CA1059904A - Compositions for preparation of aqueous solutions of salts of lower valence99 technetium - Google Patents
Compositions for preparation of aqueous solutions of salts of lower valence99 technetiumInfo
- Publication number
- CA1059904A CA1059904A CA262,177A CA262177A CA1059904A CA 1059904 A CA1059904 A CA 1059904A CA 262177 A CA262177 A CA 262177A CA 1059904 A CA1059904 A CA 1059904A
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- group
- salts
- technetium
- soluble
- alkyl
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- G—PHYSICS
- G21—NUCLEAR PHYSICS; NUCLEAR ENGINEERING
- G21H—OBTAINING ENERGY FROM RADIOACTIVE SOURCES; APPLICATIONS OF RADIATION FROM RADIOACTIVE SOURCES, NOT OTHERWISE PROVIDED FOR; UTILISING COSMIC RADIATION
- G21H5/00—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for
- G21H5/02—Applications of radiation from radioactive sources or arrangements therefor, not otherwise provided for as tracers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Abstract
ABSTRACT OF THE DISCLOSURE
Aqueous solutions of 9 technetium salts wherein the 99technetium is in reduced valence state, when administered to mammals, permit identification of the skeleton and of calcareous tumors by scintigraphy (radiographic scanning). The solutions are conveniently prepared by mixing one or more phosphonic acids (or their salts) with one or more reducing salts, and adding the mixture to an aqueous solution of a pharmaceutically acceptable 99pertechnetate salt. Reduction of the valence of the technetium occurs rapidly, and the resulting solution is adequately stable for use in scintigraphy.
The phosphonic acid and reducing salt components can be premixed. Aqueous solutions of the premix are stable for long periods of time in the absence of free oxygen and the premix is stable to air so long as it is dry.
Aqueous solutions of 9 technetium salts wherein the 99technetium is in reduced valence state, when administered to mammals, permit identification of the skeleton and of calcareous tumors by scintigraphy (radiographic scanning). The solutions are conveniently prepared by mixing one or more phosphonic acids (or their salts) with one or more reducing salts, and adding the mixture to an aqueous solution of a pharmaceutically acceptable 99pertechnetate salt. Reduction of the valence of the technetium occurs rapidly, and the resulting solution is adequately stable for use in scintigraphy.
The phosphonic acid and reducing salt components can be premixed. Aqueous solutions of the premix are stable for long periods of time in the absence of free oxygen and the premix is stable to air so long as it is dry.
Description
The present invention relates to water-soluble com-positionsor complexes of certain water-soluble phosphonic acids and salts with certain water-soluble polyvalent metal salts, for use in the preparation of stable aqueous soiuti~ containing radio-g9m active technetium.
The invention includes the compositions of the phos-. phonic-polyvalent metal components in tableted dry mix and in .
aqueous solution forms.The invention also includes aqueous solu-tions of low valence 99 technetium compounds hav~ng a content . 16 of said phosphonic-polyvalent metal compositions as stabilizer, and methods for the preparation.of said solutions.
. :, -~ -- ~ ~
It has been known for some time that X-ray investiga-tions for recognizing skeletal diseases and tumoræ, especially in the early stages, are not entirely satisfactory, even when ~ .
. effective treatment ispossible. Newer methods have therefore :~ been developed in.which the radioactive isotopes fluorine-18 and - . :, strontium-85 are used, which are selectively adsorbed in the skeleton and in partlcular by diseased portions Or the skeleton.
` . These radioactive isotopes concentrate even in calcareous tumors~
-Bone or tissue diseases can then be recognized and their sites identified by radlography. The production of 18F, ho~ever, re-quires complex apparatus which is usually not present in hospita1s, and in addition 18F has an extremely short half-life (only 110 minutes). The isotope 85Sr, on the other hand, has a very long half-life (65 days), but this isotope requires very long scannlng perlods because of its slow rate of decomposition and consequent low radio-emission rate.
Because of these disadvantages, interest has recently been directed to the radio isotope technetium-99 , which has a -1- ' ~
lOS9904 hal~-life of 6 hours. Very convcnient apparatus is available for its production, by which the isotope is obtained in the form of sodium ggm pertechnetate by ex-traction with isotonic sodium chlo-ride solution. In this form the tecllnetium has a valence of 7.
The pertechnetate-99m ion differs from ions containing l8F and from aSSr2~ in that in the body the pertechnetate ion is not specially bound in the skeleton or to calcareous tumors. It is therefore not practically useful for the scintigraphic examin-ation of bones and calcareous tumors. In order to use it, there-fore, the pertechnetium in the ion must be reduced to a relativelylow oxidation state (i.e., to a low valence state) and then stabilized with a suitable complex former in this oxidation state.
The valence of the technetium in this reduced state is 4. The complex former must also have a high selectivity for preferred adsorption by the skeleton or by calcareous tumors. Initial successes were achieved with certain polyphosphates whose com-plexes, however, have only moaerate stability with low oxidation state technetium. A suitable complex was produced by mixing 99m pertechnetate solution with an aqueous solution of ditin (II) ethane-l-hydroxy-l,l-diphosphonate (described in J. NUcl. Med.
13, 947 and 14~ 73). The stability of this ditin (II) ethane-l-hydroxy-l,l-diphosphonate solution was restricted, however, with an ex,~ess of ethane-l-hydroxy-l,l-diphosphonate,especially since the tin (II) ion has a tendency to hydrolyze. ~ cGmposition for the preparation of a material for the scintographic scanning of bones on this basis is described in German Patent Specification No. 2,424,496, It has now been found that certain carboxy phosphonic acids and their salts are very desirable complexing agents because of the high stability of their complexes with ions containing low m~p/~ 2--`` 1059904 oxidation stAte technetium ions and because of the high selec-tivity with which the 99m Tc deposits itself in t~e bone tissue or in calcareous tumors.
The object o~ prod~ing a soluble-stable composition which - gn addition to aqueous pertechnetate salt solutions pro~ides a stable, effective and selective form of 99 technetium suitable for the radio~raphy of bones and calcareous tumors, is attained by preparations which contain a mixture of:
(A) at least one water-soluble carboxyphosphonic compound of the.
theoretical formula:
H Rl ; CO2H 2 wherein R represents H or Cl 3 alkyl, and Rl represents -PO3H~, , I P03H2 . - C - R and - C - R
and wherein R represents H, Cl 3 alkyl, - CH2 - CHRC02H, - CH2 - CHRPO3H2 or - CH - CH2P3H2 ' II pharmaceutically use~ul water-soluble salts of the abo~e com-pounds, and (B) a pharmaceutically acceptable water-soluble tin tII)~ iron (II~
or chromium (II) salt in less than stoichiometric quantities, based on component (A).
. ' . . ' `` ' .
