CN1404389A - 时控脉冲给药系统 - Google Patents

时控脉冲给药系统 Download PDF

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CN1404389A
CN1404389A CN01804761A CN01804761A CN1404389A CN 1404389 A CN1404389 A CN 1404389A CN 01804761 A CN01804761 A CN 01804761A CN 01804761 A CN01804761 A CN 01804761A CN 1404389 A CN1404389 A CN 1404389A
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P·J·波塞尔
G·M·万卡泰什
K·维什努派德
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Adele Drug Cos
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Abstract

一种药物剂型，如胶囊，其能以时间控制或者位点控制的释放形式将治疗剂传输到体内，该剂型由一种或多种珠粒制成的多种多重包衣的颗粒(珠粒、小丸、颗粒等等)组成。除了快速释放的珠粒之外，每一种珠粒至少含有两层包衣膜屏障。其中一种膜屏障由肠溶性聚合物组成，第二种由水不溶性聚合物和肠溶性聚合物的混合物组成。聚合物膜屏障的组成和厚度决定了迟滞时段和药物从每一种珠粒中释放的时间间隔。任选地，可使用含有机酸的中间膜以进一步调节迟滞时段和/或药物释放时间间隔。脉冲传送可以包含一种或多种脉冲以提供治疗剂的血浆浓度－时间特性，该特性可在药动学和药效学因素及体外/体内关系的基础上预知。

Description

时控脉冲给药系统
发明背景
已知口服剂型以零级或一级释放，其中药物在每一时间单元内基本上以稳定的速率释放。这样的剂型对于很多药物剂型的给药都是适宜的。但在某些情况下，这样的剂型不能得到持续稳定的血药浓度。在这些情况下(例如，化疗的优化方案中，需要减轻局部缺血性心脏病、哮喘、关节炎等慢性疾病的夜间或清晨的病情时，避免对硝酸酯、抗生素和甾体避孕药的耐受性的增加或吸收窗的产生时)，使用一种“按时间控制”的脉冲给药系统将更为有利。还有些时候，使用“位点控制”给药系统(例如治疗结肠疾病或者将结肠作为肽类和蛋白质产品的吸收位点时)将更为有效。
脉冲给药系统可在指定迟滞时段后的预定时间点上或者特定位点上提供一种或多种快速的释放脉冲。然而，由于该剂型所用的尺寸和物料的潜在的限制性，可用的口服脉冲释放系统只有一小部分。Ishino等在Chemical Pharm.Bull.Vol.40(11)，p3036-3041(1992)上公开了一种干性包衣片剂。P.R Magruder等的1989年7月25日授权的美国专利No.4,851,229；K.Fujioka等的1991年4月30日授权的美国专利5,011,692；Maruyama和R.Cortese的1991年5月21日授权的美国专利No.5,017,381；F.Philippon等的1993年7月20日授权的美国专利No.5,229,135；以及J.P.-F.Bai的1998年11月24日授权的美国专利No.5,840,329公开了脉冲释放系统的制备方法。其它的一些给药系统公开于Y.Ueda等的1989年10月3日授权的美国专利No.4,871,549、C.M.Chen的1993年11月9日授权的美国专利No.5,260,068和No.5,260,069以及C.M.Chen的1996年4月16日授权的美国专利No.5,508,040之中。