 |
Description  |
|
|
FIELD OF THE INVENTION
The field of the invention is that of nuclear magnetic resonance (NMR)
imaging for diagnostic examination of the body, and the contrast agents
used to enhance the NMR image. In particular, this invention is concerned
with contrast agents which may be administered either orally or rectally
for examination of the gastrointestinal system.
BACKGROUND AND PRIOR ART
Oral and rectal contrast agents for identification of the gastrointestinal
tract are needed in NMR imaging. In the search for intraabdominal disease,
fluid or feces filled loops of bowel must be distinguished from
inflammatory or neoplastic disease, which may also present as mass
lesions. In pancreatic imaging, the c-loop of the duodenum must be
visualized in order to identify the pancreatic head.
By opacification of the c-loop of the duodenum, the location of the
pancreatic head may be determined and differentiated from surrounding soft
tissue. In NMR, like CT, soft tissue masses in the abdomen are difficult
to distinguish from fluid or feces filled bowel loops. This discrimination
could be made with the use of a safe, effective contrast agent. This would
enable the diagnosis by NMR imaging of intraabdominal abscesses or
neoplastic tissue masses.
Barium sulfate and the iodinated contrast agents used in conventional
radiology do not cause a marked change consistently in proton density,
T.sub.1 or T.sub.2, in patient examinations necessitating attempts to find
new agents. Mineral oil may be used to opacify bowel loops on NMR imaging,
increasing the proton density signal. Newhouse et al, Radiology 142: 246
(1982). However, administration of sufficient quantities may be hazardous
to the patient. Ferric chloride has been tried experimentally to enhance
spin-lattice relaxation (T.sub.1) and allow visualization of the stomach.
Young et al, J. Comp. Tomo. 5: 543-546 (1981). Absorption of iron with
associated acute symptomatology prevents widespread clinical application
of this approach.
SUMMARY OF INVENTION
A contrast agent by definition must produce a significant change in the
signal being observed. A large change in signal intensity, provided by a
relatively small quantity of compound, is desired. These characteristics
can produce a consistent observable change which increases the diagnostic
information available from radiological procedures. For example, barium
sulfate and iodinated compounds absorb X-rays and thus act as effective
contrast agents in both conventional radiology and X-ray computed
tomography (CT). The use of these agents cannot, however, be extended to
nuclear magnetic resonance (NMR) imaging. The four parameters measurable
by NMR, proton density, T.sub.1, T.sub.2, and flow, are not greatly
influenced by the presence of barium or iodine. Paramagnetic compounds can
enhance proton relaxation in NMR imaging. This enhancement of relaxation,
which is equivalently described as a reduction in the spin-lattice
(T.sub.1) and/or spin-spin (T.sub.2) relaxation times, is produced by the
interaction of unpaired electrons from the paramagnetic species with the
hydrogen nuclei of water.
Heretofore NMR contrast agents have been administered, (viz. intravenously
or orally) in the form of water-soluble paramagnetic compounds. However,
paramagnetic ions in their free ion form are generally toxic. The most
effective paramagnetic metals such as gadolinium or chromium, are highly
toxic as free ions at the concentrations needed for effective NMR imaging.
Consequently, for intravenous administration it has been proposed that the
paramagnetic metal ions can be chelated to reduce their toxity. (See, for
example, the published European Patent Application No. 0 071 564, and/or
Australian application 86330-82.). Because the paramagnetic metal ions
must interact with the protons of the water, it has been generally
believed that effective contrast agents should be in water-soluble form,
such as free or chelated ions in solution.
This invention is based on the discovery that water-insoluble paramagnetic
compounds can be employed for NMR imaging of the gastrointestinal system
when administered either orally or rectally in an aqueous suspension
containing finely divided particles of the particulate contrast agent.
