Use of honokiol in the preparation of a medicament for treating meningioma

Abstract

The present invention relates to the medical use of honokiol, in particular to the use of honokiol in the preparation of a drug for treating meningioma.Experiments have demonstrated that honokiol can effectively inhibit the growth of meningioma and remove and / or reduce the lesions of meningioma.Furthermore, clinical trials have shown that honokiol is safe and well tolerated.

Description

Technical Field

[0001] 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.

Background Art

[0002] Meningioma is the most common primary tumor of the central nervous system. Most of them originate from the endothelial cells of the arachnoid membrane and mainly occur in the arachnoid granulations 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. Meningioma is divided into benign meningioma and malignant meningioma. The typical clinical symptoms of meningioma are increased intracranial pressure, local nervous system (including cranial nerves) disorders, and general and partial epileptic seizures due to local tumor effects. The most common ones are headache, epileptic seizure, visual symptoms, limb weakness, and mental state changes.

[0003] The incidence rate of meningioma has been increasing year by year. It was 4.52 per 100,000 people from 1998 to 2002, but it has become 8.3 per 100,000 people from 2010 to 2014. The onset of meningioma is more common in the elderly, and most of them are 70 - 80 years old.

[0004] Ionizing radiation is a risk factor for the occurrence of meningioma. In Hiroshima and Nagasaki, 88 cases of meningioma were observed among 80,160 atomic bomb survivors. Even a very small amount of radiation to the head (for example, the radiation used in dental X-ray imaging) may increase the risk of developing meningioma. However, there is no clear dose-response relationship between ionizing radiation and the incidence rate of meningioma. Epidemiological studies have shown that a history of head trauma, smoking, and the use of mobile phones are not associated with an increased risk of meningioma.

[0005] Currently, the standard protocols for treating meningiomas generally include surgery and radiotherapy. Surgery and radiotherapy have advanced, and most patients can be cured. However, the recurrence rate of malignant meningiomas is as high as 50% - 80%, and the median survival period of some patients is less than 2 years. The treatment of this disease is very difficult. So far, chemotherapy, hormone therapy, and immunotherapy have had very limited effects on patients with malignant meningiomas. Due to the particularity of brain tumors, surgical treatment for recurrent patients is also very limited, and surgery, radiotherapy, and chemotherapy reduce the patient's tolerance. With the aging of the population, the incidence of meningiomas is increasing. The development of effective treatment methods for meningiomas with excellent safety and tolerance has become increasingly clinically important and is urgently needed.

Summary of the Invention

[0006] Regarding the defects in the treatment of meningiomas in the prior art, the object of the present invention is to develop a method that can effectively treat meningiomas and has good safety and tolerance.

[0007] Honokiol, with the English name Honokiol and the chemical name 3’,5 - di - 2 - propenyl - 1,1’ - biphenyl - 2,4’ - diphenol, has the structural formula as shown in formula (I):

[0008]

Chem.

[0009] Honokiol is a low - molecular - weight compound with a wide range of biological activities, extracted and isolated from the bark of Magnolia officinalis Rehd. et Wils. The main biological activities of honokiol include anti - inflammatory, antibacterial, anti - ulcer, antioxidant, anti - anxiety, antidepressant, antithrombotic, anti - aging, cholesterol - lowering effects, etc.

[0010] Regarding the broad medicinal effects of honokiol, the inventor of the present invention further studied new uses of honokiol. In clinical research, the inventor found that honokiol effectively inhibits the growth of meningioma and causes the lesions of meningioma to disappear and / or shrink.

[0011] Therefore, one object of the present invention is to provide the use of honokiol in the preparation of a medicament for treating meningioma.

[0012] According to the use of the present invention for treating meningioma, honokiol is prepared as honokiol liposome, preferably honokiol liposome for injection.

[0013] According to the use of the present invention for treating meningioma, honokiol inhibits the cell growth of meningioma.

[0014] Another object of the present invention is to provide honokiol liposome for treating meningioma.

[0015] According to the honokiol liposome of the present invention, the honokiol liposome is honokiol liposome for injection.

[0016] According to the honokiol liposome of the present invention, the dosage forms of the honokiol liposome include freeze-dried powder preparations including freeze-dried powder preparations for injection and freeze-dried powder preparations for oral administration; tablets including immediate-release tablets and sustained-release tablets; capsules including hard capsules, soft capsules, sustained-release capsules and enteric-coated capsules; or transdermal absorption preparations, etc.

