US3832457A

US3832457A - Ferrite contrast media with metallic oxides

Info

Publication number: US3832457A
Application number: US00046913A
Authority: US
Inventors: M Sugimoto; K Funaki; Y Saeki
Original assignee: RIKEN Institute of Physical and Chemical Research
Current assignee: RIKEN Institute of Physical and Chemical Research
Priority date: 1969-06-20
Filing date: 1970-06-17
Publication date: 1974-08-27
Anticipated expiration: 1991-08-27
Also published as: DE2065532A1; DE2030690A1; FR2053000A1; DE2030690B2; GB1315391A; DE2030690C3; FR2053000B1; DE2065532B2

Abstract

Contrast media for radiography of organs comprises a sufficient amount of fine solid particles of at least one kind of soft magnetic ferrites suspended in a liquid carrier, wherein said carrier contains at least one kind of additive agents selected from the group consisting of organic thickening compounds such as starch, sodium alginate and polyvinyl alcohol, fine powder of metallic oxides selected from Ba, Bi, Ce, W, Zr, Sn, Ta, Vb, La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho and Y.

Description

United States Patent [191 Sugimoto et al.

[111 3,832,457 [451 Aug. 27, 1974 FERRITE CONTRAST MEDIA WITH METALLIC OXIDES Inventors: Mitsuo Sugimoto; Koemon Funaki;

Yuzo Saeki, all of Tokyo, Japan Assignee: Rikagaku Kenkyusho,

Kitaodachi-gun, Saitama-ken, Japan Filed: June 17, 1970 Appl. No.1 46,913

Foreign Application Priority Data June 20, 1969 Japan 44-48724 June 20, 1969 Japan 44-48725 Nov. 15, 1969 Japan 44-91718 May 13, 1970 Japan 45-40656 US. Cl. 424/4, 128/2 R, 424/131, 424/141, 424/144, 424/145, 424/147 Int. Cl A61k 27/08 Field of Search 424/4, 131, I41, 144, 145, 424/147; 128/2 R References Cited UNITED STATES PATENTS 9/1910 Gros 424/4 FOREIGN PATENTS OR APPLICATIONS 657,979 10/195] Great Britain 424/4 750,173 5/1933 France ..424/4 7/1971 Frei et a]. 424/4 X OTHER PUBLICATIONS The Merck Index, 8th Ed;, Merck & Co., Rahway, N. J., (1968), pp. 120-121.

Primary Examiner-Albert T. Meyers Assistant Examiner-Vera C. Clarke [57] ABSTRACT 3 Claims, 6 Drawing Figures PAIENIEB Aucz 71914 FIG.I

SIIEEI 1 U 3 TIME IN AN ARTIFICIAL GASTRIC JUICE HRS.

O -0 5 0 w 0 -0 9 w T 0 -0 5 3 2 .l O n o. o O O O FIG.2

ROASTING TEMPERATURE, C

A MINIMUM FIELD STRENGTH NECESSARY FOR MAINTAINING FERRITE POWDER IN LIQUID MINIMUM FIELD STRENGTH FOR MOVING FERRITE POWDER IN LIQUID Mn-Zn-FERRITE Ni 'ZWFERRITE I-I POWDER SIZE (0.4,0)

Cu-Zn-FERRITE I---I Mn-Zn-FERRITE I-I N i-Zn-FERRITE }POWDER SIZE (0.2/1) Cu-Zn-FERRITE Mg-FERRITE -I P .4 mm SOLUTION OWDER '9 OF Mg-FERRITE I% AND M90 Mg-FERRITE I---I OF Mg-FERRITE I-- M AND MgO Fe304 A N D Fe-zn-FERRITE }PowDER SIZE(0.2 U-FezOa O 5 0 I00 I50 MAGNETIC FIELD STRENGTH, OERSTED ATTO RN EY PATENTED M32719 3.832.457

SHEH 30$ 3 AMOUNT OF ADDED OXIDE,% BY WEIGHT FIG.5

l 1 l l 55 6O 65 TO 75 8O CHARGED VALTAGE OF X-RAY TUBE, KV

F IG. 6

INVENTORS ATTORNEY FERRITE CONTRAST MEDIA WITH METALLIC OXIDES This invention relates to contrast media of ferrites having excellent magnetic properties and X-ray absorbing powers useful for angiography, gastrointestinal diagnosis and general use in radiotherapy.

