Preparation method of isavuconazole sulfate capsule

Abstract

The invention relates to a preparation method of an isavuconazole sulfate capsule, which comprises the following steps: drying a filled capsule under reduced pressure, pre-treating a hollow capsule, controlling a production environment, packaging in a damp-proof manner and the like to quickly reduce the moisture of a product to a lower level, so that the moisture of the product is effectively controlled, the control requirement on the humidity of the production environment is reduced, and the production cost is reduced. The relative humidity is controlled to be not more than 40% RH. The product produced by the invention can also meet the requirement of product stability by adopting conventional packaging modes such as bottling and the like, large-scale production is easy to realize, and the cost is reduced. The patient can be prevented from mistakenly eating the drying agent, and the medicine taking safety of the patient is improved.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a method for preparing isavuconazole sulfate capsules. Background Art

[0002] Invasive fungal diseases are common complications with high morbidity and mortality in immunocompromised patients, such as those with advanced HIV infection and cancer. The incidence of the disease is increasing year by year, and it is one of the major public health challenges facing the world today. For patients diagnosed with invasive aspergillosis and mucormycosis, there are currently very limited treatment options available, and resistance to other available therapies is increasing.

[0003] Isavuconazole is a triazole antifungal drug that inhibits 14-α-ergosterol demethylase and thus inhibits the synthesis of ergosterol, an important component of fungal cell membranes, resulting in fungal membrane dysfunction, playing an antibacterial and bactericidal role. It is a novel antifungal drug for the treatment of invasive aspergillosis and mucormycosis in adults. The emergence of isavuconazole provides an important new treatment option for patients suffering from this life-threatening fungal infection. According to literature reports, isavuconazole has a broad antibacterial spectrum, and in vitro studies and clinical trials have shown antibacterial activity against molds, yeasts, bispecific fungi and some rare fungi. It is effective in the clinical treatment of infections in special parts, such as the central nervous system. Its blood drug concentration is stable, and its safety and tolerability are good, and there are few adverse reactions related to long-term use of drugs. At present, multiple European guidelines have recommended isavuconazole as a first-line treatment for invasive aspergillosis in patients with hematological diseases.

[0004] However, the isavuconazole sulfate raw material is extremely unstable, and high temperature and moisture can accelerate the degradation of isavuconazole sulfate. Therefore, there is a need for an isavuconazole sulfate capsule preparation that can well maintain the stability of isavuconazole sulfate. Summary of the invention

[0005] In view of the above background, the present application provides a method for preparing isavuconazole sulfate capsules, comprising the following steps:

[0006] 1) Pretreatment: drying the hollow capsules and sealing them for storage;

[0007] 2) Granulation: weighing isavuconazole sulfate and excipients to prepare drug granules;

[0008] 3) Filling: filling the hollow capsule with the drug particles prepared in step 2) to obtain a filled capsule;

[0009] 4) Drying: placing the filled capsules and the desiccant in step 3) in a drying device and drying under reduced pressure to obtain the product.

[0010] On the other hand, the present application also provides a product, comprising the isavuconazole sulfate capsules prepared according to the preparation method described herein, a desiccant and a sealed bottle, wherein the isavuconazole sulfate capsules and the desiccant are sealed and placed in the sealed bottle.

[0011] The present application reduces the moisture content of the product to a lower level quickly by drying the filled capsules under reduced pressure, thereby effectively controlling the moisture content of the product and reducing the requirements for controlling the humidity of the production environment. Traditional capsule production does not require the environment to be controlled at a lower humidity, but since isavuconazole sulfate is very sensitive to humidity, the existing technology for capsules requires that the ambient humidity be controlled to no more than 15%. The present application removes the moisture of the capsules by drying the hollow capsules and drying the filled capsules under reduced pressure, so there is no need to control the ambient humidity to as low as 15% RH. Under the process conditions of the present application, no more than 40% RH can ultimately guarantee product quality.

[0012] At the same time, the risk of moisture introduction during production and storage is further controlled by means of hollow capsule pretreatment, production environment control, moisture-proof packaging, etc., to ensure that product quality meets the requirements. In addition, the product produced by the preparation method of the present application can meet the product stability requirements by using conventional packaging methods such as bottling, which is easy to achieve large-scale production and reduce costs.

