CN117679520A - 用于防治后遗症期面神经麻痹的药物组合物及其应用 - Google Patents
用于防治后遗症期面神经麻痹的药物组合物及其应用 Download PDFInfo
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- Vascular Medicine (AREA)
Abstract
本发明涉及用于防治后遗症期面神经麻痹的药物组合物,选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、脑蛋白、吡拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、茴拉西坦、神经酸、具有修复功效的神经修复细胞蛋白提取物或神经修复蛋白组合物的任一种或其组合。本发明采用射频治疗和药物联用,各组分协同增效,药物组合物起效快、持续作用时间延长、治疗效果好。
Description
技术领域
本发明属于生物医药技术领域,具体涉及用于防治后遗症期面神经麻痹的药物组合物及其应用。
背景技术
面神经麻痹(又称面神经炎、Bell麻痹、口僻、口眼歪斜等)为常见的面神经疾病(占比60%-75%),其病理早期多发生面神经水肿和/或髓鞘水肿,面神经受压或局部循环障碍,晚期可出现轴索变性,并以茎乳孔及面神经管内部分最为显著。按照患者发病时长,将面神经麻痹其分为急性期(发病15天以内)、恢复期(发病16天至6个月)和后遗症期(发病超过6个月)。
面神经麻痹病因尚不明确。病毒感染(如潜伏的I型单纯疱疹病毒和带状疱疹病毒)及病毒感染后的重新激活被广泛接受。家族性面神经麻痹可能继发于遗传性人类白细胞抗原的自身免疫性疾病。面神经管解剖结构异常、面神经管狭窄、气候及温度的急剧变化等,均可能成为导致面瘫的危险因素。面神经的不同部位损害(包括膝状神经节前损害、膝状神经节损害、茎乳孔附近病变等)而表现不同的临床症状。面神经麻痹患者若恢复不彻底,常伴发瘫痪肌的萎缩、眼睑痉挛、连带运动、患侧面部牵拉感,且可能呈现病损后导致再生的神经纤维向邻近其他神经纤维通路生长,而支配原来属于其他神经纤维效应器所致的其他症状。
面神经麻痹包括中枢性面瘫和周围性面瘫。周围性面瘫中约有75%的患者为特发性面神经麻痹,约有25%患者的病因包括吉兰-巴雷综合征、莱姆神经螺旋体病、糖尿病性神经损害、继发性面神经麻痹、外伤性面瘫等。面神经麻痹重度患者早期出现严重面神经水肿,神经鞘膜内高压,面神经出现缺血、缺氧、水肿加重等恶性循环,甚至导致神经轴突坏死、崩解、脱髓鞘等病理改变,患者后期则错位再生而引起面部连带运动。
面神经麻痹的治疗方法包括药物(脱水药或去水肿药物、抗病毒药物、B族维生素、糖皮质激素等)治疗、针灸、理疗、面部康复训练等。轻度及中度患者经2周至2个月的治疗,明显改善症状,显效率和临床治愈率为60%-70%,但超过30%的中度及重度患者存在后遗症。截至目前,临床尚没有用于治疗面神经麻痹后遗症的有效方案。
专利申请(CN2023100429139、PCT/CN2023/073566、CN2023100429143、PCT/CN2023/073582)公开了有关具有修复功效的神经修复蛋白提取物及神经修复蛋白组合物的技术内容,前述申请及内容作为本申请必不可少的技术参考和组成部分。
发明内容
本发明的目的在于提供用于一种药物组合物用于制备防治后遗症期面神经麻痹的药物中的应用,所述防治后遗症期面神经麻痹的药物组合物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合。
本发明的优选技术方案中,所述防治后遗症期面神经麻痹的药物组合物含有鼠神经生长因子、甲钴胺、腺苷钴的任一种或其组合。
本发明的优选技术方案中,所述用于防治后遗症面神经麻痹的药物组合物由单次口服用的药物组合物和单次穴位注射用的药物组合物组成。
本发明的优选技术方案中,单次给药的药物组合物含有甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg的任一种或其组合。
本发明的优选技术方案中,口服用药物组合物的给药方案为:口服甲钴胺0.5mg/次,3-4次/天,隔月服用;腺苷钴胺0.5mg/次,3次/天,连续3周,停1周,然后继续重复半年;
