CN101278929B - Method for preparing medicament containing gambogic acid compounds and clathrate of gambogic acid compounds - Google Patents
Method for preparing medicament containing gambogic acid compounds and clathrate of gambogic acid compounds Download PDFInfo
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- CN101278929B CN101278929B CN2007100207882A CN200710020788A CN101278929B CN 101278929 B CN101278929 B CN 101278929B CN 2007100207882 A CN2007100207882 A CN 2007100207882A CN 200710020788 A CN200710020788 A CN 200710020788A CN 101278929 B CN101278929 B CN 101278929B
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- acid compounds
- gambogic acid
- cyclodextrin
- clathrate
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Abstract
The invention discloses a drug containing gambogic acid compound and a preparation method of inclusion compound containing the gambogic acid compound. Cyclodextrin and derivative inclusion compound of the gambogic acid compound of the invention is the cyclodextrin and derivative inclusion compound of various effective components with biological activity in traditional Chinese medicine-gamboge. The preparation mainly contains powder and injection preparation, freeze-dry powder and injection preparation, troche (plain tablet, coating tablet, delayed release tablet and controlled release tablet), capsule, microcapsule, emulsion, micro emulsion and lipid body, etc. The inclusion compound containing the gambogic acid compound is added into the drug by the invention, thereby reducing toxicity and irritation of the drug, strengthening water-solubility, stability, security, etc. and having important theoretical and utility value for the gambogic acid compound in clinical application.
Description
Technical field
The invention belongs to a kind of pharmaceutical preparation, tool is the preparation method of the clathrate of a kind of medicine that contains gambogic acid compounds and gambogic acid compounds entirely.
Background technology
Resina garciniae is the excretory dry resin of Guttiferae plant gamboge tree (Garcinia hanbaryi Hook.f.), and by American Pharmacopeia is recorded, its active component is mainly gambogic acid compounds such as gamlogic acid, neogambogic acid, allogambogic acid (sieve's Ah acid).They have antitumor action mostly, and are all effective for pulmonary carcinoma, hepatocarcinoma, intestinal cancer, ovarian cancer, leukemia etc.Found through experiments neogambogic acid to S as Qu Baoxi etc.
180, solid carcinoma such as ARS ehrlich ascites carcinoma, Lewis lung cancer, leukemia has good inhibitory effect.Gamlogic acid shows stronger anti-tumor activity to kinds of tumors, and toxic and side effects is smaller in effective dosage ranges, inhibition to tumor cell has very high selectivity, kill cancer cell optionally, and to intact animal's hemopoietic system and not influence of immunologic function, this is that present tumor chemotherapeutic drug is not available.Pharmacokinetic also shows that gamlogic acid has higher distribution and long persistent period in tumor tissues.Gamlogic acid is the broad-spectrum anti-tumor medicine, and kinds of tumors is had significant curative effect, and is especially preferable to the curative effect of digestive system tumor.
Gambogic acid compounds is a liposoluble constituent, be insoluble in water, general chemical method or the adding solubilizing agent improvement water solublity of adopting, as the Chinese patent 02124510.x (complex of gambogic acid compounds, its preparation method and be the pharmaceutical composition of active ingredient with this complex, (02128822.4 total Gambogic acid preparation and its preparation method), 02148321.3 (the salt of gambogic acid compounds, its preparation method and be the pharmaceutical composition of active component with this salt), (03131511.9 the drug combination preparation of gamlogic acid and gamlogic acid complex), 200610037904.7 (polyethylene glycol prodrug of gambogicacid, its preparation method, preparation and purposes).Though these methods have solved water miscible problem, can't overcome weakness such as its zest is big, unstable chemcial property, haemolysis, limited the application of gambogic acid compounds.
By retrieving other documents and patent both at home and abroad, find no the pass gambogic acid compounds and adopt cyclodextrin derivative that it is carried out the patent and the document of enclose.
Summary of the invention
The technical issues that need to address of the present invention are the preparation methoies that disclose the clathrate of a kind of medicine that contains gambogic acid compounds and gambogic acid compounds, make that the application of gambogic acid compounds is safer, and patient's human body is not had zest.
