MXPA96004899A - Compositions of contrast for x-rays containing clays pharmaceutically accepted - Google Patents

Abstract

X-ray contrast compositions are described for oral or retrograde examination of the gastrointestinal tract comprising an X-ray contrast agent in combination with a pharmaceutically acceptable clay in a pharmaceutically acceptable carrier, and methods for use in diagnostic radiology of the tract gastrointestin

Description

CONTRAST COMPOSITIONS FOR X-RAYS CONTAINING PHARMACEUTICALLY ACCEPTABLE CLAYS DESCRIPTION OF THE INVENTION This invention relates to a contrast composition for X-rays, for oral or retrograde administration, to a mammal, comprising an X-ray contrast agent and a pharmaceutically acceptable clay. Roentgenographic examination uses x-rays and CT scans (below) CT) of fractures and other conditions associated with the skeletal system are usually carried out without the use of contrast agents. X-ray visualization of organs containing soft tissue such as the gastrointestinal tract (below Gl) requires the use of contrast agents which attenuate the radiation by X-rays. D. P. Swanson et al in "Pharmaceuticals In Medical Imaging ", 1990, MacMillan Publishing Company, provides an excellent background in imaging systems in medicine that use contrast agents.The roentgenographic examination of the Gl tract is indicated for conditions of digestive disorders, changes in bowel habit, abdominal pain, Hemorrhage Gl and the like: Prior to radiological examination, it is necessary to administer a radiopaque contrast medium for REF: 23201 to allow adequate delineation of the respective lumen or mucosal surfaces of surrounding soft tissues. contrast medium to visualize the mouth, pharynx, esophagus, stomach, duodenum or proximal small intestine.The contrast medium is administered rectally for examination of the distal small intestine and the colon.The contrast agent used most widely for visualization of the Gl tract is barium sulfate administered orally as a suspension, or rect Almente like an enema. { see, for example, U.S. Patent Nos .: 2,659,690; 2,680,089; 3,216,900; 3,235,462; 4,038,379 and 4,120,946). Regardless of their relatively good contrast characteristics, the negligible absorption from the Gl tract from oral or rectal administration and the rapid excretion of the body, barium sulfate have certain disadvantages. In the presence of intestinal fluids, it lacks homogeneity and adheres poorly to mucous membranes, which can result in poor X-ray imaging. In the colon, when administered as an enema, flocculate in the form of irregular lumps with fecal matter. Iodinated organic compounds have also been used as contrast agents since the iodine atom is an atom that effectively absorbs X-rays.

It has more versatility and is used in a wide variety of procedures. It is very absorptive to X-rays, with which iodine interacts and produces the so-called photoelectric effect which is a large contrast enhancement caused by photons that stop in the medium containing iodine. The contrast magnification exceeds the level that would be expected from relative changes in density. Due to this extension, relatively low concentrations of contrast agent can be used (for iodinated agents see, for example, US Patents Nos .: 2,786,055, 3,795,698, 3,360,436, 3,574,718, 3,733,397, 4,735,795 and 5,047,228.) Decisions for an agent of ideal contrast for Gl include: good toxicological profile, - ability to completely fill the intestine / lumen and provide a uniform lining of the intestinal mucosa so that the presence of the intestine is detectable when the lumen is not distended; palatability and lack of irritation to the intestinal mucosa; and pass through the Gl tract without producing artifacts or stimulating vigorous intestinal peristalsis. These requirements are solved by many researchers, and their efforts result in great improvements over the years. The requirement of a uniform lining of the intestinal mucosa and adherence, enough to it, a contrast agent to effectively cover the walls of the intestines proves to be rather difficult. Without satisfaction of these requirements, it is impossible to obtain high precision x-ray images. For this purpose, the use of certain polymeric adhesives is proposed as illustrations in the following. U.S. Patent No. 4,069,306 describes an X-ray contrast preparation which is said to adhere to the walls of body cavities. The preparation comprises a finely divided inorganic X-ray contrast agent, insoluble in water, and are tiny particles of a hydrophilic polymer which is insoluble in water but wettable in water. The body cavity is supplied with a preparation suspended in water. The X-ray contrast agent is present in the mixture and / or is included in, and / or is adhered to, the tiny polymer particles. U.S. Patent No. 4,120,946 describes a pharmaceutical composition for opacification of the digestive tract with barium, comprising colloidal barium sulfate and a polyacrylamide in an aqueous vehicle. The polyacrylamide forms a viscous solution at a low concentration which makes it possible to keep the barium sulphate in suspension and at the same time allows good adherence and preparation to the walls of the organ which it is desired to subject to X-rays. 5,019,370 discloses a biodegradable radiographic contrast medium consisting of biodegradable polymer spheres which carry a radiographically opaque element such as iodine, bromine, samarium or erbium. The contrast medium is provided either in the dry or liquid state, and can be administered intravenously, orally or intraarterially. Although these polymeric materials greatly improve the binding of the contrast agent used with the present to the walls of the organs for a better visualization thereof, there is still a need for an improved X-ray imaging medium uniform soft tissues undergoing diagnostic X-ray examination. It has now been discovered that the use of certain natural clays in combination with an X-ray producing agent improves the uniformity of coating in the gastrointestinal tract and the quality of the lightning images X. In addition, these clays mask the unpleasant smell and taste of the X-ray contrast formulations as well as improve the physical stability of the same.

