Medicinal solution containing pemetrexed or salt thereof and preparation method thereof

Abstract

The present disclosure provides a pharmaceutical solution formulation containing pemetrexed or a salt thereof and a preparation method thereof. The solution formulation of the present disclosure has a residual oxygen content of 2.5 v / v% or less, is stable for at least 24 months, and employs a high temperature and high pressure terminal sterilization process. The pemetrexed medicine solution preparation provided by the invention has good stability, administration convenience and higher sterility guarantee level, and is easy for large-scale commercial preparation.

Description

Technical Field

[0001] The present disclosure relates to the field of pharmaceutical preparations, and in particular to a stable pharmaceutical solution preparation containing pemetrexed or a salt thereof for injection and a preparation method thereof. Background Art

[0002] Pemetrexed, chemical name: N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-alkyl)ethyl]benzoyl]-L-glutamic acid, molecular formula: C 20 H 21 N5O6, molecular weight is 427.41, its structural formula is as follows:

[0003]

[0004] Pemetrexed is a folic acid analog metabolic inhibitor that enters cells through membrane carriers and is converted into polyglutamate form by polyglutamate synthetase. It is retained in the cells and inhibits the activity of thymidylate synthase (TS) and glycinamide ribonucleotide transferase (GARFT), thereby destroying the folic acid-dependent metabolic process that is critical for tumor cell replication, thereby exerting an anti-tumor effect in non-squamous non-small cell lung cancer and mesothelioma.

[0005] There are many active groups in the pemetrexed molecule, which is easy to degrade under high temperature conditions. It is also sensitive to oxygen. It is easy to produce various impurities such as pemetrexed ketone through oxidation in the injection medium (such as water for injection), which reduces the safety of clinical medication. Pemetrexed was initially approved by the FDA for sale in the United States in the form of lyophilized powder injection, with the trade name ALIMTA, and the specifications are 100mg and 500mg. However, the lyophilized preparation needs to be re-dissolved and diluted with 0.9% sodium chloride injection before administration. The steps are cumbersome, increasing the risk of microbial contamination, and must be used within the specified time after reconstitution. In addition, during the preparation process of the lyophilized preparation, large-scale equipment is required for freeze drying, which has a long cycle, a complicated preparation process, and a high production cost. Considering the production cost and the convenience and safety of clinical administration, it is necessary to develop a stable, ready-to-use liquid preparation that can be stored for a long time.

[0006] Patent applications and products of pemetrexed solution preparations disclosed at home and abroad all ensure the stability of drugs that decompose based on oxidation mechanisms by reducing the contact between the solution and oxygen, or ensure the stability of the product by adding antioxidants; if antioxidants are not added, the residual oxygen content needs to be strictly controlled to below 0.2% v / v (CN103476397A), which puts pressure on large-scale production.

[0007] Currently available ready-to-use pemetrexed solution products cannot withstand terminal sterilization due to stability issues, and are all sterilized by sterilization filtration, which is not considered a production technology with a higher level of sterility assurance. Therefore, the storage temperature of available ready-to-use pemetrexed solution products is generally 2-8°C to ensure storage stability. For example, Eagle disclosed in CN109152778A a solution preparation with a pemetrexed dosage concentration of more than 95% that can be stored at 2-8°C for 18-24 months. Although the products marketed by Sandoz and Accord can be stored at room temperature, there are some stability issues.

[0008] Therefore, the present disclosure is intended to provide a new pemetrexed solution preparation pharmaceutical composition, the production of which is a production technology with a higher level of sterility assurance, and the samples prepared by this technology have smaller impurity changes during storage, can be stored at room temperature, and have a shelf life of up to 24 months. Summary of the invention

[0009] The present invention provides a stable pemetrexed solution preparation that can be terminally sterilized and can be stored at room temperature, which not only takes into account the convenience and safety during use, but also takes into account the simplicity of the production, storage and transportation processes.

[0010] The technical solution disclosed in the present invention is:

[0011] A drug solution containing pemetrexed, comprising: ① pemetrexed or a pharmaceutically acceptable salt thereof; ② at least one of the following antioxidants: thioglycerol, cysteine ​​hydrochloride, methionine; ③ propylene glycol or ethanol; ④ water for injection; characterized in that: the residual oxygen content in the drug solution is ≤2.5% v / v, and the drug solution is stable for at least 24 months; and the drug solution is terminally sterilized by a hot pressure sterilization process;

[0012] In one technical solution of the present disclosure, the concentration of pemetrexed or a pharmaceutically acceptable salt thereof is 20-100 mg / ml.

