WO1997006132A1 - Esters triiodoalkylphenyliques comme nouveaux agents de contraste pour les rayons x - Google Patents

Esters triiodoalkylphenyliques comme nouveaux agents de contraste pour les rayons x Download PDF

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Publication number
WO1997006132A1
WO1997006132A1 PCT/US1996/012220 US9612220W WO9706132A1 WO 1997006132 A1 WO1997006132 A1 WO 1997006132A1 US 9612220 W US9612220 W US 9612220W WO 9706132 A1 WO9706132 A1 WO 9706132A1
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WO
WIPO (PCT)
Prior art keywords
contrast
ray
compound
carbon atoms
independently
Prior art date
Application number
PCT/US1996/012220
Other languages
English (en)
Inventor
Edward R. Bacon
Shaughnessy Robinson
Kurt A. Josef
Original Assignee
Nanosystems L.L.C.
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
Application filed by Nanosystems L.L.C. filed Critical Nanosystems L.L.C.
Priority to AU65974/96A priority Critical patent/AU6597496A/en
Publication of WO1997006132A1 publication Critical patent/WO1997006132A1/fr

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Classifications

    • 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
    • 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
    • A61K49/0476—Particles, beads, capsules, spheres
    • A61K49/0485—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton

Definitions

  • This invention relates to methods of x-ray diagnostic imaging the blood pool, liver, spleen and/or lymph system of a mammal employing particulate compounds as a contrast agent, and to certain novel compounds useful as contrast agents in x-ray contrast compositions and methods of diagnostic imaging.
  • X-ray imaging is a well known and extremely valuable tool for the early detection and diagnosis of various disease states in the human body.
  • the use of contrast agents for image enhancement in medical x-ray imaging procedures is widespread.
  • An excellent background on iodinated and other contrast agents for medical imaging is provided by D.P. Swanson, et al, Pharmaceuticals in Medical Imaging. 1990, MacMillan Publishing Company.
  • Great Britain Patent No. 889339 describes an x-ray contrast composition comprising an iodinated benzoic acid derivative and a non-toxic carrier. The compounds collect in the gall bladder.
  • R* is H or lower alkyl; R ⁇ is H or lower alkanoyl; R ⁇ is H or lower alkanoylamino and R ⁇ is lower alkyl.
  • the agents are useful as x-ray contrast agents for visualizing the gall bladder (cholecystography) when administered orally, in the free acid form or in the form of a non-toxic salt, or intravenously, in the form of a water soluble, non-toxic salt.
  • Example 15 therein describes ethyl 2-(3,5-diacetamido-2,4,6-triiodobenzoyloxy) hexanoate, i.e., ( - 0 2 C 2 H 5
  • Bacon et al commonly assigned U.S. Patent 5,322,679 issued 21 June 1994 describes nanop articulate iodinated aroyloxy esters which are useful as contrast agents in x-ray imaging compositions and methods.
  • all of the compounds described by Bacon et al feature an ester group linked through a C2 or higher alkylene group to another ester group on an iodinated aromatic ring.
  • EP-A-498,482 describes nanoparticulate x-ray contrast compositions which have proven to be extremely useful in medical imaging.
  • the compositions comprise particles of an organic x-ray contrast agent and a surface modifier adsorbed on the surface thereof and have an effective average particle size of less than 400 nm.
  • the agents can be delivered to a specific tissue or fluid site, e.g., the blood pool, liver, spleen, kidney or lymph nodes.
  • Example 8 therein describes a formulation comprising ethyl 2-(3,5-bis(acetylamino)-2,4,6- triiodobenzoyloxy) butyrate, i.e.,
  • nanoparticulate formulations of ethyl 2-(3,5-bis(acetylamino)-2,4,6-triiodobenzoyloxy) butyrate do not exhibit good stability during autoclaving, i.e., conventional heat sterilization.
  • a method of medical x-ray diagnostic imaging which comprises administering to tlie blood pool, liver, spleen or lymph system of a mammal a contrast-effective amount of a particulate contrast agent (triiodoalkyl phenyl esters) having structure 1 :
  • R is independently alkyl having from 1 to 12 carbon atoms
  • X is CO 2 , CH O, O or NH
  • Y and Z are independently H, CO2 2 or
  • R 2 and R 3 are independently H, alkyl having from 1 to 12 carbon atoms or aryl having from 6 to 11 carbon atoms, and n is 0 to 12.
  • novel compounds having structure 1 above wherein R is C5H13 and X is
  • This invention further provides an x-ray contrast composition comprising such novel compounds and a method for medical x-ray diagnostic imaging which comprises administering to a mammal an effective contrast-producing amount of the above-described x-ray contrast composition.
  • x-ray diagnostic imaging the blood pool, liver, spleen and lymphatic system employing an x-ray contrast composition featuring a compound which exhibits a consistent crystal morphology during purification and thus is particularly amenable to reproducible scale up and has optimum hydrolysis, solubility and a high melting point.
  • x-ray contrast compositions are provided for blood pool, liver, spleen and lymphatic system imaging which exhibit improved visualization.
  • the contrast agent hydrolyzes quickly and results in fast systemic clearance from the body.
