Pharmaceutical compositions for treating cancer, their preparation methods and uses

Abstract

A pharmaceutical composition for treating cancer, its preparation method and use. The pharmaceutical composition consists of or contains dimethyl sulfoxide and esters, ketones and alcohols. The pharmaceutical composition has great value for the prevention and treatment of cancer.

Description

[Technical Field]

[0001] The present invention relates to the field of pharmaceutical technology, specifically to a pharmaceutical composition for treating cancer, its preparation method and use. [Background technology]

[0002] The global medical community is largely at a loss when it comes to treating cancer, or malignant tumors. Conventional treatments primarily involve surgery, radiation therapy, and chemotherapy, with only a small percentage of patients achieving a cure through early surgical resection. Radiation therapy has a low curative effect, and existing chemotherapy drugs have limited efficacy, only able to maintain or extend lifespan. Current clinically used chemotherapy drugs are highly toxic and ineffective, preventing effective treatment of malignant tumors. Targeted therapy and immunotherapy emerged in the late 1990s and have shown some success, but the emergence of drug-resistant genes has hindered improvements in therapeutic efficacy.

[0003] Therefore, there is an urgent need for drugs with significant efficacy, low toxicity and side effects, and good stability to treat malignant tumors. Summary of the Invention

[0004] To solve the problems in the prior art, the present invention provides a pharmaceutical composition for treating or preventing cancer, its preparation method, and use. This pharmaceutical composition comprises dimethyl sulfoxide and an ester compound. The pharmaceutical composition of the present invention is of great value for the prevention and treatment of cancer.

[0005] The present invention is realized by the following technical means.

[0006] In one aspect, the present invention provides a pharmaceutical composition for treating or preventing cancer, the pharmaceutical composition comprising an ester compound and dimethyl sulfoxide, Preferably, the ester compound is C 2-8 lower esters of, preferably C 2-4a lower ester of, more preferably ethyl acetate; Preferably, the pharmaceutical composition consists of ethyl acetate and dimethyl sulfoxide.

[0007] Preferably, the volume ratio of the ethyl acetate to the dimethyl sulfoxide is 1:1 to 1:200; Preferably, the volume ratio of the ethyl acetate to the dimethyl sulfoxide is 1:100-1:200.

[0008] Preferably, the volume ratio of the ethyl acetate to the dimethyl sulfoxide is 1:75-1:150.

[0009] Preferably, the volume ratio of the ethyl acetate to the dimethyl sulfoxide is 1:100.

[0010] Preferably, the ethyl acetate and dimethyl sulfoxide, or a mixture of both, can be diluted with water and then directly administered orally, by injection, spray, etc., as a dosage form for treating or preventing diseases in animals and humans.

[0011] Preferably, the pharmaceutical composition further comprises 4.55 v / v % lactic acid.

[0012] The present invention further provides a pharmaceutical composition for treating or preventing cancer, the pharmaceutical composition comprising a ketone compound and dimethyl sulfoxide, Preferably, the ketone compound is an alkanone, preferably C 3-6 more preferably acetone, Preferably, the pharmaceutical composition consists of acetone and dimethyl sulfoxide; Preferably, the volume ratio of the acetone to the dimethyl sulfoxide is 1:1 to 1:200; Preferably, the volume ratio of the acetone to the dimethyl sulfoxide is 1:100-1:200; Preferably, the volume ratio of the acetone to the dimethyl sulfoxide is 1:75-1:150; Preferably, the acetone and the dimethyl sulfoxide, or a mixture of both, are diluted with water and then can be directly administered orally, by injection, spray, etc., as a dosage form for treating or preventing diseases in animals and humans.

[0013] Preferably, the pharmaceutical composition further comprises 4.55 v / v % lactic acid.

[0014] Furthermore, the present invention provides a pharmaceutical composition for treating or preventing cancer, the pharmaceutical composition comprising an alcohol compound and dimethyl sulfoxide, Preferably, the alcohol compound is C 1-6 Alkanols, preferably C 1-4 alkanol, more preferably ethanol, Preferably, the pharmaceutical composition consists of ethanol and dimethyl sulfoxide; Preferably, the volume ratio of the ethanol to the dimethyl sulfoxide is 1:1 to 1:200; Preferably, the volume ratio of the ethanol to the dimethyl sulfoxide is 1:100-1:200; Preferably, the volume ratio of the ethanol to the dimethyl sulfoxide is 1:75-1:150; Preferably, the ethanol and the dimethyl sulfoxide, or a mixture of both, are diluted with water and then can be directly administered orally, by injection, spray, etc., as a dosage form for treating or preventing diseases in animals and humans.

