DK156620B - STABLE COMPOSITION TO USE IN THE PREPARATION OF TECHNETIUM-99M-BASED RADIOGRAPHIC SCANNING MEASURES, PROCEDURE FOR PREPARING THE COMPOSITION AND USING THE SAME - Google Patents

Description

DK 156620 B

The invention relates to a stable composition for use in the preparation of technetium-99m-based radiographic scanning means, comprising a pertechnetate reducing agent.

5 Scintigraphy and similar radiographic methods are finding increasing use in biological and medical research and diagnostic work. In general, scintigraphic methods include the preparation of radioactive scanning agents which, upon introduction into a biological subject, are located in specific organs, tissues or skeletal material under observation. When the radioactive material is located in this way, traces, images or scintiographs of the distribution of the radioactive material can be made by various radiation detectors, such as scanning scanners, scintillation cameras and the like. The resulting distribution and corresponding relative intensities can then be used to indicate the position in which the tissue is located, as well as to indicate the occurrence of shear, pathological conditions and the like.

.20 For newly developed scintigraphic organ and skeletal scanning agents ÛQm, technetium-99m (Te) has been used as a radionuclide source.

QQm

Technetium-99m is obtained as a Tc solution in the pertechnetate oxidation QQm stage (TcO4) of commercial generators by eluting them with an isotonic saline solution. A commercial generator, currently available for the manufacture of a pertechnetate solution, is provided by E.R. Squibb Company and negotiated under the trademark

D

Technetope HiCon. In addition, methyl ethyl ketone-extracted pertech-netate is obtained in isotonic site from New Engl and Nuclear of Boston, Massachussetts, under the designation Instant Technetium.

30 QQm

Generally, -Tc-labeled scanning agents are prepared by combining an isotonic saline solution of pertechnetate-99m with a pertechnetate reducing agent, such as the stannous, ferrous or chromium salt of sulfuric acid or hydrochloric acid. Eg. describes Yano, et al. in Journal of 35 Nuclear Medicine, Volume 14, No. 2. Pages 73-78, and Subramanian, et al. in Journal of Nuclear Medicine, Vol. 13, No. 12, pages QQm 947-49, Tc skeletal scanning agents prepared by mixing a pertechnetate solution with an aqueous solution of a stannophospho-reducing agent and distanno-ethane-1-hydroxy-1 , l-diphosphonate;

DK 156620B

2

Although such methods provide scanning means that are better than those available so far, they have disadvantages. In particular, it has been found that conventional technetium-containing scintigraphic scanning agents are unstable in the presence of oxygen and radiolysis products. Accordingly, the previously described technetium-based scanning means have been rendered oxygen-free by saturating the agent with oxygen-free nitrogen gas or by preparing the agent in an oxygen-free atmosphere or in a vacuum. Even such careful precautions are not entirely satisfactory as it is extremely difficult to maintain oxygen-free conditions. Eg. For example, pertechnetate solutions may contain dissolved oxygen which, if not detected before combination with the per-technetate reducing agent, forms a product which is unstable and results in the formation of free pertechnetate-99m.

Further, from the description to Danish Immigration Publication No. 128,555, a method for the preparation of a diagnostic composition based on an iron complex marked with 99-m-Tc is known. According to this process, a solution of ascorbic acid and ferric chloride is added to a pertechnetate solution. The present invention differs from the process described in that the critical amount of ascorbic acid according to the present invention relates to either the total composition containing the reducing agent, but without the presence of pertechnetate solution (in the example described in Example 1), or in relation to an The pertechnetate solution (described in Example 2) is neither described nor proposed in the patent.

From the specification of US Patent No. 3,740,418, a preparation of radioactive scanning agents is known, and more particularly, a combination of a ferric salt with ascorbic acid is disclosed. The preferred reagent solutions prepared include ratios of from 0.5 to 25 mg / ml of ferric chloride-6H 0.5 to 25 mg / ml ascorbic acid with equal amounts of ferric chloride »6H2O and ascorbic acid, cf. column 2 lines 30-35 of the patent. Thus, in this patent there is no indication or indication of the critical extent of ascorbic acid which is the subject of the invention according to the present application. According to the patent, the amounts of ascorbic acid actually used in the Examples are far greater than what is provided by the present invention.

