Abstract:
Disclosed are x-ray contrast compositions for oral or retrograde examination of the gastrointestinal tract comprising a polymeric material capable of forming a coating on the gastrointestinal tract and an x-ray producing agent of the formula ##STR1## wherein Z=H, halo, C 1  -C 20  alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups; 
     R=C 1  -C 25  alkyl, cycloalkyl, or halo-lower-alkyl, optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl or lower-alkoxycarbonyloxy, (CR 1  R 2 ) p  --(CR 3  ═CR 4 ) m  Q, or (CR 1  R 2 ) p  --C.tbd.C--Q; 
     R 1 , R 2 , R 3  and R 4  are independently lower-alkyl, optionally substituted with halo; 
     x is 1-3 
     y is 1-4; 
     n is 1-5; 
     m is 1-15; 
     p is 1-10; and 
     Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower alkyl.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to x-ray contrast compositions containing the contrast agents iodobenzoic acid derivatives and methods for their use in diagnostic radiology of the gastrointestinal tract. 
     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. 
     Roentgenographic examination of the GI tract are indicated for conditions of digestive disorders, changes in bowel habit, abdominal pain, GI bleeding and the like. Prior to radiological examination, administration of a radiopaque contrast medium is necessary to permit adequate delineation of the respective lumen or mucosal surface from surrounding soft tissues. Accordingly, a contrast medium is administered orally to visualize the mouth, pharynx, esophagus, stomach, duodenum and proximal small intestine. The contrast medium is administered rectally for examination of the distal small intestine and the colon. 
     The most widely used contrast agent 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 and poorly adheres to mucus membranes 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. 
     Iodinated organic compounds have also been used as GI contrast agents since the iodine atom is an effective X-ray absorber. They have the most versatility and are utilized in the widest variety of procedures. They are very absorptive of X-rays with which the iodine interacts and produce a so-called photoelectric effect which is a large magnification in contrast caused by the photons stopped in the iodine-containing medium. The magnification of contrast exceeds the level that would be expected from relative changes in density. Because of this magnification, relatively low concentrations of the contrast agent can be utilized. (For iodinated agents see, for example, U.S. Pat. Nos.: 2,786,055; 3,795,698; 2,820,814; 3,360,436; 3,574,718, 3,733,397; 4,735,795 and 5,047,228.) 
     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; and nonirritation to the intestinal mucosa; and passage through the GI tract without producing artifacts or stimulating vigorous intestinal peristalsis. 
     These requirements were addressed by many investigators and their efforts resulted in great improvements over the years. The requirement of evenly coating the gut mucosa with a contrast agent to effectively cover the walls of the intestines proved to be rather difficult. Without meeting these requirements it is impossible to obtain X-ray pictures of high precision. 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 water-swellable. 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. 
     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. To that end, a thin coating is formed on the inner surface of the GI tract effected by ingesting, prior to visualization by an X-ray emitting device, a polymeric film former, which has incorporated therein an X-ray contrast agent, capable of coating the GI tract. The removal of the coating occurs as a result of the normal turnover of cells, that is, within about 24 to 48 hours. Such compositions must meet several requirements: both the X-ray contrast agent and the film former must be nontoxic; must not contain leachable or digestible components that would deleteriously affect the patient; and the composition must be capable of forming a film in the pH range of from about 5 to about 8. 
     The object of the present invention is achieved by a composition comprising: an X-ray contrast agent; a polymeric material which is at least partially water soluble and contains polarizable or ionizable groups; and a divalent metal ion selected from the group consisting of Mg ++ , Ca ++ , Zn ++  and Ba ++  which potentiates the effect of the polymeric material as a film former on the mucosa of the GI tract. 
     The contrast agent, polymeric film former and the divalent metal ion are incorporated in a solid or liquid media for administration to a mammal for X-ray visualization of the GI tract. 
     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 one of the above-described x-ray contrast compositions. 
