Solid oral composition containing a carbamate compound and a method for its preparation

Abstract

FIELD: pharmaceuticals.SUBSTANCE: solid oral dosage form containing, as an active ingredient, a carbamate compound of the following formula 1, and methods for its production.Formula 1:where R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and one of A1 and A2 is CH and the other is N. The oral solid dosage form includes granules that include, wt.% based on the total weight of the dosage form: a carbamate compound of formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof 25-70, a diluent 6-40, a binder 3-40, where the diluent and binder are selected from the list of specific substances; wherein the solid dosage form contains outside the granules in wt.% based on the total weight of the dosage form: lubricant 0.1-2, disintegrant 1-10 and glidant 0.1-1 %, where the lubricant, disintegrant and glidant are selected from the list of specific substances. Methods for producing the said solid dosage form include obtaining granules containing the active ingredient in combination with excipients including a diluent and a binder; mixing the obtained granules with excipients including a disintegrant, a lubricant and a glidant; forming a solid dosage form.EFFECT: solid dosage form with a high content of a carbamate compound of formula 1 as an active ingredient, which satisfies the requirements for uniformity of composition and dissolution rate of the active ingredient and has a suitable size for oral administration.26 cl, 3 dwg, 7 tbl, 14 ex

Description

[0001] Technical field

[0002] The present application relates to an oral solid dosage form which comprises granules containing a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient; a diluent; and a binder; and a method for producing the same:

[0003] [Formula 1]

[0004]

[0005] where

[0006] R1, R2, A1, and A2 have the meanings as defined herein.

[0007] Technology Level

[0008] Central nervous system diseases are a group of neurological disorders affecting the structure or function of the brain or spinal cord, which make up the central nervous system. Causes of central nervous system diseases include trauma, infection, degeneration, structural defects, central nervous system tumors, autoimmune diseases, stroke, and the like.

[0009] The carbamate compound (carbamic acid aryl-2-tetrazolylethyl ester) represented by the following formula 1 and the method for producing the same are described in detail in International Patent Publication Nos. WO 2006 / 112 685 A1, WO 2010 / 15 0946 A1 and WO 2011 / 046380 A2, which are incorporated herein by reference:

[0010] [Formula 1]

[0011]

[0012] wherein R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8perfluoroalkyl, C1-C8alkyl, C1-C8thioalkoxy and C1-C8alkoxy; and one of A1 and A2 is CH and the other is N.

[0013] A specific example of the carbamate compound of formula 1 may be a carbamate compound of the following formula 2 ((R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-carbamic acid ethyl ester):

[0014] [Formula 2]

[0015]

[0016] The carbamate compound of formula 2 is known to be an effective antiepileptic drug used for diseases of the central nervous system, but studies of a specific oral dosage form for human use have not been disclosed. For drugs to be suitable for human use, dosage form design is essential. To be effective as drugs, specialized dosage forms such as tablets, capsules, injections, and ointments are required.

[0017] To achieve pharmacological activity by administering a drug containing the specified compound, the effect must manifest itself quickly and it must be possible to maintain a uniform concentration of the active ingredient in the blood through repeated administration over a long period of treatment. An injectable drug may be suitable for achieving a rapid effect, but its use is limited due to the route of administration. Therefore, there is an urgent need to develop a new solid oral dosage form to achieve this goal. Furthermore, dysphagia is a common symptom in patients with central nervous system diseases, and it is desirable to keep the drug size as small as possible, as this may cause difficulty swallowing oral medications.

[0018] Clinical studies of carbamates indicate the need for high doses (200-400 mg). For ease of oral administration, tablet weights exceeding 800 mg are generally not preferred. Since a large number of tablets per dose can cause compliance issues, it would be commercially desirable to develop a formulation that reduces the number of tablets per dose to improve patient compliance.

[0019] Therefore, there is a need to develop tablet dosage forms containing carbamates that have 1) a suitable size for easy swallowing by the patient, 2) a high carbamate content per tablet to minimize the number of tablets required per dose, and 3) a pharmacological behavior capable of producing the desired effect with suitable properties with respect to the release of carbamates from the tablet.

[0020] Meanwhile, the overall physical properties and manufacturing feasibility of low-dose dosage forms are entirely determined by the inactive ingredients and excipients in the formulation. This is because the physical properties of excipients used in formulations dominate the tablet properties, not the physical properties of the active ingredients. However, for high-dose drugs, the physical properties of pharmaceutically active ingredients significantly influence the manufacturing feasibility of dosage forms. As the amount of drug in a single tablet increases, the physicochemical properties of the active ingredients significantly predominate over those of the powder mixtures used in tablet manufacturing. Not all active ingredients may have the appropriate compressibility properties required to produce high-dose tablets.

[0021] The carbamate compound used as the active ingredient is an extremely brittle substance with low physical plasticity. This complicates the production of oral solid dosage forms with high carbamate content. To counteract the brittleness of carbamate during tablet production, attempts can be made to dilute the carbamate by using large amounts of excipients that traditionally exhibit viscous / plastic properties, but excessive tablet weight can cause dysphagia. Furthermore, pressing tablets with a high brittle content with the required good hardness and low friability requires high compression pressure, while a low deformation rate increases the proportion of voids in the tablets, leading to poor tablet quality, such as delamination of the upper or lower convex portion of the tablet and delamination.The present application discloses an oral solid dosage form with a high active ingredient content, which can minimize the tablet weight, has excellent hardness, and resistance to delamination of the upper or lower convex portion of the tablet and abrasion.

[0022] Description of the invention

[0023] Technical task

[0024] Accordingly, one object of the present application is to provide an oral solid dosage form that comprises a carbamate compound of formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient in a large amount and has uniformity of composition, improved convenience of drug administration and rapid dissolution rate, and a method for producing the same.

[0025] Furthermore, another object of the present application is to provide an oral solid dosage form comprising a high content of an active ingredient, which not only has an excellent dissolution rate and a minimum tablet weight, but also has improved physical properties required for producing a tablet, thereby having good compression properties, specified good hardness and abrasion resistance.

[0026] Solution to the problem

[0027] The present invention relates to an oral solid dosage form, which includes granules containing a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient; a diluent; and a binder:

[0028] [Formula 1]

[0029]

[0030] where

[0031] R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and

[0032] One of A1 and A2 is CH, and the other is N.

[0033] Furthermore, one aspect of the present invention relates to a method for producing an oral solid dosage form, comprising:

[0034] i) mixing a carbamate compound of formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent, a lubricant and a binder, and then compacting;

[0035] ii) grinding and sifting the compacted product obtained in step (i);

[0036] iii) subsequently mixing the granules sieved in step (ii) with excipients including a diluent, a lubricant and a disintegrating agent; and

[0037] iv) forming an oral solid dosage form from the mixture of granules and excipients obtained in step (iii).

[0038] Furthermore, one aspect of the present invention relates to a method for producing an oral solid dosage form, comprising:

[0039] a) mixing a carbamate compound of formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent and a binder, and a solvent;

[0040] b) granulating the mixture obtained in step (a), and then successively drying and sieving;

[0041] c) subsequently mixing the dried granules obtained in step (b) with excipients including a lubricant and a disintegrant; and

[0042] d) forming an oral solid dosage form from the mixture of granules and excipients obtained in step (c).

[0043] According to one embodiment of the present invention, there is provided an oral solid dosage form that satisfies the requirements of uniformity of composition and dissolution rate without micronization of the active ingredient and has a suitable size for administration.

