JP2002145805A - Ultrasonic wave scatterer, and method for selecting and detecting the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ultrasonic waver scatterer having the high certainty of sub-harmonic echo generation, especially a contrast medium for ultrasonic diagnoses. SOLUTION: This ultrasonic wave scatterer characterized in that the transmission of continuous low pressure ultrasonic waves having a sound pressure of 0.5 to 10 kPa reduces and reaches the minimum transmission (Pm) within 4 μsec just after the irradiation of continuous four or more high pressure ultrasonic waves having a sound pressure of 20 kPa to 2 MPa, and further that the ratio (Pm/Po) of the minimum transmission (Pm) to the transmission (Po) of the low pressure ultrasonic waves just before the irradiation of the high pressure ultrasonic waves is 0.01 to 0.6.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an ultrasonic scatterer, a contrast agent for ultrasonic diagnosis, a method for selecting an ultrasonic scatterer having a strong subharmonic echo, and a method for detecting an ultrasonic scatterer. Echo (subharmonic ech
o) Ultrasonic confusion with high certainty of generation and its application.

[0002]

2. Description of the Related Art In recent years, in diagnosing the chest and abdomen, an ultrasonic diagnostic method capable of obtaining blood flow information has been remarkably developed. In particular, ultrasonic imaging using a contrast agent has been developed, and more accurate blood flow information has been obtained. In these ultrasonic contrasts, a microbubble contrast agent obtained by mixing a large number of microbubbles having a diameter of 1 to several μm into a liquid is used. Microbubbles are harmless gases for living organisms,
It is sealed in a shell made of a substance harmless to living organisms.

In the ultrasonic imaging apparatus, the use of Doppler signals and harmonic signals has progressed, and it has become possible to acquire more tissue and blood flow information. In particular, the evaluation of the blood flow dynamics is more accurately performed in combination with the ultrasonic imaging. However, some Doppler signals include strong signals from highly moving tissues such as myocardium,
Some of the harmonic signals originate from the tissue itself. Therefore, it is not possible to detect only microbubbles in a blood vessel.

[0004] So-called sub-harmonic imaging, in which an image is formed based on sub-harmonic echoes generated only from microbubbles in a blood vessel by irradiating ultrasonic waves having a plurality of continuous waves, is being studied. . Further, as a method of strengthening the sub-harmonic with a diagnostic device, a method of devising a waveform of an ultrasonic wave to be transmitted as described in Japanese Patent Application Laid-Open No. 2000-5167 has been proposed.

On the other hand, many contrast agents for ultrasonic diagnosis are on the market or in clinical trials. For example, Echo
vist ^R , Levovist ^R (Shering AG), Imagent ^R (Allianc
^{s Pharmceutical Corp.), Optison TM} (Molecular Biosy
^{stems, Inc.), EchoGen TM} (SONUS Pharmaceutical, In
^{c.), Sonazoid TM (Nucomed} Amersham plc), Definity T M
(DuPont Pharmaceutical Co.), SonoVue TM (Bracco Di
agnostics Inc.), Quantison? (Quadrant Healthcare
plc) and the like. These contrast agents are microbubbles in which air or perfluorocarbon gas is wrapped with a surfactant or a polymer compound to stabilize bubbles having a particle size of several μm. These contrast agents have been developed mainly to maintain stability in blood during storage as a drug or after injection, and a technique for increasing the strength of subharmonics has not been used.

[0006] There are many papers on ultrasonic contrast agents.
(E.Leen, medicalmudi, 43 (3), 17p (1999); Nico de Jo
ng and Folkert J. Ten Cate, Ultrasonics, 34, 587p
(1996); PJAFrinking et al, J. Acoust. Soc, 105
(3), 1989p (1999), PJAFrinking and Nico de Jon
g, J. Acoust. Soc, 105 (3), 1989p (1999), PADayton
etal, IEE Trans. Ultrason., 46 (1), 220p (1999), A.
Bouakaz and KKShung, 1999IEEE Ultrasonics Symposi
um, 1963p) and patents (U.S. Pat.
6,080,386, 5,948,387, Tokuyohei 10-5
JP 05900, JP 2000-501745 JP, JP 2000-50204
No. 7, JP-T-2000-506122) are disclosed, but the method of enhancing the subharmonic is not known.

