WO2022143984A1 - 一种用于治疗癌症的药物组合物及其制备方法和用途 - Google Patents

一种用于治疗癌症的药物组合物及其制备方法和用途 Download PDF

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WO2022143984A1
WO2022143984A1 PCT/CN2021/143696 CN2021143696W WO2022143984A1 WO 2022143984 A1 WO2022143984 A1 WO 2022143984A1 CN 2021143696 W CN2021143696 W CN 2021143696W WO 2022143984 A1 WO2022143984 A1 WO 2022143984A1
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cancer
dimethyl sulfoxide
pharmaceutical composition
carcinoma
tumor
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PCT/CN2021/143696
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French (fr)
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邓亚琴
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邓亚琴
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Priority to US18/259,402 priority Critical patent/US20240058292A1/en
Priority to JP2023540688A priority patent/JP2024502336A/ja
Publication of WO2022143984A1 publication Critical patent/WO2022143984A1/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
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/12—Ketones
    • A61K31/121—Ketones acyclic
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
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    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to the technical field of medicine, in particular to a pharmaceutical composition for treating cancer and a preparation method and application thereof.
  • the global medical community is almost at a loss for the treatment of cancer, that is, malignant tumors.
  • the traditional treatment methods mainly include surgery, radiation therapy, and chemotherapy. Only a very small number of patients may be cured when they receive surgical resection at the early stage of the disease.
  • the effect of radiotherapy is weak, and the existing chemotherapeutic drugs have limited effects, which can only maintain or prolong a short life.
  • the currently used chemotherapeutic drugs have high toxicity and little effect, and cannot effectively cure malignant tumors.
  • targeted therapy and immunotherapy began to emerge. Although there are certain curative effects, the emergence of drug resistance genes is the main obstacle to further improve the curative effect.
  • the present invention provides a pharmaceutical composition for treating or preventing cancer and its preparation method and use.
  • the pharmaceutical composition is composed of dimethyl sulfoxide and ester compounds, and the pharmaceutical composition of the present invention has great value for the prevention and treatment of cancer.
  • the present invention is achieved through the following technical solutions.
  • the present invention provides a pharmaceutical composition for treating or preventing cancer, the pharmaceutical composition is composed of an ester compound and dimethyl sulfoxide,
  • the ester compound is a C 2-8 lower ester, preferably a C 2-4 lower ester, more preferably ethyl acetate;
  • the pharmaceutical composition consists of ethyl acetate and dimethyl sulfoxide.
  • the volume ratio between the ethyl acetate and the dimethyl sulfoxide is 1:1-1:200;
  • the volume ratio between the ethyl acetate and the dimethyl sulfoxide is 1:100-1:200.
  • the volume ratio between the ethyl acetate and the dimethyl sulfoxide is 1:75-1:150.
  • the volume ratio between the ethyl acetate and the dimethyl sulfoxide is 1:100.
  • the ethyl acetate and the dimethyl sulfoxide are used alone or mixed with water to dilute with water and directly orally, inject, spray, etc., as the administration methods for treating or preventing diseases in animals and humans.
  • the pharmaceutical composition further includes 4.55v/v% lactic acid.
  • the present invention also provides another pharmaceutical composition for treating or preventing cancer, the pharmaceutical composition is composed of a ketone compound and dimethyl sulfoxide,
  • the ketone compound is an alkanone, preferably a C 3-6 alkanone, more preferably acetone;
  • the pharmaceutical composition consists of acetone and dimethyl sulfoxide,
  • the volume ratio between the acetone and the dimethyl sulfoxide is 1:1-1:200;
  • the volume ratio between the acetone and the dimethyl sulfoxide is 1:100-1:200;
  • the volume ratio between the acetone and the dimethyl sulfoxide is 1:75-1:150;
  • the acetone and the dimethyl sulfoxide are used alone or mixed with water to dilute with water and directly orally, inject, spray, etc. as an administration mode for treating or preventing diseases in animals and humans.
  • the pharmaceutical composition further includes 4.55v/v% lactic acid.
