JP2002212108A - Ultrasonic scattering material - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ultrasonic scattering material which generates sub- harmonic echoes in high certainty. SOLUTION: This ultrasonic scattering material comprising gas-containing fine particles having an average particle diameter of 0.01 to 10 μm is characterized in that the gas-containing fine particles having a distance of 0.01 to 10 μm between the center of the nearest particle and the center of the second near particle are contained in an amount of 20 to 100% based on the total number of the particles.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an ultrasonic scatterer having high reliability in generating a subharmonic echo. The ultrasonic confusion body of the present invention is particularly useful as a contrast agent for ultrasonic diagnosis.

[0002]

2. Description of the Related Art In recent years, ultrasonic diagnosis has remarkably developed in the diagnosis of the thoracic region and the abdominal region due to its characteristic of obtaining blood flow information. 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. The microbubble is obtained by encapsulating a gas harmless to a living body in a shell made of a substance harmless to the living body.
In addition, the use of Doppler signals and harmonic signals has advanced in the ultrasonic imaging apparatus, and it has become possible to acquire more tissue and blood flow information. In particular, blood flow dynamics have been more accurately evaluated in combination with ultrasonic imaging.

On the other hand, a Doppler signal includes a strong signal from a tissue with a large motion such as a myocardium, and a harmonic signal includes a harmonic signal generated from the tissue itself, and it is impossible to detect only microbubbles in a blood vessel. Therefore, so-called subharmonic imaging, which generates an image based on subharmonic echo generated only from microbubbles in a blood vessel by irradiation of ultrasonic waves having a plurality of continuous waves, has begun to be studied. The subharmonic echo of microbubbles is described in the well-known document "P.
M. Shankar et al, J. Acoust. Soc. Am., 106 (4), 210
4 (1999) ", it is known to be generated by continuous ultrasonic waves, and an ultrasonic ultrasonic wave having a plurality of continuous waves called burst waves is used for subharmonic imaging. Such a plurality of continuous ultrasonic waves have a problem that a set of waves becomes longer and spatial resolution is reduced, and a method of enhancing subharmonics with a diagnostic device is described in JP-A-2000-5167. A method of devising the waveform of the transmitted ultrasonic wave so as to collapse such bubbles has also been proposed, however, in a method involving the collapse of bubbles as a contrast agent, the contrast agent collapses over the entire sound ray to be irradiated. Therefore, there is a problem that an image cannot be acquired until the contrast agent is refilled on the sound ray, and the real-time property is lost.

[0004] Many contrast agents for ultrasonic diagnostics are on the market or in clinical trials. Examples include Echovist ^R ,
Levovist ^R (Shering AG), Imagent ^R (Alliancs Pharmceut
^{icalCorp.), Optison TM (Molecular} Biosystems, Inc.), E
choGen ^TM (SONUS Pharmaceutical, Inc.), Sonazoid ^TM (Nu
^{comed Amersham plc), Definity TM (} DuPont Pharmaceutic
^{al Co.), SonoVue TM (} Bracco Diagnostics Inc.), Quantis
on ^TM (Quadrant Healthcare plc). 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 with a view to maintaining stability in blood during storage as a medicine or after parking, and a technique for increasing the strength of subharmonics has not been used.

[0005] Also, there are many articles on ultrasonic contrast agents (E. Leen, medicalmudi, 43 (3), 17p (1999); Nico de
Jong 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
et al, IEE Trans. Ultrason., 46 (1), 220p (1999),
A. Bouakaz and KK Shung, 1999 IEEE Ultrasonics Sympo
sium, 1963p, etc.) and patents (US Pat. No. 5,855,86).
5, 5,080,386, 5,9
No. 48,387, Japanese Patent Application Laid-Open No. 10-505900, Japanese Patent Application Laid-Open No. 2000-501745, Japanese Patent Application Laid-open No. 2000
Japanese Patent Application Laid-Open No. -502047 and Japanese Patent Publication No. 2000-506122), but there is no known method for enhancing subharmonics.

