CN1074228A - 球团化微晶纤维素组合物 - Google Patents
球团化微晶纤维素组合物 Download PDFInfo
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
- C08L1/02—Cellulose; Modified cellulose
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2300/00—Characterised by the use of unspecified polymers
- C08J2300/14—Water soluble or water swellable polymers, e.g. aqueous gels
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
- C08L1/08—Cellulose derivatives
- C08L1/26—Cellulose ethers
- C08L1/28—Alkyl ethers
Abstract
一种颗粒状的、共加工的、未研磨的微晶纤维素:
水解胶体组合物,其中相应组分的存在,按重量比为
约99∶1到70∶30。该组合物用于生产尺寸和球度
均匀的并且高药载的球状物的球团化剂。该组合物
通过干燥微晶纤维素在水解胶体的水溶液中的浆料
而制备。优选的水解胶体是甲基纤维素。
Description
本发明涉及球团组合物和基于它的固态药物剂型。更具体地,本发明是关于微晶纤维素:能产生高百分比的大小均匀和球度均匀球形体的水解胶体球团组合物,并含有大大提高的药物剂量。
在食品和药物领域,制备和使用每个颗粒呈球形结构的颗粒状组合物早已是习惯做法,这种外形的颗粒具有许多优点。球形具有最小的表面积/体积比。球状物能在容器中均匀装填,这样便于通过体积准确测量颗粒物的数量。在药物领域,球状物对应用薄膜包衣以有效地控释药物(drugs)和/或药物(medicinals)而言是理想的几何形状固体。
人们已经开发出了许多制备球团化药物组合物的方法。例如,通过成丸模具和压机制备球形口服剂型可以追溯到许多年前。长期来在工艺技术上已有了许多改进。
近年来,越来越引起药物界重视的一种制备球形颗粒的方法是球团化。这种技术的主要特征,典型地包括以下步骤:形成干的粉末组分的混合物;在粘合剂存在下,用液体,通常是水,湿润干混合物,得到塑胶状物或者形成颗粒物;将该物料通过筛网或染色后挤出形成一种实心细条挤出物;将挤出物切成短的圆柱体,然后是将圆柱体在压型槽的表面上滚成球状物的滚圆阶段。关于该方法的详述可参考“A New Technique for the Production of Spherical Particles”,A.D.Reynolds,Manufacturing Chemist & Aerosol News,June 1970。
随着使用多颗粒控释口服剂型的增长,球团化作为一种制备球型颗粒物或通常所称的球体的方法也受到了重视。由直径约0.8到1.2mm的含有药剂的球体所组成的这些药物,盛于胶囊中或压成药片。通过采用具有不同药物释放特性的球状物的组合,能配制出所要求的药物释放体系的剂型。
在进行球团化时,配方中要包括微晶纤维素,作为活性组分的优选的载体或基体介质。
微晶纤维素(MCC)是经过特殊纯化的解聚态的纤维素,它是通过用无机酸处理来自含纤维的植物的浆料而得。酸优先与纤维素聚合物链的较不规则的或者无定形部分起化学反应,从而暴露和解放出可形成纤维素晶粒聚集体的结晶位点。洗涤反应混合物以除去降解的副产物,将得到的湿饼脱水,取得干的纤维素晶粒聚集体,或者通常称作微晶纤维素。
微晶纤维素是一种白色、无臭、无味、较易自由流动的粉末,它不溶于水、有机溶剂、稀碱和稀酸。它广泛地用作药物的赋形剂,在直接压制法制造片剂中用它作为粘合剂特别有效。
在配制药物释放体系中,药物组合物由球形颗粒组成,要求球体具有某些性质。这些性质包括低脆性、尺寸和球度的均匀性或完整性、以及表面光滑性。这些性质确保了在包衣时,附着在球体上的包衣层厚度,精确地符合药物的释放速率。
采用微晶纤维素作为药物载体的赋形剂和成球团剂,能够在相当程度上获得显示出上述性质的含药球体,它可包含少量与微晶纤维素相结合的其他吸水性纤维素衍生物(一种可水解的纤维素)。这种纤维素衍生物的例子是羧甲基纤维素钠、低级羟烷基(C1-C6)纤维素,例如,羟丙基纤维素和羟丙基甲基纤维素。
