RADIOGRAPHIC IMAGING AGENTS

Abstract: Imaging kits for radiodiagnosis containing major levels of aminophosphonate bone-seeking carriers and additive levels of stannous reductants.

Description: RADIOGRAPHIC IMAGING AGENTS BACKGROUND OF THE INVENTION This invention relates to radiodiagnostic agents, including compositions which can be reconstituted to form radiodiagnostic agents particularly useful for skeletal imaging (bone scanning). Scintigraphic skeletal imaging and similar radiographic techniques for visualizing other tissues are finding ever-increasing application in biological and medical research and in diagnostic procedures. Generally, scintigraphic procedures involve the preparation' of radioactive agents which, upon introduction into a biological subject, become localized in specific organs, tissues, or skeletal structures that are under study. When so localized, traces, plots, or scintiphotos of the distribution of the radiographic materials can be made by various radiation detectors, e.g., traversing scanners and scintilation cameras. The distribution and corresponding relative intensity of the detected radioactive material not only indicates the position occupied by the tissue in which the radionuclide is localized, but also indicates the presence of aberrations, pathological conditions, and the like. In general, depending on the type of radionuclide used and the organ of interest, a scintigraphic imaging agent as used in a hospital comprises a radionuclide, a carrier agent designed to target the specific organ, various auxiliary agents which affix the radionuclide to the carrier, water or other delivery vehicles suitable for injection into, or aspiration by, the patient, physiologic buffers and salts, and the like. The carrier attaches or complexes with the radionuclide and localizes the material in the location where the carrier naturally concentrates in a biologic subject. Technetium-99m (99mTc) is a radionuclide which is widely used in tissue imaging agents. This radionuclide is conveniently available commercially in tne oxidized pertechnetate form ,99mTc04 , hereinafter "pertechnetate-Tc99m"). However, the technetium in pertechnetate has a valence state of +7 and, thus, will not complex with the most commonly used carriers for radionuclide tissue imaging. This problem is easily overcome by reducing the technetium to what is believed to be the +3, +4, and/or +5 valence state. Thus, technetium-labeled imaging agents are generally prepared by admixing pertechnetate-Tc99m isotonic saline solution with a technetium reductant (reducing agent) such as the stannous, ferrous, or chromous salt of sulfuric or hydorchloric acid, and the desired carrier agent for targeting the organ of interest. For example, organophosphonates are known as suitable carrier agents which target technetium radionuclide to bone tissue. U.S. Patent 3,983,227, Tofe and Francis, issued September 28, 1976, discloses the use of reducing salts with radioactive pertechnetate-Tc99m solutions and organophosphonate bone-seeking carriers to prepare skeletal imaging agents. Technetium-containing scintigraphic imaging agents are known to be unstable in the presence of oxygen, primarily since oxidation of the reductant and/or the technetium destroys the reduced technetiumltargeting carrier complex. Accordingly, such imaging agents are generally made oxygen-free by saturating the compositions with oxygen-free nitrogen gas or by preparing the agents in an oxygen-free atmosphere. However, such methods are not suited to commercial practice. Stabilization of imaging agents can also be achieved through chemical means. German Offenlegungsschrift 2,618,337, Tofe, published November 11, 1976, discloses the use of ascorbate stabilizers with technetium imaging agents. U.S. Patent 4,232,000, Fawzi, issued November 4, 1980, discloses the use of gentisyl alcohol as a stabilizer for technetium imaging agents. Similarly, U.S. Patent 4,233,284, Fawzi, issued November 11, 1980, discloses the use of gentisic acid as a stabilizer. Commercial products for use in skeletal imaging are generally provided in liquid or dry powder mixture imaging "kits" with vials containing phosphate or