Although much research has been started on the mechanism of generating 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 the applied ultrasonic waves (Nippon Super Medical Fundamental Technology Workshop vol.100 No.2 29p; PMShankar et al,
J. Acoust.Soc.Am., 106 (4), 2104 (1999); Zhen Ye, J.
Acoust.Soc.Am., 100 (4), 2011 (1996); Nico de Jong
et al, 1st US Contrast abstracts, 29p (1999)). The analysis of microbubble vibration is progressing in a dilute solution system, but 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 an external sweep (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.

[0007]

SUMMARY OF THE INVENTION In view of these problems of the prior art, an object of the present invention is to provide an ultrasonic scatterer having high reliability of generating a subharmonic echo. In particular, it is an object of the present invention to provide an ultrasonic scatterer which has high reliability of generating a subharmonic echo under conditions in which bubbles do not collapse and is useful as an ultrasonic contrast agent.

[0008]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that, in an ultrasonic scatterer composed of particles containing gas having an average particle diameter of 0.01 μm to 10 μm, the particle size of the particles containing the gas is reduced. According to the ultrasonic scatterer of the present invention, particles having a center-to-center distance of 0.01 μm to 10 μm between the nearest particle and the second closest particle are 20% to 100% of the total number of particles. It has been found that the above problem can be solved. In addition, the above-mentioned problem is that the average particle size is from 0.01 μm to 1
In an ultrasonic scatterer comprising particles containing a gas of 0 μm, the particles containing the gas have a center-to-center distance of 0.01 μm.
The problem can also be solved by the ultrasonic scatterer of the present invention, which is characterized in that 3 to 100 continuous particle aggregates of 10 to 10 μm are formed. It is preferable that the line connecting the centers of the particles constituting the particle aggregate is not a straight line. Further, among these ultrasonic scatterers, the distance between the centers of the nearest particles and the second closest particles when diluted with pure water so that the average distance between the particles containing gas is 1 mm is 0.1 mm. Particles having a size of 01 μm to 10 μm account for 10% of the total number
It is preferably from 100% to 100%. In particular, it is preferable that 10% to 100% of all particles contain no gas-containing particles and the closest particles not in contact with each other via the intermediate film.

According to the present invention, the average particle size is 0.01 μm to 10 μm.
m-containing particles and average particle size 0.01 μm to 1 μm
The present invention also provides an ultrasonic scatterer comprising m inorganic or organic solid fine particles. In this ultrasonic scatterer, particles having a center-to-center distance of 0.01 μm to 10 μm between the gas-containing particles and the closest particles account for 20% of the total number of particles.
It is preferably from 100% to 100%. Further, when the particles containing gas are diluted with pure water so that the average distance between the particles is 1 mm, the distance between the centers of the particles and the nearest particles is 0.01 μm or more.
It is also preferable that particles having a size of 10 μm account for 10% to 100% of the total number of particles.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The ultrasonic scatterer of the present invention will be described below in detail. In this specification, “to” means a range including the numerical values described before and after it as a minimum value and a maximum value, respectively.

The gas-containing particles contained in the ultrasonic scatterer of the present invention may be of any type as long as they can scatter ultrasonic waves.
μm to 10 μm. In particular, when the ultrasonic scatterer of the present invention is used as a contrast agent for ultrasonic diagnosis, the average particle size is preferably from 0.1 μm to 10 μm. Usually, the contrast agent for ultrasonic diagnosis is injected into a human body by intravenous injection and diagnosed 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 a peripheral blood vessel. If the ultrasonic scatterer is too small, the signal intensity with an ultrasonic scatterer in a living body such as a blood cell approaches, and it is difficult to analyze an obtained echo signal. Becomes A method for determining the particle size of the gas-containing particles will be described below. The dispersion of the particles containing the gas is spread on a slide glass, and is 10 μm to 100 μm.
A cover glass is placed so as to provide a clearance, and determined by observation with an optical microscope or a digital microscope. The number for measuring the particle size of each particle is preferably 200 or more, and more preferably 600 or more, in order to reduce statistical errors.