[0007] Although much research has begun on the generation mechanism of subharmonic echoes in which microbubbles are generated, there is no situation in which a sufficient theoretical explanation has been given. According to recent research, bubbles are chaotically vibrated by irradiated ultrasonic waves (Nippon Super Medical Fundamental Technology Workshop Vol.100 No.2 29p; PMShankar et a
l, J. Acoust. Soc. Am., 106 (4), 2104 (1999); Zhen Ye,
J. Acoust. Soc. Am., 100 (4), 2011 (1996); Nico de Jo
ng et al, 1st US Contrast abstracts, 29p (1999)). Analysis of microbubble vibration is progressing in a dilute solution system.However, in a high concentration region corresponding to the actual ultrasonic contrast agent concentration, the behavior as an aggregate of microbubbles (bubble cloud) also appears. It has also been found that it does not result in sweeping out (Nichiyo Medical Basic Technology Research Group material vol.100 No.2 1p). In other words, the subharmonic echo from the microbubbles is a source of chaos whose theoretical optimal region cannot be explained, and has a more complicated behavior as a bubble cloud. Cannot be defined.

As a method of detecting the sub-harmonic intensity, a method of performing a fast Fourier transform (FFT) of a received waveform is used. However, the FFT has a problem that the operation time is long and is not suitable for real-time image display. Further, it is difficult to detect only the sub-harmonics generated at a plurality of frequencies between the fundamental wave and the higher harmonics by a method of filtering only the circuit and acquiring only the target frequency.

[0009]

SUMMARY OF THE INVENTION In view of the above-mentioned problems of the prior art, the present invention provides an ultrasonic scatterer, particularly a contrast agent for ultrasonic diagnostics, having high reliability of generating subharmonic echo. Was an issue. Another object of the present invention is to provide a method for selecting an ultrasonic scatterer having a strong subharmonic echo. It is a further object of the present invention to provide a method for detecting an ultrasonic scatterer, in particular, an ultrasonic diagnostic method using an ultrasonic disturber.

[0010]

As a result of intensive studies, the present inventors have found that an ultrasonic scatterer having a property that the transmission amount of low-pressure ultrasonic waves falls within a specific range after irradiation of high-pressure ultrasonic waves is a subharmonic echo. Found that the probability of occurrence was high,
The present invention has been reached.

That is, the present invention provides a sound pressure of 20 kPa to 2 MPa and 4
Immediately after irradiating multiple high-pressure ultrasonic waves
minimum permeability of transmittance of the low pressure ultrasonic wave is reduced continuous sound pressure 0.5kPa~10kPa between μsec reached (P _m), ultra low permeation amount the high-pressure ultrasonic wave irradiation just prior to the the (P _m) an ultrasound scatterers ratio low pressure ultrasonic transmission amount _{(P 0) (P m /} P 0) is characterized in that 0.01 to 0.6. The ultrasonic confusion body of the present invention is particularly useful as a contrast agent for ultrasonic diagnosis.

Further, the present invention relates to a method for preparing an ultrasonic confusion body from 0.5 kPa to 10 kPa.
a step of determining the transmission amount (P ₀ ) when continuous low-pressure ultrasonic waves of kPa are applied; sound pressure of 20 kPa to 2 M
irradiating a plurality of continuous high-pressure ultrasonic waves at pa and 4 or more waves; continuously irradiating the ultrasonic confusion body with low-pressure ultrasonic waves having a sound pressure of 0.5 kPa to 10 kPa within 4 μsec from the end of irradiation of the high-pressure ultrasonic waves For obtaining the minimum transmission amount (P _m ) at the time; P _m / P
There is also provided a method for selecting an ultrasonic scatterer having a strong subharmonic echo, comprising a step of selecting an ultrasonic scatterer in which ₀ is 0.01 to 0.6.

