Voriconazole freeze-dried powder injection for injection and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and discloses a voriconazole freeze-dried powder injection for injection and a preparation method of the voriconazole freeze-dried powder injection. The freeze-dried powder injection comprises voriconazole, sulfobutyl-beta-cyclodextrin, sorbitol, sodium chloride and methanesulfonic acid, and the solubility and stability of the medicine are remarkably improved by optimizing the ratio of auxiliary materials and the pH value (4.0-5.0). Experiments show that in an acceleration test (40 + / -2 DEG C, 75% RH) and a long-term stability test (25 + / -2 DEG C, 60% RH), the content decrease rate of the preparation is less than or equal to 3%, the total impurity content is less than or equal to 0.1%, the moisture content is less than or equal to 0.5%, and the validity period can reach 24 months. In addition, after redissolution, the compatibility with various clinical diluents (such as 0.9% sodium chloride and 5% glucose) is good, and precipitation or degradation is avoided. The problems that in the prior art, auxiliary materials are high in toxicity and poor in stability, and diluent is easy to separate out are solved, and the clinical application value is remarkable.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and more particularly, to voriconazole for injection and a preparation method thereof. Background Art

[0002] Voriconazole has the chemical name of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol, and its molecular formula is C 16 H 14 F2N5O, with a molecular weight of 349.3, and the structural formula is:

[0003]

[0004] Voriconazole is a new type of the third-generation triazole broad-spectrum antifungal drug. Compared with fluconazole, it has a broader antibacterial spectrum and stronger antibacterial efficacy. Its preparations are widely used clinically to treat invasive aspergillosis, severe invasive infections caused by fluconazole-resistant Candida albicans, and severe infections caused by Actinomyces and Fusarium.

[0005] Voriconazole is a weak base, with low water solubility (0.61 mg / ml at pH 7; 0.2 mg / ml at pH 3), and is unstable in water. Its hydrolysis retro-aldol product will recombine into an inactive enantiomer. Given the low solubility and poor stability of voriconazole in water, it is very crucial to effectively increase the solubility of voriconazole in water and maintain the stability of the drug when preparing it into a freeze-dried powder injection. Currently, the voriconazole for injection marketed by Pfizer uses sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as the main excipient to increase the solubility of voriconazole. The commercially available voriconazole freeze-dried powder injection preparation contains 200 mg of voriconazole, and is intended to be reconstituted with water for injection to obtain a solution containing 10 mg / mL of voriconazole and 160 mg / mL of sulfobutyl ether β-cyclodextrin. The resulting solution is further diluted before being administered as an intravenous infusion.

[0006] However, sulfobutyl-β-cyclodextrin has certain physiological toxicity, and currently, the commercially available voriconazole freeze-dried powder injection has problems such as poor stability, easy precipitation of the diluent, and low purity. To solve the above problems, there are mainly three types of methods in the currently published literature: The first type is to use HP-β-CD excipients as solubilizers. HP-β-CD, as the first β-CD derivative approved by the FDA for intravenous injection, has advantages such as good water solubility, low hemolysis, no irritation to muscles, and can increase the drug stability after inclusion. For example, EP2018866A1 uses HP-β-CD as an excipient; CN1813751A discloses a voriconazole injection using HP-β-CD as an excipient and polyethylene glycol as an excipient; CN101849945A uses HP-β-CD-dextran as an excipient; CN1788725A uses HP-β-CD as an excipient and mannitol as a diluent to prepare a freeze-dried powder injection; CN1686136A adds HP-β-CD, Tween and other excipients; CN103251565A uses HP-β-CD as an excipient and mannitol as a diluent to prepare a freeze-dried powder injection; CN1788725A uses HP-β-CD as an excipient and mannitol, lactose and other diluents to prepare a freeze-dried powder injection; WO2012171561A1 uses HP-β-CD as an excipient and contains a stable amount of lactose; EP2409699A1 uses HP-β-CD as an excipient and glycine as a stabilizer. Although the above methods replace sulfobutyl-β-cyclodextrin, due to the strong physiological toxicity of cyclodextrin and Tween and other excipients, they cannot be widely used, and the existing technology has not deeply studied the substitution degree distribution of hydroxypropyl-β-cyclodextrin and the embedding, stability, etc. of voriconazole, resulting in unstable quality of voriconazole freeze-dried preparations. Therefore, the combined effect of hydroxypropyl-β-cyclodextrin with different substitution degrees, the active ingredient voriconazole, and other excipients is still unknown; The second type is to use organic solvents as solvents, such as patents CN1861044A, CN1861044A. Although these methods do not use excipients with large toxic and side effects such as cyclodextrin and Tween, organic solvents also have certain toxic and side effects. The third type is to use excipients such as poloxamer as solubilizers, such as WO2010084505A2, CN101390861A, but poloxamer is not suitable for injections.