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 the Gl tract examination can be carried out. For this purpose, a thin coating is formed on the inner surface of the Gl tract effected by ingestion, before visualization by an X-ray emitting device, a composition containing a pharmaceutically acceptable clay and an X-ray contrast agent. Such compositions they must satisfy several requirements: both the X-ray contrast agent and the clay must be non-toxic; they must not contain leachable or digestible components that may adversely affect the patient, and none of the components must be absorbed as they pass through the inner surface of the intestine. The object of the present invention is obtained by a composition comprising: an X-ray contrast agent and a pharmaceutically acceptable clay in a pharmaceutically acceptable, aqueous carrier. According to the invention, there is further provided a method for X-ray diagnostic imaging of the Gl tract, which comprises orally or rectally administering to the patient an effective contrast producing amount of the X-ray contrast composition. described in the above. The contrast agent and the pharmaceutically acceptable clay are incorporated into a liquid medium for administration to a mammal for X-ray visualization of the Gl tract. The contrast agents used in the present invention are selected from (1) compounds of the formula (I) wherein R is a substituted or unsubstituted alkyl group containing 2 to 8 carbon atoms, wherein the substituents are selected from the group consisting of alkyl of 1 to 6 carbon atoms and alkoxy; and n is l to 5; (2) a compound of the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, alkyl of 1 to 20 carbon atoms, cycloalkyl, lower alkoxy, alkoxycarbonyl, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups; R is alkyl of 1 to 25 carbon atoms, cycloalkyl, or lower haloalkyl, each of which may be optionally substituted with halo, lower fluoroalkyl, aryl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy; or (CR ^ -Jp- (CR3 = CR4) mQ, or (CRiRaJp-C = C-Q; Rl t R2, R3 and R4 are independently H or lower alkyl, optionally substituted with halo; x is 1-4; n is 1-4; m is 1-15; p is 1-20; and Q is H, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or arylalkyl; (3) a compound of the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, alkyl of 1 to 20 carbon atoms, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups; Rx and R2 are independently H, alkyl of 1 to carbon atoms, cycloalkyl, acetyl or lower haloalkyl, wherein alkyl of 1 to 25 carbon atoms, cycloalkyl and lower haloalkyl optionally is substituted with lower fluoroalkyl, aryl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy, and acetyl is optionally substituted with lower fluoroalkyl, aryl, lower alkoxy, hydroxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy; n is 1-4; and it is 1-4; and x is 1 or 2; (4) a compound of the formula wherein Z is H, halo, alkyl of 1 to 20 carbon atoms, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups; R is alkyl of 1 to 25 carbon atoms, cycloalkyl or lower haloalkyl, each of which optionally may be substituted with halo, lower fluoroalkyl, aryl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy; or R1; R2, R3 and R4 are independently lower alkyl, optionally substituted with halo; x is 1-3 and 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 arylalkyl; (5) a compound of the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, alkyl of 1 to 20 carbon atoms, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups, - R is methyl, ethyl, propyl, alkyl of 9 to 25 carbon atoms, cycloalkyl or lower haloalkyl, optionally substituted with halo, lower fluoroalkyl, aryl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy; or (CR ^^ p- (CR3 = CR4) mQ, or (CR ^ Jp-C = CQ; Rl t R2, R3 and R4 are independently lower alkyl, optionally substituted with halo; x 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 arylalkyl, (6) a compound of the formula wherein X is O -C- O -S02-; Z is H, halo, methyl, ethyl, n-propyl, alkyl of 4 to 20 carbon atoms, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups; R is alkyl of 1 to 25 carbon atoms, cycloalkyl or aryl, each of which may be optionally substituted with halo, lower fluorohalkyl, lower alkoxy, hydroxy, carboxy or lower alkoxycarbonyl; lower alkenyl, lower alkynyl, lower alkylene or lower alkoxycarbonyloxy; n is 1-5; and it is 0-4; and w is 1-4; (7) a crystalline, particulate, X-ray contrast agent having a surface modifier absorbed on the surface thereof. As used herein, the term halogen (or halo) means fluorine, chlorine, bromine or iodine. As used herein, the term "cycloalkyl" means carbocyclic rings having 3 to 8 carbon atoms, in the ring including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl, which may be substituted on any carbon atom of the ring 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 that include branched chain radicals, of one to ten carbon atoms. Therefore, the lower alkyl portion of such groups includes, 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 terms "lower alkenyl" and "lower alkynyl" mean monovalent unsaturated radicals which include branched chain radicals of from 3 to 10 carbon atoms and which therefore include 1-ethenyl, 1- (2-propenyl), - (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 that include branched chain radicals of from two to ten carbon atoms that have their free valencies on different carbon atoms and that therefore include 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. Preferred aryl groups are phenyl, substituted phenyl and naphthyl substituted with one to three, the same or different members of the group consisting of lower alkyl, halogen, lower hydroxyalkyl, lower alkoxyalkyl and hydroxy. X-ray contrast compounds may be composed of one, two, three or more iodine atoms per molecule; the preferred species contain at least two and more preferably three iodine atoms per molecule. 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 crushed or milled to the desired size by using conventional grinding methods such as air jet grinding or by fragmentation. It has been found that an effective average particle size of less than about 100 μ provides good distribution and coating in the Gl tract. As used herein, particle size is preferred over the average number of particle sizes measured by conventional techniques, such as fractionation of sediment field flow and disk centrifugation. An effective average particle size of less than about 100 μ means that at least about 90% of the particles have an average particle size weight of less than about 100 μ, as measured by techniques recognized in the art. The compositions may be in the form of dispersions, suspensions when the X-ray contrast agent is a solid, or emulsions when the X-ray contrast agent becomes an oil; it is preferred to use emulsions as the preferred embodiment. The natural clays incorporated in the compositions of the present invention are selected from the group consisting of montmorillonite, beidelite, nontronite, hectorite and saponite. A method for diagnostic imaging of the Gl tract for use in medical procedures in accordance with this invention comprises oral or rectal administration to the mammalian patient in need of an X-ray examination of an effective contrast producing amount of a composition of the present invention. After administration, at least a portion of the Gl tract containing the composition administered is exposed to X-rays to produce an X-ray image pattern corresponding to the presence of the contrast agent, subsequently, the X-ray image is visualized and interpreted using techniques known in the art. The compounds of type (1) defined in the above are described in EP-A-568155. For example, 2,4,6-triiodophenoxy-2-octane, 2,4,6-triiodophenoxy-2-butane, 2,4,6-triiodophenoxy-2-hexane and 4-iodophenoxy-2-octane are described herein. Preferred contrast agents of type (1) have the formula: wherein R is a secondary alkyl group containing 4 to 8 carbon atoms. The most preferred contrast agent of type (1) is 2, 4, 6-triiodophenol sec-octyl ether having the formula: The compounds of type (2) defined in the above are described in EP-A-614670. For example, the bis- (4-iodophenyl) ether of polyethylene glycol-400, 1, 8-bis-0- (2,4,6-triiodophenyl) -triopropylene glycol, 1,1-bis (2,4,6) -triyodofenoxi) -3,6, 9-trioxaundecane, 1, 2-bis- (2,4,6-triiodophenoxy) -ethane, the bis-O- (2,4,6-triiodophenyl) ether of polyethylene glycol 400, 1 - (3-Iodophenoxy) -3,6, 9-trioxadecane, 1, 3-bis- (2,4,6-triiodophenoxy) -butane, 1- (3-iodophenoxy) -6- (2,4,6-trimethioxy) -hexane and 1,22-bis- (2, 4) , 6-triiodophenoxy) -dodecane are described herein.

