WO2019210836A1 - 一种联合用药物及其在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途 - Google Patents

一种联合用药物及其在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途 Download PDF

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WO2019210836A1
WO2019210836A1 PCT/CN2019/085092 CN2019085092W WO2019210836A1 WO 2019210836 A1 WO2019210836 A1 WO 2019210836A1 CN 2019085092 W CN2019085092 W CN 2019085092W WO 2019210836 A1 WO2019210836 A1 WO 2019210836A1
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temozolomide
chlorogenic acid
preparation
grade
treatment
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French (fr)
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张洁
陈晓光
李文斌
杨华蓉
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四川九章生物科技有限公司
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Priority to US17/053,037 priority Critical patent/US20210161866A1/en
Publication of WO2019210836A1 publication Critical patent/WO2019210836A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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

Definitions

  • the present invention specifically relates to the use of a combination drug and a pharmaceutical composition for the preparation of a medicament for treating a high-grade brain tumor in which the standard treatment for postoperative recurrence is ineffective.
  • Brain tumors also known as intracranial tumors, brain tumors, are tumors of the nervous system that occur in the cranial cavity, including tumors originating from the neuroepithelial, peripheral nerve, meninges, and germ cells, lymphoid and hematopoietic tumors, and the sellar region. Craniopharyngioma and granulosa cell tumor. According to the World Health Organization Central Nervous System (CNS) Tumor Classification (2016), the classification of CNS tumors with tissue phenotype and gene phenotype is integrated. Brain tumors include diffuse astrocytes and oligodendrocyte tumors.
  • CNS Central Nervous System
  • High-grade brain tumor refers to brain tumors of grade III and IV in the classification of WHO central nervous system tumors, such as glioblastoma, diffuse midline glioma, pineal mesoma, medulloblastoma, Malignant nerve sheath tumor, anaplastic astrocytoma, anaplastic oligodendroglioma, etc.
  • This part of the high-grade brain tumor that is ineffective after standard recurrence is about 50% of adult primary malignant brain tumors.
  • the main pathological types include glioblastoma, anaplastic astrocytoma, and anaplastic oligodendromas. Between stenosis and astrocytoma. Among them, the incidence of malignant gliomas has increased in recent years, especially the incidence of glioblastoma, which accounts for 46.1% of primary malignant central nervous system tumors, and increases with age. The incidence rate is highest in the elderly population. Most of the malignant gliomas are located in the cerebral hemisphere. The tumors grow faster and the tumor occupying effect is obvious.
  • the main clinical manifestations are symptoms of high blood pressure, namely headache, nausea and vomiting, visual impairment, etc., accounting for about 90% of all cases, and other mental changes, seizures, focal neurological symptoms, etc., the severity of symptoms and tumors The size, location, age of the patient, etc.
  • High-grade brain tumors with ineffective standard treatment for malignant postoperative recurrence have rapid progression and high mortality.
  • the standard treatment plan is to maximize the surgical resection under the premise of ensuring neurological function. Local radiotherapy was followed by oral temozolomide (100 mg/m2) orally, followed by 6 cycles of adjuvant chemotherapy with temozolomide (150-200 mg/m2). With the application of standard treatment regimen, the median survival time can reach 14 months. However, due to its high degree of malignancy, strong invasiveness, and invasive growth and other biological characteristics, it is difficult to completely remove the surgery, and residual tumor cells make malignant. High-grade brain tumors with ineffective standard of recurrence after surgery are prone to recurrence. The prognosis of malignant glioma after recurrence is poor, and the median survival time is only about 7 months.
  • the present invention provides a combination drug and a pharmaceutical composition for treating a high-grade brain tumor in which standard treatment for postoperative recurrence is ineffective.
  • the present invention provides a combination drug for treating high-grade brain tumors in which standard treatment for postoperative recurrence is ineffective, comprising chlorogenic acid and temozolomide for simultaneous or separate administration of the same or different unit preparations, and pharmacy An acceptable carrier.
  • the mass ratio of the chlorogenic acid to temozolomide is 35:100 to 350:100.
  • the mass ratio of the chlorogenic acid to temozolomide is 85:100 to 200:100; the mass ratio of the chlorogenic acid to temozolomide is 85:100 to 175:100; preferably, the chlorogenic acid and The mass ratio of temozolomide is 100:100 or 200:100.
  • the preparation is an oral preparation or an injection preparation.
  • the present invention also provides the use of the above-mentioned combination drug for the preparation of a medicament for treating high-grade brain tumors in which the standard treatment for postoperative recurrence is ineffective.
  • the brain tumor comprises: glioblastoma, anaplastic astrocytoma, anaplastic oligodendroma, and interstitial oligodendroglioma.
  • the invention also provides a pharmaceutical composition comprising chlorogenic acid and temozolomide.
  • the mass ratio of the chlorogenic acid to temozolomide is 35:100 to 350:100.
  • the mass ratio of the chlorogenic acid to temozolomide is 85:100 to 200:100; the mass ratio of the chlorogenic acid to temozolomide is 85:100 to 175:100; preferably, the chlorogenic acid and temozolomide are The mass ratio is 100:100 or 200:100.
  • the present invention also provides a method for preparing the above pharmaceutical composition, which comprises chlorogenic acid and temozolomide as active ingredients, and a pharmaceutically acceptable auxiliary agent is added to prepare a pharmaceutically acceptable pharmaceutical preparation.
  • the preparation is an oral preparation or an injection preparation.
  • the present invention also provides the use of the above pharmaceutical composition for the preparation of a medicament for treating high-grade brain tumors in which standard treatment for recurrence is not effective.
  • the invention also provides the use of chlorogenic acid in the preparation of a medicament for treating high-grade brain tumors in which standard treatment for recurrence is not effective.