[0017] According to the honokiol liposome of the present invention, the honokiol liposome can be administered by routes such as intravenous injection, intramuscular injection, subcutaneous injection, oral administration, intraocular administration, pulmonary administration, transdermal administration and nasal administration.

[0018] 〔Beneficial effects〕 In clinical trials, honokiol has been found to effectively treat meningiomas, effectively inhibit the growth of meningiomas, and cause the disappearance and / or reduction of meningioma lesions. Furthermore, clinical trials have shown that honokiol has good safety and tolerance.

Brief Description of the Drawings

[0019]

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Mode for Carrying Out the Invention

[0020] In order to further illustrate the use of honokiol in the preparation of a therapeutic agent for meningioma, examples are shown below.

[0021] Abbreviations of technical terms related to the examples are shown in Table 1 below.

[0022]

Table 1

[0023] The test materials used in this example are as follows.

[0024] The injectable honokiol liposome is derived from Chengdu Jinrui Fund Biotechnology Co., Ltd., or 50 mg of honokiol, 500 mg of soybean lecithin, 200 mg of cholesterol, and 200 mg of astragalus phosphatidylethanolamine are completely dissolved in 50 mL of absolute ethanol. The obtained solution is injected into 300 mL of purified water and stirred. Then, ethanol is removed by rotary evaporation, 800 mg of sucrose is added as a lyophilization excipient, and it can also be prepared by the method of lyophilization.

Example

[0025] 〔Example 1〕 〔Description of the Subject〕 Male, 20 years old.

[0026] On January 20, 2018, the cranial MR of the subject showed a space-occupying lesion in the right CPA and jugular foramen region.

[0027] On November 27, 2018, the subject underwent resection of a deep skull base lesion, which was an endothelial meningioma, locally showed an angiomatous meningioma, was accompanied by bleeding, and showed an atypical meningioma, invasion of bone tissue, and a comprehensive malignant meningioma. Immunohistochemistry: EMA (positive), PR (scattered with a little positivity), SSTR (locally positive), CD34 (vascular positive), CD99 (+), S100 (-), Syn (-), CgA (-), CK (occasionally positive), Ki67 (about 8 - 20%).

[0028] In February 2019, the subject received treatment for intracranial infection.

[0029] In June 2019, the subject received whole - brain radiotherapy.

[0030] On March 5, 2021, the subject underwent a re - examination of cranial MR, and the tumor recurred. In order to further proceed with the treatment, the subject was admitted to the outpatient department of Beijing Tiantan Hospital, Capital Medical University, and the Comprehensive Treatment Ward for Neurological Tumors, and received "maintenance treatment for malignant tumors".

[0031] On May 13, 2021, the subject entered the "Phase I Clinical Trial on the Clinical Safety and Tolerance of Honokiol Liposome (HK) Injection for Progressive Malignant Solid Cancer Patients", and the selected criteria are as follows. (1) 18 years old ≤ age ≤ 80 years old, gender is not limited. (2) Patients with histologically or cytologically diagnosed progressive malignant solid tumors, whose previous standard treatment plan has failed, are unable to tolerate or have refused existing treatment methods, and tumor types such as lung cancer, liver cancer, glioma, ovarian cancer, and colon cancer are preferred. (3) There are evaluated tumor lesions according to the RECIST 1.1 criteria (or RANO criteria). (4) Except for glioma, brain - metastasis patients selected for other tumor types need to meet the following conditions: no clinical symptoms related to brain metastasis, no need for systemic corticosteroid or anti - epilepsy drug treatment, no progression in the re - examination 28 days after the end of treatment for treated brain - metastasis patients, and no risk of intracranial hemorrhage. (5) Those without severe hematopoietic dysfunction (absolute neutrophil count ≥ 1.5×109 / L, platelets ≥ 80 × 10 9 / L, hemoglobin ≥ 100 g / L). (6) Subjects without severe organic diseases in the heart, lungs, liver, and kidneys (LVEF (left ventricular ejection fraction) ≥ 50%, total bilirubin ≤ 1.5 × ULN, alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN if there is liver metastasis); aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN if there is liver metastasis); serum creatinine ≤ 1.5 × ULN or CCr > 40 mL / min). (7) Subjects without severe coagulation disorders (PT ≤ 1.5 × ULN, APTT ≤ 1.5 × ULN, TT ≤ 1.5 × ULN). (8) At least 4 weeks have passed since the last anti-tumor treatment (chemotherapy, radiotherapy, biological therapy, hormonal therapy, targeted therapy) before enrollment in the group. (9) Predicted survival period ≥ 12 weeks. (10) For glioma patients, the KPS score exceeds 50 points. (11) For other solid cancer patients, the ECOG score ≤ 1. (12) Subjects who agreed to participate in this study and signed the informed consent.

