Preparation containing dihydropyridazine-3,5-dione derivative

Abstract

The present invention provides: a pharmaceutical composition having excellent elution properties and uniform content, provided by mixing a p-toluenesulfonate of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifuluromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]deca-9-ene-9-carboxamide with a specific additive to prepare a pharmaceutical preparation; and a method for producing the pharmaceutical composition.

Description

Preparations containing dihydropyridazine-3,5-dione derivatives

[0001] The present invention relates to a preparation containing a dihydropyridazine-3,5-dione derivative.

[0002] It is known that patients with renal dysfunction, such as chronic kidney disease (CKD) and end-stage renal disease (ESKD), accumulate phosphorus in the body, causing hyperphosphatemia. Vascular calcification due to hyperphosphatemia can lead to cardiovascular dysfunction. It can also lead to excessive secretion of parathyroid hormone, which can cause bone lesions. Thus, hyperphosphatemia can be a factor that worsens the prognosis and quality of life of patients with end-stage renal failure and those undergoing dialysis (Non-Patent Document 1).

[0003] CKD is classified into stages 1 to 5 according to the degree of progression (Non-Patent Document 2, Non-Patent Document 3). Blood phosphorus levels in patients with CKD stages 3 and 4 are related to the incidence and mortality of cardiovascular disease, and suppressing blood phosphorus levels in these patients may lead to the alleviation or prevention of cardiovascular disease. Furthermore, controlling patients' phosphate load at an earlier stage may alleviate and / or prevent the progression of the disease in early-stage CKD patients (Non-Patent Document 4).

[0004] Current treatments for hyperphosphatemia involve the use of phosphate binders designed to inhibit phosphate absorption in the gastrointestinal tract. Phosphate binders include non-metallic polymer binders such as sevelamer hydrochloride, calcium salt preparations such as precipitated calcium carbonate, and metallic binders such as lanthanum carbonate. However, these require the administration of several grams per day, leading to poor compliance and reported side effects due to calcium accumulation in the body. Therefore, there is a strong need for the development of a new hyperphosphatemia treatment that overcomes these problems with phosphate binders (Non-Patent Document 4).

[0005] Three families of sodium-dependent phosphate transporters are known: NaPi-I, NaPi-II, and NaPi-III. These families are further classified into isotypes, and in the case of the NaPi-II family, NaPi-IIa, NaPi-IIb, and NaPi-IIc are known. In particular, phosphate transporters such as NaPi-IIb, PiT-1, and PiT-2 are known to be responsible for phosphorus absorption in the gastrointestinal tract. Selective inhibition of only these phosphate transporters involved in phosphorus absorption is expected to produce a strong inhibitory effect on phosphorus absorption in the gastrointestinal tract and reduce blood phosphorus levels (Non-Patent Documents 5 to 8).

[0006] To date, NTX1942 (Patent Document 1) and fused thiophene derivatives (Patent Documents 2 to 5) have been reported as NaPi-IIb inhibitors. Dihydropyridazine-3,5-dione derivatives, such as 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide represented by Formula 1, have been reported to exhibit inhibitory effects against NaPi-IIb, PiT-1, and PiT-2 (Patent Documents 6 and 7 and Non-Patent Document 9).

[0007]

[0008] When treating chronic diseases such as hyperphosphatemia, pharmaceutical formulations with an orally administrable dosage form that can be self-administered by patients are preferable over injections that require a hospital visit each time medication is administered. Among pharmaceutical formulations, solid formulations are preferred, particularly when the active ingredient is contained in a solid form. Examples of solid formulations include powders, powders, granules, tablets, and capsules. In providing these solid formulations, it is important that the active ingredient is effectively absorbed in the digestive tract after the formulation disintegrates in the digestive tract. For example, among the formulation forms, capsule formulations are administered in which the active ingredient (drug substance) is encapsulated in a small space. After the capsule disintegrates in the digestive tract, the filler in the capsule disperses, dispersing the drug substance. Furthermore, optimized drug substance particle shape and drug substance particle size provide an appropriate surface area for the drug substance from the perspective of solubility, which can lead to efficient dissolution and easy absorption from the digestive tract. Therefore, optimized drug substance particles are preferably used as the drug substance used in pharmaceutical formulations. Furthermore, since drug substances with controlled particle size are more easily mixed with excipients, it is possible to obtain highly homogenized pharmaceutical compositions and pharmaceutical formulations in addition to the stability of the drug substance in pharmaceutical compositions and pharmaceutical formulations (Patent Document 8). By encapsulating highly homogenized filling powders, the dispersion of the filling powders in the digestive tract after capsule dissolution is efficiently achieved, promoting the absorption of the active ingredient. Furthermore, maintaining the homogeneity of the mixed filling powders at a certain level or above is essential for the quality control of the formulation.

[0009] International Publication No. WO 2012 / 006475 International Publication No. WO 2011 / 136269 International Publication No. WO 2013 / 062065 International Publication No. WO 2014 / 003153 International Publication No. WO 2018 / 034883 International Publication No. WO 2014 / 142273 International Publication No. WO 2016 / 039458 International Publication No. WO 2016 / 026822

[0010] Hruska, KA et al., Kidney Int., 2008, 74(2), 148-157.“Chapter 1: Definition and classification of CKD” Kidney Int. Suppl., 2013, 3(1), 19-62.Levey, AS et al., Kidney Int., 2005, 67(6), 2089-2100.Ritter, CS et al., Clin. J.Am.Soc.Nephrol.2016, 11(6), 1088-1100.Miyamoto, K et al., J. Pharm. Sci., 2011, 100(9), 3719-3730.Sabbagh, Y et al., J. Am. Soc. Nephrol., 2009, 20(11), 2348-2358.Forster IC et al., Mol Aspects Med., 2013, 34(2-3), 386-395.Lederer E et al., Eur. J. Physiol., 2019, 471(1), 137–148.

[0011] Pharmaceutical compositions and pharmaceutical preparations containing the compound represented by Formula 1, or a salt thereof, or a solvate thereof as an active ingredient have not been known that can exhibit sufficient efficacy due to the low solubility of the active ingredient. Specifically, in pharmaceutical compositions and pharmaceutical preparations containing the p-toluenesulfonate salt of 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide (Compound I) as an active ingredient, delayed dissolution of the active ingredient was confirmed in pharmaceutical compositions and pharmaceutical preparations using an unground drug substance. It has been confirmed that when a surfactant is added to a pharmaceutical composition with the intention of improving the solubility of the active ingredient in water, the pharmaceutical composition of the pharmaceutical formulation raw material containing Compound I, i.e., the powder mixture (bulk powder), becomes highly viscous during stirring, resulting in poor stirring and insufficient uniformity of the resulting bulk powder.

[0012] The present inventors have conducted extensive research to solve these problems. They have found that the use of a specific additive and a drug substance with a specific particle size improves the delayed dissolution of the active ingredient. They have also found that the use of a specific lubricant as an additive allows the bulk powder to be mixed well without increasing its viscosity and causing poor mixing. They have also found that the use of one or more additives selected from specific excipients and disintegrants allows the stable production of bulk powders with a certain level of uniformity without increasing the viscosity and causing poor mixing. They have also found pharmaceutical compositions and pharmaceutical formulations from which the active ingredient is efficiently released from the bulk powders obtained in this way. Specifically, they have found that capsules in which bulk powder containing Compound I as an active ingredient is encapsulated as a filler efficiently release the active ingredient, thereby completing the invention.

[0013] The present specification includes the disclosure of the following inventions: [1-1] Formula 1

[0014]

[0015] or a salt thereof, or a solvate thereof, and a lubricant. [1-2] The pharmaceutical composition according to [1-1], further comprising an excipient and a disintegrant. [1-3] The pharmaceutical composition according to [1-1] or [1-2], wherein the lubricant is contained in an amount of 0.5% by weight or more relative to the total amount of the pharmaceutical composition.

[0016] [1-4] The pharmaceutical composition according to any one of [1-1] to [1-3], wherein the lubricant is contained in an amount of 0.5% by weight to 15% by weight based on the total weight of the pharmaceutical composition. [1-5] The pharmaceutical composition according to any one of [1-1] to [1-4], wherein the lubricant is contained in an amount of 6.0% by weight or more based on the total weight of the pharmaceutical composition.

[0017] [1-6] The pharmaceutical composition according to any one of [1-1] to [1-5], wherein the lubricant is contained in an amount of 7.0% by weight or more based on the total weight of the pharmaceutical composition. [1-7] The pharmaceutical composition according to any one of [1-1] to [1-6], wherein the lubricant is contained in an amount of 5.3% by weight or more and 15% by weight or less based on the total weight of the pharmaceutical composition.

[0018] [1-8] The pharmaceutical composition according to any one of [1-1] to [1-7], wherein the lubricant is contained in an amount of 6.0% by weight or more and 13% by weight or less based on the total weight of the pharmaceutical composition. [1-9] The pharmaceutical composition according to any one of [1-1] to [1-8], wherein the lubricant is contained in an amount of 7.0% by weight or more and 11% by weight or less based on the total weight of the pharmaceutical composition.

[0019] [1-10] The pharmaceutical composition according to any one of [1-2] to [1-9], wherein the excipient is contained in an amount of 21% by weight or more relative to the total weight of the pharmaceutical composition. [1-11] The pharmaceutical composition according to any one of [1-2] to [1-10], wherein the excipient is contained in an amount of 21% by weight or more and 72% by weight or less relative to the total weight of the pharmaceutical composition.

[0020] [1-12] The pharmaceutical composition according to any one of [1-2] to [1-11], wherein the excipient is contained in an amount of 27% by weight or more and 66% by weight or less based on the total weight of the pharmaceutical composition. [1-13] The pharmaceutical composition according to any one of [1-2] to [1-12], wherein the disintegrant is contained in an amount of 10% by weight or more based on the total weight of the pharmaceutical composition.

[0021] [1-14] The pharmaceutical composition according to any one of [1-2] to [1-13], wherein the disintegrant is contained in an amount of 10% by weight or more and 30% by weight or less relative to the total weight of the pharmaceutical composition. [1-15] The pharmaceutical composition according to any one of [1-2] to [1-14], wherein the disintegrant is contained in an amount of 18% by weight or more and 22% by weight or less relative to the total weight of the pharmaceutical composition.

[0022] [1-16] The pharmaceutical composition according to any one of [1-1] to [1-15], wherein the lubricant comprises at least one lubricant selected from the group consisting of sodium stearyl fumarate, zinc stearate, aluminum stearate, calcium stearate, magnesium stearate, talc, and sucrose fatty acid esters.

[0023] [1-17] The pharmaceutical composition according to any one of [1-1] to [1-16], wherein the lubricant comprises sodium stearyl fumarate, magnesium stearate, calcium stearate, or talc.

[0024] [1-18] The pharmaceutical composition according to any one of [1-1] to [1-17], wherein the lubricant comprises sodium stearyl fumarate. [1-19] The pharmaceutical composition according to any one of [1-2] to [1-18], wherein the excipient comprises at least one excipient selected from the group consisting of mannitol, lactose hydrate, fructose, glucose, sorbitol, corn starch, potato starch, wheat starch, and rice starch.

[0025] [1-20] The pharmaceutical composition according to any one of [1-2] to [1-19], wherein the excipient is mannitol or lactose hydrate. [1-21] The pharmaceutical composition according to any one of [1-2] to [1-20], wherein the excipient is mannitol.

[0026] [1-22] The pharmaceutical composition according to any one of [1-2] to [1-21], wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, carmellose sodium, hydroxypropyl cellulose, carmellose, carmellose calcium, methylcellulose, crystalline cellulose, sodium lauryl sulfate, povidone, and polysorbate.

[0027] [1-23] The pharmaceutical composition according to any one of [1-2] to [1-22], wherein the disintegrant comprises croscarmellose sodium, carmellose sodium, carmellose calcium, or hydroxypropyl cellulose.

[0028] [1-24] The pharmaceutical composition according to any one of [1-2] to [1-23], which contains croscarmellose sodium or carmellose calcium as the disintegrant. [1-25] The pharmaceutical composition according to any one of [1-1] to [1-24], which contains the compound represented by formula 1, or a salt thereof, or a solvate thereof in an amount of 1% by weight to 65% by weight based on the total weight of the pharmaceutical composition.

