CN101683322A - Method for preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method - Google Patents
Method for preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method Download PDFInfo
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- CN101683322A CN101683322A CN200810200546A CN200810200546A CN101683322A CN 101683322 A CN101683322 A CN 101683322A CN 200810200546 A CN200810200546 A CN 200810200546A CN 200810200546 A CN200810200546 A CN 200810200546A CN 101683322 A CN101683322 A CN 101683322A
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Abstract
The invention discloses a method for preparing nano berberine hydrochloride liposome by a supercritical carbon dioxide method. The invention has the following specific operation steps: 1) forming a film; 2) encapsulating drugs; a) preparing berberine hydrochloride liposome injectable suspension; b) incubating in supercritical carbon dioxide fluid; and 3) after finishing releasing the carbon dioxide incubation, releasing carbon dioxide gas and reducing the system pressure into normal pressure to obtain the product. Compared with the prior art, the invention adopts the supercritical carbon dioxide fluid as a medium to prepare the nano berberine hydrochloride liposome with good monodispersity and high drug encapsulation rate according to the characteristics of even mass transferring and highvelocity and the like of the supercritical carbon dioxide fluid, and controls the dimension of the liposome by regulating and preparing pressure.
Description
Technical field
The invention belongs to and relate to the pharmaceutical carrier preparation field, specifically a kind of preparation method of nano berberine hydrochloride liposome.
Background technology
After medicine combined with carrier and forms medicament carrier system, the absorption of medicine and distributing no longer determined by medicine itself, but was subjected to the influence of carrier physicochemical property.Select suitable drug carrier material according to clinical requirement, not only can conduct drugs to target organ, and play useful effect for the physicochemical property and the pharmacologically active of medicine.
Berberine hydrochloride (berberine) is a kind of isoquinoline alkaloid that extracts from plant drying rhizomes such as Rhizoma Coptidis, Cortex Phellodendri, Radix Berberidis, is mainly used in the past by intestinal canal administration and treats gastroenteritis, bacillary dysentery and general intestinal infection etc.In recent years discover berberine hydrochloride to the human liver cancer cell, colon tumor cell, esophageal cancer cell system, malignant teratoma cell, rat 9L brain tumor cell, Lewis lung cancer cell etc. all has certain inhibition and killing action.But research finds that also tumor-inhibiting action does not have interaction in vitro obvious in the berberine hydrochloride body, may be because the berberine hydrochloride intestinal absorption is relatively poor, is difficult in vivo reach to the direct acting higher blood drug level of tumor cell.The berberine hydrochloride intravenously administrable may cause side effect such as drug eruption, anaphylaxis, hematochrome and erythrocytopenia, drug sensitivity shock, and nineteen eighty-two, China banned use of the berberine hydrochloride intravenously administrable.Because berberine hydrochloride has cheap, safe characteristics, make it become a kind of medicine that is worth further investigation aspect treatment and prevention of tumour.Therefore, how to bring into play the effect of berberine hydrochloride in treatment of cancer, suppressing its side effect is the big problem that we face.In order to improve the berberine hydrochloride curative effect, reduce its toxic and side effects simultaneously, this patent proposes the new method of preparation nano berberine hydrochloride liposome.
Liposome is the superminiature spheroid that the class lipid bilayer forms, similar biofilm structure, and it can be wrapped in pharmaceutical pack in the capsule and become a kind of new drug carrier.Its solvent phospholipid is inherent composition in the organism, degrades through biotransformation in vivo, and avirulence and immunogenicity, therefore, liposome is considered to one of pharmaceutical carrier of tool development prospect.
