CN113117080A - 一种向脑部递送β2肾上腺素受体激动剂的方法 - Google Patents
一种向脑部递送β2肾上腺素受体激动剂的方法 Download PDFInfo
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Abstract
本发明属于医药领域，具体涉及向脑部递送β2肾上腺素受体激动剂的经鼻给药制剂在治疗阿尔茨海默病和帕金森病等中枢神经系统疾病的药物应用。
Description
技术领域
本发明属于医药领域，具体涉及一种向脑部递送β2肾上腺素受体激动剂的经鼻给药制剂在治疗阿尔茨海默病和帕金森病等中枢神经系统退行性疾病以及精神性疾病的药物应用。
背景技术
β2肾上腺素受体属于G蛋白偶联受体，广泛地参与生理功能的调节过程，包括调控血管张力、调节心脏的新陈代谢以及参与记忆的形成等。β2肾上腺素受体激动剂如沙丁胺醇临床主要用于治疗哮喘。但研究表明激动β2肾上腺素受体有利于治疗阿尔茨海默病和帕金森病等神经退行性疾病。注射β2肾上腺素受体激动剂对帕金森病具有治疗效果。阿尔茨海默病和帕金森病属于中枢神经系统疾病，治疗中枢神经系统疾病的药物需要在脑中达到一定的暴露量才能产生治疗效果。由于β2肾上腺素受体激动剂主要被用于治疗哮喘，大多数常用β2肾上腺素受体激动剂为口服、静注或经肺吸入制剂，在该给药条件下药物不能透过血脑屏障，因此到达脑部的含量较低。例如研究表明大鼠静脉给予沙丁胺醇后药物在大脑中的浓度只占到血浆浓度的5％。目前并没有β2肾上腺素受体激动剂在临床上被用于治疗中枢神经系统疾病，主要原因之一是现有的给药途径和药物制剂不易透过血脑屏障到达脑部。因此寻找向脑部递送β2肾上腺素受体激动剂的最佳方法是具有重要临床意义。
经鼻给药制剂是将药物递送至鼻腔，然后经鼻粘膜吸收进而发挥局部或全身疗效的一种制剂。但有部分药物，经鼻该药后可以通过嗅神经和三叉神经末梢转运至脑部中枢神经系统(Dahlin,等Pharm.Res.2000,17,737–742)。因此，对于不能透过血脑屏障的药物，经鼻给药制剂有可能提高药物的脑靶向性。但也有研究表明亲水性的美托洛尔鼻腔、舌下和口服给药后的生物利用度没有明显差别，脑靶靶向性低。由于静脉或口服给药β2肾上腺素受体激动剂沙丁胺醇后，药物基本不能穿过血脑屏障到达脑部，因此经鼻腔给药β2肾上腺素受体激动剂沙丁胺醇可能是该类药物向脑部递送的有效方式，从而可能用于治疗相关中枢神经系统疾病。目前并没有研究将沙丁胺醇等β2肾上腺素受体激动剂的消旋及异构体开发成经鼻给药制剂，也没有将用上述药物制成鼻腔给药制剂用于治疗阿尔茨海默病和帕金森病等中枢神经系统疾病的报道。因此将β2肾上腺素受体激动剂开发成经鼻给药制剂，通过脑神经末梢转运进入脑组织达到治疗阿尔茨海默病和帕金森病等中枢神经系统疾病的效果是未被满足的临床需求。
发明内容
为了克服现有的技术中存在的缺点和不足之处，本发明的首要目的在于提出β2肾上腺素受体激动剂经鼻给药制剂可以成为治疗阿尔茨海默病和帕金森病等中枢神经系统疾病的新方法。
本发明的目的通过下述技术方案实现：
本发明使用β2肾上腺素受体激动剂消旋体及其手性对映体沙丁胺醇制备鼻腔递送用药物。本发明意外地发现经鼻腔给药通过使用质谱成像技术可以在脑部检测到明显的左旋沙丁胺醇分布。然而，在血液中基本检测不到沙丁胺醇。另一方面，本发明通过静脉或腹腔或口服给药左旋沙丁胺醇后，意外地发现在脑中则完全没有检测到左旋沙丁胺醇，说明通过静脉或口服给药，药物不能透过血脑屏障。此外，本发明通过在造模成功的帕金森大鼠模型上进行鼻腔给药后行为学药效实验，意外发现β2肾上腺素受体激动剂消旋体及其手性对映体(优映体)具有帕金森疾病治疗作用。而口服或腹腔及静脉给药同样剂量或更高剂量的沙丁胺醇或其他β2肾上腺素受体激动剂消旋体及其手性对映体，却没有类似的治疗作用。本发明证明，经鼻腔给药的途径是β2肾上腺素受体激动剂治疗神经退行性疾病的最佳方法。本发明的这一结果是普通业内人士不可推测的。
