CN102357071A - Taxol-carried nano microbubble and preparation method thereof - Google Patents
Taxol-carried nano microbubble and preparation method thereof Download PDFInfo
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- CN102357071A CN102357071A CN2011103308082A CN201110330808A CN102357071A CN 102357071 A CN102357071 A CN 102357071A CN 2011103308082 A CN2011103308082 A CN 2011103308082A CN 201110330808 A CN201110330808 A CN 201110330808A CN 102357071 A CN102357071 A CN 102357071A
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Abstract
The invention discloses a taxol-carried nano microbubble and a preparation method thereof. The microbubble has a membrane consisting of a lipoid bilayer and containing N2; the lipoid bilayer comprises hydrophilic groups and hydrophobic groups; the hydrophilic groups are bonded with taxol and the taxol is carried in the membrane consisting of the lipoid bilayer; and the lipoid bilayer is formed by compounding lecithin, cholesterol, polyethylene glycol (PEG)-4000, glucan, Span 80, methanol, ether, 3 percent human serum albumin, a taxol standard substance, and phosphate buffered saline (PBS) liquid. The taxol-carried nano microbubble does not have toxicity or side effect, can be used for peripheral intravenous injection, can pass through the lung and a capillary bed of the whole body (the diameter is generally less than 5 um), can be circulated to tissues of the whole body along with blood after the intravenous injection, has high stability, has a long duration in blood circulation, and does not influence blood flow dynamic of the whole body or a certain system.
Description
Technical field
The invention belongs to the medical medicine field, specifically, relate to a kind of year paclitaxel nano microvesicle and preparation method thereof.
Background technology
Restenosis often takes place in congenital or posteriority blood vessel angiostenosis pathological changes after the intervene operation treatment.Its main pathological basis is that vascular smooth muscle cell curing moves caused new intima hypertrophy.Microtubule inhibitor paclitaxel has the effect of microtubule dynamic stabilization, suppresses the normal formation of spindle, and inhibition transmembrane signal transduction and the gene expression relevant with cell division, so its blocking-up cell mitogen and outgrowth definite effect.Experiment shows that paclitaxel can suppress division and the propagation of VSMCs, can obviously alleviate the new intima hypertrophy in restenosis model.
Paclitaxel is white or off-white powder, fat-soluble height, the dissolubility＜0.004gL in water
-1Oral absorption hardly.(50: 50, the colourless thick concentrated solution of v/v) processing was diluted to 0.3-1.2gL with 5% dextran or normal saline during use to the paclitaxel injection of existing clinical practice by cremophor EL (cremoophor EL contains polyoxyethylene castor oil)/dehydrated alcohol
-1Solution posterior vein instillation 3-24h, infusion dosage is 135-175mgm
-2, maximum tolerated dose (MTD) is infusion 225-240mgm in the 3h
-2Though solved the problems of dissolution of paclitaxel, because toxic and side effects is big, the patient is difficult to tolerance.So the dosage form that exploitation is new, especially supplying the targeting novel form of injection is present research focus.
Summary of the invention
For solving above technical problem, the object of the present invention is to provide a kind of having no side effect, year paclitaxel nano microvesicle of good stability and preparation method thereof.
One of the object of the invention is achieved in that a kind of year paclitaxel nano microvesicle, and its key is: said microvesicle constitutes film by the lipoids bilayer, includes N
2Said lipoids bilayer comprises hydrophilic group and hydrophobic group; Said hydrophilic group link paclitaxel; Paclitaxel is written in the film of lipoids bilayer formation, said lipoids bilayer is by the compound formation of lecithin, cholesterol, PEG-4000, glucosan, span-80, methanol, ether, 3%～6%HSA (human albumin), paclitaxel standard substance, PBS liquid.
