CN102836167B - 一种复方庆大霉素普鲁卡因胃漂浮缓释微丸 - Google Patents
一种复方庆大霉素普鲁卡因胃漂浮缓释微丸 Download PDFInfo
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Abstract
本发明提供了一种复方庆大霉素普鲁卡因胃漂浮缓释微丸,该缓释微丸从内向外依次为载药丸芯、控释层、产气层和阻滞层,由含有药物的微丸依次进行控释层、产气层和阻滞层包衣制得。本发明胃漂浮微丸圆整度良好,在胃液中的起漂时间小于2min,且能持续漂浮8h以上,且具有良好的缓释性能,可以显著延长药物在胃内的滞留时间,提高药物对胃炎的治疗效果。
Description
(一)技术领域
本发明涉及一种复方庆大霉素普鲁卡因胃漂浮缓释微丸。
(二)背景技术
庆大霉素普鲁卡因复方制剂为临床治疗慢性胃炎的常用药,其中庆大霉素对幽门螺旋杆菌有较强的杀灭作用,在胃中发挥局部杀菌作用;普鲁卡因对损伤黏膜表面的神经末梢起封闭作用,能阻断病灶对中枢神经***的刺激作用,对胃部能起到缓解疼痛、改善血液微循环、调节胃动力等作用;因此联合应用庆大霉素与普鲁卡因,对急、慢性胃炎既起到消炎作用又可以减轻疼痛,提高胃炎治愈率,缩短住院时间,降低医疗费用,提高了患者生活质量,具有良好的胃炎治疗效果。但目前市场上的庆大霉素普鲁卡因复方制剂主要为口服液、颗粒、胶囊等普通剂型,药物在胃内的停留时间短,限制了其药效的进一步发挥。
胃漂浮型制剂是依据流体动力学平衡原理设计的密度小于胃内容物(1.004~1.01g/cm3)的新型口服缓控释制剂。由于该制剂能长时间漂浮在胃液上,可增加药物在胃和十二指肠的吸收,增强药物在胃局部的治疗作用,从而可提高药物的生物利用度,降低毒副作用。自1968年Davis等提出这种新型制剂的概念后,其研究报道非常活跃。其中以胃漂浮缓释片的报道最多,但这种单元剂型易产生突释或个别制剂漂浮性能不好,被胃迅速排空,起不到预期的缓控释效果,而且由于患者胃排空速率的个体差异,常导致其胃内滞留时间延长的不确定和缺乏重现性,所以药物释放的个体差异较大。
漂浮制剂根据漂浮机制的不同,又可分为非泡腾型漂浮***和泡腾型漂浮胃内滞留***。非泡腾型漂浮***利用自身密度小于胃内容物密度而于胃液中呈漂浮状态。泡腾漂浮型胃内滞留***则通常含有一种成分,即起泡剂,起泡剂常为碳酸氢钠、碳酸钠和碳酸钙。当起泡剂与胃液接触时,发生化学反应生成二氧化碳,使制剂漂浮,是目前研究和使用最多的胃滞留制剂。目前常用的泡腾漂浮型胃内滞留***是在凝胶骨架材料中加入起泡剂,进入体内产生气泡附于制剂表面而使其漂浮,但这种气泡易于破裂或脱离制剂表面,尤其在体内环境中。
(三)发明内容
本发明的目的是提供一种含有庆大霉素普鲁卡因的胃漂浮型缓释微丸制剂,该制剂可以显著延长药物在胃内的滞留时间,提高药物对胃炎的治疗效果。
本发明采用的技术效果是:
一种复方庆大霉素普鲁卡因胃漂浮缓释微丸,从内向外依次为载药丸芯、控释层、产气层和阻滞层,其原料质量配比如下:
载药丸芯:
控释层:
