CN100453077C - Injectable micelle prepn containing garcinolic acid and its prepn process - Google Patents
Injectable micelle prepn containing garcinolic acid and its prepn process Download PDFInfo
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- CN100453077C CN100453077C CNB2007100205622A CN200710020562A CN100453077C CN 100453077 C CN100453077 C CN 100453077C CN B2007100205622 A CNB2007100205622 A CN B2007100205622A CN 200710020562 A CN200710020562 A CN 200710020562A CN 100453077 C CN100453077 C CN 100453077C
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- chitosan
- gamlogic acid
- acid
- octyl group
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- 239000000693 micelle Substances 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 title claims description 17
- VDSCKSOYNLTQSY-UHFFFAOYSA-N Garcinolic acid Chemical compound O1C2(C(OC3(C)C)(CC=C(C)C(O)=O)C(O)=O)C3CCC=C2C(=O)C2=C1C(CC=C(C)C)=C1OC(CCC=C(C)C)(C)C=CC1=C2O VDSCKSOYNLTQSY-UHFFFAOYSA-N 0.000 title abstract 4
- 229920001661 Chitosan Polymers 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims description 63
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 18
- 239000006228 supernatant Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 14
- 238000000502 dialysis Methods 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
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- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 12
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- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
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- XTVYWYLMVSZOSU-LPYMAVHISA-N allogambogic acid Chemical compound O1C2(C(C3=O)(C\C=C(/C)C(O)=O)OC4(C)C)C4CC3C=C2C(=O)C2=C1C(CC=C(C)C)=C(O)C1=C2OC(CCC=C(C)C)(C)C=C1 XTVYWYLMVSZOSU-LPYMAVHISA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
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- GEZHEQNLKAOMCA-GXSDCXQCSA-N gambogic acid Natural products C([C@@H]1[C@]2([C@@](C3=O)(C\C=C(/C)C(O)=O)OC1(C)C)O1)[C@H]3C=C2C(=O)C2=C1C(CC=C(C)C)=C1O[C@@](CCC=C(C)C)(C)C=CC1=C2O GEZHEQNLKAOMCA-GXSDCXQCSA-N 0.000 description 2
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- QALPNMQDVCOSMJ-UHFFFAOYSA-N isogambogic acid Natural products CC(=CCc1c2OC(C)(CC=C(C)C)C=Cc2c(O)c3C(=O)C4=CC5CC6C(C)(C)OC(CC=C(C)/C(=O)O)(C5=O)C46Oc13)C QALPNMQDVCOSMJ-UHFFFAOYSA-N 0.000 description 2
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- 229960003194 meglumine Drugs 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- BLDWFKHVHHINGR-FYJGNVAPSA-N neo-gambogic acid Chemical compound C1C2C(C)(C)OC3(C\C=C(/C)C(O)=O)C(=O)C1C=C1C(=O)C(C(O)=C4C(O)CC(OC4=C4CC=C(C)C)(C)CCC=C(C)C)=C4OC123 BLDWFKHVHHINGR-FYJGNVAPSA-N 0.000 description 2
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
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- 206010020751 Hypersensitivity Diseases 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention relates to natural medicine preparation, and is especially water soluble or injectable garcinolic acid preparation. The injectable garcinolic acid preparation features its N-octyl-O-sulfo-chitosan as cosolvent or N-octyl-O-sulfo-chitosan forming micelle. The freeze dried garcinolic acid micelle powder for injection has high stability, high solubility and high clinical safety.
Description
Technical field
The present invention relates to natural drug and field of pharmaceutical preparations, be specifically related to the water solublity or the injectable type preparation of gamlogic acid, disclose with N-octyl group-O-sulfonic group-chitosan and formed the injection preparation of micellar gamlogic acid as cosolvent or with N-octyl group-O-sulfonic group-chitosan.
Background technology
Resina garciniae (gamboge) is the extract that obtains by in Guttiferae plant gamboge tree (Garcinia hanbaryi) resin, contains gamlogic acid (gambogic acid), neogambogic acid (neogambogic acid), allogambogic acid compositions such as (allogambogic acid).Gamlogic acid is the main active of Resina garciniae, and kinds of tumors is all had the obvious suppression effect.
