CN100427064C - New method for preparing liposome - Google Patents
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- CN100427064C CN100427064C CNB031114709A CN03111470A CN100427064C CN 100427064 C CN100427064 C CN 100427064C CN B031114709 A CNB031114709 A CN B031114709A CN 03111470 A CN03111470 A CN 03111470A CN 100427064 C CN100427064 C CN 100427064C
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Abstract
The present invention relates to a novel method for preparing liposomes. The present invention solves the problems occurring in the preparation of liposomes by medicine with the defects of easy oxidation, easy hydrolyzation and easy denaturation. The process of the preparation technology comprises the procedures: a. lipid substances used for forming liposomes are dissolved tert butyl alcohol to form a solution; b. water-soluble medicine to be encapsulated is dissolved in water to form a solution; c. a single-phase solution is obtained by mixing the two solutions according to suitable proportion; d. the obtained single-phase solution is lyophilized to remove solvent; e. liposomes for wrapping water-soluble medicine are obtained by hydrating the obtained lyophilized product. The technology has the advantages of simple process, easy realization and easy amplification and is suitable for industrialization production.
Description
Technical field:
The present invention relates to the biological medicine technology field, exactly it is a kind of new method for preparing liposome.
Background technology:
Liposome is the closed vesicle shape structure that is formed by phospholipid bilayer.Liposome can be divided into unilamellar liposome (unilamellar vesicles), multilamellar liposome (multilamellar vesicles) and multilamelar liposome (multivesicular liposomes) according to the difference of its structure.Liposome is at first found 1965 by British Bangham.After this, it is found that liposome has huge value as the carrier of medicine, so just liposome has been carried out systematic research.
Passed through the exploration of two more than ten years, the scientific research personnel has proposed many of great value method for preparing lipidosome.It seems at present, the preparation method of liposome mainly can be divided into four big classes: 1) based on film dispersion method, the phospholipid that is about to be used to form liposome is dissolved in the organic solvent---normally chloroform or chloroform and methanol mixture, and under the condition of decompression, remove solvent afterwards and form exsiccant immobilized artificial membrane.The immobilized artificial membrane aquation can be formed multilamellar liposome (multilamellar vesicles).Though the method is classic methods, but there are many shortcomings.For example: use the very big organic solvent of toxicity; Can't be applied to suitability for industrialized production; When with pastille aqueous solution aquation, drug level heterogeneity between the multilamellar liposome of formation (multilamellar vesicles) layer and the layer must be handled or the like by multigelation.2) based on w/o breast or w/o/w emulsion.Though this kind preparation method can realize large-scale production (seeing also the depofoam technology platform of skyepharma), still has some problems.Toxicity solvent when removing into breast needs special technique; Because the existence of organic solvent, parcel protide or nucleic acid drug usually can cause the medicine loss of activity.3) detergent dialysis is difficult to suitability for industrialized production, is not suitable for sealing water soluble drug.4) based on injection method, as alcohol injection.Can large-scale production (seeing also the technology of alza company and the crossflow technology of polymun).If but adopt passive medicine carrying legal system to be equipped with liposome, lower for the common envelop rate of water soluble drug, and also because the preparation under the higher temperature of being everlasting (about 60 degree) can cause that usually the medicine of easy oxidation, facile hydrolysis and changeableness loses activity.
In addition, because the Liposomal formulation that obtains by said method is generally liquid preparation.Stability of formulation usually can't solve.The instability of preparation mainly shows following three aspects:
1, liposome belongs to the disperse system of thermodynamic instability.When liposome is suspended in water, usually phenomenons such as gathering, fusion can occur, cause particle diameter to become big.Serious also layering might occur.Because the variation of particle diameter, the preparation that just might cause being used for intravenously administrable can't use.
2, because the characteristic of phospholipid itself when phospholipid is present in water, is easy to occur phenomenons such as hydrolysis, oxidation.Owing to can form lysophosphatide after the phospholipid hydrolysis, increase the toxicity of preparation on the one hand, liposome is disintegrated, cause the seepage of encapsulated medicine.
3, liposome is as being suspended in aqueous phase, and in storage process, the slow seepage of medicine meeting causes the change of entrapment efficiency.If the envelop rate of medicine changes, must influence the curative effect of preparation.
Certainly, if medicine itself is easy to hydrolysis, stability of formulation just more has been a problem so.