[0032] For the subjects, continuous administration for 5 days per week and drug withdrawal for 2 days were carried out for 3 weeks, and a 1-week rest was taken. A 28-day period was defined as one cycle. Honokiol liposome for injection was administered. The dosage was 420 mg / day of honokiol, the administration method was by peripherally inserted central venous catheter, and the infusion time was 2 hours. Such dosing was carried out for 3 cycles.

[0033] After the end of one cycle of dosing, a cranial MR reexamination was performed. Figures 1A and 1B are comparative cranial MR images before and after treatment. According to the RANO criteria, the target lesion shrank by 17.46% compared to before treatment, and the product of the two perpendicular diameters of the target lesion shrank from 77.3 mm × 65 mm before treatment to 76.1 mm × 54.5 mm. After the end of three cycles of dosing, a cranial MR reexamination was performed, and the cranial MR image is shown in Figure 1C. According to the RANO criteria, the target lesion shrank by 11.13% compared to before treatment, and the product of the two perpendicular diameters of the target lesion shrank to 70.1 mm × 63.7 mm. The therapeutic effect was evaluated as stable disease (SD) with improvement in clinical performance and no side effects.

[0034] As of May 31, 2021, according to the inclusion criteria of the above-mentioned "Phase I Clinical Trial on the Clinical Safety and Tolerance of Honokiol Liposome (HK) Injection for the Treatment of Progressive Malignant Solid Tumor Patients" in Example 1, 37 subjects were included in the safety analysis set, and different doses of honokiol liposome injection were administered. The doses were 20 mg / day: 4 cases, 40 mg / day: 3 cases, 80 mg / day: 4 cases, 140 mg / day: 3 cases, 210 mg / day: 5 cases, 300 mg / day: 6 cases, 420 mg / day: 12 cases. The administration method was administration by a peripherally inserted central venous catheter, and the infusion time was 2 hours. Four weeks was defined as one dosing cycle. In each dosing cycle, for 3 weeks (from the 1st week to the 3rd week of this cycle), it was administered once a day for 5 consecutive days and then discontinued for 2 days, and one week was for rest.

[0035] After the administration of honokiol liposome for injection, the main side effects of the subjects were neutropenia, constipation, anemia, elevated ALT, decreased fibrinogen, headache, dizziness, and hypokalemia. Most of these side effects were mild. One case of DLT (CTCAE grade 3 increase in ALT) and 4 cases of SAE were observed, but all had recovered, and no suspected unexpected serious adverse reactions were observed. Regarding the incidence of adverse events, side effects, SAE, the vital signs of the subjects, physical findings, clinical test values, 12-lead electrocardiogram, echocardiogram, and other clinically important changes, no increasing trend was observed with the increase in the dose.

[0036] Honokiol liposome for injection has been shown in clinical trials to not only effectively treat meningioma, but also have good safety and tolerance.

[0037] [Example 2] [Description of the subject] Female, 39 years old.

[0038] One year before admission, there was pain and discomfort in the neck and occipital region without any obvious inducement, which worsened after exercise. There was no motor disorder in the limbs, no obvious radiating pain in the upper limbs, and it worsened at night. For treatment, the patient visited the Second Hospital of Dalian Medical University, and a space-occupying lesion in the medulla was pointed out by head MRI. During the perioperative treatment, the patient visited the Second Hospital of Dalian Medical University. On January 10, 2020, a resection of a lower brainstem tumor under general anesthesia was performed at the same hospital. During the operation, the size of the tumor was about 1.5×1.5 cm, accompanied by tumor bleeding, looking like rotten fish, with rich blood supply, and the tumor was completely resected under the microscope. Postoperative pathological findings: Atypical meningioma (WHO II), KI-67 (25%). Hoarseness occurred after the operation.

