A stable sulindac tablet and a method for preparing the same

Abstract

The application discloses stable sulindac tablets and a preparation method thereof, which contain 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. The sulindac tablets provided by the application reduce the viscosity of particles, increase the flowability of particles, have small tablet weight difference after tabletting, reduce the RSD value of dissolution, reduce the quality difference of tablets, improve uniformity, have similar dissolution to a reference preparation, and improve the stability of products.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a stable sulindac tablet and its preparation method. Background Technology

[0002] This section provides only background information relevant to this disclosure and is not necessarily prior art.

[0003] Sulindac, chemically known as (Z)-5-fluoro-2-methyl-1-[(4-methylthionylphenyl)methylene]-1H-inden-3-acetic acid, has the molecular formula C2. 20 H 17 FO3S, with a molecular weight of 356.41, can be used for proliferative osteoarthritis, rheumatoid arthritis, chronic arthritis, periarthritis of the shoulder, cervicobrachial syndrome, tenosynovitis, etc. Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) that is metabolized into an active sulfide in the body. It inhibits cyclooxygenase and reduces prostaglandin synthesis, thus possessing analgesic, anti-inflammatory, and antipyretic effects, with minimal impact on renal blood flow and renal function.

[0004] Sulindac tablets (trade name Clinoril) are nonsteroidal anti-inflammatory drugs developed by Merck Sharp & Dohme. They are available in strengths of 50mg, 100mg, 150mg, and 200mg. They were first launched in Portugal in 1976 in the 200mg strength, and were subsequently launched in Italy, the United Kingdom, Ireland, and other European countries. They were launched in the United States in 1978 in the 150mg and 200mg strengths, and in Japan in 1981 in the 50mg and 100mg strengths.

[0005] Currently, domestically produced formulations on the market have relatively rapid dissolution and release, failing to meet the requirements for consistency with the reference formulation. The main preparation process for sulindac tablets involves mixing sulindac with other excipients, using hydroxypropyl methylcellulose to create a binder solution, wet granulation, followed by granulation, drying, and tableting. This process results in low dissolution, leading to dissimilarity with the reference formulation. Sulindac tablets are almost insoluble in 0.1 mol / L hydrochloric acid, with a dissolution rate below 12% after 60 minutes. There is an urgent need for a method to improve the solubility of sulindac tablets in 0.1 mol / L hydrochloric acid, which would be 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 its preparation method, which addresses the shortcomings of the prior art.

[0007] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:

[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 It is greater than 5μm.

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

[0017] In some embodiments, the particle size of the corn starch is 40–80 μm.

[0018] In some embodiments, the stearic acid is stearic acid that passes through a 60-80 mesh.

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

[0020] In some embodiments, 2-4 parts of corn starch are mixed with water to prepare an adhesive solution; in some embodiments, the adhesive solution is an aqueous solution of the adhesive; in some embodiments, the solid content of the adhesive in the adhesive solution is 0.03-0.13 g / ml, in some embodiments it is 0.05-0.1 g / ml, and in some embodiments it is 0.08 g / ml.

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

[0022] (1) Mix sulinic acid, microcrystalline cellulose, and corn starch (excluding binder) to obtain a premix;

[0023] (2) The obtained premix was wet-granulated with the 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 granulation machine; preferably, during the mixing, the stirring blade rotates at 80-120 rpm and the chopping blade rotates at 800-1200 rpm.

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

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

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

[0029] The packaging consists of a solid pharmaceutical composite rigid sheet made of polyvinyl chloride / polyvinylidene chloride and pharmaceutical aluminum foil.

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

[0031]

[0032] The D of sulindac 90 30-40μm, D 50 The particle size is 5μm or larger; the particle size of the microcrystalline cellulose is 40-80μm; the particle size of the corn starch is 40-80μm; the stearic acid is stearic acid that passes through a 60-80 mesh.

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

[0034] (1) Take 2-4 parts of corn starch and water to prepare a binder solution with a solid content of 0.05-0.1g / ml; mix sulinic acid, microcrystalline cellulose and corn starch (excluding binder) in a wet granulator, with the stirring blade speed at 80-120rpm and the chopping blade speed at 800-1200rpm to obtain a premix.