Compounds of type (3) as defined above are described in EP-A-613689. For example, N-acetyl-N-2-octyl-4-iodoaniline and N- (4'-iodophenyl) -2-aminooctane are described herein. Compounds of type (4) as defined above are described in EP-A-614669. For example, 2, 3, 5-triiodobenzoate 2-octyl, 2, 3, 5-triiodobenzoate of 3,3,4,4,5,5,6,6,7,7,8 are described herein, 8-dodecafluoro-2-octyl, 2, 3, 5, 6-tetraiodoterephthalate of bis (2-hexyl), 3- (2-octyloxy) -2,4,6-triiodobenzoate of ethyl and 5- (2-octyloxy) -2, 4, 6-bis (2-octyl) triiodoisophthalate. Compounds of type (5) as defined above are described in EP-A-609587. For example, 2- (4-iodophenoxy) -decano, 2- (2,4,6-triiodophenoxy) -pentadecane, 2- (2,4,6-trimethiophene) decane, (2,4,6-trimethiophene) - 1H, 1H, 2H, 2H-perfluorooctane, 1- (2,4,6-rhodiodo-3-trifluorophenoxy) octane, 2- (2,4,6-triiodophenoxy) -nonano, 2-ethyl-1- (2, 4,6-triiodophenoxy) -hexane, 3,3-diphenyl-1- (2,4,6-triiodophenoxy) propane, 3- (2,4,6-triiodophenoxy) -nonano, 2- (4-iodophenoxy) - undecano, 2-iodophenoxicyclopentane, 3-iodophenoxycyclopentane, (3,5-dimethyl-2,4,6-triiodophenoxy) cyclopentane, 2- (4-iodophene) -pentadecane, 4-Iodophenoxycyclopentane, 2,4,6-triiodophenoxycyclopentane, 2,4,6-triiodophenoxymethylcyclopentane, 2- (2,4,6-triiodophenoxy) ethyl cyclopentane, (E, E) -l- (2,4,6-triiodophenoxy) ) -3,7, ll-trimethyl-2, 6, 10-dodecatriene, 1- (2,4,6-triiodophenoxy) -3,7-dimethyl-6-octene, (E) -1- (3.5 -dimethyl-2,4,6-triiodophenoxy) -3,7-dimethyl-2, 6-octadiene, (E) -1- (2,4,6-triiodophenoxy) -3,7-dimethyl-2,6- octadiene, l- (2,4,6-triiodophenoxy) -3-ocno, 2- (2,4,6-triiodophenoxy) -4-octino, 1- (2,4,6-triiodophenoxy) -3-octino , 2- (2,4,6-triiodophenoxy) -1,3-diethyl propanedioate, 2- (2,4,6-triiodophenoxy) -1,3-diisopropyl propanedioate 2,2-bis- (3- iodophenoxy) ethyl acetate, ethyl 5- (2,4-, 6-triiodophenoxy) hexanoate, 5- (2,4-, 6-triiodophenoxy) -hexan-1-ol, 10- (4-iodophene) -undecan- 1-ol, ethyl 5- (2,4,6-trimodiophenoxy) hexylcarbonate, and ethyl 10- (3-iodophenoxy) -undecanoate as described herein. Compounds of type (6) as defined above are described in EP-617970. For example, 2,4,6-triiodophenyl 2-ethylhexanoate, 2,4,6-triiodophenyl 2-methylpentanoate, 2,4,6-triiodophenyl 3-cyclopentylpropionate, (2-propyl) pentanoate 2,4, 6-triiodophenyl, 2,4,6-triiodophenyl perfluoroeptanoate, 2,4,6-triiodophenyl-tris- (2-ethyl) -hexanoate, 2,4,6-triiodophenyl dodecanoate, 3-trifluoromethyl- 2-ethylhexanoate , 4,6-triiodophenyl, 2,4,6-triiodophenyl-bis- (2-methylpentanoate), 2,4,6-triiodophenyl hexasulfonate, 2,4,6-triiodophenyl heptanesulfonate and 2,4,6-decansulfonate -triyodiphenyl as described herein. The compounds used in the compositions of type (7) defined above are non-radioactive and exist 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 those described in US Pat. No. 4, 826,689 indicated above. The organic substance may be present in one or more suitable crystalline phases. The invention can be carried out with a wide variety of contrast agents for non-radioactive, crystalline X-rays. However, the X-ray contrast agent must be poorly soluble and dispersible in at least one liquid medium. By "sparingly soluble" is meant that the agent has a solubility in the liquid dispersion medium, for example, water, of less than about 10 mg / ml, and preferably less than about 1 mg / ml. The preferred liquid dispersion medium is water. Additionally, the invention can be practiced with other liquid media in which the selected X-ray contrast agent is sparingly soluble and dispersible, including, for example, aqueous saline solutions, such as phosphate buffered saline. (PBS), plasma, mixed aqueous and non-aqueous solutions, for example, water and alcohol and any suitable non-aqueous solvent such as alcohol, glycerol and the like. The X-ray contrast agent can be an iodinated compound. The iodinated compound may be aromatic or non-aromatic. The aromatic compounds are preferred. The iodinated compound may be constituted by one, two, three or more atoms per molecule. The preferred species contain at least two, and more preferably at least three, iodine atoms per molecule. Selected iodinated compounds may contain substituents that do not impart solubility to the compound such as, for example, alkylureido, alkoxyacylamido, hydroxyacetamido, butyrolactamido, succinimido, trifluoroacetamido, carboxy, carboxyamido, hydroxy, alkoxy, acylamino and similar substituents. A preferred class of contrast agents includes several esters of iodinated aromatic acid amides. Preferably, the esters 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 may be an ester or amide of a substituted triiodobenzoic acid such as triiodobenzoic acid substituted with acyl, carbamyl and / or acylmethyl. Illustrative representative examples of the iodated aromatic acids include, but are not limited to, diatrizoic acid, metrizoic acid, yotalamic acid, trimesic acid, uroconic acid, ioxagic acid (hexabrix), ioxydamoic acid, tetraiodoterephthalic acid, iodopamide, ichric 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. art. It is contemplated that this invention can be practiced with iodinated compounds poorly soluble in monomeric, dimeric, trimeric and polymeric forms. The classes of preferred contrast agents have the following structural formulas: A. [diatrizoate] B . [yotalamato] [yodipamide] In the above structures R can be OR1, NR2R3, alkylene, -CO.OR1 or -0-alkylene-OC.OR1, wherein R1 is alkyl and R2 and R3 are independently H or alkyl. Each alkyl group can independently contain from 1 to 20, preferably from 1 to 8, more preferably from 1 to 4 carbon atoms. Preferably, the alkylene group contains from 1 to 4 carbon atoms such as methylene, ethylene, propylene and the like. Particularly preferred contrast agents include diatrizoic acid ethyl ester, ie ethyl 3,5-diacetamido-2,4,6-triiodobenzoate, also known as 3,5-bis (acetylamino) -2,4,6. ethyl-triiodobenzoate or ethyl diatrizoate, having the structural formula A above, wherein R = -OCH2CH3; the ethyl glycol ester of diatrizoic acid, ie, (3,5-bis (acetylamino) -2,4,6-triiodobenzoyloxy) ethyl acetate, also known as ethyl diatrizoxyacetate, - and 2- (3, 5 ethyl-bis (acetylamino) -2,4, 6-tri-iodobenzoyloxy) butyrate, also known as ethyl 2-diatrizoxybutyrate. In addition, the invention can be practiced in conjunction with water-insoluble iodinated carbonate esters described in PCT / EP90 / 00053.

