CN101732349B - Venenum bufonis nanometer long-circulating liposome and preparation method thereof - Google Patents
Venenum bufonis nanometer long-circulating liposome and preparation method thereof Download PDFInfo
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- CN101732349B CN101732349B CN2008102027342A CN200810202734A CN101732349B CN 101732349 B CN101732349 B CN 101732349B CN 2008102027342 A CN2008102027342 A CN 2008102027342A CN 200810202734 A CN200810202734 A CN 200810202734A CN 101732349 B CN101732349 B CN 101732349B
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Abstract
The invention discloses a venenum bufonis nanometer long-circulating liposome and a preparation method thereof. The venenum bufonis nanometer long-circulating liposome comprises the following components in part by weight: 1 part of venenum bufonis extract, 10-100 parts of phosphatide, 1-10 parts of cholesterol, 0.1-50 parts of surfactant and 0.1-10 parts of film-modified material. The venenum bufonis nanometer long-circulating liposome effectively prolongs the stay time of an active component of venenum bufonis in the blood of the body, reduces the highest concentration of a medicament, has remarkably lower toxicity than that of the traditional product, has the target treatment effect and uniform distribution of granularity of products, and can be used for treating various tumor diseases.
Description
Technical field
The present invention relates to a kind of plasmalogen preparation, particularly a kind of Venenum Bufonis nanometer long-circulating liposome and preparation method thereof.
Background technology
Venenum Bufonis is the ear rear gland of Bufo siccus or Bufo melanostictus and the white serosity of skin gland secretion, processes through dry processing.The Bufo siccus of proved recipe extensive use at all times, Venenum Bufonis draw out pus by applying a plaster to the affected part detumescence, analgesic therapy parasite killing, heart tonifying diuresis.Through modern scientific research; The mixture of the bufogenin in the discovery Venenum Bufonis, cinobufacin, three kinds of liposoluble constituents of Toadpoison Medicine not only has obvious antineoplastic, and can also be effects such as normal cell (inducing tumor cell differentiation), inducing apoptosis of tumour cell, the formation of inhibition tumor cell new vessels, reduction neoplasm metastasis with tumour cell transformation, especially Lymphocytic leukemia is had effect (Jiang Kaixian chief editor preferably; Clinical and the research of Venenum Bufonis; TCM Document, Maritime Press, Beijing; 1994, P58).But above-mentioned several kinds of compositions have certain toxicity, and clinical use is restricted, and therefore how to improve its performance and become one of focus of people's concern.
The Venenum Bufonis complicated component, contain 10 surplus kind of bufotalin and a large amount of indoles alkaloid, directly use possibly cause uncontrollable toxic reaction, and is not suitable for directly processing injection preparation.The inventor obtains a kind of Venenum Bufonis extract through a large amount of experimental exploring, is bufogenin, cinobufacin and the three kinds of bufotalin mixture of Toadpoison Medicine that contain percentage by weight >=90%, and has applied for Chinese patent that application number is 200710041880.7.
Liposome is with drug encapsulation made ultra micro spheroid carrier preparation in the thin film that the class lipid bilayer forms; It can be used as the targeted delivery of drugs carrier of all kinds of medicines; Through various route of administration, make the medicine of parcel have targeting property, can arrive diseased region, tissue and cell by selectivity; Thereby increase the curative effect of medicine, reduce the therapeutic dose and reduction drug toxicity of medicine.But, after liposome gets into blood circulation, because of the effect of the albumen in the blood, opsonin, antibody, enzyme etc., easy breaking, the quick seepage of the medicine of sealing is absorbed by reticuloendothelium system (RES) identification, thereby has reduced using value.So people are devoted to study long circulating liposomes (longcirculatingliposomes).
