Oral pharmaceutical composition containing carbamate compound and method for manufacturing the same

Abstract

To provide an oral pharmaceutical composition containing a carbamate compound, its isomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof as an active ingredient, which consistently achieves an excellent dissolution rate of the active ingredient, and to provide a method for manufacturing the same.SOLUTION: Provided is a method for manufacturing an oral pharmaceutical composition, comprising: mixing particles of a compound of formula (1) as an active ingredient, a diluent, a disintegrant, and a lubricant; and compressing the mixture into tablets, a particle size d (0.9) of the active ingredient particles being less than 300 μm.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a compound represented by the following formula (1) as an active ingredient: [ka] (1) (In the formula, R1, R2, A1, and A2 are as defined in this specification.) The present invention relates to an oral pharmaceutical composition containing a carbamate compound represented by the formula: [Background technology]

[0002] The following formula (1) [ka] (1) (In the formula, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; One of A1 and A2 is CH, and the other is N. The carbamate compound represented by the formula (carbamic acid aryl-2-tetrazolylethyl ester) and a method for producing the same are described in detail in Patent Documents 1, 2 and 3, which are incorporated herein by reference.

[0003] Specific examples of the carbamate compound of formula (1) include those of formula (2) below: [ka] (2) Examples of suitable carbamate compounds include those represented by the following formula (carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester).

[0004] The carbamate compound of formula (2) is known as an effective antiepileptic drug used for central nervous system diseases, but no research has been disclosed on specific oral administration formulations for its application to the human body. To administer a drug to the human body, formulation design is essential. To be effective as a drug, specific formulations such as tablets, capsules, injections, and ointments are required.

[0005] When administering the compound to achieve pharmacological activity, the effect must be rapid, and it must be suitable for ensuring a uniform concentration of the active ingredient in the blood by repeated administration over a long period of time. To achieve a rapid effect, an injectable formulation may be suitable, but its use is limited by the administration route. Thus, there is a growing demand for the development of a new oral solid formulation to achieve this purpose. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2006 / 112685 [Patent Document 2] International Publication No. 2010 / 150946 [Patent Document 3] International Publication No. 2011 / 046380 Summary of the Invention [Problem to be solved by the invention]

[0007] The solubility of the carbamate compound of formula (1) (1.8-2.0 mg / mL) in the in vivo pH range (pH 1.2-6.8) does not limit the absorption of tablets containing 12.5-400 mg of active ingredient (BCS; Amidon, GL et al., Pharmaceutical Research, 12: 413-420 (1995)). Based on the dose, the particle size of the compound is not expected to significantly affect dosage unit uniformity. Rather, micronization is not recommended for dosage unit uniformity purposes because it directly affects the flowability and stability of the active pharmaceutical ingredient, thereby affecting content uniformity and content.

[0008] However, the present inventors have found that the carbamate compound of formula (1) has a variable dissolution rate despite its high solubility. The dissolution rate of a formulation is essential for rapid and consistent therapeutic effects and quality control. Furthermore, a variable dissolution rate can cause problems in the quality control of the formulation. Therefore, the present inventors have repeatedly conducted research to solve this problem.

[0009] On the other hand, generally, particle micronization is not adopted because it may directly affect the flowability and stability of the drug, thereby affecting the content uniformity and content of the formulation.However, through repeated research, the present inventors have devised a formulation that consistently achieves an excellent dissolution rate by controlling the average particle size of the particles of the carbamate compound of formula (1) contained in the formulation through micronization.That is, the present invention is surprising in that a person skilled in the art would not have easily imagined that the dissolution rate of the carbamate compound of formula (1) could be adjusted by micronization.

[0010] Therefore, an object of the present invention is to provide a pharmaceutical composition for oral administration containing, as an active ingredient, the carbamate compound of formula (1), its isomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a method for producing the same. [Means for solving the problem]

[0011] According to one aspect of the present invention, a compound represented by the following formula (1) is used as an active ingredient: [ka] (1) (In the formula, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; One of A1 and A2 is CH, and the other is N. Particles of a carbamate compound represented by the formula: a pharmaceutically acceptable carrier; wherein the particle size d(0.9) of the active ingredient particles is less than 300 μm.

