CN111265487A - 一种盐酸环丙沙星口服固体制剂 - Google Patents
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Abstract
本发明涉及一种盐酸环丙沙星口服固体制剂及其制备工艺，该制剂由盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆、崩解剂及润滑剂制备而成，是将盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆溶解在水中，喷雾干燥，所得含药颗粒与崩解剂、润滑剂混合均匀，充填胶囊壳或压片而成。本发明制备的制剂稳定，能有效避免盐酸环丙沙星与金属离子络合，形成黄斑的问题。
Description
技术领域
本发明属于药物制剂技术领域，具体而言，涉及一种含有盐酸环丙沙星固体 口服制剂及其制备工艺。
背景技术
盐酸环丙沙星化学名称为：l-环丙基-6-氟-1，4.二氢.4.氧代-7-(1-哌嗪基) -3-喹啉羧酸盐酸盐分子式：C17H18FN3O3·HCL，具广谱抗菌作用，尤其对需氧 革兰阴性杆菌的抗菌活性高，对下列细菌在体外具良好抗菌作用：肠杆菌科的大 部分细菌，包括枸橼酸杆菌属、阴沟、产气肠杆菌、大肠埃希菌、克雷伯菌属、 变形杆菌属、沙门菌属、志贺菌属、弧菌属、耶尔森菌等。常对多重耐药菌也具 有抗菌活性。对青霉素耐药的淋病奈瑟菌、产酶流感嗜血杆菌和莫拉菌属均具有 高度抗菌活性。对铜绿假单胞菌等假单胞菌属的大多数菌株具抗菌作用。该品对 甲氧西林敏感葡萄球菌具抗菌活性，对肺炎链球菌、溶血性链球菌和粪肠球菌仅 具中等抗菌活性。对沙眼衣原体、支原体、军团菌亦具良好作用，对结核杆菌和非典型分枝杆菌也有抗菌活性。对厌氧菌的抗菌活性差。环丙沙星为杀菌剂，通 过作用于细菌DNA螺旋酶的A亚单位，抑制DNA的合成和复制而导致细菌死 亡，临床使用广泛。
然而，在制备盐酸环丙沙星片剂或胶囊剂过程中，由于盐酸环丙沙星属于喹 诺酮类药物，其结构中3,4位羧基和酮基极易与金属离子络合，形成黄斑，导致 药效降低。
CN108567754A公开了盐酸环丙沙星片，包括盐酸环丙沙星，碳酸钙，D- 氨基葡萄糖硫酸钾盐和淀粉，虽然能在低温环境下进行预处理，降低了盐酸环丙 沙星原料的热源风险，但由于淀粉等辅料含有大量金属离子，导致压片前的药物 颗粒出现黄斑。
CN107669645A公开了一种盐酸环丙沙星片的制备方法，以盐酸环丙沙星为 主料，以填充剂、崩解剂和润滑剂为辅料，采用粉末直压工艺，制得所述的盐酸 环丙沙星片；所述填充剂为乳糖或微晶纤维素中的一种或两种与淀粉的混合物； 所述崩解剂为交联聚维酮、或低取代羟丙基纤维素中的一种或两种，虽然采用粉 末直接压片工艺，较好地解决了盐酸环丙沙星片易裂片、粘冲、溶出度差异大等 缺点，但由于使用的辅料含有金属离子，仍没有解决盐酸环丙沙星与金属离子络 合，形成黄斑的问题。
CN104188893A一种盐酸环丙沙星口服固体制剂及其制备工艺，该制剂包 含盐酸环丙沙星、羟丙基甲基纤维素、崩解剂及润滑剂，是将盐酸环丙沙星与羟 丙基甲基纤维素溶解在水中，喷雾干燥，所得分散体与崩解剂、润滑剂混合均匀， 充填胶囊壳或压片而成。本发明制备的制剂在碱性条件下稳定，能有效避免盐酸 环丙沙星在碱性肠道环境中析出的问题。在实施例中采用羧甲基淀粉钠、硬脂酸 镁等带有金属离子的辅料，仍然导致颗粒出现黄斑。
发明内容
为解决上述技术问题，发明人通过对制剂的处方和工艺进行大量试验研究后 发现，将盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆溶解在水中喷雾干燥后， 形成的含药颗粒不会出现黄斑，原因可能是辅料不含有金属离子。
