CN116712568B - 一种利塞膦酸钠包合物、制剂及用途 - Google Patents
一种利塞膦酸钠包合物、制剂及用途 Download PDFInfo
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Abstract
本发明属于药物制剂技术领域,具体涉及一种利塞膦酸钠包合物、制剂及用途。本发明利用一定比例的羧甲淀粉钠和桃胶参与利塞膦酸钠包合物的制备,提高了利塞膦酸钠包合物的载药量和包封率,大大提高了利塞膦酸钠包合物的质量,又利用利塞膦酸钠包合物制成利塞膦酸钠制剂,克服了利塞膦酸钠对温度和光照敏感的缺陷,解决了在高温和光照条件下易产生有关物质的问题,提高了利塞膦酸钠制剂的稳定性。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种利塞膦酸钠包合物、制剂及用途。
背景技术
利塞膦酸钠,细白色至灰白色结晶粉末,最早由美国宝洁公司Hoechst MarionRoussrl公司研制开发,是一种吡啶二膦酸盐骨吸收抑制剂。1998年美国食品及药物管理局(FDA)批准利塞膦酸钠用于治疗Paget骨病,2004年4月批准其用于绝经后骨质疏松症(PMOP)和糖皮质类固醇性OP的防治。
利塞膦酸钠主要通过直接或间接影响破骨细胞而抑制骨吸收从而增加骨矿物密度减少骨折发生率。但与其他所有双磷酸盐一样,利塞膦酸钠在分子水平上的作用机制仍未明确。它对破骨细胞的影响,现在认为主要有以下四种途径:①阻碍破骨细胞与骨基质的结合;②抑制破骨细胞的骨吸收活性;③抑制破骨细胞的更新和修复;④加速破骨细胞凋亡,缩短破骨细胞的生存。
公开号为CN101601661A的中国专利公开了一种利塞膦酸钠片剂,采用直接压片法,虽然在生产工艺、成本等方面具有一定优势,但仍然存在有关物质含量较高、用药安全性低等缺陷。
公开号为CN104721165A的中国专利公开一种利塞膦酸钠包衣片组合物及其制备方法,包含壳聚糖、羟丙甲纤维素、聚乙二醇、微晶纤维素等辅料,在25℃/60%RH的条件下,有关物质含量较低。
但是通过研究发现利塞膦酸钠对温度和光照更加敏感,在高温和光照条件下,易产生有关物质,未发现现有技术解决该问题。
发明内容
针对现有技术的不足,本发明解决了利塞膦酸钠对温度和光照敏感、在高温和光照条件下易产生有关物质的问题,提供了一种由利塞膦酸钠包合物组成的利塞膦酸钠制剂。具体是利用包合物技术将利塞膦酸钠制备成利塞膦酸钠包合物,并提高了利塞膦酸钠包合物的载药量高、包封率高,提高递送药物的效率。
具体而言,本发明的技术方案如下:
本发明的第一个目的在于提供一种利塞膦酸钠包合物,所述利塞膦酸钠包合物的制备方法为:
将利塞膦酸钠、羧甲淀粉钠溶于pH5.5~6.5的缓冲溶液,加入β-环糊精饱和水溶液,搅拌,加入用35℃~45℃溶解的桃胶水溶液,于30℃~35℃恒温搅拌,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
在多个实施例中,所述利塞膦酸钠、羧甲淀粉钠、β-环糊精、桃胶的重量份比为1:0.1~0.3:2~4:0.1~0.3。
在一个较优的实施例中,所述利塞膦酸钠、羧甲淀粉钠、β-环糊精、桃胶的重量份比为1:0.2:3:0.2。
在多个实施例中,所述缓冲溶液为磷酸盐缓冲溶液或枸橼酸盐缓冲溶液。
在一个较优的实施例中,所述缓冲溶液为磷酸盐缓冲溶液。
在一个较优的实施例中,所述缓冲溶液的pH为6.0。
在多个实施例中,所述恒温搅拌的时间为2~4h。
本发明的第二个目的在于提供一种利塞膦酸钠制剂,所述制剂由利塞膦酸钠包合物和药学上可接受的辅料组成。
在实施例方案中,所述制剂为片剂、胶囊剂、颗粒剂。
进一步的,所述药学上可接受的辅料选自填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂、着色剂、矫味剂中的一种或多种。
本发明的第三个目的在于提供上述利塞膦酸钠包合物在制备治疗骨质疏松药物中的用途。
与现有技术相比,本发明的有益效果在于:
