Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
  • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
  • A61K51/04—Organic compounds
  • A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
• • 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
  • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
  • C07F13/005—Compounds without a metal-carbon linkage

Definitions

• the present invention relates to technetium-99m, mono-, di-, and polyphosphonate complexes, to a method of preparation of the complexes, and to the radiopharmaceuti- cal compositions of the complexes.
• Technetium, as pertechnetate, from generators is in the +7 oxidation state, which does not combine with bone-seeking agents (mono-, di-, and polyphosphonates) to provide bone scans. This problem is easily overcome by reducing the pertechnetate to the +3, +4 and/or +5 oxidation state.
• Technetium-99m does not itself seek or react with the skeleton, but must first be complexed to an agent which does react with the skeleton.
• 99m Tc bone scanning agents are prepared by mixing a pertechnetate-99m saline solution with a pertechnetate reducing agent in the presence of a bone- seeking agent to produce the radiolabelled complex.
• Kits containing the bone-seeking agent (generally, a diphosphonate) and a pertechnetate-99m reducing agent are readily available from commercial sources.
• the technetium-99m diphosphonate solutions consist of a complex mixture of components as identified by numerous peaks in the high performance liquid chromatogram (HPLC) , indicating that the agent is not a single, pure species in solution (T.C. Pinkerton, .R. Heineman, E. Deutsch, Anal. Chem. , 52, 1106-1110, 1980) .
• HPLC high performance liquid chromatogram
• the various components of the technetium-99m diphosphonate formulations characterized and isolated by HPLC have dramatically different biodistribution patterns evidenced by different bone, blood, and soft tissue uptakes of the isolated species.
• the complex composition of the technetium-99m diphosphonate formulations can be altered by heating as determined by HPLC characterization of the formulation (T.C. Pinkerton, D.L.
• Preparations of radiolabelled bone scanning agents can be inproved by adding energy, in the form of heat, to a reconstituted kit containing a phosphonate ligand, 99ra Tc pertechnetate solution, a reducing agent, and optionally a stabilizer.
• the added energy improves the bone scanning agent by i ⁇ proving blood and soft tissue clearance. This allows patients to be scanned at shorter times after injection of the agent and lowers the radiation dose to non-target tissues.
• the bone scanning agent may be heated within the scope of the present invention using such methods as an autoclave, boiling water bath, microwave oven, or ultrasonic bath. Combinations of the foregoing methods may also be use.
• Figure 1 shows the HPLC of 99m Tc-HMDP kit at room temperature, pH 4.2.
• Figure 2 shows the HPLC of 99 ⁇ Tc-HMDP kit autoclaved for 60 minutes, pH 4.2.
• Figure 3 shows the HPLC of 99 ⁇ Tc-HMDP kit autoclaved for 60 minutes at pH 2.5-3.0.
• Figure 4 shows the HPLC of 99m Tc-MDP Kit prepared at room temperature.
• Figure 5 shows the HPLC of 99 ⁇ Tc-MDP kit autoclaved for 60 minutes, pH 6.85.
• Figure 6 shows the HPLC of 99 ⁇ Tc-MDP kit autoclaved for 60 minutes at pH 2.5.
• Figure 7 shows the HPLC of ""Tc-HEDP Kit prepared at room temperature.
• Figure 8 shows the HPLC of 99n Tc-HEDP kit autoclaved for 60 minutes, pH 4.5.
• Figure 9 shows the HPLC of 99m Tc-HEDP kit autoclaved for 60 minutes at pH 2.5.
• the present invention includes a method of preparing bone scanning agents by heating the compositions and in some cases lowering the pH of the composition during the heating process.
• the kit is comprised of pertechnetate 99m Tc, a phosphonate, a reductant, and an optional stabilizer at about pH 1-10, preferably from pH 1-5, heated from 50°C-150°C for 5 minutes to 2 hours, preferably greater than 75°C for 5 to 60 minutes, or microwaved at 300-750 watts for 10 seconds to 5 minutes, preferably at 300-500 watts for 30 seconds to 2 minutes, or sonicated in an ultrasonic bath for 5 to 30 minutes, preferably with heating for 5 to 15 minutes.
