CN1287792C - 孟鲁司特钠的分散片剂型 - Google Patents
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Abstract
本发明属医药技术，特别是一种孟鲁司特钠的分散片剂型。本发明提供一种孟鲁司特钠的分散片剂型，含孟鲁司特钠主成分和崩解剂及辅助添加剂，崩解剂为制备分散片剂型的常用的分散片剂型崩解剂，辅助添加剂是制备分散片剂型常用的分散片剂型添加剂。该分散片剂型克服了孟鲁司特钠常规制剂由于崩解慢导致的溶出缓慢，从而影响药物的充分吸收及治疗效果等缺点，具有方便老人和儿童患者服用，且制剂稳定，吸收快，生物利用度高，不良反应少，适用于成人哮喘的预防和长期治疗，包括预防白天和夜间的哮喘症状，治疗对阿司匹林敏感的哮喘患者以及预防运动引起的支气管收缩等病症。
Description
技术领域
本发明涉及一种适用于成人哮喘的预防和长期治疗，包括预防白天和夜间的哮喘症状，治疗对阿司匹林敏感的哮喘患者以及预防运动引起的支气管收缩等病症的药物，特别是涉及一种孟鲁司特钠分散片剂型。
背景技术
哮喘是一种以器官高反应性及可逆性气道阻塞为特点的慢性炎症性疾病。白三烯(leukotrienes)是支气管哮喘的重要介质之一，它对于哮喘的发生、发展起着关键作用，有研究表明无论在体内或体外它所引起的反应酷似哮喘的病理改变，而且在哮喘病人中无论发作期或稳定期其水平均高于正常人。白三烯受体拮抗剂成为哮喘治疗的新途径。
孟鲁司特是一个特异性强效白三烯(LTD4)受体拮抗剂，它阻断半胱氨酰白三烯与受体间的相互作用，从而阻断器官对白三烯的反应，达到控制哮喘的目的。对治疗哮喘具有显著疗效。孟鲁司特既是炎症的预防药(拮抗白三烯的促炎症活性)，也是扩张支气管的缓解药(拮抗白三烯引起的平滑肌性支气管收缩)。对慢性支气管炎大鼠气道粘蛋白高分泌作用的试验，证实了孟鲁司特可以明显抑制慢性支气管炎大鼠气道粘蛋白高分泌，既抑制杯状细胞增生，又可抑制粘蛋白合成，降低分泌细胞粘蛋白表达水平，并抑制分泌释放机制，最终使BALF中的粘蛋白极显著减少。
致敏的气道对特异抗原的反应有速发相哮喘反应和迟发相哮喘反应两种。作为一种常见慢性疾病，它困扰着发达国家近10％的人口，造成的社会经济损失达数百亿美元。据WHO的有关统计资料显示，目前我国的哮喘的发病率为1％，儿童发病率高达3-5％，较10年前有明显增加。现今有许多药物用于治疗哮喘病，主要有糖皮质激素(倍氯米松等)、β2受体激动剂(沙丁胺醇等)、抗胆碱药(异丙阿托品)、黄嘌呤类(茶碱等)、过敏介质阻释药(色甘酸钠)、干扰白三烯受体功能药等，在这些药物中没有一种药物是完全无害的，也没有任何一种单一的药物证明对中重度哮喘完全有效。白三烯受体拮抗剂是过去30年中获得的一类新的抗哮喘药。其独特的性质是兼有抗炎症和支气管扩张作用，且能口服。
孟鲁司特钠是一种用于治疗哮喘的白三烯受体拮抗剂，是目前世界上最畅销的哮喘治疗药物。
孟鲁司特钠是孟鲁司特的钠盐，由于其具有独特的化学结构，它的口服生物利用度，临床疗效和安全性均优于以往同类药物。默沙东公司于1998年2月获得FDA的批准在美国首次上市该药，剂型为膜衣片，用于预防和长期治疗15岁以上的哮喘病患者。
孟鲁司特钠自1998年获准在美国上市以来已陆续在多个国家和地区上市，2000年得到我国的进口批准，由默沙东(中国)有限公司在我国上市，商品名为顺尔宁TM，剂型为薄膜衣片，进口注册证号X19990397，规格10mg。
发明目的
本发明提供一种孟鲁司特钠分散片剂型。对于孟鲁司特钠的普通制剂，如片剂，其规格为10mg/片，因崩解和药物溶出缓慢而影响药物的充分吸收，老人、儿童和吞咽困难的患者服用时常有困难，同时在治疗过程中，尚存在头痛、腹泻、咽炎、恶心等不良反应。本发明的目的在于克服上述缺点。
技术方案
本发明去氧氟尿苷剂型为分散片剂型，主药成分去氧氟尿苷量优化为1～200mg，更优化为5～50mg，最优化为10mg。
