CN104173304A - 林可霉素分散片 - Google Patents
林可霉素分散片 Download PDFInfo
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- CN104173304A CN104173304A CN201410427602.5A CN201410427602A CN104173304A CN 104173304 A CN104173304 A CN 104173304A CN 201410427602 A CN201410427602 A CN 201410427602A CN 104173304 A CN104173304 A CN 104173304A
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- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 title claims abstract description 80
- 229960005287 lincomycin Drugs 0.000 title claims abstract description 80
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Abstract
本申请涉及一种林可霉素包合物分散片，先将林可霉素制备成包合物，然后再制备成分散片。
Description
技术领域
本申请涉及一种分散片，具体地，是林可霉素包合物分散片。
背景技术
林可霉素，英文名Lincomycin。作用于敏感菌核糖体的50S亚基，阻止肽链的延长，从而抑制细菌细胞的蛋白质合成。化学名：6-(1-甲基-反-4-丙基-L-2-吡咯烷甲酰氨基)-1-硫代-6，8-二脱氧-D-赤式-α-D-半乳辛吡喃糖苷盐酸盐一水合物。林可霉素为白色结晶性粉末；有微臭或特殊臭；味苦。林可霉素在水或甲醇中易溶，在乙醇中略溶。林可霉素作用于敏感菌核糖体的50S亚基，阻止肽链的延长，从而抑制细菌细胞的蛋白质合成。林可霉素一般系抑菌剂，但在高浓度下，对高度敏感细菌也具有杀菌作用。
林可霉素口服可自胃肠道吸收，不为胃酸灭活，空腹口服仅20～30％被吸收，进食后服用则吸收更少。吸收后除脑脊液外，广泛及迅速分布于各体液和组织中，高浓度见于肾、胆汁和尿液。注射给药后在眼中可达有效浓度。可迅速经胎盘进入胎儿循环，在胎血中的浓度可达母血药浓度的25％。蛋白结合率为77～82％。林可霉素主要在肝中代谢，某些代谢物具有抗菌活性，儿童的代谢率较成人为高。T1/2为4～5.4小时。肾功能减退时，T1/2为10～13小时；肝功能减退时，T1/2则为9小时。血药浓度达峰值时间，口服为2～4小时，肌注0.5小时，静注后即刻。可经肾、胆道和肠道排泄，口服后40％以原形随粪便排出，也可分泌入乳汁中。林可霉素不为血或腹膜透析所清除，术后无需加用。
林可霉素临床主要用于敏感金葡菌等革兰阳性球菌和厌氧菌所致呼吸道感染、骨髓炎、关节及皮肤软组织感染、胆道感染、菌血症等。
分散片放入水中后可迅速崩解，形成分散均匀地混悬液，具有使用方便，生物利用度高的特点。分散片的制备方法、生产条件和生产工艺简单，服用方法方便，可以像普通片剂一样吞服，也可以分散到水中服用。
发明内容
本发明为了解决现有林可霉素制剂起效慢、生物利用度低的缺点，发明了林可霉素包合物分散片。
分散片相对于普通片剂，在崩解介质中崩解时限小于3分钟，崩解后的颗粒能够全部通过2号筛，与其他类型制剂相比，分散片具有溶出迅速，吸收快，生物利用度高，服用方便等优点。
包合物具有以下优点：掩盖不良臭味，降低刺激性；增加药物溶出度与生物利用度；提高药物稳定性。
本申请先将林可霉素制备成包合物，然后再制备成分散片，将包合与分散技术合二为一，发挥两方面的优点。
林可霉素包合物包括活性成分和包合材料，活性成分为林可霉素，包合材料为α-环糊精，β-环糊精，γ-环糊精、羟基β-环糊精，羟丙基β-环糊精的一种或几种。优选γ-环糊精。活性成分与包合材料的重量比例为2:3.7。
