Liquid formulations and methods for inhibiting the degradation of pentiazem

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a liquid formulation and method for inhibiting the degradation of pentetidine. The liquid formulation includes a drug solution sealed within a drug container and an ambient gas above the drug solution. The drug solution includes one or more of the following: an active pharmaceutical ingredient, pentetidine, and vitamin C and its salts; the ambient gas is primarily composed of non-oxidizing gases. This invention, by establishing a non-oxidizing gas environment in a liquid formulation system containing vitamin C or its salts and DTPA, can significantly reduce the oxidation and degradation rate of DTPA during storage, effectively inhibit the formation of new impurities derived from it, thereby improving the physicochemical stability of the formulation, extending its shelf life, and enhancing the safety and reliability of the product.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a liquid formulation and method for inhibiting the degradation of pentiazem. Background Technology

[0002] Vitamin C's chemical name is L-(+)-threose-type 2,3,4,5,6-pentahydroxy-2-hexenoic acid-4-lactone, also known as L-ascorbic acid. Its molecular structure contains dienoyl alcohol, which allows it to readily release hydrogen atoms in aqueous solution, exhibiting reducing properties. It readily undergoes redox reactions with oxygen atoms in the environment, demonstrating excellent antioxidant function. Sodium vitamin C, as a derivative of vitamin C, has similar functions to vitamin C.

[0003] Diethylenetriaminepentaacetic acid (DTPA), also known as penteacin, contains multiple N and O atoms in its molecular structure, making it commonly used as a complexing agent for radioactive metal isotopes and heavy metals. It can accelerate the rapid metabolism of metals such as Pb, Zn, and Fe, as well as radioactive metal isotopes, in the body.

[0004] Based on the aforementioned properties of vitamin C and its derivatives, as well as pentiformin, they are often widely used as pharmaceutical excipients in pharmaceutical preparations.

[0005] The sources of impurities in pharmaceutical preparations mainly include process impurities in the active pharmaceutical ingredient, new impurities generated by the degradation of active molecules during the preparation process, new impurities generated by the interaction of excipients, and impurities introduced during the process. Therefore, research on impurities in pharmaceutical preparations containing vitamin C or its salts and pentiacin is of great significance for drug safety, efficacy and quality control. Summary of the Invention

[0006] This invention provides a liquid formulation for inhibiting the degradation of pentilic acid, which can effectively inhibit the degradation of pentilic acid in pharmaceutical preparations containing vitamin C or its salts and pentilic acid.

[0007] In some embodiments, the liquid formulation for inhibiting the degradation of pentiazem provided by the present invention includes a drug solution sealed within a drug container and an ambient gas above the drug solution, the drug solution comprising: (1) Active pharmaceutical ingredient, (2) Pentate acid, and (3) One or more of vitamin C and its salts; The ambient gases are mainly composed of non-oxidizing gases.

[0008] The inventors discovered in their research on process impurities in pharmaceutical formulations that when vitamin C or its salts coexist with pentiphos as pharmaceutical excipients in the same aqueous solution system and are exposed to air, pentiphos is prone to oxidative degradation and the generation of new impurities, thereby reducing the stability of the formulation quality. Based on this, the present invention replaces the air in the formulation system with a non-oxidizing gas, creating a low-oxygen environment within the container. This effectively inhibits DTPA degradation and the generation of oxidatively derived impurities, reduces the stability risks caused by interactions between excipients, and thus significantly improves the overall physicochemical stability of liquid formulations.

[0009] Pentiic acid exhibits a significant degradation trend, leading to the introduction of new impurities in the aqueous solution system. This degradation is particularly pronounced at higher temperatures or when the aqueous solution contains radioactive isotopes; temperature and radiation further exacerbate the degradation. By filling the container of liquid formulations containing vitamin C or its salts and pentiic acid with a non-oxidizing gas, the degradation of pentiic acid in the liquid formulation can be effectively inhibited, thus effectively controlling the introduction of new impurities in the pharmaceutical formulation due to the interaction between vitamin C / its salts and pentiic acid.

[0010] The beneficial effects of this invention are as follows: In existing technologies, vitamin C is generally considered an antioxidant stabilizer. However, this invention discovers that vitamin C, when coexisting with DTPA in air, actually promotes DTPA degradation. This phenomenon deviates significantly from conventional understanding, and no similar insights have been provided in existing literature. This invention significantly inhibits the degradation process by controlling the oxygen content in the formulation environment, particularly by using a non-oxidizing gas to replace air, without introducing additional chemical stabilizers. This demonstrates a novel formulation stabilization pathway based on gas-phase environment regulation. The method of this invention is highly safe, requires minimal process intervention, and has strong adaptability. It can be widely applied to various liquid formulation systems containing both metal chelating agents and antioxidant excipients, showing broad application prospects. Detailed Implementation

[0011] To more clearly illustrate the overall concept of this application, a detailed description is provided below in conjunction with a detailed description of the invention and embodiments. Numerous specific details are set forth in the following description to provide a more thorough understanding of the invention.

