CN101590017A - A kind of preparation method of taxol magnetic nano liposome - Google Patents
A kind of preparation method of taxol magnetic nano liposome Download PDFInfo
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- CN101590017A CN101590017A CNA2008100283791A CN200810028379A CN101590017A CN 101590017 A CN101590017 A CN 101590017A CN A2008100283791 A CNA2008100283791 A CN A2008100283791A CN 200810028379 A CN200810028379 A CN 200810028379A CN 101590017 A CN101590017 A CN 101590017A
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Abstract
Paclitaxel is the great discovery of field of antineoplastic medicaments over nearly 20 years, has the height lipotropy, and is water insoluble.Existing listing dosage form is an injection-type, and with the poly-hydroxyethyl Oleum Ricini: ethanol (1: 1) is solvent, is diluted to dextrorotation glucoside etc. before using and is diluted to 0.3-1.2mg/ml.Because the toxic and side effects of solvent and paclitaxel itself has hindered its application clinically.At present, paclitaxel does not have the targeting preparation of better targeting effect as yet.Purpose of the present invention just provides the taxol magnetic nano liposome targeting preparation, the preparation method of this magnetic liposome is to adopt the method preparation of microemulsion-low-temperature setting, its process is as follows: oil phase (stearic acid), surfactant (tween 80), cosurfactant (ethanol) mixes in 73 ± 2 ℃ of water-baths, be added dropwise to a certain amount of distilled water, form transparent system, add scattered magnetic liquid rapidly, stir, formation contains magnetic flaw detection ink, this suspension is injected the aqueous dispersion that places ice bath, obtain the product pellet suspension, the suspension dialysis is cleaned, lyophilization promptly gets magnetic retention lipid nanometer granule product.
Description
Technical field:
The present invention relates to a kind of liposome of anticancer medicine preparation and preparation method thereof, relate in particular to the preparation method of Paclitaxel liposome.
Background technology:
Paclitaxel
[57]Be the great discovery of field of antineoplastic medicaments over nearly 20 years, molecular formula is C
47H
51O
14N, molecular mass 853.9 has the height lipotropy, and is water insoluble, plasma protein binding rate 89%-98%, the t1/2 meansigma methods is 5.3-17.4h, mainly through liver metabolism, kidney only removes 5%.This medicine began with the clinical research of opening ovarian cancer and breast carcinoma in nineteen eighty-three, and 1992 through FDA approval listing.Its mechanism of action uniqueness, can promote that tubulin is assembled into microtubule, but suppress the depolymerization of microtubule, thereby cause cell death, thereby cause fascicular arrangement unusual, make spindle lose normal function and cause cell death, it has therapeutic effect to kinds of tumors, and is especially more outstanding to breast carcinoma, ovarian cancer, nonsmall-cell lung cancer and melanoma therapeutic effect.Paclitaxel mainly extracts from Ramulus et folium taxi cuspidatae, but content of taxol is not high in the Ramulus et folium taxi cuspidatae, as content in the highest bark of content of taxol also only is 0.01%-0.02%, the paclitaxel that extracts 1kg needs 15-30 ton bark, but the market demand of paclitaxel is higher, at present year demand of the U.S. is 300kg, and with the speed increment in every year 20%.
Existing listing dosage form is an injection-type, with the poly-hydroxyethyl Oleum Ricini: ethanol (1: 1) is solvent, and concentration is the paclitaxel injection of 6g/L, can stablize 5 months under 4 ℃, be diluted to dextrorotation glucoside etc. before using and be diluted to 0.3-1.2mg/ml, dosage is 135mg/m
2Because the toxic and side effects of solvent and paclitaxel itself has hindered its further application clinically.This present situation for a change, research worker has been carried out the research that production and pharmaceutical dosage form change to paclitaxel.On producing, realize other explained hereafter paclitaxel, as synthetic method, biotechnology method, fungi fermentation method etc.The method of modifying of pharmaceutics aspect has prodrug method, Emulsion method, liposome method and cyclodextrin embedding etc.Wherein liposome method can improve the dosage of medicine, realizes medicine slow release in vivo, has increased the medicine metabolism time in vivo, simultaneously, because of liposome can use water as solvent, avoided toxic and side effects because of with an organic solvent producing, have development prospect preferably.
