A method of preparing eslicarbazepine acetate capsules

Abstract

The application discloses a preparation method of esconazole sulfate capsules, which comprises the following steps: filling capsules, reducing pressure drying, and rapidly reducing the moisture content of the product to a low level through hollow capsule pretreatment, production environment control, moisture-proof packaging and other means, effectively controlling the moisture content of the product while reducing the control requirements for the humidity of the production environment, and the relative humidity can be controlled to be not more than 40% RH. The product produced by the application can meet the stability requirements of the product by adopting conventional packaging methods such as bottle packaging, and the product is easy to realize large-scale production and reduce the cost. Moreover, the method can avoid the mistake of patients eating dry agents and improve the medication safety of patients.

Description

Technical Field

[0001] This article relates to the field of pharmaceutical preparations, and in particular to a method for preparing isaconazole sulfate capsules. Background Technology

[0002] Invasive fungal infections are a common complication with high morbidity and mortality rates in immunocompromised patients, such as those with advanced HIV infection and cancer. The incidence of these diseases is increasing annually, posing a significant global public health challenge. Currently, treatment options for patients diagnosed with invasive aspergillosis and mucormycosis are very limited, and resistance to other existing therapies is also on the rise.

[0003] Isaconazole is a triazole antifungal drug that inhibits 14-α-ergosterol demethylase, thereby inhibiting the synthesis of ergosterol, an important component of the fungal cell membrane, leading to fungal membrane dysfunction and exerting bacteriostatic and bactericidal effects. It is a novel antifungal drug for the treatment of invasive aspergillosis and mucormycosis in adults. The advent of issaconazole provides an important new treatment option for patients suffering from these life-threatening fungal infections. According to literature reports, issaconazole has a broad antibacterial spectrum, and in vitro studies and clinical trials suggest antibacterial activity against molds, yeasts, diversifying fungi, and some rare fungi. It is clinically effective in treating infections in specific sites, such as the central nervous system. Its blood concentrations are stable, and it has good safety and tolerability with few drug-related adverse reactions with long-term use. Currently, several European guidelines recommend issaconazole as a first-line treatment for invasive aspergillosis in patients with hematologic disorders.

[0004] However, isaconazole sulfate raw material is extremely unstable, and high temperature and moisture can accelerate its degradation. Therefore, there is a need for an isaconazole sulfate capsule formulation that can effectively maintain the stability of isaconazole sulfate. Summary of the Invention

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

[0006] 1) Pretreatment: Dry the empty capsules and seal them for storage;

[0007] 2) Granulation: Weigh isaconazole sulfate and excipients to prepare drug granules;

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

[0009] 4) Drying: Place the filling capsule and desiccant from step 3) into a drying device for vacuum drying to obtain the final product.

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

[0011] This application utilizes vacuum drying of the filled capsules to rapidly reduce the product's moisture content to a low level, effectively controlling product moisture while reducing the requirements for controlling the humidity of the production environment. Traditional capsule production does not require maintaining a low humidity environment, but because isaconazole sulfate is highly sensitive to humidity, existing capsule technologies require controlling the ambient humidity to no more than 15%. This application, by drying the empty capsules and then using vacuum drying on the filled capsules to remove moisture, eliminates the need to control the ambient humidity to such a low level as 15% RH. Under the process conditions of this application, a RH level not exceeding 40% is sufficient to ultimately guarantee product quality.

[0012] Meanwhile, by employing methods such as pretreatment of empty capsules, production environment control, and moisture-proof packaging, the risk of moisture introduction during production and storage is further controlled, ensuring that product quality meets requirements. Furthermore, the product produced by the preparation method described in this application can achieve product stability requirements using conventional packaging methods such as bottling, facilitating large-scale production and reducing costs.

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

[0014] 1) This application uses vacuum drying technology to dry the filled capsules, quickly controlling the product moisture content to a low level, thereby ensuring product quality.

[0015] 2) This application, through the pretreatment of empty capsules, control of environmental humidity and screening of packaging materials, can ensure that the product moisture content is kept at a low level during storage while controlling the product moisture content at a low level.

[0016] 3) Bottled desiccants can be placed individually or integrated into the cap or body of the bottle. Individually placed desiccants are in ordinary bagged or cylindrical form, making them easy to identify; integrated desiccants cannot be removed by the patient, making them safer. Therefore, while ensuring product quality, it can also prevent patients from accidentally ingesting desiccants, improving patient medication safety.

