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CN1303998C - 含有达非那新的药物制剂 - Google Patents

含有达非那新的药物制剂 Download PDF

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CN1303998C
CN1303998C CNB961969776A CN96196977A CN1303998C CN 1303998 C CN1303998 C CN 1303998C CN B961969776 A CNB961969776 A CN B961969776A CN 96196977 A CN96196977 A CN 96196977A CN 1303998 C CN1303998 C CN 1303998C
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darifenacin
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T·F·多兰
M·J·胡夫雷
D·J·尼科尔斯
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Abstract

本发明提供了一种适合给予患者胃肠道的药物剂型，该剂型包括达非那新或其药学上能接受的盐和药学上能接受的辅料、稀释剂或载体，其特征在于该剂型适合于至少10%重量的达非那新或其药学上能接受的盐释放到患者的较低的胃肠道部分。该剂型使不希望的副作用减到最小，并增加达非那新的生物利用度。

Description

含有达非那新的药物制剂
本发明涉及达非那新及其药学上能接受的盐的药物剂型。
达非那新为(S)-2-{1-〔2-(2，3-二氢苯并呋喃-5-基)乙基〕-3-吡咯烷基}2，2-二苯基乙酰胺，并在欧洲专利N°0388054(实施例1B和8)中公开，被称作为3-(S)-(-)-(1-氨基甲酰基-1，1-二苯基甲基)-1-〔2-(2，3-二氢苯并呋喃-5-基)乙基〕吡咯烷。已指出其可用于治疗尿失禁和肠激惹综合征，其结构式如下：
临床研究表明达非那新的主要代谢产物为以下的3′-羟基衍生物：
与达非那新比较，似乎其代谢产物对毒草碱M3受体的选择性比对M1受体的选择性低6倍，因此代谢产物很可能比达非那新更多地产生不希望的副作用如口干，意识模糊，视力模糊。
已经发现，在系统循环中使达非那新及其药学上能接受的盐释放到较低的胃肠道部份(Lower gastrointestinal tract)(例如持续释放剂型)产生达非那新与代谢产物之间较大的比例。从而增加了达非那新的生物利用度，很可能使不希望的副作用减到最小。这是出人意外的，因为在正常情况下，较慢的释放速率导致较慢释放至肝酶，并使给予的药物得到较大程度的代谢。
因此，根据本发明提供的药物剂型适合于患者的胃肠道给药，包括达非那新或其药学上能接受的盐，和药学上能接受的辅料，稀释剂或载体；其特征在于该剂型适合于将至少10％重量的达非那新或其药学上能接受的盐投递到患者的较低的胃肠道部分。
本发明的剂型可以是持续的或延时的释放形式，并因此在将该剂型施用患者之后的持续时期内或以后，使达非那新或其药学上能接受的盐释放到患者的胃肠道。然而，当将剂型作直肠给药时，可采用常规的直肠剂型。
“较低的胃肠道部分”的意思是指回盲肠接点和直肠之间的胃肠道部分。
“患者”主要是指人类的患者，虽然本发明的制剂可以用于治疗非人类的动物。
优选本发明的剂型适合于将至少25％，更优选地将50％重量的达非那新或其药学上能接受的盐投递到较低的胃肠道部分。
优选服药后4小时，不超过90％重量的达非那新或其药学上能接受的盐被释放；更优选服药后8小时，不超过90％重量的达非那新或其药学上能接受的盐被释放，最优选服药后16小时，不超过90％重量的达非那新或其药学上能接受的盐被释放。
考虑用USP XXll p1578中所描述的装置1体外再造胃肠道内的状况，该装置具有40目(381μm孔径)的篮子，100rpm的转速，溶出介质为37℃时水。因此本发明的持续释放的剂型可以定义为适合于患者胃肠道给药的，包含达非那新或其药学上能接受的盐，和药学上能接受的辅料、稀释剂或载体的药物剂型；其特征在于该剂型适合于USPXXll，p1578中所描述的，具有40目(381μm孔径)蓝子的，转速为100rpm和溶出介质为37℃水的装置1中，在持续时期内释放达非那新或其药学上能接受的盐。
