Note: Descriptions are shown in the official language in which they were submitted.
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CONTRAST ~EDrU~l
Field of the Invention
The invention relates to contrast media, in particular
contrast media containing contrast: agents, preferably
orally administrable particulate contrast agents, for
administration into the gastrointestinal tract, and to
the use of such contrast media in methods of diagnostic
imaging, especially X-ray, CT, magnetic resonance (MR)
or ultrasound investigations of the colon.
Background to the Invention
The use of contrast media for enhancing contrast in
imaging of the gastrointestinal (GI) tract is well
established in several imaging modalities, such as X-
ray, CT, ultrasound and MR imaging for example.
In such cases, the contrast medium may be administered
either orally or rect;ally, the administration route
generally depending on the section of the GI tract of
interest to the physician.
Thus for imaging of the colon or rectum~ ~or example in
an investigati~n for colorectal cancers, polyps or
pseudopolyps, rectal administration of contrast is
common. However, where certain pathological conditions
contraindicate contrast by way of a barium enema, it has
been an alternative to administer an oral contrast
medium.
Contrast enhanced imaging of the lower portion of the GI
tract is generally effected with either volume rendering
~in which the contrast medium fills the lumen of the
tract) or surface rendering (in which the contrast
medium simply -oats the mucosa and the tract may be
SUBSTITUTE SHEET (RUEE 26)
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1nsufflated wlth air or another non-toxlc gas).
Where the contrast medium is administered by the oral
route however, surface rendering of the colon is
frequently unsatisfactory with coating being patchy and
non-uniform.
More particularly, current formulations do not provide
an adequately long-lasting and uniform coating of the
colonic mucosai accordingly, the examination is
primarily conducted by examin1ng the initial flow of
barium over the mucosa ~the "leading edge") and then
obtaining confirmatory films ~during fluoroscopy and
after evacuation and air insufflation~. This results in
linking the barium administration with the availability
of the imaging suite. A formulation with a prolonged
and consistent imaging window would permit greater
flexibility in patient scheduling.
In addition, examining the "leading edge" of current
formulations mandates the use of manipulation which
involves patient rotation and the use of ccmpression to
highlight flow and edge detail around the area of
interest. Use of the "leading edge" technique also
increases the -hances of missing anatomical lesions
since the technique only permits visualisation of a
small part of the image field. An improved product with
uniform coating characteristics could reduce both study
time and patient discomfort by reducing the number of
manipulations necessary to obtain a quality study.
The procedure l~f administering the currenr barium
formulations i 3 also tied to the fluoroscopic portion of
the e~AminAtion. In addition to the time and C08t of
labor associated with the imaging, fluoroscopic
e~AminAtions involve higher radiation exposures for both
patients and for the technical staff. A formulation
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with improved colonic mucosal coat:ing characteristics
could serve to reduce fluoroscopic exposure during
examinations.
The discomfort associated with the rectal route of
administration and wlth the manipulations involved in
.imaging give t::he barfum enema an aesthetically
displeasing reputation among patients and among
physicians. For patlents, the out:come is that many
patients refuse to undergo this pl~ocedure on an elective
basis, even when it has documenteci value as a screening
and/or diagnostic procedure. For physicians, the lack
of prestige and the need for extensive physical labor to
obtain studies of high quality leads to the adoption of
more expensive and risky examinat~ons to obtain
identical information (eg. colonoscopy).
~t is thus an objective of this invention to provide an
oral contrast medium with improved surface rendering of
the lower port:ion of the GI tract.
We have now found that such improved surface rendering
can be achieved by the formulation of the contrast agent
ln a composition that contains an osmotic modifier which
helps to maint:ain the hydration balance of the
formulation as it passes through t:he upper GI tract
thereby preventing caking of the composition and a
mucoadhesive viscosity modifier (eg. a cellulosic agent)
which causes t:he composition to aclhere to the walls of
the lower GI t:ract and so reduces pooling of the
composition.
Sllmm~ry of the Invention
Thus viewed from one aspect the lnvention provides an
aqueous diagnostic composition suitable for oral
administration for colonic imaging, said composition
comprising a diagnostically effect:ive amount of a
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contrast agenl~, eg. an X-ray, CT, MR, ultrasound or
radionuclide-containing agent preferably a heavy metal
or iodine containing X-ray contrast agent, and
especlally preferably a particulate agent, together with
an amount of an osmotic modifier (eg. a polyol or
polyalkyleneg;ycol) sufficient to prevent caking of the
composition iIl the GI tract and an amount of an organic
mucoadhesive ~iscosity modifier sufficlent to cause
substantially uniform coating of tolonic mucosa by the
composition. It is the appropriate balance of an
osmotic modifier to enable delivery of the contrast
agent to the c-olon and a viscositv modifier to assure
mucoadherence of the contrast agent to the colonic
surface that is disclosed herein.