[0013] Compared with the prior art, this application has the following beneficial effects:

[0014] 1) The present application uses reduced pressure drying technology to dry the filled capsules and quickly control the moisture content of the product at a low level, thereby ensuring product quality.

[0015] 2) The present application can control the moisture content of the product at a low level and ensure that the moisture content of the product is maintained at a low level during storage by pretreatment of the hollow capsules, environmental humidity control and packaging material screening.

[0016] 3) Bottled desiccant can be placed independently or integrated into the bottle cap or bottle body. Independently placed desiccant is common bagged or columnar desiccant, which is easy to identify; integrated desiccant cannot be taken out by patients, which is safer; therefore, under the premise of ensuring product quality, it can also prevent patients from accidentally ingesting desiccant, improving the safety of patients' medication.

[0017] Other features and advantages of the present application will be described in the following description, and partly become apparent from the description, or be understood by implementing the present application. Other advantages of the present application can be realized and obtained by the schemes described in the description. DETAILED DESCRIPTION

[0018] Unless otherwise stated, the technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the application belongs. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range, or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is equivalent to specifically revealing any range by combining any pair of upper range limits or preferred numerical values ​​with any lower range limit or preferred numerical value, regardless of whether the range is specifically disclosed. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

[0019] The terms "about" and "approximately" when used with a numerical variable generally refer to the value of that variable and all values ​​of that variable are within experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the specified value, or a wider range.

[0020] The expression "comprising" or its synonymous similar expressions "including", "containing" and "having" etc. are open-ended and do not exclude additional unrecited elements, steps or ingredients. 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 elements, steps or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of" and "consisting of".

[0021] The expression "at least one" or "one or more" means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.

[0022] Isavuconazole sulfate was jointly developed by Astellas and Basilea Pharmaceuticals of Switzerland. In 2015, isavuconazole sulfate preparations were approved by the US FDA for the treatment of invasive aspergillosis and mucormycosis. In 2020, isavuconazole sulfate preparations were approved for marketing in my country: the trade name is The chemical name of isavuconazole sulfate is: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate. The chemical structural formula is:

[0023]

[0024] Since the isavuconazole sulfate API is extremely unstable, high temperature and moisture can accelerate the degradation of isavuconazole sulfate, and it needs to be sealed and stored at low temperature. In order to ensure product stability, the commercially available oral isavuconazole sulfate capsules use a special aluminum-aluminum blister packaging method. The blister of each capsule is connected to a blister containing a desiccant, so that each capsule is equipped with a desiccant protection. This packaging method is complex, has high equipment requirements, and has high packaging costs. The desiccant is similar in shape to a tablet and is easily taken by patients by mistake, bringing risks to medication safety. In addition, the API and capsule contents of this product are highly hygroscopic, and the humidity of the production environment needs to be strictly controlled to ensure product quality. According to the material moisture absorption curve, the relative humidity of the material exposure environment during the production process should be controlled below 15% RH, and the requirements for factory facilities are very high.

[0025] Based on this, the present application provides a method for preparing isavuconazole sulfate capsules, comprising the following steps:

[0026] 1) Pretreatment: drying the hollow capsules and sealing them for storage;

[0027] 2) Granulation: weighing isavuconazole sulfate and excipients to prepare drug granules;

[0028] 3) Filling: filling the hollow capsules with the drug particles prepared in step 2) to obtain filled capsules;

[0029] 4) Drying: placing the filled capsules and the desiccant in step 3) in a drying device and drying under reduced pressure to obtain the product.

[0030] In some embodiments, the hollow capsule is a plant capsule. In some embodiments, the plant capsule is selected from starch capsules, pullulan capsules and hydroxypropyl methylcellulose (HPMC) capsules. In some embodiments, the plant capsule is a hydroxypropyl methylcellulose capsule.

[0031] In some embodiments, after the pretreatment of step 1), the moisture content of the empty capsule is no more than 1.5%. In some embodiments, after the pretreatment of step 1), the moisture content of the empty capsule is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4% or 1.5%.