• the foregoing time periods are based upon a typical imaging agent volume of about 10 mL. Those skilled in the art will appreciate that for smaller volumes, the time periods may be reduced.
• These temperature-modified formulations are also more stable than the formulations prepared at room temperature based upon changes in HPLC over time.
• a broad range of mono-, di- and polyphosphonic acids and their pharmaceutically acceptable salts are now known to concentrate on the skeleton upon injection of solutions thereof into a patient.
• Operable species for this purpose include mono-, di- and polyphosphonates selected from the group consisting of:
• each R is hydrogen or CH 2 OH and n is an integer of from 3 to 10;
• n is an integer of from 3 to 9;
• each R 3 is hydrogen or lower alkyl (e.g., methyl, ethyl, propyl and butyl) ;
• n is an integer of from 2 to 4.
• Suitable reactive phosphonate salts for use with the present invention include sodium, potassium, ammonium and low molecular weight substituted ammonium (e.g., mono-, di and tri-ethanolamine and quaternary ammonium) salts of the above phosphonates and mixtures thereof.
• Operable polyphosphonates of the above formula (I) 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-pentaphosphonic 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; octane-1,2,3,4,5,6,7,8-octaphosphonic acid, nonane-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, triethanolammonium, diethanolammonium, and
• Butane-l,2,3,4-tetraphosphonic acid and salts thereof can be prepared by a process disclosed in U.S. Pat. No. 3,755,504 to D. Allan Nicholson and Darrel Campbell.
• the higher aliphatic vicinal polyphosphonates and salts thereof can be prepared by the process disclosed in U.S. Pat. No. 3,584,035 granted June 8, 1971.
• operable polyphosphonates encompassed by the above formula (II) are et__ane-l-hydroxy-l,l-diphosphonic acid; methanediphosphonic acid; methanehydroxydiphosphonic acid; ethane-1,1,2-triphosphonic acid; ethane-2-phenyl-1,1- diphosphonic acid; ethane-2-naphthyl-l,l-diphosphonic acid; methanephenyldiphosphonic acid; ethane-1-amino-1,1- diphosphonic acid; methanedichlorodiphosphonic acid; nonane-5,5-diphosphonic acid; n-pentane-1,1-diphosphonic acid; methanedifluorodiphosphonic acid; methanedibromodi-
• any pharmaceutically acceptable salt of ethane- 1-hydroxy-1, 1-diphosphonic acid can be used in the practice of this invention, mixtures of the disodium and trisodium salts are most preferred.
• mixtures of the disodium and trisodium salts are most preferred.
• sodium, potassium, ammonium, and mono-, di-, and triethanolammonium salts and mixtures thereof are also suitable, provided caution is observed in regulating the total intake of cation species in the salt composition.
• These compounds can be prepared by any suitable method, however, an especially preferred method is disclosed in U.S. Patent No. 3,400,149 granted Sept. 3, 1968.
• Methanehydroxydiphosphonic acid and related conpounds operable herein can be prepared, for example, by reaction of phosgene with an alkali metal dialkylphosphite. A complete description of these conpounds and a method for preparing same is found in U.S. Pat. No. 3,422,137 granted Jan. 14, 1969.
• Methanedihydroxydiphosphonic acid and salts useful herein and a method for preparing same are disclosed in U.S. Pat. No. 3,497,313 granted Feb. 24, 1970.
• Methanediphosphonic acid and related compounds useful herein are described in detail in U.S. Pat. No. 3,213,030, granted Oct. 19, 1965. A preferred method of preparing such compounds is disclosed in U.S. Pat. No. 3,251,907 granted May 17, 1966.
• Ethane-1,1,2-triphosphonic acid and related conpounds which can be used in the compositions of this invention, as well as a method for their preparation, are fully described in U.S. Pat. No. 3,551,339 granted Dec. 29, 1970.
• Propane-l,l,3,3-tetraphosphonic acid and related conpounds useful herein, and a method for preparing same are fully disclosed in U.S. Pat. No. 3,400,176 granted
• the higher methylene interrupted methylene diphosphonate polymers can be prepared by the polymerization of ethylene-1,1-diphosphonate.
