Oral soild preparations

Abstract

The objective of this invention is to provide an oral solid dosage form that exhibits rapid dissolution even when the content of linzagoli or its pharmacologically acceptable salt varies over a wide range. This invention relates to an oral solid dosage form containing: linzagoli or its pharmacologically acceptable salt; crystalline cellulose; low-substituted hydroxypropyl cellulose; and a disintegrant selected from one or more of the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium.

Description

Oral solids This invention relates to an oral solid preparation containing a condensed heterocyclic compound or a pharmacologically acceptable salt thereof. More specifically, this invention relates to an oral solid preparation having gonadotropin-releasing hormone antagonistic activity, used as a preventive or therapeutic agent for sex hormone-dependent diseases such as benign prostatic hyperplasia, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, and dysmenorrhea, containing a useful compound represented by the following formula (chemical name: 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-disideloxy-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid, hereinafter referred to as "Linzagolix") or a pharmacologically acceptable salt thereof as the active ingredient. [Chemical 1] Preferably, the present invention relates to an oral solid preparation containing a compound represented by the following formula (chemical name: 3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2,4-disideloxy-1,2,3,4-tetrahydrothieno[3,4-d]pyrimidine-5-carboxylic acid choline salt, hereinafter referred to as "linzagoli choline salt") as an active ingredient. [Chemical 2] Linzagoribe is known to have gonadotropin-releasing hormone antagonistic effects and is useful as a preventive or therapeutic agent for sex hormone-dependent diseases such as benign prostatic hyperplasia, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, and dysmenorrhea (see, for example, Patent Documents 1 and 2). To date, pharmaceutical compositions containing linzagoribe or its pharmacologically acceptable salts as active ingredients have been reported. General descriptions of condensed heterocyclic derivatives containing linzagoribe as a general formula have illustrated oral administration formulations as the delivery form of pharmaceutical compositions, which can be formulated by mixing with conventional formulation carriers (see, for example, Patent Document 1). However, the general description in Patent Document 1 does not provide any indication of a specific formulation for selecting an oral solid dosage form, and this oral solid dosage form contains linzagoribe or its pharmacologically acceptable salts as active ingredients, which have rapid dissolution properties. Patent Document 1: International Patent Publication No. WO2007 / 046392; Patent Document 2: International Patent Publication No. WO2011 / 099507. (The problem the invention aims to solve) The inventors conducted research to develop formulations that exhibit rapid dissolution even when the content of the active ingredient varies over a wide range. They found that increasing the content of linzagoli or its pharmacologically acceptable salts in oral solid formulations (e.g., 60% by mass) reduced dissolution, failing to meet the requirement of rapid dissolution. The objective of this invention is to provide an oral solid formulation that exhibits rapid dissolution even when the content of linzagoli or its pharmacologically acceptable salts varies over a wide range. Furthermore, the objective of this invention is to provide an oral solid formulation containing linzagoli or its pharmacologically acceptable salts, which exhibit good storage stability. (Technical means to solve the problem) In order to solve the above-mentioned problems, the inventors conducted in-depth research and found that the problems could be solved by the following means, thus completing the present invention. That is, the present invention relates to the following [1] to

[18] . [1] An oral solid preparation comprising the following 1) to 4): 1) linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; 3) low-substituted hydroxypropyl cellulose; and 4) a disintegrant selected from one or more of the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium. [2] An oral solid preparation as described above [1] comprises the following A) and B): A) a granule comprising the following 1) to 3); 1) linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; and 3) low-substituted hydroxypropyl cellulose; and B) a disintegrant selected from one or more of the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium. [3] The oral solid preparation described in [1] or [2] above, wherein linzagoli or a pharmacologically acceptable salt thereof is linzagoli-choline salt. [4] The oral solid preparation described in any of [1] to [3] above, wherein the oral solid preparation has a dissolution rate of 80% or more after 15 minutes in a test solution or water at pH 6.8. [5] The oral solid preparation described in any of [1] to [4] above, wherein the total amount of low-substituted hydroxypropyl cellulose and disintegrant in the oral solid preparation is 20% by mass or less, and the disintegrant is one or more selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium. [6] The oral solid preparation described in any of [1] to [5] above contains a binder. [7] The oral solid dosage form described in [6] above, wherein the binder is selected from one or more of the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol. [8] The oral solid dosage form described in [6] or [7] above, wherein the content of the binder in the oral solid dosage form is 5% by mass or less. [9] The oral solid dosage form described in any one of [1] to [8] above, wherein the content of linzagoli or its pharmacologically acceptable salt in the oral solid dosage form is 15% to 65% by mass.

[10] The oral solid dosage form described in any one of [1] to [9] above, wherein the content of crystalline cellulose in the oral solid dosage form is 15% by mass or more.

[11] The oral solid dosage form described in any one of [1] to

[10] above contains an excipient.

[12] In the oral solid preparations described in

[11] above, the excipient is selected from one or more of the group consisting of lactose hydrate and D-mannitol.

[13] In the oral solid preparations described in any of [1] to

[12] above, the amount of linzagoli or its pharmacologically acceptable salt in each oral solid preparation is 75 mg, 100 mg or 200 mg, calculated as linzagoli.

[14] The oral solid preparation described in any of [1] to

[13] above is an tablet.

[15] The oral solid preparation described in

[14] above is a film-coated tablet.

[16] The oral solid preparation described in

[15] above is film-coated using one or more coating agents selected from the group consisting of hydroxypropyl methylcellulose and polyvinyl alcohol-polyethylene glycol graft copolymer.

[17] The oral solid preparation described in any of [1] to

[16] above is an elliptical tablet with a longest dimension of 20 mm or less.

