A gastro-retentive double-release sustained-release tablet of meloxicam besylate and a preparation method thereof

Abstract

This invention provides a merogalaline besylate gastric retention dual-release sustained-release tablet and its preparation method. This gastric retention sustained-release tablet is a rapid-release formulation, a bilayer tablet composed of a rapid-release layer and a sustained-release layer. The sustained-release layer includes merogalaline besylate, a sustained-release matrix material, a swelling agent, a diluent, and other pharmaceutical excipients; the rapid-release layer includes merogalaline besylate, a diluent, a binder, a disintegrant, a stabilizer, and other pharmaceutical excipients. This invention also discloses a method for preparing the merogalaline besylate gastric retention dual-release sustained-release tablet. The merogalaline besylate dual-release sustained-release tablet prepared using this method combines rapid-release and sustained-release technologies. The rapid-release layer dissolves quickly, resulting in rapid onset of action after administration; the sustained-release layer releases slowly, retaining the long-term efficacy characteristic of pure sustained-release formulations, aiming to achieve rapid and sustained analgesia and fully meet the analgesic needs of patients.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a merogbalin besylate gastric retention dual-release sustained-release formulation and its preparation method, suitable for once-daily administration. Background Technology

[0002] Mirogabalin Besilate is a novel medication for treating chronic pain that exerts its analgesic effect by selectively binding to the α2δ-1 subunit of voltage-dependent calcium channels (1 and 2).

[0003] Merogabalin benzenesulfonic acid is a white to slightly yellowish-white powder, readily soluble in 1,3-dimethyl-2-imidazolinone, methanol, and ethanol (99.5%), slightly soluble in water, insoluble in acetone, extremely insoluble in acetonitrile, and sparingly soluble in anisole and methyl tert-butyl ether. Its chemical name is [(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid benzenesulfonate, and its structural formula is shown below. Peripheral neuropathic pain (PNP) is caused by peripheral nerve damage or dysfunction due to various reasons. Typical PNPs include diabetic PNP (DPNP) and postherpetic neuralgia (PHN). DPNP and PHN are typical examples of PNP caused by nerve damage.

[0004] Diabetic peripheral neuropathy is one of the most common long-term complications in diabetic patients. Symptoms include acute pain or hypersensitivity, numbness, loss of balance and coordination, tingling, and burning sensations, which worsen at night. Approximately 50% of diabetic patients develop peripheral neuropathy, and it is estimated that 11% to 26% of diabetic patients will have diabetic peripheral neuropathy; however, reporting and treatment of this disease are often severely inadequate.

[0005] Shingles occurs due to a weakened immune system against the varicella-zoster virus, which forms a latent infection in the nerve ganglia. In shingles-related neuralgia (PHN), the burning or electric shock-like pain persists even after the rash has healed; the disease is considered intractable and can lead to muscle weakness and, in rare cases, paralysis. In Japan, 500,000 to 600,000 people contract shingles annually, with 10% to 25% of these cases developing PHN.

[0006] Mirogabalin is an α2δ ligand originally developed by Daiichi Sankyo Co., Ltd. of Japan. Administered orally, it preferentially and selectively binds to the α2δ-1 subunit of voltage-dependent calcium channels (1 and 2), exhibiting significantly higher potency than pregabalin. These calcium channels are widely distributed throughout the nervous system, mediating pain transmission and processing in various regions of the body. Mirogabalin possesses unique binding properties and a long-lasting effect. Mirogabalin, along with gabapentin and pregabalin, belongs to the class of drugs called gabapentinoids.

[0007] Tarlige (merogabalin besylate) tablets from Daiichi Sankyo Co., Ltd. in Japan, available in 2.5 mg, 5 mg, 10 mg, and 15 mg tablets, are currently approved for the treatment of peripheral neuropathic pain (PNP). Merogabalin besylate tablets have a Tmax of only 1.00 hour and a T1 / 2 of approximately 3 hours, making them a fast-acting drug with a short half-life. To maintain blood drug concentrations, multiple daily doses are necessary. Generally, the initial dose for adult patients is 5 mg twice daily, titrated up to the prescribed dose by increasing by 5 mg weekly. Dosage can be adjusted appropriately between 10 mg and 15 mg twice daily based on age and symptoms.

[0008] Developing a once-daily dual-release sustained-release formulation can improve patient adherence and reduce or prevent adverse reactions related to blood drug concentration (by lowering peak blood drug concentration C). max Merogabalin besylate is a weakly acidic drug, typically better absorbed in the stomach and upper small intestine. If developed into a conventional sustained-release formulation, its residence time in the stomach and small intestine is usually 6-8 hours, posing a risk of prolonged and insufficient absorption. Furthermore, merogabalin besylate reaches peak concentration and is eliminated rapidly, requiring prolonged and sustained absorption to maintain adequate blood concentrations. Therefore, for the absorption site of merogabalin besylate, a formulation should be designed that not only controls the drug release rate but also ensures prolonged residence in the stomach and small intestine. Thus, a gastric retention sustained-release formulation can be chosen, achieving a prolonged residence in the stomach and small intestine while continuously and slowly releasing the drug. For analgesics, both long-lasting treatment and rapid onset of action are required; therefore, this product is designed as a rapid-release formulation. The rapid-release portion provides immediate action, while the sustained-release portion maintains efficacy over a long period, meeting the clinical need for both rapid and long-lasting analgesics.

[0009] Chinese patent application CN116509811A discloses a milobalin besylate sustained-release tablet and its preparation method. The sustained-release tablet contains milobalin besylate, high-viscosity polyethylene oxide, low-viscosity polyethylene oxide, and a filler. However, the formulation described is not gastric retention type and cannot remain in the gastrointestinal tract for an extended period, thus failing to achieve the purpose of prolonged drug release and absorption in the body.

[0010] Chinese patent application CN117860707A discloses melogabalin besylate sustained-release capsules and their preparation method, but the preparation described therein is not a gastric retention type and cannot stay in the gastrointestinal tract for a long time, so it cannot achieve the purpose of long-term drug release and absorption in the body.

[0011] Chinese patent application CN110917164A discloses a milobalin besylate sustained-release tablet and its preparation method. Specifically, it discloses high-viscosity hydroxypropyl methylcellulose, low-viscosity hydroxypropyl methylcellulose; fillers: lactose / sucrose / D-mannitol / sorbitol / xylitol; colored film coating material: Opadry 02N-650001-CN; binder: hydroxypropyl cellulose / sodium carboxymethyl cellulose / povidone; lubricant: magnesium stearate / talc / micronized silica / sodium stearate fumarate. This formulation is not a gastric retention sustained-release tablet and cannot remain in the gastrointestinal tract for an extended period, thus failing to achieve the purpose of prolonged drug release and absorption in the body.

[0012] Chinese patent application CN118806716A discloses a once-daily oral merogabarine besylate sustained-release formulation. This sustained-release formulation contains merogabarine besylate, a matrix material, a diluent, a stabilizer, and other pharmaceutical excipients. However, this formulation is not a gastric retention type and cannot remain in the gastrointestinal tract for an extended period, thus failing to achieve the goal of prolonged drug release and absorption in the body.

[0013] Chinese patent application CN118806715A discloses a once-daily oral merogabarine besylate sustained-release formulation. This sustained-release formulation contains merogabarine besylate, a matrix material, a swelling agent and a buoyancy aid, a stabilizer, and other pharmaceutical excipients. The gastric retention mechanism of the formulation described in this patent is achieved by prolonged floating in the stomach, thus achieving gastric retention and a sustained-release effect. We prepared a sample according to Example 10 and tested it according to the second method (paddle method) of the dissolution test in Part II of the 2025 edition of the Chinese Pharmacopoeia. The test medium was 0.06 mol / L hydrochloric acid solution, with a medium volume of 900 ml, a rotation speed of 50 rpm, and a solvent temperature of 37℃±5℃. Unexpectedly, the sample did not float from the time it was placed in the dissolution vessel until 24 hours later. The sample did not float at all, indicating that the product could not achieve gastric retention through prolonged floating in the stomach. It is not significantly different from ordinary sustained-release tablets and is not a gastric retention type sustained-release tablet. Existing pure sustained-release designs have a clear analgesic gap period, which cannot meet the rapid analgesia needs of patients with chronic pain during acute attacks. More importantly, it is generally believed in the field that floating-swelling gastric retention tablets are highly sensitive to surface hydration behavior. Adding an extra fast-release layer will disrupt the uniform formation of the sustained-release gel layer, resulting in uneven swelling and floating failure. Therefore, there has been no dual-release modification scheme for merogbalin besylate gastric retention formulations for a long time.

