Pharmaceutical compositions, methods of making and pharmaceutical formulations

Abstract

The present application relates to the technical field of medicine, in particular to a kind of pharmaceutical composition and preparation method and pharmaceutical preparation thereof.The pharmaceutical composition includes: (a) the radio-pharmaceutical targeting FAP;(b) stabilizer;Wherein, the FAP-targeting molecule contains pyrrolidine-2-boric acid structural unit, and the stabilizer is composed of N-acetyl methionine and ascorbic acid.The pharmaceutical composition provided by the present application and preparation method and pharmaceutical preparation thereof can effectively reduce the generation of radiation decomposition impurities, and maintain the stability of radio-pharmaceutical for a long time.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition, its preparation method, and pharmaceutical formulation. Background Technology

[0002] Tumors are composed of tumor cells and tumor stroma, with the stroma making up the majority of the tumor. Tumor-associated fibroblasts (CAFs) are an important component of the tumor stroma.

[0003] Numerous studies have shown that CAF exists in more than 90% of epithelial tumors, including pancreatic cancer, colon cancer, and breast cancer. It can affect the occurrence, invasion, and metastasis of tumors through various means, such as promoting the transformation between epithelium and stroma, promoting tumor microangiogenesis, and inducing immunosuppression.

[0004] Among them, fibroblast activator protein (FAP) is overexpressed in CAF and participates in the growth, invasion and metastasis of tumor cells. FAP is absent or expressed at low levels in normal tissues, so it can serve as an ideal target to kill CAF and inhibit the growth of tumor cells.

[0005] Small-molecule radiopharmaceuticals targeting free radical angiotensin II (FAP) have seen significant development in recent years. Among them, radiopharmaceuticals using pyrrolidine-2-boronic acid (PRA) structural units as targeting ligands are generally considered first-generation FAP-targeting small-molecule radiopharmaceuticals, exhibiting high selectivity and affinity for FAP, making them a relatively ideal targeting drug. However, the PRA structural unit has poor stability, and the boric acid structure is prone to side reactions such as oxidation, hydrolysis, and cyclization, and is particularly sensitive to the radiodecomposition effects of radionuclides.

[0006] Radiation decomposition leads to an increase in chemical and radiochemical impurities in radiopharmaceutical formulations, resulting in a decrease in the chemical and radiochemical purity of the radiopharmaceutical. This increase in radiation decomposition impurities increases noise signals in diagnostic radiopharmaceuticals, reduces the therapeutic efficacy of therapeutic radiopharmaceuticals, and may cause unnecessary radiation damage to other normal tissues. Therefore, reducing the formation of radiation decomposition impurities and developing a formulation and preparation process that can maintain the stability of radiopharmaceuticals over a longer period are urgent problems to be solved by those skilled in the art. Summary of the Invention

[0007] The purpose of this invention is to provide a pharmaceutical composition, its preparation method, and a pharmaceutical formulation to solve the above-mentioned problems in the prior art, reduce the generation of radiation decomposition impurities, and maintain the stability of radiopharmaceuticals over a longer period of time.

[0008] The pyrrolidine-2-boronic acid structural unit, as a ligand targeting FAP, gives the FAP-targeting molecule a high targeting affinity, enabling it to effectively bind to the FAP protein. However, the boronic acid structure has poor stability and is sensitive to conditions such as high temperature, oxidation, and radiation, easily undergoing various degradation reactions, leading to… 177 Products labeled with Lu contain a significant amount of radioactive impurities, and these impurities are generated during storage. Adding stabilizers during and after the radiolabeling process is an effective method to address the radioactive decomposition of radiopharmaceuticals.

[0009] In the prior art, compounds such as PNT6555, PNT6522, and PNT6592 disclosed in patent application CN115697413A also contain the same pyrrolidine-2-boronic acid targeting structural unit, and N-acetylmethionine is reported as being used as a target structural unit in Examples 17 and 18. 177 Stabilizers in the Lu-labeled reaction process have limited effectiveness when used alone, with initial radiochemical purity (HPLC) generally >85%. Examples 19 and 20 use a mixture of N-acetylmethionine, sodium ascorbate, and gentianic acid as a stabilizer, achieving an initial radiochemical purity generally >90%, and a radiochemical purity >90% after 3 days at room temperature. However, there is still room for further improvement in the stability of this type of radioactive molecule.

