Epalrestat gastric floating tablet, preparation method and application thereof

Abstract

The present invention relates to an epalrestat gastric floating tablet, which is composed of a sustained-release layer and a quick-release layer, wherein, by weight percentage, the quick-release layer contains 30-55% (w / w) of epalrestat or its derivatives, and the sustained-release layer contains 20-50% (w / w) of epalrestat or its derivatives, and the derivatives are selected from any one or a combination of cocrystals, salts, free acids, prodrugs, esters, polymorphs, and solvates. The epalrestat gastric floating tablet of the present invention has the advantages of good floating performance, long-acting sustained release, good quality uniformity, good stability, small variability, high bioavailability, etc., and significantly improves the patient's medication compliance and the safety and effectiveness of medication.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine, and specifically relates to an epalrestat gastric floating tablet, a preparation method thereof and an application thereof. Background Art

[0002] Epalrestat (5-[(1Z,2E)-2-methyl-3-phenyl-2-propenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid) is an aldose reductase inhibitor drug that reversibly inhibits the aldose reductase that converts glucose into sorbitol in the metabolism of polyols related to the pathogenesis of diabetic complications. Sorbitol can affect the function of nerve cells, and accumulation in neurons can cause symptoms of diabetic peripheral neuropathy that control sensory motor function. Epalrestat is clinically used to inhibit the accumulation of sorbitol in red blood cells of patients with diabetic peripheral neuropathy to improve patients' subjective symptoms and nerve dysfunction, and to prevent, improve and treat diabetes and its complications of peripheral nerve disorders (numbness, pain). However, patients need to take epalrestat tablets or epalrestat capsules three times a day. Taking medicine multiple times a day reduces patients' compliance with medication, and easily leads to patients missing medication, resulting in increased blood sugar, and even causing problems such as diabetic ketoacidosis (DKA). There is also a poor control of fasting blood sugar, postprandial blood sugar, and nighttime blood sugar, which leads to the incidence of hypoglycemia, affecting the therapeutic effect of the drug and the safety and effectiveness of the medication. The epalrestat gastric floating tablets reported in the literature require the addition of gas-generating agents (such as sodium bicarbonate, etc.) and bleaching agents (such as octadecyl alcohol, etc.), and have defects such as high cost and complex preparation. For this reason, it is necessary to develop a safe and effective epalrestat sustained-release preparation to meet clinical treatment needs. Summary of the invention

[0003] The object of the present invention is to provide an epalrestat gastric floating tablet, which consists of a sustained-release layer and a quick-release layer, wherein, by weight percentage, the quick-release layer contains 30-55% (w / w) of epalrestat or its derivatives, and the sustained-release layer contains 20-50% (w / w) of epalrestat or its derivatives, and the derivatives are selected from any one or a combination of cocrystals, salts, free acids, prodrugs, esters, polymorphs, and solvates.

[0004] In a preferred technical solution of the present invention, the mass ratio of the sustained-release layer to the immediate-release layer in the gastric floating tablet is 1-8:1, preferably 2-6:1.

[0005] In a preferred technical solution of the present invention, the mass ratio of epalrestat in the sustained-release layer to epalrestat in the immediate-release layer is 1-5:1, preferably 2-4:1.

[0006] According to a preferred technical solution of the present invention, the immediate-release layer contains 35-50% epalrestat, preferably 40-45% by weight.

[0007] In a preferred technical solution of the present invention, the pharmaceutically acceptable carrier contained in the immediate-release layer is selected from any one of a filler, a disintegrant, a binder, a lubricant, or a combination thereof.

[0008] In a preferred technical solution of the present invention, the filler is selected from any one of starch, sucrose, pregelatinized starch, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, and microcrystalline cellulose, or a combination thereof.

[0009] In a preferred technical solution of the present invention, the immediate-release layer contains 30-55% filler by weight, preferably 32-50%, and more preferably 35-47%.

[0010] In a preferred technical solution of the present invention, the disintegrant is selected from any one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked calcium carboxymethyl cellulose, or a combination thereof.

[0011] In a preferred technical solution of the present invention, the disintegrant contained in the immediate-release layer is 1-10% by weight, preferably 1.2-9.5%, and more preferably 1.4-9%.

[0012] In the preferred technical solution of the present invention, the adhesive is selected from any one of hydroxypropyl cellulose, low viscosity cellulose, acrylic polymer, hyaluronic acid, alginic acid, polysaccharide, polysaccharide glycoside, hydroxypropyl methylcellulose, starch slurry, methyl cellulose, ethyl cellulose, povidone, polyvinyl pyrrolidone or a combination thereof.

[0013] In a preferred technical solution of the present invention, the binder contained in the quick-release layer is 1-15% by weight, preferably 2-13%, and more preferably 5-12%.

[0014] In a preferred technical solution of the present invention, the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycols, and sodium lauryl sulfate, or a combination thereof.

[0015] In a preferred technical solution of the present invention, the lubricant contained in the quick-release layer is 1-10% by weight, preferably 1.5-8%, and more preferably 2-5%.

[0016] In the preferred technical solution of the present invention, the immediate-release layer contains, by weight percentage, 30-55% epalrestat, 30-55% filler, 1-10% disintegrant, 1-15% binder and 1-10% lubricant.

[0017] In the preferred technical solution of the present invention, the immediate-release layer contains 35-50% epalrestat, 32-50% filler, 1.2-9.5% disintegrant, 2-13% binder and 1.5-8% lubricant by weight percentage.

[0018] In the preferred technical solution of the present invention, the immediate-release layer contains, by weight percentage, 40-45% epalrestat, 35-47% filler, 1.4-9% disintegrant, 5-12% binder and 2-5% lubricant.

[0019] In the preferred technical scheme of the present invention, the immediate-release layer contains, by weight percentage, 30-55% epalrestat, 30-55% lactose or microcrystalline cellulose, 1-10% of any one of cross-linked carboxymethyl cellulose sodium, cross-linked povidone, and low-substituted hydroxypropyl cellulose, 1-15% hydroxypropyl cellulose or polyvinyl pyrrolidone, 1-5% magnesium stearate, and 1-5% sodium lauryl sulfate.

[0020] In the preferred technical scheme of the present invention, the immediate-release layer contains, by weight percentage, 35-50% epalrestat, 32-50% lactose or microcrystalline cellulose, 1.2-9.5% of any one of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, and low-substituted hydroxypropyl cellulose, 2-13% hydroxypropyl cellulose or polyvinyl pyrrolidone, 1-5% magnesium stearate, and 1-5% sodium lauryl sulfate.

[0021] In the preferred technical scheme of the present invention, the immediate-release layer contains, by weight percentage, 40-45% epalrestat, 35-47% lactose or microcrystalline cellulose, 1.4-9% of any one of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, and low-substituted hydroxypropyl cellulose, 5-12% hydroxypropyl cellulose or polyvinyl pyrrolidone, 1-5% magnesium stearate, and 1-5% sodium lauryl sulfate.

[0022] In the preferred technical solution of the present invention, the immediate release layer contains, by weight percentage, 41.7% epalrestat, 46.5% lactose, 2.5% cross-linked sodium carboxymethyl cellulose, 5.8% hydroxypropyl cellulose, 1.5% magnesium stearate and 2% sodium lauryl sulfate.

[0023] In the preferred technical solution of the present invention, the immediate-release layer contains, by weight percentage, 41.7% epalrestat, 35.1% microcrystalline cellulose, 8.3% crospovidone, 11.4% polyvinyl pyrrolidone, 1.5% magnesium stearate and 2% sodium lauryl sulfate.

[0024] In the preferred technical solution of the present invention, the immediate release layer contains, by weight percentage, 41.7% epalrestat, 47.6% microcrystalline cellulose, 1.4% crospovidone, 5.8% hydroxypropyl cellulose, 1.5% magnesium stearate and 2% sodium lauryl sulfate.

[0025] In the preferred technical solution of the present invention, the immediate release layer contains, by weight percentage, 41.7% epalrestat, 44.8% microcrystalline cellulose, 4.2% low-substituted hydroxypropyl cellulose, 5.8% hydroxypropyl cellulose, 1.5% magnesium stearate and 2% sodium lauryl sulfate.

[0026] In the preferred technical solution of the present invention, the sustained-release layer contains 20-50% of epalrestat or its derivatives and a pharmaceutically acceptable carrier by weight, wherein the pharmaceutically acceptable carrier is selected from any one of hydrogel materials, skeleton materials, fillers, disintegrants, adhesives, lubricants, and glidants, or a combination thereof.

[0027] In a preferred technical solution of the present invention, the content of epalrestat or its derivatives in the sustained-release layer is 25-45% by weight, preferably 30-40%.

[0028] In a preferred technical solution of the present invention, the hydrogel material in the sustained-release layer is 5-20% by weight, preferably 8-18%, and more preferably 9-15%.

[0029] In the preferred technical scheme of the present invention, the hydrogel material is selected from any one of polyvinyl alcohol, water-swellable cellulose, carrageenan, xanthan gum, guar gum, gum arabic, polyvinyl acetate, carbomer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), hydroxypropyl methylcellulose K4M, hydroxyethyl cellulose, alginate, polyethylene oxide, carboxymethyl cellulose, povidone, chitosan or a combination thereof.

[0030] In a preferred technical solution of the present invention, the skeleton material in the sustained-release layer is 5-20% by weight, preferably 8-18%, and more preferably 10-15%.

[0031] In a preferred technical solution of the present invention, the skeleton material is selected from any one of water-insoluble cellulose, polyvinyl pyrrolidone, acrylic resin, polyacrylate, ethyl cellulose, and ethyl cellulose N10, or a combination thereof.

[0032] In a preferred technical solution of the present invention, the filler in the sustained-release layer is 5-40% by weight, preferably 10-35%, and more preferably 15-30%.

[0033] In a preferred technical solution of the present invention, the filler is selected from any one of starch, sucrose, pregelatinized starch, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose, microcrystalline cellulose SH-101, and microcrystalline cellulose 102, or a combination thereof.

[0034] In a preferred technical solution of the present invention, the disintegrant in the sustained-release layer is 10-35% by weight, preferably 12-30%, and more preferably 15-20%.

[0035] In a preferred technical solution of the present invention, the disintegrant is selected from any one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked calcium carboxymethyl cellulose, or a combination thereof.

[0036] In a preferred technical solution of the present invention, the binder in the sustained-release layer is 0-5% by weight, preferably 0.5-2.5%, and more preferably 1.5-2%.

[0037] In the preferred technical scheme of the present invention, the adhesive is selected from any one of low-viscosity cellulose, acrylic polymer, hyaluronic acid, alginic acid, polysaccharides, polysaccharide glycosides, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, starch slurry, methyl cellulose, ethyl cellulose, and povidone, or a combination thereof.

