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WO2024125654A1 - Sustained-release epalrestat composition, method for preparing same, and use thereof - Google Patents

Sustained-release epalrestat composition, method for preparing same, and use thereof Download PDF

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Publication number
WO2024125654A1
WO2024125654A1 PCT/CN2023/139300 CN2023139300W WO2024125654A1 WO 2024125654 A1 WO2024125654 A1 WO 2024125654A1 CN 2023139300 W CN2023139300 W CN 2023139300W WO 2024125654 A1 WO2024125654 A1 WO 2024125654A1
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WO
WIPO (PCT)
Prior art keywords
epalrestat
sustained
cellulose
present
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/139300
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French (fr)
Chinese (zh)
Inventor
徐鹏飞
边聪
周子琳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Jitai Pharmaceutical Technology Co Ltd
Hangzhou Jitai Pharmaceutical Technology Co Ltd
Original Assignee
Beijing Jitai Pharmaceutical Technology Co Ltd
Hangzhou Jitai Pharmaceutical Technology Co Ltd
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Publication of WO2024125654A1 publication Critical patent/WO2024125654A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to an epalrestat sustained-release composition, a preparation method thereof and an application thereof.
  • 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 its 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 the patient's subjective symptoms and nerve dysfunction, and is used to prevent, improve and treat diabetes and its complications of peripheral nerve disorders (numbness, pain).
  • 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).
  • DKA diabetic ketoacidosis
  • the object of the present invention is to provide an epalrestat sustained-release composition, which contains 20-50% epalrestat or its derivatives and a pharmaceutically acceptable
  • the carrier is selected from any one or a combination of co-crystals, salts, free acids, prodrugs, esters, polymorphs, and solvates
  • the pharmaceutically acceptable carrier is selected from any one or a combination of hydrogel materials, skeleton materials, fillers, disintegrants, adhesives, lubricants, and glidants.
  • the content of epalrestat or its derivatives in the composition is 25-45% by weight, preferably 30-40% by weight.
  • the hydrogel material in the composition is 5-20% by weight, preferably 8-18%, and more preferably 9-15%.
  • 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.
  • the skeleton material in the composition is 5-20% by weight, preferably 8-18%, and more preferably 10-15%.
  • 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.
  • the filler in the composition is 5-40% by weight, preferably 10-35%, and more preferably 15-30%.
  • 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.
  • the disintegrant in the composition is 10-35% by weight, preferably 12-30%, more preferably 15-20%.
  • 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.
  • the binder in the composition is 0-5% by weight, preferably 0.5-2.5%, and more preferably 1.5-2%.
  • 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.
  • the lubricant in the composition is 0.1-2% by weight, preferably 0.15-1.8%, and more preferably 0.2-0.5%.
  • 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.
  • the glidant in the composition is 0-1% by weight, preferably 0.2-0.8%, and more preferably 0.4-0.6%.
  • the glidant is selected from any one of colloidal silicon dioxide, talcum powder, and micro-powdered silica gel, or a combination thereof.
  • 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.
  • 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.
  • the composition comprises 30-40% epalrestat, 9-15% hydrogel material, 10-15% skeleton material, 15-30% filler, Disintegrant 15-20%, binder 1.5-2%, lubricant 0.2-0.5% and glidant 0.4-0.6%.
  • 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.
  • 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.
  • 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.
  • 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% colloidal silicon dioxide.
  • 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.
  • 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.
  • the epasidine in the composition is calculated by weight percentage. He 34.88%, microcrystalline cellulose 9.30%, hypromellose K4M 13.95%, ethyl cellulose 16.28%, hypromellose E5 0.81%, crospovidone 23.26% and magnesium stearate 1.51%.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% sodium stearyl fumarate.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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 magnesium stearate. 1.51%.
  • the composition comprises, by weight percentage, 34.88% epalrestat, 13.60% microcrystalline cellulose, 10.47% hydroxypropyl methylcellulose K4M, 11.63% ethyl cellulose E5, 27.91% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the sustained-release composition optionally contains a solvent, preferably The solvent is selected from any one of water, ethanol or a combination thereof.
  • the sustained-release composition is a gastric floating tablet.
  • the gastric floating tablet floats immediately in simulated gastric fluid (pH 1.2).
  • the floating time of the gastric floating tablet in simulated gastric fluid is ⁇ 8h, preferably ⁇ 24h, and more preferably ⁇ 72h.
  • the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 8 hours is ⁇ 80%, preferably ⁇ 90%.
  • the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 12 hours is ⁇ 90%, preferably ⁇ 95%.
  • 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.
  • the content of epalrestat or its derivatives in the composition is 25-45% by weight, preferably 30-40% by weight.
  • the hydrogel material in the composition is 5-20% by weight, preferably 8-18%, and more preferably 9-15%.
  • the hydrogel material is selected from 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, alginic acid Any one of salt, polyoxyethylene, carboxymethyl cellulose, povidone, chitosan or a combination thereof.
  • the skeleton material in the composition is 5-20% by weight, preferably 8-18%, and more preferably 10-15%.
  • 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.
  • the filler in the composition is 5-40% by weight, preferably 10-35%, and more preferably 15-30%.
  • 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.
  • the disintegrant in the composition is 10-35% by weight, preferably 12-30%, more preferably 15-20%.
  • 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.
  • the binder in the composition is 0-5% by weight, preferably 0.5-2.5%, and more preferably 1.5-2%.
  • 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.
  • the lubricant in the composition is 0.1-2% by weight, preferably 0.15-1.8%, and more preferably 0.2-0.5%.
  • 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.
  • the glidant in the composition is 0-1% by weight, preferably 0.2-0.8%, and more preferably 0.4-0.6%.
  • the glidant is selected from any one of colloidal silicon dioxide, talcum powder, and micro-powdered silica gel, or a combination thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition comprises 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hypromellose, and ethyl cellulose in weight percentage. 10-15%, crospovidone 15-20%, any one of magnesium stearate or sodium stearyl fumarate or a combination thereof 0.2-0.5% and colloidal silicon dioxide 0.4-0.6%.
  • 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.
  • 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.
  • 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.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% sodium stearyl fumarate.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • the composition comprises, by weight percentage, 34.88% epalrestat, 13.60% microcrystalline cellulose, 10.47% hydroxypropyl methylcellulose K4M, 11.63% ethyl cellulose E5, 27.91% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.
  • 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.
  • the composition 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 0.2% colloidal dioxygenase. Silicon dioxide 0.4%.
  • 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.
  • 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.
  • 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.
  • 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.
  • the sustained-release composition is a gastric floating tablet.
  • the gastric floating tablet floats immediately in simulated gastric fluid (pH 1.2).
  • the floating time of the gastric floating tablet in simulated gastric fluid is ⁇ 8h, preferably ⁇ 24h, and more preferably ⁇ 72h.
  • the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 8 hours is ⁇ 80%, preferably ⁇ 90%.
  • the solubility of the gastric floating tablet placed in a phosphate buffer solution (pH 6.8) for 12 hours is ⁇ 90%, preferably ⁇ 95%.
  • the powder direct tableting method comprises the following steps: weighing the required amount of epalrestat, hydrogel material, skeleton material, filler, disintegrant, Any one or a combination of a disintegrating agent, a binder, a lubricant and a glidant is mixed evenly and then tabletted to obtain the product.
  • 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.
  • 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 to obtain, wherein the solvent is selected from any one or a combination of water and ethanol.
  • the drying temperature is 55-75°C, preferably 60-70°C.
  • the moisture content of the dry particles is ⁇ 5.0%, preferably ⁇ 3.0%.
  • 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 sustained-release preparation is 0.25-0.4:1, and the mass ratio of the skeleton material:epalrestat is 0.2-0.5:1,
  • 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
  • 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.
  • the mass ratio of the skeleton material to epalrestat in the sustained-release preparation is 0.3-0.5:1.
  • 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.
  • 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.
  • the sustained-release preparation optionally contains any one of a disintegrant, a binder, a solvent, a glidant, a lubricant, or a combination thereof.
  • the disintegrant is cross-linked polyvinylpyrrolidone.
  • the mass ratio of disintegrant to epalrestat in the sustained-release preparation is 0.5-0.8:1.
  • 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.
  • the mass ratio of the binder in the sustained-release preparation to epalrestat is 1:50-1:15.
  • the lubricant is magnesium stearate.
  • the glidant is colloidal silicon dioxide.
  • the mass ratio of the glidant in the sustained-release preparation to epalrestat is 0.005-0.05:1.
  • Another object of the present invention is to provide use of the epalrestat sustained-release composition or sustained-release preparation of the present invention in preparing a medicament for preventing and treating diabetes and its complications.
  • the complication is any one or a combination of peripheral nerve disorder, numbness, and pain complicated by diabetes.
  • 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 is 150 mg) once a day.
  • 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 (the volume ratio of mobile phase A: mobile phase B is 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 10 ⁇ l.
  • 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 aceton
  • the percentage 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.
  • the present invention has the following beneficial technical effects:
  • the present invention scientifically screens the components and proportions of the epalrestat sustained-release composition, and omits the use of gas-generating agents (such as sodium bicarbonate, etc.) and bleaching agents (such as octadecyl alcohol, etc.).
  • gas-generating agents such as sodium bicarbonate, etc.
  • bleaching agents such as octadecyl alcohol, etc.
  • the preparation of the epalrestat sustained-release composition of the present invention is simple to operate and has better cost performance. It is green, environmentally friendly and suitable for industrial production.
  • FIG1 is an investigation of the in vitro release of the epalrestat sustained-release composition of the present invention.
  • FIG. 2 shows an in vivo absorption study of the epalrestat sustained-release composition of the present invention.
  • composition of epalrestat sustained-release composition (batch 400 tablets):
  • 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 5.58 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 float immediately, and the floating time is greater than 8 hours.
  • composition of epalrestat sustained-release composition (batch 400 tablets):
  • 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.
  • the preparation of the sustained-release composition of epalrestat includes the following steps: weighing the required amount of components, mixing them evenly, and directly compressing them into tablets (tablet thickness 5.78 mm). The tablets were tested by the method of stable quality and complete tablet shape without cracks and fragments.
  • the preparation of the epalrestat sustained-release composition comprises the following steps: weighing the required amounts of components, After uniform mixing, the tablets were directly compressed to obtain tablets (thickness 6.08 mm). According to the conventional method in the art, the tablets were tested to have stable quality and complete tablet shape without cracks and fragments.
  • 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).
  • the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments.
  • composition of epalrestat sustained-release composition (batch 600 tablets):
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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).
  • composition of epalrestat sustained-release composition (batch 600 tablets):
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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).
  • the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments.
  • composition of epalrestat sustained-release composition (batch 600 tablets):
  • 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).
  • the quality of the prepared tablets is stable, the tablet shape is complete, and there are no cracks and fragments.
  • composition of epalrestat sustained-release composition (batch 400 tablets):
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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).
  • 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), they immediately floated for more than 8 hours.
  • composition of epalrestat sustained-release composition (batch 400 tablets):
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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).
  • 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), they immediately floated for more than 8 hours.
  • composition of the epalrestat sustained-release composition is provided.
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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), they immediately floated for more than 12 hours.
  • composition of the epalrestat sustained-release composition is provided.
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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), they immediately floated for more than 12 hours.
  • composition of the epalrestat sustained-release composition is provided.
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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.
  • composition of the epalrestat sustained-release composition is provided.
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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.
  • composition of epalrestat sustained-release composition Composition of epalrestat sustained-release composition:
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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), they immediately floated for more than 12 hours.
  • composition of epalrestat sustained-release composition Composition of epalrestat sustained-release composition:
  • the preparation of the epalrestat sustained-release composition comprises the following steps:
  • 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), they immediately floated for more than 12 hours.
  • Test Example 1 Stability Study of the Epalrestat Sustained-Release Composition of the Present Invention
  • Example 26 Taking the sustained-release composition of Example 26 as an example, it was placed at 40° C. and 75% relative humidity (RH) for 6 months, and the stability of the sustained-release composition of the present invention was investigated and 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.
  • RH relative humidity
  • sustained-release compositions of the remaining examples of the present invention were examined using this method and showed similar excellent stability.
  • Example 25 Taking the sustained-release compositions prepared in Example 25 and Example 26 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.
  • the absorption of the epalrestat sustained-release preparation of the present invention in vivo was studied.
  • the epalrestat sustained-release tablets prepared in Example 2 and Example 6 were subjected to biological experimental tests with the original common tablets, and oral administration was performed using a miniature pig animal model.
  • the sustained-release tablets prepared in Example 2 and Example 6 were both administered once, with a single dose of 150 mg of epalrestat.
  • the dosage was administered once every 8 hours, with a dosage of 50 mg of epalrestat each time. The results are shown in FIG2A.
  • 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.
  • 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.
  • Experimental Group 1 The sustained-release composition of Example 25 was administered by intragastric administration at a dosage of 150 mg, once a day.
  • Experimental Group 2 The sustained-release composition of Example 26 was administered by intragastric administration at a dosage of 150 mg, once a day.
  • Blood samples were collected for detection in the control group before 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; blood samples were collected for detection in the experimental group before and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 16h, and 24h after administration. The results are shown in Figure 2B.
  • 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.

