CN111904935A - 一种阿奇霉素干混悬剂 - Google Patents
一种阿奇霉素干混悬剂 Download PDFInfo
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- CN111904935A CN111904935A CN202010907546.0A CN202010907546A CN111904935A CN 111904935 A CN111904935 A CN 111904935A CN 202010907546 A CN202010907546 A CN 202010907546A CN 111904935 A CN111904935 A CN 111904935A
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- azithromycin
- solid dispersion
- dry suspension
- weight ratio
- crospovidone
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- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 title claims abstract description 98
- 229960004099 azithromycin Drugs 0.000 title claims abstract description 97
- 239000000725 suspension Substances 0.000 title claims abstract description 29
- 239000007962 solid dispersion Substances 0.000 claims abstract description 53
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960000913 crospovidone Drugs 0.000 claims abstract description 14
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 14
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 14
- 125000005456 glyceride group Chemical group 0.000 claims abstract description 12
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims abstract description 11
- 239000000463 material Substances 0.000 claims abstract description 11
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- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 9
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
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- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 2
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A61K9/1629—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明属于药物制剂领域，具体涉及一种阿奇霉素干混悬剂，含有阿奇霉素固体分散体、填充剂、崩解剂以及润滑剂，由如下方法制备而成：阿奇霉素与大分子聚合物、交联聚维酮、可溶性辅料等制成固体分散体，固体分散体粉碎过筛，用月桂酰聚氧乙烯‑32甘油酯及药学上可接受的辅料制粒后，即得，制备得到的药物无苦味，溶出速度快，且生物利用度显著提高。
