CN102861345A - Preparation method of polymer microvesicle ultrasonic contrast agent - Google Patents
Preparation method of polymer microvesicle ultrasonic contrast agent Download PDFInfo
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Abstract
The invention discloses a preparation method of a polymer microvesicle ultrasonic contrast agent. The preparation method comprises the steps as follows: dissolving polylactic acid or polylactic acid-glycolic acid copolymer into dichloromethane; adding ammonium bicarbonate aqueous solution and twain 80; ultrasonically emulsifying for 1 to 2 minutes to obtain high-pressure nitrogen for the mixing liquid; extruding the high-pressure nitrogen from an SPG (shirasu porous glass) membrane; diffusing into an external water phase containing polyving akohol, so as to obtain composite latex; pouring the composite latex into the sodium chloride aqueous solution; solidifying and agitating for 3 to 5 hours at room temperature; centrifugally separating; removing the supernate; washing the rest solid precipitate through the distilled water; and then freezing and drying to obtain a white powder material which is applicable to ultrasonic contrast agent.
Description
Technical field
The present invention relates to the preparation method of contrast agent, be specifically related to the preparation method of polylactic acid and polylactic-co-glycolic acid microcapsular ultrasound contrast agent.
Background technology
The ultrasonic diagnosis technology is to utilize ultrasound wave to transmit biology interior information in reflection and the strong and weak difference of scattered signal of organizational interface's generation of human body, thereby reaches the technology of diagnostic purpose.Acoustic contrast agent is the chemicals that a class can significantly strengthen ultrasonic backscattering intensity, microvesicle is a kind of broad research and modal acoustic contrast agent on the market, cardinal principle is to utilize the hollow structure of microvesicle, at ultrasonic lower generation harmonic wave, thereby reaches the purpose that strengthens humorous intensity of wave.Ultrasonic diagnosis is a kind of noinvasive, painless, convenient, effective detection methods intuitively, can be used for the ultrasonic diagnosis of cardiovascular and liver system.Microbubble contrast agent is a kind of hollow minute particle by protein, lipid, surfactant or macromolecular material parcel air or other noble gases.Polylactic acid is the biodegradation rate that a class can be regulated, and can be absorbed by metabolism in vivo, and catabolite is free from side effects to living organism, therefore obtains widely clinical practice at medical domain.
Summary of the invention
Technical problem to be solved by this invention provides a kind of preparation method of polymer microvesicle acoustic contrast agent.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of preparation method of polymer microvesicle acoustic contrast agent, polylactic acid (PLA) or Poly(D,L-lactide-co-glycolide (PLGA) are dissolved in the dichloromethane, add ammonium bicarbonate aqueous solution and Tween 80, ultrasonic emulsification 1 ~ 2min, obtaining mixed liquor (water/oil) extrudes it with high pressure nitrogen from the SPG film, be distributed to the outer aqueous phase that contains polyvinyl alcohol, obtain double emulsion (water/oil/water), again double emulsion is poured in the sodium-chloride water solution, solidify under the room temperature and stirred 3 ~ 5 hours, supernatant is removed in centrifugalize, with the remaining solid precipitation of distilled water wash, then lyophilization obtains white product.
Wherein, described polylactic acid and Poly(D,L-lactide-co-glycolide are medical rank; Wherein, Poly(D,L-lactide-co-glycolide is that polylactic acid and polyglycolic acid are by weight the copolymer of 75:25 or 50:50.
Wherein, for every 1g polylactic acid or Poly(D,L-lactide-co-glycolide, the use amount of dichloromethane is 20 ~ 80ml.
Wherein, the mass percentage concentration of ammonium bicarbonate aqueous solution is that the mass percentage concentration of 0 ~ 1%(ammonium bicarbonate aqueous solution is when being 0%, namely use the water that does not contain ammonium bicarbonate), the adding volume of ammonium bicarbonate aqueous solution is 10 ~ 20% of methylene chloride volume, the addition of Tween 80 be the addition of 0 ~ 1%(Tween 80 of methylene chloride volume be methylene chloride volume 0% the time, namely do not add Tween 80).
Wherein, described high pressure nitrogen, condition is 1 ~ 2.5 atmospheric pressure.
Wherein, described SPG membrane aperture is 0.5 micron.
