CN107233583A - A kind of acoustic contrast agent with the overlength duration and preparation method thereof - Google Patents
A kind of acoustic contrast agent with the overlength duration and preparation method thereof Download PDFInfo
- Publication number
- CN107233583A CN107233583A CN201610188537.4A CN201610188537A CN107233583A CN 107233583 A CN107233583 A CN 107233583A CN 201610188537 A CN201610188537 A CN 201610188537A CN 107233583 A CN107233583 A CN 107233583A
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- Prior art keywords
- gas
- microvesicle
- contrast agent
- preparation
- coated fertilizer
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 239000011668 ascorbic acid Substances 0.000 description 1
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- 229910001873 dinitrogen Inorganic materials 0.000 description 1
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- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- 238000005538 encapsulation Methods 0.000 description 1
- DNVPQKQSNYMLRS-SOWFXMKYSA-N ergosterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H](CC[C@]3([C@H]([C@H](C)/C=C/[C@@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 DNVPQKQSNYMLRS-SOWFXMKYSA-N 0.000 description 1
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
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- 238000005984 hydrogenation reaction Methods 0.000 description 1
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- 229940058690 lanosterol Drugs 0.000 description 1
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- 210000004072 lung Anatomy 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
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- 229960004624 perflexane Drugs 0.000 description 1
- KAVGMUDTWQVPDF-UHFFFAOYSA-N perflubutane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)F KAVGMUDTWQVPDF-UHFFFAOYSA-N 0.000 description 1
- ZJIJAJXFLBMLCK-UHFFFAOYSA-N perfluorohexane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZJIJAJXFLBMLCK-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 235000015500 sitosterol Nutrition 0.000 description 1
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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- 238000012800 visualization Methods 0.000 description 1
- 235000008979 vitamin B4 Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Acoustics & Sound (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to field of medicaments, a kind of acoustic contrast agent with the overlength duration and preparation method thereof is specifically disclosed.The advantage of the contrast agent is to reach more than 2h to the radiography duration of the internal organs such as liver, kidney and spleen, duration is most long can to reach more than 6h, be a ultrasonic contrast duration most long class contrast agent in the microbubble class acoustic contrast agent reported at present.The preparation technology of the other contrast agent is simply controllable, it is easy to carry out large-scale production, raw materials for production are all the injectable pharmaceutic adjuvants having been approved by present, with very wide potential applicability in clinical practice.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of acoustic contrast agent with the overlength duration and its
Preparation method.
Background technology
Acoustic contrast agent is typically gas of the diameter of lipid, polymer or protein encapsulation below 10 microns
Microvesicle, can be used for strengthening the echo signal of detection position in ultrasonic imaging.Acoustic contrast agent is micro- in human body
Thin vessels and tissue blood flow's perfusion detection have great advantage with imaging side mask.In addition, research table in recent years
Bright acoustic contrast agent shows wide in terms of the targeted imaging and medicine delivery of tumour or inflammation part
Application prospect, it can thus be anticipated that acoustic contrast agent in the near future will turn into clinically Ultrasonic Diagnosis or
Indispensable reagent in treatment.
Current acoustic contrast agent had many products enter on clinical practice, international market as Definity,
Optison, Sonazoid, Sonovue etc., can be used on domestic market now with Sonovue, Xue Ruixin.
Although acoustic contrast agent there are many application advantages in Ultrasonic Diagnosis, surpass at present in country's clinical diagnosis
Sound contrast agent is but seldom used by general public, and typically the hospital only more than front three just has more
Use.The reason for one critically important among these is exactly that the price of contrast agent is very expensive, such as every bottle Sonovue
Price in 700 RMB or so, Xue Ruixin price is more up to every bottle of RMB more than 900, common old
The common people are difficult to afford, and significantly limit the popularization of acoustic contrast agent.Existing ultrasound is made at present in addition
The imaging time of shadow agent is all shorter (Sonovue effective time is 4-8 minutes, and Xue Ruixin was less than 2 minutes),
It is difficult to the demand for meeting a complete ultrasonic examination.It is right especially with the development of the technologies such as Interventional Ultrasound
The demand of contrast agent with long duration is just more urgent.
In addition, with the development of ultrasound molecular image and PCI, the microvesicle of sub-micron is (i.e. containing certain
The ultrasonic microbubble of the nanometer bubble of ratio) start to show huge application potential.Nanometer bubble is under high frequency ultrasound
Stability more preferably, with the ability for preferably penetrating blood vessel, and the ultrasonic contrast enhancing effect of micron order microvesicle
More preferably, the microvesicle of sub-micron combines both Heterosis and goes out more preferable application value.For example research is found
Definity has more preferable ultrasound thrombolysis effect due to being steeped containing a certain proportion of nanometer, and under equal conditions
Albumin microvesicle is due to being micron order size then no this effect.
