CA1116084A - Negative contrast agent - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A system is disclosed for inflating the stomach of a patient to enable double-contrast barium meal radiography.
The system comprises two liquid formulations to be swallowed sequentially. The first formulation is a non-toxic alkaline solution or suspension of a carbonate or bicarbonate which may be coloured, flavoured and thickened. The second formulation comprises a solution of a food grade acid.

Description

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This invention relates to certain technlques for diagnosis of abnormalities of the gastro-intestinal tract such as the administration of barium meals, computerized tomography and other "visualizirlg" examinations in humans and animals.
For over fifty years barium sulphate has been used in varying concentrations and varying degrees of fineness of particle size to visualise the gastro-intestinal tract by exposure to x-rays.
The present invention is concerned with the so-called barium swallow and barium meal which involves the oral administration of the X-ray opaque substance, usually a suitable suspension of barium sulphate, which is intended to visualise the alimentary canal from the throat to the first fifteen to twenty centimetres of the colon, which can be followed by a "barium follow through", which is a time sequence of x-ray photographs of the progress of the opaque media through the entire colon.
In that early technique, and still in practice today, the aim was to produce a stable suspension of barium sulphate to fill the entire void of the stomach and/or colon, in the hope that abnormalities would evidence themselves when multiple x-radiographs were taken, one after the other, as ~;
` the patient was turned, and a "fresh edge" of the outline of the tract came into view. The concept of introducing air as a co-contrast medium, or as it has now become known, as ;-a double contrast medium, was suggested by Fischer in the .,, ~ ' .... . . . . . . . . .

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The Japanese in the l95O's revived these techniques, as ~ar as their technology in ob-taining suitable suspensions o~
barium sulphate -to ally with the process permitted.
The pxesent invention relates to a system for introducing an "inert" gas into the stomach in conjunction with an X-ray opaque substance such as a suspension of barium sulphate.
The "i.nert" gas is used in the double contrast technique to extend the stomach, un~olding and distending the collapsed walls, enabling the visualisa-tion by the X-rays of both near and far walls simultaneously as the rays pass through the hollow gas filled stomach to expose the film. The thin films of barium sulphate ~ormulation provide the positive contrast, the gas filled void becomes the "negative" contrast.
The two contrasting aspects are the so called "Double"
contrast.
The system which gives the radiologist maximum control of the negative contrast is for the patient to swallow a tube of plastic or rubber, by which means air is pumped into the stomach. This is very unpleasant for the patient and, since local anaesthesia is usually required, under most circumstances it is not medically appropriate.
Thus, various products have been developed and are used for generating an "inert" gas in the tract by means o~ oral administration. The most widely used "inert" gas for this purpose is carbon dioxide. Current techniques for introducing the "inert" gas include reactive powders in combination, , ., ~ . .......................... . ; :

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either packed anhydrous in one measured pac~ or separately, tablets of these powders and the preparation of ready use BaS04suspensions in pressure containers to which a pre-measured dose of carbon dioxide is charged, enabling its solution in the water o~ suspension. The powders and tablets usually contain a de-foaming compound, usually a silicone type, in an endeavour to control consequent foam generati.on in the barium meal, which foams tend to be extremely stable due to the presence of colloids in the tablets themselves and in the formulated barium meal.
It has been ascertained that the average adult human stomach requires approximately 500-600 cm3 of gas to produce a satisfactory inflation and display of all surfaces. To achieve this, the existing products have certain limitations, some of which are severe:
(a) The Powders_packed Anhydrous in one part or two separate par-ts Deficiencies Common to both forms of packagin~
(1) Being very fine powders, they can be inhaled by a nervous patient during administration, with consequent extreme discomfort and actual physical danger if taken into the lungs.

(2) They cannot be satisfactorily swallowed in their dry state.

(3) They require water from some source to liberate their contained gas. If this ..

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water comes fro~ the barium meal already ingested by the patient, there can be excessive thickening of the meal due to its having to dissolve the salts of reaction. If the water is taken additionally a~ter attempting to swallow the powder dry by mouth, then gas generation can occur all the way from the mouth to the stomach, thereby reducing the necessary volume required in the stomach. If the barium meal itself is used to swallow the powders, there is considerable generati.on of foam stabilised by the colloids or suspension agents in the meal. This foam tends to persist during the entire examination, possibly giving rise to radiographs of doubtful diagnostic quality.

