CN116270515B - 一种提高贝前列素钠片产品质量的制备方法 - Google Patents
一种提高贝前列素钠片产品质量的制备方法 Download PDFInfo
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- CN116270515B CN116270515B CN202310087255.5A CN202310087255A CN116270515B CN 116270515 B CN116270515 B CN 116270515B CN 202310087255 A CN202310087255 A CN 202310087255A CN 116270515 B CN116270515 B CN 116270515B
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Abstract
本发明公开了一种提高贝前列素钠片产品质量的制备方法,本发明的药物组合物包括以重量计0.02份的贝前列素钠、0.2‑1.2份的高分子聚合物以及其他药学上可接受的添加剂。该药物组合物采用具有优势的组合,使得贝前列素钠片的混合均匀度显著提升,提高了贝前列素钠片的应用价值。
Description
技术领域
本发明属于药物制剂领域,涉及含贝前列素钠的药物组合物及其制备方法。
背景技术
贝前列素钠片是日本东丽株式会社(Toray Industries, Inc.)研制的药物,规格20 μg,1992年4月日本上市,现在是日本安斯泰来旗下的品种,商品名Dorner,日本橙皮书规定为20 μg规格参比制剂;2004年4月进口国内,商品名德纳。日本武田梯瓦制药株式会社(武田テバファーマ株式会社(Teva Pharma Japan Inc.))的贝前列素片仿制药为20 μg和40 μg规格产品日本上市时间分别为2002年7月和2003年7月,其中40 μg规格为日本橙皮书参比制剂。
该产品是通过血小板和血管平滑肌的前列环素受体,激活腺苷酸环化酶、使细胞内cAMP浓度升高,抑制Ca2+流入及血栓素A2生成,从而有抗血小板和扩张血管的作用。适应症为改善慢性动脉闭塞性疾病引起的溃疡、间歇性跛行、疼痛和冷感等症状。
贝前列素钠片中贝前列素钠含量极低,成品含量均匀度风险非常高,存在有效性风险,因此需要严格控制成品含量均匀度。
发明内容
为了弥补现有技术的不足,本发明的发明人通过潜心研究,对制备方法进行了大量筛选,提供了以下实验技术方案。
本发明的目的是提供了包含贝前列素钠的药物组合物及其制备方法。
为了实现上述的发明目的,本发明采用了如下的技术方案:
本发明提供了含贝前列素钠的药物组合物,所述药物组合物包括贝前列素钠、高分子聚合物、含二氧化硅的预混物料、压片添加剂。
进一步,所述高分子聚合物为水溶性高分子聚合物。
在本发明所使用的术语“高分子聚合物”是指由许多相同的、简单的结构单元通过共价键重复连接而成的高分子量(通常可达104-106)的化合物。术语“水溶性高分子聚合物”则是指与纯质水有良好相容性的高分子聚合物。
进一步,所述水溶性高分子聚合物选自羟丙甲纤维素、羟丙纤维素、羟乙纤维素、甲基纤维素、羧甲纤维素钠、聚维酮、明胶、阿拉伯胶、聚乙二醇中的一种或几种。
进一步,所述水溶性高分子聚合物选自羟丙纤维素HF、羟丙纤维素EF、羟丙纤维素LF、羟丙纤维素JF、羟丙纤维素GF、羟丙纤维素MF、羟丙纤维素EXF、羟丙纤维素HXF、羟丙甲纤维素E3、羟丙甲纤维素E5、羟丙甲纤维素E6、羟丙甲纤维素E15、羟丙甲纤维素E50、羟丙甲纤维素E4M、羟丙甲纤维素E10M、羟丙甲纤维素K100LV、羟丙甲纤维素K4M、羟丙甲纤维素K15M、羟丙甲纤维素K100M、羟丙甲纤维素A15LV、羟丙甲纤维素A4C、羟丙甲纤维素A15C、羟丙甲纤维素A4M中的一种或几种。