[0007] Voriconazole is essentially semi-polar, which means that it usually cannot be dissolved by conventional means, such as oils, surfactants, or water-miscible cosolvents. Voriconazole drug is a white to off-white solid powder. To obtain a water-soluble preparation of voriconazole suitable for intravenous infusion, the solubility of the active compound must be increased.

[0008] Given the irreplaceability of voriconazole as a third-generation triazole broad-spectrum antifungal drug in the treatment of invasive fungal infections, the clinical demand shows a significant growth trend. However, the semi-polar chemical properties of this drug lead to difficult dissolution, and conventional solubilization methods such as oil phase, surfactants, or water-miscible cosolvents are ineffective, forcing formulation development to rely on complex excipient systems. Although sulfobutyl ether-β-cyclodextrin currently used in clinical applications can partially improve solubility, its physiological toxicity and the lack of injectable grade products severely limit the long-term use safety. Although hydroxypropyl-β-cyclodextrin has been approved by the FDA for intravenous injection, the existing technology lacks a systematic study on the correlation mechanism between its degree of substitution distribution and drug entrapment efficiency, resulting in significant fluctuations in the performance of excipients from different sources and difficult to guarantee the stability of the formulation. At the same time, although the organic solvent solvent system can avoid the toxicity of cyclodextrin, its own liver and kidney toxicity and injection pain problems cannot be ignored. Although poloxamer excipients have solubilization potential, they are difficult to be actually applied due to poor compatibility with injection dosage forms. Therefore, developing a customized formulation technology that can significantly improve the solubility and stability of voriconazole and also has clinical safety has become a bottleneck problem that urgently needs to be broken through in the field of antifungal treatment. Therefore, it is urgent to combine the synergistic effects of multiple excipients to construct a new type of stable voriconazole formulation in order to break through the limitations of existing technologies and meet the urgent clinical needs. Summary of the Invention

[0009] Regarding the problems of high toxicity and poor stability of excipients in the prior art, the present invention proposes the following solutions. The present invention provides a voriconazole freeze-dried powder injection, which includes 200 mg of voriconazole, 1500 - 2000 mg of sulfobutyl betadextrin, 200 - 300 mg of sorbitol, 50 - 100 mg of sodium chloride, 20 - 60 mg of methanesulfonic acid, and pH 4 - 5.

[0010] Preferably, the voriconazole freeze-dried powder injection includes 200 mg of voriconazole, 1600 mg of sulfobutyl betadextrin, 250 mg of sorbitol, 70 mg of sodium chloride, 55 mg of methanesulfonic acid, and pH 4.3 - 4.6.

[0011] Experimental data show that the voriconazole freeze-dried powder injection provided by the present invention has a low drug degradation rate. The components synergistically improve the long-term storage stability of the freeze-dried preparation, and there is no precipitation after 6 months under the accelerated test conditions of 40°C / 75% RH.

[0012] On the other hand, the present invention provides a preparation method of a voriconazole freeze-dried powder injection, which includes the steps:

[0013] 1) Weigh the prescribed amounts of sulfobutyl betadextrin, sorbitol, sodium chloride, and methanesulfonic acid, add 50% - 80% of the total preparation volume of water, and adjust the temperature to 20°C - 30°C, and stir until clear and transparent;

[0014] 2) Add the prescribed amount of voriconazole and continue stirring until clear and transparent;

[0015] 3) Add water to make up the volume, mix evenly, and filter to obtain the mixed liquid medicine;

[0016] 4) Sterilize, fill, and freeze-dry the obtained mixed liquid medicine to obtain voriconazole for injection;

[0017] Preferably, the sterilization described in step 4) includes moist heat sterilization, dry heat sterilization, radiation sterilization, and sterile filtration, etc.

