HK1230960A1

HK1230960A1 - Preparation containing tetracyclic compound at high dose

Info

Publication number: HK1230960A1
Application number: HK17104723.7A
Authority: HK
Inventors: Takashi Tomimatsu; Kensuke Okazaki; Yumi Ogawa; Takahiro Yamamura
Original assignee: 中外制药株式会社
Priority date: 2014-04-25
Filing date: 2015-04-24
Publication date: 2017-12-15

Description

Formulations containing tetracyclic compounds in high amounts

Technical Field

The present invention relates to a pharmaceutical composition of a tetracyclic compound having an ALK inhibitory activity, and more particularly to an oral preparation and the like.

Background

Anaplastic Lymphoma Kinase (ALK) is one of receptor-type tyrosine kinases belonging to the insulin receptor family (non-patent document 1 and non-patent document 2), and it has been reported that genetic abnormality of ALK causes an abnormal Kinase produced by fusion with another gene.

As diseases accompanied by an abnormality of ALK, for example, cancer and cancer metastasis (non-patent document 1, patent document 1), depression, cognitive dysfunction (non-patent document 2), and the like are known, and provision of an ALK inhibitor provides an effective therapeutic and prophylactic agent for these diseases.

As a compound having an ALK inhibitory action, a compound represented by formula (I) (compound name: 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile) and the like are known (patent document 2, patent document 3, patent document 4).

[ solution 1]

。

The pharmaceutical agent is expected to be developed into a dosage form capable of oral administration, but whether the pharmaceutical agent can be developed into an orally administrable preparation depends on the level of bioavailability of the drug. One of the factors affecting bioavailability is the water solubility of the drug, and generally, when a poorly water-soluble or insoluble compound is orally administered, bioavailability is low. It is also important to improve the bioavailability and oral absorbability of the active ingredient to stably exert the drug effect of the active ingredient.

On the other hand, it is considered to use a drug in a high dose in order to increase the blood concentration of a drug which is a poorly water-soluble or insoluble compound and to improve the therapeutic effect. However, for the administration of orally administered preparations, it is desired to reduce the number of administrations per one time and the number of administrations, and to improve the convenience of patients. Therefore, there is a need for formulations containing high levels of drug per 1 unit of formulation.

A composition in which a compound represented by formula (I) or a salt thereof and a dissolution assistant coexist has been reported (patent document 4). In addition, for the purpose of improving the solubility and oral absorbability of poorly soluble substances, a composition containing a poorly water-soluble component such as a steroid, a surfactant and an organic polymer and wet granulated in the presence of water has been reported (patent document 5).

Documents of the prior art

Patent document

Patent document 1: JP2009100783(A)

Patent document 2: japanese patent No. 4588121

Patent document 3: japanese patent No. 4918630

Patent document 4: japanese patent laid-open No. 2012-

Patent document 5: japanese patent laid-open No. 2008-280352

Non-patent document

Non-patent document 1: nature, volume 448, page 561 and 566, 2007

Non-patent document 2: neuropsychpharmacolgy, volume 33, page 685-700, 2008.

Disclosure of Invention

The present inventors have found that, in the elution of a preparation containing a compound represented by the formula (I) or a salt thereof in a high dose, the compound or salt thereof aggregates without disintegrating, and as a result, the elution property is lowered. As a result of intensive studies to solve the above problems, the present inventors have found that a preparation containing a compound represented by the formula (I) or a salt thereof in a high amount and having good dissolution properties can be obtained by forming granules containing a compound represented by the formula (I) or a salt thereof which is hardly soluble or insoluble in water and allowing the granules to coexist with a disintegrant.

The present inventors have also found that a method for producing sodium lauryl sulfate as a surfactant affects the elution property of a compound that is hardly water-soluble or insoluble.

The present inventors have further studied based on these findings, and have completed the present invention.

Means for solving the problems

Namely, the present invention is as follows.

(1-1) a pharmaceutical composition comprising: (i) granules containing a compound represented by the formula (I) or a salt thereof and (ii) a disintegrant,

[ solution 2]

。

(1-2) the composition according to (1-1), wherein the disintegrant of (ii) is contained in an amount of 5% by weight or more based on the whole composition.

(1-3) the composition according to (1-1) or (1-2), wherein the disintegrant of (ii) is contained in an amount of 5 to 30% by weight based on the whole composition.

(1-4) the composition according to any one of (1-1) to (1-3), wherein the disintegrant of (ii) is contained in an amount of 7.5% by weight or more based on the whole composition.

(1-5) the composition according to any one of (1-1) to (1-4), wherein the disintegrant of the above-mentioned (ii) is contained in an amount of 7.5 to 30% by weight based on the whole composition.

(1-6) the composition according to any one of (1-1) to (1-5), wherein the disintegrant of the above (ii) is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, alphatized starch, sodium chloride, cornstarch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethylcellulose.

(1-7) the composition according to any one of (1-1) to (1-6), wherein the disintegrant of (ii) is a disintegrant which has a volume of 2.5 times or more when 20mL of solution 1 of the revised Japanese pharmacopoeia dissolution test, sixteenth edition, is added to 1.0g of the disintegrant.

(1-8) the composition according to any one of (1-1) to (1-6), wherein the disintegrant of the above (ii) is selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate and alphalized starch.

(1-9) the composition according to any one of (1-1) to (1-8), wherein the disintegrant of (ii) is calcium carboxymethylcellulose.

(1-10) the composition according to any one of (1-1) to (1-9), wherein the granules contain a disintegrant.

(1-11) the composition according to any one of (1-1) to (1-9), comprising: (i) a granule comprising a disintegrant and a compound represented by formula (I) or a salt thereof, and (ii) a disintegrant.

(1-12) the composition according to any one of (1-10) or (1-11), wherein the disintegrant contained in the aforementioned granules is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, alphalized starch, sodium chloride, cornstarch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethylcellulose.

(1-13) the composition according to any one of (1-10) or (1-11), wherein the disintegrant contained in the aforementioned granules is a disintegrant whose volume is 2.5 times or more as large as that of a solution 1 in the modified Japanese pharmacopoeia dissolution test in which 20mL of a sixteenth version is added per 1.0g of the disintegrant.

(1-14) the composition according to any one of (1-10) to (1-13), wherein the disintegrant contained in the particles is selected from the group consisting of calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, sodium starch glycolate, and gelatinized starch.

(1-15) the composition according to any one of (1-10) to (1-14), wherein the disintegrant contained in the particles is carboxymethylcellulose calcium.

(1-16) the composition according to any one of (1-1) to (1-15), wherein the granules contain a dissolution aid in the granules.

(1-17) the composition according to any one of (1-1) to (1-15), comprising: (i) granules containing a disintegrant, a dissolution assistant and a compound represented by formula (I) or a salt thereof, and (ii) a disintegrant.

(1-18) the composition according to (1-16) or (1-17), wherein the aforementioned dissolution auxiliary is selected from the group consisting of:

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium stearyl fumarate, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, polyoxyethylene (40) stearate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbic acid stearate, L-aspartic acid, adipic acid, aminoalkyl methacrylate copolymer E, propylene glycol alginate, casein, sodium caseinate, carboxyvinyl polymer, carboxymethyl ethyl cellulose, agar powder, guar gum, succinic acid, copovidone, cellulose acetate phthalate, tartaric acid, dioctyl sodium sulfosuccinate, zein, skim milk powder, sorbitan trioleate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, sodium methacrylate succinate, sodium lauryl sulfate, polyoxyethylene (40) stearate, purified shellac, sodium lauryl sulfate, sodium caseinate, carboxymethyl cellulose, guar gum, succinic acid, copovidone, cellulose acetate phthalate, tartaric acid, dioctyl sulfosuccinate, zein, skim milk powder, sorbitan trioleate, lactic acid, Polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (35) castor oil, poly (sodium 4-styrenesulfonate), polyvinylacetal diethylaminoacetate, polyvinyl alcohol, maleic acid, methacrylic acid copolymer S, lauroyl alcohol, sulfuric acid, aluminum sulfate, phosphoric acid, calcium dihydrogenphosphate, sodium dodecylbenzenesulfonate, vinylpyrrolidone-vinyl acetate copolymer, sodium lauroyl sarcosinate, acetyltryptophan, sodium methylsulfate, sodium ethylsulfate, sodium butylsulfate, sodium octylsulfate, sodium decylsulfate, sodium tetradecylsulfate, sodium hexadecylsulfate, and sodium octadecylsulfate.

(1-19) the composition according to any one of (1-16) to (1-18), wherein the dissolution aid is sodium lauryl sulfate.

(1-20) the composition according to (1-19), wherein the sodium lauryl sulfate is obtained by crystallization.

(1-21) the method according to (1-19) or (1-20), wherein the sodium lauryl sulfate is NIKKOL SLS.

(1-22) the composition according to any one of (1-19) to (1-21), wherein the sodium lauryl sulfate is 1/8 crystal of hydrate.

