CN1524003A - 包含白介素-2抑制剂和抗菌剂的局部给药组合物 - Google Patents
包含白介素-2抑制剂和抗菌剂的局部给药组合物 Download PDFInfo
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- CN1524003A CN1524003A CNA028135768A CN02813576A CN1524003A CN 1524003 A CN1524003 A CN 1524003A CN A028135768 A CNA028135768 A CN A028135768A CN 02813576 A CN02813576 A CN 02813576A CN 1524003 A CN1524003 A CN 1524003A
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- hydrogen atom
- alkyl
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- inhibitor
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Abstract
本发明提供一种用于局部给药的组合物，其包含白介素2抑制剂和抗菌剂作为其有效成分，其中所述白介素2抑制剂包含如通式(I)所示的三环化合物或其药用盐。本发明另外提供用于治疗炎症和/或感染的方法，其包含对需要炎症和/或感染治疗的受试者局部给药有效量的白介素2抑制剂和抗菌剂。
Description
技术领域
本发明涉及用于局部给药的组合物，其包含白介素2抑制剂和抗菌剂作为其有效成分。更具体地，本发明涉及用于局部给药的组合物，其包含白介素2抑制剂和抗菌剂作为其治疗炎症和/或感染的有效成分。
背景技术
白介素2抑制剂是具有白介素2抑制活性的物质。已知为该物质的实例有白介素2生产抑制物质和白介素2信号转导抑制物质。白介素2对于激活T细胞增殖是必需的。白介素2抑制剂在T细胞的激活机制中显示免疫抑制作用。
近年来，已经尝试将白介素2用于各种炎症或或疾病伴发炎症的治疗。例如，已知大环内酯化合物如FK506和环孢菌素对于变应性结膜炎，过敏性皮炎和过敏性鼻炎是有效的(美国专利号5,514,686，5,385,907等)。此前，本发明人已经报道包含大环内酯化合物如FK506的白介素2抑制剂对于干眼病的治疗(WO00/66122)和眼部炎病的局部眼科治疗(美国临时申请号60/283,169，现在PCT/JP02/03664)有效。
然而，在使用白介素2抑制剂的各种炎症的治疗中，由白介素2抑制剂导致的免疫抑制作用可导致像感染那样的副作用。因此，希望开发减小该副作用而对白介素2抑制剂的主效应(main effect)无不利影响的抗炎剂。
同时，已经将抗菌剂用于眼部或皮肤感染和手术后感染的抑制。在治疗该感染中，抑制微生物在病理改变部位的增殖和扩散是非常重要的。同样，抑制伴发炎症或防御作用后的过度免疫-炎性反应是非常重要的。为了满足该要求，主要将甾体化合物药物用作附加抗炎剂。然而，使用甾体化合物药物有导致像微生物在病理改变部位的感染加重；皮肤变薄和毛囊皮脂腺异常激活；气管或鼻腔中血管壁变弱；和眼中甾体青光眼那样的副作用的危险。因此，希望开发安全和有效的用于治疗感染和它们的伴生炎症，或者在防御作用后的过度免疫-炎性反应的抗菌剂。
发明内容
本发明人已经进行深入的研究，并发现在炎症和/或感染的局部治疗中，组合的白介素2(以下，可以简称为IL-2)抑制剂和抗菌剂能抑制炎症和/或感染而对每种试剂的主效无不利影响，由此完成了本发明。
因此，本发明提供下列各项。
(1)用于局部给药的组合物，其包含白介素2抑制剂和抗菌剂作为其有效成分。
(2)(1)中的组合物，其中所述白介素2抑制剂是大环内酯化合物或环孢菌素。
(3)(2)中的组合物，其中所述大环内酯化合物是如以下通式(I)所示的三环化合物或其药用盐。
其中相邻的一对R1和R2，R3和R4，以及R5和R6各自独立地
a)表示两个相邻的氢原子，其中R2任选为烷基，或
b)任选在与所述对的成员相连的碳原子之间形成另一个键；
R7为氢原子，羟基，烷氧基或保护的羟基，或者可以与R1形成氧代；
R8和R9分别独立表示氢原子或羟基；
R10是氢原子，烷基，链烯基，被一个或多个羟基取代的烷基，被一个或多个羟基取代的链烯基或被氧取代的烷基；
X为氧，(氢原子，羟基)，(氢原子，氢原子)，或式-CH2O-的基团；
Y为氧，(氢原子，羟基)，(氢原子，氢原子)，或式N-NR11R12或N-OR13的基团；
R11和R12分别独立为氢原子，烷基，芳基或甲苯磺酰基；
R13、R14、R15、R16、R17、R18、R19、R22和R23分别独立为氢原子或烷基；