[0018] Existing studies have shown that voriconazole for injection is sensitive to temperature, cannot tolerate moist heat sterilization and dry heat sterilization, nor can it tolerate radiation sterilization. Therefore, in the prior art, a sterilization process combining sterile filtration and aseptic production process is adopted, such as CN114432252A. The research of the present invention shows that the freeze-dried product of voriconazole for injection can tolerate dry heat sterilization conditions of 160 °C × 120 minutes and 170 °C × 60 minutes. The freeze-dried product of voriconazole for injection can tolerate sterilization conditions with a radiation dose of 30 kGy and 15 kGy. Under the dry heat sterilization and radiation sterilization conditions, the pH, content, and related substances of the voriconazole lyophilized powder prepared by the present invention have not shown obvious changes.

[0019] Preferably, the freeze-drying described in step 4) includes pre-freezing, primary drying, and secondary drying. The pre-freezing temperature is -10 to -5 °C, and the pre-freezing time is 5 - 30 minutes. The freezing of the mixed liquid medicine is completed within a few seconds, and the obtained ice body is uniform up and down, with a complete shape, no layering, protrusions, etc. The temperature of the primary drying is set at 20 °C, and the heating rate is 0.5 °C / min. The obtained sample has a good shape, the water content is less than 2%, and the drying cycle is shortened. The primary drying takes 15 - 20 hours. In the present invention, the main factor affecting the drying time is the drying temperature, and the influence of the vacuum degree is relatively small. The present invention sets the primary drying temperature at 20 °C, which is higher than the eutectic point of the product but lower than the glass transition temperature, which is an operation with certain risks. Therefore, whether melting or even voids appear at the bottom is observed during and after the process. No adverse results have occurred. The temperature of the secondary drying is 30 °C, and the drying time is 2 - 5 hours. After the primary drying is completed, a part of the water is still adsorbed on the capillaries and polar groups of the dried substance. These waters are not frozen. When they reach a certain content, they provide conditions for certain chemical reactions. In order to improve the product stability, it is reasonable to control the secondary drying temperature of the product at 30 °C. After the secondary drying, the water content is less than 0.5%.

[0020] Adopting the technical scheme of the present invention significantly improves the solubility of voriconazole under the condition of pH 4 - 5. And there is no need for excessive cyclodextrin, reducing the risk of excipient toxicity.

[0021] Reduce the reconstitution time and improve the clarity of the reconstituted solution. It has good compatibility with various clinical diluents (such as 0.9% sodium chloride, 5% glucose) after reconstitution, without precipitation or degradation. The reconstituted solution can be stored at 2 - 8 °C for more than 24 hours.

[0022] It is known that the degradation of voriconazole leads to the formation of the following impurities. However, the freeze-dried powder for injection provided by the present invention does not generate impurities B and D, and after accelerated test and long-term stability test, the total impurities can still be controlled within the range of <0.2%.

[0023] Impurity A: 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone

[0024] Impurity B: (2RS,3SR)-2-(2,4-difluorophenyl)-3-pyrimidin-4-yl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0025] Impurity C: 4-ethyl-5-fluoropyrimidine

[0026] Impurity D: (2S,3R)-1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)butan-2-ol (voriconazole enantiomer).

[0027] Voriconazole is sensitive to degradation by alkali and heat. The pH value of the aqueous solution of the present invention is in the range of 4 - 5, which can prevent the formation of impurities.

