CN103948557A - 一种新型控释片 - Google Patents
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Abstract
本发明提供了一种新型控释片,包括片芯和包在片芯外的包衣,所述的片芯包括活性药物和缓释材料,所述的包衣包括包衣材料和可有可无的活性成分,所述的片芯的顶部表面裸露。药物释放不受环境pH影响,只与药片释放表面积有关,实现药物恒速释放。
Description
技术领域
本发明涉及一种新型控释片,属于医药技术领域。
背景技术
控释制剂系指在规定释放介质中,按设计好的程序缓慢地恒速或近恒速释放的制剂,药物的释放符合零级速度过程,并且释药速度仅受制剂本身设计的控制,而不受外界条件的影响,如渗透泵片。其与相应的普通制剂比较,具备以下优点:①减少服药次数,大大提高病人的顺应性;②释药徐缓,使血药浓度平稳,避免峰谷现象,有利于降低药物的毒副作用;③缓控释制剂可发挥药物的最佳治疗效果;④某些缓控释制剂可以按要求定时、定位释放,更加有利于疾病的治疗。适于制备成控释制剂的药物主要有三类,一是首过作用强的药物,二是半衰期很短或很长的药物,三是一些成瘾性药物,在保证有效治疗浓度的同时,降低药物的毒副作用,避免耐药性的产生。随着缓控释药物所需辅料研究逐步深入,更多优良的缓控释辅料的发现,缓控释药物越来越受到人们的重视。片剂作为现代药物制剂中应用最广泛的剂型之一,其向缓控释制剂发展,在扩大其适用范围,减少使用限制方面有着重要作用。这其中骨架型缓控释片剂、膜控型缓控释片剂、渗透泵型控释片剂、胃漂浮型片剂尤为常见。骨架片是依靠其骨架材料作为阻释剂的缓控释片剂。药物被包藏在不同的骨架中,以减缓药物的溶出速度和扩散速率而达到缓释效果。传统的骨架片按制剂骨架材料的不同分为水溶性骨架片、肠溶性骨架片、蜡质骨架片、不溶性骨架片和亲水凝胶骨架片。膜控型缓控释片剂是通过将片芯和小丸的表面包制一层适宜的衣层,使其在一定条件下溶解或部分溶解而释出药物,从而达到缓控释作用。其原理属于扩散释放,能源是基于膜腔内的渗透压,或者药物分子在聚合物中的溶出扩散行为。包衣缓控释制剂是口服缓控释制剂中最广泛应用的类型之一。其中缓控释微丸能提高药物与胃肠道的接触面积,使药物吸收完全,从而提高生物利用度;通过几种不同释药速率的小丸组合,可获得理想的释药速率,取得预期的血药浓度,并能维持较长的作用时间,避免对胃黏膜的刺激等不良反应;可由不同药物分别制成小丸组成复方制剂,可增加药物的稳定性,而且也便于质量控制;制成小丸可改变药物的某些性质,如成丸后流动性好、不易碎等。它既可袋装后服用,也可作为制备片剂、胶囊剂等的基础,易制成缓、控释或定位制剂。渗透泵制剂是口服缓控释制剂中释药行为最理想的给药系统之一,其释药速度不受胃肠道pH值影响,且个体差异的影响较小。目前开发的制剂多是以水溶性药物为主的单室渗透泵,这和渗透泵的释药原理有关。难溶性药物通常采取双层渗透泵(或称推拉型渗透泵)技术,使药物与含药层高分子以混悬液形式被助推层高分子推出释药孔,以达到恒速释药的目的。口服渗透泵制剂以零级释药过程为基本特征,能够以恒定的释药速率释放出一定量的治疗药物,体内药物动力学研究表明,它能够避免普通口服片剂必然造成的血药浓度波动较大的现象,减少用药次数与全身副作用,提高药物的安全性和有效性。近年来越来越多的药学工作者投入到缓控释片剂的研究与开发当中,大量的关于缓控释片剂的药物动力学研究也在积极开展,并用于指导新的缓控释片剂的研发。随着药物动力学和药用高分子材料学的发展,及生产工艺的改进,化学药品缓控释制剂得到了长足的发展。
已有缓控释技术中,凝胶骨架片可以通过简单工艺实现,但很难达到零级释放或控制初始释放速度。渗透泵技术可以实现药物的恒速释放,有效控制体内药物血药浓度保持平稳,但渗透泵片在体内释放时会首先产生时滞现象,药物在服用后活性成分不能很快释放。另外由于其释药孔极小,所以在体内容易堵塞。
发明内容
本发明的目的是克服现有技术的不足之处,提供一种新型控释片。
