CN1718184A - Neo-garcinolic acid composition having anti-neoplastic activity, prepn. method and use thereof - Google Patents
Neo-garcinolic acid composition having anti-neoplastic activity, prepn. method and use thereof Download PDFInfo
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Abstract
An antineoplastic neomorellic acid composition composed of the neomorellic acid and alkaline antiviral drug or antineoplastic drug, its products, its preparing process and its application in treating lung cancer, liver cancer, intestinal cancer, etc are disclosed.
Description
Technical field
The present invention relates to novel be the compound of main active with the neogambogic acid and be the preparation of drug combination and the preparation thereof of active component with this compound complex, and the application of this pharmaceutical composition in the various tumors of treatment.
Background technology
Resina garciniae is the excretory dry resin of Guttiferae plant gamboge tree, and is cold in nature, sour in the mouth, suffering, puckery, poisonous.Resina garciniae is recorded by American Pharmacopeia, and its active component is mainly gamlogic acid and neogambogic acid.Lu Gui Bao in 1984 etc. separate from Gamboge first and obtain another kind of new acid ingredient, and with its called after neogambogic acid (Neogambogic acid).Research work to neogambogic acid deepens constantly later on.Qu Baoxi etc. show that by experiment neogambogic acid is to S
180, ARS ehrlich ascites carcinoma, Lewis lung cancer, leukemia P
388, solid carcinoma such as adenocarcinoma of lung all has good inhibitory effect, and the effect of certain selectivity metastasis arranged, toxicity test shows that also neogambogic acid has the characteristics lower than gamlogic acid toxicity.Therefore it is compared with cancer therapy drug commonly used in the market as antitumor drug and have peculiar advantage.
In the existing patented technology, publication number CN1309125A (application number 01108049.3), the main preparation method that proposes to contain N organic base, aminoacid formation complex of the patent of China Medicine University " complex of gambogic acid compounds with anticancer activity and preparation method thereof " with gambogic acid compounds and metal ion, C1-C8.People such as Jin Biao have proposed gambogic acid compounds (containing neogambogic acid), and (application number: 02124510.X discloses day on January 15th, 2003 with containing formation salt compounds such as N organic base such as procaine, lauryl amine, meglumine, glucosamine and preparation method thereof; Publication number: CN 1470516A, application number: 02126647.6; Publication number: CN 1498889A, application number: 021148321.3).The patent of Wang Shulong proposes the neogambogic acid series derivates mainly with resin, amides compound (application number: 200410033298.2, open day on January 12nd, 2005).Though above patent has solved the water solublity problem of neogambogic acid, its stability and effectiveness a bit deficient in.Neogambogic acid complex involved in the present invention has not only solved water miscible problem, and its antitumor action obviously strengthened after neogambogic acid and antineoplastic agent, antiviral agents with alkalescence formed complex.
Summary of the invention
Technical problem to be solved by this invention is at the deficiencies in the prior art, what proposed a class novelty forms the preparation method and the various drug combination preparation thereof of medicinal composites with neogambogic acid chemical compound and antineoplastic agent, antiviral agents with alkalescence, and such pharmaceutical preparation can be used for all kinds of tumor treatment.
Technical problem to be solved by this invention is achieved through the following technical solutions.
Neogambogic acid complex with anti-tumor activity is characterized in that having the medicinal composites of the neogambogic acid compounds of following general formula:
B represents to have antiviral agents, antitumoral compounds medicine monomer or other alkali compounds of alkalescence in the formula.
Described neogambogic acid complex is characterized in that B represents Moroxydine, amantadine, cytosine arabinoside, matrine or camptothecine series, vincristine series.
The preparation method of neogambogic acid complex is characterized in that: neogambogic acid and antiviral agents, antitumoral compounds medicine monomer or other alkali compounds with alkalescence react in organic solvents such as water and/or alcohol with 1: 0.5～2.0 molar ratio.
The preparation method of described neogambogic acid complex is characterized in that: neogambogic acid is with 1: 0.5～2.0 molar ratio, with Moroxydine or amantadine or cytosine arabinoside or matrine or camptothecine series or vincristine serial reaction.