[0028] In view of the technical defects of the existing voriconazole freeze-dried powder injection, through the design of a multi-component synergistic system, the comprehensive optimization of dissolution performance, stability, freeze-drying efficiency and quality control is realized. Specifically, by optimizing the excipient combination (sulfobutyl beta-cyclodextrin, sorbitol, sodium chloride, methanesulfonic acid) and pH control (4.0 - 5.0), the solubility of voriconazole is significantly increased (10 mg / mL), and in the accelerated test (40°C ± 2°C / 75% RH) and long-term stability test (25°C ± 2°C / 60% RH), the content decline rate ≤ 3%, the total impurities ≤ 0.1%, the water content ≤ 0.5%, and the shelf life is extended to 24 months. The dosage of sulfobutyl beta-cyclodextrin (SBECD) is optimized to avoid the risks of hemolysis and nephrotoxicity caused by excessive cyclodextrin. The freeze-drying process is optimized, the production efficiency is improved, the freeze-drying cycle is shortened to 24 hours, and the energy consumption is reduced by 30%. The water content after freeze-drying < 0.5%, and the reconstitution time ≤ 30 seconds, significantly improving the clinical use efficiency. It can withstand dry heat sterilization (160°C × 120 minutes) and irradiation sterilization (30 kGy). After sterilization, the pH fluctuation ≤ 0.1, and the impurity increment ≤ 0.02%, breaking through the limitation of the existing technology that cannot be sterilized at high temperature. The reconstituted liquid has no precipitation within 24 hours after being compatible with diluents such as 0.9% sodium chloride and 5% glucose, the total impurities ≤ 0.2%, and the osmotic pressure is stable (285 - 310 mOsmol / kg), solving the problem that the commercially available products are prone to crystallization after dilution. Methanesulfonic acid adjusts the pH to 4 - 5, effectively inhibiting the retro-aldol hydrolysis reaction of voriconazole and reducing the generation of inactive enantiomers (impurity D). HPLC detection shows that the total amount of related substances < 0.5%, and the content of key impurities A / C ≤ 0.05%. Detailed implementation manners

[0029] In order to better understand the technical solution of the present invention, the following further describes the technical solution of the present invention in combination with specific embodiments. The embodiments are only for helping to understand the present invention and should not be regarded as specific limitations on the present invention.

[0030] 1. Preparation of voriconazole solution and investigation of preparation conditions

[0031] (1) Solution preparation

[0032] Table 1

[0033]

[0034]

[0035] Weigh SBECD according to the dosage in Table 1 Sorbitol, sodium chloride and methanesulfonic acid are added, 80% of the total formulation volume of water is added, and the temperature is adjusted to 20°C - 30°C. Stir for 5 minutes until clear and transparent. Add the prescribed amount of voriconazole and continue to stir for 10 minutes until clear and transparent. Add water to make up the volume, mix evenly, filter to obtain the mixed medicinal liquid, measure the pH value, control the pH of the solution with methanesulfonic acid, and the pH is 4 - 5.

[0036] (2) Investigation on the influence of excipients on the clarity of the solution

[0037] Prepare voriconazole solution according to the ratio in Table 1, that is, the concentration of voriconazole is 1 g / 100 mL, 55 mg of methanesulfonic acid, pH 4.3 - 4.6, and other excipients remain unchanged. Investigate the influence of replacing the excipient sorbitol on the clarity of voriconazole.

[0038] Table 2

[0039] 1# 2# 3# 4# 5# 6# 7# Excipients Sorbitol Mannitol Glucose Xylitol Lactose Trehalose Sucrose Solution clarification time Greater than 24 h Less than 10 h Less than 10 h Turbid Turbid Slightly turbid Slightly turbid

[0040] Result analysis:

[0041] The clarification time of voriconazole solution with sorbitol as the excipient > 24 h, which is significantly better than other excipients (the clarification time of mannitol, glucose, etc. < 10 h), indicating that it can effectively maintain the dispersed state of drug molecules, inhibit crystallization or aggregation, and ensure the long-term clarity of the solution. Although mannitol (2#) and glucose (3#) can be clarified within 10 h, their stability is insufficient, presumably related to the relatively weak ability of their molecular conformations to embed the drug; while xylitol (4#), lactose (5#), trehalose (6#), and sucrose (7#) directly cause the solution to be turbid, possibly related to poor drug-excipient compatibility or crystallization induction.

[0042] (3) Investigation on the influence of acid on the clarity of the solution

[0043] Prepare voriconazole solution according to the ratio in Table 1, that is, the concentration of voriconazole is 1 g / 100 mL, other excipients remain unchanged, and the pH is 4 - 5. Investigate the influence of replacing the excipient acid on the clarity of voriconazole.

[0044] Table 3

[0045] 1# 2# 3# 4# 5# 6# 7# Acid Methanesulfonic acid Lactic acid Tartaric acid Citric acid Succinic acid Acetic acid Hydrochloric acid Solution clarification time Greater than 24 h N / A N / A N / A N / A Slightly turbid N / A

[0046] The situation where N / A appears is that voriconazole cannot be dissolved, so the investigation of clarity is meaningless.

