Isavuconazole freeze-dried preparation for injection and preparation method thereof

Abstract

The invention provides an isavuconazole freeze-dried preparation for injection and a preparation method of the isavuconazole freeze-dried preparation. The preparation method sequentially comprises the following steps: a) putting a liquid medicine bottle filled with a pharmaceutical composition solution into a freeze dryer with the shelf temperature set to be 5-15 DEG C; b) performing a freezing step; c) performing primary drying; and d) performing secondary drying. According to the preparation method disclosed by the invention, the freeze-drying time can be shortened, and the prepared freeze-drying preparation is low in moisture content and total impurity content and has excellent stability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a lyophilized isavuconazole preparation for injection and a preparation method thereof. Background Art

[0002] Isavuconazole is a new triazole antifungal drug with a broad antibacterial spectrum. In vitro studies and clinical trials have shown that it has antibacterial activity against molds, yeasts, bifida and some rare fungi. It is effective in the clinical treatment of infections in special parts, such as the central nervous system. It has stable blood drug concentration, good safety and tolerance, and few adverse reactions related to long-term use. Isavuconazonium sulfate is a water-soluble prodrug of isavuconazole. When it enters the body, it will achieve the corresponding therapeutic effect in the form of isavuconazole.

[0003] The lyophilized powder of isavuconazole sulfate for injection developed by Astellas was approved by the U.S. FDA in March 2015 and by the National Medical Products Administration in June 2022 for the treatment of invasive aspergillosis and invasive mucormycosis infections in adults and pediatric patients aged 1 year and above.

[0004] In the prior art, the lyophilized preparation of isavuconazole sulfate prepared by freeze-drying method generally has the problems of high water content, high total impurity content, poor stability, long freeze-drying time, low production efficiency, etc., which is not conducive to the storage, transportation and commercialization of the product.

[0005] CN115300467A discloses a lyophilized powder of isavuconazole sulfate for injection and its preparation process. In the technical solution involved in the embodiment, the freeze-drying time is as long as about 40 hours to about 53 hours, and the moisture content of the obtained lyophilized powder is as high as 0.52%.

[0006] CN116898814A discloses an isavuconazole sulfate lyophilized powder injection and a preparation method thereof, wherein in the technical solution involved in the embodiment, the freeze-drying time is as long as about 39 hours to about 42 hours, and the total impurity content of the obtained lyophilized powder is as high as 0.86%.

[0007] CN107661298A discloses a freeze-dried powder of isavuconazole sulfate for injection and a freeze-drying process thereof, wherein in the technical solution involved in the embodiment, the freeze-drying time is as long as about 47 hours to about 50 hours. Summary of the invention

[0008] The object of the present invention is to provide a method for preparing a lyophilized isavuconazole preparation for injection which overcomes the above-mentioned defects of the prior art and a lyophilized isavuconazole preparation for injection prepared by the preparation method.

[0009] In a first aspect, the present invention provides a method for preparing a lyophilized preparation of isavuconazole for injection, comprising the following steps performed in sequence:

[0010] a) placing the vial containing the pharmaceutical composition solution into a freeze dryer with the shelf temperature set at 5-15°C;

[0011] b) performing a freezing step;

[0012] c) performing a primary drying; and

[0013] d) performing secondary drying;

[0014] in,

[0015] The pharmaceutical composition solution is an aqueous solution of isavuconazole or a pharmaceutically acceptable salt thereof;

[0016] The freezing step comprises the following steps performed in sequence:

[0017] Under normal pressure, the shelf temperature is lowered to -35°C to -45°C at a rate of 0.3-1.0°C / min and maintained for 60-120 min;

[0018] Under normal pressure, the shelf temperature is raised to -10°C to -20°C at a rate of 0.3-1.0°C / min, and maintained for 30-90 minutes;

[0019] The primary drying comprises the following steps:

[0020] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 15-25°C at a rate of 0.3-1.0°C / min and maintained for 480-720 min;

[0021] The secondary drying comprises the following steps performed in sequence:

[0022] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 25-35°C at a rate of 0.3-1.0°C / min and maintained for 180-300 min;

[0023] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 40-46°C at a rate of 0.3-1.0°C / min and maintained for 120-180 min;

[0024] Maintain the shelf temperature at 40-46°C and extreme vacuum for 120-180 minutes;

[0025] Under extreme vacuum conditions, the shelf temperature was cooled to 5-15°C at a rate of 0.5-1.5°C / min and maintained for more than 10 minutes.

[0026] In a second aspect, the present invention provides a lyophilized preparation of isavuconazole for injection prepared by the preparation method described in the first aspect.

[0027] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention, as well as the technical features specifically described below (such as embodiments), can be combined with each other to form new or preferred technical solutions. DETAILED DESCRIPTION

[0028] The present invention will be further described in detail below. Such description is for illustrative purposes only and is not intended to limit the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments. Those skilled in the art can make various modifications and changes without departing from the spirit of the present invention.

[0029] General Definitions and Terminology

[0030] Unless otherwise indicated, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of a conflict, the definitions provided herein shall prevail.

[0032] Unless otherwise indicated, all percentages, parts, ratios, etc. are by weight.

[0033] When quantity, concentration or other value or parameter is given as range, preferred range or preferred upper limit and lower limit or specific value, it should be understood as specifically disclosing all ranges formed by paired values ​​from any upper limit range or preferred value and any lower limit range or preferred value, regardless of whether the range is disclosed separately. Unless otherwise stated, when numerical range is quoted herein, the range refers to including its endpoints and integers and fractions within all such ranges. The scope of the present invention is not limited to the specific numerical value quoted when defining the range. For example, "0.5-1.5" covers 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 or 1.5, and any sub-range consisting of any two values ​​therein, such as 0.6-1.4, 0.8-1.2, 0.9-1.1, etc.

[0034] The terms "about" and "approximately" when used in conjunction with a numerical variable generally refer to the value of that variable and all values ​​of that variable are within the experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified value, or within a wider range (e.g., within ±15%, within ±20%, within ±25%, or within ±30%).

