Definitions

• the present invention relates to improvements in and relating to magnetic resonance imaging (MRI) and in particular to compositions for use as or in the preparation of MRI contrast media for imaging of the stomach, intestine, liver, bile duct and gall bladder.
• MRI magnetic resonance imaging
• MRI Magnetic resonance Imaging
• imaging nuclei generally water protons in body fluids and tissues
• MR magnetic resonance
• contrast agents raise the signal level of the target site relative to that of its surroundings are termed “positive” contrast agents whilst those lowering the signal level relative to surroundings are termed “negative” contrast agents.
• MRI contrast media achieve a contrast effect because they contain paramagnetic, superparaitvagnetic or ferromagnetic species.
• the enhanced image contrast derives primarily from the reduction in the spin reequilibration parameter known as T 2 or as the spin-spin relaxation time, a reduction arising from the effect on the imaging nuclei of the fields generated by the ferromagnetic or superparamagnetic particles.
• Paramagnetic contrast agents may be either positive or negative MRI contrast agents.
• the effect of paramagnetic substances on magnetic resonance signal intensities is dependent on many factors, the most important of which are the concentration of the paramagnetic substance at the imaged site, the nature of the paramagnetic substance itself and the pulse sequence and magnetic field strength used in the imaging routine.
• paramagnetic contrast agents are positive MRI contrast agents at low concentrations where their T lowering effect dominates and negative MRI contrast agents at higher concentrations where their T 2 lowering effect is dominant. In either event, the relaxation time reduction results from the effect on the imaging nuclei of the magnetic fields generated by the paramagnetic centres.
• paramagnetic, ferromagnetic and superparamagnetic materials as MRI contrast agents has been widely advocated and broad ranges of suitable materials have been suggested in the literature.
• An example of a physiologically tolerable paramagnetic material known for use as an MRI contrast agent is manganese ion, which may conveniently be used in the form of its salts or chelates. Indeed, even at very low i.v. dosages (about 5-10 ⁇ mol/kg bodyweight) manganese has been found to be particularly effective as a contrast agent for imaging of the liver.
• manganese when administered intravenously as a contrast agent, may be teratogenic at clinical dosages. Administered intravenously, manganese is also known to interfere with the normal functioning of the heart by replacement of calcium in the calcium pump of the heart.
• MnCl 2 as a liver imaging MR contrast agent has been proposed and orally administered MnCl 2 has not been found to be teratogenic.
• the absorption of MnCl 2 through the gut is poor, and as a result the dosage required for clinical efficacy is of the order of 100-1000 ⁇ mol/kg bodyweight.
• such a high dosage level still has the potential for causing undesired adverse effects, eg. cardiac effects.
• gastrointestinal tract manganese contrast agents suitable for imaging of the liver may be produced by the incorporation of an uptake promoter capable of enhancing manganese transport across the membranes of the g.i. tract.
• Compounds which have been found to be suitable for use as uptake promoters include reducing compounds containing an ⁇ -hydroxy ketone group (-C(OH) -CO-) , acids containing ⁇ - and/or ⁇ -hydroxy or amino groups, as well as vitamin D.
• the present invention provides a contrast medium composition
• a physiologically tolerable manganese compound comprising a physiologically tolerable manganese compound, an uptake promoter and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0.3mM or being in a dosage unit form containing at least 300 ⁇ mol manganese
• the uptake promoter comprises a physiologically tolerable reducing compound containing an ⁇ -hydroxy ketone group, a physiologically tolerable acid containing ⁇ - and/or ⁇ -hydroxy or amino groups, or a salt thereof, and/or vitamin D.
• the expression "acid containing ⁇ - and/or ⁇ -hydroxy or amino groups” is intended to include aromatic acids containing ortho-hydroxy or ortho-amino groups.
• the contrast medium composition according to the invention may comprise a manganese compound together with a mixture of several uptake promoters.
• the manganese compound which preferably is soluble in gastrointestinal fluid may for example be a chelate or a salt, or may be a mixture of different salts and/or chelates. Particularly preferred are metal chelates and salts in which the manganese is present as Mn(II) rather than Mn(III) since the former has a higher magnetic moment and thus is more effective as an MR contrast agent.
