JP2023126209A - Stable concentrated radionuclide complex solution - Google Patents

Abstract

To provide a radionuclide complex solution having high concentration and high chemical stability which enables its use as a pharmaceutical product for diagnostic and/or therapeutic purposes.SOLUTION: There is provided a medicinal aqueous solution which contains (a) a complex formed by (ai) a radionuclide and (aii) a cell receptor binding organic moiety linked to a chelating agent, and (b) at least one stabilizer for radiolytic deterioration, wherein the radionuclide is present at a concentration that provides a volumetric radioactivity at least 100 MBq/mL, preferably at least 250 MBq/mL.SELECTED DRAWING: None

Description

Application for application of Article 30, Paragraph 2 of the Patent Act <1> (1) Publication date: January 17, 2018 (published online) (2) Publication: Lutathera: EPAR-Product Information https://www. ema. europa. eu/en/documents/product-information/lutathera-epar-product-information_en. pdf (3) Publisher: Advanced Accelerator Applications SA (4) Contents of the disclosed invention: Composition of Lutathera additives (6.1 List of excipients (page 20))

Application for application of Article 30, Paragraph 2 of the Patent Act <2> (1) Publication date: January 17, 2018 (published online) (2) Publication: Lutathera: EPAR-Public assessment report https://www. ema. europa. eu/en/documents/assessment-report/lutathera-epar-public-assessment-reort_en. pdf (3) Publisher: Advanced Accelerator Applications SA (4) Contents of the disclosed invention: Composition of Lutathera additives (2.2.1 Introduction: Other ingredients (page 18), 2.2.3 Finished Medicinal Product: Description of the product and pharmaceutical development: Other ingredients (Page 25)

Application for application of Article 30, Paragraph 2 of the Patent Act <3> (1) Publication date: March 12, 2018 (published online) (2) Publication: Printed Labeling https://www. accessdata. fda. gov/drugsatfda_docs/nda/2018/208700Orig1s000lbll. pdf (3) Publisher: Advanced Accelerator Applications USA, Inc. (4) Contents of the disclosed invention: Composition of Lutathera additive (HIGHLIGHTS OF PRESCRIBING INFORMATION: 11 DESCRIPTION (pages 9-10))

Application for application of Article 30, Paragraph 2 of the Patent Act <4> (1) Publication date: March 12, 2018 (published online) (2) Publication Chemistry Review(s) https://www. accessdata. fda. gov/drugsatfda_docs/nda/2018/208700Orig1s000ChemR. pdf (3) Publisher: Advanced Accelerator Applications USA, Inc. (4) Contents of the disclosed invention: Composition of Lutathera additive (NDA 208700 (Resubmission) OPQ Integrated Quality Assessment final: B .Drug Product [Established Name] Quality Summary (Page 3, lines 2-3), NDA 208700 OPQ N208700 Integrated Quality Assessment Final: Introduction (Page 4, Lines 9-10)

The present invention relates to highly concentrated and highly chemically and radiochemically stable radionuclide complex solutions that enable their use as commercially available pharmaceutical products for diagnostic and/or therapeutic purposes.

The concept of targeted drug delivery is based on cellular receptors that are overexpressed on target cells as opposed to non-targeted subject cells. If a drug has binding sites for such overexpressed cellular receptors, it is possible to deliver high concentrations of the drug to those target cells after systemic administration, leaving other unrelated cells unaffected. It becomes possible. For example, if tumor cells are characterized by the overexpression of specific cellular receptors, drugs with binding affinity for said receptors can be administered at high concentrations after intravenous injection, leaving normal tissues unaffected. will accumulate in tumor tissue.

This targeted drug delivery concept has also been used in radiopharmaceuticals to selectively deliver radionuclides to target cells for diagnostic or therapeutic purposes. In this radiopharmaceutical application, the target cell receptor binding moiety is typically linked to a chelating agent capable of forming a strong complex with the metal ion of the radionuclide. The radiopharmaceutical agent is then delivered to the target cells, and decay of the radionuclide releases high-energy electrons, positrons, or alpha particles, as well as gamma rays, at the target site.

One of the technical problems with such radiopharmaceutical drug products is that the decay of radionuclides always occurs, for example during the manufacture and also during storage of the drug product, and the released high-energy emitters can be used to disintegrate the molecules that form part of the drug product. inducing the cleavage of chemical bonds. This is often referred to as radiolysis or radiolytic degradation. Radiolytic degradation of the receptor binding portion of a drug can result in a decrease in its efficacy to act as a diagnostic and/or therapeutic agent.

Due to the insufficient stability of such radiopharmaceutical drug products and their lack of significant shelf life, it has so far been difficult to manufacture the drugs in hospital laboratories as individual patient dose units; It had to be administered to the patient immediately and required that the patient already be in the hospital awaiting radiological treatment.

Various strategies have been explored to reduce radiolysis of radiopharmaceutical drug products.
It has been more or less successful. That is, the drug product can be stored at low temperatures, or manufactured at high dilution, or stabilizers can be added.

However, the addition of stabilizers can be problematic as such chemicals can adversely affect the complexation of the radionuclide to the chelating agent.

The production of highly dilute drug products has the disadvantage of requiring large volumes of infusion solution to be administered to the patient. For reasons of patient convenience and drug tolerability, it would be highly desirable to provide highly concentrated radiopharmaceutical drug products. However, such highly concentrated solutions are particularly susceptible to radiolysis. The contradictory positions of avoiding radiolysis by diluting the drug product on the one hand and avoiding patient discomfort during treatment by providing a concentrated drug solution on the other hand pose technical challenges in the design of radiopharmaceutical drug products. leave.

