Preparation method of sulindac capsule

Abstract

The invention discloses a sulindac capsule and a preparation method thereof. The preparation method comprises the following steps: weighing, mixing 1, wet granulation, wet size stabilization, drying, dry size stabilization, mixing 2, total mixing, capsule filling and packaging. According to the invention, by selecting proper auxiliary materials, the requirements of a sulindac preparation process are met; according to the invention, water is used as a wetting agent for wet granulation to obtain sulindac particles with proper particle size and moderate viscosity; the surfactant lauryl sodium sulfate is used for increasing the wettability of particles and improving in-vitro dissolution, and the paddle method 75rpm dissolution curve of the obtained sulindac capsule in an SDS medium with the pH being 4.0 + 0.3% is consistent with that of a reference preparation.

Description

[0001] This invention is a divisional application. The name of the original application is "A Sulindac Capsule and Its Preparation Method", the application number is 202411011010.5, and the application date is July 26, 2024. Technical Field

[0002] The present invention relates to the technical field of pharmaceutical manufacturing, and in particular to a sulindac capsule and a preparation method thereof. Background Art

[0003] Sulindac is a nonsteroidal anti-inflammatory drug (NSIA) from the arylalkanoic acid class. Sulindac is a prodrug and is biologically inactive. Upon oral absorption, sulindac is converted by hepatic enzymes into a reversibly reduced sulfide (bioactive) and an irreversible sulfide (inactive). The active sulfide inhibits cyclooxygenase and prostaglandin synthesis, resulting in anti-inflammatory and analgesic effects. The sulfide enters the enterohepatic circulation and is reoxidized in the kidneys to inactive sulindac, ultimately excreted in the feces and urine as unchanged drug, inactive metabolites, or glucuronide conjugates. At the same dose, sulindac's anti-acute inflammatory activity is comparable to that of ibuprofen and 0.3-0.5 times that of indomethacin. Its anti-protein edema activity is 16 times that of aspirin. Its analgesic activity is comparable to that of indomethacin and ten times that of ibuprofen. Sulindac does not inhibit prostaglandin synthase, and its active sulfur metabolite is only 0.2 times more potent than indomethacin at inhibiting prostaglandin synthase. In patients with arthritis, sulindac is 12 times more effective than aspirin, and the incidence of overall adverse reactions, mild gastrointestinal reactions, and tinnitus is lower than in patients taking aspirin. In patients with ankylosing spondylitis, sulindac 300-400 mg / day is as effective as phenylbutazone 400-600 mg / day, and has better durability than phenylbutazone.

[0004] The original preparation process for sulindac capsules involved wet mixing sulindac with other excipients, using hypromellose as a binder, wet granulation, oven drying the wet granules, and then granulating them before filling them into capsules. The wet granulation process presented the following problems:

[0005] (1) The binder is hypromellose, and the resulting granules are highly viscous, resulting in low dissolution. The dissolution curve in pH 4.0 + 0.3% SDS medium is not similar to that of the reference preparation.

[0006] (2) The wet granules are dried in an oven, which takes a long time and requires manual turning, resulting in low efficiency.

[0007] (3) The prepared particles have poor wettability and will float on the water surface, which may lead to low dissolution due to insufficient wettability. Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the technical defects of the background art and provide a sulindac capsule and a preparation method thereof. The present invention meets the requirements of the sulindac preparation process by selecting suitable excipients; the present invention uses water as a wetting agent for wet granulation to obtain sulindac granules with an appropriate particle size and moderate viscosity; the present invention uses the surfactant sodium lauryl sulfate to increase the wettability of the granules and improve in vitro dissolution. The resulting sulindac capsule has a paddle dissolution curve at 75 rpm in a pH 4.0 + 0.3% SDS medium that is consistent with that of a reference preparation.

