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Metal complex-containing pharmaceutical agentsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory CompositionsMetal complex-containing pharmaceutical agents description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060165591, Metal complex-containing pharmaceutical agents. Brief Patent Description - Full Patent Description - Patent Application Claims
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, diethylenetriaminepentaacetic acid DTPA and many others), DE-OS 3401052 (e.g., 1,4,7,10-tetraazacyclododecane-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-oxapentamethylenecarbamoylmethyl-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-tri- azaundecanedioic 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: Continue reading about Metal complex-containing pharmaceutical agents... 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