Viewed from another aspect the invention also provides a
diagnostic composition comprising a diagnostically
effective amount of a contrast agent together with a
~iscosity modifier and an osmotic modifier, said
modifiers together being present at a weight ratio
relative to said agent of at least 1:20, said viscosity
~odifier being selected from the c~roup consist_ng of
polyvinylpyrrclidone, natural gums, polysaccharides and
polysaccharide derivatives, and said osmotic modifier
being selected from the group consisting of C3-polyhydric
alkanols, polyalkyleneoxides and polyalky'~eneoxide
derivatives.
These viscosity and osmotic modifiers seem to have a
synergistic effect as, by way of example, colloidal
inorganic viscosity modifiers did not show such synergy
and did not produce efficient coating of the colon in
the dog model.
Preferred compositions in accordance with the invention
are those having a viscosity in the range of from 2 to
2000 cPs and an osmolality in the range Or from 50 to
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500 mOsm.
Viewed from a further aspect the ~nvention also provides
an improved method of imaging a human or non-human,
preferably mammalian, animal subject, which involves
administering a contrast medium into the
gastrointestir.al tract of the sub~ect and generating an
-mage of at least part of said tract, the improvement
comprising administering as said contrast medium a
composition according to the invention.
Viewed from a yet further aspect the invention provides
a process for the preparation of a diagnostic
composition, said process compris1ng admixing a contrast
agent together with a viscosity modifier and an osmotic
modifier as defined above, in a weight ratio of
modifiers to contrast agent of at least 1:20.
Viewed from a still further aspect the invention
provides the use of a viscosity modifier and an osmotic
modifier for the manufacture of a diagnostic composition
according to the invention for use in a method of
diagnosis invclving imaging of the gastrointestinal
tract.
The compositlons of the invention may preferably be in a
low-viscosity li~uid form and especially a ready-to-use
form, eg. a storage stable form possibly requiring some
shaking but not requiring dilution before use. Such
compositions advantageously have viscosit1es below 500
cP, preferably below 200 cP at ambient temperature
~21~C) and contain the contrast agent at concentrations
of 5 to 25~, Freferably 10 to 20~ by weight, for x-ray
imaging at concentrations of 0.05 to 10% for CT imaging
and at concentrations of 0.001 to 0.5% for MR imaging.
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Although the ~echanism of action is not -ully understood
for the described formulations, ~t was observed that a
synergistic interaction between the modifiers occurs
resulting in surprising unexpected visco-osmotic
properties for the contrast medium which allow high
quality imaging of the colon after oral administration
of the contrast medium.
Since the appropriate combination of v~scosity and
osmotic modifiers is effective at delivering an orally
administered diagnostic agent to the colon and there
providing a u:niform coating of the agent on the colonic
~ucosa, this delivery system is also applicable for the
delivery of tnerapeutic (and by this term prophylatic is
included) agents to the walls of lower GI tract and of
the colon in particular, via the oral route. Thus
viewed from a further aspect the invention also provides
an aqueous ph.~rmaceutical composition sultable for oral
administration for drug delivery to the lower GI tract
of a patient, said composition comprising a therapeutic
agent (eg. any of the conventional agents which
delivered orally or rectally are taken up through the
lining of the gut) together with an organic viscosity
modifier present at from 0.1 to 50~ w/v ~nd an osmotic
modifier present at 0.1 to 50~ w/v, the concentrations
of said modifiers being sufficient to produce on oral
administration a substantially uniform coating of said
agent on the patient's colonic mucosa.
Brief Descr~ption of the Accompanying Drawinqs
The invention is illustrated further by the accompanying
drawings in which:
Figures 1 and 2 show X-ray images of the GI tract in the
dog pre and post oral administration of the formulation
of Example l;
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Figures 3, 4, 5 and 6 show X-ray images Gf the GI tract
ln the dog after oral administration of the formulation
of Example l and, by way of compa~-ison, of the
commercial barium preparation (50~ Liquid Polibar (EZM))
and the commercial iodinated contrast media Gastrografin
and Omnipaque (90 mgI/mL);
Figures 2 and 7 show X-ray images of the GI tract in the
dog after orai and rectal administ:ration respectively of
the formulation of Example l;
Figures 2 and 8 show X-ray images of the GI tract in the
dog after ora~ administration of t:he formulation of
Example l and of an equivalent coloured and flavoured
formulation.
