Abstract:
Disclosed are x-ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising a crystalline contrast agent in a pharmaceutically acceptable carrier comprising a cellulose derivative; and methods for their use in diagnostic radiology of the gastrointestinal tract.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to an x-ray contrast composition for oral or retrograde administration to a mammal comprising particles consisting essentially of a crystalline organic x-ray contrast producing agent in a pharmaceutically acceptable carrier comprising a cellulose derivative. 
     2. Reported Developments 
     Roentgenographic examination utilizing x-rays and computed tomography (hereinafter CT) scans of fractures and other conditions associated with the skeletal system is routinely practiced without the use of contrast agents. X-ray visualization of organs containing soft tissue, such as the gastrointestinal (hereinafter GI) tract, requires the use of contrast agents which attenuate x-ray radiation. D. P. Swanson et al in &#34;Pharmaceuticals In Medical Imaging&#34;, 1990, MacMillan Publishing Company, provides an excellent background in medical imaging utilizing contrast agents and compositions therewith. 
     The desiderata for an ideal GI contrast agent includes: good toxicological profile; the ability to fill the entire bowel/lumen and evenly coat the gut mucosa so that the presence of the bowel is detectable when the lumen is not distended; palatability and nonirritation to the intestinal mucosa; and passing through the GI tract without producing artifacts or stimulating vigorous intestinal peristalsis. 
     The most widely used contrast agents for the visualization of the GI tract is barium sulfate administered as a suspension orally or rectally as an enema. (See for example, U.S. Pat. Nos. 2,659,690; 2,680,089; 3,216,900; 3,235,462; 4,038,379 and 4,120,946) Notwithstanding its relatively good contrast characteristics, negligible absorption from the GI tract following oral or rectal administration and speedy excretion from the body, barium sulfate has certain disadvantages. In the presence of intestinal fluids, it lacks homogeneity which can result in poor x-ray images. In the colon, when administered as an enema, it flocculates and forms irregular clumps with fecal matter. The prior art considers as a serious problem the difficulty in achieving uniform adherence, and coating of, the mucosa of the GI tract by the water insoluble barium sulfate to provide high quality x-ray photographs. As a result of inadequate adherence to, and non-uniform coating of the mucosa, the x-ray results are often inferior, misleading to the practitioner and the imaging process must be repeated. It has also been observed that the barium sulfate, and other solid inorganic particulate radiopaque agents tend to settle out in the patient after evacuation but before and during x-ray imaging, which again deleteriously affects the quality of the x-ray pictures. 
     These drawbacks were addressed by many investigators and their efforts resulted in great improvements over the years. The drawbacks of unevenly coating of the mucosa with an insufficiently adherence thereto proved to be rather difficult to solve. To that end, the use of certain polymer additives were proposed as illustrated hereunder. 
     U.S. Pat. No. 4,069,306 discloses an x-ray contrast preparation which is said to adhere to the walls of body cavities. The preparation comprises a finely divided water-insoluble inorganic x-ray contrast agent and minute particles of a hydrophilic polymer which is insoluble in water but is waterswellable. The body cavity is supplied with such preparation suspended in water. The x-ray contrast agent is present in admixture with and/or enclosed in and/or adhered to said minute polymer particles. 
     U.S. Pat. No. 4,120,946 discloses a pharmaceutical composition for barium opacification of the digestive tract, comprising colloidal barium sulfate and a polyacrylamide in an aqueous vehicle. The polyacrylamide forms a viscous solution at low concentration which makes it possible to maintain the barium sulfate in suspension and at the same time permit good adherence of the preparation to the walls of the organ which it is desired to x-ray. 
     U.S. Pat. No. 5,019,370 discloses a biodegradable radiographic contrast medium comprising biodegradable polymeric spheres which carry a radiographically opaque element, such as iodine, bromine, samarium and erbium. The contrast medium is provided either in a dry or liquid state and may be administered intravenously, orally and intra-arterially. 
     While these polymeric materials greatly enhance attachment of the contrast agent used therewith to the walls of organs for better visualization thereof, they do not provide a uniform coating thereon. As such, there is still a need for an improved x-ray imaging medium that uniformly coats the soft tissues subjected to diagnostic x-ray examination. 