3 DK 156620

Finally, from Danish Immigration Publication No. 131,546 there is known a method for preparing injectable preparations of technetium-99m ions. Example 3 describes how 20 mg of ascorbic acid is deposited on the sediment prepared according to Example 2 of the disclosure, which sediment is an iron hydroxide precipitate.

It is apparent from the example that the amount of ascorbic acid which occurs in connection with the technetium solution far exceeds the scope used in the present invention. The resulting composition prepared according to the present disclosure will be 10 fold worse than that which can be prepared with the composition of the present invention.

The invention is based on the recognition that a relatively small amount of ascorbic acid or pharmaceutically acceptable salts or esters thereof can be used to produce highly stable technetium-99m-based scintigraphic scanning agents. As mentioned earlier, Qûm is manufactured

Tc-labeled scanning means by mixing a pertechnetate solution with a pertechnetate reducing agent. It has been found that small amounts of ascorbic acid, its salts or esters, can be combined with either the pertechnetate solution or the pertechetate reducing agent prior to their mixing, thereby providing agents such as QQm which are particularly suitable for the preparation of improved Tc scanning agents. . The composition of the invention is thus characterized in that it also comprises an effective amount of not more than 25% by weight of ascorbic acid or a pharmaceutically acceptable site or pharmaceutically acceptable ester thereof. In a particularly preferred embodiment, the composition is peculiar in that it comprises no more than approx. 10% by weight of ascorbic acid or a pharmaceutically acceptable ester or a pharmaceutically acceptable ester thereof.

30

Ascorbic acid, the most preferred compound of the invention, occurs naturally in a wide variety of plant and animal species. Particularly good sources include citrus fruits, acerola and fresh tea leaves. Ascorbic acid can be synthesized by the acid-catalyzed oxidation of 35 L-sorbose.

The pharmaceutically acceptable salts and esters of ascorbic acid can be prepared by conventional well known neutralization and esterification methods. A thorough discussion of suitable procedures for 4

DK 156620 B

preparation of ascorbic acid salts and esters can be found in The Chemistrv of Qraanic Compounds. Part Three, Noller (ed.) 1966. In general, the pharmaceutically acceptable salts of ascorbic acid can be prepared by acid-base neutralization using an equivalent of a selected base. Similarly, the pharmaceutically acceptable esters of ascorbic acid can be prepared by reacting equimolar amounts of the acid with selected all alcohols.

In practice, the salts and esters of ascorbic acid suitable for use in the present invention may be selected on the basis of their solubility in a pertechnetate solution. It is, of course, preferred that the salts and esters of ascorbic acid be readily soluble in a pertechnetate solution. Accordingly, suitable ascorbic acid salts include alkali metal, alkaline earth metal, heavy metal and ammonium salts.

The alkali metal salts, such as the sodium, potassium and lithium salts of ascorbic acid, are readily digestible and are therefore preferred for use herein. Various ascorbic acid ammonium salts wherein the cations are N (R ') ^ are also suitable for use herein. Such include, for example, alkylammonium, alkanol, ammonium and arylammonium salts of ascorbic acid. Of course, the solubility of ammonium salts depends largely on the number and nature of the substituent groups on the nitrogen atom. Generally, and as used herein, preferred soluble ammonium salts include those wherein each R 'is either hydrogen or C 1 -C 6 hydrocarbyl. Non-limiting examples of pharmaceutically acceptable ammonium salts of ascorbic acid useful for the invention include ammonium, methylammonium, dimethylammonium, tetramethylammonium, bis (tetramethylammonium) -, 2-hydroxypropylammonium, bis (2) ) -, ethanol ammonium, diethanol ammonium, triethanol ammonium, bis (triethanol ammonium), phenylammonium, naphthylammonium and quinolylammonium salts.

The alkaline earth metal salts, e.g. the calcium and magnesium salts, although less soluble, are also suitable for use herein.

The heavy metal salts, e.g. the iron and tin salts, are also useful for use herein.

