Abstract:
The present invention relates to a contrast medium composition (formulation) comprising a highly concentrated contrast agent for use in an imaging method. 
     The contrast medium composition according to the present invention, which comprises iodine working as a contrast agent in a higher concentration than the concentration used before, shows higher contrast enhancement effect in both of arterial phase and portal phase when used for liver CT than a composition comprising the contrast medium in a concentration used before. Accordingly, images having excellent resolution and discrimination can be obtained.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to a contrast medium composition for using in an imaging method, particularly to a contrast medium composition comprising a highly concentrated contrast agent so as to have high contrast enhancement effect. 
       BACKGROUND OF THE INVENTION 
       [0002]    CT (computed tomography) is an imaging method that X-ray is radiated from various directions to the desired human body part, the transmitted X-ray is collected using a detector, and then a computer calculates the X-ray absorption difference of the part followed by reconstructing the data using mathmatical technique. The basic principle of CT is that an X-ray tube radiates X-ray beam while rotating around a section of the human body; a detector collects strength data; and then a computer calculates absorption strength by part using the data and reconstructing images using the calculated data followed by showing them on a monitor. 
         [0003]    CT has better resolution and contrast in distinguishing blood, cerebrospinal fluid, white matter, gray matter, tumor and the like than previous X-ray images, and can express absorption difference at a fine part. Accordingly, it occupies a very important position in image diagnosis fields. 
         [0004]    The most significant feature of CT is using X-ray, but the x-ray examination can&#39;t distinguish a structure having similar density. The X-ray of short wavelength is effective for imaging a dense structure such as bones, but it has low sharpness for imaging soft tissues. Accordingly, there is a limit to distinguish tissues and their peripheral areas with only X-ray examination. Therefore, contrast media are needed to artificially provide contrast between the examined organs and their peripheral tissues. Namely, unlike gastrointestinal radiologic diagnosis, the X-ray examinations such as urography and angiography are needed to administer safe, aqueous and radiopaque contrast media intravenously. 
         [0005]    Presently, iodine-based contrast media are being most widely used, and specifically, in triiodobenzene-based X-ray contrast medium fields, non-ionic triiodobenzoic acid derivatives such as iopamidol, iohexol and ioversol were developed and rapidly grown: 
         [0006]    Iomeprol {C 17 H 22 I 3 N 3 O 8 ; N,N′-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)methylamino]-2,4,6-triiodo-1,3-benzene dicarboxamide; CAS[RN] [78649-41-9]}, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0007]    Iopromide {C 18 H 24 I 3 N 3 O 8 ; N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino]-N-methyl-1,3-benzene dicarboxamide; CAS [RN][73334-07-3]}, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0008]    Ioversol {C 18 H 24 I 3 N 3 O 9 ; N,N′-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)(2-hydroxyethyl)amino]-2,4,6-triiodo-1,3-benzene dicarboxamide; CAS [RN][87771-40-2]}, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0009]    Iohexol {C 19 H 26 I 3 N 3 O 9 ; 5-[acetyl(2,3-dihydroxypropyl)amino]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzene dicarboxamide; CAS [RN][66108-95-0]}, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0010]    Iopentol {C 20 H 28 I 3 N 3 O 9 ; 5-[acetyl(2-hydroxy-3-methoxypropyl)amino]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzene dicarboxamide; CAS [RN][89797-00-2]}, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0011]    Iopamidol {C 17 H 22 I 3 N 3 O 8 ; 5-[(2-hydroxy-1-oxopropyl)amino]-N,N′-bis(2-hydroxy-1-(hydroxymethyl)ethyl)-2,4,6-triiodo-1,3-benzene dicarboxamide; CAS [RN][60166-93-0]}, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0012]    Iobitridol {C 20 H 28 I 3 N 3 O 9 ; N,N′-bis(2,3 -dihydroxypropyl)-5-[[3-hydroxy-2-(hydroxymethyl)-1-oxopropyl]amino]-2,4,6-triiodo-N,N′-dimethyl-1,3-benzene dicarboxamide; CAS [RN][136949-58-1]}. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0013]    Like this, the iodine is used as a contrast agent because it absorbs X-ray well due to its high density and thereby shows excellent contrast enhancement effect. Namely, when X-ray reaches the iodine contained in the contrast medium, X-ray is absorbed and looks white on CT. Accordingly, the organ to diagnose looks bright. 
         [0014]    Injection speed and iodine concentration of the contrast medium may vary according to a purpose of the test. Particularly, the iohexol was previously clinically admitted to be used for enhancing CT contrast in amounts of 140 mgI/mL, 180 mgI/mL, 240 mgI/mL, 300 mgI/mL, and up to 350 mgI/mL. 
         [0015]    However, due to explosive demands and expectations (early diagnosis and precise diagnosis) of medical market for the development of medical skills and diagnosis, the contrast medium composition, which was previously admitted, could not satisfy the demands for more precise and accurate diagnosis of image diagnosis. Therefore, in order to achieve high quality imaging, a novel contrast medium composition comprising a highly concentrated contrast agent and thereby showing contrast enhancement effect is needed. 
       SUMMARY OF THE INVENTION 
       [0016]    In order to solve the above-described problems associated with prior art, the present invention is objected to provide a novel contrast medium composition having a highly concentrated contrast agent and/or low Hounsfield value. 