  • the brain tumor comprises: glioblastoma, anaplastic astrocytoma, anaplastic oligodendroma, and interstitial oligodendroglioma.
  • Standard recurrence in the present invention after the high-level brain tumor therapy, recurrence refers to standard therapy after surgery through high-level brain tumor.
  • Standard treatment refers to surgical treatment, chemotherapy, and radiotherapy in accordance with international and domestic guidelines (for example, Guidelines for the Diagnosis and Treatment of Central Nervous System Glioma in China, Chinese Medical Journal, February 23, 2016, Vol. 96, No. 7).
  • High-grade brain tumors refer to brain tumors of grade III and IV in the classification of WHO central nervous system tumors.
  • the invention provides a new method: treating brain malignant tumor, recurrence of high-grade malignant brain tumor, invalidation after international and domestic standard treatment (recurrence after surgery, radiotherapy, chemotherapy, re-treatment according to international and domestic guidelines, progress of disease)
  • the patient that is, the use of a. chlorogenic acid for injection, oral chlorogenic acid combination (temozolomide) and a pharmaceutical composition for treating glioma; b. chlorogenic acid for injection and oral green genus alone acid.
  • the pharmaceutical composition or the combined drug of the invention; chlorogenic acid and temozolomide can be used simultaneously or sequentially; it can treat patients who have relapsed after treatment with international and domestic standards, re-treatment is invalid, and the disease progresses. It can effectively control, reduce, and eliminate the lesions of brain malignant tumors, and significantly prolong the survival of patients with malignant brain tumors (especially high-grade).
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • temozolomide 100 g was aseptically weighed and aseptically divided into capsules.
  • the temozolomide was administered orally first, and the chlorogenic acid injection was continued at a mass ratio of 300 (chlorogenic acid): 150 (temozolomide).
  • temozolomide 100 g was aseptically weighed and aseptically divided into capsules.
  • the temozolomide was administered orally first, and the chlorogenic acid tablet was continued at a mass ratio of 300 (chlorogenic acid): 150 (temozolomide).
  • temozolomide 100 g was aseptically weighed and aseptically divided into capsules.
  • Temozolomide capsules and chlorogenic acid injections were used at a mass ratio of 100 (chlorogenic acid): 100 (temozolomide).
  • temozolomide 100 g was aseptically weighed and aseptically divided into capsules.
  • the chlorogenic acid injection was first used, and then the temozolomide capsule was continued at a mass ratio of 100 (chlorogenic acid): 100 (temozolomide).
  • the chlorogenic acid powder injection was first used, and then the temozolomide capsule was continued at a mass ratio of 35 (chlorogenic acid): 100 (temozolomide).
  • Preparation method chlorogenic acid and temozolomide are weighed according to the prescription, and evenly mixed, and then dispersed into a powder.
  • Preparation method chlorogenic acid, temozolomide, filler, binder, granulation, granules, granules and granules are weighed according to the prescription.
  • Preparation method chlorogenic acid, temozolomide, filler, binder, granulation, granule, lubricant, tableting, tableting are obtained according to the prescription.
  • the above filler is one or more of mannitol, lactose, starch, microcrystalline cellulose, dextrin; the binder is sodium carboxymethylcellulose, PVP; the lubricant is magnesium stearate, talc, Micronized silica gel.
  • Preparation method chlorogenic acid and temozolomide are weighed according to the prescription, and evenly mixed, and then aseptically divided into powder injection.
  • Preparation method chlorogenic acid and temozolomide are weighed according to the prescription, dissolved in water for injection, filtered and sterilized, and freeze-dried to obtain a lyophilized powder injection.
  • Preparation method chlorogenic acid, temozolomide, scaffold, antioxidant, weighed according to the prescription, dissolved in water for injection, filtered and sterilized, and lyophilized to obtain lyophilized powder injection.
  • the above scaffolding agents are mannitol, lactose, and glucose; and the antioxidants are sodium hydrogen sulfite, vitamins, glutathione, and folic acid.
  • the subjects enrolled in this study were all patients with high-grade glioma who had recurrence and had standard failure after standard operation.
  • the standard treatment was chemoradiotherapy.
  • chemotherapy is treated with temozolomide, temozolomide is 50-50 mg/m 2 orally, and the administration period is 4-30 cycles, of which 58% of the subjects have a treatment cycle of 10 cycles; radiotherapy is 60-200 GY, and chemotherapy is 10-50 times.
  • Invalid refers to tumor progression.
  • Mode of administration and dosage It is administered by intramuscular injection of chlorogenic acid for injection, and each injection of chlorogenic acid (30 mg) is dissolved in 0.5 ml of physiological saline (if physiological saline cannot be used, 5% glucose injection can be used. Liquid instead of), then intramuscularly, administered at a dose of 2.0 mg/kg to 7.0 mg/kg for 28 days for one administration cycle, with a dosing period of 1 to 10 cycles; administration with chlorogenic acid for injection Thereafter, temozolomide was administered orally according to the patient's condition, 50-150 mg/m 2 /d, continuous administration for 7 days, discontinuation for 7 days, 2 weeks for one administration cycle, and the administration cycle was 0-10 cycles.
  • the RAO standard is as follows:
  • the condition is considered stable: a non-enhancing lesion (T2 image) at the same dose or lower dose of hormone compared to the pre-treatment baseline Or FLAIR like) is stable and the clinical symptoms are stable.
  • the time point of the disease stabilization should be the last confirmed disease without increasing the hormone dose. Stable imaging scan time points.
  • T2 or FLAIR appears to increase significantly in non-enhancing lesions, but should exclude other comorbidities (radiation, demyelination, infection, postoperative changes, ischemic injury, epilepsy, etc.); any new Lesions; non-measurable lesions show significant progression; clinical symptoms are significantly worse, but non-tumor factors (epilepsy, adverse drug reactions, treatment complications, cerebrovascular events, infections, etc.) or hormone dose-modifying factors should be excluded; Death or worsening of the condition cannot complete the follow-up assessment.