[0035] The terms "comprises", "includes", "has", "contains" or "involves" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. It will be understood by those skilled in the art that the above terms such as "comprising" encompass the meaning of "consisting of". The expression "consisting of" excludes any element, step or ingredient not specified. The expression "consisting essentially of" means that the scope is limited to the specified elements, steps or ingredients, plus the optional presence of elements, steps or ingredients that do not substantially affect the basic and novel features of the claimed subject matter. It will be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of".

[0036] Unless otherwise specified, the terms "combination thereof" and "mixture thereof" refer to a multi-component mixture of the elements, such as a two-component mixture, a three-component mixture, a four-component mixture and the maximum possible multi-component mixture.

[0037] The terms "one or more" or "at least one" as used herein refer to one, two, three, four, five, six, seven, eight, nine or more.

[0038] In addition, if the number of parts or components of the present invention is not indicated before, it means that there is no limit to the number of occurrences (or existence) of the parts or components. Therefore, it should be interpreted as including one or at least one, and the singular form of the parts or components also includes the plural form, unless the numerical value obviously represents the singular.

[0039] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring of said event or circumstance.

[0040] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0041] The term "pharmaceutically acceptable excipient" or "excipient" refers to those carrier materials that have no obvious irritation to the organism and do not damage the biological activity and performance of the active compound. "Pharmaceutically acceptable excipients" include, but are not limited to, fillers, pH regulators, preservatives, antioxidants, anti-photolysis agents, local analgesics, etc. In one embodiment of the present invention, the excipients in the pharmaceutical composition solution used in the preparation method of the present invention include fillers, preferably mannitol. In another embodiment, the excipients in the pharmaceutical composition solution used in the preparation method of the present invention include pH regulators, such as sulfuric acid.

[0042] The terms "pharmaceutically active ingredient" and "active ingredient" refer to a chemical entity that can effectively treat or prevent a target disease or condition. In an embodiment of the present invention, the active ingredient may be isavuconazole and its various forms of salts, esters, prodrugs, derivatives, solvates (such as hydrates), isomers (such as enantiomers), polymorphs, complexes and any mixtures thereof; preferably, these forms are pharmaceutically acceptable. In a preferred embodiment, the active ingredient is isavuconazole or a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the active ingredient is isavuconazole sulfate.

[0043] The term "drug solution" or "pharmaceutical composition solution" refers to a solution comprising a pharmaceutically active ingredient and optionally a pharmaceutically acceptable excipient. In one embodiment of the present invention, the pharmaceutical composition solution is an aqueous solution comprising active ingredients isavuconazole sulfate and mannitol. In another embodiment of the present invention, the pharmaceutical composition solution is an aqueous solution comprising active ingredients isavuconazole sulfate, mannitol and sulfuric acid.

[0044] The term "pharmaceutical preparation" refers to a pharmaceutical composition administered to a patient in need of treatment, and can generally be in the following forms depending on its administration route: oral preparation, injection, external preparation or inhalation preparation. In an embodiment of the present invention, the preparation prepared by the preparation method of the present invention is a lyophilized preparation for isavuconazole injection.

[0045] The term "lyophilized preparation" is a form of drug preparation, in which the active ingredients and excipients of the drug are dissolved in a solvent (such as water), prepared into a solution of a certain concentration, and then packaged in containers such as medicine bottles (for example, vials), frozen at low temperatures in a sterile and closed environment, and then the solvent (such as water) is sublimated by reducing the air pressure and / or increasing the temperature, leaving a loose block or powdered drug in solid form. When in use, a solvent (such as sodium chloride aqueous solution or glucose aqueous solution) needs to be added to dissolve the drug into a solution for injection or infusion to treat the disease. Lyophilized preparations can also be called "lyophilized powder injection" or "lyophilized powder injection".

[0046] As used herein, the term "related substances" refers to impurities that are structurally related to the active ingredient (such as isavuconazole sulfate). These impurities include substances (starting materials, intermediates, etc.) used to directly or indirectly synthesize the active ingredient, as well as other products (side reaction products, isomers, etc.) produced in the synchronous reaction, and also include derivatives of the active ingredient, such as degradation impurities.

[0047] As used herein, the term "absolute pressure" refers to a pressure value relative to a perfect vacuum.

[0048] As used herein, the term "normal pressure" refers to one atmosphere, which is approximately 101.325 kPa or 760 mm of mercury under standard conditions.

[0049] As used herein, the term "ultimate vacuum" means that the absolute pressure in the head box of the freeze dryer is below 100 μbar.

[0050] The term "half-pressing" means that the rubber plug is partially pressed into the mouth of the liquid medicine bottle, which allows air circulation while preventing the loss of active ingredients and the entry of foreign matter. In one embodiment of the present invention, the rubber plug is placed at the mouth of the vial for half-pressing.

[0051] The term "full plugging" refers to a plugging operation performed under negative pressure conditions filled with protective gas after the freeze-drying process is completed in order to protect the freeze-dried preparation from contamination and ensure sterility. The full plugging of the present invention can be performed in a freeze dryer front box filled with sterile nitrogen and in a negative pressure state, for example, under the condition of being filled with sterile nitrogen and the pressure in the freeze dryer front box being -0.010±0.005MPa. After the full plugging of the medicine bottle, the front box of the freeze dryer is restored to normal pressure, which can be achieved by continuing to fill with gas or directly connecting the front box of the freeze dryer to the external environment.

[0052] Preparation method of the present invention

[0053] The present invention provides a method for preparing a lyophilized isavuconazole injection preparation, which comprises the following steps performed in sequence:

[0054] a) placing the vial containing the pharmaceutical composition solution into a freeze dryer with the shelf temperature set at 5-15°C;

[0055] b) performing a freezing step;

[0056] c) performing a primary drying; and

[0057] d) performing secondary drying;

[0058] in,

[0059] The pharmaceutical composition solution is an aqueous solution of isavuconazole or a pharmaceutically acceptable salt thereof;

[0060] The freezing step comprises the following steps performed in sequence:

[0061] Under normal pressure, the shelf temperature is lowered to -35°C to -45°C at a rate of 0.3-1.0°C / min and maintained for 60-120 min;

[0062] Under normal pressure, the shelf temperature is raised to -10°C to -20°C at a rate of 0.3-1.0°C / min, and maintained for 30-90 minutes;

[0063] The primary drying comprises the following steps:

[0064] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 15-25°C at a rate of 0.3-1.0°C / min and maintained for 480-720 min;

[0065] The secondary drying comprises the following steps performed in sequence:

[0066] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 25-35°C at a rate of 0.3-1.0°C / min and maintained for 180-300 min;

[0067] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 40-46°C at a rate of 0.3-1.0°C / min and maintained for 120-180 min;

[0068] Maintain the shelf temperature at 40-46°C and extreme vacuum for 120-180 minutes;

[0069] Under extreme vacuum conditions, the shelf temperature was cooled to 5-15°C at a rate of 0.5-1.5°C / min and maintained for more than 10 minutes.

