CN106943606A - A kind of acoustic contrast agent - Google Patents
A kind of acoustic contrast agent Download PDFInfo
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- CN106943606A CN106943606A CN201710155416.4A CN201710155416A CN106943606A CN 106943606 A CN106943606 A CN 106943606A CN 201710155416 A CN201710155416 A CN 201710155416A CN 106943606 A CN106943606 A CN 106943606A
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- 239000002872 contrast media Substances 0.000 title claims abstract description 82
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 52
- 239000000243 solution Substances 0.000 claims abstract description 44
- 150000001413 amino acids Chemical class 0.000 claims abstract description 30
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 23
- 239000012266 salt solution Substances 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 239000007789 gas Substances 0.000 claims description 45
- 239000000463 material Substances 0.000 claims description 23
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- 239000007788 liquid Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 7
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 7
- 239000004475 Arginine Substances 0.000 claims description 7
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 7
- 239000004472 Lysine Substances 0.000 claims description 7
- 229910018503 SF6 Inorganic materials 0.000 claims description 7
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000011261 inert gas Substances 0.000 claims description 7
- 235000010445 lecithin Nutrition 0.000 claims description 7
- 229940067606 lecithin Drugs 0.000 claims description 7
- 239000000787 lecithin Substances 0.000 claims description 7
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 229940083466 soybean lecithin Drugs 0.000 claims description 7
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 claims description 7
- 229960000909 sulfur hexafluoride Drugs 0.000 claims description 7
- 239000006228 supernatant Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 3
- 238000002604 ultrasonography Methods 0.000 claims description 2
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 claims 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims 1
- 210000004556 brain Anatomy 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 125000005456 glyceride group Chemical group 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 239000002245 particle Substances 0.000 abstract description 3
- 238000004458 analytical method Methods 0.000 abstract description 2
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- 241000283973 Oryctolagus cuniculus Species 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 6
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 6
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 208000019065 cervical carcinoma Diseases 0.000 description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 238000011161 development Methods 0.000 description 4
- 238000003745 diagnosis Methods 0.000 description 4
- 238000002607 contrast-enhanced ultrasound Methods 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000002601 radiography Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
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- 230000010412 perfusion Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000004088 pulmonary circulation Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- GOLXNESZZPUPJE-UHFFFAOYSA-N spiromesifen Chemical compound CC1=CC(C)=CC(C)=C1C(C(O1)=O)=C(OC(=O)CC(C)(C)C)C11CCCC1 GOLXNESZZPUPJE-UHFFFAOYSA-N 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
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- -1 wherein step (2) 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to belonging to medical domain, more particularly to a kind of acoustic contrast agent；The acoustic contrast agent is made up of solution, parcel gas, wherein the formula of described solution is：Carbopol, basic amino acid, phosphide class, ethanol, PLA, glycerin monostearate, concentration are 1.2~2.3% salt solution；Microvesicle has no toxic side effect, and vacuolar membrane Stability Analysis of Structures, preparation technology simplicity is controllable,, can be widely applicable as effective acoustic contrast agent with good acoustic response ability, 95% microvesicle particle size range is at 2~4 μm, and particle diameter distribution is homogeneous, with wide potential applicability in clinical practice.
Description
Technical field
The present invention relates to belonging to medical domain, more particularly to a kind of acoustic contrast agent.
Background technology
Cervical carcinoma is one of most common malignant tumour of global women.According to the statistics of the World Health Organization, it is sent out
Sick rate is only second to breast cancer, and in the trend of gradually rejuvenation.The new cases of annual cervical carcinoma have 46.6 ten thousand or so, wherein
80% case occurs in developing country.The annual new cases of China there are about 100,000, account for the 1/5 of world's new cases sum,
And the phenomenon that area increases and age of onset shifts to an earlier date is presented in recent years.Due to its significant damage to women's health and its caused by
Social concern, the correlative study for cervical carcinoma is always focus of concern.
