Preparation method of 68Ga-Isotreotide

Abstract

The invention relates to a preparation method of < 68 > Ga-Isotreotide. Specifically, glacial acetic acid-sodium acetate is adopted as a buffer solution in the reaction process of the isotreotide and 68GaCl3 in the preparation method.

Description

Technical Field

[0001] This disclosure relates to a 68 The preparation method of Ga-isetropeptide belongs to the pharmaceutical field. Background Technology

[0002] Radiopharmaceuticals, also known as nuclear medicine, are radioactive nuclides used in nuclear medicine. They are radioactive nuclide preparations or their labeled compounds used for clinical diagnosis or treatment, and are currently widely used in tumor diagnosis and treatment, myocardial imaging, early detection of neurodegenerative diseases, and imaging diagnosis of inflammatory tissues. In recent years, 68 Ga-labeled somatostatin analogs (SSAs) are increasingly used in clinical diagnosis and treatment. Currently, they are commonly used in clinical practice. 68 Ga-labeled SSA, for example 68 Ga-DOTATATE, 68 Ga-isetrotide and other similar drugs have become the gold standard for the diagnosis of neuroendocrine tumors (NETs).

[0003] The structure of isotrieptide is shown below: CN103889930A provides a method for the production of isotrieptide in the presence of formate and base.

[0004]

[0005] The process of labeling this structure takes into account that the appropriate pH provided by the buffer is crucial for the labeling reaction. In addition, the buffer will enter the body as the final excipient of the product, and the safety of the excipient cannot be ignored. Therefore, more labeling processes need to be developed. Summary of the Invention

[0006] This disclosure is a kind of 68 A method for preparing Ga-isetropeptide, wherein itropeptide and... 68 The reaction of GaCl3 includes the following steps:

[0007] i) Use a rinsing solution containing hydrochloric acid to rinse the product generated by the commercial generator. 68 Ga was rinsed into vial 1 containing itoprene.

[0008] ii) Take the glacial acetic acid-sodium acetate buffer solution from bottle 2 and add it to bottle 1, then heat to 90-100℃ for reaction;

[0009] iii) Not present or diluted with 0.9% sodium chloride solution;

[0010] iv) Collect the products;

[0011] The buffer solution maintains the pH of the reaction system between 2.8 and 4.3.

[0012] In an optional implementation, step iii) is not present.

[0013] In an optional implementation, step iii) is present.

[0014] In an optional implementation, step iii) involves diluting the solution with a 0.9% sodium chloride solution.

[0015] In some embodiments, the pH of the reaction system is between 3.2 and 3.8, specifically selected from 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, or any value between two points.

[0016] In some embodiments, the pH of the glacial acetic acid-sodium acetate buffer solution is between about 4.2 and 4.7.

[0017] In an optional implementation, the reaction temperature is selected from 90℃, 91℃, 92℃, 93℃, 94℃, 95℃, 96℃, 97℃, 98℃, 99℃, 100℃, or any value between any two points.

[0018] In an optional implementation, the reaction is heated to 95°C and maintained for 7-10 minutes.

[0019] In some embodiments, the preparation method provided in this disclosure provides that the product has a radiometric thin-layer chromatography (iTLC) purity greater than 97.0% at T0 (0 h after the reaction ends).

[0020] In an optional embodiment, the preparation method provided in this disclosure yields a product with a radioactive thin-layer chromatography (iTLC) purity greater than 98.0% at T0 (0 h after the reaction ends).

[0021] In some embodiments, the preparation method provided in this disclosure involves detecting the product at T0 using radioactive thin-layer chromatography (iTLC). 68 The content of Ga-related radioactive impurities is less than 3.0%.

[0022] In an optional embodiment, the preparation method provided in this disclosure, wherein the product is detected by radioactive thin-layer chromatography (iTLC) at T0. 68 The content of Ga-related radioactive impurities is less than 2.0%.

[0023] In an optional embodiment, the preparation method provided in this disclosure, wherein bottle 1 contains gentian acid, 1,10-phenanthroline, and mannitol.