B~
" lOS9904 More in detail, we have found that a stable aqueous solution of a physiologically acceptable water-soluble salt of ~9technetium which is preferentially absorbed by bone and by calcareous tumors, is formed when to an aqueous solution of a 99pertechnetate salt-is added a sufficient amount of a composi-tion of a water-soluble phosphonic compound and a water-soluble reducing salt to reduce the technetium in said pertechnetate salt to a lower valence. The reduction in valence occurs rapidly, and the resulting solution, containing 1 to 20 mCi per ml of com-bined technetium is suitable for intravenous administration forthe above purpose. The valence of the reduced technetium is 4.
According to the present invention a suitable amount of 99technetium compound which is administered for radiographic purposes, is in ~he range of 0.05 to 0.3 mCi per kilogram of body weight.
It is possible, with these compounds, to produce in simple fashion highly stable compositions which are suitable for distribution and storage in solid form as tablets or in the form of solutions in an ampoule. After being added to an aqueous so~u-tion of a pertechnetate salt, the resulting solution is a veryeffective agent for diagnosing bone tumors, local disorders in bone metabolism and calcareous tissue tumors by the radiation scanning method.
The above phosphonic compounds can be used in free acid form. However, they can also be used for pharmaceutical purposes in the form of their pharmacologically harmless salts such as their sodium, potassium, magnesium, zinc, and ammonium salts, as well as their substituted ammonium salts such as mono-, di- or trialkanolammonium salts. Moreover, the phosphonic acids can be used in the form of their partial salts (where only a portion of the acid protons is substituted by other cations) and in the form of their whole salts. The partial salts, which react mjp/~ 4-substantially neutrally in aqueous solution (providing a pH in the range of 5-9 at 1% concentration) are preferred. Mixtures of the above-mentioned salts may also be used.
Suitable phosphonoalkanepolycarboxylic acids are listed in the Table shown below. Instead of the acids mentioned therein the water-soluble salts of these acids with physiologically harm-less cations such as those named above can also be used.
Phosphono-ethane-1,2-dicarboxylic acid l-Phosphono-propane-1,2-dicarboxylic acid l-Phosphono-pentane-1,2-dicarboxylic acid
The invention includes the compositions of the phos-. phonic-polyvalent metal components in tableted dry mix and in .
aqueous solution forms.The invention also includes aqueous solu-tions of low valence 99 technetium compounds hav~ng a content . 16 of said phosphonic-polyvalent metal compositions as stabilizer, and methods for the preparation.of said solutions.
. :, -~ -- ~ ~
It has been known for some time that X-ray investiga-tions for recognizing skeletal diseases and tumoræ, especially in the early stages, are not entirely satisfactory, even when ~ .
. effective treatment ispossible. Newer methods have therefore :~ been developed in.which the radioactive isotopes fluorine-18 and - . :, strontium-85 are used, which are selectively adsorbed in the skeleton and in partlcular by diseased portions Or the skeleton.
` . These radioactive isotopes concentrate even in calcareous tumors~
-Bone or tissue diseases can then be recognized and their sites identified by radlography. The production of 18F, ho~ever, re-quires complex apparatus which is usually not present in hospita1s, and in addition 18F has an extremely short half-life (only 110 minutes). The isotope 85Sr, on the other hand, has a very long half-life (65 days), but this isotope requires very long scannlng perlods because of its slow rate of decomposition and consequent low radio-emission rate.
Because of these disadvantages, interest has recently been directed to the radio isotope technetium-99 , which has a -1- ' ~
lOS9904 hal~-life of 6 hours. Very convcnient apparatus is available for its production, by which the isotope is obtained in the form of sodium ggm pertechnetate by ex-traction with isotonic sodium chlo-ride solution. In this form the tecllnetium has a valence of 7.
The pertechnetate-99m ion differs from ions containing l8F and from aSSr2~ in that in the body the pertechnetate ion is not specially bound in the skeleton or to calcareous tumors. It is therefore not practically useful for the scintigraphic examin-ation of bones and calcareous tumors. In order to use it, there-fore, the pertechnetium in the ion must be reduced to a relativelylow oxidation state (i.e., to a low valence state) and then stabilized with a suitable complex former in this oxidation state.
The valence of the technetium in this reduced state is 4. The complex former must also have a high selectivity for preferred adsorption by the skeleton or by calcareous tumors. Initial successes were achieved with certain polyphosphates whose com-plexes, however, have only moaerate stability with low oxidation state technetium. A suitable complex was produced by mixing 99m pertechnetate solution with an aqueous solution of ditin (II) ethane-l-hydroxy-l,l-diphosphonate (described in J. NUcl. Med.
13, 947 and 14~ 73). The stability of this ditin (II) ethane-l-hydroxy-l,l-diphosphonate solution was restricted, however, with an ex,~ess of ethane-l-hydroxy-l,l-diphosphonate,especially since the tin (II) ion has a tendency to hydrolyze. ~ cGmposition for the preparation of a material for the scintographic scanning of bones on this basis is described in German Patent Specification No. 2,424,496, It has now been found that certain carboxy phosphonic acids and their salts are very desirable complexing agents because of the high stability of their complexes with ions containing low m~p/~ 2--`` 1059904 oxidation stAte technetium ions and because of the high selec-tivity with which the 99m Tc deposits itself in t~e bone tissue or in calcareous tumors.
The object o~ prod~ing a soluble-stable composition which - gn addition to aqueous pertechnetate salt solutions pro~ides a stable, effective and selective form of 99 technetium suitable for the radio~raphy of bones and calcareous tumors, is attained by preparations which contain a mixture of:
(A) at least one water-soluble carboxyphosphonic compound of the.
theoretical formula:
H Rl ; CO2H 2 wherein R represents H or Cl 3 alkyl, and Rl represents -PO3H~, , I P03H2 . - C - R and - C - R
and wherein R represents H, Cl 3 alkyl, - CH2 - CHRC02H, - CH2 - CHRPO3H2 or - CH - CH2P3H2 ' II pharmaceutically use~ul water-soluble salts of the abo~e com-pounds, and (B) a pharmaceutically acceptable water-soluble tin tII)~ iron (II~
or chromium (II) salt in less than stoichiometric quantities, based on component (A).
. ' . . ' `` ' .
B~
" lOS9904 More in detail, we have found that a stable aqueous solution of a physiologically acceptable water-soluble salt of ~9technetium which is preferentially absorbed by bone and by calcareous tumors, is formed when to an aqueous solution of a 99pertechnetate salt-is added a sufficient amount of a composi-tion of a water-soluble phosphonic compound and a water-soluble reducing salt to reduce the technetium in said pertechnetate salt to a lower valence. The reduction in valence occurs rapidly, and the resulting solution, containing 1 to 20 mCi per ml of com-bined technetium is suitable for intravenous administration forthe above purpose. The valence of the reduced technetium is 4.
According to the present invention a suitable amount of 99technetium compound which is administered for radiographic purposes, is in ~he range of 0.05 to 0.3 mCi per kilogram of body weight.
