CN114246837A - Epalrestat micro-tablet and preparation method thereof - Google Patents

Epalrestat micro-tablet and preparation method thereof Download PDF

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Publication number
CN114246837A
CN114246837A CN202111513897.4A CN202111513897A CN114246837A CN 114246837 A CN114246837 A CN 114246837A CN 202111513897 A CN202111513897 A CN 202111513897A CN 114246837 A CN114246837 A CN 114246837A
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epalrestat
tablet
micro
parts
coating
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张威风
马莉
胡醒
何淑旺
田兵
高迪
范卫平
肖尧
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Beijing Dayin High Tech Children Medicine Research Institute Co ltd
Shandong Dyne Marine Biopharmaceutical Co Ltd
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Beijing Dayin High Tech Children Medicine Research Institute Co ltd
Shandong Dyne Marine Biopharmaceutical Co Ltd
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Priority to CN202111513897.4A priority Critical patent/CN114246837A/en
Publication of CN114246837A publication Critical patent/CN114246837A/en
Priority to ZA2022/10605A priority patent/ZA202210605B/en
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/282—Organic compounds, e.g. fats
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
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    • A61P3/00—Drugs for disorders of the metabolism
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Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an epalrestat micro-tablet and a preparation method thereof. The invention provides an epalrestat micro-tablet which consists of a tablet core and a coating material, wherein the tablet core comprises the following components in parts by mass: 25-50 parts of epalrestat, 25-60 parts of a filler, 1-10 parts of an adhesive, 4-10 parts of a disintegrating agent and 0.5-3 parts of a lubricant, wherein the coating material accounts for 4-20% of the mass of the tablet core; the maximum size of the epalrestat microchip is less than or equal to 3 mm. The epalrestat micro-tablet provided by the invention obtains an epalrestat micro-tablet product with the maximum size less than or equal to 3mm by controlling the mass ratio relationship of the epalrestat raw material medicine, the pharmaceutic adjuvant filler, the adhesive, the disintegrant, the lubricant and the coating material, has a remarkable compliance advantage, and can meet the clinical medication requirements of patients with swallowing dysfunction.

Description

Epalrestat micro-tablet and preparation method thereof
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to an epalrestat micro-tablet and a preparation method thereof.
Background
Epalrestat (Epalrestat) is an aldose reductase inhibitor which reversibly inhibits the activity of aldose reductase which plays a role in the metabolism of polyhydric alcohol involved in the pathogenesis of chronic complications of diabetes, and inhibits the conversion of glucose into sorbitol and the accumulation of sorbitol in cells, thereby playing a role in treating chronic complications of diabetes such as peripheral neuropathy. The structural formula of epalrestat is shown as formula I:
Figure BDA0003406171220000011
epalrestat was first developed by nippon drug co-products, and was marketed in japan in the 90 s of the 20 th century, and subsequently in china, india and southeast asia, and marketed products including tablets, capsules and other dosage forms are the only aldose reductase inhibitors marketed worldwide, and have a good therapeutic effect on complications such as peripheral neuropathy of diabetic patients.
The elderly are the main group of patients with diabetes, and the proportion of diabetes in elderly over 65 years old is as high as about 25%. Meanwhile, old people are often accompanied by swallowing dysfunction, and research data shows that the proportion of people over 50 years old is up to 20%, and most of the old people over 80 years old are accompanied by swallowing dysfunction. However, conventional solid oral preparations such as tablets and capsules of epalrestat are not suitable for the elderly who have difficulty in swallowing.
Disclosure of Invention
In view of the above, the epalrestat micro-tablets and the preparation method thereof provided by the invention can obviously improve the medication compliance of patients with swallowing dysfunction, and are particularly suitable for the old to take.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an epalrestat micro-tablet which consists of a tablet core and a coating material, wherein the tablet core comprises the following components in parts by mass: 25-50 parts of epalrestat, 25-60 parts of a filler, 1-10 parts of an adhesive, 4-10 parts of a disintegrating agent and 0.5-3 parts of a lubricant; the coating material accounts for 4-20% of the mass of the tablet core; the maximum size of the epalrestat microchip is less than or equal to 3 mm.
