CN1103289A - 鸦片类药物延缓控释制剂 - Google Patents
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Abstract
本发明涉及固体控释口服剂型,它含有治疗有效
量的鸦片类止痛药或其盐,能延长止痛持续时间至
24小时其中剂型的体外溶出速率(用USP将法或转
兰法在100rpm下于900ml水性缓冲液(pH在1.6
-7.2)中在37℃下测定)1小时后释放的约为12.5-
42.5(重量),2小时后释放约25-55%(重量)的鸦片
型药物,4小时后释放了45-75%(重量)的鸦片型
药物,8小时后释放大于60%(重量)的鸦片型药物,
体外释放率基本上与pH无关,该剂型服用后2-8
小时可达到体内鸦片类药物的血浆浓度的峰值。
Description
本发明涉及一种用于治疗疼痛的固体控释口服剂型。
所有的控释(缓释)制剂的目的在于服用后,其维持药理作用的时间比速释剂型长,这种较长时间的药效为临床治疗提供了许多相应的短作用速释制剂所没有的优点。这样就可以持续治疗而不会打扰病人的睡眠,例如治疗中等程度至剧痛的病人(例如手术后的病人、癌症病人等),或治疗那些清醒时有周期性偏头痛的病人及睡眠必不可少的虚弱病人这类优点尤为重要。
除非很小心地以频繁的间隔进行常规的速效药物的治疗以维持有效的稳态血药浓度水平,否则由于快速吸收、化合物的全身排泄及通过代谢失活,有效药物的血药水平出现峰谷现象,从而在病人的维持治疗中产生特殊的问题。长效药物制剂更进一步的优点是可以避免病人因忘记而没有遵照医嘱按时服药。
吗啡是典型的鸦片类止痛药,已制成12小时控释的制剂(即,MS Contin
片剂,LL Frederick公司买到)。
该技术领域已知鸦片类或其盐的控释组合物能制成一种适宜的骨架。例如,美国专利4,990,341和4,844,909(Goldie等)(已转让于本发明的申请人),阐述了氢吗啡酮组合物,当用USP浆法或转兰法在100转/分(rpm)于900ml水性缓冲液(pH在1.6-7.2间)中,在37℃下测得其体外溶出速率为1小时后释放氢吗啡酮12.5-42.5%(重量),2小时后释放约25-55%(重量),4小时后释放45-75%(重量),6小时后释放55-85%(重量),在pH1.6和7.2间,体外释药速率和pH无关,所选择的释放体外释放速率,使服药后2-4小时间体内氢吗啡酮的血药水平达峰值,用这类氢吗啡酮制剂至少可得到12小时的止痛效果。
该领域的进一步目的是开发出一种持效时间长于12小时的药物制剂,使病人一天只需服药一次。
很清楚,人们需要使用方便、可靠且能比目前所用的这类药物服用频率少的鸦片类止痛药的制剂。目前,最常用的这一类口服鸦片类止痛药制剂需要每4至6小时服一次而12小时以上服一次药物的制剂则很少。每天服用一次制剂的明显优点是增加了便利性和病人按时服药的可能性,许多药物制剂提供较长时间间隔服药时具有上述优点。
当今,人们还没有一致认为以较少频率服用的口服鸦片类止痛药(a)与制剂相同药物,相同每月总剂量的常规速释口服制剂相比对药物反药物副作用和/或其发生率有任何影响,或者对(b)与短作用口服鸦片类止痛药制剂就一定时间里所需的剂量相比,在较长的止痛效果有任何不同。许多合适的控制良好的双肓的、随机的、安全性和有效性的评估结果表明相同日剂量的长作用和短作用口服鸦片类止痛药具有类似的鸦片类副作用的发生率和强度,它们的止痛作用也相似。
当非鸦片类止痛药和鸦片类止痛药共同给药时,有证据表明非鸦片类止痛药具有“阿片节制”以前报道的降低对鸦片的需求的作用的唯一方法是在通过非胃肠道给药的途径中与按需给药(PRN)相比采用病人控制止痛药(PCA)的方法以减少对鸦片型止痛药的需要。在后面所述的情形中,给药不是固定间隔的,而是按需给药(PRN)即病人采用PCA作为主要的服药控制者,病人及另一些人员控制按需的给药时间,但PRN药剂更为普遍使用。
本发明的一个目的是提供一种能从实质上改进止痛疗效及质量的方法及鸦片类止痛药制剂。
本发明的另一个目的提供了一种从实质上改进止痛疗效及质量的治疗方法。
本发明的再一个目的是提供控释鸦片类制剂,与以前所知的控释鸦片类制剂比较其药效持续时间大大增加。
上述目的及其它目的可凭借本发明得以实现,本发明涉及固体控释口服剂型,该剂型包括具有控释包衣或在控释骨架中的治疗有效量的止痛药,较好的是鸦片类止痛药或其盐,其体外溶出速率(用USP浆法或转兰法在100rpm下,于900ml水性缓冲液(pH在1.6-7.2)中在37℃下测定)1小时后释放鸦片型药物约12.5-42.5%(重量),2小时后释放约25-56%(重量)鸦片型药物,4小时后释放约45-85%(重量)的鸦片型药物,8小时后释放大于60%(重量)的鸦片类药物,体外释放率基本上与pH血药浓度可达峰值。本发明的口服剂型能提供24小时的止痛作用,从而一天只需服用一次。
如上所述,剂型含有鸦片类止痛药为佳,较佳鸦片类药包括诸如氢吗啡酮、羟考酮、吗啡、左啡诺、美沙酮、哌替啶、海洛因、双氢可待因、可待因、双氢吗啡、丁丙诺啡的mμ-激动剂,它们的盐,前述药物的任何混合物,混合的mμ-激动剂/止痛药,mμ-激动剂/止痛药的合并物之类。
浆法或转兰法为美国药典第XXⅡ版(1990)中述及的浆法或转兰法。
在本申请中,“基本与pH无关”的意义是指于任何给定的时间内,在如pH1.6和任何及其它pH值如7.2下鸦片类药物的释放量(用USP浆法或转兰法在100rpm,于900ml水性缓冲液中体外测定)的差别为10%(重量)或更少。在所有情况下,释放量为至少3个实验的平均值。
本发明也涉及到一种治疗病人疼痛的方法,即服用本发明的口服剂型。
本发明的控释口服固体剂型有令人惊奇的结果,即这些制剂可节省阿片类药物用量。首先,与常规的速释产品相比,本发明的控释口服固体剂型的每月服用剂量更低,而止痛效果无区别。其次,在类似的每月剂量下,本发明的控释口服固体剂型比常规的速释产品的药效大。
