WO1995028969A1 - Compositions de contraste radiologique contenant des argiles acceptables sur le plan pharmacologique - Google Patents

Compositions de contraste radiologique contenant des argiles acceptables sur le plan pharmacologique Download PDF

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Publication number
WO1995028969A1
WO1995028969A1 PCT/GB1995/000566 GB9500566W WO9528969A1 WO 1995028969 A1 WO1995028969 A1 WO 1995028969A1 GB 9500566 W GB9500566 W GB 9500566W WO 9528969 A1 WO9528969 A1 WO 9528969A1
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Prior art keywords
alkyl
halo
alkoxy
ray contrast
cycloalkyl
Prior art date
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PCT/GB1995/000566
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English (en)
Inventor
Stephen B. Ruddy
Gregory L. Mcintire
Mary E. Roberts
John Toner
Edward R. Bacon
Tom Caulfield
Eugene R. Cooper
Brent D. Douty
Carl R. Illig
Kimberly Estep
Original Assignee
Nycomed Imaging As
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/230,580 external-priority patent/US5476646A/en
Priority claimed from US08/236,287 external-priority patent/US5424056A/en
Priority claimed from US08/237,502 external-priority patent/US5492687A/en
Priority claimed from US08/239,090 external-priority patent/US5484585A/en
Priority claimed from US08/247,438 external-priority patent/US5531979A/en
Priority claimed from US08/247,424 external-priority patent/US5360604A/en
Priority claimed from US08/249,424 external-priority patent/US5472682A/en
Priority to JP7527425A priority Critical patent/JPH09512029A/ja
Application filed by Nycomed Imaging As filed Critical Nycomed Imaging As
Priority to AU18977/95A priority patent/AU1897795A/en
Priority to EP95911399A priority patent/EP0756497A1/fr
Publication of WO1995028969A1 publication Critical patent/WO1995028969A1/fr
Priority to MXPA/A/1996/004899A priority patent/MXPA96004899A/xx
Priority to NO964451A priority patent/NO964451L/no
Priority to FI964212A priority patent/FI964212A0/fi

