CN104083326A - Method for preparing lipidosome coated with protein drugs - Google Patents
Method for preparing lipidosome coated with protein drugs Download PDFInfo
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Abstract
The invention relates to a novel method for preparing small-particle-size high-encapsulation-efficiency lipidosome coated with protein drugs and belongs to the technical field of biological medicines. The preparation process comprises the following steps: a, dissolving lipids for forming the lipidosome in an organic solvent, mixing the lipids, a protein solution and a proper amount of surfactant according to a proper ratio, and preparing a micro-emulsion phase; b, dissolving the lipids for forming the lipidosome in an organic solvent, mixing and hydrating by using water or a buffer solution or alcohol according to a proper ratio, and preparing a micellar phase; and c, mixing the micro-emulsion phase and the micellar phase, reversing the phase b into a reverse micelle, reversing the phase b again in the process of removing the organic solvent under reduced pressure, finally covering the surface of the phase a micelle with the reverse micelle, and forming the lipidosome. The encapsulated protein drug lipidosome has the average particle size of about 80nm, and the encapsulation ratio can be over 90 percent. The preparation process is simple in process, the production cost is reduced, and industrial production is easily realized.
Description
Technical field
The present invention relates to field of biological pharmacy, the preparation method of the definite high envelop rate liposome of small particle diameter that says a kind of novel protein class medicine.
Background technology
Nanometer liposome (nanoliposomes) refers to that particle diameter is less than the liposome of 100nm, structure mostly is unilamelar liposome, the aspect such as distribute in stability, absorption and body has the special effects of nanoparticle, can carry hydrophilic, hydrophobicity and amphipathic medicine, directly be delivered to target tissue performance drug action, thereby improve the toxicity of the therapeutic index of medicine, the therapeutic dose that reduces medicine and reduction medicine.
At present, the preparation method of liposome has: reverse evaporation, film dispersion method, alcohol injection, active loading method etc., but the deficiency such as that these methods all exist is low to protein medicaments envelop rate, particle diameter is uncontrollable, operation is too complicated.For example: reverse evaporation, be usually used in coating large molecular water soluble drug, but the liposome particle diameter making is large and skewness; Film dispersion method, in hydration process, it is swelling and by eluting from level to level that lipid occurs, and drug distribution is inhomogeneous between layers to cause lipid film, and water soluble drug envelop rate is lower; Alcohol injection need to be prepared under higher temperature, and easily causes structural change or the loss of activity of protein medicaments; Active loading method, though prepare liposome encapsulation increase comparatively loaded down with trivial details, the poor reproducibility of operation and be only applicable to ionizable medicine, range of application is relatively limited.Hou Dongzhi etc. " study on determination method of bovine serum albumin liposome encapsulation " ([J]. Acta Pharmaceutica Sinica, 2007,42 (5): 545-549) in make bovine serum albumin liposome by reverse evaporation envelop rate be 32.5%; Liang Xiaohui etc. " preparation and the physicochemical property research of liver targeting bovine serum albumin liposome " ([J]. Nanjing Medical University's journal: natural science edition; 2008; 28 (10): 1229-1233) in, first adopt reverse phase evaporation to prepare negative charge liposome; modify with O-carboxymethyl-N-lactose acylation chitosan again; the mean diameter of preparation liver target liposomes is 284.1nm, and envelop rate is 34.21%.The low waste that not only can cause raw material of envelop rate, and may not reach effective dose, can not embody the advantage of Liposomal formulation.Publication number is in the patent of mono-kind of the CN1633990A method for preparing lipidosome that water soluble drug had to higher envelop rate, prepare after gel lipid at reverse evaporation, can reach 70% by the liposome obtaining under the current field condition optimizing to the envelop rate of water soluble drug.Adopting reverse evaporation to prepare reason that water soluble drug liposome encapsulation is lower is completing in the transition process of continuous phase from oil phase to water, drug leakage is to due to water, the starting point of this patent design is exactly to wish to overcome the leakage process of medicine, thereby obtains higher envelop rate.