• the reducing nature of the uptake promoter is important since normal uptake of manganese by the gut tends to favour Mn(II) rather than Mn(III) .
• compositions according to the invention are those in which the reducing compound further contains an oxygen atom in a heterocyclic ring structure.
• an uptake promoter in the compositions of the invention is ascorbic acid which has been found to increase the uptake of manganese in the liver about 5-fold compared with oral administration of MnCl 2 alone. This surprising increase is demonstrated in Figure 2 of the accompanying drawings. Moreover ascorbic acid (vitamin C) is particularly preferred as an uptake promoter since it is cheap, readily available and particularly well tolerated by the body.
• compositions in accordance with the invention are those in which the uptake promoter is kojic acid.
• the uptake promoter is kojic acid.
• acids which have been found to be particularly effective as uptake promoters in the compositions of the invention include carboxylic acids, e.g. gluconic and salicyclic acid.
• carboxylic acids e.g. gluconic and salicyclic acid.
• salicylic acid to MnCl 2 on MRI enhancement of the liver can be seen in Figure 8 of the accompanying drawings
• ⁇ - and ⁇ - amino acids have also been found to be useful as uptake promoters, in particular ⁇ -amino acids, e.g. glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine, especially arginine, lysine and aspartic acid.
• ⁇ -amino acids e.g. glycine, valine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine and methionine, especially arginine, ly
• compositions in accordance with the invention are those which comprise vitamin D as an uptake promoter.
• the liver can be effectively MR imaged with a significant reduction in the dosage of manganese otherwise required.
• a 50% enhancement of the liver can be obtained by oral administration of 100 ⁇ mol manganese/kg body weight and 1 mmol ascorbic acid/kg.
• Such a dosage results in the same degree of enhancement of the liver as 5 ⁇ mol Mn(II)/kg body weight (MnCl 2 , i.v.) or as 500 ⁇ mol Mn(II)/kg body weight (MnCl 2 , p.o.).
• Figure 1 hereto demonstrates the effect of p.o. administration of MnCl 2 and ascorbic acid on MR liver enhancement compared with p.o. administration of MnCl 2 alone.
• composition in accordance with the invention enables the dynamics of uptake of the contrast agent by the liver to be monitored (see for example Figure 2) . This is of particular importance in enabling identification of areas of healthy tissue and areas of possible tumor growth.
• the preferred molar ratio of manganese to uptake promoter is from 1:0.2 to 1:50, eg. 1:1 to 1:20, especially 1:3 to 1:6, particular preferably about 1:5.
• the uptake promoter may if desired be present in whole or in part as the counterion to the manganese ions.
• the composition of the invention comprises as both manganese compound and uptake promoter a manganese salt of a reducing compound containing an ⁇ -hydroxy ketone group or a manganese salt of an acid containing ⁇ - and/or ⁇ - hydroxy or amino groups, eg. manganese (II) ascorbate or manganese salicylate.
• compositions according to the invention may be used to achieve a so-called “double contrast effect” by increasing the signal level from the liver whilst at the same time decreasing that from the surrounding tissues, in particular from the gut.
• double contrast effect enables yet further enhancement of the liver.
• a double contrast effect and margin definition can be achieved with the compositions of the invention since the resulting manganese ion concentration within the g.i. tract will generally be such as to create a signal suppressing effect there.
• a viscosity enhancing agent and desirably also an osmoactive agent. Examples of suitable viscosity enhancers and osmoactive agents are described in WO 91/01147 and WO 91/01148.
• the compositions of the invention may be used in combination with a second contrast agent having either a positive or negative contrast effect.
• the compositions of the invention are used in combination with a second contrast agent having an opposing contrast effect. This results in a "double contrast effect" enabling visualisation and margin definition of the liver to be particularly enhanced.
• paramagnetic materials such as manganese ions may act as either positive or negative MRI contrast agents depending upon a number of factors, including the concentration of the ions at the imaging site and the magnetic field strength used in the imaging procedure.
• the manganese-containing contrast agent will, in general, function as a positive contrast agent.
• the second contrast agent is therefore conveniently a negative contrast agent and may be any negative MRI contrast agent suitable for oral administration.
