CN115154435B - 一种微泡型胃滞留缓控释片剂及其制备方法 - Google Patents
一种微泡型胃滞留缓控释片剂及其制备方法 Download PDFInfo
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- CN115154435B CN115154435B CN202210802914.4A CN202210802914A CN115154435B CN 115154435 B CN115154435 B CN 115154435B CN 202210802914 A CN202210802914 A CN 202210802914A CN 115154435 B CN115154435 B CN 115154435B
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Abstract
本发明提供了一种微泡型胃滞留缓控释片剂及其制备方法，所述片剂含有有效量的药物活性成分，聚环氧乙烷，发泡剂，各组分的重量百分比为：本发明制剂是协同型胃滞留制剂，较单一胃滞留制剂有更优的胃滞留效果，可以实现优良的零级缓释效应。
Description
技术领域
本发明属于药物制剂范畴，涉及一种协同型胃滞留缓控释微泡制剂，以及多种缓释辅料、药物活性成分、发泡剂、填充剂的广泛应用。特别涉及聚环氧乙烷(PEO)作为凝胶骨架缓控释材料的应用。
背景技术
与其他给药途径相比，口服给药途径具有方便、安全、成本低、患者可接受程度高的优点。为了减少口服给药的频率，提高药物的安全性，临床上对能稳定释放药物的缓控释口服制剂的需求越来越大，但往往因为缓控释口服制剂的制备工艺复杂、成本较高而不能在临床上广泛应用。
胃滞留缓控制制剂系统(Gastric Retention-type Sustained and ControlledRelease Drug Delivery System)，目前主要分为
1.漂浮型胃滞留缓控释给药系统
2.黏附型胃滞留缓控释给药系统
3.膨胀型胃滞留缓控释给药系统
4.高密度系统的设计
5.协同型胃滞留缓控释给药系统
目前，各类胃滞留给药系统的研究都已经取得了一定的进展，但是复杂的人体生理结构与胃部复杂的环境存在着诸多影响药物递送和释放的因素。因此，大多数胃滞留给药制剂还停留在研究阶段，市场上广泛使用的胃滞留型给药制剂较少。结合多种不同胃滞留机制的协同型胃滞留给药系统是改善制剂胃滞留能力的新途径。基于此，本发明在制备片剂不但可以实现快速漂浮、生物黏附，更重要的是其遇水可迅速膨胀，创制出了一种基于漂浮黏附膨胀机制的新型协同型胃滞留缓控释制剂。
聚环氧乙烷作为新型亲水性高分子材料在口服凝胶骨架片中的应用越来越广泛，但是国内应用报道甚少。聚环氧乙烷化学性能稳定，具有优良的相容性、流动性、可压性、稳定性，低毒性、有一系列相对分子质量的产品可供不同需求，且易形成凝胶，吸水可以较快膨胀。聚环氧乙烷具有亲水性，
聚环氧乙烷在药剂学领域中应用广泛，尤其在口服凝胶缓释片中具有较大的应用潜力，在药物制剂的生产中正逐渐取代传统的缓释辅料。
胃漂浮片(floatingtablets)又称胃内滞留片、漂浮给药系统或水动力平衡系统,是指口服后能保持自身密度小于胃内容物密度,而在胃液中呈漂浮状态的制剂，利用浮力延长制剂在胃部的停留时间。
