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Publication numberUS3852414 A
Publication typeGrant
Publication dateDec 3, 1974
Filing dateSep 13, 1972
Priority dateSep 13, 1972
Also published asCA1029655A1
Publication numberUS 3852414 A, US 3852414A, US-A-3852414, US3852414 A, US3852414A
InventorsAdler N, Gamin L
Original AssigneeNew England Nuclear Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Bone seeking technetium 99m stannous phosphate complex
US 3852414 A
Abstract
A metabolizable radioactive technetium-99m-stannous-ring phosphate complex in which at least 15 to 20% by weight, and preferably 40 to 100%, of the phosphate moiety is a ring or cyclic phosphate of molecular weight less than 300 and in which no more than 5 to 15% or 20% by weight of such phosphate moiety is a linear polyphosphate of molecular weight greater than pyrophosphate, a method of making the same, a method of using the same by in vivo intravenous administration to a mammal of the sterile-non-pyrogenic complex followed by radioassay scanning or imaging the skeletal structure, and a kit made up of a stannous-phosphate complex in which at least 15 to 20% and preferably 40 to 99% of the phosphate moiety is the aforesaid ring or cyclic phosphate and in which no more than 5 to 15% or 20% by weight of such phosphate moiety is a linear polyphosphate of molecular weight greater than pyrophosphate.
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United States Patent 191 Adler et al.

[ Dec. 3, 1974 BONE SEEKING TECHNETIUM 99M STANNOUS PHOSPHATE COMPLEX [75] Inventors: Norman Adler, Arlington; Leopoldo Lazaro Gamin, Lexington, both of Mass.

[73] Assignee: New England Nuclear Corporation,

Boston, Mass.

[22] Filed: Sept. 13, 1972 [21] Appl. No.: 288,683

[52] US. Cl 424/1, 252/301.l R, 423/249 OTHER PUBLICATIONS Subramanian et al., Radiology, Vol. 99, pp. 192-196, April 1971.

Primary Examiner--Leland A. Sebastian Attorney, Agent, or Firm-Dike, Bronstein, Roberts, Cushman & Pfund ABSTRACT A metabolizable radioactive technetium-99mstannous-ring phosphate complex in which at least 15 to 20% by weight, and preferably 40 to 100%, of the phosphate moiety is a ring or cyclic phosphate of molecular weight less than 300 and in which no more than 5 to 15% or 20% by weight of such phosphate moiety is a linear polyphosphate of molecular weight greater than pyrophosphate, a method of making the same, a method of using the same by in vivo intravenous administration to a mammal of the sterile-nonpyrogenic complex followed by radioassay scanning or imaging the skeletal structure, and a kit made up of a stannous-phosphate complex in which at least 15 to 20% and preferably 40 to 99% of the phosphate moiety is the aforesaid ring or cyclic phosphate and in which no more than 5 to 15% or 20% by weight of such phosphate moiety is a linear polyphosphate of molecular weight greater than pyrophosphate.

10 Claims, No Drawings- BONE SEEKING TECI-INETJUIVI 99M STANNOUS PHOSPHATE CUMPLEX BACKGROUND OF THE INVENTION 53-55 (1959); Journal of Labelled Compounds,-

April-June 1970, Vol. VI, No. 2, pages 166-173; Journal of Nuclear Medicine, Vol. 11, No. 6, pages 380-381, 1970; Journal of Nuclear Medicine, Vol. 1, No. 1, January 1960, pages l-13'. In these cases a phosphorous atom or atoms of the phosphate are radioactive, i.e.,

It has also been known for some time that technetium-99m Tc) is a preferred radionuclide for radioactively scanning organs because of its short half life and because it radiates gamma rays which can be easily measured, compared, for example, to beta rays. See Radiology, Vol. 99, April 1971, pages 192-196.