[0029] [1-26] The pharmaceutical composition according to any one of [1-1] to [1-25], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is contained in an amount of 8% by weight to 45% by weight relative to the total weight of the pharmaceutical composition. [1-27] The pharmaceutical composition according to any one of [1-1] to [1-25], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is the compound represented by formula 1 or a salt thereof. [1-28] The pharmaceutical composition according to any one of [1-1] to [1-25], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is a salt of the compound represented by formula 1. [1-29] The pharmaceutical composition according to any one of [1-1] to [1-25], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is the compound represented by formula 1.

[0030] [1-30] The pharmaceutical composition according to any one of [1-1] to [1-28], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is a p-toluenesulfonate salt of the compound represented by formula 1.

[0031] [1-31] ​​The pharmaceutical composition according to [1-30], wherein the p-toluenesulfonate salt of the compound represented by formula 1 is a crystalline form. [1-32] The pharmaceutical composition according to [1-30] or [1-31], wherein the p-toluenesulfonate salt of the compound represented by formula 1 is a crystalline form 1.

[0032] [1-33] The pharmaceutical composition according to [1-31] ​​or [1-32], wherein the powder X-ray diffraction pattern of the crystal has a peak at at least one diffraction angle (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0033] [1-34] The pharmaceutical composition according to any one of [1-31] ​​to [1-33], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least two diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0034] The powder X-ray diffraction pattern of the [1-35] crystal was 4.9° and 9.4° (±0.2°), 4.9° and 9.9° (±0.2°), 4.9° and 15.2° (±0.2°), 4.9° and 15.8° (±0.2°), 4.9° and 18.9° (±0.2°), 4.9° and 22.6° (±0.2°), 9.4° and 9.9° (±0.2°), 9.4° and 15.2° (±0.2°), 9.4° and 15.8° (±0.2°), 9.4° and 18.9° (±0.2°), 9.4° and 22.6° (±0.2°), 9.9° and 15.2° (±0.2°), 9.9° and 15.8° (±0.2°), The pharmaceutical composition according to [1-34], having peaks at diffraction angles (2θ) of 9.9° and 18.9° (±0.2°), 9.9° and 22.6° (±0.2°), 15.2° and 15.8° (±0.2°), 15.2° and 18.9° (±0.2°), 15.2° and 22.6° (±0.2°), 15.8° and 18.9° (±0.2°), 15.8° and 22.6° (±0.2°), or 18.9° and 22.6° (±0.2°).

[0035] [1-36] The pharmaceutical composition according to any one of [1-31] ​​to [1-35], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least three diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0036] The powder X-ray diffraction pattern of the [1-37] crystal was 4.9°, 9.4°, and 9.9° (±0.2°), 4.9°, 9.4°, and 15.2° (±0.2°), 4.9°, 9.4°, and 15.8° (±0.2°), 4.9°, 9.4°, and 18.9° (±0.2°), 4.9°, 9.4°, and 22.6° (±0.2°), 4.9°, 9.9°, and 15.2° (±0.2°), 4.9°, 9.9°, and 15.8° (±0.2°), 4.9°, 9.9°, and 18.9° (±0.2°), 4.9°, 9.9°, and 22.6° (±0.2°), 4.9°, 15.2°, and 15.8° (±0.2°), 4.9°, 15.2° and 18.9° (±0.2°), 4.9°, 15.2° and 22.6° (±0.2°), 4.9°, 15.8° and 18.9° (±0.2°), 4.9°, 15.8° and 22.6° (±0.2°), 4.9°, 18.9° and 22.6 (±0.2°)°, 9.4°, 9.9° and 15.2° (±0.2°), 9.4°, 9.9° and 15.8° (±0.2°), 9.4°, 9.9° and 18.9° (±0.2°), 9.4°, 9.9° and 22.6° (±0.2°), 9.4°, 15.2° and 15.8° (±0.2°), 9.4°, 15.2° and 18.9° (±0.2°), 9.4°, 15.2° and 22.6° (±0.2°), 9.4°, 15.8° and 18.9° (±0.2°), 9.4°, 15.8° and 22.6° (±0.2°), 9.4°, 18.9° and 22.6° (±0.2°), 9.9°, 15.2° and 15.8° (±0.2°), 9.9°, 15.2° and 18.9° (±0.2°), 9.9°, 15.2° and 22.6° (±0.2°), 9.9°, 15.8° and 18.9° (±0.2°), 9.9°, 15.8° and 22.6° (±0.2°), 9.9°, 18.9° and 22.6° (±0.2°), 15.2°, 15.8° and 18.9° (±0.2°), 15.2°, 15.8° and 22.6° (±0.2°), 15.2°, 18.9° and 22.6° (±0.2°), orThe pharmaceutical composition according to [1-36], having peaks at diffraction angles (2θ) of 15.8°, 18.9°, and 22.6°.

[0037] [1-38] The pharmaceutical composition according to any one of [1-31] ​​to [1-37], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least four diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0038] The powder X-ray diffraction pattern of the [1-39] crystal was: 4.9°, 9.4°, 9.9° and 15.2° (±0.2°), 4.9°, 9.4°, 9.9° and 15.8° (±0.2°), 4.9°, 9.4°, 9.9° and 18.9° (±0.2°), 4.9°, 9.4°, 9.9° and 22.6° (±0.2°), 4.9°, 9.4°, 15.2° and 15.8° (±0.2°), 4.9°, 9.4°, 15.2° and 18.9° (±0.2°), 4.9°, 9.4°, 15.2° and 22.6° (±0.2°), 4.9°, 9.4°, 15.8° and 18.9° (±0.2°), 4.9°, 9.4°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 18.9° and 22.6° (±0.2°), 4.9°, 9.9°, 15.2° and 15.8° (±0.2°), 4.9°, 9.9°, 15.2° and 18.9° (±0.2°), 4.9°, 9.9°, 15.2° and 22.6° (±0.2°), 4.9°, 9.9°, 15.8° and 18.9° (±0.2°), 4.9°, 9.9°, 15.8° and 22.6° (±0.2°), 4.9°, 9.9°, 15.8° and 22.6° (±0.2°), 4.9°, 15.2°, 15.8° and 18.9° (±0.2°), 4.9°, 15.2°, 15.8° and 22.6° (±0.2°), 4.9°, 15.2°, 18.9° and 22.6° (±0.2°), 4.9°, 15.8°, 18.9° and 22.6° (±0.2°), 9.4°, 9.9°, 15.2° and 15.8° (±0.2°), 9.4°, 9.9°, 15.2° and 18.9° (±0.2°), 9.4°, 9.9°, 15.2° and 22.6° (±0.2°), 9.4°, 9.9°, 15.8° and 18.9° (±0.2°), 9.4°, 9.9°, 15.8° and 22.6° (±0.2°), 9.4°, 9.9°, 18.9° and 22.6° (±0.2°), 9.4°, 15.2°, 15.8° and 18.9° (±0.2°), 9.4°, 15.2°, 15.8° and 22.6° (±0.2°), 9.4°, 15.2°, 18.9° and 22.6° (±0.2°),The pharmaceutical composition according to [1-38], having peaks at diffraction angles (2θ) of 9.4°, 15.8°, 18.9°, and 22.6° (±0.2°), 9.9°, 15.2°, 15.8°, and 18.9° (±0.2°), 9.9°, 15.2°, 15.8°, and 22.6° (±0.2°), 9.9°, 15.2°, 18.9°, and 22.6° (±0.2°), 9.9°, 15.2°, 18.9°, and 22.6° (±0.2°), 9.9°, 15.8°, 18.9°, and 22.6° (±0.2°), or 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0039] [1-40] The pharmaceutical composition according to any one of [1-31] ​​to [1-39], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least five diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0040] The powder X-ray diffraction pattern of the [1-41] crystal was 4.9°, 9.4°, 9.9°, 15.2° and 15.8° (±0.2°), 4.9°, 9.4°, 9.9°, 15.2° and 18.9° (±0.2°), 4.9°, 9.4°, 9.9°, 15.2° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8° and 18.9° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 15.2°, 15.8° and 18.9° (±0.2°), 4.9°, 9.4°, 15.2°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 15.2°, 18.9° and 22.6° (±0.2°), 4.9°, 9.4°, 15.8°, 18.9° and 22.6° (±0.2°), 4.9°, 9.9°, 15.2°, 15.8° and 18.9° (±0.2°), 4.9°, 9.9°, 15.2°, 15.8° and 22.6° (±0.2°), 4.9°, 9.9°, 15.2°, 18.9° and 22.6° (±0.2°), 4.9°, 9.9°, 15.8°, 18.9° and 22.6° (±0.2°), 4.9°, 15.2°, 15.8°, 18.9° and 22.6° (±0.2°), 9.4°, 9.9°, 15.2°, 15.8° and 18.9° (±0.2°), 9.4°, 9.9°, 15.2°, 15.8° and 22.6° (±0.2°), 9.4°, 9.9°, 15.2°, 18.9° and 22.6° (±0.2°), 9.4°, 9.9°, 15.8°, 18.9° and 22.6° (±0.2°), The pharmaceutical composition according to [1-40], having peaks at diffraction angles (2θ) of 9.4°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°), or 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0041] [1-42] The pharmaceutical composition according to any one of [1-31] ​​to [1-41], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least six diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0042] The powder X-ray diffraction pattern of the [1-43] crystal was 4.9°, 9.4°, 9.9°, 15.2°, 15.8° and 18.9° (±0.2°), 4.9°, 9.4°, 9.9°, 15.2°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.2°, 18.9° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8°, 18.9° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8°, 18.9° and 22.6° (±0.2°), The pharmaceutical composition according to [1-42], having peaks at diffraction angles (2θ) of 4.9°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°), or 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0043] [1-44] The pharmaceutical composition according to any one of [1-31] ​​to [1-43], wherein the powder X-ray diffraction pattern of the crystal has peaks at diffraction angles (2θ) of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0044] [1-45] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is less than 5.76 μm, d ５０ is less than 8.81 μm, or d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-44], wherein the average particle size is less than 13.08 μm.

[0045] [1-46] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is 5.00 μm or less, d ５０ is 8.00 μm or less, or d ９０The pharmaceutical composition according to any one of [1-31] ​​to [1-45], wherein the particle size is 12.00 μm or less.

[0046] [1-47] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is 4.00 μm or less, d ５０ is 6.00 μm or less, or d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-46], wherein the particle size is 11.00 μm or less.

[0047] [1-48] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is 3.00 μm or less, d ５０ is 5.00 μm or less, or d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-47], wherein the particle size is 8.00 μm or less.

[0048] [1-49] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is in the range of 1.50 μm or more and less than 5.76 μm, d ５０ is in the range of 2.60 μm or more and less than 8.81 μm, or d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-48], wherein the particle size is in the range of 4.80 μm or more and less than 13.08 μm.

[0049] [1-50] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is in the range of 1.90 μm or more and less than 5.76 μm, d ５０ is in the range of 3.40 μm or more and less than 8.81 μm, or d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-49], wherein the particle size is in the range of 5.80 μm or more and less than 13.08 μm.

[0050] [1-51] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is in the range of 2.00 μm or more and less than 5.76 μm, d ５０ is in the range of 3.50 μm or more and less than 8.81 μm, or d ９０The pharmaceutical composition according to any one of [1-31] ​​to [1-50], wherein the particle size is in the range of 5.90 μm or more and less than 13.08 μm.

[0051] [1-52] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is less than 5.76 μm, d ５０ is less than 8.81 μm, and d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-51], wherein the average particle size is less than 13.08 μm.

[0052] [1-53] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is 5.00 μm or less, d ５０ is 8.00 μm or less, and d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-52], wherein the particle size is 12.00 μm or less.

[0053] [1-54] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is 4.00 μm or less, d ５０ is 6.00 μm or less, and d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-53], wherein the particle size is 11.00 μm or less.

[0054] [1-55] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is 3.00 μm or less, d ５０ is 5.00 μm or less, and d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-54], wherein the particle size is 8.00 μm or less.

[0055] [1-56] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is in the range of 1.00 μm or more and less than 5.76 μm, d ５０ is in the range of 2.30 μm or more and less than 8.81 μm, and d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-55], wherein the particle size is in the range of 4.30 μm or more and less than 13.08 μm.

[0056] [1-57] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is in the range of 1.20 μm or more and less than 5.76 μm, d ５０ is in the range of 2.40 μm or more and less than 8.81 μm, and d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-56], wherein the particle size is in the range of 4.50 μm or more and less than 13.08 μm.

