A gastric retentive sustained-release tablet

Abstract

A gastric-retentive sustained-release tablet comprises a blank retention layer and a drug-loaded sustained-release layer, both disposed on the surface of a plain tablet of the gastric-retentive sustained-release tablet; the blank retention layer comprises a skeleton-type sustained-release material, a bleaching agent, and a swelling agent; and the drug-loaded sustained-release layer comprises a skeleton-type sustained-release material, a bleaching agent, and an active pharmaceutical ingredient. The present invention utilizes low-bulk-density calcium silicate and a highly absorbent resin as the bleaching agent and swelling agent, respectively, enabling the gastric-retentive sustained-release tablet of the present invention to have a gastric retention capacity similar to that of a conventional single-layer tablet while also providing a superior sustained-release effect. The provision of the blank retention layer and the drug-loaded sustained-release layer allows drugs with low acid solubility to be sustained-released in the form of a gastric-retentive sustained-release tablet.

Description

Technical Field

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

[0002] Gastric retentive sustained-release tablets are a type of sustained-release drug that can remain in the stomach. They can greatly prolong the residence time of the drug in the stomach, allowing the gastrointestinal tract sufficient time to absorb the drug. They are particularly suitable for drugs absorbed in the duodenum and for the treatment of local gastric diseases.

[0003] The narrow part that gastric contents must pass through is the pylorus, which has an average size of about 12.8mm. An expandable gastric-retaining dosage form is a dosage form that expands rapidly after entering the stomach, causing it to directly exceed the diameter of the pylorus, thereby retaining in the stomach, and has a stable gastric retention effect. Gastric floating preparations are also a type of gastric-retaining 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 the gastric fluid. Gastric floating tablets that usually only contain a gastric floating mechanism are significantly affected by human body position, movement, food, etc., resulting in unstable floating performance in the stomach. To overcome this problem, most of the gastric-retaining preparations currently approved for marketing at home and abroad combine the gastric floating and expansion mechanisms to ensure their gastric retention effect, such as the pregabalin sustained-release tablets developed and approved for marketing by Hengrui Medicine.

[0004] However, due to the acidic environment in the stomach, gastric-retentive sustained-release tablets are still not suitable for the sustained-release of many drugs, such as drugs whose dissolution is pH-dependent, whose solubility in acid is low, and whose absorption is concentrated in the upper small intestine. With current technology, even if such drugs are made into gastric-retentive sustained-release tablets, they still have difficulty in being released in the body due to their poor solubility, and thus cannot achieve a sustained-release effect. Some studies have chosen to take measures to promote drug release based on gastric-retentive sustained-release tablets, but this has instead caused a burst release, failing to resolve the problem of balancing gastric retention with dissolution release. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a gastric retentive sustained-release tablet that is suitable for drugs with low solubility in acid.

[0006] The technical solution adopted by the present invention to solve the technical problem is as follows: a gastric retentive sustained-release tablet, comprising a blank retentive layer and a drug-loaded sustained-release layer, wherein the blank retentive layer and the drug-loaded sustained-release layer are both arranged on the surface layer of the plain tablet of the gastric retentive sustained-release tablet;

[0007] The raw materials of the blank retention layer include skeleton-type sustained-release material, bleaching agent and swelling agent;

[0008] The raw materials of the drug-loaded sustained-release layer include skeleton-type sustained-release materials, bleaching agents, and active pharmaceutical ingredients (APIs).

[0009] The bleaching aid comprises calcium silicate, and the bulk density of the calcium silicate is less than 0.2 g / mL;

[0010] The expansion agent includes a highly absorbent resin, and the water absorption rate of the highly absorbent resin is above 100 g / g;

[0011] The raw materials of the gastric retention sustained-release tablets also include auxiliary materials;

[0012] In the blank retention layer, the mass of calcium silicate accounts for 4% to 28% of the blank retention layer;

[0013] In the blank retention layer, the mass of the super absorbent resin accounts for 3% to 40% of the blank retention layer;

[0014] In the drug-loaded sustained-release layer, the mass of calcium silicate accounts for 4% to 28% of the drug-loaded sustained-release layer.

[0015] Preferably, in the blank retention layer, the mass of calcium silicate accounts for 4.5% to 25% of the blank retention layer.

[0016] Preferably, in the blank retention layer, the mass of the super absorbent resin accounts for 4% to 35% of the blank retention layer.

[0017] Preferably, 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.

[0018] Preferably, the mass ratio of the blank retention layer to the drug-loaded sustained-release layer is 400-700:300-600.

[0019] Preferably, in the blank retention layer, the mass ratio of the bleaching aid is less than 30%.

[0020] Preferably, the mass ratio of the expansion agent in the blank retention layer is less than 40%.

[0021] Preferably, in the drug-loaded sustained-release layer, the mass ratio of the bleaching aid is less than 25%.

[0022] Preferably, the mass ratio of the swelling agent in the drug-loaded sustained-release layer is less than 15%.

[0023] Preferably, in the blank retention layer, the mass ratio of the skeleton-type sustained-release material is 25% to 80%.

[0024] Preferably, in the drug-loaded sustained-release layer, the mass ratio of the skeleton-type sustained-release material is 15% to 60%.

[0025] Preferably, the highly absorbent resin is acrylic acid grafted starch.

[0026] Preferably, the skeleton-type sustained-release material in the blank retention layer includes a hydrophilic gel skeleton material and / or an insoluble skeleton material.

[0027] Preferably, the mass of the hydrophilic gel skeleton material in the skeleton-type sustained-release material in the drug-loaded sustained-release layer accounts for more than 60%.

[0028] Preferably, the specific surface area of ​​the calcium silicate is 100m 2 / g or above.

[0029] Preferably, the highly absorbent resin is acrylic acid grafted starch obtained by graft copolymerizing acrylic acid monomer and natural starch at a molar ratio of 2 to 10:1.

[0030] Preferably, the skeleton-type 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 stearyl ether.

[0031] Preferably, the skeleton-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, povidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, gum arabic, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, and hydroxypropyl methylcellulose stearyl ether.

[0032] Preferably, the gastric retentive sustained-release tablet is a plain tablet, or contains a gastric-soluble coating.

[0033] Preferably, the gastric retentive sustained-release tablet has a tablet weight excluding the coating weight of 600-1300 mg.

[0034] Preferably, the tablet width diameter of the gastric-retention sustained-release tablet is ≥10 mm.

[0035] Preferably, the auxiliary material includes one or more of a filler, a binder and a lubricant.

[0036] Preferably, the solubility of the active pharmaceutical ingredient under acidic conditions is as follows: a single dose of the active pharmaceutical ingredient is dissolved in a hydrochloric acid solution with a pH value of 1.0 to 3.0, and the required volume of hydrochloric acid solution is greater than 250 mL.