本发明利用一定比例的羧甲淀粉钠和桃胶参与利塞膦酸钠包合物的制备,大大提高了利塞膦酸钠包合物的质量,为后续利塞膦酸钠制剂夯实基础。
本发明利用包合物技术将利塞膦酸钠制成利塞膦酸钠包合物,从而制成制剂,克服了利塞膦酸钠对温度和光照敏感的缺陷,解决了在高温和光照条件下易产生有关物质的问题,提高了利塞膦酸钠制剂的稳定性。
附图说明
图1 pH对利塞膦酸钠包合物质量的影响;
图2 利塞膦酸钠片的光照试验含量影响;
图3 利塞膦酸钠片的光照试验有关物质影响;
图4 利塞膦酸钠片的高温试验含量影响;
图5 利塞膦酸钠片的高温实验有关物质影响。
具体实施方式
为了使本发明的目的、技术方案更加清楚明白,以下结合实施例,对本发明做进一步的说明,但是本发明的保护范围并不限于这些实施例,实施例仅用于解释本发明。本领域技术人员应该理解的是,凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。
一、利塞膦酸钠包合物
实施例1 利塞膦酸钠包合物
配方:
制备方法:
将利塞膦酸钠、羧甲淀粉钠溶于pH6.0的磷酸盐缓冲溶液,加入β-环糊精饱和水溶液,搅拌,加入用35℃~45℃溶解的桃胶水溶液,30℃~35℃恒温搅拌3h,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
实施例2 利塞膦酸钠包合物
配方:
制备方法:
将利塞膦酸钠、羧甲淀粉钠溶于pH5.5的磷酸盐缓冲溶液,加入β-环糊精饱和水溶液,搅拌,加入用35℃~45℃溶解的桃胶水溶液,30℃~35℃恒温搅拌2h,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
实施例3 利塞膦酸钠包合物
配方:
制备方法:
将利塞膦酸钠、羧甲淀粉钠溶于pH6.5的缓冲溶液,加入β-环糊精饱和水溶液,搅拌,加入用35℃~45℃溶解的桃胶水溶液,30℃~35℃恒温搅拌4h,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
对比实施例1 利塞膦酸钠包合物
配方:
制备方法:
将利塞膦酸钠溶于pH6.0的磷酸盐缓冲溶液,加入β-环糊精饱和水溶液,搅拌,加入用35℃~45℃溶解的桃胶水溶液,30℃~35℃恒温搅拌3h,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
对比实施例2 利塞膦酸钠包合物
配方:
制备方法:
将利塞膦酸钠、羧甲淀粉钠溶于pH6.0的磷酸盐缓冲溶液,加入β-环糊精饱和水溶液,30℃~35℃恒温搅拌3h,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
对比实施例3 利塞膦酸钠包合物
配方:
制备方法:
将利塞膦酸钠、羧甲淀粉钠溶于pH6.0的磷酸盐缓冲溶液,加入β-环糊精饱和水溶液,搅拌,加入用35℃~45℃溶解的桃胶水溶液,30℃~35℃恒温搅拌3h,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
对比实施例4 利塞膦酸钠包合物
配方:
制备方法:
将利塞膦酸钠溶于pH6.0的磷酸盐缓冲溶液,加入β-环糊精饱和水溶液,30℃~35℃恒温搅拌3h,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
二、利塞膦酸钠包合物的质量评价
对实施例1~3、对比实施例1~4利塞膦酸钠包合物进行载药量、包封率方面的评价。
表1 对实施例1~3、对比实施例1~4利塞膦酸钠包合物的载药量、包封率
表1可知,本发明利塞膦酸钠包合物载药量高、包封率高。在后续进一步制备成利塞膦酸钠制剂时,奠定良好的基础,如果利塞膦酸钠包合物的载药量、包封率过低,后续制剂制备中则需要加入大量利塞膦酸钠包合物以保证含量标示量合格,从而会对制剂的质量产生影响,例如,硬度、脆碎度等。
三、单因素实验
1. 缓冲溶液对利塞膦酸钠包合物质量的影响
设计单因素实验,探究缓冲溶液的种类是否对利塞膦酸钠包合物的质量有影响。
