CN115702891A - 和厚朴酚在制备用于治疗脑膜瘤的药物中的用途 - Google Patents
和厚朴酚在制备用于治疗脑膜瘤的药物中的用途 Download PDFInfo
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- BYTORXDZJWWIKR-UHFFFAOYSA-N Hinokiol Natural products CC(C)c1cc2CCC3C(C)(CO)C(O)CCC3(C)c2cc1O BYTORXDZJWWIKR-UHFFFAOYSA-N 0.000 title claims abstract description 52
- VVOAZFWZEDHOOU-UHFFFAOYSA-N honokiol Natural products OC1=CC=C(CC=C)C=C1C1=CC(CC=C)=CC=C1O VVOAZFWZEDHOOU-UHFFFAOYSA-N 0.000 title claims abstract description 52
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Abstract
本发明涉及和厚朴酚的医药用途，具体是和厚朴酚在制备用于治疗脑膜瘤的药物中的用途，试验证明和厚朴酚能够有效抑制脑膜瘤的生长，并且消除和/或减小脑膜瘤病灶。而且，临床试验表明，和厚朴酚的安全性及耐受性良好。
Description
技术领域
本发明涉及和厚朴酚的医药用途。具体地，本发明涉及和厚朴酚在治疗脑膜瘤中的用途。
背景技术
脑膜瘤是中枢神经系统最常见的原发性肿瘤，多起源于蛛网膜内皮细胞，主要发生于蛛网膜颗粒或绒毛。脑膜瘤约占所有原发性中枢神经系统肿瘤的36.6％，在非恶性原发性中枢神经系统肿瘤中占53.2％。脑膜瘤分为良性脑膜瘤和恶性脑膜瘤。典型临床症状是颅内压升高、局灶性神经系统(包括脑神经)缺陷和局灶性肿块效应引起的全身性和部分性癫间疒发作，其中最常见的是头痛、癫间疒发作、视觉症状、肢体无力和精神状态改变。
脑膜瘤的发病率有逐年增长的趋势，从1998～2002年期间的4.52/10万增长至2010～2014年期间的8.3/10万。脑膜瘤发病多见于老年患者，多为70～80岁。
电离辐射是脑膜瘤发展的危险因素。在广岛和长崎，80160例原子弹幸存者中观察到脑膜瘤88例。很小的头部放射剂量(如用于牙科放射照相的剂量)即可能增加脑膜瘤发展的风险。但电离辐射与脑膜瘤发生没有明确的剂量反应关系。流行病学研究显示：头部外伤、吸烟和使用手机的病史，均未显示与脑膜瘤风险增加相关。
目前，治疗脑膜瘤的标准流程一般包括手术和放疗。尽管在手术和放射治疗方面取得进展，大部分患者可以治愈，但恶性脑膜瘤复发率高达50％～80％，部分患者中位生存时间低于2年，该疾病治疗难度非常大。迄今为止，化疗、激素治疗和免疫治疗对恶性脑膜瘤患者的疗效都非常有限；因脑部肿瘤的特殊性，对于复发患者手术治疗也非常局限；且手术、放射治疗和化疗让患者耐受性差。而随着人口老龄化，脑膜瘤的发生率升高，针对脑膜瘤具有良好安全性和耐受性的有效疗法在临床上变得更加重要且迫切需要开发。
发明内容
针对现有技术中脑膜瘤治疗方面的不足，本发明的目的在于开发能够有效治疗脑膜瘤的方法，且该方法具有良好的安全性和耐受性。
和厚朴酚，英文名为Honokiol，化学名为3',5-二-2-丙烯基-1,1'-联苯-2,4'-二酚，结构式如下式(I)所示：
和厚朴酚是从厚朴Magnolia officinalisRehd.etWils.的皮中提取分离出来的一种具有广泛生物活性的小分子化合物，其主要生物活性包括抗炎、抗微生物、抗溃疡、抗氧化、抗焦虑、抗抑郁、抗血栓、抗衰老和降低胆固醇等。
鉴于和厚朴酚有着广泛的药用价值，发明人进一步研究了和厚朴酚的新用途。在临床研究中，发明人发现，和厚朴酚能够有效抑制脑膜瘤的生长，并且消除和/或减小脑膜瘤病灶。
因此，本发明的目的之一在于提供和厚朴酚在制备用于治疗脑膜瘤的药物中的用途。
根据本发明的用于治疗脑膜瘤的用途，其中所述和厚朴酚被制备成和厚朴酚脂质体，优选为注射用和厚朴酚脂质体。
根据本发明的用于治疗脑膜瘤的用途，其中所述和厚朴酚抑制脑膜瘤的细胞增殖。
本发明的另一目的在于提供用于治疗脑膜瘤的和厚朴酚脂质体。
根据本发明的和厚朴酚脂质体，其中所述和厚朴酚脂质体为注射用和厚朴酚脂质体。
根据本发明的和厚朴酚脂质体，其中所述和厚朴酚脂质体包括如下剂型：冻干粉制剂，包括注射冻干粉制剂，口服冻干粉制剂；片剂，包括速释片剂和缓释片剂；胶囊剂，包括硬胶囊，软胶囊、缓释胶囊和肠溶胶囊；透皮制剂，等等。
根据本发明的和厚朴酚脂质体，其中所述和厚朴酚脂质体可以通过如下途径给药：静脉注射、肌内注射、皮下注射、口服给药、眼部给药、肺部给药、经皮给药和鼻腔给药等。
有益效果
临床试验中发现，和厚朴酚能够有效治疗脑膜瘤，其有效抑制脑膜瘤的生长，并且消除和/或减小脑膜瘤病灶。而且，临床试验表明，和厚朴酚的安全性及耐受性良好。
