Pharmaceutical composition containing poorly soluble basic drug

Abstract

To provide a method for producing high-dose formulations of poorly soluble basic drugs.SOLUTION: Provided is a method for producing a solid dosage form containing a pharmaceutical composition containing a compound represented by formula (I) or a salt thereof, a surfactant, and a basic substance, the production method comprising: mixing the compound represented by formula (I) with the surfactant, the basic substance, and an additive, and then subjecting it to compression molding, and the basic substance being one or more substances selected from the group consisting of magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, magnesium hydroxide, magnesium carbonate, and sodium hydrogencarbonate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition suitable for a high-dose formulation of a poorly soluble basic drug, particularly a compound represented by formula (I), and to high-dose tablets thereof. [Background technology]

[0002] Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor family (Non-patent Document 1, Non-patent Document 2), and it has been reported that genetic abnormalities in ALK cause the production of abnormal kinases fused with other genes. Diseases known to be associated with ALK abnormalities include, for example, cancer and cancer metastasis (Non-Patent Document 1, Patent Document 1), depression, and cognitive dysfunction (Non-Patent Document 2), and the provision of an ALK inhibitor would provide an effective therapeutic and preventive agent for these diseases. As a compound having an ALK inhibitory effect, 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) [ka] etc. are known (Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5). The compound represented by formula (I) is a poorly soluble basic drug, and in its formulation, it has been reported that a composition containing a solubilizing agent is prepared (Patent Document 3), or that granules containing the compound represented by formula (I) or a salt thereof are formed and then the granules are made to coexist with a disintegrant to produce a capsule having good dissolution properties (Patent Document 5). Pharmaceutical preparations containing poorly soluble basic drugs as active ingredients, such as the compound represented by formula (I), generally have low bioavailability when administered orally, and therefore high-dose preparations are usually used to improve the bioavailability of the active ingredient and improve oral absorbability. On the other hand, in the case of poorly water-soluble or insoluble drugs, when compressed (tableted) at a high dose, the drugs tend to become poorly water-soluble or insoluble, which is a characteristic of the drugs, and this causes problems in dissolution and oral absorbability. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP2009-100783(A) [Patent Document 2] Patent No. 4588121 [Patent Document 3] Patent No. 4918630 [Patent Document 4] Patent No. 5006987 [Patent Document 5] Patent No. 5859712 [Non-patent literature]

[0004] [Non-Patent Document 1] Nature, Vol. 448, No. 561-566, 2007 [Non-Patent Document 2] Neuropsychopharmacology, Vol. 33, pp. 685-700, 2008 Summary of the Invention [Problem to be solved by the invention]

[0005] In order to realize improved absorption of a poorly soluble basic drug, particularly a pharmaceutical composition containing a compound represented by formula (I) or a salt thereof, there is a need for a high-dose formulation having excellent disintegration and dissolution properties. [Means for solving the problem]

[0006] Under such circumstances, the present inventors have conducted extensive research to solve the above problems, and have found that by preparing a pharmaceutical composition in which a basic substance is added to a poorly soluble basic drug, particularly a compound represented by formula (I) or a salt thereof, the formation of an impermeable coating upon disintegration when the composition is tableted can be prevented, and a high-dose tablet with good dissolution properties can be obtained. That is, the present invention is as follows. (1) A pharmaceutical composition comprising a compound represented by formula (I) or a salt thereof, a surfactant and a basic substance. [ka] (2) The composition according to (1), wherein the surfactant is an anionic surfactant. (3) The composition described in (2), wherein the anionic surfactant is sodium lauryl sulfate. (4) The composition according to any one of (1) to (3), further comprising a disintegrant. (5-1) The composition according to any one of (1) to (4), wherein the weight ratio of the compound represented by formula (I) or a salt thereof to the surfactant is 100:3 to 100:50. (5-2) The composition according to any one of (1) to (4), wherein the weight ratio of the compound represented by formula (I) or a salt thereof to the surfactant is 100:12.5 to 100:25. (5-3) The composition according to any one of (1) to (4), wherein the weight ratio of the compound represented by formula (I) or a salt thereof to the surfactant is 100:25. (6-1) The composition according to (4) or (5), containing 5% by weight or more of the disintegrant. (6-2) The composition according to (4) or (5), containing 7.5% by weight or more of the disintegrant. (6-3) The composition according to (4) or (5), containing 8.5% by weight or more of the disintegrant. (6-4) The composition according to (4) or (5), containing 10% by weight or more of the disintegrant. (7-1) The composition according to any one of (4) to (6), wherein the disintegrant is one or more substances selected from the group consisting of sodium starch glycolate, low-substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride and carmellose. (7-2) The composition according to any one of (4) to (6), wherein the disintegrant is one or more substances selected from the group consisting of carmellose calcium, crospovidone, sodium starch glycolate, and croscarmellose sodium. (7-3) The composition according to any one of (4) to (6), wherein the disintegrant is calcium carmellose. (8) The composition according to any one of (1) to (7), wherein the basic substance is one or more substances selected from the group consisting of inorganic basic substances and organic basic substances. (9-1) The composition according to any one of (1) to (8), wherein the basic substance is one or more substances selected from the group consisting of L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium bicarbonate, sodium bicarbonate, magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, and magnesium carbonate. (9-2) The composition according to any one of (1) to (8), wherein the basic substance is one or more substances selected from the group consisting of magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, magnesium hydroxide, and magnesium carbonate. (9-3) The composition according to any one of (1) to (8), wherein the basic substance is one or more substances selected from the group consisting of magnesium aluminometasilicate, magnesium oxide, and magnesium carbonate. (9-4) The composition according to any one of (1) to (8), wherein the basic substance is magnesium aluminometasilicate. (9-5) The composition according to any one of (1) to (8), wherein the magnesium aluminometasilicate is one or more substances selected from the group consisting of Neusilin (registered trademark) US2, S2, UFL2, FH2, NS2N (Fuji Chemical Industry Co., Ltd.) and PTU-F (Tomita Pharmaceutical Co., Ltd.). (9-6) The composition according to any one of (1) to (8), wherein the magnesium aluminometasilicate is Neusilin (registered trademark) US2 or S2 (Fuji Chemical Industry Co., Ltd.). (10-1) The composition according to any one of (1) to (9), containing the basic substance in an amount of 5% by weight or more. (10-2) The composition according to any one of (1) to (9), containing the basic substance in an amount of 5% by weight or more and 30% by weight or less. (10-3) The composition according to any one of (1) to (9), containing the basic substance in an amount of 7.5% by weight or more. (10-4) The composition according to any one of (1) to (9), containing the basic substance in an amount of 7.5% by weight or more and 30% by weight or less. (10-5) The composition according to any one of (1) to (9), wherein the weight ratio of the compound represented by formula (I) or a salt thereof to the basic substance is 100:5 to 100:60 in terms of a free form. (10-6) The composition according to any one of (1) to (9), wherein the weight ratio of the compound represented by formula (I) or a salt thereof to the basic substance is 100:10 to 100:50 in terms of a free form. (10-7) The composition according to any one of (1) to (9), wherein the weight ratio of the compound represented by formula (I) or a salt thereof to the basic substance is 100:20 to 100:40 in terms of a free form. (10-8) The composition according to any one of (1) to (9), wherein the compound represented by formula (I) or a salt thereof is contained in an amount of 20 to 70% by weight, calculated as a free form, based on the total weight of the composition. (10-9) The composition according to any one of (1) to (9), wherein the compound represented by formula (I) or a salt thereof is contained in an amount of 35 to 60% by weight, calculated as a free form, based on the total weight of the composition. (10-10) The composition according to any one of (1) to (9), wherein the compound represented by formula (I) or a salt thereof is contained in an amount of 45 to 50% by weight, calculated as a free form, based on the total amount of the composition.

