CN102088975B - 基于激肽b2受体拮抗剂和皮质类固醇的药物组合物及其用途 - Google Patents
基于激肽b2受体拮抗剂和皮质类固醇的药物组合物及其用途 Download PDFInfo
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Abstract
本文公开的是含有作为活性成分的皮质类固醇和激肽B2受体拮抗剂的混合物的药物组合物。所述的组合物已经被证明特别有效,尤其在炎症疾病如哮喘、眼科疾病或皮肤疾病、并尤其是与关节相关的炎性疾病(关节炎)的治疗中特别有效。
Description
技术领域
本发明公开了含有作为活性成分的皮质类固醇和激肽B2受体拮抗剂的混合物的药物组合物。所述的组合物已经被证明特别有效,尤其在炎症疾病如哮喘、眼科疾病或皮肤疾病、并尤其是与关节相关的炎性疾病(关节炎)的治疗中特别有效。
现有技术水平
骨关节炎(OA),也称作退行性关节疾病,是一种疼痛的、进行性的关节退行性疾病。OA的主要病理生理学特征是关节软骨破坏和损失、肥大、滑膜的炎症和随后的关节肿胀。这些效应产生例如疼痛、僵硬和功能丧失的症状。与平均预期寿命的增长有关的OA在老年人群中的高发病率表明受此种疾病影响的患者的数量在不久的将来可能极大地增长。OA患者认为减轻疼痛对他们的生活质量很重要。
当前没有能够阻止此种疾病恶化的药物。现有的治疗主要是减轻疼痛症状和恢复关节功能。扑热息痛和非甾体抗炎药(NSAIDs)被普遍开处用于治疗骨关节炎疼痛。但是,长期使用所述药物可能伴随有主要的副作用,尤其是在胃肠道水平(溃疡)和血小板聚集方面。
缓激肽(BK)是激肽的成员,激肽是在被有肽酶活性的酶(激肽释放酶)攻击后来源于高分子量的前体(激肽原)的小肽(8-11个氨基酸)家族。激肽形成在各种情况包括炎症、缺血和免疫过程或细菌和病毒感染下被激活。
两种激肽受体已被药理鉴定:B1受体,其在正常条件下极少表达,但被上面所列的刺激诱导表达;和B2受体,其被许多细胞类型组成性表达。缓激肽,通过B2受体的刺激,是炎症和疼痛最重要的介质之一,并与促炎和痛觉过敏介质的释放有关。
已经证实缓激肽(BK)在各种水平上参与OA的病理生理学。
长期已知激肽被释放于OA患者的滑液中。而且,在这些患者中,已在内衬地滑液腔的细胞、成纤维细胞和血管内皮细胞中发现B2受体。
各种临床前模型的许多研究表明BK,当通过关节内途径给药时,比其他炎症介质如P物质、组胺和降钙素基因相关的肽更有效地诱导大鼠的滑液中浆液外渗和中性粒细胞聚集。而且,BK减少关节软骨中的蛋白聚糖含量并在鼠OA模型中引起前列腺素的释放。
已证明一些缓激肽B2受体拮抗剂各种动物滑膜炎模型中有效抑制炎症事件和痛觉过敏。
释放后,BK刺激和敏化分布于关节囊的感觉神经纤维。
BK的临床重要性已经被在58名膝盖有OA症状的患者中进行的II期临床试验证实,其中B2受体拮抗剂艾替班特(90μg/1ml)单剂量关节内给药比安慰剂更大程度地减少膝盖中的疼痛强度(55名患者)。赛诺菲-安万特(Sanofi-Aventis)最近报道在患有膝盖OA的患者中,艾替班特关节内浸润(每隔一周3×500μg注射)引起强烈的镇痛反应,在治疗后持续达3个月,并且在有略微的或无副作用的情况下获得此种显著的镇痛作用。
激肽在呼吸道和其它地方是强效的炎症物质。呼吸道中局部应用缓激肽或内源性释放的激肽在哮喘患者中产生炎症作用和支气管收缩,但在健康的志愿者中几乎没有作用。激肽拮抗剂,尤其是激肽B2受体拮抗剂,可用于治疗过敏性哮喘。
许多缓激肽B2受体拮抗剂已经描述在文献中:Steward,J.M.等免疫药理学(Immunopharmacology),1999,43,155-61(化合物B10056、B9430)。
Pruneau,D等.英国药理学杂志(Br.J.Pharmacol)1998,125,365-72(化合物FR167344、FR173657、LF160687、Bradizide、LF160335)。
EP370453描述了一些作为缓激肽拮抗剂的具有肽结构的化合物,并且所述的化合物包括艾替班特。艾替班特还构成专利EP1594520的主题,其中公开了它在骨关节炎的预防和治疗中的用途。