在C.M.Chen的1993年7月20日授权的美国专利No.5,229,135及1996年10月22日授权的美国专利No.5,567,441中公开了一种由用缓释或水不溶性聚合物膜包衣的小丸组成的脉冲释放系统，其中的水不溶性聚合物膜含有疏水性的水不溶性试剂或肠溶性聚合物以调整膜的通透性。A.M.Mehta等的1998年11月17日授权的美国专利5,837,284中公开了一种剂型，其可提供口服给药后methylphthidate的快速释放剂量，之后一种或多种随后的剂量在数小时内铺展性的溶出。因此这就需要一种能保证同时传输单一药物或药物结合体的脉冲给药系统，以及能有效治疗疾病的脉冲给药的时间控制装置，这样的治疗具有最大的病人依从性与最小的副作用。本发明所将阐明的时控的脉冲释放给药系统即指在口服给药数小时后提供一种单一靶向脉冲，其伴随或不伴随有口服给药时迅速的药物释放。
发明概述
本发明提供了一种制造药学上优良的多微粒剂型的方法，所述剂型具有时控的脉冲释放特性，即，在口服给药后数小时内产生一种时控的系列脉冲，其伴随或不伴随有给药后迅速的释放脉冲。本发明同时还提供了一种新颖的多重包衣颗粒剂型，其具有一活性核芯，第一层膜为肠溶性聚合物，第二层膜为水不溶性和肠溶性聚合物的混合物。含有机酸的膜可夹在上述的第一和第二膜层之间以提供有时段间隔的脉冲。所述膜层可以任何顺序包衣，通常，将肠溶性聚合物作为最内层膜。发明详述
本发明新型剂型的活性核芯可含有一种惰性颗粒，如商业上可得到的non-pareil糖球。核芯中的药量依所需药物和剂量而定。通常，核芯中含有大约5-60重量％的药物，其以核芯总重计。本领域技术人员能够选择适宜量的药物用于包衣或者加入核芯中以得到所需剂型。
一种水性的或者药学上可接受的溶剂介质可用于制备核芯颗粒。用于将水溶性的药物粘结到惰性颗粒上的惰性粘合剂的类型并无严格要求，通常使用的是水溶性或醇溶性的粘合剂。可将粘合剂，诸如聚乙烯吡咯烷酮(PVP)、羧烷基纤维素、聚乙烯氧化物、多糖如葡聚糖、谷物淀粉、羟丙基甲基纤维素(HPMC)、羟丙基纤维素分散于水中，达到0.5-5重量％浓度时使用。药物可以溶液形式存在于包衣制剂中，也可混悬于其中。药物浓度由包衣制剂的粘度决定，其范围在约10-30重量％之间。
在一项实施方案中，活性核芯可以制粒、挤压和球化的方式制备。在高速剪切制粒机(如Fielder制粒机)或者流化床制粒机(如GlattGPCG制粒机)中，将活性药物、粘合剂如PVP、任选的控制溶解速率的聚合物如高粘度HPMC、和任选的其它药学上可接受的赋型剂一起混合，通过加入/喷入一种制粒液体如水或醇制粒以形成所需物块，然后干燥。湿物料可用挤压机/球形造粒机(marumerizer)挤压及球化以制备球形的颗粒(珠粒)。在这些实施方案中，药物重量可高达90重量％，其以挤压或成颗粒的核芯总重量计。
含有药物的水溶性/可分散的颗粒上的其中一层包衣膜可含有增塑的肠溶性聚合物，而另一层可含有水不溶性聚合物和增塑的水分散性/肠溶性聚合物的混合物，其中所述水不溶性聚合物和所述水分散性聚合物可以10∶1-1∶1的重量比存在，典型地为大约4∶1-1∶1，包衣的总重量大约是15-80重量％，更典型地为大约20-60重量％，其以多微粒剂型的总重量计。
中间含酸的膜，如果存在的话，其可以包括一种有机酸，如富马酸、柠檬酸、琥珀酸、酒石酸、苹果酸和马来酸；以及一种粘合剂如PVP。对粘合剂的性质没有严格的要求，但通常使用的是水溶性或醇溶性的聚合物。所述酸性包衣的重量大约是5-20％，其以被包衣的珠粒的总重量计。此膜层中的酸延缓了最内层肠溶性聚合物的溶解，因而在延长了迟滞时间的同时降低了活性成分从包衣颗粒中的释放速率。优化外层聚合物膜的组成、以及内层，中间层和外层膜单独的重量以获得所给治疗剂或试剂的脉冲释放特性，而此特性可根据体内/体外相互关系而预知。