     The composition for radiological examination of the GI tract comprises a compound of the formula: ##STR2## wherein Z=H, halo, C 1  -C 20  alkyl, cycloaklyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups; 
     R=C 1  -C 25  alkyl, cycloalkyl, or halo-lower-alkyl, optionally substituted with halo, fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl or lower-alkoxycarbonyloxy, (CR 1  R 2 ) p  --(CR 3  ═CR 4 ) m  Q, or (CR 1  R 2 ) p  --C.tbd.C--Q; 
     R 1 , R 2 , R 3  and R 4  are independently lower-alkyl, optionally substituted with halo; 
     x is 1-3 
     y is 1-4; 
     n is 1-5; 
     m is 1-15; 
     p is 1-10; and 
     Q is H, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower alkyl. 
     As used herein, the term halogen (or halo) means fluorine, chlorine, bromine or iodine. 
     As used herein, the term cycloalkyl means carbocyclic rings having from three to eight ring carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl which may be substituted on any ring carbon atom thereof by one or more lower-alkyl groups, lower-alkoxy groups or halogens. 
     As used herein the terms lower-alkyl and lower-alkoxy mean monovalent aliphatic radicals, including branched chain radicals, of from one to ten carbon atoms. Thus, the lower-alkyl moiety of such groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl, 1,1,3,3-tetramethylpentyl, 1,1-dimethyloctyl and the like. 
     As used herein, the term lower-alkenyl and lower-alkynyl means monovalent, unsaturated radicals including branched chain radicals of from three to ten carbon atoms and thus include 1-ethenyl, 1-(2-propenyl), 1-(2-butenyl), 1-(1-methyl-2-propenyl), 1-(4-methyl-2-pentenyl), 4,4,6-trimethyl-2-heptenyl, 1-ethynyl, 1-(2-propynyl), 1-(2-butynyl), 1-(1-methyl-2-propynyl), 1-(4-methyl-2-pentynyl) and the like. 
     As used herein, the term alkylene means divalent saturated radicals, including branched chain radicals of from two to ten carbon atoms having their free valences on different carbon atoms and thus includes 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1-methyl-1,2-ethylene, 1,8-octylene and the like. 
     As used herein, the term aryl means an aromatic hydrocarbon radical having six to ten carbon atoms. The preferred aryl groups are phenyl, substituted phenyl and naphthyl substituted by from one to three, the same or different members of the group consisting of lower-alkyl, halogen, hydroxy-lower-alkyl, alkoxy-lower-alkyl and hydroxy. 
     The x-ray contrast 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 solid x-ray contrast agents in particulate forms useful in the practice of the present invention can be prepared by techniques known in the art. The solid agents are comminuted to the desired size using conventional milling methods, such as airjet or fragmentation milling. We have found that an effective average particle size of less than about 100μ provides for good distribution and coating in the GI tract. As used herein, particle size refers to a number average particle size as measured by conventional techniques, such as sedimentation field flow fractionation and disk centrifugation. An effective average particle size of less than about 100μ means that at least about 90% of the particles have a weight average particle size of less than about 100μ as measured by art recognized techniques. 
     The polymers that were found to be suitable for forming a thin coating on the GI tract can be classified as anionic, cationic and neutral polymers, a description of which follows. U.S. Pat. No. 4,623,539, the disclosure of which is incorporated by reference, pertains to such polymers. 
     The contrast agent is incorporated in the polymeric material along with the divalent cation by any suitable techniques, such as by mixing, blending, precipitating or by enclosing the contrast agent into minute polymeric particles. 
     The contrast agent, polymeric material and divalent cation blend is then formulated for administration using physiologically acceptable carriers or excipients in a manner within the skill of the art. The contrast agent 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, suspension or emulsion. Alternatively, the contrast agent, polymeric material and divalent cation may be formulated into a solid form, such as tablets or capsules. 
     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 
     Compounds of the present invention can be made according to the schematic procedure shown or other methods using commerically available starting materials, intermediates and reagents. Starting materials, reagents and solvents can be obtained from chemical suppliers such as Aldrich, Baker and Eastman Chemical Companies, or they may be prepared by techniques known in the art. 
    
