CN102670504B - CLA (conjugated linoleic acid)-PTX (paclitaxel) containing micro-emulsion preparation - Google Patents
CLA (conjugated linoleic acid)-PTX (paclitaxel) containing micro-emulsion preparation Download PDFInfo
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Abstract
The invention relates to a passive-targeting drug delivery system, in particular to a CLA (conjugated linoleic acid)-PTX (paclitaxel) containing micro-emulsion preparation. The invention also relates to a preparation method of the micro-emulsion preparation and application of the micro-emulsion preparation in preparing a medicine for treating malignant tumors.
Description
Technical field
The present invention relates to a kind of passive target drug-supplying system, particularly relate to a kind of microemulsion formulation comprising CLA-PTX.The invention still further relates to preparation method and the purposes of described microemulsion formulation in the medicine for the preparation for the treatment of malignant tumor of described microemulsion formulation.
Background technology
Microemulsion (microemulsion) is that water, oil, surfactant and cosurfactant mix in suitable ratio, the isotropism of spontaneous formation, transparent, thermodynamically stable dispersion, it has the special benefits such as particle diameter is little, transparent, Thermodynamically stable, therefore in useful in preparing drug formulations and clinical treatment, has increasingly extensive purposes.Now, microemulsion is generally considered the drug release carrier of a new type ideal, this pharmaceutical carrier have transparent, stable, absorb completely, the advantages such as targeting drug release can be realized, particularly oil-in-water type (O/W type) microemulsion can increase the solvability of fat-soluble medicine in water, thus improves the curative effect of medicine, reduces its toxic and side effects, therefore the clinical value of microemulsion improves day by day, has boundless development prospect.
New type antineoplastic medicine CLA-PTX (" conjugated linoleic acid-paclitaxel conjugate ") is the novel conjugates be connected to form by traditional anti-tumor medicine PTX (paclitaxel) and CLA (conjugated linoleic acid) being carried out chemistry, and it has by blood brain barrier thus realizes the targeted therapy effect to cerebral glioma.But CLA-PTX dissolubility extreme difference in aqueous, cannot reach desirable dosage when carrying out intravenous administration, therefore needs the solubilising carried out when administration to a certain degree.But, traditional solubilizing agent can produce certain toxic and side effects in vivo, free drug in vivo supersession rate is fast and can not realize the targeted therapy of non-brain tumor, and therefore how improving CLA-PTX in the concentration of tumor locus and the toxicity that reduces its internal skin reticular system and normal structure is the greatest problem faced in the research of described medicine.
Summary of the invention
Innovative point of the present invention is passive target microemulsion formulation to combine with new type antineoplastic medicine CLA-PTX, realize coordinating of targeting technology and newtype drug, to improve the dissolubility of antitumor drug, stability and targeting, reduce toxic and side effects, strengthen its antitumous effect.
For this reason, an object of the present invention is to provide a kind of water oil-packaging type micro-emulsion preparation, described preparation comprises oil phase and aqueous phase, it is characterized in that the raw material for making described oil phase is made up of antitumor drug CLA-PTX, oil medium, surfactant, cosurfactant and other optional raw material for the preparation of oil phase.
Another object of the present invention is to provide the preparation method of described microemulsion formulation.
Another object of the present invention is to provide the purposes of described microemulsion formulation in the medicine for the preparation for the treatment of malignant tumor.
Technical scheme of the present invention and main points will elaborate below.
The invention still further relates to following technical scheme:
The preparation method of the microemulsion formulation 1, as described in any one of claim 1-10, is characterized in that described method comprises the steps:
By oil medium, surfactant, cosurfactant and optional other for the preparation of being added in container after the raw material accurate weighing of oil phase;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take CLA-PTX, be added in oil phase, standing or water bath sonicator dissolves completely to CLA-PTX;
The raw material added again after CLA-PTX dissolves completely for making aqueous phase carries out dilution proportion, obtains water oil-packaging type micro-emulsion preparation.
