CN101279967B - Medicinal composition of trimethyl xanthone-4-acetic acid for treating cancer and use thereof - Google Patents
Medicinal composition of trimethyl xanthone-4-acetic acid for treating cancer and use thereof Download PDFInfo
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- CN101279967B CN101279967B CN2008100478624A CN200810047862A CN101279967B CN 101279967 B CN101279967 B CN 101279967B CN 2008100478624 A CN2008100478624 A CN 2008100478624A CN 200810047862 A CN200810047862 A CN 200810047862A CN 101279967 B CN101279967 B CN 101279967B
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Abstract
The invention relates to a medicine combination, in particular to a medicine combination of trimethyl-genicide-4-acetic acid to cure cancers. The medicine combination contains effective dosages of trimethyl-genicide-4-acetic acid, pharmaceutically acceptable salt or ester thereof, and effective dosages of anticarcinogenic drug. The medicine combination strengthens the antineoplastic activity of the medicine and is of good effect to cancers due to the synergism of the medical components.
Description
Technical field
The present invention relates to a kind of drug regimen, is a kind of trimethylammonium xanthone-4-acetate medical composition and its use for the treatment of cancer specifically.
Background technology
Cancer is a big class disease of serious threat human health.Operation, chemicotherapy and cancer drug therapy are three main method for the treatment of cancer at present.Traditional medicine that acts on tumour cell is a cytotoxic drug, but its major defect is to the solid tumor weak curative effect, and poor selectivity when the poisoning tumour cell, has also been killed normal cell, erious adverse reaction, and easily produce resistance.1971, professor Folkman of medical college of Harvard University proposed famous " tumour hungry to death " theory, promptly by the nutrition supply of the tumor neovasculature generation cut-out of blocking-up tumour, reached the purpose of inhibition and treatment tumour.Act on tumor neovasculature medicine and divide two classes: a kind of be angiogenesis inhibitor (tumor angiogenesi inhibitor, TAI), another kind be destroy tumor neovasculature medicine (vascular targeting agents, VTA).In binding mode and treatment application facet, TAI requires to continue some months or medication in several years, and VTA is an intermittent use, and it can directly destroy existing tumor vessel, causes cancer cell death.Small molecules VTA can reduce the tumor vessel volume of blood flow fast, the necrosis on a large scale of the rapid minimizing of blood flow and tumour, and therapeutic domain is wide, and the characteristics that persister is difficult for producing make it receive increasing concern.But only in inside tumor powerful destruction is arranged, and the cell of borderline tumor is not had restraining effect, such exercising result makes it single not obvious with tumor killing effect.Borderline tumor blood is abundant, and traditional radiotherapy and chemotherapy medicine is relatively more responsive to this part cell, so VTA class medicine will be united use with traditional radiotherapy and chemotherapy medicine.DMXAA is the VTA class medicine that can cause the tumor vessel damage fast and selectively.At present, it is clinical that DMXAA has entered the III phase.
The compound trimethylammonium xanthone that the present invention relates to-4-acetate (TMXAA) is the compound similar to the DMXAA chemical structure.Specifically be included as: a) 2,5,6-trimethylammonium xanthone-4-acetate; B) 5,6,7-trimethylammonium xanthone-4-acetate; C) 5,6,8-trimethylammonium xanthone-4-acetate, the chemical structural formula of these three compounds is as follows:
In Chinese patent 200710053403.2, the preparation of TMXAA and the purposes in anticancer there is detailed description.(TMXAA) is the same with DMXAA for trimethylammonium xanthone-4-acetate, also is the tumor neovasculature VTA class of a kind of destruction medicine.Show that in animal experiment its antitumour activity is better than carrying out at present clinical DMXAA of III phase.
Trimethylammonium xanthone-4-acetate (TMXAA) influences tumor vascular endothelial cell and the inducing cell factor is optionally blocked tumor vessel by direct, and the result has blocked the blood confession of tumour, causes neoplasm necrosis.
