|Numéro de publication||US3592185 A|
|Type de publication||Octroi|
|Date de publication||13 juil. 1971|
|Date de dépôt||18 avr. 1967|
|Date de priorité||18 avr. 1967|
|Autre référence de publication||DE1767206B1|
|Numéro de publication||US 3592185 A, US 3592185A, US-A-3592185, US3592185 A, US3592185A|
|Inventeurs||Frei Ephraim H, Gunders Efrom|
|Cessionnaire d'origine||Yeda Res & Dev|
|Exporter la citation||BiBTeX, EndNote, RefMan|
|Citations de brevets (3), Citations hors brevets (2), Référencé par (29), Classifications (33)|
|Liens externes: USPTO, Cession USPTO, Espacenet|
United States Patent l 13,592,l85
 [mentors Ephnlmltl'rd: 3,235,46l 2/1966 Habichtetal [67/95 Eh'orn cunmbolh flhho hd rl l 3,356,575 l2/[967 Arbaeusetal [67/95 Apr. [8, 1967 July [3, I97 I Yeda Research and Development (20., Ltd. ltehovoth, [Ind [21 I Appl. No.  Filed [45) Patented [73) Assignee  IERROMAGNETIC CONTRAST MEDIA AND METHOD OF USE 4 Claims. No Drawings  US. Cl it [28/2, [28/260, 424/4, 424/[58 [5!] lnt.C[ ..A6lk27/08  Field 0! Search [67/55, 95, 84.5; 424/4; [28/260, 2 R
 References Cited UNITED STATES PATENTS 2,67l,45l 3/1954 Bolger [67/95 X OTHER REFERENCES Bozorth, Ferromagnetism," D, Van Mostrand Co., New York,( [95 pp, 244- 249.
JAMA, Vol. [95, No. ll, p. 28- 29 [966) Husa' s Pharmaceutical Dispensing, Eric Martin et a[ Mack Publishing Co., Easton, Pa. [959) Primary ExaminerA[bert T. Meyers Assistant Examiner-Vera C. Clarke Atrorney-0strolenk, Faber, Gerb and Soffen ABSTRACT: Ferromagnetic contrast media incorporating magnetic ferrites such as magnesium ferrite, barium ferrite, manganese ferrite, manganese-zinc ferrite, nickel ferrite, magnetite, or ferromagnetic garnets; -ferric oxide and a guar gum stabilizer Such media are used for diagnostic or therapeutic treatments of the gastrointestinal or lymph tracts, by subjecting the patient to external magnetic fields to concentrate the medium in the body region to be diagnosed or treated.
FERROMAGNETIC CONTRAST MEDIA AND METHOD OF USE This invention relates to improved ferromagnetic contrast media, and more particularly to a method for the diagnostic and/or therapeutic administration of such media.
It is well known to employ barium sulfate as a contrast material in the gastrointestinal tract. The ingestion of "barium meals" (slurries of barium sulfate in water, with or without a stabilizing agent) provides a valuable diagnostic tool, enabling radiological investigation of the stomach and intestines, examination of contractions and movements, and determination of the location and size of ulcers and growths. Similarly. the use of barium enemas facilitates radiological detection of the existence and location of growths along the colon.
The use of barium contrast media, while relatively simple, is not free from complication. Misinterpretation may arise due to the presence in the region opacified of food remnants, feces, and air bubbles, which are sometimes difficult to distinguish from tumors. In some cases as, for example, in the duodenum, the barium compound passes rapidly, making diagnosis quite difficult. Moreover, the radiologist has practically no control over the internal diffusion of the barium compound, despite the frequent desirability or necessity to concentrate the contrast medium in regions to which it might not naturally diffuse. In such instances, the radiologist has been compelled to selectively apply pressure to the abdomen and tilt the examination table to vary the patients orientation as may be desirable.
The use of barium sulfate contrast media additionally poses problems as to patient acceptability, Thus, frequent variation of the patient's orientation as may be required in connection with barium therapy, may result in disorientation and even nausea of the patient during diagnosis or treatment. Additionally, the chalky taste of barium contrast media further complicates their use in human diagnosis or therapy.
The use of magnetic particles as contrast or therapeutic media has previously been proposed in, for example, the fol lowing publications: Magnetism in Medicine," "Journal of Applied Physics," Vol. 3|, No. 5 (May, I960), pages 404s- 405s; Experimental Approach in the Use and Magnetic Control of Metallic lron Particles in the Lymphatic and Vascular System of Dogs as a Contrast and Isotopic Agent," American Journal of Radiology, Vol. 90, No. 5 (Nov. 1963), pages 1068- I077;Magnet Attracts iron to Thrombose Aneurysms, Journal of the American Medical Association, Vol. 195, No. ll (Mar. I4, 1966), pages 28-29; Particles Iron Out Cranial Aneurysm, Medical World News (May 27, I966), pages 30--3 l.