R24为含有一个或多个杂原子的任选取代的环；和
n为1或2。
除了上述定义，Y、R10和R23可以与它们相连的碳原子一起形成含有氮原子、硫原子和/或氧原子的饱和或不饱和5或6-元杂环基，其中杂环基可以被一个或多个选自烷基、羟基、烷氧基、苄基、式-CH2Se(C6H5)的基团和被一个或多个羟基取代的烷基的基团取代。
(4)(3)中的组合物，其中所述三环化合物是FK506。
(5)(1)至(4)中任何一项的组合物，其中所述抗菌剂是喹诺酮抗菌剂。
(6)(5)中的组合物，其中所述喹诺酮抗菌剂是萘啶酸，吡哌酸，吡咯米酸，诺氟沙星，氧氟沙星，左氧氟沙星，环丙沙星，洛美沙星，托氟沙星，氟罗沙星，司帕沙星，恩氟沙星和依诺沙星或其混合物。
(7)(6)中的组合物，其中所述喹诺酮抗菌剂是氧氟沙星。
(8)用于治疗炎症和/或感染的方法，其包含对需要炎症和/或感染治疗的受试者局部给药有效量的干扰素2抑制剂和有效量的抗菌剂。
(9)白介素2抑制剂和抗菌剂在制备用于治疗炎症和/或感染的局部给药的组合物中的用途。
(10)(9)的用途，其中所述白介素2抑制剂是大环内酯化合物或环孢菌素。
(11)(10)的用途，其中所述大环内酯化合物是如通式(I)所示的三环化合物或其药用盐。
(12)(11)的用途，其中所述三环化合物是FK506。
(13)(9)至(12)中任何一项的用途，其中所述抗菌剂是喹诺酮抗菌剂。
(14)(13)的用途，其中所述喹诺酮抗菌剂是萘啶酸，吡哌酸，吡咯米酸，诺氟沙星，氧氟沙星，左氧氟沙星，环丙沙星，洛美沙星，托氟沙星，氟罗沙星，司帕沙星，恩氟沙星和依诺沙星或其混合物。
(15)(14)的用途，其中所述喹诺酮抗菌剂是氧氟沙星。
发明详述
本发明涉及用于局部给药的组合物，其包含白介素2抑制剂和抗菌剂作为其有效成分。
本发明另外涉及用于治疗炎症和/或感染的方法，其包含对需要炎症和/或感染治疗的受试者局部给药有效量的干扰素2抑制剂和有效量的抗菌剂。
此外，本发明涉及白介素2抑制剂和抗菌剂在制备用于治疗炎症和/或感染的局部给药的组合物中的用途。
不应该具体限制本发明的里-2抑制剂，只要它们具有IL-2抑制活性。该试剂的具体实例是IL-2生产抑制物质。该试剂的另一个具体实例是IL-2信号转导抑制物质。上述的优选具体实例是大环内酯化合物(例如FK506，子囊霉素衍生物和雷帕霉素衍生物)和环孢菌素。可以单独使用或者使用两种或多种IL-2抑制剂的组合。
本发明包含其中IL-2抑制剂和抗菌剂被包含在单一药物制剂中的实施方案和其中它们分别形成药物制剂且同时局部给药的实施方案，后者被称为组合使用。
大环内酯化合物的具体实例是如以下通式(I)所示的三环化合物或其药物可接受的盐。
其中相邻的一对R1和R2，R3和R4，以及R5和R6各自独立地
a)组成为两个相邻的氢原子，其中R2任选为烷基，或
b)任选在与所述对的成员相连的碳原子之间形成另一个键；
R7为氢原子，羟基，烷氧基或保护的羟基，或者可以与R1形成氧代；
R8和R9分别独立表示氢原子或羟基；
R10是氢原子，烷基，链烯基，被一个或多个羟基取代的烷基，被一个或多个羟基取代的链烯基或被氧取代的烷基；
X为氧，(氢原子，羟基)，(氢原子，氢原子)，或式-CH2O-的基团；
Y为氧，(氢原子，羟基)，(氢原子，氢原子)，或式N-NR11R12或N-OR13的基团；
R11和R12分别独立为氢原子，烷基，芳基或甲苯磺酰基；
R13、R14、R15、R16、R17、R18、R19、R22和R23分别独立为氢原子或烷基；
R24为含有一个或多个杂原子的任选取代的环；和
n为1或2。
除了上述定义，Y、R10和R23可以与它们相连的碳原子一起形成含有氮原子、硫原子和/或氧原子的饱和或不饱和5或6-元杂环基，其中杂环基可以被一个或多个选自烷基、羟基、烷氧基、苄基、式-CH2Se(C6H5)的基团和被一个或多个羟基取代的烷基的基团取代，或它的药物可接受盐。
在通式(I)中，优选的R24是，例如任选具有适当取代基的环(C5-C7)烷基，如下列各项。
(a)3，4-二氧环己基，
(b)3-R20-4-R21-环己基，
其中R20是羟基，烷氧基或-OCH2OCH2CH2OCH3，并且R21是羟基，-OCN，烷氧基，具有适当取代基的杂芳氧基，-OCH2OCH2CH2OCH3，保护的羟基，氯，溴，碘，氨基草酰氧基，叠氮化物，对甲苯氧基硫基羰基氧基或R25R26CHCOO-(其中R25是任选地在期望处被保护的羟基，或保护的氨基，R26是氢原子或甲基，或者R20和R21结合形成环氧化物环的氧原子)；或者
(c)被甲氧基甲基、任选地在期望处被保护的羟基甲基、酰氧基甲基(其中酰基部分为如果需要任选被季铵化的二甲基氨基，或任选酯化了的羧基)、一个或多个任选保护的氨基和/或羟基、或氨基草酰氧甲基取代的环戊基，优选的例子包括2-甲酰-环戊基。
