High-stability isavuconazole sulfate capsule and preparation method thereof

Abstract

The invention relates to the technical field of capsule preparation, and discloses a high-stability isavuconazole sulfate capsule and a preparation method thereof.The preparation method comprises the following steps that S1, isavuconazole sulfate, a polymer carrier, a disintegrating agent and a surfactant are dissolved in an organic solvent to obtain an organic phase, and a water-soluble stabilizer is dissolved in purified water to obtain a water phase; s2, dropwise adding the organic phase into the water phase by using an injection pump while stirring, continuously stirring after dropwise adding to form primary emulsion, homogenizing the primary emulsion, adding a spray drying protective agent, stirring for dissolving, performing spray drying, performing cyclone separation, collecting powder, and drying until the water content is less than or equal to 3.0 to obtain a pretreated prodrug; and S3, mixing the pretreated prodrug, a filler, an alkalizer and a lubricant, and filling a capsule shell with the mixture to obtain the capsule. The isavuconazole sulfate capsule prepared by the invention has high drug loading capacity, excellent in-vitro dissolution performance and outstanding long-term chemical and physical stability, and provides a high-quality oral preparation choice for clinic.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of capsule preparation, in particular to a high-stability esconazole sulfate capsule and a preparation method thereof. BACKGROUND

[0002] Esconazole sulfate is a broad-spectrum triazole antifungal drug, and its clinical application value is significant, but its extremely low water solubility seriously limits its oral bioavailability and preparation development, making it a typical Class II poorly soluble drug in the biopharmaceutics classification system.

[0003] In order to improve the dissolution behavior, the existing technology generally uses solid dispersion or nanocrystal strategy, but these methods have obvious limitations. The traditional solid dispersion technology often faces the core challenge of insufficient long-term physical stability. The drug is prone to recrystallization from amorphous form during storage, resulting in rapid decline of dissolution performance. When used alone, the polymer used for drug loading often cannot balance the processing characteristics and stability effect. Some carriers lack sufficient crystallization inhibition ability, and others are prone to cause chemical degradation of heat-sensitive drugs due to narrow processing temperature window or excessively high required temperature.

[0004] In addition, the role of the added disintegrant starts from the outside of the particles, and the water penetration and disintegration process is relatively slow, which prolongs the residence time of the drug in the humid but not completely disintegrated matrix, thereby increasing the risk of water-mediated recrystallization or hydrolytic degradation.

[0005] Therefore, there is an urgent need in the art for an innovative formulation scheme that must be able to simultaneously and effectively solve the three major interrelated technical problems of processing stability, long-term storage stability and rapid complete dissolution of esconazole sulfate under mild process conditions, so as to develop high-quality and high-performance oral capsule preparations. SUMMARY

[0006] Technical problems to be solved In view of the deficiencies of the prior art mentioned in the background, the present application provides a high-stability esconazole sulfate capsule and a preparation method thereof.

[0007] Technical scheme In order to achieve the above-mentioned purpose, the present application provides the following technical scheme: A preparation method of a high-stability esconazole sulfate capsule, comprising the following steps: S1, dissolve esconazole sulfate, polymer carrier, disintegrant and surfactant in organic solvent to obtain an organic phase; dissolve water-soluble stabilizer in purified water to obtain an aqueous phase; S2, under stirring, use a syringe pump to drop the organic phase into the aqueous phase, continue stirring after dropping is completed, form a primary emulsion; homogenize the primary emulsion, add the prescribed amount of spray drying protective agent to the system, stir until completely dissolved, then spray dry, collect the powder by cyclone separation, dry until the water content is ≤3.0, obtain a pretreated prodrug; S3, mix the pretreated prodrug, filler, alkalizing agent and lubricant, fill into a capsule shell, obtain the high-stability esconazole sulfate capsule.

