Lacosamide pharmaceutical composition, its manufacturing method and application

Abstract

The present invention provides a lacosamide pharmaceutical composition, its preparation method and application. The dissolution of the lacosamide pharmaceutical composition of the present invention simultaneously satisfies the following requirements: dissolution of 40% or less of the lacosamide or its pharma- ceutical acceptable salt within 1 hour, dissolution of 20% to 70% within 6 hours, and dissolution of 65% or more within 24 hours. The lacosamide pharmaceutical composition prepared by the present invention has good sustained release properties, the tablet size can expand rapidly during the in vitro dissolution process, has good rigidity and elasticity after expansion, has a significant gastric retention effect, and the cumulative release rate within 24 hours can reach 80% or more. The preparation process of the present invention significantly improves the problems such as poor fluidity and low bulk density of the drug substance, difficulty in filling during the tableting process, and unstable tablet weight, and the process is stable and the process parameters can be adjusted and controlled, which is favorable for the expansion of production of the product and has good market prospects.

Description

[Technical Field]

[0001] This application claims priority to a prior Chinese patent application filed with the China National Intellectual Property Administration on March 17, 2021, application number 202110286177.2, titled "Lacosamide Pharmaceutical Composition, Method for Producing the Same and Applications." The aforementioned prior application is incorporated herein by reference in its entirety.

[0002] (Technical field) This invention relates to a lacosamide pharmaceutical composition, its manufacturing method, and its applications, and belongs to the field of drug formulation. [Background technology]

[0003] Lacosamide has the chemical name (2R)-2-acetamido-N-benzyl-3- Methoxypropanamide, molecular formula C 13 H 18 Lacosamide is N2O3 with a molecular weight of 250.29400. It is suitable for the treatment of focal epilepsy in patients aged 4 years and older and is also useful as an adjunct to primary tonic-clonic epilepsy in patients aged 4 years and older. Lacosamide is a BCS class I drug, is relatively water-soluble, readily soluble in methanol or acetone, and slightly soluble in acetonitrile or ethanol.

[0004] Lacosamide is a novel N-methyl-D-aspartate (NMDA) receptor glycine site antagonist and belongs to the category of novel functional amino acids. It is currently generally recognized that lacosamide can selectively enhance the slow inactivation of voltage-gated sodium channels (VGSCs) but does not affect the rapid inactivation of sodium channels. At the same time, lacosamide may exert anticonvulsant effects via a pathway of cross-linking with Collapsin Response Mediator Protein 2 (CRMP-2), although the mechanism of action is not fully understood.

[0005] Lacosamide generally exhibits excellent anticonvulsant activity and tolerance, but its dosage is somewhat limited due to adverse reactions. When treating patients with severe epilepsy or those who have developed clear drug resistance, a significant increase in lacosamide dosage can lead to relatively serious adverse reactions. Furthermore, in patients with epilepsy or neuralgia, multiple daily doses are inconvenient for their daily lives and can easily lead to unstable blood drug concentrations, inducing adverse reactions. In addition, the lacosamide active pharmaceutical ingredient has extremely poor fluidity and low bulk density, and when compressed into tablets as a powder, it results in poor uniformity, excessive depth of compression, and difficulty in material insertion.

[0006] Therefore, there is a strong need for the development of a lacosamide drug formulation that can be administered infrequently, improve medication compliance in epilepsy patients, has low toxic side effects, high therapeutic efficacy, and good stability of blood drug concentration. [Overview of the project]

[0007] To improve the above-mentioned problems, the present invention provides a lacosamide pharmaceutical composition that is a 24-hour sustained-release drug. Preferably, the elution of the lacosamide pharmaceutical composition is performed under the conditions of the USP method (elution apparatus method 2: 900 mL, 0.1 N hydrochloric acid, 50 rpm and / or elution apparatus method 2: 900 mL, pH 4.5 acetate buffer, 50 rpm). A) Elute 40% or less (preferably 35% or less, more preferably 30% or less) of the drug active ingredient within 1 hour. B) Elute 20% to 70% (including two point values, 20% and 70%, preferably 25% to 60%, more preferably 30% to 55%) of the drug active ingredient within 6 hours. C) It simultaneously satisfies three characteristics: 65% or more (preferably 70% or more, more preferably 80% or more) of the drug active ingredient is eluted within 24 hours, Of these, the drug-active ingredient is selected from lacosamide, a pharmaceutically acceptable complex of lacosamide, a pharmaceutically acceptable salt of lacosamide, a pharmaceutically acceptable solvate of lacosamide, and a pharmaceutically acceptable hydrate of lacosamide, and is preferably lacosamide or a pharmaceutically acceptable salt of lacosamide.

[0008] According to embodiments of the present invention, the drug active ingredient of the lacosamide pharmaceutical composition elutes by 30% or less within 1 hour, by 30% to 55% within 6 hours, and by 80% or more within 24 hours.

[0009] The present invention further provides a lacosamide pharmaceutical composition comprising a drug-active ingredient, a skeletal material, and a swelling material. Of these, the above-mentioned drug active ingredient is selected from lacosamide, a pharmaceutically acceptable complex of lacosamide, a pharmaceutically acceptable salt of lacosamide, a pharmaceutically acceptable solvate of lacosamide, and a pharmaceutically acceptable hydrate of lacosamide. The above-mentioned skeletal material is one or more selected from polyvinyl acetate-povidone mixture, sodium alginate, and hydroxypropyl methylcellulose. The above-mentioned swelling material is one or more selected from polyoxyethylene, carbomer, and sodium alginate.

[0010] According to embodiments of the present invention, the lacosamide pharmaceutical composition is a lacosamide gastric retention composition, and preferably a lacosamide gastric retention tablet.

[0011] According to embodiments of the present invention, in the lacosamide pharmaceutical composition described above, the drug active ingredient is preferably lacosamide.

[0012] According to embodiments of the present invention, the particle size of the drug-active component is 30 mesh or less.

[0013] According to an embodiment of the present invention, the weight percentage of the above drug active ingredient is preferably 1.0% to 50.0%, more preferably 5.0% to 40.0%, for example 20.00% or 18.18%, and among them, the above weight percentage refers to the percentage of the weight of the drug active ingredient relative to the total weight of the lacosamide pharmaceutical composition.

[0014] According to an embodiment of the present invention, in the above lacosamide pharmaceutical composition, the weight percentage of the above swelling material is preferably 1.0% to 60.0%, for example 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0% or 60.0%, and among them, the above weight percentage refers to the percentage of the weight of the swelling material relative to the total weight of the lacosamide pharmaceutical composition.

