CN1321697C - Ultrasound contrast medium composition with phospholipid as membrane material and its preparation method - Google Patents
Ultrasound contrast medium composition with phospholipid as membrane material and its preparation method Download PDFInfo
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- CN1321697C CN1321697C CNB2003101224213A CN200310122421A CN1321697C CN 1321697 C CN1321697 C CN 1321697C CN B2003101224213 A CNB2003101224213 A CN B2003101224213A CN 200310122421 A CN200310122421 A CN 200310122421A CN 1321697 C CN1321697 C CN 1321697C
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Abstract
The present invention relates to an ultrasound contrast agent composition using phospholipid components as film-forming materials, and a preparation method of the contrast agent composition. The contrast agent composition is composed of the film-forming materials and fluorocarbon class inert gases, wherein the film-forming materials are composed of the phospholipid components, foaming agents, polymers and stabilizing agents. The present invention is characterized in that the components of the film-forming materials have the weight percentage: 1 to 10% of the phospholipid components, 5 to 15% of the foaming agents, 0.5 to 10% of the stabilizing agents, and 70 to 90% of the polymers. The composition of the present invention exists in a form a unit dosage, and in each unit dosage, the quantity of the contained fluorocarbon class inert gases is 0.15 to 0.5 ml.
Description
Technical field:
The present invention relates to a kind of ultrasound contrast agent composition, being specifically related to a kind of is the ultrasound contrast agent composition and preparation method thereof of the parcel fluorine carbon noble gas of filmogen with the phospholipid composition.
Technical background:
Novel acoustic contrast agent can effectively strengthen parenchymatous organs' such as cardiac muscle, liver, kidney, brain two-dimensional ultrasound image and blood flow doppler signal in conjunction with ultrasonic new technique, reflection normal structure and the different blood perfusion of pathological tissues (tumor, ischemic myocardium) obviously improve the sensitivity and the specificity of ultrasonic diagnosis.In addition the acoustic contrast agent that carries gene, medicine also has wide practical use aspect treatment.Ideal novel acoustic contrast agent possesses following characteristics: high scattering, low dispersivity, low-solubility, abiology activity (harmless) can freely be passed through blood capillary, the microvesicle size evenly, tissue develops, and effectively strengthens the tissue development and enough satisfies the review time.
A new generation's acoustic contrast agent is many to be the core of microvesicle with the fluoro-gas, and because of fluorine-containing carbon gas is noble gas, molecular weight is big, and dissolubility and dispersivity in blood are poor, good stability.Different and albumin class, surfactant-based, phospholipid, high molecular polymer class arranged by the material of parcel fluorocarbon gas.Comparing in the enhancing video picture of ultrasonic contrast with regard to it, is that the filmogen contrast agent has more superiority with the phospholipid composition, and reason is: (1) targeting.After the phospholipid contrast agent entered human body, the tissue such as liver, spleen and the bone marrow that easily preferentially are rich in reticuloendothelial cell absorbed.(2) good stability.Phospholipid contrast agent chemical property is stable, can preserve the several months under the room temperature not change, and is easy to commercialization; (3) safety.The immobilized artificial membrane that constitutes the phospholipid contrast agent is biodegradable, harmless; And albumin class contrast agent remains the danger of propagating blood disease owing to being carrier with human albumin.
Summary of the invention:
The purpose of this invention is to provide a kind of improved be the contrast agent composition of filmogen with the phospholipid composition; The present invention also provides a kind of preparation method of contrast agent of optimization; By realizing that purpose of the present invention can improve the productive rate of microbubble, prolong the effective enhancing time of contrast agent in the tissue development.