进一步,所述药物溶液中高分子聚合物的浓度为0.5%-6%。
进一步,所述药物溶液中高分子聚合物的浓度为1%-5%。
进一步,所述羟丙纤维素分子量为80000-370000。
进一步,所述羟丙甲纤维素为2910类别,粘度3-50 mPa·s。
在本发明中使用的术语“药物组合物”是指包含至少一种药物有效成分的任何组合物。在本发明中使用时,术语“药物组合物”还指包含待递送到对象以例如实现治疗、预防、诊断、阻止或预后效果的药物有效成分的组合物。在某些实施方式中,所述药物组合物包含药物有效成分和可药用载体。
在一些具体的实施方案中,药物有效成分为贝前列素钠。
进一步,所述预混物料包括填充剂、崩解剂、粘合剂中的部分或全部。
进一步,所述压片添加剂作为制药片剂过程中需要增加片剂润滑度等选择添加的物理或化学试剂或粉剂。
本发明中所述的片剂的形状不受特别限定,可以是具有如圆形、椭圆形、长方形等形状的无包衣片剂及上述形状的包衣片剂。
进一步,所述二氧化硅包括胶态二氧化硅、凝胶二氧化硅、沉淀二氧化硅。
进一步,所述二氧化硅为胶态二氧化硅。
进一步,所述填充剂选自乳糖、山梨醇、海藻糖、蔗糖、右旋糖酐、糊精、壳聚糖、甘露醇、玉米淀粉、微晶纤维素中的一种或几种。
在一些优选的技术方案中,含贝前列素钠的药物组合物添加了乳糖、玉米淀粉、微晶纤维素作为药物填充或框架物。
进一步,所述崩解剂选自玉米淀粉、交联聚维酮、交联羧甲基纤维素钠、低取代羟丙纤维素中的一种或几种。
在一些优选的技术方案中,药物组合物添加低取代羟丙纤维素作为药物的崩解剂。
进一步,所述粘合剂选自玉米淀粉、羟丙甲纤维素、果胶、黄芪胶、黄原胶、阿拉伯胶、瓜尔胶、糊精中的一种或几种。
在一些优选地技术方案中,药物组合物添加羟丙甲纤维素作为药物的粘合剂。
进一步,所述胶态二氧化硅用量为处方量的0.1%-5%。
进一步,所述胶态二氧化硅的用量为处方量的1%-3%。
进一步,所述药物组合物中含有按重量计:0.02份的贝前列素钠、0.2-1.2份的高分子聚合物、1-3份胶态二氧化硅、79.3-92份的填充剂、3份的崩解剂、3份的粘合剂、0.5份的压片添加剂。
本发明提供了一种含贝前列素钠的药物组合物的制备方法,所述制备方法包括前面所述的药物组合物。
进一步,制备方法包括下述步骤:
1)贝前列素钠和高分子聚合物溶解于纯化水中制成一定浓度的药物溶液;
2)药物溶液加入含有二氧化硅的预混辅料中采用湿法制粒或一步制粒方法制成颗粒;其中,预混物料湿法制粒锅中预混3分钟;喷入药物溶液制粒的喷入时间为3~6min,制粒时间为2~3min;进风温度50℃干燥至水分不超过5.0%;
3)将颗粒和压片添加剂混合制成总混颗粒;其中,干颗粒于门式整粒机中整粒的筛网孔径为0.8mm,转速以转子尖端线速度计为10m/s;
对从所述步骤3)获得的干颗粒,根据需要可以添加并混合药学上允许的颗粒外添加剂例如稳定剂、表面活性剂、滑泽剂 (Slip Modifier)、润滑剂、乳化剂、缓冲剂、甜味剂、基剂、吸附剂、矫味剂、结合剂、固化剂、抗氧化剂、光亮剂、着香剂、调味剂、颜料、涂层剂、调湿剂、填充剂、消泡剂、清凉剂、咀嚼剂、防静电剂、着色剂、糖衣剂、等张剂、软化剂、粘合剂、增粘剂、pH 调节剂、赋形剂、分散剂、崩解剂、防水剂、防腐剂、保存剂、助溶剂或流动剂等。