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Abstract

Provided is a sustained-release epalrestat composition, comprising, in percentage by weight: 20-50% of epalrestat or a derivative thereof, and a pharmaceutically acceptable carrier. The derivative is selected from any one or a combination of a co-crystal, a salt, a free acid, a prodrug, an ester, a polymorph, and a solvate, and the pharmaceutically acceptable carrier is selected from any one or a combination of a hydrogel material, a skeleton material, a filler, a disintegrant, an adhesive, a solvent, a lubricant, and a glidant. The sustained-release epalrestat composition features good floating performance, long-acting sustained release, good quality uniformity, good stability, small variability, high bioavailability, and the like, and significantly improves the medication compliance of patients and the safety and efficacy.

Description

一种依帕司他缓释组合物及其制备方法和其应用An epalrestat sustained-release composition, preparation method thereof and application thereof 技术领域Technical Field

本发明属于生物医药领域，具体涉及一种依帕司他缓释组合物及其制备方法和其应用。The present invention belongs to the field of biomedicine, and specifically relates to an epalrestat sustained-release composition, a preparation method thereof and an application thereof.

背景技术Background technique

依帕司他(5-[(1Z,2E)-2-甲基-3-苯基-2-丙烯亚基]-4-氧代-2-硫代-3-噻唑烷乙酸)为醛糖还原酶抑制剂类药物，可逆地抑制与糖尿病性并发症的发病机制相关的多元醇代谢中葡萄糖转化为山梨醇的醛糖还原酶而发挥作用。山梨醇能影响神经细胞功能，并在神经元内蓄积会引起糖尿病性支配感觉运动的外周神经病症状。临床将依帕司他用于抑制糖尿病外周神经病变患者红细胞中的山梨醇积累，以改善患者的自觉症状和神经功能障碍，用于预防、改善和治疗糖尿病及其并发的末梢神经障碍(麻木感、疼痛)。但患者需每天服用依帕司他片或依帕司他胶囊三次。每日多次服药降低了患者用药顺应性，且容易导致患者漏服药物而导致血糖升高，甚至造成糖尿病酮症酸中毒(DKA)等问题，并存在空腹血糖控制、餐后血糖控制和夜间血糖控制不佳而导致的低血糖发生率，影响药物的治疗效果及用药的安全有效性。文献报道的依帕司他胃漂浮片需要加入产气剂(如碳酸氢钠等)和助漂剂(如十八醇等)，且存在成本高、制备复杂等缺陷。为此，需要开发安全有效的依帕司他缓释制剂，以满足临床治疗需求。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 its 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 the patient's subjective symptoms and nerve dysfunction, and is used 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 an incidence of hypoglycemia caused by poor fasting blood sugar control, postprandial blood sugar control, and nighttime blood sugar control, which affects 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.