[0032] In some embodiments, the excipients in step 2) are selected from one or more of microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid and anhydrous magnesium citrate. In terms of mass percentage, microcrystalline cellulose accounts for 17.5%-20% of the total mass of the drug particles, anhydrous magnesium citrate accounts for 38%-45% of the total mass of the drug particles, stearic acid accounts for 1.5%-2.0% of the total mass of the drug particles, talc accounts for 6.5%-7.5% of the total mass of the drug particles, colloidal silicon dioxide accounts for 0.5%-1.5% of the total mass of the drug particles, and isavuconazole sulfate accounts for 25%-35% of the total mass of the drug particles.

[0033] In some embodiments, microcrystalline cellulose accounts for 18%-19% of the total mass of the drug particles, anhydrous magnesium citrate accounts for 40%-43% of the total mass of the drug particles, stearic acid accounts for 1.7%-1.9% of the total mass of the drug particles, talc accounts for 6.8%-7.3% of the total mass of the drug particles, colloidal silicon dioxide accounts for 0.8%-1.3% of the total mass of the drug particles, and isavuconazole sulfate accounts for 28%-32% of the total mass of the drug particles.

[0034] In some embodiments, step 2) further comprises the following steps:

[0035] a) Weighing: weighing microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid, anhydrous magnesium citrate and isavuconazole sulfate according to the formula;

[0036] b) premixing: adding microcrystalline cellulose, talc, colloidal silicon dioxide, anhydrous magnesium citrate and isavuconazole sulfate into a mixer and mixing;

[0037] c) adding the premixed powder in step b) into a dry granulator to prepare pre-granules;

[0038] d) Total mixing: the pre-granules prepared in step c) and the external material stearic acid are added into a mixer and mixed to obtain drug granules.

[0039] In some embodiments, the desiccant is selected from one or more of molecular sieves, high polymers, silica gel, and calcium oxide.

[0040] In some embodiments, the amount of desiccant used is not less than 0.05 g per filled capsule. In some embodiments, the amount of desiccant used is about 0.05 g-0.45 g per filled capsule. In some embodiments, the amount of desiccant used is about 0.05 g, 0.06 g, 0.07 g, 0.08 g, 0.09 g, 0.10 g, 0.12 g, 0.14 g, 0.16 g, 0.18 g, 0.20 g, 0.22 g, 0.24 g, 0.26 g, 0.28 g, 0.30 g, 0.32 g, 0.34 g, 0.36 g, 0.38 g, 0.40 g, 0.41 g, 0.42 g, 0.43 g, 0.44 g or 0.45 g per filled capsule.

[0041] In some embodiments, the reduced pressure drying is static drying or dynamic drying, the drying temperature is about 30°C-60°C, the drying vacuum is about -0.05MPa to -0.1MPa, the drying time is about 6h-48h, and the moisture content of the isavuconazole sulfate capsules after drying is not higher than 1%.

[0042] In some embodiments, the drying temperature of the reduced pressure drying is about 35-55° C., 38-53° C., 40-50° C., 42-48° C., or 44-46° C. In some embodiments, the drying temperature of the reduced pressure drying is about 45° C.

[0043] In some embodiments, the drying vacuum degree of the reduced pressure drying is about -0.05 MPa, -0.06 MPa, -0.07 MPa, -0.08 MPa, -0.09 MPa, or -0.1 MPa.

[0044] In some embodiments, the drying time of the reduced pressure drying is about 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, 24 h, 28 h, 32 h, 36 h, 40 h, 44 h or 48 h.

[0045] In some embodiments, the moisture content of the isavuconazole sulfate capsules after drying under reduced pressure is about 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%.

[0046] In some embodiments, after step 4), the method further comprises:

[0047] Step 5) Bottling: The isavuconazole sulfate capsules obtained in step 4) are bottled in a high-density polyethylene bottle; a desiccant is placed in the high-density polyethylene bottle. In some embodiments, 1.5 g to 4 g of the desiccant is placed in a 40 ml high-density polyethylene bottle. In some embodiments, 1.5 g, 1.8 g, 2.0 g, 2.4 g, 2.8 g, 3.2 g, 3.6 g or 4 g of the desiccant is placed in a 40 ml high-density polyethylene bottle.

[0048] In some embodiments, the placement of the desiccant is selected from one or more of the following: independent placement, integrated placement in the bottle cap, and integrated placement in the bottle body.