The preceding literature refers to the use ofiron particles as contrast media or as therapeutic agents employed to thrombose intracranial aneurysms. Such iron particles are not, however, fully inert within a patients body and, moreover, possess relatively high densities, necessitating the administration of relatively large quantities by weight to achieve a desired opacifying function.
It is accordingly among the objects of the present invention to provide novel contrast media, and a method for the diagnostic and/or therapeutic administration of same, which may be readily administered and accurately employed to opacify and predetermined body region.
A further object of the invention is to provide such a medium which is ferromagnetic in nature and which may thus be administered to a patient and thereafter subjected to a magnetic field applied externally of the patient's body to facilitate its concentration in any portion of the body.
It is yet a further object of the invention to provide such a contrast medium which is chemically inert to body fluids and tissue and which possesses a density such that relatively small quantities by weight of the material are required to produce adequate contrast ofdesired body organs.
These and other objects and advantages of the present in vention will be more fully apparent from a consideration of the following detailed description of preferred embodiments of the ferromagnetic contrast medium and diagnostic and/or therapeutic method hereof.
We have found that improved diagnostic and/or therapeutic results may be achieved by administering to the patient to be treated a ferromagnetic contrast medium incorporating a magnetic ferrite having a particle size of 50 microns or less and exhibiting a remanence magnetization approaching, and nearly approximating, saturization magnetization values of from about 30 to e.m.u. Upon the administration of such a composition, the patient may be subjected to an externally applied magnetic field to concentrate the composition in the particular body organ or cavity to be diagnosed or treated.
The ferromagnetic contrast media hereof may thus be concentrated in given portions of, for example, the gastrointestinal or lymph tracts, without continually shifting the orientation of the patient or the treatment table. Moreover, it is possible to utilize the contrast material hereof to differentiate, for example, between air bubbles or feces and polyps by initially moving the magnetic contrast material relative to such objects, and thereafter moving the entire mass. Upon fluoroscopic examination employing such technique, polyps would appear stationary whereas air bubbles or feces would move.
Use of ferromagnetic contrast media of the present invention additionally facilitates the development of new therapeutic techniques. Thus, it is possible to treat ulcers by covering the same for prolonged periods with compositions containing such magnetic media; such compositions may additionally contain suitable medicaments such as magnesium hydroxide, currently employed in ulcer therapy.
It has been found that the novel contrast media of this invention possess several specific advantageous properties, in addition to facilitating the improvements referred to hereinabove, Thus, the ferrite materials employed in accordance herewith are sufficiently ferromagnetic, exhibiting saturation magnetizations of from about 30 to 80 e.m.u., to facilitate effective concentration of the same by means of an externally applied magnetic field or fields. Secondly, such materials have been found to absorb X-rays for diagnostic purposes, and to adhere to the walls of, for example, the stomach and intestines without clumping of flocculating. Moreover, the ferrite materials may be provided in extremely fine size ranges of 50 microns or lesser magnitudes.
Additionally, only small amounts of the ferrite contrast media hereof are required to satisfactorily effect any particularly desired contrast function. Thus, in some cases, only about grams of ferrite would be suspended in [50 cc. of water to facilitate examination of the human stomach. On the other hand, and as indicated above, it is presently necessary to utilize, for example, about 200 grams of barium sulfate for a suspension to fill the human stomach to effect X-ray examination thereof.
The magnetic ferrites so utilized are ferromagnetic ceramic oxides containing two magnetic lattices which are opposed to one another but which do not cancel each other out. Ferrites which may be employed as contrast media include magnesium ferrite, barium ferrite, manganese ferrite, manganese-zinc ferrite, magnesium-zinc ferrite, nickel ferrite, magnetite, and the ferromagnetic garnets. Other ferrites, e.g., cadmium, zinc and copper ferrite, are not so suitable in that they are not sufficiently magnetic, viz, do not possess a high enough magnetization of 30 e.m.u., per gram, at body temperature to permit control by magnetic fields.
It is preferred to employ magnesium ferrite (MgFe O, as a contrast medium for diagnostic and/or therapeutic examination of the gastrointestinal tract. Such material crystallizes with a spinel structure after preparation by sintering at temperatures between l,0OO and l,300 C. It is substantially insoluable in either water or hydrochloric acid at body temperatures and can be milled into particles having grain sizes similar to the commercially available barium sulfate materials, i.e., from about 1 to 50 microns.
