WO2018049997A1 - Pemetrexed disodium pharmaceutical composition and preparation method therefor - Google Patents

Abstract

A pemetrexed disodium pharmaceutical composition contains pemetrexed disodium, a stabilizer, and an excipient. The weight ratio of the pemetrexed disodium to the stabilizer is 50: 0.5-5.0, and the weight ratio of the pemetrexed disodium to the excipient is 50: 5-50. The stabilizer is selected from methionine, and the excipient is selected from mannitol.

Description

Pemetrexed disodium pharmaceutical composition and preparation method thereof Technical field

The technical field of the pharmaceutical preparation of the invention relates to a pharmaceutical composition and a preparation method thereof, in particular to a pharmaceutical composition of pemetrexed disodium and a preparation method thereof.

Background technique

Pemetrexed disodium, its chemical name is: N-[4-[2-(2-amino-4,7-dihydro-4-carbonyl-1H-pyrrole[2,3-d]-pyrimidine-5 -yl)ethyl]benzoyl]-L glutamic acid disodium salt. The molecular formula is: C20H19N5Na2O6. Pemetrexed disodium 2.5 hydrate is clinically used, and its chemical structure is:

Pemetrexed is an antifolate preparation whose structure contains a pyrrolizidine group, which inhibits cell growth by disrupting the normal metabolic process of folate-dependent cells and inhibiting cell replication. In vitro studies have shown that pemetrexed inhibits the activity of thymidylate synthase, dihydrofolate reductase, and glycinamide nucleotide formyltransferase, which are essential enzymes for the synthesis of folic acid and are involved in thymidine nucleus. Bioresynthesis of glycosides and purine nucleotides. Pemetrexed enters the cell by a carrier carrying folic acid and a folate-binding protein transport system on the cell membrane. Once pemetrexed enters the cell, it is converted to the form of polyglutamate by the action of folate polyglutamate synthetase. Polyglutamate remains in the cell and becomes an inhibitor of thymidylate synthase and glycinamide nucleotide formyltransferase. Polyglutamination exhibits a time-concentration-dependent process in tumor cells with a low concentration in normal tissues. The half-life of the polyglutamate metabolite in the tumor cells is prolonged, thereby prolonging the action time of the drug in the tumor cells.

Preclinical studies have shown that pemetrexed inhibits the growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) in vitro. A study of the mesothelioma cell line MSTO-211H showed a synergistic effect of pemetrexed in combination with cisplatin. Pemetrexed combined with cisplatin is used to treat inoperable malignant pleural mesothelioma.

It is speculated from the mechanism of action of pemetrexed that it should be a broad-spectrum anti-tumor drug. Preclinical and clinical studies have also shown that in addition to the two approved indications, pemetrexed has a certain effect on a variety of other solid tumors. Moreover, pemetrexed and more The combination of other anticancer drugs has synergistic effects and can reduce toxicity, which brings hope to some patients who suffer from drug resistance problems and have no suitable drugs available.

Pemetrexed disodium has poor stability, is prone to degradation under high temperature and oxidizing conditions, and produces impurities which may cause toxic side effects. It is not suitable for injections requiring high temperature sterilization, and thus pemetrexed disodium is usually It is made into lyophilized powder injection, but in the process of transportation and storage, the existing pemetrexed disodium lyophilized powder injection is often caused by the temperature control is not strict, resulting in a significant increase in the content of impurities in the lyophilized powder injection. There is no suggestion to improve the above deficiencies in the technical and public knowledge.

The prior art discloses various pemetrexed disodium and related formulations, such as improvements proposed from the perspective of formulation formulation and preparation methods:

CN102525955A discloses a process for preparing pemetrexed disodium for injection. The prescription is: pemetrexed disodium 200g, mannitol 200g, hydrochloric acid or sodium hydroxide and 10000mL of water for injection, the technical solution can not significantly improve the stability of the preparation.

CN102266298A discloses a pharmaceutical composition of pemetrexed disodium. Formulation: 110 parts of pemetrexed disodium, 60-105 parts of trehalose, 0-40 parts of lyophilized excipient; the excipient is selected from one or more of mannitol, sorbitol and lactose, preferably Mannitol. The technical problem solved is that pemetrexed disodium is unstable and easily degraded, and it is conventional to add an antioxidant, but the stability of the solution is difficult to meet the requirements of the preparation, and the liquid preservation solution has the problem of degradation of the active ingredient and the increase of related substances, resulting in a decrease in efficacy. And the risk of adverse reactions. Lilly has listed a lyophilized preparation, and mannitol is the only excipient with remarkable curative effect. However, infusion of lyophilized powder for injection often occurs during infusion pain, and even local inflammatory reactions occur. It is reported that clinical application of pemetrexed disodium sometimes needs to be combined with hormonal drugs or local anesthetics to reduce patients. Discomfort. Most of the local stimulating effects of the drug are due to the strong irritancy of the main drug itself, but some cases are due to the compatibility between the main and auxiliary drugs, and the latter can be solved by changing the type and proportion of the auxiliary materials. However, the amount of the auxiliary material used in the preparation is too large, which has a large influence on the main drug and is likely to cause side effects.