一种典型的球状物的制备包括,形成微晶纤维素、可水解的纤维素衍生物和药物的干的混合物。然后向混合物加水,直到得到稠密的颗粒化物料。再将这种物料通过经调整过的挤出机上的圆管(通常1mm),得到一种均匀的、可自由流动的挤出物,然后将它球团化。这些配方物的典型介绍可以从美国专利4,844,910;4,867,985和4,867,987中找到。
尽管这种配方和方法能在低到中的药物含量下得到高百分率颗粒大小均匀的球状物,但是,当药物含量超过约60%,球状物的颗粒尺寸分布开始变宽。随着载药量进一步增加到约80%以上,球状物尺寸和球度变化更大,从而它们不再能用作控释配方物的组分。
用药物与在美国专利3,539,365中所描述的这类经高度改性的微晶纤维素的混合物,经成球团化方法处理,可以制得具有良好的尺寸和球度均匀性,以及药物含量提高到80%以上的球状物。
这种纤维素衍生物是通过用强力研摩处理经洗涤的由纤维素酸解得到的含约40%微晶固体的滤饼而制得,其结果是,纤维素微晶聚集物进一步被分散,超细颗粒增加。在研磨过程中,向含水混合物中加入足量的羟甲基纤维素钠以包覆相互分离的微晶颗粒。研磨完毕后,干燥并回收混合物。干燥后的产物很易重新分散于水性介质中形成凝胶。它含有约5%到15%(重量)的羟甲基纤维素钠。
FMC Corporation制造并出售这种产品,在Avicel
RC和CL商标下有多种规格的产品。它在球团化过程中的应用,在FMC Technical Bulletin“Avicel Spheres”中有说明。
虽然研磨处理过的微晶纤维素:羟甲基纤维素钠组合物一般能得到令人满意的球状物,但是它会形成粘性的颗粒粘附在球团化加工的设备上。为了保持球状物的出料,必须定期拆洗设备。这降低了这种微晶纤维素组合物作为成球团剂在工业化生产和使用的实用性。
现在业已发现一种微晶球团化组合物,出乎意料地优于现有技术中的组合物。
根据本发明,一种用于生产具有高药载的球状物的微晶球团化组合物,它是由共加工成颗粒状的非研磨微晶纤维素和非离子水解胶体构成的,这两种组分相互紧密结合。本发明还包括一种生产球团化组合物的方法,一种生产基于该球团化组合物的固体剂型的方法,以及所得到的固体剂型。
本发明的共加工成颗粒状的球团化组合物包括作为其两个基本组分的微晶纤维素和药物级非离子水解胶体。水解胶体在这里的含意应理解为亲水性树脂或聚合物。尽管这两种组分的百分含量可在相当大的范围内变动,但是微晶纤维素对水解胶体的重量比要求保持在约99∶1到约70∶30的范围,或者,当水解胶体是甲基纤维素时,较好的范围在约97.5∶2.5到约90∶10,并且最好的范围在约96∶4到94∶6。
微晶纤维素的来源较好是常规微晶纤维素制造方法中得到的湿饼。还未被干燥的湿饼有时被称作“永不干的”或水解纤维素。可以使用干燥过的微晶纤维素,但是它必须在含水介质中经强烈搅拌,以重新组成纤维素微晶聚集体。
本发明的球团化组合物的一个经济上的优点是:它的制得无需采用现有技术的组合物中的价格相当昂贵的高度研磨的微晶纤维素。本发明的组合物中的微晶纤维素组分,不论是湿饼还是干燥过的,都理解为是未研磨的微晶纤维素。
非离子水解胶体溶液的浓度应当足以允许微晶纤维素与水解胶体相互作用。这种相互作用被认为包括纤维素微晶聚集物表面对水解胶体分子的吸附作用,它形成了非研磨微晶纤维素的结构。
球团化性质的不同表明,从一个部分到另一个部分,水解胶体对纤维素微晶的亲合力、吸引力或其他性质不相同。
业已发现特别适于制备本发明的微晶球团化组合物的水解胶体是甲基纤维素。含这种水解胶体的颗粒物在球团化设备中加工时非常干净,无粘附迹象,并且制得具有优异的尺寸分布和球度均匀性的高百分比球形物。
许多非离子型亲水性聚合物是已知的,并已记载于技术文献中;多数可从市场上购得其醚化或酯化纤维素,以及其他的合成或衍生物形式。除了甲基纤维素外,这些聚合体的其他较好的类型和例子是改性(半合成)凝胶,包括低级羟烷基(C1-C6)纤维素,诸如羟乙基纤维素、羟丙基纤维素和羟丙基甲基纤维素,以及合成凝胶,包括乙烯基聚合物,诸如聚乙烯基吡咯烷酮。对于其他的改性或合成凝胶的例子,参见Glicksman,“Gum Technology in the Food Industry”(1969),第8页。在非离子型的范围内,水溶性的醋酸纤维素也可采用。它们是醋酸纤维素的部分水解衍生物,其醋酸基的含量范围在约17-27%(按结合醋酸计算-美国专利3,482,011)或13-19%(Eastman Chemical Products Publication No.E-140B,February 1981,“Eastman
