CN1194763C - 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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- CN1194763C CN1194763C CNB021337209A CN02133720A CN1194763C CN 1194763 C CN1194763 C CN 1194763C CN B021337209 A CNB021337209 A CN B021337209A CN 02133720 A CN02133720 A CN 02133720A CN 1194763 C CN1194763 C CN 1194763C
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Abstract
The present invention relates to a liposome ultrasonic contrast agent which comprises film forming materials, liposomes, foaming agents, polymer ingredients and high leakage saccharide. Each milliliter of the contrast agent for use comprises 0.1 to 5 wt% of the liposomes, 0.01 to 1 wt% of the foaming agents, 70 to 90 wt% of the high leakage saccharide (the constituent ratio of high molecular polymers), and 0.15 to 0.5 ml of bioactivity gases. The liposome contrast agent comprises the preparation processes that the film forming materials of the contrast agent contact aqueous media and non aqueous media to form water suspended substances or solutions respectively, obtained lipid solid substances are frozen and dried contact water solutions, and sound vibration or oscillation treatment is carried out; simultaneously, the bioactivity gases are led in semifinished products, and the semifinished products are detected, controlled and subpackaged so as to make finished products. The contrast agent can enhance tissue display for a long time when used in a small dose, and effectively enhance time by more than 30 minutes. The microsphere of the present invention has the advantages of high yield rate, good uniformity and high effective concentration.
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 lipid 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 wrapping biological active gas.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 (as liver, spleen and bone marrow) that easily preferentially is 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.
It is the contrast agent of lapping with the lipid that Chinese invention patent prospectus CN1306442A (application number is 99107622.8) discloses a kind of, this contrast agent is to be lapping with phospholipid, be enclosed with biological activity 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 described gas, and another is injectable O/w emulsion.On the one hand, transportation, storage, use are all inconvenient; On the other hand, it organizes the effective time that strengthens video picture to have only 5～20 minutes 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.In addition, present acoustic 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.
Summary of the invention
One of purpose of the present invention is to improve the filmogen composition of lipide supersonic contrast medium; Two of purpose of the present invention is to optimize the preparation technology of this contrast agent.By realizing that two purposes of the present invention can improve the productive rate of microvesicle, 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% (seeing accompanying drawing 1); 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:
Lipide supersonic contrast medium of the present invention is made of the filmogen wrapping biological active gas that contains lipid, and wherein filmogen comprises phospholipid molecule, non-ionic surface active agent, Macrogol 4000, hyperosmotic glucose class or alcohols.In the described filmogen, the ratio that the phospholipid molecule occupies is 0.1～5 weight %, and the ratio of non-ionic surface active agent is 0.01～0.05 weight %, and the ratio of hyperosmotic glucose or alcohols is 1～30 weight %, the ratio of Macrogol 4000 is 5～30 weight %, and all the other are aqueous solution.Add biological activity gas 0.15～0.5ml in every milliliter of filmogen.
Above said phospholipid molecule; specifically be selected from 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, in 2-two palmityls-sn-glyceryl-3-phosphatidylcholine (DPPC) at least two kinds.
Above-mentioned non-ionic surface active agent comprises Tween 80 and sorbester p17 specifically.The purpose of using non-ionic surface active agent is in order to increase the output capacity of microvesicle, simultaneously adipose membrane to be played Stabilization, to prolong the effective enhancing time of contrast agent in the tissue development.
Using of Macrogol 4000 (PEG4000) is to provide a supporting structure as lipide component and non-ionic surface active agent when constituting the contrast agent film.
The hyperosmotic glucose that uses is glucose, fructose and isomer thereof; 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, to 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 is: with the phospholipid molecule in the contrast agent filmogen, Macrogol 4000 mix with aqueous solution or nonaqueous solvent the lipid solids that forms aqueous suspension or solution → lyophilization → lyophilization gained respectively mix with aqua liquid → sound shakes or oscillation treatment imports biological activity gas preparation contrast agent microbubble → quality testing, packing → lyophilization → finished product simultaneously.Sound shake or oscillation treatment before carry out sterilization, later operation is all carried out in aseptic of strictness control.