[0014] Chinese patent application CN119970683A relates to a dual-release formulation of merobalin besylate and its preparation method, comprising immediate-release microspheres and sustained-release microspheres, both encapsulated within a hollow capsule. The immediate-release microspheres include an immediate-release blank core, an immediate-release drug layer, and an immediate-release film coating layer; the sustained-release microspheres include a sustained-release blank core, a sustained-release drug layer, a sustained-release layer, and a sustained-release film coating layer. The primary absorption site of merobalin besylate is the upper small intestine. This product features a dual-release design. The immediate-release microspheres rapidly disintegrate in the stomach, meeting the needs of acute analgesia. However, while the sustained-release microspheres release the drug slowly, their short residence time in the stomach means that most of the drug is released after reaching the absorption window, directly leading to reduced bioavailability.

[0015] Chinese patent application CN122075429A relates to a 20mg core-type or core-shell type biphasic-release tablet containing merogabarine or a pharmaceutically acceptable salt thereof, and a method for preparing the same. The tablet is only a core-type, compressed coated tablet, or core-shell type film-coated tablet, comprising an immediate-release portion located in the outer layer or outer coating and a sustained-release portion located in the core, wherein the core is continuously surrounded by the outer layer in the radial direction; the immediate-release portion of the outer layer carries 20%–30% of the total drug content, and the sustained-release portion of the core carries 70%–80% of the total drug content; the core contains hydroxypropyl methylcellulose K15M, polyethylene oxide, and ethylcellulose, suitable for development into an oral sustained-release formulation for once-daily administration. Existing core-shell / core-release formulations have inherent drawbacks: First, the preparation process is complex, requiring the preparation of a sustained-release core before outer layer compression, making process parameter control difficult and prone to chip misalignment and uneven outer layer thickness, resulting in large fluctuations in the release behavior of the immediate-release portion; second, the space of the sustained-release core is limited, making it difficult to accommodate sufficient swelling and floating excipients, thus failing to achieve a stable gastric retention effect; third, industrial production efficiency is low, the scrap rate is high, and the cost is significantly higher than that of ordinary bilayer tablets; fourth, due to the short residence time in the stomach, most of the drug is released after reaching the absorption window, which directly leads to reduced bioavailability.

[0016] Chinese patent application CN121313580A discloses a merogabalin besylate combined pulse-release formulation, comprising a sustained-release layer and a pulse-rapid-release layer; the sustained-release layer is formed of drug-containing sustained-release particles, and the pulse-rapid-release layer is formed of drug-containing pulse microcapsules and drug-containing rapid-release particles; the mass ratio of merogabalin besylate in the drug-containing pulse microcapsules, drug-containing rapid-release particles, and drug-containing sustained-release particles is 8.78~17.56:8.78~17.56:17.56~26.34; the drug-containing sustained-release particles contain besylate by mass content. The drug-containing fast-release granules contain the following components by mass: 8.78-13.17% merogabaline, 38-58% hydrophilic gel material hydroxypropyl methylcellulose, 15.5-45.5% hydrophobic material ethyl cellulose, 6.22-16.22% filler, 1-2% glidant, and 0.5-1% lubricant; 8.78-17.56% merogabaline benzyl sulfonate, 45-74% diluent, 3-5% disintegrant, 2-4% binder, 10-30% filler, and 0.25-1% lubricant. The preparation method of the drug includes: pre-compressing the drug-containing sustained-release granules to obtain a pre-compressed sustained-release layer; mixing the drug-containing fast-release granules with drug-containing pulse microgranules; and double-compressing the resulting mixed granules with the pre-compressed sustained-release layer to obtain a composite tablet. Although this formulation has multi-stage drug release characteristics, it is not designed with gastric retention function as a whole. The residence time of the drug in the stomach and upper small intestine is still limited by the physiological gastric emptying rate, which cannot effectively prolong the in vivo absorption window of melogabalin besylate, making it difficult to achieve true once-daily long-acting dosing. At the same time, its immediate release part relies on the time-delayed drug release of pulsatile microparticles, which cannot achieve the immediate analgesic effect of rapid disintegration and drug release after administration and rapid achievement of effective blood drug concentration. In addition, the formulation contains multiple dosage form units such as microparticles and granules, making the preparation process complex and the double-layer tableting difficult to form, and the quality stability of industrial mass production is difficult to control.

[0017] Chinese patent application CN108159011A discloses a biphasic controlled-release pregabalin pharmaceutical composition, wherein the composition comprises 5% to 60% by weight of the active pharmaceutical ingredient, 5% to 60% by weight of an insoluble matrix controlled-release phase, 1% to 50% by weight of a gel matrix controlled-release phase, 0% to 30% by weight of a filler, and 0.5% to 5% by weight of a lubricant; the insoluble matrix controlled-release phase is selected from ethyl cellulose, polyacrylic acid resin, crosslinked povidone, ethylene-vinyl acetate copolymer, and cellulose acetate. Or mixtures thereof; the gel matrix controlled-release phase is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, sodium alginate, xanthan gum, polyoxyethylene or mixtures thereof; the filler is selected from starch, lactose, sucrose, mannitol, microcrystalline cellulose, pregelatinized starch, dextrin, inorganic salts or mixtures thereof; the preparation method comprises (a) mixing pregabalin or a pharmaceutically acceptable salt thereof with an insoluble matrix controlled-release phase and a gel matrix controlled-release phase; (b) mixing the mixture obtained in (a) with a lubricant, and then compressing to obtain a tablet. KR1020130023127A discloses a pregabalin sustained-release formulation comprising a hydroxypropyl cellulose matrix and a gas generator. WO2015114509A1 Pregabalin gastric retention tablets comprising a swelling agent selected from cellulose polymers, polyepoxides, polysaccharides, acrylic polymers, and vinylpyrrolidone polymers. The aforementioned technical solutions all use pregabalin as the active ingredient and do not address the unique physicochemical properties and pharmacokinetic characteristics of melogabalin besylate in their formulation design. Furthermore, these formulations are all single-release formulations without a separate immediate-release drug unit, failing to meet the clinical needs of patients with neuropathic pain for rapid analgesia. More importantly, melogabalin besylate and pregabalin differ significantly in their gastrointestinal absorption sites, membrane permeability, and elimination rates in vivo. Therefore, the existing technologies cannot be directly applied, nor can they simultaneously achieve the dual therapeutic goals of "extended absorption window through gastric retention" and "rapid onset of action in the immediate-release portion."

[0018] The existing technology CN101330907A discloses a pregabalin single-layer gastric floating sustained-release formulation, using Kollidon SR, carbomer, crospovidone, and polyoxyethylene as the floating framework. However, this scheme has several technical limitations: First, the active ingredient is pregabalin, with a half-life of about 6 hours, which is completely different from the kinetics of melogabalin besylate, and cannot be directly adapted to the latter's requirement of stable drug release over 24 hours; Second, this patent only broadly discloses the types of excipients, without optimizing the excipient compatibility for melogabalin besylate, which is prone to producing lactam impurities, and it prefers mannitol as a filler, which has poor compatibility with the active pharmaceutical ingredient, and impurities increase significantly with long-term storage; Third, this patented formulation is only a single-layer tablet, and there is no hydration interference problem coexisting with the immediate-release layer, which cannot solve the technical problem of the immediate-release layer destroying the sustained-release gel layer in a double-layer tablet; Fourth, its swelling size only needs to reach 9 mm, which is smaller than the average pyloric diameter of 13 mm in the human body, resulting in a short gastric retention time, which is difficult to meet the long-term absorption requirements of melogabalin. If the pregabalin formulation is directly applied to melogabalin besylate formulation, multiple defects will occur, such as insufficient floating time, excessive impurities, and failure of bilayer compatibility. Therefore, there is no motivation in the field to directly transfer this excipient system.

[0019] In summary, existing melogabalin besylate formulations either lack gastric retention function, resulting in insufficient absorption window and inability to achieve once-daily long-acting dosing, or are only single sustained-release formulations, resulting in slow onset of action and inability to quickly relieve pain. There is no formulation that can simultaneously achieve rapid onset of action, long-term maintenance, and gastric retention, and further development and optimization are still needed. Summary of the Invention

[0020] The purpose of this invention is to provide a merogalaline besylate gastric retention dual-release sustained-release tablet. This merogalaline besylate dual-release sustained-release tablet is a rapid-release formulation that combines rapid-release and sustained-release technologies. The rapid-release layer dissolves quickly, resulting in rapid onset of action after administration; the sustained-release layer releases slowly, retaining the long-term efficacy characteristic of pure sustained-release formulations, aiming to achieve rapid and sustained analgesia, fully meeting the analgesic needs of patients and satisfying the clinical demand for rapid-acting and long-lasting analgesics.

[0021] This invention provides a melogabalin besylate gastric retention dual-release sustained-release tablet, which is a fast-release and slow-release formulation, and is a bilayer tablet formed by pressing a fast-release layer and a sustained-release layer together; the weight ratio of melogabalin besylate in the sustained-release layer and the fast-release layer is 7:2 to 9:2, preferably 4:1.