Preferably, the filler comprises one or more of lactose, sucrose, maltodextrin, mannitol, sorbitol, pregelatinized starch, amylolytic oligosaccharides, dibasic calcium phosphate and microcrystalline cellulose.
Preferably, the binder comprises one or more of hydroxypropyl cellulose, povidone, methyl cellulose, ethyl cellulose, hypromellose, sodium carboxymethylcellulose and polyethylene glycol.
Preferably, the disintegrant comprises one or more of sodium carboxymethyl starch, crospovidone, and croscarmellose sodium.
Preferably, the lubricant comprises one or more of stearic acid, magnesium stearate, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, polyethylene glycol, leucine, glycine, liquid paraffin, and glyceryl behenate.
Preferably, the coating material comprises a film-forming material, a plasticizer and an anti-adhesive agent; the mass ratio of the film forming material, the plasticizer and the anti-bonding agent is (70-93): (4-10): 3-20).
The invention provides a preparation method of epalrestat micro-tablets in the technical scheme, which comprises the following steps:
(1) mixing epalrestat, a filling agent, an adhesive, a disintegrating agent and a lubricating agent to obtain an intermediate material;
(2) pressing the intermediate material to obtain a microchip core;
(3) mixing the coating material and a coating solvent to obtain a coating solution;
(4) coating the micro-tablet core by using the coating solution to obtain the epalrestat micro-tablet;
the step (3) and the steps (1) to (2) are not limited in chronological order.
Preferably, in the step (2), the pressing pressure is 5-30 kN.
Preferably, the diameter of the micro tablet core is 1.5-3 mm, and the height of the micro tablet core is 1.2-3 mm.
The invention provides an epalrestat micro-tablet capsule, which comprises the epalrestat micro-tablet in the technical scheme or the epalrestat micro-tablet and a capsule shell prepared by the preparation method in the technical scheme.
The invention provides an epalrestat micro-tablet which consists of a tablet core and a coating material, wherein the tablet core comprises the following components in parts by mass: 25-50 parts of epalrestat, 25-60 parts of a filling agent, 1-10 parts of an adhesive, 4-10 parts of a disintegrating agent and 0.5-3 parts of a lubricant, wherein the coating material accounts for 4-20% of the mass of the tablet core; the maximum size of the epalrestat microchip is less than or equal to 3 mm. The epalrestat micro-tablet provided by the invention obtains an epalrestat micro-tablet product with the maximum size less than or equal to 3mm by controlling the mass ratio relationship of the epalrestat raw material drug, the pharmaceutical adjuvant filler, the adhesive, the disintegrant, the lubricant and the coating material, and has regular appearance and good fluidity. Compared with other common epalrestat solid preparations (tablets, capsules and the like), the epalrestat solid preparation has obvious compliance advantages, can meet the clinical medication requirements of patients with swallowing dysfunction, and is particularly suitable for the old to take.
Drawings
FIG. 1 is a schematic diagram of an epalrestat microchip prepared in example 1 of the present invention.
Detailed Description
The invention provides an epalrestat micro-tablet which consists of a tablet core and a coating material, wherein the tablet core comprises the following components in parts by mass:
25-50 parts of epalrestat, 25-60 parts of a filling agent, 1-10 parts of an adhesive, 4-10 parts of a disintegrating agent and 0.5-3 parts of a lubricant, wherein the coating material accounts for 4-20% of the mass of the tablet core; the maximum size of the epalrestat microchip is less than or equal to 3 mm.
In the present invention, the starting materials are all commercially available products well known to those skilled in the art, unless otherwise specified.
The epalrestat microchip provided by the invention comprises 25-50 parts of epalrestat, preferably 30-45 parts.
