Pharmaceutical composition containing Iguratimod and preparation method thereof

Abstract

According to the pharmaceutical composition containing iguratimod and the preparation method of the pharmaceutical composition, the microcrystalline cellulose colloidal silicon dioxide co-treatment substance and the anhydrous calcium hydrogen phosphate are adopted as filling agents, the flowability and compressibility of particles can be obviously improved, and the problems that due to the fact that the active ingredients are large in proportion and need to be subjected to micronization treatment, the particle size is large, and the particle size is large are solved. And the traditional Chinese medicine composition has the advantages of being simple in preparation method, rapid and complete in dissolution, stable in quality, high in bioavailability and the like. Polacrilin potassium is used as a disintegrating agent, the tablet can be decomposed into very small particles, and the effective surface area for absorbing active substances is increased, so that the dissolution rate and bioavailability of the active substances are improved. Meanwhile, magnesium silicate is used as a flow aid, so that the flowability of total mixed powder can be greatly improved, and the tablet weight difference during tabletting is small.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition containing iguratimod and a preparation method thereof Background Art

[0002] Iguratimod was developed by China Innovent Biologics and approved for marketing by the China Food and Drug Administration (CFDA) on August 15, 2011. It was also approved for marketing by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) on June 29, 2012. It is marketed in China by Innovent Biologics under the trade name Iremod for the treatment of rheumatoid arthritis (RA).

[0003] Rheumatoid arthritis (RA) is an autoimmune disease with erosive arthritis as the main clinical manifestation, which can occur at any age. The pathogenesis of RA is still unclear. The basic pathological manifestations are synovitis, pannus formation, and gradual destruction of articular cartilage and bone, which eventually lead to joint deformity and loss of function. It can be complicated by lung disease, cardiovascular disease, malignant tumors and depression.

[0004] The main mechanism of action of elamod is: reducing the production of prostaglandins in inflammatory tissues by selectively inhibiting cyclooxygenase-2; inhibiting the release of bradykinin from inflammatory tissues; inhibiting the proliferation of antigen-specific T cells; reducing the level of proinflammatory factors produced by B cells in patients with rheumatoid arthritis; stimulating osteoblast differentiation and the construction of chemical book bone; inhibiting the expression of synovial cell co-stimulatory factors and the production of cytokines, which can inhibit the production of immunoglobulins, inhibit the production of cytokines, inhibit bone resorption and promote bone formation, and can inhibit the increase of bradykinin in kaolin-induced inflammatory reactions. Its analgesic effect may be related to the inhibition of bradykinin.

[0005] Iguratimod is a poorly soluble drug, which is extremely insoluble in ethanol and almost insoluble in water; therefore, improving the water solubility of Iguratimod and increasing its bioavailability are the key to the preparation; currently, Chinese patents CN1931159B, CN107582537A, and CN117462497A all disclose compositions containing Iguratimod and preparation methods thereof, wherein the methods are to prepare a solid dispersion followed by granulation or wet granulation, which improves the bioavailability of Iguratimod to a certain extent, but the processes are relatively complicated, and during the preparation process, Iguratimod needs to be exposed to high humidity and high temperature conditions, which may cause changes in the crystal form of the active ingredient and an increase in related substances. Summary of the invention

[0006] The purpose of the present invention is to provide a pharmaceutical composition containing iguratimod on the basis of the prior art, which has the advantages of simple preparation method, rapid and complete dissolution, stable quality, high bioavailability, etc.

[0007] Another object of the present invention is to provide a method for preparing the above-mentioned pharmaceutical composition containing iguratimod.

[0008] The technical solution of the present invention is as follows:

[0009] A pharmaceutical composition containing iguratimod, which is prepared from an active ingredient iguratimod, a filler, a disintegrant, a glidant and a lubricant. During its preparation, iguratimod is uniformly mixed with a disintegrant and a filler, and then a glidant and a lubricant are added and mixed uniformly, and the obtained mixed powder is tableted by a powder direct compression method.

[0010] In a preferred embodiment, during the preparation process, the active component is firstly mixed with the disintegrant polacrilin potassium, then mixed with the microcrystalline cellulose colloidal silicon dioxide co-processed product, and then anhydrous calcium hydrogen phosphate is added in batches for mixing; finally, magnesium silicate and sodium stearyl fumarate are added for total mixing.

