EP0746339A1 - Compositions de contraste radiologique contenant des derives de la cellulose - Google Patents

Compositions de contraste radiologique contenant des derives de la cellulose

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Publication number
EP0746339A1
EP0746339A1 EP95909853A EP95909853A EP0746339A1 EP 0746339 A1 EP0746339 A1 EP 0746339A1 EP 95909853 A EP95909853 A EP 95909853A EP 95909853 A EP95909853 A EP 95909853A EP 0746339 A1 EP0746339 A1 EP 0746339A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkoxy
halo
ray contrast
composition
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP95909853A
Other languages
German (de)
English (en)
Inventor
Carl R. Illig
John Toner
Edward James Baker
Robert Lee
Tom Caulfield
Brent D. Douty
Kurt Josef
Edward R. Bacon
Kimberly Estep
Saul Daum
Eugene R. Cooper
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GE Healthcare AS
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 US08/201,731 external-priority patent/US5422114A/en
Priority claimed from US08/206,552 external-priority patent/US5443814A/en
Priority claimed from US08/217,138 external-priority patent/US5385721A/en
Priority claimed from US07/216,988 external-priority patent/US5385720A/en
Priority claimed from US08/222,787 external-priority patent/US5466435A/en
Priority claimed from US08/227,423 external-priority patent/US5368837A/en
Priority claimed from US08/227,415 external-priority patent/US5525327A/en
Priority claimed from US08/227,422 external-priority patent/US5543132A/en
Priority claimed from US08/229,048 external-priority patent/US5385722A/en
Priority claimed from US08/246,888 external-priority patent/US5607660A/en
Application filed by Nycomed Imaging AS filed Critical Nycomed Imaging AS
Publication of EP0746339A1 publication Critical patent/EP0746339A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K49/0404—X-ray contrast preparations containing barium sulfate
    • 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
    • A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
    • 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
    • A61K49/0442—Polymeric X-ray contrast-enhancing agent comprising a halogenated group
    • 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

Definitions

  • This invention relates to x-ray contrast compositions containing contrast agents and cellulose derivatives, and methods for their use in diagnostic radiology of the gastrointestinal tract.
  • 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 GI contrast agents since the iodine atom is an effective X-ray absorber. They have the most versatility and are utilized in the widest variety of procedures. They are very absorptive of X-rays with which the iodine interacts and produce a so-called photoelectric effect which is a large magnification in contrast caused by the photons stopped in the iodine-containing medium. The magnification of contrast exceeds the level that would be expected from relative changes in density. Because of this magnification, relatively low concentrations of the contrast agent can be utilized. (For iodinated agents see, for example, U.S. Patent Nos. : 2,786,055; 3,795,698; 2,820,814; 3,360,436; 3,574,718, 3,733,397; 4,735,795 and 5,047,228.)
  • the desiderata for an ideal GI contrast agent 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 passage 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 polyacrylamide forms a viscous solution at low concentration which makes it possible to maintain the barium sulfate in suspension and at the same time permit good adherence of the preparation to the walls of the organ which it is desired to x-ray.
  • U.S. 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.
  • Japanese Patent Application No. 55-127322 discloses x-ray contrast compositions containing barium sulfate and a polymeric substance selected from carboxy ⁇ ethyl cellulose salts, propylene glycol alginate, cellulose sulfate polyacrylate, pectin and tragacanth gum.
  • the polymeric substance is used to increase the viscosity of the compositions.
  • 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 cellulose derivative, which has incorporated therein an x-ray contrast agent, capable of coating the GI tract.
  • Such compositions must meet several requirements: both the x-ray contrast agent and the cellulose derivative 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 in a pharmaceutically acceptable vehicle comprising a cellulose derivative.
  • 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.