Description
技术领域
本发明属于医药技术领域，具体涉及一种阿奇霉素干混悬剂。
背景技术
阿奇霉素(Azithromycin)为半合成的十五元大环内酯类抗生素，白色结晶性粉末。化学名称：(2R，3S，4R，5R，8R，10R，11R，12S，13S，14R)-13-[(2，6-二脱氧-3-C-甲基-3-O-甲基-α-L-核-己吡喃糖基)氧]-2-乙基-3，4，10-三羟基-3，5，6，8，10，12，14-七甲基-11-[[3，4，6-三脱氧-3-(二甲氨基)-β-D-木-己吡喃糖基]氧]-1-氧杂-6-氮杂环十五烷-15-酮
化学结构式为：
二水合物分子式：C38H72N2O12·2H2O
二水合物分子量：785.03
阿奇霉素适用于敏感细菌所引起的下列感染：支气管炎、肺炎等下呼吸道感染；皮肤和软组织感染；急性中耳炎；鼻窦炎、咽炎、扁桃体炎等上呼吸道感染(青霉素是治疗化脓性链球菌咽炎的常用药，也是预防风湿热的常用药物。阿奇霉素可有效清除口咽部链球菌，但目前尚无阿奇霉素治疗和预防风湿热疗效的资料)。阿奇霉素可用于男女性传播疾病中由沙眼衣原体所致的单纯性生殖器感染。阿奇霉素亦可用于由非多重耐药淋球菌所致的单纯性生殖器感染及由杜克嗜血杆菌引起的软下疳(需排除梅毒螺旋体的合并感染)。
阿奇霉素口服后迅速吸收，生物利用度为37％。单剂口服0.5g后，达峰时间为2.5～2.6小时。
CN 101966156 B公开了一种阿奇霉素干混悬剂，由阿奇霉素颗粒与糖颗粒混合而成，阿奇霉素颗粒中含有黄原胶-丝素蛋白-微粉硅胶组合物，此发明避免了药物突释，减少了不良反应，提高患者的顺应性。
CN 110151704 A公开了一种阿奇霉素干混悬的制备方法，此干混悬剂采用两步制粒提高产品稳定性，改善了口感。
CN 1813683 B公开了一种阿奇霉素干混悬剂，利用高分子粘合剂甲基丙烯酸酯等，具有稳定性好、起效快，生物利用度高等优点，提高了病人用药顺应性。
各专利文献均不能完全克服阿奇霉素的生物利用度低的缺点。针对现有技术的不足，有必要对阿奇霉素的剂型做出更多摸索和试验，找到更佳的组方和制备方法，提高阿奇霉素的生物利用度。
发明内容
本发明所要解决的技术问题是提供一种药物利用率高、制备工艺简单、物理性质稳定、并能显著提高阿奇霉素干混悬稳定性、能够使药物快速溶出且能提高生物利用度的干混悬剂及其制备方法。
针对现有技术的缺陷，发明人意识到，将阿奇霉素制成固体分散体可以提高稳定性和生物利用度，但固体分散体制备后成块较硬，不容易粉碎，且使溶出度降低。
发明人考虑到，既然固体分散体可以提高稳定性，如果将阿奇霉素固体分散体中加入其它药学可接受的辅料，如稀释剂等，有可能解决固体分散体较硬，不易粉碎过筛的缺点，结果表明，固体分散体中加入其它辅料可以改善硬度，但是溶出度仍然不理想。
进一步的，发明人进行了大量实验，惊奇的发现阿奇霉素固体分散体制备过程中加入超级崩解剂交联聚维酮，粉碎后再与其他药学上可接受的辅料混合，，得到的稳定性、及含量均匀度均较好的干混悬剂。但进一步的实验表明，阿奇霉素干混悬溶出度有所提高但仍不能快速溶出，发明人进一步考虑，阿奇霉素制备固体分散体时加入适量水溶性较好的辅料与超级崩解剂交联聚维酮，固体分散体粉碎后加入辅料月桂酰聚氧乙烯-32甘油酯制粒，可有效提高阿奇霉素干混悬的溶出度。
具体而言，本发明是通过如下技术实现的：
本发明提供了一种阿奇霉素干混悬剂，含有阿奇霉素固体分散体、填充剂、崩解剂以及润滑剂，由如下方法制备而成：阿奇霉素与大分子聚合物、交联聚维酮、可溶性辅料等制成固体分散体，固体分散体粉碎过筛，用月桂酰聚氧乙烯-32甘油酯及药学上可接受的辅料制粒后，即得。
所述的大分子聚合物包括羟丙甲基纤维素、聚乙烯吡咯烷酮。
所述的可溶性辅料包括乳糖、蔗糖、葡萄糖、甘露醇、山梨醇中的一种或多种。
所述的阿奇霉素固体分散体，阿奇霉素与大分子聚合物的重量比为1:0.5-1:2。优选地，重量比为1:1。
所述的阿奇霉素固体分散体，阿奇霉素与交联聚维酮的的重量比为1：0.05-1:0.2。优选地，重量比为1:0.1。
所述的阿奇霉素固体分散体，阿奇霉素与可溶性辅料的重量比为1：0.1-1:1。优选地，重量比为1:0.5。
