WO2023016519A1 - 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 PDF

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WO2023016519A1
WO2023016519A1 PCT/CN2022/111765 CN2022111765W WO2023016519A1 WO 2023016519 A1 WO2023016519 A1 WO 2023016519A1 CN 2022111765 W CN2022111765 W CN 2022111765W WO 2023016519 A1 WO2023016519 A1 WO 2023016519A1
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honokiol
liposome
meningioma
injection
treatment
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PCT/CN2022/111765
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French (fr)
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李文斌
王策
赖新天
王晓波
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成都金瑞基业生物科技有限公司
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Priority to EP22855499.4A priority Critical patent/EP4385504A1/en
Priority to CN202280007912.4A priority patent/CN116761593A/zh
Priority to US18/282,410 priority patent/US20240165047A1/en
Publication of WO2023016519A1 publication Critical patent/WO2023016519A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/57—Magnoliaceae (Magnolia family)
    • A61K36/575—Magnolia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the present invention relates to the medical use of honokiol. Specifically, the present invention relates to the use of honokiol in the treatment of meningioma.
  • Meningioma is the most common primary tumor of the central nervous system, mostly originating from arachnoid endothelial cells, mainly in arachnoid granules or villi. Meningioma accounts for about 36.6% of all primary central nervous system tumors and 53.2% of non-malignant primary central nervous system tumors. Meningiomas are divided into benign meningiomas and malignant meningiomas. Typical clinical symptoms are generalized and partial epileptic seizures caused by increased intracranial pressure, focal nervous system (including cranial nerve) defects, and focal mass effects, the most common of which are headache, epileptic seizures, and epileptic seizures. , visual symptoms, weakness, and altered mental status.
  • meningioma The incidence rate of meningioma has been increasing year by year, from 4.52/100,000 in 1998-2002 to 8.3/100,000 in 2010-2014. The onset of meningioma is more common in elderly patients, mostly 70 to 80 years old.
  • Ionizing radiation is a risk factor for the development of meningiomas.
  • Hiroshima and Nagasaki 88 meningiomas were observed among 80,160 atomic bomb survivors.
  • Even small doses of radiation to the head, such as those used in dental radiography, may increase the risk of meningioma development.
  • Epidemiological studies have shown that a history of head trauma, smoking, and cell phone use has not been shown to be associated with an increased risk of meningioma.
  • the standard protocol for treating meningioma generally includes surgery and radiation therapy. Although progress has been made in surgery and radiotherapy, most patients can be cured, but the recurrence rate of malignant meningioma is as high as 50% to 80%, and the median survival time of some patients is less than 2 years. The treatment of this disease is very difficult. So far, chemotherapy, hormone therapy and immunotherapy have very limited curative effects on patients with malignant meningioma; due to the particularity of brain tumors, surgical treatment for recurrent patients is also very limited; and surgery, radiotherapy and chemotherapy are poorly tolerated by patients . As the population ages and the incidence of meningioma increases, effective therapies for meningioma with good safety and tolerability become more clinically important and urgently need to be developed.
  • the purpose of the present invention is to develop a method that can effectively treat meningiomas, and the method has good safety and tolerance.
  • Honokiol is a small molecular compound with a wide range of biological activities isolated from the bark of Magnolia officinalis Rehd.etWils. Its main biological activities include anti-inflammatory, anti-microbial, anti-ulcer, anti-oxidation, and anti-anxiety , anti-depression, anti-thrombotic, anti-aging and lower cholesterol.
  • honokiol In view of the extensive medicinal value of honokiol, the inventor further studied the new application of honokiol. In clinical research, the inventors found that honokiol can effectively inhibit the growth of meningioma, and eliminate and/or reduce the focus of meningioma.
  • one of the objects of the present invention is to provide the application of honokiol in the preparation of medicine for treating meningioma.
  • the honokiol is prepared as a honokiol liposome, preferably a honokiol liposome for injection.
