Radiopharmaceutical and methods

Abstract

A radiopharmaceutical 177Lu-DOTATATE compound, a composition, and a kit are provided. Further provided are methods of synthesis of a 177Lu-DOTATATE compound and methods of treatment that comprise a 177Lu-DOTATATE compound.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 (a) a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE);   (b) one or more stabilizer compounds in a concentration of at least 25 mg/mL.   
     
     
         2 . The composition of  claim 1  wherein the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is present in an amount of at least 5 mCi/mL. 
     
     
         3 . The composition of  claim 1  wherein the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is present in an amount of at least 10 mCi/mL. 
     
     
         4 . The composition of any one of  claims 1  through  3  wherein the composition comprises two or more stabilizers. 
     
     
         5 . The method of any one of  claims 1  through  4  wherein the one or more stabilizers comprise one or more ascorbate compounds. 
     
     
         6 . The method of any one of  claims 1  through  5  wherein the one or more stabilizers comprise one or more gentisate compounds. 
     
     
         7 . The composition of any one of  claims 1  through  6  wherein the composition comprises at least one ascorbate compound and at least one gentisate compound. 
     
     
         8 . The composition of any one of  claims 1  through  7  wherein the one or more stabilizer compounds are present in an amount of 30 mg/mL or greater. 
     
     
         9 . The composition of any one of  claims 1  through  7  wherein the one or more stabilizer compounds are present in an amount of 40 mg/mL or greater. 
     
     
         10 . The composition of any one of  claims 1  through  7  wherein the one or more stabilizer compounds are present in an amount of 50 mg/mL or greater. 
     
     
         11 . The composition of any one of  claims 1  through  10  wherein the composition is an aqueous formulation. 
     
     
         12 . The composition of any one of  claims 1  through  11  wherein the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) corresponds to the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The pharmaceutical composition of any one of  claims 1  through  12  wherein the radiochemical purity of the composition is 95% or greater for 3 days by HPLC analysis. 
     
     
         14 . The pharmaceutical composition of any one of  claims 1  through  12  wherein the radiochemical purity of the composition is 95% or greater for 5 days by HPLC analysis. 
     
     
         15 . A method for preparing  177 Lu-DOTATATE, comprising:
 admixing lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) in the presence of one or more stabilizer compounds,   wherein the one or more stabilizer compounds are present in an amount of 10 mg/mL or greater,   thereby forming a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE).   
     
     
         16 . The method of  claim 15  wherein an aqueous formulation comprising tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is admixed with lutetium-177. 
     
     
         17 . The method of  claim 15  or  16  wherein the one or more stabilizer compounds are present in an amount of 20 mg/mL or greater. 
     
     
         18 . The method of any one of  claims 15  through  17  wherein the one or more stabilizer compounds are present in an amount of 30 mg/mL or greater. 
     
     
         19 . The method of any one of  claims 15  through  17  wherein the one or more stabilizer compounds are present in an amount of 40 mg/mL or greater. 
     
     
         20 . The method of any one of  claims 15  through  17  wherein the one or more stabilizer compounds are present in an amount of 50 mg/mL or greater. 
     
     
         21 . The method of any one of  claims 15  through  20  wherein each of the one or more stabilizer compounds are present in an amount of 10 mg/mL or greater. 
     
     
         22 . The method of any one of  claims 15  through  21  wherein the one or more stabilizers comprise one or more ascorbate compounds. 
     
     
         23 . The method of any one of  claims 15  through  22  wherein the one or more stabilizers comprise one or more gentisate compounds. 
     
     
         24 . The method of any one of  claims 15  through  23  wherein the one or more stabilizers comprise one or more gentisate compounds in an amount of at least 10 mg/mL and one or more ascorbate compounds in an amount of at least 30 mg/mL. 
     
     
         25 . The method of any one of  claims 15  through  23  wherein the one or more stabilizers comprise one or more gentisate compounds in an amount of at least 15 mg/mL and one or more ascorbate compounds in an amount of at least 40 mg/mL. 
     