[0038] In a preferred technical solution of the present invention, the lubricant in the sustained-release layer is 0.1-2% by weight, preferably 0.15-1.8%, and more preferably 0.2-0.5%.

[0039] In a preferred technical solution of the present invention, the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycols, and sodium lauryl sulfate, or a combination thereof.

[0040] In a preferred technical solution of the present invention, the glidant in the sustained-release layer is 0-1% by weight, preferably 0.2-0.8%, and more preferably 0.4-0.6%.

[0041] In a preferred technical solution of the present invention, the glidant is selected from any one of colloidal silicon dioxide, talcum powder, and micro-powdered silica gel, or a combination thereof.

[0042] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 20-50% epalrestat, 5-20% hydrogel material, 5-20% skeleton material, 5-40% filler, 10-35% disintegrant, 0-5% binder, 0.1-2% lubricant and 0-1% glidant.

[0043] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 25-45% epalrestat, 8-18% hydrogel material, 8-18% skeleton material, 10-35% filler, 12-30% disintegrant, 0.5-2.5% binder, 0.15-1.8% lubricant and 0.2-0.8%.

[0044] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 30-40% epalrestat, 9-15% hydrogel material, 10-15% skeleton material, 15-30% filler, 15-20% disintegrant, 1.5-2% binder, 0.2-0.5% lubricant and 0.4-0.6% glidant.

[0045] In the preferred technical scheme of the present invention, the sustained-release layer contains, by weight percentage, 20-50% epalrestat, 5-40% microcrystalline cellulose, 5-20% hypromellose, 5-20% ethyl cellulose, 10-35% cross-linked polyvinylpyrrolidone, 0.1-2% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0-1% colloidal silicon dioxide.

[0046] In the preferred technical scheme of the present invention, the sustained-release layer contains, by weight percentage, 25-45% epalrestat, 10-35% microcrystalline cellulose, 8-18% hypromellose, 8-18% ethyl cellulose, 12-30% cross-linked polyvinylpyrrolidone, 0.15-1.8% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.2-0.8% colloidal silicon dioxide.

[0047] In the preferred technical scheme of the present invention, the sustained-release layer contains, by weight percentage, 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hypromellose, 10-15% ethyl cellulose, 15-20% cross-linked polyvinylpyrrolidone, 0.2-0.5% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.4-0.6% colloidal silicon dioxide.

[0048] In the preferred technical scheme of the present invention, the sustained-release layer contains, by weight percentage, 20-50% epalrestat, 5-40% microcrystalline cellulose, 5-20% hydroxypropyl methylcellulose, 5-20% ethyl cellulose, 1-5% hydroxypropyl cellulose, 10-35% cross-linked polyvinylpyrrolidone, 0.1-2% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.1-1% colloidal silicon dioxide.

[0049] In the preferred technical scheme of the present invention, the sustained-release layer contains, by weight percentage, 25-45% epalrestat, 10-35% microcrystalline cellulose, 8-18% hydroxypropyl methylcellulose, 8-18% ethyl cellulose, 1-5% hydroxypropyl cellulose, 12-30% cross-linked polyvinylpyrrolidone, 0.15-1.8% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.2-0.8% colloidal silicon dioxide.

[0050] In the preferred technical scheme of the present invention, the sustained-release layer contains, by weight percentage, 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hydroxypropyl methylcellulose, 10-15% ethyl cellulose, 1-5% hydroxypropyl cellulose, 15-20% cross-linked polyvinylpyrrolidone, 0.2-0.5% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.4-0.6% colloidal silicon dioxide.

[0051] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 34.88% epalrestat, 9.30% microcrystalline cellulose, 13.95% hypromellose K4M, 16.28% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% magnesium stearate.

[0052] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 34.88% epalrestat, 11.63% microcrystalline cellulose, 12.79% hypromellose K4M, 15.12% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% magnesium stearate.

[0053] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 34.88% epalrestat, 6.98% microcrystalline cellulose, 12.79% hypromellose K4M, 15.12% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0054] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 34.88% epalrestat, 11.62% microcrystalline cellulose, 10.47% hypromellose K4M, 12.79% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0055] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 34.88% epalrestat, 9.30% microcrystalline cellulose, 13.95% hypromellose K4M, 16.28% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% sodium stearyl fumarate.

[0056] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 34.88% epalrestat, 13.95% microcrystalline cellulose, 9.30% hypromellose K4M, 11.63% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0057] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 34.88% epalrestat, 15.12% microcrystalline cellulose, 8.72% hypromellose K4M, 11.05% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0058] In the preferred technical solution of the present invention, by weight percentage, the sustained-release layer contains 34.88% epalrestat, 13.60% microcrystalline cellulose, 10.47% hypromellose K4M, 11.63% ethyl cellulose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0059] In the preferred technical solution of the present invention, the sustained-release layer contains, by weight percentage, 31.25% epalrestat, 30.31% microcrystalline cellulose, 9.9% hypromellose K4M, 10.42% ethyl cellulose, 0.73% hypromellose E5, 16.67% crospovidone, 0.52% magnesium stearate and 0.21% colloidal silicon dioxide.

[0060] In the preferred technical solution of the present invention, the sustained-release layer contains, by weight percentage, 30% epalrestat, 27.9% microcrystalline cellulose, 9% hypromellose K4M, 11% ethyl cellulose, 1.5% hypromellose E5, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0061] In the preferred technical solution of the present invention, the sustained-release layer contains, by weight percentage, 30% epalrestat, 27.4% microcrystalline cellulose, 9% hydroxypropyl methylcellulose, 11% ethyl cellulose, 2% hydroxypropyl cellulose, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0062] In the preferred technical solution of the present invention, the sustained-release layer contains, by weight percentage, 30% epalrestat, 22.4% microcrystalline cellulose, 11% hydroxypropyl methylcellulose, 14% ethyl cellulose, 2% hydroxypropyl cellulose, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0063] In the preferred technical solution of the present invention, the sustained-release layer contains, by weight percentage, 30% epalrestat, 26.6% microcrystalline cellulose, 12% hydroxypropyl methylcellulose, 14% ethyl cellulose, 1% hydroxypropyl cellulose, 16% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.2% colloidal silicon dioxide.

[0064] In the preferred technical solution of the present invention, the sustained-release layer contains, by weight percentage, 31.3% epalrestat, 27.7% microcrystalline cellulose, 12.5% ​​hydroxypropyl methylcellulose, 14.6% ethyl cellulose, 1% hydroxypropyl cellulose, 12.5% ​​cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.2% colloidal silicon dioxide.

[0065] In a preferred technical solution of the present invention, the sustained-release layer optionally contains a solvent, and the solvent is preferably selected from any one of water and ethanol or a combination thereof.

[0066] In a preferred technical solution of the present invention, the floating time of the gastric floating tablet in simulated gastric fluid (pH 1.2) is ≤ 5 min.

[0067] In a preferred technical solution of the present invention, the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 8 hours is ≥85%, preferably ≥90%.

[0068] In a preferred technical solution of the present invention, the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 12 hours is ≥90%, preferably ≥95%.

[0069] Another object of the present invention is to provide a method for preparing an epalrestat gastric floating tablet, wherein the gastric floating tablet consists of a sustained-release layer and a quick-release layer, wherein, by weight percentage, the quick-release layer contains 30-55% (w / w) of epalrestat or its derivatives, and the sustained-release layer contains 20-50% (w / w) of epalrestat or its derivatives, and the derivatives are selected from any one of cocrystals, salts, free acids, prodrugs, esters, polymorphs, and solvates, or a combination thereof, and the mass ratio of the sustained-release layer to the quick-release layer in the gastric floating tablet is 1-8:1. The method comprises the following steps: placing the separately prepared sustained-release layer and quick-release layer in a double-layer tablet press, and tableting to obtain the tablet.

[0070] In a preferred technical solution of the present invention, the mass ratio of the sustained-release layer to the immediate-release layer in the gastric floating tablet is 2-6:1.

[0071] In a preferred technical solution of the present invention, the mass ratio of epalrestat in the sustained-release layer to epalrestat in the immediate-release layer is 1-5:1, preferably 2-4:1.

[0072] In a preferred technical solution of the present invention, the preparation of the quick-release layer comprises the following steps: weighing the required amounts of components and uniformly mixing them to obtain the quick-release layer.

[0073] In a preferred technical solution of the present invention, the preparation of the sustained-release layer comprises the following steps: weighing the required amounts of components and uniformly mixing them to obtain the sustained-release layer.

[0074] In the preferred technical scheme of the present invention, the preparation of the sustained-release layer comprises the following steps: 1) weighing the required amount of epalrestat, filler, hydrogel material, skeleton material, disintegrant, any one or a combination thereof, uniformly mixing, adding solvent, granulating, drying, and obtaining dry granules; 2) uniformly mixing the obtained dry granules with the required amount of binder, lubricant, glidant, any one or a combination thereof, wherein the solvent is selected from any one or a combination of water and ethanol.

[0075] In a preferred technical solution of the present invention, the drying is selected from any one of reduced pressure drying, vacuum drying and spray drying.

[0076] In the preferred technical solution of the present invention, the drying temperature is 55-75°C, preferably 60-70°C.

[0077] In a preferred technical solution of the present invention, the moisture content of the dry particles is ≤5.0%, preferably ≤3.0%.

[0078] The object of the present invention is to provide an epalrestat sustained-release composition, which contains 20-50% of epalrestat or its derivatives and a pharmaceutically acceptable carrier in weight percentage, wherein the derivative is selected from any one or a combination of cocrystals, salts, free acids, prodrugs, esters, polymorphs, and solvates, and the pharmaceutically acceptable carrier is selected from any one or a combination of hydrogel materials, skeleton materials, fillers, disintegrants, adhesives, lubricants, and glidants.

[0079] According to a preferred technical solution of the present invention, the content of epalrestat or its derivatives in the composition is 25-45% by weight, preferably 30-40% by weight.

[0080] In the preferred technical solution of the present invention, the hydrogel material in the composition is 5-20% by weight, preferably 8-18%, and more preferably 9-15%.

[0081] In the preferred technical scheme of the present invention, the hydrogel material is selected from any one of polyvinyl alcohol, water-swellable cellulose, carrageenan, xanthan gum, guar gum, gum arabic, polyvinyl acetate, carbomer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), hydroxypropyl methylcellulose K4M, hydroxyethyl cellulose, alginate, polyethylene oxide, carboxymethyl cellulose, povidone, chitosan or a combination thereof.

[0082] In a preferred technical solution of the present invention, the skeleton material in the composition is 5-20% by weight, preferably 8-18%, and more preferably 10-15%.

