CN116570581A - 一种含硫普罗宁的稳定性优异的药用组合物及其制备工艺 - Google Patents
一种含硫普罗宁的稳定性优异的药用组合物及其制备工艺 Download PDFInfo
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- CN116570581A CN116570581A CN202310720675.2A CN202310720675A CN116570581A CN 116570581 A CN116570581 A CN 116570581A CN 202310720675 A CN202310720675 A CN 202310720675A CN 116570581 A CN116570581 A CN 116570581A
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- tiopronin
- tablet
- corn starch
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Classifications
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- Life Sciences & Earth Sciences (AREA)
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- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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Abstract
本发明提供了一种含硫普罗宁的稳定性优异的药用组合物及其制备工艺,所述的稳定性优异的药用组合物为片剂,包含盐酸半胱氨酸或半胱氨酸作为抗氧剂,以及水分不高于5.0%的玉米淀粉,占处方重量不低于0.1%。此外,还公开了该药用组合物的制备工艺。本发明的技术方案有效地解决了二硫代杂质快速增长的问题。
Description
技术领域
本发明涉及医药技术领域,特别涉及一种稳定性优异的硫普罗宁片处方及其制备工艺。
背景技术
硫普罗宁为一种新型含游离巯基的甘氨酸衍生物,其化学名N-(2-巯基丙酰基)-甘氨酸,结构式为CH3CHSCONHCH2COOH。其作用机制是因为硫普罗宁的化学结构式为N-(2-巯基丙酰基)-甘氨酸,是一种含游离巯基的甘氨酸衍生物,能与自由基可逆性结合为二硫化物,成为自由基清除剂。它能抑制肝细胞线粒体过氧化脂质体形成,可保护线粒体某些特异巯基功能,增加线粒体膜小分子多肽,恢复并维持肝脏线粒体谷光甘肽含量,保护肝细胞膜,促进肝细胞的修复和再生;参与肝细胞蛋白质、糖代谢、防止甘油三酯在体内积聚,改善肝脏脂肪代谢,从而改善肝功能,达到治疗脂肪肝的目的。硫普罗宁的抗氧化作用可能主要通过四个途径:清除有害自由基、调整体内谷光甘肽平衡、螯合金属离子和调节体内抗氧化酶体系。
由于硫普罗宁含有巯基,极易被水解和氧化产生降解产物。对于这种湿热敏感药物通常采用直接压片或干法制粒工艺制得固体制剂,但由于硫普罗宁原料药的结晶形态为针状晶体,流动性差、即使经过粉碎后其可压性表现还是极差,难以采用粉末直压工艺以及干法制粒工艺来制备成片剂。若采用现在普遍使用的常规的湿法制粒工艺和辅料,就需解决制粒和干燥过程中硫普罗宁降解出杂质III“二硫代”杂质和干颗粒水分问题,以及制成的片剂在长期储藏过程中硫普罗宁降解出杂质III“二硫代”杂质从而影响片剂的稳定性问题,降解出杂质III“二硫代”杂质会加重特异性气味产生而影响患者服用顺应性。已知的本品的其他杂质如:丙酰甘氨酸、杂质I、杂质II,在现有制剂工艺制得的产品中无显著变化。
中国专利CN103705482A公布了一种制备工艺,先将稀释剂和崩解剂加入粘合剂后湿法制粒,得到干燥后颗粒再外加混入硫普罗宁和润滑剂进行压片、包衣,然而尽管避免了硫普罗宁湿法制粒,但该种方法无法解决硫普罗宁原料药可压性,同时所得成品片剂的在加速40℃/75%RH条件下本产品普遍存在的问题-杂质III“二硫代”杂质快速增长的问题仍未得到解决。
硫普罗宁作为新型代谢改善解毒剂,通过消除自由基,保持生物膜的完整性和流动性,促进肝蛋白酶和能量合成以及直接和间接增强肝脏解毒功能而发挥保护肝脏作用,具有显著治疗效果。根据现有的技术无法制备得到有关物质质量稳定且具有服用顺应性良好的片剂,迫切需要开发出处方工艺优异稳定,制备得到的硫普罗宁片剂有关物质质量稳定,在长期储藏过程中不发生分解的具有服用顺应性的片剂。
发明内容
本发明所要解决的技术问题是提供一种硫普罗宁片的处方组成适用于湿法制粒工艺,同时解决片剂稳定性问题,抑制硫普罗宁降解产生杂质III。本品已知的其他杂质如:丙酰甘氨酸、杂质I、杂质II,在本发明的工艺制得的产品中无显著变化。
