JP7358451B2 - Stable concentrated radionuclide complex solution - Google Patents

Description

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 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 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 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 with varying degrees of success to reduce radiolysis of radiopharmaceutical drug products. 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;
said radionuclide is present at a concentration providing a volumetric radioactivity of at least 100 MBq/mL, preferably at least 250 MBq/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 DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) linked to a chelating agent;
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, for ¹⁷⁷ Lu-DOTA-TATE, a high dose of 7.4 GBq can be delivered in a small volume of 20.5-25.0 mL, completing IV infusion administration within about 20-30 minutes.

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. 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).

Although one single stabilizer can already achieve sufficient stability, the use of two stabilizers 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. Batch sizes of 74 GBq or 148 GBq provide drug product in multiple dose units, allowing for centralized pharmaceutical manufacturing.

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;
said radionuclide is present at a concentration providing a volumetric radioactivity of at least 100 MBq/mL, preferably at least 250 MBq/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. Pharmaceutical aqueous solution according to any one of embodiments 1 or 2, wherein the radionuclide is present at a concentration providing a volumetric radioactivity of 100 to 1000 MBq/mL, preferably 250 to 500 MBq/mL.

4. The stabilizer is 0.2 to 20.0 mg/mL, preferably 0.5 to 10.0 mg/mL, more preferably 1.0 to 5.0 mg/m, even more preferably 2.7 to 4 A 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, more preferably 0.5 to 2 mg/mL, even more preferably 0.5 to 1 mg/mL, and Pharmaceutical aqueous solution according to any one of embodiments 5-6, more preferably present in a concentration of 0.5-0.7 mg/mL.

8. 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 The aqueous pharmaceutical solution according to embodiment 6, present at a concentration of ˜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. The radionuclide is selected from ¹⁷⁷ Lu, ⁶⁸ Ga, ¹⁸ F, ^99m Tc, ²¹¹ At, ⁸² Rb, ¹⁶⁶ Ho, ²²⁵ Ac, ¹¹¹ In, ¹²³ I, ¹³¹ I, ⁸⁹ Zr, ⁹⁰ Y, preferably ¹⁷⁷ Lu and Pharmaceutical aqueous solution according to any one of embodiments 1 to 12, selected from ⁶⁸ Ga, more preferably ¹⁷⁷ Lu.

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. Pharmaceutical aqueous solution according to any one of embodiments 1 to 14, wherein the chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA.

16. The cell receptor binding moiety and the chelating agent are together selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP. , preferably selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.

17. The radionuclide, the cell 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 Pharmaceutical aqueous solution according to any one of embodiments 1 to 16, forming Lu-DOTA-TATE.

18. It further comprises a buffering agent, preferably said buffering agent preferably comprises acetic acid at a concentration of 0.3-0.7mg/mL (preferably about 0.48mg/mL) and 0.4-0.9mg/mL (preferably about 0.48mg/mL). The pharmaceutical aqueous solution of any one of embodiments 1-17, wherein the acetate buffer is in an amount to provide a sodium acetate of 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 48h at ≦25°C, at least 72h at ≦25°C, 24h to 120h at ≦25°C, 24h to 96h at ≦25°C, 24h to 84h at ≦25°C, ≦ Pharmaceutical aqueous solution according to any one of embodiments 1 to 19, having a shelf life of 24h to 72h at 25°C, in particular a shelf life of 72h at ≦25°C.

21. Pharmaceutical aqueous solution according to any one of embodiments 1 to 20, wherein said 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.

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 DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) linked to a chelating agent;
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 (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/mL;
24. The pharmaceutical aqueous solution of embodiment 23, further comprising:

25. (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 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. A pharmaceutical aqueous solution according to any one of embodiments 5 to 26, present upon complexation of components (ai) and (aii) in an amount resulting in a concentration of .5 to 0.7 mg/mL.

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; Pharmaceutical aqueous solution according to any one of embodiments 6 to 27, added after complex formation of ai) and (aii).

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. 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. The medicament according to any one of embodiments 1 to 30 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). Aqueous solution.

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) The filtered solution obtained in step (3) is 5.0 to 10 MBq, preferably 7.0 to 8.0 MBq, more preferably 7.3 to 7.7 MBq, and even more preferably 7.4 to 8.0 MBq. a process step of dispensing into a dose unit container the 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, even more preferably 20 to 30 mL; a process step of 25 mL;
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. In any one of embodiments 32-41, the solution of step (1.2) comprises ¹⁷⁷ Lu-DOTA-TATE or ¹⁷⁷ Lu-DOTA-TOC, gentisic acid, acetic acid, and sodium acetate. Process described.