Summary of the invention
In order to overcome the deficiency of above-mentioned liposome technology of preparing, we have invented the preparation method that a kind of new bag carries the high envelop rate liposome of protein medicaments small particle diameter, and the formation theory of microemulsion and micelle is incorporated in the preparation of liposome, to improve the envelop rate of liposome to protein medicaments.The method is called to double-deck micelle and reverses method.This preparation method comprises the following steps:
A. after the lipid material that is used to form liposome being dissolved in to organic solvent reduction vaporization film forming, add appropriate organic solvent that film is redissolved, and mix and emulsifying by pseudo-ternary phase diagram preferred proportion with aqueous solution and the surfactant of medicine, obtain w/o type microemulsion;
B. the lipid material that is used to form liposome is dissolved in to organic solvent reduction vaporization film forming, water or buffer (phosphate, citrate or carbonate buffer solution system) and alcohol is mixed to aquation in suitable ratio and obtain micellar phase.
C. the micellar phase that w/o type microemulsion step a being obtained and step b obtain is mixed, and micellar phase is turned into reverse micelle state immediately, immediately, vacuum rotary steam and nitrogen purging eliminate organic solvent, micellar phase reverse micelle takes a turn for the worse again, and is again covered in microemulsion phase micellar surface, obtains liposome;
D. reduce and homogenize particle diameter and get final product.
We are described in detail the concrete operations with regard to this technology below.
Organic solvent in step a, b refers to and low, the volatile organic solvent of removing of water miscibility, or its mixture, and the preferably volatile organic solvent of low boiling, as ether, chloroform, dichloromethane etc.
The lipid material that is used to form liposome mainly comprises: the phospholipid of natural or synthetic, regulates the cholesterol of immobilized artificial membrane character; And the mixture of different lipids; Described phospholipid is selected from phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, phosphatidyl glycerol, diphosphatidylglycerol, two myristoyl ovum Phosphorylcholines, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, DMPEA, two myristoyl Phosphatidylserine, DPPG, dipalmitoyl phosphatidyl choline, DPPE, distearoyl phosphatidylcholine, DSPG, DSPE; DOPG, DOPC, DOPE, hydrogenated soybean lecithin; The cholesterol of described adjusting immobilized artificial membrane character is selected from cholesterol, cholesterol succinate, amido formacyl cholesterol, plant sterol and composition thereof.In step a and lipid described in b, the amount of substance ratio of phospholipid is less than 1:1, preferably 1:3～4:5.
Described protein medicaments is selected from the water-solubility protein medicine obtaining by chemosynthesis or gene recombination technology or biological extraction mode, optional bovine serum albumin, ovalbumin, Thymopentin, insulin, calcitonin etc.
In order to improve the envelop rate of protein medicaments to be encapsulated, also can add positive charge lipid, as stearmide, oleoyl aliphatic amine derivative, cholesterol derivative etc., realize the loading of protein medicaments by charge effect.
In order to improve the oxidation resistance of phospholipid, also can add fat-soluble antioxidant.
Further, in step a, must obtain the stable w/o type microemulsion that has light blue opalescence.In microemulsion prepared by step a, pharmaceutical aqueous solution and organic solvent volume ratio are less than 1:5, and preferred ratio is 1:8～1:25; The micelle of preparing in step b, water and alcohol volume ratio are 1:1～10:1, preferred ratio is 2:1～8:1.
Emulsifying in step a refers to stirring, or vibration, or even breast, or the operation of ultrasonic mechanical work, or is stirring, vibration, even breast, ultrasonic combination operation, or is that prescription composition is automatic emulsified.The preferred vortex vibration of described vibration, the even breast of the preferred high pressure of even breast, w/o type microemulsion can adopt pseudo-ternary phase diagram to be optimized, make the stable homogeneous Emulsion of clear and bright or light blue opalescence, if the aqueous solution ratio of organic solvent and medicine is improper, Emulsion is unstable, layering and precipitating, material to be encapsulated cannot be encapsulated in to interior water, thereby cause envelop rate to reduce.
Aquation in step b, can adopt distilled water or buffer and alcohol to complete at suitable temperature, be acceleration of hydration, also can under the effect of mechanical force, complete, as stirred or vibrate, described buffer is selected from phosphate, citrate or carbonate buffer solution system.
In step a, surfactant comprises the nonionic surfactant such as Tween-80, Poloxamer, Cremophor EL, Cremophor RH40, Solutol HS15, or is the mixture of several surfactants.
In step b, alcohol used comprises the conventional cosurfactants such as ethanol, propylene glycol, Macrogol 200, PEG400.
