CN101721718A - Lipid microbubble and preparation method thereof - Google Patents
Lipid microbubble and preparation method thereof Download PDFInfo
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- CN101721718A CN101721718A CN200810216909A CN200810216909A CN101721718A CN 101721718 A CN101721718 A CN 101721718A CN 200810216909 A CN200810216909 A CN 200810216909A CN 200810216909 A CN200810216909 A CN 200810216909A CN 101721718 A CN101721718 A CN 101721718A
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Abstract
The invention relates to a lipid microbubble which mainly comprises phospholipid components and chitosan components. A middle gas containing structure of a composite bubble film is formed after the lipid microbubble is coated with gas. The middle gas containing structure has good stability, pressure resistance and drug carrying capacity, not only can be used as an ultrasonic contrast agent but also can be used as a drug carrier, a drug preparation, a disinfectant, a preservative or a cosmetic additive, and is applied to skin protection, health care, food processing, fruit and vegetable disinfection, wound flushing, meat refreshing and cosmetics.
Description
[technical field]
The present invention relates to a kind of lipid microbubble and preparation method thereof, be specifically related to lipid microbubble of a kind of middle gassiness 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.
In addition, the lipid microbubble range of application of the middle gassiness of existing report also is only limited to as acoustic contrast agent and pharmaceutical carrier.
[summary of the invention]
The technical problem to be solved in the present invention is the weak point at the lipid microbubble of gassiness in the middle of existing, and a kind of lipid microbubble of middle gassiness is provided, and it possesses better stability, resistance to pressure and medicine carrying ability as acoustic contrast agent, and application is more extensive.
Another technical problem that the present invention will solve is the manufacture method that a kind of lipid microbubble of the middle gassiness that possesses better stability, resistance to pressure and medicine carrying ability will be provided.
A kind of lipid microbubble, mainly form compound vacuolar membrane by phospholipid composition and constituent of chitosan, be filled with gas in the described compound vacuolar membrane, phospholipid composition wherein is selected from one or more in natural phospholipid, hydrogenated phospholipid, synthetic phospholipid and the polyethyleneglycol modified derivant thereof, and constituent of chitosan wherein is selected from one or more in chitosan, chitosan salt or the chitosan derivatives.
A kind of preparation method of lipid microbubble 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 chitosan, 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 lyophilization or spray drying process to obtain the lipid microbubble drying solid;
Step (c) is suitably pulverized the lipid microbubble drying solid that step (b) obtains, and charges into specific gas, contains the lipid microbubble dried frozen aquatic products of gas in the middle of promptly obtaining.
Lipid microbubble of the present invention 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, and raw material is easy to get.(3) have good acoustic response ability, can be used as effective acoustic contrast agent.(4) widely applicable, can be used as pharmaceutical carrier and preparation, disinfectant, antistaling agent, cosmetics additive, be applied in skin-protection and health-care, food processing, fruit and vegerable sterilization, wound flushing, meat preservation and the cosmetics.
[specific embodiment]
The inventor finds that by a large amount of tests matrix material and chitosan material have electrically opposite, 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 composite of character.Relying on phospholipid and chitosan is the lipid microbubble of main constituent preparation, and its vacuolar membrane structure is more stable than the lipid microbubble of chitosan-containing composition not, and resistance to pressure and medicine carrying ability are better.
Thus, the lipid microbubble filmogen of middle gassiness of the present invention mainly is made up of phospholipid composition and constituent of chitosan, and wherein phospholipid composition and constituent of chitosan form compound vacuolar membrane, is filled with gas in the middle of the described compound vacuolar membrane.
Above-mentioned phospholipid composition is selected from wherein one or more of natural phospholipid, hydrogenated phospholipid, synthetic phospholipid and polyethyleneglycol modified derivant synthetic phospholipid thereof and polyethyleneglycol modified derivant thereof, and natural phospholipid comprises egg yolk lecithin, soybean phospholipid, phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE; Hydrogenated phospholipid comprises hydrogenation egg yolk lecithin and hydrogenated soya phosphatide; 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 wherein one or more combination and their polyethyleneglycol modified derivant.