[0044] Dysphagia is a common symptom in patients with central nervous system diseases. It is preferable to adjust the size of the oral solid dosage form to suit oral administration, as difficulty in swallowing oral medications may occur. When producing a tablet with a high content of the compound of Formula 1 as an active ingredient by direct compression, in order to increase the density and improve the flowability of the powder, it is necessary to significantly increase the excipient content (e.g., ≥75% (w / w)), and in this case, the tablet size may need to be increased. Therefore, a drug containing a high content of the compound of Formula 1 will be difficult to take.

[0045] Generally, micronization of active ingredient particles is not used because it can reduce the flowability and stability of drugs, affecting the compositional uniformity and content. That is, when capsules or tablets are produced by micronization of the carbamate compound of Formula 1, some problems may arise related to increased production costs due to a decrease in yield caused by static electricity and poor flowability due to a low density of 0.50 g / mL or less. However, when producing capsules or tablets containing a high content of non-micronized carbamate compound of Formula 1, problems related to content inhomogeneity and a slow dissolution rate can be expected due to the large particle size of the active ingredient.One embodiment of the present invention provides a dosage form that can satisfy the requirements for composition uniformity and dissolution rate regardless of whether the main component is micronized or not.

[0046] According to one aspect of the present invention, a high content (for example, ≥25% (w / w), ≥50% (w / w), or ≥60% (w / w) in the composition) of the carbamate compound of formula 1 in a single dosage form can be obtained by wet granulation of the carbamate compound of formula 1. In addition, when producing granules by the wet granulation method, it is preferable to use a micronized carbamate compound of formula 1 to improve the uniformity of the composition and the dissolution rate of the drug.

[0047] According to another aspect of the present invention, a large amount (for example, ≥25% (w / w), ≥50% (w / w), or ≥60% (w / w) in the composition) of the carbamate compound of formula 1 in a single dosage form can be obtained by dry granulation of the carbamate compound of formula 1. In the case of the dry granulation method, there are advantages in that it is possible to produce at a lower cost through a simpler process since there is no need for wetting and drying steps according to the use of a binder solution, and it can be processed even in the case of unstable active ingredients that are sensitive to moisture or heat. However, the dry granulation method is not suitable for all active ingredients, and there are limitations on the active ingredients that can be used.In one embodiment of the present invention, when producing an oral solid dosage form by dry granulation, the active ingredient may or may not be micronized. In particular, by producing an oral solid dosage form by dry granulation of a carbamate compound of Formula 1 having a large particle size without the micronization process, it is possible to achieve not only patient compliance by producing an oral solid dosage form containing a large amount of the active ingredient, but also acceptable compositional uniformity and rapid dissolution.

[0048] Thus, granulating the carbamate compound of formula 1 according to the present invention makes it possible to provide a high content (for example, ≥25% (w / w), ≥50% (w / w) or ≥60% (w / w) in the composition) of the carbamate compound of formula 1 in a single dosage form, and the size of the dosage form can be adjusted.

[0049] Meanwhile, the present invention provides an oral solid dosage form comprising a high content of an active ingredient, which has improved physical properties required for tablet production while minimizing tablet weight and at the same time has an excellent dissolution rate. The oral solid dosage form according to the present invention is not affected by the particle size of the carbamate during granulation of a preparation comprising a relatively high content of the carbamate compound of Formula 1, and can further provide improved compressibility in terms of acceptable hardness and resistance to delamination of the upper or lower convex portion of the tablet. In particular, even if the granulation process is carried out using the carbamate compound of Formula 1 in which the particle size is not adjusted, good tableting and dissolution properties can be ensured.

[0050] As one specific embodiment, an oral solid dosage form is provided that further comprises a disintegrant in the granules, and further comprises a disintegrant and a lubricant outside the granules.

[0051] As one specific embodiment, a method for producing an oral solid dosage form is provided, comprising:

[0052] I) mixing a carbamate compound of formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent, a lubricant, a binder and a disintegrant, and then compacting;

[0053] II) grinding and sifting the mixture obtained in step (I) by sifting through a sieve;

[0054] III) subsequently mixing the granules sieved in step (II) with excipients including a disintegrant and a lubricant; and

[0055] IV) forming an oral solid dosage form from the mixture of granules and excipients obtained in step (III).

[0056] Invention Effect

[0057] According to the present invention, it is possible to provide an oral solid dosage form that exhibits rapid and stable therapeutic effects due to excellent disintegration, rapid dissolution rate and uniformity of composition.

[0058] According to one embodiment of the present invention, it is possible to provide an oral solid dosage form that satisfies the requirements of uniformity of composition and dissolution rate without micronization of the active ingredient and has an oral solid dosage form size suitable for administration. Furthermore, according to one embodiment of the present invention, it is possible to provide an oral solid dosage form that includes a high content of the compound of Formula 1 and also has an appropriate oral solid dosage form size that does not cause inconvenience during oral administration by reducing the content of excipients.In addition, according to one embodiment of the present invention, it is possible to provide an oral solid dosage form that has improved compressibility in terms of acceptable hardness and resistance to delamination of the upper or lower convex portion of the tablet.

[0059] Brief description of drawings

[0060] Fig. 1 is a graph showing the results of the solubility test of Examples 1 to 8.

[0061] Fig. 2 is a graph showing the results of the solubility test of Comparative Examples 1 and 2.

[0062] Fig. 3 is a graph showing the results of the solubility test of Examples 9 and 10.

[0063] Principle of the invention

[0064] The present invention is described in detail below.

[0065] All technical terms used in this disclosure, unless otherwise defined, have the same meaning as commonly understood by one of ordinary skill in the art of this disclosure. Furthermore, although preferred methods and examples are described herein, similar or equivalent methods are also included within the scope of the present invention.

[0066] According to one aspect of the present invention, there is provided an oral solid dosage form, which comprises granules comprising a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient; a diluent; and a binder:

[0067] [Formula 1]

[0068]

[0069] where

[0070] R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and

[0071] One of A1 and A2 is CH, and the other is N.

[0072] A constant dissolution rate of dosage forms is a prerequisite for rapid and consistent therapeutic effect and quality control. Variable dissolution rates of active ingredients can cause problems in the quality control of dosage forms. Despite high aqueous solubility in the in vivo pH range (pH 1.2-6.8), the dissolution rate varies depending on the drug. The present invention provides an oral solid dosage form comprising a compound of Formula 1 that exhibits a constant dissolution rate in the in vivo pH range (pH 1.2-6.8).

[0073] Conventional oral solid dosage forms can be produced by the direct compression method, in which all the ingredients are mixed and directly pressed into tablets; the dry granulation method, in which the mixture is compacted and crushed to obtain dry granules, and then pressed into tablets; and the wet granulation method, in which a binder solution prepared using water or an organic solvent is added to the mixture, and the processes of kneading, granulation, drying and sizing are carried out to obtain wet granules, and then pressed into tablets.

[0074] In one embodiment of the present invention, the oral solid dosage form may comprise 15-90% by weight of the active ingredient (the carbamate compound of Formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof). In another embodiment of the present invention, the oral solid dosage form may comprise 25-65% by weight of the active ingredient. In another embodiment of the present invention, the oral solid dosage form may comprise 15-70% by weight or 20-65% by weight of the active ingredient. In another embodiment of the present invention, the oral solid dosage form may comprise about 50% by weight or more, such as about 50-70% by weight of the active ingredient. In another embodiment of the present invention, the oral solid dosage form may comprise about 55% by weight or more, such as about 55-70% by weight of the active ingredient.