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. As the gas used in the present invention, for example, air; nitrogen; oxygen; carbon dioxide; hydrogen; nitrous oxide; an inert gas such as helium, argon, xenon, or krypton; Selenium hexafluoride; optionally halogenated silanes such as tetramethylsilane; low molecular weight hydrocarbons (eg containing up to 7 carbon atoms) such as alkanes such as methane, ethane, propane Butane or pentane, cycloalkanes such as cyclobutane or cyclopentane, alkenes such as propene or butene, or alkynes such as acetylene; ethers; ketones; esters; halogenated small hydrocarbons (eg containing up to 7 carbon atoms); Contains any mixture of compounds Door can be. Advantageously, at least some of the halogen atoms of the halogenated gas are fluorine atoms. Thus, biocompatible halogenated hydrocarbon gases include, for example, bromochlorodifluoromethane, chlorodifluoromethane, dichlorodifluoromethane, bromotrifluoromethane, chlorotrifluoromethane, chloropentafluoroethane, dichlorotetrafluoroethane, and perfluorocarbons such as perfluorocarbons. Alkanes such as perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane (e.g. perfluoro-n, optionally in a mixture with other isomers such as perfluoro-iso-butane)
-Butane), perfluoropentane, perfluorohexane and perfluoroheptane; perfluoroalkenes such as perfluoropropene, perfluorobutene (e.g. perfluorobut-2-ene) and perfluorobutadiene; perfluoroalkynes such as perfluorobuta- 2-in; and perfluorocycloalkanes such as perfluorocyclobutane, perfluoromethylcyclobutane, perfluorodimethylcyclobutane, perfluorotrimethylcyclobutane, perfluorocyclopentane, perfluoromethylcyclopentane, perfluorodimethylcyclopentane, perfluorocyclohexane, It can be selected from perfluoromethylcyclohexane and perfluorocycloheptane. Other halogenated gases include fluorinated, eg, perfluorinated ketones, such as perfluoroacetone, and fluorinated, eg, perfluorinated ethers, such as perfluorodiethyl ether. Particularly preferably, the gas is a perfluoroalkane, especially perfluoropropane, perfluorobutane, perfluoropentane or perfluorohexane.

In the present invention, the gas is preferably stabilized by the shell. The shell material used in the present invention may be a surfactant, a natural or synthetic polymer compound, an amphiphilic substance, or the like, but a so-called biocompatible compound is preferable for use as a contrast agent for ultrasonic diagnostics. Those which do not coagulate blood upon contact are more preferred, and those which are biodegradable are particularly preferred. Hereinafter, specific examples of the shell material of the present invention will be described, but the shell material that can be used in the present invention is not limited thereto. Examples of amphipathic substances include phospholipids (lecithin, dipalmitoyl phosphatidylcholine, sodium dipalmitoyl phosphatidylate, dipalmitoyl phosphatidylethanolamine polyethylene glycol ether, etc.), higher carboxylic acids (lauric acid, sodium laurate, Palmitic acid, potassium palmitate, stearic acid, arachidic acid, behenic acid, etc.),
Higher alcohols (such as stearyl alcohol and palmitoyl alcohol) and higher amines (such as stearylamine) are exemplified. High molecular compounds include natural high molecular compounds (gelatin, collagen, albumin, chitosan, agar, silk fibroin, starch, cellulose, dextran, etc.), chemically modified natural high polymers (acetylated gelatin, phthalated gelatin, enzyme-degraded low molecular gelatin) , Hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc.), synthetic polymer compounds (polylactic acid, polylactic acid butyric acid copolymer, polyvinyl alcohol, polyethylene glycol, polyethylene glycol propylene glycol copolymer, urea resin, nylon, polyacrylic) Acid polyethylene glycol ester), anionic surfactants (sodium dodecyl sulfonate, diisobutyl sulfosuccinate, sodium dodecyl benzene sulfonate) Etc.), nonionic surfactant (low molecular weight polyethylene glycol,
Nonylphenol polyethylene glycol, low molecular weight polyethylene glycol propylene glycol copolymer, alkyl-modified saccharides, etc.), cationic surfactants, fluorine surfactants and the like. These may be used alone or in combination. In the present invention, the shell material is preferably stabilized by crosslinking, denaturation or the like, and the method may be any means such as chemical reaction, heat, ultraviolet irradiation, and radiation irradiation.

The dispersion medium of the ultrasonic scatterer dispersion of the present invention may be any dispersion medium as long as the ultrasonic scatterer is not denatured with time, but when used as a contrast agent for ultrasonic diagnosis, physiological saline is used. It is preferable to use it as a main component. The dispersion medium may contain a polyhydric alcohol (glycerin, propylene glycol, ethylene glycol), a saccharide (such as glucose or fructose), a polysaccharide (such as dextran), or a water-soluble polymer (such as polyvinyl Alcohol, gelatin, albumin, etc.).