Two of the object of the invention is achieved in that the method for preparing of a kind of year paclitaxel nano microvesicle, and its key is to carry out as follows:
(1) with 0.1～0.15g lecithin, 0.04～0.06g cholesterol is put into the reaction bulb of Rotary Evaporators, adds ether dissolution lecithin and cholesterol; 40 ℃ of water-baths, Rotary Evaporators work sees that the reaction bulb bottom forms one deck dry film and finishes reaction, ether is recovered in the bottle appropriate preservation;
(2) configuration 0.01M, the PBS buffer of PH=7.4;
(3) in step (1) reaction bulb, add PBS liquid, 45 ℃ of water-baths, magnetic stirring apparatus at the uniform velocity stirs, and adds 0.4～0.6gPEG-4000 simultaneously, 0.07g～0.105g glucosan, class of 0.1～0.15ml department, homogenizing shaker vibration 6.0 * 10
3R/min 5min, ultrasonic cavitation 5min; 45 ℃ of water bath condition lower magnetic force agitators stir, and feed N simultaneously
25min;
(4) the thick suspension of gained in (3) is obtained multicell nanometer microvesicle suspension through the mocromembrane filtration successively;
(5) 1mg paclitaxel standard substance are dissolved in 1ml methanol, sonic oscillation 1min, miniature eddy mixer vibration 5min obtains the paclitaxel standard substance of 1mg/ml;
(6) get the nanometer microvesicle suspension 1ml that step (3) prepares, adding 0.125ml 3%～6%HSA (human albumin) mixes vibration 10min with the paclitaxel standard substance 0.125ml of the 5mg/ml that step (5) obtains, obtains final year paclitaxel nano microvesicle.
Buffer in the above-mentioned steps (2) is by 8.0g Nacl; 0.20g Kcl; 3.6g Na
2HPO
412H
2O; 0.25g KH
2PO
4Add about 800ml-900ml tri-distilled water at the about 20min of magnetic stirrer, final standardize solution is to 1000ml, and the back is through LanGe-Pump peristaltic pump 0.22 μ m membrane filtration, and 15 pounds of 20min autoclavings make.
By 0.45 μ m filtering with microporous membrane 2 times, 0.22 μ m filtering with microporous membrane obtains multicell nanometer microvesicle suspension for 2 times to the thick suspension of above-mentioned steps (4) successively.
The paclitaxel nano microvesicle that carries of gained of the present invention detects
1. observation by light microscope
Get an amount of paclitaxel nano microvesicle suspension that carries, with 5 times of PBS liquid dilutings, the blood cell counting plate counting is counted four big lattice, the only meter left side of line ball and top.
The big lattice sum/4*10 of microvesicle number/ml=4
4Count results is 8*10
9Individual/ml
Carrying the paclitaxel nano microvesicle observes form and is spheroidal, rule, big or small uniformity under optical microscope.(see figure 2)
2. fluorescence microscope
Carry the fluorescence picture → (see figure 3) of paclitaxel nano microvesicle
3. particle diameter detects
Ma Erwen laser particle size measurer is measured the particle size distribution of microvesicle
Carry paclitaxel nano microvesicle particle diameter between 700nm～800nm.(seeing Fig. 4,5)
Carry Paclitaxel liposome medicament contg stability study 4.HPLC detect
4.1 chromatographic condition chromatographic column: Venusil MP C18; Mobile phase: methanol: water (70: 30); Column temperature: room temperature; Flow velocity is 1.4mLmin
-1The ultraviolet detection wavelength is 227nm;
Sample introduction
Measure 20 μ l.The chromatogram (see figure 6)
4.2 interference test
。Get pure methanol solution,, draw chromatogram by " 4.1 " chromatographic condition sample introduction; The paclitaxel titer of getting solubility again and be 5 μ g/ml draws chromatogram by " 4.1 " chromatographic condition sample introduction.(see figure 7)
The result shows that the peak time that solvent methanol and paclitaxel occur is at a distance of very big, and solvent methanol is noiseless to the mensuration of paclitaxel.
4.3 linear relationship is investigated
Get 0.5 μ g/ml; 1.0 μ g/ml; 2.5 μ g/ml; 5.0 μ g/ml; 7.5 μ g/ml paclitaxel standard solution is sample introduction respectively, is vertical coordinate with peak area A (mAU*s), paclitaxel mass concentration C (μ g/mL) gets equation of linear regression for abscissa carries out linear regression:
A=28.734C+4.3239 (R
2=0.9982) (see figure 8)
4.4 different solubility HSA carry drug loading and envelop rate in the paclitaxel nano microvesicle
Year paclitaxel nano microvesicle for preparing different solubility HSA: (do not add HSA; 1%HSA-PLM; 3%HSA-PLM; 6%HSA-PLM; 10%HSA-PLM)
Supercentrifugal process: get year Ramulus et folium taxi cuspidatae nanometer microvesicle suspension 0.5ml of the HSA of the different solubility that prepare, add the methanol of 3.5ml, vibration 5min, the centrifugal 25min of 15000rpm.Get supernatant 20 μ l sample introductions.