[0012] According to another aspect of the present invention, there is provided a method for producing an oral pharmaceutical composition, comprising the steps of mixing particles of the carbamate compound of formula (1), its isomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof as an active ingredient with a pharmaceutically acceptable carrier, and compressing the mixture into tablets, wherein the particle size d(0.9) of the active ingredient particles is less than 300 μm. [Effects of the Invention]

[0013] According to the present invention, it is possible to provide a solid oral preparation that exhibits a rapid and consistent therapeutic effect by achieving excellent disintegration force and a rapid dissolution rate. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is a graph showing the results of the dissolution tests of Examples 1 to 5 and Comparative Examples 1 to 3. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention will be described in detail below. Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art of the present invention. In addition, although preferred methods and samples are described herein, similar or equivalent methods and samples are also within the scope of the present invention.

[0016] It should be understood that all numerical designations used throughout this specification (e.g., pH, temperature, time, concentration, d(0.9), and d(0.5)) can be modified in all instances by the term "about." When the term "about" is used in describing the present invention, it can mean ±10%, ±5%, ±2%, or ±1% on a percentage basis. In one embodiment, it can mean ±5%, ±2%, or ±1%. For example, "about 5" means to include 4.5 to 5.5, 4.75 to 5.25, 4.9 to 5.1, or any value between 4.95 and 5.05.

[0017] As used herein, the term "particle" refers to an individual particle of a drug substance, whether the particle is present singly or in aggregate. That is, the pharmaceutical composition of the present invention containing the carbamate compound of Formula (1) may contain aggregates having a particle size d(0.9) of 300 μm or more. However, if the particle size d(0.9) of the primary drug particles constituting the aggregate is less than 300 μm, 250 μm or less, 200 μm or less, 150 μm or less, 130 μm or less, or 100 μm or less, respectively, the aggregate itself satisfies the particle size requirement defined in the present invention, and the composition is considered to be within the scope of the present invention.

[0018] As used herein, references to particle size, such as particle size d(0.9), particle size d(0.5), etc., with respect to particles of a carbamate compound of Formula (1) mean that the average of all particles of the carbamate compound of Formula (1) in a sample has an estimated volume less than or equal to the volume calculated for a spherical particle having a diameter equal to the specified diameter, based on the assumption that the particles are spherical in shape. Particle size distributions are well known to those skilled in the art and can be measured by laser light scattering techniques, as disclosed and discussed below. In one embodiment of the present invention, the particle size of the carbamate compound of Formula (1) was measured using a Malvern particle size analyzer.

[0019] As used herein, "d(0.9)" means that 90% of the particle volume has a diameter within a specific diameter d range. Specifically, it means that the particle diameter d(0.9) at the point where the cumulative frequency of the volume distribution reaches 90% when accumulating from particles with smaller particle diameters is within the specific diameter d range.

[0020] As used herein, "d(0.5)" means that 50% of the particle volume has a diameter within a specific diameter d range. Specifically, it means that the particle diameter ((0.5)) at the point where the cumulative frequency of the volume distribution reaches 50% when accumulating from particles with smaller particle diameters is within the specific diameter d range.

[0021] The present invention provides an oral pharmaceutical composition containing a carbamate compound of the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a method for producing the same.

[0022] All specific details relating to the present invention described below can be clearly applied to the oral pharmaceutical composition of the present invention and the method for producing the same. [ka] (1) (In the formula, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; One of A1 and A2 is CH, and the other is N.

