CN108125917B - 一种米格列奈钙制剂的制备的方法 - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及一种米格列奈钙制剂及其制备方法，本发明制剂优选片剂，其制备方法如下：先将米格列奈钙盐二水合物和辅料低温超微粉碎，后将米格列奈钙盐二水合物、乳糖、淀粉、微晶纤维素、低取代羟丙纤维素、羧甲淀粉钠混合，加处方量1％羟丙甲纤维素水溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料羧甲淀粉钠、硬脂酸镁，混合，压片。
Description
发明领域
本发明属于医药技术领域,涉及到米格列奈钙制剂的制备方法。
技术背景
米格列奈，在体内、体外都可以刺激双相胰岛素分泌，而且效果逆转迅速。最近研究人员利用轻度、中度和重度链脲素诱导的大鼠模型比较了米格列奈、那格列奈和伏格列波糖(voglibose)对降低餐后血糖的效果。在餐前向试验动物给药米格列奈(0、1和3mg/kg)、那格列奈(25、50和100mg/kg)或伏格列波糖(0.03、0.1 和0.3mg/kg)。结果证明米格列奈的降糖效果最显著。在轻度和中度动物模型中，米格列奈显著而且迅速降低了血糖水平和血糖AUC。在严重糖尿病模型中，也观察到了米格列奈抑制进食诱导的血糖水平升高的趋势。该试验表明米格列奈可以预防Ⅱ型糖尿病出现的餐后高血糖。利用糖尿病狗模型比较了米格列奈和格列齐(gliclazide)的降糖效果和促胰岛素分泌作用。结果，米格列奈降低血糖的效力较格列齐特更强，而且不象后者那样容易产生低血糖。同时米格列奈显示了迅速的促胰岛素分泌作用。
米格列奈钙片由米格列奈钙盐二水合物加辅料，制成适宜湿颗粒，干燥，整粒，加入硬脂酸镁，混合，压片；米格列奈钙胶囊米格由米格列奈钙二水合物加适宜辅料制备而成。
橘生药品工业株式会社的米格列奈钙片，滑石粉，玉米淀粉，羟丙基纤维素，硬脂酸钙，微晶纤维素，乳糖水合物，无水硅酸，由于滑石粉对人体有一定的副作用，硬脂酸钙购买较难。因此寻找适合辅料更适合工业化生产。
发明内容
本发明目的在于提供一种稳定性好、溶解度高的米格列奈钙片。
为此，本发明提供一种米格列奈钙片的制备方法，其特征在于，所述米格列奈钙片是由下列重量配比的原辅料药制备而成：
所述制备方法，步骤如下：先将米格列奈钙盐二水合物和辅料低温超微粉碎，后将米格列奈钙盐二水合物、乳糖、淀粉、微晶纤维素、低取代羟丙纤维素、羧甲淀粉钠混合，加处方量1％羟丙甲纤维素水溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料羧甲淀粉钠、硬脂酸镁，混合，压片。
优选的，本发明所述米格列奈钙片是由下列重量配比的原辅料药制备而成：
具体的，本发明的制备方法，包括以下步骤：
将米格列奈钙盐二水合物、乳糖、淀粉、微晶纤维素、低取代羟丙纤维素、羧甲淀粉钠(内加)依次加入高速混合制粒机内，混合3分钟，加处方量1％羟丙甲纤维素水溶液，再混合2～4分钟后制成适宜湿颗粒，于60～70℃温度下干燥20～30分钟，用18目筛网整粒，将整粒后的颗粒加入二维混合机内，然后加入外加辅料羧甲淀粉钠、硬脂酸镁，进行混合30分钟，选用ф6.5mm字冲压片。
本发明制备的米格列奈钙盐二水合物不局限制备米格列奈钙片剂，还可以制备米格列奈钙胶囊和米格列奈钙散剂等。根据需要加上适宜的辅料制备而成，其中可以加入药学上必要的辅料成分，选自：淀粉、预胶化淀粉、低取代低取代羟丙纤维素、蔗糖、微晶纤维素、糊精、羟丙甲纤维素、乳糖、滑石粉、微粉硅胶、硬脂酸镁，硫酸钙、氢氧化铝等。
本发明的配方是经过科学筛选得到的，证明其具有最优良的特性。其筛选过程如下：
一、粉碎方式的选择
其操过程如下：将米格列奈钙盐二水合物加入粉碎机进行粉碎，以通过200 目为指标，定义为通过率；
有关物质测定：取米格列奈钙盐二水合物粉末，加水-甲醇-乙腈(25∶35∶ 40)制成每1ml中约含米格列奈钙0.2mg的溶液，滤过，取续滤液作为供试品溶液；精密量取适量，加水-甲醇-乙腈(25∶35∶40)稀释制成每1ml中含米格列奈钙2μg的溶液，作为对照溶液。照含量测定项下的色谱条件试验，取对照溶液 20μl注入液相色谱仪，调节检测灵敏度，使主成分色谱峰高约为满量程的5％～ 10％，再精密量取供试品溶液和对照溶液各20μl，分别注入液相色谱仪，记录色谱图至主成份峰保留时间的2倍，供试品溶液色谱图中如有杂质峰，除溶剂峰外，单一杂质峰面积不得大于对照溶液主峰面积的1/5(0.2％)，各杂质峰面积之和不得大于对照溶液主峰面积(1.0％)。