Figures 9 and lO show CT images of the dog after oral
administration of the formulation of Example ll; and
Figure ll shows MR images of the dog after oral
administration of the formulation of Example 12.
Detailed Description
The contrast agent in the diagnostic composition of the
invention may be any material capable of enhancing image
contrast in a diagnostic imaging modalityr eg. X-ray,
CT, ultrasound, MR, electrical impedance tomography,
magnetotomography, SPECT, scintigraphy, etc. The
invention is howe~er particularly sulted to compositions
containing particulate contrast agents or emulsions, eg.
inorganic, orcanic or organometallic particles or, less
preferably, molecular aggregates or liposomes. These
particulate agents will conveniently be substantially
insoluble, or at most poorly soluble, in the composition
and in gastric fluid.
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The precise nature of the contrast: agent will of course
depend upon the imaging modality and contrast agents
conventionally administered orall~r or rectally in any
modality may ~e formulated according to the in~ention.
Particularly preferably, for use in X-ray imaging, the
contrast agent is an inorganic hea~y metal compound,
such as barium sulphate or a poor y solu~le or
essentially water insoluble iodinated organic compound,
for example an iodinated compound as discussed in US-A-
5330739, US-A- 5318768, ~S-A-5310537, US-A-5308607, US-A-
5312616, US-A-5316755, US-A-S260099, US-A-5326553, US-A-
5310538, US-A-5260478, US-A-5318767 and US-A-5264610.
For use in MR imaging or magnetometry, the contrast
agent is preferably an inorganic ferromagnetic,
ferrimagnetic, superparamagnetic or paramagnetic
material opticnally provided with a coating or matrix
material, eg. a gastric juice resistant polymeric
coating such as a silane or polystyrene. Particles of
the type present in Nycomed's ABDC)SCAN product or
Advanced Magnetics' Biomag M4200 ~1roduct may thus be
used. Alternati~ely particles of gadolinium oxalate or
another relatively insoluble paramagnetic compound may
be used. For ultrasound imaging any echogenic material
may be used as a contrast agent and for the composition
according to the in~ention these may, for example, be
particles of greater or lesser density than gastric
fluid, eg. inorganic particulates (eg. barium sulphate)
cr gas filled synthetic polymer capsules. For
scintigraphy and SPECT the contrast agent must obviously
contain an appropriate radionuclide, eg in a
radionuclide metal ion chelate complex, or a
radionuclide containing organic or inorganic material.
Preferably the contrast agent is ~n inorganic
particulate, and especially preferably a barium
compound, in particular barium sulphate. Oral
administration of barium sulphate compositions according
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g
to the invention has resulte~ in ~eneratlon of excellent
X-ray images of the lower GI tract and of the colon in
particular.
Where the con~rast agent is particulate, as with barium
sulphate, or where the agent is a water-immiscible
liquid which :LS present in suspensed droplets (ie. as an
emulsion), the particle or droplet size ls not critical
but preferabl~ lies in the range L nm to 100 ~m,
especially 5 nm to 10 ~m, particu:Larly 10 nm to 5 ~m.
Such particle.s or droplets can be prepared by milling or
precipitation or emu~sification for example. For image
uniformity it is preferred that the particle or droplet
size distribution be narrow and preferably substantially
monodisperse.
The contrast ~lgent concentration Ln the compositions of
the invention [where these are not concentrates for
dilution with water (or another appropriate, preferably
aqueous, vehicle) prior to administration] will be
selected to be appropriate for the particular contrast
agent and imaging modality but will preferably be in the
range 0.001 to 95% w/v, preferably ~ to gr3 W/V,
particularly preferably 5 to 30~ w/v and especially
preferably 10 to 20~ w/v. Too high a concentration of
an X-ray contrast agent may make the GI tract too radio-
opaque and not: allow sufficient delineation of the
tract. For X-ray imaging, contrast agent concentration
will preferab:Ly be 10 to 20% w/v. For MR contrast
agents, too hlgh a concentration may result in
susceptibility artefacts in the image. For MR imaging,
contrast agent: concentration will generally be below 1%
w/v. For all contrast agents too low a concentration
may not provide sufficient contrast enhancement of the
image.
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The viscosity modifier used according to the invention
is preferably a natural gum (eg. ~uar gum or xanthan
gum), polyvinylpyrrolidone or a polysaccharide or
polysaccharide derlvative. Polysc2ccharides which are
branched, or which carry mono or oligosaccharide side
chains or ether derivatives of polysaccharides are
preferred. Examples of suitable rnaterial~ include
alginates, pectin, amylopectin, methylcellulose,
carboxymethylcellulose, hydroxyprc~pylcellulose,
hydroxypropylmethylcellulose, and microcrystalline
cellulose/carboxymethyl cellulose, cellulosic ethers
however are preferred.