特定的口服剂型包括：
(a)其中达非那新或其药学上能接受的盐被包埋在基质中，通过扩散或侵蚀药物可从该基质中释放出来的那些剂型；
(b)其中达非那新或其药学上能接受的盐存在于微粒核心的那些剂型；
(c)其中有非渗透性涂层的那些剂型，其中所述涂层具有一种孔径，通过孔径释放达非那新或其药学上能接受的盐；
(d)其中有低水溶性涂层的那些剂型；
(e)其中有半透性的涂层的那些剂型；
(f)其中达非那新以离子交换树脂的复合物的形式存在的那些剂型；
(g)在胃肠道的特定位点达非那新从脉冲装置中释放的那些剂型。
显然，本领域的技术人员都明白：达到持续释放的上述剂型可以联合使用：例如含有活性化合物的基质可以形成多微粒子和/或用带孔非渗透性的涂层涂布。
依次论述每个类型：
(a)在基质系统中，优选使活性化合物被包埋或分散到阻碍活性化合物释放到水性环境中的另一种材料的基质中，合适的基质材料包括羟丙基甲基纤维素和羟丙基纤维素。根据本发明的基质的配方优选包含高分子量(即85,000-95,000质量单位)的羟丙基甲基纤维素。
(b)在多微粒核心中，活性化合物存在于含有辅料、稀释剂或载体的许多颗粒中。合适的辅料、稀释剂和载体包括微晶纤维素(优选50μm大小的颗粒)和乳糖(优选具有相当于110目(137.5μm孔径)的颗粒)。典型地，混合成分形成一种湿的材料，这种材料被挤压成球状形成带孔的小球，然后干燥。
(c)非渗透性涂层被应用于含有活性化合物的片剂。“非渗透性”的意思是指在制剂预期的释放期间，活性物质没有穿过涂层发生明显的运转。合适的材料包括成膜多聚物和腊〔例如热塑多聚物如聚(乙烯-乙酸乙烯酯)，聚(氯乙烯)，乙基纤维素和醋酸纤维素〕，涂层厚度优选大于100μm。孔眼可通过钻孔形成，或如果涂层制剂是圆锥形的，可通过切割掉顶部尖端形成孔眼。
(d)低水溶性涂层包括聚合物。这种聚合物的溶解度是pH-依赖性的，例如在pH＜5时实际上不溶解(所以在胃中不发生溶解)，pH＞5时，则水溶。优选的pH敏感的聚合物包括紫胶，邻苯二甲酸酯衍生物(包括邻苯二甲酸醋酸纤维素酯，邻苯二甲酸聚乙酸乙烯酯)，聚丙烯酸衍生物和乙酸乙烯基酯和巴豆酸共聚物。
(e)半透膜涂层允许活性化合物穿过膜或通过膜中充满液体的孔扩散。适合的半透膜涂层材料包括聚合物如纤维素酯或纤维素醚和丙烯酸聚合物。优选的半透膜材料包括乙基纤维素，醋酸纤维素和醋酸纤维素丁酯。
(f)达非那新的树脂酸盐可通过用达非那新的酸加成盐处理阴离子交换树脂小球(例如聚苯乙烯磺酸钠)的方法制备。
(g)脉冲装置能在胃肠道的不同点释放药物。这种作用取决于引发释放的渗透压(见US Patent N°3,952,741)或取决于因pH改变或微生物的降解而引起的聚合物材料的侵蚀。合适的聚合物材料包括果胶〔Rubinstein et al，1991，果胶盐作为结肠的释放系统，ProceedItern.Symp.Control.Rel.Bioact.Mater.〕，异丁烯酸盐-半乳甘露聚糖〔Lehman et al，1991，异丁烯酸盐-半乳甘露聚糖涂层用于结肠特殊药物释放，出处同上〕，含有偶氮键的物质〔Kopeckova etal，1991，生物粘合剂聚合物用于结肠特殊药物的释放，出处同上〕，软骨素〔Sintov et al，1991，用改进的插套管狗模型结肠给予消炎痛，出处同上〕，葡聚糖水凝胶〔Bronsted et al，1993，控制药物释放到结肠的新型水凝胶系统，出处同上〕，异丁烯酸共聚物〔Siefke etal，1993，β-环糊精基质膜用于结肠特殊药物的释放，出处同上〕，和直链淀粉〔Milojevik et al，直链淀粉涂层小球用于结肠特殊药物释放的体内外评价，出处同上〕。胃肠道特殊位点的释放也可用多层片剂〔Gazzaniga et al，1993，时间依赖口服释放系统用于结肠特殊释放，同上〕或胶囊中的水凝胶管塞〔Binns et al，无pH-依赖的PEG水凝胶提供脉冲药物释放的应用。〕达到目的。
优选在本发明的剂型中，达非那新为其氢溴酸盐的形式(当达非那新以离子交换树脂复合物存在时除外)。