How Liposomal formulation sterilizes also is a big problem.Because the characteristic of phospholipid itself is considered to unacceptable usually to final preparation heat sterilization.So just require whole process of production must adopt the sterile working.This can't realize in some liposome preparation technology.
The particle diameter control of liposome also is very important.Obtain small particle diameter liposome (less than 200nm) is the target that the scientific research personnel pursues always.This be because:
1, the liposome of big particle diameter is easy to be engulfed by the huge system of biting of intravital monokaryon, thereby is removed rapidly.
2, the liposome of small particle diameter can passive target tumor area and ischemic myocardium.Because tumor growth is very fast, the vascular permeability in tumor district is good, can allow the liposome of small particle diameter to pass through.During myocardial ischemia, vascular permeability increases, and the liposome passive target of small particle diameter is increased.In order to obtain the small particle diameter liposome, need carry out the liposome that has obtained usually ultrasonic, grind or extrude.This often causes the complexity of production technology.And the heat that these means produce also can cause the oxidation and the hydrolysis of phospholipid.
In sum, have only the real the problems referred to above that solved, could obtain effective Liposomal formulation.
Summary of the invention:
In order to overcome the deficiency of above-mentioned liposome preparation technology, we have invented a kind of brand-new liposome preparation technology.New technique by our invention can solve the difficult problem that present Liposomal formulation faces.We also are called this technology butanol/water single phase soln lyophilization.
This preparation method may further comprise the steps:
A, the lipid material that will be used to form liposome and material to be encapsulated maybe will be used to form the lipid material of liposome, material and carrier mass to be encapsulated is dissolved in the butanol/water mixed solvent system, obtain single phase soln;
B, solvent is removed in single phase soln lyophilization that obtains;
C, the lyophilized products aquation that obtains is obtained liposome.
Below we will be described in detail with regard to the concrete operations and the advantage of this technology.
Concrete operations:
The preferred organic solvent of step a is the tert-butyl alcohol, and the lipid material that is used to form liposome mainly comprises phosphatidylcholine, and (phosphatidylcholine is PC) with the cholesterol (cholesterol) of regulating immobilized artificial membrane character.In addition,, can add an amount of electrically charged lipid material in order to improve the envelop rate of material to be encapsulated: when parcel negative charge material, can add the lipid material of lotus positive electricity, as 1,2-diacyl-SN-glycerol-3-ethyl phosphatidylcholine etc.When parcel positive charge water soluble drug, can add the lipid material of bear electricity, as phosphatidyl glycerol and Phosphatidylserine etc.In order to improve the oxidation resistance of phospholipid, can add fat-soluble antioxidant such as vitamin E etc.Single phase soln among the step a can obtain by the following method:
a：
(1) lipid material that will be used to form liposome is dissolved in the tert-butyl alcohol, obtains solution A,
(2) be dissolved in the tert-butyl alcohol as material to be encapsulated, it is dissolved in solution A
Water-soluble as material to be encapsulated, with its water-soluble solution B that obtains, as the adding carrier mass, in the carrier mass water soluble,
(3) solution A and solution B mixing are obtained single phase soln, or solution A and water mixing are obtained single phase soln.
b：
(1) tert-butyl alcohol and water mixing are obtained mixed solvent,
(2) lipid material and the material to be encapsulated that will be used to form liposome maybe will be used to form the lipid material of liposome, material and carrier mass to be encapsulated, add in the above-mentioned mixed solvent system, make its dissolving obtain single phase soln.
Successful implementation of the present invention requires must obtain single phase soln among the step a.Single phase soln refers to clear and bright uniform solution, and is improper as the ratio of t-butanol solution and aqueous solution, muddiness then can occur or precipitate forming single phase soln, can't guarantee to obtain the diffusing thing of being divided into of material/fat to be encapsulated.T-butanol solution and aqueous solution should be by suitable mixed to form single phase soln.The volume ratio of the tert-butyl alcohol and water usually should be greater than 1: 3 in the solution.We are recommended in and prepare phasor when investigating prescription for this reason.
The method that step b preferably removes solvent is a freeze-drying, and single phase soln should be in liquid nitrogen or cryogenic system quick freezing, lyophilizing in freeze dryer then.
Step c is the aquation lyophilized products to form liposome, can adopt distilled water or suitable buffer to finish under suitable temperature, for quickening aquation, also can finish under the effect of mechanical force, as stirring or vibration etc.