[0022] The sustained-release layer of this product utilizes a mixture of polyvinyl acetate and povidone, cross-linked povidone, polyoxyethylene, and carbomer to form a sustained-release gel framework. The resulting melogabalin besylate sustained-release tablets float and expand in the stomach upon contact with gastric juices. This expansion allows the longest linear dimension of its smallest cross-sectional area to exceed the pyloric diameter (approximately 13 mm in adults), effectively prolonging its retention time in the stomach. Simultaneously, the sustained-release gel framework effectively controls the release rate of the active pharmaceutical ingredient, enabling melogabalin besylate to be released continuously and for an extended period in the stomach and small intestine, thus achieving the goal of once-daily dosing.

[0023] The disadvantages of simple sustained-release tablets are that peak blood concentration is reached late, onset of action is slow, and pain relief is not rapid. Therefore, this invention designs it as a rapid-release and slow-release dual-release formulation, which includes a rapid-release layer in addition to the aforementioned sustained-release layer. The original Daiichi Sankyo merogalaline besylate tablets' package insert states that the 3mg C... max The concentration was 48.6 ng / ml. Pharmacology states that the minimum effective plasma concentration (MIPD) is generally one-third of the maximum effective plasma concentration (MAPD). Therefore, the MIPD of meropenem besylate can be estimated to be approximately 16.2 ng / ml. Furthermore, the C60 of meropenem... max The dosage increases proportionally, suggesting that the immediate-release portion needs to contain more than 1 mg to achieve an effective dose. The weight ratio of melogabalin besylate in the sustained-release and immediate-release layers is 7:2 to 9:2, preferably 4:1. For example, considering the minimum designed strength of this product is 5.5 mg, the immediate-release portion is designed to contain 1.1 mg of active ingredient, corresponding to a 4.4 mg sustained-release layer. A 1:4 ratio of active ingredient to sustained-release formulation is used for the development of the immediate-release formulation. Experimental results show that the immediate-release layer dissolves rapidly, achieving rapid onset of action. Combined with the release of drug from the sustained-release layer, an effective blood drug concentration can be rapidly achieved and maintained over a long period.

[0024] The sustained-release layer of the melogabalin besylate gastric retention dual-release sustained-release tablet of the present invention contains melogabalin besylate as the active ingredient, a sustained-release matrix material, a swelling agent, a diluent, and other pharmaceutical excipients; wherein the sustained-release matrix material includes a mixture of polyvinyl acetate and povidone (polyvinyl acetate to povidone weight ratio 8:2, such as BASF's Kollidon® SR) and carbomer, the swelling agent includes cross-linked povidone and polyoxyethylene, and the diluent contains lactose.

[0025] The specific excipients for the sustained-release layer are as follows: The sustained-release matrix material comprises a polyvinyl acetate-povidone mixture (polyvinyl acetate to povidone weight ratio 8:2, such as BASF's Kollidon® SR), with a molecular weight (Mw) typically around 1 × 10⁻⁶. 5 To approximately 1×10 6Based on the total weight of the sustained-release layer of the pharmaceutical composition, the polyvinyl acetate-povidone mixture in this composition preferably accounts for 21% to 31%, more preferably 23% to 29%. In addition to the polyvinyl acetate-povidone mixture, the sustained-release matrix material used in this formulation also includes carbomer. When carbomer comes into contact with water, it forms a viscous mixture that can delay the diffusion of the drug through the dosage form, thereby prolonging the time for drug release from the dosage form. Carbomer is an acrylic polymer that is crosslinked with allyl sucrose or pentaerythritol allyl ether, and is also referred to in various cases as carboxylated polymethylene polymer, polyacrylic acid, and carboxyvinyl polymer. On a dry matter basis, carbomer has a carboxyl fragment content of about 56% to about 68% and a molecular weight of about 3 × 10⁻⁶. 9 To approximately 4×10 9 Based on the total weight of the sustained-release layer of the pharmaceutical composition, the preferred proportion of carbomer is 2% to 9%, and more preferably 4% to 7%.

[0026] As its name suggests, the swelling agent in the sustained-release layer absorbs water from gastric juice, causing the solid dosage form to expand in size, and can also affect the drug release rate by forming a hydrophilic colloid. The swelling agent may be water-soluble or water-insoluble. The swelling agent used in this formulation, crospovidone, typically has a molecular weight (Mw) of at least about 1 × 10⁻⁶. 6 Cross-linked povidone is insoluble in water. Based on the total weight of the sustained-release layer of the pharmaceutical composition, the preferred proportion of cross-linked povidone is 20%–31%, and more preferably 23%–28%. In addition to cross-linked povidone, the swelling agents used in this formulation include polyethylene oxide (PEO), also known as polyoxirane and polyoxyethylene. Polyoxyethylene is a homopolymer of ethylene oxide, and its molecular weight (Mw) is typically about 2 × 10⁻⁶. 6 Approximately. When used in combination with crospovidone, the preferred proportion of polyethylene oxide (PEO) is 16% to 25%, and more preferably 18% to 23%, based on the total weight of the sustained-release layer of the pharmaceutical composition.

[0027] The diluent in the sustained-release layer improves the flowability of the pharmaceutical composition and enhances the compressive strength or hardness of the tablets during component mixing and tableting. Lactose is preferably used as the diluent in the sustained-release layer. As a water-soluble diluent, lactose aids in tablet formation. Because it dissolves rapidly in water, it creates channels in the gel matrix, facilitating drug release. Based on the total weight of the sustained-release layer of the pharmaceutical composition, the preferred proportion of lactose is 14% to 26%, more preferably 16% to 23%.

[0028] The sustained-release layer also includes other excipients, such as lubricants. Lubricants facilitate component mixing and tableting. The lubricant used in this formulation is magnesium stearate. The preferred percentage of magnesium stearate is 0.3% to 2%.

[0029] The present invention relates to an immediate-release layer of melogabalin besylate gastric retention dual-release sustained-release tablets, comprising the active ingredient melogabalin besylate, a diluent, a binder, a disintegrant, a stabilizer, and other pharmaceutical excipients. Immediate-release layer scheme one: the diluent comprises mannitol and microcrystalline cellulose, the binder comprises hydroxypropyl cellulose, the disintegrant comprises calcium carboxymethyl cellulose, and the stabilizer comprises butylated hydroxytoluene and citric acid; immediate-release layer scheme two: the diluent comprises lactose and microcrystalline cellulose, the binder comprises hydroxypropyl cellulose, the disintegrant comprises low-substituted hydroxypropyl cellulose, and the stabilizer comprises ascorbyl palmitate and tartaric acid.

[0030] The specific excipients for immediate-release layer scheme one are as follows: The diluent for the immediate-release layer includes mannitol and microcrystalline cellulose. Mannitol, with a molecular weight of 182.17, is non-hygroscopic due to its chemical properties and high purity; it only becomes hygroscopic at temperatures between 20 and 40°C and relative humidity above 97%. Based on the total weight of the immediate-release layer of the pharmaceutical composition, the preferred proportion of mannitol is 50% to 77%, more preferably 58% to 70%. The diluent used in the immediate-release layer composition of this formulation also includes microcrystalline cellulose, which aids in tablet formation. Based on the total weight of the immediate-release layer of the pharmaceutical composition, the preferred proportion of microcrystalline cellulose is 0% to 26%, more preferably 6% to 17%.

[0031] The binder in the immediate-release layer can aggregate the material into particles, improving the compressibility strength of the pharmaceutical composition and increasing the hardness and smoothness of the tablets. The binder is selected from hydroxypropyl cellulose, and based on the total weight of the immediate-release layer of the pharmaceutical composition, the preferred proportion of hydroxypropyl cellulose is 0% to 12%, more preferably 2% to 9%.

[0032] The disintegrant of the immediate-release layer is calcium carboxymethyl cellulose, a calcium salt of polycellulose carboxymethyl ether. Upon contact with water, it expands to several times its original volume, thus making it an effective tablet disintegrant. Based on the total weight of the immediate-release layer of the pharmaceutical composition, the preferred proportion of calcium carboxymethyl cellulose is 4% to 15%, more preferably 7% to 13%.

[0033] Stabilizers in the immediate-release layer help improve the stability of the formulation. The stabilizers used in this formulation composition are butylated hydroxytoluene (BHT) and citric acid. Based on the total weight of the immediate-release layer of the pharmaceutical composition, BHT preferably comprises 0.2% to 1.0%, more preferably 0.4% to 0.8%. Citric acid preferably comprises 2% to 6%, more preferably 3% to 5%.

[0034] The immediate-release layer also includes other excipients, such as lubricants and flow aids. Lubricants facilitate component mixing and tableting. The lubricant used in this formulation is magnesium stearate; the preferred proportion of magnesium stearate is 0.3% to 2%. Flow aids help improve the flowability of the components; the preferred flow aid is silica, preferably in a proportion of 0.3% to 2%.