• Pentane-2,2-diphosphonic acid and related compounds can be prepared in accordance with the method described by
• Cperable phosphonates of formula (III) above include the following: Methanecyclobutylhydroxydiphosphonic acid
• Methanecyclooctylhydroxydiphosphonic acid Methanecyclononylhydroxydiphosphonic acid
• the preferred phosphonates of formula (IV) for the purpose of this invention are tris (phosphonomethyl)mine; tris (1-phosphonoethyl)amine; tris(2-phosphonopropyl)amine; and their pharmaceutically acceptable salts.
• Tris (phos- phonomethyl)amine is especially preferred.
• the following are exemplary of conpounds which can also be used:
• the pharmaceutically acceptable salts of acids (a) through (f) e.g., sodium, potassium, ammonium triethanol ⁇ ammonium, diethanolammonium, andmonoethanolammonium salts.
• the tris(phosphonoalkyl)amines can be prepared, for example, by first preparing the corresponding ester accordance with the general reaction:
• R is alkyl and R ⁇ and R 2 are hydrogen or low alkyl.
• the free acids can be prepared by hydrolysis of ester using strong mineral acids such as hydrochloric acid.
• the salts are, of course prepared by neutralizing the acid with the base of the desired cation.
• the preparation of tris(phosphonoalkyl)amines is fully disclosed by Irani, et al., in Canadian Pat. No. 753,207, issued Feb 21, 1967.
• the phosphonates of formula (V) include the following; (1) 3,3,4,4,5,5-hexafluoro-1,2-diphosphonocyclopent-l-ene;
• the perfluorodiphosphonocycloalkenes can be prepared, for exanple, by reacting trialkyl phosphites with 1,2- dichloroperfluorocycloalk-1-enes in accordance with the procedures fully described by Frank in J. O. Chem., 31, #5, p. 1521.
• the phosphonates of formula (VI) is referred to herein as cyclic tetraphosphonic acid.
• This compound and its pharmaceutically acceptable salts can be prepared by any suitable method, however, an especially preferred method is disclosed by Oscar T. Quimby, U.S. Pat. No. 3,387,024 granted June 4, 1968. Operable phosphonates encompassed by the above formula
• VTI are ethane-l,2-dicarboxy-l-phosphonic acid; and the pharmaceutically acceptable salts of these acids, e.g., sodium potassium, ammonium, triethanolammonium, diethanol- ammonium, and monoethanolammonium salts. While the above formula (VII) is representative of cis-isomers, the corresponding trans-isomers are also useful herein. Reference hereinafter to ethane-1,2-dicarboxy-1-phosphonic acid or salts thereof, unless otherwise specified, is intended as contemplating the cis- and trans-isomers and mixtures thereof.
• Ethane-1,2-dicarboxy-1-phosphonic acid and related compounds useful herein can be prepared by reaction of an ester of acetylenedicarboxylic acid and a dialkyl phosphite followed by hydrolysis and saponification. This method is more fully described in U.S. Patent No. 3,584,124, granted June 8, 1971.
• the sodium salt of formula (VIII) can be made by the rearrangement reaction of a 2-haloethane-1-hydroxy-1,1- diphosphonic acid with about 3 equivalents of sodium hydroxide as disclosed in U.S. Patent No. 3,641,126.
• the phosphonate of formula (IX) can be made by the method of German Offenlegunsschrift No. 2,076,078.
• Operable carboxyphosphonates of the above formula (X) include ethane-l,2-dicarboxy-l,2-diphosphonic acid; ethane- 1,2-dicarboxy-1,2-dihydroxy-1,2-diphosphonic acid; ethane- 1,2-dicarboxy-1-hydroxy-1,2-diphosphonic acid; and the pharmaceutically acceptable salts of these acids, e.g., sodium, potassium, ammonium, triethanolammonium, diethanol- ammonium and monoethanolammonium salts.
• Ethane-1,2-dicarboxy-1,2-diphosphonic acid a preferred carboxyphosphonate herein, has the molecular formula CH(COOH) (P0 3 H 2 )CH(COOH) (P0 3 H 2 ) .