  • the median OS randomization start
  • the median OS beginning after relapse
  • the experimental results show that the combination of chlorogenic acid or chlorogenic acid and temozolomide can effectively treat high-grade brain tumors with recurrence after standard treatment failure, and prolong the survival of patients with high-grade brain tumors who have failed after standard treatment.
  • the pathological tissue of cell culture is a high-grade brain tumor tissue sample which is ineffective after surgical resection and is not treated by standard treatment.
  • Glioblastoma cells, high-grade interstitial astrocytoma cells obtained by pathological tissue isolation and culture, High-grade neutrophiloma cells, high-grade interstitial oligodendroglioma cells, and brain tumor cells with undefined pathological type were placed in DMEM complete medium containing 10% FBS, at 37 °C, 5% carbon dioxide incubator, saturated humidity routine culture.
  • TMZ was dissolved in DMSO solution at a stock concentration of 100 mg/mL.
  • the tumor cells in logarithmic growth phase were made into cell suspension 1 ⁇ 10 5 ⁇ mL -1 .
  • TMZ 0.25 ⁇ g ⁇ mL -1
  • the culture was continued for 15-20 days.
  • each induced concentration was cultured for 15-20 days, and the final concentration of TMZ was 16.00 ⁇ g ⁇ mL -1 to obtain cell suspensions with different pathological types.
  • the cell suspension of 1 was inoculated in situ to the rats, and an animal model of glioblastoma with no standard treatment for recurrence was prepared.
  • the animals were divided into the test groups listed in the table below.
  • the chlorogenic acid injection was administered intraperitoneally at a dose of 20 mg/kg or 35 mg/kg per day for 10 days, and temozolomide was orally administered at 10 mg/kg or 20 mg/kg for 5 consecutive days. On the 5th day after the administration was stopped, the size of the tumor in situ in the mouse brain was observed and the tumor weight was weighed. Calculate the tumor inhibition rate.
  • chlorogenic acid alone has a significant inhibitory effect on glioblastoma, which is ineffective in the treatment of postoperative recurrence, because temozolomide is used alone; the combination of chlorogenic acid and temozolomide can further improve the therapeutic effect.
  • the effect of chlorogenic acid and temozolomide at 20 mg/kg was particularly excellent, and the weight ratio of chlorogenic acid to temozolomide was 2:1.
  • the cell suspension of 1 was inoculated in situ to the rats, and a high-grade interstitial astrocytoma animal model in which the standard of recurrence was not treated was prepared.
  • the animals were divided into the test groups listed in the following table.
  • the chlorogenic acid injection was administered intraperitoneally at a dose of 20 mg/kg or 35 mg/kg per day for 10 days, and temozolomide was orally administered at 10 mg/kg or 20 mg/kg for 5 consecutive days. On the 5th day after the administration was stopped, the size of the tumor in situ in the mouse brain was observed and the tumor weight was weighed. Calculate the tumor inhibition rate.
  • chlorogenic acid alone has a significant inhibitory effect on high-grade interstitial astrocytoma that is ineffective in the treatment of postoperative recurrence.
  • temozolomide is used alone, the combination of chlorogenic acid and temozolomide can further improve treatment.
  • the effect is particularly excellent when the dosage of chlorogenic acid and temozolomide is 20 mg/kg, and the weight ratio of the chlorogenic acid to temozolomide is 2:1.
  • the cell suspension in 1 was inoculated in situ to the rats, and a high-grade neutropenic brain tumor animal model in which the standard of recurrence was not treated was prepared.
  • the animals were divided into the test groups listed in the following table.
  • the chlorogenic acid injection was administered intraperitoneally at a dose of 20 mg/kg or 35 mg/kg per day for 10 days, and temozolomide was orally administered at 10 mg/kg or 20 mg/kg for 5 consecutive days.
  • the size of the tumor in situ in the mouse brain was observed and the tumor weight was weighed. Calculate the tumor inhibition rate.
  • chlorogenic acid alone has a significant inhibitory effect on high-grade interstitial oligodendrocyte brain tumors that are ineffective in the treatment of postoperative recurrence. Because temozolomide is used alone, the combination of chlorogenic acid and temozolomide can further improve The therapeutic effect is particularly excellent when the dosage of chlorogenic acid and temozolomide is 20 mg/kg, and the weight ratio of the chlorogenic acid to temozolomide is 2:1.
  • the cell suspension of 1 was inoculated in situ to the rats, and a high-grade interstitial oligodendroblastoma animal model for treating postoperative recurrence standard treatment was prepared, and the animals were divided into the test groups listed in the following table.
  • the chlorogenic acid injection was administered intraperitoneally at a dose of 20 mg/kg or 35 mg/kg per day for 10 days, and temozolomide was orally administered at 10 mg/kg or 20 mg/kg for 5 consecutive days. On the 5th day after the administration was stopped, the size of the tumor in situ in the mouse brain was observed and the tumor weight was weighed. Calculate the tumor inhibition rate.
  • chlorogenic acid alone has a significant inhibitory effect on high-grade interstitial oligodendrogliomas that are ineffective in the treatment of postoperative recurrence, because temozolomide is used alone; the combination of chlorogenic acid and temozolomide can further The therapeutic effect is improved, and the effect is particularly excellent when the dosage of chlorogenic acid and temozolomide is 20 mg/kg, and the weight ratio of the chlorogenic acid to temozolomide is 2:1.
  • the cell suspension of 1 was inoculated in situ to the rats, and an animal model of recurrence and unrecognized pathological brain tumor of the recurrence standard treatment was prepared.
  • the animals were divided into the test groups listed in the following table.