But animal experiment is found, though TMXAA demonstrates the anti-angiogenic active tumor blood flow effect that suppresses for a long time that produces, can the necrosis of induced tumor big area middle section, yet the normal adjacent tissue place still can observe the tumour cell of survival around tumour, and acceptable explanation is that they have accepted supply from the healthy tissues blood vessel to this part tumor survival, and these remaining tumor tissues can be used as the source of tumor regrowth.Therefore, single effect with TMXAA treatment tumour has been still circumscribed.
We find unexpectedly, are used in combination with TMXAA and pharmacy acceptable salt thereof or ester and other drug, can play to strengthen the anti-tumor synergetic result of treatment.
Summary of the invention
The object of the invention is exactly the defective at existing cancer therapy drug, and a kind of trimethylammonium xanthone-4-acetate pharmaceutical composition for the treatment of cancer is provided, and it has strengthened the anti-tumor activity of medicine, and the synergy by several drugs has good effect to the treatment cancer.
Technical scheme of the present invention is achieved in that it comprises that effective dose is the trimethylammonium xanthone-4-acetate of 10mg-2000mg and the cancer therapy drug of pharmacy acceptable salt or ester and effective dose thereof.
Wherein said trimethylammonium xanthone-4-acetate is 2,5,6-trimethylammonium xanthone-4-acetate and salt thereof or ester, 5,6,7-trimethylammonium xanthone-4-acetate and salt thereof or ester, 5,6, one or more in 8-trimethylammonium xanthone-4-acetate and salt or the ester.
Wherein said cancer therapy drug is one or more medicines in cytotoxic drug, anti-tumor biological engineering medicine, anoxic alternative medicine, anti-inflammatory drug, vasoactive agent and the Chinese herbal medicine for preventing.
Described cytotoxic drug is a n-formyl sarcolysine, melphalan, Chlorambucil, endoxan, ifosfamide, the chlorine phosphamide, busulfan, semustine, ranomustine, Dacarbazine, cis-platinum, carboplatin, DNA-2114, Lip river platinum, S 254, oxaliplatin, Rheumatrex, cytosine arabinoside, 5 FU 5 fluorouracil, doxifluridine, capecitabine, gemcitabine, dactinomycin, ametycin, daunorubicin, Dx, mitoxantrone, vincristine(VCR), Vinorelbine, taxol, Docetaxel, camptothecine, in hydroxycamptothecine or the irinotecan one or more.
Described anti-tumor biological engineering medicine is anti-CEA antibody, recombinant mutant tumour necrosis factor or anti-tumor monoclonal antibody targeted drug.
Described anoxic alternative medicine is one or more in Win-59075, dinitrobenzene mustard, 2-nitroimidazole alkylating agent CI-1010, hydroxycamptothecine, Hycamtin, Squamocin A or the Etoposide.
Described anti-inflammatory drug is one or more in diclofenac sodium, Ibuprofen BP/EP, Naproxen Base or the Ketoprofen.
Described vasoactive agent is one or more in serotonin, Scopolamine, Dopamine HCL, dobutamine, racephedrine, metaraminol, Vasoxyl, suprarenin, Racemic isoproterenol, synephrine, norepinephrine, amrinone, the left-handed nitro arginine.
Described Chinese herbal medicine for preventing is one or more in cinobufagin capsule, anticancer pill ball, inaction XIAOAIPING PIAN, ginseng tablet or the compound Balanophora dioica R Br ex Royle particle.
More than the effective dose of various medicines in Chinese Pharmacopoeia and domestic and international disclosed clinical data, all can find, therefore do not enumerate one by one.
Trimethylammonium xanthone-4-acetate (TMXAA) is selected from cytotoxic drug, anti-tumor biological engineering medicine, anoxic alternative medicine, anti-inflammatory drug, vasoactive agent and the Chinese herbal medicine for preventing one or more and uses with the synergy ratio with above-mentioned, strengthen anti-tumor activity, played the effect of Synergistic treatment cancer.