It is possible, with these compounds, to produce in simple fashion highly stable compositions which are suitable for distribution and storage in solid form as tablets or in the form of solutions in an ampoule. After being added to an aqueous so~u-tion of a pertechnetate salt, the resulting solution is a veryeffective agent for diagnosing bone tumors, local disorders in bone metabolism and calcareous tissue tumors by the radiation scanning method.
The above phosphonic compounds can be used in free acid form. However, they can also be used for pharmaceutical purposes in the form of their pharmacologically harmless salts such as their sodium, potassium, magnesium, zinc, and ammonium salts, as well as their substituted ammonium salts such as mono-, di- or trialkanolammonium salts. Moreover, the phosphonic acids can be used in the form of their partial salts (where only a portion of the acid protons is substituted by other cations) and in the form of their whole salts. The partial salts, which react mjp/~ 4-substantially neutrally in aqueous solution (providing a pH in the range of 5-9 at 1% concentration) are preferred. Mixtures of the above-mentioned salts may also be used.
Suitable phosphonoalkanepolycarboxylic acids are listed in the Table shown below. Instead of the acids mentioned therein the water-soluble salts of these acids with physiologically harm-less cations such as those named above can also be used.
Phosphono-ethane-1,2-dicarboxylic acid l-Phosphono-propane-1,2-dicarboxylic acid l-Phosphono-pentane-1,2-dicarboxylic acid
2-Phosphono-propane-2,3-dicarboxylic acid 2-Phosphono-pentane-1,2-dicarboxylic acid 2-Phosphono-butane-2,3-dicarboxylic acid 2-Phosphono-pentane-2,3-dicarboxylic acid 4-Phosphono-octane-4,5-dicarboxylic acid 2-Phosphono-butane-1,2,4-tricarboxylic acid 2-Phosphono-pentane-1,2,4-tricarboxylic acid 2-Phosphono-hexane-1,2,4-tricarboxylic acid 2-Phosphono-heptane-1,2,4-tricarboxylic acid
3-Phosphono-pentane-2,3,5-tricarboxylic acid 3-Phosphono-heptane-1,3,4-tricarboxylic acid 3-Phosphono-hexane-2,3,5-tricarboxylic acid
4-Phosphono-octane-3,4,6-tricarboxylic acid
5-Phosphono-nonane-4,5,7-tricarboxylic acid 3-Phosphono-octane-2,3,5-tricarboxylic acid iP/~!~ ' J -5-1~59904 1,3-Diphosphono-butane-3,4-dicarboxylic acid 2~4-Diphosphono-pentane-4,5-dicarboxylic acid 3,5-Diphosphono-hexane-5,6-dicarboxylic acid 2,4-Diphosphono-heptane-1,2-dicarboxylic acid 1,3-Diphosphono-pentane-3,4-dicarboxylic acid 1,3-Diphosphono-hexane-3,4-dicarboxylic acid 2,4-Diphosphono-hexane-4,5-dicarboxylic acid 3,5-Diphosphono-octane-5,6-dicarboxylic acid 3,5-Diphosphono-nonane-5,6-dicarboxylic acid 3,5-Diphosphono-octane-2,3-dicarboxylic acid 1,3-Diphosphono-butane-2,3,4-tricarboxylic acid 1,3-Diphosphono-pentane-2,3,4-tricarboxylic acid 1,3-Diphosphono-heptane-2,3,4-tricarboxylic acid l-Phosphono-propane-1,2,3-tricarboxylic acid 2-Phosphono-butane-2,3,4-tricarboxylic acid 3-Phosphono-pentane-1,2,3-tricarboxylic acid 3-Phosphono-hexane-1,2,3-tricarboxylic acid 3-Phosphono-heptane-2,3,4-tricarboxylic acid 2-Phosphono-hexane-2,3,4-tricarboxylic acid 4-Phosphono-nonane-4,5,6-tricarboxylic acid 2-Phosphono-pentane-2,3,4-tricarboxylic acid 3-Phosphono-heptane-3,4,5-tricarboxylic acid l-Phosphono-2-methyl-propane-1,2,3-tricarboxylic acid 2-Phosphono-3-ethyl-butane-2,3,4-tricarboxylic acid 3-Phosphono-4-methyl-pentane-3,4,5-tricarboxylic acid 4-Phosphono-5-propyl-hexane-4,5,6-tricarboxylic acid 2-Phosphono-3 methyl-hexane-2,3,4-tricarboxylic acid 4-Phosphono-5-methyl-nonane-4,5,6-tricarboxylic acid l-Phosphono-2-methyl-pentane-1,2,3,-tricarboxylic acid 2-Phosphono-3-methyl-pentane-2,3,4-tricarboxylic acid 3-Phosphono-4-ethyl-heptane-3,4,5-tricarboxylic acid ~59904 1,1-Diphosphono-propane-2,3-dicarboxylic acid 2,2-Diphosphono-butane-3,4-dicarboxylic acid 3,3-Diphosphono-pentane-4,5-dicarboxylic acid 3,3-Diphosphono-hexane-1,2-dicarboxylic acid 2,2-Diphosphono-pentane-3,4-dicarboxylic acid 4,4-Diphosphono-heptane-2,3-dicarboxylic acid 1,1-Diphosphono-pentane-2,3-dicarboxylic acid 3,3-Diphosphono-heptane-4~5-dicarboxylic acid 1,1-Diphosphono-2-methyl-propane-2,3-dicarboxylic acid 2,2-Diphosphono-3-methyl-butane-3,4-dicarboxylic acid 2,2-Diphosphono-3-methyl~entan~3,4-dicarboxylic acid 3,3-Diphosphono-4-ethyl-heptane-4,5-dicarboxylic acid 2,2-Diphosphono-3-propyl-heptane-3,4-dicarboxylic acid l-Phosphono-butane-2,3,4-tricarboxylic acid l-Phosphono-pentane-2,3,4-tricarboxylic acid l-Phosphono-3-methyl-pentane-2,3,4-tricarboxylic acid l-Phosphono-3-methyl-heptane-2,3,4-tricarboxylic acid l-Phosphono-3-propyl-hexane-2,3,4-tricarboxylic acid l-Phosphono-3-methyl-butane-2,3,4-tricarboxylic acid 1-Phosphono-3-propyl-butane-2,3,4-tricarboxylic acid Particularly good results in respect of the stabilization of 99m Tc ions in the complex, the avoidance of formation of col-loidal particles, and the selectivity of the deposition of 99m Tc in the skeleton and in calcareous tumors are obtained with the partial sodium salts of the following preferred carboxyphosphonic acids:
1. Phosphono-ethane-1,2-dicarboxylic acid, 2:1 mixture of disodium : trisodium salts, 2. 1-Phosphono-propane-1,2-dicarboxylic acid, 2:1 mix-3o ture of disodium : trisodium salts, ~059904 3. 2-Phosphono-butane-1,2,4-tricarboxylic acid, trisodium salt.