下面附图用于阐述本发明的实施例,但本发明的范围系由权利要求所包括,而不是由这些附图所限定。
图2是实施例5所得的血浆浓度曲线;
图3是实施例6所得的血浆浓度曲线;
图4是实施例7所得的血浆浓度曲线;
图5是实施例8所得的血浆浓度曲线;
图6是实施例5所得的血浆浓度对照实施例A所得血药浓度比较图;
图7为比较实施例B和C所得的血浆浓度曲线图;
图8是实施例9和10所得的血浆浓度曲线图;
图9是实施例11和12所得的血浆浓度和实施例D所得结果的比较图;
图10是实施例11和12所得的血浆浓度的曲线图;
图11是实施例13所得的血浆浓度和比较实施例E所得的血浆浓度的比较图。
本发明部分是基于这样一个惊人的发现,即鸦片类止痛药的控释剂型有一个延长的药效持续时间,例如,约24小时,服药后2-8小时处出现血药浓度的峰值,(即Tmax),较好的在约4-6小时处达到血浓峰值,从而止痛时间大大超过12小时,更好的是在服药后,止痛时间达约24小时。
此外,就本发明的剂型而言,一般可以达到治疗水平而不明显地增加同时发生的副作用的强长和/或程度,如恶心、呕吐、眩晕等,这些副作用常常是与鸦片类药物的高血药浓度相关。也有证据提示使用本发明的剂型可减少药物成瘾的危险。
本发明组合物的进一步优点是鸦片型药物的释药率基本上与pH无关,例如在pH1.6-7.2间,这样就可避免口服时剂量一下子释放。
口服鸦片类止痛药第一次被制成止痛作用持续时间增加,每一天服用一次的制剂。令人惊奇的是,这些制剂,每天以常规速释药物类似的剂量给药,严重的药物副作用发生率低,也可以比常规口服药物的每月剂量低仍能控制疼痛。因此,本发明的24小时服用一次的剂型可以是“节省鸦片”的。
本发明的口服剂型可以,例如以在胶囊中的颗粒小,球或小丸形式或其它任何合适的固体形式存在。
在一个尤为优化的实施方案中,口服剂型是将有效数量的小球包含在胶囊里。
在一个优化的实例中,本发明的控释鸦片类口服剂型以氢吗啡酮作为治疗活性组份,较好的是含有约4-64mg氢吗啡酮盐酸盐。该剂型也可用等摩尔当量的其它氢吗啡酮盐或氢吗啡酮碱替代。在鸦片型止痛药不用氢吗啡酮的其它较好实例中,制剂中查含有适当量的药物以得到基本相当的疗效。
例如,当鸦片类止痛药为吗啡时,本发明的控释口服制剂中含有约15-800mg吗啡。
另一方面,当鸦片类止痛药为羟考酮时,本发明的控释口服制剂即含有约10-400mg羟可酮。
剂量效应研究和对阿片mμ-受体激动剂的鸦片类止痛剂的相对昌能作用测定的综述表明它们的剂量-效应关系都是平行的,无显著的偏差。这就能建立相应的止痛效能因子和剂量比率,当病人从一种阿片mμ-受体激动剂止痛药转换成另一种时,不管前者的剂量是什么就可以使用上述的比率。
在本发明的一个较好的实例中,控释剂型是用控释包衣包覆的含有活性组份的小球。术语“球体”是药学领域已知的含义,例如,直径为0.1-2.5mm,特别是0.5-2mm的球型颗粒,小球最好用能使鸦片类药物(或盐)在水性介质中以控制的速率释放的材料进行膜包衣。包衣膜的选用以得到其它所述的性质,此外,要求能达到前述的体外释放率(1小时后释放12.5%-42.5%(重量)等等),本发明的包衣制剂应当能形成牢固、连续的薄膜,且外观光滑美观,能承载染料及其它包衣添加剂,无毒、惰性且不易剥落。
在一个较好的实例中,本发明涉及到的固体控释剂型为含阿片类药物的囊片用疏水性材料包衣,所述的疏水材料选自诸如乙基纤维素的烷基纤维素,烯丙型聚合物、虫胶、玉米朊、疏水性蜡类制品,如氢化蓖麻油或氢化植物油及其混合物。
在更佳的实例中,包衣是从疏水性聚合物的水性分散液中形成的,然后将含有鸦片类药物的包衣基蕊(如,片芯或惰性药物小珠或小球)固化直至片芯能稳定溶出即为点。固化终点可通过比较剂型固化后的即剂溶出曲线与在加速的贮存条件下,例如在40℃及75%相对温度下放置至少一个月的溶出曲线测得。这些制剂在本申请人的美国共同待批申请07/814,111和07/826,084中作了详尽的阐述,这里列出供作参考。
本发明中作包衣用的疏水性聚合物的水性分散液可配合用于片剂、小型剂(或小珠)、微球、晶粒、丸剂、离子交换树脂小表及其它多颗粒系统以得到所需的治疗活性药物的控制释放。根据本发明制得的颗粒、小球或小丸等可制成胶囊或其它合适的剂型。
为了得到控释制剂,虽然包衣或多或少取决于治疗活性药的物理性质及所需的释药速率、水性分散液中增塑剂的加入及其掺入方式等,但是,常常需要用足量的,例如乙基纤维素或丙烯酸聚合物的水性分散液来包衣含有治疗活性药物的芯子,包衣增重量约为2-25%。
虽然乙基纤维素是可用作本发明包覆基蕊的一个较好聚合物,但本领域的技术人员喜欢用其它的纤维素聚合物。包括其它的烷基纤维素聚合物部分或全部地代替乙基纤维素,以作为本发明的疏水聚合物包衣材料。
在本发明的另外一些较好实例中,组成控释包衣的疏水聚合物是药用丙烯酸聚合物,包括但不局限于丙烯酸和甲基丙烯酸共聚物,甲基丙烯酸共聚物,甲基丙烯酸甲酯共聚物,甲基丙烯酸环氧乙酸,甲基丙烯酸氰乙酯,甲基丙烯酸甲酯,共聚物,甲基丙烯酸共聚物,甲基丙烯酸甲酯共聚物,甲基丙烯酸氨烷酯共聚物,聚(丙烯酸),聚(甲基丙烯酸),甲基丙烯酸烷酰受共聚物,聚(甲基丙烯酸甲酯),聚(甲基丙烯酸酐,聚甲基丙烯酸酯,聚(甲基丙烯酸甲酯)共聚物,聚丙烯酰胺,甲基丙烯酸氨烷酯共聚物,聚(甲基丙烯酸酐)及甲基丙烯酯缩水甘油酯共聚物。
在特定的优选实例中,丙烯型聚合物是由一个或多个甲基丙烯酸氨酯共聚物所组成的,甲基丙烯酸氨酯在该技术领域中是已知的,在NF X Ⅶ中作为丙烯酸和甲基丙烯酸酯与低含量的季氨基团完全聚合的共聚物描述。
为了得到所需的溶出曲线,必需将两种或多种有不同物理性质的甲基丙烯酸氨酯共聚物,如不同摩尔比的季氨基团与中性(甲)丙烯酸酯混合。
