CN114588121B - 一种辛伐他汀片及其制备方法 - Google Patents
一种辛伐他汀片及其制备方法 Download PDFInfo
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- 229960002855 simvastatin Drugs 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 28
- BGNXCDMCOKJUMV-UHFFFAOYSA-N Tert-Butylhydroquinone Chemical compound CC(C)(C)C1=CC(O)=CC=C1O BGNXCDMCOKJUMV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000004250 tert-Butylhydroquinone Substances 0.000 claims abstract description 18
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- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 4
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- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
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- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
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- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
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- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- Pharmacology & Pharmacy (AREA)
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- Public Health (AREA)
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- Epidemiology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物制剂技术领域，涉及一种辛伐他汀片及其制备方法。所述的辛伐他汀片含有辛伐他汀、填充剂、崩解剂、抗氧化剂、润滑剂；抗氧化剂由叔丁基对苯二酚(TBHQ)、枸橼酸、维生素C、维生素E、棕榈酸维生素C酯中的一种或两种组成。本发明提供的抗氧化剂微粉化混合原辅料、粉末直接压片的辛伐他汀片制备工艺能显著改善现有生产工艺生产过程中导致主药受热、氧化、含量下降的情况，而且生产过程缩短，可操作性强，连续生产有保证，节省了生产成本，更有利于节能降耗减排，有极大的经济效益和社会效益。
Description
技术领域
本发明涉及一种药物辛伐他汀片，尤其涉及一种辛伐他汀片剂及其制备方法，属于药物制剂领域。
背景技术
近年来，随着饮食习惯改变、生活水平提高、工作压力增大，高脂血症和高蛋白血症患者越来越多，而且，患者群越来越年轻化。随着医药科学的不断发展，人们认识到胆固醇、脂肪等含量过高是发生心血管疾病的基本病因，高血脂是发生冠心病及高血压的主要危险因素。因此，人们开始把血脂调节药的开发作为防治心血管疾病的重点。医药界对调脂药在防治心血管疾病方面的作用充满信心，调脂疗法将成为21世纪预防心血管疾病的主要方法。
辛伐他汀(simvastatin)是一种新型强效的半合成调脂药物，通过抑制内源性胆固醇的合成而降低低密度脂蛋白(LDL)和极低密度脂蛋白(VLDL)，中等程度升高高密度脂蛋白(HDLC)，降低甘油三酯，从而降低胆固醇，对高胆固醇、冠心病等有明显的疗效，是治疗高血脂的首选药物之一。
辛伐他汀与多种药用辅料存在配伍禁忌，容易发生水解和氧化，在高湿条件下内酯键断裂开环生成其活性代谢物辛伐他汀羟基酸，在高温条件下分子内部二烯键发生缓慢的氧化共聚反应生成二聚物或多聚物。
发明内容
本发明的目的在于提供一种辛伐他汀片，所述的辛伐他汀片含有辛伐他汀、填充剂、崩解剂、抗氧化剂、润滑剂；所述的抗氧化剂由叔丁基对苯二酚(TBHQ)、枸橼酸、维生素C、维生素E、棕榈酸维生素C酯中的一种或两种组成；所述的填充剂由微晶纤维素、乳糖、淀粉中的一种或多种组成；所述的崩解剂由低取代羟丙纤维素、交联聚维酮、羧甲基淀粉钠中的一种或多种组成；所述的润滑剂为硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇中的一种或多种组成。
本发明还提供了上述辛伐他汀片的具体组成，即所述的辛伐他汀片含有以下组分：
优选的，所述的辛伐他汀片含有以下组分：
上述的抗氧化剂为叔丁基对苯二酚(TBHQ)、维生素C的混合物。
具体的，所述的叔丁基对苯二酚(TBHQ)、维生素C的比例为1:5-300；
优选的，所述的叔丁基对苯二酚(TBHQ)、维生素C的比例为1:20-200；
进一步优选的，所述的叔丁基对苯二酚(TBHQ)、维生素C的比例为1:20-100。
本发明还提供了上述辛伐他汀片的制备方法，即所述的辛伐他汀片的制备方法为：先取等量的微粉化的叔丁基对苯二酚(TBHQ)、维生素C混合，然后加入剩余维生素C，混合后加入辛伐他汀混合，再加入填充剂、崩解剂，混合后加入硬脂酸镁，混合均匀，压片即得。
与现有技术相比，本发明具有本品制备工艺简单易行，通过抗氧化剂二丁基羟基甲苯和枸橼酸粉碎、过筛、等量递增混合工艺，使抗氧化剂更好的均匀分布，再混合原料和其他辅料，更好的使物料分布均匀，解决了主药易氧化、含量下降快的问题，与同类产品相比有明显优势。
具体实施方式
下面结合具体实施例对本发明作进一步详细说明，但本发明的实施例方式并不受下述实施例的限制，其他任何在本发明实质的基础上所作的进一步改变、修饰、替代、组合以及简化均应视为等效替换，包含在本发明的保护范围之内。