[0013] In a technical solution of the present disclosure, the antioxidant is thioglycerol with a concentration of 1.5-5.3 mg / ml, preferably 1.5-4.4 mg / ml.

[0014] In a technical solution of the present disclosure, the antioxidant is cysteine ​​hydrochloride with a concentration of 0.1-15 mg / ml.

[0015] In a technical solution of the present disclosure, the antioxidant is methionine with a concentration of 0.1-1.6 mg / ml.

[0016] In a technical solution of the present disclosure, the solvent is propylene glycol or ethanol, and the concentration is 20-200 mg / ml.

[0017] In a technical solution of the present disclosure, the pemetrexed drug solution further comprises a pharmaceutically acceptable pH adjuster, selected from at least one of the group consisting of hydrochloric acid, sodium hydroxide, sulfuric acid or its salts, acetic acid or its salts, phosphoric acid or its salts, citric acid or its salts, triethanolamine, tromethamine and disodium edetate, and the pH value is 6.5-10.0, preferably 7.5-9.0.

[0018] In a technical solution of the present disclosure, the method for making the residual oxygen content of the pemetrexed drug solution ≤2.5% v / v is to fill it with an inert gas or to backfill it with an inert gas after vacuuming; the inert gas is nitrogen, helium, neon, argon or carbon dioxide; the method for backfilling it with an inert gas after vacuuming can be performed by a freeze dryer that cyclically vacuums to 20-200 Tor and backfills it with an inert gas, with the number of cycles being at least 1; preferably, a freeze dryer is used to cyclically vacuumize to 30-50 Tor, with the number of cycles being at least 1.

[0019] In a technical solution of the present disclosure, the temperature range of terminal sterilization of the pemetrexed drug solution is 109-134° C.; the terminal sterilization F0 (standard sterilization time) is ≥8, preferably F0 ≥12.

[0020] In a preferred technical solution of the present disclosure, the pemetrexed drug solution is 4 ml per bottle, comprising: ① 100 mg (according to C 20 H 21 N5O6) pemetrexed disodium 2.5 hydrate; ② 17.6 mg of thioglycerol; ③ 200 mg of propylene glycol; ④ appropriate amount of hydrochloric acid and / or sodium hydroxide to adjust the pH value to 7.5-9.0; the rest is water for injection; the residual oxygen content in the drug solution is ≤2.5% v / v, and it is stable for at least 24 months; and the drug solution is terminally sterilized by hot pressure sterilization process.

[0021] The preferred technical solutions of the present disclosure are as follows:

[0022] Table 1

[0023] name Dosage per bottle Pemetrexed disodium 2.5 hydrate <![CDATA[100 mg (calculated as C 20 H 21 N5O6)]]> 20 H 21 N5O6]]> Propylene glycol 200mg Thioglycerol 17.6mg hydrochloric acid Moderate Sodium hydroxide Moderate Water for injection Up to 4ml

[0024] The residual oxygen content of the drug solution is ≤2.5% v / v and is stable for at least 24 months; and the drug solution is terminally sterilized by hot pressure sterilization process;

[0025] The preparation process of the preferred technical solution of the present invention is as follows: adding the prescribed amount of thioglycerol, propylene glycol and pemetrexed disodium 2.5 hydrate to water for injection for dissolution, adjusting the pH value to 7.5-9.0 with sodium hydroxide (NaOH) and / or hydrochloric acid (HCl) solution, making up to volume with water for injection, filtering and sterilizing with a 0.22 μm filter membrane, filling, filling with inert gas to reduce the oxygen content in the top space of the sealed container to 2.5% or less, plugging, capping, and terminal sterilization.

[0026] Technical effects of the present disclosure:

[0027] (1) The pemetrexed solution preparation disclosed herein is prepared by terminal sterilization, has a high level of sterility assurance, and can be stably stored at room temperature for at least 24 months;

[0028] (2) The process is suitable for large-scale commercial production and can reduce the risk of bacterial contamination in patients’ medication to a greater extent. DETAILED DESCRIPTION

[0029] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0030] Before describing the present disclosure below, it should be understood that the present disclosure is not limited to the specific methodology, schemes and reagents described herein, as these may vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein are subject to the same meaning as those of ordinary skill in the art described in the present disclosure.