• any MR contrast agent, negative or positive may be used.
• a non-magnetic matrix material such as a polysaccharide eg. LUMIREM and sulphonated polystyrene eg. ABDOSCAN ® .
• compositions of the invention When using the compositions of the invention to achieve a double contrast effect, it is particularly preferable to incorporate a viscosity enhancing agent which attains its full viscosity enhancing effect only after administration of the contrast medium.
• the contrast medium is thus able to be ingested in a relatively tolerable form while yet developing the desired viscosity at or during passage towards the site which is to be imaged.
• compositions of the invention are particularly suited to use, if required after dispersion in aqueous media, for imaging of the liver.
• the compositions may be administered into the gastrointestinal tract orally, rectally or via a stomach tube.
• the present invention provides a method of generating a magnetic resonance image of a human or non-human, preferably mammalian, animal body which method comprises administering into the gastrointestinal tract of a said body a contrast medium comprising a physiologically tolerable manganese compound and a physiologically tolerable reducing compound containing an ⁇ -hydroxy ketone group or a physiologically tolerable acid containing ⁇ - and/or ⁇ - hydroxy or amino groups, or a salt thereof, and/or vitamin D, and generating a magnetic resonance image of the liver and the gastro ⁇ intestinal tract of said body.
• a contrast medium comprising a physiologically tolerable manganese compound and a physiologically tolerable reducing compound containing an ⁇ -hydroxy ketone group or a physiologically tolerable acid containing ⁇ - and/or ⁇ - hydroxy or amino groups, or a salt thereof, and/or vitamin D, and generating a magnetic resonance image of the liver and the gastro ⁇ intestinal tract of said body.
• the invention also provides a method of generating a magnetic resonance image of a human or non-human animal body, which method comprises administering into the gastrointestinal tract of a said body an effective amount of a composition comprising: (a) a first contrast agent comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an ⁇ -hydroxy ketone group or a physiologically tolerable acid containing ⁇ - and/or ⁇ - hydroxy or amino groups, or a salt thereof, and/or vitamin D, preferably having a manganese concentration of at least 0.3mM or being in a dosage unit form containing at least 300 ⁇ mol manganese, together with (b) a second contrast agent and generating a magnetic resonance image of the liver and abdomen of said body.
• a first contrast agent comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an ⁇ -hydroxy ketone group or a physiologically tolerable acid containing ⁇ - and/or
• the invention also provides an MRI contrast agent kit comprising in a first container a physiologically tolerable manganese compound, and in a second container a physiologically tolerable reducing compound containing an ⁇ -hydroxy ketone group or a physiologically tolerable acid containing ⁇ - and/or ⁇ - hydroxy or amino groups, or a salt thereof, and/or vitamin D.
• the invention also provides an MRI contrast agent kit comprising in a first container a first contrast agent comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an ⁇ -hydroxy ketone group or a physiologically tolerable acid containing ⁇ - and/or ⁇ - hydroxy or amino groups, or a salt thereof, and/or vitamin D, preferably having a manganese concentration of at least 0.3mM or being in a dosage unit form containing at least 300 ⁇ mol manganese, and in a second container a second contrast agent comprising a particulate ferromagnetic or superparamagnetic material or Gd or Dy ions bound to a polymeric matrix.
• a first contrast agent comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an ⁇ -hydroxy ketone group or a physiologically tolerable acid containing ⁇ - and/or ⁇ - hydroxy or amino groups, or a salt thereof, and/or vitamin
• contrast agent compositions of the invention may of course include components other than the uptake promoter, the manganese compound, the viscosity enhancing and osmoactive agents, for example conventional pharmaceutical formulation aids such as wetting agents, buffers, disintegrants, binders, fillers, flavouring agents and liquid carrier media such as sterile water, water/ethanol etc.
• conventional pharmaceutical formulation aids such as wetting agents, buffers, disintegrants, binders, fillers, flavouring agents and liquid carrier media such as sterile water, water/ethanol etc.
• the pH of the composition is preferably in the acid range, eg. 2 to 7 and while the uptake promoter may itself serve to yield a composition with this pH, buffers or pH adjusting agents may be used.