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

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 This means that it can vary 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 can then be captured by stabilizers, making them undesirable and potentially ineffective. Any other chemical reactions that might lead to toxic or even toxic molecules are avoided to be 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 "quenchers."

"The stabilizer is present in solution upon complex formation of components (ai) and (aii)": the first stabilizer and optionally the second stabilizer are also present. That is, the first stabilizer is present either alone or in combination with the 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)": the first 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 suppliers such as piCHEM Forschungs-und Entwicklungs GmbH, Austria. All other ingredients of the drug product are commercially available from various sources.

Example 1: Composition of a Pharmaceutical Product The pharmaceutical product ( ¹⁷⁷ Lu-DOTA ⁰ -Tyr ³ -octreotate 370 MBq/mL Injection Solution) has a concentration of 370 MBq/mL 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 drug substance with volumetric radioactivity. The calibration time (tc) corresponds to the end of production (EOP=t0), which is the time of measuring the radioactivity of the first QC vial. 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 complete. The certificate of analysis reports both the exact activity and the time at which this activity is achieved. This value is specified as "Injection time: {DD MM YYYY}{hh:mm}UTC". Considering the variable injection time and steady decay of the radionuclide, the fill volume required for 7.4 GBq of radioactivity at the injection time can be calculated to be in the range of 20.5-25.0 mL.

