JPH0235727B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to an ultrasound diagnostic contrast agent comprising a perfluorocarbon emulsion that does not accumulate in the body and has low toxicity. [Prior Art/Problems to be Solved by the Invention] Ultrasound imaging (contrast echo method) involves injecting a contrast agent into blood vessels from peripheral blood vessels to visualize the heart and blood within the blood vessels during ultrasound examination of the heart. This is an inspection method performed for the purpose of obtaining information regarding flow. In other words, it corresponds to a cardiovascular angiography test in the form of an X-ray test. This imaging method is clinically very useful and can detect shunts, blood flow direction, blood flow velocity,
A wide range of applications can be considered in analyzing information related to hemodynamics such as blood flow patterns. Conventional contrast media include physiological saline, 5% sugar solution, autologous blood, and indocyanine green (ICG).
etc. are used, but no matter which substance is used,
In 100% of cases, it is not possible to produce a satisfactory contrast echo, and there are cases in which a good contrast echo does not appear, or in which it quickly stops appearing after several repetitions. Although it is very useful clinically, it has little diagnostic meaning if a satisfactory contrast echo does not appear, and therefore, at present, this test method does not produce a satisfactory contrast echo in all cases. This has become a major obstacle. In addition, the contrast echo using the above-mentioned contrast agent currently in use is
It cannot pass through the capillaries of the lungs and usually does not appear in the left heart system, but if a substance that causes contrast echoes to appear in the left heart system is found,
It is expected that it will greatly contribute to non-invasive diagnosis. Therefore, the first object of the present invention is to provide an ultrasonic diagnostic contrast agent that can always produce satisfactory contrast echoes. A second object of the present invention is to provide an ultrasonic diagnostic contrast agent that also passes through the capillaries of the lungs and produces contrast echoes in the left heart system. Other objects of the invention will become apparent from the description below. [Means for Solving the Problems] In order to improve contrast agents in accordance with these objectives, the present inventors conducted various studies, discovered the use of perfluorocarbon as a contrast agent, and completed the present invention. Ivy. That is, the present invention aims to provide an ultrasonic diagnostic contrast agent comprising an emulsion of perfluorocarbon (hereinafter collectively referred to as PFC). One embodiment of the present invention has 6 to 12 carbon atoms.
PFC, at least one emulsifier selected from phospholipids, hydrogenated phospholipids, and polymeric nonionic surfactants with a molecular weight of 2,000 to 20,000, and if the emulsifier is the above-mentioned surfactant, phosphorus as an emulsification aid. Contains lipids and has a particle size of 0.05 to 0.4μ
The present invention relates to an ultrasound diagnostic contrast agent comprising an emulsion of PFC of m. Furthermore, in another embodiment of the present invention,
It is preferable to contain a fatty acid having 6 to 22 carbon atoms, a salt of the fatty acid, and a monoglyceride of the fatty acid as an emulsifying agent, and when the emulsifying agent is a phospholipid, a physiologically acceptable antioxidant. It is preferable to contain. The PFC used in the present invention has 6 to 6 carbon atoms.
A fluorocarbon containing 12 atoms and no hydrogen atoms, and one that does not accumulate in organs such as the liver and spleen is used. As the PFC, for example, two or more types disclosed in Japanese Patent Application Laid-Open No. 52-96722.
Compositions of PFC, PFCs having 9 to 11 carbon atoms disclosed in Japanese Patent Publication No. 53-31209, perfluorocyclohexylpyrrolidine compounds disclosed in Japanese Patent Application Publication No. 59-39870, Japanese Patent Application Publication No. 58-225013 Perfluorodecahydroquinoline compounds disclosed in JP-A-59-46218, perfluorooctahydroquinolidine compounds disclosed in JP-A-59-46218, and the like are also suitably used. However, PFC is not limited to these, and by using an appropriate emulsifier, the particle size can be reduced to 0.05~
It is possible to prepare an emulsion with ultrafine particles of 0.4 μm, and it can be used as long as it does not accumulate in the liver or spleen. The phospholipid used as an emulsifier is preferably egg yolk phospholipid or soybean phospholipid, and the hydrogenated phospholipid is preferably one derived from the above-mentioned phospholipids. Polymeric nonionic surfactants have a molecular weight of
2,000 to 20,000, such as polyoxyethylene/polyoxypropylene copolymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, etc. Fatty acids used as emulsification aids are those having 6 to 22 carbon atoms, such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, palmitoleic acid, oleic acid, linoleic acid, arachidonic acid. Examples include. Further, as the salt of the fatty acid, preferably used are alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, etc. of those specifically listed above. Furthermore, monoglycerides of the fatty acids listed in the above specific examples are preferably used as monoglycerides of the fatty acids. Also, as a phospholipid as an emulsification aid,
Preferably, egg yolk phospholipids and soybean phospholipids are used. The physiologically acceptable antioxidant used in the present invention preferably includes vitamin E. The composition ratio of each component in the contrast medium according to the present invention is preferably PFC5 to 50 w/v%, emulsifier 2 to
6w/v%, and if necessary, emulsification auxiliary
0.01~0.1w/v% and antioxidants if necessary
It is preferably 0.002 to 0.006 w/v%. The contrast agent of the present invention is produced, for example, as follows. That is, in a predetermined amount of a saline solution such as physiological saline or lactated Ringer's solution, 2 to 6 w/v% of an emulsifier, if necessary, 0.001 to 0.1 w/v% of an emulsifying adjuvant, and if necessary, 0.002 to 0.006 w/v%. v% of an antioxidant is added to coarsely emulsify, and PFC is added to this rough emulsion so that the final content is 5 to 50w/v%,
A coarse emulsion is prepared by stirring with a mixer, and the coarse emulsion is homogenized with an emulsifier so that the particle size becomes 0.05 to 0.4 μm, thereby producing an emulsion of ultrafine PFC particles. In the above method, particles larger than 0.4 μm are not substantially formed, but
In order to remove particles larger than 0.4 μm,
After preparing the emulsion, a centrifugation operation may be added.
The emulsion of the PFC is preferably a physiological aqueous solution,
For example, NaCl 3-7%, CaCl ₂ 0.15-0.4%,
_MgCl2 0.1-0.5%, D-glucose 0.7-2.0%,