[0035] The specific excipients for immediate-release layer scheme two are as follows: The diluent for the immediate-release layer includes lactose and microcrystalline cellulose. Lactose, with a molecular weight of 360.31, is preferred due to its chemical properties. Based on the total weight of the immediate-release layer of the pharmaceutical composition, the preferred proportion of lactose is 50% to 73%, more preferably 58% to 65%. The diluent used in the immediate-release layer composition of this formulation also includes microcrystalline cellulose, which aids in tablet formation. Based on the total weight of the immediate-release layer of the pharmaceutical composition, the preferred proportion of microcrystalline cellulose is 0% to 22%, more preferably 7% to 19%.

[0036] The binder in the immediate-release layer can aggregate the material into particles, improving the compressibility of the pharmaceutical composition and increasing the hardness and smoothness of the tablets. The binder is selected from hydroxypropyl cellulose, and based on the total weight of the immediate-release layer of the pharmaceutical composition, the preferred proportion of hydroxypropyl cellulose is 2% to 14%, more preferably 4% to 12%.

[0037] The disintegrant of the immediate-release layer is low-substituted hydroxypropyl cellulose, which can be used in rapidly disintegrating tablets prepared by direct compression. Based on the total weight of the immediate-release layer of the pharmaceutical composition, the low-substituted hydroxypropyl cellulose preferably accounts for 1% to 19%, and more preferably 6% to 15%.

[0038] Stabilizers in the immediate-release layer help improve the stability of the formulation. The stabilizers used in this formulation composition are ascorbyl palmitate and tartaric acid. Based on the total weight of the immediate-release layer of the pharmaceutical composition, ascorbyl palmitate preferably comprises 0.1% to 4.0%, more preferably 0.3% to 1.5%. Tartaric acid preferably comprises 1% to 9%, more preferably 3% to 6%.

[0039] The immediate-release layer also includes other excipients, such as lubricants and flow aids. Lubricants facilitate component mixing and tableting. The lubricant used in this formulation is magnesium stearate; the preferred proportion of magnesium stearate is 0.3% to 2%. Flow aids help improve the flowability of the components; the preferred flow aid is silica, preferably in a proportion of 0.3% to 2%.

[0040] Film coating materials are commonly used to improve tablet appearance and stability. This sustained-release formulation uses a gastrointestinal film coating premix, such as brand 85F605015-CN; the coating weight gain is 1% to 5% of the tablet core weight.

[0041] Both immediate-release layer scheme 1 and immediate-release layer scheme 2 can achieve ideal in vivo effects in sample preparation. However, in terms of formulation stability, samples prepared using immediate-release layer 2 are superior.

[0042] In a preferred embodiment of the present invention, the gastric retention type dual-release sustained-release formulation is a fast-slow bilayer tablet, which has the advantages of simple process, clear release mechanism and excellent release effect compared with other dosage forms.

[0043] The melogabalin besylate gastric retention dual-release sustained-release tablet of the present invention has a weight ratio of melogabalin besylate in the sustained-release layer and the immediate-release layer of 7:2 to 9:2, preferably 4:1; and a weight ratio of the sustained-release layer and the immediate-release layer of 2:1 to 4:1, preferably 2.8:1 to 3.8:1.

[0044] The preparation method of the melogabalin besylate gastric retention dual-release sustained-release tablets of the present invention is as follows: Sustained-release layers of a pharmaceutical composition are prepared by mixing the drug with sustained-release materials, swelling materials, diluents, and lubricants; immediate-release layers are prepared by mixing the drug with diluents, binders, disintegrants, stabilizers, gliding agents, and lubricants; the sustained-release and immediate-release layers are then co-pressed into bilayer tablets and coated with a film. Alternatively, to improve product homogeneity, the components can be mixed in stages. For example, the drug can first be dry-mixed with one or more gel matrix materials, and then subsequently mixed with other excipients, such as diluents, lubricants, etc., in one or more mixing operations. If necessary, the particle size of one or more components can be controlled before mixing by sieving or pulverizing, or both. Compressed tablets can be coated using conventional coating machines.

[0045] The beneficial effects of the merogbalin besylate gastric retention dual-release sustained-release tablets of the present invention are as follows: This study provides a solution for developing a long-acting, sustained-release formulation of merogalaline besylate. Merogalaline besylate is primarily absorbed in the stomach and small intestine, and its rapid elimination and short half-life necessitate sustained release at the absorption site to maintain effective blood concentrations. Due to gastric emptying and intestinal peristalsis, conventional sustained-release formulations are quickly excreted from the small intestine, resulting in a narrow absorption window and hindering the achievement of a long-acting, sustained-release effect. For analgesics, developing a gastric retention, rapid-release formulation allows for rapid onset of action, while the sustained-release portion maintains efficacy over a long period, meeting the clinical need for both rapid and long-acting analgesics.

[0046] The immediate-release formulation of this invention, upon contact with water present in human gastric juice, exhibits rapid dissolution of the immediate-release layer. After dissolution, the sustained-release layer floats and swells, expanding to a maximum size of 13 mm or larger from its minimum cross-sectional area. Furthermore, the formulation retains good shape and rigidity upon contact with water, thus demonstrating superior gastric retention. The sustained-release tablet can remain in the stomach for several hours via size rejection, administration with meals, bedtime administration, or a combination of these methods, thereby maximizing the absorption of melogabalin besylate in the stomach and upper small intestine.

[0047] Because food slows gastric emptying, and the pylorus closes better at night, slowing gastrointestinal motility, the sustained-release formulation of this invention is preferably taken after dinner or before bedtime, which further prolongs the drug's residence and release time in the stomach. Merogabalin besylate sustained-release tablets taken once daily (16.5 mg pure sustained-release formulation and 16.5 mg rapid-release formulation) and ordinary tablets taken twice daily (three 2.5 mg tablets per dose, equivalent to a 7.5 mg dose, bid) both exhibit significant sustained-release characteristics, with peak concentrations (C0.05) reaching higher levels. max The concentration of the drug decreased significantly, and the area under the plasma concentration curve (AUC) decreased. 0-t The effects are comparable, with blood drug concentrations maintained for 24 hours. However, pure sustained-release formulations have a slower onset of action, with almost no blood drug concentration in the first 2 hours, while rapid-release formulations have a rapid onset of action. For analgesics, designing rapid-release and sustained-release formulations is more reasonable, as the rapid-release portion can take effect quickly, while the sustained-release portion can maintain efficacy for a long time, meeting the clinical need for rapid and long-lasting analgesics. Furthermore, it is expected that they can effectively replace twice-daily ordinary tablets in clinical practice.

[0048] Chinese patent application CN118806715A discloses a once-daily oral merogabarine besylate sustained-release formulation. This sustained-release formulation contains merogabarine besylate, a matrix material, a swelling agent and a buoyancy aid, a stabilizer, and other pharmaceutical excipients. The gastric retention mechanism of the formulation described in this patent is achieved by prolonged floating in the stomach, thus achieving gastric retention while simultaneously releasing the drug. We prepared a sample according to Example 10 of the patent and tested it according to the second method (paddle method) of the dissolution test in Part II of the 2025 edition of the Chinese Pharmacopoeia. The test medium was 0.06 mol / L hydrochloric acid solution, with a medium volume of 1000 ml, a rotation speed of 50 rpm, and a solvent temperature of 37℃±5℃. Unexpectedly, we found that the sample did not float from the time it was placed in the dissolution vessel until 24 hours later. The sample did not float at all throughout the entire process. This indicates that the product cannot achieve gastric retention by prolonged floating in the stomach, and it is not significantly different from ordinary sustained-release tablets; therefore, it is not a gastric retention-type sustained-release tablet.

[0049] The core of floating-swelling gastric retention tablets lies in the rapid formation of a continuous and uniform hydrated gel layer upon contact with water by the sustained-release layer, thereby supporting buoyancy and controlling the swelling rate. If an immediate-release layer is directly stacked on one side of the sustained-release layer, the rapid disintegration of the immediate-release layer will disrupt the continuity of the gel layer, leading to asymmetrical tablet swelling, a shift in the center of gravity of the float, and even problems such as settling and a significantly shortened gastric retention time. This application, through the screening of excipients for the immediate-release layer, the control of interlayer bonding force, and the optimization of the tableting process, achieves rapid disintegration and drug release of the immediate-release layer without interfering with the formation and swelling behavior of the sustained-release gel layer, ensuring that the gastric retention time is essentially equivalent to that of a single-layer sustained-release tablet. This application employs a quaternary synergistic system of polyvinyl acetate-povidone mixture (Kollidon SR), cross-linked povidone, polyoxyethylene, and carbomer in its sustained-release layer. Gastric retention is achieved through a quadruple mechanism of "gel matrix controlled release, swelling size retention, low-density floating, and high-viscosity mucus adhesion." This differs substantially from the "matrix material, swelling agent, buoyancy aid, and stabilizer" system of CN118806715A in terms of component selection and mechanism of action, making the sustained-release formulation itself non-obvious. This application not only achieves rapid analgesia with a more than 30% reduction in onset time, but also maintains a floating time and 12-hour swelling size essentially identical to single-layer gastric retention sustained-release tablets, indicating that gastric retention performance is not affected by the immediate-release layer. Furthermore, the peak-to-trough ratio of blood drug concentration is comparable to that of single-layer sustained-release tablets, eliminating the risk of burst release. This effect of "rapid onset and long-term gastric retention without interference" is something that those skilled in the art could not have predicted based on existing technology.