The viscosity modifier will preferably be a natural gum
or a polysaccharide having a molecular weight in the
range 25 kD tc 2MD.
Such cellulosic ether viscosity modifiers may be any
soluble cellulose ether, for example C16 alkyl or
substituted Cl6alkyl, eg. hydroxyalkyl, alkoxyalkyl or
carboxyalkyl, ether for example et:hyl cellulose, methyl
cellulose, propyl cellulose, hydroxyethyl cellulose,
methylcarboxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose
land its saltc~ with physiological~y tolerable
counterions such as alkali metals, eg. sodium), etc.
Examples of sL.itable, commerciall~ available cellulosic
ethers include Methocel K4M, K50, KlOOLVP and E5,
Pharmacoat 61~ and Avicel CL-611.
While viscoslty modifiers capable of producing a range
of viscositiec, eg. 2-2000 cP at 1.5% w/v in water at
ambient temperature, may be used, the lower viscosity
modifiers are particularly preferred, eg. ones capable
of yielding viscosities as above i.n the range 2-100 cP,
preferably 2 to 60 cP and especially 2-50 cP. In
general, the v-iscosity and the viscosity modifier
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content should be kept as low as feasible within the
ranges mentioned in order to maximize patient
acceptance. The viscosity modifier will generally be
used at 0.1 to 50% w/v of the compositions in aqueous
ready-to-use form, preferably 0.1 to 10% w/v more
e~pecially 1 to 2.5~ w/v.
The osmotic modifier used according to the invention is
preferably a C3-polyhydric alcohol (eg. propylene glycol
or more preferably glycerine) or â polyalkylene oxide or
polyalkylene oxide derivative~ fo~ example a
polyalkylene glycol.
Such polyalkyleneglycol osmotic modifiers may be
homopolymers or co-polymers, eg a block copolymer.
Conveniently the alkylene units contain 2 to 6,
preferably 2, 3 or 4 carbons and may be the same or
different. Thus for example this modifier may be a
polyethyleneglycol (PEG), polypropyleneglycol, a
poloxamer or a poloxamine. Such polyalkyleneglycols are
available commercially in a wide range of molecular
weights and preferably those used according to the
invention have molecular weights cf 150 to 200000 D,
especially 200 to 10000 D, and parti~ularly 200 to 4000
. Examples of suitable commercially available
polyalkyleneglycols include PEG types 200, 400, 600,
1450, 3350, 4000, 6000 200K, and 2M. Examples of
suitable block copolymers include the pluronics and
tetronics, eg pluronic F127 and F108 and tetronic 1508.
The polyethylene glycols however are preferred.
The amount of osmotic modifier used is conveniently 0.1
to 50~ w/v in the aqueous ready-tc-use formulations,
preferably 0.1 to 25~ w/v (eg. 1 to 25% w/v), more
preferably 1 to 10~ w/v, especially 2 to 8~ w/v. As
with the viscosity modifier, the quantity of osmotic
modifier will generally be kept as low as feasible.
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The osmotic modifier preferably contrlbutes 5 to 500
mOsm, especially 10 to 300 mOsm, and particularly 15 to
150 mOsm, to the overall osmolar~ty of a~ueous
formulations according to the invention.
The o~erall ~eight ratio of the t:wo ~odifiers to the
contrast agert is, as stated abo~re, ~t least 1:20. More
preferably, particularly with oral barium sulphate
compositions, the ratio will be at least 1:10,
especially at least 1:5, particu~arly at least 1:3, and
preferably less than 1:1.
The weight râtio of the osmotlc modifer ~o the viscosity
modifier is Freferably in the range 1:2 to 10:1,
especially 1:3 to 8:1, particularly 1:1 to 4:1.
As is demonstrated by the Examples below, the
compositions according to the invention achieve good
coating of the small bowel and effectively coat the
colon, whether administered orally or rectally, and
exhibit apprcpriate colonic residence times. Unlike
existing barium sulphate products, they do not exhibit
pooling or settling in the small or large intestines,
they demonstrate transradiation proper~ies (ie. the
ability to allow visualization of multiple overlapping
bowel loops) over wide regions, and they demonstrate
good edge appearance. By consistently providing high
quality mucosal coating the compositions reduce operator
work load and interdependencies lie. the ability to coat
the mucosal surface, to provide transradiation and to
permit detection of edge appearance) and reduce or
eliminate the need for patient manipulatlon and for
excessive radiation exposure for both patients and
radiographers and in particular, the need for
fluoroscopic e~mination may be reduced.