  • the chlorogenic acid injection was administered intraperitoneally at a dose of 20 mg/kg or 35 mg/kg per day for 10 days, and temozolomide was orally administered at 10 mg/kg or 20 mg/kg for 5 consecutive days. On the 5th day after the administration was stopped, the size of the tumor in situ in the mouse brain was observed and the tumor weight was weighed. Calculate the tumor inhibition rate.
  • chlorogenic acid alone has a significant inhibitory effect on the recurrence of glioblastoma and postoperative recurrence standard treatment, and has no significant effect on the pathological type of brain tumor model, because temozolomide is used alone;
  • the therapeutic effect can be further improved by the combination with temozolomide.
  • the effect of chlorogenic acid and temozolomide at 20 mg/kg is particularly excellent.
  • the weight ratio of chlorogenic acid to temozolomide is 2:1.
  • chlorogenic acid is a high-grade brain tumor that is ineffective in the treatment of postoperative recurrence, including high-grade interstitial astrocytoma, high-grade interstitial oligodendrocyte tumors, and high-grade interstitial oligodendroglioma.
  • the treatment effect is better than that of temozolomide, and the combination of chlorogenic acid and temozolomide can further improve the therapeutic effect.
  • the pharmaceutical composition or the combination drug of the present invention chlorogenic acid and temozolomide are combined with each other, and the curative effect is excellent; the recurrent high-grade brain tumor with standard treatment failure can be treated, the survival time of the patient is prolonged, and the clinical application prospect is excellent.

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Abstract

一种用于治疗术后复发标准治疗无效的高级别脑瘤的联合用药物，其含有相同或不同规格单位制剂的用于同时或者分别给药的绿原酸和替莫唑胺，以及药学上可接受的载体。一种药物组合物，其含有绿原酸和替莫唑胺，及其制备方法。上述联合用药物和药物组合物在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途。

Description

一种联合用药物及其在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途 技术领域
本发明具体涉及一种联合用药物及药物组合物在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途。
背景技术
脑瘤，又称颅内肿瘤、颅脑肿瘤，是指发生于颅腔内的神经系统肿瘤，包括起源于神经上皮、外周神经、脑膜和生殖细胞的肿瘤，淋巴和造血组织肿瘤，蝶鞍区的颅咽管瘤与颗粒细胞瘤。根据《世界卫生组织中枢神经系统(CNS)肿瘤分类(2016年)》中整合了组织表型和基因表型的CNS肿瘤分类原则，脑瘤包括弥漫性星形细胞和少突胶质细胞肿瘤、其他星形细胞肿瘤、室管膜肿瘤、脉络丛肿瘤、神经元及混合性神经元-胶质肿瘤、松果体区肿瘤、胚胎性肿瘤等17类肿瘤。高级别脑瘤是指是指WHO中枢神经系统肿瘤分类中Ⅲ、Ⅳ级别的脑瘤，比如，胶质母细胞瘤、弥漫性中线胶质瘤、松果体母细胞瘤、髓母细胞瘤、恶性神经鞘膜瘤、间变星形细胞瘤、间变少突胶质细胞瘤等。