本发明人在胃滞留片中研究中将聚环氧乙烷作为亲水性凝胶骨架，意外发现，聚环氧乙烷和发泡剂具有协同作用，聚环氧乙烷在片剂中可以使胃滞留片遇到液体后能够形成凝胶层，提高胃滞留片的黏附性，同时制剂遇到胃液会快速膨胀，使片剂不易通过幽门，延长片剂在胃内的滞留时间。发泡剂在片剂中均匀分布在缓释骨架中，其能够与胃酸反应生成极其微小CO2气泡，附着在片剂上，增加本滞留片的胃液中漂浮力；CO2等气体的释放使片剂产生孔道，有利于水分渗入和药物释出；同时，聚环氧乙烷具有亲水性形成的凝胶层可以封闭产生的气泡阻碍其扩散使片剂能够达到零级释放。
我们在研究开发胃滞留缓控释微泡制剂的实验过程中，发现了聚环氧乙烷的控释效果以及具有开发出协同型胃滞留制剂的巨大前景，并基于此成功制备出在胃内可实现零级释放的协同型胃滞留控释片剂。
本发明提供的制剂服用方便，药物释放时间长，且有恒速释药的释放动力学特性，可以减少血药浓度波动，提高药物的安全性和生物利用度。本发明示例之中，罗通定胃滞留微泡控释片适用于长期疼痛、围手术期、癌痛患者镇痛，或联合其他药品辅助戒毒；硝酸异山梨酯胃滞留微泡控释片临床可用于治疗各种类型冠心病心绞痛和预防发作；卡比多巴胃滞留微泡控释片作为协同治疗帕金森病的药物，有更为广阔的应用前景。
发明内容
基于以上问题，本发明的目的是为了克服上述现有制剂的不足，提供一种处方简洁，制备工艺简单，服用方便，作用持久且稳定的胃滞留缓控释微泡制剂处方及其制备方法。活性成分可选用但不限制于下述药物，如中枢神经以及外周神经类药物、生物碱类药物、镇痛药、非甾体抗炎药等或临床应用中有缓控释需求的各类药物，其他为辅料。
本发明提供一种微泡型胃滞留缓控释片剂及其制备方法，所述片剂含有有效量的药物活性成分，聚环氧乙烷，发泡剂。
其中，各组分的重量百分比为
优选的，
其中，所述药物活性成分选自：中枢神经以及外周神经类药物、生物碱类药物、镇痛药、非甾体抗炎药等或临床应用中有缓控释需求的各类药物。其中优选生物碱类药物，抗抑郁、镇静等中枢神经类药物、镇痛药。最优选的药物活性成分为：生物碱类镇痛药罗通定、抗帕金森药物卡比多巴，冠心病长期治疗药物硝酸异山梨酯。
其中，所述发泡剂选自：碳酸氢钠、碳酸钠、碳酸氢钾、碳酸钙、碳酸氢铵等或它们的混合物。优选微粉化以及纳米化发泡剂，帮助制剂产生微小气泡(<100μm)附着于本制剂，进一步帮助本制剂悬浮滞留于胃液中。
其中，所述其他成分包括填充剂和润滑剂，所述填充剂选自：微晶纤维素(MCC)、淀粉、预胶化淀粉、乳糖、糊精、甘露醇、蔗糖、无机盐等其他可帮助制剂增加体积及重量的辅料或它们的混合物。所述润滑剂选自：硬脂酸镁、硬脂酸、硬脂酸锌、硬脂酸钙、滑石粉、十二烷基硫酸镁、微粉硅胶、氢化植物油、聚乙二醇类等或它们的混合物。
其中，所述聚环氧乙烷可以使用其他任何一种功能相同或相似的适合的缓控释骨架材料替代，如：溶性骨架材料、蜡质骨架材料、亲水凝胶骨架材料以及混合骨架材料。可选用材料如乙基纤维素(EC)、聚乙烯、聚丙烯、聚硅氧烷、聚氧乙烯、羟丙甲基纤维素、十八烷(SA)等或它们的混合物。这些材料可以帮助本制剂实现控释效果，同时在胃内快速膨胀，使制剂不易通过幽门，本制剂缓释凝胶骨架可黏附滞留于胃中，进一步帮助本制剂滞留于胃中并锁住气泡。
本发明进一步提供本发明微泡型胃滞留缓控释片剂的制备方法，可以采用如熔融制粒压片、湿法制粒压片、干法制粒压片等或其他工艺制备。优选熔融法制粒，直接压片法制备。
具体制备方法如下所述：将药物活性成分、填充剂、发泡剂、聚环氧乙烷按量分别称取，其中发泡剂过200目及以上筛，后将全部处方过筛混合均匀，熔融制粒，趁热过筛混匀，加入适量润滑剂，再次过筛混匀，对中间体进行含量测定，按规格量直接压片，即得微泡型胃滞留缓控释片剂。
