Epalrestat sustained release tablet and preparation method thereof

Abstract

The invention relates to an epalrestat sustained release tablet and a preparation method thereof. The epalrestat sustained-release tablet is composed of 20-30 parts by weight of epalrestat, 10-50 parts by weight of a sustained-release framework material, 30-60 parts by weight of a filler, 3 parts by weight of an adhesive and 1-5 parts by weight of a lubricant. The preparation method comprises the following steps: uniformly mixing the epalrestat, the sustained-release framework material and the filler according to the prescription dosage, adding the adhesive to prepare a soft material, granulating, drying, adding the lubricant, uniformly mixing, and tabletting to obtain the epalrestat sustained-release tablet. The epalrestat sustained-release tablet is simple in prescription, only contains epalrestat, the sustained-release framework material, the filler, the adhesive and the lubricant, and is low in auxiliary material cost; the adopted preparation process is simple, low in technical difficulty, low in production cost and suitable for industrial production. Compared with an epalrestat quick-release preparation, the epalrestat sustained-release tablet prepared by the invention has the characteristics of stable in-vivo and in-vitro drug release, high bioavailability, reduced medication frequency and improved medication compliance of patients.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to an epalrestat sustained-release tablet and a preparation method thereof. Background Art

[0002] Diabetes is a metabolic disease characterized by high blood sugar. Long-term and severe hyperglycemia can lead to chronic damage to the eyes, kidneys, cardiovascular system, and nerves. Among them, diabetic neuropathy is one of the most common chronic complications of diabetes. The lesions can affect the central and peripheral nerves and are the main cause of death and disability from diabetes. At present, drugs for the treatment of diabetic neuropathy include antioxidant stress drugs (such as α-lipoic acid), drugs for improving nerve microcirculation (such as alprostadil), nerve nutrition drugs (such as methylcobalamin), drugs for correcting metabolic disorders (such as epalrestat), etc. Among them, epalrestat, as a non-competitive, reversible aldose reductase inhibitor, can control the polyol pathway by inhibiting the activity of aldose reductase, reduce the accumulation of sorbitol in nerve cells, and thus treat diabetic neuropathy. It is currently a commonly used drug for the clinical treatment of the disease.

[0003] Epalrestat, chemical formula: C 15 H 13 NO3S2, molecular weight is 319.40. It is yellow to orange crystal or crystalline powder, which will gradually fade and decompose when exposed to light. It is soluble in N, N-dimethylformamide, slightly soluble in methanol and ethanol, and almost insoluble in water. Its melting point is 222-227°C. Its chemical structure is as follows:

[0004]

[0005] At present, only five companies including Yangtze River Pharmaceutical Group have approved epalrestat preparations for marketing in China, and all of them are immediate-release preparations. However, epalrestat reaches its peak blood concentration 1.05 hours after oral administration, and is metabolized quickly, with a plasma half-life of only 1.8 hours. Therefore, patients need to take the drug three times a day to maintain its efficacy. In addition, frequent medication not only reduces patients' medication compliance, but also easily causes patients to miss medications, resulting in unsatisfactory treatment effects. Compared with immediate-release preparations, sustained-release preparations can release drugs smoothly and slowly, maintain stable blood drug concentrations, and reduce drug toxicity and side effects; they can also reduce the number of medications and improve patients' medication compliance. Therefore, it is urgent to develop epalrestat sustained-release preparations to meet clinical needs.

[0006] In the prior art, epalrestat is mixed with a sustained-release skeleton material to prepare a micropill, and then an isolation layer, an enteric layer, and a protective layer are coated, and the epalrestat enteric-coated sustained-release capsule (CN112137990A) is prepared by filling the capsule shell, but the technology needs to adopt multiple preparation means such as extrusion, spheronization, multi-layer coating, and capsule filling, which is technically difficult and complex, and is not conducive to industrial production. CN104940156A discloses an epalrestat sustained-release preparation using high-viscosity hydroxypropyl methylcellulose as a sustained-release material. According to the experimental results of the inventor, only using high-viscosity hydroxypropyl methylcellulose as a sustained-release material will cause the viscosity of the sustained-release skeleton to be too high, and the drug release is too slow. WO2012100208A1 also discloses an epalrestat sustained-release preparation, but the preparation has been proven by CN104940156A to have the disadvantages of being released too quickly and unevenly in alkali. In CN102440976A, high-viscosity hydroxypropyl methylcellulose and ethyl cellulose are mixed as sustained-release materials. Although the sustained-release effect can be achieved, the high-viscosity hydroxypropyl methylcellulose has too high a viscosity, which makes it difficult to release the drug. In addition, epalrestat is a poorly soluble drug, and the ethyl cellulose used in this technology is a water-insoluble material, which is more unfavorable for the drug to dissolve from the inside of the tablet to the outside, resulting in the drug not being completely released within the specified time.