[0057] [1-58] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is in the range of 1.30 μm or more and less than 5.76 μm, d ５０ is in the range of 2.50 μm or more and less than 8.81 μm, and d ９０ The pharmaceutical composition according to any one of [1-31] ​​to [1-57], wherein the particle size is in the range of 4.70 μm or more and less than 13.08 μm.

[0058] [1-59] The pharmaceutical composition according to any one of [1-1] to [1-58], which is a powder containing p-toluenesulfonate of the compound represented by formula 1 as an active ingredient in the form of a 1-type crystal, and further containing mannitol, croscarmellose sodium, and sodium stearyl fumarate.

[0059] [1-60] A pharmaceutical preparation containing the pharmaceutical composition according to any one of [1-1] to [1-59]. [1-61] The pharmaceutical preparation according to [1-60], wherein the dosage form of the pharmaceutical preparation is selected from the group consisting of powders, powders, granules, tablets, and capsules.

[0060] [1-62] The pharmaceutical preparation according to any one of [1-60] or [1-61], wherein the dosage form of the pharmaceutical preparation is a powder or a capsule. [1-63] The pharmaceutical preparation according to any one of [1-60] to [1-62], wherein the pharmaceutical preparation is in the form of a capsule containing the p-toluenesulfonate salt of the compound represented by formula 1 as an active ingredient in the form of a 1-type crystal, and further containing mannitol, croscarmellose sodium, and sodium stearyl fumarate.

[0061] [1-64] The pharmaceutical composition according to [1-59], wherein the powder is used as a filler for capsules.

[0062] [2-1] Formula 1

[0063]

[0064] and a lubricant. [2-2] The pharmaceutical formulation according to [2-1], wherein the pharmaceutical composition further comprises an excipient and a disintegrant. [2-3] The pharmaceutical formulation according to [2-1] or [2-2], wherein the dosage form of the pharmaceutical formulation is selected from the group consisting of dust, powder, granules, tablets, and capsules.

[0065] [2-4] The pharmaceutical formulation according to any one of [2-1] to [2-3], wherein the dosage form of the pharmaceutical formulation is a powder or a capsule. [2-5] The pharmaceutical formulation according to any one of [2-1] to [2-4], wherein the dosage form of the pharmaceutical formulation is a capsule.

[0066] [2-6] The pharmaceutical formulation according to any one of [2-1] to [2-5], wherein the capsule contains a powdered pharmaceutical composition. [2-7] The pharmaceutical formulation according to any one of [2-1] to [2-6], wherein the lubricant is contained in an amount of 0.5% by weight or more based on the total weight of the pharmaceutical composition.

[0067] [2-8] The pharmaceutical formulation according to any one of [2-1] to [2-7], wherein the lubricant is contained in an amount of 0.5% by weight or more and 15% by weight or less based on the total weight of the pharmaceutical composition. [2-9] The pharmaceutical formulation according to any one of [2-1] to [2-8], wherein the lubricant is contained in an amount of 6% by weight or more based on the total weight of the pharmaceutical composition.

[0068] [2-10] The pharmaceutical formulation according to any one of [2-1] to [2-9], wherein the lubricant is contained in an amount of 7% by weight or more relative to the total weight of the pharmaceutical composition. [2-11] The pharmaceutical formulation according to any one of [2-1] to [2-10], wherein the lubricant is contained in an amount of 5.3% by weight or more and 15% by weight or less relative to the total weight of the pharmaceutical composition.

[0069] [2-12] The pharmaceutical formulation according to any one of [2-1] to [2-11], wherein the lubricant is contained in an amount of 6% by weight to 11% by weight based on the total weight of the pharmaceutical composition. [2-13] The pharmaceutical formulation according to any one of [2-2] to [2-12], wherein the excipient is contained in an amount of 21% by weight or more based on the total weight of the pharmaceutical composition.

[0070] [2-14] The pharmaceutical formulation according to any one of [2-2] to [2-13], wherein the excipient is contained in an amount of 21% by weight or more and 72% by weight or less relative to the total weight of the pharmaceutical composition. [2-15] The pharmaceutical formulation according to any one of [2-2] to [2-14], wherein the excipient is contained in an amount of 27% by weight or more and 66% by weight or less relative to the total weight of the pharmaceutical composition.

[0071] [2-16] The pharmaceutical formulation according to any one of [2-2] to [2-15], wherein the disintegrant is contained in an amount of 10% by weight or more relative to the total weight of the pharmaceutical composition. [2-17] The pharmaceutical formulation according to any one of [2-2] to [2-16], wherein the disintegrant is contained in an amount of 10% by weight or more and 30% by weight or less relative to the total weight of the pharmaceutical composition.

[0072] [2-18] The pharmaceutical formulation according to any one of [2-2] to [2-17], wherein the disintegrant is contained in an amount of 18% by weight or more and 22% by weight or less relative to the total weight of the pharmaceutical composition. [2-19] The pharmaceutical formulation according to any one of [2-1] to [2-18], wherein the lubricant is at least one selected from the group consisting of sodium stearyl fumarate, zinc stearate, aluminum stearate, calcium stearate, magnesium stearate, talc, and sucrose fatty acid esters.

[0073] [2-20] The pharmaceutical formulation according to any one of [2-1] to [2-19], wherein the lubricant comprises sodium stearyl fumarate, magnesium stearate, calcium stearate, or talc.

[0074] [2-21] The pharmaceutical formulation according to any one of [2-1] to [2-20], which contains sodium stearyl fumarate as the lubricant. [2-22] The pharmaceutical formulation according to any one of [2-2] to [2-21], which contains at least one excipient selected from the group consisting of mannitol, lactose hydrate, fructose, glucose, sorbitol, corn starch, potato starch, wheat starch, and rice starch.

[0075] [2-23] The pharmaceutical formulation according to any one of [2-2] to [2-22], wherein the excipient comprises mannitol or lactose hydrate. [2-24] The pharmaceutical formulation according to any one of [2-2] to [2-23], wherein the excipient comprises mannitol.

[0076] [2-25] The pharmaceutical formulation according to any one of [2-2] to [2-24], wherein the disintegrant comprises at least one selected from the group consisting of croscarmellose sodium, carmellose sodium, hydroxypropyl cellulose, carmellose, carmellose calcium, methylcellulose, crystalline cellulose, sodium lauryl sulfate, povidone, and polysorbate.

[0077] [2-26] The pharmaceutical formulation according to any one of [2-2] to [2-25], wherein the disintegrant comprises croscarmellose sodium, carmellose sodium, carmellose calcium, or hydroxypropyl cellulose.

[0078] [2-27] The pharmaceutical formulation according to any one of [2-2] to [2-26], which contains croscarmellose sodium or carmellose calcium as the disintegrant. [2-28] The pharmaceutical formulation according to any one of [2-1] to [2-27], which contains the p-toluenesulfonate in an amount of 1% by weight to 65% by weight based on the total weight of the pharmaceutical composition.

[0079] [2-29] The pharmaceutical preparation according to any one of [2-1] to [2-28], wherein the p-toluenesulfonate salt is contained in an amount of 8% by weight to 45% by weight based on the total weight of the pharmaceutical composition.

[0080] [2-30] The pharmaceutical formulation according to any one of [2-1] to [2-28], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is a compound represented by formula 1 or a salt thereof. [2-31] The pharmaceutical formulation according to any one of [2-1] to [2-28], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is a salt of the compound represented by formula 1.

[0081] [2-32] The pharmaceutical preparation according to any one of [2-1] to [2-27], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is the compound represented by formula 1. [2-33] The pharmaceutical preparation according to any one of [2-1] to [2-28], wherein the compound represented by formula 1, or a salt thereof, or a solvate thereof is a p-toluenesulfonate salt of the compound represented by formula 1.

[0082] [2-34] The pharmaceutical formulation according to any one of [2-1] to [2-33], wherein the p-toluenesulfonate salt of the compound represented by formula 1 is a crystalline form. [2-35] The pharmaceutical formulation according to any one of [2-1] to [2-34], wherein the p-toluenesulfonate salt of the compound represented by formula 1 is a crystalline form 1.

[0083] [2-36] The pharmaceutical preparation according to [2-34] or [2-35], wherein the powder X-ray diffraction pattern of the crystal has a peak at at least one diffraction angle (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0084] [2-37] The pharmaceutical preparation according to any one of [2-34] to [2-36], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least two diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0085] The powder X-ray diffraction pattern of the [2-38] crystal was 4.9° and 9.4° (±0.2°), 4.9° and 9.9° (±0.2°), 4.9° and 15.2° (±0.2°), 4.9° and 15.8° (±0.2°), 4.9° and 18.9° (±0.2°), 4.9° and 22.6° (±0.2°), 9.4° and 9.9° (±0.2°), 9.4° and 15.2° (±0.2°), 9.4° and 15.8° (±0.2°), 9.4° and 18.9° (±0.2°), 9.4° and 22.6° (±0.2°), 9.9° and 15.2° (±0.2°), 9.9° and 15.8° (±0.2°), The pharmaceutical formulation according to [2-37], having peaks at diffraction angles (2θ) of 9.9° and 18.9° (±0.2°), 9.9° and 22.6° (±0.2°), 15.2° and 15.8° (±0.2°), 15.2° and 18.9° (±0.2°), 15.2° and 22.6° (±0.2°), 15.8° and 18.9° (±0.2°), 15.8° and 22.6° (±0.2°), or 18.9° and 22.6° (±0.2°).

[0086] [2-39] The pharmaceutical preparation according to any one of [2-33] to [2-38], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least three diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0087] The powder X-ray diffraction pattern of the [2-40] crystal was 4.9°, 9.4°, and 9.9° (±0.2°), 4.9°, 9.4°, and 15.2° (±0.2°), 4.9°, 9.4°, and 15.8° (±0.2°), 4.9°, 9.4°, and 18.9° (±0.2°), 4.9°, 9.4°, and 22.6° (±0.2°), 4.9°, 9.9°, and 15.2° (±0.2°), 4.9°, 9.9°, and 15.8° (±0.2°), 4.9°, 9.9°, and 18.9° (±0.2°), 4.9°, 9.9°, and 22.6° (±0.2°), 4.9°, 15.2°, and 15.8° (±0.2°), 4.9°, 15.2° and 18.9° (±0.2°), 4.9°, 15.2° and 22.6° (±0.2°), 4.9°, 15.8° and 18.9° (±0.2°), 4.9°, 15.8° and 22.6° (±0.2°), 4.9°, 18.9° and 22.6 (±0.2°)°, 9.4°, 9.9° and 15.2° (±0.2°), 9.4°, 9.9° and 15.8° (±0.2°), 9.4°, 9.9° and 18.9° (±0.2°), 9.4°, 9.9° and 22.6° (±0.2°), 9.4°, 15.2° and 15.8° (±0.2°), 9.4°, 15.2° and 18.9° (±0.2°), 9.4°, 15.2° and 22.6° (±0.2°), 9.4°, 15.8° and 18.9° (±0.2°), 9.4°, 15.8° and 22.6° (±0.2°), 9.4°, 18.9° and 22.6° (±0.2°), 9.9°, 15.2° and 15.8° (±0.2°), 9.9°, 15.2° and 18.9° (±0.2°), 9.9°, 15.2° and 22.6° (±0.2°), 9.9°, 15.8° and 18.9° (±0.2°), 9.9°, 15.8° and 22.6° (±0.2°), 9.9°, 18.9° and 22.6° (±0.2°), 15.2°, 15.8° and 18.9° (±0.2°), 15.2°, 15.8° and 22.6° (±0.2°), 15.2°, 18.9° and 22.6° (±0.2°), orThe pharmaceutical preparation according to any one of [2-39], having peaks at diffraction angles (2θ) of 15.8°, 18.9°, and 22.6° (±0.2°).

