A kind of Favipiravir solution for atomization inhalation and preparation method thereof

Abstract

The present invention provides a kind of favipiravir solution for atomized inhalation, preparation method and application. The inhalation solution contains 1-50mg / ml favipiravir, excipients and solvent in a single dose, and the pH value is 5.5-9.0, and the inhalation solution single dose specification is 2-5ml. The excipients include a cosolvent, a pH regulator and an osmotic pressure regulator. The cosolvent is selected from meglumine, and the mass ratio of favipiravir to meglumine is 1:1.25-1:1.34, and the pH regulator can be selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, and one or more of potassium dihydrogen phosphate, the osmotic pressure regulator is selected from sodium chloride, and the solvent is selected from sterile water for injection. The solution of favipiravir can be used in combination with a liquid atomizer to provide a convenient, safe, effective and stable pharmaceutical dosage form and drug delivery system of favipiravir.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a favipiravir solution for atomized inhalation and a preparation method thereof. Background Art

[0002] In 1999, favipiravir was first reported. Its chemical name is 6-fluoro-3-hydroxypyrazine-2-carboxamide, which is a nucleoside analog drug. In March 2014, favipiravir was approved for marketing in Japan as a new broad-spectrum anti-RNA virus drug for the antiviral treatment of influenza A and B.

[0003] Favipiravir has a good inhibitory effect both in vitro and in vivo on members of virulent RNA virus families such as Filoviridae, Bunyaviridae, Arenaviridae, and Togaviridae, as well as members of other RNA virus families such as Orthomyxoviridae, Paramyxoviridae, Picornaviridae, and Flaviviridae. After entering the cell, Favipiravir can be converted into a triphosphate active form, which is incorporated into the RNA chain during the transcription and replication of viral RNA, non-specifically terminating the extension of the viral RNA chain, thereby achieving an antiviral effect.

[0004] Among the Favipiravir preparations disclosed in the prior art, except for tablets which are clinically used, other dosage forms, such as lyophilized preparations for injection, inhalation sprays and injection solutions, have not entered the clinical application stage.

[0005] Chinese patent CN111297838A discloses a spray for inhalation. It records a single preparation of favipiravir or a compound preparation of favipiravir with erythromycin, azithromycin, etc., and selects 82%-91% propylene glycol as a solvent, and mint essence and xylitol as flavoring agents. According to the excipient manual, the amount of propylene glycol in general dosage forms does not exceed 30%, injections generally do not exceed 60%, and even topical dosage forms should not exceed 80%. According to the metabolic and toxicity test data, the WTO sets the daily intake at 25 mg per kilogram of body weight, and a prescription containing 35% propylene glycol can cause hemolysis. According to the prescription disclosed in the above patent, it contains a high concentration of propylene glycol, and the risk of toxic and side effects is very high, and it has no clinical application value so far. And through experimental observation, it was found that when the prescription contains 5% propylene glycol, it is impossible to achieve an effective atomized particle size, it is impossible to atomize and inhale, and the stability is extremely poor, so the above spray and its prescription are not suitable for atomization and inhalation administration.

[0006] In view of the sublimation, poor solubility and photo-oxidation instability of Favipiravir, Chinese patents CN111228226A and CN103209967A each disclose a freeze-dried preparation for injection to overcome the above problems. CN111228226A uses Favipiravir as the active ingredient, sodium hydroxide as the pH regulator, mannitol as the excipient, and tert-butyl alcohol as the freeze-drying additive. Among them, tert-butyl alcohol has slight toxicity, anesthetic and mucosal irritation, and is flammable when mixed with air. Its vapor and air can form an explosive mixture, which can cause combustion and explosion when exposed to high heat. The patent prescription contains 3%-30% tert-butyl alcohol. The tolerability, safety and strict requirements for the preparation process of the drug have brought very large technical obstacles to the practical application of the drug. CN103209967A discloses a crystalline Favipiravir meglumine salt, which is prepared by reaction, crystallization, and reduced pressure drying with Favipiravir and meglumine as raw materials under the action of 2-propanol, and can be used for injection after packaging; Patent Example 5 also discloses that Favipiravir and meglumine are dissolved in water and then freeze-dried for 109 hours to obtain amorphous Favipiravir meglumine salt for injection. The common features of the above two patents are that they are to solve the solubility and stability problems of Favipiravir, and both adopt lyophilized dosage forms. The preparation process is cumbersome and time-consuming, and the injection needs to be injected by skilled people according to the doctor's advice to ensure safety. Generally, patients cannot use it by themselves, and the injection method can cause pain.

