U.S. patent application number 10/461384 was filed with the patent office on 2003-11-06 for metal complex-containing pharmaceutical agents.
This patent application is currently assigned to Schering AG. Invention is credited to Gries, Heinz, Niendorf, Hans Peter, Seifert, Wolfgang, Speck, Ulrich, Weinmann, Hanns-Joachim.
Application Number | 20030206858 10/461384 |
Document ID | / |
Family ID | 6315011 |
Filed Date | 2003-11-06 |
United States Patent
Application |
20030206858 |
Kind Code |
A1 |
Gries, Heinz ; et
al. |
November 6, 2003 |
Metal complex-containing pharmaceutical agents
Abstract
Improved metal complex-containing pharmaceutical agents are
described which, as an additive, contain one or more complexing
agents and/or one or more weak metal complex(es) or mixtures
thereof.
Inventors: |
Gries, Heinz; (Berlin,
DE) ; Speck, Ulrich; (Berlin, DE) ; Weinmann,
Hanns-Joachim; (Berlin, DE) ; Niendorf, Hans
Peter; (Berlin, DE) ; Seifert, Wolfgang;
(Berlin, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Assignee: |
Schering AG
Berlin
DE
|
Family ID: |
6315011 |
Appl. No.: |
10/461384 |
Filed: |
June 16, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10461384 |
Jun 16, 2003 |
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09253985 |
Apr 10, 1998 |
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09253985 |
Apr 10, 1998 |
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08388902 |
Feb 14, 1995 |
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5876695 |
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08388902 |
Feb 14, 1995 |
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07848600 |
Mar 9, 1992 |
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07848600 |
Mar 9, 1992 |
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07601594 |
Oct 22, 1990 |
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5098692 |
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07601594 |
Oct 22, 1990 |
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07126099 |
Nov 30, 1987 |
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Current U.S.
Class: |
424/1.11 ;
424/9.36; 424/9.363; 424/9.365; 424/9.42 |
Current CPC
Class: |
Y10T 436/24 20150115;
Y10S 424/90 20130101; A61K 47/6887 20170801; A61K 49/0002 20130101;
A61K 47/547 20170801; A61P 43/00 20180101 |
Class at
Publication: |
424/1.11 ;
424/9.36; 424/9.363; 424/9.365; 424/9.42 |
International
Class: |
A61K 051/00; A61K
049/04 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 28, 1986 |
DE |
P 36 40 708.9 |
Claims
What is claimed is:
1. In a pharmaceutical agent comprising a metal complex, useful for
NMR, X-ray, ultrasound or radio-diagnostics or radiotherapy, the
improvement wherein said agent further comprises a metal complexing
agent, a weak metal complex or a mixture thereof.
2. An agent of claim 1, comprising said metal complexing agent.
3. An agent of claim 1, comprising said weak metal complex, wherein
said metal is physiologically acceptable and the binding constant
of said weak metal complex is lower than that of said
diagnostically or therapeutically useful metal complex.
4. An agent of claim 1, wherein the metal of said weak metal
complex is calcium, magnesium, zinc or iron.
5. An agent of claim 2, wherein the complex portion of all of said
complexes and complexing agents is, independently., e.g.,
ethylenediaminetetraacetic acid. (EDTA),
diethylenetriaminepentaacetic acid (DTPA),
1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA),
trans-1,2-cyclohexylenediamine-N,N,N',N'-tetraacetic acid,
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-[2,3-dihydroxy-N-methylpropylcarbam-
oylmethyl]-3,6,9-triazaundecanedioic acid,
N.sup.6-carboxymethyl-N.sup.3,N-
.sup.9-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid,
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9-3-oxapentamethylene-carbamoylm-
ethyl-3,6,9-triazaundecanedioic acid or
N.sup.3,N.sup.6-bis(carboxymethyl)-
-N.sup.9-[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl-carbamoylmethyl]-3,-
6,9-triazaundecanedioic acid.
6. An agent of claim 3, wherein the complex portion of all of said
complexes and completing agents is, independently, e.g.,
ethylenediaminetetraacetic acid (EDTA),
diethylenetriaminepentaacetic acid (DTPA),
1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA),
trans-1,2-cyclohexylenediamine-N,N,N',N'-tetraacetic acid,
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-[2,3-dihydroxy-N-methylpropylcarbam-
oylmethyl]-3,6,9-triazaundecanedioic acid,
N.sup.6-carboxymethyl-N.sup.3,N-
.sup.9-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid,
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9-3-oxapentamethylene-carbamoylm-
ethyl-3,6,9-triazaundecanedioic acid or
N.sup.3,N.sup.6-bis(carboxymethyl)-
-N.sup.9-[3,3-bis(dihydroxyphosphoryl)-3-hydroxypropyl-carbamoylmethyl]3,6-
,9-triazaundecanedioic acid.
7. An agent of claim 1, wherein the total amount of said complexing
agent and/or weak metal complex is 0.01.-50 mol % based on the
amount of said diagnostically or therapeutically effective complex,
up to a maximum of 250 mmol/l of said effective complex.
