Method of use for therapeutic bone agents

Abstract

To provide radioactive, bone-seeking, pharmaceutical compositions that are administered multiple times to a patient, have a lower impurity profile and a longer shelf life, and are less expensive to prepare.SOLUTION: A composition possesses an extended expiration date of the Sm-153 used to prepare the composition greater than or equal to about 5 days based on Eu-154 present in the formulation being less than 0.093 μCi Eu-154 / mCi Sm-153. The composition comprises LSA Sm-153 and DOTMP or a physiologically acceptable salt thereof.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to a method of using a bone-loving radioactive metal chelator suitable for administration to a patient suffering from bone pain, one or more calcified tumors, or a patient in need of a myelosuppressive procedure, wherein said method of treating the patient comprises multiple treatments with low specific activity (LSA) Sm-153 1,4,7,10-tetraazacyclododecane tetramethylene phosphonic acid (DOTMP). [Background technology]

[0002] Description of Related Art Bone cancer can be primary or metastatic. Primary cancer occurs when the bone cells themselves are cancerous, and although it is a relatively rare disease, it is very aggressive and mainly affects younger patients. Current treatment options include chemotherapy and external beam radiation therapy, and many patients have amputated the affected limb. Metastatic bone cancer occurs when cancer cells from soft tissue cancer grow on the bone. Cancers originating from the prostate, breast, and lung tend to metastasize to the bone in this way. Metastatic bone cancer can be very painful and reduces the patient's function. Pain control is achieved by increasing amounts of anesthetic drugs, greatly reducing the patient's quality of life.

[0003] Radiopharmaceuticals, which are radioactive drugs, are used as treatments for bone cancer. Cancer cells growing in bone cause higher turnover of bone in close proximity to them. The strategy of these drugs is to target this rapidly growing bone. Note that these bone-loving radiopharmaceuticals target the nearby bone tissue, not the cancer cells themselves.

[0004] Two classes of these radiopharmaceuticals are used for this purpose. The first class includes radioactive metal salts. Examples of such agents are Sr-89 and Ra-223, both formulated as chloride salts. These metals are similar to calcium, so they are concentrated in bone. Strontium-89 has a long half-life (50.57 days) and high beta energy (maximum beta energy is 1.463 MeV). These two properties, combined with the lack of imageable gamma photons, have greatly reduced the use of this Sr-89 agent. Radium-223 is a radioactive isotope that emits alpha radiation that follows a decay chain, producing a variety of daughter isotopes. The range of alpha particles is very short (approximately 0.1 mm) compared to the range of beta particles (approximately 0.3 mm), which may limit the usefulness of Ra-223 to effectively treat bone cancer.

[0005] The second class of bone-affinity radiopharmaceuticals consists of phosphonate chelates such as Sm-153-ethylenediaminetetramethylenephosphonic acid, in which radioactive Sm is chelated to the phosphonic acid ethylenediaminetetramethylenephosphonic acid (EDTMP). One such example is Quadramet® (a trademark of EUSA PHARMA (USA), INC), a commercially available chelate formed between Sm-153 and EDTMP, whose current indication is pain associated with bone metastases (U.S. Pat. No. 4,898,724).

[0006] No. 5,059,412 teaches the use of Sm-153, Gd-159, Ho-166, Lu-177, and Yb-175 chelates using chelating agents derived from the 1,4,7,10-tetraazacyclododecane moiety, including 1,4,7,10-tetraazacyclododecanetetraazacyclododecane-tetramethylenephosphonic acid (DOTMP), while U.S. Pat. No. 5,064,633 teaches the above metals in addition to Y-90.

[0007] Therapeutically effective biodistribution (fate of radioactivity after administration) for a therapeutic bone agent includes high bone uptake, low soft tissue uptake, rapid clearance of non-bone-bound radioactivity, and a high lesion-to-normal bone ratio. Compositions that do not have these properties would be harmful to the patient. For example, high soft tissue uptake would result in the patient receiving a high radiation dose to the liver, bone marrow, or other soft tissues, causing undesirable side effects.