  • the x-ray contrast agent of the present invention is selected from.- (1) compounds of the formula:
  • 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 x and R 2 are independently H, C 1 -C 25 alkyl, cycloalkyl, acetyl or halo-lower-alkyl, wherein said C 1 -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;
  • 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; ( 3 ) compounds ' of the formula
  • Z is H, halo, C - 2o alkyl, cycloalkyl 5 " -lower alkoxy, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;
  • R lf 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;
  • R 1( R 2 , R 3 and R 4 are independently H, lower-alkyl, optionally substxtuted with halo; n is 2-5; ⁇ Tl is 2-5 ; p is 1-10; and
  • Q is ( i, lower-alkyl, lower-alkenyl, lower-alkynyl, lower-alkylene, aryl, or aryl-lower-alkyl; or a pharmaceutically acceptable salt thereof;
  • Z is H, halo, C -C ⁇ alkyl, cycloalkyl, lower alkoxy, alkoxycarbonyl, cyano, where the alkyl and cycloalkyl groups can be substituted with halogen or halo-lower-alkyl groups;
  • R lf 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; or a pharmaceutically acceptable salt thereof; (6) compounds of the formula
  • X is -C- or -S0 2 -;
  • Z is H, halo, C 3 -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, aryl or halo-lower- alkyl, each of which may be optionally substituted with lower-alkoxy, hydroxy, carboxy or lower-alkoxy-carbonyl, lower-alkenyl, lower-alkynyl, lower-alkylene or lower- alkoxy-carbonyloxy,- n is 1-5; y is 0-4; and w is 1-4; or a pharmaceutically acceptable salt thereof;
  • 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 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;
  • A is a repeating organic unit in the backbone chain of the polymer.
  • X is an organic moiety containing an iodinated aromatic group and a hydrophilic group, said moiety having an iodine content within the range of from about 40 to about 80 weight percent based on the molecular weight of X;
  • 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, t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1- meth lpentyl, 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 l-ethenyl, 1- (2-propenyl) , l-(2- butenyl) , 1- (1-methyl-2-propenyl) , 1- (4-methy1-2- 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-l, 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 of types (1) - (7) above can comprise one, two, three or four iodine atoms per molecule; preferred species contain at least two, and more preferably, at least three iodine atoms per molecule.
  • Solid x-ray contrast agents in particulate form useful in the practice of the present invention can be prepared by techniques known in the .'rt.
  • the solid agents are comminuted to the des.irec'. 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 lOO ⁇ as measured by art recognized techniques.
  • the cellulose derivatives utilized in the present invention include methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose; and macrocrystalline cellulose; having an average particle size of from 0.01 to lOO ⁇ , more preferably of from 0.05 to lO ⁇ , and most preferably of 0.1 to 1 ⁇ m.
  • the contrast agent and the cellulose derivative are formulated for administration using physiologically acceptable carriers or excipients in a manner within the skill of the art.
  • the contrast agent and the cellulose derivative with the addition of pharmaceutically acceptable aids (such as surfactants and emulsifiers) and excipients are suspended or partially dissolved in an aqueous medium resulting in a dispersion, solution, suspension or emulsion.
  • a method for diagnostic imaging of the GI tract for use in medical procedures in accordance with this, invention comprises orally or rectally administering to the mammalian patient in need of x-ray examination, an effective contrast producing amount of a composition of the present invention. After administration, at least a portion of the GI tract containing the administered composition is exposed to x-rays to produce an x-ray image pattern ⁇ corresponding to the presence of the contrast agent, then the x-ray image is visualized and interpreted using techniques known in the art.
  • Preferred contrast agents of type (2) have the formula:
  • R is a secondary alkyl group containing from 4 to 8 carbon atoms.
  • the most preferred contrast agent of type (2) is the sec-octyl ether of 2,4,6-triiodophenol having the formula:
  • the contrast agents of type (2) are slightly soluble in water, having a partition coefficient equal or greater than 10. This degree of solubility allows the formation of stable formulations ii: the form of emulsions and suspensions when the formulations contain the requisite excipients.