Heretofore, barium sulfate has been used for X-ray examination of the esophagus and gastrointestinal tract. Barium sulfate, with a strong X-ray absorbing power, deposits in relatively large amounts on affected parts and gives X-ray pictures with sufficient contrast for detection of new seats of diseases or for diagnosis of the conditions. Difficulties are involved, however, in causing deposition of a desired amount of the contrast medium on a particular part desired. Thus a high degree of clinical skill is needed today in detecting a small affected part or in exactly diagnosing a disease condition.

In view of this, attempts have been made to orally administer a certain magnetic material in powder form to the patient and guide the magnetic powder to the affected part on which it is to deposit, or adjust the amount to be deposited, by means of a permanent magnet manipulated outside of the body. Also, it was reported recently by Frei, Gunders et al. (in the Journal of Applied Physics, 39 (1968) p. 999 1001) that powders prepared by adding powder of MgO or 'y-Fe O to a ferrite, as for example the powder of the solid solution of MgFe O and MgO, are excellent contrast media for radiography.

Those ferrite contrast media were reported to be well comparable to the ordinary barium sulfate ones with high rates of X-ray absorption, and, moreover, light in tone, adhesive to the walls of the gastrointestinal tract, free of toxicity, and are able to be magnetically controlled from the outside by means of a permanent magnet in the X-ray visualization of a stomach or bowel disorder. However, the paper has no mention of the method of producing such ferrite contrast media and gives no detail of the properties to be possessed by the media. With this in view, we conducted experiments to be described later, which led to a number of discoveries useful for the manufacture of valuable contrast media of ferrites. It is upon these discoveries that the present invention is predicated.

This invention will be better understood from the following detailed description taken in conjunction with the accompanying drawings showing embodiments thereof.

In the drawings:

FIG. 1 is a graph showing the amounts of various soft magnetic ferrite powders dissolved in an artificial gastric juice;

FIG. 2 is a graph illustrating the relationship between the firing temperatures and the amounts of ferrites made of Fe O in the form of either coarse particles or finely divided particles dissolved in an artificial gastric uice;

J FIG. 3 is a graphic representation of measurements of the minimum field strengths necessary for free movement of various soft magnetic ferrite powders in liquid, or the minimum field strengths necessary for maintaining such powders in certain positions in the liquid;

FIG. 4 is a schematic perspective view of an instrument for determining the 'X-ray absorbing powers of contrast media;

FIG. 5 is a graph showing changes in saturation magnetization with the addition of BaO to a Ni-Zn ferrite, W0 to a Mn-Zn ferrite, and Ce O to a Cu-Zn ferrite;

FIG. 6 is a graph giving the results of comparative measurements of the relationship between the voltage applied on the X-ray tube and the X-ray absorbing power of barium sulfate contrast medium and a contrast medium prepared by adding BaO to a Mn-Zn ferrite.

First, a typical soft magnetic material ferrite with a spine] type crystalline structure was placed in an artificia.l gastric juice and an artificial intestinal juice, and the amounts dissolved were measured. The rerults were as shown in FIG. 1. In the figure, the curve 1 represents a Cu-Zn ferrite powder (with a composition of a molar ratio of 25 CuO 25 ZnO 50 Fe O fired in air at 950C for 5 hours), the curve 2 shows a powder of the solid solution of MgFe O and MgO (with the composition proposed by Frei, Gunders et al., fired in air at l,300C for 5 hours), the curve 3 shows a Ni-Zn ferrite powder with a composition of a molar ratio of 25 NiO 25 ZnO 50 Fe O fired in air at l,300C for 5 hours), the curve 4 shows a Mn-Zn ferrite powder (composed at a molar ratio of 25 MnO 25 ZnO 50 Fe O and fired in air at l,300C for 5 hours), and the curve 5 shows a overlap result of Fe O powder and a Fe-Zn ferrite powder (composed at a molar ratio of 25 FeO 25 ZnO 5O Fe O fired under a reduced pressure at l,l00C for 5 hours. The curve 6 represents 'y-Fe O obtained by heating the Fe O powder of the curve 5 in air at 200C for 24 hours. The starting materials used for the preparation of these ferrites, which had to be as pure as possible, were carbonates and oxides as commercially available special-grade reagents. The materials were thoroughly mixed and each mixture was heated. After cooling, the mixture was ground well in an agate mortar to a particle size of 0.1 to 0.2 micron in diameter. Ten gram of each ferrite powder were placed in 200 cc. of an artificial gastric juice or intestinal juice for from 30 minutes to 3 hours, and the filtrates were chemically analyzed and the amounts of the ferrite dissolved were estimated. From FIG. 1 it can be seen that the Cu-Zn, Mg, and Ni-Zn ferrites are relatively highly soluble in the artificial gastric juice while Mn-Zn ferrite, Fe O 'Fe-Zn ferrite, and 'y-Fe o are among the 'group relatively hard to dissolve. All of the ferrites tested dissolved little in the artificial intestinal uice.