Further, the present invention includes a step of irradiating a sample to which the above-mentioned ultrasonic scatterer is applied with an ultrasonic wave and detecting an echo (particularly a subharmonic echo) of the ultrasonic scatterer. Also provided is a method for detecting

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION In the following, an ultrasonic scatterer, a contrast agent for ultrasonic diagnosis, a method for selecting an ultrasonic scatterer having a strong subharmonic echo, and a method for detecting an ultrasonic scatterer according to the present invention will be described in detail. I do. In this specification, “to” indicates a range including numerical values described before and after the range as a minimum value and a maximum value, respectively.

First, the ultrasonic scatterer of the present invention will be described. Ultrasonic scatterer of the present invention is transmitted through the amount of the low pressure ultrasonic wave between 4μsec immediately after irradiation with high-pressure ultrasonic wave decreases reaches minimum transmission amount (P _m), ultra low permeation amount of (P _m) the low-pressure ultrasonic transmission amount of the high-pressure ultrasonic wave just before the ratio _{(P 0) (P m /} P 0) is 0.01 to 0.6, preferably characterized in that 0.01 to 0.4.

The details of the configuration of the ultrasonic scatterer of the present invention are not particularly limited as long as the above conditions are satisfied.
Preferred embodiments are as follows. The particle size of the ultrasonic scatterer of the present invention is 0.01 μm as a circle equivalent diameter average value.
It is preferably from m to 100 μm. In particular, when using the ultrasonic scatterer of the present invention as a contrast agent for ultrasonic diagnosis, 0.
It is preferably from 05 μm to 20 μm, more preferably from 0.05 μm to 10 μm.

The contrast medium for ultrasonic diagnosis is usually injected into a human body by intravenous injection, and the diagnosis is usually made at the timing of reaching the affected part. Here, if the ultrasonic scatterer as the contrast agent is too large, there is a risk of causing occlusion of peripheral blood vessels.If the ultrasonic scatterer is too small, the signal strength of the ultrasonic scatterer such as a blood cell and the like becomes closer to the in vivo ultrasonic scatterer. Analysis becomes difficult. Therefore, it is desirable to determine the optimum range of the particle size of the ultrasonic scatterer in consideration of conditions such as the age of the patient to be applied, the type of disease, blood pressure, blood viscosity, and the like.

The material of the ultrasonic scatterer of the present invention may be any material as long as it has a different acoustic impedance from the liquid into which the ultrasonic scatterer is injected, such as a dispersion medium or water or blood.
Gas, gas-containing particles, particles that evaporate at the temperature of the liquid into which the ultrasonic scatterer is injected, and particles that evaporate by ultrasonic irradiation are preferable. As the gas used in the present invention, for example, air; nitrogen; oxygen; carbon dioxide; hydrogen; nitrous oxide; an inert gas (for example, helium, argon, xenon or krypton); sulfur fluoride (for example, sulfur hexafluoride, Disulfur, trifluoromethylsulfur pentafluoride); selenium hexafluoride; optionally halogenated silanes (eg, tetramethylsilane); alkanes (eg, methane, ethane, propane, butane or pentane), cycloalkanes ( For example cyclobutane or cyclopentane), alkenes (for example propene or butene),
Or low molecular weight hydrocarbons such as alkyne (eg, acetylene) (preferably having 7 or less carbon atoms); ethers; ketones; esters; halogenated low molecular weight hydrocarbons (preferably having 7 or less carbon atoms); or a mixture of any of the above compounds Can be mentioned.

Preferably, at least some of the halogen atoms in the halogenated gas are fluorine atoms. Therefore, as biohalogenated halogenated hydrocarbon gas, for example, bromochlorodifluoromethane, chlorodifluoromethane,
Dichlorodifluoromethane, bromotrifluoromethane, chlorotrifluoromethane, chloropentafluoroethane, dichlorotetrafluoroethane and perfluorocarbon can be mentioned. Examples of the perfluorocarbon include perfluoroalkanes (eg, perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, perfluoropentane,
Perfluorohexane and perfluoroheptane, for example, perfluoroisobutane and perfluoro-n
Perfluoroalkenes (e.g. perfluoropropene, perfluorobutene (e.g. perfluorobut-2-ene) and perfluorobutadiene); perfluoroalkynes, including also mixtures of two or more isomers, such as mixtures with butane. (E.g. perfluorobut-2-yne);
And perfluorocycloalkane (for example, perfluorocyclobutane, perfluoromethylcyclobutane, perfluorodimethylcyclobutane, perfluorotrimethylcyclobutane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclopentane, perfluorocyclohexane, perfluoromethyl Cyclohexane and perfluorocycloheptane). Other halogenated gases include fluorinated (perfluorinated) ketones (eg, perfluoroacetone) and fluorinated (perfluorinated) ethers (eg, perfluorodiethyl ether)
Can be mentioned.