CN101411710A discloses a pemetrexed disodium lyophilized powder injection and a preparation method thereof. Prescription: 50 parts of pemetrexed disodium, 10 to 50 parts of mannitol, 0.1 to 1 part of sodium sulfite, pH 7-8. The technical problem solved is that the stability of pemetrexed disodium is poor, and it is easy to be degraded under high temperature, oxidation and light conditions, and impurities which may cause toxic and side effects are generated, and the stability of the lyophilized preparation is poor, and the compatibility solution cannot be used in clinical use. Leave it for a long time. However, its freeze-drying is complicated and the production cost is high, so it is not suitable for promotion.

CN102106833A discloses a pemetrexed disodium lyophilized powder injection and a preparation method thereof. Pemetrexed disodium lyophilized powder injection prescription: pemetrexed disodium: mannitol is 1:0.8 ~ 2.0. The technical problem solved is that the stability of pemetrexed disodium is poor. It is prone to degradation under high temperature and oxidizing conditions to produce impurities which may cause toxic side effects, and is not suitable for supporting injection. However, the existing pemetrexed disodium lyophilized powder needle is often used in transportation and storage process because of the temperature control is not strict. The content is significantly increased. Moreover, the prior art freeze-drying process is rough, the moisture content of the finished product is high, and the temperature rise is slow during the freeze-drying process, the energy consumption is large, and the benefit is low. The improvement effect of the solution given by the application on the above problems is not obvious.

CN1907284A discloses a pharmaceutical composition of pemetrexed disodium containing pemetrexed and a stabilizer in a weight ratio of 5:2-7, and the stabilizer is selected from the group consisting of arginine, cysteine and methionine. Or glycine or the like, further may be added with a pharmaceutically acceptable excipient such as dextran, mannitol or lecithin, and preferably the excipient is mannitol in an amount of 0.5 to pemetrexed. 1:1, preferably 0.7:1. However, the amount of amino acids used in the prior art is very large, increasing the cost of the drug and other invisible adverse factors.

Therefore, there is still a need to find an ideal pemetrexed disodium pharmaceutical composition to further obtain a composition preparation which is superior in quality, stability and manufacturing cost over the prior art.

Summary of the invention

The technical problem to be solved by the present invention is to provide a pharmaceutical composition of pemetrexed disodium having good stability, and in particular, the present invention provides a pharmaceutical composition of pemetrexed disodium, the pharmaceutical composition Containing pemetrexed disodium, a stabilizer and an excipient, wherein the weight ratio of pemetrexed disodium to the stabilizer is 50:0.5 to 5.0, and the weight ratio to the excipient is 50:5 to 50, The stabilizer is selected from the group consisting of methionine and the excipient is selected from the group consisting of mannitol.

In the pharmaceutical composition of the present invention, the pemetrexed disodium is a hydrate, preferably 2.5 hydrate.

The weight ratio of pemetrexed disodium to the stabilizer according to the present invention is

It is preferably 50: 2.0 to 3.0, further preferably 50: 2.0, 50: 2.5, and 50: 3.0.

The weight ratio of pemetrexed disodium to the excipient is from 50:20 to 40, preferably from 50:25 to 35, further preferably from 50:28, 50:30 or 50:32.

The pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention can be prepared by a lyophilization process to obtain a lyophilized powder injection. Specifically, the lyophilized powder injection is prepared by the following steps: stabilizing agent and excipient are dissolved in water for injection, adding pemetrexed disodium, stirring and dissolving, adding activated carbon to stir, filtering, and the filtrate is placed in a freeze dryer. Pre-freezing, to -30 ~ -40 ° C for 2.5 to 4 hours, preferably

maintain

In the hour, the vacuum is sublimated to obtain the powder injection.

In the preparation process of the lyophilized powder injection, the weight ratio of the water for injection to pemetrexed disodium is 0.05 to 100:1, preferably

The amount of the activated carbon is 0.05 to 1% of the water for injection, preferably

The activated carbon stirring time is 2 to 60 minutes, preferably

Minute; the pre-freezing temperature is -20 ~ -40 ° C, preferably

The vacuum sublimation time is 20 to 120 hours, preferably

hour.

The technical solution of the present invention can be carried out by measuring the pemetrexed disodium content and measuring the impurities by a known method, such as the method described in CN102206218A.

