JP2694342B2 - Contrast agent for CT scan - Google Patents

Description

TECHNICAL FIELD The present invention relates to a contrast agent for CT scan. In particular, it relates to a contrast agent for CT scan by a method of administering a contrast agent and utilizing the phagocytosis of the reticuloendothelial system of the liver.

[Problems to be solved by the prior art and the invention]

CT (computed tomograph)
y) A scan is a type of X-ray diagnostic apparatus, which applies X-rays from various angles to a plane that intersects the human body, reconstructs it using a computer, and forms an image. Since the results obtained by CT scan are excellent in objectivity and reproducibility, they occupy an important position in image diagnosis of various organs in the living body. However, it may be difficult to diagnose the diseased site by CT scan depending on the organ and the nature of the disease.

For example, some liver tumors are difficult to detect due to a small difference in absorption value from normal liver tissue even in a simple CT scan or a contrast CT scan using a water-soluble contrast agent. Especially, it is extremely rare to diagnose a liver tumor of 2 cm or less. As a method to enhance the diagnostic ability for liver tumors by CT scan, Dinamic CT by rapid intravenous injection of water-soluble contrast agent and Angio CT by intra-arterial injection of hepatic artery or superior mesenteric artery are performed, and CT scan accurately visualizes liver tumor Is being attempted. However, these methods are highly invasive and cannot be used as screening tests for liver tumors.

As another method, development of a tissue-friendly contrast agent has been attempted. In this method, a colloid having a high X-ray absorption value is intravenously administered to utilize the phagocytosis of the reticuloendothelial system of the liver. An emulsion of an oily contrast medium, liposomes containing a water-soluble contrast medium, and fine particles of barium sulfate are used. Crystals, perfluorooctyl bromide, have been reported to date. Among these, it is considered that the emulsion of the oil-based contrast agent can satisfy the essential conditions as a contrast agent that have few side effects, have good contrasting ability, and excrete rapidly. In the United States, clinical tests have already begun using an emulsion of an oily contrast medium, but this type of contrast medium called EOE-13 has poor particle stability and is limited to test use.

The present inventor focused on this oily emulsion and tried to image normal liver parenchyma using an emulsion of Lipiodol (Journal of the Medical Radiological Society, Vol. 44, No. 7, 988-991).
Page, 1984). This contrast agent succeeded in selective imaging of the liver and spleen, but the stability of the emulsion was poor, and the particles increased in size due to aggregation and fusion of particles with each other. Therefore, it could not reach clinical use.

In contrast, a contrast agent containing iodine necessary and sufficient to obtain a sufficient organ contrast is administered, but for the purpose of reducing side effects, the amount of iodine contained in a certain emulsion particle is increased to increase the contrast. It is necessary to reduce the dose of the drug.

Therefore, an object of the present invention is to provide a contrast agent for CT scan having low toxicity, particularly a contrast agent suitable for liver and spleen imaging.

Another object of the invention is to provide a highly stable CT of the emulsion.
It is to provide a contrast agent for scanning.

Still another object of the present invention is to provide a contrast agent for CT scan, which contains a larger amount of iodine in emulsion particles.

Still another object of the present invention is to provide a contrast agent for CT scan capable of diagnosing a tumor of 2 cm or less, especially a liver tumor.

[Means for solving the problem]

That is, the present invention provides a positive contrast agent for CT scan, which comprises an emulsion of a positive water-soluble nonionic contrast agent and a positive oily contrast agent.

The water-soluble nonionic contrast agent (hereinafter also referred to as a nonionic contrast agent) used in the present invention has a nonionic surface-active effect, is water-soluble, and contains an iodine atom in its molecule to provide contrast. There is no particular limitation as long as it has an action, and for example, a contrast agent containing a nonionic compound as a main component which is made water-soluble by binding a hydrophilic atomic group to an iodinated benzene nucleus is exemplified as a preferable example. Specific examples of such a nonionic contrast agent include iopamidol, iohexol, ioscimide, iopromide, iotrolane, etc., preferably iopamidol, iohexol,
An example is iotrolane.

When the nonionic contrast agent is a powder, it is used in the present invention after being dissolved in a suitable solvent (eg, distilled water for injection, an aqueous solution in a physiological electrolysis chamber). The iodine content in the aqueous solution of the nonionic contrast agent is preferably about 200 to 400 mgI / ml.