[0012] Unless otherwise specified in the examples, the conditions shall be performed according to the standard conditions or the conditions recommended by the manufacturer.

[0013] Unless otherwise specified, in the following embodiments, reagents or instruments whose manufacturers are not indicated are all conventional products that can be purchased commercially. 1. Detailed Description of the Invention In a first aspect, the present invention provides a liquid formulation for inhibiting the degradation of pentiazem, comprising a drug solution sealed within a drug container and an ambient gas above the drug solution, wherein the drug solution comprises: (1) Active pharmaceutical ingredient, (2) Pentate acid, and (3) One or more of vitamin C and its salts; The ambient gases are mainly composed of non-oxidizing gases.

[0015] The inventors discovered in their research on process impurities in pharmaceutical formulations that when vitamin C or its pharmaceutically acceptable salts coexist with DTPA in the same aqueous solution system and are exposed to air, DTPA is prone to oxidative degradation, generating new impurities and affecting the quality and storage stability of the formulation. This patent finds that by filling the pharmaceutical container with a non-oxidizing gas, the aforementioned degradation process and impurity generation can be significantly reduced, thereby improving the physicochemical stability of the liquid formulation.

[0016] In some embodiments, the drug container is a sealable container for storing or dispensing drug solutions, preferably an ampoule or vial, to ensure that the non-oxidizing environment inside the formulation remains stable.

[0017] In some embodiments, the vitamin C salt includes sodium vitamin C, calcium vitamin C, sodium ascorbate phosphate, and magnesium ascorbate phosphate; preferably sodium vitamin C.

[0018] In some embodiments, the non-oxidizing gas may include one or more of helium, neon, argon, hydrogen, nitrogen, or carbon dioxide; nitrogen is preferred considering its environmental friendliness, low cost, and easy availability.

[0019] In some implementations, the oxygen volume concentration of the ambient gas is less than 3%, which can significantly reduce the degradation rate of DTPA.

[0020] Through a series of studies, the inventors discovered that the degradation of pentilic acid occurs when it is present in the same solution system as sodium vitamin C or its salts and exposed to air. These conditions lead to the degradation of pentilic acid, and replacing the air in the liquid formulation with a non-oxidizing gas can effectively inhibit this degradation. Therefore, any pharmaceutical active ingredient suitable for combination with pentilic acid and vitamin C and its salts is applicable to the liquid formulation system for inhibiting pentilic acid degradation of this invention.

[0021] In some embodiments, the active pharmaceutical ingredient is selected from small molecule compounds, peptides, antibodies, fusion proteins, nucleic acids, radiopharmaceuticals, and drug conjugates.

[0022] In some embodiments, the conjugated drug may include antibody-drug conjugates, small molecule conjugates, radionuclide conjugates, peptide conjugates, fusion protein conjugates, and nucleic acid ligand conjugates, etc.

[0023] In some embodiments, the formulation may further comprise pharmaceutically acceptable excipients, including but not limited to one or more of pH adjusters, isotonic adjusters, solubilizers, emulsifiers, antioxidants, or adsorbents.

[0024] In a second aspect, the present invention provides a radiopharmaceutical formulation comprising a radiopharmaceutical solution sealed within a drug container and an ambient gas above the radiopharmaceutical solution, wherein the radiopharmaceutical solution comprises: (1) Target-binding ligands labeled with radionuclides, (2) Stabilizers against radiation degradation, and (3) Pentate acid; The stabilizer comprises one or more of vitamin C and its salts; The ambient gases are mainly composed of non-oxidizing gases.

[0025] Because radiopharmaceuticals are radioactive, when penteacin and vitamin C or its salts are used together as pharmaceutical excipients, the radiation generated by the radionuclide accelerates the degradation of penteacin in the penteacin and vitamin C or its salt system. The radiopharmaceutical formulation provided by this invention, by replacing the ambient gas in the formulation with a non-oxidizing gas, can effectively inhibit the degradation of penteacin in radiopharmaceutical formulations containing penteacin and vitamin C or its salts, thereby ensuring the stability of the formulation quality.

