CN101647771B - 一种水飞蓟宾琥珀酸酯二钠盐口服制剂及其制备方法 - Google Patents
一种水飞蓟宾琥珀酸酯二钠盐口服制剂及其制备方法 Download PDFInfo
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- CN101647771B CN101647771B CN200810054107A CN200810054107A CN101647771B CN 101647771 B CN101647771 B CN 101647771B CN 200810054107 A CN200810054107 A CN 200810054107A CN 200810054107 A CN200810054107 A CN 200810054107A CN 101647771 B CN101647771 B CN 101647771B
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- silybin
- disodium
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- silibinin
- silybin dihemisuccinate
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Abstract
本发明提供了一种水飞蓟宾琥珀酸盐制剂，该制剂含有1-95wt％的水飞蓟宾琥珀酸酯二钠。该制剂克服了注射制剂长期给药不便、以及药物在溶液状态稳定性差的缺点，特别适合慢性肝病患者的长期给药、且储藏稳定。另外还提供了水飞蓟宾琥珀酸酯二钠口服制剂的制备方法，该制剂具有优良的润湿、崩解性能，能快速而完全地释放药物，充分发挥活性成分水飞蓟宾的治疗作用。
Description
技术领域
本发明属于医药领域，特别是涉及含活性成分水飞蓟宾琥珀酸酯二钠盐的口服制剂及其制备方法。
背景技术
肝炎是指由于不同病因的肝脏炎症，日常生活中病毒性肝炎最常见，它具有发病率高，病程长，病势反复性强，危害性大的特点，若不进行及时治疗，有转变为肝硬化及肝癌的可能。我国又是肝炎高发的国家，据统计，我国有超过1.2亿人感染乙肝病毒，慢性乙肝病人约3000万，3800万人携带丙肝病毒，仅从乙肝病毒携带者的数字来说，差不多占国民十分之一。
目前，虽然肝病药物种类很多，但尚无一种药物能真正杀灭乙肝病毒。目前多采用抑制病毒复制、或改善症状、控制病情发展两种治疗思路。前者虽然能快速抑制病毒复制，但存在长期用药风险。如肝病一线药物拉米夫定虽可以将乙肝病毒抑制在较低水平(DNA＜103拷贝/ml)，但需要长期用药(通常2-3年)，并不能随意停用，不仅费用高昂，而且长期用药直接导致部分患者乙肝病毒出现耐药变异株，病情更趋复杂。因此，研制一种能有效改善肝病症状、适合长期用药、且价格合理的药物，符合当前的国情，满足临床需要。
水飞蓟，菊科，是优良的护肝植物，其主要成分为水飞蓟宾(silybin)。药理实验证明，水飞蓟宾有保护肝细胞膜，改善肝功能的作用，预防多种肝脏毒物所致的肝损伤，促进肝细胞再生，主要用于治疗各种急慢性肝炎、初期肝硬化和肝中毒等症。
水飞蓟宾非常难溶于水，限制了其口服吸收，成盐后水溶性有所增加。目前，主要研究集中在水飞蓟宾葡甲胺盐，西利宾安片的主要成分即是水飞蓟宾葡甲胺，但仍存生物利用度不高的缺点。