(4) Because of the necessity to maintain the powders in an anhydrous state, they have very limited storage life, and require exceptional packaging.

(5) Because the powders are anhydrous, incorporation of an integral water dispersible de-foaming compound, which is most desirable, poses real :
formulation problems. These compounds are ;-preferably high molecular weight silicone oils thickened with finely divided silica aerogels and exist in the pure state as semi-grease-like substances. Normally when used to control foam - . .. . .. , . : ; ~: ,. .

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in water-base systems, emulsions have to be made to render the extremely hydrophobic silicone dispersible, Once dried, ~hese emulsions are not re-dispersible without heat and agitation, but the efficiency of the base silicone compound in the absence of the emulsifying agents when used in an aqueous system is very poor indeed. Thus, if a silicone de-foaming compound is to be included ln an anhydrous powder system it is necessary either to use excessi~e amounts to try and achieve an effect or, alternatively, to use normal amounts and tolerate the inefficiency of the defoamer. Both of these two alternatives produce unfortunate results. If sufficient compound is added to effectively control foam, the quantity of compound is significant in the system and has been demonstrated to preferentially wet both the barium particles and the stomach wall, leading to loss of sharp definition and poor diagnostic quality.
Where negative contrast producing substances do not contain any or contain insufficient defoamer, supplementary defoamer usually has to be added to the barium meal or one o~ its components by the radiographic staff to ensure absolute freedom from -foam in the subsequent radiographs.
Additional Deficiency_in a Twin Pack cont~aining the Powdered Reactants packed separately (1) Any variation in the size of dose is virtually ,, . i - ~. . , :,- :

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impossible slnce the powders must be administered in exact stoichiometric proportions.
(b) Tablets - Deficiencies (l)Require up to 5 minutes to dissolve in plain tap water. When using the water of the X~ray opaque suspension ingested at approximately 12-20C, a much longer time period is required. Many experi-ments ~n vivo indicate the persistence of foam generation from tablet:s in the barium sulphate suspension during -the full course of the X-ray examination, which takes a minimum of about three minutes and a maximum o~ about twenty minutes.
(2)If the tablets are crushed prior to use, the foam generation time is much reduced, but this introduces an additional unwanted delay in the examination since the crushing must take place just before the meal is swallowed to reduce the degradation of the highly reactive powdered material by atmospheric moisture.
~c) Pressure Package X-ray Opaque Suspension containing Carbon Dioxide (l)The gas volume contained in the can is theoretically llmited by the amount of C02 that can be held by the water at the packaging pressure. Approximately 500 - 600 cm of gas is required per patient.
Present cans of product have been measured to contain approximately 200 cm of usable gas from `:

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300 ml. of suspension. This ls insufficient gas, and 300 ml. is more suspension than can be comfortably swallowed by one patient. Hence, either examination proceeds with insufficient inflation of the stomach, or an additional dose of gas is required from some other source, thus defeating the object of the single unit of packaging.
One aspect of the present invention provides a novel method for producing inert gas in the stomach of a patient by sequential administration of two small doses of novel liquid compositions. Other aspects of the invention reside in the novel compositions themselves and in their cornbin-ations for carrying out the novel method.
In accordance with one aspect of this invention there is provided a two component system for generating carbon dioxide gas in the stomach of a patient to facilitate examination of the gastro-intestinal tract, comprising:
(i) an alkaline liquid formulation comprising from 5% to 75% by weight thereof of a carbon dioxide source selected from the group consisting of non-toxic alkali metal carbonates, non-toxic alkali earth metal carbonates and non-toxic alkali metal bicarbonates, and from 95% to 25~ of water, the pH of said formulation being between

7.1 and 10;
(ii) an aqueous solution comprising at least one medically safe acid, the respective quantities of acid and alkali being stoichiometrically related so that upon mixing of the two components the resultant pH of the mixture is between 5.5 and 7.

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In one preferred form of the invention, an alkali metal bicarbonate, ~preferably sodium bicarbonate) is used at a ,, , - 8a - .

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concentration above its solubility, the excess being dispersed as a solid throughout a saturated aqueous solution of the alkali metal bicarbonate, The dispersion is stabilized by a chemically compatible, pharmacologicall.y acceptable colloidal stabilizer or suspending agent. If the carbonate or bicarbonate is sufficiently soluble (such as potassium bicarbonate) it may e~ist entirely in solution, in which case a stabilizer or suspending agent will not be necessary.
Alternatively, a substantially insoluble substance such as magnesium carbonate may be used, almost all of the carbonate then being present in the dispersed solid phase.
Optionally, such other ingredients as flavouring and colouring agents may be included, to make the formulation _ ~ b _ , . : , , : `: .