  • the present invention also provides another pharmaceutical composition for treating or preventing cancer, the pharmaceutical composition is composed of an alcohol compound and dimethyl sulfoxide,
  • the alcohol compound is a C 1-6 alkanol, preferably a C 1-4 alkanol, more preferably ethanol;
  • the pharmaceutical composition consists of ethanol and dimethyl sulfoxide,
  • the volume ratio between the ethanol and the dimethyl sulfoxide is 1:1-1:200;
  • the volume ratio between the ethanol and the dimethyl sulfoxide is 1:100-1:200;
  • the volume ratio between the ethanol and the dimethyl sulfoxide is 1:75-1:150; preferably, the ethanol and the dimethyl sulfoxide are diluted with water alone or directly orally after mixing , injection, spray, etc. as the mode of administration for the treatment or prevention of animal and human diseases.
  • the pharmaceutical composition further includes 4.55v/v% lactic acid.
  • the present invention provides the above-mentioned pharmaceutical composition prepared for the prevention and/or treatment of cancer, cancer complications, cerebral edema, diabetes, hypertension, cardiovascular and cerebrovascular diseases, lupus erythematosus, pleural effusion, ascites and gout, etc. Use in medicine for disease.
  • the administration route of the pharmaceutical composition includes, but is not limited to, oral administration, intravenous drip, intravenous injection, transdermal administration and other administration routes.
  • the cancer includes, but is not limited to, 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, esophagus cancer, cervical cancer, uterine or endometrial cancer, oral cancer, pharyngeal cancer, liver cancer, kidney cancer, testicular cancer, biliary tract cancer cancer, small bowel or appendix cancer, salivary gland cancer, thyroid cancer, adrenal cancer, osteosarcoma, chondrosarcoma, blood tissue cancer, adenocarcinoma, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), colon cancer, Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), soft tissue sarcoma, fibrosarcoma, myedi
  • the target of the pharmaceutical composition of the present invention is the aldehyde compound attached to the cell membrane, and the aldehyde compound or aldehyde attached to the cell membrane is anchored by the reaction of alcohol, ester, ketone, acid and other compounds with the aldehyde compound At the same time, it inhibits tumor cell proliferation and infiltration or aggregation by changing the surrounding environment of tumor cells, thereby inhibiting tumor growth.
  • the pharmaceutical composition of the present invention is a kind of broad-spectrum anticancer drug, and clinically, doctors with rich experience should give different doses of different doses according to different stages and different symptoms of the patient's condition, and the therapeutic effect will be better.
  • the pharmaceutical composition of the present application has the following advantages:
  • the present invention directly mixes the solvent, which is simple and easy to implement, but in animal experiments, adding 4.55% of lactic acid to each composition in proportion will show a better effect on tumor control. Applicable to the treatment of various cancers.
  • the pharmaceutical composition of the present invention is a precise tumor suppressor, only has a medicinal effect on malignant tumor cells, does not damage normal tissue cells, can avoid killing and inhibiting normal tissue cells, and only suppress malignant tumor cells proliferation and infiltration of normal tissue cells.
  • the pharmaceutical composition of the present invention has low toxicity, even negligible, compared with the cancer treatment drugs already on the market at home and abroad, and does not have any side effects, and the accurate and normal dose administration will not cause any harm to the human body.
  • the pharmaceutical composition of the present invention is different from the existing anti-tumor drugs. While inhibiting the growth of solid tumors, it can also effectively inhibit the secondary growth of tumor cells and nodules in other tissues (so-called tumor metastasis).
  • the pharmaceutical composition of the present invention can effectively reduce the transmembrane impedance, enhance the cell membrane permeability, make the body tissue cells utilize glucose, salt, water, etc. in a timely and effective manner, and enhance the patient's physical energy.
  • the pharmaceutical composition of the present invention suppresses the massive proliferation of tumor cells and prevents tumor cells from infiltrating into normal tissue cells by denaturing the outer membrane proteins of tumor cells and affecting the environment.
  • the drug makes the proliferation rate slower than normal
  • the tissue cells stopped infiltrating normal tissue cells the tumor volume gradually decreased or remained unchanged.
  • Fig. 1 tumor inhibition rate of the pharmaceutical composition of the present invention
  • Figure 2 Tumor anatomy map, in which from top to bottom are the experimental results of the solvent control group, the 5-fluorouracil group, the temozolomide group, and the high, middle, and low dose groups;
  • Figure 4 Trend of body weight change during administration.
  • Example 4 The effect of the pharmaceutical composition of the present invention in the treatment of cancer
  • Disinfectants saline for injection, medical alcohol, etc.
  • Packaging glass ampoules
  • Acceptance and quarantine of experimental animals are carried out according to the test requirements. Adaptive observation was carried out for 5 days. During the observation period, the eyes, ears, nose, mouth, fur, abdomen, vulva, perianal, limbs, claws, flesh toes, gait, behavior, excretion, food intake, and drinking water were observed and recorded. normal mice.