         [0017]    In order to accomplish one object of the present invention, the present invention provides a contrast medium composition comprising an aqueous contrast agent selected from the group consisting of iopentoljotrolan, iohexol, ioversol, ioxilan, iodixanol and iobitridol in an amount of 360 mgI/mL to 450 mgI/mL. 
         [0018]    In the present invention, the contrast medium composition comprising the aqueous contrast agent in a concentration of 360 mgI/mL to 450 mgI/mL refers a composition containing iodine atoms of 360 mg to 450 mg per the contrast medium composition of 1 ml. 
         [0019]    The present invention is characterized that the aqueous contrast agent is iohexol. The iohexol is known for having generally lower chemical toxicity and neurotoxicity than other non-ionic contrast agents because it contains six intramolecular —OH groups so as to show high hydrophilicity. The iopromide can&#39;t be used for imaging spiral cord due to its high neurotoxicity, and the ioversol doesn&#39;t have any indications for imaging abdominal cavity and spiral cord. But the iohexol has very wide adaptive domain and, for this reason, the iohexol is the best-selling contrast agent in the world. 
         [0020]    The present invention is characterized that the concentration of the iohexol as the aqueous contrast agent in the contrast medium composition is higher as 360 mgI/mL to 450 mgI/mL, preferably 380 mgI/mL, 400 mgI/mL or 420 mgI/mL than the concentration used before as 350 mgI/mL. In the present invention, when the concentration of the iohexol in the contrast medium composition is 360 mgI/mL to 450 mgI/mL, the contrast medium composition can provide contrast enhancement effect in both of arterial phase and portal phase when used for liver CT imaging. 
         [0021]    The present invention is characterized that contrast medium composition further comprises an aqueous buffer, sterile water for injection, a chelating agent and pH controlling agent. 
         [0022]    The present invention is characterized that the aqueous buffer is tromethamine. In the present invention, the aqueous buffer comprises 2-amino-2-(hydroxymethyl)-1,3-propanediol, also known as the tromethamine. The tromethamine is toxicologically acceptable, and is described in U. S. Pharmacopoeia, XXI edition, U.S. Pharmacopeial Convention, Rockville, Md. 1985 (U.S.P XXI) at page 1102. The tromethamine (Chemical Name: 2-amino-2-hydroxymethyl-1,3-propanediol) is also known as other names of Trimethylol aminomethane; Tris(hydroxymethyl)aminomethane; Trisamine; Tris buffer; Trometamol; Tromethane; THAM; TRIS; Talatrol; Trisamino; 
         [0023]    Tris-steril; and Trizma, as described in Merck Index(11 th  edition, Merck Co. Inc., Rahway, N.J. 1989). The tromethamine and its salts are known for working as a buffer in the pH range of 6-9. 
         [0024]    The present invention is characterized that the chelating agent is at least one selected from the group consisting of ethylenediamine, edetate calcium disodium and edetate disodium. 
         [0025]    The chelating agent added to the composition may any pharmaceutically acceptable chelating agent, but it may be ethylenediamine, edetate calcium disodium or edetate disodium, preferably. Among them, the edetate disodium is more preferable. The concentration of the chelating agent may be preferably 0.01 to 1 mg/mL, particularly 0.05 to 0.5 mg/mL. When the amount of the chelating agent is less than the range described above, stabilizing effect of the contrast medium comprising the iohexol and the like is not enough. When the amount of the chelating agent excesses the range described above, the stabilizing effect by the chelating agent reaches to the upper limit and, in addition, the excessive amount is not desirable regarding to the safety. 
         [0026]    Regarding to stability of the contrast medium comprising the iohexol and the like, the pH of the contrast medium composition of the present invention can be preferably controlled to 7.0 to 8.0 by using pharmaceutically acceptable buffer for injection formulation such as hydrochloric acid or its salt, citric acid or its salt, phosphoric acid or its salt and acetic acid or its salt. 
         [0027]    Further, the injection formulation of the present invention can be prepared by adding any necessary pharmaceutically acceptable isotonic agent, preservative and the like. 
         [0028]    The present invention is characterized that CEA and CEP of the contrast medium composition comprising the aqueous contrast agent in a concentration of 360 mgI/mL to 450 mgI/mL satisfies the following relationship with CEA 350  and CEP 350  of the contrast medium composition comprising the aqueous contrast agent in a concentration of 350 mgI/ml. 
         [0000]      CEA&gt;CEA 350    
         [0000]      CEP&gt;CEP 350    
         [0029]    The CEA is a contrast enhancement value in arterial phase, and it represents the result of measuring Hounsfield unit (HU) of the abdominal aorta at the level showing the celiac artery; and the CEP is a contrast enhancement value in portal phase, and it represents the result of measuring Hounsfield unit (HU) of the portal vein at the level showing the main portal vein. 
         [0030]    Namely, the present invention shows an effect of improving the CEA and CEP in both of arterial phase and portal phase when used for liver CT imaging by using the iohexol at a higher concentration than the concentration of 350 mgI/mL, which was clinically used before. 
         [0031]    The present invention is characterized that CEA 380  and CEP 380  of the contrast medium composition comprising the aqueous contrast agent in a concentration of 380 mgI/mL satisfies the following relationship with CEA 350  and CEP 350  when using the aqueous contrast agent in an amount of 350 mgI/ml. 
         [0000]      1.7≧ CEA   380   /CEA   350 ≧1.1
 
