Stable sulindac tablet and preparation method thereof

Abstract

The invention discloses a stable sulindac tablet and a preparation method thereof. The stable sulindac tablet comprises the following components in parts by weight: 53-65 parts of sulindac, 17.4-35.4 parts of microcrystalline cellulose, 10.7-17.2 parts of corn starch and 1-3.8 parts of stearic acid. According to the sulindac tablet provided by the invention, the viscosity of particles is reduced, the flowability of the particles is improved, the tablet weight difference after tabletting is small, the RSD value of dissolution is reduced, the tablet quality difference is reduced, the uniformity is improved, the sulindac tablet also has dissolution similar to that of a reference preparation, and the stability of the product is improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a stable sulindac tablet and a preparation method thereof. Background Art

[0002] This section merely provides background information related to the present disclosure and is not necessarily prior art.

[0003] Sulindac, chemical name is (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinylphenyl)methylene]-1H-indene-3-acetic acid, molecular formula is C 20 H 17 FO3S, with a molecular weight of 356.41, can be used for hyperplastic osteoarthritis, rheumatoid arthritis, chronic arthritis, periarthritis of shoulder, cervical shoulder-wrist syndrome, tenosynovitis, etc. Sulindac is a nonsteroidal anti-inflammatory drug. After entering the human body, it is metabolized into active sulfides, which can inhibit cyclooxygenase and reduce the synthesis of prostaglandins, thus having analgesic, anti-inflammatory and antipyretic effects, and has little effect on renal blood flow and renal function.

[0004] Sulindac tablets (trade name Clinoril) are non-steroidal anti-inflammatory drugs developed by Merck Sharp & Dohme. The specifications are 50mg, 100mg, 150mg, and 200mg. They were first launched in Portugal in 1976 with a specification of 200mg, and later launched in many European countries including Italy, the United Kingdom, and Ireland. They were launched in the United States in 1978 with specifications of 150mg and 200mg; and in Japan in 1981 with specifications of 50mg and 100mg.

[0005] The dissolution and release of domestic preparations currently on the market are relatively fast and cannot meet the requirements of being consistent with the reference preparations. The main preparation process of sulindac tablets is to mix sulindac with other excipients, use hydroxypropyl methylcellulose to make a binder solution, dry the whole granules after wet granulation and press them into tablets, which will make the dissolution low and result in dissimilarity with the reference preparation. Sulindac tablets are almost insoluble in 0.1 mol / L hydrochloric acid medium, and the dissolution in 60 minutes is less than 12%. There is an urgent need for a method to improve the solubility of sulindac tablets in 0.1 mol / L hydrochloric acid medium, which is more conducive to the preparation of stable sulindac tablets. Summary of the invention

[0006] Purpose of the invention: The technical problem to be solved by the present invention is to provide a stable sulindac tablet and a preparation method thereof in view of the deficiencies in the prior art.

[0007] In order to solve the above technical problems, the present invention discloses the following technical solutions:

[0008] In a first aspect, the present invention discloses a sulindac composition.

[0009] In some embodiments, the sulindac composition contains the following components in parts by weight:

[0010]

[0011] In some embodiments, the sulindac composition contains the following components in parts by weight:

[0012]

[0013] In some embodiments, the sulindac composition contains the following components in parts by weight:

[0014]

[0015] In some embodiments, the D of sulindac 90 30-40μm; D 50 5μm or more.

[0016] In some embodiments, the particle size of the microcrystalline cellulose is 40-80 μm.

[0017] In some embodiments, the corn starch has a particle size of 40 to 80 μm.

[0018] In some embodiments, the stearic acid is stearic acid with a mesh size of 60-80.

[0019] In a second aspect, the present invention discloses a sulindac tablet, which is made from the composition described in the first aspect.

[0020] In some embodiments, 2-4 parts of corn starch are mixed with water to form an adhesive solution; in some embodiments, the adhesive solution is an aqueous solution of an adhesive; in some embodiments, the solid content of the adhesive in the adhesive solution is 3% g / ml to 13% g / ml, in some embodiments, 5% g / ml to 10% g / ml, and in some embodiments, 8% g / ml.

[0021] In some embodiments, the preparation comprises the following mixing steps:

[0022] (1) mixing sulindac, microcrystalline cellulose, and corn starch except a binder to obtain a premix;

[0023] (2) wet granulating the obtained premix with a binder solution to obtain an intermediate;

[0024] (3) The obtained intermediate is mixed with a lubricant.