[0024] In an optional implementation, the preparation method provided in this disclosure uses bottle 1 as a lyophilized powder.

[0025] In some embodiments, the preparation method provided in this disclosure uses a reaction liquid volume of less than 3.0 mL, specifically, for example, 2.9 mL, 2.8 mL, 2.7 mL, 2.6 mL, 2.5 mL, 2.4 mL, 2.3 mL, 2.2 mL, 2.1 mL, 2.0 mL, 1.9 mL, 1.8 mL, 1.7 mL, 1.6 mL, 1.5 mL, 1.4 mL, 1.3 mL, 1.2 mL, 1.1 mL, 1.0 mL, 0.9 mL, 0.8 mL, 0.7 mL, 0.6 mL, 0.5 mL, 0.4 mL, 0.3 mL, 0.2 mL, 0.1 mL, or any value between any two points.

[0026] In an optional embodiment, the volume of the reaction liquid is 2 mL.

[0027] In an optional embodiment, the volume of the product is 5.5 mL.

[0028] In an optional embodiment, the hydrochloric acid rinsing solution is 0.04M to 0.6M.

[0029] In an optional embodiment, the concentration of the hydrochloric acid rinsing solution is 0.1M.

[0030] In an optional implementation, this disclosure provides 68 The preparation method of Ga-isetropeptide includes the following steps:

[0031] i) Elute the product generated by the commercial generator with a rinsing solution containing 1.5 mL of 0.1 M hydrochloric acid. 68 Ga was rinsed into lyophilized powder bottle 1 containing itostrapeptide, gentianic acid, 1,10-phenanthroline, and mannitol;

[0032] ii) Take 0.5 mL of glacial acetic acid-sodium acetate buffer from bottle 2 and add it to bottle 1. Heat to 95°C and react for 7-10 minutes.

[0033] iii) Dilute with 3.5 mL of 0.9% sodium chloride solution;

[0034] iv) Collect the products;

[0035] The buffer solution maintains the pH of the reaction system between 3.2 and 3.8.

[0036] This disclosure further provides a composition obtained according to the aforementioned preparation method.

[0037] The term "about" means that a value is within an acceptable margin of error for a specific value determined by a person skilled in the art, the value being partly dependent on how it is measured or determined.

[0038] In this disclosure, " 68"Ga-related radioactive impurities" refers to free Ga-related radioactive impurities. 68 Ga and 68 The sum of Ga colloids. Detailed Implementation

[0039] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0040] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available pharmaceutical excipients or reagents.

[0041] The germanium-gallium generator is from Eckert & Ziegler Radiopharma GmbH. Isotropin is manufactured in-house.

[0042] Example 1. Formulation and preparation of lyophilized powder bottle 1

[0043] Table 1. Formula for lyophilized powder bottle 1

[0044]

[0045] Add 50%–90% sterile water for injection to the container, then add the prescribed amounts of 1,10-phenanthroline, gentian acid, mannitol, and DOTATOC in sequence. Stir and mix thoroughly, then add more water for injection and stir until well mixed. Fill the injection vials with the solution, add rubber stoppers (theoretical filling volume is 1 mL), partially stopper, freeze-dry, then stopper and remove from the container.

[0046] Example 2. Investigating the effects of buffer system and reaction volume on the labeled reaction.

[0047] The following labeling method was used, and the products were obtained by operating according to the conditions corresponding to each process in Table 2. The radiochemical purity of the products was then tested.

[0048] 1) Use a syringe to draw up the reaction buffer solution for later use;

[0049] 2) Slowly push a 10mL sterile syringe without a stopper to dispense the corresponding amount of gallium chloride (containing 0.1M hydrochloric acid). 68 The Ga solution was injected directly into the coating bottle (bottle 1) through a needle, and the lyophilized powder was reconstituted using the rinsing solution.

