B4 (de) | 1999-08-31 | 1999-08-31 | Retardierte, orale, pharmazeutische Darreichungsformen |
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DE19927688A1 (de) * | 1999-06-17 | 2000-12-21 | Gruenenthal Gmbh | Mehrschichttablette zur Verabreichung einer fixen Kombination von Tramadol und Diclofenac |
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1999
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110755396A (zh) * | 2019-12-06 | 2020-02-07 | 北京悦康科创医药科技股份有限公司 | 一种布洛芬缓释小丸及其制备方法 |
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