The preparation method of the microemulsion formulation 2, as described in item 1, is characterized in that described method comprises the steps:
By soybean oil, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol according to 5 ~ 10: 15 ~ 22: 10 ~ 20: 50 ~ 70 quality than being added in container after accurate weighing;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take CLA-PTX, be added in oil phase, standing or water bath sonicator dissolves completely to CLA-PTX, makes the concentration of CLA-PTX in oil phase be 20mg/ml ~ 200mg/ml, such as 20mg/ml, 50mg/ml, 100mg/ml, 150mg/ml or 200mg/ml;
Add again after CLA-PTX dissolves completely injection normal saline or mass fraction be 5% glucose injection carry out dilution proportion, obtain water oil-packaging type micro-emulsion preparation.
The preparation method of the microemulsion formulation 3, as described in item 1 or 2, is characterized in that described dilution proportion is according to mass ratio=1 between oil phase and aqueous phase: carry out dilution proportion at 10 ~ 1: 100.
The preparation method of the microemulsion formulation 4, as described in item 1 or 2, is characterized in that the bath temperature of described water bath sonicator is 25-35 DEG C, such as 30 DEG C.
5, the purposes of the microemulsion formulation as described in any one of claim 1-10 in the medicine for the preparation for the treatment of malignant tumor.
6, the purposes as described in item 5, is characterized in that described malignant tumor is cerebral glioma, such as mouse cerebral glioma.
Term
" CLA " represents conjugated linoleic acid, and it has the effect of the anti-cerebral tumor and cerebral tumor new vessels.
" PTX " represents antitumor drug paclitaxel.
" CLA-PTX " represents conjugated linoleic acid-paclitaxel conjugate.
" medicine fat ratio " represents: the mass ratio (w/w) of medicine and fat material, fat material is the general name of the raw material for making described oil phase except antitumor drug CLA-PTX, and namely fat material is made up of oil medium, surfactant, cosurfactant and other optional raw material for the preparation of oil phase.
" PBS solution " represents the phosphate buffer of pH=7.4.
" IC50 " represents drug level corresponding when causing 50% death of neoplastic cells.
" C6 cell " is for being primary in the brain glioblastoma cell of brain.When carrying out effect experiment, described cell is inoculated in oxter on the right side of nude mice, forms dystopy tumor model.
Describe in detail
Can combine arbitrarily between following technical characteristic of the present invention, to form different technical schemes.These technical schemes are all included within the scope of the present invention
The synthetic method of CLA-PTX (" conjugated linoleic acid-paclitaxel conjugate ") is described in list of references Ke XY, Zhao BJ, Zhao X, Wang Y, Huang Y, Chen XM, Zhao BX, Zhao SS, Zhang X, Zhang Q.The therapeutic efficacy of conjugated linoleic acid-paclitaxel on glioma in therat.Biomaterials.2010 Aug; In 31 (22): 5855-64.Content whole disclosed in it to be introduced in the application as a reference at this.
First aspect of the present invention provides a kind of water oil-packaging type micro-emulsion preparation, described preparation comprises oil phase and aqueous phase, it is characterized in that the raw material for making described oil phase is made up of antitumor drug CLA-PTX, oil medium, surfactant, cosurfactant and other optional raw material for the preparation of oil phase.
The example of available oil medium includes but not limited to vegetable oil (such as soybean oil, Oleum Gossypii semen), animal oil, synthetic ester oil and its mixture.
The example of available surfactant includes but not limited to the mixed surfactant of lecithin (such as Ovum Gallus domesticus Flavus lecithin, soybean lecithin) and non-ionic surface active agent (such as polyoxyethylene castor oil (as CremophorELP), polyoxyethylene hydrogenated Oleum Ricini (as CremophorRH), tween (as Tween 80)).
The example of available cosurfactant includes but not limited to ethanol, propylene glycol, glycerol and its mixture.
Other example for the preparation of the raw material of oil phase available includes but not limited to other activating agent (such as other is used for the treatment of the medicine of malignant tumor), antiseptic and antibacterial.
In a preferred embodiment, the raw material for making described oil phase is made up of vegetable oil (for oil medium), lecithin, non-ionic surface active agent (lecithin and non-ionic surface active agent are mixed surfactant) and ethanol (for cosurfactant).
