CN1137680C - 气雾剂组合物 - Google Patents
气雾剂组合物 Download PDFInfo
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- CN1137680C CN1137680C CNB961981660A CN96198166A CN1137680C CN 1137680 C CN1137680 C CN 1137680C CN B961981660 A CNB961981660 A CN B961981660A CN 96198166 A CN96198166 A CN 96198166A CN 1137680 C CN1137680 C CN 1137680C
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Abstract
本发明描述的是,利用中链脂肪酸甘油三酯作为分散剂来制备包含分散在液化氢氟烷烃推进剂中的三环化合物(I)的药用气雾剂组合物。当将液化氢氟烷烃加到捏和好的、三环化合物(I)和中链脂肪酸甘油三酯的预混物中时,活性组分均匀地分散在液化氢氟烷烃中。因此,通过首先将捏和好的预混物分配到分散混合器中,然后,在冷却或加压下填充液化氢氟烷烃,得到活性组分含量均匀性改善的药用气雾剂组合物。
Description
技术领域:
本发明涉及药用气雾剂组合物及其制备方法,并发现该组合物在药学领域中的应用。
背景技术:
已知,本发明所使用的三环化合物(I)及其可药用盐具有极好的药理活性,如免疫抑制活性和抗菌活性,因此可用于治疗和/或预防由器官移植或组织移植,移植物-宿主疾病,各种抗免疫疾病和感染性疾病引起的排异反应(例如,见EP-A-0184162和WO 89/05304)。
尤其,属于三环化合物(I)且称作FR900506(= FK506),FR900520,FR900523和FR900525的化合物是由链霉菌属,特别是tsukubaensis链霉菌No.9993(保藏机构:1-3,Higashi 1 chome,Yatabe-machi,Tsukuba-gun,Ibaraki-ken,日本,FermentationResearch Institute Agency of Industrial Science and Technology,Ministry of International Trade and Industry;保藏日期:1984年10月5日;登记号:FERM BP-927)或吸水链霉菌亚种vakushimaensisNo.7238(保藏机构:1-3,Higashi 1 chome,Yatabe-machi,Tsukuba-gun,Ibaraki-ken,日本,Fermentation Research InstituteAgency of Industrial Science and Technology,Ministry ofInternational Trade and Industry;保藏日期:1985年1月12日;登记号:FERM BP-928)。该方面内容见EP-A-0184162。
在那些三环化合物(I)中,由下列结构式表示的FK506是典型的化合物。属名:Tacrolimus化学名:17-烯丙基-1,14-二氢基-12-〔2-(4-羟基-3-甲氧基环已基)-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〕二十八环-18-烯-2,3,10,16-四酮。
另一方面,药用气雾剂是一种将具有药用活性的物质以细碎的形式与吸入气体一起传送到受体气道中,例如。用于治疗支气管哮喘发作的药物释放系统,并且广泛地用于药学领域中。
常规的药用气雾剂利用一种或多种液化含氯氟烃(下文统称CFC)作为推进剂并且用于某系统中,使得在适宜的分散剂辅助下,细碎的可药用活性物质分散在CFC中。
例如,含该种CFC的三环化合物(I)气雾剂已在WO 90/14826中提出。
然而,CFC与大气臭氧层的不断破坏有关并且预计,在本世纪内,全世界将禁止使用CFC。在这种形势下,期望利用液化氢氟烷烃(下文有时统称HFA)作为气雾剂推进剂取代品。然而,尽管与CFC比较,HFA的好处是臭氧范围扩大,但是它也有不足之处,由于其中常规分散剂(例如,大豆卵磷脂)的不溶解性,药用活性物质不能很好地分散在HFA中。
为了克服上述缺点,提出了一种可以将药用活性物质均匀分散的气雾剂系统,它包含HFA和作为分散剂的聚合物,所述聚合物包含HFA可溶解的酰胺或羧酸酯作为再重复单位(如聚乙烯吡咯烷酮,聚乙酸乙烯酯,丙烯酸-异丁烯酸酯共聚物)(WO 93/05765)。
