Pemetrexed disodium liquid composition as well as preparation method and application thereof

Abstract

The invention discloses a pemetrexed disodium liquid composition as well as a preparation method and application thereof. The pemetrexed disodium liquid composition provided by the invention comprises a pharmaceutical active ingredient and a stabilizer, the active pharmaceutical ingredient is one or more of pemetrexed disodium, a pharmaceutically acceptable complex of the pemetrexed disodium, salt, a solvate and a hydrate; the stabilizer is one or more of an organic solvent, a pH regulator and an antioxidant. The pemetrexed disodium liquid composition disclosed by the invention has the advantages of simple preparation process, good physical and chemical stability, convenience in clinical use, no need of redissolution, low microbial pollution risk in the preparation process, suitability for industrial production and the like.

Description

[0001] This application claims the priority of the prior application with the patent application number 202210645147.0, the title of "Pemetrexed disodium liquid composition, its preparation method and application", which was filed on June 9, 2022, with the State Intellectual Property Office of China. The entire contents of the prior application are incorporated herein by reference.

[0002] This application is a divisional application of the patent application with the application number 202380012675.5, the title of "Pemetrexed disodium liquid composition, its preparation method and application", which was filed on June 9, 2023. TECHNICAL FIELD

[0003] The present application relates to a pemetrexed disodium liquid composition, its preparation method and application. BACKGROUND

[0004] Pemetrexed is a multi-target anti-metabolism antitumor drug, which is a folate antagonist. It can inhibit folate-dependent enzymes such as thymidylate synthetase, dihydrofolate reductase, and glycine ribonucleoside acetyltransferase, which are involved in the biosynthesis of thymidine and purine nucleosides, thereby achieving the effect of anti-tumor. Pemetrexed disodium was first developed by Lilly Company. It was approved for marketing by FDA in 2004, and obtained import drug permit in China in August 2005, and began to be used in clinical practice in China. The drug is used in combination with cisplatin for first-line treatment of unresectable malignant pleural mesothelioma, and as a single agent for second-line treatment of non-squamous non-small cell lung cancer.

[0005] It has been marketed in many countries and regions around the world. The drug is a lyophilized powder for injection. Before use, it needs to be reconstituted into a concentrated solution with a concentration of 25 mg / ml using 0.9% sodium chloride solution according to the drug specification, and then diluted twice for administration. The reconstitution process may cause errors in the dose of the drug administered to patients, causing safety concerns and the risk of microbial contamination.

[0006] Therefore, it is an urgent technical problem to find a pemetrexed dosage form that is convenient to use, has good physical and chemical stability, has a simple preparation process, and is suitable for industrial production. SUMMARY

[0007] The present application provides a pemetrexed disodium liquid composition, comprising: a pharmaceutical active ingredient and a stabilizer, the pharmaceutical active ingredient is selected from one or more of pemetrexed disodium, and pharmaceutically acceptable complexes, salts, solvates and hydrates of pemetrexed disodium; the stabilizer is selected from one or more of organic solvents, pH adjusters and antioxidants.

[0008] According to embodiments of the present application, the pharmaceutically active ingredient is present in an amount of 1 mg / mL to 50 mg / mL, preferably 15 mg / mL to 30 mg / mL, such as 20 mg / mL, 25.00 mg / mL, 27.57 mg / mL, 30 mg / mL, 40 mg / mL, the amount referring to the mass of the pharmaceutically active ingredient per total volume of the liquid pemetrexed disodium composition.

[0009] According to embodiments of the present application, the organic solvent is selected from one or more of ethanol, propylene glycol and polyethylene glycol. For example, the polyethylene glycol is selected from polyethylene glycol 400 (PEG 400) and / or polyethylene glycol 300 (PEG 300).

[0010] According to some embodiments of the present application, the organic solvent is present in an amount of 70 mg / mL to 300 mg / mL, such as 90 mg / mL to 260 mg / mL, exemplarily 90 mg / mL, 180 mg / mL, 260 mg / mL or 280 mg / mL, the amount referring to the mass of the organic solvent per total volume of the pemetrexed disodium pharmaceutical composition.

[0011] According to embodiments of the present application, the pH adjusting agent can be an acidic pH adjusting agent and / or a basic pH adjusting agent. For example, the acidic pH adjusting agent is preferably hydrochloric acid and / or citric acid, further preferably citric acid. For example, the basic pH adjusting agent can be one or more of sodium hydroxide, lysine, arginine, meglumine and tromethamine, preferably tromethamine. For example, the lysine can be L-lysine and / or D-lysine. For example, the arginine can be L-arginine and / or D-arginine.

[0012] According to embodiments of the present application, the antioxidant is selected from one or more of anhydrous sodium sulfite, cysteine hydrochloride, acetylcysteine and methionine, further preferably cysteine hydrochloride. The antioxidant is preferably present in an amount of 0 to 15 mg / mL, further preferably 0.1 mg / mL to 10 mg / mL, such as 0.3 mg / mL, 1 mg / mL, 1.63 mg / mL or 3 mg / mL, the amount referring to the mass of the antioxidant per total volume of the pemetrexed disodium pharmaceutical composition.