These preferred carboxyphosphonic acid partial salts provide excellent absorption through the skeleton and very low absorption in the soft tissues except in calcareous tumors. They are predominantly suitable for identifying bone metastases of masto- or prostato- carcinomae.
The phosphonoalkanepolycarboxylic acids used can be produced according to known methods.
1-Phosphonoethane-1,2-dicarboxylic acid can be produced by reacting maleic acid ester with diethylphosphite in ~he presence of sodium alcoholate and by subsequent saponification of the ester.
2-Phosphonopropane-2,3-dicarboxylic acid can be obtained similarly, but another reaction with methyl chloride is effected before saponification.
l-Phosphonopropane-1,2,3-tricarboxylic acid can be pro-duced by reacting maleic acid ester with phosphonoacetic acid ester in the present of an alcoholate and by subsequent saponifi-cation of the ester thus obtained. l-Phosphonobutane-2,3,4-tri-carboxylic acid can be prepared by reacting dimethylphosphite withl-butene-2,3,4-tricarboxylic acid ester in the presence of sodium alcoholate and by subse~uently saponifying the resultant ester to form the desired acid.
By reacting methanediphosphonic acid alkylester with maleic acid alkylester in the presence of sodium alcoholate, an ester is obtained which is converted to l,l-diphosphono-propane-2,3-dicarboxylic acid by acid hydrolysis.
2-Phosphonobutane-2,3,4-tricarboxylic acid can be prepared by reacting ~-diethylphosphonopropionic acid methyl ester with maleic acid diethylester in the presence of an alcoholate and by subsequently saponifying the ester obtained.
2,2-Diphosphonobutane-3,4-dicarboxylic acld can be pre-pared by reacting maleic acid ester with ethane~ diphosphonic acid ester in the presence of sodium alcoholate ~ollowed by acid saponification of the product.
The other phosphonoalkanepolycarboxylic acids are obtained by analogous methods, citraconic acid ester bein~ preferably used instead of the ~aleic acid ester.
The water-soluble salts referred to above can be pro-duced by complete or partial neutralization o~ the acids with inorganic bases such as NaOH, KOH and NH40H, or with organic bases such as alkanolamines, and also with alkali metal-carbonates.
i The salts of tin (II), iron (II) and chromium (II) with pharmaceutically acceptable anions are added as the reducing agent. Chlorides and sulfates are preferred as anions because of-their universally acknowledged safety. Anhydrous tin (II) chlo-ride is preferred because of its high reducing power and also because of the absence of water of crystallization.
This addition serves to reduce the valence of the techne-tium in the pertechnetate ion which is produced by commercial 99 pertechnetate generators. The resulting low-oxidation state 99m Tc ion can then be complexed by one of the carboxy phosphonate complex formers mentioned and introduced into the organism for absorption by the skeleton or by calcareous tumorsin the organism.
Aqueous solutions of the above-mentioned phosphonic acids and tin ~II), iron (II) or chromium (II) salts have the undesir-able property of oxidizing or hydrolyzing over a relatively long periods of time in contact with air. This behavior can be over-come by sealing the solutions under nitrogen in ampoules, by preparing lyophilizates sealed under nitrogen or under vacuum tso that the mixture contains no free oxygen) or by preparing the B g composition of the invention in the form of an anhydrous tablet or dragee, so that the composition contains no water. The composi-tions of the invention may thus be treated and preserved in stable hydrous and anhydrous forms and are not added to the 99mpertech-netate solution until the solution is to be used. An excellent agent for bone and tumor radiography is thereby obtained which supplies superior scintillation images with minimal absorption of metal ions by structures in the body.
The required 99mTc activity is extremely low with sub-stantially 10 to 15 millicuries (mCi), and the quantity of tin (II)required for its reduction to lower valent state is also extremely small. The amount of reducing agent which is added is at least sufficient to reduce substantially all of the technetium in the pertechnetate ions to a lower valent state. The preferred quantity of tin or other reducing agent, however, is above the quantity stoichiometrically required for the complete reduction of the technetium content of 99m pertechnetate ion. Together with the again substantially larger amount of thè phosphonate a 99mTc-Sn-phosphonate complex (the exact structure of which is not known) is formed which is stabilized by excess phosphonate.
Preferably the compositions of the invention contain the reducing agent in amounts of 1 % to 5 % based on the weight of the phosphonic components present. It is added at least in suffi-cient amount to reduce substantially all the technetium present in the pertechnetate salt to lower valence state, and preferably is added in excess thereover.
It is advantageous for pharmaceutically-compatible fillers, such as glucose or sodium chloride, to be present as agents facilitating the handling and measuring of small quantities of the reducing complex-forming composition. Sodium chloride is preferred for this purpose since it helps to maintain the iso~onia even when the pertechneta~e solution is diluted with sterile water, as i5 mjp/ ~ 10-liOS9904 necessary occasionally.
The active components of the composition are mixed until homogeneous and the mixture in any particulate form is placed in standard glass ampoules, or the mixture is compressed to form tablets when it contains glucose, sodium chloride etc.
filler. However, it is pre~erable to produce a solution of the components which is put into standard ampoules in unit dose amount under nitrogen and lyophilized. The lyophilizate is stable under nitrogen or vacuum, that is, in the absence of free oxygen. An a~ueous isotonic solution of the components can also be preserved by excluding free oxygen, e.g., by maintaining the solution under nitrogen. The solution thus contains substantially no dissolved free oxygen.
The present invention will be further described, by means of the following Examples. These ~xamples illustrate pre-ferred embodiments of the invention and are not to be construed - in limitation thereof.
~A) COMPOSITIONS
: ~ ~ =
Into a standard glass ampoule (10 - 20 ml.) is poured an aqueous sterile solution containing 8 mg. of a 2:1 mixture of disodium and trisodium phosphonoethane-1,2-dicarboxylates, together with 2 ml. of water and 0.15 mg. of SnCl2. The solution is lyophilized and the ampoule is sealed under vacuum. For the purpose of use, the substance mixture is dissolved in sterile isotonic 99m pertechnetate solution and the resulting solution is injected intravenously into a mammal.
Into a graduated 10 ml. standard ampoule are poured 8 mg.
of a 2:1 mixture of disodium and trisodium l-phosphono-propane-1,2-dicarboxylates and 0.10 mg. of chromium (II) chloride dissolved mjp/,~
10599(~4 in 5 ml. of sterile aqueous solution and lyophilized.
Into a graduated 20 ml. standard ampoule are poured 8 mg.
of trisodium 2-phosphono-butane-1,2,4-tricarboxylate and 0.15 mg.
of iron ~I)sulfate dissolved in 5 ml. of sterile isotonic sodium chloride solution and processed according to Example 1.
Into a graduated 5 ml. standard ampoule are poured 8 mg.
of trisodium 2-phosphono-butane-1,2,4-tricarboxylate and 0.15 mg.
of tin (II) chloride dissolved in 5 ml. of sterile aqueous solution and lyophilized.
