Radiopharmaceuticals and methods

Abstract

Radiopharmaceuticals 177 Compositions comprising an Lu-DOTATATE compound, one or more ascorbate compounds in the substantial or complete absence of a gentisate compound, single or multi-dose kits, and hermetically sealed containers are provided. 177 Methods for synthesizing Lu-DOTATATE compounds and methods for treating patients suffering from cancer, specifically neuroendocrine tumors, are further provided.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 315,974, filed March 2, 2022, and U.S. Provisional Application No. 63 / 316,381, filed March 3, 2022. The entire contents of the foregoing applications are incorporated herein by reference.

[0002] Radiopharmaceuticals 177 Lu-DOTATATE ( 177 Lu-octreotate) and pharmaceutical compositions thereof are provided. 177 A method for preparing Lu-DOTATATE compounds, and 177 Pharmaceutical compositions comprising Lu-DOTATATE are provided. [Background technology]

[0003] Radiopharmaceuticals have been used in a variety of therapeutic and diagnostic applications. In particular, radiolabeled molecules are useful in treating a variety of malignancies.

[0004] The use of these agents presents certain challenges, including those related to stability and shelf life. Specifically, therapeutic compositions containing radionuclides may undergo radiolysis during preparation and storage. During radiolysis, the radionuclide release may react with other pharmaceutical agents, thereby resulting in drug degradation and undesirable effects.

[0005] It would therefore be desirable to have additional and improved radiopharmaceutical agents. Summary of the Invention

[0006] Here, the inventors have found, inter alia, that radiopharmaceuticals 177 Lu-DOTATATE COMPOUNDS, METHODS FOR PREPARATION THEREOF, AND 177 Pharmaceutical compositions and methods of treatment comprising Lu-DOTATATE are provided.

[0007] Here, the inventors have demonstrated, inter alia, that 1) high levels of 177 High purity, including Lu incorporation, mild reaction temperatures, and / or shortened reaction times 177 1) a novel method for producing Lu-DOTATATE; and 2) a novel method for producing Lu-DOTATATE that maintains radiochemical purity for extended storage times after preparation (e.g., >90 or 95%, 3, 4, or 5 days or longer, 25° C.). 177 A pharmaceutical composition of Lu-DOTATATE has been discovered.

[0008] Preferred methods and pharmaceutical compositions include one or more ascorbate compounds, such as ascorbic acid, but do not contain other stabilizers. In certain embodiments, the methods and pharmaceutical compositions are substantially or completely free of gentisate compounds, such as gentisic acid.

[0009] As referred to herein, one or more gentisate compounds are substantially absent (or the mixture comprising lutetium-177 and EuK-Sub-kf-iodo-y-DOTAGA is substantially free of gentisate compounds) when they are present in an amount of less than 10, 8, 5, 4, 3, 2, 1, 0.5, 0.25 or 0.1 weight percent relative to the weight of one or more ascorbate compounds.In certain embodiments, gentisate compounds such as gentisic acid can be completely absent (e.g., virtually undetectable (e.g., by HPLC or other analysis), including 0 weight percent relative to the weight of one or more ascorbate compounds by such analysis).

[0010] More specifically, in one embodiment, a pharmaceutical composition is provided that comprises (a) a complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE), and (b) one or more ascorbate compounds, in the substantial or complete absence of gentisate compounds, such as gentisic acid. Such pharmaceutical compositions may include one or more other ingredients, such as one or more sequestering agents, organic or inorganic bases, salts, and / or buffers.

[0011] In a further aspect, there is provided a pharmaceutical composition comprising (a) a complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE), and (b) one or more ascorbate compounds, such as ascorbic acid, in the substantial or complete absence of gentisate compounds (e.g., gentisic acid) or additional stabilizer compounds other than the ascorbate compounds. Such pharmaceutical compositions may include one or more other ingredients, such as one or more sequestering agents, organic or inorganic bases, salts, such as NaCl, and / or one or more buffering agents.

[0012] In one preferred embodiment, a pharmaceutical composition is provided that consists essentially of (a) a complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE), and (b) one or more ascorbate compounds, such as ascorbic acid, in the substantial or complete absence of gentisate compounds, such as gentisic acid. Such pharmaceutical compositions may include one or more other ingredients, such as one or more sequestering agents, organic or inorganic bases, salts, such as NaCl, and / or one or more buffering agents.

[0013] In certain embodiments, preferably the complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is present in an amount of at least 5, 10, 15, 20, 25, or 30 mCi / mL.

[0014] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 1 mg / mL or greater.

[0015] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 2 mg / mL or greater.

[0016] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 3 mg / mL or greater.

[0017] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 4 mg / mL or greater.

[0018] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 5 mg / mL or greater.

[0019] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 6 mg / mL or greater.

[0020] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 7 mg / mL or greater.

[0021] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 8 mg / mL or greater.

[0022] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / mL or more.

[0023] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount not exceeding 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 mg / mL.

[0024] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount not exceeding 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 mg / mL.

[0025] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 2-10 mg / mL.

[0026] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 2-5 mg / mL.

[0027] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 3-5 mg / mL.

[0028] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 3-4 mg / mL.

[0029] In certain preferred embodiments, the one or more ascorbate compounds, such as ascorbic acid, are present in the pharmaceutical composition in an amount of 3.3 mg / mL, 3.4 mg / mL, 3.5 mg / mL, 3.6 mg / mL, 3.7 mg / mL, or 3.8 mg / mL.

[0030] In certain embodiments, the pharmaceutical composition contains a single ascorbate compound. In certain additional preferred embodiments, the pharmaceutical composition contains a single ascorbate compound that is ascorbic acid.

[0031] It has been found that the substantial or complete absence of one or more gentisate compounds during the incorporation reaction can reduce or avoid the occurrence or formation of impurities detected by high-performance liquid chromatography (HPLC).

[0032] In certain embodiments, the pharmaceutical composition is substantially or completely free of gentisate adduct impurities. For example, during the incorporation reaction to form a complex between lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE), the impurity(s) observed during the use of one or more gentisate compounds, such as gentisic acid, or otherwise present in the incorporation reaction mixture or pharmaceutical composition may be referred to herein as "gentisate adduct impurities". The gentisate adduct impurities can be evaluated by HPLC. If the HPLC analysis shows that there is minimal or no observation of the gentisate adduct impurity (visual observation of the HPLC chromatograph), the pharmaceutical composition is substantially free of the gentisate adduct impurity. If the HPLC analysis shows that there is no observation of the gentisate adduct impurity (visual observation of the HPLC chromatograph), the pharmaceutical composition is completely free of the gentisate adduct impurity.

