Iguratimod tablet and preparation method thereof

Abstract

The invention provides an Iguratimod tablet and a preparation method thereof. The iguratimod tablet is prepared from iguratimod, mannitol, polyvinylpolypyrrolidone, poloxamer, magnesium stearate and the like, and the preparation method comprises the following steps: dissolving or dispersing the poloxamer and the iguratimod in purified water, spraying into a fluidized bed, and performing one-step granulation together with proper pharmaceutic adjuvants; and drying, adding a lubricant, mixing, and tabletting. The iguratimod tablet prepared by the preparation method disclosed by the invention is good in stability and relatively good in dissolution effect; the method is simple in process, easy to operate and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparation, and particularly relates to an iguratimod tablet and a preparation method thereof. Technical Background

[0002] Iguratimod (IGU), as a new type of small molecule disease-modifying antirheumatic drug (DMARDs), has the following mechanisms of action: ① Anti-inflammatory and analgesic effects: The pathogenesis of RA is relatively complex, mainly due to the destruction of the body's own immune system, immune dysfunction, and the lack of effective control of the inflammatory response. IGU selectively inhibits cyclooxygenase 2 (COX2) to reduce the production of prostaglandins in inflamed tissues and inhibits the release of bradykinin from inflamed tissues, thereby reducing the inflammatory response. ② Affecting the synthesis of immunoglobulins: IGU interacts with B lymphocytes and inhibits the formation of immunoglobulins such as IgG, IgA, and IgM, directly affecting the expression of immunoglobulins in RA patients. ③ Inhibiting cytokines: Among cytokines, IL-1, IL-6, IL-17, α-tumor necrosis factor (TNF), etc. are important cell inflammatory factors in the pathogenesis of RA. IGU has significant inhibitory effects on a variety of cytokines, including TNF-α, IL-6, IL-4, and IL-17. ④ Alleviating bone destruction and promoting bone formation: The pathological changes of bone loss in RA joints are closely related to the activation of osteoclasts and bone resorption by pro-inflammatory factors. The RANKL / RANK / OPG signaling pathway plays an important role in the regulation of bone metabolism and is the key pathway to maintain the balance between osteoclast bone resorption and osteoblast bone formation. RANK is located on the cell membrane surface of osteoclast precursor cells or mature osteoclasts and is a transmembrane molecule. Both OPG and RANKL are produced by osteoblasts. RANKL is a member of the tumor necrosis factor family and is the ligand of RANK. It can bind to the RANK receptor on the surface of osteoclasts to promote the activation and differentiation of osteoclasts and inhibit osteoclast apoptosis. OPG competes with RANK for binding to RANKL and has an inhibitory effect on the formation of osteoclasts. Th17 and Treg cells maintain a balanced state under normal immune conditions. Among them, Th17 cells exhibit a high degree of pro-inflammatory effects and promote osteoclasts and bone destruction. Th17 cells mainly exert their effects by producing cytokines such as IL-17 and tumor necrosis factor-α. IL-17 can not only directly promote the expression of RANKL but also act as a pro-inflammatory mediator and play an important role in the generation of inflammation. The expression of Treg cells can reduce the degree of inflammatory response and bone damage. Treg cells can directly act on osteoblasts to promote the expression of OPG. IGU can down-regulate Th17 cells and up-regulate Treg cells, thereby inhibiting bone destruction.

[0003] Iguratimod is a white crystalline powder, poorly soluble in acetonitrile, very poorly soluble in ethanol (99.5), and almost insoluble in water. Molecular formula: C 17 H 14 N 2 O 6 S, molecular weight: 374.37, and its structural formula is as follows:

[0004]

[0005] Due to the physicochemical properties and pathological characteristics of iguratimod, iguratimod is usually administered orally. Currently, the main dosage form on the market is iguratimod tablets. There are already many patents on iguratimod tablets, but they all have problems in different aspects.

[0006] Publication number CN117462497A discloses a preparation method of a rapid-release pharmaceutical composition containing iguratimod tablets. This method uses micronized iguratimod raw material drug and adopts an equal increment premixing method. After mixing, wet granulation is carried out. The premixing of this invention adopts an equal increment premixing method, with a cumbersome process, many steps, and poor production compliance.