The lyophilized powder preparation provided by the invention is suitable for human clinical application and veterinary use for animals. Combined with cisplatin for the treatment of unresectable or surgically ineffective malignant pleural mesothelioma; single drug can treat locally advanced and metastatic non-small cell lung cancer after early chemotherapy.

The lyophilized preparation auxiliary material provided by the invention is easily available, does not contain other organic solvents, can be placed at room temperature, can be obtained by dilution with isotonic saline before use, and can be used for parenteral administration.

The invention achieves the requirement of pharmaceutically stable pemetrexed preparation which can be prepared for parenteral administration, has less dosage of preparation auxiliary materials, and has the advantages of stable color and long storage period, and avoids pemetrexed to the utmost extent. Degradation of adversely related substances.

detailed description

Example 1

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	280g
Methionine	18g
Water for Injection	Moderate amount

Preparation Process:

Weigh the prescribed amount of mannitol and methionine into 6000 mL of water for injection, and stir to completely dissolve it;

Add a prescribed amount of pemetrexed disodium, stir to dissolve, and make up to 10000mL with water for injection;

Weigh 8g of activated carbon, add to the above liquid, stir for 15min, filter and decarbonize, filter and sterilize through 0.22μm filter membrane;

Determine the content of the intermediate, determine the amount of loading, according to the filling amount, about 10mL per branch;

It was pre-frozen in a freeze dryer, kept at -36 ° C for 2 hours, vacuumed to sublimate water (10 Pa), taken out at 24 hours, stoppered, rolled, and obtained.

The obtained product is a white-like block with a full shape and good resolubility.

Example 2

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	280g
Methionine	20g
Water for Injection	Moderate amount

Preparation Process:

Weigh the prescribed amount of mannitol and methionine into 15000 mL of water for injection and stir to dissolve completely;

Add a prescribed amount of pemetrexed disodium, stir to dissolve, and make up to 20000mL with water for injection;

Weigh 10g of activated carbon, add to the above liquid, stir for 15min, filter and decarbonize, filter and sterilize through 0.22μm filter membrane;

Determine the content of the intermediate, determine the amount of loading, according to the filling, about 20mL each;

It was pre-frozen in a freeze dryer, kept at -32 ° C for 2.5 hours, vacuumed to sublimate moisture (vacuum degree 10 Pa), taken out at 20 hours, stoppered, rolled, and obtained.

The obtained product is a white-like block with a full shape and good resolubility.

Example 3

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	320g
Methionine	18g
Water for Injection	Moderate amount

Preparation Process:

Weigh the prescribed amount of mannitol and methionine into 12000 mL of water for injection and stir to completely dissolve it;

Add a prescribed amount of pemetrexed disodium, stir to dissolve, and make up to 15000mL with water for injection;

Weigh 12g of activated carbon, add it to the above liquid, stir for 20min, filter and decarbonize, filter and sterilize through 0.22μm filter membrane;

Determine the content of the intermediate, determine the amount of loading, according to the filling, about 15mL each;

It was pre-frozen in a freeze dryer, kept at -30 ° C for 3.5 hours, vacuumed to sublimate water (10 Pa), taken out at 26 hours, stoppered, rolled, and obtained.

The obtained product is a white-like block with a full shape and good resolubility.

Example 4

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	350g
Methionine	25g
Water for Injection	Moderate amount

Preparation Process:

Weigh the prescribed amount of mannitol and methionine into 8000 mL of water for injection and stir to completely dissolve it;

Add a prescribed amount of pemetrexed disodium, stir to dissolve, and make up to 12000mL with water for injection;

Weigh 12g of activated carbon, add it to the above liquid, stir for 20min, filter and decarbonize, filter and sterilize through 0.22μm filter membrane;

Determine the content of the intermediate, determine the amount of loading, according to the filling amount, about 10mL per branch;

It was pre-frozen in a freeze dryer, kept at -36 ° C for 2 hours, vacuumed to sublimate water (10 Pa), taken out at 24 hours, stoppered, rolled, and obtained.

The obtained product is a white-like block with a full shape and good resolubility.

Comparative example 1

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	500g
Methionine	20g
Water for Injection	Moderate amount

Preparation Process:

Weigh the prescribed amount of mannitol and methionine into 20,000 mL of water for injection and stir to dissolve completely;

Add a prescribed amount of pemetrexed disodium, stir to dissolve, and make up to 25000mL with water for injection;

Weigh 10g of activated carbon, add to the above liquid, stir for 15min, filter and decarbonize, filter and sterilize through 0.22μm filter membrane;

Determine the content of the intermediate, determine the amount of loading, according to the filling, about 25mL each;

It was pre-frozen in a freeze dryer, kept at -30 ° C for 3 hours, vacuumed to sublimate water (10 Pa), and taken out at 20 hours. Gaze, roll cover, that is.