[0050] Sustained-release formulations with gastric retention require sufficient tablet size and swelling space to ensure that the swollen size exceeds the pyloric diameter. Core-shell structures have a small core portion, failing to achieve sufficient swelling and resulting in rapid expulsion from the stomach. Most of the drug is released after reaching the absorption window, directly leading to reduced bioavailability. In contrast, the sustained-release layer of a bilayer tablet is an independent, complete layer that can accommodate sufficient swelling and gelling materials, making it easier to achieve a stable floating-swelling gastric retention effect. This application's choice of a bilayer tablet structure is not a conventional dosage form replacement, but a targeted selection based on the technical goal of dual release with gastric retention. The compatibility between the two is not illustrated by existing technologies.

[0051] The sustained-release layer of this invention uses a quaternary synergistic system of polyvinyl acetate-povidone mixture, carbomer, cross-linked povidone, and polyoxyethylene, with strictly limited narrow weight ranges for each component, unlike simple replication of existing pregabalin floating formulations. The four excipients each play a specific role and work synergistically: Kollidon SR provides the basic hydrophobic sustained-release framework; carbomer enhances the viscosity of the hydration gel, delaying drug release in the mid-to-late stages; cross-linked povidone rapidly absorbs water to achieve initial swelling; and PEO maintains tablet size for a long time, preventing excessive shrinkage and pyloric emptying after 8 hours. The ratio of the four excipients has undergone multi-gradient screening; deviations from the range specified in this application result in significant deterioration in at least one of the following: floating time, dissolution stability, and impurity control. This achieves a triple unexpected technical effect—long-lasting floating, low impurities, and bilayer compatibility—that cannot be achieved in existing pregabalin monolayer formulations. If the specific proportion of polyvinyl acetate-povidone composite framework of this invention is removed, the tablet hydration gel strength is insufficient, and the long-lasting floating time is significantly shortened, failing to meet the requirement of 24-hour continuous drug release. Without the addition of a limited amount of polyoxyethylene, the tablets shrink rapidly in size after 8 hours of hydration, becoming smaller than the diameter of the human pylorus, significantly reducing their gastric retention effect. Using conventional hydroxypropyl methylcellulose instead of the quaternary synergistic system of this invention not only results in a loss of flotation performance but also a significant increase in impurity content over long-term storage. The original formulation commonly uses a rapid-release combination of mannitol, calcium carboxymethyl cellulose, and butylated hydroxytoluene. Compatibility testing of raw materials and excipients showed that the increase in lactam impurities under high temperature and humidity was far greater than that of the lactose and low-substituted hydroxypropyl cellulose system in this application. Directly copying the pregabalin sustained-release formulation for melogabalin besylate, even with changes in the diluent having limited impact on dissolution and flotation, resulted in long-term stability indicators inferior to the sustained-release layer formulation of this invention. Attached Figure Description

[0052] Figure 1 Example 2: Average drug duration curves of subjects in Comparative Example 1 (T1, T2) and the original merogabarine besylate tablets (R, 2.5mg specification).

[0053] Figure 2 Example 11 (T, 16.5mg strength) and the original merogabarine besylate tablets (R, 2.5mg strength) mean drug duration curves of subjects. Detailed Implementation

[0054] The present invention will be further described in detail through the following embodiments and experimental examples. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0055] Dissolution determination of pharmaceuticals Dissolution was determined using Method II (paddle method) of General Chapter 0931 in the Chinese Pharmacopoeia (ChP2020). Dissolution conditions: 1000 ml of 0.06 mol / L hydrochloric acid solution was used as the dissolution medium, and the rotation speed was 50 rpm. The procedure was followed, and 10 ml of solution was taken at 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours, and dissolution medium of the same temperature and volume was added immediately.

[0056] Test solution: Take the dissolution at 1, 2, 4, 6, 8, 12, 16, 20 and 24 hours respectively, filter, and collect the filtrate.

[0057] Reference solution: Take an appropriate amount of melogabalin besylate reference standard and dilute it quantitatively with a dissolution medium to prepare a reference solution containing approximately 15 μg of reference standard per 1 ml.

[0058] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; methanol-0.02 mol / L dipotassium hydrogen phosphate solution (pH 6.0) (15:85) was used as the mobile phase; the detection wavelength was 200 nm; the flow rate was 1.0 mL per minute; the column temperature was 30 °C; and the injection volume was 20 μL.

[0059] Assay: Accurately measure the test solution and reference solution and inject them separately into the liquid chromatograph. Calculate the dissolution amount of each tablet at different times using the peak area according to the external standard method.

[0060] Drug flotation property determination The buoyancy performance was determined using Method II (paddle method) of General Chapter 0931 in the Chinese Pharmacopoeia (ChP2020) at 50 revolutions in a 0.06 mol / L hydrochloric acid solution. The samples were immersed in the dissolution medium, and their initial floating time and duration of floating were observed over a period of 24 hours.

[0061] Swelling property determination of pharmaceuticals The swelling characteristics were determined using Method II (paddle method) of General Chapter 0931 in the Chinese Pharmacopoeia (ChP2020) at 50 revolutions per minute in a 0.06 mol / L hydrochloric acid solution. Samples were immersed in the dissolution medium and periodically removed. The length, width, and height were measured using calipers and recorded. Sampling points were set at 0, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours.

[0062] The methods for determining related substances are as follows: Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0512).

[0063] Solvent 1: Methanol Solvent 2 Water For the test solution, accurately weigh 10 tablets of this product, grind them into a fine powder, and accurately weigh an appropriate amount of the powder (approximately equivalent to 10 mg of meregabrine). Place the powder in a stoppered conical flask, accurately add 30 ml of methanol, and manually shake to disperse the powder. Place the flask on a shaker at 200 rpm for 15 minutes. Transfer the solution to a stoppered centrifuge tube and centrifuge at 10,000 rpm for 5 minutes. Accurately measure 3 ml of the supernatant and transfer it to a 10 ml volumetric flask. Dilute with water to the mark, shake well, filter, and use the filtrate as the test solution (equivalent to 0.1 mg / ml of meregabrine).

[0064] Accurately measure 1 ml of the test solution into a 100 ml volumetric flask, dilute with water to the mark, and shake well.

[0065] Chromatographic conditions: An octadecylsilane-bonded silica gel column was used as the packing material; methanol was used as mobile phase A, and 0.05 mol / L dipotassium hydrogen phosphate solution (adjusted to pH 6.0 with phosphoric acid) was used as mobile phase B, with gradient elution performed according to the program in the table below; the flow rate was 1.0 mL / min; the detection wavelength was 210 nm; the column temperature was 25 °C; and the injection volume was 50 μL. The gradient was as follows: The assay involves precisely measuring the test solution and the control solution, injecting them into the liquid chromatograph, and recording the chromatograms.

[0066] Examples 1, 2, 3, and 4 Batch size: 400 pieces The prescription is shown in Table 1 below: Table 1. Prescriptions for Examples 1, 2, 3, and 4 (16.5 mg strength) Note [1] The active ingredient of this product is melogabalin besylate. The specification is calculated in melogabalin. Conversion factor: M(C 12 H 19 NO2·C6H6O3S) / M (C 12 H 19 NO2)=1.756, and the active ingredient is added at 100%.

[0067] The preparation process is as follows: (1) Mix the prescribed amounts of cross-linked povidone, carbomer, active pharmaceutical ingredient, polyvinyl acetate povidone mixture Kollidon SR, polyoxyethylene, and lactose in a wet granulator for 15 min; then add magnesium stearate and mix for 5 min to obtain sustained-release total mixed granules. (2) Mix the prescribed amount of mannitol, raw material, microcrystalline cellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose, dibutylhydroxytoluene, citric acid (passed through a 200-mesh sieve) and silica in a wet granulator for 15 minutes, then add magnesium stearate and mix for 5 minutes to obtain the total mixed granules of the immediate release layer. (3) Tableting: A seed-shaped die with a size of 22mm×10.8mm is used for tableting.

