US3851044A - Bone seeking technetium 99m stannous phosphate complex - Google Patents

Bone seeking technetium 99m stannous phosphate complex Download PDF

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US3851044A
US3851044A US00288577A US28857772A US3851044A US 3851044 A US3851044 A US 3851044A US 00288577 A US00288577 A US 00288577A US 28857772 A US28857772 A US 28857772A US 3851044 A US3851044 A US 3851044A
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phosphate
pyrophosphate
bone
complex
stannous
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N Adler
L Camin
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Bristol Myers Squibb Pharma Co
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New England Nuclear Corp
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Priority to US00288577A priority Critical patent/US3851044A/en
Priority to CA000179088A priority patent/CA1120687A/en
Priority to DE19732344802D priority patent/DE2344802A1/en
Priority to DE2344802A priority patent/DE2344802C2/de
Priority to DE2366614A priority patent/DE2366614C2/de
Priority to GB2236375A priority patent/GB1441146A/en
Priority to GB4268673A priority patent/GB1441145A/en
Priority to US05/410,086 priority patent/US4016249A/en
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • Tc technetium- 99m
  • 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 Tccontaining complex and the ratios of such bone uptake to uptake of the 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.
  • the phosphate moiety of the Tc-stannous-phosphate complex which has been suggested in the aforesaid Radiology publication, comprises pyrophosphate (P O (which is a linear polyphosphate moiety of molecular weight less than 300), the bone uptake, bone/blood ratio, bone/liver ratio, bone/ G.I. ratio and bone/kidneys ratio are substantially increased.
  • P O pyrophosphate
  • 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 linear or branched chain polyphosphate (formula P O of molecular weight greater than that of pyrophosphate.
  • Tc-Sn++-pyrophosphate complex is administered to the mammal in relatively small dosages of substantially less than 20 or 25, preferably substantially less than 8 or 10 and still more preferably less than 5 or 6 (between 0.01 or 0.10 and 3 and even less provide excellent results), milligrams pyrophosphate moiety per kilogram of body weight of the mammal.
  • phosphate moiety refers to the phosphorus and oxygen atoms only of the phosphate.
  • polyphosphates of formula P 0 (n+2) and molecular weight greater than that of pyrophosphate seems to reduce bone take-up and the aforesaid ratios, as compared to complexes without such higher molecular weight polyphosphate.
  • 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 is preferably a ring phosphate of formula P O (with n preferably being 3 which is trimetaphosphate) and/ or ortho phosphate, and preferably a ring phosphate only, although the aforesaid limited amounts of higher molecular weight linear polyphosphates can be tolerated.
  • the complex is made from a water soluble alkali metal (preferably sodium) or ammonium salt or acid salt of the pyrophosphate, e.g. sodium pyrophosphate.
  • a water soluble alkali metal preferably sodium
  • ammonium salt or acid salt of the pyrophosphate e.g. sodium pyrophosphate.
  • the sodium pyrophosphate is admixed with a stannous salt, e.g. SnCl (the stannous salts of other acids which are pharmaceutically acceptable, i.e. safely intravenously administered, can be used) to form the stannous-pyrophosphate complex, the pH of which is adjusted to 3-8, preferably -8, by a pharmaceutically acceptable acid, such as HCl, or base, such as NaOH or Na CO or NaHCO followed by admixing with the stannous-pyrophosphate complex, an aqueous saline solution of radioactive sodium pertechnetate Tc) to form the Tc-stannous-pyrophosphate complex at the time it is desired to intravenously administer the Tc complex.
  • a stannous salt e.g. SnCl (the stannous salts of other acids which are pharmaceutically acceptable, i.e. safely intravenously administered, can be used
  • a pharmaceutically acceptable acid such as HCl, or base, such as NaOH
  • the stannous-pyrophosphate complex may be sealed in a sterile non-pyrogenic container or vial as a solution or a lyophilized solid and shipped as a kit with the freshly generated sterile and non-pyrogenic Tc being added aseptically at the situs just prior to use.
  • a fifth acetone fraction of the EMU Glass H (oonta g the next higher molecular weight polyphosphates) (composition given in Table 2) is precipitated out of the remaining supernatant solution of 1-4, as an oil, 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 1-6, as a solid precipitate of the next higher molecular weight polyphosphates by adding more acetone.
  • Sodium tripolyphosphate 10 Sodium tetrapolyphosphate-NanP4013-a polyphosphate-phosphate moiety having a MW. of 348. It, together with the pyrophosphate and tripolyphosphate, fall in the class of linear chain polyphosphates having the general formula PHOsni-F -An aqueous solution of each of the phosphate composition samples 1 through 1 0 (40 mg. phosphate/1 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 two hours. The water and phosphates were mixed to form the solutions in a nitrogen atmosphere and in a nitrogen flushed container.
  • aqueous solution 3N sodium hydroxide (sodium carbonate or bicarbonate can also be used), in the case of samples 1 through 7 and 9 and 10, and 3N HCl, in the case of sample 8, is then added to each sample to give a pH of 5.0 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.