Technical scheme of the present invention:
A kind of medicine that contains gambogic acid compounds, it is characterized in that wherein containing the clathrate of the gambogic acid compounds for the treatment of effective dose, described gambogic acid compounds is meant by the total cambogic acid that extracts in the Resina garciniae, gamlogic acid, neogambogic acid, allogambogic acid, morellin etc. to have one or more mixture in the acidic materials of active component.
The clathrate of described gambogic acid compounds is meant the cyclodextrin of gambogic acid compounds and/or the clathrate of cyclodextrin derivative.Described clathrate does not contain water of crystallization or contains one or more water of crystallization.
The above-mentioned medicine that contains gambogic acid compounds is characterized in that its preparation formulation is: aqueous solution, powder pin, lyophilized injectable powder, tablet, plain sheet, coated tablet, slow, controlled release tablet, capsule, liposome, granule, soft gelatin capsule, suppository, ointment or suck powder.
In the cyclodextrin of described gambogic acid compounds and/or the clathrate of cyclodextrin derivative, the mol ratio of gambogic acid compounds and cyclodextrin or derivant is 1:1～100.
Cyclodextrin derivative comprises one or more in the alpha-cyclodextrin derivant, beta-cyclodextrin derivative, gamma-cyclodextrin derivant of various replacements.
Cyclodextrin derivative is the derivant of already used beta-schardinger dextrin-in the various pharmaceuticss such as HP-, G 1-CD, G 2-CD, 2G1-, G 3-, sulfobutyl ether-beta-cyclodextrin.
The preparation method that contains the clathrate of the gambogic acid compounds in the medicine of gambogic acid compounds, it is characterized in that comprising the steps: the gambogic acid compounds input is contained in the aqueous solution or organic solvent of cyclodextrin and/or cyclodextrin derivative, ultrasonic backflow 1～3 hour to medicine dissolves fully under heating or the room temperature, vacuum volatilizes organic solvent or frozen drying is flung to moisture under heating condition, promptly gets the clathrate of gambogic acid compounds.
Said organic solvent includes but not limited to: the mixture of one or more in methanol, ethanol, petroleum ether, acetone, acetonitrile, n-butyl alcohol, isopropyl alcohol, the tert-butyl alcohol, the oxolane.
The mol ratio of described gambogic acid compounds and cyclodextrin or derivant is 1:1～100, and cyclodextrin derivative is the derivant of already used beta-schardinger dextrin-in the various pharmaceuticss such as HP-, G 1-CD, G 2-CD, 2G1-, G 3-, sulfobutyl ether-beta cyclodextrin.
Said cyclodextrin derivative comprises alpha-cyclodextrin derivant, beta-cyclodextrin derivative, the gamma-cyclodextrin derivant of various substitution values.Most convenient is used, and optimally is chosen as in HP-, G 1-CD, G 2-CD, 2G1-, G 3-, the sulfobutyl ether-beta-cyclodextrin one or more.
The gambogic acid compounds input is contained in the aqueous solution or organic solvent of cyclodextrin, reflux 1～3 hour is dissolved fully to medicine, and vacuum volatilizes organic solvent under heating condition, promptly gets clathrate.
Clathrate of the present invention also can adopt additive method preparation, as supercritical ultrasonics technology, be about to above-mentioned contain gambogic acid compounds solution and be added to cyclodextrin derivative solution after, place supersonic generator, in ultrasonic washing unit, vibrating machine etc., carry out sonic oscillation, can obtain clathrate.Or the employing polishing, be about to gambogic acid compounds solution and add in the cyclodextrin derivative, add an amount of water and grind well, cold drying obtains clathrate.Perhaps use the clathrate that additive method prepares gambogic acid compounds.
Medicine of the present invention can be used for treatment of diseases such as pulmonary carcinoma, hepatocarcinoma, intestinal cancer, ovarian cancer.Its dosage (by the object medicine) is identical with the method for the gambogic acid compounds of routine with using method.The preparation method of the clathrate of gambogic acid compounds of the present invention is compared with the similar technology in existing field, shortened the time (shortening to 3 hours) of preparation clathrate greatly from 3 days, this inclusion technique has quite high practical value, the enclose that can be used for gambogic acid compounds also can be used for the enclose of other drug.
