TW210957B - Gaseous ultrasound contrast media and method for selecting gases for use as ultrasound contrast media - Google Patents

Abstract

Disclosed herein are agents for enhancing the contrast in an ultrasound image. These agents are extremely small bubbles, or "microbubbles," comprised of specially selected gases. The microbubbles described herein exhibit long life spans in solution and may be produced at a size small enough to traverse the lungs, thus enabling improved ultrasound imaging of the cardiovascular system and other vital organs. Also disclosed herein is a method for selecting gases from which contrast agents may be produced. The method is based on calculations using inherent physical properties of gases and describes a means to associate the properties of a gas with the time for dissolution of microbubbles comprised of the gas.

Description

Printed by the Ministry of Economic Affairs of the People's Republic of China quasi Qu Zhigongxu Cooperative Society II 6 210957-V. Description of Invention () Xiang Yan You Zhuo This case is part of US Application No. 07 / 893,657 filed on June 5, 1992 The entanglement case, and the latter case is part of the entanglement case in the US No. 07 / 761,311 application filed on September 17, 1991. Description The present invention relates to an agent for contrast enhancement of ultrasound images generated for medical diagnosis. The contrast-enhancing medium shown in this article includes extremely small bubbles that exist as a solution. This solution infiltrates into the body during or just before the ultrasound image is generated. The present invention is also directed to a method of enhancing these images, by selecting a gas with novel and excellent properties, from which a collection of free gas microbubbles can be prepared. The defoaming composed of gas skeletons selected by the method of the present invention is extremely small in size, and can exist in the bloodstream for a long enough time, thus allowing those previously thought to be incapable of being defoamed by free gas. Contrast-enhanced imaging of cardiovascular system, peripheral vascular system, and vital organs. When using ultrasound to obtain images of the internal organs and structures of the human or animal body, the ultrasound waves are reflected at a frequency higher than the sound energy waves that can be distinguished by the human ear through the body. Different types of body tissues reflect ultrasound waves in different ways. The reflected waves are often appropriately described as "echoes", which are produced by ultrasound waves reflected by different internal structures. The echoes are detected electronically and transferred Into a video display. This type of video shows that it has proved to be of great value to the tutor or other diagnostician, including the assessment of the progression of cardiovascular disease, or the presence of a tumor, or its nature. ^ Paper scales are in the middle song (CHS) A4 specifications (210x297 g; tf ·) ^ ^ * '*' (please fill in this first wift back to the ii- 意 事 f #! Ί Install · line. 210957 Λ 6 Η 6 V. Description of the invention () Printing by the Ministry of Economic Affairs of the Ministry of Economic Affairs Employee Consumer Cooperatives for certain medical conditions • It is particularly difficult to obtain useful and interesting images of organs or structures. In the absence of contrast-enhancing agents, the details of the organ or configuration in the ultrasound image generated by ultrasound reflection cannot be fully distinguished from the Zhou tissue. In addition, the quality and resolution of traditional ultrasound images are poor It is notorious. Therefore, by infiltrating the contrast-enhancing agent into the organ or other structure of interest to enhance the contrast of the ultrasound image, it can greatly improve the detection and observation of certain physiological conditions. In other cases. The movement of the contrast-enhancing agent itself is particularly important. For example, it is known that the type of exclusive blood flow caused by certain cardiovascular abnormalities can only be achieved by infiltrating the contrast agent into the blood flow and examining the hemodynamics. Branch office. Research was conducted at the end, using solids, gas, and liquids, with the intent to find ultrasound contrast enhancers suitable for specific diagnostic purposes. Compound substances, such as microvesicles encapsulated in Mingji, lipids that incorporate gas, have also been studied The body, partially denatured proteins processed by sound waves, and emulsions containing highly vaporized organic compounds are intended to develop a contrast enhancer with certain ideal qualities. These qualities are mainly for in vivo stability and provide ultrasound imaging. Contrast enhancement of chopsticks. Using standard ultrasound imaging technology, small bubbles can be easily picked up in the generated image, and the name is "defoaming". When defoaming infiltrates blood flow or specific parts of the body, it can enhance the area containing bubbles and surrounding tissues. Contrast between. A lot of research is devoted to the use of extremely small bubbles as contrast enhancers. Researchers have long known that bubbles have unique physical properties. When bubbles are guided through the body, they can affect ultrasonic energy; free bubbles can provide Highly effective contrast agent. The advantages provided by free bubbles, please read the ift and contrast enhancement liquid first. This production · Binding line f paper standard edge use 8 Η home standard (CNS) specifications (210 father 29 '/ male dragon) _4 · 81. 7. 20.000 sheets (II) 2 Λ 6 Ιϊ 6 Ministry of Economic Affairs Printed by the Bureau of Consumer Goods Cooperatives 3i V. Description of the invention () The opposite of the body or the solid agent. For details, see the discussion of ultrasonic diagnostic technology later in question. However, despite its known advantages, free bubbles quickly dissolve in the solution. Such as blood, or a variety of intravenous aqueous solutions, greatly limit its use as an ultrasound contrast enhancer. The most important restrictions are the size of the bubble and the length of time before the bubble is dissolved in the solution. Closer inspection of the removal of bubbles The size requirement, of course, needs to be small enough, so that the bubble suspension will not cause the danger of embolization of the organism it is infiltrating. At the same time, the extremely small free bubbles composed of gas, which is usually used for ultrasound contrast imaging, quickly dissolve in the solution, so its image enhancement effect appears only in the immediate vicinity of the infiltration site. There is another obstacle to ultrasound imaging of the cardiovascular system. Medical researchers study the time required for a bubble composed of ordinary air, pure nitrogen, pure gas, or bismuth to dissolve into a solution. These gases are small enough to pass through the lungs and reach the left heart. The diameter is less than about 8 w and the life span is shorter than about 0.25 seconds. Meltzer, RS, Tickner, EG, Popp, L., " Vhy Do the Lungs Clear Ultrasonic Contrast? &Quot; U 1 t. Rasn ii η Η ι η M edi π ί np and Biology. Vo 1. 6, P. 263, 267 (1980). It takes 2 seconds for the microbubble to pass through the lungs, so it completely dissolves during the passage and cannot reach the left heart at all (same text). This is mainly due to the trade-off between bubble size and lifetime. Many researchers have concluded that free gas microbubbles cannot be used as contrast enhancers in ultrasound diagnosis of certain parts of the cardiovascular system. However, the article describes ultrasonic contrast-enhancing media, including a blister composed of a biocompatible gas (the selection method of which is also provided by the present invention), whose size is small enough to penetrate the blood vessel of the lung with a diameter of approximately 100% Please read the precautions first, then write this book, install < order _-line · this paper 5 good scales to use in a B home sample standard (CHS) T4 specifications (210X25) 7 male: ":> '5 -81. 7. 20.0〇 < k (H) 210957 Λ 6 Π 6 V. Description of the invention () Ministry of Economic Affairs + Central Bureau of Industry and Economics Beigongxiao 1ν · Cooperative Duin 5i Left inverted chamber for contrast enhancement Sonic diagnosis. The free gas has survived long enough in the bloodstream, so it can infiltrate the peripheral veins, pass through the right heart and lungs, and enter the left inverted chamber of the heart without dissolving into a solution. In addition, some media are in solution The entanglement time is extremely long, so it can enhance the comparison of other organs and structures. The present invention overcomes the unique limitation of using free gas to remove bubbles, and part of the way to overcome it is to provide a method for selecting a special gas based on a specific physical standard. Wait for the gas to bubble up The bubble-removing limitation of the study. Therefore, it was found that the physical and chemical parameters shown in the text, a biocompatible gas or gas combination selected to produce a through-bubble composition, the text includes the super-composition of this composition. The sonic contrast enhancement medium can exist for a long enough time and has a small enough size, so it is stable in the blood flow and can be enhanced. Ultrasonic contrast imaging of a specific structure in the pen that was previously thought to be impossible to achieve by the removal of free gas bubbles. The term "biocompatible gas" stands for a chemical skeleton, which can function in a living organism in an acceptable manner without undue toxic or physiological or pharmacological effects; when it is at a body temperature in a living organism, it is available Solid or liquid-resolved material states: its density and viscosity are low, with the change of temperature and pressure, the expansion and contraction are quite large, and the tendency to automatically and evenly spread throughout any container. The following table lists the estimated body temperature of various living organisms: organic magpie (Sus Sc "ofa) sheep (0v is sp.) Rabbit (Oryctolaqus cuniculus) alfalfa sighting temperature (° F) 101.5-102.5 101-103 102- 103.5 please-first m ih back Note. Intentions 塥% This binding line is used in paper size. 8 8 抣 戣 bi (CNS) T4 specification (210x297 g *) — 6 · 81. 7. 20.000ik (H) Ministry of Economic Affairs Bureau of Standards Printed by the Gongxiao Cooperative Society, Λ 6 η 6 5. Description of the invention () Rat (Tattus morvegicus) 99.5-100.6 Monkey (Macaca Tianulatta) 101-102 Mouse (Mus Musculus) 98-101 Goat (Capra hi reus) 101 -103 guinea pig (Cavia porcellus) 102-104 squirrel (Mesocricetus sp ·) 101-103 person (Homo sapiens) 98.6-100.4 horse (Equussp.) 101-102.5 dog (Can ί nf am i 1 i ar is) 101- 102 Papio 98-100 l§ (Fe.lis catus) 101-102 Cattle (Bos taurus) 101.5-102.5 Chimpanzee (Pan) 96-100 Kazuo oil against the Bubu 梢 phenomenon For a more complete understanding of the subject of the present invention, to explain the currently known ultrasound imaging technology, and in view of this, study how to improve the ultrasound contrast enhancer. The operation method of the substance that can be used as an ultrasound contrast agent is acting on ultrasound and reflecting when passing through the body to produce an image, from which the image can be used for medical diagnosis. In an attempt to develop an effective image contrast agent, people in the industry understand that different types of substances can be ultrasounded in different ways and to varying degrees. In addition, the effects caused by some contrast enhancers are easier to measure and observe than others. Therefore, when selecting the ideal composition of the contrast enhancer, it is preferable to use a substance that has the greatest effect on ultrasound when passing through the body. At the same time, for the binding line paper produced by ultrasound, the standard side is used in a B home «Bi (CNS) T4 specification (210X297; it) 81. 7. 20.000 sheets (II), please read first

