CN113521318A - Simethicone microbubble ultrasonic contrast agent and preparation method and application thereof - Google Patents
Simethicone microbubble ultrasonic contrast agent and preparation method and application thereof Download PDFInfo
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- CN113521318A CN113521318A CN202110862140.XA CN202110862140A CN113521318A CN 113521318 A CN113521318 A CN 113521318A CN 202110862140 A CN202110862140 A CN 202110862140A CN 113521318 A CN113521318 A CN 113521318A
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Classifications
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- 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
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- 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
Abstract
The invention relates to the technical field of ultrasonic contrast agents, and particularly discloses a simethicone microbubble ultrasonic contrast agent as well as a preparation method and application thereof. The contrast agent comprises a shell and inert gas and buffer liquid which are wrapped in the shell, wherein: the material of the shell comprises simethicone. The method comprises the following steps: (1) providing a sterile suspension comprising sodium chloride, a buffer, simethicone. (2) Mixing the obtained sterilized suspension with inert gas, and processing by acoustic right heart contrast to obtain suspension A. (3) And mixing the suspension A with inert gas again, and then carrying out ultrasonic crushing treatment to obtain a suspension B. (4) And standing the suspension B, and taking the middle-layer microbubble liquid after layering to obtain the suspension B. The microbubble ultrasound contrast agent using simethicone as a film-forming material has good in-vivo enhanced imaging capability on ultrasound for clinical diagnosis, good biocompatibility and simple and convenient preparation process.
Description
Technical Field
The invention relates to the technical field of ultrasonic contrast agents, in particular to a simethicone microbubble ultrasonic contrast agent as well as a preparation method and application thereof.
Background
The information disclosed in this background of the invention is only for enhancement of understanding of the general background of the invention and is not necessarily to be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person skilled in the art.
The ultrasonic contrast agent is a diagnostic reagent capable of obviously enhancing ultrasonic scattering signals, and has a good application prospect in the aspect of medical image diagnosis. The ideal ultrasonic contrast agent can be used as a blood cell tracer agent which is distributed to all parts of the whole body along with blood flow to reflect the blood flow perfusion condition of organs, and does not interfere with the blood flow dynamics. The blood cell tracing technology has wide application prospect in ultrasonic diagnosis of organs such as cardiac muscle, liver, kidney, superficial lymph node and the like.
An ideal ultrasound contrast agent should have the following characteristics: no toxic side effect; the medicine can be injected through peripheral vein, and bubbles capable of enhancing echo signals can be generated after the medicine contains or enters a human body, and the influence on a circulatory system is avoided; the size is proper, the dispersibility is good, and the acoustic echo characteristic is strong and the acoustic echo can pass through pulmonary circulation and capillary circulation; has a suitable half-life in vivo and remains sufficiently stable during diagnosis; the hemodynamics of the whole body or a certain system is not influenced, and the whole body blood flow state is not influenced.
The ultrasound contrast agent is not only the leading edge of the current research, but also has great social and economic benefits. The ultrasonic contrast agent with simple research and development process, convenient preparation, safety, no toxicity, good imaging effect, high specificity, low dosage and low cost becomes an important direction for the development of future ultrasonic medicine. Surfactants generally have the ability to reduce the surface tension of solutions, and therefore, most of them have good foaming properties and are widely used in the research of microbubble preparation. During bubble formation, the hydrophobic end of the surfactant faces the gas and the hydrophilic end faces the liquid. In addition, the surfactant film layer typically also has the ability to self-heal after being damaged. The ultrasonic contrast agent used clinically at present mainly depends on import, is expensive and high in cost, and has become an urgent task for the research of Chinese medicine and other related technical fields.
Disclosure of Invention
Aiming at the problems, the invention provides a simethicone microbubble ultrasonic contrast agent as well as a preparation method and application thereof, and the microbubble ultrasonic contrast agent taking simethicone as a film forming material has good in-vivo enhanced imaging capability on the ultrasonic wave for clinical diagnosis, good biocompatibility and simple and convenient preparation process. In order to achieve the purpose, the invention discloses the following technical scheme:
in a first aspect of the present invention, a simethicone microbubble ultrasound contrast agent is disclosed, which comprises an outer shell, and an inert gas and a buffer liquid which are wrapped in the outer shell, wherein: the material of the shell comprises simethicone.
Further, the buffer is phosphate buffered saline (PBS buffer).
Furthermore, the ultrasonic contrast agent is located in a solution to form a suspension, the solution is a PBS buffer solution, and freeze-dried powder is more stable and convenient to store and transport.