基于以上研究成果，本发明的目的在于提供一种盐酸环丙沙星口服固体制 剂，采用该处方的制剂稳定，能有效避免盐酸环丙沙星和金属离子络合出现黄斑 的问题。
本发明的第一个目的是通过如下技术方案实现的：一种盐酸环丙沙星口服固 体制剂，由盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆、崩解剂及润滑剂制 备而成。
进一步地，本发明所述的盐酸环丙沙星口服固体制剂，其中盐酸环丙沙星、 微晶纤维素、聚维酮、泊洛沙姆的重量用量比为1：0.2-0.5:0.1-0.2:0.1-0.2。 优选盐酸环丙沙星与羟丙基甲基纤维素的重量用量比为1：0.4：0.1：0.2。
再进一步地，本发明所述的盐酸环丙沙星口服固体制剂，其中所述的崩解剂 为低取代羟丙基纤维素，润滑剂为微粉硅胶。
需要说明的是，本发明所述的盐酸环丙沙星口服固体制剂，其优选的剂型为 片剂或胶囊。
本发明的另一个目的是提供一种盐酸环丙沙星口服固体制剂的制备工艺，采 用该工艺制备的制剂稳定，能有效避免盐酸环丙沙星和金属离子络合出现黄斑的 问题。
具体地，该工艺包括如下步骤：
(1)将盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆溶解在水中，喷雾 干燥，得到含药颗粒；
(2)将步骤(1)的含药颗粒与崩解剂、润滑剂混合均匀，充填胶囊壳或压 片。
与现有技术相比，本发明的制备工艺简单，稳定性高，避免盐酸环丙沙星和 金属离子络合出现黄斑，减少有关物质的产生，提高了患者用药的生物利用度， 保证了患者的用药安全性和有效性。
具体实施方式
以下是本发明盐酸环丙沙星口服固体制剂的制备实施例和效果试验例，以此 进一步描述本发明的制备过程和实施效果，实施例仅用于例证的目的，不用于限 制本发明的保护范围，同时本领域普通技术人员根据本发明所做出的显而易见的 改变和修饰均包含在本发明范围之内。
实施例1
制备工艺：
(1)处方量称取盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆，加入到 2000ml水中，搅拌，喷雾干燥，收集喷雾干燥后细粉，得到含药颗粒；
(2)按比例称取上述含药颗粒，与处方量的低取代羟丙基纤维素、微粉硅 胶置混合机中，混合10min，测定半成品含量，然后在自动胶囊充填机上进行充 填，得到盐酸环丙沙星胶囊。
实施例2
制备工艺：
(1)处方量称取盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆，加入到 2000ml水中，搅拌，喷雾干燥，收集喷雾干燥后细粉，得到含药颗粒；
(2)按比例称取上述含药颗粒，与处方量的低取代羟丙基纤维素、微粉硅 胶置混合机中，混合10min，测定半成品含量，然后在自动胶囊充填机上进行充 填，得到盐酸环丙沙星胶囊。
实施例3
制备工艺：
(1)处方量称取盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆，加入到 2000ml水中，搅拌，喷雾干燥，收集喷雾干燥后细粉，得到含药颗粒；
(2)按比例称取上述含药颗粒，与处方量的低取代羟丙基纤维素、微粉硅 胶置混合机中，混合10min，测定半成品含量，压片，得到盐酸环丙沙星片。
对比例1
制备工艺：
处方量称取过盐酸环丙沙星、微晶纤维素、羟丙基甲基纤维素、十二烷基 硫酸钠、硬脂酸镁，置于混合机中，混合，使用淀粉浆制粒，测定半成品颗粒， 然后在自动胶囊充填机上进行充填，得到盐酸环丙沙星胶囊。
对比例2参考《实用药物制剂技术》(2009年8月1日化学工业出版社出版) 第178页处方
制备工艺：将上述原辅料混合均匀，加入HPMC制软材，14目筛制粒，60 度烘干，加硬脂酸镁混匀，压片，包薄膜衣。
实施例4盐酸环丙沙星制剂颗粒的外观试验
取本发明实施例和对比例制备的盐酸环丙沙星制剂颗粒，进行颜色观察，如 表1。