(1-23) the composition according to any one of (1-16) to (1-22), wherein the weight ratio of the compound represented by the formula (I) to the dissolution aid is 100:2 to 100: 60.

(1-24) the composition according to any one of (1-16) to (1-23), wherein the weight ratio of the compound represented by the formula (I) to the dissolution aid is 100:2 to 100: 30.

(1-25) the composition according to any one of (1-1) to (1-24), wherein the granules contain a binder.

(1-26) the composition according to (1-25), wherein the binder is hydroxypropylcellulose.

(1-27) the composition according to any one of (1-1) to (1-26), wherein the granules are obtained by wet granulation.

(1-28) the composition according to any one of (1-1) to (1-27), wherein the average particle diameter of the particles is 150 μm or more.

(1-29) the composition according to any one of (1-1) to (1-28), wherein the average particle diameter of the particles is 180 μm or more.

(1-30) the composition according to any one of (1-1) to (1-29), wherein the average particle diameter of the particles is 200 μm or more.

(1-31) the composition according to any one of (1-1) to (1-30), wherein the average particle diameter of the particles is 250 μm or more.

(1-32) the composition according to any one of (1-1) to (1-31), wherein the average particle diameter of the particles is 1mm or less.

(1-33) the composition according to any one of (1-1) to (1-32), wherein the granules have a bulk density of 0.5g/mL or more and a tap density of 0.6g/mL or more.

(1-34) the composition according to any one of (1-1) to (1-33), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 20 to 70 wt% in terms of an amount of the free body with respect to the entire composition.

(1-35) the composition according to any one of (1-1) to (1-34), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 35 to 60% by weight in terms of an amount of the free body relative to the entire composition.

(1-36) the composition according to any one of (1-1) to (1-35), wherein the compound represented by the formula (I) or a salt thereof is a monohydrochloride of the compound represented by the formula (I).

(1-37) the composition according to (1-36), wherein the monohydrochloride of the compound represented by formula (I) is a crystal characterized by having a peak at a diffraction angle (2. theta.) in the vicinity of 8.4 °, 14.0 °, 16.7 °, 18.8 °, 23.3 ° in a powder X-ray diffraction pattern.

(1-38) A pharmaceutical preparation comprising the composition according to any one of (1-1) - (1-37).

(1-39) the pharmaceutical preparation according to (1-38), which is an orally administrable preparation.

(1-40) the pharmaceutical preparation according to (1-39), wherein the orally administrable preparation is a solid preparation.

(1-41) the pharmaceutical preparation according to (1-40), wherein the solid preparation is a tablet, a capsule or a granule.

(1-42) a capsule filled with the composition described in any one of (1-1) - (1-37).

(1-43) the pharmaceutical preparation according to any one of (1-38) - (1-42), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 60-240 mg per unit of the preparation in terms of an episome.

(1-44) the pharmaceutical preparation according to any one of (1-38) to (1-43), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 140mg to 190mg per unit of the preparation in terms of an episome.

(2-1) a pharmaceutical preparation comprising: (i) granules containing a compound represented by the formula (I) or a salt thereof, and (ii) a disintegrant.

(2-2) the preparation according to (2-1), wherein the disintegrant of (ii) is contained in an amount of 5% by weight or more based on the whole preparation.

(2-3) the preparation according to (2-1) or (2-2), wherein the disintegrant of (ii) is contained in an amount of 5 to 30% by weight based on the whole preparation.

(2-4) the preparation according to (2-1) or (2-2), wherein the disintegrant of (ii) is contained in an amount of 7.5% by weight or more based on the whole preparation.

(2-5) the preparation according to any one of (2-1) to (2-4), wherein the disintegrant of the above-mentioned (ii) is contained in an amount of 7.5 to 30% by weight based on the whole preparation.

(2-6) the pharmaceutical preparation according to any one of (2-1) to (2-5), wherein the disintegrant of the above (ii) is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, pregelatinized starch, sodium chloride, cornstarch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethylcellulose.

(2-7) the pharmaceutical preparation according to any one of (2-1) to (2-6), wherein the disintegrant of the above (ii) is selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate and alphalated starch.

(2-8) the preparation according to any one of (2-1) to (2-7), wherein the disintegrant of (ii) is calcium carboxymethylcellulose.

(2-9) the preparation according to any one of (2-1) to (2-8), wherein the granule contains a disintegrant.

(2-10) the composition according to any one of (2-1) to (2-9), comprising: (i) a granule comprising a disintegrant and a compound represented by formula (I) or a salt thereof, and (ii) a disintegrant.

(2-11) the preparation according to (2-10), wherein the disintegrant contained in the aforementioned granules is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, alphatized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethylcellulose.

(2-12) the preparation according to any one of (2-9) to (2-11), wherein the disintegrant contained in the particles is selected from the group consisting of calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose and sodium starch glycolate.

(2-13) the preparation according to any one of (2-9) to (2-12), wherein the disintegrant contained in the particles is carboxymethylcellulose calcium.

(2-14) the preparation according to any one of (2-1) to (2-13), wherein the granules contain a dissolution aid in the granules.

(2-15) the formulation according to any one of (2-1) to (2-14), comprising: (i) granules containing a disintegrant, a dissolution assistant and a compound represented by formula (I) or a salt thereof, and (ii) a disintegrant.

(2-16) the formulation according to any one of (2-14) or (2-15), wherein the aforementioned dissolution auxiliary is selected from the group consisting of:

(2-17) the preparation according to any one of (2-14) to (2-16), wherein the dissolution aid is sodium lauryl sulfate.

(2-18) the preparation according to (2-17), wherein the sodium lauryl sulfate is obtained by crystallization.

(2-19) the preparation according to (2-17) or (2-18), wherein the sodium lauryl sulfate is 1/8 crystal of hydrate.

(2-20) the preparation according to any one of (2-14) to (2-19), wherein the weight ratio of the compound represented by the formula (I) to the dissolution aid is 100:2 to 100: 60.

(2-21) the preparation according to any one of (2-14) to (2-20), wherein the weight ratio of the compound represented by the formula (I) to the dissolution aid is 100:2 to 100: 30.

(2-22) the preparation according to any one of (2-1) to (2-21), wherein the granules are obtained by wet granulation.

(2-23) the preparation according to any one of (2-1) to (2-22), wherein the average particle diameter of the particles is 150 μm or more.

(2-24) the preparation according to any one of (2-1) to (2-23), wherein the average particle diameter of the particles is 180 μm or more.

(2-25) the preparation according to any one of (2-1) to (2-24), wherein the average particle diameter of the particles is 200 μm or more.

(2-26) the preparation according to any one of (2-1) to (2-25), wherein the average particle diameter of the particles is 250 μm or more.

(2-27) the preparation according to any one of (2-1) to (2-26), wherein the granules have an average particle diameter of 1mm or less.

(2-28) the composition according to any one of (2-1) to (2-27), wherein the granules have a bulk density of 0.5g/mL or more and a tap density of 0.6g/mL or more.

(2-29) the preparation according to any one of (2-1) to (2-28), wherein the compound represented by the formula (I) or a salt thereof is a monohydrochloride of the compound represented by the formula (I).

(2-30) the formulation according to (2-29), wherein the monohydrochloride of the compound represented by formula (I) is a crystal characterized by having a peak at diffraction angles (2. theta.) near 8.4 °, 14.0 °, 16.7 °, 18.8 °, 23.3 ° in a powder X-ray diffraction pattern.

(2-31) the preparation according to any one of (2-1) to (2-30), which is an orally administrable preparation.

(2-32) the preparation according to (2-31), wherein the preparation for oral administration is a solid preparation.

(2-33) the preparation according to (2-32), wherein the solid preparation is a tablet, a capsule or a granule.

(2-34) the preparation according to (2-33), wherein the solid preparation is a capsule.

(2-35) the pharmaceutical preparation according to any one of (2-1) to (2-34), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 20 to 70 wt% in terms of an amount of the free form with respect to the entire pharmaceutical preparation.

(2-36) the pharmaceutical preparation according to (2-34), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 35 to 60% by weight in terms of free body based on the whole components filled in the capsule.

(2-37) the pharmaceutical preparation according to any one of (2-1) to (2-36), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 60 to 240mg per unit of the preparation in terms of an episome.

(2-38) the pharmaceutical preparation according to any one of (2-1) to (2-37), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 140mg to 190mg per unit of the preparation in terms of an episome.

(3-1) a method for producing a preparation having improved dissolution properties of the compound represented by the formula (I) or a salt thereof, which comprises (I) granulating particles containing the compound represented by the formula (I) or a salt thereof; (ii) as additives (latter), in combination with disintegrating agents and other additives,

。

(3-2) the process according to (3-1), wherein the disintegrant of the aforementioned (ii) is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, alphatized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethylcellulose.