[0068] (4) Coating with colored film: The above-mentioned core was coated with Opadry 85F605015-CN, and the weight gain was about 3%.

[0069] The dissolution, flotation, and swelling characteristics of the melogabalin benzyl sulfonate dual-release sustained-release tablets in Examples 1, 2, 3, and 4 were determined according to the experimental methods described above.

[0070] The floating results of Examples 1, 2, 3, and 4 are summarized in Table 2 below: Table 2 Comparison of buoyancy performance in Examples 1-4 The swelling results of Examples 1, 2, 3, and 4 are summarized in Table 3 below: Table 3 Comparison of swelling results in Examples 1-4 The dissolution results of Examples 1, 2, 3, and 4 are summarized in Table 4 below. Table 4 Comparison of dissolution results in Examples 1-4 Examples 1-4 all exhibited rapid floating, with a floating time exceeding 18 hours. After 8 hours, both tablet length and thickness exceeded 13 mm, effectively prolonging the retention time in the stomach. Furthermore, all demonstrated excellent sustained-release characteristics. The effect of the amount of functional excipients on formulation performance was investigated, and the results showed that variations in the active ingredient and excipients within a certain range did not significantly affect the formulation characteristics.

[0071] Examples 5, 6, and 7 Batch size: 400 pieces The prescriptions are shown in Table 5: Table 5 shows the prescriptions for Examples 5, 6, and 7 (16.5 mg strength). Note [1] The active ingredient of this product is melogabalin besylate. The specification is calculated in melogabalin. Conversion factor: M(C 12 H 19 NO2·C6H6O3S) / M (C 12 H 19 NO2)=1.756, and the active ingredient is added at 100%.

[0072] Examples 2, 5, 6, 7 and the reference formulation were stored at 40°C / 75% RH for 6 months. The results of the detection of related substances are summarized in Table 6 below: Table 6. Results of related substances in Examples 2, 5, 6, 7 and the reference formulation. Examples 2 and 5-7 investigated the effect of different stabilizer dosages on stability. Samples from Examples 2 and 5-7 were placed at 40℃ / 75% RH for one month, and all showed good stability. Although related substances remained within limits after six months at 40℃ / 75% RH, a significant increase was still observed.

[0073] Based on the significant increase in related substances observed in samples from Examples 2 and 5-7 under conditions of 40°C / 75% RH, the stability of the sustained-release and immediate-release layers was investigated separately to determine which layer had poorer stability. Examples 8 and 9 were then prepared.

[0074] Examples 8 and 9 Batch size: 400 pieces The prescriptions are shown in Table 7: Table 7. Prescriptions for Examples 8 and 9 (16.5 mg strength) Note [1] The active ingredient of this product is melogabalin besylate. The specification is calculated in melogabalin. Conversion factor: M(C 12 H 19 NO2·C6H6O3S) / M (C 12 H 19 NO2)=1.756, and the active ingredient is added at 100%.

[0075] Examples 8 and 9, along with the reference formulation, were stored at 40°C / 75% RH for 3 months. The results of the detection of related substances are summarized in Table 8 below: Table 8. Results of related substances in Examples 8 and 9 and the reference formulation. Examples 8 and 9 involved preparing sustained-release and immediate-release layers separately and storing them at 40°C / 75% RH for one month. It was clearly found that the related substances in the immediate-release layer were inferior. Therefore, a compatibility study of the raw materials and excipients was conducted.

[0076] Table 9 Results of Raw Material Compatibility Study The table above is from the specification of the original patent CN104334169B.

[0077] Overall results on the compatibility of raw materials and excipients revealed that only antioxidants protected the active pharmaceutical ingredient (API), while the addition of other excipients led to a decrease in API stability. In the disintegrant assay, low-substituted hydroxypropyl cellulose showed better compatibility with the API than calcium carboxymethyl cellulose in the original formulation. In the diluent assay, lactose produced lower levels of milobalinolactam impurities than mannitol in the original formulation. In the antioxidant assay, both ascorbate palmitate and butylated hydroxytoluene (BHT) provided good protection for the API, with ascorbate palmitate showing superior protection. The optimal results were obtained using the following ingredients in the simulated tablet core formulation: API, 100-mesh lactose, KG802 microcrystalline cellulose, SH-LH11 low-substituted hydroxypropyl cellulose, ascorbate palmitate, tartaric acid, silica, and magnesium stearate. Furthermore, the only difference between simulated tablet 2 and simulated tablet 1 is that mannitol is replaced with lactose. The results of simulated tablet 2 are far superior to those of simulated tablet 1, indicating that the compatibility of lactose with the active pharmaceutical ingredient is far better than that of mannitol.

[0078] In the raw material compatibility test, the excipients that were omitted in the original patent were selected, but unexpected results were obtained, which were even far better than the excipients selected in the original patent.

[0079] Examples 10, 11, 12, and 13 Batch size: 400 pieces The prescriptions are shown in Table 10: Table 10. Prescriptions for Examples 10, 11, 12, and 13 (16.5 mg strength) Note [1] The active ingredient of this product is melogabalin besylate. The specification is calculated in melogabalin. Conversion factor: M(C 12 H 19 NO2·C6H6O3S) / M (C 12 H 19 NO2)=1.756, and the active ingredient is added at 100%.

[0080] The preparation process is as follows: (1) Mix the prescribed amounts of cross-linked povidone, carbomer, active pharmaceutical ingredient, polyvinyl acetate povidone mixture Kollidon SR, polyoxyethylene, and lactose in a wet granulator for 15 min; then add magnesium stearate and mix for 5 min to obtain sustained-release total mixed granules. (2) Mix the prescribed amount of lactose, active pharmaceutical ingredient, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, ascorbate palmitate, tartaric acid (passed through a 200-mesh sieve) and silica in a wet granulator for 15 minutes, then add magnesium stearate and mix for 5 minutes to obtain the total mixed granules of the immediate release layer. (3) Tableting: A seed-shaped die with a size of 22mm×10.8mm is used for tableting.

[0081] (4) Coating with colored film: The above-mentioned core was coated with Opadry 85F605015-CN, and the weight gain was about 3%.

[0082] The dissolution, flotation, and swelling characteristics of Merogabalin benzyl sulfonate dual-release sustained-release tablets in Examples 10, 11, 12, and 13 were determined according to the experimental methods described above.

[0083] The floating results of Examples 10, 11, 12, and 13 are summarized in Table 11 below: Table 11 Comparison of buoyancy performance of Examples 10-13 The swelling results of Examples 10, 11, 12, and 13 are summarized in Table 12 below: Table 12 Comparison of swelling results in Examples 10-13 The dissolution results of Examples 10, 11, 12, and 13 are summarized in Table 13 below: Table 13 Comparison of dissolution results in Examples 10-13 Examples 10-13 all exhibited rapid buoyancy, with a floating time of approximately 17 hours. After 8 hours, both the tablet length and thickness exceeded 13 mm, effectively prolonging the retention time in the stomach. Furthermore, all demonstrated excellent sustained-release characteristics.

[0084] Examples 10, 11, 12, 13 and the reference formulation were stored at 40°C / 75% RH for 6 months. The results of the detection of related substances are summarized in Table 14 below: Table 14 Results of related substances in Examples 10-13 and the reference formulation Although the related substances in the samples of Examples 10-12 increased to some extent after being placed at 40°C / RH75% for 6 months, they were still superior to the reference preparation.

[0085] Comparative Example 1: Pure sustained-release formulation The prescriptions are shown in Table 15 below: Table 15 Comparative Example 1 Prescription (16.5mg strength) The preparation process of the melogabalin besylate sustained-release formulation for Comparative Example 1 is as follows: (1) Mix the prescribed amounts of cross-linked povidone, carbomer, active pharmaceutical ingredient, polyvinyl acetate povidone mixture Kollidon SR, polyoxyethylene, and lactose in a wet granulator for 15 min; then add magnesium stearate and mix for 5 min to obtain sustained-release total mixed granules. (2) Tableting: A seed-shaped die with a size of 22mm×10.8mm is used for tableting.

[0086] (3) Coating with colored film: The above-mentioned core was coated with Opadry 85F605015-CN, and the weight gain was about 3%.

[0087] Pharmacokinetic Study 1 In vivo pharmacokinetic studies were conducted using Example 2 (test formulation T1), Comparative Example 1 (test formulation T2), and commercially available merogabarine besylate tablets (reference formulation R, specification: 2.5 mg, manufacturer: Daiichi Sankyo Co., Ltd., batch number: YAB2147). A single-center, open-label, randomized, three-period, three-sequence, crossover pharmacokinetic study was employed.