         [0000]      1.7≧ CEP   380   /CEP   350 ≧1.1
 
         [0032]    The present invention is characterized that CEA 400  and CEP 400  of the contrast medium composition comprising the aqueous contrast agent in a concentration of 400 mgI/mL satisfies the following relationship with CEA 350  and CEP 350  when using the aqueous contrast agent in an amount of 350 mgI/ml. 
         [0000]      1.7≧ CEA   400   /CEA   350 ≧1.1
 
         [0000]      1.7≧ CEA   400   /CEP   350 ≧1.1
 
         [0033]    The present invention is characterized that CEA 420  and CEP 420  of the contrast medium composition comprising the aqueous contrast agent in a concentration of 420 mgI/mL satisfies the following relationship with CEA 350  and CEP 350  when using the aqueous contrast agent in an amount of 350 mgI/ml. 
         [0000]      1.7≧ CEA   420   /CEA   350 ≧1.1
 
         [0000]      1.7&gt; CEP   420   /CEP   350 ≧1.05
 
         [0034]    In the present invention, the contrast medium composition is characterized by being generally used for liver CT imaging. 
       Advantageous Effects of the Invention 
       [0035]    The contrast medium composition according to the present invention, which comprises iodine working as a contrast agent in a higher concentration than the concentration used before, can provide CT images having excellent sharpness and discrimination due to its high contrast enhancement effect. Particularly, it shows contrast enhancement effect in both of arterial phase and portal phase when used for liver CT. 
     