The oily contrast agent is not particularly limited as long as it is oily and contains an iodine atom in its molecule and has an imaging effect, and examples thereof include unsaturated fatty acids made into saturated fatty acids with iodine. Preferred is a vegetable oil or a vegetable oil fatty acid ester into which iodine is introduced, and examples of the vegetable oil include pharmacologically acceptable ones, such as poppy oil and sesame oil. Examples of the ester residue of the vegetable oil fatty acid ester include alkyl (preferably lower alkyl having 1 to 4 carbon atoms). Specific examples of the oil-based contrast agent include iodized poppy oil, iodized poppy oil fatty acid ethyl ester, and the like. Although the oily contrast agent is a slightly viscous liquid, it can be directly used in the present invention. In addition, when the viscosity is high, it may be dissolved in a physiologically acceptable vegetable oil (eg poppy oil, sesame oil) or the like, if necessary. The degree of iodination of the oily contrast agent depends on the iodine content.
20-60% by weight, preferably 30-50% by weight, particularly preferably about 40% by weight.

The specific gravities of the oil-based contrast agent and the nonionic contrast agent are preferably approximated from the viewpoint of stability during preparation of the emulsion or storage.

The contrast agent of the present invention is an emulsion composed of a water-soluble nonionic contrast agent and an oily contrast agent, and is a mode in which the nonionic contrast agent is adsorbed as a surfactant on the surface of the oily contrast agent.

In the contrast agent of the present invention, the mixing ratio of the nonionic contrast agent and the oily contrast agent is usually about 1 to 5 parts by volume, preferably 2 parts by volume of the oily contrast agent.
~ 4 parts by volume. If the compounding ratio is out of this range, the stability of the emulsion tends to deteriorate, and the oil-based contrast agent and the nonionic contrast agent tend to be easily separated, which is not preferable. Further, when the following stabilizers are added, the stability of the emulsion is not affected by the above compounding ratio, and even if it is in the range of 0.5 to 5.0 parts by volume with respect to 1 part by volume of the oily contrast medium, Although it is good, it is preferably 2 to 4 parts by volume in view of the iodine content in the emulsion particles.

It is preferable to add an emulsion stabilizer to the contrast agent of the present invention, and the stability of the emulsion is remarkably improved. As a stabilizer, gelatin hydrolyzate repolymer,
Examples include lecithin (eg, soybean lecithin), polyoxyethylene glycol, and the like. The amount added is preferably about 10 mg per 1 ml of emulsion.

Examples of the emulsification method include the following methods. That is, a method is exemplified in which an aqueous solution of the nonionic contrast agent is added to an oil-based contrast agent to prepare a mixed solution, and an apparatus such as an ultrasonic homogenizer, a pressure jet homogenizer, and a colloid mill that is usually used for emulsification is used.

The particle size of the emulsion is 6 μm or less, preferably 3 μm
m or less. This is because if the particle size is 6 μm or more, the particles may cause infarction at the pulmonary artery capillary site, or the particles may be taken into the lungs to prevent imaging of the liver, spleen and the like.

The specific gravity of the obtained emulsion is preferably in the range of 1.25 to 1.3, and when it is lower than 1.25 or higher than 1.3, the emulsion and the dispersion solvent are separated by long-term storage, and there are adverse effects such as sedimentation or floating of emulsion particles. May occur.

[Action / Effect]

The contrast agent of the present invention is particularly preferable as a liver contrast agent, and when it is used as a liver contrast agent, the contrast agent is incorporated into hepatocytes by utilizing the phagocytosis of the reticuloendothelial system of the liver, and only normal liver tissue is obtained. Is a contrast agent that can be used to detect liver tumor as a contrast defect portion. In particular, it is useful for discovering small initial tumors that are conventionally difficult to detect. The contrast agent of the present invention is also extremely excellent as a contrast agent for the spleen.

Since the contrast agent of the present invention uses a nonionic contrast agent as a surfactant and an emulsion base, the emulsion is stabilized by a strong surfactant action, and the nonionic contrast agent is adsorbed on the surface of the oil-based contrast agent particles. It is possible to increase the iodine content in the particles. Therefore, in clinical use, the contrast agent of the present invention can reduce the amount of oily contrast agent,
The burden on the patient or side effects can be reduced. In addition, an increase in the iodine content increases the iodine uptake amount in the normal tissue of the liver, and a clear liver shadow with a high X-ray absorption value can be obtained.

Further, the contrast agent of the present invention has low toxicity and is excellent in emulsion stability.