The epalrestat micro-tablet provided by the invention comprises 25-60 parts of a filling agent, preferably 30-50 parts, and more preferably 35-45 parts by mass based on the parts by mass of the epalrestat. In the present invention, the filler preferably includes one or more of lactose, sucrose, maltodextrin, mannitol, sorbitol, pregelatinized starch, starch hydrolyzed oligosaccharide, calcium hydrogen phosphate and microcrystalline cellulose, more preferably one or more of mannitol, lactose, starch hydrolyzed oligosaccharide and microcrystalline cellulose, and in a specific embodiment of the present invention, the lactose is specifically lactose monohydrate. In the present invention, when the filler is preferably two or more of the above-mentioned substances, the mass ratio of the specific substances is not particularly required in the present invention.
The epalrestat microchip provided by the invention comprises 1-10 parts of adhesive, preferably 3.5-7 parts, more preferably 5-6 parts by weight based on the mass parts of epalrestat. In the present invention, the binder preferably comprises one or more of hydroxypropyl cellulose, povidone, methyl cellulose, ethyl cellulose, hypromellose, sodium carboxymethyl cellulose and polyethylene glycol, more preferably hydroxypropyl cellulose and/or povidone, and in a specific embodiment of the present invention, povidone is particularly povidone K30. In the present invention, when the binder is preferably two or more of the above substances, the mass ratio of the specific substances is not particularly required in the present invention.
The epalrestat micro-tablet provided by the invention comprises 4-10 parts of disintegrating agent by mass, preferably 5.5-8 parts by mass. In the present invention, the disintegrant preferably comprises one or more of sodium carboxymethyl starch, crospovidone, and croscarmellose sodium. In the present invention, when the disintegrant is preferably two or more of the above substances, the mass ratio of the specific substances is not particularly required in the present invention.
The epalrestat micro-tablet provided by the invention comprises 0.5-3 parts of lubricant, preferably 1-2.5 parts, and more preferably 1.5-2 parts by weight based on the mass parts of the epalrestat. In the present invention, the lubricant preferably includes one or more of stearic acid, magnesium stearate, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, polyethylene glycol, leucine, glycine, liquid paraffin, and glyceryl behenate, and in particular embodiments of the present invention, the lubricant is preferably magnesium stearate, sodium stearyl fumarate, and calcium stearate. In the present invention, when the lubricant is preferably two or more of the above substances, the mass ratio of the specific substances is not particularly required in the present invention.
The epalrestat micro-tablet provided by the invention comprises a coating material, wherein the coating material accounts for 4-20% of the mass of the tablet core, and is preferably 7-16%. In the present invention, the coating material preferably includes a film-forming material, a plasticizer and an anti-adhesive agent. In the present invention, the film-forming material preferably includes a gastric-soluble type material, a sustained-release type material or an enteric type material. In the present invention, the gastric soluble material preferably comprises one or more of hypromellose, polymethacrylate, polyvinylacetal diethylaminoacetate and hydroxypropyl dibutylacetic ether, the polymethacrylate preferably being of the yutecky E series. In the present invention, when the gastric soluble material is preferably two or more of the above substances, the mass ratio of the specific substances is not particularly required in the present invention.
In the present invention, the slow release type material preferably includes one or more of polymethacrylate, polyvinyl acetate, ethyl cellulose, and cellulose acetate. In the present invention, when the sustained-release material is preferably two or more of the above substances, the mass ratio of the specific substance in the present invention is not particularly limited.
In the present invention, the enteric material preferably includes one or more of cellulose acetate phthalate, polyvinyl phthalate, methacrylic acid-methyl methacrylate copolymer, preferably the ewing L series or the ewing S series, and shellac. In the present invention, when the enteric material is preferably two or more of the above substances, the present invention has no particular requirement on the mass ratio of the specific substance.
In a specific embodiment of the present invention, the film material is specifically preferably hypromellose or methacrylic acid-methyl methacrylate copolymer of the ewing L series or the ewing S series.
In the present invention, the plasticizer preferably includes one or more of propylene glycol, polyethylene glycol 400, triethyl citrate, and castor oil. In the present invention, when the plasticizer is preferably two or more of the above substances, the mass ratio of the specific substances is not particularly required in the present invention.