The preferred gas used in the ultrasonic disturber of the present invention is perfluoroalkane, and particularly preferred is perfluoropropane, perfluorobutane, perfluoropentane or perfluorohexane.

It is preferable that the gas used in the ultrasonic confusion body of the present invention is stabilized by a shell. The shell material may be a surfactant, a natural or synthetic polymer compound, an amphipathic substance, or the like, but a so-called biocompatible compound is preferable for use as a contrast agent for ultrasonic diagnostics, and blood is contacted. Those which do not coagulate are more preferred, and those which are biodegradable are particularly preferred. Examples of amphiphilic substances that can be used as shell materials include phospholipids.
(E.g. lecithin, dipalmitoyl phosphatidylcholine, sodium dipalmitoyl phosphatidylate,
Dipalmitoyl phosphatidylethanolamine polyethylene glycol ether, etc.), higher carboxylic acids (eg, lauric acid, sodium laurate, palmitic acid, potassium palmitate, stearic acid, arachidic acid, behenic acid, etc.), higher alcohols (eg, stearyl alcohol) , Palmitoyl alcohol and the like), higher amines (eg stearylamine and the like) and the like. As the polymer compound, natural polymer compounds (e.g., gelatin, collagen, albumin, chitosan, agar, silk fibroin, starch, cellulose, dextran, etc.), chemically modified natural polymers (e.g., acetylated gelatin,
Phthalated gelatin, enzyme-degraded low molecular gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc.), synthetic high molecular compounds (for example, polylactic acid, polylactic acid butyric acid copolymer, polyvinyl alcohol, polyethylene glycol, polyethylene glycol propylene glycol Polymers, urea resins, nylons, polyethylene glycol esters of polyacrylic acid, etc.), anionic surfactants (e.g., sodium dodecyl sulfonate, diisobutyl sulfosuccinate, sodium dodecyl benzene sulfonate, etc.), nonionic surfactants (e.g., low molecular weight polyethylene) Glycol, nonylphenol polyethylene glycol, low molecular weight polyethylene glycol propylene glycol copolymer, alkyl-modified sugar Etc.), cationic surfactants, and the like fluorine-based surfactant. These may be used alone or in combination. The shell material used in the present invention is preferably stabilized by cross-linking, modification and the like, and the method may be any means such as chemical reaction, heat, ultraviolet irradiation, and radiation irradiation.

The ultrasonic scatterer of the present invention is preferably used as a dispersion. The dispersion medium used for dispersion may be any as long as it does not denature the ultrasonic scatterer over time, but when used as a contrast agent for ultrasonic diagnosis, it is preferable to use physiological saline as a main component. . In addition, the dispersion medium contains a polyhydric alcohol for the purpose of viscosity adjustment and the like.
(Eg, glycerin, propylene glycol, ethylene glycol), saccharides (eg, glucose, fructose, etc.), polysaccharides (dextran, etc.), or water-soluble polymers (eg, polyvinyl alcohol, gelatin, albumin, etc.).

The ultrasonic scatterer according to the present invention is an ultrasonic scatterer having high reliability of generating subharmonic echo. Therefore, by confirming whether or not the condition of the present invention is satisfied, it is possible to select an ultrasonic scatterer having high reliability of generation of a subharmonic echo. The method for selecting an ultrasonic scatterer having a strong subharmonic echo according to the present invention is provided from such a viewpoint and includes at least the following four steps.