分组如下:
A:替换为枸橼酸盐缓冲液,其他试验条件同实施例1。
B:替换为枸橼酸盐缓冲液,其他试验条件同实施例2。
C:替换为枸橼酸盐缓冲液,其他试验条件同实施例3。
对A、B、C三组制备所得的利塞膦酸钠包合物进行载药量和包封率的测定,结果如下:
表2 A、B、C三组利塞膦酸钠包合物的载药量和包封率
实验结果显示,枸橼酸盐缓冲溶液也能够使利塞膦酸钠包合物的质量达到理想的效果。
2. pH对利塞膦酸钠包合物质量的影响
设计单因素实验,探究缓冲溶液的pH对利塞膦酸钠包合物的质量的影响,以磷酸盐缓冲溶液为例进行展示,需要说明的是,枸橼酸盐缓冲溶液的pH单因素试验也显现出相似的趋势和效果。
实验设计:以实施例1的制备为定量条件,将磷酸盐缓冲溶液的pH设置为变量条件,探究在pH为5.0~7.0范围内,利塞膦酸钠包合物的质量情况。
图1显示,在pH为5.0~7.0范围内,利塞膦酸钠包合物的载药量和包封率较高。
四、利塞膦酸钠制剂
将实施例1~3、对比实施例1~4利塞膦酸钠包合物与药学上可接受的辅料制备成片剂,用相同的辅料分别制备成利塞膦酸钠片-1、利塞膦酸钠片-2、利塞膦酸钠片-3,利塞膦酸钠片-对1、利塞膦酸钠片-对2、利塞膦酸钠片-对3、利塞膦酸钠片-对4。
将实施例1~3、对比实施例1~4利塞膦酸钠包合物与药学上可接受的辅料制备成胶囊,用相同的辅料分别制备成利塞膦酸钠胶囊-1、利塞膦酸钠胶囊-2、利塞膦酸钠胶囊-3,利塞膦酸钠胶囊-对1、利塞膦酸钠胶囊-对2、利塞膦酸钠胶囊-对3、利塞膦酸钠胶囊-对4。
将实施例1~3、对比实施例1~4利塞膦酸钠包合物与药学上可接受的辅料制备成颗粒剂,用相同的辅料分别制备成利塞膦酸钠颗粒-1、利塞膦酸钠颗粒-2、利塞膦酸钠颗粒-3,利塞膦酸钠颗粒-对1、利塞膦酸钠颗粒-对2、利塞膦酸钠颗粒-对3、利塞膦酸钠颗粒-对4。
需要说明的是,药学上可接受的辅料为填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂、着色剂、矫味剂,可按照制剂类型进行调整和选择,其中填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂、着色剂、矫味剂的种类也均为药学上常用辅料,可根据实际情况进行用量调整和选择。
五、利塞膦酸钠制剂的光稳定性
以利塞膦酸钠片为例,进行强光照射实验。
将利塞膦酸钠片-1、利塞膦酸钠片-2、利塞膦酸钠片-3,利塞膦酸钠片-对1、利塞膦酸钠片-对2、利塞膦酸钠片-对3、利塞膦酸钠片-对4、市售制剂(国药准字H20080235)分别作为供试品,开口放在装有日光灯的光照箱中,于照度为4500lx±500lx的条件下放置30天,分别于第0天、第10天、第20天和第30天取样,检测利塞膦酸钠含量和有关物质总含量。
图2、图3显示,本发明利塞膦酸钠片在光照条件下,稳定性高,含量稳定,有关物质含量低。需要说明的是,本发明利塞膦酸钠胶囊、利塞膦酸钠片颗粒也能够达到相同或类似的技术效果,在此不一一列举。
六、利塞膦酸钠制剂的热稳定性
以利塞膦酸钠片为例,进行高温实验。
将利塞膦酸钠片-1、利塞膦酸钠片-2、利塞膦酸钠片-3,利塞膦酸钠片-对1、利塞膦酸钠片-对2、利塞膦酸钠片-对3、利塞膦酸钠片-对4、市售制剂(国药准字H20080235)分别作为供试品,开口放在恒温设备中,于温度为30℃的条件下放置30天,分别于第0天、第10天、第20天和第30天取样,检测利塞膦酸钠含量和有关物质总含量。
图4、图5显示,本发明利塞膦酸钠片在高温条件下,含量稳定,有关物质含量低,稳定性高。需要说明的是,本发明利塞膦酸钠胶囊、利塞膦酸钠片颗粒也能够达到相同或类似的技术效果,在此不一一列举。
七、利塞膦酸钠制剂的质量控制
以利塞膦酸钠片为例,进行效果展示,需要注意的是,本发明利塞膦酸钠胶囊、利塞膦酸钠片颗粒也能够达到相同或类似的技术效果,在此不一一列举。
加速试验:对利塞膦酸钠片-1、利塞膦酸钠片-2、利塞膦酸钠片-3,利塞膦酸钠片-对1、利塞膦酸钠片-对2、利塞膦酸钠片-对3、利塞膦酸钠片-对4、市售制剂(国药准字H20080235)分别进行外观性状、硬度、脆碎度、含量均匀度的检查。