[0088] A total of 12 subjects (male and female) were randomly assigned to one of three groups (T1T2R, T2RT1, RT1T2) according to the randomization table. In Group 1 (T1T2R), when taking the test formulations (T1 and T2), subjects ate a standardized breakfast and lunch at 8:00 AM and 12:00 PM on Day 1, followed by a high-fat dinner at 5:30 PM, which was to be consumed within 30 minutes. At 6:00 PM that evening, the first subject took one tablet of either T1 or T2 (16.5 mg) with 240 mL of water. Subjects were prohibited from drinking water for 2 hours before and 2 hours after each cycle (except for the 240 mL of water required for medication and any beverages included in the high-fat dinner). The timing of meals on the day of each cycle was to remain consistent. Subjects were required to remain standing or sitting for 4 hours after medication administration and were not allowed to lie down.

[0089] When taking the reference formulation (R), subjects ate a standard breakfast and lunch at 8:00 AM and 12:00 PM on Day 1. At 6:00 PM on Day 1 and 6:00 AM on Day 2, the first subject took 2.5 mg of the reference formulation (R) orally (3 tablets twice) on an empty stomach, with 240 mL of water. Subjects were prohibited from drinking water for 2 hours before and 2 hours after each dose. Subjects ate a standard dinner at 9:00 PM on Day 1 and a standard breakfast at 8:00 AM on Day 2. After 7 days, a second cycle of treatment was initiated with crossover.

[0090] Group 2 (T2RT1): Subjects were given oral administration of test formulation (T2) 16.5 mg (1 tablet), reference formulation (R) 2.5 mg (3 tablets / time, 2 times) or test formulation (T1) 16.5 mg (1 tablet). The administration and meal times were the same as in the first cycle. After a 7-day washout period, the third cycle of the study was conducted.

[0091] Group 3 (RT1T2): Subjects orally received the reference formulation (R) 2.5 mg (3 tablets / dose, 2 times), the test formulation (T1) 16.5 mg (1 tablet), and the test formulation (T2) 16.5 mg (1 tablet). The dosing and meal times were the same as in the previous two cycles. The detailed crossover dosing regimen is shown in the table below: Note: T1 and T2 are single doses administered after a high-fat meal, and R is two doses administered on an empty stomach.

[0092] Biological sample collection and processing: Test formulations (T1 and T2): Venous blood was collected from subjects at 24 collection points during each cycle, at 0h (within 30 minutes before administration) and at 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 14h, 16h, 18h, 20h, 24h, and 36h after administration.

[0093] Reference formulation (R): Venous blood was collected from subjects at 23 collection points each cycle, at 0 h (within 1 h before) and at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 12.25 h, 12.5 h, 13 h, 13.5 h, 14 h, 14.5 h, 15 h, 16 h, 18 h, 20 h, and 24 h after the first dose.

[0094] Each time, approximately 3 mL of blood is collected into a pre-labeled vacuum blood collection tube containing K2EDTA anticoagulant. The tube is gently inverted to mix, and then temporarily placed in an ice bath. Within 1 hour of blood collection, the sample is placed in a pre-cooled centrifuge and centrifuged at 1700g for 10 minutes at 2–8°C (set to 4°C). After centrifugation, the plasma sample is divided into two portions under ice bath conditions, with approximately 0.7 mL transferred to each tube (prioritizing the plasma volume in the test tube; if the remaining plasma volume is less than 0.7 mL, the remaining plasma is added to the backup tube as needed). Whole blood is centrifuged within 1 hour of collection, and plasma is stored in a low-temperature freezer (≤-20°C) within 1 hour after centrifugation and then transferred to an ultra-low temperature freezer (≤-60°C) within 24 hours, or directly stored in an ultra-low temperature freezer at ≤-60°C, for pharmacokinetic analysis.

[0095] Analytical methods for biological samples: The plasma concentration of melogabalin in human plasma was determined by HPLC-MS / MS.

[0096] In this study, subjects orally administered the self-prepared formulation (T1, T2) and the reference formulation (R) according to the dosing regimen. Results showed that, compared to the reference formulation, the self-prepared formulation had a significantly higher AUC per subject. 0-t The mean relative bioavailability was 102.3% (T1) and 91.4% (T2), respectively, and the C1 of T1 and T2 was... max All showed a significant decrease, with 24-hour blood drug concentrations similar to the reference formulation (R), i.e., the original immediate-release tablet, maintaining effective blood drug concentrations for a prolonged period. Human trial data indicate that pure sustained-release formulations have a slower onset of action, with almost no blood drug concentration in the first 2 hours, while the rapid-release and sustained-release dual-release formulation (T1) has a rapid onset of action. For analgesics, designing a rapid-release and sustained-release formulation is more reasonable, as the immediate-release portion can act quickly, while the sustained-release portion can maintain efficacy for a long time, meeting the clinical need for rapid-acting and long-lasting analgesics. Furthermore, it is expected to effectively replace twice-daily immediate-release tablets in clinical practice. The mean pharmacokinetic curves for the test formulation and the reference formulation are attached. Figure 1 .

[0097] The results of in vivo PK studies of the reference formulation R in Example 2 (test formulation T1) and Comparative Example 1 (test formulation T2) are summarized below: Blood concentration of the test formulation T1 (ng / mL) Blood concentration of the test formulation T2 (ng / mL) Blood concentration of reference formulation R (ng / mL) Pharmacokinetic parameters of the test formulation T1 Pharmacokinetic parameters of the test formulation T2 Pharmacokinetic parameters of reference formulation R Pharmacokinetic Studies 2 Example 11 (test formulation T) and commercially available merogabarine besylate tablets (reference formulation R, specification: 2.5 mg, manufacturer: Daiichi Sankyo Co., Ltd., batch number: YDA2030) were selected for an in vivo pharmacokinetic comparison study. A single-center, open-label, randomized, two-period, two-sequence, crossover pharmacokinetic study was conducted.

[0098] The study included 12 participants (male and female). All participants ate a standard breakfast and lunch on Day 1. Participants in the test formulation group (T) ate a high-fat, high-calorie dinner 30 minutes before administration, which was required to be 100% consumed and finished within 30 minutes. They were scheduled to take one tablet (16.5 mg) of the test formulation orally that evening, with 240 mL of water. Participants in the control formulation group (R) were scheduled to take three tablets (3 tablets of 2.5 mg each, totaling 7.5 mg) of the control formulation orally on an empty stomach on the evening of Day 1 and the morning of Day 2.

[0099] Biological sample collection and processing: Test formulation (T): Venous blood was collected from study participants at 24 collection points in each cycle, at 0 h (within 30 min before administration) and at 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 14 h, 16 h, 18 h, 20 h, 24 h, and 36 h after administration.

[0100] Control formulation (R): Venous blood was collected from study participants at 25 collection points at 0 h (within 1 h before dosing) and 0.25 h, 0.5 h, 0.75 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 6 h, 8 h, 12 h, 12.25 h, 12.5 h, 12.75 h, 13 h, 13.5 h, 14 h, 14.5 h, 15 h, 16 h, 18 h, 20 h, and 24 h after each cycle.

[0101] Each time, approximately 3 mL of blood is collected into a pre-labeled vacuum blood collection tube containing K2EDTA anticoagulant. The tube is gently inverted to mix, and then temporarily placed in an ice bath. Within 1 hour of blood collection, the sample is placed in a pre-cooled centrifuge and centrifuged at 1700g for 10 minutes at 2–8°C (set to 4°C). After centrifugation, the plasma sample is divided into two portions under ice bath conditions, with approximately 0.7 mL transferred to each tube (prioritizing the plasma volume in the test tube; if the remaining plasma volume is less than 0.7 mL, the remaining plasma is added to the backup tube as needed). Whole blood is centrifuged within 1 hour of collection, and plasma is stored in a low-temperature freezer (≤-20°C) within 1 hour after centrifugation and then transferred to an ultra-low temperature freezer (≤-60°C) within 24 hours, or directly stored in an ultra-low temperature freezer at ≤-60°C, for pharmacokinetic analysis.

[0102] Analytical methods for biological samples: The plasma concentration of melogabalin in human plasma was determined by HPLC-MS / MS.

[0103] In this study, subjects orally administered the test formulation (T) and the reference formulation (R) according to the dosing regimen. Results showed that the AUC of the test formulation was equivalent to that of the reference formulation. The mean pharmacokinetic curves for the test and reference formulations are attached. Figure 2 .

[0104] The results of the in vivo PK study of Example 11 (test formulation T) and reference formulation (R) are summarized below: Blood concentration of test formulation T (ng / mL) Blood concentration of reference formulation R (ng / mL) Based on the above pharmacokinetic study results, samples prepared using either immediate-release layer scheme one or immediate-release layer scheme two can achieve the expected in vivo effects.

