CN111000983A - 一种新的重组人白细胞介素-1受体拮抗剂的药用用途 - Google Patents
一种新的重组人白细胞介素-1受体拮抗剂的药用用途 Download PDFInfo
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Abstract
本发明涉及重组人白细胞介素‑1受体拮抗剂对急性痛风的炎症和疼痛有治疗作用，本发明公开了重组人白细胞介素‑1受体拮抗剂能够有效控制急性痛风的急性关节炎症状，可以减轻患者的疼痛感。而且本发明并没有秋水仙碱、非甾体类抗炎药和糖皮质激素这三类常见控制痛风症状的药物的严重不良反应。
Description
技术领域
本发明涉及一种新的重组人白细胞介素-1受体拮抗剂的药用用途，具体涉及重组人白细胞介素-1受体拮抗剂对急性痛风的炎症和疼痛有治疗作用。
背景技术
重组白细胞介素-1受体拮抗剂(rhIL-1Ra)是存在于人体的蛋白质类细胞因子受体拮抗剂，通过特异性结合白细胞介素-1受体，竞争性地阻止重组白细胞介素-1与其受体的结合，使重组白细胞介素-1无法发挥生物学效应。重组白细胞介素-1受体拮抗剂是人源性的白细胞介素-1受体拮抗剂的重组产品，是由153个氨基酸组成，分子量为17.3KD。
rhIL-1Ra在机体的炎症反应中起着极为关键的启动作用。人类许多疾病的发生、发展过程中都有rhIL-1Ra参与，rhIL-1Ra本身不仅可以趋化体内的炎性反应细胞聚集至炎症发生部位，还可刺激体内的多种炎症介导介质的产生，而使炎症反应进一步加剧。因此，如何消除rhIL-1Ra的影响将对治愈某些炎症疾病起着重要作用。rhIL-1Ra是体内自然存在的rhIL-1Ra拮抗剂。它可以特异地与细胞表面的rhIL-1Ra受体结合而不激活靶细胞，从而阻断rhIL-1Ra的生物学活性。rhIL-1Ra是迄今为止发现的唯一细胞因子拮抗剂。自从rhIL-1Ra被发现以来，人们就试图将其开发为可供临床应用的药品，大量基础研究和初步临床研究结果显示rhIL-1Ra对人类的许多炎性疾病确有疗效。此类报道更激起了人们对rhIL-1Ra成为新药的企盼。
国家风湿病数据中心(Chinese Rheumatism Data Center，CRDC)网络注册及随访研究的阶段数据显示，目前我国高尿酸血症患者人数已达1.7亿，其中痛风患者超过8000万人，痛风的患病率在1％～3％，并呈逐年上升趋势。我国痛风患者平均年龄为48岁。逐步趋年轻化，男性发病率高于女性，超过50％的痛风患者为超重或肥胖。全球范围内，发达国家的痛风患病率高于发展中国家。北美和西欧国家痛风较为常见，患病率为1％～4％。
痛风是因血尿酸增高及尿酸盐结晶在关节和肾脏组织沉积而引起的一种常见且复杂的关节炎类型综合征，它包括关节炎、痛风石、泌尿道尿酸性结石及痛风性肾病等。引起痛风的原因为体内嘌呤代谢的最终产物—尿酸过剩，高于正常值。这可因尿酸氧化酶(或尿酸酶)的缺乏使尿酸不能被氧化而增多；亦可因肾脏功能不全使尿酸排泄减少，两者均可造成高尿酸血症。基础研究证实，痛风性关节炎患者关节腔内沉积的尿酸盐晶体能够激活中性粒细胞碱性磷酸酶3(neutrophilic alkaline phosphatase-3，NALP3)炎症体，促进IL-1β的成熟及分泌，最终导致痛风炎症反应。通常来说，造成痛风的主要原因包括但不限于：①饮食原因。吃了太多的肉类和海鲜，畅饮了过多的啤酒之后，人体的尿酸水平升高，就可能造成尿酸盐沉积；②肥胖。肥胖导致的后果是体内尿酸的增加，肾脏无法彻底代谢多余的尿酸；③服用了某些药物。这些药物会导致体内尿酸水平升高；④家族史。如果家人患有痛风，那么你患病的概率也会大大增加。痛风患者常在夜晚反复发病，关节部位出现严重的疼痛、水肿、红肿和炎症。水肿后组织变软，活动受限，最后影响日常生活。如果没有及时治疗，拖延的后果是疼痛感将越来越强，让人难以忍受。一旦出现炎症，就会发烧，关节会受到损害，骨质会被腐蚀，导致关节变形(肾脏也会受损，严重的会发生肾结石甚至是肾衰竭，危及生命。