The pharmaceutically acceptable esters of ascorbic acid which are readily soluble in pertechnetate solutions include, e.g. Cj-Cg 5

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1 aversion alkyl esters, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl esters of ascorbic acid.

The invention further relates to a process for preparing 5 technetium-based radiographic scanning agents, wherein a per-technetate-reduced agent is admixed with ascorbic acid or a pharmaceutically acceptable site or ester thereof, the method being characterized in that the ascorbic acid, its site or ester is used. an effective amount not exceeding 25% by weight.

10

The choice of the reducing agent is not critical. In this context, "pertechnetate reducing agent" should include compounds, complexes, el. like. containing a reducing ion capable of reducing heptavalent technetium to tetravalent and / or pentavalent technetium. Suitable pertechnetate reducing agents can be combined with numerous additives such as fillers and skeletal or other organ specific carriers. Eg. For example, skeletal scanning agents have been prepared using metal salts of sulfuric acid and hydrochloric acid, such as stannous chloride, chromochloride, and ferrous sulfate, as the pertechnetate reducing agent in combination with various organic phosphonates and / or phosphates as a bone-bearing carrier. Pulmonary and organ scanning agents have been prepared using buffered solutions of a denatured microprotein to which divalent tin is bound as the pertechnetate reducing agent. Other systems capable of reducing pertechne-tat-99m include e.g. acid thiosulfates, acid hydrogen sulfates, iron colloids and acid borohydrides. From the disclosures of U.S. Patent Nos. 3,735,001, 1973; No. 3,863,004, 1975; No. 3,466,361, 1969; No. 3,720,761, 1973; No. 3,723,612, 1973; No. 3,725,295, 1973; no.

No. 3,803,299, 1974 and No. 3,749,556, 1973, various pertechnetate reducing agents are known comprising reducing ions which are capable of reducing heptavalent pertechnetate to tetravalent and / or pentavalent technetium-99m.

The concentration of ascorbic acid compound used in embodiments of the invention in which the ascorbic acid compound is combined with a reducing agent will be contingent upon the final use of the intermediate and the concentration of inert materials or fillers used. However, it has been found that 6

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concentrations of the ascorbic acid compound of over ca. 25% generate the formation of an acceptable scanning agent and should be avoided. For most forms, concentrations from approx. 0.1% to 5% appropriate.

3 Where it is desirable to incorporate the ascorbic acid compound directly into the pertechnetate solution, the ascorbic acid compound may simply be dissolved either during or after elution of the pertechnetate generator. The elution process is thoroughly described in the specification of US Patent No. 3,369,121.

In embodiments of the present invention in which the ascorbic acid compound is dissolved in a pertechnetate solution, the concentration of the ascorbic acid compound will vary with the degree of salt dilution. It has been found that a concentration of the ascorbic acid compound in excess of ca. 0.1% generates the formation of an acceptable scanning agent. For most purposes, a concentration of not more than 0.1%, preferably not more than 0.05% (weight basis) is appropriate. A concentration between approx. 0.01% and approx. 0.001% is acceptable for many purposes.

The invention also relates to the use of the composition of the invention for the preparation of a technetium-99m-based radiographic scanning agent, whereby the composition is dissolved in an oxidized pertechnetate solution in such an amount that the ascorbic acid, its pharmaceutically acceptable site or ester is present. amount of 33 not more than 0.1% by weight.

Appropriate concentrations of the ascorbic acid compound will vary somewhat with the pH conditions. For the purposes of the present invention, a normal physiological pH of about 5 to approx. 7th

30

A preferred embodiment of the process of the invention comprises co-dissolution of ascorbic acid compound and a pertechnetate reducing agent in a pertechnetate solution. As described above, the ascorbic acid compound and the pertechnetate reducing agent can be dissolved either simultaneously or in succession in the pertechnetate solution. Both co-solution methods result in an improved technetium-based scanning agent.