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0461—Dispersions, colloids, emulsions or suspensions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0495—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound intended for oral administration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • This invention relates to an x-ray contrast composition for oral or retrograde administration to a mammal comprising an x-ray contrast producing agent and a pharmaceutically acceptable clay.
  • CT computed tomography
  • Roentgenographic examination of the GI tract is indicated for conditions of digestive disorders, changes in bowel habit, abdominal pain, GI bleeding and the like.
  • administration of a radiopaque contrast medium 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.
  • 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 orally as a suspension or rectally as an enema.
  • barium sulfate administered orally as a suspension or rectally as an enema.
  • Iodinated organic compounds have also been used as 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 produces 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. Patent Nos.: 2,786,055; 3,795,698; 3,360,436; 3,574,718, 3,733,397; 4,735,795 and 5,047,228.)
  • the desiderata for an ideal GI contrast agent include: 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.
  • U.S. Patent 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. Patent 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 polyacrylaraide 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. Patent 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.
  • 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.
  • 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 composition containing a pharmaceutically acceptable clay and an x-ray contrast agent.
  • Such compositions must meet several requirements: both the x-ray contrast agent and the clay must be nontoxic,* must not contain leachable or digestible components that would deleteriously affect the patient; and no components of the coating should be absorbed by, and pass through, the inner surface of the intestine.
  • composition comprising: an x-ray contrast agent and a pharmaceutically acceptable clay in an aqueous pharmaceutically acceptable vehicle.
  • 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 compostion.
  • contrast agent and the pharmaceutically acceptable clay are incorporated in liquid media for administration to a mammal for x-ray visualization of the GI tract.
  • contrast agents utilized in the present invention are selected from
  • R is a substituted or unsubstituted alkyl group containing from 2 to 8 carbon atoms, wherein said substituents are selected from the group consisting of Ci-Cg alkyl, hydroxy and alkoxy,* and n is 1 to 5;
  • Ru R 2 , R 3 and R 4 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 aryl-lower alkyl,*
  • Z is H, halo, Ci-C ⁇ alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups,*
  • R x and R 2 are independently H, C ⁇ Cas alkyl, cycloalkyl, acetyl or halo-lower-alkyl, wherein said C- L - C 25 alkyl, cycloalkyl and halo lower-alkyl are optionally substituted with fluoro-lower-alkyl, aryl, lower- alkoxy, hydroxy, carboxy, lower-alkoxy carbonyl or lower-alkoxy-carbonyloxy and said acetyl is optionally substituted with fluoro-lower-alkyl, aryl, lower-alkoxy, hydroxy, lower-alkoxy carbonyl or lower-alkoxy- carbonyloxy,* n is 1-4; y is 1-4,* and x is 1 or 2,*
  • Z is 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- L , 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;
  • Z is H, halo, C- L -C 20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups,*
  • R 1# R 2 , R 3 and R 4 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 aryl-lower alkyl; (6) a compound of the formula
  • Z is H, halo, methyl, ethyl, n-propyl, C 4 -C 20 alkyl, cycloalkyl, lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups,*
  • R is C 1 -C 25 alkyl, cycloalkyl or aryl each of which may be optionally substituted with halo, fluoro-lower- alkyl, lower-alkoxy, hydroxy, carboxy or lower-alkoxy carbonyl; lower-alkenyl, lower-alkynyl, lower-alkylene or lower-alkoxy-carbonyloxy; n is l-5 y is 0-4; and w is 1-4
  • a particulate crystalline x-ray contrast agent having a surface modifier adsorbed on the surface thereof.
  • halogen means fluorine, chlorine, bromine or iodine.
  • 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.
  • lower-alkyl and lower- alkoxy mean monovalent aliphatic radicals, including branched chain radicals, of from one to ten carbon atoms.
  • the lower-alkyl moiety of such groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, -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.
  • 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.
  • 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.
  • 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 compounds can comprise one, two, three * .r more iodine atoms per molecule,* preferred speci- contain at least two, and more preferably, at least chree 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 comminuted to the desired size using conventional milling methods, such as airjet or fragmentation milling.
  • an effective average particle size of less than about lOO ⁇ provides for good distribution and coating in the GI tract.
  • 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 lOO ⁇ means that at least about 90% of the particles have a weight average particle size of less than about 10O ⁇ as measured by art recognized techniques.
  • 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 is an oil; we prefer 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 GI tract for use in medical procedures in accordance with this invention comprises orally or rectally administering to the mammalian patient in need of an 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.
  • R is a secondary alkyl group containing from 4 to 8 carbon atoms.
  • the most preferred contrast agent of type (1) is the sec-octyl ether of 2,4,6-triiodophenol having the formula:
  • 2-octyl 2,3,5- triiodobenzoate, 3,3,4,4,5,5,6,6,7,7,8,8-dodecafluoro-2- octyl 2,3,5-triiodobenzoate, bis (2-hexyl) 2,3,5,6- tetraiodoterephthalate, ethyl 3- (2-octyloxy) -2,4,6- triiodobenzoate and bis(2-octyl) 5- (2-octyloxy) -2,4, 6- triiodoisophthalate are described therein.
  • 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 described in U.S. Patent 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 least one liquid medium.
  • 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 preferred liquid dispersion medium is water.
  • the invention can be practiced with other liquid media in which the selected x-ray contrast agent is poorly soluble and dispersible, including, for example, aqueous saline solutions, such as phosphate buffered saline (PBS) , plasma, mixed aqueous and nonaqueous solutions, for example, water and alcohol, and suitable nonaqueous solvents such as alcohol, glycerol and the like.
  • PBS phosphate buffered saline
  • suitable nonaqueous solvents such as alcohol, glycerol and the like.
  • 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, trifluoroacetamido, 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.
  • 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.
  • 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.
  • Classes of preferred contrast agents have the following structural formulae:
  • R can be OR 1 , NR 2 R 3 , alkylene, -CO.OR 1 or -O-alkylene-CO.OR 1 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.
  • the invention can be practiced in conjunction with the water insoluble iodinated carbonate esters described in PCT/EP90/00053.