[0025] In step (1), the mixing is carried out in a wet granulator; preferably, during the mixing, the rotation speed of the stirring blade is 80-120 rpm, and the rotation speed of the chopping blade is 800-1200 rpm;

[0026] In step (2), the wet granulation includes soft material preparation, wet granulation, drying and dry granulation; preferably, when preparing the soft material, the rotation speed of the stirring blade is 100-140 rpm, the rotation speed of the chopping blade is 1000-1400 rpm, and the mixing time is more than 5 min, preferably 5-8 min; preferably, when wet granulation, the mesh aperture is 0.6-1.0 mm, preferably 0.8 mm; preferably, when dry granulation, the mesh aperture is 1-4 mm, preferably 2 mm;

[0027] In step (3), the mixing is performed in a mixer for 1 to 3 times; preferably, the charging factor of the mixer is 40% to 70%; preferably, during mixing, the rotating speed of the mixer is 10 to 20 rpm; preferably, the mixing time is 1 to 5 min.

[0028] In some embodiments, the manufacturing process further includes tableting and packaging.

[0029] The packaging is made of polyvinyl chloride / polyvinylidene chloride solid medicinal composite hard sheet and medicinal aluminum foil.

[0030] In some embodiments, the sulindac tablets have the following components in parts by weight:

[0031]

[0032] The D of sulindac 90 30-40μm, D 50 The particle size of the microcrystalline cellulose is 40-80 μm; the particle size of the corn starch is 40-80 μm; the stearic acid is stearic acid with a particle size of 60-80 mesh;

[0033] The preparation method of the sulindac tablets comprises the following steps:

[0034] (1) preparing a binder solution having a solid content of 5% g / ml to 10% g / ml by mixing 2-4 parts of corn starch with water; mixing sulindac, microcrystalline cellulose, and corn starch other than the binder in a wet granulator with the stirring blade rotating at 80-120 rpm and the chopping blade rotating at 800-1200 rpm to obtain a premix;

[0035] (2) wet granulating the obtained premix with a binder solution to obtain an intermediate;

[0036] (3) mixing the intermediate obtained with a lubricant in a mixer for 1 to 3 times;

[0037] (4) Tableting and packaging;

[0038] In step (2), the wet granulation includes soft material preparation, wet granulation, drying and dry granulation; when preparing the soft material, the rotation speed of the stirring blade is 100-140 rpm, the rotation speed of the chopping blade is 1000-1400 rpm, and the mixing time is 5-8 min; when wet granulation is performed, the mesh aperture is 0.6-1.0 mm; when dry granulation is performed, the mesh aperture is 1-4 mm;

[0039] In step (3), the charging factor of the mixer is 40% to 70%; during mixing, the rotating speed of the mixer is 10 to 20 rpm; and the mixing time is 1 to 5 min.

[0040] In a second aspect, the present invention discloses a method for preparing the sulindac tablets described in the first aspect.

[0041] In some embodiments, 2-4 parts of corn starch are mixed with water to form an adhesive solution; in some embodiments, the adhesive solution is an aqueous solution of an adhesive; in some embodiments, the solid content of the adhesive in the adhesive solution is 3% g / ml to 13% g / ml, in some embodiments, 5% g / ml to 10% g / ml, and in some embodiments, 8% g / ml.

[0042] In some embodiments, the preparation comprises the following mixing steps:

[0043] (1) mixing sulindac, microcrystalline cellulose, and corn starch except a binder to obtain a premix;

[0044] (2) wet granulating the obtained premix with a binder solution to obtain an intermediate;

[0045] (3) The obtained intermediate is mixed with a lubricant.

[0046] In step (1), the mixing is carried out in a wet granulator; preferably, during the mixing, the rotation speed of the stirring blade is 80-120 rpm, and the rotation speed of the chopping blade is 800-1200 rpm;

[0047] In step (2), the wet granulation includes soft material preparation, wet granulation, drying and dry granulation; preferably, when preparing the soft material, the rotation speed of the stirring blade is 100-140 rpm, the rotation speed of the chopping blade is 1000-1400 rpm, and the mixing time is more than 5 min, preferably 5-8 min; preferably, when wet granulation, the mesh aperture is 0.6-1.0 mm, preferably 0.8 mm; preferably, when dry granulation, the mesh aperture is 1-4 mm, preferably 2 mm;

[0048] In step (3), the mixing is performed in a mixer for 1 to 3 times; preferably, the charging factor of the mixer is 40% to 70%; preferably, during mixing, the rotating speed of the mixer is 10 to 20 rpm; preferably, the mixing time is 1 to 5 min.