[0026] Because radiopharmaceutical preparations contain radioactive metals, their formulations often employ multiple liquid formulation systems containing metal chelating agents and antioxidant excipients. The radiopharmaceutical preparations provided by this invention are universally applicable to liquid formulation systems formed by pentimic acid and vitamin C or its salts, and have broad application prospects.

[0027] The radionuclides mentioned include, but are not limited to: 11 C 13 N、 15 O、 18 F, 32 P, 44 Sc、 47 Sc、 51 Mn, 52m Mn, 52 Fe、 62 Cu、 64 Cu、 67 Cu、 67 Ga、 68 Ga、68 Ge, 72 As, 75 Br, 76 Br, 82m Rb, 83 Sr, 86 Y, 89 Sr, 89 Zr, 90 Y, 99m Tc, 105 Rh, 110 In, 111 In, 117 mSn, 120 I, 123 I, 124 I, 125 I, 131 I, 134 Ce, 148 Gd, 149 Tb, 149 Pm, 152 Tb, 153 Sm, 154-158 Gd, 160 Gd, 161 Tb, 165 Ho, 166 Ho, 167 Tm, 175 Yb,[[ID="]]66]] 177 Lu, 186 Re, 188 Re, 197 Au, 198 Au, 199 Au, 201 Ti, 209 Bi, 211 At, 212 Pb, 212 Bi, 213 Bi, 213 Po, 223 Ra, 223 Fr, 225 Ac, 227 Th and 229 Th.

[0028] In some embodiments, the radionuclide-labeled target-binding ligands include radionuclide-labeled small molecule ligands, antibody ligands, peptide ligands, fusion protein ligands, and nucleic acid ligands capable of binding to the target. These small molecule ligands, antibody ligands, peptide ligands, fusion protein ligands, and nucleic acid ligands can specifically bind to the target. The targeting structural units of these ligands can be directly bonded to the chelating agent or bonded to the chelating agent through a linker. The radionuclide is labeled onto the chelating agent by coordinating with it. Therefore, in small molecule ligands, antibody ligands, peptide ligands, fusion protein ligands, and nucleic acid ligands, the targeting structural units in the ligands are merely for recognizing and binding the target, while the chelating agent in the ligand molecule is used to chelate with the radionuclide. The radiopharmaceutical formulation provided by this invention can effectively inhibit the decomposition of penteacin in the formulation by replacing the ambient gas in the formulation with a non-oxidizing gas. It is applicable to various types of ligands targeting different units, such as small molecule ligands, antibody ligands, peptide ligands, fusion protein ligands, and nucleic acid ligands, which are common target-binding ligands in radiopharmaceuticals.

[0029] Chelating agents in ligand molecules include, but are not limited to: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), diethylenetriaminepentaacetic acid (DTPA), N,N'-bis(2-hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED-CC), 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) or triazacyclononane phosphate (TRAP), RESCA, EDTA, NETA, CB-TE2A, Cyclen, Cyclam, Bispidine, TACN, ATSM, SarAr, AmBaSar, MAG3, MAG2, HYNIC, AAZTA, BAT, BAT-TM, Crown, Cyclen, DO2A, CB-DO2A, DO3A, DADT, EC, NS3, H2dedpa, HBED, DFO, PEPA, MACROPA, HEHA, DOTA-GA, p-BnDOTA, p-Bn-SCN-DOTA, NH2-DOTA, NH2-DOTA-GA, p-N CS-Bn-DOTA-GA, p-NH2-Bn-OxODO3A, p-SCN-Bn-oxo-DO3A, NODA-GA, NH2-NODA-GA, p-NCS-Bn-NODA-GA, p-NH2Bn-NOTA, p-SCN-Bn-NOTA, NCS-MP-N ODA, NH2-MPAA-NODA, PCTA, p-NH2-Bn-PCTA, pSCN-Bn-PCTA, p-SCN-Bn-HEHA, H2-MACROPA-NCS, H1-MACROPA, H2-MACROPA-NH2, H4OCTAPA, tetra-(S,S,S,S)-Me-DOTA, SHBED, (HBED-CC)TFP, DMSA, DMPS, DHLA, tetra-(S,S,S,S)-Et-DOTA, tetra-(S,S,S,S)-iBu-DOTA, and maleimide-nBu-DOTA and their derivatives.

[0030] In some embodiments, the non-oxidizing gas may include one or more of helium, neon, argon, hydrogen, nitrogen, or carbon dioxide; nitrogen is preferred considering its environmental friendliness, low cost, and easy availability.