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X-ray imaging of mammals (eg. dogs) to which the
compositions cf the invention have been administered
orally demonstrated transport to the colon, complete and
efficient coating of the ascendinc~, transverse and
descending colon, transradiation with good edge
delineation without retention in the stomach or small
bowel. No manipulation was required to obtain high
auality images.
The compositions of the invention may conveniently be
administered into the GI tract orally or rectally, in
doses of 0.1 to 15 mL/kg bodyweight. However the
compositions are especially suited for oral
administration and for this route dosages of 1.5 to 15
mL/kg, especially 4 mL to 10 mL/kg, are preferred.
For rectal ad~inistration, the volume of composition
administered will depend on whether surface rendering or
volume rendering is intended. In the former case a
volume of 0.1 to 10 mL/kg may be sufficient whereas in
the latter case a larger volume of 10 to 15 ~L/kg may be
required. For surface rendering studies, gas sufflation
of the lower portion of the GI tract will generally be
desirable.
Following rectal administration, image generation may be
effected immediately or within a period of up to 60
minutes. If the composition is administered orally
however enough time must be allowed post administration
to permit the composition to pass to the desired portion
of the gut. Generally, for colonic imaging of an adult
human, this will be in the range of l to 12 hours.
The imaging technique used may be any of the known
imaging modalities. However the compositions of the
invention are particularly suitable for use in
ultrasound and MR imaging, and especially in a wide
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range of X-ray imaging modalities (eg CT, flat-film,
digital, fluoroscopy, spiral CT, virtual colonoscopy,
etc).
Besides the cellulose ether viscosity modifier, the
polyalkyleneglycol osmotic modifier and the contrast
agent, the compositions of the invention may contain a
liquid carrier medium (eg. water, juice cr a
water/alcohol mixture) or one or more of the other
additives conventional in contrast media formulated for
administration into the GI tract, eg. further viscosity
or osmotic moliifiers, and conventional pharmaceutical or
veterinary formulation agents such as preservatives,
wetting agents, disintegrants, binders, fillers,
stabilizers, flavouring agents, colourlng agents,
buffers and pH adjusting agents.
The contrast media compositions of the invention may be
formulated in a physiologically tolerable aqueous
carrier medium leg. as a suspension/ emulsion, solution
or dispersion) ready for use or in concentrate form for
dilution before use. Concentrates may be diluted, eg.
with water, juice, etc. prior to 3dministration.
Alternatively, the contrast medium may be formulated in
a dry form/ eg. in powder, granule, pellet or tablet
form for dispersion before use. Ready-to-use aqueous
formulations may however be preferred.
The compositions of the invention may contain further
(alternative) osmotic and viscosity modifiers.
Alternative viscosity modifiers include bentonite,
dextrin, veegum, polyvinyl alcohol, carboxymethyl-
cellulose sodium, ethylcellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose and polyacrylic
acids. Alternative osmotic modifiers include
polyethylene glycol, glycerin, propylene glycol,
sorbitol, mannitol, alpha amino acids and ionic species,
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e.g. NaCl, cit.ric acid etc.
The invention will now be described further with
reference to the following non-lirniting Examples:
Example 1
Barium sulfate formulation containinq a viscoslty
modifier and an osmotic modifier
Ingredient Concentration (w/v)
Barium Sulfate, USP 15.00
Polyethylene CJ1YCO1~ NF 1450 5 OO%
Hydroxypropyl methylcellulose
2910, USP* 1 . 50%
Microcrystalli.ne Cellulose and
Carboxymethylcellulose Sodium, NF 1.00~
Simethicone Emulsion, USP 30~ 0.33%
Anhydrous Citric Acid, USP 0.19%
Potassium Sorbate, NF 0.15
Sodium Benzoate, NF 0 .12%
Sodium Lauryl Sulfate, NF 0.05%
Anhydrous Saccharin Sodium, USP 0.04%
Purified Water, USP ad 100 ml
*Available as Methocel E5
~Dow Chemical Company, Midland, Ml.chigan)
X-ray imaging with the above formulation administered
orally to dogs demonstrated transport to the colon,
complete and efficient coating of ascending, transverse
and descending colon, transradiat'.on with good edge
appearance, (all of which enhance the diagnostic quality
of the radiograph) without retenti.on in the stomach or
small bowel. No manipulation was required to obtain
high quality images. Pre and post.-contrast images
appear as Figures 1 and 2 hereto.