The content of the invention
Based on above demand and problem, the present invention provides a kind of acoustic contrast agent with the overlength duration
Preparation method, this method is simple to operate, and microvesicle coated fertilizer can disperse to obtain under very mild conditions
One stable solution, can carry out filtration sterilization, easily carry out industrialization production.Ultrasound of the present invention is made
Shadow agent is lyophilized formulations, in order to prepare lyophilized formulations, it is necessary to first prepare the suspension of ultrasonic microbubble coated fertilizer,
Composition in suspension is amphiphilic coated fertilizer, freeze drying protectant and solvent.
Technical solution of the present invention is as follows：
A kind of preparation method of the acoustic contrast agent with the overlength duration, comprises the following steps：
1) microvesicle coated fertilizer suspension is prepared, wherein the solvent of the suspension is the tert-butyl alcohol and water mixed liquid；
2) suspension is freeze-dried, microvesicle freeze-dried powder is made；
3) the microvesicle freeze-dried powder is filled with filling gas, the filling gas is mixed gas.
Coated fertilizer of the present invention is amphiphilic coated fertilizer, and its key component is the phosphatide with negative electrical charge,
The length of hydrophobic chain is advisable with 18 carbon, and suitable phosphatide includes distearyl acyl group-phosphatidyl glycerol, distearyl
One kind in acyl group-phosphatidylserine, distearyl acyl group-phosphatidic acid etc..Research is found, due to these phosphatide
Net charge is negative in physiological conditions, it is ensured that microvesicle carries stronger negative electrical charge, so that stability is big
It is big to improve.And longer hydrophobic chain ensure that and can form stable membrane structure to prevent microvesicle internal gas
Spilling.The structures such as phosphoric acid, glycerine, serine in the hydrophilic head of these other phosphatide can pass through
Hydrogen bond or electrostatic interaction form stable hydrophilic layer, greatly improve the stability of microvesicle.
In amphiphilic coated fertilizer of the present invention in addition to the above-mentioned phosphatide with negative electrical charge, also may be used
To mix some other amphiphilic filmogens, however, to ensure that the stability of microvesicle, above-mentioned
With negative electrical charge phosphatide (i.e. distearyl acyl group-phosphatidyl glycerol, distearyl acyl group-phosphatidylserine and
Distearyl acyl group-phosphatidic acid) part by weight should more than 70%, preferably more than 90%, more preferably
100%.Other amphiphilic materials include various natural, semi-synthetic phosphatide cpds, such as lecithin, ovum
Phosphatidyl glycerol, hydrogenated soya phosphatide, hydrogenation yolk phospholipid, hydrogenated phospholipid acyl serine, hydrogenated phospholipid acyl
Glycerine etc..Also phosphatidyl choline, phosphatidyl ethanol of the various synthetic phospholipids as carried various fatty acid chains are included
Amine, phosphatidyl glycerol, phosphatidic acid, phosphatidylserine etc..Also modified phosphatide, such as poly- second two are included
The phosphatide of alcoholization.Also the cation lipid of various synthesis, such as phosphatide of AEEA base, second are included
The derivative (such as 1,2- distearyls acid-sn- glyceryls -3- monoethyl cholines phosphoric acid) of base phosphatidyl choline, with alkane
Ammonium salt (such as stearoyl ammonium chloride, dodecyl bromination amine) of base chain etc..Also various surface-actives are included
Agent, such as spans, Tweens, the aliphatic acid of Pegylation, glycerin monostearate, sucrose list are stearic
Acid esters, rilanit special, tetrahexydecyl ascorbate fat etc..Also include steroidal compounds (such as cholesterol,
Lanosterol, sitosterol, stigmasterol, ergosterol) and its derivative, vitamin E and its derivative,
Aliphatic acid (such as stearic acid, palmitic acid, arachidic acid, laurate, myristic acid, oleic acid).
Research finds that amphiphilic coated fertilizer of the present invention is optimal using a kind of single phosphatide, that is, selects two
In stearyl-phosphatidyl glycerol, distearyl acyl group-phosphatidylserine and distearyl acyl group-phosphatidic acid
One kind is used as microvesicle coated fertilizer.On the one hand a kind of single phosphatide is avoided because a variety of phosphatide mixing inequality is led
The problem of microvesicle homogeneity and repeatability difference of cause.On the other hand, phosphorus is conducive to using a kind of single phosphatide
Fat forms homogeneous microvesicle capsule structure, and stability is greatly improved.
