CN100536925C - Emulsion spray drying method for preparing ultrasound microbubble contrast agent in batch - Google Patents
Emulsion spray drying method for preparing ultrasound microbubble contrast agent in batch Download PDFInfo
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- CN100536925C CN100536925C CNB2006101039428A CN200610103942A CN100536925C CN 100536925 C CN100536925 C CN 100536925C CN B2006101039428 A CNB2006101039428 A CN B2006101039428A CN 200610103942 A CN200610103942 A CN 200610103942A CN 100536925 C CN100536925 C CN 100536925C
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Abstract
A process for preparing the ultrasonic microvesicle contrast medium by O/W emulsified solvent evaporating method and spray drying method includes such steps as dissolving ester in water, stirring while adding perfluorohexane liquid, homogenizing, mixing it with a physiocompatible solution containing hydroxyethyl starch, spray drying to obtain liposome microvesicles, and loading them in a vacuum environment while filling mixed F-C-N gas for disinfecting.
Description
Technical field
The present invention relates to the preparation method of ultrasound microbubble contrast agent, be specifically related to adopt the method for O/W emulsified solvent evaporation and spray drying process preparing ultrasound microbubble contrast agent in batch.
Background technology
Ultrasound microbubble contrast agent has been brought into play enormous function as a kind of novel acoustic contrast agent in the ultrasonoscopy of organ, tissue.Perfect along with the development of ultrasonic technique and contrast agent technology of preparing, the ultrasonic microbubble agent will promising more wide application prospect.
At present domestic relevant ultrasound microbubble contrast agent technology of preparing is the employing sound method technology of preparing of shaking mainly, but the research of adopting this technology to carry out the ultrasonic microbubble preparation still is confined in the laboratory, and this mainly is the requirement that can't satisfy industrialized mass production because of the method technology of preparing of shaking by sound.
Summary of the invention
The preparation method that the purpose of this invention is to provide ultrasound microbubble contrast agent is to realize the industrialized mass production of ultrasound microbubble contrast agent.
In one aspect of the invention, the invention provides the preparation method of ultrasound microbubble contrast agent, its principle is to adopt the self emulsifying solvent evaporated method to prepare liquid fluorocarbon liposome microsphere Emulsion (interiorly to be liquid fluorocarbon, the outsourcing lipid), remove liquid fluorocarbon by spray drying method then, and the solidified microsphere lipidic shell, promptly get the liposome microvesicle.This method comprises the steps:
(a) ester is soluble in water, stir adding perfluor hexane liquid and make the liquid fluorocarbon colostrum;
(b) the gained colostrum is homogenized, obtain uniform Emulsion;
(c) physiological compatibile solution that gained Emulsion and equivalent is contained the 6-10% hetastarch mixes, and makes the liposome microvesicle by spray drying method; With
(d) microvesicle is placed vacuum environment after about 1 hour, feed fluorine carbon nitrogen mixture body, after sterilization, obtain stable ultrasound microbubble contrast agent to air pressure and atmospheric pressure balance.
In one embodiment of the invention, described ultrasound microbubble contrast agent is the lipide supersonic microbubble contrast agent.Wherein the ester in the step (a) is a phosphatidylcholine.The water-soluble concentration of phosphatidylcholine is 1-2%, is preferably 1.2%.Mother-in-law Luo Shamu 188 water-soluble concentration are 0.4-1.0%, are preferably 0.8%.Perfluor hexane that is added and water volume ratio are 0.06-0.08:100, preferred 0.07:100.
In another embodiment of the invention, wherein said ultrasound microbubble contrast agent is the saccharide ultrasound microbubble contrast agent.Wherein the ester in the step (a) is a glycolipid, and its water-soluble concentration is preferred 0.7-1.0%.
Wherein homogenizing of the colostrum in the step (b) can be undertaken by well known to a person skilled in the art any means.In a preferred embodiment, described colostrum homogenizes by high pressure homogenizer.
Physiological compatibile solution in the step (c) can be that the physiology goes up acceptable any solution, and the kind of these solution and compound method are well known to a person skilled in the art.In a preferred embodiment, described physiological compatibile solution is a normal saline solution.