[0023] In the present invention, the carbamate compound of formula (1), its isomer, or its pharmaceutically acceptable salt, solvate, or hydrate has a particle size distribution in which the particle size d(0.9), the point at which the cumulative frequency of the volume distribution reaches 90% when the particle size is smallest, is less than 300 μm, and more specifically, the particle size d(0.9) may be 250 μm or less, 200 μm or less, 150 μm or less, 130 μm or less, or 100 μm or less. The lower limit of the particle size d(0.9) is not particularly limited, and may be, for example, more than 0 μm, 30 μm or more, or 50 μm or more, but is not limited thereto.

[0024] In one embodiment of the present invention, the carbamate compound of formula (1), its isomer, or its pharmaceutically acceptable salt, solvate, or hydrate may have a particle size d(0.5) of 5 to 80 μm, at which the cumulative frequency of the volume distribution reaches 50% when accumulated from particles with a small particle size, and more specifically, the particle size d(0.5) may be within a range of 7 to 70 μm, 10 to 60 μm, or 15 to 50 μm.

[0025] The pharmaceutical composition of the present invention may be any solid formulation known in the art.Specifically, the solid formulation may be in the form of a tablet or capsule, more specifically, in the form of a compressed tablet, a multiply compressed tablet, a sugar-coated tablet, a film-coated tablet, a hard capsule or a soft capsule.Preferably, the solid formulation may be in the form of a tablet, particularly, but not limited to, a compressed tablet or a film-coated tablet.

[0026] The oral solid dosage form according to the present invention preferably exhibits the following dissolution criteria when tested for in vitro dissolution: the oral solid dosage form exhibits a dissolution profile in which more than 81% by weight of the drug dissolves within 30 minutes. Preferably, the oral solid dosage form exhibits a dissolution profile in which 85% by weight or more, more preferably 90% by weight or more, and even more preferably 91% by weight or more of the drug dissolves within 30 minutes.

[0027] Traditionally, dissolution test results are established as an average across a given number of dosage forms (e.g., tablets, capsules, suspensions, or other dosage forms), usually six. Dissolution tests are typically performed in aqueous media buffered to the pH range observed in the gastrointestinal tract (1-7.4) and adjusted to 37°C (±1°C) to maintain physiologically relevant conditions. When the dosage form being tested is a tablet, a rotating paddle at 50-75 rpm is typically used to test the tablet's dissolution rate. The amount of dissolved carbamate compound of Formula (1) can typically be determined by HPLC. Dissolution tests serve as a quality control tool.

[0028] In one embodiment, the oral pharmaceutical composition of the present invention can contain the active ingredient (i.e., the carbamate compound of formula (1), its isomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof) in a dosage range of 5 mg to 400 mg. More specifically, the active ingredient can be contained in a dosage of 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg.

[0029] In one embodiment, when the solid pharmaceutical composition for oral administration of the present invention is a tablet, the tablet can be prepared by directly mixing the carbamate compound of Formula (1), its isomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a pharmaceutically acceptable excipient, or by dry / wet granulation tableting.

[0030] In one embodiment, the pharmaceutically acceptable carrier can be selected from the group consisting of, but not limited to, a diluent, a disintegrant, a lubricant, and any combination thereof.

[0031] In one embodiment, the pharmaceutically acceptable carrier may further comprise a surfactant.

[0032] In one embodiment, the diluent may be one or more selected from the group consisting of cornstarch, pre-gelatinized starch, potato starch, wheat flour starch, glutinous rice starch, sweet potato starch, tapioca starch, rice starch, beeswax cornstarch, sucrose, lactose anhydrous, lactose hydrate, mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, synthetic aluminum silicate, hydroxypropyl starch, microcrystalline cellulose, and crystalline cellulose. Specifically, the diluent may be one or more selected from the group consisting of lactose hydrate, synthetic aluminum silicate, hydroxypropyl starch, microcrystalline cellulose, and crystalline cellulose. More specifically, the diluent may be one or more selected from the group consisting of lactose hydrate and microcrystalline cellulose, but is not limited thereto. In one embodiment, the first diluent may be microcrystalline cellulose, and the second diluent may be lactose.

