Gastric retention type sustained release tablet

Abstract

The gastric retention type sustained-release tablet comprises a blank retention layer and a drug-loaded sustained-release layer which are arranged on the surface layer of a plain tablet of the gastric retention type sustained-release tablet, the blank retention layer is prepared from the following raw materials: a skeleton type slow-release material, a floating aid and an expanding agent; the medicine-carrying sustained-release layer is prepared from the following raw materials: a skeleton type sustained-release material, a floating aid and an active medicine component. According to the invention, calcium silicate with low bulk density and super absorbent resin are respectively used as a floating aid and an expanding agent, so that the gastric retention type sustained-release tablet has similar gastric retention capability with a common single-layer tablet, and has a very good sustained-release effect at the same time; through the arrangement of the blank retention layer and the drug-loaded sustained-release layer, the sustained release of drugs with low solubility in acid can also be realized in the form of gastric retention type sustained-release tablets.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and particularly to a sustained-release tablet. Background Art

[0002] The gastric retention-type sustained-release tablet is a sustained-release dosage form drug that can stay in the stomach, which can greatly prolong the residence time of the drug in the stomach, enabling the gastrointestinal tract to have sufficient time to absorb the drug, and is particularly suitable for drugs that are absorbed in the duodenum and drugs for treating local diseases in the stomach.

[0003] The narrow passage that gastric contents must pass through is the pylorus, with an average size of about 12.8 mm; the swelling-type gastric retention dosage form is a dosage form that rapidly swells after entering the stomach, directly exceeding the pylorus diameter, thus staying in the stomach, and the gastric retention effect is stable; the gastric floating preparation is also a type of gastric retention preparation, which refers to a preparation that can maintain its own density less than the density of gastric contents after oral administration and floats in gastric juice. Usually, the gastric floating tablet that only contains the gastric floating mechanism is significantly affected by the body position, movement, food, etc. of the human body, resulting in unstable gastric floating performance. To overcome this problem, most of the currently approved gastric retention preparations at home and abroad combine the two mechanisms of gastric floating type and swelling type to ensure their gastric retention effect, such as the pregabalin sustained-release tablet developed and approved by Hengrui Medicine.

[0004] However, due to the acidic environment in the stomach, the gastric retention-type sustained-release tablet still cannot be used for the sustained release of many drugs, such as drugs with pH-dependent dissolution, low solubility in acid, and absorption concentrated in the upper part of the small intestine; in the current technology, even if such drugs are made into gastric retention-type sustained-release tablets, there are still problems of difficult release in the body due to difficult dissolution, and the sustained release effect cannot be achieved; some studies have selected to take measures to promote drug release on the basis of the gastric retention-type sustained-release tablet, but instead caused burst release, and the problem of the balance between gastric retention and dissolution release has not been solved. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the above-mentioned defects existing in the prior art and provide a gastric retention-type sustained-release tablet applicable to drugs with low solubility in acid.

[0006] The technical solution adopted by the present invention to solve its technical problems is as follows: a gastric retention-type sustained-release tablet, comprising a blank retention layer and a drug-loaded sustained-release layer, both of which are arranged on the surface layer of the core tablet of the gastric retention-type sustained-release tablet; The raw materials of the blank retention layer include a matrix-type sustained-release material, a buoyancy aid, and a swelling agent; The raw materials of the drug-loaded sustained-release layer include a matrix-type sustained-release material, a buoyancy aid, and an active pharmaceutical ingredient (abbreviated as API); The buoyancy aid includes calcium silicate, and the bulk density of the calcium silicate is below 0.2 g / mL; The swelling agent includes a superabsorbent resin, and the water absorption rate of the superabsorbent resin is above 100 g / g; The raw materials of the gastric retention sustained-release tablets further include excipients; In the blank retention layer, the mass of calcium silicate accounts for 4% - 28% of the blank retention layer; In the blank retention layer, the mass of the superabsorbent resin accounts for 3% - 40% of the blank retention layer; In the drug-loaded sustained-release layer, the mass of calcium silicate accounts for 4% - 28% of the drug-loaded sustained-release layer.

[0007] Preferably, in the blank retention layer, the mass of calcium silicate accounts for 4.5% - 25% of the blank retention layer.

[0008] Preferably, in the blank retention layer, the mass of the superabsorbent resin accounts for 4% - 35% of the blank retention layer.

[0009] Preferably, in the drug-loaded sustained-release layer, the mass of calcium silicate accounts for 4.5% - 25% of the drug-loaded sustained-release layer.

[0010] Preferably, the mass ratio of the blank retention layer to the drug-loaded sustained-release layer is 400 - 700∶300 - 600.

[0011] Preferably, in the blank retention layer, the mass ratio of the buoyant aid is below 30%.

[0012] Preferably, in the blank retention layer, the mass ratio of the swelling agent is below 40%.

[0013] Preferably, in the drug-loaded sustained-release layer, the mass ratio of the buoyant aid is below 25%.

[0014] Preferably, in the drug-loaded sustained-release layer, the mass ratio of the swelling agent is below 15%.

[0015] Preferably, in the blank retention layer, the mass ratio of the matrix-type sustained-release material is 25% - 80%.

[0016] Preferably, in the drug-loaded sustained-release layer, the mass ratio of the matrix-type sustained-release material is 15% - 60%.

[0017] Preferably, the superabsorbent resin is acrylic acid grafted starch.

[0018] Preferably, the matrix-type sustained-release material in the blank retention layer includes a hydrophilic gel matrix material and / or an insoluble matrix material.

[0019] Preferably, in the matrix-type sustained-release material of the drug-loaded sustained-release layer, the mass of the hydrophilic gel matrix material is above 60%.

[0020] Preferably, the specific surface area of the calcium silicate is 100 m 2 / g or more.

[0021] Preferably, the superabsorbent resin is an acrylic acid grafted starch obtained by graft copolymerization of an acrylic acid monomer and natural starch at a molar ratio of 2 to 10:1.

[0022] Preferably, the matrix sustained-release material in the blank retention layer includes one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene oxide, water-swellable cellulose, povidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, gum arabic, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, and hydroxypropyl methylcellulose stearoxy ether.

[0023] Preferably, the matrix sustained-release material in the drug-loaded sustained-release layer includes one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene oxide, water-swellable cellulose, povidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, gum arabic, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, and hydroxypropyl methylcellulose stearoxy ether.

[0024] Preferably, the gastric retention sustained-release tablet is a plain tablet or contains a gastric-soluble coating.

[0025] Preferably, the tablet weight of the gastric retention sustained-release tablet excluding the coating weight is 600 to 1300 mg.

[0026] Preferably, the width and diameter size of the gastric retention sustained-release tablet is ≥10 mm.

[0027] Preferably, the excipients include one or more of fillers, binders, and lubricants.

[0028] Preferably, the solubility of the active pharmaceutical ingredient under acidic conditions is as follows: for the single-dose of the active pharmaceutical ingredient, it dissolves in a hydrochloric acid solution with a pH value of 1.0 to 3.0, and the volume of the hydrochloric acid solution required is higher than 250 mL.

[0029] Preferably, the active pharmaceutical ingredient includes one or more of poorly soluble drugs in hydrochloric acid solution, their pharmaceutically acceptable salts, hydrates, and hydrates of salts; the poorly soluble drugs in hydrochloric acid solution include: epalrestat, cyclosporine, carbamazepine, lovastatin, azithromycin, albendazole, atorvastatin, allopurinol, azathioprine, bicalutamide, celecoxib, digoxin, diazepam, acetazolamide, clofazimine, acyclovir, paracetamol, clarithromycin, clozapine, fenofibrate, gliclazide, glimepiride, glipizide, glibenclamide, granisetron, ibuprofen, ketoprofen, flurbiprofen, irbesartan, isotretinoin, tretinoin, ursodeoxycholic acid, valsartan, teprenone, spironolactone, simvastatin, roxithromycin, rofecoxib, risperidone, rifampicin, rebamipide, oxcarbazepine, nimesulide, nifedipine, nevirapine, nelfinavir, nabumetone, meloxicam, medroxyprogesterone, lopinavir, indomethacin, etc., one or more of them.