In order to obtain sterile preparation, can be by the liposome aseptic filtration obtaining in step c, other step adopts sterile working to complete.
The material to be encapsulated of mentioning in the present invention, can be water-solubility protein class medicine, can be also other material, as polypeptide, DNA, RNA etc.
Preparation technology's tool of the present invention has the following advantages:
Liposome suitability for industrialized production must solve several problems, for example: sterilizing, depyrogenation, production technology are simply convenient to amplify, ensures that liposome is stablized in shelf time.And we preparation technology of invention can address the above problem: 1) can be by the liposome aseptic filtration obtaining in step c, other step adopts sterile working to complete; 2) technique is relatively simple, only needs the common equipments such as simple emulsifying, aquation and homogenizing, is easy to amplify; 3) gained liposome outward appearance clarification, has light blue opalescence, steady quality, and its stability is investigated, show that through the accelerated test of 6 months quality is without significant change.
The present invention can effectively control liposome particle diameter, only needs homogenizing processing, can obtain the small particle diameter liposome of homogeneous grain diameter, has increased using value of the present invention.
This preparation method is greater than 90% to protein medicaments envelop rate.Due to protein medicaments be contained in all the time the interior water of microemulsion, in order phospholipid layer inside, reverse mutually secondary by reverse micelle again and seal, greatly improved the medicine amount of carrying of unit mass lipid, therefore envelop rate is higher.Meanwhile, our preparation technology can fully ensure the activity of protein medicaments.Because preparation technology completes at low temperatures, avoided hydrolysis and the oxidation of medicine, and protein medicaments directly do not contact organic solvent, therefore there is good biological activity and physical stability.
Brief description of the drawings
Fig. 1 is the ternary phase diagrams of EL-PC-water.
Fig. 2 is the ternary phase diagrams of EL/PC=4:6.
Fig. 3 is the ternary phase diagrams of EL/PC=3:7.
Detailed description of the invention
Illustrate concrete preparation method of the present invention by following example, but protection scope of the present invention is not limited to this.
Embodiment 1:
The present embodiment is that the method that adopts the present invention to propose is prepared bovine serum albumin nanometer liposome.Step a: the preparation of microemulsion phase.Take 12mg phosphatidylcholine, add 5ml ether, reduction vaporization film forming.Add 5ml ether that film is redissolved, and add Cremophor EL8mg, under magnetic agitation, dripping 0.2ml concentration is extremely light blue opalescence of 2mg/ml Bovine Serum Albumin in Aqueous Solution, obtains microemulsion phase.The ratio of oil phase, water and surfactant adopts pseudo-ternary phase diagram to be optimized: taking Cremophor EL and phospholipid as blended emulsifier according to Km as 9:1,8:2,7:3,6:4,5:5,4:6,3:7,2:8,1:9 mix homogeneously, ether is oil phase, under magnetic agitation, dropwise add distilled water, observe system by turbid to clear or by clear to turbid phenomenon, each component percentages while recording critical point can obtain microemulsion as seen from Figure 1 near Km=4:6 or 3:7; Again respectively taking Cremophor EL and phospholipid as 4:6 and 3:7 as a summit, ether and water are two other summit, obtain the ternary phase diagrams of emulsifying agent-ether-water, see Fig. 2 and Fig. 3, preferably.
Step b: the preparation of micellar phase.Take 24mg phosphatidylcholine, 6mg cholesterol, adds appropriate ether, reduction vaporization film forming.Add 2ml distilled water and 0.5ml ethanol in 40 DEG C of aquations, obtain micellar phase;
Step c: micellar phase adds in microemulsion phase, vortex 5min, after ultrasonic 10min, 40 DEG C of rotary evaporations are removed ether, further eliminate ether residual in system by nitrogen purging, obtain nanometer liposome, and adopt the even mode of high pressure breast further to reduce particle diameter.Adopting the mean diameter of dynamic light scattering determination bovine serum albumin nanometer liposome is 62.7nm, and it is 91.34% that Sepharose4B agarose gel post records envelop rate.
Embodiment 2
Step a: the preparation of microemulsion phase.Take 24mg phosphatidylcholine, add dichloromethane, reduction vaporization film forming.Add 9ml ether that film is redissolved, and add Cremophor EL16mg, under magnetic agitation, dripping 0.6ml concentration is extremely light blue opalescence of 1mg/ml Bovine Serum Albumin in Aqueous Solution, obtains microemulsion phase.