本发明所采用的技术方案是:片剂处方中增加抗氧剂,并以外加形式加入经高温干燥后的辅料保护片剂受水分影响,进一步提高片剂稳定性,包衣后片剂性质稳定且能长期有效掩盖不良气味,改善患者服用顺应性。
本发明提供了一种含硫普罗宁的稳定性优异的药用组合物,即硫普罗宁口服固体制剂,所述的口服固体制剂为片剂,包含盐酸半胱氨酸或半胱氨酸作为抗氧剂,以及水分不高于5.0%的玉米淀粉。
在一些实施方案中,所述玉米淀粉经高温干燥处理至水分不高于5.0%后,以外加形式与制粒干燥后颗粒混合。在一些实施方案中,所述玉米淀粉的水分含量为5.0%、3.2%或1.5%。
在一些实施方案中,所述抗氧化剂占处方重量不低于0.1%,或为0.1%至1%,0.1%至0.7%,或者0.1%、0.15%、0.2%、0.25%、0.3%、0.35%、0.4%、0.45%、0.5%、0.55%或0.6%。
在一些实施方案中,玉米淀粉占处方重量不低于2.0%,或者为2.0%至10%,2.0%至7%,或3.0%至6.5%。
在一些实施方案中,所述的硫普罗宁片的组成还包括50重量%~70重量%的硫普罗宁或其盐、20重量%~40重量%填充剂、2.0重量%~7.0重量%粘合剂、0.5重量%~1.5重量%崩解剂和1.0重量%~2.0重量%润滑剂。
在一些实施方案中,所述的硫普罗宁片的组成包括0.1重量%至1重量%的盐酸半胱氨酸或半胱氨酸作为抗氧剂、2.0重量%至10重量%的水分不高于5.0%的玉米淀粉、50重量%~70重量%的硫普罗宁或其盐、20重量%~40重量%填充剂、2.0重量%~7.0重量%粘合剂、0.5重量%~1.5重量%崩解剂和1.0重量%~2.0重量%润滑剂。
在一些实施方案中,所述填充剂选自淀粉、糊精、麦芽糊精、蔗糖、乳糖(无水物或水合物)、甘露醇、磷酸氢钙、淀粉、预胶化淀粉和微晶纤维素中的一种或多种;优选地,为一水乳糖。
在一些实施方案中,所述粘合剂选自明胶、淀粉、蔗糖、聚乙烯吡咯烷酮、羟丙纤维素、羟丙甲纤维素和羧甲纤维素钠中的一种或多种;优选地,为羟丙甲纤维素。
在一些实施方案中,所述崩解剂选自微晶纤维素、淀粉、羧甲纤维素钠、交联羧甲基纤维素钠、低取代羟丙纤维素、波拉克林钾、交联聚乙烯吡咯烷酮和羧甲纤维素钙中的一种或多种;优选地,为低取代羟丙纤维素。
在一些实施方案中,所述润滑剂选自硬脂酸镁、滑石粉、硬脂酸钙、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯、多库酯钠中的一种或多种;优选地,为硬脂酸。
在一些实施方案中,玉米淀粉全部以外加形式与颗粒混合。
在一些实施方案中,所述填充剂为一水乳糖,所述粘合剂为羟丙甲纤维素,所述崩解剂为低取代羟丙纤维素,和所述润滑剂为硬脂酸。
另一方面,本发明提供了上述硫普罗宁片的制备工艺,所述的制备工艺为湿法制粒工艺,包括如下步骤:
a)原辅料处理;
b)预混;
b)制粒、干燥;
c)总混:向干颗粒中加入水分低于5.0%的玉米淀粉和润滑剂混合后压片,即得硫普罗宁片。
在一些实施方案中,所述制备工艺包括如下步骤:
a)原辅料处理:将硫普罗宁过80目筛处理,备用;将辅料过60目筛处理,备用;
b)预混:将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀,得预混粉;
b)制粒、干燥:向预混粉中加入盐酸半胱氨酸或半胱氨酸的水溶液制粒,用14目筛制粒后投入流化床中干燥至水分不高于2.0%,用24目筛整粒得干颗粒;
c)总混:向干颗粒中加入水分低于5.0%的玉米淀粉和硬脂酸混合后压片,即得硫普罗宁片。
再一方面,本发明提供了上述制备工艺得到硫普罗宁片。
本发明技术表现在采用盐酸半胱氨酸或半胱氨酸作为抗氧剂进行湿法制粒,提高片剂可压性保护硫普罗宁受湿热条件降解,同时与干燥后玉米淀粉外加联用,进一步提高在影响因素和稳定性试验过程中片剂的稳定性,抑制杂质III降解。
硫普罗宁有关物质杂质III的检测仪器:安捷伦1260
检测条件:照高效液相色谱法(中国药典2020年版四部通则0512)测定。
色谱条件用十八烷基硅烷键合硅胶为填充剂(如:Inertsil ODS-3,4.6*250mm,5μm或效能相当的色谱柱);以0.1%磷酸水溶液为流动相A,乙腈为流动相B,照下表进行梯度洗脱;流速为每分钟1.0ml,检测波长为210nm,柱温为30℃,进样体积为10μl。
样品溶液临用新制。取本品1片,压碎,置100ml量瓶,加水-乙腈(95:5)约80ml,超声5min并适当振摇分散(XM-P15H型超声波清洗机,水温约20℃,功率40%),用水-乙腈(95:5)稀释至刻度,摇匀,用0.45μm尼龙膜滤过,弃去初滤液约5ml,取续滤液。
系统适用性溶液取丙酰甘氨酸、杂质I、杂质II、杂质III对照品各约10mg,置同一50ml量瓶中,用乙腈溶解并稀释至刻度,摇匀,作为储备液。取硫普罗宁约100mg,置100ml量瓶,加入上述储备液1ml,用水-乙腈(95:5)稀释至刻度,摇匀。
系统适用性要求系统适用性溶液色谱图中,硫普罗宁峰与杂质I峰分离度应符合规定。
结果定量面积归一化统计各个杂质的含量。
附图说明
附图1硫普罗宁杂质III以及丙酰甘氨酸、杂质I、杂质II的结构式。