phosphonate bone seeking carriers. Such kits typically contain relatively substantial amounts of a reducing metal salt, such as stannous chloride. It has now been discovered that certain amino diphosphonates, when used in compositions containing low levels of stannous ions, unexpectedly provide excellent skeletal images. SUMMARY OF THE INVENTION This invention encompasses a composition for the preparation of a skeletal imaging agent1 comprising: (1) an aminodiphosphonate bone-seeking carrier; and (2) an effective amount of a stannous reductant; wherein the molar ratio of the diphosphonate to stannous tin exceeds 50:1. This invention is based on the discovery that a skeletal imaging kit containing aminodiphosphonates and low levels of a stannous reductant yields a skeletal imaging agent having excellent performance, manifested through fast blood clearance and high skeletal uptake of the technetium imaging agent, i.e., the bone-targeting carrier, complexed with technetium, is concentrated in bone tissue as compared to surrounding soft tissues in the body. DESCRIPTION OF THE INVENTION As used herein, the term "imaging" refers to all radiographic tissue imaging processes for which the instant compositions may be used, including (but not limited to) skeletal imaging. The term "imaging agent" herein refers to compositions useful for imaging, including (but not limited to) skeletal imaging, such compositions comprising the product of admixing pertechnetate-Tc99m, or other useful radioisotope, to an imaging kit comprising an aminodiphosphonate tissue-seeking carrier, stannous reductant, and, optionally, a stabilizer. Hence, the term "imaging kit," or "kit," refers to the imaging agent before addition of a solution of pertechnetate-Tc99m, or similar radionuclide. The components of the composition herein, as well as methods of producing the composition, are described below. The quantity of these components incorporated into a preferred kit is enough to form multiple doses of imaging agent, as when reconstituted with a pertechnetate solution containing about 1 to 400 millicuries (mCi) of technetium-Tc99m. (The number of doses ultimately obtained from such a kit depends upon such factors as the weight of the dosed subject and the type of tissue to be imaged.) Generally, then, a preferred kit comprises: : (a) an amount of aminodiphosphonate carrier sufficient to target the technetium in a pertechnetate solution containing from about 1 to 400 mCi of techne tium-99m; (b) an effective amount of stannous reductant suffi cient to reduce the technetium in a pertechnetate solution containing from about 1 to 400 mCi tech netium-99m, and (c) an amount of stabilizer sufficient to prevent oxidation of the reductant and the reduced tech netium-99m. Components The aminodiphosphonate bone-seeking carriers useful in the instant invention are selected from the group of compounds and mixtures of compounds having the formulae: EMI4.1 wherein n is an integer from 0 to 5; R is hydrogen, hydroxy, halogen, or amino; R' is hydrogen or lower alkyl (containing from 1 to about 5 carbon atoms); R" is hydrogen, halogen, lower alkyl (containing from 1 to about 8 carbon atoms), or aryl; X is hy drogen, lower alkyl (containing from 1 to about 8 carbon atoms), aryl, alkylaryl, acetylin or haloaryl; and the pharmaceuticallyacceptable salts thereof. Among the operable aminodiphosphonate carriers of formula (I) are: propane-i -hydroxy-3-amino-i ,1 -diphosphonic acid; ethane-1 -hydroxy-2-amino-1 , 1 -diphosphonic acid; butane-i -hy- droxy-3-amino-l ,1 -diphosphonic acid; propanel -hydroxy-2-amino1 , 1 -diphosphonic acid; p ropa ne-l -hyd roxy-3-dimethy lami no-1,1 , 1 - diphosphonic acid; propane-l -hydroxy-3-diethylamino-1 ,1 -diphosphonic acid; ethane 1 -hydroxy-2-dimethylamino-1,1 -diphosphonic acid; propane-1- hydroxy-1-dimethylamino-1,1-diphosphonic acid; and butane-1- hydroxy-3-dimethylamino-1,1 -diphosphonic acid. Among the operable aminodiphosphonate carriers of formula (Il) are: methaneaminohydroxydiphosphonic acid; methaneaminodiphosphonic acid; methaneaminochlorodiphosphonic acid; methanediaminodi- phosphonic acid; methane-N-methylaminohydroxydiphosphonic acid; methane-N-methylami