CN114073698B - 一种止痛止痒药物组合物及其应用方法 - Google Patents
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Abstract
一种止痛止痒药物组合物及其应用方法，属于医药化学技术领域。本发明的研究发现单独抑制Nav1.7或Nav1.8的活性所产生的镇痛效果随着外周神经损伤的时程而降低，而且发现对Nav1.7小分子抑制剂响应不佳的神经病理性疼痛小鼠对Nav1.8的小分子抑制剂有较好的响应。根据此发现，我们研究不同Nav1.7抑制剂和Nav1.8抑制剂联合给药的镇痛效果，并发现联合给予合适剂量的Nav1.7抑制剂PF‑05089771和Nav1.8抑制剂PF‑04885614能显著增加镇痛效果和提高响应率至100％。因此PF‑05089771和PF‑04885614的组方可以治疗涉及Nav1.7或Nav1.8活性过高引起的疾病，包括但不限于顽固性的疼痛和瘙痒。
Description
技术领域
本发明涉及医药化学领域，具体涉及钠离子通道Nav1.7和Nav1.8抑制剂在治疗Nav1.7和Nav1.8活性过高引起的疾病中的应用。
背景技术
神经病理性疼痛是一种难治的疼痛，目前临床一线药物Gabapentin和Pregabalin都只能对40％-60％的神经病理性疼痛患者有缓解效果，且有镇静(如嗜睡、疲劳、眩晕等)的副作用。因而需效果更好的治疗慢性疼痛的药物来救助患者。电压门控钠离子通道(Voltage-gated sodium channel，Nav)Nav1.7和Nav1.8在躯体感觉神经元中高表达，在瘙痒和疼痛传导中起重要作用，是一类跨膜糖蛋白复合体，由一个α亚基和数个β亚基构成。例如，编码Nav1.7的α亚基的SCN9A的功能获得突变会引起遗传性红斑性肌痛和特发性小纤维神经性痛(SFN)，而缺失Nav1.7导致人先天性对疼痛不敏感和敲除Nav1.7小鼠没有任何疼痛(包括炎症性疼痛和神经性疼痛)。编码Nav1.8的α亚基的SCN10A的功能获得性突变与SFN、神经病理性疼痛和糖尿病周围神经病变疼痛有关，而SCN10A的功能丧失突变会使人的机械疼痛敏感性降低，以及SCN10A敲除小鼠对伤害性机械刺激和热刺激具有更高的阈值(A.Kanellopoulos et al.,Voltage-gated sodium channels and pain-relateddisorders.Clin Sci(Lond).2016Dec 1；130(24):2257-2265)。基因敲除实验也证实Nav1.7和Nav1.8也是痒觉传导所必须的，表明它们是治疗痒的靶点(H.Kühn et al.,Complementary roles of murine Nav1.7,Nav1.8 and Nav1.9 in acute itchsignalling.Sci Rep.2020Feb 11；10(1):2326.)。最近报道Nav1.7和Nav1.8在一部分背根神经节中的感觉神经元中共同表达，且需同时抑制Nav1.7和Nav1.8的活性才能抑制这部分感觉神经元的动作电位发放(D.Jurcakova et al.,Voltage-Gated Sodium ChannelsRegulating Action Potential Generation in Itch-,Nociceptive-,and Low-Threshold Mechanosensitive Cutaneous C-Fibers.Mol Pharmacol.2018 94,1047-1056)。因此推测可能需要同时抑制Nav1.7和Nav1.8的功能才能取得足够好的治疗某些疼痛的效果。
虽然已报道很多Nav1.7选择性小分子抑制剂和很多Nav1.8选择性小分子抑制剂，但都还没有开发至临床应用。其中两个Nav1.7选择性抑制剂PF-05089771、GNE-0439，和两个Nav1.8选择性抑制剂PF-04885614、PF-04531083的结构如下所示：
PF-05089771：
GNE-0439：
PF-04885614:
PF-04531083:
PF-05089771抑制人Nav1.7的IC50值是11nM，但在治疗糖尿病神经病理性疼痛的临床研究中因效果不佳而失败(A.McDonnell.,Efficacy of the Nav1.7blocker PF-05089771in a randomised,placebo-controlled,double-blind clinical study insubjects with painful diabetic peripheral neuropathy.Pain.2018Aug；159(8):1465-1476.)，其体内镇痛效果不佳的原因不清楚。
