CN106310286A - 一种甲苯磺酸妥舒沙星组合物 - Google Patents
一种甲苯磺酸妥舒沙星组合物 Download PDFInfo
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- CN106310286A CN106310286A CN201610694295.6A CN201610694295A CN106310286A CN 106310286 A CN106310286 A CN 106310286A CN 201610694295 A CN201610694295 A CN 201610694295A CN 106310286 A CN106310286 A CN 106310286A
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- tosufloxacin tosilate
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- WUWFMDMBOJLQIV-UHFFFAOYSA-N 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid Chemical compound C1C(N)CCN1C(C(=C1)F)=NC2=C1C(=O)C(C(O)=O)=CN2C1=CC=C(F)C=C1F WUWFMDMBOJLQIV-UHFFFAOYSA-N 0.000 title claims abstract description 94
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
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Abstract
本发明公开了一种甲苯磺酸妥舒沙星组合物,包括以下成分:甲苯磺酸妥舒沙星45‑60重量份、淀粉15‑25重量份、低取代羟丙基纤维素5‑15重量份、羧甲基淀粉钠5‑10重量份、羟丙甲基纤维素1‑5重量份、二氧化硅0.5‑1重量份、硬脂酸镁0.5‑1重量份,本发明的甲苯磺酸妥舒沙星组合物具有较好的稳定性,崩解时间短,溶出度高,本发明还利用制备的甲苯磺酸妥舒沙星晶体制得的甲苯磺酸妥舒沙星组合物比采用甲苯磺酸妥舒沙星粗品制备的组合物具有更好的效果,通过本发明的包衣片的制备方法,提高了甲苯磺酸妥舒沙星包衣片的溶出度。
Description
技术领域
本发明属于医药技术领域,具体的说,涉及一种甲苯磺酸妥舒沙星组合物。
背景技术
甲苯磺酸妥舒沙星,其化学名称为:7-[3-氨基-1-(吡咯烷基)]-1-(2,4-二氟苯基)-6-氟-1,4-二氢-4-氧-1,8-奈啶-3-羧酸对甲苯磺酸盐一水物,分子式为C26H23F3N4O6S·H2O,分子量为594.57,是喹诺酮类广谱抗菌药,为白色至淡黄色粉末,无臭、味微苦,有吸湿性,遇光色渐变深,其在氢氧化钠试液中微溶,在水或氯仿中几乎不溶,在二甲基甲酰胺或冰醋酸中易溶。
甲苯磺酸妥舒沙星作为一种喹诺酮类抗菌药,是由日本富山化学工业株氏会社研制开发,1990年最先在日本上市,据报道,甲苯磺酸妥舒沙星对革兰氏阳性菌、革兰氏阴性菌、厌氧菌支原体和衣原体等具有很强的杀菌能力,适用于治疗成年患者因妥舒沙星敏感菌引起的多个系统的感染症,如浅表性和深部皮肤感染、外伤或热伤及手术创伤等的继发感染、骨髓炎、关节炎、急性支气管炎、肺炎、肾盂肾炎、前列腺炎、尿道炎等。
Kohno对甲苯磺酸妥舒沙星在临床上的应用进行了调查和整理,调查中主要针对呼吸道感染的抗菌能力,有些病菌表现出对头孢类、碳青霉烯类等抗菌药的耐药性,甲苯磺酸妥舒沙星在将来的应用中将更加受到重视,甲苯磺酸妥舒沙星属于难溶性药物,在制备成普通片剂时具有水溶性差,药效产生慢,生物利用度低等缺点,限制了它的应用。