[18] The oral solid preparation described in any of [1] to

[16] above is a round tablet with a diameter of 13 mm or less. (Compared to the efficacy of the prior art). The oral solid formulation of this invention exhibits rapid dissolution even when the content of linzagoli or its pharmacologically acceptable salts varies over a wide range. Furthermore, the oral solid formulation of this invention demonstrates good storage stability. The following describes embodiments of the present invention in more detail. In this invention, unless otherwise stated, all terms have the following meanings. The linzagoli or its pharmacologically acceptable salt used in this invention can be commercially available or manufactured by methods described in the literature (e.g., see Patent Document 1) or based on such methods. In this invention, "linzagoli or its pharmacologically acceptable salt" is preferably linzagoli-choline salt. The linzagoli or its pharmacologically acceptable salt used in this invention is, for example, a particle without agglomeration, and can be crushed, pulverized, etc., as needed. The average particle size (50% particle size, D50) of the linzagoli or its pharmacologically acceptable salt is, for example, 50 μm or less, preferably 40 μm or less. As an embodiment, the average particle size of the linzagoli or its pharmacologically acceptable salt is 1 to 40 μm, more preferably 1 to 30 μm. In this invention, the amount of linzagoline or its pharmacologically acceptable salt in the oral solid dosage form is 25–200 mg, preferably 50–200 mg, and more preferably 75–200 mg, calculated in linzagoline. As an embodiment, the amount of linzagoline or its pharmacologically acceptable salt in the oral solid dosage form is 25, 50, 75, 100, 125, 150, 175, or 200 mg, calculated in linzagoline, preferably 50, 75, 100, or 200 mg. In this invention, the content of linzagoli or its pharmacologically acceptable salt in the oral solid dosage form is, for example, 10-65% by mass, 15-65% by mass, 15-60% by mass, or 20-60% by mass. As an embodiment, the content of linzagoli or its pharmacologically acceptable salt in the oral solid dosage form is preferably 25-65% by mass, more preferably 30-60% by mass. As an embodiment, each oral solid dosage form of this invention contains 15-60% by mass of linzagoli-choline salt. As one embodiment, the oral solid dosage form is a tablet containing 25, 50, 75, 100, 125, 150, 175, or 200 mg of linzagol or a pharmacologically acceptable salt thereof, preferably 50, 75, 100, or 200 mg, and the tablet diameter is 10 mm or less, preferably 8 mm or less, and more preferably 6 mm or less. As one embodiment, the oral solid dosage form is a tablet containing 50, 75, 100, or 200 mg of linzagol or a pharmacologically acceptable salt thereof, and the tablet diameter is 10 mm or less. In this invention, the term "wide range of active ingredient content" means that the content of linzagol or a pharmacologically acceptable salt thereof in the oral solid dosage form is, for example, 15-60% by mass. The oral solid formulation of the present invention can also be used in combination with other pharmaceutical agents. When the oral solid formulation of the present invention is used in combination with other pharmaceutical agents, the timing of administration is not limited; they can be administered simultaneously or at intervals. Furthermore, the oral solid formulation of the present invention can be administered as a separate formulation with other pharmaceutical agents, or as a single formulation comprising the oral solid formulation of the present invention and other pharmaceutical agents. As an embodiment, the oral solid formulation of the present invention may contain one or more other pharmaceutical agents besides linzagoli or its pharmacologically acceptable salts. Examples of "other pharmaceutical agents" used in the present invention include, for example, estrogen (e.g., estradiol) and progesterone (e.g., norethindrone acetate). The "low-substituted hydroxypropyl cellulose" used in this invention is not particularly limited by the user as it is used as a pharmaceutical additive, and one or more types can be used. In this invention, "low-substituted hydroxypropyl cellulose" means low-substituted hydroxypropyl cellulose containing 5.0% to 16.0% (dry weight) of hydroxypropoxy groups after drying. Preferably, it contains 8% to 14% (dry weight), and more preferably, 11% (dry weight) of hydroxypropoxy groups. Examples of low-substituted hydroxypropyl cellulose include: LH-11, LH-21, LH-31, LH-22, and LH-32 (manufactured by Shin-Etsu Chemical Industry). In this invention, the low-substituted hydroxypropyl cellulose is preferably LH-11, LH-21, or LH-31, more preferably LH-21 or LH-31, and most preferably LH-21. In this invention, the content of low-substituted hydroxypropyl cellulose in the oral solid formulation is preferably 5-20% by mass, more preferably 5-15% by mass, and most preferably 5-10% by mass. As an embodiment, the content of low-substituted hydroxypropyl cellulose in the oral solid formulation is preferably 5% by mass, 10% by mass, 15% by mass, or 20% by mass. The "crystalline cellulose" used in this invention is not particularly limited by the user as it is used as a pharmaceutical additive, and one or more types can be used. Examples of crystalline cellulose include: CEOLUS (registered trademark) PH-101, CEOLUS (registered trademark) PH-301 (Asahi Kasei Chemicals), etc. In this invention, the crystalline cellulose is preferably CEOLUS (registered trademark) PH-101 (Asahi Kasei Chemicals). In this invention, the content of crystalline cellulose in the oral solid dosage form is preferably 15-30% by mass, more preferably 15-25% by mass. As an embodiment, the content of crystalline cellulose in the oral solid dosage form is preferably 15% by mass, 20% by mass, 25% by mass, or 30% by mass. The use of "sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium" in this invention is not particularly limited by the user as it is used as a pharmaceutical additive; one or more can be used. In this invention, "one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium" can be added to the granules or added as a post-powder component outside the granules. As an embodiment, it is preferred that one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium are added as a post-powder component outside the granules containing linzagoli or a pharmacologically acceptable salt thereof. In this invention, "post-powder component" means an additive added to the outside of the granules. As an embodiment, in the oral solid formulation of the present invention, one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium are used, preferably one or more disintegrants selected from the group consisting of calcium carboxymethyl cellulose and croscarmellose sodium. In the present invention, the content of one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium in the oral solid formulation is preferably 5-15% by mass, more preferably 5-10% by mass. In this invention, the total amount of "low-substituted hydroxypropyl cellulose" and "one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium" in the oral solid formulation is, for example, 25% by mass or less, 20% by mass or less, 15% by mass or less, or 10% by mass or less. In this invention, the total amount of "low-substituted hydroxypropyl cellulose" and "one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium" in the oral solid formulation is 10 to 25% by mass, preferably 10 to 20% by mass, and more preferably 10 to 15% by mass. As an embodiment, the combination of "low-substituted hydroxypropyl cellulose" and "one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium" in the oral solid formulation of the present invention can be exemplified by, for example, a combination of low-substituted hydroxypropyl cellulose and croscarmellose sodium, or a combination of low-substituted hydroxypropyl cellulose and calcium carboxymethyl cellulose. A preferred combination is a combination of low-substituted hydroxypropyl cellulose and croscarmellose sodium. In this invention, "mass%" means the mass percentage of the component in an orally administered solid dosage form. In the case of film coating, the "mass%" is calculated by removing the mass of the film-coated portion. In this invention, "average particle size" means the 50% particle size (mass median particle size, D50). This 50% particle size can be determined using a laser diffraction particle size distribution measuring device (e.g., LMS-2000e, manufactured by SEISHIN) via a wet method. In this invention, "rapid dissolution" means, based on the Japanese Pharmacopoeia Dissolution Test Method 2, for example, under the conditions of Test Example 1 or Test Example 2, when conducting a dissolution test on an