  • the solutions are sterilized by passing them through a Millipore biological filter of 0.22 micron pore size under a nitrogen atmosphere. Thereafter milliliter portions of each of the sterile solutions are poured into individual sterile and non-pyrogenic storage glass vials under a nitrogen atmosphere.
  • vials are lyophilized by conventional freeze drying equipment under aseptic conditions to remove water. This provides a solid stannousphosphate complex which aids in shipping and storage 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 stannous-phosphate complex at the use situs.
  • sample 11 An eleventh sample was prepared in the manner set forth above by diluting sample 8 to a concentration of 1 mg. of phosphate per ml. of solution. This was labeled sample 11.
  • Each of the technetium-99m-stannous-phosphate com refers to the phosphate moiety of sodium trimetaphosphate
  • Tetrameta R refers to the phosphate moiety of sodium tetrametaphosphate, both trimeta and tetrametaphosphates falling within the class of cyclic or ring phosphates having the formula P O in which Pentapoly plex-contammg solutlons 1s aseptically 1ntravenously 1nand Longer Llnear Cha1ns refers to the phosphate moiected 1n VlVO 1nto a ve1n 1n the tail of adult mice (average ety of sodium pentapolyphosphate and longer linear (linwelght 0.040 kgs.) 1n an amount equal to between 1 and car as used herein includes straight and branched linear 3 mC1 and a volume of (M2 ml.
  • sample 8 (8 mg. of phosphate per phosphate chains) polyphosphates of formula ml. solutlon in samples 1 through and 1 mg. phosphate 10 P O per ml. solution in sample 11). Also sample 8 was inn jected in the same manner except that a volume of 0.015 in which Average M.W. refers to the average molecular ml. was injected instead of 0.12 ml. to reduce the dosage weight of the phosphate moiety of the sample and in of the complex by a factor of 8. This was labeled sample which Fraction in Raw Stock with reference to sam- 12.
  • ples 1-1, 12, 13, 14, 1-6, l-7 and l-8 refer to the Three hours after intravenous administration, some of normalized percent by weight of each of these samples the mice to which each sample was administered were in sample 1, whlch is the raw stock which is fractionated.
  • Phosphate sample 1 (FMC) 1-1 1-2 1-3 1-4 1-6 1-7 1-8 2 4 5 6 7 8 9 10 11 12 5 4 4 4 5 5 1s 29 17 30 58 32 2 34 13 5 35 24 0.5 7 6 7 8 3 29 19 24 32 78 38 2 5 20 3 47 36 5 6 8 7 11 11 37 63 36 55 140 55 17 49 31 11 81 32 Bone/kidneys 1 1 1 1 3 2 9 12 8 9 13 12 3 9 5 1 12 6 Percent having phosphate moiety M.W. less than 300 15 3 3 5 13 17 90 100 55 99 98 98 100 100 100 10 100 100 Phosphate composition:
  • 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 three hours after in vivo intravenous injection, in which the ratio amounts are computed from the uptake amounts adjusted to compen sate for the different weights of the organs and the different weights of the animals by dividing each uptake amount by the ratio expressed in percentage of the weight of such organ to the weight of the animal, in which Percent Having Phosphate Moiety M.W.
  • phosphate moiety as used herein is limited to that part of the compound or complex made up of phosphate phosphorus and oxygen atoms
  • Ortho P refers to the phosphate moiety of sodium orthophosphate
  • Pyro P refers to the phosphate moiety of sodium pyrophosphate
  • Tripoly P refers to the phosphate moiety of sodium tripolyphosphate
  • Tetrapoly P refers to the phosphate moiety of sodium tetrapolyphosphate
  • Trimeta R 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 sci
  • the Tc-Sn++ pyrophosphate complexes of the present invention are rapidly cleared from the blood by deposition in bone and excretion into urine.
  • the technetium-99m-stannouspyrophosphate complexes are metabolizable.
  • the deposition of the -Tc-stannous-pyrophosphate 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.
  • Radiopharmaceutical Localized areas of abnormal accumulation of the radiopharmaceutical 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.
  • mice The acute toxicity level in mice (LD for sample No. 2 has been determined to be 150 mg./kg. body weight and for sample 6 it is 800 mg./kg. and for sample 8 it is 70 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.
  • samples 4 and 6 were only one fourth 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 par-t of a work-up in patients with known or suspected malignancy, to follow the response of metastatic or primary bone lesions to radiation therapy, metabolic bone disease, to diagnose arthritis and osteomyelitis, and to diag nose and determine healing rate of bone fractures.
  • the technetium-99m Tc labelling reactions involved in preparing the Tc-stannous-phosphate complexes of the invention depend on maintaining the tin in the reduced or stannous (Snstate. Oxidants present in the pertechnetate supply may adversely affect quality.
  • the radioactive dosage of the Te complex of the invention may vary from 1 to 25 mCi (millicuries) but preferably is from to mCi.
  • the dosage should preferably be substantially less than or 25, preferably less than 8 or 10 and more preferably less than 5 or 6 mg. of pyrophosphate moiety per kilogram of body weight of the mammal since greater pyrophosphate dosages than this reduces the bone-liver ratio too much. Note for example the low bone-liver ratio in sample 8 where the dosage was mg. pyrophosphate per kg. body weight compared to the bone-liver ratio of sample 11 where the dosage was 3.1 mg./kg. body weight.
