U.S. patent number 3,592,185 [Application Number 04/631,597] was granted by the patent office on 1971-07-13 for ferromagnetic contrast media and method of use.
This patent grant is currently assigned to Yeda Research and Development Co., Ltd.. Invention is credited to Ephraim H. Frei, Efrom Gunders.
United States Patent |
3,592,185 |
Frei , et al. |
July 13, 1971 |
FERROMAGNETIC CONTRAST MEDIA AND METHOD OF USE
Abstract
Ferromagnetic contrast media incorporating magnetic ferrites
such as magnesium ferrite, barium ferrite, manganese ferrite,
manganese-zinc ferrite, nickel ferrite, magnetite, or ferromagnetic
garnets; .gamma.-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.
Inventors: |
Frei; Ephraim H. (Rehovoth,
IL), Gunders; Efrom (Rehovoth, IL) |
Assignee: |
Yeda Research and Development Co.,
Ltd. (Rehovoth, IL)
|
Family
ID: |
24531910 |
Appl.
No.: |
04/631,597 |
Filed: |
April 18, 1967 |
Current U.S.
Class: |
424/9.41;
424/641; 424/647; 424/689; 604/28; 424/9.42; 424/646; 424/682;
424/722; 600/431; G9B/5.267 |
Current CPC
Class: |
C01G
49/0036 (20130101); A61K 49/04 (20130101); G11B
5/70678 (20130101); C01G 49/0018 (20130101); H01F
1/44 (20130101); C01G 49/009 (20130101); C01G
49/0072 (20130101); C01P 2006/60 (20130101); C01P
2006/42 (20130101); C01P 2004/61 (20130101); C01P
2002/32 (20130101) |
Current International
Class: |
C01G
49/00 (20060101); A61K 49/04 (20060101); H01F
1/44 (20060101); G11B 5/706 (20060101); A61k
027/08 () |
Field of
Search: |
;167/55,95,84.5 ;424/4
;128/260,2R |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Bozorth, "Ferromagnetism," D. Van Mostrand Co., New York, (1951),
pp. 244--249. .
JAMA, Vol. 195, No. 11, p. 28--29 (1966) "Husa's Pharmaceutical
Dispensing," Eric Martin et al., Mack Publishing Co., Easton, Pa.
(1959).
|
Primary Examiner: Meyers; Albert T.
Assistant Examiner: Clarke; Vera C.
Claims
What we claim is:
1. 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 80 e.m.u. per gram, and the
contrast medium containing of the order of 100 grams of said
ferrite per dose;
b. applying an external magnetic field in the region of the
patient's gastrointestinal tract to affect the disposition of the
contrast medium therein; and
c. detecting the presence of said contrast medium in the
gastrointestinal tract by X-ray examination.
2. The method as defined in claim 1, 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 100 grams per 150
cc. of the aqueous medium and the stabilizer in an amount of from 1
percent to 2 percent by weight thereof.
4. The aqueous suspension of claim 3, wherein said 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.
Description
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 patient's 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 following
publications: "Magnetism in Medicine," "Journal of Applied
Physics," Vol. 31, No. 5 (May, 1960), pages 404s--405s;
"Experimental Approach in the Use and Magnetic Control of Metallic
Iron 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--1077;"Magnet Attracts Iron to
Thrombose Aneurysms," Journal of the American Medical Association,
Vol. 195, No. 11 (Mar. 14, 1966), pages 28--29; "Particles Iron Out
Cranial Aneurysm," Medical World News (May 27, 1966), pages
30--31.
The preceding literature refers to the use of iron particles as
contrast media or as therapeutic agents employed to thrombose
intracranial aneurysms. Such iron particles are not, however, fully
inert within a patient's 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
of desired body organs.
These and other objects and advantages of the present invention
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 80 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 100
grams of ferrite would be suspended in 150 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.sub.2 O.sub.4 )
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 1,000.degree. and 1,300.degree. 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 10 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 dark-brown, 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).sub.x.sup.. MgFe.sub.2
0.sub.4, 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 of
operation.
In one particular instance, i.e., for diagnostic and/or therapeutic
treatment of the lymph tract, it is preferred to employ 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 0.1 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 .gamma.-ferric oxide. The
.gamma.-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 .gamma.-ferric oxide is substantially
inert, dissolving only slightly in hydrochloric acid at a pH of 1
and at body temperatures. The mixture of magnesium ferrite and
.gamma.-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 percent)
primarily comprises mannose and galactose. It is suitably admixed
with the magnesium or other ferrite in amounts of from about 1
percent to 2percent by weight of the 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
1,000.degree.C. The magnesium oxide may be employed in amounts of
from about 10 percent to 100 percent by weight of the magnesium
ferrite material. Use of lesser proportions of the magnesium oxide,
preferably about 10 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 of
a ball mill with 119 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 12 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
150.degree. C.
The ferrite was prepared by a prefiring operation conducted for 2
hours in a furnace heated at 1,000.degree. C. in an oxygen
atmosphere. While conventional magnesium ferrite compositions are
thereafter subjected to a firing operation at between 1200.degree.
C. and 1350.degree. 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 reddish-brown color.
Accordingly, although the magnetization of the prefired 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 .gamma.-ferric oxide magnetization
adjuvant. 245 grams of the magnesium ferrite were thus admixed with
250 grams of the .gamma.-ferric oxide to produce about 1,000 cc. of
the desired aqueous suspension.
Fifty or 150 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 1 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).sub.2. Such composition,
when administered in the manner described in Example 1, produced
like X-ray opacification and could, moreover, be utilized in
connection with ulcer therapy.
EXAMPLE 3
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.sub.x Zn.sub.1-x Fe.sub.2
O.sub.4, wherein x 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 15 minutes. A stable
suspension of the ferrite was thus produced from which the solids
did not separate by gravity or by magnetic attraction.
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 10 cc. of the contrast material
thereto. Each test animal was thereafter fluoroscoped approximately
1 hour after administration of the 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 1.7 kilo-oersted. The
field strength some 2 cm. away from the gap along the perpendicular
to the center of its face was approximately 0.4 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-oersted 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's 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 any 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 attracted 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 05--7)
EXAMPLE 4
A contrast medium similar to that formulated in Example 1 was
prepared. The contrast medium incorporated 245 grams of the
magnesium ferrite prepared as described in such example, 250 grams
of the .gamma.-ferric oxide and 10 grams of a guar gum stabilizer,
in about 1 liter of aqueous suspension.
EXAMPLE 5
A mixture of 843 grams MgCO.sub.3 was mixed with 798 grams of
Fe.sub.2 O.sub.3 and 7 liters of water in a large ball mill. This
was a material with 100 percent excess of MgO. The mixture was
fired in two portions at 100.degree. C. for 4 hours each. It was
then rapidly removed from the oven and quenched in an ice-water
bath. The magnesium ferrite composition attained a saturation
magnetization of 48 e.m.u. per gram.
EXAMPLE 6
A material with 30 percent excess MgO was prepared by mixing 676
grams MgCO.sub.3 with 1038 grams Fe.sub.2 O.sub.3 and 5 liters of
water. It was fired for 6 hours at 1000.degree. C. and quenched in
an ice water bath, as described above. The magnesium ferrite
composition attained a saturation magnetization of 53 e.m.u. per
gram.
EXAMPLE 7
A material with 10 percent excess MgO was prepared by mixing 371
grams MgCO.sub.3 with 639 grams Fe.sub.2 O.sub.3 and 4.5 liters
water. It was fired at 1100.degree. 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.
* * * * *