[0011] In a more preferred embodiment, anhydrous calcium hydrogen phosphate is divided into two equal parts and mixed in two times.

[0012] In the present invention, the filler is a co-processed product of microcrystalline cellulose colloidal silicon dioxide and anhydrous calcium hydrogen phosphate, the disintegrant is polacrilin potassium, the glidant is magnesium silicate, and the lubricant is sodium stearyl fumarate.

[0013] In a preferred embodiment, the active ingredient iguratimod is pulverized by air flow pulverization at a pulverizing pressure of 0.2 to 0.6 MPa, preferably, at a pulverizing pressure of 0.3 MPa to 0.4 MPa.

[0014] After air flow milling, the particle size of Iguratimod is D 90 Not higher than 30 μm; preferably not higher than 10 μm; more preferably 8.15 μm.

[0015] The pharmaceutical composition containing iguratimod provided by the present invention uses a co-processed microcrystalline cellulose colloidal silicon dioxide and anhydrous calcium hydrogen phosphate as fillers, which can significantly improve the fluidity and compressibility of the particles, and solves the problem that the fluidity and compressibility of the particles are poor due to the large proportion of active ingredients and the need for micronization. The mass ratio of microcrystalline cellulose to colloidal silicon dioxide in the co-processed microcrystalline cellulose colloidal silicon dioxide is 49:1.

[0016] The present invention uses polacrilin potassium as a disintegrant, which can decompose the tablet into very small particles, increase the effective surface area for absorbing the active substance, and thus improve the dissolution rate and bioavailability of the active substance.

[0017] The invention provides a pharmaceutical composition containing iguratimod, which is prepared from the following components in parts by weight: 20-30 parts of iguratimod, 20-60 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 60-120 parts of anhydrous calcium hydrogen phosphate, 5-40 parts of polacrilin potassium, 0.5-5 parts of magnesium silicate, and 2-10 parts of sodium stearyl fumarate.

[0018] The invention provides a pharmaceutical composition containing iguratimod, which is prepared from the following components in parts by weight: 23-27 parts of iguratimod, 35-45 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 85-105 parts of anhydrous calcium hydrogen phosphate, 15-25 parts of polacrilin potassium, 1-3 parts of magnesium silicate, and 2-4 parts of sodium stearyl fumarate.

[0019] The pharmaceutical composition containing iguratimod provided by the present invention is prepared from the following components in parts by weight: 25 parts of iguratimod, 42 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 98 parts of anhydrous calcium hydrogen phosphate, 20 parts of polacrilin potassium, 2 parts of magnesium silicate, and 3 parts of sodium stearyl fumarate.

[0020] The invention provides a pharmaceutical composition containing iguratimod, which is prepared from the following components in parts by weight: 25 parts of iguratimod, 35 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 105 parts of anhydrous calcium hydrogen phosphate, 22 parts of polacrilin potassium, 1 part of magnesium silicate, and 2 parts of sodium stearyl fumarate.

[0021] The pharmaceutical composition containing iguratimod provided by the present invention is prepared from the following components in parts by weight: 25 parts of iguratimod, 45 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 95 parts of anhydrous calcium hydrogen phosphate, 18 parts of polacrilin potassium, 3 parts of magnesium silicate, and 4 parts of sodium stearyl fumarate.

[0022] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition containing iguratimod, comprising the following steps:

[0023] (1) Pretreatment: The active ingredient iguratimod is crushed and the excipients are sieved;

[0024] (2) Premixing: The active ingredient iguratimod is mixed with the disintegrant and filler in multiple batches to make them uniform;

[0025] (3) Total mixing: adding a glidant and a lubricant to the powder obtained in step (2) and mixing evenly;

[0026] (4) Tableting: The total mixed powder obtained in step (3) is tableted by a powder direct compression method.

[0027] In the present invention, in step (1), the active ingredient iguratimod is pulverized by air flow pulverization at a pulverizing pressure of 0.2 to 0.6 MPa, preferably, at a pulverizing pressure of 0.3 MPa to 0.4 MPa.