下面详细描述式(I)中使用的每个符号的定义、它们具体的例子和它们的优选实施方案。
除非另有说明，“低级”指具有1-6个碳原子的基团。
“烷基”和“烷氧基”中烷基部分的优选例子包括直链或支链脂肪族烃基残基，如低级烷基(例如甲基，乙基，丙基，异丙基，丁基，异丁基，戊基，新戊基，己基等)。
“链烯基”的优选例子包括具有一个双键的直链或支链脂肪族烃基残基，如低级链烯基(例如乙烯基，丙烯基(例如烯丙基等)，丁烯基，甲基丙烯基，戊烯基，己烯基等)。
“芳基”的优选例子包括苯基，甲苯基，二甲苯基，异丙苯基，2，4，6-三甲苯基，萘基等。
“保护的羟基”和“保护的氨基”的保护基团的优选例子包括1-(低级烷硫基)(低级)烷基，如低级烷硫基甲基(例如甲硫基甲基，乙硫基甲基，丙硫基甲基，异丙硫基甲基，丁硫基甲基，异丁硫基甲基，己硫基甲基等)，更优选C1-C4烷硫基甲基，最优选甲硫基甲基；
三取代的甲硅烷基，如三(低级)烷基甲硅烷基(例如三甲基甲硅烷基，三乙基甲硅烷基，三丁基甲硅烷基，叔丁基二甲基甲硅烷基，三叔丁基甲硅烷基等)，和低级烷基二芳基甲硅烷基(例如，甲基二苯基甲硅烷基，乙基二苯基甲硅烷基，丙基二苯基甲硅烷基，叔丁基二苯基甲硅烷基等)，更优选三(C1-C4)烷基甲硅烷基和(C1-C4)烷基二苯基甲硅烷基，最优选叔丁基二甲基甲硅烷基，叔丁基二苯基甲硅烷基；
酰基，如衍生于羧酸、磺酸、和氨基甲酸的脂肪族酰基、芳香族酰基和被芳香族基团取代的脂肪族酰基等。
脂肪族酰基的例子是任选具有一个或多个合适取代基(例如羧基)的低级烷酰基，如甲酰基，乙酰基，丙酰基，丁酰基，异丁酰基，戊酰基，异戊酰基，新戊酰基，己酰基，羧基乙酰基，羧基丙酰基，羧基丁酰基，羧基己酰基，等等；
任选具有一个或多个适当取代基(例如低级烷基)的环(低级)烷氧基(低级)烷酰基，如环丙氧基乙酰基，环丁氧基丙酰基，环庚氧基丁酰基，mentyl氧基乙酰基，mentyl氧基丙酰基，mentyl氧基丁酰基，mentyl氧基戊酰基，mentyl氧基己酰基等；
樟脑磺酰基；
具有一个或多个适当取代基如羧基或保护的羧基等的烷基氨基甲酰基，如羧基(低级)烷基氨基甲酰基(例如羧基甲基氨基甲酰基，羧基乙基氨基甲酰基，羧基丙基氨基甲酰基，羧基丁基氨基甲酰基，羧基戊基氨基甲酰基，羧基己基氨基甲酰基)和三(低级)烷基甲硅烷基(低级)烷氧基羰基(低级)烷基氨基甲酰基(例如三甲基甲硅烷基甲氧基羰基乙基氨基甲酰，三甲基甲硅烷基乙氧基羰基丙基氨基甲酰基，三乙基甲硅烷基乙氧基羰基丙基氨基甲酰基，叔丁基二甲基甲硅烷基乙氧基羰基丙基氨基甲酰基，三甲基甲硅烷基丙氧基羰基丁基氨基甲酰基)。
芳香族酰基的例子是任选具有一个或多个合适取代基(例如硝基)的芳酰基，如苯甲酰基，甲苯酰基，二甲苯酰基，萘甲酰基，硝基苯甲酰基，二硝基苯甲酰基，硝基萘甲酰基等；和任选具有一个或多个合适取代基(例如卤素)的芳香烃磺酰基，如苯磺酰基，甲苯磺酰基，二甲苯磺酰基，萘磺酰基，氟代苯磺酰基，氯代苯磺酰基，溴代苯磺酰基，碘代苯磺酰基，等等。
被芳香族基团取代的脂肪族酰基例如可以是任选具有一个或多个合适取代基(例如低级烷氧基，或三卤代(低级)烷基等)的芳代(低级)烷酰基，其中具体的例子为苯乙酰基，苯丙酰基，苯丁酰基，2-三氟甲基-2-甲氧基-2-苯乙酰基，2-乙基-2-三氟甲基-2-苯乙酰基，2-三氟甲基-2-丙氧基-2-苯乙酰基，等等。
在上述提到的酰基中，更优选的酰基包括任选具有羧基的C1-C4烷酰基，在环烷基部分具有两个(C1-C4)烷基的环(C5-C6)烷氧基(C1-C4)烷酰基，樟脑磺酰基，羧基(C1-C4)烷基氨甲酰基，三(C1-C4)烷基甲硅烷基(C1-C4)烷氧基羰基(C1-C4)烷基氨甲酰基，任选具有1或2个硝基基团的苯甲酰基，具有卤素的苯磺酰基，和具有C1-C4烷氧基和三卤素(C1-C4)烷基的苯基(C1-C4)烷酰基。在它们当中，最优选乙酰基，羧基丙酰基，mentyl氧基乙酰基，樟脑磺酰基，苯甲酰基，硝基苯甲酰基，二硝基苯甲酰基，碘代苯磺酰基，2-三氟甲基-2-甲氧基-2-苯乙酰基，等等。
“组成为含有氮原子、硫原子和/或氧原子的饱和或不饱和5或6-元环的杂环”的优选例子为吡咯基(pyrolyl)，四氢呋喃等。
“任选具有适当取代基的杂芳氧基”的“任选具有适当取代基的杂芳基”部分的例子是EP-A-532,088的式I化合物的R1，优选为1-羟基乙基吲哚-5-基。本文引用该发明公开作为参考。
用于本发明的三环化合物(I)在出版物EP-A-184162，EP-A-323042，EP-A-423714，EP-A-427680，EP-A-465426，EP-A-480623，EP-A-532088，EP-A-532089，EP-A-569337，EP-A-626385，WO89/05303，WO93/05058，WO96/31514，WO91/13889，WO91/19495，WO93/5059等中描述。在此引用这些公开出版物作为参考。