[0007] In summary, the favipiravir preparations disclosed in the prior art have various defects to varying degrees and are not suitable for inhalation administration. Therefore, in order to meet the market demand for safe, convenient and effective medication, it is an urgent problem to be solved in the application of this drug preparation to develop a new safe, effective and quality-stable new dosage form of favipiravir. Summary of the invention

[0008] The present invention aims to solve the deficiencies in the above-mentioned related technologies to a certain extent, and provides the following technical solutions:

[0009] In a first aspect, the present invention provides a favipiravir solution for nebulized inhalation, wherein the solution comprises favipiravir, excipients and a solvent.

[0010] The single-dose inhalation solution contains 1-50 mg / ml Favipiravir, more preferably 5-40 mg / ml Favipiravir.

[0011] The single dose specification of the inhalation solution is 2-5 ml, preferably, the single dose specification is 5 ml.

[0012] The auxiliary materials include a cosolvent, a pH regulator, and an osmotic pressure regulator.

[0013] The solvent is selected from water for sterile injection.

[0014] The co-solvent is selected from meglumine, and its content is 1.25-62.5 mg / ml.

[0015] The pH regulator can be selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and sodium citrate, and the amount thereof is such that the pH value of the inhalation solution is 5.5-9.0.

[0016] The osmotic pressure regulator is selected from sodium chloride and glucose, and its dosage is such that the molar osmotic pressure of the inhalation solution is 270-330 mOsmol / kg.

[0017] The mass ratio of favipiravir to meglumine in the inhalation solution is 1:1.25-1:1.34.

[0018] In a second aspect, the present invention provides a method for preparing a favipiravir solution for aerosol inhalation, comprising the following steps:

[0019] (1) Add 80% of the total amount of solvent required to prepare the solution into the dispensing device, then introduce nitrogen to deoxygenate and avoid light throughout the process, add the prescribed amount of Favipiravir, and stir until it is fully dispersed in the solution.

[0020] (2) Gradually add meglumine and stir until it is fully dissolved; then add osmotic pressure regulator and stir until it is fully dispersed.

[0021] (3) Use a pH adjuster to adjust the pH of the solution to 5.5-9.0, add solvent to make up to the total volume of the prescription, and stir to mix evenly.

[0022] (4) Use a 0.45 μm filter membrane for primary filtration and a 0.22 μm filter membrane for fine filtration. After sterile filtration, the product is divided and filled.

[0023] The third aspect: The present invention provides a favipiravir solution nebulization inhalation system, comprising 1ml-5ml of the favipiravir solution for inhalation as described in the first aspect of the present invention and a liquid nebulizer. After the favipiravir solution for inhalation is atomized, its aerodynamic mass diameter is 2-5μm, and the percentage of fine particles is 30%-70%.

[0024] The administration time of the inhaled favipiravir solution after atomization using a liquid nebulizer is 10-30 minutes.

[0025] The beneficial effects of the present invention are:

[0026] 1. The favipiravir solution for aerosol inhalation provided by the present invention solves the solubility and stability problems of the favipiravir solution, has a simple process, good reproducibility, and is easy for large-scale industrial production.

[0027] 2. The favipiravir solution atomization inhalation system of the present invention provides a new type of safe and effective drug preparation and drug delivery system for infants and children who are unable to inhale autonomously and patients with active breathing difficulties.

[0028] 3. The preparation method of the present invention adopts a filtration sterilization process, which not only ensures the sterility level of the product, but also further improves the stability of the preparation and has reliable quality. DETAILED DESCRIPTION

[0029] In order to better illustrate the present invention, numerous specific details are given in the following specific embodiments. It should be understood by those skilled in the art that the present invention can also be implemented without certain specific details.

[0030] Example 1 200 vials of Favipiravir solution for aerosol inhalation

[0031] Prescription composition:

[0032] name Dosage Favipiravir 1g Meglumine 1.25g 1mol / L sodium citrate Moderate Sodium chloride 3.6g Add water for injection to 400ml

[0033] Preparation process:

[0034] Add solvent to the dispenser, then pass nitrogen gas throughout the process to deoxygenate and avoid light, add the prescribed amount of favipiravir, stir until it is fully dispersed in the solution, add sodium chloride, and stir until it is fully dispersed and dissolved. Add meglumine gradually, stir until it is fully dissolved, adjust the pH to 7.5 with 1 mol / L sodium citrate, add solvent to the total volume of the prescription, and stir to mix it evenly. Use a 0.45 μm filter membrane for primary filtration, a 0.22 μm filter membrane for fine filtration, and after sterile filtration, fill it.