[0013] In some embodiments, the stabilizer (e.g. basic pH adjusting agent) is present in the pemetrexed disodium liquid composition in an amount of preferably 0.5 mg / mL to 50 mg / mL, further preferably 1 mg / mL to 10 mg / mL, such as 2.4 mg / mL, the amount referring to the mass of the stabilizer (e.g. basic pH adjusting agent) per total volume of the pemetrexed disodium liquid composition.

[0014] According to some embodiments of the present application, the stabilizer contains at least one or more of citric acid, tromethamine, cysteine hydrochloride, meglumine and arginine; in other embodiments, the stabilizer can further contain propylene glycol.

[0015] According to embodiments of the present application, the pH of the liquid composition of pemetrexed disodium is preferably 7.5-9.5, further preferably 8.0-9.0. According to embodiments of the present application, the liquid composition of pemetrexed disodium can further comprise an osmotic pressure regulator. The osmotic pressure regulator is preferably selected from one or more of sodium chloride, mannitol, glycerol and propylene glycol. The content of the osmotic pressure regulator is preferably 1 mg / mL-300 mg / mL, for example 1 mg / mL-100 mg / mL, further preferably 2 mg / mL-30 mg / mL, for example 5.8 mg / mL, 11 mg / mL, 15 mg / mL or 23 mg / mL, the content referring to the mass of the osmotic pressure regulator relative to the total volume of the liquid composition of pemetrexed disodium. When the liquid composition of pemetrexed disodium contains propylene glycol, the propylene glycol serves both to regulate the osmotic pressure and to enhance the stability of the liquid composition of pemetrexed disodium.

[0016] According to embodiments of the present application, the liquid composition of pemetrexed disodium further comprises water, for example water for injection, for volume adjustment. Exemplarily, water is added for volume adjustment to 1 mL.

[0017] According to embodiments of the present application, the liquid composition of pemetrexed disodium is selected from any one of the following compositions: Composition I: comprising a pharmaceutically active ingredient, which is pemetrexed disodium, a pharmaceutically acceptable complex, salt or hydrate thereof, a stabilizer selected from tromethamine and citric acid, and water; Preferably, in the composition I, the content of the pharmaceutically active ingredient is 25 mg / mL, and the content of the tromethamine is 2.4 mg / mL. Composition II: comprising a pharmaceutically active ingredient, which is pemetrexed disodium, a pharmaceutically acceptable complex, salt or hydrate thereof, a stabilizer comprising tromethamine and citric acid, further comprising anhydrous sodium sulfite, acetylcysteine, sodium thiosulfate and / or cysteine hydrochloride, and water; Preferably, in the composition two, the content of the pharmaceutically active ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL or 40 mg / mL, the content of the tromethamine is 2.4 mg / mL, the content of the anhydrous sodium sulfite is 1 mg / mL, the content of the acetylcysteine is 1.63 mg / mL, the content of the cysteine hydrochloride is 0.3 mg / mL, and the content of the sodium thiosulfate is 1 mg / mL; Composition three: comprising a pharmaceutically active ingredient, a stabilizer and water; the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex, salt or hydrate thereof; the stabilizer comprises citric acid and cysteine hydrochloride, further comprising meglumine and / or arginine; Preferably, in the composition three, the content of the pharmaceutically active ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL or 40 mg / mL, the content of the cysteine hydrochloride is 0.3 mg / mL, the content of the meglumine is 2.4 mg / mL, and the content of the arginine is 2.4 mg / mL; Composition four: comprising a pharmaceutically active ingredient, a stabilizer and water; the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex, salt or hydrate thereof; the stabilizer comprises tromethamine and citric acid, further comprising propylene glycol and / or polyethylene glycol (such as polyethylene glycol 300 or polyethylene glycol 400); Preferably, in the composition four, the content of the pharmaceutically active ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL or 40 mg / mL, the content of the tromethamine is 2.4 mg / mL, the content of the propylene glycol is 70-300 mg / mL (such as 90, 180, 260 mg / mL), and the content of the polyethylene glycol is 70-300 mg / mL (such as 90, 180, 280 mg / mL); Composition five: comprising a pharmaceutically active ingredient, a stabilizer, an osmotic pressure regulator and water; the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex, salt or hydrate thereof; the stabilizer comprises tromethamine and citric acid; the osmotic pressure regulator is selected from sodium chloride, mannitol, glycerol and / or propylene glycol; Preferably, in the composition five, the content of the pharmaceutically active ingredient is 20 mg / mL, 25 mg / mL, 27.57 mg / mL, 30 mg / mL or 40 mg / mL, the content of the tromethamine is 2.4 mg / mL, the content of the sodium chloride is 5.8 mg / mL, the content of the mannitol is 23 mg / mL, the content of the glycerol is 15 mg / mL, and the content of the propylene glycol is 11 mg / mL. The pH of any of the above compositions is 8.0-9.0.