[0037] Preferably, the active pharmaceutical ingredient comprises one or more of a low-solubility drug in hydrochloric acid solution, a medically acceptable salt thereof, a hydrate thereof, and a hydrate of a salt thereof; the low-solubility drug in hydrochloric acid solution comprises: epalrestat, cyclosporine, carbamazepine, lovastatin, azithromycin, albendazole, atorvastatin, allopurinol, azathioprine, bicalutamide, celecoxib, digoxin, diazepam, acetazolamide, clofazimine, acyclovir, acetaminophen, clarithromycin, clozapine , fenofibrate, gliclazide, glimepiride, glipizide, glyburide, 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, one or more of the following.

[0038] Preferably, the active pharmaceutical ingredient comprises one or more of epalrestat, epalrestat salt, epalrestat hydrate, and hydrate of epalrestat salt; 15 H 13 Each tablet contains 100mg~180mg of active pharmaceutical ingredient based on NO3S2.

[0039] The present invention has the following beneficial effects:

[0040] (1) The present invention provides a blank retention layer and a drug-loaded sustained-release layer, so that drugs with low solubility in acid can also be released in vivo in the form of gastric retention sustained-release tablets;

[0041] (2) Low bulk density calcium silicate and highly absorbent resin are used as bleaching aid and swelling agent, respectively, so that the gastric retentive sustained-release tablets of the present invention can have gastric retention capacity similar to that of conventional single-layer tablets, while also having a good sustained-release effect;

[0042] (3) The buoyancy time in the release medium at pH 1.2 to pH 6.8 is less than 1s. It immediately buoys under various pH conditions in the stomach (including the phenomenon of increased pH in the stomach due to food effects, elderly patients, etc.). The tablet can expand to a size of >12.8mm within 2 hours within a wide pH range in the stomach, exceeding the diameter of the pylorus.

[0043] In addition to the above-described objects, features and advantages, the present invention has other objects, features and advantages. The present invention will be further described in detail below with reference to the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The accompanying drawings, which constitute part of this application, are intended to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are intended to explain the present invention and do not constitute an undue limitation of the present invention. In the accompanying drawings:

[0045] Figure 1 Graphs showing the in vitro average cumulative release curves of epalrestat gastric-retentive sustained-release tablets of Examples 2, 8, 9 and 11 of the present invention in a release medium at a pH of 6.8;

[0046] Figure 2 This is a graph showing the blood drug concentration-dosage time curve of the original epalrestat ordinary tablets and the epalrestat gastric retention sustained-release tablets of Example 2 of the present invention absorbed by the human body. DETAILED DESCRIPTION

[0047] In order to make the purpose, scheme and beneficial technology of the present invention clearer, the present invention is further described in detail below with reference to the embodiments and drawings. It should be noted that the embodiments described in this specification are only for explaining the present invention and are not intended to limit the present invention.

[0048] For simplicity, only some numerical ranges are explicitly disclosed herein. However, any lower limit can be combined with any upper limit to form an unspecified range; and any lower limit can be combined with other lower limits to form an unspecified range, and similarly, any upper limit can be combined with any other upper limit to form an unspecified range. In addition, although not explicitly stated, each point or individual value between the endpoints of a range is included in the range. Thus, each point or individual value can serve as its own lower limit or upper limit and be combined with any other point or individual value, or with other lower limits or upper limits, to form an unspecified range.

[0049] In the description of this article, it should be noted that, unless otherwise specified, "above" and "below" are inclusive of the number itself, and the "multiple" in "one or more" means two or more, and the "multiple" in "one or more" means two or more.

[0050] Further explanation of water absorption rate: It means weighing a certain amount of a certain adsorbent, placing it in a certain amount of deionized water, letting it stand for 3 hours, and filtering it with a 100-mesh nylon bag. The water absorption rate is formally calculated according to: Water absorption rate (g / g) = (weight of added water - weight of filtered water) / weight of adsorbent.

[0051] An embodiment of the present invention provides a gastric retentive sustained-release tablet comprising a blank retentive layer and a drug-loaded sustained-release layer, wherein the blank retentive layer and the drug-loaded sustained-release layer are both disposed on the surface of a plain tablet of the gastric retentive sustained-release tablet;

[0052] The raw materials of the blank retention layer include skeleton-type sustained-release material, bleaching agent and swelling agent;

[0053] The raw materials of the drug-loaded sustained-release layer include skeleton-type sustained-release materials, bleaching agents, and active pharmaceutical ingredients (APIs).

[0054] The bleaching aid comprises calcium silicate, and the bulk density of the calcium silicate is below 0.2 g / mL; 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;

[0055] The expansion agent includes a super absorbent resin, and the water absorption rate of the super absorbent resin is above 100 g / g; 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;

[0056] The raw materials of the gastric retention sustained-release tablets also include auxiliary materials;

[0057] 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%;

[0058] In the blank retention layer, the mass of the super absorbent 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%;

[0059] 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%.

[0060] The gastric-retention sustained-release tablet of the present invention comprises a blank retention layer and a drug-loaded sustained-release layer. The swelling material (including a skeleton-type sustained-release material and a swelling agent) exerts its sustained-release skeleton and swelling functions after being wetted by gastric acid or a release medium. Simultaneously, upon contact with gastric acid or a release medium, a high-strength gel skeleton is formed on the contact surface. The high-strength gel prevents or slows further wetting by gastric acid or the release medium, thereby achieving gastric retention and sustained release. The blank retention layer primarily plays a gastric retention role, while the drug-loaded sustained-release layer forms an erosion-type sustained-release skeleton, which enables the API to diffuse as the sustained-release skeleton erodes, thereby dissolving and releasing in the upper small intestine. Both the blank retention layer and the drug-loaded sustained-release layer need to be in contact with gastric acid or release medium to be effective, so they are arranged on the surface layer of the plain tablet of the gastric-retention sustained-release tablet; if only the blank retention layer (containing API) is set, there is a problem of difficulty in releasing drugs with low solubility in acid; if only the drug-loaded sustained-release layer is set, the skeleton of the drug-loaded sustained-release layer will dissolve as the drug is released, and its size will continue to shrink, resulting in insufficient gastric retention capacity; therefore, both layers need to exist at the same time to achieve a better sustained-release effect.

[0061] However, due to the layered structure of the gastric-retaining sustained-release tablets of the present invention, the surface area of ​​the blank retentive layer that functions as a gastric retentive agent and is exposed to gastric acid or the release medium is less than that of a monolayer tablet (while the entire surface of a monolayer tablet functions as a gastric retentive agent, the sustained-release tablets of the present invention require a portion of the surface area to be allocated to the drug-loaded sustained-release layer). Therefore, it is very difficult for tablets with the present invention structure to maintain the same gastric flotation and dimensional expansion capabilities as monolayer tablets. Furthermore, when the intragastric pH rises (e.g., due to food effects or in elderly patients), the gastric retentive effect of the gastric retentive agent is further limited, and ensuring that the sustained-release effect is not affected by this is another challenge encountered in the research of the present invention.