本发明使用的肠溶性聚合物的代表性实施例包括纤维素酯及其衍生物(醋酸纤维素邻苯二甲酸酯、羟丙基甲基纤维素邻苯二甲酸酯、醋酸羟丙基甲基纤维素琥珀酸酯)、醋酸聚乙烯邻苯二甲酸酯、pH-敏感的甲基丙烯酸-甲基丙烯酸甲酯共聚物和虫胶(shellac)。这些聚合物可作为干粉末或者水性分散体使用。某些可使用的、可在市场上获得的物料是由Rhom制药公司生产的以Eudragit(L100，S100，L30D)商标出售的甲基丙烯酸共聚物；Eastman化学公司生产的Cellacefate(醋酸纤维素邻苯二甲酸酯)；FMC公司的Aquateric(醋酸纤维素邻苯二甲酸酯水性分散体)；及Shin Etsu K.K.生产的Aqoat(醋酸羟丙基甲基纤维素琥珀酸酯水性分散体)。
本发明使用的水不溶性聚合物的代表性的实施例包括纤维素衍生物(如乙基纤维素)、聚醋酸乙烯酯(Kollicoat SR30D，BASF生产)、以丙烯酸乙酯和甲基丙烯酸甲酯为基础的中性共聚物、含季铵基团的丙烯酸酯和甲基丙烯酸酯的共聚物，如Eudragit NE、RS或RS30D、RL或RL30D等。
用于成膜的肠溶性和水不溶性聚合物通常需要增塑。用于使膜增塑的增塑剂的代表性实施例包括甘油三乙酸酯、柠檬酸三丁酯、柠檬酸三乙酯、乙酰柠檬酸正三丁酯、邻苯二甲酸二乙酯、蓖麻油、癸二酸二丁酯、乙酰化单酸甘油酯等，或者它们的混合物。增塑剂含量大约为3-30重量％，更典型为大约10-25重量％，其以聚合物重量计。增塑剂的类型及含量根据一种或多种聚合物、包衣体系的性质(例如，水性的或溶剂基底、溶液或分散体基底及全部固体)来确定。
通常，在包衣脉冲释放膜之前需要先填注颗粒表面，或用薄层羟丙基甲基纤维素(HPMC)(Opadry Clear)薄膜隔离不同的膜层。比较常用的是HPMC，其它如羟丙基纤维素(HPC)等底物也可使用。
在核芯上包膜衣可用任一药剂工业上常用的包衣技术，流化床包衣技术是特别有用的。
本发明同时还提供了一种生产时控的脉冲释放剂型的方法，其包括：
用药物和聚合粘合剂一起包衣惰性颗粒如non-pareil粒种(糖球)，或者通过制粒或/和挤压/球化制备一种含有药物的颗粒以获得一种活性药物颗粒；
用已增塑的肠溶性包衣对所述活性药物颗粒进行包衣，其可获得一种已增塑的肠溶性包衣药物颗粒；及
用一种水不溶性聚合物和一种肠溶性聚合物的混合物包衣所述已增塑的肠溶性包衣药物颗粒。
第二步和第三步操作顺序可互换，在调节所述药物颗粒的释放特性中，这一特点将使其灵活性增加。本发明另一使灵活性增加的操作是在第二和第三包衣操作之间，任选地应用一种含有机酸(如富马酸或琥珀酸)的膜，以进一步调整迟滞时间及药物颗粒的释放特性。
含有多层包衣药物的剂型可以有很多种类型，其中该多层包衣药物中含有与本发明相应的颗粒。在一项实施方案中，该制剂可使用单一的颗粒形式以提供一种口服给药后数小时内时控的药物脉冲释放形式或者对准特定的吸收位点，如在十二指肠/空肠或结肠内部或附近释放的形式。在另一实施方案中，制剂可含有两种或多种释放性质不同的药物颗粒，即，一种或多种修饰了的释放珠粒相结合，其具有明显不同的迟滞时间和释放速率，伴随有或不伴随有一种快速释放以形成所述的时控脉冲释放给药系统的颗粒。两种或多种药物多层包衣的颗粒可结合在一起以获得一种协同效果及病人的依从性。
适合包入这些时间控制或位点控制的脉冲释放系统中的治疗剂包括酸性、碱性、两性离子型或中性的有机/无机生物活性分子或其盐类。药物可选自药学上可接受的，对于人类具有已被证明的药理学活性的有机或无机化学物质。代表性的活性化合物包括镇痛药、抗惊厥药、麻醉剂、抗糖尿病药物、抗传染药、抗肿瘤药、抗帕金森药、抗风湿病药、心血管药物、中枢神经系统(CNS)激动剂、多巴胺受体激动剂、胃肠道剂、精神病治疗剂或者尿道药物。本发明特定治疗剂或适宜药物的代表性实施例包括，但不限于硫酸沙丁胺醇、阿莫西林、盐酸安非他酮、卡比多巴、头孢克洛、双氯酚酸钠、红霉素、非洛地平、氯雷他定、碳酸锂、methyl phenidate、酒石酸美托洛尔、硝苯地平、奥美拉唑、盐酸索他洛尔、盐酸维拉帕米或者它们的与治疗相关的结合体。上述药物列表并非是详尽的。许多其它的药物也是适用于本发明的，既可单独使用，也可与其它药物结合使用。药物的水溶解度范围可从大约0.01至大约1,000mg/mL。