具体地，被称为FR900506(＝FK506)、FR900520(子囊霉素)，FR900523和FR900525的化合物通过链霉菌属制备，如Streptomyces tsukubaensisNo.9993(保藏于国家高等工业科学与技术研究所，国际专利组织储藏所，中心6，1-1，Higashi 1-chome，Tsukuba-shi，Ibaraki-ken，日本(原名国际商业和工业部工业科学与技术代办处发酵研究所)，保藏日：1984年10月5日，保藏号FERM BP-927)或者吸水链霉菌Yakushimaensis亚种，No.7238(保藏于国家高等工业科学和技术研究所，国际专利组织储藏所，中心6，1-1，Higashi 1-chome，Tsukuba-shi，Ibaraki-ken，日本(原名国际商业和工业部工业科学与技术代办处发酵研究所)，保藏日：1985年1月12日，保藏号FERM BP-928(EP-A-0184162))，下式的化合物FK506(通用名藤霉素)是有代表性的化合物。
化学名：17-烯丙基-1，14-二羟基-12-[2-(4-羟基-3-甲氧基环己基)-1-甲基乙烯基]-23，25-二甲氧基-13，19，21，27-四甲基-11，28-二氧杂-4-氮杂三环[22.3.1.04，9]二十八碳-18-烯-2，3，10，16-四酮
在这些三环化合物中，最优选的化合物是其中相邻的一对R3和R4、R5和R6分别独立任选在与所述对的成员相连的碳原子之间形成另一个键；
R8和R23分别独立为氢原子；
R9为羟基；
R10为甲基，乙基，丙基或烯丙基；
X为(氢原子，氢原子)或氧；
Y为氧；
R14、R15、R16、R17、R18、R19、和R22分别独立为甲基；
R24为3-R20-4-R21-环己基，其中R20为羟基，烷氧基，或-OCH2OCH2CH2OCH3，和R21为羟基，-OCN，烷氧基，任选具有适当取代基的杂芳氧基，-OCH2OCH2CH2OCH3，保护的羟基，氯，溴，碘，氨基草酰氧基，叠氮化物，对甲苯氧基硫基羰基氧基，或R25R26CHCOO-(其中R25是当需要时任选被保护的羟基，或保护的氨基，R26为氢原子或甲基)，或者R20和R21一起形成环氧化物环的氧原子，和
n为1或2；
特别优选的三环化合物(I)除了FK506还包括子囊霉素衍生物，如EP-A-427,680中实施例66a中描述的33-表-氯-33-脱氧子囊霉素的卤化衍生物等。
其它优选的IL-2抑制剂(大环内酯化合物)包括在MERCK INDEX，12版，No.8288中描述的雷帕霉素及其衍生物。其优选实施例包括在WO95/16691的第一页，式A描述的O-取代衍生物，其中第40个羟基是-OR1(其中R1是羟烷基，羟基烷氧基烷基(hydroalkyloxyalkyl)，酰氨基烷基和氨烷基)，如40-O-(2-羟基)乙基雷帕霉素，40-O-(3-羟基)丙基雷帕霉素，40-O-[2-(2-羟基)乙氧基]乙基雷帕霉素和40-O-(2-乙酰氨基乙基)-雷帕霉素。通过在适当的条件下雷帕霉素(或者二氢或脱氧雷帕霉素)和与离去基团(例如RX，其中R是作为O-取代基的理想有机基，如烷基，烯丙基和苄基部分，并且X是离去基团如CCl3C(NH)O和CF3SO3)结合的有机基反应可以生产这些O-取代衍生物。条件可以是：当X是CCl3C(NH)O时，酸性或中性条件，如在三氟甲磺酸，樟脑磺酸，对甲苯磺酸或它们相应的吡啶鎓或取代的吡啶鎓盐的存在下，当X是CF3SO3时，在碱如吡啶，取代吡啶，二异丙基乙胺和五甲基哌啶的存在下。最优选的雷帕霉素衍生物是在WO94/09010中公开的40-O-(2-羟基)乙基雷帕霉素，其在此引入本说明书作为参考。
三环化合物(I)，雷帕霉素和其衍生物的药物可接受的盐是非毒性的药物可接受的常规盐，例如与无机或有机碱形成的盐，如碱金属盐(例如钠盐、钾盐等)，碱土金属盐(例如钙盐、镁盐等)，铵盐和胺盐(例如三乙基胺盐、N-苄基-N-甲胺盐等)。
在本发明的IL-2抑制剂中，特别是大环内酯化合物，由于不对称碳原子和双键，会出现构象异构体或一对或多对立体异构体，如光学异构体和几何异构体。本发明还包括这些构象异构体和异构体。另外，三环化合物可以形成溶剂化物，它也包含在本发明中。优选的溶剂化物的例子是水合物和乙醇合物(ethanolate)。
从MERCK INDEX，第12版，No.2821，美国专利号4,117,118，4,215,199，4,288,431，4,388,307，Helv.Chim.Acta，60，1568(1977)和65，1655(1982)以及Transplant.Proc.17，1362(1985)等中已知其它IL-2抑制剂。具体地，它们是环孢菌素类如环孢菌素A，B，C，D，E，F和G及其衍生物。特别优选的是环孢菌素A。这些出版物的公开内容在此引入本说明书作为参考。