附图2表示的是本发明的一种含硫普罗宁的稳定性医药组合物的工艺流程图。
具体实施方式
下面通过实施例来进一步描述本发明。对于本领域技术人员而言,根据本发明的教导,采用现有技术对下列实施例进行等同替换式改进仍属于本发明的保护范围。
比较例
按照专利CN103705482A制备片剂作比较例,制备工艺如下:
(1)辅料制粒:将稀释剂和崩解剂加入粘合剂后,采用湿法混合制粒;
(2)将步骤(1)制得的湿颗粒干燥、整粒;
(3)加入硫普罗宁原料和外加辅料,混合;
(4)压片,制成硫普罗宁素片。
制备上述1000片硫普罗宁素片所用原辅料的重量如下表所示:
实施例1-2
按下表处方制备批量为2000片的素片。
实施例1制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素、玉米淀粉投入湿法制粒机中混合均匀;
3)以水为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例2制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)以水为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的水分为3.2%的玉米淀粉和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例3-5
按下表处方制备批量为2000片的素片。
实施例3制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素和玉米淀粉投入湿法制粒机中混合均匀;
3)将盐酸半胱氨酸溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例4制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)将盐酸半胱氨酸溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的水分为3.2%的玉米淀粉和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例5制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)将半胱氨酸溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的水分为3.2%的玉米淀粉和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例6-8
按下表处方制备批量为2000片的素片。
实施例6制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)将焦亚硫酸钠溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;湿法制粒过程中释放大量特异臭味气体。
4)干颗粒过24目筛整粒后,加入处方量的水分为3.2%的玉米淀粉和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例7制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)将L-赖氨酸溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的水分为3.2%的玉米淀粉和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例8制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)将L-精氨酸溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的水分为3.2%的玉米淀粉和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例9-11
按下表处方制备批量为2000片的素片。
实施例9-11制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)将焦亚硫酸钠溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;湿法制粒过程中释放大量特异臭味气体。
4)干颗粒过24目筛整粒后,分别加入处方量的玉米淀粉(不同水分)和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例12-13
按下表处方制备批量为2000片的素片。
实施例12制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)将半胱氨酸溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的水分为2.8%的马铃薯淀粉和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