Cellulose Acetate For Coatings”)。
在制备本发明的球团化组合物中,将微晶纤维素加入到非离子水解胶体的水溶液中,混合物在高能剪切下形成一种浆料。该微晶纤维素较好是常规的纤维素浆料酸解时形成的湿饼。干的微晶纤维素也可使用,但要求高剪切混合使纤维素微晶充分地重新分散。
微晶纤维素与含水的水解胶体的混合一直进行到水解胶体与纤维素微晶相互作用完全或达到平衡。通常,这需要约10到60分钟。如前述,水解胶体被认为在纤维素微晶表面上形成吸附层。
微晶纤维素和水解胶体在含水浆料中的浓度为:这些组分呈干的固态时的重量比,微晶纤维素∶水解胶体落在特定的99∶1到70∶30的范围内。一般地说,按重量计,浆料固体的总量可在约5%到约25%内变化。
在水性介质中,某些水解胶体可以形成粘性溶液或者甚至凝胶,从而难于或者不可能制得可流动的浆料。对此,通常采用更稀的水解胶体溶液;也可升高温度来增大流动性。例如,在水溶液中甲基纤维素可有不同的粘度,其范围在约10到400厘泊或者更高。当使用较高粘度的物料时,可采用较低的浓度。
混合完成后,将浆料干燥,较好是采用喷雾干燥。可采用常规的喷雾干燥设备和操作步骤。干燥气体的出口温度通常用于控制共加工颗粒物的残余水分含量。令人满意的含水量为约0.5%到8.0%,较好为约3.0%到5.0%。
干燥后的球团化组合物的颗粒大小大约与微晶纤维素的相仿,但是有些微晶聚集体可以形成较大的颗粒团。
按照已知的球团化加工方法,由本发明的球团化微晶纤维素组合物制备球形体,包括挤出球团化和旋转成粒/旋转加工等技术。首先制得组合物和药物的干混物。然后慢慢加水,不断混合,直至形成具有必要稠度的颗粒。或者,如果药物是水溶性的,可将它溶于水中,再将该溶液加入到MCC:水解胶体颗粒组合物中。加入的药物量内填充物来选定,该填充物可为球状物接受,加入的药物量可按常规试验预先测定。
湿的颗粒用适当尺寸的穿孔筛挤出,并用具有研磨面的转盘使其球团化。然后球状物在流化床中或其它干燥方式干燥,使其达到合适的湿度,典型的是约0.5%到5%。
正如在药物学工艺技术中所知道的,术语“球”或“球状物”的含义是指球形颗粒,其直径范围在约0.1到2.5mm,更好是0.5到2mm,最好是0.8到1.4mm。
本发明的共加工的微晶纤维素:水解胶体组合物比用现有技术所需要的微晶纤维素、水解胶体和药物三组分颗粒进行球团化能产生出乎意料地高百分比的在0.8-1.4mm窄范围内的球状物;参看前面提到的美国专利4,844,910;4,867,985和4,867,987。由于目前尚不清楚的原因,无法证明在上述三组分体系中,微晶纤维素与水解胶体相互作用或亲合。
由于具有优异的尺寸和球度均匀性,用本发明的球团化组合物制备的球状物能被均匀地包衣,从而精确地控释药物。
本发明的另一优点是:这里的共加工组合物的颗粒不象通常情况那么容易过湿。这一“宽容性”意味着:即使由缺乏经验者操作,也不大可能产生不期望的颗粒。
再有一个优点是:本发明的共加工组合物不粘稠,于是不会粘附于进行球团化的设备上,因而适合于大型的工业化、多批量球团化生产。
本发明的球团化组合物实际上能与所有的药学制剂和药物,包括混合药物,形成球状物,并且不论药物是水溶性的,还是不溶的。典型的这类药物如下:
○止痛药-扑热息痛,布洛芬,优洛酚和诸如此类的,消炎痛,萘普生,含可待因的扑热息痛,和含萘磺酸丙氧芬的扑热息痛。
○抗生素-红霉素,头孢菌素,盐酸二甲胺四环素。
○抗癫痫药-苯琥胺,苯妥因钠和丙戊酸钠。
○抗组胺药-扑尔敏,盐酸苯海拉明,盐酸吡咯吡胺。
○咳嗽和感冒药-美沙芬氢溴酸盐,硫酸麻黄碱,愈创木酚甘油醚,盐酸苯丙醇胺,盐酸异丙嗪,和盐酸假麻黄碱。
○胃肠药-甲氰咪胍,盐酸氯苯哌酰胺和呋喃硝胺。
○呼吸道药物-硫酸舒喘宁,氨茶碱,茶碱。
以下实施例更具体地阐述本发明。
实施例1
球团化组合物的制备
用97.9磅(44.4kg)水水解粘度为15厘泊的甲基纤维素[6.3磅(2.86kg),湿度为5%](Dow Chemical Co.出品,商品名Methocel
A-15LV)形成含6%固体的溶液。将水解胶体一边缓慢加入到水中,一边用可从市场购得的可调速的混合器从上部搅拌。在另一单独的浆料槽中,用287.8磅(130.5kg)水稀释微晶纤维素[274.7磅(124.6kg),41.5%的湿饼]。将微晶纤维素加入到水中,用高能分散器(如Cowles混合器)以1500RPM进行分散,直到形成均匀的膏状浆料。在该微晶纤维素中一边加入甲基纤维素溶液,一边用高能混合器持续搅拌40分钟,从而形成均匀的分散物。最后所得的浆料含固量为18%。然后将浆料喷雾干燥,系采用单流喷头雾化。干燥条件为1500psi(10.342×103KPa)线压和流率为0.5gpm。出口温度保持230°F-240°F(110℃-115.6℃)。在这些条件下的生产速率为46磅/小时(20.87kg/小时)。