[0018] The present application also provides a preparation method of the above liquid composition of pemetrexed disodium, which can comprise a nitrogen filling process; the nitrogen filling process can be selected from liquid nitrogen filling and / or filling nitrogen during filling, preferably liquid nitrogen filling and filling nitrogen during filling. In some embodiments, the dissolved oxygen content in the nitrogen filling into the liquid composition of pemetrexed disodium is less than 5 mg / L, preferably less than 3 mg / L; the dissolved oxygen content refers to the mass ratio of oxygen to the volume of the liquid composition of pemetrexed disodium. In some embodiments, the residual oxygen content in the headspace is less than 6%, preferably less than 4%; the residual oxygen content in the headspace refers to the volume fraction of oxygen in the mixed gas at the top of the directly contacted packaging sealed container.

[0019] According to an embodiment of the present application, the preparation method comprises non-terminal sterilization.

[0020] The present application also provides the use of the liquid composition of pemetrexed disodium in the preparation of an antitumor drug. Preferably, the antitumor drug can be a liquid drug preparation, such as an oral liquid or an injection.

[0021] The present application also provides an antitumor drug containing or prepared from the above liquid composition of pemetrexed disodium. For example, the antitumor drug can be an oral liquid or an injection.

[0022] The present application also provides a method for treating tumors, which provides a therapeutically effective amount of the liquid composition of pemetrexed disodium or the antitumor drug to a patient in need thereof.

[0023] On the basis of not violating the common sense in the art, the above preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application.

[0024] The reagents and raw materials used in the present application are commercially available.

[0025] The present application has the following beneficial effects: The liquid composition of pemetrexed disodium of the present application has the advantages of simple preparation process, good physical and chemical stability, convenient clinical use without the need for reconstitution, low risk of microbial contamination during preparation process, and suitability for industrial production.

[0026] The present application effectively overcomes the defects in the prior art, such as the need for reconstitution before use, then the need for secondary dilution for administration, complicated operation, the risk of dose difference and microbial contamination during the reconstitution process, etc. BRIEF DESCRIPTION OF DRAWINGS

[0027] Figure 1 shows the force ratio of prescription 16 and control drug in beagle dogs after intravenous injection.® Average plasma concentration-time profiles (N=6) after Average plasma concentration-time profiles after Average plasma concentration-time profiles after

[0028] Fig. 2 Trend of impurity PMQS-IM-B in accelerated test of Formulation 16 Fig. 3 Trend of impurity PMQS-IM-C in accelerated test of Formulation 16 Fig. 4 Trend of impurity PMQS-IM-F in accelerated test of Formulation 16 Fig. 5 Trend of impurity PMQS-IM-B in long-term test of Formulation 16 Fig. 6 Trend of impurity PMQS-IM-C in long-term test of Formulation 16 Fig. 7 Trend of impurity PMQS-IM-F in long-term test of Formulation 16. DETAILED DESCRIPTION

[0029] The present application is further illustrated by the following examples without thereby limiting the present application to the examples described. The experimental methods in the following examples, if not otherwise specified, are carried out according to the conventional methods and conditions, or according to the commercial instructions.

[0030] The amount of pemetrexed disodium in the formulations involved in the examples and comparative examples is based on pemetrexed disodium anhydrous.

[0031] Comparative Example 1

[0032] The drug solution was prepared according to the amount of Formulation 1, and the drug solution was pre-filtered by 0.22 µm filter cartridge. The obtained solution was filled into a cleaned and sterilized vial, and then sealed.

[0033] Example 1

[0034] The drug solution was prepared according to the amount of Formulation 2, and the drug solution was pre-filtered by 0.22 µm filter cartridge. The obtained solution was filled into a cleaned and sterilized vial, and then sealed.

[0035] Example 2 The samples obtained from Formulations 1-2 were placed in high temperature / light conditions (high temperature: 40℃±2℃ / 75%±5%RH, light: total illumination 1.2×10 5 lux hr, near ultraviolet energy 24w hr / m 2 ) System stability, test sample solution appearance, pH, related substances, data summary as follows:

[0036] Solution appearance results show that in prescription 1, the pemetrexed solution is directly filled, and the solution appearance changes under high temperature and light conditions; in prescription 2, the stabilizer - tromethamine and citric acid are added to the prescription, and the solution appearance changes only under light.

[0037] The pH results show that the pH of prescription 1 decreases under high temperature and light conditions, with a maximum decrease of 1.7; the pH of prescription 2 is stable under high temperature and light conditions.

[0038] The related substance results show that the total impurities of prescription 1 increase significantly under high temperature and light conditions; although the total impurities of prescription 2 increase, the growth trend is lower than that of prescription 1.

[0039] In summary, compared with prescription 1, prescription 2 adds a stabilizer and is filled with nitrogen, and the physical and chemical stability of the solution is significantly increased.

[0040] Example 3

[0041] According to the prescription 3-7, the drug solution is prepared, the drug solution is pre-filtered by 0.22 μm filter core, the obtained solution is filled into a cleaned and sterilized vial, then nitrogen is purged, the residual oxygen in headspace is <4%, and it is sealed.

[0042] Example 4 The samples obtained from prescription 3-5 are placed under high temperature / light conditions for investigation (high temperature: 40℃±2℃ / 75%±5%RH, light: total illumination 1.2×10 5 lux hr, near ultraviolet energy 24w hr / m 2 ) System stability, test sample solution appearance, pH, related substances, and prescription 2 for comparison, data summary as follows:

[0043] Solution appearance results show that no antioxidant is added in prescription 2, and the color of the system changes after being placed under light for a period of time; different types of antioxidants are added in prescription 3-5, and the appearance does not change after being placed under high temperature and light for 5 days and 10 days.