8. An agent of claim 1, wherein the total amount of said complexing
agent and/or weak metal complex is 0.1-10 mol % based on the amount
of said diagnostically or therapeutically effective complex, up to
a maximum of 50 mmol/l of said effective complex.
9. An agent of claim 1, further comprising a pharmaceutically
acceptable carrier.
10. An agent of claim 1, comprising the di-N-methylglucamine salt
of the gadolinium(III) complex of DTPA and the calcium trisodium
salt of DTPA.
11. An agent of claim 1, comprising the di-N-methylglucamine salt
of the gadolinium(III) complex of DTPA and the
penta-N-methylglucamine salt of DTPA.
12. An agent of claim 1, comprising the sodium salt of the
gadolinium(III) complex of
1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)
and the calcium disodium salt of DOTA.
13. An agent of claim 1, comprising the lysine salt of the
gadolinium(III) complex of DOTA and the zinc disodium salt of
DOTA.
14. An agent of claim 1, comprising the di-N-methylglucamine salt
of the gadolinium(III)-complex of
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-bis(meth-
ylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid and
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-bis(methylcarbamoylmethyl)-3,6,9-tr-
iazaundecanedioic acid.
15. An agent of claim 1, comprising the di-N-methylglucamine salt
of the gadolinium(III) complex of N.sup.6-carboxymethyl-N.sup.3
,N.sup.9-bis
(3-oxapentamethylene-carbamoylmethyl)-3,6,9-triazaundecanedioic
acid and the tetrasodium salt of
N.sup.3,N.sup.6-bis-(carboxymethyl)-N.sup.9-3-oxa-
pentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioic acid.
16. An agent of claim 1, comprising the disodium salt of the
manganese(II) complex of trans-1,2-cyclohexylenediaminetetraacetic
acid and trans-1,2-cyclohexylenediaminetetraacetic acid.
17. An agent of claim 1, comprising the N-methyl-glucamine salt of
the iron(III) complex of
ethylenediamine-N-N'-bis(2-hydroxyphenylacetic acid) (EHPG) and
EHPG.
18. An agent of claim 1, comprising the sodium salt of the
gadolinium(III) complex of
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9-[3,3-bis(dihydroxyp-
hosphoryl)-3-hydroxypropyl
carbamoylmethyl]-3,6,9-triazaundecanedioic acid and
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9-[3,3-bis(dihydroxyphosphor-
yl)-3-hydroxypropyl carbamoylmethyl]-3,6,9-triazaundecanedioic
acid.
19. An agent of claim 1, comprising the gadolinium(III) complex of
the conjugate of DTPA with a monoclonal antibody and the calcium
disodium salt of DTPA.
20. An agent of claim 1, comprising the gadolinium(III) complex of
the dextran-DTPA conjugate and the calcium disodium salt of
EDTA.
21. In a method of performing an NMR, X-ray, ultrasound or
radio-diagnosis or image, or radiotherapy of a patient, comprising
administering an effective amount of a metal complex, the
improvement wherein there is coadministered a metal complexing
agent, a weak metal complex or a mixture thereof.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates, e.g., to improved agents based
metal-containing complex compounds suitable for NMR, X-ray,
ultrasound and radiodiagnosis and therapy and a process for their
production.
[0002] Soon after the discovery of X-rays the most varied
substances were experimentally tested as "contrast media" to boost
the insufficient contrast of body fluids and soft tissues (Barke,
R. Roentgenkontrastmittel [X-ray Contrast Media]; Chemie,
Physiologie, Klinik VEB Georg Thieme Leipzig, 1970). Heavy elements
were suitable as the X-ray absorbing elements of such contrast
media. In the course of a long selection and optimization process,
finally only contrast media based on iodine (in a stable organic
bond) or barium (as a nearly insoluble sulfate) remained. Barium
sulfate is used exclusively for visualization of the
gastro-intestinal tract and it does not penetrate the body.
[0003] With the development of nuclear medicine, e.g., the use of
radioactive elements for visualizing certain structures of the
organism and pathological areas and especially for functional
diagnosis and for radiotherapy, a series of other metals was
accepted for in vivo diagnosis. The so-called radiopharmaceuticals
used in nuclear medicine contain either a radioactive isotope of
iodine (.sup.131I or .sup.123I) or preferably a metal such as
.sup.99mtechnetium. These elements are bonded to an organic
substance in many cases or, in the case of the radioactive metal
isotope, are administered in complexed form. Most often, the
stability of the complexing of the metals is such that, during its
stay in the body, a more or less large portion of the metal cannot
be prevented from being released from its bond to the organic
molecule. Thus, in general, the metal ion loses its desired
pharmacokinetic and diagnostic properties produced by the
complexing, is eliminated only very slowly, disturbs the
distribution picture, specific in itself, of the isotope that is
still bonded and can exhibit its inherently toxic properties.