针对痛风的不同临床阶段，抗痛风药可分为控制急性关节炎症状和抗高尿酸血症两大类药物。控制痛风性关节炎症状的药物主要包括秋水仙碱、非甾体类抗炎药和糖皮质激素等；抗高尿酸血症类药物主要包括抑制尿酸生成药(如别嘌醇)和促进尿酸排出药(如苯溴马隆和丙磺舒等)。这些药物均会产生一些不良反应，主要包括①胃肠道症状：包括腹泻、恶心、呕吐和腹痛等，偶有引起胃溃疡、胃出血、胃穿孔；②肌肉、周围神经系统症状：包括头痛、发热、嗜睡、眩晕、乏力和精神异常等；③过敏反应：包括呼吸困难、脱发、皮肤瘙痒及丘疹或荨麻疹等；④偶引起白细胞减少、血小板减少、贫血、骨髓抑制、肝肾功能损害、糖尿病及高血压等少见不良反应。
综上所述，目前治疗痛风的药物都不太理想，都存在一些不良反应，所以开发理想的治疗急性痛风的药物成为很重要的课题。
发明内容
本发明为解决现有技术中的用于治疗急性痛风的药物使用具有一定的不良反应的缺陷，从而为患者提供一种新的用于治疗急性痛风的炎症和疼痛的重组人白细胞介素-1受体拮抗剂。
本发明的重组人白细胞介素-1受体拮抗剂能够有效控制急性痛风的急性关节炎症状，可以减轻患者的疼痛感，除了各别患者会出现注射部位刺激反应，出现红肿，没有其他严重不良反应。
本发明的重组人白细胞介素-1受体拮抗剂是利用大肠杆菌表达技术构建含有白细胞介素-1受体拮抗剂基因的重组质粒，并转化至大肠杆菌中获得稳定的工程菌，工程菌发酵后纯化获得重组人白细胞介素-1受体拮抗剂原液，加入辅料制成重组人白细胞介素-1受体拮抗剂注射液。
本发明的重组人白细胞介素-1受体拮抗剂，其特征在于：剂型是注射剂，规格是80mg/0.8ml，在2～8℃避光保存下可保存至少24个月。
本发明的重组人白细胞介素-1受体拮抗剂注射液采用的包装材料是带注射针的预灌封注射器组合件，直接注射，减少了二次污染的机会，患者可以在医生的指导下，实现自行注射给药。
本发明的重组人白细胞介素-1受体拮抗剂对急性痛风的治疗相对于传统药物具有不良反应小，安全有效、质量稳定、患者依从性好等优势。
有益效果
本发明提供了重组人白细胞介素-1受体拮抗剂的新用途，重组人白细胞介素-1受体拮抗剂对于各种程度的急性痛风具有一定的效果，与现有的控制急性关节炎症状和抗高尿酸血症两大类药物相比，效果显著，且治疗急性痛风时除了各别患者会出现注射部位刺激反应，出现红肿，没有其他严重不良反应，为重组人白细胞介素-1受体拮抗剂找到了新的适应症。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
应当理解的是，在说明书和权利要求书中使用的术语或词语不应当理解为具有在字典中限定的含义，而应理解为在以下原则的基础上具有与其在本发明上下文中的含义一致的含义：术语的概念可以适当地由发明人为了对本发明的最佳说明而限定。
实施例1：
本申请所述的rhIL-1Ra的氨基酸序列如SEQ ID NO:1所示，其制备方法如下：本发明的重组人白细胞介素-1受体拮抗剂是利用大肠杆菌表达技术构建含有白细胞介素-1受体拮抗剂基因的重组质粒，并转化至大肠杆菌中获得稳定的工程菌，工程菌发酵后纯化获得重组人白细胞介素-1受体拮抗剂原液，加入辅料制成重组人白细胞介素-1受体拮抗剂注射液。
实施例2：药效学试验
本发明人以60只雌性SD大鼠观察了rhIL-1Ra对尿酸钠致大鼠急性痛风的治疗作用。
方法：