  • the dosage of pyrophosphate can be kept small either by use of more dilute dosage solutions of the pure pyrophosphate, as in sample 11 or by administering smaller doses of a more concentrated complex solution, the phosphate moiety of which contains a high concentration of pyrophosphate or by more concentrated solutions of phosphate containing, in addition to the pyrophosphate, ring phosphate and/or orthophosphate which effectively dilute the pyrophosphate concentration of the dose.
  • Tc-Sn++-phosphate solution containing between 0.1 and 40, more preferably between 0.5 and 4 or 5 mgs. of pyrophosphate moiety per ml. of solution.
  • An advantage of a complex containing a relatively large amount of ring phosphate and a smaller amount of pyrophosphate is that the ring phosphate in addition to providing excellent bone up-take and bone-to-other-organ ratios is less toxic than pyrophosphate, although pyrophosphate, alone, is still not unduly toxic.
  • 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 .2H O and 100 mg. of sodium pyrophosphate 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).
  • 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 pyrophosphate under aseptic conditions to form the Tc-stannous-pyrophosphate, adjusting the pH to 3-8, followed by intravenous injection.
  • Tc-stannousphosphate complex in which the phosphate moiety comprises pyrophosphate and in which such moiety contains no more than 25% by weight of linear polyphosphate of molecular weight greater than that of pyrophosphate (samples l-7, l-8, 2, 4, 5 and 6, 8, l1 and 12) gives surprising higher bone uptake and ratio of bone uptake to other organs, as compared to orthophosphate and other polyphosphates, e.g. tripolyphosphate, tetrapolyphosphate and longer chain polyphosphates (see samples 1, 1-2 to 1-6, 7, 9' and 10).
  • the pyrophosphate moiety of the Tc-stannous-phosphate complex may be from 1 or 2% or even less up to 100% by weight of the total phosphate moiety.
  • the pyrophosphate moiety consists of 5 or 10% or more of the total phosphate moiety, more preferably 50% or 60% or more and most preferably between and
  • 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 by adding the Tc solution.
  • the Weight ratio of Sn++ ion to the pyrophosphate moiety may vary over a wide range, i.e. from 10- to 0.50, preferably 0.01 to 0.4. It is preferred that the molecular ratio of Sn++ to pyrophosphate moiety not exceed 2/ 1. The maximum ratio is dictated by the amount beyond which the precipitation of Sn' occurs. The minimum amount required is that amount necessary to bind a sufficient amount of Tc to the pyrophosphate to achieve good bone uptake and contrast. This can be determined by routine experiment.
  • the pH of the stannous-phosphate complex may be between 3 and 8.
  • the water used for making the complexes of the invention is distilled and is at an elevated temperature of 200 F. during removal 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++-pyrophosphate complex to bind the Tc. This can be determined by routine thin layer radiochro-matography to determine the percent of free or unbound Tc in the complex. The minimum amount is diqated 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.
  • the amount of Tc added to the Sn++ pyrophosphate 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.
  • sodium pyrophosphates 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.
  • saline water was used as the vehicle, any other vehicle which is pharmaceutically acceptable for intravenous administration can be used.
  • a metabolizable radioactive bone seeking composition for in vivo concentrating Tc in the skeletal structure of mammals comprising a technetium-99m-stannousphosphate complex, the phosphate moiety of which comprises pyrophosphate, said phosphate moiety containing no more than 25% by weight of linear polyphosphate of formulation P having a molecular weight greater than pyrophosphate.
  • composition according to claim 1 substantially 100% by weight of said phosphate moiety being said pyrophosphate.
  • a metabolizable, radioactive bone seeking composition according to claim 1 at least the major portion of 10 any phosphate in said phosphate moiety other than pyrophosphate being selected from the group consisting of orthophosphate and ring phosphate of formula P O f and combinations thereof.
  • composition according to claim 5 where the n of said P O is equal to 3.
  • composition according to claim 1 at least 5% by weight of said phosphate moiety being said pyrophosphate.
  • composition according to claim 1 said phosphate moiety comprising a mixture of said pyrophosphate, an orthophosphate and a ring phosphate of formula P O 9.
  • n is 3.
  • composition according to claim 1 wherein at least about of said phosphate moiety is said pyrophosphate.
  • a composition according to claim 1 substantially any phosphate in said phosphate moiety other than pyrophosphate being selected from the group consisting of a ring phosphate of formula P O one or more phosphates of formula (P O of which not more than 10% by weight has an n value greater than 2 and combinations thereof.
  • composition according to claim 11 wherein not more than 5% by weight of said (P O has an n value greater than 2.

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Abstract

1. A METABOLIZABLE RADIOACTIVE BONE SEEKING COMPOSITION FOR IN VIVO CONCENTRATING 99M TC IN THE SKELETAL STRUCTURE OF MAMMALS COMPRISING A TECHNETIUM-99M-STANNOUSPHOSPHATE COMPLEX, THE PHOSPHATE MOETY OF WHICH COMPRISES PYROPHOSPHATE, SAID PHOSPHATE MOIETY CONTAINING NO MORE THAN 25% BY WEIGHT OF LINEAR POLYPHOSPHATE OF FORMULATION PNO3N+1-(N+2) HAVING A MOLECULAR WEIGHT GREATER THAN PYROSPHOSPHATE.