iA Contrary to note, #-% 910957 Λ 6 η 6 V. Description of invention () The printing effect of the Beigong Xiaotuo Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs must be easy to measure. Three contrast enhancement effects can be seen in the ultrasound image: backscattering, energy beam attenuation, and sonic velocity difference. The effects are detailed below. A. Skin scattering When the ultrasonic waves passing through the body meet a structure, such as an organ or other body tissue, the structure reflects part of the ultrasonic waves. Different structures in the body reflect ultrasound energy in different ways and with different intensities. This reflection can be detected and used to generate an image of the structure through which ultrasound passes. The term "backscattering" stands for ultrasonic energy, which is scattered back to the source by substances with certain physical properties. It has long been known that the contrast observed by ultrasound images can be enhanced by the presence of substances known to cause large amounts of backscattering. When such a substance is administered to a specific part of the body, the contrast between the ultrasound image of this part of the stirrup and the surrounding tissue that does not contain this substance is enhanced. It is well understood that due to the different physical properties of different substances, it causes backscattering of varying degrees. According to this, the research focus of contrast enhancers is on: stable, non-toxic, and substances with maximum backscattering. Making certain assumptions about the way that matter reflects ultrasonic energy, a mathematical formula has been developed to describe the phenomenon of backscattering. With this mathematical formula, experienced researchers can estimate the degree of backscatter caused by gas, liquid, and hip contrast enhancers, and the degree of measurable backscatter caused by specific substances, which can be compared with other substances based on knowledge. The physical properties that cause the backscattering phenomenon are compared. As a simple example, if all other factors are equal and substance A is larger than substance B, then A's ability to cause backscatter will be greater than B. In this way, when two substances irradiate ultrasonic waves, a larger substance scatters a larger amount of ultrasonic waves. Please read the precautions and fill in the %% of this binding line paper ft standard use + a B home standard (CNS) Ή specification (210 > < 297 public ":) 81. 7. 20,000ik (H) -8 -2 ^ 0953- V. Description of the invention (The ability of a substance to cause ultrasonic backscatter is also related to the other properties of the substance, such as the ability of the substance to compress. The most important thing is caused by the phenomenon of bubble resonance Backscattering has increased rapidly (to be described in detail later). When detecting indifferent substances, a specific measurement value of the scattering ability caused by the comparable substances is called "scattering cross-section". A scattering cross-section and scattering of a pending substance The radius of the body is proportional, and also depends on the ultrasonic energy and other physical properties of matter, J. Ophir and KJ Parker, Contrast. A g ft nt, s in Diagnostic Ultrasound. Ultrasound in Medicine & Biology, vol. IS, n. 4, p. 319, 323 (1989). The scattering cross-section of the small scatterer a can be determined by the known equation: First read the note on the back of δ-Note Matter Er · Fill% σ

rraz (ka) Ks-K 2 1 K 3 2 (p,-p) 2p,-P Threaded by the Ministry of Economy, Ministry of Economic Affairs, Employee Consumer Cooperatives, printed by Μ, where κ = 2π / λ, where λ is the wavelength; scattering Radius of the volume; ks = pseudo-number of adiabatic compression of the scatterer; > c = adiabatic compression of the medium in which the scatterer exists; ps = density of the scatterer; and P = density of the medium in which the scatterer exists . PH Horse and KU Ingard, Theoretical_Acoustics, p. 427, McGraw Hill, New York (1968). When evaluating the use of different substances as image contrast agents, this mathematical formula can be used to determine which agent has a higher scattering cross section. What agent can provide the ultra-sonic fcUli scale side-use medium Η Η 戳 楳 Bi (CNS) TM specifications (210x297 public; ":) -9- 81. 7. 20.000¾ (||) gTt) 52. The maximum contrast of the image. With reference to the above formula, the number of brackets in the first can be assumed to be a constant for comparison of solid, liquid and gas scatterers. The compression of solid particles can be assumed. The number is much lower than the surrounding medium, and the density of the particles is much larger than the medium. Using this assumption, the estimated scattering cross section of the solid particle contrast enhancer is 1.75. Ophir and Parker (see above), p. 325. As for the pure liquid scatterer, the scatterer ^: * and the adiabatic compression number and density of the surrounding medium κ, possibly orange, etc., can be obtained from the above formula. The result is that the liquid has a scattering cross-section of zero. Liquid, the liquid may also With a number of backscatters, the presumed reason is that the term a in the number of brackets in the first type of the above formula becomes large enough. For example, if the liquid agent passes from a very small container to a very large one, and the liquid agent generally occupies the entire container, it has a measurable Scattering. Even so, in view of the above formula and the following, people in the industry understand that pure liquid is a relatively ineffective scatterer compared to the free bubble. The known nature of the substance is in the two-phase, that is, the interface between the liquid and the gas phase. The change is noticeable, due to the significant change in the reflection characteristics of ultrasound at this interface. In addition, because the compressibility of bubbles is much greater than that of liquids or solids, the scattering cross section of gas is roughly the same as that of liquids or solids. No. Knowing the physical properties of bubbles in solution, the above formula uses the standard values of normal air's shrinkage and density data. Using these standard values, the result of the second bracket in the above formula is about 101 * (Ophir and Parker, supra, p. 325), the total scattering cross-section varies with the bubble radius a. Again, free bubbles will vibrate in the liquid, and at certain frequencies, the bubbles will be close to the ultrasound commonly used in medical imaging frequency The result is that the cross-section of the scattering floor of the bubble can be larger than its physical size ih- first read the back-notes-intentions-then * the crucible% of this binding line and the paper size in the middle a Η 家 榲 准 (CHS) T4 Specifications (210X297 mm) 10- 81. 7. 20.000iMH) 21095 ^ Λ 6 η 6 V. Description of the invention (Ministry of Economics, Biyang Junjun 13: 工 消 # 合作社 印 32. More than a thousand times. So understand the gas Defoaming is an excellent scatterer of ultrasonic waves, as long as it can overcome the obstacle of its rapid dissolution into the solution, it is an ideal contrast enhancer. R. Examination ram reduction There are some solid contrast enhancers, and another effect observed is ultrasonic attenuation. Due to the limitation of gonad reduction between certain tissue categories, conventional imaging has observed image contrast. KJ parker and RC Wang, " Measu-renent of Ultrasonic Attenuation Within Regions selected iron B-Scan Images, " IEEE Trans. Biomed. Enar · BHE 30 (8), p. 431-37 (1983); KJ Parker, RC Wang, and RM Lerner, " Attenuation of Ultras-ound Magnitude and Frequency Dependence for Tissue Characterization, " Radiology. 153 (3), p. 785-88 (1984). There is a hypothesis: before and after the infiltration of an agent, the attenuation of the tissue in a zone is measured to obtain an enhanced image. However, based on attenuation comparison, the technology used as a means to enhance contrast in the measurement liquid has not yet been developed and mature; even if it has been thoroughly developed, there are still limitations on the internal organs or portability of this technology. For example, it is impossible to observe in the cardiovascular strip image, which can be attributed to the decay and loss of the liquid contrast agent. The loss is due to the presence of a large amount of liquid contrast agent in a specific container in order to detect the substantial subtraction difference. It has been completed in a test tube test to measure the deflation comparison caused by the removal of the ball by Albunex (Mdec-ular Biosystems. San Diego, California), suggesting that the deflation comparison measurement can be completed in vivo. H. Bleeker, K. Shung, J. Burnhart, " On the Application of Ultras-

