WO1980001244A1 - X-ray contrast media solutions - Google Patents
X-ray contrast media solutions Download PDFInfo
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- WO1980001244A1 WO1980001244A1 PCT/EP1979/000100 EP7900100W WO8001244A1 WO 1980001244 A1 WO1980001244 A1 WO 1980001244A1 EP 7900100 W EP7900100 W EP 7900100W WO 8001244 A1 WO8001244 A1 WO 8001244A1
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- Prior art keywords
- contrast media
- ray contrast
- media solutions
- solutions according
- active agent
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- 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.
Abstract
It has been found, that the vessel damaging effects of aqueous X-ray contrast media solutions to be introduced intravasally can be reduced by adding surface-active agents.
Description
X-Ray contrast media SolutionsX-Ray contrast media solutions
The invention relates to aqueous X-raycontrast media Solutions which are to be introduced intravasally and are miscible with body fluids.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 (the endotheliu ) 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.The inner lining of human and animal blood vessels (the endothelium) 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.
When taking X-rays of blood vessels, aqueous Solutions of iodine-contain- ing compounds are injected in to produce an increased absorption of X-rays in the vessels. These so-called X-ray contrast media are hypertonic Solu¬ tions which as a rule cause clearly detectable damage to the endothelium.When taking X-rays of blood vessels, aqueous solutions of iodine-contain- ing compounds are injected in to produce an increased absorption of X-rays in the vessels. These so-called X-ray contrast media are hypertonic solutions which as a rule cause clearly detectable damage to the endothelium.
By reduciπg 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. Nevertheless, accidents caused by contrast media still cannot always be excluded with certainty,- Endothelium damage is to be particularly expected when introducing X-ray contrast media Solutions into vessels with an abnormally reduced or i paired circula¬ tion, such as, for example, in cases of varicose veins or closures of the veins in the leg, since the contrast media Solutions are in contact with the endothelium for a significantly longer period of ti e because the flow through the vessels is reduced. The Situation is aggravated by the fact that the endothelium of abnormally changed veins is as a rule already damaged and is thus less able to withstand stress, that is to say reacts more sensitively to the action of the X-ray contrast me- dium.By reduciπg 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. Nevertheless, accidents caused by contrast media still cannot always be excluded with certainty, - Endothelium damage is to be particularly expected when introducing X-ray contrast media Solutions into vessels with an abnormally reduced or i paired circulation, such as, for example, in cases of varicose veins or closures of the veins in the leg, since the contrast media solutions are in contact with the endothelium for a significantly longer period of ti e because the flow through the vessels is reduced. The situation is aggravated by the fact that the endothelium of abnormally changed veins is as a rule already damaged and is thus less able to withstand stress, that is to say reacts more sensitively to the action of the X-ray contrast medium.
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.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.
Another form of 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).Another form of 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).
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.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.
It has now been found that the damaging effects of X-ray contrast media introduced intravasally on the endothelium and permeability can be greatly reduced by adding surface-active agents which are tolerated by the body.It has now been found that the damaging effects of X-ray contrast media introduced intravasally on the endothelium and permeability can be greatly reduced by adding surface-active agents which are tolerated by the body.
The addition of surface-active agents to X-ray contrast media in e ul- sion form or Suspension form for taking X-rays of various body cavities is known. Thus, Austrian Patent Specification 218,175 describes a bili- ary contrast medium, to be administered orally in capsules, to which a surface-active agent is added for better solubility. Oil-in-water emul- sions for radiographical investigation of the gastrointestinal tract are known frorn German Offenlegungsschrift 2,216,402, the oil phase of these emulsions consisting of iodine-containing compounds to which anti- foaming surface-active agents which stabilise the emulsion are added. Swiss Patent Specification 373,866 discloses 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. From Austrian Patent Specification 175,974 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, i.e. for a nonintravasal use. In the literature reference M. Guerbet,The addition of surface-active agents to X-ray contrast media in e ulusion form or suspension form for taking X-rays of various body cavities is known. Thus, Austrian Patent Specification 218,175 describes a biliary contrast medium, to be administered orally in capsules, to which a surface-active agent is added for better solubility. Oil-in-water emulsions for radiographical investigation of the gastrointestinal tract are known frorn German Offenlegungsschrift 2,216,402, the oil phase of these emulsions consisting of iodine-containing compounds to which anti-foaming surface-active agents which stabilize the emulsion are added. 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. From Austrian Patent Specification 175,974 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. In the literature reference M. Guerbet,
Therapie, 1966, XXI, 1585-1592, an oily X-ray contrast medium formula- tion is described, with which the & } K-£ OMPTherapy, 1966, XXI, 1585-1592, an oily X-ray contrast medium formula- described is, with which the & } K- £ OMP
♦ . ■ * . P
formation of an e ulsion with the blood serum is said to be improved, in order to reduce the danger of e bolisms-, by the addition of a surface-ac¬ tive agent. The addition of surface-active agents to aqueous X-ray contrast media Solutions which are miscible with body fluids, and which are intro- duced intravasally is thus new and is not suggested by the State of the art.♦. ■ *. P formation of an e ulsion with the blood serum is said to be improved, in order to reduce the danger of e bolisms-, by the addition of a surface-active agent. The addition of surface-active agents to aqueous X-ray contrast media Solutions which are miscible with body fluids, and which are intro- duced intravasally is thus new and is not suggested by the State of the art.