[0015] Preferably, the pharmaceutical composition further comprises 4.55 v / v % lactic acid.

[0016] In another aspect, the present invention provides use of the pharmaceutical composition in the manufacture of a medicament for preventing and / or treating various diseases, such as cancer, cancer complications, cerebral edema, diabetes, hypertension, cardiovascular and cerebrovascular diseases, lupus erythematosus, pleural effusion, ascites, and gout.

[0017] Preferably, the route of administration of said pharmaceutical composition includes various routes of administration such as, but not limited to, oral administration, intravenous infusion, intravenous injection, transdermal administration, and the like.

[0018] Preferably, the cancer is selected from the group consisting of glioma, astrocytoma, brain or central nervous system cancer, peripheral nervous system cancer, such as melanoma, B-cell cancer, multiple myeloma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, bladder cancer, esophageal cancer, cervical cancer, uterine cancer, or endometrial cancer, oral cancer, pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small intestine cancer, appendix cancer, salivary gland cancer, thyroid cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, blood cancer, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), soft tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma. , synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, bladder cancer, epithelial carcinoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, head and neck cancer, small cell carcinoma, idiopathic myeloid metaplasia, eosinophilia, chronic eosinophilic leukemia, neuroendocrine carcinoma, carcinoid tumor, and their metastatic and invasive lesions. The pharmaceutical composition of the present invention is also applicable to the treatment of diabetes, cardiovascular and cerebrovascular diseases, lupus erythematosus, pleural effusion, ascites, and gout.

[0019] The target of action of the pharmaceutical composition of the present invention is aldehyde compounds that adhere to cell membranes, and the aldehyde compounds or aldehyde proteins that adhere to cell membranes are anchored by reacting with compounds such as alcohols, esters, ketones, and acids, and the aldehyde compounds, and the growth of tumors is suppressed by changing the environment surrounding the tumor cells and suppressing the proliferation, invasion, or aggregation of tumor cells.

[0020] The pharmaceutical composition of the present invention is a broad-spectrum anticancer drug, and in clinical practice, better therapeutic effects can be achieved by an experienced physician administering different doses of the drug alone, alternately, or in combination according to the patient's condition and symptom stage.

[0021] The pharmaceutical composition of the present invention has the following advantages over the prior art. (1) The present invention is easy to operate because the solvents are mixed directly. In animal experiments, the addition of 4.55% lactic acid to each composition showed a better tumor suppression effect, making it suitable for the treatment of various cancers.

[0022] (2) The pharmaceutical composition of the present invention is a highly accurate tumor inhibitor that acts only on malignant tumor cells, does not damage normal tissue cells, and can avoid killing and inhibiting normal tissue cells, and only inhibits the proliferation of malignant tumor cells and their infiltration into normal tissue cells.

[0023] (3) The physical or chemical characteristics of the solvent used in the pharmaceutical composition of the present invention are clear and easy to control, making it easy for experts and patients to clearly determine the pharmacokinetics and toxicity.

[0024] (4) Compared with cancer treatment drugs commercially available at home and abroad, the pharmaceutical composition of the present invention has negligible toxicity, no side effects, and will not harm the human body if administered in accurate and normal doses.

[0025] (5) Unlike conventional antitumor drugs, the pharmaceutical composition of the present invention can suppress the growth of solid tumors and also effectively suppress the secondary growth of tumor cells and nodules in other tissues (so-called tumor metastasis).

[0026] (6) The pharmaceutical composition of the present invention can effectively reduce transmembrane resistance, increase cell membrane permeability, enable tissue cells in the body to utilize glucose, salt, water, etc. in a timely and effective manner, and enhance the physical strength of patients.

[0027] (7) The pharmaceutical composition of the present invention inhibits the proliferation of tumor cells and their invasion into normal tissue cells through the denaturing effect on tumor cell outer membrane proteins and environmental influences. The drug slows the proliferation rate of tumor cells compared to normal tissue cells, and the invasion into normal tissue cells is stopped, resulting in a gradual reduction in tumor volume or a constant tumor volume.