     
         26 . The method of any one of  claims 15  through  25  wherein the admixture of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is heated. 
     
     
         27 . The method of  claim 26  wherein the admixture is heated for 60 minutes or less. 
     
     
         28 . The method of  claim 26  wherein the admixture is heated for 50 minutes or less. 
     
     
         29 . The method of  claim 26  wherein the admixture is heated for 40 minutes or less. 
     
     
         30 . The method of  claim 26  wherein the admixture is heated for 30 minutes or less. 
     
     
         31 . The method of  claim 26  wherein the admixture is heated for 20 minutes or less. 
     
     
         32 . The method of  claim 26  wherein the admixture is heated for 15 minutes or less. 
     
     
         33 . The method of any one of  claims 15  through  32  wherein the admixture of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is heated at about 80° C.±10° C. 
     
     
         34 . The method of any one of  claims 15  through  32  wherein the admixture lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is heated at about 80° C.±5° C. 
     
     
         35 . The method of any one of  claims 15  through  34  further comprising cooling the admixture following heating. 
     
     
         36 . The method of any one of  claims 15  through  35  wherein following the admixing, the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is mixed with a formulation composition. 
     
     
         37 . The method of  claim 36  wherein the formulation composition is an aqueous composition that comprises one or more stabilizer compounds. 
     
     
         38 . The method of  claim 37  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 10 mg/mL or greater. 
     
     
         39 . The method of  claim 37  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 20 mg/mL or greater. 
     
     
         40 . The method of  claim 37  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 30 mg/mL or greater. 
     
     
         41 . The method of  claim 37  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 40 mg/mL or greater. 
     
     
         42 . The method of  claim 37  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 50 mg/mL or greater. 
     
     
         43 . The method of any one of  claims 36  through  42  wherein the formulation composition further comprises one or more sequestering agents. 
     
     
         44 . The method of any one of  claims 15  through  43  wherein incorporation of lutetium-177 with tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) provides  177 Lu-DOTATATE in greater than 98 mole percent. 
     
     
         45 . The method of any one of  claims 15  through  43  wherein incorporation of lutetium-177 with tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) provides  177 Lu-DOTATATE in greater than 99 mole percent. 
     
     
         46 . The method of any one of  claims 15  through  43  wherein an acidic aqueous formulation of lutetium-177 is admixed with the tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE). 
     
     
         47 . The method of any one of  claims 15  through  43  wherein a hydrogen halide or acid halide aqueous formulation of lutetium-177 is admixed with the tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE). 
     
     
         48 . The method of any one of  claims 1  through  47  wherein a hydrochloride acid aqueous formulation of lutetium-177 is admixed with the tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE). 
     
     
         49 . A method for preparing  177 Lu-DOTATATE, comprising:
 admixing lutetium-177 and an aqueous formulation comprising tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) in the presence of one or more ascorbate compounds,   wherein the one or more ascorbate compounds are present in an amount of 30 mg/mL or greater,   thereby forming a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE).   
     
     
         50 . A method for preparing  177 Lu-DOTATATE, comprising:
 admixing lutetium-177 and an aqueous formulation comprising tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) in the presence of one or more gentisate compounds,   wherein the one or more gentisate compounds are present in an amount of 10 mg/mL or greater,   thereby forming a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE).   
     
     
         51 . A method for preparing  177 Lu-DOTATATE, comprising:
 admixing lutetium-177 and an aqueous formulation comprising tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) in the presence of one or more stabilizer compounds that are selected from one or more ascorbate compounds and one or more gentisate compounds,   wherein the one or more stabilizer compounds are present in an amount of 10 mg/mL or greater,   thereby forming a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE).   
     
     
         52 . The method of  claim 51  wherein the one or more stabilizer compounds are present in an amount of 20 mg/mL or greater. 
     