[0075] In another embodiment of the present invention, the particle diameter d(0.9) of the active ingredient may be 35 μm-1300 μm. In another embodiment of the present invention, the active ingredient may be micronized or not, and when the active ingredient is micronized, the particle diameter d(0.9) may be 300 μm or less. More specifically, the particle diameter d(0.9) may have a particle size distribution of 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 diameter 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. When the active ingredient is not micronized, the particle diameter d(0.9) of the active ingredient may be 300 μm-1300 μm. In particular, the particle diameter d(0.9) of the active ingredient may be 600 μm - 1000 μm, more specifically 700 μm - 1000 μm, and more specifically 800 μm - 900 μm.

[0076] The term “d(0.9)” used in this document means that 90% of the volume of particles has a diameter within a certain diameter range d. Specifically, this means that the particle diameter d(0.9) at the point where the cumulative frequency of the volume distribution reaches 90% due to the accumulation of particles of smaller diameter is within the range of a certain diameter d.

[0077] In another embodiment of the present invention, the particle diameter d(0.9) of the active ingredient may be 86 μm to 460 μm. In this case, the active ingredient may be micronized, and the dosage form may be obtained by using a wet granulation method or a dry granulation method.

[0078] Furthermore, in another embodiment of the present invention, the particle diameter d(0.9) of the active ingredient may be 300 μm to 1300 μm. In this case, the active ingredient may not be micronized, and the dosage form may be obtained by using a dry granulation method.

[0079] It should be understood that all numerical designations, such as pH, temperature, time, concentration and d(0.9), used in the present description can be modified by the term "about" in all instances. When the term "about" is used in the description of the present invention, it can mean ±10%, ±5%, ±2% or ±1% with respect to a percentage. In one embodiment, it can mean ±5%, ±2% or ±1%. For example, "about 5" means any value from 4.5 to 5.5, from 4.75 to 5.25, from 4.9 to 5.1 or from 4.95 to 5.05.

[0080] The term "particle" as used herein refers to individual particles of a drug substance, regardless of whether the particles exist individually or in the form of aggregates. That is, the oral solid dosage form of the present invention comprising the carbamate compound of Formula 1 may contain aggregates having a particle diameter d(0.9) outside the above-mentioned numerical range. However, when the particle diameter d(0.9) of the main drug particles constituting the aggregate is within the above-mentioned numerical range, the aggregate itself is considered to satisfy the particle size limitations defined herein and is within the scope of the present invention.

[0081] Herein, with respect to particles of the carbamate compound of Formula 1, reference to a particle size such as a particle diameter d(0.9) means that the average particle size of the carbamate compound of Formula 1 in a sample has a calculated volume less than or equal to the volume calculated for spherical particles with a diameter equal to a given diameter, based on the assumption that the particle shape is spherical. The particle size distribution should be well known to those skilled in the art and can be measured using a laser light scattering method such as described and discussed below. In one embodiment of the present invention, the particle size of the carbamate compound of Formula 1 was measured using a particle size analyzer from Malvern.

[0082] In another embodiment of the present invention, the oral solid dosage form may be a tablet dosage form. In another embodiment of the present invention, the tablet may comprise a carbamate compound of Formula 1 or a pharmaceutically acceptable salt, isomer, solvate, or hydrate thereof; a diluent, and a binder; and may be produced using a dry granulation method or a wet granulation method.

[0083] In another embodiment of the present invention, the granules may have a density of 0.5 g / ml to 1.5 g / ml, in particular, 0.8 g / ml to 1.2 g / ml. In addition, the granules may have a particle size of which 50% or more, in particular 60% or more, remain within the range of 30 to 80 mesh (mesh: according to standard KSA5101-1). In addition, the granules may have a hardness of 1-5 kp, in particular, may have a hardness of 2-3 kp.

[0084] In another embodiment of the present invention, the oral solid dosage form may further comprise a diluent outside the granules. In another embodiment of the present invention, an example of a diluent may be one or more selected from the group consisting of corn starch, pregelatinized starch, potato starch, wheat starch, sweet potato starch, tapioca starch, rice starch, beeswax, sucrose, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, aluminum silicate, hydroxypropyl starch, microcrystalline cellulose, crystalline cellulose and silicified microcrystalline cellulose, but are not limited to them. In another embodiment of the present invention, the diluent contained in the granules and the diluent further contained outside the granules may be the same or different.

[0085] In another embodiment of the present invention, the diluent may be contained in an amount of 6-75 wt.%, 8-73 wt.%, 10-70 wt.%, or 15-70 wt.%, based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the diluent may be contained in an amount of 24-60 wt.%, and preferably 24.07-59 wt.%, based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the diluent may be contained in an amount of 6-40 wt.% or 10-35 wt.% in the granules. In another embodiment of the present invention, the diluent may be contained in an amount of 0-50 wt.% or 5-50 wt.% outside the granules. In another embodiment of the present invention, the diluent may be contained in an amount of 6-40 wt.% or 10-35 wt. in granules, and at the same time in an amount of 0-50% by weight or 5-50% by weight outside the granules.

[0086] In another embodiment of the present invention, the oral solid dosage form may further comprise a lubricant. In another embodiment of the present invention, the oral solid dosage form may further comprise a lubricant within the granules, outside the granules, or both.In another embodiment of the present invention, an example of a lubricant may be one or more selected from the group consisting of, but not limited to, glyceryl bigenate, magnesium stearate, mineral oil, polyethylene glycol, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, starch, stearic acid, talc, and zinc stearate. In another embodiment of the present invention, the lubricant contained in the granules and the lubricant contained outside the granules may be the same or different.

[0087] In another embodiment of the present invention, the lubricant may be contained in an amount of 0.2-2% by weight, 0.2-1.8% by weight, 0.3-1.6% by weight, or 0.3-1.5% by weight based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the lubricant may be contained in an amount of 0.4-0.7% by weight, and preferably 0.3-0.8% by weight based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the lubricant may be contained in an amount of 0.1-1% by weight in the granules. In another embodiment of the present invention, the lubricant may be contained in an amount of 0.1-2% by weight outside the granules. In another embodiment of the present invention, the lubricant may be contained in an amount of 0.1-1% by weight. in granules, and at the same time in an amount of 0.1-2% by weight outside the granules.

[0088] In another embodiment of the present invention, an example of a binder may be one or more selected from the group consisting of alginic acid, ammonium methacrylate copolymer, ammonium methacrylate copolymer dispersion, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, sodium carboxymethylcellulose, microcrystalline cellulose, copovidone, dextrin,

[0089] Ethyl cellulose, gelatin, glucose syrup, guar gum, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, maltodextrin, maltose, methylcellulose, polyethylene oxide, povidone, corn starch, potato starch, pregelatinized starch, modified pregelatinized starch and tapioca starch, but not limited to.

[0090] In another embodiment of the present invention, the binder may be contained in an amount of 2-60% by weight, 2-50% by weight, 3-40% by weight, 3-35% by weight, or 3-30% by weight, based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the binder may be contained in an amount of 4-13% by weight, and especially 4.47-12.5% ​​by weight, based on the total weight of the oral solid dosage form.

[0091] In another embodiment of the present invention, the oral solid dosage form may further comprise a disintegrant. In another embodiment of the present invention, the oral solid dosage form may further comprise a disintegrant in the granules, outside the granules, or both. In another embodiment of the present invention, an example of a disintegrant may be one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, anhydrous lactose, lactose monohydrate, sodium starch glycolate, crospovidone, carboxymethylcellulose and its pharmaceutically acceptable salt, hydroxypropyl cellulose, corn starch, and croscarmellose, but are not limited thereto. In another embodiment of the present invention, the disintegrant contained in the granules and the disintegrant contained outside the granules may be the same or different.