In order to obtain sterile preparation, the single phase soln that obtains among the step a can be able to be filtered sterilization, other step is finished under aseptic condition.The t-butanol solution and the aqueous solution that perhaps will be used to form single phase soln filter sterilization respectively, and other step is finished under aseptic condition.
Implement in the single phase soln that obtains among the step a,, can also comprise carrier mass such as sucrose, lactose or mannitol the time of the present invention except lipid material and material to be encapsulated.The adding of these carrier mass has following several advantage: 1, can be used as freeze drying protectant, make the lyophilized products that obtains have good form.2, the adding of carrier mass makes the lyophilized products that obtains be difficult for the moisture absorption, can long term storage.By the time when needing to use, carry out aquation again and form liposome.3, the speed that the lyophilized products aquation forms liposome has been accelerated in the adding of carrier mass greatly.Ratio as carrier mass is suitable, add entry after, lyophilized products aquation immediately forms liposome.4, by adjusting the ratio of carrier mass, can change the particle diameter of liposome.Less or when not adding carrier mass, the liposome that obtains after the aquation is generally visible multilamellar liposome under the optical microscope when the amount of carrier mass, particle diameter is a micron order.When the large percentage of carrier mass, can form the small particle diameter liposome.For example selecting sucrose for use is carrier mass, when sucrose/lipid material greater than 2 the time, can obtain liposome less than 200nm.
The material of mentioning among the present invention to be encapsulated can be that medicine also can be other material.When adopting passive medicine carrying method, material to be encapsulated is a medicine.Be about to medicine, lipid material and carrier mass and be dissolved in the butanol/water mixed solvent system, obtain lyophilizing behind single phase soln.But the lyophilized products long term store that obtains.By the time when using, aquation forms Liposomal formulation.
If the employing active loading method, material to be encapsulated can be materials such as ammonium sulphate, sodium acetate.When for example adopting the ammonium sulphate gradient method to carry out the active medicine carrying.Ammonium sulphate, lipid material and carrier mass can be dissolved in the butanol/water mixed solvent system, obtain lyophilizing behind single phase soln.But the lyophilized products long term store that obtains.By the time when using, add water hydratable and form the liposome that is encapsulated with ammonium sulphate.Then with liposome dilution, make the ammonium sulphate concentration difference that liposome is inside and outside, and then cause H
+Gradient.Afterwards medicine is added, realize initiatively medicine carrying process.
When and for example adopting traditional PH gradient method to seal alkaloid, citric acid, lipid material and carrier mass can be dissolved in the butanol/water mixed solvent system, obtain lyophilizing behind single phase soln.But the lyophilized products long term store that obtains.By the time when using, add the liposome that water hydratable forms the parcel citric acid earlier.And then, cause the inside and outside pH value gradient of liposome with sodium bicarbonate adjusting foreign minister pH value.Add alkaloids medicament afterwards, hatch and obtain the pastille liposome, realize initiatively medicine carrying process.
From above-mentioned steps we as can be seen, we the invention preparation technology have following advantage:
This preparation technology is fit to large-scale production very much.The liposome suitability for industrialized production must solve several problems, for example: sterilize, simply be convenient to amplify except that thermal source, production technology, guarantee that liposome is stablized in shelf time.We preparation technology of invention can address the above problem fully.1) our solution that a step can be obtained filters sterilization, and other steps adopt sterile workings, obtain sterile preparation.2) our technology is very simple and except freeze dryer, needs other equipment hardly, and is very easy to amplify.3) for stable in the shelf time that guarantees liposome, we can be with lyophilized products aquation formation before use liposome.Experiment shows as being used for freeze dried single phase soln and contains carrier mass, and the mass ratio of carrier mass and lipid material is greater than 1: 1, and the lyophilized products that then obtains can long term storage; As be used for freeze dried single phase soln and do not contain carrier mass, lyophilized products can not long term store, aquation immediately after the lyophilizing.Therefore after adding an amount of carrier mass, lyophilized products can long term store.When needs used, adding after the entry immediately, aquation formed liposome.
The present invention has found a kind of method of effective control liposome particle diameter in addition.As previously mentioned, by adjusting the ratio of carrier mass and lipid material, can effectively control the particle diameter of liposome.Because small particle diameter liposome that can homogeneous grain diameter has increased using value of the present invention greatly.