Described drug combination preparation with neogambogic acid complex of anti-tumor activity, it is characterized in that, to be the neogambogic acid complex mix the drug combination preparation that forms with other at acceptable pharmaceutical carrier pharmaceutically for it, and its dosage form is a said following dosage form on the pharmaceutics: comprise tablet, capsule, soft capsule, microcapsule, spray, gel, the gel inhalant, oral liquid, suspensoid, electuary, patch, ointment, pill, powder, cataplasma, injection, infusion solution, freeze dried injection, lipidosome injection, the target administration injection, suppository, slow, controlled release preparation.
Described drug combination preparation is characterized in that, it is the tablet form or the capsule of the complex that forms of neogambogic acid and tool alkalescence antiviral agents, antitumoral compounds medicine monomer and filler, disintegrating agent assembly; Or the slow releasing tablet or the capsule of the medicinal composites that forms of the antiviral agents of neogambogic acid and neogambogic acid and tool alkalescence, antitumoral compounds medicine monomer and filler, hypromellose K4M assembly; Or the neogambogic acid complex is scattered in and obtains neogambogic acid complex soft capsule in the oil phase; Or the injection of neogambogic acid complex and solubilizing agent or cosolvent formation; Or the lyophilizing powder ampoule agent for injection of neogambogic acid complex formation; Or the neogambogic acid complex is scattered in the injectable emulsion that obtains in the oil phase, or suspension type injection, described suspension type injection be with neogambogic acid complex micropowder and polyoxyethylene sorbitan monoleate mix grind after, be dissolved into the aqueous solution of phosphoric acid potassium dihydrogen, sodium dihydrogen phosphate, Nipagin ester and sodium carboxymethyl cellulose, make through grinding.
Described drug combination preparation is characterized in that, described filler is sucrose, lactose, microcrystalline Cellulose, dextrin, starch or calcium phosphate; Described disintegrating agent is hyprolose, carboxymethyl starch sodium, polyvinylpolypyrrolidone or cross-linking sodium carboxymethyl cellulose; Described oil phase is soybean oil, PEG400, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum Sesami, Semen Maydis oil or olive oil; In described oil phase, can add solubilizing agent or cosolvent and antioxidant.
Described drug combination preparation is characterized in that, described solubilizing agent is polyoxyethylene ether Oleum Ricini, tween, pluronic; Described cosolvent is arginine, lysine, aminoacids complex (arginine+lysine), ornithine, histidine, tryptophan, removes acetyl chitosan, Na
2HPO
4Meglumine, diethylamine, triethylamine, carbamide, glucosamine, nicotiamide, proline, citric acid and sodium salt thereof.
The described application of neogambogic acid complex in tumors such as treatment hepatocarcinoma, intestinal cancer, pulmonary carcinoma, gastric cancer, breast carcinoma, ovarian cancer, leukemia with anti-tumor activity.
The described application of drug combination preparation in tumors such as treatment hepatocarcinoma, intestinal cancer, pulmonary carcinoma, gastric cancer, breast carcinoma, ovarian cancer, leukemia with neogambogic acid complex of anti-tumor activity.
The inventor thinks, because of the neogambogic acid poorly water-soluble, therefore its research mainly is to solve water solublity.But with regard to medicine, the water solublity that solves medicine is not unique approach.Improve its water solublity, stability and the key that is only modern new drug development safe and effective for medication.The present invention was with new Resina garciniae class salt or complex were different in the past, it adopts neogambogic acid and antitumor drug, antiviral agents or the alkaline matter formation complex favourable to activity, not only its anti-tumor activity reaches the complex of gambogic acid compounds in the past (especially with neogambogic acid Moroxydine complex no less than gambogic acid compounds, neogambogic acid amantadine complex, neogambogic acid camptothecine complex is for outstanding), and in the white mice body, show in the inhibition test, it has better tumour inhibiting rate and survival rate, the white mice toxicity test finds that its zest is little simultaneously, toxicity is low, has the excellent drug developmental research to be worth.
Technical problem to be solved by this invention can also further realize by following technical scheme.Except above neogambogic acid complex with anti-tumor activity is provided, also provides at acceptable pharmaceutical carrier pharmaceutically and mixed the drug combination preparation that forms.Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field, for example: diluent, excipient and water etc., filler such as starch, sucrose, lactose, microcrystalline Cellulose etc.; Binding agent such as cellulose derivative, alginate, gelatin, agar and polyvinylpyrrolidone; Wetting agent such as tween, glycerol; Disintegrating agent such as carboxymethyl starch sodium, hyprolose, cross-linked carboxymethyl cellulose, agar, calcium carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Surfactant such as hexadecanol, sodium lauryl sulphate; Absorb carrier such as Kaolin and soap clay; Lubricant such as Pulvis Talci, magnesium stearate and calcium, micropowder silica gel and Polyethylene Glycol etc.; Flavouring agent, sweeting agent etc.