Draw the curve that variable concentrations HSA carries the HPLC of paclitaxel nano microvesicle free paclitaxel, draw peak area.According to the equation of linear regression that " 4.3 " draw, calculate free drug amount (W trip).Envelop rate=(1-W trip/W is total) * 100%.Draw and do not add HSA; 1%HSA; 3%HSA; 6%HSA; The envelop rate that 10%HSA carries the paclitaxel nano microvesicle is respectively 81.78%; 83.75%; 93.51%; 89.08%; 84.88%.
The result shows, does not compare with adding HAS, adds HSA and can improve the envelop rate that carries the paclitaxel nano microvesicle, and have statistical significance (P＜0.05).In each concentration group HSA, 3%HSA, the envelop rate of 6%HSA are higher than other each groups, and have statistical significance (P＜0.05).The result shows, adds 3%～6%HSA and can obviously improve the envelop rate that carries the paclitaxel nano microvesicle.(see figure 9),
5. carry the secondary experiment of paclitaxel nano microvesicle rat body endogenous toxin
5.1. material and method
5.1.1 experiment material: healthy male SD rat, body weight 180～250g (purchasing animal center) in Medical University Of Chongqing; Paclitaxel nano microvesicle, 0.9% sodium chloride injection (purchasing in Tai Ji Xinan Pharmaceutical Co., Ltd.) are carried in self-control
5.1.2 experimental technique: 30 male SD rats are divided into matched group, the treatment group.Matched group gives 0.9% sodium chloride (NS) the injection tail vein injection of 1ml/kg; The treatment group gives year paclitaxel nano microvesicle (PLM) the suspension tail vein injection of 1ml/kg.At injection 24h, 48h puts to death the SD rat in batches behind the 72h, and cardiac puncture phlebotomizes, 3500rpm, and 5min is centrifugal, gets supernatant.Full automatic biochemical apparatus detects liver function (TP, AS/AL, ALT, AST, ALP, kidney merit (BUN, Crea).
5.2 experimental result
Rat body weight result of variations (x ± s, n=8) in the secondary experiment of table 1. whole body poison
Beneficial effect: paclitaxel nano microvesicle avirulence is carried in the present invention, has no side effect; The ability peripheral intravenous injection; Can through lung and whole body capillary bed (diameter usually＜5um), after intravenous injection, can arrive body tissue with blood circulation; Good stability, the persistent period is longer in blood circulation; Do not influence the hemodynamic of whole body or a certain system.Ultrasound microbubble contrast agent can constantly be compressed with the vibration of sound wave and expand in sound field as cavitation nucleus, and when acoustic energy reached certain condition, it was cavitation effect that microvesicle can be smashed by moment.It produces the capillary rupture that ground microjet, shock ripple etc. can make local diameter≤7, the broadening of endotheliocyte gap, and permeability of cell membrane obviously increases, and to the of short duration opening of macromolecular substances, the exogenous macromolecular substances of cellular uptake increases.In this course, microvesicle produces cavitation effect as cavitation nucleus, relies on the energy emission effect, makes the medicine that discharges after the microbubble destruction can intravasation wall even interstice, thus the performance therapeutical effect.
Description of drawings
Fig. 1 is for carrying paclitaxel nano microbubble structure sketch map;
Fig. 2 is for carrying paclitaxel nano microvesicle optical microscope figure;
Fig. 3 is for carrying the fluorescence picture of paclitaxel nano microvesicle;
Fig. 4, Fig. 5 detect figure for the particle diameter that carries the paclitaxel nano microvesicle;
Fig. 6 is the paclitaxel titer, do not carry the blank nanometer microvesicle (LM) of paclitaxel, carry the chromatogram of free paclitaxel in the paclitaxel nano microvesicle (PLM);
Fig. 7 is the chromatogram of solvent methanol, standard substance paclitaxel (5 μ g/ml);
Fig. 8 is that peak area A (mAU*s) is a vertical coordinate, and paclitaxel mass concentration C (μ g/mL) is the linear relationship chart of abscissa;
Fig. 9 is the human albumin's of the different solubility of adding the free paclitaxel chromatogram that carries the paclitaxel nano microvesicle.
