Note: Descriptions are shown in the official language in which they were submitted.
The present invention provides a preparation for
influencing the relaxation times in NMR-diagnostics.
According to the present invention there is pro-
vided a pharmaceutical preparation for use in influencing
the relation ti.mes in NMR diagnostics which comprises a
physiologically acceptable carrier and at least one phy-
siologically compatible paramagnetic complex salt from
ani.mopolycarboxyl.ic acids having the formulae I to IV
],0
ooCC~i
z Cii C~Or.
N- ( C ~ ~ Z
~ 0~ CCil/ CH2COO~ (I)
N-hydroxy-ethyl-N,N',N'-ethylene-diamine -tri.acetic acid,
~50~:. C C~2C0~-; /c~ZC^
2 ~_(rH~ -(C~
u_r'~zC~ ~ 2 2 2 ~ C~i2c~c~(1~)
N,N,N',N",N"-diethylene-triamine pentaacetic acid,
HOH2C-CH2N(cH2cOoH)2 (III)
N-hydroxy-ethyl-imino diacetic acid,
nl C~
0 ~ N-(C'~ ) -(C~ ) -(CH ) -~\ l
H3GrCH2/ ~ 2 2 n .z m 2 H(IV),
wherein m represents the numbers 1 to 4, n represents tlle
numbers 0 to 2, Rl represents a saturated or unsaturated
hydrocarbon radical containing 1 to 4 hydrocarbon atoms or
the group -CH2-COOH, or disphosphonic acids having the general
.~ 2
formula V
P3H2
. ' '.
R - C R
~ 1 3 (V),
P3H2
where.i.n R2 represents hydrogen, alkyl containing 1 to 4
carbon atoms, halogen, the hydroxy, amino or-CH2-COOH group
and R3 represents hydrogen, alkyl containing 1 to 4 carbon
atoms, the -Cl-12-COOH group or also halogen when R2 represents
halogen, and from the ions of the lanthanide elements having
the atomic numbers 57 to 7 or from the ions of the transi-
tion metals having the atomic numbers 21 to 29, 42 and 44,
and, if desired, an inorganic base.
Suitable aminopolycarboxylic acids are those com-
pounds of this class of substances which can form chelate
complexes, for example:
1~185~7
formula
N-hydroxyethyl-N,N',N'-ethylenediamine-
triacetic acid (HEDTA)
s
N~N~Nl~Nll~N~-diethylenetriamine-penta-
acetic acid (DTPA), and II
N-hydroxyethylimino-diacetic acid III
DTPA is preferred.
Also suitable are the aminopolycarboxylic acids of
the ~eneral formula
R5
CH3 / CHzCOOH
N-(CH2)m~(CH2_N_CH2)n (CH2)m (IV)
HOOCCH
2 CH2COOH
- 4 -
., ~
~21~5~
wherein m represents the integers 1 to 4, n represents the
integers 0 to 2, and R5 represents a saturated or unsatura-
ted hydrocarbon radical having from 4 to 12 carbon atoms or
the group -CH2-COOH. Preferred is N,N,N',N'-ethylenediamine-
tetra acetic acid (EDTA)
~ ;
~21~9'~
There are also suitable phosphoric acids of the
general f ormula
P3H2
1,
R2~ R3 (V)
P3H2
wherein R2 represents hydrogen, alkyl containing 1 to 4
carbon atoms, halogen, the hydroxy, amino or-cH2-cooH group
and R3 represents hydrogen, alkyl containing 1 to 4 carbon
atoms, the -CH2-COOH group or also halogen when R2 represents
lS halogen. There may be mentioned, more especially, ethane-
l-hydroxy-l,l-diphosphonic acid, methane-diphosphonic acid
and ethane-l-amino-l,l-diphosphonic acid.
If desired, it is also possible to bind the phy-
siologically tolerable complex salts of the invention tobio-molecules in order in this way to enable the complex
salt to be conveyed to a particular area of the living body.
Bio-molecules which may be used are, for example,
immunoglobulins, hormones such, for example, as insulin,
glucagon, prostaglandins, steroidal hormones, proteins,
peptides, amino-sugars and lipids.
The coupling of the paramagentic complex salts
to the desired bio-molecules may be effected by means of
methods which are known per se, for example by reacting the
nucleophilic group of a bio-molecule such as the amino,
phenol, mercapto or imidazole group with an activated deri-
vative of the complex compound.