(3-3) the method according to (3-1) or (3-2), wherein the disintegrant of (ii) is a disintegrant which has a volume of 2.5 times or more as large as that of a solution 1 in the revised Japanese pharmacopoeia dissolution test of 20mL per 1.0g of the disintegrant.

(3-4) the method according to any one of (3-1) to (3-3), wherein the disintegrant of (ii) is contained in an amount of 7.5 to 30 wt% based on the entire preparation.

(3-5) the method according to any one of (3-1) to (3-4), wherein the average particle diameter of the particles is 150 μm or more and 1mm or less.

(3-6) the method according to any one of (3-1) to (3-5), wherein the average particle diameter of the particles is 180 μm or more and 1mm or less.

(3-7) the composition according to any one of (3-1) to (3-6), wherein the granules have a bulk density of 0.5g/mL or more and a tap density of 0.6g/mL or more.

(3-8) the method according to any one of (3-1) to (3-7), wherein the granule of (i) contains a disintegrant.

(3-9) the method according to (3-8), wherein the disintegrant contained in the aforementioned granules is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, alphatized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethylcellulose.

(3-10) the method according to any one of (3-8) or (3-9), wherein the disintegrant contained in the aforementioned granules is a disintegrant whose volume is 2.5 times or more as large as that of solution 1 in the revised Japanese pharmacopoeia dissolution test in 20mL of sixteenth edition per 1.0g of disintegrant.

(3-11) the method according to any one of (3-1) to (3-10), wherein the granules contain a dissolution assistant in the granules.

(3-12) the method according to any one of (3-1) to (3-11), wherein the dissolution aid is selected from the group consisting of:

(3-13) the method according to any one of (3-1) to (3-12), wherein the dissolution aid is sodium lauryl sulfate obtained by crystallization.

(3-14) the method according to any one of (3-11) to (3-13), wherein the dissolution aid is NIKKOL SLS.

(3-15) the method according to any one of (3-11) to (3-14), wherein the weight ratio of the compound represented by the formula (I) to the dissolution aid is 100:2 to 100: 60.

(3-16) the method according to any one of (3-1) to (3-15), wherein the granule contains a binder.

(3-17) the method according to (3-16), wherein the binder is hydroxypropylcellulose.

(3-18) the method according to any one of (3-1) to (3-17), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 20 to 70 wt% in terms of an amount of the free form with respect to the entire preparation.

(3-19) the method according to any one of (3-1) to (3-18), wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 60 to 240mg per unit of the preparation in terms of an episome.

(3-20) the method according to any one of (3-1) to (3-19), wherein the preparation has a dissolution rate of 65% or more of the compound represented by the formula (I) or the salt thereof 75 minutes after the start of the dissolution test at 37 ℃.

(3-21) a preparation produced by the method described in any one of (3-1) to (3-20).

Drawings

FIG. 1 is a graph showing the measurement results of powder X-ray diffraction of form I crystals.

FIG. 2 is a graph showing the dissolution curves obtained by the Japanese pharmacopoeia dissolution test paddle method (rotation 100 times per minute) of examples 1 to 4 and 7.

FIG. 3 is a graph showing the dissolution curves obtained by the Japanese pharmacopoeia dissolution test paddle method (rotation 100 times per minute) of examples 1 and 4 to 7.

Fig. 4 is a graph of the dissolution curves obtained by the japanese pharmacopoeia dissolution test paddle method (100 rotations per minute) of examples 8 and 9.

FIG. 5 is a graph showing the dissolution curves obtained by the Japanese pharmacopoeia dissolution test paddle method (100 rotations per minute) in examples 10 to 14.

FIG. 6 is a graph showing the dissolution curves obtained by the Japanese pharmacopoeia dissolution test paddle method (rotation 100 times per minute) of examples 10 and 15 to 10 (FIG. 6-1) and examples 10 and 21 to 25 (FIG. 6-2).

Fig. 7 is a graph of the dissolution curves obtained by the japanese pharmacopoeia dissolution test paddle method (100 rotations per minute) of examples 26 and 27.

Fig. 8 is a graph of the dissolution curves obtained by the japanese pharmacopoeia dissolution test paddle method (100 rotations per minute) of examples 28 and 29.

Detailed Description

In the present invention, the term "granule" refers to a granule having a substantially uniform shape and size obtained by granulating a raw material such as a powder, a block, a solution, or a molten liquid by a wet granulation method, a dry granulation method, a thermal granulation method, or the like. As a machine used for granulation, a high-speed stirring granulator is more preferable than a mortar in view of elution property. It should be noted that the size and shape of the granules may vary during the formulation process (e.g., tableting step) used to obtain the formulation of the present invention.

The average particle diameter of the particles of the present invention is, for example, 150 μm or more, preferably 180 μm or more, more preferably 200 μm or more, further preferably 250 μm or more, and particularly preferably 300 μm or more. The upper limit of the average particle diameter of the particles is not particularly limited, and is, for example, 1 mm.

The average particle diameter is obtained by performing the following steps: (i) overlapping sieves (pore size: 850, 500, 355, 250, 180, 106, 75, 53, 0 μm) having different pore sizes, and adding the granulated product obtained by sampling thereto; (ii) shaking the sieve for 3 minutes; (iii) measuring the weight of the granulated material remaining on each of the sieves; (iv) the particle size corresponding to 50% of the cumulative rate was calculated from the pore size of each sieve and the cumulative rate under the sieve by approximation of a log-normal distribution. When 10% by weight or more of particles having a particle diameter of more than 850 μm are present, the particle diameter corresponding to 50% of the accumulation rate is calculated from the pore diameter and the oversize accumulation rate of each sieve by using Rosin-Rammler distribution.

The pellet of the present invention preferably has a bulk density of 0.5g/mL or more and a tap density of 0.6g/mL or more, and more preferably has a bulk density of 0.6g/mL or more and a tap density of 0.7g/mL or more. The upper limit of the bulk density and tap density is not particularly limited, but is preferably 1.0 g/mL. Here, the bulk density and the tap density were measured according to the method described in the sixteenth revised japanese pharmacopoeia.

In the present invention, "wet granulation" refers to a method of granulating a powder by adding, spraying or scattering water or a mixed solution of water and alcohol or the like as a solvent for granulation while granulating.

The size of the particle diameter can be adjusted by increasing or decreasing the amount of water or the liquid mixture used in wet granulation.

The pharmaceutical composition or pharmaceutical preparation of the present invention is a composition or preparation comprising (I) granules containing a compound represented by formula (I) or a salt thereof and (ii) a disintegrant having good dissolution properties. (ii) The disintegrant of (1) is a substance added in the form of an external agent. The "disintegrant" in the present invention means a component for promoting the rapid disintegration of a solid preparation after the internal solid preparation. In the present invention, "admixture" and "admixture component" mean additives added to the outside of the granulated particles. As the additive, additives such as a lubricant and a fluidizing agent may be optionally added in addition to the disintegrant.

Examples of the disintegrant in (ii) include sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogen carbonate, gelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, and carboxymethylcellulose, and more preferably a disintegrant having a volume of 2.5 times or more, and still more preferably a disintegrant having a volume of 5 times or more, when 20mL of solution 1 of the modified japanese pharmacopoeia dissolution test is added to 1.0g of the disintegrant. Preferable specific examples of the disintegrant include low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, and gelatinized starch.

(ii) The amount of the disintegrant in (b) is, for example, 5% by weight or more, preferably 7.5% by weight or more, more preferably 8.5% by weight or more, and particularly preferably 10% by weight or more, based on the whole composition or the whole preparation of the present invention. The upper limit of the amount used is not particularly limited, and is, for example, 30% by weight or 25% by weight. When the preparation of the present invention is a preparation having a coating such as a capsule or a coated tablet, the amount used is the amount used relative to the whole of the components covered with the coating (the whole of the components filled in the capsule or the whole of the components covered with the coating).

The particles (I) in the present invention may contain various additives in addition to the compound represented by the formula (I) or a salt thereof.

In one embodiment of the present invention, the granule of (I) contains a compound represented by formula (I) or a salt thereof, a disintegrant, a dissolution aid, an excipient, and a binder. The granules may further comprise one or more additives selected from lubricants, coating agents, stabilizers, flavoring agents and diluents.

Examples of the disintegrant contained in the granules of (i) in the present invention include sodium starch glycolate, low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, gelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, carboxymethylcellulose, and the like, and a disintegrant having a volume of 2.5 times or more, preferably 5 times or more, is added to 1.0g of the disintegrant when 20mL of solution 1 of the modified japanese pharmacopoeia dissolution test is added. Preferable specific examples of the disintegrant include low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium hydrogencarbonate, and gelatinized starch.

The "dissolution assistant" contained in the particles (i) in the present invention means a surfactant, an organic polymer, or a pH adjuster.

"surfactant" refers to a substance having both hydrophilic and hydrophobic groups in its molecule. The surfactant includes ionic surfactants and nonionic surfactants.

