Iguratimod preparation and preparation method thereof

Abstract

The invention relates to an Iguratimod preparation and a preparation method thereof, and belongs to the technical field of medicament preparation, and the preparation method specifically comprises the following steps: S1, treating a cyclodextrin derivative by using a compound enzyme to obtain enzyme-treated cyclodextrin; then carrying out oxidation crosslinking on the cyclodextrin subjected to enzyme treatment to prepare modified cyclodextrin; s2, mixing an iguratimod raw material medicine with a suspending aid, carrying out micronization treatment, then adding into a dispersion medium, and uniformly stirring to obtain an iguratimod suspension; s3, the modified cyclodextrin obtained in the step S1 and the iguratimod suspension obtained in the step S2 are homogenized and mixed, then freeze drying is conducted, and the iguratimod preparation is obtained. Through unique preparation design and optimization process, the dissolving property of the iguratimod is remarkably improved, the dissolution rate and bioavailability of the medicine are improved, the stability of the preparation and the medication convenience of a patient are ensured, and a more reliable and efficient solution is provided for clinical application of the iguratimod.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparation, and more specifically, to an elamod preparation and a preparation method thereof. Background Art

[0002] In the field of drug research and development, as a compound with significant pharmacological effects, Aguratimod has broad prospects for clinical application. However, the physical properties of Aguratimod have brought great challenges to the development of its formulations. Specifically, Aguratimod has extremely low solubility in a variety of common solvents such as water, acid, methanol and ethanol. This property directly limits its application in traditional formulations, such as oral solutions, suspensions, etc.

[0003] In addition, after micronization of iguratimod, the surface energy of the particles increases and the electrostatic phenomenon is significant, resulting in poor powder fluidity and easy agglomeration, which in turn affects the uniformity and stability of the preparation. This not only increases the complexity and difficulty of preparation production, but also significantly affects the dissolution rate and bioavailability of the drug, which may ultimately reduce the therapeutic effect of the drug.

[0004] In view of the above technical difficulties, the preparation methods of existing iguratimod preparations are mostly limited, and it is difficult to maintain good preparation stability while improving the drug dissolution rate and bioavailability. Therefore, developing a new preparation and a preparation method thereof that can effectively overcome the above shortcomings of iguratimod has become an important issue to be solved in the current field of drug research and development. Based on the above statements, the present application provides an iguratimod preparation and a preparation method thereof. Summary of the invention

[0005] In order to solve the problems raised in the background technology, the present application provides an iguratimod preparation and a preparation method thereof. The purpose of the present invention is to provide an innovative iguratimod preparation and a preparation method thereof, which significantly improves the solubility performance of iguratimod, improves the dissolution rate and bioavailability of the drug through a unique formulation design and optimized process, while ensuring the stability of the formulation and the convenience of medication for patients, and provides a more reliable and efficient solution for the clinical application of iguratimod.

[0006] The present application provides an iguratimod preparation and a preparation method thereof, which adopts the following technical scheme: A method for preparing an iguratimod preparation comprises the following preparation steps: S1, treating a cyclodextrin derivative with a composite enzyme to obtain an enzyme-treated cyclodextrin; then oxidatively cross-linking the enzyme-treated cyclodextrin to obtain a modified cyclodextrin; S2, mixing the iguratimod API with the suspending agent, and performing micronization treatment, and then adding the mixture to the dispersion medium, stirring the mixture evenly, to obtain an iguratimod suspension; S3. Homogenize and mix the modified cyclodextrin obtained in step S1 and the iguratimod suspension obtained in step S2, followed by freeze-drying to obtain an iguratimod preparation.

[0007] Furthermore, in step S1, the modified cyclodextrin is prepared by the following steps: A1. Add the complex enzyme to the buffer solution, stir at room temperature until uniform, then add the cyclodextrin derivative to the system, adjust the pH value of the system to 5.0-6.0, increase the system temperature to 50-55°C, and treat for 20-40 minutes to obtain enzyme-treated cyclodextrin; A2. Add the enzyme-treated cyclodextrin to the ethanol solution, stir evenly, then add the oxidant to the system, stir in a dark environment, then add the cross-linking agent and catalyst to the system, increase the system temperature to 50-60°C, react for 3-4 hours, filter, wash, and dry to obtain the modified cyclodextrin.