  • Another object of the present invention is to provide honokiol liposomes for treating meningioma.
  • the honokiol liposome of the present invention wherein the honokiol liposome is injection honokiol liposome.
  • Honokiol liposomes according to the present invention, wherein said honokiol liposomes include the following dosage forms: lyophilized powder preparations, including injection lyophilized powder preparations, oral lyophilized powder preparations; tablets, including immediate release Tablets and sustained-release tablets; capsules, including hard capsules, soft capsules, sustained-release capsules and enteric-coated capsules; transdermal preparations, etc.
  • honokiol liposome of the present invention wherein said honokiol liposome can be administered through the following routes: intravenous injection, intramuscular injection, subcutaneous injection, oral administration, eye administration, pulmonary administration Drug administration, transdermal administration and nasal administration, etc.
  • honokiol can effectively treat meningiomas, effectively inhibit the growth of meningiomas, and eliminate and/or reduce meningioma lesions. Moreover, clinical trials have shown that honokiol is safe and well tolerated.
  • 1A to 1C are the cranial magnetic resonance images of patients with meningioma before treatment with honokiol and after one cycle and three cycles of treatment in Example 1, respectively.
  • 2A to 2C are the cranial magnetic resonance images of patients with meningioma before treatment with honokiol and after one cycle and three cycles of treatment in Example 2, respectively.
  • 3A to 3C are the cranial magnetic resonance images of patients with meningioma before treatment with honokiol and after one cycle and three cycles of treatment in Example 3, respectively.
  • 4A to 4C are the cranial magnetic resonance images of patients with meningioma before treatment with honokiol and after one cycle and three cycles of treatment in Example 4, respectively.
  • Honokiol liposomes for injection come from Chengdu Jinrui Jiye Biotechnology Co., Ltd., or can be prepared according to the following method: take 50 mg of honokiol, 500 mg of soybean lecithin, 200 mg of cholesterol, 200 mg of cultured phosphatidylethanolamine, dissolve Dissolve completely in 50 mL of absolute ethanol and pour into 300 mL of purified water, stir, remove ethanol by rotary evaporation, add 800 mg of sucrose as a freeze-drying excipient, and freeze-dry.
  • Endothelial meningioma Endothelial meningioma, local hemangioma-type meningioma, with hemorrhage, atypical meningioma, bone tissue infiltration, comprehensively malignant meningioma; Immunohistochemistry: EMA (focal positive), PR (scattered positive), SSTR (focal positive), CD34 (vessel positive), CD99(+), S100(-), Syn(-), CgA(-) , CK (occasionally positive), Ki67 (about 8-20%);
  • the subject On March 5, 2021, the subject re-examined the brain MRI, and the tumor recurred; for further treatment, the subject received "malignant tumor maintenance treatment" in the neurotumor comprehensive treatment ward for further treatment at the outpatient clinic of Beijing Tiantan Hospital affiliated to Capital Medical University;
  • patients with brain metastases selected for other tumor types must meet the following conditions: no clinical symptoms related to brain metastases, no need for systemic corticosteroids or anticonvulsant drug treatment; treated patients with brain metastases must be within 28 days of treatment. There was no progress in reexamination after 2 days; no risk of cerebral hemorrhage;
  • LVEF left ventricular ejection fraction
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • KPS score 50 points
  • the ECOG score is ⁇ 1;
  • Three cycles of medication were carried out on the subjects: a cycle of 28 days, in which the drug was given continuously for 5 days a week, and the drug was stopped for 2 days for 3 weeks, with a rest of 1 week; administration of honokiol liposome for injection, The dose is 420mg/day honokiol; administration method: administer via peripheral venous puncture and central venous catheter, and the infusion time is 2h.
  • the target lesion was reduced by 17.46% compared with before treatment, and the product of the two vertical diameters of the target lesion was reduced from 77.3mm ⁇ 65mm before treatment to 76.1mm ⁇ 54.5mm.
