CN114983960A - 一种药物组合物及其制备方法 - Google Patents
一种药物组合物及其制备方法 Download PDFInfo
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Abstract
本发明涉及医药技术领域,IPC分类号为A61K/31,具体涉及一种药物组合物及其制备方法,所述一种药物组合物,其制备原料,按重量份计:帕利哌酮1‑3份,高分子聚合物70‑90份,粘合剂80‑90份、助流剂0.5‑2份,抗氧剂0.04‑1份,增色剂2‑4份,成膜剂50‑70份。通过将高分子聚合物、帕利哌酮、粘合剂、抗氧剂、助流剂、增色剂进行混合,随后加入成膜剂,包衣制备得到一种药物组合物,通过调整粘合剂的加入顺序,使羟丙基纤维素有效包裹卡波姆,减少卡波姆与药物有效成分接触,在微晶纤维素的紧密压合包覆作用下,提高压合制备得到的一种药物组合物的稳定性。
Description
技术领域
本发明涉及医药技术领域,IPC分类号为A61K/31,具体涉及一种药物组合物及其制备方法。
背景技术
由于先天遗传、后天精神刺激及压力、成长过程中遭遇过创伤性刺激都会导致精神衰弱,在强烈的精神刺激下甚至会导致患者出现精神分裂、意识涣散等症状,精神分裂症不仅影响自身健康,严重后还会给家庭社会造成危害。
精神分裂症是一种慢性严重的精神障碍,患者往往表现出个人情感行为、知觉等方面的异常,出现反应迟钝、言行过激、思维逻辑混乱等症状,精神分裂症发病期较长,给自身家庭等都会造成不同程度的影响,帕利哌酮作为新型抗精神病药物,具有依从性好、起效快、药效持久稳定等优点,被广泛推广使用。
专利CN201510333612.7公开了一种帕利哌酮缓释微球注射剂的制备方法,其制备工艺为:将帕利哌酮与酸酐类试剂分别溶于溶剂中,碱性催化剂作用下使其发生酯化反应,随后催化剂、聚乳酸,利用溶剂挥发法制备帕利哌酮缓释微球,经冷冻干燥后制成微球注射剂,其具有释药时间长,缓释效果好等优点,但其保存稳定性不好。
专利CN201711139459.X公开了一种帕利哌酮口服速溶膜制剂及其制备工艺,其制备原料包括帕利哌酮、聚乙烯醇、纯化水、聚山梨酯80、甘油、甜味剂等,所制得口服速溶膜型帕利哌酮产品可以提高精神分裂症患者服药顺应性,降低患者咬破药片产生的严重毒副反作用,但其药物杂质含量较高。
因此,研制一种杂质低,药物稳定性好,药效优异的帕利哌酮药物组合物是十分必要的。
发明内容
本发明的第一方面提供了一种药物组合物,按重量份计,包括:帕利哌酮1-3份,高分子聚合物70-90份,粘合剂80-90份、助流剂0.5-2份,抗氧剂0.04-1份,增色剂2-4份,成膜剂50-70份。
优选的,所述高分子聚合物为聚氧乙烯、聚乙烯吡咯烷酮、聚乙二醇400中的一种或几种的组合;
进一步优选的,所述高分子聚合物为聚氧乙烯;
优选的,所述粘合剂为卡波姆、甲基纤维素、羟乙基纤维素、微晶纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素钠、壳聚糖中的一种或几种的组合;
进一步优选的,所述粘合剂为卡波姆、微晶纤维素、羟丙基纤维素的复配,卡波姆、微晶纤维素、羟丙基纤维素的质量比为2:5-7:1;
优选的,所述助流剂为胶态二氧化硅、硬酯酸镁、微粉硅胶、淀粉、硬脂酸中的一种或几种的组合;
进一步优选的,所述助流剂为胶态二氧化硅、硬酯酸镁的复配,胶态二氧化硅、硬酯酸镁的质量比为0.9-1.3:1.0-1.4;