In recent years, with the development of science and technology, medical image has become diagnosis and treats the important auxiliary of disease
Assistant's section.Wherein, contrast-enhanced ultrasound technique is monitored after being widely used in medical diagnosis, treatment and treatment with its unique advantage
Deng links.Its advantage includes：It is safe, noninvasive, cheap；Simple to operate, "dead" pollution, without ionization spoke
Penetrate；Image taking speed is fast, and change that can be in real time to histoorgan carries out dynamic image acquisition etc.；Contrast-enhanced ultrasound technique mainly leads to
Intravenous injection microvesicle state contrast agent is crossed, scanning object interface echo acoustic impedance difference shows tumor focus from surrounding tissue convexity
Come, in diagnosis of cervical cancer, can as cervical carcinoma screening conventional meanses, it has also become the focus of cervical disease diagnosis research it
One；The key of contrast-enhanced ultrasound technique is contrast agent, and the contrast agent used at present is mainly microbubble contrast agent, and microbubble contrast agent can
Clearly to show the Abnormal Perfusion region caused due to vascular problem or lesion tissue, so as to provide accurate, dynamic for clinic
Perfused tissue information, still, this microbubble contrast agent still suffers from many problems, such as：1. there is no affinity to pathological tissues, only
Pathological tissues can be carried out with non-specific development, it is impossible to judge lesion nature；2. it (is generally 2-6 μm that microbubble diameter is relatively large
Level), although pulmonary circulation can be passed freely through, but can not penetrate blood wall arrival target cell；3. the gas included in microvesicle is in itself
Feature with inborn reflex and backscattering, usually make it that the contrast of observed object and background is not strong；4. half-life short,
Effective Enhanced time only tens of seconds, to the lesion for needing the long period to check, it can only could be met by bolus administration of contrast agent repeatedly
It is required that, therefore, to reach the detection efficiency for improving early cervical carcinoma, this researcher is verified by substantial amounts of clinical test, is studied
One kind can keep concentration in cervical tissue, extend half-life period, the microbubble contrast agent of the detection cervical carcinoma of full apparent, be ultrasound
The faster and better development of shadowgraph technique provides a kind of new way.
The content of the invention
The present invention is in order to solve the above technical problems, there is provided a kind of acoustic contrast agent.
Realized particular by following technical scheme：
A kind of acoustic contrast agent, the acoustic contrast agent is made up of solution, parcel gas, wherein the formula of described solution
For：Carbopol, basic amino acid, phosphide class, ethanol, PLA, glycerin monostearate, concentration are 1.2~2.3% salt
Water.
Further, the mass ratio of described acoustic contrast agent, its solution and parcel gas is 1: 0.8~1.2.
Further, the phosphide class, refers to two kinds or two or more mixing of lecithin, soybean lecithin and cephalin
Thing.
Further, described solution, its formula ratio is following raw material composition by weight：Carbopol 20~30,
Basic amino acid 8~12, phosphide class 8~12, ethanol 20~30, PLA 12~18, glycerin monostearate 10~15, concentration
For 1.2~2.3% salt solution 35~45.
Further, the parcel gas refers to inert gas, sulfur hexafluoride, two kinds of perfluorinated butane or two or more mixed
Compound.
Further, the basic amino acid refers to lysine, arginine, histidine by 0.25~0.3: 0.65~0.7:
0.12~0.18 mass ratio mixing.
Further, described acoustic contrast agent, preparation method comprises the following steps：
(1) carbopol and basic amino acid are mixed, added water, be made into the solution that solid-liquid ratio is 1: 1.8~2.2, heating
Mix thoroughly, obtain material 1；
(2) ethanol and salt solution are mixed, mixed thoroughly, be heated to 45~50 DEG C, constant temperature adds the phosphide class of formula ratio, poly- breast
Acid, glycerin monostearate, 15~20min of magnetic stirrer, ultrasonically treated 8 under 100~120KHz frequency~
10min, obtains material 2；
(3) material 2 is added to 40~50 DEG C, magnetic stirrer adds material 1 with 2~3 drops/s speed, depressurized back
Ethanol is received, 4~6min is centrifuged under 4000~5000r/min frequency, supernatant is removed, parcel gas is passed through in sinking liquid
Body, you can.
Further, described acoustic contrast agent, its pH value is 5.5~7.
Further, described parcel gas, is that will wrap up gas first in 0.2~0.25MPa, 2000~3000r/min's
8~12min is handled under the closed environment of rotating speed, then is passed through solution formation acoustic contrast agent.
Further, phosphide class in described acoustic contrast agent, wherein step (2), PLA, glycerin monostearate plus
Entering order is：First add PLA, 20~30min of magnetic stirrer adds phosphide class, magnetic stirrer 8~
12min, is eventually adding glycerin monostearate.
In summary, the beneficial effects of the present invention are：Microvesicle has no toxic side effect, vacuolar membrane Stability Analysis of Structures, preparation technology letter
Just it is controllable, can be widely applicable as effective acoustic contrast agent with good acoustic response ability, 95% microvesicle grain
Footpath scope is at 2~4 μm, and particle diameter distribution is homogeneous, with wide potential applicability in clinical practice.