(First step) 0.5 kPa to 10 kPa is applied to the ultrasonic confusion body.
(P ₀ ) when continuous low-pressure ultrasonic wave is applied
(2nd step) a step of irradiating the ultrasonic confusion body with a plurality of high-pressure ultrasonic waves having a sound pressure of 20 kPa to 2 MPa and 4 or more continuous waves; (3rd step) 4 μsec from the end of the irradiation of the high-pressure ultrasonic waves Obtaining a minimum transmission amount (P _m ) when the ultrasonic confusion is irradiated with continuous low-pressure ultrasonic waves having a sound pressure of 0.5 kPa to 10 kPa; (4th step) P _m / P ₀ is 0.01 to The process of selecting an ultrasonic confusion body that is 0.6

The high-pressure ultrasonic wave referred to in this specification has a sound pressure of 20 kPa
It is a plurality of continuous sound waves of up to 2 MPa and four or more waves. The preferable range of the sound pressure is 40 kPa to 1.5 MPa, and the number of continuous waves is preferably 4 to 100 waves, and more preferably 10 to 50 waves. The low-pressure ultrasonic wave referred to in the present invention has a sound pressure of 0.5 kPa
A plurality of continuous sound waves of ~ 10 kPa. The preferred range of sound pressure is 0.5 kPa to 5 kPa, and the number of continuous waves is 10
Waves to 200 waves are preferable, and 20 to 100 waves are more preferable. The frequency of high-pressure ultrasonic waves and low-pressure ultrasonic waves are each 0.
The frequency is preferably 5 MHz to 30 MHz, and more preferably 1 MHz to 10 MHz. The frequency of the low-pressure ultrasonic wave and the frequency of the high-pressure ultrasonic wave may be different, but are preferably the same.

A specific example of a method of irradiating a low-pressure ultrasonic wave and a high-pressure ultrasonic wave to an ultrasonic confusion body will be described with reference to FIG. However, the method of irradiating low-pressure ultrasonic waves and high-pressure ultrasonic waves in the present invention is not limited to the embodiment shown in FIG. A pure water 102 is placed in a water tank 101, and a transducer 121, a hydrophone 123, and a cell 11 made of agar are placed in the pure water.
Sink one. Inside the agar cell 111, the ultrasonic scatterer dispersion liquid 11
Inject 3 The ultrasonic scatterer dispersion liquid can be appropriately stirred by the stirrer 112. A signal is sent from the arbitrary waveform generator 122 to the transducer 121, and a transmission ultrasonic wave oscillates. Arbitrary waveform generator 122 is transducer 1
The trigger signal is transmitted to the oscilloscope 124 at the same time as transmitting the signal to 21. The oscilloscope 124 captures the signal received by the hydrophone 123 in response to the trigger signal transmitted from the arbitrary waveform generator 122. Computer 1
Reference numeral 25 is connected to the oscilloscope 124, and analyzes the reception waveform of the hydrophone.

FIG. 2 shows an example of a signal transmitted from the arbitrary waveform generator 122 to the transducer 121. However, the signal transmitted in the present invention is not limited to the embodiment shown in FIG. First, the low-pressure ultrasonic signal 201 is transmitted, and thereafter, the high-pressure ultrasonic signal 202 is continuously transmitted. Further, the low-pressure ultrasonic signal 203 is continuously transmitted. Here, the voltage and frequency of the low-pressure ultrasonic signals 201 and 203 are the same, and the voltage value, frequency and wave number are set so that the ultrasonic waves generated by the transducer 121 satisfy the requirements of the low-pressure ultrasonic waves. . Also, the voltage value of the high-pressure ultrasonic signal 202,
The frequency and the wave number are set so that the ultrasonic waves generated by the transducer 121 satisfy the requirements of the high-pressure ultrasonic waves.

In the present invention, high-pressure ultrasonic waves and low-pressure ultrasonic waves may be transmitted from different transducers. In this case, the high-pressure ultrasonic wave and the low-pressure ultrasonic wave may have sound rays generated from the same axis, but may have different axes if the axes intersect in the ultrasonic scatterer dispersion. Good.