[0004] At the beginning of the 1980s the interest in metal
complexes in diagnostics and therapy increased further. With the
development of nuclear spin tomography there arose the question of
producing contrast, e.g., signal-influencing substances that could
be introduced into the body from the outside. Such substances help
to recognize diseases earlier and more accurately. As an effective
principle, complex paramagnetic metal ions were introduced which,
despite a relatively high dosage (e.g., several grams of complex
that contain about 1-2 g of heavy metal) and rapid intravenous
injection, have proven to be surprisingly well tolerated (R. Felix,
W. Schoerner, M. Laniado, H. P. Niendorf, C. Claussen, W. Fiegler,
U. Speck; Radiology 156, 3: 681-688 (1985)). Especially notable is
the obviously outstanding acute tolerance of gadolinium-DTPA
(European patent application 71564), the most advanced preparation
to date in clinical use. The extremely low number and the mild
nature of the acute side effects caused by gadolinium-DTPA make it
appear suitable also for use in connection with certain X-ray
techniques. The necessity of higher dosages and of repeated
administration exists for a series of diagnostic problems in
nuclear spin tomography and very generally in X-ray diagnosis. In
this connection, the question of long-term tolerance of substances
containing heavy metals must be given great attention.
[0005] Unlike the case for iodine in the iodine-containing X-ray
contrast media, the central atoms in the metal-containing complex
compounds that are suitable for NMR, X-ray, ultrasound and
radiodiagnosis and for therapy are not bonded covalently. The bond
of the metal ion is subject to equilibrium with the surroundings
which, according to nature, should be on the side of the complex as
much as possible. However, a permanent bond can never be attained.
In addition it should be noted that the stability constants, some
very high, indicated for the complexes relate to unphysiologically
high pH values and do not apply for the in vivo situation. Further,
in vivo, a concurrence of different ions is involved in the bond to
the complexing agents so that the probability for the undesired and
sometimes dangerous release of heavy metal ions in the organism
increases.
[0006] The danger becomes greater
[0007] the higher the dosage of the heavy metal complex
[0008] the more often the complex is used
[0009] the longer it remains in the body
[0010] the more chemically or metabolically unstable the complexing
agent is and
[0011] the more it penetrates the cells of the body.
[0012] On the other hand, tissue-specific complexes, for example
also those complexes bonded to biomolecules or macromolecules,,
desired-for diagnosis and radiotherapy of certain types of
pathological changes are precisely those, in comparison to
gadolinium-DTPA, characterized by a longer and more intracellular
stay in the body.
[0013] Thus, for diverse purposes, there is a need for better
tolerated agents in which a release of the heavy metal ion in
question from the complex compound is prevented as much as
possible.
SUMMARY OF THE INVENTION
[0014] Thus, it is an object of the invention to make available
such a pharmaceutical agent, as well as a process for its
production.
[0015] Upon further study of the specification and appended claims,
further objects and advantages of this invention will become
apparent to those skilled in the art.
[0016] It has been found that adding one or more free complexing
agent(s) and/or one or more weak metal complex(es) or their
mixtures to pharmaceutical agents based on metal complexes
surprisingly yields unobjectionably tolerable complexes.
[0017] In this connection, the complexing agent can be identical or
different in all three components, i.e., in the diagnostic agent or
therapeutic agent, in the additive complexing agent, and in the
additive of a weaker metal complex. Suitable such complexing agents
include, for example, the complexing agents disclosed in patent
applications EP 71.564 (e.g., ethylenediaminetetraacetic acid EDTA,
diethylenetriaminepentaaceti- c acid DTPA and many others), DE-OS
3401052 (e.g., 1,4,7,10-tetraazacyclod-
odecane-N,N',N",N"'-tetraacetic acid DOTA,
trans-1,2-cyclohexylenediamine-- N,N,N',N'-tetraacetic acid and
many others), EP 130934 (e.g.,
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-[2,3-dihydroxy-N-methylpropylcarbam-
oylmethyl]-3,6,9-triazaundecanedioic acid and many others) and, for
example,
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-bis(methylcarbamoylmethyl)-
-3,6,9-triazaundecanedioic acid,
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.-
9-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioic
acid,
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9[3,3-bis(dihydroxyphosphoryl)-3-
-hydroxypropyl-carbamoylmethyl]-3,6,9-triazaundecanedioic acid,
etc. Suitable complexing agents are also disclosed in U.S. Pat. No.
4,647,447 and U.S. Ser. Nos. 936,055 of Nov. 28, 1986, 020,992 of
Mar. 2, 1987, 627,143 of Jul. 2, 1984, 063,355 of Jun. 18, 1987,
078,507 of Jul. 28, 1987, 100,681 of Sep. 24, 1987, and others.
[0018] Among suitable weaker metal complexes are those that have a
relatively low stability constant; preferred are those that have,
as a central atom, a metal ion of elements occurring naturally in
the organism such as calcium, magnesium, zinc and iron.