崩解剂是制备分散片剂型的常用分散片剂型崩解剂，本发明中崩解剂含量优化为1～80％，更优化为10～30％。优化原则：在保证本发明崩解迅速溶出快的前提下，崩解剂的用量少。
发明优点
本发明孟鲁司特钠分散片剂型的优点在于能够进一步改善主药溶解度，即遇水能迅速形成均匀粘性混悬液，可在胃肠道迅速崩解分散成小颗粒，使药物分布面积增大，吸收点增多，避免普通制剂在胃肠道局部药物浓度过高，刺激胃肠粘膜等缺点，减少不良反应，提高患者适应性，具有服用方便、吸收快、生物利用度高等特点，且方便老人和儿童患者服用。
经过大量反复的实验研究，确定了孟鲁司特钠分散片的最终工艺处方，并在动物试验中证实本发明确实具有上述优点。在试验中，我们选择了多种具有崩解特性的药用崩解剂进行比较后发现，并不是所有的可用于分散片剂的崩解剂都能够应用于本发明。本发明解决的技术难题，也是技术特征是对崩解剂的选择，最终选出了崩解剂为淀粉、预胶化淀粉、羧甲基淀粉钠、羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羟丙基淀粉、羧甲基纤维素钙、海藻酸钠、羟乙酸纤维素、羧甲基纤维素钠、甲基丙烯酸、二乙烯苯共聚酯、IRP-88、瓜耳胶、苍耳胶、葡聚糖、羧甲基纤维素钙等崩解剂中的一种或多种。
在研究过程中，考察了孟鲁司特钠分散片的制备工艺，确定了其制备工艺是处方量的孟鲁司特钠、崩解剂混合均匀，制粒烘干后加入处方量润滑剂混匀压片或直接在上述混合粉中加入处方量润滑剂混匀压片，即得。
附图说明：
图1：处方A的体外溶出曲线：图2：处方B的体外溶出曲线：图3：处方C的体外溶出曲线：图4：处方D的体外溶出曲线：图5：处方E的体外溶出曲线：图6：处方F的体外溶出曲线：图7：处方G的体外溶出曲线：图8：处方H的体外溶出曲线：
具体实施方式
实施例(处方量为1000片)：
八种具体处方：
处方A：
孟鲁司特钠 1g
微晶纤维素(填充剂) 48g
羟丙基纤维素(崩解剂) 0.5g
硬脂酸镁(润滑剂) 0.5g
制备工艺：主药过100目筛，填充剂、崩解剂过80目筛，称取处方量的填充剂、崩解剂混合均匀，然后将处方量的主药与其按等量递加法混匀，加入处方量润滑剂，混匀，压片即得。分散片分散时限为2.7min。
处方B：
孟鲁司特钠 2.5g
微晶纤维素(填充剂) 90g
羧甲基淀粉钠(崩解剂) 5g
4％PVPK30无水乙醇溶液(粘合剂) 50g
硬脂酸镁(润滑剂) 0.5g
制备工艺：主药过100目筛，填充剂、崩解剂过80目筛，称取处方量的填充剂、崩解剂混合均匀，然后将处方量的主药与其按等量递加法混匀，加入粘合剂适量制粒，干燥后加入处方量润滑剂混匀，压片即得。分散片分散时限为2.5min。
处方C：
孟鲁司特钠 5g
微晶纤维素(填充剂) 81g
交联聚乙烯吡咯烷酮(崩解剂) 10g
5％PVPK30无水乙醇溶液(粘合剂) 60g
硬脂酸镁(润滑剂) 1g
制备工艺：同处方B。分散片分散时限为2.0min。
处方D：
孟鲁司特钠 10g
微晶纤维素(填充剂) 66g
交联聚乙烯吡咯烷酮(崩解剂) 20g
5％PVPK30无水乙醇溶液(粘合剂) 60g
硬脂酸镁(润滑剂) 1g
制备工艺同处方C。分散片分散时限为1.6min。
处方E：
孟鲁司特钠 20g
乳糖(填充剂) 47g
交联聚乙烯吡咯烷酮(崩解剂) 30g
4％PVPK30无水乙醇溶液(粘合剂) 50g
硬脂酸镁(润滑剂) 1g
制备工艺同处方C。分散片分散时限为1.2min。
处方F：
孟鲁司特钠 50g
羧甲基淀粉钠(崩解剂) 80g
乳糖(填充剂) 63g
4％PVPK30水溶液(粘合剂) 150g
硬脂酸镁(润滑剂) 1g
制备工艺同处方C。分散片分散时限为0.7min。
处方G：
孟鲁司特钠 100g
羧甲基淀粉钠(崩解剂) 60g
微晶纤维素(填充剂) 31g
5％PVPK30水溶液(粘合剂) 160g
硬脂酸镁(润滑剂) 1g
制备工艺同处方C。分散片分散时限为0.4min。