[0105] Examples 14, 15, and 16 (Investigation of the Dosage of Active Substances) Batch size: 400 pieces The prescriptions are shown in Table 16 below: Table 16 Prescriptions for Examples 14, 15, and 16 Note: The active ingredient in this product is meregabalin besylate. The specification is calculated in meregabalin. Conversion factor: M(C) 12 H 19 NO2·C6H6O3S) / M (C 12 H 19 NO2) = 1.756, and the active ingredient was added at 100%. Example 14 had a specification of 5.5 mg; Example 15 had a specification of 11 mg; Example 16 had a specification of 33 mg.

[0106] Preparation process: Same as Examples 1-4.

[0107] The comparison of buoyancy performance is shown in Table 17 below: Table 17 Comparison of buoyancy performance in Examples 2, 14, and 16 The swelling results of Examples 2, 14, and 16 are summarized in Table 18 below: Table 18 Comparison of swelling results in Examples 2, 14, and 16 The dissolution results of Examples 2, 14, 15, and 16 are summarized in Table 19 below: Table 19 Comparison of dissolution results in Examples 2, 14, 15, and 16 The effect of the dosage of active ingredient on the performance of the formulation was investigated. The results showed that changes in the dosage of active ingredient within a certain range did not have a significant impact on the characteristics of the formulation.

[0108] Comparative Example 2: Merogabalin besylate sustained-release formulation (Patent CN 118806715 A Example 10).

[0109] The prescription composition is shown in Table 20 below: Table 20 Comparative Example 2 Prescription Preparation process: The active pharmaceutical ingredient and excipients are mixed using a mixing device. A lubricant is then added and mixed thoroughly. The resulting mixture is compressed into tablets (punch type: φ9mm round shallow concave), and the uncoated tablets are coated using a coating machine to obtain film-coated tablets.

[0110] The buoyancy performance of Examples 1-4, Example 14, Example 16 and Comparative Example 2 were compared using the methods described above, as shown in Table 21 below: Table 21 Floating results of Examples 1-4, Example 14, Example 16 and Comparative Example 2 Comparing the flotation results of Comparative Example 2 with those of Examples 1-4, 14, and 16, the sample in Comparative Example 2 did not float from the time it was placed in the dissolution vessel until 24 hours later. The sample did not float at all, and therefore could not achieve gastric retention through prolonged floating in the stomach. It was not significantly different from ordinary sustained-release tablets and was not a gastric retention type sustained-release tablet. Therefore, the embodiments of the present invention have better gastric retention characteristics.

Claims

1. A merogbalin besylate gastric retention dual-release sustained-release tablet, characterized in that, This gastric retention dual-release sustained-release tablet is a rapid-release formulation, consisting of a rapid-release layer and a sustained-release layer compressed together; the weight ratio of melogabalin besylate in the sustained-release layer and the rapid-release layer is 7:2 to 9:2, preferably 4:

1.

2. The merogbalin besylate gastric retention dual-release sustained-release tablet as described in claim 1, characterized in that, The sustained-release layer contains melogabalin benzyl sulfonate as the active ingredient, a sustained-release matrix material, a swelling agent, a diluent, and other pharmaceutical excipients; wherein the sustained-release matrix material includes a mixture of polyvinyl acetate and povidone and carbomer, the swelling agent includes cross-linked povidone and polyoxyethylene, and the diluent contains lactose.

3. The merogbaline besylate gastric retention dual-release sustained-release tablet as described in claim 2, characterized in that, Based on the total weight of the sustained-release layer, the proportion of melogabalin benzyl sulfonate in the sustained-release layer is 0.5% to 5%; the preferred proportion of the sustained-release matrix material, a mixture of polyvinyl acetate and polyvinyl chloride, is 21% to 31%, more preferably 23% to 29%; the preferred proportion of the sustained-release matrix material, carbomer, is 2% to 9%, more preferably 4% to 7%; the preferred proportion of the swelling agent, crosslinked polyvinyl chloride XL, is 20% to 31%, more preferably 23% to 28%; the preferred proportion of the swelling agent, polyethylene oxide (PEO), is 16% to 25%, more preferably 18% to 23%; the preferred proportion of the diluent, lactose, is 14% to 26%, more preferably 16% to 23%; preferably, the other pharmaceutical excipients include a lubricant, and the preferred proportion of the lubricant, magnesium stearate, is 0.3% to 2%.

4. The merogbalin besylate gastric retention dual-release sustained-release tablet as described in claim 1, characterized in that, The immediate-release layer contains melogabalin besylate as the active ingredient, a diluent, a binder, a disintegrant, a stabilizer, and other pharmaceutical excipients.

5. The merogbaline besylate gastric retention dual-release sustained-release tablet as described in claim 4, characterized in that, The immediate-release layer diluent contains mannitol and microcrystalline cellulose, the binder includes hydroxypropyl cellulose, the disintegrant includes calcium carboxymethyl cellulose, and the stabilizer includes butylated hydroxytoluene and citric acid.

6. The merogbaline besylate gastric retention dual-release sustained-release tablet as described in claim 4, characterized in that, The immediate-release layer diluent contains lactose and microcrystalline cellulose, the binder includes hydroxypropyl cellulose, the disintegrant includes low-substituted hydroxypropyl cellulose, and the stabilizers include ascorbyl palmitate and tartaric acid.

7. The merogbalin besylate gastric retention dual-release sustained-release tablet as described in claim 5, characterized in that, Based on the weight of the immediate-release layer, the proportion of melogabalin benzenesulfonic acid is 0.2% to 3.5%; the preferred proportion of mannitol as a diluent in the immediate-release layer is 50% to 77%, more preferably 58% to 70%; the preferred proportion of microcrystalline cellulose as a diluent is 0% to 26%, more preferably 6% to 17%; the preferred proportion of hydroxypropyl cellulose as a binder is 0% to 12%, more preferably 2% to 9%; the preferred proportion of calcium carboxymethyl cellulose as a disintegrant is 4% to 15%, more preferably 7% to 13%; the preferred proportion of butylated hydroxytoluene as a stabilizer is 0.2% to 1.0%, more preferably 0.4% to 0.8%; and the preferred proportion of citric acid as a stabilizer is 2% to 6%, more preferably 3% to 5%.

8. The merogbalin besylate gastric retention dual-release sustained-release tablet as described in claim 6, characterized in that, Based on the weight of the immediate-release layer, the proportion of melogabalin benzyl sulfonate in the immediate-release layer is 0.2% to 3.5%; the preferred proportion of lactose as a diluent in the immediate-release layer is 50% to 73%, more preferably 58% to 65%; the preferred proportion of microcrystalline cellulose as a diluent is 0% to 22%, more preferably 7% to 19%; the preferred proportion of hydroxypropyl cellulose as a binder is 2% to 14%, more preferably 4% to 12%; the preferred proportion of low-substituted hydroxypropyl cellulose as a disintegrant is 1% to 19%, more preferably 6% to 15%; the preferred proportion of ascorbyl palmitate as a stabilizer is 0.1% to 4.0%, more preferably 0.3% to 1.5%; and the preferred proportion of tartaric acid as a stabilizer is 1% to 9%, more preferably 3% to 6%.

9. The merogbaline besylate gastric retention dual-release sustained-release tablet as described in claim 7 or 8, characterized in that, The other pharmaceutical excipients include lubricants and flow aids. The preferred proportion of magnesium stearate as a lubricant is 0.3% to 2%, and the preferred proportion of silica as a flow aid is 0.3% to 2%.

10. The merogbaline besylate gastric retention dual-release sustained-release tablet as described in claim 1, characterized in that, The weight ratio of the sustained-release layer to the immediate-release layer is 2:1 to 3:1, preferably 2.8:1 to 3.8:

1.

11. The merogbalin besylate gastric retention dual-release sustained-release tablet as described in claim 1, characterized in that, In addition to the double-layer tablets, a film coating material is also included, wherein the preferred proportion of the film coating material is 1% to 5% based on the total weight of the formulation.

12. A method for preparing merogbaline besylate gastric retention dual-release sustained-release tablets as described in any one of claims 1 to 11, characterized in that, Includes the following steps: (1) Mix melogabalin benzenesulfonic acid, polyvinyl acetate polyvinyl ketone mixture, cross-linked polyvinyl ketone, carbomer, polyoxyethylene and lactose thoroughly; (2) Add lubricant and mix to obtain the total powder of the slow-release layer; (3) Immediate-release layer scheme 1: Merogabalin benzenesulfonic acid, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, calcium carboxymethyl cellulose, butylated hydroxytoluene, citric acid, and silica are thoroughly mixed evenly; Immediate-release layer scheme 2: Merogabalin benzenesulfonic acid, lactose, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, ascorbate palmitate, tartaric acid, and silica are thoroughly mixed evenly; (4) Add lubricant, mix, and obtain the total powder of the quick-release layer; (5) Compress the above-mentioned sustained-release layer and immediate-release layer into tablets; (6) Coat the above core with a thin film to obtain the final product.

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