[0049] In some embodiments, during the preparation process, the ambient humidity is controlled at a relative humidity of ≤40%.

[0050] In some embodiments, the preparation method of isavuconazole sulfate capsules comprises the following steps:

[0051] 1) Pretreatment: Dry the hollow capsules, seal and store the dried hollow capsules for future use.

[0052] 2) Weighing: weigh microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid, anhydrous magnesium citrate, and isavuconazole sulfate in sequence and set aside.

[0053] 3) Premixing: Add microcrystalline cellulose, talc, colloidal silicon dioxide, anhydrous magnesium citrate and isavuconazole sulfate into a mixer and mix. Those skilled in the art can make the matching according to experience.

[0054] 4) Granulation: Add the premixed powder from step 3) to a dry granulator to prepare pre-granules. There are no special requirements for the roller pressure, roller speed and feed speed of dry granulation. The three can be matched to control the roller gap. Those skilled in the art can match them according to the roller gap.

[0055] 5) Total mixing: The pre-granules prepared in step 4) and the external material stearic acid are added to a mixer and mixed to obtain drug granules. There is no special requirement for the loading amount of the materials, and it can be within the conventional loading amount range of the mixing equipment. Those skilled in the art can select according to actual needs.

[0056] 6) Capsule filling: Add the drug particles obtained in step 5) into a capsule filling machine to fill empty capsules.

[0057] 7) Capsule drying: The capsules and desiccant filled in step 6) are placed in a reduced pressure drying device for drying. There is no special requirement for the loading amount of the capsules. During the drying process, the conventional loading amount range can be used, and those skilled in the art can select it according to actual needs.

[0058] 8) Bottle packaging: The capsules dried in step 7) are bottled in a high-density polyethylene bottle, 1.5g-4g of desiccant is placed in the bottle, and the bottle cap is covered and sealed. Preferably, the environmental humidity of step 1) to step 8) is controlled to RH≤30%.

[0059] On the other hand, the present application also provides a product, including isavuconazole sulfate capsules prepared according to the preparation method described herein, a desiccant and a sealed bottle, wherein the isavuconazole sulfate capsules and the desiccant are sealed and placed in the sealed bottle.

[0060] In some embodiments, the sealed bottle is selected from a high density polyethylene bottle.

[0061] In some embodiments, the amount of desiccant in the sealed bottle is 1.5 g to 4 g of desiccant in a 40 ml sealed bottle.

[0062] The present application describes a plurality of embodiments, but the description is exemplary rather than restrictive, and it is apparent to those skilled in the art that there may be more embodiments and implementations within the scope of the embodiments described in the present application. Although many possible feature combinations are shown in the specification and discussed in the specific embodiments, many other combinations of the disclosed features are also possible. Unless specifically limited, any feature of any embodiment may be used in combination with any other feature in any other embodiment, or may replace any other feature in any other embodiment.

[0063] The present application includes and contemplates combinations of features known to those of ordinary skill in the art. The embodiments and features disclosed in the present application may also be combined with any conventional features to form a unique invention scheme defined by the claims. Any feature of any embodiment may also be combined with features from other invention schemes to form another unique invention scheme defined by the claims. Therefore, it should be understood that any feature shown and / or discussed in the present application may be implemented individually or in any appropriate combination. Therefore, except for the limitations made according to the attached claims and their equivalents, the embodiments are not subject to other restrictions. In addition, various modifications and changes may be made within the scope of protection of the attached claims.

[0064] In addition, when describing representative embodiments, the specification may have presented the method and / or process as a specific sequence of steps. However, to the extent that the method or process does not rely on the specific order of the steps described herein, the method or process should not be limited to the steps of the specific order described. As will be understood by those of ordinary skill in the art, other sequences of steps are also possible. Therefore, the specific sequence of the steps set forth in the specification should not be interpreted as a limitation to the claims. In addition, the claims for the method and / or process should not be limited to the steps of performing them in the order written, and those skilled in the art can easily understand that these sequences can be changed and still remain within the spirit and scope of the embodiments of the present application.

