CN105434383B - 一种苯磺酸左旋氨氯地平片剂及其制备方法 - Google Patents
一种苯磺酸左旋氨氯地平片剂及其制备方法 Download PDFInfo
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- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 title claims abstract description 69
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
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Abstract
本发明公开一种苯磺酸左旋氨氯地平片剂，将微晶纤维素、薄荷脑与左旋氨氯地平碱制备成微丸后，加入到乙醇中，搅拌，然后加入苯甲酸溶液中，左旋氨氯地平碱与碱液反应形成苯磺酸左旋氨氯地平，过滤，干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸。然后和药学上可接受的辅料上混合，压片而成。本发明与现有技术相比，药物稳定性良好，工艺简单。
Description
技术领域
本发明属于医药技术领域，具体涉及一种苯磺酸左旋氨氯地平片剂。
背景技术
苯磺酸氨氯地平有左旋和右旋两种异构体，左旋体钙离子拮抗活性是右旋体的1000倍，是消旋体的两倍。苯磺酸左旋氨氯地平是苯磺酸氨氯地平的左旋体，是1，4-二氢吡啶类钙离子拮抗剂或慢通道阻滞剂，是目前治疗高血压病常用药物。苯磺酸左旋氨氯地平为白色或类白色粉末，在甲醇、乙醇中易溶，在水中微溶；其英文名称为LevamlodipineBesylate，化学名称为(S)-(-)3-乙基-5-甲基-2-(2-氨基乙氧甲基)-4-(2-氯苯基)-1，4-二氢-6-甲基-3，5-吡啶二羧酸酯苯磺酸盐，分子式为C20H25N2O5Cl·C6H6O3S，分子量为567.05。临床应用苯磺酸左旋氨氯地平片主要具有两种作用：一种作用是治疗高血压病，用于轻度和中度的高血压患者(单独或与其他药物合并使用)。另一种作用是治疗心绞痛，尤其自发性心绞痛(单独或与其他药物合并使用)。苯磺酸左旋氨氯地平具有许多独特性质而与其它钙拮抗剂有所不同，表现为长效、缓慢吸收，逐渐产生血管扩张效应。降血压和抗心绞痛作用时间长，每日服用一次即可，作用时间可维持近24小时。副作用比较轻微，病人一般都能耐受，因而越来越广泛地应用于临床。
苯磺酸左旋氨氯地平选择性抑制钙离子跨膜进入平滑肌细胞和心肌细胞，对平滑肌的作用大于心肌。其与钙通道的相互作用决定于它和受体位点结合和解离的渐进性速率，因此药理作用逐渐产生。苯磺酸左旋氨氯地平是外周动脉扩张剂，直接作用于血管平滑肌，降低外周血管阻力，从而降低血压。苯磺酸左旋氨氯地平缓解心绞痛的准确机制尚不明确，但可能在运动时，苯磺酸左旋氨氯地平通过降低外周阻力(后负荷)减少心脏做功和速率血压乘积，减少心肌需氧治疗劳力型心绞痛；通过抑制钙离子、肾上腺素、5-羟色胺和血栓素A2引起的冠状动脉和小动脉收缩，恢复缺血区供血治疗自发性心绞痛。
CN105106161A，制备苯磺酸左旋氨氯地平固体分散体，分散体含有苯磺酸左旋氨氯地平、聚乙烯吡咯烷酮、β-环糊精、大豆磷脂。
CN104257619A，通过将稀释剂和崩解剂加入粘合剂后，采用湿法混合制粒；干燥、整粒；然后将苯磺酸左旋氨氯地平乙醇溶液喷入上述颗粒并加入外加辅料，混合，常温下干燥；压片。
CN102697743B，微晶纤维素、硫酸钙、羟丙纤维素、硬脂酸镁。不含乳糖，制剂工艺简单，有关物质少，仍能保持较高溶出性能以及较高稳定性。
但以上专利，均未从根本上解决苯磺酸左旋氨氯地平见光易分解的问题。
发明内容
现有技术中，为保证药物对光的稳定性，仅加入遮光剂和在包装上避光外，并未彻底解决生产过程中对光不稳定的问题。针对现有技术的缺陷，发明人拟提供一种稳定性好的苯磺酸左旋氨氯地平片剂。