  • Still another advantageous feature of this invention is that novel compounds are provided which find particular utility as particulate x-ray contrast agents.
  • R is independently alkyl having from 1 to 12 carbon atoms.
  • the alkyl groups can be either straight chain or branched.
  • alkyl groups examples are methyl, ethyl, isopropyl, butyl, octyl and the like. In the preferred embodiment, both R groups are C5H13.
  • X is CO 2 , CH 2 O, O or NH.
  • Y and Z are independentiy H, CO 2 , R 3 or NR 2 COR 3 .
  • R 2 and R 3 are independently H, alkyl having from 1 to 12 carbon atoms or aryl.
  • alkyl groups can be branched or straight chained.
  • Examples of useful alkyl groups are methyl, ethyl, propyl, isobutyl, octyl and the like.
  • the aryl groups preferably can be from 6 to 11 carbon atoms such as phenyl and the like, n is 0 to 12.
  • the preferred triiodoalkylphenyl ester in accordance with this invention has the formula:
  • the compounds of this invention can be prepared by contacting a compound having the structure
  • reaction can take place at an ambient pressure, although higher and lower pressures are contemplated.
  • the reaction can take place in any suitable solvent.
  • suitable solvents include, N,N-dimethylformamide (DMF) and dimethylsulfoxide (DMSO).
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • the iodinated compounds can contain substiments which do not deleteriously affect the contrast-enhancing capability of the compound.
  • alkyl and aryl groups in structure I above can be unsubstituted or substituted with various substituents which do not adversely affect the stability or efficacy of the compounds as x-ray contrast agents such as alkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, acyloxy, halogen, such as chlorine, bromine and iodine, acylamino, carboalkoxy, carbamyl and the like.
  • substituents such as alkyl, cycloalkyl, aryl, aralkyl, alkoxy, hydroxy, acyloxy, halogen, such as chlorine, bromine and iodine, acylamino, carboalkoxy, carbamyl and the like.
  • the compound of this invention When used as an x-ray contrast agent, the compound of this invention preferably comprises at least about 30%, more preferably at least 35%, and most preferably at least 40% iodine by weight.
  • the compounds of this invention can be formulated into particulate x-ray contrast compositions, preferably nanoparticulate x-ray contrast compositions, as described in commonly-owned EP-a 498,482.
  • Preferred compounds exhibit a melting point of greater than 150°C.
  • Such nanoparticulate compositions can be prepared by dispersing the compounds of the invention in a liquid dispersion medium, and wet grinding the compound in the presence of rigid grinding media and a surface modifier to form the nanoparticles.
  • the surface modifier can be contacted with the compound after attrition.
  • Preferred surface modifiers include nonionic surfactants.
  • the surface modifier is a high molecular weight nonionic surfactant.
  • Preferred surfactants include poloxamers such as Pluronica F68 and F108, which are block copolymers of ethylene oxide and propylene oxide, poloxamines, such as Tetronica 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, and dialkyi esters of sodium sulfosuccinic acid, such as dioctylsulfosuccinate sodium (DOSS).
  • the concentrations of the surface modifier can vary from about 0.1-75%, preferably 1- 60%, and more preferably 5-25% by weight based on the total combined weight of the contrast agent and surface modifier.
  • the x-ray contrast composition in the form of surface modified nanoparticles can be associated with a cloud point modifier to further enhance stability during steam heat autoclaving, i.e., the cloud point modifier can reduce particle aggregation during heat sterilization.
  • Preferred cloud point modifiers include nonionic cloud point modifiers, such as polyethylene glycols such as PEG 400, propylene glycol, ethanol, hydroxypropylcyclodextrin and glycerol; ionic cloud point modifiers, such as those described in U.S. Patent No.
  • 5,298,262 including dialkylesters of sodium sulfosuccinic acid such as the dioctylester of sodium sulfosuccinic acid (DOSS); and charged phospholipids, such as diacylphosphatidyl glycerol and dimyristoylphosphatidyl glycerol.
  • the cloud point modifier can be present in an amount of 0.005-50%, preferably 0.01-30% and more preferably 0.05-20% by weight based on the total weight of the x-ray contrast composition.
  • the x-ray contrast compositions of this invention comprise the above-described compounds, preferably in the form of particles, and a physiologically acceptable carrier therefor.
  • the particles can be dispersed in an aqueous liquid which serves as the carrier for the x-ray contrast agent.
  • suitable carriers include liquid carriers such as mixed aqueous and nonaqueous solvents, such as alcohol; gels; gases, such as air; and powders.
  • the x-ray contrast composition can comprise from about 1-99.9, preferably 2-45 and more preferably 10-30% by weight of the above-described particles, the remainder of the composition being the carrier, additives and the like. Compositions up to about 100% by weight of the particles are contemplated when the composition is in a lyophilized form.
  • the dose of the contrast agent to be administered can be selected according to techmques known to those skilled in the art such that a sufficient contrast enhancing effect is obtained.