Because gamlogic acid is insoluble in water, the gamlogic acid injection of report mainly is to use boric acid solution to prepare at present.CN1452960A discloses a kind of method for preparing the injection gambogic acid preparation by cosolvents such as interpolation L-arginine, meglumine, lysines; CN1391892A also is by adding the lyophilized formulations that L-arginine hydrotropy prepares gamlogic acid; CN1513448A is by adding the ejection preparation that solubilizing agents such as polyoxyethylene castor oil, tween prepare gamlogic acid, CN1718183A use L-arginine, meglumine, lysine etc. as cosolvent with preparation gamlogic acid lyophilized formulations.These solubilizing agents of life-time service or cosolvent can cause a series of untoward reaction as allergy, nephrotoxicity, neurotoxicity, Cardiovascular Toxicity etc., perhaps need big consumption just can obtain stable and solubilizing effect effective dose.
The inventor is prepared into polyethyleneglycol prodrug with gamlogic acid in the research in early stage, effectively improved the water solublity of gamlogic acid.After medicine reached in the body, gamlogic acid separated with Polyethylene Glycol, the performance drug effect.
The inventor finds that in the research to chitosan derivatives chitosan derivatives particularly N-octyl group-O-sulfonic group-chitosan has certain solubilization, and is good for some insoluble drug such as solubilizing effects such as paclitaxel, ciclosporin.CN1439655A discloses these technology.
Summary of the invention
The invention discloses a kind of with the gamlogic acid injectable formulation of N-octyl group-O-sulfonic group-chitosan as solubilizing agent.
The inventor finds uncannily: N-octyl group-O-sulfonic group-chitosan also has solubilization to gamlogic acid, and the solubilizing effect of gamlogic acid is better than insoluble medicines such as paclitaxel, ciclosporin, and the dissolubility of gamlogic acid can reach 4.36mg/ml behind its solubilising.
N-octyl group-O-sulfonic group-chitosan can spontaneous formation micelle in water, and micelle inside is hydrophobic group, gamlogic acid can be wrapped up, and the micelle outside is a hydrophilic group, can make micelle soluble in water.This invention efficiently solves the deliquescent problem of gamlogic acid.
Research is also found, gamlogic acid is different with N-octyl group-O-sulfonic group-chitosan dosage, and solubilizing effect is also different, when the gamlogic acid parts by weight are 1, N-octyl group-O-sulfonic group-chitosan parts by weight are not obvious less than 0.2 o'clock solubilizing effect, and the dissolubility of gamlogic acid this moment in water is less than 1mg/ml.The inventor surprisingly finds again, and when the gamlogic acid parts by weight are 1, N-octyl group-O-sulfonic group-chitosan parts by weight are not high greater than the dissolubility of 10 o'clock gamlogic acids in water yet, and dissolubility is also less than 1mg/ml.Therefore, the inventor has carried out deep research to N-octyl group-O-sulfonic group-chitosan different amounts again to the influence of gamlogic acid dissolubility, is the part test data below:
N-octyl group-O-sulfonic group-the chitosan of table 1 different amounts is to the influence of gamlogic acid dissolubility
Therefore, the weight ratio of the preferred gamlogic acid of the present invention and N-octyl group-O-sulfonic group-chitosan is 1: 0.2～1: 10.The weight ratio of further preferred gamlogic acid and N-octyl group-O-sulfonic group-chitosan is 1: 1～1: 8.
Gamlogic acid preparation method of composition of the present invention is simple, can be about to gamlogic acid with direct addition method preparation, and add and contain in the aqueous solution or organic solvent of chitosan derivatives, centrifuging and taking supernatant after the stirring at room, aseptic filtration, promptly.
Preferred manufacturing procedure is that gamlogic acid is dissolved in the organic solvent, and with N-octyl group-O-sulfonic group-chitosan in the water-soluble or ethanol, it is ultrasonic that two kinds of solution mix the back, and distill water dialysis is centrifugal, gets supernatant promptly.Described organic solvent particular methanol, ethanol, dichloromethane, chloroform, dimethyl sulfoxine, N, one or more mixed solvents in the dinethylformamide etc.The further preferred alcohol of organic solvent.The also direct addition method height of the micelle medicine carrying amount height for preparing in this way, envelop rate, envelop rate is greater than 98%.