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The compositlon of Example l is preferably formulated
containing co~or and flavoring agents, eg. FD&C yellow
No. 6 Powder 0.015% w/v and Natural and Artificial
Citrus Flavour No. 325070 0.5% W/~r.
Example 2
Barium sulfa~e formulation containin~ a ~iscosity
modifier and an osmotic modifier
Ingredient Concentratlon (w~v)
Barium Sulfate, USP 15~
Polyethyleneglycol, NF-1450 2.5-10%
Pharmacoat 615 (hydroxy propyl methyl
cellulose) 2.0%
Microcystalline Cellulose anci 1.0
Carboxymethyl Cellulose Sodi.um, NF*
Simethicone emulsion, USP 30~; o 33%
Monohydrate Citric Acid, USP 0.21
Potassium Sorbate, NF 0.15
Sodium Benzoate, NF 0.12
Saccharin. Sodium, USP 0.04~
Sodium Laurel Sulphate, NF 0.075%
Purified Water, USP ad 100 ml
* Available as Avicel CL 611 from FMC Corporation
Exam~le 3
Barium sulfate formulation containing a viscosity
modifier and an osmotic modifier
In~redient Concentration (w/v~
Barium Sulfate, USP 15
Polyethyleneglycol, NF-3350 2.5-10
Pharmacoat 615 2.0
Microcystalline Cellulose and 1.0
Carboxy~ethyl Cellulose Sodium, NF*
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Simethicone emulsion, USP 30~ 0.33%
Monohydrate Citric Acid, USP 0.21
Potassium Sorbate, NF 0.15
Sodium Benzoate, NF 0.12%
Saccharin Sodium, USP
Sodium Lauryl Sulphate, NF 0.075
Purified Water, USP ad 100 ml
Exam~le 4
Magnetic Dartlcle formulation
Inqredient Concentration (w/v)
Polyethylene (,lycol, NF 1450 5.00%
Hydroxypropyl Methylcellulose
2910, USP* 1.50%
Microcrystalllne Cellulose and
Carboxymethy cellulose Sodium, NF 1.00%
Magnetic partlcles (eg. USPIOs) 0.5%
Simethicone Emulsion, USP 30% 0.33%
Citric Acid, USP 0.19%
Potassium Sorbate, NF 0.15%
Sodium Benzoat:e, NF 0.12%
Sodium Lauryl Sulfate, NF 0.05~
Saccharin Sod-um, USP 0.04%
Purified Water, USP 3~ 100 ml
*Available as Methocel E5
(Dow Chemical Company, Midland, M_chigan)
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Example S
Com~arison of prototype barium sulfate formulations to
leading commerclal formulations
A side-by-side comparison of the formulation of Example
l with a 50~ ~the clinically optimal concentration)
commercial barium sulfate suspens~on and two iodine
containing fo~mulations was performed ln the canine
model following oral administration Representative of
the images generated are Figures 3 ~Example l), 4 ~50
Liquid Polibar), 5 (Gastrografin) and 6 fOmnipaque 90
mgI/mL) of the accompanying drawiags The X-ray images
were compared for percent colon coatins, uniformity,
transradiatlon, edge appearance and mucosal coating of
the ascending, transverse and desrending colon. The
results demonstrated that the performance of the
formulation of- Example l was far superior to that of the
prior art, ancl that the formulation of Example l
delivered high image quality more consistently and was
the only product to meet the need, for dlagnostic
maging of the colon via the oral route.
Exam~le 6
Performance reproducibility evaluation of ~rototype
barium sulfate formulations
The reproducibility of image qual:~ty and consistent
colonic imaging of the formulation of Example l per oral
and rectal routes were determined using â 20 dog
reproducibility study in beagles. The study utilized an
oral and rectal crossoYer design. The results of this
study show that the formulation ol- Examp~e l
demonstrates highly reproducible, high quality colonic
lmaging per oral and rectal routes. The X-ray images
were compared by three independent e~aluators using the
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same grading criterla as described in Example 5. The
results demonstrated excellent imaging and
reproducibility for the formulation
The colon was defined into six areas: proximal
ascending, dlstal ascending, prox.imal transverse, distal
transverse, proximal descending and distal descending.
Ta~le 1 below shows the duration of coating when all
areas in the colon were coated, i.e. when all areas were
scored as 100~ by all three evaluators.