It has also been known for some time to use divalent stannous tin (SN in the form of stannous chloride, or divalent iron (Fe or reduced zirconium to bind radioactive Tc to carriers, such as chelating agents, red blood cells, albumin and other proteins, which selectively seek out certain organs of the body, in order to carry the '"Tc with them to such organs of the body where it is concentrated, whereby such organ can be radioactively scanned or imaged for diagnostic or other purposes, e.g. radioactive treatment of a pathological condition. See Journal of Nuclear. Medicine, .Vol. 11, N0. 12, 1970, page 761; Journal of Nuclear Medicine, Vol. 12,No. l, 1971, pages 22-24; Journal of Nuclear Medicine, Vol. 13,No. 2, 1972, pages 180-181; Journal of Nuclear Medicine, Vol. 12, No. 5, May 1971, pages 204-211; Radiology, Vol. 102, January 1972, pages 185-196; Journal of Nuclear Medicine, Vol. 13, No. l, 1972, pages 58-65.

Also, it has been suggested to label a stannous compound with '"To for radioactively imaging bone marrow, Journal of Nuclear Medicine, Vol. 1 1, 1970, pages 365-366.

It has also been known for some time that the stannous ion Sn forms soluble complexes with long chain polyphosphates, Journal Inorganic Nuc. Chem., Vol. 28, 1966, pages 493-502.

It has been suggested to employ the aforesaid '"Tc for radioactively scanning the skeletal bone structure of mammals by complexing or binding it to tripolyphosphate carrier byuse of the aforesaid stannous ion as a binding agent in order for such phosphate to selectively carry the '"Tc to, and concentrate it in, the skeletal bone structure upon in vivo intravenous administration for subsequent radioactive scanning or imaging the skeletal structure. Radiology, Vol. 99, April 1971, pages 192-196. The use of Te in this manner in alleged to have certain advantages over the use of strontium, e.g. Sr, as the radioactive label which has been used for radioactive bone scanning in the past. These advantages are those which are inherent in '"Tc, i.e. short half life and lower energy gamma rays. However, the bone uptake (the percent of the total dosage which becomes concentrated in the skeletal structure within a certain time after in vivo intravenous administration) of such '"Tc by the other organs of the body (the higher these ratios the better), i.e.. radioactive contrast, are not nearly as high as with radioactive strontium.

STATEMENT OF THE. lNVENTION It has been discovered that if, in the aforesaid '"Tcstannous-phosphate complex the phosphate moiety comprises a cyclic or ring (meta) phosphate of formula P O preferably having a molecular weight of less than 300, rather than a polyphosphate, which is a linear straight or branched chain phosphate having the general formula P O bone-uptake of the "To and the ratios of bone uptake to uptake of '"Tc by other organs, i.e. the liver, blood, kidneys and gastrointestinal system (G.I.) are substantially increased. It has also been discovered that optimum results are achieved if at least 15 to 25% by weight, preferably at least 30 to 40% (between and to is more preferred), of such phosphate moiety is made up of such ring phosphate and if such phosphate moiety contains no more than about 15 to 20% or 25%, preferably no more than 5 to 10% and more preferably no more than 5% (less than 5% is the most preferred), by weight of such polyphosphate of molecular weight greater than that of pyrophosphate.

The term phosphate moiety as used herein refers to the phosphorus and oxygen atoms only of the phosphate.

The presence of polyphosphates of formula P O fi and molecular weight greater than 300, more particularly greater than that of p yrophosphate, seems to reduce bone take-up and the aforesaid ratios, as compared to complexes without such higher molecular weight polyphosphates. However, as aforesaid, some of such higher molecular weight polyphosphates can be tolerated, preferably not more than about 15 to 20% or 25%, more preferably no more than 5 to 10% and still more preferably not more than 5% (less than 5% is the most preferred), by weight of the total phosphate moiety.

The rest of the phosphate moiety of the complex, where the ring-phosphate does not constitute 100% of the phosphate moiety, is preferably ortho (1 0 and pyrophosphate (phosphate moiety molecular weight of less than 300) and more preferably pyrophosphate only.

