CN1178662C - 2-甲基-噻吩并-苯并二氮杂�口服制剂 - Google Patents
2-甲基-噻吩并-苯并二氮杂�口服制剂 Download PDFInfo
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Abstract
本发明提供特别适于药用的奥氮平固体口服制剂和制备该制剂的方法。
Description
本发明提供改进的特别适于药用的2-甲基-4-(4-甲基-1-哌嗪基)-10H-噻吩并〔2，3-b〕〔1，5〕苯并二氮杂(下文中称为奥氮平(Olanzapine))片剂，和其制备方法。
奥氮平在精神病的治疗中极具前景并且正被广泛地用于此目的。奥氮平的某些片剂是已知的，如美国专利5,229,382中所述。但是，由于奥氮平的湿敏性，亚稳性，现有的奥氮平片剂不合需要的变色倾向，和奥氮平的意想不到的有效性，需要改进其口服制剂。
本申请要求的发明提供特别适于药用的奥氮平固体口服制剂，该制剂包括将奥氮平与填充剂、粘合剂、崩解剂、为满足脆性的干粘合剂，和润滑剂直接混合而成；其中固体口服制剂可以用选自下列的聚合物包衣：羟丙甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮、异丁烯酸二甲氨基乙酯-丙烯酸甲酯共聚物、丙烯酸乙酯-异丁烯酸甲酯共聚物，甲基纤维素，和乙基纤维素。
特别优选的聚合物包衣不含有聚乙二醇。
本发明提供特别适于药用的，稳定的固体口服奥氮平制剂的制备方法，该制剂具有选自下列的聚合物包衣：羟丙甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮、异丁烯酸二甲氨基乙酯-丙烯酸甲酯(dimethylaminoethylmethacrylatemethylacrylate acid ester)共聚物、丙烯酸乙酯-异丁烯酸甲酯(ethylacrylate-methylmethacrylate)共聚物，甲基纤维素；和乙基纤维素。该制剂的制备方法包括使用具有流床干燥的高速剪切湿法成粒法。
奥氮平，在用于治疗精神病患者方面显示很有前途的活性的有效化合物，具有亚稳性倾向，发生药用不合需要的变色作用，因此需要小心确保其已制成的固体制剂的均一性。
申请人已经发现当奥氮平与某些赋形剂包括粉状配料接触时会发生不合需要的变色作用。而且，变色作用会因周围空气状况，高温和潮湿环境而加重。
虽然变色现象不会导致相关物质总量的增加，但是褐变和斑点的出现一般被认为不具药用商业意义了。而且，当给精神病患者服用片剂量，脱色便成为特别的干扰，因为患者特别容易受其药品外观变化的干扰。
申请人已经发现用选自下列的聚合物包衣的固体口服制剂：羟丙甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮、异丁烯酸二甲氨基乙酯-丙烯酸甲酯共聚物、丙烯酸乙酯-异丁烯酸甲酯共聚物，甲基纤维素和乙基纤维素，用这些聚合物包衣和内包衣可得到均一的物理性能稳定的并能有效阻止不合需要的变色现象的制剂。特别优选的剂型是片剂；而且，颗粒剂等等也能满足要求。
最优选的聚合物包衣是羟丙甲基纤维素、羟丙基纤维素、甲基纤维素和乙基纤维素。特别优选的聚合物包衣是羟丙甲基纤维素。
特别优选的制剂含有最稳定的无水形式的奥氮平，此处是指形式II；其它形式的奥氮平也可以。形式II(奥氮平)具有典型的由下列面间距代表的粉末X-射线衍射图谱：
d
10.2689
8.577
7.4721
7.125
6.1459
6.071
5.4849
5.2181
5.1251
4.9874
4.7665
4.7158
4.4787
4.3307
4.2294
4.141
3.9873
d