[0062] Low-bulk-density calcium silicate is generally produced from silicate minerals through various chemical and physical processing. 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 agent in pharmaceutical preparations. The inventors unexpectedly discovered during experiments that low-bulk-density calcium silicate has unique effects as a bleaching agent in gastric floatation preparations. Due to its porous structure and large specific surface area, gastric floatation or gastric retention preparations prepared with calcium silicate can maintain a density lower than that of gastric contents, thereby achieving gastric floatation and gastric retention. Qualified calcium silicates are currently commercially available and can be purchased directly, such as pharmaceutical-grade calcium silicate produced by KirschPharma (Germany), Tomita Pharmaceutical Co., Ltd., and Jiangxi Hanjiang Pharmaceutical Co., Ltd. The present invention also uses a superabsorbent resin as a swelling agent in the gastric retentive sustained-release tablet. When the water absorption rate of the superabsorbent resin reaches 100 g / g or above, the effect changes dramatically, enhancing the ability of gastric acid or release media to enter the gel matrix, thereby achieving a good swelling effect between the matrix-type sustained-release material and the swelling agent. By using low-bulk-density calcium silicate and superabsorbent resin as raw materials, the gastric retentive sustained-release tablet of the present invention can achieve gastric retention similar to that of conventional single-layer tablets while also providing a good sustained-release effect.

[0063] The gastric retentive sustained-release tablets provided in the embodiments of the present invention have the following advantages:

[0064] (1) By setting up a blank retention layer and a drug-loaded sustained-release layer, drugs with low solubility in acid can also be released in the form of gastric retention sustained-release tablets;

[0065] (2) Low bulk density calcium silicate and highly absorbent resin are used as bleaching aid and swelling agent, respectively, so that the gastric retentive sustained-release tablets of the present invention can have gastric retention capacity similar to that of conventional single-layer tablets, while also having a good sustained-release effect;

[0066] (3) The buoyancy time in the release medium at pH 1.2 to pH 6.8 is less than 1s. It immediately buoys under various pH conditions in the stomach (including the phenomenon of increased pH in the stomach due to food effects, elderly patients, etc.). The tablet can expand to a size of >12.8mm within 2 hours within a wide pH range in the stomach, exceeding the diameter of the pylorus.

[0067] In some embodiments of the present invention, the gastric retentive sustained-release tablet is a double-layer tablet or a multi-layer tablet.

[0068] In some embodiments of the present invention, the blank retention layer is arranged on one of the upper surface layer or the lower surface layer of the gastric-retaining sustained-release tablet; the drug-loaded sustained-release layer is arranged on the other of the upper surface layer or the lower surface layer of the gastric-retaining sustained-release tablet.

[0069] In an 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.

[0070] In an embodiment of the present invention, in the blank retention layer, the mass of the super absorbent resin accounts for 4% to 35% of the blank retention layer.

[0071] In an 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.

[0072] In an embodiment of the present invention, the mass ratio of the blank retention layer to the drug-loaded sustained-release layer is 400-700:300-600.

[0073] In an embodiment of the present invention, the mass ratio of the bleaching agent in the blank retention layer is less than 30%. The blank retention layer may contain additional bleaching agents other than the calcium silicate, or it may not contain any bleaching agents. However, the total amount of bleaching agents should not be too much. Excessive use of the total amount of bleaching agents may result in an excessively large volume of the material before tableting, which is not conducive to tableting, and may also easily result in an excessively low proportion of the skeleton material or the expansion agent, thereby affecting the expansion effect.

[0074] In an embodiment of the present invention, the weight ratio of the swelling agent in the blank retention layer is less than 40%. A swelling agent other than the superabsorbent resin may be used in the blank retention layer, or it may not be used. However, the total swelling agent amount should not be too high. Excessive swelling agent may result in an excessively low proportion of the skeleton material or the bleaching agent, thereby affecting the swelling effect or the bleaching effect.

[0075] In an embodiment of the present invention, the weight ratio of the bleaching agent in the drug-loaded sustained-release layer is less than 25%. A bleaching agent other than the calcium silicate may be used in the drug-loaded sustained-release layer, or it may not be used. However, the total amount of bleaching agents should not be too high. Excessive use of the total amount of bleaching agents may result in an excessively low proportion of the skeleton material or the expander, thereby affecting the sustained-release effect.

[0076] In an embodiment of the present invention, the weight ratio of the swelling agent in the drug-loaded sustained-release layer is less than 15%. The swelling agent may be used in the drug-loaded sustained-release layer or not, but the total swelling agent amount should not be too high. Excessive swelling agent amount may result in an excessively low proportion of the skeleton material or the bleaching agent, thereby affecting the sustained-release effect.

[0077] In an embodiment of the present invention, in the blank retention layer, the mass ratio of the skeleton-type sustained-release material is 25% to 80%; for example, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% and 80%.

[0078] In some embodiments of the present invention, the mass ratio of the skeleton-type sustained-release material in the blank retention layer is 30% to 75%.

[0079] In an embodiment of the present invention, the mass ratio of the matrix-type sustained-release material in the drug-loaded sustained-release layer is 15% to 60%, for example, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, and 60%. Because the drug-loaded sustained-release layer contains the API while the blank retention layer does not, a relatively higher content of the matrix-type sustained-release material can be used in the blank retention layer.

[0080] In some embodiments of the present invention, in the drug-loaded sustained-release layer, the mass ratio of the skeleton-type sustained-release material is 20% to 55%.

[0081] In an embodiment of the present invention, the highly absorbent resin is acrylic acid grafted starch. Acrylic acid grafted starch is a functional material made by grafting acrylic acid monomers with natural starch. It combines the biocompatibility of starch with the physicochemical properties of acrylic acid, has a strong water absorption capacity, and is often used as an excipient for external preparations in pharmaceutical preparations. Currently, there are acrylic acid grafted starches that meet the requirements on the market, which can be purchased and used directly, 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.

[0082] In an embodiment of the present invention, the skeleton-type sustained-release material in the blank retention layer includes a hydrophilic gel skeleton material and / or an insoluble skeleton material.

[0083] In an embodiment of the present invention, the mass of the hydrophilic gel skeleton material in the skeleton-type sustained-release material in the drug-loaded sustained-release layer accounts for more than 60%.

[0084] In the embodiment of the present invention, the specific surface area of ​​the calcium silicate is 100m 2 / g or above.

[0085] In an embodiment of the present invention, the highly absorbent resin is acrylic acid grafted starch obtained by graft copolymerizing acrylic acid monomer with natural starch at a molar ratio of 2 to 10:1.

[0086] In an embodiment of the present invention, the skeleton-type 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 stearyl ether.

[0087] In an embodiment of the present invention, the skeleton-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, povidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, gum arabic, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, and hydroxypropyl methylcellulose stearyl ether.

[0088] In an embodiment of the present invention, the gastric retentive sustained-release tablet is a plain tablet, or contains a gastric-soluble coating.

[0089] The gastric retentive sustained-release tablet can be in various shapes; in some embodiments of the present invention, the tablet is circular; in some embodiments of the present invention, the tablet is irregularly shaped.

[0090] In an embodiment of the present invention, the tablet weight of the gastric retentive sustained-release tablet excluding the weight of the coating is 600-1300 mg.