在上述气雾剂系统中使用的聚合物是一种固体物质,当将聚合物和活性物质预先混合好的混合物分散在推进剂中时,引起活性组分的分离。因此,通常将活性物质和聚合物分别加到冷却的搅拌槽或压力槽中,然后在冷却下或在升压搅拌下加入HFA,将活性物质分散在HFA中,并将分散体分配到分配器中。然而,该方法不仅复杂,而且有缺点,因为活性组分的比例相当小,对于各分散剂来说,在使分散活性组分的推进剂分批分配的阶段,几乎不可能确保其含量的均匀性。
发明概述
本发明者做了大量研究来克服上述缺点并且发现,当使用中链脂肪酸甘油三酯作为分散剂来生产药用气雾剂时,可通过首先将三环化合物(I)与中链脂肪酸甘油三酯捏和,将捏和体分配到气雾剂分散混合器中,并且在冷却或升压下,将HFA填充到各分散混合器中来将三环化合物(I)均匀地分散在HFA中,结果,不仅气雾剂制备方法简单化,而且在活性组分的含量中,最终气雾剂具有最小的分散混合器到分散混合器变化。他们因此完成了本发明。本发明详细说明
本发明气雾剂组合物包含三环化合物(I)或其下述可药用盐,液化氢氟烷烃和中链脂肪酸甘油三酯。
(a)为两个相邻的氢原子,或
(b)可在它们所连接的碳原子之间形成另一键,此外,R2可以为烷基;
R7为氢原子,羟基,保护的羟基或烷氧基,或者与R1一起为氧代基;
R8和R9各独立地为氢原子或羟基;
R10为氢原子,烷基,由一个或多个羟基取代的烷基,链烯基,由一个或多个羟基取代的链烯基或由氧代基取代的烷基;
X为氧代基,(氢原子和羟基),(氢原子和氢原子),或由式-CH2O-表示的基团;
Y为氧代基,(氢原子和羟基),(氢原子和氢原子),或由式N-NR11R12或N-OR13表示的基团;
R11和R12各独立地为氢原子,烷基,芳基或甲苯磺酰基;
R13、R14、R15、R16、R17、R18、R19、R22和R23各独立地为氢原子或烷基;
R20和R21各独立地为氧代基或(R20a和氢原子)或(R21a和氢原子),其中,R20a和R21a各独立地为羟基,烷氧基或由式-OCH2OCH2CH2OCH3表示的基团,或者R21a为保护的羟基,或者R20a和R21a一起可以代表环氧环中的氧原子;
n为整数1,2或3;并且
除上述定义外,Y,R10和R23与它们所连接的碳原子一起可以代表饱和的或不饱和的、含氮、硫和/或氧的5-或6-元杂环,该杂环可任意地由一个或多个下列基团取代。所述基团包括烷基、羟基、由一个或多个羟基取代的烷基、烷氧基、苄基和式-CH2Se(C6H5)基。
优选,本发明的气雾剂组合物中,三环化合物(I)为这样的化合物,其中,各相邻基团对R3和R4或R5和R6可独立地在它们所连接的碳原子之间形成另一键;
R8和R23各独立地为氢原子;
R9为羟基;
R10为甲基,乙基,丙基或烯丙基;
X为(氢原子和氢原子)或氧代基;
Y为氧代基;
R14、R15、R16、R17、R18、R19和R22各为甲基;
R20和R21各独立地为(R20a和氢原子)或(R21a和氢原子),其中,R20a和R21a为羟基或烷氧基,或者R21a为保护的羟基;和
n为整数1或2。
更优选,本发明的气雾剂组合物中,三环化合物(I)为这样的化合物,其中,R7为氢原子,羟基或保护的羟基;X为氧代基;R20a为甲氧基;R21a为羟基或保护的羟基。
在下文中,将定义在本发明范围内所包含的各种术语。
在式(I)中的各定义如下详细说明。
除非另外说明,术语“低级”指具有1-6个碳原子的基团。优选的“烷基”的实例包括直链或支链脂族烃基,例如低级烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、新戊基和己基。优选的“链烯基”的实例包括直链或支链、具有一个双键的脂族烃基,例如低级链烯基,如乙烯基、丙烯基(例如,烯丙基)、丁烯基、甲基丙烯基、戊烯基和己烯基。优选的“芳基”的实例 包括苯基、甲苯基、二甲苯基、异丙基苯、基和萘基。
在“保护的羟基”中的优选保护基为1-(低级烷基硫基)(低级)烷基,如低级烷基硫甲基(例如甲基硫甲基,乙基硫甲基,丙基硫甲基,异丙基硫甲基,丁基硫甲基,异丁基硫甲基,己基硫甲基等),更优选C1-4烷基硫甲基,最优选甲基硫甲基;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),或低级烷基-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(C1-4)烷基甲硅烷基和C1-4烷基二苯基甲硅烷基、最优选叔丁基二甲基甲硅烷基和叔丁基二苯基甲硅烷基;或酰基,如脂族酰基、芳族酰基或由芳基取代的脂族酰基,它是由羧酸,磺酸或氨基甲酸衍生的。