8 mg. of a 2:1 mixture of disodium and trisodium l-phos-phono-propane-1,2-dicarboxylates, 0.2 mg. of tin (II) chloride, 45 mg. of sodium chloride, and 26.8 mg. of glucose are compressed to form 80 mg. of mini-tablets. The tablets dissolved quickly in 5 ml. of sterile water and produce an isotonic solution.
4 mg. of a 2:1 mixture of disodium and trisodium l-phos-phono-propane-1,2-dicarboxylates, 4 mg. of trisodium 2-phosphono-butane-1,2~4-tricarboxylate, 0.2 mg. of iron (II) sulfate, 45 mg.
of sodium chloride, and 26.8 mg. of glucose are compressed to form 80 mg. of mini-tablets. The tablets dissolve quickly in 5 ml. of sterile water and produce an isotonic solution.
Into a 5 ml. standard ampoule are put 8 mg. of a 2:1 mix-ture of disodium and trisodium phosphono-ethane-1,2-dicarboxylates, 10599~4 0.07 mg. o~ tin (I~) chloride, and 0.08 mg. of iron (II) sulfate, dissolved in 5 ml. of sterile isotonic sodium chloride solution.
EXAMPLE ~
The procedure o~ Example 1 is repeated except that the - ~lask is ~lushed with dry nitrogen before sealing. Results are the same.
(B) From each of these compositions, after the addition of sub-stantially 5 ml. of sodium 99 pertechnetate solution with an activity of substantially 50 mCi/ml. and after careful shaking, an agent is obtained in dissolved form which can be dispensed to warm-blooded animals (i.e., to mammals) by intravenous injection.
In the case of adult humans weighing about 70 kg., about 1 ml. of the solution is used for skeletal scintillography, the solution being in~ected slowly. In the case of young mammals, correspond-ingly smaller quantities based on body weight may be used where necessary. Larger amounts are used for the scintillography of calcareous soft tissue, e.g. calcareous tumors or in cases of advanced calcification atherosclerosis. The solutions are in~ected preferably 1 - 2 hours after preparation.
~C) Solutions produced from the mixture according to Example 3 provided excellent results in skeletal scintillography. They proved particularly successful when searching for bone metastases in mammals having mastocarcinoma or prostatocarcinoma and they provide an ideal supplement to X-ray diagnostics.
Distribution studies in rats, which are a good model ~or the human being in these investigations, with activities of 0.01 to 1.0 mCi on 99 Tc, showed that in the case of the preferred compositions typically about 60% to 70% of the dose passes into - the skeleton. After th ~ hours 5% o~ the activity can still be 3o found in the blood, the remainder being excreted with the urlne.
.
~,~.
c.~
This distribution should be considered excellent. The optimum time for the scintillographical scanning is about 3 hours after injection. In the scintillography of calcareous soft tissue, such as tumors, muscular tissue or advanced calcification atheroscler-osis other times are optimum after injection. The optional time depends upon the regional blood clearance of the tissue being 7 examined.
1. Phosphono-ethane-1,2-dicarboxylic acid, 2:1 mixture of disodium : trisodium salts, 2. 1-Phosphono-propane-1,2-dicarboxylic acid, 2:1 mix-3o ture of disodium : trisodium salts, ~059904 3. 2-Phosphono-butane-1,2,4-tricarboxylic acid, trisodium salt.
These preferred carboxyphosphonic acid partial salts provide excellent absorption through the skeleton and very low absorption in the soft tissues except in calcareous tumors. They are predominantly suitable for identifying bone metastases of masto- or prostato- carcinomae.
The phosphonoalkanepolycarboxylic acids used can be produced according to known methods.
1-Phosphonoethane-1,2-dicarboxylic acid can be produced by reacting maleic acid ester with diethylphosphite in ~he presence of sodium alcoholate and by subsequent saponification of the ester.
2-Phosphonopropane-2,3-dicarboxylic acid can be obtained similarly, but another reaction with methyl chloride is effected before saponification.
l-Phosphonopropane-1,2,3-tricarboxylic acid can be pro-duced by reacting maleic acid ester with phosphonoacetic acid ester in the present of an alcoholate and by subsequent saponifi-cation of the ester thus obtained. l-Phosphonobutane-2,3,4-tri-carboxylic acid can be prepared by reacting dimethylphosphite withl-butene-2,3,4-tricarboxylic acid ester in the presence of sodium alcoholate and by subse~uently saponifying the resultant ester to form the desired acid.
By reacting methanediphosphonic acid alkylester with maleic acid alkylester in the presence of sodium alcoholate, an ester is obtained which is converted to l,l-diphosphono-propane-2,3-dicarboxylic acid by acid hydrolysis.
2-Phosphonobutane-2,3,4-tricarboxylic acid can be prepared by reacting ~-diethylphosphonopropionic acid methyl ester with maleic acid diethylester in the presence of an alcoholate and by subsequently saponifying the ester obtained.
2,2-Diphosphonobutane-3,4-dicarboxylic acld can be pre-pared by reacting maleic acid ester with ethane~ diphosphonic acid ester in the presence of sodium alcoholate ~ollowed by acid saponification of the product.
The other phosphonoalkanepolycarboxylic acids are obtained by analogous methods, citraconic acid ester bein~ preferably used instead of the ~aleic acid ester.
The water-soluble salts referred to above can be pro-duced by complete or partial neutralization o~ the acids with inorganic bases such as NaOH, KOH and NH40H, or with organic bases such as alkanolamines, and also with alkali metal-carbonates.
i The salts of tin (II), iron (II) and chromium (II) with pharmaceutically acceptable anions are added as the reducing agent. Chlorides and sulfates are preferred as anions because of-their universally acknowledged safety. Anhydrous tin (II) chlo-ride is preferred because of its high reducing power and also because of the absence of water of crystallization.
This addition serves to reduce the valence of the techne-tium in the pertechnetate ion which is produced by commercial 99 pertechnetate generators. The resulting low-oxidation state 99m Tc ion can then be complexed by one of the carboxy phosphonate complex formers mentioned and introduced into the organism for absorption by the skeleton or by calcareous tumorsin the organism.
Aqueous solutions of the above-mentioned phosphonic acids and tin ~II), iron (II) or chromium (II) salts have the undesir-able property of oxidizing or hydrolyzing over a relatively long periods of time in contact with air. This behavior can be over-come by sealing the solutions under nitrogen in ampoules, by preparing lyophilizates sealed under nitrogen or under vacuum tso that the mixture contains no free oxygen) or by preparing the B g composition of the invention in the form of an anhydrous tablet or dragee, so that the composition contains no water. The composi-tions of the invention may thus be treated and preserved in stable hydrous and anhydrous forms and are not added to the 99mpertech-netate solution until the solution is to be used. An excellent agent for bone and tumor radiography is thereby obtained which supplies superior scintillation images with minimal absorption of metal ions by structures in the body.