[0035] (2) The obtained premix was wet-granulated with the binder solution to obtain an intermediate;

[0036] (3) The obtained intermediate and lubricant are mixed in a mixer 1 to 3 times;

[0037] (4) Tableting and packaging;

[0038] In step (2), the wet granulation includes preparing soft material, wet granulation, drying, and dry granulation; when preparing soft material, the stirring blade rotates at 100-140 rpm, the chopping blade rotates at 1000-1400 rpm, and the granulation time is 5-8 minutes; when wet granulation, the screen aperture is 0.6-1.0 mm; when dry granulation, the screen aperture is 1-4 mm.

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

[0040] Secondly, the present invention discloses a method for preparing sulindac tablets as described in the first aspect above.

[0041] In some embodiments, 2-4 parts of corn starch are mixed with water to prepare an adhesive solution; in some embodiments, the adhesive solution is an aqueous solution of the adhesive; in some embodiments, the solid content of the adhesive in the adhesive solution is 0.03-0.13 g / ml, in some embodiments it is 0.05-0.1 g / ml, and in some embodiments it is 0.08 g / ml.

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

[0043] (1) Mix sulinic acid, microcrystalline cellulose, and corn starch (excluding binder) to obtain a premix;

[0044] (2) The obtained premix was wet-granulated with the 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 granulation machine; preferably, during the mixing, the stirring blade rotates at 80-120 rpm and the chopping blade rotates at 800-1200 rpm.

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

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

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

[0050] The packaging consists of a solid pharmaceutical composite rigid sheet made of polyvinyl chloride / polyvinylidene chloride and pharmaceutical aluminum foil.

[0051] The sulindac tablets provided by this invention have the following release characteristics: When measured using a paddle dissolution apparatus (50 pm, pH 7.2, phosphate medium, and Chinese Pharmacopoeia dissolution device 2) at 37°C, the cumulative dissolution rate is 42.5%-59.1% at 5 minutes, 68.9%-88.1% at 10 minutes, 83.5%-93.2% at 15 minutes, and 94.6%-99.2% at 45 minutes. After being stored at 40°C for 10 days, the sulindac tablets have a dissolution rate of 97%-99%, related substances of 0.64%-0.67%, and a content of 99.6%-100.6%.

[0052] Beneficial effects:

[0053] This invention provides a sulindac tablet and its preparation method. By selecting appropriate excipients and preparation processes, the viscosity of the granules is reduced, the flowability of the granules is increased, the difference in tablet weight after compression is small, the RSD value of dissolution is reduced, the quality difference of tablets is reduced, the uniformity is improved, and the dissolution is similar to that of the reference formulation, thus improving the stability of the product. Attached Figure Description

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

[0055] Figure 1 The dissolution curves are for Example 1 and Comparative Examples 1-4. Detailed Implementation

[0056] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

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

[0058] The present invention provides a stable sulindac tablet with a designed tablet weight of 337 mg. The starch and microcrystalline cellulose used in the present invention have a particle size of 40-80 μm and a particle size of 40-80 μm, respectively. The amounts of both are within the range published in the FDA Inactive Ingredient Search for Approved Drug Products database.

[0059] Starch is a basic excipient in oral preparations, mainly used as a filler, disintegrant, and binder. As a binder, the commonly used concentration is 5%-25%, with 10% starch paste being the most frequently used. As a disintegrant, the commonly used concentration is 3%-15%. Types of starch include wheat starch, corn starch, and potato starch, with corn starch being the most commonly used in my country.

[0060] Microcrystalline cellulose is widely used in pharmaceutical formulations, primarily as a binder, filler, or diluent in oral tablets and capsules. In this invention, microcrystalline cellulose serves as both a filler, aiding in formulation formation and increasing tablet compressibility, and a means of disintegration, ensuring tablet disintegration.

[0061] The unit of solid content mentioned in this invention is g / ml.