  • the head MRI was rechecked, and the head MRI image is shown in Figure 1C.
  • the target lesion was reduced by 11.13% compared with before treatment, and the product of the two vertical diameters of the target lesion was reduced to 70.1mm ⁇ 63.7mm.
  • the curative effect was evaluated as stable disease (SD), and the clinical manifestations were improved without adverse reactions.
  • Dosing method Administer via peripheral venous puncture and central venous catheter, infusion time is 2 hours; every 4 weeks is a dosing cycle, every 3 weeks (1st to 3rd week of this cycle), continuous every week Administration for 5 days, once a day, drug withdrawal for 2 days, rest for 1 week.
  • Example 1 Phase I Clinical Trial of Clinical Safety and Tolerability of Honokiol Liposomes for Injection (HK) in the Treatment of Patients with Advanced Malignant Solid Tumors.
  • Three cycles of medication were carried out on the subjects: a cycle of 28 days, in which the drug was given continuously for 5 days a week, and the drug was stopped for 2 days for 3 weeks, with a rest of 1 week; administration of honokiol liposome for injection, The dose is 420mg/day honokiol; administration method: administer via peripheral venous puncture and central venous catheter, and the infusion time is 2h.
  • the target lesion was reduced by 22.97% compared with before treatment, and the product of the two vertical diameters of the target lesion was reduced from 14.3mm ⁇ 12.9mm before treatment to 14.1mm ⁇ 10mm.
  • the head MRI was checked again, and the head MRI image is shown in Figure 2C.
  • the target lesion was reduced by 29.13% compared with before treatment, and the product of the two vertical diameters of the target lesion was reduced to 13.8mm ⁇ 9.4mm.
  • the curative effect was evaluated as stable disease (SD), and the clinical manifestation was stable and resistant to drugs.
  • Three cycles of medication were carried out on the subjects: a cycle of 28 days, in which the drug was given continuously for 5 days a week, and the drug was stopped for 2 days for 3 weeks, with a rest of 1 week; administration of honokiol liposome for injection, The dose is 420mg/day honokiol; administration method: administer via peripheral venous puncture and central venous catheter, and the infusion time is 2h.
  • the target lesion was reduced by 35.30% compared with that before the treatment, and the product of the two vertical diameters of the target lesion was reduced from 12.5mm ⁇ 30.8mm before treatment to 10.9mm ⁇ 22.5mm.
  • the head MRI was checked again, and the head MRI image is shown in Figure 3C.
  • the target lesion was reduced by 13.42% compared with that before treatment, and the product of the two vertical diameters of the target lesion was reduced to 12.3mm ⁇ 27.1mm.
  • the curative effect was evaluated as stable disease (SD), with improved clinical manifestations and drug tolerance.
  • meningioma Changes after frontotemporal craniotomy, right parasphenoid peak, middle cranial fossa, infratemporal fossa, and right orbital mass: meningioma recurrence, with multiple enhancements at the right orbital apex, anterior cranial fossa floor, and right tentorial border ; Multiple ischemic white matter lesions in the brain, pathology: anaplastic meningioma (WHO III), Ki-67 (about 40-60%).
  • the outpatient was admitted to the hospital as "meningioma".
  • Three cycles of medication were carried out on the subjects: a cycle of 28 days, in which the drug was given continuously for 5 days a week, and the drug was stopped for 2 days for 3 weeks, with a rest of 1 week; administration of honokiol liposome for injection, The dose is 420mg/day honokiol; administration method: administer via peripheral venous puncture and central venous catheter, and the infusion time is 2h.
  • the target lesion was shown to be 15.68% smaller than before treatment, and the product of the two vertical diameters of the target lesion was reduced from 23.3mm ⁇ 35.3mm before treatment to 22.3mm ⁇ 31.1mm.