[0070] Step a) Place the liquid medicine bottle into the freeze dryer

[0071] The preparation of the pharmaceutical composition solution in step a) can be carried out in a liquid preparation tank or in a liquid preparation bag.

[0072] The order in which isavuconazole or a pharmaceutically acceptable salt thereof (e.g., isavuconazole sulfate) and an optional pharmaceutically acceptable excipient are added to water (e.g., water for injection) is not particularly limited. For example, the pharmaceutically acceptable excipient may be added to water first, and then isavuconazole or a pharmaceutically acceptable salt thereof (e.g., isavuconazole sulfate) may be added. Alternatively, isavuconazole or a pharmaceutically acceptable salt thereof (e.g., isavuconazole sulfate) may be added to water first, and then a pharmaceutically acceptable excipient may be added. When there is no pharmaceutically acceptable excipient, isavuconazole or a pharmaceutically acceptable salt thereof (e.g., isavuconazole sulfate) may be added to water directly.

[0073] In one embodiment, pharmaceutically acceptable excipients include, but are not limited to, one or more of fillers, pH adjusters, preservatives, antioxidants, anti-photolysis agents, and local analgesics.

[0074] The filler can be selected from a polyol of about 5 to about 9 carbon atoms, such as mannitol, sorbitol and galactitol, etc.; a monosaccharide of about 5 to 10 carbon atoms, especially a natural aldohexose, such as glucose (dextrose), mannose and galactose, etc.; a disaccharide of 12 carbon atoms, such as natural sucrose and lactose, etc.; a polysaccharide, such as starch; or one or more of the above sugars. In a preferred embodiment, the filler is one or more of mannitol, sorbitol and lactose. In a specific embodiment, the pharmaceutical composition solution of the present invention comprises isavuconazole sulfate, mannitol and water for injection.

[0075] Mannitol is an isomer of sorbitol. The hydroxyl groups on the second carbon atom of the two alcohols face in different directions. Mannitol is easily soluble in water and is a white, transparent solid with a sweet taste similar to sucrose. Mannitol can be selected from the D-Mannitol model, such as the commercial product from Pall Corporation. and Roquette's commercially available products Mannitol that can be used includes, but is not limited to, forms of β-mannitol and δ-mannitol.

[0076] The freeze-dried pharmaceutical composition solution for the present invention has a specific pH. In one embodiment, the pH of the pharmaceutical composition solution is 1.3-2.0, for example, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0. When the pH of the pharmaceutical composition solution is not within the range of 1.3-2.0, an appropriate amount of pH adjusting agent (such as sulfuric acid) can be added to adjust the pH to 1.3-2.0. When the pH of the pharmaceutical composition solution is within the range of 1.3-2.0, it is not necessary to add a pH adjusting agent.

[0077] In one embodiment, the pH adjusting agent includes one or more of the following: borate, acetate, phosphate, citrate, tartrate, carbonate, formates, oxalates, succinates; and / or, strong acid, strong base, weak acid, weak base. In a preferred embodiment, the pH adjusting agent includes one or more of the following: phosphate; and / or, sulfuric acid, boric acid, hydrochloric acid, citric acid, acetic acid, tartaric acid, phosphoric acid, formic acid, oxalic acid, succinic acid, maleic acid, sodium hydroxide, potassium hydroxide, ammonia water. In a more preferred embodiment, the pH adjusting agent includes one or more of the following: phosphate; and / or, sodium hydroxide, potassium hydroxide, sulfuric acid, phosphoric acid. In a specific embodiment, the pH adjusting agent is sulfuric acid. In a more specific embodiment, the pH adjusting agent is 8-10 mol / L (e.g., 9 mol / L) sulfuric acid aqueous solution.

[0078] In one embodiment, the optional pharmaceutically acceptable excipient (such as mannitol) is present in an amount of about 10%-30% based on the total weight of the pharmaceutically active ingredient (such as isavuconazole sulfate) and the optional pharmaceutically acceptable excipient (such as mannitol), preferably about 15%-25%, more preferably about 18%-22%, and even more preferably about 19%-21%. For example, the amount of the optional pharmaceutically acceptable excipient (such as mannitol) includes, but is not limited to, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 20.1%, 20.2%, 20.3%, 20.4%, 20.5%, 20.6%, 20.7%, 20.8%, 20.9%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% based on the total weight of the active pharmaceutical ingredient (such as isavuconazole sulfate) and the optional pharmaceutically acceptable excipient (such as mannitol).

[0079] In the present invention, the pharmaceutically acceptable excipients listed above are only illustrative and representative. Therefore, the excipients contained in the pharmaceutical composition solution of the present invention are not limited to the pharmaceutically acceptable excipients listed above. It should be understood that those skilled in the art can make various changes, adjustments or equivalent substitutions to the above excipients according to conventional techniques, which do not exceed the scope of protection of the present invention.

