Peramivir injection and preparation method thereof

Abstract

The invention relates to a peramivir injection and a preparation method thereof. The invention relates to a peramivir injection and a preparation method thereof, the peramivir injection is characterized in that every 3000 ml of the peramivir injection contains 30 g of peramivir, thiourea and cyclanic acid sodium, preferably, 3.2 g of thiourea and 2.5 g of cyclanic acid sodium are contained in every 3000 ml of the peramivir injection, and the preferable specification is 15 ml: 0.15 g. The peramivir injection prepared according to a prescription process has extremely high quality stability and is obviously superior to the prior art.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technologies, and particularly to a peramivir injection and a preparation method thereof. Background Art

[0002] Peramivir, developed by BioCryst Pharmaceuticals, Inc. of the United States, is another novel neuraminidase (NA) inhibitor anti-influenza virus drug after zanamivir and oseltamivir were successfully developed and launched in 1999, and is used for the treatment and prevention of influenza A and B in adults and children. Peramivir has currently been developed as an antiviral drug and is specifically used for influenza treatment. As a neuraminidase inhibitor, Peramivir can effectively inhibit the replication of all types of influenza viruses. Peramivir can be administered by injection and is known to have good tolerance and only cause mild side effects. Peramivir is an influenza neuraminidase inhibitor that can kill highly pathogenic H5N1 avian influenza virus and can effectively combat H5N1 avian influenza virus. Preclinical study results show that it can effectively act on a variety of influenza viruses (including H5N1 virus). It is a novel cyclopentane anti-influenza drug targeting the influenza virus surface glycoprotein neuraminidase. Laboratory tests show that Peramivir can effectively combat every known H5N1 virus and has a particularly strong killing power, and it is not easy for the virus to develop drug resistance. Since the oral utilization rate of Peramivir is relatively low, it is mainly formulated into an injection for clinical use. Chinese application CN107281096A discloses a water injection containing Peramivir and its preparation method, in which the average particle size of the pharmaceutical excipient containing nano-sized montmorillonite is 12nm - 15nm. This application adds the excipient nano-sized montmorillonite that is not commonly used in injections, and the sterilization process is sterilization at 121°C for 10 minutes, using the survivor probability method, and the sterility assurance level is not as high as the terminal sterilization process, with relatively large safety risks; Chinese application CN114177135B discloses a Peramivir pharmaceutical composition and its preparation method. The preparation method includes: S100, dissolving Peramivir in an organic solvent to obtain an oil-phase solution; S200, dissolving the excipient in water for injection to obtain an aqueous solution; S300, dropping the aqueous solution into the oil-phase solution and ultrasonic emulsifying, with a cumbersome process; Chinese application CN112245388A discloses a Peramivir sodium chloride injection and its preparation method, which consists of Peramivir and pharmaceutical excipients, wherein the pharmaceutical excipients include the osmotic pressure regulator sodium chloride and pH regulators such as hydrochloric acid or sodium hydroxide. The Peramivir injection prepared by this application can only remain relatively stable under acidic conditions and has poor stability under alkaline conditions. Chinese application CN107343878A discloses a safe and stable Peramivir lipid microsphere injection for intravenous injection and its preparation method, which consists of 1 part of Peramivir, 20 parts of ethyl oleate, 7.3 parts of polyoxyethylene castor oil, 10 parts of nicotinamide, 4.2 parts of sodium sulfite, 0.75 part of polysorbate and water for injection. This technical solution uses microsphere preparation, with a complex process and too many excipients, which limits the application of the preparation. Summary of the Invention

[0003] The object of the present invention is to provide a peramivir injection and a preparation method thereof. The injection has few excipients and a simple process. At the same time, compared with the prior art, all quality indicators are stable, the impurity content is low, and the impurities do not change before and after sterilization. It can ensure that peramivir remains stable under both acidic and strongly alkaline conditions, which is significantly superior to the prior art.

[0004] The solution adopted by the present invention to solve the above technical problems is as follows:

[0005] The peramivir injection contains 30 g of peramivir, as well as thiourea and cyclamate in every 3000 ml of the injection.

[0006] Preferably, the dosage of thiourea in every 3000 ml of the injection is 3.2 g, and the dosage of cyclamate is 2.5 g.

[0007] Preferably, the specification of the peramivir injection is 15 ml: 0.15 g.

[0008] The present invention also provides a preparation method of the above peramivir injection, which includes the following steps:

[0009] (1) Dissolve the prescribed amount of thiourea in 2000 ml of injection water at 50 °C to 56 °C, and adjust the pH with hydrochloric acid or sodium hydroxide;

[0010] (2) Keep the temperature at 50 °C to 56 °C, and successively add the prescribed amounts of cyclamate and peramivir and stir to dissolve, then add injection water to 3000 ml;

[0011] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and sterilize to obtain the peramivir injection.