[0033] Preferably, the pharmaceutical composition is an aqueous formulation. In certain preferred embodiments, the pharmaceutical composition does not contain alcohol such as ethanol or other organic solvents. In certain preferred embodiments, the pharmaceutical composition is at least substantially free of alcohol such as ethanol or other organic solvents (i.e., less than 5, 4, 3, 2, 1, or 0.5 weight percent based on the total composition weight).

[0034] In certain preferred embodiments, the pharmaceutical composition has a pH of 4.0 to 6.5. In additional preferred embodiments, the pharmaceutical composition has a pH of 4.5 to 6.0.

[0035] The compound tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) has the following structure 1:

[0036] [ka]

[0037] 177Lu-DOTATATE is the lutetium-177 complex of compound 1 above and can be represented by structure 2 below.

[0038] [ka]

[0039] In one aspect, 177 A method for preparing Lu-DOTATATE (structure 2 above) is provided, which comprises combining lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE, structure 1 above) in the presence of one or more ascorbate compounds; 177 The method includes forming a complex between Lu and DOTATATE. 177 The method may include combining Lu with DOTATATE. 177 This reaction to form a complex of Lu with DOTATATE (eg, such a complex comprising structure 2 above) is sometimes referred to herein as the "incorporation reaction."

[0040] The one or more ascorbate compounds are suitably present in the incorporation reaction and / or pharmaceutical composition in an amount of 20 g / mL or less, including 18, 16, 14, 12, 0, 9, 8, 7, 6, 5, 4, 3, or 2 mg / mL or less.

[0041] In a preferred embodiment, tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is combined with lutetium-177 as an aqueous formulation in the incorporation reaction mixture.

[0042] In certain embodiments, the one or more ascorbate compounds in the incorporation reactants and / or pharmaceutical compositions include ascorbic acid. In certain embodiments, the one or more ascorbate compounds in the incorporation reactants and / or pharmaceutical compositions include an ascorbate salt, such as sodium ascorbate.

[0043] Preferably, for providing a pharmaceutical composition 177Prior to the incorporation reaction or addition to Lu-DOTATATE, the ascorbate compound, such as sodium ascorbate or ascorbic acid, is evaluated for purity or absence of materials that may inhibit the incorporation reaction of lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE). For example, a sample from a lot of an ascorbate compound, such as an ascorbate metal salt, for example sodium ascorbate, can be tested, such as in a pilot-scale (small-scale) incorporation reaction with lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE), to ensure that the lot does not adversely affect the formation of a complex between lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) or the radiochemical stability of the complex formed over time.

[0044] Thus, there is provided a method comprising determining the purity of an ascorbate compound prior to mixing the ascorbate compound with lutetium-177 and / or tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) and / or a complex of lutetium-177 and / or tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE). Advantageously, the ascorbate compound is determined to be effective in an incorporation reaction, and the method comprises mixing the effective ascorbate compound with lutetium-177 and / or tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) and / or a complex of lutetium-177 and / or tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE). In such a method, the ascorbate compound may be ascorbic acid or an ascorbate salt, such as sodium ascorbate.

[0045] In certain preferred embodiments, the mixture of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is heated, hi certain embodiments, the mixture is heated for 60 minutes or less, 50 minutes or less, 40 minutes or less, 30 minutes or less, 20 minutes or less, or 15 minutes or less.

[0046] In certain preferred embodiments, the mixture of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is heated to about 80°C ± 10°C or about 80°C ± 5°C.

[0047] In certain preferred embodiments, the method includes cooling the admixture after heating.

[0048] In certain preferred embodiments, after mixing, the complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is mixed with the formulation composition.Preferably, the formulation composition is an aqueous composition containing one or more stabilizer compounds, particularly one or more ascorbate compounds, such as ascorbic acid.The formulation composition suitably contains one or more additional stabilizer compounds present in an amount of 1, 2, 3, 5, 6, 7, 8, 9, 100, 11, 12, 13, 14, 15, or 20 mg / mL or more.As discussed above, the formulation composition is preferably at least substantially or completely free of gentisate compounds, such as gentisic acid.

[0049] In certain preferred embodiments, the pharmaceutical composition further comprises one or more sequestering agents.

[0050] In certain preferred embodiments, 177 Incorporation of lutetium-177 into or with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) to provide Lu-DOTATATE is preferably greater than 98 mole percent, or greater than 99 mole percent, based on the molar equivalent of lutetium-177 used in the incorporation reaction.

[0051] In certain preferred embodiments, an acidic aqueous formulation of lutetium-177 is mixed with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE). Preferably, an aqueous hydrogen halide or acid halide formulation of lutetium-177 is mixed with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE). For example, an aqueous hydrochloric acid formulation of lutetium-177 is mixed with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE).

[0052] In one aspect, the compound is obtainable or obtained by the methods described herein. 177 Lu-DOTATATE is provided.

[0053] In one aspect, the method described herein 177 A pharmaceutical composition comprising Lu-DOTATATE is provided.Preferably, the radiochemical purity of the composition is 95% or more for 3 days or less at 25° C., or 95% or more for 4 days or less at 25° C., or 95% or more for 5 days or less at 25° C.As referred to herein, the radiochemical purity is preferably assessed via HPLC analysis, particularly HPLC radiometric detection (i.e., radio-HPLC).

[0054] In one aspect, the method of claim 1, 177 Single dose kits containing Lu-DOTATATE or pharmaceutical compositions are provided. 177 Multi-dose kits containing Lu-DOTATATE or pharmaceutical compositions are provided.

[0055] In one aspect, a method of treating a subject suffering from cancer is provided, comprising administering to a subject an effective amount of a compound as described herein. 177 The method includes administering Lu-DOTATATE or a pharmaceutical composition to a subject.

[0056] In certain aspects, the subject is afflicted with a neuroendocrine tumor, hi certain aspects, the subject is afflicted with a neuroendocrine tumor originating in the foregut, hindgut, midgut, lung, ovary, medulla, adrenal medulla, adrenal gland, kidney, pituitary gland, thyroid gland, or paraganglia.

