Voriconazole lyophilized powder for injection and preparation method thereof

Abstract

The present application relates to the field of pharmaceutical preparations, and discloses a voriconazole freeze-dried powder injection and a preparation method thereof.The freeze-dried powder injection comprises voriconazole, sulfobutyl betacyclodextrin, sorbitol, sodium chloride and methanesulfonic acid, and the solubility and stability of the drug are significantly improved by optimizing the proportion of the excipients and the pH value (4.0-5.0). Experiments show that in the accelerated test (40℃±2℃, 75%RH) and the long-term stability test (25℃±2℃, 60%RH), the content decrease rate is ≤3%, the total impurities are ≤0.1%, the moisture is ≤0.5%, and the effective period can reach 24 months. In addition, after reconstitution, the compatibility with various clinical diluents (such as 0.9% sodium chloride and 5% glucose) is good, without precipitation or degradation. The present application solves the problems of high toxicity of excipients, poor stability and easy precipitation of diluents in the prior art, and has significant clinical application value.

Description

TECHNICAL FIELD

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

[0002] Voriconazole is a new type of third-generation triazole broad-spectrum antifungal drug, compared with fluconazole, it has the characteristics of wider antibacterial spectrum and stronger antibacterial efficacy, and its preparation is widely used in the treatment of invasive aspergillosis, severe invasive infections caused by fluconazole-resistant Candida albicans, and severe infections caused by actinomycetes and fusarium. 16 H 14 F2N5O, with a molecular weight of 349.3, and a structural formula of:

[0003]

[0004] Voriconazole is a new type of third-generation triazole broad-spectrum antifungal drug, compared with fluconazole, it has the characteristics of wider antibacterial spectrum and stronger antibacterial efficacy, and its preparation is widely used in the treatment of invasive aspergillosis, severe invasive infections caused by fluconazole-resistant Candida albicans, and severe infections caused by actinomycetes 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, and its hydrolysis reverse aldol product can recombine into an inactive enantiomer. Due to the low solubility and poor stability of voriconazole in water, it is very important to effectively increase the solubility of voriconazole in water and maintain the stability of the drug when preparing a lyophilized powder injection. At present, the injection of voriconazole marketed by Pfizer uses sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as the main excipient to improve the solubility of voriconazole. The commercially available voriconazole lyophilized powder injection contains 200 mg of voriconazole, which 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 obtained solution is further diluted before being used as an intravenous infusion for administration.

[0006] However, sulfobutyl-β-cyclodextrin has certain physiological toxicity, and the currently marketed voriconazole lyophilized powder for injection has the problems of poor stability, unstable diluent, and low purity. To solve the above problems, there are mainly three types of methods in the current public literature: the first type is to use HP-β-CD excipient as a solubilizer. HP-β-CD is the first FDA-approved β-CD derivative that can be used for intravenous injection. It has the advantages of good water solubility, low hemolyticity, no muscle irritation, and increased 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 lyophilized powder; 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 lyophilized powder; CN1788725A uses HP-β-CD as an excipient and mannitol, lactose and other diluents to prepare a lyophilized powder; 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. The above methods replace sulfobutyl-β-cyclodextrin, but since cyclodextrin and Tween and other excipients also have strong physiological toxicity, they cannot be widely used, and the existing technology does not have in-depth research on the degree of substitution of hydroxypropyl-β-cyclodextrin and the embedding and stability of voriconazole, resulting in unstable quality of voriconazole lyophilized preparations. Therefore, the study of different degrees of hydroxypropyl-β-cyclodextrin, active ingredient voriconazole, and other excipients is still in an unknown state; the second type is to use organic solvents as solvents, such as patents CN1861044A and CN1861044A. These methods do not use cyclodextrin and Tween and other excipients with high toxicity and side effects, but organic solvents also have certain toxicity and side effects. The third type is to use poloxamer and other excipients as solubilizers, such as WO2010084505A2 and CN101390861A, but poloxamer is not suitable for injection.