[0088] [2-41] The pharmaceutical preparation according to any one of [2-33] to [2-40], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least four diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0089] The powder X-ray diffraction pattern of the [2-42] crystal was 4.9°, 9.4°, 9.9° and 15.2° (±0.2°), 4.9°, 9.4°, 9.9° and 15.8° (±0.2°), 4.9°, 9.4°, 9.9° and 18.9° (±0.2°), 4.9°, 9.4°, 9.9° and 22.6° (±0.2°), 4.9°, 9.4°, 15.2° and 15.8° (±0.2°), 4.9°, 9.4°, 15.2° and 18.9° (±0.2°), 4.9°, 9.4°, 15.2° and 22.6° (±0.2°), 4.9°, 9.4°, 15.8° and 18.9° (±0.2°), 4.9°, 9.4°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 18.9° and 22.6° (±0.2°), 4.9°, 9.9°, 15.2° and 15.8° (±0.2°), 4.9°, 9.9°, 15.2° and 18.9° (±0.2°), 4.9°, 9.9°, 15.2° and 22.6° (±0.2°), 4.9°, 9.9°, 15.8° and 18.9° (±0.2°), 4.9°, 9.9°, 15.8° and 22.6° (±0.2°), 4.9°, 9.9°, 15.8° and 22.6° (±0.2°), 4.9°, 15.2°, 15.8° and 18.9° (±0.2°), 4.9°, 15.2°, 15.8° and 22.6° (±0.2°), 4.9°, 15.2°, 18.9° and 22.6° (±0.2°), 4.9°, 15.8°, 18.9° and 22.6° (±0.2°), 9.4°, 9.9°, 15.2° and 15.8° (±0.2°), 9.4°, 9.9°, 15.2° and 18.9° (±0.2°), 9.4°, 9.9°, 15.2° and 22.6° (±0.2°), 9.4°, 9.9°, 15.8° and 18.9° (±0.2°), 9.4°, 9.9°, 15.8° and 22.6° (±0.2°), 9.4°, 9.9°, 18.9° and 22.6° (±0.2°), 9.4°, 15.2°, 15.8° and 18.9° (±0.2°), 9.4°, 15.2°, 15.8° and 22.6° (±0.2°), 9.4°, 15.2°, 18.9° and 22.6° (±0.2°),The pharmaceutical formulation according to [2-41], having peaks at diffraction angles (2θ) of 9.4°, 15.8°, 18.9°, and 22.6° (±0.2°), 9.9°, 15.2°, 15.8°, and 18.9° (±0.2°), 9.9°, 15.2°, 15.8°, and 22.6° (±0.2°), 9.9°, 15.2°, 18.9°, and 22.6° (±0.2°), 9.9°, 15.2°, 18.9°, and 22.6° (±0.2°), 9.9°, 15.8°, 18.9°, and 22.6° (±0.2°), or 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0090] [2-43] The pharmaceutical preparation according to any one of [2-33] to [2-42], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least five diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0091] The powder X-ray diffraction pattern of the [2-44] crystal was 4.9°, 9.4°, 9.9°, 15.2° and 15.8° (±0.2°), 4.9°, 9.4°, 9.9°, 15.2° and 18.9° (±0.2°), 4.9°, 9.4°, 9.9°, 15.2° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8° and 18.9° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 15.2°, 15.8° and 18.9° (±0.2°), 4.9°, 9.4°, 15.2°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 15.2°, 18.9° and 22.6° (±0.2°), 4.9°, 9.4°, 15.8°, 18.9° and 22.6° (±0.2°), 4.9°, 9.9°, 15.2°, 15.8° and 18.9° (±0.2°), 4.9°, 9.9°, 15.2°, 15.8° and 22.6° (±0.2°), 4.9°, 9.9°, 15.2°, 18.9° and 22.6° (±0.2°), 4.9°, 9.9°, 15.8°, 18.9° and 22.6° (±0.2°), 4.9°, 15.2°, 15.8°, 18.9° and 22.6° (±0.2°), 9.4°, 9.9°, 15.2°, 15.8° and 18.9° (±0.2°), 9.4°, 9.9°, 15.2°, 15.8° and 22.6° (±0.2°), 9.4°, 9.9°, 15.2°, 18.9° and 22.6° (±0.2°), 9.4°, 9.9°, 15.8°, 18.9° and 22.6° (±0.2°), The pharmaceutical preparation according to any one of [2-33] to [2-43], having peaks at diffraction angles (2θ) of 9.4°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°), or 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0092] [2-45] The pharmaceutical preparation according to any one of [2-33] to [2-44], wherein the powder X-ray diffraction pattern of the crystal has peaks at at least six diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0093] The powder X-ray diffraction pattern of the [2-46] crystal was 4.9°, 9.4°, 9.9°, 15.2°, 15.8° and 18.9° (±0.2°), 4.9°, 9.4°, 9.9°, 15.2°, 15.8° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.2°, 18.9° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8°, 18.9° and 22.6° (±0.2°), 4.9°, 9.4°, 9.9°, 15.8°, 18.9° and 22.6° (±0.2°), The pharmaceutical formulation according to [2-45], having peaks at diffraction angles (2θ) of 4.9°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°), or 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0094] [2-47] The pharmaceutical preparation according to any one of [2-33] to [2-46], wherein the powder X-ray diffraction pattern of the crystal has peaks at diffraction angles (2θ) of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0095] [2-48] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is less than 5.76 μm, d ５０ is less than 8.81 μm, or d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-47], wherein the particle size is less than 13.08 μm.

[0096] [2-49] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is 5.00 μm or less, d ５０ is 8.00 μm or less, or d ９０The pharmaceutical preparation according to any one of [2-33] to [2-48], wherein the particle size is 12.00 μm or less.

[0097] [2-50] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is 4.00 μm or less, d ５０ is 6.00 μm or less, or d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-49], wherein the particle size is 11.00 μm or less.

[0098] [2-51] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is 3.00 μm or less, d ５０ is 5.00 μm or less, or d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-50], wherein the particle size is 8.00 μm or less.

[0099] [2-52] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is in the range of 1.00 μm or more and less than 5.76 μm, d ５０ is in the range of 2.30 μm or more and less than 8.81 μm, or d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-51], wherein the particle size is in the range of 4.30 μm or more and less than 13.08 μm.

[0100] [2-53] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is in the range of 1.20 μm or more and less than 5.76 μm, d ５０ is in the range of 2.40 μm or more and less than 8.81 μm, or d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-52], wherein the particle size is in the range of 4.50 μm or more and less than 13.08 μm.

[0101] [2-54] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is in the range of 1.30 μm or more and less than 5.76 μm, d ５０ is in the range of 2.50 μm or more and less than 8.81 μm, or d ９０The pharmaceutical preparation according to any one of [2-33] to [2-53], wherein the particle size is in the range of 4.70 μm or more and less than 13.08 μm.

[0102] [2-55] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is less than 5.76 μm, d ５０ is less than 8.81 μm, and d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-54], wherein the particle size is less than 13.08 μm.

[0103] [2-56] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is 5.00 μm or less, d ５０ is 8.00 μm or less, and d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-55], wherein the particle size is 12.00 μm or less.

[0104] [2-57] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is 4.00 μm or less, d ５０ is 6.00 μm or less, and d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-56], wherein the particle size is 11.00 μm or less.

[0105] [2-58] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is 3.00 μm or less, d ５０ is 5.00 μm or less, and d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-57], wherein the particle size is 8.00 μm or less.

[0106] [2-59] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is in the range of 1.00 μm or more and less than 5.76 μm, d ５０ is in the range of 2.30 μm or more and less than 8.81 μm, and d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-58], wherein the particle size is in the range of 4.30 μm or more and less than 13.08 μm.

[0107] [2-60] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is in the range of 1.20 μm or more and less than 5.76 μm, d ５０ is in the range of 2.40 μm or more and less than 8.81 μm, and d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-59], wherein the particle size is in the range of 4.50 μm or more and less than 13.08 μm.

[0108] [2-61] The volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is in the range of 1.30 μm or more and less than 5.76 μm, d ５０ is in the range of 2.50 μm or more and less than 8.81 μm, and d ９０ The pharmaceutical preparation according to any one of [2-33] to [2-60], wherein the particle size is in the range of 4.70 μm or more and less than 13.08 μm.

[0109] [2-62] The pharmaceutical preparation according to any one of [2-1] to [2-61], which is in the form of a capsule containing p-toluenesulfonate of the compound as an active ingredient in the form of Type 1 crystals, and further containing mannitol, croscarmellose sodium, and sodium stearyl fumarate.

[0110] [2-63] The pharmaceutical preparation according to any one of [2-1] to [2-62], which is a powder containing p-toluenesulfonate of the compound as an active ingredient in the form of Type 1 crystals, and further containing mannitol, croscarmellose sodium, and sodium stearyl fumarate.

[0111] [2-64] The pharmaceutical preparation according to [2-63], wherein the powder is used as a filler for a capsule. [3-1] Formula 1

[0112]

[0113] [3-2] A method for producing the pharmaceutical composition according to any one of [1-1] to [1-59] or [1-64], comprising pulverizing a p-toluenesulfonate salt of a compound represented by formula 1

[0114]

[0115] [3-3] The method according to [3-1] or [3-2], further comprising a step of mixing the p-toluenesulfonate of the compound represented by formula 1, an excipient, a disintegrant, and a lubricant to obtain a mixture. [3-4] The method according to [3-2] or [3-3], further comprising a step of filling the mixture into a capsule.

[0116] [4-1] A method for producing a pharmaceutical composition, comprising a step of mixing a p-toluenesulfonate salt of the compound represented by formula 1 and a lubricant to obtain a mixture. [4-2] A method for producing a pharmaceutical composition, comprising a step of mixing a p-toluenesulfonate salt of the compound represented by formula 1, an excipient, a disintegrant, and a lubricant to obtain a mixture.

[0117] [4-3] The manufacturing method according to [4-1] or [4-2], wherein the lubricant is contained in an amount of 5.3% by weight or more and 15% by weight or less based on the total weight of the pharmaceutical composition. [4-4] The manufacturing method according to any one of [4-1] to [4-3], wherein the lubricant is contained in an amount of 7.0% by weight or more and 11% by weight or less based on the total weight of the pharmaceutical composition.

[0118] [4-5] The manufacturing method according to any one of [4-2] to [4-4], wherein the excipient is contained in an amount of 21% by weight or more and 72% by weight or less relative to the total weight of the pharmaceutical composition. [4-6] The manufacturing method according to any one of [4-2] to [4-5], wherein the excipient is contained in an amount of 27% by weight or more and 66% by weight or less relative to the total weight of the pharmaceutical composition.

[0119] [4-7] The manufacturing method according to any one of [4-2] to [4-6], wherein the disintegrant is contained in the range of 10% by weight or more and 30% by weight or less based on the total weight of the pharmaceutical composition. [4-8] The manufacturing method according to any one of [4-2] to [4-7], wherein the disintegrant is contained in the range of 18% by weight or more and 22% by weight or less based on the total weight of the pharmaceutical composition.

[0120] [4-9] The manufacturing method according to any one of [4-1] to [4-8], wherein the lubricant comprises sodium stearyl fumarate, magnesium stearate, calcium stearate, or talc.

[0121] [4-10] The manufacturing method according to any one of [4-1] to [4-9], wherein the lubricant comprises sodium stearyl fumarate. [4-11] The manufacturing method according to any one of [4-2] to [4-10], wherein the excipient comprises mannitol or lactose hydrate.

[0122] [4-12] The manufacturing method according to any one of [4-2] to [4-11], wherein the excipient comprises mannitol. [4-13] The manufacturing method according to any one of [4-2] to [4-12], wherein the disintegrant comprises croscarmellose sodium, carmellose sodium, carmellose calcium, or hydroxypropyl cellulose.

[0123] [4-14] The manufacturing method according to any one of [4-2] to [4-13], wherein the disintegrant is croscarmellose sodium or carmellose calcium. [4-15] The manufacturing method according to any one of [4-1] to [4-14], wherein the pharmaceutical composition contains the compound represented by formula 1, or a salt thereof, or a solvate thereof in an amount of 1% by weight to 65% by weight based on the total weight of the pharmaceutical composition.

[0124] [4-16] The method according to any one of [4-1] to [4-15], wherein the p-toluenesulfonate salt of the compound represented by formula 1 is contained in the range of 8% by weight to 45% by weight based on the total weight of the pharmaceutical composition.

[0125] [4-17] The manufacturing method according to any one of [4-1] to [4-16], wherein the p-toluenesulfonate salt of the compound represented by formula 1 is a type 1 crystal. [4-18] The manufacturing method according to any one of [4-1] to [4-17], comprising pulverizing the p-toluenesulfonate salt of the compound represented by formula 1.

[0126] [4-19] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is less than 5.76 μm, d ５０is less than 8.81 μm, or d ９０ [4-20] The process according to [4-17] or [4-18], wherein the volume-based particle diameter of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1 is d １０ is 4.00 μm or less, d ５０ is 6.00 μm or less, or d ９０ The manufacturing method according to any one of [4-17] to [4-19], wherein the average particle size is 11.00 μm or less.