[0008] The phosphonate ligand keeps the Sm soluble and delivers it to the bone. In this case, the decay of Sm-153 releases beta particles that are useful for treating the tumor, and gamma photons that help determine the fate of the isotope via gamma camera imaging. Sm-153 also has a half-life of about 46 hours. Although these conditions seem ideal, the EDTMP / Sm complex is relatively unstable, so a large excess of chelating agent relative to Sm must be used (approximately 300:1 ligand to metal ratio). This excess ratio also requires the use of high specific activity (HSA) Sm-153. Preparing HSA samarium-153 generates large amounts of long-lived radionuclide impurities (see Figure 2). These long-lived isotopes make waste disposal more difficult, and when patients undergo multiple treatments, these isotopes accumulate in the patient's bones. In a study by Sinzinger et al. (QJ NUCL MED MOL IMAGING 2001;55:420-30), they discuss the presence of long-lived impurities like Eu-154 in Sm-153 EDTMP when administered multiple times to patients, using high-resolution gamma spectroscopy as a whole-body counter (see Figure 3). Their results showed that the unwanted dose from the Eu isotope increases with every treatment. This accumulation is undesirable, since the effects of the long-lived isotopes in the patient are unknown.

[0009] All of the radiopharmaceuticals currently available for this purpose have drawbacks and improved radiopharmaceuticals for treating bone cancer are needed.

[0010] To that end, the inventions discussed in WO2015 / 054173 and WO2016 / 191413 have been made by the present applicant and are incorporated herein by reference. WO2015 / 054173 discloses a method of treating a patient with LSA Sm-153 DOTMP and a two-vial kit. WO2016 / 191413 discloses an improved kit formulation with three vials that allows LSA Sm-153 DOTMP to be more accurately and easily produced in radiopharmacy.

[0011] Radionuclides such as Sm-153 are prepared in nuclear reactors by bombarding a purified elemental target that is one neutron short with particles, creating radionuclide impurities in the process. For example, to create Sm-153, the target that is irradiated is Sm-152, and Eu-154 is the unwanted impurity that is formed.

[0012] These impurities can be harmful to the facility both from a patient and waste disposal perspective. For example, if too much Eu-154 is administered to a patient, the isotope will give the patient undesirable doses over an extended period of time, especially if multiple injections for treatment are given. Additionally, the dose excreted in urine by patients with Eu-154 is a concern, and facilities may be forced to collect radioactive urine. Disposal of product vials containing residual radioactivity can be problematic. These vials and syringes are typically allowed to decay for 10 half-lives before disposal. This is a reasonable time for Sm-153 (approximately 20 days), but not for Eu-154 (approximately 86 years). Procedures must be taken to address waste disposal of used vials and syringes. This makes the use of these types of radiopharmaceuticals more complicated, and facilities may choose not to use the drug.

[0013] Furthermore, these long-lived impurities pose a problem for the facility's radiological licensing process. Typically, a facility is only permitted small amounts of long-lived radionuclides (half-lives greater than 120 days) before it is required to have financial assurances. Financial assurances can be very expensive, especially for facilities that only work with short-lived isotopes.

[0014] The specifications for Quadramet (registered trademark) (Sm-153 EDTMP) state that the product will be used until its expiration date ( http: / / health.phys.iit.edu / extended_archive / 0001 / msg00922.html , http: / / acnp-cal.org / SM153INS.html ) or on the 4th day after the date of manufacture ( http: / / www.ibamolecular.eu / products / quadramet ) contains less than 0.093 microcuries of Eu-154 per millicurie of Sm-153. This limit limits the shelf life of the drug. The longer the Sm-153 solution decays, the greater the amount of Eu-154 in the sample compared to Sm-153, since Sm-153 decays faster than Eu-154. Thus, the shelf life of the compounded Quadramet® (e.g., Ca-EDTMP+Sm-153) as well as the Sm-153 used to make Quadramet® is limited by the amount of Eu-154 in the sample.

