CN112168794A - 一种布瑞哌唑片的制备方法 - Google Patents
一种布瑞哌唑片的制备方法 Download PDFInfo
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Abstract
本发明公开了布瑞哌唑片的制备方法，属于药物制剂领域。是以布瑞哌唑固体分散体颗粒与辅料直接压片而成，所述的布瑞哌唑固体分散体颗粒按如下方法制备而成：将枸橼酸钾、山梨醇和布瑞哌唑在热熔挤出机中加热熔融，将熔融物挤出制粒，布瑞哌唑与枸橼酸钾的重量比为1:0.5‑2，布瑞哌唑与山梨醇的重量比为1:1‑5。本发明增加了布瑞哌唑体外溶出度。
Description
技术领域
本发明属于药物制剂领域，涉及一种布瑞哌唑片及其制备方法。
背景技术
布瑞哌唑，化学名：7-[4-(4-苯并[B]噻吩-4-基-1-哌嗪)丁氧基]-2(1H)-喹啉酮，CAS号:913611-97-9，分子式:C25H27N3O2S，分子量:433.57，其化学结构式如下：
布瑞哌唑是白色或类白色晶体或结晶性粉末，溶于N-甲基吡咯烷酮，微溶于N，N-二甲基乙酰胺，不溶于甲醇，极不溶于乙醇（99.5），几乎不溶于水。布瑞哌唑溶解性差是影响临床疗效的关键因素。
布瑞哌唑，临床用于精神分裂症和重度抑郁症，是由丹麦灵北制药和日本大冢公司共同研发的首个多巴胺D2、5-HT1A受体激动剂以及5-HT2A受体拮抗剂化合物。与阿立哌唑相比，布瑞唑派与5-HT受体的亲和力增加，对D2受体的活性有所降低，耐受性表现更好，静坐不能的副反应发生率更低，在精神分裂症的阴性症状和认知功能方面的疗效有更好的趋势，用于抑郁症的辅助治疗时，起效快。
公开号为CN104023750A的大塚制药株式会社提出的专利申请公开了包含ΒREXPIPRAZOLE和取代的β-环糊精的药物制剂，该专利申请采用羟丙基或者磺丁基-β-环糊精进行包合后制成水溶液，将包合物做成注射液，从而获得冻干注射液，在此过程中包合收率不高，增加了生产成本。
公开号为CN107397730A（对比文件1）的大塚制药株式会社提出的专利申请公开了含有7-[4-(4-苯并[b]噻吩-4-基-哌嗪-1-基)丁氧基]-1H-喹啉-2-酮或其盐的片剂，该专利的实施例中采用湿法制粒工艺，压片后包衣，从而制备得到布瑞哌唑片，包衣含有羟丙甲纤维素、滑石、二氧化钛和着色剂，所制备的素片含有作为活性成分的7-[4-(4-苯并[b]噻吩-4-基-哌嗪-1-基)丁氧基]-1H-喹啉-2-酮或其盐，并且还含有：乳糖、玉米淀粉、结晶纤维素或其它赋形剂；低取代的羟丙基纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、或其它崩解剂；羟丙基纤维素或其它粘合剂；和硬脂酸盐或其它润滑剂。但溶出在15min均未达到85%以上。
因此，研制一种溶出速率好、收率高，质量稳定的布瑞哌唑片，及适合工业化生产的方法具有重要意义。
热熔技术是近年来在国内制药领域迅速发展起来的用于难溶性药物的新技术，具有无需添加有机溶剂、连续化生产，易于商业化等优点。徐承智等研究了“热熔分散法制备依巴斯汀分散片”《药学实践杂志》（2017年05期），是将依巴斯汀原料熔融分散于羟丙甲纤维素热水溶液中，以甘露醇吸附药液，制备分散片。结果显示，热熔分散体中的依巴斯汀仍具有原料晶型的主要特征,体外溶出结果显示,结论以羟丙甲纤维素为载体的热熔分散技术,可显著提高依巴斯汀的溶出度。布瑞哌唑几乎不溶于水，采用常规的热熔条件制备时，布瑞哌唑分散颗粒在高温热熔时易发生降解，低温热熔时布瑞哌唑难以提高溶出度的问题。
发明内容
鉴于现有技术的不足，本发明的目的在于提供一种生产工艺简单，体外溶出好，收率高，安全稳定的布瑞哌唑片的制备方法。采用热熔挤出的布瑞哌唑片，具有以下优点：（1）生产工艺简单，易操作，收率高，可以实现产业化大生产；（2）布瑞哌唑与载体以固体分散体的方式存在，体外溶出度高，达到崩解即是溶出完全；（3）制剂受环境影响较小，体外溶出曲线平稳，批间差异小。
本发明的目的是通过以下方案实现的：
一种布瑞哌唑片，该片是以布瑞哌唑固体分散体颗粒与其药学上可接受的辅料直接压片而成。
发明人在实验初期单独采用熔点较低的山梨醇作为布瑞哌唑固体分散颗粒，发现熔点降低有限，布瑞哌唑稳定性不能很好保证。通过多辅料组合作为载体组合物，发现加入枸橼酸钾后布瑞哌唑固体分散颗粒不仅共熔点明显降低，布瑞哌唑的热稳定性明显提高，而且溶出度明显提高。因此，本发明所述的布瑞哌唑固体分散体颗粒为布瑞哌唑、枸橼酸钾和山梨醇的组合物颗粒。