[0028] After air flow milling, the particle size of Iguratimod is D 90 Not higher than 30 μm; preferably not higher than 10 μm; more preferably 8.15 μm.

[0029] In the present invention, in step (2), the active ingredient iguratimod is first mixed evenly with the disintegrant polacrilin potassium, then mixed evenly with the co-processed product of microcrystalline cellulose and colloidal silicon dioxide, and then anhydrous calcium hydrogen phosphate is added in batches for mixing; preferably, the anhydrous calcium hydrogen phosphate is divided into two equal parts and mixed in two batches.

[0030] In the present invention, in step (3), an 8 mm shallow concave round punch is used for tableting, and the tablet core hardness is 60 to 120N, preferably, the tablet core hardness is 80 to 100N.

[0031] Adopt the technical scheme of the present invention, the advantages are as follows:

[0032] (1) The pharmaceutical composition containing iguratimod provided by the present invention uses a co-processed product of microcrystalline cellulose colloidal silica and anhydrous calcium hydrogen phosphate as fillers, which can significantly improve the fluidity and compressibility of the particles, thereby solving the problem that the fluidity and compressibility of the particles are poor due to the large proportion of active ingredients and the need for micronization.

[0033] (2) The present invention uses polacrilin potassium as a disintegrant, which can break down the tablet into very small particles, increase the effective surface area for absorbing the active substance, and thus improve the dissolution rate and bioavailability of the active substance.

[0034] (3) The present invention adopts a powder direct compression method, and the active ingredients will not be directly exposed to high temperature and high humidity conditions, thus avoiding the risk of crystal transformation and increase of related substances; and the intermediate has good compressibility, and the drug composition disintegrates quickly. The results of long-term stability studies show that the quality of the finished preparation is stable and reliable.

[0035] (4) The mixing method adopted in the present invention can ensure that the active ingredients are mixed evenly, solving the problems of poor fluidity of the active components and high static electricity. At the same time, magnesium silicate is used as a glidant, which can greatly improve the fluidity of the total mixed powder and reduce the difference in tablet weight during tableting.

[0036] (5) The present invention uses sodium stearyl fumarate as a lubricant, which reduces the risk of slow dissolution due to excessive lubrication compared to hydrophobic lubricants. DETAILED DESCRIPTION

[0037] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0038] Example 1

[0039] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0040]

[0041] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0042] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D 90 =8.15μm; auxiliary materials: microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate, polacrilin potassium, magnesium silicate, sodium stearyl fumarate are sieved through 60 mesh sieves respectively and set aside;

[0043] (2) Premixing: Mix iguratimod and polacrilin potassium evenly, continue to add microcrystalline cellulose colloidal silicon dioxide co-processed product and mix evenly, then add half of anhydrous calcium hydrogen phosphate and mix evenly, and finally add the remaining anhydrous calcium hydrogen phosphate and mix evenly;

[0044] (3) Total mixing: Add magnesium silicate to the mixture obtained in step (2), mix well, then add sodium stearyl fumarate, and continue mixing well.

[0045] (4) Tableting: The total mixed powder obtained in step (3) is added to a tablet press, and 8 mm shallow concave round punching tablets are selected to obtain a pharmaceutical composition containing iguratimod.

[0046] The test results of the pharmaceutical composition containing iguratimod obtained in Example 1 are shown in Table 1.

[0047] Table 1 Test results of products in Example 1

[0048]

[0049] As shown in Table 1, the product obtained in Example 1 has a total mixed particle repose angle of 31° and a Carr index of 11.8%, and has very good fluidity; when the main pressure is 6 to 8 KN, the tablet hardness reaches 80 to 100 N; the dissolution in a pH 7.4 medium reaches more than 85% in 10 minutes, and the release is complete in 15 minutes.

[0050] Example 2

[0051] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0052]

[0053] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0054] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D 90 =8.15μm; auxiliary materials: microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate, polacrilin potassium, magnesium silicate, sodium stearyl fumarate are sieved through 60 mesh sieves respectively and set aside;

[0055] (2) Premixing: Mix iguratimod and polacrilin potassium evenly, continue to add microcrystalline cellulose colloidal silicon dioxide co-processed product and mix evenly, then add half of anhydrous calcium hydrogen phosphate and mix evenly, and finally add the remaining anhydrous calcium hydrogen phosphate and mix evenly;

[0056] (3) Total mixing: Add magnesium silicate to the mixture obtained in step (2), mix well, then add sodium stearyl fumarate, and continue mixing well.