The magnetization of magnesium ferrite is dependent upon its mode of preparation and quenching. With air quenching, the materials are taken out of the oven and left to cool at room temperature in the containers they were fired in, and attain a saturation magnetization of 30-40 e.m.u. per gram, depending on firing temperature and percent excess MgO in the material. With ice water quenching, the sample is taken out of the oven very quickly and dumped out of the hot container and into an ice bath. A saturation magnetization of up to 60 e.m.u. per gram may be attained in this manner.
While it is thus desirable to utilize a quenched magnesium ferrite in the practice of the present invention (since the magnetization of such material is substantially greater than that of the corresponding unquenched ferrite), other ferrites need not be necessarily so treated. Thus, while magnesium-zinc ferrites, e.g., one in which about percent zinc is incorporated, possess saturation magnetizations of 59 e.m.u. per gram if quenched after firing, such ferrites possess saturation magnetizations of as much as 48 e.n.u. per gram when prepared without quenching.
Magnesium ferrite is particularly acceptable for oral consumption, as its color varies from orange-brown to a darkbrown, depending upon its mode of preparation. On the other hand, other magnetic ferrites are black and may thus be less acceptable for patient administration. Moreover, unlike barium sulfate, the oral administration of magnesium ferrite in, for example, an aqueous slurry, leaves no after-taste and is thus particularly suitable for use as an X-ray contrast medium.
it is believed that the magnesium ferrite, when so administered, coats the mucosa of the gastrointestinal tract, the coating comprising a material of the formula (MgO),MgFe 0,, which does not agglomerate, which may readily be concentrated by magnetic force, and which is readily X-ray absorptive. It will, however, be understood that the present invention is not restricted to the preceding proposed mechanism ofoperation,
In one particular instance, i.e., for diagnostic and/or therapeutic treatment of the lymph tract, it is preferred to em ploy as the contrast medium the so-called ferromagnetic garnets. Such materials may be readily sized into extremely fine particles, i.e., having particle sizes of from (H to 10 microns. It has been found that the use of a ferromagnetic contrast medium possessing such a particle size range is important to effect satisfactory X-ray examination of the lymph tract.
The magnetic ferrite contrast material of the present invention may be administered together with other known adjuvants employed in connection with barium contrast media. It is, however, desirable, particularly in the case of the preferred magnesium ferrite material, to admix the same with 'yferric oxide. The 'y-ferric oxide is admixed with the magnesium ferrite in amounts of up to 60 percent by weight of the mixture to increase the saturation magnetization of the latter material and thereby facilitate improved concentration of the same by an externally applied magnetic field. The y-ferric oxide is substantially inert, dissolving only slightly in hydrochloric acid at a pH of l and at body temperatures. The mixture of magnesium ferrite and -y-ferric oxide in the amounts specified above, viz, in proportions of up to about 60 percent by weight of the mixture, may possess a saturation magnetization of up to 80 e.m.u. per gram, generally from about 45 to 70 e.m.u. per gram.
Preferably, the magnesium ferrite or other ferrite contrast medium is orally administered in aqueous suspension. It has been determined that stable suspensions of such materials may be produced by admixing the ferrite composition with a Guar gum stabilizing agent, other known stabilizers such as pectin, carboxy methyl cellulose and sodium alginate not being so effective. Guar gum, which is recognized as a safe food additive, consists of the ground endosperms of the Guar bean (leguminous seed Cyamopsis tetragonolobus), the water-soluble fraction of which (85 percentl primarily comprises mannose and galactose, It is suitably admixed with the magnesium or other ferrite in amounts of from about l percent to Zpercent by weight ofthe mixture.
it is additionally desirable to admix the magnesium ferrite contrast agent with magnesium oxide for ulcer therapy applications. The magnesium oxide, a recognized medicament in ulcer treatment, forms a solid solution with magnesium ferrite when such materials are prepared in admixture by sintering at temperatures of about l,0O0C. The magnesium oxide may be employed in amounts of from about 10 percent to lOO percent by weight of the magnesium ferrite material. Use oflesser proportions of the magnesium oxide, preferably about [0 percent has been found to increase the magnetization of the ferrite. The addition of greater proportions of the magnesium oxide, e.g., amounts of the order of 50 percent or greater, lowers the magnetization but markedly improves the texture of the ferrite composition and lightens its color to facilitate improved patient acceptance.