Wherein, contain the outer aqueous phase of polyvinyl alcohol, the mass percentage concentration of polyvinyl alcohol is 1 ~ 4%; The volume that uses that contains the outer water of polyvinyl alcohol is 6 ~ 8 times of methylene chloride volume.
Wherein, in the described sodium-chloride water solution, the mass percentage concentration of sodium chloride is 1%; The volume that uses of sodium-chloride water solution is 10 ~ 20 times of the dichloromethane consumption.
Wherein, centrifugal condition is 3000 ~ 4000rpm, 10 ~ 20min.
Beneficial effect: the present invention adopted PLA and with the copolymer p LGA of the polyglycolic acid PGA different proportion capsule material as microcapsule, such material is the biodegradable material of a class, its degradation rate can be regulated, catabolite is safe from harm to body, end product can be a kind of material of environmental protection by metabolism or absorption, and the adding of PGA has improved the hydrophilicity of material, so that the degradation speed quickening, so that.The microgranule that double emulsion-solvent method of waving is sent out preparation is the hollow microcapsule, and echo response is arranged, and can be used as acoustic contrast agent and uses.Adopt SPG film emulsion process when second time emulsifying, this utilization method is simple, mild condition, and it is low consume energy, is conducive to expanding production, and by the emulsion particle diameter homogeneous that this technology prepares, its size can be controlled by the fenestra size.
Description of drawings
Fig. 1 is the photo in kind of polymer microvesicle powder.
Fig. 2 is the SEM figure of PLA microcapsule, and wherein, 1 is less amplification, and 2 are larger amplification.
The SEM figure of Fig. 3 PLGA50/50 microcapsule, 1 is less amplification, 2 are larger amplification.
The SEM figure (1) of Fig. 4 PLGA75/25 microcapsule and TEM figure (2).
External development effect figure (1) water (2) PLA(3 of Fig. 5 polymer microcapsule) PLGA75/25(4) PLGA50/50.
The specific embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described content of embodiment only is used for explanation the present invention, and should also can not limit the present invention described in detail in claims.
In following examples:
PLA is available from Shandong medical device research institute, intrinsic viscosity 0.57d1/g (CHCL
3/ 25 ° of C), medical rank.PLGA5050 be polylactic acid and polyglycolic acid by weight the copolymer of 50:50, available from Shandong medical device research institute, intrinsic viscosity 0.29dl/g (CHCL
3/ 25 ° of C), medical rank.
PLGA7525 be polylactic acid and polyglycolic acid by weight the copolymer of 75:25, available from Shandong medical device research institute, intrinsic viscosity 0.50dl/g (CHCL
3/ 25 ° of C), medical rank.
Embodiment 1:
0.2g PLA is dissolved in the 10ml dichloromethane, getting the 1ml aqueous solution splashes into wherein, (1 is equivalent to 0.05 milliliter to add 1, below identical) Tween 80, ultrasonic emulsification 1min, obtain the solution of water/oil, with the nitrogen of pressure 100kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase that 60ml 2wt% PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify under the room temperature and stirred 3 hours, 4000rpm centrifugalize 10min also cleans the centrifugal solids precipitation with distilled water, and triplicate is got the solid precipitation lyophilization and obtained white product.
Embodiment 2:
0.2g PLA is dissolved in the 10ml dichloromethane, getting 1ml 0.1% ammonium bicarbonate soln splashes into wherein, add 1 Tween 80, ultrasonic emulsification 1min, obtain the solution of water/oil, with the nitrogen of pressure 150kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 70ml 2wt% PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify to be stirred under the room temperature 3 hours, 4000rpm centrifugalize 20min also cleans the centrifugal solids precipitation with distilled water, triplicate is got the solid precipitation lyophilization and is obtained white product.
Embodiment 3:
0.3g PLA is dissolved in the 10ml dichloromethane, getting the 1ml aqueous solution splashes into wherein, ultrasonic emulsification 1min, obtain the solution of water/oil, with the nitrogen of pressure 200kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 75ml 2wt%PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify under the room temperature and stirred 3 hours, 4000rpm centrifugalize 15min also cleans the centrifugal solids precipitation with distilled water, and triplicate is got the solid precipitation lyophilization and obtained white product.