我们知道，药物盐形的选择是药品开发成功与否的关键步骤，药物的每一种盐形都具有独特的性质，盐形的最终确定其实就是在物理化学性质和生物药学性质之间寻找平衡。
而关于水飞蓟宾琥珀酸盐(水飞蓟宾宾琥珀酸酯二钠盐、水飞蓟宾宾琥珀酸酯钠钾盐)报道有限。我们实验发现，水飞蓟宾做成琥珀酸盐后，在水中的溶解度优于水飞蓟宾葡甲胺盐，且琥珀酸本身具有解毒作用，而葡甲胺盐不具备这个作用，在相同给药量的情况下，水飞蓟宾琥珀酸值二钠盐对肝病的治疗作用优于水飞蓟宾葡甲胺盐。目前，文献仅记载了水飞蓟宾琥珀酸盐主要做成注射剂型，例如，专利文献200510080657.4提及了“水飞蓟宾二偏琥珀酸盐可作静脉注射用粉针”，但注射制剂不适合长期给药，特别是不适合慢性肝病人群的治疗。
因此，有必要制备一种生物利用度更高、适合长期给药、储藏稳定的水飞蓟宾盐口服给药制剂，能满足临床上急、慢性肝病治疗的需要。
发明内容
本发明克服了上述现有技术的特点和不足，提供了一种水飞蓟宾琥珀酸盐口服制剂，该制剂含有1-95wt％的水飞蓟宾琥珀酸酯二钠。该制剂克服了注射制剂长期给药不便、以及药物在溶液状态稳定性差的确定，特别适合慢性肝病患者的长期给药、且储藏稳定。另外还提供了水飞蓟宾琥珀酸酯二钠口服制剂的制备方法，该制剂具有优良的润湿、崩解性能，能快速而完全地释放药物，充分发挥活性成分水飞蓟宾的治疗作用，适于患者每天服用3-4次，每次1-4个制剂单位，以治疗急、慢性肝脏疾病。
本发明采用的水飞蓟宾琥珀酸盐通常采用水飞蓟宾琥珀酸酯二钠盐(Silybindihemisuccinate disodium)分子式：C33H28Na2O16，分子量：726.54536。
本发明采用的水飞蓟宾琥珀酸盐还可以是钠钾盐或二钾盐：
口服给药制剂：是指在胃肠道内崩解完全，释放活性成分的制剂，该制剂适于患者方便地每天服用3-4次，每次1-4个制剂单位，以使活性成分在患者体内发挥其应有治疗作用。
本发明的水飞蓟宾琥珀酸盐口服制剂，它包括制成的一定形状的紧密混合物，如压制片或颗粒，也可以在紧密混合物外层覆盖胃溶性包衣层以改善制剂的外观和稳定性等。本发明水飞蓟宾琥珀酸酯二钠口服制剂，是指水飞蓟宾琥珀酸酯二钠在人工胃液内(通常的体外试验是制剂在0.1mol/L的盐酸溶液)或肠液(PH6.8磷酸缓冲液)45分钟内崩解释放不少于75％，即表明释放完全。
为了使水飞蓟宾琥珀酸酯二钠在人体内崩解释放完全，有必要选择一种或多种惰性赋形剂。该赋形剂既能保证水飞蓟宾琥珀酸酯二钠崩解释放完全，又能符合我国工业化大生产实际，生产工艺简单易行。
因此本发明的治疗肝病病的口服制剂包括至少1wt％的水飞蓟宾琥珀酸酯二钠和一种或多种可药用惰性赋形剂，所述的口服制剂包括片剂、颗粒剂、胶囊；所述的惰性赋形剂包括稀释剂、粘合剂、崩解剂、抗粘着剂和润滑剂；所述的稀释剂选自微晶纤维素、乳糖、甘露醇、磷酸氢钙、淀粉、预胶化淀粉、及其混合物；所述的粘合剂选自海藻酸钠、羧甲基纤维素钠、羟乙基纤维素、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、明胶、聚维酮、醋酸纤维素、淀粉、预胶化淀粉、及其混合物；所述的崩解剂选自海藻酸、海藻酸钠、羧甲基纤维素钠、微晶纤维素、粉末纤维素、交联羧甲基纤维素钠、交联聚维酮、预胶化淀粉、淀粉、及其混合物；所述的抗粘着剂选自微粉硅胶、三硅酸镁和滑石粉、及其混合物；所述的润滑剂选自硬脂酸镁、滑石粉、及其混合物。
本发明的口服制剂中含有：1-95wt％的水飞蓟宾琥珀酸酯二钠、1-45wt％的稀释剂、2-20wt％的粘合剂、1-10wt％的崩解剂、0.1-5wt％的抗粘着剂、0.1-5wt％的润滑剂。