The following examples illustrate preferred, nonlimiting embodiments of the X-ray contrast media, and the diagnostic and/or therapeutic method of administering such media, of the present invention:
EXAMPLE 1 A magnesium ferrite was prepared by filling each of the two jars ofa ball mill with N9 grams of ferric oxide, 62.9 grams of magnesium carbonate, 560 ml. water, 25 porcelain porcelain balls 19 mm. in diameter, and 20 porcelain balls l2 mm. in diameter. The mixture was milled at 50 r.p.m. for 3 hours, after which the material from both jars was emptied into a Buchner funnel and most of the water extracted therefrom. The material was thereafter dried in a suitable porcelain container placed in an oven for 15 hours at l50 C.
The ferrite was prepared by a prefiring operation conducted for 2 hours in a furnace heated at l,000 C. in an oxygen atmosphere. While conventional magnesium ferrite compositions are thereafter subjected to a firing operation at between ]200 C. and 1350 C., such darkens the color of the composition to a black or brown-black hue. The prefired magnesium ferrite, on the other hand, had a less objectionable reddishbrown color. Accordingly, although the magnetization of the preflred material was only about 27 e.m.u. per gram as compared with a 36 e.m.u. per gram magnetization attainable after firing of the composition, the former material was preferred.
The magnesium ferrite contrast material was placed in an aqueous suspension containing a y-ferric oxide magnetization adjuvant. 245 grams of the magnesium ferrite were thus admixed with 250 grams of the y-ferric oxide to produce about 1,000 cc. of the desired aqueous suspension.
Fifty or cc. doses of the aqueous suspension were orally administered to human patients. The patients were subjected to radiological examination approximately 5 minutes after ingesting the contrast medium.
A permanent magnet was simultaneously moved across each patient's abdomen during irradiation to determine the effects of the same upon the contrast material in the gastrointestinal tract. The magnetic ferrite produced opacification on the fluoroscope and on X-ray film in the same manner as characteristic of barium sulfate. Moreover, it was found that movement of the externally applied magnet effected concentration of the ferrite material in predetermined portions of the gastrointestinal region.
EXAMPLE 2 A contrast material similar to that utilized in Example l was prepared, employing twice the stoichiometric amount of magnesium carbonate set forth in the preceding example. Upon reacting the ferrite-forming constituents in the manner set forth above, a material was produced containing MgO dissolved in the ferrite which, when suspended in the aqueous medium, provided a distinctly basic reaction by the formation of Mg(OH),. Such composition, when administered in the manner described in Example I, produced like X-ray opacification and could, moreover, be utilized in connection with ulcer therapy.
EXAMPLE3 A mixture of 8 grams of a commercially available barium sulfate formulation (available under the trade designation Barotrast" and comprising barium sulfate plus an emulsifier) and 6.4 grams of powdered manganese-zinc ferrite (Mn,Zn, ,Fe,0.. wherein it was about 0.5) were initially mixed by hand and 25 cc. of milk were thereafter added thereto with agitation. Finally. the mixture was ball milled for about minutes. A stable suspension of the ferrite was thus produced from which the solids did not separate by gravity or by magnetic at traction.
The contrast material was administered to a number of test guinea pigs by inserting a flexible tube through each animal's mouth into its stomach and passing from 5 to It) cc. of the contrast material thereto. Each test animal was thereafter fluoroscoped approximately l hour after administration ofthc contrast medium, the test magnet being passed over the abdomen and sides of the animal simultaneous with X-ray irradiation to determine the effect of the magnetic field thus produced upon the contrast material in the gastrointestinal tract.
Two permanent magnets were thus employed. The first such magnet was a strong horseshoe type magnet having a 2 cm. wide gap. and a maximum field strength within the gap of L7 kilo-oersted. The field strength some 2 cm. away from the gap along the perpendicular to the center of its face was approximately (L4 kilo oersted. which corresponded to the field strength produced within the test animals during the experiments. The second magnet was substantially a half disc in shape, 7 cm. in diameter. 2 cm. thick. and magnetized along the axis of a cylinder from which the half disc was cut. Such magnet produced a field strength of about 0.4 kilo-(worsted l cm. from either flat face.
Employing the preceding magnet elements, it was found possible to move the contrast material through the stomach of each test animal to effect concentration of the medium adjacent to one side of the animal in proximity to the magnet. It was additionally possible, by placing a horseshoe magnet against the animal's side. to pull its small intestine between the pole pieces of the magnet. Movement of such magnet along the animal: side caused the adjacent sections of the intestine to follow the magnet, removal of the same resulting in an apparent unfolding of the intestinal sections and return of the same to their normal relation. Such operation could, and was. repeated several times during fluoroscopic examination.