Because of the substantial insolubility of the compounds in the form
administered, the paramagnetic metals are rendered relatively non-toxic
and safe for introduction into and passage through the gastrointestinal
tract. According to the mechanism of the present invention, the resulting
paramagnetic effect as observed is due to the particles in suspension. Any
trace amounts of the metal ions that may have dissolved are incidental to
the NMR imaging. The contrast agents and method of the invention can
therefore be used effectively to effectively achieve discriminating
opacification of the gastrointestinal tract.
Although not previously recognized, the experimental observations
underlying the present invention have demonstrated that the solid phase
undissolved paramagnetic metal ions do sufficiently interact with the
protons of the water to achieve proton relaxation by significantly
affecting the T.sub.1 and/or T.sub.2 of the protons. A short T.sub.1 and
T.sub.2 lying outside the range of tissue relaxation times can be
satisfactorily achieved provided that the paramagnetic particles are in a
very finely divided condition. This provides a large surface area for
contact with the water protons when the particles are in aqueous
suspension. In this way, a greater number of the solid phase paramagnetic
ions interact with water protons at a sufficiently close distance to
effect relaxation, even though it is only the metal ions on the outer
surfaces of the particles which can contribute to the interaction.
DETAILED DESCRIPTION
The metals which display paramagnetic properties are well known. These
include transition metals such as titanium, vanadium, chromium, manganese,
iron, cobalt, nickel, and copper; lanthnide metals such as europium and
gadolinium; and actinide metals such as protactinium. Such paramagnetic
metals are potentially capable of enhancing protein relaxation in NMR
imaging. However, these paramagnetic metals if introduced into the
gastrointestinal tract in water-soluble form are markedly toxic at
concentration levels required for effective NMR imaging. Further,
objectionable side effects on the gastrointestinal tract are quite likely.
However, the present invention utilizes the paramagnetic metals in
substantially water-insoluble forms, such as water-insoluble salts,
oxides, or complexes of the metals.
In one embodiment, the suitability of compounds for use in the present
invention, such as for oral administration, can be determined by testing
the solubility of the compound in the finely divided condition in which it
is to be administered in aqueous hydrochloric acid, thereby simulating the
gastric fluid of the stomach. For example, it can be determined that the
paramagnetic compound is insoluble at least to the extent that less than
1% by weight (in the particulate form to be administered) dissolves in 30
minutes at a temperature of 37.degree. C. in water adjusted to a pH of 1.2
with hydrochloric acid. The concentration used and the degree of agitation
are not particularly critical. However, for uniformity five parts by
weight of the paramagnetic compound may be used per 100 parts of aqueous
hydrocholoric acid, and the mixture may be subjected to mild agitation for
the 30 minutes of the test. The test criteria is particular application to
compounds of the most highly toxic paramagnetic metals, a number of which
exhibit the greatest effect on NMR imaging. These metals include
gadolinium and chromium.
The foregoing solubility test is related to the simulated gastric fluid
prepared as described in U.S.P. XX, page 1105. According to the procedure
there described 2.0 g of sodium chloride and 3.2 g of pepsin and 7 ml of
hydrochloric acid are combined with sufficient water to make 1000 ml. The
resulting test solution has a pH of about 1.2. If desired, a solubility
test with the particulate paramagnetic compound may be conducted using the
U.S.P. simulated gastric fluid and the conditions described above.
As a further test for insolubility if required, the particulate
paramagnetic compound may be subjected to the simulated intestinal fluid
described in U.S.P. XX, page 1105. The conditions of the test may be the
same as described above for the pH 1.2 aqueous HCl. However, if the fine
particles of the paramagnetic compound are sufficiently insoluble
according to the standard defined above in aqueous hydrochloric acid, it
may be assumed that the compound is sufficiently insoluble for rectal as
well as for oral administration, even though no other precautions are
taken to maintain insolubility during passage through the gastrointestinal
system.
In another embodiment, which may be used with paramagnetic compounds which
are more readily solubilized by acid pH's, the particulate compound may be
dispersed in an aqueous buffered solution. The buffer system may be
selected to maintain a pH at which the compound remains insoluble, for
example, an approximately neutral or weakly alkaline pH (viz. 6.0 to 8.5).
