CN112754999A - 一种醋酸巴多昔芬组合物及醋酸巴多昔芬薄膜衣片制备方法 - Google Patents
一种醋酸巴多昔芬组合物及醋酸巴多昔芬薄膜衣片制备方法 Download PDFInfo
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Abstract
本发明公开了一种醋酸巴多昔芬组合物及醋酸巴多昔芬薄膜衣片制备方法,涉及医药技术领域,以重量分数计,含有:20‑26份醋酸巴多昔芬、250‑350份填充剂、30‑50份粘合剂、8‑15份崩解剂、3‑6份抗氧剂、2‑6份助流剂、0.1‑0.5份润滑剂、1‑3份润湿剂、适量纯化水溶剂,其中醋酸巴多昔芬为BCSⅡ类药物、粒径D90在30μm;所述抗氧剂为维生素C,所述填充剂由乳糖和微晶纤维素组成,以重量分数计,所述乳糖和微晶纤维素的比例1:2~2:1,采用本工艺制备,流化床制粒技术工艺简单、成本更低,且易于工业化生产。
Description
技术领域
本发明涉及药物制备技术领域,尤其涉及一种醋酸巴多昔芬组合物及醋酸巴多昔芬薄膜衣片制备方法。
背景技术
醋酸巴多昔芬的化学名称是(1-[4-(2-氮杂环庚-1-基-乙氧基)-苄基]-2-(4-羟基-苯基)-3-甲基-1H-吲哚-5-ol乙酸),具有如下所示的化学结构:
它是一种新型的第三代选择性***受体调节剂(selective estro-genreceptor modulators,SERMs),它能够竞争性地抑制17β-***与***受体ERα和ERβ的结合,从而对骨骼组织的***受体起到活化作用,进而增加脊椎与髋部的骨密度。该药物主要用于绝经后妇女骨质疏松症的预防和治疗,它对***和子宫几乎没有刺激,不会导致乳腺和子宫内膜增生,疗效确切,耐受性高,毒副作用小,是较为理想的抗骨质疏松药物,具有广阔的市场前景。
巴多昔芬由惠氏原研,后转让给辉瑞制药,已经于2009年4月27通过欧洲药监局的批准在意大利和西班牙上市,商品名为Conbriza,2010年7月在日本上市,商品名为Viviant。未查到原研相关制剂专利。
现有国内技术专利也公开了几种组合物和制剂专利以提高其在组合物中的稳定性,并促进或控制药物的释放。如申请号为CN201410109188.3的中国专利文献公开了一种缓释滴丸制剂的制备方法;申请号为CN201410109189.8的中国专利文献公开了一种将醋酸巴多昔芬被分散于固体溶液和/或固体溶胶中制备制剂的方法。因醋酸巴多昔芬易氧化降解,故在组合物中需加入抗氧剂以提高组合物或制剂产品的稳定性。申请号为CN201410109188.3的中国专利文献公开了一种缓释滴丸制剂的制备方法;申请号为CN201410109189.8的中国专利文献公开了一种将醋酸巴多昔芬被分散于固体溶液和/或固体溶胶中制备制剂的方法。两个专利文献中的抗氧剂均选择维生素E,但是维生素E(Vitamin E)是一种脂溶性维生素,在已有专利可制片剂的实施例中,需将维生素E TPGS加热熔化后,加入醋酸巴多昔芬混匀后再加入PEG 6000混匀后成混悬共熔液,将上述共熔液冷却至室温并粉碎,以完成维生素E与醋酸巴多昔芬的混合并制粒,工艺过程比较繁琐。
发明内容
本发明的目的在于解决现有醋酸巴多昔芬制备过程中存在的问题,提供一种醋酸巴多昔芬组合物及醋酸巴多昔芬薄膜衣片制备方法,采用本工艺制备,选用维生素C作为片剂中的抗氧剂,可直接与醋酸巴多昔芬和其他物料进行混合以简化工艺,并选用流化床制粒工艺,流化床制粒技术的应用也适用于放大生产提高产量。
为了实现以上目的,本发明采用的技术方案是:
一种醋酸巴多昔芬组合物,以重量分数计,由20-26份醋酸巴多昔芬、250-350份填充剂、30-50份粘合剂、8-15份崩解剂、3-6份抗氧剂、2-6份助流剂、0.1-0.5份润滑剂、1-3份润湿剂、适量纯化水溶剂,其中醋酸巴多昔芬为BCSⅡ类药物、粒径D90在30μm;所述抗氧剂为维生素C,所述填充剂由乳糖和微晶纤维素组成,以重量分数计,所述乳糖和微晶纤维素的比例1:2~2:1。