本发明的口服制剂优选组分为：10-80wt％的水飞蓟宾琥珀酸酯二钠、1-40wt％的稀释剂、5-15wt％的粘合剂、2-9wt％的崩解剂、0.1-4wt％的抗粘着剂、0.1-4wt％的润滑剂。
本发明的口服制剂每单位含有30-200mg的水飞蓟宾琥珀酸酯二钠，适于患者每天服用3-4次，每次1-4个制剂单位。
本发明的口服制剂优选的稀释剂为微晶纤维素；粘合剂为预胶化淀粉；崩解剂为交联羧甲基纤维素钠；抗粘着剂为微粉硅胶；润滑剂为硬脂酸镁。
也可以在本发明制剂外层覆盖胃溶性包衣层以改善制剂的外观、味觉和稳定性等，包衣增重与压制片的重量比为0.1～20％，优选0.5-18％，最佳为1.0~15％。
特别优选的本发明口服制剂由下述组分组成：
| 组分 | 重量范围(％) | 优选重量范围(％) |
| 水飞蓟宾琥珀酸酯二钠 | 1～95 | 10～80 |
| 预胶化淀粉 | 2～20 | 2～20 |
| 微晶纤维素 | 1～45 | 2～25 |
| 交联羧甲基纤维素钠 | 1～10 | 2～8 |
| 微粉硅胶 | 0.1～5 | 0.2～4.0 |
| 硬脂酸镁 | 0.2～5 | 0.5～2.0 |
| 乙醇水溶液 | 至润湿量 | 至润湿量 |
其中乙醇水溶液中乙醇的浓度为5～95％，优选20~70％。
本发明的治疗肝脏疾病的口服制剂按如下方法制备：
1)压制片：将水飞蓟宾琥珀酸酯二钠和可选择的稀释剂和内加崩解剂置混合机中，加适量润湿剂或粘合剂制成软材，软材压过适宜的筛网即成湿颗粒，将其立即干燥，过筛整粒，将外加崩解剂与可选择的润滑剂与所得干颗粒混合均匀，压片即得片芯。优选的制粒方法是搅拌制粒或者沸腾制粒后干燥。
2)硬胶囊剂：将水飞蓟宾琥珀酸酯二钠和可选择的赋形剂混合均匀得干混合物，直接灌装胶囊；或采用湿法制粒后，将湿颗粒干燥、过筛整粒，与可选择的润滑剂(如硬脂酸镁)和其它助剂混合均匀，装入硬胶囊中。
3)颗粒剂：将水飞蓟宾琥珀酸酯二钠和可选择的赋形剂和矫昧剂混合均匀得干混合物，采用湿法制粒后，将湿颗粒干燥、过筛整粒，分装在药用铝塑复合膜袋中。
上述制备方法的优点是：
选用水飞蓟宾琥珀酸盐作为有效成分，其治疗作用强于水飞蓟宾葡甲胺盐，这是因为水飞蓟宾琥珀酸盐吸收后重新游离成水飞蓟宾和琥珀酸，琥珀酸具有解毒的作用，与水飞蓟宾起到协同增效的作用。这种性质是水飞蓟宾葡甲胺盐不具备的。
同时，将水飞蓟宾琥珀酸酯二钠制成固体给药制剂，服用方便，适合慢性肝病患者的服用，避免了注射给药途径的不便。并且本制剂既可在胃中溶解吸收，也可在肠道中吸收，这样，使药物吸收利用得更加完全，可以减少制剂在患者体内吸收和疗效的个体差异。
本发明使用的粘合剂是乙醇水溶液，用量少，且制备工艺简单，适合于国内生产技术和设备条件。
说明书附图
图1水飞蓟宾琥珀酸酯二钠盐代表实施例溶出度测定图
图2水飞蓟宾琥珀酸酯钠钾盐代表实施例溶出度测定图
具体实施方式
给出下列实施例使该领域的技术人员能更清楚的理解和实施本发明。它们不应被看作限制本发明的范围，而仅是说明性和代表性的例子。
实施例1 60mg水飞蓟宾琥珀酸酯二钠压制片的组成和制备方法
将水飞蓟宾琥珀酸酯二钠60.0g、微晶纤维素100.0g、磷酸氢钙40.0g、微粉硅胶4.0g混合均匀，以羟丙甲纤维素的30％乙醇溶液为润湿剂制软材，20目筛制粒，55℃通风干燥4小时，整粒，加入羧甲基纤维素钠5.0g、硬脂酸镁5.0g混匀压得约1000片，每片含水飞蓟宾琥珀酸酯二钠60mg，即得压制片。
