CN103127025A - 消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法 - Google Patents
消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
本发明涉及一种消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法。为了解决活性成分消旋2-(α-羟基戊基)苯甲酸盐在常规片剂的制备工艺中容易发生降解，稳定性差的问题，其制备方法采用原料药粉末直接压片或在制备工艺中采用碱化处理工艺，能够使消旋2-(α-羟基戊基)苯甲酸盐片的主药稳定性明显增加，适用于该药片剂的制备。
Description
技术领域
本发明涉及一种消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法。
背景技术
消旋2-(α-羟基戊基)苯甲酸盐是消旋丁基苯酞的药物前体，在体内能够快速的转化为消旋丁基苯酞而发挥药效。大鼠或Beagle犬灌胃给予消旋2-(α-羟基戊基)苯甲酸盐后，在体内能快速转化为消旋丁基苯酞，且血浆中消旋丁基苯酞的药-时曲线下面积，较直接口服等摩尔浓度的消旋丁基苯酞的血浆药-时曲线下面积增加40％(大鼠)和100％(Beagle犬)。药效学研究表明，消旋2-(α-羟基戊基)苯甲酸盐具有与消旋丁基苯酞相似或更强的生物效应。
早在中国医学科学院药物研究所申请的专利CN01109795.7中就公开了消旋2-(α-羟基戊基)苯甲酸盐及其制法和用途，并提到了关于消旋2-(α-羟基戊基)苯甲酸盐，可以制成片剂、胶囊剂、针剂或冻干剂等，并在实施例中就公开了一种片剂的配方和制备方法。
由于消旋2-(α-羟基戊基)苯甲酸盐在中性和酸性水溶液中的稳定性较差，在常规的制备工艺中，即专利CN01109795.7中公开的配方和制备方法中容易发生降解，稳定性差。因此，对于2-(α-羟基戊基)苯甲酸盐片剂的制备工艺进行了一系列的摸索。
发明内容
本发明为了解决活性成分消旋2-(α-羟基戊基)苯甲酸盐在常规片剂的制备工艺中容易发生降解，稳定性差的问题，提供了一种消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法。消旋2-(α-羟基戊基)苯甲酸盐为含有通式I的化合物，其中通式I中，n＝1或2，M是钾、钠、锂、钙、镁、锌离子或苯胺基、苄氨基、吗啉基和二乙胺基。
消旋2-(α-羟基戊基)苯甲酸盐片的制备方法如下：
制备方法1：将粘合剂的水溶液或醇溶液调，或两者混合液的pH值调至11.0-13.0，与消旋2-(α-羟基戊基)苯甲酸盐或消旋2-(α-羟基戊基)苯甲酸盐与其他片剂可药用辅料的组合物制成软材，然后制颗粒、干燥、整粒；将所获得的颗粒与润滑剂混合；用普通压片机或高速压片机，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣，即得消旋2-(α-羟基戊基)苯甲酸盐片。
制备方法2：将消旋2-(α-羟基戊基)苯甲酸盐溶于水或醇溶液后，将pH值调至11.0-13.0后，加入药用辅料，搅拌，采用喷雾干燥法、冷冻干燥法或旋转蒸发法得到固体粉末；加入适量粘合剂，制颗粒、干燥、整粒；与润滑剂混合；用普通压片机或高速压片机压片，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣即得消旋2-(α-羟基戊基)苯甲酸盐片；
制备方法3：将消旋2-(α-羟基戊基)苯甲酸盐或制备方法2中获得的固体粉末，直接用普通压片机或高速压片机压片，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣，即得消旋2-(α-羟基戊基)苯甲酸盐片。
消旋2-(α-羟基戊基)苯甲酸盐片制备方法中其他片剂可药用辅料选自填充剂、崩解剂、润滑剂、粘合剂、或包衣材料等常规辅料。
填充剂可选乳糖、蔗糖、淀粉、可压性淀粉、木糖醇、葡萄糖、甘露醇、微晶纤维素、低取代羟丙基纤维素或羧甲基淀粉钠，或以上两种或两种以上的混合物。
崩解剂选交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、微晶纤维素、低取代羟丙基纤维素、羟丙甲纤维素、乙基纤维素，或以上两种或两种以上的混合物。
润滑剂选硬脂酸镁、微粉硅胶或滑石粉，或以上两种或两种以上的混合物。
粘合剂选水、乙醇、淀粉浆、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、1-10％的羟丙基甲基纤维素的水溶液或醇溶液、2-10％的明胶溶液、1-10％的聚乙烯吡咯烷酮水溶液或醇溶液，或以上两种或两种以上的混合物。