实施例2
用与实施例1所述类似的方法与条件制备含95%微晶纤维素和5%羟丙基甲基纤维素的共加工物料。
实施例3
A.本发明的球状物的制备
在用通常所指的挤出/球团化的入法制备含有80%茶碱的球状物时,是使用如实施例1所述的共加工物料(95/5微晶纤维素/甲基纤维素-MCC/MC)。将共加工的95/5MCC/MC(200g)与800g无水茶碱一起加入到一个12夸脱行星式混合器内,使其混合5分钟,直到得到一种均匀混合物。向混合物中缓慢加入600g水,并继续混合15分钟使水在其中充分分布。这一弄润湿粉末的方法即通常所指的造粒。然后将所得到的润湿物加入到Nica挤出机的进料斗内。通过筛孔1.0mm的筛网将其挤出,速度为14-16RPM,从而形成长度大致在0.25-1.0cm的丸状挤出物。然后将挤出物加入到Nica制球机中。这个装置包含一个具有静止不动的侧壁和一个转动底(即通常所指的盘)的辊筒。在制球机中加工挤出物8分钟,保持盘速650RPM。在8分钟结束后,将球状物排放入一个合适的接受器中。然后将球状物移到一个常用的强制空气流动的烘箱的盘上在50℃时干燥6小时。90%的所得到的球状物在0.8-1.4mm范围内。
B.现有技术的球状物
将未经研磨的微晶纤维素(商品牌号Avicel
PH-101,FMC-Corporation出品,190g),甲基纤维素(10g)和800g无水茶碱干搅拌,并按实施例3A的步骤使其球化。73%的所得到的球状物在0.8-1.4mm大小范围内。本实施例说明的是将前述所有三种组分球化的制球方法,揭示于美国专利4,867,985和4,867,987中。
C.现有技术的球状物
将未经研磨的微晶纤维素(商品名Avicel
PH101,FMC Corporation出品,200g)和800g无水茶碱干搅拌,并按实施例3A的步骤球化。得到的球状物的68%在0.8-1.4mm大小范围内。本实施例说明的是微晶纤维素为唯一球化剂的制球方法。
从前述的对照实施例3中显然容易看到,使用本发明的球化组合物所得到的在所需0.8-1.4mm范围内的球状物百分比,惊人地大大高于用现有技术组合物(实施例3B和3C)所得到的。
Claims (20)
1、一种用于经球团化作用制备球状物的组合物,其特征在于,共加工的非研磨的微晶纤维素和非离子水解胶体的干燥的细颗粒,两种组分的比例按重量计为99∶1到70∶30微晶纤维素∶水解胶体,所述组分相互紧密结合。
2、如权利要求1所述的组合物,其特征在于,水解胶体是甲基纤维素,并且两组分的重量比范围在97.5∶2.5到90∶10微晶纤维素∶水解胶体。
3、如权利要求1所述的组合物,其特征在于,水解胶体是甲基纤维素,并且两组分重量比范围在96∶4到94∶6微晶纤维素∶水解胶体。
4、如权利要求1所述的组合物,其特征在于,微晶纤维素组分的来源是湿饼。
5、如权利要求1所述的组合物,其特征在于,水解胶体是甲基纤维素。
6、如权利要求1所述的组合物,其特征在于,水解胶体组分是羟丙基甲基纤维素。
7、一种制备颗粒物的方法,用于经球团化作用制备球状物,其特征在于:
形成非研磨的微晶纤维素在非离子水解胶体水溶液中充分分散的浆料,微晶纤维素和水解胶体组分的量为能提供下面提到的组分比范围的颗粒状共加工产品,和
干燥含水浆料得到颗粒状共加工产品,其中非研磨的微晶纤维素对水解胶体的重量比在99∶1到70∶30的范围内。
8、如权利要求7所述的方法,其特征在于,含水浆料经喷雾干燥。
9、如权利要求2所述的方法,其特征在于,微晶纤维素是湿饼。
10、如权利要求8所述的方法,其特征在于,喷雾干燥是在干燥机出口温度在230°F到240°F(110℃到115.6℃)下进行的。
11、一种生产颗粒状球团化固体剂型的方法,其特征在于,使药物与权利要求1所述的组合物的混合物球团化。
12、一种生产颗粒状球团化固体剂型的方法,其特征在于,使药物与权利要求2所述的组合物的混合物球团化。
13、一种生产颗粒状球团化固体剂型的方法,其特征在于,使药物与权利要求3所述的组合物的混合物球团化。
14、一种生产颗粒状球团化固体剂型的方法,其特征在于,使药物与权利要求4所述的组合物的混合物球团化。
15、一种生产颗粒状球团化固体剂型的方法,其特征在于,使药物与权利要求5所述的组合物的混合物球团化。