  • the term ' stable means that there is no separation of the ingredients contained in the compositions after oral or rectal administration thereof and during radiological examination of the GI tract.
  • the slight solubility of the contrast agents in aqueous media permits diffusion of the contrast agents into the intestinal mucosa and secretions thereby forming a coating on the intestines. On the other hand, due to their slight solubility, the absorption of the contrast agent into the intestinal walls is minimal which reduces the possibility of toxic side effects.
  • compositions of type (8) 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.
  • 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.
  • the x-ray contrast agent must be poorly soluble and dispersible in at least one liquid medium.
  • “poorly soluble” it is meant that the agent has a solubility in the liquid dispersion medium, e.g., water, of less than about 10 mg/ml, and preferably of less than about 1 mg/ml.
  • the x-ray contrast agent can be an iodinated compound.
  • the iodinated compound can be aromatic or nonaromatic. Aromatic compounds are preferred.
  • the iodinated compound can comprise, one, two, three or more iodine atoms per molecule. Preferred species contain at least two, and more preferably, at least three iodine atoms per molecule.
  • the iodinated compounds selected can contain substituents that do not impart solubility to the compound, such as, for example, alkylureido, alkoxyacylamido, hydroxyacetamido, butyrolactamido, succinimido, 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 orms.
  • 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 compositions of type (8) defined above 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 modxfxers include 0d"e gelatin, casein, lecithin (phosphatides) , gum acacxa, cholesterol, tragacanth, stearic acid, benzalkonium ' chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g..
  • macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available Tweens, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethycellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP) .
  • Most of these surface modifiers are known pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the
  • 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 ⁇ ?.
  • Tetronic 908 also known as Poloxamine 908
  • Aerosol OT which is a dioctyl este
  • Other useful surface modifiers include: decanoyl-N-methylglucamide; n-decyl ⁇ -D-glucopyranoside; n-decyl ⁇ -D-maltopyranoside; n-dodecyl ⁇ -D-glucopyranoside; n-dodecyl ⁇ -D-maltoside,- heptanoyl-N-methylglucamide n-heptyl ⁇ -D-glucopyranoside; n-heptyl ⁇ -D-thioglucoside; n-hexyl ⁇ -D-glucopyranoside; nonanoyl-N-methylglucamide; n-nonyl ⁇ -D-glucopyranoside; octanoyl-N-methylglucamide; n-octyl ⁇ -D-glucopyranoside,- octyl ⁇ -D-thioglucopyranoside; and the like.
  • 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 sum 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 useful in the compositions of type (8) defined above 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 100 ⁇ 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 particles' distribution in the film forming composition when the GI tract is coated therewith, yet insures against absorption through the intestinal walls.
  • the general structural formula of iodinated polymers of the invention is represented by structural formula I above.
  • the backbone chain of the iodinated polymer can represen :
  • condensation polymer such as a polyester, polya ide, polyurethane, polycarbonate, polyepoxide, polyether, a phenol-formaldehyde polymer and equivalent condensation polymers
  • an addition ,polymer produced by the polymerization of one or more addition polymerizable monomers containing a polymerizable unsaturated double bond e.g., vinyl monomers..-including such addition polymers as poly(vinyl alcohol)", poly(alkylmethacrylates) , poly(alkylacrylates) , and equivalent addition polymers,- or
  • a naturally occurring polymer for example, a polysaccharide containing repeating glucose units such as starch, glycogen, cellulose, cellulosic derivatives, and equivalent naturally occuring polymers.
  • repeating units A of formula I represent the residue of a repeating unit having an appended hydroxyl group, such as the repeating unit of poly (vinyl alcohol) , the repeating epoxy unit of a polyepoxide, the repeating unit of a hydroxylated acrylic polymer such as poly (hydroxyethylacylate) , or the repeating glucose unit of a naturally occurring polysaccharide.