[0019] The additives to be used in accordance with this invention
can be routinely selected by those of skill in the art in
accordance with this specification. The complexing agents used as
additives, as noted elsewhere, can be selected from the wide
variety of complexing agents known to be useful chelating agents
for metals, and especially from those disclosed as being useful in
conjunction with forming metal complexes useful for the mentioned
diagnostic or therapeutic procedures. The magnitude of the
difference between the stability constants of the active complex
and the additive complex is not critical; it is important only that
the stability constant of the additive complex be lower than that
of the active complex. Typically, however, the difference between
the stability constants of the two complexes will be on the order
of at least 10.sup.2.
[0020] The metal of the metal complex additive will in all cases be
different from the metal of the active metal complex and, as
mentioned below, most preferably will be a physiologically
well-tolerated metal such as one which is natural in the organism
but, in all cases, will have a biological tolerance which is
greater than that of the metal per se in the active metal
complex.
[0021] The complexing agents (chelating agents) and metal complexes
can be used in the form of physiologically aceptable salts of
inorganic (e.g., potassium, sodium, lithium hydroxide) or organic
(e.g., primary, secondary, tertiary amines such as ethanolamine,
morpholine, glucamine, N-methyl, N,N-dimethylglucamine) bases,
basic amino acids and amino acid amides (e.g., lysine, arginine,
ornithine) or acids (e.g., glucuronic acid, acetic acid), etc.,
e.g., as disclosed in the documents cited above.
[0022] The production of exemplary additives is described by the
following examples:
[0023] 1) Calcium-disodium salt of
1,4,7,10-tetraazacyclododecane-N,N',N",- N"'-tetraacetic acid
(DOTA)
[0024] 40.40 g (0.1 mol) of DOTA (Parish Chemical Comp.) is
refluxed with 10.0 g (0.1 mol) of calcium carbonate in 100 ml of
water until generation of gas has ended. Then, by adding 200 ml of
a 1 n sodium hydroxide solution, a neutral saline solution is
produced which is evaporated to dryness in a vacuum. 50.5 g of a
monohydrate is obtained as a white powder with a decomposition
point above 250.degree. C.
[0025] Analysis (relative to an anhydrous substance):
1 C 39.50 H 4.97 N 11.52 Ca 8.24 (calculated) C 39.65 H 5.05 N
11.30 Ca 8.18 (found)
[0026] The zinc disodium salt of DOTA is obtained in an analogous
way from DOTA, zinc carbonate and sodium hydroxide solution.
[0027] 2.
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-bis(methylcarbamoylmethyl)-
-3,6,9-triazaundecanedioic acid
[0028] 17.9 g (50 mmol) of
1,5-bis(2,6-dioxomorpholino)-3-azapentane-3-ace- tic acid is mixed
in 50 ml of water with 100 ml of an aqueous molar solution of
methylamine. It is stirred for 12 hours at room temperature and the
weak, yellow solution is bleached by filtration through activated
carbon. After evaporation in a vacuum, 20.5 g (=98% of the
theoretical) of a white hygroscopic powder with a melting point of
78-82.degree. C. is obtained.
[0029] Analysis (relative to an anhydrous substance):
2 C 45.81 H 6.97 N 16.70 (calculated) C 45.62 H 7.03 N 16.52
(found)
[0030] 3. a)
N.sup.3-(2,6-dioxomorpholinoethyl)-N.sup.6-(ethoxycarbonylmet-
hyl)-3,6-diazaoctanedioic acid.
[0031] A suspension of 21.1 g (50 mmol) of
N.sup.3,N.sup.6-bis(carboxymeth-
yl)-N.sup.9-(ethoxycarbonylmethyl)-3,6,9-triazaundecanedioic acid
(J. Pharm. Sci. 68, 1979, 194) in 250 ml of acetic anhydride is
stirred, after the addition of 50 ml of pyridine, for 3 days at
room temperature. Then the precipitate is suctioned off, it is
washed three times, each time with 50 ml of acetic anhydride and it
is finally stirred up for several hours with absolute diethyl
ether. After suctioning off, washing with absolute diethyl ether
and drying in a vacuum at 40.degree. C., 18.0 g (=89% of theory) of
a white powder with a melting point of 195.degree.-196.degree. C.
is obtained.
[0032] Analysis:
3 C 47.64 H 6.25 N 10.42 (calculated) C 47.54 H 6.30 N 10.22
(found)
[0033] b) Tetrasodium salt of
N.sup.3,N.sup.6-bis-(carboxymethyl)-N.sup.9--
3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioic
acid.
[0034] 2.42 g (6 mmol) of the compound obtained in a) is suspended
in 30 ml of dimethyl formamide. Then, at -5.degree. C., 3.04 g (30
mmol) of triethylamine and 0.52 ml (6 mmol) of morpholine are
added, left at this temperature for 2 hours, then it is further
stirred overnight, evaporated in a vacuum to dryness and the
residue is mixed with 100 ml of diisopropyl ether. After suctioning
off and drying, the substance is dissolved in 40 ml of water and 24
ml of 0.1 n sodium hydroxide solution. It is stirred for 2 hours at
room temperature and the solution is evaporated in a vacuum to
dryness. The residue is mixed with 10 ml of isopropanol, suctioned
off, washed with isopropanol and dried at 60.degree. C. in a
vacuum. 2.85 g (=86% of theory) is obtained as a white powder with
a decomposition point above 250.degree. C.