3.7206
3.5645
3.5366
3.3828
3.2516
3.134
3.0848
3.0638
3.0111
2.8739
2.8102
2.7217
2.6432
2.6007
形式II X-射线衍射图的典型实例是下列其中d代表面间距和I/I1代表典型相对密度的图谱：
d I/I1
10.2689 100.00
8.577 7.96
7.4721 1.41
7.125 6.50
6.1459 3.12
6.071 5.12
5.4849 0.52
5.2181 6.86
5.1251 2.47
4.9874 7.41
4.7665 4.03
4.7158 6.80
4.4787 14.72
4.3307 1.48
4.2294 23.19
4.141 11.28
d I/I1
3.9873 9.01
3.7206 14.04
3.5645 2.27
3.5366 4.85
3.3828 3.47
3.2516 1.25
3.134 0.81
3.0848 0.45
3.0638 1.34
3.0111 3.51
2.8739 0.79
2.8102 1.47
2.7217 0.20
2.6432 1.26
2.6007 0.77
此处的X-射线衍射图是用具有波长λ＝1.541A的铜Kα辐射源的Siemens D5000粉末X-射线衍射仪测定得到的。
本发明的制剂优选地含有基本上纯的形式II为活性成分。
此处所用的“基本上纯的”是指与形式II结合的不合需要的多晶型形式的奥氮平(此处称为“不合需要形式”)少于约5％，优选少于2％不合需要形式，更优选少于1％不合需要形式。而且“基本纯的”形式II含有少于约0.5％的相关物质，其中“相关物质”是指不合需要的化学杂质或残留的溶剂或水。特别地，“基本纯的”形式II优选含有少于约0.05％的乙腈，更优选地含有少于约0.005％的乙腈。此外，形式II优选含有少于0.5％的结合水。
此处所用术语“哺乳动物”是指高级脊椎动物哺乳纲动物。术语“哺乳动物”包括，但不限于人类。此处所用术语“治疗”包括所述疾病的预防或当疾病一旦形成而对其的改善或消除。
形式II是已知最稳定的奥氮平无水形式，因此对最适于药用的制剂的，商业开发很重要。在某些溶剂和赋形剂存在下，奥氮平可形成不合需要的晶体形式。因此，在制备本发明组合物时，最满意的是用不需要溶解奥氮平的方法来制备该制剂。例如，想要的形式II可以通过与二氯甲烷接触转化成不合需要的多晶型形式。此外，例如，聚乙二醇与奥氮平物质接触，特别是在潮湿环境中会导致不合需要的变色。
申请人相信在制备固体口服制剂中使用干燥粘合剂直接压制法或干法成粒法将极有可能出现极差的均一性。由于奥氮平的有效性，良好的均一性是必须的。根据本发明，申请人已经发现具有流床干燥的高速剪切含水湿法成粒是最有效的制备特别适于药用的，稳定的奥氮平口服制剂的方法。
未包衣的片剂储存在琥珀色的，高密度聚乙烯瓶中(约23℃和40％的相对湿度)，24个月后未见变色迹象；但是，如果瓶子是开口的即片剂暴露于空气中则5天后出现变色。
新的固体口服制剂是用羟丙甲基纤维素作内包衣并用白色包衣制备而成的。新的制剂储存在开口器皿中于40℃、60℃、40℃/75％ RH，室温和75％ RH，或室温与85％ RH中，90天后未出现变色。没有聚乙二醇的羟丙甲基纤维素包衣优选能确保在片剂表面不变色的。它可以在提供可接受的印迹介质的白色包衣和产品的颜色修饰之间提供一个有效的屏障。羟丙甲基纤维素包衣可提供足够的屏障以阻止由于白色包衣中的聚乙二醇引起的变色。其它的含有另外的增塑剂的白色膜包衣配方也可使用；但是，没有材料在所有试验条件下储存90天后能阻止变色。因此，羟丙甲基纤维素包衣或内包衣在特别适于药用的奥氮平固体口服制剂中是意想不到的重要成分。