The specific embodiment
A kind of year paclitaxel nano microvesicle, said microvesicle constitutes film by the lipoids bilayer, includes N
2Said lipoids bilayer comprises hydrophilic group and hydrophobic group; Said hydrophilic group link paclitaxel; Paclitaxel is written in the film of lipoids bilayer formation, said lipoids bilayer is made up of lecithin, cholesterol, PEG-4000, glucosan, span-80, methanol, ether, 3%HSA, paclitaxel standard substance, the compound of PBS liquid, and its structure is as shown in Figure 1.
Carry the method for preparing of paclitaxel nano microvesicle, carry out as follows:
(1) with 0.1g lecithin, the 0.04g cholesterol is put into the reaction bulb of Rotary Evaporators, adds ether dissolution lecithin and cholesterol; 40 ℃ of water-baths, Rotary Evaporators work sees that the reaction bulb bottom forms one deck dry film and finishes reaction, ether is recovered in the bottle appropriate preservation;
(2) configuration 0.01M, the PBS buffer of PH=7.4;
(3) in step (1) reaction bulb, add PBS liquid, 45 ℃ of water-baths, magnetic stirring apparatus at the uniform velocity stirs, and adds 0.4gPEG-4000 simultaneously, 0.07g glucosan, class of 0.1ml department, homogenizing shaker vibration 6.0 * 10
3R/min 5min, ultrasonic cavitation 5min; 45 ℃ of water bath condition lower magnetic force agitators stir, and feed N simultaneously
25min;
(4) the thick suspension of gained in (3) is obtained multicell nanometer microvesicle suspension through the mocromembrane filtration successively;
(5) 5mg paclitaxel standard substance are dissolved in 1ml methanol, sonic oscillation 1min, miniature eddy mixer vibration 5min obtains the paclitaxel standard substance of 5mg/ml;
(6) get the nanometer microvesicle suspension 2.5ml that step (3) prepares, adding 0.3ml 3%HSA mixes vibration 10min with the paclitaxel standard substance 0.7ml of the 5mg/ml that step (5) obtains, obtains final year paclitaxel nano microvesicle.
A kind of year paclitaxel nano microvesicle, said microvesicle constitutes film by the lipoids bilayer, includes N
2Said lipoids bilayer comprises hydrophilic group and hydrophobic group; Said hydrophilic group link paclitaxel; Paclitaxel is written in the film of lipoids bilayer formation, said lipoids bilayer is made up of lecithin, cholesterol, PEG-4000, glucosan, span-80, methanol, ether, 3%HSA, paclitaxel standard substance, the compound of PBS liquid, and its structure is as shown in Figure 1.
Carry the method for preparing of paclitaxel nano microvesicle, carry out as follows:
(1) with 0.15g lecithin, the 0.06g cholesterol is put into the reaction bulb of Rotary Evaporators, adds ether dissolution lecithin and cholesterol; 40 ℃ of water-baths, Rotary Evaporators work sees that the reaction bulb bottom forms one deck dry film and finishes reaction, ether is recovered in the bottle appropriate preservation;
(2) configuration 0.01M, the PBS buffer of PH=7.4; Said buffer is by 8.0g Nacl; 0.20g Kcl; 3.6g Na
2HPO
412H
2O; 0.25g KH
2PO
4Add about 800ml-900ml tri-distilled water at the about 20min of magnetic stirrer, final standardize solution is to 1000ml, and the back is through LanGe-Pump peristaltic pump 0.22 μ m membrane filtration, and 15 pounds of 20min autoclavings make.