Long circulating liposomes is through in the composition of liposome, adding film modified material of certain proportion such as Polyethylene Glycol lipoid derivant; Make surface of liposome expose modes such as some hydrophilic polysaccharide or polyhydroxy group; Reduce with blood plasma in the combining of conditioning ingredients, thereby increase it in stability in blood.Long circulating liposomes is the time of prolong drug in blood flow more enduringly, avoids engulfing of reticuloendothelial system (RES), arrives targeting moiety to obtain the more competent time.At present; There are a plurality of drugmakers to be engaged in the research of (or specializing in) liposome abroad; The liposome of cancer therapy drug abroad goes on the market; Be mainly the product of long circulating liposomes, like Doxil, Daunoxome and
.Therefore, long circulating liposomes is the extensive cancer therapy drug targeting drug delivery system of a kind of application prospect.
Patent application document CN1647799A discloses a kind of injection Venenum Bufonis extract Liposomal formulation and preparation method thereof.Its liposome comprises Venenum Bufonis extract, phospholipid, cholesterol, is a kind of conventional liposome, and it is not bufogenin, cinobufacin and the three kinds of bufotalin mixture of Toadpoison Medicine that contain percentage by weight >=90% that the wherein said Venenum Bufonis that is extracts.
Patent application document CN1951400A discloses a kind of arenobufagin nanoliposome and preparation method thereof.Its liposome comprises Venenum Bufonis extract, phospholipid, and cholesterol, surfactant is a kind of conventional liposome, wherein said Venenum Bufonis extract composition is comparatively complicated.Therefore, be necessary long circulating liposomes as pharmaceutical carrier, in conjunction with a kind of nanometer long-circulating liposome that contains Venenum Bufonis extract of Venenum Bufonis extract development.
Summary of the invention
Therefore; The technical problem that the present invention will solve is exactly the deficiency that exists to existing Venenum Bufonis liposome; A kind of Venenum Bufonis nanometer long-circulating liposome preparation and preparation method thereof is provided, and this Venenum Bufonis nanometer long-circulating liposome preparation has significantly reduced the Venenum Bufonis maximum concentration in the blood; Significant prolongation the release time of Venenum Bufonis, have good long-acting.
The present invention solves the problems of the technologies described above one of technical scheme of being adopted; A kind of Venenum Bufonis nanometer long-circulating liposome, it comprises following components in part by weight: 1 part of Venenum Bufonis extract, 0～100 part of phosphatidase 11; 1～10 part in cholesterol, 0.1～10 part of 0.1～50 part in surfactant and film modified material.
Among the present invention, described Venenum Bufonis extract preferably contains the mixture of bufogenin, cinobufacin and three kinds of bufotalins of Toadpoison Medicine of percentage by weight >=90%, and one Chinese patent application 200710041880.7 is seen in its source for details.When Venenum Bufonis nanometer long-circulating liposome of the present invention was used for medical field, wherein the amount of Venenum Bufonis extract was the treatment effective dose.
Among the present invention, described phospholipid can be natural phospholipid, like in soybean phospholipid, the lecithin one or both.The preferred natural phospholipid of the present invention:, little because of its liposome particle diameter that makes, envelop rate is high, safety good like soybean phospholipid, lecithin.The content of phospholipid is relevant with envelop rate, and too low, then envelop rate is low; Otherwise, too high, then envelop rate is not had obvious improvement, and influence product stability because of its easy oxidation, hydrolysis.
Among the present invention, described cholesterol level and film permeability-related, too low, then permeability is bad; Otherwise, too high, then produce seepage.
Among the present invention, described surfactant is the pharmaceutical adjuvant with solubilising, emulsifying, Stabilization.One or both of preferred poloxamer of the present invention (Poloxamer) 188 and Tween 80.When the content of surfactant is too low, then emulsifying effectiveness is bad, and liposome is unstable; Otherwise, too high, can bring the haemolysis safety issue during then as intravenous formulations.
Among the present invention, described film modified material can make surface of liposome expose some hydrophilic polysaccharide or polyhydroxy group.Preferable, it is 1000～5000 Polyethylene Glycol that described film modified material is selected from molecular weight, and molecular weight is that 6000～20000 polyvinyl alcohol and molecular weight are one or more in the quasi-grease derivative of 6000～20000 Polyethylene Glycol.Preferred Polyethylene Glycol-the phosphatidylcholine of the quasi-grease derivative of described Polyethylene Glycol (PEG-PC), Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE (PEG-PE), Polyethylene Glycol-DSPC (PEG-DSPC) and Polyethylene Glycol-distearyl ethanolamine (PEG-DSPE).