[0008] Furthermore, in step S1, the modified cyclodextrin is prepared by the following steps: A1. Add the complex enzyme to the phosphate buffer at a mass volume ratio of 1 g: 2-6 mL, stir until uniform at room temperature, then add the cyclodextrin derivative to the system, adjust the pH value of the system to 5.0-6.0, increase the system temperature to 50-55° C., and treat for 20-40 minutes to obtain enzyme-treated cyclodextrin; A2, the enzyme-treated cyclodextrin according to the mass volume ratio of 5-6g: 50-60mL was added to 80% ethanol solution, and the oxidant was added to the system after stirring, and stirred at a rate of 30-90rpm for 2-3 hours under light-proof conditions, and then the cross-linking agent and catalyst were added to the system, and the system temperature was increased to 50-60 ° C. After reacting for 3-4 hours, the system was filtered, and the system was washed with pure ethanol and dried at 60-80 ° C to obtain modified cyclodextrin; Wherein, the cross-linking agent is ethylenediamine, the catalyst is glacial acetic acid, and the usage amount is 1-2 mL.

[0009] In the above reaction process, in step A1, a composite enzyme is used to treat a cyclodextrin derivative, so that the cyclodextrin is partially degraded to obtain an enzyme-treated cyclodextrin containing a mixed system of oligosaccharide fragments and cyclodextrin derivatives; then, an oxidant is used to treat the enzyme-treated cyclodextrin to oxidize the hydroxyl groups in the system to generate aldehydes, and then, under the action of a cross-linking agent and a catalyst, the amino group on the ethylenediamine reacts with the aldehyde group through a Schiff base to form a stable covalent bond to obtain a modified cyclodextrin.

[0010] Furthermore, in step A1, the composite enzyme is obtained by mixing pullulanase and cyclodextrin hydrolase in a mass ratio of 1:0.1-0.2.

[0011] Furthermore, in step A2, the mass ratio of the complex enzyme, enzyme-treated cyclodextrin, oxidant and cross-linking agent is 0.01-0.3:1:0.4-2.5:0.1-0.7.

[0012] Furthermore, in step S1, the cyclodextrin derivative is hydroxypropyl-β-cyclodextrin.

[0013] Further, in step S2, the iguratimod suspension is specifically prepared by the following steps: The ailatimod raw material is mixed with a suspending agent in a mass ratio of 1:3-5, and then input into a micronizing device for micronization. During the pulverization process, the pulverization time is controlled at 20-30 minutes and the pulverization temperature is 30-40°C. After screening by air flow classification, a mixture with a particle size in the range of 10-50 μm is obtained. The mixture is then added to a dispersion medium and stirred at a rate of 30-90 rpm for 20-30 minutes at room temperature to obtain an ailatimod suspension.

[0014] Furthermore, the suspending agent is obtained by mixing sodium carboxymethyl cellulose, polyethylene glycol, and sucrose fatty acid ester in a mass ratio of 10:4-5:1-2.

[0015] Furthermore, the dispersion medium is obtained by mixing purified water, glycerol and acetone in a volume ratio of 70:10-20:1-10.

[0016] Furthermore, in step S3, the homogenization rate is 1000-3000 rpm, and the homogenization time is 20-40 minutes; the freeze-drying temperature is minus 20°C to minus 40°C, the vacuum degree is less than 0.1 mbar, and the freeze-drying time is 3-6 hours.