The inventors have now discovered a method for designing and producing highly concentrated radionuclide complex solutions that are chemically and radiochemically very stable even when stored at ambient or short-term elevated temperatures.

The invention is provided in various aspects as outlined below.

(a) Below:
(ai) a radionuclide;
(aii) a cell receptor binding organic moiety linked to a chelating agent;
A complex formed by
(b) at least one stabilizer against radiolytic degradation;
including;
The radionuclide is at least 100 MBq/mL, preferably at least 250 MBq/mL.
present at a concentration providing a volumetric radioactivity of q/mL;
Pharmaceutical aqueous solution.

Said stabilizer (component (b)) has a total amount of at least 0.2 mg/mL, preferably at least 0.5 mg/mL, more preferably at least 1.0 mg/mL, even more preferably at least 2.7 mg/mL. Exist in concentrations.

(a) Below:
(ai) the radionuclide lutetium ^-177 (Lu-177) present at a concentration providing a volumetric radioactivity of 250-500 MBq/mL;
(aii) a somatostatin receptor-binding organic moiety DO linked to a chelating agent;
TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide),
A complex formed by
(bi) gentisic acid or a salt thereof as a first stabilizer against radiolytic degradation present at a concentration of 0.5 to 1 mg/mL;
(bii) ascorbic acid or a salt thereof as a second stabilizer against radiolytic degradation present at a concentration of 2.0 to 5.0 mg/mL;
Pharmaceutical aqueous solutions containing.

(1) Below:
(1.1) preparing an aqueous solution containing a radionuclide;
(1.2) preparing an aqueous solution comprising a cell receptor-binding organic moiety linked to a chelating agent, a first stabilizing agent, and optionally a second stabilizing agent;
(1.3) heating the mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2);
forming a complex of a radionuclide with a cell receptor-binding organic moiety linked to a chelating agent;
(2) Below:
(2.1) preparing a dilute aqueous solution optionally comprising a second stabilizer;
(2.2.) Mixing the complex solution obtained in step (1) and the diluted solution obtained in step (2.1);
a process step of diluting the complex solution obtained in step (1);
The process for producing the pharmaceutical aqueous solution as defined above, comprising:

The present invention provides the following advantages.

High concentrations allow administration of high doses within short frames. For example, ¹⁷⁷ Lu-D
For OTA-TATE, IV infusion administration is completed within approximately 20-30 minutes.
A high dose of 7.4 GBq can be provided in a small volume of 25.0 mL.

Using a suitable stabilizer according to the invention as described herein, the chemical purity of the cell receptor binding molecule after 72 hours at 25°C, even if this molecule is a sensitive peptide molecule, is at least 95% %, 96%, 97%, 98%, 99% or 100% chemical stability. For example, in the case of DOTA-TATE, 100% chemical purity was found after 72 hours at 25°C and even after 48 hours at 32°C. Such high stability in terms of radiochemical purity was found even under short-term elevated temperature conditions (12 h at 32°C and 60 h at 25°C).

Furthermore, the use of suitable stabilizers according to the invention as described herein ensures a high stability with respect to the radiochemical purity of the radionuclide complexes, with a radiochemical stability of at least 95%. For example, in the case of ¹⁷⁷ Lu-DOTA-TATE, a radiochemical purity of at least 95% was found after 72 hours at 25°C. Short-term elevated temperature conditions (12 hours at 32℃
and 60 h at 25° C.) such high stability with respect to radiochemical purity was found.

While one single stabilizer can already achieve sufficient stability, the use of two stabilizers
It has been found to be particularly suitable for stabilizing sensitive radiopharmaceutical solutions. Specifically, the presence of one stabilizer during complex formation and another stabilizer added after complex formation protects the cell receptor binding molecules from radiolysis already during the complexation reaction and This is advantageous because it ensures that other stabilizers enhance the protective effect over the shelf life.

Additionally, this sequential application of two stabilizers ensures that only a relatively small amount of stabilizer is present during complexation (thus minimizing the potential for interference of that stabilizer with the complexation reaction). It is ensured that a large amount of the stabilizer combination is present after complexing (thus increasing the protective power of the stabilizer over the subsequent drug product storage period).

Such sequential application of two stabilizers also reduces the overall thermal stress of such stabilizers since one of them is not present when complexation reactions involving high temperatures are carried out.

Furthermore, especially when using two different stabilizers, this combination provides a better opportunity to reduce the number of different radicals that can be formed by radiolysis of cell receptor-bound molecules than one single stabilizer. This is advantageous because the reaction to is effective.

A shelf life of at least three days is required to be able to manufacture a radiopharmaceutical drug product from a centralized pharmaceutical manufacturing site and to commercialize it as a ready-to-use drug product.

Therefore, thanks to its high stability (72 h at 25° C.), the present invention can be used at the highest quality standards (e.g. cGMP) and on an industrial scale, e.g. with dose units sufficient to treat 10-20 patients simultaneously. 74GBq or 148GB to provide drug products in multiple dose units
Enables centralized pharmaceutical manufacturing with batch sizes of q.

Furthermore, due to the high stability, with the present invention there is sufficient time for transportation from the central pharmaceutical manufacturing site to remote clinical centers.

Furthermore, due to its high stability, the present invention can be provided as a ready-to-use infusion solution that can be immediately administered to a patient without requiring any preparatory work to be performed by clinical staff prior to administration.

The present invention is particularly suitable for somatostatin receptor binding peptides, particularly octreotide and octreotate, the very sensitive somatostatin analogs that are particularly susceptible to degradative reactions. Furthermore, the invention is particularly suitable for the radionuclide lutetium-177, which has specific radioactivity properties.

In the following, the invention will be described and illustrated in further detail.