[0007] Publication number CN101375834A discloses a preparation method and pharmaceutical application of a solid dispersion of iguratimod. This invention uses organic solvents with relatively high toxicity; the methods for removing solvents and drying are complex processes.

[0008] Publication number CN1531925A discloses a process for a solid preparation of guratimod (iguratimod) and its solid preparation. The guratimod (iguratimod) raw material drug used in this invention is ground with mechanical water-carrying. After solid-liquid separation and drying, guratimod microparticles are made and mixed with pharmaceutically acceptable excipients to make a guratimod solid preparation. The process of changing the particle size by water grinding is complex, and the grinding machine uses a colloid mill or a ball mill, which are unconventional preparation instruments. Moreover, ethanol granulation is used and is restricted by GMP or other quality requirements for use.

[0009] Since iguratimod is almost insoluble in water and has a light mass and small density, when using the wet granulation process in production, the pharmaceutical excipients cannot fully contact the raw material drug, which may lead to problems such as low dissolution rate of the preparation, poor granulation effect, and poor particle fluidity. Although the preparation method using solid dispersion technology can effectively improve the bioavailability of iguratimod, due to its complex process, poor operability, and the introduction of organic solvents, which have a certain impact on the health of the production workshop operators, it is not the best choice. Summary of the Invention

[0010] The object of the present invention is to provide a new tablet of iguratimod and its preparation method. The preparation method described in the present invention is a fluidized bed granulation process; innovatively, iguratimod and poloxamer are dispersed in purified water to prepare an iguratimod aqueous solution; the active pharmaceutical ingredient is fully contacted with poloxamer, greatly improving the problem of low solubility of the active pharmaceutical ingredient; and avoiding the problem of uneven mixing caused by the light weight and low density of the iguratimod active pharmaceutical ingredient itself during the mixing process; spraying the iguratimod aqueous solution into the fluidized bed for granulation and drying, overcoming the problems of poor wet granulation effect, poor particle fluidity, and low dissolution rate of the preparation. The preparation method described in the present invention does not use organic solvents and does not use dodecyl sulfate, which has a stimulating effect on the respiratory mucosa, as a solubilizer, and has strong compliance and safety in actual production.

[0011] To achieve the above object, the present invention provides the following technical solutions:

[0012] A tablet of iguratimod and its preparation method, wherein the tablet of iguratimod is prepared from iguratimod as the active ingredient and a variety of pharmaceutically acceptable excipients; each 1000 tablets of the tablet of iguratimod are composed of the following weight ratios:

[0013] Iguratimod 10 - 30 g, mannitol 135 - 160 g, crospovidone 4 - 10 g, poloxamer 2 - 5 g, magnesium stearate 1 - 3 g, polyvinylpyrrolidone 4 - 10 g. It is prepared by the following method:

[0014] Step 1: Dissolve poloxamer in purified water, and then add iguratimod to prepare an iguratimod aqueous solution;

[0015] Step 2: Put mannitol, crospovidone and polyvinylpyrrolidone into the fluidized bed, and spray the iguratimod aqueous solution described in Step 1 for granulation and drying;

[0016] Step 3: Screen the granules prepared in Step 2 with a 1.0 mm sieve;

[0017] Step 4: Put the granules sieved in Step 3 into a mixer, add magnesium stearate, and mix for 5 minutes;

[0018] Step 5: Use a rotary tablet press to press tablets, and control the tablet hardness at 6 - 10 kg.