" synergy ratio " term represents that in TMXAA and pharmacy acceptable salt or ester and cytotoxic drug, anti-tumor biological engineering medicine, anoxic alternative medicine, anti-inflammatory drug, vasoactive agent and the Chinese herbal medicine for preventing one or more use with such ratio; The anti-tumor activity of combination is greater than the anti-tumor activity of independent TMXAA and pharmacy acceptable salt thereof or ester or independent cytotoxic drug, anti-tumor biological engineering medicine, anoxic alternative medicine, anti-inflammatory drug, vasoactive agent and Chinese herbal medicine for preventing, perhaps greater than the adduction activity of the combination of expecting according to the activity of each component.Therefore, each component is used with the synergy ratio, and then their composition generation synergistic therapeutic action reaches better curative effect.
The present invention can make compound preparation, is applicable to oral administration.These oral preparations comprise tablet, capsule, granule, dispersible tablet, but are not limited only to above-mentioned formulation.The present invention can also make injection liquid, is applicable to drug administration by injection.These injection liquids comprise intravenous fluid, intramuscular injection, but are not limited only to above-mentioned formulation.
Embodiment
By the following examples the present invention is further described:
Embodiment 1:
With 2 of effective dose; 5; 6-trimethylammonium xanthone-4-sodium acetate prepares 2,5 in phosphate buffered saline (PBS), 6-trimethylammonium xanthone-4-sodium acetate storing solution; the effective dose cis-platinum is dissolved in makes cis-platinum solution in 0.9% salt solution; then with 2,5,6-trimethylammonium xanthone-4-sodium acetate storing solution and cis-platinum solution mix and with mixing after the salt solution dilution; obtain injection liquid of the present invention, lucifuge protection and refrigerated storage.
Experimentation on animals:
Realize people's tumour xenotransplantation (PSN1) by right flank subcutaneous injection 5 * 106 cells female MF1 nude mice.PSN1 is a carcinoma of the pancreas.Making tumor growth to diameter is 6-8 millimeter (volume is approximately 0.15 cubic centimetre), treats then.Random assignment treatment group is not so that the average-volume of treatment each group on the same day has difference statistically.The nude mice that injection liquid of the present invention is had its intravenous injection to length tumour by back tail vein.For combination therapy, use two kinds of medicines by tail vein after injecting two successively.Control mice is not treated.
The result:
Following table shows, title is with containing and do not contain 2,5 for the hurdle of " on average ", and the gross tumor volume of the PSN1 pancreatic neoplasm allogeneic of the plus cisplatin in treatment of 6-trimethylammonium xanthone-4-sodium acetate increases to 3 times mean time.Title is represented the treatment group for the hurdle of " treatment-contrast " and contrasts time poor of triplication that promptly medicine or drug regimen are better than untreated tumour part.
The cis-platinum data were analyzed as the double time of volume and the time of triplication.In both cases, two kinds of drug regimens all are synergic, the treatment group of combination and the summation of the difference that contrasts greater than individually dosed medicine.See the following form 1 and table 2.
The time of table 1:PSN1 volume triplication (my god)
Cis-platinum adds 2,5,6-trimethylammonium xanthone-4-sodium acetate
| Treatment | On average | Treatment-contrast |
| Contrast | 5.0 |
| Treatment | On average | Treatment-contrast |
| 25 milligrams/kilogram 2,5,6-trimethylammonium xanthone-4-sodium acetate | 6.0 | 1.0 |
| 35 micrograms/kilogram cis-platinum | 12.0 | 7.0 |
| 25 milligrams/kilogram 2,5,6-trimethylammonium xanthone-4-sodium acetate+35 micrograms/kilogram cis-platinum | Be longer than 18 | Greater than 13 |
The time that table 2:PSN1 volume is double times (my god)
Cis-platinum adds 25,6-trimethylammonium xanthone-4-sodium acetate
| Treatment | On average | Treatment-contrast |
| Contrast | 3.0 |
| 25 milligrams/kilogram 2,5,6-trimethylammonium xanthone-4-sodium acetate | 4.0 | 1.0 |
| 35 micrograms/kilogram cis-platinum | 10.0 | 7.0 |
| 25 milligrams/kilogram 2,5,6-trimethylammonium xanthone-4-sodium acetate+35 micrograms/kilogram cis-platinum | 15 | 12 |
Embodiment 2:
5,6, the composite tablet that 7-trimethylammonium xanthone-4-acetate and antitumor drug endoxan are formed.
