CN1404878A - Novel lipide supersonic contrast medium and preparation method thereof - Google Patents
Novel lipide supersonic contrast medium and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a liposome ultrasonic contrast medium, which comprises film-forming material, liposome, foaming agent, polymer component and hypertonic glucose, and every millilitre of said contrast medium contains 0.1-5 wt% of liposome, 0.01-1 wt% of foaming agent, 70-90 wt% of polymer component, 0.15-0.5 ml of biological active gas. Its preparation process includes: making film-forming material contact with water medium or non-water medium to respectively form water suspension or solution, freeze-drying, making obtained lipid solid material contact with hydrate solution, sound vibration and oscillation treatment, and introducing biological active gas to obtain semi-product, detecting and controlling, filling to obtain finished product which can obtain long-time intensified tissue development effect.
Description
Technical field
The present invention relates to acoustic contrast agent, be specifically related to contain lipide supersonic contrast medium of this lipid mixture and preparation method thereof by a kind of liposome mixture composition and wrapping biological active gas.
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 (as 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 pass through blood capillary, the microvesicle size is evenly organized and is developed, and effective enhancing tissue develops 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 fluoro-gas is a 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 coating active biogas.Compare in the enhancing video picture of ultrasonic contrast with regard to it, the lipid contrast agent has more superiority, and reason is that the lipid contrast agent has: (1) targeting.After liposome 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.On the one hand lipid contrast agent chemical property is stable, can preserve the several months under the room temperature not change, and is easy to commercialization; On the other hand more can be withstand voltage in blood circulation, the radiography longer duration; (3) safety.The immobilized artificial membrane that constitutes liposome is biodegradable, harmless; And albumin class contrast agent remains the danger of propagating blood disease owing to being carrier with human albumin.
Chinese invention patent prospectus CN1306442A (application number is 99107622.8) discloses the contrast agent that a kind of lipid is a lapping, this contrast agent is to be lapping with phospholipid, be enclosed with bioactive gas in the microgranule, its combination preparation is two kinds of compositionss, one of them is to contain the aqueous injectable medium that disperses gas and be used to stablize the material of described institute gas, and another is injectable O/w emulsion.And it organizes enhancing video picture effective time to have only 5-20 minute in application, can not satisfy the needs of clinical examination fully; It is also generally shorter that all kinds of acoustic contrast agents of at present domestic and international simultaneously pertinent literature report effectively strengthen the time, and the output capacity of radiography microvesicle is on the low side, reports that as U.S.'s patent of invention (patent No. 6033646) prospectus its microbubble concentration is 1 * 10
8～1.6 * 10
9/ ml.And present contrast agent cost height, commercially available costing an arm and a leg is 110 U.S. dollars as every price of liposome contrast agent SonoVue.
The content of invention
One of purpose of the present invention is to improve the filmogen composition of liposome contrast agent; Two of purpose of the present invention is to optimize the preparation technology of contrast agent; By realizing that two purposes of the present invention can improve the productive rate of microbubble, prolong the effective enhancing time of contrast agent in the tissue development.
The present invention has realized above-mentioned purpose, shows: 1. microvesicle output capacity height, microbubble concentration reaches 7 * 10
9/ ml is higher than present bibliographical information, and the microvesicle homogeneity is good, and the microsphere of diameter 2～6 μ m accounts for 75～80% (see figure 1)s; 2. contrast agent was long in effective enhancing time that tissue develops, greater than 30 minutes; 3. cost is low, and the product cost is far below external like product.
One of for achieving the above object, the present invention has adopted following technical scheme:
The filmogen wrapping biological active gas formation that liposome contrast agent of the present invention is served as reasons and contained lipid, wherein filmogen comprises liposome, foaming agent, polymer composition, hyperosmotic glucose class or alcohols; In described composition, the ratio that liposome occupies in the contrast agent is 0.1～5 weight %, the ratio of foaming agent is 0.01～5 weight %, hyperosmotic glucose or alcohols ratio are 1-30 weight %, the high molecular polymer constituent ratio is 5-30 weight %, biological activity gas is 0.15～0.5ml, and all the other are solvent.