附图说明
图1A和图1B分别为用和厚朴酚治疗前和治疗后脑膜瘤患者的头颅核磁图。
具体实施方式
下面提供实施例以进一步说明和厚朴酚在制备用于治疗脑膜瘤的药物中的用途。
实施例中涉及到的专业术语的缩写列于下表1中。
表1
实施例1：和厚朴酚在制备用于治疗脑膜瘤的药物中的用途。
1.试验材料：
注射用和厚朴酚脂质体来源于成都金瑞基业生物科技有限公司，或者可根据以下方法制备获得：取和厚朴酚50mg，大豆磷脂500mg，胆固醇200mg，培化磷脂酰乙醇胺200mg，溶于无水乙醇50mL中，完全溶解后注入到纯化水300mL中，搅拌，旋转蒸发除去乙醇，加入蔗糖800mg作为冻干赋形剂，冷冻干燥。
2.试验方法及结果
受试者1情况描述：
男性，年龄20岁；
2018年1月20日，受试者1头颅MR示右侧CPA及颈静脉孔区占位；
2018年11月27日，受试者1颅底深部病灶切除术，内皮型脑膜瘤，局灶呈血管瘤型脑膜瘤，伴出血，呈非典型脑膜瘤，浸润骨组织，综合为恶性脑膜瘤；免疫组化：EMA(灶状阳性)、PR(散在少许阳性)、SSTR(局灶阳性)、CD34(血管阳性)、CD99(+)、S100(-)、Syn(-)、CgA(-)、CK(偶见阳性)、Ki67(约8-20％)；
2019年2月，受试者1颅内感染治疗；
2019年6月，受试者1全脑放疗；
2021年3月5日，受试者1复查头颅核磁，肿瘤复发；为进一步治疗，受试者1在首都医科大学附属北京天坛医院门诊以“恶性肿瘤维持治疗”收入神经肿瘤综合治疗病区治疗；
2021年5月13日，受试者1入组“注射用和厚朴酚脂质体(HK)治疗晚期恶性实体瘤患者临床安全性、耐受性的I期临床试验”，入选标准如下：
1)18岁≤年龄≤80岁，性别不限；
2)经组织学或细胞学确诊的，既往标准治疗方案失败、不能耐受或拒绝现有疗法的晚期恶性实体瘤患者，优选肺癌、肝癌、脑胶质瘤、卵巢癌和结肠癌等瘤种；
3)按RECIST1.1标准(或RANO标准)存在可评估的肿瘤病灶；
4)除脑胶质瘤外，其他瘤种入选的脑转移患者须符合下列条件：无脑转移相关临床症状，无需全身皮质类固醇或抗惊厥药物治疗；治疗过的脑转移患者须在治疗后28天后复查没有进展；无脑出血风险；
5)无严重造血功能异常者(中性粒细胞绝对值≥1.5x109/L，血小板≥80x109/L，血红蛋白≥100g/L)；
6)心、肺、肝、肾无严重器质性病变者(LVEF(左室射血分数)≥50％；总胆红素≤1.5×ULN；谷丙转氨酶(ALT)≤2.5×ULN(如果有肝脏转移则≤5×ULN)；谷草转氨酶(AST)≤2.5×ULN(如果有肝脏转移则≤5×ULN)；血清肌酐≤1.5×ULN或CCr>40mL/min)；
7)无严重凝血功能异常者(PT≤1.5×ULN、APTT≤1.5×ULN、TT≤1.5×ULN)；
8)入组前患者接受上一次抗肿瘤治疗(化疗、放疗、生物治疗、激素治疗和靶向治疗)后至少4周；
9)预期生存时间≥12周；
10)对于脑胶质瘤患者，KPS评分>50分；
11)对于其他实体瘤患者，ECOG评分≤1分；
12)同意参加本研究并签署知情同意书者。
对受试者1进行第一周期用药：一周期28天，其中每周连续给药5天，停药2天，为期3周，休息1周；给药注射用和厚朴酚脂质体，给药剂量为420mg和厚朴酚；给药方法：经外周静脉穿刺中心静脉置管给药，输注时间2h。
完成第一周期用药后，复查头颅核磁，头颅核磁前后对比图如图1A和图1B所示。按照RANO标准，显示靶病灶较用药前缩小17.46％，其中靶病灶两垂直直径的乘积由治疗前77.3mm×65mm缩小到76.1mm×54.5mm，疗效评价为疾病稳定(SD)，临床症状评价为好转，无不良反应。
截至2021年5月31日，按本实施例1上述“注射用和厚朴酚脂质体(HK)治疗晚期恶性实体瘤患者临床安全性、耐受性的I期临床试验”入选标准，37例受试者纳入安全性分析集，分别给予不同剂量的注射用和厚朴酚脂质体，给药剂量分别为：4例20mg、3例40mg、4例80mg、3例140mg、5例210mg、6例300mg、12例420mg。给药方法：经外周静脉穿刺中心静脉置管给药，输注时间2h；每4周为一个给药周期，每周期给药3周(本周期第1周～第3周)，每周连续给药5天，每天1次，停药2天，休息1周。
给药注射用和厚朴酚脂质体后，受试者的不良反应主要为中性粒细胞减少、便秘、贫血、ALT升高，纤维蛋白原下降，头痛，眩晕、低钾血症等，多为轻度，出现1例DLT(CTCAE 3级ALT升高)，观察到SAE 4例次，转归均为缓解，并未出现可疑的非预期的严重不良反应。不良事件、不良反应、SAE的发生率、受试者生命体征、体格检查、实验室检查、12导联心电图、超声心动图等有临床意义的改变没有出现随着剂量的升高而增加的趋势证明。
临床试验表明，注射用和厚朴酚脂质体不仅能有效治疗脑膜瘤，同时还具有良好的安全性及耐受性。
Claims (8)
1.和厚朴酚在制备用于治疗脑膜瘤的药物中的用途。