本发明还采用分散片特殊辅料，崩解迅速，起效快。
林可霉素包合物的制备方法包括：
(1)在水或含水乙醇介质中，按一定比例，将林可霉素与γ-环糊精反应，将所得溶液经微孔滤膜过滤至澄清，从混合物中分离出包合物；或
(2)以固体形式，将林可霉素与γ-环糊精反应；或
(3)林可霉素与γ-环糊精反应进行高能研磨。
实验证明，α-环糊精、β-环糊精，羟基β-环糊精，羟丙基β-环糊精制备得到的枸橼酸他莫昔芬包合物在崩解速度、稳定性、溶出度等方面效果远远次于γ-环糊精制备得到的包合物。
不同包合材料对枸橼酸他莫昔芬包合物的影响
| 包合材料 | 溶解速度(min) | 稳定性 | 包合率 |
| γ-环糊精 | 5 | 好 | 97％ |
| α-环糊精 | 11 | 一般 | 81％ |
| β-环糊精 | 14 | 一般 | 82％ |
| 羟基β-环糊精 | 12 | 一般 | 78％ |
| 羟丙基β-环糊精 | 12 | 一般 | 80％ |
试验方法参照2010版中国药典二部规定的方法。
将上述制备得到的林可霉素包合物制备成分散片，所述分散片包括按重量计，1-80％的崩解剂，1-80％的填充剂，0.1-10％的润滑剂，0.1-10％的助流剂，0.1-10％的香味剂，其余为林可霉素包合物。具体地，崩解剂为聚维酮和羧甲基纤维素钠的组合物，二者重量比例为2.7:4.1，填充剂为山梨醇、淀粉、微晶纤维素或者甘露醇，润滑剂为硬脂酸或硬脂酸镁，助流剂为微粉硅胶或滑石粉，香味剂为甜蜜素或阿斯巴甜。优选地，填充剂为微晶纤维素，润滑剂为硬脂酸镁，三者的重量比例为5:7:2，当采用此特定配比的辅料时能够显著提高分散片的制剂效果，提高崩解速度，增加制剂的稳定性。
本发明所述计量均为重量。
本发明提供了一种林可霉素分散片，其中活性成分为林可霉素。
本发明提供了一种林可霉素分散片，其中林可霉素为包合物。
本发明提供了一种林可霉素分散片，其中林可霉素包合物由林可霉素和γ-环糊精组成，二者重量比例为2:3.7。
本发明提供了一种林可霉素分散片，其处方(按重量计)为：
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为：
实施例1
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为(按重量计)：
制备方法：
1.按照下述方法制备林可霉素包合物：
(1)在水或含水乙醇介质中，按一定比例，将林可霉素与γ-环糊精反应，将所得溶液经微孔滤膜过滤至澄清，从混合物中分离出包合物；或
(2)以固体形式，将林可霉素与γ-环糊精反应；或
(3)林可霉素与γ-环糊精反应进行高能研磨。
2.将处方量的聚维酮，羧甲基纤维素钠，微晶纤维素，甜蜜素与林可霉素包合物按等量递加法混合均匀后，再加入硬脂酸镁，微粉硅胶，混匀，压片，得到林可霉素包合物分散片。
对比实施例1
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为(按重量计)：
制备方法同上
对比实施例2
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为(按重量计)：
制备方法同上
对比实施例3
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为(按重量计)：
制备方法同上
对比实施例4
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为(按重量计)：
制备方法同上。
对比实施例5
分散片的处方为(按重量计)：
制备方法同上。
对比实施例6
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为(按重量计)：
制备方法同上。
对比实施例7
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为(按重量计)：
制备方法同上。
对比实施例8
林可霉素包合物：林可霉素:α-环糊精为2:3.7