[0057] (4) Tableting: The total mixed powder obtained in step (3) is added to a tablet press, and 8 mm shallow concave round punching tablets are selected to obtain a pharmaceutical composition containing iguratimod.

[0058] The test results of the pharmaceutical composition containing iguratimod obtained in Example 2 are shown in Table 2.

[0059] Table 2 Test results of products in Example 2

[0060]

[0061] As shown in Table 2, the product obtained in Example 2 has a total mixed particle repose angle of 33°, a Carr index of 17.0%, and very good fluidity, which is slightly worse than that of Example 1; when the main pressure is 6 to 8 KN, the tablet hardness reaches 80 to 100 N; the dissolution in a pH 7.4 medium reaches more than 85% in 10 minutes, and the release is complete in 15 minutes, which is slightly slower than that of Example 1.

[0062] Example 3

[0063] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0064]

[0065] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0066] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D 90 =8.15μm; auxiliary materials: microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate, polacrilin potassium, magnesium silicate, sodium stearyl fumarate are sieved through 60 mesh sieves respectively and set aside;

[0067] (2) Premixing: Mix iguratimod and polacrilin potassium evenly, continue to add microcrystalline cellulose colloidal silicon dioxide co-processed product and mix evenly, then add half of anhydrous calcium hydrogen phosphate and mix evenly, and finally add the remaining anhydrous calcium hydrogen phosphate and mix evenly;

[0068] (3) Total mixing: Add magnesium silicate to the mixture obtained in step (2), mix well, then add sodium stearyl fumarate, and continue mixing well.

[0069] (4) Tableting: The total mixed powder obtained in step (3) is added to a tablet press, and 8 mm shallow concave round punching tablets are selected to obtain a pharmaceutical composition containing iguratimod.

[0070] The test results of the pharmaceutical composition containing iguratimod obtained in Example 3 are shown in Table 3.

[0071] Table 3 Test results of products in Example 3

[0072]

[0073] As shown in Table 3, the product obtained in Example 3 has a total mixed particle repose angle of 35° and a Carr index of 19.2%, and has very good fluidity, which is slightly worse than that of Example 1 and Example 2. When the main pressure is 6 to 8 KN, the tablet hardness reaches 80 to 100 N. The dissolution in a pH 7.4 medium reaches more than 85% in 10 minutes, and the release is complete in 15 minutes, which is slightly slower than that of Example 1.

[0074] Comparative Example 1

[0075] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0076]

[0077] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0078] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D90 =8.15μm; Excipients: microcrystalline cellulose, colloidal silicon dioxide, anhydrous calcium hydrogen phosphate, polacrilin potassium, magnesium silicate, sodium stearyl fumarate are sieved through 60 mesh sieves respectively and set aside;

[0079] (2) Premixing: Mix iguratimod and polacrilin potassium evenly, continue to add microcrystalline cellulose colloidal silicon dioxide co-processed product and mix evenly, then add half of anhydrous calcium hydrogen phosphate and mix evenly, and finally add the remaining anhydrous calcium hydrogen phosphate and mix evenly;

[0080] (3) Total mixing: Add magnesium silicate to the mixture obtained in step (2), mix well, then add sodium stearyl fumarate, and continue mixing well.

[0081] (4) Tableting: The total mixed powder obtained in step (3) is added to a tablet press, and 8 mm shallow concave round punching tablets are selected to obtain a pharmaceutical composition containing iguratimod.

[0082] The test results of the pharmaceutical composition containing iguratimod obtained in Comparative Example 1 are shown in Table 4.

[0083] Table 4 Test results of products in comparative example 1

[0084]

[0085] As shown in Table 4, the filler was replaced by microcrystalline cellulose, colloidal silicon dioxide and anhydrous calcium hydrogen phosphate from a co-processed product of microcrystalline cellulose and colloidal silicon dioxide, and microcrystalline cellulose, colloidal silicon dioxide and anhydrous calcium hydrogen phosphate, and the angle of repose of the total mixed particles was 46°; when the main pressure was 8 to 10 KN, the tablet hardness was 40 to 70 N, and the fluidity and compressibility were significantly deteriorated.