[0091] In an embodiment of the present invention, the tablet width and diameter of the gastric-retention sustained-release tablet is ≥10 mm.

[0092] In some embodiments of the present invention, the tablet has a width dimension of ≥7 mm.

[0093] In an embodiment of the present invention, the auxiliary material includes one or more of a filler, a binder and a lubricant.

[0094] In an embodiment of the present invention, the solubility of the active pharmaceutical ingredient under acidic conditions is as follows: a single dose of the active pharmaceutical ingredient is dissolved in a hydrochloric acid solution with a pH value of 1.0 to 3.0, and the required volume of hydrochloric acid solution is greater than 250 mL.

[0095] In an embodiment of the present invention, the active pharmaceutical ingredient includes one or more of a low-solubility drug in hydrochloric acid solution, a medically acceptable salt thereof, a hydrate thereof, and a hydrate of a salt thereof; the low-solubility drug in hydrochloric acid solution includes: epalrestat, cyclosporine, carbamazepine, lovastatin, azithromycin, albendazole, atorvastatin, allopurinol, azathioprine, bicalutamide, celecoxib, digoxin, diazepam, acetazolamide, clofazimine, acyclovir, acetaminophen, clarithromycin, chloramphenicol ... One or more of the following: azepam, fenofibrate, gliclazide, glimepiride, glipizide, glyburide, 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, and indomethacin.

[0096] In an embodiment of the present invention, the active pharmaceutical ingredient comprises one or more of epalrestat, epalrestat salt, epalrestat hydrate, and hydrate of epalrestat salt; 15 H 13 Each tablet contains 100mg to 180mg of the active pharmaceutical ingredient (AMI), calculated as NO₃S₂. Epalrestat, chemically known as 5-[(1Z,2E)-2-methyl-3-phenyl-2-propenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid, is an aldose reductase inhibitor clinically used for the prevention, improvement, and treatment of diabetic neuropathy. Diabetic patients experience high blood sugar levels, which leads to the conversion of glucose to sorbitol via the polyol metabolic pathway, resulting in sorbitol accumulation. Sorbitol affects cellular osmotic pressure, which in turn affects nerve cell function. Accumulation within nerve cells can cause delayed diabetic complications such as neuropathy, retinopathy, and nephropathy. As an aldose reductase inhibitor, epalrestat works by reversibly inhibiting the enzyme aldose reductase, which converts glucose to sorbitol during polyol metabolism, a process implicated in the pathogenesis of diabetic complications. Epalrestat is the first and only ARI approved for marketing in China and abroad and is now widely used clinically as a first-line treatment for diabetic neuropathy.

[0097] Epalrestat was first developed and approved for marketing in Japan by Ono Pharmaceutical in 1992 as an immediate-release tablet in a 50 mg strength, marketed under the trade name KINEDAK. Generic epalrestat tablets were subsequently launched in 2004 and subsequently, and the dosage was changed to immediate-release capsules, still in a 50 mg strength. The recommended dosage for epalrestat tablets or capsules is one tablet three times daily, before meals.

[0098] Currently marketed formulations of epalrestat are all immediate-release formulations. This requires frequent dosing in clinical practice, making administration extremely inconvenient, especially for elderly patients with diabetes. Elderly patients often take a wide variety of medications due to multiple underlying medical conditions, making them prone to missed or forgotten doses. Therefore, reducing the frequency of medications, or even dosing once daily, can significantly improve medication compliance. On the other hand, immediate-release formulations of epalrestat are rapidly absorbed after oral administration, reaching peak plasma concentration (tmax) in only approximately one hour, and have a short half-life (approximately 1.8 hours). This results in significant fluctuations in plasma concentrations and poses a high safety risk. Therefore, there is a clinical need for a once-daily sustained-release formulation of epalrestat that can be administered more frequently to improve medication compliance, while also providing rapid onset to ensure efficacy and significantly reducing fluctuations in plasma concentrations (primarily by lowering the peak concentration Cmax) to mitigate dose-related toxicities and side effects.

[0099] Due to the drug properties of epalrestat, there are many difficulties in developing a once-daily epalrestat sustained-release formulation. (1) The elimination half-life of epalrestat in the body is short (about 1.8 hours). Such a short elimination half-life is a major challenge for sustained-release design. Since the drug is rapidly metabolized and eliminated after absorption into the blood, it is necessary for the drug to stay in the gastrointestinal tract for a long enough time so that it can be slowly released and then slowly absorbed into the blood. (2) In addition, clinical studies have shown that the peak time tmax of epalrestat immediate-release formulations is only about 1 hour. The absorption of epalrestat depends on the active transport system in the upper small intestine. It only shows good absorption in the upper small intestine (duodenum) and is very poorly absorbed in the middle and lower small intestine (jejunum and ileum) and large intestine. This indicates that the average absorption window of epalrestat is only 4 hours or less. If it is developed into a conventional sustained-release formulation, when it is transferred to the middle and lower small intestine and large intestine after about 4 hours, these drugs will be wasted and will not play any role. (3) Epalrestat is extremely insoluble in gastric acid (its solubility in hydrochloric acid at pH 1.2 is only 0.1 μg / mL; based on a gastric fluid volume of 250 mL, the maximum solubility is only 25 μg, which is 2000-6000 times lower than the administered dose of 50-150 mg). It is also only slightly soluble in the upper small intestine (its solubility at pH 6.8 is 496 μg / mL; based on a liquid volume of 250 mL at the dissolution site, the maximum solubility is only 124 mg). In the present invention, the above problems can be well solved. By means of the above technical means, a sustained-release tablet can be obtained that includes epalrestat as an active pharmaceutical ingredient and truly achieves a once-daily sustained-release effect in vivo.

[0100] The gastric retentive sustained-release tablets described in the embodiments of the present invention are used in the prevention and treatment of diabetes and its complications. The gastric retentive sustained-release tablets can effectively exert the effect of the API.

[0101] The gastric retentive sustained-release tablets can be prepared using conventional tablet preparation methods, such as: mixing the raw materials for each layer, including the blank retentive layer and the drug-loaded sustained-release layer, to obtain a blank retentive layer mixed powder, a drug-loaded sustained-release layer mixed powder, and mixed powders for each of the other layers (if any); and compressing the tablets using a bilayer tablet press or a multilayer tablet press to obtain the gastric retentive sustained-release tablets. The raw materials can be mixed with the aid of a solvent (the solvent can be removed before tableting), or no solvent can be used.

[0102] Example

[0103] The following examples describe the present disclosure in more detail and are intended to be illustrative only, as various modifications and variations within the scope of the present disclosure 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 available through conventional commercial sources or synthesized according to conventional methods and can be used directly without further processing. Unless otherwise stated, all instruments used in the examples are available through conventional commercial sources.