Endoxan (Cytoxan, Endoxan, CTX) be the most frequently used alkylating agent class antitumour drug, after entering in the body, under the hepatomicrosome enzyme catalysis, divide and explain the very strong chloroethyl phosphamide of alkanisation (or claiming the phosphamide mustargen), and tumour cell is produced cytotoxicity, this product also has remarkable immunization in addition.The clinical malignant lymphoma that is used for, multiple myeloma, leukemia, mammary cancer, ovarian cancer, cervical cancer, prostate cancer, colorectal carcinoma, bronchogenic carcinoma, lung cancer etc. have certain curative effect.Also can be used for the treatment of rheumatoid arthritis, children's nephrotic syndrome and autoimmune disease.5,6,7-trimethylammonium xanthone-4-acetate and antitumor drug are united use can strengthen antineoplastic effect, also can be made into compound preparation.Therefore, we have prepared contains 5,6, the composite tablet of 7-trimethylammonium xanthone-4-acetate 100mg and endoxan 50mg.1) prescription:
5,6,7-trimethylammonium xanthone-4-acetate 100g
Endoxan 50g
Hydroxypropylcellulose 10g
Microcrystalline Cellulose 50g
Amylum pregelatinisatum 40g
Micropowder silica gel 0.8g
β-lactose hydrous 67.5g
Talcum powder 1.5g
Amount to 1000
2) technology
The main ingredient porphyrize is crossed 100 mesh sieves, and auxiliary material is crossed 80 mesh sieves.Take by weighing TMXAA and endoxan, amylum pregelatinisatum, β-lactose hydrous, Microcrystalline Cellulose and 3% hydroxypropylcellulose of recipe quantity, abundant mixing is with ethanol system softwood, cross 12 order nylon mesh, 60 ℃ of dryings, the whole grain of 30 mesh sieves, add micropowder silica gel and talcum powder, fully mixing.Particle is through after the assay was approved, with particle powder with 12mm towards direct compression, promptly.
The pharmaceutical excipient that the present invention selects for use comprises tackiness agent, disintegrating agent, weighting agent, glidant and lubricant.The tackiness agent of selecting for use is that amylum pregelatinisatum, disintegrating agent are hydroxypropylcellulose, and weighting agent is β-lactose hydrous and Microcrystalline Cellulose, and glidant is a micropowder silica gel, and lubricant is a talcum powder.Pharmaceutical excipient is selected for use well behaved disintegrating agent such as hydroxypropylcellulose to be aided with other pharmaceutical excipients and is made compound preparation, and not only release is quick but also physicals is good to make it, and the outstanding advantage of the tablet for preparing is can snap-out release, and disperses fully.
Embodiment 3:
Prescription high-capacity injection of the present invention
5,6,8-trimethylammonium xanthone-4-acetate 100g
Fluracil 250 grams
Sodium-chlor 900g
Water for injection is to 100000ml
Make 1000 bottles of injection liquids altogether
Preparation technology:
The preparation of soup:
Take by weighing sodium-chlor by recipe quantity, add among the water for injection 5000ml, be stirred to dissolving fully; Take by weighing the gac of 0.3% solution amount, stir evenly, heated and boiled 15 minutes, after the cooling, the filtering gac; Accurately take by weighing 5,6 by recipe quantity, 8-trimethylammonium xanthone-4-acetate, Fluracil adds in the above-mentioned sodium chloride solution, and adds the injection water to nearly full dose; Regulate pH to 7.5～8.5 with 0.1% sodium hydroxide, add the injection water, measure intermediate content and should be 93.0%～107.0% to specified amount, qualified after, use the 0.45um filtering with microporous membrane, after the inspection clarity is qualified, filtrate friendship can group.
Can:
The infusion bottle that can is used is cleaned with injection water, oven dry.The plated film butyl rubber plug is clean with the injection water rinsing simultaneously.The above-mentioned soup for preparing is added the injection liquid filling machine, and can behind the capping plug, is suppressed compound aluminium lid in infusion bottle.
