Method of preparing X-ray contrast media containing ores of hafnium, tantalum and tungsten

A method of preparing enteric X-ray contrast media particularly suited to the use of high energy X-ray sources are disclosed. The disclosed media comprise hafnium, tantalum, tungsten, oxides or insoluble salts thereof in purified form, mixtures thereof and, more particularly, partially purified ores containing one or more of them in combination with a suitable carrier.

BACKGROUND OF THE INVENTION 
Radiopaque materials utilized today are generally of two types, viz, barium 
sulfate preparations and preparations containing iodinated organic 
compounds. The first of these types of preparations, i.e. preparations 
containing barium sulfate, suffer a number of disadvantages most of which 
are related to difficulty in obtaining a stable, high density, homogeneous 
suspension of the extremely insoluble barium sulfate and causing such 
suspensions to adhere to the intestinal mucosa. Even if such problems were 
to be overcome by the discovery of an ideal vehicle for barium sulfate, 
the resulting preparations would still not be amenable to the use of high 
energy X-rays. It is recognized that the use of high energy X-rays results 
in a decrease in the radiation dose absorbed by the body relative to the 
amount of information-bearing X-rays which reach the radiation detector 
system. It is also recognized in the art of radiopaque preparations that, 
as the energy level of X-rays utilized increases above the K-absorption 
edge of barium, the relative absorption of barium and its salts decreases. 
The same is true for the organic iodine preparations. 
The fact that barium sulfate and the iodine preparations are optimally 
suited for use with medium energy X-rays and are inefficient in absorbing 
high energy X-rays whose energy significantly exceeds their K-absorption 
edge is of critical importance to the patient. The type of studies 
contemplated with such preparations, particularly the barium sulfate 
preparations, require the use of not only a large quantity of the 
preparation itself but also, because of their X-ray absorption properties, 
a very large dose of radiation. This is unfortunate but necessary to 
obtain satisfactory diagnostic information, e.g. when conducting a 
gastrointestinal tract study. It has been long established that the higher 
the energy level of radiation passing through the human body the less 
energy is absorbed thereby. Therefore, it is readily apparent that X-ray 
contrast preparations which are optimally suited for use with high energy 
X-rays would be highly advantageous in comparison with the barium sulfate 
and iodinated preparations in terms of the amount of radiation absorbed by 
the patient. Such preparations are provided by the present invention.

DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the present invention, compositions are provided which 
are well suited for contrast media diagnostic procedures. The compositions 
of the present invention utilize high energy X-rays which can be generated 
utilizing conventional equipment commonly utilized in X-ray laboratories, 
hospitals and the like. The preparations of the present invention comprise 
one or a mixture of high Z elements tantalum, tungsten and hafnium, 
purified insoluble salts or oxides thereof or a partially purified ore 
containing one or more of them in a suitable liquid carrier. Wherein the 
preparations of the invention comprise an ore containing one or a mixture 
of tantalum, tungsten or hafnium in a suitable liquid carrier, said ore is 
in a partially purified state. The partial purification comprises 
comminuting the ores to a fine particulate state and then treating the 
particles to remove soluble matter therefrom. 
The fact that the compositions of the present invention are suitable to be 
used with high-energy X-rays makes them advantageous over similar 
preparations which are used with medium- or low-energy Z-rays. An 
advantage of 65-70 KeV X-rays, which correspond to the K-absorption edge 
of hafnium, tantalum and tungsten, is that they produce sharper X-ray 
images because of a significantly low probability of scatter in the low-Z 
elements of the body. 
Additionally, the use of such higher X-ray energies results in a higher 
contrast between the radiographic agent and tissue than with medium- or 
low-energy X-rays. High energy X-rays also show less contrast between bone 
and soft tissue than lower energy X-rays. Since boney background is known 
to interfere with imaging of radiographic agents which use medium- or 
low-energy X-rays, a sharper contrast is realized in accordance with the 
present invention due to the use of high energy X-rays. 
Also, a marked improvement in contrast enhancement is possible utilizing 
high-energy X-rays and high-Z radiographics by the use of double-exposure 
image subtraction techniques. This method takes advantage of the fact that 
the effective absorption coefficient of tissue and bone are essentially 
the same for X-rays just below and just above the 65-70 keV K-absorption 
edge for hafnium, tantalum and tungsten. Therefore, subtraction of an 
image obtained using X-rays of principal energy slightly below 65 keV from 
an image obtained using X-rays of principal energy at or slightly above 
the 65-70 keV range should result in marked enhancement of the image cast 
by the high-Z radiographic agent. 