[0007] (11) A tablet comprising the composition according to any one of (1) to (10). (12-1) The tablet according to any one of (1) to (11), containing 150 mg to 800 mg of the compound represented by formula (I) or a salt thereof in terms of free form per unit dosage form. (12-2) The tablet according to any one of (1) to (11), containing 150 mg to 400 mg of the compound represented by formula (I) or a salt thereof in terms of free form per unit dosage form. (12-3) The tablet according to any one of (1) to (11), containing 200 mg to 300 mg of the compound represented by formula (I) or a salt thereof in terms of free form per unit dosage form. (13-1) The tablet according to (11) or (12), in which the dissolution rate in 30 minutes is 45% or more in the Japanese Pharmacopoeia dissolution test paddle method using the Japanese Pharmacopoeia dissolution test fluid No. 1 containing 4% polyoxyethylene (10) octylphenyl ether. (13-2) The tablet according to (11) or (12), in which the dissolution rate in 30 minutes is 60% or more in the Japanese Pharmacopoeia dissolution test paddle method using the Japanese Pharmacopoeia dissolution test fluid No. 1 containing 4% polyoxyethylene (10) octylphenyl ether. (13-3) The tablet according to (11) or (12), in which the dissolution rate in 30 minutes is 75% or more in the Japanese Pharmacopoeia dissolution test paddle method using the Japanese Pharmacopoeia dissolution test fluid No. 1 containing 4% polyoxyethylene (10) octylphenyl ether. (13-4) The tablet according to (11) or (12), in which the dissolution rate in 75 minutes is 70% or more in the Japanese Pharmacopoeia dissolution test paddle method using the Japanese Pharmacopoeia dissolution test fluid No. 1 containing 4% polyoxyethylene (10) octylphenyl ether. (13-5) The tablet according to (11) or (12), in which the dissolution rate is 45% or more in 30 minutes using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether, as measured by the paddle method of the Japanese Pharmacopoeia dissolution test. (13-6) The tablet according to (11) or (12), in which the dissolution rate is 60% or more in 30 minutes using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether, as measured by the paddle method of the Japanese Pharmacopoeia dissolution test. (13-7) The tablet according to (11) or (12), in which the dissolution rate is 75% or more in 30 minutes using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether, as measured by the paddle method of the Japanese Pharmacopoeia dissolution test. (13-8) The tablet according to (11) or (12), in which the dissolution rate is 70% or more in 75 minutes using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether, as measured by the paddle method of the Japanese Pharmacopoeia dissolution test. (13-9) A tablet according to (11) or (12), in which in the Japanese Pharmacopoeia disintegration test using water as the test liquid, sample residue is found at the 30 minute mark, but only a small amount of soft or muddy material is found. (13-10) A tablet according to (11) or (12), in which no residue of the sample is found at the 30 minute point in the Japanese Pharmacopoeia disintegration test using water as the test liquid. (13-11) The tablet according to (11) or (12), in which in a Japanese Pharmacopoeia disintegration test using Japanese Pharmacopoeia Dissolution Test Fluid No. 1 as the test fluid, sample residue is found at the 30 minute point, but soft material or muddy material is minimal. (13-12) The tablet according to (11) or (12), in which no residue of the sample is found at 30 minutes in a Japanese Pharmacopoeia disintegration test using the Japanese Pharmacopoeia dissolution test fluid No. 1 as the test fluid. (14) A pharmaceutical composition comprising a compound represented by formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium bicarbonate, magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, and magnesium carbonate; carmellose calcium, hydroxypropylcellulose, sodium lauryl sulfate, and magnesium stearate. (14-1) A pharmaceutical composition comprising a compound represented by formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium bicarbonate, magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, and magnesium carbonate, one or more basic substances selected from the group consisting of carmellose calcium, D-mannitol, and sodium lauryl sulfate. (14-2) A pharmaceutical composition comprising a compound represented by formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium bicarbonate, magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, and magnesium carbonate; crospovidone; lactose hydrate; and sodium lauryl sulfate. (14-3) A pharmaceutical composition comprising a compound represented by formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium bicarbonate, magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, and magnesium carbonate, one or more basic substances selected from the group consisting of carmellose calcium, D-mannitol, sodium lauryl sulfate, hydroxypropylcellulose, and magnesium stearate. (14-4) A pharmaceutical composition comprising a compound represented by formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium bicarbonate, magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, and magnesium carbonate, one or more basic substances selected from the group consisting of crospovidone, lactose hydrate, sodium lauryl sulfate, hydroxypropylcellulose, and magnesium stearate. (15) A tablet containing the composition described in (14). (16-1) The tablet according to (15), containing 150 mg to 800 mg of the compound represented by formula (I) or a salt thereof in terms of free form per unit dosage form. (16-2) The tablet according to (15), containing 150 mg to 600 mg of the compound represented by formula (I) or a salt thereof in terms of free form per unit dosage form. (16-3) The tablet according to (15), containing 200 mg to 300 mg of the compound represented by formula (I) or a salt thereof in terms of free form per unit dosage form. (17-1) The tablet according to (15) or (16), in which the dissolution rate in 30 minutes is 45% or more in the Japanese Pharmacopoeia dissolution test paddle method using the Japanese Pharmacopoeia dissolution test fluid No. 1 containing 4% polyoxyethylene (10) octylphenyl ether. (17-2) The tablet according to (15) or (16), in which the dissolution rate in 30 minutes is 60% or more in the Japanese Pharmacopoeia dissolution test paddle method using the Japanese Pharmacopoeia dissolution test fluid No. 1 containing 4% polyoxyethylene (10) octylphenyl ether. (17-3) The tablet according to (15) or (16), in which the dissolution rate in 30 minutes is 75% or more in the Japanese Pharmacopoeia dissolution test paddle method using the Japanese Pharmacopoeia dissolution test fluid No. 1 containing 4% polyoxyethylene (10) octylphenyl ether. (17-4) The tablet according to (15) or (16), in which the dissolution rate in 75 minutes is 70% or more in the Japanese Pharmacopoeia dissolution test paddle method using the Japanese Pharmacopoeia dissolution test fluid No. 1 containing 4% polyoxyethylene (10) octylphenyl ether. (17-5) The tablet according to (15) or (16), in which the dissolution rate in 30 minutes is 45% or more in the Japanese Pharmacopoeia dissolution test paddle method using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether. (17-6) The tablet according to (15) or (16), in which the dissolution rate in 30 minutes is 60% or more in the Japanese Pharmacopoeia dissolution test paddle method using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether. (17-7) The tablet according to (15) or (16), in which the dissolution rate in 30 minutes is 75% or more in the Japanese Pharmacopoeia dissolution test paddle method using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether. (17-8) The tablet according to (15) or (16), in which the dissolution rate is 70% or more in 75 minutes in the Japanese Pharmacopoeia dissolution test paddle method using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether. (17-9) A tablet according to (15) or (16), in which in the Japanese Pharmacopoeia disintegration test using water as the test liquid, sample residue is found at the 30 minute mark, but only a small amount of soft or muddy material is found. (17-10) A tablet according to (15) or (16), in which no residue of the sample is found at the 30 minute point in the Japanese Pharmacopoeia disintegration test using water as the test liquid. (17-11) The tablet according to (15) or (16), in which in a Japanese Pharmacopoeia disintegration test using Japanese Pharmacopoeia dissolution test fluid No. 1 as the test fluid, sample residue is found at the 30 minute point, but there is only a small amount of soft material or muddy material. (17-12) The tablet according to (15) or (16), in which no residue of the sample is found at 30 minutes in a Japanese Pharmacopoeia disintegration test using the Japanese Pharmacopoeia dissolution test fluid No. 1 as the test fluid. (18) The tablet according to (15) or (16), which shows a dissolution rate of 45% or more after 30 minutes and / or 75% or more after 70 minutes in a dissolution test by the paddle method rotating at 100 rpm using a test solution containing 4% polyoxyethylene (10) octylphenyl ether prepared from a solution of about pH 1.2 prepared by dissolving 2.0 g of sodium chloride in 7.0 ml of hydrochloric acid and water to make 1000 mL. Effect of the Invention