[0010] This invention reveals that, for radiopharmaceuticals using pyrrolidine-2-boronic acid structural units as targeting ligands, the poor formulation stability is due not only to the product's inherent sensitivity to radiodegradation, but also primarily to the potential cyclization reaction between gentic acid and pyrrolidine-2-boronic acid, leading to the degradation of the radioactive API and reducing its radiochemical purity. Therefore, the addition of gentic acid exacerbates the radiodegradation of such radioactive molecules, negatively impacting the stability of radioactive molecules containing pyrrolidine-2-boronic acid structural units.

[0011] Based on this, the present invention conducted extensive screening and research on stabilizers for this type of radiopharmaceutical. The results showed that when the combination of N-acetylmethionine and ascorbic acid is used as a stabilizer, it can effectively improve both the initial radiochemical purity of the radioactive API and the stability of the radioactive API.

[0012] Specifically, in a first aspect, the present invention provides a pharmaceutical composition comprising: (a) a radiopharmaceutical targeting FAP; and (b) a stabilizer; wherein the molecule targeting FAP contains a pyrrolidine-2-boronic acid structural unit, and the stabilizer is composed of N-acetylmethionine and ascorbic acid.

[0013] According to the pharmaceutical composition of the present invention, the stabilizer is composed of N-acetylmethionine and ascorbic acid in a mass ratio of (1~10):1.

[0014] In this invention, the weight ratio of N-acetylmethionine and ascorbic acid can be any ratio among 1:1, 2:1, 3:1, 4:1, 6:1, 8:1, and 10:1, or a range of ratios with any two of the above ratios as endpoints.

[0015] According to the pharmaceutical composition of the present invention, the concentration of N-acetylmethionine in the pharmaceutical composition is 12 mg / mL to 120 mg / mL; and the concentration of ascorbic acid is 3 mg / mL to 20 mg / mL.

[0016] In some respects, the stabilizers of the present invention, with different ratios of N-acetylmethionine and ascorbic acid and at different concentrations, still provide good protection for pharmaceutical compositions with lower specific activities. However, for pharmaceutical compositions with higher specific activities, further optimization of the stabilizer formulation and concentration is required.

[0017] Preferably, the weight ratio of N-acetylmethionine to ascorbic acid in the stabilizer is (4~8):1. When the stabilizer combination with this ratio is used for radiolabeling, the radiochemical purity of the labeled API is not less than 95%, which is significantly higher than the radiochemical purity of API using a single stabilizer or other stabilizer combinations.

[0018] Preferably, the concentration of N-acetylmethionine in the pharmaceutical composition is 12 mg / mL to 120 mg / mL, for example, it can be any value among 12 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, and 120 mg / mL, or a range of values ​​with any two of the above values ​​as endpoints.

[0019] Preferably, in the pharmaceutical composition, the concentration of ascorbic acid is 3 mg / mL to 20 mg / mL, for example, it can be any value among 3 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, and 20 mg / mL, or a range of values ​​with any two of the above values ​​as endpoints.

[0020] Preferably, the above-mentioned preferred stabilizer formulation and concentration still have a good stabilizing effect on the drug composition with high specific activity, and the scale-up of production does not have a significant impact on the initial radiochemical purity and stability of the API in the drug composition. The radiochemical purity of the drug composition is not less than 90% after preparation and is kept at 25°C for 72 hours.

[0021] In practice, the stabilizer can be used in different concentrations for the radiolabeling reaction, and it exists in the pharmaceutical composition at a total concentration of 20-150 mg / mL.

[0022] According to the pharmaceutical composition of the present invention, the radiopharmaceutical targeting FAP includes radioactive elements. 177 Lu、 90 Y、 161 Tb or 225 Ac, the molecule that targets FAP contains pyrrolidine-2-boronic acid structural units.

[0023] According to the pharmaceutical composition of the present invention, the radiopharmaceutical targeting FAP comprises compounds with any of the following structures:

[0024] .