发明内容Summary of the invention

本发明的目的在于提供一种依帕司他缓释组合物，以重量百分比计，组合物中含有20-50％的依帕司他或其衍生物和药学上可接受 的载体，其中，所述衍生物选自共晶体、盐、游离酸、前药、酯、多晶型物、溶剂化物的任一种或其组合，所述的药学上可接受载体选自水凝胶材料、骨架材料、填充剂、崩解剂、粘合剂、润滑剂、助流剂的任一种或其组合。The object of the present invention is to provide an epalrestat sustained-release composition, which contains 20-50% epalrestat or its derivatives and a pharmaceutically acceptable The carrier is selected from any one or a combination of co-crystals, 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.

本发明优选的技术方案，以重量百分比计，组合物中的依帕司他或其衍生物为25-45％，优选为30-40％。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.

本发明的优选技术方案中，以重量百分比计，组合物中的水凝胶材料为5-20％，优选为8-18％，更优选为9-15％。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%.

本发明的优选技术方案中，所述水凝胶材料选自聚乙烯醇、水溶胀型纤维素、卡拉胶、黄原胶、瓜尔胶、阿拉伯胶、聚乙烯乙酸酯、卡波姆、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素(羟丙甲纤维素)、羟丙基甲基纤维素K4M、羟乙基纤维素、海藻酸盐、聚氧乙烯、羧甲纤维素、聚维酮、壳聚糖中的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的骨架材料为5-20％，优选为8-18％，更优选为10-15％。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%.

本发明的优选技术方案中，所述骨架材料选自非水溶性纤维素、聚乙烯吡咯烷酮、丙烯酸树脂、聚丙烯酸盐、乙基纤维素、乙基纤维素N10中的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的填充剂为5-40％，优选为10-35％，更优选为15-30％。In a 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%.

本发明的优选技术方案中，所述填充剂选自淀粉、蔗糖、预胶化淀粉、乳糖、硫酸钙、磷酸钙、碳酸钙、甘露醇、山梨醇、微晶纤维素、微晶纤维素SH-101、微晶纤维素102的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的崩解剂10-35％，优选为12-30％，更优选为15-20％。 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%.

本发明的优选技术方案中，所述崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基淀粉钠、交联羧甲基纤维素钙中的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的粘合剂为0-5％，优选为0.5-2.5％，更优选为1.5-2％。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%.

本发明的优选技术方案中，所述粘合剂选自低粘度纤维素、丙烯酸聚合物、透明质酸、海藻酸、多糖、多糖糖苷、羟丙基甲基纤维素、羟丙甲纤维素E5、羟丙纤维素EXF、淀粉浆、甲基纤维素、乙基纤维素、聚维酮中的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的润滑剂0.1-2％，优选为0.15-1.8％，更优选为0.2-0.5％。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%.

本发明的优选技术方案中，所述润滑剂选自硬脂酸镁、硬脂酸、氢化植物油、硬脂富马酸钠、聚乙二醇类、十二烷基硫酸钠的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的助流剂0-1％，优选为0.2-0.8％，更优选为0.4-0.6％。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%.

本发明的优选技术方案中，所述助流剂选自胶态二氧化硅、滑石粉、微粉硅胶的任一种或其组合。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他20-50％、水凝胶材料5-20％、骨架材料5-20％、填充剂5-40％、崩解剂10-35％、粘合剂0-5％、润滑剂0.1-2％和助流剂0-1％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他25-45％、水凝胶材料8-18％、骨架材料8-18％、填充剂10-35％、崩解剂12-30％、粘合剂0.5-2.5％、润滑剂0.15-1.8％和助流剂0.2-0.8％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30-40％、水凝胶材料9-15％、骨架材料10-15％、填充剂15-30％、 崩解剂15-20％、粘合剂1.5-2％、润滑剂0.2-0.5％和助流剂0.4-0.6％。In the preferred technical solution of the present invention, the composition comprises 30-40% epalrestat, 9-15% hydrogel material, 10-15% skeleton material, 15-30% filler, Disintegrant 15-20%, binder 1.5-2%, lubricant 0.2-0.5% and glidant 0.4-0.6%.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他20-50％、微晶纤维素5-40％、羟丙甲纤维素5-20％、乙基纤维素5-20％、交联聚维酮10-35％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.1-2％和胶态二氧化硅0-1％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他25-45％、微晶纤维素10-35％、羟丙甲纤维素8-18％、乙基纤维素8-18％、交联聚维酮12-30％、硬脂酸镁或硬脂富马酸钠的任一种或其组合0.15-1.8％和胶态二氧化硅0.2-0.8％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30-40％、微晶纤维素15-30％、羟丙甲纤维素9-15％、乙基纤维素10-15％、交联聚维酮15-20％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.2-0.5％和胶态二氧化硅0.4-0.6％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他20-50％、微晶纤维素5-40％、羟丙甲纤维素5-20％、乙基纤维素5-20％、羟丙纤维素1-5％、交联聚维酮10-35％、硬脂酸镁或硬脂酸富马酸的任一种或其组合0.1-2％和胶态二氧化硅0.1-1％。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% colloidal silicon dioxide.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他25-45％、微晶纤维素10-35％、羟丙甲纤维素8-18％、乙基纤维素8-18％、羟丙纤维素1-5％、交联聚维酮12-30％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.15-1.8％和胶态二氧化硅0.2-0.8％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30-40％、微晶纤维素15-30％、羟丙甲纤维素9-15％、乙基纤维素10-15％、羟丙纤维素1-5％、交联聚维酮15-20％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.2-0.5％和胶态二氧化硅0.4-0.6％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司 他34.88％、微晶纤维素9.30％、羟丙甲纤维素K4M 13.95％、乙基纤维素16.28％、羟丙甲纤维素E5 0.81％、交联聚维酮23.26％和硬脂酸镁1.51％。In the preferred technical solution of the present invention, the epasidine in the composition is calculated by weight percentage. He 34.88%, microcrystalline cellulose 9.30%, hypromellose K4M 13.95%, ethyl cellulose 16.28%, hypromellose E5 0.81%, crospovidone 23.26% and magnesium stearate 1.51%.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素11.63％、羟丙甲纤维素K4M 12.79％、乙基纤维素15.12％、羟丙甲纤维素E5 0.81％、交联聚维酮23.26％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素6.98％、羟丙甲纤维素K4M 12.79％、乙基纤维素15.12％、羟丙甲纤维素E5 0.81％、交联聚维酮27.91％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素11.62％、羟丙甲纤维素K4M 10.47％、乙基纤维素12.79％、羟丙甲纤维素E5 0.81％、交联聚维酮27.91％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素9.30％、羟丙甲纤维素K4M 13.95％、乙基纤维素16.28％、羟丙甲纤维素E5 0.81％、交联聚维酮23.26％和硬脂富马酸钠1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% sodium stearyl fumarate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素13.95％、羟丙甲纤维素K4M 9.30％、乙基纤维素11.63％、羟丙甲纤维素E5 0.81％、交联聚维酮27.91％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素15.12％、羟丙甲纤维素K4M 8.72％、乙基纤维素11.05％、羟丙甲纤维素E5 0.81％、交联聚维酮27.91％和硬脂酸镁 1.51％。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 magnesium stearate. 1.51%.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素13.60％、羟丙甲纤维素K4M 10.47％、乙基纤维素E5 11.63％、交联聚维酮27.91％和硬脂酸镁1.51％。In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 13.60% microcrystalline cellulose, 10.47% hydroxypropyl methylcellulose K4M, 11.63% ethyl cellulose E5, 27.91% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他31.25％、微晶纤维素30.31％、羟丙甲纤维素K4M 9.9％、乙基纤维素10.42％、羟丙甲纤维素E5 0.73％、交联聚维酮16.67％、硬脂酸镁0.52％和胶态二氧化硅0.21％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30％、微晶纤维素27.9％、羟丙甲纤维素K4M 9％、乙基纤维素11％、羟丙甲纤维素E5 1.5％、交联聚维酮20％、硬脂酸镁0.2％和胶态二氧化硅0.4％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30％、微晶纤维素27.4％、羟丙甲纤维素9％、乙基纤维素11％、羟丙纤维素2％、交联聚维酮20％、硬脂酸镁0.2％和胶态二氧化硅0.4％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30％、微晶纤维素22.4％、羟丙甲纤维素11％、乙基纤维素14％、羟丙纤维素2％、交联聚维酮20％、硬脂酸镁0.2％和胶态二氧化硅0.4％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30％、微晶纤维素26.6％、羟丙甲纤维素12％、乙基纤维素14％、羟丙纤维素1％、交联聚维酮16％、硬脂酸镁0.2％和胶态二氧化硅0.2％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他31.3％、微晶纤维素27.7％、羟丙甲纤维素12.5％、乙基纤维素14.6％、羟丙纤维素1％、交联聚维酮12.5％、硬脂酸镁0.2％和胶态二氧化硅0.2％。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.

