CN116688135A - 一种骨关节炎药物治疗组合物及其制备方法和应用 - Google Patents
一种骨关节炎药物治疗组合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于药物领域,具体涉及一种骨关节炎药物治疗组合物及其制备方法和应用。在实验中意外发现:肾素抑制剂和血管紧张素转化酶抑制剂的联合给药可以更加有效地对抗骨关节炎,减少关节软骨损失,诱发关节软骨再生。其中,所述肾素抑制剂为阿利吉仑,所述血管紧张素转化酶抑制剂为卡托普利。所述卡托普利和阿利吉仑的重量比为1:4。无论是从药物安全性还是价格方面考虑,这两类药物的重组药物具有较好的安全性、治疗骨关节炎的有效性和药物可选择性。
Description
技术领域
本发明属于药物领域,具体涉及一种骨关节炎药物治疗组合物及其制备方法和应用。
背景技术
骨关节炎(osteoarthritis,OA)是一种由多因素引起的关节软骨退化性损伤、关节边缘和软骨下骨反应性增生、关节边缘新生骨赘和关节变形,继而导致关节疼痛、畸形和活动障碍为主要症状的常见疾病。骨关节炎有较高的发病率、致畸率和致残率,但目前尚不能完全阐明其发病机制,也缺乏有效的治疗手段。
骨关节炎疾病通常表现为关节软骨损失和滑囊、关节、关节周围骨质的结构改变,其中关节软骨损伤是骨关节炎发病和病程进展的关键环节,关节软骨不仅自身修复能力极度有限,而且不可再生,因此保护关节软骨便成为治疗骨关节炎的重要目标。通过评估骨关节炎患者的关节软骨发现,其呈现不可逆性破坏,加之炎性因子的增多,这无疑会加重软骨损伤和降低关节日常活动度。骨关节炎已成为损害老年人群健康的突出问题,主要表现在日常活动时的疼痛感和身体功能障碍,以及不同程度的关节运动障碍、疼痛障碍、肌肉松弛障碍、关机畸形障碍、挛缩障碍和生活质量降低。
非甾体类药剂是治疗骨关节炎的最早药物之一,主要通过抗炎、镇痛来缓解骨关节炎症状。此外,透明质酸、硫酸软骨素钠等关节软骨保护剂也被用来治疗骨关节炎。这两大类药物主要作用是缓解骨关节炎症状,但未能有效控制骨关节炎的进展,更无法从骨关节炎发病机制上对其实现有效干预。目前,新型抗骨关节炎药物的研发成果也颇少,如IL-1具备促进软骨再生的能力,但在药剂制备中收效甚微;以及p21活性化激活酶(PKA)拮抗剂(包含反义核苷酸、核酶和小分子干扰RNA等活性物)的药物组合体也未有效控制骨关节炎进程。
本发明人所在课题组的在先研究(CN110075304A)发现了血管紧张素转化酶抑制剂和血管紧张素Ⅱ受体拮抗剂联合给药可以有效对抗骨关节炎,减少关节软骨损失,诱发关节软骨再生。在此基础上,有需要进一步研发疗效更佳的治疗骨关节炎疾病的药物,且这类药物能从发病机制上改善骨关节炎症状和延缓骨关节炎进程。
发明内容
为解决上述技术问题,本发明人在实验中意外发现:相比于现有技术,肾素抑制剂和血管紧张素转化酶抑制剂的联合给药可以更加有效地对抗骨关节炎,减少关节软骨损失,诱发关节软骨再生。
为实现上述目的,本发明采用的技术方案是:
第一方面,包含肾素抑制剂和血管紧张素转化酶抑制剂的药物组合物在制备用于治疗骨关节炎的药物中的用途。
第二方面,包含肾素抑制剂和血管紧张素转化酶抑制剂的药物组合物在制备用于减少关节软骨损失或诱发关节软骨再生的药物中的用途。
优选地,本发明中使用的肾素抑制剂可以选自阿利吉仑、依那吉仑。
优选地,本发明中使用的血管紧张素转化酶抑制剂可以选自卡托普利、依那普利、依那普利拉、赖诺普利、雷米普利、佐芬普利、西罗普利、阿拉普利、贝那普利、地拉普利、喷托普利、喹那普利、喹那普利拉、莫昔普利、伦唑普利、喹那普利、螺普利、西拉普利、培哚普利和福辛普利。
优选地,所述肾素抑制剂为阿利吉仑,所述血管紧张素转化酶抑制剂为卡托普利。
优选地,所述卡托普利和阿利吉仑的重量比为1:2-10,更优选为1:4。
优选地,所述药物组合物为片剂、胶囊或颗粒剂的形式。