所述的阿奇霉素干混悬剂，阿奇霉素与月桂酰聚氧乙烯-32甘油酯的重量比为1：0.02-0.1。优选地，重量比为1:0.06。
所述的药学上可接受的辅料为吸附剂、填充剂、崩解剂、润滑剂。
所述的填充剂选自微晶纤维素、乳糖、甘露醇、淀粉和糊精中的一种或多种。
所述的崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮和低取代羟丙基纤维素中的一种或多种。
所述的润滑剂选自硬脂酸镁、聚乙二醇、硬脂酸富马酸钠和氢化植物油中的一种或多种。
本发明与现有技术相比，药物无苦味，溶出速度快，且生物利用度显著提高。
具体实施方式
以下实施例进一步描述本发明的有益效果，实施例仅用于例证的目的，不限制本发明的范围，同时本领域普通技术人员根据本发明所做的显而易见的改变和修饰也包含在本发明范围之内。
实施例1
制备工艺：
将处方量的羟丙甲基纤维素用95％乙醇溶解，再溶液中加入处方量的阿奇霉素、交联聚维酮以及乳糖，搅拌使其混合均匀，使用旋转蒸发仪去除95％的乙醇水溶液，即得阿奇霉素固体分散体，将固体分散体取出并50℃烘干，粉碎过80目筛，称取处方量的微晶纤维素，交联羧甲基纤维素钠与固体分散体混合均匀，使用月桂酰聚氧乙烯-32甘油酯制粒并过20目筛，即得。
实施例2
制备工艺：
将处方量的聚乙烯吡咯烷酮用95％乙醇溶解，再溶液中加入处方量的阿奇霉素、交联聚维酮以及甘露醇，搅拌使其混合均匀，使用旋转蒸发仪去除95％的乙醇水溶液，即得阿奇霉素固体分散体，将固体分散体取出并50℃烘干，粉碎过80目筛，称取处方量的淀粉，羧甲基淀粉钠与固体分散体混合均匀，使用月桂酰聚氧乙烯-32甘油酯制粒过20目筛，即得。
实施例3
制备工艺：
将处方量的羟丙甲基纤维素用95％乙醇溶解，再溶液中加入处方量的阿奇霉素、交联聚维酮以及乳糖，搅拌使其混合均匀，使用旋转蒸发仪去除95％的乙醇水溶液，即得阿奇霉素固体分散体，将固体分散体取出并50℃烘干，粉碎过80目筛，称取处方量的甘露醇，低取代羟丙基纤维素与固体分散体混合均匀，使用月桂酰聚氧乙烯-32甘油酯制粒并过20目筛，即得。
实施例4
制备工艺：
将处方量的聚乙烯吡咯烷酮用95％乙醇溶解，再溶液中加入处方量的阿奇霉素、交联聚维酮以及甘露醇，搅拌使其混合均匀，使用旋转蒸发仪去除95％的乙醇水溶液，即得阿奇霉素固体分散体，将固体分散体取出并50℃烘干，粉碎过80目筛，称取处方量的乳糖，羧甲基淀粉钠与固体分散体混合均匀，使用月桂酰聚氧乙烯-32甘油酯制粒并过20目筛，即得。
实施例5
制备工艺：
将处方量的羟丙甲基纤维素用95％乙醇溶解，再溶液中加入处方量的阿奇霉素、交联聚维酮以及乳糖，搅拌使其混合均匀，使用旋转蒸发仪去除95％的乙醇水溶液，即得阿奇霉素固体分散体，将固体分散体取出并50℃烘干，粉碎过80目筛，称取处方量的微晶纤维素，低取代羟丙基纤维素与固体分散体混合均匀，95％乙醇制粒过20目筛，干燥即得。
实施例6
制备工艺：
将处方量的聚乙烯吡咯烷酮用95％乙醇溶解，再溶液中加入处方量的阿奇霉素搅拌使其混合溶解，使用旋转蒸发仪去除95％的乙醇水溶液，即得阿奇霉素固体分散体，将固体分散体取出并50℃烘干，粉碎过80目筛，称取处方量的淀粉，羧甲基淀粉钠与固体分散体混合均匀，使用月桂酰聚氧乙烯-32甘油酯制粒并过20目筛，即得。
对比实施例1
制备工艺：
阿奇霉素粉碎过80目筛，然后加入微晶纤维素、乳糖和低取代羟丙基纤维素混合均匀，再加入5％聚乙烯吡咯烷酮水溶液制粒过20目筛，干燥即得。
对比实施例2
制备工艺：
将处方量的羟丙甲基纤维素用95％乙醇溶解，在溶液中加入处方量的阿奇霉素搅拌使其溶解，使用旋转蒸发仪去除95％的乙醇水溶液，即得阿奇霉素固体分散体，将固体分散体取出并50℃烘干，粉碎过80目筛，称取处方量的微晶纤维素，低取代羟丙基纤维素与固体分散体混合均匀，95％制粒过20目筛，干燥即得。
验证实施例
1.溶出度与有关物质
溶出度测定
照溶出度与释放度测定法(通则0931第二法)测定。
溶出条件以磷酸盐缓冲液(pH6.0)(0.lmol/L磷酸氢二钠溶液6000ml，加盐酸约40ml，调节pH值至6.0士0.05)900ml为溶出介质0.lg和0.125g规格溶出介质为500ml)，转速为每分钟100转，依法操作，经45分钟时取样。供试品溶液取溶出液适量，滤过，精密量取续滤液适量，用溶出介质定量稀释制成每lml中约含阿奇霉素0.2mg的溶液。
