CN100518721C - 一种含有乌头碱的肠溶速释片及其制备方法 - Google Patents
一种含有乌头碱的肠溶速释片及其制备方法 Download PDFInfo
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Abstract
一种含有乌头碱的肠溶速释片及其制备方法，本发明涉及含有有机化合物的药物，特别是含有乌头碱的口服制剂及其该制剂的制备方法。该发明配方组份及含量的重量比为：乌头碱类药物0.14%～20%，速释片辅料2.3%～85%；肠溶性聚合物5%～25%，增塑剂0.2%～5%，以及体积比为70%～93%的溶剂。该发明制备方法为先将乌头碱类药物进行超细化过1000目；根据以上权利要求提出的配方，速释片片芯辅料经细化过60～100目直接压片，或用溶剂湿法制成速溶片芯；根据以上权利要求提出的配方，用肠溶材料对片芯进行薄膜包衣。本发明对胃肠道刺激小、肠溶速释性良好、生物利用度和活性均提高5%以上及较长的稳定性。
Description
技术领域
本发明涉及含有有机化合物的药物，特别是含有乌头碱的口服制剂及其该制剂的制备方法。
背景技术
具有镇痛消炎作用的药物乌头碱类是从毛莨科乌头属植物(Aconitum)中分离的乌头类生物碱，主要用于治疗风湿、类风湿及骨关节炎等疾病，临床应用这类化合物已有20多年的历史，它的制剂包括注射液、片剂、口服液、软胶囊。注射液在使用时经常伴有剧烈疼痛以及注射部位红肿，病人依从性不好；普通的口服剂型在服用后口腔发麻、对消化道有较强的刺激。研究证明，乌头碱分散不开、局部浓度过高会强烈地刺激黏膜和其他组织，产生灼烧等不良反应，甚至损坏局部的生物组织，为此，药物在消化道的分散程度和速度是导致药物不良反应的重要原因。公开号CN1107697A的中国专利文件‘草乌甲素口服片剂、胶囊剂’以及专利号ZL98106595.3的中国专利文件‘草乌甲素软胶囊及其生产方法’都是以草乌甲素为主要原料制成的普通口服药物，通过上消化道崩解、吸收。但是，草乌甲素在强烈的胃酸条件下，易水解而降解有效成分；另外，草乌甲素是一种生物碱，在胃酸中与盐酸反应生成生物碱的盐使产品的生物利用度降低，这两个因素的综合作用会降低草乌甲素口服制剂的有效性。前者仍存在服用后口麻、刺激胃肠道等不良反应；而后者因药物延释及患者依从性差，不能充分发挥草乌甲素的功效。而使用药物的患者多为慢性病，受这些病痛的影响，多数病人体质弱，胃肠道功能差。因此，需要消除乌头碱类强烈的刺激性、不稳定性、吸收性问题。
提出本发明之前，我们针对乌头碱类药物临床应用中对胃肠道的强烈刺激出现的不良反应，研究了该类药物吸收的动力学过程，将该类药物制成肠溶片，企图免除药物对胃的刺激并避免药物在胃液中全部或部分分解造成的失活，但实验说明，普通肠溶衣片不能免除对肠道的刺激。
发明内容
本发明的目的在于提供一种不刺激胃肠道，易吸收，能充分发挥药物特性的乌头碱类肠溶速释片口服制剂。
本发明通过制成在肠道内快速释放的肠溶片、消除该类药物对整个消化道的刺激作用来实现上述目的。具体方案如下：
肠溶速释片配方组份及含量的重量比为：乌头碱类药物0.14％～20％，崩解剂1.3％～50％，片芯辅料1.0％～35％；肠溶性聚合物5％～25％，增塑剂0.2％～5％；以及体积比为以上组份70％～93％的溶剂。
所述肠溶速释片含有乌头碱类药物0.2～10mg。
所述的片芯崩解剂为交联羧甲纤维素钠、交联羧甲淀粉钠、环糊精、低取代羟丙基纤维素、微晶纤维、可溶性淀粉中的一种或几种。
所述的肠溶性聚合物为醋酸纤维素酞酸酯、聚乙烯酸酞酸酯、聚丙烯酸树脂II或III号、虫胶、甲基丙烯酸共聚物、醋酸纤维素苯三酸酯、羟丙甲纤维素酞酸酯的一种或几种。
所述片芯辅料中含有柠檬酸、L-苹果酸、丁二酸、马来酸、延胡素酸、葡萄糖、橘子香精、草莓香精、苹果香精中的一种或几种，以改善感官嗅觉或香味。
针对以上方案的含有乌头碱的肠溶速释片的制备方法，具有以下步骤：
(1)称量乌头碱类药物进行超细化过1000目，
(2)根据以上提出的配方，崩解剂经细化过60目，辅料经细化过100目，并与步骤(1)细化后药物混匀后，直接压片或用溶剂湿法制成速溶片芯，
(3)根据以上权利要求提出的配方，用肠溶材料对片芯进行薄膜包衣。
本发明制备的肠溶速释制剂产品经过实验表明：它是一种对患者胃肠道刺激小、生物利用度高的草乌甲素类乌头碱药物制剂——肠溶快速释放口服剂；在胃液内溶出<10％，肠溶性好；速释性实验表明样品能在肠液内迅速崩解成微粒；生物利用度能提高5％以上；乌头碱类的镇痛消炎活性提高5％以上；且在常温下放置2年，产品各项指标均符合要求。