优选的,以重量分数计,由22.6份醋酸巴多昔芬、310份填充剂、44.6份粘合剂、12份崩解剂、4.5份抗氧剂、4.5份助流剂、0.3份润滑剂、1.5份润湿剂、余量为纯化水溶剂,其中醋酸巴多昔芬为BCSⅡ类药物、粒径D90在30μm;所述抗氧剂为维生素C,所述填充剂由乳糖和微晶纤维素组成,以重量分数计,所述乳糖和微晶纤维素的比例1:2~2:1。
优选的,以重量份数计,所述乳糖和微晶纤维素的比例1:1。
优选的,所述粘合剂为预胶化淀粉,所述崩解剂为羧甲基淀粉钠、交联羧甲基淀粉钠中的一种,所述助流剂为二氧化硅,所述润滑剂为硬脂酸镁或滑石粉,所述润湿剂为十二烷基硫酸钠。
一种制备醋酸巴多昔芬薄膜衣片的方法,包括以下步骤:
步骤一:制备溶液A,按照成分比例,将润湿剂溶解于适量的纯化水溶剂中,配置成溶液A备用;
步骤二:制备原药混合料,将醋酸巴多昔芬和填充剂崩解剂粘合剂混合均匀,制得原药混合料B,用于制粒;
步骤三、制粒,将步骤二混合均匀后制得的原药混合料B加入溶液A进行制粒,50-60℃干燥后整粒;
步骤四,压片,将步骤三制粒后的颗粒添加外加辅料,总混后压片,包衣即得醋酸巴多昔芬薄膜衣片制剂。
优选的,所述步骤四中包衣粉为非功能性淡黄色胃溶型薄膜包衣。
本发明的有益效果是:
1、相比于现有技术中采用维生素E,但是维生素E(VitaminE)是一种脂溶性维生素,在已有专利可制片剂的实施例中,需将维生素ETPGS加热熔化后,加入醋酸巴多昔芬混匀后再加入PEG 6000混匀后成混悬共熔液,将上述共熔液冷却至室温并粉碎,以完成维生素E与醋酸巴多昔芬的混合并制粒,工艺过程比较繁琐,本发明中将选用维生素C作为片剂中的抗氧剂,维生素为水溶性维生素,可直接与醋酸巴多昔芬和其他物料进行混合以简化工艺。
2、考虑到醋酸巴多昔芬的不稳定性,本发明为一种片剂,片剂相对于缓释滴丸和颗粒剂等剂型,更有优势,且稳定性也会更好。并选用流化床制粒工艺,流化床制粒技术的应用也适用于放大生产提高产量。本发明为一种片剂,相对于其他剂型,在存放过程中的稳定性也会更好。本发明采用流化床制粒技术工艺简单、成本更低,且易于工业化生产,进一步,本发明中采用包衣粉为非功能性胃溶型薄膜包衣,因处方中维生素C氧化后会使片的颜色变黄(素片为类白色片)影响美观,故选择淡黄色包衣粉进行包衣,本制备工艺选择的干燥温度为50-60℃,为该制备过程中的最高温度。对比已有专利中将维生素ETPGS加热熔化后,加入醋酸巴多昔芬混匀后再加入PEG 6000混匀后成混悬共熔液80-85℃保温,制备温度条件要求更低,能耗更少,也更有利于提高醋酸巴多昔芬片剂制备过程中的稳定性。
说明书附图
图1为醋酸巴多昔芬片的溶出曲线;
具体实施方式
实施例1:一种醋酸巴多昔芬片的处方组成
实施例2:一种醋酸巴多昔芬片的处方组成
组分 | g/1000片 | 比例% | 功能 |
醋酸巴多昔芬 | 22.6 | 7.53 | 活性成分 |
乳糖 | 105 | 35 | 填充剂 |
微晶纤维素 | 105 | 35 | 填充剂 |
预胶化淀粉 | 44.63 | 14.87 | 粘合剂 |
羧甲基淀粉钠 | 12 | 4 | 崩解剂 |
维生素C | 4.5 | 1.5 | 抗氧剂 |
十二烷基硫酸钠 | 4.5 | 1.5 | 润湿剂 |
二氧化硅 | 0.3 | 0.1 | 助流剂 |
硬脂酸镁 | 1.5 | 0.5 | 润滑剂 |
实施例3:一种醋酸巴多昔芬片的处方组成
醋酸巴多昔芬片的制剂工艺描述:
将十二烷基硫酸钠与纯化水配置成10%左右浓度的溶液备用。
将醋酸巴多昔芬和填充剂、粘合剂、崩解剂、抗氧剂称量后共同混合,混合后添加润湿剂溶液进行湿法制粒或者流化床制粒工艺。制粒后50~60℃干燥控制水分1~4%,过40目筛网整粒。加入剩余物料总混后压片并包衣即得。对比例:制备样品的体外释放测试