[0017] In summary, this application has the following beneficial effects: In the technical solution of the present invention, a composite enzyme including cyclodextrin hydrolase and pullulanase is used to treat cyclodextrin derivatives. Through the action of the composite enzyme, cyclodextrin is efficiently degraded to generate glucose or other oligosaccharide fragments; and the α-1,4-glycosidic bonds in the cyclodextrin molecules are cut, thereby reducing the molecular size of the cyclodextrin. By controlling the conditions of the enzymatic reaction, partial degradation of the cyclodextrin derivatives is achieved. Subsequently, an oxidant is used to treat the enzyme-treated cyclodextrin, and the hydroxyl groups in the system are oxidized to generate aldehydes. Subsequently, under the action of a cross-linking agent and a catalyst, the amino groups on ethylenediamine react with the aldehyde groups through a Schiff base to form a stable covalent bond to obtain a modified cyclodextrin. This modified cyclodextrin can more effectively encapsulate the Ailamod API to form a stable complex, thereby improving the solubility and bioavailability of Ailamod in the body.

[0018] In the technical solution of the present invention, the Ailamod raw material is mixed with a suspending agent and micronized, then added to a dispersion medium and stirred evenly to obtain an Ailamod suspension. This step helps to reduce the particle size of drug particles, increase the dispersibility and stability of the drug, and prevent the drug from aggregating and precipitating during storage and use. Among them, sodium carboxymethyl cellulose, polyethylene glycol and sucrose fatty acid ester are selected as components of the suspending agent. Sodium carboxymethyl cellulose, as the main suspending agent, can increase the viscosity of the solution and form a network structure, and the polyethylene glycol component can increase the suspension stability of the preparation; sucrose fatty acid ester, as a surfactant, can improve the dispersibility of drug particles in the solvent, make the drug particles more evenly distributed in the preparation, effectively prevent them from settling or aggregating, and improve the bioavailability of the drug. Through compounding, the system will not make the system viscosity too large while maintaining a good suspension effect, affecting the absorption and release of the drug.

[0019] In the technical solution of the present invention, a variety of technical means such as enzyme treatment, oxidative cross-linking, micronization, suspension and freeze drying are combined to optimize the preparation process of the Aguratimod preparation. The combined application of these technical means not only improves the preparation efficiency of the preparation, but also ensures the quality and stability of the preparation. The inclusion complex of modified cyclodextrin can reduce the degradation and metabolism of the Aguratimod raw material in the gastrointestinal tract, thereby increasing the concentration and retention time of the drug in the target organ and improving the efficacy of the drug. At the same time, due to the reduction in particle size of the drug particles and the improvement in dispersibility, the distribution of the drug in the body is more uniform, reducing the stimulation and adverse reactions of the drug to local tissues, and improving the safety of the drug. DETAILED DESCRIPTION

[0020] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0021] The specific implementation methods of this application involve: Hydroxypropyl-β-cyclodextrin: CAS No. 128446-35-5, provided by Zibo Qianhui Biotechnology Co., Ltd.; Dimethyl-β-cyclodextrin: CAS No. 94035-02-6, provided by Zibo Qianhui Biotechnology Co., Ltd. β-Cyclodextrin: CAS No. 7585-39-9, provided by Zibo Qianhui Biotechnology Co., Ltd.; Cyclodextrin hydrolase: provided by Jiangsu Jiujia Biotechnology Co., Ltd., catalog number 03241621; Pullulanase: CAS No. 9075-68-7, provided by Wuhan Lanabai Pharmaceutical Chemical Co., Ltd.; α-Amylase: provided by Hubei Boyuan Biotechnology Co., Ltd.; Sodium carboxymethyl cellulose: CAS No. 9004-32-4, provided by Xi'an Hongyao Pharmaceutical Excipients Co., Ltd. Sucrose fatty acid ester: content 99%, provided by Hebei Runbu Biotechnology Co., Ltd.

[0022] Polyethylene glycol: PEG-6000, provided by Shandong Huiheng Biotechnology Co., Ltd.