The present invention is neutralized using carbopol and basic amino acid, and gel is made, and further controls the pH value of gel, is carried
Stability, emulsibility and the film forming of gel are risen, film-forming carrier stably is provided for the parcel gas that is passed through, is the system of contrast agent
It is standby that basis is provided, the addition of phosphatide is further reduced, production cost is greatly reduced, passes through the poly- breast of degradable biomaterial
The addition of acid, by its good biological degradability, after film forming so that the contrast agent of preparation has good gas permeability, oxygen flow
Property, effectively reduce film thickness so that contrast agent has antibacterial function, it is ensured that the safe handling of contrast agent, meanwhile, make
It with rear, can also be decomposed by natural microorganisms, reduce the pollution to environment, by the addition of salt solution, change contrast agent
Osmotic concentration, improves the stability of the film forming of contrast agent, so as to extend the Enhanced time of radiography, strengthens radiography peak value, is super
Sound shadowgraph technique provides new approaches.
Embodiment
The embodiment to the present invention is described in further detail below, but the invention is not limited in these realities
Mode is applied, any improvement or replacement on the present embodiment essence spirit still falls within the claims in the present invention claimed
Scope.
Embodiment 1
A kind of acoustic contrast agent, the acoustic contrast agent is made up of solution, parcel gas, wherein the formula of described solution
For：Carbopol, basic amino acid, phosphide class, ethanol, PLA, glycerin monostearate, concentration are 1.2~2.3% salt
Water.
The mass ratio of described acoustic contrast agent, its solution and parcel gas is 1: 0.8.
The phosphide class, refers to two kinds or two or more mixtures of lecithin, soybean lecithin and cephalin.
Described solution, its formula ratio is following raw material composition by weight：Carbopol 20kg, basic amino acid
8kg, phosphide class 8kg, ethanol 20kg, PLA 12kg, glycerin monostearate 10kg, concentration are 1.2% salt solution 35kg.
The parcel gas refers to inert gas, sulfur hexafluoride, two kinds of perfluorinated butane or two or more mixtures.
The basic amino acid refers to that lysine, arginine, histidine are mixed by 0.25: 0.65: 0.12 mass ratio.
Described acoustic contrast agent, preparation method comprises the following steps：
(1) carbopol and basic amino acid are mixed, added water, be made into the solution that solid-liquid ratio is 1: 1.8, heating is mixed thoroughly,
1 must be expected；
(2) ethanol and salt solution are mixed, mixed thoroughly, be heated to 45 DEG C, constant temperature, the phosphide class of addition formula ratio, PLA, list
Tristerin, magnetic stirrer 15min, the ultrasonically treated 8min under 100KHz frequency, obtains material 2；
(3) material 2 is added to 40 DEG C, magnetic stirrer adds material 1 with 2~3 drops/s speed, second is recovered under reduced pressure
Alcohol, centrifuges 4min under 4000r/min frequency, removes supernatant, parcel gas is passed through in sinking liquid, you can.
Described acoustic contrast agent, its pH value is 5.5.
Described parcel gas, is first to handle parcel gas under 0.2MPa, the closed environment of 2000r/min rotating speed
8~12min, then it is passed through solution formation acoustic contrast agent.
Phosphide class, PLA, the addition sequence of glycerin monostearate in described acoustic contrast agent, wherein step (2)
For：PLA is first added, magnetic stirrer 20min adds phosphide class, and magnetic stirrer 8min is eventually adding
Glycerin monostearate.
Embodiment 2
A kind of acoustic contrast agent, the acoustic contrast agent is made up of solution, parcel gas, wherein the formula of described solution
For：Carbopol, basic amino acid, phosphide class, ethanol, PLA, glycerin monostearate, concentration are 2.3% salt solution.
The mass ratio of described acoustic contrast agent, its solution and parcel gas is 1: 1.2.
The phosphide class, refers to two kinds or two or more mixtures of lecithin, soybean lecithin and cephalin.
Described solution, its formula ratio is following raw material composition by weight：Carbopol 30kg, basic amino acid
12kg, phosphide class 12kg, ethanol 30kg, PLA 18kg, glycerin monostearate 15kg, concentration are 2.3% salt solution 45kg.
The parcel gas refers to inert gas, sulfur hexafluoride, two kinds of perfluorinated butane or two or more mixtures.
The basic amino acid refers to that lysine, arginine, histidine are mixed by 0.3: 0.7: 0.18 mass ratio.