脂族酰基的实例包括具有或不具有一个或多个适宜取代基如羧基的低级烷酰基,例如,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;具有或不具有一个或多个适宜取代基如低级烷基的环(低级)烷氧基(低级)烷酰基,例如环丙氧基乙酰基,环丁氧基丙酰基,环庚氧基丁酰基,氧基乙酰基,氧基丙酰基,氧基丁酰基,氧基戊酰基,氧基己酰基等;樟脑磺酰基;或具有一个或多个适宜取代基如羧基或保护的羧基的低级烷基氨基甲酰基,例如,羧基(低级)烷基氨基甲酰基(例如羧甲基氨基甲酰基,羧乙基氨基甲酰基,羧丙基氨基甲酰基,羧丁基氨基甲酰基,羧戊基氨基甲酰基,羧己基氨基甲酰基等),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基,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等),等等。
芳族酰基的实例包括具有或不具有一个或多个适宜取代基如硝基的芳酰基,例如,苯甲酰基,甲苯甲酰基,二甲苯甲酰基,萘甲酰基,硝基苯甲酰基,二硝基苯甲酰基,硝基萘甲酰基等;和具有或不具有一个或多个适宜取代基如卤素的芳基磺酰基,例如苯磺酰基,甲苯磺酰基,二甲苯磺酰基,萘磺酰基,氟代苯磺酰基,氧代苯磺酰基,溴代苯磺酰基,碘代苯磺酰基等。
由芳基取代的脂肪酰基的实例包括具有或不具有一个或多个适宜取代基如低级烷氧基或三卤代(低级)烷基的芳基(低级)烷酰基,例如,苯基乙酰基,苯基丙酰基,苯基丁酰基,2-三氟甲基-2-甲氧基-2-苯基乙酰基,2-乙基-2-三氟甲基-2-苯基乙酰基,2-三氟甲基-2-丙氧基-2-苯基乙酰基等。
在上述酰基中,更优选的酰基是具有或不具有羧基的C1-4烷酰基,在环烷基部分具有二个(C1-4)烷基的环(C5-6)烷氧基(C1-4)烷酰基,樟脑磺酰基,羧基(C1-4)烷基氨基甲酰基,三(C1-4)烷基甲硅烷基(C1-4)烷氧基羰基(C1-4)烷基氨基甲酰基,具有或不具有1个或2个硝基的苯甲酰基,具有卤素的苯磺酰基或具有C1-4烷氧基或三卤代(C1-4)烷基的苯基(C1-4)烷酰基,其中,最优选的是乙酰基,羧基丙酰基,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,碘代苯磺酰基和2-三氟甲基-2-甲氧基-2-苯基乙酰基。
优选的“5-或6-元含氮、硫和/或氧的杂环”包括吡咯基和四氢呋喃基。
三环化合物(I)的可药用盐包括常规无毒性的和可药用的盐,如与无机或有机碱生成的盐,特别是碱金属盐如钠盐和钾盐,碱土金属盐如钙盐和镁盐,铵盐和胺盐如三乙胺盐和N-苄基-N-甲胺盐。
关于三环化合物(I),已知,由于有不对称碳原子和双键,因此可能存在构象异构体和一种或多种立体异构体,如光学和几何异构体,并且该构象异构体和立体异构体也包括在本发明范围内。
式(I)三环化合物及其盐可以是溶剂化物的形式,它包括在本发明范围内,优选地,溶剂化物包括水合物和乙醇化物。
FK506是最优选的、属于三环化合物(I)的化合物。其它优选的化合物如下列出。
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-13,19,17,21,27-五甲基-11,28-二氧杂-4-氮杂三环〔22.3.1.04,9〕二十八环-18-烯-2,3,10,16-四酮,
12-〔2-(4-乙酰氧基-3-甲氧基环己基)-1-甲基乙烯基〕-17-烯丙基-1,14-二羟基-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〕二十八环-18-烯-2,3,10,16-四酮,
17-烯丙基-1,14-二羟基-23,25-二甲氧基-13,19,21,27-四甲基-12-〔2-〔4-(3,5-二硝基苯甲酰氧基)-3-甲氧基环己基〕-1-甲基乙烯基〕-11,28-二氧杂-4-氮杂三环〔22.3.1.04,9〕二十八环-18-烯-2,3,10,16-四酮,
17-烯丙基-12-〔2-〔4-〔(-)-2-三氟甲基-2-甲氧基-2-苯基乙酰氧基〕-3-甲氧基环己基〕-1-甲基乙烯基〕-1,14-二羟基-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〕二十八环-18-烯-2,3,10,16-四酮,
17-乙基-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〕二十八环-18-烯-2,3,10,16-四酮(FR900520),和
17-乙基-1,14,20-三羟基-12-〔2-(3,4-二羟基环己基)-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〕二十八环-18-烯-2,3,10,16-四酮。
可在本发明药用气雾剂组合物中用作推进剂的液化氢氟烷烃包括但不限制于1,1,1,2-四氟乙烷(CH2FCF3,下文称HFA-134a)和1,1,1,2,3,3,3-七氟丙烷(CF3CHCF3,下文称HFA-227)并且这些液化氢氟烷烃可单独或联合使用。