orally administered solid formulation, the dissolution rate at the 15-minute time point is 80% or more, 85% or more, 90% or more, or 95% or more. Furthermore, as an embodiment, the dissolution rate at the 30-minute time point is preferably 90% or more, 95% or more, 97% or more, or 99% or more. In this invention, "good storage stability" means that when the oral solid formulation is stored under certain storage conditions, the amount of total linzagoli-derived compounds is less than 1%. As an embodiment, the oral solid formulation of this invention exhibits rapid dissolution even when stored under open conditions (e.g., 6 months) at a temperature of 40°C and a relative humidity of 75%, and has good storage stability because the total linzagoli-derived compounds do not increase over time. For example, storage stability can be evaluated by the method described in Test Example 3. As an embodiment, the oral solid formulation of the present invention exhibits rapid dissolution even when the content of linzagoli or its pharmacologically acceptable salts is high (e.g., 50% by mass or more). Therefore, the oral solid formulation can be miniaturized, and improved patient compliance is expected. As an embodiment, the content of linzagoli or its pharmacologically acceptable salts in the oral solid formulation is preferably 50-65% by mass, more preferably 55-65% by mass. The oral solid dosage form of the present invention is preferably the following formulation. [Oral Solid Dosage Form 1] An oral solid dosage form comprising the following (1) to (7): [Oral solid preparation 2] An oral solid preparation containing the following (1) to (7): [Oral solid preparation 3] An oral solid preparation containing the following (1) to (7): As one embodiment, the present invention is a tablet. A tablet comprising the following 1) to 3): 1) 15 to 60% by mass of linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; and 3) 10 to 20% by mass of a disintegrant; wherein the disintegrant is a combination of at least two disintegrants, and the mass percentage of the disintegrant is the total amount of the two or more disintegrants. As one embodiment, the present invention is a tablet comprising the following 1) to 4): 1) 15 to 60% by weight of linzagoli or a pharmacologically acceptable salt thereof; 2) 15 to 25% by weight of crystalline cellulose; 3) 5 to 10% by weight of low-substituted hydroxypropyl cellulose; and 4) 5% by weight of croscarmellose sodium. As one embodiment, the present invention is a tablet comprising the following 1) to 4): 1) 55 to 65% by weight of linzagoli or a pharmacologically acceptable salt thereof; 2) 15 to 25% by weight of crystalline cellulose; 3) 5 to 10% by weight of low-substituted hydroxypropyl cellulose; and 4) 5% by weight of croscarmellose sodium. As an embodiment, the present invention is the following tablet. A tablet comprising the following A) and B): A) comprising the following granules 1) to 3): 1) linzagoli or a pharmacologically acceptable salt thereof with an average particle size of less than 40 μm; 2) crystalline cellulose; and 3) low-substituted hydroxypropyl cellulose; and B) croscarmellose sodium cellulose. As an embodiment, the present invention is a tablet comprising the following A) to C): A) granules comprising the following 1) to 3): 1) 15-60% by mass of linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; and 3) low-substituted hydroxypropyl cellulose; B) croscarmellose sodium; and C) hydroxypropyl cellulose; wherein the total amount of the low-substituted hydroxypropyl cellulose and croscarmellose sodium is 10-20% by mass. As an embodiment, the present invention is a tablet comprising the following A) to C): A) granules comprising the following 1) to 3): 1) 55-65% by mass of linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; and 3) low-substituted hydroxypropyl cellulose; B) croscarmellose sodium; and C) hydroxypropyl cellulose; wherein the total amount of the low-substituted hydroxypropyl cellulose and croscarmellose sodium is 10-20% by mass. As an embodiment, the present invention is a tablet comprising the following A) and B): A) granules comprising the following 1) to 3): 1) 15 to 60% by weight of linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; and 3) low-substituted hydroxypropyl cellulose; and B) croscarmellose sodium. As an embodiment, the present invention is a tablet comprising the following A) and B): A) granules comprising the following 1) to 3): 1) 55 to 65% by weight of linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; and 3) low-substituted hydroxypropyl cellulose; and B) croscarmellose sodium. As an embodiment, the present invention is a tablet. A tablet comprising the following A) and B) as a powder component: A) comprising granules comprising the following 1) to 3): 1) linzagoli or a pharmacologically acceptable salt thereof with an average particle size of 1 to 40 μm; 2) crystalline cellulose; and 3) low-substituted hydroxypropyl cellulose; and B) croscarmellose sodium; and the content of linzagoli or a pharmacologically acceptable salt thereof is 15 to 60% by mass. As one embodiment, the present invention is a tablet comprising the following: 1) to 5): 1) linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; 3) low-substituted hydroxypropyl cellulose; 4) a disintegrant selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium; and 5) a coating agent selected from the group consisting of hydroxypropyl methyl cellulose and polyvinyl alcohol-polyethylene glycol graft copolymers. As one embodiment, the present invention is a tablet comprising the following 1) to 5): 1) linzagoli choline salt; 2) crystalline cellulose; 3) low-substituted hydroxypropyl cellulose; 4) croscarmellose sodium; and 5) polyvinyl alcohol-polyethylene glycol graft copolymer. (Oral Solid Formulations) The oral solid formulations of the present invention, as dosage forms, may include, for example, tablets (e.g., uncoated tablets, film-coated tablets (FC tablets), sugar-coated tablets), pills, granules, capsules, etc. The oral solid formulations of the present invention are preferably tablets, and more preferably film-coated tablets. The oral solid formulations of the present invention can be manufactured using pharmaceutical additives commonly used in oral solid formulations, by methods conventional in the pharmaceutical field. As additives used in the oral solid formulations of the present invention, various additives that do not mix with linzagoli can be used, and appropriate additives may include, for example, disintegrants, excipients, binders, lubricants, coating agents, colorants, plasticizers, gloss agents, etc. However, they are not limited to these. Examples of disintegrants include, for example, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium. Examples of excipients include crystalline cellulose, lactose, lactose hydrate, fructose, D-mannitol, erythritol, xylitol, maltose, D-sorbitol, and maltitol. Lactose hydrate and D-mannitol are preferred excipients, and lactose hydrate is even more preferred. In this invention, the content of excipients other than crystalline cellulose in the oral solid formulation is 0-60% by mass, preferably 0-35% by mass, and even more preferably 10%-35% by mass. Examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol. Hydroxypropyl cellulose and hydroxypropyl methylcellulose are preferred binders, and hydroxypropyl cellulose is even more preferred. In this invention, the content of binders in the oral solid formulation is, for example, 5% by mass or less, 4% by mass or less, 3% by mass or less, or 2% by mass or less. As an embodiment, the content of the binder in the oral solid formulation is preferably 5% by mass, 4% by mass, 3% by mass, or 2% by mass. As an embodiment, the content of the binder in the oral solid formulation is preferably 4% by mass or less, more preferably 3% by mass or less, and most preferably 2% by mass or less. Examples of lubricants include: magnesium stearate, calcium stearate, stearic acid, talc, light anhydrous silica, sucrose fatty acid esters, sodium stearate fumarate, polyethylene glycol, glyceryl monostearate, etc. Examples of coating agents include: hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, etc. The coating agent is preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, or polyvinyl alcohol-polyethylene glycol graft copolymer, more preferably hydroxypropyl methylcellulose or polyvinyl alcohol-polyethylene glycol graft copolymer, and most preferably polyvinyl alcohol-polyethylene glycol graft copolymer. Specifically, examples include KOLLICOAT (registered trademark) IR (manufactured by BASF). As plasticizers, examples include: polyethylene glycol, propylene glycol, glyceryl triacetate, triethyl citrate, glycerol, glyceryl fatty acid esters, polyethylene