Description

United States Patent 3,851,044 BONE SEEKING TECHNETIUM 99M STANNOUS PHOSPHATE COMPLEX Norman Adler, Arlington, and Leopoldo Lazaro Camin, Lexington, Mass, assignors to New England Nuclear Corporation, Boston, Mass. No Drawing. Filed Sept. 13., 1972, Ser. No. 288,577 Int. 1C1. A611: 27/04; C01g 1/00 U.S. Cl. 423249 12 Claims ABSTRACT OF THE DISCLOSURE A technetium 99m stannous-phosphate complex in which the phosphate moiety includes pyrophosphate and in which no more than to or 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 the phosphate moiety is pyrophosphate 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.
BACKGROUND OF THE INVENTION It has been known for some time that phosphates, including long chain linear polyphosphates, when introduced into the blood stream of mammals will selectively seek out and collect in the bone or skeletal structure. Pro. Soc. Exp. Biol. Med, Volume 100, pages 53-55 (1959); Journal of Labelled Compounds, AprilJune 1970, Vol. VI, No. 2, pages 166-173; Journal of Nuclear Medicine, Vol. 11, N0. 6, pages 380-381, 1970; Journal of Nuclear Medicine, Vol. 1, No. 1, January 1960, pages 113. In these cases a phosphorous atom or atoms of the phosphate are radioactive, i.e. F.
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, No. 12, 1970, page 761; Journal of Nuclear Medicine, Vol. 12, No. 1, 1971, pages 2224; Journal of Nuclear Medicine, Vol. 13, No. 2, 1972, pages 180481; Journal of Nuclear Medicine, Vol. 12, N0. 5, May 1971, pages 204- 211; Radiology, Vol. 102, January 1972, pages 185-196; Journal of Nuclear Medicine, Vol. 13, No. 1, 1972, pages 58-65.
Also, it has been suggested to label a stannous compound with Tc for radioactively imaging bone marrow, Journal of Nuclear Medicine, Vol. 11, 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 493502.
It has been suggested to employ the aforesaid Tc Ice for radioactively scanning the skeletal bone structure of mammals by complexing or binding it to tripolyphosphate carrier by use 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 To in this manner is 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 pure, near optimal 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 Tccontaining complex and the ratios of such bone uptake to uptake of the 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 INVENTION It has been discovered that if the phosphate moiety of the Tc-stannous-phosphate complex, which has been suggested in the aforesaid Radiology publication, comprises pyrophosphate (P O (which is a linear polyphosphate moiety of molecular weight less than 300), the bone uptake, bone/blood ratio, bone/liver ratio, bone/ G.I. ratio and bone/kidneys ratio are substantially increased.
It has also been discovered that optimum results are achieved 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 linear or branched chain polyphosphate (formula P O of molecular weight greater than that of pyrophosphate.
Maximum bone/liver ratios are achieved when the Tc-Sn++-pyrophosphate complex is administered to the mammal in relatively small dosages of substantially less than 20 or 25, preferably substantially less than 8 or 10 and still more preferably less than 5 or 6 (between 0.01 or 0.10 and 3 and even less provide excellent results), milligrams pyrophosphate moiety per kilogram of body weight of the mammal.
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 0 (n+2) and molecular weight greater than that of pyrophosphate seems to reduce bone take-up and the aforesaid ratios, as compared to complexes without such higher molecular weight polyphosphate. 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.
Where the pyrophosphate does not constitute of the phosphate moiety of the Tc-Sn++-phosphate complex, the rest of the phosphate moiety is preferably a ring phosphate of formula P O (with n preferably being 3 which is trimetaphosphate) and/ or ortho phosphate, and preferably a ring phosphate only, although the aforesaid limited amounts of higher molecular weight linear polyphosphates can be tolerated.
The complex is made from a water soluble alkali metal (preferably sodium) or ammonium salt or acid salt of the pyrophosphate, e.g. sodium pyrophosphate.
Preferably, the sodium pyrophosphate is admixed with a stannous salt, e.g. SnCl (the stannous salts of other acids which are pharmaceutically acceptable, i.e. safely intravenously administered, can be used) to form the stannous-pyrophosphate complex, the pH of which is adjusted to 3-8, preferably -8, by a pharmaceutically acceptable acid, such as HCl, or base, such as NaOH or Na CO or NaHCO followed by admixing with the stannous-pyrophosphate complex, an aqueous saline solution of radioactive sodium pertechnetate Tc) to form the Tc-stannous-pyrophosphate complex at the time it is desired to intravenously administer the Tc complex. The stannous-pyrophosphate complex may be sealed in a sterile non-pyrogenic container or vial as a solution or a lyophilized solid and shipped as a kit with the freshly generated sterile and non-pyrogenic Tc being added aseptically at the situs just prior to use.