In a particular embodiment of the invention, the plasticizer is particularly preferably triethyl citrate.
In the present invention, the anti-caking agent preferably comprises one or more of magnesium stearate, talc and colloidal silica. In the present invention, when the anti-caking agent is preferably two or more of the above substances, the mass ratio of the specific substances is not particularly required in the present invention.
In a specific embodiment of the present invention, the anti-caking agent is particularly preferably talc.
In the invention, the mass ratio of the film forming material, the plasticizer and the anti-bonding agent is preferably (70-93): 4-10): 3-20, and more preferably (75-90): 5-8): 5-18.
The maximum size of the epalrestat microchip provided by the invention is less than or equal to 3mm, and preferably 1.5-3 mm. In the present invention, the maximum size of the epalrestat microchip is specifically the diameter or height of the epalrestat microchip.
The invention provides a preparation method of epalrestat micro-tablets in the technical scheme, which comprises the following steps:
(1) mixing epalrestat, a filling agent, an adhesive, a disintegrating agent and a lubricating agent to obtain an intermediate material;
(2) pressing the intermediate material to obtain a microchip core;
(3) mixing the coating material and a coating solvent to obtain a coating solution;
(4) coating the micro-tablet core by using the coating solution to obtain the epalrestat micro-tablet;
the step (3) and the steps (1) to (2) are not limited in chronological order.
The intermediate material is obtained by mixing epalrestat, a filler, a binder, a disintegrant and a lubricant (hereinafter referred to as first mixing).
In the present invention, when the angle of repose of the intermediate material obtained after the first mixing of epalrestat, filler, binder, disintegrant and lubricant is > 36 °, the first mixing preferably comprises the steps of:
mixing the epalrestat, the filler, the adhesive and the disintegrating agent to obtain a mixed material, and adding a granulating solvent into the mixed material in a wet granulator to carry out wet granulation to obtain initial wet granules;
drying the initial material particles to obtain initial dry material particles;
second mixing the initial dry pellets and the lubricant to obtain the intermediate material.
The epalrestat, the filler, the adhesive, the disintegrant and the granulating solvent are granulated by a wet method to obtain initial wet material granules.
In the present invention, the granulating solvent is preferably ethanol and/or water, and the water is preferably purified water.
In the present invention, the mass ratio of the granulating solvent to the mixed material is preferably (6-18): 100.
In the present invention, the wet granulation preferably includes the following three modes:
the first mode is as follows: and thirdly, mixing the epalrestat, the filling agent, the adhesive and the disintegrating agent to obtain a dry material, and then adding a granulating solvent to carry out wet granulation to obtain initial wet material granules.
The second mode is as follows: and fourthly, mixing the epalrestat, the filling agent and the disintegrating agent to obtain a dry material, adding a solution obtained by dissolving the adhesive in a granulating solvent, and carrying out wet granulation to obtain initial wet material granules.
The third mode is as follows: and fifthly, mixing the epalrestat, the filling agent, part of the adhesive and the disintegrating agent to obtain a dry material, adding a solution obtained by dissolving the rest of the adhesive in a granulating solvent, and performing wet granulation to obtain initial wet material granules.
In the present invention, in the first mode, the third mixing is preferably performed in a wet granulator. In the present invention, the third mixing is preferably performed under a stirring condition, and the rotation speed of the stirring is preferably 150 to 250rpm, and more preferably 175 to 200 rpm. In the invention, the time for mixing the three components is preferably 5-15 min.
In the first mode of the present invention, during the wet granulation, the rotation speed of the stirring paddle is preferably 250 to 350rpm, the rotation speed of the cutter is preferably 1200 to 1800rpm, the time for wet granulation is preferably 2 to 8min, and the time for adding the granulation solvent is preferably 1 to 3 min.