[0039] Before admission, there were dizziness, weakness, and occasional cough. The patient visited Tiantan Hospital, and cranial MRI was taken one week before admission, showing progressive medullary lesions. Two cycles of self-funded PD-1 immunotherapy were performed, and the course was smooth. Currently, for further treatment, the outpatient is admitted with "meningioma".

[0040] On October 14, 2021, as described in Example 1 "Phase I Clinical Trial on the Clinical Safety and Tolerance of Honokiol Liposome (HK) Injection for the Treatment of Patients with Progressive Malignant Solid Tumors", the subject was selected into the standard dosing group.

[0041] For the subject, continuous administration for 5 days per week and drug withdrawal for 2 days were carried out for 3 weeks, and a 1-week rest was taken. Taking 28 days as one cycle, honokiol liposome for injection was administered. The dosage was 420 mg / day of honokiol, the administration method was by peripherally inserted central venous catheter, and the infusion time was set to 2 hours. Such a dosing regimen was carried out for 3 cycles.

[0042] After one cycle of dosing was completed, a cranial MR reexamination was performed. Figures 2A and 2B are comparative cranial MR images before and after treatment. According to the RANO criteria, the target lesion shrank by 22.97% compared to before treatment, and the product of the two perpendicular diameters of the target lesion shrank from 14.3 mm × 12.9 mm before treatment to 14.1 mm × 10 mm. After three cycles of dosing were completed, a cranial MR reexamination was performed, and the cranial MR image is shown in Figure 2C. According to the RANO criteria, the target lesion shrank by 29.13% compared to before treatment, and the product of the two perpendicular diameters of the target lesion shrank to 13.8 mm × 9.4 mm. The therapeutic effect was evaluated as stable disease (SD), the clinical symptoms were stable, and drug resistance was observed.

[0043] Example 3 Description of the subject Male, 53 years old.

[0044] Five years before admission, the patient had "spasms in the hands and feet while blowing bubbles from the mouth, and rounding at the 4th hour" without an obvious cause, and there were no memory disorders, headaches, dizziness, nausea, vomiting, motor disorders of the hands and feet, or hearing and vision loss. Cranial MRI confirmed an intracranial occupation, and related examinations were performed at the First People's Hospital of Jining City. On February 21, 2016, a right frontal tumor resection was performed, and the postoperative pathological diagnosis was: meningioma. After the operation, gamma knife treatment was performed once at the Shandong Armed Police General Hospital. In October 2017, a cranioplasty was performed.

[0045] On February 13, 2019, a seizure occurred, and tumor recurrence was considered during the reexamination. On February 18, 2019, a pelvic artery embolization for meningioma was performed. On February 21, 2019, a tumor resection via the original incision approach was performed. Postoperative pathology: meningioma (WHO I), and postoperative whole-brain radiotherapy was performed. In April 2021, tumor recurrence was considered during the reexamination, and no treatment was given. In May 2021, a seizure occurred, and treatment was given with Debakin. In June 2021, a grand mal seizure occurred, improved with symptomatic treatment, and a larger tumor than before was observed on head MRI.

[0046] On July 21, 2021, resection of the tumor in the right frontal lobe was performed again. Postoperative pathology: anaplastic meningioma (WHO III), Ki-67 (50%). On August 17, 2021, tislelizumab was administered for 1 cycle. For future treatment, the patient was admitted to the outpatient department with the diagnosis of "meningioma".

[0047] On October 21, 2021, as described in Example 1, "Phase I Clinical Trial on the Clinical Safety and Tolerance of Honokiol Liposomes (HK) Injection for the Treatment of Patients with Progressive Malignant Solid Tumors", the patient was selected into the standard dosing group.

[0048] The subject was administered injectable honokiol liposomes in a cycle of 28 days, with continuous administration for 5 days per week and drug withdrawal for 2 days, followed by a 1-week rest. This cycle was repeated 3 times. The dosing amount was 420 mg / day of honokiol, the dosing method was by peripherally inserted central venous catheter, and the infusion time was 2 hours.