    
     The following examples will further illustrate the compounds used in the present invention. 
     EXAMPLE 1 
     2-Octyl 2,3,5-triiodobenzoate ##STR4## 
     A mixture of 15.0 g (30.0 mmol) of 2,3,5-triiodobenzoic acid and 19.0 g (150 mmol) of oxalyl chloride in 60 ml of dry dichloromethane was placed under nitrogen and cooled to 0° C. Two drops of dry DMF were added, the ice bath was removed and the resulting suspension was stirred at room temperature for 1.5 hrs. The resulting brown solution was concentrated in vacuo to produce a tan solid. The solid was dissolved in 30 ml of dry toluene and was concentrated in vacuo. The toluene concentration was repeated two more times to yield 2,3,5-triiodobenzoyl chloride as a tan solid. 
     The 2,3,5-triiodobenzoyl chloride was dissolved in 60 ml of dry dichloromethane. The solution was cooled to 0° C. and 6.07 g (60.0 mmol) of triethylamine was added. The brown solution was placed under nitrogen and 4.30 g (33.0 mmol) of 2-octanol was added in 10 ml of dry dichloromethane. Dimethylaminopyridine (0.367 g, 3.00 mmol) was added and the resulting solution was stirred at room temperature for 72 hrs. The brown solution was partitioned between 100 ml of dichloromethane and 100 ml of 1M HCl. The dichloromethane layer was washed with saturated NaHCO 3  solution (50 ml) and brine (50 ml). The solution was dried over Na 2  SO 4  and concentrated in vacuo to yield a dark brown oil (17.43 g). The oil was purified by flash chromatography using 436 g of silica gel and 5% ethyl acetate/hexane as the eluent. The first 600 ml to elute contained nothing while the pure product eluted with the next 700 ml. Concentration in vacuo afforded 15.68 g (85%) of the product as a yellow tinted oil. 
     Title Compound:  1  H-NMR (300 MHz) and  13  C (75 MHz) NMR Spectra were consistent with the desired structure. FAB/MS: (M+1) +  613. Calculated for C 15  H 19  I 3  O 2  : C, 29.44; H, 3.13. Found: C, 29.65; H, 3.03. 
     EXAMPLE 2 
     3,3,4,4,5,5,6,6,7,7,8,8-Dodecafluoro-2-octyl 2,3,5-triiodobenzoate ##STR5## 
     Using the same procedure as for 2-octyl-2,3,5-triiodobenzoate, 2,3,5-triiodobenzoyl chloride was prepared from 2.00 g of 2,3,5-triiodobenzoic acid and 2.54 g of oxalyl chloride in dry dichloromethane. The 2,3,5-triiodobenzoyl chloride was dissolved in 8 ml of dry dichloromethane. The solution was cooled to 0° C. and 0.810 g (8.00 mmol) of triethylamine was added. The brown solution was placed under nitrogen before 1.52 g (4.40 mmol) of 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluoro-2-octanol was added dropwise. Dimethylaminopyridine (0.049 g, 0.400 mmol) was added and the resulting solution was stirred at room temperature for 18 hrs. The brown solution was then partitioned between 100 ml of dichloromethane and 50 ml of 1M HCl. The dichloromethane layer was washed with saturated NaHCO 3  solution (50 ml) and brine (25 ml). The solution was dried over Na 2  SO 4  and concentrated in vacuo to yield 3.11 g of a brown oil. The oil was purified by flash chromatography using 125 g of silica gel and 4% ethyl acetate/hexane as the eluent. The first 475 ml to elute contained nothing, while the pure product eluted with the next 200 ml. Concentration in vacuo afforded 2.36 g (71%) of the product as a colorless oil which slowly solidified to a white, waxy solid. Mp. 32°-35° C. 
     Title Compound:  1  H-NMR (300 MHz) and  13  C (75 MHz) NMR Spectra were consistent with the desired structure. Calculated for C 15  H 7  F 12  I 3  O 2  : C, 21.76; H, 0.85; I, 45.98. Found: C, 21.86; H, 0.98; I, 46.25. 
     EXAMPLE 3 
     Bis (2-hexyl) 2,3,5,6-tetraiodoterephthalate ##STR6## 
     Cesium carbonate (1.63 g, 5.0 mmol) and 2-bromohexane (2.0 ml, 16 mmol) were added to a flask containing a stirred mixture of 2,3,5,6-tetraiodoterephthalate acid (1.4 g, 2.0 mmol) and dry DMF (20 ml). The reaction flask was immersed in an oil bath which was warmed to 76° C. over a period of 0.5 hr. After stirring under an atmosphere of N 2  for 22 hrs, the reaction was allowed to cool, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up into EtOAc (200 ml), washed with saturated aqueous sodium bicarbonate (2×50 ml), water (50 ml) and brine (50 ml), dried (Na 2  SO 4 ), filtered and evaporated in vacuo. Flash column chromatography (silica, 1:19; Et 2  O:hexanes) provided bis (2-hexyl) 2,3,5,6-tetraiodoterephthalate (0.52 g, 44%) as a light yellow solid. Mp 114°-115° C. 