Example 2: Manufacture of a Pharmaceutical Product For a 74 GBq batch size (2Ci batch size), ¹⁷⁷ LuCl ₃ solution (74 GBq in HCl), DOTA-Tyr ³ -octreotate solution (2 mg), and reaction buffer solution (antioxidant (containing an agent (ie, gentisic acid) and a buffer system (ie, an acetate buffer system)) may be mixed together to allow radiolabeling to occur 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.
The present invention may include the following aspects.
[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;
said radionuclide is present at a concentration providing a volumetric radioactivity of at least 100 MBq/mL, preferably at least 250 MBq/mL;
Pharmaceutical aqueous solution.
[2]
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 according to [1], present in a total concentration of mL.
[3]
The pharmaceutical aqueous solution according to [1] or [2], wherein the radionuclide is present at a concentration providing a volumetric radioactivity of 100 to 1000 MBq/mL, preferably 250 to 500 MBq/mL.
[4]
Said stabilizer(s) is 0.2 to 20.0 mg/mL, preferably 0.5 to 10.0 mg/mL, more preferably 1.0 to 5.0 mg/mL, even more preferably 2 The pharmaceutical aqueous solution according to any one of [1] to [3], which is present in a total concentration of .7 to 4.1 mg/mL.
[5]
The pharmaceutical aqueous solution according to any one of [1] to [4], wherein the component (b) is only one type of stabilizer against radiolytic degradation, that is, only a first stabilizer.
[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. The pharmaceutical aqueous solution according to any one of [1] to [5], which is only a drug.
[7]
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, Even more preferably, the pharmaceutical aqueous solution according to [5] or [6] is present in a concentration of 0.5 to 0.7 mg/mL.
[8]
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. Pharmaceutical aqueous solution according to [6], present in a concentration of 2 to 3.4 mg/mL.
[9]
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, The pharmaceutical aqueous solution according to any one of [1] to [8], selected from melatonin, ethanol, and Se-methionine, preferably selected from gentisic acid or a salt thereof and ascorbic acid or a salt thereof.
[10]
Pharmaceutical aqueous solution according to any one of [5] to [9], wherein the first stabilizer is selected from gentisic acid and ascorbic acid, preferably the first stabilizer is gentisic acid.
[11]
Pharmaceutical aqueous solution according to any one of [6] to [10], wherein the second stabilizer is selected from gentisic acid and ascorbic acid, preferably the second stabilizer 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 is Any one of [6] to [8], wherein the ratio to the concentration (mg/mL unit) of the second stabilizer is 1:3 to 1:7, preferably 1:4 to 1:5. Pharmaceutical aqueous solutions as described in Section.
[13]
The radionuclide is selected from 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 ¹⁷⁷ Lu and ⁶⁸ Ga, more preferably ¹⁷⁷ Lu, according to any one of [1] to [12].
[14]
said 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; 1] to [13].
[15]
Pharmaceutical aqueous solution according to any one of [1] to [14], wherein the chelating agent is selected from DOTA, DTPA, NTA, EDTA, DO3A, NOC, and NOTA, preferably DOTA.
[16]
The cellular receptor binding moiety and the chelating agent are together selected from DOTA-OC, DOTA-TOC (edotreotide), DOTA-NOC, DOTA-TATE (oxodotreotide), DOTA-LAN, and DOTA-VAP. The pharmaceutical aqueous solution according to any one of [1] to [15], forming a molecule, preferably selected from DOTA-TOC and DOTA-TATE, more preferably DOTA-TATE.
[17]
The radionuclide, the cell 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), The pharmaceutical aqueous solution according to any one of [1] to [16], preferably forming ¹⁷⁷ Lu-DOTA-TATE.
[18]
It further comprises a buffering agent, preferably said buffering agent preferably comprises acetic acid at a concentration of 0.3-0.7mg/mL (preferably about 0.48mg/mL) and 0.4-0.9mg/mL (preferably about 0.48mg/mL). The pharmaceutical aqueous solution according to any one of [1] to [17], wherein the acetate buffer is in an amount to provide a sodium acetate of 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 [1] to [18].
[20]
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, 24h to 84h at ≦25°C, ≦ Pharmaceutical aqueous solution according to any one of [1] to [19], having a shelf life of 24 h to 72 h at 25°C, in particular a shelf life of 72 h at ≦25°C.
[21]
Pharmaceutical aqueous solution according to any one of [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.
[22]
The pharmaceutical aqueous solution according to any one of [1] to [21], which is ready for use and/or for commercial use.
[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 DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) linked to a chelating agent;
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 (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/mL;
The pharmaceutical aqueous solution according to [23], further comprising:
[25]
(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;
The pharmaceutical aqueous solution according to [23] or [24], further comprising:
[26]
Pharmaceutical aqueous solution according to any one of [1] to [25], wherein the stabilizer(s) is present in the solution upon complex formation of components (ai) and (aii).
[27]
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 present upon complex formation of components (ai) and (aii) in an amount resulting in a concentration of 0.5 to 0.7 mg/mL. solution.
[28]
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 The pharmaceutical aqueous solution according to any one of [6] to [27], which is added after complex formation of components (ai) and (aii).
[29]
The pharmaceutical aqueous solution according to any one of [6] to [28], wherein the second stabilizer is added after complex formation of components (ai) and (aii).
[30]
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. Pharmaceutical aqueous solution according to [6] or [29], added after complexation of components (ai) and (aii), more preferably in an amount resulting in a concentration of 2.2 to 3.4 mg/mL.
[31]
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), according to any one of [1] to [30]. pharmaceutical aqueous solution.
[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);
The process for producing an aqueous pharmaceutical solution according to any one of [1] to [31], comprising:
[33]
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. The process according to [32], which is present in step (1.3) in an amount resulting in a concentration of 0.5-0.7 mg/mL.
[34]
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). The process according to [32] or [33], which is added in step (2.1) after.
[35]
The aqueous pharmaceutical solution according to any one of [32] to [34], wherein the second stabilizer is added in step (2.1) after step (1.3).
[36]
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. Any one of [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 as described in.
[37]
The process according to any one of [32] to [36], wherein the solution of step (1.2) further comprises a buffer, preferably an acetate buffer.
[38]
Any one of [32] to [37], wherein in step (1.3), the resulting mixture is heated to a temperature of 70 to 99°C, preferably 90 to 98°C, for 2 to 59 minutes. The process described in.
[39]
The process according to any one of [32] to [38], wherein the solution in 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) The filtered solution obtained in step (3) is 5.0 to 10 MBq, preferably 7.0 to 8.0 MBq, more preferably 7.3 to 7.7 MBq, and even more preferably 7.4 to 8.0 MBq. a process step of dispensing into a dose unit container the 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, even more preferably 20 to 30 mL; a process step of 25 mL;
The process according to any one of [32] to [39], further comprising:
[41]
The process according to any one of [32] to [40], wherein the solution in step (1.1) contains LuCl ₃ and HCl.
[42]
Any one of [32] to [41], wherein the solution in step (1.2) contains ¹⁷⁷ Lu-DOTA-TATE or ¹⁷⁷ Lu-DOTA-TOC, gentisic acid, acetic acid, and sodium acetate. The process described in section.
[43]
The process according to any one of [32] to [42], wherein the solution in step (2.1) contains DTPA and ascorbic acid.
[44]
The process according to any one of [32] to [43], wherein the dose unit container in step (4) is a vial with a stopper sealed in a lead container.

