Drug delivery strategies and clinical research progress for encephalopathy
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摘要:
血脑屏障的存在限制了药物的脑内有效递送，导致脑病疗效不佳，难以满足患者的临床需求。近年来，基于优效给药途径和新型递药系统等策略开发的创新制剂，能够突破血脑屏障的桎梏，显著提升药物的入脑效率及降低外周不良反应的发生率，为患者带来重大治疗意义。本文对脑病用药在临床研究中存在的关键问题进行分析，详尽综述了脑病治疗领域内全球创新药物制剂的发展及研发策略，并展望未来治疗策略的应用前景，以期为新一代药物研发提供新思路和方法。
Abstract:The blood-brain barrier in humans significantly restricts the effective delivery of drugs into the brain, resulting in poor therapeutic efficacy and difficulty in brain disease management. In recent years, innovative strategies and novel preparations have been studied and developed in order to circumvent the blood-brain barrier, achieve efficient drug entry into the brain, minimize the incidence of peripheral adverse effects, and bring significant therapeutic outcomes to patients. This review summarizes some key development strategies for treating encephalopathy, to provide some insights for the development of the next generation of drugs.
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表 1 临床脑病用药的鼻用制剂
活性成分 商品名 上市时间 适应证 剂 型 研发企业 上市地区 盐酸右美托咪定 特美定 2024 术前镇静 鼻用喷雾剂 四川普锐特 中国 盐酸右美托咪定 艾倍美 2023 术前镇静 鼻用喷雾剂 上海恒瑞 中国 盐酸扎维吉泮 Zavzpret 2023 偏头痛 鼻用喷雾剂 Pfizer 美国 盐酸纳美芬 Opvee 2023 阿片类药物过量 鼻用喷雾剂 Indivior 美国 盐酸纳洛酮 Rextovy 2023 阿片类药物过量 鼻用喷雾剂 Amphastar 美国 盐酸纳洛酮 Kloxxado 2021 阿片类药物过量 鼻用喷雾剂 Hikma 美国 地西泮 Valtoco 2020 癫痫 鼻用喷雾剂 Neurelis 美国 盐酸艾司氯胺酮 Spravato 2019 重度抑郁症 鼻用喷雾剂 Janssen 美国 咪达唑仑 Nayzilam 2019 癫痫 鼻用喷雾剂 UCB 美国 甲磺酸双氢麦角胺 Trudhesa 2019 偏头痛 鼻用喷雾剂 Impel 美国 舒马曲坦 Tosymra 2019 偏头痛 鼻用喷雾剂 Tonix Meds 美国 琥珀酸舒马曲坦 Onzetra Xsail 2016 偏头痛 鼻用粉雾剂 Optinose 美国 盐酸纳洛酮 Narcan 2015 阿片类药物过量 鼻用喷雾剂 Adapt 美国 佐米曲坦 Zomig 2013 偏头痛 鼻用喷雾剂 Amneal 美国 舒马曲坦 Imitrex 1999 偏头痛 鼻用喷雾剂 GSK 美国 甲磺酸双氢麦角胺 Migranal 1997 偏头痛 鼻用喷雾剂 Bausch 美国 
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表 2 临床脑病用药的口腔黏膜给药制剂
活性成分 商品名 上市时间 适应证 剂 型 研发企业 上市地区 地西泮 Libervant 2024 癫痫 口颊膜 Aquestive 美国 依达拉奉 奉易达 2022 肌萎缩侧索硬化 舌下片 南京百鑫愉 中国 盐酸右美托咪定 Igalmi 2022 精神分裂症患者的激越 舌下膜 BioXcel 美国 盐酸阿扑吗啡 Kynmobi 2020 帕金森病患者的“OFF期”症状 舌下膜 Sunovion 美国 咪达唑仑 Buccolam 2011 癫痫 颊黏膜溶液 Neuraxpharm 欧洲 酒石酸唑吡坦 Edluar 2009 失眠 舌下片 Mylan 美国 马来酸阿塞那平 Saphris 2009 精神分裂症 舌下片 Allergan 美国
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表 3 临床脑病用药的吸入制剂
活性成分 商品名 上市时间 适应证 剂 型 研发企业 上市地区 左旋多巴 Inbrija 2018 帕金森病患者的“OFF期”症状 吸入粉雾剂 Acorda 美国 洛沙平 Adasuve 2012 精神分裂症患者的激越 吸入粉雾剂 Alexza 美国 七氟烷 Ultane 1995 麻醉 吸入液体制剂 Abbvie 美国 地氟烷 Suprane 1992 麻醉 吸入液体制剂 Baxter hlthcare 美国 异氟烷 Forane 1979 麻醉 吸入液体制剂 Baxter hlthcare 美国
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表 4 临床脑病用药的经皮给药制剂