[0008] Further, a preparation method of a high-stability esconazole sulfate capsule comprises the following steps: S1, weigh the formula mass of esconazole sulfate, polymer carrier, disintegrant and surfactant, place them in an organic solvent, stir until completely dissolved, obtain an organic phase; dissolve water-soluble stabilizer in ice water bath cooled purified water to obtain an aqueous phase; S2, under stirring, use a syringe pump to drop the organic phase into the aqueous phase, continue stirring after dropping is completed, form a primary emulsion; homogenize the primary emulsion, add the prescribed amount of spray drying protective agent to the system, stir until completely dissolved, then spray dry, collect the powder by cyclone separation, and continue drying at 25-30°C until the water content is ≤3.0%, obtain a pretreated prodrug; S3, add the pretreated prodrug, pharmaceutically acceptable filler, alkalizing agent and colloidal silicon dioxide lubricant to a mixer according to the formula amount, mix for 15-20 minutes, then add magnesium stearate lubricant and continue mixing for 5-10 minutes, then fill the obtained powder into a capsule shell, the target filling amount is 500mg / grain, obtain a high-stability esconazole sulfate capsule.

[0009] In the above technical solution, first, the active ingredient is co-dissolved with the functional polymer carrier, disintegrant and surfactant in the organic phase, and the water phase containing the stabilizer is prepared. Then, through nano precipitation and high-pressure homogenization, the components form a structurally stable drug-loaded nanoparticle, and the powder is prepared by spray drying. The core purpose of this step is to disperse the drug in the polymer matrix in amorphous form and embed the disintegration functional unit under the premise of avoiding high-temperature degradation, thereby improving the physical stability and dissolution effect of the preparation. The obtained powder is filled with an appropriate amount of filler, alkalizing agent and lubricant, and the alkalizing agent is used to adjust the microenvironment pH to promote drug dissolution, and finally a high-stability esconazole sulfate capsule is obtained.

[0010] Further, in the S1 step, the polymer carrier is selected from at least one of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, hydroxypropyl methyl cellulose and derivatives thereof. More preferably, the polymer carrier is obtained by mixing polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and hydroxypropyl methylcellulose acetate succinate (hereinafter referred to as HPMCAS) in a mass ratio of (60-75):(25-40).

[0011] Furthermore, the polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is Soluplus®.

[0012] Further, in step S1, the disintegrant is selected from at least one of croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose; More preferably, in step S1, the disintegrant is croscarmellose sodium.

[0013] Further, in step S1, the surfactant is selected from at least one of vitamin E polyethylene glycol succinate, poloxamer, and polysorbate.

[0014] More preferably, the surfactant is vitamin E polyethylene glycol succinate.

[0015] Further, in step S1, the water-soluble stabilizer is poloxamer, and the concentration of poloxamer in the aqueous phase is 0.05%-0.2% (w / v).

[0016] Furthermore, the organic solvent is a mixture of dichloromethane and acetone.

[0017] Further, in step S2, the spray drying protectant is at least one of mannitol, sucrose, and trehalose, and the amount added is 5-15 wt% of the total solids in the system. Further, in step S2, the homogenization process is specifically performed as follows: the colostrum is concentrated under reduced pressure at 25-40°C to remove organic solvents, followed by high-pressure homogenization at 10000-20000psi 1-10 times.

[0018] Furthermore, in step S2, the specific parameters for spray drying are: inlet air temperature 75-85℃, outlet air temperature 40-50℃, feed rate 6-10mL / min, and atomization pressure 3-4bar.

[0019] Furthermore, the mass ratio of isaconazole sulfate, polymer carrier, disintegrant, surfactant, alkalizing agent and lubricant is 200mg:160-200mg:15-25mg; 8-12mg:5-25mg:2-10mg.