脑瘤的致死率高，是威胁人类生命的一大因素。目前治疗脑瘤的通用方法包括手术、化疗和放疗。对于高级别脑瘤，大多需要进行手术。手术后部分患者的病情好转，不会进一步发展。部分患者术后会复发，复发后的患者虽然可以再次采用标准治疗(包括放疗、化疗)，但几乎所有患者的病情都不能有效地得到控制，病灶会进展，使得标准治疗无效。
这部分术后复发标准治疗无效的高级别脑瘤约占成人原发性恶性脑瘤的50％，其主要病理类型包括胶质母细胞瘤、间变星形细胞瘤、间变少突细胞瘤、间变少突星形细胞瘤等。其中，恶性胶质瘤近年来的发病率不断增加，尤其是胶质母细胞瘤发病率最高，在原发性恶性中枢神经系统肿瘤中约占到46.1％，且随着年龄的增长而增加，在老年人群中的发病率最高。恶性胶质瘤多位于大脑半球，肿瘤生长较快，瘤肿占位效应明显，在MRI上表现为混杂密度的肿块，呈不均匀的环状强化，周围伴有水肿带。其主要临床表示是颅高压症状，即头痛、恶心呕吐、视力障碍等，约占到全部病例的90％，其它还有精神改变、癫痫发作、局灶性神经症状等，症状的严重程度与肿瘤的大小、部位、患者的年龄等有关。
恶性术后复发标准治疗无效的高级别脑瘤具有进展迅速、死亡率高等特点，以胶质母细胞瘤为例，其标准治疗方案是在保障神经功能的前提下最大程度的手术切除，术后予以局部放疗同步替莫唑胺(100mg/m2)口服化疗，随后再予以6个周期的替莫唑胺(150-200mg/m2)的辅助化疗。随着标准治疗方案的应用，其中位生存期可达到14个月，然而，由于其恶性程度高，侵袭性强，呈浸润性生长等生物学特性，手术难以完全切除，残留的肿瘤细胞使恶性术后复发标准治疗无效的高级别脑瘤极易复发。复发后的恶性胶质瘤预后较差，中位生存期仅有7个月左右。
前针对术后复发标准治疗无效的高级别脑瘤，尚无有效的化疗方案。
发明内容
为解决上述问题，本发明提供了用于治疗术后复发标准治疗无效的高级别脑瘤的联合用药物和药物组合物。
本发明提供了一种用于治疗术后复发标准治疗无效的高级别脑瘤的联合用药物，它含有相同或不同规格单位制剂的用于同时或者分别给药的绿原酸和替莫唑胺，以及药学上可接受的载体。
其中，所述绿原酸和替莫唑胺的质量比为35：100～350：100。
进一步地，所述绿原酸和替莫唑胺的质量比为85：100～200：100；所述绿原酸和替莫唑胺的质量比为85：100～175：100；优选地，所述绿原酸与替莫唑胺的质量比为100:100或者200：100。
其中所述制剂为口服制剂或注射制剂。
本发明还提供了上述联合用药物在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途。
其中，所述脑瘤包括：胶质母细胞瘤、间变星形细胞瘤、间变少突细胞瘤、间变少突星形细胞瘤。
本发明还提供了一种药物组合物，它含有绿原酸和替莫唑胺。
其中，所述绿原酸与替莫唑胺的质量比为35：100～350：100。
其中，所述绿原酸和替莫唑胺的质量比为85：100～200：100；所述绿原酸和替莫唑胺的质量比为85：100～175：100；优选地，所述绿原酸与替莫唑胺的质量比为100:100或者200：100。
本发明还提供了上述的药物组合物的制备方法，它是以绿原酸和替莫唑胺为有效成分，加入药学上可接受的辅料制备成药学上常用的药物制剂。
其中，所述制剂为口服制剂或注射制剂。
本发明还提供了上述的药物组合物在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途。
本发明还提供了绿原酸在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途。
其中，所述脑瘤包括：胶质母细胞瘤、间变星形细胞瘤、间变少突细胞瘤、间变少突星形细胞瘤。
本发明中所述的术后复发标准治疗无效的高级别脑瘤， 是指手术后复发 经过标准治疗无效的高级别脑瘤。
标准治疗是指按照国际国内指导原则(比如，中国中枢神经系统胶质瘤诊断与治疗指南，中华医学杂志2016年2月23日第96卷第7期)进行手术治疗、化疗、放疗。
高级别脑瘤是指WHO中枢神经系统肿瘤分类中Ⅲ、Ⅳ级别的脑瘤。
本发明提供了一种新的方法：治疗脑部恶性肿瘤、高级别恶性脑瘤复发、经过国际国内标准治疗无效(手术、放疗、化疗后复发，按照国际国内指导原则再治疗无效、病情进展)的患者,即采用a.注射用绿原酸、口服绿原酸联合用药物(替莫唑胺)和药物组合物在治疗脑胶质瘤中的用途；b.单独使用注射用绿原酸和口服绿原酸。
本发明的药物组合物或联合用药物；绿原酸和替莫唑胺可同时使用或者先后使用；可以治疗经国际国内标准治疗后复发、再次进行治疗无效、病情进展的患者。能有效控制、缩小、消除脑部恶性肿瘤的病灶，显著延长恶性脑瘤(特别是高级别)患者的生存期。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1 本发明联合用药物
1绿原酸注射剂
无菌称取绿原酸350g，加入甘露醇850g，配制后分装成注射剂。
2替莫唑胺胶囊剂
无菌称取替莫唑胺100g，无菌分装成胶囊剂。
3使用方法
先口服使用替莫唑胺，再按照质量比300(绿原酸)：150(替莫唑胺)继续使用绿原酸注射剂。
实施例2 本发明联合用药物
1绿原酸口服片剂
无菌称取绿原酸350g，加入甘露醇850g，微晶纤维素250g，压片后制成口服片剂。
2替莫唑胺胶囊剂
无菌称取替莫唑胺100g，无菌分装成胶囊剂。
3使用方法
先口服使用替莫唑胺，再按照质量比300(绿原酸)：150(替莫唑胺)继续使用绿原酸片剂。
实施例3 本发明联合用药物
1绿原酸注射剂
无菌称取绿原酸100g，加入甘露醇650g，配制后分装成注射剂。