The activated derivatives which may be considered
~,
"; l;~l~S~
are for example, acid chlorides, mixed anhydrides (whieh ean
be prepared from the carboxyl derivative of the eomplex
compound with chlorocarbonic acid ester), activated esters,
nitrenes or isothiocyanates.
It is also possible to reaet an aetivated deriva-
tive of the biomolecule with a nucleophilie derivative of
the eomplex compound. As organic bases for salt formation
there may be used, for example, sodium hydroxide.
~ - 7 -
The new preparations of the invention may be made
up in a manner known per se by dissolving the paramagnetic
complex salt in water or physiological salt solution, if
desired with the addition of one or more additives usual
in galenics, such as, for example, physiologically compa-
tible buffer solutions (for example sodium dihydrogen phos-
phate solution), and sterilising the solution. The aqueous
solutions can be administered orally, neurally and especially
intervascularly. If suspensions of the paramagnetic complex
salts in water or physiological salt solution are desired,
especi.ally for oral administration, the
- 8 -
5~
- 9 -
paramagnetic complex salt is mixed with one or more
auxiliaries usual in galenics and/or surfactants and/or
aromatic substances for taste correction and suspended
in water or physiological salt solution before oral
administration. In this case, preferably from 3 to
10 g of paramagnetic complex salt and from 2 to 8 g of
one or more auxiliaries, such as, for example, saccharose,
highly disperse silica, polyoxyethylenepolyoxypropylene
polymers, starch, magnesium stearate, sodium lauryl
sulphate, talcum, lactose, sodium carboxymethylcellulose
are used.
For ~MR-diagnosis in humans, the preparations
of the invention are suitable in the form of aqueous
solutions os suspensions which contain from 5 to 250
mmols/litre, preferably 50 to 200 mmols/litre, of the
paramagnetic complex salt. The p~ of the aqueous
. solutions may range between 6.5 and 8.0, preferably
between 6.5 and 7.5. As a result of the formation of
the complex salt according to the present invention the
paramagnetic salt is detoxicated, and the effect also
achieved is that the salts are stable in water and
readily soluble therein in the physiological pH range.
Solutions of the complex salts appear to be
particularly suitable for greater definition or local-
isation of lesions of the pancreas and liver, and alsoof tumours and haemorrhages in the cranial area. For
diagnosis of the area under examination an aqueous
' ;
lZ1~35~7
- 10 -
solution of the paramagnetic complex salt which is
isotonic with blood is, for example, administered
intravenously at a dosage of from 1 to ~00 ~mols/kg.
With a concentration of the complex salt of from 50
to 200 mmols/litre, approximately 1 to 50 ml of
solution is required for examination of human patients.
The exposure of the layer in question is taken approxi-
mately 15 to 60 minutes after intravenous administration
of the aqueous solution of the paramagnetic complex salt.
The physical methods of diagnosis usual in the
practice of medicine which can be carried out with
little or no operative intervention are, for example,
the irradiation of the body with X-rays, scintiscanning
and sonography. All these methods either involve risks
to health or have a limited range of application. In
the case of X-ray procedures and scintiscanning the
patient is exposed to the ionising radiation, so that
these methods cannot be used as often as might be
required or cannot be used at all for groups at risk,
for instance for babies or pregnant women.
Sonography does not in fact have these dis-
advantages, but instead has a very limited range of
ap~lication, especially in the cranial area.
Since in spite of a great deal of research it
has not yet been possible to eliminate completely the
above-mentioned disadvantages, attempts have been
made to discover image-producing processes which do
not have these disadvantages but which provide comparable
S~
- 11 _
information for diagnostic purposes.
One of these image-producing processes is
spin-imaging, which is based on the physical effect
of nuclear magnetic resonance tNMR). This method
of diagnosis makes it possible to obtain sectional
images of the living body and an insight into metabolic
processes without the use of ionising rays. The effect
of nuclear resonance is shown by atomic nuclei which,
like hydrogen - mainly present in ~iological tissues as
water - have a magnetic moment and therefrom align
themselves in a strong external magnetic field. By
means of a high-frequency impulse (resonant frequency)
they are brought out of their position of equilibrium,
to which they return at a characteristic speed. The
duration of the return to the state of equilibrium,
the so-called relaxation time, provides information on
the classification of the atoms and on their interaction
with their surroundings.