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

[0063] Example 1

[0064] A stable method for preparing sulindac tablets, 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. The particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac was pulverized into micro powder using a hammer mill and passed through a 30-mesh sieve. The D90 was 30-40 μm and the D50 was greater than 5 μm. Stearic acid was passed through a 60-mesh sieve. Take 3 parts of corn starch and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 8%.

[0066] (2) Mixing: Take the sulindac micro powder, all the microcrystalline cellulose, and 10.2 parts of corn starch from step (1) and add them to a wet granulator for premixing. The stirring blade speed is 100 rpm and the chopping blade speed is 1000 rpm. After premixing, add the binder solution prepared in step (1) to form a soft mass. When forming the soft mass, the stirring blade speed is 120 rpm and the chopping blade speed is 1200 rpm. Granulate for 6 minutes. Then, wet granulate through a granulator with a screen aperture of 0.8 mm. After drying, dry granulate with a screen aperture of 2 mm.

[0067] (3) Mixing: Add the intermediate obtained in step (2) to the mixing tank, add the amount of stearic acid in the formula, mix once at 12 rpm for a total of 5 minutes, and the loading coefficient 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 weight of the tablets to be pressed is calculated based on the content of the intermediate. The weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0069] (5) Packaging: The packaging uses polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

[0070] Example 2

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

[0072] (1) Pretreatment of raw materials and auxiliary materials: Weigh out 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. The particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is pulverized into micro powder using a hammer mill and passed through a 30-mesh sieve. The D90 is 30-40 μm and the 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 put them in a beaker to prepare a binder solution with a solid content (g / ml) of 8%.

[0073] (2) Mixing: Take the sulindac micro powder, all the microcrystalline cellulose, and 14.2 parts of corn starch from step (1) and add them to a wet granulator for premixing. The stirring blade speed is 100 rpm and the chopping blade speed is 1000 rpm. After premixing, add the binder solution prepared in step (1) to form a soft mass. When forming the soft mass, the stirring blade speed is 120 rpm and the chopping blade speed is 1200 rpm. Granulate for 6 minutes. Then, wet granulate through a granulator with a screen aperture of 0.8 mm. After drying, dry granulate with a screen aperture of 2 mm.

[0074] (3) Mixing: Add the intermediate obtained in step (2) to the mixing tank, add the amount of stearic acid in the formula, mix once at 12 rpm for a total of 5 minutes, and the loading coefficient 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 weight of the tablets to be pressed is calculated based on the content of the intermediate. The weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0076] (5) Packaging: The packaging uses polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

[0077] Example 3

[0078] A stable method for preparing sulindac tablets, 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. The particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac was pulverized into micro powder using a hammer mill and passed through a 30-mesh sieve. The D90 was 30-40 μm and the D50 was greater than 5 μm. Stearic acid was passed through a 60-mesh sieve. Take 3 parts of corn starch and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 8%.

[0080] (2) Mixing: Take the sulindac micro powder, all the microcrystalline cellulose, and 9.7 parts of corn starch from step (1) and add them to a wet granulator for premixing. The stirring blade speed is 100 rpm and the chopping blade speed is 1000 rpm. After premixing, add the binder solution prepared in step (1) to form a soft mass. When forming the soft mass, the stirring blade speed is 120 rpm and the chopping blade speed is 1200 rpm. Granulate for 6 minutes. Then, wet granulate through a granulator with a screen aperture of 0.8 mm. After drying, dry granulate with a screen aperture of 2 mm.

[0081] (3) Mixing: Add the intermediate obtained in step (2) to the mixing tank, add the amount of stearic acid in the formula, mix once at 12 rpm for a total of 5 minutes, and the loading coefficient 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 weight of the tablets to be pressed is calculated based on the content of the intermediate. The weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0083] (5) Packaging: The packaging uses polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

[0084] Comparative Example 1

[0085] The particle size of the sulindac raw material after pulverization was larger than that in Example 1. The production of 1,000 tablets included 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. The particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is pulverized into micro powder using a hammer mill and passed through a 20-mesh sieve. The D90 is 40-50 μm and the 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 put them in a beaker to prepare a binder solution with a solid content (g / ml) of 8%.