优选的口服制剂为高分子量的羟丙基甲基纤维素基质与无水磷酸氢二钙和硬脂酸镁一起制成的主要含有达非那新氢溴酸盐的片剂。该片剂可以用常规方法着色。优选羟丙基纤维素构成片剂重量的56-58％，硬脂酸镁大约构成片重的1％，达非那新氢溴酸盐和无水磷酸氢二钙组成平衡。根据被释放的剂量，达非那新氢溴酸盐的含量范围可为4mg-54mg/片。这样的片剂适合于每天给药一次。
优选本发明的剂型适合于口服给药，而且也适合于直肠给药，直肠栓剂配方可以用常规方法将活性成分分散到硬化油或蜡中来制备。
另一个方面，本发明提供了治疗肠激惹综合征或尿失禁的方法，该方法包括达非那新或其药学上能接受的盐被释放到患者较低的胃肠道部分以满足这种治疗的需要。将本发明的剂型给予需要这种治疗的患者的胃肠道来实施该方法。
通过下面的实施例阐明本发明，这些例子中采用以下材料：
MethocelTM K4M：一种高分子量的羟丙基甲基纤维素，分子量的平均数为89,000。在USP中将其归入2208，2％的水溶液达到正常粘度4000cps。其甲氧基的含量为19-24％，羟丙基的含量为7-12％；
MethocelTM E4M：一种高分子量的羟丙基甲基纤维素，分子量的平均数为93,000。在USP中将其归入2910，2％的水溶液达到正常粘度4000cps。其甲氧基的含量为28-30％，羟丙基的含量为7-12％；
MethocelTM K100LV：一种低分子量的羟丙基甲基纤维素。在USP中被归入2208，2％水溶液有正常粘度100cps。其甲氧基的含量为19-24％，羟丙基的含量为7-12％；
Klucel  EFTM：为羟丙基纤维素，分子量的平均数为60,000；
EthocelTM：为乙基纤维素；
AvicelTM PH101：为微晶纤维素，平均颗粒大小为50μm；
正规乳糖(Lactose regular)：为颗粒大小相当于110目(孔径137.5μm)的乳糖；
Lactose Fast F10TM：为喷雾干燥的乳糖；和
EmcomPressTM：为磷酸氢二钙(无水)。
Aerosil 200：为胶态的无水硅胶。
实施例1(比较用)
快速释放基质片剂
  成分   规格   毫克/单位(理论上)   克/批(实际上)
  达非那新氢溴酸盐   Pfizer   23.810   30.19
  Methocel K4M   Ph Eur   12.000   15.00
  Methocel K100LV Premium   USP   28.000   35.00
  Fast flo Lactose   Ph Eur   134.190   167.70
  硬脂酸镁   Ph Eur   2.000   2.50
  总计   200.000mg
将Methocel K4M，K100LV premium，达非那新和Fast-flolactose在有涡轮推动的混合器中混和10分钟，然后将混合物用30目(500μm孔径)的筛子过筛，再进一步混和10分钟。将硬脂酸镁过30目(500μm孔径)筛，加入上述混合物，进一步混和5分钟，然后将混合物置于安装8mm标准凸圆形冲模的压片机上压制1250片。
实施例2
中速释放基质片
  成分   规格   毫克/单位(理论上)   克/批(实际上)
  达非那新氢溴酸盐   Pfizer   23.810   30.19
  Methocel K4M   Ph Eur   30.000   37.50
  Methocel E4M   Ph Eur   30.000   37.50
  Fast flo Lactose   Ph Eur   114.190   142.70
  硬脂酸镁   Ph Eur   2.000   2.50
  总计   200.000mg
将Methocel K4M，E4M，达非那新和Fast flo lactose在一个合适的混合器中混和10分钟，然后将混合物用30目(500μm孔径)的筛子过筛，再进一步混和10分钟。将硬脂酸镁过30目(500μm孔径)筛，加入上述混合物中，再进一步混和5分钟。然后将混合物置于安装8mm标准的凸圆形冲模的压片机上压制1250片。
实施例3
慢速释放基质片
  成分   规格   毫克/单位(理论上)   克/批(实际上)
  达非那新氢溴酸盐   Pfizer   23.810   30.19
  无水磷酸氢二钙   USP   59.790   74.70
  Methocel  K4M   Ph Eur   114.400   143.00