[0044] The pH results show that after adding different types of antioxidants, the pH value of the system is relatively stable.

[0045] The results of the related substances show that the total impurities of prescription 2 (without adding an antioxidant) remain basically unchanged under high temperature conditions; in prescriptions 3-5, the impurities of prescription 3 (the antioxidant is anhydrous sodium sulfite) and prescription 4 (the antioxidant is acetylcysteine) increase rapidly; and the single impurity of prescription 5 (the antioxidant is cysteine hydrochloride) is 0.06% or less, and the total impurities are only 0.32% or less, showing better stability.

[0046] In summary, among the prescriptions of antioxidants, cysteine hydrochloride as an antioxidant added to the pemetrexed solution has good solution stability; and at the same time, the prescription without adding an antioxidant can also ensure good stability under high temperature conditions, and the single impurity detection amount is also low.

[0047] Example 5

[0048] The pharmaceutical solution was prepared according to the amounts of prescriptions 8-9, the pharmaceutical solution was pre-filtered with a 0.22 µm filter core, the obtained solution was filled into a cleaned and sterilized vial, then nitrogen was blown, the residual oxygen in the headspace was <4%, and the vial was sealed.

[0049] Example 6 The samples obtained from prescriptions 8-9 were placed under high temperature / light conditions for investigation (high temperature: 40℃±2℃ / 75%±5%RH, light: total illumination 1.2×10 5 lux hr, near ultraviolet energy 24w hr / m 2 ) system stability, the appearance, pH, and related substances of the sample solution were detected, and prescription 5 (the pH adjuster is tromethamine) was used for comparison, and the data are as follows:

[0050] From the above results, it can be seen that by adding the pH adjusters meglumine, arginine, and tromethamine in the prescription, the appearance of the system did not change after the sample was placed under 40℃ high temperature / light conditions for 5 days and 10 days, the single impurity was 0.08% or less, and the total impurities were only 0.33% or less, indicating that meglumine, arginine, and tromethamine have a very good stabilizing effect on the pemetrexed solution, and play the role of stabilizers.

[0051] Example 7

[0052] The pharmaceutical solution was prepared according to the amounts of prescriptions 10-12, the pharmaceutical solution was pre-filtered with a 0.22 µm filter core, the obtained solution was filled into a cleaned and sterilized vial, then nitrogen was blown, the residual oxygen in the headspace was <4%, and the vial was sealed.

[0053] The samples obtained in Formulations 10-12 were placed in a high temperature condition (high temperature: 40°C ± 2°C / 75% ± 5% RH) system to investigate the stability, and the relevant substances of the sample solution were detected, and compared with Formulation 5 (pH regulator is tromethamine). The data are as follows:

[0054] From the above results, when the organic solvent propylene glycol is added to the formulation to 180 mg / ml or more, the stability is comparable to that of Formulation 5 with the addition of an antioxidant. This shows that the addition of propylene glycol to the formulation also has a stabilizing effect on the product.

[0055] Example 8

[0056] The pharmaceutical solution was prepared according to the amount of Formulations 13-15, the pharmaceutical solution was pre-filtered with a 0.22 μm filter, the obtained solution was filled into a cleaned and sterilized vial, then nitrogen was blown, the residual oxygen in the headspace was <4%, and it was sealed.

[0057] Example 9

[0058] The pharmaceutical solution was prepared according to the amount of Formulations 16-19, the pharmaceutical solution was pre-filtered with a 0.22 μm filter, the obtained solution was filled into a cleaned and sterilized vial, then nitrogen was blown, the residual oxygen in the headspace was <4%, and it was sealed.

[0059] Example 10 The samples obtained in Formulations 16-19 were placed in a high temperature condition (high temperature: 40°C ± 2°C / 75% ± 5% RH) system to investigate the stability, and the relevant substances of the sample solution were detected, and compared with Formulation 5 (pH regulator is tromethamine). The data are as follows:

[0060] From the above table, different types of osmotic pressure regulators have no obvious effect on the stability of the product.

[0061] In addition, sample solutions were prepared according to the dilution ratio during clinical use, and the osmotic pressure was detected, and the results are shown in the following table:

[0062] The results show that under the proposed clinical method, the samples prepared in this example can meet the isotonicity requirements.

[0063] Example 11 The pharmaceutical solution was prepared according to the amount of Formulation 16, and the pharmaceutical solution was filled into a colorless borosilicate glass injection vial, and nitrogen was filled into the solution to reduce the oxygen content. The oxygen content in the solution was detected, and the results are as follows:

[0064] The stability of the system, appearance, and related material data of the samples obtained after ampoule sealing were investigated under high temperature conditions (40℃±2℃ / 75%±5%RH). The data are summarized in the table below:

[0065] The results above show that reducing the dissolved oxygen content in the solution resulted in a smaller increase in total impurities in the pemetrexed disodium solution, indicating that the dissolved oxygen content has a certain impact on the stability of pemetrexed disodium. Therefore, to reduce the influence of dissolved oxygen in the water, the water for injection can be purged with high-purity nitrogen during solution preparation to replace the dissolved oxygen and reduce its impact on the pemetrexed disodium solution.