在本发明气雾剂组合物中用作活性组分分散剂的中链脂肪酸甘油三酯(MCT)主要由饱和脂肪酸〔CH3(CH2)nCOOH,n=4-10〕的甘油三酯组成,并且可使用该商品化产品Miglyol(Dynamit Novel的商标)812,Panacete(NOF Corporation的商标)810,Coconard(Kao Corporation的商标),Myritol(Hankel-Hakusui的商标)GM,ODO(The Nisshin Oil Mills,Ltd.的商标)等。上述MCT可单独或联合使用。
所述中链脂肪酸甘油三酯的配制量依赖于活性组分的种类和数量,但是通常在0.05-5w/v%并且优选在0.1-2w/v%范围变化。
优选地,在本发明气雾剂组合物中所使用的上述三环化合物(I)或其可药用盐为细粒。并且,在该情况下,可通过常规方法,如使用喷射磨,将其预先粉化成粒度大约为0.5-5μm,更优选1-3μm。在本发明气雾剂组合物中所包含的三环化合物(I)或其可药用盐的量为治疗有效量,并且依赖于气雾剂组合物的种类和各个要治疗indimisual病人的年龄和病情而改变。然而,通常为0.001-10w/v%并且优选0.005-5w/v%。
此外,本发明气雾剂组合物可进一步包含常规添加剂,如分散剂(例如聚乙烯吡咯烷酮,聚乙烯醇,脱水山梨醇脂肪酸酯,聚氧乙烯-山梨醇脂肪酸酯(例如吐温20,司盘85等),脂肪酸酯,聚乙二醇-脂肪酸酯,聚氧乙烯烷基醚,蔗糖酯,卵磷脂,HCO-60(聚氧乙烯氢化蓖麻油),油酸,肉豆蔻酸异丙酯等,其比例为0.0001-0.05w/v%,和/或三环化合物(I)或其可药用盐的助溶剂(例如,乙醇,甘油,聚乙二醇,丙二醇等),其比例为1-20w/v%。
优选,本发明的气雾剂组合物进一步包含一种任选的添加剂,该添加剂选自聚乙烯吡咯烷酮和乙醇。
制备本发明气雾剂组合物方法的特点是,将三环化合物(I)或其可药用盐和中链脂肪酸甘油三酯一起捏和,将捏和体分配到分散混合器中,并且在冷却或升压下,将液化氢氟烷烃填充到各分散混合器中。
以下,用实例更详细地说明制备本发明气雾剂组合物的方法。
首先,将细碎的三环化合物(I)或其可药用盐与所述中链脂肪酸甘油三酯,和任选的添加剂如聚乙烯吡咯烷酮等捏和,并将捏和体分配到分散混合器(通常为铝罐)中。然后,用预先冷却到-20℃的液化氢氟烷烃来填充各分散混合器以便将活性组分分散在氢氟烷烃中。然后,将分散混合器上安装阀门,得到成品。
或者,将上述捏和体分配到分散容器中后,可将各得到的分散混合器上安装阀门,然后在20-30大气压和常温下,将所述液化氢氟烷烃填充到分散混合器中。
每次阀门驱动所喷射的本发明药用气雾剂的量为25-150μl。依据活性物质的量,每次剂量驱动1-3次阀门并且每天给予1-5次剂量。本发明的效果
(1)三环化合物(I)或其盐在液化氢氟烷烃中是不溶解的或不分散的,即使与常规分散剂,如大豆卵磷脂混合。
然而,通过加入中链脂肪酸甘油三酯(MCT),不仅改善了三环化合物(I)的分散状况,而且戏剧性地增加三环化合物(I)在液化氢氟烷烃中的溶解度。
如表1所示,通过将MCT混入液化氢氟烷烃中,增加了作为代表性三环化合物(I)的FK506的溶解度。加入MCT能够将FK506以溶液的形式填充到气雾剂系统中。结果将不会由FK506结晶颗粒的聚集而引起喷雾性能的改变,并且FK506喷射剂量的均匀性可能是更可靠的。本研究所用气雾剂组合物按照实施例2相似的方法制备。表1.MCT含量对FK506在HFAs中溶解度的影响
MCT含量(%) | FK506在HFA-227中的含量(w/v%) | FK506在HFA-134a中的含量(w/v%) | ||||
0.05 | 0.1 | 0.2 | 0.5 | 0.05 | 0.2 | |
0.050.525 | ○○○○ | -○○○ | --○○ | ---- | ○○○○ | --○○ |
○:溶液
-:悬浮液
而且,因为在室温下,中链脂肪酸甘油三酯具有油样粘稠性,它可以很好地与三环化合物(I)捏和,并且在将得到的捏和体分配到分散混合器中后,可在冷却或升压下,将HFA填充到其中。上述方法可使每个分散混合器中所含三环化合物(I)具有明显的均匀性。
因此,当阀门驱动时,所释放活性组分的剂量没有变化。
本发明气雾剂组合物的形式可以是溶液型或悬浮液型。
因此,依据三环化合物(I)或其可药用盐和/或MCT的含量,可选择本发明气雾剂组合物的形式。
(2)而且发现,在FK506气雾剂组合物中加入MCT产生新的特性。例如,如下由空气动力学粒度分布计算得到的捏和体中值空气动力学半径(MMAD)依所加MCT的量增加(表2)。空气动力学粒度分布:
按照USP23中的常规方法(装置1),在通过喷射FK506气雾剂组合物,将1mg FK506应用到多级串联冲击器中后,可由各阶段FK506的量来确定空气动力学粒度分布。通过HPLC方法进行FK506测定并且由粒度分布计算MMAD。按照下述实施例2类似的方法制备FK506气雾剂组合物。表2.MCT含量对含HFAs的0.05%FK506气雾剂组合物空气动力学粒