If the contrast agent is a liver contrast agent, for example, CT of the liver
Performs intravenous administration within 15-60 minutes before scan inspection construction,
Perform a normal liver CT scan. At this time, it is not necessary to administer a large amount of the water-soluble contrast agent conventionally used.

〔Example〕

The present invention will be described below with reference to experimental examples. In the experimental examples, the following were used.

Iodinated poppy oil fatty acid ethyl ester (hereinafter referred to as poppy oil ester): iodine content 38w / w%, 480mgI / ml, specific gravity
1.275-1.290 (Brand name: Lipiodol Ultrafluid, manufactured by Laboratoire Guerbet) Iopamidol aqueous solution ... An aqueous solution prepared by dissolving Iopamidol in distilled water for injection to be 612.4 mg / ml and 300 mgI / ml. ...... Aqueous solution prepared by dissolving iosexol in distilled water for injection to prepare 647.1 mg / ml and 300 mgI / ml iotrolan aqueous solution …… Dissolving iotrolane in distilled water for injection 512.59 mg / ml, 240 mgI / ml Aqueous solution hemacell (trade name, manufactured by Hoechst) prepared to have a volume of 500 ml ... 500 ml of electrolyte solution
Electrolyte Solution Containing 17.5 Repolymer of Gelatin Hydrolyzate Experimental Example 1 (Emulsion Stability) Iopamidol, Iohexol, and Iotrolane
1 ml of poppy oil ester was added to 1 ml of each type of nonionic contrast agent to emulsify each (Example 2 below).
By the same operation). 5 ml of distilled water was added to each emulsion, the mixture was centrifuged at 2000 rpm for 30 minutes, and then left at room temperature for 1 month. Separately, for comparison, 0.05 to 1.00 ml of poppy oil S-L was decomposed in the same centrifuge spitz and distilled water was added to centrifuge to prepare 20 scales. The amount of the poppy oil ester that was aggregated and fused after standing was compared with these scales to determine the amount of the poppy oil ester.

After standing at room temperature, the amount of poppy oil ester used to prepare the emulsion was about 10 for iopamidol and iohexol.
% Poppy oil ester was agglutinated and almost no agglutinated fusion was seen with iotrolane.

Next, instead of 5 ml of distilled water, 2 ml of hemacells and 3 ml of distilled water
The emulsion added with was similarly centrifuged and observed after 3 months. With Iopamiron, no oil layer appeared,
About 5% of the amount of the precipitated emulsion was observed in iohexol, and a slight oil drop was observed in iotrolane.

Experimental Example 2 (Stability of Contrast Agent of the Present Invention by Various Mixing Ratios) Poppy oil S was 0.5 ml in total, and the aqueous solution of iopamidol was changed from 2.5 ml to 0.25 ml, and emulsified (by the same operation as in Example 2). Then, distilled water was added again to make a total volume of 6 ml. This was centrifuged at 2000 rpm for 30 minutes. As a result, some of the poppy oil ester particles aggregated and returned to the oil state, and the amount in this oil tank was measured.

The amount of aggregated poppy oil ester was the smallest when the ratio of poppy oil ester: iopamidol aqueous solution was 1: 3.5-
At 2.5, 90% or more of the poppy oil ester floats in the emulsion as unaggregated emulsion particles. The emulsion showed an O / W morphology at a ratio of 1: 5.0 to 1.0, but a W / O morphology at 1: 0.5.

Next, hemacell was added as a stabilizer instead of double-distilled water and diluted to a total volume of 6 ml, and the mixture was centrifuged in the same manner, but no poppy oil ester layer was observed.

The mixing ratio of the oily contrast agent and the nonionic contrast agent of the contrast agent of the present invention is particularly preferably in the range of 1: 3.5 to 2.5 when the stabilizer is not added. When a stabilizer is added, the emulsion is not affected by this blending ratio at all, and no aggregation of emulsion particles is observed even after centrifugation at 2000 rpm for 30 minutes, indicating sufficient stability. Conceivable. Therefore, the contrast agent of the present invention, by adding a stabilizer,
(If the iodine content in emulsion particles shown in Experimental Example 3 described later is not taken into consideration), it is possible to mix regardless of the mixing ratio when not added, and as is clear from Experimental Example 1, a stabilizer is added. The better the emulsion stability, the better.