[0066] Example 12

[0067] Prepare the drug solution according to the prescription in the table above, fill the solution into colorless borosilicate glass injection bottles, and investigate the effect of nitrogen purging on stability under headspace conditions.

[0068] The stability of the prepared sample system was investigated under high-temperature conditions (40℃±2℃ / 75%±5%RH). The appearance and related substances of the sample solution were also tested. The results are shown in the table below:

[0069] The results of the solution appearance showed that the unnitrogenated sample began to change in appearance after being placed under high temperature for 10 days, changing from a colorless clear liquid to a yellow clear liquid; while after adding the headspace nitrogen filling process, the solution systems with different residual oxygen contents did not show obvious changes in appearance when placed under high temperature for different times, and remained colorless clear solutions.

[0070] Related matter analysis results showed that the headspace nitrogen-purged sample had an impurity level of 0.31% after 10 days at 40°C, which was 0.26% less than the impurity increase in the unpurged sample. Therefore, headspace nitrogen purging is necessary for the product.

[0071] Headspace nitrogen filling was investigated for prescription 5 to determine the limit of residual oxygen in the headspace.

[0072]

[0073] Prepare the drug solution according to the prescription in the table above. The solution is pre-filtered using a 0.22µm filter cartridge. The resulting solution is then filled into cleaned and sterilized vials to investigate the effect of different nitrogen filling processes on stability.

[0074] The stability of the prepared samples with different residual oxygen contents was investigated under high temperature conditions (40℃±2℃ / 75%±5%RH). The appearance and related substances of the sample solutions were also tested. The results are shown in the table below:

[0075] The total impurity of the samples with 3.9% and 1.8% residual oxygen in the headspace increased slightly, and was similar to the result at 0 day, and the difference between the two groups was not large.

[0076] In summary, the nitrogen charging process has a great influence on the stability of the system, and when the residual oxygen in the headspace is controlled below 4%, the system has good stability.

[0077] Example 13 According to the prescription 16 and the corresponding process: before liquid preparation, inject water to replace oxygen with nitrogen; the freeze dryer is vacuumed and filled with nitrogen, and the residual oxygen in the headspace is controlled within 4%. Three batches of products are produced commercially, and the codes are 1, 2 and 3 respectively. The obtained three batches of samples are placed under accelerated conditions (25℃ / 60%RH) and long-term conditions (5±3℃). The related substance test results are shown in Tables A-B and Figs. 2-7 .

[0078] Table A

[0079] From Tables A and Figs. 2-4 It can be seen that under the accelerated conditions, the stability data of 6 months is far within the limit range, which meets the standard.

[0080] Table B

[0081] From Tables B and Figs. 5-7 It can be seen that under the long-term conditions (5±3℃), the 6-month data shows that the related substance is far within the limit, and the stability is good.

[0082] From the above data, it can be seen that the liquid composition of pemetrexed disodium in the application has good stability, the preparation process is stable, and is suitable for commercial production.

[0083] Considering the general principle of keeping the injection formula as simple as possible, prescription 16 is selected for subsequent non-clinical experiment investigation.

[0084] Example 14 In this experiment, 12 Beagle dogs, half male and half female, were used, and prescription 16 and the control drug Alimta ® were respectively given intravenously according to a two-period crossover experimental design, and the dose was 25mg / kg. The sampling time points were before administration and immediately after administration (0~1min), 5min, 20min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h. The average pharmacokinetic parameters of pemetrexed in the plasma of each group of Beagle dogs are shown in Table 1, and the average drug concentration-time curve is shown in Fig. 1 .

[0085] Table 1: Beagle dogs intravenous injection of prescription 16 and control drug forces ratio of the Tai ® The average pharmacokinetic parameters after (Mean ± SD, N = 12)

[0086] The above results show that prescription 16 can achieve similar exposure to the control drug, and the key pharmacokinetic parameters are basically the same.

[0087] Example 15 The equilibrium dialysis method was used to investigate the binding rate of different concentrations of prescription 16 (according to the pharmacokinetic results of beagle dogs intravenous injection of prescription 16, combined with the preclinical test data of the reference preparation, the experimental group low, medium and high concentrations were set to 10, 100, 1000 μg / mL) with human plasma protein, and compared with the human plasma protein binding rate of the control drug force ratio of the Tai ® . At the concentrations of 10, 100, 1000 μg / mL, the prescription 16 and human plasma protein binding rate were 86.50%, 90.19% and 74.72% respectively; the control drug (force ratio of the Tai ® ) at the corresponding concentration and human plasma protein binding rate were 86.14%, 89.94% and 80.96% respectively. The detailed data of plasma protein binding rate are shown in Table 2.

[0088] Table 2: Prescription 16 and control drug at different concentrations of human plasma protein binding rate

[0089] The results show that under the conditions of this test, the prescription 16 and the control drug force ratio of the Tai ® pemetrexed disodium in 10 μg / mL, 100 μg / mL, 1000 μg / mL, the binding rate of human plasma protein is in the medium binding level (50%~90%).