Technical problem to be solved by this invention can also further realize by following technical scheme.The above drug combination preparation is characterized in, described pharmaceutical composition can be used for treating hepatocarcinoma, pulmonary carcinoma, intestinal cancer and other tumors.
It is 0.1～99.5% the compound active component of neogambogic acid that Pharmaceutical composition of the present invention preferably contains weight ratio, most preferably contains weight ratio and be the active component of 0.5～97% neogambogic acid complex.
Complex provided by the invention and Pharmaceutical composition can be according to variations such as the type of route of administration, patient age, body weight, body surface area, sex, the disease for the treatment of and the orders of severity, and its daily dose can be 0.01～100mg/m
2Body surface area is preferably 0.1～100mg/m
2Body surface area.Can use by one or many.
The specific embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment 1
The preparation of neogambogic acid Moroxydine complex
Get neogambogic acid 10 grams and put in the appropriate vessel, add water, add Moroxydine 2.5 grams and stir evenly to dissolving, taking out under the reduced pressure anhydrates obtains light yellow solid 12 grams.
Embodiment 2
The preparation of neogambogic acid amantadine complex
Get neogambogic acid 10 grams and put in the appropriate vessel, add water, add amantadine 2.5 grams and stir evenly to dissolving, taking out under the reduced pressure anhydrates obtains light yellow solid 12 grams.
Embodiment 3
The preparation of neogambogic acid camptothecine complex
Get neogambogic acid 10 grams and put in the appropriate vessel, add water, add camptothecine 2.5 grams and stir evenly to dissolving, taking out under the reduced pressure anhydrates obtains light yellow solid 12 grams.
Embodiment 4
The preparation of neogambogic acid vincristine complex
Get neogambogic acid 10 grams and put in the appropriate vessel, add water, add vincristine 2.5 grams and stir evenly to dissolving, taking out under the reduced pressure anhydrates obtains light yellow solid 12 grams.
Embodiment 5
The preparation of neogambogic acid Moroxydine complex injectable powder
Embodiment 1 complex 10 grams
Mannitol 30 grams
Get embodiment 1 complex and put in the appropriate vessel, add the about 1600ml of injection water, add mannitol and stir; add the injection water to 2000ml, with the filtering with microporous membrane of 0.22 μ m, under the aseptic condition; fill in the 10ml cillin bottle, every bottle of 10ml, part fourth rubber stopper beyond the Great Wall; sabot is sent in the freeze drying box, inserts eutectic point and temperature probe; close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed; the product relaxing the bowels with purgatives of warm nature of making falls, and when the product temperature reaches eutectic point (-25 ℃ approximately), continues refrigeration; when the product temperature reached more than-35 ℃, trading halt was cold, the open cold condenser; when condenser temperature reaches-45 ℃; open vacuum system, open and sublime up into drying, the final drying temperature is 35 ℃; shut down; close plug, venting, outlet; Zha Gai gets final product.
Embodiment 6
The preparation of neogambogic acid Moroxydine complex tablet
Embodiment 1 complex 10 grams
Microcrystalline Cellulose 40 grams
Lactose 50 grams
Carboxymethyl starch sodium 6 grams
10% starch slurry is an amount of
Magnesium stearate 1 gram
Get embodiment 1 complex and cross 160 mesh sieves, microcrystalline Cellulose, lactose, carboxymethyl starch sodium is crossed 100 mesh sieves respectively, with complex and above-mentioned adjuvant mix homogeneously, is binding agent system soft material with 10% starch slurry, cross 20 mesh sieve system granules, but wet granular is in 50 ℃ of baking oven forced air dryings; Dried granule is crossed 20 mesh sieve granulate, with magnesium stearate mixing, tabletting.