The particle containing the gas of the present invention has a center-to-center distance between the nearest particle and the second closest particle of 0.01 μm.
Particles having a diameter of 10 to 10 μm are 20% to 100% of the total number of particles, preferably 30% or more, and more preferably 50% or more. The method for obtaining the center-to-center distance between the closest particle and the second closest particle in the gas-containing particles according to the present invention will be described below. The gas-containing particle dispersion is spread on a slide glass, a cover glass is placed thereon so as to have a clearance of 10 μm to 100 μm, and the center coordinates of each particle are obtained by observation with an optical microscope or a digital microscope. As the cover glass used here, a method in which a gap is formed in advance so that the distance from the slide glass becomes uniform (such as a gap cover glass manufactured by Matsunami Glass Industry Co., Ltd.) and a slide glass, or a method using a cover glass and a slide A method of injecting a liquid into a gap in which a gap is previously formed in glass (Sekisui Chemical Co., Ltd. Sekisui Microscope plate) is preferably used. The center coordinates of the second closest particle to the center coordinates of each particle obtained in this way are searched, and the ratio of particles having a size of 10 μm or less to the total number of measured particles is calculated. The number for measuring the central coordinates of each particle is preferably 200 or more, and more preferably 600 or more, in order to reduce statistical errors. In the ultrasonic confusion body of the present invention, when the particles containing gas having an average particle size of 0.01 μm to 10 μm are used in combination with inorganic or organic solid fine particles having an average particle size of 0.01 μm to 1 μm, It is not necessary to consider the center ring distance with the nearest particle.

The gas-containing particles of the present invention may form an aggregate of 3 to 100 particles continuous at a center distance of 0.01 μm to 10 μm. At this time, it is preferable that the line connecting the centers of the particles constituting the particle aggregate is not a straight line. As the method of evaluating the linearity of the center, the distance between centers from the coordinates of the center obtained by the above method is 0.01 μm or more.
Continuous particle aggregates are selected in a relationship of 10 μm. Next, the relationship between the center coordinates is approximated by a straight line, and a correlation coefficient is obtained. A case where the average of the correlation coefficients thus obtained is less than 90% is regarded as not a straight line.

Further, when the particles containing the gas of the present invention are diluted with pure water so that the average distance between the particles is 1 mm, the distance between the centers of the closest particles and the second closest particles is 0.01 μm or more. 10 μm particles are 10% of the total number of particles
It is preferably from 100% to 100%, and more preferably from 20% or more. In the present invention, a method of diluting with pure water so that the average interparticle distance is 1 mm will be described. First, the number of particles per unit volume (n / ml) is determined from observation with an optical microscope, and the occupied volume (V ₀ ml) is calculated by dividing the volume by the number of particles. Assuming that it is the honey filling, the relationship between the occupied volume (Vml) and the center-to-center distance (Lcm) of adjacent particles is expressed by the following equation.

V × 0.641 = 4/3 × π ×
(L / 2) ³ Here, the occupied volume V when L is 1 mm is obtained, and V is calculated as V
_{The value obtained} by dividing by ₀ is the dilution ratio for making the average interparticle distance 1 mm.

The particles containing the gas of the present invention and those closest to the particles are not in contact with each other via the interlayer film.
% To 100%, more preferably 20% or more.

As a method for shortening the distance between particles of the gas-containing particles of the present invention, a method of adding a compound having two or more functional groups that form an ion complex or a chemical bond with the shell of a bubble, or a solid-state method A method of adding fine particles and bonding them with particles containing the gas from the surface energy relaxation mode may be mentioned, but a method of adding solid fine particles is preferable.

The inorganic or organic solid fine particles of the present invention having an average particle size of 0.01 μm to 1 μm will be described. As a method for measuring the particle diameter of the solid fine particles, any method such as a method by direct observation using an electron microscope, an optical microscope, or the like, a method using a laser scattering particle size meter, or the like may be used. The compound forming the solid particles may be any of an organic substance, an inorganic substance, and an organic-inorganic composite, but it is necessary that the compound is solid in water, and an organic polymer compound is particularly preferably used. The solid here indicates that the solubility in water is low, and includes so-called hydrogels, micelles, liposomes, etc. which are impregnated with water but are not dissolved.