According to the present invention, the following embodiments are provided.

1. (a) Below:
(ai) a radionuclide;
(aii) a cell receptor binding organic moiety linked to a chelating agent;
A complex formed by
(b) at least one stabilizer against radiolytic degradation;
including;
The radionuclide is at least 100 MBq/mL, preferably at least 250 MBq/mL.
present at a concentration providing a volumetric radioactivity of q/mL;
Pharmaceutical aqueous solution.

2. said stabilizers (component (b)) in a total amount of at least 0.2 mg/mL, preferably at least 0.5 mg/mL, more preferably at least 1.0 mg/mL, even more preferably at least 2.7 mg/mL. present in concentration,
Pharmaceutical aqueous solution according to embodiment 1.

3. The radionuclide is 100 to 1000 MBq/mL, preferably 250 to 500 MBq/mL.
The pharmaceutical aqueous solution according to any one of embodiments 1 or 2, present at a concentration providing a volumetric radioactivity of MBq/mL.

4. The stabilizer is 0.2 to 20.0 mg/mL, preferably 0.5 to 10.0 m
g/mL, more preferably 1.0 to 5.0 mg/m, even more preferably 2.7 to 4.
Pharmaceutical aqueous solution according to any one of embodiments 1-3, present at a total concentration of 1 mg/mL.

5. component (b) is only one stabilizer against radiolytic degradation, i.e. only the first stabilizer;
Pharmaceutical aqueous solution according to any one of embodiments 1-4.

6. Component (b) comprises at least two stabilizers against radiolytic degradation, i.e. at least a first and a second stabilizer, preferably only two stabilizers, i.e. a first and a second stabilizer. Only,
Pharmaceutical aqueous solution according to any one of embodiments 1-5.

7. the first stabilizer is 0.2 to 5 mg/mL, preferably 0.5 to 5 mg/mL,
Any of embodiments 5-6, more preferably present at a concentration of 0.5-2 mg/mL, even more preferably 0.5-1 mg/mL, even more preferably 0.5-0.7 mg/mL. Pharmaceutical aqueous solution according to one.

8. The second stabilizer is 0.5 to 10 mg/mL, more preferably 1.0 to 8.0 m
g/mL, even more preferably 2.0 to 5.0 mg/mL, even more preferably 2.
The aqueous pharmaceutical solution according to embodiment 6, present at a concentration of 2-3.4 mg/mL.

9. The stabilizer is gentisic acid (2,5-dihydroxybenzoic acid) or a salt thereof, ascorbic acid (L-ascorbic acid, vitamin C) or a salt thereof (for example, sodium ascorbate), methionine, histidine, melatonin, ethanol, and Pharmaceutical aqueous solution according to any one of embodiments 1 to 8, selected from Se-methionine, preferably selected from gentisic acid or its salts and ascorbic acid or its salts.

10. Pharmaceutical aqueous solution according to any one of embodiments 5 to 9, wherein the first stabilizing agent is selected from gentisic acid and ascorbic acid, preferably the first stabilizing agent is gentisic acid.

11. Pharmaceutical aqueous solution according to any one of embodiments 6 to 10, wherein the second stabilizing agent is selected from gentisic acid and ascorbic acid, preferably the second stabilizing agent is ascorbic acid.

12. The first stabilizer is gentisic acid or a salt thereof, and the second stabilizer is ascorbic acid or a salt thereof, and the concentration (in mg/mL) of the first stabilizer and the second stabilizer are Pharmaceutical aqueous according to any one of embodiments 6 to 8, wherein the ratio to the concentration of the stabilizer (in mg/mL) is from 1:3 to 1:7, preferably from 1:4 to 1:5. solution.

13. Radionuclides include ¹⁷⁷ Lu, ⁶⁸ Ga, ¹⁸ F, ^99m Tc, ²¹¹ At, ⁸²
selected from Rb, ¹⁶⁶ Ho, ²²⁵ Ac, ¹¹¹ In, ¹²³ I, ¹³¹ I, ⁸⁹ Zr, ⁹⁰ Y, preferably selected from ¹⁷⁷ Lu and ⁶⁸ Ga, more preferably ¹⁷⁷ L
The pharmaceutical aqueous solution according to any one of embodiments 1 to 12, which is u.

14. An embodiment in which the cell receptor binding moiety is a somatostatin receptor binding peptide, preferably said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate. 14. The pharmaceutical aqueous solution according to any one of 1 to 13.

15. The chelating agent is DOTA, DTPA, NTA, EDTA, DO3A, NOC,
and NOTA, preferably DOTA.
Pharmaceutical aqueous solution as described in.

16. The cell receptor binding moiety and the chelating agent together form DOTA-OC,
selected from DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably selected from DOTA-TOC and DOTA-TATE DOTA-T
The pharmaceutical aqueous solution according to any one of embodiments 1 to 15, forming a molecule that is an ATE.

17. The radionuclide, cell receptor binding moiety, and chelating agent together form the complex ¹⁷⁷ Lu-DOTA-TOC ( ¹⁷⁷ Lu-edotreotide) or ¹⁷⁷ Lu-DO
TA-TATE ( ¹⁷⁷ Lu-oxodotreotide), preferably ¹⁷⁷ Lu-DOTA
- an aqueous pharmaceutical solution according to any one of embodiments 1 to 16, forming a TATE.

18. further comprising a buffer, preferably the buffer is preferably 0.3 to 0.7 m
acetic acid at a concentration of g/mL (preferably about 0.48 mg/mL) and 0.4 to 0.9 mg/mL.
18. A pharmaceutical aqueous solution according to any one of embodiments 1 to 17, wherein the acetate buffer is in an amount to provide a sodium acetate (preferably about 0.66 mg/mL).