[0015] According to an embodiment of the present invention, when the above swelling material is polyoxyethylene, the weight percentage of the above polyoxyethylene is preferably 5.0% to 60.%, for example 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0% or 60.0%, more preferably 10.0% to 40.0%, for example 16.73%, and among them, the above weight percentage refers to the percentage of the weight of polyoxyethylene relative to the total weight of the lacosamide pharmaceutical composition.

[0016] According to an embodiment of the present invention, when the above swelling material is carbomer, the weight percentage of the above carbomer is preferably 1.0% to 15.0%, more preferably 1.5% to 10%, for example 3.00% or 6.00%, and among them, the above weight percentage refers to the percentage of the weight of carbomer relative to the total weight of the lacosamide pharmaceutical composition.

[0017] According to embodiments of the present invention, when the swelling material is sodium alginate, the weight percentage of the sodium alginate is preferably 1.0% to 50.0%, for example 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, or 50.0%, and more preferably 1.0% to 40.0%, for example 35.09%, 25.45%, or 5.00%, where the weight percentage refers to the percentage of the weight of sodium alginate relative to the total weight of the lacosamide pharmaceutical composition.

[0018] According to embodiments of the present invention, in the lacosamide pharmaceutical composition, the polyvinyl acetate-povidone mixture may be a mixture containing polyvinyl acetate (PVAc) and polyvinylpyrrolidone (PVP), for example, a mixture in which the weight ratio of PVAc to PVP is 80:19, preferably manufactured by BASF and traded as KOLLIDON. @ It is an SR (abbreviated as "KSR") mixture containing 80 / 19 (w / w) PVAc and PVP.

[0019] According to embodiments of the present invention, the weight percentage of the skeletal material is preferably 1.0% to 60.0%, for example, 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, 55.0%, or 60.0%, where the weight percentage refers to the percentage of the weight of the skeletal material relative to the total weight of the lacosamide pharmaceutical composition.

[0020] According to embodiments of the present invention, when the skeletal material is KSR, the weight percentage of KSR is preferably 5.0% to 60.0%, more preferably 20.0% to 50.0%, for example 24.68% or 18.36%, where the weight percentage refers to the percentage of the weight of KSR relative to the total weight of the lacosamide pharmaceutical composition.

[0021] According to embodiments of the present invention, when the skeletal material is hydroxypropyl methylcellulose, the weight percentage of hydroxypropyl methylcellulose is preferably 1.0% to 30.0%, more preferably 2.0% to 20.0%, for example 17.27%, 8.00%, 16.73%, or 9.09%, where the weight percentage refers to the percentage of the weight of hydroxypropyl methylcellulose relative to the total weight of the lacosamide pharmaceutical composition.

[0022] According to embodiments of the present invention, when the skeletal material is sodium alginate, the weight percentage of sodium alginate is preferably 1.0% to 50.0%, more preferably 1.0% to 40.0%, for example 35.09%, 25.45%, or 5.00%, where the weight percentage refers to the percentage of the weight of sodium alginate relative to the total weight of the lacosamide pharmaceutical composition.

[0023] According to embodiments of the present invention, the above-mentioned skeletal material (e.g., sodium alginate) can be further used in combination with a skeletal strength modifier.

[0024] According to embodiments of the present invention, the above-mentioned skeletal strength modifier may be selected from water-soluble calcium salts, thereby generating a sodium alginate and insoluble calcium alginate gel skeleton.

[0025] According to embodiments of the present invention, the water-soluble calcium salt may be selected from calcium hydrogen phosphate and / or calcium hydrogen phosphate dihydrate, etc.

[0026] According to embodiments of the present invention, the weight percentage of the skeletal modifier is preferably 0% to 30.0%, for example 0%, 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, or 30.0%, and more preferably 0% to 15.0%, for example 11.73% or 10.91%, where the above weight percentage refers to the percentage of the weight of the skeletal strength modifier relative to the total weight of the lacosamide pharmaceutical composition.

[0027] According to embodiments of the present invention, the lacosamide pharmaceutical composition described in the present invention may further contain one or more selected from disintegrants, diluents, and lubricants.

[0028] According to embodiments of the present invention, the disintegrant may be one or more selected from, for example, cross-linked povidone, sodium carboxymethyl starch, cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, and low-substituted hydroxypropylcellulose.

[0029] According to embodiments of the present invention, the weight percentage of the disintegrant is preferably 0% to 30.0%, for example 0%, 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, and 30.0%, and more preferably 5% to 30.0%, for example 20.00%, 16.64%, 13.64%, or 16.36%, where the weight percentage refers to the percentage of the weight of the disintegrant relative to the total weight of the lacosamide pharmaceutical composition.

[0030] According to embodiments of the present invention, in the lacosamide pharmaceutical composition described above, the diluent is preferably one or more selected from dextrose, lactose monohydrate, anhydrous lactose, sucrose, mannitol, xylitol, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, cyclodextrin, and its derivatives.

[0031] According to embodiments of the present invention, the weight percentage of the diluent is preferably 0 to 40%, for example 0%, 1.0%, 5.0%, 10.0%, 15.0%, 20.0%, 25.0%, 30.0%, 30.5%, or 40.0%, for example 20.00% or 15.00%, where the weight percentage refers to the percentage of the weight of the diluent relative to the total weight of the lacosamide pharmaceutical composition.

[0032] According to embodiments of the present invention, in the lacosamide pharmaceutical composition described above, the lubricant refers to a substance that assists in processing steps such as mixing, granulation, and tableting of the components, and may be one or more selected from talc, stearic acid, metal stearate, stearate, colloidal silica, glycerol behenate, sodium lauryl sulfate, hydrogenated vegetable oil, mineral oil, poloxamer, polyethylene glycol, and sodium chloride.

[0033] According to embodiments of the present invention, the metal stearate salt may be magnesium stearate, and the stearate may be glycerol stearate.

[0034] According to embodiments of the present invention, the weight percentage of the lubricant is preferably 0 to 3.0%, for example 0%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, or 3.0%, and more preferably 0.5% to 2.0%, for example 1.10%, 1.20%, or 1.65%, where the weight percentage refers to the percentage of the total weight of the lubricant relative to the total weight of the lacosamide pharmaceutical composition.