[0030] Preferably, the active pharmaceutical ingredient includes one or more of epalrestat, epalrestat salts, epalrestat hydrates, and hydrates of epalrestat salts; calculated as C 15 H 13 NO3S2, each tablet contains 100 mg to 180 mg of the active pharmaceutical ingredient.

[0031] The present invention has the following beneficial effects: (1) Through the setting of the blank retention layer and the drug-loaded sustained-release layer, the present invention enables drugs with low solubility in acid to achieve in-vivo sustained release in the form of gastric retention sustained-release tablets. (2) Using calcium silicate with low bulk density and superabsorbent resin as the buoyancy aid and swelling agent respectively, the gastric retention sustained-release tablets of the present invention can have a gastric retention ability similar to that of ordinary single-layer tablets, and at the same time play a good sustained-release role. (3) The floating time in the release medium with a pH value of 1.2 to 6.8 is <1 s, and it starts to float immediately under various gastric pH conditions (covering the phenomenon of increased gastric pH caused by factors such as food effect and elderly patients), and it can be realized that within a wide gastric pH range, the tablet expands to a size >12.8 mm within 2 hours, exceeding the diameter of the gastric pylorus.

[0032] In addition to the purposes, features, and advantages described above, the present invention has other purposes, features, and advantages. The following will refer to the drawings for a further detailed description of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The drawings forming a part of this application are used to provide a further understanding of the present invention. The schematic embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation to the present invention. In the drawings: Figure 1 It is the in vitro average cumulative release curve of the epalrestat gastric retention sustained-release tablets of Example 2, Example 8, Example 9 and Example 11 of the present invention in the release medium with a pH value of 6.8; Figure 2 It is the human in vivo absorption blood drug concentration - administration time curve of the original research ordinary tablet of epalrestat and the epalrestat gastric retention sustained-release tablet of Example 2 of the present invention. Detailed implementation manners

[0034] In order to make the purpose, solution and beneficial technologies of the present invention clearer, the present invention will be further described in detail below with reference to examples and drawings. It should be noted that the examples described in this specification are only for explaining the present invention and not for limiting the present invention.

[0035] For simplicity, only some numerical ranges are explicitly disclosed herein. However, any lower limit can be combined with any upper limit to form a range not explicitly recorded; and any lower limit can be combined with other lower limits to form a range not explicitly recorded, and similarly any upper limit can be combined with any other upper limit to form a range not explicitly recorded. In addition, although not explicitly recorded, each point or single value between the range endpoints is included in this range. Thus, each point or single value can be used as its own lower limit or upper limit and combined with any other point or single value or combined with other lower limits or upper limits to form a range not explicitly recorded.

[0036] In the description herein, it should be noted that unless otherwise specified, "above" and "below" include this number, the meaning of "multiple" in "one or more" is two or more, and the meaning of "multiple" in "one or more" is two or more.

[0037] Further explanation of the water absorption rate: It refers to weighing a certain adsorbent, placing it in a certain amount of deionized water, standing for 3 hours, filtering with a 100-mesh nylon bag, and calculating the water absorption rate according to the formula: Water absorption rate (g / g) = (weight of added water - weight of filtered water) / weight of adsorbent.

[0038] The embodiments of the present invention provide a gastric retention sustained-release tablet, which includes a blank retention layer and a drug-loaded sustained-release layer, and both the blank retention layer and the drug-loaded sustained-release layer are disposed on the surface layer of the core tablet of the gastric retention sustained-release tablet; The raw materials of the blank retention layer include a matrix-type sustained-release material, a buoyant aid, and a swelling agent; The raw materials of the drug-loaded sustained-release layer include a matrix-type sustained-release material, a buoyant aid, and an active pharmaceutical ingredient (abbreviation: API); The floating aid includes calcium silicate, and the bulk density of the calcium silicate is 0.2 g / mL or less; for example, 0.2 g / mL, 0.18 g / mL, 0.16 g / mL, 0.14 g / mL, 0.12 g / mL, 0.10 g / mL, 0.08 g / mL, and 0.06 g / mL; The swelling agent includes a superabsorbent resin, and the water absorption rate of the superabsorbent resin is 100 g / g or more; for example, 100 g / g, 150 g / g, 200 g / g, 300 g / g, 500 g / g, 800 g / g, 1000 g / g, and 2000 g / g; The raw materials of the gastric retention sustained-release tablets further include excipients; In the blank retention layer, the mass of calcium silicate accounts for 4% to 28% of the blank retention layer; for example, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 8.0%, 12.0%, 18.0%, 22.0%, 24.0%, 25.0%, 26.0%, 27.0%, and 28.0%; In the blank retention layer, the mass of the superabsorbent resin accounts for 3% to 40% of the blank retention layer; for example, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 7.0%, 9.0%, 13.0%, 20.0%, 26.0%, 31.0%, 32.0%, 34.0%, 36.0%, 38.0%, 39.0%, and 40.0%; In the drug-loaded sustained-release layer, the mass of calcium silicate accounts for 4% to 28% of the drug-loaded sustained-release layer; for example, 4.0%, 4.2%, 4.4%, 4.6%, 4.8%, 5.0%, 6.0%, 10.0%, 15.0%, 19.0%, 21.0%, 23.0%, 25.0%, 26.0%, 27.0%, and 28.0%.

[0039] The gastric retention sustained-release tablets of the present invention comprise a blank retention layer and a drug-loaded sustained-release layer; the swelling materials (including matrix-type sustained-release materials and swelling agents) exert their sustained-release matrix and swelling effects after contacting gastric acid or a release medium and getting wetted, and at the same time, a high-strength gel matrix will be formed on the contact surface after contacting gastric acid or the release medium, and this high-strength gel will prevent or slow down the further wetting of gastric acid or the release medium, achieving gastric retention and sustained release; wherein the blank retention layer mainly plays a role in gastric retention, and the drug-loaded sustained-release layer forms an erodible sustained-release matrix, enabling the API to diffuse as the sustained-release matrix erodes, and then dissolving and releasing in the upper part of the small intestine. Both the blank retention layer and the drug-loaded sustained-release layer need to contact gastric acid or the release medium and get wetted to exert their effects, so they are arranged on the surface layer of the plain tablets of the gastric retention sustained-release tablets; in the case of only setting the blank retention layer (containing the API), there is a problem of difficult release for drugs with low solubility in acid; in the case of only setting the drug-loaded sustained-release layer, since the matrix of the drug-loaded sustained-release layer erodes as the drug is released and the size continuously shrinks, the gastric retention ability is insufficient; therefore, a better sustained-release effect can be achieved only when both layers exist simultaneously.

[0040] However, compared with single-layer tablets, due to the layered structure of the gastric retention sustained-release tablets of the present invention, the surface area of the blank retention layer that plays a role in gastric retention contacting gastric acid or the release medium is smaller than that of single-layer tablets (the entire surface of the single-layer tablet plays a role in gastric retention, while the sustained-release tablets of the present invention also need to allocate a part of the surface position to the drug-loaded sustained-release layer), so it is very difficult for the tablets of the structure of the present invention to maintain the same gastric floating ability and size swelling ability as single-layer tablets. In addition, when the pH value in the stomach rises (caused by factors such as food effect, elderly patients, etc.), the gastric retention effect of the gastric retention agent is further restricted, and making the sustained-release effect not affected by it is also a challenge encountered in the research of the present invention.