以下非限制性的实施例阐述了本发明相应的药物剂型。实施例1
将索他洛尔HCl(194.7g)缓慢地加入到聚乙烯吡咯烷酮(9.8gPovidone K-30)水性溶液中，混合均匀。将糖球(750g，20-25目)在Versa Glatt流化床制粒机中用药物溶液包衣。含有药物的颗粒干燥后用Opadry Clear(2％w/w)包膜。通过喷洒如下成分的混悬液将第一层包衣包于活性颗粒上：Eudragit L30D(480.8g)；乙酰柠檬酸三正丁酯(14.4g)；微分滑石粉(28.8g)和纯化水(462.8g)。第二层或外层包衣通过混合两种独立的水性的分散体来制备。第一种分散体通过向纯化水(995.9g)中加入乙酰柠檬酸正三丁酯(26.7g)和Eudragit L30D(891.5g)来制备。第二种分散体通过向Aquacoat，一种30重量％乙基纤维素分散体(从FMC购得)，中加入癸二酸二丁酯(59.5g)来得到。两种分散体在连续搅拌中以1∶1比例混合。然后将结合的包衣制剂缓慢的喷在已被第一层包衣包衣的活性颗粒上。将多重包衣颗粒置于45-70℃下固化直至聚合物完全融合。实施例1的多重包衣颗粒的最终组合物示于表1。
两批最终颗粒的药物含量和内层包衣相同，但是外层包衣含量分别为45和55％w/w。此两批颗粒使用美国药典(USP)的溶解装置2作体外溶解特性的测试，其先在37℃下，桨速为50rpm的0.1N HCL中测试2小时，随后再在pH6.8的溶液中测试4小时。得到的结果见于表2中。溶解结果显示有3到4小时的迟滞时段，该时段与第二/外层包衣的含量有关，其能在90分钟内将药物几乎完全释放。在使用实施例1的组合物和方法的盐酸methylphenidate药物中也得到了相同的结果。实施例1
                        表1：实施例1的制剂
成分  第二包衣(45％w/w)  第二包衣(55％w/w)
核芯
索他洛尔HCl，USP  8.80  7.20
#25目糖球，NF  33.91  27.72
Povidone，USP  0.43  0.36
包封衣膜
Opadry Clear YS-1-7006  0.88  0.72
内层包衣
甲基丙烯酸共聚物，C型，NF  8.46  6.92
滑石粉，USP  1.69  1.39
乙酰柠檬酸正三丁酯  0.85  0.69
外层包衣
甲基丙烯酸共聚物  20.47  25.04
乙酰柠檬酸正三丁酯  2.02  2.47
乙基纤维素水性分散体，NF  18.14  22.16
癸二酸二丁酯，NF  4.36  5.33
纯化水，USP  痕量  痕量
         表2：实施例1中的溶解数据
 时间(小时)  第二包衣(45％w/w)  第二包衣(55％w/w)
 1  0  0
 2  0  0
 3  0  0
 4  81.2  0.2
 4.33  95.0  --
 5  --  70
 5.67  --  92.5
虽然发明人并不希望被任一操作理论所约束，然而释放机理确定如下：第二包衣，其为骨架包衣，被乙基纤维素聚合物支持在适当的位置。在0.1N盐酸液中进行溶解测试的前两小时内，药物不能释放，因为内层和外层的肠溶性聚合物膜不能通透0.1N HCl。当溶解介质换成pH6.8时，肠溶性聚合物从外层膜处开始溶解，形成小孔和通道。溶解介质进入到核芯溶解活性物质及触发其释放需要一段时间，因此导致了另外的迟滞时段的产生。实施例2