对照样品:商品名为Viviant的醋酸巴多昔芬片(规格20mg),生产厂家为PfizerJapan Inc./ファイザー株式会社,批号CJ6968,包装规格10片/板;10板/盒。
实验例样品:按照实施例2制备的样品(规格20mg)。
实验二:用实施例2的样品和对照样品进行体外溶出实验,对比体外释放度。溶出条件为:pH6.8磷酸盐缓冲液+0.3%吐温80,桨法900ml,50rpm。结果见图1。
结果显示,实施例2的溶出曲线与对照样品相似,说明实施例中的组合物能达到与对照品一致的体外释放效果。
实验三:醋酸巴多昔芬片组合物中维生素C的考察
3.1.处方组成:在实施例2的基础上调整维生素C的用量,差量用处方中内加制粒微晶纤维素的用量进行调整。
处方用量 | 处方A(1500片) | 处方B(1500片) | 处方C(1500片) |
维生素C(%) | 0.5 | 1.5 | 3.0 |
其他原辅料 | 同实施例1 | 同实施例1 | 同实施例1 |
3.2.制剂工艺描述:
将十二烷基硫酸钠与纯化水配置成10%左右浓度的溶液备用。
将醋酸巴多昔芬和填充剂、粘合剂、崩解剂、抗氧剂称量后共同混合,混合后添加润湿剂溶液进行流化床制粒。制粒后50~60℃干燥控制水分1~~4%,过40目筛网整粒。加入剩余物料总混后压片并包衣即得。
3.3.稳定性实验数据:
将处方A、B、C的样品置于以下条件按下放置
醋酸巴多昔芬含量变化:
维生素C变化:
结果显示,添加了维生素C的组合物处方(0.5~3%),在高温、高湿和光照条件下,醋酸巴多昔芬片的含量(0~30天)均没有明显的下降,说明稳定性良好,能够发挥其对醋酸巴多昔芬的保护作用。
Claims (6)
1.一种醋酸巴多昔芬组合物,其特征在于:以重量分数计,由20-26份醋酸巴多昔芬、250-350份填充剂、30-50份粘合剂、8-15份崩解剂、3-6份抗氧剂、2-6份助流剂、0.1-0.5份润滑剂、1-3份润湿剂、适量纯化水溶剂,其中醋酸巴多昔芬为BCSⅡ类药物、粒径D90在30μm;所述抗氧剂为维生素C,所述填充剂由乳糖和微晶纤维素组成,以重量分数计,所述乳糖和微晶纤维素的比例1:2~2:1。
2.根据权利要求1所述的一种醋酸巴多昔芬组合物,其特征在于:以重量分数计,每1000片制剂中含有:22.6份醋酸巴多昔芬、310份填充剂、44.6份粘合剂、12份崩解剂、4.5份抗氧剂、4.5份助流剂、0.3份润滑剂、1.5份润湿剂、余量为纯化水溶剂,其中醋酸巴多昔芬为BCSⅡ类药物、粒径D90在30μm;所述抗氧剂为维生素C,所述填充剂由乳糖和微晶纤维素组成,以重量分数计,所述乳糖和微晶纤维素的比例1:2~2:1。
3.根据权利要求1所述的一种醋酸巴多昔芬组合物,其特征在于:以重量份数计,所述乳糖和微晶纤维素的比例1:1。
4.根据权利要求1所述的一种醋酸巴多昔芬组合物,其特征在于:所述粘合剂为预胶化淀粉,所述崩解剂为羧甲基淀粉钠、交联羧甲基淀粉钠中的一种,所述助流剂为二氧化硅,所述润滑剂为硬脂酸镁或滑石粉,所述润湿剂为十二烷基硫酸钠。
5.一种制备醋酸巴多昔芬薄膜衣片的方法,其特征在于,包括以下步骤:
步骤一:制备溶液A,按照成分比例,将润湿剂溶解于适量的纯化水溶剂中,配置成溶液A备用;
步骤二:制备原药混合料,将醋酸巴多昔芬和填充剂崩解剂粘合剂混合均匀,制得原药混合料B,用于制粒;
步骤三、制粒,将步骤二混合均匀后制得的原药混合料B加入溶液A进行制粒,50-60℃干燥后整粒;
步骤四,压片,将步骤三制粒后的颗粒添加外加辅料,总混后压片,包衣即得醋酸巴多昔芬薄膜衣片制剂。
6.根据权利要求5所述的一种制备醋酸巴多昔芬薄膜衣片的方法,其特征在于:所述步骤四中包衣粉为非功能性淡黄色胃溶型薄膜包衣。
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