  • Typical doses can range from 20 to 450 mg of iodine per kilogram of body weight of the subject for many imaging applications. For some applications, e.g., lymphography, lower doses, e.g., 0.5-20 mg I/kg, can be effective.
  • the dose can range from 50 to 450 mg of iodine per kilogram of body weight and preferably from 100 to 250 mg of iodine per kilogram of body weight.
  • the dose can range from 1 to 20 mg/kg.
  • the x-ray contrast composition can contain one or more conventional additives used to control and/or enhance the properties of the x-ray contrast agent.
  • thickening agents such as dextran or human serum albumin, buffers, viscosity regulating agents, suspending agents, peptizing agents, anti-clotting agents, mixing agents, and other drugs and the like can be added.
  • a partial listing of certain specific additives includes gums, sugars such as dextran, human serum albumin, gelatin, sodium alginate, agar, dextrin, pectin and sodium carboxymethyl cellulose.
  • Such additives, surface active agents, preservatives and the like can be inco ⁇ orated into the compositions of the invention.
  • a method for diagnostic imaging for use in medical procedures in accordance with this invention comprises administering to the body of a test subject in need of an x-ray an effective contrast producing amount of the above- described x-ray contrast composition.
  • the test subject can include mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like.
  • the body containing the administered contrast agent is exposed to x-rays to produce an x- ray image pattern corresponding to the presence of the contrast agent.
  • the image pattern can then be visualized.
  • any x-ray visualization technique preferably, a high contrast technique such as computed tomography, can be applied in a convention manner.
  • the image pattern ca be observed directly on an x-ray sensitive phosphor screen-silver halide photographic film combination.
  • compositions of this invention can be administered by a variety of routes depending on the type of procedure and the anatomical orientation of this tissue being examined. Suitable administration routes include intravascular (arterial or venous) administration by catheter, intravenous injection, rectal administration, subcutaneous administration, intrathecal administration, intracisternal administration, oral administration, administration via inhalation, administration directly into a body cavity, e.g., arthrography, and the like.
  • intravascular arterial or venous
  • rectal administration subcutaneous administration
  • intrathecal administration intracisternal administration
  • oral administration administration via inhalation
  • administration directly into a body cavity e.g., arthrography, and the like.
  • the x-ray contract compositions of this invention are also expected to be useful as contrast agents for any organ or body cavity.
  • the compositions of this invention are expected to be useful as angiographic contrast media, urographic contrast media, myelographic contrast media, gastrointestinal contrast media, cholecystographic and cholangiographic contrast media, arthrographic contrast media, hysterosalpingographic contrast media, oral contrast media and bronchographic contrast media.
  • Compound 1 is added to each of 3 x 1.5 oz brown glass bottles containing approximately 12 ml of zirconium silicate (1.1 mm dia.) beads in an amount sufficient to be 15% (w/v) of the final suspension.
  • Bottle A contains 3%
  • Bottle B contains 3% (w/v) Pluronic F108.
  • Bottle C contains 3% (w/v) Tetronic T-908. The resulting suspensions are milled on a roller mill at approximately 150 ⁇ m for a total of 9 days.
  • Compound 1 can be milled with 4% Pluronic F- 108 in the present of zirconium silicate (1.1 mm dia) beads for 3 days under aseptic conditions. No additional salts or surfactants are added.
  • This sample is examined for imaging efficacy.
  • the sample is injected into white New Zealand rabbits at a dose of 3 ml/kg as a slow bolus injection.
  • CT computed tomography
  • the opacification of the liver, spleen, and blood pool as measured in the aorta and within the left ventricle is determined by computed tomography (CT) using a Toshiba 900S Imager CT scanner and associated software. Results from this analysis are expected to show that this formulation of Compound 1 has excellent blood pool opacification in excess of 30 min. followed by very good liver and very good spleen opacification for 120 min. Imaging at 24 hours post injection should show complete clearance from the blood with partial clearance from the liver and spleen.
  • Compound 1 is milled with zirconium silicate (1.1 mm dia) beads in the presence of Pluronic F-108 for 3 days. The final particle size is determined.
  • sterile PEG 400 is added to the suspension such that at completion, the formulation contains 15% (w/v) WIN 70146, 3% (w/v) Pluronic F-108, and
  • This formulation is evaluated for both blood pool and lymphographic imaging in New Zealand White Rabbits using the above-described protocol (3 ml/kg) for blood pool imaging and 2 injections (0.25 ml) per paw for lymphography.
  • the results should indicate that Compound 1 is capable of blood pool opacification to at least 30 min. and is an excellent lymphography agent affording the highest level of opacification noted to date in this indication.