对照品溶液取阿奇霉素对照品适量，精密称定，加适量乙醇(每2mg约加乙醇lml)使溶解，用溶出介质定量稀释制成每lml中约含0.2mg的溶液。
照高效液相色谱法(通则0512)测定。
系统适用性溶液取阿奇霉素系统适用性对照品适量，加乙腈溶解并稀释制成每lml中含l0mg的溶液。
色谱条件用十八烷基硅烷键合硅胶为填充剂；以磷酸盐缓冲液(取0.05mol/L磷酸氢二钾溶液，用20％磷酸溶液调节pH值至8.2)-乙腈(45:55)为流动相；检测波长为210nm；进样体积50μ1。计算每个单位的溶出度。
限度标示量的75％，应符合规定。
有关物质照高效液相色谱法(通则0512)测定。临用新制或使用低温进样器。
稀释液磷酸二氢铵溶液(称取磷酸二氢铵1.73g，加水溶解并稀释至1000ml，用氨试液调节pH值至10.0士0.05)甲醇－乙腈(7:7：6)。
供试品溶液取本品适量，精密称定，加稀释液溶解并定量稀释制成每lml中约含l0mg的溶液。
对照溶液精密量取供试品溶液lml，置200ml量瓶中，用稀释液稀释至刻度，摇匀。杂质S对照品与杂质A对照品溶液取杂质S对照品与杂质A对照品各适量，加稀释液溶解并稀释制成每lml中各约含0.05mg的溶液。
系统适用性溶液取阿奇霉素系统适用性对照品(含杂质R、杂质Q、杂质J、杂质I、杂质H、阿奇霉素和杂质B)适量，加杂质S对照品与杂质A对照品溶液溶解并稀释制成每lml中约含l0mg的溶液。灵敏度溶液精密量取对照溶液l0ml，置50ml量瓶中，用稀释液稀释至刻度，摇匀。
色谱条件用十八烷基硅烷键合硅胶为填充剂；以磷酸盐缓冲液(取0.05mol/L磷酸氢二钾溶液，用20％的磷酸溶液调节pH值至8.2)-乙腈(45:55)为流动相A，以甲醇为流动相B，柱温为30℃(必要时适当调整)；按下表进行线性梯度洗脱；流速为每分钟1.0ml，检测波长为210nm；进样体积为50μl。
系统适用性要求系统适用性溶液色谱图中，各峰之间的分离度均应大于1.2，阿奇霉素峰的保留时间应在30～40分钟之间。灵敏度溶液色谱图中，主成分峰峰高的信噪比应大于10。测定法精密量取供试品溶液与对照溶液，分别注入液相色谱仪，记录色谱图。
限度供试品溶液色谱图中如有杂质峰，杂质B峰面积得大于照对溶液主峰面积的4倍(2.0％)杂，质H与杂质Q按校正后的峰面积计算(分别乘以校正因子0.1、0.4)不得大于照对溶液主峰面积的2倍(1.0％)，其他单个杂质峰面积不得大于照对溶液主峰面积的2倍(1.0％)，各杂质峰面积的和按校正后的峰面积计算不得大于对照溶液主峰面积的8倍(0.4％)，小于灵敏度溶液主峰面积的峰忽略不计
结果见表1：
实施例1-4所得制剂能够完全溶出，并达到了极好的稳定性及含量均与度。实施例5和6只采用固体分散体技术，没使用辛酸癸酸聚乙二醇甘油酯制粒增溶，保证了阿奇霉素的稳定性及很好含量均匀度，但是溶出度较低；对比实施例1为普通方法制得阿奇霉素干混悬，对比实施例2为普通的固体分散体技术。
2.药代动力学试验
实施例1-6和对比实施例1-4进行药代动力学实验，每组健康Beagle犬6只，体重12.5-15kg，服药前12h给食一次，口服阿奇霉素干混悬剂量0.1g，同时给予25ml温水，给药后5min、15min、30min、45min、60min、90min、2h、4h、8h、12h于前肢内测皮下静脉采血约3ml，置于肝素化试管中，测定其血药浓度，计算Cmax、AUC，并同市售阿奇霉素干混悬(商品名：
)对比，进一步计算对于
的Cmax、AUC的比值。
表2药代动力学测定结果
Claims (10)
1.一种阿奇霉素干混悬剂，其特征在于，含有阿奇霉素固体分散体、填充剂、崩解剂以及润滑剂，由如下方法制备而成：阿奇霉素与大分子聚合物、交联聚维酮、可溶性辅料等制成固体分散体，固体分散体粉碎过筛，用月桂酰聚氧乙烯-32甘油酯及药学上可接受的辅料制粒后，即得。
2.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的大分子聚合物包括羟丙甲基纤维素、聚乙烯吡咯烷酮。
3.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的可溶性辅料包括乳糖、蔗糖、葡萄糖、甘露醇、山梨醇中的一种或多种。