A highly preferred ring phosphate is trimetaph'osphate (P O,, -molecular .weight of 237) of the formula:

The complex is made from water soluble alkali metal (preferably sodium) or ammonium salt or acid salt of the ring phosphate, e.g. sodium trimetaphosphate.

Preferably the sodium trimetaphosphate is admixed with a stannous salt, e.g. SnCl (the stannous salts of other acids which are pharmaceutically acceptable,

the time it is desired to intravenously administer the '"Tc complex. The stannous-trimetaphosphate complex may be sealed in a sterile non-pyrogenic container or vial as a solution or a dry lyophilized solid and shipped as a kit with the freshly generated sterile and nonpyrogenic '"Tc being added aseptically at the situs just prior to use.

DETAILED DESCRIPTION OF INVENTION (INCLUDING EXAMPLES) The following compositions were prepared:

TABLE 1 Description 1 A commercial sodium polyphosphate sold by FMC Corporation under the trade name FMC Glass H (average chain length of 2 l and average M.W. about 2100). A first high molecular weight fraction of the FMC Glass H of Sample I obtained by fractionating an aqueous solution of Sample 1 with acetone according to the technique described in Van Wazer, Phosphorous And Its Compounds, lnterscience Publishers, Inc. 1961 (pages 744747) to precipitate out of the aqueous solution of the FMC Glass H, as an oil, the highest molecular weight fraction of polyphosphates (composition given in TABLE 2). A second acetone fraction of FMC Glass H achieved by. adding more acetone to precipitate out of the remaining supernatant of l-l as an oil, the next higher molecular weight polyphosphates (composition given in TABLE 2). The acetone decreases the solubility of the polyphosphates in the water; the higher the molecular weight of the polyphosphate the less soluble it is so that the highest molecular weights are forced out of solution first. A third acetone fraction of FMC Glass H containing the next higher molecular weight polyphosphates is precipitated out of the remaining supernatant solution of l-2, as an oil, upon addition of further amounts of acetone (composition given in TABLE 2). A fourth acetone fraction of FMC Class H containing the next higher molecular weight polyphosphates (composition given in TABLE 2) is precipitated out of the supernatantsolution of l-3, as an 'oil, by adding more acetone. A fifth acetone fraction of the FMC Glass H (containing the next higher molecular weight polyphosphates) (composition given in TABLE 2) is precipitated out of the remaining supernatant solution of l-4, as an oil, by adding more acetone. A sixth acetone fraction of FMC Glass H (composition given in TABLE 2 )is precipitatedout of the remaining supernatant solution of l-5, as a solid precipitate of the next higher molecular weight polyphosphates by adding more acetone. A seventh acetone fraction of FMC Glass'H (composition given in TABLE 2) is precipitated out of the remaining supernatant solution of l6, as a solid precipitate of the next higher molecular weight polyphosphate by adding more acetone. The residue fraction in the supernatant liquid left after removal of the l-7 fraction (composition given in TABLE 2) is recovered by evaporating off the supernatant liquid. 2 An acetone end fraction of sample 1 after 90% by weight had been previously fractionated off and leaving by removal of such end fraction 3% by weight in the supernatant (composition given in TABLE'2). 4 A mixture of 86% sodium trimetaphosphate (Na P O J, 3% sodium orthophosphate (Na PO (molecular weight of phosphate moiety-95) and 10% sodium pyrophos (Na P,O-,) (linear polyphosphate-molecular weight of phosphate moiety-W4) obtained by acetone fractionation of sodium trimetaphosphate obtained from Monsanto. Sodium trimetaphosphate as aforesaid, is one of a plurality of cyclic phosphates having the general formula P,,O:,,, Sodium orthophosphate is a phosphate monomer. Sodium pyrophosphate is a dipolyphosphate. 5 An acetone end fraction ofa food grade polyphosphate sold by FMC under the name FMC FG (composition given in TABLE 2). g 6 A commercial cyclic trimetaphosphate sold by Stauffer Chemical, (composition given in TABLE 2) Sodium orthophosphate. Sodium pyrophosphate.