The invention thus relates to aqueous X-ray contrast media Solutions which are miscible with body fluids and are characterised 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 in¬ vention are to be understood as those which are to be introduced intra¬ vasally, that is for arteriographic and phlebographic application.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.
It has been found that it is appropriate to employ the surface-active agents, which are tolerated by the body, in amounts such that the inter¬ facial tension of the X-ray contrast media Solutions according to the invention with respect to the vessel walls is approximately reduced to'-the interfacial tension which prevails between the blood and the vessel walls.It has been found that it is appropriate to employ the surface-active agents, which are tolerated by the body, in amounts such that the inter ¬ facial tension of the X-ray contrast media Solutions according to the invention with respect to the vessel walls is approximately reduced to ' -the interfacial tension which prevails between the blood and the vessel walls.
The invention thus preferably relates to aqueous X-ray contrast media Solutions which are miscible with body fluids and are characterised 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 ten¬ sion which prevails between the blood and the vessel walls.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.
It has furthermore been found that in the case of osmotically hypertonic X-ray contrast media, the interfacial tension is appropriately reduced to values which are below that of blood with respect to the vessel walls. Endothelium damage which can be attributed to osmotic shrinkage is simul- taneously reduced by this measure according to the invention.It has furthermore been found that in the case of osmotically hypertonic X-ray contrast media, the interfacial tension is appropriately reduced to values which are below that of blood with respect to the vessel walls. Endothelium damage which can be attributed to osmotic shrinkage is simulta- neously reduced by this measure according to the invention.
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. By choosing particularly hydrophilic surface-active agents, not only can the inter¬ facial tension be adjusted to that of the blood, but at the same time the increased lipophilic character, which apparently leads to permeability disorders, can also be reduced.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. By choosing particularly hydrophilic surface-active agents, not only can the inter¬ facial tension be adjusted to that of the blood, but at the same time the increased lipophilic character, which apparently leads to permeability disorders, can also be reduced.
Surface-active agents which are tolerated by the body are to be under¬ stood as those surface-active agents which show neither haemolytic nor toxic reactions on establishing the required interfacial tension. The conέentration required largely depends on the choice of surface-active agent, and an excessively increased value for the interfacial tension given by the addition of X-ray contrast media must be taken as the start- ing point. The increase in the interfacial tension by X-ray contrast media is also different for individual contrast media custo ary in dia- gnostics. However, a hypertonic reaction is common to all X-ray contrast media and can be at least partly compensated by reduction of the inter¬ facial tension values to beyond that of the blood.Surface-active agents which are tolerated by the body are to be under¬ stood as those surface-active agents which show neither haemolytic nor toxic reactions on establishing the required interfacial tension. The concentration required largely depends on the choice of surface-active agent, and an excessively increased value for the interfacial tension given by the addition of X-ray contrast media must be taken as the start- ing point. The increase in the interfacial tension by X-ray contrast media is also different for individual contrast media custo ary in diagnostics. However, a hypertonic reaction is common to all X-ray contrast media and can be at least partly compensated by reduction of the inter¬ facial tension values to beyond that of the blood.
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 minimised.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.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.