[0015] In reactors such as those at the University of Missouri (Columbia MO), Sm-152 samples are irradiated in a "flux trap" (see Figure 1) for a week to produce the high specific activity (HSA) Sm-153 required for the production of Quadramet®. Because the flux trap is only accessed once a week, high specific activity Sm-153 can only be produced on a weekly basis. Because of the increasing amount of Eu-154 compared to Sm-153 over time, the Sm-153 isotope is only available for a short time. Thus, the drug is only available to treat patients for a few days a week. Additionally, the flux trap portion of the reactor is very expensive to access (requiring reactor shutdown), increasing the cost of producing the HSA Sm-153 isotope. Summary of the Invention [Problem to be solved by the invention]

[0016] There is a clear need for products with longer shelf life and better impurity profiles for use in multiple patient treatments. [Means for solving the problem]

[0017] The present invention provides a method for treating a patient suffering from bone pain, one or more calcified tumors, or in need of myelosuppressive treatment, comprising administering to said patient multiple doses of a pharma- ceutically acceptable formulation of a chelating composition comprising a Clinically Relevant Dosage of the chelating composition that is therapeutically effective upon multiple injections without accumulation of long-lived isotopes in the patient, wherein the Sm-153 used to prepare said composition has an extended shelf life of about 5 days or more, based on less than 0.093 μCi of Eu-154 per mCi of Sm-153 present in the formulation. The chelating composition comprises LSA Sm-153 and DOTMP or a physiologically acceptable salt thereof, and the dosage of Sm-153 is at least about 30 mCi per dose.

[0018] Each treatment is less toxic to bone marrow and results in less accumulation of long-lived radionuclide isotopes in patients when compared to the use of HSA Sm-153 chelates. The present invention includes such treatments of bone cancer using low specific activity (LSA) Sm-153 chelated to a macrocyclic chelator, DOTMP. LSA Sm-153-DOTMP is easier to prepare, more readily available, and significantly less costly than high specific activity (HSA) Sm-153. This was discussed in WO2015 / 054173 (incorporated herein by reference). The present invention provides for the use of this LSA Sm-153 DOTMP as a multiple injection treatment in patients without unwanted accumulation of long-lived isotopes such as Eu-154. [Brief description of the drawings]

[0019] [Figure 1] Schematic of the irradiation locations available at the University of Missouri Research Reactor (MURR). High specific activity (HSA) Sm-153 is prepared in flux traps, which require reactor shutdown and are expensive. Low specific activity (LSA) Sm-153 is prepared in reflectors, which are much easier to access and can be performed more frequently. Courtesy of MURR. [Diagram 2] High-resolution gamma spectrum of HSA Sm-153 showing long-lived radioactive impurities. H. Fisher, et al., “Radionuclidic purity aspects of Sm-153 for radionuclide therapy,” Proceedings of the International Congress of the International Radiation Protection Agency, May, 2004. [Diagram 3] Radioactive Eu impurities detected in bone after 1, 7, and 10 treatments with 153Sm-EDTMP. H. Fisher, et al., “Radionuclidic purity aspects of Sm-153 for radionuclide therapy,” Proceedings of the International Congress of the International Radiation Protection Agency, May, 2004. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Detailed Description of the Invention It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used herein, the singular forms "a," "an," and "the" include plural references unless the content specifically dictates otherwise. The following terms in the glossary used in this application are defined as set forth below, and for these terms, the singular includes the plural.

[0021] Various headings are provided to assist the reader, but these are not exclusive of all aspects of the subject matter addressed and should not be construed as limiting the location of such discussion.

[0022] Additionally, certain U.S. patents and published PCT applications are incorporated by reference. However, the text of such patents is incorporated by reference only to the extent that there is no conflict between such text and other statements contained herein. In the event of such a conflict, such conflicting text in the incorporated by reference U.S. patent or PCT application is not specifically incorporated into this patent.

[0023] Glossary % means percent by weight unless otherwise specified. By patient it is meant a warm-blooded animal, mammal, or human, any of which may be treated as described in the present invention.