WO03103671描述了一组很强效的非肽缓激肽拮抗剂。WO2006040004中报道了特别强效的拮抗剂的选择,包括化合物MEN16132;这些拮抗剂也已被证明在骨关节炎的预防和治疗中、尤其在膝盖的关节内治疗中具有高效。
天然可的松类(cortisones)(糖皮质激素或皮质类固醇)、可的松和皮质醇产生于肾上腺皮质中,并且具有甾体分子结构。
它们的抗炎和抗过敏作用主要通过诱导酶脂皮质蛋白(其抑制磷脂酶A2)的合成而产生。此酶将膜磷脂转化成花生四烯酸,花生四烯酸接着,经环氧合酶和脂氧酶,转化成炎症介质如前列腺素和白三烯。而且,可的松类干扰蛋白质和酶的合成,并稳定细胞膜。
皮质类固醇抑制炎症反应,无论引起炎症反应的刺激物质是化学的、感染性的或免疫的。虽然可的松给药具有症状治疗的性质,因为可的松类不作用于疾病的起因、炎症的抑制及其后果,使得这些药物在临床实践中非常有用。可的松类不仅抑制炎症过程的早期症状(水肿,以及血液和淋巴微循环的改变),还抑制随后的症状如发红和疼痛。
衍生自胆酸的合成的皮质类固醇,与天然皮质类固醇稍有不同;引入的修饰被设计用于增加所述物质的半衰期,保持天然化合物的生物化学活性不变。
可的松类一般不通过口服途径用于退行性或炎性骨关节疾病,这是因为它们的低效和特别是在长期治疗中出现的潜在的严重系统性副作用,长期治疗在慢性炎症疾病中经常是必要的。
通过局部浸润给药近年来在骨关节疾病和骨骼肌疾病的治疗中变得日益重要。此种治疗方法被推荐用于与疼痛和功能限制相关的急性炎症过程,和退行性关节疾病如骨关节炎、非感染性关节炎、肌腱炎、滑囊炎、筋膜炎、纤维肌痛和根综合征中。
用可的松类浸润的目的是减少或消除关节或关节周围的炎症并阻止系统性扩散。具有长溶出时间的微晶混悬剂延长作用的持续时间,其用于此目的。引入关节中的微晶的存在可引起浸润后疼痛;它们因此与局部麻醉剂共同给药以减少疼痛。患者被建议使关节休息至少24小时以阻止药物的系统性吸收。高剂量的可的松类,即使局部应用,必须被避免以阻止药物的系统性吸收,其禁用于一系列常见疾病如溃疡、糖尿病、心力衰竭、骨质疏松症和高血压。
对于关节内或囊内给药和注射至腱鞘以及腱囊肿形成内,可的松类的剂量当时评价,取决于症状的严重程度和关节的大小或其他将被治疗的局部区域(剂量一般在1和100mg之间)。在具有多关节症状的进展型(evolving forms)中给与高剂量,有时通过在不同位点同时进行单次注射。
任何情况中,可的松类的无数的副作用,在系统和局部水平上,已致使寻找旨在减少可的松类的剂量或使用的替代的解决方案。
两类化合物(B2受体拮抗剂和可的松类)的抗炎和镇痛活性是科学文献中众所周知的。根据现有技术水平,认为可的松类和缓激肽B2受体拮抗剂均以类似的机理产生镇痛和抗炎作用是完全合理的。具体地讲,二者均抑制前列腺素合成以及对其他促炎化合物(细胞因子)的合成有抑制作用。基于这些因素,当一起给药时所述的两类化合物将有叠加作用是不可预期的。但是,我们的实验观察已经证实缓激肽B2受体拮抗剂和可的松类之间不仅有叠加作用还具有出乎意料的协同作用,在抑制所研究的模型中的炎症和疼痛反应中有显著的增强作用,并且此发现构成了本发明的核心。
还众所周知的是合成的皮质类固醇,尤其是重复、长期给药后,引起严重的副作用,并被禁用于如上所述的一些疾病中,因为这些药可使所述的疾病恶化。而且,正如例如在使用实验性膝盖骨关节炎模型的临床前研究中证实的那样,可的松类的作用是部分的,而没有解决50%以上的被炎症过程如疼痛、促炎细胞增加和水肿改变的参数。
从治疗的角度看,在更低剂量完全抑制炎症的含有可的松类的制剂将因此是合乎需要的。
现在已经发现源于激肽B2受体拮抗剂和皮质类固醇的联用在减少炎症过程中的出乎意料的和令人惊讶的活性。由于所述两类化合物的显著的叠加和协同作用,该活性对于各种疾病如骨关节炎、类风湿性关节炎、哮喘、COPD、或炎性眼科疾病和皮肤疾病是非常有用的。
例如,在膝盖的骨关节炎中,B2拮抗剂和可的松类的联用产生1)完全的抗炎治疗作用,2)持续更长时间的作用,和3)皮质类固醇的剂量减少最高达十倍。