Above said liposome constitute the phospholipid molecule; specifically comprise 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).
The said foaming agent in front is non-ionic surfactant, comprises tween specifically
80And span
80The 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 a high molecular polymer, is Macrogol 4000 (PEG4000) when specifically using, and using of high molecular polymer is to provide a supporting structure as lipide component and foaming agent when constituting the contrast agent film.
The hyperosmotic glucose that uses is glucose, fructose and isomer thereof, polysaccharide; Alcohols is propylene glycol, glycerol, and the purpose of using hyperosmotic glucose or alcohols is in order to increase the viscosity of microvesicle in solution, reduce the mutual fusion tendency of radiography microvesicle, simultaneously the hydrogen bond on the sugar also directly and the interaction of hydrogen bond of lipid, both have strengthened the stability of radiography microvesicle jointly.
The effect of biological activity gas in contrast agent is to provide a reflecting interface that acoustic impedance difference is bigger for ultrasound wave jointly with filmogen, described biological activity gas is mainly fluoride gas, include pfc gas, sulfur fluoride gas specifically, in application, be mainly perfluoropropane, sulfur hexafluoride.
For achieving the above object two, the present invention has adopted following preparation technology:
The preparation flow that is described liposome contrast agent be with the contrast agent filmogen through contact the lipid solids that forms aqueous suspension or solution-lyophilization-lyophilization gained respectively with aqueous medium or non-aqueous media and contacts with aqua liquid-shake or oscillation treatment simultaneously with importing-half-finished detection control of biological activity gas and packing-make finished product.Sound shake or oscillation treatment before carry out sterilization, later operation is all carried out in aseptic of strictness control.Step (a):
(1) described needed filmogen (for example DPPG, DSPC and PEG4000) is contacted with aqueous medium, make it become a suspended state system.Filmogen intersperses among in the aqueous medium better in this system in order to make, and serviceability temperature is 45～55 ℃, and the time is 20～40 minutes.
Or (2) contact described required filmogen (for example DPPG, DSPC and PEG4000) with non-aqueous media, makes it become a uniform solution system.Dissolve more evenly for making, the temperature of use is 45～55 ℃, and the time is 20～40 minutes.
At the aqueous medium described in the above-mentioned step is deionized water, distilled water or normal saline.Aqueous medium described in the preferred embodiment is a deionized water.Non-aqueous media recited above is the tert-butyl alcohol, the positive tert-butyl alcohol.Non-aqueous media described in the preferred embodiment is the tert-butyl alcohol.Above-mentioned when doing filmogen and interspersing among aqueous medium and be dissolved in non-aqueous media desired temperature be 45～55 ℃, the time is 20～40 minutes.Step (b):
Lipid suspension thing behind the sterilization or lipid solute are gone solution-treated with the negative pressure freeze drier, lyophilization operation 1～5 time, can carry out multigelation and handle, carrying out the cryodesiccated time is 24～36 hours, and the pressure of vacuum suction described in the lyophilization is 50～65 * 10
-3MBar, the lyophilization temperature is controlled to be-50～-70 ℃.Step (c):
The lipid solids that lyophilization is good is dissolved with aqua liquid in the sterilizing room of strictness control.