优选的,所述抗氧剂为丁基羟基甲苯、没食子酸烷酯、2,6二叔丁基对甲酚、抗环血酸棕榈酸酯、叔丁基对羟基茴香醚中的一种或几种的组合;
进一步优选的,所述抗氧剂为丁基羟基甲苯;
优选的,所述增色剂为氧化铁红、钛白粉、氧化铁红中的一种或几种的组合;
进一步优选的,所述增色剂为氧化铁红;
优选的,所述成膜剂为欧巴代、醋酸纤维素、滑石粉、聚乙二醇6000、氧化钛中的一种或几种的组合;
进一步优选的,所述成膜剂为欧巴代、醋酸纤维素的复配,欧巴代、醋酸纤维素的质量比为1:2.5-3;
本发明的第一方面提供了一种药物组合物的制备方法,具体步骤包括:
(1)将粘合剂加入造粒机中制粒,随后加入帕利哌酮、配方量40-60%的高分子聚合物、配方量40-60%的抗氧剂、配方量40-60%的助流剂混合4-8min,制备得到混合物a;
(2)将配方量40-60%的高分子聚合物、配方量40-60%的抗氧剂、配方量40-60%的助流剂,增色剂加入到锥形混合机中混合,制备得到混合物b;
(3)将混合物a与混合物b移入旋转压片机中,将其压制成双层片,随后加入成膜剂,然后利用激光打孔机打孔,随后进行包衣,制备得到一种药物组合物。
有益效果:
(1)本发明通过将高分子聚合物、帕利哌酮、粘合剂、抗氧剂、助流剂、增色剂进行混合,随后加入成膜剂,包衣制备得到一种药物组合物,通过调整粘合剂的加入顺序,使羟丙基纤维素有效包裹卡波姆,减少卡波姆与药物有效成分接触,在微晶纤维素的紧密压合包覆作用下,有效提高压合制备得到的一种药物组合物的稳定性。
(2)本申请人发现,通过添加粘合剂可提高所制得一种药物组合物的稳定性,尤其是粘合剂为卡波姆、微晶纤维素、羟丙基纤维素的复配,卡波姆、微晶纤维素、羟丙基纤维素的质量比为2:5-7:1时,所制得一种药物组合物具有优异的药物稳定性与药物溶解性,其药用功效优异,羟丙基纤维素的网状分子链与卡波姆分子间存在较强的分子间作用力,通过分子间氢键作用,充分包裹卡波姆分子,减少卡波姆与药物有效成分接触,很好地提高药物稳定性,粘合剂分子间氢键受压时通过氢键缔合,具有高度的可压性,其在外力冲击下可形成致密包覆结构,有效抑制杂质分子进入药物分子内部,在微晶纤维素的紧密压合包覆作用下,进一步提高药物组合物稳定性,且由于分子间氢键的缓冲作用,使压制药片不易崩解,在高分子聚合物的共同作用下,进一步提高药物稳定性,且压制的药片遇到液体后,水分迅速进入含有羟丙基纤维素、微晶纤维素的片剂内部,氢键即刻断裂,药物有效成分快速释放,可能会导致短时间,由于药物浓度过大出现的副作用,而卡波姆中的活性基团可与羟丙基纤维素、微晶纤维素相互作用,抑制羟丙基纤维素、微晶纤维素的崩解速度,进而控制药物释放速度,使药物平稳的发挥疗效,且高分子聚合物与粘合剂、助流剂间具有协同作用,助流剂可降低粘合剂、高分子聚合物与药物颗粒分子间的摩擦力,增强药物分子流动性,进一步提高药物功效,且申请人发现高分子聚合物、粘合剂、助流剂的具体成份的加入先后顺序及制备工艺条件,会极大影响所制得药物组合物的药物稳定性,只有在特定的粘合剂组分比例及特定的高分子聚合物、粘合剂、助流剂的先后加入顺序与制备工艺条件下,所制得药物组合物的稳定性能优异,在60℃,75%RH条件下,放置1个月后,仍具有优异的稳定性。