[0008] The composition of the present invention can prevent the formation of an impermeable film during disintegration by tableting, and can provide a high-dose formulation containing a poorly soluble basic drug, particularly a compound represented by formula (I) or a salt thereof, as an active ingredient, with good dissolution and disintegration properties. In addition, by enabling the formulation of a high-dose formulation with a good dissolution profile, the number of doses of the formulation can be reduced, which contributes to improving compliance. Furthermore, the pharmaceutical composition of the present invention can give high-dose tablets with good dissolution properties, regardless of whether granules are formed during tableting. [Brief description of the drawings]

[0009] [Figure 1] FIG. 2 shows the dissolution profile of the tablets of Reference Example 1. [Diagram 2] Photographs of the tablet of Reference Example 1 a) before the test, b) after the test, and c) the central cut surface after the test are shown. [Diagram 3] FIG. 1 shows the dissolution profiles of Examples 8 to 10. [Figure 4] FIG. 1 shows the dissolution profiles of Examples 11 to 14. [Diagram 5] FIG. 1 shows the dissolution profiles of Examples 15 to 18. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] The present invention will be described in detail below. In the present invention, the term "pharmaceutical composition" refers to a mixture of two or more substances used for the treatment or prevention of a disease. In one embodiment of the present invention, the pharmaceutical composition is used for the manufacture of a pharmaceutical preparation. The term "pharmaceutical preparation" refers to a preparation for the treatment or prevention of a disease, and in the present invention, an oral preparation is preferred. The term "oral preparation" refers to a preparation that can be administered orally, and the active ingredient is mainly absorbed from the intestinal tract. Orally administered preparations include solid preparations and liquid preparations, but in the present invention, solid preparations are preferred. Specific examples of solid preparations include tablets, capsules, liquid preparations, powders, lozenges, chewable tablets, granules, gels, and films, with tablets being particularly preferred. In the present invention, granules may or may not be used when producing tablets. When granules are used to produce tablets, the average particle size of the granules may be the average particle size used in ordinary pharmaceutical preparations.

[0011] "Compound represented by formula (I)" means a compound represented by formula (I) [ka] The compound represented by the formula (I) is 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile. The "salt" of the compound represented by formula (I) is preferably a pharma- ceutically acceptable salt, and examples of the "pharma- ceutically acceptable salt" include hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, sulfonate such as methanesulfonate, p-toluenesulfonate, etc., carboxylate such as acetate, citrate, malate, tartrate, succinate, salicylate, etc., alkali metal salt such as sodium salt, potassium salt, etc., alkaline earth metal salt such as magnesium salt, calcium salt, etc., ammonium salt such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, tetraalkylammonium salt, etc. Preferred is the hydrochloride salt, most preferably the monohydrochloride salt. The compound represented by formula (I) or a salt thereof can be produced by known methods (for example, the method described in Patent Document 2). The monohydrochloride of the compound represented by formula (I) may be amorphous or crystalline, and in the case of a crystal, a crystal having peaks at diffraction angles (2θ) of about 8.4°, 14.0°, 16.7°, 18.8°, and 23.3° in a powder X-ray diffraction pattern is preferable. The amorphous form of the monohydrochloride of the compound represented by formula (I) can be produced by the method described in WO2016 / 021707, and the crystal having such peaks can be produced by the method described in WO2015 / 163447. The compound represented by formula (I) or a salt thereof is contained in an amount of 20 to 70% by weight, preferably 35 to 60% by weight, and more preferably 45 to 50% by weight, calculated as a free form, based on the total composition. The preparation obtained from the composition of the present invention contains 150 mg to 800 mg, preferably 150 mg to 400 mg, particularly preferably 200 mg to 300 mg of the compound represented by formula (I) or a salt thereof, calculated as a free form, per unit preparation.

[0012] The term "surfactant" refers to a substance having both hydrophilic and hydrophobic groups in the molecule, and surfactants include ionic surfactants and nonionic surfactants. Ionic surfactants refer to those which, when dissolved in water, dissociate to form ions (charged atoms or atomic groups). Ionic surfactants are further classified into anionic surfactants, cationic surfactants, and amphoteric surfactants, depending on the charge of the ions produced.