glycol, etc. As colorants, examples include: food yellow No. 4, food yellow No. 4 aluminum lake, food yellow No. 5, food red No. 2, food red No. 3, food red No. 102, food blue No. 1, food blue No. 2, food blue No. 2 aluminum lake, etc.; titanium dioxide, talc, yellow iron oxide, yellow ferric oxide, ferric oxide, brown iron oxide, etc. Preferred colorants are titanium dioxide, talc, yellow ferric oxide, and ferric oxide. As gloss agents, examples include: carnauba wax, etc. (Method for Manufacturing Oral Solid Formulations) The oral solid formulations of the present invention can be manufactured by compressing a mixture of linzagoli or its pharmacologically acceptable salts, excipients, disintegrants, binders, and other additives. For example, a method can be described by directly compressing a mixture of linzagoli or its pharmacologically acceptable salts, excipients, disintegrants, binders, and other additives using a suitable mixer to manufacture tablets. Alternatively, a method can be used to manufacture tablet granules by dry granulation using a roller press; or a method can be used to manufacture tablet granules by wet granulation using a solution of a binder, such as dissolved in a solvent like water, or water. Specifically, the oral solid formulations of the present invention can be manufactured according to the following manufacturing steps. In the present invention, "granulation," "mixing," "sizing," "sieving," "compressing," and "film coating" can be performed using methods conventional in the field of pharmaceutical technology. The method for manufacturing an oral solid dosage form of the present invention comprises the following steps (a) to (d): (a) mixing linzagoli or a pharmacologically acceptable salt thereof, crystalline cellulose, low-substituted hydroxypropyl cellulose and additives; (b) granulating the mixture obtained in step (a); (c) mixing the granules obtained in step (b) with additives; and (d) compressing the mixture obtained in step (c) into tablets. The method for manufacturing an oral solid dosage form of the present invention may, if necessary, further comprise a film coating step, wherein the film coating step involves coating the tablets (uncoated tablets) obtained in step (d) with a film to manufacture film-coated tablets. Step (a) is the step of mixing linzagoli or its pharmacologically acceptable salts, crystalline cellulose, low-substituted hydroxypropyl cellulose, and additives. This can be done by mixing linzagoli or its pharmacologically acceptable salts, crystalline cellulose, low-substituted hydroxypropyl cellulose, and additives. In one embodiment of step (a), additives may include, for example, excipients and disintegrants. Preferably, the additives are disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium; excipients such as lactose hydrate and D-mannitol. Mixing can also be performed using mixers such as V-type mixers and Bohle containers. Alternatively, mixing can be performed using granulators such as stirred granulators, fluidized bed granulators, and dry granulators used in step (b). Step (b) is the step of granulating the mixture obtained in step (a). Alternatively, the mixture obtained in step (a) can be granulated using a binder (e.g., hydroxypropyl cellulose). Furthermore, the obtained granules can be granulated as needed. Granulation can be performed using, for example, high-shear granulation, fluidized bed granulation, or dry granulation. Granulation can also be performed using, for example, fluidized bed granulators, rolling fluidized bed granulators, or high-speed mixing granulators. Granulation can be performed using either wet granulation or dry granulation. Granulation can also be performed using, for example, speed mills, COMIL, or FIORE granulators. For example, granulation can also be performed on the mixture obtained in step (a) by spraying a solution of the binder, such as dissolved in a solvent like water, and / or water, while granulating, drying, and then sizing as needed to obtain granules. The granulation in step (b) is preferably performed using a stirred granulation method to increase the content of linzagoli or its pharmacologically acceptable salts. In the case of stirred granulation, wet sizing can also be performed as needed before drying the granules. As an example, granules containing linzagoli or its pharmacologically acceptable salts can also be manufactured by mixing 15-60% by mass of linzagoli or a pharmacologically acceptable salt thereof, 15-30% by mass of crystalline cellulose, and 5-10% by mass of low-substituted hydroxypropyl cellulose, and then granulating the resulting mixture while spraying an aqueous solution of a binder and water as needed. As an example, granules containing linzagoli or its pharmacologically acceptable salts can also be manufactured by mixing 15-60% by mass of linzagoli or a pharmacologically acceptable salt thereof, 15-30% by mass of crystalline cellulose, 5-10% by mass of low-substituted hydroxypropyl cellulose, 1-60% by mass of lactose hydrate, and 5-10% by mass of one or more disintegrants selected from the group consisting of cross-linked sodium carboxymethyl cellulose and calcium carboxymethyl cellulose, and then granulating the resulting mixture while spraying an aqueous solution of the binder and water as needed. Step (c) is the step of mixing the granules obtained in step (b) with the additives. Alternatively, additives can be added to the granules obtained in step (b) and mixed to obtain a mixture for pressing. Mixing can also be performed using a mixer such as a V-type mixer or a Bohle container. In one embodiment of step (c), the additives may include, for example, disintegrants and lubricants. Preferably, the additives are disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium; lubricants such as magnesium stearate. As an example, in this step, 5-10% by mass of a disintegrant and 1-5% by mass of a lubricant may be used. Step (d) is the step of pressing the mixture obtained in step (c) into a mold. The pressing (compression molding) can be performed by pressing the mixture obtained in step (c) into a mold using, for example, a single-shot pressing machine or a rotary pressing machine, at a pressing pressure of 1 to 20 kN, preferably 5 to 15 kN. The film coating step can also involve spraying a coating solution onto the uncoated tablets obtained by the above method to obtain film-coated tablets. The film coating method is not particularly limited; for example, film-coated tablets can be manufactured by placing the obtained uncoated tablets into a coating machine and spraying a coating solution. For example, film-coated tablets can also be manufactured by spraying a coating solution containing coating agents such as hydroxypropyl methylcellulose and polyvinyl alcohol-polyethylene glycol graft copolymer (plasticizers, colorants, etc., can be added to the coating solution as needed) onto the uncoated tablets of the present invention while coating them. The amount of coating agent used in film coating is typically 1 to 20 parts by weight, preferably 2 to 15 parts by weight, and more preferably 2 to 10 parts by weight, relative to 100 parts by weight of the uncoated tablets. Coating agents can also be used in combination with plasticizers, colorants, lubricants, etc. Furthermore, if necessary, gloss agents such as carnauba wax can be added after film coating for polishing (buffing). Polishing can be performed using conventional methods; for example, adding gloss agents such as carnauba wax to polish the film-coated ingots is sufficient. The amounts of coating agent, plasticizer, lubricant, and colorant in the above-mentioned film coating can be prepared according to conventional methods. The excipients, disintegrants, binders, and lubricants used in the manufacturing method of this invention are as mentioned in the specification of this invention. Although the following describes a method for manufacturing an orally administered solid preparation of this invention, it is not limited to these methods. [Example 1 of manufacturing uncoated tablets] For example, granules containing linzagoli or its pharmacologically acceptable salts can be manufactured by mixing linzagoli or a pharmacologically acceptable salt thereof, crystalline cellulose, and low-substituted hydroxypropyl cellulose using a mixer, followed by granulation of the mixture while spraying an aqueous solution of a binder (hydroxypropyl cellulose) and water as needed. The aforementioned mixing and granulation steps can be performed using high-speed mixing granulation, rolling flow bed granulation, or flow bed granulation, with high-speed mixing granulation being preferred. Secondly, the obtained granules can be mixed with one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium, using a mixer. Then, one or more