[0035] According to embodiments of the present invention, the lacosamide pharmaceutical composition preferably comprises a drug active ingredient, a skeletal material, a skeletal strength modifier (optionally present), a swelling material, a disintegrant, and a lubricant, or consists of the above composition. Of these, the above-mentioned drug active ingredient is selected from lacosamide, a pharmaceutically acceptable complex of lacosamide, a pharmaceutically acceptable salt of lacosamide, a pharmaceutically acceptable solvate of lacosamide, and a pharmaceutically acceptable hydrate of lacosamide. The above-mentioned skeletal material is one or more selected from polyvinyl acetate-povidone mixture (such as KSR), sodium alginate, and hydroxypropyl methylcellulose. The above-mentioned swelling material is polyoxyethylene and / or carbomer and / or sodium alginate.

[0036] According to embodiments of the present invention, the lacosamide pharmaceutical composition is more preferably Composition 1 consists of lacosamide, sodium alginate, cross-linked povidone, anhydrous calcium hydrogen phosphate, magnesium stearate, carbomer, and hydroxypropyl methylcellulose. Composition 2 is lacosamide, polyvinyl acetate / povidone mixture, cross-linked povidone, magnesium stearate, sorbitol, carbomer, hydroxypropyl methylcellulose. Composition 3 consists of lacosamide, sodium alginate, cross-linked povidone, hydroxypropyl methylcellulose, colloidal silica, magnesium stearate, and anhydrous calcium hydrogen phosphate. Composition 4 consists of lacosamide, sodium alginate, cross-linked povidone, polyoxyethylene, colloidal silica, magnesium stearate, and anhydrous calcium hydrogen phosphate. Composition 5 consists of lacosamide, sodium alginate, cross-linked povidone, colloidal silica, magnesium stearate, hydroxypropyl methylcellulose, polyvinyl acetate / povidone mixture, and calcium hydrogen phosphate dihydrate. Composition 6 comprises lacosamide, polyvinyl acetate / povidone mixture, cross-linked povidone, magnesium stearate, sorbitol, sodium alginate, carbomer, and hydroxypropyl methylcellulose, or consists of these compositions, respectively.

[0037] According to exemplary embodiments of the present invention, the lacosamide pharmaceutical composition further comprises: Formulation 1 consists of 18.18% lacosamide, 35.09% sodium alginate, 13.64% cross-linked povidone (Kollidon CL, BASF), 11.73% anhydrous calcium hydrogen phosphate, 1.10% magnesium stearate, 3.00% carbomer (971 PNF, Lubrizol), and 17.27% hydroxypropyl methylcellulose (K 4M, Ashland). Formulation 2 consists of 20.00% lacosamide, 24.80% polyvinyl acetate / povidone mixture, 20.00% cross-linked povidone (Kollidon CL, BASF), 1.20% magnesium stearate, 20.00% sorbitol, 6.00% carbomer (971 PNF, Lubrizol), and 8.00% hydroxypropyl methylcellulose (K 4M, Ashland). Formulation 3 consists of 18.18% lacosamide, 35.09% sodium alginate, 16.64% cross-linked povidone (Kollidon CL, BASF), 16.73% hydroxypropyl methylcellulose (K 15M, Ashland), 0.55% colloidal silica, 1.10% magnesium stearate, and 11.73% anhydrous calcium hydrogen phosphate. Formulation 4 consists of 18.18% lacosamide, 35.09% sodium alginate, 16.64% cross-linked povidone (Kollidon CL, BASF), 16.73% polyoxyethylene (WSR COAGULANT, Dow DuPont), 0.55% colloidal silica, 1.10% magnesium stearate, and 11.73% anhydrous calcium hydrogen phosphate. Formulation 5 consists of 18.18% lacosamide, 25.45% sodium alginate, 16.36% cross-linked povidone (Kollidon CL, BASF), 0.55% colloidal silica, 1.10% magnesium stearate, 9.09% hydroxypropyl methylcellulose (K 15M, Ashland), 18.36% polyvinyl acetate / povidone mixture, and 10.91% calcium hydrogen phosphate dihydrate. One of the following formulations is preferred: Formulation 6, which consists of 20.00% lacosamide, 24.80% polyvinyl acetate / povidone mixture, 20.00% cross-linked povidone (Kollidon CL, BASF), 1.20% magnesium stearate, 15.00% sorbitol, 5.00% sodium alginate, 6.00% carbomer (971 PNF, Lubrizol), and 8.00% hydroxypropyl methylcellulose (K 4M, Ashland).

[0038] Preferably, the lacosamide pharmaceutical composition described above is a 24-hour sustained-release drug. Preferably, the lacosamide pharmaceutical composition is eluted under the conditions of the USP method (elution apparatus method 2: 900 mL, 0.1 N hydrochloric acid, 50 rpm and / or elution apparatus method 2: 900 mL, pH 4.5 acetate buffer, 50 rpm). A) Elute 40% or less (preferably 35% or less, more preferably 30% or less) of the above-mentioned drug active ingredient, such as lacosamide or a pharmaceutically acceptable salt thereof, within 1 hour. B) Elute 20% to 70% (including two point values, 20% and 70%, preferably 25% to 60%, more preferably 30% to 55%) of the above-mentioned pharmacoactive ingredient, such as lacosamide or a pharmaceutically acceptable salt thereof, within 6 hours. The following three characteristics are simultaneously met: C) Elution of 65% or more (preferably 70% or more, more preferably 80% or more) of the above-mentioned drug active ingredient, such as lacosamide or a pharmaceutically acceptable salt thereof, within 24 hours.

[0039] For example, the above lacosamide pharmaceutical composition dissolves at a rate of 30% or less within 1 hour, 30% to 55% within 6 hours, and 80% or more within 24 hours.

[0040] The present invention further provides a method for producing the above-mentioned lacosamide pharmaceutical composition, including a dry granulation process.

[0041] According to exemplary embodiments of the present invention, the dry granulation process described above is Step 1 involves sieving the above-mentioned drug-active ingredient (also called "lacosamide active ingredient") to remove clumps and obtain the sieved lacosamide active ingredient, Step 2 involves mixing the sieved lacosamide active pharmaceutical ingredient obtained in Step 1 with some skeletal materials and optionally present skeletal strength modifiers and disintegrants to obtain a premix. Step 3 involves drying and sizing the premix obtained in Step 2 using a granulator, then adding an internal lubricant (such as magnesium stearate) and mixing it, followed by dry granulation to obtain granules. Step 4 includes mixing the remaining skeletal material, swelling material, and filler with the granules produced in step 3, adding an external lubricant (such as magnesium stearate) and continuing to mix for a certain period of time, and then compressing to obtain the lacosamide pharmaceutical composition, for example, lacosamide gastric retention tablets.

