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
• • 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

Definitions

• This invention relates to an x-ray contrast composition for oral or retrograde administration to a mammal comprising a barium salt as the
• CT 20 tomography
• GI gastrointestinal
• the desiderata for an ideal GI contrast agent includes: good
• 3 5 The most widely used contrast agents for the visualization of the GI tract is barium sulfate administered as a suspension orally or rectally as an enema. (See for example, U.S. Patent Nos.
• the prior art considers as a serious problem the difficulty in achieving uniform adherence to, and coating of, the mucosa of the GI tract by the water insoluble barium sulfate to provide high quality x- ray photographs.
• the x-ray results are often inferior, misleading to the practitioner and the imaging process must be repeated.
• the barium sulfate, and other solid inorganic particulate radiopaque agents tend to settle out in the patient after evacuation but before and during x-ray imaging, which again deleteriously affects the quality of the x-ray pictures.
• 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.
• 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 polymeric film former, which has incorporated therein a barium salt, capable of coating the GI tract.
• the removal of the coating occurs as a result of the normal turnover of cells, that is, within about 24 to 48 hours.
• Such compositions must meet several requirements: the film former must be nontoxic; must not contain leachable or digestible components that would deleteriously affect the patient; and the composition must be capable of forming a film in the pH range of from about 5 to about 8.
• composition comprising: a barium salt; a polymeric material which is at least partially water soluble and contains polarizable or ionizable groups; and a divalent metal ion selected from the group consisting of Mg ++ , Ca ++ , Zn ++ and Ba ++ which potentiates the effect of the polymeric material as a film former on the mucosa of the GI tract.
• the barium salt, the polymeric film former and the divalent metal ion are incorporated in a solid or liquid media for administration to a mammal for x-ray visualization of the GI tract.
• the preferred x-ray contrast agent utilized in the present invention 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 solids, dispersions, colloids or suspensoids, however, we prefer to use colloids as the preferred embodiment.
• reagents and solvents can be obtained from chemical suppliers, such as Aldrich, Baker and Eastman Chemical Companies; alternatively, they may be prepared by techniques known in the prior art.
• the polymers that were found to be suitable for forming a thin coating on the GI tract can be classified as anionic, cationic and neutral polymers, a description of which follows.
• U. S. Patent No. 4,623,539 the disclosure of which is incorporated by reference, pertains to such polymers.
• the barium salt is incorporated in the polymeric material along with the divalent cation by any suitable techniques, such as by mixing, blending, precipitating or by enclosing the contrast agent into minute polymeric particles.
• the barium salt, polymeric material and divalent cation blend is then formulated for administration using physiologically acceptable carriers or excipients in a manner within the skill of the art.
• the barium salt, with the addition of pharmaceutically acceptable aids (such as surfactants and emulsifiers) and excipients may be suspended in an aqueous medium resulting in a dispersion, suspension or colloid.
• the barium salt, polymeric material and divalent cation may be formulated into a solid form, such as tablets or capsules.
• Solid compositions of the present invention shall contain, instead of surfactants/emulsifiers and water used in the liquid compositions, bulking agents and other pharmaceutically acceptable ingredients advantageously employed to render the compositions palatable.
• the bulking agent should have good compression characteristics. Suitable bulking agents are well known in the art and include a sweetener such as sugars, e.g. sucrose, and polyhydric alcohols, e.g. mannitol, sorbitol and xylitol, and mixtures thereof.
• a sweetener such as sugars, e.g. sucrose
• polyhydric alcohols e.g. mannitol, sorbitol and xylitol
• mixtures thereof e.g. mannitol, sorbitol and xylitol, and mixtures thereof.
• tablet lubricating agents such as stearic acid, magnesium stearate and talc.
• the amount of the tablet lubricating agents as well as any other ingredients required to easily prepare the solid compositions can readily be determined by the skilled formulator.
• the solid compositions may have incorporated therein optional pharmaceutically acceptable ingredients in order to impart thereto additional desirable properties, such as flavorants
• Liquid compositions of the present invention comprise the following pharmaceutically acceptable components based on % w/w:
• compositions of the present invention comprise the following pharmaceutically acceptable components based on % w/w:
• Excipients advantageously used in the formulations include viscosity mediating and stabilizing agents, such as macrocrystalline cellulose, ethylcellulose, hydroxypropyl methylcellulose and gum arabic.
• Physiologically acceptable substances may also be included, such as sodium citrate, sodium chloride, therapeutic substances, antacid substances and flavoring agents.
• antimicrobial/antiseptic agents such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxy-benzoate, benzoic acid, benzyl alcohol, phenol, sodium benzoate, EDTA or sorbic acid may also be desirable in some formulations.
• Surfactants or emulsifiers 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 and silica aerogel, 14% w/v stearate emulsifiers and 0.075% w/v sorbic acid, the balance being water, may be used by itself.