The scanning agent can be formed by the direct addition of a 7

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pertechnetate enrichment for a composition comprising: a pertechnetate reducing agent containing a salt-reducing metal ion, such as stannous chloride, from ca. 0.3 to approx. 1.5% by weight of an ascorbic acid compound and a skeleton-specific carrier compound in the form of a mono-, di- or polyphosphonate. A wide range of mono-, di- and polyphosphonates is now known to be concentrated in the skeleton after injection of solutions thereof in a patient. Effective types thereof include mono-, di- and polyphosphonates of the general formulas: 10 - H - R - C - R (I) PO, H, L 'Jn 15 where each R is hydrogen or CH 2 OH and n is one integers between 3 and 10, PO, H, | 3 2 20 R 1 -C-R 2 (II) po 3 h 2 where R 1 is hydrogen, alkyl containing from 1 to about 20 carbon atoms, alkenyl containing from ca. 2 to approx. 20 carbon atoms, aryl (e.g. phenyl, naphthyl), phenylethenyl, benzyl, halogen (e.g.

chlorine, bromine and fluoro), hydroxyl, amino, substituted amino (e.g., dimethylamino, diethylamino, N-hydroxy-N-ethylamino, acetylamino), -CH2C00H, -CH2PO3H2, CH (PO3H2) (OH) or - [CH 2 C (PO 3 H 2) 2] n ~ H where n is 1-15, R 2 is hydrogen, lower alkyl (e.g., methyl, ethyl, propyl and butyl), amino, benzyl, halogen (e.g. (chlorine, bromine and fluorine), hydroxyl, -CH2C00H, -CHgPOgHg or -CH2CH2PO3H2, PO, H, <-1 | 2 (CH CH) „CH-C-OH (III) 35. 2 "I | po3h2 where n is an integer from 3 to 9, 8

DK 156620 B

ΡΟ, Ηο ι3 2 R3 ^ R3 5 R3 N R3 (IV) H2 ° 3P— ^ Ç-P03H2 R3 R3

Where R 3 is hydrogen or 1 aryl alkyl (e.g. methyl, ethyl, propyl 10 and butyl), -c-po 3 H 2 CF 2) n (V) 15 -c-po 3 H 2 where n is an integer from 2 to 4, 2 ° O OH-P-OH n I C-O-P-OH (VI)

1 I

OH-P-0-C

25 ° OH-P-OH

H

0

C00H COOH

I I

C == c (VII)

I I

H PO3H2 H 0 i_ / 35 H I I (VIII)

0 = P-OH 0 = P-OH

I I

OH OH

9

DK 156620 B

OH

H 0 “P-OH

I I (IX)

c -'C

5 I I

H 0 “P-OH

OH

COOH COOH

m I I

X-C-C-Y (X)

I I

Wherein X and Y are each hydrogen or hydroxy, as well as the non-toxic salts of all of the above phosphonates, which in a largely I® neutral aqueous solution will react with the reducing / complexing materials below, i.e. stanno, ferro or chromo salts to form the corresponding stanno, ferro or chromo phosphonate salts. Suitable reactive phosphonate salts (hereinafter referred to as pharmaceutically acceptable salts) for use in the present invention include sodium, potassium, ammonium and substituted ammonium salts (e.g., mono-, di- and tri-ethanol amine and quaternary ammonium salts) of the above phosphonates and mixtures thereof.

OC

Useful polyphosphonates of formula (I) above include propane-1,2,3-triphosphonic acid, butane-1,2,3,4-tetraphosphonic acid, hexane-1, 2,3,4,5,6-hexaphosphonic acid, hexane-1 -hydroxy-2,3,4,5,6-penta-phosphonic acid, hexane-1,6-dihydroxy-2,3,4,5-tetraphosphonic acid, pentane-1,2,3,4,5-pentaphosphonic acid, heptane -1,2,3,4,5,6,7-heptaphosphonic acid, nn octane-1,2,3,4,5,6,7,8-octaphosphonic acid, nonan-1,2,3,4,5, 6,7,8,9-nonaphosphonic acid, decane-1, 2,3,4,5,6,7,8,9,10-decaphosphonic acid and the pharmaceutically acceptable salts of these acids, e.g. sodium, potassium, ammonium, triethanol, ammonium,. diethanol ammonium and monoethanolammonium salts.

35

Propane-1,2,3-triphosphonic acid and its salts can be prepared by a process described in U.S. Patent No. 3,743,688.

Butane-1,2,3,4-tetraphosphonic acid and its salts can be prepared at 10

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a method described in the specification of US Patent No. 3,755.