产气层:
阻滞层:
载药丸芯中,所述轻质材料为下列之一或其中两种以上的混合物:十六醇、十八醇、硬脂酸、单硬脂酸甘油酯,所述黏合剂为下列之一:聚维酮溶液、羟丙甲纤维素溶液、乙醇、水、十二烷基硫酸钠水溶液;
控释层中,所述包衣材料为丙烯酸树脂,优选丙烯酸树脂Eudragit RS,如Eudragit RS100(粉末)、Eudragit RS30D(水分散体,固含量30%)等,所述增塑剂为下列之一:聚乙二醇、柠檬酸三乙酯、二丁基癸二酸酯、邻苯二甲酸二乙酯,所述分散介质为乙醇、水或其混合物;
产气层中,所述包衣材料为羟丙甲纤维素或聚维酮,所述增塑剂为下列之一:聚乙二醇、柠檬酸三乙酯、邻苯二甲酸二乙酯;
阻滞层中,所述包衣材料为丙烯酸树脂,优选为渗透性较好的丙烯酸树脂Eudragit RL,如Eudragit RL100(粉末)、Eudragit RL30D(水分散体,固含量30%)等,所述增塑剂为下列之一:聚乙二醇、柠檬酸三乙酯、二丁基癸二酸酯、邻苯二甲酸二乙酯,优选聚乙二醇6000,所述分散介质为乙醇、水或其混合物。
优选的,制备所述缓释微丸的原料组成如下:
载药丸芯:
控释层:
产气层:
阻滞层:
或者,制备所述缓释微丸的原料组成如下:
载药丸芯:
控释层:
产气层:
阻滞层:
本发明将庆大霉素普鲁卡因复方制成胃漂浮型缓释微丸可使其在胃内长时间地持续释放药物,获得良好的胃炎治疗效果。
本发明所采用的微丸制剂属于多单元型的剂型,可避免了单元剂型胃排空过程中的“全有”或“全无”造成的个体差异,还可避免因单元***控制不好引起的药物突释,其分布面积大,局部刺激性小,药物毒性低,且很少受到消化道输送食物节律的影响,释放和吸收的个体差异小,重现性好。
本发明采用薄膜包衣技术,在产气层外面包裹一层具有一定弹性的能阻碍气体溢出的阻滞层,把气泡稳定地固定在制剂内部,以维持稳定的漂浮性能。
本发明胃漂浮微丸,可由以下步骤制成:
(1)载药丸芯的制备:采用挤出滚圆法,将药物、轻质材料、碳酸氢钠、微晶纤维素过筛混匀,滴加适量黏合剂制成软材,经挤出滚圆机制成微丸,取出微丸于在50℃烘箱干燥2h即得。
(2)控释层包衣:将包衣材料溶解或均匀分散在分散介质中,加入增塑剂和滑石粉,制成控释层包衣液。将载药微丸置于流化床包衣机中预热至设定温度,喷入控释层包衣液进行包衣,包衣完毕,继续于流化床包衣机中干燥40分钟。
(3)产气层包衣:将包衣材料、增塑剂溶解于水中,加碳酸氢钠溶解后,加抗黏剂制成产气层包衣液。将包有控释层的微丸置于流化床包衣机中预热至设定温度,喷入产气层包衣液进行包衣。
(4)阻滞层包衣:将包衣材料溶解或均匀分散在分散介质中,加入增塑剂和滑石粉,制成阻滞层包衣液。将包好产气层的微丸置于流化床包衣机中预热至设定温度,喷入阻滞层包衣液进行包衣,包衣完毕,将微丸于40℃烘箱中继续干燥适当时间。
本发明有益效果主要体现在:本发明胃漂浮微丸圆整度良好,在胃液中的起漂时间小于2min,且能持续漂浮8h以上,且具有良好的缓释性能。
(四)附图说明
图1为胃漂浮缓释微丸结构示意图;
图2为实施例1普鲁卡因在人工胃液中的释放曲线.