[0090] Example 16 Pemetrexed disodium is a multi-target anti-metabolism antitumor drug, which is diluted with 0.9% sodium chloride injection for intravenous infusion. The hemolysis test of prescription 16 was carried out in vitro.

[0091] The test set negative control group (0.9% sodium chloride injection, tube 1), positive control group (sterile water for injection, tube 2), control drug force ratio of the Tai ®Group (injection of pemetrexed disodium, the concentration of administration is 10 mg / mL, 0.1, 0.2, 0.3, 0.4, 0.5 mL / tube, tube 3-7), prescription 16 group (the concentration of administration is 10 mg / mL, 0.1, 0.2, 0.3, 0.4, 0.5 mL / tube, tube 8-12), each group has 3 parallel tubes. 2% red blood cell suspension, 0.9% sodium chloride injection, sterile water for injection, control drug Lipotec ® , prescription 16 group is mixed according to the set proportion, and then placed in an incubator at 37±0.5℃, and observed at 0, 15, 30, 45, 60, 120, 180 minutes (±10%) respectively, and the specific results are shown in Table 3.

[0092] Table 3: In vitro hemolysis test results of different preparations

[0093] Note: 1) "-" represents "no hemolysis or aggregation", "+" represents "partial hemolysis", "++" represents "total hemolysis", and "*" represents "aggregation".

[0094] 2) Tube 1 is the negative control group, tube 2 is the positive control group, tubes 3-7 are Lipotec ® group, tubes 8-12 are prescription 16 group. The same below.

[0095] The results show that after standing at 37±0.5℃ for 180 minutes, the red blood cells in the negative control group tube all sink, the upper liquid is colorless and clear, and after appropriate shaking, the sinking red blood cells are dispersed again, and no hemolysis and aggregation are observed. The solution in the positive control group tube is clear and red, and there is no red blood cell residue at the bottom, and the total hemolysis is observed. The above results indicate that the test system is normal and reliable.

[0096] Lipotec ® group tube red blood cells all sink, the upper liquid is colorless and clear, and no hemolysis is observed, but the sinking red blood cells can still be seen to aggregate, and after shaking, they do not disperse, and the aggregated red blood cells are also not dispersed by microscopic examination, which is determined as no hemolysis but aggregation.

[0097] Prescription 16 group tube red blood cells all sink, the upper liquid is colorless and clear, and after appropriate shaking, the sinking red blood cells are dispersed again, and no abnormality is observed by microscopic examination of red blood cells, and no hemolysis and aggregation are observed.

[0098] In summary, prescription 16 group with a concentration of 10 mg / mL has no hemolysis and aggregation effect on rabbit red blood cells, and the in vitro hemolysis test result is negative.

[0099] Example 17 When this product is used clinically, it should be diluted with 0.9% sodium chloride injection and administered intravenously. An active systemic allergy test should be performed on guinea pigs for prescription 16 to observe whether allergic reactions occur after guinea pigs are given the test product, so as to provide a reference for evaluating the safety of clinical use.

[0100] This experiment consisted of six groups: a negative control group, a positive control group, low- and high-dose groups of Alimta®, and low- and high-dose groups of Formula 16. Each group contained six guinea pigs, half male and half female. During the sensitization phase, the negative control group received an intravenous injection of 0.9% sodium chloride injection at a volume of 4 mL / kg, the positive control group received an intraperitoneal injection of 8 mg / mL egg white albumin solution at a volume of 0.5 mL / pill, and the low- and high-dose groups of Alimta® and Formula 16 received an intravenous injection of 10 mg / mL Alimta® at volumes of 2 mL / kg and 4 mL / kg, respectively. ® Alternatively, prescription 16 was administered at doses of 20 mg / kg and 40 mg / kg, approximately 1.5 and 3 times the highest clinically intended dose, respectively. Day 1 of the experiment was defined as the day of the first administration. Sensitization was performed every other day for a total of three times (i.e., sensitization on days 1, 3, and 5 of the experiment). Challenge was initiated on days 14 and 21 after the last sensitization (i.e., days 19 and 26 of the experiment) via intravenous injection at twice the sensitizing dose. Systemic reactions and mortality in the guinea pigs were observed after challenge.

[0101] Table 4. Results of systemic anaphylaxis test after the first provocation

[0102] Note: *The number of animals with allergic reactions is based on the highest level of allergic reaction observed in that animal. See Appendix 5 for the same.

[0103] Table 5. Results of systemic anaphylaxis test after the last provocation

[0104] The results showed that during the sensitization period, the guinea pigs in each group were in good general condition, had normal spontaneous activity, clean skin and fur, no abnormal secretions, and normal weight gain, with no other abnormal symptoms observed.

[0105] Within 30 minutes of the first stimulation, the negative control group and Alimta... ® No allergic reactions were observed in any of the guinea pigs in the low-dose and high-dose groups, or in prescription 16. The guinea pigs in the positive control group showed allergic symptoms and all died within 7 minutes after administration, indicating a very strong positive allergic reaction.