504th

The higher aliphatic polyphosphonates and their salts can be prepared by the process described in U.S. Patent No. 3,584,035, 1971.

Among useful polyphosphonates included in the above general formula (II) are ethane-1-hydroxy-1,1-diphosphonic acid, methane diphosphonic acid, methane hydroxydiphosphonic acid, ethane-1,1,2-triphosphonic acid, propane-1,1,3,3 -tetraphosphonic acid, ethane-2-phenyl-1,1-diphosphonic acid, ethane-2-naphthyl-1,1-diphosphonic acid, methane phenyldiphosphonic acid, ethane-1-amino-1,1-diphosphonic acid, methanedichlorodiphosphonic acid, nonane-5,5-diphosphonic acid , n-pentane-1,1-diphosphonic acid, methanedifluorodiphosphonic acid, methane dibromo diphosphonic acid, propane-2,2-diphosphonic acid, ethane-2-carboxy-1,1-diphosphonic acid, propane-1-hydroxy-1, 1,3-triphosphonic acid, ethane-2-hydroxy-1,1,2-triphosphonic acid, ethane-1-hydroxy-1,1,2-triphosphonic acid, propane-1,3-diphenyl-2,2-diphosphonic acid, nonan-1,1-diphosphonic acid, hexadecane-1,1-diphosphonic acid, pent-4-ene-1-hydroxy-1,1-diphosphonic acid, octadec-9-ene-1-hydroxy-1,1-diphosphonic acid , 3-phenyl-1,1-diphosphone-prop-2-ene, octane-1,1-diphosphonic acid, dodecane-1,1-diphosphonic acid, phenylaminomethane diphosphonic acid N, N-dimethylaminomethane diphosphonic acid, N- (2-dihydroxyethyl) -aminomethane diphosphonic acid, N-acetylaminomethane diphosphonic acid, aminomethane diphosphonic acid, dihydroxymethane diphosphonic acid, e.g. sodium, potassium, ammonium, triethanolammonium, diethanol ammonium and monoethanolammonium salts.

Ethane-1-hydroxy-1,1-diphosphonic acid, a particularly preferred polyphosphonate, has the molecular formula CH3C (OH) (PO3H2) 2 · (After the radical nomenclature, the acid can also be designated 1-hydroxyethylidene diphosphonic acid).

Although any pharmaceutically acceptable site of ethane-1-hydroxy-1,1-diphosphonic acid may be used in the practice of the invention, mixtures of the disodium and trisodium salts are particularly preferred. The other sodium, potassium, ammonium and mono-, di- and tri-ethanolammonium salts and mixtures thereof are also suitable, provided caution is advised. regulation of the total

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π inclusion of cation types in the salt composition. These compounds can be prepared by any suitable process. However, a particularly preferred method is described in the specification of U.S. Patent No. 3,400,149, 1968.

5

Methane hydroxydiphosphonic acid and related compounds which may be used in the present invention may be e.g. is prepared by reaction of phosgene with an alkali metal dialkyl phosphite. A complete description of these compounds and a process for their preparation can be found in the specification of U.S. Patent No. 3,422,137, 1969.

Methandihydroxydiphosphonic acid and salts useful for the present invention and a process for their preparation are disclosed in the specification of US Patent No. 3,497,313, 1970.

15

Methanediphosphonic acid and related compounds useful for the present invention are described in detail in the specification of U.S. Patent No. 3,213,030, 1965. A preferred process for preparing these compounds is known from the specification 20 of U.S. Patent No. 3,251,907, 1966th

Ethane-1,1,2-triphosphonic acid and related compounds which can be used in the composition of the invention and a process for their preparation are fully described in the specification of US 25 Patent No. 3,551,339, 1970.

Propane-1,1,3,3-tetraphosphonic acid and related compounds useful in the present invention as well as a process for their preparation are fully described in the specification of U.S. Patent No. 3,400,176, 1968. methylene diphosphate polymers can be prepared by polymerization of ethylene-1,1-diphosphonate.

Pentane-2,2-diphosphonic acid and related compounds can be prepared by that of G.M. Kosolopoff in J. Amer. Chem. Soc., 75, 1500 (1953).