DETAILED DESCRIPTION OF INVENTION (INCLUDING EXAMPLES) The following composition were prepared:
TABLE I Sample No. Description 1 A commercial sodium polyphosphate sold by FMC Corporation under the trade name FMC Glass H (average chain length of 21 and average M.W. about 1-1 A first high molecular weight fraction of the FMC Glass H of Sample 1 obtained by fractionating an aqueous solution of Sample 1 with acetone according to the technique described in Van Wazer Phophorous And Its Compounds, Interscience Publishers, Inc. 1961 (pages 744- 747) to precipitate out of the aqueous solution of the FMC Glass H, as an oil, the highest molecular weight gmtliog) of polyphosphates (composition given in 1-2 A second acetone fraction of FMC Glass H achieved by adding more acetone to precipitate out of the remaining supernatant of 1-1, as an oil, the next higher moecular 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 rst.
1-3 A third acetone fraction of FMO Glass H containing the next higher molecular weight polyphosphates is precipitated out of the remaining supernatant solution of 1-2, as an oil, upon addition of further amounts of acetone (composition given in Table 2). I
1-4 A fourth acetone traction of FMC Glass H Contai the next higher molecular weight polyphosphates (composition given in Table 2) is precipitated out of the supernatant solution of 1-3, as an oil, by adding more acetone.
1-5 A fifth acetone fraction of the EMU Glass H (oonta g the next higher molecular weight polyphosphates) (composition given in Table 2) is precipitated out of the remaining supernatant solution of 1-4, as an oil, by adding more acetone.
1-6 A sixth acetone fraction of FMC Glass H (composition given in Table 2) is precipitated out of the remaining supernatant solution of 1-5, as a solid precipitate of the next higher molecular weight polyphosphates by adding more acetone.
1-7 A seventh acetone fraction of FMC Glass H (composition given in Table 2) is precipitated out of the remaining supernatant solution of 1-6, as a solid precipitate of the next higher molecular weight polyphosphates by adding more acetone.
18......'. The residue fraction in the supernatant liquid left after removal of the 1-7 fraction (composition given in Table 2 is recovered by evaporating 011 the supernatant hquid.
2 An end acetone fraction of Sample 1 after 90% by weight had been previously fractionated ofi and leaving after removal of such end fraction 3% by weight in the supernatant (composition given in Table 2).
4 A mixture of 86% sodium trimeta hosphate (Naa aOn), 3% sodium orthophosphate NEaPOi) (molecular weight of phosphate moiety95) and sodium pyrophosphate (Na4P2O1) (linear polyphosphate-molecular weight of phosphate moiety-174) 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 is 3;". Sodium orthophosphate is a phosphate monomer. Sodium pyrophosphate is a dipolyphosphate.
5 .An acetone end fraction of a food grade wlyphosphate sold by FMC under the name FMO F (composition given in Table 2).
6 A commercial cyclic trimetaphosphate sold by Staufier Chemical. (Composition given in Table 2.)
7 Sodium orthophosphate.
8.- Sodium pyrophosphate.
Sodium tripolyphosphate. 10 Sodium tetrapolyphosphate-NanP4013-a polyphosphate-phosphate moiety having a MW. of 348. It, together with the pyrophosphate and tripolyphosphate, fall in the class of linear chain polyphosphates having the general formula PHOsni-F -An aqueous solution of each of the phosphate composition samples 1 through 1 0 (40 mg. phosphate/1 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 two 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, it is not essential (but highly preferred) to use nitrogentreated water or a nitrogen atmosphere or a nitrogenflushed 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 antioxidants in the products used.
Each of these solutions, samples 1 through 10, in an amount equal to ml., was mixed with 0.16 g. of solid SnCl .2H O under a nitrogen atmosphere. The SnCl .2H O was made by adding to 84.5 mg. of metallic tin, sufiicient 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++)-phos phate 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.
Sufficient aqueous solution 3N sodium hydroxide (sodium carbonate or bicarbonate can also be used), in the case of samples 1 through 7 and 9 and 10, and 3N HCl, in the case of sample 8, is then added to each sample to give a pH of 5.0 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 under a nitrogen atmosphere. Thereafter milliliter portions of each of the sterile solutions are poured into individual sterile and non-pyrogenic storage glass vials 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 stannousphosphate complex which aids in shipping and storage 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 stannous-phosphate 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 .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 (8 mg. phosphate per ml. solution when 5 ml. of pertechnetate is 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, non-pyrogenic ingredients and containers were used at all steps, such procedures being standard to those skilled in the art.
An eleventh sample was prepared in the manner set forth above by diluting sample 8 to a concentration of 1 mg. of phosphate per ml. of solution. This was labeled sample 11.