可以将三环化合物(I)，其药物可接受的盐，环孢菌素及其衍生物归类为抑制IL-2生产的“IL-2生产抑制剂”。可以将雷帕霉素及其衍生物归类为抑制IL-2信号传递的“IL-2信号转导抑制剂”。
三环化合物(I)及其药物可接受的盐是非毒性的药物可接受的常规盐，例如与无机或有机碱形成的盐，如碱金属盐(例如钠盐、钾盐等)，碱土金属盐(例如钙盐、镁盐等)，铵盐和胺盐(例如三乙基胺盐、N-苄基-N-甲胺盐等)。
在本发明的三环化合物中，由于不对称碳原子和双键，会出现构象异构体或一对或多对立体异构体，如光学异构体和几何异构体。本发明还包括这些构象异构体和异构体。另外，三环化合物可以形成溶剂化物，它也包含在本发明中。优选的溶剂化物的例子是水合物和乙醇合物(ethanolate)。
不具体限制本发明的抗菌剂，除非它们对IL-2抑制剂的抑制活性有不利影响，优选没有IL-2抑制作用的那些抗菌剂。更优选结构与大环内酯化合物(特别是如式(I)所示的化合物)和环孢菌素类不同的那些抗菌剂。该抗菌剂的优选实施例如下：青霉素类(例如青霉素G，甲氧西林，苯唑西林，氯唑西林，氨苄青霉素，海他西林，羧苄西林，磺苄西林，巴氨西林，阿莫西林，替卡西林，哌拉西林和阿扑西林)；头孢菌素类(例如头孢噻吩，头孢唑林，头孢替安，头孢噻肟，头孢哌酮，头孢唑肟，头孢甲肟，头孢匹胺，头孢他啶，头孢地秦，头孢匹罗，头孢吡肟，头孢唑兰，头孢磺啶和头孢噻利)；头霉素(例如头孢西丁，头孢美唑和头孢米诺)；氧头孢烯类(例如拉氧头孢和氟氧头孢)；单菌胺环(例如氨曲南)；碳青霉烯类(例如美罗培南)；青霉烯类(例如法罗培南)；氨基糖苷类(例如阿米卡星，妥布霉素，地贝卡星，阿贝卡星，庆大霉素和异帕米星)；林可霉素类(例如林可霉素和克林霉素)；四环素类(例如土霉素，多西环素和二甲胺四环素)；氯霉素类(例如氯霉素和甲砜霉素)；喹诺酮类(萘啶酸，吡哌酸，吡咯米酸，诺氟沙星，氧氟沙星，左氧氟沙星，环丙沙星，洛美沙星，托氟沙星，氟罗沙星，司帕沙星，恩氟沙星和依诺沙星)；和糖肽类(例如万古霉素和替考拉宁)。优选喹诺酮抗菌剂，特别优选氧氟沙星。可以单独使用或者使用两种或多种抗菌剂的组合。
这里使用的术语“治疗”包括任何方式的控制如预防，护理，缓和症状，减轻症状，和防止症状恶化等。
将本发明组合物局部给药于像眼，皮肤，气管，鼻腔，唇，耻骨和阴部那样的部位。
在施用药剂时，可以施用按照常规方法制备的制剂，其包括在眼科领域使用的用于对眼睛局部给药的所有制剂(例如滴眼剂和眼膏)和在皮肤病学和耳喉科学领域中外用的所有制剂(例如软膏，乳膏，洗剂和喷雾剂)。
滴眼剂是通过将有效成分溶解在无菌水溶液如生理盐水，缓冲液等之中制备，或者通过在使用前将准备溶解的粉末组合物组合而制备。优选如在EP-A-0406791中描述的滴眼剂。如果需要，可以加入在滴眼剂中通常使用的添加剂。此添加剂包括等渗剂(isotonizing agents)(例如氯化钠等)，缓冲剂(例如硼酸钠，磷酸氢二钠，磷酸二氢钠等)，防腐剂(例如杀藻胺，苯索氯铵，氯代丁醇等)，增稠剂(例如，糖类如乳糖，甘露醇，麦芽糖等；例如，透明质酸或其盐如透明质酸钠，透明质酸钾等；例如，粘多糖如硫酸软骨素等等；例如聚丙烯酸钠，羧基乙烯基聚合物，交联聚丙烯酸酯等)。上述出版物的公开内容作为参考在本文中引用。
通过将有效成分与基质混合来制备软膏(包括眼膏剂)。按照普通方法可以制备制剂。例如，将活性成分混合至通常用于软膏的基质之中，按照普通方法配制可以无菌制备软膏。用于软膏基质的实例包括凡士林，selen 50，Plastibase，macrogol等，但不限于其中。另外，为了增强疏水性，可以添加表面活性剂。关于眼膏，如果需要可以组合上述添加剂如防腐剂等。
本发明的组合物可以作为一种不包含防腐剂的无菌单位剂量类型来配制。
在本发明中使用的给药量和活性成分的给药次数按照患者的性别，年龄和体重，待治疗的症状，预期治疗效果，给药途径，治疗时期等而变化。通常，在使用用于成年人的滴眼剂的情形中，每只眼睛一天可以滴注几次包含0.0001-10.0W/V％，优选0.005-5.0W/V％IL-2抑制剂和0.0001-50.0W/V％，优选0.005-10.0W/V％抗菌剂的制剂，优选一至六次，更优选一至四次，一次几滴，优选一次四滴。在用于软膏，乳膏，洗剂和喷雾剂中，可以一天施用或喷雾几次包含0.0001-10.0W/V％，优选0.005-5.0W/V％IL-2抑制剂和0.0001-50.0W/V％，优选0.005-10.0W/V％抗菌剂的制剂，优选一至六次，更优选一至四次。基于炎症或感染的程度可以适当的增大或减小每种成分的配比。