[0086] Comparative Example 2

[0087] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0088]

[0089] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0090] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D 90 =8.15μm; auxiliary materials: microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate, polacrilin potassium, magnesium silicate, sodium stearyl fumarate are sieved through 60 mesh sieves respectively and set aside;

[0091] (2) Premixing: Mix iguratimod and polacrilin potassium evenly, continue to add microcrystalline cellulose colloidal silicon dioxide co-processed product and mix evenly, then add half of anhydrous calcium hydrogen phosphate and mix evenly, and finally add the remaining anhydrous calcium hydrogen phosphate and mix evenly;

[0092] (3) Total mixing: Add magnesium silicate to the mixture obtained in step (2), mix well, then add sodium stearyl fumarate, and continue mixing well.

[0093] (4) Tableting: The total mixed powder obtained in step (3) is added to a tablet press, and 8 mm shallow concave round punching tablets are selected to obtain a pharmaceutical composition containing iguratimod.

[0094] The test results of the pharmaceutical composition containing iguratimod obtained in Example 2 are shown in Table 5.

[0095] Table 5 Test results of products in comparative example 2

[0096]

[0097] As shown in Table 5, after the dosage of anhydrous calcium hydrogen phosphate was reduced from 98.0 g to 42.0 g (per 1000 units of preparation), the angle of repose of the total mixed particles was 44°, and the Carr index was 32.8%; when the main pressure was 8 to 10 KN, the tablet hardness was only 50 to 65 KN, and the fluidity and compressibility were significantly deteriorated.

[0098] Comparative Example 3

[0099] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0100]

[0101] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0102] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D 90 =8.15μm; auxiliary materials: microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate, cross-linked carboxymethyl cellulose sodium, magnesium silicate, sodium stearyl fumarate are sieved through 60 mesh sieves respectively and set aside;

[0103] (2) Premixing: Mix iguratimod and croscarmellose sodium evenly, then add microcrystalline cellulose colloidal silica co-processed product and mix evenly, then add half of anhydrous calcium hydrogen phosphate and mix evenly, and finally add the remaining anhydrous calcium hydrogen phosphate and mix evenly;

[0104] (3) Total mixing: Add magnesium silicate to the mixture obtained in step (2), mix well, then add sodium stearyl fumarate, and continue mixing well.

[0105] (4) Tableting: The total mixed powder obtained in step (3) is added to a tablet press, and 8 mm shallow concave round punching tablets are selected to obtain a pharmaceutical composition containing iguratimod.

[0106] The test results of the pharmaceutical composition containing iguratimod obtained in Comparative Example 3 are shown in Table 6.

[0107] Table 6 Test results of products in comparative example 3

[0108]

[0109] As shown in Table 6, after the disintegrant was changed from polacrilin potassium to croscarmellose sodium, the dissolution of the sample slowed down significantly, and the release rate was still not more than 85% after 15 minutes, and it was completely released after 60 minutes.

[0110] Comparative Example 4

[0111] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0112]

[0113] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0114] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D 90 =8.15μm; auxiliary materials: microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate, polacrilin potassium, sodium stearyl fumarate are sieved through 60 mesh sieves respectively and set aside;

[0115] (2) Premixing: Mix iguratimod and polacrilin potassium evenly, continue to add microcrystalline cellulose colloidal silicon dioxide co-processed product and mix evenly, then add half of anhydrous calcium hydrogen phosphate and mix evenly, and finally add the remaining anhydrous calcium hydrogen phosphate and mix evenly;

[0116] (3) Total mixing: Add sodium stearyl fumarate to the mixture obtained in step (2) and mix well.

[0117] (4) Tableting: The total mixed powder obtained in step (3) is added to a tablet press, and 8 mm shallow concave round punching tablets are selected to obtain a pharmaceutical composition containing iguratimod.

[0118] The test results of the pharmaceutical composition containing iguratimod obtained in Comparative Example 4 are shown in Table 7.