60只雌性SD大鼠检疫期结束后测热痛阈值和右后肢踝关节直径的基础值，并根据热痛阈值进行均衡分组，分出10只正常对照组动物和50只造模组动物。第二天，造模组使用异氟烷麻醉后于右后肢踝关节后侧沿跟腱内侧以30～40°方向穿刺关节腔内注射50μL尿酸钠(25mg/mL，生理盐水配制)，正常对照组注射等体积生理盐水，造模3h后测量右后肢踝关节直径和热痛阈值，并计算肿胀度。挑选造模组36只动物根据肿胀度进行分层随机分组，分为溶剂对照模型组、原料药低剂量组(9mg/kg)和原料药高剂量组(18mg/kg)。分组后按体重颈部皮下注射给药，每天1次，连续三天。正常对照组和溶剂对照模型组给予溶媒(安慰剂)，原料药低剂量组和高剂量组分别给予浓度为9mg/mL和18mg/mL的rhIL-1Ra，给药体积均为1mL/kg。测量给药后4h、24h和72h的踝关节直径和热痛阈值，计算肿胀度和肿胀抑制率以及热痛阈值提高率。
结果：
肿胀度统计结果见表1，如表1所示，造模3h后，除正常对照组外，其余各组肿胀度显著升高(均为P＜0.01)；给药后，与溶剂对照模型组比较，原料药低剂量组和高剂量组在给药后4h、24h及72h时的肿胀度均降低，且原料药高剂量组在给药后4h和24h时降低有显著性差异(均为P＜0.05)。给药组肿胀抑制率统计显示，原料药低剂量组和高剂量组在给药后4h、24h及72h时肿胀抑制率分别为(19.62％、8.99％及11.23％)和(26.67％、31.90％及9.57％)。
表1 rhIL-1Ra对急性痛风大鼠踝关节肿胀度的影响
备注：与正常对照组比较，aa，P＜0.01；与溶剂对照模型组比较，b，P＜0.05。
热痛阈值检测结果见表2及表3。如表2所示，与溶剂对照模型组比较，原料药低剂量组在给药后4h和72h的热痛阈值有升高趋势，没有统计学差异，而原料药高剂量组在给药后不同时间点的热痛阈值均升高，且在给药后4h和72h时升高有显著性差异(P＜0.01，P＜0.05)；原料药低、高剂量组间比较显示，在给药后不同时间点，高剂量组热痛阈值均比低剂量组高，且在给药后4h时有极显著性差异(P＜0.01)，表明原料药高剂量组比溶剂对照模型组和原料药低剂量组动物的疼痛减轻。
如表3所示，与造模前基础值比较，正常对照组在造模后以及给药不同时间点的热痛阈值均降低，其中在给药后24h、72h时降低有显著性差异(P＜0.05，P＜0.05)；而溶剂对照模型组、原料药低剂量组和高剂量组的热痛阈值在造模后3h的急性期先升高，继而在给药后不同时间点又降低，另外原料药高剂量组在给药后72h时热痛阈值不再降低并轻微升高。与溶剂对照模型组比较，原料药高剂量组在造模后以及给药后不同时间点的痛阈值均增加，且在给药后4h和72h时增加有显著性差异(P＜0.01，P＜0.05)。
表2 rhIL-1Ra对急性痛风大鼠热痛阈值的影响
备注：与正常对照组比较，a，＜0.05，aa，P＜0.01；与溶剂对照模型组比较，b，P＜0.05，bb，P＜0.01；与原料药低剂量组比较，c，P＜0.05，cc，P＜0.01。
表3 rhIL-1Ra对急性痛风大鼠热痛阈值提高率的影响(％)
结论：
高剂量rhIL-1Ra能够显著减轻尿酸钠诱导的大鼠踝关节肿胀，并减轻急性痛风鼠的痛觉感受，提示rhIL-1Ra对急性痛风时的炎症和疼痛有治疗作用。
实施例3：药理学试验
本发明人以小鼠和猫观察了rhIL-1Ra除急性痛风生物药效作用以外的其他广泛药理作用。
方法：
1.取体重18-22g小鼠，雌雄各半，随机分4组，每组10只，分为溶剂对照模型组、原料药低剂量组(4.5mg/kg)、原料药中剂量组(9mg/kg)和原料药高剂量组(18mg/kg)。皮下注射给药后，观察小鼠的一般行为、姿势、步态，有无振颤或麻痹，食欲、大小便有无失禁等变化。以及分别记录给药前2分钟和给药后30分钟，小鼠走动时间及双前肢上抬举次数。
2.取体重2-3kg的猫，雌雄各半，随机分4组，每组5只，分为溶剂对照模型组、原料药低剂量组(4.5mg/kg)、原料药中剂量组(9mg/kg)和原料药高剂量组(18mg/kg)。首先3％戊巴比妥钠30mg/kg腹腔注射麻醉后仰卧固定，颈总动脉插管，接水银检压计，肢体Ⅱ导联心电图，记录血压、QRS波、ST段、T波和心律。皮下注射给药后，连续记录2小时血压计心电图。比较给药前后的变化。