Wherein there is hyperosmotic glucose 0.9-0.99ml in described aqua liquid in every milliliter of aqua liquid for to be made into by hyperosmotic glucose class and foaming agent, has the foaming agent of 0.01～0.2ml; Or constitute by propylene glycol, glycerol, normal saline three's volume ratio liquid mixture prepared and the foaming agent with 8: 1: 1, in the aqua liquid by its every milliliter of constituting, there is the foaming agent of 0.01～0.1ml, there is the mixed liquor of 0.9-0.99ml.For fully being dissolved, the lipid solids can suitably vibrate in this step.Hyperosmotic glucose or alcohols are incorporated in the filmogen of contrast agent at this moment.Step (d):
(1) get the dissolved lipid soln of step (c), in the sterilizing room of strictness control the lipid soln of gained is imported by the speed of 0.5-1ml/s and carry out the sound processing of shaking in the ultrasonic acoustic Vibration Meter, from bottom importing perfluoropropane gas, speed is 0.25-0.5ml/s simultaneously; Sound Vibration Meter probe places 0.5～2cm place under the liquid level, lipid soln is subjected to supersonic vibration to produce cavitation, the gas of parcel biologically active forms the microsphere that a large amount of particle diameters differ, the sound Treatment Solution of shaking is derived to introduce by the speed of 0.25-0.5ml/s and divides in the flow container, to divide the abundant mixing of solution in the flow container, described ultrasonic acoustic Vibration Meter is meant that frequency is 25KHz, and power is the adjustable supersonic oscillations instrument of 0～650W, and the power that uses in sound shakes processing is 160W～280W.The sound time of shaking is 30s～90s.Sound Vibration Meter horn is chosen as φ 6, φ 10 or φ 15, and horn is chosen as φ 6 in more excellent embodiment, and the sound time of shaking is 60s.Measure every index of microsphere in the solution: adjust to required value as microsphere concentration, mean diameter, particle size distribution etc. and by existing method, with the abundant once more mixing of satisfactory solution, divide in the fractional pack bottle of packing into afterwards then;
Or (2) get the dissolved lipid soln of step (c), by biological activity gas and lipid soln ratio is to be sub-packed in through autoclave sterilization disinfectant little peace a word used in place name bottle or tubule at 0.5～1.5: 1, handle with the mechanical oscillation instrument, measure every index of microsphere in the solution then: adjust to required value as microsphere concentration, mean diameter, particle size distribution etc. and by existing method.Described mechanical oscillation instrument is that rotating speed is 4500 ± 100 revolutions per seconds a mechanical oscillation instrument, and temperature is controlled at 18～30 ℃ in oscillation treatment, and duration of oscillation is 30～60s, and more duration of oscillation is 45s in the embodiment of You Huaing.Step (e):
The microsphere of above-mentioned bottle packing moved in the lyophilization machine carries out the vacuum and low temperature negative pressure drying, make injectable powder, in bottle, inject with lipid in the identical biological activity gas that wraps up, capping.
Description of drawings
Accompanying drawing 1 is microbubble image under 100 times of light microscopics after 400 times of the contrast agent dilutions.
Accompanying drawing 2 carries out strengthening the video picture image through femoral vein acoustic contrast brain essence to the dog brain for contrast agent.What show among the figure is with the dosage of 0.01ml/Kg 10 seconds, 30 seconds, 1 minute brain parenchymal bluss situation after injecting preceding, contrast agent bolus respectively.
Accompanying drawing 3 carries out strengthening the video picture image through auricular vein acoustic contrast liver parenchyma to rabbit liver for contrast agent; What show among the figure is with the dosage of 0.01ml/Kg 30 seconds (B), 3 minutes (C), 10 minutes (D), 20 minutes (E), 40 minutes (F), 50 minutes (G), 60 minutes (H) liver parenchyma development situations after (A), the contrast agent bolus before injecting respectively, before liver parenchyma video picture GTG intensity is higher than not radiography in the time of 60 minutes.
Accompanying drawing 4 is for contrast agent strengthens the video picture image to dirty the carrying out of rabbit kidney through auricular vein acoustic contrast kidney essence and medullary substance, show among the figure be with the dosage of 0.01ml/kg respectively before injecting (A), inject back 10 seconds (B), 20 seconds (C), 40 seconds (D) kidney development situations.
Concrete embodiment
Embodiment 1: the preparation of liposome contrast agent
Take by weighing DPPG 2g, DSPC 4g, Macrogol 4000 300g, under 50 ℃ of conditions, intersperse among jointly in the deionized water of 1.2L, with its float lyophilized overnight, thaw after lyophilized overnight again, prepare the solid mixt of filmogen, the solid mixt autoclave sterilization for preparing is handled, and the solid mixt of in aseptic of strictness control above-mentioned sterilization treatment being crossed is dissolved in 50% glucose 90% and the tween that contain through the microporous filter membrane processing
80In 10% the aqua liquid, matched proportion density is 600mg/ml, behind the machinery mixing, the lipid soln of gained imported by the speed of 0.5ml/s carry out the sound processing of shaking in the ultrasonic acoustic Vibration Meter, from bottom importing perfluoropropane gas, speed is 0.25ml/s simultaneously, the sound power that shakes is 280W, the sound liquid of handling that shakes is derived packing by 0.25ml/s, promptly prepare the contrast agent of liquid state, it is 7.1 * 10 that initial survey concentration is observed in sampling
9/ ml, particle size distribution regulates the microbubble concentration and the particle size distribution of contrast agent at 2～10 μ m, and with the contrast agent that regulates concentration and particle diameter bottle packing, every bottle of liquid radiography dosage of packing is 2ml, prepares the injectable powder of contrast agent with the low-temperature negative-pressure seasoning.