[0019] Furthermore, the tablet of iguratimod and its preparation method can be described as:

[0020] Each 1000 tablets of the tablet of iguratimod are composed of the following weight ratios:

[0021] Iguratimod 10 - 30 g, mannitol 25C 135 - 160 g, crospovidone SL10 4 - 10 g, poloxamer 188 2 - 5 g, magnesium stearate 1 - 3 g, povidone K30 4 - 10 g. It is prepared by the following method:

[0022] Step 1: Add poloxamer 188 to purified water, stir until poloxamer 188 is completely dissolved, then add iguratimod under stirring conditions and continue stirring for at least 30 minutes to prepare an iguratimod aqueous solution;

[0023] Step 2: Put mannitol 25C, crospovidone SL10 and povidone K30 into a fluidized bed for premixing for 10 minutes, spray the iguratimod aqueous solution described in Step 1 for granulation, control the inlet air temperature at 50 - 60 °C and the material temperature at 20 - 30 °C; after granulation is completed, dry until the moisture content of the material is less than 5% and then discharge;

[0024] Step 3: Screen the prepared granules with a 1.0 mm sieve, and the screening rotation speed is 500 rpm;

[0025] Step 4: Put the screened granules into a mixer, add magnesium stearate, mix at a rotation speed of 10 rpm for 5 minutes;

[0026] Step 5: Use a rotary tablet press to press tablets with an 8.0 mm round shallow concave punch, and control the tablet hardness at 6 - 10 kg.

[0027] The excipients used in the iguratimod tablets of the present invention are all conventional oral solid pharmaceutical excipients, which are stable in nature and inexpensive; the prepared iguratimod tablets have good dissolution effect and stability. The preparation method of the present invention has a simple process and is easy to operate, and is suitable for industrial production. For pharmaceutical enterprises, it has high economic benefits and accessibility.

[0028] The present invention further discloses the application of the iguratimod tablets prepared by this method in improving the dissolution rate of the preparation and reducing the amount of impurities. The experimental results show that: the iguratimod tablets prepared by the present invention have good dissolution effect and stability, and the dissolution rate of iguratimod in pH 8.0 phosphate buffer solution can reach more than 95% in 30 minutes, and it can meet the requirement that the impurities in the related substances basically do not increase after the preparation is placed under accelerated conditions for 6 months.

[0029] It should be noted that here, in order to enable those skilled in the technical field of the present invention to more clearly and accurately understand the invention content and technical connotation of the present invention, the inventors of the present invention make the following explanations for the professional terms, symbols involved, and the reagent consumables and instruments and equipment used:

[0030] "Commercially available preparation": refers to the iguratimod tablets sold on the market The specification is 25 mg;

[0031] "0 days": refers to the time when the sample preparation is completed;

[0032] "Accelerated conditions": refer to a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. Detailed implementation manners

[0033] To facilitate the understanding of the present invention by those skilled in the technical field to which the present invention pertains, the present invention provides the following detailed implementation manners to further illustrate the said Iguratimod tablets and their preparation methods. The Iguratimod, pharmaceutical excipients, and commercially available preparations involved in the detailed implementation manners of the present invention are all sold on the market and do not involve special pharmaceutical excipients. It is easy for those skilled in the art to understand that the content described in the examples is only used to illustrate the present invention and should not and will not limit the present invention detailed in the claims.

[0034] Example 1

[0035] Prescription (for 10,000 tablets)

[0036] Names of raw and auxiliary materials Unit (g) Iguratimod 250 Mannitol 25C 1400 Crospovidone SL10 90 Poloxamer 188 40 Magnesium stearate 20 Povidone K30 50 Purified water Appropriate amount Total 1850

[0037] Preparation method:

[0038] 1. Add poloxamer 188 to purified water and stir until completely dissolved; add Iguratimod under stirring conditions and continue stirring for 30 minutes to prepare an Iguratimod aqueous solution;

[0039] 2. Premix mannitol 25C, crospovidone SL10, and povidone K30 in a fluidized bed for 10 minutes; spray the Iguratimod aqueous solution for granulation. During the granulation process, control the fan frequency at 20 - 30 Hz, the inlet air temperature at 50 - 60°C, the material temperature at 20 - 30°C, the peristaltic pump speed at 2 - 10 rpm, and the atomization pressure at 0.1 - 0.2 MPa; after granulation, dry and control the material moisture at 3%;

[0040] 3. Screen the prepared granules through a 1.0 mm sieve, with a screening speed of 500 rpm;

[0041] 4. Put the sieved granules and magnesium stearate into a mixer, with a mixing speed of 10 rpm and mix for 5 minutes;

[0042] 5. Use a rotary tablet press to press tablets with an 8.0 mm round shallow concave punch, and control the tablet hardness at 6 - 10 kg.