[0025] According to the pharmaceutical composition of the present invention, the radioactive concentration of the radiopharmaceutical targeting FAP is 10 mCi / mL or more, for example, at least 10 mCi / mL, 12 mCi / mL, 15 mCi / mL, or 20 mCi / mL or more.

[0026] Preferably, the pharmaceutical composition further comprises a buffer solution for dissolving the stabilizer and chelating agent; preferably, the buffer solution comprises a sodium acetate / acetic acid buffer solution. More preferably, the pH of the buffer solution is 3.5 to 6.0.

[0027] Preferably, the pharmaceutical composition further comprises a chelating agent for the aforementioned free metal nuclide to appropriately remove unchelated nuclides. 177 Lu. In one specific embodiment, the chelating agent is diethylenetriaminepentaacetic acid (hereinafter sometimes referred to as "DTPA") or a salt thereof.

[0028] More preferably, the concentration of the chelating agent in the pharmaceutical composition is 0.01 mg / mL to 0.15 mg / mL, for example, it can be any value among 0.01 mg / mL, 0.02 mg / mL, 0.03 mg / mL, 0.04 mg / mL, 0.05 mg / mL, 0.06 mg / mL, 0.07 mg / mL, 0.08 mg / mL, 0.09 mg / mL, 0.10 mg / mL, 0.11 mg / mL, 0.12 mg / mL, 0.13 mg / mL, 0.14 mg / mL, and 0.15 mg / mL, or a range of values ​​with any two of the above values ​​as endpoints.

[0029] In a second aspect, the present invention provides a method for preparing the pharmaceutical composition, comprising:

[0030] The target FAP molecule, stabilizer, radioactive compound and buffer solution are mixed and chelated to obtain a labeled solution, which is then diluted.

[0031] In this invention, to further improve the stability of the pharmaceutical composition, the reaction solution is diluted with a diluent containing the above-mentioned stabilizer combination after the labeling reaction.

[0032] Preferably, the method for preparing the pharmaceutical composition includes: mixing a molecule targeting FAP, a stabilizer, a radioactive compound, and a buffer solution and performing a chelation reaction to obtain a labeled solution, and then diluting the labeled solution with a diluent containing the stabilizer and the chelating agent, wherein the solvent in the diluent solution is a buffer solution.

[0033] In this invention, N-acetylmethionine and ascorbic acid are added as stabilizers during the chelation reaction to protect the stability of the marker formed during the reaction. Simultaneously, after the marker is formed, the aforementioned stabilizers are added to maintain the stability of the marker during storage.

[0034] A method for preparing a pharmaceutical composition according to the present invention includes:

[0035] S1: Mix the molecules targeting FAP, stabilizers, radioactive compounds, and buffer solutions to obtain a reaction solution;

[0036] S2: Heat the reaction solution to 75℃~100℃ and keep it at that temperature for 10min~30min; then cool it to room temperature and continue to add a buffer solution containing stabilizer and chelating agent;

[0037] In the pharmaceutical composition, the concentration of the chelating agent is 0.01 mg / mL to 0.15 mg / mL;

[0038] In the pharmaceutical composition, the concentration of N-acetylmethionine is 12-120 mg / mL, based on the total amount of the stabilizer in S1 and the stabilizer in S2; the concentration of ascorbic acid is 3-20 mg / mL; wherein the mass ratio of the stabilizer in S1 to the stabilizer in S2 is (1-3):(1-14).

[0039] In this invention, the method for preparing the pharmaceutical composition includes, in the presence of the stabilizer, adding a molecule targeting FAP and a radionuclide. 177 Lu's aqueous buffer solution is mixed and heated to form a complex solution, and the labeled solution is diluted with an aqueous buffer solution containing the stabilizer to obtain the final pharmaceutical composition.

[0040] Preferably, in S2, the molecules and radionuclides that target FAP are... 177 The aqueous buffer solution of Lu is heated at a temperature of 75°C to 100°C, preferably at 85°C to 95°C. Further, the heating time is 10 min to 30 min, more preferably 15 min to 25 min.

[0041] Thirdly, the present invention provides a pharmaceutical preparation comprising the aforementioned pharmaceutical composition.

[0042] In this invention, the pharmaceutical preparation obtained from the pharmaceutical composition is an aqueous preparation; preferably, the pharmaceutical composition can be used directly as a pharmaceutical preparation.