[0047] Result analysis:

[0048] When methanesulfonic acid is used as a salt-forming agent, the solution clarification time is > 24 h, indicating that the methanesulfonate formed by it and voriconazole has excellent dissolution stability; while other acids (such as lactic acid and tartaric acid) are not applicable because they cannot effectively dissolve the drug (N / A) or cause slight turbidity (acetic acid). Methanesulfonic acid can maintain the salt state of the drug within the pH range of 4 - 5 and avoid hydrolysis side reactions caused by excessive acidification. It is an advantageous choice that takes into account both solubility and chemical stability.

[0049] (4) Investigation on the influence of pH on related substances in the prepared solution

[0050] The mixed liquid medicine obtained in (1) was divided into 50 portions, each portion being 20 mL. Some were placed in a sealed glass container and the changes in properties, content, pH value, and related substances were investigated at 0 h, 3 h, and 24 h at 40 °C; the remaining part was filled into 30 mL vials at 20 mL per vial, freeze-dried, stoppered and crimped after freeze-drying, and accelerated investigation was carried out at 40 °C; and sterilization research was also carried out.

[0051] Table 4 Results of pH study on bulk solution - bulk solution (placed at 40 °C)

[0052]

[0053]

[0054] (5) Investigation on the influence of pH on related substances in the freeze-dried product

[0055] Table 5 Results of pH study on bulk solution - accelerated investigation of freeze-dried product placed at 40 °C

[0056]

[0057] Result analysis:

[0058] 1) When the pH value of the prepared solution is within the range of 4 - 5, as the pH value increases, after the bulk liquid medicine is placed at 40 °C for 24 hours, the total impurities of the sample show an increasing trend, but there is no obvious change compared with day 0, presenting good stability.

[0059] 2) When the pH value of the freeze-dried product is within the range of 4 - 5, the total impurities of the sample do not show an increasing trend after accelerated investigation at 40 °C.

[0060] 3) It was found during the preparation process that after the bulk solution was prepared, its pH value was about 4.4, meeting the requirements. Moreover, there were no obvious changes in the content, related substances, and pH value of the bulk solution before and after freeze-drying, indicating that the liquid medicine remained stable during the freeze-drying process.

[0061] 2. Dry heat sterilization and irradiation sterilization research

[0062] According to the EU sterilization method selection decision tree (EMA / CHMP / CVMP / QWP / BWP / 850374 / 2015), for non-solution products, dry heat sterilization at 160 °C for 120 minutes is preferred for sterilization. For products that cannot tolerate this dry heat sterilization condition, irradiation with an irradiation dose of not less than 25 kGy is used for sterilization. At the same time, moist heat sterilization is investigated. For products that still cannot tolerate it, a sterilization process combining germicidal filtration and aseptic production process is considered. Therefore, in the present invention, dry heat sterilization and irradiation sterilization were first investigated for freeze-dried products. According to the EU sterilization method selection decision tree (EMA / CHMP / CVMP / QWP / BWP / 850374 / 2015), dry heat sterilization and irradiation sterilization studies were carried out under the conditions of dry heat sterilization at 160 °C for 120 minutes, dry heat sterilization at 170 °C for 60 minutes, irradiation sterilization at 15 kGy, and irradiation sterilization at 30 kGy. The research results are as follows:

[0063] Table 6 Research results of dry heat sterilization and irradiation sterilization

[0064]

[0065] Analysis and evaluation of dry heat sterilization and irradiation sterilization results

[0066] The above research results show that under the conditions of dry heat sterilization and irradiation sterilization, there are no obvious changes in pH, content, and related substances. The freeze-dried finished product of voriconazole for injection of the present invention is not sensitive to temperature and can tolerate the dry heat sterilization conditions of 160 °C × 120 minutes and 170 °C × 60 minutes. The freeze-dried finished product of voriconazole for injection can tolerate the sterilization conditions of an irradiation dose of 30 kGy and 15 kGy.

[0067] 3. Freeze-drying process

[0068] The voriconazole liquid medicine with a specification of 20 mL / vial obtained according to 1 was filled into 30 mL vials and freeze-dried according to the process in Table 7. The pH of the liquid medicine was 4.3 - 4.6, and the addition amount of methanesulfonic acid was 55 mg at this time.

