CN113384556A - 一种治疗胃酸过多的可形成凝胶的口服固体制剂及其制备方法 - Google Patents
一种治疗胃酸过多的可形成凝胶的口服固体制剂及其制备方法 Download PDFInfo
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Abstract
一种治疗胃酸过多的可形成凝胶的口服固体制剂，其包含微丸，所述的微丸包含碳酸钙和果胶。所述的微丸为微晶纤维素微丸；所述的微晶纤维素微丸包括微丸主体，所述的微丸主体包括主成分和微丸基质；所述的微丸基质以微丸主体的质量百分比计包括：果胶10wt％‑20wt％，糖25wt％‑35wt％，碳酸钙30wt％‑40wt％，以及微晶纤维素5wt％‑15wt％。本发明还公开了上述口服固体制剂的制备方法。用药者服用该制剂入胃，在药物崩解后，在胃酸作用下，碳酸钙释放出Ca2+，与溶解的果胶形成凝胶状态，既可以起到缓释的作用，也能在一定程度上避免某些稳定性不佳的药物被胃酸破坏。
Description
技术领域
本发明属于医药领域，具体涉及一种治疗胃酸过多的可形成凝胶的口服固体制剂及其制备方法。
背景技术
消化性溃疡是消化系统的多发疾病，人群中患病率高达5％～10％，其发病机制，主要是因胃酸和幽门螺杆菌，此外还有其它一些因素对胃及十二指肠黏膜屏障造成损伤造成的。目前临床上主要用胃酸中和剂、质子泵抑制剂，胃黏膜膜保护剂和H2受体拮抗剂等药物治疗消化性溃疡。
碳酸钙是常用的、可快速中和胃酸、缓解酸相关症状的胃酸中和剂，但由于其作用基理所限，其维持时间较短。若反复服药，则容易发生碱中毒、高钙血症等。
法莫替丁为继西咪替丁、雷尼替丁后研制出的又一个H2受体拮抗剂。作用持续时间在本类药物中最长。
由于碳酸钙与胃酸的反应极为迅速，短时间内即可反应完毕，除了中和胃酸外，还会产生二氧化碳，这种快速的反应，易造成胃内不适感，严重的甚至会导致胃部穿孔，发生危险。
发明内容
本发明针对上述现有技术存在的不足，提供一种治疗胃酸过多的可形成凝胶的口服固体制剂及其制备方法。
具体技术方案如下：
本发明的目的之一是提供一种治疗胃酸过多的可形成凝胶的口服固体制剂。
一种治疗胃酸过多的可形成凝胶的口服固体制剂，包含微丸，所述的微丸包含碳酸钙和果胶。所述的果胶为高甲氧基果胶。
本发明提供了一种缓释的抗酸剂，可以延缓碳酸钙在胃酸中的反应时间，减缓二氧化碳产生的速度，降低对胃部的不利影响，也可以保护主成分不被胃酸破坏。本发明核心是利用了高甲氧基果胶在低pH值下，在Ca2+存在的条件下能转变成凝胶的特性，除用于治疗胃酸过多的药物外，其它应用了该组分的药物或保健食品等均落在本发明范围内。
进一步，所述的微丸为微晶纤维素微丸；所述的微晶纤维素微丸包括微丸主体，所述的微丸主体包括主成分和微丸基质；所述的微丸基质以微丸主体的质量百分比计包括：果胶10wt％-20wt％，糖25wt％-35wt％，碳酸钙30wt％-40wt％，以及微晶纤维素5wt％-15wt％。所述的微丸还可以是蔗糖微丸、微晶蔗糖微丸或甘露醇微丸等。
再进一步，所述的糖优选为蔗糖或乳糖，最优选为蔗糖。
再进一步，所述的果胶的甲氧基含量为8％-16％，优选为12％-15％。
再进一步，所述的主成分的用量为以微丸主体计10wt％-20wt％。
再进一步，所述的主成分为H2受体拮抗剂，优选为法莫替丁。
再进一步，所述的微晶纤维素微丸除微丸主体外，还包括粘合剂，所述的粘合剂优选为HPMC(羟丙甲纤维素)水溶液，HPMC水溶液的浓度优选为5wt％-15wt％。