At present, the method for preparing liposome mainly contains film dispersion method, reverse evaporation, the ultrasonic dispersing method, freeze-thaw method, freeze-drying, alcohol injection, the ether injection method, reverse phase evaporation, surfactant facture etc., but there is important disadvantages in above-mentioned preparation method, as: organic solvent residual causes the safety of liposome to descend in the product, and granule monodispersity difference is unfavorable for the stable of system, and the envelop rate of medicine is low etc.Supercritical carbon dioxide fluid is a kind of environmentally friendly solvent, is easy to separate with product and do not cause environmental pollution after preparation finishes, and possesses the characteristic of fine solvent.In recent years, along with the supercritical carbon dioxide fluid technology rapid development, the continuous expansion of application, it is applied in the preparation of liposome gradually.In the liposome preparation process, the advantage of supercritical carbon dioxide mainly shows the following aspects: the first, and with other preparation method comparison of liposome, the liposome particle diameter of supercritical carbon dioxide process preparation is comparatively even, the monodispersity height.The second, with operation such as evaporation, extraction or dilution relatively, utilize the liposome organic solvent-free of supercritical carbon dioxide process preparation residual, for the safe clinical practice of liposome provides may.The 3rd, in hatching process, supercritical carbon dioxide fluid can dissolve the small molecular weight impurity in the phospholipid, and impurity can be simultaneously by the stripped system of band, to reach the effect that purification phospholipid improves the liposome quality during release of carbon dioxide.The 4th, supercritical carbon dioxide fluid is a kind of emerging fine solvent, the mass transfer rate height, this helps the diffusion of hatching process Chinese medicine molecule in the export-oriented film of film, supercritical carbon dioxide fluid is that carbon dioxide forms through the high pressure effect at a certain temperature simultaneously, high pressure in the system helps the interior water that medicine enters liposome equally, and then improves the envelop rate of liposome.In addition, the supercritical carbon dioxide fluid environment can plastify the structure of phospholipid molecule, and this plastication helps phospholipid molecule and forms the more stable conformation of thermodynamics, makes the arrangement of bilayer more even, to reach the purpose that improves liposome stability.Above-mentioned advantage explanation supercritical carbon dioxide process has certain advantage aspect the preparation berberine hydrochloride liposome.
Summary of the invention
In the method at the existing preparation liposome in the ubiquitous product organic solvent residual cause the safety of liposome to descend, granule monodispersity difference is unfavorable for defectives such as stablizing of system, the present invention proposes a kind of new method of preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method, and particle diameter in the traditional preparation process method is inhomogeneous to overcome effectively, poor stability, envelop rate are low, the shortcoming of organic solvent residual.
The technical solution used in the present invention is:
Mass transfer according to supercritical carbon dioxide fluid evenly reaches characteristics such as speed height, the utilization supercritical carbon dioxide fluid is as medium, the preparation nano berberine hydrochloride liposome that monodispersity is good, entrapment efficiency is high, and can be by regulating the size of preparation pressure control liposome.
According to technique scheme, concrete operations of the present invention are:
1) film forming
Take by weighing an amount of lecithin and cholesterol and place round-bottomed flask, the weight ratio of lecithin and cholesterol is 3.8-2.5: 1.Again with volume ratio 2.5-2: the chloroform methanol mixed liquor of 1 preparation adds wherein extremely with till its dissolving.After dissolving fully, under 35-42 ℃ of constant temperature and nitrogen protection condition, film forming in Rotary Evaporators, evacuation volatilizees organic solvent fully then.
2) entrapped drug
A) preparation of berberine hydrochloride liposome suspension
Pipette the berberine hydrochloride drug solution, the round-bottomed flask that places step 1) to have, magnetic agitation comes off film, obtains the berberine hydrochloride liposome suspension.Wherein the mass ratio of berberine hydrochloride drug solution and lecithin (medicine fat ratio) is 1: 9-12.
B) in supercritical carbon dioxide fluid, hatch
The suspension that makes in a) is placed autoclave, and other adds an amount of dehydrated alcohol, again autoclave is placed water bath with thermostatic control, feed carbon dioxide, after reaching uniform temperature and pressure, carbon dioxide enters its critical region, presents the supercritical fluid state.Preparation pressure can be regulated.As 16,18,20,22,24MPa etc.As long as this pressure carbon dioxide is above-critical state.Close intake valve then, 40-45 ℃ stirred in water bath hatching half an hour.The mass ratio of dehydrated alcohol and berberine hydrochloride drug solution is 1: 4-5.5.Getting dehydrated alcohol density is 0.789g/mL, and the density of berberine hydrochloride drug solution is approximately 1g/mL.