nodiphosphonic acid; methane-N, N-dimethyl- aminohydroxydiphosphonic acid; methane-N, N-dimethylaminodiphosphonic acid; methane-N-butylaminodiphosphonic acid; methane-N-phenylaminodiphosphonic acid; methane-N-napthylaminodiphosphonic acid; methane-N-acetylaminodiphosphonic acid; methane-N- (2-hydroxyethyl ) -aminodiphosphonic acid; methane-N- (chlorophenyl)aminodiphosphonic acid; methane-N-(2-phenylethyl)aminodiphosphonic acid; ethane-1-amino-1,1-diphosphonic acid; propane-l-amino-l,l -diphosphonic acid; butane-l-amino-l.l -di- phosphonic acid; and ethane-l-amino-l .l-diphosphonic acid. Compounds of these formulae are disclosed in U.S. Patent 3,983,227, Tofe, issued September 28, 1976 (incorporated by reference herein) and U.S. Patent 4,054,598, Blum, et al., issued October 18, 1977 (incorporated by reference herein). Preferred aminodiphosphonate carriers include methaneaminodiphosphonic acid (AMDP), methane-N-methyl aminodiphosphonic acid, methane-N, N-dimethyiaminodiphosphonic acid, meth aneaminohydroxydiphosphonic acid, propane-1 -hydroxy-3-amino- I , 1 -diphosphonic acid, and ethane-1 -hydroxy-2-amino-1,1 -diphos- phonic. Any pharmaceutical ly-acceptable, water-soluble salt or hydrolyzable ester of these aminodiphosphonates are useful herein. The alkali metal and ammonium salts are preferred. Most preferred are the aminodiphosphonate free acids themselves, and the sodium salts thereof. In order for these targeting carriers to be useful with technetium, commercially available technetium (as pertechnetate) must be reduced to form trivalent, tetravalent, and/or pentavalent technetium, which is then available to attach or complex with the targeting carrier. Reducing metal cations, such as stannous ion (Sn ) are known reductants for reducing the technetium in imaging compositions. The present invention incorporates one or more water-soluble, pharmaceutically-acceptable compounds which provide stannous ion when in solution, e.g., stannous chloride, stannous fluoride, and stannous sulfate, herein referred as "reductant" or "stannous reductant." Stannous chloride (SnC12) is particularly preferred. A sufficient amount of reductant must be included in an imaging kit to ensure complete reduction of the technetium-99m added in forming the imaging agent. This amount, herein "effective amount," is greater than or equal to (not less than) the stoichiometric amount to reduce all of the technetium in the pertechnetate to be added to the imaging kit, i.e., when the reductant is dissolved, there must be enough stannous ion in solution to reduce technetium (+7) to a lower valence state, facilitating complexation with an aminodiphosphonate carrier. Preferably, the effective amount is at least two times. the molar amount of technetium to be added to the kit. The specific quantity of stannous reductant incorporated into an imaging kit encompassed by this invention may vary according to such factors as the molecular weight of the salt, the amount of pertechnetate to be added to the kit, the desired storage time of the agent made from the kit, the presence of oxidants in the agent, and the presence of anti-oxidant stabilizers, as discussed below. In the present invention, the effective amount of reductant is such that the ratio of moles of aminodiphosphonate to moles of stannous tin contained in the kit is not less than about 50:1. Preferably the effective amount is such that the ratio of moles is not less than about 55:1, more preferably 65:1 most preferably 75:1. The molar ratio should not. exceed about 2,000:1. As used herein "stannous tin" refers to elemental Sn+2 contained in the reductant compound. Although optional, the imaging kits of this invention preferably contain a stabilizing amount of a stabilizer material to prevent or inhibit the oxidation of the reductant (e.g., oxidation +2 Sn+4, during storage and/or +4 of Sn +2 to Sn ) during storage and/or to inhibit or reduce the reoxidation of reduced technetium-99m and/or to reduce the formation of technetium-labeled impurities which may form during use of the compositions. The presence of a stabilizer is especially preferred when the low levels of reductant encompassed by this invention