Further, the material of the shell also comprises a surfactant, such as span60 and the like.
Further, the inert gas includes octafluoropropane (C)3F8) Sulfur hexafluoride (SF)6) And perfluorobutane, etc.
In a second aspect of the invention, a preparation method of simethicone microbubble ultrasound contrast agent is disclosed, which comprises the following steps:
(1) providing a sterile suspension comprising sodium chloride, a buffer, simethicone.
(2) Mixing the obtained sterilized suspension with inert gas, and processing by acoustic right heart contrast to obtain suspension A.
(3) And mixing the suspension A with inert gas again, and then carrying out ultrasonic crushing treatment to obtain a suspension B.
(4) And standing the suspension B, and taking the middle-layer microbubble liquid after layering to obtain the suspension B.
Further, in the step (1), the ratio of the sodium chloride to the buffer to the simethicone is as follows: 1.0-1.5 g: 50 ml: 1-5 mL.
Further, in the step (1), a surfactant, such as Span60 (Span 60) and the like, is also included. The ratio of the surfactant to simethicone is 1.0-1.5 g: 1-5 mL.
Further, in step (2), the method for acoustic imaging of the right heart includes the steps of: connecting the nipples of the two syringes, adding the sterilized suspension and inert gas, and rapidly pushing the syringes back and forth to wrap the inert gas in the shell containing simethicone to form the contrast agent microbubbles.
Further, in the step (2), the volume ratio of the sterilization suspension to the inert gas is 4-6 ml: 1 ml. The sterilized suspension and inert gas can form a microbubble ultrasound contrast agent with larger size by a method of acoustic right heart contrast.
Further, in the step (3), the ultrasonic crushing treatment time is 2-3.5 min, and the power is 80-110W. After ultrasonic crushing, the microbubbles with larger sizes can be crushed to form finer microbubble ultrasonic contrast agents, and the more the number of the microbubbles in a unit volume is, the better the contrast effect is.
Further, in the step (3), the volume ratio of the suspension A to the inert gas is 2-5 ml: 1 ml. In the step, the upper layer liquid, the middle layer liquid and the lower layer liquid are obtained after standing and layering, wherein the upper layer liquid is foamy, unstable and easy to break, the lower layer liquid hardly contains a microbubble ultrasonic contrast agent, and the stable microbubble ultrasonic contrast agent is mainly concentrated in the middle layer liquid.
Further, in the step (4), the finally obtained simethicone microbubble ultrasonic contrast agent is mixed with a buffer solution and inert gas and then stored in an environment at the temperature of 2-6 ℃. Optionally, the buffer is PBS buffer.
Further, in the steps (2), (3) and (4), the inert gas comprises octafluoropropane (C)3F8) Sulfur hexafluoride (SF)6) And perfluorobutane, etc.
In a third aspect of the invention, the application of the simethicone microbubble ultrasound contrast agent in the medical field is disclosed.
Compared with the prior art, the invention has the following beneficial effects:
(1) simethicone, polydimethylsiloxane, changes the surface tension of air bubbles present in chyme and mucus in the digestive tract and decomposes them, and thus is currently used mainly as an antifoaming agent in a gastroenteroscopy. In the present invention, simethicone is used as the film forming agent, because simethicone contains a stable surfactant as an active ingredient, namely: polydimethylsiloxane. Polydimethylsiloxane is capable of effectively reducing surface tension, and the principle of the polydimethylsiloxane is as follows: on one hand, the state of unbalanced stress of surface molecules is improved, on the other hand, the attractive force between the surface molecules is reduced, and the 'tension' state of the surface is reduced. Considering that the surface molecular unbalanced stress is the basic factor for forming the surface tension, improving the state of the surface molecular unbalanced stress is the leading principle of the surfactant for reducing the surface tension. Thus simethicone can reduce the surface tension of the bubbles, so that the volume of the bubbles is reduced, and large bubbles are changed into small bubbles.
(2) The simethicone microbubble ultrasonic contrast agent is prepared by adopting a right heart acoustic contrast method and an ultrasonic fragmentation combined method, wherein the right heart acoustic contrast method is firstly adopted to enable the sterilization suspension and the inert gas to form a microbubble ultrasonic contrast agent with larger size, and then ultrasonic fragmentation is adopted to enable the microbubble ultrasonic contrast agent with larger size to form a finer microbubble ultrasonic contrast agent, so that the introduced inert gas is prepared into microbubbles to a greater extent, the problem of lower utilization rate of the inert gas in the existing preparation method is solved, and the two methods can be combined to prepare the introduced inert gas into the needed microbubbles to a greater extent.