[0043] In practice, the pharmaceutical composition or pharmaceutical preparation may not contain organic solvents, such as conventional solvents like ethanol.

[0044] Compared with the prior art, the technical solution of the present invention has the following beneficial effects:

[0045] The pharmaceutical composition, preparation method, and formulation provided by this invention can effectively reduce the generation of radiation decomposition impurities and maintain the stability of radiopharmaceuticals over a longer period of time. Detailed Implementation

[0046] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this invention, not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0047] This invention first used the following five methods to verify the initial radiochemical purity of formulation samples obtained by adding different stabilizers to the labeling reaction:

[0048] 1. 177 Preparation of Lu-JYT2-401 drug aqueous solution

[0049] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 1.6 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 100 mg / mL N-acetylmethionine). The reaction solution was heated to 80 °C and maintained for 20 min. After cooling to room temperature, 100 μL of dilution solution (containing 0.1 mg / mL DTPA) was added to bring the total volume of the preparation to 210 μL.

[0050] 2. 177 Preparation of Lu-JYT2-401 drug aqueous solution (N-acetylmethionine and ascorbic acid weight ratio 4:1)

[0051] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 2.3 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 40 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 120 μL of dilution solution (containing 0.1 mg / mL DTPA) was added to bring the total volume of the preparation to 230 μL.

[0052] 3. 177 Preparation of Lu-JYT2-401 drug aqueous solution (N-acetylmethionine and ascorbic acid weight ratio 6:1)

[0053] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 2.1 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 100 μL of dilution solution (containing 0.1 mg / mL DTPA) was added to bring the total volume of the preparation to 210 μL.

[0054] 4. 177 Preparation of Lu-JYT2-401 drug aqueous solution (N-acetylmethionine and ascorbic acid weight ratio 8:1)

[0055] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 2.1 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 80 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 100 μL of dilution solution (containing 0.1 mg / mL DTPA) was added to bring the total volume of the preparation to 210 μL.

[0056] The initial radiochemical purity of the API obtained from the above four schemes was determined by HPLC, and the results are shown in Table 1. Stabilizer 1 refers to N-acetylmethionine, and stabilizer 2 refers to ascorbic acid.

[0057] Table 1

[0058]

[0059] Analysis of experimental results: When only N-acetylmethionine was used as a stabilizer in the labeling reaction, the initial radiochemical purity of the formulation samples was below 90%. Compared with using a single stabilizer, the combination of N-acetylmethionine and ascorbic acid as stabilizers in the labeling reaction significantly improved the initial radiochemical purity of the formulation samples, all exceeding 95%. The experimental results indicate that the N-acetylmethionine + ascorbic acid dual stabilizer combination has a significant advantage in improving the initial radiochemical purity of the formulation samples.

[0060] The following examples further verify the effectiveness of dual stabilizer compositions obtained from N-acetylmethionine and ascorbic acid at different concentrations and formulations.

[0061] Example 1 177 Preparation of Lu-JYT2-401 drug aqueous solution (N-acetylmethionine and ascorbic acid weight ratio 1:1)

[0062] This embodiment provides a pharmaceutical composition, the preparation method of which includes the following steps:

[0063] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 2.2 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 20 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 100 μL of dilution solution (containing 0.1 mg / mL DTPA, 10 mg / mL N-acetylmethionine and 20 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 220 μL.

[0064] Example 2 177 Preparation of Lu-JYT2-401 drug aqueous solution (N-acetylmethionine and ascorbic acid weight ratio 2:1)

[0065] This embodiment provides a pharmaceutical composition, the preparation method of which includes the following steps:

[0066] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 2.0 mCi 177A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 40 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 80 μL of dilution solution (containing 0.12 mg / mL DTPA, 25 mg / mL N-acetylmethionine and 25 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 200 μL.

[0067] Example 3 177 Preparation of Lu-JYT2-401 drug aqueous solution (N-acetylmethionine and ascorbic acid weight ratio 4:1)

[0068] This embodiment provides a pharmaceutical composition, the preparation method of which includes the following steps:

[0069] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 3.6 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 240 μL of dilution solution (containing 0.1 mg / mL DTPA, 25 mg / mL N-acetylmethionine and 8.3 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 360 μL.

