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CN1261287A - 含有伏利康唑的药物制剂 - Google Patents

含有伏利康唑的药物制剂 Download PDF

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CN1261287A
CN1261287A CN98806446A CN98806446A CN1261287A CN 1261287 A CN1261287 A CN 1261287A CN 98806446 A CN98806446 A CN 98806446A CN 98806446 A CN98806446 A CN 98806446A CN 1261287 A CN1261287 A CN 1261287A
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voriconazole
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cyclodextrin
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V·D·哈丁
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    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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Abstract

本发明提供一种含有伏利康唑或其可药用衍生物和式Ⅰ所示环糊精或其可药用盐的药物制剂;其中,R1a－g、R2a－g和R3a－g独立地代表OH或O(CH2)4SO3H。

Description

含有伏利康唑的药物制剂
本发明涉及一种新的含有伏利康唑(voriconazole)和磺基丁基醚β-环糊精的药物制剂。
伏利康唑已被公开在欧洲专利申请0440372(参见实施例7)中。其结构式如下所示：并且可有效治疗真菌感染。在水中伏利康唑的溶解度较低(0.2mg/ml，pH3)并且不稳定(由水解逆羟醛产物重组为一种不活泼的对映体)。因此，难以开发出一种具有储存期足够长的静脉内含水制剂。这些问题对于半极性的化合物(log D＝1.8)尤其严重，这意味着一般无法通过常规方式如油、表面活性剂或水可混溶助溶剂将化合物溶解。
欧洲专利申请0440372提出，可以用环糊精来配制公开的化合物：然而，现在人们怀疑未衍生或未代谢的环糊精对机体有毒性作用，因而不适于作为药物赋形剂，尤其是在非肠道给药时。
国际专利申请WO 91/11172公开了式A所示的磺烷基醚环糊精衍
Figure A9880644600032
其中n为4、5或6；R1-9独立地代表O-或O-(C2-6亚烷基)-SO-，条件是R1和R2中至少一个为O-(C2-6亚烷基)-SO-；和S1-2独立地代表药学上可接受的阳离子(如H+或Na+)。
迄今已发现，利用国际专利申请WO 91/11172公开的磺烷基醚环糊精衍生物，优选n为5(一种β环糊精衍生物)并且环糊精的环被磺丁基取代的衍生物进行分子包囊可提高伏利康唑在水中的溶解度。
所以，本发明提供一种含有伏利康唑或其可药用衍生物和式I所示环糊精衍生物或其可药用盐的药物制剂：其中R1a-g、R2a-g和R3a-g独立地代表OH或O(CH2)4SO3H；条件是至少一个R1a-g代表O(CH2)4SO3H；
特别令人感兴趣的可药用盐是O(CH2)4SO3H的盐，例如其碱金属盐，如钠盐。
每个式I分子的O(CH2)4SO3H平均数优选为6.1-6.9，例如6.5。这样可增强分子包囊作用，从而提高伏利康唑的溶解度。这种作用是无法预测的，因为增加取代程度使环糊精空腔周围的位阻加大，从而降低了复合的效率。
优选每个O(CH2)4SO3H以碱金属盐(如钠盐)的形式存在。这样可以提高环糊精分子对伏利康唑的亲和力，对于不带电的vorico-nazole来说这是意料外的。
所述制剂适宜经非肠道给药，例如静脉内给药。
利用冷冻干燥(冻干)可以进一步提高伏利康唑-环糊精衍生物复合物在水中的稳定性。适用于本发明所述制剂的环糊精衍生物可确保最终的冻干产物含有高水平水分(高达3.0％)但对其稳定性无不利影响。此外，利用上述环糊精衍生物控制并且减少伏利康唑形成不活泼对映体。
通常，在本发明所述的静脉内和肌肉内含水制剂中，伏利康唑的浓度为5mg/ml-50mg/ml，例如10mg/ml-30mg/ml。式I的环糊精衍生物将以1∶1-1∶10的伏利康唑∶环糊精衍生物摩尔比存在，例如1∶2-1∶7，优选1∶2-1∶3。该制剂在使用前冷冻干燥(冻干)储存，并且在需要时加入水。
在下列实施例中，磺丁基醚β-环糊精中，每个环糊精分子的平均磺丁基醚取代度为6.5，并且各磺丁基醚单位以其钠盐存在。实施例1伏利康唑的静脉内给药制剂组分                           规格                    mg/ml伏利康唑                       辉瑞                    10.000磺丁基醚β-环糊精              辉瑞                    160.000注射用水                       欧洲药典                至1.000ml
                           总量                    1.000ml方法
1.在连续搅拌下，将磺丁基醚β环糊精(SBECD)加入到占终体积80％的注射用水中，并且继续搅拌直至SBECD溶解。
2.加入伏利康唑并且搅拌溶解。
3.用注射用水使溶液达到所需体积。
4.所得溶液经灭菌的0.2mm尼龙滤膜过滤到无菌容器内。
5.将20ml的溶液灌装到无菌冻干瓶中并且封口，冷冻干燥。