在本发明中，制剂可以包括单独的IL-2抑制剂和抗菌剂作为其有效成分或者这些试剂的两种或多种。在多种有效成分的组合中，考虑到它们的效果和安全性可以适当的增大或减小它们各自的含量。
当按照本发明将IL-2抑制剂和抗菌剂分别形成药物制剂和局部给药时，考虑到患者的性别，年龄和体重，待治疗的症状，预期治疗效果，给药途径和治疗时期可以适当地确定有效成分的剂量和给药频率。
另外，只要它们不与本发明的目的相抵触，本制剂可以适当地包括其它药理活性成分。
不具体限制本发明中的炎症和/或感染，只要它们是在眼，皮肤，气管，鼻腔，唇，耻骨和阴部等处局部治疗的疾病。这些疾病的实例如下：由微生物如细菌(例如金黄色葡萄球菌，绿脓杆菌，链球菌，淋球菌和梅毒)和真菌(毛癣菌属，马拉色霉菌属和念珠菌属)导致的感染；通常称为皮炎的疾病，如过敏性皮炎(例如过敏性皮炎和接触性皮炎)和皮脂溢性皮炎；眼部炎病伴发的疾病如葡萄膜炎，结膜炎，睫状体炎，巩膜炎，巩膜外层炎，视神经炎，眼球后视神经炎，角膜炎，睑炎，角膜溃疡和结膜溃疡；通常称为鼻炎的疾病，如过敏性鼻炎和血管运动性鼻炎；气管炎伴发的疾病如支气管哮喘，婴儿哮喘，急性支气管炎和慢性支气管炎。本发明还包括在进行眼科手术(例如针对白内障的手术)或外科手术的部位的炎症和/或感染。
本发明通过使用白介素2抑制剂和抗菌剂的组合局部治疗能够抑制炎症和/或感染而对各种成分的主效应无不利影响。与单独使用各种成分相比，本发明还能够减少有效成分的剂量，并且可以以小剂量获得强抗炎和/或抗微生物活性，从而提供具有减小的副作用的药物。因此，可以有效和安全地给药本发明组合物来治疗感染和它们的伴发炎症，或者在防御作用后显示过度免疫炎性反应的受试者的感染。另外，可以有效和安全地给药本发明组合物来治疗显示感染征兆的受试者的炎症，或者由于IL-2抑制剂或除IL-2抑制剂以外的一些原因导致的免疫抑制效应引起的扩散性感染。
参照下列实施例将详述本发明，这些实施例不是意欲限制本发明。
具体实施方式
实施例1
制备本发明用于局部治疗的药物组合物。
实施例1
FK-506 0.3mg 0.03％
氧氟沙 3mg 0.3％
苯扎氯铵 0.1mg 0.01％
氯化钠 8.56mg 0.856％
磷酸氢二钠 0.05mg 0.005％
磷酸二氢钠 0.76mg 0.076％
磷酸和/或氢氧化钠 适量，将pH值调整为5.0±0.5
净化水 适量，1mL 适量，至100％
测试实施例1(抗微生物测试)
将NAC琼脂板上绿脓杆菌IID-1210(由Department of Ophthalmology，Yokohama City University School of Medicine，日本提供)的单菌落分离株接种于2mL心浸液肉汤之中，在37℃下保持过夜。将100μl过夜培养物接种于10mL心浸液肉汤之中，然后在37℃下振荡培养约12小时。
通过静脉注射戊巴比妥钠(25mg/kg)麻醉12只日本白兔(13周龄，标准：JW/CSK，Japan SLC，Inc.)，然后通过对两眼滴注0.4％的盐酸奥布卡因来产生局部麻醉。按照Hatano H等描述的方法(Japanese Review ofClinical Ophthalmology 79：1153，1985)使用6-mm圆锯和27号针在两侧产生角膜创伤。将40μl上述制备的细菌混悬液滴注到受伤的角膜上两次(第1天，21:00)。在细菌接种后，将兔分为4组(3只兔-6只眼/组)。在细菌接种后12小时(第2天，9:00)将50μl每种测试物质或赋形剂局部施用于每只动物的两眼。
作为测试物质，使用0.06％FK-506(第2组)，0.03％氧氟沙星(第3组)，包含0.06％FK-506和0.03％氧氟沙星的混合物(第4组)和赋形剂(第1组)。
在给药测试物质4小时后，用戊巴比妥钠静脉内过量处死动物，摘出眼睛，然后使用6-mm圆锯切除角膜。称量后，在1mL无菌生理盐水中均化每个角膜。将每个匀浆的等分部分放在NAC琼脂板上，并在37℃温育24小时。然后对菌落计数。所有定量培养物的操作是一式三份，对于每个角膜确定三次测量的算术平均值。结果被表示为每克角膜重量中生物的数量(通过测量菌落形成单位[CFU]测定)。
表1显示每组的菌落形成单位。与赋形剂处理相比，用0.06％FK-506处理减小了活假单胞菌的数目，但不显著。用0.3％氧氟沙星处理消灭细菌。用包含0.06％FK-506和0.3％氧氟沙星的混合物处理也消灭细菌。该结果显示FK-506对氧氟沙星抑制感染无影响。
已经清楚表明与抗菌剂如氧氟沙星的组合使用排除了与具有免疫抑制作用的IL-2抑制剂如FK-506的单独给药相关的细菌感染的危险。
表1
每个角膜的菌落形成单位
组 处理 眼睛数量
平均值±标准偏差
1. 赋形剂(对照) 6 43382±16081
2. 0.06％FK-506 6 31225±7204
3. 0.3％氧氟沙星 6 0a)，b)
0.06％FK-506
4.