将称量好的米格列奈钙盐二水合物、乳糖、淀粉、微晶纤维素、低取代羟丙纤维素、羧甲淀粉钠(内加)依次加入高速混合制粒机内，混合3分钟，加处方量1％羟丙甲纤维素水溶液，再混合2～4分钟后制成适宜湿颗粒，于60～70℃温度下干燥20～30分钟，用18目筛网整粒，将整粒后的颗粒加入二维混合机内，然后加入外加辅料羧甲淀粉钠、硬脂酸镁，进行混合30分钟，压片。
取米格列奈钙片，照溶出度测定法(中国药典2010年版二部附录ⅩC第二法)，以水900ml为溶剂，转速为每分钟50转，依法操作，经10分钟时，取续滤液(10mg规格取续滤液适量，用溶出介质稀释1倍)作为供试品溶液；另精密称取米格列奈钙对照品约5mg，置100ml量瓶中，加甲醇50ml超声溶解两分钟左右、用水稀释至刻度，摇匀，精密量取5ml置50ml量瓶中，加水稀释定容，摇匀，作为对照品溶液。照含量测定项下的色谱条件试验，分别精密量取对照品溶液和供试品溶液各20μl注入液相色谱仪，记录色谱图，按按外标法以峰面积计算出每片的溶出量。
通过以上的试验，测得通过率，及有关物质及溶出度，见表1
表1
| 试验号 | 粉碎设备 | 通过率％ | 单个杂质％ | 总杂质％ | 溶出度％ |
| Ⅰ | 机械式粉碎机 | 80 | 0.08 | 0.21 | 60 |
| Ⅱ | 气流粉碎机 | 83 | 0.09 | 0.19 | 71 |
| Ⅲ | 研磨机 | 82 | 0.09 | 0.19 | 73 |
| Ⅳ | 低温超微粉碎机 | 90 | 0.07 | 0.15 | 79 |
从表1可以看出采用低温超微粉碎机的粉末通过200目的通过率、有关物质及溶出度均优于其他粉碎机。
低温超微粉碎机制备米格列奈钙粉末与淀粉和乳糖混合，填充胶囊，得米格列奈钙胶囊。
不同辅料与米格列奈钙的比例混合后进行低温超微粉碎，优化的方案如下表2：
表2
将米格列奈钙盐二水合物、根据比例增加乳糖、淀粉、微晶纤维素、低取代羟丙纤维素、羧甲淀粉钠，混合，加处方量1％羟丙甲纤维素水溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料羧甲淀粉钠、硬脂酸镁，混合，压片，并测定溶出度及有关物质。
表3筛选结果
| 试验号 | 通过率％ | 单个杂质％ | 总杂质％ | 溶出度％ |
| Ⅰ | 98 | 0.06 | 0.16 | 81 |
| Ⅱ | 97 | 0.07 | 0.14 | 82 |
| Ⅲ | 98 | 0.08 | 0.15 | 80 |
| Ⅳ | 99 | 0.05 | 0.13 | 95 |
| Ⅴ | 94 | 0.06 | 0.18 | 80 |
由以上实验结果可知，米格列奈钙盐二水合物、乳糖、淀粉混合，加入低温超微粉碎机中粉碎，米格列奈钙盐二水合物一份，淀粉一份，乳糖二份，超低温粉碎，得混合粉，混合粉通过200目的通过率、有关物质及溶出度均优于其它比例。
二、配方的筛选
米格列奈钙片剂(5mg)的处方优选过程，各辅料量扣除混合粉中的辅料，表中为各自总辅料的量，试验见表4
表4
含量均匀度
标准为：取米格列奈钙片1片，置25ml量瓶中，加水数滴，使片剂崩解，再加适量甲醇，超声使米格列奈钙溶解，加适量甲醇稀释至刻度，摇匀，滤过，取续滤液5ml置50ml量瓶中，加甲醇稀释至刻度，作为供试品溶液。照含量测定项下的方法测定含量，应符合规定(中国药典2010年版二部附录ⅩE)，均匀度用A+1.80S进行计算。
表5筛选结果
| 试验号 | 均匀度 | 片重差异％ | 溶出度％ |
| Ⅰ | 10 | 7 | 90 |
| Ⅱ | 12 | 6 | 93 |
| Ⅲ | 8 | 4 | 95 |
| Ⅳ | 14 | 6 | 92 |
从上表上看，试验Ⅲ，A+1.80S＝8≤15符合要求，片重差异为4％与溶出度达到95％，取得到意想不到的效果。
米格列奈钙片剂(10mg)的处方优选过程如下，各辅料量扣除混合粉中的辅料，表中为各自总辅料的量，试验见表6。
表6
表7筛选结果
| 试验号 | 均匀度 | 片重差异％ | 溶出度％ |