表1盐酸环丙沙星制剂颗粒的外观比较
| 实施例 | 10min | 30min | 60min |
| 实施例1 | 白色 | 白色 | 白色 |
| 实施例2 | 白色 | 白色 | 白色 |
| 实施例3 | 白色 | 白色 | 白色 |
| 对比例1 | 白色 | 略黄 | 发黄 |
| 对比例2 | 白色 | 略黄 | 发黄 |
根据表1的试验结果可以看出，将本发明实施例1-3制备的盐酸环丙沙星 制剂颗粒随着颗粒放置时间的推移，颜色仍然是白色的，而对比实施例1和2 随着放置时间的延长，颜色发黄，可能是由于盐酸环丙沙星与辅料中含有的金属 离子络合后产生的颜色变化。
实施例5盐酸环丙沙星制剂的有关物质和含量测定试验
精密称取本品细粉(片剂直接粉碎，胶囊剂取内容物粉碎)适量，加流动相 A(参照原料药质量标准)溶解并定量稀释制成每1ml中约含环丙沙星0.5mg的 溶液，滤过，取续滤液作为供试品溶液，照盐酸环丙沙星项下的方法测定。杂质 A(262nm检测)按外标法以峰面积计算，不得过标示量的0.3％。杂质C(278nm 检测)按校正后的峰面积计算(乘以校正因子0.6)，不得大于对照溶液主峰面 积的2.5倍(0.5％)；杂质B、D和E(278nm检测)按校正后的峰面积计算(分 别乘以校正因子0.7、1.4和6.7)，均不得大于对照溶液主峰面积(0.2％)；其他单个杂质(278nm检测)峰面积不得大于对照溶液主峰面积(0.2％)；各杂 质(278nm检测)校正后峰面积的和不得大于对照溶液主峰面积的3.5倍(0.7％)。
取本品10片或粒(片剂直接粉碎，胶囊剂取内容物粉碎)，精密称定，研 细，精密称取细粉适量(约相当于环丙沙星0.2g)，置200ml量瓶中，加流动 相适量振摇使溶解并稀释至刻度，摇匀，滤过，精密量取续滤液5ml，置50ml 量瓶中，用流动相稀释至刻度，摇匀，作为供试品溶液，照盐酸环丙沙星项下的 方法测定，即得。
表2盐酸环丙沙星制剂的有关物质和含量测定
通过表2的实验结果可知，本发明实施例制备的盐酸环丙沙星制剂经加速试 验考察后，其有关物质、含量基本不变；而对比实施例1-2制备的盐酸环丙沙星 制剂经加速试验考察后，有关物质均增加明显，含量有一定程度下降。
Claims (5)
1.一种盐酸环丙沙星口服固体制剂，其特征在于，所述的口服固体制剂由盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆、崩解剂及润滑剂制备而成。
2.根据权利要求1所述的盐酸环丙沙星口服固体制剂，其特征在于，盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆的重量用量比为1：0.2-0.5:0.1-0.2:0.1-0.2。
3.根据权利要求1所述的盐酸环丙沙星口服固体制剂，其特征在于，所述的崩解剂为低取代羟丙基纤维素，润滑剂为微粉硅胶。
4.根据权利要求1所述的盐酸环丙沙星口服固体制剂，其特征在于，所述的口服固体制剂为片剂或胶囊。
5.根据权利要求1所述的盐酸环丙沙星口服固体制剂，其特征在于，制备工艺包括如下步骤：
(1)将盐酸环丙沙星、微晶纤维素、聚维酮、泊洛沙姆溶解在水中，喷雾干燥，得到含药颗粒；
(2)将步骤(1)的含药颗粒与崩解剂、润滑剂混合均匀，充填胶囊壳或压片。
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| US20080206329A1 (en) * | 2004-12-03 | 2008-08-28 | Sanjay Verma | Modified Release Ciprofloxacin Compositions |
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