[0057] In certain aspects, the subject is afflicted with gastroenteropancreatic neuroendocrine tumor (GEP-NET), foregut, midgut, and hindgut neuroendocrine tumor.

[0058] In certain aspects, the subject is afflicted with an unresectable or metastatic neuroendocrine tumor.

[0059] In certain embodiments, the method includes, for example, 68 The method includes identifying the patient for treatment by assessing the patient's neuroendocrine tumor as somatostatin receptor positive using Ga-DOTATATE and positron emission tomography.

[0060] For treating a disease or disorder disclosed herein 177 Uses of Lu-DOTATATE compounds and compositions are also provided.

[0061] Further, for treating the diseases or disorders disclosed herein, 177 Methods are provided for the preparation of pharmaceutical agents containing Lu-DOTATATE compounds and compositions.

[0062] Other aspects of the invention are disclosed below. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] As discussed above, 177 Lu-DOTATATE is the lutetium-177 ( 177 Lu 3+ ) complex,

[0064] [ka] It can be represented by the following structure 2.

[0065] [ka]

[0066] 177 Lu-DOTATATE is also 177 Lu-tetraazacyclododecanetetraacetic acid-octreotate or 177 It is represented using the chemical (IUPAC) name Lu-4,7,10-tricarboxymethyl-1,4,7,10-tetraaza-cyclododecan-1-yl-acetyl-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH. 177 Lu-DOTATATE is C 65 H 90 [ 177 Lu]N 14 O 19 It has a molecular formula of S2 and a molecular weight (average molecular weight) of 1610.61 g / mol.

[0067] definition The present invention, including the compounds, methods, and pharmaceutical compositions / formulations, will be described for convenience with reference to the following definitions set forth below. Unless otherwise stated, the following terms used herein are defined as follows:

[0068] As used herein, the terms "a," "an," "the," and similar terms as used in the context of the present invention (particularly in the context of the claims) are to be construed to encompass both the singular and the plural, unless otherwise specified herein or clearly contradicted by context.

[0069] The term "and / or" is used herein as a shorthand for expressing the phrase "and" describing a combination of items, and "or" describing items in alternative form.

[0070] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0071] The term "about" as used herein refers to an acceptable margin of error for a particular value, which depends, in part, on how the value is measured or determined. In certain aspects, "about" as used herein will be understood by one of ordinary skill in the art to mean up to plus or minus 20% of the particular term. In further aspects, "about" as used herein will be understood by one of ordinary skill in the art to mean up to plus or minus 10% of the particular term.

[0072] As used herein, the term "substantially pure" means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and mass spectrometry (MS), or sufficiently pure that further purification does not detectably alter the physical and chemical properties, or the biological and pharmacological properties, such as enzymatic and biological activity, of the material. In certain embodiments, "substantially pure" refers to a collection of molecules in which at least about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 97%, about 98%, about 98.5%, about 99%, about 99.5%, or about 99.9% or more of the molecules are a single compound, including a racemic mixture or a single stereoisomer thereof, as determined by standard analytical methods.

[0073] As used herein, unless otherwise specified, the terms "treat", "treating" and "treatment" refer to the eradication or amelioration of a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. In certain aspects, the terms refer to minimizing the progression or worsening of a disease, disorder or condition resulting from administration of a formulation of the invention to a patient / animal having such a disease, disorder or condition. In some aspects, these terms refer to administration of a formulation provided herein after the onset of symptoms of a particular disease, disorder or condition. The terms "treat", "treating", "treatment" and the like, as used herein, encompass the treatment of a disease, disorder or condition in a subject, e.g., a mammal, and include at least one of: (i) inhibiting the disease, disorder or condition, i.e., partially or completely halting its progression; (ii) alleviating the disease, disorder or condition, i.e., causing regression of the symptoms of the disease, disorder or condition or improving the symptoms of the disease, disorder or condition; and (iii) reversing or regressing the disease, disorder or condition, preferably eliminating or curing the disease, disorder or condition.

[0074] In certain embodiments, the terms "treat", "treating", "treatment", and the like encompass treatment of a disease, disorder, or condition in a mammal, e.g., a primate, e.g., a human, including at least one of (i), (ii), and (iii) above. Adjustments for age, weight, general health, sex, diet, time of administration, drug interactions, and severity of the condition may be necessary as known in the art and are ascertainable with routine experimentation by one of ordinary skill in the art based on the invention described herein.

[0075] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals such as mammals, including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans). In certain embodiments, the subject is a human.

[0076] synthesis In one aspect, 177 Lu-DOTATATE (including structure 2) is 177 Lu (lutetium 177) or 177 It can be prepared by complexing or incorporating its halide, such as LuCl3, with DOTATATE (containing structure 1 below).

[0077] [ka]

[0078] Compound 1, DOTATATE, may be suitably formed as previously described, such as in Raheem et al. Bioconjugate Chem. 2020. https: / / doi.org / 10.1021 / acs.bioconjchem.0c00325. Compound 1, DOTATATE, is also commercially available.

[0079] As referred to herein 177 Lu-DOTATATE is represented by the above structure 2 and 177 It is understood that other complexes of Lu-DOTATATE are included. For example, 177 References to Lu-DOTATATE generally correspond to Structure 2, 177 Includes compounds in which Lu is substantially complexed with other portions or moieties of the DOTATATE molecule other than those shown under 2 above (such as one or more other nitrogens). 177 Reference to Lu-DOTATATE may also include stereoisomers other than those shown in 1 and 2 above, although the stereoisomers shown in 1 and 2 are preferred.

[0080] 177 To synthesize Lu-DOTATATE, lutetium-177 ( 177 Lu) can be mixed with DOTATATE. 177Lu may suitably be carrier-added or, more preferably, non-carrier-added (nca) lutetium-177. To facilitate the incorporation (e.g., complexation, including chelation) of lutetium-177 with the DOTATATE compound, the admixture of the compounds is preferably in the presence of one or more ascorbate compounds. In certain embodiments, the incorporation reaction is substantially or completely free of other stabilizer compounds, particularly gentisate compounds such as gentisic acid.

[0081] In one aspect, 177 A method for preparing Lu-DOTATATE includes combining lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) in the presence of one or more ascorbate compounds, such as ascorbic acid, to form a complex of lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE). In certain embodiments, the incorporation reaction is substantially or completely free of other stabilizer compounds, particularly gentisate compounds such as gentisic acid.