In an especially preferred embodiment, the raw material for making described oil phase is made up of soybean oil, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol.
In this embodiment, soybean oil, Ovum Gallus domesticus Flavus lecithin, mass ratio (w/w) between polyoxyethylene castor oil and ethanol can be: 5 ~ 10: 15 ~ 22: 10 ~ 20: 50 ~ 70, such as 5: 15: 15: 65,5: 20: 10: 65,5: 20: 20: 55,6: 17: 11: 66 and 8: 22: 10: 60, be preferably 8: 22: 10: 60.
In one embodiment, the drug level of antitumor drug CLA-PTX in oil phase is 20mg/ml ~ 200mg/ml, such as 20mg/ml, 50mg/ml, 100mg/ml, 150mg/ml or 200mg/ml.。
In one embodiment, the raw material making described aqueous phase is the upper acceptable aqueous medium of any physiology, and such as injection normal saline or mass fraction are the glucose injection (namely containing 5g glucose in every 100g injection) of 5%.
Another aspect of the present invention provides the preparation method of described microemulsion formulation compositions, and described method comprises the steps:
By oil medium, surfactant, cosurfactant and optional other for the preparation of being added in container after the raw material accurate weighing of oil phase;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take CLA-PTX, be added in oil phase, standing or water bath sonicator dissolves completely to CLA-PTX;
The raw material added again after CLA-PTX dissolves completely for making aqueous phase carries out dilution proportion, obtains water oil-packaging type micro-emulsion preparation.
In a preferred embodiment, described method comprises the steps:
By soybean oil, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol according to 5 ~ 10: 15 ~ 22: 10 ~ 20: 50 ~ 70 quality than being added in container after accurate weighing;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take CLA-PTX, be added in oil phase, standing or water bath sonicator dissolves completely to CLA-PTX, makes the concentration of CLA-PTX in oil phase be 20mg/ml ~ 200mg/ml, such as 20mg/ml, 50mg/ml, 100mg/ml, 150mg/ml or 200mg/ml;
After CLA-PTX dissolves completely, add injection normal saline again or mass fraction is that 5% glucose injection carries out dilution proportion, obtain water oil-packaging type micro-emulsion preparation.
In one embodiment, described dilution proportion is according to mass ratio=1 between oil phase and aqueous phase: carry out dilution proportion at 10 ~ 1: 100.
In one embodiment, the bath temperature of described water bath sonicator is 25-35 DEG C, such as 30 DEG C.
Another aspect of the present invention provides the purposes of described microemulsion formulation in the medicine for the preparation for the treatment of malignant tumor.
In one embodiment, described malignant tumor is cerebral glioma, such as mouse cerebral glioma.
Microemulsion formulation of the present invention can pass through intravenous administration.
Advantage of the present invention and/or the effect that can produce are:
CLA-PTX bag is loaded in the administration concentration that can improve CLA-PTX after in microemulsion formulation, and passive target is to dystopy tumor locus simultaneously, thus plays better antitumor action, and the toxic and side effects of normal tissue reduces simultaneously.
Accompanying drawing explanation
Fig. 1 is the living imaging experimental result of the microemulsion formulation comprising DiR.
Fig. 2 is the tumor bearing nude mice volume of tumor and the relation curve of time upon administration.
Detailed description of the invention
Embodiment 1
Comprise the structure of the microemulsion formulation of CLA-PTX
To be added in container after the soybean oil of above-mentioned mass ratio, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol accurate weighing;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take 20mgCLA-PTX, be added in the oil phase of 1ml, leave standstill and dissolve or adopt water bath sonicator 30s to carry out accelerate dissolution, make the concentration of CLA-PTX in oil phase be 20mg/ml;
Add again after CLA-PTX dissolves completely injection normal saline or mass fraction be the glucose injection of 5% according to oil phase: aqueous phase=1: 10w/w carries out dilution proportion, obtains water oil-packaging type micro-emulsion preparation.
The bath temperature of wherein said water bath sonicator is 30 DEG C.