TABLE 1
Summary of length of time of 100~ coating of all areas
of the colon*
Oral administration
Dogs combined
DIJRATION F.~ue.. ~,~ Percent
3 1 5.0
-C2HR 5 25.0
2-<4HR 9 45.0
4-<5HR 2 10.0
5-c6HR I 5.0
Timepoints when all evaluators rated the coating as
lOOg6
** 2 dogs had 100~ coating of al_ areas of the colon at
8 hours, which was the final .maging time point in
the study. 1 dog had 100~ coating of all areas of
the colon, except the descendlng distal colon, from
4 hours through ~ hours. The descending distal
colon became 100~ coated at 8 hours; however, at 8
hours the mean coating evaluat:ion for the ascending
proximal colon was 87%.
Table 2 ~elow shows the mean percentage of colon coated
over time.
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TABLE 2
Mean percent colon coa-ed over time
Oral administration
Dogs combined
Area of colon 15 4~ 75 105 4 hr 5 hr 6hr 8 hr
n~in Il~in m~n min
A~ct~n~inp: proximal 0 19 60 83 100 100 100 97
~c~n-lin~ distal O 19 64 84 100 100 100 100
T~ prox~mal 0 14 63 84 100 100 100 100
Tlallav~e distal 0 10 56 7~ 98 100 100 100
Desc~nf~in~ proximal 0 10 24 43 82 94 98 100
D~scc.. ~ distal 0 10 18 26 73 89 93 100
EXamD1e 7
~ral and rectal ad~inistration of prototy?e barium
sulfate formulations
~he utility o~- oral and rectal adrninistration in
obtaining slm:Llar high quality coLonic imaging was
demonstrated :Ln the study mentioned in Example 6 in
which image quality, as evaluated by percent colon
coating, uniformity, transradiation, edge appearance and
mucosal coating of the ascending, transverse and
descending co:Lon, exhibited similar qualities. These
qualities were consistent throughout the reproducibility
study. An interesting observation was made with
retrograde administration of the .ormulation, in which
lt performed well in coating the colon and disp~ayed
excellent image quality after 5-10 minutes post dosing.
This image quality persisted over 60 minutes post rectal
dosing.
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Example 8
~n~anced resi~ency time of protot~pe barium sulfate
formulations -n colonic imaqinq
A distlnct ad~.~antage that was observed with the
formulation oi Example 1 over ComE~etitor products was
the imaging w~ndow seen with oral and rectal
administration. Diagnostic imaging persistence of 1-4
hours was observed. Coating of the colon occurred from
4 hours post nosing to at least 8 hours post dosing, in
most cases, when the formulation of Example 1 was
administered orally to canine dog models. Rectal
administratior~ demonstrated high quality imaging,
similar to oral administration, over at least a 60
minute window (duration of study). These are
demonstrated i.n the images wh.ich appear as Figures 2 (5
hours post dose - oral administrat:ion) and 7 ~30 minutes
post dose - rectal administration~ of the accompanying
drawings.
Example 9
A~ition of flavour and colour enhancers to barium
sulfate prototype formulations
Prototype suspensions were formulated containing flavour
and colouring agents to enhance patient acceptance and
palatability cf the dosage form and compared with the
formulation of Example 1 for image quality per oral
administratior.. These imaging studies demonstrated that
the addition of flavouring and col.ouring agents did not
change the image ~uality of the formulation which
appears to be independent of the flavour and colour
used. An exemplary formulation is set out below.
Representatives of the images obtained are presented in
Figures 2 (formulation of Example 1~ and 8 (flavoured
and coloured formulations) of the accompanying drawlngs.
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Prototype forrnulation with flavour and colour:
In~redient Concentration (w/v)
3arium Sulfat~, USP 15.00%
?olyethylene Glycol, NF 1450 5.00%
Hydroxypropyl Methylcellulose
2910, USP* 1.50%
Microcrystall~ne Cellulose and
Carboxymethylcellulose Sodium, M-1.00%
Citrus Flavour** 0.50
Simethicone Emulsion, USP 0.33%
Anhydrous Citric Acid, USP 0.19%
Potassium Sorbate, NF 0.15~
Sodium Benzoate, NF 0.12%
Sodium Lauryl Sulfate, NF 0 05%
Saccharin Sodium, USP o 04%
FD&C Yellow No. 6 0.01
Purified Water, USP ad 100 ml
*Available as Methocel E5
~Dow Chemical Company, Midland, M~chigan)
**eg Tastemaker No. 325070
This may be used as either an X-ray contrast agent or an
ultrasound cor,trast agent. Other ethogenic materials,
eg. gas-filled particulates or microballoons may be
substituted for the barium sulphat:e.