进一步，所述的微丸的粒径为20-60目，优选30-40目。
进一步，所述的微丸可用离心造粒法、挤出滚圆法或流化床制粒法等方法制备。
再进一步，所述的微晶纤维素微丸经包衣后制备成片剂或胶囊，也可制备成其他药学上可接受的剂型。
具体地，以乙基纤维素水分散体为包衣材料，将隔离衣包裹于微丸上，制成包衣微丸。乙基纤维素水分散体的用量为微丸用量的10wt％-20wt％，优选15wt％。
本发明的目的之二是提供上述口服固体制剂的制备方法，其包括如下步骤：
(1)制备微丸；
(2)对微丸进行包衣；
(3)向包衣后的微丸中加入填充剂、崩解剂，制粒后加入润滑剂，混合成均匀的颗粒；
(4)将步骤(3)获得的颗粒制备成药学上可接受的剂型。
进一步，步骤(1)中，使用离心造粒法、挤出滚圆法或流化床制粒法制备微晶纤维素微丸。
具体地，挤出滚圆法示例如下：
a.将主成分、果胶、糖、碳酸钙、微晶纤维素投入高速混合制粒机中混合均匀，加入HPMC水溶液制成软材；
b.将上述软材置挤出机中，挤出并用滚圆机滚圆；
c.将滚圆的微丸干燥至水分不超过2.0wt％。
其中，步骤a中，主成分、果胶、糖、碳酸钙、微晶纤维素的混合转速为80-100rpm，优选混合5min。
其中，步骤a中，制备软材时，工作条件为加液速度0.5-1kg/min，转速80-100rpm，切碎速度1000-1500rpm，优选运行3min。
其中，步骤b中，挤出转速为5-10rpm，筛网孔径0.6mm。
其中，步骤b中，滚圆速度500rpm，滚圆时长60s。
其中，步骤c中，所述的干燥可以是流化床干燥或鼓风干燥箱干燥；
流化床干燥时的进风温度为60-80℃，物料温度为40-50℃；
鼓风干燥箱中50-60℃干燥2-3h。
进一步，步骤(1)中，所述的微晶纤维素微丸的粒径为20-60目，优选为30-40目。
进一步，步骤(2)中，使用乙基纤维素水分散体作为包衣液。所述的包衣液的固含量优选为8wt％-12wt％。
具体地，取乙基纤维素水分散体包衣粉，加入搅拌着的水中，配制成固含量8wt％-12wt％的乙基纤维素水分散体包衣液，将干燥的微丸加入流化床中包衣，流化床工作条件为进风温度80-100℃，物料温度40-50℃，出风温度40-50℃；包衣增重至微丸重量的10wt％-20wt％，优选15wt％，继续干燥至水分不超过1.5wt％。
进一步，步骤(3)中，所述的填充剂为乳糖、蔗糖、淀粉、预胶化淀粉、微晶纤维素、糊精等常用填充剂中的一种或两种以上。
进一步，步骤(3)中，所述的崩解剂为微晶纤维素、羟丙纤维素、羧甲淀粉钠、交联聚维酮、淀粉等常用崩解剂中的一种或两种以上。
进一步，步骤(3)中，所述的润滑剂为硬脂酸镁、硬脂酸钙、硬脂酸、二氧化硅等的一种或两种以上。
进一步，步骤(3)中，取20-80目的包衣微丸进行操作。
进一步，步骤(4)中，将步骤(3)获得的颗粒用压片机压片或填充胶囊。
本发明的有益效果如下：
将包衣微丸加入其它辅料，制成片剂或者胶囊或者其它药学上可接受的口服固体剂型。用药者服用该制剂入胃后，药物崩解后，在胃酸作用下，碳酸钙释放出Ca2+，与果胶形成凝胶状态，既可以起到缓释的作用，也能在一定程度上避免某些稳定性不佳的药物被胃酸破坏。
附图说明
图1为测试1中实施例1、实施例2、实施例3与对比例1的制酸力曲线对比；
图2为测试2中实施例1、实施例2、实施例3与对比例1的溶出曲线检测对比。
具体实施方式
以下结合实例对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。