[0083] In a preferred technical solution of the present invention, the skeleton material is selected from any one of water-insoluble cellulose, polyvinyl pyrrolidone, acrylic resin, polyacrylate, ethyl cellulose, and ethyl cellulose N10, or a combination thereof.

[0084] In the preferred technical solution of the present invention, the filler in the composition is 5-40% by weight, preferably 10-35%, and more preferably 15-30%.

[0085] In a preferred technical solution of the present invention, the filler is selected from any one of starch, sucrose, pregelatinized starch, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose, microcrystalline cellulose SH-101, and microcrystalline cellulose 102, or a combination thereof.

[0086] In a preferred technical solution of the present invention, the disintegrant in the composition is 10-35% by weight, preferably 12-30%, more preferably 15-20%.

[0087] In a preferred technical solution of the present invention, the disintegrant is selected from any one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked calcium carboxymethyl cellulose, or a combination thereof.

[0088] In a preferred technical solution of the present invention, the binder in the composition is 0-5% by weight, preferably 0.5-2.5%, and more preferably 1.5-2%.

[0089] In the preferred technical scheme of the present invention, the adhesive is selected from any one of low-viscosity cellulose, acrylic polymer, hyaluronic acid, alginic acid, polysaccharides, polysaccharide glycosides, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, starch slurry, methyl cellulose, ethyl cellulose, and povidone, or a combination thereof.

[0090] In the preferred technical solution of the present invention, the lubricant in the composition is 0.1-2% by weight, preferably 0.15-1.8%, and more preferably 0.2-0.5%.

[0091] In a preferred technical solution of the present invention, the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycols, and sodium lauryl sulfate, or a combination thereof.

[0092] In a preferred technical solution of the present invention, the glidant in the composition is 0-1% by weight, preferably 0.2-0.8%, and more preferably 0.4-0.6%.

[0093] In a preferred technical solution of the present invention, the glidant is selected from any one of colloidal silicon dioxide, talcum powder, and micro-powdered silica gel, or a combination thereof.

[0094] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 20-50% epalrestat, 5-20% hydrogel material, 5-20% skeleton material, 5-40% filler, 10-35% disintegrant, 0-5% binder, 0.1-2% lubricant and 0-1% glidant.

[0095] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 25-45% epalrestat, 8-18% hydrogel material, 8-18% skeleton material, 10-35% filler, 12-30% disintegrant, 0.5-2.5% binder, 0.15-1.8% lubricant and 0.2-0.8% glidant.

[0096] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 30-40% epalrestat, 9-15% hydrogel material, 10-15% skeleton material, 15-30% filler, 15-20% disintegrant, 1.5-2% binder, 0.2-0.5% lubricant and 0.4-0.6% glidant.

[0097] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 20-50% epalrestat, 5-40% microcrystalline cellulose, 5-20% hypromellose, 5-20% ethyl cellulose, 10-35% cross-linked polyvinylpyrrolidone, 0.1-2% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0-1% colloidal silicon dioxide.

[0098] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 25-45% epalrestat, 10-35% microcrystalline cellulose, 8-18% hypromellose, 8-18% ethyl cellulose, 12-30% cross-linked polyvinylpyrrolidone, 0.15-1.8% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.2-0.8% colloidal silicon dioxide.

[0099] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hypromellose, 10-15% ethyl cellulose, 15-20% cross-linked polyvinylpyrrolidone, 0.2-0.5% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.4-0.6% colloidal silicon dioxide.

[0100] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 20-50% epalrestat, 5-40% microcrystalline cellulose, 5-20% hydroxypropyl methylcellulose, 5-20% ethyl cellulose, 1-5% hydroxypropyl cellulose, 10-35% cross-linked polyvinylpyrrolidone, 0.1-2% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.1-1% colloidal silicon dioxide.

[0101] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 25-45% epalrestat, 10-35% microcrystalline cellulose, 8-18% hydroxypropyl methylcellulose, 8-18% ethyl cellulose, 1-5% hydroxypropyl cellulose, 12-30% cross-linked polyvinylpyrrolidone, 0.15-1.8% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.2-0.8% colloidal silicon dioxide.

[0102] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hydroxypropyl methylcellulose, 10-15% ethyl cellulose, 1-5% hydroxypropyl cellulose, 15-20% cross-linked polyvinylpyrrolidone, 0.2-0.5% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.4-0.6% colloidal silicon dioxide.

[0103] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 9.30% microcrystalline cellulose, 13.95% hypromellose K4M, 16.28% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% magnesium stearate.

[0104] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 11.63% microcrystalline cellulose, 12.79% hypromellose K4M, 15.12% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% magnesium stearate.

[0105] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 6.98% microcrystalline cellulose, 12.79% hypromellose K4M, 15.12% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0106] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 11.62% microcrystalline cellulose, 10.47% hypromellose K4M, 12.79% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0107] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 9.30% microcrystalline cellulose, 13.95% hypromellose K4M, 16.28% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% sodium stearyl fumarate.

[0108] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 13.95% microcrystalline cellulose, 9.30% hypromellose K4M, 11.63% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0109] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 15.12% microcrystalline cellulose, 8.72% hypromellose K4M, 11.05% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0110] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 13.60% microcrystalline cellulose, 10.47% hypromellose K4M, 11.63% ethyl cellulose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0111] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 31.25% epalrestat, 30.31% microcrystalline cellulose, 9.9% hypromellose K4M, 10.42% ethyl cellulose, 0.73% hypromellose E5, 16.67% cross-linked polyvinylpyrrolidone, 0.52% magnesium stearate and 0.21% colloidal silicon dioxide.

[0112] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30% epalrestat, 27.9% microcrystalline cellulose, 9% hypromellose K4M, 11% ethyl cellulose, 1.5% hypromellose E5, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0113] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30% epalrestat, 27.4% microcrystalline cellulose, 9% hydroxypropyl methylcellulose, 11% ethyl cellulose, 2% hydroxypropyl cellulose, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0114] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30% epalrestat, 22.4% microcrystalline cellulose, 11% hydroxypropyl methylcellulose, 14% ethyl cellulose, 2% hydroxypropyl cellulose, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0115] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30% epalrestat, 26.6% microcrystalline cellulose, 12% hydroxypropyl methylcellulose, 14% ethyl cellulose, 1% hydroxypropyl cellulose, 16% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.2% colloidal silicon dioxide.

[0116] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 31.3% epalrestat, 27.7% microcrystalline cellulose, 12.5% ​​hydroxypropyl methylcellulose, 14.6% ethyl cellulose, 1% hydroxypropyl cellulose, 12.5% ​​cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.2% colloidal silicon dioxide.

[0117] In a preferred technical solution of the present invention, the sustained-release composition optionally contains a solvent, and the solvent is preferably selected from any one of water and ethanol or a combination thereof.

[0118] In a preferred technical solution of the present invention, the sustained-release composition is a gastric floating tablet.

[0119] In a preferred technical solution of the present invention, the gastric floating tablet floats immediately in simulated gastric fluid (pH 1.2).

[0120] In a preferred technical solution of the present invention, the floating time of the gastric floating tablet in simulated gastric fluid (pH 1.2) is ≥8h, preferably ≥24h, and more preferably ≥72h.

[0121] In a preferred technical solution of the present invention, the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 8 hours is ≥80%, preferably ≥90%.

[0122] In a preferred technical solution of the present invention, the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 12 hours is ≥90%, preferably ≥95%.

[0123] Another object of the present invention is to provide a method for preparing an epalrestat sustained-release composition, wherein the composition contains 20-50% of epalrestat or its derivatives and a pharmaceutically acceptable carrier, by weight percentage, wherein the derivatives are selected from any one or a combination of cocrystals, salts, free acids, prodrugs, esters, polymorphs, and solvates, and the pharmaceutically acceptable carrier is selected from any one or a combination of hydrogel materials, skeleton materials, fillers, disintegrants, adhesives, lubricants, and glidants, and the preparation of the composition is selected from any one of a powder direct tableting method and a wet granulation method.

[0124] According to a preferred technical solution of the present invention, the content of epalrestat or its derivatives in the composition is 25-45% by weight, preferably 30-40% by weight.

[0125] In the preferred technical solution of the present invention, the hydrogel material in the composition is 5-20% by weight, preferably 8-18%, and more preferably 9-15%.

[0126] In the preferred technical scheme of the present invention, the hydrogel material is selected from any one of polyvinyl alcohol, water-swellable cellulose, carrageenan, xanthan gum, guar gum, gum arabic, polyvinyl acetate, carbomer, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose), hydroxypropyl methylcellulose K4M, hydroxyethyl cellulose, alginate, polyethylene oxide, carboxymethyl cellulose, povidone, chitosan or a combination thereof.

[0127] In a preferred technical solution of the present invention, the skeleton material in the composition is 5-20% by weight, preferably 8-18%, and more preferably 10-15%.

[0128] In a preferred technical solution of the present invention, the skeleton material is selected from any one of water-insoluble cellulose, polyvinyl pyrrolidone, acrylic resin, polyacrylate, ethyl cellulose, and ethyl cellulose N10, or a combination thereof.

[0129] In the preferred technical solution of the present invention, the filler in the composition is 5-40% by weight, preferably 10-35%, and more preferably 15-30%.

[0130] In a preferred technical solution of the present invention, the filler is selected from any one of starch, sucrose, pregelatinized starch, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, microcrystalline cellulose, microcrystalline cellulose SH-101, and microcrystalline cellulose 102, or a combination thereof.

[0131] In a preferred technical solution of the present invention, the disintegrant in the composition is 10-35% by weight, preferably 12-30%, more preferably 15-20%.

[0132] In a preferred technical solution of the present invention, the disintegrant is selected from any one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked calcium carboxymethyl cellulose, or a combination thereof.

[0133] In a preferred technical solution of the present invention, the binder in the composition is 0-5% by weight, preferably 0.5-2.5%, and more preferably 1.5-2%.

[0134] In the preferred technical scheme of the present invention, the adhesive is selected from any one of low-viscosity cellulose, acrylic polymer, hyaluronic acid, alginic acid, polysaccharides, polysaccharide glycosides, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, starch slurry, methyl cellulose, ethyl cellulose, and povidone, or a combination thereof.

[0135] In the preferred technical solution of the present invention, the lubricant in the composition is 0.1-2% by weight, preferably 0.15-1.8%, and more preferably 0.2-0.5%.

[0136] In a preferred technical solution of the present invention, the lubricant is selected from any one of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycols, and sodium lauryl sulfate, or a combination thereof.

[0137] In a preferred technical solution of the present invention, the glidant in the composition is 0-1% by weight, preferably 0.2-0.8%, and more preferably 0.4-0.6%.

[0138] In a preferred technical solution of the present invention, the glidant is selected from any one of colloidal silicon dioxide, talcum powder, and micro-powdered silica gel, or a combination thereof.