The preparation of embodiment 7 neogambogic acid Moroxydine composition capsule agent
Embodiment 1 complex 10 grams
Microcrystalline Cellulose 40 grams
Lactose 50 grams
Carboxymethyl starch sodium 6 grams
10% starch slurry is an amount of
Magnesium stearate 1 gram
Micropowder silica gel 1 gram
Get embodiment 1 complex and cross 160 mesh sieves, microcrystalline Cellulose, lactose, carboxymethyl starch sodium is crossed 100 mesh sieves respectively, with complex and above-mentioned adjuvant mix homogeneously, is binding agent system soft material with 10% starch slurry, cross 20 mesh sieve system granules, but wet granular is in 50 ℃ of baking oven forced air dryings; Dried granule is crossed 20 mesh sieve granulate, and with magnesium stearate and micropowder silica gel mixing, fill is in capsule.
The preparation of embodiment 8 neogambogic acid amantadine complex injectable powder
Embodiment 2 complex 10 grams
Mannitol 30 grams
Get embodiment 2 complex and put in the appropriate vessel, add the about 1600ml of injection water, add mannitol and stir; add the injection water to 2000ml, with the filtering with microporous membrane of 0.22 μ m, under the aseptic condition; fill in the 10ml cillin bottle, every bottle of 10ml, part fourth rubber stopper beyond the Great Wall; sabot is sent in the freeze drying box, inserts eutectic point and temperature probe; close chamber door, open freeze dryer, utilize conduction oil that flaggy is freezed; the product relaxing the bowels with purgatives of warm nature of making falls, and when the product temperature reaches eutectic point (-23 ℃ approximately), continues refrigeration; when the product temperature reached more than-35 ℃, trading halt was cold, the open cold condenser; when condenser temperature reaches-45 ℃; open vacuum system, open and sublime up into drying, the final drying temperature is 35 ℃; shut down; close plug, venting, outlet; Zha Gai gets final product.
Embodiment 9 neogambogic acid Moroxydine complex are to the influence of transplanted tumor S180, EC and the Heps solid tumor of mice
The experiment Kunming mouse of body weight 18-22g, inoculate S180 respectively by the transplanted tumor organon, EC and Heps solid tumor, inoculation 4h weighs, each tumor kind is respectively inoculated 50, and is divided into five groups at random, 10 every group, male and female half and half, embodiment 1 complex establish three dosage groups (8,4,2mg/kg), 5-Fu (30mg/kg) group is as positive controls, normal saline group (0.4ml/20g) is as negative control group, the 24h intravenous administration behind the inoculated tumour cell, and per 2 days are once, administration is 4 times altogether, after drug withdrawal, weighed in the 2nd day, put to death mice and also separate the tumor piece, weigh and carry out statistical procedures (t check).Result of study sees Table 1,2,3.
Table 1 embodiment 1 complex iv to the inhibitory action of the transplanted tumor S180 of mice (x ± SD, n=10)
| Group | Dosage (mg/kg) | Body weight (g) | Tumor heavy (g) | Tumour inhibiting rate (%) | |
| Before the administration | After the administration | ||||
| Matched group embodiment 1 complex 5-Fu group | 8 4 2 30 | 19.2±1.09 19.4±1.07 19.6±1.06 19.3±1.17 19.8±1.22 | 26.4±1.53 25.6±1.32 25.8±1.18 25.3±1.03 22.3±1.53 ** | 2.29±0.36 1.09±0.35 ** 1.32±0.33 ** 1.55±0.30 ** 0.71±0.29 ** | 52.4 42.4 32.3 69.0 |
*P＜0.01 is compared with the normal saline matched group
Table 2 embodiment 1 complex iv is to the inhibitory action of the transplanted tumor EC of mice
( x±SD，n＝10)
| Group | Dosage | Body weight (g) | Tumor heavy (g) | Tumour inhibiting rate |
| (mg/kg) | Before the administration | After the administration | (％) | ||
| Matched group embodiment 1 complex 5-Fu group | 8 4 2 30 | 20.2±1.19 20.4±1.27 20.6±1.16 20.3±1.27 20.8±1.23 | 26.9±1.43 25.5±1.22 25.3±1.17 25.3±1.23 22.4±1.43 ** | 2.52±0.38 1.29±0.31 ** 1.42±0.23 ** 1.62±0.20 ** 0.75±0.30 ** | 48.8 43.6 35.7 70.2 |
*P＜0.01 is compared with the normal saline matched group
Table 3 embodiment 1 complex iv to the inhibitory action of the transplanted tumor Heps of mice (x ± SD, n=10)
| Group | Dosage (mg/kg) | Body weight (g) | Tumor heavy (g) | Tumour inhibiting rate (%) | |
| Before the administration | After the administration | ||||
| Matched group embodiment 1 complex 5-Fu group | 8 4 2 30 | 19.6±1.18 19.8±1.13 19.7±1.05 19.9±1.29 19.8±1.24 | 26.2±1.20 25.9±1.25 25.8±1.00 25.2±1.33 22.1±1.13 ** | 2.32±0.37 0.88±0.30 ** 1.15±0.13 ** 1.32±0.10 ** 0.78±0.18 ** | 62.1 50.4 43.1 66.4 |
*P＜0.01 is compared with the normal saline matched group
The result shows: compare the tumor growth effect that iv injection embodiment 1 complex can suppress transplanted tumor S180, EC and the Heps solid tumor of mice significantly with the blank group, and the body weight gain of mice is not had obvious influence.And the 5-Fu group has the body weight growth effect that has a strong impact on mice.Iv injection embodiment 1 complex is the strongest to the inhibitory action of mice transplanted tumor Heps.