该实施例以肠溶性聚合物溶液和有机溶剂中的乙基纤维素的使用为基础。按照实施例1的方法制备含盐酸索他洛尔的颗粒。通过将含98份丙酮和2份水的肠溶性聚合物(羟丙基甲基纤维素邻苯二甲酸酯)溶液喷洒到这些颗粒上包衣直至重量增加20％。第二包衣使用的是含98份丙酮和2份水的溶剂中溶有相同量的乙基纤维素10cps和羟丙基甲基纤维素的溶液。实施例2中多重包衣颗粒的最终组合物见于表3中。最终包衣颗粒进行如实施例1所描述的体外溶解测试，所得结果示于表4中。表3：实施例2的制剂
成分  第二包衣(35％w/w)  第二包衣(40％w/w)
核芯
索他洛尔HCl  10.40  9.60
#25目糖球  40.05  36.97
Povidone  0.51  0.47
包封衣膜
Opadry Clear YS-1-7006  1.04  0.96
内层包衣
HPMC邻苯二甲酸酯，NF  10.40  9.6
邻苯二甲酸二乙酯  2.60  2.4
外层包衣
HPMC邻苯二甲酸酯  14.00  16.00
乙基纤维素10cps，NF  15.93  18.20
邻苯二甲酸二乙酯  5.07  5.80
               表4：实施例2的溶出数据
 时间(小时)  第二包衣(35％w/w)  第二包衣(40％w/w)
 1  0  0
 2  0  0
 3  0  0
 4  2.74  1.6
 4.33  7.1  2.1
 4.67  21.5  4.1
 5  45.3  10
 5.33  70.5  22.9
 5.67  89.7  42.8
 6.0  101.9  65.1
 6.33  84.8
 6.67  99.3
从表4中可明显看出，使用含溶剂的包衣导致了与含量较高的水性包衣相同的迟滞时段。例如，一种35重量％溶剂包衣导致的迟滞时段与55重量％水性包衣的时段相同。
                        实施例3
制备实施例1中含第二包衣(与增重45％w/w的量相等的重量)的多重包衣的珠粒，但是其中的内层包衣和外层包衣互换了位置。所得的溶解数据示于表5中，该数据显示本发明能适应互换内外包衣的变化。
   表5：实施例3的溶解数据
 时间(小时)  内层包衣(45％w/w)
 1  0
 2  0
 2.5  0
 3  71.3
 3.5  95.1
 4  101.7
实施例4
按照实施例1的操作，将覆有药物的non-pareil粒种用EudragitL30D分散体包衣至增重20％。一种富马酸/PVP组合物用于这些包衣珠粒上至增重24％w/w。所用的外层膜由肠溶性聚合物和乙基纤维素以1∶1的比例组成。实施例4中多重包衣颗粒的最终组合物示于表6中。所得的包衣颗粒进行如实施例1中所述的体外溶解测定，所得结果示于表7中。从表2和表7中可看出，外层含量为45％w/w时，可得到4小时的明显延长的迟滞时段。此外，药物并不以脉冲的形式释放，而是在6-7小时内铺展性地溶出。
                       表6：实施例4的制剂
 成分  外层包衣(30％w/w)  外层包衣(45％w/w)
 核芯
 索他洛尔HCl  8.51  6.42
 糖球(20-25目)  32.78  26.03
 Povidone  0.42  0.33
 包封衣膜
 Opadry Clear YS-1-7006  0.85  0.67
 内层包衣
 甲基丙烯酸共聚物  8.18  6.43
 乙酰柠檬酸正三丁酯  0.82  0.64
 滑石粉  1.64  1.29
 中间包衣
 富马酸  15.12  11.88
 Povidone  1.68  1.32
 外层包衣
 甲基丙烯酸共聚物  13.65  20.46
 乙酰柠檬酸正三丁酯  1.35  2.03
 乙基纤维素分散体  12.09  18.14