发明人考虑到，苯磺酸左旋氨氯地平对光稳定性差，不论添加何种辅料，在片剂生产过程中，均可能降解，除非药物本身对光稳定性好，因此，发明人计划通过工艺技术，以提高苯磺酸左旋氨氯地平原料对光的稳定性。
现有技术中，均是通过加入遮光剂或者生产过程中尽量避光来保证药物的稳定性，难以彻底解决上述问题。
发明人尝试加入一种稳定剂，经过大量实验，均不能很好的改善。意外的，发明人考虑苯磺酸左旋氨氯地平的光降解与其表面积有关，如果减少其表面积，则应该会提高稳定性，结果证明了发明人的猜想，但是仍有降解。
进一步的，发明人创造性考虑到将微晶纤维素、薄荷脑与氨氯地平碱制备成微丸后，加入到乙醇中，薄荷脑溶于乙醇形成空洞，然后在此体系中加入苯磺酸，酸液通过空洞进入微丸内部，左旋氨氯地平碱与酸液反应形成苯磺酸左旋氨氯地平，过滤，干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸，相当于苯磺酸左旋氨氯地平包裹在微晶纤维素空洞中。该技术制备的微丸由于苯磺酸左旋氨氯地平原料被包裹在微晶纤维素微丸中，光稳定性良好。
具体而言，本发明是通过如下技术实现的：
本发明提供了一种苯磺酸左旋氨氯地平片剂，具体为将微晶纤维素、薄荷脑与左旋氨氯地平碱制备成微丸后，加入到乙醇或乙醇溶液中浸泡；之后滤出微丸，加入到苯磺酸水溶液中，搅拌，过滤，干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸；然后和药学上可接受的辅料混合，压片而成。
所述的左旋氨氯地平碱与微晶纤维素的重量比为1:5-30。
所述的左旋氨氯地平碱与微晶纤维素的重量比为1:15。
所述的薄荷脑与微晶纤维素的重量比为1:5-12。
所述的薄荷脑与微晶纤维素的重量比为1:8。
所述的左旋氨氯地平碱与苯磺酸的重量比优选为100：38-200。
所述的药学上可接受的辅料为填充剂、崩解剂、润滑剂。
所述的填充剂为乳糖、甘露醇、淀粉、糊精中的一种或多种。
所述的崩解剂为羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素中的一种或多种。
所述的润滑剂为硬脂酸镁、硬脂酸富马酸钠、滑石粉、二氧化硅中的一种或多种。
与现有技术相比，本发明具有如下优势：
1)药物被包封在微晶纤维素空洞中，稳定性大大提高；
2)制备工艺简单，适于工业化生产。
具体实施方式
以下实施例进一步描述本发明的有益效果，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
实施例1
制备工艺：
按处方量，将微晶纤维素、薄荷脑与左旋氨氯地平碱制备成微丸后，加入到乙醇中浸泡1小时，之后滤出微丸，加入到苯磺酸水溶液(将处方量的苯磺酸溶于处方量的水)中，搅拌半小时，过滤，干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸；然后和羧甲基淀粉钠、乳糖、硬脂酸镁混合，压片而成。
实施例2
制备工艺：
按处方量，将微晶纤维素、薄荷脑与左旋氨氯地平碱制备成微丸后，加入到乙醇中浸泡半小时，之后滤出微丸，加入到苯磺酸水溶液(将处方量的苯磺酸溶于处方量的水)中，搅拌半小时，过滤，干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸；40摄氏度干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸。然后和交联聚维酮、乳糖、硬脂酸镁混合，压片而成。
实施例3
制备工艺：
按处方量，将微晶纤维素、薄荷脑与左旋氨氯地平碱制备成微丸后，加入到乙醇中浸泡1小时，之后滤出微丸，加入到苯磺酸水溶液(将处方量的苯磺酸溶于处方量的水)中，搅拌1小时，过滤，干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸；40摄氏度干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸。然后和羧甲基淀粉钠、乳糖、硬脂酸镁混合，压片而成。