度的影响
(3)而且,按照下述溶解试验,研究FK506由雾状颗粒中释放的速度。由此确定,如表3所示,随着MCT的加入,FK506的释放速度下降。尤其,该释放速度在溶液中比在悬浮液中往往更慢。这些结果说明,可通过控制MCT的量来调节FK506的释放速度。溶解试验:
推进剂 | MCT含量(%) | 捏和体中值空气动力学半径 |
(μm) | ||
HFA-227 | 0.050.5125 | 1.51.72.53.14.0 |
HFA-134a | 0.5 | 1.6 |
按照JP12中的溶解试验方法,利用在50rpm下搅拌的方法,在37℃下,在蒸馏水中测定喷射FK506气雾剂组合物后,FK506由雾状颗粒中的溶解。将气雾剂组合物的喷射剂量调节到试验液体中含FK506总量为1mg。通过HPLC方法测定FK506。按照实施例2类似的方法制备FK506气雾剂组合物。表3.MCT含量对FK506溶解速度的影响
推进剂 | MCT含量(%) | T 50%(min) | |
FK506 0.05% | FK506 0.2% | ||
HFA-227 | 00.5125 | 530384351 | 912152837 |
HFA-134a | 0.52 | 2941 | 1125 |
这些新特性表明,可以使肺部药物释放的选择性最佳化并且可以调节药物在释放部位的吸收速度,它意味着,可持续地释放三环化合物(I)或其可药用盐并且因此可减小其毒性。工业领域的应用:
本发明气雾剂组合物用于治疗和/或预防各种局部的和/或全身性疾病。
尤其,由于三环化合物(I)的药理活性,包含它的本发明气雾剂组合物用于治疗和/或预防可逆阻塞性气道疾病,它包括气喘病(支气管哮喘,过敏性哮喘,内源性哮喘,外源性哮喘和粉尘性哮喘),尤其是慢性或顽固性哮喘(例如,迟发性哮喘和气道过度反应性),支气管炎等。
此外,由于三环化合物(I)的药理活性,如免疫抑制活性和抗菌活性,本发明气雾剂组合物用于治疗和/或预防免疫介导的疾病,如由器官或组织,如心脏、肾脏、肝脏、骨髓、皮肤、角膜、肺、胰腺、小肠、肢、肌肉、神经、椎间盘、气管等的移植而引起的排异反应;由骨髓移植引起的移植物-宿主疾病;自身免疫性疾病,如类风湿性关节炎,系统性红斑狼疮,淋巴瘤样甲状腺肿,多发性硬化病,重症肌无力,I型糖尿病等;和由致病性微生物引起的感染性疾病。
而且,本发明气雾剂组合物也用于治疗和预防炎性和过度增殖性皮肤病和通过皮肤表现的免疫学介导的疾病,如牛皮癣,特应性皮炎,接触性皮炎,湿疹性皮炎,皮脂溢性皮炎,扁平苔癣,天疱疮,大泡样天疱疮,表皮松解性大泡(bullosa),荨麻疹,血管神经性水肿,脉管炎(vasculitides),红斑,皮肤嗜曙红细胞增多,红斑狼疮,痤疮和簇状脱发;各种眼疾病,如自身免疫性疾病等(例如,角膜结膜炎,春季结膜炎,与贝切特病有关的眼色素层炎,角膜炎,疮疹性角膜炎,圆锥形角膜炎,营养不良性上皮炎角膜,角膜白斑,眼天疱疮,莫伦溃疡,巩膜炎,突眼性眼病(Graves′ophthalmopathy)纹状体Koyanagi-Harada综合症,肉样瘤病等);粘膜和血管炎症,如胃溃疡,由局部缺血病和血栓形成而引起的血管损伤,局部缺血性肠道疾病,肠炎,引起坏死的小肠结肠炎,由热灼烧有关的肠损伤,白细胞三烯B4介导的疾病;肠炎过敏反应,如腹腔疾病,直肠炎,嗜曙红细胞性胃肠炎,肥大细胞病,节段性回肠炎和溃疡性结肠炎;食物引起的过敏性疾病,它具有离胃肠道甚远的症状表现,例如,偏头疼、鼻炎和湿疹;肾病如间质肾炎,古德帕斯彻综合症,溶血性尿毒症和糖尿病型肾病;神经疾病如多发性肌炎,急性感染性多神经炎,梅尼埃尔病和神经根病;内分泌疾病如甲状腺机能亢进和巴塞多病;血液病如完全性红细胞发育不全,再生障碍性贫血,发育不全性贫血,特发性血小板减少性紫癜,自身免疫性溶血性贫血,粒细胞缺乏症,恶性贫血,红母细胞贫血和红细胞发生不能;骨疾病如骨质疏松症;呼吸疾病如肉样瘤病,肺纤维化和特发性间质性肺炎;皮肤病如皮肤肌炎,寻常白斑病,寻常磷癣,光变态反应性过敏和皮肤T细胞淋巴瘤;循环性疾病如动脉硬化,动脉粥样硬化,主动脉炎综合症,结节性多动脉炎和非炎性心肌病;胶原性疾病如硬皮病,韦格纳肉芽肿和斯耶格伦综合症;肥胖症;嗜曙红细胞性筋膜炎;牙周病如龈损伤,牙周组织损伤,牙槽骨损伤,Substantia Ossea Clentis;肾病综合症如肾小球性肾炎;男性模式脱发或脱发性早老;肌营样不良;脓皮病和Sezary′s综合症;阿狄森病;活性氧介导的疾病,例如,局部缺血再灌注引起的器官(例如心脏、肝脏、肾脏、消化道)损伤,它在防腐、移植或局部缺血(例如血栓形成,心梗)时发生;肠道疾病如内毒素休克,假膜结肠炎,由药物或辐射引起的结肠炎;肾病如局部缺血性急性肾功能不全,慢性肾功能不全;肺病如由肺氧或药物(例如Paracort,博来霉素)引起的中毒,肺癌,肺气肿;眼病如白内障,眼铁质沉着病,视网膜炎,色素沉着(Pigmentosa),老年斑变性,玻璃体结疤,角膜碱灼伤;皮炎;和其它疾病如龈炎,牙周炎,脓毒病,胰腺炎,由环境污染(例如空气污染)。衰老、致癌物、癌转移、高空病引起的疾病;由组胺或白细胞三烯C4释放引起的疾病等。