[0049] In some embodiments, the manufacturing process further includes tableting and packaging.

[0050] The packaging is made of polyvinyl chloride / polyvinylidene chloride solid medicinal composite hard sheet and medicinal aluminum foil.

[0051] The sulindac tablets provided by the present invention have the following release characteristics: when measured at 37°C using a paddle method 50 pm, a pH 7.2 phosphate medium, and a Chinese Pharmacopoeia dissolution apparatus 2, the cumulative dissolution in 5 minutes is 42.5%-59.1%, the cumulative dissolution in 10 minutes is 68.9%-88.1%, the cumulative dissolution in 15 minutes is 83.5%-93.2%, and the cumulative dissolution in 45 minutes is 94.6%-99.2%; after the sulindac tablets are placed at 40°C for 10 days, the dissolution is 97%-99%, the related substances are 0.64%-0.67%, and the content is 99.6%-100.6%.

[0052] Beneficial effects:

[0053] The present invention provides a sulindac tablet and a preparation method thereof. By selecting suitable auxiliary materials and preparation processes, the viscosity of the particles is reduced, the fluidity of the particles is increased, the weight difference of the tablets after tableting is small, the RSD value of dissolution is reduced, the quality difference of the tablets is reduced, the uniformity is improved, the dissolution is similar to that of a reference preparation, and the stability of the product is improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0055] Figure 1 It is the dissolution curve diagram of Example 1 and Comparative Examples 1-4. DETAILED DESCRIPTION

[0056] 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.

[0057] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0058] The present invention provides a stable sulindac tablet, the tablet weight of which is designed to be 337 mg. The particle size of the starch used in the present invention is 40-80 μm, and the particle size of the microcrystalline cellulose is 40-80 μm; and the dosage thereof is within the range published in the FDA inactive ingredient database (Inactive Ingredient Search for Approved Drug Products).

[0059] Starch is a basic excipient for oral preparations, mainly used as a filler, disintegrant, adhesive, etc. The common concentration of starch as an adhesive is 5%-25%, among which 10% starch slurry is the most commonly used; the common concentration of starch as a disintegrant is 3%-15%. There are wheat starch, corn starch and potato starch, among which corn starch is the most commonly used in my country.

[0060] Microcrystalline cellulose is widely used in pharmaceutical preparations, mainly as a binder, filler or diluent in oral tablets and capsules. In the present invention, microcrystalline cellulose is both a filler, which helps the molding of the preparation and increases the compressibility of the tablet, and at the same time has a certain disintegration property to ensure the disintegration of the tablet.

[0061] The unit of solid content in the present invention is g / ml.

[0062] The parameter conditions of the hammer mill crushing described in the following embodiments are 6000-8000 rpm, which can be specifically adjusted according to the particle size requirements.

[0063] Example 1

[0064] A method for preparing a stable sulindac tablet, comprising the following steps when producing 1,000 tablets:

[0065] (1) Pretreatment of raw materials and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio, 59 parts of sulindac, 25.4 parts of microcrystalline cellulose, 13.2 parts of corn starch, and 2 parts of stearic acid, wherein the particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is crushed into fine powder using a hammer mill, passed through a 30-mesh sieve, D90 is 30-40 μm, and D50 is greater than 5 μm. Stearic acid is passed through a 60-mesh sieve. Take 3 parts of corn starch and purified water and place them in a beaker to prepare an adhesive solution with a solid content (g / ml) of 8%.

[0066] (2) Mixing: Take the sulindac powder and all the microcrystalline cellulose and 10.2 parts of corn starch in step (1), add them into a wet granulator for premixing, the rotating speed of the stirring blade is 100 rpm, the rotating speed of the chopping blade is 1000 rpm, and the adhesive solution prepared in step (1) is added after the premixing to make a soft material, the rotating speed of the stirring blade is 120 rpm, the rotating speed of the chopping blade is 1200 rpm, and the granulation is carried out for 6 minutes. Then, wet granulation is carried out by a granulator, and the screen aperture is 0.8 mm. After drying, dry granulation is carried out again, and the screen aperture is 2 mm.