(五)具体实施方式
下面结合具体实施例对本发明进行进一步描述,但本发明的保护范围并不仅限于此:
实施例1:
以生产本发明胃漂浮缓释微丸50g为例,所用的物料种类及其配比为:
载药丸芯:
物料名称 | 用量 |
盐酸普鲁卡因 | 15g |
硫酸庆大霉素 | 3g |
微晶纤维素 | 30g |
十八醇 | 7.5g |
碳酸氢钠 | 1.5g |
2%(w/w)十二烷基硫酸钠 | 16mL |
控释层包衣液:
物料名称 | 用量 |
Eudragit RS100 | 8g |
柠檬酸三乙酯 | 1.6g |
滑石粉 | 2g |
乙醇 | 100mL |
产气层包衣液:
物料名称 | 用量 |
羟丙甲纤维素 | 2g |
碳酸氢钠 | 8g |
聚乙二醇6000 | 0.2g |
水 | 80mL |
阻滞层包衣液:
物料名称 | 用量 |
Eudragit RL100 | 8g |
柠檬酸三乙酯 | 1.6g |
滑石粉 | 2g |
乙醇 | 100mL |
1.载药丸芯的制备
称取处方量盐酸普鲁卡因、硫酸庆大霉素、微晶纤维素、十八醇和碳酸氢钠,混合均匀,滴加2%的十二烷基硫酸钠溶液制成软材,经挤出滚圆机制成微丸(挤出转速为25~30r/min、滚圆转速为1200~1500r/min、滚圆时间5min),取出微丸在50℃烘箱干燥2h,即得大小均匀、圆整度良好的载药丸芯。
2.控释层包衣
称取处方量的Eudragit RS100(赢创德固赛特种化学有限公司)和柠檬酸三乙酯,用100mL 95%乙醇在45℃下完全溶解后,加入滑石粉,用磁力搅拌器搅拌均匀,即得控释层包衣液。取载药丸芯50g于流化床包衣机中,设置风机频率为30Hz,进风温度为35℃,物料温度为30℃。当物料温度达到预设温度后,喷入控释层包衣液(喷枪喷雾压力为0.20~0.22MPa,包衣液流速为1ml/min左右),包衣液喷完后继续在流化床中干燥40min。
3.产气层包衣
称取处方量的羟丙甲纤维素E50和聚乙二醇6000,用80mL蒸馏水完全溶解后加入碳酸氢钠,用磁力搅拌器搅拌均匀,即得产气层包衣液。取包有控释层的微丸50g于流化床包衣机中,设置风机频率为25Hz,进风温度为45℃,物料温度为35℃。当物料温度达到预设温度后,喷入产气层包衣液(喷枪喷雾压力为0.18~0.20MPa,包衣液流速为2ml/min左右),包衣液喷完后继续在流化床中干燥40min。
4.阻滞层包衣
称取处方量的Eudragit RL100(赢创德固赛特种化学有限公司)和柠檬酸三乙酯,用100mL 95%乙醇在45℃下完全溶解后,加入滑石粉,用磁力搅拌器搅拌均匀,即得阻滞层包衣液。取包有产气层的微丸50g于流化床包衣机中,设置风机频率为30Hz,物料温度为35℃,当物料温度达到预设温度后,喷入控释层包衣液(喷枪喷雾压力为0.20~0.22MPa,包衣液流速为1ml/min左右),包衣液喷完后继续在流化床中干燥20min,取出微丸置于40℃烘箱中老化24h。
5.漂浮性能测定
取100粒微丸,置于37℃装有0.1mol/L稀盐酸100ml的烧杯中,剧烈搅拌使微丸全部浸没于介质中,肉眼观察各时间点漂浮在液面的微丸个数。结果发现,微丸快速起漂,2min时全部漂浮于液面,2h时有2粒微丸下沉于杯底,8h后还有92粒微丸漂浮于液面。表明本微丸漂浮性能良好,完全符合胃滞留制剂的要求。
6.体外释放性能测定