在本发明的由疏水性聚合物的水分散液组成的包衣的实例中,于疏水性聚合物的水性分散液中加入有效量的增塑剂可以进一步改进膜的物理性质,例如,由于乙基纤维素有相当高的玻璃转化温度,在一般的包衣条件下不能形成弹性膜,故在使用这类包衣材料前必须先增塑乙基纤维素。一般而言,用于包衣溶液中的增塑剂的量按膜形成物的浓度来计算,例如最常用的量约为膜形成物的1-50%(重量)。但是,增塑剂的浓度只能在小心仔细地对特定的包衣溶液和施用方法实验后方可作出适宜的判定。
用作乙基纤维素的合适的增塑剂例子包括水不溶性增塑剂,如癸二酸二丁酯,邻苯二酸二乙酯,枸橼酸三乙酯,枸橼酸三丁酯及三醋精,但其它的水不溶性增塑剂(如乙酰化的单甘油,邻苯二甲酸酯,蓖麻油等)也可用。对于本发明的乙基纤维素的水性分散液,枸橼酸三乙酯是尤为优选的增塑剂。
用于本发明丙烯酸聚合物的适当的增塑剂例子包括,但不局限于枸橼酸酯,如枸橼酸三乙酯NFXⅥ,枸橼酸三丁酯、邻苯二甲酸二丁酯1,2-丙三醇也可解用。适用于增加膜弹性的其他增塑剂是由丙烯酸膜组成,诸如Endragit
RL/RS添用溶液包括聚乙二醇、丙三醇、邻苯二甲酸二乙酯、蓖麻油和三醋精。对于本发明的乙基纤维素的水性分散液,枸橼酸三乙酯是一种特别优选的增塑剂。
进一步发现,加入少量的滑石粉可以减少加工时水性分散液的粘结倾向,并可作为抛光剂。
一种市售的乙基纤维素水性分散液是Aquacoat
(FMC公司,Philadelphia,宾州,美国)。通过将乙基纤维素溶于与水不混溶的有机溶剂中,然后加表面活性剂和稳定剂乳化。制得Aquacoat
。在均匀化至亚微液滴后,真空蒸去有机溶剂以形成伪乳胶。在制备过程中不要将增塑剂掺入伪乳胶中。因此在使用该包衣材料前需将Aquacoat
与适当的增塑剂密切混合。
另一种乙基纤维素水性分散液是Surelease
(Colorcon公司,西点,宾夕法尼亚州,美国)。在加工制备过程中将增塑剂掺入分散液而制得该产品,将热熔的聚合物、增塑剂(癸二酸二丁酯)和稳定剂(油酸)制成均匀混合物,然后用碱溶液稀释,得到可直接用于基蕊的水性分散液。
在一个优选实例中,丙烯酸类包衣是呈水性分散液形式的丙烯酸树脂漆溶液,如Rohm Pharma的产品,商品名为Eudragit
。在更佳实例中,丙烯酸型包衣包括两种丙烯酸树脂清漆的混合物,其都是Romm Pharma的产品。各自的商品名为Eudragit
RL 30D和Eudragit
RS 30D。这两种物质都是丙烯酸和甲基丙烯酸酯常有与低含量季氨基团的共聚物,在Eudragit
RL 30D中的摩尔比为1∶40,平均分子量约150,000。字母RL(商通透性)和RS(低通透性)是指这些试剂的通透性。Eudragit
RL/RS混合物不溶于水消化液。但是,其形成的包衣在水溶液和消化液中是可溶胀且可渗透的。
本发明的Eudragit
RL/RS分散液可以任何所需的比率混合以得到且有所需溶出曲线的控制制剂。例如,LL100%Eudragit
RL,50%Eudragit
RL50%Eudragit
RS,以及10%Eudragit
RL:90%Eudragit
RS形成的阻滞膜可得到所需的控释制剂。当然,该领域的技术人知道也可用其它的丙烯酸型聚合物,如Eudragit
L。
除了通过改变不同丙烯酸树脂的相对用量来修饰溶出曲线外,也可以通过诸如增加或减少阻滞包衣层的厚度修饰最终产品的溶出曲线。
当疏水聚合物的水性分散液被用来包覆诸如Nu-pareil 18/20珠的药物惰性小珠时,然后可将许多所得的稳定的固体控释小珠足量置于明胶胶囊中,当接触胃液被吸收消化时给出有效的控释剂量。
当接触胃以及至肠液时本发明的稳定控释制剂慢慢释放治疗活性药。本发明制剂的控释特性可以改变,例如通过改变包衣用的疏水如聚合物水性分散液的用量,改变增塑剂加至疏水性聚合物水性分散液的方法,通过改变相对于疏水性聚合物的增塑剂的量,通过加入附加剂或赋形剂,通过变换制备方法等改变。
将治疗活性药溶于水中,然后用Wuster插入器将溶液喷涂在基蕊上,如Nu-pareil 18/20珠上,可制得用治疗活性药物包衣小珠或小珠。任选的附加组份也可在小珠包衣前加入以帮助氢吗啡酮结合于小珠和/或给溶液着色等。例如,包括羟丙基甲基纤维素等的有或无着色剂的产物在施用至小珠以前可选加至溶液,混合(例如约1小时),在该例举的小珠中所得的包衣基片然后可用屏障剂作任选地包衣,从而将治疗活性剂与疏水控释包衣隔开。适当屏障剂的例子为羟丙基甲基纤维素的物质,但是也可用该技术领域中已知的任何膜形成剂。较佳的屏障剂不会影响最终产品的溶出速率。
吗啡酮,MPMC保护的任意的小珠然后可用疏水性聚合物的水性分散液包衣。疏水性聚合物的水性分散液包含有效量的增塑剂量更好,例如构橼酸三乙酯,可使用预先配成的乙基纤维素的水分散液,如Aquacoat
或Surelease
。若使用Surelease
,则无需加入增塑剂。也可使用诸如Eudragit
的预先配好的丙烯酸聚合物的水分散液。
本发明的包衣溶液除了含有膜形成剂、增塑剂和溶剂系统(即水)外,最好含有着色剂使外观美观并供区分用。着色剂可被加至治疗活性药物的溶液中或加至疏水性聚合的水分散液中。例如,可以通过使用以醇或甘油作介质的颜色分散液、研磨过的铝湖兰及诸如二氧化钛的乳白粉,在剪切下将着色剂加至如溶性聚合物溶液中,然后再用低剪切力至增塑的Aquacoat
中,从而将着色剂加至了Aquacoat
中。也可用任何合适的为本发明制剂着色的方法。当使用丙烯酸型共聚物的水分散液时,制剂着色的适当组分包括二氧化钛及颜料,如氧化铁染料。但是,掺入颜料会增加包衣的延迟作用。
通过用该技术领域已知的任何适当的喷雾器将增塑的疏水性聚合物的水分散液施用在包含治疗活性药的基蕊。在优选的方法中使用了Wurster流化床系统,其中从底下注入的空气喷气使该材料流化并干燥,同时也将丙烯酸型聚合物包衣喷雾上去,较好地是结合考虑治疗活性剂的物理特征,掺入增塑剂的方法等来使用足量的疏水性聚合,使所述的包衣基蕊暴露于如溶液,如胃液时能得到预定的所述治疗活性剂的释放速率,在用疏水聚合物包衣后,可任选地给小珠作膜形成物的包衣,如Opadry