According to the invention, 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 of 8 to 15.10 N/cm, and are usually about 12.10 -5 N/cm. Since it is not possible to determine the interfacial tension with respect to the vessel wall without Problems, it has been found that the interfacial tension of a reference substance of 0.5 % by volume of oleic acid in pure olive oil with respect to blood plasma approximately corresponds to that of the vessel wall with respect to blood plasma, and that the values measured with respect to this reference substance essentially correspond to the assu ed values wit respect to the vessel wall. In the context of the present invention, in¬ terfacial tensions between X-ray'contrast media or body fluids and vesselAccording to the invention, 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. Since it is not possible to determine the interfacial tension with respect to the vessel wall without Problems, it has been found that the interfacial tension of a reference substance of 0.5% by volume of oleic acid in pure olive oil with respect to blood plasma approximately corresponds to that of the vessel wall with respect to blood plasma, and that the values measured with respect to this reference substance essentially correspond to the assu ed values wit respect to the vessel wall. In the context of the present invention, interfacial tensions between X-ray'contrast media or body fluids and vessel
According to the invention, the interfacial tension with respect to theAccording to the invention, the interfacial tension with respect to the
-5 vveesssseell \wall is reduced to at least 16.10 N/cm by the surface-active agents.-5 vveesssseell \ wall is reduced to at least 16.10 N / cm by the surface-active agents.
Particularly favourable results are achieved with values in the rängeParticularly favorable results are achieved with values in the ranks
-5 -5 from 8 to 15.10 N/cm, and especially with values of about 12.10 N/cm.-5 -5 from 8 to 15.10 N / cm, and especially with values of about 12.10 N / cm.
An essential criterion of the usefulness of a surface-active agent is given by the so-called HLB number. This nu ber represents the "hydrophi- lic/lipophilic balance" and a high numerical value corresponds to a pro- nounced hydrophilic character whilst a low numerical value represents pro¬ nounced lipophilic character. The lipophilic character is preferably re¬ duced 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.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 relati- vely 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 sorbitane mono¬ oleate. 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 triiodo- benzoic 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.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.
Surface-active agents which are preferably used according to the inven¬ tion are the non-ionic surface-active agents, such as, for example, natu- rally 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®).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®).
The invention is illustrated in more detail below, with the aid of embo- diment examples.The invention is illustrated in more detail below, with the aid of emotional examples.
A number of anionic, cationic and non-ionic detergents were tested, the dosage being such that haemolysis could not be observed. Significant differences with respect to X-ray contrast media without the addition of surface-active substances were observed when lecithin with polyunsatu- rated fatty acids or essential phospholipids suspended by ultrasound (EPL US) were added if the final concentration of these additives is about 0.1 g to 1 g/100 ml, preferably 0.5 g/100 ml. When 75 mg/100 ml 0f polyoxyethylene sorbitane monooleate were added to a solution of the methylglucamine salt of diacetyl-3,5-diamino-2,4,6-triiodobenzoic acid, a significant reduction in the interfacial tension with respect to theA number of anionic, cationic and non-ionic detergents were tested, the dosage being such that haemolysis could not be observed. Significant differences with respect to X-ray contrast media without the addition of surface-active substances were observed when lecithin with polyunsaturated fatty acids or essential phospholipids suspended by ultrasound (EPL US) were added if the final concentration of these additives is about 0.1 g to 1 g / 100 ml, preferably 0.5 g / 100 ml. When 75 mg / 100 ml 0 f polyoxyethylene sorbitane monooleate were added to a solution of the methylglucamine salt of diacetyl-3,5-diamino-2,4,6- triiodobenzoic acid, a significant reduction in the interfacial tension with respect to the
-5 vessel wall to values of below 16.10 N/cm was observed, as was the case when about 50 mg/100 ml of an octylphenyl-polyethylene glycol ethyl-form- aldehyde polymer, 0.4mg/ml of cetylpyridine Chloride or 3 mg/100 ml of sodium dodecylsulfate were added. None of these surface-active agents exhibited any adverse effects after administration.-5 vessel wall to values of below 16.10 N / cm was observed, as was the case when about 50 mg / 100 ml of an octylphenyl-polyethylene glycol ethyl-form-aldehyde polymer, 0.4mg / ml of cetylpyridine Chloride or 3 mg / 100 ml of sodium dodecyl sulfate were added. None of these surface-active agents exhibited any adverse effects after administration.
_'•_____
Example_ '• _____ Example
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, whilst 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 ste¬ rile conditions and is made up to 300 1 with doubly distilled water. The solution is filled into 30 ml ampoules and these are sterilised in an autoclave at 120°C for 20 minutes.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 Solu¬ tions which are to be introduced intravasally.
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.