[0139] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 20-50% epalrestat, 5-20% hydrogel material, 5-20% skeleton material, 5-40% filler, 10-35% disintegrant, 0-5% binder, 0.1-2% lubricant and 0-1% glidant.

[0140] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 25-45% epalrestat, 8-18% hydrogel material, 8-18% skeleton material, 10-35% filler, 12-30% disintegrant, 0.5-2.5% binder, 0.15-1.8% lubricant and 0.2-0.8% glidant.

[0141] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 30-40% epalrestat, 9-15% hydrogel material, 10-15% skeleton material, 15-30% filler, 15-20% disintegrant, 1.5-2% binder, 0.2-0.5% lubricant and 0.4-0.6% glidant.

[0142] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 20-50% epalrestat, 5-40% microcrystalline cellulose, 5-20% hypromellose, 5-20% ethyl cellulose, 10-35% cross-linked polyvinylpyrrolidone, 0.1-2% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0-1% colloidal silicon dioxide.

[0143] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 25-45% epalrestat, 10-35% microcrystalline cellulose, 8-18% hypromellose, 8-18% ethyl cellulose, 12-30% cross-linked polyvinylpyrrolidone, 0.15-1.8% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.2-0.8% colloidal silicon dioxide.

[0144] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hypromellose, 10-15% ethyl cellulose, 15-20% cross-linked polyvinylpyrrolidone, 0.2-0.5% magnesium stearate or sodium stearyl fumarate and 0.4-0.6% colloidal silicon dioxide.

[0145] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 20-50% epalrestat, 5-40% microcrystalline cellulose, 5-20% hydroxypropyl methylcellulose, 5-20% ethyl cellulose, 1-5% hydroxypropyl cellulose, 10-35% cross-linked polyvinylpyrrolidone, 0.1-2% of any one or a combination of magnesium stearate or stearic fumaric acid, and 0.1-1% of colloidal silicon dioxide.

[0146] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 25-45% epalrestat, 10-35% microcrystalline cellulose, 8-18% hydroxypropyl methylcellulose, 8-18% ethyl cellulose, 1-5% hydroxypropyl cellulose, 12-30% cross-linked polyvinylpyrrolidone, 0.15-1.8% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.2-0.8% colloidal silicon dioxide.

[0147] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hydroxypropyl methylcellulose, 10-15% ethyl cellulose, 1-5% hydroxypropyl cellulose, 15-20% cross-linked polyvinylpyrrolidone, 0.2-0.5% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.4-0.6% colloidal silicon dioxide.

[0148] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 9.30% microcrystalline cellulose, 13.95% hypromellose K4M, 16.28% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% magnesium stearate.

[0149] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 11.63% microcrystalline cellulose, 12.79% hypromellose K4M, 15.12% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% magnesium stearate.

[0150] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 6.98% microcrystalline cellulose, 12.79% hypromellose K4M, 15.12% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0151] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 11.62% microcrystalline cellulose, 10.47% hypromellose K4M, 12.79% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0152] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 9.30% microcrystalline cellulose, 13.95% hypromellose K4M, 16.28% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% sodium stearyl fumarate.

[0153] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 13.95% microcrystalline cellulose, 9.30% hypromellose K4M, 11.63% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0154] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 15.12% microcrystalline cellulose, 8.72% hypromellose K4M, 11.05% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0155] In the preferred technical solution of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 13.60% microcrystalline cellulose, 10.47% hypromellose K4M, 11.63% ethyl cellulose E5, 27.91% crospovidone and 1.51% magnesium stearate.

[0156] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 31.25% epalrestat, 30.31% microcrystalline cellulose, 9.9% hypromellose K4M, 10.42% ethyl cellulose, 0.73% hypromellose E5, 16.67% cross-linked polyvinylpyrrolidone, 0.52% magnesium stearate and 0.21% colloidal silicon dioxide.

[0157] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30% epalrestat, 27.9% microcrystalline cellulose, 9% hypromellose K4M, 11% ethyl cellulose, 1.5% hypromellose E5, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0158] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30% epalrestat, 27.4% microcrystalline cellulose, 9% hydroxypropyl methylcellulose, 11% ethyl cellulose, 2% hydroxypropyl cellulose, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0159] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30% epalrestat, 22.4% microcrystalline cellulose, 11% hydroxypropyl methylcellulose, 14% ethyl cellulose, 2% hydroxypropyl cellulose, 20% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

[0160] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 30% epalrestat, 26.6% microcrystalline cellulose, 12% hydroxypropyl methylcellulose, 14% ethyl cellulose, 1% hydroxypropyl cellulose, 16% cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.2% colloidal silicon dioxide.

[0161] In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 31.3% epalrestat, 27.7% microcrystalline cellulose, 12.5% ​​hydroxypropyl methylcellulose, 14.6% ethyl cellulose, 1% hydroxypropyl cellulose, 12.5% ​​cross-linked polyvinylpyrrolidone, 0.2% magnesium stearate and 0.2% colloidal silicon dioxide.

[0162] In a preferred technical solution of the present invention, the sustained-release composition is a gastric floating tablet.

[0163] In a preferred technical solution of the present invention, the gastric floating tablet floats immediately in simulated gastric fluid (pH 1.2).

[0164] In a preferred technical solution of the present invention, the floating time of the gastric floating tablet in simulated gastric fluid (pH 1.2) is ≥8h, preferably ≥24h, and more preferably ≥72h.

[0165] In a preferred technical solution of the present invention, the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 8 hours is ≥80%, preferably ≥90%.

[0166] In a preferred technical solution of the present invention, the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 12 hours is ≥90%, preferably ≥95%.

[0167] In the preferred technical solution of the present invention, the powder direct tableting method comprises the following steps: weighing the required amount of epalrestat, hydrogel material, skeleton material, filler, disintegrant, binder, lubricant, glidant or any one or a combination thereof, mixing them evenly, and tableting to obtain the product.

[0168] In a preferred technical solution of the present invention, the sustained-release layer optionally contains a solvent, and the solvent is preferably selected from any one of water and ethanol or a combination thereof.

[0169] In the preferred technical scheme of the present invention, the wet granulation method comprises the following steps: 1) weighing the required amount of epalrestat, filler, hydrogel material, skeleton material, disintegrant, any one or a combination thereof, uniformly mixing them, adding solvent, granulating, drying, and obtaining dry granules; 2) uniformly mixing the obtained dry granules with the required amount of binder, lubricant, glidant, any one or a combination thereof, and tableting, wherein the solvent is selected from any one or a combination of water and ethanol.

[0170] In a preferred technical solution of the present invention, the drying is selected from any one of reduced pressure drying, vacuum drying, spray drying and fluidized bed drying.

[0171] In the preferred technical solution of the present invention, the drying temperature is 55-75°C, preferably 60-70°C.

[0172] In a preferred technical solution of the present invention, the moisture content of the dry particles is ≤5.0%, preferably ≤3.0%.

[0173] Another object of the present invention is a sustained-release preparation of epalrestat, which comprises at least a sustained-release floating layer, wherein the sustained-release floating layer contains a hydrogel material and a skeleton material, wherein the mass ratio of the hydrogel material:epalrestat in the composition is 0.25-0.4:1, and the mass ratio of the skeleton material:epalrestat is 0.2-0.5:1, and the hydrogel material is selected from any one of polyvinyl alcohol, water-swellable cellulose, carrageenan, xanthan gum, guar gum, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and hydroxypropyl methylcellulose K4M, or a combination thereof, and the skeleton material is selected from any one of water-insoluble cellulose, polyvinyl pyrrolidone, acrylic resin, polyacrylate, and ethyl cellulose N10, or a combination thereof.

[0174] In the preferred technical solution of the present invention, the mass ratio of the skeleton material to epalrestat in the sustained-release preparation is 0.3-0.5:1.

[0175] In a preferred technical solution of the present invention, the sustained-release preparation further contains a filler, and the filler is selected from any one of microcrystalline cellulose, microcrystalline cellulose SH-101, and microcrystalline cellulose 102, or a combination thereof.

[0176] In a preferred technical solution of the present invention, the mass ratio of filler to epalrestat in the sustained-release preparation is 0.2-1:1, preferably 0.3-0.4:1, and more preferably 0.7-1:1.

[0177] In a preferred technical solution of the present invention, the sustained-release preparation optionally contains any one of a disintegrant, a wetting agent, a glidant, and a lubricant, or a combination thereof.

[0178] In a preferred technical solution of the present invention, the disintegrant is cross-linked polyvinylpyrrolidone.

[0179] In a preferred technical solution of the present invention, the mass ratio of disintegrant to epalrestat in the sustained-release preparation is 0.5-0.8:1.

[0180] In a preferred technical solution of the present invention, the adhesive is selected from any one of low-viscosity cellulose, acrylic polymer, hyaluronic acid, alginic acid, polysaccharide, polysaccharide glycoside, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, or a combination thereof.

[0181] In a preferred technical solution of the present invention, the mass ratio of the binder in the sustained-release preparation to epalrestat is 1:50-1:15.

[0182] In a preferred technical solution of the present invention, the lubricant is magnesium stearate.

[0183] In a preferred technical solution of the present invention, the mass ratio of lubricant to epalrestat in the sustained-release preparation is 0.005-0.05:1.

[0184] In a preferred technical solution of the present invention, the glidant is colloidal silicon dioxide.

[0185] In the preferred technical solution of the present invention, the mass ratio of the glidant in the sustained-release preparation to epalrestat is 0.005-0.05:1.

[0186] Another object of the present invention is to provide use of the epalrestat gastric floating tablet or sustained-release composition or sustained-release preparation of the present invention in the preparation of drugs for preventing and treating diabetes and its complications.

[0187] In a preferred technical solution of the present invention, the complication is any one or a combination of peripheral nerve disorder, numbness, and pain complicated by diabetes.

[0188] The preferred technical solution of the present invention selects the appropriate dosage and course of treatment according to the patient's condition, medication, age, gender, type of pain, etc. Adult patients take one tablet (dosage of 150 mg) once a day.

[0189] Unless otherwise specified, the immediate floating mentioned in the present invention means that the gastric floating tablet floats within 5 minutes after being placed in simulated gastric fluid (pH 1.2).

[0190] Unless otherwise specified, the impurity content detection described in the present invention adopts high performance liquid chromatography, and its chromatographic conditions are: octadecylsilane bonded silica gel is used as filler, mobile phase A is disodium hydrogen phosphate solution-(pH is adjusted to 6.0 with phosphoric acid)-acetonitrile (75:25), mobile phase B is acetonitrile, gradient elution (volume ratios of mobile phase A: mobile phase B are 100:0, 85:15, 80:20, 20:80, 0:100, respectively, elution 0-60min), flow rate 1.0ml / min, column temperature 35°C, detection wavelength 280nm, injection volume 10μl.