[0031] Certain embodiments disclosed herein include numerical ranges, and certain aspects of the present disclosure may be described in a range manner. Unless otherwise stated, it should be understood that numerical ranges or the manner of range description are only for the purpose of brevity and convenience, and should not be considered as a strict limitation of the scope of the present disclosure. Therefore, the description using the range manner should be considered to specifically disclose all possible sub-ranges and all possible specific numerical points within the range, as these sub-ranges and numerical points have been clearly written in this article. For example, the description from 1 to 6 should be considered to specifically disclose sub-ranges from 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and specific numerical points within these ranges, such as 1, 2, 3, 4, 5, 6. Regardless of the width of the numerical value, the above principles are equally applicable. When using range description, the scope includes the endpoints of the scope.

[0032] The term "pharmaceutical composition" refers to a preparation or combination of preparations containing one, two or more active ingredients, which allows the active ingredients contained therein to exist in a biologically effective form and does not contain additional ingredients that are unacceptably toxic to the subject to which the preparation is administered.

[0033] Example 1 and Comparative Examples 1-3: Preparation of the disclosed prescription and the pemetrexed solution preparation already marketed abroad

[0034] Table 2 (Prescription of pemetrexed solution disclosed herein)

[0035] name Dosage per bottle Pemetrexed disodium 2.5 hydrate <![CDATA[100 mg (calculated as C 20 H 21 N5O6)]]> Propylene glycol 200mg Thioglycerol 17.6mg hydrochloric acid Moderate Sodium hydroxide Moderate Water for injection Up to 4ml

[0036] Table 3 (Prescription of Pemetrexed Solution Marketed by Hospi ra)

[0037] name Dosage per bottle Pemetrexed disodium 2.5 hydrate <![CDATA[100 mg (calculated as C 20 H 21 N5O6)]]> 20 H 21 N5O6]]> Thioglycerol 4.8mg Sodium hydroxide Moderate Water for injection Up to 4ml

[0038] Table 4 (Prescriptions of pemetrexed solution available on the market from Accord)

[0039] name Dosage per bottle Pemetrexed disodium 2.5 hydrate <![CDATA[100 mg (calculated as C 20 H 21 N5O6)]]> 20 H 21 N5O6]]> Anhydrous citric acid 60mg Methionine 2mg Thioglycerol 17.6mg hydrochloric acid Moderate Sodium hydroxide Moderate Water for injection Up to 4ml

[0040] Table 5 (Prescription of Pemetrexed Solution Marketed by Sandoz)

[0041]

[0042]

[0043] Example 1: According to Table 2, the prescribed amount of thioglycerol, propylene glycol and pemetrexed disodium 2.5 hydrate is added to water for injection and dissolved, the pH value is adjusted with NaOH and / or HCl solution, the volume is made up with water for injection, and the product is sterilized by filtration using a 0.22 μm filter membrane, filled, filled with inert gas to reduce the oxygen content in the top space of the sealed container to 2.5% or less, plugged, capped, and terminally sterilized to obtain the pemetrexed solution prescription product disclosed herein.

[0044] Comparative Example 1: According to Table 3, the prescribed amount of thioglycerol and pemetrexed disodium 2.5 hydrate were added to water for injection and dissolved, the pH value was adjusted with NaOH solution, the volume was fixed with water for injection, and the product was sterilized by filtration using a 0.22 μm filter membrane, filled, and filled with inert gas to reduce the oxygen content in the top space of the sealed container to 2.5% or less, and the container was plugged and capped to obtain the pemetrexed solution prescription product already on the market of Hospi ra.

[0045] Comparative Example 2: According to Table 4, the prescribed amount of thioglycerol, anhydrous citric acid, methionine and pemetrexed disodium 2.5 hydrate was added to water for injection and dissolved, the pH value was adjusted with NaOH and / or HCl solution, the volume was made up with water for injection, and the product was sterilized by filtration using a 0.22 μm filter membrane, filled, and filled with inert gas to reduce the oxygen content in the top space of the sealed container to 2.5% or less, and the container was plugged and capped to obtain the pemetrexed solution prescription product that has been marketed by Accord.