此外,三环化合物(I)具有肝再生活性和/或刺激肝细胞肥大和增生的活性。因此,本发明气雾剂组合物用于治疗和/或预防肝病如致免疫性疾病(例如,慢性自身免疫性肝病,如由自身免疫性肝病,原发性胆汁性肝硬变和硬化的胆管构成的疾病),部分肝切除,急性肝坏死(例如,由毒素、病毒性肝炎、休克或缺氧引起的坏死)B型肝炎,非-A/非-B型肝炎,硬变和肝衰竭如暴发性肝炎,迟发性肝炎和“慢转急性”肝衰竭(在慢性肝病期间发生急性肝衰竭)。
此外,本发明气雾剂组合物因具有有用的药理活性,如化学治疗作用的加强活性,巨细胞病毒感染的预防或治疗活性,抗炎活性等,可用于治疗各种疾病。
当用专利申请中所公开的化合物和雷帕霉素类如雷帕霉素代替三环化合物(I)或其可药用盐时,也可以得到本发明气雾剂组合物,其中,所述专利申请如EP-A-353678,日本专利申请No.2(1990)-74330,PCT/GB90/01262,EP-A-413532,PCT/JP91/00314,英国专利申请No.9012963.6,No.9014136.7,No.9014681.2,No.9014880.0,No.9014881.8,No.9015098.8,No.9016115.9,和No.9016693.5,EP-A-323865,EP-A-349061,EP-A-358508,EP-A-364031,EP-A-364032,EP-A-378317,EP-A-378320,EP-A-378321,EP-A-388153,EP-A-396399,EP-A-396400,EP-A-399579,EP-A-403242,EP-A-428365,EP-A-356399,GB 2225576A,EP-A-402931,EP-A-427680,EP-A-445975,EP-A-455427,EP-A-463690,EP-A-464895,EP-A-466365,EP-A-478235,EP-A-480623,EP-A-509753,EP-A-515071,EP-A-520554,EP-A-526934,EP-A-530888,EP-A-532089,和EP-A-532088,WO92/06992,WO92/20688,WO93/04679,WO93/05059,and WO93/04680,美国专利申请No.5149701,德国专利申请A-4021404,A-4028664,A-4028665,A-4028666,A-4028667,A-4028675,A-4028676,A-4028677,A-4028678,和A-4039587;
下面将参考下述实施例来描述本发明,但它不限制本发明范围。
实施例1
通过使用喷射磨,将FK506粉碎到粒度为2-3μm并将得到的粉末与Miglyol 812捏和在一起。将捏和体分配后,将预先冷却到-20℃下的HFA-227填充到各分散混合器中并安装上阀门,得到每单位(5ml)含下列组分的气雾剂产品(冷填充法)。
FK506 10mg(0.2(w/v)%)
Miglyol 812 25mg(0.5(w/v)%)
HFA-227 5ml
实施例2
将按照实施例1类似方法得到的、每单位(5ml)含下列组分的捏和体填充到分散混合器中,并且,在安装好阀门后,在室温下,将加压到20大气压下的HFA-227填充到各分散混合器中,得到如实施例1中相同组分的药用气雾剂组合物(压力填充法)。
FK506 5mg(0.1(w/v)%)
Miglyol 812 10mg(0.2(w/v)%)
HFA-227 5ml
实施例3-11
用实施例1或实施例2类似的方法,得到下列气雾剂组合物。
实施例12
实施例 | 三环化合物(含量(w/v%)) | 中链脂肪酸甘油三酯(w/v%) | 推进剂(5ml) |
3 | FK506(0.05) | Miglyol 812(0.05) | HFA-227 |
4 | FK506(0.1) | Miglyol 812(0.5) | HFA-227 |
5 | FK506(0.2) | Miglyol 812(2) | HFA-227 |
6 | FK506(0.5) | Miglyol 812(5) | HFA-227 |
7 | FK506(0.05) | Miglyol 812(0.05) | HFA-134a |
8 | FK506(0.2) | Miglyol 812(5) | HFA-134a |
9 | FK506(0.1) | Miglyol 812(0.2) | HFA-134a |