3.取体重2-3kg的猫，雌雄各半，随机分4组，每组5只，分为溶剂对照模型组、原料药低剂量组(4.5mg/kg)、原料药中剂量组(9mg/kg)和原料药高剂量组(18mg/kg)。首先3％戊巴比妥钠30mg/kg腹腔注射麻醉后仰卧固定，于胸部呼吸运动最明显部位牵引一根线与滑轮和描笔相连接，猫呼吸运动频率和深度记录与记纹鼓上。皮下注射给药后，连续记录2小时内呼吸运动频率和深度。比较给药前后呼吸运动的变化。
结果：
清醒小鼠皮下注射rhIL-1Ra给药后，其一般行为表现，姿势、步态、肌张力和食欲、大小便均无明显变化。表明rhIL-1Ra对小鼠精神和神经系统未产生不良反应，无兴奋和抑制作用。rhIL-1Ra对麻醉猫血压、心电图、呼吸运动等指标观察，其给药前后并无明显改变。
结论：
因此，rhIL-1Ra除抗炎、镇痛作用外，无其他广泛药理作用。
实施例4：毒理学试验一、急性毒性试验本发明人以小鼠来观察rhIL-1Ra大剂量单次给药的毒性反应。
方法：
取体重18-22g小鼠，雌雄各半，随机分2组，每组10只，分为溶剂对照模型组、原料药高剂量组(400mg/kg、相当于小鼠药效高剂量的20倍，相当临床使用剂量的200-300倍)。皮下注射一次给药后，连续观察14天，观察小鼠是否出现震颤、惊厥、僵直、流涎、稀便、嗜睡、昏迷、呼吸及四肢活动异常、死亡等。
结果：
所有小鼠均存活，其一般行为表现、食欲等均无异常，体重增加。未观察到明显的毒性或异常反应。
结论：
rhIL-1Ra以临床人用200倍的剂量单次给药对小鼠无毒性，说明rhIL-1Ra对小鼠的LD50大于400mg/kg。
二、长期毒性试验本发明人以恒河猴观察了连续皮下注射rhIL-1Ra180天的长期毒性。
方法：
32只健康恒河猴，雌雄分别按体重随机分为4组，试验设对照组、低、中和高剂量组，每组8只，雌雄各半。根据临床推荐量为100mg/人天，给药剂量分别设为5、30和180mg/kgd，按体重计算分别相当于推荐临床剂量的2.5、15.0和90.0倍，每天上午喂食前皮下注射给药，溶剂对照组sc等量溶媒。180天给药后每组各处死2只动物(雌雄各半)做病理解剖，其余动物继续给药。观察症状和检测指标包括：(1)一般症状及指标：观察猴的外观、行为、活动、步态、精神、食欲、大小便、皮毛、有无流涎、恶心、呕吐、有无死亡等。一般指标包括体重、食量、肛温、呼吸、瞳孔共5项。(2)心电图：肢体Ⅱ导心电图之心率，P-R间期、QRS波群、S-T段和Q-T间期。(3)血液学指标：红细胞(RBC计数、血红蛋白(Hb)定量、红细胞压积(HC、红细胞平均容积MCV)、红细胞平均血红蛋白含量MCH、红细胞平均血红蛋白浓度MCHC、血小板(Plat)计数、白细胞(WBC)计数及分类(淋巴细胞和粒细胞)、血浆凝血酶时间(T)、血浆凝血酶原时间PT)、活化部分凝血活酶时间aPTT、血浆纤维蛋白原(Fig)含量血小板聚集率共16项。(4)血液生化指标：丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、碱性磷酸酶(ALP)、总胆红素(Tbi)、尿素氮BUN)、肌酐(CT)、总蛋白(TP)、白蛋白(AB)、血糖(GIU)、总胆固醇(TCH)、乳酸脱氢酶(LDH)、纤维蛋白(FIB)、pH值、血清K+、Na+、Cr-、iCa2+、TCa2+、Mg2+、TCO2、P和阴离子隙(AG)。(5)尿液检查项目：亚硝酸盐、pH、蛋白质、潜血、葡萄糖、酮体、胆红素和尿胆原共8项。(6)抗体测定：ELISA方法检测抗体滴度及生物活性法测定是否为中和抗体。(7)骨髓检查：观察各系各阶段细胞有无改变及增生程度。(8)病理检查：大体观察各脏器有无阳性病变。对心、肝、脾、肺、肾、脑、肾上腺、胸腺、甲状腺、前列腺、睾丸、子宫及卵巢13个脏器称重，分别计算各的相对重量。组织学检查：观察心、肝、脾、肺、肾、脑、胃、十二指肠、回肠结肠、垂体、甲状腺、肾上腺、胸腺、胰腺、肠系膜淋巴结、前列腺、膀胱、睾丸及附睾、子宫及卵巢、眼球、视神经、注射部位皮下组织有无病变。