The artificial gastric juice was prepared in conformity with the Japanese Pharmacopoeia by diluting a mixture of 2.0 g sodium chloride, 3.2 g pepsin, and 24.0 ml dilute hydrochloric acid with distilled water to a total volume of 1,000 ml. The artificial intestinal juice was prepared of 15.0 g sodium hydrogen carbonate and 2.8 g pancreatin diluted altogether with purified water to a total volume of 1,000 ml.

By alkali coprecipitation (whereby, for example, a Ni-Zn ferrite is formed by introducing a mixed aqueous solution of nickel sulfate, zinc sulfate, and ferric sulfate in an aqueous solution of caustic soda and thereby coprecipitating the Ni-Zn ferrite salt) were produced Cu- Zn, Ni-Zn, and Mn-Zn ferrites, and then those ferrites were placed in the artificial gastric juice to determine the amounts dissolved. The solubility of the ferrites formed by the coprecipitation technique 'was five to six times as much as the Cu-Zn ferrite in FIG. 1. The ferrites obtained by the alkali coprecipitation, when boiled in distilled water at lOfor many hours, showed a common tendency of decreasing solubility to the artificial gastric juice. Also, the coprecipitated ferrites upon treatment with boiling water in an autoclave exhibited remarkable decreases in the amounts dissolved in the artificial gastric juice. It was observed that, when heated to about 600C, the various ferrites obtained by the coprecipitation show almost the same rates of dissolution as in FIG. 1.

It will be noted from FIG. 1 that the amounts of the ferrites dissolved in the artificial gastric juice are relatively small. However, these amounts of dissolution are nevertheless not negligible because the X-ray examination requires a fairly large amount of a ferrite at one time. This means that preclusion of the dissolution of such ferrites in the artificial gastric juice is necessary.

FIG. 2 illustrates the effect of particle size of the material a-Fe O upon the solubility of the product Mn-Zn ferrite. The curve 7 represents the relationship between the firing temperature and the amount of dissolution in the artificial gastric juice for Mn-Zn ferrite (with a composition of a molar ratio of 30 MnO 20 ZnO O Fe O made of coarse-particle a-Fe O (0.2 micron in diameter). The curve 8 represents the similar relationship for Mn-Zn ferrite made of an a-Fe O with high purity and fine particle size (0.05 micron in diameter) prepared by decomposing iron chloride in an oxygen atmosphere. Ferrites made of the fine-particle material, even if fired at a low temperature, showed a small solubility. The firing temperature, however, only has to be increased in order to reduce the amount of a ferrite that is dissolved in the artificial gastric juice. FIG. 2 indicates that the heating at a temperature of at least 1,000C is preferable and that, when fired at 1,300C or upwards, the solubility of ferrite is saturated. An elevated firing temperature, on the contrary, would make the ferrite so dense and tight that grounding of fired ferrites into finely divided powder is rendered difficult. For these reasons, it is important for the manufacture of a ferrite contrast medium to fire the raw material mixture at a lowest possible temperature without fabricating it to any shape.

After diversified experiments we have found that a convenient and best method of making ferrite contrast media completely inert to the artificial gastric juice is to immerse a given ferrite powder in an acidic solution, e.g., an aqueous solution of hydrochloric acid, with a pH of about 1.0 for many hours, and then thoroughly wash the powder with distilled water. By way of exemplification, ferrite powders were placed each in 10 to times by weight of an aqueous solution of hydrochloric acid with a pH of about 1.0, agitated continuously for 5 to 10 hours, and filtered. Each filtrate was washed several times with distilled water and then dried. The ferrite contrast media obtained in this way were placed in the artificial gastric juice for 3 hours. Subsequent chemical analysis showed no evidence of dissolution of the ferrites in the liquid. This treatment also rendered the colloidal ferrites formed by the coprecipitation totally insoluble in the artificial gastric juice. If the pH is far less than l.0 (i.e., if the acidity is remarkably increased), the amount of the ferrite which dissolves in the artificial gastric juice is accordingly reducedQlf the pH exceeds 1.0 (i.e., if the acidity is decreased), the ferrite becomes markedly soluble in the artificial gastric juice. Therefore, thorough washing of a ferrite powder with an acid of about pH 1.0 is an indispensable procedure for the use of a ferrite contrast medium in the radiotherapy of human beings.