Step (a):
(1) with phospholipid molecule, Macrogol 4000 and aqueous solution in the contrast agent filmogen, make it become a suspended state system, serviceability temperature is 45～55 ℃, the time is 20～40 minutes;
Or (2) mix the phospholipid molecule in the contrast agent filmogen, Macrogol 4000 with nonaqueous solvent, makes it become a uniform solution system, and serviceability temperature is 45～55 ℃, and the time is 20～40 minutes.
At the aqueous solution described in the above-mentioned steps is deionized water, distilled water or normal saline.Aqueous solution described in the preferred embodiment is a deionized water.Nonaqueous solvent recited above is the tert-butyl alcohol, n-butyl alcohol.Nonaqueous solvent described in the preferred embodiment is the tert-butyl alcohol.Above-mentioned when filmogen is interspersed among aqueous solution and is dissolved in nonaqueous solvent desired temperature be 45～55 ℃, the time is 20～40 minutes.
Step (b):
With the lipid suspension thing behind the sterilization or lipid solute with the processing of desolvating of 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.
Described aqua liquid is made into by hyperosmotic glucose class and non-ionic surface active agent, wherein has hyperosmotic glucose 0.95～0.99ml in every milliliter of aqua liquid, non-ionic surface active agent 0.01～0.05ml; Or be made into by alcohols and non-ionic surface active agent, wherein contain propylene glycol 0.1ml in every milliliter of aqua liquid, glycerol 0.1ml, non-ionic surface active agent 0.01～0.05ml, normal saline surplus (being aqueous phase solvent).Can suitably vibrate for the lipid solids is fully dissolved in this step, this moment, hyperosmotic glucose or alcohols were incorporated in the filmogen of contrast agent.
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 supersonic oscillations instrument, from bottom importing biological activity gas, speed is 0.25～0.5ml/s simultaneously; Sound Vibration Meter probe places 0.5～2cm place under the liquid level.When sound shakes, 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 contrast agent suspension that sound shakes after handling is introduced in the branch flow container by funnel, by funnel foam or excessive microsphere are removed, then the contrast agent suspension is fully mixed, measure wherein every index of microsphere: adjust to required value as microsphere concentration, mean diameter, particle size distribution etc. and by existing method, divide in the fractional pack bottle of packing into then.
Or (2) get the dissolved lipid soln of step (c), is to be sub-packed in through autoclave sterilization disinfectant parcel bottling at 0.5～1.5: 1 by biological activity gas and lipid soln ratio, handles with the mechanical oscillation instrument.
Above-mentioned supersonic oscillations instrument frequency is 25KHz, and power is that 0～650W is adjustable, and horn is chosen as φ 6, φ 10 or φ 15.Horn is chosen as φ 6 in sound shakes processing, and the power that uses is 160W～280W, and the sound time of shaking is 30s～90s.In more excellent embodiment, the sound time of shaking is 60s.
Above-mentioned mechanical oscillation instrument rotating speed is 4500 ± 100 revolutions per seconds, and temperature is controlled at 18～30 ℃ in oscillation treatment, and duration of oscillation is 30～60s.In the embodiment of more optimizing, duration of oscillation is 45s.
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 a contrast agent microbubble image under the light microscopic;
Accompanying drawing 2 carries out strengthening the video picture image through femoral vein acoustic contrast brain essence to the dog brain for contrast agent;
Accompanying drawing 3 carries out strengthening the video picture image through auricular vein acoustic contrast liver parenchyma to rabbit liver for contrast agent;
Accompanying drawing 4 strengthens video picture image to dirty the carrying out of rabbit kidney through auricular vein acoustic contrast kidney essence and medullary substance for contrast agent;
The specific 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, prepare the solid mixt of filmogen, the solid mixt autoclave sterilization for preparing is handled, the solid mixt of in aseptic of strictness control above-mentioned sterilization treatment being crossed is dissolved in the aqua liquid that contains 50% glucose 90% and Tween 80 10% that microporous filter membrane is handled, 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 supersonic oscillations instrument, import perfluoropropane gas simultaneously from the bottom, speed is 0.25ml/s, the sound power that shakes is 280W, and the sound contrast agent suspension of handling that shakes is derived packing by 0.25ml/s, promptly prepares 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 packing 2ml prepares the injectable powder of contrast agent with the low-temperature negative-pressure seasoning.