[0042] Alternatively, according to an exemplary embodiment of the present invention, the dry granulation process described above is: Step 1 involves sieving the lacosamide active pharmaceutical ingredient to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient, Step 2 involves mixing the sieved lacosamide active pharmaceutical ingredient obtained in Step 1 with a skeletal material, a swelling material, a disintegrant, and a lubricant (such as colloidal silica) to obtain a premix. Step 3 involves drying and sizing the premix obtained in Step 2 using a granulator, then adding an internal lubricant (such as magnesium stearate) and mixing it, followed by dry granulation to obtain granules. The process includes step 4, in which a skeletal strength modifier is mixed with the granules produced in step 3, an external lubricant (such as magnesium stearate) is added and the mixture is continued for a certain period of time before the tablets are compressed to obtain the lacosamide pharmaceutical composition, for example, lacosamide gastric retention tablets.

[0043] Alternatively, according to an exemplary embodiment of the present invention, the dry granulation process described above is: Step 1 involves sieving the lacosamide active pharmaceutical ingredient to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient, Step 2 involves mixing the sieved lacosamide active ingredient obtained in Step 1 with a swelling material, a disintegrant, and a lubricant (such as colloidal silica) to obtain a premix. Step 3 involves drying and sizing the premix obtained in Step 2 using a granulator, then adding an internal lubricant (such as magnesium stearate) and mixing it, followed by dry granulation to obtain granules. The process includes step 4, in which a skeletal strength modifier and a skeletal material are mixed with granules produced in step 3, an external lubricant (such as magnesium stearate) is added and the mixture is continued for a certain period of time before the tablets are compressed to obtain the lacosamide pharmaceutical composition, for example, lacosamide gastric retention tablets.

[0044] Alternatively, according to an exemplary embodiment of the present invention, the dry granulation process described above is: Step 1 involves sieving the lacosamide active pharmaceutical ingredient to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient, Step 2 involves mixing the sieved lacosamide active ingredient obtained in Step 1 with a swelling material, a disintegrant, and a lubricant (such as colloidal silica) to obtain a premix. Step 3 involves drying and sizing the premix obtained in Step 2 using a granulator, continuing to mix it for a certain period of time, then adding an internal lubricant (such as magnesium stearate) and mixing it, followed by dry granulation to obtain granules. The process includes step 4, in which a skeletal strength modifier and a skeletal material are mixed with granules produced in step 3, an external lubricant (such as magnesium stearate) is added and the mixture is continued for a certain period of time before the tablets are compressed to obtain the lacosamide pharmaceutical composition, for example, lacosamide gastric retention tablets.

[0045] The present invention further provides applications of the lacosamide pharmaceutical composition in the manufacture of drugs, preferably drugs for treating and / or preventing acute and chronic pain.

[0046] According to embodiments of the present invention, the above-mentioned "acute and chronic pain" refers in particular to non-neuroinflammatory pain, including chronic inflammatory pain such as rheumatoid arthritis pain and / or secondary osteoarthritis pain.

[0047] According to embodiments of the present invention, the term "chronic pain" means that the pain persists for a certain period, for example, 3 to 6 months or more, but that characteristic symptoms of vegetative neurological dysfunction, such as fatigue, sleep disturbances, loss of appetite, loss of taste, weight loss, decreased libido, and / or constipation, are present before or after this period.

[0048] The present invention further provides a method for treating and / or preventing acute and chronic pain, the method comprising orally administering the lacosamide pharmaceutical composition or lacosamide intragastric tablets to a patient once daily.

[0049] The present invention further provides a lacosamide gastric retention tablet containing the above-mentioned lacosamide pharmaceutical composition. Preferably, the specification of the above-mentioned lacosamide gastric retention tablet may be selected from 100 mg to 400 mg, for example, 100 mg, 200 mg, or 400 mg.

[0050] According to embodiments of the present invention, the lacosamide pharmaceutical composition or lacosamide gastric retention tablet, when ingested as a whole, rapidly expands or swells in gastric juice upon entering the patient's stomach, and after expansion, possesses good rigidity and elasticity, and exhibits a remarkable gastric retention effect.

[0051] In the context of the present invention, "pharmaceutically acceptable" means a substance that, within the bounds of ordinary medical judgment, does not cause inappropriate toxicity, irritation, allergic reactions, etc., is applied to contact with a patient's tissue, has a suitable balance of advantages and disadvantages, and is effectively used for its intended purpose and application.

[0052] In the context of the present invention, the term "solvate" refers to a molecular complex comprising a drug (e.g., lacosamide) and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol), either stoichiometric or non-stoichiometric. When the solvent binds tightly to the drug, the formed complex is humidity-independent and exhibits clear stoichiometric properties. However, when the solvent has weak binding properties (e.g., in channel solvates and hygroscopic compounds), the solvent content depends on humidity and dry conditions. In this case, the complex is usually non-stoichiometric.

[0053] In the context of the present invention, the term "hydrate" refers to a solvate containing a drug and stoichiometric or non-stoichiometric water.

[0054] In the context of the present invention, the above-mentioned cross-linked povidone (PVPP), also known as Crospovidone or Crospovidonum, is a water-insoluble synthetic cross-linked N-vinyl-2-pyrrolidone homopolymer. Since the material itself is water-insoluble, the exact molecular weight has not yet been determined. The cross-linked povidone may be manufactured by BASF under the trade name KOLLIDON, or may be manufactured by ISP, supplied by Ashland, and under the trade name POLYPLASDONE TM either.

[0055] According to an embodiment of the present invention, the above-mentioned polyvinyl acetate (PVAc) is a homopolymer of vinyl acetate, and the molecular weight (Mw) is usually about 1×10 5 ~ about 1×10 6 .

[0056] According to an embodiment of the present invention, the above-mentioned polyethylene oxide (PEO) is also called polyoxirane and polyoxyethylene. Polyethylene oxide is a homopolymer of oxyethylene, and its molecular weight (Mw) is usually about 1×10 5 ~ about 1×10 7 or about 1×10 6 ~ about 1×10 7 . Polyethylene oxide has various grades depending on the molecular weight and may be manufactured by Union Carbide under the trade name POLYOX (registered trademark).

[0057] Without departing from the common knowledge in this field, any combination of the above-mentioned preferred conditions can obtain respective preferred examples of the present invention.

[0058] The reagents and raw materials used in the present invention are all commercially available.