At present, paclitaxel does not have the targeting preparation with better targeting effect as yet.
Summary of the invention:
Purpose of the present invention is exactly not have the shortcoming of the preparation of targeting preferably at present in order to overcome, and taxol magnetic nano liposome is provided, and the present invention also provides the preparation method of this magnetic liposome.
Preparation method of the present invention:
1, Fe
3O
4The preparation of nanometer magnetic nuclear
Prepare Fe with coprecipitation
3O
4Magnetic nano-particle, adding certain volume pH in reaction system is the ammonia of 8-12, constantly stirs to drip Fe down
2+, Fe
3+Mixed liquor (is pressed Fe
2+/ Fe
3+The mixed of=2-0), and keeps system pH, apply ultrasonication simultaneously with the ammonia of pH=12.After iron salt solutions dropwises, continue stirring reaction a period of time,, use the deionized water eccentric cleaning afterwards, to detecting no Cl in the water bath with thermostatic control ripening
-Till the existence, the reuse absolute ethanol washing applies ultrasonication in the process of cleaning.The solution for vacuum drying is ground, and promptly gets Fe
3O
4The magnetic nano-particle powder.Its appreciable impact factor and suitable reaction condition are after deliberation: the consumption of precipitant ammonia is 1: 8 the best with iron salt mixed liquor and ammonia volume ratio, keeps reaction system pH=10, and applies nitrogen protection; Iron salt solutions concentration is with 1.0molL
-1Be advisable, and Fe
2+: Fe
3+=1: 2, apply supersound process respectively at synthesis phase and wash phase, the ultrasound condition that synthesis phase is suitable: the sound intensity is 348w.cm
-2, number of processes 6 times; The ultrasound condition that wash phase is suitable: the sound intensity is 276w.cm
-2, number of processes 4 times.Can make mean diameter about 10nm, mass susceptibility is 9.05 * 10
-2m
3Kg
-1Fe
3O
4Magnetic nano-particle.
2.Fe
3O
4Magnetic nano-particle shows modification
With the Fe that has made
3O
4The magnetic nano particle powder joins in the 100mL ammonia of modulated good pH value, and heated and stirred slowly adds a certain amount of oleic acid to a certain temperature, insulation 20min, and cooling holds flocculent deposit with Magnet, and waste liquid inclines.Remaining wadding hypostasis adds a certain amount of acetone treatment, removes unnecessary oleic acid and acetone, promptly gets product.Investigate the influence of different pH value, oleic acid consumption and modification temperature to modified effect.The pH value range of choice is pH=6-10; The oleic acid consumption is an oleic acid: magnetic powder (W/W)=1: 1.5-1: 5; Temperature is investigated scope at 40-80 ℃.The result shows, pH=9, oleic acid consumption are oleic acid: magnetic powder=1: 2, temperature have comparatively ideal surface modification effect when being 70 ℃.Oleic coating process need absorbs energy, and below 70 ℃, the rising oleic acid adsorbance increase along with temperature reaches balance during to 70 ℃, and along with temperature continues to raise, the speed of desorbing also increases rapidly even greater than adsorption rate, adsorbance descended on the contrary again.
The preparation of taxol magnetic nano liposome
Oil phase (stearic acid), surfactant (tween 80), cosurfactant (ethanol) mix in 73 ± 2 ℃ of water-baths, be added dropwise to a certain amount of distilled water, form transparent system, add scattered magnetic liquid rapidly, stir, formation contains magnetic flaw detection ink, this suspension is injected the aqueous dispersion that places ice bath, obtain the product pellet suspension, the suspension dialysis is cleaned, lyophilization promptly gets magnetic retention lipid nanometer granule product.The preparation condition of comparatively ideal taxol magnetic solid lipid nanoparticle drug delivery system is: stearic acid is 0.5g, K (stearic acid/(Tween80+ ethanol))=1: 8, Tween 80: ethanol: water=9.8: 39.3: 50.9, stearic acid: modification magnetic grain=1: 1 (W/W), the paclitaxel consumption is 100mg, prepared taxol magnetic solid lipid nanoparticle mean diameter is 150-170nm, and sealing dose is 98.29mg, and entrapment efficiency is 98.29% (w/w).