Embodiment 2: saccharide is to the influence of microsphere productive rate 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 80 is to the influence of microsphere productive rate and particle diameter
Table 2 has been listed and has been added the result of the Tween 80 of variable concentrations to microsphere productive rate and grain diameter influence in the preparation process:
| 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, the concentration of Tween 80 microvesicle productive rate when the 0.02ml/ml lipid soln is the highest, and particle diameter is also better, and the slight change of Tween 80 concentration is bigger to the productive rate influence of microvesicle.
Application verification: to rabbit, dog in-vivo imaging
Use the contrast agent of second kind of aqua liquid preparation that the dosage of dog brain with 0.01ml/kg is carried out through the femoral vein acoustic contrast, video picture, peaked in 30 seconds (seeing accompanying drawing 2) 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 accompanying drawing 3,4) before the radiography.
Claims (5)
1. a lipide supersonic contrast medium is made of the filmogen wrapping biological active gas that contains lipid, and it is characterized in that: filmogen comprises phospholipid molecule, non-ionic surface active agent, Macrogol 4000, hyperosmotic glucose or alcohols; Described phospholipid molecule is selected from 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, in 2-two palmityls-sn-glyceryl-3-phosphatidylcholine (DPPC) at least two kinds; In the described filmogen, the ratio that the phospholipid molecule occupies is 0.1～5 weight %, and the ratio of non-ionic surface active agent is 0.01～0.05 weight %, and the ratio of hyperosmotic glucose or alcohols is 1～30 weight %, the ratio of Macrogol 4000 is 5～30 weight %, and all the other are aqueous solution; Add biological activity gas 0.15～0.5ml in every milliliter of filmogen.
2. lipide supersonic contrast medium according to claim 1 is characterized in that: ionic surfactant pack is drawn together Tween 80 and sorbester p17.
3. lipide supersonic contrast medium according to claim 1 is characterized in that: hyperosmotic glucose is glucose, fructose and isomer thereof, and alcohols is propylene glycol, glycerol.
4. lipide supersonic contrast medium according to claim 1 is characterized in that: aqueous solution is deionized water, distilled water or normal saline.
5. the preparation method of a lipide supersonic contrast medium as claimed in claim 1 is characterized in that: may further comprise the steps:
Step (a)
(1) with phospholipid molecule, Macrogol 4000 and aqueous solution in the contrast agent filmogen, make it become a suspended state system, serviceability temperature is 45～55 ℃, the time is 20～40 minutes;
Or (2) mix the phospholipid molecule in the contrast agent filmogen, Macrogol 4000 with nonaqueous solvent, makes it become a uniform solution system, and serviceability temperature is 45～55 ℃, and the time is 20～40 minutes;
Step (b)
With the lipid suspension thing behind the sterilization or lipid solute with the processing of desolvating of 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; Wherein said aqua liquid is made into by hyperosmotic glucose and non-ionic surface active agent, wherein has hyperosmotic glucose 0.95～0.99ml in every milliliter of aqua liquid, has non-ionic surface active agent 0.01～0.05ml; Or be made into by alcohols and non-ionic surface active agent, wherein contain propylene glycol 0.1ml in every milliliter of aqua liquid, glycerol 0.1ml, non-ionic surface active agent 0.01～0.05ml, normal saline surplus;
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 wrap up identical biological activity gas, capping.
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Cited By (1)
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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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| CN101721718B (en) * | 2008-10-28 | 2013-05-22 | 浙江海正药业股份有限公司 | Lipid microbubble and preparation method thereof |
| CN101745126B (en) * | 2008-12-10 | 2012-04-25 | 温州医学院 | Method for preparing water soluble medicament-entrapping ultrasound contrast agent |
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| WO2019051752A1 (en) * | 2017-09-14 | 2019-03-21 | 吴金凤 | Method for preparing lipidosome nano-bubble ultrasound contrast agent |
| CN109513016A (en) * | 2018-12-12 | 2019-03-26 | 四川大学华西医院 | Microbubble preparation method, gas supply system and preparation equipment thereof |
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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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