6 0a)，b)
0.3％氧氟沙星
a)p＜0.05显著不同于组1(Tukey检验)
b)p＜0.01显著不同于组2(Tukey检验)
测试实施例2(抗炎测试)
如测试实验1所述对12只日本白兔(13周龄，Std：JW/CSK)诱导实验性假单胞菌角膜炎。在细菌接种后，将兔分为4组(3只兔-6只眼/组)。在细菌接种后12小时(第2天，9:00)将50μl每种测试物质或赋形剂局部施用于每只动物的两眼，在细菌接种后12小时开始，相隔4小时每天4次。测试物质和赋形剂与测试实施例1中使用的相同。
用狭缝灯生物显微镜检查兔眼，基于Kuriyama H等描述的方法通过给下列征兆赋予数值来评估在细菌接种48小时后的结膜炎和在细菌接种60小时后角膜炎的严重性。通过角膜混浊(记分0-8)与角膜溃疡(记分0-3)的总和来评估角膜炎。通过眼睑结膜炎的发红(记分0-4)，睑结膜的水肿(记分0-4)，瞬膜状态(记分0-3)和排除物(discharge)(记分0-3)的总和来评估结膜炎。
如表2所示，用0.06％FK-506或0.3％氧氟沙星的处理趋于减少结膜炎。与用赋形剂处理相比，用包含0.06％FK-506和0.3％氧氟沙星的混合物的处理显著减少了结膜炎。
表2
记分(结膜)
组 处理 眼睛数量
平均值±标准偏差
赋形剂
1. 6 7.3±0.6
(对照)
2. 0.06％FK-506 6 6.7±0.4
3. 0.3％氧氟沙星 6 6.0±0.5
4.0.06％FK-506
6 5.5±0.3a)
0.3％氧氟沙星
a)p＜0.05显著不同于组1(Tukey检验)
如表3所示，用0.06％FK-506的处理趋于减少角膜炎。与赋形剂处理相比，用包含0.06％FK-506和0.3％氧氟沙星的混合物的处理显著减少了角膜炎。与用0.06％FK-506处理相比，用包含0.06％FK-506和0.3％氧氟沙星的混合物的处理显著减少了角膜炎。
表3
记分(角膜)
组 处理 眼睛数量
平均值±标准偏差
赋形剂
1.
6 7.3±1.0
(对照)
2. 0.06％FK-506 6 6.0±0.0
3. 0.3％氧氟沙星 6 2.1±0.4a)
4. 0.06％FK-506
6 1.6±0.3a)，b)
0.3％氧氟沙星
a)p＜0.05显著不同于组1(Tukey检验)
b)p＜0.01显著不同于组2(Tukey检验)
上述结果显示使用FK-506和氧氟沙星的组合的局部治疗抑制了炎症和/或感染而对每种组分的主效无不利影响。该结果说明当组合使用时FK-506和氧氟沙星对炎症显示加合效应(addictive effect)和/或协同效用。
工业适用性
包含白介素2抑制剂和抗菌剂作为有效成分的用于局部给药的组合物显示抗炎效果，同时抑制副作用如感染性疾病等。本发明用于局部给药的组合物提供感染性疾病，与之相关的炎症或者与由于防御作用导致的过度免疫炎症反应伴发的感染性疾病的预防或治疗，同时抑制炎症。因此，将本发明适于局部给药的组合物用于炎症和/或感染性疾病的治疗。
本发明是基于在美国提交的申请号60/303,148，其内容在此引入作为参考。
Claims (15)
1.用于局部给药的组合物，其包含白介素2抑制剂和抗菌剂作为其有效成分。
2.权利要求1的组合物，其中所述白介素2抑制剂是大环内酯化合物或环孢菌素。
3.权利要求2的组合物，其中所述大环内酯化合物为如以下通式(I)所示的三环化合物或其药物可接受的盐：
其中相邻的一对R1和R2，R3和R4，以及R5和R6各自独立地
a)表示两个相邻的氢原子，其中R2任选为烷基，或
b)任选在与所述对的成员相连的碳原子之间形成另一个键；
R7为氢原子，羟基，烷氧基或保护的羟基，或者可以与R1形成氧代；
R8和R9分别独立表示氢原子或羟基；
R10是氢原子，烷基，链烯基，被一个或多个羟基取代的烷基，被一个或多个羟基取代的链烯基或被氧取代的烷基；
X为氧，(氢原子，羟基)，(氢原子，氢原子)，或式-CH2O-的基团；
Y为氧，(氢原子，羟基)，(氢原子，氢原子)，或式N-NR11R12或N-OR13的基团；
R11和R12分别独立为氢原子，烷基，芳基或甲苯磺酰基；
R13、R14、R15、R16、R17、R18、R19、R22和R23分别独立为氢原子或烷基；
R24为含有一个或多个杂原子的任选取代的环；和
n为1或2；
Y、R10和R23可以与它们相连的碳原子一起形成含有氮原子、硫原子和/或氧原子的饱和或不饱和5或6-元杂环基，其中杂环基可以被一个或多个选自烷基、羟基、烷氧基、苄基、式-CH2Se(C6H5)的基团和被一个或多个羟基取代的烷基的基团取代。
4.权利要求3的组合物，其中所述三环化合物是FK506。
5.权利要求1至4中任何一项的组合物，其中所述抗菌剂是喹诺酮抗菌剂。
6.权利要求5的组合物，其中所述喹诺酮抗菌剂是萘啶酸，吡哌酸，吡咯米酸，诺氟沙星，氧氟沙星，左氧氟沙星，环丙沙星，洛美沙星，托氟沙星，氟罗沙星，司帕沙星，恩氟沙星和依诺沙星或其混合物。
7.权利要求6的组合物，其中所述喹诺酮抗菌剂是氧氟沙星。
8.用于治疗炎症和/或感染的方法，其包含对需要炎症和/或感染治疗的受试者局部给药有效量的干扰素2抑制剂和有效量的抗菌剂。
9.白介素2抑制剂和抗菌剂在制备用于治疗炎症和/或感染的局部给药的组合物中的用途。
10.权利要求9的用途，其中所述白介素2抑制剂是大环内酯化合物或环孢菌素。
11.权利要求10的用途，其中所述大环内酯化合物是如通式(I)所示的三环化合物或其药物可接受的盐：
其中相邻的一对R1和R2，R3和R4，以及R5和R6各自独立地
a)表示两个相邻的氢原子，其中R2任选为烷基，或
b)任选在与所述对的成员相连的碳原子之间形成另一个键；