Ifr- first read the back and the precautions # * fill in this gutter paper "standard side use a Η home sample standard (CUS) Ή specification (210X297 public;" :) -11- 81. 7. 20.000 sheets (Η) , 2 Ιϋ & -5 ·?-Λ 6 η 6 V. Description of the invention () Ministry of Economics + Central Department of the Ministry of Economics and the Central Government only 1 Consumers on the ic Contrast Agents for Blood F1owometry and Assessment of Cardiac Perfusion, " J . Ultrasound Med. 9: 461-471 (1990). Albunex is a 2-4w air-filled suspension for removing the ball. It has acceptable stability in vivo and is small enough in size to enhance contrast in the left atrium or left ventricle. It was also found that the attenuation of iodipainide ethyl ester (IDE) particles caused by accumulation of hepatic halide. In these cases, the contrast enhancement phase is caused by the presence of dense particles in the soft medium, which causes ultrasonic attenuation. The absorption of ultrasonic energy by particles is caused by a mechanism called "relative motion". The attenuation change caused by the relative motion can increase linearly with the particle concentration, which is the square of the density difference between the particle and the surrounding medium. K. J. Parker, et al., &Quot; A Particulate Contrast Agent with Potent-ia 1 for Ultrasound Imaging of Liver, " Ultrasound in Medicine & Biology, vo1. 13, No. 9, p. 555, 561 (1987). Therefore, where solid particles actually accumulate, attenuation contrast can be an important mechanism for observing the enhancement of image contrast. However, the effect of reducing contrast is much smaller than that of reverse astigmatism, and has very little use for cardiovascular diagnosis. Γ. 咅 迪 菏 葉 Another possible technique for enhancing the contrast of ultrasound images is based on the fact that the speed of sound varies with the medium through which it travels. Therefore, if there are enough agents to infiltrate the target area (the speed of sound is different from that of the surrounding group), the speed difference of the area passing through the target can be measured. This technique is currently only for experiments. Therefore, considering the aforementioned three techniques for enhancing the contrast of ultrasound images, the backscattering of free gas caused by the increase of free gas is the most amazing effect; if it can overcome the obstacles of limited stability in solution, use this rule Like ih first read the back and pay attention to matters # -fill% of this binding line ΜΛ sheet size side use B Η 家 ft 毕 (CNS) Ή specification (210x297 public A) 81.7 20.000ik (II) -12- 210 ^ V. Description of invention () Λ 6 Π 6 The contrast enhancement printed by the Beigong Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs is the most beneficial. At present, due to the various technologies mentioned above, we tried to develop a contrast enhancer. Its presence can produce substantial contrast in ultrasound images, and it survives in vivo long enough to make cardiovascular Ito's imaging contrast enhancement has led to the study of a wide variety of substances—gases, liquids, solid eels, and combinations thereof—for possible contrast enhancers. A. Solid carbohydrate particles typically study solids used as possible contrast enhancers Substances are made into very small particles of uniform size. Large particles can infiltrate and circulate freely in the bloodstream, or can be injected into a specific structure or area in the body. IDE particles are solid particles, which can be mass produced, and the size distribution of the particles It is quite narrow, about 0.5-2.0 meters away. Sterile saline injections that can inject these particles can easily accumulate in the liver. Once it has accumulated a large amount, it can be enhanced by contrast reduction or backscattering. Although including these solid particles dispersed in the suspension of the liquid skull, with acceptable stability, but compared to free bubbles, the backscattering or angulation effect is quite small, so it must be substantial Polyparticles can only be compared with an observable stool on ultrasound images. Thus, these suspensions are limited to particles that are easy to coagulate, and some cell types, because unless the suspension is highly concentrated in a specific tissue, the contrast is enhanced Che Xiao. SHU-454 (Sche "ing, AG, Germany, West Berlin) is an experimental powder form, contrast enhancer, when mixed with diluent diluent, it generates various cuboids and polyhedrons ranging in size from 5 to 10w Crystal suspension. Although the exact mechanism of these crystal-enhanced ultrasound comparisons will not be clear, but it is suspected that the crystals can be read in advance. Please fill in this binding line, paper size, and use the national standard (CNS) ) 1Μ specification (210X297 g *) 81. 7. 20,000 sheets (II) —13- Λ 6 η 6 S10957 V. Description of invention ()

Tk first read ift, and note the matter. Fill in. Capture the defoaming in its structure, or the crystal itself can use the undetermined mechanism to reverse the ultrasonic energy. R. Clamp Emulsion In another attempt to obtain a satisfactory agent, the body group iron-compatible chemical species, combined with a substance that can provide a high degree of ultrasound contrast enhancement, are combined to prepare an emulsion. The European Patent Application No. 0231109 shows that oil / water emulsions containing highly fluorinated organic compounds have been studied as possible blood substitutes. They can also provide contrast enhancement of ultrasound images. Also check the emulsion containing gold fluorooctyl bromide (PF0B). Gold «octyl bromide emulsion is a liquid compound known to carry gas. PF0B emulsion is easy to accumulate in certain types of cells, so its use as an ultrasound contrast agent is limited. Although the action mechanism of PF0B emulsion is not known, it can provide ultrasound contrast because of its high density and considerable compression constant. Printed by the Cooperative Society of the Ministry of Economic Affairs, Bureau of Standards and Technology, US Patent No. 4,900,540, stating that phospholipid-based liposomes containing gas or gas precursors are used as contrast enhancers. Liposomes are significantly withdrawn, a balloon. The bilayer consisting of phospholipids and other amphiphilic molecules, and the internal water-containing chamber are all compatible with somatic cells. In most applications, liposomes are used as tools to contain biologically active substances. The pre-open reference shows that the gas or gas parent material is incorporated into the core of liposomes, and that the gas-infiltrating body provides a long life span. The stable production process of liposomes is expensive, time-consuming, and requires special materials and device. CJSU £ _ As mentioned in the previous section, one of the key parameters that must be satisfied when using Che foam as a contrast enhancer is the “size”. The free bubble removal larger than about 8ϋ is still small enough paper ", the standard side is used in the middle of the Β ΒΙ home stubby (CNS)« M specifications (210x297 mm) —14- 81.7 20.000ife (ll) 9Λ 0957 η 6 βIndustrial and Commercial Cooperation of the Ministry of Economic Affairs's Central Standards Bureau, Du Yin 5i V. Description of the invention (), which can avoid obstructing blood flow or obstructing the vascular bed. Only when blood flows through the lungs, more than 8 / U of microbubbles are removed from the bloodstream. As mentioned earlier, medical researchers reported in medical literature that the small bubbles that can be removed through the lungs will dissolve quickly, so that the use of free air bubbles cannot enhance the contrast of the left heart image. Meltzer ·, R.S., Tickner, E.G., Popp, R.L., " Why Do the Lungs Clear Ultrasonic Contrast? &Quot; Ultrasound l n Medicine and Biology, vol. 6, p. 263, 267 (1980). However, it is recognized that defoaming is used as a contrast enhancer because of its large scattering cross-section. The advantages that can be obtained are focused on the stable, foam-containing mixture in the solution. The stability can be increased in various ways. The following technologies mainly involve the suspension of the defoaming collection in the matrix. When the bubbles are in this matrix, they are more stable than in the bloodstream. In one method, a full bubble is generated in the liquid in the sticky cabinet, which is injected or infiltrated into the body during the ultrasound diagnosis. Using the theory behind the sticky fluid, Meng tried to slow down the rate at which the gas skeleton dissolves into the liquid, and in doing so, it provides a more stable chemical environment for the bubbles, thus extending its life. I have explained several variations of this strategy. EP0 Shenye Case No. 0324 938 states that it contains a viscous solution of microbubbles, biocompatible substances (eg, human protein). The viscous protein solution is sonicated to form a full bubble in the solution. Partial denaturation of the protein by chemical treatment or heat can provide additional stability to the solution by reducing the surface tension between the air cooling and the solution. Therefore, the former method can be categorized as: Trying to use it which contains a complete bubble, please (please read the precautions first and then write a copy of the f affix · order · line < this paper ruler A side uses the middle a Ming family sample Standard (CNS) T4 specifications (210X297;?! :) 81. 7. 20,000 sheets (Π) 210957 Ministry of Economic Affairs: Biography:? A Gongxin «· Cooperative Duin 51 V. Description of invention () Qualitative media Improve the stability of the bubble. However, no method has pointed out the main physical and chemical properties of the gas, and its weight limits the free and complete bubbles for ultrasound diagnosis, especially for the diagnosis of cardiovascular strips. There is no method proposed : The gas is selected according to the exact standard, and it can be allowed to pass through the lungs, enhance the contrast of ultrasound imaging, and the size of the production is stable. The Xie bubble is the performance of the solution, which can be based on the gas generated by the bubble and the presence of the bubble. Some parameters and characteristics of the solution are described by mathematical formulas. Depending on whether the solution is saturated to generate the gas for defoaming, the survival time of defoaming can be skipped. Ps Epstein, MS Plesset, ”On the Stability of Gas Bubbles in Liquid-G As So 1 -U ti 〇nS, " Th p. Journal of Phvsins · Vo 1.18, n. 11, 1505 (195 <?) e From this calculation, it is obvious that as the bubble decreases, the bubble and surrounding The surface tension between the solutions increases. As the surface tension increases, the speed at which the bubbles dissolve into the solution increases rapidly. Therefore, the shrinkage of the bubbles becomes faster and faster. Thus, the shrinkage rate of the bubbles accelerates as the gas shrinks. The final effect is ordinary A group of small free air composed of air releases bubbles and dissolves quickly, so the contrast enhancement effect is extremely short-lived. Using known mathematical formulas, calculate the 8-meter-diameter air bubbles (small enough to pass through the lungs), depending on Depending on the saturation of the surrounding solution, it will dissolve between 190 and 550 milliseconds. Medical researchers studying the way in which lung ultrasound removes ultrasound contrast agents, based on these calculations, calculate the gas and nitrogen to be defoamed in human blood and dog blood The dissolution time comes down to: because the II life of the bubble removal is too short, the free bubble removal will not allow the contrast imaging of the tb agent to be enhanced in the ventricle. The physical properties of the special system of bubbles or gas dissolving in the liquid solution have been detailed. -I (please read ift first And the precautions # fill in this one 1, install. Thread · line-the size of this paper is used in the BB home «Bi (CNS) T4 specifications (2 丨 0X297 public; it) 81. 7. 20.000ft (II) • 16 -210957 Λ 6 Η 6 Ministry of Economic Affairs, Bureau of Economics, Biyang, Bureau of Industry and Commerce «-Cooperative Printing M. V. Description of the invention () plus research, including the cavityized flow of the generated bubbles diffused into the liquid, and light and sound in the water Bubble scattering. The stability of air bubbles in liquid-gas solution has been theoretically studied in Epstein PS and Plesset MS, On the Stability of Gas Bubbles in Liquid-Gas Solutions, J. Chen. Phys. 18 · 1505-1509 (1950) and experiments , Yang WJ, Dynamics of Gas Bubbles in Whole Blood and Plasma, "J. Biomech 4: 119-125 (1971); Yang WJ, Echigo R ·, Wotton DR, and Hwang JB, Experimental Studies of the Dissolution of Gas Bubbles in Whole Blood and Plasma-I, Stationary Bubbles. J. Biomech 275-281 (1971); Vang WJ, Echigo R., Wotton DR, Hwang JB, Experimental Studies of the Dissolution of Gas Bubbles in Whole Blood and Plasna-II. Moving Bubb-les or Liquids. JBiomech 4: 283-288 (1971). The physical and chemical properties of liquids and gases determine the dynamics and thermodynamics of the system. The chemical properties of the system that affect the stability of the bubble, and therefore its life, are: the rate and extent of reaction that can be consumed, transformed, or produces gas molecules. For example, when carbon dioxide gas is present in water, there is a well-known reaction between gas and liquid. As the gas dissolves into the aqueous solution, the two gasification gas hydrates to produce sulfonic acid. Because the dioxide is easily soluble in water, the gas quickly diffuses into the solution, and the bubbles shrink rapidly. The presence of a master acid in the solution changes the acid-alkali chemistry of the aqueous solution; when the chemical nature of the solution is changed by the gas dissolution, the two gases (please read the precautions first and save the writing book-賞 · line · The size of this paper is used in the National Beta (CNS) Xuan 4 specification (210x297 male dragons) 81. 7. 20.000iit (II) Λ 6 Π 6 210957 V. Description of the invention () The stability of chemical bubbles changes with the solution Saturated and changed. In this system, the dissolution rate of bubbles depends partly on the concentration of the second gasification gas dissolved in the solution. However, depending on the specific gas or liquid present in the body strip, the gas is large Fishy does not dissolve in liquid, and bubbles dissolve more slowly. In this case, it is found that by checking some physical parameters of the gas, the stability of bubbles in the gas / liquid system can be calculated. The simple description of the invention 'can be identified Among them, the extremely small bubbles are not reactive chemical systems in aqueous solution. Relying on the method shown in the article, the industry can choose specific gases based on the physical and chemical properties used in ultrasound imaging. These gases can be used to produce enhanced This medium is also the subject of the present invention. Defoaming can be produced using some existing technologies of ordinary air, and can be infiltrated like conventional ultrasound diagnosis. The method requirements of the subject of the present invention conform to the equations provided herein, Calculations are based on the essential physical properties of gases and liquids. In particular, the density of gaseous alcohol, the solubility of gas in solution, and the pseudo-number of gas diffusion in solution (which is related to the molar volume of gas and the viscosity of solution) are used in the following The equation shown here. So. By the method shown in the article, the physical properties of a specific gas-liquid system can be evaluated, and the rate and degree of bubble collapse can be estimated. Based on the calculated value, the constituent gas of the effective contrast enhancer can be selected. Use the current technology. It can produce a substantially improved contrast enhancer, and is used to improve the quality and use of ultrasound imaging. Development: > _Detailed description of this paper standard for easy use Η Η 家 «Bi (CNS) TM specifications (2 丨 0 father 297 Gonglong) (Please read the precautions first and then write the first book. 装-线 · The Ministry of Economic Affairs, Ministry of Economic Affairs, Employee Approval, and the Cooperative Cooperative printed 81. 7. 20,000 copies (I I) Detailed 95. V. Description of the invention () Λ 6 Π 6 To understand the method of the present invention. The mathematical formula can be deduced. The formula describes the parameters of the gas-liquid mixture and when one or more of the parameters change, The effect on the stability of the bubble W. Assuming the initial T., the spherical bubble of the gas X of the radius R. is placed in the solution, and the initial concentration of the gas X dissolved in the solution is equal to zero. After a period of time, the bubble X dissolves into the solvent In this case, the bubble radius R is zero. It is further assumed that the solution is at a constant temperature and pressure, and the dissolved gas concentration of the solution saturated with a specific gas is marked as cs. Thus. At T, the gas in the solution has a zero degree of gas, representing the gas None of them have been dissolved, and all the gas is still contained in the bubbles of radius Ro. Over time, due to the difference between the gas in the bubble and the solution, when the gas in the bubble is dissolved into the liquid by diffusion, the bubble shrinks. The bubble radius is changed from the original R〇 to a smaller radius R after a certain period of time. Pseudo-formula (1) is shown in Table 1. J? 2 DC. 1/2 *-One: (please read it first. And the precautions # 蜞 写 本 ί ,. installed. Τ-line · Ministry of Economic Affairs Benyang Standard Bureau s: Printed by Cooperative Society