[0082] Preferably, as discussed, in the incorporation reaction, one or more ascorbate compounds, such as ascorbic acid, are present in an amount of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / mL or more.

[0083] Preferably, the one or more ascorbate compounds include an ascorbate salt, such as sodium ascorbate and / or ascorbic acid.

[0084] Gentisate compounds referred to herein include, for example, gentisic acid.

[0085] Preferably, the mixture of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is heated. In certain embodiments, the mixture is heated for 20 minutes or less. In certain embodiments, the mixture is heated for 15 minutes or less.

[0086] Preferably, the mixture of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is heated at a temperature of about 80° C.±10° C. In one particular embodiment, the mixture of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is heated at a temperature of about 80° C.±5° C.

[0087] The method further includes cooling the admixture after heating.

[0088] In certain embodiments, after mixing, the complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is mixed with a formulation composition.Preferably, the formulation composition is an aqueous composition.In certain embodiments, the formulation composition comprises one or more ascorbate compounds, such as ascorbic acid, for example, in an amount of 0.5, 1, 2, or 3 mg / mL or more.

[0089] In certain embodiments, the pharmaceutical composition further comprises one or more sequestering agents.

[0090] Preferably, 177 The incorporation of lutetium-177 into or with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) to provide Lu-DOTATATE is greater than 98 mole percent based on the molar equivalents of lutetium-177 used in the incorporation reaction. 177 The incorporation of lutetium-177 into or with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) to provide Lu-DOTATATE is greater than 99 mole percent, based on the molar equivalents of lutetium-177 used in the incorporation reaction.

[0091] Preferably, an acidic aqueous formulation of lutetium-177 is mixed with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE). In certain embodiments, an aqueous hydrogen halide or acid halide formulation of lutetium-177 is mixed with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE).

[0092] 177 A preferred preparation of Lu-DOTATATE may include one or more, preferably each, of the following steps. 1. Lutetium-177 is provided in a vial or other container that can act as a reaction vessel. Lutetium-177 may suitably be present in an aqueous acidic formulation, for example an HCl formulation. 2. The DOTATATE peptide is mixed with an aqueous buffer composition (reaction buffer) that contains one or more ascorbate compounds (e.g., sodium ascorbate and / or ascorbic acid) and is preferably substantially or completely free of other stabilizer compounds, such as gentisate compounds (e.g., gentisic acid). 3. Combine the DOTATATE peptide from step 2 with the lutetium-177 composition of step 1. For example, the DOTATATE peptide composition from step 2 can be added to a vial containing lutetium-177. 4. The mixture of DOTATATE peptide and lutetium-177 can then be heated, preferably with stirring, for example, with shaking while heating to 70-90° C., more typically 75-85° C., for up to 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes. 5. After completion of the heat treatment, allow the admixture from step 4 above to cool below room temperature for about 0.1, 0.25, 0.5, 1, 2, 3, 4, 5, 6, or 7 minutes. Cooling can be facilitated by adding an aqueous composition (formulation composition) containing one or more ascorbate compounds (e.g., sodium ascorbate and / or ascorbic acid), preferably substantially or completely free of other stabilizer compounds such as gentisate compounds (e.g., gentisic acid). The formulation composition added to the admixture can be below room temperature. 6. The admixture from step 5 can then be transferred to a tank containing an aqueous composition (which may be the same formulation composition used in step 5) that includes one or more ascorbate compounds (e.g., sodium ascorbate and / or ascorbic acid), and in certain systems is preferably substantially or completely free of other stabilizer compounds, such as gentisate compounds (e.g., gentisic acid). The mixture can be sterile filtered, such as through one or more 0.22 μm filters, and transferred to a container, such as a syringe, vial, or IV bag. For administration to a patient, the desired dose can be dispensed, preferably within 5, 4, or 3 days after completion of step 6.

[0093] Preferred reaction buffers and formulation compositions are provided in the Examples below.

[0094] Pharmaceutical Compositions In a further aspect, a pharmaceutical composition is provided.

[0095] A preferred pharmaceutical composition may include an aqueous composition comprising 1) a complex of lutetium-177 and DOTATATE, and 2) one or more ascorbate compounds. In certain embodiments, such compositions are preferably substantially or completely free of other stabilizer compounds, such as gentisate compounds (e.g., gentisic acid).

[0096] Preferably, the radiochemical purity of the pharmaceutical composition is at least 95% when the composition is maintained at or below 25° C. for 3 days or more after preparation of the composition. Radiochemical purity is suitably determined by HPLC radiometric detection (i.e., radio-HPLC).

[0097] In certain preferred embodiments, the pharmaceutical composition contains no unchelated lutetium-177 in an amount of 2, 1.5, 1.0, or 0.5% by weight or less based on the total weight of the pharmaceutical composition, as can be determined by radiometric detection (including HPLC radiometric detection) where the composition is maintained at or below 25° C., and such purity levels are exhibited for 3 days or more after preparation of the composition.

[0098] In additional preferred embodiments, the pharmaceutical composition is free of radiochemical impurities in an amount of 5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5% by weight or less based on the total weight of the pharmaceutical composition, as determined by radiometric detection (including HPLC radiometric detection) where the composition is maintained at or below 25° C., and such purity levels are exhibited for 3 days or more after preparation of the composition.

[0099] In still further additional preferred embodiments, the pharmaceutical composition is free of chemical impurities in an amount of 5, 4, 3, 2, 1, or 0.5% by weight or less based on the total weight of the pharmaceutical composition as can be determined by HPLC / UV analysis where the composition is maintained at or below 25° C., and such purity levels are exhibited for 3, 4, or 5 days or more after preparation of the composition.

[0100] In still further additional preferred embodiments, the pharmaceutical composition is 1) free of unchelated lutetium-177 in an amount of 2, 1.5, 1.0, or 0.5% by weight or less (as can be determined by radiometric detection (including HPLC radiometric detection)); 2) free of radiochemical impurities in an amount of 5, 4, 3.5, 3, 2.5, 2, 1.5, 1, or 0.5% by weight or less (as can be determined by radiometric detection (including HPLC radiometric detection)); and 3) free of chemical impurities in an amount of 5, 4, 3, 2, 1, or 0.5% by weight or less (as can be determined by HPLC / UV analysis), all weight percentages being based on the total weight of the pharmaceutical composition, and the composition being maintained at or below 25° C., and such purity levels are exhibited for 3 or more days after preparation of the composition.