实施例2 120mg水飞蓟宾琥珀酸酯二钠压制片的组成和制备方法
将水飞蓟宾琥珀酸酯二钠120.0g、微晶纤维素40.0g、乳糖100.0g、预胶化淀粉40g，交联聚维酮5g混合均匀，以含15％聚维酮的水溶液为润湿剂制软材，20目筛制粒，55℃通风干燥3小时，整粒，加入滑石粉3.0g、硬脂酸镁3.0g，混匀压得约1000胶囊型片，每片含水飞蓟宾琥珀酸酯二钠120mg，即得压制片。
实施例3 200mg水飞蓟宾琥珀酸酯二钠压制片的组成和制备方法
将水飞蓟宾琥珀酸酯二钠200.0g、微晶纤维素50.0g、乳糖100.0g、淀粉50g、甲基纤维素5.0g，混合均匀，以30％乙醇水溶液为润湿剂制软材，20目筛制粒，60℃通风干燥3小时，整粒，加入微粉硅胶5.0g、、硬脂酸镁5.0g，混匀压得异型片，每片含水飞蓟宾琥珀酸酯二钠200mg，即得压制片。
实施例4 60mg水飞蓟宾琥珀酸酯二钠胶囊的组成和制备方法
将水飞蓟宾琥珀酸酯二钠60.0g、乳糖50.0g、甘露醇40.0g、羧甲淀粉钠8g置入快速搅拌制粒机KJZ-IO中，喷洒30％乙醇水溶液制粒，60℃通风干燥3小时，20目筛整粒，加入硬脂酸镁3.0g混匀，灌装1号明胶硬胶囊，使每粒胶囊含水飞蓟宾琥珀酸酯二钠60mg。
实施例5 120mg水飞蓟宾琥珀酸酯二钠颗粒的组成和制备方法
将水飞蓟宾琥珀酸酯二钠120g，乳糖500.0g、甘露醇360.0g、明胶5.0g、阿司帕坦5g橘子香精5.0g混匀，喷洒10％的海藻酸水溶液制软材，14目制粒，鼓风烘箱干燥3小时，12目筛整粒，测定含量，定量分装在PVC复合铝箔袋中，使每袋含水飞蓟宾琥珀酸酯二钠120mg。
实施例6 200mg水飞蓟宾琥珀酸酯二钠薄膜衣片的组成和制备方法
将实施例3压制的片以胃溶型OPADRY-85G II包薄膜衣，即得每片含水飞蓟宾琥珀酸酯二钠200mg，薄膜衣片。
实施例7 30mg水飞蓟宾琥珀酸酯二钠分散片的组成和制备方法
将水飞蓟宾琥珀酸酯二钠30.0g、甘露醇20.0g、乳糖80.0g、羧甲基纤维素钠3.0g、微晶纤维素15g、聚维酮2g、硬脂酸镁3g混合均匀后，干法制粒，粉碎过24目以下筛，然后与10g交联聚维酮混合均匀，直接压片，使每片含水飞蓟宾琥珀酸酯二钠30mg。
实施例8 60mg水飞蓟宾琥珀酸酯二钠分散片的组成和制备方法
将水飞蓟宾琥珀酸酯二钠60.0g、乳糖60.0g、低取代羟丙纤维素钠10.0g、羟丙甲纤维素3g、微晶纤维素15g混合均匀，用30％聚乙二醇6000乙醇制软材，过24目筛，55℃烘箱干燥。干颗粒加微粉硅胶3g、硬脂酸镁5g，混合均匀，压片，每片含水飞蓟宾琥珀酸酯二钠60mg。
实施例9 120mg水飞蓟宾琥珀酸酯二钠分散片的组成和制备方法
将水飞蓟宾琥珀酸酯二钠120.0g、甘露醇20.0g、乳糖55.0g、交联聚维酮10.0g、聚维酮3g、微晶纤维素15.0g、微粉硅胶5g、硬脂酸镁5g混合均匀，干法制粒，粉碎过24目筛，再加交联聚维酮5g混合均匀，压片，每片含水飞蓟宾琥珀酸酯二钠120mg。
实施例10 30mg水飞蓟宾琥珀酸酯二钠口腔崩解片的组成和制备方法
将水飞蓟宾琥珀酸酯二钠30.0g、甘露醇150.0g、羧甲淀粉钠6.0g、羧甲纤维素3.0g、桔子香精1.0g、阿巴斯甜1.0g，水或乙醇润湿，过30目筛制软材，55℃烘箱干燥，干颗粒加微粉硅胶3.0g、硬质富马酸钠3.0g混合均匀，压片，每片含水飞蓟宾琥珀酸酯二钠30mg。