     We have now discovered that high quality x-ray results can be obtained by utilizing a formulation comprising an x-ray contrast agent in solid, particulate form in a pharmaceutically acceptable vehicle comprising a cellulose derivative. 
     SUMMARY OF THE INVENTION 
     It is the object of the present invention to provide compositions for coating the gastrointestinal tract of mammals to form an effective radiopaque coating thereon by which diagnostic examination of the GI tract may be accomplished. 
     The object of the present invention is achieved by a composition comprising: an organic x-ray contrast agent in particulate form in a pharmaceutically acceptable vehicle comprising a cellulose derivative. 
     In accordance with the invention there is further provided a method for x-ray diagnostic imaging of the GI tract which comprises orally or rectally administering to the patient an effective contrast producing amount of the above-described x-ray contrast compostions. 
     The cellulose derivative utilized in the present invention includes methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose; and microcrystalline cellulose having an average particle size of from 0.01 to 100 μ, more preferably of from 0.05 to 10 μ, and most preferably of 0.1 to 1 μ. 
     The contrast agent and the cellulose derivative are formulated for administration using physiologically acceptable carriers or excipients in a manner within the skill of the art. The contrast agent and the cellulose derivative with the addition of pharmaceutically acceptable aids (such as surfactants and emulsifiers) and excipients are suspended or partially dissolved in an aqueous medium resulting in a dispersion, solution, suspension or emulsion. 
     A method for diagnostic imaging of the GI tract for use in medical procedures in accordance with this invention comprises orally or rectally administering to the mammalian patient in need of x-ray examination, an effective contrast producing amount of a composition of the present invention. After administration, at least a portion of the GI tract containing the administered composition is exposed to x-rays to produce an x-ray image pattern corresponding to the presence of the contrast agent, then the x-ray image is visualized and interpreted using techniques known in the art. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Starting materials, reagents and solvents can be obtained from chemical suppliers, such as Aldrich, Baker, DuPont and Eastman Chemical Companies, or they may be prepared by techniques known in the prior art. 
     The x-ray contrast agent useful in the practice of this invention is non-radioactive and exists as a discrete, crystalline phase of an organic substance. The crystalline phase differs from an amorphous or non-crystalline phase which results from solvent precipitation techniques such as described in U.S. Pat. No. 4,826,689 noted above. The organic substance can be present in one or more suitable crystalline phases. The invention can be practiced with a wide variety of crystalline, non-radioactive x-ray contrast agents. However, the x-ray contrast agent must be poorly soluble and dispersible in at l medium. By &#34;poorly soluble&#34;, it is meant that the agent has a solubility in the liquid dispersion medium, e.g., water, of less than about 10 mg/ml, and preferably of less than about 1 mg/ml. 
     The x-ray contrast agent can be an iodinated compound. The iodinated compound can be aromatic or nonaromatic. Aromatic compounds are preferred. The iodinated compound can comprise, one, two, three or more iodine atoms per molecule. Preferred species contain at least two, and more preferably, at least three iodine atoms per molecule. The iodinated compounds selected can contain substituents that do not impart solubility to the compound, such as, for example, alkylureido, alkoxyacylamido, hydroxyacetamido, butyrolactamido, succinimido, trifiuoroacetamido, carboxy, carboxamido, hydroxy, alkoxy, acylamino, and the like substituents. 
     A preferred class of contrast agents includes various esters and amides of iodinated aromatic acids. The esters preferably are alkyl or substituted alkyl esters. The amides can be primary or secondary amides, preferably alkyl or substituted alkyl amides. For example, the contrast agent can be an ester or amide of a substituted triiodobenzoic acid such as an acyl, carbamyl, and/or acylmethyl substituted triiodobenzoic acid. Illustrative representative examples of iodinated aromatic acids include, but are not limited to, diatrizoic acid, metrizoic acid, iothalamic acid, trimesic acid, urokonic acid, ioxaglic acid (hexabrix), ioxitalamic acid, tetraiodoterephthalic acid, iodipamide, icarmic acid, and the like. 
     Many of the iodinated molecules described above, if in monomeric form, can also be prepared as dimers (sometimes referred to as bis compounds), trimers (sometimes referred to as tris compounds), etc., by techniques known in the art. It is contemplated that this invention can be practiced with poorly soluble-iodinated compounds in monomeric, dimeric, trimeric and polymeric forms. Representative illustrative compounds are described by Sovak, cited above, pages 40-53. 