In the formula, R is the bubble radius at time T, D is the diffusion pseudo-number of the specific gas in the liquid, and P is the density of the holding gas skeleton that makes up the bubble. R Set the time required for complete dissolution of R〇: Equation (2) and solve for T, which can be determined by equation (1).

ο P 2DC: 81. 7. 20.00〇 < k (H) ft ruler Λ edge of the original paper B B Jia Jia Bi (CNS) TM regulation «} (210Χ297 Gong *) -19- Λ 6 η 6

210 Fine-V. Description of the invention () The results obtained are indicated quantitatively: by increasing the initial bubble size R. , Or borrow a tool with higher density P, lower solubility in the liquid phase (:》, or lower diffusion pseudo-number D, can improve the stability of the bubble, thus extending its life. The number D 傜 depends on the molar volume of the gas (V „) and the viscosity of the solution (Π), as shown by the known equation, formula (3) D = 13.26X l〇-a ♦ η -1. 14 · V »-0… By substituting equation (3) D into equation (2), it shows that by using a gas with a larger molar volume V«> (and thus a higher molecular weight), and a liquid with a higher viscosity. It can improve the stability of air bubbles. For example, the stability of air bubbles can be compared with the micro-bubble composed of the gas specially selected by the method described in the article. Taken at 221 :, the D value of air in water is 2X10_scm * sec -1, and Cs / p ratio = 0.02 (Epstein and Plesset, same text), for the time t, to obtain a complete solution of air bubble in water (unsaturated with air), get the following resource: H_I (please read the back first Matters needing attention, please write a book and install it. Order &Line; Central Bureau of Standards, Ministry of Economic Affairs, Beigong Consumer Cooperative Cooperative Print 51 Bubble Initial Diameter Time _U_ ms sn 12 450 10 313 8 200 6 113 5 78 4 50 paper rulers / 1 using Chinese 戳 楳 准 (CNS) Ή specification (210x297 g; «:) 81. 7. 20.000 ^ (11) 210957 economy Printed by the Ministry of Education, Employee Promise and Cooperative Society V. Invention Instructions () 3 28 2 13 1 3 If the blood transition time from the lung blood vessel to the left ventricle is 2 seconds or more (Hamilton, WF editor, Handbook of Physiology , Vol. 2, section 2, CIRCULATION. American Physiology Society, Washington, DC, p. 709, (1963)), and recognize that only about 8w or less of the bubbles are small enough to pass through the lungs, obviously there are no bubbles in The life time in the solution is long enough to be used as a contrast agent for ultrasound contrast enhanced imaging of the left ventricle. The method of the present invention identifies the possibility by comparing the properties of a specific gas (marked as gas X in the following description) with air Useful gas. From equations (2) and (3) above, the equation for the number Q of the specific gas X can be obtained. Q describes the stability of the defoaming in the specific gas composed of the gas skeleton X. By this The Q value of the dung number determined by the method for a specific gas X can be used to measure that the gas skull X is relatively empty 3. Used as an ultrasound contrast enhancer. From the above formula (2), an equation can be written based on the physical properties of gas X and air, which shows that under the conditions of the same solution temperature and solution viscosity as the finished metal, gas X Compared with ordinary air bubbles of the same size, the time required to dissolve the gold is: Equation (4) Dair 13.2.6 X 10 · 5 · Qiao-1.1 *. D) ;. 589

Tx τ, air (please read the back-end notes first #fill in this li, install · book- -line <

Px (cs) air P air (C,) x The size of this paper uses the Chinese B home standard (CNS) Yu 4 specifications (210x297 g; «:) 81. 7. 20.000 sheets (II) 210957 Λ 6 Ιί 6 5 2. Description of invention () Or, if D of X is known, formula (5)