选择稀释剂或填充剂以增加片剂的大小。技术人员可用已知方法选择填充剂以达到可满足药用的硬度、脆性、和崩解时间。选择填充剂以得到既满足患者需要又与常规的规章路线一致的片剂。
特别优选的稀释剂或填充剂是乳糖。各种形式的乳糖包括无水的、含水的、和喷雾干燥形式均适用于这种制剂。最合需要的乳糖可根据所需要的溶解性、均一性、硬度、脆性和崩解时间来选择。本领域技术人员可知道硬度、脆性和崩解时间的常规要求并可用已知技术调节稀释剂或填充剂以达到所需物理特性。
制剂配方应包括用于成粒步骤中的粘合剂。技术人员可根据可接受的粘度，和所需的水合作用选择适宜的粘合剂。羟丙基纤维素是特别优选的用于成粒步骤中的粘合剂。羟丙基纤维素可根据具体尺寸变化。细的羟丙基纤维素是大多数权利要求制剂中特别优选的。
合需要的配方应包括成粒中和滚动粉末中使用的以促进崩解过程的崩解剂。可用的崩解剂有多种级别，级别的选择根据可接受的批料变化而定。特别优选的崩解剂是交联聚乙烯吡咯酮。细的交联聚乙烯吡咯酮在各批料间特别能满足需要。
技术人员可用已知方法选择适宜的干粘合剂。该粘合剂的选择应能确保达到所需脆性。特别优选地，干粘合剂是微晶纤维素；但是，也可选择其它适宜的干粘合剂。这种微晶纤维素可以是粒状的。
技术人员可以选择适宜的润滑剂以防止药片与压片器的粘联和聚集。优选的润滑剂是硬脂酸镁。
在羟丙甲基纤维素层上，技术人员可以容易地选择使用适宜的水分散膜包衣(颜料混合物)。典型地，着色混合物是分散在水中的干粘合剂并用作固体制剂的水分散膜包衣。着色混合物的典型实例是由羟丙甲基纤维素、聚乙二醇、吐温80，和钛白组成的混合物。
技术人员熟知的各种食用墨(ink)可用作已完成制剂的着色。例如，典型的食用颜料是由虫胶、乙醇、异丙醇、正丁醇、丙二醇、氢氧化铵，和FD & C蓝组成的。
最优选的固体制剂是由羟丙甲基纤维素内包衣，由颜料层包衣的，和用食用墨压印的制剂。固体制剂如果需要，可以用标准方法例如用巴西棕榈蜡抛光法抛光。
奥氮平在很宽的剂量范围内有效，服用的准确剂量取决于所要治疗的疾病。例如，在对成人的治疗中，每天使用的剂量为约0.25至50mg，优选1至30mg，最优选1至20mg。一天一剂使足够了，但也可以分次服用。对于中枢神经系统疾病的治疗，适宜的剂量范围是1至30mg，优选1至20mg每天。放射性标记的2-甲基-4-(4-甲基-1-哌嗪基)-10H-噻吩并-〔2，3-b〕〔1，5〕苯并二氮杂形式II，可以在唾液中被检测，因此该化合物在病人中可有效地监测以鉴定其适应性。
本发明优选的制剂是含有约1至约20mg奥氮平为活性成分的固体口服制剂，其中该固体口服制剂用羟丙甲基纤维素包衣。特别优选的口服制剂是含有1至20mg无水的形式II的奥氮平为有效量的活性成分，该固体口服制剂用羟丙甲基纤维素包衣。
优选的制剂含有1至3％w/w奥氮平；69.5至87.5％w/w乳糖；3.5至4.5％w/w羟丙基纤维素；4至6％w/w交联聚乙烯吡咯酮；9至11％w/w微晶纤维素；和0.25至1％硬脂酸镁。优选的，其中每片所含奥氮平的剂量为1、2.5、5、7.5、10、15和20mg。
本发明的固体口服制剂被一种聚合物包衣，该聚合物选自羟丙甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮、异丁烯酸二甲氨基乙酯-丙烯酸甲酯共聚物，丙烯酸乙酯-异丁烯酸甲酯共聚物，甲基纤维素，和乙基纤维素，其中该聚合物包衣不含聚乙二醇。
更优选地，固体口服制剂含有包装材料以保护制剂免受潮湿和光的损害。例如，包装材料包括琥珀色的聚乙烯瓶，琥珀色的玻璃瓶，和其它能阻止光通过的容器。更优选地，包装包括除湿包装。容器可以用铝箔泡密封以达到所需的保护并保持产品的稳定性。