[0191] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage; the rest are weight / weight percentages.

[0192] Compared with the prior art, the present invention has the following beneficial technical effects:

[0193] 1. The present invention scientifically screens the components and ratios of the sustained-release layer and the immediate-release layer of the epalrestat gastric floating tablets and omits the use of gas-generating agents (such as sodium bicarbonate, etc.) and bleaching aids (such as octadecyl alcohol, etc.). The prepared gastric floating tablets have good floating performance, the dual advantages of faster onset and long-acting sustained release, better quality (including good quality uniformity, complete tablet shape, no cracks or fragments, smaller tablet weight, etc.), good stability, small variability, high bioavailability, safety and effectiveness, etc., are beneficial to fasting blood sugar control, postprandial blood sugar control, nighttime blood sugar control, significantly reduce the incidence of hypoglycemia, significantly improve patients' medication compliance, treatment compliance and sustainability, and significantly improve the safety and effectiveness of clinical medication.

[0194] 2. The preparation of the epalrestat gastric floating tablet and sustained-release composition of the present invention has the advantages of simple operation, better cost, green environmental protection, and suitability for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0195] FIG. 1 is an investigation of the in vitro release of the epalrestat gastric floating tablets of the present invention.

[0196] FIG. 2 shows an in vivo absorption study of the epalrestat gastric floating tablets of the present invention. DETAILED DESCRIPTION

[0197] The present invention is described below with reference to Examples, but the present invention is not limited to the Examples.

[0198] The numbering and composition of the relevant substances (impurities) of the specific implementation method:

[0199] serial number Impurity composition Impurity A 1E,2Z isomer of epalrestat Impurity B 1E,2E isomers of epalrestat Impurity C 1Z,2Z isomers of epalrestat Impurity D α-Methylcinnamaldehyde Impurity F Epalrestat dimer Impurity H Epalrestat ethyl ester

[0200] Example 1 Preparation of epalrestat gastric floating tablets of the present invention

[0201] Composition of gastric floating tablets (batch 400 tablets):

[0202]

[0203]

[0204] The preparation of the gastric floating tablet comprises the following steps:

[0205] (1) Weigh the required amount of sustained-release layer components and mix them evenly to obtain;

[0206] (2) Weigh the required amount of the immediate-release layer components and mix them evenly to obtain;

[0207] (3) The prepared sustained-release layer and immediate-release layer were placed in a double-layer tablet press respectively and tableted to obtain tablets (hardness 29.9N, tablet thickness 5.69 mm). The quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks or fragments.

[0208] Example 2 Preparation of epalrestat gastric floating tablets of the present invention

[0209] Composition of gastric floating tablets (batch 400 tablets):

[0210]

[0211]

[0212] The preparation of the gastric floating tablet comprises the following steps:

[0213] (1) Weigh the required amount of sustained-release layer components and mix them evenly to obtain;

[0214] (2) Weigh the required amount of the immediate-release layer components and mix them evenly to obtain;

[0215] (3) The prepared sustained-release layer and immediate-release layer were placed in a double-layer tablet press respectively and tableted to obtain tablets (hardness 38.9N, tablet thickness 5.62 mm). The quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks or fragments.

[0216] Example 3 Preparation of epalrestat gastric floating tablets of the present invention

[0217] Composition of gastric floating tablets (batch 400 tablets):

[0218]

[0219]

[0220] The preparation of the gastric floating tablet comprises the following steps:

[0221] (1) Weigh the required amount of sustained-release layer components and mix them evenly to obtain;

[0222] (2) Weigh the required amount of the immediate-release layer components and mix them evenly to obtain;

[0223] (3) The prepared sustained-release layer and immediate-release layer were placed in a double-layer tablet press respectively and tableted to obtain tablets (hardness 46.6N, tablet thickness 5.76 mm). The quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks or fragments.

[0224] Example 4 Preparation of Epalrestat Gastric Floating Tablets of the Present Invention

[0225] Composition of gastric floating tablets (batch 400 tablets):

[0226]

[0227]

[0228] The preparation of the gastric floating tablet comprises the following steps:

[0229] (1) Weigh the required amount of sustained-release layer components and mix them evenly to obtain;

[0230] (2) Weigh the required amount of the immediate-release layer components and mix them evenly to obtain;

[0231] (3) The prepared sustained-release layer and immediate-release layer are placed in a double-layer tablet press respectively and compressed into tablets. The prepared tablets have stable quality and complete tablet shape without cracks and fragments.

[0232] Example 5 Preparation of Epalrestat Gastric Floating Tablets of the Present Invention

[0233] Composition of gastric floating tablets (batch 400 tablets):

[0234]

[0235] The preparation of the gastric floating tablet comprises the following steps:

[0236] (1) Weigh the required amount of sustained-release layer components and mix them evenly to obtain;

[0237] (2) Weigh the required amount of the immediate-release layer components and mix them evenly to obtain;

[0238] (3) The prepared sustained-release layer and immediate-release layer are placed in a double-layer tablet press respectively and compressed into tablets. The prepared tablets have stable quality and complete tablet shape without cracks and fragments.

[0239] Example 6 Preparation of Epalrestat Gastric Floating Tablets of the Present Invention

[0240] Composition of gastric floating tablets (batch 400 tablets):

[0241]

[0242] The preparation of the gastric floating tablet comprises the following steps:

[0243] (1) Weigh the required amount of sustained-release layer components and mix them evenly to obtain;

[0244] (2) Weigh the required amount of the immediate-release layer components and mix them evenly to obtain;

[0245] (3) The prepared sustained-release layer and immediate-release layer are placed in a double-layer tablet press respectively and compressed into tablets. The prepared tablets have stable quality and complete tablet shape without cracks and fragments.

[0246] Example 7 Preparation of the epalrestat sustained-release composition of the present invention

[0247] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0248] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 40 Hydroxypropyl methylcellulose K4M 60 Ethyl cellulose N10 70 Hydroxypropyl methylcellulose E5 3.5 Cross-linked polyvinylpyrrolidone KCL 100 Magnesium Stearate 6.5 total 430

[0249] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (tablet thickness 5.75 mm). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 8 hours.

[0250] Example 8 Preparation of the epalrestat sustained-release composition of the present invention

[0251] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0252] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 50 Hydroxypropyl methylcellulose K4M 55 Ethyl cellulose N10 65 Hydroxypropyl methylcellulose E5 3.5 Cross-linked polyvinylpyrrolidone KCL 100 Magnesium Stearate 6.5 total 430

[0253] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing the components into tablets (tablet thickness 5.58 mm). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they immediately float, and the floating time is greater than 8 hours.

[0254] Example 9 Preparation of the epalrestat sustained-release composition of the present invention

[0255] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0256]

[0257] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (tablet thickness 5.6 mm). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 8 hours.

[0258] Example 10 Preparation of the epalrestat sustained-release composition of the present invention

[0259] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0260]

[0261]

[0262] The preparation of the epalrestat sustained-release composition comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (thickness 5.68 mm). According to conventional methods in the art, the quality of the tablets obtained is stable, the tablet shape is complete, and there are no cracks or fragments.

[0263] Embodiment 11 Preparation of the epalrestat sustained-release composition of the present invention

[0264] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0265] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH102 40 Hydroxypropyl methylcellulose K4M 60 Ethyl cellulose N10 70 Hydroxypropyl methylcellulose E5 3.5 Cross-linked polyvinylpyrrolidone KCL 100 Sodium stearyl fumarate 6.5 total 430

[0266] The preparation of the epalrestat sustained-release composition comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (thickness 6.08 mm). According to conventional methods in the art, the quality of the tablets obtained is stable, the tablet shape is complete, and there are no cracks or fragments.

[0267] Example 12 Preparation of the epalrestat sustained-release composition of the present invention

[0268] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0269] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 60 Hydroxypropyl methylcellulose K4M 40 Ethyl cellulose N10 50 Hydroxypropyl methylcellulose E5 3.5 Cross-linked polyvinylpyrrolidone KCL 120 Magnesium Stearate 6.5 total 430

[0270] The preparation of the epalrestat sustained-release composition comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (thickness 5.78 mm). According to conventional methods in the art, the quality of the tablets obtained is stable, the tablet shape is complete, and there are no cracks or fragments.

[0271] Embodiment 13 Preparation of the epalrestat sustained-release composition of the present invention

[0272] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0273] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 65 Hydroxypropyl methylcellulose K4M 37.5 Ethyl cellulose N10 47.5 Hydroxypropyl methylcellulose E5 3.5 Cross-linked polyvinylpyrrolidone KCL 120 Magnesium Stearate 6.5 total 430

[0274] The preparation of the epalrestat sustained-release composition comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (thickness 6.15 mm). According to conventional methods in the art, the quality of the tablets is stable, the tablet shape is complete, and there are no cracks or fragments.

[0275] Embodiment 14 Preparation of the epalrestat sustained-release composition of the present invention

[0276] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0277] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 58.5 Hydroxypropyl methylcellulose K4M 45 Ethyl cellulose N10 50 Cross-linked polyvinylpyrrolidone KCL 120 Magnesium Stearate 6.5 total 430

[0278] The preparation of the epalrestat sustained-release composition comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (thickness 6.08 mm). According to conventional methods in the art, the quality of the tablets obtained is stable, the tablet shape is complete, and there are no cracks or fragments.

[0279] Embodiment 15 Preparation of the epalrestat sustained-release composition of the present invention

[0280] Composition of epalrestat sustained-release composition (batch 400 tablets):

[0281] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 145.5 Hydroxypropyl methylcellulose K4M 47.5 Ethyl cellulose N10 50 Hydroxypropyl methylcellulose E5 3.5 Cross-linked polyvinylpyrrolidone KCL 80 Magnesium Stearate 2.5 Colloidal Silica 1 total 480

[0282] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0283] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

[0284] 2. The obtained granules were uniformly mixed with the required amount of hydroxypropyl methylcellulose E5, magnesium stearate and colloidal silicon dioxide, and tablets were obtained (tablet thickness: 6.42 mm).

[0285] According to the conventional method in the field, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments.

[0286] Example 16 Preparation of the epalrestat sustained-release composition of the present invention

[0287] Composition of epalrestat sustained-release composition (batch 600 tablets):

[0288] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 139.5 Hydroxypropyl methylcellulose K4M 45 Ethyl cellulose N10 55 Hydroxypropyl methylcellulose E5 7.5 Cross-linked polyvinylpyrrolidone KCL 100 Magnesium Stearate 1 Colloidal Silica 2 total 500

[0289] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0290] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

[0291] 2. The obtained granules were uniformly mixed with the required amount of hydroxypropyl methylcellulose E5, magnesium stearate and colloidal silicon dioxide, and tablets were obtained (tablet thickness: 6.59 mm).