[0049] After 1 cycle of dosing, a cranial MR reexamination was performed. Figures 3A and 3B are comparative cranial MR images before and after treatment. According to the RANO criteria, the target lesion shrank by 35.30% compared to before treatment, and the product of the two perpendicular diameters of the target lesion shrank from 12.5 mm × 30.8 mm before treatment to 10.9 mm × 22.5 mm. After 3 cycles of dosing, a cranial MR reexamination was performed, and the cranial MR image is shown in Figure 3C. According to the RANO criteria, the target lesion shrank by 13.42% compared to before treatment, and the product of the two perpendicular diameters of the target lesion shrank to 12.3 mm × 27.1 mm. The therapeutic effect was evaluated as stable disease (SD) with improvement of clinical symptoms and tolerance to the drug.

[0050] 〔Example 4〕 〔Description of the Subject〕 Female, 53 years old.

[0051] In 2012, due to epileptic seizures, the patient visited a local hospital for examination, and intracranial occupation was pointed out. Right frontotemporal craniotomy and resection of the space-occupying lesion were performed. Postoperative pathological findings: meningioma in the lower right middle cranial fossa (WHO I). Regular reexamination was performed every year after the operation.

[0052] In 2016, 2018, gamma knife treatment was performed due to recurrence. Since 1 year ago, the vision on the right side has gradually decreased, and then there has been no intermittent headache, no limb spasm, no incontinence, no nausea and vomiting, and no limb movement disorder. Three months before admission, the patient visited a local hospital and underwent a head MRI, which showed, as postoperative changes after right frontotemporal craniotomy, space occupancy in the right sphenoid ridge, middle cranial fossa, inferior cranial fossa, and right eye socket: recurrence of meningioma with multiple enhancements at the roof of the right eye socket, anterior cranial fossa, and right parietal margin; multiple cerebral ischemic white matter lesions were found. Pathological findings: anaplastic meningioma (WHO III), Ki-67 (about 40 - 60%). For future treatment, the outpatient is admitted with the diagnosis of "meningioma".

[0053] On October 28, 2021, as described in Example 1, "Phase I Clinical Trial on the Clinical Safety and Tolerance of Honokiol Liposome (HK) Injection for the Treatment of Patients with Progressive Malignant Solid Tumors", the patient was selected into the standard dosing group.

[0054] For the subject, continuous administration for 5 days per week and drug withdrawal for 2 days were carried out for 3 weeks, and a 1-week rest was taken. Taking 28 days as one cycle, honokiol liposome for injection was administered. The dosage was 420 mg / day of honokiol, the administration method was by peripherally inserted central venous catheter, and the infusion time was 2 hours. Such medication was carried out for 3 cycles.

[0055] After one cycle of medication was completed, a re-examination of the cranial MR was performed. Figures 4A and 4B are comparative images of the cranial MR before and after treatment. According to the RANO criteria, the target lesion shrank by 15.68% compared with that before treatment, and the product of the two perpendicular diameters of the target lesion shrank from 23.3 mm × 35.3 mm before treatment to 22.3 mm × 31.1 mm. After 3 cycles of medication were completed, a re-examination of the cranial MR was performed, and the cranial MR image is shown in Figure 4C. According to the RANO criteria, the target lesion shrank by 15.68% compared with that before treatment, and the product of the two perpendicular diameters of the target lesion shrank to 22.3 mm × 31.1 mm. The therapeutic effect was evaluated as stable disease (SD) with improvement of clinical symptoms and tolerance to the drug.

Claims

1. Use of honokiol in the manufacture of a therapeutic agent for meningioma.

2. The use according to claim 1, characterized in that honokiol is manufactured as honokiol liposomes.

3. The use according to claim 2, characterized in that the honokiol liposomes are injectable honokiol liposomes.

4. The use according to any one of claims 1 to 3, characterized in that honokiol inhibits the cell proliferation of meningioma.

5. Use of honokiol liposomes in the preparation of a medicament for the treatment of meningioma.

6. The use according to claim 5, characterized in that the honokiol liposomes are injectable honokiol liposomes.

7. The honokiol liposomes are lyophilized powder preparations including injectable lyophilized powder preparations and 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; or the use according to claim 5, characterized in that they include the dosage form of a transdermal absorption preparation.

8. The use according to claim 5, characterized in that the honokiol liposomes are administered by routes of intravenous injection, intramuscular injection, subcutaneous injection, oral administration, ophthalmic administration, pulmonary administration, transdermal administration and nasal administration.

Images