[0080] In one embodiment, the pharmaceutical composition solution of the present invention comprises isavuconazole sulfate, mannitol, water for injection and optionally sulfuric acid. In one embodiment, the volume of the pharmaceutical composition solution is about 3.0-3.3mL, such as about 3.0mL, 3.1mL, 3.15mL, 3.18mL, 3.2mL or 3.3mL. In one embodiment, the pharmaceutical composition solution includes 372-410mg of isavuconazole sulfate, 96-106mg of mannitol, water for injection of the amount supplemented to the volume of the pharmaceutical composition solution and optionally sulfuric acid. In another embodiment, the pharmaceutical composition solution includes 200-220mg of isavuconazole, 96-106mg of mannitol, water for injection of the amount supplemented to the volume of the pharmaceutical composition solution and optionally sulfuric acid. In a preferred embodiment, the pharmaceutical composition solution includes 372.60mg of isavuconazole sulfate, 96.00mg of mannitol, water for injection of the amount supplemented to the volume of the pharmaceutical composition solution of 3.00mL and optionally sulfuric acid. In a more preferred embodiment, the pharmaceutical composition solution includes 394.96 mg of isavuconazole sulfate, 101.76 mg of mannitol, water for injection and optionally sulfuric acid to make up to 3.18 mL of the volume of the pharmaceutical composition solution. In one embodiment, the pH of the mixed solution formed by isavuconazole sulfate, mannitol and water for injection is 1.3-2.0, and sulfuric acid is not required to obtain a pharmaceutical composition solution with a pH of 1.3-2.0. In another embodiment, the pH of the mixed solution formed by isavuconazole sulfate, mannitol and water for injection is not 1.3-2.0, and the amount of sulfuric acid added is an amount that can adjust the pH of the mixed solution to 1.3-2.0, thereby obtaining a pharmaceutical composition solution with a pH of 1.3-2.0. The above-mentioned sulfuric acid is preferably an aqueous solution of sulfuric acid of 8-10 mol / L (e.g., 9 mol / L).

[0081] In one embodiment, the pharmaceutical composition solution is contained in a medicine bottle, for example, a vial with a filling volume of 3.18 mL can be used.

[0082] In one embodiment, when the liquid medicine bottle containing the pharmaceutical composition solution is placed in the freeze dryer, the preset temperature of the freeze dryer shelf can be about 5-15° C. In one embodiment, the freeze dried bottle containing the pharmaceutical composition solution is placed in the freeze dryer with the shelf temperature set to 8-12° C. In a preferred embodiment, the liquid medicine bottle containing the pharmaceutical composition solution is placed in the freeze dryer with the shelf temperature set to 10° C.

[0083] In one embodiment, sterilization is optionally performed before step a). For example, the pharmaceutical composition solution can be sterilized before freeze-drying. The sterilization method is not particularly limited, for example, a filtration sterilization method can be used. In one embodiment of the present invention, the pharmaceutical composition solution before freeze-drying is sterilized by filtration. In the present invention, filtration sterilization is a technology that removes microorganisms in a liquid by physical methods to achieve the purpose of sterility. This process mainly relies on filters containing micropore filter membranes, through which microorganisms such as bacteria and viruses can be effectively intercepted and removed. In a preferred embodiment, a filter with a hydrophilic microporous filter membrane of 0.45μm is used for filtration sterilization. In another preferred embodiment, a filter with a hydrophilic microporous filter membrane of 0.22μm is used for filtration sterilization. The microporous filter membrane material used in the present invention can be a polyethersulfone (PES) material, for example, a commercially available product Pall One or more of the EKVs may also be made of polyvinylidene fluoride (PVDF), such as commercially available products from Merck. In a specific embodiment, the microporous filter membrane used for filtration and sterilization is made of PES material, for example, a commercial product Pall In a particularly preferred embodiment, the filtration sterilization can be performed by first filtering with a filter having a hydrophilic microporous membrane of 0.45 μm, and then the subsequent filtrate is further filtered with a filter having a hydrophilic microporous membrane of 0.22 μm.

[0084] Step b) Freezing step

[0085] Through a suitable freezing step, the water molecules in the pharmaceutical composition solution can be formed into ice crystals of suitable size and shape, which is convenient for the subsequent drying step.

[0086] The freezing step of the present invention can be carried out under the following conditions in sequence:

[0087] Under normal pressure, the shelf temperature is lowered to -35°C to -45°C at a rate of 0.3-1.0°C / min and maintained for 60-120 min;

[0088] Under normal pressure, the shelf temperature is raised to -10°C to -20°C at a rate of 0.3-1.0°C / min and maintained for 30-90 min.

[0089] In one embodiment, in the freeze-drying step of the preparation method of the present invention, the freezing step comprises the following steps performed sequentially:

[0090] Under normal pressure, the shelf temperature was cooled to -38°C to -42°C at a rate of 0.4-0.6°C / min and maintained for 85-95 min;

[0091] Under normal pressure, the shelf temperature was raised to -14°C to -16°C at a rate of 0.4-0.6°C / min and maintained for 55-65 min.

[0092] In another embodiment, in the freeze-drying step of the preparation method of the present invention, the freezing step comprises the following steps performed sequentially:

[0093] Under normal pressure, the shelf temperature was cooled to -40°C at a rate of 0.5°C / min and maintained for 90 min;

[0094] Under normal pressure, the shelf temperature was raised to -15°C at a rate of 0.5°C / min and maintained for 60 min.

[0095] The present invention uses the above-mentioned freezing step so that the water molecules in the aqueous solution of the pharmaceutical composition of the present invention (e.g., the isavuconazole sulfate aqueous solution) form ice crystals of suitable size and shape suitable for the subsequent drying step of the present invention, which plays an important role in forming a freeze-dried preparation with low moisture content, low total impurity content and stable properties.

[0096] Step c) primary drying

[0097] Primary drying mainly refers to sublimation drying. This stage mainly uses low temperature and vacuum to directly transform the frozen free water (ice crystals) from solid to gaseous state and escape, and it is necessary to select a suitable vacuum degree and drying temperature. The freeze-drying step of the preparation method of the present invention can achieve primary drying at a higher temperature without negatively affecting the properties of the prepared isavuconazole lyophilized preparation.

[0098] The primary drying of the present invention can be carried out under the following conditions:

[0099] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 15-25°C at a rate of 0.3-1.0°C / min and maintained for 480-720 min.

[0100] In one embodiment, the primary drying of the present invention comprises the following steps:

[0101] Under an absolute pressure of 180-220 μbar, the shelf temperature was raised to 18-22°C at a rate of 0.4-0.6°C / min and maintained for 580-620 min.