本发明使用的β2肾上腺素受体激动剂包括沙丁胺醇、班布特罗、特布他林、奥西那林、非诺特罗、氯丙那林、妥洛特罗、克仑特罗、丙卡特罗、甲氧那明、福莫特罗、沙美特罗、海索那林、茚达特罗、奥达特罗、维兰特罗、卡莫特罗、川丁特罗等的消旋体和优映体。
本发明使用上述药物还可以制成药学上可接受的盐包括硫酸盐、硫酸氢盐、盐酸盐、氢溴酸盐、磷酸二氢盐、甲基磺酸盐、溴化盐、醋酸盐、草酸盐、马来酸盐、富马酸盐、琥珀酸盐、2-萘基硫酸盐、葡糖酸盐、柠檬酸盐、酒石酸盐、乳酸盐、丙酮酸盐、羟乙基磺酸盐、苯磺酸盐、对甲苯磺酸盐。
本发明使用上述药物还可以制备成经鼻给药的溶液剂、纳米粒、脂质体、外泌体、乳剂、磷脂复合物、原位凝胶、微球、环糊精包合物制剂。制剂的方式可以为滴鼻水剂、滴鼻乳剂、滴鼻凝胶剂、鼻喷雾化剂或干粉鼻吸入剂。
本发明还发现的经鼻给药治疗神经系统疾病特别适用于水溶性较强的β2肾上腺素受体激动剂消旋体和优映体；同时也适用于脂溶性较强的β2肾上腺素受体激动剂消旋体和优映体。以及适用于任何口服或静注肌注而不能充分透过血脑屏障达到脑部从而发挥治疗作用的β2肾上腺素受体激动剂消旋体和优映体。
本发明使用上述药物可以用于治疗的中枢神经系统退行性疾病包括阿尔茨海默病和帕金森病等。本发明使用上述药物还可以用于治疗精神性疾病如偏头痛、癔症或癫痫等。
附图说明
图1为脑组织分区和样品摆放示意图
图2为左旋沙丁胺醇加氢准分子离子经鼻给药和静脉给药成像结果图
图3为左旋沙丁胺醇给药后药效学评价行为学网格测试结果
图4为左旋沙丁胺醇给药后药效学评价行为学跨步测试结果
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实例1：左旋沙丁胺醇鼻滴剂和注射剂的制备
配制左旋沙丁胺醇药液：40mg/mL(鼻腔给药)和10mg/mL(静脉注射)，4℃保存待用。
实例2：给药及样品制备
1)标准品制备：大鼠麻醉心脏灌流后，取脑并称重。加入2倍体积的生理盐水研磨，将药液用生理盐水配成浓度分别为20μg/mL，2μg/mL，200ng/mL和20ng/mL的药液，取50μL脑匀浆分别置于5个离心管，再分别加入50μL不同浓度的药液和生理盐水配成标准品待用。
2)经鼻给药样品制备：大鼠麻醉后。用10μL移液枪取40mg/mL药液(每次取10μL)向左右鼻腔各滴20μL，共40μL，给药剂量为8mg/kg。分别在给药时间(15min，30min和45min)后取脑组织，并进行冰冻切片，将取得的大鼠脑分为四个区域(如图1的A图所示)，每个区域切一片，切片厚度20μm。
3)静脉给药样品制备：大鼠麻醉后。用1mL注射器吸取0.16mL的10mg/mL药液由尾静脉部位给药，给药剂量为8mg/kg。分别在给药时间(15min，30min和45min)后取脑组织，并进行冰冻切片，将取得的大鼠脑分为四个区域(如图1的A图所示)，每个区域切一片，切片厚度20μm。
4)样品摆放：将同一种给药方式下的同一区域不同时间点的组织切片置于载玻片上，之后分别取2.5μL不同浓度标准品涂抹于含有脑组织切片的玻片上，晾干，等待检测。脑冷冻切片及标准品摆放如图1的B图所示。
实例3：检测大鼠脑组织中的左旋沙丁胺醇
1)仪器：高分辨质谱仪SYNAPT G2-Si(WATERS公司)配备解吸电喷雾电离离子源(WATERS公司)。
2)测定方法：正离子模式，喷雾毛细管电压为4.5kV、样品锥孔电压为60V，离子源温度为100℃，解吸附溶剂为95％甲醇，5％水，1‰甲酸，含有内标亮氨酸脑啡肽，浓度为6μg/mL，流速为2μL/min。
结果如图2所示。对于经鼻和静脉给药的1区，我们发现经鼻给药后左旋沙丁胺醇可以更多的进入到脑组织，药物主要分布在脑组织边缘和中间区域，而静脉给药组的脑组织切片没有检测到有药物分布。对于2区，同样是经鼻给药组检测到了药物分布，特别是30min脑组织切片，而静脉给药组没有检测到药物。对于3区，经鼻给药组和静脉给药组都没有检测到明显的药物。对于4区，我们发现左旋沙丁胺醇经鼻给药后30min处的边缘有药物分布，静脉给药组没有检测到药物。上述结果说明左旋沙丁胺醇鼻滴剂可以更好地将药物递送到脑部。
实例4：行为学研究