[0101] In certain embodiments, the pharmaceutical composition is formulated for parenteral administration, such as intravenous, intramuscular, intradermal, subcutaneous, intrathecal, or intraperitoneal administration. For example, the pharmaceutical composition is formulated for intravenous, intramuscular, subcutaneous, or intradermal injection. In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration. In a typical embodiment, the pharmaceutical composition may be administered in the form of an aqueous pharmaceutical solution.

[0102] In certain embodiments, the pharmaceutical composition is an aqueous solution, dispersion, or other admixture, such as for injection; 177 Lu-DOTATATE and one or more ascorbate compounds, such as sodium ascorbate and / or ascorbic acid. In certain embodiments, the pharmaceutical compositions are preferably substantially or completely free of other stabilizer compounds, such as gentisate compounds (e.g., gentisic acid). 177 Lu-DOTATATE is suitably present at a concentration that provides a volumetric radioactivity of at least 100 MBq / mL, preferably at least 250 MBq / mL, or at least 300 or 400 MBq / mL within 1, 2, 3, or 4 days after preparation. 177 The Lu-DOTATATE is present at a concentration that provides a volumetric radioactivity of 100-1000 MBq / mL, preferably 250-800 MBq / mL, within 1, 2, 3, or 4 days after preparation.

[0103] In certain embodiments, one or more ascorbate compounds, such as ascorbic acid, may be present in the pharmaceutical composition at a total concentration of about 10 mg / mL or less, or 9 mg / mL or less, or 8 mg / mL or less, or 7 mg / mL or less, or 6 mg / mL or less, or 5 mg / mL or less, or 4 mg / mL or less.

[0104] In certain embodiments, the aqueous pharmaceutical formulation has a shelf life of at least 24 hours at or below about 25° C., at least 48 hours at or below about 25° C., at least 72 hours at or below 25° C., or between 24 hours and 120 hours at or below 25° C., between 24 hours and 96 hours at or below 25° C., between 24 hours and 84 hours at or below 25° C., between 24 hours and 72 hours at or below 25° C., particularly a shelf life of 72 hours at or below 25° C. Shelf life can be assessed by radiochemical purity (as determined by radio-HPLC) remaining greater than 90%, 92%, 95%, or 98% for the specified period of time.

[0105] In certain embodiments, as discussed, one or more ascorbate compounds, such as ascorbic acid, can be added after the formation of a complex between lutetium-177 and DOTATATE, for example, at the completion of heating the mixture of lutetium-177 and DOTATATE, for example, such one or more ascorbate compounds, such as ascorbic acid, are added at the end of the heating step at the temperature reduction. Addition of an aqueous formulation (e.g., containing one or more ascorbate compounds, such as ascorbic acid) immediately after the heating is completed can 177 The Lu DOTATATE reaction mixture may then be cooled.

[0106] In certain embodiments, the aqueous pharmaceutical solution may further comprise a sequestering agent, for example, added after formation of the complex between lutetium-177 and DOTATATE, preferably to remove uncomplexed lutetium-177. Suitable sequestering agents include, for example, one or more aminopolycarboxylic acids, such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA), or salts thereof, preferably in aqueous solution. 177 The Lu-DOTATATE may be included in an amount that results in a concentration of 0.01-0.50 mg / mL of the composition.

[0107] In a particularly preferred embodiment, 177 Lu-DOTATATE is provided as a sterile solution for intravenous use. Single-dose vials preferably contain between 3.6±10% GBq and 11.1±10% GBq. 177 Containing a dose of Lu-DOTATATE. Represented as one injection per treatment cycle, four treatment cycles result in a cumulative dose of 14.4 ± 10% GBq to 44.4 ± 10% GBq.

[0108] Preferably, 177 The pH range of the Lu-DOTATATE solution is 4.5 to 8.5. 177 The pH range of the Lu-DOTATATE solution is 5-7.

[0109] Treatment method As will be considered, 177 Uses of Lu-DOTATATE (including 2 above) are provided to treat cancers, including cancers originating in the foregut (e.g., stomach or duodenum), hindgut (e.g., left colon or rectum), midgut (e.g., jejunum, ileum, right colon, or appendix), lung, and other organs (e.g., ovary, medulla, adrenal medulla, adrenal gland (pheochromocytoma), kidney, pituitary gland, thyroid gland, or paraganglia).

[0110] in particular, 177Lu-DOTATATE (including 2 above) can be used to treat neuroendocrine tumors, including reducing neuroendocrine tumor size.

[0111] In such a method, 177 Lu-DOTATATE (comprising structure 2 above) can be administered to a subject, such as a human, in an amount effective to treat cancer (e.g., reduce tumor size), such as a dose of about 3.6 GBq to about 11.1 GBq, suitably administered from a unit dose in a vial or syringe, or as a bulk solution in a vial or syringe prepared from a cold kit prepared with lutetium-177 at a local or central radiopharmaceutical pharmacy or through cGMP central manufacturing. The total dose administered for a treatment including four treatment cycles is about 14.4 GBq to about 40.8 GBq or 44.4 GBq.

[0112] Administered to patients 177 The effective amount of Lu-DOTATATE radiopharmaceuticals is generally determined by considering the patient's records. However, the effective amount can suitably be within the range of about 3.6GBq to 11.1GBq per dose, for example, about 3.6, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.4, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.1GBq per dose, or any range between two of the above values. This dose can be administered from unit doses in vials or syringes, or as bulk solutions in vials or syringes prepared from cold kits prepared with lutetium-177 at a local or central radiopharmaceutical pharmacy or through cGMP central manufacturing.

[0113] If necessary or desired, treatment may include administering an effective amount of 177 This may involve two or more administrations of Lu-DOTATATE. 177 It may be beneficial to repeat the Lu-DOTATATE administration after 7 to 56 days, such as at 4- to 8-week intervals.

[0114] In a particularly preferred protocol, 177 The dosage form of Lu-DOTATATE is a sterile aqueous solution administered by intravenous injection. The dosing regimen may include multiple injections, such as four injections, each at an effective dose, such as 3.6 GBq±10% to 11.1 GBq±10%, administered about 4, 5, 6, 7, or 8 weeks apart.