The resulting product is light yellow with cracks.

Comparative example 2

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	400g
Low molecular dextran-40	100g or 300g
Methionine	20g
Water for Injection	Moderate amount

Preparation Process:

Weigh the prescribed amount of mannitol, low molecular weight dextran-40, methionine into 7000 mL of water for injection, and stir to completely dissolve;

Add a prescribed amount of pemetrexed disodium, stir to dissolve, and make up to 12000mL with water for injection;

Weigh 10g of activated carbon, add to the above liquid, stir for 15min, filter and decarbonize, filter and sterilize through 0.22μm filter membrane;

Determine the content of the intermediate, determine the amount of loading, according to the filling amount, about 12mL each;

It was pre-frozen in a freeze dryer, kept at -32 ° C for 3 hours, vacuumed to sublimate water (10 Pa), taken out at 20 hours, stoppered, rolled, and obtained.

The resulting product is light yellow with tiny particles on the surface.

Comparative example 3

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	600g
Methionine	20g
Water for Injection	Moderate amount

Preparation process: the same as Comparative Example 1.

The resulting product is light yellow, cracked, and sprayed.

Comparative example 4

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	800g
Methionine	25g
Water for Injection	Moderate amount

Preparation process: the same as Comparative Example 1.

The resulting product is light yellow, cracked, and sprayed.

Comparative example 5

Prescription composition:

ingredient	Feeding amount
Pemetrexed disodium 2.5 hydrate	500g (based on pemetrexed disodium)
Mannitol	200g
Methionine	18g
Water for Injection	Moderate amount

Preparation process: the same as Comparative Example 1.

The resulting product has collapse and voids.

Example 10 influencing factors

Strong light irradiation test:

The sample was taken, the label was removed, and the film was allowed to stand for 10 days under the light intensity of 4500 Lx, and samples were taken on the 5th day and the 10th day, respectively, and the appearance of the sample, the clarity of the solution, the impurities, and the content were examined.

The results are as follows:

The results show that the sample of the present invention has an impurity increase of no more than 4.1% after 10 days of intense light irradiation, and good stability results are obtained.

High temperature test:

The samples were taken and placed at 60 ° C for 10 days, and samples were taken on the 5th and 10th days respectively, and the properties of the samples, the clarity and color of the solution, the impurities, and the contents were examined.

The results are as follows:

The results show that the sample of the present invention has an impurity increase of not more than 6% after 10 days at 60 ° C, and good stability results are obtained.

Claims (10)

1. A pharmaceutical composition of pemetrexed disodium containing pemetrexed disodium, a stabilizer and an excipient, characterized in that the weight ratio of pemetrexed disodium to the stabilizer is 50:0.5 to 5.0, The weight ratio to the excipient is from 50:5 to 50, the stabilizer is selected from the group consisting of methionine, and the excipient is selected from the group consisting of mannitol.
2. The pharmaceutical composition according to claim 1, characterized in that the pemetrexed disodium is a hydrate, preferably 2.5 hydrate.
3. The pharmaceutical composition according to claim 1, wherein the weight ratio of pemetrexed disodium to the stabilizer is 50: 1.5 to 3.5, preferably 50: 2.0 to 3.0, further preferably 50: 2.0, 50: 2.5, 50. :3.0.
4. The pharmaceutical composition according to claim 1, characterized in that the weight ratio of pemetrexed disodium to the excipient is from 50:20 to 40, preferably from 50:25 to 35, further preferably from 50:28 to 50:30 or 50:32.
5. The pharmaceutical composition of claim 1 further comprising a pharmaceutically acceptable carrier.
6. A lyophilized powder injection comprising a pharmaceutical composition of pemetrexed disodium according to claims 1-5.
7. The lyophilized powder injection according to claim 6, which is prepared by the steps of: dissolving a stabilizer and an excipient in water for injection, adding pemetrexed disodium, stirring and dissolving, adding activated carbon to stir, filtering, and filtrate. Pre-freeze in a freeze dryer, hold it at -30~-40 °C for 2.5 to 4 hours, and vacuum the sublimation water to obtain the powder injection.
8. The lyophilized powder injection according to claim 7, wherein the weight ratio of the water for injection to pemetrexed disodium is from 5 to 100:1.
9. The lyophilized powder injection according to claim 7, wherein the activated carbon is used in an amount of from 0.05 to 1.0% by weight of the water for injection.
10. The freeze-dried powder injection according to claim 7-9, characterized in that the activated carbon is stirred for 2 to 60 minutes, the pre-freezing temperature is -20 to -40 ° C, and the vacuum sublimation time is 20 to 120 hours.