[0023] Example 1 A method for preparing an iguratimod preparation comprises the following preparation steps: S1. Using a composite enzyme to treat a cyclodextrin derivative to obtain an enzyme-treated cyclodextrin; then oxidatively cross-linking the enzyme-treated cyclodextrin to prepare a modified cyclodextrin, the specific operation is as follows: A1. Add the complex enzyme to the phosphate buffer at a mass volume ratio of 1 g: 2 mL, stir at room temperature until uniform, then add the cyclodextrin derivative to the system, adjust the pH value of the system to 5.0, increase the system temperature to 50°C, and treat for 20 minutes to obtain enzyme-treated cyclodextrin; The composite enzyme is obtained by mixing pullulanase and cyclodextrin hydrolase in a mass ratio of 1:0.1; The cyclodextrin derivative is hydroxypropyl-β-cyclodextrin, and the mass ratio of the cyclodextrin derivative to the complex enzyme is 1:0.05.

[0024] A2, the enzyme-treated cyclodextrin was added to 80% ethanol solution at a mass volume ratio of 6g:50mL, and the oxidant was added to the system after stirring, and stirred at a rate of 30rpm for 2 hours under light-proof conditions, and then the cross-linking agent and catalyst were added to the system, and the system temperature was increased to 50°C, and the reaction was filtered after 3 hours, and the system was washed with pure ethanol and dried at 60°C to obtain modified cyclodextrin; The usage amounts of the complex enzyme, enzyme-treated cyclodextrin, oxidant, cross-linking agent and catalyst are 0.01 g: 1 g: 0.4 g: 0.1 g: 1 mL.

[0025] Wherein, the cross-linking agent is ethylenediamine and the catalyst is glacial acetic acid.

[0026] S2, mixing the iguratimod API with the suspending agent, and performing micronization treatment, then adding it to the dispersion medium, stirring evenly, to obtain an iguratimod suspension, the specific operation is as follows: The iguratimod raw material was mixed with a suspending agent at a mass ratio of 1:3, and then input into a micronizing device for micronization. During the pulverization process, the pulverization time was controlled to be 20 minutes and the pulverization temperature was 30°C. After screening by an air flow classification method, a mixture with a particle size in the range of 10-50 μm was obtained. Then, the mixture was added to a dispersion medium at a mass volume ratio of 1 mg: 10 mL, and stirred at a rate of 30 rpm for 20 minutes at room temperature to obtain an iguratimod suspension; The suspending agent is prepared by mixing sodium carboxymethyl cellulose, polyethylene glycol, and sucrose fatty acid ester in a mass ratio of 10:4:1; Wherein, the dispersion medium is obtained by mixing purified water, glycerol and acetone in a volume ratio of 70:10:1; S3, homogenously mixing the modified cyclodextrin obtained in step S1 and the iguratimod suspension obtained in step S2, and then freeze-drying to obtain an iguratimod preparation; Among them, the homogenization rate is 1000 rpm, the homogenization time is 20 minutes, the freeze-drying temperature is minus 20°C, the vacuum degree is 0.1 mbar, and the freeze-drying time is 3 hours.

[0027] Example 2 A method for preparing an iguratimod preparation comprises the following preparation steps: S1. Using a composite enzyme to treat a cyclodextrin derivative to obtain an enzyme-treated cyclodextrin; then oxidatively cross-linking the enzyme-treated cyclodextrin to prepare a modified cyclodextrin, the specific operation is as follows: A1. Add the complex enzyme to the phosphate buffer at a mass volume ratio of 1 g: 4 mL, stir until uniform at room temperature, then add the cyclodextrin derivative to the system, adjust the pH value of the system to 5.5, increase the system temperature to 53°C, and treat for 30 minutes to obtain enzyme-treated cyclodextrin; The composite enzyme is obtained by mixing pullulanase and cyclodextrin hydrolase in a mass ratio of 1:0.15; The cyclodextrin derivative is hydroxypropyl-β-cyclodextrin, and the mass ratio of the cyclodextrin derivative to the complex enzyme is 1:0.05.