[0013] Nonionic surfactants include sugar ester surfactants such as sorbitan fatty acid esters (C12-18), POE sorbitan fatty acid esters (C12-18), and sucrose fatty acid esters; fatty acid ester surfactants such as POE fatty acid esters (C12-18), POE resin acid esters, and POE fatty acid diesters (C12-18); alcohol surfactants such as POE alkyl ethers (C12-18); alkylphenol surfactants such as POE alkyl (C8-12) phenyl ether, POE dialkyl (C8-12) phenyl ether, and POE alkyl (C8-12) phenyl ether formalin condensates; polyoxyethylene-polyoxypropylene block polymers, Examples of the surfactants include polyoxyethylene-polyoxypropylene block polymer surfactants such as alkyl (C12-18) polyoxyethylene-polyoxypropylene block polymer ether; alkylamine surfactants such as POE alkylamine (C12-18) and POE fatty acid amide (C12-18); bisphenol surfactants such as POE fatty acid bisphenyl ether; polyaromatic ring surfactants such as POA benzylphenyl (or phenylphenyl) ether and POA styrylphenyl (or phenylphenyl) ether; POE ether and ester type silicone and fluorine surfactants; vegetable oil surfactants such as POE castor oil and POE hydrogenated castor oil. Preferred surfactants include polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, and lauromacrogol.

[0014] Anionic surfactants include alkyl sulfate (C12-18, Na, NH4, alkanolamine), POE alkyl ether sulfate (C12-18, Na, NH4, alkanolamine), POE alkyl phenyl ether sulfate (C12-18, NH4, alkanolamine, Ca), POE benzyl (or styryl) phenyl (or phenylphenyl) ether sulfate (Na, NH4, alkanolamine), polyoxyethylene, polyoxypropylene block polymer sulfate (Na, NH4, alkanolamine), amines); paraffin (alkane) sulfonates (C12-22, Na, Ca, alkanolamines), AOS (C14-16, Na, alkanolamines), dialkyl sulfosuccinates (C8-12, Na, Ca, Mg), alkyl benzene sulfonates (C12, Na, Ca, Mg, NH4, alkyl amines, alkanols, amines, cyclohexylamines), mono- or di-alkyl (C3-6) naphthalene sulfonates (Na, NH4, alkanolamines, Ca, Mg), naphthalene sulfonates, formalin Sulfonate type surfactants such as condensates (Na, NH4), alkyl (C8-12) diphenyl ether disulfonates (Na, NH4), lignin sulfonates (Na, Ca), POE alkyl (C8-12) phenyl ether sulfonates (Na), POE alkyl (C12-18) ether sulfosuccinic acid half esters (Na); carboxylic acid type surfactants such as fatty acid salts (C12-18, Na, K, NH4, alkanolamines), N-methyl-fatty acid sarcosinates (C12-18, Na), and resin salts (Na, K); 18) Phosphate-type surfactants such as ether phosphate (sodium, alkanolamine), POE mono- or dialkyl (C8-12) phenyl ether phosphate (sodium, alkanolamine), POE benzyl (or styryl) phenyl (or phenylphenyl) ether phosphate (sodium, alkanolamine), polyoxyethylene-polyoxypropylene block polymer (sodium, alkanolamine), phosphatidylcholine-phosphatidylethanolimine (lecithin), and alkyl (C8-12) phosphate.Preferred examples of the monoalkyl sulfates include sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate; dioctyl sodium sulfosuccinate; sodium lauroyl sarcosine; and sodium dodecylbenzenesulfonate. In the present invention, two or more types of surfactants may be used in combination at an appropriate ratio. In the present invention, the surfactant is preferably an anionic surfactant.

[0015] Preferred surfactants are selected from the group consisting of monoalkyl sulfates, polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, lauromacrogol, dioctyl sodium sulfosuccinate, sodium lauroyl sarcosine, sodium dodecylbenzenesulfonate, and mixtures thereof. More preferred surfactants are selected from the group consisting of monoalkyl sulfates, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, dioctyl sodium sulfosuccinate, sodium lauroyl sarcosine, sodium dodecylbenzenesulfonate, and mixtures thereof. More preferred surfactants are selected from the group consisting of sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, and mixtures thereof. A particularly preferred surfactant is a mixture of sodium lauryl sulfate and polyoxyethylene (105) polyoxypropylene (5) glycol. The most preferred surfactant is sodium lauryl sulfate. In the present invention, the ionic surfactant is more preferably sodium lauryl sulfate. When sodium lauryl sulfate is used in the present invention, the crystals may be those obtained by spray drying or crystallization. Note that sodium lauryl sulfate is known to have polymorphic forms, such as monohydrate, hemihydrate, octave hydrate, and nonsolvate (Journal of Crystal Growth 263 (2004) 480-490), and any of these crystals may be used in the composition or formulation of the present invention. The surfactant is contained in an amount of 5% by weight or more, preferably 5% by weight or more and 30% by weight or less, more preferably 7.5% by weight or more, and most preferably 7.5% by weight or more and 30% by weight or less, based on the total weight of the composition. The surfactant contained in the composition or preparation of the present invention is preferably such that the weight ratio of the compound represented by formula (I) or a salt thereof to the surfactant is 100:3 to 100:50, more preferably 100:12.5 to 100:25, and most preferably 100:25.

[0016] The "basic substance" is preferably a substance defined as a base according to the Lewis definition, more preferably a substance defined as a base according to the Bronsted-Lowry definition, and is not particularly limited as long as it is a pharmacologically acceptable component, and any known basic substance can be used. The basic substance may be an inorganic basic substance or an organic basic substance. As the basic substance, one type may be used alone, or two or more types may be used in combination.

[0017] Examples of inorganic basic substances include metal oxides such as magnesium oxide, calcium oxide, and aluminum oxide; metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and aluminum hydroxide; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate; metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal phosphates such as trisodium phosphate, tripotassium phosphate, tricalcium phosphate, trimagnesium phosphate, sodium pyrophosphate, potassium pyrophosphate, sodium polyphosphate, and potassium polyphosphate; metal hydrogen phosphates such as sodium monohydrogen phosphate and potassium monohydrogen phosphate; metal silicates such as sodium silicate, magnesium silicate, calcium silicate, synthetic aluminum silicate, synthetic magnesium sodium silicate, and talc; composite silicate-aluminum compounds such as magnesium aluminosilicate, magnesium aluminum silicate, and magnesium aluminometasilicate; composite aluminum-magnesium compounds such as synthetic hydrotalcite; and inorganic ammonium salts such as ammonium hydroxide, ammonium carbonate, ammonium hydrogen carbonate, and ammonium monohydrogen phosphate.

[0018] Examples of the organic basic substance include metal salts of organic acids, organic amines, and basic amino acids. Examples of metal salts of organic acids include sodium salts, potassium salts, magnesium salts and calcium salts of organic acids such as citric acid, succinic acid, tartaric acid, fumaric acid, maleic acid, malonic acid and malic acid. Examples of organic amines include meglumine, monoethanolamine, diisopropanolamine, triethanolamine, monoisopropanolamine, diisopropanolamine, triisopropanolamine, 2-amino-2-methyl-1-propanol, 2-amino-2-methyl-1,3-propanediol, and polyoxyethylene alkylamines. Examples of basic amino acids include lysine, arginine, phenylalanine, tyrosine, histidine, proline, oxyproline, ornithine, hydroxylysine, and derivatives thereof.