[0031] In some embodiments, the radiopharmaceutical preparation contains two or more stabilizers against radiodegradation. In addition to vitamin C and its salts, the stabilizers against radiodegradation include one or more of gentian acid or its salts, histidine, cysteine ​​or its salts, methionine, selenomethionine, ethanol, and melatonin.

[0032] In some embodiments, the anti-radiation degradation stabilizer includes vitamin C or a salt thereof, and gentianic acid or a salt thereof.

[0033] In some embodiments, the radiopharmaceutical preparation further includes a buffer solution. Optionally, the buffer solution includes one or more of acetate, citrate, phosphate, and formate solutions.

[0034] In a third aspect, the present invention provides a radiopharmaceutical formulation comprising a radiopharmaceutical solution sealed within a drug container and an ambient gas above the radiopharmaceutical solution; the radiopharmaceutical solution comprising: 0.5-5.0 mg / mL sodium acetate, 0.1-2.0 mg / mL gentic acid, 10-100 mg / mL vitamin C or its salt, 0.05-2 mg / mL penteacin, 0.1-5 μg / mL radionuclide-labeled targeted PSMA ligand, and 1-35 μg / mL targeted PSMA ligand; the ambient gas is a non-oxidizing gas.

[0035] Prostate-specific membrane antigen (PSMA) is highly expressed in almost all prostate cancer cells, but its expression is extremely low in normal tissues. It exhibits strong targeting specificity and is one of the most mature targets in the field of radiopharmaceuticals. Radionuclide-labeled PSMA-targeting ligands, whether used for diagnosis or treatment, exacerbate the degradation of penteac in formulations containing penteac and vitamin C and its salts due to the radiation energy released by the radionuclide. The radiopharmaceutical formulation provided by this invention uses gentianic acid and sodium vitamin C as dual stabilizers and penteac as a metal chelating agent. By replacing the ambient gas in the formulation with a non-oxidizing gas, the degradation of penteac in the formulation can be effectively inhibited. The PSMA-targeting radiopharmaceutical formulation provided by this invention is applicable to various types of PSMA-targeting ligands labeled with radionuclides capable of releasing radiation energy.

[0036] The PSMA-targeting ligand is formed covalently from a targeting molecule, a linker, and a chelating agent capable of specifically binding to the PSMA antigen. The targeting molecule may be an antibody or a small molecule ligand.

[0037] In some embodiments, the targeted PSMA ligand is selected from PSMA-11, PSMA-617, PSMA-1007, DCFBC, DCFPyL, PSMA-101, and PSMA-102.

[0038] In some embodiments, the radionuclide-labeled targeted PSMA ligand is selected from: 18 PSMA-101 marked with F 177 Lu-marked PSMA-102 225 Ac-labeled PSMA-102 68 Ga-labeled PSMA-102. 18 The F-marked PSMA-101 can be understood as using... 18 F or 18 PSMA-101 marked with FAl.

[0039] In some embodiments, the radiopharmaceutical solution contains: 0.5-5.0 mg / mL sodium acetate, 0.02-2.0 mg / mL gentianic acid, 10-100 mg / mL sodium vitamin C, 0.05-2 mg / mL penteacin, and 0.1-5 μg / mL... 177 Lu-labeled PSMA-102, 1~35 μg / mL PSMA-102.

[0040] In some embodiments, the radiopharmaceutical solution contains: 0.5-5.0 mg / mL sodium acetate, 0.02-2.0 mg / mL gentianic acid, 10-100 mg / mL sodium vitamin C, 0.05-2 mg / mL penteacin, and 0.1-5 μg / mL... 225 Ac-labeled PSMA-102, 1~35 μg / mL PSMA-102.

[0041] In some embodiments, the non-oxidizing gas is selected from one or more of helium, neon, argon, hydrogen, nitrogen, and carbon dioxide.

[0042] In a fourth aspect, the present invention provides a method for inhibiting the degradation of pentiazem in a drug solution, wherein the drug solution is placed in a drug container, a non-oxidizing gas is introduced into the drug container, and then the container is sealed. The drug solution contains the active pharmaceutical ingredient, pentilic acid, and vitamin C or its salt.

[0043] In some embodiments, the active pharmaceutical ingredient is selected from small molecule compounds, peptides, antibodies, fusion proteins, nucleic acids, radiopharmaceuticals, and drug conjugates.

[0044] In some embodiments, the conjugated drug may include antibody-drug conjugates, small molecule conjugates, radionuclide conjugates, peptide conjugates, fusion protein conjugates, and nucleic acid ligand conjugates, etc.

[0045] In some embodiments, the radiopharmaceutical is a radionuclide-labeled targeted PSMA ligand.