具体实施方式
(一)本发明配方及制备工艺
1、草乌甲素肠溶速释片
按表1实施例规定的组分和含量，将超细化、过1000目的草乌甲素与其他辅料混匀后，进行粉碎混匀，过100目，常规制粒，压片即得片芯。将醋酸纤维素酞酸酯溶于丙酮，另将虫胶溶于95％乙醇中，临用时两液合用，再加入苯二酸二乙酯，混合均匀即可使用。按包衣法包衣，得成品，每片含草乌甲素(规格)分别为0.2mg和0.4mg。
表1 草乌甲素肠溶速释片 配方(1000片)
2、3-乙酰乌头碱肠溶速释片
按表2实施例规定的组分和含量，将3-乙酰乌头碱进行超细化，过1000目，与其他各种做片芯的原料混匀后，常规制粒，压片即得片芯。按肠溶包衣处方量称取聚丙烯酸树脂II、III号置于50ml容器中，加入95％乙醇，在搅拌下使树脂完全浸湿，加盖放置12～24小时，使之完全溶解，在依次加入吐温-80、苯二酸二乙酯、蓖麻油，搅拌均匀后备用。按包衣法包衣，得成品，每片含3-乙酰乌头碱(规格)分别为0.3mg和1.0mg。
表2 3-乙酰乌头碱肠溶速释片 配方(1000片)
3、氢溴酸高乌甲素肠溶速释片
按表3实施例规定的组分和含量，将氢溴酸高乌甲素等各种制片芯的原料过1000目超细化混匀，直接压片即得片芯，按肠溶包衣处方量称取聚丙烯酸树脂II号和苯二酸二乙酯置于60ml容器中，加入95％乙醇，在搅拌下使树脂完全浸湿，加盖放置12～24小时，使之完全溶解，待用。吐温-80、硅油、蓖麻油在包衣前加入上述待用液，搅拌均匀后备用。按包衣法包衣，得成品，每片含氢溴酸高乌甲素(规格)分别为6mg和10mg。
表3 氢溴酸高乌甲素肠溶速释片 配方(1000片)
(二)本发明各肠溶速释薄膜衣片片芯的速释性和肠溶性试验
在肠液中试验表明本发明所制备的片芯样品崩解时间在5～20秒之内，达到质量要求。
在片剂崩解仪中用0.1mol/L HC1试验2小时，片剂在此阶段保持完整，在胃液内溶出<10％。在pH6.8的磷酸缓冲液中处理45分钟，片剂崩解，其很快分散成小微粒。
(三)草乌甲素肠溶速释薄膜衣片药效学动物对比实验及不良反应观察
(1)草乌甲素肠溶速释薄膜衣片的镇痛作用
用小鼠扭体法：取小鼠30只，随机分成3组，每组10只，口服给药后120min，小鼠腹腔注射0.7％醋酸0.1ml/10g，记录5～15min小鼠扭体反应次数，计算并比较组间差异显著性，
表4：草乌甲素肠溶速释薄膜衣片的镇痛作用
| 组别 | 体重 | 剂量(mg/Kg) | 扭体次数 | 抑制率 |
| 空白组 | 20±1.0 | 等体积 | 30.7±7.88 | |
| 吗啡组 | 20±1.3 | 10 | 2.4±1.50 | 92.5％ |
| 草乌甲素片 | 20±1.1 | 0.2 | 10.5±3.42 | 76.04％ |
| 肠溶速释片 | 20±1.2 | 0.2 | 7.5±3.00 | 87.2％ |
(2)草乌甲素肠溶速释薄膜衣片的抗炎作用
用Whitle法，取小鼠30只，随机分成3组，每组10只，口服给药后120min，小鼠尾静脉注射0.5％伊文思兰0.2ml/只后及时腹腔注射0.7％醋酸0.2ml/10g，15min后处死小鼠，腹腔注射生理盐水5ml轻揉后抽取腹腔液，离心，上清液于620nm处测定光密度值，计算并比较组间差异显著性，
表5：草乌甲素肠溶速释薄膜衣片的抗炎作用
| 组别 | 体重 | 剂量(mg/Kg) | 光密度值 | 抑制率 |
| 空白组 | 20±1.12 | 等体积 | 0.28±0.05 | |
| 阿司匹林 | 20±1.13 | 200 | 0.13±0.03 | 62.5％ |
| 草乌甲素片 | 20±1.12 | 0.2 | 0.10±0.02 | 71.4％ |
| 肠溶速释片 | 20±1.1 | 0.2 | 0.09±0.002 | 79.5％ |
由于产品在胃中没有释放，从而消除了胃酸对草乌甲素的水解分解，而在肠液中快速释放和吸收，相应的增加了生物利用度，进而表现出更好的镇痛、抗炎功效。
该实验中，本发明生物利用度提高5％以上，镇痛消炎活性提高5％以上。
(四)本发明乌头碱类肠溶衣速释片的刺激性
自愿者口服试验：
口服没有口麻等刺激口腔的直接反应；45名试验者统计表明，全身性的不良反应也优于普通口服制剂。
草乌甲素肠溶速释薄膜衣片的消化道刺激性试验：