实施例11 水飞蓟宾琥珀酸酯二钠滴丸的组成和制备方法
取聚乙二醇-6000 40.0g，置85℃水浴中加热熔融，加入过100目筛的水飞蓟宾琥珀酸酯二钠10.0g，羧甲淀粉钠1g搅拌均匀，继续置85℃水浴中加热、搅拌至料液由浑浊态变为混悬液，以二甲基硅油为冷凝剂，冷凝温度为-5~10℃，以50滴/分滴制，除去冷凝剂，即得每粒滴丸重约50mg，含主药10mg。
实施例12 水飞蓟宾琥珀酸酯二钠滴丸的组成和制备方法
取聚乙二醇-4000、聚乙二醇-6000各30.0g，混合，置80℃水浴中加热熔融，加入过100目筛的水飞蓟宾琥珀酸酯二钠20.0g，羧甲纤维素8g，继续置80℃水浴中加热、搅拌均匀，搅拌至料液由浑浊态变为均匀混悬液，以液体石蜡为冷凝剂，冷凝温度为-5~10℃，以30滴/分滴制，除去冷凝剂，即得每粒滴丸重约45mg，含主药10mg。
实施例13 60mg水飞蓟宾琥珀酸酯钠钾压制片的组成和制备方法
将水飞蓟宾琥珀酸酯钠钾60.0g、微晶纤维素20.0g、磷酸氢钙60.0g、羧甲基纤维素钠5.0g、海藻酸2g混合均匀，以30％乙醇水溶液为润湿剂制软材，20目筛制粒，55℃通风干燥2小时，18目筛整粒，加入微粉硅胶5.0g、硬脂酸镁5.0g混匀压片，每片含水飞蓟宾琥珀酸酯钠钾60mg，即得压制片。
实施例14 30mg水飞蓟宾琥珀酸酯钠钾盐分散片的组成和制备方法
将水飞蓟宾琥珀酸酯钠钾30.0g、甘露醇20.0g、乳糖60.0g、交联聚维酮10.0g、聚维酮2g、微晶纤维素10g、硬脂酸镁1g混合均匀，干法制粒。粉碎，过24目筛，再加羧甲基淀粉钠4g、硬脂酸镁1g混合均匀，压片，每片含水飞蓟宾琥珀酸酯钠钾30mg。
实施例15 60mg水飞蓟宾琥珀酸酯钠钾口腔崩解片的组成和制备方法
将水飞蓟宾琥珀酸酯钠钾60.0g粉碎，用聚维酮K30 2.0制粒，水或乙醇润湿，过30目筛，55℃烘干，备用；另将交联聚维酮14.0g、羧甲基纤维素钠6.0g、微粉硅胶3.0g、硬质富马酸钠3.0g、桔子香精6.0g、阿巴斯甜3.0g，分别过40目筛，混合均匀，再加入已制粒的水飞蓟宾琥珀酸酯钠钾盐颗粒，混合均匀；压片，制的每片含水飞蓟宾琥珀酸酯钠钾60mg。
实施例16 150mg水飞蓟宾琥珀酸酯二钠颗粒的组成和制备方法
将水飞蓟宾琥珀酸酯二钠150g，乳糖500.0g、甘露醇300.0g、羟丙甲纤维素5.0g、阿司帕坦5g橘子香精5.0g混匀，2％的羟丙甲纤维素水溶液制软材，14目制粒，鼓风烘箱干燥3小时，12目筛整粒，测定含量，定量分装在PVC复合铝箔袋中，使每袋含水飞蓟宾琥珀酸酯二钠150mg。
实施例17 水飞蓟宾琥珀酸酯钠钾滴丸的组成和制备方法
取聚乙二醇-6000 42.0g，置85℃水浴中加热熔融，加入过100目筛的水飞蓟宾琥珀酸酯钠钾5.0g，泊罗沙姆1g、羧甲淀粉钠1g搅拌均匀，继续置85℃水浴中加热、搅拌至料液由浑浊态变为均匀混悬液，以二甲基硅油为冷凝剂，冷凝温度为-5~10℃，以40滴/分滴制，除去冷凝剂，即得每粒滴丸重约50mg，含主药5mg。
实施例18 60mg水飞蓟宾琥珀酸酯二钾分散片的组成和制备方法
将水飞蓟宾琥珀酸酯二钾60.0g、乳糖60.0g、低取代羟丙纤维素钠10.0g、羟丙甲纤维素3g、微晶纤维素15g混合均匀，用30％聚乙二醇6000乙醇制软材，过24目筛，55℃烘箱干燥。干颗粒加微粉硅胶3g、硬脂酸镁5g，混合均匀，压片，每片含水飞蓟宾琥珀酸酯二钾60mg。
实施例19 对上述实施例1、4、5、6、14、15、17进行体外溶出度实验，测定方法如下：