对装在具有除湿包装的琥珀色瓶中的羟丙甲基包衣的片剂储存在粗糙的，40℃/75％RH条件下6个月的研究表明其具有0.4％至约1.2％相关物质总量增加的药用稳定性。
本发明所用的材料可以商购或用本领域已知方法制备。奥氮平可以用Chakrabarti在美国专利5,229,382(`382)中所述的方法制备，在此将该专利全文引作参考。最合需要的是制备含有基本上纯的晶体形式II的速溶制剂。基本上纯的奥氮平晶体形式II可用下文中制备部分所述的技术制备。
化合物鉴定方法包括，例如，粉末X-射线图谱分析，热量分析法(TGA)，差式扫描量热法(DSC)，测定水的滴定分析法，和1H-NMR分析溶剂含量。
用13C交叉极化/幻角离心(CP/MAS)NMR研究制剂以确保形式II多晶型物是基本上纯的。光谱是用操作时碳频率为100,577MHz的VarianVnity 400MHz的波谱仪得到的，该波谱仪装有完全固体配件和Varian5mm或7mm VT CP/MAS探针。最适合奥氮平形式II的测定条件如下：90℃质子r.f.脉冲4.5ms，接触时间1.1ms，脉冲重复时间5s，MSA频率7.0KHz，频谱宽度50KHz，捕获时间50ms。化学位移以通过样品置换的六甲基苯的CH3(d＝17.3ppm)为参考。需要明确的是基本上纯的形式II多晶型物存在于该申请所要求的全部制剂方法中。因此，本发明制剂提供在特别适于药用的制剂中不会发生不合需要的多晶型转换的基本上纯的奥氮平形式II。
本发明还涉及本发明的固体制剂在制备用于治疗下列疾病：精神病、精神分裂症、精神分裂症样疾病、轻微焦虑症、胃肠机能紊乱，和急性躁狂的药物中的用途。
下列实施例是为了说明本发明但不能理解为是对本发明权利要求的限制。
制备1
工业纯奥氮平
中间体1
在适宜的三颈瓶中加入下列物质：
二甲基亚砜(分析纯) ： 6体积份
中间体1 ： 75g
N-甲基哌嗪(试剂) ： 6当量
中间体1可以用本领域技术人员已知的方法制备。例如，中间体1可以用’382专利所述方法制备。加入一个液面下氮气喷射系统以除去反应中生成的氨。将反应加热至120℃并在整个反应过程中保持该温度。将反应液进行HPLC直至剩余的未反应的中间体1≤5％。当反应完全后，将混合物缓慢冷却至20℃(约2小时)。将反应混合物转入适宜的三颈圆底烧瓶中并置于水浴中。搅动下在该溶液中加入10体积份试剂纯甲醇并将反应物在20℃搅拌30分钟。在30分钟内缓慢加入3体积份的水。将反应浆液冷却至0至5℃并搅拌30分钟。将产物过滤并用冷甲醇洗涤湿饼。将湿饼在真空45℃干燥过夜。产物与工业纯奥氮平一致。
产率： 76.7％； 效价： 98.1％。
制备2
形式II
将270g工业纯2-甲基-4-(4-甲基-1-哌嗪基)-10H-噻吩并-〔2，3-b〕〔1，5〕苯并二氮杂悬浮于无水乙酸乙酯中(2.7L)。将混合物加热至76℃并在76℃保持30分钟。将混合物冷却至25℃。将所得产物用真空过滤分离。产物用粉末X-射线分析，与形式II一致。
收率：197g。
上述制备形式II的方法得到特别适于药用的具有效价≥97％，相关物质总量＜0.5％和分离收率＞73％的产品。
实施例1
将一部分羟丙基纤维素溶解在纯水中形成用于成粒的溶液。将余下的特细号的羟丙基纤维素(总量为最终片剂重量的4.0％w/w)，与奥氮平(1.18％w/w)，乳糖(79.32％w/w)和一部分交联聚乙烯吡咯酮(5％w/w)在高速剪切成粒机中混合。所有成分在加入前均过筛并将干粘合剂加入成粒机中。将此混合物在高速剪切成粒机中用羟丙基纤维素溶液成粒。将湿颗粒用标准方法过筛。将湿颗粒在流床干燥器上干燥并过筛。然后将材料加入滚动箱混合器中。
将含有微晶纤维素(粒状)(10％w/w)，硬脂酸镁(0.5％w/w)，和余下的交联聚乙烯吡咯酮加入到过筛的颗粒中。将混合物粘合并在压片机上用适宜的工具压片。