Next, the minimum magnetic field strengths required for moving the ferrite particles in dispersions of various ferrites in distilled water and also the minimum field strengths required for holding the ferrite particles in certain positions in the liquid were determined. The results, graphically shown in FIG. 3, are those of experiments with ferrites having two different particle size, i.e., 0.4 micron and 0.2 micron in diameter. Particle size being equal, the Mn-Zn ferrite would be able to be freely moved or held at a place by the smallest magnetic field. The experiments led to the discovery that large magnetic fields are required in the reducing order of the Mn-Zn ferrite, Cu-Zn ferrite, solid solution of Mg ferrite and MgO, Mg ferrite, and Fe O -Fe-Zn ferrite, and 'y-Fe O It is manifest from FIG. 3 that, the smaller the particle size, the less the strength of the magnetic field that is required for holding or moving the ferrite particles in the liquid. However, it has been experimentally confirmed that, even if the particle size is extremely small, the strength of the minimum magnetic field required for moving the particles is not appreciably decreased. In the case of the Mn-Zn ferrite, for example, the minimum field-strength necessary for moving the ferrite particles, 0.05 micron in diameter, was 35 oersteds. As a result, it has now been found that a contrast medium of soft ferrite for radio-therapy is moved by the magnetic field correspond to saturation magnetization among the magnetic characteristics of the ferrite.

When dispersed in liquid, a ferrite powder of an excessively large particle size will immediately settle down. Experiment disclosed that the particles should be not more than 0.2 micron in diameter. A ferrite powder 0.2 micron in diameter upon dispersion in distilled water settled down in about 2 to 3 minutes, whereas a 0.01-micron ferrite powder took about 50 minutes for the complete settling. Thus ferrites, when dispersed in liquid, tend to separate from the liquid and settle down within relatively short periods of time.

In order to maintain a ferrite powder dispersed uniformly in liquid for a lengthy period of time, it is necessary to use various addition agents. Extensive study and experiments on dispersants clarified the following. When starch (in an amount of l.5 percent by weight of the total weight of the liquid), sodium alginate (0.25 percent by weight), or polyvinyl alcohol (5.5 percent by weight) was added to the powder of the Cu-Zn or Mn-Zn ferrite having a particle size of 0.2 micron in diameter, 'the powder could be kept unsettled and uniformly dispersed in the liquid for about one hour. When one of the above addition agents was added to the Mn-Zn ferrite powder 0.01 micron in diameter, the powder could be similarly kept in suspension for about 3 hours.

If the amount of any such additive is much in excess of the percentage proportion above given, it increases the viscosity of the suspension to such an extent that the ferrite powder is no longer moved by the action of a magnetic field applied from the outside. It is therefore desirable to limit the proportion of such an addition agent, that is, starch to not more than 2 percent by weight of the total weight of the liquid, sodium alginate to not more than 0.3 percent by weight, or polyvinyl alcohol to not more than 6 percent by weight. Preferably, in the respective ranges of 1.0 2.0 percent, 0.1 0.3 percent, and 4 6 percent by weight, the three addition agents displayed sufficient high degrees of dispersibility.

Combined use of two or more of those addition agents gave even better results.

For example, three combinations of such addition agents, i.e., 1 percent by weight of starch and 4.5 percent by weight of polyvinyl alcohol, 5 percent by weight of polyvinyl alcohol and 0.1 percent by weight of sodium alginate, and 5 percent 'by weight of polyvinyl alcohol and 1 percent by weight of starch, all on the basis of the total weight of the liquid, were added to equal portions of the liquid which contained either the powder of the Cu-Zn ferrite or the Mn-Zn ferrite 0.2 micron in diameter. In the resulting solutions the ferrite powders were kept uniformly dispersed without any settling of the particles for periods of about 3 to 4 hours.

It has been found that, even when a combination of two or more addition agents is employed, the total amount that is added should be in the range specified for either of the components if a statisfactory result is to be attained.