[0050] 3) After rinsing, push the buffer solution into the coating bottle;

[0051] 4) Place the medicine bottle into the hole of the 95℃ dry heater and let the medicine bottle react at 95℃ for 10 minutes;

[0052] 5) Remove the vial from the dry heater, let it cool, add 0.9% sodium chloride injection, and place it in a lead-shielded container with an appropriate label.

[0053] 6) The measurement system measures the radioactivity in the vial and records the results.

[0054] Table 2. Process conditions 1 to 9

[0055]

[0056] Table 3. Radiochemical purity corresponding to process conditions 1 to 9

[0057] serial number 1 2 3 4 5 6 7 8 9 Radiochemical purity 87.30 91.11 99.09 98.44 97.28 No product No product 13.85 41.09

[0058] Through investigation of various process conditions, it was found that the buffer system and pH are among the key factors affecting the purity of the label. Under conditions numbered 3 and 4, the radiochemical purity of the product was optimal.

[0059] Example 3. Investigating the effects of reaction volume and pH of the reaction solution on the labeling reaction.

[0060] Referring to the labeling method in Implementation 2, the product was obtained by operating according to the conditions corresponding to each process in Table 4, and its radiochemical purity was tested.

[0061] Table 4. Process conditions 10 to 17

[0062]

[0063]

[0064] Through investigation of various process conditions, it was found that the products obtained by reacting with small volumes (numbered 13 to 17) had a radiochemical purity of over 98.0%, which met the standard, while the products obtained by reacting with large volumes (numbered 10 to 12) did not meet the standard.

Claims

1. A 68 A method for preparing Ga-isotreotide, wherein isotreotide and 68 The reaction of GaCl3 includes the following steps: i) The commercial generator was washed with hydrochloric acid 68 Ga was eluted into bottle 1 containing isotreotide, ii) Take the glacial acetic acid-sodium acetate buffer in bottle 2 and add it to bottle 1, and heat it to 90-100°C for reaction; iii) dilute with 0.9% sodium chloride solution; iv) collecting the product; The buffer solution maintains the pH of the reaction system between 2.8 and 4.

3. Preferably, the pH of the reaction system is between 3.2 and 3.

8.

2. The preparation method according to claim 1, wherein the reaction is heated to 95°C and maintained for 7-10 minutes.

3. The preparation method according to any one of claims 1 to 2, wherein the radioactive thin layer chromatography (iTLC) purity of the product at T0 is greater than 97.0%, preferably greater than 98.0%.

4. The preparation method according to any one of claims 1 to 2, wherein the product is tested by radioactive thin layer chromatography (iTLC) at T0, 68 The content of Ga-related radioactive impurities is less than 3.0%, preferably less than 2.0%.

5. The preparation method according to any one of claims 1 to 4, wherein the bottle 1 contains gentisic acid, 1,10-phenanthroline and mannitol.

6. The preparation method according to any one of claims 1 to 5, wherein the bottle 1 is a freeze-dried powder.

7. The preparation method according to claims 1 to 6, wherein the reaction liquid volume is less than 3 mL, preferably, the reaction volume is 2 mL.

8. According to the preparation method according to any one of claims 1 to 7, the product volume is 5.5 mL.

9. The preparation method according to any one of claims 1 to 8, wherein the concentration of the hydrochloric acid eluent is 0.1 M.

10. The preparation method according to claim 1, comprising the following steps: i) The commercial generator was washed with 1.5 mL of 0.1 M hydrochloric acid. 68 Ga was eluted into freeze-dried powder bottle 1 containing isotreotide, gentisic acid, 1,10-phenanthroline and mannitol; ii) Take 0.5 mL of glacial acetic acid-sodium acetate buffer from bottle 2 and add it to bottle 1, heat to 95°C and react for 7-10 minutes; iii) dilute with 3.5 mL of 0.9% sodium chloride solution; iv) collecting the product; The buffer solution maintains the pH of the reaction system between 3.2 and 3.

8.

11. A composition obtained by the preparation method according to any one of claims 1 to 10.

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