How to use therapeutic bone agent

Abstract

The present invention relates to radioactive, bone-compatible pharmaceutical compositions that may be administered multiple times to a patient, have a lower impurity profile, a longer shelf life, and are cheaper to prepare.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a method of using a bone-loving radioactive metal chelator suitable for administration to patients with bone pain, one or more calcified tumors, or patients requiring myelosuppressive procedures, 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 bone cells themselves are cancerous, and although this is a relatively rare disease, it is very aggressive and primarily affects younger patients. Current treatment options include chemotherapy and external beam radiation therapy, and many patients end up with amputation of the affected limb. Metastatic bone cancer occurs when cancer cells from soft tissue cancers 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, resulting in decreased patient function. Pain control is achieved through increased anesthetic doses, significantly reducing the patient's quality of life.

[0003] Radiopharmaceuticals, which are radioactive drugs, are used to treat bone cancer. Cancer cells growing in bone cause higher turnover of bone in their vicinity. The strategy of these drugs is to target this rapidly growing bone. Note that these bone-targeting radiopharmaceuticals target the nearby bone tissue, not the cancer cells themselves.

[0004] Two classes of 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 and therefore concentrate 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 significantly reduced the use of this Sr-89 agent. Radium-223 is a radioactive isotope that emits alpha particles that follow a decay chain, producing various 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), potentially limiting the usefulness of Ra-223 for effectively treating bone cancer.

[0005] A 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, currently indicated for the treatment of pain associated with bone metastases (U.S. Pat. No. 4,898,724).

[0006] U.S. Pat. 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 (the 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 are harmful to the patient. For example, high soft tissue uptake could result in the patient receiving high radiation doses 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 bone. The decay of Sm-153 in this case emits beta particles, useful for tumor treatment, and gamma photons, useful for determining the isotope's fate via gamma camera imaging. Furthermore, Sm-153 has a half-life of approximately 46 hours. While these conditions seem ideal, the EDTMP / Sm complex is relatively unstable, necessitating the use of a large excess of chelating agent relative to Sm (approximately a 300:1 ligand-to-metal ratio). This excess ratio also necessitates 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 these isotopes accumulate in patients' bones when they undergo multiple treatments. In a study by Sinzinger et al. (QJ NUCL MED MOL IMAGING 2001;55:420-30), they used high-resolution gamma spectroscopy (see Figure 3) as a whole-body counter to discuss the presence of long-lived impurities such as Eu-154 in Sm-153 EDTMP when administered multiple times to patients. Their results showed that the unwanted dose from the Eu isotope increased with every treatment. This accumulation is undesirable, as the effects of long-lived isotopes within the patient are unknown.

[0009] All currently available radiopharmaceuticals 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 patients 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 produced more accurately and easily in radiopharmacy settings.

[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 facilities both from a patient and waste disposal perspective. For example, if too much Eu-154 is administered to a patient, the isotope can deliver unwanted doses to the patient over an extended period of time, especially if multiple therapeutic injections are administered. Additionally, the dose excreted in urine by patients containing 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 implemented 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 problems 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 assurance. Financial assurance can be very expensive, especially for facilities that only handle 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 from the date of manufacture ( http: / / www.ibamolecular.eu / products / quadramet ) must contain less than 0.093 microcuries of Eu-154 per millicurie of Sm-153. This limit limits the shelf life of the drug. Because Sm-153 decays faster than Eu-154, the longer the decay time of the Sm-153 solution, the greater the amount of Eu-154 in the sample relative to Sm-153. Therefore, the shelf life of not only the formulated Quadramet® (e.g., Ca-EDTMP + Sm-153) but also the Sm-153 used to manufacture Quadramet® is limited by the amount of Eu-154 in the sample.

[0015] In nuclear reactors such as those at the University of Missouri (Columbia, MO), Sm-152 samples are irradiated for a week in a "flux trap" (see Figure 1) to produce the high-specific activity (HSA) Sm-153 required for Quadramet® production. Because the flux trap is accessed only once a week, high-specific activity Sm-153 can only be produced on a weekly basis. Over time, the amount of Eu-154 increases relative to Sm-153, making the Sm-153 isotope only available for short periods of time. Therefore, the drug is only available for patient treatment 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 lives 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 requiring myelosuppressive treatment, comprising administering to the patient multiple doses of a pharmaceutically acceptable formulation of a chelating composition comprising a clinically relevant dose of the composition that is therapeutically effective upon multiple injections without accumulation of long-lived isotopes in the patient, wherein the Sm-153 used to prepare the composition has an extended shelf life of about 5 days or more, based on the Eu-154 present in the formulation being less than 0.093 μCi of Eu-154 per mCi of Sm-153. The chelating composition comprises LSA Sm-153 and DOTMP or a physiologically acceptable salt thereof, and the dose of Sm-153 is at least about 30 mCi per administration.