  • the appended hydroxyl group can serve either as a crosslinking site or as a reaction site for precursor compounds of the organic moiety X in formula I.
  • precursor compounds can be chemically linked to the repeating units of the polymer backbone chain through a condensation reaction with the appended hydroxy group.
  • the organic moiety X of formula I above represents an iodine-containing organic fragment comprising an iodinated aromatic group and one or more hydrophilic groups.
  • the iodinated aromatic group have multiple iodine substituents bonded directly to the aromatic carbon ring atoms.
  • Especially preferred among these iodinated aromatic groups are aromatic groups containing three, preferably four, carbon ring atoms substituted by iodine.
  • a preferred iodinated aromatic group is an iodinated phenyl ring, although napthyl rings and nitrogen-containing heterocyclic rings containing 5 to 7 ring atoms can also be used.
  • An especially preferred iodinated aromatic group is a phenyl ring bearing iodine substituents on a 4 of the carbon ring atoms.
  • hydrophilic group( ⁇ ) of X are typically present as a substituent(s) bonded directly, or indirectly through a chemical linking group, to one or more of the carbon ring atoms o the iodinated aromatic group.
  • Preferred linking groups include short chain aliphatic groups, e.g., alkylene groups, amido groups and equivalent aliphatic groups, having 1 to 4 carbon atoms.
  • hydrophilic groups can be selected from a variety of such groups including carboxyl groups; sulfo groups,- amino groups; salts thereof such as carboxylate salts, sulfonate salts, ammonium salts; polyols such as glucose groups; and equivalent hydrophilic groups.
  • the precursors from which the organic moiety X of formula I is derived contains a reactive group which forms a chemical linking group with the repeating unit of the polymer backbone chain.
  • the reactive group contained on the precursor of X is a group reactive with the hydroxy group.
  • the reactive group can be a carboxyl group which condenses with the appended hydroxy group of the backbone chain to form an ester group linking an iodinated aromatic moiety of the polymer backbone.
  • a variety of other reactive groups which react with a hydroxy group to form such chemical linking groups as ethers, amides, thioesters, carbonates, carbamates, sulfides, and equivalents, can also be used.
  • a partial listing of precursors for the moiety X of formula I includes, for example, 3- (3-amino-2,4, 6 - triiodophenyl) -2-ethylpropionic acid; 3- (3-hydroxy- 2,4,6-triiodophenyl) -2-ethylpropionic acid; sodium 3- (3- butyrylamino--2,4,6-triiodophenyl) -2-ethylacrylate; 3,5- diiodo-4-pyridone-N-acetic acid; 3-acetamido-2,4, 6- criiodobenzoic acid; tetraiodophthalic anhydride; and the like,, , ⁇ Tetraiodophthalic anhydride can be particularly useful because of its high iodine content.
  • A is as defined in formula I above;
  • X is as defined in formula I above;
  • L represents one of the above-described linking groups, e.g. ester, ether, amide, thioester, carbonate, carbamate, sulfide and the like,- and each of R 1 to R 6 which may be the same or different, represents hydrogen, an iodine-containing substituent, or a hydrophilic group-containing substituent, with the proviso that the iodine content of X is from about 40 to 80 percent (based on the molecular weight of X) .
  • Preferred iodinated polymers are crosslinked. This can enhance the water-insolubility and resistance to swell properties of the polymer.
  • Crosslinking can be effected by incorporation of suitable crosslinking sites either on the polymer backbone chain or on the moiety X or both.
  • a hydroxyl group appended to the backbone chain of one polymer can react with the carboxyl gru ⁇ p attached to the sidechain X of another polymer, thereby crosslinking the two polymers through an ester linkage.
  • the polymeric contrast agents of the invention contain both hydrophilic and hydrophobic groups. Repeating backbone units A of formula I are substantially hydrophobic as are many portions of the moiety X. Of course X also contains one or more hydrophilic groups. This combination of hydrophobic and hydrophilic groups is believed important to provide the proper polymer surface and electrical characteristics which, in turn, provide proper polymer compatibility with body organs and tissues.