[0041] Calcium silicate with low bulk density is generally made from silicate minerals through various chemical treatments and physical processes. It is a porous white or off-white substance with a large specific surface area. Calcium silicate is commonly used as a glidant and anti-adherent in pharmaceutical preparations. The inventors of the present invention unexpectedly found in experiments that calcium silicate with low bulk density has a unique effect when used as a buoyancy aid in gastric floating preparations. Due to the porous structure and the characteristic of having a large specific surface area of calcium silicate, the gastric floating preparation or gastric retention preparation prepared by adding calcium silicate can maintain its own density less than the density of gastric contents, thereby achieving gastric floating and gastric retention. Currently, there are calcium silicates that meet the requirements on the market and can be directly purchased and used, such as pharmaceutical-grade calcium silicate produced by KirschPharma in Germany, pharmaceutical-grade calcium silicate produced by Tomita Pharmaceutical Co., Ltd., and pharmaceutical-grade calcium silicate produced by Jiangxi Hanjiang Pharmaceutical Co., Ltd. In the present invention, a superabsorbent resin is also used as a swelling agent in gastric retention sustained-release tablets. When the water absorption rate of the superabsorbent resin used reaches more than 100 g / g, the effect undergoes a qualitative change, which can enhance the ability of gastric acid or release medium to enter the inside of the gel matrix, thereby achieving a good swelling effect between the matrix-type sustained-release material and the swelling agent. By using calcium silicate with low bulk density and a superabsorbent resin as raw materials, the gastric retention sustained-release tablets of the present invention can have a gastric retention ability similar to that of ordinary single-layer tablets and at the same time play a good sustained-release role.

[0042] The gastric retention sustained-release tablets provided by the embodiments of the present invention have the following advantages: (1) Through the setting of the blank retention layer and the drug-loaded sustained-release layer, drugs with low solubility in acid can also be slowly released in vivo in the form of gastric retention sustained-release tablets; (2) By using calcium silicate with low bulk density and a superabsorbent resin as a buoyancy aid and a swelling agent respectively, the gastric retention sustained-release tablets of the present invention can have a gastric retention ability similar to that of ordinary single-layer tablets and at the same time play a good sustained-release role; (3) The floating start time in the release medium with a pH value of 1.2 to a pH value of 6.8 is <1 s, and it starts to float immediately under various pH value conditions in the stomach (covering the phenomenon of rising gastric pH value caused by factors such as food effect and elderly patients). It can be realized that within a wide pH value range in the stomach, the tablet expands to a size >12.8 mm within 2 hours, exceeding the diameter of the gastric pylorus.

[0043] In some embodiments of the present invention, the gastric retention sustained-release tablet is a double-layer tablet or a multi-layer tablet.

[0044] In some embodiments of the present invention, the blank retention layer is provided on one of the upper surface layer or the lower surface layer of the plain tablet of the gastric retention sustained-release tablet; the drug-loaded sustained-release layer is provided on the other of the upper surface layer or the lower surface layer of the plain tablet of the gastric retention sustained-release tablet.

[0045] In the embodiment of the present invention, in the blank retention layer, the mass of calcium silicate accounts for 4.5% to 25% of the blank retention layer.

[0046] In the embodiment of the present invention, in the blank retention layer, the mass of the superabsorbent resin accounts for 4% to 35% of the blank retention layer.

[0047] In the embodiment of the present invention, in the drug-loaded sustained-release layer, the mass of calcium silicate accounts for 4.5% to 25% of the drug-loaded sustained-release layer.

[0048] In the embodiment of the present invention, the mass ratio of the blank retention layer to the drug-loaded sustained-release layer is 400 to 700:300 to 600.

[0049] In the embodiment of the present invention, in the blank retention layer, the mass ratio of the bleaching aid is 30% or less. In the blank retention layer, a bleaching aid other than calcium silicate can be additionally used, or not used, but the total amount of the bleaching aid used should not be too much; too much total amount of the bleaching aid may cause the volume of the material before tabletting to be too large, which is not conducive to tabletting, and may also cause the proportion of the skeleton material or the swelling agent to be too low, thereby affecting the swelling effect.

[0050] In the embodiment of the present invention, in the blank retention layer, the mass ratio of the swelling agent is 40% or less. In the blank retention layer, a swelling agent other than the superabsorbent resin can be additionally used, or not used, but the total amount of the swelling agent used should not be too much; too much total amount of the swelling agent may cause the proportion of the skeleton material or the bleaching aid to be too low, thereby affecting the swelling effect or the bleaching effect.

[0051] In the embodiment of the present invention, in the drug-loaded sustained-release layer, the mass ratio of the bleaching aid is 25% or less. In the drug-loaded sustained-release layer, a bleaching aid other than calcium silicate can be additionally used, or not used, but the total amount of the bleaching aid used should not be too much; too much total amount of the bleaching aid may cause the proportion of the skeleton material or the swelling agent to be too low, thereby affecting the sustained-release effect.

[0052] In the embodiment of the present invention, in the drug-loaded sustained-release layer, the mass ratio of the swelling agent is 15% or less. In the drug-loaded sustained-release layer, a swelling agent can be used, or not used, but the total amount of the swelling agent used should not be too much; too much total amount of the swelling agent may cause the proportion of the skeleton material or the bleaching aid to be too low, thereby affecting the sustained-release effect.

[0053] In the embodiment of the present invention, in the blank retention layer, the mass ratio of the matrix-type sustained-release material is 25% to 80%; for example, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% and 80%.

[0054] In some embodiments of the present invention, in the blank retention layer, the mass ratio of the matrix-type sustained-release material is 30% to 75%.

[0055] In the embodiments of the present invention, in the drug-loaded sustained-release layer, the mass ratio of the matrix-type sustained-release material is 15% to 60%; for example, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% and 60%. The drug-loaded sustained-release layer contains API while the blank retention layer does not, so relatively higher contents of the matrix-type sustained-release material can be used in the blank retention layer.

[0056] In some embodiments of the present invention, in the drug-loaded sustained-release layer, the mass ratio of the matrix-type sustained-release material is 20% to 55%.

[0057] In the embodiments of the present invention, the superabsorbent resin is acrylic acid grafted starch. Acrylic acid grafted starch is a functional material prepared by graft copolymerization of acrylic acid monomers with natural starch, combining the biocompatibility of starch and the physicochemical properties of acrylic acid, having a strong water absorption capacity, and is commonly used as an excipient for external preparations in pharmaceutical preparations. There are already commercially available acrylic acid grafted starches that meet the requirements and can be directly purchased and used, such as acrylic acid grafted starch 300 and acrylic acid grafted starch 1000, where 300 and 1000 correspond to water absorption rates of 300 g / g and 1000 g / g; these two specifications were first developed by Sanyo Chemical Industries, Ltd. of Japan.

[0058] In the embodiments of the present invention, the matrix-type sustained-release material in the blank retention layer includes a hydrophilic gel matrix material and / or an insoluble matrix material.

[0059] In the embodiments of the present invention, the mass of the hydrophilic gel matrix material in the matrix-type sustained-release material in the drug-loaded sustained-release layer accounts for more than 60%.

[0060] In the embodiments of the present invention, the specific surface area of the calcium silicate is 100m 2 / g or more.

[0061] In the embodiments of the present invention, the superabsorbent resin is acrylic acid grafted starch obtained by graft copolymerization of acrylic acid monomers and natural starch in a molar ratio of 2 to 10:1.

[0062] In the embodiments of the present invention, the matrix-type sustained-release material in the blank retention layer includes one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene oxide, water-swellable cellulose, polyvinylpyrrolidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, gum arabic, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, and hydroxypropyl methylcellulose stearoxy ether.