(3) in step (1) reaction bulb, add PBS liquid, 45 ℃ of water-baths, magnetic stirring apparatus at the uniform velocity stirs, and adds 0.6gPEG-4000 simultaneously, 0.105g glucosan, class of 0.15ml department, homogenizing shaker vibration 6.0 * 10
3R/min 5min, ultrasonic cavitation 5min; 45 ℃ of water bath condition lower magnetic force agitators stir, and feed N simultaneously
25min;
(4) with thick suspension of gained in (3) successively by 0.45 μ m filtering with microporous membrane 2 times, 0.22 μ m filtering with microporous membrane obtains multicell nanometer microvesicle suspension for 2 times;
(5) 1mg paclitaxel standard substance are dissolved in 1ml methanol, sonic oscillation 1min, miniature eddy mixer vibration 5min obtains the paclitaxel standard substance of 1mg/ml;
(6) get the nanometer microvesicle suspension 1ml that step (3) prepares, adding 0.125ml 3%～6%HSA mixes vibration 10min with the paclitaxel standard substance 0.125ml of the 1mg/ml that step (5) obtains, obtains final year paclitaxel nano microvesicle.
A kind of year paclitaxel nano microvesicle, said microvesicle constitutes film by the lipoids bilayer, includes N
2Said lipoids bilayer comprises hydrophilic group and hydrophobic group; Said hydrophilic group link paclitaxel; Paclitaxel is written in the film of lipoids bilayer formation, said lipoids bilayer is made up of lecithin, cholesterol, PEG-4000, glucosan, span-80, methanol, ether, 3%HSA, paclitaxel standard substance, the compound of PBS liquid, and its structure is as shown in Figure 1.
Carry the method for preparing of paclitaxel nano microvesicle, carry out as follows:
(1) with 0.12g lecithin, the 0.05g cholesterol is put into the reaction bulb of Rotary Evaporators, adds ether dissolution lecithin and cholesterol; 40 ℃ of water-baths, Rotary Evaporators work sees that the reaction bulb bottom forms one deck dry film and finishes reaction, ether is recovered in the bottle appropriate preservation;
(2) configuration 0.01M, the PBS buffer of PH=7.4; Said buffer is by 8.0g Nacl; 0.20g Kcl; 3.6g Na
2HPO
412H
2O; 0.25g KH
2PO
4Add about 800ml-900ml tri-distilled water at the about 20min of magnetic stirrer, final standardize solution is to 1000ml, and the back is through LanGe-Pump peristaltic pump 0.22 μ m membrane filtration, and 15 pounds of 20min autoclavings make.
(3) in step (1) reaction bulb, add PBS liquid, 45 ℃ of water-baths, magnetic stirring apparatus at the uniform velocity stirs, and adds 0.5gPEG-4000 simultaneously, 0.10g glucosan, class of 0.12ml department, homogenizing shaker vibration 6.0 * 10
3R/min 5min, ultrasonic cavitation 5min; 45 ℃ of water bath condition lower magnetic force agitators stir, and feed N simultaneously
25min;
(4) with thick suspension of gained in (3) successively by 0.45 μ m filtering with microporous membrane 2 times, 0.22 μ m filtering with microporous membrane obtains multicell nanometer microvesicle suspension for 2 times;
(5) 1mg paclitaxel standard substance are dissolved in 1ml methanol, sonic oscillation 1min, miniature eddy mixer vibration 5min obtains the paclitaxel standard substance of 1mg/ml;
(6) get the nanometer microvesicle suspension 1ml that step (3) prepares, adding 0.125ml 3%HSA mixes vibration 10min with the paclitaxel standard substance 0.125ml of the 1mg/ml that step (5) obtains, obtains final year paclitaxel nano microvesicle.
Claims (4)
1. one kind carries the paclitaxel nano microvesicle, and it is characterized in that: said microvesicle constitutes film by the lipoids bilayer, includes N
2Said lipoids bilayer comprises hydrophilic group and hydrophobic group; Said hydrophilic group link paclitaxel; Paclitaxel is written in the film of lipoids bilayer formation, said lipoids bilayer is made up of lecithin, cholesterol, PEG-4000, glucosan, span-80, methanol, ether, 3%～6%HSA, paclitaxel standard substance, the compound of PBS liquid.