are used in multi-dose kits. The stabilizers optionally used herein are characterized by their toxicological acceptability under the conditions of use, their ability to stabilize the product for a reasonable period of storage and/or under usage conditions, and by their substantial non-interference with the delivery of the technetium radionuclide to bone mineral. Stabilizers that meet the foregoing requirements and that are quite suitable for intravenous injection include hydroquinone, gentisyl alcohol, gentisic acid, ascorbic acid, erythorbic acid, and their water-soluble salts and esters. Gentisic acid, ascorbic acid erythorbic acid, and their sodium salts are all known, commercially-available materials. The following documents, all incorporated by reference herein, describe useful stabilizers: U.S. Patent 4,232,200, Fawzi, issued November 4, 1980 (gentisyl alcohol); U.S. Patent 4,233,284, Fawzi, issued November 11, 1980 (gentisic acid); U.S. Patent 4,229,427, Whitehouse, issued October 21, 1980 ( hydroquinone); and German Offenlegungsschrift 2,618,337, Tofe, published November 11, 1976 (ascorbic acid). The sodium salt of ascorbic acid is a preferred stabilizer for use in a multi-dose dry-powder embodiment of this invention. Also preferred are the "reductate" stabilizers described in concurrently filed European Patent plication N , "Stable Radiographic Imaging Agents," Fawzi, et al. (incorporated by reference herein). As is known in the literature, stabilizer materials such as ascorbic acid can chelate/complex with technetium and cause it to be deposited in uncalcified soft tissue. Since the user of a kit encompassed by the present invention will wish to avoid all unnecessary deposition of technetium in soft tissue, it will be appreciated that the amount of stabilizer material optionally included should not be so great as to overshadow the bone-directing effect of the diphosphonate carrier thereby interfering with the bone scan. Appropriate, non-interfering amounts of stabilizer materials for use in combination with the diphosphonates may vary according to the diphosphonate and/or stabilizer used. Guidelines for determining such amounts are known in the art. Composition and Methods The composition of this invention comprises: (1) an aminodiphosphonate carrier; (2) a stannous reductant, and optionally (3) a stabilizer; wherein the molar ratio of diphosphonate to stannous tin is greater than or equal to about 50:1, preferably greater than or equal to about 55:1, more preferably by greater than or equal to 65:1 most preferably greater than or equal to about 75:1. This "molar ratio," or "[DP/Sn]" herein, is the ratio of the number of moles of diphosphonate present in the composition to the number of moles of stannous tin present. A single unit-dose kit (that may be reconstituted to form an amount of imaging agent suitable for a single injection) for diphosphonates useful in the invention, containing no more than the maximum quantity of reductant encompassed by this invention, comprises at least from about 2 x 10 7 to about 2 x 10 moles of diphosphonate and about 4 x moles stannous tin. The imaging agents made with the kits of this invention are intended for intravenous injection into humans or lower animals. Accordingly, appropriate manufacturing and operating conditions are employed so as to provide suitably sterile, pyrogen-free compositions. Although not necessary to the practice of the present invention, it is preferable to use a pharmaceutically-acceptable extender or filler to dilute the reducing and diphosphonate salts in order to simplify metering the requisite small quantities of such salts. Sodium chloride and glucose are preferred; sodium chloride is especially preferred inasmuch as its addition will assure that the resulting agent is at least isotonic even if the pertechnetate-Tc99m solution is hypotonic (as is the case when it must be diluted with sterile water to reduce its activity.) The compositions of the present invention can be prepared by simply dry mixing the technetium reductant and the diphosphonate carrier. The optional stabilizer can also be dryblended into such mixtures, as can any additional, non-interfering