CN1248690C - 一种治疗心血管疾病含盐酸雷诺嗪的口服制剂 - Google Patents
一种治疗心血管疾病含盐酸雷诺嗪的口服制剂 Download PDFInfo
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Abstract
一种治疗心血管疾病含盐酸雷诺嗪的口服制剂，它以盐酸雷诺嗪为原料，包括一种或多种可药用的赋形剂。其制备方法是将盐酸雷诺嗪和可选择的稀释剂、粘合剂、崩解剂、抗粘着剂和润滑剂，加适量的润湿剂制成软材，过筛制成湿颗粒，将湿颗粒干燥，过筛整粒，将其制成口服制剂。其中盐酸雷诺嗪占制剂重量百分比为50～95%，该制剂适于每天给予3-4次，每次1-2个制剂单位，以用于控制人体血浆中雷诺嗪的浓度，从而使雷诺嗪发挥其应有的治疗作用。
Description
技术领域：
本发明涉及治疗心血管疾病含盐酸雷诺嗪的口服制剂及制备方法。服用该制剂使人体血浆中的雷诺嗪维持在治疗水平。
背景技术：
雷诺嗪即(±)-N-(2，6-二甲基苯基)-4-[2-羟基-3-(2-甲氧基苯氧基)-丙基]-1-哌嗪乙酰胺最早为美国专利US4567264公开，它说明了雷诺嗪及其药学上可接受的盐有优越的医疗功能，公开了它用于治疗包括心率不齐、变异性和运动性心绞痛、以及心肌梗塞等心血管疾病。
美国专利US5506229公开了雷诺嗪极其在药学上可接受的盐用于治疗受到物理和化学损伤的组织的用途，包括心麻痹、心脏和骨骼肌或脑组织的缺氧或再灌注损伤，还公开了用于移植的用途。公开了常规口服和非肠道制剂，包括控制释放制剂。其中该专利实施例7C和7D分别描述了包衣片剂和胶囊形式的控制释放制剂，后者包括雷诺嗪微球和包覆有控制释放聚合物的微晶纤维素。
中国专利CN1045884C，公开了雷诺嗪的高剂量口服制剂，该制剂适用仍为液体的含有有效量的选自麦考酚酸吗啉代乙酯、麦考酚酸和雷诺嗪作为明胶硬胶囊或软胶囊的填充溶液。
中国专利CN1354665A公开了一种雷诺嗪持续释放制剂，该制剂的主要成分使雷诺嗪的紧密混合物和PH值依赖性粘合剂——丙烯酸树脂，其抑制雷诺嗪在胃中释放，而促进雷诺嗪在肠道中释放。该制剂适于一天1～2次，每次2片；该专利实施例4中表明盐酸雷诺嗪400mg，每天3次，治疗慢性稳定性心绞痛是有效的，而且人体对该制剂的血药峰浓度是耐受的，而且提高剂量和用药频率后其效果更明显。该专利实施例5健康志愿者单次给药结果表明，即时释放制剂的AUC0～24(6530ng小时/ml)大于持续释放的A(AUC0-245640ng小时/ml)、B(AUC0-245280ng小时/ml)、C(AUC0-245820ng小时/ml)制剂，表明即时释放制剂的生物利用度优于持续释放制剂。该专利制剂的原料药是雷诺嗪游离碱，而该专利未能提供确切的数据证明pH值依赖性粘合剂促进雷诺嗪游离碱在肠道中释放，而且其制剂的AUC0～24明显小于速释制剂，提示很可能释放不完全导致人体吸收不完全。由于丙烯酸树脂和雷诺嗪游离碱紧密混合，前者在肠液中可溶胀，而雷诺嗪游离碱在肠液中微溶至几乎不溶，因此该粘合剂会阻止雷诺嗪游离碱的完全释放从而导致人体吸收不完全。
因此有必要制备一种能完全释放以充分发挥雷诺嗪的在人体内应有治疗作用的制剂。
发明内容：