该微泡型胃滞留缓控释片剂硬度在20-100N之间，重量差异±5％，采用100r/min转篮法测定溶出，在37℃的pH＝1.2盐酸溶液(人工胃液)中立即漂浮，漂浮时间可长达72小时，8-72小时内,溶出度显示累积释放百分率要求达到90％以上。
该微泡型胃滞留缓控释片剂溶胀实验在含0.004％亚甲基蓝的pH＝1.2的盐酸溶液中进行，制剂可在30min内膨胀度大于250％，平衡后在人工胃液中的膨胀度大于400％，进而帮助本制剂更好的滞留于胃中。
本发明的具体实施案例分别将生物碱类镇痛药罗通定、抗帕金森药物卡比多巴，冠心病长期治疗药物硝酸异山梨酯作为药物活性成分，实现了在胃内持续长时间控制释药，解决了现有制剂作用时间短需多次服药的不足。本胃滞留缓控释片采用普通片剂制药设备，采用熔融制粒压片工艺，制得该制剂应具有适当硬度，便于携带，便于服用。
本发明发现，聚环氧乙烷可以封闭气泡阻碍其扩散，在口服凝胶骨架片中可以达到零级释放。具体实例如本发明实施例1和4。
聚环氧乙烷，结构如下：
-[-CH2─CH2─O-]-n
使用聚环氧乙烷+发泡剂制备的微泡型胃滞留缓控释片没有文献报道。
其他口服凝胶骨架材料无法达到本发明的效果，如《帕利哌酮胃滞留片及其制备方法》专利中实施例涉及HPMC亲水凝骨架+发泡剂并没有达到零级释放。
因此，本发明基于漂浮黏附膨胀机制利用凝胶骨架吸水膨胀空间对微小气泡进行有效包封，同时基于凝胶骨架的粘附作用，可以使制剂实现更好的胃滞留效果，最终制出新型协同型胃滞留缓控释制剂。
以下通过实验数据进一步说明本发明的有益效果
实验一、采用聚环氧乙烷+发泡剂制备的微泡型胃滞留缓控释片进行实验，有关实验结果如下：
释放效果实验：可达到较好的零级控释效果
实验方法：将制备好的片剂分别于0.004％亚甲基蓝的pH＝1.2的盐酸溶液中进行溶胀实验结果测定；于37℃的pH＝1.2盐酸溶液(人工胃液)中100r/min转篮法测定溶出结果。
实验药物：罗通定。
实验结果：溶胀结果如图1显示，溶出结果如实施例1溶出释放曲线所示。
如图1显示，按上述实验一方法制备的片剂于300ml含0.004％亚甲基蓝的pH＝1.2的盐酸溶液中进行溶胀实验，观察到片剂内部含有微小气泡，且气泡没有溢出。由此证明本发明片剂中凝胶骨架对微小气泡进行了有效包封。
如图2显示，24h内以PEO做缓释骨架的片剂在人工胃液中膨胀体积变化示意图。根据测量结果得出本片剂可实现30min内快速膨胀，24h内膨胀度大于250％。
如图3片剂长短直径随时间变化曲线，图3显示，24h内以PEO做缓释骨架的片剂在人工胃液中溶胀实验，控制片剂纵向溶胀，测量片剂横向溶胀。溶胀实验测量结果进一步量化片剂膨胀体积变化。膨胀速率、膨胀度越大越有利于维持片剂胃滞留效果。
实验二、其他亲水凝胶骨架材料+发泡剂制备的微泡型胃滞留缓控释片实验：释放效果实验：不能达到零级控释效果，但可产生缓释效果
实验方法：将制备好的片剂分别于0.004％亚甲基蓝的pH＝1.2的盐酸溶液中进行溶胀实验结果测定；于37℃的pH＝1.2盐酸溶液(人工胃液)中100r/min转篮法测定溶出结果。
实验药物：硝酸异山梨酯。
实验结果：溶胀结果如图4显示，溶出结果如实施例三溶出释放曲线所示。
如图4显示，按上述实验二方法制备的片剂于300ml含0.004％亚甲基蓝的pH＝1.2的盐酸溶液中进行溶胀实验，观察到片剂外周有密集微小气泡产生。由此证明普通亲水凝胶骨架对微小气泡无包封作用。
实验结果对比：