活性成分 商品名 上市时间 适应证 剂 型 研发公司 上市地区 盐酸多奈哌齐 Adlarity 2023 阿尔茨海默病 储库型贴剂 Corium 美国 多奈哌齐 Allydone 2023 阿尔茨海默病 骨架型贴剂 Teikoku Seiyaku 日本 右旋安非他命 Xelstrym 2022 注意缺陷多动症 骨架型贴剂 Noven 美国 多奈哌齐 Donerion 2021 阿尔茨海默病 骨架型贴剂 Icure 韩国 利斯的明 Rivalif 2021 阿尔茨海默病 储库型贴剂 Luye 欧洲 盐酸罗匹尼罗 Haruropi 2019 帕金森病 骨架型贴剂 Hisamitsu 日本 布南色林 Lonasen 2019 精神分裂症 骨架型贴剂 Sumitomo 日本 阿塞那平 Secuado 2019 精神分裂症 骨架型贴剂 Hisamitsu 美国 利斯的明 Exelon 2007 阿尔茨海默病 骨架型贴剂 Sandoz 美国 罗替高汀 Neupro 2006 帕金森病 骨架型贴剂 UCB 欧洲 司来吉兰 Emsam 2006 重度抑郁症 骨架型贴剂 Somerset 美国 哌甲酯 Daytrana 2006 注意缺陷多动症 骨架型贴剂 Noven 美国 东莨菪碱 Transderm Scop 1979 晕动病 储库型贴剂 Alza 美国
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表 5 处于临床试验阶段的脑室内注射给药
活性成分 开始时间 研发阶段 临床试验编号 适应证 研发企业 ETX101 2024 Ⅰ/Ⅱ期 NCT05419492 Dravet综合征 Encoded NGN401 2023 Ⅰ/Ⅱ期 NCT05898620 雷特综合征 Neurogene GC1123 2022 Ⅰ期 NCT05422482 黏多糖贮积症Ⅱ型 GC Biopharma MB101 2021 Ⅰ期 NCT04661384 复发或难治性恶性胶质瘤 Mustang CT010 2020 Ⅱ期 NCT04153175 难治性癫痫 Cerebral Neurostem 2017 Ⅰ/Ⅱ期 NCT03172117 阿尔茨海默病 Medipost sNN0031 2015 Ⅰ/Ⅱ期 NCT02408562 帕金森病 Newron sNN0029 2009 Ⅰ/Ⅱ期 NCT01384162 肌萎缩侧索硬化 Newron
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表 6 处于临床试验阶段的对流增强给药技术
活性成分 开始时间 研发阶段 临床试验编号 适应证 研发企业 RGL193 2023 Ⅰ期 NCT06195124 帕金森病 Regenelead AMT260 2023 Ⅰ/Ⅱ期 NCT06063850 难治性颞叶癫痫 uniQure AMT130 2021 Ⅰ/Ⅱ期 NCT05243017 亨廷顿舞蹈病 uniQure OS2966 2021 Ⅰ期 NCT04608812 复发/进展性高级别胶质瘤 OncoSynergy MTX110 2018 Ⅰ/Ⅱ期 NCT03566199 弥漫性桥脑神经胶质瘤 Midatech NBIb1817 2018 Ⅰ期 NCT03562494 帕金森病 Neurocrine PVSRIPO 2017 Ⅱ期 NCT02986178 复发性胶质母细胞瘤 Istari Oncology MDNA55 2017 Ⅱ期 NCT02858895 复发性胶质母细胞瘤 Medicenna DNX2401 2016 Ⅱ期 NCT02798406 复发性胶质母细胞瘤 DNAtrix AB1005 2013 Ⅰ期 NCT01621581 帕金森病 AskBio PRX321 2009 Ⅱ期 NCT00797940 复发性胶质母细胞瘤 Protox AP12009 2008 Ⅲ期 NCT00761280 继发性胶质母细胞瘤 Isarna
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表 7 处于临床试验阶段的鞘内注射给药
活性成分 开始时间 研发阶段 临床试验编号 适应证 研发企业 RJK002 2024 Ⅰ期 NCT06454682 肌萎缩侧索硬化 Rejuko ALN-APP 2024 Ⅱ期 NCT06393712 脑淀粉样血管病 Alnylam ION717 2024 Ⅰ/Ⅱ期 NCT06153966 传染性海绵状脑病 Ionis BIIB080 2022 Ⅱ期 NCT05399888 阿尔茨海默病 Biogen ION464 2022 Ⅰ期 NCT04165486 多系统萎缩 Ionis ION582 2021 Ⅰ/Ⅱ期 NCT05127226 Angelman综合征 Ionis WVE003 2021 Ⅰ/Ⅱ期 NCT05032196 亨廷顿舞蹈病 Wave Life ION373 2021 Ⅲ期 NCT04849741 亚历山大病 Ionis STK001 2021 Ⅱ期 NCT04740476 Dravet综合征 Stoke BIIB105 2020 Ⅱ期 NCT04494256 肌萎缩侧索硬化 Biogen GTX102 2020 Ⅰ/Ⅱ期 NCT04259281 Angelman综合征 Ultragenyx BIIB094 2019 Ⅰ期 NCT03976349 帕金森病 Biogen
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表 8 处于临床阶段的受体介导转胞吞递药系统
活性成分 靶向受体 开始时间 研发阶段 临床试验编号 适应证 研发企业 ANG1005 低密度脂蛋白受体相关蛋白1 2023 Ⅲ期 NCT03613181 乳腺癌脑转移 AngioChem ABL301 胰岛素样生长因子1受体 2022 Ⅰ期 NCT05756920 帕金森病 ABL DNL310 转铁蛋白受体 2022 Ⅱ/Ⅲ期 NCT05371613 黏多糖贮积症Ⅱ型 Denali DNL593 转铁蛋白受体 2022 Ⅰ/Ⅱ期 NCT05262023 额颞叶痴呆 Denali RG6102 转铁蛋白受体 2021 Ⅰ/Ⅱ期 NCT04639050 阿尔茨海默病 Roche JR171 转铁蛋白受体 2021 Ⅰ/Ⅱ期 NCT04453085 黏多糖贮积症Ⅰ型 JCR AGT181 胰岛素受体 2016 Ⅰ/Ⅱ期 NCT03071341 黏多糖贮积症Ⅰ型 ArmaGen AGT182 胰岛素受体 2015 Ⅰ期 NCT02262338 黏多糖贮积症Ⅱ型 ArmaGen
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