4. inside and outside magnetic targeting
Taxol magnetic nano liposome of the present invention, extracorporeal releasing experiment show to have enough magnetic responsivenesses, and it can arrive and accumulate in target site smoothly under the effect of externally-applied magnetic field.In external magnetic steering positioning experiment, under the magnetic field range of setting (0.4T, 0.6T, 0.8T), action time (10-120min) condition, prepared taxol magnetic solid lipid nanoparticle demonstrates good external magnetic targeting, especially be 0.8T in magnetic field intensity, can reach 100% retention rate in target area when being 30min action time.
Intravital targeting experiment gives rat Paclitaxel liposome and taxol magnetic nano liposome respectively, apply the magnetic field of 0.5T in the liver position, put to death the back and measure the paclitaxel concentration of target site, experimental results show that there are marked difference (P＜0.2) in target site and non-targeting moiety.
5. targeted therapy nude mice tumor
The take the logarithm SPCA-I cell of trophophase, injection nude mice forelimb oxter when treating tumor growth to 6mm, is divided into six groups at random with nude mice, gives injectable drug respectively and is respectively: 1) tail vein injection saline (NS) group; 2) tail vein injection blank liposome (LPS); 3) tail vein Paclitaxel liposome (Taxol-LPS); 4) tail vein injection magnetic blank liposome (Mag-LPS); 5) tail vein injection magnetic target liposome (Taxol-Mag), the external magnetic field that do not apply; 6) tail vein injection magnetic target liposome (Taxol-Mag), the external magnetic field that applies, magnetic field intensity is 0.5 tesla (T).The content of paclitaxel is that injection volume is 0.05ml/10g in the taxol magnetic nano liposome emulsion of injection.The weight tumour inhibiting rate is:
Annotate: * is P＜0.05, relative physiologic saline.
We can see that magnetic liposome still has bigger development prospect as a kind of pharmaceutical dosage form from existed test results.
Claims (4)
1, adopt the method for microemulsion-low-temperature setting to prepare taxol magnetic nano liposome, its process is as follows: oil phase (stearic acid), surfactant (tween 80), cosurfactant (ethanol) mix in 73 ± 2 ℃ of water-baths, be added dropwise to a certain amount of distilled water, form transparent system, add scattered magnetic liquid rapidly, stir, formation contains magnetic flaw detection ink, this suspension is injected the aqueous dispersion that places ice bath, obtain the product pellet suspension, the suspension dialysis is cleaned, and lyophilization promptly gets magnetic retention lipid nanometer granule product.
2, the described magnetic nano liposome of claim 1, its prescription is: stearic acid is 5-10g, oleic acid is 1.5-2.5g, Fe
3O
4Be 5-10g, tween 80 is 6-12g, and ethanol is 2-5g, and the liposome particles particle diameter that water prepares during for 35-65g is between 150nm～170nm, and liposome has stability and magnetic responsiveness preferably; When the paclitaxel consumption has maximum entrapment efficiency during for 1g, be 98.29% (W/W).
3, the described magnetic nano liposome of claim 1, its liposome kernel is Fe
3O
4Magnetic nano-particle can be delivered to target site with liposome by the effect of externally-applied magnetic field.