10 | FK506(0.4) | Miglyol 812(1) | HFA-134a |
11 | FR900520(0.1) | Miglyol 812(0.2) | HFA-227 |
按照实施例2类似的方法,也可以制备每单位(5ml)含下列组分的气雾剂组合物。
FK506 10mg
Miglyol 812 25mg
聚乙烯吡咯烷酮 0.25mg
HFA-227 5ml
Claims (8)
1.一种气雾剂组合物,它包含下式三环化合物(I)或其可药用盐,液化氢氟烷烃和中链脂肪酸甘油三酯,其中中链脂肪酸甘油三酯为Miglyol812:其中,各相邻基团对R1和R2,R3和R4或R5和R6独立地
(a)为两个相邻的氢原子,或
(b)可在它们所连接的碳原子之间形成另一键,此外,R2可以为烷基;
R7为氢原子,羟基,保护的羟基或烷氧基,或者与R1一起为氧代基;
R8和R9各独立地为氢原子或羟基;
R10为氢原子,烷基,由一个或多个羟基取代的烷基,链烯基,由一个或多个羟基取代的链烯基或由氧代基取代的烷基;
X为氧代基,(氢原子和羟基),(氢原子和氢原子),或由式-CH2O-表示的基团;
Y为氧代基,(氢原子和羟基),(氢原子和氢原子),或由式N-NR11R12或N-OR13表示的基团;
R11和R12各独立地为氢原子,烷基,芳基或甲苯磺酰基;
R13、R14、R15、R16、R17、R18、R19、R22和R23各独立地为氢原子或烷基;
R20和R21各独立地为氧代基或(R20a和氢原子)或(R21a和氢原子),其中,R20a和R21a各独立地为羟基,烷氧基或由式-OCH2OCH2CH2OCH3表示的基团,或者R21a为保护的羟基,或者R20a和R21a一起可以代表环氧环中的氧原子;
n为整数1,2或3;并且
除上述定义外,Y,R10和R23与它们所连接的碳原子一起可以代表饱和的或不饱和的、含氮、硫和/或氧的5-或6-元杂环,该杂环可任意地由一个或多个下列基团取代,所述基团包括烷基、羟基、由一个或多个羟基取代的烷基、烷氧基、苄基和式-CH2Se(C6H5)基。
2.权利要求1中所要求的气雾剂组合物,其中,三环化合物(I)或其可药用盐的含量为0.001-10%(w/v)。
3.权利要求1中所要求的气雾剂组合物,其中,三环化合物(I)为这样的化合物,其中,各相邻基团对R3和R4或R5和R6可独立地在它们所连接的碳原子之间形成另一键;
R8和R23各独立地为氢原子;
R9为羟基;
R10为甲基,乙基,丙基或烯丙基;
X为(氢原子和氢原子)或氧代基;
Y为氧代基;
R14、R15、R16、R17、R18、R19和R22各为甲基;
R20和R21各独立地为(R20a和氢原子)或(R21a和氢原子),其中,R20a和R21a为羟基或烷氧基,或者R21a为保护的羟基;和
n为整数1或2。
4.权利要求3中所要求的气雾剂组合物,其中,三环化合物(I)为这样的化合物,其中,R7为氢原子,羟基或保护的羟基;X为氧代基;R20a为甲氧基;R21a为羟基或保护的羟基。
5.权利要求4中所要求的气雾剂组合物,其中,三环化合物(I)为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-13,19,2 1,27-四甲基-11,28-二氧杂-4-氮杂三环〔22.3.1.04,9〕二十八环-18-烯-2,3,10,16-四酮。
6. 利要求1中所要求的气雾剂组合物,其中,液化氢氟烷烃为1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷。
7.权利要求1中所要求的气雾剂组合物,它进一步包含一种任选的添加剂,该添加剂选自聚乙烯吡咯烷酮和乙醇。
8.制备权利要求1中所要求的气雾剂组合物的方法,其特征是包含下列步骤:
(1)将三环化合物(I)或其可药用盐与中链脂肪酸甘油三酯捏和,
(2)将所得到的捏和体分配到分散混合器中,和
(3)在冷却或升压下,将液化氢氟烷烃填充到各分散混合物中。
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US4894366A (en) * | 1984-12-03 | 1990-01-16 | Fujisawa Pharmaceutical Company, Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
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-
1996
- 1996-09-18 ZA ZA967887A patent/ZA967887B/xx unknown
- 1996-09-18 CN CNB961981660A patent/CN1137680C/zh not_active Expired - Fee Related