[0063] In the embodiments of the present invention, the matrix sustained-release materials in the drug-loading sustained-release layer include one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene oxide, water-swellable cellulose, polyvinylpyrrolidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, gum arabic, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, and hydroxypropyl methylcellulose stearoxy ether.

[0064] In the embodiments of the present invention, the gastric retention sustained-release tablets are plain tablets or contain gastric-soluble coatings.

[0065] The gastric retention sustained-release tablets can be in various shapes; in some embodiments of the present invention, the tablet shape is circular; in some embodiments of the present invention, the tablet shape is irregular.

[0066] In the embodiments of the present invention, the tablet weight of the gastric retention sustained-release tablets excluding the coating weight is 600 - 1300 mg.

[0067] In the embodiments of the present invention, the width diameter dimension of the gastric retention sustained-release tablets ≥ 10 mm.

[0068] In some embodiments of the present invention, the width diameter dimension of the tablets ≥ 7 mm.

[0069] In the embodiments of the present invention, the excipients include one or more of fillers, binders, and lubricants.

[0070] In the embodiments of the present invention, the solubility of the active pharmaceutical ingredient under acidic conditions is as follows: for the active pharmaceutical ingredient with a single-dose administration, it dissolves in hydrochloric acid solution with a pH value of 1.0 - 3.0, and the volume of hydrochloric acid solution required is higher than 250 mL.

[0071] In the embodiments of the present invention, the active pharmaceutical ingredient includes one or more of poorly soluble drugs in hydrochloric acid solution, their pharmaceutically acceptable salts, hydrates, and hydrates of salts; the poorly soluble drugs in hydrochloric acid solution include: epalrestat, cyclosporine, carbamazepine, lovastatin, azithromycin, albendazole, atorvastatin, allopurinol, azathioprine, bicalutamide, celecoxib, digoxin, diazepam, acetazolamide, clofazimine, acyclovir, paracetamol, clarithromycin, clozapine, fenofibrate, gliclazide, glimepiride, glipizide, glibenclamide, granisetron, ibuprofen, ketoprofen, flurbiprofen, irbesartan, isotretinoin, tretinoin, ursodeoxycholic acid, valsartan, teprenone, spironolactone, simvastatin, roxithromycin, rofecoxib, risperidone, rifampicin, rebamipide, oxcarbazepine, nimesulide, nifedipine, nevirapine, nelfinavir, nabumetone, meloxicam, medroxyprogesterone, lopinavir, indomethacin.

[0072] In the embodiments of the present invention, the active pharmaceutical ingredient includes one or more of epalrestat, epalrestat salts, epalrestat hydrates, and hydrates of epalrestat salts; calculated as C 15 H 13 NO3S2, each tablet contains 100 mg to 180 mg of the active pharmaceutical ingredient. Epalrestat's chemical name is 5-[(1Z,2E)-2-methyl-3-phenyl-2-propenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid. It is an aldose reductase inhibitor and is mainly used clinically for the prevention, improvement, and treatment of diabetic neuropathy. Diabetic patients have high blood sugar and are prone to converting glucose into sorbitol through the polyol metabolic pathway in the body, resulting in the accumulation of sorbitol. Sorbitol can affect cell osmotic pressure and then affect nerve cell function. Its accumulation in nerve cells can cause late-onset diabetic complications such as neuropathy, retinopathy, and nephropathy. As an aldose reductase inhibitor, epalrestat works by reversibly inhibiting aldose reductase, which converts glucose into sorbitol in polyol metabolism related to the pathogenesis of diabetic complications. Epalrestat is the first and only aldose reductase inhibitor approved for marketing at home and abroad and has now been widely used clinically. It is a first-line drug for the treatment of diabetic neuropathy.

[0073] The epalrestat preparation was first developed by Ono Pharmaceutical Co., Ltd. in Japan in 1992 and approved for marketing in Japan. The marketed dosage form is an immediate-release tablet, and the marketed specification is 50 mg, with the trade name KINEDAK. Since 2004, generic epalrestat tablets have been successively launched on the market, and the dosage form has been synchronously changed to an immediate-release capsule, with the specification still being 50 mg. The dosage of epalrestat tablets or capsules is 1 tablet (capsule) each time, 3 times a day, taken before meals.

[0074] Currently, all marketed preparations of epalrestat are immediate-release preparations, which require too many dosing times clinically and are extremely inconvenient to take, especially since the population taking this drug clinically mainly consists of elderly diabetic patients. Elderly patients usually take many medications due to multiple underlying diseases and are prone to missing or forgetting to take medications. Therefore, reducing the dosing frequency or even achieving once-daily dosing can significantly improve their medication compliance. On the other hand, the immediate-release preparation of epalrestat is rapidly absorbed after oral administration, and the time to reach the peak blood drug concentration (tmax) is only about 1 hour, and the half-life is relatively short (about 1.8 hours), resulting in significant fluctuations in the blood drug concentration in the body and posing a relatively high safety risk. Therefore, there is a clinical need for an epalrestat sustained-release preparation with once-daily dosing, which can not only reduce the dosing frequency to improve medication compliance, but also take effect quickly to ensure effectiveness, and can also significantly reduce the fluctuations in blood drug concentration (mainly reducing the peak concentration Cmax) to reduce dose-related toxic and side effects.

[0075] Due to the drug properties of epalrestat, there are many difficulties in developing a once-daily sustained-release formulation of epalrestat. (1) The elimination half-life of epalrestat in vivo is relatively short (about 1.8 h), and such a short elimination half-life poses a significant challenge for sustained-release design. Since the drug is rapidly metabolized and eliminated after being absorbed into the bloodstream, it is necessary for the drug to have a long enough residence time in the gastrointestinal tract to enable slow release and then slow absorption into the bloodstream. (2) Moreover, clinical studies have shown that the peak time tmax of the immediate-release formulation of epalrestat is only about 1 h. The absorption of epalrestat depends on the active transport system in the upper part of the small intestine, and it shows good absorption only in the upper part of the small intestine (duodenum), while the absorption in the middle and lower parts of the small intestine (jejunum and ileum) and the large intestine is very poor; indicating that the average absorption window of epalrestat is only 4 hours or shorter; if developed into a conventional sustained-release formulation, when it is transferred to the middle and lower parts of the small intestine and the large intestine after about 4 hours, these drugs will be wasted and cannot play any role. (3) Epalrestat is extremely poorly soluble in gastric acid (the solubility in 0.1 μg / mL hydrochloric acid at pH 1.2; calculated based on the gastric juice volume of 250 mL, the maximum dissolved amount is only 25 μg, showing a difference of 2000 - 6000 times compared with the administration dose of 50 - 150 mg), and is only slightly soluble in the upper part of the small intestine (the solubility is 496 μg / mL under the condition of pH value 6.8; calculated based on the liquid volume of 250 mL at the dissolution site, the maximum dissolved amount is only 124 mg). In the present invention, all the above problems can be well solved. Through the above technical means, a sustained-release tablet containing the active pharmaceutical ingredient epalrestat and truly achieving the once-daily in vivo sustained-release effect can be obtained.

[0076] Use of the gastric retention type sustained-release tablet described in the embodiments of the present invention in the prevention and treatment of diabetes and its complications. The gastric retention type sustained-release tablet can effectively exert the effect of the API.

[0077] The gastric retention type sustained-release tablet can be prepared by the conventional preparation method of tablets, such as: mixing the raw materials of each layer including the blank retention layer and the drug-loaded sustained-release layer respectively to obtain the mixed powder of the blank retention layer, the mixed powder of the drug-loaded sustained-release layer, and the mixed powder of other layers (if there are other layers); using a double-layer tablet press or a multi-layer tablet press to press tablets to obtain the gastric retention type sustained-release tablet. The raw materials can be mixed with the aid of a solvent (the solvent is removed before tableting), or a solvent can be not used.