3) release of carbon dioxide
After hatching finished, carbon dioxide gas was reduced to normal pressure with system pressure, promptly gets product.
Compare prior art, the present invention has following good effect:
The particle size dispersion of the berberine hydrochloride liposome that 1) prepares is even, and monodispersity is good, stability high (Fig. 1, Fig. 2, table 1);
2) as table 2 as seen, the envelop rate of the medicine of gained of the present invention is higher than traditional method;
3) Determination of Residual Organic Solvents is few;
4) can be when regulating hatching the size and the stability (seal pressure to size and dispersive influence thereof, see Fig. 3) of the pressure control liposome particle diameter of supercritical carbon dioxide in the autoclave.The relation of preparation pressure and berberine hydrochloride liposome particle diameter: pressure is big more, and particle diameter is more little.
Description of drawings
Fig. 1 is the particle diameter and the form (atomic force microscope) of nano berberine hydrochloride liposome
Fig. 2 a and Fig. 2 b are the size ratios (laser light scattering measurement result) of the berberine hydrochloride liposome of the preparation method that proposes of the present invention and traditional film dispersion method preparation.
Wherein Fig. 2 a is particle diameter and the particle size distribution that supercritical carbon dioxide process that the present invention proposes prepares nanometer liposome, and Fig. 2 b is the particle diameter and the particle size distribution of the liposome of film dispersion method preparation.
Fig. 3 shows by regulating the preparation pressure of supercritical carbon dioxide, can control the size and the dispersibility of nano berberine hydrochloride liposome
Embodiment
Further specify the present invention by the following examples:
Embodiment 1: preparation berberine hydrochloride liposome suspension, take by weighing 50mg lecithin and the 16.5mg cholesterol places round-bottomed flask, with 2.2: 1 chloroform of 3mL volume ratio and methyl alcohol mixed liquor dissolving, dissolve back rotary evaporation film forming fully, bath temperature is set at 41 ℃, and evacuation makes solvent evaporates again.Pipette 6ml 1mg/mL berberine hydrochloride solution, place above-mentioned round-bottomed flask, magnetic agitation comes off film.Above-mentioned suspension and magneton are placed autoclave, and other adds the 1.3mL dehydrated alcohol, and logical carbon dioxide is to 12MPa.Close intake valve then, in the stirred in water bath hatching half an hour of uniform temperature.After hatching finished, carbon dioxide gas was reduced to normal pressure with system pressure, promptly gets product.
Embodiment 2: preparation berberine hydrochloride liposome suspension, take by weighing 50mg lecithin and the 16.5mg cholesterol places round-bottomed flask, with 2: 1 chloroform of 4mL volume ratio and methyl alcohol mixed liquor dissolving, the back rotary evaporation film forming of dissolving fully, bath temperature is set at 45 ℃, and evacuation makes solvent evaporates again.Pipette 5mL 1mg/mL berberine hydrochloride solution, place above-mentioned round-bottomed flask, magnetic agitation comes off film.Above-mentioned suspension and magneton are placed autoclave, and other adds the 1.3mL dehydrated alcohol, and logical carbon dioxide is to 16MPa.Close intake valve then, in the stirred in water bath hatching half an hour of uniform temperature.After hatching finished, carbon dioxide gas was reduced to normal pressure with system pressure, promptly gets product.
Embodiment 3: preparation berberine hydrochloride liposome suspension, take by weighing 50mg lecithin and the 16.5mg cholesterol places round-bottomed flask, with 2.5: 1 chloroform of 3.5mL volume ratio and methyl alcohol mixed liquor dissolving, dissolve back rotary evaporation film forming fully, bath temperature is set at 42 ℃, and evacuation makes solvent evaporates again.Pipette 5mL 1mg/mL berberine hydrochloride solution, place film forming round-bottomed flask, magnetic agitation comes off film.Above-mentioned suspension and magneton are placed autoclave, and other adds the 1.3mL dehydrated alcohol, and logical carbon dioxide is to 20MPa.Close intake valve then, in the stirred in water bath hatching half an hour of uniform temperature.After hatching finished, carbon dioxide gas was reduced to normal pressure with system pressure, promptly gets product.