本发明提供一种治疗心血管疾病含盐酸雷诺嗪的口服制剂，该制剂含50～95wt％的盐酸雷诺嗪。该制剂具有优良的润湿、崩解性能，能快速而完全地释放药物，充分发挥活性成分雷诺嗪的治疗作用。另一方面，本发明还提供盐酸雷诺嗪的口服制剂的制备方法，该制剂适于患者每天服用3～4次，每次1～2个制剂单位，以治疗患有心绞痛或其它冠状动脉疾病。
本发明包括该制剂治疗心率不齐、变异性和运动性心绞痛、以及心肌梗塞的心血管疾病的服用方法，制剂单位中含有盐酸雷诺嗪量，以使血浆中雷诺嗪水平维持至少24小时，其中该剂量是按24小时内分三次或四次给予。
“盐酸雷诺嗪”是化合物(±)-N-(2，6-二甲基苯基)-4-[2-羟基-3-(2-甲氧基苯氧基)-丙基]-1-哌嗪乙酰胺二盐酸盐的半水合物。除非另有说明，本发明说明书和实施例中盐酸雷诺嗪的重量和浓度是指雷诺嗪的二盐酸盐。
“持续释放制剂”，是指按照中国专利CN1354665A所公开的技术，即通过pH值依赖性粘合剂来控制药物的释放，使药物在大约6小时或更长时间内在胃和肠道中缓慢且连续溶解和吸收的制剂。
“口服制剂”是指在胃肠内崩解完全，释放活性成分的制剂，该制剂适于患者方便地每天服用3～4次，每次1～2个制剂单位，以使活性成分在患者体内发挥其应有治疗作用。
“转化系数”，是指盐酸雷诺嗪和雷诺嗪游离碱的转化关系，当用碱和二盐酸盐两种方式表示剂量，二盐酸盐转化为碱的转化系数为0.854，表示的意义是1g的盐酸雷诺嗪(分子量500.53)相当于0.854g雷诺嗪游离碱(分子量427.54)。
本发明的盐酸雷诺嗪口服制剂，它包含盐酸雷诺嗪和适宜的药用惰性赋形剂制成的一定形状的紧密混合物，如压制片或颗粒，也可以在紧密混合物外层覆盖胃溶性包衣层以改善制剂的外观和稳定性等，本发明盐酸雷诺嗪口服制剂，是指盐酸雷诺嗪在人工胃液内(通常的体外试验是制剂在0.1mol/L的盐酸溶液)45分钟内崩解释放不少于70％，即表明释放完全。表1综述了盐酸雷诺嗪在不同pH值下的溶解性能(参照中国药典2000年版)
表1 盐酸雷诺嗪在不同pH值下的溶解性能
| PH值 | 1.0 | 3.0 | 5.0 | 6.5 | 7.0 | 7.5 | 8.0 | 8.5 |
| 溶解性 | 易溶 | 易溶 | 易溶 | 易溶 | 易溶 | 溶解 | 溶解 | 溶解 |
其中易溶表明1g溶质在10～30ml溶剂中完全溶解，溶解表明1g溶质在30～100ml溶剂中完全溶解。
为了使盐酸雷诺嗪在人体内崩解释放完全，有必要选择一种或多种惰性赋形剂。该赋形剂既能保证盐酸雷诺嗪崩解释放完全，又能符合我国工业化大生产实际，生产工艺简单易行。如果盐酸雷诺嗪制剂在人体内不能完全溶出和被吸收，使得个体血浆中盐酸雷诺嗪浓度差异很大，不便于治疗，并有可能发生预料不到的不良反应。
因此本发明的治疗心血管疾病的口服制剂包括至少50wt％的盐酸雷诺和一种或多种可药用惰性赋形剂，所述的口服制剂包括片剂、颗粒剂、胶囊；所述的惰性赋形剂包括稀释剂、粘合剂、崩解剂、抗粘着剂和润滑剂；所述的稀释剂是选自微晶纤维素、乳糖、淀粉和预胶化淀粉、及其混合物；所述的粘合剂是选自海藻酸钠、羧甲基纤维素钠、羟乙纤维素、羟丙纤维素、羟丙基甲基纤维素、甲基纤维素、明胶、聚乙烯吡咯烷酮、醋酸纤维素、淀粉、预胶化淀粉、及其混合物；所述的崩解剂是选自海藻酸、海藻酸钠、羧甲基纤维素钠、微晶纤维素、粉末纤维素、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、预胶化淀粉、淀粉、及其混合物；所述的抗粘着剂是选自微粉硅胶、二氧化硅、三硅酸镁和滑石粉、及其混合物；所述的润滑剂是选自硬脂酸镁、滑石粉、及其混合物，所用润湿剂是乙醇水溶液。