Experimental Example 3 (Measurement of Adsorption Amount of Nonionic Contrast Agent to Poppy Oil Ester Particles) All the aqueous iopamidol solution was 1 ml and the emulsion was prepared by changing the poppy oil ester from 0.25 ml to 1.5 ml (Example 2 and By the same operation). 99 ml of distilled water was added to the obtained emulsion to dilute the dispersion medium, iopamidol aqueous solution, 100 times, and the microfilter 0.22μ
The poppy oil ester particles were filtered by m. The filtrate was colorless and transparent and contained no emulsion particles under an optical microscope. The iodine content of the filtrate was measured using an IPC emission spectrophotometer.

The adsorption amount of Iopamidol reaches the maximum when the ratio of poppy oil ester and iopamidol aqueous solution is 1: 3, and 200mgI of Iopamidol can be adsorbed to 1ml of poppy oil ester (480mgI / ml), and the iodine content of emulsion particles can be increased. It could be increased by about 42% compared to poppy oil ester alone. From these results, the most optimal mixing ratio of poppy oil ester and iopamidol aqueous solution is 1: 3.

From the viewpoint of iodine content, the preferable mixing ratio of the oil-based contrast agent and the nonionic contrast agent is in the range of 1: 2 to 4, and this range is also preferable from the viewpoint of stability of emulsion particles.

Experimental Example 4 (Examination of Amount of Contrast Agent Incorporated Into Organ) A total of 17 rabbits were used in the experiment. The composition of the contrast medium administered to the rabbit is the same as that of the contrast medium prepared in Example 2 (described later). Iopamideol aqueous solution 3 ml, hemacell 2 ml to poppy oil ester 1 ml, poppy oil ester equivalent 80 mg I in 1 ml, containing 114 mg I as emulsion particles, prepared contrast agent 30 mg I / kg to 90 mg I / kg
Was injected through the ear vein of 12 rabbits, and 1 hour later, pancuronium bromide (trade name myoblock) 1 mg was injected through the ear vein to cause cardiac arrest, and a CT scan was immediately performed. The remaining 5 birds were subjected to CT scan without injecting a contrast agent in order to measure the absorption value of normal liver tissue.

The CT scanner used was a GE CT / T8800,9000 type, and all CT scans had the same imaging conditions (tube voltage 120 kV, tube current 100 m).
A, 5 mm width). The CT scan sites are from the lower lung field to the lower spleen border and to the bladder. The adsorption value is measured by RIO bo
An x, 4 square mm was measured at 10 or more points in the liver and inferior vena cava, and the average value was calculated.

It was revealed that the contrast agent of the present invention has a large amount of iodine taken into the liver parenchyma. That is, the value obtained by subtracting the blood vessel value from the liver value indicates the degree of the contrast agent amount in the normal liver tissue. The larger this value, the greater the amount taken into the liver parenchyma, which is convenient for the CT scan of the liver. It is a thing. In order to make it easier to understand that the contrast agent of the present invention is incorporated into the liver parenchyma more than the emulsion containing only poppy oil ester, FIG. 1 is a graph showing blood vessel values and liver values,
Photographs of CT scan results of rabbit liver by administration of various contrast agents are provided in FIGS. 2 to 7. In the contrast agent of the present invention, the time from intravenous administration to CT scan is 1 hour in total. The difference in the mean absorption value between the liver and inferior vena cava for each was 16 HU, 30 mgI / kg 42 HU, 60 HU for the control.
It was mgI / kg68HU and 90 mgI / kg70HU. On the other hand, with an emulsion of poppy oil ester alone, the time from intravenous administration to CT scan was 4 hours or 24 hours, and the difference in the mean absorption value between the liver and inferior vena cava for each was 16 HU, 30 mg for the control.
I / kg28HU, 60mgI / kg34HU, 90mgI / kg32HU (12 for 24 hours)
It was 0 mgI / kg20HU).