[0104] Examples 1 to 7

[0105] The gastric-retentive sustained-release tablets of Examples 1-7 are bilayer tablets (a blank retentive layer and a drug-loaded sustained-release layer). The tablets are coated with a gastric-soluble film coating made from a gastric-soluble film coating premix. The blank retentive layer is composed of a matrix sustained-release material, a bleaching agent, a bulking agent, a filler, and a lubricant. The drug-loaded sustained-release layer is composed of the API, a matrix sustained-release material, a bleaching agent, a binder, a filler, and a lubricant. The detailed formulations of the gastric-retentive sustained-release tablets of Examples 1-7 are shown in Table 1.

[0106] The calcium silicate used in Examples 1 to 7 is 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 above.

[0107] The super absorbent resin used in Examples 1-7 is acrylic acid grafted starch 300 produced by Sanyo Chemical Industries, Ltd. of Japan. It is obtained by graft copolymerizing acrylic acid monomer with natural starch at a molar ratio of 4-6:1, and has a water absorption rate of approximately 300 g / g.

[0108] The preparation method of the gastric retentive sustained-release tablets of Examples 1 to 7 is as follows:

[0109] (1) After the raw materials of the blank retention layer are prepared in proportion, they are placed in a mixing device and mixed to obtain a blank retention layer mixed powder;

[0110] (2) After all the raw materials except the binder and lubricant in the drug-loaded sustained-release layer are prepared in proportion, they are placed in a high-speed stirring granulation device for stirring and mixing, and the binder aqueous solution is added according to the formula ratio for wet granulation to obtain a wet soft material; the wet soft material is granulated using a granulation device, and placed in a fluidized bed drying device for drying until the moisture content is less than 3% to obtain dry granules of the drug-loaded sustained-release layer; the dry granules of the drug-loaded sustained-release layer and the lubricant are placed in a mixing device for mixing to obtain the total mixed granules of the drug-loaded sustained-release layer;

[0111] (3) The blank retention layer mixed powder and the drug-loaded sustained-release layer total mixed granules were placed in the two hoppers of a double-layer tablet press respectively, and double-layer tablets were pressed using two types of punches, 20 mm × 10 mm special-shaped punches and 19 mm × 7 mm special-shaped punches. The tablet hardness was controlled at 100~300 kN, and the epalrestat sustained-release tablets were obtained. The tablets were then placed in a high-efficiency coating machine for film coating to obtain epalrestat sustained-release tablets.

[0112] Table 1 Detailed formulations of the gastric retentive sustained-release tablets of Examples 1 to 7

[0113]

[0114] The film coating weight of the gastric retentive sustained-release tablets of Example 1 was 38.94 mg, which was 4.0% of the weight of the plain tablets.

[0115] The film coating weight of the gastric retentive sustained-release tablets of Example 2 is 40 mg, which is 4.0% of the weight of the plain tablets.

[0116] The film coating weight of the gastric retentive sustained-release tablets of Example 3 was 31.875 mg, which was 3.0% of the weight of the plain tablets.

[0117] The film coating weight of the gastric retentive sustained-release tablets of Example 4 was 28.425 mg, which was 3.0% of the weight of the plain tablets.

[0118] The film coating weight of the gastric retentive sustained-release tablets of Example 5 was 33.21 mg, which was 3.0% of the weight of the plain tablets.

[0119] The film coating weight of the gastric retentive sustained-release tablets of Example 6 was 29.205 mg, which was 3.0% of the weight of the plain tablets.

[0120] The film coating weight of the gastric retentive sustained-release tablets of Example 7 was 31.875 mg, which was 3.0% of the weight of the plain tablets.

[0121] Examples 8 to 13

[0122] The gastric retentive sustained-release tablets of Examples 8 to 13 are bilayer tablets (consisting of a blank retentive layer and a drug-loaded sustained-release layer, respectively). The outer surface of the plain tablets is coated with a gastric-soluble film coating made from a gastric-soluble film coating premix; the blank retentive layer is composed of a matrix-type sustained-release material, a bleaching agent, a swelling agent, a filler, a binder, and a lubricant; and the drug-loaded sustained-release layer is composed of an API, a matrix-type sustained-release material, a bleaching agent, a swelling agent, a binder, a filler, and a lubricant.

[0123] The detailed formula of the blank retention layer of the gastric-retentive sustained-release tablets of Examples 8 to 13 is shown in Table 2, and the detailed formula of the drug-loaded sustained-release layer is shown in Table 3.

[0124] Table 2 Detailed formulation of the blank retention layer of the gastric retentive sustained-release tablets of Examples 8 to 13

[0125]

[0126] The calcium silicate used in Examples 8 to 13 was 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 above.

[0127] The super absorbent resin used in Examples 8 to 13 was acrylic acid grafted starch 300 produced by Sanyo Chemical Industries, Ltd. of Japan. It is obtained by graft copolymerizing acrylic acid monomer with natural starch at a molar ratio of 4 to 6:1, and has a water absorption rate of approximately 300 g / g.

[0128] Table 3 Detailed formula of the sustained-release layer of the gastric-retentive sustained-release tablets of Examples 8 to 13

[0129]

[0130] The preparation methods of the gastric retentive sustained-release tablets of Examples 8 to 13 were the same as those of Example 2. The total weight of the plain tablet of Example 8 was 800 mg, and the weight of the film coating was 32 mg, with the film coating accounting for 4% of the weight of the plain tablet.

[0131] The total tablet weight of Example 9 is 900 mg, the film coating weight is 36 mg, and the film coating accounts for 4% of the weight of the plain tablet.

[0132] The total tablet weight of Example 10 is 1000 mg, the weight of the film coating is 30 mg, and the film coating accounts for 3% of the weight of the plain tablet.

[0133] The total tablet weight of Example 11 is 1100 mg, the film coating weight is 33 mg, and the film coating accounts for 3% of the weight of the plain tablet.

[0134] The total tablet weight of Example 12 is 1200 mg, the film coating weight is 36 mg, and the film coating accounts for 3% of the weight of the plain tablet.

[0135] The total tablet weight of Example 13 is 1000 mg, the film coating weight is 30 mg, and the film coating accounts for 3% of the weight of the plain tablet.

[0136] Examples 14 to 18

[0137] In order to eliminate the influence of API on the floating performance and sustained-release performance of sustained-release tablets, blank tablets using microcrystalline cellulose to simulate API were prepared.

[0138] The gastric-retentive sustained-release tablets of Examples 14-18 are bilayer tablets (a blank retention layer and a [simulated] drug-loaded sustained-release layer). The plain tablets are coated with a gastric-soluble film coating made from a gastric-soluble film coating premix. The blank retention layer is composed of a matrix sustained-release material, a bleaching agent, a bulking agent, a filler, a binder, and a lubricant. The [simulated] drug-loaded sustained-release layer is composed of microcrystalline cellulose, a matrix sustained-release material, a bleaching agent, a bulking agent, a binder, a filler, and a lubricant. The microcrystalline cellulose serves as a simulated API, and its use as a simulated API does not affect the evaluation of its gastric retention effect (floating and swelling properties). Microcrystalline cellulose is also insoluble or has extremely low solubility in acid, and exhibits properties similar to APIs with low acid solubility. The detailed formulations of the blank retention layer of the plain tablets of Examples 14-18 are shown in Table 4, and the detailed formulations of the [simulated] drug-loaded sustained-release layer are shown in Table 5.