[0067] (3) Total mixing: Add the intermediate obtained in step (2) into the total mixing barrel, add the formulated amount of stearic acid, mix once at 12 rpm for a total of 5 minutes, and the charging factor is 40% to 70%.

[0068] (4) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 60%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0069] (5) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0070] Example 2

[0071] A method for preparing a stable sulindac tablet, comprising the following steps when producing 1,000 tablets:

[0072] (1) Pretreatment of raw materials and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio, 59 parts of sulindac, 21.4 parts of microcrystalline cellulose, 17.2 parts of corn starch, and 2 parts of stearic acid, wherein the particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is crushed into fine powder using a hammer mill, passed through a 30-mesh sieve, D90 is 30-40 μm, and D50 is greater than 5 μm. Stearic acid is passed through a 60-mesh sieve. Take 3 parts of corn starch and purified water and place them in a beaker to prepare an adhesive solution with a solid content (g / ml) of 8%.

[0073] (2) Mixing: Take the sulindac powder and all the microcrystalline cellulose and 14.2 parts of corn starch in step (1), add them into a wet granulator for premixing, the rotating speed of the stirring blade is 100 rpm, the rotating speed of the chopping blade is 1000 rpm, and the adhesive solution prepared in step (1) is added after the premixing to make a soft material, the rotating speed of the stirring blade is 120 rpm, the rotating speed of the chopping blade is 1200 rpm, and the granulation is carried out for 6 minutes. Then, wet granulation is carried out by a granulator, and the screen aperture is 0.8 mm. After drying, dry granulation is carried out again, and the screen aperture is 2 mm.

[0074] (3) Total mixing: Add the intermediate obtained in step (2) into the total mixing barrel, add the formulated amount of stearic acid, mix once at 12 rpm for a total of 5 minutes, and the charging factor is 40% to 70%.

[0075] (4) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 59%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0076] (5) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0077] Example 3

[0078] A method for preparing a stable sulindac tablet, comprising the following steps when producing 1,000 tablets:

[0079] (1) Pretreatment of raw materials and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio, 59 parts of sulindac, 25.4 parts of microcrystalline cellulose, 12.7 parts of corn starch, and 2.5 parts of stearic acid, wherein the particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is crushed into fine powder using a hammer mill, passed through a 30-mesh sieve, D90 is 30-40 μm, and D50 is greater than 5 μm. Stearic acid is passed through a 60-mesh sieve. Take 3 parts of corn starch and purified water and place them in a beaker to prepare an adhesive solution with a solid content (g / ml) of 8%.

[0080] (2) Mixing: Take the sulindac powder and all the microcrystalline cellulose and 9.7 parts of corn starch in step (1), add them into a wet granulator for premixing, the rotating speed of the stirring blade is 100 rpm, the rotating speed of the chopping blade is 1000 rpm, and the adhesive solution prepared in step (1) is added after the premixing to make a soft material, the rotating speed of the stirring blade is 120 rpm, the rotating speed of the chopping blade is 1200 rpm, and the granulation is carried out for 6 minutes. Then, wet granulation is carried out by a granulator, and the screen aperture is 0.8 mm. After drying, dry granulation is carried out again, and the screen aperture is 2 mm.

[0081] (3) Total mixing: Add the intermediate obtained in step (2) into the total mixing barrel, add the formulated amount of stearic acid, mix once at 12 rpm for a total of 5 minutes, and the charging factor is 40% to 70%.

[0082] (4) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 62%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0083] (5) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0084] Comparative Example 1

[0085] The particle size of the sulindac raw material after crushing is larger than that in Example 1. When producing 1,000 tablets, the process includes the following steps:

[0086] (1) Pretreatment of raw materials and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio, 59 parts of sulindac, 25.4 parts of microcrystalline cellulose, 13.2 parts of corn starch, and 2 parts of stearic acid, wherein the particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is crushed into fine powder using a hammer mill, passed through a 20-mesh sieve, D90 is 40-50 μm, and D50 is greater than 10 μm. Stearic acid is passed through a 60-mesh sieve. Take 3 parts of corn starch and purified water and place them in a beaker to prepare an adhesive solution with a solid content (g / ml) of 8%.