The ionic surfactant is an ionic surfactant which is ionized when dissolved in water to become ions (atoms or atomic groups having electric charges). Ionic surfactants are further classified into anionic surfactants, cationic surfactants, and amphoteric surfactants according to the generated ionic charges. In the present invention, a nonionic surfactant and an anionic surfactant are preferable.

Examples of the nonionic surfactant include sugar ester type surfactants such as sorbitan fatty acid esters (C12-18), POE sorbitan fatty acid esters (C12-18), and sucrose fatty acid esters; POE fatty acid ester types such as POE fatty acid ester (C12-18), POE resin acid ester, POE fatty acid diester (C12-18) and the like; POE alkyl ether (C12-18) and other alcohol types; alkyl phenol surfactants such as POE alkyl (C8-12) phenyl ether, POE dialkyl (C8-12) phenyl ether, POE alkyl (C8-12) phenyl ether formaldehyde condensate, and the like; polyoxyethylene-polyoxypropylene block polymer surfactants such as polyoxyethylene-polyoxypropylene block polymers and alkyl (C12-18) polyoxyethylene-polyoxypropylene block polymer ethers; alkyl amine types such as POE alkylamine (C12-18) and POE fatty acid amide (C12-18); a bisphenol surfactant such as POE fatty acid bisphenyl ether; polyaromatic surfactants such as POA benzyl phenyl (or phenylphenyl) ether and POA styrylphenyl (or phenylphenyl) ether; POE ether and ester type silicon and fluorine based surfactants; POE castor oil, POE hydrogenated castor oil, and other vegetable oil type surfactants. Preferred examples thereof include polyoxyethylene (40) stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) diol, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (35) castor oil, and lauromacrogol.

Examples of the anionic surfactant include alkyl sulfates (C12-18, Na, NH)₄Alkanolamine), POE alkyl ether sulfate (C12-18, Na, NH)₄Alkanolamine), POE alkyl phenyl ether sulfate (C12-18, NH)₄Alkanolamine, Ca), POE benzyl (or styryl) phenyl (or phenylphenyl) ether sulfate (Na, NH)₄Alkanolamines), polyoxyethylene-polyoxypropylene block polymer sulfates (Na, NH)₄Alkanolamine), and the like; paraffin (alkane) sulfonates (C12-22, Na, Ca, alkanolamine), AOS (C14-16, Na, alkanolamine), dialkyl sulfosuccinates (C8-12, Na, Ca, Mg), alkylbenzenesulfonates (C12, Na, Ca, Mg, NH)₄Alkylamine, alkanol, amine, cyclohexylamine), monoalkyl or dialkyl (C3-6) naphthalene sulfonate (Na, NH)₄Alkanolamine, Ca, Mg), naphthalenesulfonate/formaldehyde condensate (Na, NH)₄) Sulfonate surfactants such as alkyl (C8-12) diphenyl ether disulfonate (Na, NH4), lignosulfonate (Na, Ca), POE alkyl (C8-12) phenyl ether sulfonate (Na), POE alkyl (C12-18) ether sulfosuccinate half ester (Na) and the like; fatty acid salts (C12-18, Na, K, NH)₄Carboxylic acid type surfactants such as alkanolamines), N-methyl-fatty acid sarcosinates (C12-18, Na), and resinates (Na, K); POE alkyl (C12-18) ether phosphate (Na, alkanolamine), POE monoalkyl or dialkyl (C8-12) phenyl ether phosphate (Na, alkanolamine), POE benzyl (or styryl) phenyl (or phenylphenyl) ether phosphate (Na, alkanolamine), polyoxyethylene-polyoxypropylene block polymer (Na, alkanolamine), phosphatidylcholine-phosphatidyl ethanolamine (lecithin), alkyl (C8-12) phosphate and the likeAgents, and the like. Preferable examples thereof include monoalkyl sulfates such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate, dioctyl sulfosuccinate, sodium lauroyl sarcosinate and sodium dodecylbenzenesulfonate.

The organic polymer is a substance having a molecular weight of 1 ten thousand or more and mainly containing carbon as a skeleton. The organic polymer includes proteins, polysaccharides, synthetic resins, etc. derived from animals and plants.

Specific examples of the organic polymer include polysaccharides such as hydroxypropyl cellulose (hereinafter, also referred to as HPC), hydroxypropyl methylcellulose, propylene glycol alginate, agar powder, guar gum, zein, and hydroxyethyl methylcellulose; synthetic resins such as carboxyvinyl polymer, polyvinyl alcohol, or vinyl acetate resin, sodium polystyrene sulfonate; phosphoproteins such as casein and sodium caseinate.

Among organic polymers, polymers having a solubility of 1g/100g or more in water are referred to as water-soluble polymers. Specific examples thereof include hydroxypropyl cellulose, hydroxypropyl methylcellulose, propylene glycol alginate, sodium caseinate, carboxyvinyl polymer, agar powder, guar gum, copovidone, hydroxyethyl methylcellulose, polyvinyl alcohol, and the like.

Among organic polymers, those which dissolve under acidic conditions of gastric juice pH, i.e., 1.2 to 3.5, are called gastric polymers, and those which dissolve rapidly under intestinal pH6 to 8 are called enteric polymers. Examples of the stomach-soluble polymer include aminoalkyl methacrylate copolymer E and polyvinylacetal diethylaminoacetate, and examples of the intestine-soluble polymer include methacrylic acid copolymer LD (emulsion), methacrylic acid copolymer S, purified shellac, carboxymethylethylcellulose, cellulose acetate phthalate (cellulose acetate), hydroxypropylmethylcellulose acetate succinate, casein, zein, and the like.

The pH adjuster is a substance that improves the solubility of a poorly water-soluble or insoluble compound by adjusting the pH of a solution by adding an acid agent or an alkali agent. The pH adjuster may be appropriately selected depending on the nature of the substance to be dissolved, and for example, in the case of a basic water-insoluble or insoluble compound, the solubility may be improved by adding an acid agent to make the pH acidic.

Examples of the pH adjuster include adipic acid, citric acid, trisodium citrate, gluconic acid, sodium gluconate, glucono-lactone, potassium gluconate, succinic acid, monosodium succinate, disodium succinate, sodium acetate, L-tartaric acid, potassium L-hydrogen tartrate, sodium L-tartrate, DL-tartaric acid, potassium DL-hydrogen tartrate, sodium DL-tartrate, sodium hydrogen carbonate, potassium carbonate (anhydrous), sodium carbonate, carbon dioxide, lactic acid, sodium lactate, glacial acetic acid, disodium dihydrogen pyrophosphate, fumaric acid, monosodium fumarate, DL-malic acid, sodium DL-malate, phosphoric acid, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and disodium hydrogen phosphate.

Preferred examples of the acid agent include adipic acid, citric acid, gluconic acid, glucono-lactone, succinic acid, L-tartaric acid, DL-tartaric acid, carbon dioxide, lactic acid, glacial acetic acid, fumaric acid, DL-malic acid, and phosphoric acid.

In the present invention, two or more dissolution aids may be used in combination at an appropriate ratio.

In the present invention, the dissolution aid is preferably the following:

In the present invention, the dissolution aid is more preferably the following:

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-ascorbyl stearate, L-aspartic acid, adipic acid, propylene glycol alginate, casein, sodium caseinate, carboxymethylethyl cellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, ascorbyl palmitate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene (35) castor oil, poly (4-sodium styrene sulfonate), polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer S, lauroyl alcohol, sulfuric acid, aluminum sulfate, sodium dodecylbenzenesulfonate, sodium lauryl sulfate, sodium caseinate, casein, sodium lauryl sulfate, sodium sulfoacetate, sodium sulfovinlylate, sodium laurylsulfonate, sodium lauryl sulfate, sodium sulfovinly, Vinyl pyrrolidone-vinyl acetate copolymer, acetyl tryptophan, sodium decyl sulfate, sodium tetradecyl sulfate, and sodium octadecyl sulfate.

In the present invention, the dissolution aid is more preferably the following:

citric acid, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methacrylic acid copolymer LD, methylcellulose, sodium lauryl sulfate, refined shellac, sodium dehydroacetate, fumaric acid, DL-malic acid, L-aspartic acid, adipic acid, propylene glycol alginate, sodium caseinate, carboxymethyl ethylcellulose, succinic acid, copovidone, dioctyl sodium sulfosuccinate, lactic acid, aluminum lactate, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, poly (sodium 4-styrenesulfonate), polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer S, sulfuric acid, aluminum sulfate, vinylpyrrolidone-vinyl acetate copolymer.

The dissolution aid contained in the composition or the preparation of the present invention is preferably 2 to 60% by weight, and more preferably 20 to 60% by weight, based on the compound (free form) represented by formula (I).

In the present invention, when sodium lauryl sulfate is used, crystals obtained by crystallization are more preferable than those obtained by spray drying. As polymorphic forms of sodium lauryl sulfate, 1 hydrate, 1/2 hydrate, 1/8 hydrate and non-solvate (trade name: Journal of Crystal Growth 263 (2004)) (480- & 490) are known, and any Crystal can be used in the composition or preparation of the present invention.