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more acceptable to a patient.
~ ~urther aspect of the present invention resides in a two part system, the first part consisting of an alkaline form~llation as previously described, and the second part consisting of any organic or inorganic acid which ls pharmacologically acceptable for ingestion by humans or animals requiring diagnosis. The acid is dissolved in water to a concentration suffi.cient such that predetermined (and p~eferably equal) volumes of the all~aline formulation and the acid solution contain the reactive ingredients which can be stoichiometrically balanced but in prac~ice they are preferably adjusted resulting in a slight deliberate surplus acidity (between about 5.5 and 7, preferably of the order of pH6) in the resultant mixture to ensure as fast as possible gas evolution when the two liquids are brought toget,her. This eliminates any possibility of unreactedcarbonate c~' bicarbonate giving off its C02 during the X-ray examination which would degrade the diagnostic quality of the X radio-graphs. On these radiographs a foam bubble can present a similar visualisation to an abnormality~ Hence foam elimination is very important and any chemical system for producing negative contrast gas must consider and deal with this aspect and should preferably include, or be accompanied by and be compatible with, an appropriate defoaming substance. , Systems according to the present invention exhibit the following benefits:
(1) I'he liquids are easily swallowed by patients, , . . .
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(2) Little or no gas is produced until the two liquids are brought together in the stomach.
(3) Easy variations in gas volume are possible, ~or example to allow a lesser dose for children or for patients with gastrec-tomy, or to allow a greater amount for those with gross abdominal development who would clearly require a larger volume.
The most satisfactory source of carbon dioxide acceptable to drug authorities for ingestion are the bicarbonates of sodium and to a lesser degree potassium. It is desirable to obtain the most gas from the minimum amount oE liquid in the administered system, since any added non radio-opaque materials tends to reduce the critical degree of high contrast which is the very basis of the so called double contrast barium meal. ~lthough potassium bicarbonate is more soluble than sodium bicarbonate and can be used to make solutions of up to approximately 20% by weight, it must be used with care t since potassium salt shock can be potentiaIly dangerous to persons with particular health problems. Sodium bicarbonate is regarded as a safer source of carbon dioxide under this invention, and its limited solubility can be overcome by suitable formulating. Sodium and potassium bicarbonates even when finely dispersed in water at levels above their respective saturated solutions, . . ' ' ' , ' ` ~ :' `: ` ` ` , ,`: ";: ' ` : :`
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tend to settle to dense indispersable layers. Without allowance in the formulation, they tend to slowly liberate their carbon dioxide, leading to loss of activity in use and possibly to a dangerous pressure build-up in storage containers. In contrast,an alkaline bicarb~na~e ~r carbon~te ~ormuIation according to the present invention neither settles nor liberates its carbon dioxide during storage.
Both parts of the system can be buffered vr not, and may be rendered palatable and can easily be swallowed even by infants and by the very aged and those with restricted oesophageal capacity. In respect of viscosity it has been , de~onstrated that there is an improvement in double contrast visualisation of the oesophagus if the viscosity of the first swallowed part is higher than the second, since a suitable thickened fluid or one which has its surface tension increased tends to line the oesophagus after swallowing and this produces a degree of gas generation during the swallowing of the second part. This effect can be photographed by the X-ray camera enabling a superior diagnosis which is known as a double contrast study of the oesophagus. Because the carbon dioxide containing component incorporates a col,loidal stabiliser or suspending agent, it is this part of the system which is preferably thickene~d , and which is preferably swallowed first. In addition to the aspect of double contrast study of the oesophagus, there is a further advantage in having the first part of the negative contrast system suitably thickened and that is that `:,' :