     Classes of preferred contrast agents have the following structural formulae: ##STR1## 
     In the above structures, ##STR2## wherein R 1  is alkyl, and R 2  and R 3  are independently H or alkyl. 
     Each alkyl group can independently contain from 1-20, preferably 1-8, and more preferably, 1-4 carbon atoms. 
     The alkylene group preferably contains from 1 to 4 carbon atoms such as methylene, ethylene, propylene and the like. 
     Particularly preferred contrast agents include the ethyl ester of diatrizoic acid, i.e., ethyl 3,5-diacetamido-2,4,6-triiodobenzoate, also known as ethyl 3,5-bis(acetylamino)-2,4,6-triodobenzoate or ethyl diatrizoate, having the structural formula A above wherein R═--OCH 2  CH 3  ; the ethyl glycolate ester of diatrizoic acid, i.e., ethyl (3,5-bis(acetylamino)-2,4,6-triiodobenzoyloxy)acetate, also known as ethyl diatrizoxyacetate, having the structural formula A above wherein ##STR3## and ethyl 2-(3,5-bis(acetylamino )-2,4,6triiodobenzoyloxy)butyrate, also known as ethyl 2-diatrizoxybutyrate. 
     In addition, the invention can be practiced in conjunction with the water insoluble iodinated carbonate esters described in PCT/EP90/00053. 
     The above described x-ray contrast agents are known compounds and/or can be prepared by techniques known in the art. For example, water-insoluble esters and terminal amides of acids such as the above-described iodinated aromatic acids can be prepared by conventional alkylation or amidation techniques known in the art. The above-noted acids and other acids which can be used as starting materials are commercially available and/or can be prepared by techniques known in the art. The examples which follow contain illustrative examples of known synthetic techniques. 
     EXAMPLE 1 
     Synthesis of Ethyl 3,5-bis(acetylamino)-2,4,6-triiodobenzoate 
     To 8.11L of dry N,N-dimethylformamide was added 1.01 kg (1.65 mol) of diatrizoic acid. To the vigorously stirred suspension was carefully added 274 g (1.99 mol) of milled potassium carbonate. During the addition there was significant gas evolution. Before all of the suspended solid had gone into solution, a second solid began to form toward the end of the carbonate addition. The mixture was stirred for 30 min. at room temperature. Ethyl iodide (608 g, 3.90 mol) was added dropwise and the mixture was stirred overnight at room temperature at which point the reaction mixture was nearly homogeneous. The reaction was poured into 25L of water, filtered and the solid washed with water and dried at reduced pressure at 60° C. to afford 962 g (91% yield) of a white solid, mp 280°-290° C. (dec.). Analysis for C 13  H 13  I 3  N 2  O 4  : Calculated/Found: C,24.32/24.27;H,2.05/1.93;N,4.36/4.28. 
     EXAMPLE 2 
     Synthesis of Ethyl (3,5-bis(acetylamino)-2,4,6-triiodo-benzoyloxy)acetate 
     To 175mL of dry N,N-dimethylformamide (DMF) was added 63.6 g (0.100 mol) sodium diatrizoate and 14.7 g (0.120 mol) of ethyl chloroacetate and the mixture was heated on a steam bath for 6 hr. The reaction was filtered while hot and the filtrate cooled to room temperature and diluted to 500 ml with water. The mixture was cooled and filtered and the collected solid washed with water. The solid was then dissolved in 350 ml hot DMF, filtered and added to an equal volume of water. The mixture was cooled, filtered, washed with water, and the solid dried at 100° C. overnight to afford 53.0 g (76% yield) of a white powder, mp 269.5°-270.5° C. Analysis for C 15  H 15  I 3  N 2  O 6  : Calculated/Found: C,25.73/25.80;H,2.15/2.77;I,54.4/53.8. 
     EXAMPLE 3 
     Synthesis of Ethyl 2-(3,5-bis(acetylamino )-2,4,6-triiodobenzoyloxy)butyrate 
     To 500mL of dry N,N-dimethylformamide was added 159 g (0.250 mol) sodium diatrizoate and 54.5 g (0.280 mol) of ethyl 2-bromobutyrate. The mixture was heated on a steam bath for 20 h, cooled to room temperature and poured into 3L of dilute ammonium hydroxide. The solid was filtered, washing with water, and air-dried. The solid was further purified by crystallization from 50% aqueous ethanol (after treatment with decolorizing carbon) affording two crops which were dried at 100° C. overnight to afford 121 g (66%) of a white powder, m.p. 288°-290 ° C. (dec.). Analysis for C 17  H 19  I 3  N 2  O 6  : Calculated/Found: C,28.05/28.36/H,2.63/2.55;I,52.3/52.3 
     The particles useful in the practice of this invention include a surface modifier. Surface modifiers useful herein physically adhere to the surface of the x-ray contrast agent but do not chemically react with the agent or itself. Individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinkages. Suitable surface modifiers can be selected from known organic and inorganic pharmaceutical excipients such as various polymers, low-molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Representative examples of surface modifiers include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these surface modifiers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986, the disclosure of which is hereby incorporated by reference in its entirety. 