  硬脂酸镁   Ph Eur   2.000   2.50
  总计   200.000
将Methocel K4M，达非那新和无水磷酸氢二钙在一个有涡轮推动的混合器中混和10分钟，然后将混合物用30目(500μm孔径)的筛子过筛，加入上述混合物中再进一步混和5分钟。然后将混合物置于安装8mm标准的凸圆形冲模的压片机上压制1250片。
实施例4
包衣核心微球胶囊
(a)非包衣微球心的制备
  成分   规格   克/千克(理论上)   克/批(实际上)
  达非那新氢溴酸盐   Pfizer   119.048   119.76
  Avicel PH101   Ph Eur   359.499   359.50
  Lactose Regular   Ph Eur   359.499   359.50
  富马酸   NF   161.954   161.95
  纯化水   Ph Eur   (500.000)   500.0
  总计   1000.000g   1000.71
将Avicel PH101，lactose regular，达非那新和富马酸在一个Apex 2L朝上开口的Y锥形混合器中混和10分钟。然后将混合物用30目(500μm孔径)的筛子过筛，再次混和10分钟。加入纯水形成经得起挤压的湿材。生成的湿材用Nica E 140挤压机(1mm筛孔)挤压，用Caleva成形器团成球状形成微球。然后在温度为50℃的干燥床上干燥1小时以除去过量的湿气。
(b)最后剂型的制备
  成分 规格   毫克/单位(理论上)   克/批(实际上)
  未包衣的达非那新微核 Pfizer   200.000   150.30
  乙基纤维素N-10 NF   17.750   13.32
  Klucel EF NF   7.250   5.44
  乙酸乙酯 NF   237.500   178.2
  异丙醇 NF   237.500   178.1
总计   225.000
注入白色的2号大小的明胶胶囊壳
将乙酸乙酯和异丙醇置于一个合适的容器中搅拌确保彻底混合。向该混合物中加入Klucel EF和乙基纤维素N10，将该溶液搅拌直至完全溶解。将未包衣的微球加入一个流动床包衣器，在入口温度40℃时，将微球用含有羟丙基纤维素EF和乙基纤维素N10的溶液包衣，包衣完后，将微球于床温大约50℃时干燥10分钟，给药前将包过衣的小球装入胶囊壳。
实施例5
离子交换树脂剂型
  成分   克/批
  达非那新氢溴酸盐   60.39
  聚苯乙烯磺酸钠   187.00
  乙二胺四乙酸二钠，二水合物   1.53
  水   2000.00
将乙二胺四乙酸二钠和聚苯乙烯磺酸钠悬浮于水中。然后将悬浮液在搅拌下加热到50℃。向悬浮液中加入达非那新氢溴酸盐，进一步将该悬浮液于50℃搅拌2小时。然后将生成的达非那新聚苯乙烯磺酸盐滤出，洗涤至无溴化物离子。然后将达非那新树脂酸盐在25℃的真空条件下干燥约16小时。
实施例6(比较用)
即时释放胶囊7.5mg
  成分   规格   毫克/单位(理论上)   克/批(实际上)
  达非那新氢溴酸盐   Pfizer   8.929   547.46
  乳糖   Ph Eur   104.453   6267.20
  玉米淀粉   Ph Eur   34.818   2089.10
  Aerosil 200   Ph Eur   0.300   18.00
  硬脂酸镁   Ph Eur   1.500   84.88
  总计   150.000
将1467.2克的乳糖加入所有的达非那新氢溴酸盐中，在一个Aper8L上开口双锥形滚转式混合器中混合20分钟。然后用Fitz-粉碎机(高速前进重锤型)通过1毫米筛粉碎，该粉碎机用剩下的乳糖(4800.0克)洗涤，然后将此洗涤所得乳糖，Aerosil 200和玉米淀粉加到预先混合好的达非那新氢溴酸盐/乳糖中，再在加氏28L双锥形滚转式混合器中混合20分钟。然后将此混合物用Fitz-粉碎机(低速前进刀式)通过1毫米筛粉碎，再用28L混合器进一步混合20分钟。然后加入硬脂酸镁(88.88克)，用28L混合器继续混合5分钟。将最后的混合物用Zanasi胶囊填装机装入2号大小的硬胶囊壳中。
实施例7
体外释放速率的测定
溶出方法