The X-ray contrast agents described in the above are known compounds and / or can be prepared by techniques known in the art. For example, the water-insoluble terminal esters and amides of acids such as the iodinated aromatic acids written therein can be prepared by conventional alkylation or amidation techniques known in the art. The acids indicated above and other acids which can be used as starting materials are commercially available and / or can be prepared by techniques known in the art. Particles useful in contrast agents of type (7) include a surface modifier. The surface modifiers useful herein physically adhere to the surface of the X-ray contrast agent but do not react chemically with the agent or with themselves. The individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinks. 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), acacia gum, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying silk, sorbitan esters , polyexyethylenealkyl ethers, for example, macrogol ethers, such as cetomacrogol 1000, polyoxyethylene and castor oil derivatives, poliexythylene sorbitan fatty acid esters, for example, commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, silicon dioxide colloidal, phosphates, sodium dodecylsulfate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, non-crystalline cellulose, aluminum magnesium silicate, triethanolamine, polyvinyl alcohol and polyvinylpyrrolidone (PVP). Most of these surface modifiers are known pharmaceutical excipients and are described in detail in Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986, the description of which is incorporated herein 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, dialkyl esters 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 alkylaryl 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 glycol available from Union Carbide. Surface modifiers in which they 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-D-glucopyranoside, -n-decyl-D-maltopyranoside, -n-dodecyl-β-D-glucopyranoside, -n-dodecyl / SD-maltoside, - heptanoyl-N-methylglucamide n-heptyl ß-D-glucopyranoside, - n-heptyl / 3-D-thioglucoside; n-hexyl ß-D-glucopyranoside, -nonanoyl-N-methylglucamide; n-nonyl / S-D-glucopyranoside, -octanoyl-N-methylglucamide; n-octyl 0-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 R1 I CONCH2 (CHOH) xCH2OH \ C0NCH2 (CHOH) and CH2OH R 2 where (CH2) a- / L is R-CH L 'is a chemical bond, -O-, -S-, -NH-, -CONH- or -S02NH-; R is unsubstituted or substituted hydrophobic alkyl, substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted aryl group; each of R1 and R2 independently is hydrogen or an alkyl group having 4 carbon atoms, - each of a and b independently is 0 or an integer from 1 to 3 with the proviso that the sum of a and b is not greater of 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 a group n -alkyl containing from 6 to 18 carbon atoms, each of R1 and R2 independently is a methyl, ethyl, propyl or butyl group is already 0 and b is 0. This class of surface modifiers is described in the patent application of Great Britain No. 9104957.7 deposited on March 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 of 140 to 200 ° C. C. 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 can be prepared according to the wet milling process described in U.S. Patent No. 5,145,684. The process comprises dispersing a poorly soluble X-ray contrast agent in a liquid dispersion medium and wet-wetting the agent in the presence of a grinding medium to reduce the particle size of the contrast agent to an average particle size. effective from about 0.05 μ to about 100 μ, preferably from 0.05 μ to about 5 μ, and more 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 grinding. As used herein, the particle size refers to the average number of particle size measured by conventional particle size measurement techniques well known to those skilled in the art, such as fractionation of sediment field flow, spectroscopy of photon correlation or disk centrifugation. By "an effective average particle size from about 0.05 μ to about 100 μ" is meant that at least 90% of the particles have an average particle size weight from about 0.05 μ to about 100 μ when measured by the techniques indicated in the above. The range of particle size allows a sufficient number of particles to be distributed in the film-forming composition when the Gl tract is coated therewith, and furthermore ensures the prevention of absorption through the intestinal walls. The pharmaceutically acceptable natural clays incorporated in the present invention comprise aluminum silicates. They are used in pure form, suitable for administration in patients. The natural, pharmaceutically acceptable clays of the present invention are generally mentioned as smectites, consist of dioctahedral smectites and trioctahedral smectites. The dioctahedral smectites include: montmorillonite, which have the formula M + Al3y (FeMg) and Si4O10 (OH) 2 • nH20; beidelite, which has the formula M + Ala (Si4-XA1X) 010 (OH) 2 • nH20; nontronite, which has the formula M + Fe2 (Si4-XA1X) 010 (OH) 2 • nH20; where M + is Na, Ca or Mg. Trioctahedral smectites include: saponite, which has the formula M + (Mg3-y (AlFe) y) (Si4-XA1X) O10 (OH) 2 • nH20; hectorite, which has the formula M + (Mg3- and Liy) Si4O10 (OH) 2 • nH20; where M + is Na, Ca or Mg. The clays are available from chemical suppliers such as, for example, American Colloid Company, Arlington Heights, IL, under the trade names: MAGNABRITEMRHS; HECTABRITEMRDP, HECTABRITEMRLT, CARMARGOMRWhite, POLARGELMRNF, POLARGELMRHV, and VOLCLAYMRNF-BC. Other providers include: Engelhard Corp., Iselin, NJ; Ashland Chemical Inc., Colombus, OH; RT Vanderbilt Co., Inc., Norwalk, CT and Whittaker Clark & Daniels, Inc., S. Plainifield, NJ. The contrast agent and pharmaceutically acceptable clay is formulated for administration by the use of physiologically acceptable carriers or excipients in a manner that is within the skill or ability of the art. The contrast agent with the addition of pharmaceutically acceptable auxiliaries (such as surfactants and emulsifiers) and excipients can be suspended or emulsified in an aqueous medium, resulting in a suspension or emulsion. The compositions of the present invention are comprised of the following pharmaceutically acceptable components, in a base in% w / v: Ingredients Interval Interval Most Wide Preferred Preferred Interval Contrast agents 5 - 45 10 - 35 15 - 25 Clay 0.1 - 10 0.5 - 5 1 - 2 Surfactants 1 - 20 2 - 10 3 - 5 Excipients 0 - 15 0.5 - 5 1 - 2 Water - c.s. for 100%, in volume The excipients contemplated by the present invention include antifoaming agents such as simethicone, siloxyalkylene polymers and polyoxyalkylated natural oils, preservatives or preservatives such as methyl paraben, propyl paraben, benzoic acid and sorbic acid, flavoring / sweetening agents such as sodium saccharin; and coloring agents such as lacquers and dyes. Although the iodophenoxyalkanes of the present invention in the formulations with a pharmaceutically acceptable carrier provide good quality x-ray images, the addition of a pharmaceutically acceptable clay to the formulations greatly increases the quality of the images by X-rays. lower of the concentration range there is little or no benefit obtained, while above the upper end of the concentration range, the formulation is too viscous for administration. The following formulation examples further illustrate the invention.