     
         53 . The method of  claim 51  wherein the one or more stabilizer compounds are present in an amount of 25 mg/mL or greater. 
     
     
         54 . The method of  claim 51  wherein the one or more stabilizer compounds are present in an amount of 30 mg/mL or greater. 
     
     
         55 . The method of  claim 51  wherein the one or more stabilizer compounds are present in an amount of 40 mg/mL or greater. 
     
     
         56 . The method of  claim 51  wherein the one or more stabilizer compounds are present in an amount of 50 mg/mL or greater. 
     
     
         57 . The method of any one of  claims 51  through  56  wherein the one more gentisate compounds are present in an amount of 10 mg/mL or greater. 
     
     
         58 . The method of any one of  claims 51  through  57  wherein the one or more stabilizers comprise one or more gentisate compounds in an amount of at least 10 mg/mL and one or more ascorbate compounds in an amount of at least 30 mg/mL. 
     
     
         59 . The method of any one of  claims 51  through  57  wherein the one or more stabilizers comprise one or more gentisate compounds in an amount of at least 15 mg/mL and one or more ascorbate compounds in an amount of at least 40 mg/mL. 
     
     
         60 . The method of any one of  claims 51  through  57  wherein the admixture of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is heated. 
     
     
         61 . The method of  claim 60  wherein the admixture is heated for 40 minutes or less. 
     
     
         62 . The method of  claim 60  wherein the admixture is heated for 30 minutes or less. 
     
     
         63 . The method of  claim 60  wherein the admixture is heated for 20 minutes or less. 
     
     
         64 . The method of any one of  claims 51  through  63  wherein the admixture of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is heated at about 80° C.±10° C. 
     
     
         65 . The method of any one of  claims 51  through  64  further comprising cooling the admixture following heating. 
     
     
         66 . The method of any one of  claims 51  through  65  wherein following the admixing, the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is mixed with a formulation composition. 
     
     
         67 . The method of  claim 66  wherein the formulation composition is an aqueous composition that comprises one or more stabilizer compounds. 
     
     
         68 . The method of  claim 67  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 10 mg/mL or greater. 
     
     
         69 . The method of  claim 67  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 20 mg/mL or greater. 
     
     
         70 . The method of  claim 67  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 30 mg/mL or greater. 
     
     
         71 . The method of  claim 67  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 40 mg/mL or greater. 
     
     
         72 . The method of  claim 67  wherein the formulation composition comprises the one or more stabilizer compounds in an amount of 50 mg/mL or greater. 
     
     
         73 . The method of any one of  claims 66  through  72  wherein the formulation composition further comprises one or more sequestering agents. 
     
     
         74 . The method of any one of  claims 51  through  73  wherein incorporation of lutetium-177 with tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) provides  177 Lu-DOTATATE in greater than 98 mole percent. 
     
     
         75 . The method of any one of  claims 51  through  73  wherein incorporation of lutetium-177 with tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) provides  177 Lu-DOTATATE in greater than 99 mole percent. 
     
     
         76 . The method of any one of  claims 51  through  75  wherein a hydrogen halide or acid halide aqueous formulation of lutetium-177 is admixed with the tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE). 
     
     
         77 . The method of any one of  claims 51  through  75  wherein a hydrochloride acid aqueous formulation of lutetium-177 is admixed with the tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE). 
     
     
         78 . The method of any one of  claims 51  through  77  wherein a composition is provided that comprises 1) a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) and 2) one or more stabilizer compounds in a concentration of at least 25 mg/mL. 
     
     
         79 . The method of  claim 78  wherein the composition comprises the one or more stabilizer compounds in an amount of 30 mg/mL or greater. 
     
     
         80 . The method of  claim 78  wherein the composition comprises the one or more stabilizer compounds in an amount of 40 mg/mL or greater. 
     
     
         81 . The method of  claim 78  wherein the composition comprises the one or more stabilizer compounds in an amount of 50 mg/mL or greater. 
     