Each of the technetium-99m-stannous-phosphate comrefers to the phosphate moiety of sodium trimetaphosphate, Tetrameta R refers to the phosphate moiety of sodium tetrametaphosphate, both trimeta and tetrametaphosphates falling within the class of cyclic or ring phosphates having the formula P O in which Pentapoly plex-contammg solutlons 1s aseptically 1ntravenously 1nand Longer Llnear Cha1ns refers to the phosphate moiected 1n VlVO 1nto a ve1n 1n the tail of adult mice (average ety of sodium pentapolyphosphate and longer linear (linwelght 0.040 kgs.) 1n an amount equal to between 1 and car as used herein includes straight and branched linear 3 mC1 and a volume of (M2 ml. (8 mg. of phosphate per phosphate chains) polyphosphates of formula ml. solutlon in samples 1 through and 1 mg. phosphate 10 P O per ml. solution in sample 11). Also sample 8 was inn jected in the same manner except that a volume of 0.015 in which Average M.W. refers to the average molecular ml. was injected instead of 0.12 ml. to reduce the dosage weight of the phosphate moiety of the sample and in of the complex by a factor of 8. This was labeled sample which Fraction in Raw Stock with reference to sam- 12. ples 1-1, 12, 13, 14, 1-6, l-7 and l-8 refer to the Three hours after intravenous administration, some of normalized percent by weight of each of these samples the mice to which each sample was administered were in sample 1, whlch is the raw stock which is fractionated.
TABLE 2 Phosphate sample 1 (FMC) 1-1 1-2 1-3 1-4 1-6 1-7 1-8 2 4 5 6 7 8 9 10 11 12 5 4 4 4 5 5 1s 29 17 30 58 32 2 34 13 5 35 24 0.5 7 6 7 8 3 29 19 24 32 78 38 2 5 20 3 47 36 5 6 8 7 11 11 37 63 36 55 140 55 17 49 31 11 81 32 Bone/kidneys 1 1 1 1 3 2 9 12 8 9 13 12 3 9 5 1 12 6 Percent having phosphate moiety M.W. less than 300 15 3 3 5 13 17 90 100 55 99 98 98 100 100 100 10 100 100 Phosphate composition:
Ortho P (percent) 3 1.0 1 2 5 5 10 50 5 3 15 4.0 100 0 0 0 0 0 Pyro P2 (percent) 2 0.5 0.5 1 2 1 15 10 10 10 5.0 8.0 0 100 0 0 100 100 Tripoly1 (percent) 2 0.5 0.5 l 2 1 5 0 0 0 0 0 100 0 0 0 Tetra poly P4 (P81081104 2 0.5 0.5 1 3 10 5 1 0 1.0 0 0 0 90 0 0 Trimeta R3 (percent) cyc'c 8 0.5 0.5 1 4 10 60 40 86 78 86 0 0 0 0 0 0 Cyclic tetra meta R4 (percent) 4 0.5 0.5 1 4 5 40 0 0 0 0 0 10 0 0 Penta poly 1 and longer linear chains- 79 96. 5 96. 5 93 80 23 0 0 5 2 1 0 0 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 16. 2 7. 5 5. 0 6. 1 0. 7
sacrificed and the various organs of their bodies (skeletal, Conventional gamma counting techniques for measurliver, G.I., blood, kidneys) were counted by conventional ing technetium 99m take-up in the organs are convengamma ray counting techniques to determine uptake of tional gamma ray-excitable scintillation counters for Tc by each organ and thereby determine contrast of radioassaying multiple samples of the organs of the sacribone uptake as compared to uptake by the other organs. ficed mice.
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.
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 three hours after in vivo intravenous injection, in which the ratio amounts are computed from the uptake amounts adjusted to compen sate for the different weights of the organs and the different weights of the animals by dividing each uptake amount by the ratio expressed in percentage of the weight of such organ to the weight of the animal, 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 P refers to the phosphate moiety of sodium orthophosphate, Pyro P refers to the phosphate moiety of sodium pyrophosphate, Tripoly P refers to the phosphate moiety of sodium tripolyphosphate, Tetrapoly P refers to the phosphate moiety of sodium tetrapolyphosphate, Trimeta R 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.
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 Tc-Sn++ pyrophosphate complexes of the present invention are rapidly cleared from the blood by deposition in bone and excretion into urine. Thus, the technetium-99m-stannouspyrophosphate complexes are metabolizable. The deposition of the -Tc-stannous-pyrophosphate 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 radiopharmaceutical 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 (LD for sample No. 2 has been determined to be 150 mg./kg. body weight and for sample 6 it is 800 mg./kg. and for sample 8 it is 70 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.
It was found that samples 4 and 6 were only one fourth 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 par-t of a work-up in patients with known or suspected malignancy, to follow the response of metastatic or primary bone lesions to radiation therapy, metabolic bone disease, to diagnose arthritis and osteomyelitis, and to diag nose and determine healing rate of bone fractures.
The technetium-99m Tc) labelling reactions involved in preparing the Tc-stannous-phosphate complexes of the invention depend on maintaining the tin in the reduced or stannous (Snstate. Oxidants present in the pertechnetate supply may adversely affect quality.
The radioactive dosage of the Te complex of the invention may vary from 1 to 25 mCi (millicuries) but preferably is from to mCi. The dosage should preferably be substantially less than or 25, preferably less than 8 or 10 and more preferably less than 5 or 6 mg. of pyrophosphate moiety per kilogram of body weight of the mammal since greater pyrophosphate dosages than this reduces the bone-liver ratio too much. Note for example the low bone-liver ratio in sample 8 where the dosage was mg. pyrophosphate per kg. body weight compared to the bone-liver ratio of sample 11 where the dosage was 3.1 mg./kg. body weight.