Of the high-Z, i.e., high atomic number, elements utilized in the present 
invention only tantalum has been previously utilized for diagnostic 
procedures. In such use, pure tantalum as a very fine powder is inhaled 
without a carrier for bronchiography. Further, U.S. Pat. No. 3,937,800 
discloses a composition for bronchiography comprising finely divided 
tantalum and a metallic soap in an oily vehicle. Such use is, in part, 
limited by the fact that pure tantalum is a very expensive material. 
The fact that the elements of the present invention are expensive in their 
pure form can be a drawback to their widespread use in radiopaque 
formulations since a large quantity, e.g. 200 to 250 grams of material, 
may be required to conduct a single enteric study. Therefore, it is 
preferred in accordance with the present invention to utilize ores 
containing one or more of the high-Z elements named herein in insoluble 
form, e.g., oxides and/or insoluble salts which ores have been comminuted 
to a fine particulate state and treated to remove soluble material. 
Tantalum, hafnium and tungsten are principally present in their ores as 
simple or complex oxides. They may also be present to a much lesser degree 
as silicates, borates or complexes thereof with oxides. Depending on the 
extraction and purification process utilized, tantalum, hafnium and 
tungsten may variously be produced in a purified form as the free metal, 
oxides, e.g. tantalum pentoxide or, less frequently, in the form of 
insoluble salts, e.g., hafnium nitride, tungsten carbide and the like. The 
terminology "purified oxides and insoluble salts" as utilized herein 
refers to such compounds. 
Among the contrast media utilized in accordance with the present invention, 
the partially purified ores of tantalum, hafnium and tungsten are 
preferred. The ores are preferred because they are only partially purified 
and the elements therein are not isolated, thus they are substantially 
less expensive to the patient than the pure elements and are equally 
effective. For example, the cost of tantalite, an ore containing tantalum 
which will be discussed hereinafter, is approximately 1/6 that of the same 
quantity of pure tantalum. The relative cost of other ores to be discussed 
thereinafter will vary in comparison with the pure elements. In addition, 
the ores are preferred for use in this invention because a mixture of 
elements is present, thus the preparation containing them will absorb a 
wider range of radiation therefore allowing for use of a broader band of 
X-ray energies that that which would be optimal for use with a radiopaque 
agent consisting of a single element. 
The ores useful in accordance with the present invention are those which 
contain at least one of the elements hafnium, tantalum or tungsten. For 
example, among the principal tantalum-containing ores, many of which 
usually also contain niobium (columbium), are columbite, tantalite, 
loparite, fergusonite and the like. Other elements which are often found 
in these ores include titanium, tin and iron. The elements are usually 
present in these ores as the oxide, multiple oxides and hydroxide. The two 
principal ores containing hafnium are zircon and baddeleyite, both of 
which contain hafnium in a ratio of at least 1:50 with zirconium wherein 
both are present as the oxide. Principal ores containing tungsten include 
huebnerite, wolframite, ferberite, scheelite and powellite. Preferred ores 
in accordance with the present invention are tantalite, columbite and 
scheelite. It is also preferred to mix two or more of the above named ores 
to achieve a wider range of absorbtion of high energy X-rays or to mix a 
small quantity of a particular element with an ore containing one of the 
others. A preferred combination of this type is scheelite with added 
tantalite. 
As stated above, the ores utilized in the preferred compositions of the 
present invention are prepared for use by a simple process which makes 
their use for radiographic procedures economically attractive. Initially, 
the ores are comminuted to a fine particle size, i.e. the majority of 
particles are substantially no larger than one micron in diameter. After 
the ore has been reduced to the proper particle size, the particles are 
then extracted by washing with aqueous solutions containing solutes 
comparable to those formed in the human gastrointestinal tract. The 
washing procedure would, for example, be initially with an acidic solution 
to similate conditions in the stomach and thereafter with an alkaline 
solution to simulate conditions in the gut. The washing solutions may 
additionally contain enzymes such as are found in the gastrointestinal 
tract. Several washings are required and it is also preferred that the 
solutions are heated, e.g. to a temperature of at least 90.degree. C. The 
washing operation is intended to purify the ore in the sense that any 
soluble salts or other materials are removed thereby thus preventing their 
absorbtion into the body. The result of the grinding and washing 
procedures is a fine granular powder which, in a suitable carrier, is 
capable of forming a film on intestinal mucosal surfaces. The powder 
produced from tantalum, hafnium or tungsten-containing ores in accordance 
with the invention absorbs high energy X-rays and is not absorbed into the 
body. This powder is then incorporated into a suitable contrast media 
carrier therefor. 