[0017] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application may be realized and obtained by means of the methods described in the description. Detailed Implementation

[0018] Unless otherwise stated, the technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this application pertains. When a quantity, concentration, or other value or parameter is expressed as a range, preferred range, or preferred upper and lower numerical limits, it should be understood that this is equivalent to specifically disclosing any range by combining any pair of upper or preferred values ​​with any lower or preferred 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 that range.

[0019] When used with a numerical variable, the terms "about" or "approximately" usually mean that the value of the variable and all values ​​of the variable are within the 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 similar expressions such as "including," "containing," and "having," is open-ended and does not exclude additional unlisted elements, steps, or components. The expression "consisting of," excludes any unspecified elements, steps, or components. The expression "substantially consisting of," limits the scope to the specified elements, steps, or components, plus optional elements, steps, or components that do not materially affect the essential and novel features of the claimed subject matter. It should be understood that the expression "comprising" encompasses both the expressions "substantially consisting of" and "consisting of."

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

[0022] Isaconazole sulfate was jointly developed by Astellas and Basila, Switzerland. In 2015, the isaconazole sulfate formulation received FDA approval in the United States for the treatment of invasive aspergillosis and mucormycosis. In 2020, the isaconazole sulfate formulation was approved for marketing in my country under the trade name [Brand Name Missing]. The chemical name of isaconazole sulfate is: 1-{(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazolyl-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-onium monosulfate. Its chemical structural formula is:

[0023]

[0024] Because isaconazole sulfate raw material is extremely unstable, high temperatures and moisture can accelerate its degradation, necessitating sealed, low-temperature frozen storage. Commercially available oral isaconazole sulfate capsules utilize a special aluminum-aluminum blister packaging method to ensure product stability. Each capsule's blister is connected to a corresponding desiccant packet, providing protection for each capsule. This packaging method is complex, requires sophisticated equipment, and is costly. The desiccant, resembling a tablet, is easily ingested by patients, posing a medication safety risk. Furthermore, the raw material and capsule contents are highly hygroscopic, requiring strict control of the humidity in the production environment to ensure product quality. Based on the material's hygroscopic curve, the relative humidity of the environment exposed to the materials during production should be controlled below 15% RH, placing extremely high demands on factory facilities.

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

[0026] 1) Pretreatment: Dry the empty capsules and seal them for storage;

[0027] 2) Granulation: Weigh isaconazole sulfate and excipients to prepare drug granules;

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

[0029] 4) Drying: Place the filled capsules and desiccant from step 3) into a drying device for vacuum drying to obtain the final product.

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

[0031] In some embodiments, after the pretreatment in step 1), the moisture content of the empty capsules does not exceed 1.5%. In some embodiments, after the pretreatment in step 1), the moisture content of the empty capsules is approximately 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 silica, stearic acid, and anhydrous magnesium citrate. By mass percentage, microcrystalline cellulose accounts for 17.5%-20% of the total mass of the drug particles, anhydrous magnesium citrate accounts for 38%-45%, stearic acid accounts for 1.5%-2.0%, talc accounts for 6.5%-7.5%, colloidal silica accounts for 0.5%-1.5%, and isaconazole sulfate accounts for 25%-35%.

[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 silica accounts for 0.8%-1.3% of the total mass of the drug particles, and isaconazole sulfate accounts for 28%-32% of the total mass of the drug particles.

[0034] In some implementations, step 2) further includes the following steps:

[0035] a) Weighing: Weigh out microcrystalline cellulose, talc, colloidal silica, stearic acid, anhydrous magnesium citrate and isaconazole sulfate according to the formula;

[0036] b) Premixing: Microcrystalline cellulose, talc, colloidal silica, anhydrous magnesium citrate and isaconazole sulfate are added to a mixer and mixed.

[0037] c) Add the premixed powder from step b) to a dry granulator to prepare pre-granules;

[0038] d) Mixing: Add the pre-granules obtained in step c) and the added material stearic acid to a mixer for mixing to obtain drug granules.

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

[0040] In some embodiments, the amount of desiccant used per filler capsule is not less than 0.05 g. In some embodiments, the amount of desiccant used per filler capsule is about 0.05 g to 0.45 g. In some embodiments, the amount of desiccant used per filler capsule 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.

[0041] In some implementations, the reduced pressure drying is either static or dynamic drying, with a drying temperature of approximately 30°C to 60°C, a drying vacuum of approximately -0.05 MPa to -0.1 MPa, and a drying time of approximately 6 hours to 48 hours. After drying, the moisture content of the isaconazole sulfate capsules is no higher than 1%.