[0092] In another embodiment of the present invention, the disintegrant may be contained in an amount of 1-15% by weight, 1.5-13% by weight, 2-12% by weight, or 2-10% by weight, based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the disintegrant may be contained in an amount of 2-3.5% by weight, and preferably 2.35-3.01% by weight, based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the disintegrant may be contained in an amount of 1-10% by weight or 0.5-5% by weight in the granules. In another embodiment of the present invention, the disintegrant may be contained in an amount of 1-10% by weight or 0.5-5% by weight outside the granules. In another embodiment of the present invention, the disintegrant may be contained in an amount of 1-10% by weight or 0.5-5% by weight in granules, and at the same time in an amount of 1-10% by weight or 0.5-5% by weight outside the granules.

[0093] In another embodiment of the present invention, the oral solid dosage form may comprise 15-90% by weight of the active ingredient, 6-75% by weight of the diluent, 0.2-2% by weight of the lubricant, 2-50% by weight of the binder, and 1-15% by weight of the disintegrant. In another embodiment of the present invention, the oral solid dosage form may comprise 15-70% by weight of the active ingredient, 8-73% by weight of the diluent, 0.2-1.8% by weight of the lubricant, 3-40% by weight of the binder, and 1.5-13% by weight of the disintegrant. In another embodiment of the present invention, the oral solid dosage form may comprise 20-65% by weight of the active ingredient, 10-70% by weight of the diluent, 0.3-1.6% by weight lubricant, 4-35% by weight of binder and 2-12% by weight of disintegrant. In another embodiment of the present invention, the oral solid dosage form may include 25-65% by weight of active ingredient, 15-70% by weight of diluent, 0.3-1.5% by weight oflubricant, 4-30% by weight of binder and 2-10% by weight of disintegrant.

[0094] In another embodiment of the present invention, the oral solid dosage form may further comprise a glidant. In another embodiment of the present invention, the oral solid dosage form may further comprise a glidant in the granules, outside the granules, or both. In another embodiment of the present invention, an example of a glidant may be one or more selected from the group consisting of colloidal silicon dioxide, talc, silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate, calcium hydrogen phosphate, and calcium carbonate, but is not limited thereto.

[0095] In another embodiment of the present invention, the glidant may be contained in an amount of 0.2-2% by weight, 0.2-1.8% by weight, 0.3-1.6% by weight, or 0.3-1.5% by weight based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the glidant may be contained in an amount of 0.2-0.4% by weight, and preferably 0.28-0.36% by weight based on the total weight of the oral solid dosage form. In another embodiment of the present invention, the glidant may be contained in an amount of 0.1-1% by weight in the granules, and at the same time in an amount of 0.1-1% by weight outside the granules.

[0096] In another embodiment of the present invention, the oral solid dosage form may further comprise a surfactant. In another embodiment of the present invention, the oral solid dosage form may further comprise a surfactant in the granules, outside the granules, or both. In another embodiment of the present invention, an example of a surfactant may be one or more selected from the group consisting of polysorbate 80, oleoyl macrogolglycerides, caprylocaproyl polyoxylglycerides, linoleoyl polyoxylglycerides, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, sodium oleate, and sodium dioctyl sulfosuccinate, but is not limited thereto.

[0097] In another embodiment of the present invention, the oral solid dosage form may further comprise a solvent in the granules. The solvent is commonly used in this field and is not particularly limited thereto. In another embodiment of the present invention, the solvent may be an organic solvent. In another embodiment of the present invention, the solvent may be selected from water, ethanol, isopropanol, methanol, acetone, and combinations thereof. In another embodiment of the present invention, the solvent is ethanol.

[0098] In addition to the above-mentioned ingredients, the oral solid dosage form of the present invention may include other ingredients such as a film-forming agent, a coloring agent, a flavoring agent, a sweetening agent, a flavoring agent, a pigment, and a preservative, within a range that does not affect the intended use of the oral solid dosage form of the present invention. Specifically, these ingredients may be contained within the granules, outside the granules, or in both cases.

[0099] In another embodiment of the present invention, the carbamate compound of formula 1 may be (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-carbamic acid ethyl ester of the following formula 2:

[0100] [Formula 2]

[0101]

[0102] The oral solid dosage form of the present invention may be any solid dosage form known in the art. In particular, the solid dosage form may be in the form of tablets or capsules, and more specifically, may be in the form of compressed tablets, multi-compressed tablets, sugar-coated tablets, film-coated tablets, hard capsules, or soft capsules. Preferably, the solid dosage form may be in the form of tablets, in particular, in the form of compressed tablets or film-coated tablets, but is not limited thereto.

[0103] The oral solid dosage form according to the present invention can be subjected to a dissolution test in accordance with the United States Pharmacopeia (USP) Apparatus II (a method using a paddle stirrer) and preferably exhibits the following dissolution criteria when conducting an in vitro dissolution test. That is, the oral solid dosage form has such dissolution characteristics that more than 80% of the drug is dissolved within 30 minutes, preferably 85% or more, more preferably 90% or more, and even more preferably 91% or more, or 92.5% or more of the drug is dissolved within 30 minutes.

[0104] Typically, dissolution test results are reported as the average value for a specified number, usually six (6) dosage forms (e.g., tablets, capsules, suspensions, or other dosage forms). Dissolution tests are typically conducted in an aqueous medium buffered to a pH range observed in the gastrointestinal tract (pH 1 to 7.4) and adjusted to 37°C (±1°C) to maintain physiologically relevant conditions. If the dosage form being tested is a tablet, a device with a stirring paddle rotating at 50-75 rpm is typically used to test the tablet dissolution rate. The amount of dissolved carbamate compound of Formula 1 can be routinely determined using HPLC. The dissolution test serves as a quality control tool.

[0105] In another embodiment of the present invention, the oral solid dosage form may include 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 600 mg. More specifically, the active ingredient may be contained in a dose of 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 550 mg, or 600 mg.

[0106] According to one aspect of the present invention, there is provided an oral solid dosage form comprising a large amount of an active ingredient, which not only has an excellent dissolution rate and a minimal tablet weight, but also has improved physical properties necessary for tablet production. In particular, according to the experimental examples of the present invention, there is provided a pharmaceutical composition and a method for producing the same, which has good compressibility, a specified hardness, resistance to abrasion, and good disintegration and dissolution characteristics without the occurrence of tableting defects such as delamination of the upper or lower convex portion of the tablet during tablet production.

[0107] In one embodiment of the present invention, there is provided an oral solid dosage form that further comprises a disintegrant in the granules, and further comprises a disintegrant and a lubricant outside the granules.

[0108] In one embodiment of the present invention, the disintegrant contained in the granules and the disintegrant contained outside the granules may each independently be crospovidone; clays such as bentonite, montmorillonite or veegum; cellulose and cellulose derivatives such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; algins such as sodium alginate or alginic acid; or a mixture thereof. The inclusion of a disintegrant can help increase the disintegration rate without gelling. In one embodiment of the present invention, the disintegrant contained in the granules may be contained in an amount of 0.5-5% by weight based on the total weight of the oral solid dosage form, and the disintegrant contained outside the granules may be contained in an amount of 0.5-5% by weight based on the total weight of the oral solid dosage form.