agents such as sodium chloride. Such compositions are preferably placed in sterile vials fitted with a rubber septum, thereby facilitating mixing with a pertechnetate-Tc99m solution and convenient use in the hospital. The vials are preferably nitrogen-filled as an added protection against oxidation of the technetium reductant on storage. In an alternate mode, the compositions herein can be provided as aqueous solutions in sterile, pyrogen-free water. Preferably, the water is deoxygenated and the composition is stored under nitrogen, thereby minimizing undesirable oxidation of the pertechnetate reductant on storage. Since the reductant is more prone to oxidize in solution than in the dry powder and freeze-dried composition forms, it is especially preferred that aqueous compositions contain a stabilizer. In a preferred mode, the compositions herein can be provided in freeze-dried (lyophilized) form. Such compositions are prepared by co-dissolving the diphosphonate carrier and the technetium reductant in an aqueous solution, together with any desired optional stabilizers, and freeze-drying the composition using standard equipment. Preferably, sterile, deoxygenated water is used in processing and the product is stored under nitrogen. Although somewhat more complicated to manufacture than the dry mixture product, the freeze-dried product offers the advantage that water-insoluble particulate matter which might be present in the raw materials can be removed by filtration prior to the freeze drying step. A preferred method of producing a lyophilized kit includes the steps of: (1) preparing an aqueous solution bf diphosphonate carrier, reductant, and optional stabilizer. (2) adjusting the solution formed in step 1 to pH with a particular range; and (3) Iyophilizing the pH-adjusted solution. The particular pH range employed in the process described above is dependent upon the presence and/or nature of stabilizer used in the kit composition. If there is no stabilizer used, or if gentisic acid, gentisyl alcohol, hydroquinone, or pharmaceuti cally-acceptable salts thereof are used as a stabilizer, then the pH range employed is from about 4.2 to about 4.8, preferably about 4.5. If ascorbic acid, erythorbic acid, the pharmaceuti cally-acceptable salts thereof, or reductate stabilizers are used, then the pH range employed is from about 5.5 to about 6.5, preferably about 6.0. The preferred process of producing lyophilized kits, as described above, is described in concurrently filed European Patent Appllcation Number , "Process for Making a Lyophi lized Product For Use in Skeletal Imaging," Van Duzee (process incorporating diphosphonates with or without gentisic acid sta bilizers) and in concurrently filed Eblrol?ean Patent Application Number , "Process for Making a Lyophilized Product For Use in Skeletal Imaging," Van Duzee and Degenhardt (process incorporating diphosphonates with ascorbate or reductate stabi lizers). These aforementioned applications are incorporated by reference herein. The compositions of this invention are dissolved with a pertechnetate-Tc99m isotonic solution from a commercial technetium source to yield an imaging agent suitable for intravenous injec tion. The stability of such imaging agents is ample under ordinary hospital conditions. Administration is preferably done within about eight hours after addition of the pertechnetate-Tc99m solution. Preferably, the concentration of reagents and tech netium radionuclide is sufficient that about 1 milliliter of the solution is used in an adult of about 50-100 kg body weight. One milliliter of solution is preferably injected intravenously over a period of about 30 seconds. The total dosage of radionuclide for a sharp skeletal or myocardial infarct scan ranges from about 5 mCi to about 30 mCi, preferably from about 10 mCi to about 20 mCi. See also (incorporated by reference herein), U.S. Patent 4,234,562, Tofe et al., issued November 18, 1980; and U.S. Patent 4,247,534, Bevan, issued January 27, 1981. The following non-limiting examples illustrate the composition, production, and use of the present invention. EXAMPLE I An imaging kit, emcompassed by the present invention, was produced with