CN101721719A - Ultrasound contrast agent and preparation method thereof - Google Patents
Ultrasound contrast agent and preparation method thereof Download PDFInfo
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- CN101721719A CN101721719A CN200810217176A CN200810217176A CN101721719A CN 101721719 A CN101721719 A CN 101721719A CN 200810217176 A CN200810217176 A CN 200810217176A CN 200810217176 A CN200810217176 A CN 200810217176A CN 101721719 A CN101721719 A CN 101721719A
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Abstract
The invention relates to an ultrasound contrast agent and a preparation method thereof. The composite lipid-coated microbubble ultrasound contrast agent comprises a phospholipid ingredient and a glycolipid ingredient which are coated with gas to form the stable composite lipid-coated microbubble having good acoustic response property and drug loading capacitor. The composite lipid-coated microbubble can be used as the ultrasound contrast agent, a drug carrier and a preparation. The invention further provides a preparation method of the ultrasound contrast agent.
Description
[technical field]
The present invention relates to a kind of acoustic contrast agent and preparation method thereof, relate in particular to a kind of microcapsular ultrasound contrast agent and preparation method thereof.
[background technology]
Along with the development of ultrasonic diagnostic imaging technology, it is found that small bubble can effectively improve ultrasonoscopy to specific mass, develop the acoustic contrast agent that the microvesicle form of gassiness exists in the middle of thus.Acoustic contrast agent is used to strengthen organa parenchymatosums' such as cardiac muscle, liver, kidney, brain two-dimensional ultrasound image and blood flow doppler signal, obviously improves ultrasonicly for diseased region form and type resolution capability, strengthens the sensitivity and the specificity of ultrasonic diagnosis.
The acoustic contrast agent of at present external FDA approval clinical practice has: the Albunex and the Optison that with the albumin are the vacuolar membrane structure, with the saccharide is the Levovist of vacuolar membrane structure, with be the Sonovue of vacuolar membrane structure with phospholipid, wherein the acoustic contrast agent of China's Ministry of Public Health approval clinical practice is Sonovue, does not still have home-made acoustic contrast agent listing so far.
Patent 02133720.9 discloses a kind of lipide supersonic contrast medium, and its filmogen comprises phospholipid molecule, non-ionic surface active agent, Macrogol 4000, hyperosmotic glucose or alcohols; In the described filmogen, the ratio that the phospholipid molecule occupies is 0.1-5 weight %, the ratio of non-ionic surface active agent is 0.01-0.05 weight %, the ratio of hyperosmotic glucose or alcohols is 1-30 weight %, the ratio of Macrogol 4000 is 5-30 weight %, all the other are aqueous solution, add biological activity gas 0.15-0.5ml in every milliliter of filmogen.
It is the ultrasound contrast agent composition and preparation method thereof of filmogen with the phospholipid composition that patent 200310122421.3 discloses a kind of, this contrast agent composition is made up of filmogen and fluorine carbon noble gas, filmogen is made up of phospholipid composition, foaming agent, polymer and stabilizing agent, the percentage by weight of each component in the filmogen, the phospholipid composition is 1%-10%, foaming agent is 5%-15%, stabilizing agent is 0.5%-10%, polymer is 70%-90%, and the amount that contains the fluorine carbon noble gas in the per unit dosage is 0.15-0.5ml.
Patent application 200480002975.2 relates to a kind of preparation lyophilized matrix, and obtains the method for injection contrast agent on the basis that rebuilds this substrate, and this contrast agent comprises main liquid water-soluble suspension by the stable inflation microbubble of phospholipid.This method comprises a kind of Emulsion of preparation from a kind of aqueous medium, phospholipid and water organic solvent immiscible, then with this Emulsion lyophilizing, then rebuilds in the water solublity suspension of inflation microbubble.
Patent application 200510057375.2 discloses the microvesicle suspension that the method for using mechanical oscillation prepares fluorine-containing carbon gas, imports fluorocarbon gas again by moisture content in the freeze drying process removal suspension then and prepares ultrasonic microbubble.
Patent application 200710119440.9 relates to a kind of lipid microvesicle ultrasound angiography powder agent that includes mixture gas of fluorine carbon/nitrogen gas; this microvesicle filmogen is by the phospholipid composition; protective agent and polymer are formed; wherein the phospholipid composition is selected from phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE; protective agent is selected from the light ethyl starch of middle and high molecular weight and polymer and is selected from that poloxamer 188 or other are pharmaceutically acceptable to be used for intravenous surfactant.By lipid filmogen parcel fluorocarbon liquid is formed the Emulsion microgranule, make the liquid fluorocarbon gasification form the lipid microsphere of hollow through the TRANSIENT HIGH TEMPERATURE method, further import mixture gas of fluorine carbon/nitrogen gas, obtain a kind of stable lipid microsphere that can be used for ultrasonoscopy.