• Intralipid which is an emulsion of fatty acids needs the presence of a suspending agent for it to form an acceptable emulsion with contrast agents of the present invention.
• the amount of such surfactants may be in the range of from 0.01 to 20% w/w of the aqueous formulations, although the amount, in general, is kept as low as possible, preferably in the range of 0.05 to 5% w/w.
• 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 they act as neutral molecules. The pH at which the zwitterion concentration is maximum is known as the isoelectric point.
• 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 charge on the molecule and , for that reason, are generally less 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 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.
• 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, 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.
• 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 diethylamides 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:
• y is the number of ethylene oxide groups in the hydrophilic chain, typically 10-60;
• the film former polymeric materials used in accordance with the present invention include anionic polymers, cationic polymers and neutral polymers.
• anionic polymers carry negative charges in the ionized form and are capable of binding to cell surfaces mainly by electrostatic forces.
• Suitable anionic polymers include the following: 0 0 0
• R is the polymeric chain
• M ++ is a divalent cation.
• Specific anionic polymers useful in the practice of the present invention include:
• R 0-S — 0 — M ++ II 0 wherein R is 3,6-anhydro-D-galactose linked through C-4 to D-galactose; (kappa carrageenan) ⁇ -D-galactose units (1-3) linked; (lambda carrageenan) D-galactose
• M ++ is Mg+ + , Ca ++ , Zn ++ , Ba ++ or mixtures thereof.
• R is D-galacturonoglycan; and (Pectin) anhydro-D-mannuronic acid and anhydro-L-guluronic acid (Algin) residues; and
• M ++ is Mg ++ , Ca ++ , Zn ++ , Ba ++ or mixtures thereof.
• R is an anhydroglucose residue
• R' is CH 3 , C 2 H 5 or C 3 H 7 ;
• R" is CH3 or C2H5;
• M ++ is Mg ++ , Ca ++ , Zn ++ , Ba ++ or mixtures thereof.
• cellulose derivatives include: sodium ethylcellulose sulfate, sodium cellulose acetate sulfate and sodium carboxymethyl cellulose.
• R is an aliphatic or aromatic hydrocarbon, such as polystyrene, poly(sulfon) resin or carboxylated (poly) vinyl;
• M ++ is Mg ++ , Ca ++ , Zn ++ , Ba ++ or mixtures thereof.
• the cationic polymers carry positive charges in the ionized form.
• Suitable polymers for practicing the present invention include: dermatan sulfate, keratosulfate, hyaluronic acid, heparin and chitin.
• Neutral polymers having polarizable electrons such as oxygen, nitrogen, sulfur, fluoride, chloride, bromide and iodide are also suitable for practicing the present invention.
• a cation such as Mg ++ , Ca ++ , Zn ++ or Ba ++
• the polymers are partially polarized thereby providing intermolecular interactions between the polymer and the intestinal wall.
• these polymers include: (a) Polysaccharides, such as starch, glycogen, glucan, fructans, mannans, galactomannas, glucomannas, galactans, xylans, glycuranans, dextran and starch amylose;
• Cellulose derivatives such as methylcellulose, hydroxyethylcellulose, ethylhydroxyethyl cellulose , hydroxypropyl methylcellulose and hydroxypropyl cellulose;
• Synthetic polymers such as polyvinylpyrrolidone, polyvinyl alcohol and ethylene oxide polymers.
• compositions of the invention may be administered orally to the patient for radiological examination of the GI tract.
• compositions of the invention may also be administered rectally in the form of enemas to a patient for radiologic examination of the colon.
• the dosages of the contrast agent used according to the method of the present invention will vary according to the precise nature of the ingredients used. Preferably, however, the dosage should be kept as low as is consistent with achieving contrast enhanced imaging. By employing as small amount of the composition as possible, toxicity potential is minimized.
• dosages will be in the range of from about 0.1 to about 20.0 g Ba/kg body weight, preferably in the range of from about 0.4 to about 8.0 g Ba/kg of body weight, and most preferably, in the range of from about 1.0 to about 3.0 g Ba/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 800 mg Ba kg body weight, preferably in the range of from about 15 to about 250 mg Ba/kg body weight, and most preferably in the range of from about 35 to about 90 mg Ba/kg body weight.
• the concentration of the contrast agent should be in the range of from about 5% w/w to about 95% w/w of the formulation, preferably from about 10% w/w to about 60% w/w and most preferably of from about 15% w/w to about 40% w/w.
• the concentration of the film forming polymeric material depends on the particular polymer used, however, it should be in the range of 0.001 to about 25% w/w or higher in combination with a divalent substance, such as calcium lactate, having a concentration range of 0.001 to 20% w/w. Dosage level of the polymeric material may be in the range of from about 2 to about 20 g/kg body weight or higher.
• compositions of the present invention possess very good adherence to the walls of the gastrointestinal tract by forming an essentially uniform coating thereon.

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• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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• 1993
  • 1993-08-23 EP EP94908872A patent/EP0658121A1/de not_active Withdrawn
  • 1993-08-23 JP JP6507251A patent/JPH08500604A/ja active Pending
  • 1993-08-23 WO PCT/US1993/007900 patent/WO1994005336A1/en not_active Application Discontinuation
  • 1993-08-23 AU AU50867/93A patent/AU5086793A/en not_active Abandoned
  • 1993-08-31 MX MX9305314A patent/MX9305314A/es unknown
  • 1993-08-31 IL IL106848A patent/IL106848A0/xx unknown

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