[0035] Example 2: 200 vials of Favipiravir solution for aerosol inhalation

[0036] Prescription composition:

[0037] name Dosage Favipiravir 0.4g Meglumine 0.5g 1mol / L sodium citrate Moderate Sodium chloride 3.6g Add water for injection to 400ml

[0038] Preparation process:

[0039] Add solvent to the dispenser, then pass nitrogen gas throughout the process to deoxygenate and avoid light, add the prescribed amount of favipiravir, stir until it is fully dispersed in the solution, add sodium chloride, and stir until it is fully dispersed and dissolved. Add meglumine gradually, stir until it is fully dissolved, and adjust the pH to 5.5 with 1 mol / L sodium citrate, add solvent to the total volume of the prescription, and stir to mix it evenly. Use a 0.45 μm filter membrane for primary filtration, a 0.22 μm filter membrane for fine filtration, and after sterile filtration, fill it.

[0040] Example 3: 200 vials of Favipiravir solution for aerosol inhalation

[0041] Prescription composition:

[0042] name Dosage Favipiravir 5g Meglumine 6.45g 1mol / L disodium hydrogen phosphate Moderate glucose 44g Add water for injection to 1000ml

[0043] Preparation process:

[0044] Add solvent to the dispenser, then pass nitrogen gas throughout the process to deoxygenate and avoid light, add the prescribed amount of favipiravir, stir until it is fully dispersed in the solution, add glucose, and stir until it is fully dispersed and dissolved. Add meglumine gradually, stir until it is fully dissolved, and adjust the pH to 8.0 with 1 mol / L disodium hydrogen phosphate, add solvent to the total volume of the prescription, and stir to mix it evenly. Use a 0.45μm filter membrane for primary filtration, a 0.22μm filter membrane for fine filtration, and after sterile filtration, fill it.

[0045] Example 4: 200 vials of Favipiravir solution for aerosol inhalation

[0046] Prescription composition:

[0047] name Dosage Favipiravir 6g Meglumine 7.5g 1mol / L potassium dihydrogen phosphate Moderate Sodium chloride 3.9g Add water for injection to 600ml

[0048] Preparation process:

[0049] Add solvent to the dispenser, then pass nitrogen gas throughout the process to deoxygenate and avoid light, add the prescribed amount of favipiravir, stir until it is fully dispersed in the solution, add sodium chloride, and stir until it is fully dispersed and dissolved. Add meglumine gradually, stir until it is fully dissolved, and adjust the pH to 8.5 with 1 mol / L potassium dihydrogen phosphate, add solvent to the total volume of the prescription, and stir to mix it evenly. Use a 0.45μm filter membrane for primary filtration, a 0.22μm filter membrane for fine filtration, and after sterile filtration, fill it.

[0050] Example 5: 200 vials of Favipiravir solution for aerosol inhalation

[0051] Prescription composition:

[0052] name Dosage Favipiravir 20g Meglumine 25.8g 1mol / L potassium dihydrogen phosphate Moderate Sodium chloride 2g Add water for injection to 1000ml

[0053] Preparation process:

[0054] Add solvent to the dispenser, then pass nitrogen gas throughout the process to deoxygenate and avoid light, add the prescribed amount of favipiravir, stir until it is fully dispersed in the solution, add sodium chloride, and stir until it is fully dispersed and dissolved. Add meglumine gradually, stir until it is fully dissolved, and adjust the pH to 9.0 with 1 mol / L potassium dihydrogen phosphate, add solvent to the total volume of the prescription, and stir to mix it evenly. Use a 0.45μm filter membrane for primary filtration, a 0.22μm filter membrane for fine filtration, and after sterile filtration, fill it.

[0055] Example 6: 200 vials of Favipiravir solution for aerosol inhalation

[0056] Prescription composition:

[0057] name Dosage Favipiravir 40g Meglumine 50g 1mol / L sodium dihydrogen phosphate Moderate Add water for injection to 1000ml

[0058] Preparation process:

[0059] Add solvent to the dispenser, then pass nitrogen gas throughout the process to deoxygenate and avoid light, add the prescribed amount of favipiravir, and stir until it is fully dispersed in the solution. Add meglumine gradually, stir until it is fully dissolved, and adjust the pH to 8.0 with 1 mol / L sodium dihydrogen phosphate, add solvent to the total volume of the prescription, and stir to mix it evenly. Use a 0.45μm filter membrane for primary filtration, a 0.22μm filter membrane for fine filtration, and after sterile filtration, fill it.