Useful phosphonates of the above formula (III) include the following: 12

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Methancyclohexylhydroxydiphosphonic acid Methancyclohexylhydroxydiphosphonic acid Methancycloheptylhydroxydi phosphonic acid Methancyclooctylhydroxydi phosphonic acid

Methancyclononyl hydroxydi phosphonic acid Methancyclodecyl hydroxydi phosphonic acid.

All the sodium, potassium, ammonium, monoethanolammonium, diethanol-10 ammonium and triethanol ammonium salts of the above-mentioned methane cycloalkylhydroxydiphosphonic acids and any pharmaceutically acceptable site of these acids also selectively contribute to the skeleton.

The phosphonates of formula (III) can be prepared by methods fully described in the specification of U.S. Patent No. 3,584.

125, 1971.

The preferred phosphonates of formula (IV) are for the formis tris (phosphonomethyl) amine, tris (1-phosphonoethyl) amine, tris (2-phosphono-2-propyl) amine and their pharmaceutically acceptable salts. Tris (phosphonomethyl) amine is particularly preferred. The following are examples of compounds which may also be used: (a) bi s (phosphonomethyl) -1-phosphonoethylamine, (b) bis (phosphonomethyl) -2-phosphono-2-propylamine, (c) bi s (1- phosphonoethyl) phosphonomethylamino, (d) bi s (2-phosphono-2-propyl) phosphonomethylamino, (e) tris (1-phosphono-1-pentyl) amine, (f) bis (phosphonomethyl) 2-phosphono-2- hexyl amine; and (g) the pharmaceutically acceptable salts of the acids (a) - (f), e.g. the sodium, potassium, ammonium, triethanol ammonium, diethanol ammonium and the monoethanolammonium salts.

The tris (phosphonoalkyl) amines can e.g. is prepared by first producing the corresponding ester according to the general reaction: î1? I1

3 (R0) 2P (O) (H) +3 C = O + NH 3 - [(R0) 2-P-C] 3N

r2 r2 13

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wherein R is alkyl and R 1 and R 2 are hydrogen or 1 lower alkyl.

The free acids can be prepared by hydrolysis of the ester using strong mineral acids, such as hydrochloric acid. The salts are naturally prepared by neutralizing the acid with the base of the desired cation. The preparation of tris (phosphonoalkyl) amines is fully described by Irani et al. in the specification of CA Patent No. 753,207, 1967.

The phosphonates of formula (V) include the following: (1) 3,3,4,4,5,5-hexafluoro-1,2-diphosphonocyclopent-1-ene, (2) 3,3,4,4-tetrafluoroalkyl 1,2-diphosphonocyclobut-1-ene, and (3) 3,3,4,4,5,5,6,6-octafluoro-1,2-di phosphonocyclohexen-1-ene.

The perfluorodiphosphonocycloalkenes may e.g. are prepared by reacting trialkylphosphites with 1,2-dichloro-perfluorocycloalk-1-enes according to those of Frank in J. Ora. Chem. 31, No. 5, in the procedures described in 1521.

The phosphonate of formula (VI) is herein referred to as cyclic tetraphosphonic acid. This compound and its pharmaceutically acceptable salts can be prepared by any suitable method. However, a particularly preferred method is known from the disclosure of U.S. Patent No. 3,387,024, 1968.

25

Useful phosphonates encompassed by the above formula (VII) are ethene-1,2-dicarboxy-1-phosphonic acid and the pharmaceutically acceptable salts thereof, e.g. the sodium, potassium, ammonium, triethanol ammonium, diethanol ammonium and monoethanolammonium salts. Although the above formula (VII) is representative of cis isomers. the corresponding trans isomers are also useful herein. Reference hereinafter to the ethene-1,2-dicarboxy-1-phosphonic acid and its salts, unless otherwise indicated, should include the cis and trans isomers and mixtures thereof.

35

Ethene-1,2-dicarboxy-1-phosphonic acid and related compounds useful for the present invention can be prepared by reacting an ester of acetylenedicarboxylic acid and a dialkylphosphite followed by hydrolysis and saponification. The procedure is

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14 described in greater detail in U.S. Patent No. 3,584,124, 1971.