The present invention also needs to add freeze drying protectant during preparing microvesicle coated fertilizer suspension.
Present invention preferably employs freeze drying protectant be polyethylene glycol, mean molecule quantity should be in 1000-10000
Between be advisable, preferably mean molecule quantity be 4000 or so polyethylene glycol.The main function of polyethylene glycol
Being can be to supporting filmogen when suspension is freeze-dried, the stable dispersion kept it in solution
State and be unlikely to collapse aggregation so that freeze-dried powder can be easily dispersed in aquation and obtain stable homogeneous
Solution.In addition, polyethylene glycol can largely be adhered in water with the phosphatide on microvesicle film surface by hydrogen bond action,
The attachment of polymer can be greatly enhanced the stability of microvesicle, can also reduce what microvesicle was identified in vivo
Probability is so as to extend the circulation time of microvesicle.
In order to obtain the microvesicle coated fertilizer suspension of stable homogeneous, it is necessary to which a kind of solvent can be by microvesicle coating
Uniformly mixing is scattered for material (and freeze drying protectant).In addition, in order to obtain microvesicle freeze-dried powder, this solvent
Also need to suitable fusing point and saturated vapor pressure.
Water is the most frequently used solvent in freeze drying process, but amphiphilic material is easy to self assembly in water
Into the structure such as micella or liposome, a variety of amphiphilic materials are directly dispersed in water molecular level difficult to realize
On uniform mixing.
The most preferred nonaqueous solvents that can be used in freeze-drying at present is the tert-butyl alcohol, because it is with higher
Fusing point (25.7 DEG C) and saturated vapor pressure (26.8mmHg, 20 DEG C), with common freeze drying equipment
Freeze-drying is realized, it is greatly cost-effective.In addition, relatively low toxicity also causes the tert-butyl alcohol to be more suitable for
The freeze-drying of pharmaceutical preparation.Although the pure tert-butyl alcohol can dissolve most of amphiphilic materials and different molecular
The polyethylene glycol of amount, but most freeze drying protectant can not be dissolved.In addition, usual during microvesicle preparation
Need to add a certain proportion of phosphatide with negative electrical charge such as phosphatidylserine, phosphatidyl glycerol or phosphatidic acid
Deng, and solubility of this kind of phosphatide in the tert-butyl alcohol is poor.
In the present invention be used for prepare microvesicle coated fertilizer suspension solvent be the tert-butyl alcohol and water mixed liquor.It is excellent
The mass content of the tert-butyl alcohol is 1%~99% in selection of land, the tert-butyl alcohol and water mixed liquid, more preferably
30%~70%.
Filmogen employed in the present invention is mainly the phosphatide with negative electrical charge, and this kind of phosphatide is difficult in water
With scattered, the dissolubility in most of organic solvents such as chloroform, methanol, n-hexane, the tert-butyl alcohol, ethanol
It is all bad.And except phosphatide to be ensured can be fully dispersed, also to ensure that suspension can be general cold
Freeze in drying equipment and be lyophilized.We have found only have the mixed liquor of the tert-butyl alcohol and water to expire by many experiments
Sufficient demand, negatively charged phosphatide can easily be dissolved in this solvent, the solvent in suspension
Easily it can be removed by being freeze-dried, and the bio-toxicity of this solvent is very low, trace residue
Solvent toxicity can be ignored.
In addition, present invention research is found, it can be dissolved simultaneously absolutely mostly as solvent using the tert-butyl alcohol and water mixed liquid
The amphiphilic coated fertilizers of number and freeze drying protectant, and course of dissolution need not too high temperature, 40 DEG C or so
Even lower temperature can just dissolve, and be cooled to after room temperature and will not separate out after dissolving.The institute finally obtained
State suspension clarification, it is homogeneous, stably, and be readily available filtering carry out it is degerming.In addition, using tertiary fourth
When alcohol and water mixed liquor is that solvent is freeze-dried, the tert-butyl alcohol can form acicular crystal in water, significantly
Shorten the cycle of freeze-drying.
Microvesicle coated fertilizer suspension of the present invention generally also needs to be filtered after preparing, than more preferably
Be to be filtered with 220nm filter membrane.It can be easy to coating material as solvent using the tert-butyl alcohol and water
Material dissolving obtains the solution of clear, it is easy to filtered.On the one hand the purpose of filtering can remove can
The trace impurity that can exist, on the other hand can play the purpose to suspension filtration sterilization.