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

[0043] In some implementations, the 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 implementations, the vacuum drying time is approximately 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h, 24h, 28h, 32h, 36h, 40h, 44h, or 48h.

[0045] In some embodiments, after vacuum drying, the water content of the isaconazole sulfate capsules is approximately 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 implementations, step 4) is followed by:

[0047] Step 5) Bottling: The isaconazole sulfate capsules obtained in Step 4) are packaged into high-density polyethylene (HDPE) bottles; the HDPE bottles contain a desiccant. In some embodiments, 1.5g-4g of the desiccant is placed in a 40ml HDPE bottle. In some embodiments, 1.5g, 1.8g, 2.0g, 2.4g, 2.8g, 3.2g, 3.6g, or 4g of desiccant is placed in a 40ml HDPE bottle.

[0048] In some implementations, the desiccant is placed in one or more of the following locations: independently, integrated into the cap, and integrated into the bottle body.

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

[0050] In some implementation methods, the preparation of isaconazole sulfate capsules includes the following steps:

[0051] 1) Pretreatment: Dry the empty capsules, then seal and store them for later use.

[0052] 2) Weighing: Weigh out microcrystalline cellulose, talc, colloidal silica, stearic acid, anhydrous magnesium citrate, and isaconazole sulfate in sequence for later use.

[0053] 3) Premixing: Microcrystalline cellulose, talc, colloidal silica, anhydrous magnesium citrate, and isaconazole sulfate are added to a mixer and mixed. Those skilled in the art can adjust the proportions based on experience.

[0054] 4) Granulation: Add the premixed powder from step 3) to a dry granulator to prepare granules. No special requirements are placed on the roller pressure, roller speed, and feed speed of the dry granulator; these three parameters are simply coordinated to control the roller gap. Those skilled in the art can match these parameters according to the roller gap.

[0055] 5) Final Mixing: The pre-granules obtained in step 4) and the added material stearic acid are added to a mixer and mixed to obtain drug granules. There are no special requirements for the loading amount of materials; the conventional loading amount of the mixing equipment is sufficient. Those skilled in the art can select according to actual needs.

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

[0057] 7) Capsule Drying: Place the filled capsules and desiccant from step 6) into a vacuum drying apparatus for drying. No special requirements are placed on the capsule loading amount; a conventional loading range can be used during the drying process. Those skilled in the art can select the appropriate amount based on actual needs.

[0058] 8) Bottling: The dried capsules from step 7) are placed into high-density polyethylene bottles containing 1.5g-4g of desiccant. The bottles are then capped and sealed. Preferably, the ambient humidity (RH) during steps 1)-8) is controlled to be ≤30%.

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

[0060] In some implementations, the sealing bottle is selected from high-density polyethylene bottles.

[0061] In some implementations, the amount of desiccant in the sealed bottle is 1.5g-4g per 40ml bottle.

[0062] This application describes several embodiments, but these descriptions are exemplary and not restrictive, and it will be apparent to those skilled in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein. Although many possible combinations of features are shown in the specification and discussed in the detailed description, 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] This application includes and contemplates combinations of features known to those skilled in the art. The embodiments and features disclosed in this application can also be combined with any conventional features to form a unique inventive scheme as defined by the claims. Any feature of any embodiment can also be combined with features from other inventive schemes to form another unique inventive scheme as defined by the claims. Therefore, it should be understood that any feature shown and / or discussed in this application can be implemented individually or in any suitable combination. Therefore, the embodiments are not limited except by the limitations imposed by the appended claims and their equivalents. Furthermore, various modifications and changes can be made within the scope of the appended claims.

[0064] Furthermore, in describing representative embodiments, the specification may have presented methods and / or processes as a specific sequence of steps. However, the method or process should not be limited to the specific order of steps described herein, to the extent that it does not depend on such a specific order. As will be understood by those skilled in the art, other sequences of steps are also possible. Therefore, the specific order of steps set forth in the specification should not be construed as a limitation of the claims. Moreover, the claims concerning the method and / or process should not be limited to the steps performed in the written order, and those skilled in the art will readily understand that these orders can be varied and still remain within the spirit and scope of the embodiments of this application.

[0065] Experimental methods in the following embodiments without specific conditions are generally determined according to national standards. Experimental materials in the following embodiments without specified sources are all commercially available raw materials. The equipment used in each step of the following embodiments is conventional equipment. If there is no corresponding national standard, then generally accepted international standards, conventional conditions, or conditions recommended by the manufacturer are followed. Unless otherwise defined or stated, all technical and scientific terms used in this application have the same meaning as those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein may be applied to the methods of this application.