As described above, the soft magnetic ferrite powders having particle sizes of 0.2 micron or less in diameter can be kept uniformly dispersed for many hours in the liquid by the addition of one or more members of the addition agent family consisting of starch, sodium alginate and polyvinyl alcohol.

The liquid in which the ferrite powders are to be dispersed is not limited to distilled water, but, for example, a carcinostatic liquid may be employed as well. In v the latter case, it is possible to mix a ferrite powder in an anti-cancer liquid medicine and, after oral administration of the liquid dispersion, keep the medicine in contact with the malignantly affected part for many hours by taking advantage of the magnetism of the ferrite.

ln dispersing a ferrite powder in a liquid, it is necessary to disperse the powder in an amount of 10 to 65 percent by weight (i.e., at a liquid to ferrite powder ratio by weight of 90 35 l0 65). It was experimentally found that more than 65 percent by weight of a ferrite powder dispersed in a liquid gives a turbid or muddy mixture, in which the ferrite particles can no longer be moved by the application of a magnetic field. Conversely if the proportion of the ferrite powder is too small, the X-ray absorption will decrease remarkably and the advantage of the powder as a contrast medium will be accordingly reduced. In view of these, at least 10 percent by weight of the ferrite powder must be dispersed in the liquid. An optimum mixing ratio of a ferrite powder as a contrast medium that utilizes a magnetic field to a liquid is, on the weight basis, 30 to 50 of the ferrite powder to 70 to 50 of the liquid. The ferrite contrast media of this invention, when administered to mice, showed no toxicity.

Another important consideration for a contrast medium for use in radiotherapy is a sufficiently great X-ray absorbing power. On the basis of the X-ray absorption factor of a dispersion of barium sulfate in distilled water (in 50 wt. percent concentration) which immersed in a row and held upright in the center of a water tank as shown in FIG. 4, at a distance of 5 centimeters each from the front and rear panels of the tank, the space in between being filled with water, and then the X-ray absorption factors were determined. The voltage applied to the X-ray tube was 60 kilovolts.

Table 1 X-ray absorption Type of contrast medium factor Barium sulfate I00 UJi OA F3204 9 3 Fe -,O 88 'Y'FGZOI! hs on z -i 78 Solid solution of 72 Mg ferrite and MgO 0.; 0.4 z -i 7O LG OA 2 4 67 It is seen from Table 1 that ferrites have relatively high X-ray absorption factors. Above all, the Fe O Fe- Zn, and 'y-Fe O ferrites were found to be highly absorptive of X-rays. In order toincrease the X-ray absorption factors of the ferrite contrast media, experiments were conducted with the addition of many diverse oxides. As a result, BaO (to be added in the form of BaCO Bi O Ce O W0 and the like were found effective in remarkably increasing the factors.

In Table 2 there are given results of measurements on the X-ray absorption factors of the contrast media that contained the abovenamed addition agents.

Table 2 X-ray absorption Type of contrast medium factor Barium sulfate Mn Zn Fe O with 93 the addition of 5 wt.% Ce O Cu,, Zn,, Fe O with 98 the addition of 8 wt.% W0

As can be seen from Table 2, the addition of the oxides referred to above increases the X-ray absorption factors of the ferrite contrast media of this invention to oxide to the ferrite. When any such oxide is to be added, it should be added in an amount of to 20 percent by weight of the total weight of the ferrite. The reason is that, since these addition agents of oxides scarcely form solid solutions with the ferrites as already pointed out, the increase in the amount of such an oxide to be added will raise the X-ray absorption factor but, on the other hand, lower the magnetism of the particular ferrite. This is exemplified in FIG. 5, wherein the curve 9 represents the Ni-Zn ferrite with BaO added, the curve 10 the Mn-Zn ferrite with W0 added, and the curve 11 the Cu-Zn ferrite with Ce O added. In any case, the addition of the oxide causes a substantially linear decline of the intensity of saturation magnetization of the specific ferrite (as determined with 7,000 oersteds). Accordingly, if the magnetism is lowered by the excessive addition of the oxide, the ferrite powder will become hardly movable upon the application of a magnetic field. Thus, in consideration of the relationship between the magnetic field strength that is required for the movement of the ferrite powder in the liquid and the X-ray absorption factor, it was experimentally confirmed that the addition of the oxide in an amount between 5 and percent by weight is most beneficial. The above rangeis chosen on the ground that, if the amount of the oxide to be added is less than 5 percent by weight, the increment of the X-ray absorption factor thereby attained is too little and, if the amount is in excess of 20 percent by weight, the magnetism is badly affected although the X-ray absorption factor is considerably increased.