4, the preparation method of the described taxol magnetic nano liposome of claim 1 is made of following steps:
(1) prepares Fe with iron salt and ammonia coprecipitation
3O
4Magnetic nano-particle, its appreciable impact factor and suitable reaction condition are after deliberation: the consumption of precipitant ammonia is 1: 8 the best with iron salt mixed liquor and ammonia volume ratio, keeps reaction system pH=10, and applies nitrogen protection; Iron salt solutions concentration is with 1.0molL
-1Be advisable, and Fe
2+: Fe
3+=1: 2, apply supersound process respectively at synthesis phase and wash phase, can make mean diameter about 10nm, mass susceptibility is 9.05 * 10
-2m
3Kg
-1Fe
3O
4Magnetic nano-particle;
(2) select microemulsion-low-temperature setting legal system to be equipped with paclitaxel magnetic targeting solid lipid nanoparticle drug-supplying system, the result is as follows: oleic acid can be effectively to Fe
3O
4Magnetic nano-particle (magnetic nuclear) carries out surperficial oleophylic modification, makes it can be well by the matrix material embedding, and keeps stable; The preparation condition of comparatively ideal taxol magnetic nano liposome is: stearic acid is 0.5g, the Fe of modification
3O
4Particle is 0.5g, and tween 80 is 0.8g, and ethanol is 3.2g, and water is 4g, and the paclitaxel consumption is 100mg; About prepared taxol magnetic solid lipid nanoparticle mean diameter 200nm, entrapment efficiency is 87.70% (w/w), and visible microemulsion-the low-temperature setting method is the comparatively ideal method for preparing the taxol magnetic solid lipid nanoparticle;
(3) liposome for preparation carries out frozen drying, obtains taxol magnetic solid nano liposome;
The amount of the Polyethylene Glycol that (4) applies is to the influence of experimental result: liposome the ratio of each component is: Fe
3O
41.00g, tween 80 1.60g, ethanol 6.40g, stearic acid 1.00g after water 8g hybrid reaction prepares the taxol magnetic nano liposome emulsion, pours in the 36ml normal saline group that contains 6g Polyethylene Glycol-800, has stability preferably.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102048697A (en) * | 2011-01-20 | 2011-05-11 | 浙江大学 | Method for preparing solid lipid nanoparticles of water-soluble anti-tumor medicine |
| CN103289445A (en) * | 2013-05-23 | 2013-09-11 | 铜陵瑞莱科技有限公司 | Method for preparing high-temperature-resistant iron oxide black granules |
| CN107998978A (en) * | 2017-12-11 | 2018-05-08 | 江南大学 | A kind of composition, preparation and the application of magnetic liposome vesica |
| RU2697802C1 (en) * | 2018-08-23 | 2019-08-20 | Федеральное Государственное Бюджетное Учреждение Науки Институт Биохимической Физики Им. Н.М. Эмануэля Российской Академии Наук (Ибхф Ран) | Method of producing magnetic liposomes |
| CN112391598A (en) * | 2019-08-12 | 2021-02-23 | 湖南早晨纳米机器人有限公司 | Drug-loaded packaging nano robot and preparation method thereof |
-
2008
- 2008-05-29 CN CNA2008100283791A patent/CN101590017A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102048697A (en) * | 2011-01-20 | 2011-05-11 | 浙江大学 | Method for preparing solid lipid nanoparticles of water-soluble anti-tumor medicine |
| CN103289445A (en) * | 2013-05-23 | 2013-09-11 | 铜陵瑞莱科技有限公司 | Method for preparing high-temperature-resistant iron oxide black granules |
| CN103289445B (en) * | 2013-05-23 | 2014-11-19 | 铜陵瑞莱科技有限公司 | Method for preparing high-temperature-resistant iron oxide black granules |
| CN107998978A (en) * | 2017-12-11 | 2018-05-08 | 江南大学 | A kind of composition, preparation and the application of magnetic liposome vesica |
| CN107998978B (en) * | 2017-12-11 | 2019-08-06 | 江南大学 | A kind of composition, preparation and the application of magnetic liposome vesica |
| RU2697802C1 (en) * | 2018-08-23 | 2019-08-20 | Федеральное Государственное Бюджетное Учреждение Науки Институт Биохимической Физики Им. Н.М. Эмануэля Российской Академии Наук (Ибхф Ран) | Method of producing magnetic liposomes |
| CN112391598A (en) * | 2019-08-12 | 2021-02-23 | 湖南早晨纳米机器人有限公司 | Drug-loaded packaging nano robot and preparation method thereof |
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Open date: 20091202 |