R7为氢原子，羟基，烷氧基或保护的羟基，或者可以与R1形成氧代；
R8和R9分别独立表示氢原子或羟基；
R10是氢原子，烷基，链烯基，被一个或多个羟基取代的烷基，被一个或多个羟基取代的链烯基或被氧取代的烷基；
X为氧，(氢原子，羟基)，(氢原子，氢原子)，或式-CH2O-的基团；
Y为氧，(氢原子，羟基)，(氢原子，氢原子)，或式N-NR11R12或N-OR13的基团；
R11和R12分别独立为氢原子，烷基，芳基或甲苯磺酰基；
R13、R14、R15、R16、R17、R18、R18、R22和R23分别独立为氢原子或烷基；
R24为含有一个或多个杂原子的任选取代的环；和
n为1或2；
Y、R10和R23可以与它们相连的碳原子一起形成含有氮原子、硫原子和/或氧原子的饱和或不饱和5或6-元杂环基，其中杂环基可以被一个或多个选自烷基、羟基、烷氧基、苄基、式-CH2Se(C6H5)的基团和被一个或多个羟基取代的烷基的基团取代。
12.权利要求11的用途，其中所述三环化合物是FK506。
13.权利要求9至12中任何一项的用途，其中所述抗菌剂是喹诺酮抗菌剂。
14.权利要求13的用途，其中所述喹诺酮抗菌剂是萘啶酸，吡哌酸，吡咯米酸，诺氟沙星，氧氟沙星，左氧氟沙星，环丙沙星，洛美沙星，托氟沙星，氟罗沙星，司帕沙星，恩氟沙星和依诺沙星或其混合物。
15.权利要求14的用途，其中所述喹诺酮抗菌剂是氧氟沙星。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30314801P | 2001-07-06 | 2001-07-06 | |
| US60/303,148 | 2001-07-06 |
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| US (2) | US7033604B2 (zh) |
| EP (1) | EP1406700A1 (zh) |
| JP (1) | JP2005502621A (zh) |
| KR (1) | KR20040019034A (zh) |
| CN (1) | CN1259049C (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105555364A (zh) * | 2013-04-09 | 2016-05-04 | 克雷瑟特分子学探索有限公司 | 炎症性眼科疾病的局部治疗 |
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- 2002-07-02 CN CNB028135768A patent/CN1259049C/zh not_active Expired - Fee Related
- 2002-07-02 CA CA002452372A patent/CA2452372A1/en not_active Abandoned
- 2002-07-02 JP JP2003510107A patent/JP2005502621A/ja active Pending
- 2002-07-02 WO PCT/JP2002/006670 patent/WO2003004098A1/en active Application Filing
- 2002-07-02 NZ NZ530845A patent/NZ530845A/xx unknown
- 2002-07-02 EP EP02741390A patent/EP1406700A1/en not_active Withdrawn
- 2002-07-02 KR KR10-2003-7017245A patent/KR20040019034A/ko not_active Application Discontinuation
- 2002-07-02 US US10/187,013 patent/US7033604B2/en not_active Expired - Fee Related
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105555364A (zh) * | 2013-04-09 | 2016-05-04 | 克雷瑟特分子学探索有限公司 | 炎症性眼科疾病的局部治疗 |
Also Published As
| Publication number | Publication date |
|---|---|
| NZ530845A (en) | 2006-03-31 |
| US20060034892A1 (en) | 2006-02-16 |
| CA2452372A1 (en) | 2003-01-16 |
| KR20040019034A (ko) | 2004-03-04 |
| JP2005502621A (ja) | 2005-01-27 |
| US7033604B2 (en) | 2006-04-25 |
| WO2003004098A8 (en) | 2003-02-27 |
| US20030044452A1 (en) | 2003-03-06 |
| EP1406700A1 (en) | 2004-04-14 |
| AR036127A1 (es) | 2004-08-11 |
| WO2003004098A1 (en) | 2003-01-16 |
| CN1259049C (zh) | 2006-06-14 |
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