[0106] Within 30 minutes of the last stimulation, the negative control group and Alimta... ® No allergic reactions were observed in any of the guinea pigs in the low-dose and high-dose groups, as well as in prescription 16.

[0107] In conclusion, under the conditions of this test, the results of the active systemic anaphylaxis test were negative in guinea pigs of British strain, which were injected intravenously with 10 mg / mL of Formula 16 at a volume of 2, 4 mL / kg, i.e. at a dose of 20, 40 mg / kg.

[0108] Example 18 The rabbit single intravenous injection stimulation test was performed on Formula 16 to observe the irritant reaction and the degree of reversibility of the test product on the rabbit auricular marginal vein and the surrounding tissues, thereby providing a reference for the safety of clinical use.

[0109] This test was divided into 2 groups, i.e. the Libi Tai ® group and the Formula 16 group, with 8 rabbits in each group, half male and half female. The rabbits in each group were injected with 10 mg / mL of Libi Tai ® or Formula 16 at a volume of 4 mL / kg through the right auricular marginal vein, at a dose of 40 mg / kg, which was about 3 times the highest dose to be used in the clinic. At the same time, the left auricular marginal vein was injected with the same volume of 0.9% sodium chloride injection solution as a self-control. Single administration was performed, and the rabbits were continuously observed for 21 days after administration. The day of administration was defined as the first day of the test.

[0110] During the test period, the general condition and injection site of the rabbits were observed every day. On the 3rd and 21st day after administration (i.e. the 4th and 22nd day of the test), 4 rabbits (half male and half female) in each group were euthanized for dissection, the injection site was observed macroscopically, and the tissues were subjected to pathological examination.

[0111] During the observation period after administration, no redness, congestion, necrosis or other reactions were observed at the bilateral injection sites of the rabbits in each group. The general condition of the rabbits was good, and the autonomous activities were normal. No other abnormal symptoms were observed.

[0112] On the 3rd and 21st day after administration, no macroscopically abnormal changes were found at the bilateral injection sites of the rabbits in each group.

[0113] On the 3rd day after administration, 1 injection site (1 / 8 proportion) on the control side showed mild vascular inflammation related to mechanical stimulation of the injection and puncture. Except for this, no abnormalities were observed at the remaining injection sites in each group on the 3rd and 21st day after administration.

[0114] The above results showed that, under the conditions of this test, no irritation was observed at the blood vessels and surrounding tissues of the injection site in Japanese white rabbits of large ears, which were injected with 10 mg / mL of Formula 16 at a volume of 4 mL / kg through the right auricular marginal vein, i.e. at a dose of 40 mg / kg.

[0115] In summary, the liquid composition of the present application can achieve similar exposure as the commercial control product, while having less irritation in vivo, lower adverse reactions, being safer, more convenient, improving patient compliance and the convenience of clinical medication, and having good market prospects.

[0116] While the application has been described in detail with respect to specific embodiments thereof, it will be apparent to those skilled in the art that various alterations and modifications can be made therein without departing from the spirit and scope of the application. Such alterations and modifications are intended to be included within the scope of the application as defined by the appended claims.

Claims

1. A liquid composition of pemetrexed disodium, characterized in that, The pemetrexed disodium liquid composition comprises: a pharmaceutical active ingredient and a stabilizer; The active pharmaceutical ingredient is one or more of pemetrexed disodium, and pharmaceutically acceptable complexes, salts, solvates and hydrates of pemetrexed disodium. The stabilizer is one or more of organic solvents, pH adjusters, and antioxidants; The organic solvent is one or more of ethanol, propylene glycol, and polyethylene glycol; The pH adjuster is an acidic pH adjuster and / or an alkaline pH adjuster; the acidic pH adjuster is hydrochloric acid and / or citric acid, and the alkaline pH adjuster is one or more of sodium hydroxide, lysine, arginine, meglumine, and tromethamine. The antioxidant is one or more of anhydrous sodium sulfite, cysteine ​​hydrochloride, acetylcysteine, and methionine.

2. The pemetrexed disodium liquid composition according to claim 1, characterized in that: The content of the active pharmaceutical ingredient is 1 mg / mL to 50 mg / mL, preferably 15 mg / mL to 30 mg / mL. The content refers to the ratio of the mass of the active pharmaceutical ingredient to the total volume of the pemetrexed disodium liquid composition. And / or, the active pharmaceutical ingredient is pemetrexed disodium.

3. The pemetrexed disodium liquid composition as described in claim 1 or 2, characterized in that: The stabilizer is selected from one or more of citric acid, tromethamine, cysteine ​​hydrochloride, meglumine, arginine, and propylene glycol.

4. The pemetrexed disodium liquid composition according to claim 1, characterized in that: The polyethylene glycol is polyethylene glycol 300 and / or polyethylene glycol 400; And / or, the lysine is L-lysine and / or D-lysine; And / or, the arginine is L-arginine and / or D-arginine.