本发明的优选技术方案中,所述口服用药物组合物选自同时给药或序贯给药的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物为鼠神经生长因子30ug、甲钴胺0.5mg、维生素B1 200mg的组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物含有鼠神经生长因子30-90ug、甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg,地塞米松2-5mg的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物为鼠神经生长因子30-90ug、甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg,地塞米松2-5mg、100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松2mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,组合物中,单次穴位注射的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射的药物组合物由鼠神经生长因子60ug、甲钴胺0.8mg、腺苷钴胺0.5mg,地塞米松3mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物临配临用。
本发明的优选技术方案中,选取患侧面部的阳白穴、太阳穴、四白穴、迎香穴、巨髎穴、地仓穴和颊车穴进行穴位注射。
本发明的优选技术方案中,单次穴位注射用的药物组合物每天穴位注射一次,7天为疗程。
本发明的优选技术方案中,每次穴位注射治疗2-6个疗程,优选为4-5个疗程。
本发明的优选技术方案中,所述用于防治后遗症期面神经麻痹的药物组合物任选地与射频手术、康复训练操的任一种或其组合联合使用。
本发明的优选技术方案中,所述射频手术在41℃-42℃、90V-140V、2Hz-6Hz条件下,基于长时程温控高电压变频脉冲射频800秒-1400秒。
本发明的优选技术方案中,所述射频手术在41℃-42℃、100V-120V、3Hz-5Hz条件下,基于长时程温控高电压变频脉冲射频960秒-1200秒。
本发明的优选技术方案中,所述康复训练操为发明人独创的面瘫康复训练操(著作权登记号:国作登字-2022-I-10250228和著作权登记号:国作登字-2022-F-10250229)。
本发明的优选技术方案中,所述的康复操训练选自第一套康复操训练、第二套康复操训练的任一种或其组合。
本发明的优选技术方案中,第一套康复操训练包括,一是照镜子;二是慢闭眼,闭眼5秒后,睁开眼保持5秒,同时控制不出现口角连带上提动作,纠偏纠正连带运动;每天训练第一套康复操三组,每组训练30遍。
本发明的优选技术方案中,第二套康复操训练包括,一是照镜子;二是睁眼,尽量保持静默神经分支;三是口周噘嘴、呲牙和鼓腮;每天训练第一套康复操三组,每组训练10遍。
本发明的优选技术方案中,所述防治恢复期面神经麻痹的治疗方案为,脉冲射频手术、术后口服给药和穴位注射给药以及术中和术后康复操训练。
本发明的优选技术方案中,所述面神经麻痹选自面肌痉挛、面瘫/连带运动、三叉神经痛、舌咽神经痛、面神经炎、周围性面瘫、眼肌痉挛修复中的任一种或其组合。
本发明的另一目的在于提供用于一种防治后遗症期面神经麻痹的药物组合物,所述防治后遗症期面神经麻痹的药物组合物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合。
本发明的优选技术方案中,所述防治后遗症期面神经麻痹的药物组合物含有鼠神经生长因子、甲钴胺、腺苷钴的任一种或其组合。
本发明的优选技术方案中,所述用于防治后遗症面神经麻痹的药物组合物由单次口服用的药物组合物和单次穴位注射用的药物组合物组成。
本发明的优选技术方案中,单次给药的药物组合物含有甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg的任一种或其组合。