[0102] In another embodiment, the primary drying of the present invention comprises the following steps:

[0103] Under an absolute pressure of 200 μbar, the shelf temperature was raised to 20°C at a rate of 0.5°C / min and maintained for 600 min.

[0104] Step d) Secondary drying

[0105] Secondary drying is often referred to as desorption drying. Its purpose is to remove the remaining bound water. These water molecules are tightly bound to the solid structure through hydrogen bonds and need to be dried at a higher temperature and appropriate pressure to ensure that the residual moisture content in the final product is further reduced.

[0106] The secondary drying of the present invention can be carried out under the following conditions in sequence:

[0107] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 25-35°C at a rate of 0.3-1.0°C / min and maintained for 180-300 min;

[0108] Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 40-46°C at a rate of 0.3-1.0°C / min and maintained for 120-180 min;

[0109] Maintain the shelf temperature at 40-46°C and extreme vacuum for 120-180 minutes;

[0110] Under extreme vacuum conditions, the shelf temperature is cooled to 5-15° C. at a rate of 0.5-1.5° C. / min and maintained for more than 10 min, such as 10-60 min or 15-60 min.

[0111] In one embodiment, the secondary drying of the present invention comprises the following steps performed in sequence:

[0112] Under an absolute pressure of 180-220 μbar, the shelf temperature is raised to 28-32°C at a rate of 0.4-0.6°C / min and maintained for 220-260 min;

[0113] Under an absolute pressure of 180-220 μbar, the shelf temperature is raised to 41-45°C at a rate of 0.4-0.6°C / min and maintained for 140-160 min;

[0114] Maintain the shelf temperature at 41-45°C and extreme vacuum for 140-160 minutes;

[0115] Under extreme vacuum conditions, the shelf temperature is cooled to 8-12° C. at a rate of 0.8-1.2° C. / min and maintained for 10-20 min, such as 15-20 min.

[0116] In another embodiment, the secondary drying of the present invention comprises the following steps performed in sequence:

[0117] Under an absolute pressure of 200 μbar, the shelf temperature was raised to 30°C at a rate of 0.5°C / min and maintained for 240 min.

[0118] Under an absolute pressure of 200 μbar, the shelf temperature was raised to 43°C at a rate of 0.5°C / min and maintained for 150 min.

[0119] Maintain the shelf temperature at 43°C and extreme vacuum for 150 min;

[0120] Under extreme vacuum conditions, the shelf temperature was cooled to 10°C at a rate of 1°C / min and maintained for 15 min.

[0121] The "ultimate vacuum" of the freeze dryer during the freeze drying process is achieved by setting the absolute pressure to 0, because the above setting method will close the air inlet valve of the freeze dryer front box, and the vacuum operation will continue, so that the absolute pressure in the freeze dryer front box is infinitely close to 0. In the present invention, setting the freeze dryer front box to the ultimate vacuum means that the absolute pressure in the freeze dryer front box is reduced to below 100 μbar.

[0122] In one embodiment, the time for reducing the absolute pressure in the freeze dryer front box to the ultimate vacuum is about 0.5-10min, such as 0.5min, 1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min or 10min. In one embodiment, the time for reducing the absolute pressure in the freeze dryer front box from 150-250μbar to the ultimate vacuum is about 0.5-10min, such as 0.5min, 1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min or 10min. In another embodiment, the time for reducing the absolute pressure in the freeze dryer front box from 180-220μbar to the ultimate vacuum is about 0.5-10min, such as 0.5min, 1min, 2min, 3min, 4min, 5min, 6min, 7min, 8min, 9min or 10min. In another embodiment, the time for reducing the absolute pressure in the freeze dryer head box from 200 μbar to ultimate vacuum is about 0.5-10 min, such as 0.5 min, 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min or 10 min.

[0123] The preparation method of the present invention prepares a pharmaceutical composition solution (e.g., isavuconazole sulfate aqueous solution) into a lyophilized preparation through the above-mentioned specific freezing step, primary drying and secondary drying, which greatly shortens the time required for freeze drying and improves production efficiency. The prepared lyophilized preparation has excellent properties such as low moisture content and low total impurity content, and also has excellent stability.

[0124] Isavuconazole lyophilized preparation for injection prepared by the preparation method of the present invention

[0125] The isavuconazole lyophilized preparation for injection prepared by the preparation method of the present invention has a 2-butenal content of not higher than 50 ppm (e.g., not detected), a total impurity content of not higher than 3.0% (e.g., about 0.5%), a moisture content of not higher than 0.3% (e.g., about 0.1%), a reconstitution time of not higher than 5 min (e.g., about 10 s), and a content of 95.0%-105.0%, which meets the shelf life standard of the lyophilized preparation of isavuconazole.

[0126] The isavuconazole lyophilized preparation for injection prepared by the preparation method of the present invention has an accelerated storage condition of 25±2°C / 60±5%RH for 3 months, and the content of 2-butenal is not higher than 150ppm (e.g., about 55ppm), the total impurity content is not higher than 5.0% (e.g., about 0.8%), the moisture content is not higher than 0.4% (e.g., about 0.1%), the reconstitution time is not higher than 5min (e.g., about 10s), and the content is 93.0%-105.0%, which meets the shelf life standard of the accelerated test of the isavuconazole lyophilized preparation.

[0127] The isavuconazole lyophilized preparation for injection prepared by the preparation method of the present invention has an accelerated storage condition of 25±2°C / 60±5%RH for 6 months, and the content of 2-butenal is not higher than 150ppm (e.g., about 96ppm), the total impurity content is not higher than 5.0% (e.g., about 1.1%), the moisture content is not higher than 0.4% (e.g., about 0.2%), the reconstitution time is not higher than 5min (e.g., about 10s), and the content is 93.0%-105.0%, which meets the shelf life standard of the accelerated test of the isavuconazole lyophilized preparation.