结果：
(1)rhIL-1Ra给药初期高剂量组有1只猴(26号猴)出现食量过性减少，第二周后逐渐恢复，其它31只猴未发现该现象。给药后动物未见外观体征及行为活动异常，无腺体分泌和呼吸异变，无恶心呕吐、流涎、发热，腹泻等等症状。(2)体重变化：与对照组相比，给药期间各组猴体重变化未见明显差异，给药期间各组动物体重均正常增长。(3)心电图检测显示：与对照组相比，各组心电基本正常，未见显著变化。(4)血液生化学检查结果显示：与对照组相比，高剂量组血清生化指标AST、ALT略有下降，但未见显著差异(p>005)，ALB明显升高(p<0.05)，其余各项指标均在正常范围内波动，未见显著变化。(5)血液学检查结果显示各组动物的各项指标均在正常范围内波动，未见显著变化；(6)抗体测定数据表明：给药1月给药组动物的血清中可检测到抗药抗体，且低、中剂量组和高剂量组的动物均有抗体出现，但均未测出有中和抗体。这与文献报道是一致的。(7)尿液检查：与对照组相比，各项指标均在正常范围内波动，未见明显异常。(8)组织病理学结果：与对照组相比，高剂量组1只猴肺轻度局部点状出血，2只猴肾个别近曲小管空泡化，2只猴肝胞浆轻度疏松化，1只猴心肌有轻度炎症。其余脏器未见明显病变。中、低剂量组各脏器未见明显病变。
结论：
(1)rhIL-1Ra对猴的一般状况无显著不良影响。(2)rhIL-1Ra对猴凝血系统无显著影响，但高剂量(180mgkg)对蛋白质代谢可能有一定的影响。(3)给药1月后给药组动物的血清中可检测到抗药抗体，且低、中剂量组和高剂量组的动物均有抗体出现，但均未测出有中和抗体。(4)rhIL-1Ra高剂量对猴肝、肾功能可能有轻微影响，对中、低剂量组无影响。
三、免疫毒性试验本发明人以猴观察了注射rhIL-1Ra后出现抗IL-1Ra抗体的时间、滴度以及是否有中和作用。
方法：
用ELISA方法检测抗IL-1Ra抗体，用IL-1Ra生物活性测定法检测是否为中和抗体。
结果：
给药1月后给药组动物的血清中可检测到抗IL-1Ra抗体，且低、中剂量组和高剂量组的动物均有抗体出现，无剂量相关性，但均未测出有中和抗体。
四、溶血性试验本发明人以空白为对照，观察rhIL-1Ra注射液对兔红细胞的溶血及凝集作用。
方法：
取新西兰家兔雄性1只，抽取兔血5ml,去除纤维蛋白原后，加生理盐水，离心至上清为无色，取红细胞，加生理盐水稀释成2％的混悬液。取6支试管，分别加入0.1、0.2、0.3、0.4、0.5ml(80mg/ml)的rhIL-1Ra注射液，用生理盐水调至2.5ml，分别加入2％兔红细胞混悬液2.5ml，置隔水式恒温培养箱，分别于给药0.5、1、2和3小时后，观察各管溶血及凝集情况，用显微镜观察血球的破裂情况。
结果：
给予0.1、0.2、0.3、0.4、0.5ml的rhIL-1Ra注射液，与兔血作用0.5、1、2、3hr后均未观察到溶血及凝集现象，观察结果同对照组比，不存在差异。
结论：
rhIL-1Ra注射液浓度达80mg/ml时无溶血作用。
五、局部刺激试验本发明人以恒河猴观察rhIL-1Ra的局部刺激毒性反应。
方法：
取恒河猴，随机分4组，分为溶剂对照模型组、原料药低剂量组(5mg/kg)、原料药中剂量组(30mg/kg)和原料药高剂量组(180mg/kg)。每日注射一次，四肢交替皮下注射，连续给药180天。
结果：
对照组及给药的低剂量组未出现异常，而中、高剂量组部分动物给药后观察到注射部位的皮肤红肿，有些还伴有抓痕，但无溃破或感染出现，两月内基本消失。