16、一种生产颗粒状球团化固体剂型的方法,其特征在于,使药物与权利要求6所述的组合物的混合物球团化。
17、一种固体剂型,其特征在于,球状物包含相互结合的权利要求1的组合物和药学上有效量的至少一种药物。
18、一种固体剂型,其特征在于,球状物包含相互结合的权利要求2的组合物和药学上有效量的至少一种药物。
19、一种固体剂型,其特征在于,球状物包含相互结合的权利要求3的组合物和药学上有效量的至少一种药物。
20、一种固体剂型,其特征在于,球状物包含相互结合的权利要求6的组合物和药学上有效量的至少一种药物。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US81602791A | 1991-12-30 | 1991-12-30 | |
US816,027 | 1991-12-30 |
Publications (1)
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CN1074228A true CN1074228A (zh) | 1993-07-14 |
Family
ID=25219497
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN92115100A Pending CN1074228A (zh) | 1991-12-30 | 1992-12-21 | 球团化微晶纤维素组合物 |
Country Status (16)
Country | Link |
---|---|
US (1) | US5725886A (zh) |
EP (1) | EP0619731B1 (zh) |
JP (1) | JP2628230B2 (zh) |
CN (1) | CN1074228A (zh) |
AT (1) | ATE196733T1 (zh) |
AU (1) | AU663146B2 (zh) |
BR (1) | BR9206996A (zh) |
CA (1) | CA2126441C (zh) |
DE (1) | DE69231499T2 (zh) |
ES (1) | ES2150438T3 (zh) |
FI (1) | FI943121A (zh) |
IL (1) | IL104087A (zh) |
MX (1) | MX9207438A (zh) |
NO (1) | NO942457L (zh) |
WO (1) | WO1993012768A1 (zh) |
ZA (1) | ZA929161B (zh) |
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CN102215825A (zh) * | 2008-11-19 | 2011-10-12 | 安万托特性材料股份有限公司 | 可直接压制的颗粒状的基于微晶纤维素的赋形剂、其制备方法及应用 |
CN105193738A (zh) * | 2015-09-21 | 2015-12-30 | 段民英 | 一种微晶纤维素丸芯的制备工艺 |
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-
1992
- 1992-11-18 JP JP5511647A patent/JP2628230B2/ja not_active Expired - Fee Related
- 1992-11-18 EP EP93900553A patent/EP0619731B1/en not_active Expired - Lifetime
- 1992-11-18 BR BR9206996A patent/BR9206996A/pt not_active Application Discontinuation
- 1992-11-18 WO PCT/US1992/009983 patent/WO1993012768A1/en active IP Right Grant
- 1992-11-18 DE DE69231499T patent/DE69231499T2/de not_active Expired - Fee Related
- 1992-11-18 ES ES93900553T patent/ES2150438T3/es not_active Expired - Lifetime