  • the laboratory temperature was 20-25°C, the humidity was 40-70%, the ventilation frequency was 10-20 times/hour, the light was alternated between light and dark for 12 hours, and the stocking density was less than 5 per cage.
  • the breeding environment is strictly in accordance with the relevant standards of "National Standards of the People's Republic of China - Laboratory Animals".
  • the same method was used for tumor grinding and transplantation modeling. After tumor inoculation, the mice were weighed, and the mice were randomly selected and divided into 6 groups with 7 mice in each group. Dosing was started after tumor colonization and was recorded as day 1 (D1).
  • mice were divided into 6 groups according to body weight, with 7 animals in each group.
  • the doses of animals in each group are as follows:
  • Observation frequency and time During the experiment, observe once before each administration, and record the administration and observation. Observation content: including but not limited to tumor growth, animal mental state, diet, etc.
  • Detection time grouping (ie, before the first administration) (D1), before each administration, and before euthanasia, the body weight of the animals was weighed, and the body weight was recorded.
  • the tumor tissue needs to be peeled off, the tumor weight is weighed, and the tumor weight difference of each group is calculated to further calculate the tumor inhibition rate IRTW.
  • the calculation formula is as follows:
  • IRTW(%) (W model group-W administration group)/W model group ⁇ 100%
  • the tumor tissue was stripped and photographed.
  • the protocol requires that the measured and observed data results need to be recorded by hand on an appropriate form or the data can be collected directly by a computer.
  • the data is used as raw data for analysis, processing and reporting. Results are expressed as mean and standard deviation (Mean ⁇ SD). The t-test was used to compare the two groups, and both statistical significance and biological significance were considered in the analysis of the results.