[0028] The present invention is not limited to particular methods, experiments, or reagents, since these do not vary. The discussion and examples provided herein are merely illustrative of particular embodiments and do not limit the scope of the invention, which is limited only by the claims. [Brief explanation of the drawings]

[0029] [Figure 1] 1 shows the tumor inhibition rate of the pharmaceutical composition of the present invention. [Figure 2] Tumor anatomical images are shown, and from top to bottom, the experimental results are for the vehicle control group, the 5-fluorouracil group, the temozolomide group, and the high, medium, and low dose groups. [Figure 3] The graph shows the trend of changes in tumor volume during the administration period. [Figure 4] The trend of weight change during the administration period is shown. DETAILED DESCRIPTION OF THE INVENTION

[0030] In the following examples, the origin of the experimental materials is as follows: Dimethyl sulfoxide: (≥99.5%), China National Pharmaceutical Group Chemical Reagents Co., Ltd., Batch No.: 20181010 Ethanol: (≥95.0%), China National Pharmaceutical Group Chemical Reagents Co., Ltd., Batch No.: 20200810 Acetone: (≥99.5%), China National Pharmaceutical Group Chemical Reagents Co., Ltd., Batch No.: 20140221 Ethyl acetate (≥99.5%), China National Pharmaceutical Group Chemical Reagents Co., Ltd., Batch No.: 20161026

[0031] Example 1: Pharmaceutical composition of the present invention Formulation: 200 mL dimethyl sulfoxide, 1 mL ethyl acetate; Formulation: 180 mL dimethyl sulfoxide, 1 mL ethyl acetate; Formulation: 160 mL dimethyl sulfoxide, 1 mL ethyl acetate; Formulation: dimethyl sulfoxide 140 mL, ethyl acetate 1 mL; Formulation: 120 mL dimethyl sulfoxide, 1 mL ethyl acetate; Formulation: 100 mL dimethyl sulfoxide, 1 mL ethyl acetate; Formulation: dimethyl sulfoxide 80 mL, ethyl acetate 1 mL; Formulation: dimethyl sulfoxide 60 mL, ethyl acetate 1 mL; Formulation: dimethyl sulfoxide 40 mL, ethyl acetate 1 mL; Formulation: 20 mL dimethyl sulfoxide, 1 mL ethyl acetate; Formulation: 1 mL dimethyl sulfoxide, 1 mL ethyl acetate.

[0032] Example 2: Pharmaceutical Composition of the Present Invention Formula: 200 mL dimethyl sulfoxide, 1 mL acetone; Formula: 180 mL dimethyl sulfoxide, 1 mL acetone; Formula: 160 mL dimethyl sulfoxide, 1 mL acetone; Formula: 140 mL dimethyl sulfoxide, 1 mL acetone; Formula: 120 mL dimethyl sulfoxide, 1 mL acetone; Formula: 100 mL dimethyl sulfoxide, 1 mL acetone; Formula: dimethyl sulfoxide 80 mL, acetone 1 mL; Formula: 60 mL dimethyl sulfoxide, 1 mL acetone; Formula: 40 mL dimethyl sulfoxide, 1 mL acetone; Formulation: 20 mL dimethyl sulfoxide, 1 mL acetone; Formulation: 1 mL dimethyl sulfoxide, 1 mL acetone.

[0033] Example 3: Pharmaceutical composition of the present invention Formulation: 200 mL dimethyl sulfoxide, 1 mL ethanol; Formula: 180 mL dimethyl sulfoxide, 1 mL ethanol; Formula: 160 mL dimethyl sulfoxide, 1 mL ethanol; Formula: dimethyl sulfoxide 140 mL, ethanol 1 mL; Formulation: 120 mL dimethyl sulfoxide, 1 mL ethanol; Formulation: 100 mL dimethyl sulfoxide, 1 mL ethanol; Formula: dimethyl sulfoxide 80 mL, ethanol 1 mL; Formula: 60 mL dimethyl sulfoxide, 1 mL ethanol; Formulation: dimethyl sulfoxide 40 mL, ethanol 1 mL; Formulation: 20 mL dimethyl sulfoxide, 1 mL ethanol; Formulation: 1 mL dimethyl sulfoxide, 1 mL ethanol.

[0034] Example 4: Cancer treatment effect of the pharmaceutical composition of the present invention 1. Major equipment and facilities Common laboratory equipment includes dissecting instruments, biological microscopes, animal balances, analytical balances, water baths, pipettes, vortex mixers, biological safety cabinets, cell incubators, etc.