[0128] The isavuconazole lyophilized preparation for injection prepared by the preparation method of the present invention is placed at 2-8° C. for 3 months, and the content of 2-butenal is not higher than 150 ppm (for example, lower than the quantitative limit of 7.5 ppm), the total impurity content is not higher than 5.0% (for example, about 0.5%), the moisture content is not higher than 0.4% (for example, about 0.1%), the reconstitution time is not higher than 5 min (for example, about 10 s), and the content is 93.0%-105.0%, which meets the shelf life standard of the long-term test of the isavuconazole lyophilized preparation.

[0129] The isavuconazole lyophilized preparation for injection prepared by the preparation method of the present invention is placed at 2-8° C. for 6 months, and the content of 2-butenal is not higher than 150 ppm (for example, lower than the quantitative limit of 7.5 ppm), the total impurity content is not higher than 5.0% (for example, about 0.5%), the moisture content is not higher than 0.4% (for example, about 0.1%), the reconstitution time is not higher than 5 minutes (for example, about 10 seconds), and the content is 93.0%-105.0%, which meets the shelf life standard of the long-term test of the isavuconazole lyophilized preparation.

[0130] Therefore, in another aspect, the present invention provides a lyophilized preparation of isavuconazole for injection prepared by the preparation method of the present invention.

[0131] Beneficial Effects

[0132] The preparation method of the isavuconazole lyophilized preparation for injection provided by the present invention has a short freeze-drying time (about 27 hours, for example, 26.75 hours) and high production efficiency, which can significantly reduce batch production time, production energy consumption and product production cost, and is conducive to commercial production; the lyophilized preparation prepared by the preparation method of the present invention also has excellent properties such as low moisture content (as low as 0.1%), low total impurity content (as low as less than 0.6%) and good stability.

[0133] In addition, the freeze-dried preparation prepared by the preparation method of the present invention has a total impurity content of only 0.8% under accelerated test conditions (25±2°C / 60±5%RH) for 3 months, a total impurity content of only 1.1% under accelerated test conditions (25±2°C / 60±5%RH) for 6 months, and a total impurity content of only about 0.5% under long-term stability test conditions (2°C-8°C) for 3 months and 6 months, which is far below the total impurity content limit of 5.0%. It has excellent stability and is conducive to storage and transportation in various complex environments.

[0134] Example

[0135] The solution of the present invention is further described in detail below in conjunction with specific embodiments.

[0136] It should be noted that the following examples are merely examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description, and it is not necessary and impossible to exhaustively list all the embodiments here, and the obvious changes or modifications derived therefrom are still within the scope of protection of the present invention. Unless otherwise specified, the instruments, equipment, and reagents used herein are all commercially available.

[0137] 1. Raw materials and auxiliary materials:

[0138] Element Manufacturer Isavuconazole sulfate Sichuan Inodabo Pharmaceutical Technology Co., Ltd. Mannitol Merck KGaA sulfuric acid Nanjing Chemical Reagent Co., Ltd.

[0139] 2. Reference preparation

[0140]

[0141] 3. Test methods

[0142] (1) Test methods for related substances (except 2-butenal)

[0143] The determination was carried out according to the high performance liquid chromatography method in accordance with General Chapter 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0144] Solvent: Aqueous solution containing 35mmol / L citric acid and 6mmol / L sodium hydroxide.

[0145] Test solution: Take 5 bottles of isavuconazole lyophilized preparation prepared by the preparation method of the present invention, mix them, take an appropriate amount of sample, accurately weigh, add solvent to dissolve and quantitatively dilute to prepare a solution containing about 2.8 mg of isavuconazole sulfate per 1 mL, centrifuge it if necessary, and take the supernatant.

[0146] Reference solution: Take an appropriate amount of isavuconazole sulfate reference substance, weigh accurately, dissolve in solvent and quantitatively dilute to make a solution containing approximately 2.8 mg per 1 mL.

[0147] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler (Phenomenex Aqua C18, 4.6 mm × 150 mm, 3 μm); water-acetonitrile-trifluoroacetic acid (99:1:0.2) was used as mobile phase A, acetonitrile-trifluoroacetic acid (100:0.1) was used as mobile phase B, and gradient elution was performed according to the table below; the flow rate was 1.5 mL per minute; the column temperature was 40°C; the autosampler temperature was 4°C; the detection wavelength was 250 nm; and the injection volume was 20 μL.

[0148] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 98.5 1.5 3 98.5 1.5 18 93.0 7.0 35 73.0 27.0 60 65.0 35.0 65 60.0 40.0 69 55.0 45.0 74 45.0 55.0 78 35.0 65.0 79 98.5 1.5

[0149] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0150] (2) Test method for 2-butenal

[0151] The determination was carried out according to the high performance liquid chromatography method in accordance with General Chapter 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0152] Solvent: water-acetonitrile-trifluoroacetic acid (50:50:0.05).

[0153] Test solution: Take 2 bottles of isavuconazole lyophilized preparation prepared by the preparation method of the present invention, add a proper amount of solvent to dissolve, transfer the whole amount to a 10 mL volumetric bottle, dilute to the scale with solvent, and shake well.

[0154] Reference solution: Take an appropriate amount of 2-butenal reference substance, weigh accurately, dissolve in solvent and quantitatively dilute to make a solution containing approximately 12 μg per 1 mL.

[0155] Chromatographic conditions: octadecylsilane bonded silica gel was used as filler (Phenomenex Aqua C18, 4.6 mm × 150 mm, 3 μm); water-acetonitrile-trifluoroacetic acid (99:1:0.2) was used as mobile phase A, acetonitrile-trifluoroacetic acid (100:0.1) was used as mobile phase B, and gradient elution was performed according to the table below; the flow rate was 1.0 mL per minute; the column temperature was 40°C; the autosampler temperature was 5°C; the detection wavelength was 220 nm; and the injection volume was 10 μL.

[0156] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 92 8 8 92 8 13 5 95 20 5 95 22 92 8 32 92 8

[0157] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0158] (3) Moisture testing method

[0159] Take 1 bottle of isavuconazole lyophilized preparation prepared by the preparation method of the present invention, and measure the water content according to the first method (Fischer method) of the general rule 0832 of the fourth volume of the Chinese Pharmacopoeia 2020 edition.

[0160] (4) Test method for reconstitution time

[0161] Take the isavuconazole lyophilized preparation prepared by the preparation method of the present invention, add 5 mL of water for injection, shake gently, and record the time required for dissolution.