[0028] A2, the enzyme-treated cyclodextrin was added to 80% ethanol solution at a mass volume ratio of 1g:10mL, and the oxidant was added to the system after stirring evenly, and stirred at a rate of 60rpm for 2.5 hours under light-proof conditions, and then a cross-linking agent and a catalyst were added to the system, and the system temperature was increased to 55°C. After reacting for 3.5 hours, the system was filtered, washed with pure ethanol, and dried at 70°C to obtain modified cyclodextrin; Among them, the usage amounts of the complex enzyme, enzyme-treated cyclodextrin, oxidant, cross-linking agent and catalyst are 0.2g:1:1.5g:0.4g:1.5mL.

[0029] Wherein, the cross-linking agent is ethylenediamine and the catalyst is glacial acetic acid.

[0030] S2, mixing the iguratimod API with the suspending agent, and performing micronization treatment, then adding it to the dispersion medium, stirring evenly, to obtain an iguratimod suspension, the specific operation is as follows: The iguratimod raw material was mixed with a suspending agent at a mass ratio of 1:4, and then input into a micronizing device for micronization. During the pulverization process, the pulverization time was controlled to be 25 minutes and the pulverization temperature was 35° C. After sieving by air flow classification, a mixture with a particle size in the range of 10-50 μm was obtained. Then, the mixture was added to a dispersion medium at a mass volume ratio of 2 mg: 10 mL, and stirred at a rate of 60 rpm for 25 minutes at room temperature to obtain an iguratimod suspension; The suspending agent is prepared by mixing sodium carboxymethyl cellulose, polyethylene glycol, and sucrose fatty acid ester in a mass ratio of 10:4.5:1.5; Wherein, the dispersion medium is obtained by mixing purified water, glycerol and acetone in a volume ratio of 70:10-20:1-10; S3, homogenously mixing the modified cyclodextrin obtained in step S1 and the iguratimod suspension obtained in step S2, and then freeze-drying to obtain an iguratimod preparation; Among them, the homogenization rate is 2000 rpm, the homogenization time is 30 minutes, the freeze-drying temperature is minus 30°C, the vacuum degree is 0.1 mbar, and the freeze-drying time is 4.5 hours.

[0031] Example 3 A method for preparing an iguratimod preparation comprises the following preparation steps: S1. Using a composite enzyme to treat a cyclodextrin derivative to obtain an enzyme-treated cyclodextrin; then oxidatively cross-linking the enzyme-treated cyclodextrin to prepare a modified cyclodextrin, the specific operation is as follows: A1. Add the complex enzyme to the phosphate buffer at a mass volume ratio of 1 g:6 mL, stir at room temperature until uniform, then add the cyclodextrin derivative to the system, adjust the pH value of the system to 6.0, increase the system temperature to 55°C, and treat for 40 minutes to obtain enzyme-treated cyclodextrin; The composite enzyme is obtained by mixing pullulanase and cyclodextrin hydrolase in a mass ratio of 1:0.2; The cyclodextrin derivative is hydroxypropyl-β-cyclodextrin, and the mass ratio of the cyclodextrin derivative to the complex enzyme is 1:0.05.

[0032] A2, the enzyme-treated cyclodextrin was added to an 80% ethanol solution at a mass volume ratio of 6g:60mL, and the oxidant was added to the system after stirring, and stirred at a rate of 90rpm for 3 hours under light-proof conditions, and then a cross-linking agent and a catalyst were added to the system, and the system temperature was increased to 60°C. After reacting for 4 hours, the system was filtered, washed with pure ethanol, and dried at 80°C to obtain modified cyclodextrin; The usage amounts of the complex enzyme, enzyme-treated cyclodextrin, oxidant, cross-linking agent and catalyst are 0.3g:1:2.5g:0.7g:2mL.

[0033] Wherein, the cross-linking agent is ethylenediamine and the catalyst is glacial acetic acid.