精密称取微丸成品适量(含普鲁卡因0.1g左右),按照《中国药典》2010年版二部附录转篮法测定。转篮转速为100r/min,温度为37℃,0.1mol/L盐酸900ml为释放介质,分别于预定时间点取样5ml,同时补充同体积同温度的释放介质。样品经0.45μm微孔滤膜过滤,续滤液以紫外分光光度法在280nm波长处测定吸光度,代入标准曲线方程求得普鲁卡因累积释放量,计算累积释放百分率,以释放百分率对时间作图可得体外释放曲线见图2。从图中可看出,所得微丸的体外药物释放较为平稳,无明显的突释现象,具有良好的缓释性能。
实施例2:
以生产本发明胃漂浮缓释微丸50g为例,所用的物料种类及其配比为:
载药丸芯:
物料名称 | 用量 |
盐酸普鲁卡因 | 15g |
硫酸庆大霉素 | 3g |
维生素B12 | 3mg |
微晶纤维素 | 30g |
十八醇 | 7.5g |
碳酸氢钠 | 1.5g |
2%十二烷基硫酸钠 | 16mL |
控释层包衣液:
物料名称 | 用量 |
Eudragit RS 30D | 17mL |
柠檬酸三乙酯 | 1g |
滑石粉 | 1.5g |
水 | 33mL |
产气层包衣液:
物料名称 | 用量 |
羟丙甲纤维素 | 2g |
碳酸氢钠 | 8g |
聚乙二醇6000 | 0.2g |
水 | 80mL |
阻滞层包衣液:
物料名称 | 用量 |
Eudragit RL30D | 17mL |
柠檬酸三乙酯 | 1g |
滑石粉 | 1.5g |
水 | 33mL |
1.载药丸芯的制备
称取处方量盐酸普鲁卡因、硫酸庆大霉素、微晶纤维素、十八醇和碳酸氢钠,混合均匀,将维生素B12溶解在2%的十二烷基硫酸钠溶液中作为润湿剂,将润湿剂加入上述混合粉中制成软材,经挤出滚圆机制成微丸(挤出转速为25~30r/min、滚圆转速为1200~1500r/min、滚圆时间5min),取出微丸在50℃烘箱干燥2h,即得大小均匀、圆整度良好的载药丸芯。
2.控释层包衣
称取处方量滑石粉和柠檬酸三乙酯,加入1/2处方量的水,用高速分散器匀化10min,将其缓慢加入Eudragit RS30D水分散体(赢创德固赛特种化学有限公司)中,加入剩余水量,用磁力搅拌器搅拌均匀,即得控释层包衣液。取载药丸芯50g于流化床包衣机中,设置风机频率为30Hz,进风温度为35℃,物料温度为27℃,当物料温度达到预设温度后,喷入控释层包衣液(喷枪喷雾压力为0.20~0.22MPa,包衣液流速为0.8ml/min左右),包衣液喷完后继续在流化床中干燥40min。
3.产气层包衣
产气层包衣工艺同实施例1。
4.阻滞层包衣
除将Eudragit RS30D改成Eudragit RL30D(赢创德固赛特种化学有限公司)外,其余操作同控释层包衣。
制得微丸漂浮性能良好,完全符合胃滞留制剂的要求,且具有良好的缓释性能。
Claims (3)
1.一种复方庆大霉素普鲁卡因胃漂浮缓释微丸,从内向外依次为载药丸芯、控释层、产气层和阻滞层,其原料质量配比如下:
载药丸芯:
控释层:
产气层:
阻滞层:
载药丸芯中,所述轻质材料为下列之一或其中两种以上的混合物:十六醇、十八醇、硬脂酸、单硬脂酸甘油酯,所述黏合剂为下列之一:聚维酮溶液、羟丙甲纤维素溶液、乙醇、水、十二烷基硫酸钠水溶液;
控释层中,所述包衣材料为丙烯酸树脂,所述增塑剂为下列之一:聚乙二醇、柠檬酸三乙酯、二丁基癸二酸酯、邻苯二甲酸二乙酯,所述分散介质为乙醇、水或其混合物;
产气层中,所述包衣材料为羟丙甲纤维素或聚维酮,所述增塑剂为下列之一:聚乙二醇、柠檬酸三乙酯、邻苯二甲酸二乙酯;
阻滞层中,所述包衣材料为丙烯酸树脂,所述增塑剂为下列之一:聚乙二醇、柠檬酸三乙酯、二丁基癸二酸酯、邻苯二甲酸二乙酯,所述分散介质为乙醇、水或其混合物。
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