[0127] [4-21] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is less than 5.76 μm, d ５０ is less than 8.81 μm, and d ９０ The manufacturing method according to any one of [4-17] to [4-20], wherein the average particle size is less than 13.08 μm.

[0128] [4-22] Regarding the volume-based particle size of the crystals of the p-toluenesulfonate salt of the compound represented by formula 1, d １０ is 4.00 μm or less, d ５０ is 6.00 μm or less, and d ９０ The manufacturing method according to any one of [4-17] to [4-21], wherein the average particle size is 11.00 μm or less.

[0129] [4-23] The method for producing a powder according to any one of [4-1] to [4-22], which contains p-toluenesulfonate of the compound represented by formula 1 as an active ingredient in the form of a 1st-type crystal, and further contains mannitol, croscarmellose sodium, and sodium stearyl fumarate.

[0130] [4-24] The method according to any one of [4-1] to [4-23], further comprising filling the mixture into a capsule.

[0131] The present invention enables Compound I, a poorly water-soluble compound that has strong inhibitory effects on NaPi-IIb, PiT-1, and PiT-2, to be formulated to have improved solubility in the gastrointestinal tract. Furthermore, the present invention enables the stable production of formulations of Compound I that have a certain level of uniformity or higher.

[0132] FIG. 1 is a graph showing the results of dissolution tests of Compound I for the formulations of Example 1 (F59) and Example 2 (F61). FIG. 2 is a graph showing the results of dissolution tests of Compound I for the formulations of Example 3 (F50), Example 4 (F51), Example 5 (F52), and Example 2 (F66). FIG. 3 is a graph showing the results of dissolution tests of Compound I for the capsules of Example 12 (R4L02). FIG. 4 is a graph showing the results of dissolution tests of Compound I for the capsules of Example 13 (R4L05). FIG. 5 is a graph showing the results of measurements of particle size distribution of Compound I. FIG. 6 is a graph showing the results of measurements of particle size distribution of Compound I. FIG. 7 is a graph showing the results of measurements of particle size distribution of Compound I. FIG. 8 is a graph showing the results of dissolution tests of Compound I for formulations using a pulverized drug substance of Compound I.

[0133] The present specification relates to a formulation containing 7-[[2,3-difluoro-4-[2-[2-methoxyethyl(methyl)amino]ethoxy]phenyl]methyl]-10-hydroxy-6-methyl-8-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-6,7-diazaspiro[4,5]dec-9-ene-9-carboxamide, or a salt thereof, or a solvate thereof as a drug substance, for example, a formulation containing the p-toluenesulfonate salt of the compound (Compound I) as a drug substance.

[0134]

[0135] The above-mentioned compound I can be produced by converting the compound obtained by the method described in Example 14 of Patent Document 6 into a p-toluenesulfonic acid salt. More specifically, compound I can be produced by the method described in Non-Patent Document 9.

[0136] As used herein, salts of the compound of Formula 1 are not particularly limited as long as they are pharmaceutically acceptable salts formed with an acid or base that is acceptable for ingestion accompanying pharmaceutical administration. Examples include organic acid salts, inorganic acid salts, organic base salts, and inorganic base salts, specifically carboxylate salts such as acetate, citrate, malate, tartrate, and succinate; sulfonate salts such as methanesulfonate, benzenesulfonate, and p-toluenesulfonate; hydrochloride; hydrobromide; hydroiodide; sulfate; phosphate; nitrate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. These salts are produced, for example, by contacting the compound of Formula 1 with an acid or base that can be used in pharmaceutical production.

[0137] When referring to a solvate herein, the term "solvate" refers to a compound and a solvent forming a single molecular group, and is not particularly limited as long as it is a pharmaceutically acceptable solvate formed with a solvent that is acceptable for ingestion accompanying pharmaceutical administration. Examples of solvates include solvates with a single solvent such as hydrates, alcoholates (ethanolates, methanolates, 1-propanolates, 2-propanolates, etc.), and dimethyl sulfoxide, as well as solvates formed with multiple solvents per compound molecule, or solvates formed with multiple types of solvents per compound molecule.

[0138] In producing a pharmaceutical composition or pharmaceutical formulation containing Compound I, powdery crystals of Compound I can be used. For example, powdery crystals obtained by the method described in Non-Patent Document 9, specifically powdery crystals obtained by precipitating from a solution containing acetone, ethyl acetate, ethanol, or heptane, or a mixture of these solvents, can be used.

[0139] The compounds used herein may contain unnatural proportions of isotope atoms in one or more atoms constituting such compounds. The present invention also includes compounds in which any atom in a compound is substituted with another isotope atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons), thereby substituting isotopes with an abundance ratio different from the abundance ratio of isotopes in nature, i.e., compounds labeled with isotope atoms. Examples of isotope elements contained in the compounds herein include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, etc., and each of these isotopes is 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 32 P, 35 S, 18 F, 36 Isotopically labeled compounds include Cl and the like. Compounds labeled with isotope atoms are useful as therapeutic or preventive agents, research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging diagnostic agents). Compounds herein containing radioactive or non-radioactive isotopes in all proportions are encompassed within the scope of the present invention. Compounds labeled with isotope atoms can be produced using reagents and solvents containing the corresponding isotope atoms in the same manner as for producing unlabeled compounds.

[0140] As used herein, the term "pharmaceutical composition" refers to a formulation of a pharmacologically active compound of the present invention with a vehicle such as an excipient, carrier, or diluent that is generally accepted in the art for delivery to a mammal, e.g., a human.

[0141] As used herein, "preparation" and "pharmaceutical preparation" refer to a product in which the active ingredient used in a pharmaceutical product has been processed into an optimal shape or properties suited to the method and purpose of use. Additives can be added as needed depending on the method and purpose of use and the properties of the active ingredient. Examples of types of pharmaceutical preparations, i.e., "dosage forms," ​​include liquid pharmaceutical preparations (liquids) such as injections, suspensions, emulsions, and eye drops, and solid pharmaceutical preparations (solid preparations) such as tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, lozenges, and suppositories, but are not limited to these.

[0142] The "preparation" and "pharmaceutical preparation" herein are produced by well-known methods using additives such as excipients, disintegrants, lubricants, binders, lubricating colorants, flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, and antioxidants.

[0143] As used herein, "solid preparation" refers to dosage forms such as tablets, powders, fine granules, granules, coated tablets, capsules, dry syrups, lozenges, and suppositories. The dosage form refers to the shape of a shaped pharmaceutical or the like. Of these, the solid preparations according to the present specification are preferably capsules or tablets, and more preferably capsules. These preparations are not particularly limited in form, etc., as long as they have ingredients, a normal shape, and a normal size commonly used in the pharmaceutical field.

[0144] As used herein, the term "excipient" refers to an additive added for the purpose of shaping, expanding, diluting, etc. of a solid preparation, and includes, but is not limited to, sugars (e.g., lactose, lactose hydrate, fructose, glucose, etc.), sugar alcohols (e.g., mannitol, etc.), starches (corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, etc.), cellulose (e.g., crystalline cellulose), inorganic salts (e.g., calcium silicate, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, etc.). More specific examples include corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, lactose hydrate, fructose, glucose, mannitol, anhydrous calcium hydrogen phosphate, crystalline cellulose, and precipitated calcium carbonate, with mannitol, lactose, crystalline cellulose, etc. being preferred.

[0145] The term "disintegrant" as used herein refers to an additive added for the purposes of promoting disintegration of a solid preparation administered to the body and increasing the release rate of the active ingredient from the preparation, and is not particularly limited, but examples thereof include croscarmellose sodium, carmellose sodium, hydroxypropyl cellulose, carmellose, carmellose calcium, methylcellulose, crystalline cellulose, sodium lauryl sulfate, povidone, polysorbate, etc. Preferred examples include croscarmellose sodium, carmellose sodium, etc.

[0146] The term "lubricant" as used herein refers to an additive used in the production process of a solid preparation, which is added for the purpose of increasing the fluidity of a mixture containing an active ingredient so that it is mixed uniformly, or to make it easier for the solid preparation to be compressed and molded, and is not particularly limited to, but examples thereof include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate, hydrogenated oil, etc. Preferred examples include sodium stearyl fumarate, magnesium stearate, and hydrogenated oil, more preferred examples include sodium stearyl fumarate and magnesium stearate, and most preferred examples include sodium stearyl fumarate.

[0147] As used herein, "% by weight" refers to the ratio of the weight of a specific substance to the weight of all components. When used to describe the amount of a component in a pharmaceutical composition, pharmaceutical formulation, or solid formulation, it refers to the ratio of the weight of a specific component to the weight of all components contained in the pharmaceutical composition, pharmaceutical formulation, or solid formulation. Unless otherwise specified, packaging containers such as ampoules, plastic bottles, or boxes, and capsules for capsules, used to prevent loss of a pharmaceutical composition, pharmaceutical formulation, or solid formulation during transportation, storage, or handling, such as administration, are not included in the weight of the entire components.

[0148] In this specification, when the content of an additive in a pharmaceutical composition is expressed as a weight percent relative to the total weight of the pharmaceutical composition, the weight percent refers to the ratio of the weight of the additive to the weight of the entire pharmaceutical composition, which consists of the active ingredient and the additive(s) added to the active ingredient. If the pharmaceutical formulation is pre-encapsulated in a container, the container is not included in the weight of the entire pharmaceutical formulation. Examples of pharmaceutical formulations encapsulated in a container include pharmaceutical formulations that are opened and the contents are administered, such as pills encapsulated in a bottle, tablets encapsulated in an aluminum foil, and injections encapsulated in a syringe. Examples also include pharmaceutical formulations in which a filler (a mixture of an active ingredient and an additive, also known as a capsule filler, filler, filling powder, or bulk powder) is encapsulated in a capsule-shaped container, and the capsule with the encapsulated filler is administered as is. In one aspect of the present invention, the pharmaceutical composition is a filler, which is the content of a capsule, and the filler is preferably a powder. The powder may be used as a pharmaceutical formulation encapsulated in a capsule, and may be administered as a capsule.

[0149] When the pharmaceutical composition of the present specification is formulated as a capsule, the capsule may be one typically used in capsule formulations, such as those described in the Japanese Pharmacopoeia (17th or 18th edition). The type of capsule is not particularly limited, and capsules typically used in the art may be used. Examples of capsule types include hard capsules and soft capsules. Materials preferably used for hard capsules include, for example, gelatin, hydroxypropyl methylcellulose, pullulan, or mixtures thereof, with gelatin capsules being preferred. Materials preferably used for soft capsules include, for example, gelatin, starch, carrageenan, agar, glycerin, sorbitol, or mixtures thereof, with gelatin capsules being preferred.

[0150] In this specification, when the content of an active ingredient is expressed as a weight percentage relative to the total weight of the pharmaceutical composition, it represents the ratio of the weight of the active ingredient to the weight of the total pharmaceutical composition consisting of the active ingredient and additives added to the active ingredient, i.e., the content rate.

[0151] In the present specification, the content of Compound I, an active ingredient, relative to the total pharmaceutical composition is exemplified by a lower limit of 1 wt%, 3 wt%, 5 wt%, 7 wt%, or 8 wt%, and an upper limit of 65 wt%, 60 wt%, 55 wt%, 50 wt%, or 45 wt%. The lower limit is preferably 8 wt%, and the upper limit is preferably 45 wt%. Preferred content ranges include 1 wt% to 65 wt%, 3 wt% to 60 wt%, 5 wt% to 55 wt%, and 7 wt% to 50 wt%, and more preferably 8 wt% to 45 wt%.

[0152] In the present specification, excipients can be used as additives. When the content of an excipient is expressed as a weight percent relative to the total weight of the pharmaceutical composition, this refers to the ratio of the weight of the excipient to the weight of the total pharmaceutical composition consisting of the active ingredient and additives added to the active ingredient, i.e., the content rate.

[0153] In this specification, the excipient content relative to the total pharmaceutical composition is exemplified by a lower limit of 21 wt%, 23 wt%, 25 wt%, 26 wt%, or 27 wt%, and by an upper limit of 72 wt%, 70 wt%, 68 wt%, 67 wt%, or 66 wt%. A preferred lower limit is 27 wt%, and a preferred upper limit is 66 wt%. Preferred content ranges include 21 wt% to 72 wt%, 23 wt% to 70 wt%, 25 wt% to 68 wt%, and 26 wt% to 67 wt%, and more preferably 27 wt% to 66 wt%. An example of a preferred excipient is mannitol.