  • the iodinated polymers can be prepared by any of a variety of conventional polymerization and chemical reaction techniques.
  • a preferred reaction sequence is to chemically react precursor compounds for the side ⁇ chain group X with a preformed polymer containing appended groups serving as suitable reaction sites, e.g., hydroxyl groups.
  • the preformed polymer can be prepared by addition or condensation polymerization, depending on the polymer; or it can be obtained from naturally occurring sources in the case of naturally occurring polymers; e.g., polysaccharides.
  • the precursor compounds for the moiety X can be reacted with the reaction site on the polymer backbone by a variety of well-known reaction procedures, depending on the nature of the linking group L in formula II above which is formed in this reaction.
  • reaction of these precursor compounds is carried out under emulsifying conditions so that the resultant polymers are obtained in finely-divided particulate form.
  • Crosslinking can be carried out during or following attachment of the moiety X of the polymer backbone.
  • the polymer can be subjected to grinding or milling treatment to obtain polymer particles of the appropriate size range.
  • the polymers may already have an appropriate particle size so that additional milling or grinding may be unnecessary.
  • a useful particle size for these polymer particles is within the range of from about 0.01 to 1000 microns , preferably 0.1 to 100 microns.
  • the preferred barium salt (the contrast agent of type (10) mentioned above) is barium sulfate which is a white, radiopaque, crystalline powder that is essentially insoluble in water. It is commercially available in the particle size range of 0.001 to 0.1 micron diameter. However, good results are obtainable with other finely-divided, inorganic, essentially water- insoluble salts of barium including barium hexaboride, barium chromite, barium fluogallate, barium tri-ortho phosphate, barium metasilicate, barium titanate, barium zirconate and zirconium oxide.
  • the compositions of the present invention contain from about 5% w/w to about 95% w/w of the barium salt.
  • the compositions may be in the form of dispersions, colloids or suspensoids, however, we prefer to use colloids as the preferred embodiment.
  • the contrast agents used in the invention may be formulated for administration using physiologically - 29 - acceptable carriers or excipients in a manner within the skill of the art.
  • the compounds with the addition of pharmaceutically acceptable aids (such as surfactants and emulsifiers) and excipients may be suspended or partially dissolved in an aqueous medium resulting in a dispersion, solution or suspension.
  • pharmaceutically acceptable aids such as surfactants and emulsifiers
  • excipients may be suspended or partially dissolved in an aqueous medium resulting in a dispersion, solution or suspension.
  • tne oily contrast agents are preferably made into emulsions.
  • compositions of the present invention utilising contrast agents of types (1) to (8) defined above comprise the following pharmaceutically acceptable components based on % w/v:
  • Oily Vehicle 0.0 - 55 0.1 25 7 - 15
  • compositions of the present invention utilising contrast agents of type (9) defined above comprise the following pharmaceutically acceptable components based on % w/v: Ingredients Broad Range Preferred Range
  • Viscosity modifying 0.001 - 4 0.05 - 1 excipients (% w/v)
  • compositions of the present invention utilising barium salts comprise the following pharmaceutically acceptable components based on % w/v:
  • the concentration of the x-ray contrast agent should be in the range of from 0.01 to 40 mg I/ml, more preferably of from 0.25 to 25 mg I/ml and most preferably of from 4-12 mg I/ml.
  • the preferred cellulose derivative utilized in the present invention is AVICEL ® RC-591, which is a mixture of about 89 parts microcrystalline cellulose and about 11 parts of sodium carboxymethylcellulose.
  • the x-ray contrast agent present in concentrations lower than the above-stated minimum in formulations does not provide good quality x-ray or CT images, while concentrations above the maximum concentration render the GI tract too radiopaque and do not allow sufficient delineation of the GI tract.
  • an oil-in- water emulsion is preferred over a water-in-oil emulsion, suspension and dispersion.
