CN114903850A - 一种盐酸法莫替丁缓释混悬制剂及其制备方法 - Google Patents
一种盐酸法莫替丁缓释混悬制剂及其制备方法 Download PDFInfo
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- CN114903850A CN114903850A CN202210492825.4A CN202210492825A CN114903850A CN 114903850 A CN114903850 A CN 114903850A CN 202210492825 A CN202210492825 A CN 202210492825A CN 114903850 A CN114903850 A CN 114903850A
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- famotidine hydrochloride
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Abstract
本发明属于药物制剂制备技术领域，具体涉及一种盐酸法莫替丁缓释混悬制剂及其制备方法。本发明创造性地同时采用离子交换和乳化溶剂包衣的方法，制备得到盐酸法莫替丁缓释混悬剂。利用萃取原理使外相不断萃取内相，高分子溶液中内相的量不断减少，继而使包衣阻滞材料从高分子溶液中固化析出，初步形成亚稳态微囊体系，继续干燥可固化成包衣微囊。本发明通过处方工艺的调整，控制药物浸渍树脂复合物的释药速度，从而减缓药物的释放，利用乳化溶剂包衣得到可缓释的盐酸法莫替丁缓释混悬剂，从而使得盐酸法莫替丁体内血药浓度更平稳，药效更持久，病患服用药物的次数更少，一日给药1‑2次即可实现治疗目的，大大提高患者的药物依从性。
Description
技术领域
本发明属于药物制剂制备技术领域，具体涉及一种盐酸法莫替丁缓释混悬制剂及其制备方法。
背景技术
盐酸法莫替丁（Famotidine）是第三代组胺H2受体抑制剂，其分子式为C8H15N7O2S3；分子量为337.445；为白色或略微呈现黄色的结晶性粉末；无臭；味略苦；在二甲基甲酰胺和冰醋酸中易溶，难溶于甲醇，极难溶于水、乙腈、无水乙醇或丙酮，在氯仿或乙醚中几乎不溶；熔点为163-164°C；在266nm的波长处有最大吸收。在临床上，盐酸法莫替丁多被用于治疗消化性溃疡且作用强于西咪替丁、雷尼替丁。同时，法莫替丁也被用于治疗上消化道出血、反流性食管炎、卓-艾综合征等疾病。由于法莫替丁存在着半衰期短（约2-3h）、生物利用率低（约30%-40%）等问题，导致患者需多次服药并且血药浓度波动大、不稳定。现有的剂型主要有片剂、胶囊剂以及注射剂。
由于适应老龄人和婴幼儿等特殊群体的制剂类型有限，和青壮年患者相比较，特殊群体患者更容易出现吞咽苦难、顺应性差等问题。口服液体制剂与传统的片剂、胶囊剂等相比较具有吸收快、药物刺激性少等优点，易于吞咽更方便特殊群体用药。现有的盐酸法莫替丁均为普通制剂，仅能在一定程度上缓解胃部疾病引起的不适，而且存在服用次数多，体内释药不平稳，不良反应较大等缺点，目前尚未有盐酸法莫替丁缓释混悬制剂。
发明内容
为了解决上述技术问题，本发明的目的在于提供一种盐酸法莫替丁缓释混悬制剂及其制备方法。本发明同时采用离子交换（强酸性离子和如酸性离子相结合）和包衣膜两种技术来延缓药物释放，制备得到一种盐酸法莫替丁缓释混悬剂。患者每日只需服用1-2次即可达到治疗效果。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种盐酸法莫替丁缓释混悬剂，所述的盐酸法莫替丁缓释混悬剂包括盐酸法莫替丁、缓释材料和其他药学上可接受的辅料。所述的缓释材料包括强酸性离子交换树脂和弱酸性离子交换树脂的结合物；按重量百分比计，每个剂量单位中含有盐酸法莫替丁25%~40%，缓释材料60%~75%，辅料余量。
在本发明的一些具体实施方案中，所述的缓释材料为阳离子交换树脂与乙基纤维素（EC），羟丙甲基纤维素（HPMC），聚维酮（PVP），丙烯酸树脂（Eudragit）中的一种或几种的混合物。
所述的阳离子交换树脂与盐酸法莫替丁的质量比为1~6:1。