本发明的新型控释片,包括片芯和包在片芯外的包衣,所述的片芯包括活性药物和缓释材料,所述的包衣包括包衣材料和可有可无的活性成分,所述的片芯的顶部表面裸露。
所述的缓释材料选自海藻酸钠、甲基纤维素、羟乙基纤维素、羟丙甲基纤维素、羟丙基纤维素、聚维酮或聚乙烯氧化物。
所述的包衣材料为水可溶性或水不溶性的。
所述的水可溶性的包衣材料选自羟丙甲基纤维素、羟丙基纤维素中的一种或几种;所述的水不溶性的包衣材料选自乙基纤维素、醋酸纤维素聚合物、丙烯酸树脂中的一种或几种。所述的包衣材料中还可以含有水溶性致孔剂。所述的水溶性致孔剂可以是聚维酮、乳糖、氯化钠中的一种或几种。
所述的片芯和包衣还包括药用辅料,所述的药用辅料选自填充剂、崩解剂、润滑剂、助流剂中的一种或几种。
所述的填充剂选自乳糖、预交化淀粉和微晶纤维素的一种或几种;所述的崩解剂选自羧甲基纤维素钠、交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚维酮中的一种或几种;所述的润滑剂选自硬脂酸、硬脂酸镁和滑石粉的一种或几种;所述的助流剂为微粉硅胶。
所述的片芯为单层片、双层片或多层片。
所述的片芯包含一层或一层以上的缓释层或者同时包含速释层与缓释层。
本发明的新型控释片的制备方法,包括如下步骤:
1)选择两种型号的冲头,Ⅰ号冲头直径小于Ⅱ号;
2)使用Ⅰ号冲头将活性成分与辅料混合,压制片芯;
3)更换Ⅱ号冲头,将外层包衣材料装填如中模中,再将压制好的片芯装填到中模中央,进行二次压制,即得。该步骤也可以采用如下方式:
将压制好的片芯放置在Ⅱ号冲头的冲模中央,装填外层包衣材料进行二次压制,即得。
本发明具有如下技术效果:
药物释放不受环境pH影响,只与药片释放表面积有关,实现药物恒速释放。
附图说明
图1为片芯是实施例1中单层片的控释片的结构示意图,其中1为片芯,2为包衣;
图2为片芯是实施例2中双层片的控释片的结构示意图,其中1为片芯-缓释层;2为片芯-速释层;3为包衣;
图3为片芯是实施例4中双层片的控释片的结构示意图,其中1为片芯-缓释1层;2为片芯-缓释2层;3为包衣;
图4为实施例1中片芯和控释片的溶出曲线;
图5为实施例2中片芯和控释片的溶出曲线;
图6为实施例3中片芯和控释片的溶出曲线;
图7为实施例4中片芯和控释片的溶出曲线;
图8为实施例1、实施例5、实施例6、实施例7中控释片的溶出曲线对照。
图9为实施例1、实施例8、实施例9、实施例10中控释片的溶出曲线对照。
具体实施方式
本发明中的药物溶出检测方法:按照中国药典2010版二部附录XD释放度测定第一法(用于缓释、控释、迟释制剂),将药片投入900ml0.1mol/L盐酸溶液中,篮法,100转/分钟,37℃,在规定取样点吸取适量溶出液计算药片累计释放度,绘制溶出曲线。
实施例1
本实施例的新型控释片,如图1所示,包括片芯和包在片芯外的包衣,片芯为只有一个缓释层的单层片。
控释片的成分和含量如下:按照1000片计,每片重800mg。
制备方法:
1、将片芯原辅料按照处方进行称量,充分混合后备用;选择两种型号的冲头,Ⅰ号冲头直径小于Ⅱ号;
2、使用旋转式压片机,安装冲头Ⅰ,调整压片机填充深度和压片力,压制片芯,片重为每片300mg,片芯硬度90N;
3、按照处方称量包衣用辅料,充分混合备用;
4、使用旋转式压片机,安装冲头Ⅱ,调整压片机工艺参数,将压制好的片芯先放置在冲模中央,填加混合好的包衣材料,压制药片,使片芯的底面和侧面全部被包衣材料覆盖,药片总重800mg,硬度100N。
检测药物溶出,溶出曲线见图4。从图4可以看出:片芯释放呈一级释放趋势,添加了外层包衣制备成控释片后,药片释放呈恒速。
实施例1中,片芯仅顶面裸露在外,溶出过程中,片芯中的有效成分只能通过顶面释放,由于释放面积恒定,故可达到零级释放的效果。实施例1中制备的药物模型适合于心脑血管类药物,可以替代渗透泵技术达到药物恒速释放的目的。
实施例2
本实施例的新型控释片,如图2所示,包括片芯和包在片芯外的包衣,片芯为双层片,由缓释层和速释层组成。
控释片的成分和含量如下:按照1000片计,每片重800mg。
制备方法:
1、按照处方将片芯-缓释层、片芯-速释层原辅料进行称量,分别充分混合后备用;选择两种型号的冲头,Ⅰ号冲头直径小于Ⅱ号;
2、使用旋转式压片机,安装冲头Ⅰ,调整压片机填充深度和压片力,压制片芯,其中片芯-缓释层重为200mg,片芯-速释层重100mg,片芯硬度80N;
3、按照处方称量包衣用辅料,充分混合备用;
4、使用旋转式压片机,安装冲头Ⅱ,调整压片机工艺参数,将压制好的片芯带有颜色的速释层朝上先放置在冲模中央,填加混合好的包衣材料,压制药片,使片芯的底面和侧面全部被包衣材料覆盖,药片总重800mg,硬度100N。
检测药物溶出,溶出曲线见图5。从图5可以看出:单独的片芯因为速释层很快就崩解了,溶出速度较快,药物溶出90%仅需6小时。当制备成带有包衣的控释片后,溶出呈现了先慢,后快的释放趋势。
实施例2中片芯由缓释-速释双层片组成溶出过程中片芯中缓释部分先溶蚀,缓释层中的活性成份缓慢释放,待缓释层释放完毕后,速释层快速崩解,达到快速给药的目的。
实施例2中制备的药物模型适合于治疗晨僵、心梗等在凌晨易发病的药物,速释层释放的时间可以控制在药物服用后的4-6小时后,患者睡前服药后可避免凌晨发病的可能性。另外,也适用于绝大部分在胃中吸收好,在胃的下部吸收较差的药物。低pH条件下,药物缓慢释放,释放的部分基本都能被吸收利用,当环境pH升高时,药物的溶解度降低,机体对药物的吸收变差,此时,增加药物的释放量可以弥补生物利用度低的问题。
实施例3
本实施例的新型控释片,如图1所示,包括片芯和包在片芯外的包衣,,片芯为只有一个缓释层的单层片。
控释片的成分和含量如下:按照1000片计,每片重800mg。
制备方法:
1、将片芯原辅料按照处方进行称量,充分混合后备用;选择两种型号的冲头,Ⅰ号冲头直径小于Ⅱ号;
2、使用旋转式压片机,安装冲头Ⅰ,调整压片机填充深度和压片力,压制片芯,片重为每片300mg,片芯硬度90N;
3、按照处方称量包衣用辅料,充分混合备用;
4、使用旋转式压片机,安装冲头Ⅱ,调整压片机工艺参数,将压制好的片芯先放置在冲模中央,填加混合好的包衣材料,压制药片,使片芯的底面和侧面全部被包衣材料覆盖,药片总重800mg,硬度100N。
检测药物溶出,溶出曲线见图6。从图6可以看出:单独的片芯在4小时后即溶蚀完全,药物释放度达到90%以上,包被了外层包衣制备控释片后,4小时内药物释放缓慢,4小时以后药物释放速度加快,8小时溶出结束。
实施例3的片芯为单层片,包衣中含有活性成分,包衣材料选用可溶的羟丙甲基纤维素,溶出实验中药片外层包衣逐渐溶蚀,包衣中的活性成分逐步释放,补充了药物仅从顶面释放,累计释放量不够的问题。待外壳溶蚀掉以后,片芯完全裸露在外,药物从四面开始扩散,释药量增加。这种药物模型也可以用于辰时发作的疾病的治疗药物。作用效果类似于实施例2。
实施例4
本实施例的新型控释片,如图3所示,包括片芯和包在片芯外的包衣,片芯为双层片,由缓释1层和缓释2层组成。
控释片的成分和含量如下:按照1000片计,每片重800mg。
制备方法:
1、按照处方将片芯-缓释1层、片芯-缓释2层原辅料进行称量,分别充分混合后备用;选择两种型号的冲头,Ⅰ号冲头直径小于Ⅱ号;
2、使用旋转式压片机,安装冲头Ⅰ,调整压片机填充深度和压片力,压制片芯,其中片芯-缓释1层重,片芯-缓释2层均重150mg,片芯总重300mg,硬度90N;
3、按照处方称量包衣用辅料,充分混合备用;
4、使用旋转式压片机,安装冲头Ⅱ,调整压片机工艺参数,将压制好的片芯带有颜色的速释层朝上先放置在冲模中央,填加混合好的包衣材料,压制药片,使片芯的底面和侧面全部被包衣材料覆盖,药片总重800mg,硬度100N。
检测药物溶出,溶出曲线见图7。从图7可以看出:片芯溶出曲线呈1级释放,0.5h即已释放30%以上,10小时累计溶出量达90%以上,控释片的释放呈现了两个阶段的特点,即0~5h时释放速度慢,5~12h释放速度变快,但两个阶段都呈恒速释放。
实施例4的药片片芯是由两种不同释放速度组成的双层片,上层释放速度慢,下层释放速度较快。
实施例5~10
实施例5~10的新型控释片,如图1所示,包括片芯和包在片芯外的包衣,片芯为单层片。