2.根据权利要求1所述的用途，其中所述和厚朴酚被制备成和厚朴酚脂质体。
3.根据权利要求2所述的用途，其中所述和厚朴酚脂质体为注射用和厚朴酚脂质体。
4.根据权利要求1-3中任一项所述的用途，其中所述和厚朴酚抑制脑膜瘤的细胞增殖。
5.一种用于治疗脑膜瘤的和厚朴酚脂质体。
6.根据权利要求5所述的和厚朴酚脂质体，其中所述和厚朴酚脂质体为注射用和厚朴酚脂质体。
7.根据权利要求5所述的和厚朴酚脂质体，其中所述和厚朴酚脂质体包括如下剂型：冻干粉制剂，包括注射冻干粉制剂，口服冻干粉制剂；片剂，包括速释片剂和缓释片剂；胶囊剂，包括硬胶囊，软胶囊、缓释胶囊和肠溶胶囊；或者透皮制剂。
8.根据权利要求5所述的和厚朴酚脂质体，其中所述和厚朴酚脂质体通过如下途径给药：静脉注射、肌内注射、皮下注射、口服给药、眼部给药、肺部给药、经皮给药或鼻腔给药。
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| CN202280007912.4A CN116761593A (zh) | 2021-08-12 | 2022-08-11 | 和厚朴酚在制备用于治疗脑膜瘤的药物中的用途 |
| US18/282,410 US20240165047A1 (en) | 2021-08-12 | 2022-08-11 | Use Of Honokiol In Preparation Of Drug For Treating Meningioma |
| PCT/CN2022/111765 WO2023016519A1 (zh) | 2021-08-12 | 2022-08-11 | 和厚朴酚在制备用于治疗脑膜瘤的药物中的用途 |
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| CN117503736A (zh) * | 2024-01-05 | 2024-02-06 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备治疗卵黄囊瘤药物中的用途 |
| CN117503737A (zh) * | 2024-01-05 | 2024-02-06 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备治疗脂肪肉瘤药物中的用途 |
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| CN116270473B (zh) * | 2023-05-25 | 2023-12-19 | 成都金瑞基业生物科技有限公司 | 一种共载脂质体及其制备方法 |
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| EP2162123A4 (en) * | 2007-05-03 | 2011-10-26 | Jack L Arbiser | HONOKIOL ANALOGS AND THEIR USE IN THE TREATMENT OF CANCERS |
| CN102178666B (zh) * | 2011-03-21 | 2014-06-18 | 四川大学 | 和厚朴酚在制备预防或治疗颅内占位性病变和颅内组织器官炎症的药物中的用途 |
| CA2831403A1 (en) * | 2011-05-19 | 2012-11-22 | Glax L.L.C. | Compositions and methods for treating and preventing cancer by targeting and inhibiting cancer stem cells |
| CN112076179A (zh) * | 2020-09-27 | 2020-12-15 | 成都金瑞基业生物科技有限公司 | 和厚朴酚的医药用途 |
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| CN117503736A (zh) * | 2024-01-05 | 2024-02-06 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备治疗卵黄囊瘤药物中的用途 |
| CN117503737A (zh) * | 2024-01-05 | 2024-02-06 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备治疗脂肪肉瘤药物中的用途 |
| CN117503737B (zh) * | 2024-01-05 | 2024-04-16 | 成都金瑞基业生物科技有限公司 | 和厚朴酚在制备治疗脂肪肉瘤药物中的用途 |
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