[0009] The technical solutions adopted by the present invention to solve the above technical problems are as follows:

[0010] A method for preparing sulindac capsules comprises the following steps: weighing → mixing 1 → wet granulation → wet granulation → drying → dry granulation → mixing 2 → total mixing → capsule filling → packaging:

[0011] (1) Weighing: Weigh the raw materials and excipients according to the prescribed amount of each sulindac capsule, namely, 100 mg of sulindac, 30-70 mg of microcrystalline cellulose, 0.2-40 mg of starch, 0.17-1.51 mg of sodium lauryl sulfate, and 0.5-1.0 mg of magnesium stearate, and set aside;

[0012] (2) Mixing 1: Add all the sulindac, microcrystalline cellulose, and starch from step (1) into a wet granulator and mix;

[0013] (3) Wet granulation: Start stirring, spray purified water, start shearing knife, granulate, and obtain material a for later use;

[0014] (4) Wet granulation: sieve the material a in step (3) to obtain material b for later use;

[0015] (5) Drying: The material b in step (4) is subjected to boiling drying to obtain material c, which is set aside;

[0016] (6) Dry granulation: Dry granulate the material c described in step (5) with a sieve to obtain material d, which is set aside;

[0017] (7) Mixing 2: Add the material d described in step (6) and all the sodium lauryl sulfate in step (1) into a mixer and mix them evenly to obtain material e, which is set aside;

[0018] (8) Total mixing: The material e described in step (7) and all the magnesium stearate in step (1) are mixed uniformly in a mixer to obtain material f, which is set aside;

[0019] (9) Capsule canning: The material f described in step (8) is capsule canned to obtain capsules;

[0020] (10) Packaging: Packing the capsules described in step (9) to obtain the product.

[0021] Preferably, in step (1), raw materials and auxiliary materials are weighed according to the prescription amount of each sulindac capsule, namely 100 mg of sulindac, 32.52-66.12 mg of microcrystalline cellulose, 0.2-33.80 mg of starch, 0.17-1.51 mg of sodium lauryl sulfate, and 0.84 mg of magnesium stearate, and set aside.

[0022] Preferably, in step (1), the microcrystalline cellulose is microcrystalline cellulose PH101.

[0023] Preferably, in step (1), the starch is pregelatinized starch.

[0024] Preferably, in step (2), the rotation speed during mixing is 150 to 250 rpm, and the mixing time is 1 to 10 minutes.

[0025] More preferably, in step (2), the rotation speed during mixing is 200 rpm and the mixing time is 5 min.

[0026] Preferably, in step (3), the stirring speed is 150-250 rpm, the shearing speed of the shearing knife is 800-2000 rpm, the amount of water added is 70-130 mg / granule, and the granulation time is 0.5-5 min; the amount of water added is more preferably 80-95 mg / granule.

[0027] More preferably, in step (3), the stirring speed is 200 rpm, the shearing speed of the shearing knife is 1500 rpm, the amount of water added is 95 mg / granule, and the granulation time is 1 min.

[0028] Preferably, in step (4), the mesh size of the sieve is 4 to 24 meshes.

[0029] Preferably, in step (4), the screen is made of nylon or stainless steel.

[0030] Preferably, in step (5), the air inlet temperature during drying is 60-85° C., and the loss on drying (LOD) is ≤3%.

[0031] Preferably, in step (6), the pore size of the sieve is 0.8 to 2.0 mm.

[0032] More preferably, in step (6), the pore size of the sieve is 1.0 mm.

[0033] Preferably, in step (6), the screen is made of stainless steel.

[0034] Preferably, in step (7), the mixing time is 1 to 20 minutes.

[0035] More preferably, in step (7), the mixing time is 10 minutes.

[0036] Preferably, in step (8), the mixing time is 1 to 20 minutes.

[0037] Preferably, in step (10), the packaging is aluminum-plastic packaging.