[0035] 2. Reagents Disinfectants, injectable saline solution, medical alcohol, etc. 3. Positive drugs 3.1 Positive control 1 Name: Fluorouracil injection Manufacturer:Shanghai Asahi DonghaiPharmaceutical Co., Ltd. Batch number: FA181206 Packaging: Glass ampoule Specifications: 10mL: 0.25g Properties: Colorless transparent liquid Storage conditions: 15-25°C, protect from light (do not freeze) Valid until December 12, 2020

[0036] 3.2 Positive control 2 Name: Injectable temozolomide Manufacturer: Jiangsu Hengrui Pharmaceutical Co., Ltd. Batch number: 190711AM Packaging: Nishibayashi bottle Specifications: 100mg / bottle Properties: white freeze-dried lumps Storage conditions: Closed storage (2~8℃) Valid until July 10, 2021

[0037] 4. Experimental animals Animal species / strain: BALB / C-nu / nu mouse Animal grade: SPF grade Gender and number: 42 females Animal age at the start of the test: 6 weeks old Animal weight at the start of the test: 18±2g Animal source: Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0038] 5. Quarantine Experimental animals were received and quarantined according to the test requirements. They were observed for five days for adaptation. During the observation period, the eyes, ears, nose, oral cavity, fur, abdomen, vulva, anal area, limbs, nails, toes, gait, behavior, excretion, feeding, and drinking were observed and recorded. Experiments were performed using mice that had undergone normal quarantine.

[0039] 6. Grouping In the experiment, mice that passed quarantine were selected, inoculated with tumors, randomly divided into groups, placed in different cages, labeled, and kept separately.

[0040] 7. Breeding conditions Qingdao Marine Biomedical Research Institute Co., Ltd. Experimental Animal Use License Number: SYXK(Lu)2015 0011 The laboratory temperature was 20-25°C, humidity was 40-70%, ventilation rate was 10-20 times / hour, light exposure was 12 hours light and 12 hours dark, and the breeding density was less than 5 animals / cage. The breeding environment strictly complied with the relevant standards of the "National Standard of the People's Republic of China - Laboratory Animals."

[0041] 8. Information on tumor cell lines Cell source and culture conditions: U-87MG human cerebral astrocytoma cells were obtained from the Cell Resources Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. The culture medium used was MEM medium containing 1% penicillin-streptomycin sulfate double antibody mixture (100x) and 10% fetal bovine serum (Aozhouyuan). The culture conditions were 5% CO2, 37°C, and the cells were cryopreserved at our center.

[0042] 9. Cell resuscitation and passaging U-87MG cells were resuscitated with liquid nitrogen, placed in a medium containing 10% FBS (fetal bovine serum), 100 U / ml penicillin, and 100 μg / ml streptomycin, and cultured in a cell incubator at 37°C and 5% CO2. They were passaged every two days.

[0043] 10. Tumor inoculation After 4 passages, the cells were collected by digestion with 0.05% trypsin-EDTA, counted under a microscope, and diluted to 5 × 10 7 The cells were resuspended in a 1 / ml cell suspension and, after standard disinfection, inoculated subcutaneously into the right forelimb axilla of mice at 0.2 ml per mouse. The cells were aseptically removed, weighed, diluted with sodium chloride injection at a mass / volume ratio of 1:4, crushed, and, after standard disinfection, inoculated subcutaneously into the right forelimb axilla of mice at 0.2 ml per mouse. This was passaged twice. During this time, the mice were maintained under normal conditions, and their condition and tumor status were observed and recorded weekly.

[0044] The tumor volume of tumor-bearing mice was approximately 1200 mm 3 After tumor establishment, the mice were weighed and randomly divided into six groups of seven mice each. Treatment began on day 1 (D1).

[0045] 11. Animal grouping and dosage The animals were randomly divided into 6 groups of 7 animals each according to their body weight. The doses given to the animals in each group are shown in the table below.

[0046] JPEG0007748786000001.jpg85170

[0047] 12. Clinical observation 12.1 General Clinical Observations Observed animals: All animals Observation frequency and time: During the experiment, observations were made before each administration and after each administration, and the observations were recorded. The observations included, but were not limited to, tumor growth, the mental state of the animals, and their eating and drinking habits.

[0048] 12.2 Weight Detected animals: All animals Detection time: grouping (i.e., before the first administration) (D1); thereafter, the animals were weighed and recorded before each administration and before euthanasia.

[0049] When an animal died unexpectedly, its weight was measured and recorded, and relevant records were kept.

