Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
  • A61K31/05—Phenols
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
  • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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 relates to a pharmaceutical composition and its use in the preparation of a medicament for treating cancer, in particular to a pharmaceutical composition comprising resveratrol and a resveratrol derivative and a Bcl-2 inhibitor and preparation thereof Use in the treatment of drugs for colon cancer, liver cancer, lung cancer, kidney cancer, gastric cancer, brain tumor, sarcoma, glioma, pancreatic cancer, ovarian cancer, breast cancer or prostate cancer.
• Background technique
• the World Health Organization survey shows that the global cancer situation is getting worse. The number of new patients will increase from the current 10 million to 15 million in the next 20 years, and the number of deaths due to cancer will increase from 6 million to 10 million per year.
• Primary liver cancer is a cancer that occurs in hepatocytes and intrahepatic bile duct epithelial cells. It is one of the most common malignant tumors in humans.
• the incidence of colon cancer is related to the environment, living habits, especially the way of eating. It is generally considered to be a high-fat diet and Insufficient cellulose is the main cause of the disease. With the improvement of living standards and the changes in diet structure, the incidence of colon cancer is increasing year by year.
• Glioma is a tumor originating from glial cells and occurring in the neuroectodermal layer. Its main features are diffuse infiltration and growth of tumor cells, no clear boundaries, infinite proliferation and high invasiveness. Despite the continuous improvement of neurosurgery skills, the precise positioning of radiotherapy and the continuous development of chemotherapy drugs in recent years, the recovery of glioma patients is still unsatisfactory, so the treatment of glioma is imminent.
• anti-tumor drugs such as alkylating agents, anti-metabolites, anti-tumor antibiotics, immunomodulators, etc.
• drugs are intolerant due to their toxicity.
• a large number of clinical practices have proved that Chinese medicine or combination of traditional Chinese and Western medicine can effectively treat malignant tumors, and at the same time can alleviate the side effects of radiotherapy and chemotherapy.
• it was found that some active natural products can effectively inhibit the growth of tumor cells and induce apoptosis.
• Many of the antibiotics and anti-tumor drugs currently in use are either directly derived from natural products or have been structurally modified. Therefore, the use of highly safe active natural products for clinical treatment of cancer will have broad prospects.
• molecular targeted therapy for a variety of evils Sexual tumors have received extensive attention and high attention.
• Molecular targeting drugs have high selectivity and wide language, and their safety is superior to cytotoxic chemotherapy drugs, which is a new direction in the field of cancer therapy.
• Resveratrol is a polyphenolic compound widely found in various plants such as grapes, Polygonum cuspidatum, and peanut. It is a natural phytoalexin and a green anticancer drug for cancer prevention and treatment. In vivo and in vivo, the resveratrol showed inhibition and even reversal of the three major stages of initiation, proliferation and development of most tumors. Its anti-tumor mechanism can inhibit tumor cell angiogenesis, inhibit cell cycle, promote tumor cell apoptosis, induce tumor cell differentiation, inhibit epoxidase and cytochrome P450 activity, interfere with related signal transduction pathways, and inhibit tumor angiogenesis. And so on.
• Apoptosis (programmed cell death) is a natural pathway by which the body removes abnormal or unwanted cells, which, if affected, can lead to various diseases such as cancer.
• Bc l-2 family proteins are important regulators of apoptosis, and Bc l-2 and Bc l-xL are overexpressed in various types of tumors, which are thought to be related to tumorigenesis, development and drug resistance. Therefore, the development of anti-apoptotic proteins against Bc l-2 and Bc l-xL has become a research hotspot in anti-tumor therapy in recent years.
• ABT-263 and ABT-737 are small molecule Bc l-2 inhibitors developed by Abbott Pharmaceuticals. They have a remarkable effect on a variety of tumors and can be used orally. They have good application prospects.
• the present invention provides a pharmaceutical composition and application thereof in the preparation of a medicament for treating cancer, specifically a pharmaceutical composition comprising resveratrol and a resveratrol derivative and a Bc l-2 inhibitor And its preparation in the treatment of colon cancer, liver cancer, lung cancer, kidney cancer, stomach cancer, Use in drugs for brain tumors, sarcomas, gliomas, pancreatic cancer, ovarian cancer, breast cancer or prostate cancer.
• the -2 inhibitor can be ABT-263 or ABT-737, or a corresponding structural analog of the two, ⁇ [stained organism.
• resveratrol and resveratrol derivatives in the pharmaceutical composition of the present invention are preferably resveratrol, and the corresponding structural formula is as shown in Formula I.
• the component is not limited to the resveratrol drug itself, but may be a pharmaceutically acceptable salt, hydrate or derivative thereof.
• the Bc l-2 inhibitor may be a drug of any structural type of Bc l-2 inhibitor, preferably ABT-263 or ABT-737.