内包衣：
将羟丙甲基纤维素(10％w/w)与纯水混合以形成溶液。将片芯分成大约相等的部分并用羟丙甲基纤维素溶液喷包衣。操作是在多孔包衣盘上进行的。
片芯的包衣：
将白色颜料混合物(羟丙甲基纤维素、聚乙烯二醇、吐温80，和钛白)与纯水混合形成包衣悬浮液。用前述方法将内包衣片分成大约相等的部分并用包衣悬浮液喷洒包衣。操作是在多孔包衣盘上进行的。
将包衣的片轻轻涂上巴西棕榈蜡并印上适宜的标志。
实施例2
用下列成分重量与实施例1基本相同的方法得到特别适于药用的每片分别含有1、2.5、5、7.5，和10mg奥氮平的片剂：
每片1mg奥氮平
| 成分名称 | 量(mg/片) |
| 活性成分奥氮平 | 1.0 |
| 其它成分乳糖羟丙基纤维素交联聚乙烯吡咯酮微晶纤维素硬脂酸镁内包衣羟丙甲基纤维素包衣白色颜料混合物抛光巴西棕榈蜡印迹食用蓝 | 67.433.404.258.500.421.703.47痕量 |
每片2.5mg奥氮平
| 成分名称 | 量(mg/片) |
| 活性成分奥氮平 | 2.5 |
| 其它成分乳糖羟丙基纤维素交联聚乙烯吡咯酮微晶纤维素硬脂酸镁内包衣羟丙甲基纤维素包衣白色颜料混合物抛光巴西棕榈蜡印迹食用蓝 | 102.155.206.5013.000.652.605.30痕量痕量 |
每片5mg奥氮平
| 成分名称 | 量(mg/片) |
| 活性成分奥氮平 | 5.0 |
| 其它成分乳糖羟丙基纤维素交联聚乙烯吡咯酮微晶纤维素硬脂酸镁内包衣羟丙甲基纤维素包衣白色颜料混合物抛光巴西棕榈蜡印迹食用蓝 | 156.008.0010.0020.001.004.008.16痕量痕量 |
每片7.5mg奥氮平
| 成分名称 | 量(mg/片) |
| 活性成分奥氮平 | 7.50 |
| 其它成分乳糖羟丙基纤维素交联聚乙烯吡咯酮微晶纤维素硬脂酸镁内包衣羟丙甲基纤维素包衣白色颜料混合物抛光巴西棕榈蜡印迹食用蓝 | 234.0012.0015.0030.001.506.0012.24痕量痕量 |
每片10.0mg奥氮平
| 成分名称 | 量(mg/片) |
| 活性成分奥氮平 | 10.00 |
| 其它成分乳糖羟丙基纤维素交联聚乙烯吡咯酮微晶纤维素硬脂酸镁内包衣羟丙甲基纤维素包衣白色颜料混合物抛光巴西棕榈蜡印迹食用蓝 | 312.0016.0020.0040.002.008.0016.32痕量痕量 |
Claims (16)
1.固体口服制剂，包括与填充剂直接混合的作为活性成分的奥氮平；粘合剂、崩解剂、干粘合剂，和润滑剂；其中固体口服制剂用选自下列的聚合物包衣：羟丙甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮、异丁烯酸二甲氨基乙酯-丙烯酸甲酯共聚物、丙烯酸乙酯-异丁烯酸甲酯共聚物，甲基纤维素，和乙基纤维素，其中该聚合物包衣不含聚乙二醇。
2.按照权利要求1的制剂，其中聚合物包衣选自羟丙甲基纤维素、羟丙基纤维素、甲基纤维素，和乙基纤维素。
3.按照权利要求2的制剂，其中聚合物包衣是羟丙甲基纤维素。
4.按照权利要求1至3中任一项的制剂，其中填充剂是乳糖。
5.按照权利要求1至3中任一项的制剂，其中粘合剂是羟丙基纤维素并且崩解剂是交联聚乙烯吡咯酮。
6.按照权利要求1的制剂，其中干粘合剂是微晶纤维素。
7.按照权利要求1的制剂，其中润滑剂是硬脂酸镁。
8.按照权利要求1的制剂，其中固体制剂用食用墨加标记。
9.按照权利要求1的制剂，其中制剂含有1至3％w/w奥氮平；69.5至87.5％w/w乳糖；3.5至4.5％w/w羟丙基纤维素；4至6％w/w交联聚乙烯吡咯酮；9至11％w/w微晶纤维素；和0.25至1％硬脂酸镁。