发明内容
本发明的研究发现单独抑制Nav1.7或Nav1.8的活性所产生的镇痛效果随着外周神经损伤的时程而降低，而且发现对Nav1.7小分子抑制剂响应不佳的神经病理性疼痛小鼠对Nav1.8的小分子抑制剂有较好的响应。根据此发现，我们研究不同Nav1.7抑制剂和Nav1.8抑制剂联合给药的镇痛效果，并发现联合给合适剂量的Nav1.7抑制剂PF-05089771和Nav1.8抑制剂PF-04885614能显著增加镇痛效果和提高个体响应率至100％。因此PF-05089771和PF-04885614的组方可以治疗涉及Nav1.7和Nav1.8活性的疾病，包括但不限于难治性的疼痛和瘙痒。
给出本发明需要保护的技术方案，如下：
一种止痛止痒药物组合物，其特征在于，由PF-05089771和PF-04885614联合，所述药物在治疗Nav1.7和Nav1.8共相关的疾病中的应用。
上述疾病包括瘙痒和疼痛，其中疼痛包括炎症疼痛和/或神经病理性疼痛，可以选自偏头痛、牙痛、三叉神经痛、癌症相关疼痛、术后及创伤性疼痛、肌肉骨骼疼痛(如关节痛)、痛经、内脏疼痛、糖尿病周围神经病变引起的疼痛中的至少一种。
所述PF-05089771和PF-04885614的质量配比为100：1至1：100。
其中优选的为50：1至1：1。
再优选的为20：1至30：1。
所述药物组合物，其特征在于，作为药物，其给药的途径可以包括但不限于：口服、口腔内、注射、呼吸道、皮肤、眼部、鼻粘膜、直肠、阴道、耳部、透析等。
进一步说明，所述药物，具体应用时还包括药学上可接受的载体。所述载体包括任何溶剂，赋形剂、分散介质，包衣，等渗剂和/或吸收延迟剂，等等。例如，可以选自淀粉、微晶纤维素、乳糖、蔗糖、露醇、无机盐类(如硫酸钙、磷酸氢钙、碳酸钙、二水硫酸钙等)、羟丙基纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、海藻酸钠、琼脂、羟丙基甲基纤维素、甲基纤维素、羟乙基纤维素、卡波普、聚乙烯醇、丙烯酸树脂、壳聚糖、蜂蜡和硬脂酸中的至少一种。
附图说明
图1：实施例1中与SNI手术前的基础值相比，小鼠术后2周、4周、6周的机械疼痛阈值显著性降低。n＝20-28，****P<0.0001，with Mann-Whitney test。
图2：实施例1中腹腔注射2mg/kg剂量的PF-05089771(Nav1.7抑制剂)在SNI小鼠上的镇痛效果(△PWT)从术后2周到6周是逐渐降低的。n＝20-28，*P<0.05，****P<0.0001，with Mann-Whitney test。
图3：实施例1中腹腔注射45μg/kg剂量的PF-04885614(Nav1.8抑制剂)在SNI小鼠上的镇痛效果从术后2周到6周是逐渐降低的。n＝17-21，*P<0.05，***P<0.001，****P<0.0001，with Mann-Whitney test。
图4：实施例2中与溶剂组相比，腹腔注射2mg/kg的PF-05089771和45μg/kg PF-04885614能显著抑制SNI术后6周小鼠的机械疼痛，其镇痛效果比给单个药物的组的好。n＝12，*P<0.05，***P<0.001，with Mann-Whitney test。
图5：实施例2中与溶剂组相比，腹腔注射2mg/kg的PF-05089771和90μg/kg PF-04885614能显著抑制SNI术后6周小鼠的机械疼痛，其镇痛效果比给单个药物的组的好。n＝12，*P<0.05，***P<0.001，****P<0.0001，with Mann-Whitney test。
图6：实施例2中与溶剂组相比，腹腔注射100mg/kg的Gabapentin能显著抑制SNI术后6周小鼠的机械疼痛。n＝12，****P<0.0001，with Mann-Whitney test。
图7：实施例2中与溶剂组相比，腹腔注射1mg/kg的PF-05089771和45μg/kg PF-04885614能显著抑制SNI术后6周小鼠的机械疼痛，其镇痛效果比给单个药物的组的好。n＝12，*P<0.05，with Mann-Whitney test。