[0007] Voriconazole is essentially a semi-polar, which means that it is not normally soluble by conventional means, such as oil, surfactant or water-miscible cosolvents. Voriconazole drug is a white to off-white solid powder. In order to obtain a water-soluble preparation of voriconazole suitable for administration by intravenous infusion, the solubility of the active compound must be increased.

[0008] In view of the irreplaceable role of voriconazole as a third-generation triazole broad-spectrum antifungal drug in the treatment of invasive fungal infections, its clinical demand shows a significant growth trend. However, the chemical characteristics of the drug's semi-polarity lead to solubility difficulties, and conventional solubilization methods such as oil phase, surfactant or water-miscible cosolvent are difficult to work, forcing the preparation development to rely on complex excipient systems. Although sulfobutyl ether-β-cyclodextrin can partially improve the solubility, its physiological toxicity and the lack of injection-grade products seriously limit the long-term use safety. Although hydroxypropyl-β-cyclodextrin is approved by FDA for intravenous injection, the existing technology lacks systematic study on the correlation mechanism of its degree of substitution distribution and drug embedding efficiency, resulting in significant performance fluctuations of excipients from different sources, and the stability of the preparation is difficult to guarantee. At the same time, although the organic solvent solvent system can avoid the toxicity of cyclodextrin, its liver and kidney toxicity and injection pain problems also cannot be ignored. The solubilization potential of poloxamer excipients is poor, and it is difficult to be practically applied due to poor compatibility with injection dosage forms. Therefore, developing a customized preparation technology that can significantly improve the solubility and stability of voriconazole while ensuring clinical safety has become a bottleneck problem that needs to be broken through in the field of antifungal therapy. Therefore, it is urgent to combine the synergistic effect of multiple excipients to construct a new stable voriconazole preparation in order to break through the limitations of existing technologies and meet the urgent needs of clinical practice. SUMMARY

[0009] To solve the problems of high toxicity and poor stability of excipients in the prior art, the present application provides a voriconazole lyophilized powder injection, which comprises components voriconazole 200mg, sulfobutyl betacyclodextrin 1500-2000mg, sorbitol 200-300mg, sodium chloride 50-100mg, methanesulfonic acid 20-60mg, and pH 4-5.

[0010] Preferably, the voriconazole lyophilized powder injection comprises components voriconazole 200mg, sulfobutyl betacyclodextrin 1600mg, sorbitol 250mg, sodium chloride 70mg, methanesulfonic acid 55mg, and pH 4.3-4.6.

[0011] Experimental data show that the voriconazole lyophilized powder injection provided by the present application has low drug degradation rate. The components synergistically improve the long-term storage stability of the lyophilized preparation, and there is no precipitation under accelerated testing at 40℃ / 75% RH for 6 months.

[0012] On the other hand, the present application provides a preparation method of a voriconazole lyophilized powder injection, comprising the following steps:

[0013] 1) Weigh the prescribed amount of sulfobutyl betacyclodextrin, sorbitol, sodium chloride and methanesulfonic acid, add 50%-80% of the total amount of water, and adjust the temperature to 20-30℃, 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 constant volume, mix well, and filter to obtain a mixed drug solution;

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

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

[0018] Previous studies have shown that voriconazole for injection is sensitive to temperature and cannot withstand moist heat sterilization and dry heat sterilization, nor can it withstand irradiation sterilization. Therefore, the sterilization process in the prior art adopts a combination of sterilization filtration and aseptic production process, such as CN114432252A. The research of the present application shows that the freeze-dried product of voriconazole for injection can withstand dry heat sterilization conditions of 160℃×120 minutes and 170℃×60 minutes. The freeze-dried product of voriconazole for injection can withstand sterilization conditions of 30kGy and 15kGy of irradiation dose. Under the conditions of dry heat sterilization and irradiation sterilization, the pH, content, and related substances of the voriconazole freeze-dried powder prepared by the present application do not change significantly.