10.按照权利要求1的制剂，其中固体制剂为片剂。
11.按照权利要求10的制剂，其中每片所含奥氮平的剂量为1、2.5、5、7.5、10、15和20mg。
12.按照权利要求1的制剂，其中奥氮平是基本上纯的具有下列面间距表示的典型的粉末X-射线衍射图谱的形式II多晶型物；
d(A)
10.2689
8.577
7.4721
7.125
6.1459
6.071
5.4849
5.2181
5.1251
4.9874
4.7665
4.7158
4.4787
4.3307
4.2294
4.141
3.9873
3.7206
3.5645
3.5366
3.3828
3.2516
3.134
3.0848
3.0638
3.0111
2.8739
2.8102
2.7217
2.6432
2.6007
13.制备稳定的特别适于药用的固体口服制剂的方法，其中口服制剂含有奥氮平为活性成分和选自下列的聚合物包衣：羟丙甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮、异丁烯酸二甲氨基乙酯-丙烯酸甲酯共聚物、丙烯酸乙酯-异丁烯酸甲酯共聚物，甲基纤维素，和乙基纤维素，其中该聚合物包衣不含聚乙二醇，该方法包括具有流床干燥的高速剪切含水湿法成粒法。
14.按照权利要求13的方法，其中奥氮平是基本上纯的具有下列面间距表示的典型的粉末X-射线衍射图谱的形式II多晶型物：
d(A)
10.2689
8.577
7.4721
7.125
6.1459
6.071
5.4849
5.2181
5.1251
4.9874
4.7665
4.7158
4.4787
4.3307
4.2294
4.141
3.9873
3.706
3.5645
3.5366
3.3828
3.2516
3.134
3.0848
3.0638
3.0111
2.8739
2.8102
2.7217
2.6432
2.6007
15.按照权利要求1的固体制剂在制备用于治疗下列疾病：精神病、精神分裂症、精神分裂症样疾病、轻微焦虑症、胃肠机能紊乱，和急性躁狂的药物中的用途。
16.一种包含奥氮平的固体口服制剂，其中该制剂被一种聚合物包衣，该聚合物选自羟丙甲基纤维素、羟乙基纤维素、甲基羟乙基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮、异丁烯酸二甲氨基乙酯-丙烯酸甲酯共聚物，丙烯酸乙酯-异丁烯酸甲酯共聚物，甲基纤维素，和乙基纤维素，其中该聚合物包衣不含聚乙二醇。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41046595A | 1995-03-24 | 1995-03-24 | |
| US08/410,465 | 1995-03-24 |
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| Publication Number | Publication Date |
|---|---|
| CN1179102A CN1179102A (zh) | 1998-04-15 |
| CN1178662C true CN1178662C (zh) | 2004-12-08 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2018192590A3 (zh) * | 2017-04-21 | 2018-12-20 | 浙江京新药业股份有限公司 | 一种稳定的口服药物组合物及其制备方法 |
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