Described acoustic contrast agent, preparation method comprises the following steps：
(1) carbopol and basic amino acid are mixed, added water, be made into the solution that solid-liquid ratio is 1: 2.2, heating is mixed thoroughly,
1 must be expected；
(2) ethanol and salt solution are mixed, mixed thoroughly, be heated to 50 DEG C, constant temperature, the phosphide class of addition formula ratio, PLA, list
Tristerin, magnetic stirrer 20min, the ultrasonically treated 10min under 120KHz frequency, obtains material 2；
(3) material 2 is added to 50 DEG C, magnetic stirrer adds material 1 with 2~3 drops/s speed, second is recovered under reduced pressure
Alcohol, centrifuges 6min under 5000r/min frequency, removes supernatant, parcel gas is passed through in sinking liquid, you can.
Described acoustic contrast agent, its pH value is 7.
Described parcel gas, is first to locate parcel gas under 0.25MPa, the closed environment of 3000r/min rotating speed
12min is managed, then is passed through solution formation acoustic contrast agent.
Phosphide class, PLA, the addition sequence of glycerin monostearate in described acoustic contrast agent, wherein step (2)
For：PLA is first added, magnetic stirrer 30min adds phosphide class, and magnetic stirrer 12min is eventually adding
Glycerin monostearate.
Embodiment 3
A kind of acoustic contrast agent, the acoustic contrast agent is made up of solution, parcel gas, wherein the formula of described solution
For：Carbopol, basic amino acid, phosphide class, ethanol, PLA, glycerin monostearate, concentration are 2% salt solution.
The mass ratio of described acoustic contrast agent, its solution and parcel gas is 1: 1.
The phosphide class, refers to two kinds or two or more mixtures of lecithin, soybean lecithin and cephalin.
Described solution, its formula ratio is following raw material composition by weight：Carbopol 25kg, basic amino acid
10kg, phosphide class 10kg, ethanol 25kg, PLA 15kg, glycerin monostearate 13kg, concentration are 2% salt solution 40kg.
The parcel gas refers to inert gas, sulfur hexafluoride, two kinds of perfluorinated butane or two or more mixtures.
The basic amino acid refers to that lysine, arginine, histidine are mixed by 0.28: 0.68: 0.15 mass ratio.
Described acoustic contrast agent, preparation method comprises the following steps：
(1) carbopol and basic amino acid are mixed, added water, be made into the solution that solid-liquid ratio is 1: 2, heating is mixed thoroughly, obtained
Material 1；
(2) ethanol and salt solution are mixed, mixed thoroughly, be heated to 48 DEG C, constant temperature, the phosphide class of addition formula ratio, PLA, list
Tristerin, magnetic stirrer 18min, the ultrasonically treated 9min under 110KHz frequency, obtains material 2；
(3) material 2 is added to 45 DEG C, magnetic stirrer adds material 1 with 2~3 drops/s speed, second is recovered under reduced pressure
Alcohol, centrifuges 5min under 4500r/min frequency, removes supernatant, parcel gas is passed through in sinking liquid, you can.
Described acoustic contrast agent, its pH value is 6.
Described parcel gas, is first to locate parcel gas under 0.23MPa, the closed environment of 2500r/min rotating speed
10min is managed, then is passed through solution formation acoustic contrast agent.
Phosphide class, PLA, the addition sequence of glycerin monostearate in described acoustic contrast agent, wherein step (2)
For：PLA is first added, magnetic stirrer 25min adds phosphide class, and magnetic stirrer 10min is eventually adding
Glycerin monostearate.
Embodiment 4
A kind of acoustic contrast agent, the acoustic contrast agent is made up of solution, parcel gas, wherein the formula of described solution
For：Carbopol, basic amino acid, phosphide class, ethanol, PLA, glycerin monostearate, concentration are 1.2% salt solution.
The mass ratio of described acoustic contrast agent, its solution and parcel gas is 1: 0.8.
The phosphide class, refers to two kinds or two or more mixtures of lecithin, soybean lecithin and cephalin.
Described solution, its formula ratio is following raw material composition by weight：Carbopol 20kg, basic amino acid
12kg, phosphide class 8kg, ethanol 30kg, PLA 12kg, glycerin monostearate 10kg, concentration are 1.2% salt solution 35kg.
The parcel gas refers to inert gas, sulfur hexafluoride, two kinds of perfluorinated butane or two or more mixtures.
The basic amino acid refers to that lysine, arginine, histidine are mixed by 0.25: 0.7: 0.12 mass ratio.
