CA2247041A1

CA2247041A1 - Contrast medium

Info

Publication number: CA2247041A1
Application number: CA002247041A
Authority: CA
Inventors: Natarajan Rajagopalan; Kevin Darryl Ostrander; Evan Gustow; Brian Doty; Phillip Harnish
Original assignee: Individual
Current assignee: GE Healthcare AS
Priority date: 1996-02-20
Filing date: 1997-02-20
Publication date: 1997-08-28
Also published as: HUP9901323A2; WO1997030736A3; GB9603547D0; JP2000504742A; BR9710946A; NO983828D0; NO983828L; CN1215342A; KR19990087196A; EP0881916A2; AU1885297A; WO1997030736A2

Abstract

The invention provides a contrast medium having good lower GI tract coating properties following oral administration. The medium comprises a diagnostically effective amount of a contrast agent together with a viscosity modifier and an osmotic modifier, said modifiers together being present at a weight ratio relative to said agent of at least 1:20.

Description

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) 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 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 CA 02247041 1998-08-lg W097/30736 pcTlGBs7loo473 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 CA 0224704l l998-08-l9 w~97/30736 PCT/GB97/00473 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.

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;

CA 02247041 1998-08-lg 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.

CA 02247041 1998-08-lg ~VO97/30736 PCT/GB97/00473 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 CA 0224704l l998-08-l9 W097/30736 PCTIGB97/0~73 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.

WO g7/30736 PCTIGB97/00473 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 WOg7/30736 PCT/GB97/00473 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.

W097l30736 pcTlGs97loo473 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.

CA 0224704l l998-08-l9 w097l30736 PCT/GB97/00473 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 CA 02247041 1998-08-lg w097/30736 PCT/GB97/~473 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, W097/30736 PCTtGB97/~73 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.

CA 0224704l l998-08-l9 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*

CA 0224704l l998-08-l9 W097l30736 PCT/GB97100473 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) CA 02247041 1998-08-lg W097130736 PCT/GB971~473 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 CA 0224704l l998-08-l9 WO 97130736 PCTtGBg7/00473 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.

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.

CA 02247041 1998-08-lg 'W097J30736 PCT/GB97/00473 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.

CA 02247041 1998-08-lg 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.

CA 0224704l l998-08-l9 W097/30736 PCT/GB97t00473 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 CA 0224704l l998-08-l9 W097/30736 PCT/GB97l~473 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 CA 0224704l l998-08-l9 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~.

CA 0224704l l998-08-l9 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

W'O 97130736 PCT/GB97100473 PEG 2 OOK 1 - 3 mg/mL
Tetronic 1508 5 . 0 mg/mL

Claims

1. A diagnostic composition comprising a diagnostically effective amount of an inorganic particulate contrast agent together with a viscosity modifier and a polyalkylene glycol osmotic modifier, said modifiers together being present at a weight ratio relative to said agent of at least 1:30, and said viscosity modifier being selected from the group consisting of polyvinylpyrrolidone, natural gums, polysaccharides and polysaccharide derivatives.

2. A composition as claimed in claim 1 wherein said viscosity modifier is selected from the group consisting of cellulosic ethers, branch polysaccharides, side chain carrying polysaccharides, natural gums, alginates and polyvinylpyrrolidone.

3. A composition as claimed in claim 1 wherein said viscosity modifier comprises a cellulosic ether.

4. A composition as claimed in any one of claims 1 to 3 wherein said osmotic modifier comprises a polyethylene glycol.

5. A composition as claimed in claim 1 wherein said viscosity modifier is a cellulosic ether.

6. A composition as claimed in any one of claims 1 to 5 wherein said osmotic modifier has a molecular weight of from 150 to 200000 D.

7. A composition as claimed in any one of claims 1 to 6 in the form of an aqueous solution, suspension or dispersion to the camolarity of which said osmotic modifier contributes to 5 to 500 mOsm.

8. A composition as claimed in any one of the claims 1 to 6 in the form of an acqueous solution, suspension or dispersion to the osmolarity of which said osmotic modifier contributes 15 to 150 mOsm.

9. A composition as claimed in any one of claims 1 to 6 in the form of an aqueous solution, suspension or dispersion containing 1 to 10% w/v of said osmotic modifier.

10. A composition as claimed in any one of claims 1 to 9 wherein said viscosity modifier has a molecular weight of from 25000 to 2000000 D.

11. A composition as claimed in any one of claims 1 to 10 in the form of an aqueous solution, suspension or dispersion to the viscosity of which said viscosity modifier contributes 2 to 2000 cP.

12. A composition as claimed in any one of claims 1 to 10 in the form of an aqueous solution, suspension or dispersion to the viscosity of which said viscosity modifier contributes 2 to 60 cP.

13. A composition as claimed in any one of claims 1 to 12 in the form of an aqueous solution, suspension or dispersion containing 0.1 to 10% w/v of said viscosity modifier.

14. A composition as claimed in any one of claims 1 to 13 wherein said contrast agent is a heavy metal or iodine containing X-ray contrast agent.

15. A composition as claimed in claim 14 wherein said contrast agent is barium sulphate.

16. A composition as claimed in claim 15 wherein said modifiers are together present in a weight ratio relative to the barium sulphate of at least 1:5.

17. A composition as claimed in any one of claims 1 to 16 having a viscosity in the range 2 to 100 cP.

18. A composition as claimed in any one of claims 1 to 17 in ready-to-use form suitable for oral administration.

19. A composition as claimed in any one of claims 1 to 18 wherein said osmotic modifier and said viscosity modifier are present at a weight ratio of 1:2 to 10:1.

20. An aqueous diagnostic composition suitable for oral administration for colonic imaging, said composition comprising a diagnostically effective amount of an inorganic particulate contrast agent together with an amount of a polyalkylene glycol osmotic modifier sufficient to prevent caking of the composition in the upper GI tract and an amount of an organic mucoadhesive viscosity modifier sufficient to cause substantially uniform coating of colonic mucosa by the composition.

21. In a method of imaging a human or non-human animal subject, which involves administering a contrast medium into the gastrointestinal tract of the subject and generating an image of at least part of said tract, the improvement comprising administering as said contrast medium a composition as claimed in any one of claims 1 to 20.

22. A method as claimed in claim 21 wherein said image is an X-ray image.

23. A method as claimed in claim 21 wherein said image is an MR image.

24. A method as claimed in claim 21 wherein said image is an ultrasound image.

25. A process for the preparation of a diagnostic composition, said process comprising admixing an inorganic particulate contrast agent together with a viscosity modifier and a polyalkylene glycol osmotic modifier as defined in claim 1, in a weight ratio of modifiers to contrast agent of at least 1:20.

26. The use of a viscosity modifier and a polyalkylene glycol osmotic modifier for the manufacture of a diagnostic composition as defined in any one of claims 1 to 20 for use in a method of diagnosis involving imaging of the gastrointestinal tract.

27. An aqueous pharmaceutical composition suitable for oral administration for drug delivery to the lower GI
tract of a patient, said composition comprising a therapeutic agent together with an organic viscosity modifier present at from 0:1 to 50% w/v and a polyalkylene glycol 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.