Embodiment 2
Comprise the structure of the microemulsion formulation of CLA-PTX
To be added in container after the soybean oil of above-mentioned mass ratio, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol accurate weighing;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take 20mgCLA-PTX, be added in the oil phase of 1ml, leave standstill and dissolve or adopt water bath sonicator 30s to carry out accelerate dissolution, make the concentration of CLA-PTX in oil phase be 20mg/ml;
Add again after CLA-PTX dissolves completely injection normal saline or mass fraction be the glucose injection of 5% according to oil phase: aqueous phase=1: 10w/w carries out dilution proportion, obtains water oil-packaging type micro-emulsion preparation.
The bath temperature of wherein said water bath sonicator is 30 DEG C.
Embodiment 3
Comprise the structure of the microemulsion formulation of CLA-PTX
To be added in container after the soybean oil of above-mentioned mass ratio, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol accurate weighing;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take 20mgCLA-PTX, be added in the oil phase of 1ml, leave standstill and dissolve or adopt water bath sonicator 30s to carry out accelerate dissolution, make the concentration of CLA-PTX in oil phase be 20mg/ml;
Add again after CLA-PTX dissolves completely injection normal saline or mass fraction be the glucose injection of 5% according to oil phase: aqueous phase=1: 10w/w carries out dilution proportion, obtains water oil-packaging type micro-emulsion preparation.
The bath temperature of wherein said water bath sonicator is 30 DEG C.
Embodiment 4
Comprise the structure of the microemulsion formulation of CLA-PTX
To be added in container after the soybean oil of above-mentioned mass ratio, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol accurate weighing;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take 20mgCLA-PTX, be added in the oil phase of 1ml, leave standstill and dissolve or adopt water bath sonicator 30s to carry out accelerate dissolution, make the concentration of CLA-PTX in oil phase be 20mg/ml;
Add again after CLA-PTX dissolves completely injection normal saline or mass fraction be the glucose injection of 5% according to oil phase: aqueous phase=1: 10w/w carries out dilution proportion, obtains water oil-packaging type micro-emulsion preparation.
The bath temperature of wherein said water bath sonicator is 30 DEG C.
Embodiment 5
Comprise the structure of the microemulsion formulation of CLA-PTX
To be added in container after the soybean oil of above-mentioned mass ratio, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol accurate weighing;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take 20mgCLA-PTX, be added in the oil phase of 1ml, leave standstill and dissolve or adopt water bath sonicator 30s to carry out accelerate dissolution, make the concentration of CLA-PTX in oil phase be 20mg/ml;
Add again after CLA-PTX dissolves completely injection normal saline or mass fraction be the glucose injection of 5% according to oil phase: aqueous phase=1: 10w/w carries out dilution proportion, obtains water oil-packaging type micro-emulsion preparation.
The bath temperature of wherein said water bath sonicator is 30 DEG C.
Experimental section
For checking the antitumous effect of microemulsion formulation of the present invention, we are for the microemulsion formulation comprising CLA-PTX of embodiment 5, have carried out the investigation of following aspect:
1, the sign of microemulsion character
Adopt dynamic light scattering method (dynamic light scattering, DLS) it to be carried out to the mensuration of particle diameter and zeta current potential, the results are shown in Table 1.Result shows that the preparation method of microemulsion formulation of the present invention is excellent, feasible.
Table 1*
* table 1 is the result of three horizontal surveies.
2, cytotoxicity experiment
Adopt ammonium thiocyanate B (sulforhodamineB) (SRB) assay method, at the 0th day, C6 cell is inoculated in 96 orifice plates with the concentration in 5000/hole.At the 1st day, dissociate the CLA-PTX be formulated in DMSO medicine mother solution (concentration is 10mg/ml) and comprise microemulsion formulation (the preparation-obtained oil phase of Example 5 of CLA-PTX, and the PBS being used as aqueous phase is according to oil phase: the ratio of aqueous phase=1: 10w/w is diluted, the concentration being prepared into CLA-PTX is the microemulsion formulation comprising CLA-PTX of 2mg/ml) dilute further with cell culture medium, be prepared into diluent (the 20.0 μ g/ml of a series of medicine, 16.0 μ g/ml, 10 μ g/ml, 8.0 μ g/ml, 4.0 μ g/ml, 2.0 μ g/ml, 1.0 μ g/ml and 0.5 μ g/ml), often kind of diluent is joined inoculation with the volume of 200 μ l to be had in the hole of tumor cell, diluent parallel assay 3 hole of often kind of concentration, then 48 hours are hatched, discard culture medium, with 10% trichloroacetic acid (w/w) 4 DEG C of fixed cells 1 hour, after tap water, dry and use 0.4%SRB (w/w) 4 DEG C of dyeing 10 minutes, take out and rinse with 0.1% acetic acid (v/v), the Tris solution of 10 μMs is added after drying, put after shaking table shakes 30 minutes, light absorption value is measured at 540nm place by microplate reader, thus determine the IC50 value of medicine for C6 cell line.
