CN1179101A - 贮存稳定的剂型 - Google Patents
贮存稳定的剂型 Download PDFInfo
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- CN1179101A CN1179101A CN 96192739 CN96192739A CN1179101A CN 1179101 A CN1179101 A CN 1179101A CN 96192739 CN96192739 CN 96192739 CN 96192739 A CN96192739 A CN 96192739A CN 1179101 A CN1179101 A CN 1179101A
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Landscapes
- Medicinal Preparation (AREA)
Abstract
本发明涉及固态的剂型,它可以通过挤压一种熔融物得到,该熔融物除含有一种或多种活性物质以外还含有N-乙烯基吡咯烷酮的均聚物和/或共聚物与降解的淀粉的混合物。
Description
本发明涉及固态的剂型,它可以通过挤压无溶剂的熔融物并随后成形而得到,该熔融物除了含有一种或多种活性物质以外还含有以下物质的混合物:a)10-99重量%一种或多种水溶性的、可热塑处理的N-乙烯基吡咯烷酮的均聚物或共聚物,b)1-90重量%降解的淀粉,c)0-50重量%一种或多种常用的药物佐剂
通过挤压含有活性物质和基于N-乙烯基吡咯烷酮的聚合物的熔融物并接着成形来制备固态剂型例如由EP-B 240 904公开。
在WO 93/10758中说明了以无定型碳水化合物玻璃基质为基础的缓释剂型,它们含有聚乙烯基吡咯烷酮或麦芽糖糊精作为用于再结晶的物质。制备基质时将基质成份的水溶液加热直至得到粘滞的混合物,通过捏和将活性物质搀和其中,在此基础上可以将含有活性物质的混合物例如通过挤压而处理加工。
通过挤压含有活性物质的熔融物制备固态剂型时根本的困难在于:用于构成基质的聚合物一方面必须具备足够的可热塑处理性,另一方面在其成品剂型中即使长期贮存也能保持形状稳定。良好的可热塑处理性主要存在于这样的聚合物中,即这些聚合物具有相对较低的分子量并由此具有相对较低的玻璃化温度;和/或含有增塑单体例如乙酸乙烯酯,但也正是这些聚合物在处理成固态剂型时产生不希望的“冷流”现象。
本发明的任务是:寻找出贮存稳定的固态剂型,它们能够简单地通过挤压含有活性物质的熔融物和紧接着的成形而获得。
由此发现了前面所定义的剂型。
合适的活性物质例如有:β-美沙松、硫辛酸、索他洛尔、沙丁胺醇、去甲苯福林、水飞蓟素、双氢麦角胺、丁咯地尔、依托贝托、吲哚美辛、去甲羟安定、β-乙酰地高辛、吡罗昔康、氟哌啶醇、ISMN、阿密曲替林、双氯芬酸、心痛定、戊脉安、吡硫醇、尼群地平、强力霉素、溴黑辛、甲基强的松龙、可乐定、苯非贝特、别嘌醇、哌仑西平、左旋甲状腺素、塔莫克西芬、甲地高辛、邻-(β-羟乙基)芸香甙、苯丙西林、阿西洛韦一硝酸盐、扑热息痛、萘呋胺酯、己酮可可碱、普罗帕酮、醋丁酰比安、L-甲状腺素、曲马多、溴隐亭、氯苯哌酰胺、酮替芬、酚丙喘宁、Ca-Dobelisat、萘心安、二甲胺四环素、麦角溴烟酯、氨溴索、美托洛尔、β-谷固素、衣那普利氢化马来酸盐、苯扎贝特、ISDN、加罗帕米、烟胺羟丙茶碱、洋地黄毒甙、氟硝安定、苄环烷、右泛酰醇、吲哚洛尔、劳拉西泮、地尔硫卓、脑复康、苯氧基甲基青霉素、呋喃苯胺酸、溴西泮、二氟脑益嗪、红霉素、甲氧氯普胺、阿西美辛、雷尼替丁、比哌立簦、安乃近、多塞平、二钾-Chlorazepat、四西泮、雌