Embodiment 4:
0.5gPLGA7525 be dissolved in the 10ml dichloromethane, getting the 2ml aqueous solution splashes into wherein, add 1 Tween 80, ultrasonic emulsification 1min, obtain the solution of water/oil, with the nitrogen of pressure 150kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 80ml 2wt% PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 200ml 1wt% sodium chloride solution again, solidify to be stirred under the room temperature 3 hours, 4000rpm centrifugalize 10min also cleans the centrifugal solids precipitation with distilled water, triplicate is got the solid precipitation lyophilization and is obtained white product.
Embodiment 5:
0.5gPLGA5050 be dissolved in the 10ml dichloromethane, getting 2ml 1wt% ammonium bicarbonate soln splashes into wherein, add 2 Tween 80s, ultrasonic emulsification 1min, obtain the solution of water/oil, with the nitrogen of pressure 150kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 80ml 1wt% PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify to be stirred under the room temperature 3 hours, the 3500rpm centrifugalize is also cleaned centrifugal product with distilled water, triplicate, then lyophilization obtains white product.
Embodiment 6:
0.5gPLGA7525 be dissolved in the 10ml dichloromethane, getting 1ml 1wt% ammonium bicarbonate soln splashes into wherein, emulsifying 1min, obtain the solution of water/oil, with the nitrogen of pressure 200kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 80ml 4wt% PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify under the room temperature and stirred 3 hours, 4000rpm centrifugalize 10min also cleans the centrifugal solids precipitation with distilled water, and triplicate is got the solid precipitation lyophilization and obtained white product.
Embodiment 7:
0.5gPLGA5050 be dissolved in the 10ml dichloromethane, getting 1ml 1wt% ammonium bicarbonate soln splashes into wherein, emulsifying 1min, obtain the solution of water/oil, with the nitrogen of pressure 250kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 80ml 2wt% PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify under the room temperature and stirred 3 hours, 4000rpm centrifugalize 10min also cleans the centrifugal solids precipitation with distilled water, and triplicate is got the solid precipitation lyophilization and obtained white product.
Embodiment 8:
0.5gPLGA5050 be dissolved in the 10ml dichloromethane, getting 1ml 1wt% ammonium bicarbonate soln splashes into wherein, emulsifying 1min, obtain the solution of water/oil, with the nitrogen of pressure 150kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 80ml 2wt% PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify under the room temperature and stirred 3 hours, 4000rpm centrifugalize 10min also cleans the centrifugal solids precipitation with distilled water, and triplicate is got the solid precipitation lyophilization and obtained white product.
Embodiment 9:
0.5gPLA be dissolved in the 10ml dichloromethane, getting 1ml 0.1wt% ammonium bicarbonate soln splashes into wherein, emulsifying 1min, obtain the solution of water/oil, with the nitrogen of pressure 150kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 80ml 2wt% PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify under the room temperature and stirred 3 hours, 3000rpm centrifugalize 10min also cleans the centrifugal solids precipitation with distilled water, and triplicate is got the solid precipitation lyophilization and obtained white product.
Embodiment 10:
0.125g PLA is dissolved in the 10ml dichloromethane, getting 1ml 0.1wt% ammonium bicarbonate soln splashes into wherein, ultrasonic emulsification 1min, obtain the solution of water/oil, with the nitrogen of pressure 150kpa it from being 0.5 micron SPG film, the aperture is extruded, be distributed to the outer aqueous phase of 80ml 2wt%PVA is housed, obtain the double emulsion of water/oil/water, emulsion is poured in the beaker that contains 100ml 1wt% sodium chloride solution again, solidify under the room temperature and stirred 3 hours, 3000rpm centrifugalize 15min also cleans the centrifugal solids precipitation with distilled water, and triplicate is got the solid precipitation lyophilization and obtained white product.
The product of gained after the lyophilization (embodiment 1) as shown is white powder, sees Fig. 1.
From Fig. 2 ~ 4, can see, the sample that we obtain ( embodiment 2,4,8) is globulate all, the surface smoother, size uniform does not significantly link, and adopts the prepared emulsion size droplet diameter of the film emulsion process emulsion drop more prepared than mechanical mixing method even, each emulsion droplets surface free energy is almost identical, therefore in double emulsion formation and solidification process, the cohesion between the emulsion drop and the probability of breaking are very little, and resulting microcapsule dispersibility is better.Can see that in transmission electron microscope figure spherical particle is the microcapsule of a hollow structure, wall is thinner.