这种出乎意料的叠加性质,并且尤其是两类化合物的相互促进,适用于激肽发挥重要作用的所有其他形式的炎症,如哮喘,其中皮质类固醇的效力是众所周知的。总的来说,用较低量的皮质类固醇即能够获得显著的作用是在炎症过程的治疗中的重要的和创新的前景。
发明详述
现在已经令人惊讶地发现天然或合成的可的松类与激肽B2受体拮抗剂联合给药的应用在炎症疾病的治疗中令人惊讶地有效,所述炎症疾病例如但不限于骨关节炎和退行性关节疾病、关节炎、类风湿性关节炎、哮喘和COPD、眼科疾病和皮肤疾病。
本发明涉及药物组合物,其含有作为活性成分的:
-a)天然或合成的皮质类固醇
-b)激肽B2受体拮抗剂
和药学上可接受的载体和赋形剂,以及
所述的活性成分用于制备所述的组合物的用途。
所述的活性成分不仅可以以其中两种活性成分同时存在的组合物给药,还可以以独立的形式同时或顺序给药,其中用含有激肽B2受体拮抗剂的组合物的治疗可先于或后于用含有皮质类固醇的组合物的治疗,两种治疗之间的间隔时间为1分钟至高达8小时,优选为1至30分钟。
在皮质类固醇中,特别优选的为:
可的松、氢化可的松、倍氯米松、倍他米松、布地奈德、地塞米松、氟米松、氟尼缩松、氟可龙(Fluocortone)、氟替卡松、甲泼尼龙、甲基强的松(Methylprednisone)、帕拉米松、泼尼松龙、曲安西龙,
它们为其本身的形式,或者为与乙酸、苯甲酸、己酸、琥珀酸、磷酸、丙酸或戊酸形成的酯的形式,或为丙酮化合物(acetonides)的形式;
B2激肽受体拮抗剂可选自:
H-D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-F5F-Igl-Arg-OH(B10056),
H-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg-OH(B9430),
H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH(艾替班特),
4-[2-[([[3-(3-溴-2-甲基-咪唑并[1.2-a]吡啶-8-基氧基甲基)-2.4-二氯-苯基]-甲基-氨基甲酰基]-甲基)-氨基甲酰基]-乙烯基]-N,N-二甲基-苯甲酰胺(FR167344)
3-(6-乙酰氨基-吡啶-3-基)-N-([[2.4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯基]-甲基-氨基甲酰基]-甲基)-丙烯酰胺,(FR173657 op.FK3657)
1-[2.4-二氯-3-(2.4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基]-吡咯烷-2-甲酸[3-(4-甲脒基-苯甲酰基氨基)-丙基]-酰胺(LF160687,阿替班特)
Bradizide,
4-(4-[1-[2.4-二氯-3-(2.4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基]-吡咯烷-2-羰基]-哌嗪-1-羰基)-苄脒(LF160335)
2-[5-(4-氰基-苯甲酰基)-1-甲基-1H-吡咯-2-基]-N-[2.4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯基]-N-甲基-乙酰胺,
或者WO2006/04004中公开的具有通式(I)的化合物之一,
其中
-R为氢或甲基;
-W代表单键或氧原子;
-n=3、4;
-X为氢或胺基团-NR1R2,其中R1和R2相互独立地为氢或选自甲基、乙基、正丙基、异丙基;
-Y为季铵-NR3R4R5,其中R3、R4、R5相互独立地为甲基、乙基、正丙基、异丙基、丁基、异丁基、正戊基;
-且A-是形式上衍生自药学上可接受的酸的阴离子;
以及其药学上可接受的盐、对映异构体和对映异构体的混合物。
对于本发明的目的,药学上可接受的酸是选自盐酸、氢溴酸、磷酸、碳酸、乙酸、硫酸、三氟乙酸、甲磺酸(methansulphuric acid)、琥珀酸、马来酸、苹果酸、丙二酸、拘橼酸、依地酸;其中所述阴离子带有两个或更多个负电荷,A-应为部分值(fractional value)。