[0046] In some embodiments, the PSMA ligand is selected from PSMA-11, PSMA-617, PSMA-I&T, PSMA-1007, DCFBC, DCFPyL, PSMA-101, and PSMA-102.

[0047] In some embodiments, the radionuclide-labeled targeted PSMA ligand is selected from: 18 PSMA-101 marked with F 177 Lu-marked PSMA-102 225 Ac-labeled PSMA-102 68 Ga-labeled PSMA-102. 18 The F-marked PSMA-101 can be understood as using... 18 F or 18 PSMA-101 marked with FAl.

[0048] The labeling methods for radionuclides can all refer to existing methods for labeling radionuclides and chelating agents, which are all conventional methods well known to those skilled in the art. For example, 177 The labeling method for Lu with small molecule ligands linked to DOTA is to heat at 90°C for 5–30 minutes at a pH of approximately 5–6. 68 Ga can be labeled with small molecule ligands of the chelating agents DOTA / NOTA at room temperature, pH 4.0–5.0.

[0049] The structural formulas of PSMA-101 and PSMA-102 are as follows: The preparation methods for PSMA-101 and PSMA-102 are described in patent CN112062695B.

[0050] 2. Example Example 1: Effect of different sodium vitamin C concentrations on the stability of DTPA content Experimental objective: To evaluate the effect of different concentrations of sodium vitamin C on the content change of DTPA under accelerated conditions, in order to determine the trend of the antioxidant's role in the system and the appropriate range of addition.

[0051] Preparation method: Prepare an aqueous solution of DTPA to a final concentration of 0.1 mg / mL. Add different concentrations of sodium vitamin C (20 mg / mL, 35 mg / mL, and 50 mg / mL) to this solution, and set up a blank control solution without added sodium vitamin C. Dispense the above-obtained solutions of different formulations into 10 mL pharmaceutical vials at 3 mL volumes.

[0052] Testing and analysis methods: High-performance liquid chromatography (HPLC) was used to determine the contents of sodium vitamin C and pentiformin, respectively. Sodium vitamin C was determined using a T3 column (4.6 mm × 150 mm, 3 μm) with a mobile phase of 0.1% trifluoroacetic acid aqueous solution and 0.1% trifluoroacetic acid acetonitrile, at a column temperature of 30℃, a flow rate of 1.0 mL / min, and a detection wavelength of 240 nm. The test and reference solutions were prepared by precise dilution and then directly analyzed by chromatography. Pentiformin was determined using a C18 column (4.6 mm × 150 mm, 3 μm) with a mobile phase of pH 4.5 buffer and methanol, at a column temperature of 15℃, a flow rate of 1.0 mL / min, and a detection wavelength of 320 nm. The test and reference solutions were reacted with FeCl3 solution for 20 minutes before quantitative analysis by HPLC. This method, with standard solution comparison, can accurately determine the contents of sodium vitamin C and pentiformin in the samples.

[0053] Experimental groups: Each formulation was divided into two groups: a nitrogen-filled group (high-purity nitrogen was introduced into the headspace of the container and then sealed) and a non-nitrogen-filled group (no gas replacement was performed, and the container was sealed directly).

[0054] Stability testing conditions: All samples were placed in a 40℃ stability test chamber. During storage, samples were periodically taken to determine the DTPA content to evaluate the effect of different concentrations of sodium vitamin C on the stability of DTPA in the system. The test results are shown in Table 1.

[0055] Table 1: Changes in DTPA content in different concentrations of sodium vitamin C at 40℃ The experimental results showed that DTPA aqueous solution alone remained relatively stable under accelerated conditions at 40℃, with no significant degradation observed. However, when sodium vitamin C was added to the system, the DTPA content in the untreated sample decreased significantly with storage time, exhibiting a clear degradation trend. In contrast, under the same sodium vitamin C addition conditions, the DTPA content in the nitrogen-purged sample remained stable, with almost no degradation. These results indicate that DTPA degradation does not occur spontaneously in aqueous solution, but only in the presence of sodium vitamin C and when the system is exposed to air. Given that air is mainly composed of approximately 78.1% nitrogen and 20.95% oxygen, the degradation phenomenon of DTPA essentially disappeared after replacing the headspace gas with nitrogen to reduce oxygen exposure. Therefore, it can be determined that DTPA degradation occurs only under the condition of the simultaneous presence of oxygen and sodium vitamin C, and oxygen is one of the key influencing factors in this degradation process.

[0056] Example 2: Effect of different temperature conditions on DTPA content Experimental objective: To investigate the changes in DTPA content under different concentrations of sodium vitamin C at different temperatures.