[0035] Analysis (relative to an anhydrous substance):
4 C 39.28 H 4.76 N 10.18 (calculated) C 39.11 H 5.01 N 10.23
(found)
[0036] 4)
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9[3,3-bis(dihydoxyphosp-
horyl)-3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaundecandioic
acid.
[0037] 2.35 g (10 mmol) of
3-amino-1-hydroxypropane-1,1-diphosphonic acid, produced according
to DE 2,943,498, is suspended in 200 ml of water and mixed with 20
ml of n sodium hydroxide solution to pH9. Then, while keeping the
pH constant, 12.10 g (30 mmol) of N.sup.3-(2,6-dioxomorpholin-
oethyl)-N.sup.6-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid is
added and it is stirred overnight. Then the solution is brought to
a pH of 12.5 with n sodium hydroxide solution and further stirred
for 3 hours. After addition of cation exchanger IR 120 to pH 7, the
solution is filtered and chromatographed on silica gel (mobile
solvent: butanol/ammonia/ethanol/wa- ter=5/2/1/1). The combined
substance-containing eluates are evaporated in a vacuum to dryness.
1.3 g of a white powder with a melting point of 145.degree. C. is
obtained.
[0038] Analysis (relative to an anhydrous substance):
5 C 33.45 H 5.28 N 9.18 P 10.15 (calculated) C 33.56 H 5.50 N 9.30
P 10.02 (found)
[0039] 5) Calcium-trisodium salt of DTPA (CaNa.sub.3DTPA)
[0040] 196.6 g (0.5 mol) of DTPA is refluxed with 50 g (0.5 mol) of
calcium carbonate in 800 ml of water until gas generation is
finished. Then, by adding 750 ml of a 2 n sodium hydroxide
solution, a neutral saline solution (pH 7.1) is produced that is
evaporated in a vacuum to dryness. After drying overnight in a
vacuum, 246.2 g of the complex salt is obtained as monohydrate with
a melting point near 178-180.degree. C.
[0041] Analysis (relative to an anhydrous substance):
6 C 35.45 H 3.82 N 8.86 Ca 8.45 (calculated) C 35.30 H 3.96 N 8.80
Ca 8.39 (found)
Pharmacological Studies
[0042] In pharmacological tests it was established that, despite an
absolute and relatively low dosage, an added portion of free
complexing agents or of a weaker metal complex very significantly
promoted the complete elimination of the heavy metal ion.
[0043] Thus Table 1 shows that by adding only 10% of calcium
trisodium DTPA to the contrast medium, the portion of gadolinium
remaining in the bodies of rats one week after i.v. injection of
GdDTPA is reduced by greater than 30%, the concentration in the
bones by even about 45%.
7TABLE 1 .sup.153Gd in the rat 7 days after i.v. injection as
GdTPA/- dimeglumine in a dose of 0.1 mmol/kg, n = 3, average .+-.
standard deviation Formulation A Formulation B 0.1 mmol 0.1 mmol
GdDTPA + 0.01 mmol GdDTPA/kg KG CaNa.sub.3DTPA/kg KG Bones 1.46
.+-. 0.21 0.79 .+-. 0.22 (nmol/g) Amount in 0.99 .+-. 0.24 0.68
.+-. 0.09 the whole animal (% of the dose)
[0044] The values in Table 2 show that adding only 2 mol % of free
DTPA (formulation B) to a contrast medium based on GdDTPA reduces
the gadolinium concentration in the liver of rats by more than 50%
in contrast to a control with 0.08 mol % of free DTPA (formulation
A) up to the 28th day after injection.
8TABLE 2 .sup.153Gd in the liver of the rat after i.v. injection of
GdDTPA/dimeglumine in a dose of 0.5 mmol/kg; mmol/g net weight of
tissue; n = 3; average .+-. standard deviation. 28 d 2 h 6 h 1 d 3
d 7 d 14 d p. inj. Formulation A 0.5 mmol GdDTPA + 20 20 10 5.6 2.3
1.1 0.4 0.0004 mmol DTPA/kg .+-.2 .+-.3 .+-.3 .+-.0.9 .+-.0.6
.+-.0.3 .+-.0.1 Formulation B 0.5 mmol GdDTPA +22 17 10 5.2 1.6 0.6
0.13 0.01 mmol DTPA/kg .+-.7 .+-.1 .+-.2 .+-.1.4 .+-.0.1 .+-.0.2
.+-.0.01
[0045] This observed effect of the addition of complexing agents or
of a weak metal complex to pharmaceutical preparations based on
metal complexes was in no way predictable; in fact, it contradicts
corresponding in-vitro determinations.