[0019] Preferably, the freeze-drying in step 4) includes pre-freezing, primary drying, and secondary drying, the pre-freezing temperature is -10 to -5℃, the pre-freezing time is 5-30 minutes, the freezing of the mixed drug solution is completed within a few seconds, the obtained ice body is uniform in upper and lower parts, has a complete shape, and has no layering, protrusion, or other phenomena. The primary drying temperature is set to 20℃, the temperature rising rate is 0.5℃ / min, the obtained sample has a good shape, the water content is less than 2%, and the drying cycle is shortened, and the primary drying needs 15-20 hours. In the present application, the main factor affecting the drying time is the drying temperature, and the vacuum degree has less effect. In the present application, the primary drying temperature is set to 20℃, which is higher than the eutectic point of the product but lower than the glass transition temperature, and it is a certain risk operation, so the bottom is observed after the process and at the end for whether melting or even hollow phenomena occur. The results do not show adverse results. The secondary drying temperature is 30℃, and the drying time is 2-5 hours. After the primary drying is completed, there is still a part of water adsorbed on the capillary vessels and polar groups of the dried substance, and these water is not frozen. When they reach a certain content, they provide conditions for certain chemical reactions. In order to improve the stability of the product, it is reasonable to control the secondary drying temperature of the product at 30℃. After the secondary drying, the water content is less than 0.5%.

[0020] The technical solution of the present application significantly improves the solubility of voriconazole under the condition of pH 4-5. And no excess cyclodextrin is needed, reducing the toxicity risk of excipients.

[0021] The reconstitution time is reduced and the clarity of the reconstituted solution is improved. The reconstituted solution is compatible with various clinical diluents (e.g. 0.9% sodium chloride, 5% glucose) 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, but the injection lyophilized powder provided by the present application does not generate impurities B and D, and after the accelerated test and long-term stability test, the total impurities can still be controlled within <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 alkaline and thermal degradation, and the pH value of the aqueous solution of the present application is in the range of 4-5, which can prevent the formation of impurities.

[0028] The present application aims at the technical defects of the existing voriconazole lyophilized powder injection, realizes the comprehensive optimization of the solubility, stability, and lyophilization efficiency and quality control through the design of multi-component synergistic system, and is specifically shown in the following aspects: through the optimization of the combination of excipients (sulfobutyl betadex, sorbitol, sodium chloride, and methanesulfonic acid) and pH control (4.0-5.0), the solubility of voriconazole is significantly improved (10 mg / mL), and in the accelerated test (40℃±2℃ / 75% RH) and long-term stability test (25℃±2℃ / 60% RH), the content decrease rate is ≤3%, the total impurities are ≤0.1%, the moisture is ≤0.5%, and the shelf life is extended to 24 months. The dosage of sulfobutyl betadex (SBECD) is optimized to avoid the risk of hemolytic and nephrotoxicity caused by excessive cyclodextrin. The lyophilization process is optimized, the production efficiency is improved, the lyophilization cycle is shortened to 24 hours, and the energy consumption is reduced by 30%. After lyophilization, the moisture content is <0.5%, the reconstitution time is ≤30 seconds, and the clinical use efficiency is significantly improved. It is resistant to dry heat sterilization (160℃×120 minutes) and radiation sterilization (30kGy), and after sterilization, the pH fluctuation is ≤0.1, and the impurity increment is ≤0.02%, which breaks through the limitation of high-temperature sterilization in the prior art. The reconstituted solution is compatible with 0.9% sodium chloride, 5% glucose and other diluents without precipitation within 24 hours, the total impurities are ≤0.2%, the osmotic pressure is stable (285-310 mOsmol / kg), and the problem of easy crystallization after dilution of the marketed product is solved. The pH is adjusted to 4-5 by methanesulfonic acid to effectively inhibit the reverse hydrolysis reaction of voriconazole, and reduce the generation of non-active enantiomers (impurity D). HPLC detection shows that the total amount of related substances is <0.5%, and the content of key impurities A / C is ≤0.05%. DETAILED DESCRIPTION

[0029] In order to better understand the technical solutions of the present application, the technical solutions of the present application will be further described below in combination with specific examples, which are only used to help understand the present application and should not be regarded as a specific limitation on the present application.