The required 99mTc activity is extremely low with sub-stantially 10 to 15 millicuries (mCi), and the quantity of tin (II)required for its reduction to lower valent state is also extremely small. The amount of reducing agent which is added is at least sufficient to reduce substantially all of the technetium in the pertechnetate ions to a lower valent state. The preferred quantity of tin or other reducing agent, however, is above the quantity stoichiometrically required for the complete reduction of the technetium content of 99m pertechnetate ion. Together with the again substantially larger amount of thè phosphonate a 99mTc-Sn-phosphonate complex (the exact structure of which is not known) is formed which is stabilized by excess phosphonate.
Preferably the compositions of the invention contain the reducing agent in amounts of 1 % to 5 % based on the weight of the phosphonic components present. It is added at least in suffi-cient amount to reduce substantially all the technetium present in the pertechnetate salt to lower valence state, and preferably is added in excess thereover.
It is advantageous for pharmaceutically-compatible fillers, such as glucose or sodium chloride, to be present as agents facilitating the handling and measuring of small quantities of the reducing complex-forming composition. Sodium chloride is preferred for this purpose since it helps to maintain the iso~onia even when the pertechneta~e solution is diluted with sterile water, as i5 mjp/ ~ 10-liOS9904 necessary occasionally.
The active components of the composition are mixed until homogeneous and the mixture in any particulate form is placed in standard glass ampoules, or the mixture is compressed to form tablets when it contains glucose, sodium chloride etc.
filler. However, it is pre~erable to produce a solution of the components which is put into standard ampoules in unit dose amount under nitrogen and lyophilized. The lyophilizate is stable under nitrogen or vacuum, that is, in the absence of free oxygen. An a~ueous isotonic solution of the components can also be preserved by excluding free oxygen, e.g., by maintaining the solution under nitrogen. The solution thus contains substantially no dissolved free oxygen.
The present invention will be further described, by means of the following Examples. These ~xamples illustrate pre-ferred embodiments of the invention and are not to be construed - in limitation thereof.
~A) COMPOSITIONS
: ~ ~ =
Into a standard glass ampoule (10 - 20 ml.) is poured an aqueous sterile solution containing 8 mg. of a 2:1 mixture of disodium and trisodium phosphonoethane-1,2-dicarboxylates, together with 2 ml. of water and 0.15 mg. of SnCl2. The solution is lyophilized and the ampoule is sealed under vacuum. For the purpose of use, the substance mixture is dissolved in sterile isotonic 99m pertechnetate solution and the resulting solution is injected intravenously into a mammal.
Into a graduated 10 ml. standard ampoule are poured 8 mg.
of a 2:1 mixture of disodium and trisodium l-phosphono-propane-1,2-dicarboxylates and 0.10 mg. of chromium (II) chloride dissolved mjp/,~
10599(~4 in 5 ml. of sterile aqueous solution and lyophilized.
Into a graduated 20 ml. standard ampoule are poured 8 mg.
of trisodium 2-phosphono-butane-1,2,4-tricarboxylate and 0.15 mg.
of iron ~I)sulfate dissolved in 5 ml. of sterile isotonic sodium chloride solution and processed according to Example 1.
Into a graduated 5 ml. standard ampoule are poured 8 mg.
of trisodium 2-phosphono-butane-1,2,4-tricarboxylate and 0.15 mg.
of tin (II) chloride dissolved in 5 ml. of sterile aqueous solution and lyophilized.
8 mg. of a 2:1 mixture of disodium and trisodium l-phos-phono-propane-1,2-dicarboxylates, 0.2 mg. of tin (II) chloride, 45 mg. of sodium chloride, and 26.8 mg. of glucose are compressed to form 80 mg. of mini-tablets. The tablets dissolved quickly in 5 ml. of sterile water and produce an isotonic solution.
4 mg. of a 2:1 mixture of disodium and trisodium l-phos-phono-propane-1,2-dicarboxylates, 4 mg. of trisodium 2-phosphono-butane-1,2~4-tricarboxylate, 0.2 mg. of iron (II) sulfate, 45 mg.
of sodium chloride, and 26.8 mg. of glucose are compressed to form 80 mg. of mini-tablets. The tablets dissolve quickly in 5 ml. of sterile water and produce an isotonic solution.
Into a 5 ml. standard ampoule are put 8 mg. of a 2:1 mix-ture of disodium and trisodium phosphono-ethane-1,2-dicarboxylates, 10599~4 0.07 mg. o~ tin (I~) chloride, and 0.08 mg. of iron (II) sulfate, dissolved in 5 ml. of sterile isotonic sodium chloride solution.
EXAMPLE ~
The procedure o~ Example 1 is repeated except that the - ~lask is ~lushed with dry nitrogen before sealing. Results are the same.
(B) From each of these compositions, after the addition of sub-stantially 5 ml. of sodium 99 pertechnetate solution with an activity of substantially 50 mCi/ml. and after careful shaking, an agent is obtained in dissolved form which can be dispensed to warm-blooded animals (i.e., to mammals) by intravenous injection.
In the case of adult humans weighing about 70 kg., about 1 ml. of the solution is used for skeletal scintillography, the solution being in~ected slowly. In the case of young mammals, correspond-ingly smaller quantities based on body weight may be used where necessary. Larger amounts are used for the scintillography of calcareous soft tissue, e.g. calcareous tumors or in cases of advanced calcification atherosclerosis. The solutions are in~ected preferably 1 - 2 hours after preparation.
~C) Solutions produced from the mixture according to Example 3 provided excellent results in skeletal scintillography. They proved particularly successful when searching for bone metastases in mammals having mastocarcinoma or prostatocarcinoma and they provide an ideal supplement to X-ray diagnostics.
Distribution studies in rats, which are a good model ~or the human being in these investigations, with activities of 0.01 to 1.0 mCi on 99 Tc, showed that in the case of the preferred compositions typically about 60% to 70% of the dose passes into - the skeleton. After th ~ hours 5% o~ the activity can still be 3o found in the blood, the remainder being excreted with the urlne.
.
~,~.
c.~
This distribution should be considered excellent. The optimum time for the scintillographical scanning is about 3 hours after injection. In the scintillography of calcareous soft tissue, such as tumors, muscular tissue or advanced calcification atheroscler-osis other times are optimum after injection. The optional time depends upon the regional blood clearance of the tissue being 7 examined.
Claims (14)
1. A composition for use in the preparation of aqueous solutions containing 99m technetium for use in the scintigraphy of bones and calcareous tumors, comprising:
(A) one or more water-soluble carboxyphosphonic compounds hav-ing three carboxylic acid groups selected from the group con-sisting of compounds of the formula:
I
wherein R represents a substituent selected from the group consisting of H and C1-3 alkyl;
R1 represents a substituent selected from the group consisting of -PO3H2 and ;
R2 represents a substituent selected from the group consisting of H, C1-3 alkyl, - CH2 - CHR - CO2H and , with the proviso that when R1 is - PO3H2, R2 is other than H or C1-3 alkyl; and the pharmaceutically - acceptable water-soluble salts of the above acids; and (B) a pharmaceutically acceptable water-soluble salt selected from the group consisting of tin (II), iron (II) and chromium (II) salts in less than stoichiometric quantities based on component (A).