Claims
1. Aqueous X-ray contrast media Solutions which are to be introduced intra¬ vasally and which are miscible with body fluids, characterised by the addition of pharmacologicalTy acceptable surface-active agents.1. Aqueous X-ray contrast media solutions which are to be introduced intravasally and which are miscible with body fluids, characterized by the addition of pharmacologicalTy acceptable surface-active agents.
2. X-ray contrast media Solutions according to Claim 1, characterised by an 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 tension which prevails between the blood and the vessel walls of the body.2. X-ray contrast media Solutions according to Claim 1, characterized by an 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 tension which prevails between the blood and the vessel walls of the body.
3. X-ray contrast media Solutions according to Claim 1 or 2, characterised by an interfacial tension with respect to the vessel walls of the body of at most 16.10" N/cm, preferably of at most 12.10 N/cm.3. X-ray contrast media solutions according to Claim 1 or 2, characterized by an interfacial tension with respect to the vessel walls of the body of at most 16.10 " N / cm, preferably of at most 12.10 N / cm.
4. X-rray contrast media Solutions according to Claim 1 or 2, characterised by an interfacial tension with respect to the vessel wall of 8 to 15.10"5 N/cm, preferably of about 12.10"5 N/cm.4. X-ray contrast media solutions according to Claim 1 or 2, characterized by an interfacial tension with respect to the vessel wall of 8 to 15.10 "5 N / cm, preferably of about 12.10 " 5 N / cm.
5. X-ray contrast media Solutions according to one of Claims 1 to 4, characterised in that they contain a lecithin, in particular a lecithin with polyunsaturated fatty acids, in an amount of preferably about 0.5 g/100 ml as the surface-active agent.5. X-ray contrast media solutions according to one of Claims 1 to 4, characterized in that they contain a lecithin, in particular a lecithin with polyunsaturated fatty acids, in an amount of preferably about 0.5 g / 100 ml as the surface-active agent.
6. X-ray contrast media Solutions according to one of Claims 1 to 4, characterised in that they contain polyoxyethylene sorbitane fatty acid esters, in particular polyoxyethylene sorbitane monooleate, pre- ferably in an amount of 75 mg/100 ml, as the surface-active agent.6. X-ray contrast media solutions according to one of Claims 1 to 4, characterized in that they contain polyoxyethylene sorbitane fatty acid esters, in particular polyoxyethylene sorbitane monooleate, preferrably in an amount of 75 mg / 100 ml, as the surface -active agent.
7. X-ray contrast media Solutions according to one of Claims 1 to 4, characterised in that they contain a block copolycondensate of propy- lene glycol and polyethylene glycol, in the ratio 2 : 9, as the surface- active agent. 7. X-ray contrast media solutions according to one of Claims 1 to 4, characterized in that they contain a block copolycondensate of propylene glycol and polyethylene glycol, in the ratio 2: 9, as the surface active agent.
8. X-ray contrast media Solutions according to one of Claims 1 to 4, characterised in that they contain an octylphenyl-polyethylene glycol ether-formaldehyde poly er, preferably in a concentration of 50 mg/ 100 ml, as the surface-active agent.8. X-ray contrast media solutions according to one of Claims 1 to 4, characterized in that they contain an octylphenyl-polyethylene glycol ether-formaldehyde poly er, preferably in a concentration of 50 mg / 100 ml, as the surface-active agent .
55
9. X-ray contrast media Solutions according to one of Claims 1 to4 , characterised in that they contain cetylpyridine Chloride in an amount of preferably 0.4 mg/ 100 ml as the surface-active agent.9. X-ray contrast media Solutions according to one of Claims 1 to4, characterized in that they contain cetylpyridine Chloride in an amount of preferably 0.4 mg / 100 ml as the surface-active agent.
10 10. X-ray contrast media Solutions according to one of Claims 1 to5 , characterised in that they contain essential phospholipids, preferably finely dispersed by ultrasound, in an amount of preferably 0.05 to 0.5 g/100 ml as the surface-active agent.10. 10. X-ray contrast media Solutions according to one of Claims 1 to5, characterized in that they contain essential phospholipids, preferably finely dispersed by ultrasound, in an amount of preferably 0.05 to 0.5 g / 100 ml as the surface-active agent.