莫司汀磷酸盐、叔丁喘宁、卡托普利、马普替林、哌唑嗪、阿替洛尔、优降糖、头孢克罗、乙苯福林、西米替丁、茶碱、氢化吗啡酮、布洛芬、扑癫酮、氯巴占、奥沙西罗、甲孕酮、氟卡胺、镁-吡哆醛-5-磷酸盐谷氨酸盐、羟甲香豆素、益多酯、长春胺、肉桂苯哌嗪、安定、酮洛芬、三氟噻吨、吗斯酮胺、甲磺二冰脲、二甲茚定、美哌隆、索喹洛尔、双氢可待因、氯美噻唑、可立马丁、格列派特、卡里定原酶、奥昔麻黄碱、氯苯氨丁酸、羧基甲基半胱氨酸、甲硫哒嗪、倍它西丁、L-色氨酸、桃金娘油、菠萝蛋白酶、心可定、柳氮磺胺吡啶、阿斯咪唑、舒比利、左旋多巴、二苯西平、乙酰水杨酸、霉康唑、Nystatin、酮康唑、钠-Picosulfat、消胆胺、Gemfibrocil、利福平、Fluorcortolon、美西律、阿莫西林、特非那定、粘多糖聚硫酸酯、三唑仑、米安舍林、噻咯芬酸、甲硫酸阿美齐铵、甲氟喹、丙丁酚、Chinidin、卡马西平、L-天冬氨酸镁、喷布洛尔、吡咯他尼、阿米替林、环丙孕酮、丙戊酸钠、美贝维林、比沙可啶、5-氨基-水杨酸、双肼苯哒嗪、镁加铝、苯丙香豆素、金钢胺、萘普生、Carteolol、法莫替丁、甲基多巴、金洛芬、雌三醇、纳多洛尔、左美丙嗪、阿霉素、美托奋乃酯、硫唑嘌呤、氟硝丁酰胺、诺氟沙星、芬地林、丙缓脉灵重酒石酸盐、马栗树皮素、乙酰氨基苯酚(=4-乙酰氨基酚)、醋磺环己脲、乙酰洋地黄毒甙、乙酰水杨酸、山油柑碱、阿尼帕米、苯卡因、β-胡萝卜素、氯霉素、利眠宁、氯化孕酮、氯噻嗪、肉桂苯哌嗪、氯硝安定、可待因、地塞米松、安定、双香豆精、洋地黄毒甙、地高辛、氢麦角碱、氢乙罂粟碱、氟硝安定、呋喃苯胺酸、短杆菌肽、灰黄霉素、海索比妥、氢氯酸噻嗪、氢化可的松、氢氟噻嗪、异丁苯丙酸、吲哚美辛、酮洛芬、Lonetil、美达西潘、美夫西特、去氢甲基睾丸素、甲泼尼龙、甲硫酸二嗪蓝(=Sulfaperin)、萘定酸、尼非地平、硝基安定、呋喃坦啶、制霉菌素、雌二醇、罂粟碱、非那西丁、苯巴比妥、苯基保太松、苯妥英、脱氢可的松、利血平、螺内酯、链霉素、磺胺二甲嘧啶(=磺胺二甲嘧啶)、磺胺甲基硫二嗪、磺胺甲基异恶唑(=Sulfameter)、磺胺培林、磺胺噻唑、硫代异恶唑、睾丸素、甲磺氮卓脲、甲磺丁脲、甲氧苄氨嘧啶、短杆菌素。
按照本发明维生素类也可配入制剂中。包括维生素A族、B族,其中不仅包括B1、B2、B6和B12以及烟酸和烟酰胺,还包括具备维生素B特性的化合物类,例如腺嘌呤、胆碱、泛酸、维生素H、腺甙酸、叶酸、乳清酸、潘氨酸、肉碱、对-氨基苯甲酸、肌-肌醇和α-脂酮酸。此外还有C族、D族、E族、F族、H族、I族和J族、K族和P族的维生素。
按照本发明尤其优选的活性物质为布洛芬、乙酰水杨酸、扑热息痛、非那宗、氟比洛芬、卡托普利、硝苯地平、乙酰半胱氨酸、萘呋胺、维拉帕米和呋喃苯胺酸。
也可以使用活性物质混合物。
基于固态剂型的活性物质的量依其作用和释放速度不同而在很大的范围内有所变化。活性物质含量可以在0.1至90,优选0.5至60重量%的范围内。
除活性物质以外,本发明的剂型还含有以下构成基质的物质:a)10-99,优选40-95重量%一种或多种水溶性的、可热塑处理的N-乙烯基吡咯烷酮的均聚物或共聚物,b)1-90,优选5-60重量%降解的淀粉,c)0-50重量%一种或多种常用的药物佐剂其中所述量基于a),b)和必要时c)的剂量的总和。
作为成份a)考虑水溶性的、可热塑处理的N-乙烯基吡咯烷酮的均聚物或共聚物或者这些聚合物的混合物。这些聚合物具备的玻璃化温度范围一般为80-190,优选90-175℃。合适的均聚物为例如按照Fikentscher的K值在10至30范围内的聚合物。合适的共聚物可以含有作为共聚单体的不饱和羧酸,例如异丁烯酸、巴豆酸、马来酸、衣康酸,及其与具有1至12,优选1至8个碳原子的醇的酯,此外还有羟乙基-或羟基丙基丙烯酸酯和-甲基丙烯酸酯,(甲基)丙烯酰胺,马来酸和衣康酸的酐和半酯(半酯优选在聚合反应后产生),N-乙烯基己内酰胺和丙酸乙烯酯。