[0033] In one embodiment, the disintegrant may be one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, lactose anhydrous, lactose hydrate, sodium starch glycolate, crospovidone, carboxymethylcellulose and its pharmaceutically acceptable salts, hydroxypropyl cellulose, cornstarch, and croscarmellose and its pharmaceutically acceptable salts. Specifically, the disintegrant may be one or more selected from the group consisting of sodium starch glycolate, crospovidone, carboxymethylcellulose and its pharmaceutically acceptable salts, hydroxypropyl cellulose, cornstarch, and croscarmellose and its pharmaceutically acceptable salts. More specifically, the disintegrant may be sodium starch glycolate, but is not limited to these.

[0034] In one embodiment, the lubricant may be one or more selected from the group consisting of silicon dioxide, colloidal anhydrous silica, magnesium trisilicate, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, powdered cellulose, starch, talc, magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, mineral oil, hydrogenated vegetable oil, zinc stearate, and stearic acid, and more specifically, may be, but is not limited to, colloidal silicon dioxide, magnesium stearate, or a combination thereof.

[0035] In one embodiment, the surfactant may be one or more selected from the group consisting of polysorbate 80, oleoyl macrogolglyceride, linoleoil, caprylocaproyl macrogolglyceride, polyoxyglyceride, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethylcellulose, polyvinylpyrrolidine, sodium lauryl sulfate, sodium oleate, and dioctyl sodium sulfosuccinate. Specifically, the surfactant may be one or more selected from the group consisting of sodium lauryl sulfate, sodium oleate, and dioctyl sodium sulfosuccinate. More specifically, the surfactant may be, but is not limited to, sodium lauryl sulfate.

[0036] In one embodiment, the oral pharmaceutical composition of the present invention may contain the following ingredients when prepared by direct blend tableting (direct powder compression method, direct compression).

[0037] Based on the total weight of the composition, the active ingredient is 5% by weight to 35% by weight, the diluent is 55% by weight to 90% by weight, the disintegrant is 2% by weight to 6% by weight, and the lubricant is 0.1% by weight to 4% by weight. In another embodiment, the oral pharmaceutical composition of the present invention, when prepared by direct compound tableting, may comprise the following ingredients: Based on the total weight of the composition, the active ingredient is 10% by weight to 30% by weight, the diluent is 65% by weight to 85% by weight, the disintegrant is 3% by weight to 5% by weight, and the lubricant is 0.3% by weight to 1% by weight.

[0038] In addition to the above ingredients, the pharmaceutical composition of the present invention may contain ingredients such as binders, film coating agents, colorants, fragrances, sweeteners, flavorings, preservatives, etc., within ranges that do not impair the object of the present invention.

[0039] In one embodiment, when the pharmaceutical composition according to the present invention is in the form of a film-coated tablet, the pharmaceutical composition may contain a film coating agent. Typically, the film coating agent may be contained in an amount of 2% by weight to 4% by weight based on the total weight of the pharmaceutical composition, and includes a film-forming agent, a plasticizer, a lubricant, and optionally one or more pigments. As will be explained below, in the present invention, a preferred active ingredient is a compound represented by the following formula (2): [ka] (2) or an isomer thereof, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0040] Furthermore, the present invention provides a method for producing an oral pharmaceutical composition, which comprises mixing particles of the carbamate compound of formula (1), its isomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof as an active ingredient with a pharmaceutically acceptable carrier, and compressing the mixture into tablets, wherein the average particle size d(0.9) of the lowest 90% of the active ingredient particles is less than 300 μm.

[0041] The tableting can be carried out according to any method known in the art, and preferably, direct blend tableting.

[0042] The oral pharmaceutical compositions prepared by the above method may be in any shape, such as round, oval, oblong, rectangular, cylindrical or any other suitable shape, and may vary in size depending on the concentration of the active ingredient.

