CN114432455A - 一种慢性疼痛-抑郁共病治疗药物的制备及其应用 - Google Patents
一种慢性疼痛-抑郁共病治疗药物的制备及其应用 Download PDFInfo
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Abstract
本发明公开了一种慢性疼痛‑抑郁共病治疗药物的制备和应用。涉及TSPO激动剂及其衍生物在制备慢性疼痛‑抑郁共病药物中的应用，TSPO激动剂及其衍生物能够特异性上调相关脑区及组织的TSPO蛋白的表达量。涉及TSPO激动剂及其衍生物在药物制剂中的应用。药物制剂包括片剂、口服液、胶囊剂、颗粒剂、粉剂、丸剂或注射剂。所述药物制剂进一步包括生理学上可接受的载体，本发明所述的TSPO激动剂及其衍生物在慢性疼痛‑抑郁共病中具有显著的镇痛和抗抑郁作用。
Description
技术领域
本发明属于医药技术领域，具体涉及一种慢性疼痛-抑郁治疗药物的制备及其应用。
背景技术
疼痛是躯体存在实际或潜在的损伤而引起的一种不愉快的感觉和情感体验。疼痛可分为急性和慢性疼痛两种。急性疼痛是引导躯体趋利避害的预警标志。而慢性疼痛是指持续或反复发作超过3个月的疼痛，其发病及发展过程较为复杂。世界卫生组织于2018年在新修订的国际疾病分类（ICD-11）中首次将慢性疼痛列为独立疾病。根据流行病调查结果，我国受慢性疼痛影响的人群占人口总数的20~30%，大约有超过2亿中国人口正在忍受慢性疼痛的折磨。慢性疼痛会导致神经生理系统、认知及社交等多方面发生紊乱。其中，慢性疼痛患者病人普遍存在焦虑及抑郁症状。抑郁症以显著而持久的情绪低落或兴趣丧失为主要症状的一组心境或情感障碍。在临床上，抑郁和疼痛常常伴随发生。慢性疼痛患者的抑郁发病率是普通人群的数倍，而抑郁样症状也会增加患慢性疼痛的风险。慢性疼痛-抑郁共病治疗难度较两种疾病单发时治疗难度更大，并伴随着残疾和更高的死亡率。
神经病理性疼痛（NP）是临床常见的躯体感觉神经系统损伤或疾病直接导致的慢性疼痛，临床上主要表现为自发性疼痛、痛觉超敏和感觉异常。NP的发生涉及多种因素参与，例如外周的敏化和异常放电、中枢敏化、炎症反应和胶质细胞的活化等。药物治疗、微创介入治疗和手术治疗是临床上常见的治疗措施，但治疗效率较低，开发新的治疗靶点尤为重要。
18kDa转运蛋白（TSPO）是位于线粒体外模上的一种高度保守的疏水性跨膜蛋白质，可介导胆固醇进入线粒体。TSPO在人体中合成类固醇激素相关腺体组织中表达水平最高，中枢系统中TSPO主要分布在神经胶质细胞和少量神经元中。TSPO可以参与细胞增殖分化、细胞凋亡、免疫调节、氧化应激及类固醇激素合成等。多项研究表明，TSPO参与了神经系统多种疾病的发生发展，如脑损伤、神经退行性变、焦虑抑郁、疼痛等。无论是鞘内注射TSPO激动剂或是背根神经节给予TSPO配体，都可有效缓解大鼠痛觉超敏的现象。此外，TSPO配体可有效缓解啮齿类动物模型中的焦虑抑郁样行为，并且没有产生与苯二氮卓类药物类似的副作用。因此，TSPO可作为慢性疼痛-抑郁共病治疗的切入点，并可以针对该靶点开发新的高疗效药物。
发明内容
本发明的第一目的在于提供一种慢性疼痛-抑郁共病治疗药物；第二目的在于提供所述慢性疼痛-抑郁共病治疗药物的制剂。
本发明的第一目的是这样实现的，所述慢性疼痛-抑郁共病治疗药物由TSPO激动剂及其衍生物组成。
本发明的第二个目的是这样实现的，所述慢性疼痛-抑郁共病治疗药物的制剂是将所述TSPO激动剂及其衍生物加入辅料制备成片剂、口服液、胶囊剂、颗粒剂、粉剂、丸剂或注射剂。
本发明的TSPO激动剂及其衍生物的施用可通过口服来进行。除了活性成分，该激动剂及其衍生物可包含合适的药物载体，包括赋形剂和其他成分，其促进将活性成分加工成施用药物施用的制剂形式。
可利用药物载体将用于口服施用TSPO激动剂及其衍生物配制剂量成使用口服施用的剂量。这样的载体能将药物配置成片剂，丸剂，糖锭剂，胶囊，液体，凝胶，糖浆，结晶浆液，混悬液等，适于患者摄入。