• the most convenient crystallizable salts of this acid are obtained when three, four or five of the acid hydrogens are replaced by sodium.
• any pharmaceutically acceptable salt of ethane- 1,2-dicarboxy-1,2-diphosphonic acid can be used in the practice of this invention, the tetrasodium dihydrogen 15 atom; lower alkenyl (containing from 2 to about 8 carbon atoms) ; nicotinic acid and nicotinamide complexes thereof and pharmaceutically-acceptable salts, esters, and amides thereof.
• Preferred conpounds of formula (XI) include halogen- substituted ascorbic acids of the formula:
• Compounds of this formula (XII) include 6-bromo-6-deoxyascorbic acid, 6-chloro-6- 0 deoxyascorbic acid, and 6-iodo-6-deoxyascorbic acid.
• Another class of preferred compounds of formula XI include conpounds of the formula:
• Conpounds of this formula (XIII) include reductic acid, 4-methyl reductic 0 acid, 5-ethyl reductic acid, 5-methyl reductic acid, and 5- ethyl reductic acid.
• a third group of preferred conpounds include the nicotinamide complexes of compounds of formula (XI); i.e.:
• X, Y, and R are as defined above, and Z is OH or NH 2 .
• Compounds of this formula XIV include nicotinic acid and nicotinamide complexes of 6-bromo-6-deoxyascorbic acid, 6-chloro-6-deoxyascorbic acid, reductic acid, and 5- methylreductic acid.
• the salt and ester forms of reductate stabilizers suitable for use in the present invention can be selected for use according to their solubility in a pertechnetate solution. It is, of course, preferable that the salts and esters be readily soluble in a pertechnetate solution.
• suitable salts include the alkali metal, alkaline earth metal, heavy metal and ammonium salts.
• the alkali metal salts such as sodium, potassium and lithium salts are readily soluble and accordingly preferred for use herein.
• Various ammonium salts, wherein the cation is N(R') 4 are also suitable for use herein. These include, for example, alkylammonium, alkanolammonium and arylammonium salts.
• ammonium salts are largely dependent upon the number and nature of the substituent groups on the nitrogen atom.
• preferred readily soluble ammonium salts include those wherein each R' is either hydrogen or C ⁇ to about C 5 hydrocarbyl.
• Nonlimiting examples of pharmaceutically-acceptable ammonium salts useful herein include the ammonium, methyl- ammonium, dimethylammonium, tetramethylammonium, bis- (tetramethylammonium) .
• 2-hydroxypropylammonium, bis- (2- hydroxypropylammonium) , ethanolamnonium, diethanolammonium, 13 salt, the trisodium trihydrogen salt, the disodium tetrahydrogen salt, the monosodium pentahydrogen salt, and the mixtures thereof are useful.
• the other potassium, ammonium, and mono-, di-, and triethanolammonium, etc., salts and mixtures thereof are also suitable provided caution is observed in regulating the total intake of cation species in the salt composition.
• Ethane-1,2-dicarboxy-1,2-diphosphonic acid and suitable salts thereof can be prepared in any convenient manner.
• the reaction described by Pudovik in "Soviet Research on Organo-Phosphorus Conpounds", 1949- 1956, Part III, 547-85c. can be used to prepare the ester of ethane-l,2-dicarboxy-l,2-diphosphonic acid which in turn can, by ordinary hydrolysis reactions, be converted to the free acid form.
• Neutralization by alkali compounds such as sodium hydroxide, potassium hydroxide, carbonates and the like can be used to prepare a desired salt of the acid.
• a more detailed description of the preparation of these compounds is described in U.S. Pat. No. 3,562,166 granted Feb. 9, 1971.
• Ethane-1,2-dicarboxy-1,2-dihydroxy-l,2-diphosphonic acid and related conpounds useful herein can be prepared by reaction of an ester of ethane-1,2-dicarboxy-1,2- diphosphonic acid and an alkali metal hypohalite followed by hydrolysis and saponification. This method is more fully described in U.S. Pat. No. 3,579,570 granted May 18, 1971.