本技术方案的药物联合或组合或组合物中,既可以是原形活性成分的形式,也可以是其可药用盐形式。首先,药物化合物合适的可药用盐包括酸加成盐,其可以通过将化合物的溶液与多种可药用酸组合后混合而形成。此外,本技术方案的化合物携带酸性部分适合的可药用盐包括碱金属盐、碱土金属盐和合适的有机配体形式的盐。本技术方案的药物组合物可以任选地包含可药用的载体、赋形剂或稀释剂,以及活性药物化合物可与任何合适的粘结剂、润滑剂、助悬剂、包衣剂和(或)增溶剂混合,例如,根据常规的药物配混技术,通过将化合物与药用载体充分混合来制备含有本技术方案中的活性成分或药物组合物。适当的情况下,可以每次施用单个或两个或更多个该组合物的片剂或胶囊剂,或在持续释放制剂中施用该配混物。另外,根据不同的给药途径或方式,药物组合物的载体可以采取多种形式,对于诸如混悬剂、溶液之类的液体口服制剂,合适的载体和添加剂包括水、油类、调味剂等;对于固体口服剂,如散剂、片剂,合适的载体包括淀粉、糖和稀释剂等;对于胃肠外给药,载体通常有无菌水组成,并且可加入其他成分以增加可溶性或防腐性。
对于某些应用,优选将该组合物以含有赋形剂如淀粉或乳糖的片剂形式经口施用,或以胶囊剂单独地或与赋形剂混合经口施用,或以含有调味剂或着色剂的酏剂、溶液剂或混悬剂的形式经口施用。本技术方案的化合物组合还可以经胃肠外注射,例如静脉注射、肌内注射或皮下注射。在这种情况下,该组合物将包含合适的载体或稀释剂。对于胃肠外施用,该组合型组合物最好以无菌水溶液形式使用,其可含其他物质,例如足够的盐或单糖以制备与血液等渗的溶液。对于面颊或舌下施用,该组合型组合物可以片剂或锭剂形式施用,其可以常规方式配制。
在本技术方案中的用途、治疗方法和药物组合物所涉及的实施方案中,可以涉及有效量的药物组合。在技术方案中,治疗有效量指可在治疗、改善或减缓任一种待治疗疾病/症状或在其中产生积极效果的量。在本技术方案中,通过对组合物中包含的制剂成分和其质量比例的调整来观测疗效,最终确定为优选、更优选、特别优选3个等级。此外,本技术方案中的有效精确剂量可由主治医师确定,考虑接受治疗的受试者的具体情况、治疗持续时间、疾病严重性和合理的医学判断等因素,可根据动物试验的结果用数学方法来确定给人施用药物组合物的治疗有效量。待施用的用于治疗或预防的药物组合物的治疗有效量可由本领域技术人员容易的确定,并且最佳剂量将随所使用的具体化合物、给药模式、制剂规格和疾病症状的进展而变化。此外,由于待治疗的具体受试者相关因素,包括受试者年龄、体重、饮食和施用时间,需要将剂量调至合适治疗水平。
与现有技术相比,本发明的有益效果是:
(1)骨关节炎的发病机制尚不能完全阐明,因此发现骨关节炎可能的发病机制,并利用这一机制来防治骨关节炎是与既往技术方案的最大区别。本发明人在实验中意外发现:与本发明课题组的在先研究相比,使用肾素抑制剂和血管紧张素转化酶抑制剂的联合给药可以更加有效地对抗骨关节炎,减少关节软骨损失,诱发关节软骨再生。
(2)本技术方案中的组合药物应用普遍,安全性高。本技术方案中采用肾素抑制剂和血管紧张素受体转换酶抑制剂进行重组药物,这两类药物经过临床试验、长期的临床用药和药物不良反应报道,具有相对较好的安全性,因此在临床上应用普遍。尽管这两类药物仍存有副作用,但具有多数患者对药物耐受性强、可选择治疗药物种类多和价格亲民且治疗有效等诸多优势。无论是从药物安全性还是价格方面考虑,这两类药物的重组药物具有较好的安全性、治疗骨关节炎的有效性和药物可选择性。
(3)本技术方案中药物重组的形式多样、重量比例可调。本技术方案中采用肾素抑制剂和血管紧张素转换酶抑制剂进行药物重组,能组合制成多种药物组合形式,比如粉剂、溶液、注射液、栓剂等,同时能够根据不同病人的病情特征和药物使用便宜等情况来调整药物的使用方式,以达到对骨关节炎的有效治疗。本技术方案通过试验和综合评估发现,肾素抑制剂和血管紧张素转换酶抑制剂的重量比例为4:1时,能够有效对抗骨关节炎,减少软骨损失和促进软骨再生。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
制备实施例1:本技术方案中的药物组合物(粉末)