[0115] In certain embodiments, the method includes, for example, 68 This involves assessing the patient's neuroendocrine tumor as somatostatin receptor positive using Ga-DOTATATE and positron emission tomography.

[0116] Individualized Dosing In a further embodiment, a dosing protocol can be utilized to provide dosages for a particular patient based on one or more of the patient's characteristics.

[0117] in particular, 177 Lu-DOTATATE can be administered in dosages based on dosimetry assessments. For example, 177 After administration of Lu-DOTATATE, the patient may be evaluated by SPECT (e.g., 3D SPECT-CT imaging) and planar studies or other analyses to allow for individualized dosimetry. Multiple studies may be performed, for example, at about 4, 24, and 72 hours after dosing, or at single time points or other schedules. These studies can be used to determine the dose absorbed by the patient's tumor, kidneys, bone marrow, etc. Based on that evaluation, the patient's additional dosing can be modified, particularly increased or decreased to enhance efficacy or safety.

[0118] Additionally, the patient's glomerular filtration rate (GFR) may also be assessed, typically by determination of creatinine (Cr) clearance.

[0119] Preferably, 177Patients receiving Lu-DOTATATE will be assessed by both dosimetry and Cr clearance / GFR. Such combined assessment will include patients with a GFR of 40 mL / min and those with a GFR as low as 30 mL / min. 177 Lu-DOTATATE can be administered.

[0120] Combination therapy 177 Lu-DOTATATE (comprising structure 2 above) may be suitably administered to a subject in conjunction or in combination with one or more other therapeutic agents, particularly one or more other chemotherapeutic agents.

[0121] In one embodiment, the subject is 177 Treatment with Lu-DOTATATE may be combined with a regime of one or more somatostatin compounds, such as octreotide (eg, Sandostatin) or lanreotide (eg, Somatuline Autogel).

[0122] The subject is also 177 Treatment with Lu-DOTATATE may be combined with a regime of one or more anti-cancer drugs, such as capecitabine, temozolomide, steptozotocin, 5-fluroouracil, cisplatin, carboplatin, etoposide, and / or doxorubicin.

[0123] As used herein, the term "in combination" in the context of administering a therapy to a subject refers to the use of two or more therapies for therapeutic benefit.The term "in combination" in the context of administration can also refer to the prophylactic use of a therapy to a subject when used with at least one additional therapy.The use of the term "in combination" does not limit the order in which the therapies (e.g., the first and second therapies) are administered to a subject. The therapy can be administered prior to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to) administration of the second therapy to a subject in need of the treatment disclosed herein, simultaneously with administration of the second therapy, or after (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of the second therapy. The therapies are administered to the subject in an order and within a time interval such that the therapies can act together. In certain embodiments, the therapies are administered to a subject in a sequence and within a time interval that provides increased benefit than if administered within other sequences and time intervals. Any additional therapy can be administered in any sequence with other additional therapies.

[0124] Packaged 177 Lu-DOTATATE and kits As discussed above, 177 Treatment kits are also provided, including cold kits in which Lu-DOTATATE can be prepared immediately prior to administration in a medical facility, such as a hospital laboratory or a pharmacy that handles radiopharmaceuticals. In such kits, DOTATATE may be provided in a vial or other container in a lyophilized or other form separated from the lutetium-177. DOTATATE and lutetium-177 can be reacted as disclosed herein in the medical facility to produce 177 Lu-DOTATATE can be provided, which can then be rapidly administered to a patient.

[0125] The kit may comprise any of the components described herein. 177 The kit may be a single dose kit containing Lu-DOTATATE or a pharmaceutical composition as described herein. Alternatively, the kit may be a single dose kit containing Lu-DOTATATE or a pharmaceutical composition as described herein. 177 The kit may be a multi-dose kit comprising Lu-DOTATATE or a pharmaceutical composition.

[0126] In a further aspect, 177 Packaged formulations or articles of manufacture of Lu-DOTATATE are also provided. The packaged formulations include: 1) 177 Lu-DOTATATE, and optionally 2) to treat cancers, such as neuroendocrine tumors 177 The packaged preparation may include instructions for using Lu-DOTATATE. Preferably, the packaged preparation contains a therapeutically effective amount of Lu-DOTATATE. 177 Contains Lu-DOTATATE.

[0127] In certain exemplary packaged preparations or products: 177 Lu-DOTATATE can be packaged in a suitable labeled container, for example for use as a therapy to treat a subject suffering from cancer (e.g., a neuroendocrine tumor). 177 The product may include Lu-DOTATATE and one or more suitable stabilizer compounds. 177 The article of manufacture or kit may include a container (e.g., a vial, etc.) containing Lu-DOTATATE. In addition, the article of manufacture or kit may further include packaging materials, instructions for use, a syringe, a delivery device, for example, to treat a targeted condition, such as a neuroendocrine tumor or other cancer.

[0128] A packaged system or product may also include instructions (e.g., a printed label or insert or other media (e.g., audio or video files) that explain use of the product). The instructions may be associated with (e.g., affixed to) the container and may describe the manner in which the composition therein is to be administered (e.g., frequency and route of administration), directions therefor, and other uses. The composition may be ready for immediate administration (e.g., dosages are present in suitable units) and may include one or more additional pharma- ceutically acceptable adjuvants, carriers, or other diluents.

[0129] The following non-limiting examples are illustrative.

[0130] Example 1: 177 Production of Lu-DOTATATE Table 1 below lists all the inputs to the manufacturing process to provide a preferred pharmaceutical composition.

[0131] Table 1 [Table 1] 1 At the start of synthesis 2 Depends on the number of doses / batches

[0132] Table 2 below lists the ingredients found in a preferred formulated final drug product or pharmaceutical composition.

[0133] Table 2 [Table 2] 1 Total batch volume = 35-85mL 3 Time of calibration (TOC), defined as 07:00ET on the date of manufacture

[0134] Example 2: The following compositions were prepared according to the procedure described in Example 1 above.

[0135] Below are the ingredients and amounts thereof for a preferred aqueous composition, designated herein as Composition 1.

[0136] Composition 1 [Table 3]

[0137] As used herein, the term "SWFI" refers to sterile water for injection.

[0138] Production Process Step 1 described in this section is carried out in a grade A biological safety cabinet. All subsequent steps described in this section are carried out in a grade A shielded isolator. All solutions, including reaction buffers and formulation buffers, are prepared in a grade C clean room. In summary, in the incorporation reaction, the DOTATATE peptide is added to the reaction buffer and 177 LuCl3, followed by heating and shaking to form the drug complex.