[0057] Preparation method: Prepare an aqueous solution containing DTPA and sodium vitamin C, wherein the concentration of DTPA is 0.1 mg / mL and the concentration of sodium vitamin C is 35 mg / mL. Dispense the prepared solution into 10 mL pharmaceutical vials at 3 mL volumes.

[0058] Experimental grouping: The dispensed vials were divided into the following two groups: nitrogen-filled group (high-purity nitrogen was introduced into the headspace of the container and then sealed) and non-nitrogen-filled group (no gas replacement was performed, and the vials were sealed directly).

[0059] Stability testing conditions: Both the nitrogen-filled and non-nitrogen-filled groups were subjected to stability tests at temperatures of 2–8℃, 40℃, and 60℃, respectively. Samples were taken at predetermined time points (day 0, day 2, day 3, and day 5) to determine the DTPA content. The testing and analysis methods for DTPA content were the same as in Example 1. The test results are shown in Table 2.

[0060] Table 2: Changes in DTPA content (sodium vitamin C 35 mg / mL) under different temperature conditions The experimental results showed that in DTPA aqueous solutions with added sodium vitamin C, DTPA degradation under non-nitrogen-purified conditions significantly increased with increasing temperature, with the most severe degradation occurring at 60℃. In contrast, the DTPA content in nitrogen-purified samples remained stable, and the degradation phenomenon essentially disappeared. This indicates that DTPA degradation is influenced by both atmospheric oxygen exposure and increased temperature. Replacing DTPA with a non-oxidizing gas can effectively inhibit temperature-induced degradation and improve the physicochemical stability of liquid formulations.

[0061] Example 3: Effect of dehydroascorbic acid on DTPA content Experimental objective: This example aims to evaluate the effect of dehydroascorbic acid, the main oxidation product of sodium vitamin C, on DTPA content, in order to clarify whether DTPA degradation is caused by the oxidation products of sodium vitamin C.

[0062] Preparation method: Prepare an aqueous solution containing dehydroascorbic acid and DTPA, wherein the concentration of dehydroascorbic acid is 30.8 mg / mL (equivalent to 35 mg / mL of sodium vitamin C by molar conversion), and the concentration of DTPA is 0.1 mg / mL. Dispense the prepared solution into 10 mL vials, with a volume of 3 mL, and set up nitrogen-filled and non-nitrogen-filled groups respectively.

[0063] The samples were placed in a 40℃ stability test chamber, and the DTPA content was measured at predetermined time points (0 days, 2 days, and 5 days). The test results are shown in Table 3.

[0064] Table 3: Effect of dehydroascorbic acid on DTPA content (40℃)

[0065] Experimental results showed that the DTPA content remained stable from day 0 to day 5 under both nitrogen-filled and non-nitrogen-filled conditions.

[0066] Therefore, it can be concluded that: the degradation of DTPA is not caused by dehydroascorbic acid, the oxidation product of sodium vitamin C; significant degradation of DTPA only occurs when sodium vitamin C and DTPA coexist in the presence of oxygen; DTPA itself does not chemically react with sodium vitamin C or its oxidation products in aqueous solution; and the degradation of DTPA becomes more pronounced with increasing temperature, indicating that the combined action of oxygen and sodium vitamin C is the key factor in the degradation.

[0067] This embodiment verifies the key technical principle of the present invention, namely, inhibiting the degradation of DTPA induced by sodium vitamin C through a non-oxidizing gas environment, providing experimental basis for liquid formulation stabilization strategies.

[0068] Example 4: Stability Study of Non-Radioactive Liquid Pharmaceutical Formulation Containing Vitamin C and its Salts and DTPA Experimental objective: This example aims to evaluate the stability of liquid pharmaceutical formulations containing vitamin C and its salts and DTPA under different dosages and nitrogen-filling conditions, especially to examine the change in DTPA content over time.

[0069] Preparation method: Prepare a liquid formulation containing 3.0 mg sodium acetate, 1.0 mg gentic acid, 35 mg sodium vitamin C, 0.1 mg penteacin, 5 μg Lu-175-labeled PSMA-102 (Lu-175 is non-radioactive), and 12 μg PSMA-102 per 1 mL. Specifically, mix sodium acetate, gentic acid, and PSMA-102 according to the formula, and add... 175 LuCl3 was reacted at 90℃ for 8 min, then sodium vitamin C and DTPA were added and mixed well to obtain the final product. The prepared solution was dispensed into 10 mL vials at different volumes, with separate nitrogen-filled and non-nitrogen-filled groups. Samples were stored upright at a specified temperature (40℃) and taken at predetermined time points (0, 2, 3, and 5 days) to detect their properties, sodium vitamin C (VcNa), and DTPA content.