The carriers for the contrast media in accordance with the present 
invention are pharmaceutically acceptable viscous liquids. Preferred 
liquids include propylene glycol, glycerin and some vegetable oils, e.g. 
peanut oil, safflower oil, cotton seed oil and the like. Where the 
viscosity of the liquid carriers is not sufficient to suspend the contrast 
agents, pharmaceutically acceptable thickening and/or suspending agents 
may be added to adjust the viscosity to the required level. Examples of 
suitable agents include polyvinylpyrrolidone, carboxymethylcellulose, 
lecithin, acacia and the like. The amount of contrast agent incorporated 
in the carrier is not particularly critical. Usually, however, the 
preparations in accordance with the invention contain from about 10% by 
weight to about 50% by weight of hafnium, tantalum or tungsten and/or 
their ores. The amount of the contrast media present in the final 
preparations as well as the viscosity thereof will vary considerably with 
the type of study being conducted and the mode of administration intended. 
For example, if the preparation is to be infused into a body cavity, it 
must be sufficiently fluid to be withdrawn into a syringe and easily 
installed into the cavity. The viscosities required for particular studies 
are recognized in the art. Therefore, the amounts of thickening or 
suspending agent to be incorporated within the formulations as disclosed 
herein to achieve the desired viscosities are considered to be within the 
skill of the art. 
The preparations of the present invention may additionally contain other 
ingredients such as are recognized as being conventional in such 
preparations, e.g. flavoring agents wherein such preparations are intended 
to be orally ingested for studies of the upper gastrointestinal tract, 
preservatives and the like. The incorporation of hafnium, tantalum, 
tungsten, their purified insoluble salts or oxides or their ores into the 
carrier material is carried out by techniques conventional in the art, 
preferably wet granulation. 
The radio contrast preparations in accordance with the present invention 
have been found to exhibit good adherence properties. Such properties are 
essential since the preparation must effectively coat the walls of the 
organ to be studied in order to yield a good picture. Further, the 
preparations of the invention are suited for use with conventional X-ray 
equipment since such equipment can be modified with conventional filters 
so that all but the high energy X-rays suitable for the intended study are 
filtered. The X-ray energy may be precisely filtered so that the mean 
X-ray energy approximates the K-absorption of a pure element or filtered 
to block only low and medium energy X-rays wherein an ore is utilized. 
The following examples further illustrate the invention. 
EXAMPLE 1 
Utilizing a conventional diagnostic X-ray machine equipped with aluminum 
and copper absorbers, samples of the material to be tested were placed in 
the midplane of a plexiglass phantom intended to approximate in vivo 
conditions under which such agents would be used. Conventional 
thermo-luminescent dosimeters were utilized to evaluate absorbed radiation 
dose front, mid and back plane of the phantom. Various levels of X-rays 
were passed through the phantom. All exposures were adjusted to yield 
comparable background density on the X-ray film therefor. The comparison 
made on the basis of absorbed radiation dose reasonably approximates the 
reduction in radiation dose expected in the clinical situation utilizing 
the stated operating conditions. For this experiment barium was in the 
form of barium sulfate, tantalum, hafnium and tungsten were utilized as 
oxides and iodine was in the form of sodium iodate. All substances were 
ground and passed through a U.S. Standard 250 mesh screen. 
The results of this experiment are given in the following table. In the 
table, section A represents operating parameters of the operating machine 
(kvp, in A, exposure time and filtration). Section B contains the 
absorbtion data in mR for exposure at the upper surface (front) midplane 
and lower surface (back) of the phantom. Section C gives the effective 
mass absorption coefficient (.lambda.) expressed as # per gram of the 
element /cm.sup.2 and the correlation coefficient (r) of the data to the 
regression line utilized in the determination of .lambda.. 