[0292] According to the conventional method in the field, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments.

[0293] Embodiment 17 Preparation of the epalrestat sustained-release composition of the present invention

[0294] Composition of epalrestat sustained-release composition (batch 600 tablets):

[0295] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 137 Hydroxypropyl methylcellulose K4M 45 Ethyl cellulose N10 55 Hydroxypropyl methylcellulose EXF 10 Cross-linked polyvinylpyrrolidone KCL 100 Magnesium Stearate 1 Colloidal Silica 2 total 500

[0296] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0297] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

[0298] 2. The obtained granules were uniformly mixed with the required amount of hydroxypropyl methylcellulose EXF, magnesium stearate and colloidal silicon dioxide, and tablets were obtained (tablet thickness: 6.56 mm).

[0299] According to the conventional method in the field, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments.

[0300] Embodiment 18 Preparation of the epalrestat sustained-release composition of the present invention

[0301] Composition of epalrestat sustained-release composition (batch 600 tablets):

[0302] Components Composition per tablet (mg) Epalrestat 150 Microcrystalline Cellulose SH101 112 Hydroxypropyl methylcellulose K4M 55 Ethyl cellulose N10 70 Hydroxypropyl methylcellulose EXF 10 Cross-linked polyvinylpyrrolidone KCL 100 Magnesium Stearate 1 Colloidal Silica 2 total 500

[0303] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0304] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

[0305] 2. The obtained granules were uniformly mixed with the required amount of hydroxypropyl methylcellulose EXF, magnesium stearate and colloidal silicon dioxide, and tablets were obtained (tablet thickness: 6.57 mm).

[0306] According to the conventional method in the field, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments.

[0307] Embodiment 19 Preparation of the epalrestat sustained-release composition of the present invention

[0308] Composition of the epalrestat sustained-release composition (batch 400 tablets):

[0309]

[0310]

[0311] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0312] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10, and cross-linked polyvinylpyrrolidone KCL, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

[0313] 2. The obtained granules were uniformly mixed with the required amount of hydroxypropyl methylcellulose EXF, magnesium stearate and colloidal silicon dioxide, and tablets were obtained (tablet thickness: 6.28 mm).

[0314] According to the conventional method in the art, the quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks and fragments. When the prepared tablets were placed in simulated gastric fluid (pH 1.2), they immediately floated for more than 8 hours.

[0315] Embodiment 20 Preparation of the epalrestat sustained-release composition of the present invention

[0316] Composition of the epalrestat sustained-release composition (batch 400 tablets):

[0317]

[0318]

[0319] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0320] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10, and cross-linked polyvinylpyrrolidone KCL, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

[0321] 2. The obtained granules were uniformly mixed with the required amount of hydroxypropylmethylcellulose EXF, magnesium stearate and colloidal silicon dioxide, and tablets were obtained (tablet thickness: 6.04 mm).

[0322] According to the conventional method in the art, the quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks and fragments. When the prepared tablets were placed in simulated gastric fluid (pH 1.2), they immediately floated for more than 8 hours.

[0323] Embodiment 21 Preparation of the epalrestat sustained-release composition of the present invention

[0324] Composition of the epalrestat sustained-release composition:

[0325]

[0326]

[0327] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (each tablet weighs 430 mg). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 12 hours.

[0328] Embodiment 22 Preparation of the epalrestat sustained-release composition of the present invention

[0329] Composition of the epalrestat sustained-release composition:

[0330] Components Dosage(g) Epalrestat 60 Microcrystalline Cellulose SH101 20 Hydroxypropyl methylcellulose K4M 22 Ethyl cellulose N10 26 Hydroxypropyl methylcellulose E5 1.4 Cross-linked polyvinylpyrrolidone KCL-F 40 Magnesium Stearate 2.6 total 172

[0331] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (each tablet weighs 430 mg). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 12 hours.

[0332] Embodiment 23 Preparation of the epalrestat sustained-release composition of the present invention

[0333] Composition of the epalrestat sustained-release composition:

[0334]

[0335]

[0336] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (each tablet weighs 430 mg). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 12 hours.

[0337] Embodiment 24 Preparation of the epalrestat sustained-release composition of the present invention

[0338] Composition of the epalrestat sustained-release composition:

[0339] Components Dosage(g) Epalrestat 60 Microcrystalline Cellulose SH101 20 Hydroxypropyl methylcellulose K4M 18 Ethyl cellulose N10 22 Hydroxypropyl methylcellulose E5 1.4 Cross-linked polyvinylpyrrolidone KCL-F 48 Magnesium Stearate 2.6 total 172

[0340] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (each tablet weighs 430 mg). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 12 hours.

[0341] Embodiment 25 Preparation of the epalrestat sustained-release composition of the present invention

[0342] Composition of the epalrestat sustained-release composition:

[0343] Components Dosage(g) Epalrestat 60 Microcrystalline Cellulose SH102 16 Hydroxypropyl methylcellulose K4M 24 Ethyl cellulose N10 28 Hydroxypropyl methylcellulose E5 1.4 Cross-linked polyvinylpyrrolidone KCL-F 40 Sodium stearyl fumarate 2.6 total 172

[0344] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (each tablet weighs 430 mg). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 12 hours.

[0345] Embodiment 26 Preparation of the epalrestat sustained-release composition of the present invention

[0346] Composition of the epalrestat sustained-release composition:

[0347] Components Dosage(g) Epalrestat 60 Microcrystalline Cellulose SH101 24 Hydroxypropyl methylcellulose K4M 16 Ethyl cellulose N10 20 Hydroxypropyl methylcellulose E5 1.4 Cross-linked polyvinylpyrrolidone KCL-F 48 Magnesium Stearate 2.6 total 172

[0348] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (each tablet weighs 430 mg). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 12 hours.

[0349] Embodiment 27 Preparation of the epalrestat sustained-release composition of the present invention

[0350] Composition of the epalrestat sustained-release composition:

[0351] Components Dosage(g) Epalrestat 60 Microcrystalline Cellulose SH101 26 Hydroxypropyl methylcellulose K4M 15 Ethyl cellulose N10 19 Hydroxypropyl methylcellulose E5 1.4 Cross-linked polyvinylpyrrolidone KCL-F 48 Magnesium Stearate 2.6 total 172

[0352] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (each tablet weighs 430 mg). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 12 hours.

[0353] Embodiment 28 Preparation of the epalrestat sustained-release composition of the present invention

[0354] Composition of the epalrestat sustained-release composition:

[0355]

[0356]

[0357] The preparation of the sustained-release composition of epalrestat comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly compressing them into tablets (each tablet weighs 430 mg). According to the conventional method in the art, the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments. The prepared tablets are placed in simulated gastric fluid (pH 1.2), and they float immediately, and the floating time is greater than 12 hours.

[0358] Embodiment 29 Preparation of the epalrestat sustained-release composition of the present invention

[0359] Composition of the epalrestat sustained-release composition:

[0360] Components Dosage(g) Epalrestat 60 Microcrystalline Cellulose SH101 58.2 Hydroxypropyl methylcellulose K4M 19 Ethyl cellulose N10 20 Hydroxypropyl methylcellulose E5 1.4 Cross-linked polyvinylpyrrolidone KCL-F 32 Magnesium Stearate 1 Colloidal Silica 0.4 total 192

[0361] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0362] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL-F, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and place the drug-containing wet granules in a fluidized bed (60° C.) to dry to obtain granules (water content ≤ 3.0%);

[0363] 2. Evenly mix the prepared granules with the required amount of hydroxypropyl methylcellulose E5, magnesium stearate and colloidal silicon dioxide, and press into tablets (each tablet weighs 480 mg).

[0364] According to the conventional method in the art, the quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks and fragments. When the prepared tablets were placed in simulated gastric fluid (pH 1.2), they immediately floated for more than 12 hours.

[0365] Embodiment 30 Preparation of the epalrestat sustained-release composition of the present invention

[0366] Composition of the epalrestat sustained-release composition:

[0367] Components Dosage(g) Epalrestat 90 Microcrystalline Cellulose SH101 83.7 Hydroxypropyl methylcellulose K4M 27 Ethyl cellulose N10 33 Hydroxypropyl methylcellulose E5 4.5 Cross-linked polyvinylpyrrolidone KCL-F 60 Magnesium Stearate 0.6 Colloidal Silica 1.2 total 300

[0368] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0369] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL-F, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and place the drug-containing wet granules in a fluidized bed (60° C.) to dry to obtain granules (water content ≤ 3.0%);

[0370] 2. Evenly mix the prepared granules with the required amount of hydroxypropyl methylcellulose E5, magnesium stearate and colloidal silicon dioxide, and press into tablets (each tablet weighs 500 mg).

[0371] According to the conventional method in the art, the quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks and fragments. When the prepared tablets were placed in simulated gastric fluid (pH 1.2), they immediately floated for more than 12 hours.

[0372] Embodiment 31 Preparation of the epalrestat sustained-release composition of the present invention

[0373] Composition of the epalrestat sustained-release composition:

[0374] Components Dosage(g) Epalrestat 1350 Microcrystalline Cellulose SH101 1233 Hydroxypropyl methylcellulose K4M 405 Ethyl cellulose N10 495 Hydroxypropylcellulose EXF 90 Cross-linked polyvinylpyrrolidone KCL-F 900 Magnesium Stearate 9 Colloidal Silica 18 total 4500

[0375] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0376] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL-F, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and place the drug-containing wet granules in a fluidized bed (60° C.) to dry to obtain granules (water content ≤ 3.0%);

[0377] 2. Evenly mix the obtained granules with the required amount of hydroxypropyl cellulose EXF, magnesium stearate and colloidal silicon dioxide, and press into tablets (each tablet weighs 500 mg).

[0378] According to the conventional method in the art, the quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks and fragments. The prepared tablets were placed in simulated gastric fluid (pH 1.2), and they immediately floated for 48 hours.

[0379] Embodiment 32 Preparation of the epalrestat sustained-release composition of the present invention

[0380] Composition of the epalrestat sustained-release composition:

[0381] Components Dosage(g) Epalrestat 1350 Microcrystalline Cellulose SH101 1008 Hydroxypropyl methylcellulose K4M 495 Ethyl cellulose N10 630 Hydroxypropylcellulose EXF 90 Cross-linked polyvinylpyrrolidone KCL-F 900 Magnesium Stearate 9 Colloidal Silica 18 total 4500

[0382] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0383] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL-F, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and place the drug-containing wet granules in a fluidized bed (60° C.) to dry to obtain granules (water content ≤ 3.0%);

[0384] 2. Evenly mix the obtained granules with the required amount of hydroxypropyl cellulose EXF, magnesium stearate and colloidal silicon dioxide, and press into tablets (each tablet weighs 500 mg).