  • Oily materials the density of which approximate the density of the aqueous phase impart stability to emulsions. For that reason low density oils, such as mineral oils, are desirable in preparing the emulsions.
  • low density oils such as mineral oils
  • the x-ray contrast agents are oily substances at room temperature, the presence of an additional oily vehicle is not always necessary. Above about 55% w/v of oil the emulsion is no longer an oil-in-water emulsion but shifts to a water-in-oil emulsion.
  • compositions without the presence of surfactants still provide excellent x-ray images, however, without surfactants the compositions are very difficult to emulsify and only suspensions/dispersions are produced which are less desirable for coating the GI tract and are also less stable on shelf-life. For reason of toxicity it is desirable to keep the concentration of certain surfactants as low as possible; above about 20% w/v the risk of toxicity rapidly increases.
  • viscosity modifying agents may not be necessary; at higher levels than about 15% w/v the viscosity is too high and gels will tend to form.
  • Polysorbate 80 (Tween 80) 5.00
  • Polysorbate 80 (Tween 80) 3.00
  • Polysorbate 80 (Tween 80) 5.00
  • Polysorbate 80 (Tween 80) 2.00
  • Polysorbate 80 (Tween 80) 5.00 '
  • Polysorbate 80 (Tween 80) 3.00
  • Polysorbate 80 (Tween 80) 5.00
  • Polysorbate 80 (Tween 80) 5.00
  • Polysorbate 80 (Tween 80) 5.00
  • surfactants or emulsifiers can reduce the interfacial tension between two immiscible phases, i.e., oil-in-aqueous medium. These agents can be used alone or in combination with other emulsifying agents and surfactants.
  • Dow Corning Medical Antifoam AF which is a composition of 30% w/v polydimethylsiloxane simethicone and silica aerogel, 14% w/v stearate emulsifiers and 0.075% w/v sorbic acid, the balance being water, may be used by itself.
  • Intralipid i which is an emulsion of fatty acids needs the presence
  • the surface active agents may be cationic, anionic, nonionic, zwitterionic or a mixture of two or more of these agents.
  • Suitable cationic surfactants include cetyl trimethyl ammonium bromide.
  • Suitable anionic agents include sodium lauryl sulphate, sodium heptadecyl sulphate, alkyl benzenesulphonic acids and salts thereof, sodium butylnapthalene sulfonate, and sulphosuccinates.
  • Zwitterionic surface active agents are substances that when dissolved in water they behave as diprotic acids and, as they ionize, they behave both as a weak base and a weak acid. Since the two charges on the molecule balance each other out the molecules act as neutral molecules. The pH at which the zwitterion concentration is maximum is known as the isoelectric point. Compounds, such as certain amino acids having an isoelectric point at the desired pH of the formulations of the present invention are useful in practicing the present invention.
  • 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.
  • the proportions of hydrophilic and hydrophobic groups are • about evenly balanced. They differ from anionic and cationic surfactants by the absence of charge on the molecule and, for that reason, are generally less of an irritant than the cationic or anionic surfactants.
  • Nonionic surfactants include carboxylic esters, carboxylic amides, ethoxylated alkylphenols and ethoxylated aliphatic alcohols.
  • carboxylic ester nonionic surface active agents are the partial, for example monoesters formed by the reaction of fatty and resin acids, for example of about 8 to about 18 carbon atoms, with polyhydric alcohols, for example glycerol, glycols such as mono-, di-, tetra- and hexaethylene glycol, sorbitan, and the like; and similar compounds formed by the direct addition of varying molar ratios of ethylene oxide to the hydroxy group of fatty acids.