本发明的优选技术方案中,口服用药物组合物的给药方案为:口服甲钴胺0.5mg/次,3-4次/天,隔月服用;腺苷钴胺0.5mg/次,3次/天,连续3周,停1周,然后继续重复半年;
本发明的优选技术方案中,所述口服用药物组合物选自同时给药或序贯给药的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物为鼠神经生长因子30ug、甲钴胺0.5mg、维生素B1 200mg的组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物含有鼠神经生长因子30-90ug、甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg,地塞米松2-5mg的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物为鼠神经生长因子30-90ug、甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg,地塞米松2-5mg、100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松2mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,组合物中,单次穴位注射的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射的药物组合物由鼠神经生长因子60ug、甲钴胺0.8mg、腺苷钴胺0.5mg,地塞米松3mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物临配临用。
本发明的优选技术方案中,选取患侧面部的阳白穴、太阳穴、四白穴、迎香穴、巨髎穴、地仓穴和颊车穴进行穴位注射。
本发明的优选技术方案中,单次穴位注射用的药物组合物每天穴位注射一次,7天为疗程。
本发明的优选技术方案中,每次穴位注射治疗2-6个疗程,优选为4-5个疗程。
本发明的优选技术方案中,所述用于防治后遗症期面神经麻痹的药物组合物任选地与射频手术、康复训练操的任一种或其组合联合使用。
本发明的优选技术方案中,所述射频手术在41℃-42℃、90V-140V、2Hz-6Hz条件下,基于长时程温控高电压变频脉冲射频800秒-1400秒。
本发明的优选技术方案中,所述射频手术在41℃-42℃、100V-120V、3Hz-5Hz条件下,基于长时程温控高电压变频脉冲射频960秒-1200秒。
本发明的优选技术方案中,所述康复训练操为发明人独创的面瘫康复训练操(著作权登记号:国作登字-2022-I-10250228和著作权登记号:国作登字-2022-F-10250229)。
本发明的优选技术方案中,所述的康复操训练选自第一套康复操训练、第二套康复操训练的任一种或其组合。
本发明的优选技术方案中,第一套康复操训练包括,一是照镜子;二是慢闭眼,闭眼5秒后,睁开眼保持5秒,同时控制不出现口角连带上提动作,纠偏纠正连带运动;每天训练第一套康复操三组,每组训练30遍。
本发明的优选技术方案中,第二套康复操训练包括,一是照镜子;二是睁眼,尽量保持静默神经分支;三是口周噘嘴、呲牙和鼓腮;每天训练第一套康复操三组,每组训练10遍。
本发明的优选技术方案中,所述防治恢复期面神经麻痹的治疗方案为,脉冲射频手术、术后口服给药和穴位注射给药以及术中和术后康复操训练。
本发明的优选技术方案中,所述面神经麻痹选自面肌痉挛、面瘫/连带运动、三叉神经痛、舌咽神经痛、面神经炎、周围性面瘫、眼肌痉挛修复中的任一种或其组合。
本发明的另一目的在于提供一种防治后遗症期面神经麻痹的治疗方案,所述治疗方案包括用于防治后遗症期面神经麻痹的药物组合物任选地与射频手术、康复训练操的任一种或其组合联合使用。
本发明的优选技术方案中,所述防治后遗症期面神经麻痹的药物组合物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合。
本发明的优选技术方案中,所述防治后遗症期面神经麻痹的药物组合物含有鼠神经生长因子、甲钴胺、腺苷钴的任一种或其组合。
本发明的优选技术方案中,所述用于防治后遗症面神经麻痹的药物组合物由单次口服用的药物组合物和单次穴位注射用的药物组合物组成。