Examples of the excipient optionally contained in the granules of (i) in the present invention include starches such as corn starch, potato starch, wheat starch, rice starch, partially gelatinized starch, and porous starch; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannose, and sorbitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, and the like. Preferred excipients include starch such as starch, potato starch, and corn starch, lactose hydrate, crystalline cellulose, and anhydrous calcium hydrogen phosphate, and lactose hydrate is more preferred. The amount of the excipient used is preferably 5 to 60 parts by weight, and more preferably 5 to 45 parts by weight, per 100 parts by weight of the composition or the preparation.

When the preparation of the present invention is a preparation having a coating such as a capsule or a coated tablet, the amount used is the amount used relative to the whole of the components covered with the coating (the whole of the components filled in the capsule or the whole of the components covered with the coating).

Examples of the binder optionally contained in the granules of (i) in the present invention include hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and the same compounds as the above-mentioned excipients. Specific examples of the binder include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder, and hydroxypropyl cellulose is preferably used. The amount of the binder is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight, and still more preferably 0.5 to 10 parts by weight, based on 100 parts by weight of the composition or the preparation.

Suitable examples of the lubricant optionally contained in the granules (i) in the present invention include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, and the like.

Examples of the stabilizer optionally contained in the particles of (i) in the present invention include parabens such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Examples of the taste corrigent optionally contained in the granules of the present invention include commonly used sweeteners, souring agents, and flavors.

The granules of (I) in the present invention can be produced by granulating a composition containing the compound represented by the formula (I) or a salt thereof, and optionally an additive such as a disintegrant, a dissolution assistant, an excipient, a lubricant, a coating agent, a binder, a stabilizer, a flavoring agent, or a diluent.

In the present invention, the term "pharmaceutical composition" refers to a mixture of two or more substances for the treatment and prevention of diseases and the like. As one embodiment of the present invention, the pharmaceutical composition can be used for producing a pharmaceutical preparation.

In the present invention, the "pharmaceutical preparation" refers to a preparation for treating and preventing diseases and the like.

In the present invention, the "orally administrable preparation" refers to a preparation that can be orally administered. By oral administration is meant that the formulation is swallowed so that it enters the gastrointestinal tract and the active ingredient is absorbed primarily from the intestinal tract.

Specific examples of the orally administered preparations include solid preparations and liquid preparations such as tablets, capsules, liquids, powders, troches, chewables, granules, gels, films, and sprays. Examples of the liquid preparation include suspensions, liquids, syrups, elixirs and the like. Such formulations can be used as fillers in soft or hard capsules, and generally, as a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifiers and/or suspending agents, and the like can be used. The liquid preparation can be prepared by dissolving a solid pharmaceutical composition of the present invention, which is packaged, in a carrier such as water.

In the present invention, "ALK" refers to "Anaplastic Lymphoma Kinase, which refers to a receptor-type tyrosine Kinase belonging to the insulin receptor family.

In the present invention, the salt of the compound represented by formula (I) is preferably a hydrochloride salt, and more preferably a monohydrochloride salt.

The compound represented by the formula (I) or a salt thereof can be produced by the methods described in patent documents 2 to 4.

In the present invention, the compound represented by the formula (I) or a salt thereof includes a hydrate, various pharmaceutically acceptable solvates, and a polymorph.

In one embodiment of the present invention, the monohydrochloride of the compound represented by formula (I) is a crystal characterized by having a peak at diffraction angles (2 θ) of 8.4 °, 14.0 °, 16.7 °, 18.8 °, and 23.3 ° in a powder X-ray diffraction pattern (hereinafter referred to as type I crystal).

The form I crystal can be obtained by adding dropwise the compound represented by the formula (I) to a mixed solution of ethanol and hydrochloric acid (containing 1 molar equivalent or more of hydrochloric acid with respect to the compound of the formula (I)) while maintaining the temperature of the mixed solution at about 35 ℃ or higher.

Fig. 1 shows an example of the measurement result of powder X-ray diffraction of the type I crystal, and an example of the peak in the powder X-ray diffraction pattern is shown below.

[ Table 1]

In the present invention, the analysis by powder X-ray diffraction can be performed by a conventional method such as "powder X-ray diffraction measurement method" described in japanese pharmacopoeia (revised fifth edition). Further, it is described in japanese pharmacopoeia that the diffraction angle 2 θ is generally uniform within a range of ± 0.2 degrees for the same crystal form. Therefore, the present invention includes not only crystals in which the diffraction angles of the peaks in the powder X-ray diffraction are completely uniform, but also crystals in which the diffraction angles of the peaks are uniform within an error of about ± 0.2 degrees.

An example of the measurement conditions for the powder X-ray diffraction analysis is shown below:

a measuring device: x' Pert-Pro MPD (product of PANALYTICAL Co., Ltd.)

And (3) for a cathode: cu

Tube voltage: 45kV

Tube current: 40mA

Step width: 0.017

Scanning shaft: 2 theta

Sampling time of each step: 43 seconds

Scanning range: 3 to 40 degrees.

The pharmaceutical composition and pharmaceutical preparation of the present invention are compositions or preparations comprising (I) granules containing a compound represented by formula (I) or a salt thereof and (ii) a disintegrant having good dissolution properties.

In the present invention, the "composition or preparation having good dissolution properties" and the "preparation having improved dissolution properties" are, for example, compositions or preparations having the following drug dissolution rates: the drug dissolution rate at 37 ℃ after 75 minutes from the start of the dissolution test is 65% or more, preferably 70% or more after 75 minutes from the start of the dissolution test at 37 ℃, more preferably 40% or more after 30 minutes from the start of the dissolution test at 37 ℃ and 65% or more after 75 minutes, and particularly preferably 40% or more after 30 minutes from the start of the dissolution test at 37 ℃ and 70% or more after 75 minutes. In the above dissolution test, 900mL of the sixteenth revised japanese pharmacopoeia dissolution test 1 st solution containing 4% polyoxyethylene (10) octylphenyl ether was used as the test solution, and the test was performed by the sixteenth revised japanese pharmacopoeia dissolution test paddle method with 100 rotations per minute.

The preparation of the present invention can be produced by a general production method after mixing the granules of (i) in the present invention together with a disintegrant and optional additives. The production method is preferably as follows.

1) The compound represented by the formula (I) is mixed with additives such as a disintegrant, a dissolution assistant, an excipient, and a binder, and then granulated while adding or spraying a solvent (for example, purified water, ethanol, or a mixture thereof). The preparation of the present invention is produced by adding (ii) an additive such as a disintegrant, optionally an appropriate amount of a lubricant or a fluidizing agent to the obtained granulated product (granules), mixing the mixture, and then filling the mixture into capsules or compression molding the mixture.

2) The compound represented by the formula (I) is mixed with additives such as a disintegrant, a dissolution assistant, and an excipient, and then the binder and, if necessary, other additives are dispersed or dissolved in a solvent (for example, purified water, ethanol, or a mixture thereof), and the resulting liquid is added or sprayed and granulated. The preparation of the present invention is produced by adding (ii) an additive such as a disintegrant, optionally an appropriate amount of a lubricant or a fluidizing agent to the obtained granulated product (granules), mixing the mixture, and then filling the mixture into capsules or compression molding the mixture.

In the above-mentioned methods 1) and 2), granules obtained by granulation using a dry granulation method, a thermal granulation method, or the like, instead of the wet granulation method, may be used.

In the composition and the preparation of the present invention, a lubricant or a fluidizing agent may be contained as an external additive in addition to the disintegrant of (ii). Examples of the lubricant and the fluidizing agent include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, and the like, and magnesium stearate is preferably used. The amount of the lubricant and the fluidizing agent to be used is preferably 0.01 to 20 parts by mass, and more preferably 0.05 to 15 parts by mass, based on 100 parts by weight of the composition or the preparation. When the preparation of the present invention is a preparation having a coating such as a capsule or a coated tablet, the amount used is the amount used relative to the whole of the components covered with the coating (the whole of the components filled in the capsule or the whole of the components covered with the coating).

Sugar-coated tablets or film-coated tablets may also be obtained from the tablets, using appropriate coating agents.

As the sugar coating base, sugar or sugar alcohol such as white sugar or erythritol can be used, and one or two or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like can be used in combination.

Examples of the coating agent include ethyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, and paraffin.

Examples of the enteric film coating base include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic polymers such as methacrylic acid copolymer L [ オイドラギット L (trade name), エボニックデグサ Co ], methacrylic acid copolymer LD [ オイドラギット L-30D55 (trade name), エボニックデグサ Co ], methacrylic acid copolymer S [ オイドラギット S (trade name), エボニックデグサ Co ], etc.; shellac and the like.