[0007] In the prior art, epalrestat is also prepared as a non-effervescent gastric floating tablet. The non-effervescent gastric floating sustained-release tablet uses hydrophilic polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and alginate, etc., and the above excipients are hydrated and swollen in gastric juice, and the density is reduced to achieve drug floating and slow release. However, the use of hydrophilic gel excipients alone often cannot achieve a suitable floating time and floating performance. A reasonable gastric floating prescription often must contain hydrophobic materials, such as ethyl cellulose, etc., to control the penetration rate of water and balance the sustained-release ability of the hydrogel material. CN115721621A and CN117717533A disclose an epalrestat gastric floating sustained-release tablet, which mixes high-viscosity hydroxypropyl methylcellulose and ethyl cellulose as a sustained-release floating layer, wherein high-viscosity hydroxypropyl methylcellulose is used as a hydrogel material and plays a leading role in regulating drug release; ethyl cellulose is used as a skeleton material and plays a leading role in regulating floating performance; low-viscosity hydroxypropyl methylcellulose is used in very small amounts in the prescription and is only used as an adhesive, and has no effect in regulating drug release. In addition, epalrestat has extremely low solubility in acid, and its equilibrium solubility in a pH 1.0 medium is only 0.017 μg / mL. Therefore, it is difficult for the gastric floating sustained-release tablet to release epalrestat in the stomach, which is not conducive to oral absorption and efficacy. The formulation of the preparation of the present application is significantly different from that of the gastric floating tablets. The present application selects a combination of low-viscosity hydroxypropyl methylcellulose and high-viscosity hydroxypropyl methylcellulose as sustained-release materials to synergistically regulate the release of epalrestat sustained-release tablets. The formulation does not contain ethyl cellulose at all. The release and absorption of the drug in the preparation of the present application is also significantly different from the release and absorption of the gastric floating preparation due to the delayed release and increased retention of the drug in the stomach.

[0008] Pharmacokinetic studies can reveal the dynamic changes of drugs in the body, obtain the basic pharmacokinetic parameters of drugs, and clarify the processes and characteristics of drug absorption, distribution, metabolism and excretion, which is an important basis for evaluating the characteristics and quality of drug preparations. In the prior art, only CN115721621A and CN117717533A studied the in vivo absorption of epalrestat gastric floating sustained-release tablets using miniature pigs as animal models. However, epalrestat has extremely low solubility in the stomach and cannot be fully absorbed. Gastric floating tablets are actually not suitable for the development of epalrestat preparations. In addition, compared with ordinary tablets, the bioavailability of gastric floating sustained-release tablets has not been significantly improved. Therefore, it is necessary to develop new epalrestat sustained-release tablets with high bioavailability and fully study their in vivo absorption.

[0009] In summary, it is necessary to select appropriate sustained-release materials and preparation processes to obtain sustained-release preparations of epalrestat that are easy to take and release the drug smoothly and completely, and to conduct nonclinical pharmacokinetic studies to evaluate the characteristics and quality of sustained-release preparations. Summary of the invention

[0010] The present invention is to solve the problems of too fast drug release, multiple doses, poor patient compliance and low bioavailability of epalrestat immediate-release preparations, and proposes a method for preparing epalrestat sustained-release tablets: uniformly mix the prescribed amount of epalrestat, sustained-release skeleton materials and fillers, add adhesives to make soft materials, granulate, dry, add lubricants and mix evenly, and then press into tablets. Compared with the prior art, the present invention has the following advantages: simple prescription, only containing epalrestat, sustained-release skeleton materials, fillers, adhesives and lubricants, few types of auxiliary materials, and low cost of auxiliary materials; the preparation process adopted is simple, the technical difficulty is small, the production cost is low, and it is suitable for industrial production. Compared with the epalrestat immediate-release preparation that needs to be taken orally three times a day, the epalrestat sustained-release tablets prepared by the present invention only need to be taken orally twice a day, and have the characteristics of less medication times, high patient medication compliance and high bioavailability.