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

[0031] (1) Solution preparation

[0032] Table 1

[0033]

[0034]

[0035] SBECD The sorbitol, sodium chloride and methanesulfonic acid were added to 80% of the total amount of water, and the temperature was adjusted to 20-30°C, stirred for 5 minutes to clear and transparent, the prescribed amount of voriconazole was added and stirred for 10 minutes to clear and transparent, water was added to constant volume, mixed uniformly, filtered to obtain a mixed liquor, the pH value was measured, and the pH of the solution was controlled by methanesulfonic acid, pH 4-5.

[0036] (2) Influence of adjuvants on solution clarity

[0037] According to the proportions in Table 1, voriconazole solution was prepared, i.e. voriconazole concentration 1 g / 100 mL, methanesulfonic acid 55 mg, pH 4.3-4.6, other adjuvants unchanged, and the influence of replacing sorbitol as an adjuvant on the clarity of voriconazole was investigated.

[0038] Table 2

[0039] 1# 2# 3# 4# 5# 6# 7# Excipient Sorbitol Mannitol Dextrose Xylitol Lactose Trehalose Sucrose Solution clarity time > 24 h < 10 h < 10 h Hazy Hazy Slightly hazy Slightly hazy

[0040] Result analysis:

[0041] The clarity time of voriconazole solution with sorbitol as an adjuvant was >24 h, which was significantly better than other adjuvants (mannitol, glucose, etc. clarity time <10 h), indicating that it could effectively maintain the dispersed state of drug molecules, inhibit crystallization or aggregation, and ensure long-term solution clarity. Mannitol (2#) and glucose (3#) can clarify within 10 h, but the stability is insufficient, which is speculated to be related to the weak embedding ability of their molecular conformation to the drug; while xylitol (4#), lactose (5#), trehalose (6#) and sucrose (7#) directly led to turbidity of the solution, which may be related to poor drug-adjuvant compatibility or crystallization induction.

[0042] (3) Influence of acid on solution clarity

[0043] According to the proportions in Table 1, voriconazole solution was prepared, i.e. voriconazole concentration 1 g / 100 mL, other adjuvants unchanged, pH 4-5, and the influence of replacing acid as an adjuvant on the clarity of voriconazole was investigated.

[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 clarity time > 24 h N / A N / A N / A N / A Slightly hazy N / A

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

[0047] Result analysis:

[0048] When methanesulfonic acid is used as a salting agent, the solution clarity time is >24 h, indicating that the methanesulfonic acid salt formed with voriconazole has excellent solubility stability; and other acids (lactic acid, tartaric acid, etc.) cannot effectively dissolve the drug (N / A) or cause slight turbidity (acetic acid), and are not suitable. Methanesulfonic acid can maintain the salted state of the drug in the pH 4-5 range, and avoid excessive acidification to trigger hydrolysis side reactions, which is an optimal choice that takes into account solubility and chemical stability.

[0049] (4) Effect of pH on the related substances of the preparation solution

[0050] The mixed drug solution obtained in (1) was divided into 50 parts, each of 20 mL, and part of it was placed in a sealed glass container to investigate the changes in properties, content, pH value and related substances 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, and then press-sealed and capped for 40°C accelerated investigation. Sterilization study was also conducted.

[0051] Table 4 pH study results of bulk solution - bulk solution (40°C)

[0052]

[0053]

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

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

[0056]

[0057] Results analysis:

[0058] 1) The pH value of the preparation solution is in the range of 4-5, and as the pH value increases, the total impurities of the bulk drug solution placed at 40°C for 24 h show an increasing trend, but compared with 0 days, there is no obvious change, showing good stability.

[0059] 2) When the pH value of the freeze-dried product is in the range of 4-5, the total impurities of the sample after 40°C acceleration show no increasing trend.