Microvesicle coated fertilizer suspension (is for example distributed into XiLin of pharmaceutical preparation after preparing in the present invention
Bottle), solvent (i.e. the tert-butyl alcohol and water mixed liquid) is removed by the method for freeze-drying and obtains microvesicle freeze-dried powder,
Freeze-dried powder can be stabilized, and can be preserved for a long time under normal temperature condition.The freeze-drying can be used
Method commonly used in the art.
The step of the inventive method also includes carrying out being filled with filling gas by the microvesicle freeze-dried powder prepared.For example
Freeze-drying terminates to be filled with filling gas in backward cillin bottle.Filling gas is the composition of ultrasonic microbubble kernel,
In order to improve the stability of ultrasonic microbubble, filling gas should have relatively low solubility in water, also right
Organism safety non-toxic.The filling gas of conventional acoustic contrast agent is fluorination carbons gas, but we
Research finds that finally prepd ultrasound is micro- when using fluorination carbons gas such as octafluoropropane as filling gas
The size of bubble is larger, and more bubble size is more than 10 microns, due to lung's most thin blood vessel in human body
Internal diameter is in 10 microns, and this microvesicle is difficult to be used in organism safely.On the other hand, it is molten in water
Gas higher Xie Du, as the gases such as air, nitrogen be used as filling gas prepared by microvesicle although size compared with
Small but stability extreme difference.
Filling gas used in the present invention is mixed gas, and it contains two class gases：Gas A and gas
B.The characteristics of gas A be molecular weight it is smaller (<100), it is possible to use gas include air, oxygen,
One or more of gaseous mixtures in nitrogen, carbon dioxide, helium, neon, argon gas.The characteristics of gas B
Be molecular weight it is larger (>100), and contain fluorine element, it is possible to use gas include octafluoropropane, ten fluorine
Butane, octafluorocyclobutane, perflenapent, perflexane, PFO etc. are fluorinated carbons gas and hexafluoro
Change one or more of gaseous mixtures in the sulfur fluoride class gases such as sulphur.
Gas A volume ratio is 1%~99% in filling gas (i.e. mixed gas) in the present invention, preferably
Ratio be 95%~99%.The use of mixed gas, on the one hand ensure that microvesicle has good stability,
On the other hand the size of microvesicle can be significantly reduced so that most of bubble size is all below 7 microns,
And there are many nanometers to steep.
Gas filling process can be carried out in the specific aerating device of freeze dryer external application in the present invention.Industrialization
Preferred method is that gas is filled, sealed process is carried out in freeze-drier during production.The present invention
After middle suspension is distributed into cillin bottle, after lyophilized, gas filling, sealing, aseptic process
Obtain final acoustic contrast agent (microvesicle freeze-dried powder) finished product.
In the above-mentioned preparation method of the present invention,
Step 1) include adding the coated fertilizer and freeze drying protectant in the tert-butyl alcohol and water mixed liquid, heating
Dissolving, is made microvesicle coated fertilizer suspension；Then filtration sterilization；
The part by weight of the coated fertilizer and freeze drying protectant is 1：200~1:5；Preferably 1:50~1:10.
The gross weight of the coated fertilizer and freeze drying protectant accounts for the solvent (i.e. the tert-butyl alcohol and water mixed liquid)
The 1%~50% of weight；Preferably 5%~20%；
The mass content of the tert-butyl alcohol is 1%~99%, preferably 30%~70% in the tert-butyl alcohol and water mixed liquid.
The heating for dissolving temperature is 25 DEG C~70 DEG C；Preferably 35 DEG C~50 DEG C.
The filtration sterilization is preferred to use 220nm filter membrane.