Examples of the organic substance forming the solid particles of the present invention include low molecular weight compounds, aggregates of low molecular weight compounds, and high molecular weight compounds. Aggregates of low molecular weight compounds or high molecular weight compounds are preferable. Molecular compounds are particularly preferred.
Examples of the low molecular assembly include a vehicle comprising an amphipathic substance such as a surfactant micelle or liposome. Examples of the amphipathic substances include phospholipids (lecithin, dipalmitoylphosphatidylcholine, sodium dipalmitoylphosphatidylate, dipalmitoylphosphatidylethanolamine polyethylene glycol ether, etc.), higher carboxylic acids (lauric acid, sodium laurate) , Palmitic acid, potassium palmitate, stearic acid, arachidic acid, behenic acid, etc., higher alcohols (such as stearyl alcohol and palmitoyl alcohol), and higher amines (such as stearylamine). Examples of the surfactant include anionic surfactants (sodium dodecyl sulfonate, diisobutyl sulfosuccinate, sodium dodecyl benzene sulfonate), nonionic surfactants (low molecular weight polyethylene glycol, nonylphenol polyethylene glycol,
Low-molecular-weight polyethylene glycol-propylene glycol copolymer, alkyl-modified saccharides, etc.), cationic surfactants, fluorinated surfactants, and the like, but are not limited thereto. These amphiphilic substances and surfactants may be used alone or in combination of two or more, and may be stabilized by crosslinking, denaturation or the like by a method such as a chemical reaction, heat, ultraviolet irradiation, or radiation irradiation.

Examples of the high molecular compound include natural high molecular compounds (gelatin, collagen, albumin, chitosan, agar, silk fibroin, starch, cellulose, dextran, etc.), chemically modified natural high polymers (acetylated gelatin, phthalated gelatin, enzymatic degradation) Low molecular gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc.), synthetic high molecular compounds (polylactic acid, polylactic acid butyric acid copolymer, polyvinyl alcohol, polyethylene glycol, polyethylene glycol propylene glycol copolymer, urea resin, nylon) , Polyacrylate, polyethylene glycol polyacrylate, SBR latex, polystyrene, PET, etc.), but are not limited thereto. The polymer may be stabilized by cross-linking, modification, or the like, and the method may be any means such as chemical reaction, heat, ultraviolet irradiation, and radiation irradiation.

Examples of the inorganic substance forming the solid particles of the present invention include metal oxides (colloidal silica, alumina, ferrite, etc.), composite oxides (alumina surface-modified colloidal silica, zeolite, celite, etc.), metal colloids (silver, etc.). Colloid, colloidal gold, etc.), sparingly soluble phosphates (such as calcium phosphate and hydroxyapatite), and sparingly soluble carbonates (such as calcium carbonate), but are not limited thereto. The inorganic substance forming the solid particles of the present invention may form a complex with the above organic compound.

When the ultrasonic scatterer of the present invention is used as a contrast agent for ultrasonic diagnosis, it is preferable that inorganic or organic solid fine particles are formed of a so-called biodegradable material.

The ultrasonic scatterer according to the present invention is used for confirming the state of a flow injected into a liquid portion in an image acquisition method using ultrasonic echo. In particular, it is suitably used as a contrast agent for ultrasonic diagnosis. The ultrasonic echo acquisition method of the present invention may be any method, but the effect of the present invention is remarkably exhibited in the subharmonic echo method.

[0026]

The features of the present invention will be described more specifically with reference to the following examples. Material, amount used in the following examples,
The 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.