本发明的优选技术方案中,单次给药的药物组合物含有甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg的任一种或其组合。
本发明的优选技术方案中,口服用药物组合物的给药方案为:口服甲钴胺0.5mg/次,3-4次/天,隔月服用;腺苷钴胺0.5mg/次,3次/天,连续3周,停1周,然后继续重复半年;
本发明的优选技术方案中,所述口服用药物组合物选自同时给药或序贯给药的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物为鼠神经生长因子30ug、甲钴胺0.5mg、维生素B1 200mg的组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物含有鼠神经生长因子30-90ug、甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg,地塞米松2-5mg的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物为鼠神经生长因子30-90ug、甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg,地塞米松2-5mg、100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合。
本发明的优选技术方案中,单次穴位注射用的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松2mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,组合物中,单次穴位注射的药物组合物由鼠神经生长因子90ug、甲钴胺1.0mg、腺苷钴胺0.5mg,地塞米松5mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,单次穴位注射的药物组合物由鼠神经生长因子60ug、甲钴胺0.8mg、腺苷钴胺0.5mg,地塞米松3mg和盐酸利多卡因1ml组成,其中,盐酸利多卡因的浓度选自0.8%、1%、1.5%、2%的任一种。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物任选地含有100-300mg具有修复功效的神经修复细胞蛋白提取物和/或神经修复蛋白组合物的任一种或其组合。
本发明的优选技术方案中,所述单次穴位注射用的药物组合物临配临用。
本发明的优选技术方案中,选取患侧面部的阳白穴、太阳穴、四白穴、迎香穴、巨髎穴、地仓穴和颊车穴进行穴位注射。
本发明的优选技术方案中,单次穴位注射用的药物组合物每天穴位注射一次,7天为疗程。
本发明的优选技术方案中,每次穴位注射治疗2-6个疗程,优选为4-5个疗程。
本发明的优选技术方案中,所述用于防治后遗症期面神经麻痹的药物组合物任选地与射频手术、康复训练操的任一种或其组合联合使用。
本发明的优选技术方案中,所述射频手术在41℃-42℃、90V-140V、2Hz-6Hz条件下,基于长时程温控高电压变频脉冲射频800秒-1400秒。
本发明的优选技术方案中,所述射频手术在41℃-42℃、100V-120V、3Hz-5Hz条件下,基于长时程温控高电压变频脉冲射频960秒-1200秒。
本发明的优选技术方案中,所述康复训练操为发明人独创的面瘫康复训练操(著作权登记号:国作登字-2022-I-10250228和著作权登记号:国作登字-2022-F-10250229)。
本发明的优选技术方案中,所述的康复操训练选自第一套康复操训练、第二套康复操训练的任一种或其组合。
本发明的优选技术方案中,第一套康复操训练包括,一是照镜子;二是慢闭眼,闭眼5秒后,睁开眼保持5秒,同时控制不出现口角连带上提动作,纠偏纠正连带运动;每天训练第一套康复操三组,每组训练30遍。
本发明的优选技术方案中,第二套康复操训练包括,一是照镜子;二是睁眼,尽量保持静默神经分支;三是口周噘嘴、呲牙和鼓腮;每天训练第一套康复操三组,每组训练10遍。
本发明的优选技术方案中,所述防治恢复期面神经麻痹的治疗方案为,脉冲射频手术、术后口服给药和穴位注射给药以及术中和术后康复操训练。