One of for achieving the above object, the present invention has adopted following technical scheme:
Provided by the invention is that the contrast agent composition of filmogen is a kind of like this compositions with the phospholipid composition, it uses phospholipid substance to make a kind of filmogen as main component, this filmogen and fluorine carbon noble gas is mixed uses the purpose that reaches radiography.In the composition of filmogen, comprise compositions such as phospholipid composition, foaming agent, polymer composition, stabilizing agent; These compositions shared percentage by weight in contrast agent composition is, the ratio of phospholipid substance is 1～10 weight %, the ratio of foaming agent is 5～15 weight %, the stabilizing agent ratio is 0.5～10 weight %, the high molecular polymer constituent ratio is 70～90 weight %, and all the other are the fluorine carbon noble gas.
Above contrast agent composition can exist with unit dosage form, as is distributed into bottle, and the needs according to patient during use impose different dosage, can contain fluorine carbon noble gas 0.15～0.5ml in each dosage unit.
Said phospholipid composition is selected from least a following material: lecithin (PC); hydrogenated soya phosphatide (hydrogenated soy phosphatidylcoline; HSPC); hydrogenation egg yolk lecithin (hydrogenatedegg phosphatidylcoline; HEPC); two palmityl phosphatidyl ethanol (DPPE); dipalmitoyl phosphatidyl choline (DPPC); two oleoyl phosphatidyl ethanolamines (DOPE); Polyethylene Glycol-DSPE (PEG-DSPE); 1; 2-two palmityls-sn-glyceryl-3-phosphatidic acid glyceryl-sodium salt (DPPG); 1; 2-distearyl acyl group-sn-glyceryl-3-phosphatidylcholine (DSPC); 1; 2-two palmityls-sn-glyceryl-3-phosphatidic acid-sodium salt (DPPA); 1,2-two palmityls-sn-glyceryl-3-phosphatidylcholine (DPPC).
Said foaming agent is selected from least a non-ionic surface active agent, non-ionic surface active agent concrete as Tweens material, spans material; The purpose of using foaming agent is the output capacity of microvesicle when being increased in the preparation contrast agent microbubble, simultaneously adipose membrane is played stable effect.
Said polymer is selected from least a high molecular polymer, high molecular polymer concrete as poloxamer (Poloxamer), using of high molecular polymer is to provide a supporting structure as lipide component and foaming agent when constituting the contrast agent film, and the stability to film also has contribution simultaneously.
The stabilizing agent that uses is selected from Polyethylene Glycol, glyceryl monostearate, Palmic acid, polyethylene glycol 1500 (PEG1500) preferably, the purpose of using stabilizing agent is in order to reduce the mutual fusion tendency of radiography microvesicle, improve the hydrophilic lipotropism of lipid bilayer, strengthen the stability of radiography microvesicle.
The effect of fluorine carbon noble gas in contrast agent is to provide a reflecting interface that acoustic impedance difference is bigger for ultrasound wave jointly with filmogen, described fluorine carbon noble gas is selected from fluoride gas, fluoride gas includes pfc gas, sulfur fluoride gas etc. specifically, is mainly perfluoropropane, sulfur hexafluoride in application.
Contrast agent composition of the present invention can adopt following method preparation:
Step (a):
Compositions such as described filmogen phospholipid composition, foaming agent, polymer composition, stabilizing agent (concrete as HEPC, Poloxamer 188, Tween 80 and PEG 1500) are contacted with nonaqueous solvent anhydrous or that contain minor amount of water on a small quantity, utilize ultrasonic and mode of heating to make it become a uniform solution system, the temperature of using is 45～65 ℃, and the time is 20～40 minutes.
Be anhydrous or contain the straight or branched alcohol such as butanols of minor amount of water at the nonaqueous solvent described in the above-mentioned step.Nonaqueous solvent described in the preferred embodiment is the tert-butyl alcohol.Above-mentioned when doing filmogen and scattering and be dissolved in straight or branched alcohol such as the tert-butyl alcohol desired temperature be 45～65 ℃, the time is 20～40 minutes.
Step (b):
(a) solution slowly is cooled to 0-4 ℃, liquid is solidified, or earlier be put in 0-4 ℃ of cold preservation rapidly, aqueous or multigelation mode makes the Dispersion of Particles of separating out even to milkiness to use ultrasonic (room temperature 15-22 ℃) then.Ultrasonic power is optional ultrasonic with water-bath type or probe-type, and the ultrasonic power described in the preferred embodiment is that probe-type is ultrasonic.