Be prepared into lyophilized formulations if desired, then add excipient, also claim freeze drying protectant, aseptic filtration, lyophilizing.In the preferred dextran of excipient, mannitol, glucose, lactose, sucrose, the trehalose one or more.The amount of excipient is by the micellar solution volume calculation, and 1 part of micellar solution preferably adds 0.01-0.1 part excipient, filters postlyophilization.
The gamlogic acid lyophilized formulations of method for preparing does not contain any organic solvent, can dissolve again with water for injection, glucose injection or normal saline during clinical use, when lyophilized formulations of the present invention dissolves again dissolving rapidly, and solution clarification.
The micelle that gamlogic acid and N-octyl group-O-sulfonic group-chitosan forms, the drug loading height, the highest can be up to 94%, envelop rate can reach 98-100%.Micelle particle diameter of the present invention is little, reaches nanoscale, is about 50-250nm.
Medicament contg height in the micellar unit volume of gamlogic acid of the present invention has stable drug loading and envelop rate, and the medicine in the micelle continues to discharge, can prolong drug circulation time in blood.The clinical suitable gamlogic acid micelle injection freeze-dried powder of the present invention can significantly improve bin stability, can make gamlogic acid micelle freeze-drying powder not produce precipitation again after adding glucose injection redissolution and dilution, has reduced the unsafe factor of clinical application.Pharmacological testing shows that the utilization rate (AUC) of gamlogic acid micelle freeze-dried powder injection of the present invention is significantly higher than gamlogic acid arginine salt injection, and plasma half-life obviously prolongs, and is 1.7 times (p＜0.05) of the latter.The mouse mainline LD of gamlogic acid micellar preparation
50Be 39.17mg/kg, be better than gamlogic acid arginine salt (15.96mg/kg).
Description of drawings
Fig. 1 be the injection of gamlogic acid micelle of the present invention and gamlogic acid arginine salt rat tail vein through the time curve (n=6)
The specific embodiment
Taking by weighing 20.0mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 2ml distilled water, directly pour in the cillin bottle that the 10.0mg gamlogic acid is housed, stirring at room 24 hours, form yellow suspension, centrifugal 30min (3000rpm) gets supernatant, after the aseptic filtration (filter membrane aperture 0.22 μ m), in the filtrate packing cillin bottle, lyophilization then.Measuring drug loading with the HPLC method is 15.8%, and envelop rate is 98%, particle diameter 178nm.
Take by weighing 20.0mgN-octyl group-O-sulfonic group-chitosan and be dissolved in the 2ml distilled water, join in the 0.2ml dichloromethane solution that contains the 10.0mg gamlogic acid, the room temperature lower open mouth stirred 24 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 15.7%, and envelop rate is 99%, particle diameter 198.1nm.
Embodiment 3
Taking by weighing 20.0mgN-octyl group-O-sulfonic group-chitosan is dissolved in 2ml distilled water and the 0.2ml ethanol mixed solvent, simultaneously the 10.0mg gamlogic acid is dissolved in the 0.2ml ethanol, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 32.6%, and envelop rate is 99%, particle diameter 169.3nm.
Taking by weighing 20.0mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 2ml distilled water, join in the 0.2ml alcoholic solution that contains the 10.0mg gamlogic acid, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 41.0%, envelop rate＞99%, particle diameter 155.6nm.
Taking by weighing 3.0mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 1ml distilled water, join in the 0.2ml alcoholic solution that contains the 6.0mg gamlogic acid, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 93.9%, envelop rate＞99%, particle diameter 162.5nm.
Embodiment 6
Taking by weighing 10.0mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 2ml distilled water, join in the 0.2ml alcoholic solution that contains the 10.0mg gamlogic acid, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 62.7%, envelop rate＞99%, particle diameter 168.8nm.