[0019] Preferred are metal oxides such as magnesium oxide, calcium oxide, and aluminum oxide; metal hydroxides such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and aluminum hydroxide; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate; metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; metal phosphates such as trisodium phosphate, tripotassium phosphate, tricalcium phosphate, trimagnesium phosphate, sodium pyrophosphate, potassium pyrophosphate, sodium polyphosphate, and potassium polyphosphate; metal hydrogen phosphates such as sodium monohydrogen phosphate and potassium monohydrogen phosphate; metal silicates such as sodium silicate, magnesium silicate, calcium silicate, synthetic aluminum silicate, synthetic magnesium sodium silicate, and talc; composite silicate-aluminum compounds such as magnesium aluminosilicate, magnesium aluminosilicate, and magnesium aluminometasilicate; composite aluminum-magnesium compounds such as synthetic hydrotalcite; inorganic ammonium salts such as ammonium hydroxide, ammonium carbonate, ammonium hydrogen carbonate, and ammonium monohydrogen phosphate. Alternatively, examples include glycine, L-serine, L-cystine, L-tryptophan, L-proline, L-aspartic acid, L-lysine, L-histidine, L-arginine, L-lysine hydrochloride, meglumine, magnesium aluminometasilicate, magnesium aluminometasilicate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, and calcium hydrogen carbonate. Preferred are L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium hydrogen carbonate, sodium hydrogen carbonate, magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, and magnesium carbonate. More preferred are magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, magnesium hydroxide, magnesium carbonate, and sodium hydrogen carbonate. Further preferred are magnesium aluminometasilicate, magnesium oxide, and magnesium carbonate. Most preferred is magnesium aluminometasilicate. The magnesium aluminometasilicate is preferably Neusilin (registered trademark) US2, S2, UFL2, FH2, NS2N (Fuji Chemical Industry Co., Ltd.), or PTU-F (Tomita Pharmaceutical Co., Ltd.). More preferably, the magnesium aluminometasilicate is Neusilin (registered trademark) US2 or S2 (Fuji Chemical Industry Co., Ltd.). The basic substance is preferably selected from the group consisting of L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium bicarbonate, sodium bicarbonate, magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide and magnesium carbonate, and most preferably selected from the group consisting of L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium bicarbonate, sodium bicarbonate, magnesium aluminometasilicate, L-arginine, meglumine and magnesium oxide. The basic substance is contained in an amount of 5% by weight or more, 5% by weight or more and 30% by weight or less, 7.5% by weight or more, or 7.5% by weight or more and 30% by weight or less, based on the total weight of the composition. The weight ratio of the compound represented by formula (I) or a salt thereof to the basic substance is preferably 100:5 to 100:60, more preferably 100:10 to 100:50, and most preferably 100:20 to 100:40, calculated as the free form.

[0020] The preparation of the present invention is produced by a known method using additives such as excipients, lubricants, coating agents, binders, disintegrants, stabilizers, flavoring agents, diluents, etc. Examples of the "excipient" include starches such as corn starch, potato starch, wheat corn starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol, and sorbitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc. Preferred excipients include starches such as starch, potato starch, and corn starch, lactose hydrate, crystalline cellulose, and anhydrous calcium hydrogen phosphate. The "disintegrant" in the present invention is a component that promotes rapid disintegration of a solid preparation after the solid preparation is taken orally. Examples of the disintegrants include sodium starch glycolate, low-substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic anhydride, carmellose, and the like. The amount of disintegrant used 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 entire composition or preparation of the present invention. The upper limit of the amount used is not particularly limited, but is, for example, 30% by weight. When the preparation of the present invention is a preparation having a coating such as a coated tablet, the amount used is the amount based on the entire components coated by the coating (the entire components filled in the capsule, the entire components coated by the coating).

[0021] Examples of the "binder" include polyvinylpyrrolidone, macrogol, and compounds similar to the excipients. Specific examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, povidone (polyvinylpyrrolidone), and powdered gum arabic. The amount of the binder used is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight, based on 100 parts by weight of the preparation.

[0022] Suitable examples of "lubricants" include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate, and the like. Examples of the surfactant or emulsifier include polysorbate 80, polyoxyl 40 stearate, lauromacrogol, and the like. The coloring agent may be any that is permitted to be added to pharmaceuticals, such as food dyes such as Food Yellow No. 5 (Sunset Yellow, U.S. Food Yellow No. 6), Food Red No. 2, and Food Blue No. 2, food lake color, and ferric oxide.

[0023] Examples of stabilizers include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. The "flavoring agent" includes, for example, commonly used sweeteners, acidulants, fragrances, etc. As for "fluidizing agents", they are used for the purpose of improving the fluidity of mixed powders and granules, and representative examples include talc and silicon dioxide, which are light anhydrous silicic acid and hydrous silicon dioxide. Here, the light anhydrous silicic acid may be any that has hydrous silicon dioxide (SiO2·nH2O) (n is an integer) as its main component, and specific examples include, for example, Silica 320 (trade name, Fuji Silysia Chemical Co., Ltd.) and Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.). Suitable examples of the "preservative" include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. Suitable examples of the antioxidant include sulfites and ascorbic acid. The above-mentioned additives may be used in a mixture of two or more kinds in an appropriate ratio. As a solvent for producing a liquid formulation, ethanol, phenol, chlorocresol, purified water, distilled water, etc. can be used.

[0024] The solid preparation of the present invention can be produced by mixing the compound represented by formula (I) with a basic substance and the above-mentioned additives, and then by a general production method. Preferably, the solid preparation is produced according to the following production method. 1) The solid preparation of the present invention is prepared by mixing the compound represented by formula (I) with additives such as a basic substance, an excipient, a disintegrant, and a lubricant, followed by compression molding. 2) The compound represented by formula (I) is mixed with additives such as a basic substance, an excipient, and a binder, and then granulated while adding or spraying a solvent (e.g., purified water, ethanol, or a mixture thereof). The resulting granules are mixed with an appropriate amount of a lubricant and, if necessary, a disintegrant, and then compressed to produce the solid preparation of the present invention. 3) The compound represented by formula (I) is mixed with additives such as a basic substance and an excipient, and then a binder and other additives as necessary are dispersed or dissolved in a solvent (e.g., purified water, ethanol, or a mixture thereof) and the resulting liquid is added or sprayed to granulate. An appropriate amount of a lubricant and, as necessary, a disintegrant are added to the resulting granules, and the mixture is compressed and molded to produce the solid preparation of the present invention.