Products therefrom ( embodiment 2,4,8) is dissolved in the normal saline, makes water pocket, test its radiography performance with Doppler ultrasonic diagnosis apparatus.Its radiography design sketch such as Fig. 5.From Fig. 5, we can see, the microvesicle that three kinds of different polymer obtain has apparent in view effect to ultrasonic development.
Claims (9)
1. the preparation method of a polymer microvesicle acoustic contrast agent, it is characterized in that, polylactic acid or Poly(D,L-lactide-co-glycolide are dissolved in the dichloromethane, add ammonium bicarbonate aqueous solution and Tween 80, ultrasonic emulsification 1 ~ 2min, obtaining mixed liquor extrudes it with high pressure nitrogen from the SPG film, be distributed to the outer aqueous phase that contains polyvinyl alcohol, obtain double emulsion, again double emulsion is poured in the sodium-chloride water solution, solidify under the room temperature and stirred 3 ~ 5 hours, centrifugalize, remove supernatant, with the remaining solid precipitation of distilled water wash, then lyophilization obtains white product.
2. the preparation method of polymer microvesicle acoustic contrast agent according to claim 1 is characterized in that, described polylactic acid and Poly(D,L-lactide-co-glycolide are medical rank; Wherein, Poly(D,L-lactide-co-glycolide is that polylactic acid and polyglycolic acid are by weight the copolymer of 75:25 or 50:50.
3. the preparation method of polymer microvesicle acoustic contrast agent according to claim 1 is characterized in that, for every 1g polylactic acid or Poly(D,L-lactide-co-glycolide, the use amount of dichloromethane is 20 ~ 80ml.
4. the preparation method of polymer microvesicle acoustic contrast agent according to claim 1, it is characterized in that, the mass percentage concentration of ammonium bicarbonate aqueous solution is 0 ~ 1%, the adding volume of ammonium bicarbonate aqueous solution is 10 ~ 20% of methylene chloride volume, and the addition of Tween 80 is 0 ~ 1% of methylene chloride volume.
5. the preparation method of polymer microvesicle acoustic contrast agent according to claim 1 is characterized in that, described high pressure nitrogen, and condition is 1 ~ 2.5 atmospheric pressure.
6. the preparation method of polymer microvesicle acoustic contrast agent according to claim 1 is characterized in that, described SPG membrane aperture is 0.5 micron.
7. the preparation method of polymer microvesicle acoustic contrast agent according to claim 1 is characterized in that, contains the outer aqueous phase of polyvinyl alcohol, and the mass percentage concentration of polyvinyl alcohol is 1 ~ 4%; The volume that uses that contains the outer water of polyvinyl alcohol is 6 ~ 8 times of methylene chloride volume.
8. the preparation method of polymer microvesicle acoustic contrast agent according to claim 1 is characterized in that, in the described sodium-chloride water solution, the mass percentage concentration of sodium chloride is 1%; The volume that uses of sodium-chloride water solution is 10 ~ 20 times of the dichloromethane consumption.
9. the preparation method of polymer microvesicle acoustic contrast agent according to claim 1 is characterized in that, centrifugal condition is 3000 ~ 4000rpm, 10 ~ 20min.
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| JP2020530865A (en) * | 2017-07-27 | 2020-10-29 | サムヤン バイオファーマシューティカルズ コーポレイションＳａｍｙａｎｇ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｃｏｒｐｏｒａｔｉｏｎ | Method for producing biodegradable polymer fine particles and biodegradable polymer fine particles produced thereby |
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| CN108635596A (en) * | 2018-08-07 | 2018-10-12 | 广东省第二人民医院 | A kind of acoustic contrast agent and preparation method thereof for stem cell ultrasound tracer |
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| CN109364271A (en) * | 2018-09-04 | 2019-02-22 | 中国科学院深圳先进技术研究院 | Acoustic contrast agent and its preparation method and application |
| CN109364271B (en) * | 2018-09-04 | 2024-03-19 | 广州康臣药业有限公司 | Ultrasound contrast agent, and preparation method and application thereof |
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Application publication date: 20130109 |