[0070] Table 4: Stability of liquid formulations with different fill volumes and nitrogen-filled states at 40℃ Results and conclusions: 1. For liquid drug formulations of the same volume, the degradation rate of DTPA in the nitrogen-filled group was significantly lower than that in the non-nitrogen-filled group; 2. Comparison of different dosages: The degradation rate of DTPA in the high-dosage, non-nitrogen-filled group was lower than that in the low-dosage, non-nitrogen-filled group; 3. Nitrogen purging effectively mitigates DTPA degradation.

[0071] Example 5: Stability Study of a Liquid Radiopharmaceutical Formulation Containing Vitamin C, its Salts, and DTPA Experimental objective: This example aims to evaluate the stability of a radiopharmaceutical liquid formulation containing vitamin C and its salts and DTPA under different dosages, temperatures, and nitrogen-filled conditions, especially to examine the change in DTPA content over time.

[0072] Preparation method: Using Lu-177-labeled PSMA-102 as the radiopharmaceutical active ingredient, a liquid formulation containing 3.0 mg sodium acetate, 1.0 mg gentic acid, 35 mg sodium vitamin C, 0.1 mg pentilic acid, 5 μg Lu-177-labeled PSMA-102, and 12 μg PSMA-102 per 1 mL was prepared. The preparation method is the same as in Example 4. 175 LuCl3 was replaced with 177 LuCl3. After preparing the solution, it was dispensed into vials in different volumes, with separate nitrogen-filled and non-nitrogen-filled groups. The samples were stored upright at specified temperatures (40℃ and 25℃), and samples were taken at predetermined time points (0, 2, 3, and 5 days) to detect their properties, sodium vitamin C content, and DTPA content.

[0073] Table 5: Stability of liquid formulations with different fill volumes and nitrogen-filled states at 40℃

[0074] Table 6: Stability of liquid formulations with different fill sizes and nitrogen-filled states at 25℃ The experimental results showed that, at the same temperature, the degradation degree of DTPA in the system decreased significantly with the increase of the filling amount; and under the same filling amount and temperature conditions, the degradation degree of DTPA in the sample filled with non-oxidizing nitrogen was also significantly lower than that in the sample without nitrogen filling; at the same filling amount, with the increase of temperature, the degradation degree of DTPA in the non-nitrogen filling group was more severe, and the degradation degree of DTPA in the nitrogen filling group also increased, but the degradation degree of the nitrogen filling group was significantly lower than that of the non-nitrogen filling group.

[0075] Comprehensive comparison shows that increasing the filling ratio to reduce the headspace in the vial, i.e., reducing the amount of oxygen in the vial, reduces the degradation of DTPA, indicating that oxygen is the key factor leading to DTPA degradation. Replacing the air in the vial with non-oxidizing nitrogen can effectively inhibit the degradation of DTPA in radiopharmaceutical preparations containing DTPA and sodium vitamin C.

[0076] Therefore, this invention verifies that replacing the air in a radiopharmaceutical preparation with nitrogen can effectively inhibit DTPA degradation and improve the stability of the preparation, indicating that constructing a non-oxidizing gas environment is an effective means to improve the stability of DTPA-containing liquid preparations.

[0077] Furthermore, a comparison of Tables 4 and 5 reveals that the formulations in Tables 4 and 5 are identical. The difference lies in the fact that the formulation in Table 4 is non-radioactive, while the formulation in Table 5 is radioactive. Under the same temperature and dosage, the degradation of DTPA in the radiopharmaceutical formulation is extremely severe, significantly higher than that in the non-radioactive formulation. This indicates that the radiation energy of the radiopharmaceutical formulation exacerbates the degradation process of DTPA. Replacing the air in the vial with a non-oxidizing gas can effectively inhibit the degradation of DTPA.

[0078] In summary, the liquid formulation system provided by this invention, containing DTPA and vitamin C or its salts, is not only suitable for conventional liquid drug formulations, but also for high-radioactive-energy liquid drug formulations. Furthermore, the stability of DTPA can be significantly improved through a non-oxidizing gas environment, ensuring the physicochemical stability and safety of the formulation.

[0079] All content not described in detail in this specification belongs to the prior art known to those skilled in the art. The above embodiments are only used to illustrate the invention of this application and are not intended to limit the scope of protection of this application. Those skilled in the art can make various modifications, substitutions or improvements to this application without departing from the spirit and principle of the invention. Any equivalent modifications, improvements or alternatives made based on the principles described in this application should be deemed to be included within the scope of protection of the claims of this application.