In the present invention, in the second mode, the fourth mixing is preferably performed in a wet granulator. In the present invention, the fourth mixing is preferably performed under a stirring condition, and the rotation speed of the stirring is preferably 150 to 250rpm, and more preferably 175 to 200 rpm. In the invention, the time for mixing the four components is preferably 5-15 min.
In the second aspect of the present invention, during the wet granulation, the rotation speed of the stirring paddle is preferably 250 to 350rpm, the rotation speed of the cutter is preferably 1200 to 1800rpm, the time for wet granulation is preferably 2 to 8min, and the time for adding the solution obtained by dissolving the binder in the granulation solvent is preferably 1 to 3 min.
In the present invention, in the third mode, the fifth mixing is preferably performed in a wet granulator. In the present invention, the fifth mixing is preferably performed under a stirring condition, and the rotation speed of the stirring is preferably 150 to 250rpm, and more preferably 175 to 200 rpm. In the invention, the time for mixing the five components is preferably 5-15 min.
In the third aspect of the present invention, during the wet granulation, the rotation speed of the stirring paddle is preferably 250 to 350rpm, the rotation speed of the cutter is preferably 1200 to 1800rpm, the time for wet granulation is preferably 2 to 8min, and the addition time of the solution obtained by dissolving the rest of the binder in the granulation solvent is preferably 1 to 3 min.
In the third aspect of the present invention, there is no particular requirement for the mass ratio of the partial station mixture to the remaining partial station mixture.
In the present invention, it is preferable that the wet granulation is performed to obtain wet granules, and the wet granules are preferably sieved to have a mesh size of 20 mesh.
In the present invention, the particle size of the primary wet grains is preferably 0.9mm or less.
After the initial wet material particles are obtained, the initial wet material particles are dried to obtain initial dry material particles.
In the present invention, the drying preferably includes the following two modes:
the first mode is as follows: when the drying is carried out in a drying oven, the drying temperature is preferably 35-60 ℃, and the drying time is preferably 2-5 h.
The second mode is as follows: when the drying is carried out in a fluidized bed, the air inlet temperature of air during drying is preferably 40-70 ℃, and the drying time is preferably 15-45 min.
In the present invention, it is preferable that the dried granules obtained by the drying are granulated to obtain initial dried granules, and in the present invention, the granulated dried granules are preferably sieved, and the mesh size of the sieve is preferably 20 mesh.
In the present invention, the primary dry material particles preferably have a particle size of 0.9mm or less.
After the initial dry pellet is obtained, the present invention second mixes the initial dry pellet and the lubricant to obtain the intermediate material.
In the present invention, the second mixing is preferably performed in a three-dimensional mixer, and the rotation speed of the three-dimensional mixer is preferably 15 to 25Hz and the time of the second mixing is preferably 10 to 30 min.
In the present invention, when the angle of repose of the mixture of epalrestat, filler, binder, disintegrant and lubricant is < 36 °, the first mixing preferably comprises the steps of:
sixthly, mixing the epalrestat, the filling agent, the adhesive and the disintegrating agent to obtain a mixed material;
adding a lubricant into the mixture material for seventh mixing to obtain an intermediate material.
In the present invention, the sixth mixing is preferably performed in a three-dimensional mixer, and the rotation speed of the three-dimensional mixer is preferably 15 to 25Hz and the time of the sixth mixing is preferably 10 to 30 min.
In the present invention, the seventh mixing is preferably performed in a three-dimensional mixer, and the rotation speed of the three-dimensional mixer is preferably 15 to 25Hz and the time of the sixth mixing is preferably 5 to 20min during the seventh mixing.
After the intermediate material is obtained, the intermediate material is pressed to obtain the micro-tablet core.
In the invention, the pressing pressure is preferably 5-30 kN, and more preferably 8-25 kN.
In the invention, the maximum size of the micro-tablet core is less than or equal to 3mm, in the specific embodiment of the invention, the diameter of the micro-tablet core is preferably 2-2.5 mm, and the height is preferably 2-2.7 mm.
The coating material and the coating solvent are mixed to obtain the coating liquid.