中国专利CN104523649A公开了一种小儿用甲苯磺酸妥舒沙星胶囊及其制备方法,所述小儿用甲苯磺酸妥舒沙星包括,甲苯磺酸妥舒沙星和制剂辅料,所述的制剂辅料是填充剂、崩解剂、表面活性剂、稀释剂、润滑剂、助流剂,该胶囊的制备方法复杂,不适合大规模生产,并且稳定性差,溶出度差,抗菌效果差。
鉴于以上原因,特提出本发明。
发明内容
本发明要解决的技术问题在于克服现有技术的不足,提供了一种甲苯磺酸妥舒沙星组合物,该组合物具有较好的稳定性,生物利用度高,崩解时间短。
本发明的第一目的提供了一种甲苯磺酸妥舒沙星组合物,包括以下成分:
本发明的甲苯磺酸妥舒沙星组合物中的崩解剂采用低取代羟丙基纤维素和羧甲基淀粉钠,由于低取代羟丙基纤维素具有很大的比表面积和孔隙率,有很好的吸水速度和吸水量,其吸水膨胀率在500%-700%(取代基占10%-15%时),崩解后的颗粒也较细小,有利于药物的溶出,羧甲基淀粉钠是一种白色无定型的粉末,吸水膨胀作用非常显著,吸水后可膨胀至原体积的300倍,价格低廉,本发明采用低取代羟丙基纤维素和羧甲基淀粉钠作为崩解剂,明显的增加了药物的溶出度,提高了生物利用度。
采用羟丙甲基纤维素作为粘合剂,具有较强的粘合能力,增加了片剂的可压性,采用硬脂酸镁为润滑剂,硬脂酸镁疏松细腻,有良好的黏着性,易与颗粒混匀,压片后片面光滑美观,应用最广,本发明控制硬脂酸镁的0.6-0.8重量份之间,制备的组合物具有更短的崩解时间,采用二氧化硅为助流剂,二氧化硅具有较大的表面积,可以降低粒子之间的摩擦力而能改善粉末的流动性,保证片重差异合格。
优选的,甲苯磺酸妥舒沙星组合物,包括以下成分:
本发明人经过大量的试验发现在各种药物组成在上述配比时具有较好的稳定性,溶出度和较短的崩解时间。
进一步的,所述的甲苯磺酸妥舒沙星为甲苯磺酸妥舒沙星晶体,结构式如式I所示,使用Cu-Kα射线测量得到的X-射线粉末衍射谱图如图1所示:
由于固体类药物存在多晶型现象,同种固体药物,其既可以无定型存在,也可以以不同的晶体结构形式的多晶型存在,同一种药物不同的晶型可能在溶解度、热稳定性等方面存在显著的差异,本发明甲苯磺酸妥舒沙星晶体的X-射线粉末衍射在2θ为10.13°、10.61°、13.21°、15.42°、15.81°、18.49°、21.84°、22.32°、23.04°、25.96°、26.42°、30.16°处显示有特征峰。
经试验表明,利用本发明制备的甲苯磺酸妥舒沙星晶体组成的甲苯磺酸妥舒沙星组合物具有更好的稳定性,崩解时间短,溶出度高。
本发明的第二目的提供了一种甲苯磺酸妥舒沙星晶体的制备方法,所述的制备方法包括如下步骤:
(1)在温度为40-80℃下,优选的,温度为45℃,将甲苯磺酸妥舒沙星粗品溶解于有机溶剂和水的混合溶液中,混合搅拌溶解均匀;
(2)向上述溶液中加入活性炭,脱碳过滤;
(3)降温,静置,结晶;
(4)待晶体完全析出后,洗涤、干燥,得到所述的甲苯磺酸妥舒沙星晶体。
进一步的,步骤(1)中甲苯磺酸妥舒沙星与有机溶剂和水的混合溶液的质量体积比为1:5g-15ml。
进一步的,所述的有机溶剂为体积分数为95%的乙醇,乙醇与水的体积比为10-1:1,优选的,体积比为1:1。
进一步的,所述的活性炭的质量分数为0.1-0.3%。
进一步的,步骤(3)中的降温为降至温度为28-32℃,静置时间为10-20小时。
进一步的,步骤(4)中的干燥温度为40-60℃。
进一步的,所述的组合物为片剂,优选包衣片。
进一步的,包衣片的包衣由如下成分组成:
本发明的包衣片的制备方法如下:
(1)粘合剂配制:取羟丙甲基纤维素用乙醇分散溶解;取聚乙二醇6000用纯化水分散,加入吐温80搅拌溶解;将羟丙甲基纤维素的乙醇溶液加入聚乙二醇6000水溶液中,加入热水,搅拌溶解冷却即可;
(2)制粒:按处方比例称量好甲苯磺酸妥舒沙星、淀粉、低取代羟丙基纤维素、羧甲基淀粉钠,一起投入湿法制粒机内,开启搅拌键混合,将配好的粘合剂溶液倒入混好的原辅料内,制成软材,继续搅拌,最后用制粒刀将软材制成颗粒;
(3)制粒好的颗粒转入沸腾干燥机干燥,将干燥后的颗粒过筛整粒;将全部整粒好的干燥颗粒与称量好的外加辅料羧甲基淀粉钠、二氧化硅硬脂酸镁全部投入到多向运动混合机内,开启混合键进行颗粒混合均匀;混合后的颗粒用旋转压片机压片;
(4)包衣液配制:按照处方比例取羟丙甲基纤维素用乙醇分散溶解,取聚乙二醇6000用纯化水分散,加入吐温80搅拌溶解;将羟丙甲基纤维素的乙醇溶液加入聚乙二醇6000水溶液中,加入邻苯二甲酸二乙酯、蓖麻油,热水,搅拌溶解冷却即可;
(5)包衣,内包用铝塑包装机包装,检验合格后,成品入库。
本发明包衣片中的崩解剂采用内外加法,即一部分崩解剂与主药混合共同制粒,另一部分崩解剂加入整粒后的干颗粒中,可以使片剂崩解既发生在颗粒内部又发生在颗粒之间,可以达到良好的崩解效果。
与现有技术相比,本发明的有益效果如下:本发明的甲苯磺酸妥舒沙星组合物具有较好的稳定性,崩解时间短,溶出度高,抗菌效果好,本发明还利用制备的甲苯磺酸妥舒沙星晶体制得的甲苯磺酸妥舒沙星组合物比采用甲苯磺酸妥舒沙星粗品制备的组合物具有更好的效果,通过本发明的包衣片的制备方法,提高了甲苯磺酸妥舒沙星包衣片的溶出度。
附图说明
图1本发明实施例1甲苯磺酸妥舒沙星晶体的X-射线粉末衍射图。
具体实施方式
实施例1
(1)在温度为40℃下,将甲苯磺酸妥舒沙星粗品溶解于体积分数为95%的乙醇与水的混合溶液中,混合搅拌溶解均匀,其中,乙醇与水的体积比为1:1,甲苯磺酸妥舒沙星与乙醇和水混合溶液的质量体积比为1g:10ml。
(2)向上述溶液中加入适量质量分数为0.2%活性炭,然后过滤;
(3)过滤后的溶液进行降温到30℃,静置15小时,结晶;
(4)待晶体完全析出后,洗涤,在50℃下干燥,得到所述的甲苯磺酸妥舒沙星晶体。
得到的甲苯磺酸妥舒沙星晶体使用Cu-Kα射线测量得到的X-射线粉末衍射谱图如图1所示,甲苯磺酸妥舒沙星晶体的X-射线粉末衍射在2θ为10.13°、10.61°、13.21°、15.42°、15.81°、18.49°、21.84°、22.32°、23.04°、25.96°、26.42°、30.16°处显示有特征峰。
实施例2
(1)在温度为45℃下,将甲苯磺酸妥舒沙星粗品溶解于体积分数为95%的乙醇与水的混合溶液中,混合搅拌溶解均匀,其中,乙醇与水的体积比为10:1,甲苯磺酸妥舒沙星与乙醇和水混合溶液的质量体积比为1g:5ml。
(2)向上述溶液中加入适量质量分数为0.1%活性炭,然后过滤;
(3)过滤后的溶液进行降温到28℃,静置10小时,结晶;
(4)待晶体完全析出后,洗涤,在40℃下干燥,得到所述的甲苯磺酸妥舒沙星晶体。
得到的甲苯磺酸妥舒沙星晶体使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1基本一致。
实施例3
(1)在温度为80℃下,将甲苯磺酸妥舒沙星粗品溶解于体积分数为95%的乙醇与水的混合溶液中,混合搅拌溶解均匀,其中,乙醇与水的体积比为5:1,甲苯磺酸妥舒沙星与乙醇和水混合溶液的质量体积比为1g:3ml。
(2)向上述溶液中加入适量质量分数为0.3%活性炭,然后过滤;
(3)过滤后的溶液进行降温到32℃,静置20小时,结晶;
(4)待晶体完全析出后,洗涤,在60℃下干燥,得到所述的甲苯磺酸妥舒沙星晶体。
得到的甲苯磺酸妥舒沙星晶体使用Cu-Kα射线测量得到的X-射线粉末衍射谱图与实施例1基本一致。