In this case, the oxide to be added may be premixed with the ferrite material and fired together. Alternatively, the mixture may be easily prepared by adding the oxide to a liquid mixture or a solution of the ferrite material in the liquid.

If the oxide is to be added to a coprecipitated ferrite,

it is possible to dissolve the chloride, sulfate or nitrate of the metallic ions of the oxide to be added in water and then effect the coprecipitation of the salt together with the ferrite in alkali or, as an alternative, to add a necessary amount of the carbonate or oxalate to the ferrite obtained by the coprecipitation and then heat the mixture at a temperature between 400 and 600C for a long period of time.

The X-ray absorption factor of a contrast medium depends upon the voltage to be applied to the X-ray tube. Therefore, it is important that the ferrite contrast medium obtained by the addition of the oxide should be capable of use over a wide range of the applied voltage for the X-ray tube.

Referring to FIG. 6, the curve 12 represents measured values of an ordinary contrast medium of barium sulfate, and the curve 13 represents the measured values of the ferrite contrast medium of Mn Zn Fe O with BaO added. It is obvious that the contrast media of the BaO-containing ferrite and barium sulfate exhibit properties of the same tendency with changes of the voltage applied to the X-ray tube. Thus, the ferrite contrast media were also found useful over a wide range of applied voltage for the X-ray tube.

The foregoing contrast media of ferrites according to this invention showed no toxicity when administered to mice.

As described in detail above, this invention concerns the method of producing ferrite contrast media for radiophotography characterized by the addition of one or more of the group of oxides consisting of Ba, Bi, Ce and W to one or more soft magnetic ferrites having a particle size of not more than 0.2 micron in diameter (ac-.

counting for 10 to 65 percent by weight of the total weight of the mixture with a liquid), in an amount of 5 to 20 percent by weight on the basis of the weight of the ferrite.

Further experiments were performed on the addition of various other oxides for the improvement of the X-ray absorption factors of the ferrite contrast media. Then, the addition Of ZrO S1102, Lagos, P1' O Ndzog, 2 3 z s z a z si 3/2 3 2 3 2 a Y O and Ta O was found greatly helpful in improving the X-ray absorption factors of the ferrites. 4

Table 3 shows the results of experiments conducted with a Mn-Zn ferrite by adding different percentages of ZrO It will be clear fromTable 3 that the X-ray absorption factor rises with the increase of the amount of ZrO added and that the addition of over 15 percent by weight renders the factor of the ferrite almost equal to that of barium sulfate. However, the induction begins to decrease sharply as the proportion of the ZrO exceeds 12 percent by weight. Where Zr0 is to be added, therefore, an amount in the range of 3 to 12 percent by weight is preferable.

Table 4 shows the results of experiments with a Fe-Zn ferrite with the addition of different amounts of SnO The Fe-Zn ferrite, upon the addition of SnO attains an X-ray absorption factor substantially equal to that of barium sulfate. However, if the amount added exceeds 14%, the induction sharply drops. When adding SnO to a ferrite contrast medium for radiography, therefore, the amount to be added is preferably within the range of 3 to 12 percent by weight.

In Table 5 there are given the results of experiments in which different proportions of Ta O were added to In the case where Ta O is added to the Ni-Zn ferrite, the X-ray absorption factor of the medium increases proportionally with the amount added, but the addition in excess of 14 percent by weight leads to a sharp reduction in the induction. Thus the amount to be added is preferably in the range of 3 to I2 percent by weight.

The results of experiments on the addition of Y O to a Mn-Zn ferrite are summarized in Table 6.

When Y O is added to the Mn-Zn ferrite, the X-ray absorption factor of the ferrite medium increases with the growing proportion of the addition agent, up to the point of percent by weight or more of the proportion where the ferrite exhibits an X-ray absorption substantially equal to that of barium sulfate. An additive proportion of 14 percent by weight or more, however, would bring a serious reduction of the induction. The effective range of addition is between 3 and 12 percent by weight.

To the same Mn-Zn ferrite was added various oxides of rear earth elements, e.g., La O Pr O Nd O Sm2O B11203, Gd203, Tb203, Dy203, H0203, Yb203, and the X-ray absorption factors and the inductions at 100 oersteds of the resulting ferrite mixtures were determined under the same conditions as above. The results indicated that the relationship between the amounts of the addition agents tried and the X-ray absorption factors of the contrast media so obtained has the same tendency as when the Y O is added. The same applies to the relationship between the amounts added and the induction of the resultant ferrite media. In Table 7 are shown the results of experiments on the addition of 10 percent by weight of the various oxides of rare earth elements referred to above.