(1) Subharmonics evaluation device and
The ultrasound scattering measuring device used in the evaluation of fine evaluation method subharmonic shown in FIG. A pure water 102 is placed in a water tank 101, and a transducer 121, a hydrophone 123,
The cell 111, which is a container made of agar, is sunk. Agar cell 111
An ultrasonic scatterer dispersion liquid 113 is injected into the inside. A signal is sent from the arbitrary waveform generator 122 to the transducer 121, and a transmission ultrasonic wave oscillates. Arbitrary waveform generator 1
At 22, a trigger signal is transmitted to the oscilloscope 124 at the same time as transmitting a signal to the transducer 121. The oscilloscope 124 captures a signal received by the hydrophone 123 in response to a trigger signal transmitted from the arbitrary waveform generator 122. The computer 125 is connected to the oscilloscope 124 and analyzes the received waveform of the hydrophone. Here, the transducer 121
Was measured with a 3.5 MHz wideband unfocused type A381S manufactured by Panametrics Japan, AWG2021 manufactured by Tektronix, an arbitrary waveform generator 122, a large-diameter PVDF hydrophone manufactured by Toray Techno, and an oscilloscope 124 measured by Bringo manufactured by Iwatsu. did. Agar cell 1
As 11, a dentoid middle BLUE (8 mmφ) manufactured by Dentonics with a 2.5 mmφ hole was used. As a method of evaluating subharmonics, an ultrasonic scatterer is injected into the agar cell 111, a signal received by the above method is subjected to fast Fourier transform, and a ratio of a 1/2 order subharmonic to a 2nd harmonic with respect to a transmission wave. An evaluation value was obtained by obtaining (dB).

(2) Photograph of ultrasonic scatterer after ultrasonic irradiation
It was injected into the shooting by Sekisui Chemical Co., Ltd. Sekisui speculum plate,
Digital HD microscope VH manufactured by KEYENCE CORPORATION
The image was taken using a zoom lens VH-Z450 at −700, so that the ultrasonic scatterer (Ma)
A photograph of a sample obtained by diluting OPTISON manufactured by llonckrodt Inc. to 1/100 with pure water was obtained (FIG. 2).

FIG. 2 shows that particles are gathered at 50 kPa and 14 waves, which are the limiting conditions for the appearance of subharmonics. It is known that primary and secondary Bjerknes forces act as attractive forces on bubbles, which are ultrasonic scatterers vibrating in the same phase as the irradiated ultrasonic waves, smaller than the resonance particle size due to the ultrasonic irradiation (Ida et al., Nikko Medical Basic Technology Study Group, Vol.100 No.2, p.5, September 4, 2000). It is considered that a similar effect works in this measurement system and bubbles are collected. It is known that the vibration behavior of such an aggregate of bubbles is different from that of a single bubble (Matsumoto, Nippon Super Medical Basic Technology Study Group, Vol.100 No.2, page 1, September 4, 2000)
Day). That is, it is considered that the formation of the bubble aggregate by the ultrasonic irradiation strengthens the chaotic element in the vibration behavior, and subharmonics have begun to appear.

(3) Preparation of Solid Fine Particles 1) Preparation of SBR Latex Using ammonium persulfate as a polymerization initiator and an anionic surfactant as an emulsifier, 70.5 parts by mass of styrene,
After emulsion polymerization of 26.5 parts by mass of butadiene and 3 parts by mass of acrylic acid, aging was performed at 80 ° C. for 8 hours. After that, it was cooled to 40 ° C and pH was adjusted with ammonia water.
7.0 and further added Sandet BL manufactured by Sanyo Chemical Co., Ltd. so as to be 0.22%. Next, a 5% aqueous sodium hydroxide solution was added to adjust the pH to 8.3, and further adjusted to pH 8.4 with aqueous ammonia. The molar ratio of Na ⁺ ion to NH ₄ ⁺ ion used at this time was 1:
2.3. Further, 0.15 m of a 7% aqueous solution of sodium salt of benzoisothiazolinenone was added to 1 kg of this solution.
was added to prepare an SBR latex solution. Obtained S
BR latex [-St (70.5) -Bu (26.
5) -AA (3)-latex] has a Tg of 23 ° C, an average particle size of 0.1 µm, a concentration of 43% by mass, and a relative humidity of 6 at 25 ° C.
Equilibrium water content at 0%: 0.6% by mass, ion conductivity: 4.2 mS / cm (The ion conductivity was measured using a conductivity meter CM-30S manufactured by Toa Denpa Kogyo Co., Ltd., and a latex stock solution (43% by mass) Was measured at 25 ° C.), and the pH was 8.4. This SBR dispersion was diluted with pure water to 8% by mass,
The latex liquid was used below.