• ABT-263 is a compound of formula II as described in US2007027135:
• ABT-737 is a compound of formula III as described in WO2005049594 and WO2005049593:
• the components are not limited to the above-mentioned ABT-263 and ABT-737, and may be their hydrates, analogs, derivatives and other organic or inorganic salts.
• the molar ratio of resveratrol and resveratrol derivatives to Bc l-2 inhibitor in the pharmaceutical composition containing resveratrol and resveratrol derivatives and Bc l-2 inhibitor 0 ⁇ 100. 0: 0.
• the ratio of the molar ratio of the resveratrol and the resveratrol derivative to the Bc l-2 inhibitor is 30. 0-100. 0: 1. 0-2. 0.
• the pharmaceutical composition of the present invention comprising resveratrol and a resveratrol derivative and a Bcl-2 inhibitor can be used for treating various tumors including, but not limited to, colon cancer, liver cancer, lung cancer, kidney cancer , gastric cancer, brain tumor, sarcoma, glioma, pancreatic cancer, ovarian cancer, breast cancer or prostate cancer.
• a pharmaceutical composition of resveratrol and a resveratrol derivative and a Bc l-2 inhibitor is preferably used for the preparation of a medicament for treating colon cancer, liver cancer and glioma.
• the molar ratio of the resveratrol and the resveratrol derivative to the Bc l-2 inhibitor is 30. 0.
• the pharmaceutical composition of the present invention is used in the preparation of a medicament for treating colon cancer, liver cancer and glioma.
• the ratio of the molar ratio of the resveratrol and the resveratrol derivative to the Bc l-2 inhibitor is 50. 0-100. 0: 1. 5-2 0: 2. 0 ⁇
• the molar ratio of the resveratrol and resveratrol derivatives to the Bc l-2 inhibitor is 100. 0: 2. 0.
• a composition comprising resveratrol and a resveratrol derivative and a Bcl-2 inhibitor for the treatment of colon cancer, liver cancer, lung cancer, kidney cancer, gastric cancer, brain tumor, sarcoma, glioma, pancreatic cancer,
• the resveratrol and the resveratrol derivative and the Bc l-2 inhibitor may be contained in the same pharmaceutical preparation such as a tablet or a capsule, or may be a white gourd.
• the alcohol and the resveratrol derivative and the Bc l-2 inhibitor are respectively formulated into a tablet, or a capsule, respectively, and the instructions of the instructions are taken at the same time; the composition of the present invention is formulated into a drug for sequential administration.
• the resveratrol and the resveratrol derivative and the Bc l-2 inhibitor may be separately prepared according to the order indicated in the instructions of the drug, or the two components in the above composition may be made.
• a controlled release formulation one component of the composition is first released, and then the other component of the composition is released, the patient only needs to take the controlled release composition formulation; the composition of the invention is prepared to cross
• the resveratrol and the resveratrol derivative and the Bcl-2 inhibitor may be separately formulated into different preparations and packaged or combined together in a manner conventional in the art.
• the patient then follows the instructions for the drug CROSS taking the indicated order, or the pharmaceutical composition is a controlled release formulation of resveratrol and resveratrol derivatives and Bc l-2 inhibitor to prepare a cross-release.
• Resveratrol and resveratrol derivatives and Bcl-2 inhibitor compositions are prepared for the treatment of colon cancer, liver cancer, lung cancer, kidney cancer, gastric cancer, brain tumor, sarcoma, glioma, pancreatic cancer, ovary
• the resveratrol and resveratrol derivatives and the Bcl-2 inhibitor in the composition may be used simultaneously or in any order.
• resveratrol and resveratrol derivatives and Bc l-2 inhibitors can be administered to patients at the same time; resveratrol and resveratrol derivatives can be administered to patients first, and then taken Bc l-2 inhibitor, or taking Bc l-2 inhibitor first, then taking resveratrol and resveratrol derivative drugs, there is no special requirement for the time interval between the two, but it is preferred to take two drugs The time interval is no more than one day; or two drugs are administered alternately.
• the resveratrol and resveratrol derivatives of the present invention and the Beb 2 inhibitor can be prepared into a medicament suitable for gastrointestinal administration or parenteral administration by a method conventional in the art.
• the present invention preferably comprises a resveratrol and a resveratrol derivative and a Be 1 -2 inhibitor as a pharmaceutical preparation for gastrointestinal administration, and the preparation form may be a conventional tablet or capsule, or a control Release, sustained release preparation.
• the composition is contained in the preparation according to different preparation forms and formulation specifications.
• the amount may be from 1 to 99% by mass, preferably from 10% to 90%; the excipient used in the formulation may be a conventional excipient in the art, and may not react with the composition of the present invention or affect the invention of the present invention.