所述的阳离子交换树脂为强酸性离子交换树脂和弱酸性离子交换树脂的结合物；所述强酸性离子交换树脂为Amberlite IRP69，所述弱酸性阳离子交换树脂为 AmberliteIRP88和/或Amberlite IRP64。
所述强酸性离子交换树脂和弱酸性离子交换树脂的质量比为1: 2~9。
作为优选的，所述强酸性离子交换树脂和弱酸性离子交换树脂的质量比为1: 5~9。
进一步的，所述的辅料包括浸渍剂、增塑剂和助悬剂。
所述的浸渍剂选自甲基纤维素、甘油、聚乙二醇（PEG）4000、PEG3350中的一种或几种。所述浸渍剂与阳离子交换树脂的质量比为1:0.3~1。
所述的增塑剂选自邻苯二甲酸二乙酯、癸二酸二丁酯、三醋酸甘油酯、PEG400中的一种或一种以上。
所述的助悬剂选自甘油、糖浆、淀粉、琼脂、PVP、HPMC、西黄耆胶、海藻酸钠、阿拉伯胶、微晶纤维素（MC）、PEG、卡波姆（Carbopol）、胶体微晶纤维素（Avicel）中的一种或一种以上。
作为优选的，所述的辅料还包括矫味剂、抗氧化剂和/或防腐剂。
所述的矫味剂可选自甘露醇、木糖醇、甜菊甙、乳糖、果糖、蔗糖、蛋白糖、糖精钠、麦芽糖醇、甘草甜素、环己氨基磺酸钠、明胶、阿斯巴甜、香蕉香精、菠萝香精、香兰素、香橙香精、桔子香精、薄荷香精、柠檬香精、草莓香精、枸橼酸、柠檬酸中的一种或一种以上。
所述的抗氧化剂和/或防腐剂包括但不限于焦亚硫酸钠、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、山梨酸钾、山梨酸钙。
本发明还提供了一种盐酸法莫替丁缓释混悬制剂的制备方法，所述制备方法包括以下步骤：
（1）将法莫西丁加入到HCl中，搅拌状态下加入强酸性阳离子和弱酸性阳离子的结合物，达到载药平衡后清洗树脂表面，干燥得到载药树脂；
（2）载药树脂在浸渍剂中进行浸渍得到浸渍树脂；
（3）将浸渍树脂和增塑剂加入有机溶剂中作为分散相，液体石蜡加入到司盘中作为连续相，将分散相加入到连续相中得到药物-树脂微囊；
（4）将制备的药物-树脂微囊与助悬剂和蒸馏水混匀得到盐酸法莫替丁缓释混悬制剂。
与现有技术相比，本发明的有益效果是：
本发明创造性地同时采用离子交换（强酸性阳离子和弱酸性阳离子结合）和乳化溶剂包衣的方法，制备得到盐酸法莫替丁缓释混悬剂。利用萃取原理使外相不断萃取内相，高分子溶液中内相的量不断减少，继而使包衣阻滞材料从高分子溶液中固化析出，初步形成亚稳态微囊体系，继续干燥可固化成包衣微囊。本发明通过处方工艺的调整，控制药物浸渍树脂复合物的释药速度，从而减缓药物的释放，利用乳化溶剂包衣得到可缓释的盐酸法莫替丁缓释混悬剂，从而使得盐酸法莫替丁体内血药浓度更平稳，药效更持久，病患服用药物的次数更少，一日给药1-2次即可实现治疗目的，方便老人和儿童等特殊人群服用，大大提高患者的药物依从性且毒副作用小。
附图说明
图1是实施例1制备的盐酸法莫替丁缓释混悬制剂的体外释放曲线图；
图2是盐酸法莫替丁缓释混悬制剂的体内药动学释放曲线图。
具体实施方式
本发明公开了一种盐酸法莫替丁缓释混悬制剂。本领域技术人员可以借鉴本文内容，适 当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本发明具体实施例中所用原料及试剂均可由市场购得。
实施例1
（1）药物树脂的制备：将500mg药物（法莫西丁）加入到100mL浓度为0.1moL/L的HCl中，在搅拌下加入500mg 强酸性阳离子交换树脂Amberlite IRP69和弱酸性阳离子交换树脂Amberlite IRP88的结合物（质量比1: 9），混匀，定时取样测定溶液中药物的浓度；当药物浓度不再随时间而变化时即待达到载药平衡，用去离子水洗去树脂表面的未结合药物，在45℃-65℃干燥即得载药树脂。
（2）药物树脂的浸渍：
取1g步骤（1）制备的载药树脂，加入含有20％PEG4000的水溶液中，搅拌1小时，45℃干燥过筛得浸渍树脂。
（3）药物树脂微囊的制备：将0.25g的羟丙甲基纤维素和0.75g Carbopol溶于20mL有机溶剂75%乙醇中，加入5g步骤（2）制备的浸渍树脂和1mg的PEG400，作为分散相，用磁力搅拌器在500r/min转速下搅拌；另外，将40mL 液体石蜡加入到5mL司盘80中作为连续相，将分散相加入到连续相中得到药物-树脂微囊。