[0043] Example 2

[0044] Prescription (for 10,000 tablets)

[0045]

[0046]

[0047] Preparation method:

[0048] 1. Add poloxamer 188 to purified water and stir until completely dissolved; add iguratimod under stirring conditions and continue stirring for 30 minutes to prepare an iguratimod aqueous solution.

[0049] 2. Premix mannitol 25C, crospovidone SL10, and povidone K30 in a fluidized bed for 10 minutes; spray the iguratimod aqueous solution for granulation. During the granulation process, control the fan frequency at 20 - 30 Hz, the inlet air temperature at 50 - 60 °C, the material temperature at 20 - 30 °C, the peristaltic pump speed at 2 - 10 rpm, and the atomization pressure at 0.1 - 0.2 MPa; after granulation, dry and control the material moisture at 4%.

[0050] 3. Screen the obtained granules through a 1.0 mm sieve with a screening speed of 500 rpm.

[0051] 4. Put the screened granules and magnesium stearate into a mixer, mix at a speed of 10 rpm for 5 minutes.

[0052] 5. Use a rotary tablet press to press tablets with an 8.0 mm round shallow concave punch, and control the tablet hardness at 6 - 10 kg.

[0053] Example 3

[0054] Prescription (for 10,000 tablets)

[0055] Names of raw and auxiliary materials Unit (g) Iguratimod 100 Mannitol 25C 1350 Crospovidone SL10 40 Poloxamer 188 20 Magnesium stearate 10 Povidone K30 40 Purified water Appropriate amount Total 1560

[0056] Preparation method:

[0057] 1. Add poloxamer 188 to purified water and stir until completely dissolved; add iguratimod under stirring conditions and continue stirring for 30 minutes to prepare an iguratimod aqueous solution.

[0058] 2. Premix mannitol 25C, crospovidone SL10, and povidone K30 in a fluidized bed for 10 minutes; spray the iguratimod aqueous solution for granulation. During the granulation process, control the fan frequency at 20 - 30 Hz, the inlet air temperature at 50 - 60 °C, the material temperature at 20 - 30 °C, the peristaltic pump speed at 2 - 10 rpm, and the atomization pressure at 0.1 - 0.2 MPa; after granulation, dry and control the material moisture at 2%.

[0059] 3. Screen the obtained granules through a 1.0 mm sieve with a screening speed of 500 rpm.

[0060] 4. Put the screened granules and magnesium stearate into a mixer, mix at a speed of 10 rpm for 5 minutes.

[0061] 5. Use a rotary tablet press to press tablets with an 8.0 mm round shallow concave punch, and control the tablet hardness at 6 - 10 kg.

[0062] Example 4

[0063] Prescription (for 10,000 tablets)

[0064] Names of raw and auxiliary materials Unit (g) Iguratimod 150 Mannitol 25C 1550 Crospovidone SL10 80 Poloxamer 188 20 Magnesium stearate 20 Povidone K30 60 Purified water Appropriate amount Total 1880

[0065] Preparation method:

[0066] 1. Add poloxamer 188 to purified water and stir until completely dissolved; add iguratimod under stirring conditions and continue stirring for 30 minutes to prepare an iguratimod aqueous solution.

[0067] 2. Premix mannitol 25C, crospovidone SL10, and povidone K30 in a fluidized bed for 10 minutes; spray the iguratimod aqueous solution for granulation. During the granulation process, control the fan frequency at 20 - 30 Hz, the inlet air temperature at 50 - 60 °C, the material temperature at 20 - 30 °C, the peristaltic pump speed at 2 - 10 rpm, and the atomization pressure at 0.1 - 0.2 MPa; after granulation, dry and control the material moisture at 2%.

[0068] 3. Screen the prepared granules through a 1.0 mm sieve, and the screening speed is 500 rpm.

[0069] 4. Put the screened granules and magnesium stearate into a mixer, mix at a speed of 10 rpm for 5 minutes.

[0070] 5. Use a rotary tablet press to press tablets with an 8.0 mm round shallow concave punch, and control the tablet hardness at 6 - 10 kg.