[0139] The heater / shaker is qualified for installation, operation, and performance prior to use to ensure that it can maintain the temperature and shaking conditions required for the incorporation reaction (radiolabeling) for the specified period of time, as described in step 4 below.

[0140] The amount of DOTATATE peptide used (step 2) is: 177 It is based on the total amount of Lu-DOTATATE activity (which itself is based on the number and timing of patient doses) and the volume required to obtain a radioactivity concentration of ≦0.96 GBq / mL at the time of calibration (TOC), defined as 07:00 ET on the day of manufacture (DOM).

[0141] 1. Required 177Depending on the amount of Lu starting activity, an appropriate volume of 0.04N HCl is added to 177 Add to supplier vial containing LuCl3 to bring total volume to: a. 1000 μL (if 160-320 μg of DOTATATE peptide is used) b. 2000 μL (if 480-640 μg of DOTATATE peptide is used) 2. Prepare 1-4 x 750 µL volumes of DOTATATE peptide in reaction buffer. Gently agitate the solution to ensure complete dissolution of the peptide. Each 750 µL volume of DOTATATE peptide solution contains 200 µg of DOTATATE. 3. If only a 1x or 3x 750 μL aliquot of DOTATATE solution is required, prepare an additional 1x 600 μL volume of Reaction Buffer. 4. Add 600 μL volume of DOTATATE solution from step 2 (and reaction buffer from step 3, if applicable) to the supplier vial from step 1 (diluted 177 Prepare the reaction solution by adding 100 µg of peptide (containing LuCl3) to the reaction solution. The total reaction solution volume is 2.2 mL (160-320 µg of peptide) or 4.4 mL (480-640 µg of peptide). 5. Using the qualified and preheated heater / shaker, heat the reaction solution to 80±5° C. for 15±1 minutes with shaking at 350 rpm. 6. Allow the reaction solution vial containing the drug substance to cool at room temperature for at least 5 minutes. Subsequent steps consist of transferring the drug substance (in reaction buffer) through a tandem 2 x 0.22 μm sterile filter chain into a 100 mL sterile bulk vial containing formulation buffer, and aseptically dispensing the final drug product into final container closures. These steps are accomplished using a dispensing apparatus consisting of a series of stopcocks fitted with various tubing, syringes, vials, and needles to facilitate transfer and dispensing of the drug product. Steps 7-10 are performed in a Grade A shielded isolator unit. 7. 177Immediately transfer the Lu-DOTATATE drug substance from the reaction vial through a tandem 2 x 0.22 µm sterile filter chain into a 100 mL bulk vial containing 6.95-115.6 mL of formulation buffer (to rinse the vial after the reaction). This step forms the drug product and represents the end of synthesis (EOS). 8. Remove a sample from this vial for sterility and QC testing. 9. Dispense patient doses into final 30 mL container closures.

[0142] The total synthesis time from step 3 to step 7 above is about 120 minutes.

[0143] Example 3: Treatment Protocol A human patient having a neuroendocrine tumor is treated with a 68 After showing somatostatin receptor positivity with Ga-DOTATATE and positron emission tomography, the patient is selected for treatment.

[0144] in a sterile aqueous solution designated Composition 1 in Example 2 above. 177 Lu-DOTATATE is administered to patients via intravenous injection. 177 Use single dose vials containing Lu-DOTATATE. 177 Lu-DOTATATE will be administered over four treatment cycles, with one injection per treatment cycle providing a cumulative dose of 14.4 GBq to 44.4 GBq.

[0145] Incorporation by Reference The entire contents of all patents, published patent applications, websites, and other disclosures cited herein are expressly incorporated herein by reference in their entirety.

[0146] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details can be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. 1. A pharmaceutical composition comprising: (a) a complex of lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE); (b) one or more ascorbate compounds, in the substantial or complete absence of a gentisate compound.

2. 10. The pharmaceutical composition of claim 1, wherein the composition is substantially or completely free of stabilizer compounds other than one or more ascorbate compounds.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition comprises one or more ascorbate compounds in an amount of 10 mg / mL or less.

4. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition comprises one or more ascorbate compounds in an amount of 8 mg / mL or less.

5. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition comprises one or more ascorbate compounds in an amount of 6 mg / mL or less.

6. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition comprises one or more ascorbate compounds in an amount of 4 mg / mL or less.

7. 3. The pharmaceutical composition of claim 1 or 2, wherein the composition comprises one or more ascorbate compounds in an amount of 2.5 to 4.5 mg / mL.

8. 8. The composition of claim 1, wherein the complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is present in an amount of at least 5 mCi / mL.

9. 8. The composition of claim 1, wherein the complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is present in an amount of at least 10 mCi / mL.

10. 10. The composition of claim 1, wherein the complex of lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) corresponds to the following structure: 【Chemistry 1】

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the radiochemical purity of the composition by HPLC analysis is 95% or more for 3 days.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the radiochemical purity of the composition by HPLC analysis is 95% or more for 5 days.

13. １７７ A method for preparing Lu-DOTATATE, comprising the steps of: Combining lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) in the presence of one or more ascorbate compounds and in the substantial or complete absence of a gentisate compound; thereby forming a complex of lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE).

14. 14. The method of claim 13, wherein an aqueous formulation containing tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is admixed with lutetium-177.

15. 15. The method of claim 13 or 14, wherein the one or more ascorbate compounds are present in an amount of 40 mg / mL or less.

16. 15. The method of claim 13 or 14, wherein the one or more ascorbate compounds are present in an amount of 30 mg / mL or less.

17. 15. The method of claim 13 or 14, wherein the one or more ascorbate compounds are present in an amount of 20 mg / mL or less.

18. 18. The method of any one of claims 13 to 17, wherein the mixture of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is heated.

19. 20. The method of claim 18, wherein the admixture is heated for up to 60 minutes.

20. 20. The method of claim 18, wherein the admixture is heated for 50 minutes or less.

21. 20. The method of claim 18, wherein the admixture is heated for no more than 40 minutes.

22. 20. The method of claim 18, wherein the admixture is heated for 30 minutes or less.

23. 20. The method of claim 18, wherein the admixture is heated for 20 minutes or less.