(3) The test shows that: the microbubble ultrasound contrast agent prepared by the invention avoids microbubble loss caused by repeated washing, has good in-vivo enhanced imaging capability on ultrasound for clinical diagnosis, has good material biocompatibility, simple and convenient preparation process, does not use toxic surfactant, and has wide application prospect.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention. Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a diagram showing the effect of a syringe on the suspension prepared in the first example of the present invention.
Fig. 2 is a diagram showing the effect of simethicone microbubble ultrasound contrast agent prepared in the first embodiment of the present invention under an optical microscope.
Fig. 3 is a liver perfusion development image of a normal rabbit after being administered with simethicone microbubble ultrasound contrast agent prepared in the first embodiment of the invention. Wherein: in figure a, the arrows indicate the parenchyma of rabbit liver; b, arrows in the figure indicate gall bladder of rabbit; arrows in the figure indicate rabbit gallbladder and rabbit abdominal aorta.
Fig. 4 is a renal perfusion development image of a simethicone microbubble ultrasound contrast agent prepared in the first embodiment of the invention after being administered to a normal rabbit. Wherein: a arrow in the figure indicates rabbit kidney; arrow in panel b represents rabbit kidney; arrows in the figure c indicate rabbit abdominal aorta.
Fig. 5 is a diagram illustrating the effect of simethicone microbubble ultrasound contrast agent prepared in the fourth embodiment of the present invention under an optical microscope.
Detailed Description
In the following description, further specific details of the invention are set forth in order to provide a thorough understanding of the invention. The terminology used in the description of the invention herein is for the purpose of describing particular advantages and features of the invention only and is not intended to be limiting of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise indicated, the drugs or agents used in the present invention are used according to the instructions of the product or by the conventional methods in the art.
As mentioned above, the currently clinically used ultrasound contrast agents mainly depend on import, are expensive, have high cost, and have become an urgent task for research in medical science and other related technical fields in China. Therefore, the invention provides a simethicone microbubble ultrasound contrast agent, a preparation method and an application thereof, and the technical scheme of the invention is further explained according to the drawings and the specific implementation mode of the specification.
First embodiment
A preparation method of simethicone microbubble ultrasound contrast agent comprises the following steps:
(1) span 601.48g and NaCl solid powder 1.50g are weighed on an electronic balance ME 204, then placed into a beaker with the volume of 100ml, 5ml of simethicone is extracted by a liquid transfer gun, 50ml of PBS buffer solution is weighed by a measuring cylinder, added into the beaker and stirred magnetically to obtain a premixed liquid.
(2) And (3) placing the premixed solution into a pressure cooker, storing for 30min at the high temperature and the high pressure of 121 ℃, taking out, placing the premixed solution on a magnetic stirrer again, and stirring the solution to room temperature to obtain a sterilized suspension.
(3) A three-way tube 1, 2 10ml syringes were prepared, one syringe withdrawing the sterile suspension and the other syringe withdrawing C3F8Gas, and sterilizing the suspension and C3F8The volume ratio of the gas is 5:1, then the three-way pipe is used for communicating the two injectors, and the other end of the three-way pipe is sealed by a sealing plug (refer to figure 1). Upon completion, the syringe was rapidly pushed back about 20 times (1 round trip recorded as 1 time) to give suspension A.
(4) Placing the suspension A in a SCIENTZ-IID ultrasonic disruptor, and introducing C into the suspension A3F8Gas, suspensions A and C3F8The volume ratio of the gas is 2:1, and ultrasonic treatment is continuously carried out for 3min at the power of 100w at the same time, so as to obtain a suspension B.
(5) And collecting the suspension B in a separating funnel, standing for 35min, and allowing the solution subjected to standing to have an upper layer, a middle layer and a lower layer, wherein the upper layer is foamy and unstable and is easy to break, the lower layer contains almost no microbubble ultrasonic contrast agent, and the stable microbubble ultrasonic contrast agent is mainly concentrated in the middle layer. Thus, the intermediate layer microbubble solution was collected.
(6) Placing the collected middle layer microbubble liquid in a penicillin bottle, mixing with PBS buffer solution in equal volume, and filling C3F8And (5) sealing the gas, and storing the gas in a refrigerator at 4 ℃ to obtain the simethicone microbubble ultrasonic contrast agent.