[0070] Example 4 177 Preparation of Lu-JYT2-401 drug aqueous solution (N-acetylmethionine and ascorbic acid weight ratio 6:1)

[0071] This embodiment provides a pharmaceutical composition, the preparation method of which includes the following steps:

[0072] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 3.6 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 240 μL of dilution solution (containing 0.1 mg / mL DTPA, 50 mg / mL N-acetylmethionine and 8.3 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 360 μL.

[0073] Example 5 177Preparation of Lu-JYT2-401 drug aqueous solution (N-acetylmethionine and ascorbic acid weight ratio 8:1)

[0074] This embodiment provides a pharmaceutical composition, the preparation method of which includes the following steps:

[0075] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 3.6 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 240 μL of dilution solution (containing 0.1 mg / mL DTPA, 75 mg / mL N-acetylmethionine and 8.3 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 360 μL.

[0076] The drug aqueous solutions obtained in Examples 1-5 were stored at 25°C for 72 hours, and their API radiochemical purity was detected by HPLC. The results are shown in Table 2.

[0077] Table 2

[0078]

[0079] Analysis of experimental results: N-acetylmethionine and ascorbic acid exist in different ratios in the drug formulation. They have good protective effects on drug compositions with lower specific activities, but their effects are relatively poor for drug compositions with higher specific activities.

[0080] Furthermore, this invention optimizes the formulation and concentration of the stabilizer. Experiments have shown that when the weight ratio of N-acetylmethionine to ascorbic acid in the stabilizer is (4~8):1, and the concentration of N-acetylmethionine in the pharmaceutical composition is controlled at 12 mg / mL~120 mg / mL, and the concentration of ascorbic acid is controlled at 3 mg / mL~20 mg / mL, the radiochemical purity of the labeled API is not less than 95%, which is significantly higher than the radiochemical purity of API using a single stabilizer or other stabilizer combinations. Simultaneously, the above-mentioned preferred stabilizer formulation and concentration still have a good stabilizing effect on pharmaceutical compositions with high specific activity, and scale-up production has no significant impact on the initial radiochemical purity and stability of the API in the pharmaceutical composition. The radiochemical purity of the pharmaceutical composition is not less than 90% after preparation and maintenance at 25°C for 72 hours.

[0081] Example 6 High specific activity 177 Preparation of Lu-JYT2-401 drug aqueous solution

[0082] This embodiment provides a pharmaceutical composition, the preparation method of which includes the following steps:

[0083] Add JYT2-401 solution (containing 10 nmol JYT2-401) and 14.2 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 20 min. After cooling to room temperature, 570 μL of dilution solution (containing 0.1 mg / mL DTPA, 21.0 mg / mL N-acetylmethionine and 3.5 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 710 μL.

[0084] Example 7 High specific activity 177 Preparation of Lu-JYT2-401 drug aqueous solution

[0085] This embodiment provides a pharmaceutical composition, the preparation method of which includes the following steps:

[0086] Add JYT2-401 solution (containing 10 nmol JYT2-401) and 15.8 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 20 min. After cooling to room temperature, 710 μL of diluent solution (containing 0.08 mg / mL DTPA, 42.2 mg / mL N-acetylmethionine and 7.0 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 830 μL.

[0087] Example 8 High specific activity 177 Preparation of Lu-JYT2-401 drug aqueous solution

[0088] This embodiment provides a pharmaceutical composition, the preparation method of which includes the following steps:

[0089] Add JYT2-401 solution (containing 10 nmol JYT2-401) and 15.1 mCi 177A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 20 min. After cooling to room temperature, 630 μL of diluent solution (containing 0.16 mg / mL DTPA, 133.3 mg / mL N-acetylmethionine and 22.2 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 750 μL.

[0090] The drug aqueous solutions obtained in Examples 6-8 were stored at 25°C for 72 hours, and their API radiochemical purity was detected by HPLC. The results are shown in Table 3.

[0091] Table 3

[0092]

[0093] Analysis of experimental results: The addition of N-acetylmethionine and ascorbic acid as stabilizers during and after the labeling reaction effectively protected the stability of the formulation. Even at high specific activity and high radioactive concentrations, the radiochemical purity of the formulation remained at no less than 90% for 72 hours at 25°C.