[0065] The experimental methods in the following examples without specifying specific conditions are usually measured according to national standards. The experimental materials in the following examples without specifying the source are all commercially available raw materials. The equipment used in each step in the following examples is conventional equipment. If there is no corresponding national standard, it is carried out according to the general international standards, conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise defined or specified, all professional and scientific terms used in this application have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equal to the recorded content can be applied to the method of this application.

[0066] The relevant materials used in the examples are as follows:

[0067] 1. Reagents and materials

[0068] Microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid, anhydrous magnesium citrate, isavuconazole sulfate. Among them, microcrystalline cellulose, talc, colloidal silicon dioxide, and stearic acid all meet the standards of the 2020 edition of the "Chinese Pharmacopoeia", anhydrous magnesium citrate meets the USP standards, and isavuconazole sulfate is the enterprise standard.

[0069] 2. Instruments and equipment

[0070] HSD50 mixer, TFC-220 dry granulator, GKF705 capsule filling machine, TF-2 aluminum-plastic blister packaging machine and LM5022-222 electromagnetic induction sealing machine.

[0071] Comparative Example

[0072] 1) Weighing: weigh 10.9 g of microcrystalline cellulose, 4.0 g of talc, 0.5 g of colloidal silicon dioxide, 0.5 g of stearic acid, 23.7 g of anhydrous magnesium citrate, and 20.2 g of isavuconazole sulfate in sequence and set aside.

[0073] 2) Premixing: Add microcrystalline cellulose, talc, colloidal silicon dioxide, anhydrous magnesium citrate and isavuconazole sulfate into a mixer and mix.

[0074] 3) Granulation: Add the mixed powder obtained in 2) into the hopper of a dry granulator, set the roller pressure of the dry granulator to 35 KN, the roller speed to 7 rpm, and the feed speed to 25 rpm to obtain pre-granules.

[0075] 4) Total mixing: Add the pre-granules obtained in 3) and the external material stearic acid into a mixer at a mixing speed of 20 rpm for 10 min to obtain drug granules.

[0076] 5) Capsule filling: Add the drug granules obtained in 4) into a capsule filling machine to fill hollow capsules.

[0077] 6) Aluminum-aluminum blister packaging: 4) The filled capsules are packaged in aluminum-aluminum blisters with built-in desiccant (the amount of desiccant is 1:1 of the amount of capsules), and the packaging is formed and packaged using a packaging machine.

[0078] Example 1

[0079] 1) Pretreatment: Dry the HPMC hollow capsules using a reduced pressure drying device: the drying temperature is set to 35°C, the drying time is 6 hours, and the vacuum degree is -0.05Mpa. The dried hollow capsules are sealed and stored for later use.

[0080] 2) Weighing: weigh 10.9 g of microcrystalline cellulose, 4.0 g of talc, 0.5 g of colloidal silicon dioxide, 0.5 g of stearic acid, 23.7 g of anhydrous magnesium citrate, and 20.2 g of isavuconazole sulfate in sequence and set aside.

[0081] 3) Premixing: Add microcrystalline cellulose, talc, colloidal silicon dioxide, anhydrous magnesium citrate and isavuconazole sulfate into a mixer and mix.

[0082] 4) Granulation: Add the mixed powder obtained in 3) into the hopper of a dry granulator, set the roller pressure of the dry granulator to 35 KN, the roller speed to 7 rpm, and the feed speed to 25 rpm to obtain pre-granules.

[0083] 5) Total mixing: Add the pre-granules obtained in 4) and the external material stearic acid into a mixer at a mixing speed of 10 rpm for 20 min to obtain drug granules.

[0084] 6) Capsule filling: Add the drug granules obtained in 5) into a capsule filling machine and fill capsules.

[0085] 7) Capsule drying: Place the filled capsules and desiccant in 6) in a reduced pressure or vacuum drying device for drying. The amount of desiccant is calculated as 0.05 g / capsule. The drying temperature is 60° C., the drying vacuum is -0.10 MPa, and the drying time is 6 hours.

[0086] 8) Bottling: The dried capsules prepared in 7) are placed into a 40 ml high-density polyethylene bottle, wherein a desiccant is placed in the bottle, and the amount of the desiccant is 1.5 g per bottle. The bottle is capped and sealed using an electromagnetic induction seal.