lubricants selected from the group consisting of sodium stearate fumarate, calcium stearate, magnesium stearate, talc, and light anhydrous silica are added and mixed. The mixture is then pressed into tablets to manufacture uncoated tablets. In the aforementioned mixing step, excipients may be further added as needed. [Example 2 of manufacturing uncoated tablets] For example, tablets containing linzagoli or its pharmacologically acceptable salts can be manufactured by mixing linzagoli or its pharmacologically acceptable salts, crystalline cellulose, low-substituted hydroxypropyl cellulose, and one or more disintegrants selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and croscarmellose sodium, using a mixer, and then granulating the mixture while spraying an aqueous solution of the binder (hydroxypropyl cellulose) and water as needed. The aforementioned mixing and granulation steps can be performed using high-speed mixing granulation, rolling flow layer granulation, or flow layer granulation, with high-speed mixing granulation being preferred. Alternatively, tablets (uncoated tablets) can be manufactured by adding the obtained granules and one or more lubricants selected from the group consisting of sodium stearate fumarate, calcium stearate, magnesium stearate, talc, and light anhydrous silica, mixing them using a mixer, and then pressing the mixture into tablets. In the aforementioned mixing step, one or more additives may be added as needed. Examples of additives include excipients. [Example of Manufacturing Film-Coated Ingots] For example, film-coated ingots can be manufactured by spraying a coating solution containing coating agents such as hydroxypropyl methylcellulose and polyvinyl alcohol-polyethylene glycol graft copolymer (plasticizers, colorants, etc., may be added to the coating solution as needed) onto the ingots (uncoated ingots) of the present invention while coating them. After film coating, a glossing agent such as carnauba wax may be added as needed for polishing (buffing). The oral solid dosage form of the present invention preferably has a moderate hardness for ease of manufacture or delivery. For example, in a hardness test, for an uncoated tablet with a mass of 200 mg, it is generally sufficient to adjust the hardness to 80 N or more, preferably 100 N or more, and even more preferably 150 N or more. The hardness can also be adjusted by appropriately selecting the type or amount of pharmaceutical additives, the manufacturing method (e.g., granulation method), and the manufacturing conditions (e.g., tablet compression pressure). The oral solid dosage form of the present invention, for example, has a size that is easy to swallow. For example, the longest dimension of an oval tablet or capsule is 20 mm or less, and the diameter of a round tablet is 13 mm or less. The tablet of the present invention has a hardness of, for example, 80 N or more, preferably 100 N or more, and even more preferably 150 N or more. In the oral solid formulations of the present invention, for example, in the form of tablets, the mass of each tablet may be listed as 50-1000 mg, 50-800 mg, 50-500 mg, 50-300 mg, 100-300 mg, 100-200 mg, etc. In the actual treatment of patients using the oral solid formulation of the present invention, the dosage of linzagorgil or its pharmacologically acceptable salts should be appropriately determined based on the patient's sex, age, weight, and severity of disease, but generally, the daily dosage of linzagorgil for adults can range from 0.1 mg to 1000 mg. Preferably, the daily dosage of linzagorgil for adults is 25 mg to 200 mg orally, divided into 1 to 3 doses. [Example] The contents of this invention will be further described in detail in the following test examples, embodiments and comparative examples, but the contents of this invention are not limited thereto. [Reference Example 1] 2406 mg of linzagoli choline salt, 114 mg of D-mannitol (Mannit P, manufactured by Mitsubishi Foodtech), 520 mg of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 800 mg of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Industry) were mixed in a mortar. To this mixture, 80 mg of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) dissolved in 1253 mg of purified water (6% hydroxypropyl cellulose aqueous solution) was added, followed by the addition of 1017 mg of purified water for granulation. The resulting granules were dried at 60°C for 3 hours, and then granulated using a 500 μm sieve. 3716 mg of the granulated material was mixed with 75.8 mg of magnesium stearate (manufactured by Taihei Chemical Industry). The obtained mixture was pressed into tablets using a single-gun tablet press (N-30E, manufactured by Okada Seiko) with a mortar and pestle diameter of 6 mm and a pressing pressure of about 5 kN to obtain tablets containing 60.15 mg of linzagoli choline salt (calculated as 50 mg of linzagoli) per tablet (uncoated tablets). The solubility of the tablets prepared in Reference Example 1 was evaluated in the dissolution test described in Test Example 1. Table 1 summarizes the formulation of the tablets prepared in Reference Example 1 and the results of their dissolution tests. [Table 1] [Example 1] (1) 481.2 g of linzagoli choline salt, 502.8 g of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), 400 g of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 80 g of low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Industry) were mixed using a high-speed mixing granulator (FM-VG-10, manufactured by POWREX). This mixture was then granulated by spraying a mixture of 32 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) dissolved in 425 g of purified water (7% hydroxypropyl cellulose aqueous solution) through a nozzle, while simultaneously spraying 171 g of purified water through a nozzle. The obtained granules were dried using a fluidized bed dryer (FD-LAB-1, manufactured by POWREX), and then granulated using a granulator (Granola QC-197S, manufactured by POWREX) with a screen diameter of φ1.143 mm. (2) 1420.4 g of the granulated granules and 74.8 g of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC) were mixed using a V-type mixer (DV-1, manufactured by DALTON), and then 22.5 g of magnesium stearate (manufactured by Merck Millipore) were added and mixed. The obtained mixture was pressed using a rotary press (CLEANPRESS Correct 12HUK, manufactured by Kikusui Corporation) under conditions of 8 mm mortar and pestle and a pressing pressure of about 10 kN to obtain 200 mg tablets (uncoated tablets) containing 60.15 mg of linzagoli choline salt (50 mg as linzagoli) per tablet. (3) 9.36 g of titanium dioxide (manufactured by Freund Corporation), 0.72 g of yellow ferric oxide (manufactured by Kesei Chemicals) and 14.4 g of talc (manufactured by Matsumura Corporation) were dispersed in 288 g of purified water. 47.52 g of KOLLICOAT (registered trademark) IR (manufactured by BASF) was added to the obtained dispersion and dissolved. This was then sieved through a 150 μm sieve to obtain a coating solution. (4) Using a tablet coating machine (HCT-MINI, manufactured by Furende Industrial Co., Ltd.), the tablets (uncoated tablets) obtained in (2) above are coated with the coating liquid obtained in (3) above, so that the coating amount of each tablet is 8 mg, thereby obtaining film-coated tablets. [Example 2] (1) 27 g of OPADRY YELLOW (containing hydroxypropyl methylcellulose 2910, titanium dioxide, polyethylene glycol 400, yellow ferric oxide and ferric oxide) (made by Colorcon) was dispersed in 218.5 g of purified water. This solution was sieved through a 150 μm sieve to obtain a coating solution. (2) Using a tablet coating machine (HCT-MINI, made by Furentoku Sangyo), the tablets (uncoated tablets) obtained in Example 1 were coated with the coating solution obtained in (1) above, so that the coating amount of each tablet was 6 mg. The obtained tablets were polished by adding 0.02% carnauba wax (made by WAX) relative to the mass of the uncoated tablets to obtain film-coated tablets. [Example 3] (1) 451.125 g of linzagoli choline salt (D50 6.3 μm), 471.375 g of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), 375 g of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 75 g of low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Industry) were mixed using a high-speed mixing granulator (FM-VG-01, manufactured by POWREX). The mixture was granulated while spraying a mixture of 30 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) dissolved in 545.6 g of purified water (a 5.2% hydroxypropyl cellulose aqueous solution). The obtained granules were wet-granulated using a granulator (QC-197S, POWREX) with a sieve diameter of 6.35 mm and corner holes, and then dried using a fluidized bed dryer (FD-LAB-1, POWREX). Next, the granules were granulated using a granulator (QC-197S, POWREX) with a sieve diameter of φ1.143 mm. (2) 1333.1 g of the obtained granulated granules were mixed with 71.3 g of croscarmellose sodium (Ac-Di-Sol SD-711, FMC) using a V-type mixer (DV-1, DALTON), and 21.4 g of magnesium stearate (Merck Millipore) was further added and mixed. The obtained mixture was divided into 3 parts. One of the mixtures was pressed using a rotary press (CLEANPRESS Correct 12HUK, manufactured by Kikusui Seisakusho) under conditions of a mortar and pestle φ10 mm and a pressing pressure of about 15 kN to obtain tablets containing 120.3 mg of linzagoli choline salt (100 mg as linzagoli) per tablet (uncoated tablets). (3) 18.72 g of titanium dioxide (manufactured by Tominori Sangyo), 28.8 g of talc (manufactured by Matsumura Sangyo), and 1.44 g of yellow ferric oxide (manufactured by Kesei Kasei) were dispersed in 816 g of purified water. 