Second embodiment
A preparation method of simethicone microbubble ultrasound contrast agent comprises the following steps:
(1) span 601.5g and NaCl solid powder 1.0g are weighed on an electronic balance ME 204, then the weighed materials are placed into a beaker with the volume of 100ml, 3ml of simethicone is extracted by a liquid-transferring gun, 50ml of PBS buffer solution is weighed by a measuring cylinder, the weighed materials are added into the beaker, and then magnetic stirring is carried out to obtain the premixed liquid.
(2) And (3) placing the premixed solution into a pressure cooker, storing for 30min at the high temperature and the high pressure of 121 ℃, taking out, placing the premixed solution on a magnetic stirrer again, and stirring the solution to room temperature to obtain a sterilized suspension.
(3) A three-way pipe 1 and 2 10ml syringes were prepared, wherein one syringe was used to draw the sterile suspension, the other syringe was used to draw perfluorobutane gas, and the volume ratio of the sterile suspension to the perfluorobutane gas was 6:1, and then the two syringes were connected by the three-way pipe, and the other port of the three-way pipe was sealed with a sealing plug (refer to fig. 1). Upon completion, the syringe was rapidly pushed back about 20 times (1 round trip recorded as 1 time) to give suspension A.
(4) And (3) placing the suspension A in a SCIENTZ-IID ultrasonic crusher, introducing perfluorobutane gas into the suspension A, wherein the volume ratio of the suspension A to the perfluorobutane gas is 3:1, and continuously carrying out ultrasonic treatment for 3.5min at 80w to obtain a suspension B.
(5) And collecting the suspension B in a separating funnel, standing for 35min, and allowing the solution subjected to standing to have an upper layer, a middle layer and a lower layer, wherein the upper layer is foamy and unstable and is easy to break, the lower layer contains almost no microbubble ultrasonic contrast agent, and the stable microbubble ultrasonic contrast agent is mainly concentrated in the middle layer. Thus, the intermediate layer microbubble solution was collected.
(6) And (3) placing the collected middle-layer microbubble liquid into a penicillin bottle, mixing the microbubble liquid with the PBS buffer solution in the same volume, filling perfluorobutane gas, sealing, and storing in a refrigerator at the temperature of 2 ℃ to obtain the simethicone microbubble ultrasonic contrast agent.
Third embodiment
A preparation method of simethicone microbubble ultrasound contrast agent comprises the following steps:
(1) span 601.0 g and NaCl solid powder 1.2g are weighed on an electronic balance ME 204, then the weighed materials are placed into a beaker with the volume of 100ml, 1ml of simethicone is extracted by a liquid transfer gun, 50ml of PBS buffer solution is weighed by a measuring cylinder, and the weighed materials are added into the beaker and then stirred magnetically to obtain the premixed liquid.
(2) And (3) placing the premixed solution into a pressure cooker, storing for 30min at the high temperature and the high pressure of 121 ℃, taking out, placing the premixed solution on a magnetic stirrer again, and stirring the solution to room temperature to obtain a sterilized suspension.
(3) A three-way tube 1, 2 10ml syringes were prepared, one syringe withdrawing the sterile suspension and the other syringe withdrawing SF6Gas, and sterilizing the suspension and SF6The volume ratio of the gas is 4:1, then the three-way pipe is used for communicating the two injectors, and the other end of the three-way pipe is sealed by a sealing plug (refer to figure 1). Upon completion, the syringe was rapidly pushed back about 20 times (1 round trip recorded as 1 time) to give suspension A.
(4) Placing the suspension A in a SCIENTZ-IID ultrasonic disruptor, and introducing SF into the suspension A6Gas the suspension A and SF6The volume ratio of the gas is 5:1, and ultrasonic treatment is continuously carried out for 2min at the power of 110w at the same time, so as to obtain a suspension B.
(5) And collecting the suspension B in a separating funnel, standing for 35min, and allowing the solution subjected to standing to have an upper layer, a middle layer and a lower layer, wherein the upper layer is foamy and unstable and is easy to break, the lower layer contains almost no microbubble ultrasonic contrast agent, and the stable microbubble ultrasonic contrast agent is mainly concentrated in the middle layer. Thus, the intermediate layer microbubble solution was collected.
(6) Will receivePutting the collected middle-layer microbubble liquid into a penicillin bottle, mixing with PBS buffer solution in equal volume, and filling SF6And (5) sealing the gas, and storing the gas in a refrigerator at 6 ℃ to obtain the simethicone microbubble ultrasonic contrast agent.