[0087] (2) Mixing: Take the sulindac powder and all the microcrystalline cellulose and 10.2 parts of corn starch in step (1), add them into a wet granulator for premixing, the rotating speed of the stirring blade is 100 rpm, the rotating speed of the chopping blade is 1000 rpm, and the adhesive solution prepared in step (1) is added after the premixing to make a soft material, the rotating speed of the stirring blade is 120 rpm, the rotating speed of the chopping blade is 1200 rpm, and the granulation is carried out for 6 minutes. Then, wet granulation is carried out by a granulator, and the screen aperture is 0.8 mm. After drying, dry granulation is carried out again, and the screen aperture is 2 mm.

[0088] (3) Total mixing: Add the intermediate obtained in step (2) into the total mixing barrel, add the formulated amount of stearic acid, mix once at 12 rpm for a total of 5 minutes, and the charging factor is 40% to 70%.

[0089] (4) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 57%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0090] (5) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0091] Comparative Example 2

[0092] The particle size of the sulindac raw material after crushing is smaller than that in Example 1. When producing 1,000 tablets, the process includes the following steps:

[0093] (1) Pretreatment of raw materials and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio, 59 parts of sulindac, 25.4 parts of microcrystalline cellulose, 13.2 parts of corn starch, and 2 parts of stearic acid, wherein the particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is crushed into fine powder using a hammer mill, passed through a 40-mesh sieve, D90 is 20-30 μm, and D50 is less than 4 μm. Stearic acid is passed through a 60-mesh sieve. Take 3 parts of corn starch and purified water and place them in a beaker to prepare an adhesive solution with a solid content (g / ml) of 8%.

[0094] (2) Mixing: Take the sulindac powder and all the microcrystalline cellulose and 10.2 parts of corn starch in step (1), add them into a wet granulator for premixing, the rotating speed of the stirring blade is 100 rpm, the rotating speed of the chopping blade is 1000 rpm, and the adhesive solution prepared in step (1) is added after the premixing to make a soft material, the rotating speed of the stirring blade is 120 rpm, the rotating speed of the chopping blade is 1200 rpm, and the granulation is carried out for 6 minutes. Then, wet granulation is carried out by a granulator, and the screen aperture is 0.8 mm. After drying, dry granulation is carried out again, and the screen aperture is 2 mm.

[0095] (3) Total mixing: Add the intermediate obtained in step (2) into the total mixing barrel, add the formulated amount of stearic acid, mix once at 12 rpm for a total of 5 minutes, and the charging factor is 40% to 70%.

[0096] (4) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 59%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0097] (5) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0098] Comparative Example 3

[0099] The corn starch in the filler of sulindac tablets is replaced with lactose. The production of 1,000 tablets includes the following steps:

[0100] (1) Pretreatment of raw materials and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio, 59 parts of sulindac, 25.4 parts of microcrystalline cellulose, 10.2 parts of lactose, 3 parts of corn starch, and 2 parts of stearic acid, wherein the particle size of microcrystalline cellulose, lactose and corn starch is 40-80 μm. Sulindac is crushed into fine powder using a hammer mill, passed through a 20-40 mesh sieve, D90 is 30-40 μm, and D50 is greater than 5 μm. Stearic acid is passed through a 60 mesh sieve. Take 3 parts of corn starch and purified water and place them in a beaker to prepare an adhesive solution with a solid content (g / ml) of 8%.

[0101] (2) Mixing: Take the sulindac powder and all the microcrystalline cellulose and lactose in step (1), add them into a wet granulator for premixing, the rotating speed of the stirring blade is 100 rpm, the rotating speed of the chopping blade is 1000 rpm, and the adhesive solution prepared in step (1) is added after the premixing to make a soft material, the rotating speed of the stirring blade is 120 rpm, the rotating speed of the chopping blade is 1200 rpm, and the granulation is carried out for 6 minutes. Then, wet granulation is carried out by a granulator, and the screen aperture is 0.8 mm. Then, dry granulation is carried out, and the screen aperture is 2 mm.

[0102] (3) Total mixing: Add the intermediate obtained in step (2) into the total mixing barrel, add the formulated amount of stearic acid, mix at 12 rpm for 5 minutes, and the charging factor is 40% to 70%.