Acoustic contrast agent also has certain bag loading capability, can be used as the carrier of medicine or gene.Because fluorine carbon noble gas molecular weight is big, the dissolubility in blood and characteristics such as dispersivity is poor, good stability, therefore the acoustic contrast agent of a new generation is many is filling gas in the microvesicle with the fluorine carbon noble gas.According to the difference of parcel fluorine carbon noble gas material, acoustic contrast agent can be divided into: phospholipid, albumin class, surfactant-based, macromolecule polymer class etc.Be that the lipid microbubble of vacuolar membrane structure has lot of advantages wherein with the phospholipid composition, as:, non-immunogenicity strong with the DNA adhesion, biodegradable, be easy to the PEGization modification, safety is more high, so be most widely used.
Patent application 200510127996.3 relates to the acoustic contrast agent of a kind of year gene or medicine, comprise microvesicle, fluorocarbon gas, gene or medicine, the microvesicle wall is made of lipid bilayer, parcel fluorocarbon gas in it, gene or pharmaceutical pack are embedded in the microvesicle peplos, its preparation is by the distearoyl phosphatidylcholine of proper proportion, two palmityl PHOSPHATIDYL ETHANOLAMINE, Arlacel-60, glycerol, phosphate buffer and gene or medicine, adopts the mechanical oscillation mode to be mixed and made into.
The prepared ultrasonic microbubble composition material of above-mentioned patent or patent application is phospholipid composition, other adjuvant is slightly different, the composition that constitutes filmogen is comparatively single, the vacuolar membrane structure is comparatively thin, have many deficiencies or problem, as: body-internal-circulation time is short, the medicine carrying space is less, the medicine carrying ability is lower, limited with the bonded mode of medicine, voltage endurance capability is relatively poor etc.
Patent application 200610103942.8 relates to a kind of method of emulsion spray drying method prepared in batches acoustic contrast agent, ester is soluble in water, stir adding perflexane liquid and make the liquid fluorocarbon colostrum, the back adding equivalent that homogenizes contains the physiological compatibile solution of 6-10% hetastarch, mix, make the liposome microvesicle by spray drying method, feed fluorine carbon nitrogen mixture body, after sterilization, obtain stable acoustic contrast agent.The used ester of this patent application can be phosphatidylcholine or glycolipid.But acoustic contrast agent stability, resistance to pressure and the medicine carrying ability of the preparation of this kind method are still not ideal enough.
[summary of the invention]
The technical problem to be solved in the present invention is at the weak point of existing acoustic contrast agent, and a kind of acoustic contrast agent is provided, and it possesses better stability, resistance to pressure and medicine carrying ability.
Another technical problem that the present invention will solve is that a kind of preparation method that possesses the acoustic contrast agent of better stability, resistance to pressure and medicine carrying ability will be provided.
A kind of acoustic contrast agent, it is characterized in that: this acoustic contrast agent is mainly formed compound adipose membrane by phospholipid composition and glycolipid composition, be filled with gas in the described compound adipose membrane, described phospholipid composition is selected from one or more in hydrogenated phospholipid, synthetic phospholipid and the polyethyleneglycol modified derivant thereof.
A kind of preparation method of acoustic contrast agent is characterized in that: this preparation method comprises the steps:
Step (a) phospholipid composition joins in the alcoholic solution of heat and dissolves, and is transferred in the aqueous solution that contains glycolipid, utilizes ultrasonic, vibration or stirring action to make its abundant mixing, forms the milky solution that particle diameter is even and physical property is stable;
Step (b) utilizes the reduction vaporization method to remove ethanol in the solution that step (a) obtains, utilizes freeze-drying method to obtain compound adipose membrane dried frozen aquatic products;
Step (c) charges into specific gas and promptly gets acoustic contrast agent in the compound adipose membrane dried frozen aquatic products that step (b) obtains.
Above-mentioned acoustic contrast agent has following advantage: (1) microvesicle has no side effect, the vacuolar membrane Stability Analysis of Structures, and the medicine carrying space is bigger.(2) preparation technology is easy to be controlled.(3) have good acoustic response ability, can be used as effective acoustic contrast agent.(4) widely applicable, can be used as the carrier and the preparation of medicine or gene.