[0094] Example 9 177 Preparation of Lu-JYT2-401 drug aqueous solution (without adding gentianic acid after reaction).

[0095] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 3.6 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 15 min. After cooling to room temperature, 240 μL of dilution solution (containing 0.1 mg / mL DTPA, 50.0 mg / mL N-acetylmethionine and 8.3 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 360 μL.

[0096] Example 10 177 Preparation of Lu-JYQ2-452 reaction solution (without adding gentian acid to the reaction).

[0097] Add JYQ2-452 solution (containing 10 nmol JYQ2-452) and 15.7 mCi 177A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C and maintained for 20 min. Then it was cooled to room temperature.

[0098] Example 11 177 Scale-up production of Lu-JYQ2-452 drug aqueous solution

[0099] (1) 177 LuCl3 solution was added at 96 mg / L.

[0100] JYQ2-452 solution (containing 60 nmol JYQ2-452), 96 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 420 μL of sodium acetate / acetic acid buffer solution (containing 85.7 mg / mL N-acetylmethionine and 14.3 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 22 min. After cooling to room temperature, 8.9 mL of diluent solution (containing 0.1 mg / mL DTPA, 20.2 mg / mL N-acetylmethionine and 3.4 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 9.6 mL.

[0101] (2) 177 LuCl3 solution was added at 200 mg / L.

[0102] Add JYQ2-452 solution (containing 120 nmol JYQ2-452) and 200 mL Ci 177 A reaction solution was prepared by mixing LuCl3 solution and 840 μL of sodium acetate / acetic acid buffer solution (containing 85.7 mg / mL N-acetylmethionine and 14.3 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 25 min. After cooling to room temperature, 18.6 mL of diluent solution (containing 0.05 mg / mL DTPA, 19.4 mg / mL N-acetylmethionine and 3.2 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 20 mL.

[0103] The drug aqueous solution preparation obtained in Example 11 was stored at 25°C for 72 hours, and its API radiochemical purity was detected by HPLC. The results are shown in Table 4.

[0104] Table 4

[0105]

[0106] Experimental results analysis: Even 177Even with the Lu nuclide activity increased to 200 mCi, the two stabilizers still provided effective protection. The initial radiochemical purity of the API in the drug formulation remained above 95%, and after storage at 25°C for 72 hours, the radiochemical purity of the API was still above 90%. This fully demonstrates the effective protective effect of the combination of N-acetylmethionine and ascorbic acid stabilizers on radiopharmaceutical formulations.

[0107] Comparative Example 1 177 Preparation of Lu-JYT2-401 drug aqueous solution (gentianic acid added after reaction)

[0108] Add JYT2-401 solution (containing 20 nmol JYT2-401) and 3.5 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine and 10 mg / mL ascorbic acid). The reaction solution was heated to 90 °C for 20 min. After cooling to room temperature, 230 μL of diluent solution (containing 0.1 mg / mL DTPA, 2.2 mg / mL gentianic acid, 52.2 mg / mL N-acetylmethionine and 8.7 mg / mL ascorbic acid) was added to bring the total volume of the preparation to 350 μL.

[0109] The drug aqueous solutions obtained in Example 9 and Comparative Example 1 were stored at 25°C for 72 hours, and their API radiochemical purity was detected by HPLC. The results are shown in Table 5.

[0110] Table 5

[0111]

[0112] Analysis of experimental results: After the labeling reaction, the addition of gentic acid as a stabilizer resulted in a more rapid decrease in the radiochemical purity of the drug formulation compared to using only N-acetylmethionine and ascorbic acid as stabilizers. HPLC results showed a rapid increase in the content of a certain radioactive impurity, indicating that gentic acid may be incompatible with API and is not a suitable stabilizer.

[0113] Comparative Example 2: Gentianic acid against 177 Effect of initial radiochemical purity of Lu-JYQ2-452 product

[0114] (1) Add gentianic acid to the labeling reaction

[0115] Add JYQ2-452 solution (containing 10 nmol JYQ2-452) and 14.5 mCi 177A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine, 10 mg / mL ascorbic acid, and 5 mg / mL gentianic acid). The reaction solution was heated to 90 °C for 20 min. Then it was cooled to room temperature.