处方H：
孟鲁司特钠 200g
交联聚乙烯吡咯烷酮(崩解剂) 960g
10％淀粉浆(粘合剂) 300g
硬脂酸镁(润滑剂) 10g
制备工艺同处方C。分散片分散时限为0.2min。
孟鲁司特钠分散片的动物实验
本发明的动物体内药代动力学实验方法如下：实验分为两组，每组6只狗；对照组给予口服默沙东公司的孟鲁司特钠片(10mg/片，商品名为顺尔宁)，一日一片；实验组给予口服本发明(处方A～H，10mg/片)一日一片；分别在给药1、2、3、4、5、6、7小时后，取血清测定孟鲁司特钠的血药浓度，结果表明：对照组和实验组在各个时间点的药时曲线下面积(AUC)均无显著差别，提示本发明按照一日一片服用能够达到理想的血药浓度，具有良好的治疗效果。
孟鲁司特钠分散片分散均匀性及体外溶出度检查
1、孟鲁司特钠分散片分散均匀性检查
孟鲁司特钠分散片(处方A～H)，其分散均匀性实验方法如下：取本品2片，置100ml水中振摇，在20℃+1℃水中，3分钟应全部崩解并通过2号筛。详见表说明1～8。
2、孟鲁司特钠分散片体外溶出度的测定
孟鲁司特钠分散片(处方A～H)，其体外溶出度实验方法如下：避光操作，取本品照溶出度测定法(中国药典2000年版二部附录XC溶出度测定法第一法)以0.2％十二烷基硫酸钠水溶液900ml为溶剂，转速为每分钟100转，经30分钟时取样10ml，滤过，滤液作为供试品溶液；另取孟鲁司特钠对照品适量，加0.2％十二烷基硫酸钠水溶液溶解，配制成每1ml中含10μg的溶液。取上述两种溶液照分光光度法(附录IVA)，在284nm波长处分别测定吸收度，计算出每片的溶出量，限度为标示量的80％，应符合规定。详见附图说明1～8。
表1：处方A的体外累积溶出度及分散时限
| 时间(min) | 5 | 10 | 15 | 20 | 25 | 30 |
| 累积溶出度(％) | 61 | 74 | 83 | 90 | 95 | 97 |
| 分散时限 | 2.7min崩解，并可全部通过2号筛 | |||||
表2：处方B的体外累积溶出度及分散时限
| 时间(min) | 5 | 10 | 15 | 20 | 25 | 30 |
| 累积溶出度(％) | 66 | 80 | 87 | 92 | 96 | 97 |
| 分散时限 | 2.5min崩解，并可全部通过2号筛 | |||||
表3：处方C的体外累积溶出度及分散时限
| 时间(min) | 5 | 10 | 15 | 20 | 25 | 30 |
| 累积溶出度(％) | 71 | 84 | 90 | 95 | 97 | 98 |
| 分散时限 | 2.0min崩解，并可全部通过2号筛 | |||||
表4：处方D的体外累积溶出度及分散时限
| 时间(min) | 5 | 10 | 15 | 20 | 25 | 30 |
| 累积溶出度(％) | 79 | 88 | 95 | 97 | 99 | 99 |
| 分散时限 | 1.6min崩解，并可全部通过2号筛 | |||||
表5：处方E的体外累积溶出度及分散时限
| 时间(min) | 5 | 10 | 15 | 20 | 25 | 30 |
| 累积溶出度(％) | 81 | 90 | 95 | 96 | 98 | 99 |
| 分散时限 | 1.2min崩解，并可全部通过2号筛 | |||||
表6：处方F的体外累积溶出度及分散时限
| 时间(min) | 5 | 10 | 15 | 20 | 25 | 30 |
| 累积溶出度(％) | 85 | 93 | 96 | 97 | 98 | 98 |
| 分散时限 | 0.7min崩解，并可全部通过2号筛 | |||||
表7：处方G的体外累积溶出度及分散时限
| 时间(min) | 5 | 10 | 15 | 20 | 25 | 30 |
| 累积溶出度(％) | 88 | 95 | 97 | 98 | 99 | 99 |