The specific embodiment
Embodiment 1
1 gram total cambogic acid and number gram HP-(or number gram sulfobutyl ether group-beta-cyclodextrin) are mixed with the 1000ml dehydrated alcohol, all dissolve, be evaporated to constant weight, obtain clathrate in 60 ℃ of reflux 3 hours to medicine.
Embodiment 2
1 gram gamlogic acid and number gram HP-(or number gram sulfobutyl ether group-beta-cyclodextrin) are mixed with the 1000ml dehydrated alcohol, all dissolve, be evaporated to constant weight, obtain clathrate in 60 ℃ of reflux 3 hours to medicine.
Embodiment 3
1 gram allogambogic acid and number gram HP-(or number gram sulfobutyl ether base beta-schardinger dextrin-) are mixed with the 1000ml dehydrated alcohol, all dissolve, be evaporated to constant weight, obtain clathrate in 60 ℃ of reflux 3 hours to medicine.
Embodiment 4
1 gram morellin and number gram HP-(or number gram sulfobutyl ether group-beta-cyclodextrin) are mixed with the 1000ml dehydrated alcohol, all dissolve, be evaporated to constant weight, obtain clathrate in 60 ℃ of reflux 3 hours to medicine.
Embodiment 5
Get gamlogic acid 30mg, add a small amount of anhydrous alcohol solution; Other gets PEG1500 3ml, anhydrous alcohol solution, and HP-and the 10ml water dissolution of adding 3g are put in 30 ℃ of waters bath with thermostatic control, inject gamlogic acid solution, stir 2h, put-60 ℃ of following pre-freezes, and vacuum drying obtains clathrate.
Embodiment 6
Get neogambogic acid 30mg, add a small amount of anhydrous alcohol solution; Other gets PEG1500 4ml, anhydrous alcohol solution, and HP-and the 10ml water dissolution of adding 4g are put in 30 ℃ of waters bath with thermostatic control, inject neogambogic acid solution, stir 3h, put-60 ℃ of following pre-freezes, and vacuum drying obtains clathrate.
Embodiment 7
Get allogambogic acid 30mg, add a small amount of anhydrous alcohol solution; Other gets PEG1500 5ml, anhydrous alcohol solution, and HP-and the 12ml water dissolution of adding 4g are put in 30 ℃ of waters bath with thermostatic control, inject allogambogic acid solution, stir 3h, put-60 ℃ of following pre-freezes, and vacuum drying obtains clathrate.
Embodiment 8
Get other morellin 30mg, add a small amount of anhydrous alcohol solution; Other gets PEG1500 4ml, anhydrous alcohol solution, and HP-and the 12ml water dissolution of adding 3g are put in 30 ℃ of waters bath with thermostatic control, inject morellin solution, stir 2h, put-60 ℃ of following pre-freezes, and vacuum drying obtains clathrate.
Embodiment 9
The zest of gamlogic acid and gamlogic acid clathrate, acute toxicity testing research.
Acute toxicity test:
1. material:
1.1 be subjected to the reagent product: gamlogic acid injection, gamlogic acid clathrate injection, 5mg/ props up, self-control, purity 95% is with before adding the injection dilute with water.
The white mice 1.2 animal grows up: the Kunming kind, male and female half and half are divided into six groups (body weight in the group between white mice differs as far as possible little), 8 every group by body weight.Adapt to a week at Animal House, test last night and stop eating, do not cut off the water.
2. tail intravenously administrable
Accurate each white mice body weight of weighing, the medicinal liquid that is configured to an amount of volume with 10mg/kg gives not the medicinal liquid of white mice various dose on the same group, performs labelling, the record administration time.1 week back observe white mice motion, look for food and have or not the acute poisoning symptom.
The blood vessel irritation test
1. material
1.1 be subjected to the reagent product: gamlogic acid injection, gamlogic acid clathrate injection, 10mg/ props up, self-control, purity 95% is with before adding the injection dilute with water.