Above-mentioned constituent of chitosan is selected from one or more in chitosan, chitosan salt and the chitosan derivatives, and chitosan comprises that chitin or its take off acetyl product chitosan; Chitosan salt comprises acylate, inorganic acid salt or the quaternary ammonium salt of chitosan; Chitosan derivatives is selected from the chemical derivative of chitosan or chitosan salt; the i.e. hydroxylating that the molecule of chitosan or chitosan salt is carried out; carboxylated; acyl groupization; alkylation; sulfhydrylation; Sulfation; Phosphation; glycosylation; crosslinked; complexation; the chemical modification derivant that the Polyethylene Glycol grafting forms comprises: hydroxypropyl chitosan; carboxymethyl chitosan; the esterification chitosan; the Sulfation chitosan; the Phosphation chitosan; acylation chitosan; the N-alkylated chitosan; quaternary ammonium N-carboxyetbyl chitosan; thio chitosan; the glycosylation chitosan; chitosan resin; the chitosan complex thing; the Polyethylene Glycol grafted chitosan; the grafted by beta cyclodextrin chitosan; the poloxamer grafted chitosan.
The gas of filling in the above-mentioned compound vacuolar membrane is selected from wherein one or more of air, oxygen, nitrogen, carbon dioxide, sulfur hexafluoride, fluorocarbon gas.
In the above-mentioned compound vacuolar membrane, the phospholipid composition is 0.1% to 99.9% by weight percentage, and constituent of chitosan is 0.1% to 99.9%, and more excellent percentage by weight is 10% to 90% for the phospholipid composition, and constituent of chitosan is 10% to 90%.
A kind of preparation method of the lipid microbubble of gassiness is achieved in that in the middle of above-mentioned
(a) the phospholipid composition joins in the hot alcoholic solution and dissolves, and is transferred in the aqueous solution that contains constituent of chitosan, makes 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 lyophilization or spray drying process to obtain compound vacuolar membrane drying solid;
(c) the compound vacuolar membrane drying solid that step (b) is obtained is suitably pulverized, and charges into specific gas, contains the lipid microbubble dried frozen aquatic products of gas in the middle of promptly obtaining.
The temperature range of alcoholic solution is 50-60 ℃, and concentration range is more than 90%.
Wherein above-mentioned chitosan solution is that the distilled water mixing with constituent of chitosan and 50-60 ℃ makes.
Described mixing is to reach by ultrasonic, vibration or machinery/magnetic agitation effect.
The lipid microbubble of gassiness can be used as acoustic contrast agent, pharmaceutical carrier and cosmetics and food preservative in the middle of above-mentioned.When as acoustic contrast agent or pharmaceutical carrier, join with clinical injection solvent commonly used or the aqueous solution that contains medicine in the lipid microbubble dried frozen aquatic products of the middle gassiness that step (c) obtains, slight jolting, the bag that contains gas in the middle of can forming carries the lipid microbubble of injection solvent or medicine.Its ultrasonic contrast intensity and medicine carrying ability can be by changing phospholipid composition and constituent of chitosan ratio, and constituent of chitosan 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:
The lipid microbubble of the middle gassiness of first embodiment preparation of the present invention is used for acoustic contrast agent, and wherein the phospholipid composition is selected from hydrogenated phospholipid, and constituent of chitosan is selected from the inorganic acid salt of chitosan, and gas is selected from sulfur hexafluoride.
Chitosan hydrochlorate 0.9g soaks with the 2-3ml dehydrated alcohol, adds 50-60 ℃ of distilled water of 150ml, is stirred to dissolving fully.Hydrogenation egg yolk lecithin 0.1g joins in the 120ml 50-60 ℃ ethanol solution and dissolves, and is transferred in the above-mentioned chitosan 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 ℃, utilizing freeze-drying method to obtain with phospholipid composition and constituent of chitosan is the compound vacuolar membrane drying solid of compound vacuole membrane material, be sub-packed in the 10ml cillin bottle, every bottle of 50mg, it is saturated to charge into sulfur hexafluoride, the lipid microbubble lyophilized powder of gassiness in the middle of obtaining, capping is placed.