[0046] An assessment of the in-vivo situation is made practically
impossible by the fact that all forms of the complexing agent can
interact with ions produced in the body and, on the other hand,
offer numerous and in places extremely stable bonding points
(proteins; natural complexing agents; anions that form very
slightly soluble salts) for heavy metals. In addition, to achieve
the object of making available better tolerated diagnostic media,
one prejudice of the man of the art had to be overcome: previously,
in the production of contrast media based on metal complexes,
careful attention was always paid to the fact that there was no
excess of either metal ions or free complexing agents or a weaker
com-plex in the solution, since it is known that the free
complexing agents and the weaker complexes of the complexing agents
with metal ions such as Ca.sup.2+ are less well tolerated than the
stronger complexes with the heavy metal ions suitable for
diagnostics or therapy.
[0047] A surprise of the present invention thus also is in the
extraordinarily strong effect of the addition of free complexing
agents or of weak complexes to the metal complex provided for use,
e.g., on human beings with reference to the stability of the bond
of the metal and thus its detoxification and elimination. This
advantage is, in view of the very slow elimination of heavy metals
and their inherent toxicity, of such great significance that for
this reason a somewhat reduced acute tolerance of a preparation can
possibly be accepted.
[0048] To achieve the desired object, very low concentrations and
dosages are typically sufficient. There is an upper limit on the
dosage of the complexing agent or of the weaker complexes due to
their acute tolerance. A range between 0.01 and 50 mol % (based on
the amount of the actual diagnostically or otherwise effective
complexing agent) or max. 250 mmol/l of the actual diagnostically
or otherwise effective complexing agent is suitable. These amounts
preferably are between 0.1 and 10 mol % or max. 50 mmol/l. These
values refer to the total amounts of these additives where mixtures
are used.
[0049] In no case is it necessary to add the complexing agent or
weaker complex to the preparations in such a high dose that a
relevant reduction in the tolerance of the final preparation occurs
compared with the originally selected diagnostically or
therapeutically effective metal complex. Further, there is
absolutely no necessity for an isolated or even repeated
administration of the complexing agent or weak complex.
[0050] The production of the drug according to the invention occurs
in a known way, e.g., as disclosed in the documents cited above,
by--optionally with the addition of additives common in galenic
medicine--mixing the complex compounds suspended or dissolved in an
aqueous medium with the complexing or weak metal complex(es) used
as additive and then optionally sterilizing the suspension or
solution. Suitable additives are, for example, physiologically safe
buffers (e.g., tromethamine), viscosity-enhancing additives, those
that increase the osmolality or, if necessary, electrolytes such as
sodium chloride or, if necessary, antioxidants such as ascorbic
acid.
[0051] If suspensions or solutions of the media according to the
invention in water or of physiological saline solutions are desired
for enteral administration or for other purposes, the media can be
mixed with auxiliary agents (e.g., methyl cellulose, lactose,
mannitol) and/or surfactants (e.g., lecithin, Tweens.RTM.,
Myrj.RTM.) and/or aromatics common in galenic medicine for
flavoring (e.g., ethereal oils).
[0052] If suspensions of the complex compounds in water or a
physiological saline solution are desired for oral administration
or other purposes, a slightly soluble complex compound is mixed
with one or more auxiliary agents and/or surfactants and/or
aromatics common in galenic medicine for flavoring.
[0053] The drugs according to the invention preferably contain
between 1 micromol and 1 mol/l of the diagnostically
or-therapeutically effective complex salt and are generally dosed
in amounts between 0.001 and 5.mmol/kg. They are intended for
enteral and parenteral application.
[0054] They are used in accordance with the conventional use of the
underlying diagnostic or therapeutic complexes themselves, e.g., as
disclosed in the documents cited above. The additives preferably
are co-administered in a single formulation along with the
diagnostic or therapeutic agents but could also be administered in
a separate formulation administered at essentially the same time as
the formulation of the active complex or sequentially.
[0055] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description; utilize the
present invention to its fullest extent. The following preferred
specific embodiments are, therefore, to be construed as merely
illustrative, and not limitative of the remainder of the disclosure
in any way whatsoever.
[0056] In the foregoing and in the following examples, all
temperatures are set forth uncorrected in degrees Celsius and
unless otherwise indicated, all parts and percentages are by
weight.
[0057] The entire text of all applications, patents and
publications, if any, cited above and below are hereby incorporated
by reference.
EXAMPLE 1
[0058] Production of a solution of the di-N-methylglucamine salt of
the gadolinium(III)-complex of diethylene-triaminepentaacetic acid
(DTPA) with the calcium trisodium salt of DTPA as additive.
[0059] 97.6 g (0.5 mol) of N-methylglucamine is dissolved sterile
in 50 ml of water. After the addition of 196.6 g (0.5 mol) of DTPA
and 90.6 g (0.25 mol) of gadolinium oxide, Gd.sub.2O.sub.3, it is
refluxed for 2 hours and the clear solution is brought to pH 7.2 by
adding another 97.6 g (0.5 mol) of N-methylglucamine. Next, 24.62 g
(50 mmol) of the monohydrate of the calcium trisodium salt of DTPA,
CaNa.sub.3 DTPA is added and water is added sterile to produce 1000
ml. The solution is ultrafiltered, placed in an ampule and heat
sterilized and is ready for parenteral use.