Specifically, the preparation method of the acoustic contrast agent of the present invention with the overlength duration, including with
Lower step：
1) coated fertilizer and freeze drying protectant are added in the tert-butyl alcohol and water mixed liquid, dissolved by heating, system
Obtain microvesicle coated fertilizer suspension；Then it is degerming using 220nm membrane filtration；
2) by step 1) freeze-drying of the microvesicle coated fertilizer suspension of filtration sterilization, obtain microvesicle freeze-dried powder；
3) by step 2) the microvesicle freeze-dried powder for preparing is filled with mixing filling gas；
In above-mentioned preparation method,
The coated fertilizer is that distearyl acyl group-phosphatidyl glycerol, distearyl acyl group-phosphatidylserine or two are hard
Fatty acyl group-phosphatidic acid；
The freeze drying protectant is the polyethylene glycol of mean molecule quantity 4000；
The part by weight of the coated fertilizer and freeze drying protectant is 1:50~1:10；
The gross weight of the coated fertilizer and freeze drying protectant accounts for the 5%~20% of the weight of solvent；
The heating for dissolving temperature is 35 DEG C~50 DEG C；
The mixed gas contains two class gases：Gas A and gas B；Wherein gas A molecular weight<100；
Gas B molecular weight>100, and contain fluorine element；
The gas A includes one in air, oxygen, nitrogen, carbon dioxide, helium, neon, argon gas
Plant or several gaseous mixtures；
The gas B includes one or more of gaseous mixtures in fluorination carbons gas, sulfur fluoride class gas；
Wherein, fluorination carbons gas includes octafluoropropane, ten fluorine butane, octafluorocyclobutane, perflenapent, perfluor
Hexane, PFO；Sulfur fluoride class gas includes sulfur hexafluoride.
Present invention additionally comprises acoustic contrast agent made from the above method.
Acoustic contrast agent (microvesicle freeze-dried powder) of the present invention needs into the acoustic contrast agent when in use
Hydrating fluid is injected, acoustic contrast agent suspension is made through concussion.
Specifically, acoustic contrast agent (microvesicle freeze-dried powder) of the present invention needs to packing container when in use
Injection hydrating fluid in (such as cillin bottle), the amount of hydrating fluid preferably accounts for packing container (such as cillin bottle) volume
10%~80%.The selection of hydrating fluid should be totally nontoxic, can be injected intravenously.Pure water and mostly
The parenteral solution that number is clinically used can be used as hydrating fluid, such as physiological saline, and phosphate buffer is sweet
Fat injection, glucose injection, amino acid injection etc..Can also be add a certain amount of glycerine and/
Or the physiological saline or phosphate buffer of propane diols, the addition of glycerine can improve the viscoplasticity of microvesicle and steady
Qualitative, propane diols can promote the scattered of amphiphilic coated fertilizer.
Preferably activated after acoustic contrast agent (microvesicle freeze-dried powder) aquation of the present invention by mechnical oscillator
Microvesicle can be used for the microvesicle suspension of ultrasonic imaging radiography to obtain.Mechnical oscillator and mesh adopted here
The structural principle of the Ag and Hg mixer of preceding clinically dental laboratories is basically identical.Preferably, concussion mode is past
Compound, concussion frequency is 2000~7000rpm, and shock range is 0.5~3cm, and the concussion time is 30~180s.
Preparation method of the present invention is simple, can disperse to obtain under very mild conditions between microvesicle each component
One stable solution, reaches the uniform mixing of molecular level, and each component is not susceptible to degraded in preparation process,
Sample freezes efficiency high, and sample stable homogeneous can carry out filtration sterilization, high, the easy scale of repeatability
Metaplasia is produced, and shows wide potential applicability in clinical practice.The present invention is solved in conventional method because phosphatide is in high temperature
Under the conditions of or the aqueous solution in it is long-term in the presence of easily occur degraded and produce hemolytic phosphatide, influence the stabilization of product
The technical problem of property and security.Preferred method uses a kind of single electronegative phosphatide conduct in the present invention
Filmogen, improves the homogeneity and repeatability of product.Product highly effective and safe, method repeatability are high.
(internal organs such as liver, kidney and spleen) the radiography duration reaches in contrast agent body in the present invention
More than 2-6 hours, be in the microbubble class acoustic contrast agent reported at present the ultrasonic contrast duration it is most long
A class contrast agent.Traditional cognition to gas microbubbles acoustic contrast agent stability difference is broken.It is this to make
Shadow agent is in addition to containing more microbubble, also containing many nano level bubbles.In addition, this
The composition of contrast agent is simple, cheap, and primary raw material is the injectable pharmaceutic adjuvant that FDA has been approved by,
Preparation technology is simple, repeatability is high, be easy to carry out large-scale production, it is contemplated that every bottle of life after industrialized production
It is only 2 RMB or so to produce cost.Good ultrasonic contrast effect, cheap price cause this ultrasound to make
Shadow agent has good application value, it is contemplated that will be helpful to the popularization and application of acoustic contrast agent, with very wide
Potential applicability in clinical practice.
Brief description of the drawings
Fig. 1 is microvesicle coated fertilizer suspension photo made from embodiment 1 and comparative example 1.
Fig. 2 is the microvesicle microphotograph of microvesicle suspension made from embodiment 1.