polyphosphate-phosphate moiety having a M.W. of 348. It, together with the pyrophosphate and tripolyphosphate, fall in the class of linear chain polyphosphates having the general formula 0 -o|+2) An aqueous solution of each of the phosphate composition samples 1 through 10 (40 mg. phosphate/l ml. solution) were made with distilled water in which the dissolved oxygen content was reduced in a conventional manner'by bubbling through such water gaseous nitrogen for a period of 2 hours. The water and phosphates were mixed to form the solutions in a nitrogen atmosphere and in a nitrogen flushed container. The reason for this is to reduce oxidation of the divalent Sn to be subsequently admixed with each solution sample. However, itis not essential (but highly preferred) to use nitrogen-treated water or a nitrogen at-, mosphere or a nitrogen-flushed container. Other known pharmaceutically acceptable conditions, which will inhibit oxidation of the Sn upon subsequent mixing thereof with the phosphate solution, can be used, including the use of conventional pharmaceutically acceptable reducing agents and anti-oxidants in the products used. 7

Each of these solutions, samples 1 through 10, in an amount equal to ml. was mixed with 0.16g of solid SnCl 2H O under a nitrogen atmosphere. The SnCl 2H O was made by adding to 84.5 mg. of metallic tin, sufficient concentrated HCl with mixing until all the tin has dissolved followed by removing excess acid and water by lyophilization (this operation also being carried out in a vacuum or in a nitrogen atmosphere and in a nitrogen flushed container to prevent oxidation of stannous to stannic). Antioxidants, which can be administered intravenously, may also be used. A stannous (SN -phosphate complex or mixture of some kind was formed in each case, the phosphate moiety of each sample corresponding to the phosphate moieties of the phosphates set forth in TABLE 2. Thus, in the case of sample l-7, 60% of the phosphate moiety was trimetaphosphate whereas in sample 1, 96.5% of the phosphate moiety constitutes long chain linear polyphosphates of 5 or more phosphorous atoms.

Sufficient aqueous solution of 3N NaOH (sodium carbonate or bicarbonate can also be used), in the case of all samples except 8, and 3N HCl, in the case of sample 8, is'then added to each sample to give a pH of 6.0 to achieve a pH suitable for subsequent intravenous in vivo administration into the body of a mammal, in this case adult mice. The pH adjustment is preferably done under a nitrogen atmosphere also.

After thorough mixing, the solutions are sterilized by passing them through a Millipore biological filter of 0.22 micron pore size undera nitrogen atmosphere. Thereafter milliliter portions of each of the sterile solutions are poured into individual sterile and nonpyrogenic storage glass vials under aseptic conditions and the vials are aseptically sealed so that the interior and contents of each sealed vial is sterile and nonpyrogenic and under a nitrogen, atmosphere.

In the case of each sample, vials are lyophilized by conventional freeze drying equipment under aseptic conditions to remove water. This provides a solid stannous-phosphate complex which aids in shipping and which is more stable than the complex in solution.

Each vial contains 1.35 mg. SnCl and 40 mg. of the phosphate.

The vials can be sealed and stored until needed subsequently to form the technetium-99m-stannousphosphate complex at the use situs.

To prepare the technetium-99m complex, 3 to 7 (5) ml. of fresh sodium pertechnetate, removed as a sterile non-pyrogenic eluate from a sterile NEN "*Tc Generator (any other source of pharmaceutically acceptable Tc can be used, including '"Tc generators manufactured by others than NEN), in a 0.9% saline solution is aseptically added to each vial containing the sterile and non-pyrogenic stannous-phosphate complex and the vial is swirled until a solution is obtained. In each case a technetium-99m-stannous-phosphate complex or mixture of some kind is formed in aqueous solution (9 mg. per ml. solution when 5 mil of pertechnetate are used), the phosphate moiety of which corresponds to the phosphate moieties of the phosphate compounds of each sample set forth in TABLE 2.