[0018] Each treatment is less toxic to bone marrow and results in less accumulation of long-lived radionuclide isotopes in patients compared with the use of HSA Sm-153 chelates. The present invention includes such bone cancer treatments using low specific activity (LSA) Sm-153 chelated to the macrocyclic chelator DOTMP. LSA Sm-153-DOTMP is easier to prepare, more readily available, and significantly less expensive than high specific activity (HSA) Sm-153. This was discussed in WO 2015 / 054173 (incorporated herein by reference). The present invention provides 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 explanation of the drawings]

[0019] [Figure 1]Schematic of available irradiation locations 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. [Figure 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. [Figure 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 INVENTION

[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 the exclusive locus of all aspects of the subject matter referred to and should not be construed as limiting the locus 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, the conflicting text of 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 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 pain relief or reduction in tumor burden. This dose is about 0.5 mCi / kg body weight, or about 30 mCi per dose for a 70 kg patient. More preferably, it is 1.0 mCi / kg body weight, or about 70 mCi per dose for a 70 kg patient. Larger doses of radioactivity may be administered to a patient to treat their tumor for regression or bone marrow ablation.

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

[0026] The expiration date refers to the number of days after manufacture when 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 with a neutron flux of more than 1 / 2 second for more than 120 hours. 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 means microcurie. mCi means millicuries.

[0029] By multiple doses, it is meant that the patient is treated with two or more clinically relevant doses of Sm-153 DOTMP, which can range from 2 to an infinite number of doses, e.g., 5 to 100 doses to the patient, and these doses are typically spaced apart, e.g., 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" in the journal Proceedings of the National Academy of Sciences.)

[0031] In the present invention, the specific activity of an isotope is defined as the radioactivity (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 Sm-153 activity in the sample divided by the total mass of any Sm element in the sample (e.g., radioactivity of Sm-153 / sum of masses of Sm-152 and Sm-153). The units of measurement 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, while 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 recently been awarded to provide high specific activity isotopes ( High Specific Activity Sm-153 by Post Irradiation Isotope Separation , DOE SBIR Grant Call No. DE-FOA-0000676, and “ Production of Commercial High Specific Activity Sn-117m Radiochemical and Chelates , DOE Grant No. DE-FOA-000782). Using high-specific activity (HAS) isotopes allows for a reduction in the mass of the isotope required to achieve the same amount of radioactivity. This reduces the amount of chelating agent and / or protein required for the radiopharmaceutical. Furthermore, in many cases, such as with labeled antibodies or proteins, the receptors on cells (e.g., cancer cells) targeted by the drug are limited. If the specific activity of an isotope is low (e.g., 2% of the atoms are radioactive), the amount of radiopharmaceutical reaching the target is relatively small. However, if the specific activity is high (e.g., most of the atoms are radioactive), the amount of effective drug reaching the target is much greater. For this reason, considerable effort is being devoted to the production of radioisotopes to achieve higher specific activities.

[0033] In contrast to this conventional wisdom, which favors higher specific activity isotopes, the present invention utilizes Sm-153, which is produced in a shorter time in the lower flux section of the reactor (reflector) (see Figure 1), to obtain low specific activity (LSA) isotopes at significantly reduced cost and with a 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, and lower manufacturing costs, allowing for more frequent patient use. Because the toxicity of 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, allowing for more than three 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 requiring myelosuppressive treatment, comprising administering to the patient a pharmaceutically acceptable formulation of a chelate composition comprising a clinically relevant dose of the composition that is therapeutically effective over multiple administrations without quantifiable accumulation of long-lived isotopes in the patient, wherein the composition has an extended shelf life of about 5 days or more of the Sm-153 used to prepare the composition, based on less than 0.093 μCi of Eu-154 per mCi of Sm-153 present in the formulation, and the chelate comprises LSA Sm-153 and DOTMP or a physiologically acceptable salt thereof. Clinically relevant doses range from about 0.3 to about 1.5 mCi / kg body weight, preferably about 0.5 mCi / kg body weight, or about 30 mCi per dose for a 70 kg patient, and more preferably about 1.0 mCi / kg body weight, or about 70 mCi per dose for a 70 kg patient. The expiration date, which refers to 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, 10, or more days at expiration. Multiple doses are at least five doses for patients administered at three-month intervals, or 10 doses for patients administered at six-month intervals for the last five doses.