[0066] The materials used in the embodiments are shown below:

[0067] 1. Reagents and materials

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

[0069] 2. Instruments and equipment

[0070] HSD50 mixer, TFC-220 dry granulation machine, 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 10.9g of microcrystalline cellulose, 4.0g of talc, 0.5g of colloidal silica, 0.5g of stearic acid, 23.7g of anhydrous magnesium citrate, and 20.2g of isaconazole sulfate in sequence for later use.

[0073] 2) Premixing: Add microcrystalline cellulose, talc, colloidal silica, anhydrous magnesium citrate and isaconazole sulfate to a mixer for mixing.

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

[0075] 4) Total mixing: Add the pre-particles obtained in 3) and the added material stearic acid to the mixer, mix at 20 rpm for 10 min to obtain drug particles.

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

[0077] 6) Aluminum-aluminum blister packaging: Pack the filled capsules in aluminum-aluminum blister packaging, with desiccant inside (the amount of desiccant is 1:1 of the amount of capsules), and then use a packaging machine to form and package them.

[0078] Example 1

[0079] 1) Pretreatment: The HPMC empty capsules were dried using a vacuum drying device: the drying temperature was set to 35℃, the drying time was 6 hours, and the vacuum degree was -0.05Mpa. The dried empty capsules were sealed and stored for later use.

[0080] 2) Weighing: Weigh 10.9g of microcrystalline cellulose, 4.0g of talc, 0.5g of colloidal silica, 0.5g of stearic acid, 23.7g of anhydrous magnesium citrate, and 20.2g of isaconazole sulfate in sequence for later use.

[0081] 3) Premixing: Add microcrystalline cellulose, talc, colloidal silica, anhydrous magnesium citrate and isaconazole sulfate to a mixer for mixing.

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

[0083] 5) Total mixing: Add the pre-particles obtained in 4) and the added material stearic acid to the mixer, mix at 10 rpm for 20 min to obtain drug particles.

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

[0085] 7) Capsule drying: Place the filled capsules and desiccant from step 6) into a reduced pressure or vacuum drying device for drying. The amount of desiccant is calculated at 0.05g / capsule. The drying temperature is 60℃, the drying vacuum degree is -0.10Mpa, and the drying time is 6h.

[0086] 8) Bottled: Pack the dried capsules from step 7) into 40ml high-density polyethylene bottles, add desiccant (1.5g per bottle), close the cap, and seal using electromagnetic induction sealing.

[0087] Example 2

[0088] 1) Pretreatment: The HPMC cellulose empty capsules were dried using a vacuum drying device: the drying temperature was set to 55℃, the drying time was 2 hours, and the vacuum degree was -0.1 MPa. The dried empty capsules were sealed and stored for later use.

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

[0090] 3) Premixing: Add microcrystalline cellulose, talc, colloidal silica, anhydrous magnesium citrate and isaconazole sulfate to a mixer for mixing.

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

[0092] 5) Total mixing: Add the pre-particles obtained in 4) and the added material stearic acid to the mixer, mix at 20 rpm for 10 min to obtain drug particles.

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

[0094] 7) Capsule drying: Place the filled capsules and desiccant from step 6) into a reduced pressure or vacuum drying device for drying. The amount of desiccant is calculated at 0.3g / capsule. The drying temperature is 30℃, the drying vacuum degree is -0.05Mpa, and the drying time is 48h.

[0095] 8) Bottled: Pack the dried capsules from step 7) into 40ml high-density polyethylene bottles, add desiccant (4g per bottle), close the cap, and seal using electromagnetic induction sealing.

[0096] Experimental examples: Moisture content and stability were tested on the comparative examples and Examples 1-2 above.

[0097] Isaconazole sulfate raw material is extremely unstable and sensitive to moisture, affecting the stability of capsules and their compositions. The moisture and impurity conditions in the examples are as follows compared to the control examples.

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

[0099] Moisture content of empty capsules before drying 2.85 2.85 2.85 Moisture content after empty capsules are dried / 0.32 0.34

[0100] It is evident that the embodiments of this application significantly reduce the moisture content of the empty capsules after drying, which is beneficial to the stability of the product.

[0101] Moisture content of capsules before drying 0.73 0.47 0.52 Moisture content of the capsules after drying / 0.30 0.34

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

[0103]

[0104]

[0105] As can be seen, the embodiments of this application can ensure that the capsules have low moisture content on day 0, and that the moisture content does not increase during storage, which is more beneficial to the stability of the product.