,不管以什么方式,这一层包衣的加入是为了大大减少小珠的聚结。
接着,固化包覆的珠以得到治疗活性药稳定释放的速率。
目前,试图用疏水聚合物的水性分散液来制备稳定的控释药物制剂由于稳定性的问题故没有成功。特别是当这些药物制剂用聚合物水性分散液包覆以在数小时或更长的时间里得到所需的活性药释放曲线时,该领域已知的是溶出释放曲线随老化而改变。
这问题在本发明的实例中已被解决,其中乙基纤维素的水分散液被用作控释包衣,通过在高于包衣溶液(即,乙基纤维素)的玻璃转化温度及相对湿度约60-100%下对包衣过的基片固化直至达到固化终点。
在本发明的较好实例中,通过将包衣过的基片置于烧取于升高的温度/湿度水平下固化所需的时间可得到用乙基纤维素的水分散液制得的稳定产品,对于特定制剂合适的温度、湿度和时间由实验来决定。在本发明特定的实例中,用乙基纤维素水性分散液包衣的稳定产品通过在60℃温度及相对湿度为约60-100%下在烘箱内固化48-72小时来制得,此为下面实施例所述的氢吗啡酮小珠的情况而言,但是,该领域技术的人员知道必要的固化条件可稍作改变,事实上根据特定的制剂可以比上述的温度、湿度、时间范围更宽以得到稳定的产品。
传统习惯上,对于用Eudragit
包衣的制剂,通过在包衣后于45℃的流化床中2小时来进行固化,这个标准固化是由Rohmpharma推荐的,因为它高于用枸橼酸三乙酯增塑的20%固体水平的Eudragit
RS 30D的玻璃转化温度(Tg)。正如这里列出的实施例将要显示的,这个推荐的固化过程不能使制剂在贮存时的溶出曲线稳定。
该问题在本发明的实例中得到克服,其中疏水性聚合物的水性分散液包括诸如Eudragit
的丙烯酸型聚合物的水性分散液,其中通过在高于包衣制剂的Tg的温度下在烘箱里持续固化至达终点来制得稳定的产品,在终点处包衣的制剂在暴露于升高的温度和/或湿度的贮存条件下其溶出曲线基本不变。一般而言,固化时间是例如约24小时或更长,固化温度可以是约45℃进一步发现不一定以高于氢围条件的湿度水平固化以得到稳定的终产物。
本发明优选的实例涉及丙烯酸包衣,通过在高于增塑的丙烯酸型聚合物Tg的温度下烘箱固化一段需要的时间来加工包衣过的基片以得到稳定的产品,对特定制剂的温度和时间的最佳值由实验测定,在本发明的一些实例中,通过在约45℃下进行烘箱固化24-48小时得到稳定的产品,也可以设想用本发明控释包衣材料包覆的特定产品需要固化时间长于24小时,例如固化24-48小时,或者甚至60小时或更多。
通过加入一种或多种释放调节剂或者通过包衣提供一种或多种通道,本发明控释制剂中治疗活性剂的释放可被进一步地影响,即被进一步调节至所需的释放速率。在其它因素中,根据所需的释放速率及所选择材料的溶解性质来决定疏水性聚合物与水溶性材料的比率。
作为致孔剂的释放调节剂可以是有机的或无机的,包括那些在使用环境中能溶解、萃取或能从包衣中泄出的材料。致孔剂可以是一种或多种诸如羟丙甲基纤维素的亲水性聚合物。
本发明的控释包衣也可加入如淀粉和树胶作为溶蚀促进剂。
本发明的控释包衣也可加入在使用环境中制造微孔层的材料,如碳酸的线性聚酯组成的聚碳酸酯,其中碳酸酯基团在聚合物链中重复。
释放调节剂也可包括半透性的聚合物。
在一些优选的实例中,释放调节剂选自羟丙基甲基纤维素、乳糖、硬脂酸金属盐及前述的任何混合物。
本发明的控释包衣也可包括一个至少有一条通道、孔之类的出口装置,通过道可用美国专利3,845,770;3916889;4063064和4,088864中所述的方法来形成(这里列出供作参考)。通道可以是圆形、三角形、方形、椭圆形、不规则形等等。
在另一些实例中,本发明可以(另外地或代替控释包衣地)使用使鸦片类药物体外溶出速认在所需的窄的范围里且不衣赖pH的控释骨架。包括于控释骨架中的适当的材料是:
(a)亲水聚合物,如树胶、纤维素醚类,丙烯酸树脂及蛋白质衍生物。在这些聚合物中,纤维素醚,特别是羟烷基纤维素及羧烷基纤维素较好。口服剂型可含有1%-80%(重量)的至少一种疏水性或亲水性聚合物。
(b)可消化的、聚代或非取代长链(C8-C50,特别是C12-C40)的烃类,如脂肪酸、脂肪醇、脂肪酸甘油酯、矿油和植物油及蜡。较好的烃类的熔点是25-90℃。在这些长链烃类物质中,脂肪(脂肪(脂族)醇较好,口服剂型可含有直至60%(重量)的至少一种可消化的长链烃。
(c)聚亚烷基二醇类。口服剂型可含有直至60%(重量)至少一种聚亚烷基二醇类。
一种特别合适的骨架包括至少一种水溶性羟烷基纤维素,至少一种C12-C36,较好的是C14-C22的脂族醇以及任选的至少一种聚亚烷基二醇。
至少一种羟烷基纤维素较好的是羟基(C1-C6)烷基纤维素,如羟丙基纤维素,羟丙甲基纤维素以及,最好的是羟乙基纤维素。特别是可通过羟可酮所需的精确释药率测定出本发明口服剂型中所需的至少一种羟烷基纤维素的用量。
至少一种脂族醇可以是,例如,月桂醇,肉豆蔻醇或十八烷醇。但在本发明口服剂型中较好的实施例中至少一种脂族醇是鲸蜡醇或鲸蜡基十八烷醇。如上所述,通过鸦片型药物所需的精确释药率来推定至少一种脂族醇在本发明口服剂型中的用量。这也取决于至少一种聚亚烷基二醇是否在口服剂型中存在,当无聚亚烷基二醇时,口服剂型含有20-50%(重量)的至少一种脂族醇较好。当至少一种聚亚烷基二醇存在于口服剂型中时,至少一种脂族醇和至少一种聚亚烷基二醇的总重量占整个剂型的20-50%(重量)较好。
在本发明的一个实例中,至少一种羟烷基纤维素或丙烯酸树脂与至少一种脂肪醇/聚亚烷基二醇的比率可在极大的程度上决定鸦片型药物从制剂中释放出来的速率。至少一种羟烷基纤维素与至少一种脂族醇/聚亚烷基二醇的比较在1∶2-1∶4之间较好,最好在1∶3-1∶4之间。
至少一种聚亚烷基二醇可以是,例如聚丙二醇或较好的是聚乙二醇。至少一种聚亚烷基二醇的平均分子量在1000和15000之间较好,最好在1500和12000之间。