  • x-ray contrast agents are known compounds and/or can be prepared by techniques known in the art.
  • 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 particles useful in the contrast agents of type (7) 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.
  • 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, tri
  • 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
  • a particularly preferred class of surface modifiers includes water-soluble or water-dispersible compounds having the formula
  • L' is a chemical bond, -0-, -S-, -NH-, -CONH- or -S0 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 su- ⁇ . ⁇ of a and b is not greater than 3; and, each of x and y independently is an integer from 3 to 7.
  • R contains from 6 to 36 carbon atoms
  • 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 No. 9104957.7 filed 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 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 can be prepared in accordance with the wet grinding 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-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 ⁇ to about 100 ⁇ , preferably of from about 0.05 ⁇ to about 5 ⁇ and most preferably from about 0.1 ⁇ to about 1 ⁇ .
  • 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.
  • 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.
  • an effective average particle size of from about 0.05 ⁇ to about _..0 ⁇ is meant that at least 90% of the particles have a weight average particle size of from about 0.05 ⁇ to about 100 ⁇ when measured by the above-noted techniques.
  • the particle size range allows sufficient number of rr.rticles 1 distribution in the film forming composition when the GI tract is coated therewith, yet insures against absorption through the intestinal walls.
  • the natural, pharmaceutically acceptable clays incorporated in the present invention comprise aluminum silicates. They are used in purified form, suitable for administration to patients.
  • the natural, pharmaceutically acceptable clays of the present invention generally referred to as smectities, consist of dioctohedral smectites and trioctahedral smectites.
  • Dioctahedral smectites include: montmorillonite, having the formula
  • M + is Na, Ca or Mg.
  • Trioctahedral smectites include:
  • the clays are available from chemical suppliers, such as, for example, American Colloid Company, Arlington Heights, IL, under the tradenames:
  • the contrast agent and the pharmaceutically acceptable clay are 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 emulsified in an aqueous medium resulting in a suspension or emulsion.
  • compositions of the present invention comprise the following pharmaceutically acceptable components based on % w/v: Most
  • Excipients contemplated by the present invention include antifoaming agents, such as simethicone, siloxyalkylene polymers and polyoxyalkylated natural oils,* preservatives, such as methyl paraben, propyl paraben, benzoic acid and sorbic acid; flavoring/sweetening agents, such as sodium saccharine,* and coloring agents, such as lakes and dyes.
  • antifoaming agents such as simethicone, siloxyalkylene polymers and polyoxyalkylated natural oils,* preservatives, such as methyl paraben, propyl paraben, benzoic acid and sorbic acid
  • flavoring/sweetening agents such as sodium saccharine
  • coloring agents such as lakes and dyes.
  • the iodophenoxyalkanes of the present invention in formulations with a pharmaceutically acceptable vehicle provide good quality x-ray images
  • the addition of a pharmaceutically acceptable clay to the formulations greatly increases the quality of the x- ray images.
  • the formulation is too viscous for administration.
  • Poloxamer 338 5.0 g Sodium Saccharine 0.25 g
  • Polysorbate 60 (Tween 60) 1.00 Poloxamer 338 6.50 Benzoic Acid 0.50 Sorbic Acid 0.05 q.s. with water to 100% by volume
  • N-acetyl-N-2-octyl-4-iodoaniline 18.00 g HECTABRITE ® DP 1.5 g Sorbitan Monostearate 0.5 g Polysorbate 60 (Tween 60) 1.2 g Poloxamer 338 4.0 g Sodium Saccharine 0.3 g Benzoic Acid 0.1 g Sorbic Acid 0.05 g Water q.s. to make 100 ml
  • Polysorbate 60 (Tween 60) 1.20 g
  • Sorbic Acid 0.05 g Water q.s. to make 100 ml
  • Polysorbate 20 (Tween 820) 1.30 g
  • Polysorbate 60 (Tween 60) 1.20 g
  • Sorbic Acid 0.05 g Water q.s. to make 100 ml
  • Polysorbate 20 (Tween 820) 1.30 g Polyvinyl Alcohol 4.50 g
  • Simethicone emulsion 0.10 g Water q.s. to make 100 ml
  • Polysorbate 60 (Tween 60) 1.20 g
  • Sorbic Acid 0.05 g Water q.s. to make 100 ml
  • Polysorbate 20 (Tween 820) 1.30 g
  • Simethicone emulsion 0.10 g Water q.s. to make 100 ml
  • Polysorbate 60 (Tween 60) 1.20 g
  • Polysorbate 20 (Tween 820) 1.30 g
  • Simethicone emulsion 0.10 g Water q.s. to make 100 ml
  • the surface active agents used in the present invention may be cationic, anionic, nonionic or zwitterionic.
  • Suitable cationic surfactants include cetyl trimethyl ammonium bromide, cetyl pyridinium chloride, myristyl gamma picolinium chloride and benzalkonium chloride.
  • 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 they 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.
  • 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.
  • 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 c arge on the molecule and , for that reason, are generally less irritating than the cationic or anionic surfactants.
  • Nonionic surfactants include carboxylic esters, carboxylic amides, ethoxylated alkylphenols, ethoxylated aliphatic alcohols, ethylene oxide polymer or ethylene oxide/propyiene oxide co-polymers polyvinylpyrrolidone and polyvinylalcohol.
  • 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 polyalcohols, 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.
  • polyalcohols 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.
  • carboxylic esters are 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, mono- tall 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 mono-alkylphenols 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: (a) Sorbi an esters (sold under the trade name Span) having the formula:
  • (x + 1) is the number of carbon atoms in the alkyl chain, typically:
  • y is the number of ethylene oxide groups in the hydrophilic chain, typically 10-60;
  • Polyoxyethylene stearates such as: poly(oxy-1,2-ethanediyl) , ⁇ -hydro- ⁇ -hydroxy- octadecanoate,* polyethylene glycol monostearate,* and poly(oxy-1,2-ethanediyl) - ⁇ - (1-oxooctadecyl) - ⁇ - hydroxy-polyethylene glycol monostearate.
  • PLURONICTM Polyethylene oxide/polypropylene oxide block co ⁇ polymers, sold under the name PLURONICTM, which include Poloxamer 407 (PLURONICTM F127) , Poloxamer 188 (PLURONICTM F68) , Poloxamer 237 (PLURONICTM F87) and Poloxamer 338 (PLURONICTM F108) .
  • PLURONICTM Polyethylene oxide/polypropylene oxide block co ⁇ polymers, sold under the name PLURONICTM, which include Poloxamer 407 (PLURONICTM F127) , Poloxamer 188 (PLURONICTM F68) , Poloxamer 237 (PLURONICTM F87) and Poloxamer 338 (PLURONICTM F108) .
  • PLURONICTM Polyvinylpyrrolidone.
  • 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.
  • dosages will be in the range of from about 0.1 to about 16. r g iodine/kg body weight, preferably in the range of front 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.C g iodine/kg body weight for regular x-ray visualization of the GI tract.
  • the contrast agents of the present invention will be in the range o£ 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 _ ⁇ mg iodine/kg body weight.
  • compositions of the present invention produce excellent x-ray and CT images.