Embodiment 2: saccharide is to the influence of microsphere output capacity and particle diameter
Table 1 is listed the result who uses microsphere productive rate, particle diameter and particle size distribution under aqueous phase solvent, 50% fructose, three kinds of situations of 50% glucose in the different aqua liquids
| Project | Aqueous phase solvent | Glucose | Fructose |
| Microsphere concentration (10 9/ml) | ????3.1 | ????7.2 | ???7.5 |
| Mean diameter (μ m) | ????4.01 | ????3.15 | ???3.01 |
| Microsphere percentage ratio less than 2 μ m | ????20 | ????25 | ????11 |
| The microsphere percentage ratio of 2～6 μ m | ????53 | ????63 | ????80 |
| Microsphere percentage ratio greater than 6 μ m | ????27 | ????12 | ????9 |
| Microsphere percentage ratio greater than 10 μ m | ????4 | ????1 | ????0.5 |
As can be seen from Table 1, saccharide is good than aqueous phase solvent as aqua liquid, and fructose is better than glucose, can obviously improve the percentage ratio of effective microsphere in 2～6 mu m ranges.
Embodiment 3: tween
80Influence to microsphere productive rate and particle diameter
Table 2 has been listed the tween that adds variable concentrations in the preparation process
80Result to microsphere productive rate and grain diameter influence:
| Tween 80(ml/ml) | Microsphere concentration (* 10 9/ml) | Microspherulite diameter (μ m) |
| ????0.01 ????0.02 ????0.03 ????0.04 ????0.05 | ?????1.1 ?????7.1 ?????6.9 ?????3.1 ?????0.6 | ????6.0 ????3.2 ????4.8 ????5.3 ????8.0 |
As can be seen from Table 2, tween
80Concentration the highest with microvesicle productive rate when the 0.02ml/ml lipid soln, particle diameter is also better, tween
80The slight change of concentration is bigger to the output capacity influence of microvesicle.
Application verification: to rabbit, dog in-vivo imaging
Use the contrast agent of second kind of aqua liquid preparation that the dog brain is carried out acoustic contrast, dosage with 0.01ml/kg carries out through the femoral vein acoustic contrast, video picture, 30 seconds (see figure 2)s that peak appearred obviously strengthening in brain essence in the time of about 10 seconds, the color Doppler blood flow enhancing time reaches 50 minutes; Rabbit liver, kidney are carried out acoustic contrast through auricular vein with the dosage of 0.01ml/kg, liver, kidney effectively the enhancing time surpass 50 minutes, liver parenchyma video picture shade of gray in the time of 60 minutes still is higher than not (seeing Fig. 3,4) before the radiography.
Claims (10)
1, a kind of lipide supersonic contrast medium is made of the filmogen wrapping biological active gas that contains lipid, and it is characterized in that: filmogen comprises liposome, foaming agent, polymer composition, hyperosmotic glucose class or alcohols; In the described contrast agent, the ratio that liposome occupies is 0.1～5 weight %, and the ratio of foaming agent is 0.01～5 weight %, the ratio of hyperosmotic glucose or alcohols is 1-30 weight %, the high molecular polymer constituent ratio is 5-30 weight %, and biological activity gas is 0.15～0.5ml, and all the other are solvent.