[0046] Comparative Example 3: According to Table 5, the prescribed amount of sodium thiosulfate pentahydrate, propylene glycol and pemetrexed disodium 2.5 hydrate was added to water for injection and dissolved, the pH value was adjusted with NaOH and / or HCl solution, the volume was made up with water for injection, and the product was sterilized by filtration using a 0.22 μm filter membrane, and then filled with inert gas to reduce the oxygen content in the top space of the sealed container to 2.5% or less. The product was plugged and capped to obtain the pemetrexed solution prescription product that Sandoz has marketed.

[0047] Comparative Example 4: Preparation of non-terminally sterilized pemetrexed solution preparation according to the present disclosure

[0048] Comparative Example 4 was prepared by the same process as Example 1, and after adding injection water to make up the volume, the container was filled and inert gas was introduced to reduce the oxygen content in the top space of the sealed container to 2.5% or less. After plugging and capping, terminal sterilization was not performed.

[0049] Except for the components and contents in the tables, the other components, contents and preparation processes of Examples 2-13 and Comparative Examples 5-14 are the same as those of Example 1.

[0050] Examples 2-4 and Comparative Example 5: Preparation of Pemetrexed Solution Preparations with Different Antioxidant Concentrations

[0051] Table 6

[0052]

[0053] According to the prescription in Table 6, pemetrexed solution preparations with different antioxidant concentrations were prepared using the same preparation process as in Example 1.

[0054] Examples 5-6 and Comparative Examples 6-8: Preparation of pemetrexed solution preparations with different residual oxygen contents

[0055] Table 7

[0056]

[0057] According to the prescription in Table 7, pemetrexed solution preparations with different residual oxygen amounts were prepared using the same preparation process as in Example 1.

[0058] Examples 7-8 and Comparative Examples 9-10: Preparation of Pemetrexed Solution Preparations with Different Antioxidant Types

[0059] Table 8

[0060]

[0061] According to the prescription in Table 8, pemetrexed solution preparations with different types and concentrations of antioxidants were prepared using the same preparation process as in Example 1.

[0062] Examples 9-12 and Comparative Examples 11-14: Preparation of Pemetrexed Solution Preparations with Different pH Values

[0063] Table 9

[0064] pH Example 9 7.5 Example 10 8.0 Embodiment 11 8.5 Example 12 9.0 Comparative Example 11 6.5 Comparative Example 12 7.0 Comparative Example 13 9.5 Comparative Example 14 10.0

[0065] According to the prescription in Table 9, pemetrexed solution preparations with different pH values ​​were prepared using the same preparation process as in Example 1.

[0066] Stability test

[0067] For the solution preparations prepared in the above Examples 1-12 and Comparative Examples 1-14, a 10-day stability test was carried out under the influencing factor conditions (60° C.), and the content of the generated impurities was analyzed by high performance liquid chromatography, and pemetrexedone ≤0.60%, impurity B ≤0.2%, impurity C ≤0.2%, the maximum single impurity ≤0.2%, and total impurities ≤1.30% were set as limit standards.

[0068] Table 10

[0069]

[0070]

[0071] The results in Table 10 show that compared with the prescription products already on the market of Hospi ra, Accord and Sandoz, the prescription product disclosed in the present invention has less color change, lower total impurities and better stability.

[0072] Table 11

[0073]

[0074] The results in Table 11 show that compared with non-terminal sterilized products, the impurities in the terminal sterilized products slightly increase, but the impurities change little during the stability test at 60°C and are consistent with the impurity levels of non-sterilized products. The sterility assurance level of the sterilized products is higher.

[0075] Table 12

[0076]

[0077]

[0078] From the results in Table 12, it can be seen that when the content of thioglycerol as an antioxidant is 1.5-4.4 mg / ml, after testing at 60°C for 10 days, both individual impurities and total impurities can be maintained at the standard level and lower, showing better stability.

[0079] Table 13

[0080]

[0081]

[0082] The results in Table 13 show that when the oxygen content in the headspace of the sealed container is 2.5% v / v or less, preferably 1.2% v / v or less, after testing at 60°C for 10 days, both individual impurities and total impurities can be maintained at or below the standard level, showing excellent stability. When the oxygen content exceeds this value, the impurity content changes significantly, approaching or exceeding the limit standard.

