CN114159410A - 一种双氯芬酸钠缓释胶囊及其制备方法 - Google Patents
一种双氯芬酸钠缓释胶囊及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种双氯芬酸钠缓释胶囊及其制备方法,构建以蒙脱石为骨架,将双氯芬酸及蜕皮甾酮一定比例的组合物插层于蒙脱石中,并利用聚阳离子材料改进蒙脱石颗粒的电负性,制成药物缓释输送体系,释药机理更加合理,可以明显降低双氯芬酸钠对胃部刺激性,并且由于双氯芬酸与蜕皮甾酮联合使用,进一步的降低了双氯芬酸对胃肠道的刺激作用,避免患者胃痛、烧灼感、返酸、恶心等副作用。
Description
技术领域
本发明涉及一种双氯芬酸钠缓释胶囊及其制备方法,属于医药技术领域。
背景技术
双氯芬酸是一种衍生于苯乙酸类的非甾体消炎镇痛药,在临床上被广泛用于减轻类风湿关节炎,月经痛,发烧,骨关节炎或急性损伤等疾病中的炎症和疼痛。口服给药后,其很快被吸收,血浆终末半衰期短至1~2h,只有50%的药物进入循环系统。因此,目前双氯芬酸钠口服制剂大多数为缓释制剂,分为缓释胶囊和缓释胶囊剂,其中缓释胶囊剂又分凝胶型、溶蚀型、非溶蚀性骨架缓释胶囊,而国内上市的双氯芬酸钠缓释胶囊基本都是凝胶型和溶蚀型骨架缓释胶囊,在胃内释放溶解,但由于双氯芬酸钠本身性质决定了其对胃、呼吸道、眼粘膜具有刺激性,因此在在胃内释放溶解的剂型,会产生胃痛、烧灼感、返酸、纳差、恶心等副作用。
为了解决双氯芬酸钠缓释胶囊现有技术存在的副作用明显的问题,本发明将蒙脱石作为离子交换载体材料,并添加蜕皮甾酮制备双氯芬酸缓释制剂胶囊以降低其副作用,蒙脱石为天然的铝硅酸盐层状粘土矿物,具有特殊的胶囊层结构和不均匀的电荷分布,可利用自身的胶囊层结构负载药物,通过静电作用发生阳离子交换从而将药物插层于胶囊层之间,将药物运载到治疗部位后再进行缓慢释放,从而可有效保证治疗部位的药物浓度,并且通过实验筛选出当双氯芬酸与蜕皮甾酮合用时,可以明显降低双氯芬酸的胃刺激副作用。
发明内容
双氯芬酸钠本身性质决定了其对胃、呼吸道、眼粘膜具有刺激性,因此在胃内释放溶解的剂型,会产生胃痛、烧灼感、返酸、纳差、恶心等副作用。为了解决双氯芬酸钠缓释胶囊现有技术存在的副作用明显的问题,本发明将蒙脱石作为离子交换载体材料,并添加蜕皮甾酮制备双氯芬酸缓释制剂胶囊以降低其副作用,具体技术方案如下:
本发明提供了一种双氯芬酸钠缓释胶囊,由如下质量分属的成分组成:主药30-37份,骨架材料30-80份,粘合剂8-30份,填充剂20-40份,润滑剂0-3份,经过制粒后,将制得颗粒灌装入空胶囊,得到双氯芬酸钠缓释胶囊。所述主药为双氯芬酸钠与蜕皮甾酮按30~200:1比例混合的组合物,骨架材料为蒙脱石。
进一步的,所述粘合剂为甲基纤维素、羟丙基纤维素、聚维酮中的一种或两种以上的混合物。
进一步的,所述填充剂为羟丙基淀粉、微粉硅胶、糊精、微晶纤维素、聚乙烯吡咯烷酮中的一种或两种以上的混合物。
进一步的,所述润滑剂为硬脂酸镁、滑石粉、微粉硅胶、聚乙二醇、月桂醇硫酸钠中的一种或两种以上的混合物。
进一步的,所述骨架材料为酸化蒙脱石。