Described acoustic contrast agent, preparation method comprises the following steps：
(1) carbopol and basic amino acid are mixed, added water, be made into the solution that solid-liquid ratio is 1: 1.8, heating is mixed thoroughly,
1 must be expected；
(2) ethanol and salt solution are mixed, mixed thoroughly, be heated to 45 DEG C, constant temperature, the phosphide class of addition formula ratio, PLA, list
Tristerin, magnetic stirrer 20min, the ultrasonically treated 10min under 100KHz frequency, obtains material 2；
(3) material 2 is added to 40 DEG C, magnetic stirrer adds material 1 with 2~3 drops/s speed, second is recovered under reduced pressure
Alcohol, centrifuges 4min under 5000r/min frequency, removes supernatant, parcel gas is passed through in sinking liquid, you can.
Described acoustic contrast agent, its pH value is 5.5.
Described parcel gas, is first to locate parcel gas under 0.25MPa, the closed environment of 3000r/min rotating speed
8min is managed, then is passed through solution formation acoustic contrast agent.
Phosphide class, PLA, the addition sequence of glycerin monostearate in described acoustic contrast agent, wherein step (2)
For：PLA is first added, magnetic stirrer 20min adds phosphide class, and magnetic stirrer 12min is eventually adding
Glycerin monostearate.
Embodiment 5
A kind of acoustic contrast agent, the acoustic contrast agent is made up of solution, parcel gas, wherein the formula of described solution
For：Carbopol, basic amino acid, phosphide class, ethanol, PLA, glycerin monostearate, concentration are 2.3% salt solution.
The mass ratio of described acoustic contrast agent, its solution and parcel gas is 1: 1.2.
The phosphide class, refers to two kinds or two or more mixtures of lecithin, soybean lecithin and cephalin.
Described solution, its formula ratio is following raw material composition by weight：Carbopol 20kg, basic amino acid
8kg, phosphide class 8kg, ethanol 30kg, PLA 18kg, glycerin monostearate 15kg, concentration are 2.3% salt solution 45kg.
The parcel gas refers to inert gas, sulfur hexafluoride, two kinds of perfluorinated butane or two or more mixtures.
The basic amino acid refers to that lysine, arginine, histidine are mixed by 0.3: 0.65: 0.12 mass ratio.
Described acoustic contrast agent, preparation method comprises the following steps：
(1) carbopol and basic amino acid are mixed, added water, be made into the solution that solid-liquid ratio is 1: 1.8, heating is mixed thoroughly,
1 must be expected；
(2) ethanol and salt solution are mixed, mixed thoroughly, be heated to 50 DEG C, constant temperature, the phosphide class of addition formula ratio, PLA, list
Tristerin, magnetic stirrer 15min, the ultrasonically treated 10min under 120KHz frequency, obtains material 2；
(3) material 2 is added to 40 DEG C, magnetic stirrer adds material 1 with 2~3 drops/s speed, second is recovered under reduced pressure
Alcohol, centrifuges 6min under 5000r/min frequency, removes supernatant, parcel gas is passed through in sinking liquid, you can.
Described acoustic contrast agent, its pH value is 7.
Described parcel gas, is first to handle parcel gas under 0.2MPa, the closed environment of 3000r/min rotating speed
12min, then it is passed through solution formation acoustic contrast agent.
Phosphide class, PLA, the addition sequence of glycerin monostearate in described acoustic contrast agent, wherein step (2)
For：PLA is first added, magnetic stirrer 30min adds phosphide class, and magnetic stirrer 10min is eventually adding
Glycerin monostearate.
Experimental example
1st, toxicity test：
1.1st, subjects：Choose the rabbit 100 of health health, male and female half and half, 1~1.5kg of body weight, in ventilation
Breeding observing 3d under condition good situations, is randomly divided into 2 groups, one of which is blank control examination group, is administered after preceding 12h and administration
Forbid within 4 hours feed, but can't help water.
1.2nd, method：After 3d, the medicine of the invention that the rabbit injection dosage to experimental group is 1.5ml/kg, observation
7d。
1.3rd, result：Continuous Observation 7d, whole rabbits be good for the spirit of living and whole rabbits, appetite, secretion, breathing,
Do not observed in terms of eye it is abnormal, by experimental rabbit and control group rabbit after analysing, each histoorgan without obvious sense not
Together, core, liver, spleen, lung, kidney and intestines make pathological section also without significantly different, increase twice dosage, same method injection,
Whole rabbits are still good for and lived, and are compared without exception with control group, illustrate the contrast agent safety non-toxic.
