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
  • 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

Definitions

• the invention relates to aqueous X-raycontrast media solutions which are to be introduced intravasally and are miscible with body fluids.
• the inner lining of human and animal blood vessels is an i portant structure; when damaged, formation of thro bae can occur. Minor lesions can lead to per eability disorders and thus to an increased escape of fluids into the tissue.
• aqueous solutions of iodine-contain- ing compounds are injected in to produce an increased absorption of X-rays in the vessels.
• X-ray contrast media are hypertonic solutions which as a rule cause clearly detectable damage to the endothelium.
• the hypertonic properties of the contrast media Solutions for example by using non-ionic iodine compounds, such as etrizamide, or by using iodine compounds with a relatively high molecular weight, such as.-ioxaglic acid, it has been possible in normal cases to keep the damage to healthy endothelium of blood vessels with normal circulation within acceptable limits.
• non-ionic iodine compounds such as etrizamide
• iodine compounds with a relatively high molecular weight such as.-ioxaglic acid
• the damaging effect of X-ray contrast media on the endothelium is known and can be determined se iquantitatively by the method of Gottlob and Zinner, Wien.Klin.Wschr. 77, 149 [1965] (Silver coloration of the aortas of surviving rats after the action of contrast media, - Examination of the aorta endothelia on mounted preparations, fro the surfaces, - "en face preparations" method). The percentage of damaged area of the aortas investigated can be indicated by this method.
• endothelium damage caused by X-ray contrast media can be detected by the fact that after contact with the contrast medium, the endothelium can be stained to a greater extent with dyestuffs, such as Evan's Blue or Trypan Blue. This is to be evaluated as an indication of a per eability disorder (Gottlob, R. Amipaque-Workshop, 25th May 1978, Berlin, Excerpta Medica, Amsterdam-Oxford, 1978, p. 124-132).
• dyestuffs such as Evan's Blue or Trypan Blue
• the invention is thus based on the object of improving X-ray contrast media which are to be introduced intravasally to the extent that the danger of damage to the endothelium is significantly reduced.
• Swiss Patent Specification 373,866 showing the addition of non-ionic surface-active agents to X-ray contrast media in the form of aqueous suspensions, whereupon greater adhesion of these suspensions to the sur ⁇ face of the bronchial system or of the uterus is said to be achieved.
• aqueous Solutions of iodated derivatives of pyridone are known, which ' contain a viscosity increasing agent and optionally a wetting agent, which shall enhance the adhesion of the Solutions to the surface of the Uterus or of the bronchial system, ie for a nonintravasal use.
• M. Guerbet the literature reference M. Guerbet,
• the invention thus relates to aqueous X-ray contrast media solutions which are miscible with body fluids and are characterized by the addition of pharmacologically acceptable surface-active agents.
• Body fluids are to be understood as blood.
• X-ray contrast media Solutions according to this invention are to be understood as those which are to be introduced intravasally, that is for arteriographic and phlebographic application.
• the invention thus preferably relates to aqueous X-ray contrast media Solutions which are miscible with body fluids and are characterized by the addition of pharmacologically acceptable surface-active agents in an amount such that the interfacial tension with respect to the walls of the vessels in the body is approximately reduced to the interfacial tenion which prevails between the blood and the vessel walls.
• Some X-ray contrast media which do not dissociate into ions and thus have a Tower (but in comparison with blood still increased) osmotic pressure such as, for example, metrizamide (2- (3-acetamido-5-N-methyl- acetamide-2,4,6-triiodobenzamido) -2-deoxy-D-glucose), cause damage to the vessel wall, which can be detected by an increased . ability to be stained and is possibly a result of a certain lipophilicity.
• metrizamide 3- (3-acetamido-5-N-methyl- acetamide-2,4,6-triiodobenzamido) -2-deoxy-D-glucose
• the establishment, according to the invention, of the interfacial tension can be assisted by a suitable mixture of X-ray contrast media, so that the amount of surface-active agents required for reducing the interfacial tension to the desired value can be minimized.