图8：实施例2中与溶剂组相比，腹腔注射1mg/kg的PF-05089771和45μg/kg PF-04885614(低剂量联用)的剂量组能显著抑制SNI术后6周小鼠的机械疼痛，并且2mg/kg的PF-05089771和90μg/kg的PF-04885614(高剂量联用)的镇痛效果显著优于低剂量联用组。n＝11-12，****P<0.0001，with Mann-Whitney test。
图9：实施例3中腹腔注射20μg/kg GNE-0439，或90μg/kg PF-04885614，或联用20μg/kg GNE-0439和90μg/kg PF-04885614对SNI术后6周小鼠的镇痛效果。n＝12，*P<0.05，***P<0.001，with Mann-Whitney test.
图10：实施例3中腹腔注射2mg/kg PF-05089771，或10mg/kg PF-04531083，或联合2mg/kg PF-05089771和10mg/kg PF-04531083对SNI术后6周小鼠的镇痛效果。n＝12，***P<0.001，****P<0.0001，with Mann-Whitney test。
具体实施方式
本领域公知，电压门控钠离子通道在痛觉和痒觉的传导中起重要作用。钠离子通道1.7(Nav1.7)和1.8(Nav1.8)参与生理条件下和病理条件下的疼痛的传导。
本发明团队在研究Nav1.7和Nav1.8在外周损伤诱导的小鼠神经病理性疼痛中的贡献时发现Nav1.7的抑制剂PF-05089771和Nav1.8抑制剂PF-04885614对神经病理性疼痛的镇痛效果随着疾病的时程延长而显著减弱，且个体响应率也随着疾病的时程延长而降低。并且发现对PF-05089771响应不好的个体对PF-04885614有较好的响应。从而研究联用Nav1.7和Nav1.8的抑制剂对慢性神经病理性疼痛的治疗效果，并发现不同比例的PF-05089771和 PF-04885614对慢性神经病理性疼痛有叠加的镇痛效果，且增加动物个体的响应率，最佳剂量的PF-05089771和PF-04885614组合不仅有明显的镇痛效果，而且响应率可达到100％；而联用GNE-0439和PF-04885614没有叠加的镇痛效果，联用PF-05089771和PF-04531083虽有叠加的镇痛效果，但观察到该有效剂量的PF-04531083有明显的镇静和降低体重的副作用。因此，本发明发现联合使用PF-05089771和PF-04885614可以有效缓解神经病理性疼痛，比单用PF-05089771或PF-04885614的效果优越，最佳剂量的镇痛效果与临床药物Gabapentin的效果相当，但未观察到类似于相当剂量的Gabapentin导致的镇静副作用。
以下结合附图和实施例对本发明技术方案做进一步说明。
实施例1
给单个药物的效果实施例
为了测试Nav1.7和Nav1.8抑制剂在不同时间点缓解外周神经损伤诱导的神经病理性疼痛的效果，我们购买了5-6周龄C57/BJ6小鼠(上海斯莱克实验动物有限责任公司)，饲养6个月后，把小鼠置于铁架上的透明有机玻璃罩中，30分钟后用Von Frey(DanMicGlobal,CA,USA)检测了小鼠的基础机械阈值(缩足阈值，Paw withdrawal threshold,PWT)，小鼠的平均阈值为1.54g±0.07g，见图1。根据参考文献制备了Spared nerve injury(SNI)神经损伤的神经病理性疼痛C57/BJ6小鼠模型，在术后2周、4周、6周时同样用VonFrey检测小鼠的机械疼痛阈值，其阈值显著低于术前的阈值，平均阈值分别为0.14g±0.02g、0.06g±0.01g、0.12g±0.02g，见图1。然后我们检测腹腔注射2mg/kg的PF-05089771(Nav1.7抑制剂，Bio-Techne)或45μg/kg的PF-04885614(Nav1.8抑制剂，Bio-Techne)在SNI术后2周、4周、6周小鼠上的镇痛效果。
注射药物1个小时后检测小鼠的机械疼痛阈值，结果显示注射2mg/kg的PF- 05089771能显著缓解SNI术后2周小鼠的神经性疼痛，提升小鼠的机械疼痛阈值(△PWT＝给药后阈值-给药前阈值)0.77g±0.10g，其中响应较差(△PWT≤0.2g)的小鼠占10％(2/20)；但2mg/kg的PF-05089771的效果随着术后时间的增加而递减，在SNI术后4周时只能提升小鼠的机械疼痛阈值0.39g±0.07g，其中响应较差(△PWT≤0.2g)的小鼠占41.7％(10/24)，在SNI术后6周时只能轻微提升小鼠的机械疼痛阈值0.17g±0.03g，其中响应较差(△PWT≤0.2g)的小鼠占57.1％(16/28)，见图2。