  • Figure 2 is an atlas of tumor anatomy, from top to bottom are the solvent control group, the 5-fluorouracil group, the temozolomide group, and the high, medium, and low dose groups.
  • Figure 3 shows the trend of tumor volume changes during administration.
  • Figure 4 shows the trend of body weight change during administration.
  • the tumor volume began to show significant differences. From 11 to 15 days after the administration, the tumor inhibition rate of the high-medium-low-dose group was dose-dependent. At the final autopsy, the high-dose group The tumor inhibition rate was 46.4%.
  • the body weight of the mice showed normal growth, indicating that after the mice were adapted to the drug, there was no obvious effect on activities such as eating and digestion. influences.

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Abstract

一种用于治疗癌症的药物组合物及其制备方法和用途。该药物组合物包含或由二甲基亚砜和酯类、酮类和醇类化合物组成，该药物组合物对于癌症的预防和治疗具有重大价值。

Description

一种用于治疗癌症的药物组合物及其制备方法和用途 技术领域
本发明涉及医药技术领域，具体涉及一种用于治疗癌症的药物组合物及其制备方法和用途。
背景技术
全球医学界对于癌症即恶性肿瘤的治疗几乎是束手无策，传统治疗方法主要有手术治疗、放射线治疗、化学治疗，只有极少数患者在发病初期接受手术切除治疗时有可能达到治愈目的。放疗治疗效果微弱，现有化疗药物作用有限，只能维持或延续短暂的生命。当前临床所用的化疗药物毒性大，效果小，无法有效治愈恶性肿瘤。90年代后期开始兴起靶向治疗、免疫疗法，虽然有一定疗效，但耐药基因的出现是目前阻碍进一步提高疗效的主要障碍。
因此，亟需一种效果显著毒副作用小且稳定性好的药物来治疗恶性肿瘤。
发明概述
为了解决现有技术存在的问题，本发明提供一种用于治疗或预防癌症的药物组合物及其制备方法和用途。该药物组合物由二甲基亚砜和酯类化合物组成，本发明的药物组合物对于癌症的预防和治疗具有重大价值。
本发明是通过如下技术方案来实现的。
一方面，本发明提供一种用于治疗或预防癌症的药物组合物，该药物组合物由酯类化合物和二甲基亚砜组成，
优选地，所述酯类化合物为C 2-8的低级酯，优选为C 2-4的低级酯，更优选为乙酸乙酯；
优选地，所述药物组合物由乙酸乙酯和二甲基亚砜组成。
优选地，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:1-1:200；
优选地，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:100-1:200。
优选地，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:75-1:150。
优选地，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:100。
优选地，所述乙酸乙酯和所述二甲基亚砜单独或混合后加水稀释直接口服、注射、喷剂等作为治疗或预防动物和人类疾病的给药方式。
优选地，所述药物组合物中还包括4.55v/v％的乳酸。
本发明还提供另一种用于治疗或预防癌症的药物组合物，该药物组合物由酮类化合物和二甲基亚砜组成，
优选地，所述酮类化合物为链烷酮，优选为C 3-6的链烷酮，更优选为丙酮；
优选地，所述药物组合物由丙酮和二甲基亚砜组成，