[0069] Table 7

[0070] Serial number Process Shelf temperature (°C) Vacuum (mbar) Process time (minutes) 1 Loading 10 --- --- 2 Preliminary freezing -10 --- 10 3 Evacuation --- 0.05 --- 4 Primary drying 20 0.05±0.03 1200 5 Secondary drying 30 0.05±0.03 180

[0071] Lyophilization includes pre-freezing, primary drying, and secondary drying. The pre-freezing temperature is -10°C, and the pre-freezing time is 10 minutes. The freezing of the mixed liquid medicine is completed within a few seconds. The obtained ice body is uniform up and down, with a complete shape, no stratification, protrusion, etc. The primary drying temperature is set at 20°C, and the heating rate is 0.5°C / min. The obtained sample has a good shape, the moisture content is less than 2%, and the drying cycle is shortened. The primary drying takes 20 hours. In the present invention, the main factor affecting the drying time is the drying temperature, and the influence of the vacuum degree is relatively small. In the present invention, the primary drying temperature is set at 20°C, which is higher than the eutectic point of the product but lower than the glass transition temperature, which is an operation with certain risks. Therefore, whether melting or even voids appear at the bottom is observed during and after the process. No adverse results were found. The secondary drying temperature is 30°C, and the drying time is 3 hours. After the primary drying, a part of the moisture is still adsorbed on the capillaries and polar groups of the dried substance. These moisture is not frozen. When they reach a certain content, they provide conditions for certain chemical reactions. In order to improve the product stability, it is reasonable to control the secondary drying temperature of the product at 30°C. After the secondary drying, the moisture content is less than 0.5%.

[0072] 4. Clinical Diluent Compatibility Test

[0073] A compatibility study was conducted on voriconazole for injection obtained by the freeze-drying process with 0.9% sodium chloride injection, lactated Ringer's injection, 5% glucose and 0.9% sodium chloride injection, and 5% glucose injection as clinical diluents for 24 hours. At the same time, a comparative study was carried out with the imported original research drug.

[0074] Table 8 Sample Information of Compatibility Study between Voriconazole for Injection and Clinical Diluents

[0075] Name Specification Manufacturer Imported originator drug 200 mg Pfizer Self-made sample of the present invention 200 mg Hainan Poly Pharm Co., Ltd. Sodium chloride injection 500 mL: 4.5 g Chenxin Pharmaceutical Co., Ltd. 5% Glucose injection 500 mL: 25 g Chenxin Pharmaceutical Co., Ltd. Glucose and sodium chloride injection 500 mL: Glucose 25 g and sodium chloride 4.5 g Hunan Kelun Pharmaceutical Co., Ltd. Sodium lactate Ringer's injection 500 mL Anhui Shuanghe Pharmaceutical Co., Ltd. Sterile water for injection 500 mL Zhejiang Shapuaisi Pharmaceutical Co., Ltd.

[0076] Referring to the usage method in the imported original research drug instruction manual, take voriconazole for injection, and add 19 mL of injection water to each bottle of sample with a disposable sterile syringe to dissolve it into a reconstituted solution with a concentration of 10 mg / mL.

[0077] Take the reconstituted aqueous solution after storage for 24 hours, and use a disposable sterile syringe to inject the content of the bottle into infusion bags containing 20 mL of each of the 4 clinical diluents: 0.9% sodium chloride injection, lactated Ringer's injection, 5% glucose injection, and 5% glucose and 0.9% sodium chloride injection, respectively, to prepare a clinical use solution containing voriconazole at 5 mg / mL. The reconstitution time < 30 seconds. Take it out after placing it in the refrigerator (2 - 8°C) for 24 hours, and then detect it at room temperature (25°C ± 2°C) according to the sampling plan.

[0078] Detection Method

[0079] Clarity and Color of Solution

[0080] Take the compatible solution and visually observe. The solution should be clear and colorless.

[0081] 2) pH

[0082] Take the compatible solution and determine the pH value according to the method for determining pH value (General Chapter 0631, Volume IV, Chinese Pharmacopoeia 2015 Edition).

[0083] 3) Osmotic pressure

[0084] Take an appropriate amount of the compatible solution and measure it in parallel twice. The osmolarity of the osmotic pressure should be equivalent to that of human blood (the range of osmolarity of normal human blood is 285 - 310 Osmol / kg).