EXAMPLE 1 Components 2, 4, 6-triiodophenoxy-2-butane 20.0 g HECTABRITEMR DP 1.45 g Sorbitan monostearate 0.5 g Polysorbate 60 1.0 g Poloxamer 338 5.0 g Sodium saccharin 0.25 g Benzoic acid 0.50 g Sorbic acid 0.050 g Water q.s. to make 100 ml EXAMPLE 2 Components 4-iodophenoxy-2-octane 22.5 g POLARGELM NF 2.25 g Sorbitan mono-oleate 0.40 g Polysorbate 20 1.25 g Polyvinyl alcohol 4.50 g Sodium saccharin 0.25 g Emulsion of simethicone 0.10 g (food grade) Water c.s. to make 100 ml EXAMPLE 3 Components 2, 4, 6-triiodophenoxy-2-hexane 18.5 g MAGNABRITEMR HS 1.25 g Sorbitan monopalmitate 0.6 g Polyoxyethylene myristyl ether 0.6 g Polyvinylpyrrolidone 3.5 g Vanilla flavor (artificial) 0.25 g Strawberry flavor (artificial) 0.25 g Sorbitol 1.0 g Water c.s. to make 100 ml EXAMPLE 4 Components Quantities, in% p / v Bis- (4-iodophenyl) ether of polyethylene glycol-400 17.50 HECTABRITEMRDP 1.35 Polysorbate 80 (Tween 80) 1.50 Sorbitan mono-oleate (Span 80) 1.65 c.s. with water up to 100% by volume EXAMPLE 5 Components Quantities, in% p / v 1, 8-bis-O- (2,4,6-triiodophenyl) -tripropylene glycol 25.00 POLARGELHRNF 2.30 Polysorbate 60 (Tween 60) 1.00 Poloxamer 338 6.50 Benzoic acid 0.50 Sorbic acid 0.50 c.s. with water up to 100% by volume EXAMPLE 6 Components Quantities, in% p / vl, ll-bis- (2,4,6-triiodophenoxy) -3,6,9-trioxaundecane 17.50 MAGNABRITEMRHS 1.25 Polysorbate 20 (Tween 20) 1.50 Sorbitan mono-laurate (Span 20) 2.00 Polyvinyl alcohol 4.00 Sodium saccharin 0.30 cs with water up to 100% by volume EXAMPLE 7 Components N-acetyl-N-2-octyl-4-iodoaniline 18.00 g HECTABRITEMRDP 1.5 g Sorbitan monostearate 0.5 g Polysorbate 60 (Tween 60) 1.2 g Poloxamer 338 4.0 g Sodium saccharin 0.3 g Benzoic acid 0.1 g Sorbic acid 0.05 g Water cs to constitute 100 ml EXAMPLE 8 Components N- (4 '-iodophenyl) -2-amino octane 25.00 g P0LARGELMR NF 2.0 g Sorbitan mono-oleate 0.4 g Polysorbate 20 (Tween 20) 1.2 g Polyvinyl alcohol 4.5 g Sodium saccharine 0.2 g Simethicone (food grade) 0.1 g Water q.s. to make 100 ml EXAMPLE 9 Components 2-octyl-2, 3, 5-triiodobenzoato 22.00 g HECTABRITEMRDP 1.50 g Sorbitan monostearate 0.70 g Polysorbate 60 (Tween 60) 1.20 g Poloxamer 338 4.00 g Sodium saccharin 0.30 g Benzoic acid 0.50 g Sorbic acid 0.05 g Water c.s. to constitute 100 ml EXAMPLE 10 Components 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluoro-2-octyl-2,3,5-triiodobenzoate 22.50 g POLARGELMR NF 2.30 g Sorbitan mono-oleate 0.45 g Polysorbate 20 (Tween 820) 1.30 g Polyvinyl alcohol 4.50 g Sodium saccharin 0.25 g Simethicone emulsion (food grade) 0.10 g Water q.s. to make 100 ml EXAMPLE 11 Components Ethyl-3- (2-acetyloxy) -2,4,6-triiodobenzoate 18.50 g MAGNABRITEMR HS 1.25 g Sorbitan monopalmitate 0.60 g Polyoxyethylene myristyl ether 0.60 g Polyvinylpyrrolidone 3.50 g Vanilla flavor (artificial) 0.25 g Strawberry flavor (artificial) 0.25 g -. Sorbitol 1.00 g Water c.s. to make 100 ml EXAMPLE 12 5 Components 2, 4, 6- riyodofenoximetilciclopentano 22.00 g HECTABRITEMRDP 1.50 g Sorbitan monostearate 0.70 g Polysorbate 60 (Tween 60) 1.20 g Poloxamer 338 4.00 g Sodium saccharin 0.30 g Benzoic acid 0.50 g Sorbic acid 0.05 g Water c.s. to make 100 ml EXAMPLE 13 Components 20 2- (4-iodophenoxy) pentadecane 