[0011] Specifically, the present invention is realized through the following technical solutions:

[0012] In the first aspect, the present invention provides an epalrestat sustained-release tablet, characterized in that it comprises epalrestat, a sustained-release skeleton material, a filler, a binder and a lubricant; wherein, in the epalrestat sustained-release tablet, the content of each component is, by weight, 20 to 30 parts by weight of epalrestat, 10 to 50 parts by weight of the sustained-release skeleton material, 30 to 60 parts by weight of the filler, 3 parts by weight of the binder (PVP K30) and 1 to 5 parts by weight of the lubricant.

[0013] Preferably, the epalrestat sustained-release tablets contain, by weight, 20 to 30 parts by weight of epalrestat, 25 to 35 parts by weight of sustained-release skeleton material, 30 to 50 parts by weight of filler, 3 parts by weight of binder (PVP K30), and 1 to 2 parts by weight of lubricant.

[0014] Preferably, the epalrestat sustained-release tablet comprises 25 parts by weight of epalrestat, 20 parts by weight of hydroxypropyl methylcellulose E100, 10 parts by weight of hydroxypropyl methylcellulose K4M, 44 parts by weight of filler, 3 parts by weight of binder (PVP K30), and 1 part by weight of magnesium stearate.

[0015] As an optional method, in the above-mentioned epalrestat sustained-release tablets, the sustained-release matrix material is selected from one or more of sodium carboxymethyl cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, acrylic resin, polyvinyl alcohol, and chitosan, preferably one or more of methyl cellulose, hydroxypropyl methyl cellulose, and polyvinyl pyrrolidone, and more preferably hydroxypropyl methyl cellulose.

[0016] As an optional mode, in the above-mentioned epalrestat sustained-release tablets, the hydroxypropyl methylcellulose is selected from one or more of high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose. The high-viscosity hydroxypropyl methylcellulose refers to a 2% (w / v) hydroxypropyl methylcellulose aqueous solution having a viscosity greater than or equal to 4000 mPa·s when measured at 20°C; the low-viscosity hydroxypropyl methylcellulose refers to a 2% (w / v) hydroxypropyl methylcellulose aqueous solution having a viscosity less than or equal to 100 mPa·s when measured at 20°C.

[0017] As an optional manner, in the above-mentioned epalrestat sustained-release tablets, the ratio of high-viscosity hydroxypropyl methylcellulose to low-viscosity hydroxypropyl methylcellulose is 1:4 to 6:1, preferably 1:3 to 3:1, and preferably 1:2.

[0018] As an optional manner, in the above-mentioned epalrestat sustained-release tablets, the filler is selected from one or more of starch, microcrystalline cellulose, lactose, sucrose, pregelatinized starch, sorbitol, dextrin, and mannitol, preferably one or more of sucrose, lactose, mannitol, and sorbitol.

[0019] As an optional manner, in the above-mentioned epalrestat sustained-release tablets, the lubricant is selected from one or more of talc, stearic acid, magnesium stearate, calcium stearate, and micro-powdered silica gel, preferably magnesium stearate.

[0020] In a second aspect, the present invention provides a method for preparing an epalrestat sustained-release tablet according to the first aspect, the preparation method comprising the following steps:

[0021] a. Use a mixer to mix epalrestat, sustained-release matrix material, and filler evenly, and prepare the prescribed amount of adhesive (PVP K30) into a 3% (w / v) isopropanol solution;

[0022] b. Place the mixed material obtained in step a into a high shear wet granulator and start mixing.

[0023] At the same time, an isopropyl alcohol solution of an adhesive (PVP K30) was slowly added to prepare a soft material;

[0024] After the soft material is prepared, the cutting knife is turned on for granulation;

[0025] c. After granulation, take out and dry. After drying, pass the granules through a 20-mesh sieve, add the corresponding amount of lubricant, mix evenly with a mixer, and select 7mm shallow concave punching tablets.