2) Preparation of PGALA particles Poly (DL-lactide-co-glycolide) manufactured by Aldrich (PGALA: 50:50, molecular weight 50,
10 ml of a 20% by weight methylene chloride solution (000 to 75,000) was added to 100 ml of a 1% aqueous solution of polyvinyl alcohol PVA-217 manufactured by Kuraray Co., Ltd., and the mixture emulsified with a homogenizer was subjected to reduced pressure to evaporate methylene chloride. , Fuji Photo Film Co., Ltd. Fujifilm Micro Filter AstroPore (0.45μ pore size)
m) to obtain PGALA particles. When the average particle diameter of the obtained particles was determined from a transmission electron microscope image, it was found that the average particle diameter was 0.1.
It was 1 μm.

3) Preparation of GEL particles 10 ml of a 10% by mass aqueous solution of gelatin (GEL) was added at 40 ° C.
After mixing with 100 ml of ethyl acetate and emulsifying with a homogenizer, 1 ml of 10 mass% glutaraldehyde aqueous solution
Was added and mixed and left for 3 hours. Further, after adding and mixing this dispersion in 100 ml of water and evaporating the ethyl acetate under reduced pressure, a Fujifilm micro filter AstroPore (pore diameter 0.45 μm, manufactured by Fuji Photo Film Co., Ltd.) was used.
m) to obtain GEL particles. The average particle size of the obtained particles was measured using a laser diffraction particle size distribution analyzer (Shimadzu Corporation).
It was 0.2 μm when measured with SALD-2000A.

(4) Preparation of Particles Containing Gas 1) Preparation of C ₃ F ₈ Bubbles Having Albumin Shell 5 g of human serum albumin (ALB) was added to 100 ml of physiological saline.
Then, 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 coarse particles of the bubbles with a shell thus obtained are subjected to a cyclopore membrane manufactured by Whatman ^R (hydrophilic polycarbonate membrane type, pore size: 10 μm).
m01) to obtain CA01. CA01 with 0.1 g of glutaraldehyde (GA) added to CA02
And

2) Preparation of C ₃ F ₈ bubbles with phospholipids Dipalmitoyl phosphatidylcholine 24.9 mg,
2.8m Sodium dipalmitoyl phosphatidylate
g, 2.3 mg of dipalmitoylphosphatidylethanolamine were dispersed in 6 ml of physiological saline, and C ₃ F ₈ gas was injected 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 CA03 to remove coarse particles.

3) Measurement of Average Particle Size The obtained particles and OPTISON were injected into a Sekisui Chemical Co., Ltd. Sekisui Microscope plate, and a zoom lens VH was attached to a Keyence Corporation digital HD microscope VH-700.
-Images taken with the Z450 are available from Mitani Shoji Co., Ltd.
Table 1 shows the results obtained by analyzing the images under the automatic circular separation conditions of in ROOF to determine the average particle diameter.

[0036]

[Table 1]

(5) Preparation of Ultrasonic Scatterer Each of the ultrasonic scatterers of Samples 1 to 15 was obtained by mixing particles containing gas and / or solid fine particles with water. The types of gas-containing particles and solid fine particles used for each sample were as described in Table 2. Sample 1,
As for 3, 4, 11 to 15, solid fine particles, gas-containing particles, and water were mixed at a ratio of 1: 1: 1 (mass ratio). For Samples 5 to 7, solid fine particles and water were mixed at a ratio of 1: 2 (mass ratio). Samples 2 and 8 to
For 10, the gas containing particles and the water were 1: 2
(Mass ratio).

(6) Evaluation of Particle State Microscopic images of Samples 1 and 2 are shown in FIG. Sample 1 of the present invention
As is clear from the microscopic image of the above, the particles are not aggregated via the interlayer. The ultrasonic scatterers of Samples 1 to 15 were injected into a Sekisui Chemical Co., Ltd. Sekisui Microscope plate, and photographed with a Keyence Corp. digital HD microscope VH-700 using a zoom lens VH-Z450. Taken image is WinRO made by Mitani Corporation
By analyzing the center coordinates obtained by the OF, the distance between the centers of the nearest particle and the second closest particle is 0.01 μm.
m to 10 μm (3 particle proximity ratio)
The linearity of the center position of the particles judged to be an aggregate in the particle proximity ratio measurement was evaluated. Moreover, the distance between particles is 1 with pure water.
The three-particle proximity ratio (dilution proximity ratio) when diluted so as to be mm was also measured. Table 2 shows the results.