[0154] In the present specification, a disintegrant can be used as an additive. When the content of the disintegrant is expressed as a weight % relative to the total weight of the pharmaceutical composition, this refers to the ratio of the weight of the disintegrant to the weight of the total pharmaceutical composition consisting of the active ingredient and additives added to the active ingredient, i.e., the content.

[0155] In this specification, the content of the disintegrant relative to the total pharmaceutical composition is exemplified by a lower limit of 10 wt%, 12 wt%, 14 wt%, 16 wt%, or 18 wt%, and by an upper limit of 30 wt%, 28 wt%, 26 wt%, 24 wt%, or 22 wt%. A lower limit of 18 wt% is preferred, and an upper limit of 22 wt% is preferred. Preferred content ranges include 10 wt% to 30 wt%, 12 wt% to 28 wt%, 14 wt% to 26 wt%, and 16 wt% to 24 wt%, and more preferably 18 wt% to 22 wt%. Examples of preferred disintegrants include croscarmellose sodium and / or carmellose sodium.

[0156] In this specification, a lubricant can be used as an additive. When the content of a lubricant is expressed as a weight percent relative to the total weight of the pharmaceutical composition, this refers to the ratio of the weight of the lubricant to the weight of the total pharmaceutical composition consisting of the active ingredient and additives added to the active ingredient, i.e., the content.

[0157] In this specification, the lubricant content of the entire pharmaceutical composition is exemplified by a lower limit of 5.3 wt%, 5.6 wt%, 6.0 wt%, 6.3 wt%, 6.5 wt%, 6.8 wt%, or 7.0 wt%, and by an upper limit of 15 wt%, 14 wt%, 13 wt%, 12 wt%, 11 wt%, or 10 wt%. A preferred lower limit is 7.0 wt%, and a preferred upper limit is 10 wt%. Preferred content ranges include 5.3 wt% to 15 wt%, 5.6 wt% to 14 wt%, and 6.0 wt% to 13 wt%, more preferably 6.3 wt% to 12 wt%, 6.5 wt% to 11 wt%, 6.8 wt% to 11 wt%, and 7.0 wt% to 11 wt%, and most preferably 7.0 wt% to 10 wt%.

[0158] In this specification, the ratio of lubricant to 1 part by weight of Compound I is exemplified by a lower limit of 0.10 parts by weight, 0.13 parts by weight, or 0.15 parts by weight, and by an upper limit of 0.90 parts by weight, 0.87 parts by weight, or 0.85 parts by weight. A preferred lower limit is 0.15 parts by weight, and a preferred upper limit is 0.85 parts by weight. Preferred ratio ranges are 0.10 parts by weight or more and 0.90 parts by weight or less, and 0.13 parts by weight or more and 0.87 parts by weight or less, and more preferably 0.15 parts by weight or more and 0.85 parts by weight or less. Preferred examples of lubricants include sodium stearyl fumarate or magnesium stearate, and even more preferred examples of lubricants include sodium stearyl fumarate.

[0159] The additives contained in the pharmaceutical composition and pharmaceutical formulation containing Compound I are not particularly limited as long as they are formulations used in the pharmaceutical composition and pharmaceutical formulation, and examples thereof include excipients, disintegrants, lubricants, binders, lubricant colorants, flavoring agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc. The types and amounts of additives used in the pharmaceutical composition and pharmaceutical formulation can be arbitrarily selected and optimized depending on the physical and chemical properties of the pharmaceutical composition and the active ingredient contained therein.

[0160] The "volume-based particle diameter" in this specification is a value of the particle size distribution weighted by volume among the particle diameters of a powder, and represents the particle diameter in a volume that occupies a predetermined ratio in a powder sample. １０ (d １０ ), volume-based particle diameter d ５０ (d ５０ ), or volume-based particle diameter d ９０ (d ９０ It is sometimes expressed as a volume average particle size, such as the one exemplified by d １０ , d ５０ , or d ９０ The particle diameters refer to the particle diameters at the points corresponding to 10%, 50%, or 90% of the sample volume when the cumulative frequency distribution curve for particle diameters is calculated, with the total volume of the particles being 100%. Those skilled in the art can measure the volumetric particle diameter using a commercially available particle size measurement instrument and following its instruction manual. For example, volumetric particle diameter measurement using a laser diffraction particle size distribution analyzer can be performed by dispersing the powder to be measured in a solvent (dispersion medium) for dispersing the powder, irradiating the dispersion medium with a laser beam, and measuring the change in the diffraction of the laser beam over time as the dispersed state of the powder. This measurement can also be performed according to conventional methods, such as the "Particle Size Measurement Method" described in the Japanese Pharmacopoeia (17th or 18th revision). For example, the volumetric particle diameter of Compound I can be determined according to the following method. (1) Weigh out approximately 3 g of SPAN80 and add 3,000 mL of n-hexane to prepare a 0.1 wt% SPAN80 n-hexane solution. (2) Weigh out approximately 50 mg of compound I, add 2000 mL of 0.1 wt% SPAN80 n-hexane solution, and stir to prepare a saturated solution. (3) After filtering off the insoluble matter in the saturated solution using a 0.45 μm disposable vacuum filter, use the filtrate as the dispersion medium. (4) Accurately weigh out approximately 30 mg of compound I and add 2 mL of dispersion medium to prepare the measurement sample. (5) Perform the laser diffraction test three times under the following conditions, and use the average value.

[0161] Refractive index: Sample: 1.6900, imaginary part: 0.0100, dispersion medium (hexane): 1.3760 Number of repetitions: 15 Particle size standard: volume Number of data acquisitions: 5000 Transmittance (suitable range) Red semiconductor laser: 90-80% Blue light-emitting diode: 90-70% The HORIBA LA-950V2 can be used as a measuring device.

[0162] In one embodiment of the volume-based particle size of the crystals of Compound I herein, the volume-based particle size is preferably small so that the dissolution rate can be increased in order for the solid active ingredient to dissolve and be efficiently absorbed in the body. Furthermore, it is preferable that the solid active ingredient has a certain degree of particle size distribution so that the content of the active ingredient in the pharmaceutical composition and pharmaceutical preparation is uniform.

[0163] In this specification, the volume-based particle size of the crystals of Compound I is d １０ The upper limit of d is, for example, less than 4.00 μm, 5.00 μm, or 5.76 μm. １０ The lower limit of is, for example, 1.30 μm, 1.20 μm, or 1.00 μm, the upper limit is preferably a value smaller than 5.76 μm, and the lower limit is preferably 1.00 μm. １０ The range is exemplified by a range of 1.00 μm or more and less than 5.76 μm, and a range of 1.20 μm or more and 5.00 μm or less, and more preferably a range of 1.30 μm or more and 4.00 μm or less.

[0164] In this specification, the volume-based particle size of the crystals of Compound I is d ５０ Examples of the upper limit of d are values ​​smaller than 5.00 μm, 8.00 μm, or 8.81 μm. ５０ The lower limit of is, for example, 2.50 μm, 2.40 μm, or 2.30 μm, the upper limit is preferably a value smaller than 8.81 μm, and the lower limit is preferably 2.30 μm. ５０ The range is exemplified by a range of 2.30 μm or more and less than 8.81 μm, and a range of 2.40 μm or more and 8.00 μm or less, and more preferably a range of 2.50 μm or more and 5.00 μm or less.

[0165] In this specification, the volume-based particle size of the crystals of Compound I is d ９０ Examples of the upper limit of d are values ​​smaller than 8.00 μm, 10.00 μm, 12.00 μm, or 13.08 μm. ９０ The lower limit of is 4.70 μm, 4.60 μm, 4.50 μm, or 4.30 μm, for example, and the upper limit is preferably a value smaller than 13.08 μm, and the lower limit is preferably 2.30 μm. ９０ Examples of the range are 4.30 μm or more and less than 13.08 μm, 4.50 μm or more and 12.00 μm or less, and 4.60 μm or more and 10.00 μm or less, and more preferably 4.70 μm or more and 8.00 μm or less.

[0166] In this specification, the volume-based particle size of the crystals of Compound I is d １０ is less than 5.76 μm, d ５０ is less than 8.81 μm, or d ９０ In this specification, the volume-based particle size of the crystals of Compound I is d １０ is in the range of 1.00 μm or more and 5.76 μm or less, 1.30 μm or more and 4.00 μm or less, or 1.20 μm or more and 5.00 μm or less, d ５０ is in the range of 2.30 μm or more and less than 8.81 μm, in the range of 2.40 μm or more and 8.00 μm or less, or in the range of 2.50 μm or more and 5.00 μm or less, or d ９０ is in the range of 4.30 μm or more and less than 13.08 μm, 4.50 μm or more and 12.00 μm or less, 4.60 μm or more and 10.00 μm or less, or 4.70 μm or more and 8.00 μm or less.

[0167] In this specification, the volume-based particle size of the crystals of Compound I is d １０ is less than 5.76 μm, d ５０ is less than 8.81 μm, and d ９０ In this specification, the volume-based particle size of the crystals of Compound I is d １０ is in the range of 1.00 μm or more and less than 5.76 μm, in the range of 1.30 μm or more and 4.00 μm or less, or in the range of 1.20 μm or more and 5.00 μm or less, d ５０is in the range of 2.30 μm or more and less than 8.81 μm, in the range of 2.40 μm or more and 8.00 μm or less, or in the range of 2.50 μm or more and 5.00 μm or less, and d ９０ is in the range of 4.30 μm or more and less than 13.08 μm, 4.50 μm or more and 12.00 μm or less, 4.60 μm or more and 10.00 μm or less, or 4.70 μm or more and 8.00 μm or less.

[0168] As used herein, "powder X-ray diffraction" refers to a numerical value determined using X-ray diffraction, used in the identification and structural analysis of crystalline substances, and is a value specific to any crystal. This value is typically expressed as one or more 2θ values. Those skilled in the art can measure this using a commercially available powder X-ray diffraction measurement instrument and following its instruction manual. More specifically, the 2θ value can be measured by irradiating the sample to be measured with CuKα X-rays and measuring the diffracted X-rays relative to the incident X-rays. For example, this can be performed according to a conventional method such as the "powder X-ray diffraction measurement method" described in the Japanese Pharmacopoeia (17th or 18th revision).

[0169] Peak values ​​(2θ values) in powder X-ray diffraction spectra may have some error depending on the measuring instrument or measurement conditions such as peak reading conditions. In this specification, peak values ​​may have a measurement error of ±0.2°, or a range of about ±0.2°, for example, ±0.5°. The Japanese Pharmacopoeia (17th or 18th revision) states that for the same crystalline form, the diffraction angle 2θ typically coincides within a range of ±0.2°. Therefore, the present invention encompasses not only crystals in which the diffraction angles of peaks in powder X-ray diffraction are completely identical, but also crystals in which the diffraction angles of peaks coincide with an error of about ±0.2°.

[0170] In the present specification, when the diffraction angle 2θ is expressed as "(±0.2°)" at the end of a listed diffraction angle 2θ, this means that for all listed diffraction angles 2θ, a range of ±0.2° is allowed for each listed value. The same applies to the expression "±0.5°".

[0171] As used herein, the term "powder X-ray diffraction pattern" refers to a plot of diffraction peak values ​​(also referred to as diffraction angles, 2θ values, or 2θ) and their intensities obtained by measuring a powder X-ray diffraction spectrum on the horizontal and vertical axes, respectively. A person skilled in the art can plot such peak values ​​using a commercially available powder X-ray diffraction measurement instrument and following the instructions for use. Powder X-ray diffraction analysis can be performed according to standard methods, such as those described in the "Powder X-ray Diffraction Measurement Method" in the Japanese Pharmacopoeia (17th or 18th revision).

[0172] The "form 1 crystal" of Compound I in this specification refers to one of the crystals of p-toluenesulfonate (Compound I) of the compound represented by formula (I), and it is described that the form 1 crystal of Compound I is characterized by having peaks at diffraction angles (2θ) of around 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° in a powder X-ray diffraction pattern (Non-Patent Document 9).