With the rabbit is animal pattern, adopt the auricular vein method of injecting to carry out liver ultrasonic development effect observation, and contrast commercially available acoustic contrast agent product Levovist, join in the lipid microbubble lyophilized powder bottle with the 2ml normal saline solution before using, slight jolting can form the lipid microbubble that contains sulfur hexafluoride gas with the centre.It is obvious that experimental result shows that this composite film material lipid ultrasonic microvesicle has certain development effect, develops to strengthen commercially available around acoustic contrast agent product Levovist.
Embodiment 2:
The lipid microbubble of the middle gassiness of second embodiment preparation of the present invention is used for acoustic contrast agent, wherein the phospholipid composition is selected from hydrogenated phospholipid, constituent of chitosan is selected from the inorganic acid salt of chitosan, gas is selected from sulfur hexafluoride, select for use poloxamer 188 as skeleton proppant and surfactant, to guarantee that lipid microbubble keeps homodisperse state in freezing dry process.
Chitosan hydrochlorate 0.7g soaks with the 2-3ml dehydrated alcohol, adds 50-60 ℃ of distilled water of 150ml, is stirred to dissolving fully.Hydrogenation egg yolk lecithin 0.3g joins in the 120ml 50-60 ℃ ethanol solution and dissolves, and is transferred in the above-mentioned chitosan 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 ℃, the poloxamer 188 that adds 1-3g, utilizing freeze-drying method to obtain with phospholipid composition and constituent of chitosan behind the mixing is the dried frozen aquatic products of compound vacuolar membrane, be sub-packed in the 10ml cillin bottle, every bottle of 200mg, it is saturated to charge into sulfur hexafluoride, the lipid microbubble lyophilized powder of gassiness in the middle of obtaining, and capping is placed.
With the rabbit is animal pattern, adopt the method for embodiment 1 to carry out liver ultrasonic development effect observation, and contrast commercially available acoustic contrast agent product Levovist, join in the lipid microbubble lyophilized powder bottle with the 2ml normal saline solution before using, slight jolting can form the lipid microbubble that contains sulfur hexafluoride gas with the centre.Experimental result shows that this composite film material lipid ultrasonic microvesicle development effect is obvious, the development enhancing time surpasses 5min, longer than commercially available acoustic contrast agent product Levovist developing time, illustrate that the lipid microbubble of this composite film material can be as effective acoustic contrast agent.
Embodiment 3:
The lipid microbubble of the middle gassiness of the 3rd embodiment preparation of the present invention is used for acoustic contrast agent, and the phospholipid composition is selected from synthetic phospholipid and its polyethyleneglycol modified derivant, and constituent of chitosan is selected from the chitosan acylate, and gas is selected from fluorocarbon gas.
Chitosan (molecular weight 350,000) 0.45g adds 30% acetic acid 1.5ml formation chitosan acetate, adds 50-60 ℃ of distilled water mixing of 150ml.Dipalmitoyl phosphatidyl choline: Polyethylene Glycol-DSPE (9: 1) 0.05g joins in the 120ml 50-60 ℃ ethanol solution and dissolves, be transferred in the above-mentioned chitosan aqueous solution, 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 poloxamer 188 that adds 1-3g, utilizing freeze-drying method to obtain with phospholipid composition and constituent of chitosan behind the mixing is the lipid microbubble dried frozen aquatic products of composite film material, be sub-packed in the 10ml cillin bottle, every bottle of 200mg, it is saturated to charge into perfluoropropane, and capping is placed.
With the rabbit is animal pattern, adopt the method for embodiment 1 to carry out liver ultrasonic development effect observation, the result shows that this composite film material lipid microbubble development effect is obvious, and the development enhancing time surpasses 5 minutes, illustrates that the lipid microbubble of this composite film material can be as effective acoustic contrast agent.
Embodiment 4:
The lipid microbubble of the middle gassiness of the 4th embodiment preparation of the present invention bag medicine carrying thing, the phospholipid composition is selected from natural phospholipid, constituent of chitosan is selected from chitin or it takes off acetyl product chitosan, and gas is selected from air, oxygen, nitrogen or carbon dioxide, is model drug with the hirudin.
