CN115708811A - 一种制备胃滞留型西格列汀二甲双胍复方缓释片剂的方法 - Google Patents
一种制备胃滞留型西格列汀二甲双胍复方缓释片剂的方法 Download PDFInfo
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Abstract
本发明制备一种胃滞留型复方缓释片剂，包括盐酸二甲双胍胃漂浮缓释片芯和西格列汀速释层包衣两部分。所述片芯层由药物和骨架材料制成；所述速释层由药物、抗氧剂和速释包衣材料制成，速释包衣材料包括成膜材料、增塑剂、抗粘剂制成。同时，本发明还提供了制备该片剂的制备方法。本发明提供的具有协同作用的两种口服降血糖药物制备成复方缓释制剂，使其兼具缓释制剂和复方制剂的双重优势，用于单独服用盐酸二甲双胍或西格列汀不足以控制血糖的II型糖尿病患者，不仅具有体外释放平稳，而且工艺稳定、批内批间均一性良好。
Description
技术领域
本发明属于医药技术领域，具体的讲是一种胃滞留型西格列汀二甲双胍复方缓释片及其制备方法。
背景技术
糖尿病是一种困扰全球的常见慢性综合性疾病，其发病率逐年攀升，已成为21世纪人类健康的主要威胁之一。糖尿病是以高血糖为特征的常见多发病，是由于体内胰岛素分泌、作用缺陷，或二者同时存在，引起糖、脂肪、蛋白质代谢紊乱。临床上主要有胰岛素依赖型(IDDM，I型)和非胰岛素依赖型(NIDDM，II型)两种类型，其中II型糖尿病约占糖尿病患者总数的90%以上。目前的治疗手段主要是改变生活方式，降血糖和增强胰岛素敏感性，临床上常用的口服降糖药物主要有磺酰脲类与非磺酰脲类促胰岛素分泌剂、双胍类、α-葡萄糖苷酶抑制剂、噻唑烷二酮类胰岛素增敏剂等。随着研究的深入，许多针对II型糖尿病病因的新靶点不断被开发，出现了一系列可持续控制血糖水平，有效阻滞病情发展的新型降糖药物，其中以二肽基肽酶-4 (DPP-4)为靶点的药物研究最为突出。
胃滞留给药系统是制剂口服后能够长时间停留于胃部,不被胃排空到肠道，从而实现定位释放，提高药物生物利用度的给药系统。胃滞留给药系统能够解决传统制剂由于吸收窗窄、药物半衰期短、碱性环境不稳定等缺陷，口服后生物利用度低等问题，对减少药物损失具有积极意义。胃滞留系统通常包括漂浮型、膨胀型、生物黏附型、高密度沉降型、多孔水凝胶系统和磁力给药系统。膨胀型给药系统通过添加膨胀材料使得片剂体积变大，不能通过幽门，实现胃滞留效果，生物黏附型给药系统通过使用生物黏附型材料如卡波姆、聚卡波菲等，使片剂遇水后表面能够粘附于胃黏膜，延长药物释放时间，两者合用对胃损伤小，受胃生理环境以及其他外界因素影响小，是一种比较理想的胃滞留给药系统。
盐酸二甲双胍是双胍类口服降血糖药，是治疗II型糖尿病的一线药物，其具有t1/2短，一天服药三次，胃肠道不良反应发生率高等特点。为降低药物毒副作用、减小血药浓度波动、提高患者用药顺应性，本发明将盐酸二甲双胍设计为每日给药一次的缓释制剂。本发明中通过将盐酸二甲双胍制备成胃漂浮型缓释片剂，可获得理想的释药速率，低胃肠道不良反应，取得预期的血药浓度，避免峰谷现象，并能维持较长的作用时间。
西格列汀为口服有效和高选择性的二肽基肽酶-4 (DPP-4)抑制剂，在II型糖尿病患者中可通过增加活性肠促胰岛激素的水平而改善血糖控制。肠促胰岛激素包括胰高糖素样多肽-1 (GLP-1) 和葡萄糖依赖性促胰岛素分泌多肽(GIP)，血糖浓度正常或升高时，GLP-1和GIP通过涉及环磷腺苷的细胞内信号途径增加胰腺β细胞合成并释放胰岛素，并且GLP-1 可以抑制胰腺α细胞分泌胰高糖素。胰高糖素浓度的降低和胰岛素水平的升高可降低肝葡萄糖生成，从而降低血糖水平。DPP-4抑制剂具有干扰生物活性肽GLP-1血浆水平的特性，为糖尿病的治疗提供了新的用药选择。