[specific embodiment]
For solving the problems of the technologies described above, the inventor finds that by a large amount of tests the glycolipid composition can rely on one or more physics chemical action such as charges of different polarity suction mutually, hydrogen bond, Van der Waals force, ionic bond to be combined into the more stable compound adipose membrane of character with the phospholipid composition.Relying on glycolipid composition and phospholipid composition is the compound adipose membrane microcapsular ultrasound contrast agent of main constituent preparation, and its vacuolar membrane structure is more stable than the microcapsular ultrasound contrast agent that does not contain the glycolipid composition, and resistance to pressure and medicine carrying ability are better.The present invention adopts following technical scheme:
A kind of acoustic contrast agent mainly is made up of phospholipid composition and glycolipid composition, and phospholipid composition and glycolipid composition form compound adipose membrane gassiness microvesicle.
Above-mentioned phospholipid composition is selected from wherein one or more of hydrogenated phospholipid, synthetic phospholipid and its polyethyleneglycol modified derivant, and hydrogenated phospholipid comprises hydrogenation egg yolk lecithin and hydrogenated soya phosphatide; Synthetic phospholipid and its polyethyleneglycol modified derivant comprise the wherein polyethyleneglycol modified derivant of one or more and they of two palmityl PHOSPHATIDYL ETHANOLAMINE, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, DOPE, two palmityl phosphatidyl glycerols, two palmityl phosphatidic acid.
Above-mentioned gas is selected from wherein one or more of air, nitrogen, carbon dioxide, nitrous oxide, sulfur hexafluoride, fluorocarbon gas.
In the compound adipose membrane of above-mentioned acoustic contrast agent, the percentage by weight of phospholipid and glycolipid can be arbitrary proportion, its weight percent is relevant with the medicine carrying ability with the contrast intensity of acoustic contrast agent, can regulate as required, its percentage by weight is that phospholipid composition is 0.1% to 99.9% in the embodiments of the invention, the glycolipid composition is 0.1% to 99.9%, and more excellent percentage by weight is that phospholipid composition is 10% to 90%, and the glycolipid composition is 10% to 90%.
The preparation method of above-mentioned acoustic contrast agent is achieved in that
(a) phospholipid composition joins in the hot ethanol solution and dissolves, and is transferred in the aqueous solution that contains glycolipid, utilizes ultrasonic, vibration or stirring action to make its abundant mixing, forms the milky solution that particle diameter is even and physical property is stable;
(b) utilize the reduction vaporization method to remove ethanol in the solution that step (a) obtains, add an amount of skeleton proppant, stabilizing agent and/or surfactant, utilize freeze-drying method to obtain compound adipose membrane dried frozen aquatic products;
(c) the compound adipose membrane dried frozen aquatic products that step (b) is obtained is sub-packed in the bottle, charges into specific gas, promptly gets acoustic contrast agent, and capping is preserved;
When being used for ultrasonic contrast or pharmaceutical carrier, join in the bottle that acoustic contrast agent is housed that step (c) obtains with clinical injection solvent commonly used or the aqueous solution that contains medicine, slight jolting gets final product.
Be appreciated that wherein skeleton proppant, stabilizing agent and or surfactant be stability and the uniformity that is used for strengthening compound adipose membrane, in preparation process, also can omit.
The ultrasonic contrast intensity of above-mentioned acoustic contrast agent and medicine carrying ability can be by changing phospholipid composition and glycolipid component ratio, and glycolipid composition kind and molecular weight, microvesicle particle diameter and microvesicle film thickness are regulated.
Now further describe the present invention in conjunction with following example.
Embodiment 1:
First embodiment preparation of the present invention is used to strengthen the acoustic contrast agent of ultrasonic development resolution, wherein phospholipid composition is selected from hydrogenated phospholipid, gas is selected from sulfur hexafluoride, select for use poloxamer 188 as skeleton proppant and surfactant, to guarantee that adipose membrane keeps homodisperse state in freezing dry process.
Hydrogenation egg yolk lecithin 0.08g joins in the 120ml 50-60 ℃ ethanol solution and dissolves, and is transferred in the synthermal 0.02g of the containing glycolipid of the 150ml aqueous solution, utilizes the shaking table vibration to make it form the milky solution that particle diameter is even and physical property is stable.Utilize the reduction vaporization instrument to remove ethanol in the solution at 35-40 ℃, add the poloxamer 188 of 1.5-2g, utilize freeze-drying method to obtain compound adipose membrane dried frozen aquatic products behind the mixing, be sub-packed in the 10ml cillin bottle, every bottle of 200mg, it is saturated to charge into sulfur hexafluoride, promptly obtain acoustic contrast agent, capping is placed.