[0038] A sulindac capsule. According to the prescription quantity, each sulindac capsule comprises 100 mg of sulindac, 30-70 mg of microcrystalline cellulose, 0.2-40 mg of starch, 0.17-1.51 mg of sodium lauryl sulfate, and 0.5-1.0 mg of magnesium stearate. According to the prescription quantity, the total content of each sulindac capsule is 130.87-212.51 mg.

[0039] More preferably, according to the prescription amount, the formula of each sulindac capsule includes 100 mg of sulindac, 32.52-66.12 mg of microcrystalline cellulose, 0.2-33.80 mg of starch, 0.17-1.51 mg of sodium lauryl sulfate, and 0.84 mg of magnesium stearate; according to the prescription amount, the total content of each sulindac capsule is 133.73-202.27 mg.

[0040] A sulindac capsule comprises the following raw and auxiliary materials: 100 mg of sulindac, 30-70 mg of microcrystalline cellulose, 0.2-40 mg of starch, 0.17-1.51 mg of sodium lauryl sulfate, and 0.5-1.0 mg of magnesium stearate.

[0041] More preferably, the raw material and auxiliary material composition of the sulindac capsule prescription is: sulindac 100 mg, microcrystalline cellulose 32.52-66.12 mg, starch 0.2-33.80 mg, sodium lauryl sulfate 0.17-1.51 mg, and magnesium stearate 0.84 mg.

[0042] In the above technical solution, the microcrystalline cellulose is a filler.

[0043] In the above technical solution, the starch is a disintegrant.

[0044] In the above technical solution, the sodium lauryl sulfate is a surfactant.

[0045] In the above technical solution, the magnesium stearate is a lubricant.

[0046] In the above technical solution, the water is a wetting agent.

[0047] Basic principles of the present invention:

[0048] The technical solution provided by the present invention is to improve the dissolution rate of sulindac capsule preparations. The particles in sulindac capsules do not undergo a tabletting process, but are directly canned from powder particles. Due to the larger specific surface area of the powder particles, their wettability is not as good as that of tablets. In addition, since the capsule itself disintegrates at a slower rate than that of tablets, the capsule dissolution is slower than that of tablets, and in vivo absorption may be slow due to wettability issues. The present invention uses a wet granulation process, optimizes the process of preparing the adhesive solution by screening the types and types of excipients, and avoids the problem of a low dissolution curve of the sulindac capsules due to the high viscosity of the adhesive solution in the original prescription. By adding the surfactant sodium lauryl sulfate, the lipophilic and hydrophilic properties of sodium lauryl sulfate are utilized to reduce the surface tension between the powder particles and the dissolution medium, increase the wettability of the particles in the dissolution medium after the sulindac capsules are broken, and ensure that the dissolution curve of the sulindac capsules is similar to that of the reference.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] (1) The present invention simplifies the troublesome slurry preparation process by optimizing the wet granulation process and uses purified water for granulation. At the same time, it avoids the problem of granules clumping together due to the adhesive and low dissolution.

[0051] (2) The present invention uses a boiling drying process, which reduces the trouble caused by manual operation;

[0052] (3) The present invention increases the wettability of the particles by adding sodium lauryl sulfate, so that the dissolution curve of the sulindac capsules is consistent with that of the reference preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 This is a comparison chart of the dissolution effects of sulindac capsules prepared in Examples 1 to 10 of the present invention and Comparative Example 1. DETAILED DESCRIPTION

[0054] In order to better understand the content of the present invention, the following is further described in conjunction with specific examples and accompanying drawings. It should be understood that these embodiments are only used to further illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content described in the present invention, those skilled in the art may make some non-essential changes or adjustments to the present invention, which still fall within the scope of protection of the present invention.