Experimental result shows, the average IC50 value measured for three times of microemulsion formulation comprising CLA-PTX is 1.10 ± 0.038 μMs, and the average IC50 value measured for three times of CLA-PTX free drug is 1.86 ± 1.095 μMs, result illustrates that the microemulsion formulation comprising CLA-PTX has the effect of inhibition tumor cell growth more better than CLA-PTX free drug, shows that the microemulsion formulation of the CLA-PTX of comprising of the present invention has excellent antitumous effect.
3, acute toxicity evaluation and LD50 value
For investigating free CLA-PTX and the microemulsion formulation acute toxicity in animal body comprising CLA-PTX, using ICR mice as acute toxicity testing animal, by calculating the toxicity of LD50 (median lethal dose(LD 50)) value reflection medicine.Select ICR mice (body weight 18-22g) 50, be divided into five groups at random, often organize 10, male and female half and half.Free CLA-PTX conjugate is dissolved in polyoxyethylene castor oil: ethanol: water=1: in the mixed solvent of 1: 8 (v/v/v), be mixed with five groups of solution that concentration is 4mg/ml, 4.74mg/ml, 5.64mg/ml, 6.72mg/ml and 8mg/ml, often organize respectively according to the volume of 10ml/kg by tail vein injection administration, observe the dead quantity often organized in mice one week, the mice LD50 value calculating free CLA-PTX is 103.9mg/kg.After get 10 ICR mices (body weight 18-22g), male and female half and half, to the microemulsion formulation of CLA-PTX be comprised (according to the formula of oil phase in embodiment 5, add 200mgCLA-PTX, and the mass fraction being used as aqueous phase be the glucose injection of 5% according to oil phase: the ratio of aqueous phase=1: 10w/w is diluted, obtain the microemulsion formulation comprising CLA-PTX) according to the volume of 10ml/kg by tail vein injection administration, observe the dead quantity in mice one week.There is not death in one week in result display mice, therefore the safe dose of CLA-PTX microemulsion formulation can reach 200mg/kg, illustrates that its toxicity is far smaller than free drug.
4, targeting experiment
Adopt tumor bearing nude mice (every nude mice dystopy inoculation 1 × 10
6individual C6 cell) carry out targeting experiment.Tumor size measuring method is use slide gauge to measure the length (a) of tumor and wide (b) respectively, and the computing formula of gross tumor volume (V) is V=ab
2/ 2, treat that tumor volume growth is to 100-150mm
3time, experimental group nude mice tail vein injection is comprised to the microemulsion formulation of fluorescent dye DiR, its concrete preparation method is as follows: the formula adopting embodiment 5, get fluorescent dye DiR (concentration 2mg/ml, being formulated in the mother solution in methanol) 40 μ l add in 1ml oil phase, use injection normal saline according to oil phase afterwards: the ratio of aqueous phase=1: 10w/w is diluted, form the microemulsion formulation comprising DiR of 8 μ g/ml.The microemulsion formulation comprising DiR is carried out tail vein injection according to the dosage of 80 μ g/kg, and matched group injects isopyknic normal saline, and inject and under living imaging instrument, observe the fluorescence intensity after exciting in latter 24 hours, result is see Fig. 1.
Result shows, compared with matched group, the fluorescence of microemulsion formulation has integrated distribution at tumor locus, illustrates that microemulsion formulation of the present invention has the effect of good passive target tumor.