[0026] Get epalrestat extended-release tablets.

[0027] As an optional manner, in the above-mentioned method for preparing epalrestat sustained-release tablets, in the step a, the epalrestat raw material has been sieved through a 150-mesh sieve with a pore size of 100 μm; and hydroxypropyl methylcellulose and lactose have been sieved through a 100-mesh sieve with a pore size of 150 μm.

[0028] As an optional manner, in the above-mentioned method for preparing epalrestat sustained-release tablets, in the step b, the rotation speed of the mixing blade is set to 100-600 rpm, preferably 250-450 rpm; the rotation speed of the cutting blade is set to 600-1200 rpm, preferably 800-1000 rpm.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. The present invention selects a combination of low-viscosity hydroxypropyl methylcellulose and high-viscosity hydroxypropyl methylcellulose as a sustained-release matrix material. Compared with using high-viscosity hydroxypropyl methylcellulose or low-viscosity hydroxypropyl methylcellulose alone as a sustained-release matrix material, the epalrestat sustained-release tablet prepared in the present application can release the drug steadily, slowly, and completely. While achieving sustained release of epalrestat, the technical effect of completely releasing the drug within a specified time can be achieved.

[0031] 2. In vivo experiments have shown that the T of the epalrestat sustained-release tablets prepared by the present invention is max Significantly prolonged and reduced fluctuations in blood drug concentration, with significant sustained-release characteristics; AUC 0-t Significantly improved, the drug is absorbed more completely by the body and has higher bioavailability.

[0032] 3. The prescription of the present invention is simple, containing only the active ingredient epalrestat, sustained-release skeleton material, filler, adhesive and lubricant, with few types of auxiliary materials and low cost of auxiliary materials. In addition, the epalrestat sustained-release tablet prepared by the present invention only needs to be taken orally twice a day. Compared with the immediate-release preparation that needs to be taken orally three times a day, the sustained-release tablet has an ideal in vitro drug release curve, a stable blood drug concentration in vivo, avoids peak and valley fluctuations in blood drug concentration, reduces the number of medications for patients, improves patient medication compliance, and improves bioavailability.

[0033] 4. The present invention prepares epalrestat sustained-release tablets by uniformly mixing epalrestat, sustained-release skeleton materials, and fillers, adding a binder to prepare a soft material, granulating, drying, adding a lubricant, mixing, and then tableting. Compared with fluidized bed granulation, dry granulation, hot melt extrusion and other methods, this method has a simple preparation process, low technical difficulty, low production cost, and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 , in vitro release test data diagram of Examples 1 to 6.

[0035] Figure 2 , in vitro release test data diagram of Examples 7 to 12.

[0036] Figure 3 , in vitro release test data diagram of Examples 13 to 18.

[0037] Figure 4 , in vitro release test data diagram of Examples 19 to 22.

[0038] Figure 5 , in vitro release test data diagram of Examples 23 to 26.

[0039] Figure 6 , in vitro release test data diagram of Examples 27 to 30.

[0040] Figure 7 , in vitro release test data diagram of Examples 31 to 34.

[0041] Figure 8 , in vitro release test data diagram of Examples 35 to 38.

[0042] Fig. 9 , in vitro release test data diagram of Examples 39 to 42.

[0043] Fig.10 , blood drug concentration-time data graphs of Examples 31 to 34.

[0044] Fig.11 , Blood drug concentration-time data graphs of Examples 35 to 38.

[0045] Fig.12 , Blood drug concentration-time data graphs of Examples 39 to 42. DETAILED DESCRIPTION

[0046] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention and are not intended to limit the present invention. If specific techniques or conditions are not specified in the embodiments, the techniques or conditions described in the literature in this area or the product instructions are used. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0047] In the following examples, the epalrestat bulk drug was sieved through a 150-mesh sieve, and the hydroxypropyl methylcellulose and lactose were sieved through a 100-mesh sieve. The content of each component is calculated by weight.