~Y -~ple 10
Operator independence
Testing of prctotype barium sulfat.e formulations
demonstrated that excellent flat film images of the
colon could be performed without manipulation of the
sub~ect. In normal GI examination procedures,
considerable patient manipulation (ie. rotation,
compression, etc.) is required to achieve a diagnostic
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mage to avoid pooling of the forrnulation. The
formulations described in Examples 1. and 9 above act
lndependently of the operator in obt.aining a high
c~ality coating. This effect represents a tremendous
advantage over current practice wi.th the biggest
advantages in terms of pharmacoeconomics/safety
~decreasing fluoroscopy time/exposure and physician
time) and consistency of output ~which is independent of
operator skil]s).
Exam~le 11
CT-formulatio
Inqredient Concentration (w/v)
Barium Sulfate, USP 3.5~
Polyethylene Glycol, NF 1450 5.00%
Hydroxypropyl Methylcellulose
2910, USP* 1.50%
Microcrystalline Cellulose and
Carboxymethylcellulose Sodium, NF' 1.00
Citrus Flavour** 0.50
Simethicone Emulsion, USP 0.33
Anhydrous citric Acid, USP 0.19%
Potassium Sorbate, NF 0.15%
Sodium Benzoate, NF 0.12%
Sodium Lauryl Sulfate, NF o.os%
Saccharin Sodium, USP 0.0
F~&C Yellow Nc,. 6 0.01
Purified Water, USP ad 100 ml
~Available as Methocel E5
IDow Chemical Company, Midlancl, M-.chigan)
**eg Tastemaker No. 325070
CT imaging wit.h the formulation of Example ll,
administered orally to dogs demonstrated transport to
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the colon with complete and efficlent coating with good
edge delineation. Additionally, multiple loops of the
small intestine demonstrated uniform and complete
coating with good edge delineatior. (see Flgures 9 and
10). The compositions are thus clearly useful for both
CT and non-CT applications, eg. virtual colonoscopy.
Example 12
MR-formulation
Ingredlent Concentration (w/v)
~adolinium oxalate o.oo5%
Polyethylene Glycol, NF 1450 5.00%
Hydroxypropyl Methylcellulose
2910, USP* 1.50%
Microcrystalli~e Cellulose and
Carboxymethylsellulose Sodium, NF 1.00%
Citrus Flavour** 0.50%
Simethicone Emulsion, USP 0.33%
Anhydrous Citric Acid, USP 0.19%
Potassium Sorbate, NF 0.15%
Sodium Benzoate, NF 0.12%
Sodium Lauryl ~ulfate, NF 0.05%
Saccharin Sodium, USP 0.04%
FD&C Yellow No. 6 0.01%
Purified Water, USP ad 100 ml
*Available as Methocel E5
~Dow Chemical ~ompany, Midland, Michigan)
**eg Tastemaker No. 32S070
Magnetic resonance imaging using the formulation of
Example 12 administered orally to dogs de~onstrated
efficient coating of the GI tract with good edge
delineation (see Figure 11~.
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Example 13
Performance of other viscosity modifiers
The following were satisfactorily substituted for the
celluloses in the formulation of Example l as
àemonstrated ~y colonic image quality:
Amylopectin 5.0 mg/mL
Carboxymethylcellulose, sodium NF 0.75 - 2.0 mg/mL
Guar gum NF 1.0 mg/mL
Hydroxypropyl cellulose NF 0. 75 - 2. 0 mg~mL
Methocel K4M 0. 25 mg/mL
Methocel E5 2.5 mg/mL
Methylcellulose NF (25 cP and 1500 cP~ 2.0 mg/mL
Avicel CL-611 1. 5 mg/mL
Pectin USP 2.5 mg/mL
Povidone (PVP40) USP 2.0 mg/mL
Po~idone (PVP 360) USP 2.0 mg/mL
Kollidon 90 2 - 7 mg/mL
Xanthan gum, NF 0 .25 mg/mL
Sodium alginate NF 0 .5 mg/mL
Exam~le 14
Performance of other osmotic modifiers
The following ~ere satisfactorily substituted for PEG
1450 in the formulation of Example 1 as demonstrated by
colonic image ~uality:
Glycerine USP 5 - 10 mg/mL
Pluronic F108 5.0 mg/mL
PEG 400 2/5 - 10.0 mg/mL
PEG 1450 2.5 - 10.0 mg/mL
PEG 3350 lO.0 mg/mL
PEG 20M 10.0 ng/mL
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PEG 2 OOK 1 - 3 mg/mL
Tetronic 1508 5 . 0 mg/mL