包衣材料可选羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、聚维酮、丙烯酸树脂类、聚乙烯乙醛二乙胺乙酯、聚乙二醇、虫胶、醋酸纤维素酞酸酯、丙烯酸树脂、羟丙基甲基纤维素酞酸酯、醋酸羟丙基甲基纤维素琥珀酸酯等，或以上两种或两种以上的混合物。
制备方法中调节pH值至11.0-13.0的药用碱可采用氢氧化钠、碳酸钠、碳酸氢钠、碳酸钾、氢氧化钾、磷酸氢二钠等，或以上两种或两种以上的混合物。
消旋2-(α-羟基戊基)苯甲酸盐片的质量检测方法：
消旋2-(α-羟基戊基)苯甲酸盐含量测定方法：取本品10片，精密称定，研细，混合均匀，精密称取适量(约相当主药10mg)，置100ml量瓶中，加流动相适量使溶解并用流动相稀释至刻度，摇匀，滤过，即得供试品溶液；另精密称取主药对照品10mg于100ml量瓶中，加流动相适量使溶解并用流动相稀释至刻度，摇匀，滤过，即得对照品溶液。取供试品溶液与对照品溶液各20μL分别注入液相色谱仪，记录色谱图，按外标法以峰面积计算，即得。
消旋2-(α-羟基戊基)苯甲酸盐片溶出度的测定：取本品，按照溶出度测定法(中国药典2005年版二部附录XC第一法)，以水1000ml为溶出介质，转速为每分钟100转，依法操作，经35分钟时，取溶液经滤膜滤过，取续滤液作为供试品溶液；另取本品对照品适量，加水制成每1ml中含0.1mg的溶液，作为对照品溶液。取上述两种溶液，照本品片剂的质量检测方法，计算出每片的溶出量。限度为标示量的75％，应符合规定。
在处方筛选过程中发现：
单纯的使用常规的制备工艺，发现主药与多种辅料相容性较差，主要表现为外观明显变黄、主药含量明显下降、环合降解产物消旋丁基苯酞明显增加。而未加辅料的主药，除具有吸湿性外，在高温和光照条件下是稳定的。
称取主药适量，分别与各种片剂常用药用辅料按一定比例混匀，压制成片，分别置西林瓶中密封，于恒温(45℃)放置，于第0天和30天测定有关物质变化情况，结果见表1。
表1主药与辅料相容性试验结果
此外，应用专利CN01109795.7中公开的配方和制备方法，将实施例14设为对照例，具体处方见表2。
制备方法：将主药、药用淀粉、微晶纤维素、羰甲基纤维素钠磨粉、混匀，用水均匀润湿，把湿润后的混合物制成粉，过筛并干燥，再过筛，加入硬脂酸镁、滑石粉，然后将混合物压片，加包薄膜衣即可。
表2.对照例：500片(片剂规格：200mg/片)
| 主药 | 100g |
| 药用淀粉 | 25g |
| 微晶纤维素 | 17.5g |
| 硬脂酸镁 | 0.25 |
| 滑石粉 | 0.5 |
| 羰甲基纤维素钠 | 2.5 |
结果表明：采用专利CN01109795.7中公开的配方和制备方法，在西林瓶中密封，于恒温(45℃)放置30天测定有关物质变化情况。结果片面出现淡黄色油斑的现象，经测定，消旋丁基苯酞的含量明显增加，在10％以上，而主药含量明显降低，其它杂质增加不明显。因此，专利CN01109795.7中公开的配方和制备方法不适合于该药片剂的制备。
通过试验摸索发现，采用原料药粉末直接压片，或在制备工艺中采用碱化处理工艺：将原辅料碱化(pH11.0-13.0)后，再经干燥、制粒、压片、包衣。能够使消旋2-(α-羟基戊基)苯甲酸盐片的主药稳定性明显增加，适用于该药片剂的制备。
具体实施方式
下面的实施例可以使本专业技术人员更全面地理解本发明，但不以任何方式限制本发明。
实施例1.
处方组成(1000片)
片芯 重量
2-(α-羟基戊基)苯甲酸钾 100g
制备方法：将主药，控制水分含量在1％以下，直接用普通压片机或高速压片机压片，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣，即得消旋2-(α-羟基戊基)苯甲酸钾片。
实施例2.
处方组成(1000片)
制备方法：以磷酸氢二钠-氢氧化钠调pH值至12.0的水溶液为溶剂，配制6％的HPMC水溶液，取6％的HPMC水溶液与乙醇按1∶1的比例配制，即得3％HPMC；加入主药中制得软材，制粒、干燥(控制水分含量在1％以下)、整粒；将所获得的颗粒与硬脂酸镁混合；用普通压片机或高速压片机，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣，即得消旋2-(α-羟基戊基)苯甲酸钾片。
实施例3.
处方组成(1000片)
制备方法：将主药溶于水后，pH值调至12.0，加入药用淀粉，HPMC搅拌，采用喷雾干燥法、冷冻干燥法或旋转蒸发法得到固体粉末，控制水分含量在1％以下；直接用普通压片机或高速压片机压片，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣即得消旋2-(α-羟基戊基)苯甲酸钾片。
实施例4.