Among the present invention, described Venenum Bufonis nanometer long-circulating liposome is preferable comprises following components in part by weight: 1 part of Venenum Bufonis extract, 4～50 parts in lecithin, 1～10 part in cholesterol, 1～10 part in surfactant and 0.1～1 part of film modified material.
Obviously, as required, also can in the Venenum Bufonis nanometer long-circulating liposome, add various additives, the isotonic agent that need add as as used for intravenous injection preparation or ophthalmic preparation time the: glycerol, glucose etc.; Like antioxidant: vitamin E, vitamin C, sodium sulfite etc.; The antibacterial that need add as as unsterilised oral or external preparation time the: sorbic acid and salt thereof, benzoic acid and salt thereof etc.
That the mean diameter of Venenum Bufonis nanometer long-circulating liposome of the present invention is preferable is 20～100nm.
For ease of storage and transport, the present invention also can be through the conventional drying method, above-mentioned liposome is processed the pro-liposome of dry powder doses like spray drying or lyophilization.
It is that a kind of method for preparing of above-mentioned Venenum Bufonis nanometer long-circulating liposome comprises the following steps: that the present invention solves the problems of the technologies described above two of the technical scheme that adopted
(1) with phospholipid, cholesterol, film modified material and Venenum Bufonis extract are dissolved in organic solvent;
(2) surfactant being dissolved in pH is in 4.0～9.0 the buffer;
(3) step (1) gained solution is dropwise injected step (2) the gained solution of the stirring of logical nitrogen, fully stir;
(4) rotary evaporation is removed organic solvent;
(5) then by even promptly get (aqueous dispersion) of conventional method high pressure breast.
Organic solvent in the step of said method of the present invention (1) can be selected from one or more in methanol, ethanol, the EC, preferred alcohol.
Buffer in the step (2) adopts conventional phosphate buffer (PBS), and the concentration that this surfactant is dissolved in the buffer is generally 0.1～10g/100ml.Preferred poloxamer 188 of surfactant or Tween 80.
Step can adopt magnetic agitation in (3), forms suspension.Preferable 30～70 ℃ are stirred 30～120min.
The method of step (4) for removing organic solvent for conventional rotary evaporation.
Normally adopt high pressure homogenizer to realize for 3～10 times as for the breast of high pressure described in the step (5) is even in the homogenize of 30～120MPa pressure limit internal recycle.This pressure is too little, and then the liposome particle diameter surpasses 100nm; And pressure is too big, then can cause the cohesion of liposome.
Venenum Bufonis nanometer long-circulating liposome of the present invention is a kind of aqueous dispersion, and the different dosage form specification designs in the time of can be according to pharmacy.The present invention is that example is explained with the 100ml aqueous dispersion, and this aqueous dispersion can directly be used for clinical application, like intravenous injection or instillation.
For ease of storage and transport, the present invention also can process dry powder doses like spray drying or lyophilization with aqueous dispersion through the conventional drying method.
Raw material that the present invention is used or reagent except that specifying, all commercially available getting.