1)造模：大鼠颈部皮下注射鱼藤酮1.5mg/kg/d，注射30天，每周停药一天。
2)分组:无造模对照组，鼻滴(低剂量组0.45mg/kg/d)组，鼻滴(中剂量组0.9mg/kg/d)组，鼻滴(高剂量组1.8mg/kg/d)组，造模不给药组，每组6只(n＝6)。
3)行为学测试：网格及跨步测试
大鼠网格测试，如图3A，造模组的反应时间显著高于无造模对照组，表明造模成功。如图3B，鼻腔给药组反应时间与造模组相比显著减少。跨步测试，如图4A，造模组的跨步数显著低于无造模对照组，表明造模成功。如图4B，鼻腔给药组反应时间与造模组相比显著增加。行为学结果表明，鼻腔给药左旋沙丁胺醇具有治疗帕金森疾病的效果。
基于上述研究结果，我们发现药物通过鼻腔可以进入大鼠的嗅球部位，并达到较高的药物浓度，之后可以沿着大脑横切面中轴靠下部位向大脑进一步转运。同时，给药后的行为学结果支持了左旋沙丁胺醇鼻腔给药具有治疗帕金森疾病的药效这一结论。因此左旋沙丁胺醇经鼻给药制剂具有成为治疗帕金森病新方法的潜力。
以上所述，仅是本发明的说明实施例，并非对本发明作任何形式上的限制，任何熟悉本专业的技术人员，在不脱离本发明技术方案范围内，当可利用上述揭示的方法及技术内容作出些许的更动或修饰为等同变化的等效实施例，但凡是依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰，均仍属于本发明技术方案的范围内。
Claims (7)
1.β2肾上腺素受体激动剂及其手性对映体在药学上可接受的盐经鼻给药制剂在制备治疗中枢神经系统疾病的药物中的应用。
2.根据权利要求1所述的应用，其特征在于，其中所述中枢神经系统疾病是神经退行性疾病包括：老年痴呆及帕金森疾病。
3.根据权利要求1所述的应用，其特征在于，其中所述中枢神经系统疾病是精神性疾病如偏头痛、癔症或癫痫等。
4.根据权利要求1所述的应用，其特征在于，其中所述β2肾上腺素受体激动剂包括沙丁胺醇、班布特罗、特布他林、奥西那林、非诺特罗、氯丙那林、妥洛特罗、克仑特罗、丙卡特罗、甲氧那明、福莫特罗、沙美特罗、海索那林、茚达特罗、奥达特罗、维兰特罗、卡莫特罗和川丁特罗等。
5.根据权利要求1所述的应用，其特征在于，其中所述的药学上可接受的盐包括硫酸盐、硫酸氢盐、盐酸盐、氢溴酸盐、磷酸二氢盐、甲基磺酸盐、溴化盐、醋酸盐、草酸盐、马来酸盐、富马酸盐、琥珀酸盐、2-萘基硫酸盐、葡糖酸盐、柠檬酸盐、酒石酸盐、乳酸盐、丙酮酸盐、羟乙基磺酸盐、苯磺酸盐、对甲苯磺酸盐。
6.根据权利要求1所述的应用，其特征在于，其中所述的经鼻给药制剂的辅料为溶液剂、纳米粒、脂质体、外泌体、乳剂、磷脂复合物、原位凝胶、微球、环糊精包合物。
7.根据权利要求1所述的应用，其特征在于，其中所述的经鼻给药制剂的方式为滴鼻水剂、滴鼻乳剂、滴鼻凝胶剂、鼻喷雾化剂或干粉鼻吸入剂。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114832116A (zh) * | 2022-05-19 | 2022-08-02 | 沈阳药科大学 | 基于小胶质细胞表型调节和脑内铁清除的ros响应型纳米载体及其制备方法与应用 |
| WO2022262873A3 (zh) * | 2021-06-14 | 2023-02-23 | 谭文 | R-氨基甲酸酯-β-苯乙醇胺类化合物治疗学习和记忆缺陷以及神经退行性疾病的应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040248984A1 (en) * | 2001-08-29 | 2004-12-09 | Josef Krieglstein | Use of $g(b)-adrenoceptor agonists for the treatment of neurodegenerative diseases |
| CN106413708A (zh) * | 2014-06-18 | 2017-02-15 | 上海翰森生物医药科技有限公司 | Nmda受体拮抗剂的医药用途及其药物组合物 |
-
2019