Embodiment 10 neogambogic acid Moroxydine complex are to the life prolongation effect of the transplanted tumor of mice
(I) embodiment 1 complex ip is to the life prolongation effect of the transplantability Heps ascites tumor of mice
Get and inoculate the Heps mice,, weigh, be divided into 5 groups at random in postvaccinal first day, every group 10, male and female half and half are established three dosage groups (1.5 of embodiment 1 complex, 0.75 0.5mg/kg), 5-Fu (30mg/kg) organizes as positive controls and blank group.Administration behind the inoculation 24h, lumbar injection, per 2 days are once, and administration is 4 times altogether, and write down dead Mus number and calculate survival natural law (mice of survival above 60 days was by 60 days) and survival rate (survival is more than 60 days, and asymptomatic mice) every day after reaching drug withdrawal during the administration.The gained data are carried out statistical procedures.Result of study sees Table 4.
Experimental result shows, compares with the blank group, and three dosage groups of embodiment 1 complex and 5-Fu group all have highly significant to prolong the survival natural law effect (P＜0.01) of Heps mice.The survival natural law that embodiment 1 complex high dose (1.5mg/kg) prolongs the Heps mice is better than 5-Fu (30mg/kg).
Table 4 embodiment 1 complex ip to the life prolongation effect of the transplantability Heps ascites tumor of mice (x ± SD, n=10)
| Group | Mus number (only) | Dosage (mg/kg) | The survival natural law | Increase in life span (%) | Survival rate (%) |
| Matched group embodiment 1 complex 5-Fu group | 10 10 10 10 10 | 1.5 0.75 0.50 30 | 10.5±2.65 39.8±15.8 **# 25.1±5.98 ** 17.2±3.12 ** 28.3±7.98 ** | 279.0 139.0 63.8 169.5 | 20 0 0 0 |
*P＜0.01 is compared with the blank group; #P＜0.05 is compared with 5-Fu group group
(II) embodiment 1 complex ip is to the life prolongation effect of ascitic type mice transplantability S180 ascites tumor and Emhorn EAC ascites tumor
Get the mice of inoculated tumour cell,, weigh, be divided into 5 groups at random in postvaccinal first day, every group 10, male and female half and half are established three dosage groups (1.5 of embodiment 1 complex, 0.75 0.5mg/kg), 5-Fu (30mg/kg) organizes as positive controls and blank group.Administration behind the inoculation 24h, lumbar injection, per 2 days are once, and administration is 4 times altogether, and write down dead Mus number and calculate survival natural law (mice of survival above 60 days was by 60 days) and survival rate (survival is more than 60 days, and asymptomatic mice) every day after reaching drug withdrawal during the administration.The gained data are carried out statistical procedures.Result of study sees Table 5,6.