本发明优选的技术方案中，所述缓释组合物任选地含有溶剂，优 选溶剂选自水、乙醇的任一种或其组合。In a preferred technical solution of the present invention, the sustained-release composition optionally contains a solvent, preferably The solvent is selected from any one of water, ethanol or a combination thereof.

本发明优选的技术方案中，所述缓释组合物为胃漂浮片。In a preferred technical solution of the present invention, the sustained-release composition is a gastric floating tablet.

本发明优选的技术方案中，所述胃漂浮片在模拟胃液(pH1.2)中立即起漂。In a preferred technical solution of the present invention, the gastric floating tablet floats immediately in simulated gastric fluid (pH 1.2).

本发明优选的技术方案中，所述胃漂浮片在模拟胃液(pH1.2)中的漂浮时间≥8h，优选≥24h，更优选≥72h。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.

本发明优选的技术方案中，所述胃漂浮片置于磷酸盐缓冲溶液(pH6.8)中8h的溶出度≥80％，优选≥90％。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%.

本发明优选的技术方案中，所述胃漂浮片置于磷酸盐缓冲溶液(pH6.8)中12h的溶出度≥90％，优选≥95％。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%.

本发明的另一目的在于提供一种依帕司他缓释组合物的制备方法，以重量百分比计，组合物中含有20-50％的依帕司他或其衍生物和药学上可接受的载体，其中，所述衍生物选自共晶体、盐、游离酸、前药、酯、多晶型物、溶剂化物的任一种或其组合，所述的药学上可接受载体选自水凝胶材料、骨架材料、填充剂、崩解剂、粘合剂、润滑剂、助流剂的任一种或其组合，组合物的制备选自粉末直接压片法、湿法制粒法中的任一种。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.

本发明优选的技术方案，以重量百分比计，组合物中的依帕司他或其衍生物为25-45％，优选为30-40％。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.

本发明的优选技术方案中，以重量百分比计，组合物中的水凝胶材料为5-20％，优选为8-18％，更优选为9-15％。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%.

本发明的优选技术方案中，所述水凝胶材料选自聚乙烯醇、水溶胀型纤维素、卡拉胶、黄原胶、瓜尔胶、阿拉伯胶、聚乙烯乙酸酯、卡波姆、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素(羟丙甲纤维素)、羟丙基甲基纤维素K4M、羟乙基纤维素、海藻酸 盐、聚氧乙烯、羧甲纤维素、聚维酮、壳聚糖中的任一种或其组合。In the preferred technical solution of the present invention, the hydrogel material is selected from 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, alginic acid Any one of salt, polyoxyethylene, carboxymethyl cellulose, povidone, chitosan or a combination thereof.

本发明的优选技术方案中，以重量百分比计，组合物中的骨架材料为5-20％，优选为8-18％，更优选为10-15％。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%.

本发明的优选技术方案中，所述骨架材料选自非水溶性纤维素、聚乙烯吡咯烷酮、丙烯酸树脂、聚丙烯酸盐、乙基纤维素、乙基纤维素N10中的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的填充剂为5-40％，优选为10-35％，更优选为15-30％。In a 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%.

本发明的优选技术方案中，所述填充剂选自淀粉、蔗糖、预胶化淀粉、乳糖、硫酸钙、磷酸钙、碳酸钙、甘露醇、山梨醇、微晶纤维素、微晶纤维素SH-101、微晶纤维素102的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的崩解剂10-35％，优选为12-30％，更优选为15-20％。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%.

本发明的优选技术方案中，所述崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基淀粉钠、交联羧甲基纤维素钙中的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的粘合剂为0-5％，优选为0.5-2.5％，更优选为1.5-2％。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%.

本发明的优选技术方案中，所述粘合剂选自低粘度纤维素、丙烯酸聚合物、透明质酸、海藻酸、多糖、多糖糖苷、羟丙基甲基纤维素、羟丙甲纤维素E5、羟丙纤维素EXF、淀粉浆、甲基纤维素、乙基纤维素、聚维酮中的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的润滑剂0.1-2％，优选为0.15-1.8％，更优选为0.2-0.5％。 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%.

本发明的优选技术方案中，所述润滑剂选自硬脂酸镁、硬脂酸、氢化植物油、硬脂富马酸钠、聚乙二醇类、十二烷基硫酸钠的任一种或其组合。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.

本发明的优选技术方案中，以重量百分比计，组合物中的助流剂0-1％，优选为0.2-0.8％，更优选为0.4-0.6％。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%.