Tx = TalI-Px (Cs) air 'Dair Pair · (cs) x .〇χ. If you want to find the ratio, you can get the Q value, which is used to compare the gas X and the air: Equation (6) Τχ = QT air where Q • Px (^ s) air 'Dair .Pair. (Cs) x Dx ^ Assumed for comparison, 22 C water dissolves, the density, diffusion number, and solubility of air in solution are known quantities, which can be substituted into the above formula And get: formula ⑺ r Px ο = 4.0 X ΙΟ · 7 (please read the back-up notes first and then write the book 1 £, installed. Beigongxiao & Co., Ltd. 51 of the Central Bureau of Standards of the Ministry of Economic Affairs for the number of its diffusion For the gas that Dx is not easy to know, substitute equation (3) into the above equation, and assume that the viscosity term η of 22C water is approximately equal to l.〇cP, equation ⑻ r Px 〇 = 3.Ο x 10 L (c,) x (vj -.589 As such, knowing the density, solubility, and Chil volume of a gas, this method can calculate the pseudo Q value. If Q is less than 1, the gas X will bubble in a specific solvent, which is more bubble than air. More unstable. If Q is greater than 1. The micro-bubbles generated by the gas X are more than air-based paper ". The standard side is used in the Qu Qu Jia Jia Zhun (CNS) T4 specification (210x297 g; it) -22- 81. 7. 20,000 # | k (II) Ministry of Economic Affairs The Central Bureau of Standards only works on price reduction and cooperation Du Yin ^ M0352 _--- V. Description of invention () Defoaming is more stable and can survive longer in the solution. For a specific defoaming size, when all other properties are equal, the gas The time it takes for X to completely dissolve to dissolve is equal to the time for ordinary air to dissolve and completely dissolve multiplied by the pseudo-number Q. For example, if the Q number of gas X is 10,000, then the storage time of the gas X completely soaked in the solution It is 10,000 times longer than air bubbles. Assuming that the quantities listed in the text are known or can be estimated, the Q value of any gas in any solution can be determined. It depends on the chemical structure of the gas. Different methods are required To determine or estimate different parameter values such as density, diffusion rate, and solubility. These parameter values may or may not be obtained from known scientific literature sources, such as "Gas Encyclopedia M, or the table published by the American Chemical Society. Most The density values of gases are easily obtained from, for example, the following sources: the Handbook of Chemistry and Phvsirs. CRC Press, 72d Ed. (1991-92). In addition, the solubility in water and the molar volume of some gases have been correctly measured. However, ,many For example, it may be necessary to calculate or estimate the numerical calculation values of the volume and solubility of the pods, so as to provide information to determine the Q value of the different gases by the aforementioned method. An example of calculating the Q value for the selected preferred gas, The illustration illustrates how the method of the present invention is applied to different gases. In a nutshell, many kinds of gas containing "gas has very low solubility in water. It has a very high molecular weight, a high molar volume, and a high density. To determine the Q value of several gas hips, determine the solubility of individual gas, its ear volume, and density, and substitute each value into the above formula (7) or (8). Argon compound ^ Gas roll boundary: > Measuring the method to estimate the gas solubility of the Yinshuo compound, like using Kabalnov (please read ift first and note the following t and then write the book i, installation · order-line-this paper Λ ruler> ; 1 side with medium S Η family standard (CNS) * M specifications (210 father 29 / male dragon) 81.7. 20.000 sheets (II) W— ΙΛ ac 4- n- 6 6 Ministry of Economic Affairs Central Bureau Printed by employee cooperatives V. Description of invention () AS, Makarov KM, and Scherbakova OV, " Solubility of Fluorocarbons in Water as a Key Parameter Determining Fluorocarbon Emulsion Stability, " .1. Fluor. OiifijL. 50, 271- The experimental data of 284, (1990) is extrapolated. The gas solubility of these fluorochemical compounds is determined by comparing it with gold-fluoro-n-pentane. The water solubility of gold-fluoro-n-pentane is 4.0X10 · * mol / L For analogues of unbranched fluoromonomers, for each increase or decrease in the number of additional -CF〆 groups present in the molecule, a ratio of about 8.0 can be used to increase / decrease the ratio and estimate the gas solubility. G Β 体 蒱"Via" i% SBondiA., "VanderWaalsVolu-mes and Radii, " J. Phys. Chea. 68, 441-451 (1964). The molar volume of the gas skeleton can be estimated by identifying the number, type and type of atoms that make up the gas skeleton molecule of interest. By decision The number and type of atoms present in the molecule, and how the different atoms are combined, the known value can be applied to the molecular volume of the different atoms. By considering the contribution of individual atoms and their frequency of occurrence, a certain gas molecule can be calculated The total molar volume of this algorithm can be best verified by an example. It is known that the molar volume of one of the sulfonic atoms in the carbon-sulfonic bond of the alkane is 3.3 cm3 / mo 1 of the sulfonic atom in the olefin bond. The molar volume is 10. 〇cm3 / iaol .; When there are multiple gas atoms combined with the sulfon in the alkane, the molar volume of the atom is 6.0 (:! 113 / 111〇1. Examine the eight gas propane, This molecule contains 3 atoms (3 atoms is 3.3cm3 / mol.) And 6 atoms together with the alkane in the bond of the alkane-bond of alkane (6 original ih-first read the notes on the back. "Line paper" ruler; 1 Xiaozhong Zhongqu HJ «Zhong (CNS)« M specifications (210x297 g *) 81.7. 20.000 sheets (II) In the Ministry of Economy Printed by 想 准 扃 剃 工 工業 operative cooperatives Λ 6 -η _Η6_ V. Description of the invention () is 6.0cm3 / mol.) Therefore, the molar density of octa-H propane is 58cm3 / DO 1 · 〇 Once the density is determined, Molar volume and solubility can be calculated using the above equation (8). The following table lists the Q values calculated for various gases based on the calculations detailed above. Density Solubility Mohr Body QKk / jb3 amd / 1 am3 / mo \. Argon 1.78 1500 17.9 20 n-Butane 2.05 6696 116 5 Digasification Sulphur 1.98 33000 19.7 1 Decahydrobutane 11.21 32 73 13,154 Dodecanol Burning 12.86 4 183 207,437 Ethane 1.05 2900 67 13 Diethyl ether 2.55 977,058 103 0 Krypton 0.18 388 8 5 Hexabutane-1,3-diene 9⑷ 2000 56 145 Hexa-2-butyne 9⑷ 2000 58 148 Hexafluoroethane 8.86 2100 43 116 Hexacyanopropane 10.3 260 58 1299 Krypton 3.8 2067 35 44 Neon 0.90 434 17 33 Gas parts tt 捋 1 Octafluoro-2-butene 10⑷ 220 65 1594 The size of this paper is used by China B Jiayi Bi (CNS ) A 4 gauge failure (210X297 male dragon) 81. 7. 20.000 sheets (II) ............. · · · · · · · · · · · · · : Thread (please read the backing notes first # 埸 写 本), 210957 Λ 6 η 6 V. Description of the invention () Octafluorobutane 9.97 220 61 1531 Octafluoropropane 10.3 260 58 1299 Pentium 2 1674 113 58 Propane 2.02 2902 90 30 Six gasification sulfur 5.48 220 47 722 crystal 5.90 3448 18 28