(A) one or more water-soluble carboxyphosphonic compounds hav-ing three carboxylic acid groups selected from the group con-sisting of compounds of the formula:
I
wherein R represents a substituent selected from the group consisting of H and C1-3 alkyl;
R1 represents a substituent selected from the group consisting of -PO3H2 and ;
R2 represents a substituent selected from the group consisting of H, C1-3 alkyl, - CH2 - CHR - CO2H and , with the proviso that when R1 is - PO3H2, R2 is other than H or C1-3 alkyl; and the pharmaceutically - acceptable water-soluble salts of the above acids; and (B) a pharmaceutically acceptable water-soluble salt selected from the group consisting of tin (II), iron (II) and chromium (II) salts in less than stoichiometric quantities based on component (A).
2. A composition according to Claim 1 wherein the weight of component (B) is 1% to 5% of the weight of component (A).
3. A composition according to Claim 1 wherein the phosphonic compound is a partial salt.
4. A composition according to Claim 1 wherein the phos-phonic component comprises a material selected from the group consisting of 2-phosphono-butane-1,2,4-tricarboxylic acid and its trisodium salt.
5. A compound according to Claim 1 wherein component (B) is tin (II) chloride.
6. A composition according to Claim 1 in dry mix table-ted form.
7. A composition according to Claim 1 in sterile aque-ous solution form.
8. A sterile aqueous solution of a composition accord-ing to Claim 1 and a 99m technetate salt, substantially all the technetium content of said technetate having a valence less than 7.
9. A method of preparing a stable solution of a water-soluble salt of 99m technetium which is preferentially absorbed by bone and by calcareous tumors which comprises adding to an aqueous solution of a 99m pertechnetate salt a sufficient a-mount of a composition according to Claim 1 to reduce the technetium in said pertechnetate salt to a lower valency.
10. A method according to Claim 9 wherein said composi-tion is added to said pertechnetate solution in dry tableted form.
11. A composition for use in the preparation of aqueous solutions containing 99m technetium for use in the detection by scintigraphy of bones and calcareous tumors, comprising (A) 2-phosphono-butane-1,2,4-tricarboxylic acid,and its pharmaceutically-acceptable water-soluble salts; and (B) a pharmaceutically acceptable water-soluble salt selected from the group consisting of tin (II), iron (II) or chromium (II) salts in less than stoichiometric quantities based on component (A).
12. A composition according to claim 11 wherein the weight of component (B) is 1% to 5% of the weight of compon-ent (A).
13. A method of preparing a composition in unit dosage form for the detection by scintigraphy of bones and calcareous tumors by means of 99m technetium consisting essentially of (a) introducing into an ampoule under nitrogen or vacuum an aqueous solution of (A) one or more water-soluble carboxyphosphonic com-pounds having three carboxylic acid groups selected from the group consisting of compounds of the formula I
wherein R represents a substituent selected from the group consisting of H and C1-3 alkyl;
R1 represents a substituent selected from the group consis-ting of -PO3H2, and R2 represents a substituent selected from the group consist-ing of H, C1-3 alkyl, - CH2 - CHR - COOH, and , with the proviso that when R1 is - PO3H2, R2 is other than H or C1-3 alkyl; and the pharmaceutically-acceptable water-soluble salts of the above acids; and (B) a pharmaceutically acceptable water-soluble salt selected from the group consisting of tin (II), iron (II), or chromium (II) salts in less than stoichiometric quantities based on component (A), and (b) thereafter lyophilizing and sealing said aqueous solution in said ampoule under nitrogen or vacuum.
wherein R represents a substituent selected from the group consisting of H and C1-3 alkyl;
R1 represents a substituent selected from the group consis-ting of -PO3H2, and R2 represents a substituent selected from the group consist-ing of H, C1-3 alkyl, - CH2 - CHR - COOH, and , with the proviso that when R1 is - PO3H2, R2 is other than H or C1-3 alkyl; and the pharmaceutically-acceptable water-soluble salts of the above acids; and (B) a pharmaceutically acceptable water-soluble salt selected from the group consisting of tin (II), iron (II), or chromium (II) salts in less than stoichiometric quantities based on component (A), and (b) thereafter lyophilizing and sealing said aqueous solution in said ampoule under nitrogen or vacuum.
14. A method of preparing a composition in unit dos-age form for the detection by scintigraphy of bones and cal-careous tumors by means of 99m technetium, consisting essential-ly of (a) introducing into an ampoule under nitrogen or vacuum an aqueous isotonic solution of (A) one or more water-soluble carboxyphosphonic compounds having three carboxylic acid groups selected from the group consisting of compounds of the formula I
wherein R represents a substituent selected from the group consisting of H and C1-3 alkyl;
R1 represents a substituent selected from the group con-sisting of -PO3H2, and R2 represents a substituent selected from the group consis-ting of H, C1-3 alkyl, - CH2- CHR - COOH, and , with the proviso that when R1 is -PO3H2, R2 is other than H or C1-3 alkyl; and the pharmaceutically-acceptable water-soluble salts of the above acids; and (B) a pharmaceutically acceptable water-soluble salt selected from the group consisting of tin (II), iron (II), or chromium (II) salts in less than stoichiometric quantities based on component (A), and (b) thereafter sealing said aqueous isotonic solu-tion in said ampoule under nitrogen or vacuum.