- 1992-11-18 AT AT93900553T patent/ATE196733T1/de not_active IP Right Cessation
- 1992-11-18 CA CA002126441A patent/CA2126441C/en not_active Expired - Fee Related
- 1992-11-18 AU AU31793/93A patent/AU663146B2/en not_active Ceased
- 1992-11-25 ZA ZA929161A patent/ZA929161B/xx unknown
- 1992-12-14 IL IL10408792A patent/IL104087A/en not_active IP Right Cessation
- 1992-12-18 MX MX9207438A patent/MX9207438A/es unknown
- 1992-12-21 CN CN92115100A patent/CN1074228A/zh active Pending
-
1994
- 1994-06-29 FI FI943121A patent/FI943121A/fi not_active Application Discontinuation
- 1994-06-29 NO NO942457A patent/NO942457L/no unknown
- 1994-09-26 US US08/311,800 patent/US5725886A/en not_active Expired - Lifetime
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1086189C (zh) * | 1997-06-12 | 2002-06-12 | 食品机械和化工公司 | 超细微晶纤维素组合物及其制备方法 |
CN102215825A (zh) * | 2008-11-19 | 2011-10-12 | 安万托特性材料股份有限公司 | 可直接压制的颗粒状的基于微晶纤维素的赋形剂、其制备方法及应用 |
CN105193738A (zh) * | 2015-09-21 | 2015-12-30 | 段民英 | 一种微晶纤维素丸芯的制备工艺 |
CN105193738B (zh) * | 2015-09-21 | 2018-09-04 | 珠海市东辰制药有限公司 | 一种微晶纤维素丸芯的制备工艺 |
Also Published As
Publication number | Publication date |
---|---|
CA2126441A1 (en) | 1993-07-08 |
DE69231499D1 (de) | 2000-11-09 |
NO942457D0 (no) | 1994-06-29 |
IL104087A0 (en) | 1993-05-13 |
EP0619731A1 (en) | 1994-10-19 |
WO1993012768A1 (en) | 1993-07-08 |
DE69231499T2 (de) | 2001-05-03 |
EP0619731A4 (en) | 1995-05-03 |
BR9206996A (pt) | 1995-12-05 |
US5725886A (en) | 1998-03-10 |
EP0619731B1 (en) | 2000-10-04 |
ES2150438T3 (es) | 2000-12-01 |
FI943121A0 (fi) | 1994-06-29 |
AU663146B2 (en) | 1995-09-28 |
JP2628230B2 (ja) | 1997-07-09 |
MX9207438A (es) | 1993-06-01 |
CA2126441C (en) | 1999-12-21 |
ATE196733T1 (de) | 2000-10-15 |
ZA929161B (en) | 1993-05-25 |
JPH06511255A (ja) | 1994-12-15 |
NO942457L (no) | 1994-06-29 |
IL104087A (en) | 1998-10-30 |
AU3179393A (en) | 1993-07-28 |
FI943121A (fi) | 1994-06-29 |
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