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Abstract

On décrit des compositions de contraste radiologique destinées à un examen oral ou rétrograde du tractus gastro-intestinal, comprenant un agent de production d'un contraste radiologique combiné à une argile acceptable sur le plan pharmacologique, dans un excipient également acceptable sur le plan pharmacologique; on décrit également des procédés d'utilisation de ces compositions dans la radiologie diagnostique du tractus gastro-intestinal.
PCT/GB1995/000566 1994-04-21 1995-03-16 Compositions de contraste radiologique contenant des argiles acceptables sur le plan pharmacologique WO1995028969A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP95911399A EP0756497A1 (fr) 1994-04-21 1995-03-16 Compositions de contraste radiologique contenant des argiles acceptables sur le plan pharmacologique
AU18977/95A AU1897795A (en) 1994-04-21 1995-03-16 X-ray contrast compositions containing pharmaceutically acceptable clays
JP7527425A JPH09512029A (ja) 1994-04-21 1995-03-16 薬理学的に許容される粘土を含むｘ線造影組成物
MXPA/A/1996/004899A MXPA96004899A (en) 1994-04-21 1996-10-17 Compositions of contrast for x-rays containing clays pharmaceutically accepted
FI964212A FI964212A0 (fi) 1994-04-21 1996-10-18 Röntgenvarjoainekoostumuksia, jotka sisältävät farmaseuttisesti hyväksyttäviä savia
NO964451A NO964451L (no) 1994-04-21 1996-10-18 Röntgenkontrastblandinger inneholdende farmasöytisk akseptable leirer