结论：
猴皮下注射给药后，在中高剂量时注射部位出现红肿现象，但随着给药的继续。症状消失，局部耐受情况尚好。
序列表
<110> 长春生物制品研究所有限责任公司
<120> 一种新的重组人白细胞介素-1受体拮抗剂的药用用途
<141> 2019-12-25
<160> 1
<170> SIPOSequenceListing 1.0
<210> 2
<211> 153
<212> PRT
<213> 人工序列(Artificial Sequence)
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Val Val Pro Ile Glu Pro His Ala Leu Phe Leu Gly Ile His Gly Gly
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Lys Met Cys Leu Ser Cys Val Lys Ser Gly Asp Glu Thr Arg Leu Gln
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Leu Glu Ala Val Asn Ile Thr Asp Leu Ser Glu Asn Arg Lys Gln Asp
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Lys Arg Phe Ala Phe Ile Arg Ser Asp Ser Gly Pro Thr Thr Ser Phe
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Glu Ser Ala Ala Cys Pro Gly Trp Phe Leu Cys Thr Ala Met Glu Ala
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Asp Gln Pro Val Ser Leu Thr Asn Met Pro Asp Glu Gly Val Met Val
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Thr Lys Phe Tyr Phe Gln Glu Asp Glu
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Claims (5)
1.重组人白细胞介素-1受体拮抗剂在制备治疗急性痛风的炎症和疼痛的药物中的用途,所述的人白细胞介素-1受体拮抗剂的氨基酸序列如SEQ ID NO:1所示。
2.根据权利要求1所述的重组人白细胞介素-1受体拮抗剂的能够有效控制急性痛风的急性关节炎症状，可以减轻患者的疼痛感，除了各别患者会出现注射部位刺激反应，出现红肿，没有其他严重不良反应。
3.根据权利要求1所述的重组人白细胞介素-1受体拮抗剂的用途，其特征在于，所述的人白细胞介素-1受体拮抗剂是利用大肠杆菌表达技术构建含有白细胞介素-1受体拮抗剂基因的重组质粒，并转化至大肠杆菌中获得稳定的工程菌，工程菌发酵后纯化获得重组人白细胞介素-1受体拮抗剂原液，加入辅料制成重组人白细胞介素-1受体拮抗剂注射液。
4.根据权利要求1所述的重组人白细胞介素-1受体拮抗剂的用途，其特征在于：剂型是注射剂，规格是80mg/0.8ml，在2～8℃避光保存下可保存至少24个月。
5.根据权利要求1所述的重组人白细胞介素-1受体拮抗剂的用途，其特征在于：包装材料是带注射针的预灌封注射器组合件，可直接注射，减少了二次污染的机会，患者可以在医生的指导下，实现自行注射给药。
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