Step (c):
Handle with the freezer dryer lyophilization, carrying out the cryodesiccated time is 20～25 hours, and the pressure of vacuum suction described in the lyophilization is 50～120 * 10
-3MBar, the lyophilization temperature is controlled to be-40～-50 ℃.
Step (d)
Dried frozen aquatic products in the sterilizing room of strictness control that lyophilization is good is pulverized, and is sub-packed in and makes injectable powder in the bottle, injects the fluorine carbon noble gas in bottle, capping.
Superiority of the present invention shows: 1. microvesicle output capacity height, microbubble concentration reaches 1 * 10
9/ ml, and the microvesicle homogeneity is good, and the microvesicle of diameter 2～6um accounts for 50～70% (see figure 1)s; 2. contrast agent is long in effective enhancing time that tissue develops; 3. cost is low, and the product cost is far below like product.
Description of drawings:
Fig. 1 is the microvesicle form of configuration back different time (contrast agent dilution 4 times after 400 times of light microscopics observe down).Behind a configuration 300min; Behind the b configuration 5min; Behind the c configuration 10min; Behind the d configuration 20min; Behind the e configuration 30min; Behind the f configuration 50min; Behind the g configuration 90min; Behind the h configuration 120min.
Fig. 2 is that contrast agent strengthens the video picture image to the kidney acoustic contrast after administration is annotated by rabbit ear edge vein group; What show among the figure is with the dosage of the 0.1mLl/kg kidney development situation of 30 seconds (b), 1 minute (c) after (a), the contrast agent bolus before injecting respectively.
Fig. 3 is that contrast agent strengthens the video picture image to the liver acoustic contrast after administration is annotated by rabbit ear edge vein group, and what show among the figure is to inject back 10 seconds (a), 30 seconds (b), 1 minute (c) liver parenchyma development situation respectively with the dosage of 0.1mL/kg.
The specific embodiment:
Embodiment 1: be the preparation of the contrast agent of filmogen with the phospholipid composition
Take by weighing hexadecylic acid 1.5mg, glyceryl monostearate 2mg, polyethylene glycol 1500 (PEG1500) 120mg and poloxamer 188 (Poloxamer 188) 120mg and be scattered in the tert-butyl alcohol of 3ml, 60 ℃ of dissolvings of water-bath.Other takes by weighing Ovum Gallus domesticus Flavus lecithin (PC) 20mg and is scattered in the 1ml tert-butyl alcohol, 60 ℃ of ultrasonic dissolutions of water-bath, and with last liquid mixing, rapidly in 0 ~ 4 ℃ of cold putting more than 30 minutes, liquid is and solidifies shape, lyophilizing 20 hours.Take by weighing 200mg lyophilizing sample and be loaded in the 5ml cillin bottle, fill perfluoropropane gas, close plug promptly prepares solid-state acoustic contrast agent.
Use is injected the 2ml normal saline after plug, shakes gently to form the microvesicle suspension, and it is 2 * 10 that microbubble concentration is observed in sampling
7/ ml, particle size distribution is at 2～10um, and the bubble wall thickness is the 300-1000 nanometer.
With the rabbit is simulated animal, adopts vein group to annotate injection system and carries out intravital ultrasonic development effect measuring, and the microvesicle that the result shows this product has similar development effect with commercially available acoustic contrast agent Levovist, illustrates that this product has the interior ultrasonic development effect of good body.