[0059] Beneficial effects The lacosamide pharmaceutical composition provided by the present invention has good sustained-release properties, and the tablet size can rapidly expand during the extracorporeal dissolution process. The lacosamide pharmaceutical composition produced by the present invention has good sustained-release properties, and the tablet size can rapidly expand during the extracorporeal dissolution process. After expansion, it has good rigidity and elasticity and exhibits a remarkable gastric retention effect. The lacosamide pharmaceutical composition provided by the present invention is stable in properties and suitable for once-daily oral administration. When administered in solid dosage form, the pharmaceutical composition can have a gastric retention time of 12 hours or more, and a cumulative release rate of 80% or more within 24 hours. When the pharmaceutical composition remains in the stomach, it can continuously release lacosamide.

[0060] The lacosamide gastric retention tablets provided by the present invention can achieve a cumulative release rate of 80% or more within 24 hours when subjected to dissolution experiments using the USP II method at a rotation speed of 50 rpm in a 900 mL volume, pH 1.0 hydrochloric acid solution and / or pH 4.5 acetate buffer solution.

[0061] The manufacturing process of the present invention significantly improves problems such as difficulty in filling during the tableting process due to poor fluidity and low bulk density of the active pharmaceutical ingredient, as well as instability in tablet weight. The process is stable, process parameters can be adjusted and controlled, which is advantageous for expanding the production of this product and has a good prospect for market introduction. [Brief explanation of the drawing]

[0062] [Figure 1] These are elution curves for the samples from Examples 2, 5, 6, and 7 in 0.1 N hydrochloric acid. [Figure 2] These are elution curves for the samples from Examples 1-7 in an acetate buffer solution at pH 4.5. [Figure 3] Example 8 shows the mean blood drug concentration-time curve (N=3) of lacosamide after oral administration of the formulations from Example 7 and Reference Example 1 to male beagle dogs. [Figure 4]Example 8 shows the mean blood drug concentration-time curve (N=3) of lacosamide after oral administration of the formulations from Example 7 and Reference Example 1 to female beagle dogs. [Modes for carrying out the invention]

[0063] The present invention will be further described below with reference to examples, but this does not limit the present invention to the scope of the examples described. In the following examples, experimental methods for which specific conditions are not specified are selected according to conventional methods and conditions or the product's instructions. Furthermore, by comparing the examples of the present invention with reference examples, it was confirmed that the sustained-release and gastric retention effects of the present invention are clearly superior.

[0064] Reference Example 1 We will temporarily import commercially available control drugs, lacosamide tablets (100 mg, UCB Pharma SA, USA), to prepare for use.

[0065] Example 1 Matrix tablets containing the following ingredients were manufactured in batches of approximately 70 grams using the following method.

[0066] [Table 1] Process steps: 1) The lacosamide active pharmaceutical ingredient was sieved through a 30-mesh sieve to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient. 2) Take the sieved lacosamide active ingredient obtained in step 1, and add it to a mixing tank with sodium alginate, lacosamide, cross-linked povidone, and anhydrous calcium hydrogen phosphate. Mix for approximately 20 minutes to obtain a premix. 3) The premix obtained in step 2 was sized using a granulator with a mesh diameter of 2.0 mm and a sizing speed of 200 rpm. Then, magnesium stearate was added, and the mixture was continued for about 5 minutes before dry granulation to obtain granules. The roller pressure for dry granulation was approximately 0-20 kg / cm². 2The roller rotation speed was 8 Hz, the feed speed was 3 Hz, the sizing rotation speed was 12 Hz, and the selected mesh pore size for secondary sizing was 0.8 mm. 4) The amount of external additives used was calculated, and after adding the external hydroxypropyl methylcellulose and carbomer, mixing was continued for approximately 15 minutes, and after adding the external magnesium stearate, mixing was continued for 5 minutes. The final mixture was press-molded into tablets (22.0 mm × 10.9 mm almond-shaped shallow arc die).

[0067] The in vitro release of lacosamide was measured using USP (elution device method 2, 900 mL, pH 4.5 acetate buffer, 50 rpm), and the in vitro release results were as follows.

[0068] [Table 2] The results of the size, stiffness, and elasticity tests of the tablets after dissolution were as follows.

[0069] [Table 3] Example 2 Matrix tablets containing the following ingredients were manufactured in batches of approximately 160 grams using the following method.

[0070] [Table 4]

[0071] Process steps: 1) The lacosamide active pharmaceutical ingredient was sieved through a 30-mesh sieve to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient. 2) Take the sieved lacosamide active ingredient obtained in step 1, and add it to a mixing tank along with the polyvinyl acetate / povidone mixture, lacosamide, and cross-linked povidone. Mix for approximately 20 minutes to obtain a premix. 3) The premix obtained in step 2 was sized using a granulator with a mesh size of 2.0 mm and a sizing speed of 200 rpm. Next, internal magnesium stearate was added and the mixture was continued for about 5 minutes before dry granulation to obtain granules. The roller pressure for dry granulation was approximately 0-20 kg / cm². 2 The roller rotation speed was 8 Hz, the feed speed was 2 Hz, the sizing rotation speed was 12 Hz, and the selected mesh pore size for secondary sizing was 0.8 mm. 4) The amount of external additives to be used was calculated, and hydroxypropyl methylcellulose, sorbitol, and carbomer were added to the granules obtained in step 3, and the mixture was continued for approximately 15 minutes. The amount of external magnesium stearate to be used was calculated, and external magnesium stearate was added, and the mixture was continued for approximately 5 minutes. The final mixture was then press-molded into tablets (22.0 mm × 10.9 mm almond-shaped shallow arc die).

[0072] The in vitro release of lacosamide was measured using USP (elution device method 2, 900 mL, 0.1 N hydrochloric acid and pH 4.5 acetate buffer, 50 rpm), and the in vitro release results were as follows.

[0073] [Table 5] The results of the size, stiffness, and elasticity tests of the tablets after dissolution were as follows.

[0074] [Table 6] Example 3 Matrix tablets containing the following ingredients were manufactured in batches of approximately 70 grams using the following method.

[0075] [Table 7]

[0076] Process steps: 1) The lacosamide active pharmaceutical ingredient was sieved through a 30-mesh sieve to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient. 2) Sodium alginate, the lacosamide active ingredient obtained in step 1, cross-linked povidone, hydroxypropyl methylcellulose, and colloidal silica were placed in a mixing tank and mixed for about 20 minutes to obtain a premix. 3) The premix obtained in step 2 was sized using a granulator with a mesh size of 2.0 mm and a sizing speed of 200 rpm. Next, internal magnesium stearate was added and the mixture was continued for about 5 minutes before dry granulation to obtain granules. The roller pressure for dry granulation was approximately 0-20 kg / cm². 2 The roller rotation speed was 8 Hz, the feed speed was 3 Hz, the sizing rotation speed was 12 Hz, and the selected mesh pore size for secondary sizing was 0.8 mm. 4) The amount of external additives to be used was calculated, and anhydrous calcium hydrogen phosphate was added to the granules obtained in step 3, after which mixing was continued for approximately 15 minutes. The amount of external magnesium stearate to be used was calculated, and magnesium stearate was added, after which mixing was continued for approximately 5 minutes, and the final mixture was press-molded into tablets (22.0 mm × 10.9 mm almond-shaped shallow arc die).