Fig. 3 is the microvesicle microphotograph for the microvesicle suspension that comparative example 2 is obtained.
Fig. 4 is the grain size distribution of the microvesicle of microvesicle suspension made from embodiment 1.
Fig. 5 is acoustic contrast agent made from embodiment 1 (microvesicle suspension) to the kidney of new zealand white rabbit
With liver parenchyma different time points contrasting effects figure.A, before microvesicle injection；B, 30 after microvesicle injection
Second；30 minutes after the injection of C microvesicles；D, 1 hour after microvesicle injection；E, 3 hours after microvesicle injection；F,
5 hours after microvesicle injection.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.Do not noted in embodiment
Bright particular technique or condition person, according to the technology or condition described by document in the art, or according to production
Product specification is carried out.Agents useful for same or the unreceipted production firm person of instrument, be can be by regular channel commercially available from
Available conventional products.
Embodiment 1
Accurate to weigh 128mg distearyl acyl groups-phosphatidyl glycerol, 1872mg PEG4000 add solvent (i.e.
The mixed liquor of 9g deionized waters and the 9g tert-butyl alcohols), it is heated to 45 DEG C of dissolvings and obtains the suspension of microvesicle coated fertilizer
Liquid, for the solution (see Fig. 1) of clarification, is then cooled to room temperature.By the filter of the solution 220nm after dissolving
2mL cillin bottle (actual volume is about 3.5mL) is distributed into after membrane filtration, every bottle is distributed into 250mg.
The cillin bottle dispensed is put on freeze dryer dividing plate, -40 DEG C, lyophilized overnight are quickly cooled to.Freezing
Dry after terminating, keep the vacuum state of freeze dryer, be filled into the nitrogen and eight that nitrogen volume ratio is 98%
Fluoro-propane mixed gas, after vacuum returns to normal pressure, the rubber stopper on pressure cillin bottle seals XiLin
Bottle, is made acoustic contrast agent.
Before acoustic contrast agent (freeze-dried powder preparation) use, 1mL physiological saline is injected into cillin bottle,
On the chuck for being put in medical argental mercury conditioner, frequency of oscillation is 4000rpm, and obtaining microvesicle after vibration 45s hangs
Supernatant liquid.
Embodiment 2
A kind of acoustic contrast agent, its preparation method is differed only in distearyl acyl group-phosphatide with embodiment 1
Acyl glycerin components are replaced by：128mg distearyl acyl groups-phosphatidylserine.
Embodiment 3
A kind of acoustic contrast agent, its preparation method is differed only in distearyl acyl group-phosphatide with embodiment 1
Acyl glycerin components are replaced by：128mg distearyl acyl groups-phosphatidic acid.
Embodiment 4
A kind of acoustic contrast agent, its preparation method and embodiment 1 differ only in solvent for 12.6g go from
The mixed liquor of sub- water and the 5.4g tert-butyl alcohol.
Embodiment 5
A kind of acoustic contrast agent, its preparation method differs only in solvent for 5.4g deionizations with embodiment 1
The mixed liquor of water and the 12.6g tert-butyl alcohols.
Embodiment 6
A kind of acoustic contrast agent, its preparation method and the mixed gas for differing only in filling of embodiment 1 are
Perfluoropropane and the mixed gas of nitrogen of the nitrogen volume content for 95%.
Embodiment 7
A kind of acoustic contrast agent, its preparation method and the mixed gas for differing only in filling of embodiment 1 are
Perfluoropropane and the mixed gas of air of the volume of air content for 98%.
Embodiment 8
A kind of acoustic contrast agent, its preparation method and the mixed gas for differing only in filling of embodiment 1 are
Perfluorinated butane and the mixed gas of air of the volume of air content for 98%.
Embodiment 9
A kind of acoustic contrast agent, its preparation method and the mixed gas for differing only in filling of embodiment 1 are
Perfluorinated butane and the mixed gas of nitrogen of the nitrogen volume content for 98%.
Embodiment 10
A kind of acoustic contrast agent, its preparation method and the mixed gas for differing only in filling of embodiment 1 are
Perfluoropropane and the mixed gas of oxygen of the oxygen volume content for 98%.
Comparative example 1
A kind of acoustic contrast agent, the differing only in of its preparation method and embodiment 1 prepares micro- using water as solvent
Steep coated fertilizer suspension.