[0020] Beneficial technical effects (1) In the technical solution of this invention, by using a compounded polymer carrier system, the disintegrant crosslinked sodium carboxymethyl cellulose and the surfactant vitamin E TPGS are co-dissolved and co-precipitated with the active pharmaceutical ingredient in a nanoprecipitation process, thereby achieving nanoscale uniform dispersion of the drug in the polymer matrix. On the one hand, the excellent processability of Soluplus® ensures mild production throughout the process, avoiding the risk of thermal degradation of the active pharmaceutical ingredient. On the other hand, the ionization effect of HPMCAS in the intestinal environment and its strong interaction with the drug significantly inhibit drug recrystallization, thereby improving the stability of the formulation. At the same time, it can also enhance the drug's dissolution rate and supersaturation maintenance ability. In addition, by embedding the disintegrant in the colostrum spray drying, it can work synergistically with the alkaline microenvironment created by the external alkalizing agent to ensure rapid and complete drug release. The final capsule product has high drug loading, good long-term storage stability and excellent in vitro dissolution performance.

[0021] (2) In the technical solution of this invention, Soluplus®, as a component in the polymer carrier, ensures that the preparation process of isaconazole sulfate capsules can be carried out smoothly at lower temperatures due to its low glass transition temperature and wide processing window, especially minimizing the thermal stress on isaconazole sulfate during spray drying. Furthermore, its amphiphilic structure acts as an excellent stabilizer in nanoprecipitates and can rapidly form supersaturation during dissolution. HPMCAS, another component in the polymer carrier, has carboxyl groups on its molecular chain that can form strong hydrogen bonds with the nitrogen atoms of isaconazole, acting as an anchor for drug molecules in the solid dispersion and increasing the thermodynamic stability of the amorphous form. During the post-processing storage stage, its higher Tg helps to improve the rigidity of the entire solid dispersion, better hindering the migration and recrystallization of drug molecules. The combined use of these two components can better improve the stability of isaconazole sulfate raw material during processing.

[0022] Meanwhile, the selection of composite polymers also has a positive effect on the formation of the promulgation in step S1. Specifically, at the moment of nanoprecipitation, Soluplus®, as a surfactant, can reduce the drug-water interfacial tension, promoting the initial formation and stabilization of nanodroplets / particles. The long-chain molecules of HPMCAS can synergistically adsorb at the interface and entangle with Soluplus® segments, further strengthening the interfacial film. For the emulsion prepared before spray drying, Soluplus® mainly exerts its effect through hydrophobic interactions and micellar encapsulation, while HPMCAS is bound by hydrogen bonds. The two polymers have a stronger synergistic inhibitory effect on the drug in the antisolvent, which can more effectively inhibit the excessive growth and Austronstein ripening of newly formed nanoparticles. The combined system also has a more suitable viscosity, which can better obtain a promulgation with smaller particle size, narrower distribution, and greater stability.

[0023] In this invention, the disintegrant is spray-dried together with isaconazole sulfate active pharmaceutical ingredient in an emulsion. Compared to conventional production methods that add the disintegrant as a capsule filler, this method significantly improves drug stability. In this invention, the disintegrant is co-treated with the active pharmaceutical ingredient during the nanoprecipitation stage and embedded within a nanoparticle matrix. After co-dissolving in the organic phase, the disintegrant is uniformly mixed with the drug and polymer in molecular or nanocluster form. During subsequent nanoprecipitation and spray drying, it is fixed within the pre-treated drug matrix, avoiding localized aggregation of the disintegrant that may occur due to uneven physical mixing in external methods. This ensures that the pre-treated drug powder possesses uniform disintegration characteristics. When the capsule comes into contact with water, the embedded disintegrant rapidly absorbs water and swells from within the nanoparticles, disrupting the pre-treated drug structure from the inside. This allows for faster drug release and dissolution, reducing the time window for water-mediated recrystallization and other physical transformations of the drug in a moist but incompletely disintegrated matrix. Attached Figure Description

[0024] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0025] Figure 1 The dissolution curves are for the samples in Examples 1-3 and Comparative Examples 1-4. Detailed Implementation

[0026] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] The raw materials used in the embodiments and comparative examples of this invention are as follows: Isaconazole sulfate: supplied by Hubei Weideli Chemical Reagent Co., Ltd., pharmaceutical grade, purity ≥99%; Magnesium stearate: Brand is Peter Greven (Germany), model is MgSt 5712; Colloidal silica: Evonik Aerosil® 200; Microcrystalline cellulose: pH 102; Poloxamer 188: Brand name is BASF; Vitamin E TPGS: Brand: BASF; Hydroxypropyl methylcellulose acetate succinate (hereinafter referred to as HPMCAS): Shin-Etsu Chemical AQOAT® AS-MF; Crosslinked sodium carboxymethyl cellulose: AcDiSol®, DuPont.

