Methods for Synthesis of Radionuclide Complex

• US 20200131224A1
• Filed: 04/24/2019
• Published: 04/30/2020
• Est. Priority Date: 10/31/2018
• Status: Abandoned Application

• Current Assignee: Advanced Accelerator Applications (Italy) S.R.L. (Novartis Ag)
• Original Assignee: Advanced Accelerator Applications (Italy) S.R.L. (Novartis Ag)
• Inventors: Fugazza, Lorenza, De Palo, Francesco, Barbato, Donato, Mariani, Maurizio F., Tesoriere, Giovanni, Brambati, Clementina
• Application Number:
  US16/393,103
• Publication Number:
  US 20200131224A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 51/0482 chelates from cyclic ligands, e.g. DOTA
• CPC Class Codes: A61K 51/083 the peptide being octreotide or a somatostatin-receptor-binding peptide
• CPC Class Codes: A61K 51/088 conjugates with carriers being peptides, polyamino acids or proteins antibodies A61K51/10
• CPC Class Codes: A61K 51/121 Solutions, i.e. homogeneous liquid formulation
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: C07B 59/004 Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
• CPC Class Codes: C07K 1/13 Labelling of peptides
• CPC Class Codes: C07K 14/655 Somatostatins

Abstract

The present disclosure relates to the synthesis of radionuclide complex solutions, in particular for their use in the commercial production of radioactive drug substances, for diagnostic and/or therapeutic purposes. In particular, the synthesis method comprises the following steps in the following order:

• • a. providing a radionuclide precursor solution into a first vial,
  • b. transferring the radionuclide precursor solution into a reactor,
  • c. providing a reaction buffer solution into said first vial containing residual radionuclide precursor solution,
  • d. transferring the buffer reaction solution and residual radionuclide precursor solution from said first vial into the reactor,
  • e. transferring a peptide solution comprising the somatostatin receptor binding peptide linked to a chelating agent, into the reactor,
  • f. reacting the somatostatin receptor binding peptide linked to a chelating agent with said radionuclide in the reactor to obtain the radionuclide complex,
  • g. recovering said radionuclide complex.

Claims

1-25. -25. (canceled)

26. A pharmaceutical formulation comprising ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC obtained by a method comprising the steps of:

a) providing a ¹⁷⁷LuCl₃ solution into a first vial,

b) transferring the ¹⁷⁷LuCl₃ solution into a reactor,

c) providing a reaction buffer solution into the first vial containing residual radionuclide precursor solution,

d) transferring the reaction buffer solution and residual ¹⁷⁷LuCl₃ solution from said first vial into the reactor,

e) transferring a DOTA-TATE or DOTA-TOC solution into the reactor,

f) reacting the DOTA-TATE or DOTA-TOC with the ¹⁷⁷LuCl₃ in the reactor to obtain the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC, the ratio of DOTA-TATE or DOTA-TOC and ¹⁷⁷Lu being between 1.5 and 3.5,

g) recovering the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC, and

h) diluting the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC in a formulation buffer to form a pharmaceutical formulation, wherein the formulation buffer comprises at least one sequestering agent, at least one radiolytic stabilizer, at least one pH adjuster, at least one solvent, and sodium chloride; and

wherein the pharmaceutical formulation has a pH of about 4.5 to about 6, the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC in the pharmaceutical formulation has a specific activity concentration of 370 MBq/mL, and the method does not comprise a tC18 solid phase extraction (SPE) purification step.

27. The pharmaceutical formulation of claim 26, wherein the at least one sequestering agent is diethylene triamine pentaacetic acid;

the at least one radiolytic stabilizer is gentisic acid and ascorbic acid;

the at least one pH adjuster is sodium hydroxide, acetic acid, and sodium acetate; and

the at least one solvent is water.

28. The pharmaceutical formulation of claim 27, wherein the diethylene triamine pentaacetic acid is present at a concentration of 0.05 mg/mL, the gentisic acid is present at a concentration of 0.63 mg/mL, the ascorbic acid is present at a concentration of 2.8 mg/mL, the sodium hydroxide is present at a concentration of 0.65 mg/mL, the acetic acid is present at a concentration of 0.48 mg/mL, the sodium acetate is present at a concentration of 0.66 mg/mL, and the sodium chloride is present at a concentration of 6.85 mg/mL.

29. The pharmaceutical formulation of claim 26, wherein the pharmaceutical formulation is for an infusion to treat a subject in need thereof.

30. The pharmaceutical formulation of claim 26, wherein the reacting step f) occurs over a time period of between 2 and 15 minutes at a temperature of between 80-100°

C.