     Particularly preferred surface modifiers include polyvinylpyrrolidone, tyloxapol, poloxamers such as Pluronic F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, and poloxamines such as Tetronic 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, available from BASF, dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OT, which is a dioctyl ester of sodium sulfosuccinic acid, available from American Cyanamid, Duponol P, which is a sodium lauryl sulfate, available from DuPont, Triton X-200, which is an alkyl aryl polyether sulfonate, available from Rohm and Haas, Tween 80, which is a polyoxyethylene sorbitan fatty acid ester, available from ICI Specialty Chemicals, and Carbowax 3350 and 934, which are polyethylene glycols available from Union Carbide. Surface modifiers which have been found to be particularly useful include Tetronic 908, the Tweens, Pluronic F-68 and polyvinylpyrrolidone. 
     Other useful surface modifiers include: 
     decanoyl-N-methylglucamide; 
     n-decyl β-D-glucopyranoside; 
     n-decylβ-D-maltopyranoside; 
     n-dodecyl β-D-glucopyranoside; 
     n-dodecyl β-D-maltoside; 
     heptanoyl-N-methylglucamide 
     n-heptyl β-D-glucopyranoside; 
     n-heptyl β-D-thioglucoside; 
     n-hexyl β-D-glucopyranoside; 
     nonanoyl-N-methylglucamide; 
     n-nonyl β-D-glucopyranoside; 
     octanoyl-N-methylglucamide; 
     n-octyl β-D-glucopyranoside; 
     octyl β-D-thioglucopyranoside; 
     and the like. 
     A particularly preferred class of surface modifiers includes water-soluble or water-dispersible compounds having the formula ##STR4## wherein ##STR5## 
     L&#39; is a chemical bond, --O--,--S--,--NH--,--CONH-- or--SO 2  NH--; 
     R is a hydrophobic substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted aryl group; 
     each of R 1  and R 2  independently is hydrogen or an alkyl group having from 1 to 4 carbon atoms; 
     each of a and b independently is 0 or an integer from 1 to 3, provided that the sum of a and b is not greater than 3; and, 
     each of x and y independently is an integer from 3 to 7. 
     Preferred compounds within this class conform to the above structure wherein R contains from 6 to 36 carbon atoms, for example, R is an n-alkyl group containing from 6 to 18 carbon atoms, each of R 1  and R 2  independently is a methyl, ethyl, propyl or butyl group and a is 0 and b is 0. This class of surface modifiers is described in U.K. patent application Ser. No. 9104957.7 filed Mar. 8, 1991 and can be prepared by reacting an appropriate dicarboxylic acid ester with an appropriate monosaccharide amine, preferably in the absence of a solvent, at a reaction temperature from 140° to 200° C. 
     The surface modifiers are commercially available and/or can be prepared by techniques known in the art. Two or more surface modifiers can be used in combination. 
     The particles useful in the practice of this invention can be prepared in accordance with the wet grinding process described in U.S. Pat. No. 5,145,684 which is incorporated herein by reference. The process comprises dispersing a poorly soluble x-ray contrast agent in a liquid dispersion medium and wet-grinding the agent in the presence of grinding media to reduce the particle size of the contrast agent to an effective average particle size of from about 0.05 μ to about 100 μ, preferably of from about 0.05 μ to about 5 μ and most preferably from about 0.1 μ to about 1 μ. The particles can be reduced in size in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after attrition. 
     As used herein, particle size refers to a number average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. By &#34;an effective average particle size of from about 0.05 μ to about 100 μ&#34; is meant that at least 90% of the particles have a weight average particle size of from about 0.05 μ to about 100 μwhen measured by the above-noted techniques. The particle size range allows sufficient number of particles&#39; distribution in the film forming composition when the GI tract is coated therewith, yet insures against absorption through the intestinal walls. 
     Compositions of the Present Invention 
     The contrast agents may be formulated for administration using physiologically acceptable carriers or excipients in a manner within the skill of the art. The compounds with the addition of pharmaceutically acceptable aids (such as surfactants and emulsifiers) and excipients may be suspended or partially dissolved in an aqueous medium resulting in a dispersion, solution or suspension. 
     Compositions of the present invention comprise the following pharmaceutically acceptable components based on % w/v: 
     