Aseptic techniques and sterile, nonpyrogenic ingredients and containers were used at all steps, such procedures being standard to those skilled in the art.

Each of the technetium-99m-stannous-phosphate complex-containing solutions is aseptically intravenously injected in vivo into a vein in the tail of adult mice (average weight 0.040 kgs) in an amount equal to between 1 and 3 mCi and a volume of 0.12 ml (8 mg. of phosphate per ml solution in samples 1 through 10).

Three hours after intravenous administration, some of the mice to which each sample was administered were sacrificed and the various organs of their bodies (skeletal, liver, G.l., blood, kidneys) were counted by conventional gamma ray counting techniques to deter mine uptake of '"Tc by each organ and thereby determine contrast of bone uptake as compared to uptake by other organs. As aforesaid, it is not only important to have a high bone uptake (based on total technetium- 99m dosage) but it is also important that the ratio of uptake by the bone to uptake by the other organs be high. I v i The results are set forth in TABLE 2 below, in which the uptakes (the bone uptake figures represent the average bone uptake for the skeletal system) are in terms of percent of the total technetium-99m activity injected (corrected for radioactive decay) which has collected in the various organs indicated 3 hours after in vivo intravenous injection, in which the ratio amounts are computed from the uptake amounts, in which Percent Having Phosphate Moiety M.W. Less than 300 refers to weight percent of the phosphate moiety based on the total phosphate moiety of the sample identified in the first horizontal column, in which the percents referred to under Phosphate Composition are weight percents of the whole phosphate moiety of the sample (as aforesaid, phosphate moiety as used herein is limited to that part of the compound or complex made up of phosphate phosphorus and oxygen atoms), in which Ortho P1 refers to the phosphate moiety of sodium orthophosphate, Pyro P2 refers to the phosphate moiety of sodium pyrophosphate, Tripoly P3 refers to the phosphate moiety of sodium tripolyphosphate, Tetrapoly P4 refers to the phosphate moiety of sodium tetrapolyphosphate, Trimeta R3 refers to the phosphate moiety of sodium trimetaphosphate, Tetrameta R4 refers to the phosphate moiety of sodium tetrarnetaphosphate, both trimeta and tetrametaphosphates falling within the class of cyclic or ring phosphates having the formula P O in which Pentapoly And Longer Linear Chains refers to the phosphate moiety of soidum pen tapolyphosphate and longer linear (linear as used herein includes straight and branched linear phosphate chains) polyphosphates of formula P O in which Average IVIW. refers to the average molecular weight of the phosphate moiety of the sample and in which Fraction In Raw Stock with reference to samples l-l, 1-2, 1-3, 1-4, 1-6, 1-7 and 1-8 refers to the normalized percent by weight of each of these samples in sample 1, which is the raw stock which is fraction ated. V H

CbnventionaI gam ma counting techniques for measuring technetium 99m take-up in the organs are conventional gamma ray-excitable scintillation counters for radioassaying multiple samples of the organs of the sacrificed mice.

Also, conventional scanning by radioactive imaging using a gamma ray-excited scintillation or gamma camera and a dual crystal rectilinear scanner was used in vivo. In vivo scintiphotos of the total body using the Anger camera were obtained as well as rectilinear total body scans. V

The figures given in TABLE 2 are average figures achieved by the aforesaid conventional counting techniques, each sample having been intravenously administered to mice followed by radioactive counting.

Following intravenous administration, the technetium 99m-stannous-ring phosphate complexes of the invention are rapidly cleared from the bloodby deposition in bone and excretion int-o urine. Thus, the technetium-99m-stannous-ring phosphate complexes are metabolizable. The deposition of the Tcstannous-ring phosphate complexes of the invention appears to be primarily a function of the bone blood flow as well as being related to the efficiency of the bone in extracting the complex from the blood which perfuses the bones.

It was observed that the deposition of the '"Tc in the skeleton is bilaterally symmetrical with increased accumulations being present in the axial skeleton as compared to the appendicular skeleton. There is also increased deposition in the distal aspect of long bones.