具体的添加剂如精炼糖、葡萄糖、海藻糖、乳糖、麦芽糖、甘露醇、山梨醇、木糖醇、赤藓糖醇、糖精钠、阿斯巴甜、醋磺内酯钾、三氯蔗糖、甘草提取物、甜菊苷提取物、罗汉果甜苷提取物、玉米淀粉、马铃薯淀粉、小麦淀粉、碳酸氢钠、氯化钠、结晶纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、羟丙基甲基纤维素邻苯二甲酸酯、邻苯二甲酸醋酸纤维素、糊精、预胶化淀粉、阿拉伯胶、黄蓍胶、明胶、海藻酸钠、聚乙烯吡咯烷酮、聚乙烯醇、羧乙烯聚合物、硬脂酸镁、滑石、加氢植物油、聚乙二醇 (macrogol)、聚氧乙烯固化蓖麻油 60、含水二氧化硅、硅油、琼脂、紫胶、甘油、芳香性精油类、水溶性食用色素、硫酸亚铁、氧化铁黄、三氧化二铁、氧化铁褐、氧化铁黑、二氧化钛、胭脂红、苯甲酸、苯甲酸钠、对羟基苯甲酸、聚山梨酸酯 80、脂肪酸甘油酯、白蜡、中链脂肪酸甘油三酯、抗坏血酸、生育酚、硫代硫酸钠、依地酸钠、橙子或柠檬等柑橘类香料、咖啡类香料、巧克力类香料、酸奶类香料、牛奶类香料或柠檬油、薄荷油、留兰香油、香料油 (spice oil) 等植物精油,只要是药剂学上可利用的,并不受特别限制;
4)总混颗粒通过压片机压制成片芯;其中,片重100 mg,硬度3~5 kg;
5)将片芯于高效包衣机中包衣制成薄膜包衣片;其中,片芯于包衣机中预热至40℃以上后喷入包衣液开始包衣,喷液速度和风量使片床温度在40~45℃,包衣液喷完后干燥至水分不超过5.0%。
进一步,所述药物溶液中高分子聚合物的浓度为0.5%-6%。
进一步,所述药物溶液中高分子聚合物的浓度为1%-5%。
在本发明中使用的术语“浓度”是指按照药物组合物的处方量所计算出的重量百分比,在一些具体的实施方案中,浓度的值是一个具体的数值。
在本发明的一些实施方案中,一种制备上述药物组合物的方法,该制备方法包括如下步骤:
1)称取以重量计的0.02份的贝前列素钠和以重量计的0.2-1.2份的高分子聚合物溶解于纯化水中制成一定浓度的药物溶液;
2)药物溶液加入以重量计:1-3份胶态二氧化硅、79.3-92份的填充剂、3份的崩解剂、3份的粘合剂中采用湿法制粒或一步制粒方法制成颗粒;其中,预混物料湿法制粒锅中预混3分钟;喷入药物溶液制粒的喷入时间为3~6 min,制粒时间为2~3 min;进风温度50℃干燥至水分不超过5.0%;
3)将颗粒和以重量计0.5份的压片添加剂混合制成总混颗粒;其中,干颗粒于门式整粒机中整粒的筛网孔径为0.8 mm,转速以转子尖端线速度计为10 m/s;
4)总混颗粒通过压片机压制成片芯;其中,片重100 mg,硬度3~5 kg;
5)将片芯加入以重量计4份的包片剂于高效包衣机中包衣制成薄膜包衣片;其中,片芯于包衣机中预热至40℃以上后喷入包衣液开始包衣,喷液速度和风量使片床温度在40~45℃,包衣液喷完后干燥至水分不超过5.0%。
本发明中使用的术语“干颗粒”意味着最终产品中去除如水或乙醇等从外部适用的颗粒化溶剂而形成的颗粒。
本发明还提供了一种高分子聚合物在提高药物组合物的有效成分均匀度中的应用,所述高分子聚合物包括水溶性高分子聚合物。
进一步,所述水溶性高分子聚合物包括羟丙甲纤维素、羟丙纤维素、羟乙纤维素、甲基纤维素、羧甲纤维素钠、聚维酮、明胶、阿拉伯胶、聚乙二醇中的一种或几种。
进一步,所述水溶性高分子聚合物选自羟丙纤维素HF、羟丙纤维素EF、羟丙纤维素LF、羟丙纤维素JF、羟丙纤维素GF、羟丙纤维素MF、羟丙纤维素EXF、羟丙纤维素HXF、羟丙甲纤维素E3、羟丙甲纤维素E5、羟丙甲纤维素E6、羟丙甲纤维素E15、羟丙甲纤维素E50、羟丙甲纤维素E4M、羟丙甲纤维素E10M、羟丙甲纤维素K100LV、羟丙甲纤维素K4M、羟丙甲纤维素K15M、羟丙甲纤维素K100M、羟丙甲纤维素A15LV、羟丙甲纤维素A4C、羟丙甲纤维素A15C、羟丙甲纤维素A4M中的一种或几种。