[0139] Table 4 Detailed formulation of the blank retention layer of the gastric retentive sustained-release tablets of Examples 14 to 18

[0140]

[0141] The calcium silicate used in Examples 14 to 18 was pharmaceutical grade calcium silicate produced by Jiangxi Hanjiang Pharmaceutical Co., Ltd., with a bulk density of 0.15 to 0.18 g / mL and a specific surface area of ​​100 m 2 / g or above.

[0142] The super absorbent resin used in Examples 14 to 18 was acrylic acid grafted starch 1000 produced by Sanyo Chemical Industries, Ltd. of Japan. It is obtained by graft copolymerization of acrylic acid monomer and natural starch at a molar ratio of 8:1, and has a water absorption rate of approximately 1000 g / g.

[0143] The preparation method of the gastric retentive sustained-release tablets of Examples 14 to 18 is as follows:

[0144] (1) After the raw materials of the blank retention layer are prepared in proportion, they are placed in a mixing device and mixed to obtain a blank retention layer mixed powder;

[0145] (2) After the raw materials of the [simulated] drug-loaded sustained-release layer are prepared in proportion, they are placed in a mixing device and mixed to obtain a [simulated] drug-loaded sustained-release layer mixed powder;

[0146] (3) The blank retention layer mixed powder and the [simulated] drug-loaded sustained-release layer mixed powder were placed in the two hoppers of a double-layer tablet press respectively, and double-layer tablets were pressed using two types of punches, 20 mm × 10 mm special-shaped punches and 19 mm × 7 mm special-shaped punches. The tablet hardness was controlled at 100~300 kN, and the epalrestat sustained-release tablets were obtained. The tablets were then placed in a high-efficiency coating machine for film coating to obtain epalrestat sustained-release tablets.

[0147] Table 5 Detailed formula of the drug-loaded sustained-release layer of the gastric-retentive sustained-release tablets [simulated] of Examples 14 to 18

[0148]

[0149] The total tablet weight of Example 14 is 1000 mg; the weight of the film coating is 40.0 mg, which is 4.0% of the weight of the plain tablet.

[0150] The total tablet weight of Example 15 is 1000 mg; the weight of the film coating is 40.0 mg, which is 4.0% of the weight of the plain tablet.

[0151] The total tablet weight of Example 16 is 1000 mg; the weight of the film coating is 30.0 mg, which is 3.0% of the weight of the plain tablet.

[0152] The total tablet weight of Example 17 is 1000 mg; the weight of the film coating is 30.0 mg, which is 3.0% of the weight of the plain tablet.

[0153] The total tablet weight of Example 18 is 1000 mg; the weight of the film coating is 30.0 mg, which is 3.0% of the weight of the plain tablet.

[0154] Comparative Examples 1 to 13

[0155] The tablets of Comparative Examples 1-13 are bilayer tablets (comprising a blank retention layer and a drug-loaded sustained-release layer). The tablets are coated with a gastric-soluble film coating premix. 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.

[0156] Table 6 Detailed formula of tablets of Comparative Examples 1 to 9

[0157]

[0158] The calcium silicate and super absorbent resin used in Comparative Examples 1 to 13 are the same as those in Example 2.

[0159] The preparation methods of the tablets of Comparative Examples 1 to 13 are the same as those of Example 2.

[0160] The total tablet weight of the tablets of Comparative Example 1 was 950 mg, the weight of the film coating was 38.0 mg, and the film coating accounted for 4.0% of the weight of the tablets.

[0161] The total tablet weight of the tablets of Comparative Example 2 was 960 mg, the weight of the film coating was 38.4 mg, and the film coating accounted for 4.0% of the weight of the tablets.

[0162] The total tablet weight of the tablets of Comparative Example 3 was 1215 mg, the weight of the film coating was 36.45 mg, and the film coating accounted for 3.0% of the weight of the tablets.

[0163] The total tablet weight of the tablets of Comparative Example 4 was 1000 mg, the weight of the film coating was 30.0 mg, and the film coating accounted for 3.0% of the weight of the tablets.

[0164] The total tablet weight of the tablets of Comparative Example 5 was 925 mg, the weight of the film coating was 27.75 mg, and the film coating accounted for 3.0% of the weight of the tablets.

[0165] The total tablet weight of the tablets of Comparative Example 6 was 1000 mg, the weight of the film coating was 30.0 mg, and the film coating accounted for 3.0% of the weight of the tablets.

[0166] The total tablet weight of the tablets of Comparative Example 7 was 1000 mg, the weight of the film coating was 30.0 mg, and the film coating accounted for 3.0% of the weight of the tablets.

[0167] The total tablet weight of the tablets of Comparative Example 8 was 935 mg, the weight of the film coating was 28.05 mg, and the film coating accounted for 3.0% of the weight of the tablets.

[0168] The total tablet weight of the tablets of Comparative Example 9 was 1175 mg, the weight of the film coating was 35.25 mg, and the film coating accounted for 3.0% of the weight of the tablets.

[0169] Table 7 Detailed formula of tablets of comparative examples 10 to 13

[0170]

[0171] The total tablet weight of the tablets of Comparative Example 10 is 950 mg, the weight of the film coating is 28.5 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0172] The total tablet weight of the tablets of Comparative Example 11 is 960 mg, the weight of the film coating is 28.8 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0173] The total tablet weight of the tablets of Comparative Example 12 is 1150 mg, the weight of the film coating is 34.5 mg, and the film coating accounts for 3.0% of the weight of the plain tablets.

[0174] The total tablet weight of the tablets of Comparative Example 13 is 1000 mg, the weight of the film coating is 30.0 mg, and the film coating accounts for 3.0% of the weight of the tablets.

[0175] For ease of comparison, the usage of bleaching aids and swelling agents in the Examples and Comparative Examples is summarized in Tables 8 and 9. Table 8 summarizes the mass data of each component, and Table 9 summarizes the percentage data of each component. The percentages in Table 9 refer to the proportion of the amount of the component used in the total amount of the layer (blank retention layer or drug-loaded sustained-release layer).

[0176] Table 8 Usage of bleaching aid and swelling agent in each embodiment and each comparative example (mass)

[0177]

[0178] Table 9 Usage of bleaching aid and swelling agent in each embodiment and each comparative example (mass percentage)

[0179]

[0180] Test example

[0181] (1) Process smoothness evaluation

[0182] The smoothness of the tableting process and the quality of the plain tablets (appearance, friability) were used as evaluation indicators to evaluate the smoothness of the process.

[0183] The appearance standards of plain tablets are: complete and without defects, smooth surface, uniform color; the boundary between the two layers is smooth.

[0184] The friability standard for plain tablets is: the weight loss shall not exceed 0.5%, and no broken, cracked or crushed tablets shall be detected.

[0185] The process smoothness evaluation criteria and evaluation results of each embodiment and comparative example are detailed in Table 10.