15 11. X-ray contrast media Solutions according to one of Claims 1 to 10 , characterised by an HLB number of greater than 15, preferably about 29, for the establish ent of which a hydrophilic surface-active agent is preferably added.15 11. X-ray contrast media Solutions according to one of Claims 1 to 10, characterized by an HLB number of greater than 15, preferably about 29, for the establish ent of which a hydrophilic surface-active agent is preferably added.
0 12. Use of surface-active agents as an additive to aqueous X-ray contrast media Solutions which are miscible with body,fluids and introduced intravasally.12. Use of surface-active agents as an additive to aqueous X-ray contrast media solutions which are miscible with body, fluids and introduced intravasally.
13. X-ray contrast media Solutions according to one of Claims 1 to 11, 5 characterised in that they contain as contrast medium 5-acetamido-N- (2-hydroxyethyl)-2,4,6-triiodoisophthalamic acid or its salts. 13. X-ray contrast media solutions according to one of Claims 1 to 11, 5 characterized in that they contain as contrast medium 5-acetamido-N- (2-hydroxyethyl) -2,4,6-triiodoisophthalamic acid or its salts.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT9076/78 | 1978-12-19 | ||
| AT907678 | 1978-12-19 | ||
| EP19790105091 EP0012926B1 (en) | 1978-12-19 | 1979-12-11 | Solutions of x-ray contrast agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1980001244A1 true WO1980001244A1 (en) | 1980-06-26 |
Family
ID=25605277
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1979/000100 WO1980001244A1 (en) | 1978-12-19 | 1979-12-17 | X-ray contrast media solutions |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JPS55501057A (en) |
| WO (1) | WO1980001244A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997030736A2 (en) * | 1996-02-20 | 1997-08-28 | Nycomed Imaging A/S | Contrast medium |
| WO2000021577A2 (en) * | 1998-10-09 | 2000-04-20 | Nycomed Imaging As | Compositions |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH273245A (en) * | 1948-10-14 | 1951-01-31 | Cilag Ag | Solution for the radiographic representation of body cavities. |
| DE919908C (en) * | 1952-05-24 | 1954-11-08 | Schering Ag | X-ray contrast media for bronchography and hysterosalpingography |
| GB834517A (en) * | 1958-09-15 | 1960-05-11 | Sterling Drug Inc | Radiopaque compositions |
| CH373866A (en) * | 1957-09-11 | 1963-12-15 | Bayer Ag | X-ray contrast media |
| CH375841A (en) * | 1958-10-24 | 1964-03-15 | Leo Ab | X-ray contrast medium for viewing the bile ducts |
| FR3658M (en) * | 1964-02-18 | 1965-11-02 | Michel Marie Andre Guerbet | Oily composition for intravascular injection. |
| FR5986M (en) * | 1966-11-22 | 1968-06-21 | ||
| FR6777M (en) * | 1967-07-10 | 1969-03-10 |
-
1979
- 1979-12-17 WO PCT/EP1979/000100 patent/WO1980001244A1/en unknown
- 1979-12-17 JP JP50012479A patent/JPS55501057A/ja active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH273245A (en) * | 1948-10-14 | 1951-01-31 | Cilag Ag | Solution for the radiographic representation of body cavities. |
| DE919908C (en) * | 1952-05-24 | 1954-11-08 | Schering Ag | X-ray contrast media for bronchography and hysterosalpingography |
| CH373866A (en) * | 1957-09-11 | 1963-12-15 | Bayer Ag | X-ray contrast media |
| GB834517A (en) * | 1958-09-15 | 1960-05-11 | Sterling Drug Inc | Radiopaque compositions |
| CH375841A (en) * | 1958-10-24 | 1964-03-15 | Leo Ab | X-ray contrast medium for viewing the bile ducts |
| FR3658M (en) * | 1964-02-18 | 1965-11-02 | Michel Marie Andre Guerbet | Oily composition for intravascular injection. |
| FR5986M (en) * | 1966-11-22 | 1968-06-21 | ||
| FR6777M (en) * | 1967-07-10 | 1969-03-10 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997030736A2 (en) * | 1996-02-20 | 1997-08-28 | Nycomed Imaging A/S | Contrast medium |
| WO1997030736A3 (en) * | 1996-02-20 | 1997-12-18 | Nycomed Imaging As | Contrast medium |
| WO2000021577A2 (en) * | 1998-10-09 | 2000-04-20 | Nycomed Imaging As | Compositions |
| WO2000021577A3 (en) * | 1998-10-09 | 2000-07-27 | Nycomed Imaging As | Compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55501057A (en) | 1980-12-04 |
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