进一步,所述水溶性高分子聚合物在药物溶液中的浓度为0.5%-6%。
进一步,所述水溶性高分子聚合物在药物溶液中的浓度为1%-5%。
进一步,所述药物组合物包括贝前列素钠。
本发明还提供了一种二氧化硅在提高药物组合物的有效成分均匀度中的应用,所述二氧化硅包括胶态二氧化硅。
进一步,所述胶态二氧化硅的用量为处方量的0.1%-5%。
进一步,所述胶态二氧化硅的用量为处方量的1%-3%。
进一步,所述药物组合物包括贝前列素钠。
本发明还提供了一种提高药物组合物的有效成分均匀度的方法,所述方法包括添加前面所述的高分子聚合物到药物组合物中;所述方法包括添加前面所述的二氧化硅到药物组合物中。
进一步,所述药物组合物包括贝前列素钠。
附图说明
图1是水介质溶出曲线图。
具体实施方式
下面结合具体实施例,进一步阐述本发明。但这些实施例仅限于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体实验条件的试验方法,通常按照常规条件,或按照厂商所建议的条件进行试验。
实施例1
A:片芯制备
表1 实施例1片芯组成(单位:份)
注:纯化水在制备过程中除去。
片芯制备方法:
1)取药物溶液组成物料溶解于适量纯化水中制成药物溶液;
2)将处方量预混物料置于湿法制粒锅中预混3 min,喷入药物溶液制粒,喷入时间为3~6 min,制粒时间为2~3 min,设置进风温度50℃干燥至水分不超过5.0%(卡尔费休法);
3)干颗粒于门式整粒机中整粒,筛网孔径为0.8 mm,转速以转子尖端线速度计为10 m/s;
4)将整粒后颗粒加入硬脂酸镁混合200转数;
5)总混颗粒于压片机中压制成片芯,片重100 mg,硬度3~5 kg。
B:片芯包衣
表2 包衣液组成(单位:份)
注1:欧巴代® OY-S-7366-CN为胃溶型;
注2:纯化水在制备过程中除去。
片芯包衣制备方法:
1)将欧巴代分散于于纯化水中制成15%固含量的包衣混悬液;
2)将片芯于包衣机中预热至40℃以上后喷入包衣液开始包衣,控制喷液速度和风量使片床温度在40~45℃,包衣液喷完后继续干燥至水分不超过5.0%(卡尔费休法),即得。
实施例2-8
A:片芯制备
表3 实施例2-8片芯组成(单位:份)
注:纯化水在制备过程中除去。
片芯制备方法同实施例1。
B:片芯包衣
包衣液组成和包衣方法同实施例1。
对比例1
A:片芯制备
表4 对比例1片芯组成(单位:份)
注:纯化水在制备过程中除去。
片芯制备方法同实施例1。
B:片芯包衣
包衣液组成和包衣方法同实施例1。
对比例2
表5 对比例2片芯组成(单位:份)
注:纯化水在制备过程中除去。
片芯制备方法同实施例1。
B:片芯包衣
包衣液组成和包衣方法同实施例1。
实施例9整粒后颗粒评价
取实施例1~8、对比例1~2方法获得的整粒后颗粒约50 g,用40目、60目、80目、100目、150目标准筛进行筛分,检测各层筛上部分和通过150目的颗粒或细粉比例,结果见表6。
表6 实施例及对比例的整粒后颗粒粒度(单位:%)
表6结果表明,实施例1-8、对比例1-2的颗粒粒度无明显差异。制粒过程不是产品质量差异的决定因素。
实施例10总混颗粒混合均匀度评价
实施例1~8、对比例1~2方法总混颗粒混合过程中,按照《化药口服固体制剂混合均匀度和中控剂量单位均匀度研究技术指导原则(试行)》要求考察混合均匀度,结果见表7。