wherein R represents a substituent selected from the group consisting of H and C1-3 alkyl;
R1 represents a substituent selected from the group con-sisting of -PO3H2, and R2 represents a substituent selected from the group consis-ting of H, C1-3 alkyl, - CH2- CHR - COOH, and , with the proviso that when R1 is -PO3H2, R2 is other than H or C1-3 alkyl; and the pharmaceutically-acceptable water-soluble salts of the above acids; and (B) a pharmaceutically acceptable water-soluble salt selected from the group consisting of tin (II), iron (II), or chromium (II) salts in less than stoichiometric quantities based on component (A), and (b) thereafter sealing said aqueous isotonic solu-tion in said ampoule under nitrogen or vacuum.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2543350A DE2543350C2 (en) | 1975-09-29 | 1975-09-29 | Preparations for the manufacture of ↑ 9 ↑ ↑ 9 ↑ ↑ m ↑ Technetium radio diagnostics |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1059904A true CA1059904A (en) | 1979-08-07 |
Family
ID=5957720
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA262,177A Expired CA1059904A (en) | 1975-09-29 | 1976-09-28 | Compositions for preparation of aqueous solutions of salts of lower valence99 technetium |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4133872A (en) |
| JP (1) | JPS5244244A (en) |
| AT (1) | AT357687B (en) |
| AU (1) | AU505503B2 (en) |
| BE (1) | BE846625A (en) |
| CA (1) | CA1059904A (en) |
| CH (1) | CH622705A5 (en) |
| DE (1) | DE2543350C2 (en) |
| DK (1) | DK149642C (en) |
| FR (1) | FR2325360A1 (en) |
| GB (1) | GB1501827A (en) |
| NL (1) | NL7609974A (en) |
| ZA (1) | ZA765815B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2755874A1 (en) * | 1977-12-15 | 1979-06-21 | Hoechst Ag | TIN-CONTAINING MARKING EQUIPMENT, PROCESS FOR THEIR MANUFACTURING AND PREPARATIONS FOR SKELETON REPRESENTATION |
| US4233284A (en) * | 1978-03-31 | 1980-11-11 | The Procter & Gamble Company | Stabilized radiographic scanning agents |
| US4232000A (en) * | 1978-06-28 | 1980-11-04 | The Procter & Gamble Company | Radioactive scanning agents with stabilizer |
| US4229427A (en) * | 1978-06-28 | 1980-10-21 | The Procter & Gamble Company | Radioactive scanning agents with hydroquinone stabilizer |
| US4515766A (en) * | 1980-06-23 | 1985-05-07 | The Massachusetts General Hospital | Labeled phosphonic acid compositions for investigations of in vivo deposits of calcium |
| US4512967A (en) * | 1982-08-02 | 1985-04-23 | E. I. Du Pont De Nemours And Compamy | Cationic technetium complexes useful as radiodiagnostic agents |
| DE3277201D1 (en) * | 1981-10-15 | 1987-10-15 | Du Pont | Cationic compounds useful for making radiodiagnostic agents |
| US4451450A (en) * | 1981-10-15 | 1984-05-29 | New England Nuclear Corporation | Cationic compounds useful for making radiodiagnostic agents |
| US4455291A (en) * | 1982-01-22 | 1984-06-19 | New England Nuclear Corporation | Accelerators for forming cationic technetium complexes useful as radiodiagnostic agents |
| JPS58141256A (en) * | 1982-02-16 | 1983-08-22 | Pilot Ink Co Ltd | Aqueous pigment ink for marking pen and preparation thereof |
| USRE32826E (en) * | 1982-08-02 | 1989-01-10 | E. I Du Pont De Nemours And Company | Cationic technetium complexes useful as radiodiagnostic agents |
| DE3237573A1 (en) * | 1982-10-09 | 1984-04-12 | Hoechst Ag, 6230 Frankfurt | TECHNETIUM-99M-TRI- AND TETRAPHOSPHONATES FOR SCINTIGRAPHIC PRODUCTION OF RES-CONTAINING ORGANS AND THE LYMPHATIC VESSELS AND METHOD FOR THE PRODUCTION THEREOF |
| JPS59113073A (en) * | 1982-12-18 | 1984-06-29 | Pilot Ink Co Ltd | Ink for marking pen |
| US4526776A (en) * | 1983-04-15 | 1985-07-02 | E. I. Du Pont De Nemours & Company | Cationic cyanato and thiocyanato complexes useful as radiodiagnostic agents |
| JPS61103841A (en) * | 1984-10-26 | 1986-05-22 | Nippon Mejifuijitsukusu Kk | Stable stannous chloride composition to be fed radioactivity technetium mark |
| DE3700326A1 (en) * | 1987-01-08 | 1988-07-21 | Henkel Kgaa | USE OF PHOSPHONOALCAN CARBON ACID PARTIAL ESTERS FOR METAL EXTRACTION |
| DE3733630A1 (en) * | 1987-10-05 | 1989-04-13 | Basf Ag | METHOD FOR PRODUCING WOOD MATERIALS |
| US5760021A (en) * | 1992-05-29 | 1998-06-02 | The Procter & Gamble Company | Phosphonocarboxylate compounds pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3989730A (en) * | 1972-06-15 | 1976-11-02 | Research Corporation | Bone-seeking technetium-99m complex |
| US3851044A (en) * | 1972-09-13 | 1974-11-26 | New England Nuclear Corp | Bone seeking technetium 99m stannous phosphate complex |
| US3965254A (en) * | 1973-05-23 | 1976-06-22 | The Procter & Gamble Company | Compositions for the treatment of calcific tumors |
| US3983227A (en) * | 1973-05-23 | 1976-09-28 | The Procter & Gamble Company | Dry mixture containing diphosphonates and a stannous salt useful in the preparation of Tc99M containing bone scanning agents |
| US3976762A (en) * | 1974-07-05 | 1976-08-24 | Minnesota Mining And Manufacturing Company | Multi-organ technetium complexes production and use thereof |
| US3974268A (en) * | 1975-05-30 | 1976-08-10 | Research Corporation | Bone-seeking technetium-99m imidodiphosphonate complex |
-
1975
- 1975-09-29 DE DE2543350A patent/DE2543350C2/en not_active Expired
-
1976
- 1976-08-26 AU AU17186/76A patent/AU505503B2/en not_active Expired
- 1976-09-08 NL NL7609974A patent/NL7609974A/en not_active Application Discontinuation
- 1976-09-10 DK DK408476A patent/DK149642C/en not_active IP Right Cessation
- 1976-09-23 US US05/725,772 patent/US4133872A/en not_active Expired - Lifetime
- 1976-09-27 BE BE170973A patent/BE846625A/en not_active IP Right Cessation
- 1976-09-28 GB GB40125/76A patent/GB1501827A/en not_active Expired
- 1976-09-28 ZA ZA765815A patent/ZA765815B/en unknown
- 1976-09-28 CA CA262,177A patent/CA1059904A/en not_active Expired
- 1976-09-28 CH CH1226676A patent/CH622705A5/de not_active IP Right Cessation
- 1976-09-28 AT AT718176A patent/AT357687B/en not_active IP Right Cessation
- 1976-09-29 FR FR7629196A patent/FR2325360A1/en active Granted
- 1976-09-29 JP JP51117088A patent/JPS5244244A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5244244A (en) | 1977-04-07 |
| ZA765815B (en) | 1977-12-28 |
| DE2543350A1 (en) | 1977-04-07 |
| FR2325360B1 (en) | 1979-01-12 |
| DK149642C (en) | 1987-04-21 |
| DK408476A (en) | 1977-03-30 |
| AU505503B2 (en) | 1979-11-22 |
| FR2325360A1 (en) | 1977-04-22 |
| GB1501827A (en) | 1978-02-22 |
| DE2543350C2 (en) | 1984-10-11 |
| ATA718176A (en) | 1979-12-15 |
| NL7609974A (en) | 1977-03-31 |
| DK149642B (en) | 1986-08-25 |
| US4133872A (en) | 1979-01-09 |
| BE846625A (en) | 1977-03-28 |
| JPS6133808B2 (en) | 1986-08-04 |
| CH622705A5 (en) | 1981-04-30 |
| AT357687B (en) | 1980-07-25 |
| AU1718676A (en) | 1978-03-02 |
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