In another embodiment, the vacuum environment condition described in the step (d) is that pressure is lower than 2torr.In another aspect of the present invention, provide ultrasound microbubble contrast agent, comprised lipide supersonic microbubble contrast agent and saccharide ultrasound microbubble contrast agent according to method for preparing.
Ultrasound microbubble contrast agent preparation method of the present invention has following advantage: 1. can realize the production in enormous quantities of ultrasound microbubble contrast agent; 2. adopt fluorine carbon mist,, not only increased microvesicle stability and reduced production cost with respect to perfluorocarbon gas; 3. but the microvesicle room temperature of producing is preserved; 4. using this method not only can prepared in batches liposome class ultrasound microbubble contrast agent, also can prepare the saccharide ultrasound microbubble contrast agent; 5. avirulence has no side effect; 6. stable performance, imaging results is good; 7. do not influence the hemodynamics of whole body or a certain system.
Description of drawings
Figure 1 shows that observed microbubble contrast agent under the optical microscope (light microscopic * 400), wherein microvesicle form rule is evenly big or small, average diameter 2 μ m.
Fig. 2 explanation strengthens the pig liver development with the ultrasound microbubble contrast agent of the inventive method preparation;
Fig. 3 explanation strengthens the development of Tu popliteal nest lymph node with the ultrasound microbubble contrast agent of the inventive method preparation;
The specific embodiment
Below by preferred embodiment various aspects of the present invention and feature are described more specifically.These embodiment just are used to illustrate the present invention, do not limit the scope of the invention.Scope of the present invention only is subjected to the restriction of claims.Therefore it should be appreciated by those skilled in the art, under the situation that does not deviate from the claim protection domain, any change or change that the present invention did also all are positioned within protection scope of the present invention.
In addition, unless it should be noted that and specialize, below among the embodiment used various materials and reagent all be material and reagent commonly used in this area, can obtain by conventional commercial sources; Method therefor is and well known to a person skilled in the art conventional method.
Embodiment 1: the preparation of lipide supersonic microbubble contrast agent
Reagent: phosphatidylcholine, perfluor hexane, mother-in-law Luo Shamu 188, hetastarch are all available from Chongqing City pharmaceuticals.
Equipment: high pressure homogenizer, agitator, spray dryer, blood-counter system etc. are this area routine equipment.
Method: earlier 3g phosphatidylcholine and 0.8g mother-in-law Luo Shamu 188 are dissolved in the 250g distilled water, when stirring, add 18ml perfluor hexane liquid and make liquid fluorocarbon lipid colostrum, this colostrum is made uniform Emulsion by high pressure homogenizer.After the normal saline solution that again this Emulsion and equivalent is contained 8% hetastarch mixes, make the liposome microvesicle by spray drying method.Place vacuum environment (pressure is lower than 2torr) after about 1 hour microvesicle, feed fluorine carbon nitrogen mixture body, after sterilization, obtain stable ultrasound microbubble contrast agent to air pressure and atmospheric pressure balance.
Embodiment 2: the preparation of saccharide ultrasound microbubble contrast agent
Reagent: sugar ester, perfluor hexane, polyethers, hetastarch are all available from Chongqing City pharmaceuticals.
Equipment: high pressure homogenizer, agitator, spray dryer, blood-counter system etc. are this area common equipment.
Method: earlier the 13g sugar ester is dissolved in the 1.5L distilled water, when stirring, adds 100ml perfluor hexane liquid and make the liquid fluorocarbon colostrum, this colostrum is made uniform Emulsion by high pressure homogenizer.The normal saline solution that this Emulsion and equivalent is contained 8% hetastarch mixes again, makes the liposome microvesicle by spray drying method.Place vacuum environment (pressure is lower than 2torr) after about 1 hour microvesicle, feed fluorine carbon nitrogen mixture body, after sterilization, obtain stable ultrasound microbubble contrast agent to air pressure and atmospheric pressure balance.