The suitability of the buffered suspension, may be tested in the same
manner as described above, that is, by determining that no more than 1% by
weight of the paramagnetic compound dissolves in 30 minutes in the aqueous
buffer at 37.degree. C. (the pH being that of the buffered solution).
Examples of suitable physiologically acceptable buffers are: (1) Magnesia
and Alumina Oral Suspension USP, a mixture containing 3.4 to 4.2%
magnesium hydroxide and aluminum hydroxide with hydrated aluminum oxide
equivalent to 2.0 to 2.4% aluminum oxide; (2) an aqueous solution of
bicarbonate; such as sodium or potassium bicarbonate USP; and (3) an
aqueous solution of a phosphate buffer, such as a mixture of mono- and
di-potassium phosphate. The Magnesia and Alumina Suspension can also
function as a suspending agent. The buffered pH will be slightly alkaline
(e.g. pH 8.3). With the bicarbonate buffer a slightly alkaline pH can be
obtained (e.g. pH 7.5), and with the phosphate buffer, an approximately
neutral pH. Such buffer systems can be used with any of the paramagnetic
compounds but are particularly suitable for use with paramagnetic metals
having a relatively low degree of toxicity such as the iron compounds.
With iron compounds some degree of solubilization in the digestive tract
could be accepted. Following the NMR imaging the administered dispersion
can be diluted by administering aqueous fluids, either orally or rectally,
and enemas or laxatives can be used to decrease the residence time of the
paramagnetic metals, and to limit the absorption into the circulatory
system of any of the metal which has been solubilized.
Examples of compounds which have been found to be suitable for use in
practicing this invention are: gadolinium oxalate, chromium
acetylacetonate (Cr tris acac), and iron sulfide. Other illustrative
examples of paramagnetic compounds which may be used in solid particulate
form include:
Iron(II) carbonate (siderite), FeCO.sub.3
Iron silicide, FeSi
Iron diphosphide, Fe.sub.2 P
Iron disulfide (Morcasite), FeS.sub.2
Chromium mononitride, CrN
Gd.sub.2 (C.sub.2 O.sub.4).sub.3.10H.sub.2 O, Gd (III) oxalate
Gd(CH(COCH.sub.3).sub.2).sub.3.3H.sub.2 O, Gd(III) acetylacetonate
trihydrate
Copper(II) oleate, Cu(C.sub.18 H.sub.33 O.sub.2).sub.2
Copper xanthate, Cu(C.sub.3 H.sub.5 OS.sub.2).sub.2
Water-insoluble compounds of gadolinium, chromium, and iron are believed to
be the most advantageous for the purposes of this invention. Gadolinium
and chromium are among the most highly paramagnetic metals and may
therefore be used effectively at lower concentrations, which can
contribute to the safety of their use. Iron compounds are in general less
toxic and although iron is less paramagnetic than gadolinium or chromium,
larger amounts may be safely used including administration in buffered
aqueous suspensions as described above. Additional iron compounds which
may be used in buffered suspensions include iron pyrophosphate, iron
nitride, and iron orthosilicate.
As previously indicated, the water-insoluble paramagnetic compounds should
be utilized in finely-divided condition. In general, the particles should
be sized in the range, or at least having an average size, below 100
microns diameter. Preferred embodiments utilize the particles in a size
range below 10 microns, such as in the range from 0.1 to 3 microns. If
desired, particles smaller than 0.1 microns diameter may be employed such
as particles in the colloidal size range. Preferably, the particles are
rather closely sized, such as by fine grinding and separation by sieving.
For the desired action it is also important that the particulate
water-soluble paramagnetic compound be effectively suspended in the
aqueous medium used for its administration. Techniques for accomplishing
such suspension are known, being similar to those employed in preparing
suspensions of barium sulfate particles for oral or rectal administration.