Table 7 X-ray absorp- Induction at Type of contrast medium tion factor I00 Oe. (gauss) Barium sulfate I00 0 o.ll o.4 z -l plus l0 wt.% La o 98 3200 do. Pr Q, 99 3300 do. Nd O; 99 3250 do. sm,0,, I00 3 I00 do. Eu Q, I00 3200 do. Cid- 0 3350 do. Th,0 95 3400 do. Dy Q, 96 3550 do. H0 0 96 3600 do. Yb O; 97 3400 sorption factors were measured with an anode voltage of 55 kilovolts.

As will be appreciated from the foregoing Tables 3 to 7, the addition of the various oxides help the ferrite contrast media of the invention attain X-ray absorption factors close to that of barium sulfate. X-ray powder tests indicated that those oxides will scarcely form solid solutions with the ferrites upon firing at elevated temperatures. These oxides may be added in a suitable way, for example, in such a manner that the divalent metallic ions of the particular oxide to be added substitute for the divalent metallic ions of the ferrite or that the trivalent metallic ions of the oxide substitute for the Fe of the ferrite. As a further alternative, such an oxide may be simply added to the ferrite. When any such oxide is to be added to a given ferrite, the amount should be in the range of 3 to 12 percent by weight of the total weight of the ferrite.

In such case the oxide to be added may be premixed with the ferrite material and baked together. Alternatively, an oxide-containing ferrite may be easily prepared by mixing the ferrite material with the liquid and then adding the oxide to the resulting mixed solution.

If any such oxide is to be added to a coprecipitated ferrite, it is possible to dissolve the chloride, sulfate or nitrate of the metallic ions of such an oxide in water, and then effect the coprecipitation with the ferrite in alkali, or add a necessary amount of a carbonate or oxalate to the coprecipitated ferrite and then heat the mixture at 400 to 600C for many hours.

The various ferrite contrast media produced in accordance with this invention, when administered to mice, showed no toxicity. A total of 30 mice were dosed with those ferrites at the rate of 1 gram per mouse per day for a period of about 2 months, and the dose did not prove lethal to any animal tested.

As described in detail hereinabove, the present invention pertains to a method of producing ferrite contrast media which comprises adding one or more members of the class of oxides consisting of Zr, Sn, Ta, Y, La, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho and Yb, in an amount of about- 3 to 12 percent by weight, to one or more soft magnetic ferrites having a particle size of not more than 0.2 micron (in a mixture with a liquid at the ratio of 10 to 65 percent by weight to the balance liquid). The use of the contrast media according to the invention makes it possible with ease to pinpoint any Table 8 Ferrite 40 (g) Water 54.22 Sodium alginate 0.25 Polyvinyl alcohol 5.5 Tragacanth rubber 0.02 Peppermint oil 0.01

A diagnostic X-ray apparatus provided with a magnetic device was developed to examine whether the ferrite contrast media could be carried easily to an organ to be examined and held for a long period. This apparatus comprises a conventional diagonostic X-ray apparatus and two kinds of electromagnets and a means to displace said electromagnets. More particularly, it consists of two electromagnets of 1,500 and 2,000 oersted respectively, and the device to displace these electromagnets verticularly and in horizontal plane. When a magnetic field, for example, about 350 oersted is applied, the ferrite contrast media can be displaced or fixed to any desired position.

First of all, the imitation model for the gullet and gastrointestine duct were tested utilizing the above described ferrite contrast media and diagnostic X-ray apparatus. The imitation model for the human gullet and gastrointestine duct was used for observation of capability for the controlling locations of the ferrite contrast media. The obtained result revealed to be so excellent that is proved for the sufficient availability in the examination of the gullet and gastrointestine duct.

In the next place, the test animals such as mice, rats, hares and dogs were administered with the ferrite contrast media and examined with said newly developed X-ray apparatus to serve for the fundamentalexperiments for the application to the diagnosis.

At first, various test animals were infused with the ferrite contrast media in the rectum. It was demonstrated that an enormous quantity of infusion was possible, and besides a sufficient image forming power is obtain'ed. Thus the ferrite contrast media were proved to replace perfectly the so-called barium enema. Photographs demonstrate an excellent image forming power when the ferrite contrast media were infused respectively into the gullet and gastrointestine duct.