[0385] According to the conventional method in the art, the quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks and fragments. The prepared tablets were placed in simulated gastric fluid (pH 1.2), and they immediately floated for 72 hours.

[0386] Embodiment 33 Preparation of the epalrestat sustained-release composition of the present invention

[0387] Composition of the epalrestat sustained-release composition:

[0388]

[0389]

[0390] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0391] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL-F, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and place the drug-containing wet granules in a fluidized bed (60° C.) to dry to obtain granules (water content ≤ 3.0%);

[0392] 2. Evenly mix the obtained granules with the required amount of hydroxypropyl cellulose EXF, magnesium stearate and colloidal silicon dioxide, and press into tablets (each tablet weighs 500 mg).

[0393] According to the conventional method in the art, the quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks and fragments. When the prepared tablets were placed in simulated gastric fluid (pH 1.2), they immediately floated for more than 12 hours.

[0394] Embodiment 34 Preparation of the epalrestat sustained-release composition of the present invention

[0395] Composition of the epalrestat sustained-release composition:

[0396]

[0397]

[0398] The preparation of the epalrestat sustained-release composition comprises the following steps:

[0399] 1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL-F, mix them evenly, add appropriate amount of water (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") under stirring at 450 rpm to obtain drug-containing wet granules, and place the drug-containing wet granules in a fluidized bed (60° C.) to dry to obtain granules (water content ≤ 3.0%);

[0400] 2. Evenly mix the obtained granules with the required amount of hydroxypropyl cellulose EXF, magnesium stearate and colloidal silicon dioxide, and press into tablets (each tablet weighs 480 mg).

[0401] According to the conventional method in the art, the quality of the prepared tablets was stable, the tablet shape was complete, and there were no cracks and fragments. When the prepared tablets were placed in simulated gastric fluid (pH 1.2), they immediately floated for more than 12 hours.

[0402] Test Example 1 Study on in vitro release of epalrestat gastric floating tablets of the present invention

[0403] According to the dissolution and release determination method of the second method of Part IV General Rules 0931 of the Chinese Pharmacopoeia (2020 edition), 900 ml of phosphate buffer (pH 6.8 + 0.5% Tween 80) was used as the dissolution medium, the paddle method (100 rpm), and the gastric floating tablets of Examples 1-2, 7-8, 27-29, and 31-32 were used as examples to detect the in vitro release of the gastric floating tablets of the present invention at 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h. The results are shown in Table 1. Figure 1A , Figure 1B .

[0404] Test Example 2 Study on the stability of the sustained-release composition of epalrestat of the present invention

[0405] Taking the sustained-release composition of Example 32 as an example, the sustained-release composition was placed at 40° C. and 75% relative humidity (RH) for 6 months to investigate the stability of the sustained-release composition of the present invention. The results are shown in Table 1. During the 6-month investigation period, the sustained-release composition of the present invention was intact in tablet form, and no discoloration, pitting, cracks, or fragments were observed.

[0406] Table 1 Stability study of the sustained-release composition of Example 32

[0407]

[0408] The sustained-release compositions of the remaining examples of the present invention were examined using this method and showed similar excellent stability.

[0409] Test Example 3 Investigation on the quality uniformity of the epalrestat sustained-release composition of the present invention

[0410] Taking the sustained-release compositions prepared in Example 31 and Example 32 as examples, the mass uniformity of the epalrestat sustained-release composition of the present invention was investigated, and the results are shown in Table 2. The mass uniformity of the epalrestat sustained-release composition of the present invention is good.

[0411] Table 2

[0412]

[0413] Test Example 4 Study on in vivo absorption of the epalrestat sustained-release composition of the present invention

[0414] The absorption of the sustained-release preparation of epalrestat in vivo was studied. The sustained-release tablets of epalrestat prepared in Example 8 and Example 12 were subjected to biological experimental tests with the original ordinary tablets, and oral administration was performed using a miniature pig animal model. The sustained-release tablets prepared in Example 8 and Example 12 were both administered once, with a single dose of 150 mg of epalrestat. The original ordinary epalrestat tablets were administered once every 8 hours, with a dose of 50 mg of epalrestat each time. The results are shown in Table 1. Figure 2A .

[0415] The epalrestat sustained-release composition of the present invention has a long-acting sustained release, is beneficial to fasting blood sugar control, postprandial blood sugar control, and nighttime blood sugar control, significantly reduces the incidence of hypoglycemia, improves patient medication compliance and treatment continuity, and ensures safe and effective clinical medication.

[0416] Test Example 5 Study on in vivo absorption of the epalrestat sustained-release composition of the present invention

[0417] Six Bama miniature pigs (half male and half female) weighing 9-15 kg and aged 3-6 months were selected and divided into three groups, with two pigs in each group (half male and half female) and administered by gavage. The experimental animals were fasted before administration.

[0418] Control group: The original preparation (trade name: KINEDAK) was administered by intragastric administration, with a dose of 50 mg each time, 3 times a day, with an interval of 8 hours between each administration.

[0419] Experimental Group 1: The sustained-release composition of Example 31 was administered by intragastric administration at a dosage of 150 mg, once a day.

[0420] Experimental Group 2: The sustained-release composition of Example 32 was administered by intragastric administration at a dosage of 150 mg, once a day.

[0421] Blood samples were collected from the control group before administration and 0.25h, 0.5h, 1h, 2h, 4h, 8h, 8.25h, 8.5h, 9h, 10h, 12h, 16h, 16.25h, 16.5h, 17h, 18h, 20h, and 24h after administration for testing; blood samples were collected from the experimental group before administration and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 16h, and 24h after administration for testing. Results are shown in Figure 2B .

[0422] The epalrestat sustained-release composition of the present invention has a long-acting sustained release, is beneficial to fasting blood sugar control, postprandial blood sugar control, and nighttime blood sugar control, significantly reduces the incidence of hypoglycemia, improves patient medication compliance and treatment continuity, and ensures safe and effective clinical medication.

[0423] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. An epalrestat gastric floating tablet, the gastric floating tablet comprising a sustained-release layer and a rapid-release layer, wherein: In terms of weight percentage, the mass ratio of the sustained-release layer to the immediate-release layer in the gastric floating tablet is 1-8:1; the mass ratio of epalrestat in the sustained-release layer to epalrestat in the immediate-release layer is 1-5:1; The sustained-release layer comprises 20-50% epalrestat, 5-20% hydrogel material, 5-20% skeleton material, 5-40% filler, 10-35% disintegrant, 0-5% binder, 0.1-2% lubricant and 0-1% glidant; The filler is selected from any one or a combination of starch, sucrose, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, and microcrystalline cellulose; The disintegrant is selected from cross-linked polyvinylpyrrolidone; The binder is selected from any one of hydroxypropyl cellulose, acrylic acid polymer, hyaluronic acid, alginic acid, polysaccharide, hydroxypropyl methylcellulose, starch slurry, methyl cellulose, ethyl cellulose, povidone, polyvinyl pyrrolidone or a combination thereof; The lubricant is selected from any one or a combination of magnesium stearate, stearic acid, hydrogenated vegetable oil, sodium stearyl fumarate, polyethylene glycols, and sodium lauryl sulfate; The hydrogel material is selected from hydroxypropyl methylcellulose; The skeleton material is selected from ethyl cellulose; The glidant is selected from any one of colloidal silicon dioxide, talc, and micro-powdered silica gel, or a combination thereof; In terms of weight percentage, the immediate-release layer contains 30-55% of epalrestat, 30-55% of lactose or microcrystalline cellulose, 1-10% of any one of cross-linked carboxymethyl cellulose sodium, cross-linked povidone, and low-substituted hydroxypropyl cellulose, 1-15% of hydroxypropyl cellulose or polyvinyl pyrrolidone, 1-5% of magnesium stearate, and 1-5% of sodium lauryl sulfate.

2. The gastric floating tablet according to claim 1, wherein the mass ratio of the sustained-release layer to the immediate-release layer in the gastric floating tablet is 2-6:

1.

3. The gastric floating tablet according to claim 1, wherein the mass ratio of epalrestat in the sustained-release layer to epalrestat in the immediate-release layer is 2-4:

1.

4. The gastric floating tablet according to claim 1, wherein the immediate-release layer contains 35-50% epalrestat by weight.

5. The gastric floating tablet according to claim 1, wherein the immediate-release layer contains 40-45% epalrestat by weight.

6. The gastric floating tablet according to claim 1, wherein the immediate-release layer contains, by weight percentage, 35-50% epalrestat, 32-50% lactose or microcrystalline cellulose, 1.2-9.5% of any one of cross-linked carboxymethyl cellulose sodium, cross-linked povidone, and low-substituted hydroxypropyl cellulose, 2-13% hydroxypropyl cellulose or polyvinyl pyrrolidone, 1-5% magnesium stearate, and 1-5% sodium lauryl sulfate.

7. The gastric floating tablet according to claim 6, wherein the immediate-release layer contains, by weight percentage, 40-45% of epalrestat, 35-47% of lactose or microcrystalline cellulose, 1.4-9% of any one of cross-linked carboxymethyl cellulose sodium, cross-linked povidone, and low-substituted hydroxypropyl cellulose, 5-12% of hydroxypropyl cellulose or polyvinyl pyrrolidone, 1-5% of magnesium stearate, and 1-5% of sodium lauryl sulfate.

8. The gastric floating tablet according to claim 1, wherein the immediate release layer contains, by weight percentage, 41.7% epalrestat, 46.5% lactose, 2.5% cross-linked carboxymethyl cellulose sodium, 5.8% hydroxypropyl cellulose, 1.5% magnesium stearate and 2% sodium lauryl sulfate.

9. The gastric floating tablet according to claim 1, wherein the immediate release layer contains, by weight percentage, 41.7% epalrestat, 35.1% microcrystalline cellulose, 8.3% crospovidone, 11.4% polyvinyl pyrrolidone, 1.5% magnesium stearate and 2% sodium lauryl sulfate.

10. The gastric floating tablet according to claim 1, wherein the immediate release layer contains, by weight percentage, 41.7% epalrestat, 47.6% microcrystalline cellulose, 1.4% crospovidone, 5.8% hydroxypropyl cellulose, 1.5% magnesium stearate and 2% sodium lauryl sulfate.

11. The gastric floating tablet according to claim 1, wherein the immediate release layer contains, by weight percentage, 41.7% epalrestat, 44.8% microcrystalline cellulose, 4.2% low-substituted hydroxypropyl cellulose, 5.8% hydroxypropyl cellulose, 1.5% magnesium stearate and 2% sodium lauryl sulfate.