[0173] In one embodiment, the powder X-ray diffraction pattern of the "Form 1 crystal" of Compound I herein has a peak at at least one diffraction angle (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0174] In one embodiment, the powder X-ray diffraction pattern of the "Form 1 crystal" of Compound I herein has peaks at at least two diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°). Preferred examples of the two diffraction angles include 4.9° and 9.4° (±0.2°), 4.9° and 15.2° (±0.2°), 4.9° and 18.9° (±0.2°), 4.9° and 22.6° (±0.2°), 15.2° and 18.9° (±0.2°), or 15.2° and 22.6° (±0.2°).

[0175] In one embodiment, the powder X-ray diffraction pattern of the "Form 1 crystal" of Compound I herein has peaks at at least three diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°). Preferred examples of combinations of the three diffraction angles include 4.9°, 9.4°, and 15.2° (±0.2°), 4.9°, 15.2°, and 18.9° (±0.2°), 4.9°, 15.2°, and 22.6° (±0.2°), 9.4°, 15.2°, and 18.9° (±0.2°), or 15.2°, 18.9°, and 22.6° (±0.2°).

[0176] In one embodiment, the powder X-ray diffraction pattern of the "Form 1 crystal" of Compound I herein has peaks at at least four diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°) in terms of 2θ values ​​by powder X-ray diffraction. Preferred examples of combinations of the four diffraction angles include 4.9°, 9.4°, 15.2° and 18.9° (±0.2°), 4.9°, 9.4°, 15.2° and 22.6° (±0.2°), 4.9°, 15.2°, 18.9° and 22.6° (±0.2°), 9.4°, 15.2°, 18.9° and 22.6° (±0.2°), or 15.2°, 15.8°, 18.9° and 22.6° (±0.2°).

[0177] In one embodiment, the powder X-ray diffraction pattern of the "Form 1 crystal" of Compound I herein has peaks at at least five diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°). Preferred examples of combinations of diffraction angle peaks include 4.9°, 9.4°, 15.2°, 18.9°, and 22.6° (±0.2°), or 4.9°, 9.9°, 15.2°, 18.9°, and 22.6° (±0.2°).

[0178] In one embodiment, the powder X-ray diffraction pattern of the "Form 1 crystal" of Compound I herein has peaks at at least six diffraction angles (2θ) selected from the group consisting of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°). Preferred examples of the six diffraction angle combinations include 4.9°, 9.4°, 9.9°, 15.8°, 18.9°, and 22.6° (±0.2°), or 4.9°, 9.4°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°).

[0179] The powder X-ray diffraction pattern of the "Form 1 crystal" of Compound I herein has peaks at all diffraction angles (2θ) of 4.9°, 9.4°, 9.9°, 15.2°, 15.8°, 18.9°, and 22.6° (±0.2°) as the 2θ values ​​determined by powder X-ray diffraction.

[0180] "Thermogravimetric analysis" as used herein refers to a technique for thermally analyzing changes in the physical and chemical properties of a sample, and is an analytical means for measuring changes in weight caused by heating the sample. Those skilled in the art can perform measurements using commercially available thermogravimetric analysis equipment and following the instructions for use.

[0181] As used herein, "differential thermal analysis" refers to an analytical method for detecting and measuring the heat generated or absorbed by heating a sample. Those skilled in the art can perform measurements using commercially available differential thermal analysis equipment and following its instructions. "Thermogravimetric analysis" and / or "differential thermal analysis" can be used to obtain information about physical phenomena such as sample sublimation, melting, solidification, condensation, evaporation, decomposition, adsorption, or desorption. When "thermogravimetric analysis" and / or "differential thermal analysis" are performed on multiple samples, for example, if the melting points of the solids are the same, this data can suggest that the multiple samples have the same crystalline form. Furthermore, for example, a sample with a high solid melting point can be more thermally stable than a sample with a low melting point. Thermogravimetric analysis and differential thermal analysis can be performed according to conventional methods, such as those described in the "Thermal Analysis Methods" section of the Japanese Pharmacopoeia (17th Edition).

[0182] It is described herein that in thermogravimetric analysis, Compound I exhibits peaks due to melting at 112.6°C (extrapolated point) and 126.6°C (peak top) (Non-Patent Document 9).

[0183] The "dissolution test" herein can be performed, for example, according to the method described in the "Dissolution Test Method" in the Japanese Pharmacopoeia (17th or 18th Edition). The test fluid used in the dissolution test can be the first or second dissolution test fluid in the Japanese Pharmacopoeia (17th or 18th Edition), or a solution containing an additive. Examples of additives include surfactants such as Tween 80. The dissolution test is performed by the paddle method. In one aspect of the present invention, the pharmaceutical composition has a drug dissolution rate of 75% or more, 80% or more, or 85% or more after 15 minutes in a dissolution test using 900 mL of a pH 1.2 test fluid (paddle method, 75 rpm, 37°C).

[0184] The "content uniformity test" herein can be performed, for example, according to the content uniformity test method described in the Japanese Pharmacopoeia (17th or 18th edition). In one aspect of the present invention, the pharmaceutical composition is a hard capsule, and the content uniformity test described in the Japanese Pharmacopoeia (17th or 18th edition) is performed, and the judgment value is calculated and meets the judgment criterion (the judgment value does not exceed L1% (15.0%)).

[0185] The pharmaceutical composition and pharmaceutical formulation herein can be produced by a general production method after a step of pulverizing the p-toluenesulfonate salt of the compound represented by Formula 1. The step of pulverizing the p-toluenesulfonate salt of the compound represented by Formula 1 can be carried out, for example, by using a jet mill pulverizer and performing one cycle of pulverization in the pulverization chamber in accordance with the pulverizer's instruction manual.

[0186] Furthermore, the pharmaceutical composition and pharmaceutical formulation herein can be produced by a general-purpose production method after a step of mixing the p-toluenesulfonate salt of the compound represented by Formula 1, an excipient, a disintegrant, and a lubricant. The step of mixing the p-toluenesulfonate salt of the compound represented by Formula 1, an excipient, a disintegrant, and a lubricant can be carried out, for example, by mixing the p-toluenesulfonate salt of the compound represented by Formula 1, an excipient, a disintegrant, and a lubricant in a mixer at a rotation speed of 60 rpm for 90 minutes.

[0187] Furthermore, the pharmaceutical composition and pharmaceutical formulation herein can be produced by a production method that further includes a step of filling a capsule with the mixed p-toluenesulfonate salt of the compound represented by formula 1, excipient, disintegrant, and lubricant after the step of pulverizing the p-toluenesulfonate salt of the compound represented by formula 1, or a step of mixing the p-toluenesulfonate salt of the compound represented by formula 1, excipient, disintegrant, and lubricant. The step of mixing the p-toluenesulfonate salt of the compound represented by formula 1, excipient, disintegrant, and lubricant can be carried out, for example, by filling a gelatin capsule (No. 1) with a capsule filling machine.

[0188] The compound represented by formula 1, or a salt thereof, or a solvate thereof, exhibits excellent inhibitory activity against NaPi-IIb, PiT-1, and PiT-2, has excellent stability in the body, and is easily absorbed from the gastrointestinal tract, and is useful as a preventive or therapeutic agent for chronic diseases such as hyperphosphatemia, and is particularly useful as a therapeutic agent. The compound represented by formula 1, or a salt thereof, or a solvate thereof, is useful as a preventive or therapeutic agent for various diseases caused by elevated phosphorus levels in the body, such as hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, chronic renal failure, and arteriosclerosis accompanied by vascular calcification.

[0189] When the composition of the present invention is used as an inhibitor of NaPi-IIb, PiT-1, and PiT-2, or as a preventive or therapeutic agent for hyperphosphatemia, secondary hyperparathyroidism, chronic kidney disease, chronic renal failure, and arteriosclerosis accompanied by vascular calcification, the dosage of the active ingredient, the compound represented by Formula 1, or a salt thereof, or a solvate thereof, may vary depending on the condition of the patient, age, body weight, whether or not other drugs are used concomitantly, and the like. For example, when administered to a patient as an oral preparation, the amount of the active ingredient per administration is, for example, 50 to 500 mg, 50 to 200 mg, or preferably 100 to 300 mg, calculated as the compound represented by Formula 1, or a salt thereof, or a solvate thereof. The number of administrations per day is, for example, 1 to 3 times. That is, administration is, for example, every 24 hours, every 12 hours, or every 8 hours, and examples thereof include administration before meals, between meals, after meals, or before bedtime.

[0190] As used herein, the term "and / or" includes any combination of "and" and "or." Specifically, for example, "A, B, and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, and (vii) A, B, and C.

[0191] The abbreviations used in this specification are as follows: AV: Acceptable Value cCMC-Na: Croscarmellose sodium CMC-Ca: Carmellose calcium Lac: Lactose monohydrate MAN: Mannitol MCC: Microcrystalline cellulose Mg-st: Magnesium stearate rpm: Revolutions per minute SSF: Sodium stearyl fumarate

[0192] The present invention is further described in the following examples, but is not limited thereto. All starting materials and reagents can be obtained from commercial suppliers or synthesized using known methods. Capsules commonly used in capsule formulations can be used. In this example, Pearitol 300DC (ROQUETTE) was used for mannitol, ND-2HS (Asahi Kasei Chemicals) for cCMC-Na, ECG-505 (GOTOKU Pharmaceutical) for CMC-Ca, Parteck LUB MST (Merck) for Mg-st., and PRUV (JRS PHARMA) for SSF. Pharmatose 200M (DMV-Fonterra Excipients) was used for lactose. Qualicaps gelatin (Qualicaps), No. 1, Japanese Pharmacopoeia capsules, was used.

[0193] Pulverization method of drug substance The drug substance used was powdered crystals of Compound I produced by the method described in International Publication No. 2014 / 142273 and the Japan Institute of Invention and Innovation's Disclosure Technical Report No. 2017-501666. The drug substance (1345.4 mg, lot number SGL1407010) was pulverized in one cycle in the pulverization chamber using a jet mill pulverizer (MC-ONE, manufactured by Dietrich Engineering Consultants SA) according to the pulverizer's instructions, to obtain a pulverized product (1029.0 mg). The lot numbers RGW1503010 and RGW1601010 shown in Table 7 were also pulverized in the same manner.

[0194] Compound I and additives were weighed and added to a mighty vial (No. 7, transparent, Maruemu) so that the total weight of the filled powder was 10 g. The mighty vial was rotated at 100 rpm in a MIX-ROTER VMR-5 (As One) for 60 minutes or more to mix the contents, and the mixture was used as a sample.

[0195] For the control lactose powder (Compound I: lactose monohydrate = 1:9 (006 / Lac)), Compound I and lactose were weighed and added to a Mighty Vial (No. 7, transparent, Maruem) so that the total weight of the filled powder was 10 g. The Mighty Vial was rotated at 100 rpm in a MIX-ROTER VMR-5 (As One) for 60 minutes or more to mix the contents, and the resulting mixture was used as a sample.

[0196]

[0197] When SSF was used, no lumps of powder were found on the glass wall, suggesting that it was well mixed. Dissolution test Dissolution tests of the prepared packed powder were carried out using the paddle method under the following conditions.

[0198] Amount of solution: 900 mL Temperature of solution: 37°C ± 0.2°C Dissolution test solution: 2.0 g of sodium chloride dissolved in 7.0 mL of hydrochloric acid and water to make 1000 mL, and further containing 0.05% Tween 80 (a solution obtained by adding 0.05% Tween 80 to the first solution for dissolution tests in the Japanese Pharmacopoeia (17th revision)). Sampling: Fraction method Stirring device: Paddle Stirring speed: 75 rpm Precipitation: Present UV detection wavelength: 293 nm

[0199] Measurement of dissolution rate by ultraviolet-visible absorbance test: The absorbance of the dissolution test solution at a wavelength of 293 nm was measured using an online UV dissolution test system (Shimadzu Corporation). The dissolution rates of capsule formulations containing 25 mg and 100 mg of Compound I were calculated based on the absorbance of standard solutions prepared with 50% acetonitrile aqueous solution so that the concentrations of p-toluenesulfonate of the compound represented by formula 1 (Compound I) were 34 μg / mL and 136 μg / mL.

[0200] Filling powders (300 mg) containing Compound I described in Examples 1 to 6 (Table 1) were filled into gelatin capsules (size 1), and the dissolution rate of Compound I dissolved in the dissolution test solution was measured using an ultraviolet-visible absorbance test. The results are shown in Figures 1 and 2. Note that the dissolution property of a formulation (capsules, tablets, etc.) is useful for evaluating the absorbability of the pharmaceutical agent contained in the formulation. Furthermore, since the formulation disintegrates and dissolves in an aqueous solution, the evaluation of disintegration property is a simple evaluation of dissolution property.