另一种合适的控制骨架包括烷基纤维素(特别是乙基纤维素),C12-C36脂族醇类及,任选的聚亚烷基二醇。
除了上述组份外,控释骨架也可含有适量的其它物质,例如,药学领域中常规的稀释剂、润滑剂、粘合剂、颗粒辅剂、着色剂、调味剂及助流剂。
为了有膈于制成本发明的固体、控释的口服剂型,本发明的另一个方面是提供一种固体、控释口服剂型的制备方法,该方法包括使鸦片型药物或其盐掺入控释骨架中,例如通过下列方法而使其掺入骨架,
(a)使至少一种水溶性羟烷基纤维素和鸦片型药物盐形成颗粒,
(b)将羟烷基纤维素的颗粒与至少一种C12-C36脂族醇混合,以及
(c)任意地,将颗粒压制成形,通过湿粒法将羟烷基纤维素鸦片型药物与水制成颗粒较好。在该方法特别好的实例中,在制湿粒步骤中加入水的量为干的鸦片型药物重量的1.5-5倍较好,特别是1.75-3.5倍。
在另一些替换实例中,成球剂与活性组份一起可以制成小球,较好的是微晶纤维素。合适的微晶纤维素是,例如,Avicel pH101(商标,FMC公司),在这类实例中除了活性组份和成球剂外,小球中也可含有粘合剂。该药学领域的技术人员都知道适当的粘合剂,如低粘度、水溶性聚合物。但是,较好的是水溶性羟基低烷基纤维素,如羟丙基纤维素。另外(或替换)的是,小球可含有水不溶性聚合物,特别是丙烯酸聚合物,丙烯酸共聚物,如甲基丙烯酸-丙烯酸乙酯共聚物或乙基纤维素。在这类实例中,控释包衣一般包括一种水不溶性物质,如(a)蜡,单独使用或与脂肪醇混合使用,或
(b)虫胶或玉米醇溶蛋白。
下面的实施例阐述了本发明的不同方面,它们不是用来限定权利要求的。
实施例1
8mg盐酸氢吗啡酮控释制剂
-丙烯酸聚合物包衣
实施例1制备如下:
1.药物加入。将盐酸氢吗啡酮溶于水中,加入Opadry Y-5-1442,淡粉红(Co;orcon,西美,宾夕法尼亚州,美国生产,它含有羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、聚乙二醇和D&C红第30号铝湖兰)混合1小时以得到20%(W/W)混悬液,然后用Wurster插入器将该混悬浮液喷在Nu Pareil 18/20目小珠上以制得氢吗啡酮小珠。
2.第一次包衣,然后用Wurster插入器将含有氢吗啡酮的小珠以增重5%的Opadry Light Pink包衣。该包衣作为保护层衣。
3.延迟性包衣,在第一层包衣后,用5%(增重)的90∶10的Endragit RS 30D和Eudragit RL 30D的混合物对氢吗啡酮珠包延迟性衣。枸橼酸三乙酯(增塑剂)和滑石粉(抗粘剂)也加在Eudragit混悬液中。用Wurster插入器混悬液包衣。
4.第二次包衣,一旦延迟性包衣层完成后,用Wuster插入器给氢吗啡酮珠最后一层增重5%的Opadry Light Pink的包衣。该包衣也作为保护性衣层。
5.固化,在完成了最后包衣层后,将氢吗啡酮珠放在45℃烘箱中固化2天,固化的小珠然后以8mg氢吗啡酮的量灌注入明胶胶囊中,实施例1小珠的完整处方如表1所示:
表1
制备步骤 组份 % mg/单位
药物加入 盐酸氢吗啡酮 8.2 8.0
Nu-Pareil 18/20 72.3 74.0
Opadry Lt Pink 2.1 2.0
第一次包衣 Opadry Lt Pink 4.4 4.2
延迟性包衣 Eudragit RS 30D
(干重) 4.0 3.8
Eudragit RL 30D
(干重) 0.4 0.4
枸橼酸二乙酯 0.8 0.8
滑石粉 1.8 1.7
第二次包衣 Opadry Lt Pink 5.0 4.8
总计 100.0 99.7mg
实施例1的Eudragit包衣的氢吗啡酮珠制备后的28天后进行溶出研究,结果如下表2所示:
表2
时间 1小时 2小时 4小时 8小时 12小时 18小时 24小时
最初 17.2 48.4 77.4 93.3 97.2 98.8 98.8
28天 16.8 50.6 79.7 95.2 99.0 101.9 102.7
对Eudragit包衣的氢咕啡酮珠的稳定性研究表明最初的溶出与在37℃/80下相对湿度条件下放置28天后的溶出相同(上表2所示)。
实施例2-4
8mg氢吗啡酮控释制剂
-乙基纤维素包衣
实施例2-4制备如下:
1.药物加入。将盐酸氢吗啡酮溶于水中,加入Opadry Y-5-1442,淡粉红(light pink)(Colorcon,西点,宾夕法尼亚州,美国生产),它含有羟丙基甲基纤维素、羟丙基纤维素、二氧化钛、聚乙二醇和D&C红第30号铝湖兰)混合1小时以得到20%(W/W)混悬液,然后用Wurster插入器将该混悬浮液喷在Nu Pareil 18/20目小珠上以制得氢吗啡酮小珠。
2.第一次包衣,然后用Wurster插入器将含有氢吗啡酮的小珠以增重5%的Opadry Light Pink包衣。该包衣作为保护衣层给出了速释氢吗啡酮珠,见下表3。
表3-速释珠
加工步骤 组份 % mg/单位
药物加入 盐酸氢吗啡酮 8.7 8.0
Nu-Pareil 18/20 83.9 74.0
Opadry Lt Pink 2.4 2.0
第一次包衣 Opadry Lt Pink 5.0 4.2
总计 100.0 88.2mg
3.延迟性包衣。在第一次包衣后,用含有Aquacoat ECD 30和枸橼酸三乙酯(增塑剂)的延迟性包衣材料对氢吗啡酮珠包衣至增重5%.10%和15%(以Aquacoat干重计算)。用Wurster插入器来施加包衣混悬液。
4.固化。在延迟性包衣层完成后,将珠放在60℃的烘箱中M%相对湿度(放一碟水)三批样品都固化72小时。
5.第二次包衣,将固化的珠从湿烘箱中取出。于流化床干燥器中干燥约1小时,干燥的固化珠子然后用Wurster插入器包Opadry Light Pink展示其重50%。该包衣层作为保护性衣层。最终制剂为含有5%、10%和15%的Aquacoal包衣小珠,分别如下表4,5和6所示。