The sodium salt of formula (VIII) can be prepared by the rearrangement reaction of a 2-haloethane-1-hydroxy-1,1-diphosphonic acid with approx. 35 equivalents of sodium hydroxide as described in the description to US

Patent No. 3,641,126.

The phosphonate of formula (IX) can be prepared by the process described in the specification of DOS No. 2,026,078.

10

Useful carboxyphosphonates of the above formula (X) include ethane-1,2-dicarboxy-1,2-diphosphonic acid, ethane-1,2-dicarboxy-1,2-dihydroxy-1,2-diphosphonic acid, ethane-1,2 -dicarboxy-1-hydroxy-1,2-di-phosphonic acid as well as the pharmaceutically acceptable salts of these acids, e.g. the sodium, potassium, ammonium, triethanol ammonium, diethanol ammonium and monoethanolammonium salts.

Ethane-1,2-dicarboxy-1,2-diphosphonic acid, which is a preferred carboxyphosphonate of the present invention, has the molecular formula CH (COOH) (PO ^Hg) CH (COOH) (PO ^Hg) - The most appropriate crystallizable salts of this acid are obtained when 3, 4 or 5 of the acid hydrogens are replaced by sodium.

Although any pharmaceutically acceptable site of ethanol-1,2-dicarboxy-1,2-diphosphonic acid may be used to practice the invention, the tetrasodium dihydrogen salt, trisodium trihydrogen salt, di sodium tetrahydrogen salt, mononatri umpentahydrogen salt, are useful. The other potassium, ammonium, and mono-, di- and tri-ethanol ammonium, etc. salts and mixtures thereof are also useful, provided caution is advised. regulation of the total uptake of cation types into the salt composition.

Ethane-1,2-dicarboxy-1,2-diphosphonic acid and suitable salts thereof can be prepared in any convenient manner. Eg. may 35 that of Pudovik in "Soviet Research on Organo-Phosphorus Compounds," 1949-56, they! III, 547-85c is used to prepare the ester of ethane-1,2-dicarboxy-1,2-diphosphonic acid, which in turn can be converted to the free acid form by conventional hydrolysis reactions. Neutralization with alkali compounds, such as sodium hydroxide,

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Potassium hydroxide, carbonates and the like. can be used to produce a desired site of the acid. A more detailed description of the preparation of these compounds is disclosed in the specification of U.S. Patent No. 3,562,166, 1971.

5

Ethane-1,2-dicarboxy-1,2-dihydroxy-1,2-diphosphonic acid and related compounds useful for the present invention can be prepared by reacting an ester of ethane-1,2-dicarboxy-1,2 diphosphonic acid and an alkali metal hypohalite followed by hydrolysis of saponification. This process is described in more detail in the specification of U.S. Patent No. 3,579,570, 1971.

Mixtures of any of the above phosphonic acids and / or salts may be used to practice this invention.

In a highly preferred embodiment of the invention, mixtures of disodium and trisodium-ethane-1-hydroxy-1,1-diphosphonate salts are used, wherein the mole ratio of the disodium salt to the trisodium salt is from ca. 4: 1 to 1: 1, and especially from 3: 1 to 1: 1, in the pertechnetate reducing agent together with an ascorbic acid compound and a reducing metal ion. These preferred phosphonate / reducing ion / ascorbic acid compound mixtures provide particularly good scintiscans (extremely good stability and skeletal uptake and only slight tissue uptake).

25

However, it is preferred to limit the amount of the stannous, chromo or ferrous salts of the polyphosphonates to not more than ca. 10% of the total.