95.04 g of KOLLICOAT (registered trademark) IR (manufactured by BASF) was added to dissolve it and sieved through a 150 μm sieve to obtain a coating solution. (4) Using a tablet coating machine (HCT-MINI, manufactured by Furen Toku Sangyo), the tablets obtained in (2) above (uncoated tablets) were coated with the coating solution obtained in (3) above, so that the coating amount of each tablet was 16 mg. The obtained tablets were polished by adding 0.02% carnauba wax (manufactured by WAX Japan) relative to the mass of the uncoated tablets, thereby obtaining coated tablets. [Example 4] (1) One of the mixtures divided in Example 3 was pressed using a rotary press (CLEANPRESS Correct 12HUK, manufactured by Kikusui Corporation) under conditions of a mortar and pestle of 16.5 mm x 7.7 mm and a pressing pressure of approximately 7 kN, thereby obtaining a tablet (uncoated tablet) containing 240.6 mg of linzagoli-choline salt (200 mg as linzagoli) per tablet. (2) 18.72 g of titanium dioxide (manufactured by Fumintoku Sangyo), 28.8 g of talc (manufactured by Matsumura Sangyo), and 1.44 g of yellow ferric oxide (manufactured by Kesei Chemical) were dispersed in 816 g of purified water. 95.04 g of KOLLICOAT (registered trademark) IR (manufactured by BASF) was added to dissolve it, and the solution was sieved through a 150 μm sieve to obtain a coating solution. (3) Using a tablet coating machine (HCT-MINI, manufactured by Furen Toku Sangyo), the tablets obtained in (1) above (uncoated tablets) were coated with the coating solution obtained in (2) above, so that the coating amount of each tablet was 32 mg. The obtained tablets were polished by adding 0.02% carnauba wax (manufactured by WAX Japan) relative to the mass of the uncoated tablets, thereby obtaining film-coated tablets. [Example 5] 2406 mg of linzagoli choline salt, 74 mg of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), 600 mg of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 400 mg of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Industry) were mixed in a mortar. To this mixture, 80 mg of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) dissolved in 720 mg of purified water (a 10% hydroxypropyl cellulose aqueous solution) was added, followed by the addition of 740 mg of purified water for granulation. The resulting granules were dried at 60°C for 2 hours, and the dried material was granulated using a 500 μm sieve. 3390 mg of the granulated material was mixed with 381 mg of calcium carboxymethyl cellulose (ECG-505, manufactured by Wude Pharmaceutical), and then 38 mg of magnesium stearate (manufactured by Taiping Chemical Industry) was added and mixed again. The resulting mixture was then pressed into tablets using a single-shot tablet press (N-30E, manufactured by Okada Seiko) with a mortar and pestle diameter of 6 mm and a pressing pressure of approximately 5 kN, thereby obtaining tablets containing 60.15 mg of linzagoli choline salt (equivalent to 50 mg of linzagoli) per tablet (uncoated tablets). [Example 6] 2406 mg of linzagoli choline salt, 74 mg of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), 600 mg of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 600 mg of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Industry) were mixed in a mortar. To this mixture, a 10% hydroxypropyl cellulose aqueous solution (80 mg of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) dissolved in 720 mg of purified water was added, followed by the addition of 790 mg of purified water for granulation. The resulting granules were dried at 60°C for 2 hours, and the dried material was granulated using a 500 μm sieve. 3580 mg of the granulated material was mixed with 190 mg of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC), and then 38 mg of magnesium stearate (manufactured by Merck Millipore) was added and mixed again. The resulting mixture was then pressed into tablets using a single-shot tablet press (N-30E, manufactured by Okada Seiko) under conditions of a 6 mm mortar and a pressing pressure of approximately 5 kN, thereby obtaining tablets containing 60.15 mg of linzagoli choline salt (50 mg as linzagoli) per tablet (uncoated tablets). [Comparative Example 1] 2406 mg of linzagoli choline salt, 74 mg of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), 600 mg of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 600 mg of low-substituted hydroxypropyl cellulose (LH-11, manufactured by Shin-Etsu Chemical Industry) were mixed in a mortar. To this mixture, 80 mg of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) dissolved in 720 mg of purified water (a 10% hydroxypropyl cellulose aqueous solution) was added, followed by the addition of 870 mg of purified water for granulation. The resulting granules were dried at 60°C for 2 hours, and the dried material was granulated using a 500 μm sieve. 3571 mg of the granulated material was mixed with 190 mg of crospovidone sodium (XL-10, manufactured by Ashland Japan), and further mixed with 38 mg of magnesium stearate (manufactured by Merck Millipore). The resulting mixture was then pressed into tablets using a single-shot tablet press (N-30E, manufactured by Okada Seiko) at a mortar diameter of 6 mm and a pressing pressure of approximately 5 kN, thereby obtaining tablets containing 60.15 mg of linzagoli choline salt (equivalent to 50 mg of linzagoli) per tablet (uncoated tablets). [Comparative Example 2] 4812 mg of linzagoli choline salt, 2148 mg of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), and 400 mg of low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Industry) were mixed in a mortar. To this mixture, a conjugate solution (10% hydroxypropyl cellulose aqueous solution) containing 160 mg of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) dissolved in 1440 mg of purified water was added, followed by the addition of 650 mg of purified water for granulation. The resulting granules were dried at 60°C for 3 hours, and the dried material was granulated using a 500 μm sieve. 7196 mg of the granulated material was mixed with 383 mg of croscarmellose sodium cellulose (Ac-Di-Sol SD-711, manufactured by FMC), followed by the addition of 76 mg of magnesium stearate (manufactured by Merck Millipore). The obtained mixture was pressed into tablets using a single-gun tablet press (N-30E, manufactured by Okada Seiko) under conditions of 8 mm mortar and pestle and a pressing pressure of about 5 kN, thereby obtaining tablets (uncoated tablets) containing 120.3 mg of linzagoli choline salt (100 mg as linzagoli) per tablet. [Example 7] 4812 mg of linzagoli choline salt, 2148 mg of crystalline cellulose (CEOLUS (registered trademark) PH-101, manufactured by Asahi Kasei Chemicals), and 400 mg of low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Industry) were mixed in a mortar. To this mixture, 160 mg of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) was dissolved in 1440 mg of purified water (a 10% hydroxypropyl cellulose aqueous solution), and 2650 mg of purified water was further added for granulation. The obtained granules were dried at 60°C for 3 hours, and the dried material was granulated using a 500 μm sieve. 7240 mg of the granulated material was mixed with 385 mg of croscarmellose sodium cellulose (Ac-Di-Sol SD-711, manufactured by FMC), and 76 mg of magnesium stearate (manufactured by Merck Millipore) was further added for mixing. The obtained mixture was pressed into tablets using a single-gun tablet press (N-30E, manufactured by Okada Seiko) under conditions of 8 mm mortar and pestle and a pressing pressure of about 5 kN, thereby obtaining tablets (uncoated tablets) containing 120.3 mg of linzagoli choline salt (100 mg as linzagoli) per tablet. [Example 8] 4812 mg of linzagoli choline salt, 788 mg of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), 1200 mg of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 400 mg of low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Industry) were mixed in a mortar. To this mixture, a conjugate solution (18% hydroxypropyl cellulose aqueous solution) containing 320 mg of hydroxypropyl cellulose (HPC-SL, manufactured by Nippon Soda) dissolved in 1458 mg of purified water was added, followed by the addition of 1238 mg of purified water for granulation. The resulting granules were dried at 60°C for 3 hours, and the dried material was granulated using a 500 μm sieve. 