[0071] Comparative Example 1

[0072] Prescription (for 10,000 tablets)

[0073]

[0074]

[0075] Preparation method:

[0076] 1. Mix absolute ethanol and purified water, and add hypromellose (E30) under stirring conditions and continue stirring for 30 minutes to prepare a hypromellose (E30) alcohol solution.

[0077] 2. Put iguratimod, microcrystalline cellulose (101), microcrystalline cellulose (302), sodium carboxymethyl starch, and sodium lauryl sulfate into a wet granulator. Set the stirring speed at 200 rpm, the cutter speed at 1500 rpm, and mix for 5 minutes. Keep the stirring and cutter speeds unchanged, set the atomization pressure at 0.05 MPa, and the peristaltic pump speed at 5 rpm. Spray the prepared hydroxypropyl methylcellulose (E30) alcohol solution into the wet granulator. After spraying, keep the stirring and cutter speeds unchanged and granulate for 2 min;

[0078] 3. Put the granules into a fluidized bed, set the air volume at 30 Hz, the inlet air temperature at 60 °C, and discharge when the moisture content of the material reaches 3%;

[0079] 4. Screen the dried granules through a 1.0 mm sieve, with a screening speed of 500 rpm;

[0080] 5. Transfer the screened granules to a mixer, add magnesium stearate, set the mixing speed at 10 rpm, and mix for 5 minutes;

[0081] 6. Use a rotary tablet press to press tablets with an 8.0 mm round shallow concave punch, and control the tablet hardness at 6 - 10 kg.

[0082] Comparative Example 2

[0083] Prescription (10,000 tablets)

[0084]

[0085]

[0086] Preparation method:

[0087] 1. Dissolve the prescribed amount of iguratimod and polyvinylpyrrolidone in methanol, remove methanol in a rotary evaporator, scrape the obtained solid matter, place it in a vacuum dryer, dry at 50 °C for 24 h, and pulverize through an 80 - mesh sieve to obtain a solid dispersion of iguratimod and polyvinylpyrrolidone (1:3).

[0088] 2. Put the solid dispersion of iguratimod and polyvinylpyrrolidone (1:3), mannitol 25C, microcrystalline cellulose (101), and sodium carboxymethyl starch into a mixer, set the mixing speed at 8 rpm, and mix for 10 min.

[0089] 3. Dissolve sodium lauryl sulfate in purified water, and add absolute ethanol after complete dissolution for standby.

[0090] 4. Put the mixed powder into a wet granulator, set the stirring speed at 200 rpm, the cutter speed at 1500 rpm, the atomization pressure at 0.05 Mpa, and the peristaltic pump speed at 5 rpm. Dissolve sodium dodecyl sulfate in 80% ethanol solution and spray it into the wet granulator. After spraying, keep the stirring and cutter speeds unchanged and granulate for 2 minutes.

[0091] 5. Put the granules into a fluidized bed, set the air volume at 30 Hz and the inlet air temperature at 40 °C, and discharge the material when the moisture content of the material reaches 3%.

[0092] 6. Screen the dried granules through a 18-mesh sieve.

[0093] 7. Put the sieved granules, pregelatinized starch and magnesium stearate into a mixer, set the mixing speed at 8 rpm and mix for 5 minutes.

[0094] 8. Use a rotary tablet press to press tablets with an 8.0 mm round shallow concave punch, and control the tablet hardness at 6 - 10 kg.

[0095] Test Example 1

[0096] Content uniformity test:

[0097] Test method: Take 1 tablet of this product, put it into a 100 ml volumetric flask, add an appropriate amount of acetonitrile, ultrasonically dissolve it, dilute it to the mark with the solvent [acetonitrile - water (1:1)], shake well, filter through a 0.45 μm filter membrane, accurately measure 5 ml of the subsequent filtrate, put it into a 25 ml volumetric flask, dilute it to the mark with the solvent, shake well, and use it as the test solution; take an appropriate amount of iguratimod reference substance, accurately weigh it, dissolve and dilute it with the solvent to make a solution containing about 50 μg per 1 ml, and use it as the reference solution. Determine according to the high performance liquid chromatography method. Use octadecylsilane chemically bonded silica gel as the filler; use 0.02 mol / L ammonium dihydrogen phosphate (take 2.30 g of ammonium dihydrogen phosphate, add 1000 ml of water to dissolve it, adjust the pH to 5.5 with triethylamine) - acetonitrile (60:40) as the mobile phase; the column temperature is 40 °C; the flow rate is 1.0 ml per minute; the detection wavelength is 257 nm; the injection volume is 20 μl; in the chromatogram of the reference solution, the number of theoretical plates calculated based on the iguratimod peak is not less than 3000; accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate according to the external standard method with the peak area.

[0098] Perform content uniformity tests on the samples of Examples 1 - 4, Comparative Examples 1 - 2 and commercially available preparations, and the results are as follows:

[0099] Test items Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Commercially available preparation Average content X% 99 99 99 99 98 98 99 A + 2.2S 1.98 2.33 2.29 2.12 4.53 4.64 4.64

[0100] The data in the above table show that the content uniformity of iguratimod in the iguratimod tablets prepared according to Examples 1 to 4 of the present invention is good, and the results are far less than the requirement of A + 2.2S ≤ 15.0 specified in the current Chinese Pharmacopoeia. It is superior to the commercial preparation and Comparative Examples 1 to 2 year-on-year.

[0101] Test Example 2

[0102] Dissolution test:

[0103] Test method: Take this product and, according to the dissolution test method (Method 2 in General Chapter 0931 of the Chinese Pharmacopoeia 2020 Edition), use 1000 ml of pH 8.0 phosphate buffer solution (take 5.59 g of dipotassium hydrogen phosphate and 0.41 g of potassium dihydrogen phosphate, dissolve in water and dilute to 1000 ml) as the dissolution medium, rotate at 100 revolutions per minute, operate according to the law, sample after 30 minutes, filter the dissolution solution, and take the subsequent filtrate as the test solution; take an appropriate amount of iguratimod reference substance, accurately weigh it, add an appropriate amount of acetonitrile, sonicate to dissolve it, and dilute it with acetonitrile-water (50:

[0104] 50) to prepare a solution containing about 0.25 mg per 1 ml. Accurately measure 2 ml, place it in a 20 ml volumetric flask, dilute it to the mark with the dissolution medium, and shake well. Use octadecylsilane-bonded silica gel as the filler; use 0.01 mol / L potassium dihydrogen phosphate (take 1.36 g of potassium dihydrogen phosphate, dissolve in 1000 ml of water, adjust the pH to 7.0 with triethylamine)-acetonitrile (50:50) as the mobile phase; the column temperature is 30 °C; the flow rate is 1.0 ml per minute; the detection wavelength is 257 nm; the injection volume is 10 μl; accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate the dissolution amount per tablet by the external standard method based on the peak area, and it should not be less than 80% of the labeled amount.

[0105] Samples of Examples 1 to 4, Comparative Examples 1 to 2 and commercial preparations were subjected to dissolution test, and the results

[0106] are as follows:

[0107]

[0108]

[0109] As can be seen from the above table, the dissolution of the iguratimod tablets prepared according to Examples 1 to 4 of the present invention in the pH 8.0 medium reaches more than 95% in 30 minutes. The dissolution performance is superior to that of the commercial preparation and Comparative Examples 1 to 2, and has a good dissolution effect.

[0110] Test Example 3

[0111] Stability study:

[0112] The samples of Examples 1-4 and Comparative Examples 1-2 were packaged commercially and placed under accelerated conditions together with commercially available preparations. Samples were taken at 0 and 6 months to detect items such as content, dissolution, and related substances, and the stability of the samples was investigated. The results are as follows:

[0113]

[0114] The above inspection results show that: after being placed under accelerated conditions for 6 months, the properties, content, and dissolution of the samples prepared in Examples 1-4 showed basically no obvious changes compared with those at day 0; the amounts of each impurity of related substances basically did not increase; while the dissolution of the commercially available preparations and the samples of Comparative Examples 1-2 decreased after being placed under accelerated conditions for 6 months, and the amounts of each impurity of related substances increased significantly. This shows that the preparation method described in this patent can improve the stability of iguratimod tablets.