  • carboxylic esters is the condensation products of fatty and resin partial acids, for example mono-, esters ethylene oxide, such as fatty or resin acid esters of polyoxyethylene sorbitan and sorbitol, for example polyoxyethylene sorbitan, monotall oil esters. These may contain, for example, from about 3 to about 80 oxyethylene units per molecule and fatty or resin acid groups of from about 8 to about 18 carbon atoms. Examples of naturally occurring fatty acid mixtures which may be used are those from coconut oil and tallow while examples of single fatty acids are dodecanoic acid and oleic acid.
  • Carboxylic amide nonionic surface active agents are the ammonia, monoethylamine and diethylamine amides of fatty acids having an acyl chain of from about 8 to about 18 carbon atoms.
  • the ethoxylated alkylphenol nonionic surface active agents include various polyethylene oxide condensates of alkylphenols, especially the condensation products of monoalkylphenols or dialkylphenols wherein the alkyl group contains about 6 to about 12 carbon atoms in either branched chain or particularly straight chain configuration, for example, octyl cresol, octyl phenol or nonyl phenol, with ethylene oxide, said ethylene oxide being present in amounts equal to from about 5 to about 25 moles of ethylene oxide per mole of alkylphenol.
  • Ethoxylated aliphatic alcohol nonionic surface active agents include the condensation products of aliphatic alcohols having from about 8 to 18 carbon atoms in either straight chain or branched chain configuration, for example oleyl or cetyl alcohol, with ethylene oxide, said ethylene oxide being present in equal amounts from about 30 to about 60 moles of ethylene oxide per mole of alcohol.
  • Preferred nonionic surface active agents include:
  • Sorbitan esters (sold under the trade name Span) having the formula:
  • R 3 R for sorbitan monoesters
  • Rj_ OH
  • R (C 1:L H 23 ) C00 for laurate
  • Polyoxyethylene alkyl ethers i.e. Brijs having the formula: CH 3 (CH 2 ) x (0-CH 2 -CH 2 ) y 0H
  • (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.
  • Polyethylene sorbitan fatty acid esters sold under the trade names of Polysorbates 20, 40, 60, 65, 80 & 85, having the formulae (1) and (2)
  • Polyethylene stearates such as: poly(oxy-1, 2-ethanediyl) , ⁇ -hydro- ⁇ - hydroxyoctadecanoate; polyethylene glycol monostearate,- and poly(oxy-1,2-ethanediyl) - ⁇ - (l-oxooctadecyl) - ⁇ - hydroxy-polyethylene glycol monostearate.
  • the dosages of the contrast agent used according to the method of the present invention will vary according to the precise nature of the contrast agent used. Preferably, however, the dosage should be kept as low as is consistent with achieving contrast enhanced imaging. By employing as small amount of contrast agent as possible, toxicity potential is minimized.
  • dosages will be in the range of from about 0.1 to about 16.0 g iodine/kg body weight, preferably in the range of from about 0.5 to about 6.0 g iodine/kg of body weight, and most preferably, in the range of from about 1.2 to about 2.0 g iodine/kg body weight for regular x-ray visualization of the GI tract.
  • the contrast agents of the present invention will be in the range of from about 1 to about 600 mg iodine/kg body weight, preferably in the range of from about 20 to about 200 mg iodine/kg body weight, and most preferably in the range of from about 40 to about 80 mg iodine/kg body weight.
  • the concentration of the contrast agent should be in the range of from about 0.001% w/v to about 75% w/v of the formulation, preferably from about 0.05% w/v to about 50% w/v and most preferably of from about 0.1 % w/v to about 20% w/v.

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Abstract

Ces compositions de contraste radiologique destinées à l'examen oral ou rétrograde du tractus gastro-intestinal comprennent un agent producteur de contraste radiologique dans un véhicule pharmacologiquement acceptable comportant un dérivé de la cellulose.