• phosphonic acids and/or salts can be used in the practice of this invention.
• preferred phosphonic acids and/or salts for use within the scope of the present invention include methanediphosphonic acid (MDP) , Methanehydroxydiphosphonic acid (HMDP) , ethane-1-hydroxy-1,1-diphosphonic acid (HEDP) , N,N-dimethylaminomethanediphosphonic acid (DMAD) , propane- 2,3-dicarboxy-1,1-diphosphonic acid (DAD), and pharmaceutically acceptable salts thereof.
• MDP methanediphosphonic acid
• HMDP Methanehydroxydiphosphonic acid
• HEDP ethane-1-hydroxy-1,1-diphosphonic acid
• DMAD N,N-dimethylaminomethanediphosphonic acid
• DAD propane- 2,3-dicarboxy-1,1-diphosphonic acid
• Suitable pertechnetate reducing agents include metal salts of sulfuric acid and hydrochloric acid, such as stannous chloride, chromous chloride, cuprous chloride, and ferrous sulfate.
• Other agents capable of reducing pertechnetate include, for example, cuprous and ferrous salts with ascorbic acid or salts of ascorbic acid, titanous halides, acid-thiosulfates, acid-hydrogen- sulfates, salts of sulfites, salts of bisulfites, acid- bisulfites, salts of dithionites, acid dithionites, acid-sulfites, iron colloids, acid borohydrides, salts of phosphites, acid-phosphites, salts of hypophosphites, acid- hypophosphites, salts of molybdenum(III) , salts of nitrite, hydrazines, dithiothreitol, hydroxylamines, dihydroxy- benzene
• Suitable stabilizing agents include ascorbic acid and water soluble salts and esters of ascorbic acid, gentisic acid and water soluble salts and esters of gentisic acid, hydroquinone, erythorbic acid and water soluble salts and esters of erythorbic acid, and reductate stabilizers.
• Reductate stabilizers are compounds and mixtures of compounds of the formula:
• X is CRR' , O, or NR' is hydrogen, or lower alkyl
• Y is oxygen, sulfur, nitrogen or CH 2 ;
• R is hydrogen, lower alkyl containing from
• alkaline earth metal salts for example the calcium and magnesium salts, although less soluble, are also suitable for use herein.
• the heavy metal salts, for exanple the iron and tin salts, are also suitable for use herein.
• the pharmaceutically-acceptable esters of the reductate stabilizers include, for example, the C x to C 20 alkyl esters such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, octyl, and palmityl esters.
• the choice of reductant is not critical.
• pertechnetate reductant is intended to include compounds, complexes, or the like, comprising a reducing ion capable of reducing heptavalent technetium
• Tc0 4 " trivalent, tetravalent and/or pentavalent technetium.
• Free metals such as tin are also known for use as pertechnetate reductants, although undissolved metal must be removed from the imaging solution prior to infection into the patient. Thus, it is more convenient to use metal compounds which provide the reducing-metal cation in soluble form.
• An Osteoscan ® HDP kit (Mallinckrodt Medical, Inc.) was reconstituted to 3 mL with a combination of saline and pertechnetate solution eluted from a 99 ⁇ Tc generator (MMI) in accordance with the package insert. The solution was allowed to stand for 5 minutes at room temperature.
• MMI 99 ⁇ Tc generator
• a second Osteoscan ® HDP kit was prepared as in Example 1. However, the reconstituted vial was autoclaved (121°C, 15 psi) for 60 minutes. The solution was allowed to cool to room temperature and then analyzed by HPLC chromato- graphy as in Exanple 1. The resulting chromatogram shows a single peak which elutes later than the collection of peaks shown in Exanple 1, indicating a change in the composition anddistributionof 99 ⁇ Tc-HMDPoligomers/polymers in the reaction mixture as evidenced by HPLC analysis.
• Figure 2 shows the HPLC of 99n Tc-HMDP kit autoclaved for 60 minutes, pH 4.2.