  • the graph is shown in Figure 4C.
  • the target lesion was reduced by 15.68% compared with before treatment, and the product of the two vertical diameters of the target lesion was reduced to 22.3mm ⁇ 31.1mm.
  • the curative effect was evaluated as stable disease (SD), with improved clinical manifestations and drug tolerance.

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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

和厚朴酚在制备用于治疗脑膜瘤的药物中的用途 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：
Figure PCTCN2022111765-appb-000001
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至图1C分别为实施例1中用和厚朴酚治疗前和治疗一周期、三周期后脑膜瘤患者的头颅核磁图。
图2A至图2C分别为实施例2中用和厚朴酚治疗前和治疗一周期、三周期后脑膜瘤患者的头颅核磁图。
图3A至图3C分别为实施例3中用和厚朴酚治疗前和治疗一周期、三周期后脑膜瘤患者的头颅核磁图。
图4A至图4C分别为实施例4中用和厚朴酚治疗前和治疗一周期、三周期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
Figure PCTCN2022111765-appb-000002
Figure PCTCN2022111765-appb-000003
实施例中使用的试验材料如下：
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。
实施例1
受试者情况描述：
男性，年龄20岁；
2018年1月20日，受试者头颅MR示右侧CPA及颈静脉孔区占位；
2018年11月27日，受试者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，受试者颅内感染治疗；
2019年6月，受试者全脑放疗；
2021年3月5日，受试者复查头颅核磁，肿瘤复发；为进一步治疗，受试者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≥1.5x10 9/L，血小板≥80x10 9/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。
对受试者进行三个周期用药：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/天和厚朴酚；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。完成三周期用药后，复查头颅核磁，头颅核磁图如图1C所示。按照RANO标准，显示靶病灶较用药前缩小11.13％，其中靶病灶两垂直直径的乘积缩小到70.1mm×63.7mm，疗效评价为疾病稳定(SD)，临床表现为改善，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/天、3例40mg/天、4例80mg/天、3例140mg/天、5例210mg/天、6例300mg/天、12例420mg/天。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。
实施例2
受试者情况描述：
女性，年龄39岁；
患者于入院1年前无明显诱因出现颈枕部疼痛不适，活动后加重，无肢体活动障碍，无明显上肢放射痛，夜间加重，为进一步治疗，就诊于大连医科大学附属第二医院，完善脑部MRI示延髓占位。围手术治疗，就诊于大连医科大学第二附属医院，2020年1月10日在该院进行全麻下脑干肿瘤切除术，术中见肿瘤大小约1.5*1.5cm，伴肿瘤卒中，烂鱼肉状，血供丰富，镜下全切肿瘤。术后病理：非典型脑膜瘤(WHO II)，KI-67(25％)。术后出现声音嘶哑。
入院前自觉头晕，乏力，偶有呛咳，就诊于天坛医院，入院1周前查脑部MRI示延髓病灶进展。给予自备PD-1免疫治疗2周期，过程顺利。现为进一步治疗来诊。门诊以＂脑膜瘤“收入院。
2021年10月14日按实施例1所述“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”入选标准入组给药。