[0024] "Clinically Relevant Dosage" means sufficient activity to cause relief of pain or reduction in tumor burden. This dose is about 0.5 mCi per kg of body weight, or about 30 mCi per dose for a 70 kg patient. More preferably, it is about 1.0 mCi per kg of body weight, or about 70 mCi per dose for a 70 kg patient. Larger doses of radiation may be administered to a patient to treat the patient's tumor regression or bone marrow ablation.

[0025] DOTMP means 1,4,7,10-tetraazacyclododecane tetramethylene phosphonic acid. EDTMP means ethylenediaminetetramethylenephosphonic acid.

[0026] The expiration date means the number of days after manufacture if the Sm-153 contains 0.093 μCi or more of Eu-154 per mCi of Sm-153. FDA means the United States Food and Drug Administration.

[0027] HSA stands for High Specific Activity, which for Sm-153 is defined as greater than about 4 Ci / mg, which is 1E14 neutrons / m 2 It is prepared by irradiation for more than 120 hours with a neutron flux of more than 1 second. LSA stands for low specific activity, which for Sm-153 is defined as less than about 4 Ci / mg, which is about 1E14 neutrons / m 2 It is prepared by irradiation with a neutron flux of less than 1 second for less than 120 hours.

[0028] Ci stands for Curie. μCi stands for microcurie. mCi means millicuries.

[0029] Multiple Doses means treating a patient with two or more clinically relevant doses of Sm-153 DOTMP, which can range from 2 to an indefinite number of doses, e.g., 5 to 100 doses to a patient, with these doses typically spaced apart, such as every 3 months, 6 months, or 12 months.

[0030] Consideration The specific activity of an isotope can be expressed in many ways, which can be a source of confusion ( http: / / pharmacyce.unm.edu / program_information / freelessonfiles / Vol16Lesson5.pdf(See Practical Aspects of labeling DTPA and DOTA peptides with Y-90, In-111, Lu-177 and Ga-68 for Peptide-Receptor Scintigraphy and peptide-Receptor Radionuclide Therapy in preclinical and Clinical Applications.)

[0031] In the present invention, the specific activity of an isotope is defined as the activity (mCi or Bq) of the isotope in question divided by the mass of all isotopes (stable and radioactive) of the element. For example, in the case of reactor-produced Sm-153, where starting material Sm-152 is converted to Sm-153, the specific activity of Sm-153 is the amount of activity of Sm-153 in the sample divided by the total mass of any Sm element in the sample (e.g., activity of Sm-153 / sum of masses of Sm-152 and Sm-153). The units of value are usually curies per gram (Ci / g) or curies per mole (Ci / mole). In some cases, the percentage of radioisotopes is reported. For example, in reactor-produced Sm-153, only about 2% of the Sm is Sm-153, and about 98% is non-radioactive Sm-152.

[0032] Traditionally, nuclear medicine scientists strive to increase the specific activity of the isotope of interest. For example, two government grants have been recently awarded to provide high specific activity isotopes ( High Specific Activity Sm-153 by Post Irradiation Isotope Separation , DOE SBIR Grant No. DE-FOA-0000676, and Production of Commercial High Specific Activity Sn-117m Radiochemical and Chelates, DOE Grant No. DE-FOA-000782). The use of high specific activity (HAS) isotopes allows for a reduction in the mass of isotope required to achieve the same amount of radioactivity. This reduces the amount of chelator and / or protein required for the radiopharmaceutical. Furthermore, in many cases, such as with labeled antibodies or proteins, the receptors on the cells (e.g., cancer cells) that the drug targets are limited. If the specific activity of the isotope is low (e.g., 2% of the atoms are radioactive), the amount of radiopharmaceutical that reaches the target is relatively small. However, if the specific activity is high (the majority of the atoms are radioactive), the amount of effective drug that reaches the target is much greater, and for this reason, a great deal of effort is being put into the production of radioisotopes to achieve higher specific activities.