[0162] (5) Test method for active ingredient content

[0163] The determination was carried out according to the high performance liquid chromatography method in accordance with General Chapter 0512 of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0164] The solvent, test solution, reference solution and chromatographic conditions refer to the test methods for the above-mentioned related substances (except 2-butenal).

[0165] Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram.

[0166] Example 1 Preparation of the Lyophilized Preparation of Isavuconazole Sulfate for Injection of the Present Invention

[0167] The isavuconazole lyophilized preparation for injection was prepared according to the following steps:

[0168] 1) Preparation and packaging of isavuconazole sulfate standard solution

[0169] Prepare isavuconazole sulfate standard solution according to the components and dosage in the following table:

[0170] Ingredients Unit prescription (theoretical) Isavuconazole sulfate 372.60 mg (equivalent to 200 mg isavuconazole) Mannitol 96.00mg Water for injection Add to 3mL sulfuric acid None or appropriate amount (adjust pH to 1.3-2.0)

[0171] Weigh 96.00 mg of mannitol and dissolve it in 2-10°C water for injection, add 372.60 mg of isavuconazole sulfate, stir to dissolve, and continue to add water for injection to make the solution volume 3 mL. If the pH of the above solution is not 1.3-2.0, slowly add 9 mol / L sulfuric acid aqueous solution until the pH of the solution is 1.3-2.0.

[0172] According to the preparation method of the above isavuconazole sulfate standard solution, prepare an appropriate amount (e.g., 1000 mL) of isavuconazole sulfate solution, and filter using a 0.22 μm filter membrane (Pall Company's commercially available product Pall The mixture was sterilized by filtration in EKV, and dispensed into vials at a rate of 3.18 mL / vial, and half-stoppered. During the preparation process, the temperature was maintained at 2-10° C. to obtain the isavuconazole sulfate pharmaceutical composition solution.

[0173] 2) Freeze drying

[0174] The half-stoppered vials were placed on the shelves of a freeze drying chamber (model Lyo-40 (SIP, CIP), Shanghai Dongfulong Technology Co., Ltd.), and freeze-dried according to the freeze-drying program in Table 1-1. The freeze-drying time was 1605 min (26.75 h).

[0175] Table 1-1 Freeze drying procedure

[0176]

[0177] Note: In the column of set absolute pressure (μbar), "atm" means normal pressure; "0" means ultimate vacuum.

[0178] 3) Fully pressed plug and rolled cap

[0179] After freeze drying, sterile nitrogen was used to backfill the front box of the freeze dryer so that the pressure in the front box of the freeze dryer was -0.010±0.005MPa, and the vials were fully plugged. After the front box of the freeze dryer returned to normal pressure, the vials were taken out and capped (capping machine model ZG400D (A), Chutian Technology Co., Ltd.) to obtain the isavuconazole sulfate freeze-dried preparation.

[0180] Test Example 1 Physicochemical Properties of the Lyophilized Preparation of the Present Invention

[0181] The physicochemical properties of the freeze-dried preparation prepared by the preparation method of the present invention were tested using the above test method. The results are shown in Table 1-2 below.

[0182] Table 1-2 Physicochemical properties of the lyophilized preparation of the present invention

[0183]

[0184]

[0185] Note: LOQ stands for limit of quantitation and is 0.05%, which refers to the lowest concentration that can be reliably detected.

[0186] According to the results in the above table, compared with the reference preparation, the isavuconazole sulfate lyophilized preparation prepared by the preparation method of the present invention has a lower total impurity content (only 0.5%), almost no 2-butenal (not detected), and a lower moisture content (only 0.1%).

[0187] Test Example 2 Stability of the lyophilized preparation of the present invention

[0188] 2.1 Accelerated stability of the lyophilized preparation of the present invention

[0189] The lyophilized preparation prepared by the preparation method of the present invention and the reference preparation were placed under conditions of 25±2°C / 60±5%RH for accelerated testing, and samples were taken for testing at 3 months and 6 months, respectively. The test results are shown in Table 2-1 below.

[0190] Table 2-1 Accelerated test (25±2℃ / 60±5%RH) test results

[0191]

[0192] Note: LOQ stands for limit of quantitation and is 0.05%, which refers to the lowest concentration that can be reliably detected.

[0193] According to the results in the above table, after 3 months of accelerated testing, the total impurity content, 2-butenal content and moisture content of the reference preparation were 2.4%, 103 ppm and 0.3%, respectively.

[0194] Compared with the reference preparation, the isavuconazole sulfate lyophilized preparation prepared by the preparation method of the present invention has a lower total impurity content (only 0.8%), a lower 2-butenal content (only 55ppm), and a lower moisture content (only 0.1%) after 3 months of accelerated testing. Compared with the lyophilized preparation before the accelerated test, the total impurity content, moisture content, reconstitution time, and active ingredient content of the lyophilized preparation prepared by the method of the present invention do not change significantly, and have better stability.

[0195] After 6 months of accelerated testing, the total impurity content, 2-butenal content and moisture content of the reference preparation were 3.0%, 140 ppm and 0.3%, respectively.

[0196] Compared with the reference preparation, the isavuconazole sulfate lyophilized preparation prepared by the preparation method of the present invention has a lower total impurity content (only 1.1%), a lower 2-butenal content (only 96ppm), and a low moisture content (only 0.2%) after 6 months of accelerated testing. Compared with the reference preparation, the lyophilized preparation prepared by the method of the present invention has a smaller change (difference) in the total impurity content and the active ingredient content compared with the lyophilized preparation before the accelerated test, and has better stability.

[0197] 2.2 Long-term stability of the lyophilized preparation of the present invention

[0198] The lyophilized preparation prepared by the preparation method of the present invention and the reference preparation were placed at 2°C-8°C for long-term stability testing, and samples were taken for testing at 3 months and 6 months, respectively. The test results are shown in Table 2-2 below.

[0199] Table 2-2 Long-term test results (2℃-8℃)

[0200]

[0201] Note: LOQ stands for limit of quantitation, which is 7.5 ppm and refers to the lowest concentration that can be reliably detected.