         ______________________________________Ingredients    Broad Range                     Preferred Range______________________________________Contrast agent   40-160   85-120(mg I/ml oftotal suspension)Cellulose derivative          0.1-4      0.2-1(% w/v)Oily Vehicle   0.1-25     7-15(% w/v)Surfactant     0.1-10     3-7(% w/v)Viscosity modifying          0.001-4    0.05-1excipients (% w/v)Water - q.s. to 100% by volume______________________________________ 
    
     To stabilize particulates in the compositions of the present invention electrolytes may be used in the range of from about 0.01 to about 10% w/v based on the total composition. Such electrolytes include sodium chloride, potassium chloride, citric acid and salts thereof, phosphoric acid and salts thereof and aluminum chloride. 
     When the composition is used for CT imaging of the GI tract, the concentration of the x-ray contrast agent should be in the range of from 0.01 to 40 mg I/ml, more preferably of from 0.25 to 25 mg I/ml, and most preferably of from 4-12 mg I/ml. 
     The preferred cellulose derivative utilized in the present invention is AVICEL® RC-591, which is a mixture of about 89 parts microcrystalline cellulose and about 11 parts of sodium carboxymethylcellulose. 
     In further reference to the components used in the compositions of the present invention the following should be noted. 
     The x-ray contrast agent present in concentrations lower than the abovestated minimum in formulations does not provide good quality x-ray or CT images, while concentrations above the maximum concentration render the GI tract too radiopaque and do not allow sufficient delineation of the GI tract. 
     In practicing the present invention an oil-in-water emulsion are preferred. Oily materials, the density of which approximate the density of the aqueous phase impart stability to emulsions. For that reason, low density oils, such as mineral oils, are desirable in preparing the emulsions. Above about 55% w/v of oil the emulsion is no longer an oil-in-water emulsion but shifts to a water-in-oil emulsion. 
     Compositions without the presence of surfactants still provide excellent x-ray images, however, without surfactants the compositions are very difficult to emulsify and only suspensions/dispersions are produced which are less desirable for coating the GI tract and are also less stable on shelf-life. For reason of toxicity it is desirable to keep the concentration of certain surfactants as low as possible; above about 20% w/v the risk of toxicity rapidly increases. 
     Depending on the form and amount of cellulose derivative used, additions of viscosity modifying agents may not be necessary; at higher levels than about 15% w/v the viscosity is too high and gels will tend to form. 
     The following formulation examples will further illustrate the invention. 
     EXAMPLE 4 
     