In the present invention, the coating solvent is preferably acetone, ethanol and/or water, and the water is preferably purified water.
In the invention, the ratio of the mass of the coating material to the volume of the coating solvent is preferably (5-15): 100.
The present invention does not require any particular embodiment of the coating material and coating solvent mixture.
And after obtaining a micro-tablet core and a coating solution, coating the micro-tablet core by using the coating solution to obtain the epalrestat micro-tablet.
In the invention, when the coating is carried out in a fluidized bed, the air inlet temperature is preferably 50-80 ℃, and more preferably 60-75 ℃. The temperature of the micro-tablet core is preferably 35-55 ℃, and more preferably 40-45 ℃. The weight gain of the coating is preferably 4-20%, and more preferably 5-15%.
In the invention, when the coating is carried out in a nonporous coating pan, the inlet air temperature is preferably 50-75 ℃, and more preferably 55-60 ℃. The temperature of the micro-tablet core is preferably 35-50 ℃, and more preferably 38-45 ℃. In the invention, the rotation speed of the pot body of the imperforate coating pot is preferably 3-6 rpm.
In the invention, after the coating, the coating material preferably accounts for 4-20%, more preferably 5-15% of the total mass of the epalrestat, the filler, the binder, the disintegrant and the lubricant.
The epalrestat micro-tablets provided by the invention have the maximum size of less than or equal to 3mm, can be filled into a capsule shell to prepare a capsule according to the requirement of a pharmaceutical dosage form, and also can be directly filled into an aluminum-plastic composite bag. Compared with the traditional solid oral preparations such as tablets, capsules and the like, the epalrestat micro-tablets can obviously improve the medication compliance of patients with swallowing dysfunction, and are particularly suitable for the old to take.
The invention provides an epalrestat micro-tablet capsule, which comprises the epalrestat micro-tablet in the technical scheme or the epalrestat micro-tablet and a capsule shell prepared by the preparation method in the technical scheme.
In the invention, the capsule shell is preferably a hydroxypropyl methylcellulose hollow capsule shell, a hydroxypropyl starch hollow capsule shell, a pullulan hollow capsule shell or a gelatin hollow capsule shell.
In the specific implementation of the invention, the mass (specification) of the epalrestat in the epalrestat micro-tablet capsule is 50 mg.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention.
Example 1
Epalrestat microtablets were prepared from the raw materials of table 1:
table 1 example 1 raw material composition
Figure BDA0003406171220000091
Uniformly mixing epalrestat, mannitol, hydroxypropyl cellulose and carboxymethyl starch sodium according to the prescription amount in a wet granulator (the stirring speed is 250rpm, and the time is 5 minutes) to obtain a dry material;
taking purified water with the amount of 50g as a formula as a binder, performing wet granulation on the uniformly mixed dry material in the previous step in a wet granulator (the stirring speed is 250rpm, the cutter speed is 1500rpm, the binder addition time is 2 minutes, and the granulation time is 5 minutes), and sieving with a 20-mesh sieve to obtain initial wet material granules;
drying the initial wet material particles by using an oven (the temperature is 50 ℃, the time is 3 hours), and sieving by using a 20-mesh sieve for particle stabilization to obtain initial dry material particles;
adding the magnesium stearate with the formula amount into the initial dry material particles, and mixing in a three-dimensional mixer (the rotating speed is 20Hz, the time is 15 minutes) to obtain an intermediate material;
pressing the intermediate material into a micro-tablet core with the diameter of 2.5mm and the height of 2.4-2.7 mm;
dispersing 60g of the coating material in 500mL of purified water to obtain a coating solution; coating the micro tablet core in a fluidized bed (inlet air temperature: 50-70 ℃, product temperature: 45-50 ℃ and coating weight gain: 10% -12%) to obtain epalrestat micro tablets, wherein the physical diagram is shown in figure 1.