Embodiment 4: preparation berberine hydrochloride liposome suspension, take by weighing 55mg lecithin and the 16.5mg cholesterol places round-bottomed flask, with 2.1: 1 chloroform of volume ratio and methyl alcohol mixed liquor dissolving, the back rotary evaporation film forming of dissolving fully, bath temperature is set at 43 ℃, and evacuation makes solvent evaporates again.Pipette 5mL 1mg/mL berberine hydrochloride solution, place above-mentioned round-bottomed flask, magnetic agitation comes off film.Above-mentioned suspension and magneton are placed autoclave, and other adds the 1.3mL dehydrated alcohol, and logical carbon dioxide is to 24MPa.Close intake valve then, in the stirred in water bath hatching half an hour of uniform temperature.After hatching finished, carbon dioxide gas was reduced to normal pressure with system pressure, promptly gets product.
The present invention evenly reaches characteristics such as speed height according to the mass transfer of supercritical carbon dioxide fluid, the utilization supercritical carbon dioxide fluid is as medium, preparation monodispersity is good, entrapment efficiency is high nano berberine hydrochloride liposome, and can be when regulating hatching the size of the pressure control liposome particle diameter of supercritical carbon dioxide in the autoclave.
The liposome stability of supercritical carbon dioxide process that table 1, the present invention propose and the preparation of traditional supercritical carbon dioxide process relatively
(annotate: 1, the condition determination of stability constant: a calculation of Stability Constants formula: K
E=(A
25d-A
0)/A
0The b temperature is 277.2K; 2, stability constant small liposome is stable more more)
The liposome encapsulation of supercritical carbon dioxide process that table 2, the present invention propose and the preparation of traditional supercritical carbon dioxide process relatively
(annotate: the computing formula of envelop rate: envelop rate=(1-free drug quality/medicine gross mass) * 100%)
Claims (6)
1, a kind of method of preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method is characterized in that it may further comprise the steps:
1) film forming
Take by weighing an amount of lecithin and cholesterol and place round-bottomed flask, the weight ratio of lecithin and cholesterol is 3.8-2.5: 1, and again with volume ratio 2.5-2: the chloroform methanol mixed liquor of 1 preparation adds wherein extremely with till its dissolving; After dissolving fully, under 35-42 ℃ of constant temperature and nitrogen protection condition, film forming in Rotary Evaporators, evacuation volatilizees organic solvent fully then;
2) entrapped drug
A) preparation of berberine hydrochloride liposome suspension
Pipette the berberine hydrochloride drug solution, the round-bottomed flask that places step 1) to have, magnetic agitation comes off film, obtains the berberine hydrochloride liposome suspension; The mass ratio of described berberine hydrochloride drug solution and lecithin is 1: 9-12;
B) in supercritical carbon dioxide fluid, hatch
The suspension that makes in a) is placed autoclave, and other adds an amount of dehydrated alcohol, again autoclave is placed water bath with thermostatic control, feeds carbon dioxide, and after the increase pressure, carbon dioxide enters its critical region, presents the supercritical fluid state; Close intake valve then, 40-45 ℃ stirred in water bath hatching 20-45 minute; The mass ratio of dehydrated alcohol and berberine hydrochloride drug solution is 1: 4-5.5;
3) release of carbon dioxide
After hatching finished, carbon dioxide gas was reduced to normal pressure with system pressure, obtains product.
2, the method for preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method as claimed in claim 1 is characterized in that the mass ratio of described berberine hydrochloride and lecithin is preferably 1: 10.
3, the method for preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method as claimed in claim 1 is characterized in that both mass ratioes are preferably 1: 5 in described dehydrated alcohol and the berberine hydrochloride drug solution.
4, the method for preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method as claimed in claim 1, in it is characterized in that hatching in supercritical carbon dioxide fluid, the temperature of water-bath is preferably 43 ℃.
5, the method for preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method as claimed in claim 1, in it is characterized in that hatching in supercritical carbon dioxide fluid, the time of stirring hatching is preferably 30 minutes.