盐酸二甲双胍与西格列汀作用机制互补，可发挥协同增效的作用，能更有效地控制血糖，减少低血糖风险，对糖尿病的治疗更加有利。把两种或者两种以上的药做成复方制剂后不仅减少给药次数，降低药物毒副作用，延缓药物的释放，提高患者的顺应性，而且降低辅料及包装成本，有利于降低药价和工业化生产。
发明内容
本发明的目的就是提供一种胃滞留型西格列汀二甲双胍复方缓释片及制备方法，主要是解决低剂量范围的西格列汀和高剂量范围的盐酸二甲双胍制成复方制剂以及盐酸二甲双胍生物利用度低的问题。西格列汀和盐酸二甲双胍两个主药的理化性质不同，体内药动学性质也不同，针对药物不同的性质来进行合理设计，设计盐酸二甲双胍胃漂浮缓释片和西格列汀速释层包衣，实现两个药物在体内的不同释放行为。
本发明中所述的胃滞留型复方缓释片，由盐酸二甲双胍胃漂浮缓释片芯和西格列汀速释包衣层两部分；所述片芯层由药物和骨架材料制成。所述速释层由药物、抗氧剂和速释包衣材料制成，速释包衣材料包括成膜材料、增塑剂、抗粘剂制成。
本发明中所述片芯层中药物为盐酸二甲双胍，其骨架材料可以为亲水凝胶骨架材料中的一种或多种。其亲水凝胶骨架材料为遇水膨胀后，能形成凝胶屏障而控制药物释放的材料，主要有四类：(1)天然高分子材料类，如海藻酸钠、琼脂、西黄蓍胶；(2)纤维素类，如微晶纤维素、羟丙基甲基纤维素、羧甲基纤維素及其钠盐、羟醋酸纤维素；(3)非纤维素多糖类，如壳聚糖、乳糖、半乳糖、甘露聚糖；(4)乙烯聚合物类，如卡波姆、聚乙烯醇。所述生物溶蚀性骨架材料是指本身不溶解，但是在胃肠液环境下可以逐渐溶蚀的材料：主要有两类：(1)惰性蜡质类，如蜂蜡、巴西棕榈蜡、蓖麻蜡、硬脂醇：(2)脂眆酸及其酯类，如硬脂酸及其盐、氢化植物油、聚乙二醇、十六醇、单硬脂酸甘油脂、甘油三酯。本发明选择上述材料中的一种或多种，并按照适当比例混配，将其作为片芯层的骨架材料。
所述速释层中药物为西格列汀，其在胃中快速释放控制血糖。速释层由药物、抗氧剂和速释包衣材料制成。所述速释层由药物、抗氧剂和速释包衣材料制成，速释包衣材料包括成膜材料、增塑剂、抗粘剂制成。速释包衣材料的组成主要包含(1)成膜材料，如羟丙甲纤维素、羟丙基纤维素、醋酸纤维素、乙烯-醋酸乙烯共聚物、不溶性丙烯酸树脂中的一种或多种；(2)增塑剂，如增塑剂为癸二酸二丁酯、邻苯二甲酸酯、邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、柠檬酸三乙酯、柠檬酸三丁酯、甘油单醋酸酯、甘油三醋酸酯、二丁基癸酸酯、蓖麻油、玉米油或液状石蜡中的一种或多种；(3)抗粘剂，抗粘剂选自微粉硅胶、硬脂酸钠、硬脂富马酸钠、滑石粉中的一种或多种；以及润湿剂，如蒸馏水、乙醇或乙醇-水混合液；
如上所述的胃滞留型复方缓释片剂的制备方法，包括以下步骤：
(a)准备片芯层原料药，将盐酸二甲双胍原料药、亲水凝胶骨架材料、稀释剂、崩解剂、润滑剂分别过80目筛网，混合均匀，备用；
(b)采用制粒压片法或直接压片法压制片芯层；
(c)采用高效包衣法用磷酸西格列汀一水合物、速释包衣材料和抗氧剂对(b)步制备的片剂进行包衣；
所述片芯采用平面胶囊型冲压制压制成对称型的片剂。
所述包衣层的制备采用高效包衣法，所述高效包衣法是将所述步骤(b)制备的片剂放入高效包衣锅内进行包衣，达到预定包衣增重后，将包衣片取出。
本发明提供的胃滞留型复方缓释片剂配以适当比例的药物及辅药得到，在实验检测中可以证明盐酸二甲双胍具有体外释放度缓释的性能，西格列汀药物不仅能发挥速效的作用，并且有效成分在抗氧剂的保护下，可以有效地避免光照分解：在加速实验中药物的含量和释放度均无明显变化，其稳定性很高。在不同pH环境下的释放介质中(即：消化道各个部位)释放行为基本一致，尤其在体内药物的血峰浓度降低，达峰时间延长，体内滞留时间延长，药效发挥缓慢而持久。