22.50 g P0LARGELHR NF 2.30 g Sorbitan mono-oleate 0.45 g Polysorbate 20 (Tween 820) 1.30 g Polyvinyl alcohol 4.50 g Saccharin sodium 0.25 g Simethicone emulsion (food grade) 0.10 g Water c.s. to make 100 ml EXAMPLE 14 Components 2-iodophenoxicyclopentane 18.50 g MAGNABRITEMR HS 1.25 g Sorbitan monopalmitate 0.60 g Polyoxyethylene myristyl ether 0.60 g Polyvinyl pyrrolidone 3.50 g Vanilla flavor (artificial) 0.25 g Strawberry flavors (artificial) 1.25 g Sorbitol 1.00 g Water c.s. to make 100 ml EXAMPLE 15 Components 2, 4, 6-triiodophenyl-2-ethylhexanoate 22.00 g HECTABRITEHRDP 1.50 g Sorbitan monostearate 0.70 g Polysorbate 60 (Tween 60) 1.20 g Poloxamer 338 4.00 g Sodium saccharin 0.30 g Benzoic acid 0.50 g Sorbic acid 0.05 g Water c.s. to make 100 ml EXAMPLE 16 Components 2,4,6-triiodophenyl-tris- (2-ethylhexanoate) 22.50 g P0LARGELMR NF 2.30 g Sorbitan mono-oleate 0.45 g Polysorbate 20 (Tween 820) 1.30 g Polyvinyl alcohol 4.50 g Sodium saccharin 0.25 g Simethicone emulsion (food grade) 0.10 g Water q.s. to make 100 ml EXAMPLE 17 Components 2, 4, 6-triiodophenyl, hexyl sulfonate 18.50 g MAGNABRITEMR HS 1.25 g Sorbitan monopalmitate 0.60 g Polyoxyethylene myristyl ether 0.60 g Polyvinyl pyrrolidone 3.50 g Vanilla flavor (artificial) 0.25 g Strawberry flavors (artificial) 0.25 g Sorbitol 1.00 g Water c.s. to make 100 ml EXAMPLE 18 Components 3, ethyl 5-bis (acetylamino) -2,4,6-triiodobenzoate 22.00 g HECTABRITEMRDP 1.50 g Sorbitan monostearate 0.70 g Polysorbate or polysorbate60 (Tween 60) 1.20 g Poloxamer 338 4.00 g Sodium saccharin 0.30 g Benzoic acid 0.50 g Sorbic acid 0.05 g Water c.s. to constitute 100 ml EXAMPLE 19 Components (3,5-bis (acetylamino) -2,4,6-triiodobenzyloxy) ethyl acetate 22.50 g POLARGELMR NF 2.30 g Sorbitan mono-oleate 0.45 g Polysorbate 20 (Tween 20) 1.30 g Polyvinyl alcohol 4.50 g Sodium saccharin 0.25 g Simethicone emulsion (food grade) 0.10 g Water q.s. to make 100 ml EXAMPLE 20 Components Butyrate 2- (3,5-bis (acetylamino) -2,4,6-triiodobenzoyloxy) ethyl 18.50 g MAGNABRITEMR HS 1.25 g Sorbitan monopalmitate 0.60 g Polyoxyethylene myristyl ether 0.60 g Polyvinylpyrrolidone 3.50 g Flavor of vanilla (artificial) 0.25 g Flavor of strawberry (artificial) 0.25 g Sorbitol 1.00 g Water c.s. to make 100 ml The surfactants used in the present invention may be cationic, anionic, nonionic or zwitterionic. Suitable cationic surfactants include cetyltrimethylammonium bromide, ce ilpyridinium chloride, pyridinium myristylgamma chloride and benzalkonium chloride. Suitable anionic agents include sodium lauryl sulfate, sodium heptadecyl sulfate, alkylbenzenesulfonic acids and salts thereof, sodium butylnaphthalenesulfonate and sulfosuccinates. Zwitterionic surfactants are substances that, when dissolved in water, behave as diprotic acids and, as they ionize, behave as a weak base or as a weak acid. Since the two charges in the molecule balance each other, they act as neutral molecules. The pH at which the zwitterion concentration is greatest is known as the isoelectric point. Compounds such as certain amino acids have an isoelectric point at the desired pH of the formulations of the present invention and are useful for practicing the present invention.