[0034] S2, mixing the iguratimod API with the suspending agent, and performing micronization treatment, then adding it to the dispersion medium, stirring evenly, to obtain an iguratimod suspension, the specific operation is as follows: The iguratimod raw material was mixed with a suspending agent at a mass ratio of 1:5, and then input into a micronizing device for micronization. During the pulverization process, the pulverization time was controlled to be 30 minutes and the pulverization temperature was 40° C. After screening by an air flow classification method, a mixture with a particle size in the range of 10-50 μm was obtained. Then, the mixture was added to a dispersion medium at a mass volume ratio of 3 mg:10 mL, and stirred at a rate of 90 rpm for 30 minutes at room temperature to obtain an iguratimod suspension; The suspending agent is prepared by mixing sodium carboxymethyl cellulose, polyethylene glycol, and sucrose fatty acid ester in a mass ratio of 10:5:2; Wherein, the dispersion medium is obtained by mixing purified water, glycerol and acetone in a volume ratio of 70:20:10; S3, homogenously mixing the modified cyclodextrin obtained in step S1 and the iguratimod suspension obtained in step S2, and then freeze-drying to obtain an iguratimod preparation; Among them, the homogenization rate is 3000 rpm, the homogenization time is 40 minutes, the freeze-drying temperature is minus 40°C, the vacuum degree is 0.1 mbar, and the freeze-drying time is 6 hours.

[0035] Comparative Example 1 The difference between this comparative example and Example 1 is that β-cyclodextrin is used instead of hydroxypropyl-β-cyclodextrin in this comparative example.

[0036] Comparative Example 2 The difference between this comparative example and Example 1 is that dimethyl-β-cyclodextrin is used instead of hydroxypropyl-β-cyclodextrin in this comparative example.

[0037] Comparative Example 3 The difference between this comparative example and Example 1 is that in this comparative example, the modified cyclodextrin in step S1 is specifically prepared by the following steps: Hydroxypropyl-β-cyclodextrin was added to 80% ethanol solution at a mass volume ratio of 6g:50mL, and an oxidant was added to the system after stirring evenly. The mixture was stirred at 30rpm for 2 hours under light-proof conditions, and then a cross-linking agent and a catalyst were added to the system. The system temperature was raised to 50°C, and the mixture was filtered after reacting for 3 hours. The system was washed with pure ethanol and dried at 60°C to obtain modified cyclodextrin. The usage amounts of hydroxypropyl-β-cyclodextrin, oxidant, cross-linking agent and catalyst are 1 g: 0.4 g: 0.1 g: 1 mL.

[0038] Wherein, the cross-linking agent is ethylenediamine and the catalyst is glacial acetic acid.

[0039] Comparative Example 4 The difference between this comparative example and Example 1 is that pullulanase is used instead of the complex enzyme in this comparative example.

[0040] Comparative Example 5 The difference between this comparative example and Example 1 is that in this comparative example, the composite enzyme is obtained by mixing α-amylase and cyclodextrin hydrolase in a mass ratio of 1:0.1.

[0041] Comparative Example 6 The difference between this comparative example and Example 1 is that in this comparative example, the suspending agent is obtained by mixing sodium carboxymethyl cellulose and polyethylene glycol in a mass ratio of 10:4.

[0042] Comparative Example 7 The difference between this comparative example and Example 1 is that in this comparative example, the suspending agent is sodium carboxymethyl cellulose.