实施例1-4中制剂的溶出是采用一个旋转篮式装置(装置1，USPXXll，p.1578)进行的。将制剂置于篮式装置(40目，381μm孔径)中，以转速100rpm，在37±0.5℃的900ml水中进行。在指定的间隔时间内，每10ml等分试样从溶出介质表面和距容器壁不少于1厘米的篮子顶端之间的中间区域的溶出器中排出，最初流出的7ml溶液弃去，随后接收的溶液转入HPLC小瓶，待后分析。
实施例5的剂型中达非那新的释放速率可根据USPXXll装置4(p.1794)进行测定。采用流速250ml/小时在37℃下用下列pH评定释放速率：
0-1小时pH 1.5；1-2小时pH 2.5；2-3.5小时pH 4.5；3.5-5小时pH 6.9；5-24小时pH 7.2。
实施例6剂型的溶出用一个旋转的篮式装置(装置1，USPXXll，p 1578)进行。将制剂置于篮子(40目，孔径381μm)中，以转速100rpm，在37℃±0.5℃的900ml的水中进行。在指定的间隔时间内，每20ml等分溶出的介质从溶出介质的表面和距容器壁不少于1厘米的篮顶之间的中间区域排出。将溶出物过滤(0.45μm，Acrodisc)，初滤液5ml弃去，将随后的5ml滤液在HPLC分析前用1∶1(v/v)水/甲醇稀释到25ml。
分析
对实施例1-5的剂型，用BDS Hypersil C-18柱进行HPLC测定，所用的流动相为pH 3.5的0.03M的正磷酸二氢钾水/甲醇液(1000∶800v/v)，在37℃时流速为1.5ml/分，样品量为20μl。通过激发波长288nm(狭缝宽18nm)和发射波长320nm(狭缝宽18nm)的荧光检测。
对实施例6的剂型用Novapack C18柱进行HPLC测定。流动相为含有pH6的0.2％v/v三乙胺的0.01M的乙酸钠水溶液/甲醇/乙腈(45∶54∶1，v/v/v)，流速1.0ml/分。样品量50μl。在230nm处用紫外光谱检测。
结果
实施例1的剂型(比较用)
时间(小时)    ％释放(范围)
1             65(52-81)
2             80(72-92)
4             91(87-96)
实施例2的剂型
时间(小时)    ％释放(范围)
1             41(38-46)
4             77(73-81)
8             95(94-96)
实施例3的剂型
时间(小时)    ％释放(范围)
1             6(5-7)
8             42(36-44)
16            67(59-70)
实施例4的剂型
时间(小时)    ％释放(范围)
1             11(9-15)
4             58(50-70)
8             98(95-103)
实施例5的剂型
时间(小时)    ％释放(范围)
1             11(10-12)
2             25(24-27)
6             55(51-59)
12            79(77-82)
18            90(89-91)
24            94(93-95)
实施例6的剂型(比较用)
时间(小时)    ％释放
0.25          94
0.5           99
0.75          98
实施例8
临床药物动力学研究
假定持续释放剂型与即时释放剂型进行比较，则可采用四种途径，多剂量交叉研究法来研究达非那新及其3′-羟基代谢物的生物利用度。13例正常男性接受实施例1-3制剂6天(od each for 6days？)，以及每天3次接受实施例6制剂。每个研究周期的给药的最后一天的24小时内接受药物和代谢物血浆样品的测定，从而得到药物和代谢物的药物动力学参数(24小时内的浓度-时间曲线，AUC，最大浓度，给药后24小时的浓度)。下表显示持续释放剂型对即时释放胶囊的达非那新和代谢物的AUC值(AUC达非那新∶AUC代谢物)之比及达非那新(Frel达非那新)和代谢物(Frel代谢物)的相对生物利用度。
达非那新和代谢物的AUC值之比和即时释放胶囊中
达非那新和代谢物的相对生物利用度(Frel)
  制剂   实施例6(即时释放)   实施例1   实施例2   实施例3
  AUCdar/AUCmet的比率   0.66   0.58   0.82   1.03