In a preferred embodiment of the present invention,
The ultrasonic transmission signal is measured by the method described in 1.
FIG. 3 shows an example of the obtained signal. In the ultrasonic signal 300, the low-pressure ultrasonic wave corresponding to the low-pressure ultrasonic signal 201 in FIG.
Transmitted through the ultrasonic scatterer dispersion 113 appear as low-pressure ultrasonic waves 301 before high-pressure ultrasonic wave irradiation. Subsequently, similarly, the high-pressure ultrasonic wave 302 corresponding to the high-pressure ultrasonic signal 202 in FIG. 2,
Further, a low-pressure ultrasonic wave 303 corresponding to the low-pressure ultrasonic signal 203 appears. The average of the maximum values of the signal 301 obtained in this way is represented by a zero-order straight line with respect to time is the low-pressure ultrasonic emission line 311 before the high-pressure ultrasonic irradiation, and the signal 303 connecting the maximum values is It is a low-pressure ultrasonic emission line 312 after high-pressure ultrasonic irradiation. From the low-pressure ultrasonic radiation line 312 after the high-pressure ultrasonic irradiation, a low-pressure ultrasonic minimum point 313 after the high-pressure ultrasonic irradiation within a range of 4 μsec immediately after the end of the high-pressure ultrasonic irradiation is obtained, and the sound pressure (P _m ) is obtained. Low pressure ultrasonic emission line 3 before high pressure ultrasonic irradiation
Divide by the value (P ₀ ) of 11 to obtain the reduction ratio (P _m / P ₀ ) of the transmission amount of the continuous low-pressure ultrasonic wave.

Specifically, when the values in FIG. 3 are obtained, the low-pressure ultrasonic wave is 0.63 kPa before irradiation with the high-pressure ultrasonic wave, and the transmission minimum is 0.2 kPa 0.7 μsec after the end of the high-pressure ultrasonic wave irradiation by the high-pressure ultrasonic wave irradiation. ing. From this, the minimum value of the transmission amount of the present invention is 0.32 with respect to the low-pressure ultrasonic transmission immediately before the high-pressure ultrasonic irradiation. By such a method, P _m / P ₀ of the ultrasonically disturbed object to be measured is determined, and the value is determined to be 0.01 to 0.6.
By selecting the ultrasonic disturber, the ultrasonic scatterer having a strong subharmonic echo can be selected.

The ultrasonic scatterer of the present invention in which P _m / P ₀ is 0.01 to 0.6 is effectively used for an image acquisition method using an ultrasonic echo. That is, if the ultrasonic scatterer of the present invention is applied to a sample, and the sample is irradiated with ultrasonic waves and an echo is obtained, the location and dispersion state of the ultrasonic scatterer of the present invention can be easily detected. be able to. The ultrasonic echo acquisition method may be any method, but the effect of the present invention is remarkably exhibited in the subharmonic echo method. In particular, if the ultrasonic confusion body of the present invention is injected into a liquid part such as blood,
The state of the flow can be confirmed effectively. For this reason, the ultrasonic confusion body of the present invention is particularly suitably used as a contrast agent for ultrasonic diagnosis.

[0032]

EXAMPLES The features of the present invention will be described more specifically with reference to examples and comparative examples. Materials shown in the following examples,
The usage amount, ratio, processing content, processing procedure, and the like can be appropriately changed without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the specific examples described below.

Example 1 (Preparation of Ultrasonic Scatterer) 1) Preparation of C ₃ F ₈ Bubbles Having Albumin Shell 5 g of human serum albumin (ALB) was dissolved in 100 ml of physiological saline, and C ₃ F ₈ gas was added. The injection was performed at a linear velocity of 20 m / sec from a nozzle having a diameter of 20 μm. The thus obtained foam a Whatman ^R manufactured cyclo pore membrane (hydrophilic polycarbonate membrane type, pore size 10 [mu] m) with a shell to give the CA01 to remove coarse particles. CA01 obtained by adding 50 mg of aerosol OT (manufactured by American Cyanamid) together with 5 g of ALB in CA01,
CA03 was obtained by adding 100 mg of sodium dodecylsulfonate (SDS), and CA04 was obtained by adding 1 g of gelatin (gel). CA01 was prepared by adding 0.1 g of glutaraldehyde (GA) to CA01, and CA06 was obtained by adding 5 g of urea (UR). Further, CA01 to CA06 were filtered through Whatman ^R cyclopore membrane (hydrophilic polycarbonate membrane type, pore size 5 μm) to obtain CA11 to CA16. Particles having the average particle size shown in Table 1 were obtained.