处方组成(1000片)
制备方法：将主药溶于水后，将pH值调至12.0后，加入药用淀粉，HPMC搅拌，采用喷雾干燥法、冷冻干燥法或旋转蒸发法得到固体粉末，控制水分含量在1％以下；与硬脂酸镁混合，制颗粒、干燥、整粒；与润滑剂混合；用普通压片机或高速压片机压片，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣即得消旋2-(α-羟基戊基)苯甲酸钾片。
实施例5.考察上述实施例的主药含量和溶出度
与发明内容中的对比例同期考察，采用相同的检测方法。结果见表3。
表3实施例的试验结果
Claims (8)
1.消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法，其特征在于消旋2-(α-羟基戊基)苯甲酸盐为含有通式I的化合物，其中通式I中：n＝1或2，M是钾、钠、锂、钙、镁、锌离子或苯胺基、苄氨基、吗啉基和二乙胺基；
其制备方法如下：
(1)制备方法1：将粘合剂的水溶液或醇溶液，或两者混合液，用药用碱调pH值至11.0-13.0，与消旋2-(α-羟基戊基)苯甲酸盐或消旋2-(α-羟基戊基)苯甲酸盐与其他片剂可药用辅料的组合物制成软材，然后制颗粒、干燥、整粒；将所获得的颗粒与润滑剂混合；用普通压片机或高速压片机压片，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣，即得消旋2-(α-羟基戊基)苯甲酸盐片；
(2)制备方法2：将消旋2-(α-羟基戊基)苯甲酸盐溶于水或醇溶液后，用药用碱调pH值至11.0-13.0后，加入其他片剂可药用辅料，搅拌，采用喷雾干燥法、冷冻干燥法或旋转蒸发法得到固体粉末；加入适量粘合剂，制颗粒、干燥、整粒；与润滑剂混合；用普通压片机或高速压片机压片，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣即得消旋2-(α-羟基戊基)苯甲酸盐片；
(3)制备方法3：将消旋2-(α-羟基戊基)苯甲酸盐原料药或(2)中获得的固体粉末，直接用普通压片机或高速压片机压片，获得硬度3～8公斤的片剂；将包衣材料用水或乙醇溶解后，给所获得的片剂包衣，即得消旋2-(α-羟基戊基)苯甲酸盐片。
2.根据权利要求1所述的消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法，其特征在于所用的其他片剂可药用辅料选自填充剂、崩解剂、润滑剂、粘合剂、或包衣材料等常规辅料。
3.根据权利要求2所述的消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法，其特征在于填充剂选淀粉、可压性淀粉、微晶纤维素、低取代羟丙基纤维素、羟丙甲纤维素、乙基纤维素，或以上两种或两种以上的混合物。
4.根据权利要求2所述的消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法，崩解剂选交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、微晶纤维素、低取代羟丙基纤维素或羧甲基淀粉钠，或以上两种或两种以上的混合物。
5.根据权利要求2所述的消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法，润滑剂选硬脂酸镁、微粉硅胶或滑石粉，或以上两种或两种以上的混合物。
6.根据权利要求2所述的消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法，粘合剂选水、乙醇、淀粉浆、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、1-10％的羟丙基甲基纤维素的水溶液或醇溶液、2-10％的明胶溶液、1-10％的聚乙烯吡咯烷酮水溶液或醇溶液，或以上两种或两种以上的混合物。
7.根据权利要求2所述的消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法，包衣材料可选羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、聚维酮、丙烯酸树脂类、聚乙烯乙醛二乙胺乙酯、聚乙二醇、虫胶、醋酸纤维素酞酸酯、丙烯酸树脂、羟丙基甲基纤维素酞酸酯、醋酸羟丙基甲基纤维素琥珀酸酯等，或以上两种或两种以上的混合物。
8.根据权利要求1所述的消旋2-(α-羟基戊基)苯甲酸盐片及其制备方法，其特征在于制备方法中调节pH值至11.0-13.0的药用碱可采用氢氧化钠、碳酸钠、碳酸氢钠、碳酸钾、氢氧化钾、磷酸氢二钠等，或以上两种或两种以上的混合物。
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| CN103989651A (zh) * | 2014-03-27 | 2014-08-20 | 云南昊邦制药有限公司 | 一种2-（α-羟基戊基）苯甲酸盐控释片及其制备方法 |
| CN104510721A (zh) * | 2014-12-25 | 2015-04-15 | 云南昊邦制药有限公司 | 一种2-(α-羟基戊基)苯甲酸盐滴丸及其制备方法 |
| CN104510720A (zh) * | 2014-12-25 | 2015-04-15 | 云南昊邦制药有限公司 | 一种2-(α-羟基戊基)苯甲酸盐分散片及其制备方法 |
| CN104546748A (zh) * | 2014-12-25 | 2015-04-29 | 云南昊邦制药有限公司 | 一种2-（α-羟基戊基）苯甲酸盐口崩片及其制备方法 |
| CN104586779A (zh) * | 2014-12-25 | 2015-05-06 | 云南昊邦制药有限公司 | 一种2-(α-羟基戊基)苯甲酸盐舌下片及其制备方法 |
| US11149005B2 (en) * | 2018-05-17 | 2021-10-19 | Yaopharma Co., Ltd. | Organic amine ester derivative drug of 2-(α-hydroxypentyl)benzoic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103127025B (zh) | 2016-03-09 |
| CN105616375B (zh) | 2018-08-28 |
| CN105616375A (zh) | 2016-06-01 |
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