5. The pemetrexed disodium liquid composition according to claim 1, characterized in that: In the pemetrexed disodium liquid composition, the content of the alkaline pH adjuster is 0.5 mg / mL to 50 mg / mL, preferably 1 mg / mL to 10 mg / mL. The content refers to the ratio of the mass of the alkaline pH adjuster to the total volume of the pemetrexed disodium liquid composition. And / or, The pH of the pemetrexed disodium liquid composition is 7.5–9.5, preferably 8.0–9.0; And / or, The antioxidant content is 0-15 mg / mL, preferably 0.1 mg / mL-10 mg / mL, and the content refers to the ratio of the mass of the antioxidant to the total volume of the pemetrexed disodium liquid composition.

6. The pemetrexed disodium liquid composition according to any one of claims 1-5, characterized in that: The pemetrexed disodium liquid composition further comprises an osmotic pressure regulator; Preferably, the osmotic pressure regulator is one or more selected from sodium chloride, mannitol, glycerol, and propylene glycol; And / or, The content of the osmotic pressure regulator is 1 mg / mL to 300 mg / mL, and the content refers to the ratio of the mass of the osmotic pressure regulator to the total volume of the pemetrexed disodium liquid composition.

7. The pemetrexed disodium liquid composition according to claim 1, characterized in that: The pemetrexed disodium liquid composition is selected from any of the following compositions: Composition 1: comprising a pharmaceutically active ingredient, a stabilizer, and water, wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate, and the stabilizer is selected from tromethorphan and citric acid; Composition 2: comprising a pharmaceutically active ingredient, a stabilizer, and water; wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate; wherein the stabilizer comprises tromethorphan and citric acid, and further comprises anhydrous sodium sulfite, acetylcysteine, sodium thiosulfate, and / or cysteine ​​hydrochloride; Composition 3: comprising a pharmaceutically active ingredient, a stabilizer, and water; wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate; wherein the stabilizer comprises citric acid and cysteine ​​hydrochloride, and further comprises meglumine and / or arginine; Composition 4: comprising a pharmaceutically active ingredient, a stabilizer, and water; wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate; wherein the stabilizer comprises tromethorphan and citric acid, and further comprises propylene glycol and / or polyethylene glycol; Composition 5: comprises a pharmaceutically active ingredient, a stabilizer, an osmotic pressure regulator, and water; wherein the pharmaceutically active ingredient is pemetrexed disodium, a pharmaceutically acceptable complex thereof, a salt, or a hydrate; wherein the stabilizer comprises tromethorphan and citric acid; and wherein the osmotic pressure regulator is selected from sodium chloride, mannitol, glycerol, and / or propylene glycol. The pH of any of the above compositions is 8.0 to 9.

0.

8. The pemetrexed disodium liquid composition according to claim 1, characterized in that: The pemetrexed disodium liquid composition is selected from any of the following formulations: Prescription 2: Pemetrexed disodium 25mg, tromethorphan 2.4mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 3: Pemetrexed disodium 25mg, tromethorphan 2.4mg, anhydrous sodium sulfite 1mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 4: Pemetrexed disodium 25mg, tromethorphan 2.4mg, acetylcysteine ​​1.63mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 5: Pemetrexed disodium 25mg, tromethorphan 2.4mg, cysteine ​​hydrochloride 0.3mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 6: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, anhydrous sodium sulfite 1mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 7: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, sodium thiosulfate 1mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 8: Pemetrexed disodium 25mg, meglumine 2.4mg, cysteine ​​hydrochloride 0.3mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 9: Pemetrexed disodium 25mg, arginine 2.4mg, cysteine ​​hydrochloride 0.3mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 10: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, propylene glycol 90mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 11: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, propylene glycol 180mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 12: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, propylene glycol 260mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 13: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, PEG400 90mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 14: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, PEG400 180mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 15: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, PEG400 280mg, water for injection 1ml, add citric acid to adjust pH to 8.0-9.0; Prescription 17: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, mannitol 23mg, water for injection 1ml, add citrate monohydrate to adjust pH to 8.0-9.0; Prescription 18: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, glycerin 15mg, water for injection 1ml, add citrate monohydrate to adjust pH to 8.0-9.0; Prescription 19: Pemetrexed disodium 27.57mg, tromethorphan 2.4mg, propylene glycol 11mg, water for injection 1ml, add citrate monohydrate to adjust pH to 8.0-9.0; Prescription 20: Pemetrexed disodium 25mg, tromethorphan 3mg, propylene glycol 35mg, cysteine ​​hydrochloride 1mg, water for injection 1ml, add citrate / sodium citrate to adjust pH to 8.0-9.

0.

9. The method for preparing the pemetrexed disodium liquid composition according to any one of claims 1 to 8, characterized in that: Includes nitrogen purging process; Preferably, the nitrogen filling process is nitrogen filling with solution and / or nitrogen filling during filling; Preferably, the nitrogen purging process is performed until the dissolved oxygen content in the pemetrexed disodium liquid composition is less than 5 mg / L and / or the headspace residual oxygen content is less than 6%; more preferably, the nitrogen purging process is performed until the dissolved oxygen content in the pemetrexed disodium liquid composition is less than 3 mg / L and / or the headspace residual oxygen content is less than 4%.

10. The use of the pemetrexed disodium liquid composition according to any one of claims 1 to 8 in the preparation of an antitumor drug; preferably, the antitumor drug is an oral solution or an injection.

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