EXAMPLE 2
[0060] Production of a solution of the di-N-methylglucamine salt of
the gadolinium(III) complex of diethylene-triaminepentaacetic acid
(DTPA) with the penta-N-methylglucamine salt of DTPA as
additive.
[0061] 97.6 g (0.05 mol) of N-methylglucamine is dissolved sterile
in 500 ml of water. After addition of 196.6 g (0.5 mol) of DTPA and
90.6 g (0.25 mol) of gadolinium oxide, Gd.sub.2O.sub.3, the batch
is refluxed for 2 hours and the clear solution is brought to pH 7.2
by adding another 97.6 g (0.5 mol) of N-methylglucamine. Next,
another solution of 197 mg (0.5 mmol) of DTPA and 488 mg (2.5 mmol)
of N-methylglucamine in 100 ml of water is added sterile and water
is added sterile to produce 1000 ml. The solution is finally
ultrafiltered, placed in an ampule and heat sterilized, and is
ready for parenteral use.
EXAMPLE 3
[0062] Production of a solution of the sodium salt of the
gadolinium(III) complex of
1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)
with the calcium disodium salt of DOTA as additive.
[0063] 290.3 g (0.5 mol) of the complex salt described in example
11 of DE 3401052 is dissolved sterile in 700 ml of water. After
addition of 7.44 g (30 mmol) of the calcium disodium salt of DOTA,
water is added sterile to the neutral solution to produce 1000 ml,
it is ultrafiltered, placed in an ampule and heat sterilized.
EXAMPLE 4
[0064] Production of a solution of the lysine salt of the
gadolinium(III) complex of DOTA with the zinc disodium salt of DOTA
as additive.
[0065] 80.80 g (0.2 mol) of DOTA (Parish Chemical Comp.) is
introduced sterile into a suspension of 36.26 g (0.1 mol) of
gadolinium oxide, Gd.sub.2O.sub.3, in 700 ml of water. It is heated
with stirring for 20 hours to 70.degree. C. and the solution is
neutralized by adding an aqueous 20% by weight solution of lysine.
Then 10.24 g (20 mmol) of the zinc disodium salt of DOTA is added
and water is added sterile to the solution to produce 1000 ml. The
solution is ultrafiltered, placed in an ampule and heat
sterilized.
EXAMPLE 5
[0066] Production of a solution of the di-N-methylglucamine salt of
the gadolinium(III) complex of DTPA with the calcium trisodium salt
of DTPA as additive.
[0067] 97.6 g (0.5 mol) of N-methylglucamine is dissolved in 20 l
of water. After addition of 196.6 g (0.5 mol) of DTPA and 90.6 g
(0.25 mol) of gadolinium oxide Gd.sub.2O.sub.3, it is refluxed for
5 hours. 475.4 g (1 mol) of calcium trisodium DTPA, 750 g of
mannitol and 100 g of trisodium citrate is added, the solution is
neutralized with N-methylglucamine and water is added to produce 50
l. The solution is poured into bottles for enteral application.
EXAMPLE 6
[0068] Production of a solution of the di-N-methylglucamine salt of
the gadolinium(III) complex of
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-bis(meth-
ylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid with
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-bis(methylcarbamoylmethyl)-3,6,9-tr-
iazaundecanedioic acid as additive.
[0069] 12.58 g (30 mmol) of
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-bis-(met-
hylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid is reacted with
5.44 g (15 mmol) of gadolinium oxide, Gd.sub.2O.sub.3, in 500 ml of
water for 6 hours at 90.degree. C. 12.58 g (30 mmol) of
N.sup.6-carboxymethyl-N.sup.3-
,N.sup.9-bis(methylcarbamoylmethyl)-3,6,9-triazaundecanedioic acid,
50 g of mannitol and 8 g of trisodium citrate is added, the
solution is neutralized with N-methylglucamine and water is added
to produce 1000 ml. The solution is poured into bottles for enteral
use.
EXAMPLE 7
[0070] Production of a solution of the di-N-methylglucamine salt of
the gadolinium(III) complex of
N.sup.6-carboxymethyl-N.sup.3,N.sup.9-bis(3-ox-
apentamethylenecarbamoylmethyl)-3,6,9-triazaundecanedioic acid,
with the tetrasodium salt of
N.sup.3,N.sup.6-bis-(carboxymethyl)-N.sup.9-3-oxapent-
amethylene-carbamoylmethyl-3,6,9-triazaundecanedioic acid as
additive.