可通过将TSPO激动剂及其衍生物以固体赋形剂，在如果需要添加合适的另外的化合物以获得片剂或糖锭剂核之后，研磨得到混合物，加工颗粒的混合物，获得用于口服应用的药物知己。合适的赋形剂包括糖或蛋白质填料，如糖，包括乳糖，蔗糖，甘露醇，山梨醇，来自玉米。小麦、水稻、马铃薯、或其他植物的淀粉；纤维素，如甲基纤维素，羟丙基甲基纤维素，或羧甲基纤维素钠；和树胶包括阿拉伯树胶或黄芪胶；以及蛋白质明胶和胶原蛋白。此外，也可添加崩解剂或增溶剂，如交联聚乙烯吡咯烷酮，琼脂，海藻酸或其盐。
可对糖锭剂核提供合适的包衣，如浓缩的糖溶液，其还可包含阿拉伯树胶，滑石，聚乙烯吡咯烷酮，卡博普凝胶，聚乙二醇，二氧化钛，漆溶液，和合适的有机溶剂或溶剂混合物。
可以口服使用的药物制剂包括明胶制备的压入混合（push-fit）胶囊，以及由明胶和包衣如甘油或山梨醇制备的软、密封的胶囊。压入混合胶囊可包含TSPO激动剂及其衍生物，其混合以填料或粘结剂如乳糖或淀粉，润滑剂如滑石或硬脂酸镁，和任选的稳定剂。在软胶囊中，TSPO激动剂及其衍生物可被溶解或悬浮在合适的液体中，如脂肪油，液体石蜡，或液体聚乙二醇，具有或不就稳定剂。
用于胃肠外施用的药物制剂包括TSPO激动剂及其衍生物的水溶液。可使用生理适用的缓冲液如Hank’s 溶液，Ringer’s 溶液或生理盐水将本发明药物配制成注射用水溶液。水性注射液可加入增加混悬液粘度的物质，如羧甲基纤维素钠，山梨醇或葡聚糖。另外，TSPO激动剂及其衍生物的的混悬液可被制备为适当的油性注射混悬液。合适的脂性溶剂或载体包括脂肪油如芝麻油，或合成的脂肪酸酯，如油酸乙酯或甘油三酯，或脂质体。混悬液还可以包括合适的稳定剂或增加药物溶解度的溶剂以允许制备高浓度的溶液的试剂。
对于局部或鼻内施用，可在制剂中使用适于穿透特定屏障的渗透剂。
本发明首先通过聚类分析的方法从前期建立的坐骨神经分支损伤（spared nerveinjury，SNI）小鼠中筛选出抑郁易感小鼠与非易感小鼠，并通过蛋白印迹法在抑郁易感小鼠相关脑区及组织中发现了TSPO蛋白表达量的降低，提示其可能与慢性疼痛-抑郁共病的发生发展相关，有望成为治疗该共病的靶点之一。
为了证实TSPO在慢性疼痛-抑郁共病中的确切作用，申请人通过给易感小鼠注射TSPO激动剂，特异性上调相关脑区及组织的TSPO蛋白的表达量，小鼠社会行为学试验指标显示，增加TSPO表达量不仅可以明显改善小鼠抑郁样表现，并且可以显著提高小鼠的痛阈。
本发明中，申请人运用 SPSS对结果进行统计分析，计量资料采用 t 检验及方差分析进行统计分析；P < 0.05 视为有统计学意义；柱状图由 GraphPad 作图软件完成。
有益效果：本发明提供的TSPO激动剂及其衍生物可制备慢性疼痛-抑郁共病治疗药物，通过促进TSPO的表达，在一定程度上缓解慢性疼痛和减轻抑郁样症状。上述结果为慢性疼痛伴抑郁样症状提供了新的病理生理机制，并为该共病提供了新的治疗靶点。
附图说明
图1为SNI手术组根据糖水偏好实验结果进行聚类分析图；
图2为假手术组、易感组及非易感组机械缩足反射阈值折线图，***/###P<0.001,易感组与其他两组比较有统计学意义；
图3为假手术组、易感组及非易感组糖水偏好试验的柱状图，***P<0.001,易感组与其他两组比较有统计学意义；
图4为TSPO在不同组织中的蛋白表达量柱状图，*P<0.05,**P<0.01,***P<0.001，易感组与其他两组比较有统计学意义；
图5为假手术组、易感组及TSPO激动剂处理后易感组的机械缩足反射阈值折线图，***/###P<0.001,TSPO激动剂处理的易感组与其他两组相比有统计学意义；
图6为假手术组、易感组及TSPPO激动剂处理后易感组的糖水偏好试验的柱状图，***P<0.001，TSPO激动剂处理的易感组与其他两组相比有统计学意义。
具体实施方式
下面结合附图对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
实施例1：坐骨神经分支损伤模型抑郁易感小鼠及非易感小鼠社会行为学试验的差异
1.1实验动物