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the thlckened liquid will tend to remain relatively undiverted from the swallowing path of the second component so that the gas evolution as a result of the contact is as quick and complete as possible. It has been observed that, if both components are water thin, then in some patients gas generation can occur continuously for several minutes instead of in an acceptable five to ten seconds, but this by no means limits consideration of usirlg low viscosity components for bo-th parts. The tendency of the first component swallowed to disperse before the second component can be swallowed to react with it can also be restricted by raising its surface tension by a suitable surfactant. In addi.tion, the reactants and the additives to the systems are chosen on the basis of clinically proven, non-interference with the coating mechanism of presently known barium meals and are self-compensating in respect of any viscosity change on the meals as a result of the water of dilution contained in the two-part gas system. Using this new system, the 500 - 600 cm of gas necessary for inflation can be generated by as little as 5 ml each of the two reactants.
Preferably they are prepared such that exactly 10 ml of each is required since using only 5 ml of liquid introduces the possibility of erratic results from the risk of relatively significant quantities being left in the administration vessel or in the mout.h. In the subdued light or absence of light during fluoroscopy, it is difficult to measure small amounts such as would often be ~,t~ ~

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required for supplemental negative contrast gas administration.
10 ml of each component for example would reduce the chance of error without excessively diluting -the barium meal with non radio opaque material. 20 ml or more may dilute excessively.
In addition to the carbonale or bicarbonate, the formulation contains other substances to maintain a sufficient degree of stability. For example to prevent continual loss of carbon dioxide, the pH of the water should be adjusted to a safe level prior to addition of carbonate or bicarbonate.
In practice pH 7.1 to 7.5 will provide a minimum safe level.
A higher pH only requires more acid to neutralise it before the carbon dioxide can be liberated. Suitable pharmacologically acceptable bases can be used, the hydroxides of sodium and to a lesser degree po-tassium have proven satisfactory. Further, the carbonate or bicarbonate formulation may be thickened to a suitable viscosity by using acceptable gums natural or synthetic and colloids. Particularly suitable thickening agents include carbohydrates, starch related derivatives, vegetable gums and synthetic polymers. Additionally, the composition may further include anti-settling or anti-packing agents such as a silica of suitable particle size.
Either or both of the two components of the gas producing system may contain anti-foaming agents as discussed above and flavouring compositions can be added.
In the acidic component the acidity can be reduced by buffering, and sugar or at least a sweet taste can be introduced ~o reduce the patient's reaction to the sour taste of the acid.
To avoid ~mdesirable foaming of the composition within the stomach, the formulation of either liquid reactant can include the stable dispersion of an anti-foam compound or emulsion sufficien-t to prevent foam in the barium meal from the negative contrast producing system. If the anti-foam compound is a~ready dispersecl i.n emulsion ~orm, maximum efficiency is obtained from a ~ery small level and there is no interference with the barium sulphate or preerential wetting of the stomach wall. By employing the two-part system of this invention, anti-foam compounds or emulsion can be formulated which could be adjusted to the same pH as either of the two parts and an emulsifying or dispersing system employed for the anti-foam can be selected to be compatible with and preferably similar to that of the barium dispersion itself, thus maintaining the de-foamer in an active dispersed state in the presence of the barium meal ln VlVO.
The present invention is illustrated by the following non-limiting examples:-EXAMPLE
The agent consists of two separate parts - Part A
is a bicarbonate formulation according to the invention;
Part ~ is a stable solution or dispersion of food grade acid. The necessary defoamer emulsion for foam control in the meal may be added to either or both parts.
Typical formulations of Part A would be as follows:

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First Example Preferred Ran~ Optimum Formulation Sodlum Bicarbonate 5% to 75% 25%
BP
Cellulose Ether, .05% up to 25% 2%, 80,000 molecular weight molecular weight .
between 10,000 and 2,000,000 Sodium Hydroxide To adjust pH Sufficient to adjust between 7 and 10 pH to 7.5 - B.
Silicon Dioxide 1-10~ 4%
Flavouring 0.1-1% 0.5 Defoamer 0.05-5% 0.5%
Distilled Water Balance 69%

Second Exa~le Preferred Range Optimum Formulation Potassium Bicar- 5% to 75% 20%
bonate BP
Sodium Hydroxide To adjust pEI 7.5 - 8.
between 7 and 10 Flavouring 0.1% - 1% 0.5%
Distilled Water Balance . ~ - .: :

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A typical ~ormulatic)n of Part B ~Jould be as Eollows:
Preferred Rangc~ Optimurn r`ormulation Sui~able Foocl Grade Varies with acid Phosplloric acid Acid (e.g. citric, chosen. Suffi.cient 95% foocl grade tartaric, phosphoric? should be used to 17.5%.
ascorbic) neutrali~e the bi-carbonate 5-lO~J/o beyond the s~oich;o-metric requirement.
Tri-sodium citrate 5-50% 35~/0 Sugar (e.g. sucrose, 5~50% Sucrose 15.5%
glucose, clextrose levulose etc.) - or -Synthetic sweetener 0.01-1% Calcium cyclamate, O ~ 1 ;/n And if desired, Anti- 0. 5-10% 5%
foam emu:lsion (30'~0 soli~s) Flavouring 0.1-1% 0.5%
Distilled l~ater Balance t:,il - 15a -, ..