19. further comprising a sequestering agent, preferably said sequestering agent diethylenetriaminepentaacetic acid (DTPA), preferably in an amount resulting in a concentration of 0.01 to 0.10 mg/mL (preferably about 0.05 mg/mL). or a salt thereof, the pharmaceutical aqueous solution according to any one of embodiments 1-18.

20. At least 24 hours (h) at ≦25°C, at least 48 h at ≦25°C, ≦25
at least 72 h at °C, 24 h to 120 h at ≦25 °C, 24 h to 96 h at ≦25 °C, ≦2
With a shelf life of 24h to 84h at 5°C, 24h to 72h at ≦25°C, especially ≦25°C
Pharmaceutical aqueous solution according to any one of embodiments 1 to 19, having a shelf life of 72 h at .

21. Embodiments 1 to 3, wherein the solution is manufactured in commercial scale manufacturing, in particular in a batch size of at least 20 GBq, at least 50 GBq, at least 70 GBq.
21. The pharmaceutical aqueous solution according to any one of 20.

22a. Pharmaceutical aqueous solution according to any one of embodiments 1 to 21, ready for use.

22b. A pharmaceutical aqueous solution according to any one of embodiments 1-22a, which is commercially available.

23. (a) Below:
(ai) the radionuclide lutetium ^-177 (Lu-177) present at a concentration providing a volumetric radioactivity of 250-500 MBq/mL;
(aii) a somatostatin receptor-binding organic moiety DO linked to a chelating agent;
TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide),
A complex formed by
(bi) gentisic acid or a salt thereof as a first stabilizer against radiolytic degradation present at a concentration of 0.5 to 1 mg/mL;
(bii) ascorbic acid or a salt thereof as a second stabilizer against radiolytic degradation present at a concentration of 2.0 to 5.0 mg/mL;
Pharmaceutical aqueous solutions containing.

24. (c) diethylenetriaminepentaacetic acid at a concentration of 0.01 to 0.10 mg/mL (
DTPA) or its salt,
24. The pharmaceutical aqueous solution of embodiment 23, further comprising:

25. (d) Acetic acid at a concentration of 0.3-0.7 mg/mL and 0.4-0.9 mg/mL
sodium acetate at a concentration of
25. The pharmaceutical aqueous solution of embodiment 23 or 24, further comprising:

26. Pharmaceutical aqueous solution according to any one of embodiments 1 to 25, wherein a stabilizing agent is present in the solution upon complexation of components (ai) and (aii).

27. The first stabilizer alone is preferably 0.5-5 mg/mL in the final solution, more preferably 0.5-2 mg/mL, even more preferably 0.5-1 mg/mL, even more preferably 0. Ingredients (ai) and (ai
A pharmaceutical aqueous solution according to any one of embodiments 5 to 26, present during the complex formation of i).

28. A portion of the amount of second stabilizer is already present in the solution during the complexation of components (ai) and (aii), and another portion of the amount of second stabilizer is present in the solution when components (ai) and (aii) are complexed; ai) and (aii)
28. A pharmaceutical aqueous solution according to any one of embodiments 6 to 27, added after complex formation of ).

29. Pharmaceutical aqueous solution according to any one of embodiments 6 to 28, wherein the second stabilizer is added after complexation of components (ai) and (aii).

30. The second stabilizer is preferably 0.5-10 mg/mL, more preferably 1.0-8.0 mg/mL, even more preferably 2.0-5.0 mg/mL, even more preferably in the final solution. Pharmaceutical aqueous solution according to embodiment 6 or 29, added after complexation of components (ai) and (aii), preferably in an amount resulting in a concentration of 2.2 to 3.4 mg/mL.

31. further comprising a sequestering agent added after complexation of components (ai) and (aii) to remove any uncomplexed Lu, preferably said sequestering agent comprises:
Preferably 0.01-0.10 mg/mL (preferably about 0.05 mg/mL) in the final solution.
diethylenetriaminepentaacetic acid (DTPA) or a salt thereof in an amount that provides a concentration of
Pharmaceutical aqueous solution according to any one of embodiments 1-30.

32. (1) Below:
(1.1) preparing an aqueous solution containing a radionuclide;
(1.2) preparing an aqueous solution comprising a cell receptor-binding organic moiety linked to a chelating agent, a first stabilizing agent, and optionally a second stabilizing agent;
(1.3) heating the mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2);
forming a complex of a radionuclide with a cell receptor-binding organic moiety linked to a chelating agent;
(2) Below:
(2.1) preparing a dilute aqueous solution optionally comprising a second stabilizer;
(2.2.) Mixing the complex solution obtained in step (1) and the diluted solution obtained in step (2.1);
a process step of diluting the complex solution obtained in step (1);
A process for manufacturing an aqueous pharmaceutical solution according to any one of embodiments 1-31, comprising:

33. The first stabilizer alone is preferably 0.5-5 mg/mL in the final solution, more preferably 0.5-2 mg/mL, even more preferably 0.5-1 mg/mL, even more preferably 0. The process of embodiment 32, wherein the process is present during step (1.3) in an amount resulting in a concentration of .5 to 0.7 mg/mL.

34. A portion of the amount of second stabilizer is already present in the solution during step (1.3) and another portion of the amount of second stabilizer is added to the step after step (1.3). The process according to any one of embodiments 32-33, added in (2.1).

35. Pharmaceutical aqueous solution according to any one of embodiments 32 to 34, wherein the second stabilizer is added in step (2.1) after step (1.3).