[0201] Figure 1 compares the dissolution properties of Compound I when cCMC-Na (Example 1 (F59)) and CMC-Ca (Example 2 (F61)) are used as disintegrants. It was shown that the filled powder containing cCMC-Na (Example 1 (F59)) had excellent dissolution properties of Compound I.

[0202] Figure 2 compares the dissolution of Compound I when the compounding ratio of cCMC-Na was varied from 0% to 30%. The dissolution of Compound I from the filled powders containing 20% ​​or more by weight of cCMC-Na (Example 5 (F52) and Example 6 (F66)) exceeded that of the control lactose triturated powder (Compound I:lactose monohydrate = 1:9 (006 / Lac)), demonstrating excellent dissolution. This suggests that filled powders containing 20% ​​or more by weight of cCMC-Na are preferable.

[0203] Adhesion Test The packed powder was placed in a glass container, and the adhesion to the inner wall was visually observed to conduct an adhesion test. Details of sample preparation are shown below. Compound I and additives were weighed and added to a mighty vial (No. 7, transparent, Maruemu) so that the total weight of the packed powder was 10 g. The mighty vial was rotated at 100 rpm in a MIX-ROTER VMR-5 (As One) for 60 minutes or more to mix the contents, and the resulting mixture was used as a sample.

[0204] The SSF was varied from 0.5 to 9% by weight, and the adhesion to the glass vial when compound I was mixed with the additives was compared. The adhesion to the glass wall was visually observed.

[0205]

[0206] When filling powder contained 7% or more by weight of SSF, clumps of filling powder no longer adhered to the glass wall. Reducing adhesion is important to ensure uniformity of the formulation's content. It was suggested that adding SSF in excess of 5% by weight, for example, 6% or more by weight or 7% or more by weight, is preferable.

[0207] Preparation of Capsule Formulations Compound I and additives were mixed so that the total weight of the capsule powder was 3600 g. Capsule formulations containing 25 mg or 100 mg of the active ingredient, calculated as a free base (compound represented by Formula 1), were prepared according to the following formulation. The mixture was mixed for 90 minutes at 60 rpm in a rocking mixer (model RMC-10(S)MC, manufactured by Aichi Electric Co., Ltd.) to produce a filled powder. The mixture was filled into gelatin capsules (size 1) in a capsule filling apparatus (model MODEL 300A, manufactured by Accurex Co., Ltd.) to produce a 25 mg capsule formulation (Example 12 (R4L02)) and a 100 mg capsule formulation (Example 13 (R4L05)).

[0208]

[0209] Dissolution test of capsules Dissolution tests were carried out on the 25 mg capsule formulation (Example 12) and the 100 mg capsule formulation (Example 13) using the same dissolution test method as described above. The results are shown in Figures 3 and 4.

[0210] The dissolution properties of these capsule formulations exceeded those of the control capsule formulation using lactose triturated powder (Compound I: lactose monohydrate = 1:9 (006 / Lac)), demonstrating superior dissolution properties. Content uniformity test of capsule formulations Content values ​​in the content uniformity test were measured by HPLC and determined as the average value based on the Japanese Pharmacopoeia (17th revision). Details are shown below.

[0211] Ten samples of the 25 mg capsule formulation (Example 12 (R4L02)) and 100 mg capsule formulation (Example 13 (R4L05)) were prepared according to the following method. When the calculated judgment value exceeded the maximum allowable limit (L1%), the same test was repeated with 20 samples, and the judgment value was calculated. X mL of the dissolution solvent (1000 mL of water and 1000 mL of acetonitrile) was measured in a measuring cylinder, mixed, and then 1 mL of trifluoroacetic acid was added. (Water / acetonitrile / trifluoroacetic acid mixture (1000:1000:1)) was placed in a Y mL volumetric flask (Table 4). The sample was shaken at 100 rpm for 30 minutes using a shaker (AS ONE, Model ASCM-01) to disintegrate the sample.

[0212]

[0213] The dissolution solvent was added to the volumetric flask and further mixed, followed by 15 minutes of ultrasonic treatment (shaking the volumetric flask approximately every 5 minutes after the start of ultrasonic treatment). The solution was then diluted with the dissolution solvent. The solution was filtered through a membrane filter (ADVANTEC, Model 25HP020AN, DISMIC-25HP PTFE 0.20 μm HYDROPHILIC). The first 1 mL of filtrate was discarded, and the next filtrate was used as the sample solution.

[0214] The standard solution was prepared as follows: Compound I (12 mg), which had been separately prepared as a standard substance, was precisely weighed and dissolved in a dissolution solvent to make exactly 20 mL. If the compound was not sufficiently dissolved, it was dissolved by ultrasonic treatment (for about 1 minute). The appropriate volume was then accurately adjusted with the dissolution solvent to prepare the standard solution.

[0215] The measurement conditions were as follows: System: Acquity UPLC H-class Instrument name: Quaternary Solvent Manager (H-class QSM) (Waters) Sample Manager-FTN (H-class SM-FTN) (Waters) Sample Organizer (H-class SO) (Waters) Column Heater (H-class CH) (Waters) Detector: TUV Detector (TUV) (Waters) Column: Kinetex XB-C18, 4.6 mm × 50 mm, 2.6 μm (Phenomenex) Mobile phase: A) 0.05% TFA / water, B) 0.05% TFA / acetonitrile Flow rate: 1.0 mL / min Detection wavelength: 225 nm Column temperature: 30°C Injection volume: 3.0 μL

[0216]

[0217] The results are shown in Table 6.

[0218]

[0219] The test results confirmed that the content uniformity of the 25 mg capsule formulation (R4L02) and the 100 mg capsule formulation (R4L05) met the target value of the acceptance value (AV) (maximum allowable limit value (L1) of the acceptance value is 15 or less), demonstrating excellent content uniformity.

[0220] Particle size distribution of Compound I The particle size distribution of the pulverized product obtained by the above-mentioned pulverization method of the crystalline powder of Compound I and the unpulverized product was measured by a laser diffraction method, and the volume-based particle diameter d １０ , d ５０ , and d ９０ The particle diameter (μm) was calculated. Samples for the light scattering method were prepared as follows.

[0221] (1) Approximately 3 g of SPAN80 was weighed out and 3,000 mL of n-hexane was added to prepare a 0.1 wt% n-hexane solution of SPAN80. (2) Approximately 50 mg of the unground product was weighed out and 2,000 mL of the 0.1 wt% n-hexane solution of SPAN80 was added and stirred to prepare a saturated solution.

[0222] (3) After filtering off the insoluble matter from the saturated solution using a 0.45 μm disposable vacuum filter (Millicup-LH, PTFE, 0.45 μm, manufactured by Millipore, model SJLHM4710), the filtrate was used as the dispersion medium. (4) Approximately 30 mg of the sample was precisely weighed and mixed with 2 mL of the dispersion medium to prepare the measurement sample.

[0223] (5) The test was performed three times, and the average value was used. The measurement conditions are as follows: Instrument name: LA-950V2, manufactured by HORIBA Refractive index: Sample: 1.6900, imaginary part: 0.0100, dispersion medium (hexane): 1.3760 Number of repetitions: 15 Particle size standard: Volume Number of data acquisitions: 5000 Transmittance (suitable range) Red semiconductor laser: 90-80% Blue light-emitting diode: 90-70% The measurement results are shown in Table 7 below and Figures 5 to 7.

[0224]

[0225] Effect of particle size of drug substance on dissolution 6 mg of unground or ground drug substance was mixed with 44 mg of lactose monohydrate (200 mesh), and a dissolution test was performed in a fluid simulating fasting small intestine at 37°C using the paddle method under the following conditions, and the results were measured by UPLC. Dissolution tests were performed in n=4.

[0226] <Dissolution test conditions> Solution volume: 50 mL Temperature: 37°C Solution: Fasting artificial intestinal fluid (FaSSIF) Sampling: VK8000 dissolution sampling station (Varian Medical Systems, Inc.) Equipment: VK7010 dissolution station (Varian Medical Systems, Inc.) Rotation speed: 50 rpm

[0227] <UPLC conditions> System: Acquity UPLC (Waters) Column: Acquity UPLC BEH Shield RP18, 1.7 μm, 2.1 × 50.0 mm (Waters) Mobile phase: A) 0.05% TFA / water, B) 0.05% TFA / acetonitrile Flow rate: 1.0 mL / min Detection wavelength: 260 nm Column temperature: 40°C Injection volume: 5 μL

[0228]

[0229] The results are shown in Figure 8. When the pulverized drug substance was used, higher dissolution was confirmed compared to the non-pulverized drug substance.

[0230] The present invention can provide a pharmaceutical composition used to treat hyperphosphatemia in patients with renal dysfunction such as chronic kidney disease (CKD) and end-stage renal disease (ESKD), and a method for producing the same.

Claims

1. Formula 1 【Chemical 1】 A pharmaceutical composition comprising a compound represented by the formula, or a salt or solvate thereof, and a disintegrant, wherein the amount of the disintegrant is 12% by weight or more based on the total weight of the composition, and the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose, crystalline cellulose, sodium lauryl sulfate, povidone, and polysorbate.

2. Formula 1 【Chemical 2】 A pharmaceutical composition comprising a compound represented by the formula, or a salt or solvate thereof, wherein the volume-based particle diameter of the compound, or a salt or solvate thereof, is such that d １０ is less than 4.00 μm, d ５０ is less than 5.00 μm, or d ９０ is less than 10.00 μm.

3. Further comprising a disintegrant, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose, crystalline cellulose, sodium lauryl sulfate, povidone, and polysorbate, the pharmaceutical composition according to claim 2.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising a lubricant.

5. The pharmaceutical composition according to any one of claims 1 to 3, further comprising an excipient.

6. The pharmaceutical composition according to claim 4, wherein the lubricant is contained in an amount of 5.3% by weight or more based on the total amount of the pharmaceutical composition.

7. The pharmaceutical composition according to claim 5, wherein the excipient is contained in an amount of 25% by weight or more based on the total amount of the pharmaceutical composition.

8. The pharmaceutical composition according to claim 3, which contains 12% by weight or more of the disintegrant based on the whole pharmaceutical composition.

9. The pharmaceutical composition according to claim 4, which contains at least one lubricant selected from the group consisting of sodium stearyl fumarate, zinc stearate, aluminum stearate, calcium stearate, magnesium stearate, talc, and sucrose fatty acid ester as the lubricant.

10. The pharmaceutical composition according to claim 5, which contains at least one excipient selected from the group consisting of mannitol, lactose hydrate, fructose, glucose, sorbitol, corn starch, potato starch, wheat starch, and rice starch as the excipient.

11. The pharmaceutical composition according to claim 1 or 3, wherein the disintegrant is croscarmellose sodium or sodium carboxymethyl starch.

12. The pharmaceutical composition according to any one of claims 1 to 3, which contains the compound represented by formula 1, or a salt or solvate thereof in the range of 5% by weight or more and 50% by weight or less based on the whole pharmaceutical composition.

13. The pharmaceutical composition according to any one of claims 1 to 3, wherein the compound represented by formula 1, or a salt or solvate thereof is the p-toluenesulfonate of the compound represented by formula 1.

14. The pharmaceutical composition according to any one of claims 1 to 3, wherein the p-toluenesulfonate of the compound represented by formula 1 is a type I crystal.

15. A pharmaceutical preparation containing the pharmaceutical composition according to any one of claims 1 to 3.

16. The pharmaceutical preparation according to claim 13, wherein the pharmaceutical preparation is selected from the group consisting of powder, powder for external use, granules, tablets, and capsules.

17. The pharmaceutical preparation according to claim 15, wherein the pharmaceutical preparation is in the form of a capsule.

18. The pharmaceutical composition according to any one of claims 1 to 3, which is in the form of a capsule containing the p-toluenesulfonate of the compound represented by formula 1 as the active ingredient in the form of type 1 crystals, and further containing mannitol, croscarmellose sodium, and sodium stearyl fumarate.

19. A method for producing the pharmaceutical composition according to any one of claims 1 to 3, comprising mixing a compound represented by formula 1, or a salt or solvate thereof, and a disintegrant, and optionally mixing a lubricant and / or an excipient together to obtain a mixture.

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