Claims (7)

1.一种含有伏利康唑(voriconazole)或其可药用衍生物和式I所示环糊精衍生物或其可药用盐的药物制剂：
Figure A9880644600021
R1a-g、R2a-g和R3a-g独立地代表OH或O(CH2)4SO3H；
条件是至少一个R1a-g代表O(CH2)4SO3H。
2.权利要求1所述的制剂，其中每个式I分子中的O(CH2)4SO3H平均数为6.1-6.9。
3.权利要求1或2所述的制剂，其中各O(CH2)4SO3H以碱金属盐的形式存在。
4.上述权利要求任一项所述的制剂，该制剂适于非肠道给药。
5.上述权利要求任一项所述的制剂，其中式I的环糊精衍生物以1∶1-1∶10的伏利康唑∶环糊精衍生物摩尔比存在。
6.上述权利要求任一项所述的制剂，该制剂为水溶液。
7.权利要求1-5任一项所述的制剂，其中该制剂经冷冻干燥。
CN98806446A 1997-06-21 1998-06-02 含有伏利康唑的药物制剂 Expired - Lifetime CN1125653C (zh)

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CN101390825B (zh) * 2008-10-01 2010-12-29 山东省眼科研究所 一种伏立康唑眼内释药系统
CN102058519A (zh) * 2010-11-19 2011-05-18 苏州特瑞药业有限公司 一种伏立康唑缓释栓剂及其制备方法
CN103690968A (zh) * 2013-11-21 2014-04-02 石药集团中奇制药技术（石家庄）有限公司 一种伏立康唑组合物及其制备方法
WO2018149359A1 (zh) * 2017-02-17 2018-08-23 武汉朗来科技发展有限公司 三氮唑抗菌衍生物、其药物组合物和用途
CN108778338A (zh) * 2016-01-28 2018-11-09 好利安科技有限公司 活性药物成分的连续络合
CN116570558A (zh) * 2023-06-21 2023-08-11 广州仁恒医药科技股份有限公司 一种伏立康唑眼用纳米缓释组合物及其制备方法和应用

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CN1919846B (zh) * 2006-09-14 2013-01-02 大道隆达（北京）医药科技发展有限公司 伏立康唑及其药用盐、中间体的一种新定向合成制备方法
CN1919846A (zh) * 2006-09-14 2007-02-28 北京博尔达生物技术开发有限公司 伏立康唑及其药用盐、中间体的一种新定向合成制备方法
CN101390825B (zh) * 2008-10-01 2010-12-29 山东省眼科研究所 一种伏立康唑眼内释药系统
CN102058519A (zh) * 2010-11-19 2011-05-18 苏州特瑞药业有限公司 一种伏立康唑缓释栓剂及其制备方法
CN102058519B (zh) * 2010-11-19 2013-01-02 苏州特瑞药业有限公司 一种伏立康唑缓释栓剂及其制备方法
CN103690968A (zh) * 2013-11-21 2014-04-02 石药集团中奇制药技术（石家庄）有限公司 一种伏立康唑组合物及其制备方法
CN108778338A (zh) * 2016-01-28 2018-11-09 好利安科技有限公司 活性药物成分的连续络合
CN108778338B (zh) * 2016-01-28 2022-04-01 好利安科技有限公司 活性药物成分的连续络合
WO2018149359A1 (zh) * 2017-02-17 2018-08-23 武汉朗来科技发展有限公司 三氮唑抗菌衍生物、其药物组合物和用途
CN108456194B (zh) * 2017-02-17 2021-06-22 武汉朗来科技发展有限公司 三氮唑抗菌衍生物、其药物组合物和用途
US11040958B2 (en) 2017-02-17 2021-06-22 Wuhan Ll Science And Technology Development Co., Ltd. Triazole antimicrobial derivative, pharmaceutical composition and use thereof
CN108456194A (zh) * 2017-02-17 2018-08-28 武汉朗来科技发展有限公司 三氮唑抗菌衍生物、其药物组合物和用途
CN116570558A (zh) * 2023-06-21 2023-08-11 广州仁恒医药科技股份有限公司 一种伏立康唑眼用纳米缓释组合物及其制备方法和应用
CN116570558B (zh) * 2023-06-21 2023-12-26 广州仁恒医药科技股份有限公司 一种伏立康唑眼用纳米缓释组合物及其制备方法和应用

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