(7) Measurement of Ultrasonic Scattering According to Table 2, each of the samples 1 to 15 was diluted with pure water to 1/50, and the above conditions (1) were obtained under the conditions of 50 kPa and 4 wave burst. Therefore, the results of measuring the ultrasonic response are shown.
For the sample of the present invention, occurrence of subharmonics was observed.

[0040]

[Table 2]

Table 3 shows that a sample 1 of the present invention was diluted 1/50 with pure water and a comparison sample, Mallonckrodt Inc.
The result of subharmonics evaluation of OPTISON manufactured by diluting it to 1/100 with pure water by changing the sound pressure and burst wave number is shown. It was confirmed that the sample of the present invention has a higher subharmonic intensity than the comparative sample, and also generates subharmonics at a low sound pressure and a small burst wave number. Lowering the sound pressure can prevent the collapse of the ultrasonic scatterer and enable real-time imaging. Actually 50kP
a) It was confirmed by an optical microscope that bubbles contained in the ultrasonic scatterer after subharmonics were generated under the four-wave condition were not collapsed. Also, being able to use a small number of burst waves improves the spatial resolution.

[0042]

[Table 3]

[0043]

As described above in detail, according to the present invention, it is possible to realize an ultrasonic scatterer having high reliability of generating a subharmonic echo under a condition in which bubbles do not collapse. Therefore, the ultrasonic scatterer of the present invention is useful as an ultrasonic contrast agent or the like.

[Brief description of the drawings]

FIG. 1 is a schematic diagram of an ultrasonic scattering measurement device used in Examples.

FIG. 2 is an optical microscope photograph of an ultrasonic confusion body (OPTISON) after ultrasonic irradiation.

FIG. 3 is a micrograph of the ultrasonic scatterers of Samples 1 and 2 in Examples.

[Explanation of symbols]

 101 Aquarium 102 Pure 111 Agar Cell 113 Ultrasonic Scatterer Dispersion 121 Transducer 122 Arbitrary Waveform Generator 123 Hydrophone 124 Oscilloscope 125 Computer

Claims (8)

[Claims] 1. An ultrasonic scatterer comprising particles containing a gas having an average particle size of 0.01 μm to 10 μm, wherein the distance between the centers of the particles containing the gas with the nearest particle and the second closest particle is 0. An ultrasonic scatterer wherein particles having a particle size of 0.01 μm to 10 μm account for 20% to 100% of the total number of particles. 2. An ultrasonic scatterer comprising particles containing a gas having an average particle size of 0.01 μm to 10 μm, wherein 3 to 100 particles containing the gas are continuous at a center-to-center distance of 0.01 μm to 10 μm. An ultrasonic scatterer characterized by forming an aggregate of particles. 3. The ultrasonic scatterer according to claim 2, wherein a line connecting the centers of the respective particles constituting the particle aggregate is not a straight line. 4. The distance between the center of the nearest particle and the distance of the second nearest particle when diluted with pure water so that the average particle distance of the gas-containing particles is 1 mm is 0.01 μm or more.
The ultrasonic scatterer according to any one of claims 1 to 3, wherein particles having a diameter of 10 µm account for 10% to 100% of the total number of particles. 5. Particles containing the gas and particles closest to the gas are not in contact with each other via the intermediate film, and 10% of the total particles
The ultrasonic scatterer according to any one of claims 1 to 4, wherein the ratio is 100%. 6. An ultrasonic scatterer comprising gas-containing particles having an average particle diameter of 0.01 μm to 10 μm and inorganic or organic solid fine particles having an average particle diameter of 0.01 μm to 1 μm. 7. The method according to claim 6, wherein the distance between the center of the gas-containing particles and the nearest particle is 0.01 μm to 10 μm, and the number of particles is 20% to 100% of the total number of particles. The ultrasonic scatterer according to the above. 8. The method according to claim 8, wherein the particles containing said gas have a center-to-center distance of 0.01 μm to 10 μm with respect to a nearest particle when diluted with pure water so that the average particle distance is 1 mm. The ultrasonic scatterer according to claim 6, wherein the ultrasonic scatterer is 10% to 100%.