* Density value is pseudo-estimated from the known density of similar compounds. ## The solubility / density ratio is 0.02 (see above) and the diffusion pseudo-number 2X10 ... closer · 1 · used in equation (7) to determine the Q value. Once the Q value is determined, the use of individual gases as ultrasound contrast enhancers can be determined by determining the life of the defoaming set composed of the gas under study in different sizes and sizes (as determined by air in Table I above) analysis. Take the Q value of decafluorobutane, and examine the time required for bubbles of different sizes to dissolve in water. Multiply each time value in Table I by the Q value of decafluorobutane to get the value in Table I: m_I, ζ 首 首 a 气 气 问 0 Please read the notes before you fill in # Fill in the line of the Ministry of Economic Affairs + Central Bureau of Economic Affairs and Employee Consumer Cooperative Print $ i 2 ο 1 1 8 6 5 4 3 9 9 4 5 7 1 9 6 4 2 1 1 This paper ruler A Xiaozhong Zhongqu Standard (CNS) TIM specification (210x297 g; ":") -26- 81. 7. 20.000 sheets (II) 210957 Λ 6 η 6 Ministry of Economic Affairs Printed by Dumplings and Cooperating with Consumers 5. Description of the invention () 2 2.9 1 0,7 Note that the time unit in Table I is minutes, not milliseconds as in the case of air. All decafluorobutane bubbles, all of which are less than 1μ /, can be injected from the periphery and will not dissolve in water for about 10 seconds required to reach the left ventricle. For gases with any Q pseudo-number, similar calculations can be made. Slightly larger air bubbles can pass through the lungs and remain there long enough to allow for both myocardial perfusion and dynamic abdominal organ imaging. Again, like many gases identified by this method, decafluorobutane has a low dose and low toxicity. Therefore, in the conventional ultrasound diagnosis, it can provide substantial advantages as a contrast enhancer. Several methods can be borrowed to manually generate the defoaming suspension. U.S. Patent No. 4,832,941 (the contents of which are shown and described herein for reference) describes a method for producing a microbubble suspension with a diameter of less than 7 meters by using a three-way gas nozzle to spray liquid through a quantitative gas . Although the actual technology can be different, the three-way gas nozzle is used to manually suspend the gas with a high quantitative Qiao number, and the preferred method for generating the medium for contrast enhancement described in this article. Regarding the general use technique of the three-way air nozzle device, it is well known to prepare the common Freund's adjuvant for immunization of research animals. A typical three-way air nozzle includes a pair of syringes, both of which are connected to a chamber. The chamber has an outlet. From the outlet, the suspension can be directly collected or infused. Because different gases are used in this process, the use of three-way gas nozzles can be different from U.S.P. 4,832,941. For example, if sweeping the system with ordinary air or flushing the system with another gas before generating the microbubble suspension, it may be more effective to use a gas with a high Q number shown in the text. (Please read the back to the precautions code first fill in this book ~ 装. Order · Thread · This paper "standard side use a β Jiayu standard (CNS) A 4 specifications (210x297; a ·) 81. 7. 20.000 Λ (II) Λ 6 Π6 Employed by the Ministry of Economic Affairs of the Central Bureau of the Ministry of Economic Affairs and Consumer Affairs Du Printed V. Description of the invention () In a preferred embodiment of the present invention, a 40-50% sorbitol (D-slucitol) solution, It is mixed with about 1-lOv% high pseudo-number Q gas, and about 5% of air is the best value. Sorbose is a compound commodity. When mixed into an aqueous solution, it can generally increase the viscosity of the solution. As shown in the above formula (3) ) As you can see, a solution with a higher viscosity can extend the life of the solution. 40-50% sorbose solution prefers to maintain a large dose during injection; in other words, it should be kept as complete as possible without exceeding the tolerable injection Pressure. To produce a thorough bubble suspension, collect the selected amount of gas in the syringe. The same syringe can contain a quantitative volume of sorbose fermentation solution. The quantitative sorbose fermentation solution is sucked into another syringe, so , The two volumes are combined and the appropriate gas percentage can be obtained Prevail) ^ Using these two syringes (with a very small hole for the ears), the number of liquid skulls sprayed into the gas atmosphere is about 25 times, or it is to generate a full bubble suspension (the size distribution of the micro bubbles is for the text) Acceptable for the purpose of the description) as many times as necessary. Of course, you want to obtain the microbubble suspension with the desired size at the desired concentration. This technique can be slightly changed. The size of the foam can be borrowed by known methods. , Butler, BD, ”Product ion of Hicrobubble for Use as Echo Contrast Agents, " J. Clin. Ultrasound. V.14 408, using Coulter counter (Cou 11 er Electronics Corporation), visually or electronically detected Ο EXAMPLES Example 1 Using decafluorobutane as a bubble generating gas to prepare an ultrasound contrast agent. Prepare a solution containing: (Please read the precautions first and then write this IX, install--line. This For paper scales, the Chinese Standard (CNS) TM specification (210 > < 25) 7 gongs; ":) 81. 7. 20.000¾ (II) 210957 Λ 6 η 6 V. Description of the invention (Sorbitose NaCl Soybean oil Tween 20

20.0g 0.9g 6. OmL 0.5mL 100.OmL Ministry of Economic Affairs Central Bureau of Industry and Commerce Beigongxiao «* Cooperative Society Print 3i Soap-like, transparent, yellow solution can be obtained by stirring. lOnl aliquot solution was drawn into a 10ml glass syringe. Then, the syringe was attached to the three-way stopcock. The second ΙΟβΙ injection was attached to the stopcock, and 1.0 cc ten gas butane (PCR Company, Gainesville, Florida) was sent to the empty syringe. Stop the stopcock to open the syringe containing the solution, and mix the liquid phase with the gas phase quickly 20-30 times. A milky white slightly viscous solution was obtained. Xuan Li P, the gas emulsion obtained in Example 1, diluted with water (1: 10 to 1: 1000), placed in a hemocytometer, and using an oil-immersed lens for explicit withdrawal microscopy. The emulsion mainly contains bubbles of 2-5 cm. The density is between 56 million and 100 million bubbles per ml of the original undiluted formulation. Fenxiu? Example 3 Preparation of the Suhua formulation of Example 1, and do echocardiography in dog mode. 17.51U Mongrel dogs are anesthetized with isoflu "ane, and according to Keller, MW, Fei-fi stein, SB, VI ats ο π, DD: S uccessfu 1 1 eftvent" icu 1 a "opacification following peripheral venous injection of sonicated contrast agents An experimental evaluation. Am Heart J 114: 570d (1987) establishes a monitoring system for measuring ECG, blood pressure, heart rate, and arterial blood gas as described in the method described above. The ft scale is used in a B Jiayu standard (CNS) T4 specification (210X297: «:) -29 ~ 81. 7. 20,000 sheets (II) 210957 A 6η 6 V. Description of invention () The evaluation results of safety are as follows ： Parameter measurement within five minutes after injection:> Xuanda Liao. Percentage m volume Φ ffl wrist hemp ifn Φ ffi. Skeletal heart beat ridge ® Shu Pao Jun Jun Pa02 Parn? _EH_ nun Hg O .SinL + 6, -14 +9, 0 + 8, -6 329 58.1 7.26 + 10 -19 1 OinL + 9, -2 + 5, -1 + 4, -4 +1, -4 2.0mL +5 , -3 + 5, -1 + 5, -1 0, -1 3 · OmL + 6, -2 +7, 0 + 4, -3 0, -3 4 * 0mL. + 5, -1 +3, -3 + 5, -3 0, -3 5. O mL 0, -10 + 1.-3 0, -4 +1, -1 7.OmL 0, -13 0, -δ 0, -9 313 28.6 7.36 0, -1 > I-(Please read the back first And the precautions should be re-installed and fixed-The Ministry of Economic Affairs Standard: The 3i gold changes printed by the Cooperative Cooperative Society are temporary, and typically return to the baseline value within 3-6 minutes. Validation: Changes in measured values of hemodynamic parameters are minimal. Each dose causes opaqueness of the lumen of the right and left ventricles. The intensity increases with increasing dose. Example 4 If the molecular weight of a particular gas is known, It can be calculated, or quantitatively known, that the ratio of suitability of the specific gas as an ultrasound agent can be estimated. This estimate is based on the logarithm of the measured Q value and the linear relationship between the molecular weight of the gas, as shown in the figure below. The size of this paper is for the use of the B Wai Family Sample (CNS) T4 specifications (210X297; «:) 81. 7. 20.000ife (ll) 21095 ^ V. Description of the invention (Λ 6 Π 6 1000000 100000 Q's estimated value 10000 1000 · 100 «~, (Please read the precautions first and then compose the book 1ί, 10-Ba Yi ^ · == — = J == —— ==== 5—