#其中的现有技术为《罗通定缓释片及其生产工艺》文献中对该实施例进行了复制，得到对应的药物片剂。
#其中的现有技术为《一种单硝酸异山梨酯缓释片剂及其制备方法》专利中实施例3的技术，对该实施例进行了复制，得到对应的药物片剂。
由上表可知，本发明片剂，在所有指标上优于现有技术。
附图说明：
图1实验一方法制备的片剂溶胀实验，观察到片剂内部含有微小气泡，且气泡没有溢出，由此证明本发明片剂中凝胶骨架对微小气泡进行了有效包封。
图2 24h内以PEO做缓释骨架的片剂在人工胃液中膨胀体积变化示意图。根据测量结果得出本片剂可实现30min内快速膨胀，24h内膨胀度大于250％。
图3片剂长短直径随时间变化曲线，图3显示，24h内以PEO做缓释骨架的片剂在人工胃液中溶胀实验，控制片剂纵向溶胀，测量片剂横向溶胀。溶胀实验测量结果进一步量化片剂膨胀体积变化。膨胀速率、膨胀度越大越有利于维持片剂胃滞留效果。
图4，实验二方法制备的片剂溶胀实验，观察到片剂外周有密集微小气泡产生。由此证明普通亲水凝胶骨架对微小气泡无包封作用。
图5，本发明制剂可在人工胃液环境中产生微小(<100μm)CO2气泡
图6，实例一：罗通定零级溶出释放曲线
图7，实例二：罗通定Higuchi溶出释放曲线
图8，实例三：硝酸异山梨酯一级溶出释放曲线
图9，实例四：卡比多巴零级溶出释放曲线
图10，实例五：卡比多巴一级溶出释放曲线
具体实施方式
实施例一：
采用直接压片工艺制备。具体制备方法如下所示：将罗通定、微晶纤维素、碳酸氢钠、聚环氧乙烷分别按量称取，混匀，55-70℃熔融制粒，趁热过24目筛，再加入1.5％的微粉硅胶，过筛混匀，片重差异±5％，测定含量，按规格量压片。
上述制得罗通定缓释片硬度在20-100N之间，采用100r/min转篮法测定溶出，在37℃pH＝1.2盐酸中，立即漂浮，24小时内,符合零级释放Mt/M∞＝kt，溶出度大于90％，随时间变化溶出曲线相关系数R2＞0.99。
实施例二：
采用直接压片工艺制备。具体制备方法如下所示：将罗通定、微晶纤维素、碳酸氢钠、十八醇、分别按量称取，混匀，55-70℃熔融制粒，趁热过24目筛，再加入1.5％的硬脂酸镁，过筛混匀，片重差异±5％，测定含量，按规格量压片。
上述制得罗通定缓释片硬度在20-100N之间，采用100r/min转篮法测定溶出，在37℃pH＝1.2盐酸中，立即漂浮，24小时内,溶出度大于90％，随时间变化溶出曲线R2＞0.99，释放符合Higuchi方程Mt/M∞＝kt1/2。
实施例三：
采用直接压片工艺制备。具体制备方法如下所示：将硝酸异山梨酯、乳糖、碳酸氢钠、十八醇、HPMC分别按量称取，混匀，55-70℃熔融制粒，趁热过24目筛，再加入1.5％的滑石粉，过筛混匀，测定含量，按规格量压片。
上述制得硝酸异山梨酯缓释片硬度在20-100N之间，采用100r/min转篮法测定溶出，在37℃pH＝1.2盐酸中，立即漂浮，24小时内,溶出度大于90％，随时间变化溶出曲线R2＞0.99，释放符合一级方程ln(1-Mt/M∞)＝-kt。
实施例四：
采用直接压片工艺制备。具体制备方法如下所示：将卡比多巴、微晶纤维素、碳酸氢钠、聚环氧乙烷分别按量称取，混匀，55-70℃熔融制粒，趁热过24目筛，再加入1.5％的微粉硅胶，过筛混匀，片重差异±5％，测定含量，按规格量压片。
上述制得卡比多巴缓释片硬度在20-100N之间，采用100r/min转篮法测定溶出，在37℃pH＝1.2盐酸中，立即漂浮，12小时内,符合零级释放Mt/M∞＝kt，溶出度大于90％，随时间变化溶出曲线相关系数R2＞0.99。