[0078] Example The following examples describe more specifically the disclosure of the present invention. These examples are for illustrative purposes only, as various modifications and variations within the scope of the present invention will be apparent to those skilled in the art. Unless otherwise stated, all parts, percentages, and ratios reported in the following examples are by weight. Unless otherwise stated, all reagents used in the examples are commercially available through conventional means or synthesized according to conventional methods and can be used directly without further treatment. Unless otherwise stated, the instruments used in the examples are commercially available through conventional means.

[0079] Examples 1 - 7 The gastric retention sustained-release tablets of Examples 1 - 7 are bilayer tablets (a blank retention layer and a drug-loaded sustained-release layer respectively), and the tablets have a gastric-soluble film coating made of a gastric-soluble film coating premix; the blank retention layer is composed of a matrix-type sustained-release material, a buoyancy aid, a swelling agent, a filler, and a lubricant; the drug-loaded sustained-release layer is composed of API, a matrix-type sustained-release material, a buoyancy aid, a binder, a filler, and a lubricant. The detailed formulations of the tablets of Examples 1 - 7 are shown in Table 1.

[0080] The calcium silicate used in Examples 1 - 7 is pharmaceutical-grade calcium silicate produced by Tomita Pharmaceutical Co., Ltd., with a bulk density of 0.10 - 0.15 g / mL and a specific surface area of 100 m 2 / g or more.

[0081] The superabsorbent resin used in Examples 1 - 7 is acrylic acid grafted starch 300 produced by Sanyo Chemical Industries, Ltd. in Japan, which is an acrylic acid grafted starch obtained by graft copolymerization of acrylic acid monomers and natural starch at a molar ratio of 4 - 6:1, and the water absorption rate is about 300 g / g.

[0082] The preparation method of the gastric retention sustained-release tablets of Examples 1 - 7 is as follows: (1) After formulating the raw materials of the blank retention layer in proportion, place them in a mixing device and mix evenly to obtain the mixed powder of the blank retention layer; (2) After formulating the raw materials other than the binder and lubricant in the drug-loaded sustained-release layer in proportion, place them in a high-speed stirring granulation device and stir evenly, add an aqueous binder solution according to the formula ratio for wet granulation to obtain wet soft material; use a screening device to screen the wet soft material, and place it in a fluidized bed drying device to dry until the moisture content is less than 3% to obtain the dry granules of the drug-loaded sustained-release layer; place the dry granules of the drug-loaded sustained-release layer and the lubricant in a mixing device and mix evenly to obtain the total mixed granules of the drug-loaded sustained-release layer; (3) Respectively place the blank retention layer mixed powder and the total mixed granules of the drug-loaded sustained-release layer into two hoppers of a double-layer tablet press for double-layer tablet pressing. Use two types of punching dies, namely a 20 mm × 10 mm special-shaped punch and a 19 mm × 7 mm special-shaped punch, and control the tablet hardness at 100 - 300 KN to obtain the core tablets of epalrestat sustained-release tablets. Then place these core tablets into a high-efficiency coating machine for film coating to obtain epalrestat sustained-release tablets.

[0083] Table 1 Detailed Formulations of the Core Tablets of Gastric Retention-Type Sustained-Release Tablets in Examples 1 - 7

[0084] The film coating weight of the gastric retention-type sustained-release tablet in Example 1 is 38.94 mg, which is 4.0% of the weight of the core tablet.

[0085] The film coating weight of the gastric retention-type sustained-release tablet in Example 2 is 40 mg, which is 4.0% of the weight of the core tablet.

[0086] The film coating weight of the gastric retention-type sustained-release tablet in Example 3 is 31.875 mg, which is 3.0% of the weight of the core tablet.

[0087] The film coating weight of the gastric retention-type sustained-release tablet in Example 4 is 28.425 mg, which is 3.0% of the weight of the core tablet.

[0088] The film coating weight of the gastric retention-type sustained-release tablet in Example 5 is 33.21 mg, which is 3.0% of the weight of the core tablet.

[0089] The film coating weight of the gastric retention-type sustained-release tablet in Example 6 is 29.205 mg, which is 3.0% of the weight of the core tablet.

[0090] The film coating weight of the gastric retention-type sustained-release tablet in Example 7 is 31.875 mg, which is 3.0% of the weight of the core tablet.

[0091] Examples 8 - 13 The gastric retention-type sustained-release tablets in Examples 8 - 13 are double-layer tablets (blank retention layer and drug-loaded sustained-release layer respectively), and there is a gastric-soluble film coating made of a gastric-soluble film coating premix on the core tablets; the blank retention layer is composed of a matrix-type sustained-release material, a buoyancy aid, a swelling agent, a filler, a binder, and a lubricant; the drug-loaded sustained-release layer is composed of API, a matrix-type sustained-release material, a buoyancy aid, a swelling agent, a binder, a filler, and a lubricant.

[0092] The detailed formulations of the blank retention layer of the core tablets of the gastric retention-type sustained-release tablets in Examples 8 - 13 are shown in Table 2, and the detailed formulations of the drug-loaded sustained-release layer are shown in Table 3.

[0093] Table 2 Detailed Formulations of the Blank Retention Layer of the Gastric Retention-Type Sustained-Release Tablets in Examples 8 - 13

[0094] The calcium silicate used in Examples 8 to 13 is a pharmaceutical-grade calcium silicate produced by Tomita Pharmaceutical Co., Ltd., with a bulk density of 0.10 to 0.15 g / mL and a specific surface area of 100 m 2 / g or more.

[0095] The superabsorbent resin used in Examples 8 to 13 is acrylic acid grafted starch 300 produced by Sanyo Chemical Industries, Ltd. in Japan. It is an acrylic acid grafted starch obtained by graft copolymerization of acrylic acid monomers and natural starch at a molar ratio of 4 to 6:1, and the water absorption rate is about 300 g / g.

[0096] Table 3 Detailed formulation of the drug-loaded sustained-release layer of the gastric retention-type sustained-release tablets of Examples 8 to 13

[0097] The preparation method of the gastric retention-type sustained-release tablets of Examples 8 to 13 is the same as that of Example 2. The total weight of the core tablets of Example 8 is 800 mg, the weight of the film coating is 32 mg, and the film coating is 4% of the weight of the core tablets.

[0098] The total weight of the core tablets of Example 9 is 900 mg, the weight of the film coating is 36 mg, and the film coating is 4% of the weight of the core tablets.

[0099] The total weight of the core tablets of Example 10 is 1000 mg, the weight of the film coating is 30 mg, and the film coating is 3% of the weight of the core tablets.

[0100] The total weight of the core tablets of Example 11 is 1100 mg, the weight of the film coating is 33 mg, and the film coating is 3% of the weight of the core tablets.

[0101] The total weight of the core tablets of Example 12 is 1200 mg, the weight of the film coating is 36 mg, and the film coating is 3% of the weight of the core tablets.

[0102] The total weight of the core tablets of Example 13 is 1000 mg, the weight of the film coating is 30 mg, and the film coating is 3% of the weight of the core tablets.

[0103] Examples 14 to 18 In order to exclude the influence of the API on the floating performance and sustained-release performance of the sustained-release tablets, blank tablets using microcrystalline cellulose to simulate the API were prepared.