[0071] 17.90 g (50 mmol) of
1,5-bis-(2,6-dioxomorpholino)-3-azapentane-9-a- cetic acid is
suspended in 150 ml of water and dissolved by adding 13.08 ml (150
mmol) of morpholine. It is stirred for 16 hours at room temperature
and mixed with 16.57 (50 mmol) of gadolinium(III)-acetate dissolved
in 150 ml of water. It is further stirred for 2 hours and the
solution is treated successively with the anion exchanger IRA 410
and with the cation exchanger IRC 50.. The neutral solution is then
evaporated in a vacuum to dryness. 22.25 g (32.4 mmol) of the
desired complex compound is obtained which is dissolved sterile in
a solution of 12.65 g (64.8 mmol) of N-methylglucamine in 60 ml of
water. 1.66 g (3 mmol) of the tetrasodium salt of
N.sup.3,N.sup.6-bis-(carboxymethyl)-N.su-
p.9-3-oxapentamethylene-carbamoylmethyl-3,6,9-triazaundecanedioic
acid is added and water is added sterile to produce 100 ml. The
neutral solution is ultrafiltered, placed in ampules and heat
sterilized; it is ready for parenteral use.
EXAMPLE 8
[0072] Production of a solution of the disodium salt of the
manganese(II) complex of trans-l,2-cyclohexylenediaminetetraacetic
acid with trans-1,2-cyclohexylenediaminetetraacetic acid as
additive.
[0073] 395.9 g (500 mmol) of the salt described in example 9 of DE
3401052 is suspended sterile in 500 ml of water while being exposed
to nitrogen gas. It is mixed with 1.73 g of ascorbic acid and 17.3
g (50 mmol) of trans-1,2-cyclohexylenediaminetetraacetic acid, then
it is neutralized by adding n sodium hydroxide solution and water
is added sterile to-produce 1000 ml. The solution is filtered
sterile using nitrogen and poured into ampules.
EXAMPLE 9
[0074] Production of a solution of the N-methylglucamine salt of
the iron(III) complex of
ethylenediamine-N,N'-bis(2-hydroxyphenylacetic acid) (EHPG) with
EHPG as additive.
[0075] 36.04 g (0.1 mol) of EHPG is refluxed sterile in 500 ml of
water with 15.97 g (0.1 mol) of iron(III) oxide, Fe.sub.2O.sub.3,
until a solution has occurred. 3.604 g (0.01 mol) of EHPG is added
and it is brought to pH 7.5 by adding N-methylglucamine. Water is
added sterile to produce 1000 ml and the solution is ultrafiltered,
poured into ampules and heat sterilized.
EXAMPLE 10
[0076] Production of an injection solution of the sodium salt of
the gadolinium(III) complex of
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9[3,3-
-bis(dihydroxyphosphoryl)-3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaunde-
canedioic acid, with
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9[3,3-bis(di-
hydroxyphosphoryl)-3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaundecanedio-
ic acid as additive.
[0077] 305.2 g (0.5 mol) of
N.sup.3,N.sup.6-bis(carboxymethyl)-N.sup.9-[3,-
3-bis(dihydroxyphosphoryl)3-hydroxypropylcarbamoylmethyl]-3,6,9-triazaunde-
canedioic acid is dissolved sterile in 8.5 l of water with addition
of 123.6 g (0.25 mol) of gadolinium carbonate,
Gd.sub.2(CO.sub.3).sub.3 at 50.degree. C. Then another 30.52 g
(0.05 mol) of the complexing agent is added and the pH is brought
to 7.2 during exposure to nitrogen gas by instilling 5 n sodium
hydroxide solution. Water is added sterile to the solution to
produce 10 l, it is ultrafiltered, poured into ampules and heat
sterilized.
EXAMPLE 11
[0078] Production of a solution of the gadolinium(III) complex from
the conjugate of DTPA with a monoclonal antibody with the calcium
disodium salt of DTPA as additive.
[0079] To 20 microliters of a solution of 0.3 mg of monoclonal
antibody 12 H 12 in 0.05 molar sodium bicarbonate buffer, 1 mg of
N.sup.3-(2,6-dioxomorpholinoethyl)-N.sup.6-(ethoxycarbonylmethyl)-3,6-dia-
zaoctanedioic acid is added. After stirring overnight, it is mixed
with 2 mg of gadolinium chloride, GdCl.sub.3, and the solution is
dialyzed through a 0.3 molar sodium phosphate buffer. Then 1 mg of
the calcium trisodium salt of DTPA is added. The sterile filtered
solution is poured into Multivials and lyophilized.
EXAMPLE 12
[0080] Production of a solution of the gadolinium(III) complex of
the dextran-DTPA conjugate with the calcium disodium salt of EDTA
as additive.
[0081] A solution of 6.5 g of dextran 10000 is brought to pH 11
with n sodium hydroxide solution. Then 2.12 g of bromocyanogen is
added and it is stirred for 30 minutes, and the pH is kept constant
by adding more lye. After addition of 20 g of
1-(4-aminobenzyl)DTPA, produced according to Can. Pat. 1178951, the
solution is further stirred overnight at pH 8.5. Then a solution of
8 g of gadolinium chloride, GdCl.sub.3, in 30 ml of water is
in-stilled, the solution is clarified over activated carbon and
dialyzed. The dialyzate is mixed with 3 g of the calcium disodium
salt of ethylenediaminetetraacetic acid (EDTA), filtered sterile,
poured into Multivials and lyophilized. The lyophilizate contains
about 10% of complex bonded gadolinium.
[0082] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
[0083] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention,
and without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
* * * * *