取健康家兔10只，体重：2.0～2.2kg，雌雄各半，分为两组，每组5只，分别口服草乌甲素片和溶速释薄膜衣片，药后48h处死兔子，剖检胃肠等消化道，根据表6观察刺激反应。
表6 消化道刺激反应级表
| 反应级 | 刺激反应 |
| 0 | 无变化 |
| 1 | 无明显变化 |
| 2 | 有轻度充血点 |
| 3 | 有中度充血点 |
| 4 | 有重度充血点，伴有小面积部位变化 |
结果：草乌甲素溶速释薄膜衣片的刺激性为0～1级；而草乌甲素片为3～4级。表明草乌甲素溶速释薄膜衣片的刺激性小。
(五)实施例的各肠溶速释薄膜衣片的稳定性
实施例的样品在室温下避光保管，放置1、2、3、6、12、24个月，参照中国药典项目的检查和薄膜包衣片的通则要求，检验结果表明：所有样品外观基本不变，有效成分也未发生变化。因此，初步认为本发明所制备的肠溶速释薄膜衣片各种处方制得的产品均可达到2年以上的保质期。
稳定性试验结果：质量标准中含量测定和鉴别等参照现行品种的质量标准。结果如下：
| 样品 | 1月 | 2月 | 3月 | 6月 | 12月 | 24月 |
| 例1 | 合格 | 合格 | 合格 | 合格 | 合格 | 合格 |
| 例2 | 合格 | 合格 | 合格 | 合格 | 合格 | 合格 |
| 例3 | 合格 | 合格 | 合格 | 合格 | 合格 | 合格 |
| 例4 | 合格 | 合格 | 合格 | 合格 | 合格 | 合格 |
| 例5 | 台格 | 合格 | 合格 | 合格 | 合格 | 合格 |
| 例6 | 台格 | 合格 | 台格 | 台格 | 台格 | 合格 |
结果表明该发明制备的样品，经过测定，产品质量在2年以上基本稳定。
以上实施例仅为了对本发明做进一步的说明，而本发明的范围不受所举实施例的局限。
Claims (4)
1、一种含有乌头碱的肠溶速释片，组分及重量含量为：
乌头碱类药物 0.14％～20％，
崩解剂 1.3％～50％，
片芯辅料 1.0％～35％，
肠溶性聚合物 5％～25％，
增塑剂 0.2％～5％，
肠溶性聚合物为醋酸纤维素酞酸酯、聚乙烯酸酞酸酯、聚丙烯酸树脂II或III号、虫胶、甲基丙烯酸共聚物、醋酸纤维素苯三酸酯、羟丙甲纤维素酞酸酯中的一种或几种，以上各组分含量之和为100％。
2、根据权利要求1所述的含有乌头碱的肠溶速释片，其特征在于肠溶速释片含有乌头碱类药物0.2～10mg。
3、根据权利要求1所述的含有乌头碱的肠溶速释片，其特征在于崩解剂为交联羧甲纤维素钠、交联羧甲淀粉钠、环糊精、低取代羟丙基纤维素、可溶性淀粉中的一种或几种。
4、根据权利要求1所述的含有乌头碱的肠溶速释片，其特征在于片芯辅料中含有柠檬酸、L-苹果酸、丁二酸、马来酸、葡萄糖、橘子香精、草莓香精、苹果香精中的一种或几种。
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Date of cancellation: 20160630 Granted publication date: 20090729 Pledgee: Fudian bank Limited by Share Ltd. Kunming Haiyuan Road Branch Pledgor: YUNNAN HAOPY PHARMACEUTICALS Ltd. Registration number: 2015990000544 |
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| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
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Denomination of invention: Enteric coated instant release tablet containing Aconitine and its preparation method Effective date of registration: 20230616 Granted publication date: 20090729 Pledgee: Kunming Branch of China Minsheng Bank Co.,Ltd. Pledgor: YUNNAN HAOPY PHARMACEUTICALS Ltd. Registration number: Y2023530000041 |