• a third Osteoscan ® HDP kit was prepared as in Exanple
• Example 1 The resulting chromatogram shows primarily a single peak which elutes early compared ' to either Example
• Example 4 However, the reconstituted vial was autoclaved
• Example 4 shows the HPLC of 99tI Tc-MDP kit autoclaved for 60 minutes, pH 6.85.
• FIG. 6 shows the HPLC of 99n Tc-MDP kit autoclaved for 60 minutes at pH 2.5.
• EXAMPLE 7 Preparation of Lyophilized Kits containing HEDP Lyophilized (freeze-dried) kits were prepared, each containing 5.9 mg of disodium etidronate (HEDP) , 0.19 mg of stannous chloride dihydrate (pertechnetate reductant) , and 0.56 mg of gentisic acid (stabilizer) .
• the pH of this formulation is about pH 4.5 upon reconstitution with 5 mL of isotonic saline.
• EXAMPLE 9 Preparation of an Autoclaved --TM y -- ED>? Kit
• An HEDP kit was prepared as in Example 8. However, the reconstituted vial was autoclaved (121°C, 15 psi) for 60 minutes. The solution was allowed to cool to room temperature and then analyzed by HPLC chromatography as in Example 8. The resulting chromatogram shows a single late eluting peak compared to• the chromatogram in Exanple 8, indicating a change in the composition and distribution of 99lt Tc-HDP oligomers/polymers in the reaction mixture as evidenced by HPLC analysis.
• Figure 8 shows the HPLC of 99rn Tc-HEDP kit autoclaved for 60 minutes, pH 4.5.
• Example 10 An HEDP kit was prepared as in Example 10. The pH 2.5 reconstituted vial was autoclaved for 60 minutes as in Example 2. The solution was allowed to cool to room temperature and analyzed by HPLC chromatography as in Exanple 8. The resulting chromatogram shows several peaks which elute differently compared to either Exanple 8 or Exanple 9, indicating a change in the composition and distribution of 99 ⁇ Tc-HEDP oligomers/polymers in the reaction mixture as evidenced by HPLC analysis.
• Figure 9 shows the HPLC of 99 ⁇ Tc-HEDP kit autoclaved for 60 minutes at pH 2.5.
• An Osteoscan ® HDP kit is prepared as in Exanple 1.
• the pH is adjusted to 1 with hydrochloric acid.
• the reconstituted vial is placed in a Sonicor Model SC-150TM ultrasonic bath with heat control for 5 minutes.
• the solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Exanple 1.
• the resulting chromatogram shows primarily a single peak which elutes early compared to either Example 1 or Example 2 which suggests the composition and distribution of 99tI Tc-HMDP oligomers/polymers is similar to Exanple 3.
• a Technescan ® MDP kit is prepared as in Example 4. The pH is adjusted to 8 with sodium hydroxide. The reconstituted vial is placed in a Sonicor Model SC-150TM ultrasonic bath with heat control for 30 minutes. The solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Example 4. The resulting chromatogram shows a broad late eluting peak as well as several peaks which elute similar to Example 4 which suggests the composition and distribution of 99 ⁇ Tc-MDP oligomers/polymers is similar to Example 5.
• Example 8 Preparation of a Sonicated ""T -HEDP Kit at pH 4.5
• An HEDP kit is prepared as in Example 8.
• the reconstituted vial is placed in a Sonicor Model SC-150TM ultrasonic bath with heat control for 15 minutes.
• the solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Example 8.
• the resulting chromatogram shows primarily a single peak which elutes later than Example 8 which suggests the conposition and distribution of 99 ⁇ Tc-HEDP oligomers/polymers is similar to Example 9.
• Exanple 15 Preparation of a Microwaved 99 ⁇ Tc-HMDP Kit at pH 4.2
• An Osteoscan ® HDP kit is prepared as in Example 1.
• the reconstituted vial is placed in a microwave oven having a power rating of 750 watts for 30 seconds.
• the solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Exanple 1.
• the resulting chromatogram shows primarily a single peak which elutes later than Exanple 1 which suggests the conposition and distribution of 99r Tc-HMDP oligomers/polymers is similar to Exanple 2.