[0104] The gastric retention sustained-release tablets of Examples 14 to 18 are bilayer tablets (a blank retention layer and a [simulated] drug-loaded sustained-release layer respectively), and the uncoated tablets are coated with a gastric-soluble film coating prepared from a gastric-soluble film coating premix; the blank retention layer is composed of a matrix-type sustained-release material, a buoyancy aid, a swelling agent, a filler, a binder, and a lubricant; the [simulated] drug-loaded sustained-release layer is composed of microcrystalline cellulose, a matrix-type sustained-release material, a buoyancy aid, a swelling agent, a binder, a filler, and a lubricant. Among them, the role of microcrystalline cellulose is to simulate the API. Using microcrystalline cellulose to simulate the API does not affect the evaluation of its gastric retention effect (floating performance and swelling performance); microcrystalline cellulose is also insoluble or has extremely low solubility in acid, and has similar properties to APIs with low solubility in acid. The detailed formulation of the blank retention layer of the gastric retention sustained-release tablets of Examples 14 to 18 is shown in Table 4, and the detailed formulation of the [simulated] drug-loaded sustained-release layer is shown in Table 5.

[0105] Table 4 Detailed formulation of the blank retention layer of the gastric retention sustained-release tablets of Examples 14 to 18

[0106] The calcium silicate used in Examples 14 to 18 is pharmaceutical-grade calcium silicate produced by Jiangxi Hanjiang Pharmaceutical Co., Ltd., with a bulk density of 0.15 - 0.18 g / mL and a specific surface area of 100 m 2 / g or more.

[0107] The superabsorbent resin used in Examples 14 to 18 is acrylic acid grafted starch 1000 produced by Sanyo Chemical Industries, Ltd. of Japan, which is an acrylic acid grafted starch obtained by graft copolymerization of acrylic acid monomer and natural starch with a molar ratio of 8:1, and the water absorption rate is about 1000 g / g.

[0108] The preparation method of the gastric retention sustained-release tablets of Examples 14 to 18 is as follows: (1) After formulating the raw materials of the blank retention layer in proportion, place them in a mixing device and mix evenly to obtain the blank retention layer mixed powder; (2) After formulating the raw materials of the [simulated] drug-loaded sustained-release layer in proportion, place them in a mixing device and mix evenly to obtain the [simulated] drug-loaded sustained-release layer mixed powder; (3) Place the blank retention layer mixed powder and the [simulated] drug-loaded sustained-release layer mixed powder in two hoppers of a bilayer tablet press respectively, and perform bilayer tablet pressing. Use two types of punching dies, 20 mm × 10 mm special-shaped punches and 19 mm × 7 mm special-shaped punches, and control the tablet hardness at 100 - 300 KN to obtain the uncoated tablets of epalrestat sustained-release tablets; then place these uncoated tablets in a high-efficiency coating machine for film coating to obtain epalrestat sustained-release tablets.

[0109] Table 5 Detailed formulation of the [simulated] drug-loaded sustained-release layer of the gastric retention sustained-release tablets of Examples 14 to 18

[0110] The total weight of the plain tablets of Example 14 is 1000 mg; the weight of its film coating is 40.0 mg, which is 4.0% of the weight of the plain tablets.

[0111] The total weight of the plain tablets of Example 15 is 1000 mg; the weight of its film coating is 40.0 mg, which is 4.0% of the weight of the plain tablets.

[0112] The total weight of the plain tablets of Example 16 is 1000 mg; the weight of its film coating is 30.0 mg, which is 3.0% of the weight of the plain tablets.

[0113] The total weight of the plain tablets of Example 17 is 1000 mg; the weight of its film coating is 30.0 mg, which is 3.0% of the weight of the plain tablets.

[0114] The total weight of the plain tablets of Example 18 is 1000 mg; the weight of its film coating is 30.0 mg, which is 3.0% of the weight of the plain tablets.

[0115] Comparative Examples 1-13 The tablets of Comparative Examples 1-13 are double-layer tablets (a blank retention layer and a drug-loaded sustained-release layer respectively), and there is a gastric-soluble film coating made of a gastric-soluble film coating premix outside the plain tablets. The detailed formulations of the tablets of Comparative Examples 1-9 are shown in Table 6, and the detailed formulations of the tablets of Comparative Examples 10-13 are shown in Table 7.

[0116] Table 6 Detailed Formulations of the Tablets of Comparative Examples 1-9

[0117] The calcium silicate and superabsorbent resin used in Comparative Examples 1-13 are the same as those in Example 2.

[0118] The preparation methods of the tablets of Comparative Examples 1-13 are the same as those of Example 2.

[0119] The total weight of the plain tablets of Comparative Example 1 is 950 mg, the weight of the film coating is 38.0 mg, and the film coating is 4.0% of the weight of the plain tablets.

[0120] The total weight of the plain tablets of Comparative Example 2 is 960 mg, the weight of the film coating is 38.4 mg, and the film coating is 4.0% of the weight of the plain tablets.

[0121] The total weight of the plain tablets of Comparative Example 3 is 1215 mg, the weight of the film coating is 36.45 mg, and the film coating is 3.0% of the weight of the plain tablets.

[0122] The total weight of the plain tablets of Comparative Example 4 is 1000 mg, the weight of the film coating is 30.0 mg, and the film coating is 3.0% of the weight of the plain tablets.

[0123] The total weight of the core tablets of the control tablet 5 is 925 mg, the weight of the film coating is 27.75 mg, and the film coating is 3.0% of the weight of the core tablets.

[0124] The total weight of the core tablets of the control tablet 6 is 1000 mg, the weight of the film coating is 30.0 mg, and the film coating is 3.0% of the weight of the core tablets.

[0125] The total weight of the core tablets of the control tablet 7 is 1000 mg, the weight of the film coating is 30.0 mg, and the film coating is 3.0% of the weight of the core tablets.

[0126] The total weight of the core tablets of the control tablet 8 is 935 mg, the weight of the film coating is 28.05 mg, and the film coating is 3.0% of the weight of the core tablets.

[0127] The total weight of the core tablets of the control tablet 9 is 1175 mg, the weight of the film coating is 35.25 mg, and the film coating is 3.0% of the weight of the core tablets.

[0128] Table 7 Detailed formulations of the control tablets 10 - 13

[0129] The total weight of the core tablets of the control tablet 10 is 950 mg, the weight of the film coating is 28.5 mg, and the film coating is 3.0% of the weight of the core tablets.

[0130] The total weight of the core tablets of the control tablet 11 is 960 mg, the weight of the film coating is 28.8 mg, and the film coating is 3.0% of the weight of the core tablets.

[0131] The total weight of the core tablets of the control tablet 12 is 1150 mg, the weight of the film coating is 34.5 mg, and the film coating is 3.0% of the weight of the core tablets.

[0132] The total weight of the core tablets of the control tablet 13 is 1000 mg, the weight of the film coating is 30.0 mg, and the film coating is 3.0% of the weight of the core tablets.

[0133] For the convenience of comparison, the usage of the buoyancy agent and the swelling agent in each example and control example are summarized in Table 8 and Table 9. Table 8 summarizes the mass data of each part, and Table 9 summarizes the percentage data of each part. The percentages in Table 9 refer to the proportion of the dosage of this component in the total amount of the layer (blank retention layer or drug-loaded sustained release layer) where it is located.

[0134] Table 8 Usage of the buoyancy agent and the swelling agent in each example and each control example (mass)

[0135] Table 9 Usage of the buoyancy agent and the swelling agent in each example and each control example (mass percentage)

[0136] Test Example (1) Evaluation of Process Smoothness The process smoothness was evaluated using the tablet pressing process smoothness and the quality of the plain tablets (appearance, friability) as evaluation indicators.

[0137] The appearance standard of the plain tablets was: intact without defects, smooth on the surface, uniform in color; the boundary between the two layers was smooth.

[0138] The friability standard of the plain tablets was: the weight loss should not exceed 0.5%, and no broken, cracked or crushed tablets should be detected.

[0139] The evaluation criteria and results of the process smoothness of each example and comparative example are shown in Table 10 in detail.

[0140] The results in Table 10 show that when the amount of calcium silicate in each single layer is more than 30% (Comparative Example 3, Comparative Example 12), it will cause the volume of the material to be pressed during tablet pressing to be too large, and it is impossible to press tablets according to the target tablet weight; the process smoothness of other formulations is better, and the appearance and friability of the prepared plain tablets are both good.