[0119] Table 7 Test results of products in comparative example 4

[0120]

[0121] As shown in Table 7, for the sample prepared without the retention aid magnesium silicate, the angle of repose of the total mixed particles was 43°, the Carr index was 26.2%, and the fluidity was significantly deteriorated; 10 of the 20 samples did not meet the weight difference, and 3 exceeded the weight difference by 2 times.

[0122] Comparative Example 5

[0123] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0124]

[0125] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0126] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D 90 =8.15μm; auxiliary materials: microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate, polacrilin potassium, magnesium silicate, magnesium stearate are sieved through 60 mesh sieves respectively and set aside;

[0127] (2) Premixing: Mix iguratimod and polacrilin potassium evenly, continue to add microcrystalline cellulose colloidal silicon dioxide co-processed product and mix evenly, then add half of anhydrous calcium hydrogen phosphate and mix evenly, and finally add the remaining anhydrous calcium hydrogen phosphate and mix evenly;

[0128] (3) Total mixing: Add magnesium silicate to the mixture obtained in step (2), mix well, then add magnesium stearate, and continue mixing well.

[0129] (4) Tableting: The total mixed powder obtained in step (3) is added to a tablet press, and 8 mm shallow concave round punching tablets are selected to obtain a pharmaceutical composition containing iguratimod.

[0130] The test results of the pharmaceutical composition containing iguratimod obtained in Comparative Example 5 are shown in Table 8.

[0131] Table 8 Test results of products in comparative example 5

[0132]

[0133] As shown in Table 8, when the lubricant is replaced by sodium stearyl fumarate with magnesium stearate, the dissolution of the sample will be slowed down due to its hydrophobicity.

[0134] Comparative Example 6

[0135] A pharmaceutical composition containing iguratimod, wherein each 1000 dosage units are prepared from the following components by weight:

[0136]

[0137] The preparation method of the above-mentioned pharmaceutical composition containing iguratimod comprises the following steps:

[0138] (1) Pretreatment: The active ingredient iguratimod was crushed by a jet mill at a crushing pressure of 0.3 MPa to 0.4 MPa. After crushing, the D 90 =8.15μm; auxiliary materials: microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, polacrilin potassium, magnesium silicate, sodium stearyl fumarate are sieved through 60 mesh sieves respectively and set aside;

[0139] (2) Preparation of adhesive solution: Dissolve hydroxypropyl cellulose in 98.0 g of purified water to prepare an adhesive solution containing 2% hydroxypropyl cellulose.

[0140] (3) Wet granulation: The active ingredient, microcrystalline cellulose colloidal silicon dioxide co-processed product, anhydrous calcium hydrogen phosphate and polacrilin potassium are added into a wet granulator and mixed evenly, and then the binder solution is added for granulation.

[0141] (4) Drying: The obtained wet granules are added to a fluidized bed for drying, with an inlet air temperature of 60°C and a moisture content of <5%.

[0142] (5) Granulation: The obtained dry granules were sized using a 1.0 mm round hole sieve.

[0143] (6) Total mixing: adding magnesium silicate and sodium stearyl fumarate to the granules obtained in step (5) and mixing well.

[0144] (7) Tableting: The total mixed granules are added into a tablet press and punched into 8 mm shallow concave round tablets to obtain a pharmaceutical composition containing iguratimod.

[0145] The test results of the pharmaceutical composition containing iguratimod obtained in Comparative Example 6 are shown in Table 9, and the results of the substances related to the stability study in Example 1 are shown in Table 10.

[0146] Table 9 Test results of products in comparative example 6

[0147]

[0148] Table 10 Results of stability study of related substances in Example 1 and Comparative Example 6

[0149]

[0150] It can be seen from Tables 9 and 10 that the sample prepared by the wet granulation method in Comparative Example 6 has poorer fluidity and compressibility than the sample prepared by the powder direct compression method in Example 1, and the dissolution is slow, the related substances are significantly increased, and the maximum single impurities and total impurities are significantly increased during the stability period. It can be seen that the sample prepared by the powder direct compression method of the present invention has fewer related substances and no obvious increase during the stability period.