混合均匀度标准:贝前列素钠平均值应为0.019%~0.021%(w/w);所有单值在均值的±10.0%(绝对)以内;RSD≤5.0%。
表7 实施例及对比例的整粒后颗粒含量(单位:%)
表7结果表明,本发明中实施例1-8总混颗粒的贝前列素钠片的含量平均值、单值范围、混合均匀度均取得优良的结果。对比例1单值范围和RSD超出标准范围,显示混合均匀度较差;由各实施例与对比例的片芯组成分析可知,混合均匀度差是由于药物溶液中无羟丙纤维素和羟丙甲纤维素等水溶性高分子聚合物,干燥过程中原料随水分迁移至颗粒表面,颗粒内外含量不均一导致总混颗粒混合均匀度无法满足要求。对比例2平均值超出标准范围,显示贝前列素钠含量低;由各实施例与对比例的片芯组成分析可知,贝前列素钠含量低主要是因为处方预混辅料中无二氧化硅导致干燥床内壁有原料吸附。
以上结果可知,本发明中的药物溶液添加羟丙纤维素和羟丙甲纤维素等水溶性高分子聚合物可以有效避免颗粒干燥过程中原料迁移,以及预混辅料添加二氧化硅可以有效避免原料吸附干燥床内壁。
实施例11成品含量和含量均匀度评价
将实施例1~8、对比例1~2方法获得的贝前列素钠片,检测成品含量和含量均匀度,结果见表8。
含量标准:本品含贝前列素钠(C24H29O5Na)应为标示量的95.0%~105.0%。
含量均匀度标准:取供试品10片,分别测定每一片以标示量为100的相对含量,若A+2.2S≤15.0,则供试品的含量均匀度符合规定。
表8 实施例及对比例的含量均匀度结果
表8结果表明,本发明实施例1-8成品含量和含量均匀度均符合规定;对比例1成品含量符合要求,但含量均匀度超出标准范围,根据分析其原因是总混颗粒混合均匀度RSD大导致;对比例2成品含量和含量均匀度均超出标准范围,其原因在于总混颗粒贝前列素钠含量低导致。
实施例12成品溶出曲线评价
溶出度的测定方法,取实施例1~8、对比例1~2、测试例的贝前列素钠片,按照中国药典溶出度测定第二法桨法,水溶液900 ml为溶出介质,转速50 rpm,采用高效液相色谱法测定,结果见表9,水介质溶出曲线结果如图1所示。
表9 水介质溶出曲线测定结果(单位:%)
注:测试例为东丽株式会社进口的贝前列素钠片,规格20 μg,商品名德纳。
表9和图1的结果表明,本发明实施例1-8、测试例水介质溶出曲线均15分钟大于85%以上,为非常快速溶出,体内生物等效性风险低。对比例1~2水介质溶出曲线15分钟低于85%,体内生物等效性风险高。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (5)
1.一种含贝前列素钠的药物组合物的制备方法,其特征在于,所述制备方法包括下述步骤:
1)贝前列素钠和高分子聚合物溶解于纯化水中制成一定浓度的药物溶液;
2)药物溶液加入预混辅料中采用湿法制粒或一步制粒方法制成颗粒;
3)将颗粒和压片添加剂混合制成总混颗粒;
4)总混颗粒通过压片机压制成片芯;
5)将片芯于高效包衣机中包衣制成薄膜包衣片;
所述药物溶液含有按重量计:0.02份的贝前列素钠、0.2-1.2份的高分子聚合物,所述预混辅料含有按重量计:1-3份的胶态二氧化硅、79.3-92份的填充剂、3份的崩解剂、3份的粘合剂,所述总混颗粒还含有按重量计:0.5份的压片添加剂,其中,所述高分子聚合物为羟丙甲纤维素或羟丙纤维素,所述羟丙纤维素分子量为80000-370000;所述羟丙甲纤维素为2910类别,粘度3-50 mPa·s。
2.根据权利要求1所述的制备方法,其特征在于,所述药物溶液中高分子聚合物的浓度为0.5%-6%。
3.根据权利要求2所述的制备方法,其特征在于,所述药物溶液中高分子聚合物的浓度为1%-5%。