1.2 2 of animal health rabbit (New Zealand's kind).Provide by experimental center, this school.
2. experimental technique
Get 6 of healthy rabbits, be divided into 3 groups at random, the left ear gamlogic acid injection 10mg/60ml that instils respectively, 2h drips off.Auris dextra instils with the normal saline of volume.Get blood vessel and the heart, liver, spleen, lung, pancreas, kidney and the cerebral tissue at 1cm place, injection point lower end after instillation finishes, neutral formalin is fixed, specimens paraffin embedding slices, and histopathologic examination is done in HE dyeing.
Result and discussion
Observe 7d after the The acute toxicity tests administration continuously, white mice is not all taken place to poison or is dead.Cut open main organs such as the inspection perusal heart, liver,spleen,kidney and there is no abnormal phenomena.Gamlogic acid injection group white mice the tail redness occurs, festers; And gamlogic acid clathrate injection group mice is movable normal, and tail is complete, does not have red and swollen, the phenomenon of festering.
To observe rabbit diet, hair, anus, breathing, central nervous system, extremity activity etc. all normal every day after the administration of blood vessel irritation result of the test, no poisoning manifestations.To 48h, the animal rectal mucosa of execution is smooth, no abnormal.All the other are retained animal and observe day by day, and all are normal.The animal of putting to death in the 7th day, Ministry of Public Health " study of tcm new drug " guide is pressed in observation body weight, vascular stimulation classification.The result of the histopathologic examination of rabbit vascular stimulation test is: auricle, epidermis are no abnormal; The corium vascular endothelial cell does not have swelling; That capillary wall does not have is hemorrhage, necrosis or inflammatory cell infiltration; Cartilage layers, chondrocyte do not have hypertrophy or necrosis, the chondrocyte marshalling; Internal organs such as liver, cardiac muscle, brain, lung, kidney, spleen and pancreas are all no abnormal.Gamlogic acid injection group auricle, epidermis occur unusual; The swelling of corium vascular endothelial cell; Capillary wall is hemorrhage, downright bad or inflammatory cell infiltration arranged.Matched group auricle, epidermis are no abnormal; The corium vascular endothelial cell does not have swelling; That capillary wall does not have is hemorrhage, necrosis or inflammatory cell infiltration; Cartilage layers, chondrocyte do not have hypertrophy or necrosis, chondrocyte marshalling, no necrosis or hypertrophy.Gamlogic acid clathrate injection group and matched group no significant difference on histopathology.
Claims (10)
1. medicine that contains gambogic acid compounds, it is characterized in that wherein containing the clathrate of the gambogic acid compounds for the treatment of effective dose, described gambogic acid compounds is meant by the total cambogic acid that extracts in the Resina garciniae, perhaps gamlogic acid, neogambogic acid, allogambogic acid, morellin have one or more the mixture in the acidic materials of active component, and its dosage form is an injectable powder.
2. the medicine that contains gambogic acid compounds according to claim 1 is characterized in that described injectable powder is a lyophilized injectable powder.
3. the medicine that contains gambogic acid compounds according to claim 1 is characterized in that the clathrate of described gambogic acid compounds is meant the cyclodextrin of gambogic acid compounds and/or the clathrate of cyclodextrin derivative.
4. according to claim 1 or the 3 described medicines that contain gambogic acid compounds, it is characterized in that described clathrate does not contain water of crystallization or contains one or more water of crystallization.
5. the medicine that contains gambogic acid compounds according to claim 3, it is characterized in that the mol ratio of gambogic acid compounds and cyclodextrin or derivant is 1: 1～100 in the clathrate of the cyclodextrin of described gambogic acid compounds and/or cyclodextrin derivative.
6. the medicine that contains gambogic acid compounds according to claim 3 is characterized in that, cyclodextrin derivative comprises one or more in the alpha-cyclodextrin derivant, beta-cyclodextrin derivative, gamma-cyclodextrin derivant of various replacements.
7. the medicine that contains gambogic acid compounds according to claim 6, it is characterized in that cyclodextrin derivative is HP-, G 1-CD, G 2-CD, 2G1-, G 3-, sulfobutyl ether-beta-cyclodextrin.