溶出度方法：取本品，依法测定，照溶出度测定法(中国药典2005年版二部附录XC，第一法)，以水1000ml为溶剂，转速75转/分，于每杯中投1片或1粒或1袋，依法操作，经5分，10分，20分，30分，45分，60分(或3分，5分，10分，15分，30分，45分，60分)，用0.8μm的滤膜滤过，取初滤液10ml，弃去5ml，取续滤液2ml于10ml量瓶中用水稀释至刻度，作为供试品溶液。另精密称取对照品适量，先加乙醇使之溶解，再加水溶液稀释制成20μg/ml溶液，作为对照品溶液。照紫外分光光度法(中国药典2005年版二部附录IVA)在288nm处测定吸收值，按外标法计算每片溶出度，
结果：各实施例30分钟内溶出均超过75％，符合中国药典2005年版的规定，即本发明技术是可行的。
尽管本发明结合它的专门的实施例已做了详细的描述，但是很明显对本技术领域的熟练人来说仍能做出各种各样的变化和改进，都不会偏离本发明的精神实质和保护范围。
Claims (2)
1.一种水飞蓟宾盐口服制剂，其特征在于它由治疗有效量的水飞蓟宾琥珀酸酯二钠盐和惰性赋形剂组成，其惰性赋形剂选择稀释剂、粘合剂、崩解剂、抗粘着剂、润滑剂、填充剂、增溶剂、助流剂中的一种或几种；其特征在于其口服固体制剂可以是片剂、颗粒剂、胶囊、分散片、口腔崩解片、滴丸；其中，
片剂制备方法为：
将水飞蓟宾琥珀酸酯二钠60.0g、微晶纤维素100.0g、磷酸氢钙40.0g、微粉硅胶4.0g混合均匀，以羟丙甲纤维素的30％乙醇溶液为润湿剂制软材，20目筛制粒，55℃通风干燥4小时，整粒，加入羧甲基纤维素钠5.0g、硬脂酸镁5.0g混匀压得约1000片，每片含水飞蓟宾琥珀酸酯二钠60mg，即得压制片。
胶囊制备方法为：
将水飞蓟宾琥珀酸酯二钠60.0g、乳糖50.0g、甘露醇40.0g、羧甲淀粉钠8g置入快速搅拌制粒机KJZ-IO中，喷洒30％乙醇水溶液制粒，60℃通风干燥3小时，20目筛整粒，加入硬脂酸镁3.0g混匀，灌装1号明胶硬胶囊，使每粒胶囊含水飞蓟宾琥珀酸酯二钠60mg。
颗粒制备方法为：
将水飞蓟宾琥珀酸酯二钠120g，乳糖500.0g、甘露醇360.0g、明胶5.0g、阿司帕坦5g橘子香精5.0g混匀，喷洒10％的海藻酸水溶液制软材，14目制粒，鼓风烘箱干燥3小时，12目筛整粒，测定含量，定量分装在PVC复合铝箔袋中，使每袋含水飞蓟宾琥珀酸酯二钠120mg。
滴丸制备方法为：
取聚乙二醇-6000 40.0g，置85℃水浴中加热熔融，加入过100目筛的水飞蓟宾琥珀酸酯二钠10.0g，羧甲淀粉钠1g搅拌均匀，继续置85℃水浴中加热、搅拌至料液由浑浊态变为混悬液，以二甲基硅油为冷凝剂，冷凝温度为-5～10℃，以50滴/分滴制，除去冷凝剂，即得每粒滴丸重约50mg，含主药10mg。
口腔崩解片制备方法为：
将水飞蓟宾琥珀酸酯钠钾60.0g粉碎，用聚维酮K302.0制粒，水或乙醇润湿，过30目筛，55℃烘干，备用；另将交联聚维酮14.0g、羧甲基纤维素钠6.0g、微粉硅胶3.0g、硬质富马酸钠3.0g、桔子香精6.0g、阿巴斯甜3.0g，分别过40目筛，混合均匀，再加入已制粒的水飞蓟宾琥珀酸酯钠钾盐颗粒，混合均匀；压片，制的每片含水飞蓟宾琥珀酸酯钠钾60mg。
2.如权利要求1所述的口服制剂，其水飞蓟宾琥珀酸酯二钠盐也可以用水飞蓟宾琥珀酸酯钠钾盐、水飞蓟宾琥珀酸酯二钾代替。
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