Sterilization:
The infusion bottle of building is put into the sterilization cabinet sterilize, sterilising temp is 115 ℃, sterilization time 35 minutes, and the lamp inspection is qualified, and packing gets final product.
Embodiment 4:
1) prescription:
5,6,7-trimethylammonium xanthone-4-sodium acetate 100g
Ginseng powder 100g
Hydroxypropylcellulose 10g
Microcrystalline Cellulose 50g
Amylum pregelatinisatum 40g
Micropowder silica gel 0.8g
β-lactose hydrous 67.5g
Talcum powder 1.5g
Amount to 1000
2) preparation method is with embodiment 2.
Embodiment 5:
With 2 of effective dose; 5; 6-trimethylammonium xanthone-4-ethyl acetate prepares 2,5 in phosphate buffered saline (PBS), 6-trimethylammonium xanthone-4-ethyl acetate storing solution; the effective dose carboplatin is dissolved in makes carboplatin solution in 0.9% salt solution; then with 2,5,6-trimethylammonium xanthone-4-ethyl acetate storing solution and carboplatin solution mix and with mixing after the salt solution dilution; obtain injection liquid of the present invention, lucifuge protection and refrigerated storage.
Claims (1)
1. trimethylammonium xanthone-4-acetate pharmaceutical composition for the treatment of cancer, it comprises that effective dose is the trimethylammonium xanthone-4-acetate of 10mg-2000mg and the cis-platinum of pharmacy acceptable salt and effective dose thereof, wherein trimethylammonium xanthone-4-acetate is 2,5,6-trimethylammonium xanthone-4-acetate, 5,6,7-trimethylammonium xanthone-4-acetate or 5,6,8-trimethylammonium xanthone-4-acetate.
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| CN101914084B (en) * | 2010-07-30 | 2012-10-17 | 中国人民解放军第二军医大学 | Derivative of diphenylpyrone nitrogen heterocyclic ring as well as preparation method and application thereof |
| CN104918611A (en) * | 2012-11-14 | 2015-09-16 | 百奥马克科技有限公司 | Spermidine/spermine n1-acetyltransferase substrates as anti-cancer drug compounds |
| CN104610276B (en) * | 2014-11-06 | 2016-08-17 | 浙江工业大学 | Benzo [k, l] thioxanthene-3,4-dicarboxylic acid anhydride analog derivative-uridnine conjugate and its preparation method and application |
| CN105997963B (en) * | 2016-06-15 | 2018-07-13 | 中南大学湘雅医院 | Application of isoproterenol and pharmaceutically acceptable salt thereof in preparation of antitumor drugs |
| CN110139852A (en) | 2016-11-04 | 2019-08-16 | 奥克兰联合服务有限公司 | Tricyclic heterocyclic derivatives and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1708296A (en) * | 2001-09-03 | 2005-12-14 | 癌症研究科技有限公司 | Combinations of anti-cancer agents |
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| CN1708296A (en) * | 2001-09-03 | 2005-12-14 | 癌症研究科技有限公司 | Combinations of anti-cancer agents |
Non-Patent Citations (2)
| Title |
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| 黄朝辉 等.呫吨酮类化合物及其药理活性.国外医药.植物药分册18 3.2003,18(3),93-100. |
| 黄朝辉等.呫吨酮类化合物及其药理活性.国外医药.植物药分册18 3.2003,18(3),93-100. * |
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Application publication date: 20081008 Assignee: WUHAN WUYAO PHARMACEUTICAL Co.,Ltd. Assignor: Grand Pharma (China) Co.,Ltd. Contract record no.: 2012420000120 Denomination of invention: Medicinal composition of trimethyl xanthone-4-acetic acid for treating cancer and use thereof Granted publication date: 20101110 License type: Exclusive License Record date: 20120913 |
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Address after: 430035 in Qiaokou District of Hubei city of Wuhan province Gutian Road No. 5 Patentee after: GRAND PHARMA (CHINA) CO.,LTD. Address before: 430035 in Qiaokou District of Hubei city of Wuhan province Gutian Road No. 5 Patentee before: Grand Pharma (China) Co.,Ltd. |
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