 癸二酸二丁酯  2.91  4.36
            表7：实施例4中的溶出数据
 时间(小时)  外层包衣(30％w/w)  外层包衣(45％w/w)
 1  0  0
 2  0.3  0
 3  9.6  0.1
 4  27.3  7.7
 5  56.2  18.7
 6  77.2  37.4
 7  89.5  54.8
 8  97.1  67.0
 9  76.4
 10  83.5
 11  89.8
 12  94.3
当对本发明进行详细描述且与其特定的实施方案相联系时，显然，可得到众多的对本发明作出修正和改变的方案，这些都在按照权利要求书所定义的发明范围之内。

Claims (21)

1、一种药物剂型，其含有一种含药物的核芯颗粒；所述颗粒用肠溶性聚合物的第一层膜包衣；其第二层膜是水不溶性聚合物和肠溶性聚合物的结合体，其中所述水不溶性和所述肠溶性聚合物以大约10∶1至1∶1的重量比存在于第二层膜中，第一和第二层膜的总重量大约是被包衣颗粒总重量的15至80重量％；其中的第一和第二层膜可以任意顺序对核芯颗粒包衣。
2、如权利要求1所定义的一种药物剂型，其进一步含有一种在第一和第二层膜之间含有机酸的中间层膜。
3、如权利要求1所定义的一种药物剂型，其中的药物选自酸性的、碱性的、中性的或两性离子或其任一药学上可接受的盐的型式。
4、如权利要求1所定义的一种药物剂型，其中所述药物的水溶性范围为从大约0.1mg/mL到1,000mg/mL。
5、如权利要求1所定义的一种药物剂型，其中的药物选自镇痛药、抗惊厥药、麻醉剂、抗糖尿病药物、抗传染药、抗肿瘤药、抗帕金森药、抗风湿病药、心血管药物、中枢神经系统(CNS)激动剂、多巴胺受体激动剂、胃肠道剂、精神病治疗剂和尿道药物。
6、如权利要求1所定义的一种药物剂型，其中的药物选自硫酸沙丁胺醇、阿莫西林、盐酸安非他酮、卡比多巴、头孢克洛、双氯酚酸钠、红霉素、非洛地平、氯雷他定、碳酸锂、methylphenidate、酒石酸美托洛尔、硝苯地平、奥美拉唑、盐酸索他洛尔、盐酸维拉帕米及其结合体。
7、如权利要求1所定义的一种药物剂型，其中的核芯颗粒是一种用药物和聚合粘合剂包衣的non-pareil糖粒种，或者是通过制粒和研磨形成的颗粒，或者是通过挤压/球化形成的一种活性药物颗粒。
8、如权利要求1所定义的一种药物剂型，所述肠溶性聚合物选自纤维素酯、醋酸聚乙烯邻苯二甲酸酯、pH敏感的甲基丙烯酸-甲基丙烯酸甲酯共聚物及虫胶。
9、如权利要求1所定义的一种药物剂型，所述第二包衣的水不溶性聚合物选自乙基纤维素、聚乙酸乙烯酯、以丙烯酸乙酯和甲基丙烯酸甲酯为基础的中性共聚物和含季铵基团的丙烯酸酯和甲基丙烯酸酯的共聚物。
10、如权利要求1所定义的一种药物剂型，其中至少一种所述膜进一步含有一种增塑剂。
11、如权利要求10所定义的一种药物剂型，所述增塑剂选自甘油三乙酸酯、柠檬酸三丁酯、柠檬酸三乙酯、乙酰柠檬酸正三丁酯，邻苯二甲酸二乙酯、蓖麻油、癸二酸二丁酯、乙酰化单酸甘油酯及其混合物。
12、如权利要求1所定义的一种药物剂型，所述包衣膜取自一种在药学可接受的溶剂中的溶液或者取自肠溶性聚合物、水不溶性聚合物或其混合物的水性分散体。
13、如权利要求1所定义的一种药物剂型，将所述水不溶性和肠溶性聚合物的混合物的第二层包衣喷至足够的厚度以防止口服给药时3到6小时内出现大量的药物释放。
14、如权利要求2所定义的一种药物剂型，所述用于第一和第二层膜之间的中间膜的有机酸选自富马酸、琥珀酸、酒石酸、柠檬酸、苹果酸和马来酸。
15、如权利要求1所定义的一种药物剂型，所述药物剂型是一种硬明胶胶囊。
16、如权利要求15所定义的一种药物剂型，所述胶囊含有单一形态的颗粒，能在口服给药后3到6小时提供一种时控的药物脉冲释放形式。