Localized areas of abnormal accumulation of the radio-pharmaceutical may be seen in primary malignancies of the bone, metastatic malignancies of the bone, acute or chronic osteomyelitis, arthritides, recent fractures, areas of ectopic calcification, Pagets disease, regional migratory osteoporosis, areas of aseptic necrosis and in general any pathological situation involving bone in which there is increased osteogenic activity or localized increased osseous blood perfusion.

The acute toxicity level in mice (LlD for Sample No. 2 has been determined to be 150 rng/Kg body weight and for Sample No. 6 it is 800 mg/Kg and for Sample No. 8 it is mg/Kg. Subacute toxicity studies in mice of Sample 2 have shown no signs of toxicity after 15 daily injections at dose levels as high as 63 mg/Kg body weight/day. A similar subacute study in dogs indicates no signs of toxicity at a dose level of 3.6 mg/Kg body weight/day.

A 7 w W TABLE 2 Phosphate sample 1 FMO 1-1 1-2 1-3 1-4 1-6 1-7 1-8 2 4 5 6 7 8 10 ame/blood- 4 4 4 5 5 18 29 17 30 58 32 2 34 13 5 Bone/liver. 0. 5 7 6 7 8 3 29 19 24 32 78 38 2 5 20 3 B0ne/G.1 5 6 8 7 11 11 37 63 36 55 140 55 17 49 31 11 Bone/kidneys 1 1 1 1 3 2 9 12 8 u 12 8 9 5 1 Percent having phosphate moiety M.W. less than 300. 15 3 3 5 13 17 00 100 55 99 98 08 100 100 100 Phos hate com osition:

0211110 P (p rcent) 3 1. 0 1 2 5 5 10 50 5 3 4. 0 100 0 0 0 Pyro P (percent) 2 0. 5 0. 5 1 2 1 15 10 10 10 5. 0 8. 0 0 100 I 0 0 Tripoly P (percent). 2 0. 5 0. 5 1 2 1 5 0 0 0 0 0 100 0 Tetra Poly P (percent) 2 0. 5 0. 5 1 3 10 5 1 0 1. 0 0 0 0 90 Trimeta R (percent) cyclic 8 0. 5 0. 5 1 4 10 60 40 40 86 78 86 0 0 0 10 Cyclic tetra meta R (percent) 4 0.5 0.5 1 4 50 5 40 0 0 0 0 0 0 Penta poly P and longer linear chains. 79.0 96. 5 06. 5 03 8O 23 0 0 5 2 1 0 0 0 0 Average M.W 2, 100 3, 900 2, 700 1. 800 1, 200 Fraction in raw stock 100 3. 5 61 916. 2 7. 5 5. 0 1 0. 7

It was found that samples 4 and 6 were only onefourth as toxic to mice as sample 2 and one-eighth as toxic to mice as sample 1.

The complexes of the invention have been used successfully as a skeletal imaging or scanning agent to visualize areas of altered blood flow to the bone and altered osteogenic activity, including suspected bone lesions not shown on X-ray, bone survey performed as part of the work-up in patients with known or suspected malig-;

nancy, to follow the response of metastatic or primary bone lesions to radiation therapy, metabolic bone disease, to diagnose arthritisand osteomyelitis, and to diagnose and determine healing rate of bone fractures. Thetechnetium-99m '"Tc) labeling reactions involved in preparing the T0 stannous-phosphate complexes of the invention depend on maintaining the tin in the reduced or'stannous (Sn state. Oxidants present in' the pertechnetate supply may adverselyaffect quality.

The radioactive dosage of the '"Tc complex of the invention may vary from 1 to 25 mCi (millicuri'es) but preferably is from 10 to 15 mCi. The dosage in terms of the ""TC complex may vary over a wide range, i.e. from 0.001 to 30 mg per kilogram body weight of mammal.