     Title Compound:  1  H-NMR (300 MHz) and 13C (75 MHz) NMR Spectra were consistent with the desired structure. FAB/MS: M +  838. 
     EXAMPLE 4 
     Ethyl 3-(2-Octyloxy)-2,4,6-triiodo benzoate ##STR7## 
     A mixture of 5.00 g (30.1 mmoles) of ethyl 3-hydroxybenzoate, 17.0 g (203 mmoles) of NaHCO 3  and 32.5 g (93.3 mmoles) of benzyltrimethylammonium dichloroiodate (BTMAICl 2 ) in 43.6 ml dichloromethane/ 16.6 ml methanol was placed under nitrogen and stirred for 22 hrs. The mixture was filtered and the NaHCO 3  was washed with 200 ml of dichloromethane. The filtrate was washed with 1M HCl (100 ml), 5% NaHSO 3  (100 ml) and brine (50 ml). The solution was dried over Na 2  SO 4  and concentrated in vacuo to a tan oil which partially solidified overnight. The oily solid was purified by flash chromatography using 480 g of silica gel and 50% dichloromethane/1% methanol/49% hexane as the eluent. Concentration in vacuo afforded 12.41 g (76%) of ethyl 2,4,6- triiodo-3-hydroxybenzoate as a white solid.  1  HNMR (300 MHZ) spectral data was consistent with desired structure. 
     A mixture of 5.41 g (25.7 mmoles) of 2-octylmethanesulfonate, 10.0 g (18.4 mmoles) of ethyl 2,4,6-triiodo-3-hydroxybenzoate and 5.08 g (36.8 mmoles) of potassium carbonate in 36 ml of dry DMF was stirred and heated to 72° C. under nitrogen for 17 hrs. The mixture was cooled and partitioned between 200 ml of ethyl acetate and 150 ml of 1M HCl. The ethyl acetate layer was then washed with water (200 ml) and brine (50 ml). The orange solution was dried over Na 2  SO 4  and concentrated in vacuo to yield a orange oil (13.04 g). The oil was purified by flash chromatography using 390 g of silica gel with 5% ethyl acetate/hexane as eluent. Concentration in vacuo afforded 11.4 g (94%) of the product as a colorless oil. 
     Title Compound:  1  H-NMR (300 MHz) and  13  C (75 MHz) NMR Spectra were consistent with the desired structure. FAB/MS: (M+1) +  657. Calculated for: C 17  H 23  I 3  O 3  : C, 31.12; H, 3.53; I, 58.03. Found: C, 31.41; H, 3.58; I, 57.97. 
     EXAMPLE 5 
     Bis(2-Octyl) 5-(2-octyloxy)-2,4,6-triiodoisophthalate ##STR8## 
     A mixture of 10.0 g (54.9 mmoles) of 5-hydroxyisophthalic acid, 57.2 g (439 mmoles) of 2-octanol and 0.31 ml (5.49 mmoles) of concentrated H 2  SO 4  was left open and heated to 140° C. for 3.5 hrs. The mixture was cooled and partitioned between 200 ml of ethyl acetate and 100 ml of saturated NaHCO 3 . The ethyl acetate layer was then washed with 50 ml of 1M HCl and brine (50 ml). The brown solution was dried over anhydrous Na 2  SO 4  and concentrated in vacuo to yield a brown oil. The oil was distilled under high vacuum to remove the remaining 2-octanol. The oil which remained in the pot at 145° C. was cooled and purified by flash chromatography using 650 g of silica gel with 15% ethyl acetate/hexane as eluent. Concentration in vacuo afforded 18.15 g (86%) of 2-octyl-5-hydroxy isophthalate as a yellow tinted oil.  1  H NMR (300 MHz) spectral data was consistent with the desired structure. The di-2-octyl-5-hydroxy isophthalate was iodinated and 0-alkylated using the same procedure that was used to prepare WIN 68510. The product was obtained as a colorless oil (17.64 g, 67%). 
     WIN 69716: 1H NMR (300 MHz) and  13  C (75 MHz) NMR Spectra were consistent with the desirec structure. FAB/MS: (M-1) +  895. Calculated for C 32  H 51  I 3  O 5  : C, 42.87: H, 5.73; I, 42.47. Found: C, 43.32; H, 5.81; I, 42.35. 
     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. However, the oily contrast agents are preferably made into emulsions. 
     Compositions of the present invention comprise the following pharmaceutically acceptable components based on % w/v: 
     