[0060] Example 7 200 vials of Favipiravir solution for aerosol inhalation

[0061] Prescription composition:

[0062] name Dosage Favipiravir 50g Meglumine 65g 1mol / L sodium citrate Moderate Add water for injection to 1000ml

[0063] Preparation process:

[0064] Add solvent to the dispenser, then pass nitrogen gas throughout the process to deoxygenate and avoid light, add the prescribed amount of favipiravir, and stir until it is fully dispersed in the solution. Add meglumine gradually, stir until it is fully dissolved, and adjust the pH to 7.5 with 1 mol / L sodium citrate, add solvent to the total volume of the prescription, and stir to mix it evenly. Use a 0.45 μm filter membrane for primary filtration, a 0.22 μm filter membrane for fine filtration, and after sterile filtration, fill it.

[0065] Example 8 200 vials of Favipiravir solution for aerosol inhalation

[0066] Prescription composition:

[0067] name Dosage Favipiravir 30g Meglumine 40.2g 1mol / L disodium hydrogen phosphate Moderate Add water for injection to 1000ml

[0068] Preparation process:

[0069] Add solvent to the dispenser, then pass nitrogen to deoxygenate and avoid light throughout the process, add the prescribed amount of favipiravir, and stir until it is fully dispersed in the solution. Add meglumine gradually, stir until it is fully dissolved, adjust the pH to 8.0 with disodium hydrogen phosphate, add solvent to the total volume of the prescription, and stir to mix it evenly. Use a 0.45μm filter membrane for primary filtration, a 0.22μm filter membrane for fine filtration, and after sterile filtration, fill it.

[0070] Example 9: Samples were prepared based on the formula of Example 4, the dosage of 1 mol / L dipotassium hydrogen phosphate solution was adjusted, and the stability of the preparation under different pH conditions was investigated. The results are shown in Tables 1 and 2.

[0071] Table 1 Results of the factors affecting pH value screening test after refrigeration for 0 days

[0072]

[0073]

[0074] Table 2 pH value screening test refrigeration 10 days influence factor determination results

[0075]

[0076] Comparing the results in Tables 1 and 2, it can be seen that after adjusting the pH value of the favipiravir solution with 1 mol / L potassium dihydrogen phosphate solution as a pH regulator and storing it in a refrigerator for 10 days, the solution properties, favipiravir content and total impurity content were comprehensively investigated. When the pH value was lower than 5.5 or higher than 9.0, the solution properties changed, with precipitation, a faster decrease in favipiravir content and a faster increase in impurities. The results show that when the solution pH is 5.5-9.0, the stability is better.

[0077] Example 10: Investigation of the dosage of meglumine

[0078] The samples were prepared based on the prescription of Example 4, the dosage of meglumine was adjusted, and the solubility and stability of the favipiravir solution at different mass ratios of favipiravir and meglumine were investigated. The results are shown in Tables 3 and 4.

[0079] Table 3 Solubility and stability of samples with different meglumine dosages at 0 days

[0080]

[0081] Table 4 Solubility and stability test results of samples with different meglumine dosages refrigerated for 10 days

[0082]

[0083] Comparing the measurement results in Tables 3 and 4, it can be seen that when the mass ratio of favipiravir to meglumine is 1:1.18, the sample solution has precipitation after refrigerated storage for 10 days. When the mass ratio of favipiravir to meglumine is 1:1.37, the properties of the sample solution change greatly and become dark yellow. When the mass ratio of favipiravir to meglumine is 1:1.25-1.34, the solubility of the solution and the stability after refrigerated storage for 10 days are good.

[0084] Example 11: Stability Study

[0085] The stability of the favipiravir solutions for nebulized inhalation prepared according to Examples 1-8 of the present application was tested. The results are shown in Tables 5 and 6.

[0086] Table 5 Stability 0-day test results of Examples 1-8

[0087]

[0088] Table 6 Stability test results of Examples 1-8 refrigerated for 10 days

[0089]

[0090] Comparing the measurement results in Tables 5 and 6, it can be seen that after the solutions prepared in Examples 1-8 of the present application were refrigerated and stored for 10 days, the solution properties, pH, content, and related substances did not change significantly, that is, the solution preparations of the present application had good stability.

[0091] Example 12: Aerodynamic atomization particle size determination

[0092] The atomized particle size of the samples in Examples 1-8 was measured using a Synpatek particle size analyzer. The measurement results are shown in Table 7:

[0093] Table 7 Determination of sample atomization particle size

[0094]

[0095] The results show that the atomized particle size X of the embodiment of the present invention 50 All between 2 and 4 μm, X 84 <6μm.