• the contrast media may be formulated in conventional pharmaceutical administration forms, such as tablets, capsules, powders, solutions, dispersions, syrups, suppositories etc.
• the preferred dosage of the composition according to the present invention will vary according to a number of factors, such as the administration route, the age, weight and species of the subject and the particular uptake promoter used.
• the dosage of manganese will be in the range of from 5 to 500 ⁇ mol/kg bodyweight, preferably from 5 to 150 ⁇ mol/kg bodyweight, more preferably from 10 to 100 ⁇ mol/kg bodyweight
• the dosage of the uptake promoter will be in the range of from 5 ⁇ mol to 1 mmol/kg bodyweight, preferably from 25 ⁇ mol to 0.5 mmol/kg bodyweight.
• Figure 1 is a graph illustrating the effect of p.o. administration of different Mn + salts on liver enhancement
• Figure 2 is a graph illustrating the effect of p.o. administration of MnCl 2 + ascorbic acid on liver enhancement at varying concentrations of ascorbic acid;
• Figure 3 is a graph illustrating the effect of p.o. administration of different doses of MnCl 2 containing 0.1 mmol/kg ascorbic acid on liver enhancement.
• Figure 4 is a graph illustrating the effect of the addition of ascorbic acid or ascorbic acid-palmitate to MnCl 2 on enhancement of the liver.
• Figure 5 is a graph illustrating the effect of the addition of ascorbic acid or kojic acid to MnCl 2 on enhancement of the liver.
• Figure 6 is a graph illustrating the results of a pharmacokinetic study to determine the variation in concentration of Mn(II) in the blood following administration of various Mn(II) -containing compositions.
• Figure 7 is a graph comparing the effect on liver enhancement of i.v. administration of Mn DPDP (S-095) with that of p.o. administration of MnCl 2 + ascorbic acid.
• Figure 8 is a graph illustrating the effect of the addition of ascorbic and salicylic acids to MnCl 2 on liver enhancement.
• Figure 9 is a graph illustrating the effect of the addition of different amino acids to MnCl 2 on liver enhancement.
• Figure 10 illustrates transversal Tl-weighted (SE 57/13; 2.4 T) liver images from a control rat and from three rats 2 hours after oral administration of 200 ⁇ mol/kg MnCl 2 + 1000 ⁇ mol/kg ascorbate.
• the signal intensity of the liver is substantially increased after gavage administration of Mn 2+ and ascorbate.
• Figure 11 illustrates coronal Tl-weighted (SE 90/17; 2.4 T) liver images from two rats 2 hours after oral administration of 200 ⁇ mol/kg MnCl 2 + 1000 ⁇ mol/kg ascorbate. The signal intensity in the gastrointestinal lumen is reduced after administration of Mn 2+ .
• Figures 12 and 13 are graphs illustrating the effect of the addition of ABDOSCAN ® to Mn-ascorbate on the enhancement of the liver.
• Figure 14 illustrates transversal Tl-weighted (SE 57/13; 2.4 T) liver images from a control rat and from three rats 2 hours after oral administration of 200 ⁇ mol/kg MnCl 2 + 1000 ⁇ mol/kg ascorbate + ABDOSCAN ® (21 ⁇ mol/kg Fe) .
• the addition of ABDOSCAN did not influence the signal intensity of the liver.
• Figure 15 illustrates coronal Tl-weighted (SE 90/17; 2.4 T) liver images from a control rat and from a rat 2 hours after oral administration of 200 ⁇ mol/kg MnCl 2 + 1000 ⁇ mol/kg ascorbate + ABDOSCAN ® (21 ⁇ mol/kg Fe) .
• the signal intensity in the gastrointestinal lumen is markedly reduced after co-administration of Mn 2+ and ABDOSCAN.
• Salicyclic acid sodium salt 12.8 g
• the manganese chloride and ascorbic acid are dissolved in sterile deionised water.
• the dose for a 70 kg adult human would be 350 ml, taken orally.
• the manganese chloride and kojic acid are dissolved in sterile deionised water.
• the dose for a 70 kg adult human would be 350 ml, taken orally.
• the dose for a 70 kg adult human would be 175 ml of A and 175 ml of B, taken orally.

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