7156 mg of the granulated material was mixed with 381 mg of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC), and then 76 mg of magnesium stearate (manufactured by Merck Millipore) was added and mixed again. The resulting mixture was then pressed into tablets using a single-shot tablet press (N-30E, manufactured by Okada Seiko) under conditions of 8 mm mortar and pestle and a pressing pressure of approximately 5 kN, thereby obtaining tablets containing 120.3 mg of linzagoli choline salt (100 mg as linzagoli) per tablet (uncoated tablets). [Example 9] (1) 210.525 g of linzagoli choline salt, 797.475 g of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), 210 g of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 70 g of low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Industry) were mixed using a high-speed mixing granulator (FM-VG-10, manufactured by POWREX). The mixture was then sprayed with a nozzle to dissolve 28 g of hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda) in 252 g of purified water (a 10% hydroxypropyl cellulose aqueous solution), while simultaneously spraying 170 g of purified water through a nozzle. The resulting granules were dried at 80°C using a fluidized bed dryer (FD-LAB-1, manufactured by POWREX), and the dried material was granulated using a 1 mm sieve. (2) 1260.9 g of the granules obtained in (1) above were mixed with 67.1 g of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC) using a V-type mixer (DV-1, manufactured by DALTON), and 13.4 g of magnesium stearate (manufactured by Merck Millipore) was further added and mixed. The resulting mixture was then pressed using a rotary press (CLEANPRESS Correct 12HUK, manufactured by Kikusui Corporation) under conditions of 8 mm mortar and pestle and a pressing pressure of approximately 13 kN, thereby obtaining tablets containing 30.075 mg of linzagoli choline salt (25 mg as linzagoli) per tablet (uncoated tablets). (3) Disperse 9.36 g of titanium dioxide (manufactured by Fujintoku Sangyo), 14.4 g of talc (manufactured by Matsumura Sangyo), and 0.72 g of yellow ferric oxide (manufactured by Kesei Kasei) in 288 g of purified water. Add 47.52 g of KOLLICOAT (registered trademark) IR (manufactured by BASF) to dissolve it and sieve it through a 150 μm sieve to obtain a coating solution. (4) Using a tablet coating machine (HCT-MINI, manufactured by Fujintoku Sangyo), coat the tablets (uncoated tablets) obtained in (2) above with the coating solution obtained in (3) above, so that the coating amount of each tablet is 8 mg, thereby obtaining coated tablets. [Example 10] (1) 842.1 g of linzagoli choline salt, 165.9 g of lactose hydrate (Pharmatose 200M, manufactured by DFE Pharma), 210 g of crystalline cellulose (CEOLUS PH-101, manufactured by Asahi Kasei Chemicals), and 70 g of low-substituted hydroxypropyl cellulose (LH-21, manufactured by Shin-Etsu Chemical Industry) were mixed using a high-speed mixing granulator (FM-VG-10, manufactured by POWREX). The mixture was then sprayed with a nozzle to dissolve 28 g of hydroxypropyl cellulose (manufactured by Nippon Soda) in 252 g of purified water (a 10% hydroxypropyl cellulose aqueous solution), while simultaneously spraying 250 g of purified water through a nozzle. The resulting granules were dried at 80°C using a fluidized bed dryer (FD-LAB-1, manufactured by POWREX), and the dried material was granulated using a 1 mm sieve. (2) 1256.6 g of the granules obtained in (1) above were mixed with 66.8 g of croscarmellose sodium (Ac-Di-Sol SD-711, manufactured by FMC) using a V-type mixer (DV-1, manufactured by DALTON), and 13.4 g of magnesium stearate (manufactured by Merck Millipore) was further added and mixed. The resulting mixture was then pressed using a rotary press (CLEANPRESS Correct 12HUK, manufactured by Kikusui Corporation) under conditions of 8 mm mortar and pestle and a pressing pressure of approximately 13 kN, thereby obtaining tablets containing 120.3 mg of linzagoli choline salt (100 mg as linzagoli) per tablet (uncoated tablets). (3) Using a tablet coating machine (HCT-MINI, manufactured by Furende Industrial Co., Ltd.), the tablets (uncoated tablets) obtained in (2) above are coated with the coating liquid obtained in Example 9 (3) above, so that the coating amount of each tablet is 8 mg, thereby obtaining coated tablets. [Example 11] Using Linzagoli-choline salt with a D50 of 33.6 μm, a tablet with the composition described in Table 5 was prepared based on the method of Example 3. [Experimental Example 1] Dissolution Test 1 For the tablets prepared in Reference Example 1, Comparative Examples 1, 2, and Examples 1, 2, 5-10, the dissolution test method described in the 16th revised Japanese Pharmacopoeia, using the paddle method, was conducted with a paddle speed of 50 rpm and 900 mL of purified water as the test solution. The absorbance of the sample solution containing linzagoli was measured using a UV spectrophotometer (flow cytometry) to determine the dissolution rate. The results are shown in Tables 1-5. Detector: UV spectrophotometer (measurement wavelength: 225 nm) [Experimental Example 2] Dissolution Test 2: For the tablets prepared in Examples 3, 4, and 11, the dissolution test method described in the 17th revised Japanese Pharmacopoeia formula, using the paddle method, was conducted with a paddle speed of 50 rpm and the Japanese Pharmacopoeia Dissolution Test Solution 2 (pH 6.8) as the test solution. The linzagoli in the sample liquid was quantified using high-performance liquid chromatography (HPLC) to determine the dissolution rate. Detector: Ultraviolet spectrophotometer (measurement wavelength: 275 nm) Table 2 summarizes the formulations of the tablets prepared in Examples 1 to 4 and their dissolution test results. [Table 2] Table 3 summarizes the formulations of the tablets prepared in Examples 5, 6 and Comparative Example 1 and their dissolution test results. [Table 3] Table 4 summarizes the formulations of the tablets prepared in Comparative Examples 2, 7 and 8 and the results of their dissolution tests. [Table 4] Table 5 summarizes the formulations of the tablets prepared in Examples 9-11 and their dissolution test results. [Table 5] As shown in Tables 2-5, the oral solid formulations of the present invention exhibit rapid dissolution. Furthermore, according to the results of Examples 1 and 2, the presence or absence of film coating has no effect on dissolution. According to the results of Examples 3 and 11, the oral solid formulations of the present invention exhibit rapid dissolution even at different particle sizes. [Experimental Example 3] Storage Stability Test Storage stability tests were conducted on the uncoated tablets and film-coated tablets (FC tablets) obtained in Examples 9 and 10. The uncoated tablets and FC tablets obtained in Examples 9 and 10 were stored for 6 months at a temperature of 40°C and a relative humidity of 75% under open conditions. The total content of related substances was determined by HPLC at the beginning of storage, and after 1 month, 3 months, and 6 months. The results are shown in Table 6. For the quantitative method of related substances, four tablets of the formulation in Example 9 and five tablets of the formulation in Example 10 were weighed out and prepared into sample solutions to a concentration of 0.5 mg / mL (calculated as linzagoli). The experiment was performed by liquid chromatography, and the peak area of ​​each sample was determined using an automatic integration method to calculate the total content (%) of related substances. Detector: Ultraviolet spectrophotometer (measurement wavelength: 225 nm) [Table 6] As shown in Table 6, the uncoated and film-coated tablets obtained in Examples 9 and 10 are stable formulations. Even after being stored at 40°C, 75% relative humidity, and open conditions for 6 months, the total amount of similar substances did not increase over time. Therefore, it is determined that the oral solid formulation of the present invention exhibits rapid dissolution and good storage stability even when the content of the active ingredient varies over a wide range. (Industrial Applicability) According to the present invention, an oral solid formulation is provided that exhibits rapid dissolution even when the content of the active ingredient linzagoli or its pharmacologically acceptable salt varies over a wide range.