[0109] In one embodiment of the present invention, the diluent contained in the granules may be cellulose derivatives such as microcrystalline cellulose, crystalline cellulose, or silicified microcrystalline cellulose, or a mixture thereof. The inclusion of a diluent may result in a reduction in disintegration time and an improvement in the hardness of the dosage form. In one embodiment of the present invention, the diluent contained in the granules may be present in an amount of 6-40% by weight, and in particular 5-35% by weight, based on the total weight of the oral solid dosage form.

[0110] In one embodiment of the present invention, the diluent may be located outside the granules. The diluent located outside the granules may be anhydrous lactose. The diluent located outside the granules may not be present, but the inclusion of a diluent outside the granules may improve the hardness of the dosage form. In one embodiment of the present invention, the diluent located outside the granules may be present in an amount of 5-50% by weight, based on the total weight of the oral solid dosage form.

[0111] In one embodiment of the present invention, the binder contained in the granules may be hydroxypropyl cellulose, copovidone, or a mixture thereof. The inclusion of a binder may increase the hardness of the dosage form and reduce friability. In one embodiment of the present invention, the binder contained in the granules may be present in an amount of 2-60% by weight, and in particular 3-40% by weight, based on the total weight of the oral solid dosage form.

[0112] In one embodiment of the present invention, the glidant may be contained outside the granules.

[0113] In one embodiment, in which the physical properties of the present invention are improved, the properties, size, appearance, type, content, and whether the excipients are contained in the granules or outside them, etc., which are not specifically and in detail described, correspond to the above description.

[0114] In one embodiment of the present invention, the oral solid dosage form may comprise 15-90% by weight of the active ingredient, 6-40% by weight of the diluent in the granules, 0.1-1% by weight of the lubricant in the granules, 2-60% by weight of the binder in the granules, 0.5-5% by weight of the disintegrant in the granules, 0.5-5% by weight of the disintegrant outside the granules, and 0.1-2% by weight of the lubricant outside the granules. In one embodiment of the present invention, the oral solid dosage form may comprise 25-60% by weight of the active ingredient, 5-35% by weight of the diluent in the granules, 0.1-1% by weight of the lubricant in the granules, 3-40% by weight of the binder in the granules, 0.5-5% by weight of the granular leavening agent, 0.5-5% by weight of leavening agent outside the granules and 0.1-2% by weight of lubricant outside the granules.In the above embodiment, the diluent contained in the granules may be microcrystalline cellulose, the binder contained in the granules may be hydroxypropyl cellulose, and the disintegrant contained in the granules and the disintegrant contained outside the granules may be crospovidone.

[0115] In one embodiment of the present invention, the oral solid dosage form may be a tablet dosage form. With respect to the tablet dosage form, there are no particular limitations. For example, in addition to a round shape, the tablet may have other shapes such as an elliptical shape, a ring shape, and the like. The thickness of the tablet is also not particularly limited, but the thickness of the tablet may be 1.0-10.0 mm, in particular 2.0-8.0 mm, and more specifically 3.0-5.5 mm. The size of the tablet is not particularly limited, but may be, for example, 6-20 mm in short diameter (diameter in the case of round tablets), 8.0-12.0 mm, and more specifically 9.0-10.5 mm.

[0116] According to one experimental example of the present invention, the above-described oral solid dosage form has excellent hardness, friability, and resistance to delamination of the upper or lower convex portion of the tablet. The hardness of the oral solid dosage form can be measured by the hardness test in accordance with the United States Pharmacopeia (USP) Monograph. <1217> Tablets must have sufficient mechanical strength to prevent damage during subsequent handling or transportation. The mechanical strength of a tablet can be measured using a hardness test, which is related to the tablet size. When tablet hardness is measured in kiloponds (kp), it is typically 0.8 x the tablet diameter (mm) or greater, more preferably 1.1 x the tablet diameter or greater, in particular 1.2 x the tablet diameter or greater, and in particular 1.3 x the tablet diameter or greater.The higher the hardness, the stronger the tablet, which can prevent the aforementioned damage during subsequent processing and transportation. However, with very high hardness, the problem of excessively long tablet disintegration time may arise. Therefore, it is desirable to produce tablets by selecting a hardness that avoids the aforementioned damage while ensuring an appropriate tablet disintegration time. According to one experimental example of the present invention, the above-mentioned oral solid dosage form can have a hardness of 8-20 kp, and in particular, can have a hardness of 8.5-16 kp.

[0117] Detachment of the upper or lower convex portion of a tablet refers to the complete or partial separation of the disc from the upper or lower surface of the tablet during the compression of the material to form a tablet or during subsequent processing and / or handling. Friction refers to the phenomenon in which the tablet surface is damaged, cracked, or fractured during compression or subsequent processing and / or handling, and friability refers to the physical strength of a tablet using a quantitative assessment of the degree of this phenomenon. Since the phenomena of detachment of the upper or lower convex portion of a tablet and friction may occur when the tablet hardness is too low, as a means of preventing this phenomenon, it is preferable to produce tablets by selecting an appropriate tablet hardness so that the phenomenon of detachment of the upper or lower convex portion of the tablet does not occur and at the same time, the tablet has a friability of less than 1% by weight.According to one experimental example of the present invention, the above-mentioned oral solid dosage form has a friability of 1.0% or less, in particular a friability of 0.5% or less, more specifically a friability of 0.3% or less, and more specifically a friability of 0.1-0.3%.

[0118] In another embodiment of the present invention, when the oral solid dosage form is in the form of a film-coated tablet, the oral solid dosage form may include a film-forming agent. Typically, the film-forming agent may be present in an amount of 2-4% by weight based on the total weight of the oral solid dosage form and includes a film-forming agent, a softener, a lubricant, and, optionally, one or more pigments. In another embodiment of the present invention, the film-coated tablet may be obtained by an additional coating step after tabletting. A conventional film-forming agent, such as Opadry, can be used as a film-forming agent.

[0119] According to another aspect of the present invention, there is provided a method for producing an oral solid dosage form, comprising:

[0120] i) mixing a carbamate compound of formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent, a lubricant and a binder, and then compacting;

[0121] ii) grinding and sifting the compacted product obtained in step (i);

[0122] iii) subsequently mixing the granules sieved in step (ii) with excipients comprising a diluent, a lubricant and a disintegrating agent; and

[0123] iv) forming an oral solid dosage form from the mixture of granules and excipients obtained in step (iii).

[0124] In another embodiment of the present invention, step (i) can be carried out by compacting a mixture comprising an active ingredient, a diluent, a lubricant, and a binder using a roller compaction method or an impact compaction method. In another embodiment of the present invention, step (i) can be carried out using a roller compaction method. Roller compaction refers to a method of producing granules by a constant pressure compaction method by passing powder between two rollers. In another embodiment of the present invention, the roller compaction method can be carried out using a roller press.In another embodiment of the present invention, the roller compacted mixture may then be subjected to a grinding process using a fitz mill, oscillator or the like and, if necessary, sifted to obtain granules of the appropriate size.

[0125] In another embodiment of the present invention, the active ingredient of step (i) may be micronized or not. In another embodiment of the present invention, the particle diameter d(0.9) of the micronized active ingredient in step (i) may be 300 μm or less, and the particle diameter d(0.9) of the non-micronized active ingredient may be from 300 μm to 1300 μm.

[0126] In another embodiment of the present invention, micronization of the active ingredient can be accomplished by milling. In particular, micronization can be accomplished by a method using drum mills, such as ball mills, a method using hydrodynamic mills, such as jet mills, or a method using impact mills, such as hammer mills and pin mills, but is not limited to these.