本发明特别涉及药物组合物,其中激肽B2受体拮抗剂选自:
-艾替班特或具有通式(I)的化合物。
在具有通式(I)的化合物中,特别优选下列化合物:与形式上衍生自选自盐酸、乙酸、硫酸、三氟乙酸、甲磺酸、琥珀酸和依地酸的酸的离子形成的盐形式的(4-(S)-氨基-5-(4-{4-[2,4-二氯-3-(2,4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基]-三甲基-铵;氯化物双盐酸盐是称为MEN16132的化合物(MW 871.5)。
其中每单剂量单位B2激肽受体拮抗剂的量为6×10-5至2×10-2、优选1×10-4至1×10-2、更优选3×10-4至6×10-3毫摩尔,相当于每单剂量单位MEN16132的量分别为0.05至17mg、0.09至9mg以及0.26至5mg。
根据本发明的组合物每剂量包含缓激肽拮抗剂的量在6×10-5至2×10-2毫摩尔之间(就MEN16132而言,它们相当于大约0.05至17mg的量),优选在1×10-4至1×10-2毫摩尔之间(就MEN16132而言,它们相当于大约0.09至9mg的量),甚至更优选在3×10-4和6×10-3毫摩尔之间(就MEN16132而言,它们相当于大约0.26至5mg的量)。
而且,所述的组合物每剂量包含0.05至100mg、优选0.1至10mg的皮质类固醇。
根据本发明的药物制剂还可包含一种或多种药学上可接受的载体/赋形剂。
适合局部给药的液体和半固体剂型例如溶液剂、乳膏剂、凝胶剂或透皮贴剂是优选的;特别是,适合关节内或囊内注射的剂型,例如溶液剂,和透皮应用,例如像乳膏剂或凝胶剂和透皮贴剂的半固体剂型。药物剂型也可由其中一些或所有成分是干燥形式的形式构成,所述干燥形式可能是冷冻干燥的,并待在使用前用水溶液或其他合适的载体重构。
所述的制剂可采用赋形剂如粘合剂、崩解剂、填充剂、稳定剂、稀释剂和着色剂通过现有技术中众所周知的方法来制备。它们还可包括用制技术中公知的合适的聚合物制成的延迟释放或缓慢释放的剂型。
对于制备适合注射用的液体剂型,优选药学上可接受的载体/赋形剂例如溶剂、防腐剂例如抗氧化剂和/或螯合剂和抗菌剂、等渗调节剂,以及缓冲系统。
优选水作溶剂,可能含有共溶剂如二醇类或多元醇如乙二醇。
还可以使用防腐剂或螯合剂,优选依地酸钠和焦亚硫酸钠,并且还可使用抗菌剂,优选苯甲醇。
特别优选氯化钠或甘露醇作为等渗调节剂。
优选的缓冲系统可以是磷酸盐和枸橼酸盐缓冲剂的盐混合物,优选钠盐或钾盐形式。
在适合于喷雾的液体制剂的制备中,药学上可接受的载体/赋形剂优选为含有防腐剂如抗氧化剂和/或螯合剂和抗菌剂、等渗调节剂、和缓冲系统的溶剂。
在适合气雾给药用于在气道应用的剂型中,优选药学上可接受的载体/赋形剂和抛射剂,优选氢氟碳化合物。
对于鼻腔给药,优选用合适的装置给药的干粉剂型或喷雾剂型。
根据本发明的制剂的典型实例为:
1.皮质类固醇0.1-10mg、MEN16132 0.26-5mg,在盐水溶液(0.9%NaCl)中,用适量的0.1N HCl调节pH至4.5-6,加适量水调整至1ml。
2.皮质类固醇0.1-10mg、MEN16132 0.26-5mg,在盐水溶液(0.9%NaCl)中,pH 6-8的缓冲系统,加适量水调整至1ml。
3.通过将0.26-5mg冷冻干燥的MEN16132和0.1-10mg皮质类固醇溶液、及缓冲系统溶解于盐水溶液(0.9%NaCl)中、加适量水调整至1ml而获得的即用制剂。
4.皮质类固醇0.1-10mg、艾替班特(MW 1304.5)0.39-7.8mg,在盐水溶液(0.9%NaCl)中,pH在6-8的缓冲系统,加适量水调整至1ml。
根据本发明的药物组合物可用于预防和治疗关节的急性或慢性炎性、自身免疫性、创伤性和退行性疾病,例如:骨关节炎和创伤后骨关节炎、退行性骨关节炎(膝关节炎、椎关节炎);椎关节强硬、滑膜炎、腱鞘炎、滑囊炎、挫伤、扭伤、脱臼和半脱位、痛风发作。