2, a kind of preparation method of lipide supersonic contrast medium is characterized in that: may further comprise the steps: step (a)
(1) described needed filmogen is contacted with aqueous medium, make it become a suspended state system, serviceability temperature is 45～55 ℃, and the time is 20～40 minutes;
Or (2) contact described required filmogen (for example DPPG, DSPC and PEG4000) with non-aqueous media, makes it become a uniform solution system, and the temperature of use is 45～55 ℃, and the time is 20～40 minutes; Step (b)
Lipid suspension thing behind the sterilization or lipid solute are gone solution-treated with the negative pressure freeze drier, lyophilization operation 1～5 time, carrying out the cryodesiccated time is 24～36 hours, the pressure of vacuum suction described in the lyophilization is 50～65 * 10
-3MBar, the lyophilization temperature is controlled to be-50～-70 ℃: step (c)
The lipid solids that lyophilization is good is dissolved with aqua liquid in the sterilizing room of strictness control; Step (d)
(1) get the dissolved lipid soln of step (c), in the sterilizing room of strictness control the lipid soln of gained is imported by the speed of 0.5-1ml/s and carry out the sound processing of shaking in the ultrasonic acoustic Vibration Meter, from bottom importing biological activity gas, speed is 0.25-0.5ml/s simultaneously; Sound Vibration Meter probe places under the liquid level processing of shaking of 0.5～2cm place sound, the sound Treatment Solution of shaking is derived to introduce by the speed of 0.25-0.5ml/s and divides in the flow container, to divide the abundant mixing of solution in the flow container, measure every index of microsphere in the solution: adjust to required value as microsphere concentration, mean diameter, particle size distribution etc. and by existing method, with the abundant once more mixing of satisfactory solution, divide in the fractional pack bottle of packing into afterwards then;
Or (2) get the dissolved lipid soln of step (c), by biological activity gas and lipid soln ratio is to be sub-packed in through autoclave sterilization disinfectant little peace a word used in place name bottle or tubule at 0.5～1.5: 1, handle with the mechanical oscillation instrument, measure every index of microsphere in the solution then: adjust to required value as microsphere concentration, mean diameter, particle size distribution etc. and by existing method; Temperature is controlled at 18～30 ℃ in oscillation treatment, and duration of oscillation is 30～60s; Step (e):
The microsphere of above-mentioned bottle packing moved in the lyophilization machine carries out the vacuum and low temperature negative pressure drying, make injectable powder, in bottle, inject with lipid in the identical biological activity gas that wraps up, capping.
3, lipide supersonic contrast medium according to claim 1 is characterized in that: liposome constitute the phospholipid molecule.
4, lipide supersonic contrast medium according to claim 3; it is characterized in that: the phospholipid molecule comprises 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).
5, lipide supersonic contrast medium according to claim 1 is characterized in that: foaming agent is non-ionic surfactant.
6, lipide supersonic contrast medium according to claim 5, it is characterized in that: surfactant comprises tween
80And span
80
7, lipide supersonic contrast medium according to claim 1 is characterized in that: said polymer is a high molecular polymer.
8, lipide supersonic contrast medium according to claim 1 is characterized in that: the hyperosmotic glucose that uses is glucose, fructose and isomer thereof, polysaccharide.
9, lipide supersonic contrast medium according to claim 2 is characterized in that: wherein there is hyperosmotic glucose 0.9-0.99ml in aqua liquid in every milliliter of aqua liquid for to be made into by hyperosmotic glucose class and foaming agent, has the foaming agent of 0.01～0.2ml.
10, lipide supersonic contrast medium according to claim 2 is characterized in that: aqueous medium is deionized water, distilled water or normal saline.
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| WO2006076826A1 (en) * | 2005-01-18 | 2006-07-27 | Institute Of Pharmacology Toxicology, Academy Of Military Medical Sciences | An ultrasonic contrast composition having phospholipid as film-former and the preparation method thereof |
| 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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| WO2006076826A1 (en) * | 2005-01-18 | 2006-07-27 | Institute Of Pharmacology Toxicology, Academy Of Military Medical Sciences | An ultrasonic contrast composition having phospholipid as film-former and the preparation method thereof |
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| CN101951835B (en) * | 2007-12-05 | 2015-02-11 | 马维尔生物科学公司 | Nano-scale contrast agents and methods of use |
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