4.含贝前列素钠的药物组合物,其特征在于,所述药物组合物由权利要求1-3任一项所述的制备方法制备得到。
5.一种提高药物组合物的有效成分均匀度的方法,其特征在于,所述方法包括使用权利要求1-3任一项所述的制备方法制备药物组合物。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004034959A2 (en) * | 2002-09-18 | 2004-04-29 | Elan Corporation, Plc | Multiparticulate modified release composition comprising beraprost |
CN103637994A (zh) * | 2013-11-06 | 2014-03-19 | 山东大学 | 一种预混辅料及其制备工艺 |
KR20140089918A (ko) * | 2013-01-08 | 2014-07-16 | 안국약품 주식회사 | 베라프로스트 나트륨 함유 서방성 정제 및 그 제조방법 |
CN105055354A (zh) * | 2015-09-08 | 2015-11-18 | 深圳万乐药业有限公司 | 一种利奈唑胺片及其制备方法 |
JP2017075139A (ja) * | 2016-09-05 | 2017-04-20 | 持田製薬株式会社 | 低用量薬物を含有する口腔内崩壊錠 |
CN106727392A (zh) * | 2016-12-15 | 2017-05-31 | 上海奕利制药有限公司 | 一种帕利哌酮缓释片剂及其制备方法 |
CN109498584A (zh) * | 2017-09-15 | 2019-03-22 | 万特制药(海南)有限公司 | 一种含有来曲唑的分散片及其新型制备方法 |
-
2023
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004034959A2 (en) * | 2002-09-18 | 2004-04-29 | Elan Corporation, Plc | Multiparticulate modified release composition comprising beraprost |
KR20140089918A (ko) * | 2013-01-08 | 2014-07-16 | 안국약품 주식회사 | 베라프로스트 나트륨 함유 서방성 정제 및 그 제조방법 |
CN103637994A (zh) * | 2013-11-06 | 2014-03-19 | 山东大学 | 一种预混辅料及其制备工艺 |
CN105055354A (zh) * | 2015-09-08 | 2015-11-18 | 深圳万乐药业有限公司 | 一种利奈唑胺片及其制备方法 |
JP2017075139A (ja) * | 2016-09-05 | 2017-04-20 | 持田製薬株式会社 | 低用量薬物を含有する口腔内崩壊錠 |
CN106727392A (zh) * | 2016-12-15 | 2017-05-31 | 上海奕利制药有限公司 | 一种帕利哌酮缓释片剂及其制备方法 |
CN109498584A (zh) * | 2017-09-15 | 2019-03-22 | 万特制药(海南)有限公司 | 一种含有来曲唑的分散片及其新型制备方法 |
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