(3)本发明将粘合剂进行制粒,并加入帕利哌酮、高分子聚合物、抗氧剂、助流剂进行混合,制备得到混合物a,将余量高分子聚合物、抗氧剂、助流剂、粘合剂加入锥形混合机中混合,并加入增色剂,制备得到混合物b,随后压片,激光打孔机打孔,包衣,制备得到一种药物组合物,通过调整粘合剂的加入顺序,使羟丙基纤维素有效包裹卡波姆,减少卡波姆与药物有效成分接触,在微晶纤维素的紧密压合包覆作用下,有效提高压合制备得到的一种药物组合物成份的整体稳定性,将其置于60℃,75%RH条件下,放置1个月后,仍具有优异的稳定性。
具体实施方式
实施例1
实施例1提供了一种药物组合物,按重量份计,包括:帕利哌酮1.5份,高分子聚合物80份,粘合剂87.445份、助流剂1.0份,抗氧剂0.055份,增色剂2.6份,成膜剂60.3份。
所述高分子聚合物为聚氧乙烯,购自山东腾望化工有限公司,型号OP-10;
所述粘合剂为卡波姆、微晶纤维素、羟丙基纤维素的复配,卡波姆、微晶纤维素、羟丙基纤维素的质量比为2:6.716:1,卡波姆CAS号为9007-20-9,购自上海易恩化学技术有限公司,微晶纤维素CAS号为9004-34-6,购自化夏化学北京公司,羟丙基纤维素CAS号为9004-64-2,购自上海麦克林生化科技有限公司;
所述助流剂为胶态二氧化硅、硬酯酸镁的复配,胶态二氧化硅、硬酯酸镁的质量比为0.9:1.0,胶态二氧化硅购自卡博特(中国)投资有限公司,硬酯酸镁CAS号为557-04-0,购自上海麦克林生化科技有限公司;
所述抗氧剂为丁基羟基甲苯,丁基羟基甲苯CAS号为128-37-0,购自上海麦克林生化科技有限公司;
所述增色剂为氧化铁红,氧化铁红CAS号为1332-37-2,购自陕西晨明生物科技有限公司;
所述成膜剂为黄色欧巴代、醋酸纤维素的复配,黄色欧巴代、醋酸纤维素的质量比为1:2.941,黄色欧巴代购自武汉福德化工有限公司,醋酸纤维素CAS号为9004-35-7,购自西格玛奥德里奇(上海)贸易有限公司。
本发明的第一方面提供了一种药物组合物的制备方法,具体步骤包括:
(1)将18份卡波姆加入到造粒机中,随后加入9份羟丙基纤维素的水溶液制粒,(羟丙纤维素的浓度为6%w/w),再依次加入1.5份帕利哌酮、40份聚氧乙烯、0.0275份丁基羟基甲苯、0.2份胶态二氧化硅、30.2225份微晶纤维素混合,最后加入0.25份硬脂酸镁混合5min,得混合物a;
(2)将40份聚氧乙烯,0.0275份丁基羟基甲苯,0.25份胶态二氧化硅,30.2225份微晶纤维素,2.6份氧化铁红加入到锥形混合机混合,混合转速为18r/min,混合时间为15min,然后加入0.25份硬脂酸镁混合5min,得混合物b;
(3)将混合物a与混合物b移入旋转压片机中,压制成双层片,加入45份醋酸纤维素进行包衣,然后利用激光打孔机打孔,最后加入15.3份黄色欧巴代进行包衣,制备得到一种药物组合物。
实施例2
实施例2提供了一种药物组合物,按重量份计,包括:帕利哌酮1.5份,高分子聚合物80份,粘合剂87.445份、助流剂1.0份,抗氧剂0.055份,增色剂2.6份,成膜剂60.3份。
所述高分子聚合物为聚氧乙烯,购自山东腾望化工有限公司,型号OP-10;
所述粘合剂为卡波姆、微晶纤维素、羟丙基纤维素的复配,卡波姆、微晶纤维素、羟丙基纤维素的质量比为2:5.7445:1,卡波姆CAS号为9007-20-9,购自上海易恩化学技术有限公司,微晶纤维素CAS号为9004-34-6,购自化夏化学北京公司,羟丙基纤维素CAS号为9004-64-2,购自上海麦克林生化科技有限公司;
所述助流剂为胶态二氧化硅、硬酯酸镁的复配,二氧化硅、硬酯酸镁的质量比为1.0:1.0,胶态二氧化硅购自卡博特(中国)投资有限公司,硬酯酸镁CAS号为557-04-0,购自上海麦克林生化科技有限公司;