         ______________________________________Components           Amounts in % w/v______________________________________Ethyl 3,5-bis(acetylamino)-2,4,6-                17.50triiodobenzoatePolysorbate 80 (Tween 80)                3.37Sorbitan Mono-oleate (Span 80)                1.64AVICEL ® RC-591  0.50q.s. with water to 100% by volume______________________________________ 
    
     EXAMPLE 5 
     
         ______________________________________Components           Amounts in % w/v______________________________________Ethyl 3,5-bis(acetylamino)-2,4,6-                25.00triiodobenzoyloxy)acetateLight Mineral Oil, NF                10.00Polysorbate 80 (Tween 80)                5.00AVICEL ® RC-591  6.50q.s. with water to 100% by volume______________________________________ 
    
     EXAMPLE 6 
     
         ______________________________________Components           Amounts in % w/v______________________________________Ethyl 2-(3,5-bis(acetylamino)-2,4,6-                30.00triiodobenzoyloxy)butyratePluronic F-68        10.00AVICEL ® RC-591   2.00q.s. with water to 100% by volume______________________________________ 
    
     EXAMPLE 7 
     
         ______________________________________Components           Amounts in % w/v______________________________________Ethyl 3,5-bis(acetylamino)-2,4,6-                17.50triiodobenzoateLight Mineral Oil NF 12.50Polysorbate 80 (Tween 80)                3.37Sorbitan Mono-oleate (Span 80)                1.64AVICEL ® RC-591  0.50q.s. with water to 100% by volume______________________________________ 
    
     As known by those skilled in the art, surfactants or emulsifiers can reduce the interfacial tension between two immiscible phases, i.e., oil-in-aqueous medium. These agents can be used alone or in combination with other emulsifying agents and surfactants. For example, Dow Corning Medical Antifoam AF, which is a composition of 30% w/v polydimethylsiloxane simethicone and silica aerogel, 14% w/v stearate emulsifiers and 0.075% w/v sorbic acid, the balance being water, may be used by itself. Intralipid, which is an emulsion of fatty acids needs the presence of a suspending agent for it to form an acceptable emulsion with contrast agents of the present invention. The surface active agents may be cationic, anionic, nonionic, zwitterionic or a mixture of two or more of these agents. 
     Suitable cationic surfactants include cetyl trimethyl ammonium bromide. Suitable anionic agents include sodium lauryl sulphate, sodium heptadecyl sulphate, alkyl benzenesulphonic acids and salts thereof, sodium butylnapthalene sulfonate, and sulphosuccinates. Zwitterionic surface active agents are substances that when dissolved in water they behave as diprotic acids and, as they ionize, they behave both as a weak base and a weak acid. Since the two charges on the molecule balance each other out the molecules act as neutral molecules. The pH at which the zwitterion concentration is maximum is known as the isoelectric point. Compounds, such as certain amino acids having an isoelectric point at the desired pH of the formulations of the present invention are useful in practicing the present invention. 
     In preparing the formulations of the present invention we prefer to use nonionic emulsifiers or surface active agents which, similarly to the nonionic contrast agents, possess a superior toxicological profile to that of anionic, cationic or zwitterionic agents. In the nonionic emulsifying agents the proportions of hydrophilic and hydrophobic groups are about evenly balanced. They differ from anionic and cationic surfactants by the absence of charge on the molecule and, for that reason, are generally less of an irritant than the cationic or anionic surfactants. Nonionic surfactants include carboxylic esters, carboxylic amides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols. 
     One particular type of carboxylic ester nonionic surface active agents are the partial, for example mono-, esters formed by the reaction of fatty and resin acids, for example of about 8 to about 18 carbon atoms, with polyhydric alcohols, for example glycerol, glycols such as mono-, di-, tetra- and hexaethylene glycol, sorbitan, and the like; and similar compounds formed by the direct addition of varying molar ratios of ethylene oxide to the hydroxy group of fatty acids. 
     Another type of carboxylic esters is the condensation products of fatty and resin partial acids, for example mono-, esters ethylene oxide, such as fatty or resin acid esters of polyoxyethylene sorbitan and sorbitol, for example polyoxyethylene sorbitan, monotall oil esters. These may contain, for example, from about 3 to about 80 oxyethylene units per molecule and fatty or resin acid groups of from about 8 to about 18 carbon atoms. Examples of naturally occurring fatty acid mixtures which may be used are those from coconut oil and tallow while examples of single fatty acids are dodecanoic acid and oleic acid. 
     Carboxylic amide nonionic surface active agents are the ammonia, monoethylamine and diethylamine amides of fatty acids having an acyl chain of from about 8 to about 18 carbon atoms. 
     The ethoxylated alkylphenol nonionic surface active agents include various polyethylene oxide condensates of alkylphenols, especially the condensation products of monoalkylphenols or dialkylphenols wherein the alkyl group contains about 6 to about 12 carbon atoms in either branched chain or particularly straight chain configuration, for example, octyl cresol, octyl phenol or nonyl phenol, with ethylene oxide, said ethylene oxide being present in amounts equal to from about 5 to about 25 moles of ethylene oxide per mole of alkylphenol. 
     Ethoxylated aliphatic alcohol nonionic surface active agents include the condensation products of aliphatic alcohols having from about 8 to 18 carbon atoms in either straight chain or branched chain configuration, for example oleyl or cetyl alcohol, with ethylene oxide, said ethylene oxide being present in equal amounts from about 30 to about 60 moles of ethylene oxide per mole of alcohol. 
     Preferred nonionic surface active agents include: sorbitan esters (sold under the trade name Span) having the formula: ##STR6## wherein R 1  =R 2  =OH,R 3  =R for sorbitan monoesters, 
     R 1  =OH,R 2  =R 3  =R for sorbitan diesters, 
     R 1  =R 2  =R 3  =R for sorbitan triesters, 
     where 
     