[0077] The in vitro release of lacosamide was measured using USP (elution device method 2, 900 mL, pH 4.5 acetate buffer, 50 rpm), and the in vitro release results were as follows.

[0078] [Table 8] The results of the size, stiffness, and elasticity tests of the tablets after dissolution were as follows.

[0079] [Table 9] Example 4 Matrix tablets containing the following ingredients were manufactured in batches of approximately 70 grams using the following method.

[0080] [Table 10]

[0081] Process steps: 1) The lacosamide active pharmaceutical ingredient was sieved through a 30-mesh sieve to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient. 2) Sodium alginate, the sieved lacosamide active ingredient obtained in step 1, cross-linked povidone, polyoxyethylene, and colloidal silica were placed in a mixing tank and mixed for about 20 minutes to obtain a premix. 3) The premix obtained in step 2 was sized using a granulator with a mesh size of 2.0 mm and a sizing speed of 200 rpm. Next, internal magnesium stearate was added and the mixture was continued for about 5 minutes before dry granulation to obtain granules. The roller pressure for dry granulation was approximately 0-20 kg / cm². 2 The roller rotation speed was 8 Hz, the feed speed was 2 Hz, the sizing rotation speed was 12 Hz, and the selected mesh pore size for secondary sizing was 0.8 mm. 4) The amount of external additives used was calculated, and after adding external anhydrous calcium hydrogen phosphate to the granules obtained in step 3, mixing was continued for about 15 minutes, and after adding external magnesium stearate, mixing was continued for about 5 minutes, and the final mixture was press-molded into tablets (22.0 mm × 10.9 mm almond-shaped shallow arc die).

[0082] The in vitro release of lacosamide was measured using USP (elution device method 2, 900 mL, pH 4.5 acetate buffer, 50 rpm), and the in vitro release results were as follows.

[0083] [Table 11] The results of the size, stiffness, and elasticity tests of the tablets after dissolution were as follows.

[0084] [Table 12]

[0085] Example 5 Matrix tablets containing the following ingredients were manufactured in batches of approximately 330 grams using the following method.

[0086] [Table 13] Process steps: 1) The lacosamide active pharmaceutical ingredient was sieved through a 30-mesh sieve to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient. 2) Sodium alginate, the sieved lacosamide active ingredient obtained in step 1, cross-linked povidone, and colloidal silica were placed in a mixing tank and mixed for about 20 minutes to obtain a premix. 3) The premix obtained in step 2 was sized using a granulator with a mesh size of 2.0 mm and a sizing speed of 200 rpm. Next, internal magnesium stearate was added and the mixture was continued for about 5 minutes before dry granulation to obtain granules. The roller pressure for dry granulation was approximately 0-20 kg / cm². 2 The roller rotation speed was 8 Hz, the feed speed was 2 Hz, the sizing rotation speed was 12 Hz, and the selected mesh pore size for secondary sizing was 0.8 mm. 4) The amount of external additives used was calculated, and external hydroxypropyl methylcellulose, polyvinyl acetate / povidone mixture, and calcium hydrogen phosphate dihydrate were added to the granules obtained in step 3 and mixed for approximately 15 minutes. External magnesium stearate was then added and mixed for approximately 5 minutes, and the final mixture was press-molded into tablets (22.0 mm × 10.9 mm almond-shaped shallow arc die).

[0087] The in vitro release of lacosamide was measured using USP (elution device method 2, 900 mL, 0.1 N hydrochloric acid and pH 4.5 acetate buffer, 50 rpm), and the in vitro release results were as follows.

[0088] [Table 14] The results of the size, stiffness, and elasticity tests of the tablets after dissolution were as follows.

[0089] [Table 15]

[0090] Example 6 Matrix tablets containing the following ingredients were manufactured in batches of approximately 300 grams using the following method.

[0091] [Table 16]

[0092] Process steps: 1) The lacosamide active pharmaceutical ingredient was sieved through a 30-mesh sieve to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient. 2) The polyvinyl acetate-povidone mixture, the sieved lacosamide active ingredient obtained in step 1, and cross-linked povidone were placed in a mixing tank and mixed for about 20 minutes to obtain a premix. 3) The premix obtained in step 2 was sized using a granulator with a mesh size of 2.0 mm and a sizing speed of 200 rpm. Magnesium stearate was added, and the mixture was continued for approximately 5 minutes before dry granulation to obtain granules. The roller pressure for dry granulation was approximately 0-20 kg / cm². 2 The roller rotation speed was 8 Hz, the feed speed was 3 Hz, the sizing rotation speed was 12 Hz, and the selected mesh pore size for secondary sizing was 0.8 mm. 4) The amount of external additives used was calculated, and external sorbitol, carbomer, hydroxypropyl methylcellulose, and sodium alginate were added to the granules obtained in step 3 and mixed for approximately 15 minutes. After adding external magnesium stearate, the mixture was mixed for approximately 5 minutes, and the final mixture was press-molded into tablets (22.0 mm × 10.9 mm almond-shaped shallow arc die).

[0093] The in vitro release of lacosamide was measured using USP (elution device method 2, 900 mL, 0.1 N hydrochloric acid and pH 4.5 acetate buffer, 50 rpm), and the in vitro release results were as follows.

[0094] [Table 17] The results of the size, stiffness, and elasticity tests of the tablets after dissolution were as follows.

[0095] [Table 18]

[0096] Example 7 The formulation composition was the same as in Example 5, but the batch size was increased to 11,000 grams for production.