31. The pharmaceutical formulation of claim 26, wherein the method to obtain the pharmaceutical formulation further comprises one or more rinsing steps for efficient recovery of the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC.

32. The pharmaceutical formulation of claim 26, wherein the ¹⁷⁷LuCl₃ solution comprises ¹⁷⁷LuCl₃ at a specific activity of 74 GBq±

20% in a volume of between 1 and 2 mL.

33. The pharmaceutical formulation of claim 32, wherein the DOTA-TATE or DOTA-TOC solution comprises 2 mg±

5% of DOTA-TATE or DOTA-TOC in a volume of between 1.5 and 2.5 mL.

34. The pharmaceutical formulation of claim 33, wherein the reaction buffer solution comprises 157 mg of gentisic acid±

5% in a volume of between 1.5 and 2.5 mL.

35. The pharmaceutical formulation of claim 34, wherein the pH of the reacting step f) is between 4.5 and 5.5.

36. The pharmaceutical formulation of claim 26, wherein the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC has a specific activity at the reacting step f) of at least 407 GBq/mg.

37. A pharmaceutical formulation comprising ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC obtained by a method comprising the steps of:

a) providing a ¹⁷⁷LuCl₃ solution at 74 GBq±

20% into a first vial,

b) transferring the ¹⁷⁷LuCl₃ solution into a reactor,

c) providing a reaction buffer solution comprising gentisic acid into the first vial containing residual radionuclide precursor solution,

d) transferring the reaction buffer solution and the residual ¹⁷⁷LuCl₃ solution from the first vial into the reactor,

e) transferring a solution comprising 2 mg±

5% of DOTA-TATE or DOTA-TOC into the reactor,

f) reacting the DOTA-TATE or DOTA-TOC with the ¹⁷⁷LuCl₃ in the reactor to obtain ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC,

g) recovering ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC, and

h) diluting the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC in a formulation buffer, wherein the formulation buffer comprises at least one sequestering agent, at least one radiolytic stabilizer, at least one pH adjuster, at least one solvent, and sodium chloride,

wherein the method does not comprise a tC18 solid phase extraction (SPE) purification step.

38. The pharmaceutical formulation of claim 37, wherein the ¹⁷⁷LuCl₃ solution comprises a volume of between about 1 to about 2 mL.

39. The pharmaceutical formulation of claim 37, wherein the DOTA-TATE or DOTA-TOC solution comprises a volume of between 1.5 and 2.5 mL.

40. The pharmaceutical formulation of claim 37, wherein the reaction buffer solution comprises 157 mg of gentisic acid.

41. The pharmaceutical formulation of claim 37, wherein the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC recovered at step g) has a specific activity of at least 45.0 GBq.

42. The pharmaceutical formulation of claim 37, wherein the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC is diluted to a specific activity concentration of 370 MBq/mL.

43. A pharmaceutical formulation comprising ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC obtained by a method comprising the steps of:

a) providing a ¹⁷⁷LuCl₃ solution at 148 GBq±

20% into a first vial,

b) transferring the ¹⁷⁷LuCl₃ solution into a reactor,

c) providing a reaction buffer solution comprising gentisic acid into the first vial containing residual radionuclide precursor solution,

d) transferring the reaction buffer solution and the residual ¹⁷⁷LuCl₃ solution from the first vial into the reactor,

e) transferring a solution comprising 4 mg±

5% of DOTA-TATE or DOTA-TOC into the reactor,

f) reacting the DOTA-TATE or DOTA-TOC with the ¹⁷⁷LuCl₃ in the reactor to obtain ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC,

g) recovering ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC, and

h) diluting the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC in a formulation buffer, wherein the formulation buffer comprises at least one sequestering agent, at least one radiolytic stabilizer, at least one pH adjuster, at least one solvent, and sodium chloride,

wherein the method does not comprise a tC18 solid phase extraction (SPE) purification step.

44. The pharmaceutical formulation of claim 43, wherein the ¹⁷⁷LuCl₃ solution comprises a volume of between about 2 to about 3 mL.

45. The pharmaceutical formulation of claim 43, wherein the DOTA-TATE or DOTA-TOC solution comprises a volume of between 3.5 and 4.5 mL.

46. The pharmaceutical formulation of claim 43, wherein the reaction buffer solution comprises 314 mg of gentisic acid.

47. The pharmaceutical formulation of claim 43, wherein the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC recovered at step g) has a specific activity of at least 59.0 GBq.

48. The pharmaceutical formulation of claim 43, wherein the ¹⁷⁷Lu-DOTA-TATE or ¹⁷⁷Lu-DOTA-TOC is diluted to a specific activity concentration of 370 MBq/mL.