The concentration of ring phosphate moiety in the final solution is preferably between 1 and 40, more preferably between2 and mgs per ml of solution.

Anadvantage of a complex containing a relatively large amount of ring phosphate is that the ring phosphate, in addition to providing excellent up-take and bone-to-other-organ ratios, has a low toxicity. Where the phosphate moiety contains phosphate other than ring phosphate it is advantageous for such other phosphateto be pyrophosphate because of its high bone uptake.

Scanning may be commenced as early as one hour after intravenous administration and may be as long after injection as clinically useful amounts of ""Tc remain in the organ.

Another manner of making the complex of the invention is to weigh 4 mg. of SnCl 2l-1 O and 100 mg of sodium trimetaphosphate into a flask (the flask is sterile and non-pyrogenic and is flushed with nitrogen before weighing and is kept under nitrogen during this step and for the next step). Add, under aseptic conditions, 12 ml of sterile, non-pyrogenic sodium pertechnetate in 0.9% saline solution. Shake the mixture until a solution is obtained followed by intravenous injection (preferably the pH of the mixture is aseptically adjusted to pH 4-8 before intravenous injection).

Also, the sterile stannous chloride can first be aseptically mixed with the sterile '"Tc saline solution to form a Tc-stannous complex, followed by adding the sterile sodium ring phosphate under aseptic conditions to form the '"Tc-stannous-ring phosphate, adjusting the pH to 4-8, followed by intravenous injection.

It can be seen from TABLE 2 that the '"Tcstannous-phosphate complexes, the phosphate moiety of which is cyclic (in the form of a ring) and has a molecular weight of less than 300, e.g. samples 1-7, l-8, 2, 4, 5 and 6, provide surprising and markedly higher bone uptake of ""Tc and higher ratios of bone uptake to other organs, as compared to those complexes, the phosphate moiety of which is in the form of linear long chains of molecular weight above that of pyrophosphate, e.g. samples 1, l-l, 1-2, l-3, l-4, 1-6,9 and 10.

In accordance with the invention, the ring phosphate moiety of the ""Tc-stannous-phosphate complex should be at least 15 or 20%, preferably at least 30 to 40%, more preferably more than 50 or 60% and most preferably to or more, by weight of the total phosphate moiety of the complex.

Trime taphosphate is a highly preferred ring phosphate.

Although the stannous (Sn ion is by far preferred, the divalent ferrous (Fe ion in the form of ferrous ascorbate, and reduced zirconium can also be used but without as good results. All these metals can exist in a plurality of redox states.

The phosphate may be added to the solid SnCl as an aqueous solution, or it may be added to a solution of the SnCl, to form the Sn -phosphate complex followed byadding the '"Tc solution.

Very little Sn need be used to form the complex of the invention, e.g. less than 7 to 10% of the phosphate based on molecular weights.

The weight ratio of Sn ion to the ring phosphate moiety may vary over a wide range, i.e. from 10' to 0.50, preferably 0.01 to 0.4. The maximum ratio of dictated by the amount beyond solubility of the Sn. The minimum amount required that amount necessary to bind a sufficient amount of """Ic to the ring phosphate to achieve good bone uptake and contrast. This can be determined by routine experiment.

The pH of the stannous-phosphate complex should be between 3 and 8.

The water used for making the complexes of the invention is distilled and is at an elevated termperature of 200F duringremoval of dissolved oxygen and reduction of oxidants by bubbling the nitrogen gas therethrough.

The maximum amount of "'Tc is that beyond the capacity of the Sn -ring phosphate complex to bind the '"Tc. This can be determined by routine thin layer radiochromatography to determine the percent of free or unbound To in the complex. The minimum amount is dictated by that amount below which there is an insufficient amount to give good scanning of bone uptake and contrast, which also can be determined by routine experiment. Generally, the amount of ""lc added to the Sn -ring phosphate complex should be sufficient to achieve the counting rate desired by the doctor or laboratory personnel for the volume to be injected; ordinarily, as aforesaid, the activity dosage varies from 5 to 25 millicuries.