5, the test of pesticide effectiveness
By tumor bearing nude mice (every nude mice dystopy inoculation 1 × 10
6individual C6 cell) be divided into matched group and microemulsion formulation group (often organizing 6).The the 9th, 12,15 day after tumor to be seeded, according to the microemulsion formulation comprising CLA-PTX of 20mg/kg dosage tail vein injection embodiment 5, measure gross tumor volume size in different time afterwards, continue to the 21st day after inoculated tumour.Experimental result is shown in Fig. 2.
As can be seen from the volume of tumor and the relation curve of time, the 21st day time, the average external volume of nude mice of control group tumor is 2356 ± 429mm
3, and the average external volume of microemulsion formulation group nude mouse tumor is 929 ± 274mm
3, tumour inhibiting rate is 60.5%, and result illustrates that the microemulsion formulation comprising CLA-PTX can the growth of effective Tumor suppression, has good antitumous effect.
Claims (9)
1. a water oil-packaging type micro-emulsion preparation, described preparation comprises oil phase and aqueous phase, it is characterized in that the raw material for making described oil phase is made up of antitumor drug CLA-PTX, oil medium soybean oil, surfactant Ovum Gallus domesticus Flavus lecithin and polyoxyethylene castor oil, cosurfactant ethanol; Soybean oil, Ovum Gallus domesticus Flavus lecithin, mass ratio (w/w) between polyoxyethylene castor oil and ethanol are: 5 ~ 10: 15 ~ 22: 10 ~ 20: 50 ~ 70; The drug level of CLA-PTX in oil phase is 20mg/ml ~ 200mg/ml.
2. water oil-packaging type micro-emulsion preparation as claimed in claim 1, it is characterized in that, soybean oil, Ovum Gallus domesticus Flavus lecithin, mass ratio (w/w) between polyoxyethylene castor oil and ethanol are 5: 15: 15: 65 or 5: 20: 10: 65 or 5: 20: 20: 55 or 6: 17: 11: 66 or 8: 22: 10: 60.
3. the water oil-packaging type micro-emulsion preparation as described in any one of claim 1-2, is characterized in that the drug level of antitumor drug CLA-PTX in oil phase is preferably 20mg/ml, 50mg/ml, 100mg/ml, 150mg/ml or 200mg/ml.
4. the water oil-packaging type micro-emulsion preparation as described in any one of claim 1-2, is characterized in that the raw material for making described aqueous phase is acceptable aqueous medium on any physiology.
5. water oil-packaging type micro-emulsion preparation as claimed in claim 4, is characterized in that the raw material of aqueous phase be injection normal saline or mass fraction is the glucose injection of 5%.
6. the preparation method of water oil-packaging type micro-emulsion preparation according to claim 1, is characterized in that described method comprises the steps:
By soybean oil, Ovum Gallus domesticus Flavus lecithin, polyoxyethylene castor oil and ethanol according to 5 ~ 10: 15 ~ 22: 10 ~ 20: 50 ~ 70 quality than being added in container after accurate weighing;
Mixture above-mentioned steps obtained leaves standstill or water bath sonicator dissolves, and forms the oil phase of transparent and homogeneous;
Accurately take CLA-PTX, be added in oil phase, standing or water bath sonicator dissolves completely to CLA-PTX, makes the concentration of CLA-PTX in oil phase be 20mg/ml ~ 200mg/ml;
Add again after CLA-PTX dissolves completely injection normal saline or mass fraction be 5% glucose injection carry out dilution proportion, obtain water oil-packaging type micro-emulsion preparation.
7. the preparation method of water oil-packaging type micro-emulsion preparation as claimed in claim 6, is characterized in that described dilution proportion is according to mass ratio=1 between oil phase and aqueous phase: carry out dilution proportion at 10 ~ 1: 100.
8. the preparation method of water oil-packaging type micro-emulsion preparation as claimed in claims 6 or 7, is characterized in that the bath temperature of described water bath sonicator is 25-35 DEG C.
9. the preparation method of water oil-packaging type micro-emulsion preparation as claimed in claim 8, is characterized in that the bath temperature of described water bath sonicator is 30 DEG C.
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