[0028] The capsule shells used are HPMC plant capsule shells, size 0.

[0029] Example 1 A method for preparing stable isaconazole sulfate capsules includes the following steps: S1. Weigh 200 mg of isaconazole sulfate, 180 mg of polymer carrier, 20 mg of disintegrant and 10 mg of surfactant, and place them in an organic solvent at a mass-volume ratio of 1 g: 10 mL. Stir until completely dissolved to obtain the organic phase. Dissolve the water-soluble stabilizer in purified water cooled in an ice-water bath to obtain the aqueous phase. The polymer carrier was obtained by mixing Soluplus® and HPMCAS in a mass ratio of 60:40. The disintegrant is croscarmellose sodium, the surfactant is vitamin E TPGS, and the organic solvent is a 1:1 volume ratio mixture of dichloromethane and acetone; the water-soluble stabilizer is poloxamer 188, and the concentration of poloxamer in the aqueous phase is 0.05% (w / v).

[0030] S2. Under stirring at 1000 rpm, the organic phase was added dropwise to the aqueous phase at a rate of 1 mL / min using a syringe pump. After the addition was complete, stirring was continued for 30 minutes to form a pre-emulsion. The pre-emulsion was then rotary evaporated at 30°C under reduced pressure for 30 minutes, and then transferred to a high-pressure homogenizer. It was then cycled 5 times at 15000 psi. A spray drying protectant was added to the system and stirred until completely dissolved. The mixture was then spray-dried, and the powder was collected by cyclone separation and dried at 25°C until the water content was ≤3.0%, thus obtaining the pre-treated drug. The specific parameters for spray drying are: inlet air temperature 75℃, outlet air temperature 40℃, feed rate 8mL / min, and atomization pressure 4bar; the spray drying protectant is D-mannitol, and the amount added is 5wt% of the total solids in the system.

[0031] S3. Add the pretreated drug obtained in step S2, 15mg of alkalizing agent and 5mg of colloidal silica lubricant to a mixer according to the formula amount, mix at 25rpm for 20 minutes, then add 5mg of magnesium stearate lubricant and continue mixing for 10 minutes, add pharmaceutically acceptable filler to 500mg, and then fill the resulting powder into capsule shells to obtain a highly stable isaconazole sulfate capsule. The filler is microcrystalline cellulose (pH 102), and the alkalizing agent is sodium bicarbonate.

[0032] Example 2 A method for preparing stable isaconazole sulfate capsules includes the following steps: S1. Weigh 200 mg of isaconazole sulfate, 180 mg of polymer carrier, 20 mg of disintegrant and 10 mg of surfactant, and place them in an organic solvent at a mass-volume ratio of 1 g: 10 mL. Stir until completely dissolved to obtain the organic phase. Dissolve the water-soluble stabilizer in purified water cooled in an ice-water bath to obtain the aqueous phase. The polymer carrier was obtained by mixing Soluplus® and HPMCAS in a mass ratio of 70:30. The disintegrant is croscarmellose sodium, the surfactant is vitamin E TPGS, and the organic solvent is a 1:1 volume ratio mixture of dichloromethane and acetone; the water-soluble stabilizer is poloxamer 188, and the concentration of poloxamer in the aqueous phase is 0.1% (w / v).