附图说明
图1为实施例1胃滞留型西格列汀二甲双胍缓释片释放曲线
图2为实施例2胃滞留型西格列汀二甲双胍缓释片释放曲线
图3为实施例3胃滞留型西格列汀二甲双胍缓释片释放曲线
具体实施方式
下面实施例用于进一步详细说明本发明，但不以任何形式限制本发明
实施例1
盐酸二甲双胍胃漂浮缓释片芯的制备：以100片量计，盐酸二甲双胍50g、卡波姆16.36g、羟丙甲基纤维素16.36g、微晶纤维素0.737g、交联聚乙烯吡咯烷酮6.545g、硬脂富马酸钠1.00g；西格列汀速释包衣层的制备：以100片量计，西格列汀5g、没食子酸丙酯0.16g、速释包衣材料6.225g；其中速释包衣材料由组成：聚乙烯醇50%、聚乙二醇35%、滑石粉15%组成,纯化水83.5ml。
其制备工艺为：
(1) 将盐酸二甲双胍、微晶纤维素、羟丙甲纤维素等分别粉碎，过80目筛，备用。
(2) 按处方比例称量取盐酸二甲双胍、微晶纤维素、羟丙甲基纤维素、卡波姆与硬脂富马酸钠，以等量递加法将各原辅料混合均匀
(3) 采用粉末直压的方法制备片剂，Φ19x8mm胶囊型异形冲压制，片重为910mg，硬度6-9kg/cm2。
(4) 配制12%含量西格列汀包衣混悬液:使用合适的均质器，将速释包衣材料和没食子酸丙酯均匀溶解在纯化水中，搅拌90min,直到粉末均匀地分散在包衣混悬液中。
(5) 将片剂放入高效包衣锅中进行包衣，包衣锅转速为10r/min，包衣温度保持在40~50℃，包衣增重约为步骤(3)制备片剂重量的12.5%。
(6) 停止喷雾，使片剂干燥，并从包衣浅盘中取出。得每片含盐酸二甲双胍500mg和西格列汀50mg的胃滞留型盐酸二甲双胍西格列汀缓释片。
实施例2
盐酸二甲双胍胃漂浮缓释片芯的制备：以100片量计，盐酸二甲双胍50g、卡波姆18.20g、羟丙甲基纤维素13.65g、微晶纤维素2.20g、交联聚乙烯吡咯烷酮5.46g、硬脂富马酸钠1.50g；西格列汀速释包衣层的制备：以100片量计，西格列汀5.0g、没食子酸丙酯0.068g、速释包衣材料6.225g；其中速释包衣材料由组成：聚乙烯醇50%、聚乙二醇30%、滑石粉15%、二氧化钛5%组成,纯化水70ml。
其制备工艺为：
(1) 将盐酸二甲双胍、微晶纤维素、羟丙甲纤维素等分别粉碎，过80目筛，备用。
(2) 按处方比例称量取盐酸二甲双胍、微晶纤维素、羟丙甲基纤维素、卡波姆与硬脂富马酸钠，以等量递加法将各原辅料混合均匀
(3) 采用粉末直压的方法制备片剂，Φ19x8mm胶囊型异形冲压制，片重为910mg，硬度6-9kg/cm2。
(4) 配制14%含量西格列汀包衣混悬液:使用合适的均质器，将速释包衣材料和没食子酸丙酯均匀溶解在纯化水中，搅拌90min,直到粉末均匀地分散在包衣混悬液中。
(5) 将片剂放入高效包衣锅中进行包衣，包衣锅转速为10r/min，包衣温度保持在40~50℃，包衣增重约为步骤(3)制备片剂重量的13.0%。
(6) 停止喷雾，使片剂干燥，并从包衣浅盘中取出。得每片含盐酸二甲双胍500mg和西格列汀50mg的胃滞留型盐酸二甲双胍西格列汀缓释片。
实施例3
盐酸二甲双胍胃漂浮缓释片芯的制备：以100片量计，盐酸二甲双胍50g、卡波姆10.94g、羟丙甲基纤维素16.36g、微晶纤维素8.412g、交联聚乙烯吡咯烷酮4.378g、硬脂富马酸钠0.95g；西格列汀速释包衣层的制备：以100片量计，西格列汀5.0g、没食子酸丙酯0.20g、速释包衣材料6.225g；其中速释包衣材料由组成：聚乙烯醇60%、聚乙二醇10%、滑石粉15%、二氧化钛15%组成,纯化水76ml。