[0103] (4) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 60%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0104] (5) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0105] Comparative Example 4

[0106] The corn starch in the binder of sulindac tablets is replaced with hypromellose, and the production of 1,000 tablets includes the following steps:

[0107] (1) Pretreatment of raw materials and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio, 59 parts of sulindac, 25.4 parts of microcrystalline cellulose, 10.2 parts of corn starch, 3 parts of hypromellose, and 2 parts of stearic acid, wherein the particle size of microcrystalline cellulose, corn starch and hypromellose is 40-80 μm. Sulindac is crushed into fine powder using a hammer mill, passed through a 20-40 mesh sieve, D90 is 30-40 μm, and D50 is greater than 5 μm. Stearic acid is passed through a 60 mesh sieve. Take 3 parts of hypromellose and purified water and place them in a beaker to prepare an adhesive solution with a solid content (g / ml) of 8%.

[0108] (2) Mixing: Take the sulindac powder and all the microcrystalline cellulose and corn starch in step (1), add them into a wet granulator for premixing, the rotating speed of the stirring blade is 100 rpm, the rotating speed of the chopping blade is 1000 rpm, and the adhesive solution prepared in step (1) is added after the premixing to make a soft material, the rotating speed of the stirring blade is 120 rpm, the rotating speed of the chopping blade is 1200 rpm, and the granulation is carried out for 6 minutes. Then, wet granulation is carried out by a granulator, and the screen aperture is 0.8 mm. After drying, dry granulation is carried out again, and the screen aperture is 2 mm.

[0109] (3) Total mixing: Add the intermediate obtained in step (2) into the total mixing barrel, add the formulated amount of stearic acid, mix once at 12 rpm for a total of 5 minutes, and the charging factor is 40% to 70%.

[0110] (4) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 58%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0111] (5) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0112] Comparative Example 5

[0113] The stearic acid in the lubricant of sulindac tablets is replaced with magnesium stearate, and the production of 1,000 tablets includes the following steps:

[0114] (1) Pretreatment of raw materials and auxiliary materials: Weigh each raw material and auxiliary material according to the weight ratio, 59 parts of sulindac, 25.4 parts of microcrystalline cellulose, 13.2 parts of corn starch, and 2 parts of magnesium stearate, wherein the particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is crushed into fine powder using a hammer mill, passed through a 20-40 mesh sieve, D90 is 30-40 μm, and D50 is greater than 5 μm. Stearic acid is passed through a 60 mesh sieve. Take 3 parts of corn starch and purified water and place them in a beaker to prepare an adhesive solution with a solid content (g / ml) of 8%.

[0115] (2) Mixing: Take the sulindac powder and all the microcrystalline cellulose and 10.2 parts of corn starch in step (1), add them into a wet granulator for premixing, the rotating speed of the stirring blade is 100 rpm, the rotating speed of the chopping blade is 1000 rpm, and the adhesive solution prepared in step (1) is added after the premixing to make a soft material, the rotating speed of the stirring blade is 120 rpm, the rotating speed of the chopping blade is 1200 rpm, and the granulation is carried out for 6 minutes. Then, wet granulation is carried out by a granulator, and the screen aperture is 0.8 mm. Then, dry granulation is carried out, and the screen aperture is 2 mm.

[0116] (3) Total mixing: Add the intermediate obtained in step (2) into the total mixing barrel, add the formulated amount of magnesium stearate, mix at 12 rpm for 5 minutes, and the charging factor is 40% to 70%.

[0117] (4) Tableting: The intermediate obtained in step (4) is placed in a mold for tableting. The ambient humidity is 60%. The tablet weight is calculated based on the intermediate content result. The tablet weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0118] (5) Packaging: Polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard tablets and pharmaceutical aluminum foil packaging.

[0119] Test 1

[0120] The product of Example 1 was subjected to content uniformity measurement, and the experimental results are shown in the following table. The RSD of the measurement results of three batches of content uniformity samples of this product should be less than 3.0%, and the content uniformity meets the requirements; the content uniformity of Examples 2 and 3 was measured, and the experimental results showed that the RSD of the measurement results of the samples of Examples 2 and 3 was 0.5% to 0.6%, and the content uniformity met the requirements.

[0121] Table 1

[0122] Sample batch number 01 02 03 1 101.10％ 98.84％ 100.23％ 2 101.12％ 99.02％ 100.75％ 3 100.26％ 99.73％ 101.02％ 4 100.95％ 100.63％ 100.80％ 5 101.09％ 100.14％ 101.50％ 6 100.52％ 99.53％ 101.92％ 7 101.29％ 99.34％ 101.07％ 8 100.98％ 99.76％ 100.62％ 9 101.78％ 99.66％ 101.51％ 10 101.04％ 100.23％ 100.54％ X bar 101.01％ 99.69％ 101.00％ RSD 0.4％ 0.6％ 0.5％

[0123] Note: X bar: average value of the contents of 10 tablets; RSD (%): formula for judging the uniformity of powder content.