（4）药物树脂微囊混悬剂的制备：
取20mg步骤（3）中药物-树脂微囊、0.1g甘油、加入蒸馏水到50mL混合均匀即得药物-树脂缓释混悬剂。
在本实施例中助悬剂为甘油，在其他实施例中，可以选用糖浆、淀粉、琼脂、PVP、HPMC、西黄耆胶、海藻酸钠、阿拉伯胶、微晶纤维素、PEG、Carbopol、Avicel RC591中的一种或两种以上的混合物。
另外，为了改善混悬剂的口味，在其他实施例中，还可以添加矫味剂，如甘露醇、木糖醇、甜菊甙、乳糖、果糖、蔗糖、糖精钠、蛋白糖、麦芽糖醇、甘草甜素、环己氨基磺酸钠、明胶、阿斯巴甜、香蕉香精、菠萝香精、香兰素、香橙香精、桔子香精、薄荷香精、人参香精、草莓香精、枸橼酸、柠檬酸中的一种或两种以上的混合物。
为了保证主药的稳定，在其他实施例中，还可以添加抗氧化剂和防腐剂，可以选用焦亚硫酸钠、邻苯二钾酸二甲酯、邻苯二钾酸二乙酯、山梨酸钾或山梨酸钙中的一种或两种以上的混合物。
实施例2
本实施例中按下述配方配置盐酸法莫替丁缓释混悬剂。
盐酸法莫替丁80mg，
Amberlite IRP69 60mg，
Amberlite IRP88/ Amberlite IRP64 20mg，
PEG4000 40mg，
甲基纤维素40mg，
PEG400 1mg，
邻苯二甲酸二乙酯 2mg，
HPMC 10mg，
Carbopol(934P) 30mg，
糖精钠 10mg，
对羟基苯甲酸甲酯 3mg，
蒸馏水 50mL。
实施例3
本实施例中按下述配方配置盐酸法莫替丁缓释混悬剂：
盐酸法莫替丁 72mg，
Amberlite IRP69 12mg，
Amberlite IRP88/ Amberlite IRP64 60mg，
PEG4000 40mg，
PEG400 1mg，
邻苯二甲酸二乙酯 2mg，
Eudragit RS100 30mg，
Eudragit RL100 30mg，
EC(20cps) 15mg，
HPMC(K4M) 10mg，
Avicel(RC591) 10mg，
柠檬酸 12mg，
蒸馏水 50mL。
实施例4
本实施例中按下述配方配置盐酸法莫替丁缓释混悬剂：
盐酸法莫替丁 75mg，
Amberlite IRP69 100mg，
Amberlite IRP88/ Amberlite IRP64 200mg，
PEG4000 20mg，
PEG400 2.5mg，
癸二酸二丁酯 2.5mg，
EC(45cps) 20mg，
西黄耆胶 7.5mg，
阿拉伯胶 7.5mg，
HPMC(K4M) 10mg，
Carbopol(934P) 5mg，
柠檬香精 15mg，
蒸馏水 50mL。
实施例5
本实施例中按下述配方配置盐酸法莫替丁缓释混悬剂：
盐酸法莫替丁 50mg，
Amberlite IRP69 30mg，
Amberlite IRP88 210mg，
Amberlite IRP64 60 mg，
甘油 60mg，
PEG3350 30mg，
PEG400 2.5mg，
三醋酸甘油酯 2.5mg，
EC(45cps) 20mg，
西黄耆胶 7.5mg，
阿拉伯胶 7.5mg，
HPMC(K4M) 10mg，
Carbopol(934P) 5mg，
柠檬香精 15mg，
蒸馏水 50mL。
实施例6：体外释放度实验
体外试验是筛选处方确定工艺的重要手段，而且对制剂的质量控制有着重要作用，本实施例主要通过溶出速率来考察所制备的盐酸法莫替丁缓释混悬剂的体外释放度。具体以实施例1制备的盐酸法莫替丁缓释混悬剂为待测溶液，三次平行实验考察其体外释放度情况。实验步骤包括：采用900mL 0.15moL/L Nacl为释放介质：转速75r/min，温度37℃；根据中国药典2020版附录ⅩC溶出度测定法中的桨法进行操作，分别于2、4、6、8、12、24h取样，吸取待测溶液5mL，经0.45μm微孔滤膜滤过，弃去初滤液，取续滤液备用；及时补加同温度，同体积的相应介质，将续滤液于266nm处测定吸光度，根据标准曲线计算不同时间样品液浓度，考察12小时的累计释放量与时间的关系。图1是体外释放曲线图。如图1所示，制备的盐酸法莫替丁缓释混悬剂的两小时内释放度在20%左右，到12h时释放度接近90%，符合体外释放要求。可见，制备的盐酸法莫替丁缓释混悬剂符合缓释制剂的释放度要求，能够使药物缓慢释放进入体内。