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         [0036]    The above and other objects and features of the present invention will become apparent from the following description of the invention taken in conjunction with the following accompanying drawings, which respectively show: 
           [0037]      FIG. 1 : images of liver CT after administering a 380 mgI/ml iohexol injection formulation prepared by one Example of the present invention to a rabbit; 
           [0038]      FIG. 2 : images of liver CT after administering a 400 mgI/ml iohexol injection formulation prepared by one Example of the present invention to a rabbit; 
           [0039]      FIG. 3 : images of liver CT after administering a 420 mgI/ml iohexol injection formulation prepared by one Example of the present invention to a rabbit; 
           [0040]      FIG. 4 : images of liver CT after administering a 350 mgI/ml iohexol injection formulation prepared by one Comparative Example of the present invention to a rabbit; and 
           [0041]      FIG. 5 : a graph showing the changes of CEA and CEP values as the contrast enhancement effect according to the iodine amounts used in Examples of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0042]    The following Examples are intended to further illustrate the present invention by way of help understanding the present invention, and thus are not limitative of the present invention. 
       Example 1  
     380 mgI/ml Iohexol Injection Formulation 
       [0043]    In order to make the iohexol concentration in a contrast medium composition to 380 mgI/ml, iohexol of 819.71 g, tromethamine of 1.31 g and edetate calcium disodium of 0.11 g were completely dissolved in water for injection (WFI) of 75 ml by mixing thereof at room temperature (RT). pH was controlled to 7.79 by using 1N hydrochloric acid solution, and WFI was added to make the final volume of the formulation 1 L. Then, the resulting solution was subjected to sterile filtration by using a micro filter. The obtained solution was filled to a 100 mL vial. Then, the vial was sealed with a rubber stopper and an aluminum cap to obtain an injection formulation. 
       Example 2  
     360 mgI/ml Iohexol Injection Formulation 
       [0044]    An injection formulation was obtained by using a method similar with the method of Example 1 except for using iohexol of 776.62 g and tromethamine of 1.24 g in order to make the iohexol concentration to 360 mgI/ml. 
       Example 3  
     400 mgI/ml Iohexol Injection Formulation 
       [0045]    An injection formulation was obtained by using a method similar with the method of Example 1 except for using iohexol of 862.80 g and tromethamine of 1.38 g in order to make the iohexol concentration to 400 mgI/ml. 
       Example 4  
     420 mgI/ml Iohexol Injection Formulation 
       [0046]    An injection formulation was obtained by using a method similar with the method of Example 1 except for using iohexol of 905.88 g and tromethamine of 1.45 g in order to make the iohexol concentration to 420 mgI/ml. 
       Example 5  
     450 mgI/ml Iohexol Injection Formulation 
       [0047]    An injection formulation was obtained by using a method similar with the method of Example 1 except for using iohexol of 970.5 g and tromethamine of 1.55 g in order to make the iohexol concentration to 450 mgI/ml. 
       Comparative Example 1  
     350 mgI/ml Iohexol Injection Formulation 
       [0048]    An injection formulation was obtained by using a method similar with the method of Example 1 except for using iohexol of 755.0 g and tromethamine of 1.21 g in order to make the iohexol concentration to 350 mgI/ml, which is previously admitted dosage of iohexol. 
       Test Example 1  
     Measuring Viscosity, Osmosis and pH 
       [0049]    Viscosity, osmosis and pH before and after controlling of the injection formulations of Examples 1 to 5 and Comparative Example 1 were measured, and the results thereof were listed in the following Table 1. 
         [0000]    
       
         
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                   
                 Iodine 
                   
                   
                   
               
               
                 Classification 
                 Concentration 
                 Viscosity 
                 Osmosis 
                 pH 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Example 1 
                 380 mgI/ml 
                 19 
                 905 
                 7.79 
               