本发明的优选技术方案中,所述面神经麻痹选自面肌痉挛、面瘫/连带运动、三叉神经痛、舌咽神经痛、面神经炎、周围性面瘫、眼肌痉挛修复中的任一种或其组合。
为了清楚地表述本发明,本发明所述的具有修复功效的神经修复细胞蛋白提取物或神经修复细胞蛋白组合物参照专利申请(CN2023100429139、PCT/CN2023/073566、CN2023100429143、PCT/CN2023/073582)制得。
本发明的优选技术方案中,所述具有神经修复功效的神经修复细胞蛋白提取物的制备方法,包括如下步骤:
S-1:将密度为5.0×106个/mL-5.0×107个/mL的间充质传代干细胞置于含有DMEM/F12 40-50%、RPMI1640 40-50%、牛血清蛋白(BSA)0.1-2%、表皮细胞生长因子(EGF)1-15ug/mL、成纤维细胞生长因子(FGF)1-15ug/mL、胰岛素转铁蛋白1-15ug/mL、复方氨基酸(18AA)0.01-0.1%和2-10μmol/L应激物的培养基中,再将其置于37.0℃±0.5℃、5%±1.0%CO2条件下培养2h-6h后,分离,洗涤,收集细胞,其中,所述的应激物选自化合物1-16的任一种或其组合;
S-2:将收集细胞按照密度为5.0×106个/mL-5.0×107个/mL分散于溶剂中,再将其置于2℃-8℃条件下超声处理,制得细胞裂解液,其中,所述溶剂选自选自生理盐水、5%葡萄糖溶液、磷酸盐缓冲液(PBS)、TBPS缓冲液、TBST缓冲液、Tris缓冲液的任一种或其组合;
S-3:将步骤S-2制得的细胞裂解液分离后,所得的分离液依次经0.45um、0.22um滤膜过滤,即得。
本发明的优选技术方案中,步骤S-1的培养基中含有DMEM/F12 42-45%、RPMI164042-45%、牛血清蛋白(BSA)0.5-1.5%、表皮细胞生长因子(EGF)5-10ug/mL、成纤维细胞生长因子(FGF)5-10ug/mL、胰岛素转铁蛋白5-10ug/mL、复方氨基酸(18AA)0.02-0.05%和3-8μmol/L的应激物。
本发明的优选技术方案中,步骤S-1的培养基中含有DMEM/F12 45%、RPMI164045%、牛血清蛋白(BSA)0.5%、表皮细胞生长因子(EGF)10ug/mL、成纤维细胞生长因子(FGF)10ug/mL,胰岛素转铁蛋白10ug/mL、复方氨基酸(18AA)0.05%和4-6μmol/L的应激物。
本发明的优选技术方案中,步骤S-1的间充质传代干细胞密度为8.0×106-2.0×107个/mL,优选为8.0×106-1.0×107个/mL。
本发明的优选技术方案中,步骤S-1的间充质传代干细胞在培养基中培养3h-5h,优选为3.5h-4.5h。
本发明的优选技术方案中,步骤S-1中洗涤细胞的溶剂选自生理盐水、5%葡萄糖溶液、磷酸盐缓冲液(PBS)、TBPS缓冲液、TBST缓冲液、Tris缓冲液的任一种或其组合,细胞洗涤次数为2-5次,优选为3-4次。
本发明的优选技术方案中,步骤S-1所述的分离选自离心、过滤的任一种或其组合,其中,所述离心条件为1000-2000rpm*3-15min,优选为1200rpm-1500rpm*5-10min。
本发明的优选技术方案中,步骤S-2的超声条件为:在2℃-8℃、25kHZ、360W条件下工作3s再间隙1s,超声处理1-5min。
本发明的优选技术方案中,步骤S-3所述分离选自2000-8000rpm*10-30min离心、多级离心、多级过滤的任一种或其组合,优选为3000-7000rpm*15-25min。
本发明的优选技术方案中,步骤S-3的多级离心依次为3000-4000rpm*3-5min、5000-6000rpm*3-5min和7000rpm*5-8min。
本发明的优选技术方案中,所述多级过滤的滤膜孔径选自80um、50um、30um、10um、5um的任一种。
本发明的优选技术方案中,将步骤S-3制得的细胞蛋白提取物冻存,优选冻存于-40℃至-20℃。
本发明的优选技术方案中,将步骤S-3制得的细胞蛋白提取物采用核酸酶或全能核酸酶的任一种酶解后再分离纯化。
本发明的优选技术方案中,所述间充质传代干细胞的培养或原代间充质干细胞的培养采用本领域的培养方法。