[0087] (2) Mixing: Take the sulindac micro powder, all the microcrystalline cellulose, and 10.2 parts of corn starch from step (1) and add them to a wet granulator for premixing. The stirring blade speed is 100 rpm and the chopping blade speed is 1000 rpm. After premixing, add the binder solution prepared in step (1) to form a soft mass. When forming the soft mass, the stirring blade speed is 120 rpm and the chopping blade speed is 1200 rpm. Granulate for 6 minutes. Then, wet granulate through a granulator with a screen aperture of 0.8 mm. After drying, dry granulate with a screen aperture of 2 mm.

[0088] (3) Mixing: Add the intermediate obtained in step (2) to the mixing tank, add the amount of stearic acid in the formula, mix once at 12 rpm for a total of 5 minutes, and the loading coefficient 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 weight of the tablets to be pressed is calculated based on the content of the intermediate. The weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0090] (5) Packaging: The packaging uses polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

[0091] Comparative Example 2

[0092] The particle size of the sulindac raw material after pulverization was smaller than that in Example 1. The production of 1,000 tablets 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. The particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac was pulverized into micro powder using a hammer mill and passed through a 40-mesh sieve. The D90 was 20-30 μm and the D50 was less than 4 μm. Stearic acid was passed through a 60-mesh sieve. Take 3 parts of corn starch and purified water and put them in a beaker to prepare a binder solution with a solid content (g / ml) of 8%.

[0094] (2) Mixing: Take the sulindac micro powder, all the microcrystalline cellulose, and 10.2 parts of corn starch from step (1) and add them to a wet granulator for premixing. The stirring blade speed is 100 rpm and the chopping blade speed is 1000 rpm. After premixing, add the binder solution prepared in step (1) to form a soft mass. When forming the soft mass, the stirring blade speed is 120 rpm and the chopping blade speed is 1200 rpm. Granulate for 6 minutes. Then, wet granulate through a granulator with a screen aperture of 0.8 mm. After drying, dry granulate with a screen aperture of 2 mm.

[0095] (3) Mixing: Add the intermediate obtained in step (2) to the mixing tank, add the amount of stearic acid in the formula, mix once at 12 rpm for a total of 5 minutes, and the loading coefficient 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 weight of the tablets to be pressed is calculated based on the content of the intermediate. The weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0097] (5) Packaging: The packaging uses polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

[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. The particle size of microcrystalline cellulose, lactose, and corn starch is 40-80 μm. Sulindac was pulverized into micro powder using a hammer mill and passed through a 20-40 mesh sieve. The D90 was 30-40 μm, and the D50 was greater than 5 μm. Stearic acid was passed through a 60 mesh sieve. Take 3 parts of corn starch and purified water and place them in a beaker to prepare a binder solution with a solid content (g / ml) of 8%.

[0101] (2) Mixing: Take the sulindac micropowder, all the microcrystalline cellulose, and lactose from step (1) and add them to a wet granulator for premixing. The stirring blade speed is 100 rpm, and the chopping blade speed is 1000 rpm. After premixing, add the binder solution prepared in step (1) to form a soft mass. When forming the soft mass, the stirring blade speed is 120 rpm, and the chopping blade speed is 1200 rpm. Granulate for 6 minutes. Then, wet granulate through a granulator with a screen aperture of 0.8 mm. Then, dry granulate with a screen aperture of 2 mm.

[0102] (3) Mixing: Add the intermediate obtained in step (2) to the mixing tank, add the amount of stearic acid in the formula, mix at 12 rpm for 5 minutes, and the loading coefficient 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 weight of the tablets to be pressed is calculated based on the content of the intermediate. The weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0104] (5) Packaging: The packaging uses polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

[0105] Comparative Example 4

[0106] The corn starch in the binder of sulindac tablets is replaced with hydroxypropyl methylcellulose. 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 hydroxypropyl methylcellulose, and 2 parts of stearic acid. The particle size of microcrystalline cellulose, corn starch, and hydroxypropyl methylcellulose is 40-80 μm. Sulindac is pulverized into micro powder using a hammer mill and passed through a 20-40 mesh sieve. The D90 is 30-40 μm and the D50 is greater than 5 μm. Stearic acid is passed through a 60 mesh sieve. Take 3 parts of hydroxypropyl methylcellulose and purified water and place them in a beaker to prepare a binder solution with a solid content (g / ml) of 8%.