[0033] In contrast to this conventional wisdom in which higher specific activity isotopes are desired, the present invention utilizes Sm-153, which is produced in a shorter time in the lower flux portion of the reactor (reflector) (see Figure 1), to obtain low specific activity (LSA) isotopes at significantly reduced cost and lower impurity profile. When combined with DOTMP, products containing clinically relevant doses of Sm-153-DOTMP can be produced with a lower radionuclide impurity profile, longer shelf life, lower production cost, and more frequent patient availability. Since toxicity from accumulated long-lived isotopes in multiple dose formulations is unknown (see Figure 2), it is prudent to utilize LSA Sm-153 to reduce these long-lived isotopes in the formulation. This allows for multiple administrations of LSA Sm-153 chelated to DOTMP; for example, more than 3 to up to 100 administrations to patients.

[0034] The present invention provides a method for treating a patient suffering from bone pain, one or more calcified tumors, or in need of myelosuppressive treatment, comprising administering to said patient a pharma- ceutically acceptable formulation of a chelate composition comprising a clinically relevant dose of a chelate composition that is therapeutically effective upon multiple administrations without quantifiable accumulation of long-lived isotopes in the patient, wherein said composition has an extended shelf life of about 5 days or more of Sm-153 used to prepare said composition, based on less than 0.093 μCi of Eu-154 per mCi of Sm-153 present in the formulation, and wherein said chelate comprises LSA Sm-153 and DOTMP or a physiologically acceptable salt thereof. Clinically relevant doses are about 0.3 to about 1.5 mCi per kg body weight, preferably about 0.5 mCi per kg body weight, or about 30 mCi per dose for a 70 kg patient, more preferably about 1.0 mCi per kg body weight, or about 70 mCi per dose for a 70 kg patient. The expiration date, meaning the number of days after manufacture when the Sm-153 contains 0.093 μCi or more of Eu-154 per mCi of Sm-153, is 5 days, 10 days, or more at the time of expiration. Multiple doses are at least 5 doses for patients administered at 3 month intervals, or 10 doses for patients administered at 6 month intervals for the last 5 doses.

[0035] The present invention provides a better radiopharmaceutical for the treatment of bone cancer for the following reasons: The radiopharmaceutical is composed of LSA Sm-153 combined with the chelating agent DOTMP. Unlike the chelate formed between Sm and EDTMP, a comparative commercial product, the Sm-DOTMP complex is not unstable and does not dissociate easily. Therefore, a stable complex can be prepared using a much smaller ratio of DOTMP to Sm-153 (approximately 1:1 ligand to metal ratio) compared to Sm-EDTMP (approximately 300:1 ligand to metal ratio). Furthermore, this stability may allow the use of LSA Sm-153, which is readily available, inexpensive, and contains significantly less long-lived radionuclide impurities compared to HSA Sm-153 (see Figure 2). Furthermore, the bone marrow toxicity associated with doses of Sm-153-DOTMP is lower than the equivalent doses of Sm-153-EDTMP. Without wishing to be bound by theory, it is believed that the reason for this reduced toxicity is that the Sm-DOTMP chelate is more stable, and therefore less free metal is released in the formulation, and the chelate may also be diluted in the patient's bloodstream, resulting in less available free metal. Small amounts of free metal may enter the bloodstream and precipitate as particles that are taken up by the bone marrow. Small amounts of radioactive Sm-153 thus deposited directly in the bone marrow may cause additional bone marrow toxicity. This stability is important when multiple doses are required for treatment.

[0036] The formulation of the present invention may be a kit in which the two components (chelator and isotope) are mixed at a suitable time before use, or a three-component kit as described in WO2016 / 191413. Whether premixed as a drug or a kit in which the drug is generated on-site, the formulation requires a pharma- ceutically acceptable carrier. Such carriers include any suitable pharma-ceutically acceptable carrier, such as one or more of a suitable solvent, preservative, diluent, excipient, and buffer. Useful solvents include, for example, water, aqueous alcohol, and glycol. The formulation is administered to the patient by intramuscular or intravenous injection, or near the tumor or upstream of the blood supply to the tumor.