[0096] Example 13: Determination of the atomization performance of Favipiravir solution for atomization inhalation

[0097] A PARI BOY SX nebulizer from Germany, a NEU22 Omron nebulizer (compressed air atomization), and an Innovent (compressed air atomizer) nebulizer were used respectively. 5 ml, 3 ml, and 2 ml of the nebulization inhalation solution in Examples 1-8 were taken for atomization, and the fine particle percentage FPF (%) and the aerodynamic mass median diameter MMAD (μm) were recorded. The results are shown in Table 8.

[0098] Table 8 Atomization performance test results of Favipiravir solution for atomization inhalation

[0099]

[0100]

[0101] The results in Table 8 show that the favipiravir solution for nebulized inhalation prepared by the present application has good atomization characteristics, with an aerodynamic mass diameter of 2-5 μm and a percentage of fine particles of 30%-70%, which can meet the requirements of nebulized inhalation.

[0102] Example 14: Determination of the nebulization time of the inhalation Favipiravir solution

[0103] A German PARI BOY SX nebulizer, a NEU22 Omron nebulizer (compressed air atomization), and an Yinghua Rongtai (compressed air atomizer) nebulizer were used respectively. 5 ml, 3 ml, and 2 ml of the nebulization inhalation solution in Examples 1-8 were taken for atomization, and the end time of atomization was recorded (based on the absence of white mist spray). The results are shown in Table 9.

[0104] Table 9 Nebulization time measurement results of Favipiravir solution for inhalation

[0105]

[0106] From the results in Table 9, it can be seen that the atomized inhalation administration time of the Favipiravir solution for inhalation prepared by the present invention is between 10 and 30 minutes.

[0107] The present invention is described in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method and core idea of ​​the present invention. It should be pointed out that for ordinary technicians in this field, without departing from the principles of the present invention, the present invention can also be improved and modified in a number of ways, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A favipiravir solution for aerosol inhalation, characterized in that: The single-dose inhalation solution contains 1-50 mg / ml of favipiravir, solvents, and excipients; The auxiliary materials include a cosolvent, a pH regulator and an osmotic pressure regulator, and the solvent is selected from water for sterile injection; The pH value of the inhalation solution is 5.5-9.0; The cosolvent is selected from meglumine; The mass ratio of Favipiravir to Meglumine is 1:1.25-1:1.

34.

2. The favipiravir solution for aerosol inhalation according to claim 1, characterized in that The single-dose inhalation solution contains 5-40 mg / ml Favipiravir.

3. The favipiravir solution for aerosol inhalation according to claim 1, characterized in that The single dose specification of the inhalation solution is 2-5 ml.

4. The favipiravir solution for aerosol inhalation according to claim 3, characterized in that: The single dose size is 5 ml.

5. The favipiravir solution for aerosol inhalation according to claim 1, characterized in that: The co-solvent is selected from meglumine, and its content is 1.25-62.5 mg / ml.

6. The favipiravir solution for aerosol inhalation according to claim 1, characterized in that: The pH regulator can be selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, and sodium citrate, and the amount thereof is such that the pH value of the inhalation solution is 5.5-9.

0.

7. The favipiravir solution for aerosol inhalation according to claim 1, characterized in that: The osmotic pressure regulator is selected from glucose or sodium chloride, and its dosage is such that the molar osmotic pressure of the inhalation solution is 270-330 mOsmol / kg.

8. The method for preparing the favipiravir solution for aerosol inhalation according to any one of claims 1 to 7, characterized in that: The following steps are involved: (1) Add 80% of the total amount of solvent required to prepare the solution into the dispensing device, then introduce nitrogen to deoxygenate and avoid light throughout the process, add the prescribed amount of favipiravir, and stir until it is fully dispersed in the solution; (2) gradually adding meglumine and stirring until it is fully dissolved, and adding an osmotic pressure regulator and stirring until it is fully dispersed; (3) Use a pH adjuster to adjust the pH of the solution to 5.5-9.0, add solvent to make up to the total volume of the prescription, and stir to mix evenly; (4) Use a 0.45 μm filter membrane for primary filtration and a 0.22 μm filter membrane for fine filtration. After sterile filtration, the product is divided and filled.

9. A favipiravir solution atomization inhalation system, characterized in that: It comprises 1ml-5ml of the inhalation favipiravir solution according to any one of claims 1-7 and a liquid nebulizer. After the inhalation favipiravir solution is atomized by the liquid nebulizer, its aerodynamic mass diameter is 2-5μm, the percentage of fine particles is 30%-70%, and the administration time after atomization is 10-30min.

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