Than prior art, beneficial effect of the present invention is following: the present invention adds film modified material in liposome, makes surface of liposome expose some hydrophilic polyhydroxy groups, has obtained a kind of Venenum Bufonis nanometer long-circulating liposome.Venenum Bufonis nanometer long-circulating liposome of the present invention in vivo the holdup time long.After conventional liposome gets into blood circulation, be prone to by the reticuloendothelium system identification, long circulating liposomes is the time of prolong drug in blood flow more enduringly, avoids engulfing of reticuloendothelial system (RES), arrives targeting moiety to obtain the more competent time.Rat internal metabolism dynamic experiment result shows that the time of staying obviously prolongs than conventional liposome Venenum Bufonis nanometer long-circulating liposome of the present invention in vivo.Venenum Bufonis nanometer long-circulating liposome of the present invention has reduced the medicine maximum concentration, and toxicity is starkly lower than existing product.Venenum Bufonis nanometer long-circulating liposome particle diameter of the present invention is little, can reach below the mean diameter 100nm, and particle size distribution is even, and after lyophilizing, does not have significant change.Preparation with this particle diameter has certain target function, more helps disease treatment.The active component Venenum Bufonis extract that the present invention is used, active ingredient are greater than 90%, and content is clear and definite controlled.Method for preparing step of the present invention is simple, and good reproducibility is prone to be applied to suitability for industrialized production.
Description of drawings
Below in conjunction with description of drawings characteristic of the present invention and beneficial effect.
Fig. 1 is the particle size distribution figure of the Venenum Bufonis nanometer long-circulating liposome of embodiment 1.
Fig. 2 for by left-to-right be respectively Venenum Bufonis extract solution, common Venenum Bufonis liposome, Venenum Bufonis nanometer long-circulating liposome (embodiment 4), at the intravital blood drug level～time plot of rat.
The specific embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Venenum Bufonis extract described in the following embodiment is by the method preparation of one Chinese patent application 200710041880.7, and concrete steps are following.Get Venenum Bufonis medical material 1 gram, add dehydrated alcohol 10ml, reflux 40min carries under the above-mentioned condition 2 times.With the extracting solution filtered while hot, revolve the inspissation back of contracting and add 0.9 gram silica gel mixed sample, must mix a kind silica gel.Get 20 gram silica gel with petroleum ether: acetone (volume ratio 5:1) soaks back wet method dress post, adds and mixes a kind silica gel, and use petroleum ether: acetone (volume ratio 5:1) eluant carries out isocratic elution.Collection contains the eluent of these three kinds of liposoluble constituents, and evaporate to dryness promptly gets Venenum Bufonis extract, wherein three kinds of bufotalin mixture account for whole extract percentage by weight greater than 90%.
Resulting Venenum Bufonis nanometer long-circulating liposome adopts Nicomp/Pss ZW380 type particle size analyzer (U.S. PSS company) to measure particle diameter among the following embodiment.
Phospholipid among the following embodiment is that German lipoid company produces, cholesterol is source, Shanghai consor thing Science and Technology Ltd. product, poloxamer 188 is produced for BASF Aktiengesellschaft, and tween 80 is Nanjing WeiEr chemical engineering Co., Ltd's production; Phosphate buffer is pressed the Chinese Pharmacopoeia autogamy; All the other reagent are conventional commercially available prod.
Used high pressure homogenizer is the high pressure homogenizer of the Italian Niro Soavi company NS1001L PANDA 2K model of producing.
With the 40mg Venenum Bufonis extract, the 1000mg soybean phospholipid, 10mg cholesterol and Polyethylene Glycol-DSPC (PEG-DSPC) (molecular weight 6000) 10mg is dissolved in the 5ml ethanol, gets solution A.
500mg poloxamer 188 is dissolved in the phosphate buffer (PBS) of 50ml pH=7.4, solution B.
A solution is dropwise splashed in the B solution of logical nitrogen protection and stirring rapidly, 40 ℃ are stirred 60min, and rotary evaporation is removed ethanol then, and high pressure homogenize filters, and the conventional method lyophilization promptly makes Venenum Bufonis nanometer long-circulating liposome of the present invention.
Resulting Venenum Bufonis nanometer long-circulating liposome adopts said method to measure particle diameter, and mean diameter is 50nm, does not see the particle greater than 200nm.Its particle size distribution such as Fig. 1
With the 40mg Venenum Bufonis extract, the 1000mg soybean phospholipid, 10mg cholesterol and 50mg Macrogol 4000 are dissolved in the 5ml ethanol, get solution A.Other promptly makes Venenum Bufonis nanometer long-circulating liposome of the present invention with embodiment 1.The mean diameter of resulting Venenum Bufonis nanometer long-circulating liposome is 20nm.