Only trace amounts of pyrophosphate moiety in the dosage, e.g. as low as 0.001, more preferably 0.01, mg./kg. body weight, gives good bone take-up and boneto-other organ take-up ratios.
The dosage of pyrophosphate can be kept small either by use of more dilute dosage solutions of the pure pyrophosphate, as in sample 11 or by administering smaller doses of a more concentrated complex solution, the phosphate moiety of which contains a high concentration of pyrophosphate or by more concentrated solutions of phosphate containing, in addition to the pyrophosphate, ring phosphate and/or orthophosphate which effectively dilute the pyrophosphate concentration of the dose.
It is preferred to use a Tc-Sn++-phosphate solution containing between 0.1 and 40, more preferably between 0.5 and 4 or 5 mgs. of pyrophosphate moiety per ml. of solution.
An advantage of a complex containing a relatively large amount of ring phosphate and a smaller amount of pyrophosphate is that the ring phosphate in addition to providing excellent bone up-take and bone-to-other-organ ratios is less toxic than pyrophosphate, although pyrophosphate, alone, is still not unduly toxic.
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 .2H O and 100 mg. of sodium pyrophosphate 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 3-8 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 pyrophosphate under aseptic conditions to form the Tc-stannous-pyrophosphate, adjusting the pH to 3-8, followed by intravenous injection.
It can be seen from Table 2 that a Tc-stannousphosphate complex in which the phosphate moiety comprises pyrophosphate and in which such moiety contains no more than 25% by weight of linear polyphosphate of molecular weight greater than that of pyrophosphate (samples l-7, l-8, 2, 4, 5 and 6, 8, l1 and 12) gives surprising higher bone uptake and ratio of bone uptake to other organs, as compared to orthophosphate and other polyphosphates, e.g. tripolyphosphate, tetrapolyphosphate and longer chain polyphosphates (see samples 1, 1-2 to 1-6, 7, 9' and 10).
It can also be seen by comparing samples 8, 11 and 12 in Table 2 that the bone to liver ratio is substantially increased by reducing the amount of pyrophosphate in the dosage administered to the mammal.
The pyrophosphate moiety of the Tc-stannous-phosphate complex may be from 1 or 2% or even less up to 100% by weight of the total phosphate moiety. Preferably, the pyrophosphate moiety consists of 5 or 10% or more of the total phosphate moiety, more preferably 50% or 60% or more and most preferably between and 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 by adding the Tc solution.
Very little Sn++ need be used to form the complex of the invention, e.g. less than 7 or 10% of the phosphate based on molecular weights.
The Weight ratio of Sn++ ion to the pyrophosphate moiety may vary over a wide range, i.e. from 10- to 0.50, preferably 0.01 to 0.4. It is preferred that the molecular ratio of Sn++ to pyrophosphate moiety not exceed 2/ 1. The maximum ratio is dictated by the amount beyond which the precipitation of Sn' occurs. The minimum amount required is that amount necessary to bind a sufficient amount of Tc to the pyrophosphate to achieve good bone uptake and contrast. This can be determined by routine experiment.
The pH of the stannous-phosphate complex may be between 3 and 8.
The water used for making the complexes of the invention is distilled and is at an elevated temperature of 200 F. during removal 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++-pyrophosphate complex to bind the Tc. This can be determined by routine thin layer radiochro-matography to determine the percent of free or unbound Tc in the complex. The minimum amount is diqated 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 Tc added to the Sn++ pyrophosphate 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 pyrophosphates 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 given 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 metabolizable radioactive bone seeking composition for in vivo concentrating Tc in the skeletal structure of mammals comprising a technetium-99m-stannousphosphate complex, the phosphate moiety of which comprises pyrophosphate, said phosphate moiety containing no more than 25% by weight of linear polyphosphate of formulation P having a molecular weight greater than pyrophosphate.
2. A bone seeking composition according to claim 1, said phosphate moiety being substantially free from said linear polyphosphate.
3. A mctabolizable radioactive bone seeking composition according to claim 1, said phosphate moiety containing no more than of said linear polyphosphates of molecular weight greater than pyrophosphate.
4. A composition according to claim 1, substantially 100% by weight of said phosphate moiety being said pyrophosphate.
5. A metabolizable, radioactive bone seeking composition according to claim 1, at least the major portion of 10 any phosphate in said phosphate moiety other than pyrophosphate being selected from the group consisting of orthophosphate and ring phosphate of formula P O f and combinations thereof.
6. A composition according to claim 5, where the n of said P O is equal to 3.
7. A composition according to claim 1, at least 5% by weight of said phosphate moiety being said pyrophosphate.
8. A composition according to claim 1, said phosphate moiety comprising a mixture of said pyrophosphate, an orthophosphate and a ring phosphate of formula P O 9. A composition according to claim 8 wherein n is 3.