[0127] According to another aspect of the present invention, there is provided a method for producing an oral solid dosage form, comprising:

[0128] a) mixing a carbamate compound of formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent and a binder, and a solvent;

[0129] b) granulating the mixture obtained in step (a), and then successively drying and sieving;

[0130] c) subsequently mixing the dried granules obtained in step (b) with excipients including a lubricant and a disintegrant; and

[0131] d) forming an oral solid dosage form from the mixture of granules and excipients obtained in step (c).

[0132] In another embodiment of the present invention, the active ingredient of step (a) may be micronized, and in particular, the particle diameter d(0.9) of the micronized active ingredient may be 300 μm or less.

[0133] In another embodiment of the present invention, the mixing order in step (a) is not limited. For example, the remaining ingredients can be added to a binder solution in which the solvent and binder are mixed. In addition, other ingredients, including the binder, can be added to the solvent. In another embodiment of the present invention, the solvent can be an organic solvent. In another embodiment of the present invention, the solvent can be selected from water, ethanol, isopropanol, methanol, acetone, and combinations thereof. In another embodiment of the present invention, the solvent is ethanol. The solvent can be contained within the acceptable range defined by ICH recommendations after preparation of the composition.

[0134] In another embodiment of the present invention, the solvent drying process in step (b) can be carried out at a temperature not exceeding about 70°C, preferably at a temperature not exceeding about 60°C, and more preferably at a temperature of 20°C to 50°C, taking into account the stability of the active ingredient when air-dried, fluidized-bed-dried, oven-dried, or microwave-dried.

[0135] According to one aspect of the present invention relating to the solid dosage form with improved physical properties described above, there is provided a method for producing an oral solid dosage form, comprising:

[0136] I) mixing a carbamate compound of formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent, a lubricant, a binder and a disintegrant, and then compacting;

[0137] II) grinding and sifting the mixture obtained in step (I) by sifting through a sieve;

[0138] III) subsequently mixing the granules sieved in step (II) with excipients including a disintegrant and a lubricant; and

[0139] IV) forming an oral solid dosage form from the mixture of granules and excipients obtained in step (III).

[0140] In another embodiment of the present invention, step (i) can be carried out by compacting a mixture including an active ingredient, a diluent, a lubricant, a binder, and a disintegrant using a roller compaction method or an impact compaction method. In another embodiment of the present invention, step (i) can be carried out using an impact compaction method. More specifically, the impact compaction method refers to a method of producing granules in the form of wide and flat tablets or pellets by grinding or compacting a powder mixture using a single-punch tablet press or the like. In another embodiment of the present invention, the impact compaction method can be carried out using a single-punch tablet press.In another embodiment of the present invention, the resulting compacted product may then be sieved using a sieve or subjected to a grinding process using a fitz mill, oscillator or the like, and, if necessary, sieved to obtain granules of the appropriate size.

[0141] In another embodiment of the present invention, the compacted product obtained in step (I) may have a density of 0.5-1.5 g / ml, in particular 0.8-1.2 g / ml. In addition, the compacted product obtained in step (I) may have a hardness of 1-5 kp, in particular a hardness of 2-3 kp.

[0142] The above-described oral solid dosage form can be produced by the methods for producing an oral solid dosage form according to the embodiments of the present invention. Therefore, all explanations regarding the nature, size, appearance, type, content, as well as whether the granules contain a diluent, binder, disintegrant, lubricant, glidant, and other ingredients described above are common to those used in the methods for producing an oral solid dosage form.

[0143] The oral solid dosage form obtained by the above method may have a shape such as round, oval, oblong, rectangular, cylindrical, or other suitable shape. Furthermore, the size may be varied depending on the content of the active ingredient.

[0144] In another embodiment of the present invention, when the oral solid dosage form is in the form of a coated tablet, a coating step after tabletting may be further included. In particular, the coated tablet may be a film-coated tablet. Typically, the film-forming agent may be present in an amount of 2% by weight to 4% by weight, based on the total weight of the oral solid dosage form. The film-forming agent may include a film-forming agent, a softener, a lubricant, and, optionally, one or more pigments. A conventional film-forming agent such as Opadry can be used as a film-forming agent.

[0145] The oral solid dosage form provided in accordance with the present invention can be used for the prevention or treatment of diseases of the central nervous system.

[0146] In another embodiment of the present invention, the central nervous system disease may be selected from, but is not limited to, anxiety, depression, seizures, epilepsy, migraine, bipolar disorder, drug abuse, smoking, attention deficit hyperactivity disorder (ADHD), obesity, sleep disorders, stroke, neuropathic pain, cognitive disorders, neurodegeneration, and muscle spasm.

[0147] As used herein, the terms “prevent,” “prevention,” and “prophylaxis” refer to reducing or eliminating the likelihood of a disease.

[0148] The terms “treat,” “treatment,” and “therapy” as used herein refer to the complete or partial elimination of a disease and / or its associated symptoms.

[0149] The present invention will now be explained in more detail using examples. However, the following examples are intended only to illustrate one or more embodiments and are not intended to limit the scope of the invention.

[0150] Examples 1-7

[0151] Hard granules were prepared using the ingredients and contents shown in Table 1, and the production method was as follows. After mixing (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-carbamic acid ethyl ester of formula 2 with hydroxypropyl methylcellulose and microcrystalline cellulose, magnesium stearate was added and mixed. Then, the mixture was compacted with a force of 3000-3500 LBF on a roller press (Freund Corporation, TFC-Lab) to obtain a platelet-shaped compressed product, and then granules were obtained by grinding and sieving in an oscillator (Freund Corporation, vector screen - 20 mesh). The granules were mixed with the diluent, glidant, and disintegrant shown in Table 1, then magnesium stearate was additionally added as a lubricant, and then tableted.

[0152]

[0153]

[0154]

[0155] Comparative Examples 1 and 2

[0156] According to the composition and content shown in Table 2, the ingredients were mixed and pressed (direct pressing).

[0157]

[0158] Example 8

[0159] According to the contents shown in Table 3, the ingredients were mixed in a high-speed mixer, and then hydroxypropyl cellulose and ethanol were added as a binding solution for mixing and granulation. The granules were dried in a dryer set at a temperature of 60°C until the drying loss reached 0.5-2%. The resulting dried product was sieved with a grinding sieve and sieved. The ingredients (disintegrant, lubricant, and glidant) shown in Table 3 were added to the resulting granules and finally mixed with a V-type mixer. The resulting final mixture was compressed into tablets using a tablet press.

[0160]

[0161] Examples 9-12

[0162] In addition, it was necessary to improve the physical properties, such as compressibility, required for producing a carbamate compound with low plasticity in the form of high-content tablets. Solid granules were obtained using the ingredients and contents shown in Table 4, and the production method was as follows. After mixing (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-carbamic acid ethyl ester of Formula 2 with hydroxypropyl cellulose and microcrystalline cellulose, sodium stearyl fumarate was added and mixed. The mixture was then compacted using a single-punch tablet press (Korsch AG, EK0 single-punch tablet press in combination with an AR402 central motor unit [ERWEKA GmbH]) to obtain a preform with a density of 1.0-1.1 g / ml and a hardness of 2-3 cr, and granules were obtained by sifting the preform through an 18-mesh sieve.After mixing the granules with the glidant and disintegrant listed in Table 4, sodium stearyl fumarate was further added as a lubricant and then tableted.

[0163]

[0164]

[0165] Experimental Example 1: Dissolution Test

[0166] A dissolution test was performed on the solid dosage forms obtained in Examples 1 to 10 and Comparative Examples 1 and 2 in accordance with the US Pharmacopoeia under the following conditions.