[0048] The preparation methods of the epalrestat sustained-release tablets in the following examples are the same, characterized in that the preparation of 1000 sustained-release tablets of the present invention comprises the following steps:

[0049] Epalrestat, hydroxypropyl methylcellulose and lactose are mixed evenly by a universal mixer; after mixing, the mixed material is placed in a high shear wet granulator, the mixing is started, the speed of the mixing blade is set to 400 rpm, and the isopropanol solution of the prescribed amount of PVP K30 is slowly added at the same time to prepare a soft material; after the soft material is prepared, the cutting blade is turned on, the speed of the cutting blade is set to 800 rpm, and the granulation time is 4 minutes; after granulation, the granules are taken out and dried, and the moisture content of the granules is controlled to be below 5% (w / w). After drying, the granules are sieved through a 20-mesh sieve, and the corresponding prescribed amount of magnesium stearate is added, mixed evenly, a 7mm shallow concave punch is selected, and a rotary tablet press is used for tableting, and the tablet hardness is controlled to be 7-8kg, so as to finally obtain epalrestat sustained-release tablets.

[0050] The composition of 1000 tablets of the epalrestat sustained-release tablets of the present invention is as follows:

[0051] Table 1 Prescription of Epalrestat Sustained Release Tablets in Examples 1 to 6

[0052]

[0053]

[0054] Table 2 Prescription of Epalrestat Sustained Release Tablets in Examples 7 to 12

[0055]

[0056] Table 3 Prescription of Epalrestat Sustained Release Tablets of Examples 13 to 18

[0057]

[0058]

[0059] The epalrestat sustained-release tablets of the present invention preferably have the following composition per 1000 tablets:

[0060] Table 4 Prescription of Epalrestat Sustained Release Tablets in Examples 19 to 22

[0061]

[0062] Table 5 Prescription of Epalrestat Sustained Release Tablets of Examples 23 to 26

[0063]

[0064] Table 6 Prescription of Epalrestat Sustained Release Tablets of Examples 27 to 30

[0065]

[0066] Table 7 Prescription of Epalrestat Sustained Release Tablets of Examples 31 to 34

[0067]

[0068]

[0069] Table 8 Prescription of Epalrestat sustained-release tablets of Examples 35 to 38

[0070]

[0071] Table 9 Prescription of Epalrestat Sustained Release Tablets of Examples 39 to 42

[0072]

[0073]

[0074] Embodiment 43:

[0075] In vitro release test of epalrestat sustained-release tablets: 6 epalrestat sustained-release tablets in each of Examples 1 to 42 were taken, and according to the second method of General Chapter 0931 of the 2020 edition of the Chinese Pharmacopoeia, a paddle method apparatus was used, with 900 mL of degassed phosphate buffer (pH 6.8) as the medium, the speed was set to 50 rpm, the temperature was 37 ° C, and the operation was carried out in accordance with the law. 10 mL of liquid was taken at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours, and fresh dissolution medium of the same volume and temperature was added at the same time. The solution was filtered with a 0.45 μm microporous membrane, and the filtrate was appropriately diluted and the absorbance was determined by an ultraviolet spectrophotometer. The cumulative release of the drug was calculated. The results are shown in Table 10. Figures 1 to 6 shown.

[0076] Table 10 In vitro release data of epalrestat sustained-release tablets

[0077]

[0078]

[0079]

[0080] Depend on Figures 1 to 3It can be seen that when only low-viscosity hydroxypropyl methylcellulose is used (Examples 1-3, 7-9, 13-15) at the same dosage, the strength of the gel skeleton formed is too low, the viscosity is small, the drug release is too rapid, the release amount is high, and the sustained release effect cannot be achieved; on the contrary, when only high-viscosity hydroxypropyl methylcellulose is used (Examples 4-6, 10-12, 16-18), the process from water absorption to dispersion is long, the strength of the gel skeleton formed is too high, the viscosity is too large, which is not conducive to the diffusion of the drug from the inside of the tablet to the outside, so the drug release rate is slow and the total release amount is low. In addition, when the hydroxypropyl methylcellulose model is the same, as the dosage increases (20 parts to 40 parts), the tablet is more sustained release, but it cannot achieve the purpose of stable, slow, and complete release.