Chitosan (molecular weight 350,000) 0.3g adds 30% acetic acid 1ml, and the dissolving back adds 50-60 ℃ of distilled water of 150ml and stirs.Soybean phospholipid 0.7g joins in the 120ml 50-60 ℃ ethanol solution and dissolves, and is transferred in the above-mentioned chitosan aqueous solution, and mechanical agitation 600-750rpm made its abundant mixing more than 30 minutes, forms 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 that adds 1-3g, utilizing freeze-drying method to obtain with phospholipid composition and constituent of chitosan behind the mixing is the lipid microbubble lyophilized powder of composite film material, appropriateness is sub-packed in the 10ml cillin bottle after pulverizing, every bottle of 200mg, it is saturated to charge into nitrogen, and capping is placed.
With the hirudin is model drug, be made into the hirudin aqueous solution 2ml of 0.1mg/ml, be injected in the lipid microbubble lyophilized powder bottle every plug, slight jolting, the centre that can form with the parcel hirudin contains the nitrogen lipid microbubble, change over to and use 300rpm low-speed centrifugal 5min in the centrifuge tube, the lipid microbubble that bag carries hirudin floats on the solution upper strata, utilize the concentration of free water trematodiasis element in the centrifugal back of the 275nm wavelength ultraviolet detection lower floor solution, utilize " envelop rate (%)=[(amount of hirudin total amount-free hirudin)/hirudin total amount] * 100 " formula to calculate, the envelop rate that obtains reaches more than 75%, the lipid microbubble that shows this composite film material can be applied in the pharmaceutical preparation as pharmaceutical carrier.
Embodiment 5:
The 5th embodiment preparation of the present invention is used for wound flushing and fruit and vegerable disinfectant lipid microbubble, and the phospholipid composition is selected from natural phospholipid, and constituent of chitosan is selected from the chemical derivative of chitosan salt, and gas is selected from air, is model drug with the hibitane.
Hydroxypropyl-3 ammonio methacrylate chitosan 0.5g adds 50-60 ℃ of distilled water of 150ml and stirs.Egg yolk lecithin 0.5g joins in 120ml 50-60 ℃ of 95% alcoholic solution and dissolves, is transferred in the above-mentioned chitosan aqueous solution, and in the ultrasonic cleaning machine ultrasonic 1-3 minute, 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 most of ethanol in the solution at 35-40 ℃, the gelatin or the lactose that add 1-3g, spray drying behind the mixing, obtain with phospholipid composition and constituent of chitosan is the lipid lipid microbubble dry powder of composite film material, appropriateness is sub-packed in the 10ml cillin bottle after pulverizing, every bottle of 200mg, capping is placed.
With the hibitane is model drug, be made into 1: 1000-1: the liquor hibitane 2ml of 5000 variable concentrations, be injected in the lipid microbubble dry powder bottle every plug, slight jolting, the aeriferous lipid microbubble in centre can be formed, the sterilization etc. of sterilization, wound flushing, rinsing the mouth antiinflammatory, furniture and the fruit and vegerable of hands can be used for the parcel hibitane.
Embodiment 6:
The 6th embodiment preparation of the present invention is as the additive of cosmetics or the lipid microbubble of meat antistaling agent, and the phospholipid composition is selected from natural phospholipid, and constituent of chitosan is selected from the chemical derivative of chitosan, and gas is selected from nitrogen.
Hydroxypropyl chitosan 0.5g adds 50-60 ℃ of distilled water of 150ml and stirs.Phosphatidylcholine: PHOSPHATIDYL ETHANOLAMINE (9: 1) 0.5g joins in 120ml 50-60 ℃ of 95% alcoholic solution and dissolves, be transferred in the above-mentioned chitosan aqueous solution, utilize the shaking table vibration to 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 most of ethanol in the solution at 35-40 ℃, the poloxamer 188 that adds 1-3g, utilizing freeze-drying method to obtain with phospholipid composition and constituent of chitosan behind the mixing is the lipid microbubble dried frozen aquatic products of composite film material, be sub-packed in the 10ml cillin bottle, every bottle of 200mg, it is saturated to charge into nitrogen, and capping is placed.This product can be used as the wetting agent or the meat antistaling agent of cosmetics.