[0124] Test 2

[0125] The product of Example 1 was subjected to a 10-day study of influencing factors (high temperature 40°C / 60°C, illumination 4500±500lux / h, high humidity RH75% / RH92.5%), an accelerated stability test (40°C / RH75%), a 6-month and a long-term stability test (30°C / RH65%), and a comparison of properties, dissolution (measured by paddle method 50pm, pH7.2 phosphate medium, Chinese Pharmacopoeia dissolution apparatus 2 at 37°C), related substances (measured by high performance liquid chromatography (General Rule 0512)), and content. Results The properties and content of the homemade product at each time point were in compliance with the regulations.

[0126] Table 2

[0127]

[0128] Test 3

[0129] The products of Example 2 and Example 3 were placed at 40°C for 10 days, and the properties, dissolution (measured by paddle method 50 pm, pH 7.2 phosphate medium, Chinese Pharmacopoeia dissolution apparatus 2 at 37°C), related substances, and content were compared. Results The properties and content of the homemade products at each time point were in compliance with the regulations.

[0130] Table 3

[0131]

[0132] Test 4

[0133] The multi-media dissolution curves of the samples prepared in Example 1, Example 2, and Example 3 and the reference preparation were measured using the paddle method 50 pm, pH 7.2 phosphate medium, and Chinese Pharmacopoeia dissolution apparatus 2 at 37°C. The experimental results showed that the preparations of the present invention had good dissolution uniformity and uniform dissolution, and the dissolution curves of the three batches all met the requirements.

[0134] Table 4

[0135]

[0136]

[0137] Test 5: Testing the products obtained in Comparative Examples 1-5 1. Testing the content uniformity according to Test 1, the results are as follows:

[0138] Table 5

[0139] sample Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 1 98.39％ 103.48％ 102.13％ 102.65％ 101.25％ 2 98.54％ 100.76％ 97.77％ 100.92％ 99.93％ 3 97.74％ 92.37％ 99.87％ 98.50％ 102.82％ 4 103.77％ 98.72％ 98.46％ 102.61％ 100.58％ 5 97.35％ 98.95％ 99.57％ 100.66％ 104.40％ 6 97.82％ 98.83％ 99.33％ 99.14％ 97.99％ 7 101.74％ 100.26％ 101.27％ 101.50％ 100.02％ 8 94.22％ 95.17％ 99.89％ 102.93％ 98.52％ 9 102.71％ 97.38％ 101.53％ 101.12％ 94.22％ 10 100.86％ 105.25％ 98.60％ 101.40％ 99.07％ X bar 99.31％ 99.12％ 99.84％ 100.78％ 99.88％ RSD 2.9％ 3.8％ 1.4％ 1.6％ 2.8％

[0140] 2. Test according to test 2 (high temperature 40℃), the results are as follows:

[0141] Table 6

[0142]

[0143] 3. Test the dissolution according to Test 3. The results are as follows: Figure 1 shown.

[0144] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A sulindac composition, characterized in that: Contains the following components in parts by weight:

2. The sulindac composition according to claim 1, characterized in that Contains the following components in parts by weight: Preferably, the sulindac composition contains the following components in parts by weight: Preferably, the D of sulindac 90 is 30-40 μm; preferably, the D 50 Preferably, the particle size of the microcrystalline cellulose is 40-80 μm; preferably, the particle size of the corn starch is 40-80 μm; preferably, the stearic acid is stearic acid with a mesh size of 60-80.

3. A sulindac tablet, characterized in that: Made from the sulindac composition of claim 1 or 2; preferably, 2-4 parts of corn starch are mixed with water to form an adhesive solution; preferably, the adhesive solution is an aqueous solution of an adhesive; preferably, the solid content of the adhesive in the adhesive solution is 3% g / ml to 13% g / ml, preferably 5% g / ml to 10% g / ml, preferably 8% g / ml.

4. The sulindac tablets according to claim 3, characterized in that The preparation comprises the following mixing steps: (1) mixing sulindac, microcrystalline cellulose, and corn starch except a binder to obtain a premix; (2) wet granulating the obtained premix with a binder solution to obtain an intermediate; (3) The obtained intermediate is mixed with a lubricant.