[0081] Depend on Figures 4 to 6 It can be known that, compared with other embodiments, when the mixing ratio of high viscosity hydroxypropyl methylcellulose and low viscosity hydroxypropyl methylcellulose is 1:2 (Examples 20, 24, 28), the prepared epalrestat sustained-release tablets can release the drug steadily, slowly and completely. This is because the drug can be released faster in the gel layer formed by low viscosity hydroxypropyl methylcellulose, so that the gel layer formed by high viscosity hydroxypropyl methylcellulose has more pores, and then promotes the release of some drugs from the high viscosity gel layer to the dissolution medium. Finally, while realizing the sustained release of epalrestat, the purpose of completely releasing the drug within the prescribed time is achieved. Therefore, the use of low viscosity hydroxypropyl methylcellulose and high viscosity hydroxypropyl methylcellulose in combination can make the epalrestat sustained-release tablets release the drug steadily, slowly and completely within the prescribed time.

[0082] Depend on Figures 7 to 9 It can be seen that when the prescription ratio is constant, when only the type of filler is changed, there is no significant difference in the in vitro release results, and the prepared epalrestat sustained-release tablets can release the drug steadily, slowly and completely, indicating that the type of filler has no significant effect on the in vitro release behavior of epalrestat sustained-release tablets. This is because the selected fillers are all water-soluble fillers, which have no hindering effect on the diffusion of drugs from the gel layer to the dissolution medium, thereby improving the dissolution rate of the drug, achieving a sustained-release effect and realizing complete release of the drug within a specified time.

[0083] Embodiment 44:

[0084] Epalrestat sustained-release tablets (Examples 31-42) and original rapid-release tablets (trade name 50mg / tablet) in Beagle dogs:

[0085] Experimental animals: 10 healthy Beagle dogs, half male and half female, weighing 10-12 kg, fasted for 12 h before the experiment and allowed free access to water.

[0086] Dosage regimen: For epalrestat extended-release tablets (75 mg / tablet), the drug is administered once every 12 hours. For epalrestat immediate-release tablets (trade name 50 mg / tablet), administered once every 8 hours.

[0087] Blood sampling plan: blank blood was collected before administration, and 3 mL of blood was collected from the small vein of the dog's forelimb at 0.25, 0.75, 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after administration into a vacuum blood collection tube coated with an anticoagulant. Immediately after blood collection, centrifuge at 3000 rpm for 5 minutes, remove the supernatant, and store at -20°C for later use.

[0088] Treatment of plasma samples: Take 100 μL of the plasma sample to be tested in a centrifuge tube, add 100 μL of the internal standard solution (phenacetin), add 200 μL of acetonitrile, vortex mix for 3 min, centrifuge at 13000 rpm for 5 min, take the supernatant, centrifuge again at 13000 rpm for 5 min, take the supernatant, and use ultra performance liquid chromatography tandem mass spectrometry for sample analysis. The above operations are all carried out under light-proof conditions.

[0089] The experimental results are shown in Table 11. Figures 10-12 shown.

[0090] Table 11 Pharmacokinetic parameters of epalrestat sustained-release tablets in Beagle dogs

[0091]

[0092]

[0093] Depend on Figures 10-12 It can be seen that the original rapid-release preparation T max 1.04±0.15h, C max The drug has a short onset time and a rapid rise in blood drug concentration. When the drug is taken three times a day, the blood drug concentration in the body fluctuates widely. The drug concentration in the body is too low and cannot reach an effective therapeutic concentration, resulting in a drug efficacy window period, which is easy to induce disease or slow down the entire treatment process. Compared with the original rapid-release preparation, the T of the epalrestat sustained-release tablet prepared by the present invention is max The duration of drug administration is significantly prolonged. When the drug is taken twice a day, the fluctuation range of blood drug concentration is small, which has significant sustained-release characteristics. Therefore, it can be inferred that sustained-release preparations can reduce the number of dosings while achieving better therapeutic effects, thereby improving patient compliance. In addition, the AUC of sustained-release preparations is 0-tThe drug is absorbed more completely by the body and has higher bioavailability. In addition, among the sustained-release tablets of epalrestat prepared by the present invention, the sustained-release tablets with lactose as filler (Examples 32, 36, and 40) have no significant difference in in vitro release results from other examples, but have higher C max , a smoother sustained-release curve, and higher bioavailability. This may be because mannitol and sorbitol are not easily absorbed in the intestine, which will reduce the retention time of the drug in the absorption site, thereby reducing the absorption rate of the drug. Compared with the hydrolysis products of sucrose, glucose and fructose, lactose will be broken down into glucose and galactose by lactase in the intestine. Galactose has a stronger affinity with the transport carrier and is more easily absorbed by the body, thereby interfering with the in vivo behavior of the drug and ultimately improving the oral bioavailability of the drug.