Examples of the sustained-release film coating base include cellulose polymers such as ethyl cellulose; acrylic polymers such as aminoalkyl methacrylate copolymer RS [ オイドラギット RS (trade name), エボニックデグサ Co ], ethyl acrylate-methyl methacrylate copolymer suspension [ オイドラギット NE (trade name), エボニックデグサ Co ]; cellulose acetate, and the like.

Two or more of the coating bases may be mixed at an appropriate ratio for use.

The coating agent may contain a water-soluble substance or a plasticizer for adjusting the dissolution rate, if necessary. As the water-soluble substance, water-soluble polymers selected from hydroxypropyl methylcellulose and the like; sugar alcohols such as mannitol; sugars such as white sugar and anhydrous maltose; sucrose fatty acid ester; and surfactants such as polyoxyethylene polyoxypropylene glycol, polysorbate, and sodium lauryl sulfate. As the plasticizer, one or more selected from acetylated monoglyceride, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium-chain fatty acid triglyceride, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate, dibutyl adipate, oleic acid, oleyl alcohol, and the like can be used.

In addition, as the method for coating a tablet with the coating layer, a usual method can be used, and examples thereof include a pan coating method, a flow coating method, a spin coating method, and a flow-spin coating method. Further, the coating solution used in such a method can be obtained by mixing the coating base, the talc, and a solvent (preferably ethanol or a mixture of ethanol and water). The solid content concentration of the coating liquid is preferably in the range of 5 to 15 mass% based on the entire mass of the coating liquid.

The compound represented by the formula (I) or a salt thereof has an excellent ALK inhibitory activity and excellent stability in vivo, and is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for a proliferative disease. The compound or salt represented by formula (I) is useful as a prophylactic or therapeutic agent (particularly a therapeutic agent) for diseases such as leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphatic leukemia, chronic lymphatic leukemia, and the like), malignant lymphoma (hodgkin lymphoma, non-hodgkin lymphoma, and the like), brain tumor, neuroblastoma, glioma, thyroid cancer, myelodysplastic syndrome, head and neck cancer, esophageal cancer, gastric cancer, colorectal cancer, breast cancer, ovarian cancer, lung cancer, pancreatic cancer, liver cancer, gallbladder cancer, skin cancer, malignant melanoma, kidney cancer, renal pelvis urinary tract cancer, bladder cancer, ovarian cancer, uterine cancer, testicular cancer, and prostate cancer. Further, the compound of the present invention or a salt thereof is useful as a prophylactic or therapeutic agent (particularly, a therapeutic agent) for infiltration and metastasis of solid cancer. Further, the compound is also effective as a prophylactic or therapeutic agent for other diseases associated with ALK, such as depression or cognitive dysfunction.

When the composition of the present invention is used as an ALK inhibitor, a therapeutic or prophylactic agent for proliferative diseases, or depression or cognitive dysfunction, examples of administration include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, topical (drip, powder, ointment, gel or paste) administration, and inhalation (oral or nasal spray). Examples of administration forms include tablets, capsules, granules, powders, pills, aqueous and nonaqueous oral solutions and suspensions, and non-oral solutions filled in containers corresponding to the respective dosage amounts. In addition, the form of administration may be applied to various methods of administration including controlled release formulations such as subcutaneous implants.

Oral administration by tablets, capsules, granules or powders is preferred.

When the composition or the preparation of the present invention is used as an ALK inhibitor or a therapeutic or prophylactic agent for proliferative diseases, or depression or cognitive dysfunction, the dosage of the active ingredient (the compound of the present invention represented by formula (I) or a salt thereof) varies depending on the symptoms, age, body weight, relative health state, presence of other administrations, administration method, and the like. For example, in the case of an oral preparation, the effective amount is usually 0.001 to 1000mg per 1kg of body weight per day, more preferably 0.01 to 300mg per 1kg of body weight per day, and the daily dose is preferably in the range of 1 to 1500mg per an adult patient of normal body weight, in terms of the active ingredient (the compound of the present invention represented by formula (I) or a salt thereof). In the case of a parenteral preparation, the amount is preferably 0.001 to 1000mg per 1kg body weight per day, and more preferably 0.01 to 300mg per 1kg body weight. It is desirable to administer it 1 time or divided into a plurality of times on a 1 day basis depending on the symptoms.

The composition of the present invention contains, for example, 20 to 70%, preferably 30 to 60%, and more preferably 35 to 60% by weight of the compound represented by the formula (I) or a salt thereof in terms of free bodies relative to the entire composition.

The preparation of the present invention contains, for example, 20 to 70%, preferably 30 to 60%, and more preferably 35 to 60% by weight of the compound represented by the formula (I) or a salt thereof in terms of free bodies relative to the whole preparation. When the preparation of the present invention is a preparation having a coating such as a capsule or a coated tablet, the content is the content relative to the whole of the components covered with the coating (the whole of the components filled in the capsule or the whole of the components covered with the coating). That is, when the preparation of the present invention is a capsule, the compound represented by the formula (I) or a salt thereof is contained in an amount of, for example, 20 to 70% by weight, preferably 30 to 60% by weight, and more preferably 35 to 60% by weight in terms of free body, based on the whole components filled in the capsule.

The preparation of the present invention preferably contains, for example, 60 to 240mg, preferably 100 to 200mg, and more preferably 140 to 190mg of the compound represented by the formula (I) or a salt thereof per unit preparation in terms of free body.

According to another aspect of the present invention, there are provided the following inventions (4-1) to (4-7).

(4-1) A pharmaceutical preparation comprising sodium lauryl sulfate and a poorly water-soluble or insoluble compound, wherein the sodium lauryl sulfate is obtained by crystallization.

(4-2) the preparation according to (4-1), wherein the sodium lauryl sulfate is 1/8 crystal of hydrate.

(4-3) A method for producing a pharmaceutical preparation having improved elution properties of a poorly water-soluble or insoluble compound, characterized in that sodium lauryl sulfate obtained by crystallization and optionally other additives are blended with the compound.

(4-4) A method for producing a pharmaceutical preparation having improved dissolution properties of a poorly water-soluble or insoluble compound, characterized in that NIKKOL SLS as sodium lauryl sulfate and optionally other additives are blended in the compound.

(4-5) A method for improving the elution property of a poorly water-soluble or insoluble compound in a pharmaceutical preparation containing the compound, characterized in that sodium lauryl sulfate obtained by crystallization and optionally other additives are blended with the compound.

(4-6) A method for improving the dissolution property of a poorly water-soluble or insoluble compound in a pharmaceutical preparation containing the compound, characterized in that NIKKOL SLS as sodium lauryl sulfate and optionally other additives are blended in the compound.

(4-7) the method according to any one of (4-3) to (4-6), wherein the sodium lauryl sulfate is 1/8 crystal of hydrate.

In the inventions of (4-1) to (4-7), "hardly water-soluble or insoluble" means that the solubility in water at 25 ℃ is less than 100. mu.g/mL. In one embodiment of the present invention, "sparingly water-soluble or insoluble" means that the solubility in water at 25 ℃ is less than 10. mu.g/mL. The solubility can be determined according to conventional methods. Examples of the hardly water-soluble or insoluble compound include 9-ethyl-6, 6-dimethyl-8- (4-morpholin) -4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile and a salt thereof.

In the inventions of (4-1) to (4-7), "crystallization" means that crystals of sodium lauryl sulfate are precipitated from a solution or suspension containing sodium lauryl sulfate.

In the inventions of (4-1) to (4-7), the terms "improved dissolution property" and "pharmaceutical preparation improved in dissolution property" are, for example, a preparation having a drug dissolution rate of 65% or more at 37 ℃ for 75 minutes after the start of a dissolution test, preferably 70% or more at 37 ℃ for 75 minutes after the start of a dissolution test, and having such a dissolution profile. In the above dissolution test, 900mL of the sixteenth revised japanese pharmacopoeia dissolution test solution 1 containing 4% polyoxyethylene (10) octylphenyl ether was used as a test solution, and the test was performed by the sixteenth revised japanese pharmacopoeia dissolution test paddle method at 100 rotations per minute.

The term "pharmaceutical preparation" in (4-1) - (4-7) has the meaning described above.

The preparations described in (4-1) to (4-7) can be produced by a known method using a poorly water-soluble or insoluble compound, sodium lauryl sulfate, and optional additives such as an excipient, a disintegrant, a binder, a lubricant, a coating agent, a stabilizer, a flavoring agent, and a diluent. Alternatively, the resin composition can be produced by a method described in the present specification.

Examples of the excipient include starches such as corn starch, potato starch, wheat starch, rice starch, partially gelatinized starch, and porous starch; lactose hydrate, fructose, glucose, mannose, sorbitol and other sugars or sugar alcohols: anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, and the like. Examples of the disintegrant include the same compounds as the excipient and chemically modified starch and cellulose such as croscarmellose sodium, sodium starch glycolate and crospovidone. Specific examples of the disintegrant include sodium starch glycolate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, sodium croscarmellose, crospovidone, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch. Examples of the binder include polyvinylpyrrolidone, polyethylene glycol, and the same compounds as the above excipients. Specific examples of the binder include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone (polyvinylpyrrolidone), and acacia powder. Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, and sodium stearyl fumarate.