[0055] Example 1

[0056] A method for preparing sulindac capsules comprises the following steps:

[0057] (1) Weighing: Weigh the raw materials and excipients according to the prescription amount of 1000 sulindac capsules, namely 100 g of sulindac, 9.32 g of microcrystalline cellulose PH1014, 17.00 g of pregelatinized starch, 0.84 g of sodium lauryl sulfate, and 0.84 g of magnesium stearate, and set aside;

[0058] (2) Mixing 1: Add all the sulindac, microcrystalline cellulose PH101, and pregelatinized starch from step (1) into a wet granulator and mix for 3 min at a speed of 200 rpm;

[0059] (3) Wet granulation: Start stirring at 200 rpm, spray in 88 g of purified water, then start shearing at 1500 rpm, granulate for 1 min, and obtain material a for later use;

[0060] (4) Wet granulation: Pass the material a described in step (3) through a 10-mesh stainless steel sieve for wet granulation to obtain material b, which is set aside;

[0061] (5) Drying: The material b described in step (4) is subjected to boiling drying at an inlet air temperature of 75°C until the moisture content is less than 3.0%, thereby obtaining material c, which is then set aside;

[0062] (6) Dry granulation: The material c described in step (5) is dry granulated using a 1.0 mm stainless steel sieve to obtain material d, which is set aside;

[0063] (7) Mixing 2: Add the material d described in step (6) and all the sodium lauryl sulfate in step (1) into a mixer and mix for 10 minutes to obtain material e, which is set aside;

[0064] (8) Total mixing: Mix the material e described in step (7) and all the magnesium stearate in step (1) in a mixer for 5 minutes to obtain material f, which is set aside;

[0065] (9) Capsule canning: The material f described in step (8) is capsule canned, and No. 3 capsules are used for capsule filling to obtain capsules;

[0066] (10) Packaging: The capsules described in step (9) are packaged in aluminum plastic.

[0067] Example 2

[0068] This example is basically the same as Example 1, except that 49.32 g of microcrystalline cellulose PH101 and 17.00 g of pregelatinized starch in step (1) of Example 1 are replaced with 66.12 g of microcrystalline cellulose PH101 and 0.20 g of pregelatinized starch, respectively.

[0069] Example 3

[0070] This example is substantially the same as Example 1, except that 49.32 g of microcrystalline cellulose PH101 and 17.00 g of pregelatinized starch in step (1) of Example 1 are replaced with 32.52 g of microcrystalline cellulose PH101 and 33.80 g of pregelatinized starch, respectively.

[0071] Example 4

[0072] This example is basically the same as Example 1, except that 149.32 g of microcrystalline cellulose PH10 and 0.84 g of sodium lauryl sulfate in step (1) of Example 1 are replaced with 148.65 g of microcrystalline cellulose PH10 and 1.51 g of sodium lauryl sulfate, respectively.

[0073] Example 5

[0074] This example is basically the same as Example 1, except that 149.32 g of microcrystalline cellulose PH10 and 0.84 g of sodium lauryl sulfate in step (1) of Example 1 are replaced with 149.99 g of microcrystalline cellulose PH10 and 0.17 g of sodium lauryl sulfate, respectively.

[0075] Example 6

[0076] This embodiment is basically the same as embodiment 1, except that the 1.0 mm stainless steel screen in step (6) of embodiment 1 is replaced with a 1.5 mm stainless steel screen.

[0077] Example 7

[0078] This embodiment is basically the same as embodiment 1, except that the step (3) in embodiment 1 in which 88 g of purified water is sprayed is changed to 93 g of purified water.

[0079] Example 8

[0080] This embodiment is basically the same as embodiment 1, except that the step (3) of spraying 88 g of purified water in embodiment 1 is changed to spraying 83 g of purified water.

[0081] Example 9

[0082] This embodiment is basically the same as embodiment 1, except that the stirring at 200 rpm, 88 g of purified water sprayed in, and then the shearing knife at 1500 rpm in step (3) of embodiment 1 is changed to the stirring at 230 rpm, 88 g of purified water sprayed in, and then the shearing knife at 1800 rpm.

[0083] Example 10

[0084] This embodiment is basically the same as embodiment 1, except that the stirring at 200 rpm, 88 g of purified water sprayed in, and the shearing knife at 1500 rpm in step (3) of embodiment 1 is changed to the stirring at 170 rpm, 88 g of purified water sprayed in, and the shearing knife at 1200 rpm.