The tonicity is adjusted physiologically with a hypertonic electrolyte solution consisting of 0.3-0.5% KCl and 2-4% NaHCO ₃ . The contrast agent of the present invention thus provided can be applied to ultrasound imaging of blood flow patterns and the like. The administration method is to inject it into an artery or vein depending on the type of contrast area. The amount to be used is usually 0.5 to 5 ml at a time, and the one-time amount of PFC used is rapidly injected using 5 ml of 5% sugar solution, usually using an indwelling needle with a three-way stopcock. According to the contrast agent according to the present invention, an extremely high-quality contrast echo with fine particles can be obtained as shown in FIG. 1 described later. Furthermore, the so-called "habituation phenomenon" observed with ordinary contrast agents was not observed in any of the cases even after repeating the test 5 to 10 times. Figure 2 shows the same case 10 times.
This is an echo diagram obtained when contrast echo was repeated using Fluosol-DA (a mixture of perfluorodecalin and perfluorotripropylamine, manufactured by Midori Juji Co., Ltd.; hereinafter referred to as F-DA). Good quality contrast echoes with almost no change were observed. [Example] Hereinafter, the method for producing the ultrasonic diagnostic contrast agent according to the present invention will be described in more detail with reference to Examples. Example 1 300 g of polyoxyethylene polyoxypropylene copolymer (molecular weight 8350) was dissolved in 88 g of distilled water,
This solution contains 3 kg of perfluorodecalin, 300 g of perfluorotripropylamine, and 40 g of soybean oil phospholipid.
A mixed perfluorocarbon containing 2 g of potassium oleate and 2 g of potassium oleate was added thereto and stirred with a mixer to prepare a rough emulsion. This rough emulsified liquid is put into the liquid tank of a jet emulsifier (manufactured by Manton-Gorlin) and circulated.
Emulsification was carried out under high pressure of 200 to 500 kg/cm ² while maintaining the liquid temperature at 55±5°C. The concentration of perfluorodecalin in the resulting emulsion was 30.5% w/v, and the concentration of perfluorotripropylamine was 2.9% w/v.
The average particle diameter measured by centrifugal sedimentation is 0.09
The particle size was ~0.1 μm, and no increase in particle size was observed even when the particles were dispensed into injection vials, capped, placed in a rotary sterilizer, and heat sterilized at 115° C. for 12 minutes. The average particle size of the emulsion after sterilization is 0.097 μm,
Even after storage at 4°C for 6 months, no coarsening of the particles was observed and the average particle diameter remained almost unchanged. Example 2 Add 400 g of egg yolk phospholipid and sodium palmitate to 8.5 kg of lactated Ringer's solution, stir with a mixer to prepare a rough emulsion, and add 2.5 kg of perfluoro-N-methyldecahydroisoquinoline to this.
was added and further stirred vigorously with a mixer to prepare a rough emulsion. This rough emulsified liquid is circulated in the liquid tank of a jet emulsifying machine (manufactured by Manton-Gorlin), and the liquid temperature is
Emulsification was carried out while maintaining the temperature at 50±5°C. The concentration of the PFC compound in the resulting emulsion was 27.3% w/v.
Particle size measured by centrifugal sedimentation method is 0.05~
The particle size was 0.25 μm, and no significant increase in particle size was observed even when the particles were dispensed into injection vials, capped, and stored in a rotary sterilizer for heat sterilization. Example 3 Add 400 g of egg yolk phospholipid and 4 g of sodium palmitate to lactated Ringer's solution, mix with a mixer to prepare a rough emulsion, and add to this solution.
2.5 kg of PFC compound (perfluoro-4-methyloctahydroquinolidine) was added and further stirred vigorously with a mixer to prepare a crude emulsion. This crude emulsified liquid was placed in a liquid tank of a jet emulsifying machine (manufactured by Manton-Gaulin) and circulated, and emulsification was carried out while maintaining the liquid temperature at 50±5°C. The concentration of the PFC compound in the resulting emulsion was 27.3% w/v. The particle size measured by the centrifugal sedimentation method is 0.05 to 0.25 μm, and the particle size does not significantly increase even if the vial is dispensed into an injection vial, capped, stored in a rotary sterilizer, and heat sterilized. was not accepted. Example 4 Add 400 g of egg yolk phospholipid and 4 g of sodium palmitate to lactated Ringer's solution, mix with a mixer to prepare a rough emulsion, and add to this solution.
2.5 kg of PFC compound (perfluoro-N-cyclohexylpyrrolidine) was added and further stirred vigorously with a mixer to prepare a crude emulsion. This crude emulsified liquid was placed in a liquid tank of a jet emulsifying machine (manufactured by Manton-Gaulin) and circulated, and emulsification was carried out while maintaining the liquid temperature at 50±5°C. The concentration of PFC compounds in the resulting emulsion is
It was 27.3w/v%. The particle size measured by the centrifugal sedimentation method is 0.05 to 0.25 μm, and the particle size does not significantly increase even if the vial is dispensed into an injection vial, capped, stored in a rotary sterilizer, and heat sterilized. was not accepted. Experimental example Eight anesthetized adult dogs were placed in a supine position and echocardiograms were recorded from the anterior chest wall. Ultrasound diagnostic equipment is M-mode echocardiogram,
A SystemUCG polygraph manufactured by Irex was used, and SSH-11A manufactured by Toshiba Medical Corporation and SSD-710 manufactured by Aloka were used for cardiac tomographic echocardiography. A 23G winged needle is placed in the vein of the forelimb while the patient is in a supine position, and connected to a three-way stopcock. (In two cases, a 7F catheter was inserted into the inferior vena cava from the femoral vein, and a three-way stopcock was connected to the catheter).
A disposable emulsion (in this example, the emulsion prepared in Example 1, i.e., (F-DA)) that had been bubbled with air was placed in one side of the three-way stopcock, and a 5% glucose solution was placed in the other side. Put it in a syringe and connect it. 5% glucose solution is always 5
ml, and F-DA was compared between 1 ml and 5 ml. Using an ultrasound diagnostic device, an M-mode echocardiogram mainly uses a beam direction that passes through the right ventricular outflow tract, aorta, and the left atrium (RAL direction), and a tomographic echocardiogram mainly uses a four-chamber vibw beam.
While observing, first, quickly inject F-DA, then operate the three-way stopcock to inject 5% glucose solution as rapidly as possible. Record M-mode echocardiograms using a strip chart with a paper feed speed of 50 mm/sec.
The echocardiograms were recorded on videotape using a recorder. Results: In 8 out of 8 cases (100%), the appearance of extremely high-quality contrast echoes with fine particles and uniform size was observed (see Figure 1 and Table 1).