EP95909853A 1994-02-25 1995-02-24 Compositions de contraste radiologique contenant des derives de la cellulose Withdrawn EP0746339A1 (fr)

Applications Claiming Priority (21)

Application Number Priority Date Filing Date Title
US08/201,731 US5422114A (en) 1993-03-01 1994-02-25 Compositions of iodoaniline derivatives and cellulose derivatives for visualization of the gastrointestinal tract
US201731 1994-02-25
US206552 1994-03-04
US08/206,552 US5443814A (en) 1992-05-01 1994-03-04 X-ray contrast compositions containing iodophenoxyalkanes and cellulose derivatives
US217138 1994-03-22
US08/217,138 US5385721A (en) 1993-02-04 1994-03-22 Compositions of alkylbenzenes and cellulose derivatives for visualization of the gastrointestinal tract
US07/216,988 US5385720A (en) 1993-03-11 1994-03-23 Compositions of iodobenzoic acid derivatives and cellulose derivatives for visualization of the gastrointestinal tract
US216988 1994-03-23
US08/222,787 US5466435A (en) 1993-03-11 1994-04-04 Compositions of iodophenoxy alkylene ethers and cellulose derivatives for visualization of the gastrointestinal tract
US222787 1994-04-04
US08/227,423 US5368837A (en) 1994-04-14 1994-04-14 X-ray contrast compositions containing an organic crystalline X-ray contrast agent and a cellulose derivative
US227415 1994-04-14
US08/227,415 US5525327A (en) 1994-04-14 1994-04-14 Polymeric x-ray contrast compositions containing iodinated polymeric beads and microcrystaline cellulose
US08/227,422 US5543132A (en) 1994-04-14 1994-04-14 X-ray contrast compositions containing a barium salt and a cellulose derivative
US227422 1994-04-14
US227423 1994-04-14
US08/229,048 US5385722A (en) 1993-03-31 1994-04-18 Compositions of iodophenyl esters and iodophenyl sulfonates and cellulose derivatives for visualization of the gastrointestinal tract
US229048 1994-04-18
US08/246,888 US5607660A (en) 1993-02-02 1994-05-20 Compositions of iodophenoxy alkanes and iodophenyl ethers in combination with cellulose derivatives for visualization of the gastrointestinal tract
US246888 1994-05-20
PCT/GB1995/000386 WO1995022995A1 (fr) 1994-02-25 1995-02-24 Compositions de contraste radiologique contenant des derives de la cellulose

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FI (1) FI963299A0 (fr)
HU (1) HUT76336A (fr)
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US7684852B2 (en) 2002-04-06 2010-03-23 Bracco Diagnostics Inc. System, formulation, kit and method for tagging colonic residue in an individual
US20110158909A1 (en) * 2008-02-01 2011-06-30 Trustees Of Boston University Cationic Contrast Agents and Methods of Use Thereof
EP3984560A1 (fr) 2013-03-15 2022-04-20 The Regents of the University of California Matériel de contraste entérique pour tomographie assistée par ordinateur (ct) basée sur atomes z faibles
CN117018234A (zh) 2013-08-16 2023-11-10 加利福尼亚大学董事会 硅酮基肠道ct对比材料
US10918742B2 (en) * 2016-03-25 2021-02-16 Nanoprobes, Inc. Iodine-based particles
CN109540936A (zh) * 2019-01-11 2019-03-29 大连大学附属中山医院 一种用于高分辨率ct及x线动脉、静脉或管道的室温造影剂及其制备方法
CA3201017A1 (fr) * 2020-12-28 2022-07-07 Boston Scientific Scimed, Inc. Polysaccharides presentant des proprietes ameliorees de radiocontraste

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NO963540L (no) 1996-10-23
CN1146159A (zh) 1997-03-26
HU9602321D0 (en) 1996-10-28
FI963299A (fi) 1996-08-23
WO1995022995A1 (fr) 1995-08-31
FI963299A0 (fi) 1996-08-23
JPH09509424A (ja) 1997-09-22
HUT76336A (en) 1997-08-28
MX9603611A (es) 1997-04-30
CA2184089A1 (fr) 1995-08-31
AU1816395A (en) 1995-09-11

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