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 (13)
1. lipid microbubble, it is characterized in that: this lipid microbubble is mainly formed compound vacuolar membrane by phospholipid composition and constituent of chitosan, be filled with gas in the described compound vacuolar membrane, phospholipid composition wherein is selected from one or more in natural phospholipid, hydrogenated phospholipid, synthetic phospholipid and the polyethyleneglycol modified derivant thereof, and constituent of chitosan wherein is selected from one or more in chitosan, chitosan salt or the chitosan derivatives.
2. lipid microbubble as claimed in claim 1 is characterized in that: described natural phospholipid comprises: egg yolk lecithin, soybean phospholipid, phosphatidylcholine and PHOSPHATIDYL ETHANOLAMINE.
3. lipid microbubble as claimed in claim 1 is characterized in that: described hydrogenated phospholipid comprises: hydrogenation egg yolk lecithin and hydrogenated soya phosphatide.
4. lipid microbubble as claimed in claim 1 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 one or more combination and their polyethyleneglycol modified derivant wherein.
5. described lipid microbubble as claimed in claim 1 is characterized in that: described chitosan comprises that chitin or its take off acetyl product chitosan.
6. described lipid microbubble as claimed in claim 1 is characterized in that: described chitosan salt comprises acylate, inorganic acid salt or the quaternary ammonium salt of chitosan.
7. lipid microbubble as claimed in claim 1; it is characterized in that: chitosan derivatives wherein is selected from the chemical derivative of chitosan or chitosan salt; described chemical derivative is the hydroxylating that the molecule to chitosan or chitosan salt carries out; carboxylated; acyl groupization; alkylation; sulfhydrylation; Sulfation; Phosphation; glycosylation; crosslinked; complexation; the chemical modification derivant that the Polyethylene Glycol grafting forms comprises: hydroxypropyl chitosan; carboxymethyl chitosan; the esterification chitosan; the Sulfation chitosan; the Phosphation chitosan; acylation chitosan; the N-alkylated chitosan; quaternary ammonium N-carboxyetbyl chitosan; thio chitosan; the glycosylation chitosan; chitosan resin; the chitosan complex thing; the Polyethylene Glycol grafted chitosan; the grafted by beta cyclodextrin chitosan; the poloxamer grafted chitosan.
8. lipid microbubble as claimed in claim 1 is characterized in that: gas wherein is selected from wherein one or more of air, oxygen, nitrogen, carbon dioxide, sulfur hexafluoride, fluorocarbon gas.
9. as each described lipid microbubble of claim 1-8, it is characterized in that: the phospholipid composition is 0.1% to 99.9% in the compound by weight percentage vacuolar membrane, and constituent of chitosan is 0.1% to 99.9%.
10. as the lipid microbubble of claim 9 a described middle gassiness, it is characterized in that: the phospholipid composition is 10% to 90% in the compound by weight percentage vacuolar membrane, and constituent of chitosan is 10% to 90%.
11. the preparation method of a lipid microbubble 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 chitosan, 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 lyophilization or spray drying process to obtain the lipid microbubble drying solid;
Step (c) is suitably pulverized the lipid microbubble drying solid that step (b) obtains, and charges into specific gas, contains the lipid microbubble dried frozen aquatic products of gas in the middle of promptly obtaining.
12. the preparation method of lipid microbubble as claimed in claim 11, it is characterized in that: phospholipid composition wherein is selected from one or more in natural phospholipid, hydrogenated phospholipid, synthetic phospholipid and the polyethyleneglycol modified derivant thereof, and constituent of chitosan wherein is selected from one or more in chitosan, chitosan salt or the chitosan derivatives.
13. the preparation method of lipid microbubble as claimed in claim 11 is characterized in that: in the described lipid microbubble drying solid by weight percentage the phospholipid composition be 0.1% to 99.9%, constituent of chitosan is 0.1% to 99.9%.
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| CN1321697C (en) * | 2003-12-23 | 2007-06-20 | 中国人民解放军军事医学科学院毒物药物研究所 | Ultrasound contrast medium composition with phospholipid as membrane material and its preparation method |
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