               
                 Example 2 
                 360 mgI/ml 
                 10 
                 810 
                 7.75 
               
               
                 Example 3 
                 400 mgI/ml 
                 37.5 
                 1034 
                 7.80 
               
               
                 Example 4 
                 420 mgI/ml 
                 45.0 
                 1096 
                 7.79 
               
               
                 Example 5 
                 450 mgI/ml 
                 71 
                 1204 
                 7.85 
               
               
                 Comparative 
                 350 mgI/ml 
                 19 
                 748 
                 7.55 
               
               
                 Example 1 
               
               
                   
               
             
          
         
       
     
         [0050]    It was confirmed that viscosity and osmosis were increased with increased iodine concentration. pH was controlled to the range from 7.5 to 8.0. 
       Test Example 2  
     Imaging and Measuring HU (Hounsfield Unit) in Liver Tissue Using 380 mgI/ml iohexol injection formulation of Example 1 
       [0051]    The 380 mgI/ml iohexol injection formulation prepared in Example 1, was administered to each of seven rabbits, and liver CT images were taken. The resulting images were shown in  FIG. 1 . 
         [0052]    Method for CT imaging: After anesthetizing the subject animal, a 22 G IV catheter was installed in the auricular vein of the rabbit followed by being connected to a power injector using a connector, and then a contrast medium (6.4-6.5 mL) was injected at the rate of 1.4 ml/sec followed by taking CT images with time difference using Definition (64 MDCT, Siemens, Germany). CT scan parameters were set follows: 100 mAs and 80 kVp table speed. 
         [0053]    In the images in  FIG. 1 , the left image is an image in arterial phase, and the result of measuring Hounsfield unit (HU) of the abdominal aorta at the level showing the celiac artery. The measured Hounsfield unit (HU) was considered as the Hounsfield unit (HU) in arterial phase, i.e., CEA 380  (contrast enhancement value in arterial phase). 
         [0054]    The right image in  FIG. 1  is an image in portal phase, and the result of measuring Hounsfield unit (HU) of the portal vein at the level showing the main portal vein. The measured contrast enhancement value was considered as the Hounsfield unit (HU) in portal phase, i.e., CEP 380  (contrast enhancement value in portal phase), and the results were listed in the following Table 2 with CEA 380 . 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 ID 
                 CEA 380   
                 CEP 380   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 708 
                 2157 
                 531 
               
               
                 709 
                 1835 
                 402 
               
               
                 701 
                 1358 
                 538 
               
               
                 702 
                 1975 
                 720 
               
               
                 703 
                 2323 
                 633 
               
               
                 704 
                 2542 
                 802 
               
               
                 503 
                 2115 
                 691 
               
               
                 Average 
                 2043.6 
                 616.7 
               
               
                 Standard Deviation 
                 379.2 
                 135.7 
               
               
                   
               
             
          
         
       
     
       Test Example 3  
     Imaging and Measuring HU (Hounsfield Unit) in Liver Tissue Using 400 mgI/ml iohexol injection formulation of Example 3  
       [0055]    Using the 400 mgI/ml iohexol injection formulation prepared in Example 3, images were taken by the same method of Test Example 2 for three rabbits, and the resulting images were shown in  FIG. 2 . The results of measuring CEA 400  and CEP 400  of the images in  FIG. 2  were listed in the following Table 3. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 ID 
                 CEA 400   
                 CEP 400   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1005 
                 2526 
                 667 
               
               
                 1006 
                 2412 
                 641 
               
               
                 1007 
                 1850 
                 504 
               
               
                 Average 
                 2262.7 
                 604.0 
               
               
                 Standard Deviation 
                 361.9 
                 87.6 
               
               
                   
               
             
          
         
       
     