表4含5%Aquacoat包衣小珠
加工步骤 组份 % mg单位
药物加入 盐酸氢吗啡酮 8.2 8.0
Nu-Pareil 18/20 74.8 74.0
Opadry Lt Pink 2.1 2.0
第一次包衣 Opadry Lt Pink 4.5 4.2
延迟性包衣 Aquacoat
ECD 30(干重) 4.5 4.2
枸橼酸三乙酯 0.9 0.8
第二次包衣 Opadry Lt Pink 5.0 4.7
总计 100.0 97.9mg
表5含5%Aquacoat包衣小珠
加工步骤 组份 % mg/单位
药物加入 盐酸氢吗啡酮 8.0 8.0
Nu-Pareil 18/20 70.5 74.0
Opadry Lt Pink 2.0 2.0
第一次包衣 Opadry Lt Pink 4.2 4.2
延迟性包衣 Aquacoat
ECD 30(干重) 8.5 8.4
枸橼酸三乙酯 1.7 1.7
第二次包衣 Opadry Lt Pink 5.1 5.0
总计 100.0 103.3mg
表6含5%Aquacoat包衣小珠
加工步骤 组份 % mg/单位
药物加入 盐酸氢吗啡酮 7.8 8.0
Nu-Pareil 18/20 66.8 74.0
Opadry Lt Pink 1.9 2.0
第一次包衣 Opadry Lt Pink 4.0 4.2
延迟性包衣 Aquacoat
ECD 30(干重) 12.1 12.6
枸橼酸三乙酯 2.4 2.5
第二次包衣 Opadry Lt Pink 5.0 5.2
总计 100.0 108.5mg
7.装胶囊。然后将氢吗啡酮珠按下列组成填充至明胶硬胶囊中使每个胶囊含8mg盐酸氢吗啡酮。
实施例2:所有的珠具有5%Aquacoat包衣;
实施例3:3:75%的珠含有10%Aquacoat包衣,其余的25%为速释珠;
实施例4:75%的珠含15%Aquacoat包衣,25%的为速释性珠
对实施例2-4的Aquacoat包衣的氢吗啡酮表在最初和及28天后进行溶出研究,结果如下表7-9所示。
表10-实施例2的溶出
时间 1小时 2小时 4小时 8小时 12小时 18小时 24小时
最初 33.8 54.6 71.2 85.7 92.9 97.3 99.9
28天 34.0 53.1 70.8 86.1 93.1 98.2 100.7
表11-实施例3的溶出
时间 1小时 2小时 4小时 8小时 12小时 18小时 24小时
最初 31.6 43.4 59.2 72.3 79.2 85.7 90.3
28天 32.3 43.7 59.2 72.6 80.7 86.8 91.5
表12-实施例4的溶出
时间 1小时 2小时 4小时 8小时 12小时 18小时 24小时
最初 29.3 37.2 52.1 66.4 73.9 80.4 85.4
28天 31.1 37.0 51.4 66.0 73.7 81.3 86.2
如上所示,实施例2-4Aquacoat包衣的氢吗啡酮珠的稳定性研究表明最初的溶出与37℃/80%相对湿度条件下放置样品的溶出相同。
实施例5-8
在实施例5-8中,于12个病人中进行单剂六种方式随机交叉研究(服前间隔为一周),并以等剂量的速释制剂的结果为对照,于服用后立即、0.25、0.5、0.75、1、1.5、2、2.5、3、3.5、4、6、8、10、12、18、24、30、36和48小时取血样以测定血药浓度。对照品A是8mg氢吗啡酮速释制剂(Knoll买到的两片Dilandid
4mg的片剂)、实施例5是8mg剂量的实施例1的氢吗啡酮珠胶囊剂。实施例6是实施例2的氢吗啡酮珠8mg剂量的胶囊剂。实施例7是实施例3的氢吗啡酮珠以8mg剂量胶囊剂,实施例8是mg实施例4的氢吗啡酮珠胶囊剂。
对照品A的结果如图1所示,实施例5所得的结果如图2所示,实施例6所得的结果如图3所示,实施例7所得的结果如图4所示,实施例8所得的结果如图5所示。图6为实施例5和对照品A的血浆血药水平比较图。在下表13和14中进一步列出了实施例5-8的结果数数。即曲线下面积(生物利用度)血浆峰浓度(Cmax)及达到血药峰值的时间(tmax)
表13
产品 AUC CmaxTmax
2Dilaudid片 12427 3013 1.10
实施例6 6718 1070 2.58
实施例7 9933 1265 2.39
实施例8 8695 1138 0.88
表14
产品 AUC CmaxTmaxPW
@HH
2Dilaudid 12427± 3013± 1.10± 1.67±
4mg片
1792 539 0.14 0.22
实施例5 13070± 1211± 4.42± 7.79±
1381 153 0.38 1.96
实施例5 110% 40% 402% 466%
从实施例7中可以判断,其生物利用度达88%(此为管理机构,如美国FDA可接受的);实施例7的Cmax降低为对照品A的约一半;tmax为2.39小时,对照品A的tmax为1.1小时。
已知Dilaudid在6小时内有效,从图1查得,8mg Dilandid在6小时时的血药浓度约为300pg/ml氢吗啡酮,因此,约300pg/ml的血浓可作为血浆有效止痛浓度。
可是,实施例5所得的结果表明在服药后12小时,氢吗啡酮的血药浓度超过500pg/ml氢吗啡酮,服药后24小时的血药浓度大于300pg/ml,因此该产品被认为适于一天服用一次,并被认为是含少量鸦片类药物制剂。
另一方面,实施例7在给药后的第12小时的血药水平达300pg/ml以上,给药后24小时时血浓约为250mg/ml,但是,实施例7氢吗啡酮的给药剂量仅为8mg/24小时。相反,为了保持速释制剂的昌能作用,相同时间里所需的总剂量达16mg(4mg/6小时)。从图4中可以明显看出,若服用实施例7的胶囊2枚,则在24小时中其最小或各浓度超过300pg/ml,2颗实施例7有胶囊在24小时进里的总剂量,与速释形剂的相同,但是,可调节最终制剂产品中小珠的用量使其24小时内的剂量少于速释。因此实施例7也可被认为是含少量鸦片制剂。该产品也适用于一天给药一次。