[0115] Test Example 4

[0116] Animal experiment:

[0117] Beagle dogs were selected as the test animals to study the bioavailability of Example 1 described in the present invention and the commercially available preparation. It should be noted in advance that during the implementation of the following test protocol, the Beagle dogs were fed the same standardized diet throughout the cycle to exclude the possible adverse effects of food on the results.

[0118] Selection and grouping of test animals: Female, healthy, and same-age Beagle dogs with weights all in the range of 10 ± 1.0 kg were selected, a total of 18, and randomly divided into 3 groups with 6 in each group;

[0119] Test protocol: 1) No drugs were administered 21 days before the test; 2) 7 days before the test, each test animal was given a drug of 0.1 mg iguratimod / kg body weight every day for background pre-saturation of each test animal to make the background iguratimod concentration of each test animal reach a steady-state level; 3) At 20:00 on the day before the test, each group of test animals started fasting, and at 7:00 on the test day, each test animal was given a drug of 0.5 mg iguratimod / kg body weight on an empty stomach, and at each sampling time point (0 hour, 15 minutes, 30 minutes, 45 minutes, 1.0 hour, 1.5 hour, 2.0 hour, 4.0 hour, 6.0 hour, 8.0 hour, 12.0 hour, 24.0 hour, 48.0 hour), 2 mL of blood was drawn from the median vein of the forelimb for sample retention; 4) An iguratimod ELISA kit for Beagle dogs was used to detect the iguratimod content of the samples at each sampling time point of each test group of animals, and the mean values of each evaluation item of 3 Beagle dogs in each test group were calculated. It should be pointed out here that before the sample analysis and detection, the inventors of the present invention carried out systematic methodological verifications on the precision, recovery rate, specificity, detection limit, etc. of this method, and the results showed that this analysis method is scientific and feasible.

[0120] The results of the Beagle dog bioavailability study conducted using the test examples of the present invention are shown in the following table:

[0121] Item Example 1 Commercially available preparation <![CDATA[T max (h)]]> 4.0 4.5 <![CDATA[C max (ng / ml)]]> 980 761 <![CDATA[AUC 0-∞ (ng*h / ml)]]> 10873 9042

[0122] Based on the analysis of the results in the above table, it can be seen that: the ilaprazole dispersible tablets of Example 1 obtained from the ilaprazole solid preparation and its preparation method of the present invention have a fast absorption rate, manifested as T max is 4 hours, while that of the commercially available preparation is T max is 4.5 hours; the relative bioavailability of ilaprazole in the ilaprazole dispersible tablets of the present invention is increased compared with that of the commercially available preparation by (10873 - 9042) / 9042 = 20.2%; it has a high bioavailability in vivo.

Claims

1. An iguratimod tablet, characterized in that: The described Aguratimod tablets are composed of the following weight ratios per 1000 tablets: 10-30 g of iguratimod, 135-160 g of mannitol, 4-10 g of cross-linked polyvinylpyrrolidone, 2-5 g of poloxamer, 1-3 g of magnesium stearate, and 4-10 g of polyvinylpyrrolidone. The preparation method of the iguratimod tablets is carried out according to the following steps: Step 1: dissolving poloxamer in purified water, and then adding iguratimod to prepare an iguratimod aqueous solution; Step 2: putting mannitol, cross-linked polyvinylpyrrolidone and polyvinylpyrrolidone into a fluidized bed, spraying the iguratimod aqueous solution described in step 1 into the fluidized bed for granulation, and controlling the moisture content of the granules to be less than 5% after drying; Step 3: sieve the granules obtained in step 2 through a 1.0 mm sieve; Step 4: put the granules prepared in step 3 into a mixer, add magnesium stearate, and mix for 5 minutes; Step 5: Use a rotary tablet press to compress the tablets and control the tablet hardness to 6-10kg.

2. Use of the iguratimod tablets prepared by the method of claim 1 in improving the dissolution and stability of a preparation.

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