Step b: the preparation of micellar phase.Take 30mg phosphatidylcholine, 5mg cholesterol, 5mg cholesterol succinate, adds appropriate dichloromethane, reduction vaporization film forming.Add 4ml distilled water and 0.5m propylene glycol in 50 DEG C of aquations, obtain micellar phase;
Step c: micellar phase adds in microemulsion phase, under ice bath, after Probe Ultrasonic Searching 10min, 30 DEG C of rotary evaporations are removed ether, further eliminate ether residual in system by nitrogen purging, obtain nanometer liposome.The mean diameter that records bovine serum albumin nanometer liposome is 78.06nm, and it is 90.45% that Sepharose4B agarose gel post records envelop rate.
Embodiment 3
The preparation of ovalbumin nanometer liposome.Step a: the preparation of microemulsion phase.Take phosphatidylcholine 14mg, add 5ml dichloromethane, reduction vaporization film forming.Add 5ml ether that film is redissolved, and add Cremophor RH406mg, under magnetic agitation, dripping 0.5ml concentration is extremely light blue opalescence of 3mg/ml ovalbumin phosphate buffer, obtains microemulsion phase.
Step b: the preparation of micellar phase.Take DSPE 42mg, electropositive lipid carbamoyl cholesterol 5mg, cholesterol succinate 5mg, adds appropriate dichloromethane, reduction vaporization film forming.Add 2ml phosphate buffer and 1ml ethanol in 60 DEG C of aquations, obtain micellar phase;
Step c: press step c operation in embodiment 1, the mean diameter of measuring ovalbumin nanometer liposome is 68.68nm, and it is 92.17% that Sepharose4B agarose gel post records envelop rate.
Embodiment 4:
The preparation of Thymopentin liposome.Step a: the preparation of microemulsion phase.Take 18mg DOPE, add 5ml ether, reduction vaporization film forming.Add 4ml ether, 4ml dichloromethane that film is redissolved, Solutol HS15 adds 10mg, and under magnetic agitation, dripping 1ml concentration is the extremely light blue opalescence of Thymopentin aqueous solution of 4mg/ml, obtains microemulsion phase.
Step b: the preparation of micellar phase.Take 30mg DOPE, 10mg cholesterol, adds appropriate ether, reduction vaporization film forming.Add 2ml citrate buffer and 0.2ml propylene glycol in 60 DEG C of aquations, obtain micellar phase;
Step c: according to step c operation in embodiment 2, the mean diameter of measuring Thymopentin nanometer liposome is 74.54nm, and it is 90.01% that Sepharose4B agarose gel post records envelop rate.
Comparative example
Adopt traditional reverse evaporation to prepare bovine serum albumin liposome.Take phosphatidylcholine 40mg, cholesterol 20mg, adds 5ml ether, reduction vaporization film forming.Add 5ml ether that film is redissolved, at room temperature splashing into 0.5ml concentration is the bovine serum albumin phosphate buffer of 2mg/ml, magnetic agitation 15min becomes emulsus, vortex 5min, after the ultrasonic 10min of water-bath, reduction vaporization removes organic solvent to colloidal state and continues to be evaporated to gel disintegrate, stop reduction vaporization, add the phosphate buffer of the pH=7.4 of 2ml, aquation at 40 DEG C, had both obtained liposome.Adopt the even mode of embodiment 1 step c mesohigh breast to reduce after particle diameter, the mean diameter that obtains bovine serum albumin liposome is 203.3nm, and envelop rate is 35.48%.
Claims (10)
1. bag carries a preparation method for the liposome of protein medicaments, it is characterized in that:
A. the lipid material that is used to form liposome is dissolved in to organic solvent, after decompression film forming, add again appropriate organic solvent that film is redissolved and form oil phase, and be mixed in proportion emulsifying with pharmaceutical aqueous solution and surfactant, obtain w/o type microemulsion, wherein, the ratio of oil phase, water and surfactant is carried out preferably according to pseudo-ternary phase diagram;
B. the lipid material that is used to form liposome is dissolved in to organic solvent, after decompression film forming, water or buffer and alcohol are mixed in proportion aquation, obtain micellar phase;
C. the micellar phase that w/o type microemulsion phase step a being obtained and step b obtain is mixed, and micellar phase is turned into reverse micelle state immediately, immediately, vacuum rotary steam and nitrogen purging eliminate organic solvent, micellar phase reverse micelle takes a turn for the worse again, and is again covered in microemulsion phase micellar surface, obtains liposome.