实施例4
甲苯磺酸妥舒沙星片剂的处方:
包衣处方:
甲苯磺酸妥舒沙星包衣片的制备方法:
(1)粘合剂配制:取羟丙甲基纤维素用乙醇分散溶解;取聚乙二醇6000用纯化水分散,加入吐温80搅拌溶解;将羟丙甲基纤维素的乙醇溶液加入聚乙二醇6000水溶液中,加入热水,搅拌溶解冷却即可;
(2)制粒:按处方比例称量好甲苯磺酸妥舒沙星、淀粉、低取代羟丙基纤维素、羧甲基淀粉钠,一起投入湿法制粒机内,开启搅拌键混合,将配好的粘合剂溶液倒入混好的原辅料内,制成软材,继续搅拌,最后用制粒刀将软材制成颗粒;
(3)制粒好的颗粒转入沸腾干燥机干燥,将干燥后的颗粒过筛整粒;将全部整粒好的干燥颗粒与称量好的外加辅料羧甲基淀粉钠、二氧化硅硬脂酸镁全部投入到多向运动混合机内,开启混合键进行颗粒混合均匀;混合后的颗粒用旋转压片机压片;
(4)包衣液配制:按照处方比例取羟丙甲基纤维素用乙醇分散溶解,取聚乙二醇6000用纯化水分散,加入吐温80搅拌溶解;将羟丙甲基纤维素的乙醇溶液加入聚乙二醇6000水溶液中,加入邻苯二甲酸二乙酯、蓖麻油,热水,搅拌溶解冷却即可;
(5)包衣,内包用铝塑包装机包装,检验合格后,成品入库。
实施例5
甲苯磺酸妥舒沙星片剂的处方:
包衣处方:
其中,甲苯磺酸妥舒沙星包衣片的制备方法同实施例4。
实施例6
甲苯磺酸妥舒沙星片剂的处方:
包衣处方:
其中,甲苯磺酸妥舒沙星包衣片的制备方法同实施例4。
实施例7
本实施例的甲苯磺酸妥舒沙星包衣片的处方和制备方法同实施例5,不同之处甲苯磺酸妥舒沙星为实施例1制备的甲苯磺酸妥舒沙星晶体。
实施例8
本实施例的甲苯磺酸妥舒沙星包衣片的处方和制备方法同实施例5,不同之处甲苯磺酸妥舒沙星为实施例2制备的甲苯磺酸妥舒沙星晶体。
试验例1溶出度试验
试验药1-5分别为实施例4-8制备的甲苯磺酸妥舒沙星包衣片;
对照药1:按照CN104523649A中实施例1制备的甲苯磺酸妥舒沙星胶囊;
按照溶出度测定方法(参照中国药典2005版二部附录XC第二法)分别测定试验药1-5和对照药1的溶出度,以1.0%十二烷基硫酸钠的磷酸盐缓冲液(pH值为2.0)500ml为溶剂,转速为每分钟75转,依法操作,经30分钟时,取溶液10ml,滤过,精密量取续滤液3ml至50ml量瓶中,用上述溶剂稀释至刻度,摇匀,照分光光度法(中国药典2005年版二部附录IVA),在270nm的波长处测定吸收度,另取甲苯磺酸妥舒沙星对照品适量,精密称定,溶解并稀释成相应浓度的溶液,同法测定吸收度,计算出每片的溶出量,试验结果见表1。
表1试验药和对照药的溶出度
样品 | 5分钟 | 10分钟 | 15分钟 | 30分钟 | 45分钟 |
试验药1 | 90.2 | 93.1 | 94.8 | 97.1 | 98.5 |
试验药2 | 90.6 | 93.9 | 95.1 | 97.4 | 98.7 |
试验药3 | 90.5 | 93.5 | 94.7 | 97.1 | 98.6 |
试验药4 | 92.3 | 95.6 | 96.9 | 98.1 | 99.2 |
试验药5 | 92.0 | 95.4 | 96.4 | 98.0 | 99.0 |
对照药1 | 88.5 | 91.2 | 91.6 | 93.3 | 95.6 |
从表1可以看出,本发明的甲苯磺酸妥舒沙星的包衣片具有更好的溶出度,提高了生物利用度,而且利用本发明制备的甲苯磺酸妥舒沙星晶体制备的包衣片比使用甲苯磺酸妥舒沙星原料药制备的溶出度要高,说明了甲苯磺酸妥舒沙星晶体制备的包衣片具有的效果更好,这是因为甲苯磺酸妥舒沙星晶体具有全新的分子排列结构,与原料药相比,晶格对甲苯磺酸妥舒沙星的分子束缚力减弱,从而甲苯磺酸妥舒沙星更容易从晶格中挣脱出来进入溶剂,溶出度更大。从试验药1-5和对照药1溶出度的数据可以看出,本发明的甲苯磺酸妥舒沙星包衣片比现有技术的溶出度好。