对受试者进行三个周期用药：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/天和厚朴酚；给药方法：经外周静脉穿刺中心静脉置管给药，输注时间2h。
完成一周期用药后，复查头颅核磁，头颅核磁前后对比图如图2A和图2B所示。按照RANO标准，显示靶病灶较用药前缩小22.97％，其中靶病灶两垂直直径的乘积由治疗前14.3mm×12.9mm缩小到14.1mm×10mm。完成三周期用药后，复查头颅核磁，头颅核磁图如图2C所示。按照RANO标准，显示靶病灶较用药前缩小29.13％，其中靶病灶两垂直直径的乘积缩小到13.8mm×9.4mm，疗效评价为疾病稳定(SD)，临床表现为稳定，对药物耐受。
实施例3
受试者情况描述：
男性，年龄53岁；
患者入院5年前无明显诱因“四肢抽搐伴口吐白沫、试验上翻4小时”，无记忆力下降，无头痛、头晕、无恶心、呕吐，无肢体活动障碍、无听力及视力下降，进行头部MRI示颅内占位，就诊于济宁市第一人民医院，完善相关检 查，于2016年2月21日进行右额部肿瘤切除术，术后病理：脑膜瘤。术后于山东武警总医院进行伽马刀治疗1次。2017年10月进行颅骨修补术。
2019年2月13日出现癫痫发作，复查考虑肿瘤复发，2019年2月18日进行脑膜瘤供血动脉栓塞术，2019年2月21日进行原切口入路肿瘤切除术，术后病理：脑膜瘤(WHO I)，术后给予全脑放疗。2021年4月复查考虑肿瘤复发，未予治疗，2021年5月出现癫痫发作，给予德巴金治疗。2021年6月癫痫大发作，对症治疗后好转，复查头部核磁较前增大。
2021年7月21日再次进行右额叶廉旁肿瘤切除术，术后病理：间变型脑膜瘤(WHO III)，Ki-67(50％)，2021年8月17日给予：替雷丽珠单抗1周期，为进一步治疗，门诊以“脑膜瘤”收入院。
2021年10月21日按实施例1所述“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”入选标准入组给药。
对受试者进行三个周期用药：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/天和厚朴酚；给药方法：经外周静脉穿刺中心静脉置管给药，输注时间2h。
完成一周期用药后，复查头颅核磁，头颅核磁前后对比图如图3A和图3B所示。按照RANO标准，显示靶病灶较用药前缩小35.30％，其中靶病灶两垂直直径的乘积由治疗前12.5mm×30.8mm缩小到10.9mm×22.5mm。完成三周期用药后，复查头颅核磁，头颅核磁图如图3C所示。按照RANO标准，显示靶病灶较用药前缩小13.42％％，其中靶病灶两垂直直径的乘积缩小到12.3mm×27.1mm，疗效评价为疾病稳定(SD)，临床表现为改善，对药物耐受。
实施例4
受试者情况描述：
女性，年龄53岁；
患者2012年因癫痫发作就诊于当地医院，检查发现颅内占位，进行右额颞开颅，占位切除术，术后病理：右中颅窝低脑膜瘤(WHO I)，术后每年规律复查。
2016年，2018年因复发进行伽马刀治疗。一年前，右侧视力逐渐下降，之后间断头痛，无肢体抽搐，无大小便失禁，无恶心呕吐，无肢体活动障碍，入院3个月前于当地医院就诊，并进行头部MRI，发现右额颞开颅术后改变，右蝶骨峭旁、中颅窝、颞下窝及右侧眶内占位：脑膜瘤复发，伴右侧眶尖、前颅窝底、右小脑幕缘多发强化；脑内多发缺血性白质病变，病理：间变型脑膜瘤(WHO III)，Ki-67(约40-60％)。为进一步治疗，门诊以＂脑膜瘤“收入院。
2021年10月28日按实施例1所述“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”入选标准入组给药。
对受试者进行三个周期用药：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/天和厚朴酚；给药方法：经外周静脉穿刺中心静脉置管给药，输注时间2h。
完成一周期用药后，复查头颅核磁，头颅核磁前后对比图如图4A和图4B所示。按照RANO标准，显示靶病灶较用药前缩小15.68％，其中靶病灶两垂直直径的乘积由治疗前23.3mm×35.3mm缩小到22.3mm×31.1mm，完成三周期用药后，复查头颅核磁，头颅核磁图如图4C所示。按照RANO标准，显示靶病灶较用药前缩小15.68％，其中靶病灶两垂直直径的乘积缩小到22.3mm×31.1mm，疗效评价为疾病稳定(SD)，临床表现为改善，对药物耐受。

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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