  Frel达非那新   na   0.88   1.10   1.17
  Frel代谢物   na   0.98   0.82   0.70
na＝不适用
这些数据表明：根据本发明当达非那新以持续释放剂型给药时，达非那新较代谢物的相对生物利用度为高。

Claims (18)

1.一种适于口服给药的药物剂型，它包含达非那新或其药学上能接受的盐和药学上能接受的辅药、稀释剂或载体，其中在所述剂型中的达非那新或其药学上能接受的盐是包埋于基质中，其通过扩散或侵蚀作用而从中释放；
其特征在于该剂型适合于将至少10％重量的达非那新或其药学上能接受的盐输送到患者在回盲肠接点和直肠之间的胃肠道部分。
2.根据权利要求1的适于口服给药的药物剂型，它包含达非那新或其药学上能接受的盐和药学上能接受的辅药、稀释剂或载体，其中在所述剂型中的达非那新或其药学上能接受的盐是存在于多微粒的芯中；
其特征在于该剂型适合于将至少10％重量的达非那新或其药学上能接受的盐输送到患者在回盲肠接点和直肠之间的胃肠道部分。
3.根据权利要求1的适于口服给药的药物剂型，它包含达非那新或其药学上能接受的盐和药学上能接受的辅药、稀释剂或载体，其中在所述剂型中的达非那新或其药学上能接受的盐是通过低水溶性包衣释放；
其特征在于该剂型适合于将至少10％重量的达非那新或其药学上能接受的盐输送到患者在回盲肠接点和直肠之间的胃肠道部分。
4.根据权利要求1的适于口服给药的药物剂型，它包含达非那新或其药学上能接受的盐和药学上能接受的辅药、稀释剂或载体，其中在所述剂型中的达非那新或其药学上能接受的盐是通过半透性包衣释放；
其特征在于该剂型适合于将至少10％重量的达非那新或其药学上能接受的盐输送到患者在回盲肠接点和直肠之间的胃肠道部分。
5.一种适于口服给药的药物剂型，它包含达非那新或其药学上能接受的盐和药学上能接受的辅药、稀释剂或载体，其中在所述剂型中的达非那新或其药学上能接受的盐是通过非渗透性包衣上提供的小孔释放；
其特征在于该剂型适合于将至少10％重量的达非那新或其药学上能接受的盐输送到患者在回盲肠接点和直肠之间的胃肠道部分。
6.一种适于口服给药的药物剂型，它包含达非那新或其药学上能接受的盐和药学上能接受的辅药、稀释剂或载体，其中在所述剂型中的达非那新或其药学上能接受的盐在所述剂型中是通过用达非那新的酸加成盐处理阴离子交换树脂小球制备的；
其特征在于该剂型适合于将至少10％重量的达非那新或其药学上能接受的盐输送到患者在回盲肠接点和直肠之间的胃肠道部分。
7.一种适于口服给药的药物剂型，它包含达非那新或其药学上能接受的盐和药学上能接受的辅药、稀释剂或载体，其中在所述剂型中的达非那新或其药学上能接受的盐是通过脉动装置在胃肠道的特定点释放；
其特征在于该剂型适合于将至少10％重量的达非那新或其药学上能接受的盐输送到患者在回盲肠接点和直肠之间的胃肠道部分。
8.根据权利要求1-7任一项所述的剂型，该剂型适合于将至少50％重量的达非那新或其药学上能接受的盐输送到在回盲肠接点和直肠之间的胃肠道部分。
9.根据权利要求1-7任一项所述的剂型，其中不超过90％重量的达非那新或其药学上能接受的盐于给药后8小时被释放至胃肠道。
10.根据权利要求1-7任一项所述的剂型，其中不超过90％重量的达非那新或其药学上能接受的盐于给药后16小时被释放至胃肠道。
11.根据权利要求1-10任何一项所述的剂型，其中达非那新是其氢溴酸盐的形式。
12.根据权利要求1-7任一项的药物剂型，所述剂型是片剂，其基本上由在高分子量的羟丙基甲基纤维素基质中的达非那新氢溴酸盐与无水磷酸氢二钙和硬脂酸镁组成。
13.根据权利要求12的药物剂型，其中所述羟丙基甲基纤维素的分子量为85000-95000质量单位。
14.根据权利要求12的药物剂型，其中所述羟丙基甲基纤维素的重量占所述剂型重量的56-58％。
15.根据权利要求12的药物剂型，其中所述硬脂酸镁的重量占所述剂型重量的1％。
16.根据权利要求12-15任一项的药物剂型，其中所述片剂中达非那新氢溴酸盐的含量范围为4-54mg/片。
17.根据权利要求12-15任一项的药物剂型，其还另外具有彩色包衣。
18.根据权利要求1的剂型，从中通过扩散释出达非那新或其药学上能接受的盐，其中所述的基质材料是分子量为85000-95000质量单位的羟丙基甲基纤维素。
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