[0085] Comparative Example 1

[0086] A method for preparing sulindac capsules comprises the following steps:

[0087] (1) Weighing: Weigh the raw materials and excipients according to the prescription amount of 1000 sulindac capsules, namely 100 g of sulindac, 11.20 g of microcrystalline cellulose PH10, 0.40 g of hypromellose, 1.20 g of sodium starch glycolate (internal addition), 1.80 g of sodium starch glycolate (external addition), and 3.30 g of magnesium stearate, and set aside;

[0088] (2) Slurry preparation: Dissolve all the HPMC from step (1) in purified water to prepare 34 g of adhesive solution;

[0089] (3) Mixing 1: Add all the sulindac, microcrystalline cellulose PH101, and sodium starch glycolate (added internally) from step (1) into a wet granulator and mix for 3 min at a speed of 200 rpm;

[0090] (4) Wet granulation: Start stirring at 200 rpm, spray in 34 g of the binder solution, then start the shear blade at 1500 rpm and granulate for 1 min to obtain material a, which is set aside;

[0091] (5) Wet granulation: Pass the material a described in step (4) through a 10-mesh stainless steel sieve for wet granulation to obtain material b, which is set aside;

[0092] (6) Drying: Dry the material b in step (5) in an oven at 75°C until the moisture content is less than 3.0% to obtain material c, which is then used for standby use;

[0093] (7) Dry granulation: The material c described in step (6) is dry granulated using a 1.0 mm stainless steel sieve to obtain material d, which is set aside;

[0094] (8) Mixing 2: Add the material d described in step (7) and all the sodium carboxymethyl starch (added) in step (1) into a mixer and mix for 10 minutes to obtain material e, which is set aside;

[0095] (9) Total mixing: Mix the material e described in step (8) and all the magnesium stearate in step (1) in a mixer for 5 minutes to obtain material f, which is set aside;

[0096] (10) Capsule canning: The material f described in step (9) is capsule canned, and No. 3 capsules are used for capsule filling to obtain capsules;

[0097] (11) Packaging: The capsules described in step (10) are packaged in aluminum plastic.

[0098] Effect evaluation experiment

[0099] Dissolution determination: The compositions (capsules) obtained in Examples 1 to 10 and Comparative Example 1 were compared in vitro with a reference preparation (Batch No.: 0239A241, manufacturer: WATSON). Dissolution curve method: paddle method; dissolution medium: pH 4.0 + 0.3% SDS medium; dissolution volume: 900 ml; rotation speed: 75 rpm; absorption wavelength: 327 nm; sampling time: 5 min, 10 min, 15 min, 30 min, 45 min, 60 min, 90 min, 120 min.

[0100] The comparative table and comparative graph of the dissolution effects of the sulindac capsules prepared in Examples 1 to 10 of the present invention and Comparative Example 1 are shown in Tables 1 and 2, respectively. Figure 1 .

[0101] Table 1 Comparative table of dissolution effects of sulindac capsules prepared in Examples 1 to 10 of the present invention and Comparative Example 1

[0102]

[0103] Note: f2 represents the similarity factor with the reference preparation, which is calculated at time points of 5min, 10min, 15min, 30min, 45min, 60min, 90min, and 120min. An f2 greater than 50 indicates that the dissolution performance is similar to that of the reference preparation in vitro under the dissolution conditions.

[0104] From Table 1 and Figure 1 It can be seen that compared with Comparative Example 1, the compositions (capsules) prepared in Examples 1 to 10 have better dissolution properties, and f2 is greater than 50, which is similar to the reference preparation; among them, the composition (capsule) prepared in Example 5 has the highest similarity to the reference preparation.

[0105] The above dissolution experiments show that, compared with the prior art sulindac capsule preparation process, the sulindac capsules prepared by the present invention exhibit excellent product quality, which is a significant improvement over the prior art.