本发明的优选技术方案中，所述助流剂选自胶态二氧化硅、滑石粉、微粉硅胶的任一种或其组合。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他20-50％、水凝胶材料5-20％、骨架材料5-20％、填充剂5-40％、崩解剂10-35％、粘合剂0-5％、润滑剂0.1-2％和助流剂0-1％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他25-45％、水凝胶材料8-18％、骨架材料8-18％、填充剂10-35％、崩解剂12-30％、粘合剂0.5-2.5％、润滑剂0.15-1.8％和助流剂0.2-0.8％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30-40％、水凝胶材料9-15％、骨架材料10-15％、填充剂15-30％、崩解剂15-20％、粘合剂1.5-2％、润滑剂0.2-0.5％和助流剂0.4-0.6％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他20-50％、微晶纤维素5-40％、羟丙甲纤维素5-20％、乙基纤维素5-20％、交联聚维酮10-35％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.1-2％和胶态二氧化硅0-1％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他25-45％、微晶纤维素10-35％、羟丙甲纤维素8-18％、乙基纤维素8-18％、交联聚维酮12-30％、硬脂酸镁或硬脂富马酸钠的任一种或其组合0.15-1.8％和胶态二氧化硅0.2-0.8％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30-40％、微晶纤维素15-30％、羟丙甲纤维素9-15％、乙基纤维素 10-15％、交联聚维酮15-20％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.2-0.5％和胶态二氧化硅0.4-0.6％。In the preferred technical solution of the present invention, the composition comprises 30-40% epalrestat, 15-30% microcrystalline cellulose, 9-15% hypromellose, and ethyl cellulose in weight percentage. 10-15%, crospovidone 15-20%, any one of magnesium stearate or sodium stearyl fumarate or a combination thereof 0.2-0.5% and colloidal silicon dioxide 0.4-0.6%.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他20-50％、微晶纤维素5-40％、羟丙甲纤维素5-20％、乙基纤维素5-20％、羟丙纤维素1-5％、交联聚维酮10-35％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.1-2％和胶态二氧化硅0.1-1％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他25-45％、微晶纤维素10-35％、羟丙甲纤维素8-18％、乙基纤维素8-18％、羟丙纤维素1-5％、交联聚维酮12-30％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.15-1.8％和胶态二氧化硅0.2-0.8％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30-40％、微晶纤维素15-30％、羟丙甲纤维素9-15％、乙基纤维素10-15％、羟丙纤维素1-5％、交联聚维酮15-20％、硬脂酸镁或硬脂酸富马酸钠的任一种或其组合0.2-0.5％和胶态二氧化硅0.4-0.6％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素9.30％、羟丙甲纤维素K4M 13.95％、乙基纤维素16.28％、羟丙甲纤维素E5 0.81％、交联聚维酮23.26％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素11.63％、羟丙甲纤维素K4M 12.79％、乙基纤维素15.12％、羟丙甲纤维素E5 0.81％、交联聚维酮23.26％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素6.98％、羟丙甲纤维素K4M 12.79％、乙基纤维素15.12％、羟丙甲纤维素E5 0.81％、交联聚维酮27.91％和硬脂酸镁1.51％。 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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素11.62％、羟丙甲纤维素K4M 10.47％、乙基纤维素12.79％、羟丙甲纤维素E5 0.81％、交联聚维酮27.91％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素9.30％、羟丙甲纤维素K4M 13.95％、乙基纤维素16.28％、羟丙甲纤维素E5 0.81％、交联聚维酮23.26％和硬脂富马酸钠1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% sodium stearyl fumarate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素13.95％、羟丙甲纤维素K4M 9.30％、乙基纤维素11.63％、羟丙甲纤维素E5 0.81％、交联聚维酮27.91％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素15.12％、羟丙甲纤维素K4M 8.72％、乙基纤维素11.05％、羟丙甲纤维素E5 0.81％、交联聚维酮27.91％和硬脂酸镁1.51％。In the preferred technical scheme 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% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他34.88％、微晶纤维素13.60％、羟丙甲纤维素K4M 10.47％、乙基纤维素E5 11.63％、交联聚维酮27.91％和硬脂酸镁1.51％。In the preferred technical scheme of the present invention, the composition comprises, by weight percentage, 34.88% epalrestat, 13.60% microcrystalline cellulose, 10.47% hydroxypropyl methylcellulose K4M, 11.63% ethyl cellulose E5, 27.91% cross-linked polyvinylpyrrolidone and 1.51% magnesium stearate.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他31.25％、微晶纤维素30.31％、羟丙甲纤维素K4M 9.9％、乙基纤维素10.42％、羟丙甲纤维素E5 0.73％、交联聚维酮16.67％、硬脂酸镁0.52％和胶态二氧化硅0.21％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30％、微晶纤维素27.9％、羟丙甲纤维素K4M 9％、乙基纤维素11％、羟丙甲纤维素E5 1.5％、交联聚维酮20％、硬脂酸镁0.2％和胶态二氧 化硅0.4％。In the preferred technical solution 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% crospovidone, 0.2% magnesium stearate and 0.2% colloidal dioxygenase. Silicon dioxide 0.4%.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30％、微晶纤维素27.4％、羟丙甲纤维素9％、乙基纤维素11％、羟丙纤维素2％、交联聚维酮20％、硬脂酸镁0.2％和胶态二氧化硅0.4％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30％、微晶纤维素22.4％、羟丙甲纤维素11％、乙基纤维素14％、羟丙纤维素2％、交联聚维酮20％、硬脂酸镁0.2％和胶态二氧化硅0.4％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他30％、微晶纤维素26.6％、羟丙甲纤维素12％、乙基纤维素14％、羟丙纤维素1％、交联聚维酮16％、硬脂酸镁0.2％和胶态二氧化硅0.2％。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.

本发明优选的技术方案中，以重量百分比计，组合物中的依帕司他31.3％、微晶纤维素27.7％、羟丙甲纤维素12.5％、乙基纤维素14.6％、羟丙纤维素1％、交联聚维酮12.5％、硬脂酸镁0.2％和胶态二氧化硅0.2％。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.

本发明优选的技术方案中，所述缓释组合物为胃漂浮片。In a preferred technical solution of the present invention, the sustained-release composition is a gastric floating tablet.

本发明优选的技术方案中，所述胃漂浮片在模拟胃液(pH1.2)中立即起漂。In a preferred technical solution of the present invention, the gastric floating tablet floats immediately in simulated gastric fluid (pH 1.2).

本发明优选的技术方案中，所述胃漂浮片在模拟胃液(pH1.2)中的漂浮时间≥8h，优选≥24h，更优选≥72h。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.

本发明优选的技术方案中，所述胃漂浮片置于磷酸盐缓冲溶液(pH6.8)中8h的溶出度≥80％，优选≥90％。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%.

本发明优选的技术方案中，所述胃漂浮片置于磷酸盐缓冲溶液(pH6.8)中12h的溶出度≥90％，优选≥95％。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%.

本发明优选的技术方案中，所述粉末直接压片法包括下述步骤：称取所需量的依帕司他、水凝胶材料、骨架材料、填充剂、崩 解剂、粘合剂、润滑剂、助流剂的任一种或其组合，将其均匀混合后，压片，即得。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, Any one or a combination of a disintegrating agent, a binder, a lubricant and a glidant is mixed evenly and then tabletted to obtain the product.

本发明优选的技术方案中，所述缓释组合物任选地含有溶剂，优选溶剂选自水、乙醇的任一种或其组合。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.

本发明优选的技术方案中，所述湿法制粒法包括下述步骤：1)称取所需量的依帕司他、填充剂、水凝胶材料、骨架材料、崩解剂的任一种或其组合，将其均匀混合，加入溶剂，制粒，干燥，制得干燥颗粒；2)将制得的干燥颗粒与所需量的粘合剂、润滑剂、助流剂的任一种或其组合均匀混合后，压片，即得，其中，所述溶剂选自水、乙醇的任一种或其组合。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 to obtain, wherein the solvent is selected from any one or a combination of water and ethanol.

本发明优选的技术方案中，所述干燥选自减压干燥、真空干燥、喷雾干燥、流化床干燥的任一种。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.

本发明优选的技术方案中，所述干燥温度为55-75℃，优选为60-70℃。In the preferred technical solution of the present invention, the drying temperature is 55-75°C, preferably 60-70°C.

本发明优选的技术方案中，所述干燥颗粒的含水量％≤5.0％，优选为≤3.0％。In a preferred technical solution of the present invention, the moisture content of the dry particles is ≤5.0%, preferably ≤3.0%.

本发明的另一目的在于一种依帕司他缓释制剂，所述缓释制剂至少包含缓释漂浮层，所述缓释漂浮层中含有水凝胶材料和骨架材料，其中，所述缓释制剂中的水凝胶材料：依帕司他的质量比为0.25-0.4：1，骨架材料：依帕司他的质量比为0.2-0.5：1，所述水凝胶材料选自聚乙烯醇、水溶胀型纤维素、卡拉胶、黄原胶、瓜尔胶、阿拉伯胶、羟丙基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素K4M中的任一种或其组合，所述骨架材料选自非水溶性纤维素、聚乙烯吡咯烷酮、丙烯酸树脂、聚丙烯酸盐、乙基纤维素N10中的任一种或其组合。 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 sustained-release preparation is 0.25-0.4:1, and the mass ratio of the skeleton material:epalrestat is 0.2-0.5:1, 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.

本发明优选的技术方案中，缓释制剂中的骨架材料：依帕司他的质量比为0.3-0.5：1。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.

本发明优选的技术方案中，所述缓释制剂中还含有填充剂，所述填充剂选自微晶纤维素、微晶纤维素SH-101、微晶纤维素102的任一种或其组合。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.

本发明优选的技术方案中，缓释制剂中的填充剂：依帕司他的质量比为0.2-1：1，优选为0.3-0.4:1，更优选为0.7-1：1。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.

本发明优选的技术方案中，所述缓释制剂中任选地含有崩解剂、粘合剂、溶剂、助流剂、润滑剂中的任一种或其组合。In a preferred technical solution of the present invention, the sustained-release preparation optionally contains any one of a disintegrant, a binder, a solvent, a glidant, a lubricant, or a combination thereof.

本发明优选的技术方案中，所述崩解剂为交联聚维酮。In a preferred technical solution of the present invention, the disintegrant is cross-linked polyvinylpyrrolidone.

本发明优选的技术方案中，缓释制剂中的崩解剂：依帕司他的质量比为0.5-0.8：1。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.

本发明优选的技术方案中，所述粘合剂选自低粘度纤维素、丙烯酸聚合物、透明质酸、海藻酸、多糖、多糖糖苷、羟丙基甲基纤维素E5、羟丙基纤维素EXF中的任一种或其组合。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.