2替莫唑胺胶囊剂
无菌称取替莫唑胺100g，无菌分装成胶囊剂。
3使用方法
按照质量比100(绿原酸)：100(替莫唑胺)同时使用替莫唑胺胶囊和绿原酸注射剂。
4动物模型：替莫唑胺耐药动物模型
实施例4 本发明联合用药物
1绿原酸注射剂
无菌称取绿原酸100g，加入甘露醇250g，亚硫酸氢钠6g，配制后除菌过滤，分装冻干成粉针剂。
2替莫唑胺胶囊剂
无菌称取替莫唑胺100g，无菌分装成胶囊剂。
3使用方法
先使用绿原酸注射剂，再按照质量比100(绿原酸)：100(替莫唑胺)继续使用替莫唑胺胶囊剂。
实施例5 本发明联合用药物
1绿原酸注射剂
无菌称取绿原酸35g，加入甘露醇100g，溶解于注射用水，过滤除菌，冷冻干燥，得冻干粉针剂。
2替莫唑胺胶囊剂
无菌称取替莫唑胺100g，无菌分装成胶囊剂。3使用方法
先使用绿原酸粉针剂，再按照质量比35(绿原酸)：100(替莫唑胺)继续使用替莫唑胺胶囊剂。
实施例6 本发明药物组合物口服制剂处方
1、处方一
绿原酸35g、替莫唑胺100g。
制备方法：按处方无菌称取绿原酸和替莫唑胺，混合均匀后，无菌分装成散剂。
2、处方二
绿原酸350g、替莫唑胺100g、填充剂500g、粘合剂5g。
制备方法：按照处方称取绿原酸、替莫唑胺、填充剂、粘合剂，制粒，整粒、分装成颗粒剂。
3、处方三
绿原酸100g、替莫唑胺100g、填充剂500g、粘合剂5g、润滑剂3g。
制备方法：按照处方称取绿原酸、替莫唑胺、填充剂、粘合剂，制粒，整粒，加润滑剂，压片，得片剂。
上述填充剂为甘露醇、乳糖、淀粉、微晶纤维素、糊精当中的一种或几种；粘合剂为羧甲基纤维素钠、PVP；润滑剂为硬脂酸镁、滑石粉、微粉硅胶。
实施例7 本发明药物组合物注射制剂处方
1、处方一
绿原酸35g、替莫唑胺100g。
制备方法：按处方无菌称取绿原酸和替莫唑胺，混合均匀后，无菌分装成粉针剂。
2、处方二
绿原酸350g、替莫唑胺100g。
制备方法：按照处方称取绿原酸和替莫唑胺，溶解于注射用水，过滤除菌，冷冻干燥，得冻干粉针剂。
3、处方三
绿原酸100g、替莫唑胺100g、支架剂2667g、抗氧化剂67g。
制备方法：按照处方称取绿原酸、替莫唑胺、支架剂、抗氧化剂，溶解于注射用水，过滤除菌，冷冻干燥，得冻干粉针剂。
上述支架剂为甘露醇、乳糖、葡萄糖；抗氧化剂为亚硫酸氢钠、维生素、谷胱甘肽、叶酸。
以下通过实验例的方式来验证本发明的有益效果：
实验例1 临床统计
本实验探讨了注射用绿原酸在经标准治疗失败后复发的高级别(WHO III-IV级)脑胶质瘤患者中的疗效。
1.受试者入组的基线情况
本次试验共23例受试者完成试验，其中III级脑胶质瘤5例，IV级脑胶质瘤18例。23例中KPS≥60分11例，<60分12例。
本试验入组受试者均为术后复发并经过标准无效的高级别脑胶质瘤患者，标准治疗是采用放化疗治疗。其中，化疗为替莫唑胺治疗，替莫唑胺口服50-50mg/m 2，给药周期为4-30周期，其中58％的受试者治疗周期达到10个周期；放疗为60-200GY，化疗10-50次，无效是指肿瘤进展。
给药方式、剂量：采用注射用绿原酸肌肉注射给药方式给药，每支注射用绿原酸(30mg)以0.5ml生理盐水溶解(无法使用生理盐水时，可以使用5％的葡萄糖注射液代替)，之后肌肉注射，给药剂量为2.0mg/kg至7.0mg/kg连续给药28天为1个给药周期，给药周期为1至10个周期；注射用绿原酸给药后，根据患者情况给予替莫唑胺口服，50-150mg/m 2/d，连续给药7天，停药7天，2周为一个给药周期，给药周期为0-10个周期。
2.注射用绿原酸的初步有效性评价
2.1评价标准
根据RANO标准进项有效性评价，RANO标准具体如下：
项目 完全缓解 部分缓解 稳定 进展
T1+增强 未见 缩小≥50％ 变化在-50％-+25％ 增加≥25％
T2/FLAIR 稳定或减小 稳定或减小 稳定或减小 稳定或减小
新增病灶 未见 未见 未见 可见
皮质激素应用 无需 稳定或减小 稳定或减小 不作为标准
临床表现 稳定或改善 稳定或改善 稳定或改善 恶化
判断标准所需条件 以上全部 以上全部 以上全部 以上任何一项
评定标准：
(1)完全缓解(CR)：
需满足以下全部条件：所有可测量和非可测量增强病灶完全消失持续4周以上；无新发病灶；非强化病灶(T2像或FLAIR像)稳定或改善；患者停用激素或仅使用生理替代量；临床症状稳定或改善。
(2)部分缓解(PR)：
需满足以下全部条件：与治疗前基线相比，所有可测量病灶的两垂直直径的乘积之和减少≥50％，且持续4周以上；非可测量病灶无进展；无新发病灶；在同一剂量或更低剂量激素作用下，非增强病灶(T2像或FLAIR像)稳定或改善；患者的临床症状稳定或改善。
(3)疾病稳定(SD)：
若患者不符合完全缓解、部分缓解或疾病进展，且满足以下全部条件时，则视为病情稳定：与治疗前基线相比，在同一剂量或更低剂量激素作用下，非增强病灶(T2像或FLAIR像)稳定，且临床症状稳定。
若患者因临床症状或体征加重需增加激素剂量而无影像学证实的疾病进展，但在随后的MRI复查中证实存在疾病进展，则疾病稳定的时间点应是未增加激素剂量时最后一次证实疾病稳定的影像学扫描时间点。
(4)疾病进展(PD)：
满足以下任意一项：在激素用量不变或增加的情况下，与治疗前基线(如病灶未减小)或治疗反应最佳时的最小强化病灶相比，增强病灶两垂直直径的乘积之和增加>25％；T2像或FLAIR像上非增强病灶显著增大，但应除外其他合并症(放疗、脱髓鞘、感染、术后改变、缺血性损伤、癫痫等)因素；出现任何新发病灶；非可测量病灶出现明显的进展；临床症状显著恶 化，但应除外非肿瘤因素(癫痫、药物不良反应、治疗的并发症、脑血管事件、感染等)或激素剂量改变因素；由于临床死亡或病情恶化无法完成随访评估。