类似PF-05089771，注射45μg/kg的PF-04885614能显著缓解SNI术后2周小鼠的神经病理性疼痛，提升的机械疼痛阈值为0.86g±0.14g，其中响应较差(△PWT≤0.2g)的小鼠占11.1％(2/18)；但45μg/kg的PF-04885614的效果随着术后时间的增加而急剧减弱，在SNI术后4周时只能微弱地提升小鼠的机械疼痛阈值0.21g±0.04g，且与对照组比没有统计学显著差异，其中响应较差(△PWT≤0.2g)的小鼠占52.6％(10/19)，在SNI术后6周时平均镇痛效果下降至0.10g±0.04g，其中响应较差(△PWT≤0.2g)的小鼠占76.5％(13/17)，见图3。
实施例2
联用效果实施例
基于实施例1，我们进一步的研究发现SNI术后6周时对2mg/kg PF-05089771响应不好(△PWT≤0.2g)的小鼠占总数的2/3(8/12，见表1)，而其中的一半对90μg/kg PF-04885614有较好的响应(见表1突出显示部分)，这建议联用PF-05089771和PF-04885614可能会增加镇痛效果。我们测试并发现腹腔注射2mg/kg PF-05089771和45μg/kg或90μg/kgPF-04885614确实能显著缓解SNI术后6周的小鼠的神经病理性疼痛，其镇痛效果也显著高于单个给药组的效果，见图4和图5。且100％(12/12)的小鼠对联用2mg/kg PF-05089771和90μg/kg PF-04885614的响应好(每只小鼠升高的阈值△PWT>0.5g)，见表1。这个效果与注射100mg/kg的Gabapentin的效果(见图6)相当，但没有类似Gabapentin的镇静副作用。然后我们测试低剂量的两个化合物联用的镇痛效果。结果表明腹腔注射1mg/kg PF-05089771和45μg/kg PF-04885614也能显著的提升机械疼痛阈值0.45g，比单个给药组的效果显著增加，见图7。比较分析发现，高剂量联合给药的(2mg/kg PF-05089771和90μg/kg PF-04885614)镇痛效果显著优于低剂量联合给药的(1mg/kg PF-05089771和45μg/kg PF-04885614)镇痛效果，因而联合给予PF-05089771和PF-04885614的镇痛效果具有剂量效应，见图8。
表1 SNI术后6周小鼠对PF-05089771和PF-04885614的响应效果
实施例3
为了寻找最佳镇痛的Nav1.7和Nav1.8的抑制剂种类的组合，我们测试了另一个Nav1.7抑制剂GNE-0439和PF-04885614联用的镇痛效果。腹腔注射20μg/kg GNE-0439和90μg/kg PF-04885614至SNI术后6周小鼠，一小时后用Von Frey检测小鼠的机械阈值，发现联合给GNE-0439和PF-04885614取得的镇痛效果没有显著优于单独给GNE-0439的镇痛效果(△PWT＝0.77g±0.14g，见图9)，且没有2mg/kg的PF-05089771和90μg/kg PF-04885614的联合给药的镇痛效果(△PWT＝1.38g±0.15g)好。然后我们测试了另一个Nav1.8抑制剂PF-04531083和PF-05089771联用的镇痛效果。腹腔注射2mg/kg PF-05089771和10mg/kg PF-04531083至SNI术后6周小鼠，一小时后用Von Frey检测小鼠的机械阈值，发现虽然联合给PF-05089771和PF-04531083取得的镇痛效果比单独给PF-05089771或PF-04885614的镇痛效果更好(见图10)，但观察到10mg/kg PF-04531083有明显的镇静和降低体重的副作用。
Claims (7)
1.一种止痛止痒药物组合物，其特征在于，由PF-05089771和PF-04885614联合，所述药物在治疗Nav1.7和Nav1.8共相关的疾病中的应用；
所述PF-05089771和PF-04885614的质量配比为100：1至1：100。
2.如权利要求1所述的药物组合物，其特征在于，上述疾病包括瘙痒和疼痛，其中疼痛包括炎症疼痛和/或神经病理性疼痛，选自偏头痛、牙痛、三叉神经痛、癌症相关疼痛、术后及创伤性疼痛、肌肉骨骼疼痛、痛经、内脏疼痛、糖尿病周围神经病变引起的疼痛中的至少一种。