本发明优选的技术方案中，缓释制剂中的粘合剂：依帕司他的质量比为1：50-1：15。In the 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.

本发明优选的技术方案中，所述润滑剂为硬脂酸镁。In a preferred technical solution of the present invention, the lubricant is magnesium stearate.

本发明优选的技术方案中，缓释制剂中的润滑剂：依帕司他的质量比为0.005-0.05：1。In the 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.

本发明优选的技术方案中，所述助流剂为胶态二氧化硅。In a preferred technical solution of the present invention, the glidant is colloidal silicon dioxide.

本发明优选的技术方案中，缓释制剂中的助流剂：依帕司他的质量比为0.005-0.05：1。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.

本发明另一目的在于提供本发明的依帕司他缓释组合物或缓释制剂用于制备防治糖尿病及其并发症的药物中的应用。 Another object of the present invention is to provide use of the epalrestat sustained-release composition or sustained-release preparation of the present invention in preparing a medicament for preventing and treating diabetes and its complications.

本发明优选的技术方案中，所述并发症为糖尿病并发的末梢神经障碍、麻木感、疼痛的任一种或其组合。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.

本发明的优选技术方案，根据患者的病情、用药、年龄、性别、病痛类型等因素选择合适的用量和疗程。成人患者每天服用一次，每次服用一片(剂量为150mg)。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 is 150 mg) once a day.

除非另有说明，本发明所述的立即起漂是指胃漂浮片置于模拟胃液(pH1.2)中5min内起漂。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).

除非另有说明，本发明所述的杂质含量检测采用高效液相色谱仪，其色谱条件为：以十八烷基硅烷键合硅胶为填充剂，流动相A为磷酸氢二钠溶液-(用磷酸调节pH至6.0)-乙腈(75:25)，流动相B为乙腈，梯度洗脱(流动相A：流动相B的体积比分别为100:0、85:15、80:20、20:80、0:100，洗脱0-60min)，流速1.0ml/min,柱温35℃，检测波长280nm，进样体积10μl。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 (the volume ratio of mobile phase A: mobile phase B is 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.

除非另有说明，本发明涉及液体与液体之间的百分比时，所述的百分比为体积/体积百分比；本发明涉及液体与固体之间的百分比时，所述百分比为体积/重量百分比；本发明涉及固体与液体之间的百分比时，所述百分比为重量/体积百分比；其余为重量/重量百分比。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.

与现有技术相比，本发明具有下述有益技术效果：Compared with the prior art, the present invention has the following beneficial technical effects:

1、本发明科学筛选依帕司他缓释组合物的组分及配比，并省略使用产气剂(如碳酸氢钠等)和助漂剂(如十八醇等)，制得的胃漂浮片具有良好的漂浮性能、长效缓释、质量更优(包括质量均一性好、片型完整、无裂片或碎片，片重更小等)、稳定性好、变异性小、生物利用度高、安全有效等优点，利于空腹血糖控制、餐后血糖控制、夜间血糖控制，显著降低低血糖发生率，显著提高患者的用药顺应性、治疗依从性和持续性，显著提高临床用药的安全有效性。1. The present invention scientifically screens the components and proportions of the epalrestat sustained-release composition, and omits the use of gas-generating agents (such as sodium bicarbonate, etc.) and bleaching agents (such as octadecyl alcohol, etc.). The prepared gastric floating tablets have the advantages of good floating performance, 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., which are beneficial to fasting blood sugar control, postprandial blood sugar control, and 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.

2、本发明依帕司他缓释组合物的制备具有操作简便，成本更优、 绿色环保、适合工业化生产等优点。2. The preparation of the epalrestat sustained-release composition of the present invention is simple to operate and has better cost performance. It is green, environmentally friendly and suitable for industrial production.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1本发明依帕司他缓释组合物的体外释放度考察。FIG1 is an investigation of the in vitro release of the epalrestat sustained-release composition of the present invention.

图2本发明依帕司他缓释组合物的体内吸收研究。FIG. 2 shows an in vivo absorption study of the epalrestat sustained-release composition of the present invention.

具体实施方式Detailed ways

下面结合具体实施例对本发明的详细内容做进一步解释和描述，但并不以此限制本发明的保护范围。The details of the present invention are further explained and described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

具体实施方式的有关物质(杂质)编号及组成：
The numbering and composition of the relevant substances (impurities) of the specific implementation method:

实施例1本发明依帕司他缓释组合物的制备 Example 1 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：

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

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(片厚5.75mm)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞8h。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.

实施例2本发明依帕司他缓释组合物的制备 Example 2 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(片厚5.58mm)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞8h。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 5.58 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 float immediately, and the floating time is greater than 8 hours.

实施例3本发明依帕司他缓释组合物的制备 Example 3 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：

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

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(片厚5.6mm)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞8h。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.

实施例4本发明依帕司他缓释组合物的制备 Example 4 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(片厚5.68mm)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。 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.

实施例5本发明依帕司他缓释组合物的制备 Example 5 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(片厚6.08mm)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。The preparation of the epalrestat sustained-release composition comprises the following steps: weighing the required amount of components, mixing them uniformly, and directly tableting to obtain a tablet (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.

实施例6本发明依帕司他缓释组合物的制备 Example 6 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(片厚5.78mm)。按照本领域常规 的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。The preparation of the sustained-release composition of epalrestat includes the following steps: weighing the required amount of components, mixing them evenly, and directly compressing them into tablets (tablet thickness 5.78 mm). The tablets were tested by the method of stable quality and complete tablet shape without cracks and fragments.

实施例7本发明依帕司他缓释组合物的制备 Example 7 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(片厚6.15mm)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。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 obtained is stable, the tablet shape is complete, and there are no cracks or fragments.

实施例8本发明依帕司他缓释组合物的制备 Example 8 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分， 将其均匀混合后，直接压片，即得(片厚6.08mm)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。The preparation of the epalrestat sustained-release composition comprises the following steps: weighing the required amounts of components, After uniform mixing, the tablets were directly compressed to obtain tablets (thickness 6.08 mm). According to the conventional method in the art, the tablets were tested to have stable quality and complete tablet shape without cracks and fragments.

实施例9本发明依帕司他缓释组合物的制备 Example 9 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片)：
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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%);

2、将制得颗粒与所需量的羟丙甲纤维素E5、硬脂酸镁和胶态二氧化硅均匀混合后，压片，即得(片厚6.42mm)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。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.

实施例10本发明依帕司他缓释组合物的制备 Example 10 Preparation of the Epalrestat sustained-release composition of the present invention

依帕司他缓释组合物的组成(批量600片)：
Composition of epalrestat sustained-release composition (batch 600 tablets):

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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%);

2、将制得颗粒与所需量的羟丙甲纤维素E5、硬脂酸镁和胶态二氧化硅均匀混合后，压片，即得(片厚6.59mm)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。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.

实施例11本发明依帕司他缓释组合物的制备 Example 11 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量600片)：

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

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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%);

2、将制得颗粒与所需量的羟丙甲纤维素EXF、硬脂酸镁和胶态二氧化硅均匀混合后，压片，即得(片厚6.56mm)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。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.

实施例12本发明依帕司他缓释组合物的制备 Example 12 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量600片)：

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

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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%);

2、将制得颗粒与所需量的羟丙甲纤维素EXF、硬脂酸镁和胶态二氧化硅均匀混合后，压片，即得(片厚6.57mm)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。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.

实施例13本发明依帕司他缓释组合物的制备 Example 13 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片):
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤： The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10、交联聚维酮KCL，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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%);

2、将制得颗粒与所需量的羟丙甲纤维素EXF、硬脂酸镁和胶态二氧化硅均匀混合后，压片，即得(片厚6.28mm)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞8h。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.