优选的共聚单体为丙烯酸和尤其优选乙酸乙烯酯。共聚用单体的含量可以为20至70重量%。聚合物成份a)的制备是普遍熟知的。
按照本发明应用水溶性的降解的淀粉(糊精)作为成份b)。
这些糊精是市售的,并且可以简单地由淀粉通过稀酸不完全水解、通过加热作用以及通过氧化或借助于淀粉酶的酶降解而得到。
通过在水相中水解所获得的淀粉降解产物,其重均分子量为2500至25000,与烤糊精不同通常被称为糖化淀粉,在市场上可以买到。
这样的糖化淀粉在化学上与烤糊精尤其有如此区别,即在含水介质中水解降解(通常为悬浮液或溶液,一般其固态物质含量为10至30重量%以及优选酸或酶催化进行)时基本不会有再结合和支化的可能性。这也表现在其它的分子量分布中。
糖化淀粉的制备已被广泛熟知,尤其在Guenther Tegge,淀粉和淀粉衍生物(Staerke und Staerkederivate),Behr′s出版社,汉堡,1984年,173页和220页及以后各页中,以及在EP-A 441 197中已有说明。按照本发明应用的糖化淀粉优选为这样一些物质,即其重均分子量为4000至16000,尤其优选6500至13000的范围。
淀粉降解产物具有2至40,优选2至30的右旋糖当量(DE)。DE值表现了基于无水右旋糖的还原能力的还原能力的特征,并且按照德国标准化委员会的食品和农业产品的DIN10 308,第5.71版,来确定(参见GuentherTegge,淀粉和淀粉衍生物(Staerke und Staerkederivate),Behr′s出版社,汉堡,1984年,305页)。
尤其优选的成份b)为麦芽糖糊精、其DE值在3至20的范围内,以及链长为4至10个葡糖酐单位并具有高麦芽糖含量的淀粉降解产物。
作为成份c)合适的有常用的药物佐剂例如填充剂、润滑剂、脱模剂、稳定剂、色素、增量剂或流动调节剂及其混合物。
可以在聚合物熔融之前或之后混合活性物质与构成基质的成份a)和b)和必要时c)。优选在挤压机中,更优选在双螺杆挤压机或具有混合室的单螺杆挤压机中混合。
含有活性物质的熔融物的制备是在50至180,优选60至150℃的温度下在挤压机中进行。接着将挤出的、仍可塑的挤出物条连续成形,例如按照EP-A 240 906中所说明的方法通过将挤出物条引入二个相对运动的辊之间,该辊外套内具有相对的凹槽,其中凹槽的形状决定片剂形状。还可以考虑冷切来进行成形。
熔融物不含有溶剂。意即:所使用的物质不以溶液的形式用于处理,不添加水和有机溶剂。
优选所谓的热切。这时,挤出物由挤压机的喷嘴排出来后即通过例如旋转的刀或其它合适的装置而直接粉碎,宜切成这样的小段,其长度约等于挤出物的直径。将这些切碎的熔融物小段在空气流或气流中冷却,以至其表面在与其它小段或容器壁接触之前就已不粘连,但另一方面小段仍具有足够的可塑性,以使通过相撞例如与后续的的旋风分离器的壁相撞,可获得球形。以这种简单的方式可以获得直径为0.5至4,优选0.8至2mm的大致为球形或扁豆形的小段。优选的较小的小段主要适合于充填胶囊。
剂型也可以赋予常规的涂层以改善其外观和/或味道。
令人惊异的是:通过添加降解的淀粉可以协同提高聚合物/淀粉混合物的玻璃化温度。这样就导致:即使应用具有较低玻璃化温度的较低分子量的聚合物也能避免冷流现象。此外降解的淀粉也促进了活性物质的快速释放。未所预料的还有:其本身不能无溶剂挤压并且在水溶液中不与聚合物构成共同相的降解淀粉具备对无溶剂的聚合物熔融物良好的相容性并能形成均质的混合物。