24. 20. The method of claim 18, wherein the admixture is heated for 15 minutes or less.

25. 25. The method of any one of claims 18 to 24, wherein the mixture of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is heated at about 80°C ± 10°C.

26. 25. The method of any one of claims 18 to 24, wherein the admixture lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is heated to about 60°C ± 5°C.

27. 27. The method of any one of claims 18 to 26, further comprising cooling the admixture after heating.

28. 28. The method of any one of claims 18 to 27, wherein after said blending, said complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is mixed with a pharmaceutical composition.

29. 30. The method of claim 28, wherein the formulation composition is an aqueous composition comprising one or more ascorbate compounds.

30. 30. The method of claim 28 or 29, wherein the pharmaceutical composition is an aqueous composition that is substantially or completely free of gentisate compounds, such as gentisic acid.

31. The method of any one of claims 28 to 30, wherein the pharmaceutical composition comprises the one or more ascorbate compounds in an amount of 1 mg / mL or greater.

32. The method of any one of claims 28 to 30, wherein the pharmaceutical composition comprises the one or more ascorbate compounds in an amount of 2 mg / mL or greater.

33. The method of any one of claims 28 to 32, wherein the pharmaceutical composition further comprises one or more sequestering agents.

34. Incorporation of lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is greater than 98 mole percent １７７ 34. The method of any one of claims 13 to 33, wherein Lu-DOTATATE is provided.

35. Incorporation of lutetium-177 with tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is greater than 99 mole percent １７７ The method of any one of claims 13 to 34, wherein Lu-DOTATATE is provided.

36. 36. The method of any one of claims 13 to 35, wherein an acidic aqueous formulation of lutetium-177 is admixed with the tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE).

37. 37. The method of any one of claims 13 to 36, wherein an aqueous hydrogen halide or acid halide preparation of lutetium-177 is admixed with the tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE).

38. 38. The method of any one of claims 13 to 37, wherein an aqueous hydrochloric acid preparation of lutetium-177 is admixed with the tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE).

39. 39. The method of any one of claims 13 to 38, further comprising administering to a patient in need thereof a composition comprising a complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE).

40. 1. A method for treating a patient suffering from cancer, comprising: (a) combining lutetium-177 with 1) tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE), and 2) an aqueous formulation comprising one or more ascorbate compounds in the substantial or complete absence of a gentisate compound, thereby forming a complex between lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE); A composition is provided that comprises: 1) a complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE); and 2) one or more ascorbate compounds, in the substantial or complete absence of gentisate compounds; b) administering said composition to said patient.

41. 41. The method of claim 40, wherein the composition comprises the one or more ascorbate compounds in an amount of 10 mg / mL or less.

42. 41. The method of claim 40, wherein the composition comprises the one or more ascorbate compounds in an amount of 8 mg / mL or less.

43. 41. The method of claim 40, wherein the composition comprises the one or more ascorbate compounds in an amount of 6 mg / mL or less.

44. 41. The method of claim 40, wherein the composition comprises the one or more ascorbate compounds in an amount of 4 mg / mL or less.

45. 45. The method of any one of claims 40 to 44, further comprising determining the purity of the ascorbate compound prior to combining the ascorbate compound with lutetium-177 and / or tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) and / or complexes of lutetium-177 and / or tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE).

46. 46. ​​The method of any one of claims 40 to 45, wherein the complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) corresponds to the following structure: 【Chemistry 2】

47. The complex of lutetium-177 and tetraazacyclododecanetetraacetic acid-octreotate (DOTATATE) is １７７ Lu-DOTATATE( １７７ 47. The composition or method of any one of claims 1 to 46, wherein the cation exchanger is phosphate phosphate phosphate (Pt-octreotate).

48. Obtainable by the method according to any one of claims 13 to 39. １７７ Lu-DOTATATE.

49. Obtained by the method according to any one of claims 13 to 39. １７７ Lu-DOTATATE.

50. 50. The method according to claim 48 or 49, １７７ A pharmaceutical composition comprising Lu-DOTATATE.

51. 51. The pharmaceutical composition of claim 50, wherein the radiochemical purity of the composition is 95% or greater for 3 days or more at 25°C.

52. 52. The pharmaceutical composition of claim 51, wherein the radiochemical purity of the composition is 95% or greater for 5 days or more at 25°C.

53. 53. The pharmaceutical composition of any one of claims 50-52, wherein the composition comprises one or more ascorbate compounds in an amount of 10 mg / mL or less.

54. 53. The pharmaceutical composition of any one of claims 50-52, wherein the composition comprises one or more ascorbate compounds in an amount of 8 mg / mL or less.

55. 53. The pharmaceutical composition of any one of claims 50-52, wherein the composition comprises one or more ascorbate compounds in an amount of 6 mg / mL or less.

56. 53. The pharmaceutical composition of any one of claims 50-52, wherein the composition comprises one or more ascorbate compounds in an amount of 4 mg / mL or less.

57. The pharmaceutical composition of any one of claims 50 to 56, wherein the composition has a pH of 4.0 to 6.

0.

58. １７７ A single dose kit comprising Lu-DOTATATE or the pharmaceutical composition of any one of claims 1 to 12 or any one of claims 50 to 57.

59. １７７ A multi-dose kit comprising Lu-DOTATATE or the pharmaceutical composition of any one of claims 1-12 or any one of claims 50-57.

60. １７７ A sealed container comprising Lu-DOTATATE or the pharmaceutical composition of any one of claims 1 to 12 or any one of claims 50 to 57.

61. A method of treating a subject suffering from cancer comprising administering an effective amount of １７７ 58. A method comprising administering to said subject Lu-DOTATATE or a pharmaceutical composition according to any one of claims 1 to 12 or any one of claims 50 to 57.

62. 62. The method of claim 61, wherein the subject is afflicted with a neuroendocrine tumor.

63. 62. The method of claim 61, wherein the subject is afflicted with a neuroendocrine tumor originating in the foregut, hindgut, midgut, lung, ovary, medulla, adrenal medulla, adrenal gland, kidney, pituitary gland, thyroid gland, or paraganglia.

64. 64. The method of claim 62 or 63, further comprising assessing the neuroendocrine tumor as somatostatin receptor positive.

65. The neuroendocrine tumor is ６８ 65. The method of claim 64, which is shown to be somatostatin receptor positive by Ga-DOTATATE and positron emission tomography studies.

Images