实施例1：辛伐他汀片(处方组成1000片)
TBHQ、维生素C微粉化处理，先等量混合，再加入剩余的维生素C混合，将辛伐他汀与上述抗氧化剂混合后加入上述填充剂、崩解剂，混合均匀后加入上述润滑剂，混合均匀，压片，即得。
实施例2：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
实施例3：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
实施例4：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
实施例5：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
实施例6：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
实施例7：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
实施例8：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
实施例9：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
实施例10：辛伐他汀片(处方组成1000片)
制备方法同实施例1。
对比例1：辛伐他汀片(处方组成1000片)
| 成分 | 重量(g) |
| 辛伐他汀 | 10 |
| 低取代羟丙纤维素 | 3 |
| 微晶纤维素 | 100 |
| 丁羟基茴香醚 | 0.01 |
| 羟丙甲纤维素 | 0.5 |
| 二氧化硅 | 0.8 |
| 硬脂酸镁 | 0.3 |
| 薄膜包衣预混剂 | 3 |
制备方法：将丁羟基茴香醚溶解于适量乙醇溶液，加入羟丙甲纤维素分散均匀后，加入适量水制备成凝胶状粘合剂。将粘合剂倒入辛伐他汀原料中，采用搅拌制粒搅拌成疏松均匀的小颗粒，移至流化床中干燥，干燥完加入其他辅料混合均匀，压片，包衣。
对比例2：辛伐他汀片(处方组成1000片)
| 成分 | 重量(g) |
| 辛伐他汀 | 10 |
| 低取代羟丙纤维素 | 3 |
| 微晶纤维素 | 100 |
| 丁羟基茴香醚 | 0.01 |
| 羟丙甲纤维素 | 0.5 |
| 二氧化硅 | 0.8 |
| 硬脂酸镁 | 0.3 |
| 薄膜包衣预混剂 | 3 |
制备方法：将丁羟基茴香醚、羟丙甲纤维素和辛伐他汀混合均匀后，干法制粒，再加入其他辅料混合均匀，压片，包衣。
【含量测定】照高效液相色谱法测定
色谱条件与系统适应性试验：用十八烷基硅烷键合硅胶为填充剂；以0.025mol/L磷酸二氢钠溶液(用磷酸或氢氧化钠试液调节pH值至4.5)-乙腈(35:65)为流动相；检测波长为238nm，取辛伐他汀对照品和洛伐他汀对照品各适量，加溶剂I溶解并稀释制成每1ml中各约含20μg的溶液，取20μl注入液相色谱仪，辛伐他汀峰与洛伐他汀峰之间的分离度应大于3，理论板数按辛伐他汀峰计算不低于2000.
测定法：分别取实施例1、2、3、7、8、9，对比例1、2所得辛伐他汀片20片，精密称定，研细，精密称取适量(约相当于辛伐他汀10mg)，置100ml量瓶中，加溶剂I稀释至刻度，摇匀，滤过，取续滤液作为供试品溶液，精密量取20μl注入液相色谱仪，记录色谱图；另取辛伐他汀对照品，精密称定，加溶剂I使溶解并定量稀释制成每1ml中约含0.1mg的溶液，同法测定。按外标法以峰面积计算，即得。
参比制剂为市售美国默克公司生产的舒降之，规格为5mg。
1、试验效果对比
表1产品基本参量分析
| 名称 | 可压性 | 平均硬度 | 重量差异 | 崩解时限(min) | 脆碎度 |
| 实施例1 | 较好 | 48.6 | 符合要求 | 4 | 符合要求 |
| 实施例2 | 较好 | 48.3 | 符合要求 | 4 | 符合要求 |
| 实施例3 | 较好 | 47.5 | 符合要求 | 4 | 符合要求 |
| 实施例7 | 较好 | 46.9 | 符合要求 | 4 | 符合要求 |
| 实施例8 | 较好 | 47.9 | 符合要求 | 4 | 符合要求 |
| 实施例9 | 较好 | 45.8 | 符合要求 | 4 | 符合要求 |
| 对比例1 | 较好 | 40.2 | 符合要求 | 3 | 符合要求 |
| 对比例2 | 较好 | 45.5 | 符合要求 | 3 | 符合要求 |
| 参比制剂 | ---- | 46.8 | 符合要求 | 4 | 符合要求 |
由表1可知：实施例和对比例、参比制剂相比，在可压性、硬度、崩解时限、脆碎度相差不大。
2、实施例和对比例所得片剂的稳定性比较
将实施例和对比例制备所得的片剂分别置于高温(40℃)、高湿(相对湿度75±5％)的恒湿箱内加速试验6个月，分别于0天、1个月、2个月、3个月、6个月检测含量及有关物质。
表2产品稳定性的比较
由表2的数据可知，经过加速试验分析结果可以看出，采用本发明制备的片剂在加速条件后产品含量高于对比例，和原研参比制剂相比无差别，各组实施例有关物质比对比例明显降低，和原研参比制剂相近。
Claims (3)
1.一种辛伐他汀片,其特征在于,所述的辛伐他汀片由辛伐他汀、填充剂、崩解剂、抗氧化剂、润滑剂制成；所述的抗氧化剂由叔丁基对苯二酚、维生素C组成；所述的叔丁基对苯二酚、维生素C的比例为1:20-100；所述的润滑剂为硬脂酸镁；所述的辛伐他汀片组分用量如下：
辛伐他汀 10重量份
填充剂 100-200重量份
抗氧化剂 1-3.5重量份
崩解剂 10-20重量份
润滑剂 1-5重量份；
所述的辛伐他汀片的制备方法为：先取等量的微粉化的叔丁基对苯二酚、维生素C混合,然后加入剩余维生素C混合,后加入辛伐他汀混合,再加入填充剂、崩解剂混合,后加入硬脂酸镁,混合均匀,压片即得。
2.根据权利要求1所述的辛伐他汀片,其特征在于,所述的填充剂由微晶纤维素、乳糖、淀粉中的一种或多种组成。
3.根据权利要求1所述的辛伐他汀片,其特征在于,所述的崩解剂由低取代羟丙纤维素、交联聚维酮、羧甲基淀粉钠中的一种或多种组成。
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