2) Preparation of C ₃ F ₈ bubbles containing phospholipids Dipalmitoyl phosphatidylcholine 24.9 mg, dipalmitoyl phosphatidyl sodium 2.8 mg, dipalmitoyl phosphatidylethanolamine 2.3 mg, physiological saline 6 ml And a C ₃ F ₈ gas was injected from a nozzle having a diameter of 20 μm at a linear velocity of 20 m / sec. The thus-obtained shell-equipped bubbles were removed with a Whatman ^R cyclopore membrane (hydrophilic polycarbonate membrane type, pore size 10 μm) to remove coarse particles, thereby obtaining CA21. Furthermore, what was filtered off using a Whatman ^R cyclopore membrane (hydrophilic polycarbonate membrane type, pore diameter 5 μm) was used as CA22. Particles having the average particle size shown in Table 1 were obtained.

Example 2 (Measurement of Ultrasonic Transmission Amount) In FIG. 1, a transducer 121 is A381S manufactured by Panametrics Japan, an arbitrary waveform generator 122 is an AWG2021 manufactured by Tektronix, and a hydrophone 123 is a large-diameter manufactured by Toray Techno. PVDF hydrophone, oscilloscope 124 with Iwatsu Bri
Measured as ngo. In addition, the low-pressure ultrasonic wave before the high-pressure ultrasonic irradiation is 3.5 MHz, the sound pressure is 2.5 kPa, 42 wave burst, the high-pressure ultrasonic wave is the sound pressure frequency of 3.5 MHz, 50 kPa, 14 wave burst, and the low-pressure ultrasonic wave after the high-pressure ultrasonic irradiation The signal of the arbitrary waveform generator was prepared so that the sound wave had a frequency of 3.5 MHz, a sound pressure of 2.5 kPa, and a burst of 42 waves.

Example 3 (Measurement of Ultrasonic Scattering) In order to analyze the ultrasonic scattered signal of the ultrasonic scatterer, the apparatus shown in FIG. 4 was manufactured. A pure water 402 was placed in a water tank 401, and a transducer 421, a hydrophone 423, and a cell 411, which was an agar container, were submerged in the pure water. Ultrasonic scatterer dispersion 413 was diluted 1/5000 with pure water and injected into agar cell 411. The ultrasonic scatterer dispersion liquid can be appropriately stirred by the stirrer 412. A signal was sent from the arbitrary waveform generator 422 to the transducer 421 to oscillate transmission ultrasonic waves. Arbitrary waveform generator 422 sent a trigger signal to oscilloscope 424 at the same time as sending a signal to transducer 421.
The oscilloscope 424 captures a signal received by the hydrophone 423 in response to a trigger signal transmitted from the arbitrary waveform generator 422. The computer 425 is connected to the oscilloscope 424.The FFT changes the received waveform of the hydrophone and analyzes the frequency to obtain fundamental wave scattering (fundH) at the same frequency as the transmitted wave and sub-harmonic scattering (subH) at 1/2 frequency. ) Was calculated, and the subH intensity relative to fundH was obtained in dB.

In FIG. 4, a transducer 421 is A381S manufactured by Panametrics Japan, an arbitrary waveform generator 422 is an AWG2021 manufactured by Tektronix, and a hydrophone 423 is a large-diameter PVDF hydrophone manufactured by Toray Techno, and an oscilloscope 424.
Was measured as Bringo manufactured by Iwatsu. In addition, a signal of the arbitrary waveform generator was prepared so that the transmitted ultrasonic wave had a frequency of 3.5 MHz, a sound pressure of 50 kPa, and a burst of 42 waves.