Claims

1. An oral solid preparation comprising the following 1) to 4): 1) linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; 3) low-substituted hydroxypropyl cellulose; and 4) a disintegrant selected from one or more of the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium.

2. As in claim 1, the oral solid dosage form, wherein, Includes the following A) and B): A) granules containing the following 1) to 3); 1) linzagoli or a pharmacologically acceptable salt thereof; 2) crystalline cellulose; and 3) low-substituted hydroxypropyl cellulose; and B) disintegrants selected from one or more of the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium.

3. Oral solid preparations as claimed in item 1 or 2, wherein, Linzagoli or its pharmacologically acceptable salts are linzagoli-choline salts.

4. Oral solid preparations as claimed in item 1 or 2, wherein, The oral solid formulation has a dissolution rate of over 80% after 15 minutes in a test solution or water at pH 6.

8.

5. Oral solid preparations as claimed in item 1 or 2, wherein, The total amount of low-substituted hydroxypropyl cellulose and disintegrant in the oral solid formulation is less than 20% by mass, and the disintegrant is one or more selected from the group consisting of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose and croscarmellose sodium.

6. The oral solid preparations as claimed in item 1 or 2 contain a binder.

7. The oral solid preparation as claimed in claim 6, wherein, The binder is selected from one or more of the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and polyethylene glycol.

8. The oral solid preparation as claimed in claim 6, wherein, The content of binders in oral solid preparations is less than 5% by mass.

9. Oral solid preparations as claimed in item 1 or 2, wherein, The content of linzagoli or its pharmacologically acceptable salt in oral solid preparations is 15-65% by mass.

10. Oral solid preparations as claimed in item 1 or 2, wherein, The content of crystalline cellulose in oral solid preparations is 15% by mass or more.

11. The oral solid formulation of claim 1 or 2 further contains excipients other than crystalline cellulose.

12. The oral solid dosage form as claimed in claim 11, wherein, The excipient is selected from one or more of the group consisting of lactose hydrate and D-mannitol.

13. Oral solid preparations as claimed in item 1 or 2, wherein, The amount of linzagoli or its pharmacologically acceptable salt in each oral solid formulation is 75 mg, 100 mg or 200 mg, calculated as linzagoli.

14. Oral solid preparations as claimed in item 1 or 2, wherein, Oral solid preparations are in tablet form.

15. The oral solid dosage form as claimed in claim 14, wherein, The tablets are film-coated tablets.

16. The oral solid dosage form as claimed in claim 15, wherein, The film coating is achieved by coating a film using one or more coating agents selected from the group consisting of hydroxypropyl methylcellulose and polyvinyl alcohol-polyethylene glycol graft copolymer.