Embodiment 2: the influence of tween
Take by weighing hexadecylic acid 1.5mg, glyceryl monostearate 2mg, polyethylene glycol 1500 (PEG1500) 120mg and poloxamer 188 (Poloxamer 188) 120mg and be scattered in the tert-butyl alcohol of 3ml, 60 ℃ of dissolvings of water-bath.Other takes by weighing Ovum Gallus domesticus Flavus lecithin (PC) 20mg and not commensurability Tween 80 (Tween 80) is scattered in the 1ml tert-butyl alcohol, 60 ℃ of ultrasonic dissolutions of water-bath, and with last liquid mixing, rapidly in 0 ~ 4 ℃ of cold putting more than 30 minutes, liquid is and solidifies shape, lyophilizing 20 hours.Take by weighing 200mg lyophilizing sample and be loaded in the 5ml cillin bottle, fill perfluoropropane gas, close plug promptly prepares solid-state acoustic contrast agent.
Use is injected the 2ml normal saline after plug, shakes gently to form the microvesicle suspension, and the microvesicle percentage ratio of concentration, mean diameter and the 2～8um of microvesicle microvesicle is observed in sampling, the results are shown in Table 1.
The influence of Tween 80 pairs of microbubble concentrations, particle diameter and the particle size distribution of table 1 different content
| Project | Tween 80 content (weight %) | |||||
| 3 | 6 | 8 | 10 | 14 | 18 | |
| Microbubble concentration (10 7/ ml) the microvesicle percentage ratio of mean diameter (um) 2～8um | 4 7 30 | 3 7 25 | 5 6 30 | 5 6 35 | 7 6 26 | 5 6 20 |
As can be seen from Table 1, the influence of concentration, particle diameter and the particle size distribution of 80 pairs of microvesicles of Tween of different content is comparatively remarkable, the content of Tween 80 is when 8～14 weight %, and the microvesicle percentage ratio three synthesis result of the concentration of microvesicle, mean diameter and 2～8um is best.Test finds that Tween 80 content are high more, the also corresponding increase of lyophilizing sample viscosity, and therefore the content of the Tween 80 described in the preferred embodiment is no more than 15 weight %.The development effect of the microvesicle of content 5～15 weight % of Tween 80 is better than embodiment 1 among the embodiment 2.
Embodiment 3: the influence behind the lecithin hydrogenation
There is research to think with hydrolecithin (hydrogenated egg phosphatidylcholine, HEPC) (non-hydrogenated eggphosphatidylcholine EPC) removes slowly in Zhi Bei the long circulating liposomes body long circulating liposomes of preparation than hydrolecithin not.We are with the hydrogenation of Ovum Gallus domesticus Flavus lecithin: powdery Ovum Gallus domesticus Flavus lecithin (PC) adds dissolve with ethanol, adds 5% palladium carbon, puts hydrogenation treatment on the hydrogenation instrument.After hydrogenation treatment finishes, filter, ethanol is removed in the filtrate decompression rotation, lyophilization get white hydrolecithin (hydrogenated egg phosphatidylcholine, HEPC).
With Ovum Gallus domesticus Flavus lecithin (PC) 20mg among the hydrolecithin 5mg replacement embodiment 1, all the other steps of Tween 80 25mg are identical with embodiment 1, the preparation acoustic contrast agent.It is 1 * 10 that microbubble concentration is observed in sampling
8/ ml, particle size distribution is at 2～8um, and the bubble wall thickness is the 200-800 nanometer.
The microvesicle of embodiment 3 has stronger development intensity and longer developing time than embodiment 1 and embodiment 2, illustrates that this product has better development effect than embodiment 1 and embodiment 2.
Embodiment 4: the influence of different freezing modes
Take by weighing hexadecylic acid 1.5mg, glyceryl monostearate 2mg, polyethylene glycol 1500 (PEG1500) 75mg, poloxamer 188 (Poloxamer 188) 150mg, hydrolecithin 5mg and Tween 80 25mg and be scattered in the 2ml tert-butyl alcohol 60 ℃ of ultrasonic dissolutions of water-bath.It is ℃ rapid freezing to adopt different freezing mode to handle (1)-10; (2) 0-4 ℃ of rapid cold preservation; (3) multigelation mode: " 0-4 ℃ solidify-water-bath 15-22 is ℃ ultrasonic to be solidified for aqueous-0 ~ 4 ℃ to milkiness "; (4) 15-22 ℃ of room temperature is placed to liquid and solidifies 0-4 ℃ of cold preservation 10min.Lyophilizing 20 hours.Take by weighing 200mg lyophilizing sample and be loaded in the 5ml cillin bottle, fill perfluoropropane gas, close plug promptly prepares solid-state acoustic contrast agent lyophilized powder.