[0012] Preferably, the pH is adjusted to 6.0 to 8.0 in step (1).

[0013] Preferably, the sterilization condition in step (3) is moist heat sterilization at 121 °C for 30 minutes.

[0014] The present invention uses cyclamate and thiourea as excipients for the peramivir injection. The combined use of these two excipients is beneficial to increasing the stability of the peramivir injection, achieving an unexpected effect. In particular, the best effect is achieved with a specific ratio of adding 3.2 g of thiourea and 2.5 g of cyclamate in every 3000 ml. Specific Embodiments

[0015] For a better understanding of the present invention, the following examples further illustrate the present invention, but the content of the present invention is not limited to the following examples.

[0016] Example 1

[0017] Prepare the injection according to the prescription amounts in Table 1 below by the following method:

[0018] (1) Dissolve the prescription amount of thiourea in 2000 ml of injection water at 50°C, and adjust the pH to 7.0.

[0019] (2) Keep the temperature at 50°C, and successively add the prescription amounts of sodium cyclamate and peramivir, stir to dissolve, and add injection water to 3000 ml.

[0020] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specifications, and sterilize by moist heat at 121°C for 30 minutes to obtain peramivir injection.

[0021] Table 1 Injection of Sodium Cyclamate and Thiourea with Different Prescription Amounts

[0022]

[0023] Conduct the stress testing on the above 8 prescription samples, place them under the conditions of 60°C and strong light (4500 lx ± 500 lx) for 10 days respectively, sample and test on the 10th day respectively, compare the results with those on the 0th day, and examine the stability of the samples. The results are shown in Table 2 - Table 3:

[0024] Table 2 Results of Stability Testing at 60°C

[0025]

[0026] Table 3 Results of Stability Testing under Strong Light (4500 LX)

[0027]

[0028] It can be seen from the test results in Table 2 - Table 3 that the combined use of thiourea and sodium cyclamate is beneficial to increasing the stability of peramivir injection. In particular, the specific ratio of 3.2 g of thiourea and 2.5 g of sodium cyclamate in every 3000 ml has the best effect. Even a very small change in the dosage will produce significantly different technical effects.

[0029] Compare the quality of the peramivir injection prepared from Prescription 4 before and after sterilization at 121°C for 30 minutes. The results are shown in Table 4:

[0030] Table 4 Results of Quality Testing before and after Sterilization

[0031]

[0032] It can be seen from the test results in Table 4 that the quality of the peramivir injection prepared by the combined use of thiourea and sodium cyclamate hardly changes before and after sterilization. The product quality is stable and can withstand overkill to ensure the sterility of the product.

[0033] Example 2

[0034] Preparation of Peramivir Injection (Specification: 15 ml: 0.15 g)

[0035] Prescription:

[0036] Peramivir: 30 g

[0037] Thiourea: 3.2 g

[0038] Sodium cyclamate: 2.5 g

[0039] Water for injection q.s. to 3000 ml

[0040] Manufactured into 200 vials

[0041] Process:

[0042] (1) Dissolve the prescribed amount of thiourea in 2000 ml of water for injection at 50 °C, and adjust the pH to 6.0 with hydrochloric acid or sodium hydroxide;

[0043] (2) Maintain the temperature at 50 °C, and successively add the prescribed amounts of sodium cyclamate and peramivir, stir to dissolve, and add water for injection to 3000 ml;

[0044] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and sterilize by moist heat at 121 °C for 30 minutes to obtain peramivir injection.

[0045] Example 3

[0046] Preparation of Peramivir Injection (Specification: 15 ml: 0.15 g)

[0047] Prescription:

[0048] Peramivir: 30 g

[0049] Thiourea: 3.2 g

[0050] Sodium cyclamate: 2.5 g

[0051] Water for injection q.s. to 3000 ml

[0052] Manufactured into 200 vials

[0053] Process:

[0054] (1) Dissolve the prescribed amount of thiourea in 2000 ml of water for injection at 56 °C, and adjust the pH to 8.0 with hydrochloric acid or sodium hydroxide;

[0055] (2) Maintain the temperature at 56 °C, and successively add the prescribed amounts of sodium cyclamate and peramivir, stir to dissolve, and add water for injection to 3000 ml;

[0056] (3) Measure the pH value and content of the solution, filter it with a 0.22-µm filter element, fill it into ampoules according to the specifications, and sterilize it by moist heat at 121 °C for 30 minutes to obtain peramivir injection.