         ______________________________________Non-aqueous phase       1-50Polymeric Material      0.001-15Divalent Cation         0.001-15Contrast Agent          0.001-75Excipient               0-20Aids/Surfactants/Emulsifiers)                   0.01-15Water                   q.s. to 100______________________________________ 
    
     Specific Examples of the compositions of the present invention are shown in Examples 6-8. 
     EXAMPLE NO. 6 
     
         ______________________________________2-Octyl 2,3,5-triiodobenzoate                  23.7%    (w/v)Safflower Oil          20.0%    (w/v)Kappa Carrageenan      2.0%     (w/v)Calcium Lactate        2.0%     (w/v)Tween 21               2.5%     (w/v)Hydroxypropylmethylcellulose (4000 cPs)                  0.5%     (w/v)q.s. with water to 100% volume and shake______________________________________ 
    
     EXAMPLE NO. 7 
     
         ______________________________________3,3,4,4,5,5,6,6,7,7,8,8-Dodecafluoro-2-octyl                  55.3%    (w/v)2,3,5-triiodobenzoateDow Corning Medical Antifoam AF                  40.0%    (w/v)Pectin                 4.0%     (w/v)Calcium Lactate        2.0%     (w/v)q.s. with water to 100% volume and shake______________________________________ 
    
     EXAMPLE NO. 8 
     
         ______________________________________Bis(2-hexyl)2,3,5,6-tetraiodoterephthalate                  25.9%    (w/v)Simplesse ® Dietary Fat Substitute                  30.0%    (w/v)Heparin                1.0%     (w/v)Magnesium Carbonate    1.0%     (w/v)Hydroxypropylmethylcellulose (4000 cPs)                  0.5%     (w/v)q.s. with water to 100% volume and shake______________________________________ 
    
     The nonaqueous phase comprises vegetable oils such as safflower oil; non-metabolizing fat substituents, such as Simplesse; fluorinated hydrocarbons, such as perfluorodecalin; mineral oil and simethicone. 
     Excipients advantageously used in the formulations include viscosity mediating and stabilizing agents, such as microcrystalline cellulose, ethylcellulose, hydroxypropyl methylcellulose and gum arabic. Physiologically acceptable substances may also be included, such as sodium citrate, sodium chloride, therapeutic substances, antacid substances and flavoring agents. The inclusion of antimicrobial/antiseptic agents such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, benzoic acid or sorbic acid may also be desirable in some formulations. 
     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 incombination 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 amount of such surfactants may be in the range of from 0.01 to 15% w/v of the aqueous formulations, although the amount, in general, is kept as low as possible, preferably in the range of 0.05 to 5% w/v. 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, monoethylamins 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: ##STR9## 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 11  H 23 ) COO for laurate, (C 17  H 33 ) COO for oleate, (C 15  H 31 ) COO for palmitate, (C 17  H 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. 
     Polyethylene sorbitan fatty acid esters, sold under the trade names of Polysorbates 20, 40, 60, 65, 80 and 85. 
     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 film former polymeric materials used in accordance with the present invention include anionic polymers, cationic polymers and neutral polymers. 
     Anionic Polymers 
     The anionic polymers carry negative charges in the ionized form and are capable of binding to cell surfaces mainly by electrostatic forces. Suitable anionic polymers include the following: ##STR10## wherein 
     R is the polymeric chain; ##STR11## are anionic ligands; and 
     M ++  is a divalent cation. 
     Specific anionic polymers useful in the practice of the present invention include: 
     (1) Sulfated polysaccharides of the formula: 
     