实施例五：
采用直接压片工艺制备。具体制备方法如下所示：将卡比多巴、乳糖、碳酸氢钠、HPMC、十八醇分别按量称取，混匀，55-70℃熔融制粒，趁热过24目筛，再加入1.5％的滑石粉，过筛混匀，测定含量，按规格量压片。
上述制得卡比多巴缓释片硬度在20-100N之间，采用100r/min转篮法测定溶出，在37℃pH＝1.2盐酸中，立即漂浮，8小时内,溶出度大于90％，随时间变化溶出曲线R2＞0.99，释放符合一级方程ln(1-Mt/M∞)＝-kt。
Claims (1)
1.一种微泡型胃滞留缓控释片剂的制备方法，所述片剂含有有效量的药物活性成分，聚环氧乙烷，发泡剂，及其他成分，它们的重量百分比为：药物活性成分40%-60%，发泡剂5%-10%，聚环氧乙烷20%-40%，其他成分5-20%；其中，所述药物活性成分选自罗通定、卡比多巴；其中，所述发泡剂选自：碳酸氢钠；其中，所述其他成分包括填充剂和润滑剂，所述填充剂选自：微晶纤维素；所述润滑剂选自：微粉硅胶；所述制备方法，步骤如下：将药物活性成分、填充剂、发泡剂、聚环氧乙烷按量分别称取，其中发泡剂过200目及以上筛，后将全部处方过筛混合均匀，熔融制粒，趁热过筛混匀，加入适量润滑剂，再次过筛混匀，对中间体进行含量测定，按规格量直接压片，即得微泡型胃滞留缓控释片剂。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2361615A1 (en) * | 2010-02-19 | 2011-08-31 | Alfred E. Tiefenbacher GmbH & Co. KG | Dipyridamole prolonged-release tablet |
| CN112370417A (zh) * | 2020-11-20 | 2021-02-19 | 湖北科技学院 | 用于基胃滞留剂的双网络水凝胶的预辐射制备方法 |
| CN112933055A (zh) * | 2021-03-23 | 2021-06-11 | 深圳前海九华国际投资控股有限公司 | 帕利哌酮胃滞留片及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2361615A1 (en) * | 2010-02-19 | 2011-08-31 | Alfred E. Tiefenbacher GmbH & Co. KG | Dipyridamole prolonged-release tablet |
| CN112370417A (zh) * | 2020-11-20 | 2021-02-19 | 湖北科技学院 | 用于基胃滞留剂的双网络水凝胶的预辐射制备方法 |
| CN112933055A (zh) * | 2021-03-23 | 2021-06-11 | 深圳前海九华国际投资控股有限公司 | 帕利哌酮胃滞留片及其制备方法 |
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| Title |
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| 胡满钰等.胃滞留给药系统的研究进展.《中国医药工业杂志》.2019,第50卷(第3期),第241-251页. * |
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