[0033] S2. Under stirring at 1000 rpm, the organic phase was added dropwise to the aqueous phase at a rate of 1 mL / min using a syringe pump. After the addition was complete, stirring was continued for 30 minutes to form a pre-emulsion. The pre-emulsion was then rotary evaporated at 35°C under reduced pressure for 30 minutes, and then transferred to a high-pressure homogenizer. It was cycled 5 times at 15000 psi. A spray drying protectant was added to the system and stirred until completely dissolved. The mixture was then spray-dried, and the powder was collected by cyclone separation and dried at 30°C until the water content was ≤3.0%, thus obtaining the pre-treated drug. The specific parameters for spray drying are: inlet air temperature 75℃, outlet air temperature 40℃, feed rate 8mL / min, and atomization pressure 4bar; the spray drying protectant is D-mannitol, and the amount added is 8wt% of the total solids in the system.

[0034] S3. Add the pretreated drug obtained in step S2, 15mg of alkalizing agent and 5mg of colloidal silica lubricant to a mixer according to the formula amount, mix at 25rpm for 20 minutes, then add 5mg of magnesium stearate lubricant and continue mixing for 10 minutes, add pharmaceutically acceptable filler to 500mg, and then fill the resulting powder into capsule shells to obtain a highly stable isaconazole sulfate capsule. The filler is microcrystalline cellulose (pH 102), and the alkalizing agent is sodium bicarbonate.

[0035] Example 3 A method for preparing stable isaconazole sulfate capsules includes the following steps: S1. Weigh 200 mg of isaconazole sulfate, 180 mg of polymer carrier, 20 mg of disintegrant and 10 mg of surfactant, and place them in an organic solvent at a mass-volume ratio of 1 g: 10 mL. Stir until completely dissolved to obtain the organic phase. Dissolve the water-soluble stabilizer in purified water cooled in an ice-water bath to obtain the aqueous phase. The polymer carrier was obtained by mixing Soluplus® and HPMCAS in a mass ratio of 75:25. The disintegrant is croscarmellose sodium, the surfactant is vitamin E TPGS, and the organic solvent is a 1:1 volume ratio mixture of dichloromethane and acetone; the water-soluble stabilizer is poloxamer 188, and the concentration of poloxamer in the aqueous phase is 0.2% (w / v).

[0036] S2. Under stirring at 1000 rpm, the organic phase was added dropwise to the aqueous phase at a rate of 1 mL / min using a syringe pump. After the addition was complete, stirring was continued for 30 minutes to form a pre-emulsion. The pre-emulsion was then rotary evaporated at 35°C under reduced pressure for 30 minutes, and then transferred to a high-pressure homogenizer. It was cycled 5 times at 15000 psi. A spray drying protectant was added to the system and stirred until completely dissolved. The mixture was then spray-dried, and the powder was collected by cyclone separation and dried at 30°C until the water content was ≤3.0%, thus obtaining the pre-treated drug. The specific parameters for spray drying are as follows: inlet air temperature 85℃, outlet air temperature 50℃, feed rate 8mL / min, and atomization pressure 4bar; the spray drying protectant is D-mannitol, and the amount added is 10wt% of the total solids in the system.

[0037] S3. Add the pretreated drug obtained in step S2, 15mg of alkalizing agent and 5mg of colloidal silica lubricant to a mixer according to the formula amount, mix at 25rpm for 20 minutes, then add 5mg of magnesium stearate lubricant and continue mixing for 10 minutes, add pharmaceutically acceptable filler to 500mg, and then fill the resulting powder into capsule shells to obtain a highly stable isaconazole sulfate capsule. The filler is microcrystalline cellulose, and the alkalizing agent is sodium bicarbonate.

[0038] Comparative Example 1 The difference between this comparative example and Example 2 is that a disintegrant is added as a capsule filler excipient. Specifically, a method for preparing stable isaconazole sulfate capsules includes the following steps: S1. Weigh 200 mg of isaconazole sulfate, 180 mg of polymer carrier and 10 mg of surfactant, and place them in an organic solvent at a mass-volume ratio of 1 g: 10 mL. Stir until completely dissolved to obtain the organic phase. Dissolve the water-soluble stabilizer in purified water cooled in an ice-water bath to obtain the aqueous phase. The polymer carrier was obtained by mixing Soluplus® and HPMCAS in a mass ratio of 70:30. The disintegrant is croscarmellose sodium, the surfactant is vitamin E TPGS, and the organic solvent is a 1:1 volume ratio mixture of dichloromethane and acetone; the water-soluble stabilizer is poloxamer 188, and the concentration of poloxamer in the aqueous phase is 0.1% (w / v).