2. the method for preparing of said year paclitaxel nano microvesicle of a claim 1 is characterized in that carrying out as follows:
(1) with 0.1～0.15g lecithin, 0.04～0.06g cholesterol is put into the reaction bulb of Rotary Evaporators, adds ether dissolution lecithin and cholesterol; 40 ℃ of water-baths, Rotary Evaporators work sees that the reaction bulb bottom forms one deck dry film and finishes reaction, ether is recovered in the bottle appropriate preservation;
(2) configuration 0.01M, the PBS buffer of PH=7.4;
(3) in step (1) reaction bulb, add PBS liquid, 45 ℃ of water-baths, magnetic stirring apparatus at the uniform velocity stirs, and adds 0.4～0.6gPEG-4000 simultaneously, 0.07g～0.105g glucosan, class of 0.1～0.15ml department, homogenizing shaker vibration 6.0 * 10
3R/min 5min, ultrasonic cavitation 5min; 45 ℃ of water bath condition lower magnetic force agitators stir, and feed N simultaneously
25min;
(4) the thick suspension of gained in (3) is obtained multicell nanometer microvesicle suspension through the mocromembrane filtration successively;
(5) 1mg paclitaxel standard substance are dissolved in 1ml methanol, sonic oscillation 1min, miniature eddy mixer vibration 5min obtains the paclitaxel standard substance of 1mg/ml;
(6) get the nanometer microvesicle suspension 1ml that step (3) prepares, adding 0.125ml 3%～6%HSA mixes vibration 10min with the paclitaxel standard substance 0.125ml of the 1mg/ml that step (5) obtains, obtains final year paclitaxel nano microvesicle.
3. according to the method for preparing of said year paclitaxel nano microvesicle of claim 2, it is characterized in that: buffer in the said step (2), by 8.0g Nacl; 0.20g Kcl; 3.6g Na
2HPO
412H
2O; 0.25g KH
2PO
4Add about 800ml-900ml tri-distilled water at the about 20min of magnetic stirrer, final standardize solution is to 1000ml, and the back is through LanGe-Pump peristaltic pump 0.22 μ m membrane filtration, and 15 pounds of 20min autoclavings make.
4. according to the method for preparing of said year paclitaxel nano microvesicle of claim 2, it is characterized in that:
By 0.45 μ m filtering with microporous membrane 2 times, 0.22 μ m filtering with microporous membrane obtains multicell nanometer microvesicle suspension for 2 times to the thick suspension of said step (4) successively.
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Cited By (4)
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| CN103272220A (en) * | 2013-06-06 | 2013-09-04 | 深圳翰宇药业股份有限公司 | Buserelin acetate lipid microbubble and preparation method thereof |
| CN105520939A (en) * | 2014-09-30 | 2016-04-27 | 重庆润泽医药有限公司 | Oxiracetam phospholipid-coated microbubble and preparation method thereof |
| CN105520940A (en) * | 2014-09-30 | 2016-04-27 | 重庆润泽医药有限公司 | Levo-oxiracetam phospholipid-coated microbubble and preparation method thereof |
| CN105997938A (en) * | 2016-07-15 | 2016-10-12 | 三峡大学 | Paclitaxel carried microbubble, siRNA carried microbubble, paclitaxel and siRNA carried microbubble, as well as preparation methods and applications thereof |
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| WO2011107437A1 (en) * | 2010-03-02 | 2011-09-09 | Fresenius Medical Care Deutschland G.M.B.H. | Microvesicles (mvs) derived from adult stem cells for use in the therapeutic treatment of a tumor disease |
| CN102138889A (en) * | 2011-03-25 | 2011-08-03 | 中国科学院深圳先进技术研究院 | Targeted drug-bearing ultrasonic microbubble and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103272220A (en) * | 2013-06-06 | 2013-09-04 | 深圳翰宇药业股份有限公司 | Buserelin acetate lipid microbubble and preparation method thereof |
| CN105520939A (en) * | 2014-09-30 | 2016-04-27 | 重庆润泽医药有限公司 | Oxiracetam phospholipid-coated microbubble and preparation method thereof |
| CN105520940A (en) * | 2014-09-30 | 2016-04-27 | 重庆润泽医药有限公司 | Levo-oxiracetam phospholipid-coated microbubble and preparation method thereof |
| CN105997938A (en) * | 2016-07-15 | 2016-10-12 | 三峡大学 | Paclitaxel carried microbubble, siRNA carried microbubble, paclitaxel and siRNA carried microbubble, as well as preparation methods and applications thereof |
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