Abstract

Cette invention concerne des procédés d'examen diagnostique par rayons X du système sanguin, du foie, de la rate et/ou du système lymphatique chez un mammifère, consistant à administrer une quantité suffisante d'un agent de contraste ayant la structure (1). Dans cette formule, R est, d'une manière indépendante, un alkyle à 1-12 atomes de carbone, R1 est (2), X est CO¿2?, CH2O, O ou NH, y et Z sont, d'une manière indépendante, H, CO2R?2 ou NR2COR3, R2 et R3¿ sont, d'une manière indépendante, H, alkyle à 1-12 atomes de carbone ou aryle à 6-11 atomes de carbone et n est égal à 0-12. Cette invention concerne, en outre, de nouveaux agents de contraste ayant la structure (1), où R est C¿6?H13 et R?1¿ est (3). L'invention concerne également des compositions de contraste pour rayons X contenant de tels agents et des procédés d'examen diagnostique utilisant ces agents.
PCT/US1996/012220 1995-08-10 1996-07-25 Esters triiodoalkylphenyliques comme nouveaux agents de contraste pour les rayons x WO1997006132A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65974/96A AU6597496A (en) 1995-08-10 1996-07-25 Triiodoalkylphenyl esters as novel x-ray contrast agents

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US210395P 1995-08-10 1995-08-10
US60/002,103 1995-08-10
US67770896A 1996-07-10 1996-07-10
US08/677,708 1996-07-10

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WO1997006132A1 true WO1997006132A1 (fr) 1997-02-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021577A2 (fr) * 1998-10-09 2000-04-20 Nycomed Imaging As Compositions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3409662A (en) * 1963-06-06 1968-11-05 Sterling Drug Inc 3, 3'-diamino-5, 5'-dicarboxy-hexaiodocarbanilides and derivatives
US3732293A (en) * 1968-03-15 1973-05-08 Sterling Drug Inc Iodinated bis(aminobenzoic acids) and esters thereof
US5360604A (en) * 1994-04-14 1994-11-01 Sterling Winthrop Inc. X-ray contrast compositions containing an organic crystalline X-ray contrast agent in combination with pharmaceutically acceptable clays

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3409662A (en) * 1963-06-06 1968-11-05 Sterling Drug Inc 3, 3'-diamino-5, 5'-dicarboxy-hexaiodocarbanilides and derivatives
US3732293A (en) * 1968-03-15 1973-05-08 Sterling Drug Inc Iodinated bis(aminobenzoic acids) and esters thereof
US5360604A (en) * 1994-04-14 1994-11-01 Sterling Winthrop Inc. X-ray contrast compositions containing an organic crystalline X-ray contrast agent in combination with pharmaceutically acceptable clays

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021577A2 (fr) * 1998-10-09 2000-04-20 Nycomed Imaging As Compositions
WO2000021577A3 (fr) * 1998-10-09 2000-07-27 Nycomed Imaging As Compositions

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Publication number Publication date
AU6597496A (en) 1997-03-05

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