Table 1 shows the results obtained by measuring the ultrasonic scatterer prepared in Example 1 by the above method. The minimum time in the table indicates the time from the end of high-pressure ultrasonic irradiation to the point at which the low-pressure ultrasonic minimum is reached. From Table 1, su of the ultrasonic scatterer of the present invention is shown.
It turns out that bH is strong.

[0039]

[Table 1]

[0040]

The ultrasonic confusion body of the present invention is particularly useful as a contrast agent for ultrasonic diagnostics because of its high reliability in generating a subharmonic echo. According to the ultrasonic diagnostic method of the present invention, blood flow information in a living body can be obtained more accurately. Furthermore, according to the selection method of the present invention, it is possible to easily select such a useful ultrasonic confusion body.

[Brief description of the drawings]

FIG. 1 is a block diagram showing an example of scatterer ultrasonic transmission measurement according to an embodiment of the present invention.

FIG. 2 is an example of a signal transmitted from the arbitrary waveform generator to the transducer according to the embodiment of the present invention.

FIG. 3 is a waveform diagram illustrating an example of a sound pressure waveform of a received ultrasonic wave and signal processing corresponding thereto according to the embodiment of the present invention.

FIG. 4 is a block diagram showing an example of scatterer ultrasonic transmission measurement in the embodiment of the present invention.

[Description of Signs] 101, 401 Water tank 102, 402 Pure water 111, 411 Agar cell 112, 412 Stirrer 113, 413 Ultrasonic dispersant dispersion liquid 121, 421 Transducer 122, 422 Arbitrary waveform generator 123, 423 Hydrophone 124, 424 Oscilloscope 125, 425 Computer 201 Low-pressure ultrasound signal 202 High-pressure ultrasound signal 203 Low-pressure ultrasound signal 300 Ultrasonic signal 301 Low-pressure ultrasound before high-pressure ultrasound irradiation 302 High-pressure ultrasound 303 After high-pressure ultrasound irradiation 311 Low-pressure ultrasonic sound pressure drop line before high-pressure ultrasonic irradiation 312 Low-pressure ultrasonic sound pressure drop line after high-pressure ultrasonic irradiation 313 Low-pressure ultrasonic minimum point after high-pressure ultrasonic irradiation

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/42 A61K 47/42

Claims (5)

[Claims] Claims 1. A sound pressure of 0.2 kPa for 4 μsec immediately after irradiating a plurality of high-pressure ultrasonic waves having a sound pressure of 20 kPa to 2 MPa and four or more waves.
Minimum permeability of transmittance of the low pressure ultrasonic wave is reduced to consecutive 5kPa~10kPa reached (P _m), ultra low permeation amount the low pressure ultrasonic wave transmission amount of the high-pressure ultrasonic irradiation immediately prior to (P _m) (P ultrasonic scatterer ratio _{0) (P m / P 0} ) is characterized in that 0.01 to 0.6. 2. A contrast agent for ultrasonic diagnosis, comprising the ultrasonic confusion body according to claim 1. 3. A step of obtaining a transmission amount (P ₀ ) when the ultrasonic confusion is irradiated with continuous low-pressure ultrasonic waves of 0.5 kPa to 10 kPa; a sound pressure of 20 kPa to 2 Mpa and 4 or more waves on the ultrasonic confusion Irradiating a plurality of continuous high-pressure ultrasonic waves; a sound pressure of 0.5 k is applied to the ultrasonic confusion body within 4 μsec from the end of the irradiation of the high-pressure ultrasonic waves.
A step of obtaining a minimum transmission amount (P _m ) when irradiating continuous low-pressure ultrasonic waves of Pa to 10 kPa; and a step of selecting an ultrasonic confusion body having a P _m / P ₀ of 0.01 to 0.6. Method of sorting ultrasonic scatterers with strong subharmonic echo. 4. A method for detecting an ultrasonic scatterer, comprising a step of irradiating a sample to which the ultrasonic scatterer according to claim 1 is applied with ultrasonic waves and detecting an echo with respect to the ultrasonic wave. 5. A method for detecting an ultrasonic scatterer, comprising: irradiating a sample to which the ultrasonic scatterer according to claim 1 is applied with ultrasonic waves, and detecting a subharmonic echo corresponding to the ultrasonic waves.