[0186] The results in Table 10 show that when the amount of each single-layer calcium silicate is above 30% (Comparative Example 3, Comparative Example 12), the volume of the material to be compressed is too large during tableting, and the tablets cannot be compressed according to the target tablet weight; the process smoothness of the other formulations is good, and the appearance and friability of the prepared plain tablets are good.

[0187] Table 10 Process smoothness evaluation results

[0188]

[0189] (2) Floating performance evaluation

[0190] To simulate the floating state of tablets in gastric acid in the human stomach, film-coated tablets were placed in a dissolution cup containing 240 ml of hydrochloric acid solution (pH 1.2, 37°C), and the floating time and holding time required for the tablets to float to the surface of the solution and remain floating were recorded.

[0191] Considering that factors such as elderly patients and food effects may cause transient or persistent increases in gastric pH, the same method was used to measure the onset and duration of leaching in high pH ranges (hydrochloric acid medium at pH 2.0, acetate medium at pH 4.5, and phosphate medium at pH 6.8). The test results are shown in Table 11. The onset and duration of leaching for some comparative examples were too long, making it meaningless to continue testing the duration of leaching. These are indicated as NT (not tested) in the duration of leaching in Table 11.

[0192] Table 11 Floating start time and floating hold time of Examples 1 to 18 and Comparative Examples 1 to 2, Comparative Examples 4 to 11, and Comparative Example 13

[0193]

[0194] The results in Table 11 show that:

[0195] (1) Tablets containing calcium silicate in both layers and in an appropriate dosage (Examples 1 to 13) all immediately floated in each release medium (floating time < 1s) without pH dependence, and the flocculation time was not less than 16h, meeting the sustained-release requirements. In comparison, a higher dosage of calcium silicate was more conducive to extending the flocculation time.

[0196] (2) The tablets of Comparative Example 13, in which both layers do not contain calcium silicate but use other conventional bleaching agents, and Comparative Example 4, in which the blank retention layer does not contain calcium silicate but uses other conventional bleaching agents, have significantly slower bleaching times and are significantly pH-dependent. The tablets of Comparative Example 1, in which the blank retention layer does not contain calcium silicate, and Comparative Example 10, in which the drug-loaded sustained-release layer does not contain calcium silicate, also have significantly slower bleaching times. The tablets of Comparative Example 2 and Comparative Example 11, in which the amount of calcium silicate used in the single layer is too low (2.17%), also have slower bleaching times than those of the embodiments.

[0197] (3) Expansion performance evaluation

[0198] (1) Explanation of the acceptable standard for expansion size:

[0199] Expandable gastric retentive tablets require the tablet to swell to a size larger than the pyloric size (average size of approximately 12.8 mm) upon exposure to gastric acid, thereby achieving gastric retention. Furthermore, because eating can slow gastric emptying and sleep can reduce gastrointestinal motility, if the tablet is administered with a meal, before bed, or both, then gastric retention can be achieved without the tablet being larger than the pyloric size (within 2 hours after a meal or during sleep). Literature reports indicate that in this state, tablets with an expanded length greater than 9 mm can achieve gastric retention. Drugs approved for marketing based on this principle include pregabalin extended-release tablets.

[0200] Based on the above principles, the acceptable standard for the expanded size of the gastric retentive sustained-release tablets of the present invention is as follows:

[0201] ① Administer the drug before bedtime: the tablet must swell for 2 hours and its diameter must be ≥9mm; the tablet must swell for 6 hours (sleep time) and its diameter must be ≥13.0mm.

[0202] ② For non-bedtime administration: the tablet should swell for 2 hours and its width should be ≥13.0 mm.

[0203] Note: Epalrestat gastric retentive sustained-release tablets can be used for both bedtime and non-bedtime administration.

[0204] (2) Expansion size test and results

[0205] To simulate tablet expansion in human gastric acid, three tablets were placed in a dissolution vessel containing 240 ml of hydrochloric acid solution (pH 1.2, 37°C). The dissolution test was performed using the basket method at 100 rpm. After 2 hours, the tablets were removed and their width (D) was measured using a vernier caliper. Three additional tablets were taken and measured using the same method at 6 hours (only tablets compressed using the 19 mm × 7 mm die were measured at 6 hours). For tablets compressed using the 19 mm × 7 mm die, the acceptable expansion criteria were ≥9 mm at 2 hours and ≥13 mm at 6 hours. For tablets compressed using the 20 mm × 10 mm die, the acceptable expansion criteria were ≥13 mm at 2 hours.

[0206] The test results are shown in Table 12.

[0207] Considering that factors such as elderly patients and food effects may cause transient or persistent increases in gastric pH, the tablet width (D) of the group that met the requirements in hydrochloric acid medium at pH 1.2 was further measured using the same method at various expansion times in a high pH range (phosphate medium at pH 6.8) (only tablets compressed using a 19 mm × 7 mm die were measured at 6 hours). For tablets compressed using a 19 mm × 7 mm die, the acceptable expansion dimension criteria were ≥9 mm at 2 hours and ≥13 mm at 6 hours. For tablets compressed using a 20 mm × 10 mm die, the acceptable expansion dimension criteria were ≥13 mm at 2 hours.

[0208] The test results are shown in Table 13.

[0209] Table 12 Expansion performance evaluation results of Examples 1 to 18 and Comparative Examples 5 to 9 (pH 1.2 hydrochloric acid medium)

[0210]

[0211] The results in Tables 12 and 13 show that:

[0212] (1) The tablets pressed by the die of 19 mm × 7 mm in each embodiment can have a width diameter of ≥9 mm after wetting and expansion for 2 hours; the tablets pressed by the die of 20 mm × 10 mm in each embodiment can have a width diameter of ≥13 mm after wetting and expansion for 2 hours, which meets the aforementioned acceptable standard for expansion size of gastric retentive sustained-release tablets for administration before bedtime; the tablets pressed by the die of 20 mm × 10 mm in each embodiment can have a width diameter of ≥13 mm after wetting and expansion for 2 hours, which meets the aforementioned acceptable standard for expansion size of gastric retentive sustained-release tablets for administration other than before bedtime.

[0213] (2) Under the same wetting conditions, the wetting expansion widths of Comparative Examples 5 to 8 at low pH values ​​cannot meet the established acceptable expansion size standards.

[0214] (3) In the comparative example 9, the amount of acrylic acid grafted starch was more than 30%. Although the wetting expansion width met the established acceptable expansion size standard, the wetting expansion width did not show a significant correlation with the significant increase in the amount of acrylic acid grafted starch.

[0215] Table 13 Swelling performance evaluation results of Examples 1 to 18 (pH 6.8 phosphate medium)

[0216]

[0217] (IV) In vitro release test

[0218] The in vitro release curves of Example 2, Example 8, Example 9 and Example 11 are tested. The specific data are shown in Table 14, and the average cumulative release curve is shown in Figure 1According to the in vitro release curve data of each embodiment in Table 14, the average hourly release amount during each release sampling time point interval was calculated. The results are shown in Table 15.