1SS £ —tSSSSSSSiiiiSSSSiSSSSSSSSSSSSSJJJi ^ SSSSSS ————— SSSSSS Packing-0 50 100 150 The molecular weight is based on this graph, and the following guidelines can be used to estimate the Q value: 200 250 300 Order · Line-Printed by the Employee Consumer Cooperative Cooperative Office of the Ministry of Economic Affairs Fractions 芊 卺 0 夕 伏 倌 < 35 < 5 35-70 5-20 71-100 21-80 101-170 81-1000 171-220 1001-10,000 221-270 10,001-100,000 > 270 > 100,000 The following table contains a list of gases. The higher the accompanying data such as molecular weight and Q estimate, the more promising this particular gas is. The unique hope is the Q value of the paper standard for the use of the SH home standard (CNS) > H regulations (210X297 public; ":) 81. 7. 20.000ίΜΗ) _31_ Λ 6 Π 6 2l〇95l7 V. Description of invention ( Please read ίή and pay attention to the gas greater than 5. When determining whether any specific gas is suitable for use as an ultrasound contrast agent, in addition to the derived defoaming (estimated by Q value) ringworm life, other discussion topics include Cost and Qin, but not limited to this. M__dz Molecular home Economics Standards Bureau of the Ministry of Economic Affairs, Beigongyang Cooperative Society Printed m 夂 _Q estimated acetone "six gas 166.02 81-1000 items reacetylene, isopropyl 68 5-20 written air 28.4 < 5 :: propadiene 40.06 5-20 propadiene, four gas 112.03 81-1000 k argon 39.98 5-20 borneol. Dimethyl, methyl gas 71.19 21-80 ίτ borneol, Trimethyl 55.91 5-20 m Boron dihydrate 103.84 81-1000 1,2-butadiene 54.09 5-20 1,3-butadiene 54.09 5-20 • ν 1,3-butadiene, 1,2,3-Trium 157.43 81-1000 1,3-butadiene, 2-gas 72.08 21-80 1,3-butadiene, 2-methyl 68.12 5-20-1,3-butadiene Ene Six gas 162.03 81-1000 butadiyne 50.06 5-20 n-butane 58.12 5-20 butane, fluorobutane, 2-methyl 76.11 72.15 21-80 21-80 This paper size is used in the home sample Standard (CNS) «M Regulations (210x297 public *) 81. 7. 20.000 sheets (||) Printed by the Ministry of Economic Affairs, Employee's Consumer Cooperative ^ 2109.S7 η 6 V. Description of invention () Butane, decafluoro 2 38.03 10,001-100,000 1-butene 56.11 5-20 2-butene {cis} 56.11 5-20 2-butene {trans) 56.11 5-20 1-butene, 2-methyl 70.13 5-20 1-butene, 3-methyl 70.13 5-20 2-butene, 3-methyl 68 · 5-20 1-butene, total gas 200.03 1001-10,000 2-butene, perfluorinated 200.03 1001-10,000 3 -Butene-2-one, 4-phenyl {trans} 146.19 81-1000 1-butene-3-yne, 2-methyl 66.1 5-20 butyl nitrite 103.12 81-100 butyyne 54.09 5 -20 2-butyne 54.09 5-20 butyne, 2-ambient-1,1,1,4,4,4-hexacyanogen 199 1001-10,000 butyne, 3-methyl 68.12 5-20 2-butane Alkynes, total gas 162.03 81-1000 butyraldehyde, 2-bromo 151 81-1000 digasification 44.01 5-20 carbonyl sulfide 60.08 5-20 crotononitrile 67.09 5-20 cyclobutane 56.11 5-20 Cyclobutane, methyl 70.13 5-20 Cyclobutane, octafluoro 200.03 1001-100,000 (please read the precautions before writing the book 1 |, installation · order · the size of the paper used in the SB Home Improvement (CNS) Ή Regulations (2 丨 0x297; ¢) _33_ 81. 7. 20.000ifc (II) __! 16 V. Description of the invention () Printed by the Cooperative Society of the Ministry of Economic Affairs 31 cyclobutane, gold gas 162.03 81-1000 cyclopentene, 3-atmosphere 102.56 81-1000 cyclopropanate 42.08 5-20 cyclopropanate, 1,2-dimethyl (trans, dl) 70.13 5-20 Cyclopropanol, 1,1-dimethyl 70.13 5-20 Cyclopropane, 1,2-dimethyl {cis} 70.13 5-20 Cyclopropanol, 1,2-dimethyl {trans, 1} 70.13 5-20 cyclopropionate, ethyl 70.13 5-20 cyclopropane, methyl 56.11 5-20 m 4.02 < 5 butadiyne 50.08 5-20 diaziridine, 3-ethyl-3-methyl 86.14 21-80 Zhongyi Hospital, 1,1,1-tri-gas 110.04 81-1000 dimethylamine 45.08 5-20 dimethylamine, six-gas 153.03 81-1000 dimethyl disulfide, six-gas 202,13 1001 -10,000 Dimethylethylamine 73.14 21-80 II- (Dimethylphosphino) amine 137.1 81-1000 2,3-Dimethyl-2-orphanol 140.23 81-1000 dimethylamine, gold gas 171.02 1001-10,000 atmosphere dimethyl gas, anchor 82.53 21-80 1,3-digas Wuyuan-2-one, 4-methyl 102.09 81-1000 ethane 30.07 < 5 Ethane, 1,1,1,2-Tetra gas 102.03 81-1000--(please read the notes on the back of the first # pot write this one, pack · order-line · the paper size is used in a National Standards (CNS) T4 specifications (2 丨 0X297; it) 81. 7. 20.000 sheets (II) 0 A ij 2 66 ΛΠ V. Description of invention () Ministry of Economic Affairs Standard fishing staff consumption cooperatives printed Μ B Alkane, 1,1,1-trigas 84.04 21-80 ethane, 1,1,2,2-tetrafluoro 102.03 81-1000 ethane, 1,1,2-trichloro-1.2,2-trifluoro 187.38 1001-10,000 Ethane, 1,1-Digas 98 21-80 Ethane, 1. Budi-1,2,2,2-tetrafluoro 170.92 1001-10,000 Ethane, 1,1-Digas-: 1-fluoro116.95 81-1000 ethane, 1,1-difluoro66.05 5-20 ethane, 1,2-digas-1,1,2,2-tetragas 170.92 1001-10,000 ethane, 1,2 -Diargon 66.05 5-20 ethane, 1-atmosphere-1,1,2,2,2-penta gas 154.47 81-1000 ethane ,. 1-atmosphere-1,1.2,2-tetragas 136.48 81-1000 Ethane, 2-atmosphere-1, 1, two-gas 100 21-80 ethane 2-Atmosphere-1,1,1 -Trifluoro118.49 81-1000 Ethane, Atmosphere 64.51 5-20 Ethane, Gas five gas 154.47 81-1000 Ethane, Di Atmosphere three gas 152 81-1000 Ethane, Fluorine 48.06 5-20 ethane, six gas 138.01 81-1000 ethane, nitro-pentamonium 165.02 81-1000 ethane, acetylidene-five 149.02 81-1000 ethane, all: gas 138.01 81-1000 ethylamine. Quan 171.02 1001-100,000 diethyl ether 74.12 21-80 B · A. Ether 60.1 5-20 (ίί? Read the notes beforehand Sun Guo's manuscript one dt install · order · line · this paper 5fc scale Xiaohua use the Chinese H family standard Bi (CNS) T4 specification (2 丨 0> < 297 male dragon) 81. 7. 20.000 sheets (II) 210957 V. Description of invention () Λ 6 Π 6 β Workers ’Co-operation with the Central Standards Bureau of the Ministry of Economic Affairs 51 Ethylene * Ethylene Ether 72.11 21-80 Ethylene 28.05 < 5 Ethylene, 1,1-diamine 96.94 21-80 Ethylene, 1,1-digas-2-gas 114.93 81-1000 Ethylene, 1,2- Diazo_1,2-difluoro132.92 81-1000 Ethylene, 1,2-digas 64 5-20 Ethylene, dinitrogen-1,2,2-trigas 116.47 81-1000 Ethylene, atmosphere trifluoro116.47 81 -1000 j > y — > Αφ, — 132.92 81-1000 ethylene, four 100.02 21-80 Methylenecyclopentadiene (fulvene) 78.11 21-80 気 4 < 5 1,5-heptadiyne 92.14 21-80 Hydrogen (η2) 2.02 < 5 Isobutane 58.12 5-20 iso Butane, 1,2-ring gas-3-atmosphere 106.55 81-1000 Isobutene 56.11 5-20 Isoprene 68.12 5-20 Krypton 83.8 21-80 Methane 16.04 < 5 Methanesulfonate, three gas 168.52 81 -1000 methanesulfonate, triargon 152.06 81-1000 methane, (pentaargonthio) trifluoro196.06 1001-10,000 methane, bromine digas nitroso159.92 81-1000 CNS) 肀 4 specifications (210x297 g; ϊ) 81. 7. 20,000 sheets (II) -36- 210957 V. Description of invention () The Ministry of Economic Affairs standard printed methane along the Gonggongye Cooperative Society, bromine fluoride 112.93 81- 1000 Th-methane, bromine-gas- «147.37 81-1000 first read methane, bromine-trifluoro 148.91 81-1000 read back methane, chlorine digas nitro 131.47 81-1000 Note methane, nitrogen dinitro 140.48 81 -1000 matters methane, chlorofluoride 68.48 5-20 then crucible% # methane, atmosphere three gas 104.46 81-1000 writing methane, chlorine two gas 86.47 21-80 Methane, dibromodifluoro209.82 1001-10,000 methane, dinitrogen gas 120.91 81-1000 k methane ,. two atmosphere-gas 102.92 81-1000 methane, two gas 52.02 5-20 ir methane. Two gas-iodine 177.92 1001- 10,000 -9 The first hospital, Ershayuan 76.25 21-80 The first hospital, gas 34.03 < 5 The first hospital, m 141.94 81-1000 methane, iodine-triple 195.91 1001-10,000 ft methane, nitro-trigas 115.01 81- 1000 methane, nitroso-trifluoro 99.01 21-80 * Acoustic methane, tetrafluoro 88 21-80 Jiayuan, three atmospheres 137.37 81-1000 methane, — * 2 m 70.01 5-20 sulfazonitrile, Jiayuan Trifluoro 2-methylbutane 136.52 72.15 81-1000 21-80 This paper is used in the edge of the paper aa Jiaju standard (CNS) Ή regulations (210x297 public goods) 81. 7. 20,000 sheets (11) -37- 210957 Λ 6 η 6 V. Description of the invention () The Ministry of Economic Affairs, the central government, and the employees of the Cooperative Society printed methyl ether 46.07 5-20 Please 'A · Isobutyl • Ether 74.12 21-80 First · Read! Methyl nitrite 61.04 5-20 read. Back · Methyl sulfide 62.13 5-20 · Note · Italian · A • Ethylene • Ether 58.08 5-20 Item · Neon 20.18 < 5 Sun 1 · Fill · Neopentane 72.15 21-80 write · Ben · > > «Nitrogen (Ns) 28.'01 < 5 Krypton oxide 1, 2, 3--19 Alkane tricarboxylic acid, 44.01 5-20 k 2-hydroxytrimethyl ester 500.72 > 100,000 1-nonene-3-yne 122.21 81-1000 ir oxygen (〇2) 32 < 5 ψ k 1,4-pentane Diene 68.12 5-20 n-pentane 72.15 21-80 pentane, gold fluoride 288.04 > 100,000 2-pentane, 4-amino-4-methyl 115.18 81-1000 pentene 70.13 5-20 2-pentane Enene {cis} 70.13 5-20 2-pentene {trans} 70.13 5-20 1-pentene, 3-mo 149.93 81-1000 1-pentene, perfluorinated 250.04 10,001-100,000 phthalic acid, four atmosphere 303.91 > 100,000 accounts, 2,3,6-trimethyl 127.23 81-1000 The standard size of the paper is used in a standard (CNS) T4 specification (210X297; tt) 81. 7. 20.000 sheets (II) — 38_ 伦 10〇957 V. Description of invention () Λ 6 Π 6 The Ministry of Economic Affairs, Pyongyang quasi-advised to persuade A to work on price reduction cooperation Du Yin 5Ϊ. Propane 44.1 5-20 Propane, 1,1,1,2,2,3- Six gas 152.04 81-1000 propane, 1,2-epoxy 58.08 5-20 propane, 2,2-two gas 80.08 21-80 propane, 2-amino 59.11 5-20 propane, 2-atmosphere 78.54 21-80 propane, t-nitro-nitro 215.03 1001-10,000 propane, t-fluoro-1-nitroso 199.03 1001-10,000 propane, gold argon 188.02 1001-10,000 propylene 42.08 5 -20 propyl, 1,1,1.2,3,3-hexagas-2,3-dichloro221 10,001-100,000 propylene, 1-atmosphere 76.53 21-80 propylene, 1-gas_ {trans) 76.53 5- 20 propylene, 2-atmosphere 76.53 5-20 propylene, 3-gas 60.07 5-20 propylene, gold gas 150.02 81-1000 propyne 40.06 5-20 ^ propyne, 3,3,3-tri® 94.04 21-80 benzene Ethylene, 3-Gas 122.14 81-1000 Hexaargon Sulfur 146.05 81-1000 Sulfur (di), decafluoro (Sdu) 298 > 100,000 Toluene, 2,4-diamine 122.17 81-1000 Trigas B 1 Yu 95.02 21-80 Three gas methyl peroxide 170.01 81-1000 This paper standard is used in the 8 national standard (CHS) T4 specification (210x297 g; «:) 81. 7. 20.000 sheets (II) aia957 Λ 6 η 6 5 3. Description of the invention (