6, the method for preparing nano berberine hydrochloride liposome by supercritical carbon dioxide method as claimed in claim 1 is characterized in that the optimum quality ratio of cholesterol and lecithin in the step 1) is 1: 3.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101978952A (en) * | 2010-10-22 | 2011-02-23 | 广东医学院 | Method for preparing berberine hydrochloride liposome preparation |
| CN102379847A (en) * | 2010-08-31 | 2012-03-21 | 华东理工大学 | Controlled synthesis method of nanometer polyenic taxusol liposome |
| CN102475682A (en) * | 2010-11-30 | 2012-05-30 | 沈阳药科大学 | Berberine liposome and preparation method thereof |
| CN102488656A (en) * | 2011-02-23 | 2012-06-13 | 大连大学 | Method for preparing water-soluble drug liposome by utilizing reverse evaporating process of supercritical fluid |
| CN103449533A (en) * | 2012-05-29 | 2013-12-18 | 华东理工大学 | Supercritical carbon dioxide method for extraction separation of magnetosomes from magnetotactic bacteria |
| CN110448661A (en) * | 2019-08-13 | 2019-11-15 | 合肥市未来药物开发有限公司 | A kind of oil of zedoary turmeric mixed micelle and preparation method thereof |
| CN111001000A (en) * | 2019-12-10 | 2020-04-14 | 金陵科技学院 | Berberine hydrochloride FeAg nano-alloy liposome with light-controlled drug release and magnetic-controlled drug release and preparation method thereof |
| CN113143847A (en) * | 2021-03-09 | 2021-07-23 | 厦门大学 | Preparation method and application of long-acting low-toxicity insect-expelling ointment for skin and supercritical carbon dioxide fluid |
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2008
- 2008-09-26 CN CN2008102005466A patent/CN101683322B/en not_active Expired - Fee Related
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102379847A (en) * | 2010-08-31 | 2012-03-21 | 华东理工大学 | Controlled synthesis method of nanometer polyenic taxusol liposome |
| CN102379847B (en) * | 2010-08-31 | 2013-03-13 | 华东理工大学 | Controlled synthesis method of nanometer polyenic taxusol liposome |
| CN101978952A (en) * | 2010-10-22 | 2011-02-23 | 广东医学院 | Method for preparing berberine hydrochloride liposome preparation |
| CN102475682A (en) * | 2010-11-30 | 2012-05-30 | 沈阳药科大学 | Berberine liposome and preparation method thereof |
| CN102475682B (en) * | 2010-11-30 | 2013-03-13 | 沈阳药科大学 | Berberine liposome and preparation method thereof |
| CN102488656A (en) * | 2011-02-23 | 2012-06-13 | 大连大学 | Method for preparing water-soluble drug liposome by utilizing reverse evaporating process of supercritical fluid |
| CN103449533A (en) * | 2012-05-29 | 2013-12-18 | 华东理工大学 | Supercritical carbon dioxide method for extraction separation of magnetosomes from magnetotactic bacteria |
| CN110448661A (en) * | 2019-08-13 | 2019-11-15 | 合肥市未来药物开发有限公司 | A kind of oil of zedoary turmeric mixed micelle and preparation method thereof |
| CN110448661B (en) * | 2019-08-13 | 2021-12-28 | 合肥市未来药物开发有限公司 | Zedoary turmeric oil mixed micelle and preparation method thereof |
| CN111001000A (en) * | 2019-12-10 | 2020-04-14 | 金陵科技学院 | Berberine hydrochloride FeAg nano-alloy liposome with light-controlled drug release and magnetic-controlled drug release and preparation method thereof |
| CN111001000B (en) * | 2019-12-10 | 2022-02-01 | 金陵科技学院 | Berberine hydrochloride FeAg nano-alloy liposome with light-controlled drug release and magnetic-controlled drug release and preparation method thereof |
| CN113143847A (en) * | 2021-03-09 | 2021-07-23 | 厦门大学 | Preparation method and application of long-acting low-toxicity insect-expelling ointment for skin and supercritical carbon dioxide fluid |
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