[0219] Table 14 Cumulative in vitro release results of Example 2, Example 8, Example 9, and Example 11

[0220]

[0221] Table 15 Average hourly release in vitro test of Example 2, Example 8, Example 9, and Example 11

[0222]

[0223] Release medium selection instructions: Because the API epalrestat is extremely insoluble in hydrochloric acid at pH 1.2 and slightly soluble at pH 6.8, a pH 6.8 phosphate buffer solution was selected as its release medium. Release test method: Following the dissolution and release determination method [Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2, Method 1 (Pulp Method)], 900 mL of pH 6.8 phosphate buffer solution was used as the release medium at a rotation speed of 100 rpm. Following this procedure, samples were collected after 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, 20 hours, and 24 hours. After sampling, the release amount was measured, and the average cumulative dissolution rate was calculated (6 samples were taken for each value). The results in Tables 14 and 15 demonstrate that the compositions of each example achieved complete sustained release within 24 hours (cumulative release ≥ 95%), with an average hourly release ranging from 1.4% to 8.5%. This result demonstrates a significant sustained-release effect with no burst release.

[0224] (V) Stability investigation

[0225] The stability of the sustained-release tablets of Example 2 (die 20 mm × 10 mm) was investigated under accelerated test conditions (40 ± 2°C, RH 75 ± 5%). Samples were taken at month 0 and month 6 to test appearance, floating onset time, floating duration, expansion size, release curve, and related substances. The results are shown in Table 16.

[0226] Table 16 Stability test results of gastric retentive sustained-release tablets of Example 2

[0227]

[0228] The results in Table 16 show that the gastric retentive sustained-release tablets of the present invention, as exemplified in Example 2, have excellent stability after 6 months of accelerated testing.

[0229] (VI) Pharmacokinetic studies in humans

[0230] The original common tablets (Ipalrestat tablets, specification 50mg, i.e. each tablet contains 50mg of Ipalrestat, trade name KINEDAK ® ) was used as the control preparation, and the in vivo pharmacokinetic study of the epalrestat gastric retentive sustained-release tablets prepared in Example 2 was carried out.

[0231] The experimental scheme is detailed in Table 17, the experimental results are shown in Table 18, and the drug-time curve is shown in Figure 2 .

[0232] The test results show that the epalrestat gastric retentive sustained-release tablets prepared in Example 2 of the present invention achieve a once-daily sustained-release effect in vivo, with stable blood drug concentration control, and can effectively avoid the peak and valley phenomenon of blood drug concentration of conventional preparations.

[0233] Table 17 In vivo pharmacokinetic study protocol for Example 2 and the original conventional tablets

[0234]

[0235] Table 18 Results of in vivo pharmacokinetic studies of Example 2 and the original conventional tablets

[0236]

[0237] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A gastric retentive sustained-release tablet, characterized in that: It is a double-layer tablet comprising a blank retention layer and a drug-loaded sustained-release layer; The raw materials of the blank retention layer are composed of a skeleton-type sustained-release material, a bleaching aid, an expander, a filler, a lubricant, and an optional adhesive. The raw materials of the drug-loaded sustained-release layer are composed of a skeleton-type sustained-release material, a bleaching aid, an active pharmaceutical ingredient, a binder, a filler, a lubricant, and an optional swelling agent; The bleaching agent is calcium silicate, or a combination of calcium silicate and sodium bicarbonate; the bulk density of the calcium silicate is less than 0.2 g / mL; The swelling agent in the blank retention layer is acrylic acid grafted starch, or a combination of acrylic acid grafted starch and one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and sodium carboxymethyl starch; the water absorption rate of the acrylic acid grafted starch is above 100 g / g; The swelling agent in the drug-loaded sustained-release layer is one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and sodium carboxymethyl starch; The active pharmaceutical ingredient is one or more of epalrestat, its medically acceptable salts, hydrates and salt hydrates; The skeleton-type sustained-release material is selected from one or more of hydroxypropyl methylcellulose, polyvinyl alcohol, polyethylene oxide, ethyl cellulose, povidone, copovidone, polyvinyl acetate, carrageenan, xanthan gum, guar gum, gum arabic, hydroxypropyl cellulose, hydroxyethyl cellulose, alginic acid, alginate, and hydroxypropyl methylcellulose stearyl ether; In the blank retention layer, the mass of calcium silicate accounts for 4% to 28% of the blank retention layer, and when the bleaching agent is a combination of calcium silicate and sodium bicarbonate, the mass ratio of the bleaching agent is less than 30%; In the blank retention layer, the mass of the acrylic acid grafted starch accounts for 3% to 40% of the blank retention layer, and when the swelling agent is a combination of acrylic acid grafted starch and one or more of cross-linked sodium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and sodium carboxymethyl starch, the mass ratio of the swelling agent is less than 40%; In the blank retention layer, the mass ratio of the skeleton type sustained-release material is 25% to 80%; 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, and when the bleaching agent is a combination of calcium silicate and sodium bicarbonate, the mass ratio of the bleaching agent is less than 25%; In the drug-loaded sustained-release layer, the mass ratio of the swelling agent is less than 15%; In the drug-loaded sustained-release layer, the mass ratio of the skeleton-type sustained-release material is 15% to 60%; The mass ratio of the blank retention layer to the drug-loaded sustained-release layer is 400-700:300-600.

2. The gastric retentive sustained-release tablet according to claim 1, characterized in that In the blank retention layer, the mass of calcium silicate accounts for 4.5% to 25% of the blank retention layer; In the blank retention layer, the mass of the acrylic acid grafted starch accounts for 4% to 35% of the blank retention layer.

3. The gastric retentive sustained-release tablet according to claim 1, wherein The skeleton-type sustained-release material in the blank retention layer includes a hydrophilic gel skeleton material and / or an insoluble skeleton material; The mass of the hydrophilic gel skeleton material in the skeleton-type sustained-release material in the drug-loaded sustained-release layer accounts for more than 60%.

4. The gastric retentive sustained-release tablet according to claim 1, wherein The specific surface area of ​​the calcium silicate is 100m 2 / g or above; The acrylic acid grafted starch is obtained by graft copolymerizing acrylic acid monomer and natural starch at a molar ratio of 2 to 10:

1.

5. The gastric retentive sustained-release tablet according to any one of claims 1 to 4, characterized in that: Plain tablets or tablets with gastric-soluble coating; tablet weight excluding coating weight is 600-1300 mg; The tablet width is ≥10mm.

6. The gastric retentive sustained-release tablet according to any one of claims 1 to 4, characterized in that The solubility of the active pharmaceutical ingredient under acidic conditions is as follows: a single dose of the active pharmaceutical ingredient is dissolved in a hydrochloric acid solution with a pH value of 1.0 to 3.0, and the required volume of hydrochloric acid solution is greater than 250 mL.

7. The gastric retentive sustained-release tablet according to any one of claims 1 to 4, characterized in that C 15 H 13 Each tablet contains 100mg~180mg of active pharmaceutical ingredient based on NO3S2.

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