3.如权利要求1所述的药物组合物，其特征在于，其中质量配比为50：1至1：1。
4.如权利要求3所述的药物组合物，其特征在于，质量配比为20：1至30：1。
5.如权利要求3所述的药物组合物，其特征在于，作为药物，其给药的途径包括但不限于：口服、注射、呼吸道、皮肤、眼部、鼻粘膜、直肠、阴道、耳部、透析。
6.如权利要求5所述的药物组合物，其特征在于，所述药物，具体应用时还包括药学上可接受的载体；
所述载体包括任何溶剂，赋形剂、包衣，等渗剂和/或吸收延迟剂。
7.如权利要求6所述的药物组合物，其特征在于，载体选自淀粉、微晶纤维素、乳糖、蔗糖、露醇、硫酸钙、磷酸氢钙、碳酸钙、二水硫酸钙、羟丙基纤维素、羧甲基淀粉钠、交联聚乙烯吡咯烷酮、海藻酸钠、琼脂、羟丙基甲基纤维素、甲基纤维素、羟乙基纤维素、卡波普、聚乙烯醇、丙烯酸树脂、壳聚糖、蜂蜡和硬脂酸中的至少一种。
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| CN202010845095.2A CN114073698B (zh) | 2020-08-20 | 2020-08-20 | 一种止痛止痒药物组合物及其应用方法 |
| PCT/CN2021/072071 WO2022037006A1 (zh) | 2020-08-20 | 2021-01-15 | 一种止痛止痒药物组合物及其应用方法 |
| CA3190205A CA3190205A1 (en) | 2020-08-20 | 2021-01-15 | Analgesic and antipruritic pharmaceutical composition and application thereof |
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| EP21857112.3A EP4183778A4 (en) | 2020-08-20 | 2021-01-15 | ANALGESIC AND ANTIPRURITIC PHARMACEUTICAL COMPOSITION AND METHOD OF ADMINISTRATION THEREOF |
| KR1020237006788A KR20230047412A (ko) | 2020-08-20 | 2021-01-15 | 진통 가려움 완화 약학 조성물 및 그 응용 방법 |
| US18/171,431 US11938118B2 (en) | 2020-08-20 | 2023-02-20 | Analgesic and antipruritic pharmaceutical composition and application thereof |
| US18/590,910 US20240197690A1 (en) | 2020-08-20 | 2024-02-28 | Analgesic and antipruritic pharmacertical composition and application thereof |
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| EP (1) | EP4183778A4 (zh) |
| JP (1) | JP7549405B2 (zh) |
| KR (1) | KR20230047412A (zh) |
| CN (1) | CN114073698B (zh) |
| AU (1) | AU2021329457B2 (zh) |
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| WO2017075222A1 (en) * | 2015-10-30 | 2017-05-04 | Lieber Institute For Brain Development | Treatment of neurological and neurodevelopmental diseases and disorders associated with aberrant ion channel expression and activity |
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| PE20142099A1 (es) | 2009-01-12 | 2014-12-13 | Icagen Inc | Derivados de sulfonamida |