本发明提供了一种双氯芬酸钠缓释胶囊的制备方法为:取处方量的主药及骨架材料分别溶于水中,边搅拌边进行混合,混合后于15-35℃下继续进行搅拌24h,混合液离心后弃去上清液,蒸馏水洗涤后进行冷冻干燥,即得中间体,将中间体、填充剂、粘合剂混合均匀后,加热至50-70℃,高速搅拌5-25min均匀进行热熔制粒,过筛整粒,加入润滑剂混合均匀,粉碎,得到颗粒将制得颗粒灌装入空胶囊,
具体实施方式
如前所述,本发明旨在提供一种双氯芬酸钠缓释胶囊及其制备方法,以下将结合实施例的内容进行具体描述。
特别需要指出的是,针对本发明所做出的类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
本发明如未注明具体条件者,均按照常规条件或制造商建议的条件进行,所用原料药或辅料,以及所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
药物中间体制备
实施例1:
称取1000g双氯芬酸钠、33.5g蜕皮甾酮溶解于纯净水中,1500g蒙脱石溶解于纯净水中制备成悬浮液,两种溶液混合在25℃下搅拌24h后,离心弃去上清液,蒸馏水洗涤5遍后冷冻干燥2d,得到中间体2590g。
实施例2
称取1000g双氯芬酸钠、5g蜕皮甾酮溶解于纯净水中,2000g蒙脱石溶解于纯净水中制备成悬浮液,两种溶液混合在25℃下搅拌24h后,离心弃去上清液,蒸馏水洗涤5遍后冷冻干燥2d,得到中间体3050g。
实施例3
将蒙脱石加入5%硫酸溶液,在70℃下酸化0.5h,过滤,用蒸馏水洗至中性,80℃烘干,粉碎,过200目筛,既得酸化蒙脱石。称取1000g双氯芬酸钠、35g蜕皮甾酮溶解于纯净水中,1000g酸化蒙脱石溶解于纯净水中制备成悬浮液,两种溶液混合在25℃下搅拌24h后,离心弃去上清液,蒸馏水洗涤5遍后冷冻干燥2d,得到中间体2050g。
胃粘膜保护体内实验
实施例4
取24只体重为180~220g的雄性SPF级SD大鼠,随机分成正常对照组,模型组,给药组1(实施例1),给药组2(实施例2)共4组,每组6只。每天灌胃给药1次,连续7天,造模前24h,大鼠禁食不禁水。
正常对照组:取一定量的生理盐水,加0.1%NaOH溶液和1.0%HCL溶液调节pH值为8-9,加生理盐水定容至10ml,作为空白对照组给药的溶液。
模型组:每只大鼠给予双氯芬酸钠(50mg/kg)灌胃,造成急性胃溃疡。
给药组1:每只大鼠给予实施例1所得中间体(129.5mg/kg)灌胃。
给药组2:每只大鼠给予实施例2所得中间体(152.5mg/kg)灌胃。
造模7天后,大鼠处死,迅速取出鼠胃,沿胃大弯剪开,用预冷的生理盐水洗净胃内残留物,展开并将胃组织固定于两块玻璃板之间供拍照。用图形分析软件测算溃病面积,并计算抑制率。抑制率(%)=(模型组溃疡面积-给药组溃疡面积)/模型组溃疡指数*100%
与正常组相比,模型组中大鼠胃粘膜出现明显损伤,溃疡面积为21.45mm2(P<0.01)。给药组1和给药组2中的大鼠胃粘膜损伤程度与模型组相比,均能看到有不同程度的减轻,馈荡面积显著减少(P<0.01),其中给药组2溃疡面积只有12.75mm2(P<0.01),溃疡抑制率为40.56%,给药组1溃疡面积只有9.27mm2(P<0.01);溃疡抑制率为56.78%,相对于单一使用双氯芬酸钠(模型组),给药组均可以较好的抑制胃溃疡,并且其改善效果对蜕皮甾酮呈现一定的剂量依赖关系。