[0087] Example 2

[0088] 1) Pretreatment: Dry the HPMC cellulose hollow capsules using a reduced pressure drying device: the drying temperature is set to 55°C, the drying time is 2 hours, and the vacuum degree is -0.1 MPa. The dried hollow capsules are sealed and stored for later use.

[0089] 2) Weighing: weigh 10.9 g of microcrystalline cellulose, 4.0 g of talc, 0.5 g of colloidal silicon dioxide, 0.5 g of stearic acid, 23.7 g of anhydrous magnesium citrate, and 20.2 g of isavuconazole sulfate in sequence and set aside.

[0090] 3) Premixing: Add microcrystalline cellulose, talc, colloidal silicon dioxide, anhydrous magnesium citrate and isavuconazole sulfate into a mixer and mix.

[0091] 4) Granulation: Add the mixed powder obtained in 3) into the hopper of a dry granulator, set the roller pressure of the dry granulator to 35 KN, the roller speed to 7 rpm, and the feed speed to 25 rpm to obtain pre-granules.

[0092] 5) Total mixing: Add the pre-granules obtained in 4) and the external material stearic acid into a mixer at a mixing speed of 20 rpm for 10 min to obtain drug granules.

[0093] 6) Capsule filling: Add the drug granules obtained in 5) into a capsule filling machine and fill capsules.

[0094] 7) Capsule drying: Place the filled capsules and desiccant in 6) in a reduced pressure or vacuum drying device for drying. The amount of desiccant is calculated as 0.3 g / capsule. The drying temperature is 30° C., the drying vacuum is -0.05 MPa, and the drying time is 48 h.

[0095] 8) Bottling: The dried capsules prepared in 7) are placed into a 40 ml high-density polyethylene bottle, wherein a desiccant is placed in the bottle, and the amount of the desiccant is 4 g per bottle. The bottle cap is covered and sealed using an electromagnetic induction seal.

[0096] Test example: The above comparative example and Examples 1-2 were subjected to moisture test and stability test.

[0097] Isavuconazole sulfate raw material is extremely unstable and sensitive to moisture, which affects the stability of the capsule and its composition. Compared with the control example, the moisture and impurity conditions of the embodiment are as follows.

[0098] Moisture test: The sample was extracted with anhydrous methanol and the contents of the capsule were determined according to the moisture determination method (refer to the General Rules of Part Four of the 2020 Edition of the Chinese Pharmacopoeia, Method 1 2).

[0099] Moisture (%) Comparative Example Example 1 Example 2 Moisture content of hollow capsules before drying 2.85 2.85 2.85 Moisture content of hollow capsules after drying / 0.32 0.34

[0100] It can be seen that the embodiments of the present application significantly reduce the moisture content of the hollow capsules after drying, which is beneficial to the stability of the product.

[0101] Moisture (%) Comparative Example Example 1 Example 2 Moisture content of capsule before drying 0.73 0.47 0.52 Moisture content of capsule after drying / 0.30 0.34

[0102] It can be seen that the embodiments of the present application can significantly reduce the moisture content of the capsule content, which is more beneficial to the stability of the product.

[0103]

[0104]

[0105] It can be seen that the embodiments of the present application can ensure that the moisture content of the capsule is low on day 0, and at the same time, the moisture content does not increase during storage, which is more beneficial to the stability of the product.

[0106] Impurity test:

[0107] Related substance detection method: Determine according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512). For the preparation of the test solution, take an appropriate amount of the content of this product, accurately weigh it, place it in a volumetric flask, add an appropriate amount of solvent, ultrasonically and shake it to dissolve, dilute it to the scale with solvent, filter it, and prepare a solution containing 2.8 mg / ml of isavuconazole sulfate. The reference substance was prepared with reference to the test solution. Use octadecylsilane bonded silica gel as the filler, water-acetonitrile-trifluoroacetic acid as the mobile phase A, and acetonitrile-trifluoroacetic acid as the mobile phase B, and perform gradient elution with a flow rate of 1.5 ml per minute; the column temperature is 40°C; the temperature of the automatic sampler is 5°C; the detection wavelength is 250nm, and the injection volume is 20μl.