[0043] In one embodiment, when the pharmaceutical composition according to the present invention is in the form of a coated tablet, a coating step can be further included after tableting. Specifically, the coated tablet can be a film-coated tablet, and typically, the film coating agent can be contained in an amount of 2% by weight to 4% by weight based on the total weight of the pharmaceutical composition. The film coating agent can contain a film-forming agent, a plasticizer, a heavy lubricant, and optionally one or more pigments. The film coating agent can be a conventional film coating agent such as Opadry.

[0044] The pharmaceutical compositions provided by the present invention can be used to prevent or treat central nervous system diseases.

[0045] In one embodiment, the central nervous system disorder is selected from, but is not limited to, anxiety, depression, convulsion, epilepsy, migraine, bipolar disorder, substance abuse, smoking, ADHD, obesity, sleep disorders, stroke, neuropathic pain, cognitive impairment, neurodegeneration, and muscle spasms. As used herein, the terms "prevent," "preventing," and "prevention" mean to reduce or eliminate the chance of disease.

[0046] As used herein, the terms "treat," "treating," and "treatment" refer to the complete or partial elimination of a disease and / or its associated symptoms.

[0047] The present invention will be described in more detail below through examples. However, the following examples are intended only to illustrate one or more embodiments and are not intended to limit the scope of the present invention. Coated tablets can be produced by performing an additional coating step after direct blending and compression. The film coating agent can be a conventional film coating agent, such as Opadry®.

[0048] As used herein, "d(0.9)" means that 90% of the particle volume has a diameter within a specific diameter d range. Specifically, it means that the particle diameter d(0.9) at the point where the cumulative frequency of the volume distribution reaches 90% when accumulating from particles with smaller particle diameters is within the specific diameter d range.

[0049] As used herein, "d(0.5)" means that 50% of the particle volume has a diameter within a specific diameter d range. Specifically, it means that the particle diameter ((0.5)) at the point where the cumulative frequency of the volume distribution reaches 50% when accumulating from particles with smaller particle diameters is within the specific diameter d range.

[0050] The present invention provides an oral pharmaceutical composition containing a carbamate compound of the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, and a method for producing the same.

[0051] All specific details relating to the present invention described below can be clearly applied to the oral pharmaceutical composition of the present invention and the method for producing the same.

[0052] [ka] (1) (In the formula, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; One of A1 and A2 is CH, and the other is N.

[0053] In the present invention, the carbamate compound of formula (1), its isomer, or its pharmaceutically acceptable salt, solvate, or hydrate has a particle size distribution in which the particle size d(0.9), the point at which the cumulative frequency of the volume distribution reaches 90% when the particle size is smallest, is less than 300 μm, and more specifically, the particle size d(0.9) may be 250 μm or less, 200 μm or less, 150 μm or less, 130 μm or less, or 100 μm or less. The lower limit of the particle size d(0.9) is not particularly limited, and may be, for example, more than 0 μm, 30 μm or more, or 50 μm or more, but is not limited thereto.

[0054] In one embodiment of the present invention, the carbamate compound of formula (1), its isomer, or its pharmaceutically acceptable salt, solvate, or hydrate may have a particle size d(0.5) of 5 to 80 μm, at which the cumulative frequency of the volume distribution reaches 50% when accumulated from particles with a small particle size, and more specifically, the particle size d(0.5) may be within a range of 7 to 70 μm, 10 to 60 μm, or 15 to 50 μm.

[0055] The pharmaceutical composition of the present invention may be any solid formulation known in the art.Specifically, the solid formulation may be in the form of a tablet or capsule, more specifically, in the form of a compressed tablet, a multiply compressed tablet, a sugar-coated tablet, a film-coated tablet, a hard capsule or a soft capsule.Preferably, the solid formulation may be in the form of a tablet, particularly, but not limited to, a compressed tablet or a film-coated tablet.