17、如权利要求15所定义的一种药物剂型，所述胶囊含有单一形态的颗粒，能在特定的吸收位点处或附近提供一种时控的药物释放形式。
18、如权利要求15所定义的一种药物剂型，所述胶囊含有两种或多种具有不同释放特性的多重包衣的药物颗粒。
19、如权利要求15所定义的一种药物剂型，所述胶囊含两种或多种药物的多重包衣颗粒。
20、制备一种给药系统的方法，其包括：
a)制备一种包含药物和聚合粘合剂的核芯颗粒；
b)用增塑的肠溶性聚合物膜包衣所述含药物的核芯颗粒；以及
c)用水不溶性聚合物与肠溶性聚合物的混合物包衣所述增塑的肠溶性包衣的药物颗粒，其中水不溶性聚合物和肠溶性聚合物以大约10∶1至1∶1的重量比存在；
其中所述包衣的总重量为包衣颗粒总重量的15到80重量％。
21、制备一种给药系统的方法，其包括：
a)制备一种核芯颗粒，其含有一种含药物的成膜组合物；
b)用增塑的肠溶性聚合物膜包衣所述含药物的核芯颗粒；
c)用一种含有机酸的中间膜包衣所述增塑的肠溶性包衣的药物颗粒；以及
d)用含水不溶性聚合物与肠溶性聚合物的膜包衣中间膜，其中所述水不溶性和肠溶性聚合物以大约10∶1至1∶1的重量比存在；
其中包衣的总重量是包衣颗粒总重量的15到80重量％。
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CN103417508B (zh) * 2013-08-07 2016-01-20 迪沙药业集团有限公司 一种坎地沙坦酯脉冲择时释放的药物组合物
CN104473895A (zh) * 2014-11-20 2015-04-01 美吉斯制药（厦门）有限公司 拉莫三嗪口腔崩解缓释片
CN107582541A (zh) * 2017-08-14 2018-01-16 北京悦康科创医药科技股份有限公司 抗耐药菌抗生素微球的脉冲式给药制剂
CN107582541B (zh) * 2017-08-14 2020-08-14 北京悦康科创医药科技股份有限公司 抗耐药菌抗生素微球的脉冲式给药制剂

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US20010046964A1 (en) 2001-11-29
CN1404389B (zh) 2011-08-24
JP2012107048A (ja) 2012-06-07
JP4991072B2 (ja) 2012-08-01
AU3492201A (en) 2001-08-20
MXPA02007762A (es) 2004-09-10
AU772168B2 (en) 2004-04-08
CA2398035A1 (en) 2001-08-16
JP5607670B2 (ja) 2014-10-15
HK1039569B (zh) 2004-12-03
ES2220602T3 (es) 2004-12-16
US6627223B2 (en) 2003-09-30
US20050118268A1 (en) 2005-06-02
PT1123700E (pt) 2004-07-30
WO2001058433A1 (en) 2001-08-16
NZ520706A (en) 2003-07-25
ATE266390T1 (de) 2004-05-15
EP1123700A1 (en) 2001-08-16
DE60103186D1 (de) 2004-06-17
US7048945B2 (en) 2006-05-23
HK1039569A1 (en) 2002-05-03
CA2398035C (en) 2008-08-05
DE60103186T2 (de) 2004-09-09
EP1123700B1 (en) 2004-05-12

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