the following ingredients: Component Quantity in Bulk Quantity in Kit monosodium salt of AMDP 300. mg 3.0 mg stannous chloride 4.0 mg 0.040 mg sodium chloride 3000. mg 30.0 mg The AMDP and sodium chloride were dissolved in sterile, nitrogen-purged (deoxygenated) water. After dissolution of these components, the stannous chloride was dissolved in the solution. Sodium hydroxide was added to adjust the pH to 4.5. Sterile, deoxygenated water was added to bring the solution volume to 100 ml. One milliliter aliquots of the solution were placed in sterile, nitrogen purged vials. The vials were then freeze-dried (lyophilized) in a commercial lyophilizer, stoppered and sealed. The kit composition had a [DP/Snj of about 67. An imaging agent is prepared using this kit by adding about 5 ml of a pertechnetate-Tc99m physiological saline solution, with an activity of about 75 mCi, from a commercial technetium source. The vial is agitated until the kit components are dissolved. About 1 ml of the agent is slowly injected, over a period of about 30 seconds, into an adult human subject weighing about 75 kg. Excellent skeletal images are then obtained using a scintillation camera. In the kit prepared above, methaneaminohydroxydiphosphonic acid, methane-N-methylaminodiphosphonic acid, methane N, N-dimethylaminodiphosphonic acid, propane-l -hydroxy-3-amino 1 , 1 -diphosphonic acid, ethane-i -hydroxy-2-amino-i 1 -diphosphonic acid, and the monosodium salts thereof are, respectively, used instead of AMDP, with substantially similar results. EXAMPLE II An imaging kit encompassed by the present invention, is produced with the following ingredients: monosodium salt of methane-N,N-dimethyl diphosphonic acid 3.06 mg stannous chloride 0.037 mg sodium chloride 30.0 mg gentisic acid 0.80 mg The kit is prepared by blending the dry powder ingredients into sterile, oxygen-free vials. The vials are then sealed. The kit has a [DP/Sn] of about 65. Excellent skeletal images are obtained when this kit is used to prepare an imaging agent and the agent is injected, as in Example I. In the foregoing kit, gentisyl alcohol, hydroquinone, and the sodium salts thereof are, respectively, added with substantially similar results. EXAMPLE Ill An imaging kit encompassed by the present invention is produced with the following ingredients: Component Quantity in Bulk Quantity in Kit monosodium salt of propane-l-hydroxy-3-amino-l, 1-diphosphonic acid 330.0 mg 3.3 mg stannous chloride 4.9 mg 0.049 mg ascorbic acid 71.0 mg 0.71 mg sodium chloride 600 mg 6.0 mg Kits are made according to the process described in Example I, except that the stabilizer is added and dissolved and the pH of the carrier/reductant/stabilizer solution is adjusted to a pH of about 6.0. The kits have a [DP/Snj of about 50. When an imaging agent is made with this kit, and injected as in Example I, excellent skeletal images are obtained. In the kit prepared above, erythorbic acid, 6-bromo-6deoxyascorbic acid, reductic acid, 5-methylreductic acid, nictinic acid and nicotinamide complexes thereof, and the sodium salts thereof are, respectively, used instead of ascorbic acid, with substantially similar results. Also, in the foregoing kit, stannous fluoride, stannous sulfate, stannous citrate, and stannous tartrate are, respectively, used instead of stannous chloride, in an amount sufficient to yield a [DP/Sn] of about 50 with substantially similar results. Further, in the foregoing kit, the relative amount of reductant used is varied (decreased) so that the kit has a [DP/Sn] of greater than 50, with substantially similar or better results. Lyophilized kits were made, according to the process of Example I, with the following compositions: Table I Quantity Quantity of Carrier of SnCl Kit Carrier(monosodium salt per Vial per vial [DP/Snl thereof) A AMDP 3.01 mg .02 mg 134 B AMDP 3.01 mg .04 mg 67 C AMDP 3.01 mg .08 mg 34 D AMDP 3.01 mg .16 mg 17 E AMDP 3.01 mg .24 mg 11 (These kits contained no stabilizer.) Each kit vial was reconstituted by addition of 5 ml of a pertechnetate-Tc99m physiological saline solution with an average activity of approximately 24 mCi. A 50 microliter dose of each imaging agent thus formed was injected