[0037] The chelate composition comprises a therapeutically effective, pharma- ceutically acceptable, clinically relevant dose of a composition having an extended shelf life of the Sm-153 used to prepare the composition, which is about 5 days or more, and the chelate comprises Sm-153 and DOTMP or a physiologically acceptable salt thereof. The composition is prepared from Sm-153 having a specific activity of less than 3 Ci / mg at the end of irradiation and less than 10 μCi of Eu-154 per Ci of Sm-153 at the end of irradiation. The composition is capable of delivering 1E14 neutrons / cm in a nuclear reactor. 2 Prepared from Sm-153 produced at a subsecond flux, the chelate comprises Sm-153 and DOTMP or a physiologically acceptable salt thereof, where the dose of Sm-153 is at least 30 mCi.

[0038] The invention will be further clarified by consideration of the following examples, which are intended to be purely exemplary of the invention.

[0039] Materials and equipment: Radioisotopes were purchased from the University of Missouri Research Reactor. Chelators were either purchased from commercial sources or prepared as described in US Pat. No. 5,059,412.

[0040] General Procedure In the following examples, lettered examples are comparative examples and numbered examples are inventive.

[0041] Example A Comparative Example - Production of Sm-153 in MURR Reactor Fluxtrap 1 mg of Sm-152 (as samarium oxide) was sealed in a quartz vial and irradiated for approximately 150 hours in a MURR (HSA) flux trap. At the end of the irradiation, the ratio of Eu-154 to Sm-153 was approximately 18 μCi of Eu-154 per Ci of Sm-153.

[0042] Example B Comparative Example - Treatment of a Patient with Fluxtrap Irradiated Sm-153 (HSA) Doses of Sm-153-EDTMP were prepared using Sm-153 prepared as in Example A. These doses were used to treat a patient suffering from bone cancer. The patient was repeatedly treated (10 times) with 30 mCi of Sm-153-EDTMP prepared in this example. The first 5 doses were given at 3-month intervals, and the second 5 doses were given at 6-month intervals. After the decay of Sm-153, NaI crystals were used to detect the amount of remaining radioactivity in the patient. After receiving 7 doses, a significant amount of radioactivity was detected in the patient, which increased with each subsequent dose. This radioactivity was due to long-lived radionuclide impurities generated during the target irradiation process.

[0043] Example C Comparative Example - Vienna Protocol by Dr. Helmut Sinzinger et al., QJ NCUL MED MOL IMAGING 2001; 55:420-30 Approximately 550 patients were treated with prostate and breast bone metastases for pain relief with repeated doses of 30 mCi of Sm-153-EDTMP at the following times: 5 doses at 3-month intervals; 5 doses at 6-month intervals; 5 doses at 9-month intervals; and several doses at irregular intervals of 12 months.

[0044] The results showed regression of lesions and improved survival. However, long-lived impurities in the HSA Sm-153-EDTMP were evident, as shown in Figure 2. Accumulation of these long-lived isotopes can be seen in Figure 3.

[0045] Example 1 Production of Sm-153 on the MURR reflector (LSA) One milligram of Sm-152, expressed as samarium oxide, was sealed in a quartz vial and irradiated for two days in the reactor reflector at MURR. At the end of the irradiation, the ratio of Eu-154 to Sm-153 was approximately 0.5 μCi of Eu-154 per Ci of Sm-153.

[0046] Example 2 Treatment of dogs with LSA Sm-153-DOTMP Seven dogs with osteosarcoma were treated with 1 mCi / kg of Sm-153-DOTMP made from the LSA Sm-153 of Example 1. All dogs had tumor uptake. As evidenced by platelet and neutrophil nadirs, the dogs showed approximately half the myelosuppression of similar dogs treated with 1 mCi / kg of HSA Sm-153-EDTMP.

[0047] Example 3 MTD of LSA Sm-153-DOTMP A dose escalation study of 13 dogs starting at 1.5 mCi / mg demonstrated tumor uptake in all 7 dogs studied. Maximum tolerated doses ranged from 1.75 to 2.0 mCi / kg, whereas the maximum tolerated dose for Sm-153-EDTMP was 1.0 mCi / kg. Stable or improved endpoints were experienced in 7 of 12 dogs.