本发明的优选技术方案中,所述间充质传代干细胞的培养包括下述步骤:将原代间充质干细胞按照初始密度为5.0×105-5.0×106个/ml加入到传代培养基中,再将其置于37.0℃±0.5℃、5%±1.0%CO2条件下培养10-15天,每隔2-3天,观察传代培养基变黄后,半量更换传代培养基,其中,所述传代培养基含有10%FBS、100U/ml青霉素和100ug/ml链霉素的DMEM/F12培养基。
本发明的优选技术方案中,所述原代间充质干细胞的培养包括下述步骤:
1)将脐带清洗消毒后,组织解剖,取华通胶层组织,将其切成3mm3的小块,离心,清洗,收集组织块,将其置于含10%胎牛血清FBS、100ug/ml青霉素、100ug/ml链霉素的DMEM/F12培养基中,再将其置于37.0℃±0.5℃、5%±1.0%CO2条件下培养,每间隔2-3天半量更换培养基,培养至组织块爬出细胞;
2)振摇,收集低层细胞用PBS清洗后,加入0.25%的胰蛋白酶消化2min-3min,加入等体积的胰蛋白酶终止液停止消化,吸管轻轻吹打,1200-1500rpm/min*5-8min离心后,收集细胞,即得。
除非另有说明,本发明涉及液体与液体之间的百分比时,所述的百分比为体积/体积百分比;本发明涉及液体与固体之间的百分比时,所述百分比为体积/重量百分比;本发明涉及固体与液体之间的百分比时,所述百分比为重量/体积百分比;其余为重量/重量百分比。
除非另有说明,本发明采用如下方法进行评价:
1.取穴:按照由国家技术监督局发布的中华人民共和国国家标准《腧穴名称与定位》(GB/T 12345-2006)的穴位以定位。
2.面瘫运动功能评价量表
3.面瘫生活质量评价量表
与现有技术相比,本发明具有下述有益效果:
1、本发明科学筛选神经修复药物,配置成用于治疗面瘫后遗症的药物组合物,各组分协同增效,药物组合物起效快、持续作用时间延长、治疗效果好,能降低单一药物使用时带来的副作用。同时协同采用射频方法用于面瘫后遗症的治疗,可以快速改善面瘫症状,加速面神经的恢复过程,安全可靠,无明显的副作用和并发症。
2、本发明能够节约药物使用量,显著降低生产成本,操作简便、适合于大规模工业化生产等优点。
具体实施方式
下面结合具体实施例对本发明的详细内容做进一步解释和描述,但并不以此限制本发明的保护范围。
实施例1具有修复功效的神经修复细胞蛋白提取物的制备
1、原代间充质干细胞的培养
原代间充质干细胞的培养包括下述步骤:
1)将脐带清洗消毒后,组织解剖,取华通胶层组织,将其切成3mm3的小块,离心,清洗,收集组织块,将其置于培养瓶中,加入含10%胎牛血清FBS、100ug/ml青霉素、100ug/ml链霉素的DMEM/F12培养基,再将其置于37℃、5%CO2条件下培养,促进其贴壁,每间隔2-3天,观察培养基变黄后,半量更换培养基,培养10-12天,至组织块边上可见细胞爬出;
2)轻轻摇晃,使组织块掉落,分别收集组织块和低层细胞,其中,将收集的组织块再贴壁培养;
3)将收集的低层细胞用PBS清洗后,加入适量0.25%胰蛋白酶消化2min-3min,加入等体积的胰蛋白酶终止液停止消化,吸管轻轻吹打瓶底,1500rpm*5min离心后,收集细胞,即得。
2、原代间充质干细胞的传代培养(间充质传代干细胞的培养)
原代间充质干细胞的传代培养(间充质传代干细胞的培养):将原代间充质干细胞按照初始密度为5.0×105-5.0×106个/ml加入到含有10%FBS、100U/ml青霉素和100ug/ml链霉素的DMEM/F12培养基中,再将其置于37.0℃±0.5℃、5%±1.0%CO2条件下培养10-15天,每间隔2-3天,观察培养基变黄后,半量更换培养基。
3、化合物1-16的制备参照文献1(New limonophyllines A-C from the stem ofAtalantia monophylla and cytotoxicity against cholangiocarcinoma and HepG2cell lines,Arch.Pharm.Res.(2018)41:431–437)。
具有神经修复功效的神经修复细胞蛋白提取物的制备方法,包括如下步骤:
(1)将间充质传代细胞按照密度为8.0×106个/mL加入到含有DMEM/F1245%、RPMI1640 45%、牛血清蛋白(BSA)0.5%、表皮细胞生长因子(EGF)10ug/mL、成纤维细胞生长因子(FGF)10ug/mL、胰岛素转铁蛋白10ug/mL、复方氨基酸(18AA)0.05%和5μmol/L的化合物16的培养基中,再将其置于37℃、5%CO2条件下培养4h后,将其置于1200rpm*5min离心,用PBS洗涤3次后,收集细胞;
(2)将步骤(1)收集的细胞按照密度为1.0×107个/mL分散于生理盐水中,在2-8℃、25kHz、360W条件下超声3s、间隙1s,超声2min,制得细胞裂解液;
(3)将步骤(2)制得的细胞裂解液置于7000rpm*20min离心,将所得的离心液依次经0.45um、0.22um滤膜过滤,即得细胞蛋白提取物;
(4)在步骤(3)制得的细胞蛋白提取物加入所需量的甘露醇,搅拌,混合均匀后,冻干,所得冻干制剂中含有5%的甘露醇(m/m)。
试验例1本发明药物组合物用于面瘫后遗期的治疗效果研究
选取面瘫后遗症期患者60名,分为1组(10名)、2组(30名)、3组(20名)。患者入组标准:符合面神经炎中医、西医诊断标准,患者发病超过6个月;年龄20-70岁;H-B分级在II级以上;知情同意接受本试验;依从性好。禁忌症:面神经完全断裂或缺失者;穿刺部位感染或皮肤损伤者;累及面神经的局部肿瘤或其他占位性病变者;凝血功能障碍者,可能增加出血或血肿的风险;心脏起搏器植入者,可能干扰起搏器的正常工作;孕妇或哺乳期妇女者,可能影响胎儿或婴儿的健康;对电极针或局部麻醉药过敏者,可能引起过敏反应或其他不良反应;精神障碍或无法配合康复或矫正训练治疗者。
1组的治疗方案(每个疗程7天,治疗4个疗程):单次穴位注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、维生素B1 200mg组成,临配临用,选取患侧面部的阳白穴、太阳穴、四白穴、迎香穴、巨髎穴、地仓穴和颊车穴进行穴位注射,每天穴位注射1次。
2组的治疗方案(每个疗程7天,治疗4个疗程)包括脉冲射频手术、术后口服给药和穴位注射给药以及术中和术后康复操训练。
1、脉冲射频手术:采用射频控温热凝器(型号R-2000B M1,购自北琪医疗),基于长时程温控高电压变频脉冲射频技术对病变部位进行神经激活修复调控微纠偏手术(脉冲宽度20ms、静息期480ms、最大电压值100V、脉冲频率2HZ),在41-42℃、90-140V、2-5Hz条件下脉冲射频1200秒;手术中,配合2组睁大眼保持、重复龇牙和重复鼓气的面部运动;
2、术后口服药物的同时给药和/或序贯给药的方案:
术后口服甲钴胺0.5mg/次,3次/天,隔月服用;腺苷钴胺0.5mg/次,3次/天,连续3周,停1周,然后继续服用半年;
3、术后穴位注射给药方案:
单次穴位注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、地塞米松5mg和盐酸利多卡因1ml组成,临配临用,选取患侧面部的阳白穴、太阳穴、四白穴、迎香穴、巨髎穴、地仓穴和颊车穴进行穴位注射,每天穴位注射1次。
4、术后康复操训练:
第一套康复操:一是照镜子;二是慢闭眼,闭眼5秒后,睁开眼保持5秒,同时控制不出现口角连带上提动作,纠偏纠正连带运动。每天训练三组,每组训练30遍;第二套康复操:一是照镜子;二是睁眼,尽量保持静默神经分支;三是口周噘嘴、呲牙和鼓腮。每天训练三组,每组训练10遍。
3组的治疗方案(每个疗程7天,治疗4个疗程)包括脉冲射频手术、术后口服给药和穴位注射给药以及术中和术后康复操训练。
1、脉冲射频手术:采用射频控温热凝器(型号R-2000B M1,购自北琪医疗),基于长时程温控高电压变频脉冲射频技术对病变部位进行神经激活修复调控微纠偏手术(脉冲宽度20ms、静息期480ms、最大电压值100V、脉冲频率2HZ),在41-42℃、90-140V、2-5Hz条件下脉冲射频1200秒;手术中,配合2组睁大眼保持、重复龇牙和重复鼓气的面部运动;
2、术后口服药物的同时给药和/或序贯给药的方案:
术后口服甲钴胺0.5mg/次,3次/天,隔月服用;腺苷钴胺0.5mg/次,3次/天,连续3周,停1周,然后继续服用半年;
3、术后穴位注射给药方案:
(1)单次穴位注射的药物组合物由鼠神经生长因子30ug、甲钴胺0.5mg、腺苷钴胺0.5mg、地塞米松5mg和盐酸利多卡因1ml组成,临配临用,选取患侧面部的阳白穴、太阳穴、四白穴、迎香穴、巨髎穴、地仓穴和颊车穴进行穴位注射,每天穴位注射1次。
(2)单次穴位注射实施例1制得的神经修复细胞蛋白提取物冻干制剂130ug,用2ml生理盐水溶解,选取患侧面部的阳白穴、太阳穴、四白穴、迎香穴、巨髎穴、地仓穴和颊车穴、对侧太阳穴、地仓穴,双手合谷穴进行穴位注射,每天穴位注射1次。
4、术后康复操训练:
第一套康复操:一是照镜子;二是慢闭眼,闭眼5秒后,睁开眼保持5秒,同时控制不出现口角连带上提动作,纠偏纠正连带运动。每天训练三组,每组训练30遍;第二套康复操:一是照镜子;二是睁眼,尽量保持静默神经分支;三是口周噘嘴、呲牙和鼓腮。每天训练三组,每组训练10遍。
疗效评定:满意度调查表和临床评分House-Brakmann面神经功能分级疗效评价表。
1组:1个疗程7天,重复治疗4-6个疗程,无发热、过敏、症状加重等并发症和后遗症,超过50%的患者面部肌肉改善。治疗28天的有效率70%。
2组:治疗当天有效率为70%,显效率50%,患者术后满意度80%。无发热、过敏、症状加重等后遗症。6个月内重复治疗2~3次,疗效累积。患者遵照医嘱,注意减少甚至避免熬夜、疲劳、外部感染、受凉等因素的影响,基本无复发,生活质量显著提高。
3组:面瘫后遗症症状有明显改善。治疗当天有效率为95%,显效率90%,患者术后满意度90%。全部受试患者均无副作用和不良事件。患者遵照医嘱,注意减少甚至避免熬夜、疲劳、外部感染、受凉等因素的影响,基本无复发,生活质量显著提高。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明权利要求保护的范围。
Claims (10)
1.一种药物组合物用于制备防治后遗症期面神经麻痹的药物中的应用,所述防治后遗症期面神经麻痹的药物组合物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合。
2.如权利要求1所述的应用,所述防治后遗症期面神经麻痹的药物组合物含有鼠神经生长因子、甲钴胺、腺苷钴的任一种或其组合。
3.如权利要求1-2任一项所述的应用,所述用于防治后遗症面神经麻痹的药物组合物由单次口服用的药物组合物和和单次穴位注射用的药物组合物组成。
4.如权利要求1-3任一项所述的应用,单次给药的药物组合物含有甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg的任一种或其组合。
5.如权利要求1-4任一项所述的应用,口服用药物组合物的给药方案为:口服甲钴胺0.5mg/次,3-4次/天,隔月服用;腺苷钴胺0.5mg/次,3次/天,连续3周,停1周,然后继续重复半年。
6.如权利要求1-5任一项所述的应用,单次穴位注射用的药物组合物含有鼠神经生长因子30-90ug、甲钴胺0.5-1.0mg、腺苷钴胺0.1-0.5mg,地塞米松2-5mg的任一种或其组合。
7.如权利要求1-6任一项所述的应用,患侧面部的阳白穴、太阳穴、四白穴、迎香穴、巨髎穴、地仓穴和颊车穴进行穴位注射。
8.如权利要求1-7任一项所述的应用,患所述用于防治后遗症期面神经麻痹的药物组合物任选地与射频手术、康复训练操的任一种或其组合联合使用。
9.如权利要求1-8任一项所述的防治后遗症期面神经麻痹的药物组合物,所述防治后遗症期面神经麻痹的药物组合物选自鼠神经生长因子、单唾液酸神经节苷脂(GM1)、脑苷肌肽、甲钴胺、腺苷钴胺、复合维生素B、丁苯酞、马来酸桂哌齐特、依达拉奉、依达拉奉右莰醇、胞磷胆碱、胞磷胆碱钠、神经节苷脂、奥拉西坦、吡拉西坦、茴拉西坦、神经生长因子、胞二磷胆碱、神经妥乐平、谷维素、维生素B1、维生素B6、维生素B12、维生素C、维生素E、复方脑肽节苷脂、脑蛋白、神经酸的任一种或其组合。
10.一种防治后遗症期面神经麻痹的治疗方案,所述治疗方案包括用于如权利要求1-8任一项所述的防治后遗症期面神经麻痹的药物组合物任选地与射频手术、康复训练操的任一种或其组合联合使用。
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