With the rabbit is animal pattern, adopt the auricular vein method of injecting to carry out kidney ultrasonic development effect observation, and contrast commercially available acoustic contrast agent product Levovist, join in the bottle that acoustic contrast agent is housed with the 2ml normal saline solution before using, slight jolting promptly can be used for injecting.Experimental result shows that the acoustic contrast agent development effect that present embodiment makes is obvious, the development enhancing time surpasses 300s, longer than commercially available acoustic contrast agent product Levovist developing time, illustrate that the acoustic contrast agent that present embodiment makes can be as effective acoustic contrast agent.
Embodiment 2:
Second embodiment of the present invention still prepares the acoustic contrast agent that is used to strengthen ultrasonic development resolution, phospholipid composition is selected from synthetic phospholipid and/or its polyethyleneglycol modified derivant, gas is selected from fluorocarbon gas, select for use trehalose as skeleton proppant and stabilizing agent, Tween 80 is a surfactant, to guarantee that adipose membrane keeps homodisperse state in freezing dry process.
Dipalmitoyl phosphatidyl choline: Polyethylene Glycol-DSPE (9: 1) 0.05g joins in the 120ml 50-60 ℃ ethanol solution and dissolves, be transferred in the aqueous solution of the synthermal 0.05g of the containing glycolipid of 150ml, utilize magnetic agitation 600-750rpm 30min to make it form the milky solution that particle diameter is even and physical property is stable.Utilize the reduction vaporization instrument to remove ethanol in the solution at 35-40 ℃, the trehalose and the 0.1-0.2g Tween 80 that add 1.5-2g, utilize freeze-drying method to obtain compound adipose membrane dried frozen aquatic products behind the mixing, be sub-packed in the 10ml cillin bottle, every bottle of 200mg, it is saturated to charge into perfluoropropane, promptly obtains acoustic contrast agent, and capping is placed.
With the rabbit is animal pattern, adopts the method for embodiment 1 to carry out kidney ultrasonic development effect observation, and the result shows that the acoustic contrast agent development effect that present embodiment makes is obvious, and the development enhancing time surpasses 300s.
Embodiment 3:
The acoustic contrast agent of the 3rd embodiment preparation of the present invention bag medicine carrying thing, the phospholipid composition is selected from hydrogenated phospholipid, gas is selected from air, nitrogen or carbon dioxide, with the bovine serum albumin is model drug, select for use poloxamer 188 as the skeleton proppant, sucrose fatty acid ester is a surfactant, to guarantee that adipose membrane keeps homodisperse state in freezing dry process.
Hydrogenated soya phosphatide 0.7g joins in the 120ml 50-60 ℃ ethanol solution and dissolves, be transferred to and contain in the 0.3g sucrose-fatty aqueous solution of ester, more than the mechanical agitation 600-750rpm 30min, make its abundant mixing, form the milky solution that particle diameter is even and physical property is stable.Utilize the reduction vaporization instrument to remove ethanol in the solution at 35-40 ℃, add poloxamer 188 and the 0.5g sucrose fatty acid ester of 1.5-2g, utilize freeze-drying method to obtain compound adipose membrane dried frozen aquatic products behind the mixing, be sub-packed in the 10ml cillin bottle, every bottle of 200mg, it is saturated to charge into nitrogen, and capping is placed.
With the bovine serum albumin is model drug, be made into the hirudin aqueous solution 2ml of 0.5mg/ml, be injected in the bottle that acoustic contrast agent is housed every plug, slight jolting, can form the compound adipose membrane microvesicle that contains nitrogen that bag carries bovine serum albumin, change over to and use 300rpm low-speed centrifugal 5 minutes in the centrifuge tube, the compound adipose membrane microvesicle that bag carries bovine serum albumin floats on the solution upper strata, utilize the concentration of free bovine serum albumin in the centrifugal back of the Coomassie brilliant blue G-250 staining mensuration lower floor solution, utilize " envelop rate (%)=[(amount of bovine serum albumin total amount-free bovine serum albumin)/bovine serum albumin total amount] * 100 " formula to calculate, the envelop rate that obtains reaches more than 65%, show that the acoustic contrast agent that present embodiment makes can be applied in the pharmaceutical preparation as pharmaceutical carrier.
In the above-described embodiments, only the present invention has been carried out exemplary description, but those skilled in the art can carry out various modifications to the present invention after reading present patent application under the situation that does not break away from the spirit and scope of the present invention.
Claims (10)
1. acoustic contrast agent, it is characterized in that: this acoustic contrast agent is mainly formed compound adipose membrane by phospholipid composition and glycolipid composition, be filled with gas in the described compound adipose membrane, described phospholipid composition is selected from one or more in hydrogenated phospholipid, synthetic phospholipid and the polyethyleneglycol modified derivant thereof.