• Exanple 16 Preparation of a Microwaved 99n Tc-MDP Kit at pH 2
• a Technescan ® MDP kit is prepared as in Exanple 4. The pH is adjusted to 2 with hydrochloric acid. The reconstituted vial is placed in a microwave oven having a power rating of 500 watts for 2 minutes. The solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Exanple 4. The resulting chromatogram shows primarily a single peak which elutes early compared to Exanple 4 which suggests the composition and distribution of 99 Tc-MDP oligomers/polymers is similar to Exanple 6. A second HPLC is performed after allowing the solution to sit at room temperature for 24 hours. The resulting HPLC chromatogram is essentially identical to the earlier chromatogram indicatingthat the 99n Tc-MDPoligomers/polymers in the reaction mixture are stable over time.
• An HEDP kit is prepared as in Example 8. The pH is adjusted to 1 with hydrochloric acid. The reconstituted vial is placed in a microwave oven having a power rating of
• Example 8 300 watts for 5 minutes. The solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Example 8. The resulting chromatogram shows several peaks which elute early compared to Example 8 which suggests the composition and distribution of 99tI Tc-HEDP oligomers/polymers is similar to Example 11.
• Example 18 Preparation of a Boiled 99 ⁇ Tc-HMDP Kit at pH 7
• An Osteoscan ® HDP kit is prepared as in Example 1. The pH is adjusted to 7 with sodium hydroxide. The reconstituted vial is placed in a boiling water bath for 60 minutes. The solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Example 1. The resulting chromatogram shows primarily a single peak which elutes late conpared to Example 1 which suggests a change in the composition and distribution of 99m Tc-HMDP oligomers/polymers in the reaction mixture as evidenced by HPLC analysis.
• a Technescan ® MDP kit is prepared as in Example 4. The pH is adjusted to 5 with hydrochloric acid. The reconstituted vial is placed in a boiling water bath for 10 minutes. The solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Example 4. The resulting chromatogram shows a collection of peaks which elute early compared to Exanple 4 which suggests a change in the composition and distribution of 99lI Tc-MDP oligomers/polymers in the reaction mixture as evidenced by HPLC analysis.
• Example 2Q Preparation of a Boiled 99m Tc-HEDP Kit at pH 9
• An HEDP kit is prepared as in Example 8. The pH is adjusted to 9 with sodium hydroxide. The reconstituted vial is placed in a boiling water bath for 120 minutes. The solution is allowed to cool to room temperature and is analyzed by HPLC chromatography as in Example 8. The resulting chromatogram shows a single late eluting peak compared to Exanple 8 which suggests a change in the composition anddistributionof 99 ⁇ Tc-HEDP oligomers/polymers in the reaction mixture as evidenced by HPLC analysis.
• An Osteoscan ® HDP kit is prepared as in Exanple 3. The 99n Tc-HMDP is administered to a patient at a dosage of 10 mCi. Scintigraphic skeletal images of the patient are obtained approximately one hour post injection. The skeletal images are of good quality and suggest that the 99 ⁇ Tc-HMDP cleared rapidly from blood and soft tissue.
• the 99m Tc-MDP is administered to a patient at a dosage of
• Example 23 Administration and Imaging of Microwaved 9 ⁇ Tc-HEDP
• An HEDP kit is prepared as in Example 17. The 99tn Tc-HEDP is administered to a patient at a dosage of 20 mCi. Scintigraphic skeletal images of the patient are obtained approximately two hours post injection. The skeletal images are of good quality and suggest that the 99 ⁇ Tc-HEDP cleared rapidly from blood and soft tissue.
• the present invention provides technetium-99m mono-, di- and polyphosphonate conpositions which clear rapidly from the blood and soft tissue to allow scanning of the patient in less than 4 hours post-injection and to lower the radiation dose to non-target tissues.
• the invention may be embodied in other specific forms without departing from its spirit or essential characteristics.
• the described embodiments are to be considered in all respects only as illustrative and not restrictive.
• the scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope. What is claimed is:

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• 1994
  • 1994-06-03 BR BR9408590A patent/BR9408590A/pt not_active Application Discontinuation
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