[0025] The pharmaceutical composition of the present invention also relates to a pharmaceutical composition containing (i) a compound represented by formula (I) or a salt thereof, and (ii) a basic substance. One embodiment of the pharmaceutical composition of the present invention relates to a non-granular pharmaceutical composition containing (i) a compound represented by formula (I) or a salt thereof, and (ii) a basic substance. Furthermore, one embodiment of the pharmaceutical composition of the present invention relates to a pharmaceutical composition comprising (i) granules containing a compound represented by formula (I) or a salt thereof, and (ii) a powder containing a basic substance. A further embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition comprising (i) granules containing a compound represented by formula (I) or a salt thereof and a surfactant, and (ii) powder containing a basic compound and a disintegrant. A further embodiment of the pharmaceutical composition of the present invention is a pharmaceutical composition comprising (i) granules containing a compound represented by formula (I) or a salt thereof, a surfactant, and a disintegrant, and (ii) powder containing a basic compound and a disintegrant.

[0026] In the present invention, "granules" means particles having a substantially uniform shape and size, and are obtained by granulating raw materials in the form of powder, lump, solution, or molten liquid by a wet granulation method, a dry granulation method, a heat granulation method, etc. "Non-granular" means a state in which granules are not formed. In the present invention, the granules may contain various additives in addition to the above-mentioned surfactant and disintegrant. For example, the granule may contain the compound represented by formula (I) or a salt thereof, a disintegrant, a surfactant, an excipient, and a binder. The granule may further contain one or more additives selected from a lubricant, a coating agent, a stabilizer, a flavoring agent, and a diluent, and can be produced by granulating a composition containing the compound represented by formula (I) or a salt thereof, and optionally additives such as a disintegrant, a surfactant, an excipient, a lubricant, a coating agent, a binder, a stabilizer, a flavoring agent, and a diluent, using a conventional granulation process. The average particle size of the granules may be any average particle size used in conventional pharmaceutical preparations. The average particle size is a value obtained by adding 6 g of sampled granules to a stack of sieves having different pore sizes (e.g., pore sizes: 850, 500, 355, 250, 180, 106, 75, 53, and 0 μm), shaking for 3 minutes, measuring the weight of the granules remaining on each sieve, and calculating the particle size corresponding to a cumulative rate of 50% using a log-normal distribution approximation from the pore size of each sieve and the under-sieve cumulative rate. In the present invention, the term "final" and "final component" refer to a component added to the outside of the granules. The final component may include additives such as a disintegrant, a lubricant, a flow agent, etc.

[0027] The disintegrant may be contained in the granule or in a final component, and is preferably selected from sodium starch glycolate, low-substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic acid anhydride and carmellose, more preferably carmellose calcium, crospovidone, sodium starch glycolate and croscarmellose sodium, and most preferably carmellose calcium and crospovidone.

[0028] When a disintegrant is contained in the granule or in the final component, it is selected from sodium starch glycolate, low-substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch, sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose, silicic acid anhydride and carmellose, preferably carmellose calcium, crospovidone, sodium starch glycolate and croscarmellose sodium, and most preferably carmellose calcium or crospovidone.

[0029] The granules (i) may contain a basic substance in the granules, and in that case, the pharmaceutical composition may contain (i) the granules containing the compound represented by formula (I) or a salt thereof and the basic substance, and (ii) a surfactant. The basic substance is more preferably added as a final component. The basic substance contained in the granules of (i) is a substance exemplified above as the basic substance, and is preferably selected from inorganic basic substances, metal salts of organic acids, organic amines, and basic amino acids (groups), more preferably inorganic basic substances (groups), and most preferably magnesium aluminometasilicate.

[0030] When a basic substance is contained in the final component (ii), the basic substance contained in the final component is a substance exemplified as the basic substance described above, preferably selected from the inorganic basic substances, metal salts of organic acids, organic amines, and basic amino acids (groups) described above, more preferably the inorganic basic substance (groups) described above, and most preferably magnesium aluminometasilicate. The basic substance contained within the granules (i) and in the final component (ii) is preferably contained in an amount of 5% by weight or more, 5% by weight or more to 30% by weight or less, 7.5% by weight or more, or 7.5% by weight or more to 30% by weight or less, based on the total weight of the preparation.

[0031] In addition to the surfactant, the pharmaceutical composition of the present invention may contain a solubilizing agent such as an organic polymer described below. The "solubilizing agent" includes organic polymers, and specific examples of the "organic polymer" used in the present invention include polysaccharides such as hydroxypropyl cellulose (hereinafter also referred to as HPC), hydroxypropyl methylcellulose, methylcellulose, propylene glycol alginate, powdered agar, guar gum, zein, and hydroxyethyl methylcellulose, carboxyvinyl polymers, polyvinyl alcohol, synthetic resins such as vinyl acetate resin and sodium polystyrene sulfonate, and phosphoproteins such as casein and sodium caseinate. Organic polymers with a solubility in water of 1 g / 100 g or more are called water-soluble polymers. Specific examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, propylene glycol alginate, sodium caseinate, carboxyvinyl polymer, powdered agar, guar gum, copolyvidone, hydroxyethyl methylcellulose, and polyvinyl alcohol. Among organic polymers, those that dissolve under acidic conditions of pH 1.2 to 3.5, which is the pH of gastric juice, are called gastric-soluble polymers, while those that dissolve quickly in the intestines at pH 6 to 8 are called enteric-soluble polymers. Examples of gastric-soluble polymers include aminoalkyl methacrylate copolymer E and polyvinyl acetal diethylaminoacetate, while examples of enteric polymers include methacrylic acid copolymer LD (emulsion), methacrylic acid copolymer S, purified shellac, carboxymethylethylcellulose, cellulose acetate phthalate (seraphate), hydroxypropylmethylcellulose acetate succinate, casein, and zein. Preferred solubilizing agents include, for example, casein, sodium caseinate, skim milk powder, dioctyl sodium sulfosuccinate, polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, lauromacrogol, sodium lauroyl sarcosine, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, and sodium dodecylbenzenesulfonate. The solubilizing agent may be in the form of granules or may be obtained by spray drying.

[0032] In the present invention, examples of excipients that can be contained in the granules (i) include starches such as corn starch, potato starch, wheat corn starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol, and sorbitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, and calcium silicate. Preferred excipients include starches such as starch, potato starch, and corn starch, lactose hydrate, crystalline cellulose, and anhydrous calcium hydrogen phosphate, with mannitol and lactose hydrate being more preferred. The amount of excipient used is preferably 5 to 60 parts by weight, and more preferably 10 to 30 parts by weight, based on 100 parts by weight of the composition or preparation. When the preparation of the present invention is a preparation having a coating such as a coated tablet, the above-mentioned amount used means the amount used relative to the total components coated with the coating (total components coated with the coating).

[0033] In the present invention, examples of the binder that can be contained in the granules (i) include hydroxypropyl cellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the excipients. Specific examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, povidone (polyvinylpyrrolidone), and powdered gum arabic, and preferably hydroxypropyl cellulose. The amount of the binder used is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight, and even more preferably 0.5 to 10 parts by weight, based on 100 parts by weight of the composition or preparation. When the preparation of the present invention is a preparation having a coating such as a coated tablet, the above-mentioned amount used means the amount used relative to the total components coated with the coating (total components coated with the coating). Furthermore, the granules and the final component may contain a binder, and hydroxypropyl cellulose is preferred as such a binder.

