# US 11,439,714 B2 · Radiopharmaceutical and methods

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- Number: US 11,439,714 B2
- Document ID: US11439714B2
- Status: Granted
- Kind: B2
- Application number: 17/461,860
- Filed: 2021-08-30
- Published: 2022-03-03
- Granted: 2022-09-13
- Earliest claimed: 2020-08-27
- Assignees: Centre for Probe Development and Commercialization
- Applicants: Centre for Probe Development and Commercialization (CPDC)
- Inventors: Joe McCann; Justyna Kelly; Paul Billone
- Web page: https://patentgrep.com/patent/US11439714B2

## CPC

- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- A61K 51/083: {the peptide being octreotide or a somatostatin-receptor-binding peptide}
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- A61K 51/121: {Solutions, i.e. homogeneous liquid formulation}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## 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.

## Claims

### Claim 1

A single dosage pharmaceutical composition of 3.6 GBq to 11.1 GBq 177Lu-DOTATATE, comprising:
(a) a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) having 98% or greater lutetium-177 incorporation as determined by radio-iTLC;
(b) one or more ascorbate compounds at a concentration of at least 50 mg/mL, and one or more gentistate compounds at a concentration of at least 15 mg/mL;
wherein the pharmaceutical composition has a radioactive concentration of 0.96 GBq/mL or less and maintains a radiochemical purity of 95% or greater as determined by radio-HPLC after 5 days at 25° C.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1 wherein the complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) corresponds to the following structure:

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1 wherein the radiochemical purity of the composition is 95% or greater for 5 days at 25° C. , as determined by both radio-HPLC analysis and radio-iTLC analysis.

### Claim 4

A method for preparing 177Lu-DOTATATE, comprising:
forming an incorporation reaction mixture comprising lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) in the presence of one or more ascorbate compounds and one or more gentistate compounds, wherein the ascorbate compound(s) are provided at a concentration of at least 50 mg/mL in the incorporation reaction mixture, the gentistate compound(s) are provided at a concentration of at least 15 mg/mL in the incorporation reaction mixture, and the lutetium-177 is present in the incorporation reaction mixture at a radioactive concentration of about 3.36 GBq/mL,
heating the incorporation reaction mixture to 80° C. or less thereby forming a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) having 98% or greater lutetium-177 incorporation as determined by radio-iTLC;
after cooling the incorporation reaction mixture, diluting the incorporation reaction mixture to form a pharmaceutical preparation comprising the complex at a radioactive concentration of 0.96 GBq/mL or less, and having a final concentration of ascorbate compound(s) of at least 50 mg/mL, and of gentistate compound(s) of at least 15 mg/mL, wherein the pharmaceutical composition maintains a radiochemical purity of 95% or greater as determined by radio-HPLC after 5 days at 25° C.

### Claim 5 (depends on 4)

The method of claim 4 wherein the incorporation reaction mixture is heated for 50 minutes or less.

### Claim 6

A method for treating a patient suffering from cancer, comprising:
(a) forming an incorporation reaction mixture comprising lutetium-177 and an aqueous formulation comprising tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) in the presence of one or more ascorbate compounds and one or more gentistate compounds, wherein the one or more ascorbate compounds are provided at a concentration of at least 50 mg/mL in the incorporation reaction mixture, and the one or more gentisate compounds are provided at a concentration of at least 15 mg/mL in the incorporation reaction mixture,
heating the incorporation reaction mixture to 80° C. or less thereby forming a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) having 98% or greater lutetium-177 incorporation as determined by radio-iTLC, and
after cooling the incorporation reaction mixture, diluting the incorporation reaction mixture to form a pharmaceutical preparation comprising the complex at a radioactive concentration of 0.96 GBq/mL, and having a final concentration of ascorbate compound(s) of at least 50 mg/mL, and of gentistate compound(s) of at least 15 mg/mL,
wherein the pharmaceutical composition maintains a radiochemical purity of 95% or greater as determined by radio-HPLC after 5 days at 25° C.; and ; and
b) administering the pharmaceutical preparation to the patient.

### Claim 7 (depends on 1)

A method of treating a subject suffering from cancer, comprising administering to the subject an effective amount of pharmaceutical composition of claim 1.

### Claim 8 (depends on 1)

The single dosage pharmaceutical composition of claim 1, wherein the lutetium-177 is provided as no-carrier-added lutetium-177.

### Claim 9 (depends on 7)

The method of claim 7 wherein the subject is suffering from neuroendocrine tumors.

### Claim 10

A single dosage pharmaceutical composition of 3.6 GBq to 11.1 GBq 177LU-DOTATATE, comprising:
a complex of lutetium-177 and tetraazacyclododecane tetra-acetic acid-octreotate (DOTATATE) having 98% or greater lutetium-177 incorporation as determined by radio-iTLC, being formed from an incorporation reaction carried out at a temperature of 80° C. or less in a solution including at least 15 mg/mL of one or more gentistate compounds and at least 50 mg/mL of one or more ascorbate compounds;
which complex, after formation in the incorporation reaction, is admixed to form the pharmaceutical composition having a concentration of at least 15 mg/mL of one or more gentistate compounds and at least 50 mg/mL of one or more ascorbate compounds, wherein the pharmaceutical composition maintains after 5 days at 25° C. following preparation of the composition: i) a radioactive concentration of 0.96 GBq/mL or less and ii) a radiochemical purity of 95% or greater as determined by radio-HPLC.

### Claim 11 (depends on 8)

A method of treating a subject suffering from cancer, comprising administering to the subject an effective amount of pharmaceutical composition of claim 8.

### Claim 12 (depends on 1)

The single dosage pharmaceutical composition of claim 1, further including at least 0.4 mg/mL diethylenetriaminepentaacetic acid (DTPA).

### Claim 13 (depends on 10)

The single dosage pharmaceutical composition of claim 10, wherein the lutetium-177 is provided as 177LuCl3.

### Claim 14 (depends on 10)

The single dosage pharmaceutical composition of claim 10, wherein the lutetium-177 is provided as no-carrier-added lutetium-177.

### Claim 15 (depends on 10)

The single dosage pharmaceutical composition of claim 10, wherein the pharmaceutical composition further includes 0.4 mg/mL diethylenetriaminepentaacetic acid (DTPA).

### Claim 16 (depends on 4)

The method of claim 4, wherein the lutetium-177 is provided as no-carrier-added lutetium-177.

### Claim 17 (depends on 4)

The method of claim 4, wherein the pharmaceutical composition further includes at least 0.4 mg/mL diethylenetriaminepentaacetic acid (DTPA).