[0039] S2. Under stirring at 1000 rpm, the organic phase was added dropwise to the aqueous phase at a rate of 1 mL / min using a syringe pump. After the addition was complete, stirring was continued for 30 minutes to form a pre-emulsion. The pre-emulsion was then rotary evaporated at 35°C under reduced pressure for 30 minutes, and then transferred to a high-pressure homogenizer. It was cycled 5 times at 15000 psi. A spray drying protectant was added to the system and stirred until completely dissolved. The mixture was then spray-dried, and the powder was collected by cyclone separation and dried at 30°C until the water content was ≤3.0%, thus obtaining the pre-treated drug. The specific parameters for spray drying are: inlet air temperature 75℃, outlet air temperature 40℃, feed rate 8mL / min, and atomization pressure 4bar; the spray drying protectant is D-mannitol, and the amount added is 8wt% of the total solids in the system.

[0040] S3. Add the pretreated drug obtained in step S2, 20 mg disintegrant, 15 mg alkalizing agent and 5 mg colloidal silica lubricant to a mixer according to the formula amount, mix at 25 rpm for 20 minutes, then add 5 mg magnesium stearate lubricant and continue mixing for 10 minutes, add pharmaceutically acceptable filler to 500 mg, and then fill the resulting powder into capsule shells to obtain a highly stable isaconazole sulfate capsule. The filler is microcrystalline cellulose (pH 102), and the alkalizing agent is sodium bicarbonate.

[0041] Comparative Example 2 The difference between this comparative example and Example 2 is that a single polymer carrier is used; specifically, Soluplus® is used instead of HPMCAS, i.e., 180 mg of Soluplus®.

[0042] Comparative Example 3 The difference between this comparative example and Example 2 is that a single polymer carrier is used; specifically, HPMCAS is used instead of Soluplus®, i.e., 180 mg HPMCAS.

[0043] Comparative Example 4 The difference between this comparative example and Example 2 is that no surfactant is added in step S1; specifically, a polymer carrier is used instead of vitamin E TPGS.

[0044] The products prepared in the examples and comparative examples are now subjected to performance testing. The specific testing methods are as follows: In vitro dissolution test: Dissolution was determined according to the Chinese Pharmacopoeia (paddle method). Dissolution medium: 900 mL of pH 1.0 hydrochloric acid solution for 2 hours, followed by transfer to pH 6.8 phosphate buffer. The temperature was set at 37 ± 0.5℃, and the rotation speed at 75 rpm. Samples were taken at 5, 10, 15, 20, 30, 45, and 60 minutes after the medium change. Drug concentration was determined by HPLC, and the in vitro dissolution effect of the product was judged by the dissolution percentage.

[0045] Accelerated stability testing: Capsule samples prepared from different groups were placed in a constant temperature and humidity chamber at 40℃ and 75%RH, and samples were taken at the end of 0 and 3 months, respectively. The increase in total related substances (TLS) and the Q30 retention rate at the end of 3 months were recorded to assess the storage stability of the samples. The increase in TLS refers to the increase in the total amount of impurities due to chemical degradation during the stability test, expressed as a percentage relative to the main component. A smaller value indicates better chemical stability of the formulation. The Q30 retention rate at the end of 3 months refers to the ratio of the cumulative dissolution rate of the sample at 30 minutes after 3 months of accelerated testing to the initial value at month 0. This value reflects the physical stability and dissolution behavior stability of the formulation. A higher retention rate indicates more stable dissolution performance of the formulation during storage.

[0046] The specific test results are shown in Tables 1 and 2 below. Figure 1 As shown.