对比实施例1
制备工艺：
处方量称取微晶纤维素与苯磺酸左旋氨氯地平、交联聚维酮、微晶纤维素、硬脂酸镁混合，压片而成。
对比实施例2
制备工艺：
(1)按处方量称取上述物质，所述处方量是指上述配方中所述物质及含量；
(2)将微晶纤维素、硫酸钙和羟丙纤维素分别过60目筛网，混合均匀；
(3)苯磺酸左旋氨氯地平过80目筛，分级扩散在步骤(2)获得的混合物中，投入湿法混合制粒机中，搅拌10-20分钟；
(4)加入15％酒精适量，搅拌5-10分钟，制成软材；
(5)用摇摆颗粒剂过18目筛二次，制得湿颗粒；
(6)60-70℃烘箱中干燥2.5±0.5小时，干颗粒摇摆颗粒机16目整粒；
(7)硬脂酸镁过80目筛，干颗粒加入处方量硬脂酸镁，V型混合机混合20分钟；
(8)颗粒含水量控制在2％-5％，含量控制在2.85％-3.15％；
(9)压片，硬度控制在2-5kg；
对比实施例3
制备工艺：
辅料制粒：将甘露醇、交联聚维酮混合后加入粘合剂羟丙纤维素中，制粒；将制得的颗粒在80℃干燥、当颗粒的水分含量达到1-3％时收料，用快速整粒机整粒；
将苯磺酸左旋氨氯地平溶于无水乙醇制成苯磺酸左旋氨氯地平乙醇溶液，将其喷入干颗粒并加入外加辅料(二氧化硅)，混合，常温下干燥；
测定混合颗粒中的苯磺酸左旋氨氯地平含量，将含量合格的混合颗粒进行压片，制成苯磺酸左旋氨氯地平片。
验证实施例：
1.光学纯度避光操作。照高效液相色谱法(中国药典2010年版二部附录ⅤD)测定。
色谱条件与系统适用性试验，乙腈-0.02mol/L磷酸二氢钠水溶液(pH7.0)水溶液(20：80)为流动相，检测波长360nm，左旋氨氯地平与右旋氨氯地平的分离度应符合要求。
测定法取本品细粉约0.16g，精密称定，加50％乙腈溶液制成每1ml中含有左旋氨氯地平0.2mg的溶液，摇匀，滤过，取续滤液作为供试品溶液。取20μl，注入液相色谱仪，记录色谱图，按照面积归一化法(苯磺酸溶剂峰不计)计算，左旋氨氯地平峰面积不得少于98.5％。
有关物质在含量测定项下记录的色谱图中，杂质峰面积总和(溶剂峰不计)应不大于总面积的1.0％。
2.各实施例测定结果
各实施例顺式异构体测定结果
从表中可知，与对比实施例1、2、3相比，本发明实施例1、2、3所得产品的稳定性良好。
Claims (7)
1.一种苯磺酸左旋氨氯地平片剂，其特征在于，具体为将微晶纤维素、薄荷脑与左旋氨氯地平碱制备成微丸后，加入到乙醇或乙醇溶液中浸泡；之后滤出微丸，加入到苯磺酸水溶液中，搅拌，过滤，干燥，得到含有苯磺酸左旋氨氯地平的微晶纤维素微丸；然后和药学上可接受的辅料混合，压片而成；其中，所述的左旋氨氯地平碱与微晶纤维素的重量比为1：5-30，所述的薄荷脑与微晶纤维素的重量比为1：5-12，所述的左旋氨氯地平碱与苯磺酸的重量比为100：38-200。
2.根据权利要求1所述的苯磺酸左旋氨氯地平片剂，其特征在于，所述的苯磺酸左旋氨氯地平片剂，左旋氨氯地平碱与微晶纤维素的重量比为1:15。
3.根据权利要求1所述的苯磺酸左旋氨氯地平片剂，其特征在于，所述的苯磺酸左旋氨氯地平片剂，薄荷脑与微晶纤维素的重量比为1:8。
4.根据权利要求1-3任一权利要求所述的苯磺酸左旋氨氯地平片剂，其特征在于，药学上可接受的辅料为填充剂、崩解剂、润滑剂。
5.根据权利要求4所述的苯磺酸左旋氨氯地平片剂，其特征在于，所述的填充剂为微晶纤维素、乳糖、甘露醇、淀粉、糊精中的一种或多种。
6.根据权利要求4所述的苯磺酸左旋氨氯地平片剂，其特征在于，所述的崩解剂为羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素中的一种或多种。
7.根据权利要求4所述的苯磺酸左旋氨氯地平片剂，其特征在于，所述的润滑剂为硬脂酸镁、硬脂酸富马酸钠、滑石粉、二氧化硅中的一种或多种。
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