所述抗氧剂为丁基羟基甲苯,丁基羟基甲苯CAS号为128-37-0,购自上海麦克林生化科技有限公司;
所述增色剂为氧化铁红,氧化铁红CAS号为1332-37-2,购自陕西晨明生物科技有限公司;
所述成膜剂为黄色欧巴代、醋酸纤维素的复配,黄色欧巴代、醋酸纤维素的质量比为1:2.941,黄色欧巴代购自武汉福德化工有限公司,醋酸纤维素CAS号为9004-35-7,购自西格玛奥德里奇(上海)贸易有限公司。
本发明的第一方面提供了一种药物组合物的制备方法,具体步骤包括:
(1)将20份卡波姆加入到造粒机中,随后加入10份羟丙基纤维素的水溶液制粒,(羟丙纤维素的浓度为6%w/w),再依次加入1.5份帕利哌酮、40份聚氧乙烯、0.0275份丁基羟基甲苯、0.25份胶态二氧化硅、28.7225份微晶纤维素混合,最后加入0.25份硬脂酸镁混合5min,得混合物a;
(2)将40份聚氧乙烯,0.0275份丁基羟基甲苯,0.25份胶态二氧化硅,28.7225份微晶纤维素,2.6份氧化铁红加入到锥形混合机混合,混合转速为18r/min,混合时间为15min,然后加入0.25份硬脂酸镁混合5min,得混合物b;
(3)将混合物a与混合物b移入旋转压片机中,压制成双层片,加入45份醋酸纤维素进行包衣,然后利用激光打孔机打孔,最后加入15.3份黄色欧巴代进行包衣,制备得到一种药物组合物。
对比例1
具体实施方式同实施例2,不同之处在于,所述一种药物组合物的制备方法,具体步骤包括:
(1)将1.5份帕利哌酮,40份聚氧乙烯,20份卡波姆,0.0275份丁基羟基甲苯,0.25份胶态二氧化硅,28.7225份微晶纤维素加入到造粒机中,加入10份羟丙基纤维素的水溶液制粒,(羟丙纤维素的浓度为6%w/w),然后加入0.25份硬脂镁,混合5min,得混合物a;
(2)将40份聚氧乙烯,0.275份丁基羟基甲苯,0.25份胶态二氧化硅,28.7225份微晶纤维素,2.6份氧化铁红加入到锥形混合机混合,混合转速为18r/min,混合时间为15min,然后加入0.25份硬脂酸镁,混合5min,得混合物b;
(3)将混合物a与混合物b移入旋转压片机中,压制成双层片,加入45份醋酸纤维素进行包衣,然后利用激光打孔机打孔,最后加入15.3份黄色欧巴代进行包衣,制备得到一种药物组合物。
对比例2
具体实施方式同实施例2,不同之处在于,所述一种药物组合物的制备方法,具体步骤包括:
(1)将1.5份帕利哌酮,40份聚氧乙烯,20份卡波姆,0.0275份丁基羟基甲苯,0.25份胶态二氧化硅,28.7225份微晶纤维素加入到锥形混合机中混合,混合转速为18r/min,混合时间为15min,然后加入0.25份硬脂酸镁,混合5min,得混合物a;
(2)将40份聚氧乙烯,0.275份丁基羟基甲苯,0.25份胶态二氧化硅,28.7225份微晶纤维素,2.6份氧化铁红加入到锥形混合机混合,混合转速为18r/min,混合时间为15min,然后加入硬脂酸镁,混合5min,得混合物b;
(3)将混合物a与混合物b移入旋转压片机中,压制成双层片,加入45份醋酸纤维素进行包衣,然后利用激光打孔机打孔,最后加入15.3份黄色欧巴代行包衣,制备得到一种药物组合物。
对比例3
具体实施方式同实施例2,不同之处在于,所述粘合剂为卡波姆、微晶纤维素、羟丙基纤维素的复配,卡波姆、微晶纤维素、羟丙基纤维素的质量比为1:1:1。