实施例7：体内药动学实验
药物动力学（pharmacokinetics）是应用动力学的原理与数学处理方法，定量地描述药物通过各种途径进入机体内的吸收、分布、代谢和排泄等过程的动态变化规律，即研究体内药物的存在部位、浓度与时间之间的关系，并提出解释这些数据所需要的数学关系式的科学。本实施例中采用高效液相色谱法作为检测方法，以实施例1制备的盐酸法莫替丁缓释混悬剂为例对大鼠体内的药动学进行研究，同时以盐酸法莫替丁缓释片（20mg/片）作为对照。图2是盐酸法莫替丁缓释混悬制剂的体内药动学释放曲线图；如图2所示，盐酸法莫替丁释混悬剂（TEST）在体内释药比缓释片（REFERENCE）更平稳，药效持续时间更长。
可见，本发明所制备的盐酸法莫替丁缓释混悬剂具有更好的溶出速率和稳定性，具有更为优异的控释效果，每日仅给药一次即可提供有效的血药浓度。
实施例8:盐酸法莫替丁缓释混悬剂的稳定性实验
对本发明各实施例所制备的盐酸法莫替丁缓释混悬剂进行高温、高湿、光照、暴露空气稳定性实验。结果表明，在高温(60℃)、高湿(湿度75％)、光照(光照强度4500Lx±500Lx)、暴露空气3个月的条件下，含量、有关物质、药物溶出度未见明显变化，稳定性较好。
如上所述，本发明的包含盐酸法莫替丁的缓释混悬剂可以实现改善的缓释效果，提供了改善的溶出速率和稳定性，每日仅给药一次即可提供有效的血药浓度。与传统的、改善之前的药物制剂相比具有显著的治疗效果，给患者带来很大的用药便利，提高患者的药物依从性。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (10)
1.一种盐酸法莫替丁缓释混悬剂，其特征在于，所述的盐酸法莫替丁缓释混悬剂包括盐酸法莫替丁、缓释材料和其他药学上可接受的辅料；所述的缓释材料包括强酸性离子交换树脂和弱酸性离子交换树脂的结合物；按重量百分比计，每个剂量单位中含有盐酸法莫替丁25-40%，缓释材料60-75%，辅料余量。
2.根据权利要求1所述的盐酸法莫替丁缓释混悬制剂，其特征在于，所述的缓释材料为阳离子交换树脂与乙基纤维素，羟丙甲基纤维素，聚维酮，丙烯酸树脂中的一种或几种的混合物。
3.根据权利要求2所述的盐酸法莫替丁缓释混悬制剂，其特征在于，所述的阳离子交换树脂与盐酸法莫替丁的质量比为1~6:1。
4.根据权利要求2所述的盐酸法莫替丁缓释混悬制剂，其特征在于，所述的阳离子交换树脂为强酸性离子交换树脂和弱酸性离子交换树脂的结合物；所述强酸性离子交换树脂为Amberlite IRP69，所述弱酸性阳离子交换树脂为Amberlite IRP88和/或AmberliteIRP64。
5.根据权利要求3所述的盐酸法莫替丁缓释混悬制剂，其特征在于，所述强酸性离子交换树脂和弱酸性离子交换树脂的质量比为1: 2~9。
6.根据权利要求1所述的盐酸法莫替丁缓释混悬制剂，其特征在于，所述的辅料还包括浸渍剂、增塑剂和助悬剂；。
7.根据权利要求6所述的盐酸法莫替丁缓释混悬制剂，其特征在于，所述的浸渍剂选自甲基纤维素、甘油、聚乙二醇（PEG）4000、PEG3350中的一种或几种；所述的浸渍剂与阳离子交换树脂的质量比为1:0.3~1。
8.根据权利要求6所述的盐酸法莫替丁缓释混悬制剂，其特征在于，所述的增塑剂选自邻苯二甲酸二乙酯、癸二酸二丁酯、三醋酸甘油酯、PEG400中的一种或一种以上。
9.根据权利要求6所述的盐酸法莫替丁缓释混悬制剂，其特征在于，所述的助悬剂选自甘油、糖浆、淀粉、琼脂、PVP、HPMC、西黄耆胶、海藻酸钠、阿拉伯胶、微晶纤维素、PEG、Carbopol、Avicel RC591中的一种或一种以上。
10.一种盐酸法莫替丁缓释混悬制剂的制备方法，其特征在于，所述制备方法包括以下步骤：
（1）将法莫西丁加入到HCl中，搅拌状态下加入强酸性阳离子和弱酸性阳离子的结合物，达到载药平衡后清洗树脂表面，干燥得到载药树脂；
（2）载药树脂在浸渍剂中进行浸渍得到浸渍树脂；
（3）将浸渍树脂和增塑剂加入有机溶剂中作为分散相，液体石蜡加入到司盘中作为连续相，将分散相加入到连续相中得到药物-树脂微囊；
（4）将制备的药物-树脂微囊与助悬剂和蒸馏水混匀得到盐酸法莫替丁缓释混悬制剂。
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