     
         82 . The method of any one of  claims 51  through  81  wherein composition comprises the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) present in an amount of at least 5 mCi/mL. 
     
     
         83 . The method of any one of  claims 51  through  81  wherein composition comprises the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) present in an amount of at least 10 mCi/mL. 
     
     
         84 . The method of any one of  claims 51  through  83  wherein the composition comprises two or more stabilizers. 
     
     
         85 . The method of any one of  claims 51  through  84  wherein the one or more stabilizers comprise one or more ascorbate compounds. 
     
     
         86 . The method of any one of  claims 51  through  85  wherein the one or more stabilizers comprise one or more gentisate compounds. 
     
     
         87 . A method of any one of  claims 15  through  86  further comprising administering a composition comprising a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) to a patient in need thereof. 
     
     
         88 . A method for treating a patient suffering from cancer, comprising:
 (a) admixing lutetium-177 and an aqueous formulation comprising tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) in the presence of one or more stabilizer compounds that are selected from one or more ascorbate compounds and one or more gentisate compounds, thereby forming a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE), and   wherein a composition is provided that comprises 1) a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) and 2) one or more stabilizer compounds in a concentration of at least 25 mg/mL; and   b) administering the composition to the patient.   
     
     
         89 . The method of  claim 88  wherein the composition comprises the one or more stabilizer compounds in an amount of 30 mg/mL or greater. 
     
     
         90 . The method of  claim 88  wherein the composition comprises the one or more stabilizer compounds in an amount of 40 mg/mL or greater. 
     
     
         91 . The method of  claim 88  wherein the composition comprises the one or more stabilizer compounds in an amount of 50 mg/mL or greater. 
     
     
         92 . The method of any one of  claims 88  through  91  wherein composition comprises the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) present in an amount of at least 5 mCi/mL. 
     
     
         93 . The method of any one of  claims 88  through  91  wherein composition comprises the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) present in an amount of at least 10 mCi/mL. 
     
     
         94 . The method of any one of  claims 88  through  93  wherein the composition comprises two or more stabilizers. 
     
     
         95 . The method of any one of  claims 88  through  94  wherein the one or more stabilizers comprise one or more ascorbate compounds. 
     
     
         96 . The method of any one of  claims 88  through  95  wherein the one or more stabilizers comprise one or more gentisate compounds. 
     
     
         97 . The method of any one of  claims 15  through  96  further comprising determining purity of an ascorbate compound prior to admixing the ascorbate compound with lutetium-177 and/or tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) and/or a complex of lutetium-177 and/or tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE). 
     
     
         98 . The method of  claim 97  comprising determining the ascorbate compound is effective in an incorporation reaction and admixing the effective ascorbate compound with lutetium-177 and/or tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) and/or a complex of lutetium-177 and/or tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE). 
     
     
         99 . The method of  claim 97  or  98  wherein the ascorbate compound is an ascorbate salt. 
     
     
         100 . The method of any one of claims  claim 97  through  99  wherein the ascorbate compound is sodium ascorbate. 
     
     
         101 . The method of any one of  claims 15  through  100  wherein the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) corresponds to the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         102 . The composition or method of any one of  claims 1  through  101  wherein the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) is  177 Lu-DOTATATE ( 177 Lu-octreotate). 
     
     
         103 .  177 Lu-DOTATATE obtainable by a method of any one of  claims 15 - 102 . 
     
     
         104 .  177 Lu-DOTATATE obtained by a method of any one of  claims 15 - 102 . 
     
     
         105 . A pharmaceutical composition comprising  177 Lu-DOTATATE of  claim 103  or  104 . 
     
     
         106 . The pharmaceutical composition of  claim 105  wherein the radiochemical purity of the composition is 95% or greater for 3 days or more at 25° C. 
     
     
         107 . The pharmaceutical composition of  claim 105  wherein the radiochemical purity of the composition is 95% or greater for 5 days or more at 25° C. 
     