36. The second stabilizer is preferably 0.5-10 mg/mL, more preferably 1.0-8.0 mg/mL, even more preferably 2.0-5.0 mg/mL, even more preferably in the final solution. according to any one of embodiments 32 to 35, added in step (2.1) after step (1.3), preferably in an amount resulting in a concentration of 2.2 to 3.4 mg/mL. Pharmaceutical aqueous solution.

37. The process according to any one of embodiments 32 to 36, wherein the solution of step (1.2) further comprises a buffer, preferably an acetate buffer.

38. Process according to any one of embodiments 32 to 37, wherein the resulting mixture is heated in step (1.3) to a temperature of 70 to 99°C, preferably 90 to 98°C, for 2 to 59 minutes.

39. 39. The process according to any one of embodiments 32-38, wherein the solution of step (2.1) further comprises diethylenetriaminepentaacetic acid (DTPA) or a salt thereof.

40. (3) a process step of filtering the solution obtained in step (2) through 0.2 μm;
(4) 5.0 to 10 MBq, preferably 7.0 MBq of the filtered solution obtained in step (3)
~8.0MBq, more preferably 7.3~7.7MBq, even more preferably 7.4~
a process step of dispensing into a dose unit container an amount necessary to deliver a radiation dose of 7.5 MBq, preferably said amount being 10 to 50 mL, more preferably 15 to 30 mL;
L, even more preferably 20-25 mL, a process step;
40. The process according to any one of embodiments 32-39, further comprising.

41. 41. The process according to any one of embodiments 32-40, wherein the solution of step (1.1) comprises LuCl ₃ and HCl.

42. The solution in step (1.2) is ¹⁷⁷ Lu-DOTA-TATE or ¹⁷⁷ Lu-
Embodiment 3 comprising DOTA-TOC, gentisic acid, acetic acid, and sodium acetate
42. The process according to any one of 2 to 41.

43. Embodiments 32 to 32, wherein the solution of step (2.1) comprises DTPA and ascorbic acid.
43. The process according to any one of 42.

44. 44. The process according to any one of embodiments 32-43, wherein the dose unit container of step (4) is a stoppered vial enclosed within a lead container.

DEFINITIONS The term "about" or "ca." as used herein means that the following value is ±20%, preferably ±
10%, more preferably ±5%, even more preferably ±2%, even more preferably ±
It means that it can fluctuate by 1%.

In the following, the meanings of terms used herein are defined.

"Aqueous solution": A solution of a solute in water.

“(ai) radionuclides;
(aii) a cell receptor binding organic moiety linked to a chelating agent;
Complex formed by:
The radionuclide metal ion forms a non-covalent bond with the functional group of the chelating agent, such as an amine or carboxylic acid. The chelating agent has at least two such complexing functional groups so that it can form a chelate complex.

Chelating agents relevant to the present invention are:
DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid,
DTPA: diethylenetriaminepentaacetic acid,
NTA: nitrilotriacetic acid,
EDTA: ethylenediaminetetraacetic acid,
DO3A: 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid,
NOTA: 1,4,7-triazacyclononane-1,4,7-triacetic acid,
or a mixture thereof;
It is preferably DOTA.

A particularly suitable "cell receptor binding moiety" for the present invention is a somatostatin receptor binding peptide, preferably said somatostatin receptor binding peptide is selected from octreotide, octreotate, lanreotide, vapreotide, and pasireotide, preferably octreotide. and octreotate.

"Linked": The cellular receptor binding organic moiety is either directly linked to the chelating agent or connected via a linker molecule, preferably directly linked. The link bond is either a covalent bond or a non-covalent bond between the cell receptor-binding organic moiety and the chelating agent, preferably the bond is a covalent bond.

"Stabilizer against radiolytic degradation": A stabilizer that protects organic molecules from radiolytic degradation. For example, when gamma rays emitted by radionuclides cleave bonds between atoms of organic molecules and radicals are formed, such radicals are then captured by stabilizing agents, so that
Any other chemical reactions that might result in undesirable, potentially ineffective, or even toxic molecules are avoided from being triggered by the radicals. Such stabilizers are therefore also referred to as "free radical scavengers" or, for short, "radical scavengers."
Other alternative terms for such stabilizers are "radiation stabilizers", "radiolytic stabilizers"
, or simply "quencher".

"The stabilizer is present in the solution during the complex formation of components (ai) and (aii)": 1st
and optionally a second stabilizer are also present. That is, the first stabilizer is
Present either alone or in combination with a second stabilizer.

“Present during complex formation”: The stabilizer is either in the radionuclide solution or in the chelating agent-containing solution, after which the two solutions are added and optionally elevated to promote complex formation. temperature is applied. Preferably, the stabilizing agent is in a chelating agent-containing solution.

"Only the first stabilizer is present during complex formation of components (ai) and (aii)": first
one stabilizer is present and the second is absent. In other words, only one type of stabilizer is present.

"The second stabilizer is added after complex formation of components (ai) and (aii)": whether or not the second stabilizer may already be present at the time of complex formation; After completion of the complex formation reaction, for example after the reaction solution heated to elevated temperature has been cooled again to ambient temperature, the second stabilizing agent is added.

A cell receptor binding moiety and a chelating agent can be taken together to form the following molecule.
DOTA-OC: [DOTA ⁰ , D-Phe ¹ ]octreotide,
DOTA-TOC: [DOTA ⁰ , D-Phe ¹ , Tyr ³ ]octreotide and edtreotide,
DOTA-NOC: [DOTA ⁰ , D-Phe ¹ , 1-Nal ³ ]octreotide,
DOTA-TATE: [DOTA ⁰ , D-Phe ¹ , Tyr ³ ]octreotate, oxodotreotide (INN),
DOTA-LAN: [DOTA ⁰ ,D-β-Nal ¹ ]lanreotide,
DOTA-VAP: [DOTA ⁰ , D-Phe ¹ , Tyr ³ ]vapreotide.