Use is injected the 2ml normal saline after plug, shakes gently to form the microvesicle suspension.The microvesicle percentage ratio of concentration, mean diameter and the 2～8um of microvesicle is observed in sampling, the results are shown in Table 2.
The different freezing modes of table 2 are to the influence of microbubble concentration, particle diameter and particle size distribution
| Project | Freezing mode | |||
| (1)-10 ℃ rapid freezing | (2) 0 ~ 4 ℃ of rapid cold preservations | (3) multigelation mode | (4) 15 ~ 22 ℃ of room temperatures are placed to liquid and solidify, 0 ~ 4 ℃ of cold preservation 10min | |
| Microbubble concentration (10 8/ ml) the microvesicle percentage ratio of mean diameter (um) 2～8um | 1 7 30 | 3 7 40 | 6 6 55 | 7 6 55 |
As can be seen from Table 2, the freezing mode difference is remarkable to the influence of concentration, particle diameter and the particle size distribution of microvesicle, mode (3) (multigelation mode: 0-4 ℃ solidify-water-bath 15-22 ℃ ultrasonic to milkiness aqueous-0-4 ℃ solidifies) and the microvesicle percentage result of concentration, mean diameter and the 2～8um of the microvesicle of mode (4) (15-22 ℃ of room temperature is placed to liquid and solidifies the 0-4 ℃ of cold preservation 10min in back) gained best.The development effect of mode (3) and mode (4) is better than embodiment 3.
Embodiment 5:
Take by weighing poloxamer 188 (Poloxamer 188) 150mg, hydrolecithin 5mg and Tween 80 25mg and be scattered in the 2ml tert-butyl alcohol 60 ℃ of ultrasonic dissolutions of water-bath.18-22 ℃ of room temperature is placed to liquid and solidifies (40min), 0-4 ℃ of cold preservation 10min.Lyophilizing 20 hours.Take by weighing 100mg lyophilizing sample and be loaded in the 5ml cillin bottle, fill perfluoropropane gas, close plug promptly prepares solid-state acoustic contrast agent.
Use is injected the 1ml normal saline after plug, shakes gently to form the microvesicle suspension, and it is 1 * 10 that microbubble concentration is observed in sampling
9/ ml, particle size distribution is at 2～6um, and the bubble wall thickness is the 200-500 nanometer.
Application verification: the ultrasonic development imaging of Liver and kidney in the rabbit body
Use the contrast agent of embodiment 5 preparations that liver and kidney in the rabbit body are carried out acoustic contrast, annotate administration with the dosage of 0.03ml/Kg through rabbit ear vein group, video picture appears obviously strengthening in liver, kidney in the time of about 10 seconds, peaked in 30 seconds, and effectively the enhancing time was above 1 minute.
Embodiment 6:
Take by weighing poloxamer 188 (Poloxamer 188) 150mg, hydrolecithin 8mg and Tween 80 20mg and be scattered in the 2ml anhydrous tertiary butanol 60 ℃ of ultrasonic dissolutions of water-bath.0-4 ℃ of cold preservation to liquid solidifies, and 37-39 ℃ ultrasonic aqueous to milkiness, and room temperature is placed and solidified.Lyophilizing 20 hours.Take by weighing 100mg lyophilizing sample and be loaded in the 5ml cillin bottle, fill perfluoropropane gas, close plug promptly prepares solid-state acoustic contrast agent.
Use is injected the 1ml normal saline after plug, shakes gently to form the microvesicle suspension, and sampling is observed microbubble concentration and is higher than 1 * 10
9/ ml, particle size distribution is at 2～5um, and the bubble wall thickness is the 200-500 nanometer.