优选地，所述丙酮和所述二甲基亚砜之间的体积比为1:1-1:200；
优选地，所述丙酮和所述二甲基亚砜之间的体积比为1:100-1:200；
优选地，所述丙酮和所述二甲基亚砜之间的体积比为1:75-1:150；
优选地，所述丙酮和所述二甲基亚砜单独或混合后加水稀释直接口服、注射、喷剂等作为治疗或预防动物和人类疾病的给药方式。
优选地，所述药物组合物中还包括4.55v/v％的乳酸。
此外，本发明还提供又一种用于治疗或预防癌症的药物组合物，该药物组合物由醇类化合物和二甲基亚砜组成，
优选地，所述醇类化合物为C 1-6的链烷醇，优选为C 1-4的链烷醇，更优选为乙醇；
优选地，所述药物组合物由乙醇和二甲基亚砜组成，
优选地，所述乙醇和所述二甲基亚砜之间的体积比为1:1-1:200；
优选地，所述乙醇和所述二甲基亚砜之间的体积比为1:100-1:200；
优选地，所述乙醇和所述二甲基亚砜之间的体积比为1:75-1:150；优选地，所述乙醇和所述二甲基亚砜单独或混合后加水稀释直接口服、注射、喷剂等作为治疗或预防动物和人类疾病的给药方式。
优选地，所述药物组合物中还包括4.55v/v％的乳酸。
另一方面，本发明提供上述药物组合物在制备用于预防和/或治疗癌症、癌症并发症、脑水肿、糖尿病、高血压、心脑血管疾病、红斑狼疮、胸水、腹水及痛风等多种疾病的药物中的用途。
优选地，所述药物组合物的给药途径包括但不限于口服、静脉滴注、静脉注射、透皮给药等多种给药途径。
优选地，所述癌症包括但不限于神经胶质瘤、星形细胞瘤、脑或中枢神经系统癌、外周神经系统癌、例如黑素瘤、B细胞癌、多发性骨髓瘤、乳腺癌、肺癌、支气管癌、结肠直肠癌、前列腺癌、胰腺癌、胃癌、卵巢癌、膀胱癌、食道癌、宫颈癌、子宫或子宫内膜癌、口腔癌、咽癌、肝癌、肾癌、睾丸癌、胆道癌、小肠癌或阑尾癌、唾液腺癌、甲状腺癌、肾上腺癌、骨肉瘤、软骨肉瘤、血液组织癌、腺癌、炎性肌纤维母细胞瘤、胃肠道间质瘤(GIST)、结肠癌、霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、软组织肉瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、肾母细胞瘤、膀胱癌、上皮癌、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、神经母细胞瘤、视网膜母细胞瘤、滤泡性淋巴瘤、弥漫性大B-细胞淋巴瘤、套细胞淋巴瘤、肝细胞癌、甲状腺癌、胃癌、头颈癌、小细胞癌、特发性髓样化生、嗜酸性粒细胞增多症、慢性嗜酸性粒细胞白血病、神经内分泌癌、类癌瘤，以及它们的转移性、浸润性病变。本申请的药物组合物也适用于糖尿病、心脑血管疾病、红斑狼疮、胸水、腹水及痛风的治疗。
本发明所述药物组合物作用靶点是附着在细胞膜上的醛类化合物，运用醇、酯、酮、酸类等化合物与醛类化合物反应的方式来锚定附着在细胞膜上醛类化合物或醛蛋白，同时通过改变肿瘤细胞周围环境来抑制肿瘤细胞增殖和浸润或集聚，从而遏制肿瘤生长。
本发明药物组合物是一种广谱抗癌药，临床上应该由具有丰富经验的医 师依据患者病情不同时期、不同症状，单独、交替、联合用药给予不同剂量的配比治疗效果会更好。
本申请的药物组合物与现有技术相比较具有以下优势：
(1)本发明将溶剂直接混合，简便易行，但在动物实验中，各组合物再分别按比例加入乳酸4.55％会显示出对肿瘤控制的更优异效果。适用于多种癌症的治疗。
(2)本发明的药物组合物是一种精准的肿瘤抑制剂，只针对恶性肿瘤细胞有药效作用、不损伤正常组织细胞，能够避免对正常组织细胞的杀伤和抑制，仅遏制恶性肿瘤细胞的增殖和浸润正常组织细胞。
(3)本发明的药物组合物中使用的溶剂理化指标明确，易于控制，药代、毒性等易于专业人员和患者明晰判断。
(4)本发明的药物组合物与国内外已经上市的癌症治疗药物相比毒性低，甚至可以忽略不计，而且没有任何副作用，准确、正常剂量给药不会对人体有任何伤害。
(5)本发明的药物组合物不同于现有抗肿瘤药物，在抑制实体瘤生长的同时，也会有效抑制肿瘤细胞、结节在其它组织中继发性生长(所谓肿瘤转移)。
(6)本发明的药物组合物可以能有效降低跨膜阻抗，增强细胞膜通透性，使机体组织细胞及时、有效利用葡萄糖、盐、水等，增强患者体能。
(7)本发明药物组合物是通过对肿瘤细胞外膜蛋白的变性作用和环境影响来实现遏制肿瘤细胞的大量增殖，并阻止肿瘤细胞向正常组织细胞浸润，当药物使其增殖速度慢于正常组织细胞时和停止浸润正常组织细胞时，肿瘤体积逐渐缩小或维持不变。
应当理解的是，本文所述发明不限于特定的方法学、实验方案或试剂，因为这些是可以变化的。本文所提供的论述和实例仅是为了描述特定的实施方案呈现而非意在限制本发明的范围，本发明的范围仅受到权利要求的限定。
附图说明