[0060] 3) During the preparation process, it was found that the pH value of the bulk solution after preparation was about 4.4, which met the requirements. And the content, related substances and pH value of the bulk solution before and after freeze-drying showed no obvious change, indicating that the drug solution was still stable after the freeze-drying process.

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

[0062] According to the EU sterilization method selection decision tree (EMA / CHMP / CVMP / QWP / BWP / 850374 / 2015), 160℃ dry heat sterilization for 120 minutes is preferred for non-solution products sterilization, for products that cannot tolerate this dry heat sterilization condition, using irradiation conditions with a radiation dose of not less than 25 kGy sterilization, while considering the moist heat sterilization. Still can not be tolerated products, consider taking the combination of sterile filtration and aseptic production process sterilization process. Therefore, the present invention first carried out dry heat sterilization and irradiation sterilization of freeze-dried products. According to the EU sterilization method selection decision tree (EMA / CHMP / CVMP / QWP / BWP / 850374 / 2015), using 160℃ dry heat sterilization for 120 minutes, 170℃ dry heat sterilization for 60 minutes, 15 kGy of irradiation sterilization and 30 kGy of irradiation sterilization conditions for dry heat sterilization and irradiation sterilization research, the research results are as follows:

[0063] Table 6 Dry heat sterilization and irradiation sterilization research results

[0064]

[0065] Dry heat sterilization and irradiation sterilization results analysis and evaluation

[0066] The above research results show that under the conditions of dry heat sterilization and irradiation sterilization, pH, content and related substances do not appear obvious change. The injection of voriconazole freeze-dried product of the present invention is not sensitive to temperature, can tolerate 160℃×120 minutes and 170℃×60 minutes dry heat sterilization conditions. Injection of voriconazole freeze-dried product can tolerate 30 kGy and 15 kGy of irradiation dose sterilization conditions.

[0067] 3. Freeze-drying process

[0068] The 20mL / branch specification obtained according to 1 is filled in 30mL siren bottle, and the voriconazole liquid is freeze-dried according to the process of table 7, the pH of the liquid is 4.3-4.6, at this time the amount of methanesulfonic acid added is 55mg.

[0069] Table 7

[0070] No. Process Plate temperature (℃) Vacuum (mbar) Process time (min) 1 Loading 10 --- --- 2 Pre-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] The freeze-drying includes pre-freezing, primary drying and secondary drying, the pre-freezing temperature is -10℃, the pre-freezing time is 10 minutes, the ice formation of the mixed medicine liquid is completed in several seconds, the obtained ice body is uniform in upper and lower, the shape is complete, and there is no stratification, protrusion and other phenomena. The primary drying temperature is set to 20℃, the temperature rising rate is 0.5℃ / min, the obtained sample shape is good, the moisture content is less than 2%, and the drying period is shortened, and the primary drying needs 20 hours. In the application, the main factor affecting the drying time is the drying temperature, and the influence of the vacuum degree is small. The primary drying temperature in the application is set to 20℃, which is higher than the eutectic point of the product but lower than the glass transition temperature, which belongs to the operation with certain risk, so whether melting or even hollow phenomenon appears at the bottom after the process and end is observed. The results do not appear adverse results. The secondary drying temperature is 30℃, and the drying time is 3 hours. After the primary drying is completed, a part of water is still adsorbed on the capillary blood vessels and polar groups of the dried substance, and these water is not frozen, when they reach a certain content, they provide conditions for certain chemical reactions. In order to improve the stability of the product, it is reasonable to control the secondary drying temperature of the product at 30℃, and the moisture content is less than 0.5% after the secondary drying.

[0072] 4. Clinical diluent compatibility test

[0073] The injection voriconazole obtained by the freeze-drying process is stored with 0.9% sodium chloride injection, sodium lactate Ringer's injection, 5% glucose and 0.9% sodium chloride injection, 5% glucose injection for 24 hours for compatibility research, and compared with the imported original drug.