[0050] 12.3 The therapeutic effect was evaluated according to tumor weight. After the experiment is completed, tumor tissues from animals that died unexpectedly and from surviving animals that were euthanized are excised and the tumor weight is measured, and the tumor inhibition rate (IRTW) is calculated by calculating the difference in tumor weight between each group. Calculation formula: IRTW (%) = (W model group - W administration group) / W model group × 100%

[0051] 13. Photographic Records After the animals were euthanized, the tumor tissue was excised and photographed.

[0052] 14. Data collection and statistical analysis The results of the measured or observed data should be handwritten on an appropriate sheet or collected directly by computer. This data should be analyzed, processed and reported as raw data. The results should be expressed as mean numbers and standard deviations (Mean ± SD). Comparisons between both groups should be performed by t-test, and the analysis of the results should take into account both statistical and biological significance.

[0053] 15, results 15.1 General Clinical Observations The high-dose group was administered twice a day, and on the third day, after the total dose reached 13.5ml / kg, two mice in the high-dose group died, while the remaining mice became shriveled and round, had no mucus secretion from the corners of their mouths or noses, had closed eyes, had a drop in body surface temperature as measured by hand, were inactive, and had stopped eating. The dose for the high-dose group was then reduced to 6.75ml / kg, and no more mice died until the end of the experiment. The mice in the other groups remained in good condition.

[0054] 15.2 Statistics of tumor suppression rate The statistical results of the tumor inhibition rate are shown in Figure 1 and Table 2.

[0055] [Table 2]

[0056] Figure 2 shows tumor anatomical images, showing the vehicle control group, 5-fluorouracil group, temozolomide group, and high-, medium-, and low-dose groups, respectively. Figure 3 shows the trend in tumor volume during the treatment period. Figure 4 shows the trend in body weight during the treatment period.

[0057] The experimental data showed that significant differences in tumor volume were observed on day 7 after dose adjustment. After 11-15 days of administration, the tumor inhibition rates in the high, medium, and low dose groups were dose-dependent. Final autopsy results showed that the tumor inhibition rate in the high dose group was 46.4%. During the administration period, the mice in the 5-fluorouracil group showed a weight loss in the later stages of administration, but all mice maintained normal weight and growth. This indicates that after the mice adapted to the drug, there was no significant impact on activities such as feeding and digestion.

Claims

1. A pharmaceutical composition for treating or preventing cancer, comprising: The pharmaceutical composition comprises an ester compound and dimethyl sulfoxide, The ester compound is ethyl acetate, A pharmaceutical composition, wherein the volume ratio of the ethyl acetate to the dimethyl sulfoxide is 1:75 to 1:

150.

2. 10. Use of the pharmaceutical composition of claim 1 in the manufacture of a medicament for preventing and / or treating cancer.

3. The use according to claim 2, wherein the route of administration of the pharmaceutical composition includes oral administration, intravenous infusion, intravenous injection, and transdermal administration.

4. The cancers include glioma, astrocytoma, brain or central nervous system cancer, peripheral nervous system cancer, such as melanoma, B-cell cancer, multiple myeloma, breast cancer, lung cancer, bronchial cancer, colorectal cancer, prostate cancer, pancreatic cancer, stomach cancer, ovarian cancer, bladder cancer, esophageal cancer, cervical cancer, uterine cancer, or endometrial cancer, oral cancer, pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, biliary tract cancer, small intestine cancer, appendix cancer, salivary gland cancer, thyroid cancer, adrenal gland cancer, osteosarcoma, chondrosarcoma, blood cancer, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), soft tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovium.

4. The use according to claim 2 or 3, comprising tumors including mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, bladder cancer, epithelial carcinoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, retinoblastoma, follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, hepatocellular carcinoma, thyroid cancer, gastric cancer, head and neck cancer, small cell carcinoma, idiopathic myeloid metaplasia, eosinophilia, chronic eosinophilic leukemia, neuroendocrine carcinoma, carcinoid tumor, and metastatic and invasive lesions thereof.

5. The use according to claim 2 or 3, wherein the target of action of the pharmaceutical composition is an aldehyde compound that adheres to the cell membrane, and the aldehyde compound or aldehyde protein that adheres to the cell membrane is anchored by reacting the aldehyde compound with a compound such as an alcohol, ester, ketone, or acid, and the surrounding environment of the tumor cells is changed to inhibit the proliferation, invasion, or aggregation of the tumor cells, thereby suppressing tumor growth.

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