Example 2
Epalrestat microtablets were prepared from the raw materials of table 2:
table 2 example 2 raw material composition
Figure BDA0003406171220000101
Uniformly mixing epalrestat, lactose monohydrate and crospovidone according to the prescription amount in a wet granulator (stirring speed is 200rpm, and the time is 7 minutes) to obtain a dry material;
dissolving povidone K30 in a prescribed amount in purified water in a prescribed amount to serve as a binder, performing wet granulation on the uniformly mixed dry material in the previous step in a wet granulator (the stirring speed is 250rpm, the cutter speed is 1500rpm, the binder addition time is 3 minutes, and the granulation time is 6 minutes), and sieving with a 20-mesh sieve to obtain initial wet material granules;
drying the initial wet material particles by a fluidized bed (the air inlet frequency is 10Hz, the air inlet temperature is 60 ℃, and the drying time is 40 minutes), and after the drying is finished, sieving by a 20-mesh sieve for granulating to obtain initial dry material particles;
adding the magnesium stearate with the formula amount into the initial dry material particles, and mixing in a three-dimensional mixer (the rotating speed is 20Hz, the time is 15 minutes) to obtain an intermediate material;
pressing the intermediate material into a micro-tablet core with the tablet diameter of 2.2mm and the height of 2.1-2.4 mm;
dispersing 75g of coating material in 750mL of purified water to obtain a coating solution; and (3) coating the micro-tablet core in a fluidized bed (the air inlet temperature is 55-70 ℃, the product temperature is 45-50 ℃, and the coating weight is increased by 12-15 percent) to obtain the epalrestat micro-tablet.
Example 3
Epalrestat microtablets were prepared from the raw materials of table 3:
table 3 example 3 raw material composition
Epalrestat 250g
Starch hydrolyzed oligosaccharides 300g
Microcrystalline cellulose 100g
Hydroxypropyl cellulose 52.5g
Croscarmellose sodium 45g
Magnesium stearate 2.75g
Coating material (hydroxypropyl methylcellulose, triethyl citrate, talcum powder) The weight is increased by 7 to 9 percent
Uniformly mixing epalrestat, starch hydrolysis oligosaccharide, microcrystalline cellulose, hydroxypropyl cellulose and croscarmellose sodium in a three-dimensional mixer according to the prescription amount (the rotating speed is 20Hz, and the time is 20 minutes) to obtain an initial dry material;
adding the magnesium stearate with the prescription amount into the initial dry materials, and mixing in a three-dimensional mixer (the rotating speed is 20Hz, the time is 15 minutes) to obtain an intermediate material;
pressing the intermediate material into a micro-tablet core with the diameter of 2mm and the height of 2.1-2.3 mm;
dispersing 70g of coating material in 700mL of purified water to obtain a coating solution; coating the micro-tablet core in a nonporous coating pan (the air inlet temperature is 50-70 ℃, the product temperature is 45-50 ℃, the rotating speed of the pan body is 4rpm, and the weight gain of the coating is 7-9 percent) to obtain the epalrestat micro-tablet.
Comparative example 1
Epalrestat microtablets were prepared from the raw materials of table 4:
table 4 comparative example 1 raw material composition
Figure BDA0003406171220000121
Uniformly mixing epalrestat, mannitol, hydroxypropyl cellulose and carboxymethyl starch sodium according to the prescription amount in a wet granulator (the stirring speed is 250rpm, and the time is 5 minutes) to obtain a dry material;
taking purified water with the amount of 50g as a prescription as a binding agent, and carrying out wet granulation on the dry materials uniformly mixed in the previous step in a wet granulator (the stirring speed is 250rpm, the cutter speed is 1500rpm, the binding agent adding time is 2 minutes, and the granulating time is 5 minutes); as a result, it was found that when the amount of hydroxypropyl cellulose as a binder was too large, the powder was partially agglomerated after adding purified water, and the other powder was not in a dry powder state, and the distribution of purified water was not uniform, whereby the granulation was not successful.