As polymorphic forms of sodium lauryl sulfate, 1 hydrate, 1/2 hydrate, 1/8 hydrate and non-solvate (trade name: Journal of Crystal Growth 263 (2004)480-490) are known, and any Crystal can be used in the schemes (4-1) to (4-7).

Examples

The present invention will be described in further detail with reference to examples, but the present invention is not limited thereto. In examples 1 to 27, NIKKOL SLS (trade name, sun light ケミカルズ) was used as sodium lauryl sulfate.

Examples 1 to 7: relation between SLS addition and prescription amount and solubility of raw drug

(1) Preparation of the formulations

6 formulations of formulations were prepared by changing the amount of Sodium Lauryl Sulfate (SLS) according to the amounts of the respective components shown in Table 2. Each of the prescribed granular components was put into a high-speed stirring granulator and premixed, and after spraying an appropriate amount of purified water and stirring granulation, vacuum-dried to obtain a dry powder. The dried powder was granulated with a granulator, and the obtained granulated powder and the admixture components (carboxymethylcellulose calcium, magnesium stearate) were mixed with a mixer to obtain a blended powder. The blended powder is filled in a capsule to produce a capsule.

[ Table 2]

Table 2: examples 1 to 7 (prescription amount per 1 capsule, mg)

(2) Formulation evaluation and results

In examples 1 to 4 and 7, 900mL of the 1 st solution of the Japanese pharmacopoeia dissolution test containing 5% polyoxyethylene (10) octylphenyl ether was used as the test solution, and the dissolution curve when the test was performed by the Japanese pharmacopoeia dissolution test paddle method at 37 ℃ and 100 rotations per minute is shown in FIG. 2. In examples 1 and 4 to 7, 900mL of the 1 st solution of the Japanese pharmacopoeia dissolution test containing 4% polyoxyethylene (10) octylphenyl ether was used as the test solution, and the dissolution curve when the test was performed by the Japanese pharmacopoeia dissolution test paddle method at 37 ℃ and 100 rotations per minute is shown in FIG. 3.

(3) Conclusion

As shown in the dissolution curves of fig. 2 and fig. 3, the dissolution of examples 1 to 6 containing SLS was improved over that of example 7 containing no SLS in the formulation. Specifically, the dissolution property tends to be improved as the amount of SLS in the preparation increases, and particularly, as can be seen from the comparison between examples 6 and 7 in fig. 3, even a slight amount of SLS is included in the preparation formulation, it can be confirmed that the dissolution property is significantly improved.

Examples 8 and 9: relationship between particle size of granule and solubility of crude drug

(1) Preparation of the formulations

2 formulations having different particle sizes of granules were prepared by adjusting the amount of purified water according to the amounts of the components shown in Table 3. Each of the formulation components of the granules was put into a high-speed stirring granulator and premixed, and after spraying the refined water shown in table 2 and stirring granulation, vacuum-dried to obtain a dry powder. The dried powder was granulated with a granulator, and the obtained granulated powder and the admixture components (carboxymethylcellulose calcium, magnesium stearate) were mixed with a mixer to obtain a blended powder. The blended powder is filled in a capsule to produce a capsule.

[ Table 3]

Table 3: examples 8 and 9 (prescription amount per 1 capsule, mg)

(2) Formulation evaluation and results

When the particle size distribution of the whole-particle powder was measured, the average particle size in example 8 was 172 μm, and the average particle size in example 9 was 300. mu.m. For examples 8 and 9, 900mL of the test solution was used in the japanese pharmacopoeia dissolution test 1 st solution containing 5% polyoxyethylene (10) octylphenyl ether, and the dissolution curve when the test was performed by the japanese pharmacopoeia dissolution test paddle method at 37 ℃ and 100 rotations per minute is shown in fig. 4.

Note that the average particle diameter is obtained by: sieves having different pore diameters (pore diameters: 850, 500, 355, 250, 180, 106, 75, 53, 0 μm) were stacked, 6g of the granulated substance obtained by sampling was added thereto, and after shaking for 3 minutes, the weight of the granulated substance remaining on each sieve was measured, and the particle diameter corresponding to 50% of the accumulation rate was calculated from the pore diameter of each sieve and the undersize accumulation rate by approximation using a log-normal distribution.

(3) Conclusion

As shown in FIG. 3, the dissolution property of example 9 was improved as the particle size of the particles was large.

It has been reported that if the particle size of the particles is large, the dissolution property is decreased (great field culture, "formulation study of production parameters relating to granulation step which affects dissolution characteristics of pharmaceutical", http:// mitizane. ll. chiba-u.jp/metadb/up/irwg10/IY-K-Y-049.pdf, internal Journal of pharmaceuticals 338(2007) 79-86). It was completely unexpected that the dissolution property of the preparation containing the granules having a large particle size was improved.

Examples 10 to 14: method for adding disintegrating agent and relation between addition amount and solubility of original drug

(1) Preparation of the formulations

5 formulations of formulations were prepared by changing the amount of calcium carboxymethylcellulose added to the components of the admixture in accordance with the amounts of the components described in Table 4. Each of the prescribed granular components was put into a high-speed stirring granulator and premixed, and after spraying an appropriate amount of purified water and stirring granulation, vacuum-dried to obtain a dry powder. The dried powder was granulated with a granulator, and the obtained granulated powder was mixed with an admixture component (carboxymethylcellulose calcium) to obtain a blended powder. The blended powder is filled in a capsule to produce a capsule.

[ Table 4]

Table 4: examples 10 to 14 (prescription amount per 1 capsule, mg)

(2) Formulation evaluation and results

In examples 10 to 14, 900mL of the 1 st solution of the test solution in the Japanese pharmacopoeia dissolution test containing 7% polyoxyethylene (10) octylphenyl ether was used, and the dissolution curve when the test was performed by the Japanese pharmacopoeia dissolution test paddle method at 37 ℃ and 100 rotations per minute is shown in FIG. 5.

(3) Conclusion

As shown in fig. 5, as a result of comparing the formulations to which the external additive was added, in the case of the external additive amount of 3 to 5 wt%, the dissolution was slightly improved as compared with the case of not adding the external additive, and by adding 10 wt% or more, the dissolution was significantly improved.

Examples 15 to 25: relationship between specific disintegrant containing carboxymethylcellulose calcium and solubility of drug substance

(1) Preparation of the formulations

The granules prepared in example 10 were mixed with the respective admixture components (11 in total, examples 15 to 25) shown in table 5 to obtain a mixed powder. The compounding ratio was adjusted so that the granules obtained in example 10 were 9 parts by weight and the external additive was 1 part by weight. The blended powder is filled in a capsule to produce a capsule.

[ Table 5]

Table 5: kinds of Admixture Components (examples 15 to 25)

Example 15	Starch sodium glycolate
		Example 16	Low-substituted hydroxypropyl cellulose
Example 17	Calcium carboxymethylcellulose
		Example 18	Sodium bicarbonate
Example 19	α A starch
		Example 20	Sodium chloride
Example 21	Corn starch
		Example 22	Croscarmellose sodium
Example 23	Crystalline cellulose
		Example 24	Silicic anhydride
Example 25	Carboxymethyl cellulose

(2) Formulation evaluation and results

In examples 10 and 15 to 25, 900mL of the Japanese pharmacopoeia dissolution test No. 1 solution containing 7% polyoxyethylene (10) octylphenyl ether was used as a test solution, and dissolution curves when the test was performed by the Japanese pharmacopoeia dissolution test paddle method at 37 ℃ and 100 rotations per minute are shown in FIGS. 6-1 and 6-2.

(3) Conclusion

As shown in fig. 6, the disintegrating agents showing high elution property were low-substituted hydroxypropylcellulose (example 16), carboxymethylcellulose calcium (example 17), sodium hydrogencarbonate (example 18), and gelatinized starch (example 19).

When 20mL of the solution 1 of the dissolution test of the Japanese pharmacopoeia was added per 1.0g of the disintegrant, it was confirmed that the volume of the low-substituted hydroxypropylcellulose and carboxymethylcellulose calcium was 5 times or more, and the volume of the croscarmellose sodium, sodium starch glycolate and pregelatinized starch was 2.5 times or more.

Examples 26 and 27: contrast of disintegrant

(1) Preparation of the formulations

As the disintegrant, 2 formulations were prepared by changing the type of disintegrant using low-substituted hydroxypropylcellulose and carboxymethylcellulose calcium in the amounts of the respective components shown in table 6. Each of the prescribed granular components was put into a high-speed stirring granulator and premixed, and after spraying an appropriate amount of purified water and stirring granulation, vacuum-dried to obtain a dry powder. The dry powder was granulated by a granulator, and the obtained granulated powder and the admixture component were mixed by a mixer to obtain a blended powder. The blended powder is filled in a capsule to produce a capsule. Example 26 contains the same formulation components as example 1.