制备治疗胃酸过多的可形成凝胶的口服固体制剂，包括如下步骤：
(1)制备微晶纤维素微丸：
按以下处方与工艺制备微晶纤维素微丸，微丸处方见表1。
表1微晶纤维素微丸处方表(单位kg，10万片量)
a.将法莫替丁、果胶、蔗糖、碳酸钙、微晶纤维素投入60L高速混合制粒机中混合均匀，在转速100rpm条件下混合5min；加入5wt％的HPMC水溶液制成软材，加液速度0.8kg/min，转速120rpm，切碎速度1000rpm，运行3min；
b.将上述软材置挤出机中，挤出并用滚圆机滚圆；挤出转速5-10rpm；滚圆速度500rpm，滚圆时长60s；筛板网孔0.6mm；
c.将滚圆的微丸加入流化床中干燥，流化床的进风温度70℃，物料温度40℃；干燥至水份不超过2.0wt％。
(2)对微晶纤维素微丸进行包衣：
取乙基纤维素水分散体包衣粉，加入搅拌着的水中，配制成固含量10wt％的乙基纤维素水分散体包衣液，将干燥的微丸加入流化床中包衣，流化床进风温度65℃，物料温度40-45℃，出风温度40℃；包衣增重至15wt％，继续干燥约30min，干燥至水分不超过1.5wt％。
(3)取包衣微丸，筛去大于20目和小于80目的包衣微丸；以重量份数计，取10份包衣微丸，加入蔗糖30份，淀粉40份，微晶纤维素18份，采用湿法制粒方式，加入8份浓度10wt％羟丙甲纤维素水溶液为粘合剂制软材，然后用摇摆颗粒机或高速混合制粒机等制成湿颗粒，在60℃以下干燥2小时，干燥后的颗粒用18目筛整粒，制成供压片用的颗粒，加入1.0份硬脂酸镁混合均匀，得中间体。
(4)取样测定中间体含量后，用压片机压片，或填充胶囊。用上述颗粒压成片剂，片重1180mg；装入0#胶囊，囊重约700mg(2粒胶囊相当于片剂1片)。
注：对比例1与实施例1的区别在于，微晶纤维素微丸中不含果胶，减少的果胶量用蔗糖补足。
测试1
对实施例与对比例获得的片剂测定制酸力。
制酸力测定方法如下：取样品研细，称取细粉适量(相当于碳酸钙900mg)，缓慢加入150mL纯化水，搅拌加热至37℃恒温，加入250mL恒温至37℃的0.1mol/L盐酸溶液，控制温度为37℃，采用中国药典2020年版(四部)附录0931溶出度与释放度测定法第三法装置，转速100转/min，设置检测时间点分别为1、3、5、10、15、20、30min，测试不同时间点pH值，绘制制酸力曲线。实验结果见表2与图1。
表2.实施例与对比例在不同时间点的pH值测定值
从实验数据可以看出，实施例中，碳酸钙的制酸力受到凝胶缓释作用，缓慢发生中和反应，减缓了快速反应带来的快速产气的问题；同时，由于凝胶缓释的影响，主成分与胃酸的反应也被延迟，使得主成分得以被保护在一个合理的pH值区间内，提高了主成分的稳定性。
测试2
分别对实施例和对比例的片剂在pH5.5下测定主成分(法莫替丁)溶出曲线，结果见表3与图2。
溶出曲线测试方法如下：
取本品，照中国药典2020年版溶出度测定法桨法，以pH5.5醋酸盐缓冲液900mL为溶出介质[pH5.5醋酸盐缓冲液配制方法：称取三水醋酸钠5.98g，加入2mol/L醋酸溶液3mL(2mol/L醋酸溶液：取120.0g冰醋酸，加水稀释至1000mL，摇匀，即得。)，加水溶解并稀释至1000mL，摇匀即得。]。转速为每分钟75转，依法操作，分别在5min、10min、15min、30min、45min、60min时取溶出液适量，过滤，取续滤液作为供试品溶液。