2nd, effect compares
The acoustic contrast agent and commercially available acoustic contrast agent respectively prepared by embodiments of the invention 1~5 is diluted to identical
Concentration, adjust color ultrasonic devices, female nude mice through at uterine neck inject acoustic contrast agent (0.1ml/Kg), used immediately after injection
Normal saline flushing, development of the dynamic observation acoustic contrast agent to uterine neck echo strengthens situation, with+represent to strengthen intensity, represent
As a result it is as shown in table 1：
Table 1
Claims (10)
1. a kind of acoustic contrast agent, the acoustic contrast agent is made up of solution, parcel gas, wherein the formula of described solution is：
Carbopol, basic amino acid, phosphide class, ethanol, PLA, glycerin monostearate, concentration are 1.2~2.3% salt solution.
2. the acoustic contrast agent described in claim 1, it is characterised in that described acoustic contrast agent, its solution and parcel gas
Mass ratio be 1: 0.8~1.2.
3. the acoustic contrast agent described in claim 1, it is characterised in that the phosphide class, refers to lecithin, soybean lecithin and brain
Two kinds or two or more mixtures of phosphatide.
4. the acoustic contrast agent described in claim 1, it is characterised in that described solution, its formula ratio be it is following by weight
Raw material composition：Carbopol 20~30, basic amino acid 8~12, phosphide class 8~12, ethanol 20~30, PLA 12~
18th, glycerin monostearate 10~15, concentration are 1.2~2.3% salt solution 35~45.
5. the acoustic contrast agent described in claim 1, it is characterised in that the parcel gas refer to inert gas, sulfur hexafluoride,
Two kinds of perfluorinated butane or two or more mixtures.
6. the acoustic contrast agent described in claim 1, it is characterised in that the basic amino acid refers to lysine, arginine, group
Propylhomoserin is mixed by 0.25~0.3: 0.65~0.7: 0.12~0.18 mass ratio.
7. the acoustic contrast agent described in claim 1, it is characterised in that preparation method comprises the following steps：
(1) carbopol and basic amino acid are mixed, added water, be made into the solution that solid-liquid ratio is 1: 1.8~2.2, heating is mixed thoroughly,
1 must be expected；
(2) ethanol and salt solution are mixed, mixed thoroughly, be heated to 45~50 DEG C, constant temperature, the phosphide class of addition formula ratio, PLA, list
Tristerin, 15~20min of magnetic stirrer, ultrasonically treated 8~10min, is obtained under 100~120KHz frequency
Material 2；
(3) material 2 is added to 40~50 DEG C, magnetic stirrer adds material 1 with 2~3 drops/s speed, second is recovered under reduced pressure
Alcohol, centrifuges 4~6min under 4000~5000r/min frequency, removes supernatant, parcel gas is passed through in sinking liquid, i.e.,
Can.
8. the acoustic contrast agent described in claim 1, it is characterised in that the pH value of contrast agent is 5.5~7.
9. the acoustic contrast agent described in claim 1, it is characterised in that described parcel gas, is first 0.2 by parcel gas
8~12min is handled under the closed environment of~0.25MPa, 2000~3000r/min rotating speed, then is passed through solution and forms ultrasound and make
Shadow agent.
10. the acoustic contrast agent described in claim 7, it is characterised in that phosphide class, PLA, single tristearin wherein in step (2)
The addition sequence of acid glyceride is：PLA is first added, 20~30min of magnetic stirrer adds phosphide class, and magnetic force is stirred
Mix device and stir 8~12min, be eventually adding glycerin monostearate.
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| CN114808179A (en) * | 2022-03-30 | 2022-07-29 | 华南理工大学 | Relaxation time controllable composite material and preparation method and application thereof |
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| WO1991018612A1 (en) * | 1990-06-01 | 1991-12-12 | Unger Evan C | Contrast media for ultrasonic imaging |
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| WO1991018612A1 (en) * | 1990-06-01 | 1991-12-12 | Unger Evan C | Contrast media for ultrasonic imaging |
| CN1125393A (en) * | 1993-06-11 | 1996-06-26 | ImaRx药物公司 | Novel therapeutic delivery systems |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114808179A (en) * | 2022-03-30 | 2022-07-29 | 华南理工大学 | Relaxation time controllable composite material and preparation method and application thereof |
| CN114808179B (en) * | 2022-03-30 | 2023-06-16 | 华南理工大学 | Composite material with controllable relaxation time and preparation method and application thereof |
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