3, iconography feature observation
Contrast agent is injected Canis familiaris L. or new zealand white rabbit intravenous, it strengthens the ultrasonograph characteristics of each histoorgan in ultrasonic observation down, and with Wang Zhigang professor (Medical University Of Chongqing's ultrasonic image institute, Hospital No.2 Affiliated to Chongqing Medical Univ., Chongqing, 400010) " the ultrasonic quantitative instrument " of development measures reinforced effects, the results are shown in Figure 2 and Fig. 3.It is obvious that ultrasound microbubble contrast agent of the present invention as can be seen from Figure 2 strengthens the rabbit liver development effect, and visible liver parenchyma obviously strengthens.As can be seen from Figure 3, the lymph node development behind injection 0.1ml contrast agent under the rabbit foot lift of rabbit lymph node obviously strengthens.
Claims (15)
1. method for preparing ultrasound microbubble contrast agent may further comprise the steps:
(a) ester is soluble in water, stir adding perflexane liquid and make the liquid fluorocarbon colostrum;
(b) the gained colostrum is homogenized, obtain uniform Emulsion;
(c) physiological compatibile solution that gained Emulsion and equivalent is contained the 6-10% hetastarch mixes, and makes the liposome microvesicle by spray drying method;
(d) microvesicle is placed vacuum environment after about 1 hour, feed fluorine carbon nitrogen mixture body, after sterilization, obtain stable ultrasound microbubble contrast agent to air pressure and atmospheric pressure balance.
2. the described method of claim 1, wherein said ultrasound microbubble contrast agent is the lipide supersonic microbubble contrast agent.
3. the described method of claim 1, wherein the ester in the step (a) is a phosphatidylcholine.
4. the described method of claim 3, wherein the water-soluble concentration of phosphatidylcholine is 1-2%.
5. the described method of claim 3, step (a) specifically is that phosphatidylcholine and mother-in-law Luo Shamu 188 is water-soluble, wherein mother-in-law Luo Shamu 188 water-soluble concentration are 0.4-1.0%.
6. any described method among the claim 1-5, wherein perflexane and water volume ratio are 0.06-0.08:100.
7. the described method of claim 1, wherein said ultrasound microbubble contrast agent is the saccharide ultrasound microbubble contrast agent.
8. the described method of claim 1, wherein the ester in the step (a) is a glycolipid.
9. the described method of claim 8, wherein the water-soluble concentration of glycolipid is 0.7-1.0%
10. the described method of claim 1, wherein the colostrum in the step (b) homogenizes by high pressure homogenizer.
11. the described method of claim 1, wherein the physiological compatibile solution in the step (c) is a normal saline.
12. the described method of claim 1, wherein the vacuum environment condition in the step (d) is that pressure is lower than 2torr.
13. ultrasound microbubble contrast agent according to method preparation any among the claim 1-12.
14. the described ultrasound microbubble contrast agent of claim 13, it is the lipide supersonic microbubble contrast agent.
15. the described ultrasound microbubble contrast agent of claim 13, it is the saccharide ultrasound microbubble contrast agent.
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| CNB2006101039428A CN100536925C (en) | 2006-07-28 | 2006-07-28 | Emulsion spray drying method for preparing ultrasound microbubble contrast agent in batch |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101954096A (en) * | 2010-10-13 | 2011-01-26 | 重庆医科大学 | Multifunctional ultrasound contrast agent and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101721719B (en) * | 2008-10-28 | 2011-09-28 | 温州医学院 | Ultrasound contrast agent and preparation method thereof |
| CN102772808B (en) * | 2012-07-02 | 2017-03-01 | 重庆医科大学 | A kind of multi-modality imaging microbubble construction, Preparation method and use |
| CN104399091B (en) * | 2014-10-31 | 2017-06-13 | 苏州大学 | Ultrasound/magnetic resonance bimodal contrast agent, its preparation method and application |
| CN105407177A (en) * | 2015-12-23 | 2016-03-16 | 北京奇虎科技有限公司 | Intelligent monitoring method and equipment |
| WO2019051752A1 (en) * | 2017-09-14 | 2019-03-21 | 吴金凤 | Method for preparing lipidosome nano-bubble ultrasound contrast agent |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101954096A (en) * | 2010-10-13 | 2011-01-26 | 重庆医科大学 | Multifunctional ultrasound contrast agent and preparation method thereof |
| CN101954096B (en) * | 2010-10-13 | 2013-01-23 | 重庆医科大学 | Multifunctional ultrasound contrast agent and preparation method thereof |
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