With the 40mg Venenum Bufonis extract, the 1000mg soybean phospholipid, 10mg cholesterol and 10mg Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE (PEG-PE) (molecular weight 10000) are dissolved in the 5ml ethanol, get solution A.Other promptly makes Venenum Bufonis nanometer long-circulating liposome of the present invention with embodiment 1.The mean diameter of resulting Venenum Bufonis nanometer long-circulating liposome is 100nm.
With the 40mg Venenum Bufonis extract, the 1000mg soybean phospholipid, 10mg cholesterol and 10mg Polyethylene Glycol-distearyl ethanolamine (PEG-DSPE) (molecular weight 8000) is dissolved in the 5ml ethanol, gets solution A.Other promptly makes Venenum Bufonis nanometer long-circulating liposome of the present invention with embodiment 1.The mean diameter of resulting Venenum Bufonis nanometer long-circulating liposome is 60nm.
With the 10mg Venenum Bufonis extract, 1000mg lecithin, 100mg cholesterol and 100mg Polyethylene Glycol-phosphatidylcholine (PEG-PC) (molecular weight 15000) are dissolved in the 5ml chloroform, get solution A.
The 500mg Tween 80 is dissolved in the phosphate buffer (PBS) of 50ml pH=4.0, solution B.
A solution is dropwise splashed in the B solution of logical nitrogen protection and stirring rapidly, 70 ℃ are stirred 30min, and rotary evaporation is removed chloroform then, and high pressure homogenize promptly makes Venenum Bufonis nanometer long-circulating liposome of the present invention.The mean diameter that records the Venenum Bufonis nanometer long-circulating liposome is 40nm.
With the 10mg Venenum Bufonis extract, 100mg lecithin, 10mg cholesterol and 1mg polyvinyl alcohol (molecular weight 6000) are dissolved in the 5ml ether, get solution A.
The 1mg Tween 80 is dissolved in the phosphate buffer (PBS) of 50ml pH=9.0, solution B.
A solution is dropwise splashed in the B solution of logical nitrogen protection and stirring rapidly, 30 ℃ are stirred 120min, and rotary evaporation is removed ether then, and high pressure homogenize promptly makes Venenum Bufonis nanometer long-circulating liposome of the present invention.The mean diameter that records the Venenum Bufonis nanometer long-circulating liposome is 60nm.
Embodiment 7
With the 10mg Venenum Bufonis extract, 40mg lecithin, 10mg cholesterol and 1mg polyvinyl alcohol (molecular weight 20000) are dissolved in the 5ml methanol, get solution A.
10mg poloxamer 188 is dissolved in the phosphate buffer (PBS) of 50ml pH=7.0, solution B.
A solution is dropwise splashed in the B solution of logical nitrogen protection and stirring rapidly, 50 ℃ are stirred 100min, and rotary evaporation is removed methanol then, and high pressure homogenize promptly makes Venenum Bufonis nanometer long-circulating liposome of the present invention.The mean diameter that records the Venenum Bufonis nanometer long-circulating liposome is 60nm.
Embodiment 8
With the 10mg Venenum Bufonis extract, 500mg lecithin, 100mg cholesterol and 10mg Polyethylene Glycol (molecular weight 1000) are dissolved in the 5ml methanol, get solution A.
The 100mg poloxamer is dissolved in the phosphate buffer (PBS) of 50ml pH=7.0, solution B.
A solution is dropwise splashed in the B solution of logical nitrogen protection and stirring rapidly, 50 ℃ are stirred 100min, and rotary evaporation is removed methanol then, and high pressure homogenize promptly makes Venenum Bufonis nanometer long-circulating liposome of the present invention.The mean diameter that records the Venenum Bufonis nanometer long-circulating liposome is 40nm.
Further specify beneficial effect of the present invention through Test Example below.