[0034] Suitable examples of lubricants that can be contained in the granules (i) of the present invention include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, sodium stearyl fumarate, and the like.

[0035] Stabilizers that may be contained in the granules (i) of the present invention include, for example, paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. Examples of flavoring agents that can be contained in the granules of the present invention include commonly used sweeteners, acidulants, fragrances, and the like.

[0036] Furthermore, as yet another aspect of the present invention, there is provided a pharmaceutical composition comprising a poorly soluble basic drug, an anionic surfactant and a basic substance, in which the addition of the basic substance improves the dissolution property of the poorly soluble basic drug, thereby obtaining a composition suitable for high-dose formulations. "Poorly soluble" means that the solubility in a solvent, particularly water, a buffer solution, or a gastrointestinal fluid, is 1 mg / ml or less, more preferably 100 μg / ml or less, even more preferably 10 μg / ml or less, particularly preferably 1 μg / ml or less, and most preferably 0.1 μg / ml or less. It is preferably poorly soluble in any solvent with a pH of 7 or less, more preferably poorly soluble in any solvent with a pH of 4 to 7, and even more preferably poorly soluble in a solvent with a pH of 4 and / or 7. However, in the case of a compound having a basic group in the molecule, it is preferably poorly soluble in any solvent with a pH of 7 or more, more preferably poorly soluble in any solvent with a pH of 7 to 9, and even more preferably poorly soluble in a solvent with a pH of 7 and / or 9. The solvent for measuring the solubility is not particularly limited, but examples of the solvent with a pH of 4 include acetate buffer, citrate buffer, and the like. Examples of the solvent with a pH of 5 include acetate buffer, citrate buffer, and phosphate buffer. Examples of the solvent having a pH of 7 include water and a phosphate buffer solution. Examples of the solvent having a pH of 9 include a carbonate buffer solution. In either case, the temperature at which the solubility is measured is preferably 20 to 40°C, and more preferably 37°C.

[0037] A "basic drug" has at least one basic group, such as a primary amino group (-NH2), a secondary amino group (imino group -NH-), a tertiary amino group (>N-), an amide group, a basic nitrogen-containing heterocyclic group (pyrrolyl group, imidazolyl group, pyrazolyl group, pyrazinyl group, purinyl group, quinolyl group, pyridyl group, piperidino group, piperidyl group, piperazinyl group, triazolo group, etc.). The amino group also includes a hydrazino group (-NH-NH2) and a hydrazo group (-NH-NH-). A basic drug may have at least one basic group, and may have multiple basic groups of the same or different types. In addition, the drug may form a salt (for example, a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, an organic carboxylic acid such as acetic acid, tartaric acid, citric acid, fumaric acid, or maleic acid, or an organic sulfonic acid such as mesylic acid). Cationic or basic drugs also include drugs whose metabolites or prodrugs that exhibit activity in vivo are cationic or basic. The type of basic drug is not particularly limited, and may be, for example, a drug acting on the central nervous system, autonomic nervous system, respiratory system, circulatory system, digestive system, metabolic system, etc., or may be a blood or hematopoietic drug, a drug in the ophthalmological or otolaryngological field, or an in vivo active substance (autacoid), etc. Specific types may be antipyretics, analgesics, anti-inflammatory drugs, hypnotics / sedatives, drugs for treating rheumatism, antidepressants, antiepileptic drugs, antivertigo drugs, antiallergic drugs, cardiac stimulants, β-blockers, calcium antagonists, antiarrhythmic drugs, diuretics, drugs for treating angina pectoris, drugs for treating heart failure, drugs for treating myocardial infarction, antihypertensive drugs (drugs for treating high blood pressure), drugs for treating peripheral circulatory disorders, vasopressors (drugs for treating low blood pressure), bronchodilators, drugs for treating asthma, antituberculosis drugs, drugs for treating diabetes, drugs for treating diabetic complications, drugs for treating hyperlipidemia, drugs for treating hyperuricemia, antitussives and expectorants, drugs for treating peptic ulcers, drugs for treating thyroid diseases, drugs for treating prostatic hyperplasia, anticancer drugs, drugs for treating osteoporosis, drugs for treating Alzheimer's disease, antibiotics, vitamins, antiplasmin agents, and the like.