所述的布瑞哌唑固体分散体颗粒按如下方法制备而成：将枸橼酸钾、山梨醇和布瑞哌唑在热熔挤出机中加热熔融，然后将熔融物挤出制粒。
布瑞哌唑与枸橼酸钾的重量比为1:0.5-2;布瑞哌唑与山梨醇的重量比为1:1-5。
较佳地，布瑞哌唑与枸橼酸钾的重量比为1:0.8-1.2；布瑞哌唑与山梨醇的重量比为1:2-4。因为在该比例范围内，形成低共熔混合物，其熔点低于90℃，保证药物的快速溶出，同时利于热熔挤出产能的提高。
药学上可接受的辅料包含填充剂和润滑剂。
所述的填充剂选自乳糖、甘露醇、预交化淀粉、微晶纤维素、糊精、硫酸钙和磷酸氢钙中的一种或多种。优选磷酸氢钙。
所述的润滑剂为硬脂酸镁、微粉硅胶、硬脂酸、滑石粉中的一种或者多种，优选硬脂酸镁。
再具体地讲，填充剂、润滑剂是磷酸氢钙、甘露醇、微粉硅胶和硬脂酸镁的混合物；布瑞哌唑与磷酸氢钙、甘露醇、微粉硅胶和硬脂酸镁重量比分别为1:4.5-7.5；1:9-18；1：0.125-0.5；1:0.0375-0.075。
有益效果：
1、采用所选的两种辅料制备采布瑞哌唑固体分散颗粒，能够达到降低挤出温度，抑制布瑞哌唑高温降解的发生，同时降低了对热熔挤出设备的要求利于挤出过程，保证药物稳定的特点。
2、所选辅料的组合使得制备的布瑞哌唑固体分散体具有快速完全溶出的效果，实施例中制备的片溶出速度和溶出百分数均高于目前文献报道的剂型的溶出情况。
附图说明
图1为本发明的实施例1、实施例2、实施例3与对比文件1实施例2-1、2-2、2-3，在pH4.5磷酸氢二钠-柠檬酸缓冲液中的溶出曲线图。
具体实施方式
以下将结合具体实施例和附图具体说明本发明的技术方案。
实施例1
实施例1-5的处方工艺见表1所示，所有组分的单位是：g。
表1
制备方法：
将枸橼酸钾、山梨醇和布瑞哌唑在热熔挤出机中加热熔融，然后将熔融物物挤出制粒，与甘露醇、磷酸氢钙、微粉硅胶、硬脂酸镁直接压片。
实施例6-10对各组分填充剂、润滑剂的种类、用量进行考察，处方工艺见表2，表中组分的单位是g。
表2
制备方法：
将枸橼酸钾、山梨醇和布瑞哌唑在热熔挤出机中加热熔融，然后将熔融物挤出制粒，再与每个实施例中对应的辅料混合后直接压片。
可见，使用不同填充剂选自乳糖、甘露醇、预交化淀粉、微晶纤维素、糊精、硫酸钙和磷酸氢钙中的一种或多种；不同润滑剂选自硬脂酸镁、微粉硅胶、硬脂酸、滑石粉中的一种或者多种，制备的片剂的均能都达到快速溶出的效果。
实施例11
在公开专利CN107397730A实施例2-1、2-2、2-3与本发明中实施例1、实施例2、实施例3中体外溶出曲线考察，如图1、表3。
体外溶出度检测条件：溶出试验方法（桨法，50rpm），使用pH值为4.5的磷酸氢二钠-柠檬酸缓冲液（900ml）作为测试液体。
表3
可见， 本发明将枸橼酸钾、山梨醇和布瑞哌唑在热熔挤出机中加热熔融，然后将熔融物挤出制粒，再与每个实施例中对应的辅料混合后直接压片，制备的片剂5min溶出度均高于目前公开专利及文献报道剂型的溶出度，因此将布瑞哌唑制成固体分散体，大大提高另外溶出度，并且工艺适合产业化。
Claims (6)
1.一种布瑞哌唑片的制备方法，其特征在于，由布瑞哌唑固体分散体颗粒与药学上可接受的辅料直接压片而成；所述的布瑞哌唑固体分散体颗粒按如下方法制备而成：将枸橼酸钾、山梨醇和布瑞哌唑在热熔挤出机中加热熔融，在低于90℃的熔融温度下，将熔融物挤出制粒。
2.根据权利要求1所述的布瑞哌唑片的制备方法，其特征在于，布瑞哌唑与枸橼酸钾的重量比为1:0.5-2；布瑞哌唑片与山梨醇的重量比为1:1-5。
3.根据权利要求1所述的布瑞哌唑片的制备方法，其特征在于，
所述的辅料为磷酸氢钙、甘露醇、微粉硅胶和硬脂酸镁的混合物。
4.根据权利要求3所述的布瑞哌唑片的制备方法，其特征在于，
布瑞哌唑与磷酸氢钙、甘露醇、微粉硅胶和硬脂酸镁重量比分别为1:4.5-7.5；1:9-18；1：0.125-0.5；1:0.0375-0.075。
5.根据权利要求1所述的布瑞哌唑片的制备方法，其特征在于，布瑞哌唑与枸橼酸钾的重量比为1:0.8-1.2；布瑞哌唑与山梨醇的重量比为1:2-4。
6.根据权利要求3所述的布瑞哌唑片的制备方法，其特征在于，布瑞哌唑与磷酸氢钙、甘露醇、微粉硅胶和硬脂酸镁重量比分别为1:5-6；1:12-14；1：0.2-0.4；1:0.04-0.06。
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