8. the preparation method of the clathrate of the gambogic acid compounds in claim 1, the 3 or 5 described medicines that contain gambogic acid compounds, it is characterized in that comprising the steps: the gambogic acid compounds input is contained in the aqueous solution or organic solvent of cyclodextrin and/or cyclodextrin derivative, ultrasonic backflow 1～3 hour to medicine dissolves fully under heating or the room temperature, vacuum volatilizes organic solvent or frozen drying is flung to moisture under heating condition, promptly gets the clathrate of gambogic acid compounds.
9. the preparation method of the clathrate of gambogic acid compounds according to claim 8 is characterized in that said organic solvent comprises: the mixture of one or more in methanol, ethanol, petroleum ether, acetone, acetonitrile, n-butyl alcohol, isopropyl alcohol, the tert-butyl alcohol, the oxolane.
10. the preparation method of the clathrate of gambogic acid compounds according to claim 8, the mol ratio that it is characterized in that described gambogic acid compounds and cyclodextrin or derivant is 1: 1～100, and cyclodextrin derivative is the derivant of already used beta-schardinger dextrin-in the various pharmaceuticss such as HP-, G 1-CD, G 2-CD, 2G1-, G 3-, sulfobutyl ether-beta-cyclodextrin.
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| CN2007100207882A CN101278929B (en) | 2007-04-02 | 2007-04-02 | Method for preparing medicament containing gambogic acid compounds and clathrate of gambogic acid compounds |
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| BR112012009660B8 (en) * | 2009-10-26 | 2021-05-25 | Cspc Zhongqi Pharmaceutical Tech Shijiazhuang Co Ltd | liposome having internal water phase containing sulfobutyl ether cyclodextrin salt, its preparation process, its use and liposomal pharmaceutical preparation |
| MX362278B (en) | 2011-10-28 | 2019-01-04 | Kimberly Clark Worldwide Incorporated | Sporicidal formulation including amine oxide surfactant and a mixture of oxidants. |
| EP2770837A4 (en) * | 2011-10-28 | 2015-06-17 | Kimberly Clark Co | Sporicidal formulation including botanical extracts/botanical-derived ingredients |
| CN103816147B (en) * | 2014-03-14 | 2016-01-20 | 吉林农业大学 | The medical usage of gamlogic acid, neogambogic acid and compositions thereof |
| CN108451905B (en) * | 2018-05-31 | 2020-04-07 | 中国人民解放军陆军军医大学 | Gambogic acid nanoemulsion preparation and preparation method and application thereof |
| CN111195286A (en) * | 2020-03-28 | 2020-05-26 | 新乡医学院 | Anti-tumor composition |
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| CN1123030A (en) * | 1993-05-12 | 1996-05-22 | 奇诺英有限公司 | Inclusion complexes of taxol or taxotere or taxus extract formed with cyclodextrins, its preparation and use |
| CN1309125A (en) * | 2001-01-17 | 2001-08-22 | 中国药科大学 | Composition of gambogic acid compounds with anticancer activity and its preparing process |
| US6462041B1 (en) * | 1999-05-21 | 2002-10-08 | Cytovia, Inc. | Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis |
| CN1951382A (en) * | 2006-09-30 | 2007-04-25 | 赵爱国 | Oral formulation of neogambogic acid for treating tumor |
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- 2007-04-02 CN CN2007100207882A patent/CN101278929B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1123030A (en) * | 1993-05-12 | 1996-05-22 | 奇诺英有限公司 | Inclusion complexes of taxol or taxotere or taxus extract formed with cyclodextrins, its preparation and use |
| US6462041B1 (en) * | 1999-05-21 | 2002-10-08 | Cytovia, Inc. | Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis |
| CN1309125A (en) * | 2001-01-17 | 2001-08-22 | 中国药科大学 | Composition of gambogic acid compounds with anticancer activity and its preparing process |
| CN1951382A (en) * | 2006-09-30 | 2007-04-25 | 赵爱国 | Oral formulation of neogambogic acid for treating tumor |
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