The following examples show compositions made according to the invention (the amounts of each component are given in milligrams): 35

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16 to »—1 cx>» - <

~ * h * O

XI 00 CM O CM

LO

an i — i i — i

µπ i — I O N O

CM

i — i CO

i-i CT) i-f '-I

· —11 * · *> Λ "

> IX) O O

CO i — I

i- <| and i— <

i-il ·> I "*» O

> 1 LO O CM

LO

an i — i i— * I — il ~ ~ * ·> ίο o o

CM

LO

i-i '-I

σι * - _r> 1 ο ι ~~ o m cm

_IN

LU

Q_

Σ CO

11 1 σι r — I '—I

V l-il LO 0 ^ 0

u] CM

LO

and —i 1 F — il * 1 ·> **

I — il LO O N O

—In [CM

LO

and -! 1 1-l] ·> »" lo · —'1 ίο o ^ o

.-I CM

LO

and r- · <i-il «> λ * · in o p. o

CM

p

• P tO ni C

in COQ) l >> O -E S- X X J = o.> i £ * X O 0.1 / 110 2

0 s- w o c -P

S- -O O -C O s-

Ό >> .c o .c p

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DK 156620 B

17

Each of the above compositions, after addition of approx. 5 ml of a pertechnetate-99m solution and shaking well a skeletal scanning agent suitable for intravenous injection in a patient with a stability of not more than three hours. Preferably 5 is used. 1 ml solution in an adult with a body weight of approx.

50-100 kg and it is injected slowly over a period of approx. 30 sec. Preferably, administration is made within ca. three hours from manufacture. However, the compositions may contain products or fraction of the above amounts, so that from a single composition sufficient means can be made to make any desired number of scans.

The following example shows a pertechnetate solution in which an ascorbic acid compound is dissolved:

Example XI

A collection vessel containing 0.1 mg of sodium ascorbate is placed at the elution opening of a pertechnetate-99m generator. Oxidized saline eluate is collected in the vessel and dissolves the sodium ascorbate completely.

Ca. 5 ml of the oxidized pertechnetate solution with dissolved sodium ascorbate is added to a pertechnetate reducing agent containing 5.9 mg of the sodium salt of ethane-1-hydroxy-1,1-diphosphonic acid and 0.16 mg of stannous chloride. After thorough shaking, a stable scanning agent is prepared which is suitable for intravenous injection into a patient.

In the above example, sodium ascorbate is replaced by equivalent amounts of ascorbic acid, methyl ascorbate, ethyl ascorbate, isopropyl ascorbate, butyl ascorbate, diethanolamine ascorbate, calcium ascorbate, magnesium ascorbate and potassium ascorbate, stannous ascorbate, stannous ascorbate, stannous ascorbate.

35

Claims (11)

A stable composition for use in the preparation of technetium-99m-based radiographic scanning means, comprising a pertechnetate reducing agent, characterized in that it also comprises an effective amount of not more than 25% by weight of ascorbic acid or a pharmaceutically acceptable site or a pharmaceutically acceptable ester thereof. Composition according to claim 1, characterized in that it comprises no more than approx. 10% by weight of ascorbic acid or a pharmaceutically acceptable ester or a pharmaceutically acceptable ester thereof. Composition according to claim 1, characterized in that the pertechnetate reducing agent is selected from the group consisting of metal salts of sulfuric acid or hydrochloric acid. Composition according to claim 1, characterized in that it further comprises an organ-specific carrier. 20 Composition according to claim 4, characterized in that the organ-specific carrier is the sodium salt of ethane-1-hydroxy-1,1-di-phosphonic acid. Process for the preparation of the composition according to claim 1, wherein a pertechnetate reducing agent is admixed with ascorbic acid or a pharmaceutically acceptable ester or a pharmaceutically acceptable ester thereof, characterized in that the ascorbic acid, its site or ester is used in an effective amount of 30 above 25% by weight. Process according to claim 6, characterized in that the ascorbic acid, its site or its ester is used in an amount not exceeding 10% by weight. 35 8. A process according to claim 6, characterized in that the ascorbic acid salt used is sodium ascorbate. 9. A process according to claim 6, characterized in that the DK 156620 B pertechnetate reducing agent is a metal site of sulfuric acid or hydrochloric acid. 10. A method according to claim 6, characterized in that an organ-specific carrier is also incorporated in the composition. Use of the composition according to claim 1 for the preparation of a technetium-99m based radiographic scanning agent, characterized in that the composition is dissolved in an oxidized pertechnetate solution in such an amount that the ascorbic acid, its pharmaceutically acceptable site or ester is present in an amount not exceeding 0.1% by weight. 15 20 25 30 35