Found in preparation process, only need to be in embodiment 1 when microvesicle coated fertilizer suspension is prepared
45 DEG C dissolve by heating the suspension that can be obtained by clear for 5 minutes or so, and at 45 DEG C in comparative example 1
Still many graininess insoluble matters, and the opaque (figure of suspension muddiness are can see after dissolving by heating 30 minutes
1).Suspension is filtered using traditional 220nm pvdf membrane syringe needle filters (diameter 25mm)
When, suspension does not run into obvious resistance after filtering 100mL in embodiment 1, and in comparative example 1
The resistance that filters clearly, has only filtered filter after 2mL and has just substantially completely been blocked nothing when suspension is filtered
Method proceeds.
Comparative example 2
The gas for differing only in filling of a kind of acoustic contrast agent, its preparation method and embodiment 2 is perfluor
Propane pure gas.
Comparative example 3
The gas for differing only in filling of a kind of acoustic contrast agent, its preparation method and embodiment 2 is air
Pure gas.
Comparative example 4
A kind of acoustic contrast agent, its preparation method and the gas for differing only in filling of embodiment 2 are single for nitrogen
Gas.
Experimental example 1
To obtain the image of microvesicle under an optical microscope；Concrete operation step is as follows：With isometric physiology
Salt solution dilutes obtained microvesicle suspension in embodiment 1 and comparative example 2~4 respectively, and 10 μ L are drawn with pipettor
Microvesicle suspension is dropped on clean slide, careful covered, using microscope in different object lens multiples
Size, form and the deployment conditions of lower observation microvesicle are simultaneously taken pictures.Fig. 2 is the microvesicle obtained in embodiment 1
Microphoto, it can be seen that the size of microvesicle can be clearly visible many nanometers mostly below 2 μm
Bubble.Fig. 3 is the microphoto of the microvesicle obtained in comparative example 2, it can be seen that many sizes are all located at 10 μm
More than, more large scale microvesicle easily blocks blood vessel when use in vivo, security is not guaranteed,
Internal Experimental Ultrasonic can not be used for.And the microvesicle in comparative example 3 and comparative example 4 can see in microscope
Microvesicle is all less than 2 μm mostly, small-sized, but this microvesicle is highly unstable, room temperature about 30
Just it is wholly absent after minute.
Experimental example 2
Using the Size Distribution and concentration that new microvesicle is tested using Kurt grain count instrument.Operating procedure is such as
Under：During the freshly prepd μ L of microvesicle suspension 20 of Example 1 are added in 20mL physiological saline, slightly shake
Shake well mixed.Analysis volume is set as 20 μ L, the particle diameter distribution and concentration of microvesicle is tested.Sample test weight
It is multiple three times, average.Fig. 4 is wherein once representational result, it can be seen that the Size Distribution of microvesicle
Narrow range, it is most of all below 2 μm, it is coincide with microphotograph.
Experimental example 3
Using new zealand white rabbit as experimental subjects, peripheral vein passage is set up through auricular vein in the left ear of rabbit,
The end connection three-way pipe of conduit, one of passage is used to inject acoustic contrast agent, and a passage trails life
Manage salt solution.New zealand white rabbit and is aided with 0.2% with the 3% sodium intravenous anesthesia (30mg/kg) of amobarbital
Liquaemin anticoagulation.After after rabbit holonarcosis, it is fixed on carrying on the back sleeping posture on rabbit bed.Right belly wool hair
Depilatory cream is carefully removed, and is not injected the ultrasonic examination of contrast agent, the basic shape of record to rabbit liver and kidney
Image under state.Respectively by the ultrasound in embodiment 1 and comparative example 3 and comparative example 4 after image is satisfied with
Contrast agent microbubble suspension, through rabbit auricular vein bolus, trails 2.0mL physiology at once by 20 μ L/kg dosage
Normal saline washing pipeline, realtime dynamic observation simultaneously records rabbit liver and kidney echo intensity enhancing situation and kidney
Power doppler blood flow signal strengthens situation.
Fig. 5 is microvesicle in embodiment 1 in rabbit liver and the visualisation of kidney, it can be seen that reduction of contrast signal
Have a significant contrast enhancing effects in liver and kidney, and can last very long, 5 hours after injection
Remain to see stronger signal.7 hours after injection, although the signal of kidney substantially completely disappears,
But remaining able to see significant enhancing signal in liver region.
And the contrast agent in comparative example 3 and comparative example 4 is substantially not visible radiography increasing after being injected into animal body
Strong signal.
Although above the present invention is described in detail with a general description of the specific embodiments,
But on the basis of the present invention, it can be made some modifications or improvements, this is to those skilled in the art
Obviously.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention,
Belong to the scope of protection of present invention.