[0141] Table 10 Evaluation Results of Process Smoothness

[0142] (2) Evaluation of Floating Performance In order to simulate the floating state of the tablets in gastric acid in the human body, the film-coated tablets were placed in a dissolution cup containing 240 ml of hydrochloric acid solution (pH value 1.2, 37 °C), and the floating start time and floating retention time required for the tablets to float to the surface of the solution and maintain the floating state were recorded.

[0143] Considering that factors such as elderly patients and food effects may cause the pH value in the human stomach to increase transiently or continuously, the floating start time and floating retention time in the high pH value range (hydrochloric acid medium with pH value 2.0, acetate medium with pH value 4.5, phosphate medium with pH value 6.8) were measured in the same way. The test results are shown in Table 11. The floating start time of some comparative examples was too long, and there was no meaning to continue testing the floating retention time, which was recorded as NT in the floating retention time in Table 11, indicating not tested.

[0144] Table 11 Floating Start Time and Floating Retention Time of Examples 1 - 18 and Comparative Examples 1 - 2, Comparative Examples 4 - 11, Comparative Example 13

[0145] The results in Table 11 show that: (1)Tablets with calcium silicate in both layers and appropriate dosages (Examples 1 - 13) immediately floated in each release medium (floating time < 1 s), had no pH - dependence, and the floating - holding time was not shorter than 16 h, meeting the requirements of sustained release; relatively speaking, when the dosage of calcium silicate was on the high side, it was more beneficial to extend the floating - holding time.

[0146] (2)Tablets of Comparative Example 13 with no calcium silicate in both layers but using other conventional floating - assisting agents and Comparative Example 4 with no calcium silicate in the blank retention layer but using other conventional floating - assisting agents had significantly slower floating times and obvious pH - dependence; tablets of Comparative Example 1 with no calcium silicate in the blank retention layer and Comparative Example 10 with no calcium silicate in the drug - loaded sustained - release layer also had significantly slower floating times; tablets of Comparative Example 2 and Comparative Example 11 with too low a dosage of calcium silicate (2.17%) in a single layer also had slower floating times than each example.

[0147] (III)Evaluation of swelling performance (1)Explanation of the acceptable standard for swelling size: For swelling - type gastric - retention preparations, the tablets need to swell to a size larger than the size of the gastric pylorus (average size about 12.8 mm) after being wetted by gastric acid to achieve gastric retention. In addition, since eating can slow down gastric emptying and sleep can reduce gastrointestinal motility, such as when administered at mealtime or before bedtime or both at mealtime and before bedtime, at this time (within 2 hours after eating or during sleep), it may not be necessary for the tablet size to be larger than the size of the gastric pylorus to achieve gastric retention; there are literature reports that the swollen long size of the tablet greater than 9 mm can achieve gastric retention in this state; drugs such as pregabalin sustained - release tablets have obtained marketing approvals based on this principle.

[0148] Based on the above principle, the acceptable standard for the swelling size of the gastric - retention sustained - release tablets of the present invention is set as: ① Administered before bedtime: The width diameter of the tablet after swelling for 2 h must be ≥ 9 mm; the width diameter of the tablet after swelling for 6 h (sleep time) must be ≥ 13.0 mm.

[0149] ② Not administered before bedtime: The width diameter of the tablet after swelling for 2 h must be ≥ 13.0 mm.

[0150] Note: Epalrestat gastric - retention sustained - release tablets can be used for both bedtime administration and non - bedtime administration.

[0151] (2)Swelling size test and results To simulate the swelling performance of tablets in gastric acid in the human stomach, 3 tablets were taken and placed separately into dissolution cups containing 240 ml of hydrochloric acid solution (pH value 1.2, 37 °C). The basket method of a dissolution tester was adopted, with a rotation speed of 100 rpm. After 2 h, the tablets were taken out and the width diameter (D) of the tablets was measured using a vernier caliper. Another 3 tablets were taken and, according to the above method, the width diameter at 6 h was measured (only the tablets pressed with a 19 mm × 7 mm punch die were measured at 6 h). For the tablets pressed with a 19 mm × 7 mm punch die, the acceptable swelling size standard at 2 h was ≥9 mm, and the acceptable swelling size standard at 6 h was ≥13 mm; for the tablets pressed with a 20 mm × 10 mm punch die, the acceptable swelling size standard at 2 h was ≥13 mm.

[0152] The test results are shown in Table 12.

[0153] Considering that factors such as elderly patients and food effects may cause a transient or persistent increase in the pH value in the human stomach, for the groups that met the requirements in the hydrochloric acid medium with a pH value of 1.2, the width diameter (D) of the tablets at each swelling time under the conditions of a high pH value range (phosphate medium with a pH value of 6.8) was measured in the same way (only the tablets pressed with a 19 mm × 7 mm punch die were measured at 6 h). For the tablets pressed with a 19 mm × 7 mm punch die, the acceptable swelling size standard at 2 h was ≥9 mm, and the acceptable swelling size standard at 6 h was ≥13 mm; for the tablets pressed with a 20 mm × 10 mm punch die, the acceptable swelling size standard at 2 h was ≥13 mm.

[0154] The test results are shown in Table 13.

[0155] Table 12 Evaluation results of the swelling performance of Examples 1 to 18 and Comparative Examples 5 to 9 (hydrochloric acid medium with pH 1.2)

[0156] The results in Table 12 and Table 13 show that: (1) After the tablets pressed with a 19 mm × 7 mm punch die in each example were wetted and swollen for 2 h, the width diameter could all be ≥9 mm; after being wetted and swollen for 6 h, the width diameter could all be ≥13 mm, meeting the acceptable standard for the swelling size of the gastric retention sustained-release tablets for bedtime administration formulated above; after the tablets pressed with a 20 mm × 10 mm punch die in each example were wetted and swollen for 2 h, the width diameter could all be ≥13 mm, meeting the acceptable standard for the swelling size of the gastric retention sustained-release tablets for non-bedtime administration formulated above.

[0157] (2) Under the same wetting conditions, in Comparative Examples 5 to 8, the wetted and swollen width diameters under low pH value conditions could not meet the acceptable standard for the swelling size formulated.

[0158] (3)The formulation of Comparative Example 9 has an acrylic grafted starch dosage exceeding 30%. Although the wetting expansion width meets the acceptable standard of the specified expansion size, with the significant increase in the dosage of acrylic grafted starch, there is no significant correlation between the wetting expansion width and the expansion.

[0159] Table 13 Evaluation Results of Swelling Performance of Examples 1 - 18 (pH 6.8 Phosphate Medium)

[0160] (IV)In Vitro Release Test The in vitro release curves of Example 2, Example 8, Example 9, and Example 11 were detected. The specific data are shown in Table 14, and the average cumulative release curve diagram is shown in Figure 1 . According to the in vitro release curve data of each example in Table 14, calculate the average hourly release amount during each release sampling time interval. The results are shown in Table 15.

[0161] Table 14 In Vitro Release Cumulative Results of Example 2, Example 8, Example 9, and Example 11

[0162] Table 15 Average Hourly Release Amount of In Vitro Release Test of Example 2, Example 8, Example 9, and Example 11

[0163] Explanation of release medium selection: Since API epalrestat is extremely poorly soluble in pH 1.2 hydrochloric acid and slightly soluble under pH 6.8 conditions, pH 6.8 phosphate buffer solution was selected as its release medium. Release test method: According to the dissolution and release determination method [General Principles 0931, Method 2, Method 1 (paddle method) in the Fourth Part of Chinese Pharmacopoeia 2020 Edition], using 900 mL of phosphate buffer solution with a pH value of 6.8 as the release medium, the rotation speed is 100 revolutions per minute. Operate according to the law, and sample at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 20 h, and 24 h respectively. After sampling, detect the release amount and calculate the average cumulative dissolution degree (each value is averaged by sampling 6 times). The results in Table 14 and Table 15 show that the compositions of each example can be completely sustained - released within 24 h (cumulative release amount ≥ 95%), and the average hourly release amount is in the range of 1.4% - 8.5%. This result shows an obvious sustained - release effect and no burst release.