     
         108 . The pharmaceutical composition of any one of  claims 105  through  107  wherein the composition comprises one or more stabilizer compounds in an amount of 10 mg/mL or greater. 
     
     
         109 . The pharmaceutical composition of any one of  claims 105  through  107  wherein the composition comprises one or more stabilizer compounds in an amount of 20 mg/mL or greater. 
     
     
         110 . The pharmaceutical composition of any one of  claims 105  through  107  wherein the composition comprises one or more stabilizer compounds in an amount of 25 mg/mL or greater. 
     
     
         111 . The pharmaceutical composition of any one of  claims 105  through  107  wherein the composition comprises one or more stabilizer compounds in an amount of 30 mg/mL or greater. 
     
     
         112 . The pharmaceutical composition of any one of  claims 105  through  107  wherein the composition comprises one or more stabilizer compounds in an amount of 40 mg/mL or greater. 
     
     
         113 . The pharmaceutical composition of any one of  claims 105  through  107  wherein the composition comprises one or more stabilizer compounds in an amount of 50 mg/mL or greater. 
     
     
         114 . The pharmaceutical composition of any one of  claims 108  through  113  wherein the one or more stabilizers comprise one or more ascorbate compounds. 
     
     
         113 . The pharmaceutical composition of any one of  claims 108  through  114  wherein the one or more stabilizers comprise one or more gentisate compounds. 
     
     
         114 . The pharmaceutical composition of any one of  claims 108  through  113  wherein the one or more stabilizers comprise one or more gentisate compounds in an amount of at least 10 mg/mL and one or more ascorbate compounds in an amount of at least 30 mg/mL. 
     
     
         115 . The pharmaceutical composition of any one of  claims 108  through  113  wherein the one or more stabilizers comprise one or more gentisate compounds in an amount of at least 15 mg/mL and one or more ascorbate compounds in an amount of at least 40 mg/mL. 
     
     
         116 . The pharmaceutical composition of any one of  claims 108  through  113  wherein the composition comprises one or more ascorbate compounds are present in an amount of 30 mg/mL or greater. 
     
     
         117 . The pharmaceutical composition of any one of  claims 108  through  113  wherein the composition comprises one or more ascorbate compounds are present in an amount of 40 mg/mL or greater 
     
     
         118 . The pharmaceutical composition of any one of  claims 108  through  117  wherein the composition comprises one or more gentisate compounds are present in an amount of 10 mg/mL or greater. 
     
     
         119 . A single dosage kit comprising  177 Lu-DOTATATE or pharmaceutical composition of any one of  claims 1  through  14  or any one of  claims 103  through  118 . 
     
     
         120 . A multiple dosage kit comprising  177 Lu-DOTATATE or pharmaceutical composition of any one of  claims 1  through  14  or any one of  claims 103  through  118 . 
     
     
         121 . A sealed container comprising  177 Lu-DOTATATE or pharmaceutical composition of any one of  claims 1  through  14  or any one of  claims 103  through  118 . 
     
     
         122 . A method of treating a subject suffering from cancer, comprising administering to the subject an effective amount of  177 Lu-DOTATATE or pharmaceutical composition of any one of  claims 1  through  14  or any one of  claims 103  through  121 . 
     
     
         123 . The method of  claim 122  wherein the subject is suffering from neuroendocrine tumors. 
     
     
         124 . The method of  claim 122  wherein the subject is suffering from neuroendocrine tumors that originate from foregut, hindgut, midgut, lung, ovary, medulla, adrenal medulla, adrenal, kidney, pituitary, thyroid or paraganglia. 
     
     
         125 . The method of  claim 123  or  124  further comprising assessing the neuroendocrine tumors to be somatostatin receptor positive. 
     
     
         126 . The method of  125  wherein the neuroendocrine tumors are demonstrated to be somatostatin receptor positive with  68 Ga-DOTATATE and a positron emission tomography scan.