[0083] Table 14

[0084]

[0085]

[0086] The results in Table 14 confirm that after testing at 60°C for 10 days, when the antioxidants are cysteine ​​hydrochloride and methionine, the individual impurities and total impurities are lower, and the prepared pemetrexed solution preparation has higher stability, compared with sodium bisulfite and sodium thiosulfate.

[0087] Table 15

[0088]

[0089]

[0090] From the results in Table 15, it can be seen that after testing at 60°C for 10 days, when the product pH was 6.5-7.0 and 9.5-10.0, the total impurity level was high, when the pH was 7.5-9.0, the impurity level was low and there was no obvious difference in the stability of products with different pH values.

[0091] Therefore, for a solution preparation containing pemetrexed or its salt, when monothioglycerol, methionine or cysteine ​​hydrochloride is selected as an antioxidant and the oxygen content in the top space of the sealed container is maintained at 2.5% v / v or lower, and the preparation is terminally sterilized, a solution preparation with better stability and lower impurity content can be obtained.

[0092] The above description is only an embodiment of the present disclosure and is not intended to limit the present disclosure. For those skilled in the art, the present disclosure may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present disclosure shall be included in the protection scope of the present disclosure.

Claims

1. A drug solution containing pemetrexed, comprising: ① pemetrexed or a pharmaceutically acceptable salt thereof; ② at least one of the following antioxidants: thioglycerol, cysteine ​​hydrochloride, methionine; ③ propylene glycol or ethanol; ④ water for injection; Features: The residual oxygen content in the drug solution is ≤2.5% v / v and is stable for at least 24 months; The drug solution is terminally sterilized by hot pressure sterilization.

2. The pharmaceutical solution according to claim 1, characterized in that The concentration of pemetrexed or a pharmaceutically acceptable salt thereof is 20-100 mg / ml.

3. The pharmaceutical solution according to claim 1, characterized in that The antioxidant is monothioglycerol with a concentration of 1.5-5.3 mg / ml, preferably 1.5-4.4 mg / ml.

4. The pharmaceutical solution according to claim 1, characterized in that The antioxidant is cysteine ​​hydrochloride with a concentration of 0.1-15 mg / ml.

5. The pharmaceutical solution according to claim 1, characterized in that The antioxidant is methionine, and the concentration is 0.1-1.6 mg / ml.

6. The pharmaceutical solution according to claim 1, characterized in that The solvent is propylene glycol or ethanol, and the concentration is 20-200 mg / ml.

7. The pharmaceutical solution according to claim 1, characterized in that The invention also comprises a pharmaceutically acceptable pH adjusting agent, which is selected from at least one of the group consisting of hydrochloric acid, sodium hydroxide, sulfuric acid or its salt, acetic acid or its salt, phosphoric acid or its salt, citric acid or its salt, triethanolamine, tromethamine and disodium edetate, and the pH value is 6.5-10.0, preferably 7.5-9.

0.

8. The pharmaceutical solution according to claim 1, characterized in that The method of making the residual oxygen content ≤2.5% v / v is to fill with inert gas or to backfill with inert gas after evacuation.

9. The pharmaceutical solution according to claim 8, characterized in that The inert gas is nitrogen, helium, neon, argon or carbon dioxide.

10. The drug solution as claimed in claim 8, wherein the method of backfilling the inert gas after vacuuming is to use a freeze dryer to cyclically vacuumize to 20-200 Tor and backfill the inert gas, and the number of cycles is at least 1; preferably, the freeze dryer is cyclically vacuumized to 30-50 Tor, and the number of cycles is at least 1.

11. The pharmaceutical solution according to claim 1, characterized in that The temperature range of terminal sterilization is 109-134°C; the terminal sterilization F0 (standard sterilization time) is ≥8, preferably F0 ≥12.

12. The pharmaceutical solution according to claim 1, characterized in that Each bottle of the drug solution is 4 ml, containing: ① 100 mg (according to C 20 H 21 N5O6) pemetrexed disodium 2.5 hydrate; ② 17.6 mg of thioglycerol; ③ 200 mg of propylene glycol; ④ appropriate amount of hydrochloric acid and / or sodium hydroxide to adjust the pH value to 7.5-9.0; the rest is water for injection; the residual oxygen content in the drug solution is ≤2.5% v / v, and it is stable for at least 24 months; and the drug solution is terminally sterilized by hot pressure sterilization process.

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