Table 5 embodiment 1 complex ip is to S180 ascites tumor mice life prolongation effect
( x±SD，n＝10)
| Group | Mus number (only) | Dosage (mg/kg) | The survival natural law | Increase in life span (%) | Survival rate (%) |
| Matched group embodiment 1 complex 5-Fu group | 10 10 10 10 10 | 1.5 0.75 0.50 30 | 10.3±0.65 29.8±16.8 ** 20.1±5.48 ** 13.2±4.72 * 29.3±7.98 ** | 189.3 95.1 28.2 184.5 | 0 0 0 0 |
*P＜0.05,
*P＜0.01 is compared with the blank group
Table 6 embodiment 1 complex ip to Emhorn EAC ascites tumor mice life prolongation effect (x ± SD, n=10)
| Group | Mus number (only) | Dosage (mg/kg) | The survival natural law | Increase in life span (%) | Survival rate (%) |
| Matched group embodiment 1 complex 5-Fu group | 10 10 10 10 10 | 1.5 0.75 0.50 30 | 11.3±1.65 34.8±11.8 ** 24.1±9.48 ** 16.2±6.72 ** 33.3±9.98 ** | 208.0 113.3 43.4 195.7 | 0 0 0 0 |
*P＜0.01 is compared with the blank group
Embodiment 11 neogambogic acid Moroxydine complex are to the influence of leukocyte count in the mice blood
Embodiment 1 complex iv is to the inhibitory action of the transplanted tumor Heps of mice and to the influence of leukocyte count in the peripheral blood
50 of the Kunming mouses of experiment usefulness body weight 18-22g, press transplanted tumor organon inoculation Heps solid tumor, inoculation 24h weighs, and is divided into five groups at random, 10 every group, male and female half and half, embodiment 1 complex establish three dosage groups (8,4,2mg/kg), 5-Fu (30mg/kg) group is as positive controls, the normal saline group is as negative control group, the 24h intravenous administration behind the inoculated tumour cell, and per 2 days are once, administration is 4 times altogether, put to death dissection on the 3rd day after drug withdrawal, above mice is weighed before execution and gets blood from the eye socket vein, the microscopy total white blood cells, anatomical isolation tumor piece is simultaneously weighed and is carried out statistical procedures (t check).Result of study sees Table 7.
Table 7 embodiment 1 complex iv to the inhibitory action of mice transplanted tumor Heps and to the influence of leukocyte count in the peripheral blood (x ± SD, n=10)
| Group | Dosage mg/kg | Body weight (g) | Wbc (10 9/L) | Tumor heavy (g) | Tumour inhibiting rate (%) | |
| Before the administration | After the administration | |||||
| Matched group embodiment 1 complex 5-Fu group | 8 4 2 30 | 20.2±1.19 19.8±1.37 19.6±1.16 19.5±1.21 19.8±1.42 | 26.7±1.55 25.7±1.12 25.3±1.04 25.9±1.33 22.1±1.63 ** | 11.80±3.36 11.83±3.35 11.92±2.33 11.25±2.30 3.71±0.29 ** | 2.25±0.35 0.82±0.22 ** 1.15±0.27 ** 1.62±0.37 ** 0.69±0.24 ** | 65.0 48.9 28.0 69.3 |
*P＜0.01 is compared with the normal saline matched group
The result shows: compare with the normal saline matched group, embodiment 1 complex is established three dosage groups (8,4,2mg/kg) and 5-Fu group all have and suppress mice Heps tumor growth effect (P＜0.01) very significantly, 5-Fu has and suppresses weight of mice and reduce leukocyte effect in the mice peripheral blood (P＜0.01) significantly significantly, but embodiment 1 complex does not have obvious influence to leukocyte count in weight of mice and the mice peripheral blood in effective dosage ranges.
The pharmacological evaluation of neogambogic acid amantadine complex, neogambogic acid camptothecine complex, neogambogic acid vincristine complex also has the effect of above-mentioned experiment.
Claims (10)
1. the neogambogic acid complex that has anti-tumor activity is characterized in that having the medicinal composites of the neogambogic acid compounds of following general formula:
B represents to have antiviral agents, antitumoral compounds medicine monomer or other alkali compounds of alkalescence in the formula.
2. neogambogic acid complex as claimed in claim 1 is characterized in that B represents Moroxydine, amantadine, cytosine arabinoside, matrine or camptothecine series, vincristine series.
3. the preparation method of neogambogic acid complex is characterized in that: neogambogic acid and antiviral agents, antitumoral compounds medicine monomer or other alkali compounds with alkalescence react in organic solvents such as water and/or alcohol with 1: 0.5～2.0 molar ratio.
4. according to the preparation method of the described neogambogic acid complex of claim 3, it is characterized in that: neogambogic acid is with 1: 0.5～2.0 molar ratio, with Moroxydine or amantadine or cytosine arabinoside or matrine or camptothecine series or vincristine serial reaction.