而且,所述的组合物对气道的炎症疾病,尤其是哮喘、鼻炎、慢性阻塞性肺病(COPD)、肺纤维症和其中支气管水肿或支气管痉挛起重要作用的疾病有效;并且对源于化学和物理因素或创伤的过敏和非过敏性炎性皮肤疾病和眼科疾病有效。在皮肤疾病中,主要治疗的适应症为烧伤(热或太阳灼伤)引起的皮炎、与过敏原性或刺激性物质接触引起的皮炎或湿疹、特应性皮炎和自身免疫性皮炎(银屑病),而在眼科疾病的情况下,它主要应用于睑炎、结膜炎和睑结膜炎。
剂量可根据患者的年龄和一般健康状况、疾病或病症的性质和严重程度、以及给药途径和类型而改变。在成年人类患者关节内使用的情况下,根据本发明的药物组合物可以以3×10-4至6×10-3mmol的量的缓激肽拮抗剂(对于MEN16132,这相当于大约0.26至5mg)和0.1-10mg的皮质类固醇的周剂量(单次给药)来给药。
下列含有两种活性成分的组合物的实施例更详细地阐明了本发明:
实施例1
倍他米松1mg、MEN16132 0.5mg,在盐水溶液(0.9%NaCl)中,用适量0.1N HCl调至pH 4.5,加适量水调整至1ml。将溶液置于2.25ml预填充注射器中。
实施例2
倍氯米松0.25mg、MEN16132 0.5mg,在含有磷酸盐缓冲剂(Na2HPO40.16mg、NaH2PO4 0.04mg)的盐水溶液(0.9%NaCl)中,加适量水调整至1ml。将溶液置于2.25ml预填充注射器中。
实施例3
倍他米松1mg,在含有磷酸盐缓冲剂(Na2HPO4 0.16mg、NaH2PO40.04mg)的盐水溶液(0.9%NaCl)中,加适量水调整至1ml。将冷冻干燥形式的MEN16132用上述溶液溶解。
实施例4
地塞米松4mg、艾替班特0.5mg,在含有磷酸盐缓冲剂(Na2HPO4 0.16mg、NaH2PO4 0.04mg)的盐水溶液(0.9%NaCl)中,加适量水调整至1ml。将溶液置于2.25ml预填充注射器中。
实施例5
所述的两种活性成分顺序给药的典型实例包括以下类型的两种组合物的使用:
a)将MEN16132 0.5mg溶于NaCl等渗溶液(0.9%NaCl)中,用0.1NHCl调至pH 5,加100μmol/ml EDTA,用适量等渗溶液调整至2ml,置于2.25ml容量的注射器中;通过调节关节内途径给药的体积来调整剂量(0.5ml相当于0.125mg,1ml相当于0.250mg,1.5ml相当于0.375mg,以及2ml相当于0.500mg)。剂量超过0.5mg时,可注射两支注射器的内容物。
b)将倍他米松磷酸二钠1.97mg溶于含有作为稳定剂的苯酚、依地酸钠和焦亚硫酸钠的NaCl等渗溶液中,适量至2ml,置于2.25ml容量的注射器中;通过调节关节内途径给药的体积来调整剂量。
生物活性
在通过关节内注射引起强炎症作用的角叉菜胶诱导的关节炎实验模型中测量MEN16132、艾替班特和可的松类的生物活性。
将角叉菜胶(2%溶液,25μl)注射入大鼠的右膝盖的关节内位置,而对左膝盖给与25μl盐水以提供内部对照。
角叉菜胶的给药引起关节水肿、疼痛、行走困难以及在处理的膝盖相应的爪上不能负重,给药后6小时出现峰值作用;体重因此与右爪中感受的疼痛直接成正比地主要落在左爪上。用失用测试(incapacitance test)以非侵袭方式评价的两只负重爪上的重量失衡,测量关节炎症导致的疼痛。还通过测量膝关节的直径来测量水肿。
此试验的目的是评价激肽B2受体拮抗剂对角叉菜胶诱导的关节水肿和疼痛的保护作用以及明确皮质类固醇特别是地塞米松或氢化可的松共同给药产生的作用。
角叉菜胶给药前30分钟关节内给药(i.a.)MEN16132或艾替班特(100μg/25μl i.a.),分别使刺激物诱导的水肿减少了45±3和48±5%(n=6),所述化合物给药后6小时达最大抑制作用。
给药地塞米松(100μg/25μl i.a.,角叉菜胶给药前30分钟)使水肿减少了57±3%,而证明其在10μg时无效。
MEN16132和地塞米松(100μg/25μl i.a.)共同给药显著增强了抗水肿作用,完全消除角叉菜胶引起的膝盖肿胀。甚至当地塞米松的剂量减少十倍至10μg/25μl i.a.时令人惊讶地观察到相似的结果。