[0085] 4) Related substances

[0086] Precisely measure an appropriate amount of the compatible solution, add the mobile phase to prepare a solution containing 1 mg of voriconazole per 1 mL as the test solution, and examine it according to the method under the item of related substances of voriconazole for injection. It should meet the requirements.

[0087] 5) 5-Hydroxymethylfurfural

[0088] It is formulated with reference to the detection method of 5-hydroxymethylfurfural in the monograph of tinidazole glucose injection in Volume II of Chinese Pharmacopoeia 2015 Edition. The specific method is as follows:

[0089] Chromatographic conditions and system suitability test: Use octadecylsilane chemically bonded silica gel as the filler; 0.05 mol / L potassium dihydrogen phosphate solution (adjust the pH value to 3.5 with phosphoric acid)-acetonitrile (70:30) as the mobile phase; the detection wavelength is 284 nm, the injection volume is 20 μL, and the number of theoretical plates calculated by 5-hydroxymethylfurfural should be not less than 2500. The resolution between 5-hydroxymethylfurfural and the adjacent peak should be greater than 1.5.

[0090] Precisely weigh an appropriate amount of 5-hydroxymethylfurfural, dissolve it in water and dilute it with the diluent to prepare a solution containing 10 μg per 1 mL as the reference solution. Precisely measure 20 μL each of the compatible solution and the reference solution, inject them into the liquid chromatograph, record the chromatogram. If there is a chromatographic peak in the chromatogram of the compatible solution with the same retention time as the 5-hydroxymethylfurfural peak in the reference solution, calculate by the external standard method with the peak area, and it shall not exceed 0.02% of the labeled amount of glucose.

[0091] This detection item only detects the diluent containing glucose.

[0092] 6) Content

[0093] Take an appropriate amount of the compatible solution, add the mobile phase to prepare a solution containing 0.2 mg of voriconazole per 1 mL as the test solution, and examine it according to the method under the item of content determination of voriconazole for injection. It should meet the requirements.

[0094] 7) Insoluble particles

[0095] Take the compatibility solution and determine it according to the method for the inspection of insoluble particles (General Chapter 0903, Method 1 in Part IV of the Chinese Pharmacopoeia 2015 Edition). The number of particles with a size of 10 μm or more in each mL of the compatibility solution shall not exceed 25, and the number of particles with a size of 25 μm or more shall not exceed 3.

[0096] 8) Bacterial endotoxin

[0097] Determine it according to the method for the inspection of bacterial endotoxin (General Chapter 1143 in Part IV of the Chinese Pharmacopoeia 2015 Edition). The amount of bacterial endotoxin contained in each 1 mg of voriconazole shall not exceed 1.5 EU.

[0098] Test results

[0099] The test results of the compatibility test are as follows:

[0100] Table 9 Results of the compatibility test with 0.9% sodium chloride injection (reconstituted with water for injection)

[0101]

[0102] Table 10 Results of the compatibility test with sodium lactate Ringer's injection (reconstituted with water for injection)

[0103]

[0104] Table 11 Results of the compatibility test with 5% glucose injection (reconstituted with water for injection)

[0105]

[0106] Table 12 Results of the compatibility test with 5% glucose injection and 0.9% sodium chloride injection (reconstituted with water for injection)

[0107]

[0108] Conclusion

[0109] The test results show that the voriconazole for injection prepared by the present invention and the imported original research drug have good compatibility stability with 4 clinical diluents, namely 0.9% sodium chloride injection, sodium lactate Ringer's injection, 5% glucose injection, and 5% glucose and 0.9% sodium chloride injection. The quality indicators such as the clarity and color of the solution, pH value, insoluble particles, osmotic pressure, bacterial endotoxin, 5-hydroxymethylfurfural, content, and related substances are stable within 24 hours, meeting the standard requirements and the requirements in the imported original research drug's instructions. Through comprehensive evaluation, it is comparable to the imported original research drug in quality, with no significant difference between the two. When used according to the instruction "The prepared solution should not be stored for more than 24 hours under the condition of 2 - 8°C", there is no quality risk and no safety problems will be brought.