性能测试
将实施例1-2,对比例1-3所制得一种药物组合物装入高密度聚乙烯瓶中,并加入1g干燥剂,干燥剂为硅胶,置于60℃,75%RH,放置1个月,利用液相色谱仪,通过面积归一化计算药物组合物中杂质D、杂质F的含量,其中杂质D化学式为:C23H27FN4O4,化学名为:3-[2-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]乙基]-6,7,8,9-四氢-9-羟基-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮氮氧化物,化学式为:
杂质F化学式为:C23H25FN4O3,化学名为:3-[2-[4-(6-氟苯并[d]异噁唑-3-基)-1-哌啶基]乙基]-2-甲基-7,8-二氢-4H-吡啶并[1,2-a]嘧啶-4,9(6H)-二酮,化学式为:
杂质含量测试结果如下。
Claims (10)
1.一种药物组合物,其特征在于,按重量份计,制备原料包括:帕利哌酮1-3份,高分子聚合物70-90份,粘合剂80-90份、助流剂0.5-2份,抗氧剂0.04-1份,增色剂2-4份,成膜剂50-70份。
2.根据权利要求1所述的一种药物组合物,其特征在于,所述高分子聚合物为聚氧乙烯、聚乙烯吡咯烷酮、聚乙二醇400中的一种或几种的组合。
3.根据权利要求1所述的一种药物组合物,其特征在于,所述粘合剂为卡波姆、甲基纤维素、羟乙基纤维素、微晶纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素钠、壳聚糖中的一种或几种的组合。
4.根据权利要求1、2或3所述的一种药物组合物,其特征在于,所述粘合剂为卡波姆、微晶纤维素、羟丙基纤维素的复配,卡波姆、微晶纤维素、羟丙基纤维素的质量比为2:5-7:1。
5.根据权利要求1所述的一种药物组合物,其特征在于,所述助流剂为胶态二氧化硅、硬酯酸镁、微粉硅胶、淀粉、硬脂酸中的一种或几种的组合。
6.根据权利要求5所述的一种药物组合物,其特征在于,所述助流剂为胶态二氧化硅、硬酯酸镁的复配,胶态二氧化硅、硬酯酸镁的质量比为0.9-1.3:1.0-1.4。
7.根据权利要求1所述的一种药物组合物,其特征在于,所述抗氧剂为丁基羟基甲苯、没食子酸烷酯、2,6二叔丁基对甲酚、抗环血酸棕榈酸酯、叔丁基对羟基茴香醚中的一种或几种的组合。
8.根据权利要求1所述的一种药物组合物,其特征在于,所述增色剂为氧化铁红、钛白粉、氧化铁红中的一种或几种的组合。
9.根据权利要求1所述的一种药物组合物,其特征在于,所述成膜剂为欧巴代、醋酸纤维素、滑石粉、聚乙二醇6000、氧化钛中的一种或几种的组合。
10.一种根据权利要求1-9任一项所述的药物组合物的制备方法,其特征在于,包括以下步骤:
(1)将粘合剂加入造粒机中制粒,随后加入帕利哌酮、配方量40-60%的高分子聚合物、配方量40-60%的抗氧剂、配方量40-60%的助流剂混合4-8min,制备得到混合物a;
(2)将配方量40-60%的高分子聚合物、配方量40-60%的抗氧剂、配方量40-60%的助流剂,增色剂加入到锥形混合机中混合,制备得到混合物b;
(3)将混合物a与混合物b移入旋转压片机中,将其压制成双层片,随后加入成膜剂,然后利用激光打孔机打孔,随后进行包衣,制备得到一种药物组合物。
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