         ______________________________________ ##STR12## 
    
     
         ______________________________________wherein R is3,6-anhydro-D-galactose linked                (kappa carrageenan)through C-4 to D-galactose;α-D-galactose units (1-3) linked;                (lambda carrageenan)D-galactose          (iota carrageenan)3,6-anhydro-D-galactose;D-galactose          (Agar - Agar)3,6-anhydro-L-galactose:D-galactose          (Furcellaren)3,6-anhydro-D-galactose;D-glucopyranose;     (Laminarin sulfate)Galactan; and        (Galactan sulfate)Galactosamino-glucuronans                (Chondroitin sulfates);andM.sup.++  is Mg.sup.++, Ca.sup.++, Zn.sup.++, Ba.sup.++  or mixturesthereof.______________________________________ 
    
     (2) Carboxylated polysaccharides of the formula: 
     
         ______________________________________ ##STR13## 
    
     
         ______________________________________wherein R is      D-galacturonoglycan; and                          (Pectin)      anhydro-D-mannuronic acid      and anhydro-L-guluronic acid                          (Algin)      residues; and      M.sup.++  is Mg.sup.++, Ca.sup.++, Zn.sup.++,      Ba.sup.++  or mixtures thereof.______________________________________ 
    
     (3) Cellulose derivatives of the formulae: 
     
         ______________________________________ ##STR14## ##STR15##______________________________________wherein    R is an anhydroglucose residue;      R&#39; is CH.sub.3, C.sub.2 H.sub.5 or C.sub.3 H.sub.7 ;      R&#34; is CH.sub.3 or C.sub.2 H.sub.5 ; and      M.sup.++  is Mg.sup.++, Ca.sup.++, Zn.sup.++, Ba.sup.++  or      mixtures thereof.______________________________________ 
    
     Examples of cellulose derivatives include: sodium ethylcellulose sulfate, sodium cellulose acetate sulfate and sodium carboxymethyl cellulose. 
     (4) Sulfated, sulfonated or carboxylated synthetic polymers of the formula: ##STR16## wherein R is an aliphatic or aromatic hydrocarbon, such as polystyrene, poly(sulfon) resin or carboxylated (poly) vinyl; and 
     M ++  is Mg ++ , Ca ++ , Zn ++ , Ba ++  or mixtures thereof. 
     Cationic Polymers 
     The cationic polymers carry positive charges in the ionized form. Suitable polymers for practicing the present invention include: dermatan sulfate, keratosulfate, hyaluronic acid, heparin and chitin. 
     Neutral Polymers 
     Neutral polymers having polarizable electrons such as oxygen, nitrogen, sulfur, fluoride, chloride, bromide and iodide are also suitable for practicing the present invention. In the presence of a cation, such as Mg ++ , Ca ++ , Zn ++  or Ba ++ , the polymers are partially polarized thereby providing intermolecular interactions between the polymer and the intestinal wall. Examples of these polymers include: 
     (a) Polysaccharides, such as starch, glycogen, glucan, fructans, mannans, galactomannas, glucomannas, galactans, xylans, glycuranans, dextran and starch amylose; 
     (b) Cellulose derivatives, such as methylcellulose, hydroxyethylcellulose, ethylhydroxyethyl cellulose, hydroxypropyl methylcellulose and hydroxypropyl cellulose; and 
     (c) Synthetic polymers, such as polyvinylpyrrolidone, polyvinyl alcohol and ethylene oxide polymers. 
     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 concentration of the film forming polymeric material depends on the particular polymer used, however, it should be in the range of 0.001 to about 15% w/v or higher in combination with a divalent substance, such as calcium lactate, having a concentration range of 0.001 to 15% w/v. Dosage level of the polymeric material may be in the range of from about 2 to about 15 g/kg body weight or higher. 
     The compositions of the present invention possess very good adherence to the walls of the gastrointestinal tract by forming an essentially uniform coating thereon. 
     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.