2.2评价结果
截止数据库锁库时间(2018年2月5日)进行注射用绿原酸初步有效性评价，试验共入组受试者26例，提前出组3例，可统计的23例：
(1)RANO标准进项有效性评价
针对所有受试者：I期临床试验期间给药1个周期后，12例SD(12例中有5例病灶缩小)，11例PD，I期临床试验期间给药1个周期后的DCR(疾病控制率)为52.17％；给药2个周期后的DCR为33.33％。
给药6个周期之后，001号受试者评估为CR，010号受试者评估为PR，这一结果是令人振奋的，标准治疗失败的复发高级别闹胶质瘤绝大多数患者会处于SD-PD-死亡的不可逆状态，很少(小概率事件)会出现CR或PR，因此在本次试验中23例受试者中就有2例出现CR和PR，显著的疗效反应远超出研究者预期。
针对18例IV级脑母瘤人群进行用药周期与生存情况的相关性分析，将18例完成试验的IV级胶质瘤受试者分为存活和死亡分别进行统计。初步结果显示，9例死亡的受试者对绿原酸应答不明显，应答率为11.1％(9例死亡的IV级胶母受试者用药1周期仅1人肿瘤评估结果为SD，8人PD)。9例存活的IV级胶母瘤受试者对绿原酸的应答较高，应答率为88.9％(9例存活的IV级胶母受试者用药1周期有8人肿瘤评估结果为SD，1人PD)，仍在进行生存期随访。
3.0mg/kg剂量组共入组受试者9例，给药1个周期后3例受试者的肿瘤缩小(但未达到PR)，3例肿瘤缩小受试者中，1例用药2周期后，颅内靶病灶消失，但由于肺部病灶进展，综合评估为S D，给药1个周期后的DCR为66.67％。
(2)中位OS
截止到试验数据，3.0mg/kg剂量组中位OS(随机化开始)为9.3个月；中位OS(复发后开始)为13.2个月。据公开文献报道的标准，现有治疗方法复发后的中位OS是7.2-9.6个月，而本发明药物已超出公开文献报道认可标准3.6个月。
截止目前(2018-02-05)3.0mg/kg组的9例受试者仅出现1例死亡，1例失访，目前尚未达到50％病例死亡的中位OS，现存活的受试者仍在持续随访中，因此3.0mg/kg剂量组的最终中位OS应远高于目前报告值。
实验结果证明，绿原酸或者绿原酸与替莫唑胺的组合，可以有效治疗术后复发经过标准治疗无效的高级别脑瘤，延长术后复发经过标准治疗无效的高级别脑瘤患者的存活期。
实验例2 动物实验
1.术后复发并经过标准无效的高级别脑瘤细胞培养
1.1细胞培养：细胞培养的病理组织为经手术切除的术后复发标准治疗无效的高级别脑瘤组织样本，经病理组织分离培养获得的胶质母细胞、高级别间变星形细胞瘤细胞、高级别间变少突细胞瘤细胞、高级别间变少突星形细胞瘤细胞和未明确病理分型的脑瘤细胞，置于含体积分数为10％FBS的DMEM完全培养液中，于37℃、5％二氧化碳培养箱、饱和湿度常规培养。TMZ溶于DMSO溶液，储存液质量浓度为100mg/mL。处于对数生长期的肿瘤细胞制成细胞悬液1×10 5个·mL －1，常规培养24h后加入初始诱导剂量的TMZ 0.25μg·mL －1，继续培养15～20d，待细胞生长稳定后倍增药物诱导浓度，每一诱导浓度培养15～20d，TMZ终浓度为16.00μg·mL －1，获得不同病理分型的细胞悬液。
2.绿原酸与替莫唑胺联合对术后复发标准治疗无效的高级别脑瘤动物模型抑瘤率
2.1绿原酸与替莫唑胺联合对术后复发标准治疗无效的胶质母细胞瘤动物模型抑瘤率
将1中的细胞悬液原位接种于大鼠，制备术后复发标准治疗无效的胶质母细胞瘤动物模型，动物分成下表中所列各个试验组。绿原酸注射剂每天腹腔给药20mg/kg或者35mg/kg，连续给药10天，替莫唑胺口服10mg/kg或者20mg/kg，连续给药5天。停止给药后第5天，观察小鼠脑内原位肿瘤大小并称定肿瘤重量。计算抑瘤率。
组别 剂量(mg/kg) 动物数(n) 瘤重 抑瘤率(％)
绿原酸+替莫唑胺 7+20 10 0.65±0.07 68.2
绿原酸+替莫唑胺 20+20 10 0.32±0.05 84.3
绿原酸+替莫唑胺 20+10 10 0.72±0.08 64.0
绿原酸+替莫唑胺 35+10 10 0.55±0.06 73.1
绿原酸 35 10 0.98±0.09 52.2
替莫唑胺 20 9 1.54±0.10 24.1
替莫唑胺 10 8 1.75±0.14 14.6
空白对照 ——   2.05±0.25  
由上表可以看出，绿原酸单独使用对术后复发标准治疗无效的胶质母细胞瘤有明显抑制效果，由于替莫唑胺单独使用；将绿原酸与替莫唑胺联合使用可以进一步提高治疗效果，其中绿原酸与替莫唑胺给药剂量均为20mg/kg时效果特别优良，该组绿原酸与替莫唑胺的重量比为2：1。
3.2绿原酸与替莫唑胺联合对术后复发标准治疗无效的高级别间变星形细胞瘤动物模型抑瘤率
将1中的细胞悬液原位接种于大鼠，制备术后复发标准治疗无效的高级别间变星形细胞瘤动物模型，动物分成下表中所列各个试验组。绿原酸注射剂每天腹腔给药20mg/kg或者35mg/kg，连续给药10天，替莫唑胺口服10mg/kg或者20mg/kg，连续给药5天。停止给药后第5天，观察小鼠脑内原位肿瘤大小并称定肿瘤重量。计算抑瘤率。
Figure PCTCN2019085092-appb-000001
由上表可以看出，绿原酸单独使用对术后复发标准治疗无效的高级别间变星形细胞瘤有明显抑制效果，由于替莫唑胺单独使用；将绿原酸与替莫唑胺联合使用可以进一步提高治疗效果，其中绿原酸与替莫唑胺给药剂量均为20mg/kg时效果特别优良，该组绿原酸与替莫唑胺的重量比为2：1。