2. the described acoustic contrast agent of claim 1, it is characterized in that: described hydrogenated phospholipid comprises: hydrogenation egg yolk lecithin and/or hydrogenated soya phosphatide.
3. the described acoustic contrast agent of claim 1, it is characterized in that: described synthetic phospholipid and polyethyleneglycol modified derivant thereof comprise: two palmityl PHOSPHATIDYL ETHANOLAMINE, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, dimyristoyl phosphatidyl choline, DOPE, two palmityl phosphatidyl glycerols, two palmityl phosphatidic acid are the polyethyleneglycol modified derivant of one or more and they wherein.
4. the described acoustic contrast agent of claim 1 is characterized in that: the gas of filling in the described compound adipose membrane is selected from wherein one or more of air, oxygen, nitrogen, carbon dioxide, sulfur hexafluoride, fluorocarbon gas.
5. as any described acoustic contrast agent of claim 1-4, it is characterized in that: phospholipid composition is 0.1% to 99.9% in the compound by weight percentage adipose membrane, and the glycolipid composition is 0.1% to 99.9%.
6. any described acoustic contrast agent of claim 5, it is characterized in that: phospholipid composition is 10% to 90% in the compound by weight percentage adipose membrane, the glycolipid composition is 10% to 90%.
7. the preparation method of an acoustic contrast agent, it is characterized in that: this preparation method comprises the steps:
Step (a) phospholipid composition joins in the alcoholic solution of heat and dissolves, and is transferred in the aqueous solution that contains glycolipid, utilizes ultrasonic, vibration or stirring action to make its abundant mixing, forms the milky solution that particle diameter is even and physical property is stable;
Step (b) utilizes the reduction vaporization method to remove ethanol in the solution that step (a) obtains, utilizes freeze-drying method to obtain compound adipose membrane dried frozen aquatic products;
Step (c) charges into specific gas and promptly gets acoustic contrast agent in the compound adipose membrane dried frozen aquatic products that step (b) obtains.
8. the preparation method of acoustic contrast agent as claimed in claim 7, it is characterized in that: wherein said phospholipid composition is selected from one or more in hydrogenated phospholipid, synthetic phospholipid and the polyethyleneglycol modified derivant thereof.
9. the preparation method of acoustic contrast agent as claimed in claim 7, it is characterized in that: phospholipid composition is 0.1% to 99.9% in the compound by weight percentage adipose membrane, the glycolipid composition is 0.1% to 99.9%.
10. the preparation method of the described acoustic contrast agent of claim 7 is characterized in that: wherein step (b) added skeleton proppant, stabilizing agent and/or surfactant after also being included in and removing ethanol before lyophilization.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104940960A (en) * | 2014-03-31 | 2015-09-30 | 通用电气医疗集团股份有限公司 | Ultrasound precursor preparation method |
| CN105999314A (en) * | 2016-07-11 | 2016-10-12 | 四川省人民医院 | Ultrasonic contrast agent and preparing method thereof |
| CN107551283A (en) * | 2017-09-20 | 2018-01-09 | 贺海霞 | A kind of stomach ultrasound imaging assistant and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4406474A1 (en) * | 1994-02-23 | 1995-08-24 | Schering Ag | Gas-containing microparticles, agents containing them, their use in ultrasound diagnostics, and methods for producing the particles and agents |
| GB9511488D0 (en) * | 1995-06-07 | 1995-08-02 | Nycomed Imaging As | Improvements in or relating to contrast agents |
| EP0831932B1 (en) * | 1995-06-07 | 2004-05-06 | Imarx Pharmaceutical Corp. | Novel targeted compositions for diagnostic and therapeutic use |
| CN1194763C (en) * | 2002-09-06 | 2005-03-30 | 中国人民解放军第三军医大学 | Novel lipide supersonic contrast medium and preparation method thereof |
| CN100536925C (en) * | 2006-07-28 | 2009-09-09 | 郑元义 | Emulsion spray drying method for preparing ultrasound microbubble contrast agent in batch |
-
2008
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104940960A (en) * | 2014-03-31 | 2015-09-30 | 通用电气医疗集团股份有限公司 | Ultrasound precursor preparation method |
| CN105999314A (en) * | 2016-07-11 | 2016-10-12 | 四川省人民医院 | Ultrasonic contrast agent and preparing method thereof |
| CN105999314B (en) * | 2016-07-11 | 2018-12-18 | 四川省人民医院 | A kind of acoustic contrast agent and preparation method thereof |
| CN107551283A (en) * | 2017-09-20 | 2018-01-09 | 贺海霞 | A kind of stomach ultrasound imaging assistant and preparation method thereof |
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