[0108] (2) Mixing: Take the sulindac micro powder, all the microcrystalline cellulose, and corn starch from step (1) and add them to a wet granulator for premixing. The stirring blade speed is 100 rpm and the chopping blade speed is 1000 rpm. After premixing, add the binder solution prepared in step (1) to form a soft mass. When forming the soft mass, the stirring blade speed is 120 rpm and the chopping blade speed is 1200 rpm. Granulate for 6 minutes. Then, wet granulate through a granulator with a screen aperture of 0.8 mm. After drying, dry granulate with a screen aperture of 2 mm.

[0109] (3) Mixing: Add the intermediate obtained in step (2) to the mixing tank, add the amount of stearic acid in the formula, mix once at 12 rpm for a total of 5 minutes, and the loading coefficient 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 weight of the tablets to be pressed is calculated based on the content of the intermediate. The weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0111] (5) Packaging: The packaging uses polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

[0112] Comparative Example 5

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

[0114] (1) Pretreatment of raw materials and auxiliary materials: Weigh out 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. The particle size of microcrystalline cellulose and corn starch is 40-80 μm. Sulindac is pulverized into micro powder using a hammer mill and passed through a 20-40 mesh sieve. The D90 is 30-40 μm and the 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 a binder solution with a solid content (g / ml) of 8%.

[0115] (2) Mixing: Take the sulindac micro powder, all the microcrystalline cellulose, and 10.2 parts of corn starch from step (1) and add them to a wet granulator for premixing. The stirring blade speed is 100 rpm and the chopping blade speed is 1000 rpm. After premixing, add the binder solution prepared in step (1) to form a soft mass. When forming the soft mass, the stirring blade speed is 120 rpm and the chopping blade speed is 1200 rpm. Granulate for 6 minutes. Then, wet granulate through a granulator with a screen aperture of 0.8 mm. Then, dry granulate with a screen aperture of 2 mm.

[0116] (3) Mixing: Add the intermediate obtained in step (2) to the mixing tank, add the amount of magnesium stearate in the formula, mix at 12 rpm for 5 minutes, and the loading coefficient 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 weight of the tablets to be pressed is calculated based on the content of the intermediate. The weight difference is controlled within ±5%, and the hardness is 2.5 to 6.5 kg.

[0118] (5) Packaging: The packaging uses polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

[0119] Experiment 1

[0120] The content uniformity of the product in Example 1 was determined, and the experimental results are shown in the table below. The RSD of the content uniformity test results of the three batches of this product should be less than 3.0%, and the content uniformity meets the requirements. The content uniformity of Example 2 and Example 3 was determined, and the experimental results show that the RSD of the test results of Example 2 and Example 3 samples is 0.5% to 0.6%, and the content uniformity meets 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 content of 10 tablets; RSD (%): formula for judging the uniformity of powder content.

[0124] Experiment 2

[0125] The product of Example 1 was subjected to influencing factors (high temperature 40℃ / 60℃, light 4500±500 lux / h, high humidity RH 75% / RH 92.5%) for 10 days, accelerated stability test (40℃ / RH 75%) for 6 months, and long-term stability test (30℃ / RH 65%) for 24 months. The properties, dissolution (measured using a paddle method at 50 pm, pH 7.2 phosphate medium, and Chinese Pharmacopoeia dissolution apparatus 2 at 37℃), related substances (determined by high performance liquid chromatography (General Rule 0512)), and content were compared. The results showed that the properties and content of the self-made product at each time point met the requirements.

[0126] Table 2

[0127]

[0128] Experiment 3

[0129] The products of Examples 2 and 3 were subjected to a high-temperature (40°C) test for 10 days, and their properties, dissolution (measured using a paddle method at 50 pm, pH 7.2 phosphate medium, and Chinese Pharmacopoeia dissolution apparatus 2 at 37°C), related substances, and content were compared. The results showed that the properties and content of the self-made products at each time point met the requirements.