Preferred molecules of the present invention are DOTA-TOC and DOTA-TATE,
More preferably the molecule is DOTA-TATE.

"Buffer with a pH of 4.5 to 6.0": an acetate buffer, a citrate buffer (e.g., citrate + HCl or citric acid + disodium hydrogen phosphate), or a phosphate buffer (
For example, sodium dihydrogen phosphate + disodium hydrogen phosphate) and preferably the buffer is an acetate buffer, preferably the acetate buffer is composed of acetic acid and sodium acetate. Ru.

"sequestering agent", a chelating agent suitable for complexing radionuclide metal ions;
Preferably DTPA: diethylenetriaminepentaacetic acid.

“Commercial”: A drug product is one that can be approved for marketing by a health authority, can be manufactured on a commercial scale from a pharmaceutical manufacturing site, and can be supplied to end users in remote locations, such as hospitals or patients. It is possible.

Hereinafter, the present invention will be explained in more detail and specifically with reference to Examples, but the present invention is not intended to be limited thereto.

material:
¹⁷⁷ LuCl ₃ is an I. D. B. It can be obtained from suppliers such as Holland BV. DOTA ⁰ -Tyr ³ -octreotate is available from piCHEM Forschungs
- and Entwicklungs GmbH, Austria. All other ingredients of the drug product are commercially available from various sources.

Example 1: Composition of drug product Drug product ( ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate 370 MBq/mL
Infusion solution) is 370MB on reference date and reference time (calibration time (tc)).
It is designed as a sterile, ready-to-use solution for injection containing ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate as a drug substance with a volumetric radioactivity of q/mL. The calibration time (tc) is the end of production (EOP =
t0). The shelf life of the drug product is defined as 72 hours after the calibration time. The drug product is a single-dose vial containing a suitable amount of solution to allow delivery of 7.4 GBq of radioactivity upon injection.

The manufacturing site prepares a single dose calibrated to within 7.4 GBq ± 10% (200 mCi) after manufacturing is completed. The certificate of analysis reports both the exact activity and the time at which this activity is achieved. This value is “Injection time: {DD MM YYYY}{hh:mm
}UTC”. Considering the variable injection time and steady decay of the radionuclide,
Calculating the fill amount required for 7.4 GBq of radioactivity at the time of injection, it is 20.5 to 25.
It can be in the range of 0 mL.

Example 2: Manufacture of a Pharmaceutical Product For a 74 GBq batch size (2 Ci batch size), ¹⁷⁷ LuCl ₃ solution (HCl
(74 GBq in medium), DOTA-Tyr ³ -octreotate solution (2 mg), reaction buffer solution (containing an antioxidant (i.e. gentisic acid) and a buffer system (i.e. acetate buffer system)). , may be mixed together to allow radiolabeling to be carried out for several minutes at a temperature of 90-98°C.

Synthesis is performed using a single-use disposable kit cassette installed at the front side of the synthesis module containing fluidic pathways (tubing), reactor vials, and sealed reagent vials.

The resulting mother solution was diluted with a solution containing a chelating agent (i.e. DTPA) and an antioxidant (i.e. ascorbic acid or gentisic acid) and then sterile filtered through 0.2 μm, as described in Example 1. Provides a ready-to-use solution as described.

Finally, the solution is dispensed into sterile vials in a volume of 20.5-25.0 mL. The stoppered vial is enclosed within a lead container for protective shielding.

Example 3: Stability test results after storage under various temperature conditions.
The table below provides stability test data for batches produced according to the process described in Example 2 with a 74 GBq batch size.

Very similar good stability results were obtained with batches made with a 148 GBq batch size.

Claims (44)