[0164] (V)Stability Investigation The stability of the sustained - release tablets of Example 2 (punch die 20 mm × 10 mm) was investigated. It was placed under accelerated test conditions (40 ± 2 °C, RH 75 ± 5%) for investigation. Samples were taken at 0 month and 6 months to detect appearance, floating - up time, floating - holding time, swelling size, release curve, and related substances. The results are shown in Table 16.

[0165] Table 16 Results of the stability study of the gastric retention sustained-release tablets of Example 2

[0166] The results in Table 16 show that the gastric retention sustained-release tablets of the present invention exemplified by Example 2 have excellent stability after 6 months of accelerated testing.

[0167] (VI) In vivo pharmacokinetic study in humans Using the original research ordinary tablets (epalrestat tablets, with a specification of 50 mg, that is, each tablet contains 50 mg of epalrestat, and the trade name is KINEDAK ® ) as the control preparation, an in vivo pharmacokinetic study of the epalrestat gastric retention sustained-release tablets prepared in Example 2 was carried out.

[0168] The test protocol is shown in Table 17 in detail, the test results are shown in Table 18, and the concentration-time curve is shown in Figure 2 .

[0169] The test results show that the epalrestat gastric retention sustained-release tablets prepared in Example 2 of the present invention achieved a once-daily in vivo sustained-release effect, with a stable control of blood drug concentration, and could effectively avoid the peak-valley phenomenon of blood drug concentration of ordinary preparations.

[0170] Table 17 Test protocol for the in vivo pharmacokinetic study of Example 2 and the original research ordinary tablets

[0171] Table 18 Test results of the in vivo pharmacokinetic study of Example 2 and the original research ordinary tablets

[0172] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A gastric retention sustained-release tablet, characterized in that, It includes a blank retention layer and a drug-loaded sustained-release layer, and both the blank retention layer and the drug-loaded sustained-release layer are provided on the surface of the core tablet of the gastric retention-type sustained-release tablet; The raw materials of the blank retention layer include a matrix-type sustained-release material, a buoyant aid, and a swelling agent; The raw materials of the drug-loaded sustained-release layer include a matrix-type sustained-release material, a buoyant aid, and an active pharmaceutical ingredient; The buoyant aid includes calcium silicate, and the bulk density of the calcium silicate is below 0.2 g / mL; The swelling agent includes a superabsorbent resin, and the water absorption rate of the superabsorbent resin is 100 g / g or more; The raw materials of the gastric retention-type sustained-release tablet further include excipients; In the blank retention layer, the mass of calcium silicate accounts for 4% - 28% of the blank retention layer; In the blank retention layer, the mass of the superabsorbent resin accounts for 3% - 40% of the blank retention layer; In the drug-loaded sustained-release layer, the mass of calcium silicate accounts for 4% - 28% of the drug-loaded sustained-release layer.

2. The gastric retention sustained-release tablet according to claim 1, characterized in that, In the blank retention layer, the mass of calcium silicate accounts for 4.5% - 25% of the blank retention layer; In the blank retention layer, the mass of the superabsorbent resin accounts for 4% - 35% of the blank retention layer; In the drug-loaded sustained-release layer, the mass of calcium silicate accounts for 4.5% - 25% of the drug-loaded sustained-release layer.

3. The gastric retention sustained-release tablet according to claim 1, characterized in that, The mass ratio of the blank retention layer to the drug-loaded sustained-release layer is 400 - 700∶300 - 600; In the blank retention layer, the mass ratio of the buoyant aid is 30% or less; In the blank retention layer, the mass ratio of the swelling agent is 40% or less; In the drug-loaded sustained-release layer, the mass ratio of the buoyant aid is 25% or less; In the drug-loaded sustained-release layer, the mass ratio of the swelling agent is 15% or less; In the blank retention layer, the mass ratio of the matrix-type sustained-release material is 25% - 80%; In the drug-loaded sustained-release layer, the mass ratio of the matrix-type sustained-release material is 15% - 60%.

4. The gastric retention sustained-release tablet according to claim 1, characterized in that, The superabsorbent resin is acrylic acid grafted starch; The matrix-type sustained-release material in the blank retention layer includes a hydrophilic gel matrix material and / or an insoluble matrix material; In the matrix-type sustained-release material of the drug-loaded sustained-release layer, the mass of the hydrophilic gel matrix material accounts for more than 60%; 5. The gastric retention sustained-release tablet according to claim 1, wherein The specific surface area of the calcium silicate is 100 m 2 / g or more; The superabsorbent resin is acrylic acid grafted starch obtained by graft copolymerization of acrylic acid monomer and natural starch in a molar ratio of 2 - 10:1; The matrix-type sustained-release material in the blank retention layer includes one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene oxide, water-swellable cellulose, polyvinylpyrrolidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, arabic gum, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, hydroxypropyl methylcellulose stearoxy ether; The matrix-type sustained-release material in the drug-loaded sustained-release layer includes one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene oxide, water-swellable cellulose, polyvinylpyrrolidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, arabic gum, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, hydroxypropyl methylcellulose stearoxy ether.

6. The gastric retention sustained-release tablet according to any one of claims 1 to 5, characterized in that: It is a core tablet or contains a gastric-soluble coating; the tablet weight excluding the coating weight is 600 - 1300 mg; The width diameter size of the tablet is ≥10 mm.

7. The gastric retention sustained-release tablet according to any one of claims 1 to 5, characterized in that, The excipients include one or more of a filler, a binder, and a lubricant.

8. The gastric retention sustained-release tablet according to any one of claims 1 to 5, characterized in that The solubility of the active pharmaceutical ingredient under acidic conditions is as follows: for the single-dose of the active pharmaceutical ingredient, it dissolves in hydrochloric acid solution with a pH value of 1.0 to 3.0, and the volume of hydrochloric acid solution required is higher than 250 mL.

9. The gastric retention sustained-release tablet according to any one of claims 1 to 5, characterized in that, The active pharmaceutical ingredient includes one or more of a poorly soluble drug in hydrochloric acid solution, its pharmaceutically acceptable salt, hydrate, and hydrate of the salt; The poorly soluble drug in hydrochloric acid solution includes one or more of epalrestat, cyclosporine, carbamazepine, lovastatin, azithromycin, albendazole, atorvastatin, allopurinol, azathioprine, bicalutamide, celecoxib, digoxin, diazepam, acetazolamide, clofazimine, acyclovir, paracetamol, clarithromycin, clozapine, fenofibrate, gliclazide, glimepiride, glipizide, glibenclamide, granisetron, ibuprofen, ketoprofen, flurbiprofen, irbesartan, isotretinoin, tretinoin, ursodeoxycholic acid, valsartan, teprenone, spironolactone, simvastatin, roxithromycin, rofecoxib, risperidone, rifampicin, rebamipide, oxcarbazepine, nimesulide, nifedipine, nevirapine, nelfinavir, nabumetone, meloxicam, medroxyprogesterone, lopinavir, indomethacin.

10. The gastric retention sustained-release tablet according to any one of claims 1 to 5, characterized in that, The active pharmaceutical ingredient includes one or more of epalrestat, epalrestat salts, epalrestat hydrates, and hydrates of epalrestat salts; calculated as C 15 H 13 NO3S2, each tablet contains 100 mg to 180 mg of the active pharmaceutical ingredient.

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