In general, the aqueous medium should contain sufficient and effective
amounts of suspending and/or wetting agents to maintain the contrast agent
particles in a dispersed suspended condition during administration and
imaging. Suspending agents that may be employed include methylcellulose,
agar, bentonite, gelatin, hydroxypropyl methylcellulose, magnesium
aluminum silicate, pectin, etc. Other hydrocolloids or mineral suspending
agents may be used which are non-toxic and orally or rectally
administerable.
In addition to the suspending agent, it will usually be desirable to
utilize a wetting agent. The wetting agent will aid the suspensions, and
improve the contacting between the water and the surface of the particles.
Commercially available wetting agents which may be used include: Docusate
Sodium Monoethanolamine, Nonoxynol 10, Octoxynol 9, Polyoxyethylene 50
Stearate, Polyoxyl 10 Oleyl Ether, Polyoxyl 20 Cetostearyl Ether, Polyoxyl
40 Stearate, Polysorbate 20, 40, 60, 80, or 85, Sorbitan Monolaurate,
Sorbitan Monopalmitute, Sorbitan Monostearate, and Tyloxapol.
The concentration of the particulate paramagnetic compound in the aqueous
medium may vary from 0.01 to 50 milligrams per milliliter (mg/m) based on
the total contrast medium composition, including the water, other
ingredients such as the suspending and the wetting agents, and the
particulate paramagnetic compound. Based on present information, it is
believed that the preferred range for the particulate agent is from about
0.1 to 10 mg per ml of the medium. Within the concentration ranges the
total amount administered can be controlled to give effective NMR imaging.
The amounts of the suspending agent and/or wetting agent to be used are not
particularly critical provided sufficient amounts are present to maintain
the particulate paramagnetic compound in a dispersed suspended condition.
during the administration and imaging. In general, concentrations of the
suspending agent in the range from about 2 to 30 percent by weight based
on the total composition are suitable, and for the wetting agent from
about 0.02 to 1.0 percent by weight based on the total composition.
The procedure for combining the ingredients to produce the contrast media
compositions is relatively simple. Sterile ion-free water can be used to
provide the aqueous phase, and the other ingredients dispersed therein by
simple mixing at ordinary room temperatures. No special heating or
sequence of addition is needed. However, mild heating and agitation are
desirable to promote the formation of the suspension.
The contrast media compositions and their method of use is further
illustrated by the following examples.
EXAMPLE I
Contrast media compositions were prepared from: (1) gadolinium oxalate
powder (0.1 to 80 micron particles); and (2) chromium acetylacetonate
powder (0.1 to 40 micron particles). Tween 80 (polysorbate 80) was used as
a wetting agent, and methylcellulose as a suspending agent. The
compounding procedure used was to introduce a measured quantity of the
particulate contrast agent into a mortar together with sufficient Tween 80
to wet the powder, mixing with a pestle to distribute the liquid through
the powder, and then adding a small quantity of the aqueous
methylcellulose. After forming the initial suspension, this was added to
the balance of the methylcellulose, and mixed to form a uniform
suspension. The final compositions contained a range of contrast agent
concentrations (2-10 mg/ml) in approximately 9% aqueous methylcellulose.
The suspensions were sufficiently stable for storage, but were remixed to
assure uniformity prior to administration.
EXAMPLE II
T.sub.1 and T.sub.2 were determined in vitro for suspensions of gadolinium
oxalate and chromium acetylacetonate in 25% Cologel.RTM. (Eli Lilly and
Company, Indianapolis, Ind.) at 2.5 MHz using a spin-echo pulsed NMR
spectrometer. The concentrations were varied from 0 to 50 mg/ml. The
particle size ranged from 0.5 to 100 microns for Gd oxalate. TR (the pulse
repetition rate) and TE (the echo delay) were varied over a set range,
measuring the signal intensity at each point. A least squares fit was then
performed to obtain T.sub.1 and T.sub.2 for the respective experiments.