本发明的口服制剂中含有：盐酸雷诺嗪50～95wt％，≠80wt％；稀释剂1～45wt％，≠16.5wt％；粘合剂2～20wt％；崩解剂1～10wt％，≠2wt％；抗粘着剂0.1～5wt％；润滑剂0.2～5wt％，≠0.5wt％。
本发明的口服制剂优选组分组成：盐酸雷诺嗪55～90wt％，≠80wt％；稀释剂2～40wt％，≠16.5wt％；粘合剂5～15wt％；崩解剂2wt％＜～8wt％，抗粘着剂0.2～4.0wt％；润滑剂0.5wt％＜～2.0wt％。
本发明的口服制剂的制剂单位含有200～500mg的盐酸雷诺嗪，适于患者每天服用3～4次，每次1～2个制剂单位。
本发明的口服制剂中优选的稀释剂为微晶纤维素；粘合剂为预胶化淀粉；崩解剂为交联羧甲基纤维素钠；抗粘着剂为微粉硅胶；润滑剂为硬脂酸镁。
也可以在本发明制剂外层覆盖胃溶性包衣层以改善制剂的外观、味觉和稳定性等，包衣增重与压制片的重量比为0.1～20％，优选0.5～18％，最佳为1.0～15％。特别优选的本发明口服制剂由下述组分组成：
| 组分 | 重量范围(％) | 优选重量范围(％) |
| 盐酸雷诺嗪 | 50～95 | 55～90 |
| 预胶化淀粉 | 2～20 | 5～15 |
| 微晶纤维素 | 1～45 | 2～25 |
| 交联羧甲基纤维素钠 | 1～10 | 2～8 |
| 微粉硅胶 | 0.1～5 | 0.2～4.0 |
| 硬脂酸镁 | 0.2～5 | 0.5～2.0 |
| 乙醇水溶液 | 至润湿量 | 至润湿量 |
其中乙醇水溶液中乙醇的浓度为5～95wt％，优选20～75wt％。
本发明的治疗心血管疾病的口服制剂按如下方法制备：
1)压制片：将盐酸雷诺嗪和可选择的稀释剂和内加崩解剂置混合机中，加适量润湿剂或粘合剂制成软材，软材压过适宜的筛网即成湿颗粒，将其立即干燥，过筛整粒，将外加崩解剂与可选择的润滑剂与所得干颗粒混合均匀，压片即得片芯。本发明优选圆形片形状。优选的制粒方法是搅拌制粒或者沸腾制粒后干燥。
2)明胶硬胶囊剂：将盐酸雷诺嗪和可选择的赋形剂混合均匀得干混合物，采用湿法制粒法制粒，将湿颗粒干燥、过筛整粒，与可选择的润滑剂(如硬脂酸镁)和其它助剂混合均匀，装入明胶硬胶囊中。
3)颗粒剂：将盐酸雷诺嗪和可选择的赋形剂和矫味剂混合均匀得干混合物，采用湿法制粒法制粒，将湿颗粒干燥、过筛整粒，分装在药用铝塑复合膜袋中。
上述制备方法的优点是：使用的粘合剂是乙醇水溶液，用量少，且制备工艺简单，适合于国内生产技术和设备条件。
本发明还有一个优点是：采用雷诺嗪二盐酸盐而不是雷诺嗪游离碱作为本发明盐酸雷诺嗪口服制剂的原料药，因为盐酸雷诺嗪的溶解度不随pH而发生较大的变化，故本制剂既可在胃中溶解吸收，也可在肠道中吸收，这样，使药物吸收利用得更加完全，可以减少制剂在患者体内吸收和疗效的个体差异。同时，用药频率增加至3～4次时，每次服药的剂量减少了，因此制剂的大小形状更适合需要雷诺嗪治疗的患者人群。因为该人群年龄偏大，制剂太大或形状不佳，则不利于吞服。