制剂
实施例5
按处方量准确称量实施例1方法所得中间体、填充剂、粘合剂混合均匀后,加热至50℃,高速搅拌25min均匀进行热熔制粒,过筛整粒,加入润滑剂混合均匀,经过干法制粒后,将制得颗粒灌装入空胶囊,即得规格0.1g双氯芬酸钠缓释胶囊,胶囊内容物重为390mg。
实施例6
处方量:
取处方量实施例2方法所得中间体、填充剂、粘合剂混合均匀后,加热至70℃,高速搅拌5min均匀进行热熔制粒,过筛整粒,加入润滑剂混合均匀,经过干法制粒后,将制得颗粒灌装入空胶囊,即得规格0.1g双氯芬酸钠缓释胶囊,胶囊内容物重为390mg。
实施例7
处方量:
取处方量实施例3方法所得中间体、填充剂、粘合剂混合均匀后,加热至60℃,高速搅拌15min均匀进行热熔制粒,过筛整粒,加入润滑剂混合均匀,经过干法制粒后,将制得颗粒灌装入空胶囊,即得规格0.1g双氯芬酸钠缓释胶囊,胶囊内容物重为390mg。
实施例8
处方量:
取处方量实施例3方法所得中间体、填充剂、粘合剂混合均匀后,加热至60℃,高速搅拌15min均匀进行热熔制粒,过筛整粒,加入润滑剂混合均匀,经过干法制粒后,将制得颗粒灌装入空胶囊,即得规格0.1g双氯芬酸钠缓释胶囊,胶囊内容物重为390mg。
本发明公布的一种双氯芬酸钠缓释胶囊及其制备方法,能够有效降低双氯芬酸的不良反应症状,其安全性较高,具有临床推广价值。
以上仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.一种双氯芬酸钠缓释胶囊,其特征在于:由如下质量分属的成分组成:主药30-37份,骨架材料30-80份,粘合剂8-30份,填充剂20-40份,润滑剂0-3份,经过制粒后,将制得颗粒灌装入空胶囊,得到双氯芬酸钠缓释胶囊。所述主药为双氯芬酸钠与蜕皮甾酮按30~200:1比例混合的组合物,骨架材料为蒙脱石。
2.根据权利要求1所述的一种双氯芬酸钠缓释胶囊,其特征在于:所述粘合剂为甲基纤维素、羟丙基纤维素、聚维酮中的一种或两种以上的混合物。
3.根据权利要求1所述的一种双氯芬酸钠缓释胶囊,其特征在于:所述填充剂为羟丙基淀粉、微粉硅胶、糊精、微晶纤维素、聚乙烯吡咯烷酮中的一种或两种以上的混合物。
4.根据权利要求1所述的一种双氯芬酸钠缓释胶囊,其特征在于:所述润滑剂为硬脂酸镁、滑石粉、微粉硅胶、聚乙二醇、月桂醇硫酸钠中的一种或两种以上的混合物。
5.根据权利要求1所述的一种双氯芬酸钠缓释胶囊,其特征在于:所述骨架材料为酸化蒙脱石。
6.根据权利要求1所述的一种双氯芬酸钠缓释胶囊的制备方法,其特征在于,取处方量的主药及骨架材料分别溶于水中,边搅拌边进行混合,混合后于15-35℃下继续进行搅拌24h,混合液离心后弃去上清液,蒸馏水洗涤后进行冷冻干燥,即得中间体,将中间体、填充剂、粘合剂混合均匀后,加热至50-70℃,高速搅拌5-25min均匀进行热熔制粒,过筛整粒,加入润滑剂混合均匀,粉碎,得到颗粒将制得颗粒灌装入空胶囊,即得双氯芬酸钠缓释胶囊。
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