[0057] Example 4

[0058] Preparation of peramivir injection (specification: 15 ml: 0.15 g)

[0059] Prescription:

[0060] Peramivir: 30 g

[0061] Thiourea: 3.2 g

[0062] Sodium cyclamate: 2.5 g

[0063] Water for injection q.s. to 3000 ml

[0064] Prepared into 200 vials

[0065] Process:

[0066] (1) Dissolve the prescribed amount of thiourea in 2000 ml of water for injection at 53 °C, and adjust the pH to 7.0 with hydrochloric acid or sodium hydroxide;

[0067] (2) Keep the temperature at 53 °C, sequentially add the prescribed amounts of sodium cyclamate and peramivir, stir to dissolve, and add water for injection to 3000 ml;

[0068] (3) Measure the pH value and content of the solution, filter it with a 0.22-µm filter element, fill it into ampoules according to the specifications, and sterilize it by moist heat at 121 °C for 30 minutes to obtain peramivir injection.

[0069] Example 5

[0070] Preparation of peramivir injection (specification: 15 ml: 0.15 g)

[0071] Prescription:

[0072] Peramivir: 30 g

[0073] Thiourea: 3.2 g

[0074] Sodium cyclamate: 2.5 g

[0075] Water for injection q.s. to 3000 ml

[0076] Prepared into 200 vials

[0077] Process:

[0078] (1) Dissolve the prescribed amount of thiourea in 2000 ml of water for injection at 56 °C, and adjust the pH to 10.0 with hydrochloric acid or sodium hydroxide;

[0079] (2) Maintain the temperature at 56 °C, and successively add the prescribed amounts of sodium cyclamate and peramivir, stir to dissolve, and add water for injection to make 3000 ml;

[0080] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and sterilize by moist heat at 121 °C for 30 minutes to obtain peramivir injection.

[0081] Example 6

[0082] Preparation of peramivir injection (Specification: 15 ml: 0.15 g)

[0083] Prescription:

[0084] Peramivir: 30 g

[0085] Thiourea: 3.2 g

[0086] Sodium cyclamate: 2.5 g

[0087] Water for injection q.s. to 3000 ml

[0088] Manufacture 200 vials

[0089] Process:

[0090] (1) Dissolve the prescribed amount of thiourea in 2000 ml of water for injection at 50 °C, and adjust the pH to 10.0 with hydrochloric acid or sodium hydroxide;

[0091] (2) Maintain the temperature at 50 °C, successively add the prescribed amounts of sodium cyclamate and peramivir, stir to dissolve, and add water for injection to make 3000 ml;

[0092] (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and sterilize by moist heat at 121 °C for 30 minutes to obtain peramivir injection.

[0093] The present invention provides the following test and comparison results:

[0094] 1. Sample 1 (peramivir injection prepared in Example 2 of the present invention);

[0095] 2. Sample 2 (peramivir injection prepared in Example 5 of the present invention);

[0096] Accelerated stability study (40 °C ± 2 °C, RH 75% ± 5%) was carried out on Samples 1 to 2 for 6 months, and the results are shown in Table 5:

[0097] Table 5 Results of accelerated test stability

[0098]

[0099] Samples 1 to 2 were subjected to long-term stability studies (25°C ± 2°C, RH 60% ± 10%), and the results are shown in Table 6:

[0100] Table 6 Long-term test stability results

[0101]

[0102] As can be seen from the results in Table 5 - Table 6, the peramivir injection prepared by the formulation and process of the present invention maintains extremely high stability, and high stability can also be maintained at a relatively high pH. The peramivir injection prepared by other embodiments of the present invention was also subjected to the same test and similar results were obtained.

[0103] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. Peramivir injection, characterized in that: In addition to 30 g of peramivir, every 3000 ml of the injection solution also contains thiourea and cyclamate sodium.

2. The peramivir injection according to claim 1, characterized in that: The dosage of thiourea in every 3000 ml of the injection solution is 3.2 g, and the dosage of cyclamate sodium is 2.5 g.

3. The peramivir injection according to claim 1, characterized in that: The specification of the peramivir injection is 15 ml: 0.15 g.

4. The preparation method of the peramivir injection according to any one of claims 1 to 3, characterized in that, It is prepared by the following method: (1) Dissolve the prescribed amount of thiourea in 2000 ml of injection water at 50 °C to 56 °C, and adjust the pH with hydrochloric acid or sodium hydroxide. (2) While maintaining the temperature at 50 °C to 56 °C, sequentially add the prescribed amounts of cyclamate sodium and peramivir and stir until dissolved, then add injection water to make up to 3000 ml. (3) Measure the pH value and content of the solution, filter with a 0.22 µm filter element, fill into ampoules according to the specification, and sterilize to obtain the peramivir injection.

5. The preparation method of peramivir injection according to claim 4, characterized in that, In step (1), adjust the pH to 6.0 to 8.

0.

6. The preparation method of the peramivir injection according to claim 4, characterized in that, The sterilization condition in step (3) is moist heat sterilization at 121 °C for 30 minutes.

Images