4.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的阿奇霉素固体分散体，阿奇霉素与大分子聚合物的重量比为1:0.5-1:2，优选地，重量比为1:1。
5.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的阿奇霉素固体分散体，阿奇霉素与交联聚维酮的的重量比为1：0.05-1:0.2，优选地，重量比为1:0.1。
6.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的阿奇霉素固体分散体，阿奇霉素与可溶性辅料的重量比为1：0.1-1:1，优选地，重量比为1:0.5。
7.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的阿奇霉素干混悬剂，阿奇霉素与月桂酰聚氧乙烯-32甘油酯的重量比为1：0.02-0.1，优选地，重量比为1:0.06。
8.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的药学上可接受的辅料为吸附剂、填充剂、崩解剂、润滑剂。
9.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的填充剂选自微晶纤维素、乳糖、甘露醇、淀粉和糊精中的一种或多种。
10.如权利要求1所述阿奇霉素干混悬剂，其特征在于，所述的崩解剂选自羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮和低取代羟丙基纤维素中的一种或多种，所述的润滑剂选自硬脂酸镁、聚乙二醇、硬脂酸富马酸钠和氢化植物油中的一种或多种。
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Citations (4)
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| CN1887272A (zh) * | 2006-07-13 | 2007-01-03 | 漆新国 | 阿齐霉素缓释干混悬剂及其制备方法 |
| US20150011525A1 (en) * | 2011-09-13 | 2015-01-08 | Isp Investments Inc. | Solid dispersion of poorly soluble compounds comprising crospovidone and at least one water-soluble polymer |
| CN105982858A (zh) * | 2015-01-29 | 2016-10-05 | 北京科信必成医药科技发展有限公司 | 一种阿奇霉素掩味的干混悬颗粒剂及其制备方法 |
| CN111603449A (zh) * | 2019-02-22 | 2020-09-01 | 鲁南制药集团股份有限公司 | 一种苯磺酸左旋氨氯地平片剂及其制备方法 |
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| CN1887272A (zh) * | 2006-07-13 | 2007-01-03 | 漆新国 | 阿齐霉素缓释干混悬剂及其制备方法 |
| US20150011525A1 (en) * | 2011-09-13 | 2015-01-08 | Isp Investments Inc. | Solid dispersion of poorly soluble compounds comprising crospovidone and at least one water-soluble polymer |
| CN105982858A (zh) * | 2015-01-29 | 2016-10-05 | 北京科信必成医药科技发展有限公司 | 一种阿奇霉素掩味的干混悬颗粒剂及其制备方法 |
| CN111603449A (zh) * | 2019-02-22 | 2020-09-01 | 鲁南制药集团股份有限公司 | 一种苯磺酸左旋氨氯地平片剂及其制备方法 |
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