[0116] (2) Add gentianic acid to the labeling reaction

[0117] Add JYQ2-452 solution (containing 10 nmol JYQ2-452) and 14.7 mCi 177 A reaction solution was prepared by mixing LuCl3 solution and 100 μL of sodium acetate / acetic acid buffer solution (containing 60 mg / mL N-acetylmethionine, 10 mg / mL ascorbic acid, and 10 mg / mL gentianic acid). The reaction solution was heated to 90 °C for 20 min. The mixture was then cooled to room temperature.

[0118] The API radiochemical purity of the reaction solutions obtained in Example 10 and Comparative Example 2 was determined by HPLC, and the results are shown in Table 6.

[0119] Table 6

[0120]

[0121] Analysis of experimental results: Adding gentianic acid as a stabilizer in the labeling reaction significantly decreased the initial radiochemical purity of the API compared to using only N-acetylmethionine and ascorbic acid as stabilizers. HPLC results showed a high content of a certain radioactive impurity. The higher the amount of gentianic acid used, the lower the radiochemical purity of the API.

[0122] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A pharmaceutical composition, characterized by, The application relates to a pharmaceutical composition and a preparation method thereof. The pharmaceutical composition comprises: (a) a radio pharmaceutical targeting FAP; and (b) a stabilizer; the stabilizer is composed of N-acetyl methionine and ascorbic acid in a mass ratio of (1-10):1; 。 2. The pharmaceutical composition of claim 1, wherein, The radio pharmaceutical targeting FAP comprises a compound with any one of the following structures: In the pharmaceutical composition, the concentration of the N-acetyl methionine is 12 mg / mL-120 mg / mL.

3. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, And / or, the concentration of the ascorbic acid is 3 mg / mL-20 mg / mL.

4. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, The radio pharmaceutical targeting FAP has a radio concentration of more than 10 mCi / mL. The pharmaceutical composition further comprises a buffer solution, and the buffer solution comprises a sodium acetate / acetic acid buffer solution.

5. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 1 to 3, characterized in that, And / or, the pharmaceutical composition further comprises a chelating agent, and the chelating agent comprises diethylene triamine pentaacetic acid or a salt thereof. The radio pharmaceutical targeting FAP is obtained by reacting a FAP-targeting molecule and a radioactive compound; the pharmaceutical composition further comprises a buffer solution; and the preparation method comprises the following steps:

6. The method of claim 5, wherein the pharmaceutical composition is prepared by, The FAP-targeting molecule, the stabilizer, the radioactive compound and the buffer solution are mixed and subjected to a chelation reaction to obtain a label solution, and then the label solution is diluted. The pharmaceutical composition further comprises a chelating agent; and the preparation method comprises the following steps: S1: mixing the FAP-targeting molecule, the stabilizer, the radioactive compound and the buffer solution to obtain a reaction solution; S2: heating the reaction solution to 75-100 DEG C and keeping the temperature for 10-30 min; and then cooling to room temperature and continuously adding a buffer solution containing the stabilizer and the chelating agent; In the pharmaceutical composition, the concentration of the chelating agent is 0.01 mg / mL-0.15 mg / mL.

7. The method of preparing a pharmaceutical composition according to claim 5 or 6, wherein In the pharmaceutical composition, the concentration of the N-acetyl methionine is 12 mg / mL-120 mg / mL based on the total amount of the stabilizer in S1 and the stabilizer in S2; and the concentration of the ascorbic acid is 3 mg / mL-20 mg / mL; wherein the mass ratio of the stabilizer in S1 to the stabilizer in S2 is (1-3):(1-14).

8. The method of claim 6, wherein the pharmaceutical composition is prepared by, The buffer solution comprises a sodium acetate / acetic acid buffer solution.

9. A pharmaceutical preparation, characterized in that, The chelating agent comprises diethylene triamine pentaacetic acid or a salt thereof. The pharmaceutical composition comprises the pharmaceutical composition of any one of claims 1-4 or the pharmaceutical composition prepared by the preparation method of any one of claims 5-8.

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