[0035] For the following reasons, the present invention provides a better radiopharmaceutical for the treatment of bone cancer. This radiopharmaceutical is composed of LSA Sm-153 combined with the chelating agent DOTMP. Unlike the chelate formed between Sm and EDTMP in a comparable commercial product, the Sm-DOTMP complex is not unstable and does not readily dissociate. 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 potentially allows the use of LSA Sm-153, which is readily available, inexpensive, and contains significantly fewer long-lived radionuclide impurities than HSA Sm-153 (see Figure 2). Furthermore, the bone marrow toxicity associated with doses of Sm-153-DOTMP is lower than that of equivalent doses of Sm-153-EDTMP. Without wishing to be bound by theory, the reason for this reduced toxicity is thought to be that the Sm-DOTMP chelate is more stable, thus releasing less free metal into the formulation, and that the chelate may also be diluted in the patient's bloodstream, potentially resulting in less available free metal. A small amount of free metal may enter the bloodstream and precipitate as particles that are taken up by the bone marrow. The small amount 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 formulations of the present invention may be kits in which the two components (chelator and isotope) are mixed at an appropriate time prior to use, or may be three-component kits as described in WO2016 / 191413. Whether premixed as a drug or in a kit where the drug is generated on-site, the formulation requires a pharmaceutically acceptable carrier. Such carriers include any suitable pharmaceutically 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 present chelate composition comprises a therapeutically effective, pharmaceutically acceptable, clinically relevant dose of Sm-153, the composition having an extended shelf life of about 5 days or more of the Sm-153 used to prepare the composition, 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 irradiated with 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, wherein 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. Chelants 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 the MURR (University of Missouri Research Reactor) 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 patients suffering from bone cancer. The patient was repeatedly treated (10 times) with 30 mCi of Sm-153-EDTMP prepared in this example. The first five doses were administered at three-month intervals, and the second five doses were administered at six-month intervals. After the decay of Sm-153, NaI crystals were used to detect the amount of residual radioactivity in the patient. After seven doses, a significant amount of radioactivity was detected in the patient, which increased with each subsequent dose. This radioactivity was attributed to long-lived radionuclide impurities produced 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 received repeated 30 mCi doses of Sm-153-EDTMP to treat prostate and breast bone metastases for pain relief, at the following doses: five doses at 3-month intervals; five doses at 6-month intervals; five 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 HSA Sm-153-EDTMP were evident, as shown in Figure 2. The accumulation of these long-lived isotopes can be seen in Figure 3.

[0045] Example 1 Production of Sm-153 in the Murr Reflector (LSA) One milligram of Sm-152 (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 prepared from the LSA Sm-153 of Example 1. All dogs had tumor uptake. As evidenced by platelet and neutrophil nadirs, the dogs exhibited 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 in 13 dogs, starting at 1.5 mCi / mg, demonstrated tumor uptake in all 7 dogs studied. The maximum tolerated dose was 1.75-2.0 mCi / kg, whereas the maximum tolerated dose for Sm-153-EDTMP was 1.0 mCi / kg. Stable or improved outcomes were experienced in 7 of 12 dogs.

[0048] Example 4 Treatment of patients with Sm-153 (LSA) delivered by a reflector 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. Patients are repeatedly treated (10 times) with 30 mCi of Sm-153-DOTMP as prepared in this example. The first five doses are administered at 3-month intervals, and the next five 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 amounts 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 pharmaceutically acceptable formulation for multiple doses of a chelating composition comprising a clinically relevant dose of the chelating composition that is therapeutically effective in multiple doses, resulting in less accumulation of long-lived isotopes in the patient compared to use of high specific activity Sm-153 in the patient, the formulation being for use in a method of treating a patient with bone pain, one or more calcified tumors, or requiring myelosuppressive treatment, the method comprising administering the formulation to the patient, the chelating composition having an extended shelf life of about 5 days or more of Sm-153 used to prepare the chelating composition, based on less than 0.093 μCi of Eu-154 present in the formulation per mCi of Sm-153, and the chelating composition comprising LSA Sm-153 and DOTMP or a physiologically acceptable salt thereof.

2. 10. The formulation of claim 1, wherein the clinically relevant dose of the chelating composition is about 0.3 to 1.5 mCi / kg or more.

3. 3. The formulation of claim 2, wherein the clinically relevant dose of the chelating composition is about 0.5 mCi / kg.

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

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

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

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

8. 10. The formulation 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 formulation 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. 10. The formulation of claim 1, wherein the pharmaceutically acceptable formulation comprises one or more of a suitable solvent, preservative, diluent, excipient, and buffer.

11. 11. The formulation of claim 10, wherein the solvent of the formulation is water, aqueous alcohol, or glycol.

12. 1. Use of a chelating composition in the manufacture of a multi-dose pharmaceutically acceptable formulation comprising a multi-dose therapeutically effective and pharmaceutically acceptable clinically relevant dose of said chelating composition, wherein the accumulation of long-lived isotopes in a patient is reduced compared to the use of high specific activity Sm-153 in said patient, said chelating composition having 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, and said chelating composition comprising LSA Sm-153 and DOTMP or a physiologically acceptable salt thereof.

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

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

15. The chelate composition has a neutron density of 1E14 neutrons / cm 2 13. Use of the chelate composition of claim 12, prepared from reactor-produced Sm-153 at a sub-second flux, the chelate composition 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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