[0097] Process steps: 1) The lacosamide active pharmaceutical ingredient was sieved through a 30-mesh sieve to remove clumps and obtain the sieved lacosamide active pharmaceutical ingredient. 2) Sodium alginate, the sieved lacosamide active ingredient obtained in step 1, cross-linked povidone, and colloidal silica were placed in a mixing tank and mixed for about 15 minutes to obtain a premix. 3) The premix obtained in step 2 was sized using a sizing machine with a mesh pore size of 2.0 mm and a sizing speed of 200 rpm. After sizing, mixing was continued for 5 minutes, internal magnesium stearate was added, and mixing was continued for approximately 5 minutes before dry granulation to obtain granules. The roller pressure for dry granulation was approximately 2-5 bar, the lateral pressure was 2-5 bar, the roller rotation speed was 5-15 rpm, the feed speed was 5-15 rpm, the sizing rotation speed was 176 rpm, and the selected secondary sizing mesh pore size was 1.0 mm. 4) The amount of external additives to be used was calculated, and external hydroxypropyl cellulose, polyvinyl acetate / povidone mixture, and calcium hydrogen phosphate dihydrate were added to the granules obtained in step 3, and the mixture was continued to mix for about 15 minutes. The amount of external magnesium stearate to be used was calculated, and external magnesium stearate was added, and the mixture was continued to mix for about 5 minutes, and the final mixture was press-molded into tablets (22.0 mm × 10.9 mm almond-shaped shallow arc die).

[0098] The in vitro release of lacosamide was measured using USP (elution device method 2, 900 mL, 0.1 N hydrochloric acid and pH 4.5 acetate buffer, 50 rpm), and the in vitro release results were as follows.

[0099] [Table 19]

[0100] Example 8 This invention involves a comparative study of pharmacokinetic evaluation tests in beagle dogs using the homemade lacosamide pharmaceutical composition obtained in Example 7 and the lacosamide tablets of Reference Example 1.

[0101] The study used a total of six beagle dogs, half female and half male, divided into two groups of three dogs each. In the first cycle, both groups received orally one tablet of the test drug (200 mg / tablet, single dose) and two tablets of the control drug (100 mg / tablet, single dose). After a drug-free period of at least one week, in the second cycle, both groups received orally two tablets of the control drug (100 mg / tablet, one tablet at a time, with an 8-hour interval between doses) and one tablet of the test drug (200 mg / tablet, single dose).

[0102] In the first cycle, the sampling times for Group 1 were 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 6 hr, 8 hr, 12 hr, 16 hr, 24 hr, 36 hr, and 48 hr after administration, for a total of 13 time points. In the first cycle, the sampling times for Group 2 were 0.25 hr, 0.5 hr, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, 24 hr, and 48 hr after administration, for a total of 13 time points.

[0103] In the second cycle, the sampling times for Group 1 were 0.25 hr, 0.5 hr, 1 hr, 1.5 hr, 2 hr, 2.5 hr, 3 hr, 5 hr, 8 hr (second administration after blood collection at 8 hr), 8.25 hr, 8.5 hr, 9 hr, 9.5 hr, 10 hr, 10.5 hr, 11 hr, 13 hr, 16 hr, 24 hr, and 48 hr after administration, for a total of 20 time points. In the second cycle, the sampling times for Group 2 were 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 5 hr, 6 hr, 8 hr, 12 hr, 16 hr, 24 hr, 36 hr, and 48 hr after administration, for a total of 13 time points.

[0104] Depending on the set time, approximately 500 μL of whole blood was collected from the forelimb cephalic vein or another suitable vein into a K2-EDTA-containing anticoagulant centrifuge tube and stored on moist ice before centrifugation. Within 2 hours of sampling, the sample was centrifuged (centrifuged at 3000 g at 2°C to 8°C for 5 minutes) to obtain plasma. The plasma sample was first frozen on dry ice and then stored long-term in a -60°C refrigerator until sample analysis was performed.

[0105] After plasma sample collection was complete, lacosamide concentrations in beagle dog plasma were quantitatively measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Pharmacokinetic parameters were calculated using a non-compartmental model with WinNonlin 8.2 software.

[0106] Pharmacokinetic parameter T max , C max AUC last AUC INF , T 1 / 2 and MRT INF A paired two-tailed t-test was performed using Microsoft Excel 2007. Based on the test results, Male Beagle dogs were orally administered one tablet of the BCM-332 test formulation (200 mg / tablet, single dose) and two tablets of the control formulation (100 mg / tablet, one tablet per dose, 8 hr interval between doses), followed by T max AUC last AUC INF and T 1 / 2 There was no significant difference (P>0.05) between the two, and C max and MRT INF There is a statistical difference (P<0.05), Female Beagle dogs were orally administered one tablet of the BCM-332 test formulation (200 mg / tablet, single dose) and two tablets of the control formulation (100 mg / tablet, single dose), followed by T max AUC last AUC INF and T 1 / 2 There was no significant difference (P>0.05) between the two, and C max There is a statistical difference (P<0.05) between them, and MRT INF This showed a significant statistical difference (P<0.01).

[0107] For the elution curves in 0.1 N hydrochloric acid for Examples 2 and 5-7, refer to Figure 1. For the elution curves in pH 4.5 acetate buffer for Examples 1-7, refer to Figure 2. For the results of the pharmacokinetic evaluation test in oral administration to beagle dogs described in Example 8, refer to Tables 1 and 2. For the blood drug concentration-time curves of the pharmacokinetic evaluation test in oral administration to beagle dogs described in Example 8, refer to Figures 3 and 4. For the verification results of the pharmacokinetic parameter T-test in the pharmacokinetic evaluation test in oral administration to beagle dogs described in Example 8, refer to Tables 3 and 4.

[0108] [Table 20]

[0109] [Table 21]

[0110] [Table 22]

[0111] [Table 23] During the experiment, the observations regarding the Beagle dog's condition were as follows:

[0112] [Table 24] As can be seen from the test results of Examples 1 to 8, the lacosamide pharmaceutical composition of the present invention exhibits good sustained-release effects in both in vitro and in vivo conditions, can rapidly expand during the in vitro dissolution process, and exhibits good rigidity and elasticity after expansion, providing the product with a stable and good gastric retention effect. Furthermore, all beagle dogs that administered Example 7 showed no abnormalities throughout the entire period, demonstrating that the composition of the present invention has superior safety.