实施例9-10
在实施例9-10中,对10个受试者进行4种方式随机交叉单剂量给药研究、实施例9是8mg实施例5的氢吗啡酮珠禁食给药;而实施例10是8mg实施例5的氢吗啡酮珠喂禽给药,对照实验B中,禁食用用8mg速释氢吗啡酮(Dilardid 4mg 片二片),对照实验e中,进食后服用8mg速释氢吗啡酮(2片Dildudid 4mg片剂)。
图7中列出了比较实施例B和C的血浆浓度,而实施例9和10的血药浓度见图8实施例9-10和对照实施例B和C的结果数据列于表15。即曲线下面积,与速释剂相比的吸收百分率(生物利用度)血浆峰浓度(Cmax及达到峰浓的时间(t tmax。
表15
组 AUC %IR TmaxCmax
实施例9 21059 101 4.9 1259
实施例10 25833 106 4.6 1721
对照实施例B 20903 100 0.85 3816
对照实施例C 24460 100 1.15 3766
从实施例9-10和对照实施例B和C的结果国可确证,食物对速释片剂和实施例9和10的控释珠影响很小实施例9和10的控释珠的生物利用度稍有增加。血药浓度再一次证实该产品适于一天给药一次或两次。24小时控释产品24小时时的血药浓度接还600pg/ml,12小时的血药浓度高于700pg/ml。
实施例11-12
在实施例11-12中,进行3种方式的稳态交叉研究共4天,在对照实施例D中,每6小时受试者服用8mg速释氢吗啡酮(2Dilandid 4mg片剂),在对照实施例11中,每12小时服用8mg实施例5的氢吗啡酮小珠,在实施例12中每24小时服用实施例5的8mg氢吗啡酮小珠,第4天取血样。
对照实施例D的血浆浓度与实施例11和12的血浆水平见图9,图10为对照实施例D的血药谷眼度和实施例11和12的血药浓度(实施例12的值在图10中加倍),实施例11-12和对照实施例D的结果,数据列于表16即与速释制剂相比的曲线下面积和吸收百分率(生物利用度),血浆峰浓度(Cmax及达到峰浓的时间。
表16
实验组 AUC AUC*TmaxCmaxCmax *
实施例11 62223 27595 5.5 3475 2232
实施例12 39233 28879 4.8 2730 2189
对照实施例D 47835 22236 1.0 3124 2163
*AUC*=对于Q12H,0-128小时,对于Q24H0-24小时,和对照Q6H0-12小时,对Q6H0-12小时对于06H*Cmam*=Cmax-零时值
以曲线下面积(AUC)作为测定生物利用的参数,从表16中的数据中可确证对照实施例D和实施例11和12在给药间隔内有AUC相等的增加,表明所有的给药方案都是生物可效的。
此外,在这一研究中,剂量为每24小时8mg的实施例12表明若小珠的用量加倍,即一天一次16mg的剂量,该刘量与速释制剂剂量相等,(每6小时4mg)该制剂即为一优秀的24小时制剂,图10显示的实施例12的最小或谷浓度表明该产品与4mg速释制剂(每6小时给药)相等,因此该产品为优秀的一天一次产品。
实施例13
控释硫酸吗啡30mg制剂
-丙烯酸型聚合物包衣
用实施例1相同方法制得实施例13样品实施例13小珠的完整处方如下表17所示。
表17
药物加入
组份 Amt/单
位
硫酸吗啡粉 30.0mg
微粒型含水乳糖 42.5mg
Povidone 2.5mg
Nupareil PG18/20 125.0mg
纯水 qs
Opadry Red YS-1-1841 10.5mg
纯水 qs
延迟性包衣
Eudragit RS 30D 10.3mg
Eudragit RL 30D 0.2mg
枸橼酸三乙酸 2.1mg
滑石粉 4.2mg
纯水 qs
第二次包衣
Opadry Red YS-1-1841 12.0
纯水 qs
总计 239.3mg
Eudragit RS 30D与Eudragit RL 30D的比率是98∶2,在最后的包衣完成后,将吗啡小珠放在45℃烘箱中固化2天,固化后的药珠然后以30mg量填充于明胶胶囊。
对实施例13的Eudragit包衣的吗啡珠最初及加速贮存条件下放置3个月后进行熔出研究。结果如下表18所示。
表18
贮存条件 溶出(溶出%)
时间(小时)
测定时间 1 2 4 8 12
最初 2.6 2.4 60.5 89.4 98.8
1个月40℃/75%相 5.8 27.3 62.0 89.8 99.1
对湿度
3个月40℃/75%相 6.8 26.5 65.3 87.6 95.1
对湿度
表18的溶出表明实施例13的药珠是稳定的。
然后以实施例13的剂型对标准的制剂对照实施例E在12个受试者中进行双育单剂量交叉研究,在对照实施例E中,服用市售的硫酸吗啡控释片(MS Contin
Frederick公司生产)。结果如图11所示,图11为两倍于实施例13剂量的血药浓度与对照实施例E所得的血药浓度。
上述的实施例不是专有独特的,该技术领域的人员可对本发明作出许多其它的改变。预期达到所附的权利要求书的范围。
Claims (16)
1、一种固体控释口服剂型,该剂型包括具有控药包衣或控释内架的止痛有效量的鸦片类止痛药或其盐,
其中体外溶出速率(用USP浆法或转兰法在100rpm下于900ml水性缓冲液(pH在1.6-7.2)中37℃下测定)1小时后释放的鸦片型药物为约12.5-42.5%(重量),2小时后释放约25-65%(重量)的鸦片型药物,4小时后释放约45-85%(重量)的鸦片型药物,8小时后释放大于60%(重量)的鸦片型药物选用与pH基本无关的体外释放率基本上该剂型服用后2-6小时可达到体内鸦片型药物的血浆峰浓。
2、根据权利要求1所述的剂型,其中所述的鸦片类止痛药选自氢吗啡酮、羟考酮、吗啡、左啡诺、美沙酮、哌替啶、海洛因、双氢可待因、可待因、双氢吗啡、丁丙诺啡,它们的盐及其混合物。