本发明的治疗心血管疾病含盐酸雷诺嗪的口服制剂提供了以下治疗优势：
本制剂以盐酸雷诺嗪为原料，它的溶解度不随PH值的变化发生较大的变化，药物释放得更加完全，最大程度地减少制剂在患者体内吸收和疗效的个体差异。由于服药次数的增加，制剂大小形状更适合用药人群服用。
此外，本发明的制备工艺简单，符合国内生产技术和设备条件。
因此本发明对于企业和患者都是有利的。
具体实施方式：
给出下列实施例使该领域的技术人员能更清楚的理解和实施本发明。它们不应被看作限制本发明的范围，而仅是说明性和代表性的例子。
实施例1
200mg盐酸雷诺嗪压制片的组成和制备方法
将盐酸雷诺嗪200.0g、微晶纤维素100.0g、磷酸氢钙40.0g、微粉硅胶40.0g混合均匀，以40wt％乙醇水溶液为润湿剂制软材，20目筛制粒，60℃通风干燥4小时，整粒，加入羧甲基纤维素钠5.0g、硬脂酸镁5.0g混匀压得约1000圆型片，每片含盐酸雷诺嗪200mg，即得压制片。
实施例2
300mg盐酸雷诺嗪压制片的组成和制备方法
将盐酸雷诺嗪300.0g、微晶纤维素100.0g、磷酸氢钙30.0g、微粉硅胶30.0g混合均匀，以含5wt％聚乙烯吡咯烷酮的60wt％乙醇水溶液为润湿剂制软材，20目筛制粒，60℃通风干燥3小时，整粒，加入微粉硅胶15.0g、硬脂酸镁5.0g混匀压得约1000胶囊型片，每片含盐酸雷诺嗪300mg，即得压制片。
实施例3
500mg盐酸雷诺嗪压制片的组成和制备万法
将盐酸雷诺嗪500.0g、微晶纤维素60.0g、磷酸氢钙50.0g、微粉硅胶40.0g混合均匀，以70wt％乙醇水溶液为润湿剂制软材，20目筛制粒，60℃通风干燥3小时，整粒，加入微粉硅胶10.0g、聚乙烯吡咯烷酮15.0g、硬脂酸镁5.0g混匀压得胶囊型片，每片含盐酸雷诺嗪500mg，即得压制片。
实施例4
200mg盐酸雷诺嗪胶囊的组成和制备方法
将盐酸雷诺嗪200.0g、微晶纤维素50.0g和磷酸氢钙40.0g置入快速搅拌制粒机KJZ～10中，喷洒30wt％乙醇水溶液制粒，60℃通风干燥3小时，40目筛整粒，加入硬脂酸镁10.0g混匀，灌装1号明胶硬胶囊，使每粒胶囊含盐酸雷诺嗪200mg。
实施例5
400mg盐酸雷诺嗪颗粒的组成和制备方法
将盐酸雷诺嗪400.0g、甲基纤维素50.0g、微晶纤维素100.0g、明胶10.0g、阿司帕坦0.05g和部分预胶化淀粉20.0g混匀，喷洒3wt％的聚乙烯吡咯烷酮乙醇水溶液制软材，制粒，鼓风烘箱干燥2小时，18目筛整粒，分装在PVC复合铝箔袋中，使每袋含盐酸雷诺嗪400mg。
实施例6
300mg盐酸雷诺嗪薄膜衣片的组成和制备方法
将盐酸雷诺嗪300.0g、微晶纤维素100.0g、磷酸氢钙30.0g、微粉硅胶30.0g混合均匀，以含5％聚乙烯吡咯烷酮的60wt％乙醇水溶液为润湿剂制软材，20目筛制粒，60℃通风干燥3小时，整粒，加入微粉硅胶15.0g、硬脂酸镁5.0g混匀压片，压制片包OPADRY膜，即得每片含盐酸雷诺嗪300mg，薄膜衣片。
实施例7
300mg盐酸雷诺嗪压制片的组成和制备方法