[0202] According to the results in the above table, after 3 months of long-term testing, the isavuconazole sulfate lyophilized preparation prepared by the preparation method of the present invention has low total impurity content (only 0.5%), low 2-butenal content (less than 7.5ppm), and low moisture content (only 0.1%). Compared with the lyophilized preparation before the long-term test, the total impurity content, 2-butenal content, moisture content, reconstitution time and active ingredient content of the lyophilized preparation prepared by the method of the present invention are basically the same, and have excellent stability.

[0203] After 6 months of long-term testing, the isavuconazole sulfate lyophilized preparation prepared by the preparation method of the present invention has low total impurity content (only 0.5%), low 2-butenal content (less than 7.5ppm), and low moisture content (only 0.1%). Compared with the lyophilized preparation before the long-term test, the total impurity content, 2-butenal content, moisture content, reconstitution time and active ingredient content of the lyophilized preparation prepared by the method of the present invention are basically the same, and has excellent stability.

[0204] The embodiments of the present invention are described in detail above, but the contents are only preferred embodiments of the present invention and cannot be considered to limit the scope of implementation of the present invention. The true scope and spirit of the present invention are shown by the attached claims, and the description and embodiments are only exemplary.

Claims

1. A method for preparing a lyophilized preparation of isavuconazole for injection, characterized in that: The method comprises the following steps performed in sequence: a) placing the vial containing the pharmaceutical composition solution into a freeze dryer with the shelf temperature set at 5-15°C; b) performing a freezing step; c) performing primary drying; and d) performing secondary drying; in, The pharmaceutical composition solution is an aqueous solution of isavuconazole or a pharmaceutically acceptable salt thereof; The freezing step comprises the following steps performed in sequence: Under normal pressure, the shelf temperature is lowered to -35°C to -45°C at a rate of 0.3-1.0°C / min and maintained for 60-120 min; Under normal pressure, the shelf temperature is raised to -10°C to -20°C at a rate of 0.3-1.0°C / min, and maintained for 30-90 minutes; The primary drying comprises the following steps: Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 15-25°C at a rate of 0.3-1.0°C / min and maintained for 480-720 min; The secondary drying comprises the following steps performed in sequence: Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 25-35°C at a rate of 0.3-1.0°C / min and maintained for 180-300 min; Under an absolute pressure of 150-250 μbar, the shelf temperature is raised to 40-46°C at a rate of 0.3-1.0°C / min and maintained for 120-180 min; Maintain the shelf temperature at 40-46°C and extreme vacuum for 120-180 minutes; Under extreme vacuum conditions, the shelf temperature was cooled to 5-15°C at a rate of 0.5-1.5°C / min and maintained for more than 10 minutes.

2. The preparation method according to claim 1, characterized in that Step a) of the method comprises: The liquid bottle containing the pharmaceutical composition solution is placed in a freeze dryer with the shelf temperature set at 8-12°C; preferably, the shelf temperature is set at 10°C.

3. The preparation method according to claim 1 or 2, characterized in that: The freezing step comprises the following steps performed in sequence: Under normal pressure, the shelf temperature was cooled to -38°C to -42°C at a rate of 0.4-0.6°C / min and maintained for 85-95 min; Under normal pressure, the shelf temperature was raised to -14°C to -16°C at a rate of 0.4-0.6°C / min and maintained for 55-65 min.

4. The preparation method according to claim 3, characterized in that: The freezing step comprises the following steps performed in sequence: Under normal pressure, the shelf temperature was cooled to -40°C at a rate of 0.5°C / min and maintained for 90 min; Under normal pressure, the shelf temperature was raised to -15°C at a rate of 0.5°C / min and maintained for 60 min.

5. The preparation method according to any one of claims 1 to 4, characterized in that The primary drying comprises the following steps: Under an absolute pressure of 180-220 μbar, the shelf temperature is raised to 18-22°C at a rate of 0.4-0.6°C / min and maintained for 580-620 min; Preferably, Under an absolute pressure of 200 μbar, the shelf temperature was raised to 20°C at a rate of 0.5°C / min and maintained for 600 min.

6. The preparation method according to any one of claims 1 to 5, characterized in that The secondary drying comprises the following steps performed in sequence: Under an absolute pressure of 180-220 μbar, the shelf temperature is raised to 28-32°C at a rate of 0.4-0.6°C / min and maintained for 220-260 min; Under an absolute pressure of 180-220 μbar, the shelf temperature is raised to 41-45°C at a rate of 0.4-0.6°C / min and maintained for 140-160 min; Maintain the shelf temperature at 41-45°C and extreme vacuum for 140-160 minutes; Under extreme vacuum conditions, the shelf temperature is cooled to 8-12°C at a rate of 0.8-1.2°C / min and maintained for 10-20 minutes.

7. The preparation method according to claim 6, characterized in that: The secondary drying comprises the following steps performed in sequence: Under an absolute pressure of 200 μbar, the shelf temperature was raised to 30°C at a rate of 0.5°C / min and maintained for 240 min. Under an absolute pressure of 200 μbar, the shelf temperature was raised to 43°C at a rate of 0.5°C / min and maintained for 150 min. Maintain the shelf temperature at 43°C and extreme vacuum for 150 min; Under extreme vacuum conditions, the shelf temperature was cooled to 10°C at a rate of 1°C / min and maintained for 15 min.

8. The preparation method according to any one of claims 1 to 7, characterized in that The pharmaceutical composition solution comprises isavuconazole sulfate, mannitol, water for injection and optionally sulfuric acid; the pH value of the pharmaceutical composition solution is 1.3-2.

0.

9. The preparation method according to claim 1, characterized in that: The volume of the pharmaceutical composition solution is 3.0-3.3 mL; The pharmaceutical composition solution comprises 372-410 mg of isavuconazole sulfate, 96-106 mg of mannitol, water for injection in an amount sufficient to make up the volume of the pharmaceutical composition solution, and optionally sulfuric acid; The pH of the pharmaceutical composition solution is 1.3-2.

0.

10. A lyophilized preparation of isavuconazole for injection, prepared by the preparation method according to any one of claims 1 to 9.

Images