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10 ml of either of the above Part A formulations and 10 ml of the Part B formulation taken separately by mouth produce 500 - 600 cm3 of carbon dioxide in the stomach. The preferred sequence is Part A, followed by Part B. The first example of Part ~ is a creamy white liquid. The second is a clear solution. Part B i.s a straw coloured translucent to opaque watery liquid, but ~or identification purposes, it may preferably be distinctly coloured ~y any food grade colourant.
It has been found that negative contrast agents according to the present invention can be used with barium meals which have a solids content as high as 80% by weight, some 25%
greater than hitherto considered normal levels. At such high solids levels the thickening effect of the salts of reaction of conventional negative contrast producing agents can produce virtual gellation in the meal. Under normal circumstances this is not directly observable since the thickening only occurs in the patient's stomach when the salts of reaction are absorbed in the mass o barium sulphate suspension. Many thousands of radiographic exa~inations of the upper G.I. tract have been made in which practitioners have noted extremely poor visualisation of the tract, attributing this to mucous slimes or unknown causes where ; the effect may, in fact have been due to this unrealised viscosity rise. The present applicant may be the first barium meal maker to have observed and precisely measured the effects of dissolution of the different negative contrast .. . . . . .

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-producing agents in commercial barium meals and has beenable to produce a negati~e contrast agent which, apart from its advantages when used with any barium meal, also enables the use of barium meals o~ higher-than-usual solids content.

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Claims (14)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A two component system for generating carbon dioxide gas in the stomach of a patient to facilitate examination of the gastro-intestinal tract, comprising:-(i) an alkaline liquid formulation comprising from 5%
to 75% by weight thereof of a carbon dioxide source selected from the group consisting of non-toxic alkali metal carbonates, non-toxic alkali earth metal carbonates and non-toxic alkali metal bicarbonates, and from 95% to 25% of water, the pH of said formulation being between 7.1 and 10;
(ii) an aqueous solution comprising at least one medically safe acid, the respective quantities of acid and alkali being stoichiometrically related so that upon mixing of the two components the resultant pH of the mixture is between 5.5 and 7.

2. A system according to Claim 1 further including a thickening agent in at least one of said components.

3. A system according to Claim 2 wherein said thickening agent is in said alkaline formulation.

4. A system according to Claim 3 wherein said thickening agent is a cellulose ether.

5. A system according to Claim 4 wherein said ether has a molecular weight of from 10,000 to 200,000.

6. A system according to Claim 1 further including a defoaming substance in at least one of said components.

7. A system according to Claim 6 wherein said defoaming substance is in said alkaline formulation.

8. A system according to Claim 7 wherein said defoaming agent is a silicone.

9. A system according to any one of Claims 1, 2 or 6, wherein said carbon dioxide source selected is an alkali metal bicarbonate.

10. A system according to any one of Claims 1, 2 or 6, wherein said carbon dioxide source selected is sodium bi-carbonate.

11. A system according to any one of Claims 1, 2 or 6, wherein said carbon dioxide source selected is sodium bicarbonate, and wherein said alkaline formulation comprises a dispersion of said sodium bicarbonate in a saturated solution thereof, said dispersion being stabilized by a chemically compatible pharmacologically acceptable colloidal stabilizer or suspending agent.

12. A system according to any one of Claims 1, 2 or 6, wherein said carbon dioxide source selected is sodium bicarbonate, and wherein said alkaline formulation comprises a dispersion of said sodium bicarbonate in a saturated solution thereof, said dispersion being stabilized by a chemically compatible pharmacologically acceptable colloidal stabilizer or suspending agent, said system further comprising silicon dioxide.

13. A method of generating carbon dioxide in the gastro-intestinal tract of a patient comprising the sequential oral administration to the patient of a two component system according to any one of Claims 1, 2 or 6.

14. A method of generating carbon dioxide in the gastro-intestinal tract of a patient comprising the sequential oral administration to the patient of a two component system according to any one of claims 1, 2 or 6, said alkaline formulation being administered before the acid.