Claims

1. A liquid formulation for inhibiting the degradation of pentiazem, characterized in that, The liquid formulation includes a drug solution sealed within a drug container and an ambient gas above the drug solution, wherein the drug solution comprises: (1) Active pharmaceutical ingredients, (2) Pentetracycline, and (3) One or more of vitamin C and its salts; The ambient gases are mainly composed of non-oxidizing gases.

2. The liquid formulation according to claim 1, characterized in that, The non-oxidizing gas includes one or more of helium, neon, argon, hydrogen, nitrogen, and carbon dioxide; Optionally, the non-oxidizing gas is nitrogen; Optionally, the volume concentration of oxygen in the ambient gas is less than 3%.

3. The liquid formulation according to claim 1, characterized in that, The active pharmaceutical ingredient is selected from small molecule compounds, peptides, antibodies, fusion proteins, nucleic acids, radiopharmaceuticals, and drug conjugates; Optionally, the liquid formulation may further include one or more of the following: pH adjuster, isotonic adjuster, antioxidant, emulsifier, solubilizer, and adsorbent.

4. The liquid formulation according to any one of claims 1-3, characterized in that, The liquid preparation is a radiopharmaceutical preparation, and the drug solution within the radiopharmaceutical preparation comprises: (1) Target-binding ligands labeled with radionuclides, (2) Stabilizers against radiation degradation, and (3) Pentate acid; The stabilizer contains one or more of vitamin C and its salts.

5. The liquid formulation according to claim 4, characterized in that, The anti-radiation degradation stabilizers also include one or more of gentian acid or its salts, histidine, cysteine ​​or its salts, methionine, selenomethionine, ethanol, and melatonin. Optionally, the anti-radiation degradation stabilizer includes vitamin C or a salt thereof, and gentianic acid or a salt thereof.

6. The liquid formulation according to claim 4, characterized in that, The radionuclide-labeled target-binding ligands include radionuclide-labeled small molecule ligands, antibody ligands, peptide ligands, fusion protein ligands, and nucleic acid ligands that can bind to the target.

7. The liquid formulation according to claim 4, characterized in that, The radiopharmaceutical preparation also includes a buffer solution; Optionally, the buffer solution includes one or more of acetate, citrate, phosphate, and formate solutions.

8. A radiopharmaceutical preparation, characterized in that, The radiopharmaceutical preparation includes a radiopharmaceutical solution sealed in a drug container and an ambient gas above the radiopharmaceutical solution. The radiopharmaceutical solution contains: 0.5-5.0 mg / mL sodium acetate, 0.02-2.0 mg / mL gentic acid, 10-100 mg / mL sodium vitamin C, 0.05-2 mg / mL penteacin, 0.1-5 μg / mL radionuclide-labeled targeted PSMA ligand, and 1-35 μg / mL targeted PSMA ligand; The ambient gas is a non-oxidizing gas; Optionally, the non-oxidizing gas is selected from one or more of the following: helium, neon, argon, hydrogen, nitrogen, and carbon dioxide.

9. The radiopharmaceutical preparation according to claim 8, characterized in that, The targeted PSMA ligands are selected from PSMA-11, PSMA-617, PSMA-I&T, PSMA-1007, DCFBC, DCFPyL, PSMA-101, and PSMA-102; Optionally, the radionuclide-labeled targeted PSMA ligand is selected from: 18 PSMA-101 marked with F 177 Lu-marked PSMA-102 225 Ac-labeled PSMA-102 68 Ga-labeled PSMA-102; Optionally, the radiopharmaceutical solution contains: 0.5-5.0 mg / mL sodium acetate, 0.02-2.0 mg / mL gentianic acid, 10-100 mg / mL sodium vitamin C, 0.05-2 mg / mL penteacin, and 0.1-5 μg / mL... 177 Lu-labeled PSMA-102, 1~35 μg / mL PSMA-102; Optionally, the radiopharmaceutical solution contains: 0.5-5.0 mg / mL sodium acetate, 0.02-2.0 mg / mL gentianic acid, 10-100 mg / mL sodium vitamin C, 0.05-2 mg / mL penteacin, and 0.1-5 μg / mL... 225 Ac-labeled PSMA-102, 1~35 μg / mL PSMA-102.

10. A method for inhibiting the degradation of pentilic acid in a liquid drug, said liquid drug containing a pharmaceutically active ingredient, pentilic acid, and vitamin C or a salt thereof, characterized in that, The liquid drug is placed in a drug container, a non-oxidizing gas is introduced into the drug container, and then it is sealed.

Images