Fourth embodiment
Preparation method of surfactant-coated microbubble ultrasonic contrast agent
(1) Span 601.48g and NaCl solid powder 1.50g are weighed on an electronic balance ME 204, then the mixture is placed into a beaker with the volume of 100ml, 1ml of Tween 80 is extracted by a pipette gun, 50ml of PBS buffer solution is measured in a measuring cylinder, and the mixture is added into the beaker and then is magnetically stirred to obtain the premix.
(2) And (3) placing the premixed solution into a pressure cooker, storing for 30min at the high temperature and the high pressure of 121 ℃, taking out, placing the premixed solution on a magnetic stirrer again, and stirring the solution to room temperature to obtain a sterilized suspension.
(3) A three-way tube 1, 2 10ml syringes were prepared, one syringe withdrawing the sterile suspension and the other syringe withdrawing C3F8Gas, and sterilizing the suspension and C3F8The volume ratio of the gas is 5:1, then the three-way pipe is used for communicating the two injectors, and the other end of the three-way pipe is sealed by a sealing plug (refer to figure 1). Upon completion, the syringe was rapidly pushed back about 20 times (1 round trip recorded as 1 time) to give suspension A.
(4) Placing the suspension A in a SCIENTZ-IID ultrasonic disruptor, and introducing C into the suspension A3F8Gas, C3F8The volume ratio of the gas to the suspension A was 2:1, and ultrasonic treatment was continued at a power of 100w for 3min to obtain suspension B.
(5) And collecting the suspension B in a separating funnel, standing for 35min, and allowing the solution subjected to standing to have an upper layer, a middle layer and a lower layer, wherein the upper layer is foamy and unstable and is easy to break, the lower layer contains almost no microbubble ultrasonic contrast agent, and the stable microbubble ultrasonic contrast agent is mainly concentrated in the middle layer. Thus, the intermediate layer microbubble solution was collected.
(6) Intermediate layer to be collectedPlacing the microbubble liquid in a penicillin bottle, mixing with PBS buffer solution in equal volume, and filling with C3F8And (4) sealing the gas, and storing the gas in a refrigerator at 4 ℃ to obtain the surfactant-coated microbubble ultrasound contrast agent.
When the simethicone microbubble ultrasound contrast agent prepared in the first example is observed under an optical microscope, the microbubble is seen to be in a full sphere shape, and no ruptured microbubble is found, as shown in fig. 2. The microbubbles have better dispersibility and no obvious aggregation, which shows that the contrast agent microbubbles prepared by taking simethicone as a film-forming material have better stability under a mirror and can be further used for in vivo contrast experiments. In contrast, the contrast agent prepared according to the fourth embodiment shown in fig. 5, in which Tween 80 is used instead of simethicone, is observed to have a significantly larger microbubble particle size (same magnification) than the contrast agent of the first embodiment.
Further, the simethicone microbubble ultrasound contrast agent prepared in the first embodiment is injected into a healthy New Zealand white rabbit through the ear vein, and then 5ml of physiological saline is injected, and the imaging effect of the microbubbles in the rabbit is observed, so that the perfusion enhanced imaging of the liver and the kidney of the normal rabbit in the images shown in the figures 3 and 4 is obtained. It can be seen from the figure that after the contrast agent is injected, the hepatic artery, portal vein and hepatic vein of the rabbit in figure 3 are sequentially developed and enhanced, fine uniform punctate high echoes appear in the hepatic vessel cavity, the backward echoes are not obviously attenuated, the blood flow of the tiny hepatic vessels can be clearly shown, rich blood flow information can be obtained, and the hepatic parenchyma echoes are slowly enhanced. FIG. 4 shows that the kidney cortex and medulla of rabbit are well perfused and the tiny blood flow is clearly shown. Compared with the method before radiography, more abundant blood flow information can be obtained. In the whole radiography process, the vital signs of the rabbits are stable, no arrhythmia occurs, and no adverse reaction occurs after radiography. The contrast agent microbubble prepared by taking simethicone as a film forming material can achieve an ideal effect when used for ultrasonic enhanced imaging in an animal body, and is expected to be further researched and used for ultrasonic imaging of a clinical human body.
The above description is only illustrative of several embodiments of the present invention and should not be taken as limiting the scope of the invention. It should be noted that other persons skilled in the art can make modifications, substitutions, improvements and the like without departing from the spirit and scope of the present invention, and all of them belong to the protection scope of the present invention. Therefore, the scope of the invention should be determined from the description and claims.