图1：本发明药物组合物的抑瘤率；
图2：肿瘤解剖图谱，其中从上至下依次为溶剂对照组、5氟尿嘧啶组、替莫唑胺组、高中低剂量组的实验结果；
图3：给药期间肿瘤体积变化趋势；
图4：给药期间体重变化趋势。
具体实施方式
以下实施例中实验材料、来源如下：
二甲基亚砜：(≥99.5％)，国药集团化学试剂有限公司、批号：20181010；
乙醇：(≥95.0％)，国药集团化学试剂有限公司、批号：20200810；
丙酮：(≥99.5％)，国药集团化学试剂有限公司、批号：20140221；
乙酸乙酯：(≥99.5％)，国药集团化学试剂有限公司、批号：20161026。
实施例1本发明的药物组合物
配方：二甲基亚砜200mL、乙酸乙酯1mL；
配方：二甲基亚砜180mL、乙酸乙酯1mL；
配方：二甲基亚砜160mL、乙酸乙酯1mL；
配方：二甲基亚砜140mL、乙酸乙酯1mL；
配方：二甲基亚砜120mL、乙酸乙酯1mL；
配方：二甲基亚砜100mL、乙酸乙酯1mL；
配方：二甲基亚砜80mL、乙酸乙酯1mL；
配方：二甲基亚砜60mL、乙酸乙酯1mL；
配方：二甲基亚砜40mL、乙酸乙酯1mL；
配方：二甲基亚砜20mL、乙酸乙酯1mL；
配方：二甲基亚砜1mL、乙酸乙酯1mL。
实施例2本发明的药物组合物
配方：二甲基亚砜200mL、丙酮1mL；
配方：二甲基亚砜180mL、丙酮1mL；
配方：二甲基亚砜160mL、丙酮1mL；
配方：二甲基亚砜140mL、丙酮1mL；
配方：二甲基亚砜120mL、丙酮1mL；
配方：二甲基亚砜100mL、丙酮1mL；
配方：二甲基亚砜80mL、丙酮1mL；
配方：二甲基亚砜60mL、丙酮1mL；
配方：二甲基亚砜40mL、丙酮1mL；
配方：二甲基亚砜20mL、丙酮1mL；
配方：二甲基亚砜1mL、丙酮1mL。
实施例3本发明的药物组合物
配方：二甲基亚砜200mL、乙醇1mL；
配方：二甲基亚砜180mL、乙醇1mL；
配方：二甲基亚砜160mL、乙醇1mL；
配方：二甲基亚砜140mL、乙醇1mL；
配方：二甲基亚砜120mL、乙醇1mL；
配方：二甲基亚砜100mL、乙醇1mL；
配方：二甲基亚砜80mL、乙醇1mL；
配方：二甲基亚砜60mL、乙醇1mL；
配方：二甲基亚砜40mL、乙醇1mL；
配方：二甲基亚砜20mL、乙醇1mL；
配方：二甲基亚砜1mL、乙醇1mL。
实施例4本发明的药物组合物治疗癌症的作用
1、主要仪器及设备
实验室常用解剖器械、生物显微镜、动物体重天平、分析天平、水浴锅、移液器、涡旋混合仪、生物安全柜、细胞培养箱等。
2、试剂
消毒剂、注射用生理盐水、医用酒精等。
3、阳性药
3.1阳性对照品1
名称：氟尿嘧啶注射液
生产单位：上海旭东海普药业有限公司
批号：FA181206
包装：玻璃安瓿瓶
规格：10mL：0.25g
性状：无色澄明液体
保存条件：15～25℃避光保存，勿冷冻
有效期：至2020年12月12日
3.2阳性对照品2
名称：注射用替莫唑胺
生产单位：江苏恒瑞医药股份有限公司
批号：190711AM
包装：西林瓶
规格：100mg/支
性状：白色冻干块状物
保存条件：密闭保存(2～8℃)
有效期：至2021年07月10日
4、实验动物
Figure PCTCN2021143696-appb-000001
5、检疫
按试验要求对实验动物进行验收、检疫。适应性观察5天，观察期间对眼、耳、鼻、口腔、皮毛、腹部、外阴、肛周、四肢、爪、肉趾、步态、行 为、排泄、摄食、饮水进行观察记录，实验选用检疫正常的小鼠进行。
6、分组
实验选择检疫合格的小鼠，接种肿瘤后随机分组，并分笼标记，分别饲养。
7、饲养条件
青岛海洋生物医药研究院股份有限公司实验动物使用许可证编号：
SYXK(鲁)2015 0011
实验室温度20～25℃，湿度40～70％，换气次数为10～20次/小时，光照12小时明暗交替，饲养密度每笼＜5只。饲养环境严格按照《中华人民共和国国家标准-实验动物》相关标准执行。
8、肿瘤细胞株信息
细胞来源及培养条件：U-87MG人脑星形胶质母细胞瘤细胞，来源于中国科学院上海生命科学研究院细胞资源中心，使用培养基为含1％青霉素-硫酸链霉素双抗混合液(100×)及10％胎牛血清(澳洲源)的MEM培养基，培养条件5％CO 2、37℃，由本中心冻存。
9、细胞复苏与传代
液氮复苏U-87MG细胞株，置于含10％FBS(胎牛血清)、100U/ml青霉素和100μg/ml链霉素的相应培养基中，于37℃、5％CO 2的细胞培养箱中培养。每两天传代一次。
10、肿瘤接种
传代四次后，0.05％胰酶-EDTA消化收集细胞，镜下计数细胞数量，用培养基重悬至5×10 7个/ml细胞悬液，常规消毒后按每只0.2ml，接种于小鼠右前肢腋窝部皮下，无菌取出，称重，加入质量体积比为1:4的氯化钠注射液稀释研磨，常规消毒后按每只0.2ml接种于小鼠右前肢腋窝部皮下进行传代，连续传代2次。期间小鼠正常饲养，每周观察记录小鼠状态及肿瘤情况。