In preparing the formulations of the present invention, it is preferred to use nonionic emulsifiers or surfactants which, similar to non-ionic contrast agents, have a superior toxicological profile with respect to anionic, cationic or zwitterionic agents. In nonionic emulsifying agents, the proportions of hydrophilic and hydrophobic groups are approximately uniformly balanced. They differ from anionic and cationic surfactants in the absence of charge in the molecule and for this reason, they are generally less irritating than cationic or anionic surfactants. Nonionic surfactants include carboxylic esters, carboxylic amides, ethoxylated alkylphenols, ethoxylated aliphatic alcohols, ethylene oxide polymer or ethylene oxide / propylene oxide copolymers, polyvinylpyrrolidone and polyvinyl alcohol. A particular type of carboxylic ester nonionic surfactants are the partial esters, for example the monoesters formed by the reaction of fatty acids and acid resins, for example, from about 8 to about 18 carbon atoms, with polyoalcohols, 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 variable molar proportions of ethylene to the hydroxy group of the fatty acids. Another type of carboxylic esters are the condensation products of fatty acids and partial acid resins, for example, ethylene oxide mono-esters such as fatty acid esters or polyoxyethylene sorbitan acid resin and sorbitol, for example, polyexyethylene sorbitan, esters of mono-bait oil. These may contain, for example, from about 3 to about 80 oxyethylene units per molecule and the fatty or acid resin groups from about 8 to about 18 carbon atoms. Examples of naturally occurring fatty acid mixtures which can be used are those of coconut oil and bait, while examples of single fatty acids are dodecanoic acid and oleic acid. The nonionic carboxylic amide surfactants are ammonia, monoethylamine, and diethylamine fatty acid amides having an acyl chain of from about 8 to about 18 carbon atoms. The ethoxylated alkylphenol nonionic surfactants include various condensates of polyethylene oxide of alkylphenols, especially the condensation products of mono-alkylphenols or dialkylphenols, wherein the alkyl group contains about 6 to about 12 carbon atoms in any branched chain or particularly in the straight chain configuration, for example octylcresol, octylphenol or nonylphenol, with ethylene oxide, the ethylene oxide is present in equal amounts from about 5 to about 25 moles of ethylene oxide per mole of alkylphenol. Nonionic ethoxylated aliphatic alcohol surfactants include the aliphatic alcohol concentration products having from about 8 to 18 carbon atoms in a straight chain or branched chain configuration, for example, oleyl or cetyl alcohol, with ethylene oxide , the ethylene oxide is present in equal amounts from about 30 to about 60 moles of ethylene oxide per mole of alcohol. Preferred nonionic surfactants include: (a) sorbitan esters (sold under the trade name Span) having the formula: wherein RX = R2 = OH, R3 = R for sorbitan monoesters, Rx = OH, R2 = R3 = R for sorbitan diesters, Rx = R2 = R3 = R for sorbitan triesters, where R = (C11H23) COO for laurate, (C17H33) COO for oleate, (C15H31) COO for palmitate, (C17H35) COO for stearate; (b) Polyoxyethylenealkyl ethers (for example Brijs) having the formula: CH3 (CH2) x (0-CH2-CH2) and OH where (x + 1) is the number of carbon atoms in the alkyl chain, usually: 12 lauryl (dodecyl) 14 myristyl (tetradecyl) 16 cetyl (hexadecyl) 18 stearyl (octadecyl) e y is the number of ethylene oxide groups in the hydrophilic chain, usually 10-60; (c) Polyoxyethylene sorbitan fatty acid esters, sold under the trade names of Tween or Polysorbates 20, 40, 60, 65, 80 & 85 that have the formulas (1) and (2) where 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). (d) Polyoxyethylene stearates such as: poly (oxy-1,2-ethanediyl), α-hydro-β-hydroxy-octadecanoate, polyethylene glycol monostearate; and poly (oxy-1, 2-ethanediyl) -oi (1-oxooctadecyl) -α-hydroxy-polyethylene glycol monostearate. (e) Polyethylene oxide / polypropylene oxide block copolymers, sold under the name PLUR0NICMR, which include Poloxamer 407 (PLUR0NICM F127), Poloxamer 188 (PLURONICHR F68), Poloxamer 237 (PLURONICMR F87) and Poloxamer 338 (PLUR0NICMR F108). (f) Polyvinyl pyrrolidone. (g) Polyvinyl alcohol. The dosages of the contrast agents 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 will be kept as low as is consistent to obtain improved contrast imaging. By using amounts of contrast agent as small as possible, the potential for toxicity is minimized. For most of the contrast agents of the present invention, the dosages will be in the range of from about 0.1 to about 16.0 g of iodine / kg of body weight, preferably in the range of from about 0.5 to about 6.0 g of iodine / kg of body weight, and more preferably, in the range of from about 1.2 to about 2.0 g of iodine / kg of body weight for regular X-ray visualization of the Gl tract. For CT scanning, the contrast agents of the present invention will be in the range of from about 1 to about 600 mg of iodine / kg of body weight, preferably in the range of from about 20 to about 200 mg of iodine / kg of body weight, and more preferably in the range of from about 40 to about 80 mg of iodine / kg of body weight. When administered to mammals, the compositions of the present invention produce excellent X-ray and CT images.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates. Having described the invention as above, property is claimed as contained in the following:

Claims (10)

1. A contrast composition for X-rays, for oral or retrograde examination of the gastrointestinal tract, characterized in that it comprises, on a basis of% by volume: (a) a contrast agent selected from (i) from about 5 to 45% of a contrast agent that produces x-rays that has the formula or a pharmaceutically acceptable salt thereof in which R is a substituted or unsubstituted alkyl group containing 2 to 8 carbon atoms, wherein the substituents are selected from the group consisting of alkyl of 1 to 6 carbon atoms and alkoxy; and n is 1 to 5; (ii) from about 5 to 45% of a contrast agent producing X-ray agent having the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, alkyl of 1 to 20 carbon atoms, cycloalkyl, lower alkoxy, alkoxycarbonyl, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups; R is alkyl of 1 to 25 carbon atoms, cycloalkyl, or lower haloalkyl, each of which may be optionally substituted with halo, lower fluoroalkyl, aryl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy, - or (CRxR2) p- (CR3 = CR4) mQ, or ( CR.R P-CHC-Q; R1 (R2, R3 and R4 are independently H or lower alkyl, optionally substituted with halo, x is 1-4, n is 1-4, m is 1-15, p is 1- 20, - and Q is H, lower alkyl, lower alkenyl, lower alkynyl, lower alkylene, aryl or arylalkyl, (iii) from about 5 to 45% of a contrasting X-ray producing agent having the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, alkyl of 1 to 20 carbon atoms, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups, - R? and R 2 is independently H, alkyl of 25 carbon atoms, cycloalkyl, acetyl or lower haloalkyl, wherein alkyl of 1 to 25 carbon atoms, cycloalkyl and lower haloalkyl optionally is substituted with lower fluoroalkyl, aryl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy, and acetyl is optionally substituted with lower fluoroalkyl, aryl, lower alkoxy, hydroxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy, - n is 1-4; and it is 1-4; and x is 1 or 2; (iv) from about 5 to 45% of a contrast agent producing X-ray agent having the formula or a pharmaceutically acceptable salt thereof in which Z is H, halo, alkyl of 1 to 20 carbon atoms, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups; R is alkyl of 1 to 25 carbon atoms, cycloalkyl or lower haloalkyl, each of which optionally may be substituted with halo, lower fluoroalkyl, aryl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy; or (CR ^) p- (CR3 = CR4) nQ, or (CRXR2) p-C = C-Q; R1 t R2, R3 and R4 are independently lower alkyl, optionally substituted with halo, - x is 1-3 and 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 arylalkyl; (v) from about 5 to 45% of a contrast agent producing X-ray agent having the formula or a pharmaceutically acceptable salt thereof, wherein Z is H, halo, alkyl of 1 to 20 carbon atoms, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted by halogen or lower haloalkyl groups, - R is methyl, ethyl, propyl, 9 to 25 carbon atoms, cycloalkyl or lower haloalkyl, optionally substituted with halo, lower fluoroalkyl, aryl, lower alkoxy, hydroxy, carboxy, lower alkoxycarbonyl or lower alkoxycarbonyloxy; or (CRxR2) p- (CR3 = CR4) mQ, or (CR ^ JP-QEC-Q; R1 # R2, R3 and R4 are independently lower alkyl, optionally substituted with halo; x 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 arylalkyl, (vi) from about 5 to 45% of a producing agent. X-ray contrast that has the formula or a pharmaceutically acceptable salt thereof in which Z is H, halo, methyl, ethyl, n-propyl, alkyl of 4 to 20 carbon atoms, cycloalkyl, lower alkoxy, cyano, wherein the alkyl and cycloalkyl groups may be substituted with halogen or lower haloalkyl groups; R is alkyl of 1 to 25 carbon atoms, cycloalkyl or aryl, each of which may be optionally substituted with halo, lower fluorohalkyl, lower alkoxy, hydroxy, carboxy or lower alkoxycarbonyl; lower alkenyl, lower alkynyl, lower alkylene or lower alkoxy carboxy, - n is 1-5; and it is 0-4; and w is 1-4; (vii) from about 5 to 45% of a contrast agent, crystalline, selected from the group consisting of diatrizoic acid, metrizoic acid, ethanolamic acid, tetraiodoterephthalic acid, yoxagic acid, iodipamide, 3,5-diacetamido-2, 4 , Ethyl 6-triiodobenzoate, 2- (3,5-bis (acetylamino) -2,4,6-triiodo-benzoyloxy) ethyl butyrate, and (3,5-bis (acetylamino) -2,4-6 triiodobenzoyloxy) -ethyl acetate, the crystalline contrast agent has a surface modifier absorbed on the surface thereof in an amount sufficient to maintain an effective average particle size from about 0.5 μ to about 100 μ, - and the surface modifier is selected from the group consisting of tetrafunctional block copolymers derived from the addition, in sequence, of propylene oxide and ethylene oxide to ethylenediamine; (b) from about 0.1 to 10% of a pharmaceutically acceptable clay selected from the group consisting of: montmorillonite, beidelite, nontronite, hectorite and saponite, - (c) from about 1.0 to 20% of a surfactant selected from the group consisting of nonionic, anionic, cationic and zwitterionic surfactants, - (d) from about 0 to 15% of an excipient; and (e) water up to 100% by volume.

2. The contrast composition for X-rays, according to claim 1, characterized in that the X-ray contrast producing agent is present in an amount of about 10 to 35%.

3. The contrast composition for X-rays, according to claim 1, characterized in that the pharmaceutically acceptable clay constitutes 0.5 to 5% of the composition.

4. The contrast composition for X-rays, according to claim 1, characterized in that the surfactant constitutes 2 to 10% of the composition.

5. The contrast composition for X-rays, according to claim 1, characterized in that the excipient constitutes 0.5 to 5% of the composition.

6. The contrast composition for X-rays, according to claim 1, characterized in that the nonionic surfactant is selected from the group consisting of carboxylic esters, carboxylic amides, ethoxylated alkylphenols, ethoxylated aliphatic alcohols, ethylene oxide polymer, ethylene oxide copolymer, ethylene oxide / propylene oxide, polyvinyl pyrrolidone and polyvinyl alcohol.

7. The contrast composition for X-rays, according to claim 1, characterized in that the surfactant is sorbitan ester having the formula: where Rt = R2 = OH, R3 = R for sorbitan monoesters, R1 = OH, R2 = R3 = R for sorbitan diesters, RL = R2 = R3 = R for sorbitan triesters, where R = (C11H23) COO for laurate, (C17H33) COO for oleate, (C15H31) COO for palmitate, (C17H35) COO for stearate.

8. The contrast composition for X-rays, according to claim 1, characterized in that the surfactant is polyoxyethylene stearate.

9. The contrast composition for X-rays, according to claim 1, characterized in that the surfactant is a polyoxyethylene sorbitan fatty acid ester of the formulas (1) and (2) HCO (C H O) and H l 2 4 CH20 (C2H40) zOCR Polyethylene sorbitan monoester w + x: + y + z = 20 w + x + y + z = 5 w + x + y + z 4

10. A method for carrying out an X-ray examination of a patient's gastrointestinal tract, the method is characterized in that it comprises the oral or rectal administration to the patient of an X-ray contrast formulation according to any preceding claim.