MEN16132和地塞米松对关节疼痛的作用的结果定性和定量地与对水肿获得的那些结果类似。角叉菜胶给药前30分钟关节内给药MEN16132或地塞米松100μg,使关节疼痛在刺激物给药后6小时分别减少了38±4%和44±3%。地塞米松10μg关节内给药使疼痛减少了14±4%。MEN16132(100μg i.a.)和地塞米松(100和10μg i.a.)共同给药,使关节疼痛分别减少了92±2%和91±2%,甚至地塞米松的剂量低十倍时仍有显著的增强作用。
MEN16132和氢化可的松的联用对角叉菜胶诱导的大鼠膝盖肿胀获得类似的令人吃惊的结果,氢化可的松比地塞米松效力弱大约25倍。角叉菜胶之前30分钟关节内给药MEN16132 100μg,使膝盖肿胀减少了42±3%(n=6),而氢化可的松(100μg i.a.)被证明实际上无效(-4±3%)。所述的两种化合物同时给药使肿胀减少了85±6%,证实缓激肽B2受体拮抗剂和可的松类联用的强的增强作用,这不依赖于其化学结构。
在气道的炎症疾病(哮喘、过敏原或脂多糖诱导的呼吸道高敏性)、眼科疾病(由过敏原、碱性溶液和角叉菜胶引起的结膜炎)和皮肤疾病(过敏性皮炎)的实验模型中,激肽B2受体拮抗剂和可的松类的共同给药已经产生了与之前报道的在膝盖关节炎中的那些结果相类似的结果,表明两类化合物之间有明显的叠加和协同作用。
在由脂多糖(LPS)诱导的豚鼠气道炎症的模型中,通过支气管肺泡灌洗采集的白细胞的数目与对照组相比大约增加十倍。用MEN16132或艾替班特的治疗(1mg/ml溶液的气雾,15分钟),使用LPS预处理后的气道中存在的炎症细胞的数量分别减少了6%和5%,而地塞米松(0.03mg/ml溶液的气雾,15分钟)使细胞浸润减少了8%。
激肽B2受体拮抗剂(MEN16132或艾替班特)和地塞米松以上面所示的剂量共同给药,通过两类化合物之间显著的、出乎意料的协同作用抑制了约50%的由LPS引起的豚鼠的气道中的细胞浸润。
通过体外模型获得了类似的研究结果,在以1μg/ml LPS刺激24小时的人气道肌细胞的培养物中,观察到与对照相比PGE2的产量大约增加16倍。
100nM的MEN16132或艾替班特使LPS诱导的PGE2的释放分别减少了39%和30%,而地塞米松(1μM)使其减少了45%。采用B2受体拮抗剂(MEN16132或艾替班特)和地塞米松的联合治疗消除了LPS诱导的PGE2的产生。
在本发明中,尤其在具有肽结构的化合物的描述中,下列缩写已被用于一些非天然的氨基酸:Nal=萘基-丙氨酸;NMePhe=N-甲基-苯基丙氨酸,Oic=八氢吲哚-2-甲酸,Hyp=羟基脯氨酸,Igl=氨基茚满甲酸,Cpg=1-氨基环戊烷甲酸,Tic=1,2,3,4-四氢异喹啉-3-甲酸,F5F=五氟苯基丙氨酸。
Claims (14)
1.药物组合物,其包含作为活性成分的皮质类固醇和B2激肽受体拮抗剂、以及药学上可接受的载体和赋形剂,其中:
a)皮质类固醇为天然的或合成的,其选自:可的松、氢化可的松、倍氯米松、倍他米松、布地奈德、地塞米松、氟米松、氟尼缩松、氟可龙、氟替卡松、甲泼尼龙、甲基强的松、帕拉米松、泼尼松龙、曲安西龙,它们任选地为与乙酸、苯甲酸、己酸、琥珀酸、磷酸、丙酸或戊酸成酯的形式或为丙酮化合物的形式;
b)B2激肽受体拮抗剂选自:
-H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH(艾替班特);或
(4-(S)-氨基-5-(4-{4-[2,4-二氯-3-(2,4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基)-三甲基-铵与盐酸、乙酸、硫酸、三氟乙酸、甲磺酸、琥珀酸或依地酸形成的盐。
2.根据权利要求1的药物组合物,其中化合物(4-(S)-氨基-5-(4-{4-[2,4-二氯-3-(2,4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基)-三甲基-铵盐为(4-(S)-氨基-5-(4-{4-[2,4-二氯-3-(2,4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基)-三甲基-铵双盐酸氯化物。