Simultaneously, our preparation technology can fully guarantee the pharmaceutically active that some is responsive.Because preparation technology finishes at low temperatures, has so just avoided the hydrolysis and the oxidation of medicine.We find by preparation butanol/water/fat three-phase phasor, the ratio of the tert-butyl alcohol still can form single phase soln low under 30% situation, because the ratio of the tert-butyl alcohol is very low, in addition time of in single phase soln, existing of medicine very short, almost completely avoided the degeneration inactivation of medicine.
Can avoid the application of harmful solvent and thoroughly remove solvent residual also is an advantage of the present invention.The tert-butyl alcohol is a solvent that toxicity is lower, it has been generally acknowledged that it is one human body had the solvent of slight murder by poisoning, and its toxicity will be well below chloroform and methanol.In addition because the vacuum very low (less than 10pa) of freeze dryer, so almost noresidue of the tert-butyl alcohol in the lyophilized products that obtains.
This preparation method can also improve the encapsulation efficiency of water soluble drug.Improving ideal method of envelop rate for water soluble drug is exactly that water soluble drug is prepared liposome and then dilution under higher phospholipid concentration.But adopt traditional preparation method, lipid concentration greater than 10% with regard to difficult formation liposome.And employing this method greater than 12% o'clock, still can be made into liposome at phospholipid concentration.
The present invention obviously is different from traditional preparation technology, and the present invention makes in the homodisperse phospholipid of medicine that by freeze dried means rehydration forms liposome.Therefore when not adding carrier mass, there is not the inhomogenous phenomenon of drug level between the multilamellar liposome of formation (multilamellar vesicles) layer and the layer.In fact the present invention also provides a kind of method that medicine/fat is divided into diffusing thing (or medicine/fat/carrier mass) for preparing, and being divided into of obtaining loose thing as aquation not, also can be used for preparing other dosage forms.
Concrete preparation method of the present invention is illustrated by following embodiment, but protection scope of the present invention is not limited to this.
The specific embodiment:
Embodiment 1:
The preparation of butanol/water/fat three-phase phasor.Liposoluble in the tert-butyl alcohol of preheating, is obtained the fat/t-butanol solution of variable concentrations, with the not commensurability water dilution of the solution of variable concentrations, place under constant temperature, record phase separation is made phasor.Discovery is at 10 degree, 20 degree, and 35 when spending, and less than 250mg/ml, the phase separation equals about 3/7 in butanol/water substantially in phospholipid/t-butanol solution concentration.
Embodiment 2:
Carrier mass sucrose is to the influence of lyophilized products characteristic: fat/t-butanol solution and sucrose/water solution are mixed obtaining single phase soln lyophilizing, find that the adding of sucrose obviously improves the lyophilized products form, accelerate aquation.And the lyophilized products that obtains can long term storage and is nonhygroscopic.
Embodiment 3:
Carrier mass sucrose is to the influence of liposome particle diameter: fat/t-butanol solution and sucrose/water solution are mixed obtaining single phase soln lyophilizing.The mass ratio of phospholipid/sucrose was respectively 1: 1 in the lyophilized products, and 1: 2.5,1: 5,1: 7.5.The formation phospholipid concentration is 1% liposome after adding entry.Measure particle diameter with ZETASIZER (malvern company).The particle diameter of liposome is respectively 304.3nm, 146.0nm, 131.6nm, 129.8nm (intensity mean).The particle diameter that carrier mass sucrose can change liposome preparation liquid is added in this explanation.
Embodiment 4:
With the liposome that obtains among the transmission electron microscope observation embodiment 3.Adopt negative staining to observe.Be about to liposome with 1%, the dyeing of the phosphotungstic acid of PH=7.Find that under ultramicroscope liposome is transparent ball, result big or small and with particle size analyzer determination matches.
Embodiment 5:
The preparation of oxymatrine liposome mixes 150mg/ml phosphatidylcholine/t-butanol solution 350ul to obtain single phase soln, lyophilizing with 10mg/ml oxymatrine aqueous solution 650ul.With 1ml distilled water aquation, under 1000x oil mirror, observe, to find to form liposome, particle diameter is about 2～3 microns.Separating liposome and free medicine with the post partition method, survey envelop rate, is 21%.
Embodiment 6:
Present embodiment is that a glycoside medicine is made liposome.Adjust the pH value of aqueous solution, the glycoside medicine is soluble in water.Add carrier mass sucrose in the water.Mix the back afterwards with the t-butanol solution of phospholipid and form single phase soln lyophilizing.After the lyophilized products aquation, medicine is 5mg/ml, and phospholipid is 3%, and concentration of sucrose is 10%.The liposome solutions that obtains is the clear and bright solution of optics.Particle diameter is about 150nm.Separating liposome and free medicine with the post partition method, survey envelop rate, is 40%.