3、根据权利要求1所述的剂型,其中所述剂型包括含有所述的鸦片类止痛药或其盐的止痛有效量的小球,其中的小球外包有控释包衣膜。
4、根据权利要求1-3所述的剂型,其中所述的小球用药用疏水材料进行包衣,其中所述的疏水材料选自由烷基纤维、丙烯酸型聚合物、虫胶、玉米朊,氢化蓖麻油,氢化植物油及任何上述材料的混合物。
5、根据权利要求1-3所述的剂型,其中所述的疏水性材料以水性分散液的形式施用于所述的小球。
6、根据权利要求1-5所述的剂型,其中所述的鸦片类止痛药由约4-64mg氢吗啡酮组成。
7、根据权利要求1-5所述的剂型,其中所述的鸦片类止痛药由约15-800mg吗啡组成。
8、根据权利要求7所述的剂型,其中所述的疏水性材料选自由烷基纤维素、丙烯酸型聚合物、虫胶、玉米朊、氢化蓖麻油、氢化植物油及其混合物所组成的组。
9、根据权利要求1-5所述的剂型,其中所述的鸦片类止痛药由10mg-400mg羟考酮组成。
10、根据权利要求1-5所述的剂型,给药后约4-6小时体内阿片类达血药浓度峰值。
11、根据权利要求1-2所述的剂型,其中所述的剂型是控释内架形式。
12、一种提供24小时控制人体疼痛的方法,包括,通过将止痛有效量的鸦片类药物掺入控释剂型中制得固体、控释口服剂型,其体外溶出速率(用USP将法或转兰法在100rpm下于900ml水性缓冲液(pH在1.6-7.2)中在37℃下测定)2小时后释放的鸦片型药物为12.5-42.5%(重量),2小时后释放约25-65%(重量)的鸦片型药物,4小时后释放约45-85%(重量)的鸦片型药物,8小时后释放大于60%(重量)的鸦片型药物,体外释放率基本上与pH无关,该剂型服用后2-8小时可得到体内鸦片型药物的血浆浓度峰值。
13、根据权利要求12所述的方法,它进一步包括给病人一天口服一次所述的剂型。
14、根据权利要求12所述的方法,其中所述的鸦片类止痛药选自氢吗啡酮、羟可酮、吗啡、左啡诺、美沙酮、哌苷啶、海咯因、二氢可待因、可待因、二氢吗啡、丁丙诺啡的mμ-激动剂,它们的盐及其混合物。
15、根据权利要求12所述的方法,所述服用所述的剂型后约4-6小时阿片类止痛药达血约浓度峰值。
16、根据权利要求12-15所述的方法,它进一步包括将所述的鸦片类止痛药包覆在药用小珠上制得口服基蕊,再用药用疏水材料对所述小珠进行包衣,然后将足量的包衣珠填入胶囊制得一天一次的口服剂型。
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- 1994-06-22 EP EP94109655A patent/EP0631781A1/en not_active Ceased
- 1994-06-22 EP EP10178499A patent/EP2263673A1/en not_active Withdrawn
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- 1994-06-27 ZA ZA944599A patent/ZA944599B/xx unknown
- 1994-06-29 AU AU66058/94A patent/AU6605894A/en not_active Abandoned
- 1994-06-29 SK SK786-94A patent/SK283081B6/sk not_active IP Right Cessation
- 1994-06-29 SK SK124-2000A patent/SK283082B6/sk unknown
- 1994-06-30 PL PL94304060A patent/PL175814B1/pl unknown
- 1994-06-30 NO NO942477A patent/NO942477L/no not_active Application Discontinuation
- 1994-07-01 CN CNB941076997A patent/CN1292742C/zh not_active Expired - Fee Related
- 1994-07-01 JP JP15093894A patent/JP3645589B2/ja not_active Expired - Lifetime
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- 1994-07-01 KR KR1019940015803A patent/KR0140492B1/ko not_active IP Right Cessation
- 1994-09-15 TW TW083108517A patent/TW450814B/zh not_active IP Right Cessation
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1997
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1999
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2004
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100411611C (zh) * | 2002-04-05 | 2008-08-20 | 欧洲凯尔蒂克公司 | 用于持续,不变且独立释放活性化合物的基质 |
CN103831739A (zh) * | 2014-02-11 | 2014-06-04 | 当涂县南方红月磨具磨料有限公司 | 一种耐高温陶瓷碳化硅砂轮 |
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