[0130] Table 3

[0131]

[0132] Experiment 4

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

[0134] Table 4

[0135]

[0136]

[0137] Experiment 5: Testing of the products obtained from Comparative Examples 1-5 1. The content uniformity was tested according to Experiment 1, and 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. The test was conducted according to Experiment 2 (high temperature 40℃), and the results are as follows:

[0141] Table 6

[0142]

[0143] 3. The dissolution rate was tested according to Experiment 3, and the results are as follows: Figure 1 As shown.

[0144] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A sulindac tablet, characterized in that, It is made from components containing the following parts by weight: Sulinic acid 53-65 parts Microcrystalline cellulose 17.4-35.4 parts Corn starch 10.7-17.2 parts Stearic acid 1-3.8 parts; The D of sulindac 90 30-40μm, D 50 The particle size is 5μm or larger; the particle size of the microcrystalline cellulose is 40-80μm; the particle size of the corn starch is 40-80μm; the stearic acid is stearic acid that passes through 60-80 mesh. The manufacturing process includes the following steps: (1) Take 2-4 parts of corn starch and water to prepare an adhesive solution, wherein the solid content of the adhesive in the adhesive solution is 0.03-0.13 g / ml; mix sulinic acid, microcrystalline cellulose and corn starch other than the adhesive to obtain a premix; (2) The obtained premix and binder solution are subjected to wet granulation to obtain an intermediate; (3) The obtained intermediate is mixed with a lubricant; Tableting and packaging; In step (1), the mixing is carried out in a wet granulation machine; during the mixing, the stirring blade rotates at 80-120 rpm and the chopping blade rotates at 800-1200 rpm. In step (2), the wet granulation includes preparing soft material, wet granulation, drying, and dry granulation; when preparing soft material, the stirring blade rotates at 100-140 rpm, the chopping blade rotates at 1000-1400 rpm, and the granulation time is more than 5 minutes; when wet granulation, the screen aperture is 0.6-1.0 mm; when dry granulation, the screen aperture is 1-4 mm. In step (3), the mixing is performed 1 to 3 times in a mixer; the loading coefficient of the mixer is 40% to 70%; the speed of the mixer is 10 to 20 rpm during mixing; and the mixing time is 1 to 5 minutes. In step (3), the packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

2. The sulindac tablets according to claim 1, characterized in that, It is made from components containing the following parts by weight: Sulinic acid 56-62 parts Microcrystalline cellulose 19.4-30.4 parts Corn starch 11.7-15.2 parts Stearic acid 1.5-3.3 parts.

3. The sulindac tablets according to claim 1, characterized in that, It is made from components containing the following parts by weight: 59 portions of Sulinic acid Microcrystalline cellulose 21.4-25.4 parts Corn starch 12.7-13.2 parts Stearic acid 2-2.8 parts.

4. The sulindac tablets according to claim 1, characterized in that, The adhesive solution has a solid content of 0.05-0.1 g / ml.

5. The sulindac tablets according to claim 1, characterized in that, The adhesive solution has a solid content of 0.08 g / ml.

6. A sulindac tablet, characterized in that, The sulindac tablets comprise the following components in parts by weight: 59 portions of Sulinic acid Microcrystalline cellulose 21.4-25.4 parts Corn starch 12.7-13.2 parts Stearic acid 2-2.8 parts; The D of sulindac 90 30-40μm, D 50 The particle size is 5μm or larger; the particle size of the microcrystalline cellulose is 40-80μm; the particle size of the corn starch is 40-80μm; the stearic acid is stearic acid that passes through 60-80 mesh. The preparation method of the sulindac tablets includes the following steps: (1) Take 2-4 parts of corn starch and water to prepare a binder solution with a solid content of 0.05-0.1g / ml; mix sulinic acid, microcrystalline cellulose and corn starch (excluding binder) in a wet granulator, with the stirring blade speed at 80-120rpm and the chopping blade speed at 800-1200rpm to obtain a premix. (2) The obtained premix and binder solution are subjected to wet granulation to obtain an intermediate; (3) The obtained intermediate and lubricant are mixed in a mixer 1 to 3 times; (4) Tableting and packaging; In step (2), the wet granulation includes preparing soft material, wet granulation, drying, and dry granulation; when preparing soft material, the stirring blade rotates at 100-140 rpm, the chopping blade rotates at 1000-1400 rpm, and the granulation time is 5-8 min; when wet granulation, the screen aperture is 0.6-1.0 mm; when dry granulation, the screen aperture is 1-4 mm. In step (3), the loading coefficient of the mixer is 40%~70%; during mixing, the speed of the mixer is 10~20 rpm; and the mixing time is 1~5 min. In step (4), the packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