Test Example 1
The rat body giving drugs into nose of the Venenum Bufonis nanometer long-circulating liposome that embodiment 4 makes is for dynamic test
Get 18 of SD rats, be divided into three groups at random, first group in the Venenum Bufonis nanometer long-circulating liposome test group of the present invention of tail vein injection 0.7ml embodiment 1, and second group in tail vein injection 0.7ml Venenum Bufonis conventional liposome; The 3rd group in tail vein injection 0.7ml Venenum Bufonis extract 40% propylene glycol solution as matched group, test group and matched group respectively at administration after 0.17h, 0.5h, 1h; 1.5h, 2h, 3h, 4h; 5h, 6h, 8h, 10h; 12h eye socket venous plexus is got blood, and whole blood is put in the heparinization plastic centrifuge tube, in the centrifugal 2min of 10000rpm, separated plasma.
The accurate rat plasma 0.1ml that draws places the 1.5ml plastic centrifuge tube, adds the 1ml ether, the whirlpool
Revolve extraction 2min, centrifugal, to draw upper organic phase and place point end glass centrifuge tube, 40 ℃ of water-bath nitrogen current volatilize, and residue adds the dissolving of 0.1ml mobile phase, and the centrifugal 5min of 10000rmp gets the supernatant high-performance liquid chromatogram determination.
Measure and respectively to organize each time point Toadpoison Medicine concentration after the rat administration, the result sees Figure of description 2.
Venenum Bufonis nanometer long-circulating liposome (embodiment 4) group, Toadpoison Medicine time of staying in blood is 10h; Venenum Bufonis conventional liposome, the Toadpoison Medicine time of staying in blood is 6h; Venenum Bufonis extract propylene glycol solution, Toadpoison Medicine stop 3h in blood.
Through statistical analysis, Venenum Bufonis nanometer long-circulating liposome of the present invention is compared with Venenum Bufonis solution, has significantly reduced the medicine maximum concentration, significant prolongation the release time of medicine, preparation of the present invention has certain long-acting.
Test Example 2
The acute toxicity of the Venenum Bufonis nanometer long-circulating liposome that embodiment 4 makes relatively
Get the Venenum Bufonis nanometer long-circulating liposome that embodiment 4 makes, thin up becomes to contain the aqueous dispersion of 40wt% Venenum Bufonis extract; Venenum Bufonis extract is mixed with the 40wt% propylene glycol solution.Above-mentioned two solution are respectively applied for following intravenous injection.
Mice is evenly divided into groups by body weight, each 10 mice of administration group male and female, fasting is 4 hours before the mouse experiment, freely drinks water.The administration group is by the intravenous injection of the every 0.4ml/20g volume of mice body weight.Observe reaction of animals after the administration continuously and write down dead mouse number in 7 day time.Each dose groups dead mouse number is calculated other LD of two individual characteies with bliss method in the Ministry of Public Health new drug statistical procedure
50(95% fiducial limit) value.
Result: the LD that calculates respectively with the Bliss method
50(95% fiducial limit), the LD of the 40wt% propylene glycol solution of Venenum Bufonis extract
50Be 1.1mg/kg; And the LD of the Venenum Bufonis nanometer long-circulating liposome that embodiment 4 makes
50Be 4.4mg/kg.This shows that the Venenum Bufonis nanometer long-circulating liposome toxicity that embodiment 4 makes obviously descends, and helps antineoplaston.
Test Example 3
The Venenum Bufonis nanometer long-circulating liposome stability test that embodiment 4 makes
The Venenum Bufonis nanometer long-circulating liposome that embodiment 4 is made places 40 ℃, under the condition of 75%RH (humidity), through behind the different time, measures each index.The situation of change such as the table 1 of each index.
Table 1. Venenum Bufonis nanometer long-circulating liposome stability
| Standing time (moon) | Mean diameter (nm) | Toadpoison Medicine content (%) | Bufogenin (%) | Cinobufacin (%) |
| 0 | 55 | 100.0 | 100.0 | 100.0 |
| 1 | 70 | 99.0 | 98.7 | 99.2 |
| 2 | 65 | 98.0 | 97.8 | 98.9 |
| 3 | 65 | 98.0 | 98.0 | 99.0 |
Stability test shows that the Venenum Bufonis nanometer long-circulating liposome that embodiment 4 makes was stable in 3 months.