Furthermore, relatively large animals such as hares and dogs were administered with the ferrite contrast media, and tested by means of the above described apparatus in a magnetic field. The obtained result demonstrated that the ferrite contrast media in the stomach were displaceable to any desired location by the action of a magnetic field and could serve to the repeated examination of the same location. Also these ferrite contrast media permit very easy image formation of the intestine.

From the results of fundamental animal experiments as shown above, it was demonstrated that the ferrite contrast media according to the present invention could be maintained at the desired location of gullet and gastrointestine duct for a long period and displaced from one location to others or examined repeatedly at the same location. Inasmuch as an ample prospect has been obtained for the X-ray inspection of the gullet and gastrointestine duct for a satisfactory and sufficient period, it is suggested that an earlier detection of cancer occuring in the gullet and gastrointestine duct will be more practical than before.

More detailed description of the practical effects in the diagnosis with the contrast media according to the present invention includes:

1. A mass of ferrite contrast medium is settled in the upper gullet by the effect of a magnetic field and is gradually displaced toward the stomach so that the gullet may be inspected more accurately and easily.

2. The retained period of the medium in the stomach is easily controllable due to the magnetic field.

3. The large and small intestines which have been difficult by any conventional media can be easily inspected.

4. One dose of the contrast medium is'smaller.

5. Constipation is avoided.

6. The same location of organs can be repeatedly inspected.

7. X-ray absorption is so high that a clear X-ray photograph is obtained.

We claim:

1. A radiographic contrast medium comprising an aqueous dispersion of a. from about 10 to about 65 percent by weight,

based on the total weight of said aqueous dispersion of l. at least one magnetic ferrite having a particle size of less than 0.2 l and 2. at least one metal oxide selected from the group consisting of i. from about 5 to about 20%, by weight of the ferrite, of an oxide of barium, bismuth, cerium or tungsten and ii. from about 3 to about 12 percent, by weight of the ferrite, of an oxide of zirconium, tin, tantalum, yttrium, lanthanum, praseodymium, neodymium, Samarium, europium, gadolinium, terbium, dysprosium, holmium or ytterbium, and

b. at least one dispersion agent selected from the group consisting of starch in an amount of from 1.0 to 2.0 percent by weight, based on the total weight of said aqueous dispersion, sodium alginate in an amount of from 0.1 to 0.3 percent by weight, based on the total weight of said aqueous dispersion and polyvinyl alcohol in an amount of from 4 to 6 percent by weight, based on the total weight of said aqueous dispersion. 2. A radiographic contrast medium according to claim 1 wherein the solubility of said magnetic ferrite in acid solution has been decreased by treating the ferrite with aqueous hydrochloric acid of a pH of about 1.0.

3. A radiographic contrast medium according to claim 1 wherein the magnetic ferrite is selected from the group consisting of copper-zinc ferrite, magnesium ferrite, nickel-zinc ferrite, manganese-zinc ferrite, ferrosoferric oxide, iron-zinc ferrite, and ferric oxide.

Claims

2. at least one metal oxide selected from the group consisting of i. from about 5 to about 20%, by weight of the ferrite, of an oxide of barium, bismuth, cerium or tungsten and ii. from about 3 to about 12 percent, by weight of the ferrite, of an oxide of zirconium, tin, tantalum, yttrium, lanthanum, praseodymium, neodymium, samarium, europium, gadolinium, terbium, dysprosium, holmium or ytterbium, and b. at least one dispersion agent selected from the group consisting of starch in an amount of from 1.0 to 2.0 percent by weight, based on the total weight of said aqueous dispersion, sodium alginate in an amount of from 0.1 to 0.3 percent by weight, based on the total weight of said aqueous dispersion and polyvinyl alcohol in an amount of from 4 to 6 percent by weight, based on the total weight of said aqueous dispersion.
2. A radiographic contrast medium according to claim 1 wherein the solubility of said magnetic ferrite in acid solution has been decreased by treating the ferrite with aqueous hydrochloric acid of a pH of about 1.0.
3. A radiographic contrast medium according to claim 1 wherein the magnetic ferrite is selected from the group consisting of copper-zinc ferrite, magnesium ferrite, nickel-zinc ferrite, manganese-zinc ferrite, ferrosoferric oxide, iron-zinc ferrite, and ferric oxide.