• the preparation method of the composition is not particularly limited, and both the resveratrol and the resveratrol derivative and the Beb 2 inhibitor may be directly mixed and then formulated, or separately and/or correspondingly excipients are separately mixed.
• Formulations are prepared and then packaged together in a manner conventional in the art, or separately mixed with the corresponding adjuvants and then mixed to form a formulation.
• the dosage of the pharmaceutical composition of the present invention can be appropriately changed depending on the administration target, the administration route or the preparation form of the drug, but to ensure that the pharmaceutical composition can achieve an effective blood concentration in the mammal. As a prerequisite.
• the present invention separately combines resveratrol and resveratrol derivatives and Bc l-2 inhibitors to kill DLD1 (colon cancer cell line), HUH-7 (hepatoma cell line) and U251 (glioma).
• DLD1 colon cancer cell line
• HUH-7 hepatoma cell line
• U251 glioma
• the test results of the cell strain showed that the combination of resveratrol and resveratrol derivatives and Be 1-2 inhibitor of the present invention has significant synergistic effects on colon cancer, liver cancer and glioma, and improved.
• the efficacy of the drug reduces the amount of the drug and reduces the occurrence of side effects.
• DLD1 colon cancer cell line
• HUH-7 hepatoma cell line
• U251 glioma cell line
• Drugs The pharmaceutical compositions used in the following examples were prepared as described in Method 1 or Method 2 below; Resveratrol was purchased from Nanjing Institute of Traditional Chinese Medicine; Bc l-2 inhibitors were synthesized according to the literature. , ABT-263 and ABT-737 synthetic references are: Synthes is, 15, 2398-2404, W02005049594, WO2005049593 and US2007027135.
• Method 1 Accurately weigh the components of the corresponding pharmaceutical composition, dissolve them separately with dimethyl sulfoxide, prepare 10 mM stock solutions, store at -20 ° C, and use fresh medium when using. Dilute to the appropriate concentration, then take 1 ⁇ l of each component solution and mix for use. In all tests, the final concentration of dimethyl sulfoxide should be ⁇ 5g/L so as not to affect the activity of the cells.
• cell death was measured by Trypan Blue, and the cells were trypsinized with trypsin sodium/EDTA for 10 minutes at 37 °C. Since the dead cells were detached from the incubator into the medium, all the cells were collected by centrifugation at 1200 rpm, and then the precipitate was resuspended in the medium, and mixed with the trypan blue dye. After staining, counting was performed using an optical microscope and a hemocytometer. The dyed blue color is counted as a dead cell. 500 cells were randomly selected for counting, and the dead cells were expressed as a percentage of the total counted cells.
• Method 2 Each component of the corresponding pharmaceutical composition was accurately weighed, dissolved separately with dimethyl sulfoxide, and each was formulated into a 10 mM stock solution, and stored at - 20 °C. Dilute to a suitable concentration with fresh medium, and then take 1 ⁇ l of each component solution for use. In all tests, the final concentration of dimethyl sulfoxide should be ⁇ 5g/L so as not to affect the activity of the cells.
• cell death was measured by Trypan Blue, and the cells were trypsinized with trypsin sodium/EDTA for 10 minutes at 37 °C. Since the dead cells were detached from the incubator into the medium, all the cells were collected by centrifugation at 1200 rpm, and then the precipitate was resuspended in the medium, and mixed with the trypan blue dye. After staining, counting was performed using an optical microscope and a hemocytometer. Dyed in dyed blue Cell. 500 cells were randomly selected for counting, and dead cells were expressed as a percentage of the total counted cells.
• the combination of the first to 1-6 is prepared according to the method 1
• the combination of the seventh to the fourth is prepared according to the method 1.
• Example 1 The synergistic effect of different ratios of resveratrol and ABT-263 on promoting DLD1 cell death test is shown in Table 2.
• ABT-263 1.0 3.3 ⁇ 1.1 Resveratrol+ABT-263 30.0 + 1.0 13.4 ⁇ 2.3 Medium dose resveratrol 50. 0 18. 6 ⁇ 2. 4
• Resveratrol + ABT-263 100. 0 + 2. 0 68. 3 ⁇ 4. 2
• Example 2 The synergistic effect of different ratios of resveratrol and ABT-737 on promoting DLD1 cell death test is shown in Table 3.
• Example 3 The synergistic effect of different ratios of resveratrol and strontium-263 promoted the death test of HUH-7 cells, see Table 4.
• Example 4 The synergistic effect of different ratios of resveratrol and ABT-263 on the promotion of U251 cell death test is shown in Table 5.

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Cited By (4)

• 2012
  • 2012-09-25 WO PCT/CN2012/081926 patent/WO2014047782A1/fr not_active Ceased

Non-Patent Citations (2)

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