| WO2016009303A1 (en) | 2014-07-17 | 2016-01-21 | Pfizer Inc. | Pharmaceutical combinations comprising gabapentin or pregabalin with nav1.7 inhibitors |
| SG11201909793YA (en) | 2017-06-20 | 2019-11-28 | Raqualia Pharma Inc | AMIDE DERIVATIVES AS Nav1.7 and Nav1.8 BLOCKERS |
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| WO2017075222A1 (en) * | 2015-10-30 | 2017-05-04 | Lieber Institute For Brain Development | Treatment of neurological and neurodevelopmental diseases and disorders associated with aberrant ion channel expression and activity |
Non-Patent Citations (3)
| Title |
|---|
| Jonathan W. Theile等.The Selective Nav1.7 Inhibitor, PF-05089771, Interacts Equivalently with Fast and Slow Inactivated Nav1.7 Channels.《MOLECULAR PHARMACOLOGY》.2016,第第90卷卷(第第90卷期),文章摘要. * |
| Nigel. A. Swain等.Discovery of Clinical Candidate 4‑[2-(5-Amino‑1H‑pyrazol-4-yl)-4- chlorophenoxy]-5-chloro-2-fluoro‑N‑1,3-thiazol-4- ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7.《Journal of Medicinal Chemistry》.2017,第第60卷卷(第第60卷期),文章摘要，第7029-7042页. * |
| Theile等.Nav1.7 Inhibitor, PF-05089771, Inhibits Fast- and Slow-Inactivated Channels with Similar Affinities.《BIOPHYSICAL JOURNAL:59th Annual meeting of the Biophysical-Society》.2015,第第108卷卷(第第108卷期),第573a-574a. * |
Also Published As
| Publication number | Publication date |
|---|---|
| US11938118B2 (en) | 2024-03-26 |
| EP4183778A1 (en) | 2023-05-24 |
| KR20230047412A (ko) | 2023-04-07 |
| JP2023542276A (ja) | 2023-10-06 |
| JP7549405B2 (ja) | 2024-09-11 |
| WO2022037006A1 (zh) | 2022-02-24 |
| CN114073698A (zh) | 2022-02-22 |
| US20230201170A1 (en) | 2023-06-29 |
| AU2021329457A1 (en) | 2023-03-30 |
| AU2021329457B2 (en) | 2023-08-03 |
| US20240197690A1 (en) | 2024-06-20 |
| CA3190205A1 (en) | 2022-02-24 |
| EP4183778A4 (en) | 2024-08-07 |
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