[0167] <Dissolution conditions>

[0168] Dissolution medium: 0.01N hydrochloric acid aqueous solution, 900ml.

[0169] Device: Apparatus II (method using paddle stirrer), 75 rpm

[0170] Temperature: 37°C

[0171] The results of the dissolution rate are shown in Tables 5 and 6 and Figs. 1-3. In Table 5, the dissolution rate is expressed as a % of the content of the released active ingredient based on the content of the active ingredient contained in the tablet.

[0172]

[0173]

[0174] Experimental Example 2: Hardness Test

[0175] The hardness of the tablets obtained according to Examples 9-12 was measured according to the US Pharmacopoeia Monograph <1217> , friability was measured according to the US Pharmacopoeia Monograph <1216> , the occurrence of delamination of the upper or lower convex part of the tablet was checked, and the results are presented in Table 7.

[0176]

Claims

1. An oral solid dosage form that comprises granules comprising a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient; a diluent; and a binder: where R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and one of A1 and A2 is CH and the other is N; wherein the active ingredient is contained in an amount of from 25 to 70% by weight based on the total weight of the oral solid dosage form; wherein the diluent is one or more selected from the group consisting of corn starch, pregelatinized starch, potato starch, wheat starch, sweet potato starch, tapioca starch, rice starch, beeswax, sucrose, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, aluminum silicate, hydroxypropyl starch, microcrystalline cellulose, crystalline cellulose and silicified microcrystalline cellulose; wherein said diluent contained in the granules is contained in an amount of 6 to 40% by weight based on the total weight of the oral solid dosage form; wherein the binder is one or more selected from the group consisting of alginic acid, ammonium methacrylate copolymer, ammonium methacrylate copolymer dispersion, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, sodium carboxymethylcellulose, microcrystalline cellulose, copovidone, dextrin, ethylcellulose, gelatin, glucose syrup, guar gum, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hypromellose, hypromellose acetate succinate, maltodextrin, maltose, methylcellulose, polyethylene oxide, povidone, corn starch, potato starch, pregelatinized starch, modified pregelatinized starch and tapioca starch, wherein the said binder contained in the granules is contained in an amount of from 3 to 40% by weight based on the total weight of the oral solid dosage form, wherein the oral solid dosage form contains a lubricant, a disintegrant and a glidant outside the granules; wherein the lubricant is one or more selected from the group consisting of glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, starch, stearic acid, talc and zinc stearate; wherein said lubricant contained outside the granules is contained in an amount of 0.1-2% by weight based on the total weight of the oral solid dosage form; wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, anhydrous lactose, lactose monohydrate, sodium starch glycolate, crospovidone, carboxymethylcellulose and its pharmaceutically acceptable salt, hydroxypropyl cellulose, corn starch and croscarmellose; wherein said disintegrant contained outside the granules is contained in an amount of 1-10% by weight based on the total weight of the oral solid dosage form; wherein the glidant is one or more selected from the group consisting of colloidal silicon dioxide, talc, silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate, calcium hydrogen phosphate and calcium carbonate; and wherein said glidant contained outside the granules is contained in an amount of 0.1-1 wt.% based on the total weight of the oral solid dosage form.

2. An oral solid dosage form according to claim 1, which comprises 25-65% by weight of the active ingredient.

3. An oral solid dosage form according to claim 1 or 2, wherein the particle diameter d (0.9) of the active ingredient is from 35 to 1300 μm.

4. An oral solid dosage form according to any one of claims 1-3, wherein the particle diameter d (0.9) of the active ingredient is 300 μm or less.

5. An oral solid dosage form according to any one of claims 1-4, which further comprises a diluent outside the granules, wherein the diluent is one or more selected from the group consisting of corn starch, pregelatinized starch, potato starch, wheat starch, sweet potato starch, tapioca starch, rice starch, beeswax, sucrose, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, aluminum silicate, hydroxypropyl starch, microcrystalline cellulose, crystalline cellulose and silicified microcrystalline cellulose.

6. An oral solid dosage form according to claim 5, wherein the diluent, additionally contained outside the granules, is contained in an amount of 5-50% by weight based on the total weight of the oral solid dosage form.

7. An oral solid dosage form according to any one of claims 1-6, which further comprises a lubricant in granules, wherein the lubricant is one or more selected from the group consisting of glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, starch, stearic acid, talc and zinc stearate.

8. An oral solid dosage form according to claim 7, wherein the lubricant contained in the granules is contained in an amount of 0.1-1% by weight based on the total weight of the oral solid dosage form.

9. The oral solid dosage form of claim 1, which further comprises a disintegrant in the granules, wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, anhydrous lactose, lactose monohydrate, sodium starch glycolate, crospovidone, carboxymethylcellulose and a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, corn starch and croscarmellose.

10. The oral solid dosage form according to claim 9, wherein the disintegrant contained in the granules is contained in an amount of 1-10% by weight based on the total weight of the oral solid dosage form.

11. An oral solid dosage form according to claim 1, which additionally comprises a glidant in granules.

12. An oral solid dosage form according to claim 11, wherein the glidant contained in the granules is contained in an amount of 0.1-1% by weight based on the total weight of the oral solid dosage form.

13. An oral solid dosage form according to any one of claims 1-12, which further comprises a solvent in the granules.

14. The oral solid dosage form according to claim 1, wherein the binder contained in the granules is hydroxypropyl cellulose, copovidone or a mixture thereof.

15. The oral solid dosage form according to claim 9, wherein the disintegrant contained in the granules is contained in an amount of 0.5-5% by weight based on the total weight of the oral solid dosage form and the disintegrant contained outside the granules is contained in an amount of 0.5-5% by weight based on the total weight of the oral solid dosage form.

16. An oral solid dosage form according to item 9, which has a hardness of 8-20 cr.

17. An oral solid dosage form according to claim 9, which has a friability of 1.0% or less.

18. An oral solid dosage form according to claim 1, wherein the carbamate compound of formula 1 is (R)-l-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamic acid of the following formula 2: [Formula 2] 19. A method for producing an oral solid dosage form, comprising: i) mixing a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent, a lubricant and a binder, and then compacting; ii) grinding and sieving the compacted product obtained in step i) to obtain granules; iii) subsequently mixing the granules screened in step ii) with excipients comprising a diluent, a lubricant, a glidant and a disintegrant; and iv) forming an oral solid dosage form from the mixture obtained in step iii): where R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and one of A1 and A2 is CH and the other is N; wherein the granules contain from 25 to 70% by weight of the active ingredient based on the total weight of the oral solid dosage form; wherein the diluent is one or more selected from the group consisting of corn starch, pregelatinized starch, potato starch, wheat starch, sweet potato starch, tapioca starch, rice starch, beeswax, sucrose, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, aluminum silicate, hydroxypropyl starch, microcrystalline cellulose, crystalline cellulose and silicified microcrystalline cellulose; wherein said diluent contained in the granules is contained in an amount of 6 to 40 wt.% based on the total weight of the oral solid dosage form and said diluent contained outside the granules is contained in an amount of 5 to 50 wt.% based on the total weight of the oral solid dosage form; wherein the binder is one or more selected from the group consisting of alginic acid, ammonium methacrylate copolymer, ammonium methacrylate copolymer dispersion, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, sodium carboxymethylcellulose, microcrystalline cellulose, copovidone, dextrin, ethylcellulose, gelatin, glucose syrup, guar gum, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hypromellose, hypromellose acetate succinate, maltodextrin, maltose, methylcellulose, polyethylene oxide, povidone, corn starch, potato starch, pregelatinized starch, modified pregelatinized starch and tapioca starch; wherein said binder contained in the granules is contained in an amount of from 3 to 40% by weight based on the total weight of the oral solid dosage form; wherein the lubricant is one or more selected from the group consisting of glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, starch, stearic acid, talc and zinc stearate, wherein said lubricant contained in the granules is contained in an amount of 0.1-1% by weight based on the total weight of the oral solid dosage form and said lubricant contained outside the granules is contained in an amount of 0.1-2% by weight based on the total weight of the oral solid dosage form; wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, anhydrous lactose, lactose monohydrate, sodium starch glycolate, crospovidone, carboxymethylcellulose and its pharmaceutically acceptable salt, hydroxypropyl cellulose, corn starch and croscarmellose; wherein said disintegrant contained outside the granules is contained in an amount of 1-10% by weight based on the total weight of the oral solid dosage form; wherein the glidant is one or more selected from the group consisting of colloidal silicon dioxide, talc, silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate, calcium hydrogen phosphate and calcium carbonate; and wherein said glidant contained outside the granules is contained in an amount of 0.1-1% by weight based on the total weight of the oral solid dosage form.