[0043] Performance Testing The iguratimod preparations prepared in Examples 1-3 and Comparative Examples 1-7 of the present application were pressed into iguratimod tablets at a tableting pressure of 5 kg. The formulations are shown in Table 1 below: Table 1 Iguratimod Tablets Formulation Components content effect source Iguratimod preparations 25mg API preparation lactose 56mg Fillers Jiangsu Xinde starch 147mg Fillers Anhui Mountains and Rivers Crospovidone 29mg Disintegrants Hebei Zhentian Food Additives Co., Ltd. Magnesium Stearate 3mg Lubricants Anhui Mountains and Rivers Now, the in vitro dissolution test of the prepared iguratimod tablets in different groups was performed. The iguratimod tablets were placed in 1000 mL of phosphate buffer with a pH value of 6.8, stirred at 150 rpm at 37°C, and the absorbance of the subsequent filtrate was measured at a wavelength of 345 nm by ultraviolet spectrophotometry, and the dissolution of the iguratimod tablets at different stirring times of 10 minutes, 20 minutes, 40 minutes and 60 minutes was recorded. Each sample was tested 5 times, and the average value was recorded. The specific test results are shown in Table 2 below: Table 2 In vitro dissolution test Group Dissolution in 10 minutes (%) Dissolution in 20 minutes (%) Dissolution in 40 minutes (%) Dissolution in 60 minutes (%) Example 1 50.1 60.7 72.9 80.1 Example 2 53.1 64.1 76.3 82.1 Example 3 51.8 62.4 74.4 80.6 Comparative Example 1 43.8 52.6 65.3 76.3 Comparative Example 2 47.1 57.3 70.1 77.6 Comparative Example 3 47.3 57.9 70.3 77.0 Comparative Example 4 48.9 60.0 71.6 78.4. Comparative Example 5 42.9 53.4 65.7 72.6 Comparative Example 6 40.0 52.9 65.0 73.1 Comparative Example 7 35.6 47.8 60.3 68.4 From the results in Table 2, it can be seen that the iguratimod preparations prepared in Examples 1-3 have the best dissolution effect in iguratimod tablets.

[0044] Now the stability test of the Aguratimod tablets prepared from the Aguratimod preparations in Examples 1-3 and Comparative Examples 1-7 was performed. The Aguratimod tablets prepared in different groups were placed in an environment with a temperature of 60°C, a relative humidity of 75%, and a light intensity of 5000 lux for 10 days for aging treatment. Subsequently, the dissolution of the Aguratimod tablets in different groups at 20min and 40min was tested, and the rate of change of the dissolution was recorded. The dissolution test operation was the same as above. Each sample was tested 5 times, and the average value was recorded. The specific test results are shown in Table 3 below: Table 3 Stability test Group 20min dissolution change (%) 40min dissolution change (%) Example 1 2.1 5.1 Example 2 1.3 3.9 Example 3 1.7 4.2 Comparative Example 1 3.1 8.6 Comparative Example 2 2.3 6.0 Comparative Example 3 2.9 6.3 Comparative Example 4 2.9 6.5 Comparative Example 5 2.6 6.0 Comparative Example 6 3.3 8.7 Comparative Example 7 3.6 9.5 It can be seen from the results shown in Table 3 that the sample prepared in Example 2 has the smallest dissolution change rate at 20 min and 40 min, showing the best stability.

[0045] Now the bioavailability of the prepared iguratimod tablets in different groups was tested. SD rats weighing 260g were selected, and the drug was administered by gavage after fasting for 12 hours, with a concentration of 1mg / mL and a dosage of 10mg / kg. Two hours after administration, the rats were allowed to eat freely, and 8 hours later, blood was collected venously, and 100μL of plasma samples were taken. 300μL of methanol solution containing 50ng / mL lead acetate was added, and the samples were centrifuged at 3000rpm for 10 minutes at room temperature, and then the protein precipitate was filtered out, and the blank plasma was diluted 100 times, and then HPLC analysis was performed to determine the bioavailability of different samples. Each sample was tested 5 times, and the average value was recorded. The test results are shown in Table 4 below. (Wherein, the peak time is recorded as Tmax, the maximum peak concentration is recorded as Cmax, the area under the drug-time curve is recorded as AUC, and the bioavailability is recorded as F.) Table 4 Bioavailability test Group Tmax(h) Cmax(μg / mL) AUC (h·μg / mL) F(%) Example 1 1.84 29.3 299 118 Example 2 1.88 30.9 316 128 Example 3 1.85 29.0 304 121 Comparative Example 1 1.80 29.0 291 111 Comparative Example 2 1.80 29.3 290 110 Comparative Example 3 1.70 26.0 278 101 Comparative Example 4 1.64 24.8 263 91 Comparative Example 5 1.75 26.8 284 105 Comparative Example 6 1.78 28.4 286 108 Comparative Example 7 1.68 25.4 270 95 From the results in Table 4, it can be seen that the modified cyclodextrin used in Examples 1-3 of the present application can improve the bioavailability of the iguratimod preparation, and the comprehensive performance of the prepared iguratimod tablets including dissolution effect and stability is significantly better than that of the samples prepared in Comparative Examples 1-7, that is, within the technical solution defined in the present application, the prepared iguratimod preparation has excellent comprehensive performance.