Claims (10)
1. a kind of preparation method of the acoustic contrast agent with the overlength duration, it is characterised in that including with
Lower step：
1) microvesicle coated fertilizer suspension is prepared, wherein the solvent of the suspension is the tert-butyl alcohol and water mixed liquid；
The coated fertilizer be amphiphilic coated fertilizer, including part by weight account for more than 70% carry negative electrical charge
Phosphatide, the phosphatide with negative electrical charge be distearyl acyl group-phosphatidyl glycerol, distearyl acyl group-phosphatidyl
Serine or distearyl acyl group-phosphatidic acid；
2) suspension is freeze-dried, microvesicle freeze-dried powder is made；
3) the microvesicle freeze-dried powder is filled with filling gas, the filling gas is mixed gas；
The mixed gas contains two class gases：Gas A and gas B；Wherein gas A molecular weight<100；
Gas B molecular weight>100, and contain fluorine element.
2. preparation method according to claim 1, it is characterised in that the coated fertilizer includes weight
Ratio accounts for the 90%-100% phosphatide with negative electrical charge.
3. preparation method according to claim 1 or 2, it is characterised in that the tert-butyl alcohol and water are mixed
The mass content for closing the tert-butyl alcohol in liquid is 1%~99%, preferably 30%~70%.
4. preparation method according to claim 1 or 2, it is characterised in that gas in the mixed gas
Body A volume ratio is 1%~99%, preferably 95%~99%.
5. preparation method according to claim 4, it is characterised in that the gas A include air,
One or more of gaseous mixtures in oxygen, nitrogen, carbon dioxide, helium, neon, argon gas；
The gas B includes one or more of gaseous mixtures in fluorination carbons gas, sulfur fluoride class gas；
Wherein, fluorination carbons gas includes octafluoropropane, ten fluorine butane, octafluorocyclobutane, perflenapent, perfluor
Hexane, PFO；Sulfur fluoride class gas includes sulfur hexafluoride.
6. preparation method according to claim 1 or 2, it is characterised in that step 1) prepare microvesicle
Freeze drying protectant, the weight of the coated fertilizer and freeze drying protectant are additionally added during coated fertilizer suspension
Amount ratio is 1:200~1:5；Preferably 1:50~1:10.
7. preparation method according to claim 6, it is characterised in that the freeze drying protectant is average
Polyethylene glycol of the molecular weight in 1000-10000 polyethylene glycol, preferably mean molecule quantity 4000.
8. preparation method according to claim 1, it is characterised in that comprise the following steps：
1) coated fertilizer and freeze drying protectant are added in the tert-butyl alcohol and water mixed liquid, dissolved by heating, system
Obtain microvesicle coated fertilizer suspension；Then it is degerming using 220nm membrane filtration；
2) by step 1) freeze-drying of the microvesicle coated fertilizer suspension of filtration sterilization, obtain microvesicle freeze-dried powder；
3) by step 2) the microvesicle freeze-dried powder for preparing is filled with mixing filling gas；
In above-mentioned preparation method,
The coated fertilizer is that distearyl acyl group-phosphatidyl glycerol, distearyl acyl group-phosphatidylserine or two are hard
Fatty acyl group-phosphatidic acid；
The freeze drying protectant is the polyethylene glycol of mean molecule quantity 4000；
The part by weight of the coated fertilizer and freeze drying protectant is 1:50~1:10；
The gross weight of the coated fertilizer and freeze drying protectant accounts for the 5%~20% of the weight of solvent；
The heating for dissolving temperature is 35 DEG C~50 DEG C；
The gas A includes one in air, oxygen, nitrogen, carbon dioxide, helium, neon, argon gas
Plant or several gaseous mixtures；
The gas B includes one or more of gaseous mixtures in fluorination carbons gas, sulfur fluoride class gas；
Wherein, fluorination carbons gas includes octafluoropropane, ten fluorine butane, octafluorocyclobutane, perflenapent, perfluor
Hexane, PFO；Sulfur fluoride class gas includes sulfur hexafluoride.
9. acoustic contrast agent prepared by any one of claim 1-8 methods described.
10. the application method of acoustic contrast agent described in claim 9, it is characterised in that including surpassing to described
Hydrating fluid is injected in sound contrast agent, acoustic contrast agent suspension is made through concussion；The hydrating fluid include pure water,
The parenteral solution clinically used；
Preferably, concussion mode is reciprocating, and concussion frequency is 2000~7000rpm, and shock range is 0.5~3
Cm, the concussion time is 30~180s.
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