[0047] Table 1 In vitro dissolution test

[0048] Table 2 Accelerated Stability Test

[0049] From Table 1, Table 2 and Figure 1 The results show that Figure 1The dissolution curves of the samples in the examples and comparative examples show that the products prepared in Examples 1-3 are superior to the products in the comparative examples in terms of dissolution rate, amorphous state retention, and accelerated stability. The results of Comparative Example 1 show that the dissolution rate is significantly slower than that of Example 2, especially in the early stages, indicating that the internal disintegrant process has a significant advantage in promoting rapid drug release. The results of Comparative Examples 2 and 3 show that Soluplus® ensures smooth processing at low temperatures, and HPMCAS provides long-term physical stability and pH-dependent dissolution; the synergistic effect of the two is significant. The results in Comparative Example 3 are even lower because its high processing temperature and poor dispersibility may lead to partial crystallization or particle agglomeration of the drug, resulting in a slow dissolution rate; complete dissolution was not achieved even after 60 minutes. The results of Comparative Example 4 show that the system lacks surfactant activity, resulting in poorer stability compared to the examples, leading to a decrease in both dissolution rate and extent.

[0050] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Unless otherwise specified, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0051] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0052] Those skilled in the art should understand that the above descriptions are merely several specific embodiments of the present invention, and not all embodiments.

Claims

1. A method for preparing highly stable isaconazole sulfate capsules, characterized in that, Includes the following steps: S1. Isaconazole sulfate, polymer carrier, disintegrant, and surfactant are dissolved in an organic solvent to obtain an organic phase; a water-soluble stabilizer is dissolved in purified water to obtain an aqueous phase. S2. Under stirring, the organic phase is dripped into the aqueous phase using an injection pump. After the dripping is complete, stirring continues to form a pre-emulsion. The pre-emulsion is homogenized, and the prescribed amount of spray drying protectant is added to the system. The mixture is stirred until completely dissolved, then spray dried, and the powder is collected by cyclone separation and dried to obtain the pre-treated drug. S3. Mix the pre-treated drug, filler, alkalizing agent and lubricant, and fill the capsule shell to obtain the high-stability isaconazole sulfate capsules.

2. The method for preparing a highly stable isaconazole sulfate capsule according to claim 1, characterized in that, In step S1, the polymer carrier is selected from at least one of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, hydroxypropyl methylcellulose and its derivatives.

3. The method for preparing a highly stable isaconazole sulfate capsule according to claim 1, characterized in that, The disintegrant is selected from at least one of croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose.

4. The method for preparing a highly stable isaconazole sulfate capsule according to claim 1, characterized in that, In step S1, the surfactant is selected from at least one of vitamin E polyethylene glycol succinate, poloxamer, and polysorbate.

5. The method for preparing a highly stable isaconazole sulfate capsule according to claim 1, characterized in that, In step S1, the water-soluble stabilizer is poloxamer, and the concentration of poloxamer in the aqueous phase is 0.05%-0.2% (w / v).

6. The method for preparing a highly stable isaconazole sulfate capsule according to claim 1, characterized in that, In step S2, the spray drying protectant is at least one of mannitol, sucrose, and trehalose, and the amount added is 5-15 wt% of the total solids in the system.

7. The method for preparing a highly stable isaconazole sulfate capsule according to claim 1, characterized in that, In step S2, the homogenization process specifically involves: concentrating the colostrum under reduced pressure at 25-40°C, followed by high-pressure homogenization at 10,000-20,000 psi for 1-10 times.

8. The method for preparing a highly stable isaconazole sulfate capsule according to claim 1, characterized in that, In step S2, the specific parameters for spray drying are: inlet air temperature 75-85℃, outlet air temperature 40-50℃, feed rate 6-10mL / min, and atomization pressure 3-4bar.

9. The method for preparing a highly stable isaconazole sulfate capsule according to claim 1, characterized in that, The mass ratio of isaconazole sulfate, polymer carrier, disintegrant, surfactant, alkalizing agent and lubricant is 200mg:160-200mg:15-25mg:8-12mg:5-25mg:2-10mg.

10. Isaconazole sulfate capsules prepared by the method for preparing highly stable isaconazole sulfate capsules according to any one of claims 1-9.

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