into a fasted rat of an average weight of about 200 g. One dose of an imaging agent was injected into each rat studied, with four rats injected for each kit made. Scintiscans were taken of rats that were injected with agents made from each kit described in Table I, above. The rats were then sacrificed and blood, muscle, and bone tissue removed and placed in tared scintillation counting vials. The samples were weighed and radioassayed, along with a control sample of the original imaging agent made from each kit, using a gamma-scintil lation spectrometer. Table II, below, summarizes the distribution of the tech netium-99m imaging agents in each rat's body, as a function of the [DP/Sn] of the imaging kit used to produce the agent. This distribution is a function of the carrier retention by various body tissues and is recorded in Table II as the relative bone to muscle retention ratio and the relative bone to blood retention ratio. TABLE II Kit Carrier [DP/Sn] Bone/Muscle Bone/Blood A Aminodiphosphonomethane 134 769 113 B Aminodiphosphonomethane 62 899 125 C Aminodiphosphonomethane 34 813 115 D Aminodiphosphonomethane 17 562 78 E Aminodiphosphonomethane 11 559 78 This data clearly demonstrates the effect on the distribution of technetium-99m imaging agent as a function of the [DP/Sn] of the kit used to produce the agent. In particular, at the higher values of [DP/Sn], the imaging agent is concentrated more heavily in bone tissue as compared to soft tissue and blood. Thus imaging kits comprising aminodiphosphonate carriers and stannous reductants, with a [ DP/ Sn l of at least 50, yield imaging agents with excellent imaging qualities, i.e., high bone/soft tissue retention and good blood clearance.

Claims: CLAIMS 1. An imaging kit, characterized in that it comprises: (a) a carrier selected from the group of compounds and mixtures of compounds having the formulae EMI17.1 wherein n is an integer from 0 to 5, R is hydrogen, hydroxy, halogen, or amino, R' is hydrogen or lower alkyl containing from 1 to ¯¯¯¯¯ 5 carbon atoms, R" is hydrogen, halogen, lower alkyl, or aryl, X is hydrogen, lower alkyl, aryl, alkylaryl, acetyl, or haloaryl and the pharmaceutically-acceptable salts thereof; and (b) an effective amount of reductant containing stan nous tin; wherein the molar ratio of said carrier to said stannous tin is greater than ¯ 50:1. 2. An imaging kit, according to Claim 1, characterized in that said molar ratio is at least 55:1. 3. An imaging kit, according to Claim 1 or 2, characterized in that said molar ratio is at least 65:1. 4. An imaging kit, according to any of Claims 1-3, characterized in that said molar ratio is at least 75:1. 5. An imaging kit, according to any of Claims 1-4, characterized in that said stannous reductant is stannous chloride. 6. An imaging kit, according to any of Claims 1-5, characterized in that it further comprises an effective amount of a stabilizer selected from gentisic acid, gentisyl alcohol, ascorbic acid, erythorbic acid, and pharmaceutically-acceptable salts and mixtures thereof. 7. An imaging kit, according to any of Claims 1-6, characterized in that said carrier is selected from methaheamino- diphosphonic acid and the pharmaceutically-acceptable salts and mixtures thereof. 6. An imaging kit, according to any of Claims 1-6,- characterized in that said carrier is selected from propane 1-hydroxy-3-amino-1,1-diphosphonic acid and the pharmaceuticallyacceptable salts and mixtures thereof. 9. An imaging kit, according to any of Claims 1-6, characterized in that said carrier is selected from methane N,N-dimethylaminodiphosphonic acid and the pharmaceuticallyacceptable salts and mixtures thereof. 10. An imaging kit, according to any of Claims 1-5 and 7-9, characterized in that it further comprises a reductate stabilizer selected from 6-bromo-6-deoxyascorbic acid, 6-chloro6-deoxyascorbic acid, reductic acid, 5-methylreductic, nicotinic acid and nicotinamide complexes thereof, and pharmaceuticallyacceptable salts and mixtures thereof.

Inventors: BENEDICT, JAMES JOHN, VANDUZEE, BARRY FOSTER
Applicants: MALLINCKRODT, INC. (A DELAWARE CORPORATION)
Application year: 1983
Main classification: A61K49
IPC codes: A61K51