Trifluoromethyl sulfide 170.07 81-1000 Hexamicron 298 > 100,000 Ethylene propyne 52.08 5-20 Vinyl ether 70 5-20 Mi 131.29 81-1000 Audit R R Ministry of Economics + Central Standards Bureau Employee Digest Cooperative Print the relationship between the calculated Q value of a specific gas and the degassing duration of the gas, and study to determine which Q value can be used as the lower limit of ultrasonic contrast agent. In the experiment, the 190 × 100ππη Pylex (No. 3140) evaporating dish was filled with about 2000®1 37C water. 5ml of 20% sorbitan solution is drawn into the lOinl syringe, which is connected to a bow tee to stop the cock. _2cib3 10ml syringe of subject gas (or suitable low boiling liquid such as chrysanthemum). Attached to the syringe containing sorbitol solution. Sorbitol is quickly mixed with gas or liquid 25 times to produce a defoaming suspension or a uniform liquid, and then quickly added to the water. The size of the through-bubble obtained by this method is usually about 100 w; if the through-bubble is composed of air, the calculated value of the durability is 31 seconds (0.5 minutes). Before, during and after the addition of ultrasonic scanning, like using the HP model Sonos 500 ultrasonic scanner. Operating at 5MHz. Record the observed time to remove the bubble. The results are included in Table V below. Divide the measured value of the durability of the air by the measured value of the durability of the specific gas to obtain the experimental value of Q. Boom __V The relationship between the Q value of the gas and the endurance of the defoaming-M__Mission_ The endurance of the Q value (calculated) (π 質 credit) 1 Read the price first, then the precautions before writing the binding book Chi Cen Xiao used in the Β H home standard (CNS) Ή specifications (210x297 public; !! :) 81. 7. 20.000¾ (11) 21095? A 6 Η 6 V. Description of the invention (diethyl ether 0.1 0.1 mi η (0 2) Air 1 0.6 ra i η (1 0) Butane 5 1.5 mi η (2 · 6) Gas 5 2.0 min (3,5) Propane 30 3.2 min (6 * 0) Penthouse 58 20.6 rain (36 ) Dodecanocyanate 207,437 > 5760 min (> 10,105) The test indicates that the calculated Q value is in good agreement with the experimental value. Based on these materials, the gas with the calculated Q value greater than 5 can be used for ultrasound imaging Contrast agent first read iit. Contrary to the above>% of ideas. Installed by the Ministry of Economic Affairs and the Ministry of Economic Affairs and Quarantine Bureau ts: industrial elimination cooperation to print the material state of a specific chemical entity with a high pseudo-number Q, and its use as a super The use of sonic contrast agents and the relationship between them are tested by comparing the efficiency of gold "pentane and total gas hexane as ultrasonic contrast agents. Full gas pentane (dodecyl fluoride劸) The Q value of the number Q is 207,437, and the boiling point under standard pressure is 29.510. The pseudo-number Q of the total «hexane (PCR company, Zuoen Luo, Florida) is 1,659.496, and The boiling point under standard pressure conditions is 59-60C. Therefore, at a human body temperature of 37 ° C, full pentane is a gas, and gold is hexane as a liquid. At 4C, intense homogenization generates full gas pentane and full gas hexane. Aqueous homogenous dispersion solution (2% w / v). Prepare a plastic cup containing about 1000ml of 37C water to simulate human blood, and before and after adding the samples of each of the homogenization solution as above, as shown in Example 5 above, for ultrasound Scanning. Less than 1.0ml of gold fluoropentane homogenous dispersion, when mixed with the simulated blood, the line-up paper "rule Λ Xiao Yongzhong BB's" Bi (CNS) < fM regulation (210x297 g; tt) -41-

81. 7. 20,000ife (ID η Λ 6 η 6 V. Description of the invention (It can produce a very bright ultrasonic doubling, this doubling lasts at least 30 minutes. 1: 10,000-fold dilution can still be detected. On the contrary, The sample of 1.0ml perfluorohexane homogenous liquid cannot be detected by ultrasonic scanning under the same conditions, even the ΙΟπΙ sample (dilution of 1: 100). It is concluded that the high common number Q, and the scanned Organisms are in two gaseous conditions at body temperature, which is a substance that is effectively used as an ultrasonic contrast agent according to the method of the present invention (the subject of the present invention). Although the present invention has been described in some aspects with reference to specific examples, industry professionals It will be obvious that the changes and modifications are easy to understand. Therefore, the scope of the patent application below shall not be interpreted as limiting its scope, but shall be deemed to cover the changes and modifications derived from the subject matter of the present invention shown. The invention allows people in the industry to determine whether various chemicals are suitable for use as ultrasonic contrast agents when they obtain density, solubility, and Molar volume data. Ih- Read the notes on the backside · Item Code 丨, fill in this stomach Binding line Ministry of Economic Affairs ΨCentral Bureau of quasi-bureaucratic staff cooperation cooperation Du Yinyin This paper standard is easy to use in a sleepy home standard (CNS) T4 specification (210x297 male dragon) 42- 81. 7. 20,000 sheets (II)

Claims (1)

Printed by the Staff Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, 210957 at B7 C7 --- ~~~ ___ D7_ VI. Patent application 1. A contrast medium for ultrasound imaging enhancement, including organisms with Q pseudo-number greater than 5 The complete bubble generated by the compatible gas skeleton, where Q = 4.0X 10 · 7 X p / CsD and (〇 is the density of the gas (KgnT3), Cs is the solubility of the gas in water Μ, and D is the gas skeleton in the solution The number of diffusion coefficients (era3 seC_M. 2. Contrasting medium as claimed in item 1 of the patent scope, including a suspension of bubbles less than 8 w in a biocompatible aqueous medium. 3. If applying for patent item 1 Contrast media, where the gas gangue is six non-sulfurized sulfur. 4. For example, the contrast media of the first patent application, the gas is six «propylene. 5. For the contrast media of the first patent application, of which The gas is octa-gas propane. 6. If the contrast medium of patent application item 1, the gas is hexafluoroethane institute. 7. If the contrast medium of patent application item 1, the gas is octafluoro-2- Butene. 8. For example, the contrast medium of the first patent application, in which The gas is hexafluoro-2-butanil. 9. If the contrast medium of the patent application item 1, the gas is hexafluorobutane-1,3-diluted. 10. If the patent application item 1 comparison media , The gas of which is octafluorocyclobutane. The size of this paper is suitable for Wawa Family (CNS) Ψ4 specifications (210x297 public goods) (please read the precautions on the back and then this page) • 笟. • ·· Green · rtf · 5 9 10 2 AB c D 6. Apply for a patent Fan Garden 11. For example, if the patent application scope item 1, the gas is decafluorobutane. 12. If the patent application scope item Contrast medium in item 1, where the gas is dodecane pentane. 13. A method for selecting the gas used for ultrasound image enhancement, including the following steps: Determine the solubility of the gas in solution Cs; Determine the density of the gas P; Determine the diffusion number of gas skulls in solution D; Calculate the Q pseudo-number, where Q = 4.0X ΙΟ'7 X p / CcD and select the gas with Q 庳 number greater than 5. 14. If applying for patent number 13 The method of item, where the diffusion of the number D pseudo pseudo use the following formula, from the gas Moore product ν · α Measure D = 13.26X ΙΟ * 9 · η -1 '14 · VM- ° · aa3 where τ) is the viscosity of the solution (cP). (Please read the precautions on the back before filling this page). Pack. Economy The paper printed by the Ministry of Standards and Staff's Consumer Cooperative is suitable for printing. The paper is suitable for the valve ip4 specification (210x29 " ^ vii)