[0094] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. An epalrestat sustained-release tablet, characterized in that: The invention comprises epalrestat, a sustained-release matrix material, a filler, a binder and a lubricant; wherein, in the epalrestat sustained-release tablet, the content of each component is, by weight, 20 to 30 parts by weight of epalrestat, 10 to 50 parts by weight of a sustained-release matrix material, 30 to 60 parts by weight of a filler, 3 parts by weight of a binder (PVP K30) and 1 to 5 parts by weight of a lubricant. The sustained-release matrix material is a combination of high-viscosity hydroxypropyl methylcellulose and low-viscosity hydroxypropyl methylcellulose, wherein the high-viscosity hydroxypropyl methylcellulose refers to a 2% (w / v) hydroxypropyl methylcellulose aqueous solution having a viscosity greater than or equal to 4000 mPa·s when measured at 20°C; and the low-viscosity hydroxypropyl methylcellulose refers to a 2% (w / v) hydroxypropyl methylcellulose aqueous solution having a viscosity less than or equal to 100 mPa·s when measured at 20°C.

2. The epalrestat sustained-release tablet according to claim 1, characterized in that: The model of high-viscosity hydroxypropyl methylcellulose is one or more of K4M, K10M, K15M, and K100M; the model of low-viscosity hydroxypropyl methylcellulose is one or more of E5, E15, E30, E50, E100, and E400.

3. The epalrestat sustained-release tablet according to claim 1, characterized in that: The ratio of the high-viscosity hydroxypropyl methylcellulose to the low-viscosity hydroxypropyl methylcellulose is 1:4 to 6:1, preferably 1:3 to 3:1, and preferably 1:

2.

4. The epalrestat sustained-release tablet according to claim 1, characterized in that: The filler is selected from one or more of starch, microcrystalline cellulose, lactose, sucrose, pregelatinized starch, sorbitol, dextrin, and mannitol, preferably one or more of sucrose, lactose, mannitol, and sorbitol, and most preferably lactose.

5. The epalrestat sustained-release tablet according to claim 1, characterized in that: The lubricant is selected from one or more of talc, stearic acid, magnesium stearate, calcium stearate, and micro-powdered silica gel, preferably magnesium stearate.

6. The epalrestat sustained-release tablet according to claim 1, characterized in that: The invention comprises 25 parts by weight of epalrestat, 20 parts by weight of hydroxypropyl methylcellulose E100, 10 parts by weight of hydroxypropyl methylcellulose K4M, 44 parts by weight of a filler, 3 parts by weight of a binder and 1 part by weight of magnesium stearate.

7. The epalrestat sustained-release tablet according to claim 1, characterized in that: The preparation method comprises the following steps: a. Use a mixer to mix epalrestat, sustained-release matrix material, and filler evenly, and prepare the prescribed amount of adhesive (PVPK30) into a 3% (w / v) isopropanol solution; b. Place the mixed material obtained in step a in a high shear wet granulator, start mixing, and slowly add an isopropanol solution of a binder (PVP K30) to prepare a soft material; After the soft material is prepared, the cutting knife is turned on for granulation; c. After granulation, the granules are taken out and dried. After drying, the granules are sieved through a 20-mesh sieve, and the corresponding amount of lubricant is added. The granules are mixed evenly with a mixer, and 7 mm shallow concave punching tablets are selected to obtain epalrestat sustained-release tablets.

8. The method for preparing an epalrestat sustained-release tablet according to claim 7, characterized in that: In the step a, the epalrestat raw material has been passed through a 150-mesh sieve with a sieve aperture of 100 μm; hydroxypropyl methylcellulose and lactose have been passed through a 100-mesh sieve with a sieve aperture of 150 μm; in the step b, the rotating speed of the mixing blade is set to 100 to 600 rpm, preferably 250 to 450 rpm; the rotating speed of the cutting blade is set to 600 to 1200 rpm, preferably 800 to 1000 rpm.

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