3.根据权利要求1或2的药物组合物,其中每单剂量单位皮质类固醇的量为0.05-100mg。
4.根据权利要求3的药物组合物,其中每单剂量单位皮质类固醇的量为0.1-10mg。
5.根据权利要求1或2的药物组合物,其中每单剂量单位B2激肽受体拮抗剂的量为6×10-5至2×10-2毫摩尔,相当于每单个单位剂量(4-(S)-氨基-5-(4-{4-[2,4-二氯-3-(2,4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基)-三甲基-铵双盐酸氯化物的量为0.05至17mg。
6.根据权利要求5的药物组合物,其中每单剂量单位B2激肽受体拮抗剂的量为1×10-4至1×10-2毫摩尔,相当于每单个单位剂量(4-(S)-氨基-5-(4-{4-[2,4-二氯-3-(2,4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基)-三甲基-铵双盐酸氯化物的量为0.09至9mg。
7.根据权利要求5的药物组合物,其中每单剂量单位B2激肽受体拮抗剂的量为3×10-4至6×10-3毫摩尔,相当于每单个单位剂量(4-(S)-氨基-5-(4-{4-[2,4-二氯-3-(2,4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基)-三甲基-铵双盐酸氯化物的量为0.26至5mg。
8.根据权利要求1或2的药物组合物,其为关节内或囊内注射液的形式,或为选自乳膏剂、凝胶剂、透皮绷带、喷雾剂或气雾剂溶液的透皮形式。
9.根据权利要求1或2的药物组合物,其为滴眼剂或鼻喷雾剂的形式。
10.根据权利要求8的药物组合物,其中B2激肽受体拮抗剂为结晶的、无定形或冻干的固体形式,其待在使用前溶于含有皮质类固醇的溶液中以得到关节内或囊内注射液。
11.根据权利要求1或2的药物组合物,其中药学上可接受的载体和赋形剂选自作为缓冲剂的磷酸盐或枸橼酸盐、作为张度剂的氯化钠、作为防腐剂和螯合剂的依地酸钠。
12.根据权利要求1的药物组合物在制备药物中的用途,所述药物用于预防或治疗骨关节炎。
13.根据权利要求1的药物组合物在制备药物中的用途,所述药物用于预防和治疗呼吸道炎症。
14.根据权利要求12或13的用途,其中所述的B2激肽受体拮抗剂是化合物(4-(S)-氨基-5-(4-{4-[2,4-二氯-3-(2,4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]-四氢-吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基)-三甲基-铵双盐酸氯化物。
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US20120190653A1 (en) * | 2011-01-20 | 2012-07-26 | Dow Pharmaceutical Sciences, Inc. | Therapeutic eye drop comprising doxycycline and a stabilizer |
RU2015138443A (ru) * | 2013-03-14 | 2017-04-20 | Шир Хьюман Дженетик Терапис, Инк. | Способы лечения ангионевротического отека, опосредованного рецепторами брадикинина в2 |
CN104072585A (zh) * | 2014-07-21 | 2014-10-01 | 成都圣诺生物科技股份有限公司 | 一种合成艾替班特的方法 |
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