实施例14本发明依帕司他缓释组合物的制备 Example 14 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成(批量400片):
Composition of epalrestat sustained-release composition (batch 400 tablets):

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10、交联聚维酮KCL，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散” 为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, hypromellose K4M, ethyl cellulose N10, and cross-linked polyvinylpyrrolidone KCL, mix them evenly, and add appropriate amount of water (the amount of water should be such that the particles "clump together when kneaded and fall apart when touched") under stirring at 450 rpm. The wet granules containing the drug are placed in a fluidized bed (60° C.) for drying to obtain granules (water content ≤ 3.0%);

2、将制得颗粒与所需量的羟丙甲基纤维素EXF、硬脂酸镁和胶态二氧化硅均匀混合后，压片，即得(片厚6.04mm)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞8h。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.

实施例15本发明依帕司他缓释组合物的制备 Example 15 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：
Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(每片重430mg)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例16本发明依帕司他缓释组合物的制备 Example 16 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：

Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(每片重430mg)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例17本发明依帕司他缓释组合物的制备 Example 17 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：
Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(每片重430mg)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。 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.

实施例18本发明依帕司他缓释组合物的制备 Example 18 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：
Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(每片重430mg)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例19本发明依帕司他缓释组合物的制备 Example 19 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：
Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(每片重430mg)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例20本发明依帕司他缓释组合物的制备 Example 20 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：
Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(每片重430mg)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例21本发明依帕司他缓释组合物的制备 Example 21 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：

Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(每片重430mg)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例22本发明依帕司他缓释组合物的制备 Example 22 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：
Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：称取所需量的组分，将其均匀混合后，直接压片，即得(每片重430mg)。按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例23本发明依帕司他缓释组合物的制备 Example 23 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：
Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL-F，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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 dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

2、将制得颗粒与所需量的羟丙甲纤维素E5、硬脂酸镁、胶态二氧化硅均匀混合后，压片，即得(每片重480mg)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例24本发明依帕司他缓释组合物的制备 Example 24 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：

Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL-F，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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 dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

2、将制得颗粒与所需量的羟丙甲纤维素E5、硬脂酸镁、胶态二氧化硅均匀混合后，压片，即得(每片重500mg)。2. Evenly mix the obtained granules with the required amount of hydroxypropyl methylcellulose E5, magnesium stearate and colloidal silicon dioxide, and press into tablets (each tablet weighs 500 mg).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例25本发明依帕司他缓释组合物的制备 Example 25 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：

Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL-F，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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 dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

2、将制得颗粒与所需量的羟丙纤维素EXF、硬脂酸镁、胶态二氧化硅均匀混合后，压片，即得(每片重500mg)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间48h。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.

实施例26本发明依帕司他缓释组合物的制备 Example 26 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成：

Composition of the epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL-F，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；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 dry the drug-containing wet granules in a fluidized bed (60° C.) to obtain granules (water content ≤ 3.0%);

2、将制得颗粒与所需量的羟丙纤维素EXF、硬脂酸镁、胶态二氧化硅均匀混合后，压片，即得(每片重500mg)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间72h。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.

实施例27本发明依帕司他缓释组合物的制备 Example 27 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成:
Composition of epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素 K4M、乙基纤维素N10和交联聚维酮KCL-F，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥，制得颗粒(水分≤3.0％)；1. Weigh the required amount of epalrestat, microcrystalline cellulose SH101, and hypromellose K4M, ethyl cellulose N10 and cross-linked polyvinylpyrrolidone KCL-F are uniformly mixed, and a proper amount of water is added under stirring at 450 rpm (the amount of water is preferably such that the particles "can be kneaded into a mass and fall apart when touched") to obtain drug-containing wet granules, and the drug-containing wet granules are placed in a fluidized bed (60° C.) for drying to obtain granules (water content ≤ 3.0%);

2、将制得颗粒与所需量的羟丙纤维素EXF、硬脂酸镁、胶态二氧化硅均匀混合后，压片，即得(每片重500mg)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

实施例28本发明依帕司他缓释组合物的制备 Example 28 Preparation of the Epalrestat Sustained Release Composition of the Present Invention

依帕司他缓释组合物的组成:
Composition of epalrestat sustained-release composition:

依帕司他缓释组合物的制备包括下述步骤：The preparation of the epalrestat sustained-release composition comprises the following steps:

1、称取所需量的依帕司他、微晶纤维素SH101、羟丙甲纤维素K4M、乙基纤维素N10和交联聚维酮KCL-F，将其均匀混合，在450rpm搅拌条件下，加入适量水(水的用量以颗粒呈“捏之成团、触之即散”为宜)，制得含药湿颗粒，将含药湿颗粒置于流化床(60℃)干燥， 制得颗粒(水分≤3.0％)；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 prepare drug-containing wet granules, and place the drug-containing wet granules in a fluidized bed (60°C) for drying. Granules (water content ≤ 3.0%) were obtained;

2、将制得颗粒与所需量的羟丙纤维素EXF、硬脂酸镁、胶态二氧化硅均匀混合后，压片，即得(每片重480mg)。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).

按照本领域常规的方法检测，制得片剂的质量稳定、片型完整，没有裂片和碎片。将制得片剂置于模拟胃液(pH1.2)中，其立即起漂，漂浮时间＞12h。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.

试验例1本发明依帕司他缓释组合物稳定性考察 Test Example 1: Stability Study of the Epalrestat Sustained-Release Composition of the Present Invention

以实施例26的缓释组合物作为示例，将其置于40℃、相对湿度(RH)75％条件下放置6个月，考察本发明缓释组合物的稳定性结果见表1。本发明的缓释组合物在6个月的考察期中，片型完整，且未见变色、麻点、裂片和碎片等。Taking the sustained-release composition of Example 26 as an example, it was placed at 40° C. and 75% relative humidity (RH) for 6 months, and the stability of the sustained-release composition of the present invention was investigated and 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.

表1实施例26的缓释组合物稳定性考察
Table 1 Stability study of the sustained-release composition of Example 26

用该方法考察本发明其余实施例的缓释组合物，表现类似优异的稳定性。The sustained-release compositions of the remaining examples of the present invention were examined using this method and showed similar excellent stability.

试验例2本发明依帕司他缓释组合物的体外释放度考察 Test Example 2 Investigation of the in vitro release of the epalrestat sustained-release composition of the present invention

按照《中国药典》(2020年版)四部通则0931第二法的溶出度与释放度测定法，以900ml磷酸盐缓冲液(pH6.8+0.5％吐温80)为溶出介质，浆法(100转/min)，以实施例1-2、实施例21-23、实施例25-26的缓释组合物作为示例，于1h、2h、4h、6h、8h、12h，检 测本发明依帕司他缓释组合物的体外释放度，结果见图1。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 sustained-release compositions of Examples 1-2, 21-23, and 25-26 were used as examples. The samples were tested at 1 h, 2 h, 4 h, 6 h, 8 h, and 12 h. The in vitro release rate of the epalrestat sustained-release composition of the present invention was measured, and the results are shown in FIG1 .

试验例3本发明依帕司他缓释组合物的质量均一性考察Test Example 3 Investigation of the Quality Uniformity of the Epalrestat Sustained-Release Composition of the Present Invention

以实施例25和实施例26制得的缓释组合物作为示例，考察本发明依帕司他缓释组合物的质量均一性，结果见表2。本发明依帕司他缓释组合物的质量均一性良好。Taking the sustained-release compositions prepared in Example 25 and Example 26 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.

表2
Table 2

试验例4本发明依帕司他缓释组合物的体内吸收研究 Experimental Example 4 In vivo absorption study of the epalrestat sustained-release composition of the present invention

研究本发明的依帕司他缓释制剂在体内的吸收情况。将实施例2、实施例6制得的依帕司他缓释片与原研的普通片进行生物实验测试，采用小型猪动物模型，口服给药。对实施例2和实施例6制得的缓释片，均采用一次给药的方式，单次给药依帕司他的量为150mg，对原研的依帕司他普通片，采用每8小时给药一次的方式，每次给药依帕司他的量为50mg，结果见图2A。The absorption of the epalrestat sustained-release preparation of the present invention in vivo was studied. The epalrestat sustained-release tablets prepared in Example 2 and Example 6 were subjected to biological experimental tests with the original common tablets, and oral administration was performed using a miniature pig animal model. The sustained-release tablets prepared in Example 2 and Example 6 were both administered once, with a single dose of 150 mg of epalrestat. For the original epalrestat common tablets, the dosage was administered once every 8 hours, with a dosage of 50 mg of epalrestat each time. The results are shown in FIG2A.