实施例
按照在下面的实施例中所说明的含量比例将各成份预先混合并加入双螺杆挤压机(Werner & Pfleiderer ZSK30)的入口处。以3至4kg/小时的产品通过量进行熔融挤压。挤压机各个温度区的温度以及加热的喷嘴排(diestrip)的温度在试验中分别说明。喷嘴排有7个直径为1mm的孔。将经过加热的挤压机喷嘴排出来的熔融物条通过用打浆辊粒化器(Messer-walzengranulator)(4个刀,400-850rpm.)进行空气冷却下的热切而造粒。
用搅拌翼方法(按照USP XXI的Paddle方法,美国药典)测量活性物质的释放。这种体外检测方法用于测定含活性物质的剂型例如片剂的溶解速率。
在此将900ml pH6.8的磷酸盐缓冲液添加0.1%硫酸月桂基酯钠在一个具有圆底的1L容器中调温至37℃。称量合适量(约300mg)的颗粒大小约1.25至1.60mm的小丸剂后加进。在按照US XXI的这个“不改变测验”中在100rpm的搅拌翼旋转速度下各在30分钟后用紫外光谱测定由丸剂中活性物质的释放。
作为淀粉降解产物应用了市售的麦芽糖糊精(CPUR 1910,德国Cerestar股份有限公司),其Mw为10540-12640,DE值为11-14。
实施例2至4中所应用的由60重量%乙烯基吡咯烷酮和40重量%乙酸乙烯酯所组成的共聚物的K值为30。实施例1
挤压机各区域(1-5区)的温度20,80,140,130,130℃,挤压机头的温度130℃,喷嘴排的温度130℃活性物质 成份a 成份b呋喃苯胺酸 聚乙烯基吡咯烷酮 麦芽糖糊精
K值17,20重量% 70重量% 10重量%30分钟后释放100%实施例2
挤压机各区域(1-5区)的温度60,120,120,110,120℃,挤压机头的温度130℃,喷嘴排的温度120℃活性物质 成份a 成份b硝苯地平 乙烯基吡咯烷酮- 麦芽糖糊精
乙酸乙烯酯-共聚物20重量% 75重量% 5重量%30分钟后释放80%实施例3
挤压机各区域(1-5区)的温度60,120,120,120,130℃,挤压机头的温度130℃,喷嘴排的温度160℃活性物质 成份a 成份b布洛芬 乙烯基吡咯烷酮- 麦芽糖糊精
乙酸乙烯酯-共聚物40重量% 50重量% 10重量%30分钟后释放80%实施例4
挤压机各区域(1-5区)的温度70,130,130,140,130℃,挤压机头的温度130℃,喷嘴排的温度160℃活性物质 成份a 成份b卡托普利 乙烯基吡咯烷酮- 麦芽糖糊精
乙酸乙烯酯-共聚物20重量% 65重量% 15重量%30分钟后释放80%实施例5
测定K值为17的聚乙烯基吡咯烷酮和麦芽糖糊精以及这二种成份的混合物的玻璃化温度(见表)。
用DSC仪912+TA器械公司的热分析仪990测定玻璃化温度。以常用的方式进行温度校准和热函校准。样品称重一般为13mg。首先将样品以20K/min的速度加热至190℃然后迅速冷却。在接着的第二个加热过程中测得玻璃化温度(在热流曲线中玻璃阶段的半阶段高度的温度)。这一测量程序通过记录一致的热历程而能有意义地比较各个样品。为了测定玻璃化温度,在本例中重要的是遵守所说明的温度程序。按照DIN 53 765的测定提供了玻璃化温度的误差值,因为样品在测量过程中受到热损害。此外借助于用于聚合物混合物的Gordon-Taylor公式计算混合物的玻璃化温度:Tg=(w1Tg1+kw2Tg2)/(w1+kw2)[M.Gordon,J.S.Taylor,应用化学杂志(Journal of AppliedChemistry)USSR 2(1995年)493期;引用:H.A.Schneider,聚合物(Polymer)第30期(1989年)771页]。w1和Tg1为成份i的重量含量和玻璃化温度。k为0.37的调整参数。测量值和调整值之间的差值在测量误差的范围内(约1K)。