[ Table 6]

Table 6: examples 26 and 27 (prescription amount per 1 capsule, mg)

(2) Formulation evaluation and results

For examples 26 and 27, 900mL of the Japanese pharmacopoeia dissolution test No. 1 solution containing 5% polyoxyethylene (10) octylphenyl ether was used as a test solution, and the dissolution curve when the test was performed by the Japanese pharmacopoeia dissolution test paddle method at 37 ℃ and 100 rotations per minute is shown in FIG. 7.

As shown in fig. 7, it was revealed that the dissolution properties were good when the disintegrant was either low-substituted hydroxypropylcellulose or carboxymethylcellulose calcium, and that carboxymethylcellulose calcium was more good when variations in the respective properties were taken into consideration.

Examples 28 and 29: comparison of commercial products of sodium lauryl sulfate

(1) Preparation of the formulations

2 formulations were prepared according to the amounts of the respective components shown in Table 7 using different commercial products as sodium lauryl sulfate. Each of the prescribed granular components was put into a high-speed stirring granulator and premixed, and after spraying an appropriate amount of purified water and stirring granulation, vacuum-dried to obtain a dry powder. The dry powder was granulated by a granulator, and the obtained granulated powder and the admixture component were mixed by a mixer to obtain a blended powder. The blended powder is filled in a capsule to produce a capsule. When the crystalline form of sodium lauryl sulfate used in these examples was analyzed by powder X-ray diffraction, 1/8 hydrate was confirmed.

[ Table 7]

Table 7: examples 28 and 29 (prescription amount per 1 capsule, mg)

(2) Formulation evaluation and results

For examples 28 and 29, 900mL of the test solution used in the Japanese pharmacopoeia dissolution test No. 1 solution containing 4% polyoxyethylene (10) octylphenyl ether, and the dissolution curve when the test was performed by the Japanese pharmacopoeia dissolution test paddle method at 37 ℃ and 100 rotations per minute is shown in FIG. 8.

As shown in fig. 8, it was shown that the dissolution of the formulation using NIKKOL SLS (sun ケミカルズ) was unexpectedly high compared to the formulation using sodium lauryl sulfate obtained from kolliphor (r) SLS Fine (BASF).

The properties of the sodium lauryl sulfate used in these examples were observed by an optical microscope or the like, and it was considered that NIKKOL SLS (sun ケミカルズ) was obtained by crystallization and kolliphor (r) SLS Fine (BASF) was obtained by spray drying. From this fact, it is considered that the method for producing sodium lauryl sulfate affects the elution property of the preparation.

Example 30: determination of bulk and tap Density of particles

Bulk and tap densities of the particles in the formulations of examples 1 to 9, 26 and 27 were measured by the sixteenth revised Japanese pharmacopoeia method 2. The results are shown in Table 8.

[ Table 8]

Reference example 1: form I crystals of the monohydrochloride salt of 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile

400g of 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile was dissolved in a mixed solvent of 4.8L of methyl ethyl ketone, 1.44L of acetic acid and 1.68L of distilled water at room temperature, and the solution was added dropwise to a mixture of 12L of ethanol and 0.8L of 2N hydrochloric acid at 60 ℃. The precipitated solid was collected by filtration, washed with 2L ethanol and dried to obtain 357g of the title compound as form I as a monohydrochloride salt.

Reference example 2: powder X-ray diffraction analysis

Powder X-ray diffraction was determined for form I crystals of 9-ethyl-6, 6-dimethyl-8- (4-morpholin-4-yl-piperidin-1-yl) -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile monohydrochloride by the following conditions. The measurement results of the form I crystal are shown in FIG. 1.

A measuring device: x' Pert-Pro MPD (product of PANALYTICAL Co., Ltd.)

And (3) for a cathode: cu

Tube voltage: 45kV

Tube current: 40mA

Step width: 0.017

Scanning shaft: 2 theta

Sampling time of each step: 43 seconds

Scanning range: 3 to 40 degrees.

Claims

1. A pharmaceutical composition comprising: (i) granules containing a compound represented by the formula (I) or a salt thereof and (ii) a disintegrant,

[ solution 3]

。

2. The composition according to claim 1, wherein the disintegrant of (ii) is contained in an amount of 5% by weight or more based on the whole composition.

3. The composition according to claim 1 or 2, wherein the disintegrant of (ii) is contained in an amount of 7.5% by weight or more based on the whole composition.

4. The composition according to any one of claims 1 to 3, wherein the disintegrant of (ii) is selected from sodium starch glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, gelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose.

5. The composition according to any one of claims 1 to 4, wherein the disintegrant of (ii) is selected from low-substituted hydroxypropylcellulose, carboxymethylcellulose calcium, sodium bicarbonate, and alphalated starch.

6. A composition according to any one of claims 1 to 5, wherein the granules contain a disintegrant within the granules.

7. The composition according to claim 6, wherein the disintegrant comprised within the particles is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, sodium bicarbonate, gelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, and carboxymethyl cellulose.

8. The composition according to claim 7, wherein the disintegrant comprised within the particles is selected from the group consisting of calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose and sodium starch glycolate.

9. A composition according to any one of claims 1 to 8, wherein the particles contain a dissolution aid within the particles.

10. The composition according to claim 9, wherein the dissolution aid is sodium lauryl sulfate.

11. The composition according to claim 10, wherein the sodium lauryl sulfate is obtained by crystallization.

12. The composition according to any one of claims 9 to 11, wherein the weight ratio of the compound represented by formula (I) to the dissolution assistant is 100:2 to 100: 60.

13. The composition of any one of claims 1 to 12, wherein the particles contain a binder within the particles.

14. The composition of claim 13, wherein the binding agent is hydroxypropyl cellulose.

15. The composition according to any one of claims 1 to 14, wherein the particles have an average particle diameter of 150 μm or more.

16. The composition according to any one of claims 1 to 15, wherein the particles have an average particle diameter of 200 μm or more.

17. The composition according to any one of claims 1 to 16, wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 20 to 70 wt% in terms of free body with respect to the entire composition.

18. The composition according to any one of claims 1 to 16, wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 35 to 60 wt% in terms of free body with respect to the entire composition.

19. A pharmaceutical preparation comprising the composition according to any one of claims 1 to 18.

20. The preparation according to claim 19, wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 60 to 240mg per unit preparation in terms of free body.

21. The preparation according to claim 19 or 20, wherein the compound represented by the formula (I) or a salt thereof is contained in an amount of 140mg to 190mg in terms of free body per unit preparation.

22. A process for producing a preparation having improved dissolution properties of a compound represented by the formula (I) or a salt thereof, which comprises (I) granulating granules containing the compound represented by the formula (I) or a salt thereof; (ii) as an additive, a disintegrating agent and optionally other additives are added,

[ solution 4]

。

23. The process according to claim 22, wherein the disintegrant of (ii) is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium bicarbonate, gelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carboxymethyl cellulose.

24. The method according to claim 22 or 23, wherein the disintegrant of (ii) is contained in an amount of 7.5 to 30 wt% based on the whole preparation.

25. The method according to any one of claims 22 to 24, wherein the particles have an average particle diameter of 150 μm or more and 1mm or less.

26. The method according to any one of claims 22 to 25, wherein the particles have an average particle diameter of 180 μm or more and 1mm or less.

27. A process according to any one of claims 22 to 26, wherein the (i) granules contain a disintegrant within the granules.

28. The method according to claim 27, wherein the disintegrant comprised within the particles is selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, sodium bicarbonate, gelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, and carboxymethyl cellulose.

29. A process according to any one of claims 22 to 28, wherein the particles contain a dissolution aid within the particles.

30. The method according to claim 29, wherein the dissolution aid is sodium lauryl sulfate obtained by crystallization.

31. The method of claim 29 or 30, wherein the dissolution aid is NIKKOL SLS.

32. The method according to any one of claims 29 to 31, wherein the weight ratio of the compound represented by formula (I) to the dissolution assistant is 100:2 to 100: 60.

33. The method of any one of claims 22 to 32, wherein the particles contain a binder within the particles.

34. The method of claim 33, wherein the binding agent is hydroxypropyl cellulose.

35. The method according to any one of claims 22 to 34, wherein 60 to 240mg of the compound represented by the formula (I) or a salt thereof is contained per unit preparation in terms of free body.

36. A pharmaceutical preparation comprising sodium lauryl sulfate and a poorly water-soluble or insoluble compound, wherein the sodium lauryl sulfate is obtained by crystallization.

37. A process for producing a pharmaceutical preparation having improved elution properties of a poorly water-soluble or insoluble compound, characterized by comprising blending sodium lauryl sulfate obtained by crystallization and optionally other additives with the compound.

38. A method for improving the dissolution of a poorly water-soluble or insoluble compound in a pharmaceutical preparation containing the compound, characterized in that sodium lauryl sulfate obtained by crystallization and optionally other additives are blended with the compound.