选取8-12周C57小鼠，饲养3-5天后开始正式的造模试验。试验前将C57小鼠随机分为两组：假手术组（sham）和手术组（SNI）。
1.2抑郁易感组非易感组大鼠造模流程
试验采用雄性成年C57小鼠使用坐骨神经分支损伤（spared nerve injury，SNI）构建慢性神经病理性疼痛模型。手术时采用七氟烷吸入麻醉，在小鼠左后腿大腿中部切开皮肤和肌肉，暴露坐骨神经及其三个分支。用6.0缝合线结扎腓总神经和胫神经并剪断，腓肠神经保持完好无损。术后将假手术组与SNI手术组进行糖水偏好的行为学测试，根据行为学结果对两组小鼠的抑郁样行为进行评估，依据行为学的结果，将SNI手术组划分为易感组和分易感组，如图1所示。
1.3机械缩足反射阈值（MWT）
根据up-and-dowm的方法进行测试与计算小鼠MWT。本实验采用0.008、0.02、0.07、0.16、0.4、1.0、2.0g的Von Frey纤维毛。每次试验前将大鼠防止到5*5*5cm的有机玻璃盒中适应环境，待小鼠减少探索性活动后开始试验。将纤维毛垂直刺激小鼠足底中心，使纤维毛弯曲。当小鼠出现抬脚、舔足等阳性反应时，则为阳性反应，反之，则为阴性反应。试验结束后，用50%Von Frey反应阈值公式机选出小鼠的MWT。
MWT=[(10Xf+Kδ)/10000]*50%
其中Xf为测量的最后一个von Frey细丝的值，K为阳性反应或阴性反应的模式，δ为刺激过程中出现的阴性和阳性的行为学变化。
如图2所示，SNI组痛阈值明显低于sham组。
1.4社会行为学试验
舔舐糖水可以引起小鼠的快感体验，让小鼠感到兴奋，糖水偏好程度可用于评价小鼠的快感缺失。试验第19天，给予小鼠两瓶1%蔗糖水，24h后同样给予该小鼠1%的蔗糖水和普通水各一瓶，适应24小时，之后禁食禁饮24h，再将一瓶普通水，一瓶1%的蔗糖水置入笼中，24h后称重，计算糖水偏爱程度，即SPT=[糖水消耗量/(糖水消耗量+普通水消耗量)]。
结果如图3显示，易感组糖水消耗量明显低于非易感组和假手术组。
实施例2：脑组织中TSPO表达量测定
选取sham组和易感组前额叶皮质（mPFC）、海马、脊髓、肝脏、肾及肠组织，置于预冷的研钵中剪碎，加入RIPA总蛋白提取液匀浆，将匀浆吸入0.2ml离心管中，冰上裂解30min后，1200rpm、4℃离心10min。将各管上清液移至新的离心管中，根据BCA试剂盒（博士德，武汉）指南检测待测样品的蛋白浓度。在将收集到的蛋白样品经过电泳、转模及封闭后，进行TSPO一抗及二抗的孵育。最后通过使用显影进行蛋白检测。
与sham组相比，TSPO在易感组小鼠中mPFC、海马、脊髓、肝脏、肾及肠组织中表达量明显下降，如图4所示。
实施例3：上调TSPO表达量
如实施例1所述，对小鼠进行慢性疼痛-抑郁共病造模。于SNI手术后第15天给予假手术组和易感组TSPO激动剂处理后，在第21天进行糖水偏好试验，测量小鼠机械缩足反射阈值（步骤如实施例1）。
如图4与图5所示，上调TSPO表达量后，易感组机械缩足反射阈值上升，糖水偏好比重增加，说明镇痛效果与抗抑郁作用较好。结合实验结果，我们可知TSPO激动剂及其衍生物可发挥镇痛和改善抑郁样症状，具有治疗慢性疼痛-抑郁共病的潜能。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变形，这些改进和变形也应视为本发明的保护范围。
Claims (5)
1.TSPO激动剂及其衍生物在制备慢性疼痛-抑郁共病药物中的应用。
2.根据权利要求1所述的应用，所述TSPO激动剂及其衍生物能够特异性上调相关脑区及组织的TSPO蛋白的表达量。
3.根据权利要求1-2任一项所述TSPO激动剂及其衍生物在药物制剂中的应用。
4.根据权利要求3所述的应用，所述药物制剂包括片剂、口服液、胶囊剂、颗粒剂、粉剂、丸剂或注射剂。
5.根据权利要求3所述的应用，所述药物制剂进一步包括生理学上可接受的载体，所述载体能将药物配置成片剂，丸剂，糖锭剂，胶囊，液体，凝胶，糖浆，结晶浆液或混悬液。
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