[0056] The oral solid dosage form according to the present invention preferably exhibits the following dissolution criteria when tested for in vitro dissolution: the oral solid dosage form exhibits a dissolution profile in which more than 81% by weight of the drug dissolves within 30 minutes. Preferably, the oral solid dosage form exhibits a dissolution profile in which 85% by weight or more, more preferably 90% by weight or more, and even more preferably 91% by weight or more of the drug dissolves within 30 minutes.

[0057] Traditionally, dissolution test results are established as an average across a given number of dosage forms (e.g., tablets, capsules, suspensions, or other dosage forms), usually six. Dissolution tests are typically performed in aqueous media buffered to the pH range observed in the gastrointestinal tract (1-7.4) and adjusted to 37°C (±1°C) to maintain physiologically relevant conditions. When the dosage form being tested is a tablet, a rotating paddle at 50-75 rpm is typically used to test the tablet's dissolution rate. The amount of dissolved carbamate compound of Formula (1) can typically be determined by HPLC. Dissolution tests serve as a quality control tool.

[0058] In one embodiment, the oral pharmaceutical composition of the present invention can contain the active ingredient (i.e., the carbamate compound of formula (1), its isomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof) in a dosage range of 5 mg to 400 mg. More specifically, the active ingredient can be contained in a dosage of 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg.

[0059] In one embodiment, when the solid pharmaceutical composition for oral administration of the present invention is a tablet, the tablet can be prepared by directly mixing the carbamate compound of Formula (1), its isomer, or a pharmaceutically acceptable salt, solvate, or hydrate thereof with a pharmaceutically acceptable excipient, or by dry / wet granulation tableting.

[0060] In one embodiment, the pharmaceutically acceptable carrier can be selected from the group consisting of, but not limited to, a diluent, a disintegrant, a lubricant, and any combination thereof.

[0061] In one embodiment, the pharmaceutically acceptable carrier may further comprise a surfactant. [Example]

[0062] Example 1: Preparation of test compound ((R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester) Carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester (carbamate compound of the formula (2)) was prepared according to the method described in Preparation Example 50 of International Patent Publication No. WO2010 / 150946.

[0063] Examples 1 to 5 and Comparative Examples 1 to 3: Preparation of oral formulations containing test compounds by direct compression The ingredients were mixed and compressed into tablets (direct blending and compression) according to the composition and content shown in Table 1 below, and then the tablets were film-coated with a coating agent according to a conventional tablet coating method.

[0064] [Table 1]

[0065] Test Example 1: Dissolution test Dissolution tests were carried out on the solid preparations produced in Examples 1 to 5 and Comparative Examples 1 to 3 under the following conditions in accordance with the United States Pharmacopoeia. <Elution conditions> Eluent: 0.01N hydrochloric acid aqueous solution, 900 mL Apparatus: Apparatus II (paddle method), 75 rpm Temperature: 37℃ The results of the dissolution rates are shown in Table 2 below and FIG. At 10, 20, 30, 45 and 60 minutes after the start of the test, samples were removed and analyzed for test compound by HPLC at 215 nm. [Table 2]

Claims

1. The active ingredient is a compound represented by the following formula (1): 【Chemistry 1】 （１） (In the formula, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; A 1 and A 2 One of them is CH and the other is N.) Particles of a carbamate compound represented by the formula: a pharmaceutically acceptable carrier; wherein the particle size d(0.9) of the active ingredient particles is less than 300 μm.

2. 2. The oral pharmaceutical composition according to claim 1, wherein the particle size d(0.9) of the active ingredient particles is 250 μm or less.

3. 2. The oral pharmaceutical composition according to claim 1, wherein the particle size d(0.9) of the active ingredient particles is 150 μm or less.

4. The oral pharmaceutical composition according to any one of claims 1 to 3, wherein the active ingredient is contained in an amount of 5 mg to 400 mg.

5. The oral pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of a diluent, a disintegrant, and a lubricant.

6. 6. The oral pharmaceutical composition of claim 5, wherein the pharmaceutically acceptable carrier further comprises a surfactant.