[0106] Impurity testing:

[0107] The relevant substances were determined according to the high performance liquid chromatography (HPLC) method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). For the preparation of the test solution, accurately weigh an appropriate amount of the contents of the sample, place it in a volumetric flask, add an appropriate amount of solvent, sonicate and shake to dissolve, dilute to the mark with solvent, filter, and prepare a solution containing 2.8 mg / ml of isaconazole sulfate. The reference standard was prepared according to the same method as the test solution. Gradient elution was performed using octadecylsilane-bonded silica gel as the stationary phase, water-acetonitrile-trifluoroacetic acid as mobile phase A, and acetonitrile-trifluoroacetic acid as mobile phase B. The flow rate was 1.5 ml / min; the column temperature was 40℃; the autosampler temperature was 5℃; the detection wavelength was 250 nm; and the injection volume was 20 μl.

[0108] The measurement results are as follows:

[0109] 0 days 1.06 0.67 0.65 Store at 25℃ for 1 month 1.67 0.77 0.81 Store at 25℃ for 3 months 2.19 0.83 0.92 Store at 40℃ for 1 month 2.28 1.20 1.06 Store at 40℃ for 3 months 3.76 1.52 1.50

[0110] 0 days 0.07 0.06 0.05 Store at 25℃ for 3 months 0.14 0.06 0.06 Store at 40℃ for 3 months 0.22 0.07 0.08

[0111] As can be seen, the total impurities and major single degradation impurity (isaconazole impurity 11) in the embodiments of this application show a smaller increase compared to the comparative example, which is more beneficial to product stability. Furthermore, it was found that at 40°C, the major single degradation impurity (isaconazole impurity 11) in the embodiments of this application showed no significant increase over 3 months, while the comparative example showed an increase of 0.15%, significantly higher than the embodiments. The inventive technology of this application can control impurity levels lower throughout the product's lifecycle, ensuring the safety and efficacy of medication for patients.

Claims

1. A method for preparing isaconazole sulfate capsules, comprising the following steps: 1) Pretreatment: Dry the empty capsules and seal them for storage; 2) Granulation: Weigh isaconazole sulfate and excipients to prepare drug granules: a) Weighing: Weigh out microcrystalline cellulose, talc, colloidal silica, stearic acid, anhydrous magnesium citrate and isaconazole sulfate according to the formula; b) Premixing: Microcrystalline cellulose, talc, colloidal silica, anhydrous magnesium citrate and isaconazole sulfate are added to a mixer and mixed. c) Add the premixed powder from step b) to a dry granulator to prepare pre-granules; d) Mixing: The pre-granules obtained in step c) and the added material stearic acid are added to a mixer and mixed to obtain the drug granules; 3) Filling: Fill the hollow capsule with the drug particles prepared in step 2) to obtain a filled capsule; 4) Drying: The filled capsules and desiccant from step 3) are placed in a drying device for vacuum drying to obtain isaconazole sulfate capsules; 5) Bottling: The isaconazole sulfate capsules obtained in step 4) are packed into high-density polyethylene bottles; the high-density polyethylene bottles contain a desiccant. In step 1), after pretreatment, the moisture content of the empty capsules is ≤1.5%; the vacuum drying is static or dynamic drying, with a drying temperature of 30℃-60℃, a drying vacuum degree of -0.05MPa to -0.1MPa, and a drying time of 6h-48h, and the moisture content of the isaconazole sulfate capsules after drying is ≤1%; during the preparation process, the ambient humidity is controlled at a relative humidity of ≤40%.

2. The preparation method according to claim 1, wherein, The hollow capsule is a plant-based capsule.

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

4. The preparation method according to claim 1, wherein, The desiccant in step 4) or step 5) is selected from one or more of molecular sieves, polymers, silica gel, and calcium oxide.

5. The preparation method according to claim 1, wherein, For each of the filled capsules, the amount of desiccant used is 0.05g-0.45g.

6. A product comprising the isaconazole sulfate capsules prepared according to any one of claims 1-5, a desiccant, and a sealed bottle, wherein, The isaconazole sulfate capsules and the desiccant are sealed in the sealed bottle.

7. The product according to claim 6, wherein, The sealed bottle is a high-density polyethylene bottle.

8. The product according to claim 6, wherein, The amount of desiccant in the sealed bottle is 1.5g-4g, with each 40ml sealed bottle containing 1.5g-4g of the desiccant.

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