One test animal was sacrificed and operated upon to determine whether sny particles of the contrast medium had penetrated the wall of the small intestine sections which had been subjected to the greatest magnetic force. In these histological examinations. no ferrite particles were found to have penetrated the intestines. stomach or liver of the test animal.
A further test animal was sacrificed and operated upon after having the flat permanent magnet taped to its side for 2 hours. It was found that the meal which had been fed to the animal remained primarily within its stomach. solely a small portion of the contrast medium having reached the upper section of the duodenum. Such section of the duodenum had been atrscted to the magnet. which prevented the material from moving on. thereby blocking the passage. Here. too. no ferrite particles were found deeper than the intestinal surface.
It was found. in both test animals sacrificed. that the contrast material remaining within the stomach had a pH of 3 whereas that remaining within the intestine had a pH of 8. Both such material samples appeared to have the same consistency as prior to feeding.
The following examples set forth the composition of further contrast media incorporating a guar gum stabilizer (Example 4 and illustrating the manner in which the saturation magnetization of the ferrite contrast material may be modified by variation in the method of preparation thereof (Examples EXAMPLE 4 A contrast medium similar to that formulated in Example I was prepared. The contrast medium incorporated 245 grams of the magnesium ferrite prepared as described in such example. 250 grams of the y-ferric oxide and 10 grams of a guar gum stabilizer. in about 1 liter of aqueous suspension.
EXAMPLE 5 EXAMPLEb A material with 30 percent excess MgO was prepared by mixing 676 grams MgCO, with I038 grams Fe,O,and 5 liters of water. It was fired for 6 hours at 1000C. and quenched in an ice water bath. as described above. The magnesium ferrite composition attained a saturation magnetization of $3 e.m.u. per gram.
EXAMPLE 7 A material with ID percent excess MgO was prepared by mixing 37l grams MgCO with 639 grams Fqo and 4.5 liters water. It was fired at ll00 C. for 5 hours and ice water quenched as described above. The magnesium ferrite composition attained a saturation magnetization of 58 e.m.u. per gram.
What we claim is:
I. A method for X-ray visualization gastrointestinal tract of a patient, which comprises:
a. orally administering or administering by enema to the patient a contrast medium comprising an aqueous suspension of a magnetic ferrite consisting of a ferromagnetic ceramic oxide containing two magnetic lattices which are opposed to one another but which do not cancel each other out. said magnetic ferrite having a particle size of no more than 50 microns and exhibiting a saturation magnetization of from about 30 to e.m.u. per gram. and the contrast medium containing ofthe order of I00 grams of said ferrite per dose;
b. applying an external magnetic field in the region of the patient: gastrointestinal tract to affect the disposition of the contrast medium therein; and
e. detecting the presence of said contrast medium in the gastrointestinal tract by X-ray examination.
2. The method as defined in claim I. in which said magnetic ferrite is selected from the group consisting of magnesium ferrite. magnesium-zinc ferrite. barium ferrite. manganese ferrite. manganese-zinc ferrite. nickel ferrite. magnetite and ferromagnetic garnets.
3. An aqueous suspension of a magnetic ferrite and a guar gum stabilizer. the ferrite consisting of a ferromagnetic ceramic oxide containing two magnetic lattices which are opposed to one another but which do not cancel each other out. having a particle size of no more than 50 microns. and exhibiting a saturation magnetization of from about 30 to 80 e.m.u. per gram; and the suspension incorporating the ferrite in an amount of about I00 grams per cc. of the aqueous medium and the stabilizer in an amount of from 1 percent to 2 percent by welght thereof.
4. The aqueous suspension of claim 3, wherein said ferrite is selected from the group consisting of magnesium ferrite. magneslum-zlnc ferrlte. barium ferrite. manganese ferrite. manganese-zinc ferrite. nickel ferrite, magnetite and ferromagnetic garnets.
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|Classification aux États-Unis||424/9.41, 424/9.42, 424/646, 600/431, 604/28, 424/722, 424/689, G9B/5.267, 424/647, 424/641, 424/682|
|Classification internationale||C01G49/00, H01F1/44, A61K49/04, G11B5/706|
|Classification coopérative||C01P2002/32, C01P2004/61, C01P2006/60, C01G49/0072, C01G49/0018, C01P2006/42, A61K49/04, G11B5/70678, C01G49/0036, H01F1/44, C01G49/009|
|Classification européenne||G11B5/706C6D, C01G49/00C4, C01G49/00D, A61K49/04, C01G49/00C12, C01G49/00C, H01F1/44|