Although sodium ring (meta) phosphates are preferred, any alkali metal, such as potassium and lithium, or ammonium can be used as the cation so long as it is pharmaceutically acceptable so that it can be safely administered intravenously. Also, the acid pyrophosphates of such cations can be used.

Although in the examples give above saline water was used as the vehicle, any other vehicle which is pharmaceutically acceptable for intravenous administration can be used.

It is not intended that the invention be limited to any theory which may have been given above or to the specific examples set forth above but only by the claims appended hereto and their equivalents.

We claim:

1. A metabolizabie radioactive bone seeking composition for in vivo concentratingmTc in the skeletal structure of mammals comprising a technetium-99mstannous phosphate complex, a aasvrswa"50 2715; weight of the phosphate moiety of which is a ring phosphate having the formula P,,O and a molecular weight of less than 300, said phosphate moiety containing no more than 25% by weight of linear polyphosphates of formulation P O having a molecular weight greater than that of pyrophosphate.

2. A bone seeking composition according to claim 1, said phosphate moiety being substantially free from said linear polyphosphates.

3. A metabolizable radioactive bone seeking composition according to claim 1, at least 30 to 40% by weight of said phosphate moiety being said ring phosphate.

4. A metabolizable, radioactive bone seeking composition according to claim 3, said phosphate moiety also including pyrophosphate, and at least the major portion of any remaining phosphate moiety being ortho phosphate.

5. A composition according to claim 1, where n is equal to 3.

6. A composition according to claim 1, more than 50% by weight of said phosphate moiety being said ring phosphate.

7. A composition according to claim 3, said phosphate moiety comprising a mixture'of said ring phos phate, a pyrophosphate and an orthophosphate and wherein n is 3.

8. A composition according to claim 3 wherein n is 3.

9. A composition according to claim 8, substantially the remaining phosphate moiety comprising one or more phosphates having the formula (P O f where n is less than 3.

10. A composition according to claim 8, substantially the remaining phosphate moiety being one or more phosphates of formula (P,,O of which not more than 20% by weight has an n value greater than 2.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 5 3

DATED December 3, 197

INVENTOR(S) 1 Norman Adler, Leopoldo Lazaro Camin It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

First page, the second inventor's name is Camin n+2 Column 2, lines 12 and 29, the formula should read P O The same formula should be corrected in the claims Column 10 line 6.

Signed and sealed this 6th day of May 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 335 3 DATED December 3, 197

IN ENTO (S) 1 Norman Adler, Leopoldo Lazaro Camin It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

First page, the second inventor's name is Camin n+2 Column 2, lines 12 and 29, the formula should read P o3 The same formula should be corrected in the claims Column 10 line 6.

Signed and sealed this 6th day of May 1975.

(SEAL) Attest:

C. MARSHALL DANN RUTH C. MASON Commissioner of Patents Attesting Officer and Trademarks

Non-Patent Citations
Reference
1 *Subramanian et al., Radiology, Vol. 99, pp. 192 196, April 1971.
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Classifications
U.S. Classification424/1.61, 423/249
International ClassificationA61K51/02, A61K51/04
Cooperative ClassificationA61K2123/00, A61K51/0489
European ClassificationA61K51/04P
Legal Events
DateCodeEventDescription
Nov 14, 1991ASAssignment
Owner name: DU PONT MERCK PHARMACEUTICAL COMPANY
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:E.I. DU PONT DE NEMOURS AND COMPANY;REEL/FRAME:005955/0010
Effective date: 19910426
May 29, 1984ASAssignment
Owner name: E.I. DU PONT DE NEMOURS AND COMPANY, INCORPORATED
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:NEW ENGLAND NUCLEAR CORPORATION;REEL/FRAME:004267/0211
Effective date: 19840525
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NEW ENGLAND NUCLEAR CORPORATION;REEL/FRAME:004267/0211
Owner name: E.I. DU PONT DE NEMOURS AND COMPANY, INCORPORATED,