另精密称取法莫替丁对照品约11mg，加溶出介质使溶解并制成每1ml约含法莫替丁0.011mg的溶液，作为对照品溶液。照中国药典2020年版四部通则中高效液相色谱法测定，用十八烷基硅烷键合硅胶为填充剂(C18 150*4.6mm 5μm)，以醋酸缓冲液20mmol/L醋酸钠，冰醋酸调pH至6.0乙腈(93:7)为流动相，检测波长为275nm，流速为1.5mL/min，柱温为35℃。取供试品溶液和对照品溶液各100μL注入液相色谱仪，记录色谱图。按外标法以峰面积计算溶出量，取平均值。
表3.实施例与对比例主成分溶出曲线检测结果(PH＝5.5)
| 溶出度％ | 5min | 10min | 15min | 30min | 45min | 60min |
| 实施例1 | 22 | 53 | 68 | 76 | 85 | 92 |
| 实施例2 | 28 | 52 | 65 | 72 | 84 | 93 |
| 实施例3 | 25 | 47 | 63 | 68 | 81 | 91 |
| 对比例1 | 58 | 74 | 80 | 88 | 94 | 95 |
溶出曲线检测结果表明，实施例中溶出度与对比例相比，有所减缓，在1小时内，溶出量均低于对比例，表明实施例具有一定的缓释作用。
测试3
取测试2中溶出曲线测定项下60min时样品，测定主成分的有关物质变化情况，可以看出实施例出现的杂质个数和杂质量均低于对比例杂质。结果见表4。
表4.实施例与对比例主成分有关物质
从有关物质检测结果可以看出，实施例与对比例相比，采用同样的原料情况下，利用本发明所制备的样品，有关物质中杂质总量和杂质数量均比对比例少，表明本发明可以在一定程度上保护对胃酸不稳定的主成分。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种治疗胃酸过多的可形成凝胶的口服固体制剂，其特征在于，包含微丸，所述的微丸包含碳酸钙和果胶。
2.根据权利要求1所述的口服固体制剂，其特征在于，所述的微丸为微晶纤维素微丸；所述的微晶纤维素微丸包括微丸主体，所述的微丸主体包括主成分和微丸基质；所述的微丸基质以微丸主体的质量百分比计包括：果胶10wt％-20wt％，糖25wt％-35wt％，碳酸钙30wt％-40wt％，以及微晶纤维素5wt％-15wt％。
3.根据权利要求2所述的口服固体制剂，其特征在于，所述的果胶的甲氧基含量为8％-16％。
4.根据权利要求2所述的口服固体制剂，其特征在于，所述的主成分的用量为以微丸主体计10wt％-20wt％。
5.根据权利要求2所述的口服固体制剂，其特征在于，所述的主成分为H2受体拮抗剂。
6.根据权利要求2所述的口服固体制剂，其特征在于，所述的微晶纤维素微丸还包括粘合剂。
7.根据权利要求1-6任一项所述的口服固体制剂，其特征在于，所述的微丸经包衣后制备成片剂或胶囊。
8.一种如权利要求1-7任一项所述的口服固体制剂的制备方法，其特征在于，包括如下步骤：
(1)制备微丸；
(2)对微丸进行包衣；
(3)向包衣后的微丸中加入填充剂、崩解剂，制粒后加入润滑剂，混合成均匀的颗粒；
(4)将步骤(3)获得的颗粒制备成药学上可接受的剂型。
9.根据权利要求8所述的制备方法，其特征在于，步骤(1)中，使用离心造粒法、挤出滚圆法或流化床制粒法制备微晶纤维素微丸；所述的微晶纤维素微丸的粒径为20-60目。
10.根据权利要求8所述的制备方法，其特征在于，步骤(2)中，使用乙基纤维素水分散体作为包衣液。
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