Claims (10)
1. Simethicone microbubble ultrasound contrast agent, which comprises an outer shell, and inert gas and buffer liquid which are wrapped in the outer shell, wherein: the material of the shell comprises simethicone.
2. Simethicone microbubble ultrasound contrast agent according to claim 1, wherein the buffer is a phosphate buffer.
3. Simethicone microbubble ultrasound contrast agent according to claim 1, wherein the ultrasound contrast agent is in a suspension in a solution which is a phosphate buffer.
4. Simethicone microbubble ultrasound contrast agent according to claim 1, wherein the inert gas comprises at least one of octafluoropropane, sulfur hexafluoride and perfluorobutane.
5. Simethicone microbubble ultrasound contrast agent according to any one of claims 1 to 4, wherein the material of the shell further comprises a surfactant, preferably wherein the surfactant comprises span 60.
6. A preparation method of simethicone microbubble ultrasound contrast agent is characterized by comprising the following steps:
(1) providing a sterile suspension comprising sodium chloride, a buffer, simethicone;
(2) mixing the obtained sterilized suspension with inert gas, and processing by using a right heart acoustic contrast method to obtain suspension A;
(3) mixing the suspension A with inert gas again, and then carrying out ultrasonic crushing treatment to obtain a suspension B;
(4) and standing the suspension B, and taking the middle-layer microbubble liquid after layering to obtain the suspension B.
7. The method for preparing simethicone microbubble ultrasound contrast agent according to claim 6, wherein in the step (1), the ratio of the sodium chloride to the buffer to the simethicone is as follows: 1.0-1.5 g: 50 ml: 1-5 mL;
preferably, in step (1), a surfactant is further included, more preferably, the surfactant includes span 60;
preferably, the ratio of the surfactant to the simethicone is 1.0-1.5 g: 1-5 mL.
8. The method for preparing simethicone microbubble ultrasound contrast agent as claimed in claim 6, wherein in the step (2), the method for acoustic contrast of the right heart comprises the steps of: communicating the nipples of the two syringes, adding the sterilized suspension and inert gas, and rapidly pushing the syringes back and forth to wrap the inert gas in a shell containing simethicone to form contrast agent microbubbles;
or in the step (2), the volume ratio of the sterilization suspension to the inert gas is 4-6 ml: 1 ml;
or, in the step (3), the ultrasonic crushing treatment time is 2-3.5 min, and the power is 80-110W;
or in the step (3), the volume ratio of the suspension A to the inert gas is 2-5 ml: 1 ml.
9. The preparation method of simethicone microbubble ultrasonic contrast agent according to any one of claims 6 to 8, wherein in the step (4), the finally obtained simethicone microbubble ultrasonic contrast agent is mixed with a buffer solution and an inert gas and then stored in an environment at 2-6 ℃; preferably, the buffer is PBS buffer;
preferably, in the steps (2), (3) and (4), the inert gas comprises at least one of octafluoropropane, sulfur hexafluoride and perfluorobutane.
10. Use of simethicone microbubble ultrasound contrast agents as claimed in any one of claims 1 to 5 and/or prepared by the method claimed in any one of claims 6 to 9 in the medical field.
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| US6231834B1 (en) * | 1995-06-07 | 2001-05-15 | Imarx Pharmaceutical Corp. | Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same |
| US20010031243A1 (en) * | 1997-09-15 | 2001-10-18 | Imarx Pharmaceutical Corp. | Novel methods of ultrasound treatment using gas or gaseous precursor-filled compositions |
| CN103372382A (en) * | 2012-04-23 | 2013-10-30 | 华东理工大学 | Preparation method and device of treatment type microbubble ultrasound contrast agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US6231834B1 (en) * | 1995-06-07 | 2001-05-15 | Imarx Pharmaceutical Corp. | Methods for ultrasound imaging involving the use of a contrast agent and multiple images and processing of same |
| US20010031243A1 (en) * | 1997-09-15 | 2001-10-18 | Imarx Pharmaceutical Corp. | Novel methods of ultrasound treatment using gas or gaseous precursor-filled compositions |
| US6123923A (en) * | 1997-12-18 | 2000-09-26 | Imarx Pharmaceutical Corp. | Optoacoustic contrast agents and methods for their use |
| CN103372382A (en) * | 2012-04-23 | 2013-10-30 | 华东理工大学 | Preparation method and device of treatment type microbubble ultrasound contrast agent |
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