Claims (16)

A process for producing a pharmaceutical aqueous solution, the pharmaceutical aqueous solution comprising:
(a) Below:
(ai) radionuclide ¹⁷⁷ Lu (lutetium-177);
(aii) DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide);
A complex formed by
(b) at least two different stabilizers against radiolytic degradation;
including;
the radionuclide is present at a concentration providing a volumetric radioactivity of 250-500 MBq/mL;
The component (b) is a stabilizer:
(bi) gentisic acid or a salt thereof;
(bii) ascorbic acid or a salt thereof;
including;
said stabilizer is present at a total concentration of 1.0 to 5.0 mg/mL, and said pharmaceutical aqueous solution has a radiochemical purity (determined by HPLC) of ≧95% for at least 72 hours when stored at 25°C. maintained in
(bi) gentisic acid is present at a concentration of 0.5 to 2 mg/mL, and
(bii) a pharmaceutical aqueous solution in which ascorbic acid is present at a concentration of 2.0 to 5.0 mg/mL;
The manufacturing process includes:
(1) Below:
(1.1) preparing an aqueous solution containing a radionuclide;
(1.2) Preparing an aqueous solution comprising DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) and one type of stabilizer against radiolytic degradation, the method comprising: preparing, wherein the seed stabilizer is gentisic acid or a salt thereof ;
(1.3) heating the mixture obtained by mixing the solutions obtained in steps (1.1) and (1.2);
a process step of forming a complex between the radionuclide ¹⁷⁷ Lu and DOTA-TATE (oxodotreotide) or DOTA-TOC (edotreotide) ;
(2) Below:
(2.1) preparing an aqueous dilute solution containing at least one stabilizer against radiolytic degradation different from the stabilizer used in step (1.2), the at least one stabilizer being different from the stabilizer used in step (1.2); wherein the stabilizer is ascorbic acid or a salt thereof ;
(2.2.) Mixing the complex solution obtained in step (1) and the diluted solution obtained in step (2.1) to obtain a final solution;
a process step of diluting the complex solution obtained in step (1);
including ;
and the stabilizer is present in the final solution at a total concentration of 1.0 to 5.0 mg/mL;
here,
(bi) gentisic acid is present at a concentration of 0.5 to 2 mg/mL, and
(bii) ascorbic acid is present at a concentration of 2.0 to 5.0 mg/mL;
Pharmaceutical aqueous solution manufacturing process. (bi) gentisic acid is present at a concentration of 0.5 to 1 mg/mL;
A process according to claim 1. (c) diethylenetriaminepentaacetic acid (DTPA) or a salt thereof at a concentration of 0.01 to 0.10 mg/mL;
3. The process of claim 1 or 2, further comprising: (d) Below:
(di) acetic acid at a concentration of 0.3 to 0.7 mg/mL;
(dii) sodium acetate at a concentration of 0.4 to 0.9 mg/mL;
an acetate buffer, consisting of
further including;
A process according to any one of claims 1 to 3, wherein the acetate buffer provides a pH of 4.5 to 6.0. Process according to any one of claims 1 to 4, having a shelf life of at least 72 hours when stored at ≦25°C. The solution prepared in step (1.2) contains only one stabilizer, which is gentisic acid, and the solution prepared in step (2.1) contains only one stabilizer, which is ascorbic acid. Process according to any one of claims 1 to 5 , comprising only an agent. Process according to any one of claims 1 to 6 , wherein the solution prepared in step (1.2) comprises one or more stabilizers at a total concentration of 15 to 50 mg/mL . Process according to any one of claims 1 to 7 , wherein the solution prepared in step (1.2) contains only one stabilizer, which is gentisic acid at a concentration of 20 to 40 mg/mL. . Process according to any one of claims 1 to 8 , wherein the solution of step (1.2) further comprises a buffer . Process according to any one of claims 1 to 9 , wherein in step (1.3) the mixture obtained is heated to a temperature of 70 to 99° C. for a period of 2 to 59 minutes . Process according to any one of claims 1 to 10 , 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) A process step of dispensing the filtered solution obtained in step (3) into dose unit containers in an amount necessary to deliver a radiation dose of 5.0 to 10 MB q , the amount being is between 10 and 50 mL ;
A process according to any one of claims 1 to 11 , further comprising: Process according to any one of claims 1 to 12 , wherein the solution of step (1.1) comprises LuCl ₃ and HCl. Process according to any one of claims 1 to 13 , wherein the solution of step (1.2) comprises DOTA -TATE or DOTA -TOC, gentisic acid, acetic acid and sodium acetate. . Process according to any one of claims 1 to 14 , wherein the solution of step (2.1) comprises DTPA and ascorbic acid. The process according to any one of claims 1 to 15 , wherein the dose unit container in step (4) is a stoppered vial enclosed in a lead container.