[0108] The results are as follows:

[0109] Total impurities (%) Comparative Example Example 1 Example 2 Day 0 1.06 0.67 0.65 25℃ for 1 month 1.67 0.77 0.81 25℃ for 3 months 2.19 0.83 0.92 1 month at 40℃ 2.28 1.20 1.06 40℃ for 3 months 3.76 1.52 1.50

[0110] Isavuconazole Impurity 11 Comparative Example Example 1 Example 2 Day 0 0.07 0.06 0.05 25℃ for 3 months 0.14 0.06 0.06 40℃ for 3 months 0.22 0.07 0.08

[0111] It can be seen that the total impurities and major single degradation impurities (isavuconazole impurity 11) of the examples of the present application have a smaller growth rate than the comparative example, which is more beneficial to the stability of the product. In addition, it was found that under 40°C, the single major degradation impurity (isavuconazole impurity 11) of the examples of the present application did not increase significantly in 3 months, while the increase in the comparative example reached 0.15%, which was significantly higher than that of the examples. The inventive technology of the present application can control the impurity level within the product life cycle to a lower level, ensuring the safety and effectiveness of the patient's medication.

Claims

1. A method for preparing isavuconazole sulfate capsules, comprising the following steps: 1) Pretreatment: drying the hollow capsules and sealing them for storage; 2) Granulation: weighing isavuconazole sulfate and excipients to prepare drug granules; 3) Filling: filling the hollow capsule with the drug particles prepared in step 2) to obtain a filled capsule; 4) Drying: placing the filled capsules and the desiccant in step 3) in a drying device and drying under reduced pressure to obtain the product.

2. The preparation method according to claim 1, wherein The hollow capsule is a plant capsule, preferably a hydroxypropyl methylcellulose capsule.

3. The preparation method according to claim 2, wherein After the pretreatment in step 1), the moisture content of the hollow capsule is ≤1.5%.

4. The preparation method according to any one of claims 1 to 3, wherein The auxiliary material is selected from one or more of microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid and anhydrous magnesium citrate.

5. The preparation method according to claim 4, wherein Step 2) also includes the following steps: a) Weighing: weighing microcrystalline cellulose, talc, colloidal silicon dioxide, stearic acid, anhydrous magnesium citrate and isavuconazole sulfate according to the formula; b) premixing: adding microcrystalline cellulose, talc, colloidal silicon dioxide, anhydrous magnesium citrate and isavuconazole sulfate into a mixer and mixing; c) adding the premixed powder in step b) into a dry granulator to prepare pre-granules; d) Total mixing: adding the pre-granules prepared in step c) and the external material stearic acid into a mixer and mixing them to obtain the drug granules.

6. The preparation method according to any one of claims 1 to 5, wherein The desiccant is selected from one or more of molecular sieves, high polymers, silica gel, and calcium oxide.

7. The preparation method according to claim 6, wherein: For each of the filled capsules, the amount of the desiccant used is 0.05 g to 0.45 g.

8. The preparation method according to any one of claims 1 to 7, wherein The reduced pressure drying is static drying or dynamic drying, the drying temperature is 30° C.-60° C., the drying vacuum degree is -0.05 MPa to -0.1 MPa, the drying time is 6 h-48 h, and the moisture content of the isavuconazole sulfate capsules after drying is ≤1%.

9. The preparation method according to any one of claims 1 to 8, wherein After step 4), the method further includes: Step 5) Bottling: The isavuconazole sulfate capsules obtained in step 4) are bottled into a high-density polyethylene bottle; the desiccant is placed in the high-density polyethylene bottle.

10. The preparation method according to claim 9, wherein: The placement position of the desiccant is selected from one or more of the following: independent placement, integrated placement in the bottle cap and integrated placement in the bottle body.

11. The preparation method according to any one of claims 1 to 10, wherein During the preparation process, the ambient humidity was controlled at a relative humidity of ≤40%.

12. A product comprising the isavuconazole sulfate capsules prepared by the preparation method according to any one of claims 1 to 11, a desiccant and a sealed bottle, wherein: The isavuconazole sulfate capsules and the desiccant are sealed and placed in the sealed bottle.

13. The product according to claim 12, wherein: The sealed bottle is a high-density polyethylene bottle.

14. The product of claim 12, wherein: The amount of the desiccant in the sealed bottle is 1.5 g to 4 g of the desiccant in 40 ml of the sealed bottle.

Images