Claims (5)
1. Venenum Bufonis nanometer long-circulating liposome; It is characterized in that; It comprises following components in part by weight: 1 part of Venenum Bufonis extract; 0～100 part of phosphatidase 11; 1～10 part in cholesterol; 0.1～50 part in surfactant and 0.1～10 part of film modified material contain percentage by weight that the mixture of mixture and these three kinds of bufotalins of bufogenin, cinobufacin and three kinds of bufotalins of Toadpoison Medicine accounts for whole extract greater than 90% in the described Venenum Bufonis extract, described phospholipid is to be selected from soybean phospholipid and the lecithin one or both; Described surfactant is to be selected from one or both of poloxamer 188 and Tween 80; It is 1000～5000 Polyethylene Glycol that described film modified material is selected from molecular weight, and molecular weight is that 6000～20000 polyvinyl alcohol and molecular weight are one or more in the quasi-grease derivative of 6000～20000 Polyethylene Glycol, and the quasi-grease derivative of described Polyethylene Glycol is Polyethylene Glycol-phosphatidylcholine, Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE, Polyethylene Glycol-DSPC and Polyethylene Glycol-distearyl ethanolamine.
2. Venenum Bufonis nanometer long-circulating liposome as claimed in claim 1; It is characterized in that; Described Venenum Bufonis nanometer long-circulating liposome comprises following components in part by weight: 1 part of Venenum Bufonis extract; 4～50 parts in lecithin, 1～10 part in cholesterol, 0.1～1 part of 1～10 part in surfactant and film modified material.
3. Venenum Bufonis nanometer long-circulating liposome as claimed in claim 1 is characterized in that, the mean diameter of described Venenum Bufonis nanometer long-circulating liposome is 20～100nm.
4. the method for preparing of the described Venenum Bufonis nanometer long-circulating liposome of claim 1 is characterized in that, comprises the following steps:
(1) with phospholipid, cholesterol, film modified material and Venenum Bufonis extract are dissolved in organic solvent;
(2) surfactant being dissolved in pH is in 4.0～9.0 the buffer;
(3) step (1) gained solution is dropwise injected step (2) the gained solution of the stirring of logical nitrogen, fully stir;
(4) rotary evaporation is removed organic solvent;
(5) promptly get by conventional method high pressure breast is even then.
5. method for preparing as claimed in claim 4 is characterized in that, the described organic solvent of step (1) is selected from one or more in methanol, ethanol, the EC; The described buffer of step (2) is a phosphate buffer.
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| CN103083286B (en) * | 2011-06-02 | 2014-06-18 | 江苏省中医药研究院 | Toad venom lipophilic extract dry powder inhaler, as well as preparation method and application thereof |
| CN103083239B (en) | 2012-12-26 | 2015-11-25 | 中国人民解放军第四军医大学 | A kind of bufalin liposome and its preparation method and application |
| CN104739807B (en) * | 2015-04-22 | 2017-10-20 | 合肥华方医药科技有限公司 | A kind of total toadpoison lactone nano-micelle preparations and preparation method thereof |
| CN107951861B (en) * | 2016-10-17 | 2020-12-01 | 南京绿叶制药有限公司 | Lipid nanoparticle membrane material composition |
| CN106943336B (en) * | 2017-05-25 | 2020-04-03 | 西南医科大学 | PRP/phospholipid liposome transdermal preparation and preparation method thereof |
| CN109453117A (en) * | 2018-10-26 | 2019-03-12 | 南京中医药大学 | Cardiac glycosides active ingredient composite lipidosome and preparation method thereof |
| CN116196279B (en) * | 2023-04-27 | 2023-07-25 | 上海中医药大学 | Cholesterol-free liposome of venenum bufonis extract, and preparation method and application thereof |
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