20. A method for producing an oral solid dosage form, comprising: a) mixing a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent and a binder, and a solvent; b) granulating the mixture obtained in step a), and then sequentially drying and sieving to obtain granules; c) subsequently mixing the granules obtained in step b) with excipients comprising a lubricant, a glidant and a disintegrant; and d) forming an oral solid dosage form from the mixture obtained in step c): where R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and one of A1 and A2 is CH and the other is N; wherein the granules contain from 25 to 70% by weight of the active ingredient based on the total weight of the oral solid dosage form; wherein the diluent is one or more selected from the group consisting of corn starch, pregelatinized starch, potato starch, wheat starch, sweet potato starch, tapioca starch, rice starch, beeswax, sucrose, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, aluminum silicate, hydroxypropyl starch, microcrystalline cellulose, crystalline cellulose and silicified microcrystalline cellulose; wherein said diluent contained in the granules is contained in an amount of 6 to 40% by weight based on the total weight of the oral solid dosage form; wherein the binder is one or more selected from the group consisting of alginic acid, ammonium methacrylate copolymer, ammonium methacrylate copolymer dispersion, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, sodium carboxymethylcellulose, microcrystalline cellulose, copovidone, dextrin, ethylcellulose, gelatin, glucose syrup, guar gum, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hypromellose, hypromellose acetate succinate, maltodextrin, maltose, methylcellulose, polyethylene oxide, povidone, corn starch, potato starch, pregelatinized starch, modified pregelatinized starch, and tapioca starch; and wherein the said binder contained in the granules is contained in an amount of from 3 to 40% by weight based on the total weight of the oral solid dosage form, wherein the lubricant is one or more selected from the group consisting of glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, starch, stearic acid, talc and zinc stearate; wherein said lubricant is contained in an amount of 0.2-2% by weight based on the total weight of the oral solid dosage form; wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, anhydrous lactose, lactose monohydrate, sodium starch glycolate, crospovidone, carboxymethylcellulose and its pharmaceutically acceptable salt, hydroxypropyl cellulose, corn starch and croscarmellose; wherein said disintegrant is contained in an amount of 1-15% by weight based on the total weight of the oral solid dosage form; wherein the glidant is one or more selected from the group consisting of colloidal silicon dioxide, talc, silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate, calcium hydrogen phosphate and calcium carbonate; and wherein said glidant contained outside the granules is contained in an amount of 0.1-1% by weight based on the total weight of the oral solid dosage form.

21. A method for producing an oral solid dosage form, comprising: I) mixing a carbamate compound of the following formula 1 or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as an active ingredient with excipients including a diluent, a lubricant, a binder and a disintegrant, and then compacting; II) grinding and sifting the mixture obtained in stage I) by sifting through a sieve to obtain granules; III) subsequent mixing of the granules screened in step II) with excipients comprising a disintegrant, a glidant and a lubricant; and IV) formation of an oral solid dosage form from the mixture obtained in stage III): where R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 perfluoroalkyl, C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and one of A1 and A2 is CH and the other is N; wherein the granules contain from 25 to 70% by weight of the active ingredient based on the total weight of the oral solid dosage form; wherein the diluent is one or more selected from the group consisting of corn starch, pregelatinized starch, potato starch, wheat starch, sweet potato starch, tapioca starch, rice starch, beeswax, sucrose, anhydrous lactose, lactose monohydrate, mannitol, sorbitol, xylitol, lactitol, maltitol, erythritol, aluminum silicate, hydroxypropyl starch, microcrystalline cellulose, crystalline cellulose and silicified microcrystalline cellulose; wherein said diluent contained in the granules is contained in an amount of 6 to 40% by weight based on the total weight of the oral solid dosage form; wherein the binder is one or more selected from the group consisting of alginic acid, ammonium methacrylate copolymer, ammonium methacrylate copolymer dispersion, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, sodium carboxymethylcellulose, microcrystalline cellulose, copovidone, dextrin, ethylcellulose, gelatin, glucose syrup, guar gum, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, hypromellose, hypromellose acetate succinate, maltodextrin, maltose, methylcellulose, polyethylene oxide, povidone, corn starch, potato starch, pregelatinized starch, modified pregelatinized starch and tapioca starch; wherein said binder contained in the granules is contained in an amount of from 3 to 40% by weight based on the total weight of the oral solid dosage form; wherein the lubricant is one or more selected from the group consisting of glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium lauryl sulfate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate, starch, stearic acid, talc and zinc stearate; wherein said lubricant contained in the granules is contained in an amount of 0.1-1 wt.% based on the total weight of the oral solid dosage form and the lubricant contained outside the granules is contained in an amount of 0.1-2 wt.% based on the total weight of the oral solid dosage form; wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, microcrystalline cellulose, starch, anhydrous lactose, lactose monohydrate, sodium starch glycolate, crospovidone, carboxymethylcellulose and its pharmaceutically acceptable salt, hydroxypropyl cellulose, corn starch and croscarmellose; and wherein said disintegrant contained in the granules is contained in an amount of 1-10 wt.% based on the total weight of the oral solid dosage form and said disintegrant contained outside the granules is contained in an amount of 1-10 wt.% based on the total weight of the oral solid dosage form; wherein the glidant is one or more selected from the group consisting of colloidal silicon dioxide, talc, silicon dioxide, light anhydrous silicic acid, aluminum silicate, calcium silicate, calcium hydrogen phosphate and calcium carbonate; and wherein said glidant contained outside the granules is contained in an amount of 0.1-1% by weight based on the total weight of the oral solid dosage form.

22. A method for producing an oral solid dosage form according to claim 20, wherein the active ingredient is micronized and has a particle diameter d(0.9) of 300 μm or less.

23. A method for producing an oral solid dosage form according to claim 19 or 21, wherein the active ingredient is not micronized and has a particle diameter d (0.9) from 300 to 1300 μm.

24. A method for producing an oral solid dosage form according to claim 19, wherein the carbamate compound of formula 1 is (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamic acid of the following formula 2:

25. A method for producing an oral solid dosage form according to claim 20, wherein the carbamate compound of Formula 1 is (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamic acid of the following Formula 2:

26. A method for producing an oral solid dosage form according to claim 21, wherein the carbamate compound of Formula 1 is (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of carbamic acid of the following Formula 2:

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