3.3绿原酸与替莫唑胺联合对术后复发标准治疗无效的高级别间变少突细胞脑瘤动物模型抑瘤率
将1中的细胞悬液原位接种于大鼠，制备术后复发标准治疗无效的高级别间变少突细胞脑瘤动物模型，动物分成下表中所列各个试验组。绿原酸注射剂每天腹腔给药20mg/kg或者35mg/kg，连续给药10天，替莫唑胺口服10mg/kg或者20mg/kg，连续给药5天。停止给药后第5天，观察小鼠脑内原位肿瘤大小并称定肿瘤重量。计算抑瘤率。
Figure PCTCN2019085092-appb-000002
由上表可以看出，绿原酸单独使用对术后复发标准治疗无效的高级别间变少突细胞脑瘤有明显抑制效果，由于替莫唑胺单独使用；将绿原酸与替莫唑胺联合使用可以进一步提高治疗效果，其中绿原酸与替莫唑胺给药剂量均为20mg/kg时效果特别优良，该组绿原酸与替莫唑胺的重量比为2：1。
3.4绿原酸与替莫唑胺联合对术后复发标准治疗无效的高级别间变少突星形细胞瘤动物模型抑瘤率
将1中的细胞悬液原位接种于大鼠，制备治疗术后复发标准治疗无效的高级别间变少突星形细胞瘤动物模型，动物分成下表中所列各个试验组。绿原酸注射剂每天腹腔给药20mg/kg或者35mg/kg，连续给药10天，替莫唑胺口服10mg/kg或者20mg/kg，连续给药5天。停止给药后第5天，观察小鼠脑内原位肿瘤大小并称定肿瘤重量。计算抑瘤率。
Figure PCTCN2019085092-appb-000003
由上表可以看出，绿原酸单独使用对术后复发标准治疗无效的高级别间 变少突星形细胞瘤有明显抑制效果，由于替莫唑胺单独使用；将绿原酸与替莫唑胺联合使用可以进一步提高治疗效果，其中绿原酸与替莫唑胺给药剂量均为20mg/kg时效果特别优良，该组绿原酸与替莫唑胺的重量比为2：1。
3.5绿原酸与替莫唑胺联合对标准治疗术后复发标准治疗无效的未明确病理分型脑瘤动物模型抑瘤率
将1中的细胞悬液原位接种于大鼠，制备术后复发标准治疗无效的复发未明确病理分型脑瘤动物模型，动物分成下表中所列各个试验组。绿原酸注射剂每天腹腔给药20mg/kg或者35mg/kg，连续给药10天，替莫唑胺口服10mg/kg或者20mg/kg，连续给药5天。停止给药后第5天，观察小鼠脑内原位肿瘤大小并称定肿瘤重量。计算抑瘤率。
Figure PCTCN2019085092-appb-000004
由上表可以看出，绿原酸单独使用对胶质母细胞瘤、术后复发标准治疗无效的复发未明确病理分型脑瘤动物模型有明显抑制效果，由于替莫唑胺单独使用；将绿原酸与替莫唑胺联合使用可以进一步提高治疗效果，其中绿原酸与替莫唑胺给药剂量均为20mg/kg时效果特别优良，该组绿原酸与替莫唑胺的重量比为2：1。
本实验证明了绿原酸对术后复发标准治疗无效的高级别脑瘤，包括高级别间变星形细胞瘤、高级别间变少突细胞脑瘤、高级别间变少突星形细胞瘤等在内等均有良好的治疗效果，效果优于替莫唑胺，将绿原酸与替莫唑胺联合使用可以进一步提高治疗效果。
综上，本发明的药物组合物或联合用药物，绿原酸和替莫唑胺彼此配合，疗效优良；可以治疗标准治疗无效的复发高级别脑瘤，延长患者的生存期，临床应用前景优良。

Claims (14)

  1. 一种用于治疗术后复发标准治疗无效的高级别脑瘤的联合用药物，其特征在于：它含有相同或不同规格单位制剂的用于同时或者分别给药的绿原酸和替莫唑胺，以及药学上可接受的载体。
  2. 根据权利要求1所述的联合用药物，其特征在于：所述绿原酸和替莫唑胺的质量比为35：100～350：100。
  3. 根据权利要求2所述的联合用药物，其特征在于：所述绿原酸和替莫唑胺的质量比为85：100～200：100；所述绿原酸和替莫唑胺的质量比为85：100～175：100；优选地，所述绿原酸与替莫唑胺的质量比为100:100或者200：100。
  4. 根据权利要求1～3任意一项所述的联合用药物，其特征在于：所述制剂为口服制剂或注射制剂。
  5. 权利要求1～4任意一项所述的联合用药物在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途。
  6. 根据权利要求5所述的用途，其特征在于：所述脑瘤包括：胶质母细胞瘤、间变星形细胞瘤、间变少突细胞瘤、间变少突星形细胞瘤。
  7. 一种药物组合物，其特征在于：它含有绿原酸和替莫唑胺。
  8. 根据权利要求7所述的药物组合物，其特征在于：所述绿原酸与替莫唑胺的质量比为35：100～350：100。
  9. 根据权利要求8所述的药物组合物，其特征在于：所述绿原酸和替莫唑胺的质量比为85：100～200：100；所述绿原酸和替莫唑胺的质量比为85：100～175：100；优选地，所述绿原酸与替莫唑胺的质量比为100:100或者200：100。
  10. 一种制备权利要求7～9任一项所述的药物组合物的方法，其特征在于：它是以绿原酸和替莫唑胺为有效成分，加入药学上可接受的辅料制备成药学上常用的药物制剂。
  11. 根据权利要求10所述的制备方法，其特征在于：所述制剂为口服制剂或注射制剂。
  12. 权利要求7～9任一项所述的药物组合物在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途。
  13. 绿原酸在制备治疗术后复发标准治疗无效的高级别脑瘤的药物中的用途。
  14. 根据权利要求12或13所述的用途，其特征在于：所述脑瘤包括： 胶质母细胞瘤、间变星形细胞瘤、间变少突细胞瘤、间变少突星形细胞瘤。
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