Comparative example 2
Epalrestat microtablets were prepared from the raw materials of table 5:
table 5 comparative example 2 raw material composition
Figure BDA0003406171220000122
Figure BDA0003406171220000131
Uniformly mixing epalrestat, mannitol, hydroxypropyl cellulose and carboxymethyl starch sodium according to the prescription amount in a wet granulator (the stirring speed is 250rpm, and the time is 5 minutes) to obtain a dry material;
taking purified water with the amount of 50g as a formula as a binder, performing wet granulation on the uniformly mixed dry material in the previous step in a wet granulator (the stirring speed is 250rpm, the cutter speed is 1500rpm, the binder addition time is 2 minutes, and the granulation time is 5 minutes), and sieving with a 20-mesh sieve to obtain initial wet material granules;
drying the initial wet material particles by using an oven (the temperature is 50 ℃, the time is 3 hours), and sieving by using a 20-mesh sieve for particle stabilization to obtain initial dry material particles; the dry granules obtained were found to contain more fine powder and have poor granulation effect, which was analyzed to be due to the low amount of hydroxypropyl cellulose as a binder in the formulation and the brittle granules.
Example 4
The epalrestat minitablets prepared in example 3 were filled into gelatin empty capsules to obtain epalrestat minitablets capsules (specification: 50mg) having the composition shown in table 4:
TABLE 4 EXAMPLE 4 Epalrestat micro-tablet capsule composition
Components Dosage of
Epalrestat microchip 162mg
Gelatin hollow capsule 1 granule
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. The epalrestat micro-tablet is characterized by consisting of a tablet core and a coating material, wherein the tablet core comprises the following components in parts by mass: 25-50 parts of epalrestat, 25-60 parts of a filler, 1-10 parts of an adhesive, 4-10 parts of a disintegrating agent and 0.5-3 parts of a lubricant; the coating material accounts for 4-20% of the mass of the tablet core; the maximum size of the epalrestat microchip is less than or equal to 3 mm.
2. The epalrestat microchip of claim 1, wherein the filler comprises one or more of lactose, sucrose, maltodextrin, mannitol, sorbitol, pregelatinized starch, amylolytic oligosaccharides, dibasic calcium phosphate, and microcrystalline cellulose.
3. The epalrestat minitablets of claim 1 wherein the binder comprises one or more of hydroxypropyl cellulose, povidone, methyl cellulose, ethyl cellulose, hypromellose, sodium carboxymethylcellulose, and polyethylene glycol.
4. The epalrestat minitablets of claim 1 wherein the disintegrant comprises one or more of sodium carboxymethyl starch, crospovidone, and croscarmellose sodium.
5. The epalrestat microtablets of claim 1, wherein the lubricant comprises one or more of stearic acid, magnesium stearate, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, polyethylene glycol, leucine, glycine, liquid paraffin, glyceryl behenate.
6. The epalrestat minitablets of claim 1 wherein the coating material comprises a film forming material, a plasticizer, and an anti-adhesive agent; the mass ratio of the film forming material, the plasticizer and the anti-bonding agent is (70-93): (4-10): 3-20).
7. The method for preparing epalrestat microtablets as claimed in any one of claims 1-6, characterized by comprising the following steps:
(1) mixing epalrestat, a filling agent, an adhesive, a disintegrating agent and a lubricating agent to obtain an intermediate material;
(2) pressing the intermediate material to obtain a microchip core;
(3) mixing the coating material and a coating solvent to obtain a coating solution;
(4) coating the micro-tablet core by using the coating solution to obtain the epalrestat micro-tablet;
the step (3) and the steps (1) to (2) are not limited in chronological order.
8. The method according to claim 7, wherein in the step (2), the pressure for pressing is 5 to 30 kN.
9. The preparation method of claim 7, wherein the micro tablet core has a tablet diameter of 1.5-3 mm and a height of 1.2-3 mm.
10. An epalrestat micro-tablet capsule, which is characterized by comprising the epalrestat micro-tablet of any one of claims 1 to 6 or the epalrestat micro-tablet prepared by the preparation method of any one of claims 7 to 9 and a capsule shell.
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