[0151] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A pharmaceutical composition containing iguratimod, characterized in that: The pharmaceutical composition is prepared from active ingredient iguratimod, filler, disintegrant, glidant and lubricant. During its preparation process, iguratimod is evenly mixed with disintegrant and filler, then glidant and lubricant are added, and after evenly mixing, the obtained mixed powder is tableted by powder direct compression method, wherein the filler is microcrystalline cellulose colloidal silicon dioxide co-processed product and anhydrous calcium hydrogen phosphate, the disintegrant is polacrilin potassium, the glidant is magnesium silicate, and the lubricant is sodium stearyl fumarate.

2. The pharmaceutical composition containing iguratimod according to claim 1, characterized in that The mass ratio of microcrystalline cellulose to colloidal silicon dioxide in the microcrystalline cellulose colloidal silicon dioxide co-processed product is 49:

1.

3. The pharmaceutical composition containing iguratimod according to claim 2, characterized in that: The particle size D of the iguratimod 90 Not higher than 30 μm; preferably not higher than 10 μm; more preferably 8.15 μm.

4. The pharmaceutical composition containing iguratimod according to claim 3, characterized in that The pharmaceutical composition is prepared from the following components in parts by weight: 20-30 parts of iguratimod, 20-60 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 60-120 parts of anhydrous calcium hydrogen phosphate, 5-40 parts of polacrilin potassium, 0.5-5 parts of magnesium silicate and 2-10 parts of sodium stearyl fumarate.

5. The pharmaceutical composition containing iguratimod according to claim 4, characterized in that: The pharmaceutical composition is prepared from the following components in parts by weight: 23-27 parts of iguratimod, 35-45 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 85-105 parts of anhydrous calcium hydrogen phosphate, 15-25 parts of polacrilin potassium, 1-3 parts of magnesium silicate and 2-4 parts of sodium stearyl fumarate.

6. The pharmaceutical composition containing iguratimod according to claim 5, characterized in that: The pharmaceutical composition is made from the following components in parts by weight: 25 parts of iguratimod, 42 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 98 parts of anhydrous calcium hydrogen phosphate, 20 parts of polacrilin potassium, 2 parts of magnesium silicate, and 3 parts of sodium stearyl fumarate; 25 parts of iguratimod, 35 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 105 parts of anhydrous calcium hydrogen phosphate, 22 parts of polacrilin potassium, 1 part of magnesium silicate, and 2 parts of sodium stearyl fumarate; 25 parts of iguratimod, 45 parts of microcrystalline cellulose colloidal silicon dioxide co-processed product, 95 parts of anhydrous calcium hydrogen phosphate, 18 parts of polacrilin potassium, 3 parts of magnesium silicate, and 4 parts of sodium stearyl fumarate.

7. The method for preparing the pharmaceutical composition containing iguratimod according to claim 1, characterized in that: The steps include: (1) Pretreatment: The active ingredient iguratimod is crushed and the excipients are sieved; (2) Premixing: The active ingredient iguratimod is mixed with the disintegrant and filler in multiple batches to make them uniform; (3) Total mixing: adding a glidant and a lubricant to the powder obtained in step (2) and mixing evenly; (4) Tableting: The total mixed powder obtained in step (3) is tableted by a powder direct compression method.

8. The method for preparing the pharmaceutical composition containing iguratimod according to claim 7, characterized in that: In step (1), the active ingredient is pulverized by air flow pulverization, and the pulverization pressure is 0.2-0.6 MPa, preferably, the pulverization pressure is 0.3 MPa-0.4 MPa; the particle size D of the iguratimod is 90 Not higher than 30 μm; preferably not higher than 10 μm; more preferably 8.15 μm.

9. The method for preparing the pharmaceutical composition containing iguratimod according to claim 7, characterized in that: In step (2), the active ingredient iguratimod is first mixed evenly with the disintegrant polacrilin potassium, then mixed evenly with the co-processed product of microcrystalline cellulose and colloidal silicon dioxide, and then anhydrous calcium hydrogen phosphate is added in batches for mixing; preferably, the anhydrous calcium hydrogen phosphate is divided into two equal parts and mixed in two batches.

10. The method for preparing the pharmaceutical composition containing iguratimod according to claim 7, characterized in that: In step (3), a 8 mm shallow concave round punch is used for tableting, and the tablet core hardness is 60 to 120 N, preferably, the tablet core hardness is 80 to 100 N.

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