在本技术方案中,取阿利吉伦(肾素抑制剂)和卡托普利(血管紧张素转换酶抑制剂)的药物活性成分,过筛,按重量比4:1比例混合,即得到药物组合物(粉末)。
制备实施例2:本技术方案中的药物组合物(溶液)
取上述制备实施例1中的粉末,超声下溶于50%乙醇水溶液(含有十二烷基硫酸钠)中,得到本技术方案中的药物组合物(溶液)。
实验实施例:本技术方案中的药物组合物在胶原酶诱导的兔骨关节炎模型中的软骨再生作用
步骤1:制备胶原酶诱导的兔骨关节炎模型
肌内注射麻药以麻醉新西兰白兔(雄性,11周)。用4ml磷酸盐缓冲液(PBS)将2.91mg胶原酶乳化,然后将250ul乳化的胶原酶溶液注射到每只兔经剃毛的右爪关节中。阴性对照组中,采用正常兔注射同样剂量的PBS代替。初次注射后4天,再次向每只注射胶原酶溶液以诱发骨关节炎。
步骤2:诱导骨关节炎后的软骨再生作用
第1次注射胶原酶后,每天使用胃肠管向兔口服施用测样样品2ml。实验组使用制备实施例2中得到的药物组合物溶液(卡托普利浓度为50mg/mL,阿利吉仑浓度为200mg/mL)。阴性对照组施用无菌水。阳性对照组1组(阿利吉仑浓度为200mg/mL)和阳性对照组2组(卡托普利浓度为50mg/mL)分别仅给予本技术方案中的1种施用药物。阳性对照组3组(卡托普利浓度为50mg/mL,缬沙坦浓度为200mg/mL)为在先研究中的药物组合物。口服施用5周后,进行软骨合成测定。将右爪软骨切成薄片,取30mg软骨切片溶于1ml无血清培养基中。将20mL放射性标记的[35S]Na2SO4加入其中,混合物在37℃孵育24小时。将培养基以12,000rpm离心5分钟,弃去上清,向其中加入1mL0.5MNaOH。在4℃缓慢搅拌悬液48小时,使用PD-10过滤柱进行过滤,并使用闪烁计数器测量放射性水平,进而计算软骨损失率(%)。实验结果如表1所示。
表1
由表1的实验结果可以看出:与阴性对照组相比,本发明药物组合物治疗组中兔右爪的软骨再生水平和能力更高、更强。阴性对照组中软骨损失为40%。在阳性对照组中,1组(阿利吉仑)和2组(卡托普利)的软骨损失分别为27%和22%,而3组(缬沙坦+卡托普利)的软骨损失为18%。与之相比,本技术方案中的药物组合物治疗组仅有12%的软骨损失。这些试验结果说明,本技术方案中的药物组合物通过显著减少由骨关节炎导致的软骨损失而具有软骨保护作用,且明显优于单独施用本技术方案中施用任一药物成分以及在先研究药物组合物的治疗效果。根据实验结果,利用金正均Q值法计算表明本技术方案中施用阿利吉仑和卡托普利治疗骨关节炎具有协同作用,本技术方案计算Q值约为3.6(注:Q=P1+2/(P1+P2-P1*P2),P1、P2和P1+2分别代表阳性对照1组、2组和本技术方案中药物组合物的有效率。Q<1说明两种药物具有拮抗作用,Q=1说明两种药物具有相加作用,Q>1说明两种药物具有协同作用)。同本技术方案相比,治疗骨关节炎的现有使用药物以对症治疗为多,均未能达到预防或治疗骨关节炎的预期效果,甚至无法缓解部分病人的临床症状。本技术方案提出通过RAS表达的关键点靶向防治骨关节炎,从骨关节炎可能的发病机制上来防治骨关节炎和期望有效改善目前骨关节炎的治疗现状。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域普通技术人员来说,在不脱离本发明原理的前提下,还可以对技术方案做出若干修改或等同替换,这些修改或等同替换也应视为本发明的保护范围。
Claims (4)
1.包含肾素抑制剂和血管紧张素转化酶抑制剂的药物组合物在制备用于治疗骨关节炎的药物中的用途。
2.包含肾素抑制剂和血管紧张素转化酶抑制剂的药物组合物在制备用于减少关节软骨损失或诱发关节软骨再生的药物中的用途。
3.根据权利要求1或2所述的用途,其中所述肾素抑制剂为阿利吉仑,并且所述血管紧张素转化酶抑制剂为卡托普利。
4.根据权利要求3所述的用途,其中卡托普利和阿利吉仑的重量比为1:4。
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