These measurements were repeated 10 times for each suspension to determine
a mean and standard deviation for T.sub.1 and T.sub.2.
NMR imaging was performed with the Aberdeen, Scotland spin-warp 0.04 Tesla
(1.7 MHz) resistive system. Scan time was 4 minutes for a 12 mm transverse
slice, allowing construction of proton density and calculated T.sub.1
images. Suspensions of the two protype agents were prepared to analyze the
effects of particle size, concentration of contrast, and composition of
suspending agent on the 0.04 T imaging system. NMR imaging of 8 New
Zealand rabbits (4 kg average) was performed using the head system coil
prior to and following either oral (via a nasogastric tube) or rectal
administration of contrast. Anesthesia was supplied by continuous
titration with intravenous pentobarbitol. 50-200 cc of 2-10 mg/ml
gadolinium oxalate or chromium acetylacetonate suspended in aqueous
solution with methylcellulose was utilized to provide opacification of the
gastrointestinal system on NMR imaging. The data is reported below in
Table A.
Results
As shown by the data of Table A, on NMR spectroscopy in vitro, increasing
the concentration of gadolinium oxalate in aqueous suspension led to a
decrease in both T.sub.1 and T.sub.2. Proton relaxation was enhanced.
Also, as shown, chromium acetylacetonate in suspension produced an
analogous enhancement of relaxation rates.
On NMR imaging at 0.04 Tesla, both gadolinium oxalate and chromium
acetylacetonate produced an enhancement in spin-lattice relaxation. By
increasing the concentration of either agent, T.sub.1 of the suspension
could be reduced below 200 msec. The use of a finer particle size
preparation caused a greater reduction in T.sub.1. When the proportion of
suspending agent was decreased, the particulate preparations were observed
visually to sediment and on NMR imaging to have a proportionately smaller
effect on T.sub.1. Barium sulfate in suspension and iodinated X-ray
contrast agents (hypaque) in solution did not significantly effect proton
relaxation.
Administration of either gadolinium oxalate or chromium acetylacetonate in
suspension via a nasogastric tube produced visualization of the rabbits'
stomachs on NMR imaging, identified by the low T.sub.1 values. Rectal
administration enabled visualization of the colon.
TABLE A
______________________________________
THE EFFECT OF PARTICULATE CONTRAST AGENTS
ON T.sub.1 AND T.sub.2 AT 0.04 TESLA
Concentration (mg/ml)
T.sub.1 (sec)
T.sub.2 (sec)
______________________________________
Gadolinium Oxalate in 25% Cologel & 0.02% Tween 80
0 0.964 .+-. .004
0.21 .+-. .07
0.05 0.699 .+-. .004
0.20 .+-. .08
0.5 0.425 .+-. .002
0.17 .+-. .05
5.0 0.335 .+-. .001
0.14 .+-. .03
50 0.286 .+-. .002
0.11 .+-. .01
Chromium Tris Acetylacetonate in
25% Cologel & 0.02% Tween 80
0.05 0.874 .+-. .003
0.21 .+-. .07
0.5 0.549 .+-. .003
0.19 .+-. .06
5.0 0.220 .+-. .001
0.13 .+-. .03
50 0.216 .+-. .001
0.07 .+-. .03
______________________________________
EXAMPLE III
Iron compounds which are insoluble in water at a neutral or slightly
alkaline pH, but which have a solubility in aqueous hydrochloric acid, may
be suspended and administered in Magnesia and Alumina Oral Suspension USP
having a slightly alkaline pH. Examples of such iron compounds and the
concentrations to be used include: iron pyrophosphate, 10-50 mg/ml; iron
nitride, 2-25 mg/ml; and iron orthosilicate, 10-50 mg/ml. The particulate
iron compounds are added to the suspension as powders and dispersed
therein, the particle size of the powders preferably being below 10
microns, such as from 1 to 3 microns average particle diameter.
* * * * *
|
|
 |
|
 |
Description |
|