         ______________________________________R =           (C.sub.11 H.sub.23)COO for laurate,         (C.sub.17 H.sub.33)COO for oleate,         (C.sub.15 H.sub.31)COO for palmitate,         (C.sub.17 H.sub.35)COO for stearate.______________________________________ 
    
     Polyoxyethylene alkyl ethers (i.e. Brijs) having the formula: 
     
         CH.sub.3 (CH.sub.2).sub.x (O--CH.sub.2 --CH.sub.2).sub.y OH 
    
     where (x+1) is the number of carbon atoms in the alkyl chain, typically: 
     
         ______________________________________12 lauryl            (dodecyl)14 myristyl          (tetradecyl)16 cetyl             (hexadecyl)18 stearyl           (octadecyl)______________________________________ 
    
     and y is the number of ethylene oxide groups in the hydrophilic chain, typically 10-60. 
     Polyoxyethylene sorbitan fatty acid esters (Polysorbates 20,40,60,65,80 &amp; 85) sold under the trade names of Tweens, Crillers, Sorlares and Monitans, having the formulas (1) and (2) ##STR7## wherein w+x+y+z=20 (Polysorbate 20,40,60,65,80 and 85) 
     w+x+y+z=5 (Polysorbate 81) 
     w+x+y+z=4 (Polysorbate 21 and 61). 
     Polyethylene stearates, such as: 
     poly(oxy-1,2-ethanediyl),α-hydro-Ω-hydroxyoctadecanoate; 
     polyethylene glycol monostearate; and 
     poly(oxy-1,2-ethanediyl),-α-(1-oxooctadecyl)-Ω-hydroxypolyethylene glycol monostearate. 
     The dosages of the contrast agent used according to the method of the present invention will vary according to the precise nature of the contrast agent used. Preferably, however, the dosage should be kept as low as is consistent with achieving contrast enhanced imaging. By employing as small amount of contrast agent as possible, toxicity potential is minimized. For most contrast agents of the present invention dosages will be in the range of from about 0.1 to about 16.0 g iodine/kg body weight, preferably in the range of from about 0.5 to about 6.0 g iodine/kg of body weight, and most preferably, in the range of from about 1.2 to about 2.0 g iodine/kg body weight for regular x-ray visualization of the GI tract. For CT scanning, the contrast agents of the present invention will be in the range of from about 1 to about 600 mg iodine/kg body weight, preferably in the range of from about 20 to about 200 mg iodine/kg body weight, and most preferably in the range of from about 40 to about 80 mg iodine/kg body weight. 
     The concentration of the contrast agent should be in the range of from about 0.001% w/v to about 75% w/v of the formulation, preferably from about 0.05% w/v to about 50% w/v, and most preferably of from about 0.1% w/v to about 20% w/v. 
     The invention having been fully described, it will be apparent to one skilled in the art that changes and modifications can be made thereto without departing from the spirit and scope thereof as defined by the appended claims.