       Test Example 4  
     Imaging and Measuring HU (Hounsfield Unit) in Liver Tissue Using 420 mgI/ml iohexol injection formulation of Example 4 
       [0056]    Using the 420 mgI/ml iohexol injection formulation prepared in Example 4, images were taken by the same method of Test Example 2, and the resulting images were shown in  FIG. 3 . The results of measuring CEA 420  and CEP 420  of the images in  FIG. 3  were listed in the following Table 4. 
         [0000]    
       
         
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 ID 
                 CEA 420   
                 CEP 420   
               
               
                   
               
             
             
               
                 1009 
                 2574 
                 552 
               
               
                   
               
             
          
         
       
     
       Test Example 5  
     Imaging and Measuring HU (Hounsfield Unit) in Liver Tissue Using 350 mgI/ml iohexol injection formulation of Comparative Example 
       [0057]    Using the 350 mgI/ml iohexol injection formulation prepared in Comparative Example, images were taken by the same method of Test Example 2, and the resulting images were shown in  FIG. 4 . The results of measuring CEA 350  and CEP 350  of the images in  FIG. 4  were listed in the following Table 5. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 ID 
                 CEA 350   
                 CEP 350   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 608 
                 1971 
                 493 
               
               
                 610 
                 1557 
                 461 
               
               
                 702 
                 1872 
                 553 
               
               
                 703 
                 1701 
                 497 
               
               
                 704 
                 1521 
                 623 
               
               
                 705 
                 1278 
                 421 
               
               
                 707 
                 1959 
                 473 
               
               
                 Average 
                 1694.1 
                 503 
               
               
                 Standard Deviation 
                 258.3 
                 66.4 
               
               
                   
               
             
          
         
       
     
         [0058]    CEA values and CEP values of Examples and Comparative Example measured in Test Example 2 to 5 were shown in  FIG. 5  according to each iodine concentration. 
         [0059]    As shown in  FIG. 5 , it was confirmed that CEA values were increased in the iodine concentration range of 360 to 450 mgI/ml and showed contrast enhancement effect in arterial phase, but CEP values were increased and then decreased and showed increasing and decreasing contrast enhancement effect in portal phase. 
         [0060]    Further, it was confirmed that, when the iodine concentration was 460 mgI/ml or more, CEA values were decreased but CEP values were decreased below the iodine concentration of Comparative Example of 350 mgI/mL. 
         [0061]    Accordingly, in the contrast medium composition according to the present invention, the iodine concentration may be in the range of 350 to 450 mgI/ml where showing contrast enhancement effect in arterial phase at liver CT imaging, and it may be preferably in the range of 380 to 420 mgI/ml, where showing contrast enhancement effect in both arterial phase and portal phase. 
         [0062]    Further, Hounsfield units (HU) in arterial phase and portal phase when conducting liver CT imaging in the iodine concentrations of 380, 400 and 420 mgI/ml and Hounsfield units (HU) in arterial phase and portal phase when conducting liver CT imaging in an iodine concentration of 350 mgI/ml were compared, and the results thereof were listed in the following Table 6. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                 TABLE 6 
               
               
                   
                   
               
               
                   
                 CEA/CEA 350   
                 CEP/CEP 350   
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                 380 mgI/ml 
                 CEA 380 /CEA 350  = 1.206 
                 CEP 380 /CEP 350  = 1.226 
               
               
                 400 mgI/ml 
                 CEA 400 /CEA 350  = 1.335 
                 CEP 400 /CEP 350  = 1.201 
               
               
                 420 mgI/ml 
                 CEA 420 /CEA 350  = 1.519 
                 CEP 420 /CEP 350  = 1.097 
               
               
                   
               
             
          
         
       
     
         [0063]    As shown in Table 6, with increased iodine concentration than the concentration used before of 350 mgI/ml, Hounsfield unit (HU) ratio in arterial phase was increased and Hounsfield unit (HU) ratio in portal phase was decreased. When the iodine concentration was 380 to 420 mgI/ml, Hounsfield unit (HU) in both arterial phase and portal phase were higher than HU in an iodine concentration of 350 mgI/ml used before. 
         [0064]    While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made and also fall within the scope of the invention as defined by the claims that follow.