控释片的成分和含量如下:按照1000片计,每片重800mg。
另外本专利还公开了控释片外层包衣中可溶性成分的量和片芯中缓释材料含量对药物溶出的影响,制备方法同实施例1
比较实施例1、实施例5、实施例6、实施例7药片的溶出,从图8可以看出,包衣中可溶性材料—乳糖的含量越多,包衣溶出的速度越快。
比较实施例1、实施例8、实施例9、实施例10药片溶出,从图9可以看出,片芯中缓释材料的含量越多,片芯溶出速度越慢。
Claims (11)
1.一种新型控释片,包括片芯和包在片芯外的包衣,所述的片芯包括活性药物和缓释材料,所述的包衣包括包衣材料和可有可无的活性成分,其特征在于,所述的片芯的顶部表面裸露。
2.根据权利要求1所述的新型控释片,其特征在于,所述的缓释材料选自海藻酸钠、甲基纤维素、羟乙基纤维素、羟丙甲基纤维素、羟丙基纤维素、聚维酮或聚乙烯氧化物。
3.根据权利要求1所述的新型控释片,其特征在于,所述的包衣材料为水可溶性或水不溶性的。
4.根据权利要求3所述的新型控释片,其特征在于,所述的水可溶性的包衣材料选自羟丙甲基纤维素、羟丙基纤维素中的一种或几种;所述的水不溶性的包衣材料选自乙基纤维素、醋酸纤维素聚合物、丙烯酸树脂中的一种或几种。
5.根据权利要求1所述的新型控释片,其特征在于,所述的包衣材料中还可以含有水溶性致孔剂。
6.根据权利要求5所述的新型控释片,其特征在于,所述的水溶性致孔剂可以是聚维酮、乳糖、氯化钠中的一种或几种。
7.根据权利要求1所述的新型控释片,其特征在于,所述的片芯和包衣还包括药用辅料,所述的药用辅料选自填充剂、崩解剂、润滑剂、助流剂、食用色素中的一种或几种。
8.根据权利要求5所述的新型控释片,其特征在于,所述的填充剂选自乳糖、预交化淀粉和微晶纤维素的一种或几种;所述的崩解剂选自羧甲基纤维素钠、交联羧甲基纤维素钠、羧甲基淀粉钠和交联聚维酮中的一种或几种;所述的润滑剂选自硬脂酸、硬脂酸镁和滑石粉的一种或几种;所述的助流剂为微粉硅胶;所述的食用色素为胭脂红、柠檬黄、靛蓝、二氧化钛中的一种或几种。
9.根据权利要求1所述的新型控释片,其特征在于,所述的片芯为单层片、双层片或多层片。
10.根据权利要求7所述的新型控释片,其特征在于,所述的片芯包含一层或一层以上的缓释层或者同时包含速释层与缓释层。
11.根据权利要求1-9中任意一种新型控释片的制备方法,其特征在于,包括如下步骤:
1)选择两种型号的冲头,Ⅰ号冲头直径小于Ⅱ号;
2)使用Ⅰ号冲头将活性成分与辅料混合,压制片芯;
3)更换Ⅱ号冲头,将外层包衣材料和可有可无的活性成分混合,装填到中模中,再将压制好的片芯装填到中模中央,进行二次压制,即得;该步骤也可以采用如下方式:
将压制好的片芯放置在Ⅱ号冲头的冲模中央,装填外层包衣材料和可有可无的活性成分进行二次压制,即得。
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US10973767B2 (en) | 2015-06-03 | 2021-04-13 | Triastek, Inc. | Oral drug dosage form comprising drug in the form of nanoparticles |
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CN111698983A (zh) * | 2018-01-09 | 2020-09-22 | 南京三迭纪医药科技有限公司 | 一种包含固定剂量adhd非兴奋剂和adhd兴奋剂的复方口服药物剂型 |
US11571391B2 (en) | 2018-01-09 | 2023-02-07 | Triastek, Inc. | Oral drug dosage forms compromising a fixed-dose of an ADHD non-stimulant and an ADHD stimulant |
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