12. The gastric floating tablet according to any one of claims 1 to 11, wherein the content of epalrestat in the sustained-release layer is 25-45% by weight.

13. The gastric floating tablet according to claim 12, wherein the content of epalrestat in the sustained-release layer is 30-40% by weight.

14. The gastric floating tablet according to any one of claims 1 to 11, wherein the hydrogel material in the sustained-release layer is 8-18% by weight.

15. The gastric floating tablet according to claim 14, wherein the hydrogel material in the sustained-release layer is 9-15% by weight.

16. The gastric floating tablet according to any one of claims 1 to 11, wherein the hydrogel material is selected from hydroxypropyl methylcellulose K4M.

17. The gastric floating tablet according to any one of claims 1 to 11, wherein the skeleton material in the sustained-release layer is 8-18% by weight.

18. The gastric floating tablet according to claim 17, wherein the skeleton material in the sustained-release layer is 10-15% by weight.

19. The gastric floating tablet according to any one of claims 1 to 11, wherein the skeleton material is selected from ethyl cellulose N10.

20. The gastric floating tablet according to any one of claims 1 to 11, wherein the filler in the sustained-release layer is 10-35% by weight.

21. The gastric floating tablet according to claim 20, wherein the filler in the sustained-release layer is 15-30% by weight.

22. The gastric floating tablet according to any one of claims 1 to 11, wherein the filler is selected from any one of microcrystalline cellulose SH-101, microcrystalline cellulose 102, or a combination thereof.

23. The gastric floating tablet according to any one of claims 1 to 11, wherein the disintegrant in the sustained-release layer is 12-30% by weight.

24. The gastric floating tablet according to claim 23, wherein the disintegrant in the sustained-release layer is 15-20% by weight.

25. The gastric floating tablet according to any one of claims 1 to 11, wherein the binder in the sustained-release layer is 0.5-2.5% by weight.

26. The gastric floating tablet according to claim 25, wherein the binder in the sustained-release layer is 1.5-2% by weight.

27. The gastric floating tablet according to any one of claims 1 to 11, wherein the binder is selected from hypromellose E5.

28. The gastric floating tablet according to any one of claims 1 to 11, wherein the lubricant in the sustained-release layer is 0.15-1.8% by weight.

29. The gastric floating tablet according to claim 28, wherein the lubricant in the sustained-release layer is 0.2-0.5% by weight.

30. The gastric floating tablet according to any one of claims 1 to 11, wherein the glidant in the sustained-release layer is 0.2-0.8% by weight.

31. The gastric floating tablet according to claim 30, wherein the glidant in the sustained-release layer is 0.4-0.6% by weight.

32. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 25-45% epalrestat, 8-18% hydrogel material, 8-18% skeleton material, 10-35% filler, 12-30% disintegrant, 0.5-2.5% binder, 0.15-1.8% lubricant and 0.2-0.8% glidant.

33. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer comprises, by weight percentage, 30-40% epalrestat, 9-15% hydrogel material, 10-15% skeleton material, 15-30% filler, 15-20% disintegrant, 1.5-2% binder, 0.2-0.5% lubricant and 0.4-0.6% glidant.

34. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 20-50% epalrestat, 5-40% microcrystalline cellulose, 5-20% hypromellose, 5-20% ethyl cellulose, 10-35% crospovidone, 0.1-2% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0-1% colloidal silicon dioxide.

35. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 25-45% epalrestat, 10-35% microcrystalline cellulose, 8-18% hypromellose, 8-18% ethyl cellulose, 12-30% crospovidone, 0.15-1.8% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.2-0.8% colloidal silicon dioxide.

36. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hypromellose, 10-15% ethyl cellulose, 15-20% crospovidone, 0.2-0.5% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.4-0.6% colloidal silicon dioxide.

37. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 20-50% epalrestat, 5-40% microcrystalline cellulose, 5-20% hydroxypropyl methylcellulose, 5-20% ethyl cellulose, 1-5% hydroxypropyl cellulose, 10-35% crospovidone, 0.1-2% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.1-1% colloidal silicon dioxide.

38. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 25-45% epalrestat, 10-35% microcrystalline cellulose, 8-18% hydroxypropyl methylcellulose, 8-18% ethyl cellulose, 1-5% hydroxypropyl cellulose, 12-30% crospovidone, 0.15-1.8% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.2-0.8% colloidal silicon dioxide.

39. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hydroxypropyl methylcellulose, 10-15% ethyl cellulose, 1-5% hydroxypropyl cellulose, 15-20% crospovidone, 0.2-0.5% of any one or a combination of magnesium stearate or sodium stearyl fumarate, and 0.4-0.6% colloidal silicon dioxide.

40. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 34.88% epalrestat, 9.30% microcrystalline cellulose, 13.95% hypromellose K4M, 16.28% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% magnesium stearate.

41. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 34.88% epalrestat, 11.63% microcrystalline cellulose, 12.79% hypromellose K4M, 15.12% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% magnesium stearate.

42. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 34.88% epalrestat, 6.98% microcrystalline cellulose, 12.79% hypromellose K4M, 15.12% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

43. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer comprises, by weight percentage, 34.88% epalrestat, 11.62% microcrystalline cellulose, 10.47% hypromellose K4M, 12.79% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

44. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 34.88% epalrestat, 9.30% microcrystalline cellulose, 13.95% hypromellose K4M, 16.28% ethyl cellulose, 0.81% hypromellose E5, 23.26% crospovidone and 1.51% sodium stearyl fumarate.

45. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 34.88% epalrestat, 13.95% microcrystalline cellulose, 9.30% hypromellose K4M, 11.63% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

46. ​​The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 34.88% epalrestat, 15.12% microcrystalline cellulose, 8.72% hypromellose K4M, 11.05% ethyl cellulose, 0.81% hypromellose E5, 27.91% crospovidone and 1.51% magnesium stearate.

47. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 34.88% epalrestat, 13.60% microcrystalline cellulose, 10.47% hypromellose K4M, 11.63% ethyl cellulose E5, 27.91% crospovidone and 1.51% magnesium stearate.

48. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 31.25% epalrestat, 30.31% microcrystalline cellulose, 9.9% hypromellose K4M, 10.42% ethyl cellulose, 0.73% hypromellose E5, 16.67% crospovidone, 0.52% magnesium stearate and 0.21% colloidal silicon dioxide.

49. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer comprises, by weight percentage, 30% epalrestat, 27.9% microcrystalline cellulose, 9% hypromellose K4M, 11% ethyl cellulose, 1.5% hypromellose E5, 20% crospovidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

50. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 30% epalrestat, 27.4% microcrystalline cellulose, 9% hydroxypropyl methylcellulose, 11% ethyl cellulose, 2% hydroxypropyl cellulose, 20% crospovidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

51. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 30% epalrestat, 22.4% microcrystalline cellulose, 11% hydroxypropyl methylcellulose, 14% ethyl cellulose, 2% hydroxypropyl cellulose, 20% crospovidone, 0.2% magnesium stearate and 0.4% colloidal silicon dioxide.

52. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 30% epalrestat, 26.6% microcrystalline cellulose, 12% hydroxypropyl methylcellulose, 14% ethyl cellulose, 1% hydroxypropyl cellulose, 16% crospovidone, 0.2% magnesium stearate and 0.2% colloidal silicon dioxide.

53. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains, by weight percentage, 31.3% epalrestat, 27.7% microcrystalline cellulose, 12.5% ​​hypromellose, 14.6% ethyl cellulose, 1% hydroxypropyl cellulose, 12.5% ​​crospovidone, 0.2% magnesium stearate and 0.2% colloidal silicon dioxide.

54. The gastric floating tablet according to any one of claims 1 to 11, wherein the sustained-release layer contains a solvent. The gastric floating tablet according to claim 54 , wherein the solvent in the sustained-release layer is selected from any one of water and ethanol or a combination thereof.

56. The gastric floating tablet according to any one of claims 1 to 11, wherein the floating time of the gastric floating tablet in simulated gastric fluid pH 1.2 is ≤ 5 min.

57. The gastric floating tablet according to any one of claims 1 to 11, wherein the dissolution rate of the gastric floating tablet after being placed in a phosphate buffer solution at pH 6.8 for 8 hours is ≥ 85%.

58. The gastric floating tablet according to claim 57, wherein the dissolution rate of the gastric floating tablet after being placed in a phosphate buffer solution at pH 6.8 for 8 hours is ≥ 90%.

59. The gastric floating tablet according to any one of claims 1 to 11, wherein the dissolution rate of the gastric floating tablet after being placed in a phosphate buffer solution at pH 6.8 for 12 hours is ≥ 90%.

60. The gastric floating tablet according to claim 59, wherein the dissolution rate of the gastric floating tablet after being placed in a phosphate buffer solution at pH 6.8 for 12 hours is ≥ 95%.

61. The method for preparing the epalrestat gastric floating tablet according to any one of claims 1 to 60, comprising the steps of placing the separately prepared sustained-release layer and immediate-release layer in a double-layer tablet press, and tableting to obtain the tablet.

62. The preparation method as claimed in claim 61, wherein the preparation of the immediate-release layer comprises the following steps: weighing the required amounts of components, and uniformly mixing them to obtain the immediate-release layer.

63. The preparation method according to claim 61, wherein the preparation of the sustained-release layer comprises the following steps: weighing the required amounts of components, and uniformly mixing them.

64. The preparation method according to claim 63, wherein the preparation of the sustained-release layer comprises the following steps: 1) weighing the required amount of epalrestat, filler, hydrogel material, skeleton material, disintegrant, any one or a combination thereof, uniformly mixing, adding solvent, granulating, drying, and obtaining dry granules; 2) uniformly mixing the obtained dry granules with the required amount of binder, lubricant, glidant, any one or a combination thereof, to obtain, wherein, The solvent is selected from any one of water, ethanol or a combination thereof. The preparation method according to claim 64 , wherein the drying is selected from drying under reduced pressure. The preparation method according to claim 64 , wherein the drying is selected from any one of vacuum drying and spray drying.

67. The preparation method according to claim 64, wherein the drying temperature is 55-75°C.

68. The preparation method according to claim 67, wherein the drying temperature is 60-70°C.

69. The preparation method according to claim 64, wherein the moisture content of the dried particles is ≤5.0%.

70. The preparation method according to claim 69, wherein the moisture content of the dried particles is ≤3.0%.

71. Use of the epalrestat gastric floating tablet according to any one of claims 1 to 60 in the preparation of a medicament for preventing and treating diabetes and its complications.

72. The use according to claim 71, wherein the complication is any one or a combination of peripheral neuropathy, numbness, and pain associated with diabetes.

73. The use as described in any one of claims 71-72, wherein an adult patient takes the tablet once a day, each time with a dosage of 150 mg.

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