其制备工艺为：
(1) 将盐酸二甲双胍、微晶纤维素、羟丙甲纤维素等分别粉碎，过80目筛，备用。
(2) 按处方比例称量取盐酸二甲双胍、微晶纤维素、羟丙甲基纤维素、卡波姆与硬脂富马酸钠，以等量递加法将各原辅料混合均匀
(3) 采用粉末直压的方法制备片剂，Φ19x8mm胶囊型异形冲压制，片重为910mg，硬度6-9kg/cm2。
(4) 配制13%含量西格列汀包衣混悬液:使用合适的均质器，将速释包衣材料和没食子酸丙酯均匀溶解在纯化水中，搅拌90min,直到粉末均匀地分散在包衣混悬液中。
(5) 将片剂放入高效包衣锅中进行包衣，包衣锅转速为10r/min，包衣温度保持在40~50℃，包衣增重约为步骤(3)制备片剂重量的12.0%。
(6) 停止喷雾，使片剂干燥，并从包衣浅盘中取出。得每片含盐酸二甲双胍500mg和西格列汀50mg的胃滞留型盐酸二甲双胍西格列汀缓释片。
对本发明所述片剂的性能检测
一、实施例制备的片剂的体外释放性能测定
1．实验方法：取实施例1制备的胃滞留型西格列汀二甲双胍缓释片采用释放度测定法依据中国药典2020年版二部附录XD测定药物的释放度，以0.025mol/L氯化钠溶液900mL为释放介质，转速为75r/min，温度为37℃，在设定的时间点5min、10min、15min、20min、30min、45min、60min、2h、3h、4h、6h、8h、10h、12h、24h取释放液10mL(同时补充同体积释放液)，用0.45μm微孔滤膜过滤，取续滤液，按照高效液相色谱法测定峰面积，计算药物累计释放百分率
检测结果：实施例1的释药曲线如图1所示。从图1可以看出盐酸二甲双胍胃漂浮缓释片具有良好的缓释效果，西格列汀则达到速释效果。
2. 实验方法：取实施例2制备的胃滞留型西格列汀二甲双胍缓释片采用释放度测定法依据中国药典2020年版二部附录XD测定药物的释放度，以0.025mol/L氯化钠溶液900mL为释放介质，转速为75r/min，温度为37℃，在设定的时间点5min、10min、15min、20min、30min、45min、60min、2h、3h、4h、6h、8h、10h、12h、24h取释放液10mL(同时补充同体积释放液)，用0.45μm微孔滤膜过滤，取续滤液，按照高效液相色谱法测定峰面积，计算药物累计释放百分率
检测结果：实施例2的释药曲线如图2所示。从图2可以看出盐酸二甲双胍胃漂浮缓释片具有良好的缓释效果，西格列汀则达到速释效果。
3. 实验方法：取实施例3制备的胃滞留型西格列汀二甲双胍缓释片采用释放度测定法依据中国药典2020年版二部附录XD测定药物的释放度，以0.025mol/L氯化钠溶液900mL为释放介质，转速为75r/min，温度为37℃，在设定的时间点5min、10min、15min、20min、30min、45min、60min、2h、3h、4h、6h、8h、10h、12h、24h取释放液10mL(同时补充同体积释放液)，用0.45μm微孔滤膜过滤，取续滤液，按照高效液相色谱法测定峰面积，计算药物累计释放百分率。
检测结果：实施例3的释药曲线如图3所示。从图3可以看出盐酸二甲双胍胃漂浮缓释片具有良好的缓释效果，西格列汀则达到速释效果。
实施例1-3实施例结果趋势基本一致。
二、实施例3制备的胃滞留型缓释片剂的稳定性研究
(1)强光照射试验将实例3的胃滞留型西格列汀二甲双胍缓释片在照度为4500±500Lx条件下放置5天和10天，取样测定含量和释放度。
检测结果：见表1和表2。从表中可以看到可见药物含量和释放度均无明显变化，说明西格列汀和盐酸二甲双胍，可以有效地避免光照分解。其他实施例的结果与该结果基本相似。