试验例2长期稳定性试验
试验药1:实施例5制备的甲苯磺酸妥舒沙星包衣片;
试验药2:实施例7制备的甲苯磺酸妥舒沙星包衣片;
对照药1:按照CN104523649A中实施例1制备的甲苯磺酸妥舒沙星胶囊;
根据中国药典二部标准(2005年版)测定加速试验,将测试样品放入温度为40±2℃,相对湿度为75%±5%的条件下放置6个月,分别在0、3、6月时取样测定,结果如表2所示:
表2长期稳定性试验结果
从表2可以看出,本发明的甲苯磺酸妥舒沙星包衣片具有更好的稳定性,长期存储杂质含量少,且利用本发明的甲苯磺酸妥舒沙星晶体制备的包衣片效果更好。
本发明人对其他实施例也进行了上述试验,试验结果基本一致,由于篇幅有限,不再一一列出。
试验例3抗菌试验
(1)试验药品
试验药1:实施例5制备的甲苯磺酸妥舒沙星包衣片;
试验药2:实施例7制备的甲苯磺酸妥舒沙星包衣片;
对照药1:按照CN104523649A中实施例1制备的甲苯磺酸妥舒沙星胶囊;
(2)试验菌株:肺炎链球菌、流感嗜血杆菌和革兰氏阳性菌。
(3)培养基:分别将相同数量的三组肺炎链球菌、流感嗜血杆菌和革兰氏阳性菌放在培养基中培养24小时,然后在三组中分别加入相同浓度的试验药和对照药。
(4)测定最低抑菌浓度(MIC)
经过测定试验药品和对照药品的MIC如表3所示:
表3最低抑菌浓度测定
从表3可以看出,试验药的最低抑菌浓度低于对照药,说明本发明的甲苯磺酸托书沙星包衣片的抑菌效果比对照药的效果好,并且利用甲苯磺酸妥舒沙星晶体制备的包衣片具有的抑菌效果更好。
本发明人还对其他实施例制备的甲苯磺酸妥舒沙星包衣片进行了上述的试验,其结果与此相似,由于篇幅有限,不一一列出。
上述实施例中的实施方案可以进一步组合或者替换,且实施例仅仅是对本发明的优选实施例进行描述,并非对本发明的构思和范围进行限定,在不脱离本发明设计思想的前提下,本领域中专业技术人员对本发明的技术方案作出的各种变化和改进,均属于本发明的保护范围。
Claims (10)
1.一种甲苯磺酸妥舒沙星组合物,其特征在于,包括以下成分:
2.根据权利要求1所述的甲苯磺酸妥舒沙星组合物,其特征在于,所述的甲苯磺酸妥舒沙星为甲苯磺酸妥舒沙星晶体,结构式如式I所示,使用Cu-Kα射线测量得到的X-射线粉末衍射谱图如图1所示:
3.一种权利要求2所述的甲苯磺酸妥舒沙星晶体的制备方法,其特征在于,所述的制备方法包括如下步骤:
(1)在温度为40-80℃下,优选的,温度为45℃,将甲苯磺酸妥舒沙星粗品溶解于有机溶剂和水的混合溶液中,混合搅拌溶解均匀;
(2)向上述溶液中加入活性炭,脱碳过滤;
(3)降温,静置,结晶;
(4)待晶体完全析出后,洗涤、干燥,得到所述的甲苯磺酸妥舒沙星晶体。
4.根据权利要求3所述的制备方法,其特征在于,步骤(1)中甲苯磺酸妥舒沙星与有机溶剂和水的混合溶液的质量体积比为1:5g-15ml。
5.根据权利要求3所述的制备方法,其特征在于,所述的有机溶剂为体积分数为95%的乙醇,乙醇与水的体积比为10-1:1,优选的,体积比为1:1。
6.根据权利要求3所述的制备方法,其特征在于,所述的活性炭的质量分数为0.1-0.3%。
7.根据权利要求3所述的制备方法,其特征在于,步骤(3)中的降温为降至温度为28-32℃,静置时间为10-20小时。
8.根据权利要求3所述的制备方法,其特征在于,步骤(4)中的干燥温度为40-60℃。
9.根据权利要求1或2所述的甲苯磺酸妥舒沙星组合物,其特征在于,所述的组合物为片剂,优选包衣片。
10.根据权利要求9所述的甲苯磺酸妥舒沙星组合物,其特征在于,包衣片的包衣由如下成分组成:
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