实施例13制备工艺:
1)将硫普罗宁原料药过80目筛,其余辅料过60目筛处理备用;
2)将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀;
3)将半胱氨酸溶于水后作为润湿剂,开启搅拌、剪切进行湿法制粒,得软材过14目钢丝筛整粒后采用流化床干燥至水分不超过1.0%,进风温度设定不高于50℃;
4)干颗粒过24目筛整粒后,加入处方量的直压乳糖和硬脂酸混合5分钟即得总混颗粒;
5)将总混颗粒采用8.0mm圆形浅凹冲模进行压片。
(1)影响因素试验及加速稳定性试验
考察将上述比较例1-4和实施例1-13所得到的硫普罗宁素片分别放置于高温40℃和60℃条件下考察有关物质杂质III的变化情况见表1和表2。
表1比较例1-4的硫普罗宁素片在高温条件下杂质III变化情况
表2实施例1-13的硫普罗宁素片在高温条件下杂质III变化情况
由上表有关物质检测结果可知:
1)玉米淀粉采用外加方式,对杂质III的产生有显著的抑制效果;
2)与其他抗氧剂相比,只有盐酸半胱氨酸和半胱氨酸能起到抑制杂质III增长,稳定片剂作用;
3)玉米淀粉外加和半胱氨酸或盐酸半胱氨酸的加入可以进一步提高硫普罗宁片的稳定性;
4)玉米淀粉水分对素片稳定性有影响,优选水分小于5%的玉米淀粉。
(2)加速试验考察
将对比例4、实施例2、实施例4和实施例5硫普罗宁素片分别采用羟丙甲纤维素和乳糖进行隔离包衣,再使用欧巴代88A180040-CN进行防潮层包衣得到成品片剂。将3个实施例的成品包衣片剂放置于加速40±2℃/75%±5%RH条件下进行稳定性考察。
表3对比例4、实施例2、实施例4和实施例5成品包衣片的加速稳定性试验结果
综上加速试验研究结果表明:对比例4硫普罗宁外加压片和实施例2硫普罗宁干法制粒的普通处方组成的片芯包衣后在加速试验条件下稳定性依然很差;而采用盐酸半胱氨酸或半胱氨酸作抗氧剂,玉米淀粉外加的处方片芯包衣后,在加速试验条件下放置6个月,杂质III增长缓慢,符合中国药典2020版本品质量标准的限度要求,且成品制剂无特异性臭味。
Claims (11)
1.一种硫普罗宁口服固体制剂,所述的口服固体制剂为片剂,其特征在于,其包含盐酸半胱氨酸或半胱氨酸作为抗氧剂,以及水分不高于5.0%的玉米淀粉。
2.根据权利要求1所述的硫普罗宁片,其中,所述玉米淀粉经高温干燥处理至水分不高于5.0%后,以外加形式与制粒干燥后颗粒混合。
3.根据权利要求1所述的硫普罗宁片,其中,所述抗氧化剂占处方重量不低于0.1%;和/或,玉米淀粉占处方重量不低于2.0%。
4.根据权利要求1至3中任一项所述的硫普罗宁片,其中,所述的硫普罗宁片的组成还包括50重量%~70重量%的硫普罗宁或其盐、20重量%~40重量%填充剂、2.0重量%~7.0重量%粘合剂、0.5重量%~1.5重量%崩解剂和1.0重量%~2.0重量%润滑剂。
5.根据权利要求4所述的硫普罗宁片,其中所述填充剂选自淀粉、糊精、麦芽糊精、蔗糖、乳糖(无水物或水合物)、甘露醇、磷酸氢钙、淀粉、预胶化淀粉和微晶纤维素中的一种或多种;优选地,为一水乳糖。
6.根据权利要求4至5中任一项所述的硫普罗宁片,其中所述粘合剂选自明胶、淀粉、蔗糖、聚乙烯吡咯烷酮、羟丙纤维素、羟丙甲纤维素和羧甲纤维素钠中的一种或多种;优选地,为羟丙甲纤维素。
7.根据权利要求4至6中任一项所述的硫普罗宁片,其中所述崩解剂选自微晶纤维素、淀粉、羧甲纤维素钠、交联羧甲基纤维素钠、低取代羟丙纤维素、波拉克林钾、交联聚乙烯吡咯烷酮和羧甲纤维素钙中的一种或多种;优选地,为低取代羟丙纤维素。
8.根据权利要求4至7中任一项所述的硫普罗宁片,其中所述润滑剂选自硬脂酸镁、滑石粉、硬脂酸钙、硬脂酸、硬脂富马酸钠、山嵛酸甘油酯、多库酯钠中的一种或多种;优选地,为硬脂酸。
9.根据权利要求1至8中任一项所述的硫普罗宁片,其中玉米淀粉全部以外加形式与颗粒混合。
10.如权利要求1至9中任一项所述的硫普罗宁片的制备工艺,所述的制备工艺为湿法制粒工艺,包括如下步骤:
a)原辅料处理;
b)预混;
b)制粒、干燥;
c)总混:向干颗粒中加入水分低于5.0%的玉米淀粉和润滑剂混合后压片,即得硫普罗宁片。
11.根据权利要求10所述的制备工艺,包括如下步骤:
a)原辅料处理:将硫普罗宁过80目筛处理,备用;将辅料过60目筛处理,备用;
b)预混:将硫普罗宁、一水乳糖、羟丙甲纤维素、低取代羟丙纤维素投入湿法制粒机中混合均匀,得预混粉;
b)制粒、干燥:向预混粉中加入盐酸半胱氨酸或半胱氨酸的水溶液制粒,用14目筛制粒后投入流化床中干燥至水分不高于2.0%,用24目筛整粒得干颗粒;
c)总混:向干颗粒中加入水分低于5.0%的玉米淀粉和硬脂酸混合后压片,即得硫普罗宁片。
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