[0074] Table 8 Injection voriconazole and clinical diluent compatibility research sample information

[0075] Name Specification Manufacturer Imported original drug 200 mg Pfizer Inventive self-made sample 200 mg Hainan Pule Pharmaceutical 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 Kolon Pharmaceutical Co., Ltd. Sodium lactate Ringer's injection 500 mL Anhui Shuanghe Pharmaceutical Co., Ltd. Sterilized water for injection 500 mL Zhejiang Sapiens Pharmaceutical Co., Ltd.

[0076] Referring to the use method of the imported original drug instruction, the injection voriconazole is taken, 19mL of injection water is added to each bottle sample by using a disposable sterile syringe to dissolve, and a reconstituted solution with a concentration of 10mg / mL is prepared.

[0077] The reconstituted solution after storage for 24 hours is taken, the contents of the bottle are respectively injected into 4 kinds of clinical diluent 0.9% sodium chloride injection, sodium lactate Ringer's injection, 5% glucose injection, 5% glucose and 0.9% sodium chloride injection 20mL in a transfusion bag, a clinical use solution containing voriconazole 5mg / mL is prepared, the reconstitution time is less than 30 seconds. After being taken out after being placed in the refrigerator (2-8℃) for 24 hours, it is detected again under the condition of room temperature (25℃±2℃) according to the sampling plan.

[0078] Detection method

[0079] Solution clarity and color

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

[0081] 2) pH

[0082] Take the compatible solution, and measure it according to the pH measurement method (Chinese Pharmacopoeia 2015 Edition Volume 4 General Rules 0631).

[0083] 3) Osmotic pressure

[0084] Take the compatible solution, and measure it twice. The molar concentration of the osmotic pressure should be comparable to that of human blood (the osmotic pressure molar concentration range of normal human blood is 285-310 Osmol / kg).

[0085] 4) Related substances

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

[0087] 5) 5-Hydroxymethylfurfural

[0088] The detection method of 5-hydroxymethylfurfural is formulated according to the item of tinidazole and glucose injection in Chinese Pharmacopoeia 2015 Edition Volume 2, and the specific method is as follows:

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

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

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

[0092] 6) Content

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

[0094] 7) Insoluble particulates

[0095] The compatible solution was taken, and the insoluble particulates were determined according to the Insoluble Particulates Test (Chinese Pharmacopoeia 2015 Edition Part 4 General Rules 0903 First Method). The number of particulates of 10 μm and above in each mL of the compatible solution should not be more than 25, and the number of particulates of 25 μm and above should not be more than 3.

[0096] 8) Bacterial endotoxin

[0097] The amount of bacterial endotoxin in each 1 mg of voriconazole was determined according to the Bacterial Endotoxin Test (Chinese Pharmacopoeia 2015 Edition Part 4 General Rules 1143). The amount of bacterial endotoxin should not be more than 1.5 EU.

[0098] Test results

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

[0100] Table 9 Compatibility test results with 0.9% sodium chloride injection (reconstituted with water for injection)

[0101]

[0102] Table 10 Compatibility test results with sodium lactate Ringer's injection (reconstituted with water for injection)

[0103]

[0104] Table 11 Compatibility test results with 5% glucose injection (reconstituted with water for injection)

[0105]

[0106] Table 12 Compatibility test results 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 self-made voriconazole for injection and the imported original drug are good in compatibility stability with 0.9% sodium chloride injection, sodium lactate Ringer's injection, 5% glucose injection, 5% glucose and 0.9% sodium chloride injection, the solution is stable in quality within 24 hours, the quality indexes such as clarity and color, pH value, insoluble particles, osmotic pressure, bacterial endotoxin, 5-hydroxymethyl furfural, content and related substances meet the standard requirements and the requirements in the instruction manual of the imported original drug. Comprehensive evaluation shows that the quality of the self-made voriconazole for injection is equivalent to that of the imported original drug, and there is no obvious difference between the two, and they are comparable. According to the instruction manual, the prepared liquid should be stored at 2-8℃ and used within 24 hours, and there is no quality risk and no safety problem.