7. 7. The oral pharmaceutical composition according to claim 5 or 6, wherein the diluent is one or more selected from the group consisting of corn starch, pre-gelatinized starch, potato starch, wheat flour starch, glutinous rice starch, sweet potato starch, tapioca starch, rice starch, beeswax corn starch, sucrose, lactose anhydrous, lactose hydrate, mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, synthetic aluminum silicate, hydroxypropyl starch, microcrystalline cellulose and crystalline cellulose.

8. The pharmaceutical composition for oral administration according to any one of claims 5 to 7, wherein the disintegrant is at least one selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, lactose anhydrous, lactose hydrate, sodium starch glycolate, crospovidone, carboxymethylcellulose and pharmaceutically acceptable salts thereof, hydroxypropyl cellulose, cornstarch, and croscarmellose and pharmaceutically acceptable salts thereof.

9. The pharmaceutical composition for oral administration according to any one of claims 5 to 8, wherein the lubricant is one or more selected from the group consisting of silicon dioxide, colloidal anhydrous silica, magnesium trisilicate, tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, powdered cellulose, starch, talc, magnesium stearate, talc, light anhydrous silicic acid, sodium stearyl fumarate, polyethylene glycol, mineral oil, hydrogenated vegetable oil, zinc stearate, and stearic acid.

10. The oral pharmaceutical composition according to any one of claims 5 to 9, comprising 5% by weight to 35% by weight of the active ingredient, 55% by weight to 90% by weight of the diluent, 2% by weight to 6% by weight of the disintegrant, and 0.1% by weight to 4% by weight of the lubricant, based on the total weight of the pharmaceutical composition.

11. The active ingredient is represented by the following formula (2): 【Chemistry 2】 （２） The oral pharmaceutical composition according to any one of claims 1 to 10, which is a carbamate compound represented by the following formula (I):

12. The oral pharmaceutical composition according to any one of claims 1 to 11, which is in the form of a compressed tablet, a multiple compressed tablet, a sugar-coated tablet, a film-coated tablet, a hard capsule or a soft capsule.

13. The active ingredient is a compound represented by the following formula (1): 【Transformation 3】 （１） (In the formula, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, perfluoroalkyl having 1 to 8 carbon atoms, alkyl having 1 to 8 carbon atoms, thioalkoxy having 1 to 8 carbon atoms, and alkoxy having 1 to 8 carbon atoms; A 1 and A 2 One of them is CH and the other is N.) a carbamate compound represented by the formula: Here, the method for producing an oral pharmaceutical composition, wherein the particle size d(0.9) of the active ingredient particles is less than 300 μm.

14. The method for producing an oral pharmaceutical composition according to claim 13, wherein the active ingredient and the pharmaceutically acceptable carrier are mixed by direct mix tableting.

15. The method for producing an oral pharmaceutical composition according to claim 13 or 14, wherein the particle size d(0.9) of the active ingredient particles is 250 μm or less.

16. The method for producing an oral pharmaceutical composition according to any one of claims 13 to 15, wherein the active ingredient is contained in the oral pharmaceutical composition in an amount of 5 mg to 400 mg.

17. The method for producing an oral pharmaceutical composition according to any one of claims 13 to 16, wherein the pharmaceutically acceptable carrier is at least one selected from the group consisting of a diluent, a disintegrant, and a lubricant.

18. 18. The method for producing an oral pharmaceutical composition according to claim 17, wherein the pharmaceutically acceptable carrier further comprises a surfactant.

19. The active ingredient is represented by the following formula (2): 【Chemistry 4】 （２） The method for producing the oral pharmaceutical composition according to any one of claims 13 to 18, wherein the carbamate compound is a carbamate compound represented by the formula (I), an isomer thereof, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

20. The method for producing an oral pharmaceutical composition according to any one of claims 13 to 19, wherein the oral pharmaceutical composition is in the form of a compressed tablet, a multiple compressed tablet, a sugar-coated tablet, a film-coated tablet, a hard capsule, or a soft capsule.

Images