| Ⅰ | 9 | 6.5 | 92 |
| Ⅱ | 12 | 5.7 | 92 |
| Ⅲ | 10 | 6.1 | 94 |
| Ⅳ | 6 | 3.8 | 96 |
从上表上看，格列奈钙片剂(10mg)试验Ⅳ，A+1.80S≤15符合要求，片重差异3.8％与溶出度96％有显著性差异，效果显著。
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例1：
取米格列奈钙盐二水合物0.5kg，淀粉0.5kg，乳糖1.00kg，加入低温超微粉碎机内，于-5～0℃进行粉碎1个小时，得米格列奈钙混合粉，乳糖3.8kg、淀粉1.75kg、微晶纤维素1.8kg、低取代羟丙纤维素0.65kg、羧甲淀粉钠0.8kg，混合，加1％(w/v)羟丙甲纤维素水溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料硬脂酸镁，混合，压片(5mg/片)。
实施例2：
取米格列奈钙盐二水合物1.0kg，淀粉1.0kg，乳糖2.00kg，加入低温超微粉碎机内，于-5～0℃进行粉碎1个小时，得米格列奈钙混合粉与乳糖4.8kg、淀粉2.6kg、微晶纤维素2.58kg、低取代羟丙纤维素0.82kg、羧甲淀粉钠1.0kg，混合，加1％(w/v)羟丙甲纤维素水溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料硬脂酸镁，混合，压片(10mg/片)。
实施例3：
取米格列奈钙盐二水合物1.0kg加入无水乙醇溶解，取乳糖4.8kg、淀粉 2.6kg、微晶纤维素2.58kg、低取代羟丙纤维素0.82kg、羧甲淀粉钠1.0kg，混合，加米格列奈钙乙醇溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料硬脂酸镁，混合，压片(10mg/片).
实施例4：
取1kg米格列奈钙盐二水合物加入0.5kg乳糖与0.5kg淀粉混合，加入适量水用胶体磨研磨1小时，于-1～4℃进行研磨，得到米格列奈钙研磨浆 ，各种物料按照上面处方进行配备，取乳糖4.3kg、淀粉2.1kg、微晶纤维素2.58kg、低取代羟丙纤维素0.82kg、羧甲淀粉钠1.kg 0，混合，加米格列奈钙研磨浆 ，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料硬脂酸镁，混合，压片(10mg/片)
实施例5、
取米格列奈钙盐二水合物0.5kg，淀粉0.5kg，乳糖1.0kg，加入低温超微粉碎机内，进行低温超微粉碎，于-5～0℃进行粉碎1个小时，得米格列奈钙混合粉与乳糖2.0kg、淀粉1.0kg、微晶纤维素1.6kg、低取代羟丙纤维素0.48kg、羧甲淀粉钠0.5kg，微粉硅胶0.3kg混合，加1％(w/v)羟丙甲纤维素水溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料硬脂酸镁0.1kg，混合，压片(5mg/片)。
实施例6、
取米格列奈钙盐二水合物1.0kg，淀粉1.0kg，乳糖2.0kg，加入低温超微粉碎机内，进行低温超微粉碎，于-5～0℃进行粉碎1个小时，得米格列奈钙混合粉与乳糖0.8kg、淀粉1.85kg、微晶纤维素2.03kg、低取代羟丙纤维素0.82kg、羧甲淀粉钠0.75kg混合，加1％(w/v)羟丙甲纤维素水溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料硬脂酸镁0.1kg，混合，压片(10mg/ 片)。
Claims (1)
1.一种米格列奈钙片的制备方法，其特征在于， 步骤如下：取米格列奈钙盐二水合物1.0kg，淀粉1.0 kg，乳糖2.0kg，加入低温超微粉碎机内，进行低温超微粉碎，于-5～0℃进行粉碎1个小时，得到米格列奈钙混合粉，再与乳糖0.8 kg、淀粉1.85kg、微晶纤维素2.03kg、低取代羟丙纤维素0.82kg、羧甲淀粉钠0.75kg 混合，加1%羟丙甲纤维素水溶液，制成适宜湿颗粒，干燥，整粒，将整粒后的颗粒加入外加辅料硬脂酸镁0.1kg，混合，压片。
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