[0110] 5. Stability study

[0111] According to the requirements and methods provided in the 2015 edition of Chinese Pharmacopoeia Appendix 9001 "Guiding Principles for Stability Test of Raw Materials and Preparations", three batches of voriconazole freeze-dried products prepared were subjected to 6-month accelerated test and 18-month long-term stability test. The accelerated condition was 40℃±2℃ and relative humidity 75%±5%, and samples were taken once at the end of the 1st month, 2nd month, 3rd month and 6th month for detection. The long-term stability condition was 25℃±2℃ and relative humidity 60%±10%, and samples were taken for detection at 0 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months.

[0112] (1) Accelerated test results

[0113] Table 13

[0114]

[0115]

[0116] Conclusion

[0117] After 6-month accelerated test of the three batches, the content was maintained at 95.85%-99.12%, which met the requirements of the pharmacopoeia (90%-110% of the labeled amount), and the downward trend was gentle. The total impurities were 0.05% at most, which was far lower than the conventional limit (≤1.0%), indicating that the degradation products were well controlled. The moisture was ≤0.50%, and the pH fluctuation range was 4.27-4.51, both of which were within the reasonable range. All batches remained "white freeze-dried block" without physical property change during the test period. The voriconazole freeze-dried product was stable in quality within 6 months under the accelerated condition (40℃±2℃, RH 75%±5%).

[0118] (2) Long-term stability results

[0119]

[0120]

[0121] Conclusion:

[0122] After 24-month long-term stability test, the content of all batches is stable without significant degradation trend. The degradation products are well controlled and meet the safety requirements. The chemical properties of the preparation are stable without significant acid-base changes. The data trends of the three batches are highly consistent, indicating that the production process is stable and reliable. The voriconazole freeze-dried product of the application shows excellent chemical and physical stability in the long-term stability test, and all key indicators (content, impurities, moisture, pH and appearance) meet the requirements of the Chinese Pharmacopoeia. Combined with the results of the accelerated test, it supports the setting of the effective period of 24 months, and has the stability guarantee for commercial production.

Claims

1. A voriconazole lyophilized powder for injection, characterized by, The lyophilized powder is composed of the following components per 1000 mL solution before lyophilization: voriconazole 10.0 g, sulfobutyl betacyclodextrin 8.0 g, sorbitol 12.5 g, sodium chloride 3.5 g, 1-3 g of methanesulfonic acid, water for injection; The preparation method of the lyophilized powder injection, comprising the following steps: (1) dissolve sulfobutyl betacyclodextrin, sorbitol, sodium chloride and methanesulfonic acid in 50%-80% volume of water for injection, stir at 20-30℃ until clear; (2) add voriconazole, continue to stir until completely dissolved; (3) add water for injection to constant volume, mix evenly, filter to obtain the mixed drug solution; (4) sterilize, fill and freeze dry the obtained mixed drug solution to obtain the voriconazole lyophilized powder injection for injection; The freeze drying includes: pre-freezing at -10℃ to -5℃ for 5-30 minutes, primary drying at 20℃ for 15-20 hours and secondary drying at 30℃ for 2-5 hours; The pH value of the lyophilized powder is 4.0-5.

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2. The voriconazole lyophilized powder for injection according to claim 1, characterized in that, The pH value of the lyophilized powder is 4.27-4.

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3. The voriconazole lyophilized powder for injection according to claim 1, which is characterized by, The long-term stability of the lyophilized powder meets the following conditions: The content decreases by ≤3% under the condition of 25℃±2℃, relative humidity 60%±10% for 24 months; The total impurity content is ≤0.1%; The moisture content is ≤0.5%.

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

5. The voriconazole lyophilized powder for injection according to claim 1, which is characterized by, The temperature rising rate of the primary drying stage of the freeze drying is 0.5℃ / min.

6. Use of the voriconazole lyophilized powder for injection according to any one of claims 1 to 5, characterized in that, A pharmaceutical composition for treating invasive fungal infections.

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