- 1996-09-18 PT PT96931227T patent/PT851753E/pt unknown
- 1996-09-18 KR KR1019980701910A patent/KR100523754B1/ko not_active IP Right Cessation
- 1996-09-18 WO PCT/JP1996/002670 patent/WO1997010806A1/en active IP Right Grant
- 1996-09-18 ES ES96931227T patent/ES2206590T3/es not_active Expired - Lifetime
- 1996-09-18 DE DE69630798T patent/DE69630798T2/de not_active Expired - Lifetime
- 1996-09-18 AT AT96931227T patent/ATE254450T1/de not_active IP Right Cessation
- 1996-09-18 JP JP24605396A patent/JP3266005B2/ja not_active Expired - Lifetime
- 1996-09-18 JP JP51258997A patent/JP3362394B2/ja not_active Expired - Fee Related
- 1996-09-18 AU AU69998/96A patent/AU719613B2/en not_active Ceased
- 1996-09-18 US US09/029,863 patent/US6361760B1/en not_active Expired - Fee Related
- 1996-09-18 DK DK96931227T patent/DK0851753T3/da active
- 1996-09-18 CA CA002232378A patent/CA2232378C/en not_active Expired - Fee Related
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- 1996-09-19 TW TW085111460A patent/TW429153B/zh not_active IP Right Cessation
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1999
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WO1997010806A1 (en) | 1997-03-27 |
CA2232378A1 (en) | 1997-03-27 |
US6524556B2 (en) | 2003-02-25 |
DE69630798T2 (de) | 2004-09-23 |
EP0851753B1 (en) | 2003-11-19 |
TW429153B (en) | 2001-04-11 |
CN1201384A (zh) | 1998-12-09 |
JP3266005B2 (ja) | 2002-03-18 |
HK1017845A1 (en) | 1999-12-03 |
US6361760B1 (en) | 2002-03-26 |
CA2232378C (en) | 2009-04-14 |
DK0851753T3 (da) | 2004-03-15 |
EP0851753A1 (en) | 1998-07-08 |
KR19990044656A (ko) | 1999-06-25 |
PT851753E (pt) | 2004-04-30 |
JP3362394B2 (ja) | 2003-01-07 |
AU719613B2 (en) | 2000-05-11 |
ZA967887B (en) | 1997-04-07 |
AU6999896A (en) | 1997-04-09 |
ATE254450T1 (de) | 2003-12-15 |
KR100523754B1 (ko) | 2007-06-04 |
US20020061906A1 (en) | 2002-05-23 |
JPH09143054A (ja) | 1997-06-03 |
DE69630798D1 (de) | 2003-12-24 |
ES2206590T3 (es) | 2004-05-16 |
JP2000505050A (ja) | 2000-04-25 |
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