• the interfacial tension of conventional X-ray contrast media solutions with respect to the vessel wall is as a rule between 18 and 20.10 -5 N / cm.
• a good endothelium toleration is achieved, in particular, by lowering this interfacial tension to values of below 16.10 -5 N / cm by adding surface-active agents.
• the corresponding inter ⁇ facial tension values for blood are in the order of size from 8 to 15.10 N / cm, and are usually about 12.10 -5 N / cm.
• vveesssseell ⁇ wall is reduced to at least 16.10 N / cm by the surface-active agents.
• HLB number An essential criterion of the usefulness of a surface-active agent is given by the so-called HLB number.
• This nu ber represents the "hydrophilic / lipophilic balance" and a high numerical value corresponds to a pro- nounced hydrophilic character while a low numerical value represents pro ⁇ nounced lipophilic character.
• the lipophilic character is preferably reduced to an HLB number of greater than 15, preferably between 25 and 35, in particular about 29, by the addition of suitable surface-active agents, and, above all, block copolycondensates of propylene glycol and poly - ethylene glycol have proved suitable for this.
• Suitable surface-active agents are, above all, the lecithins with poly- unsaturated fatty acids, which are well tolerated biologically. With such surface-active agents, the concentration can be adjusted to a relatively high value, in particular to a concentration of about 0.1 to 1 g / 100 ml, preferably of about 0.5 g / 100 ml.
• Another suitable surface-active agent is polyoxyethylene sorbitan mono-oleates. The amount required in each case depends on the chosen surface- active agent, but is also influenced by the chosen X-ray contrast medium.
• Customary X-ray contrast media for angiography are substituted triiodobenzoic acids, and examples which should be mentioned specifically are "the methylglucamine salt of diacetyl-3,5-diamino-2,4,6-triiodobenzoic acid, the methylglucamine salt, onoethanola ine salt and sodium salt of 5-acetamido-N- (2-hydroxy-ethyl) -2,4,6-triiodoisophthalamic acid and ioxaglic acid.
• Non-ionic surface-active agents which are preferably used according to the inven ⁇ tion are the non-ionic surface-active agents, such as, for example, naturally occuring lecithins, polyethoxy-sorbitane fatty acid esters (commer cially available, for example, under the tradename Tween®), polyethoxy-castor oil acid glycerol esters (commercially available, for example, under the tradename Cremophor EL, RH 40 and RH 60®) and polyoxyethylene / polyoxypropylene ' polymers (commercially available, for example, under the tradename Pluronics®).
• non-ionic surface-active agents such as, for example, naturally occuring lecithins, polyethoxy-sorbitane fatty acid esters (commer cially available, for example, under the tradename Tween®), polyethoxy-castor oil acid glycerol esters (commercially available, for example, under the tradename Cremophor EL, RH
• Ampoules (30 ml) containing 19.8 g meglumine-ioxitalamate, batch size 300 ml are prepared as follows: 1.5 kg of EPL US are dissolved in 100 1 of doubly distilled water of 80 ° C, while stirring with a highspeed stirrer. Thereafter 151.98 kg of ioxitalamic acid are suspended and 46.02 kg of methylglucamine are added slowly. The clear solution is cooled to about 40 ° C. After addition of 0.03 kg sodium bisulfite the pH-value is brought to 7.0 t 0.5 by adding ioxitalamic acid or methylglucamine. The batch is filtrated under sterile conditions and is made up to 300 1 with doubly distilled water. The solution is filled into 30 ml ampoules and these are sterilized in an autoclave at 120 ° C for 20 minutes.
• the invention also relates to the use of pharmacologically acceptable surface-active agents as admixture to aqueous X-ray contrast media solutions which are to be introduced intravasally.

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• Health & Medical Sciences (AREA)
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• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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Citations (8)

• 1979
  • 1979-12-17 WO PCT/EP1979/000100 patent/WO1980001244A1/de not_active Ceased
  • 1979-12-17 JP JP50012479A patent/JPS55501057A/ja active Pending

Patent Citations (8)

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