Embodiment 7
Taking by weighing 27.0mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 2ml distilled water, join in the 0.2ml alcoholic solution that contains the 9.0mg gamlogic acid, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 31.3%, envelop rate＞99%, particle diameter 153.5nm.
Embodiment 8
Taking by weighing 4mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 1ml distilled water, join in the 0.5ml alcoholic solution that contains the 20.0mg gamlogic acid, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 39.4%, envelop rate＞99%, particle diameter 158.2nm.
Embodiment 9
Taking by weighing 40mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 2ml distilled water, join in the 0.2ml alcoholic solution that contains the 10.0mg gamlogic acid, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 21.5%, envelop rate＞99%, particle diameter 163.2nm.
Taking by weighing 60mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 2.0ml distilled water, join in the 0.2ml alcoholic solution that contains the 10.0mg gamlogic acid, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 15.4%, envelop rate＞99%, particle diameter 167.3nm.
Embodiment 11
Taking by weighing 50mgN-octyl group-O-sulfonic group-chitosan is dissolved in the 2.0ml distilled water, join in the 0.2ml alcoholic solution that contains the 10.0mg gamlogic acid, both mix ultrasonic 30min, muddy liquid is used distill water dialysis 12 hours, centrifugal 30min (3000rpm), get supernatant, after the aseptic filtration, lyophilization in the packing cillin bottle.Measuring drug loading with the HPLC method is 17.6%, envelop rate＞99%, particle diameter 164.1nm.
Embodiment 12
Gamlogic acid micelle rat body giving drugs into nose of the present invention is for the investigation of kinetic property
A. administration with get the blood scheme
6 of rats, male and female half and half, body weight (200 ± 20g), by the arginine salt solution of tail vein injection gamlogic acid, injection finishes and picks up counting, after the administration respectively at 2,5,10,15,20,30,40,50,60min gets blood from eye socket, each 0.5ml, anticoagulant heparin, and separated plasma immediately.Other gets 6 of rats, Deng (embodiment 4 preparations of dosage (4mg/kg) injection gamlogic acid micellar solution of the present invention, freeze-dried powder redissolves with 5% glucose solution), after the administration 2,5, l0,15,20,30,40,50,60min eye socket get blood 0.5ml, anticoagulant heparin, separated plasma places sample cell.
B. through the time curve, see figure l.
C. blood medicine data obtain moving parameter of relevant medicine such as following table 2 after the 3p97 software processes.Each is organized data and carries out the t check, and in 95% credibility interval, all there were significant differences for every group of data.
The pharmacokinetic parameters (n=6) of table 2 rat intravenous injection gamlogic acid micellar preparation and contrast thereof
Claims (8)
1, a kind of pharmaceutical composition that contains gamlogic acid, it is characterized in that containing gamlogic acid and N-octyl group-N-sulfonic group-chitosan, wherein N-octyl group N-sulfonic group-chitosan wraps up gamlogic acid with micelle form, and the weight ratio of gamlogic acid and N-octyl group N-sulfonic group-chitosan is 1: 0.2～1: 10.
2, the pharmaceutical composition of claim 1, wherein the weight ratio of gamlogic acid and N-octyl group N-sulfonic group-chitosan is 1: 1～1: 8.
3, the pharmaceutical composition of claim 1 also contains excipient.
4, the pharmaceutical composition of claim 3, wherein excipient is selected from one or more in dextran, mannitol, glucose, lactose, sucrose, the trehalose.
5, each preparation of drug combination method in the claim 1 to 4 comprises: gamlogic acid is dissolved in the organic solvent, with N-octyl group N-sulfonic group-chitosan in the water-soluble or ethanol, it is ultrasonic after two kinds of solution mix, distill water dialysis, centrifugal, get supernatant promptly.
6, the preparation method of claim 5, wherein organic solvent is selected from methanol, ethanol, dichloromethane, chloroform, dimethyl sulfoxine, N, one or more in the dinethylformamide.
7, the preparation method of claim 6, wherein organic solvent is an ethanol.
8, the preparation method of claim 5 also comprises supernatant aseptic filtration, adds excipient, lyophilizing.
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