Claims

1. A pharmaceutical composition, The aforementioned pharmaceutical composition is a 24-hour sustained-release gastric tablet containing a drug active ingredient, a skeletal material, a swelling material, and a disintegrant. The drug-active component is lacosamide or a pharmaceutically acceptable salt of lacosamide, and the weight percentage of the drug-active component is 5.0% to 40.0%. The aforementioned skeletal material is one or more selected from a polyvinyl acetate / povidone mixture, sodium alginate, and hydroxypropyl methylcellulose. If the skeletal material is a polyvinyl acetate / povidone mixture, the polyvinyl acetate / povidone mixture contains a mixture of PVAc and PVP in a weight ratio of 80:19, and the weight percentage is 18. The range is 36% to 24.68%. When the aforementioned skeletal material is sodium alginate, the weight percentage of the sodium alginate is 5% to 35.09%. When the skeletal material is hydroxypropyl methylcellulose, the weight percentage of the hydroxypropyl methylcellulose is 8% to 17.27%. The aforementioned swellable material is one or two selected from polyoxyethylene and carbomer, and the weight percentage of the aforementioned swellable material is 1.0% to 60.0%. The disintegrant is selected from one or more of cross-linked povidone, sodium carboxymethyl starch, sodium cross-linked carboxymethylcellulose, calcium carboxymethylcellulose, and low-substituted hydroxypropylcellulose, and the weight percentage of the disintegrant is 5% to 30.0%, and Under the USP method conditions of Dissolution Apparatus Method 2: 900 mL, 0.1 N hydrochloric acid, 50 rpm or Dissolution Apparatus Method 2: 900 mL, pH 4.5 acetate buffer, 50 rpm, the dissolution of the pharmaceutical composition is as follows: A) Dissolve 40% or less of the active drug component within 1 hour. B) Elute 20% to 70% of the drug active ingredient within 6 hours, and C) Eluting 65% or more of the drug active ingredient within 24 hours, simultaneously satisfying all three characteristics, Pharmaceutical composition.

2. When the swelling material is polyoxyethylene, the weight percentage of the polyoxyethylene is 15% to 20%. If the swelling material is carbomer, the weight percentage of the carbomer is 3% to 6%, and, Under the USP method conditions of Dissolution Apparatus Method 2: 900 mL, 0.1 N hydrochloric acid, 50 rpm or Dissolution Apparatus Method 2: 900 mL, pH 4.5 acetate buffer, 50 rpm, the dissolution of the pharmaceutical composition is as follows: A) Dissolve 30% or less of the active drug component within 1 hour. B) Elute 30% to 55% of the drug active ingredient within 6 hours, and C) Eluting 80% or more of the drug active ingredient within 24 hours, simultaneously satisfying these three characteristics, The pharmaceutical composition according to claim 1.

3. The pharmaceutical composition according to claim 2, wherein the particle size of the drug active ingredient is 30 mesh or less.

4. The pharmaceutical composition further comprises one or more selected from a skeletal strength modifier, a diluent, and a lubricant. The aforementioned skeletal strength modifier is selected from calcium hydrogen phosphate and calcium hydrogen phosphate dihydrate, The weight percentage of the aforementioned skeletal strength modifier is 10% to 15.0%. The diluent is one or more selected from dextrose, lactose monohydrate, anhydrous lactose, sucrose, mannitol, xylitol, sorbitol, microcrystalline cellulose, starch, pregelatinized starch, calcium hydrogen phosphate dihydrate, anhydrous calcium hydrogen phosphate, cyclodextrin, and its derivatives, and the weight percentage of the diluent is 10 to 40%. The lubricant is one or more selected from talc, stearic acid, metal stearate, stearic acid ester, colloidal silica, glycerol behenate, sodium lauryl sulfate, hydrogenated vegetable oil, mineral oil, poloxamer, polyethylene glycol, and sodium chloride, and the weight percentage of the lubricant is 0.5% to 2.0%. A pharmaceutical composition according to any one of claims 1 to 3.

5. A pharmaceutical composition, The aforementioned pharmaceutical composition is a 24-hour sustained-release tablet that remains in the stomach, The aforementioned pharmaceutical composition, Formulation 1 consists of 18.18% lacosamide, 35.09% sodium alginate, 13.64% cross-linked povidone, 11.73% anhydrous calcium hydrogen phosphate, 1.10% magnesium stearate, 3.00% carbomer, and 17.27% hydroxypropyl methylcellulose. Formulation 2 consists of 20.00% lacosamide, 24.80% polyvinyl acetate / povidone mixture, 20.00% cross-linked povidone, 1.20% magnesium stearate, 20.00% sorbitol, 6.00% carbomer, and 8.00% hydroxypropyl methylcellulose. Formulation 3 consists of 18.18% lacosamide, 35.09% sodium alginate, 16.64% cross-linked povidone, 16.73% hydroxypropyl methylcellulose, 0.55% colloidal silica, 1.10% magnesium stearate, and 11.73% anhydrous calcium hydrogen phosphate. Formulation 4 consists of 18.18% lacosamide, 35.09% sodium alginate, 16.64% cross-linked povidone, 16.73% polyoxyethylene, 0.55% colloidal silica, 1.10% magnesium stearate, and 11.73% anhydrous calcium hydrogen phosphate. Formulation 5 consists of 18.18% lacosamide, 25.45% sodium alginate, 16.36% cross-linked povidone, 0.55% colloidal silica, 1.10% magnesium stearate, 9.09% hydroxypropyl methylcellulose, 18.36% polyvinyl acetate / povidone mixture, and 10.91% calcium hydrogen phosphate dihydrate. Formulation 6, which consists of 20.00% lacosamide, 24.80% polyvinyl acetate / povidone mixture, 20.00% cross-linked povidone, 1.20% magnesium stearate, 15.00% sorbitol, 5.00% sodium alginate, 6.00% carbomer, and 8.00% hydroxypropyl methylcellulose, has one of the following formulations: Under the USP method conditions of Dissolution Apparatus Method 2: 900 mL, 0.1 N hydrochloric acid, 50 rpm or Dissolution Apparatus Method 2: 900 mL, pH 4.5 acetate buffer, 50 rpm, the dissolution of the pharmaceutical composition is as follows: A) Dissolve 40% or less of the active drug component within 1 hour. B) Elute 20% to 70% of the drug active ingredient within 6 hours, and C) Eluting 65% or more of the drug active ingredient within 24 hours, simultaneously satisfying all three characteristics, Pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 3, wherein the gastric retention tablet is selected from 100 mg to 400 mg.

7. A method for producing a pharmaceutical composition according to any one of claims 1 to 6, Including a dry granulation process, Manufacturing method.

8. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the manufacture of a drug for treating or preventing acute or chronic pain.

9. The use according to claim 8, wherein the "acute or chronic pain" is non-neuroinflammatory pain.

10. The use according to claim 8, wherein the "acute or chronic pain" is chronic inflammatory pain.

11. The use according to claim 8, wherein the "acute or chronic pain" is rheumatoid arthritis pain or secondary osteoarthritis pain.

12. The use according to claim 8, wherein the "chronic pain" means that the pain persists for 3 to 6 months or longer, and before or after this period, one of the following characteristic symptoms is present: fatigue, sleep disturbance, loss of appetite, loss of taste, weight loss, decreased libido, and constipation, and signs of vegetative neurological dysfunction occur.

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