7. The sulindac tablets according to any one of claims 1-6, characterized in that, The sulindac tablets have the following release characteristics: When measured using a paddle method at 50 pm, pH 7.2 phosphate medium, and at 37°C, the cumulative dissolution rate was 42.5%-59.1% at 5 min, 68.9%-88.1% at 10 min, 83.5%-93.2% at 15 min, and 94.6%-99.2% at 45 min.

8. The sulindac tablets according to any one of claims 1-6, characterized in that, The sulindac tablets, after being stored at 40°C for 10 days, showed a dissolution rate of 97%-99% and a related substances rate of 0.64%-0.67%.

9. A method for preparing sulindac tablets, characterized in that, It is made from components containing the following parts by weight: Sulinic acid 53-65 parts Microcrystalline cellulose 17.4-35.4 parts Corn starch 10.7-17.2 parts Stearic acid 1-3.8 parts; The D of sulindac 90 30-40μm, D 50 The particle size is 5μm or larger; the particle size of the microcrystalline cellulose is 40-80μm; the particle size of the corn starch is 40-80μm; the stearic acid is stearic acid that passes through 60-80 mesh. (1) Take 2-4 parts of corn starch and water to prepare an adhesive solution, wherein the solid content of the adhesive in the adhesive solution is 0.03-0.13 g / ml; mix sulinic acid, microcrystalline cellulose and corn starch other than the adhesive to obtain a premix; (2) The obtained premix and binder solution are subjected to wet granulation to obtain an intermediate; (3) The obtained intermediate is mixed with a lubricant; Tableting and packaging; In step (1), the mixing is carried out in a wet granulation machine; during the mixing, the stirring blade rotates at 80-120 rpm and the chopping blade rotates at 800-1200 rpm. In step (2), the wet granulation includes preparing soft material, wet granulation, drying, and dry granulation; when preparing soft material, the stirring blade rotates at 100-140 rpm, the chopping blade rotates at 1000-1400 rpm, and the granulation time is more than 5 minutes; when wet granulation, the screen aperture is 0.6-1.0 mm; when dry granulation, the screen aperture is 1-4 mm. In step (3), the mixing is performed 1 to 3 times in a mixer; the loading coefficient of the mixer is 40% to 70%; the speed of the mixer is 10 to 20 rpm during mixing; and the mixing time is 1 to 5 minutes. In step (3), the packaging is made of polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil.

10. The method for preparing sulindac tablets according to claim 9, characterized in that, It is made from components containing the following parts by weight: Sulinic acid 56-62 parts Microcrystalline cellulose 19.4-30.4 parts Corn starch 11.7-15.2 parts Stearic acid 1.5-3.3 parts.

11. The method for preparing sulindac tablets according to claim 9, characterized in that, It is made from components containing the following parts by weight: 59 portions of Sulinic acid Microcrystalline cellulose 21.4-25.4 parts Corn starch 12.7-13.2 parts Stearic acid 2-2.8 parts.

12. The method for preparing sulindac tablets according to claim 9, characterized in that, The adhesive solution has a solid content of 0.05-0.1 g / ml.

13. The method for preparing sulindac tablets according to claim 9, characterized in that, The adhesive solution has a solid content of 0.08 g / ml.

14. The preparation method according to claim 9, characterized in that, In step (2), the granulation time is 5-8 minutes, the screen aperture is 0.8 mm during wet granulation, and the screen aperture is 2 mm during dry granulation.

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