Application verification: the ultrasonic development imaging of Liver and kidney in the rabbit body
Use the contrast agent development effect of embodiment 6 preparations to be better than embodiment 5, the kidney video picture effectively the enhancing time surpass 2 minutes, before liver parenchyma video picture shade of gray in the time of 10 minutes still is higher than not radiography.
Claims (5)
1, a kind of is the ultrasound contrast agent composition of filmogen with the phospholipid composition, constitute by the filmogen parcel fluorine carbon noble gas that contains lipid, it is characterized in that: filmogen is by the phospholipid composition, foaming agent, polymer, stabilizing agent is formed, wherein the phospholipid composition is selected from Ovum Gallus domesticus Flavus lecithin, hydrolecithin, wherein the Ovum Gallus domesticus Flavus lecithin consumption is 20mg, the hydrolecithin consumption is 5mg, and foaming agent is a Tween 80, and consumption is 25mg, polymer is a poloxamer, consumption is 120-150mg, and it is 75-120mg that stabilizing agent is selected from the polyethylene glycol 1500 consumption, and the hexadecylic acid consumption is 1.5mg, glyceryl monostearate, consumption are 2mg.
2, the ultrasound contrast agent composition of claim 1 is characterized in that: wherein the phospholipid composition is an Ovum Gallus domesticus Flavus lecithin, and consumption is 20mg, foaming agent is a Tween 80, consumption is 25mg, and polymer is a poloxamer, and consumption is 120mg, stabilizing agent is a polyethylene glycol 1500, consumption is 120mg, and hexadecylic acid, consumption are 1.5mg, and glyceryl monostearate, consumption is 2mg.
3, the ultrasound contrast agent composition of claim 1 is characterized in that: wherein the phospholipid composition is a hydrolecithin, and consumption is 5mg, foaming agent is a Tween 80, consumption is 25mg, and polymer is a poloxamer, and consumption is 120mg, stabilizing agent is a polyethylene glycol 1500, consumption is 120mg, and hexadecylic acid, consumption are 1.5mg, and glyceryl monostearate, consumption is 2mg.
4, the ultrasound contrast agent composition of claim 1, it is characterized in that: wherein the phospholipid composition is a hydrolecithin, and consumption is 5mg, and foaming agent is a Tween 80, consumption is 25mg, polymer poloxamer, consumption are 150mg, and stabilizing agent is 75mg for the polyethylene glycol 1500 consumption, hexadecylic acid, consumption is 1.5mg, and glyceryl monostearate, and consumption is 2mg.
5, the preparation method of the ultrasound contrast agent composition of claim 1, its feature may further comprise the steps:
Step (a)
Filmogen contact with a small amount of anhydrous or aqueous tert-butyl alcohol, utilize ultrasonicly to make it become a uniform solution system with mode of heating;
Step (b)
With (a) solution slowly cooling make solution solidifies, or cold preservation rapidly earlier uses then that ultrasonic aqueous or multigelation mode makes the Dispersion of Particles of separating out even to milkiness;
Step (c)
The product of lyophilization step (b);
Step (d)
The dried frozen aquatic products of step (c) is pulverized, be sub-packed in and make injectable powder in the bottle, in bottle, inject fluorine carbon noble gas, capping.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101596322B (en) * | 2007-06-06 | 2011-05-04 | 南方医院 | Aerial emulsion type ultraphonic contrast agent microballoon and preparation method thereof |
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| CN107233582B (en) * | 2016-03-29 | 2020-04-24 | 北京飞锐达医疗科技有限公司 | Method for preparing ultrasonic contrast agent based on tert-butyl alcohol/water mixed solvent |
| 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 |
| CN109260480B (en) * | 2018-10-19 | 2019-06-18 | 山东大学齐鲁医院 | A kind of preparation method for the chitosan nano meter level acoustic contrast agent carrying adriamycin |
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