[0046] In the description of the specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0047] The above contents are merely examples and explanations of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in a similar manner. As long as they do not deviate from the invention or exceed the scope defined by the claims, they shall all fall within the protection scope of the present invention.

Claims

1. A method for preparing an iguratimod preparation, characterized in that: The method comprises the following preparation steps: S1, treating a cyclodextrin derivative with a composite enzyme to obtain an enzyme-treated cyclodextrin; then oxidatively cross-linking the enzyme-treated cyclodextrin to obtain a modified cyclodextrin; S2, mixing the iguratimod API with the suspending agent, and performing a micronization treatment, and then adding the mixture to the dispersion medium, stirring the mixture evenly, to obtain an iguratimod suspension; S3. Homogenize and mix the modified cyclodextrin obtained in step S1 and the iguratimod suspension obtained in step S2, and then freeze-dry to obtain an iguratimod preparation.

2. The method for preparing an iguratimod preparation according to claim 1, characterized in that: In step S1, the modified cyclodextrin is prepared by the following steps: A1. Add the complex enzyme to the buffer solution, stir at room temperature until uniform, then add the cyclodextrin derivative to the system, adjust the pH value of the system to 5.0-6.0, increase the system temperature to 50-55°C, and treat for 20-40 minutes to obtain enzyme-treated cyclodextrin; A2. Add the enzyme-treated cyclodextrin to the ethanol solution, stir evenly, then add the oxidant to the system, stir in a dark environment, then add the cross-linking agent and catalyst to the system, increase the system temperature to 50-60°C, react for 3-4 hours, filter, wash, and dry to obtain the modified cyclodextrin.

3. The method for preparing an iguratimod preparation according to claim 2, characterized in that: In step A1, the composite enzyme is obtained by mixing pullulanase and cyclodextrin hydrolase in a mass ratio of 1:0.1-0.

2.

4. The method for preparing an iguratimod preparation according to claim 2, characterized in that: In step A1, the mass ratio of the complex enzyme, enzyme-treated cyclodextrin, oxidant and cross-linking agent is 0.01-0.3:1:0.4-2.5:0.1-0.

7.

5. The method for preparing an iguratimod preparation according to claim 1, characterized in that: In step S1, the cyclodextrin derivative is hydroxypropyl-β-cyclodextrin.

6. The method for preparing an iguratimod preparation according to claim 1, characterized in that: In step S2, the iguratimod suspension is prepared by the following steps: The elamod raw material is mixed with the suspending agent, and then micronized. During the pulverization process, the pulverization time is controlled to be 20-30 minutes, the pulverization temperature is 30-40°C, and after screening by air flow classification method, a mixture with a particle size in the range of 10-50 μm is obtained. The mixture is then added to the dispersion medium and stirred at a rate of 30-90 rpm for 20-30 minutes at room temperature to obtain an elamod suspension.

7. The method for preparing an iguratimod preparation according to claim 6, characterized in that: The suspending agent is obtained by mixing sodium carboxymethyl cellulose, polyethylene glycol, and sucrose fatty acid ester in a mass ratio of 10:4-5:1-2.

8. The method for preparing an iguratimod preparation according to claim 6, characterized in that: The dispersion medium is obtained by mixing purified water, glycerol and acetone in a volume ratio of 70:10-20:1-10.

9. The method for preparing an iguratimod preparation according to claim 1, characterized in that: In step S3, the homogenization rate is 1000-3000 rpm, and the homogenization time is 20-40 minutes; the freeze-drying temperature is minus 20°C to minus 40°C, the vacuum degree is less than 0.1 mbar, and the freeze-drying time is 3-6 hours.

10. An iguratimod preparation obtained by the method for preparing the iguratimod preparation according to any one of claims 1 to 9.