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US239,090 1981-02-27
US230,580 1994-04-21
US08/230,580 US5476646A (en) 1992-05-01 1994-04-21 X-ray contrast compositions containing iodophenoxyalkanes and pharmaceutically acceptable clays
US08/236,287 US5424056A (en) 1993-03-01 1994-04-29 X-ray contrast compositions containing iodoaniline derivatives and pharmaceutically acceptable clays
US236,287 1994-04-29
US237,502 1994-05-03
US08/237,502 US5492687A (en) 1993-03-11 1994-05-03 Compositions of iodophenoxy alkylene ethers and pharmaceutically acceptable clays for visualization of the gastrointestinal tract
US08/239,090 US5484585A (en) 1993-03-11 1994-05-05 Compositions of iodobenzoic acid derivatives and pharmaceutically acceptable clays for visualization of the gastrointestinal tract
US247,424 1994-05-23
US08/247,424 US5360604A (en) 1994-04-14 1994-05-23 X-ray contrast compositions containing an organic crystalline X-ray contrast agent in combination with pharmaceutically acceptable clays
US08/247,438 US5531979A (en) 1993-02-02 1994-05-23 Compositions of iodophenoxy alkanes and iodophenyl ethers and pharmaceutically acceptable clays for visualization of the gastrointestinal tract
US247,438 1994-05-23
US249,424 1994-05-26
US08/249,424 US5472682A (en) 1993-03-31 1994-05-26 Compositions of iodophenyl esters and iodophenyl sulfonates and pharmaceutically acceptable clays for visualization of the gastrointestinal tract

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CA (1) CA2187019A1 (fr)
FI (1) FI964212A0 (fr)
HU (1) HUT76304A (fr)
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Cited By (8)

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Publication number Priority date Publication date Assignee Title
WO1996020734A2 (fr) * 1994-12-30 1996-07-11 Nanosystems, L.L.C. Agents de contraste pour diagnostic aux rayons x combines a des argiles pharmacocompatibles et des tensioactifs
US7473711B2 (en) 2004-04-22 2009-01-06 Pfizer Inc. Androgen modulators
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7670613B2 (en) 2004-07-08 2010-03-02 Pfizer Inc. Androgen modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators
WO2015024025A1 (fr) 2013-08-16 2015-02-19 The Regents Of The University Of California Produit de contraste à base de silicium pour administration par voie entérale pour examen par scanner
US11033640B2 (en) 2013-03-15 2021-06-15 The Regents Of The University Of California Enteric CT contrast material based on low-z atoms

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JP4670229B2 (ja) * 2003-06-10 2011-04-13 味の素株式会社 Ｃｔコロノグラフィにおける消化管造影用組成物
CN1330380C (zh) * 2005-03-18 2007-08-08 山东师范大学 一种x－射线造影剂组合物
CN106075476B (zh) * 2016-07-30 2019-05-31 温州市人民医院 一种造影剂

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020734A2 (fr) * 1994-12-30 1996-07-11 Nanosystems, L.L.C. Agents de contraste pour diagnostic aux rayons x combines a des argiles pharmacocompatibles et des tensioactifs
WO1996020734A3 (fr) * 1994-12-30 1996-10-10 Eastman Kodak Co Agents de contraste pour diagnostic aux rayons x combines a des argiles pharmacocompatibles et des tensioactifs
US7576128B2 (en) 2004-02-13 2009-08-18 Pfizer Inc. Androgen receptor modulators
US7507860B2 (en) 2004-04-13 2009-03-24 Pfizer Inc. Androgen modulators
US7473711B2 (en) 2004-04-22 2009-01-06 Pfizer Inc. Androgen modulators
US7670613B2 (en) 2004-07-08 2010-03-02 Pfizer Inc. Androgen modulators
US7674819B2 (en) 2005-05-05 2010-03-09 Warner-Lambert Company Llc Androgen modulators
US7799823B2 (en) 2005-05-05 2010-09-21 Warner-Lambert Company Llc Androgen modulators
US11033640B2 (en) 2013-03-15 2021-06-15 The Regents Of The University Of California Enteric CT contrast material based on low-z atoms
WO2015024025A1 (fr) 2013-08-16 2015-02-19 The Regents Of The University Of California Produit de contraste à base de silicium pour administration par voie entérale pour examen par scanner
EP3033012A4 (fr) * 2013-08-16 2017-04-19 The Regents of the University of California Produit de contraste à base de silicium pour administration par voie entérale pour examen par scanner

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JPH09512029A (ja) 1997-12-02
CN1147206A (zh) 1997-04-09
MX9604899A (es) 1998-03-31
HU9602908D0 (en) 1996-12-30
FI964212A (fi) 1996-10-18
NO964451L (no) 1996-12-18
AU1897795A (en) 1995-11-16
FI964212A0 (fi) 1996-10-18
CA2187019A1 (fr) 1995-11-02
EP0756497A1 (fr) 1997-02-05
NO964451D0 (no) 1996-10-18
HUT76304A (en) 1997-07-28

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