The image which is obtained by measuring the
proton density or the relaxation times is of great
diagnostic value and provides information concerning
the water content and the state of the tissues being
examined~ For example, tumour tissue displays longer
relaxation times than healthy tissue. (A. Ganssen
and others, Computertomographie 1, ~1981] pp. 2-10,
Georg Thieme Verlag, Stuttgart, New York).
It has now been found that paramagnetic ions,
for example Mn++ (manganese) or Cu++ (copper~ influence the
relaxation times and thus increase the information content.
The solutions of heavy metal salts hitherto used on
experimental animals are not, however, suitable for intravenous
administration~to humans because of their high level of toxicity.
Paramagnetic substances which are well tolerated and have a
favourable influence on the imaging process are therefore being
sought. The latter effect may be produced for example, in that
the spin-lattice-relaxation time Tl is greatly reduced in a man-
ner which is as organ-specific as possible, whilst at the same
time the spin-spin-relaxation time T2 is kept constant to a great
extent. We have now found that the required detoxication of the
otherwlse toxic metal salts can be effected by complexing, with-
out the paramagnetic properties being adversely affected. Thisis surprising, since it is known that the distribution of the d-
and f-electrons over the d- and f- orbitals is altered thereby.
~.
The paramagnetic complex salts may be prepared accord-
ing to processes known per se to the man skilled in the art or
described in the literature, by dissolving the paramagnetic metal
salt of a lanthanide elemen~ having an atomic number of from 57
to 70 or of a transition metal having an atomic number of from 21
to 29, or 42 or 44, in water and/or alcohol and adding a solution
of the equivalent quantity of the organic component capable of
forming a complex in water and/or alcohol and stirring, if neces-
sary while heating at from 50C to 120C until the reaction is
complete. If alcohol is employed as the solvent, methanol or
ethanol is used. If the complex salt formed is insoluble in the
solvent used, it crystallises and can be filtered off. If it is
soluble in the solvent used, it can be isolated by evaporating
the solution to dryness.
The process is to be explained in detail, by way of
example, with the aid of the following instructions for
procedure:
- 13 -
. ~.
121~5~
Preparation of the manganese(II) complex of ethylene-
diaminetetraacetic acid:
14.6 g of ethylenediaminetetraacetic acid are
added to a suspension of 6.17 g of manganese(II) carbonate
in 500 ml of water and the whole is heated on a vapour
bath while stirring, gas being evolved. The initially
pink colour disappears after approximately 20 minutes
and the whole mixture goes into solution except for a
small residue. After stirring for one hour at 110C
the undissolved portion is filtered off and the
filtrate is cooled. After standing for 15 hours the
crystallisate is filtered off with suction and dried:
Yield = 14.1 g (molecular weight 345.17)
M.p. : 256 /258-259 C
Preparation of the gadolinium(III) complex of diethylene-
triaminepentaacetic acid:
A suspension of 435 g of gadolinium oxide (Gd203)
and 944 g of diethylenetriaminepentaacetic acid in
12 litres of water is heated while stirring to from
90C to 100C and stirred at this temperature for 48
hours. The undissolved portion is filtered off and
the filtrate is evaporated to dryness. The amorphous
residue is pulverised.
Yield 144 g, (molecular weight 547.58)
~p.: melts from 235 and remains undecomposed up to 320C.
35~
If there is/are still one or more acidic group(s)
in the resulting paramagnetic complex compound, the result-
ing complex compound can then, if desired, be dissolved
or suspended in water and the desired inorganic base can
be added thereto until the neutral point is reached. After
filtering off the undissolved constituents, the solution is
concentrated by evaporation and the desired complex salt
is obtained as the residue.
The following Example illustrates the invention:-
Example 1
Preparation of a solution of the di-sodium sal-t of the
manganese(II)-complex of ethylenediamine-tetra-acetic acid
5.55 g (15 mmoles) of the manganese(II)-complex
of ethylenediamine-tetra-acetic acid (water content: 6.9%)
are dissolved in 80 ml of water p.i. at a pH of 7.5 wi-th
the addition of dilute sodium hydroxide solution. The solu-
tion is then made up to 170 ml with water p , filtered
into ampoules and heat-sterilised.
1~
-- ~} --
1~8597
1~ .
.~`.,.
Example ~
(Composition of a powder for the preparation of a
suspension)
4.000 g gadolinium(III) complex of diethylenetriamine-
pentaacetic acid (water content 8%)
3.895 g saccharose
0,100 g polyoxyethylenepolyoxypropylene polymer
0.005 g aromatic substances
8.000 g