[0048] Example 4 Treatment of patients with reflector-irradiated Sm-153 (LSA) Doses of Sm-153-DOTMP are prepared using Sm-153 prepared as in Example 1. These doses are used to treat patients suffering from bone cancer. The patient is repeatedly (10 times) treated with 30 mCi of Sm-153-DOTMP prepared in this example. The first 5 doses are administered at 3 month intervals, and the next 5 at 6 month intervals. After the decay of Sm-153, NaI crystals are used to detect the amount of radioactivity in the patient. After 10 doses, there should be no detectable amount of radioactivity in the patient from long-lived radionuclide impurities in the treatment.

[0049] While the present invention has been described with reference to preferred embodiments thereof, those skilled in the art will recognize, upon reading and understanding this disclosure, changes and modifications which do not depart from the scope and spirit of the invention. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention.

Claims

1. 1. A method of treating a patient suffering from bone pain, one or more calcified tumors, or in need of myelosuppressive treatment comprising administering to said patient a pharma- ceutically acceptable formulation of a chelate composition comprising a clinically relevant dose of a chelate composition that is therapeutically effective in multiple doses without quantifiable accumulation of long-lived isotopes in the patient, said composition having an extended shelf life of about 5 days or more of Sm-153 used to prepare said composition, based on less than 0.093 μCi of Eu-154 per mCi of Sm-153 present in the formulation, and said chelate comprises LSA Sm-153 and DOTMP or a physiologically acceptable salt thereof.

2. 2. The method of claim 1, wherein the amount of Sm-153 is about 0.3 to 1.5 mCi / kg or more.

3. 3. The method of claim 2, wherein the amount of Sm-153 is about 0.5 mCi / kg.

4. 10. The method of claim 1, wherein the shelf life of the Sm-153 used to prepare the chelate composition is about 10 days or more.

5. 10. The method of claim 1, wherein the multiple doses are at least five doses to the patient administered at three month intervals.

6. 10. The method of claim 1, wherein the multiple doses are at least 10 doses administered to the patient at 3 month intervals for the first 5 doses and then 6 month intervals for the final 5 doses.

7. 2. The method of claim 1, wherein the composition contains less than 0.093 μCi of Eu-154 per mCi of Sm-153 at the end.

8. 10. The method of claim 1, wherein the clinically relevant dose is about 0.5 mCi per kg of body weight, or about 30 mCi for a 70 kg patient.

9. 10. The method of claim 1, wherein the clinically relevant dose is about 1.0 mCi per kg of body weight, or about 70 mCi for a 70 kg patient.

10. The method of claim 1 , wherein the pharma- ceutically acceptable formulation comprises one or more of a suitable solvent, preservative, diluent, excipient, and buffer.

11. 10. The method of claim 9, wherein the solvent of the formulation is water, hydroalcohol or glycol.

12. 1. A chelate composition comprising a therapeutically effective and pharma- ceutically acceptable clinically relevant dose of a composition, said composition having an extended shelf life of Sm-153 used to prepare said composition, said shelf life being greater than or equal to about 5 days, and said chelate comprising Sm-153 and DOTMP or a pharma- ceutically acceptable salt thereof.

13. 13. The chelate composition of claim 12, wherein the composition is prepared from Sm-153 having a specific activity at the end of radiation exposure that is less than 3 Ci / mg.

14. 13. The chelate composition of claim 12, wherein the composition is prepared from Sm-153 having a Eu-154 concentration of less than 10 μCi of Eu-154 per Ci of Sm-153 at the end of irradiation.

15. The composition has a neutron density of 1E14 neutrons / cm 2 13. The chelate composition of claim 12, prepared from reactor-produced Sm-153 at subsecond flux, said chelate comprising Sm-153 and DOTMP or a physiologically acceptable salt thereof, wherein the dose of Sm-153 is at least 30 mCi.

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