加速试验条件:按市售包装,温度40±2℃,相对湿度75%±5%,自然光条件下放置6个月,在试验期间的第1个月、6个月末分别取样检查。
表3 第1个月利塞膦酸钠片的质量评价
表4 第6个月利塞膦酸钠片的质量评价
表3、表4显示,本发明利塞膦酸钠片在加速试验中,外观性状保持不变,硬度、脆碎度、含量均匀度均符合《中国药典》的规定,且效果优于对比例片剂和市售制剂。
Claims (9)
1.一种利塞膦酸钠包合物,其特征在于,所述利塞膦酸钠包合物的制备方法为:
将1重量份的利塞膦酸钠、0.1~0.3重量份的羧甲淀粉钠溶于pH5.5~6.5的磷酸盐缓冲溶液或枸橼酸盐缓冲溶液,加入2~4重量份的β-环糊精饱和水溶液,搅拌,加入溶有0.1~0.3重量份桃胶的35℃~45℃桃胶水溶液,于30℃~35℃恒温搅拌,得到沉淀,过滤、洗涤、干燥、即得利塞膦酸钠包合物。
2.根据权利要求1所述的利塞膦酸钠包合物,其特征在于,所述利塞膦酸钠、羧甲淀粉钠、β-环糊精、桃胶的重量份比为1:0.2:3:0.2。
3.根据权利要求1所述的利塞膦酸钠包合物,其特征在于,所述缓冲溶液为磷酸盐缓冲溶液。
4.根据权利要求1所述的利塞膦酸钠包合物,其特征在于,所述缓冲溶液的pH为6.0。
5.根据权利要求1所述的利塞膦酸钠包合物,其特征在于,所述恒温搅拌的时间为2~4h。
6.一种利塞膦酸钠制剂,其特征在于,由权利要求1所述利塞膦酸钠包合物和药学上可接受的辅料组成。
7.根据权利要求6所述的制剂,其特征在于,所述制剂为片剂、胶囊剂、颗粒剂。
8.根据权利要求6所述的制剂,其特征在于,所述药学上可接受的辅料选自填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂、着色剂、矫味剂中的一种或多种。
9.权利要求1所述利塞膦酸钠包合物在制备治疗骨质疏松药物中的用途。
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CN1682739A (zh) * | 2005-03-09 | 2005-10-19 | 石家庄制药集团欧意药业有限公司 | 头孢羟氨苄干混悬及制备方法 |
WO2007009393A1 (fr) * | 2005-07-22 | 2007-01-25 | Jie Zhang | Utilisation d'acide chlorogene dans la fabrication de medicaments pour l'accroissement de l'effet de cellules de moelle osseuse |
CN101254196A (zh) * | 2008-04-03 | 2008-09-03 | 沈阳药科大学 | 一种含双膦酸化合物和维生素d包合物的复合制剂及其制备方法 |
CN105380920A (zh) * | 2015-12-16 | 2016-03-09 | 昆明积大制药股份有限公司 | 一种利塞膦酸钠缓释制剂及制备方法 |
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WO2007009393A1 (fr) * | 2005-07-22 | 2007-01-25 | Jie Zhang | Utilisation d'acide chlorogene dans la fabrication de medicaments pour l'accroissement de l'effet de cellules de moelle osseuse |
CN101254196A (zh) * | 2008-04-03 | 2008-09-03 | 沈阳药科大学 | 一种含双膦酸化合物和维生素d包合物的复合制剂及其制备方法 |
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