表1胃滞留型西格列汀二甲双胍缓释片剂在强光照射下的实验结果
(2)加速试验 将实施例3胃滞留型西格列汀二甲双胍缓释片进行加速试验，在温度40℃的条件下放置6个月，于0、1、2、3、6个月分别取样测定含量和释放度。
检测结果：见表2。从表中可以看到经6个月的加速实验，硝苯地平的含量和释放度均无明显变化，表明本制剂稳定性良好。
表2胃滞留型西格列汀二甲双胍缓释片的高温加速试验结果
Claims (10)
1.一种胃滞留型复方缓释片剂，其特征在于，包括盐酸二甲双胍胃漂浮缓释片芯以及包裹在所述片芯表面的西格列汀速释包衣层所制备的复方片剂。所述片芯层由药物和骨架材料制成。所述速释层由药物、抗氧剂和速释包衣材料制成，速释包衣材料包括成膜材料、增塑剂、抗粘剂制成。
2.根据权利要求1所述的胃漂浮缓释片芯，其特征在于，所述骨架材料为亲水凝胶骨架材料所述亲水凝胶骨架材料是指海藻酸钠、琼脂、西黄蓍胶、微晶纤维素、羟丙基甲基纤维素、羧甲基纤维素及其钠盐、羟醋酸纤维素、壳聚糖、乳糖、半乳糖、甘露聚糖、卡波姆、泊洛沙姆或聚乙烯醇中的一种或多种。
3.根据权利要求1所述的胃漂浮缓释片芯，其特征在于，所述稀释剂为乳糖、蔗糖、淀粉、糊精、预胶化淀粉、微晶纤维素、无机盐类、糖醇类中的一种或多种。
4.根据权利要求1所述的胃漂浮缓释片芯，其特征在于，所述崩解剂剂选自干淀粉、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠的一种或多种。
5.根据权利要求1所述的胃漂浮缓释片芯，其特征在于，所述润滑剂为硬脂酸镁、硬脂富马酸钠、微粉硅胶、滑石粉、氢化植物油、聚乙二醇或十二烷基硫酸钠中的一种或多种。
6.根据权利要求1所述的速释包衣层，其特征在于，所述抗氧剂选自没食子酸丙酯、叔丁基对苯二酚、酒石酸、生育酚中的一中或多种。
7.根据权利要求1所述的速释包衣层，其特征在于，所述速释包衣材料的成膜材料为羟丙甲纤维素、羟丙基纤维素、醋酸纤维素、乙烯-醋酸乙烯共聚物、不溶性丙烯酸树脂中的一种或多种；增塑剂为癸二酸二丁酯、邻苯二甲酸酯、邻苯二甲酸二乙酯、邻苯二甲酸二丁酯、柠檬酸三乙酯、柠檬酸三丁酯、甘油单醋酸酯、甘油三醋酸酯、二丁基癸酸酯、蓖麻油、玉米油或液状石蜡中的一种或多种。
8.根据权利要求1所述的速释包衣层，其特征在于，所述抗粘剂选自微粉硅胶、硬脂酸钠、硬脂富马酸钠、滑石粉中的一种或多种。溶剂为水、乙醇、丙酮或两者任意比例的混合液。
9.根据权利要求1所述的胃滞留型复方缓释片剂，其特征在于，所述片芯层为中心对称型。
10.一种如权利要求1-9所述的胃滞留型复方缓释片的制备方法，其特征在于，包括以下步骤：
(a)准备片芯层原辅料，将盐酸二甲双胍原料药、亲水凝胶骨架材料、稀释剂、崩解剂、润滑剂分别过80目筛网，混合均匀，备用；
(b)采用制粒压片法或直接压片法压制片芯层；
(c)采用高效包衣法用西格列汀、速释包衣材料和抗氧剂对(b)步制备的片剂进行包衣。
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| CN112691106A (zh) * | 2019-10-23 | 2021-04-23 | 南京正大天晴制药有限公司 | 西格列汀二甲双胍缓释片 |
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| CN112691106A (zh) * | 2019-10-23 | 2021-04-23 | 南京正大天晴制药有限公司 | 西格列汀二甲双胍缓释片 |
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