The difference between the mean absorption values of the liver and the inferior vena cava was also clear from the results of CT scan image photographs. FIG. 2 shows a control, that is, an X-ray radiograph of the liver when no contrast agent was administered.
It is a photograph of the result of CT scan. FIG. 3 shows the contrast agent of the present invention
30 mgI / kg, FIG. 4 shows the contrast agent of the present invention 60 mgI / kg, FIG. 5 shows the contrast agent of the present invention 90 mgI / kg, FIG. 6 shows an emulsion of poppy oil ester alone 60 mgI / kg, and FIG. Fig. 3 is a photograph showing the result of CT scan of an X-ray image of the liver of a rabbit to which 120 mgI / kg of an emulsion of poppy oil ester alone was administered. 4 and 5 show that the contrast agent of the present invention is absorbed in the tissues of normal liver as a bright part, and the contrast in the vascular system is low, so that the shadow of the liver becomes a dark part and an emulsion of poppy oil ester alone is formed. It is clearly reflected in comparison. Of particular note is the clear visualization of the thin vascular system. That is, from these photographs, it is confirmed that the contrast agent of the present invention has a tissue that corresponds to at least the thickness (size) of the vascular system of the rabbit and does not take up the contrast agent (that is, abnormal liver tissue that does not have a phagocytosis effect). For example, it is clear that it is possible to project this tissue part as a shadow. Therefore, the contrast agent of the present invention is also useful for early detection of early abnormal liver tissue.

As is clear from this experimental example, since the spleen also has a phagocytosis effect, it can be imaged with the contrast agent of the present invention like the liver.

All 17 lungs were scanned for lungs, but no images of pulmonary infarction were obtained. None of the 12 rabbits injected with the contrast medium had any abnormalities before breathing was stopped.

Furthermore, the tissue toxicity of poppy oil S-iopamidol is extremely low, and the toxicity of this contrast agent is extremely low. The hemacell used as a stabilizer is clinically used as a plasma substitute and has no problem in toxicity. In the rabbit experiment, no damage that could be a side effect after the administration of the contrast agent was observed in the rabbit.

The biggest problem with this type of contrast agent is pulmonary embolism. However, if the particle size is 6 μm or less, pulmonary artery embolism does not occur, and in the experimental example shown above, pulmonary artery embolism also occurred. No rabbit was observed, and there was no problem of pulmonary embolism due to contrast medium.

〔Example〕

Example 1 Iodinated poppy oil fatty acid ethyl ester (iodine content 38
w / w%, 480 mgI / ml, specific gravity 1.275-1.290) 1 part by volume, and iopamidol are dissolved in distilled water for injection to give
The mixture was added with 3 parts by volume of an aqueous solution prepared to have g / ml and 370 mgI / ml, and emulsified by using a pressure injection type device. Immediately before administration to rabbits, physiological saline was added to dilute the mixture twice and shaken well. Immediately before use, the emulsion particle size was measured under a microscope. All were 6 μm or less, and the average was 3 μm.

Example 2 Iodinated poppy oil fatty acid ethyl ester (iodine content 38
w / w%, 480 mgI / ml, specific gravity 1.275-1.290 (1 part by volume), and iopamidol powder are dissolved in distilled water for injection to prepare 612.
Immediately emulsification was carried out by adding 3 parts by volume of an aqueous solution prepared to be 4 mg / ml and 300 mgI / ml to prepare a mixed solution. For the emulsion method, two injection cylinders from which both solutions were separated were joined with a stainless steel micropore joint, and both injection cylinders were pushed to pass the micropores 100 times or more. To the obtained emulsion, 2 parts by volume of an electrolyte solution containing 1.75 w / v% of a repolymer of gelatin hydrolyzate as a stabilizer was added. Immediately before administration to rabbits, physiological saline was added to dilute and shake well. Immediately before use, the emulsion particle size was measured under an optical microscope.
The average particle size was 3 μm or less. The emulsion was allowed to stand at room temperature and examined one month later with an optical microscope. All emulsion particles were 6 μm or less, and no fusion of particles was observed.

[Brief description of the drawings]

FIG. 1 is a graph showing the amount of the contrast agent selectively taken into the liver and blood vessels 1 hour after the administration of the contrast agent of the present invention and 4 hours (or 24 hours) after the emulsion administration by the poppy oil ester alone. . FIG. 2 is a photograph showing the result of a CT scan of a control, that is, an X-ray contrast enhancement of the liver was performed without administration of a contrast agent. FIG. 3 shows the contrast medium of the present invention at 30 mgI / kg, FIG. 4 shows the contrast phase of the present invention at 60 mgI / kg, and FIG. 5 shows the contrast phase of the present invention at 90 mgI / kg.
Fig. 6 shows 60 mgI / kg emulsion of poppy oil ester alone.
, And FIG. 7 are emulsions of poppy oil ester alone.
It is a photograph of the result of the CT scan of the X-ray image of the liver of a rabbit to which 120 mgI / kg was administered.

Claims (1)

(57) [Claims] 1. A positive contrast agent for scanning, comprising an emulsion comprising a positive water-soluble nonionic contrast agent and a positive oily contrast agent.