待传代荷瘤小鼠肿瘤体积为1200mm 3左右时采用相同的方法进行肿瘤研磨移植造模，肿瘤接种完成称取小鼠体重，并随机挑选小鼠分组每组7只共6组。肿瘤定植后开始给药，记为第1天(D1)。
11、动物分组和给药剂量
采用随机分组法，根据体重将动物分为6组，每组7只动物。各组动物给药剂量如下表：
表1分组给药情况
Figure PCTCN2021143696-appb-000002
12、临床观察
12.1一般临床观察
观察动物：所有动物
观察频率及时间：实验期间每次给药前观察一次，给药及观察记录。观察内容：包括但不限于肿瘤生长情况、动物精神状态、饮食情况等。
12.2体重
检测动物：所有动物
检测时间：分组(即首次给药前)(D1)、以后每次给药前、安乐死前称取动物体重，体重记录。
动物发生意外死亡称重记录，相关记录。
12.3根据肿瘤重量进行疗效评价
实验结束，对意外死亡动物及存活动物实施安乐死后需剥离肿瘤组织，称量肿瘤重量，计算各组的肿瘤重量差异以进一步计算肿瘤抑制率IRTW，计算公式如下：
IRTW(％)＝(W模型组-W给药组)/W模型组×100％
13、照片记录
动物安乐死后剥离肿瘤组织进行拍照。
14、数据采集和统计分析
方案要求测定和观察的数据结果需要手记到适当的表格上或计算机直接采集数据。该数据作为原始数据，作分析处理及报告。结果用平均数和标准差表示(Mean±SD)。两组间比较采用t检验，结果分析时同时考虑统计学意义和生物学意义。
15、结果
15.1一般临床观察
高剂量组在按照每天两次给药给药量总共为13.5ml/kg时，第三天高剂量组出现两只死亡，其余小鼠呈蜷缩状，口角、鼻等无粘液流出，目闭合，手感体表温度降低，不活动，不进食，随及高剂量组减少给药量至6.75ml/kg，直至实验结束，再未出现死亡，其余各组小鼠状态良好。
15.2抑瘤率统计
抑瘤率统计结果见图1和表2。
表2
Figure PCTCN2021143696-appb-000003
Figure PCTCN2021143696-appb-000004
图2为肿瘤解剖图谱，从上至下依次为溶剂对照组、5氟尿嘧啶组、替莫唑胺组、高中低剂量组。图3为给药期间肿瘤体积变化趋势。图4为给药期间体重变化趋势。
由实验数据可见，在调整给药剂量之后给药第7天，肿瘤体积开始出现明显差异，给药11至15天，高中低剂量组抑瘤率有剂量依赖性，最终剖检，高剂量组抑瘤率为46.4％，给药期间除5氟尿嘧啶组在给药后期体重出现降低外，小鼠体重均呈现正常生长状体，表明在小鼠对药物适应后，未明显对进食消化等活动造成影响。

Claims (11)

  1. 一种用于治疗或预防癌症的药物组合物，该药物组合物由酯类化合物和二甲基亚砜组成；
    优选地，所述酯类化合物为C 2-8的低级酯，优选为C 2-4的低级酯，更优选为乙酸乙酯；
    优选地，所述药物组合物由乙酸乙酯和二甲基亚砜组成。
  2. 根据权利要求1所述的药物组合物，其中，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:1-1:200；
    优选地，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:100-1:200；
    优选地，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:75-1:150；
    优选地，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:75-1:150；
    优选地，所述乙酸乙酯和所述二甲基亚砜之间的体积比为1:100；
    优选地，所述乙酸乙酯和所述二甲基亚砜单独或混合后加水稀释直接口服、注射、喷剂等作为治疗或预防动物和人类疾病的给药方式；
    优选地，所述药物组合物中还包括4.55v/v％的乳酸。
  3. 一种用于治疗或预防癌症的药物组合物，该药物组合物由酮类化合物和二甲基亚砜组成；
    优选地，所述酮类化合物为链烷酮，优选为C 3-6的链烷酮，更优选为丙酮；
    优选地，所述药物组合物由丙酮和二甲基亚砜组成。
  4. 根据权利要求3所述的药物组合物，其中，所述丙酮和所述二甲基亚砜之间的体积比为1:1-1:200；
    优选地，所述丙酮和所述二甲基亚砜之间的体积比为1:100-1:200；
    优选地，所述丙酮和所述二甲基亚砜之间的体积比为1:75-1:150；