10. A composition according to claim 1, wherein at least about of said phosphate moiety is said pyrophosphate.
11. A composition according to claim 1, substantially any phosphate in said phosphate moiety other than pyrophosphate being selected from the group consisting of a ring phosphate of formula P O one or more phosphates of formula (P O of which not more than 10% by weight has an n value greater than 2 and combinations thereof.
12. A composition according to claim 11, wherein not more than 5% by weight of said (P O has an n value greater than 2.
References Cited Subramanian et al.: Radiology, vol. 99, pp. 192 to 196, April 1971.
LELAND A. SEBASTIAN, Primary Examiner US. Cl. X.R.
424-l; 25230l.1 R

Claims (1)

1. A METABOLIZABLE RADIOACTIVE BONE SEEKING COMPOSITION FOR IN VIVO CONCENTRATING 99M TC IN THE SKELETAL STRUCTURE OF MAMMALS COMPRISING A TECHNETIUM-99M-STANNOUSPHOSPHATE COMPLEX, THE PHOSPHATE MOETY OF WHICH COMPRISES PYROPHOSPHATE, SAID PHOSPHATE MOIETY CONTAINING NO MORE THAN 25% BY WEIGHT OF LINEAR POLYPHOSPHATE OF FORMULATION PNO3N+1-(N+2) HAVING A MOLECULAR WEIGHT GREATER THAN PYROSPHOSPHATE.
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US3976762A (en) * 1974-07-05 1976-08-24 Minnesota Mining And Manufacturing Company Multi-organ technetium complexes production and use thereof
US4075314A (en) * 1976-04-29 1978-02-21 Mallinckrodt, Inc. Stannous pyrophosphate technetium-99m compositions
US4104366A (en) * 1975-09-29 1978-08-01 Henkel Kommanditgesellschaft Auf Aktien Compositions for preparation of aqueous solutions of low valence 99 technitium salts
US4133872A (en) * 1975-09-29 1979-01-09 Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) Compositions for preparation of aqueous solutions of salts of lower valence 99 technetium
US4508704A (en) * 1984-02-27 1985-04-02 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of bicycloheptane bis(alkylamines)
US4515767A (en) * 1983-06-20 1985-05-07 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of dicyclopentadienebis(methylamine)
US4560548A (en) * 1984-04-10 1985-12-24 The Dow Chemical Company Bone seeking Tc-99m complexes of phosphonate derivatives of bis(aminoalkyl)piperazine
US4606907A (en) * 1984-07-02 1986-08-19 The Dow Chemical Company Bone seeking Tc-99m complexes of phosphonate derivatives of polyamidoamines
US4898724A (en) * 1984-06-04 1990-02-06 The Dow Chemical Company Organis amine phosphonic acid complexes for the treatment of calcific tumors
US4910012A (en) * 1988-03-30 1990-03-20 Hoechst Aktiengesellschaft Products containing Tc-99-m-ωalkylphosphinico-1-hydroxyalkane-1,1-diphosphonates for bone scintigraphy and a process for the preparation of these products
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FR2187314B1 (en) * 1972-06-06 1975-06-20 Commissariat Energie Atomique

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US3976762A (en) * 1974-07-05 1976-08-24 Minnesota Mining And Manufacturing Company Multi-organ technetium complexes production and use thereof
US4104366A (en) * 1975-09-29 1978-08-01 Henkel Kommanditgesellschaft Auf Aktien Compositions for preparation of aqueous solutions of low valence 99 technitium salts
US4133872A (en) * 1975-09-29 1979-01-09 Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) Compositions for preparation of aqueous solutions of salts of lower valence 99 technetium
US4075314A (en) * 1976-04-29 1978-02-21 Mallinckrodt, Inc. Stannous pyrophosphate technetium-99m compositions
US4515767A (en) * 1983-06-20 1985-05-07 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of dicyclopentadienebis(methylamine)
US4508704A (en) * 1984-02-27 1985-04-02 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of bicycloheptane bis(alkylamines)
US4560548A (en) * 1984-04-10 1985-12-24 The Dow Chemical Company Bone seeking Tc-99m complexes of phosphonate derivatives of bis(aminoalkyl)piperazine
US4898724A (en) * 1984-06-04 1990-02-06 The Dow Chemical Company Organis amine phosphonic acid complexes for the treatment of calcific tumors
US5066478A (en) * 1984-06-04 1991-11-19 The Dow Chemical Company Radio labeled organic amine phosphonic acid complexes for the treatment of calcific tumors
US5300279A (en) * 1984-06-04 1994-04-05 The Dow Chemical Company Organic amine phosphonic acid complexes for the treatment of calcific tumors
US4606907A (en) * 1984-07-02 1986-08-19 The Dow Chemical Company Bone seeking Tc-99m complexes of phosphonate derivatives of polyamidoamines
US4910012A (en) * 1988-03-30 1990-03-20 Hoechst Aktiengesellschaft Products containing Tc-99-m-ωalkylphosphinico-1-hydroxyalkane-1,1-diphosphonates for bone scintigraphy and a process for the preparation of these products
US8865123B1 (en) * 2010-09-16 2014-10-21 Mo-Sci Corporation Strontium phosphate microparticle for radiological imaging and therapy
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