(a) Below:
(ai) a radionuclide;
(aii) a cell receptor binding organic moiety linked to a chelating agent;
A complex formed by
(b) at least one stabilizer against radiolytic degradation;
including;
The radionuclide is at least 100 MBq/mL, preferably at least 250 MBq/mL.
present at a concentration providing a volumetric radioactivity of q/mL;
Pharmaceutical aqueous solution. Said stabilizer(s), component (b), is at least 0.2 mg/mL, preferably at least 0.5 mg/mL, more preferably at least 1.0 mg/mL, even more preferably at least 2.7 mg/mL. The pharmaceutical aqueous solution of claim 1, present in a total concentration of mL. The radionuclide is 100 to 1000 MBq/mL, preferably 250 to 500 MBq
3. A pharmaceutical aqueous solution according to claim 1 or 2, wherein the pharmaceutical aqueous solution is present at a concentration providing a volumetric radioactivity of /mL. The stabilizer(s) may be 0.2 to 20.0 mg/mL, preferably 0.5 to 10.0 mg/mL.
0 mg/mL, more preferably 1.0 to 5.0 mg/mL, even more preferably 2.7
Pharmaceutical aqueous solution according to any one of claims 1 to 3, present in a total concentration of ˜4.1 mg/mL. Pharmaceutical aqueous solution according to any one of claims 1 to 4, wherein component (b) is only one stabilizer against radiolytic degradation, ie only a first stabilizer. Component (b) comprises at least two stabilizers against radiolytic degradation, i.e. at least a first and a second stabilizer, preferably only two stabilizers, i.e. the first and the second stabilizer.
Pharmaceutical aqueous solution according to any one of claims 1 to 5, which is only a stabilizer. The first stabilizer is 0.2 to 5 mg/mL, preferably 0.5 to 5 mg/mL, more preferably 0.5 to 2 mg/mL, even more preferably 0.5 to 1 mg/mL, Pharmaceutical aqueous solution according to claim 5 or 6, which is even more preferably present in a concentration of 0.5 to 0.7 mg/mL. The second stabilizer is 0.5 to 10 mg/mL, more preferably 1.0 to 8.0 mg
/mL, even more preferably 2.0 to 5.0 mg/mL, even more preferably 2.2
Pharmaceutical aqueous solution according to claim 6, present at a concentration of ˜3.4 mg/mL. The stabilizer(s) may be gentisic acid (2,5-dihydroxybenzoic acid) or a salt thereof, ascorbic acid (L-ascorbic acid, vitamin C) or a salt thereof (e.g. sodium ascorbate), methionine, histidine, Pharmaceutical aqueous solution according to any one of claims 1 to 8, selected from melatonin, ethanol and Se-methionine, preferably selected from gentisic acid or its salts and ascorbic acid or its salts. The first stabilizer is selected from gentisic acid and ascorbic acid, preferably the first stabilizer is selected from gentisic acid and ascorbic acid.
Pharmaceutical aqueous solution according to any one of claims 5 to 9, wherein the stabilizer of is gentisic acid. Pharmaceutical aqueous solution according to any one of claims 6 to 10, wherein said second stabilizer is selected from gentisic acid and ascorbic acid, preferably said second stabilizer is ascorbic acid. The first stabilizer is gentisic acid or a salt thereof, and the second stabilizer is ascorbic acid or a salt thereof, and the concentration (in mg/mL) of the first stabilizer is The ratio to the concentration (mg/mL unit) of the second stabilizer is from 1:3 to 1:7, preferably from 1:4 to
Pharmaceutical aqueous solution according to any one of claims 6 to 8, in a ratio of 1:5. The radionuclides include ¹⁷⁷ Lu, ⁶⁸ Ga, ¹⁸ F, ⁹⁹ mTc, ²¹¹ At, ⁸² Rb
, ¹⁶⁶ Ho, ²²⁵ Ac, ¹¹¹ In, ¹²³ I, ¹³¹ I, ⁸⁹ Zr, ⁹⁰ Y, preferably selected from ¹⁷⁷ Lu and ⁶⁸ Ga, more preferably ¹⁷⁷ Lu. Pharmaceutical aqueous solution according to any one of the items. The cell receptor binding moiety is a somatostatin receptor binding peptide, preferably the somatostatin receptor binding peptide is octreotide, octreotate,
Pharmaceutical aqueous solution according to any one of claims 1 to 13, selected from lanreotide, vapreotide and pasireotide, preferably selected from octreotide and octreotate. Pharmaceutical aqueous solution according to any one of the preceding claims, wherein the chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, NOC and NOTA, preferably DOTA. The cellular receptor binding moiety and the chelating agent together form DOTA-OC,
selected from DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN and DOTA-VAP, preferably selected from DOTA-TOC and DOTA-TATE, more preferably selected from DOTA-TOC and DOTA-TATE DOTA-T
Pharmaceutical aqueous solution according to any one of claims 1 to 15, forming molecules that are ATE. The radionuclide, the cellular receptor binding moiety, and the chelating agent together form the complex ¹⁷⁷ Lu-DOTA-TOC ( ¹⁷⁷ Lu-edotreotide) or ¹⁷⁷ Lu-
DOTA-TATE ( ¹⁷⁷ Lu-oxodotreotide), preferably ¹⁷⁷ Lu-DO
Pharmaceutical aqueous solution according to any one of claims 1 to 16, forming a TA-TATE. further comprising a buffer, preferably the buffer is preferably 0.3 to 0.7 mg/mL
of acetic acid (preferably about 0.48 mg/mL) and sodium acetate from 0.4 to 0.9 mg/mL (preferably about 0.66 mg/mL). Item 18. Pharmaceutical aqueous solution according to any one of items 1 to 17. It further comprises a sequestering agent, preferably said sequestering agent preferably has a 0.
19. Pharmaceutical aqueous according to any one of claims 1 to 18, which is diethylenetriaminepentaacetic acid (DTPA) or a salt thereof in an amount resulting in a concentration of 0.01 to 0.10 mg/mL (preferably about 0.05 mg/mL). solution. At least 24 hours (h) at ≦25°C, at least 48h at ≦25°C, at least 72h at ≦25°C, 24h to 120h at ≦25°C, 24h to 96h at ≦25°C, 2 hours at ≦25°C
4h to 84h, with a shelf life of 24h to 72h at ≦25°C, especially 72h at ≦25°C
Pharmaceutical aqueous solution according to any one of claims 1 to 19, having a shelf life of . Pharmaceutical aqueous solution according to any one of claims 1 to 20, wherein the solution is produced in commercial scale manufacturing, in particular in a batch size of at least 20 GBq, at least 50 GBq, at least 70 GBq. Pharmaceutical aqueous solution according to any one of claims 1 to 21, which is ready for use and/or commercial. (a) Below:
(ai) the radionuclide lutetium ^-177 (Lu-177) present at a concentration providing a volumetric radioactivity of 250-500 MBq/mL;