本发明的依帕司他缓释组合物长效缓释，利于空腹血糖控制、餐后血糖控制、夜间血糖控制，显著降低低血糖发生率，提高患者用药依从性和治疗持续性，保障临床用药安全有效。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.

试验例5本发明依帕司他缓释组合物的体内吸收研究 Experimental Example 5 In vivo absorption study of the epalrestat sustained-release composition of the present invention

选取体重9-15kg、月龄3-6个月的巴马小香猪6只(雌雄各半)，将其分为3组，每组2只(雄雌各半)，灌胃给药。试验动物在给药前禁食。 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.

对照组：灌胃给药原研制剂(商品名：KINEDAK)，每次给药剂量为50mg，每天灌胃给药3次，每次间隔8h。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.

试验组1：灌胃给药实施例25的缓释组合物，给药剂量为150mg，每天灌胃给药1次。Experimental Group 1: The sustained-release composition of Example 25 was administered by intragastric administration at a dosage of 150 mg, once a day.

试验组2：灌胃给药实施例26的缓释组合物，给药剂量为150mg，每天灌胃给药1次。Experimental Group 2: The sustained-release composition of Example 26 was administered by intragastric administration at a dosage of 150 mg, once a day.

对照组在给药前及给药后0.25h，0.5h，1h，2h，4h，8h，8.25h，8.5h，9h，10h，12h，16h，16.25h，16.5h，17h，18h，20h，24h采集血液样品进行检测；试验组在给药前及给药后0.25h，0.5h，1h，2h，4h，6h，8h，12h，16h，24h采集血液样品进行检测。结果见图2B。Blood samples were collected for detection in the control group before 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; blood samples were collected for detection in the experimental group before and 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 16h, and 24h after administration. The results are shown in Figure 2B.

本发明的依帕司他缓释组合物长效缓释，利于空腹血糖控制、餐后血糖控制、夜间血糖控制，显著降低低血糖发生率，提高患者用药依从性和治疗持续性，保障临床用药安全有效。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.

以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明权利要求保护的范围。 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 (10)

一种依帕司他缓释组合物，以重量百分比计，组合物中含有20-50％的依帕司他或其衍生物和药学上可接受的载体，其中，所述衍生物选自共晶体、盐、游离酸、前药、酯、多晶型物、溶剂化物的任一种或其组合，所述的药学上可接受载体选自水凝胶材料、骨架材料、填充剂、崩解剂、粘合剂、润滑剂、助流剂的任一种或其组合。A sustained-release composition of epalrestat, comprising, by weight percentage, 20-50% of epalrestat or its derivatives and a pharmaceutically acceptable carrier, 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. 如权利要求1所述的组合物，所述水凝胶材料选自聚乙烯醇、水溶胀型纤维素、卡拉胶、黄原胶、瓜尔胶、阿拉伯胶、聚乙烯乙酸酯、卡波姆、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素(羟丙甲纤维素)、羟丙基甲基纤维素K4M、羟乙基纤维素、海藻酸盐、聚氧乙烯、羧甲纤维素、聚维酮、壳聚糖中的任一种或其组合。The composition as claimed in claim 1, wherein 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, polyoxyethylene, carboxymethyl cellulose, povidone, chitosan or a combination thereof. 如权利要求1-2任一项所述的组合物，所述骨架材料选自非水溶性纤维素、聚乙烯吡咯烷酮、丙烯酸树脂、聚丙烯酸盐、乙基纤维素、乙基纤维素N10中的任一种或其组合。The composition according to any one of claims 1 to 2, wherein the skeleton material is selected from any one of water-insoluble cellulose, polyvinyl pyrrolidone, acrylic resin, polyacrylate, ethyl cellulose, ethyl cellulose N10 or a combination thereof. 如权利要求1-3任一项所述的组合物，所述填充剂选自淀粉、蔗糖、预胶化淀粉、乳糖、硫酸钙、磷酸钙、碳酸钙、甘露醇、山梨醇、微晶纤维素、微晶纤维素SH-101、微晶纤维素102的任一种或其组合。The composition according to any one of claims 1 to 3, wherein 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. 如权利要求1-4任一项所述的组合物，所述崩解剂选自交联聚维酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲基淀粉钠、交联羧甲基纤维素钙中的任一种或其组合。The composition according to any one of claims 1 to 4, wherein 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. 如权利要求1-5任一项所述的组合物，所述粘合剂选自低粘度纤维素、丙烯酸聚合物、透明质酸、海藻酸、多糖、多糖糖苷、羟丙基甲基纤维素、羟丙甲纤维素E5、羟丙纤维素EXF、淀粉浆、甲基纤维素、乙基纤维素、聚维酮中的任一种或其组合。 The composition according to any one of claims 1 to 5, wherein the binder is selected from any one of low viscosity cellulose, acrylic polymer, hyaluronic acid, alginic acid, polysaccharide, polysaccharide glycoside, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose E5, hydroxypropyl cellulose EXF, starch slurry, methyl cellulose, ethyl cellulose, povidone or a combination thereof. 如权利要求1-6任一项所述的组合物，所述润滑剂选自硬脂酸镁、硬脂酸、氢化植物油、硬脂富马酸钠、聚乙二醇类、十二烷基硫酸钠的任一种或其组合，所述助流剂选自胶态二氧化硅、滑石粉、微粉硅胶的任一种或其组合。The composition according to any one of claims 1 to 6, wherein 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, and the glidant is selected from any one or a combination of colloidal silicon dioxide, talc, and micro-powdered silica gel. 如权利要求1-7任一项所述的依帕司他缓释组合物的制备方法，以重量百分比计，组合物中含有20-50％的依帕司他或其衍生物和药学上可接受的载体，其中，所述衍生物选自共晶体、盐、游离酸、前药、酯、多晶型物、溶剂化物的任一种或其组合，所述的药学上可接受载体选自水凝胶材料、骨架材料、填充剂、崩解剂、粘合剂、润滑剂、助流剂的任一种或其组合，组合物的制备选自粉末直接压片法、湿法制粒法中的任一种。The method for preparing the sustained-release composition of epalrestat according to any one of claims 1 to 7, wherein the composition contains 20-50% of epalrestat or its derivatives and a pharmaceutically acceptable carrier by 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, binders, 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. 一种依帕司他缓释制剂，所述缓释制剂至少包含缓释漂浮层，所述缓释漂浮层中含有水凝胶材料和骨架材料，其中，所述缓释制剂中的水凝胶材料：依帕司他的质量比为0.25-0.4：1，骨架材料：依帕司他的质量比为0.2-0.5：1，所述水凝胶材料选自聚乙烯醇、水溶胀型纤维素、卡拉胶、黄原胶、瓜尔胶、阿拉伯胶、羟丙基纤维素、羟丙基甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素K4M中的任一种或其组合，所述骨架材料选自非水溶性纤维素、聚乙烯吡咯烷酮、丙烯酸树脂、聚丙烯酸盐、乙基纤维素N10中的任一种或其组合。A sustained-release preparation of epalrestat, comprising 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 to the epalrestat in the sustained-release preparation is 0.25-0.4:1, and the mass ratio of the skeleton material to the epalrestat is 0.2-0.5:1, 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. 如权利要求1-7任一项所述的依帕司他缓释组合物或如权利要求8所述的制备方法制备得到的依帕司他缓释组合物或如权利要求9所述的依帕司他缓释制剂用于制备防治糖尿病及其并发症的药物中的应用。 Use of the epalrestat sustained-release composition according to any one of claims 1 to 7, or the epalrestat sustained-release composition prepared by the preparation method according to claim 8, or the epalrestat sustained-release preparation according to claim 9 in preparing a medicament for preventing and treating diabetes and its complications.
PCT/CN2023/139300 2022-12-16 2023-12-15 Sustained-release epalrestat composition, method for preparing same, and use thereof Ceased WO2024125654A1 (en)

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