〔Effect of the invention〕

According to the ultrasonic diagnostic contrast agent according to the present invention, the particles are fine and uniform in size, and extremely high quality contrast echoes can be stably produced. Furthermore, the contrast agent of the present invention can also pass through the capillaries of the lungs and cause contrast echoes to appear in the left heart system, and is highly safe because only a small amount is required.

[Brief explanation of drawings]

Figure 1 is a contrast echogram after administering 1 ml of F-DA, Figure 2 is a contrast echo diagram after administering 1 ml of F-DA 10 times, and Figure 3 is a control after 10 times of contrast administration with F-DA. FIG. 2 is a contrast echogram obtained with physiological saline. RVOT: right ventricular flow path, Ao: aorta, *: recorded in a region corresponding to the left atrium in humans;
In this case, it was confirmed by tomographic ultrasound that this site was part of the pulmonary artery.

Claims (1)

[Claims] 1. An ultrasound diagnostic contrast agent comprising a perfluorocarbon emulsion. 2. The emulsion contains at least one emulsifier selected from the group consisting of a perfluorocarbon having 6 to 12 carbon atoms, a phospholipid, a hydrogenated phospholipid, and a polymeric nonionic surfactant having a molecular weight of 2,000 to 20,000;
Furthermore, when the emulsifier is the above-mentioned surfactant, it contains phospholipid as an emulsification aid, and the particle size is
The ultrasonic diagnostic contrast agent according to claim 1, which has a particle size of 0.05 to 0.4 μm. 3. The ultrasonic wave according to claim 2, wherein the emulsion further contains at least one selected from the group consisting of a fatty acid having 6 to 22 carbon atoms, a salt of the fatty acid, and a monoglyceride of the fatty acid, as an emulsification aid. Diagnostic contrast agent. 4. The ultrasonic diagnostic contrast agent according to claim 2, wherein the emulsifier is a phospholipid and further comprises an emulsion containing a physiologically acceptable antioxidant.