- 2019-12-30 CN CN201911392292.7A patent/CN113117080A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040248984A1 (en) * | 2001-08-29 | 2004-12-09 | Josef Krieglstein | Use of $g(b)-adrenoceptor agonists for the treatment of neurodegenerative diseases |
| CN106413708A (zh) * | 2014-06-18 | 2017-02-15 | 上海翰森生物医药科技有限公司 | Nmda受体拮抗剂的医药用途及其药物组合物 |
Non-Patent Citations (6)
| Title |
|---|
| A A HUSSAIN ET AL: ""Intranasal administration of a beta adrenergic amine: an alternative to metered-dose inhalers"", 《COMPARATIVE STUDY》 * |
| A A HUSSAIN ET AL: ""Intranasal administration of a beta adrenergic amine: an alternative to metered-dose inhalers"", 《COMPARATIVE STUDY》, vol. 69, no. 1, 30 June 1992 (1992-06-30), pages 26 - 29 * |
| ANWAR A HUSSAIN，ET AL: ""Nasal administration of albuterol: an alternative route of delivery"", 《COMPARATIVE STUDY》 * |
| ANWAR A HUSSAIN，ET AL: ""Nasal administration of albuterol: an alternative route of delivery"", 《COMPARATIVE STUDY》, vol. 56, no. 10, 31 October 2004 (2004-10-31), pages 1211 - 1215 * |
| HENRY MILGROM MD ET AL: ""Low-dose levalbuterol in children with asthma: Safety and efficacy in comparison with placebo and racemic albuterol"", 《JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY》, vol. 108, no. 6, pages 938 - 945 * |
| 毛承樾主编: "《耳鼻咽喉科临床手册》", 1 April 1961, 上海科学技术出版社, pages: 287 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022262873A3 (zh) * | 2021-06-14 | 2023-02-23 | 谭文 | R-氨基甲酸酯-β-苯乙醇胺类化合物治疗学习和记忆缺陷以及神经退行性疾病的应用 |
| CN114832116A (zh) * | 2022-05-19 | 2022-08-02 | 沈阳药科大学 | 基于小胶质细胞表型调节和脑内铁清除的ros响应型纳米载体及其制备方法与应用 |
| CN114832116B (zh) * | 2022-05-19 | 2024-01-26 | 沈阳药科大学 | 基于小胶质细胞表型调节和脑内铁清除的ros响应型纳米载体及其制备方法与应用 |
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