[0106] The technical solution provided by the present invention is to improve the dissolution rate of sulindac capsule preparations. The particles in sulindac capsules do not undergo a tabletting process, but are directly canned from powder particles. Due to the larger specific surface area of the powder particles, their wettability is not as good as that of tablets. In addition, since the capsule itself disintegrates at a slower rate than that of tablets, the capsule dissolution is slower than that of tablets, and in vivo absorption may be slow due to wettability issues. The present invention uses a wet granulation process, optimizes the process of preparing the adhesive solution by screening the types and types of excipients, and avoids the problem of a low dissolution curve of the sulindac capsules due to the high viscosity of the adhesive solution in the original prescription. By adding the surfactant sodium lauryl sulfate, the lipophilic and hydrophilic properties of sodium lauryl sulfate are utilized to reduce the surface tension between the powder particles and the dissolution medium, increase the wettability of the particles in the dissolution medium after the sulindac capsules are broken, and ensure that the dissolution curve of the sulindac capsules is similar to that of the reference.

[0107] Compared with the prior art, the present invention has the following beneficial effects:

[0108] (1) The present invention simplifies the troublesome slurry preparation process by optimizing the wet granulation process and uses purified water for granulation. At the same time, it avoids the problem of granules clumping together due to the adhesive and low dissolution.

[0109] (2) The present invention uses a boiling drying process, which reduces the trouble caused by manual operation;

[0110] (3) The present invention increases the wettability of the particles by adding sodium lauryl sulfate, so that the dissolution curve of the sulindac capsules is consistent with that of the reference preparation.

[0111] The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Any changes, modifications, additions or substitutions made by persons of ordinary skill in the art within the spirit and scope of the present invention shall also fall within the scope of protection of the present invention.

Claims

1. A sulindac capsule, characterized in that: The components include 100 mg of sulindac, 30-70 mg of microcrystalline cellulose, 0.2-40 mg of starch, 0.17-1.51 mg of sodium lauryl sulfate, and 0.5-1.0 mg of magnesium stearate. According to the prescription amount, the total content of each sulindac capsule is 130.87-212.51 mg.

2. The method for preparing sulindac capsules according to claim 1, wherein The following steps are involved: (1) Weighing: weigh the raw materials and set aside; (2) Mixing 1: Add all the sulindac, microcrystalline cellulose, and starch from step (1) into a wet granulator and mix; (3) Wet granulation: Start stirring, spray purified water, start shearing knife, granulate, and obtain material a for later use; (4) Wet granulation: sieve the material a in step (3) to obtain material b for later use; (5) Drying: The material b in step (4) is subjected to boiling drying to obtain material c, which is set aside; (6) Dry granulation: Dry granulate the material c described in step (5) with a sieve to obtain material d, which is set aside; (7) Mixing 2: Add the material d described in step (6) and all the sodium lauryl sulfate in step (1) into a mixer and mix them evenly to obtain material e, which is set aside; (8) Total mixing: The material e described in step (7) and all the magnesium stearate in step (1) are mixed uniformly in a mixer to obtain material f, which is set aside; (9) Capsule canning: The material f described in step (8) is capsule canned to obtain capsules; (10) Packaging: Packing the capsules described in step (9) to obtain; In step (1), the microcrystalline cellulose is microcrystalline cellulose PH101; In step (2), the rotation speed during mixing is 150-250 rpm, and the mixing time is 1-10 min; in step (3), the rotation speed during stirring is 150-250 rpm, the shearing speed of the shearing knife is 800-2000 rpm, the amount of water added is 70-130 mg / granule, and the granulation time is 0.5-5 min; In step (5), the air inlet temperature during drying is 60-85° C., and the loss on drying (LOD) is ≤3%; In step (7), the mixing time is 1 to 20 minutes; in step (8), the mixing time is 1 to 20 minutes.

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