Embodiment 7:
Present embodiment is to adopt active loading method to make liposome one cancer therapy drug.Ammonium sulphate is soluble in water, add sucrose in the water.T-butanol solution with aqueous solution and phospholipid is mixed into single phase soln lyophilizing afterwards.The lyophilized products that obtains is used the low amounts of water aquation earlier, obtains the small particle diameter liposome.With 1000 times of this small particle diameter liposome dilutions, add cancer therapy drug.55 degree insulations 15 minutes.Obtain wrapping up the liposome of cancer therapy drug.Separate liposome and free medicine with the post partition method, surveying envelop rate is 99%.
Claims (4)
1, a kind of new method for preparing liposome is characterized in that:
A. prepare a single phase soln,
Its solute is: (1) is used to form the lipid of liposome, material to be encapsulated, or (2) be used to form the lipid of liposome, material and water-solubility carrier to be encapsulated, and described water-solubility carrier is sucrose, lactose or mannitol;
Its solvent is made up of the tert-butyl alcohol and water, and the volume ratio of the tert-butyl alcohol and water is greater than 1: 3,
B. freezing single phase soln is removed solvent, obtains lyophilized products,
C. the lyophilized products aquation that obtains is obtained liposome.
2, a kind of new method for preparing liposome according to claim 1 is characterized in that:
Single phase soln among the step a can obtain by a or b method:
The a method:
(1) can be dissolved in the lipid of the tert-butyl alcohol, substance dissolves to be encapsulated in the tert-butyl alcohol, obtain solution A,
(2) energy is water-soluble substance dissolves to be encapsulated obtains solution B in water,
(3) solution A and solution B mixing are obtained single phase soln;
Or b method:
(1) tert-butyl alcohol and water mixing are obtained mixed solvent,
(2) with lipid, material to be encapsulated, or lipid, material to be encapsulated and water-solubility carrier are dissolved in and obtain single phase soln in the mixed solvent.
3, a kind of new method for preparing liposome according to claim 1 is characterized in that: the lipid that is used to form liposome among the step a is phosphatidylcholine and regulates the cholesterol of immobilized artificial membrane character.
4, a kind of new method for preparing liposome according to claim 1, it is characterized in that: step b single phase soln freezes at liquid nitrogen or cryogenic system, lyophilizing in freeze dryer then.
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| CNB031114709A CN100427064C (en) | 2003-04-16 | 2003-04-16 | New method for preparing liposome |
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| CNB031114709A CN100427064C (en) | 2003-04-16 | 2003-04-16 | New method for preparing liposome |
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| CN100427064C true CN100427064C (en) | 2008-10-22 |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1299764C (en) * | 2003-12-16 | 2007-02-14 | 中国科学院长春应用化学研究所 | Preparing method of liposome endothelial chalone |
| CN1895223B (en) * | 2006-04-05 | 2012-06-27 | 沈阳药科大学 | Production method of elaioplast |
| EP2394640A1 (en) * | 2010-05-21 | 2011-12-14 | MediGene AG | Improved liposomal formulations of lipophilic compounds |
| CN102018676B (en) * | 2010-12-21 | 2012-12-05 | 中山大学 | Method for preparing water-soluble medicine naonparticles and suspension aerosol thereof |
| CN103720657B (en) * | 2013-11-19 | 2017-01-04 | 广东丸美生物技术股份有限公司 | The preparation method of a kind of deformable liposome, and the transmutability liposome of preparation |
| WO2016191547A1 (en) | 2015-05-26 | 2016-12-01 | Comfort Care For Animals Llc | Liposome loading |
| CN106265518B (en) * | 2016-08-31 | 2018-12-07 | 河南佰柯生物科技有限公司 | FGF liposome and preparation method thereof |
| CN110575437B (en) * | 2019-10-24 | 2022-06-24 | 上海交通大学 | Tigecycline liposome preparation |
| CN111701026B (en) * | 2020-06-28 | 2022-10-21 | 吴燕 | Anti-tumor combined drug nano-carrier and preparation method thereof |
| WO2023208876A1 (en) * | 2022-04-26 | 2023-11-02 | Recardio Inc. | Novel dutogliptin formulations and their preparation |
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