[0110] 5. Stability study

[0111] According to the requirements and methods provided in Appendix 9001 "Guidelines for Stability Testing of Raw Materials and Preparations" of the Chinese Pharmacopoeia (2015 Edition), 3 batches of voriconazole freeze-dried products prepared in Example 3 were taken for 6-month accelerated testing and 18-month long-term stability testing. The accelerated conditions were to place them at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%, and samples were taken for testing at the end of the 1st month, 2nd month, 3rd month, and 6th month respectively. The long-term stability conditions were to place them at a temperature of 25°C ± 2°C and a relative humidity of 60% ± 10%, and samples were taken for testing at 0 month, 3 months, 6 months, 9 months, 12 months, 18 months, and 24 months.

[0112] (1) Results of accelerated testing

[0113] Table 13

[0114]

[0115]

[0116] Conclusion

[0117] After 6 months of accelerated testing for the three batches, the content remained between 95.85% - 99.12%, meeting the pharmacopoeia requirements (90% - 110% of the labeled amount), and the downward trend was gentle. The total impurity was at most 0.05%, far lower than the general limit (≤1.0%), indicating good control of degradation products. The water content ≤ 0.50%, and the pH fluctuation range was 4.27 - 4.51, all within a reasonable range. All batches remained as "white freeze-dried lumps" during the test period without physical property changes. The voriconazole freeze-dried products were of stable quality within 6 months under accelerated conditions (40°C ± 2°C, RH 75% ± 5%).

[0118] (2) Results of long-term stability

[0119]

[0120]

[0121] Conclusion:

[0122] After the 24-month long-term stability test of three batches, the content of all batches was stable, and there was no significant degradation trend. The degradation products were well controlled and met the safety requirements. The chemical properties of the preparation were stable, and there were no significant acid-base changes. The data trends of the three batches were highly consistent, indicating that the production process was stable and reliable. The voriconazole freeze-dried product of the present invention showed excellent chemical and physical stability in the long-term stability test, and all key indicators (content, impurities, moisture, pH and appearance) met the requirements of the Chinese Pharmacopoeia. Combining with the results of the accelerated test, it supports the setting of its shelf life to be 24 months, and has the stability guarantee for commercial production.

Claims

1. A voriconazole lyophilized powder for injection, characterized in that: Includes the following components: Voriconazole 200 mg, Sulfonyl-beta-cyclodextrin 1500-2000mg, Sorbitol 200-300mg, Sodium chloride 50-100 mg, Methanesulfonic acid 20-60mg, Water for injection, The pH value of the freeze-dried powder injection is 4.0-5.

0.

2. The voriconazole lyophilized powder for injection according to claim 1, characterized in that: The following ingredients are included: voriconazole 200 mg, Sulfonyl-beta-cyclodextrin 1600mg, Sorbitol 250mg, Sodium chloride 70mg, Methanesulfonic acid 55mg, The pH value of the freeze-dried powder injection is 4.3-4.

6.

3. The voriconazole lyophilized powder for injection according to claim 1 or 2, characterized in that: The long-term stability of the lyophilized powder injection meets the following conditions: When stored at 25℃±2℃ and relative humidity 60%±10% for 24 months, the content decrease rate shall be ≤3%; Total impurity content ≤ 0.1%; Moisture content ≤0.5%.

4. The voriconazole lyophilized powder for injection according to any one of claims 1 to 3, characterized in that: The lyophilized powder injection can withstand one of the following sterilization conditions: Dry heat sterilization: 160℃×120min or 170℃×60min; Irradiation sterilization: 15-30kGy.

5. A method for preparing the voriconazole lyophilized powder for injection according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) Dissolve sulfobutyl beta-cyclodextrin, sorbitol, sodium chloride and methanesulfonic acid in 50%-80% volume of water for injection and stir at 20°C-30°C until clear; (2) Add voriconazole and continue stirring until completely dissolved; (3) adding water for injection to make up the volume, mixing evenly, and filtering to obtain a mixed drug solution; (4) sterilizing, filling and freeze-drying the obtained mixed drug solution to obtain the voriconazole freeze-dried powder injection.

6. The preparation method according to claim 5, characterized in that: The freeze drying includes pre-freezing (-10°C to -5°C, 5-30 minutes), primary drying (20°C 615-20 hours) and secondary drying (30°C, 2-5 hours).

7. The preparation method according to claim 6, characterized in that: The temperature rise rate in the primary drying stage of the freeze drying is 0.5°C / min.

8. Use of the voriconazole lyophilized powder for injection according to any one of claims 1 to 4, characterized in that: Used for preparing a pharmaceutical composition for treating invasive fungal infections.

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