2. the preparation method that a kind of bag according to claim 1 carries the liposome of protein medicaments, is characterized in that: microemulsion Chinese medicine aqueous solution and the organic solvent volume ratio in step a, prepared are less than 1:5, and preferred ratio is 1:8～1:25; Meanwhile, in the micelle of preparing in step b, water and alcohol volume ratio are 1:1～10:1, and preferred ratio is 2:1～8:1.
3. the preparation method that a kind of bag according to claim 1 and 2 carries the liposome of protein medicaments, is characterized in that: in step a and lipid described in b, the amount of substance ratio of phospholipid is less than 1:1, preferably 1:3～4:5.
4. according to preparation method that in claim 1-3, a kind of bag described in any one carries the liposome of protein medicaments, it is characterized in that: the organic solvent in step a, b refers to and the volatile organic solvent removed low with water miscibility, or its mixture, the preferably volatile organic solvent ether of low boiling, chloroform or dichloromethane.
5. according to preparation method that in claim 1-4, a kind of bag described in any one carries the liposome of protein medicaments, it is characterized in that: the emulsifying in step a refers to stirring, or vibration, or even breast, or ultrasonic mechanical work operation, or be stirring, vibration, even breast, ultrasonic combination operation, or be that prescription composition is automatic emulsified, the preferred vortex vibration of described vibration, the even breast of the preferred high pressure of even breast.
6. the preparation method of carrying the liposome of protein medicaments according to a kind of bag described in claim 1-5, it is characterized in that: the aquation in step b, adopt distilled water or buffer and alcohol to complete at suitable temperature, or complete under the effect of mechanical force, preferably stir or vortex vibration, described buffer is selected from phosphate buffer system, citrate buffer system, carbonate buffer solution system, and described alcohol comprises ethanol, propylene glycol, Macrogol 200, PEG400.
7. the preparation method that a kind of bag described in any one carries the liposome of protein medicaments according to claim 1-6, it is characterized in that: lipid material described in step a, b is natural or the phospholipid of synthetic, regulate the cholesterol of immobilized artificial membrane character, there is other amphiprotic substance of phospholipid similarity, and the mixture of different lipids; Described phospholipid is selected from phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidylinositols, phosphatidyl glycerol, diphosphatidylglycerol, two myristoyl ovum Phosphorylcholines, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, DMPEA, two myristoyl Phosphatidylserine, DPPG, dipalmitoyl phosphatidyl choline, DPPE, distearoyl phosphatidylcholine, DSPG, DSPE; DOPG, DOPC, DOPE, hydrogenated soybean lecithin; The cholesterol of described adjusting immobilized artificial membrane character comprises cholesterol, cholesterol succinate, amido formacyl cholesterol, plant sterol and composition thereof; In step a, surfactant comprises the nonionic surfactant such as Tween-80, Poloxamer, Cremophor EL, Cremophor RH40, Solutol HS15, or is the mixture of several surfactants.
8. the preparation method that a kind of bag described in any one carries the liposome of protein medicaments according to claim 1-7, is characterized in that, also adds appropriate positive charge lipid, is selected from stearmide, oleoyl aliphatic amine derivative, cholesterol derivative.
9. the preparation method that a kind of bag described in any one carries the liposome of protein medicaments according to claim 1-8, is characterized in that: can also add fat-soluble antioxidant.
10. the preparation method that a kind of bag described in any one carries the liposome of protein medicaments according to claim 1-9, is characterized in that: by the liposome aseptic filtration obtaining in step c, other step adopts sterile working to complete.
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| CN106146761A (en) * | 2016-06-03 | 2016-11-23 | 西北大学 | The nano-micelle of a kind of amphipathic multifunctional polymer and preparation thereof and application |
| CN108030088A (en) * | 2017-10-26 | 2018-05-15 | 武汉轻工大学 | A kind of preparation method of protein modified phytosterol liposome powder |
| CN111317140A (en) * | 2020-05-06 | 2020-06-23 | 永安康健药业（武汉）有限公司 | Bile salt-resistant and gastric acid-resistant probiotic preparation as well as preparation method and application thereof |
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