(aii) a somatostatin receptor-binding organic moiety DO linked to a chelating agent;
TA-TATE (oxodotreotide) or DOTA-TOC (edotreotide),
A complex formed by
(bi) gentisic acid or a salt thereof as a first stabilizer against radiolytic degradation present at a concentration of 0.5 to 1 mg/mL;
(bii) ascorbic acid or a salt thereof as a second stabilizer against radiolytic degradation present at a concentration of 2.0 to 5.0 mg/mL;
Pharmaceutical aqueous solutions containing. (c) diethylenetriaminepentaacetic acid (DTPA) at a concentration of 0.01 to 0.10 mg/mL;
) or its salt,
24. The pharmaceutical aqueous solution of claim 23, further comprising: (d) acetic acid at a concentration of 0.3 to 0.7 mg/mL and sodium acetate at a concentration of 0.4 to 0.9 mg/mL;
25. The pharmaceutical aqueous solution according to claim 23 or 24, further comprising: Pharmaceutical aqueous solution according to any one of claims 1 to 25, wherein the stabilizer(s) is present in solution upon complex formation of components (ai) and (aii). Even more preferably, said first stabilizer alone is present (preferably from 0.5 to 5 mg/mL, more preferably from 0.5 to 2 mg/mL, even more preferably from 0.5 to 1 mg/mL) in the final solution. is the amount resulting in a concentration of 0.5 to 0.7 mg/mL, and components (ai) and (aiii
27. Pharmaceutical aqueous solution according to any one of claims 5 to 26, present upon complex formation of ). a portion of the amount of said second stabilizer is already present in the solution upon complex formation of components (ai) and (aii), and another portion of the amount of said second stabilizer is Ingredients (ai) and (aii)
28. Pharmaceutical aqueous solution according to any one of claims 6 to 27, which is added after complex formation of ). Pharmaceutical aqueous solution according to any one of claims 6 to 28, wherein the second stabilizer is added after complex formation of components (ai) and (aii). Said second stabilizer is preferably 0.5 to 10 mg/mL, more preferably 1.0 to 8.0 mg/mL, even more preferably 2.0 to 5.0 mg/mL, and even more preferably 0.5 to 10 mg/mL in the final solution. More preferably, components (ai) and (a
30. Pharmaceutical aqueous solution according to claim 6 or 29, which is added after the complex formation of ii). It further comprises a sequestering agent added after complexation of components (ai) and (aii) to remove any uncomplexed Lu, preferably said sequestering agent is preferably 0.0% in the final solution. Diethylenetriaminepentaacetic acid (DTPA) or a salt thereof in an amount resulting in a concentration of 0.01 to 0.10 mg/mL (preferably about 0.05 mg/mL).
The pharmaceutical aqueous solution according to any one of 1 to 30. (1) Below:
(1.1) preparing an aqueous solution containing a radionuclide;
(1.2) preparing an aqueous solution comprising a cell receptor-binding organic moiety linked to a chelating agent, a first stabilizing agent, and optionally a second stabilizing agent;
(1.3) heating the mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2);
forming a complex of a radionuclide with a cell receptor-binding organic moiety linked to a chelating agent;
(2) Below:
(2.1) preparing a dilute aqueous solution optionally comprising a second stabilizer;
(2.2.) Mixing the complex solution obtained in step (1) and the diluted solution obtained in step (2.1);
a process step of diluting the complex solution obtained in step (1);
A process for producing an aqueous pharmaceutical solution according to any one of claims 1 to 31, comprising: Said first stabilizer alone is preferably 0.5-5 mg/mL, more preferably 0.5-2 mg/mL, even more preferably 0.5-1 mg/mL, even more preferably in the final solution. present in step (1.3) in an amount resulting in a concentration of 0.5-0.7 mg/mL;
33. Process according to claim 32. A portion of the amount of said second stabilizer is already present in the solution in step (1.3), and another portion of the amount of said second stabilizer is present in step (1.3). 34. A process according to claim 32 or 33, wherein the process is added in step (2.1) after. 32. The second stabilizer is added in step (2.1) after step (1.3).
35. The pharmaceutical aqueous solution according to any one of items 1 to 34. Said second stabilizer is preferably 0.5 to 10 mg/mL, more preferably 1.0 to 8.0 mg/mL, even more preferably 2.0 to 5.0 mg/mL, and even more preferably 0.5 to 10 mg/mL in the final solution. 36. According to any one of claims 32 to 35, added in step (2.1) after step (1.3), more preferably in an amount resulting in a concentration of 2.2 to 3.4 mg/mL. pharmaceutical aqueous solution. Claims 32 to 32, wherein the solution of step (1.2) further comprises a buffer, preferably an acetate buffer.
37. The process according to any one of 36. 38. According to any one of claims 32 to 37, in step (1.3) the mixture obtained is heated to a temperature of 70 to 99 °C, preferably 90 to 98 °C, for a period of 2 to 59 minutes. process. 39. A process according to any one of claims 32 to 38, wherein the solution of step (2.1) further comprises diethylenetriaminepentaacetic acid (DTPA) or a salt thereof. (3) a process step of filtering the solution obtained in step (2) through 0.2 μm;
(4) 5.0 to 10 MBq, preferably 7.0 MBq of the filtered solution obtained in step (3)
~8.0MBq, more preferably 7.3~7.7MBq, even more preferably 7.4~
a process step of dispensing into a dose unit container an amount necessary to deliver a radiation dose of 7.5 MBq, preferably said amount being 10 to 50 mL, more preferably 15 to 30 mL;
L, even more preferably 20-25 mL, a process step;
40. A process according to any one of claims 32 to 39, further comprising: Process according to any one of claims 32 to 40, wherein the solution of step (1.1) comprises LuCl ₃ and HCl. The solution in step (1.2) is ¹⁷⁷ Lu-DOTA-TATE or ¹⁷⁷ Lu-DOTA
- Process according to any one of claims 32 to 41, comprising: - TOC, gentisic acid, acetic acid, sodium acetate. Process according to any one of claims 32 to 42, wherein the solution of step (2.1) comprises DTPA and ascorbic acid. The dose unit container in step (4) is a vial with a stopper sealed in a lead container.
Process according to any one of claims 32 to 43.