    优选地，所述丙酮和所述二甲基亚砜单独或混合后加水稀释直接口服、注射、喷剂等作为治疗或预防动物和人类疾病的给药方式；
    优选地，所述药物组合物中还包括4.55v/v％的乳酸。
  5. 一种用于治疗或预防癌症的药物组合物，该药物组合物由醇类化合物和二甲基亚砜组成；
    优选地，所述醇类化合物为C 1-6的链烷醇，优选为C 1-4的链烷醇，更优选为乙醇；
    优选地，所述药物组合物由乙醇和二甲基亚砜组成。
  6. 根据权利要求5所述的药物组合物，其中，所述乙醇和所述二甲基亚砜之间的体积比为1:1-1:200；
    优选地，所述乙醇和所述二甲基亚砜之间的体积比为1:100-1:200；
    优选地，所述乙醇和所述二甲基亚砜之间的体积比为1:75-1:150；
    优选地，所述乙醇和所述二甲基亚砜单独或混合后加水稀释直接口服、注射、喷剂等作为治疗或预防动物和人类疾病的给药方式；
    优选地，所述药物组合物中还包括4.55v/v％的乳酸。
  7. 权利要求1至6中任一项所述的药物组合物在制备用于预防和/或治疗癌症、癌症并发症、脑水肿、糖尿病、高血压、心脑血管疾病、红斑狼疮、胸水、腹水及痛风等多种疾病的药物中的用途。
  8. 根据权利要求7所述的用途，其特征在于，所述药物组合物的给药途径包括但不限于口服、静脉滴注、静脉注射、透皮给药等多种给药途径。
  9. 根据权利要求7或8所述的用途，其特征在于，所述癌症包括但不限于神经胶质瘤、星形细胞瘤、脑或中枢神经系统癌、外周神经系统癌、例如黑素瘤、B细胞癌、多发性骨髓瘤、乳腺癌、肺癌、支气管癌、结肠直肠癌、前列腺癌、胰腺癌、胃癌、卵巢癌、膀胱癌、食道癌、宫颈癌、子宫或子宫内膜癌、口腔癌、咽癌、肝癌、肾癌、睾丸癌、胆道癌、小肠癌或阑尾癌、唾液腺癌、甲状腺癌、肾上腺癌、骨肉瘤、软骨肉瘤、血液组织癌、腺癌、炎性肌纤维母细胞瘤、胃肠道间质瘤(GIST)、结肠癌、霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、软组织肉瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、髓样癌、支气管癌、 肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、肾母细胞瘤、膀胱癌、上皮癌、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、神经母细胞瘤、视网膜母细胞瘤、滤泡性淋巴瘤、弥漫性大B-细胞淋巴瘤、套细胞淋巴瘤、肝细胞癌、甲状腺癌、胃癌、头颈癌、小细胞癌、特发性髓样化生、嗜酸性粒细胞增多症、慢性嗜酸性粒细胞白血病、神经内分泌癌、类癌瘤，以及它们的转移性、浸润性病变。
  10. 根据权利要求7或8所述的用途，其特征在于，所述药物组合物作用靶点是附着在细胞膜上的醛类化合物，运用醇、酯、酮、酸类等化合物与醛类化合物反应的方式来锚定附着在细胞膜上醛类化合物或醛蛋白，同时通过改变肿瘤细胞周围环境来抑制肿瘤细胞增殖和浸润或集聚，从而遏制肿瘤生长。
  11. 一种治疗或预防癌症的方法，该方法包括向有需要的人施用权利要求1至6中任一项所述的药物组合物，
    优选地，所述癌症包括但不限于神经胶质瘤、星形细胞瘤、脑或中枢神经系统癌、外周神经系统癌、例如黑素瘤、B细胞癌、多发性骨髓瘤、乳腺癌、肺癌、支气管癌、结肠直肠癌、前列腺癌、胰腺癌、胃癌、卵巢癌、膀胱癌、食道癌、宫颈癌、子宫或子宫内膜癌、口腔癌、咽癌、肝癌、肾癌、睾丸癌、胆道癌、小肠癌或阑尾癌、唾液腺癌、甲状腺癌、肾上腺癌、骨肉瘤、软骨肉瘤、血液组织癌、腺癌、炎性肌纤维母细胞瘤、胃肠道间质瘤(GIST)、结肠癌、霍奇金淋巴瘤、非霍奇金淋巴瘤(NHL)、软组织肉瘤、纤维肉瘤、粘液肉瘤、脂肪肉瘤、骨原性肉瘤、脊索瘤、血管肉瘤、内皮肉瘤、淋巴管肉瘤、淋巴管内皮肉瘤、滑膜瘤、间皮瘤、尤文氏瘤、平滑肌肉瘤、横纹肌肉瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、髓样癌、支气管癌、肾细胞癌、肝癌、胆管癌、绒毛膜癌、精原细胞瘤、胚胎癌、肾母细胞瘤、膀胱癌、上皮癌、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、血管母细胞瘤、听神经瘤、少突胶质细胞瘤、脑膜瘤、神经母细胞瘤、视网膜母细胞瘤、滤泡性淋巴瘤、弥漫性大B-细胞淋巴瘤、套细胞淋巴瘤、肝细胞癌、甲状腺癌、胃癌、头颈癌、小细胞癌、 特发性髓样化生、嗜酸性粒细胞增多症、慢性嗜酸性粒细胞白血病、神经内分泌癌、类癌瘤，以及它们的转移性、浸润性病变。
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