将盐酸雷诺嗪300.0g、微晶纤维素80.0g、磷酸氢钙50.0g、微粉硅胶40.0g、微粉硅胶10.0g、聚乙烯吡咯烷酮10.0g、硬脂酸镁2.0g混合均匀，采用滚压法压成大片，将大片破碎，用18目和40目筛筛分得压制用干燥颗粒，加入聚乙烯吡咯烷酮5.0g、硬脂酸镁3.0g混匀压片，得约1000压制片，每片含盐酸雷诺嗪300mg。
实施例8
体外比较实施例1～4制得的未包衣制剂。
本实施例详细描述了本发明实施例1～4制得的未包衣制剂按照《中国药典·2000年版》二部附录中有关崩解时限和溶出度测定方法测试的相应结果。
崩解时限：取样品6片或粒，分别置于吊篮的玻璃管中，启动崩解仪进行检查。
溶出度：使用900ml0.1mol/L盐酸作为溶出介质，温度37℃，采用中国药典附录溶出度测定法第一法装置，转速100转/分，30分钟后取样10ml测定。表3总结了本发明实施例1～4所制得的盐酸雷诺嗪制剂的溶出度数据。
表2.实施例1～4体外溶出对比
| 实施例 | 实施例1 | 实施例2 | 实施例3 | 实施例4 |
| 崩解时限(分钟) | 10 | 7.0 | 6.0 | 12.0 |
| 溶出百分比(％) | 96.4 | 97.1 | 97.8 | 98.2 |
上表试验数据表明，按本发明技术实施的实施例1～4的崩解时限均小于15分钟，符合中国药典2000年版的规定，即本发明技术是可行的，在酸中45分钟内基本释放完全，即释放不少于70％。
Claims (4)
1.一种治疗心血管疾病的口服制剂，其特征在于：该制剂包括盐酸雷诺嗪和一种或多种可药用惰性赋形剂，所述的口服制剂包括片剂、颗粒剂、胶囊；所述的惰性赋形剂包括稀释剂、粘合剂、崩解剂、抗粘着剂和润滑剂；制剂中含有：盐酸雷诺嗪50～95wt％，≠80wt％；稀释剂1～45wt％，≠16.5wt％；粘合剂2～20wt％；崩解剂1～10wt％，≠2wt％；抗粘着剂0.1～5wt％；润滑剂0.2～5wt％≠0.5wt％；所述的稀释剂是选自微晶纤维素、乳糖、淀粉和预胶化淀粉、及其混合物；所述的粘合剂是选自海藻酸钠、羧甲基纤维素钠、羟乙纤维素、羟丙纤维素、羟丙基甲基纤维素、甲基纤维素、明胶、聚乙烯吡咯烷酮、醋酸纤维素、淀粉、预胶化淀粉、及其混合物；所述的崩解剂是选自海藻酸、海藻酸钠、羧甲基纤维素钠、微晶纤维素、粉末纤维素、交联羧甲基纤维素钠、交联聚乙烯吡咯烷酮、预胶化淀粉、淀粉、及其混合物；所述的抗粘着剂是选自微粉硅胶、二氧化硅、三硅酸镁和滑石粉、及其混合物；所述的润滑剂是选自硬脂酸镁、滑石粉、及其混合物，所用润湿剂是乙醇水溶液。
2.如权利要求1所述的口服制剂，其特征在于制剂中含有：盐酸雷诺嗪55～90wt％，≠80wt％；稀释剂2～40wt％，≠16.5wt％；粘合剂5～15wt％；崩解剂2wt％＜～8wt％，抗粘着剂0.2～4.0wt％；润滑剂0.5wt％＜～2.0wt％。
3.如权利要求1-3所述的口服制剂，其特征在于该制剂单位含有200～500mg的盐酸雷诺嗪，适于患者每天服用3～4次，每次1～2个制剂单位。
4.如权利要求1所述的口服制剂，其特征在于其稀释剂为微晶纤维素；粘合剂为预胶化淀粉；崩解剂为交联羧甲基纤维素钠；抗粘着剂为微粉硅胶；润滑剂为硬脂酸镁。
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