| 分散时限 | 0.4min崩解，并可全部通过2号筛 | |||||
表8：处方H的体外累积溶出度及分散时限
| 时间(min) | 5 | 10 | 15 | 20 | 25 | 30 |
| 累积溶出度(％) | 91 | 95 | 97 | 97 | 98 | 99 |
| 分散时限 | 0.2min崩解，并可全部通过2号筛 | |||||
Claims (2)
1、一种孟鲁司特钠分散片剂型，其特征在于为分散片剂型，其中含有：
(1)孟鲁司特钠，化学名称为[R-(E)-]1-[[[1-[3-[2-(7氯-2-喹啉基)乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫代]甲基]环丙烷乙酸单钠盐；
(2)崩解剂；
(3)辅助添加剂，
所述的崩解剂为淀粉、预胶化淀粉、羧甲基淀粉钠、羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羟丙基淀粉、羧甲基纤维素钙、海藻酸钠、羟乙酸纤维素、羧甲基纤维素钠、甲基丙烯酸、二乙烯苯共聚酯、IRP-88、瓜耳胶、苍耳胶、葡聚糖、羧甲基纤维素钙中的一种或多种，所述的崩解剂的含量为1～80％。
2、如权利要求1所述的分散片剂型，其特征在于每片所述的孟鲁司特钠分散片中孟鲁司特钠的量为1～200mg。
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| KR100907951B1 (ko) | 2007-08-10 | 2009-07-16 | 임복환 | 조릿대 순을 이용한 차의 제조방법 및 그에 의해 제조된조릿대 순 차 |
| WO2013100564A1 (ko) * | 2011-12-26 | 2013-07-04 | 에스케이케미칼 주식회사 | 몬테루카스트 또는 이의 약학적으로 허용 가능한 염을 포함한 구강투여용 필름 |
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| CN100393305C (zh) * | 2005-12-08 | 2008-06-11 | 苏州东瑞制药有限公司 | 孟鲁司特口腔崩解片制剂的制备方法 |
| SI1976522T2 (sl) | 2005-12-30 | 2019-11-29 | Krka Tovarna Zdravil D D Novo Mesto | Farmacevtski sestavek, ki vsebuje montelukast |
| DE602006013781D1 (de) * | 2006-02-09 | 2010-06-02 | Teva Pharma | Stabile pharmazeutische Zubereitungen von Montelukast-Natrium |
| CN101732268B (zh) * | 2010-01-09 | 2012-12-05 | 鲁南制药集团股份有限公司 | 一种孟鲁司特钠片剂及其制备方法 |
| CN102552921B (zh) * | 2012-02-28 | 2013-08-21 | 南京正科制药有限公司 | 一种孟鲁司特钠组合物 |
| CN104055741B (zh) * | 2013-03-18 | 2017-02-15 | 青岛大学 | 一种孟鲁司特钠片剂及其制备方法 |
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| WO2013100564A1 (ko) * | 2011-12-26 | 2013-07-04 | 에스케이케미칼 주식회사 | 몬테루카스트 또는 이의 약학적으로 허용 가능한 염을 포함한 구강투여용 필름 |
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