TABLE 
__________________________________________________________________________ 
A: X-RAY MACHINE OPERATING CONDITIONS 
__________________________________________________________________________ 
Voltage (kvp) 
85 125 125 125 125 
Current (mA) 
132 64 162 320 160 
Exposure Time (sec) 
1/2 1/29 1/30 1/5 2.5 
mA .times. Exposure 
11 mAs 3.2 mAs 
6.4 mAs 
64 mAs 400 mAs 
time (in secs) 
Filtration used 
none none 5mm Al 5mm Al 5mm Al 
3.2mm Cu 
6.4 mm Cu 
B: ABSORBED IN mR IN PHANTOM PER EXPOSURE TO YIELD CONSTANT 
BACKGROUND FILM DENSITY 
__________________________________________________________________________ 
Upper surface 
62.4 .+-. 6.2 
32.3 .+-. 3.2 
20.4 .+-. 2.0 
10.8 .+-. 1.1 
9.6 .+-. 1.0 
Midplane 16.3 .+-. 1.6 
11.7 .+-. 1.2 
10.1 .+-. 1.0 
6.9 .+-. 0.7 
5.7 .+-. 0.7 
Lower surface 
4.4 .+-. 0.7 
3.7 .+-. 0.7 
3.9 .+-. 0.7 
3.3 .+-. 0.7 
2.4 .+-. 0.7 
C: EFFECTIVE ABSORPTION COEFFICIENT .lambda. (# PER GRAM OF 
ELEMENT/cm.sup.2) 
OVER CORRELATION COEFFICIENT (r) 
__________________________________________________________________________ 
Iodine 4.78/.96 
4.91/.97 
4.51/.93 
3.73/.96 
2.87/.98 
Barium 4.96/.98 
5.59/.99 
4.46/.98 
3.34/.99 
2.77/.96 
Hafnium 3.35/.95 
4.06/.98 
4.48/.98 
6.05/.93 
5.19/.99 
Tantalum 3.14/.97 
3.92/.98 
4.04/.98 
6.68/.97 
5.79/.99 
Tungsten 3.33/.95 
3.45/.94 
3.75/.92 
4.46/.86 
5.65/.94 
__________________________________________________________________________ 
It is readily appreciated from an examination of the data in the above 
table that, as the voltage on the X-ray machine is increased and the 
filtration utilized to allow only high energy or "hard" X-rays to pass, 
the absorbed radiation dose sharply decreases, i.e., on the upper surface 
from 62.4 mR to 9.6 mR, midplane from 16.3 mR to 5.7mR and lower surface 
from 4.4 mR to 2.4 mR. Utilizing "soft" X-rays, i.e. 85 kvp with no 
extrinsic filtration, iodine and barium have effective mass absorbtion 
coefficients approximately 50% greater than the other three elements 
tested while the opposite is true with the high energy or "hard" X-rays. 
From this data it can be appreciated that patients would receive 
considerably more radiation dose using barium sulfate and "soft" X-rays in 
comparison with a comparable weight of tantalum, hafnium or tungsten and 
"hard" X-rays. 
Even more meaningful for evaluating the relative merits of agents to be 
used for enteric studies than the comparison of effective element mass 
absorption coefficients given in the table is the comparison of linear 
effective absorption coefficient (#/cm) of the powdered agents. Such a 
comparison is important because it is the X-ray absorption of the layer of 
radiographic material on the surface of the intestinal mucosa which 
determines image contrast. 
Such an analysis was performed based on the measured weight per unit volume 
of lightly packed powders of each of the above materials with the 
exception of sodium iodate. All powders were hand ground and passed 
through a 250-mesh screen. It was found that even with "soft" X-rays (85 
kvp, no extrinsic filtration), the oxides of tantalum, hafnium and 
tungsten have effective linear absorption coefficients two or three times 
greater than that of barium sulfate. This is due largely to the greater 
effective density of the metal oxides powders than that of barium sulfate 
powder of comparable particle size. This difference is accentuated with 
the use of "hard" X-rays (125 kvp, 5 mm Al, and 3.2 mm Cu extrinsic 
filtration) where powdered hafnium and tantalum oxides have linear 
absorption coefficients of over seven times that of powdered barium 
sulfate. This data indicates that with the use of such "hard" X-rays, a 
layer of hafnium or tantalum oxides on the intestinal mucosa one-seventh 
the thickness of a layer of barium sulfate would yield comparable density 
on the X-ray film. Conversely, wherein the layers of contrast media on the 
intestinal mucosa are of comparable thickness, significantly greater 
contrast will be obtained during radiography with the use of hafnium, 
tungsten or tantalum oxides than with barium sulfate. 
EXAMPLE 2 
A sample of Ta-177 pentoxide was combined with carrier Ta.sub.2 O.sub.5, 
and formed into separate fluid suspensions in each of water, glycerin and 
vegetable oil, respectively. All suspensions were orally administered to 
rats. None showed evidence of appreciate systemic absorption. Tantalum 
pentoxide was found to form excellent homogeneous pastes in glycerin, 
propylene glycol and vegetable oil at concentrations of 10, 40 and 80% by 
weight. These pastes retained much of their wetting properties even with 
the addition of water. Pastes obtained with the oxides of tungsten and 
hafnium as well as finely ground tantalite produced comparable results. 
The viscosity of the 10% by weight suspensions in propylene glycol was 
significantly increased by the addition of 10% weight to volume of 
polyvinylpyrrolidone. These suspensions retained good wetting properties 
and exhibited marked improvement in settling of the metal oxide powders.