由此得出:各所测得的Tg值高于计算的Tg值。显然通过混合成份a)和b)可以获得Tg的协同提高(结果见表)。表
实施例6贮存稳定性试验
PVP K17 | 麦芽糖糊精含量 | ||||
100% | 25% | 50% | 75% | 100% | |
Tg测得值 | 123℃ | 153℃ | 179℃ | 182℃ | 188℃ |
Tg计算值 | - | 138℃ | 156℃ | 172℃ | - |
按照实施例3所给的条件制备制剂。活性物质 成份a 成份b布洛芬 聚乙烯基吡咯烷酮 麦芽糖糊精
K值17,20重量% 76重量% 4重量%30分钟后释放96.8%。具有以下组合的制剂活性物质 成份a布洛芬 聚乙烯基吡咯烷酮
K值17,20重量% 80重量%30分钟后显示95%的释放。
将二种制剂由熔融物加工成大丸剂形式并按照USP XXI测量其释放。
剂型在50℃恒温下在封闭的容器中贮存了4周。
只有含麦芽糖糊精的剂型未显示其特性的改变,而不含有麦芽糖糊精的剂型则发粘得厉害、部分流失或大丸剂变形。
Claims (3)
1.固态的剂型,它可以通过挤压无溶剂的熔融物并随后成形而得到,该熔融物除了含有一种或多种活性物质以外还含有以下物质的混合物:
a)10-99重量%一种或多种水溶性的、可热塑处理的N-乙烯基吡咯烷酮的均聚物或共聚物,
b)1-90重量%降解的淀粉,
c)0-50重量%一种或多种常用的药物佐剂
2.按照权利要求1的剂型,含有麦芽糖糊精作为成份b)。
3.按照权利要求1或2的剂型,含有0.1至90重量%的活性物质。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN 96192739 CN1179101A (zh) | 1995-03-21 | 1996-03-09 | 贮存稳定的剂型 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE19509806.4 | 1995-03-21 | ||
CN 96192739 CN1179101A (zh) | 1995-03-21 | 1996-03-09 | 贮存稳定的剂型 |
Publications (1)
Publication Number | Publication Date |
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CN1179101A true CN1179101A (zh) | 1998-04-15 |
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CN 96192739 Pending CN1179101A (zh) | 1995-03-21 | 1996-03-09 | 贮存稳定的剂型 |
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CN (1) | CN1179101A (zh) |
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1996
- 1996-03-09 CN CN 96192739 patent/CN1179101A/zh active Pending
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