5. A method for preparing sulindac tablets, characterized in that: Made from the sulindac composition of claim 1 or 2; preferably, 2-4 parts of corn starch are mixed with water to form an adhesive solution; preferably, the adhesive solution is an aqueous solution of an adhesive; preferably, the solid content of the adhesive in the adhesive solution is 3% g / ml to 13% g / ml, preferably 5% g / ml to 10% g / ml, preferably 8% g / ml.

6. The preparation method according to claim 5, characterized in that: The method comprises the following mixing steps: (1) mixing sulindac, microcrystalline cellulose, and corn starch except a binder to obtain a premix; (2) wet granulating the obtained premix with a binder solution to obtain an intermediate; (3) The obtained intermediate is mixed with a lubricant.

7. The sulindac tablets according to claim 4 or the preparation method according to claim 6, characterized in that: In step (1), the mixing is carried out in a wet granulator; preferably, during the mixing, the rotation speed of the stirring blade is 80-120 rpm, and the rotation speed of the chopping blade is 800-1200 rpm; In step (2), the wet granulation includes soft material preparation, wet granulation, drying and dry granulation; preferably, when preparing the soft material, the rotation speed of the stirring blade is 100-140 rpm, the rotation speed of the chopping blade is 1000-1400 rpm, and the mixing time is more than 5 min, preferably 5-8 min; preferably, when wet granulation, the mesh aperture is 0.6-1.0 mm, preferably 0.8 mm; preferably, when dry granulation, the mesh aperture is 1-4 mm, preferably 2 mm; In step (3), the mixing is performed in a mixer for 1 to 3 times; preferably, the charging factor of the mixer is 40% to 70%; preferably, during mixing, the rotating speed of the mixer is 10 to 20 rpm; preferably, the mixing time is 1 to 5 min.

8. The sulindac tablets according to claim 4 or the preparation method according to claim 6, characterized in that: The preparation method of sulindac tablets further includes tableting, and further includes packaging; Preferably, the packaging is made of polyvinyl chloride / polyvinylidene chloride solid medicinal composite hard tablets and medicinal aluminum foil packaging.

9. A sulindac tablet, characterized in that: The sulindac tablets include the following components in parts by weight: Sulindac 59 parts Microcrystalline cellulose 21.4-25.4 parts Corn starch 12.7-13.2 parts 2-2.8 parts of stearic acid; The D of sulindac 90 30-40μm, D 50 The particle size of the microcrystalline cellulose is 40-80 μm; The particle size of the corn starch is 40-80 μm; the stearic acid is stearic acid with a mesh size of 60-80; The preparation method of the sulindac tablets comprises the following steps: (1) preparing a binder solution having a solid content of 5% g / ml to 10% g / ml by mixing 2-4 parts of corn starch with water; mixing sulindac, microcrystalline cellulose, and corn starch other than the binder in a wet granulator with the stirring blade rotating at 80-120 rpm and the chopping blade rotating at 800-1200 rpm to obtain a premix; (2) wet granulating the obtained premix with a binder solution to obtain an intermediate; (3) mixing the intermediate obtained with a lubricant in a mixer for 1 to 3 times; (4) Tableting and packaging; In step (2), the wet granulation includes soft material preparation, wet granulation, drying and dry granulation; when preparing the soft material, the rotation speed of the stirring blade is 100-140 rpm, the rotation speed of the chopping blade is 1000-1400 rpm, and the mixing time is 5-8 min; During the wet granulation, the mesh size is 0.6-1.0 mm; during the dry granulation, the mesh size is 1-4 mm; In step (3), the charging factor of the mixer is 40% to 70%; during mixing, the rotating speed of the mixer is 10 to 20 rpm; and the mixing time is 1 to 5 min.

10. The sulindac tablet according to claim 3, 4, 7, 8 or 9, characterized in that: The sulindac tablets have the following release characteristics: When measured at 37°C using the paddle method at 50 pm, pH 7.2 phosphate medium, the cumulative dissolution in 5 minutes is 42.5%-59.1%, the cumulative dissolution in 10 minutes is 68.9%-88.1%, the cumulative dissolution in 15 minutes is 83.5%-93.2%, and the cumulative dissolution in 45 minutes is 94.6%-99.2%; preferably, after the sulindac tablets are placed at 40°C for 10 days, the solubility is 97%-99%, and the related substances are 0.64%-0.67%.

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