分散片的处方为(按重量计)：
制备方法同上
对比实施例9
林可霉素包合物：林可霉素:γ-环糊精为1:3
分散片的处方为(按重量计)：
制备方法同上
对比实施例1-9分别对实施例1中采用的辅料或用量进行了变化，汇总如下：
| 组别 | 变化内容 |
| 实施例1 | - |
| 对比实施例1 | 崩解剂聚维酮和羧甲基纤维素钠的重量比例为1:1 |
| 对比实施例2 | 崩解剂仅使用聚维酮，无羧甲基纤维素钠 |
| 对比实施例3 | 崩解剂仅使用羧甲基纤维素钠，无聚维酮 |
| 对比实施例4 | 各成分用量发生变化 |
| 对比实施例5 | 林可霉素不为包合物 |
| 对比实施例6 | 崩解剂为羧甲基淀粉钠 |
| 对比实施例7 | 填充剂由微晶纤维素变更为乳糖 |
| 对比实施例8 | 使用α-环糊精制备林可霉素包合物 |
| 对比实施例9 | 林可霉素:γ-环糊精为1:3 |
本发明以上实施例制备的林可霉素包合物分散片的分析测试结果：
(1)实施例1制备的林可霉素包合物分散片的重量差异小，片面光洁，硬度适中，口感好。对比实施例1-7制备的林可霉素分散片重量差异小，片面不平，硬度小，口感略差。
(2)将实施例1所述林可霉素和γ-环糊精在50％乙醇中充分研磨至形成均匀膏体，经真空干燥后得白色粉末，该粉末的水中溶解性能较未包合的林可霉素提高了17倍。
(3)分散均匀性实验结果显示：按照2010版中国药典二部规定的方法，取实施例1和对比实施例1-7各6片，置250ml烧杯中，加入约20℃的水100ml，振摇90秒，实施例1分散片1分钟内全部崩解并通过二号筛。比药典规定的3分钟时限缩短100％。对比实施例1-7分散片振摇2-3分钟后全部崩解并通过二号筛。
(4)溶出度试验结果显示：照溶出度测定法(中国药典2010版二部附录XC第二法)，以0.01mol/L盐酸溶液900ml作为溶出介质，转速为50转/分，依法操作，照紫外-可见分光光度法测定每片溶出量，结果为在40秒内实施例1分散片的溶出百分率在80-90％左右，在60秒内已基本全部溶出。对比实施例1-7分散片在2分钟后溶出百分率在80％左右，3-4分钟内基本全部溶出。结果见下表.
结果表明，本发明实施例1提供的林可霉素包合物分散片符合中国药典(2000版)关于分散片的规定，相对于选用其他辅料或用量的对比实施例1-9具有更好的分散效果。本发明请求保护的林可霉素分散片选用特定辅料和特定用量，无论是改变辅料品种还是改变各成分用量，都会显著降低分散效果。
Claims (4)
1.一种林可霉素分散片，其中活性成分为林可霉素。
2.如权利要求1所述的林可霉素分散片，其中林可霉素为包合物。
3.如权利要求1或2所述的林可霉素分散片，其中林可霉素包合物由林可霉素和γ-环糊精组成，二者重量比例为2:3.7。
4.一种林可霉素分散片，其处方(按重量计)为：
林可霉素包合物：林可霉素:γ-环糊精为2:3.7
分散片的处方为：
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| CN108606954A (zh) * | 2016-12-13 | 2018-10-02 | 河南后羿实业集团有限公司 | 一种盐酸林可霉素可溶性粉及其制备方法 |
| CN115160388A (zh) * | 2022-05-13 | 2022-10-11 | 河北圣雪大成唐山制药有限责任公司 | 一种林可霉素药物共晶及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108606954A (zh) * | 2016-12-13 | 2018-10-02 | 河南后羿实业集团有限公司 | 一种盐酸林可霉素可溶性粉及其制备方法 |
| CN115160388A (zh) * | 2022-05-13 | 2022-10-11 | 河北圣雪大成唐山制药有限责任公司 | 一种林可霉素药物共晶及其制备方法 |
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