Note: Descriptions are shown in the official language in which they were submitted.
8~
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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year 1923.
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
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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
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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
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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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even by those with restricted oesophageal
capacity, e,g, those with dysphagia.
(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
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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
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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,
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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
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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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