5. the drug combination preparation with neogambogic acid complex of anti-tumor activity according to claim 1, it is characterized in that, to be the neogambogic acid complex mix the drug combination preparation that forms with other at acceptable pharmaceutical carrier pharmaceutically for it, and its dosage form is a said following dosage form on the pharmaceutics: comprise tablet, capsule, soft capsule, microcapsule, spray, gel, the gel inhalant, oral liquid, suspensoid, electuary, patch, ointment, pill, powder, cataplasma, injection, infusion solution, freeze dried injection, lipidosome injection, the target administration injection, suppository, slow, controlled release preparation.
6. drug combination preparation according to claim 5 is characterized in that, it is the tablet form or the capsule of the complex that forms of neogambogic acid and tool alkalescence antiviral agents, antitumoral compounds medicine monomer and filler, disintegrating agent assembly; Or the slow releasing tablet or the capsule of the medicinal composites that forms of the antiviral agents of neogambogic acid and neogambogic acid and tool alkalescence, antitumoral compounds medicine monomer and filler, hypromellose K4M assembly; Or the neogambogic acid complex is scattered in and obtains neogambogic acid complex soft capsule in the oil phase; Or the injection of neogambogic acid complex and solubilizing agent or cosolvent formation; Or the lyophilizing powder ampoule agent for injection of neogambogic acid complex formation; Or the neogambogic acid complex is scattered in the injectable emulsion that obtains in the oil phase, or suspension type injection, described suspension type injection be with neogambogic acid complex micropowder and polyoxyethylene sorbitan monoleate mix grind after, be dissolved into the aqueous solution of phosphoric acid potassium dihydrogen, sodium dihydrogen phosphate, Nipagin ester and sodium carboxymethyl cellulose, make through grinding.
7. drug combination preparation according to claim 6 is characterized in that, described filler is sucrose, lactose, microcrystalline Cellulose, dextrin, starch or calcium phosphate; Described disintegrating agent is hyprolose, carboxymethyl starch sodium, polyvinylpolypyrrolidone or cross-linking sodium carboxymethyl cellulose; Described oil phase is soybean oil, PEG400, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum Sesami, Semen Maydis oil or olive oil; In described oil phase, can add solubilizing agent or cosolvent and antioxidant.
8. according to right 6 or 7 described drug combination preparations, it is characterized in that described solubilizing agent is polyoxyethylene ether Oleum Ricini, tween, pluronic; Described cosolvent is arginine, lysine, aminoacids complex (arginine+lysine), ornithine, histidine, tryptophan, removes acetyl chitosan, Na
2HPO
4Meglumine, diethylamine, triethylamine, carbamide, glucosamine, nicotiamide, proline, citric acid and sodium salt thereof.
9. claim 1 or the 2 described application of neogambogic acid complex in tumors such as treatment hepatocarcinoma, intestinal cancer, pulmonary carcinoma, gastric cancer, breast carcinoma, ovarian cancer, leukemia with anti-tumor activity.
10. the described application of drug combination preparation in tumors such as treatment hepatocarcinoma, intestinal cancer, pulmonary carcinoma, gastric cancer, breast carcinoma, ovarian cancer, leukemia of claim 5-8 with neogambogic acid complex of anti-tumor activity.
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| CN (1) | CN1718184A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101947204A (en) * | 2010-07-21 | 2011-01-19 | 彭代银 | Neo-gambogic acid SLN (solid lipid nanoparticle) and preparation method thereof |
| WO2013107189A1 (en) | 2012-01-18 | 2013-07-25 | 上海交通大学医学院附属第九人民医院 | Gambogenic acid derivatives, preparation method and application thereof |
-
2005
- 2005-04-22 CN CN 200510039060 patent/CN1718184A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101947204A (en) * | 2010-07-21 | 2011-01-19 | 彭代银 | Neo-gambogic acid SLN (solid lipid nanoparticle) and preparation method thereof |
| CN101947204B (en) * | 2010-07-21 | 2013-01-02 | 彭代银 | Neo-gambogic acid SLN (solid lipid nanoparticle) and preparation method thereof |
| WO2013107189A1 (en) | 2012-01-18 | 2013-07-25 | 上海交通大学医学院附属第九人民医院 | Gambogenic acid derivatives, preparation method and application thereof |
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