[0038] Specific examples of basic drugs include antipyretics, analgesics, and anti-inflammatory drugs (antipyretics and analgesics such as dimethothiazine mesylate, headache medicines such as dihydroergotamine mesylate, lomerizine hydrochloride, and sumatributan succinate, anti-inflammatory drugs such as fenamic acid, mefenamic acid, floctafenine, proglumetacin maleate, epirizole, and tiaramide hydrochloride), antirheumatic drugs (penicillamine, methotrexate, etc.), drugs for treating hyperuricemia (allopurinol, etc.), hypnotics and sedatives (rilmazafone hydrochloride, zolpidem tartrate, etc.), antidepressants (nortriptyline hydrochloride, imipramine hydrochloride, alkaloid hydrochloride, etc.), mitriptyline, clomipramine hydrochloride, fluvoxamine maleate, milnacipran hydrochloride, etc.), antidizziness drugs (isoprenaline hydrochloride, betahistine mesylate, etc.), antiallergic drugs (antihistamines such as diphenhydramine hydrochloride, diphenylpyraline teoclate, clemastine fumarate, chlorpheniramine maleate, alimemazine tartrate, promethazine hydrochloride, etc.; histamine H1 antagonists (or basic antiallergic drugs) such as ketotifen fumarate, azelastine hydrochloride, epinastine hydrochloride, etc.), cardiac stimulants (denopamine, isoprenaline hydrochloride, etc.), antianginal drugs drugs (niconandil, etafenone hydrochloride, dipyridamole, trapidil, trimetazidine hydrochloride, etc.), beta-blockers (propranolol hydrochloride, diphenidol hydrochloride, bufetolol hydrochloride, bupranolol hydrochloride, bopindolol malonate, oxprenolol hydrochloride, alprenolol hydrochloride, indenolol hydrochloride, acebutolol hydrochloride, celiprolol hydrochloride, etc.), calcium antagonists (manidipine hydrochloride, benidipine hydrochloride, amlodipine besylate, verapamil hydrochloride, diltiazem hydrochloride, etc.), antiarrhythmic drugs (aprindine hydrochloride, pilsicainide hydrochloride, propafenol hydrochloride, etc.), diuretics (hydrochlorothiazide, penflutizide, benzylhydrochlorothiazide, bumetanide, azosemide, triamterene, etc.), antihypertensives (sympathetic nerve suppressants such as clonidine hydrochloride, methyldopa, guanabenz acetate, guanfacine hydrochloride, reserpine, prazosin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesilate, etc.), vasodilators such as hydralazine hydrochloride, budralazine, todralazine hydrochloride, cadralazine, etc., enalapril maleate, delapril hydrochloride,ACE inhibitors such as lisinopril and benazepril hydrochloride, angiotensin II receptor antagonists such as candesartan cilexetil and valsartan, peripheral circulatory disorder treatment drugs (inositol hexanicotinate, hepronicate, trizoline hydrochloride, isoxsuprine hydrochloride, etc.), vasopressors (metaraminol hydrogen tartrate, methoxamine hydrochloride, midodrine hydrochloride, amezinium methylsulfate, etilefrine hydrochloride, phenylephrine hydrochloride, etc.), bronchodilators and asthma treatment drugs (ephedrine hydrochloride, methylephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbumol hydrochloride, Terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride and other beta-2-adrenergic receptor stimulants, theophylline, aminophylline, choline theophylline, proxyphylline and other xanthine derivatives), cough suppressants (dimemorfan phosphate, tipepidine hyphenate, oxelastine citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.), diabetes medications (tolbutamide, acetonitrile, etc.), Antibiotics (e.g., thiazole, glibenclamide, glimepiride, buformin hydrochloride, ensanmetformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L-methylcysteine ​​hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), anti-peptic ulcer drugs (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, muscarinic receptor antagonists such as pirenzepine hydrochloride, etc.), antibiotics (clarithromycin, kitasamycin, josamycin, midecamycin, isin, loxtamycin, azithromycin, etc.), narcotics (amphetamine, meperidine, etc.), vitamins [vitamin B1 such as thiamine hydrochloride, thiamine nitrate, dicethiamine hydrochloride, sicotiamine, benfotiamine, bis-ibuthiamine, fursultiamine, prosultiamine, octotiamine, bis-bentiamine, thiamine disulfide; vitamin B2 such as riboflavin, riboflavin sodium phosphate, riboflavin butyrate, flavin adenine dinucleotide sodium; pyridoxine hydrochloride, pyridoxine acetate,Vitamin B6 such as pyridoxal phosphate; nicotinic acids such as nicotinic acid and nicotinamide; vitamin B12 such as mecobalamin, cyanocobalamin, hydroxocobalamin (hydroxocobalamin hydrochloride, hydroxocobalamin acetate, etc.), and methylcobalamin; folic acid, pantothenic acids, biotin, vitamin P (hesperidin, etc.), and antiplasmin agents (epsilon-aminocaproic acid, tranexamic acid, etc.). These basic drugs can be used alone or in combination depending on the purpose of prevention or treatment.

[0039] The present invention also provides a composition comprising a poorly soluble basic drug, an anionic surfactant and a basic substance, the composition having good drug dissolution properties; A composition comprising a poorly soluble basic drug, an anionic surfactant and a basic substance, which has good drug disintegration properties; The composition, wherein the composition is an oral dosage formulation; and the composition wherein the composition is a tablet; Also included. Furthermore, the present invention includes a method for improving the dissolution property of a drug by adding a basic substance to a preparation containing a basic drug and an anionic surfactant; A method for improving the disintegration property of a formulation containing a basic drug and an anionic surfactant by adding a basic substance to the formulation; and Also included is a method for producing a formulation having good drug dissolution properties, which comprises the step of adding a basic substance to a formulation containing a basic drug and an anionic surfactant.

[0040] In the present invention, it has been found that by containing a basic pharmaceutical ingredient and an anionic surfactant, an impermeable coating is formed due to ionic interaction between the basic substance and the anionic surfactant, which results in poor disintegration, and that the basic substance can suppress the formation of the impermeable coating.

[0041] By adding a basic substance to a preparation containing a poorly soluble basic drug such as the compound represented by formula (I) and a surfactant, good dissolution of the preparation can be obtained. Here, "good dissolution" means that the dissolution rate of the preparation is 45% or more, preferably 60% or more, and more preferably 75% or more after 30 minutes when a dissolution test (dissolution test 1) is performed at 100 revolutions per minute according to the Japanese Pharmacopoeia dissolution test paddle method using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether as the test solution. Alternatively, it means that when a dissolution test (dissolution test 2) is performed by the paddle method rotating at 100 rpm using 900 mL of the Japanese Pharmacopoeia dissolution test solution No. 1 containing 4% polyoxyethylene (10) octylphenyl ether as the test solution, preferably a test solution obtained by mixing about 3 g of polyoxyethylene (10) octylphenyl ether with 75 mL of the dissolution test solution No. 1, after 30 minutes, a dissolution rate of 45% or more, preferably 60% or more, more preferably 75% or more is obtained. It means that the above dissolution rate is obtained in either dissolution test 1 or dissolution test 2, and more preferably, when dissolution test 2 is performed, a dissolution rate of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. It means that, particularly preferably, when dissolution test 2 is performed, 70% or more is dissolved in 75 minutes. The Japanese Pharmacopoeia Dissolution Test Solution No. 1 is prepared by dissolving 2.0 g of sodium chloride in 7.0 ml of hydrochloric acid and water to make 1000 mL. The solution is clear and colorless with a pH of approximately 1.2. "Improvement of dissolution" means that the dissolution of a drug below the above-mentioned dissolution range is brought within the above-mentioned dissolution range, and the improvement of dissolution allows the medicament active ingredient to be efficiently absorbed and quickly exert its medicinal effect. In the United States, Europe, Israel, and other countries other than Japan, dissolution test 2 is set as the dissolution standard test method for the approved capsule formulation of the medicament active ingredient. It is desirable that the dissolution according to dissolution test 2 is 45% or more after 30 minutes and 75% or more after 70 minutes in the United States and Israel, and 45% or more to 75% or less after 30 minutes and 75% or more after 70 minutes in the EU.

[0042] In addition, according to the present invention, good disintegration properties can be obtained by adding a basic substance to a preparation containing a poorly soluble basic drug such as a compound represented by formula (I) and a surfactant. Here, "good disintegration properties" means that the disintegration time of the preparation is usually within 30 minutes, preferably within 15 minutes, when a disintegration test (disintegration test 1) is performed in the Japanese Pharmacopoeia disintegration test using the Japanese Pharmacopoeia dissolution test liquid No. 1 as the test liquid. Alternatively, it means that the preparation disintegrates after 10 minutes, preferably within 5 minutes, when a disintegration test (disintegration test 2) is performed in the Japanese Pharmacopoeia disintegration test using water as the test liquid. Preferably, it means that the above disintegration properties are obtained in either disintegration test 1 or disintegration test 2, and more preferably, it means that the preparation disintegrates within 3 minutes when disintegration test 2 is performed. "Improvement of disintegration properties" means that the disintegration properties of the preparation, which are below the above disintegration properties range, are brought into the above disintegration properties range. Here, "disintegrate" means a state in which "sample residue is found at 30 minutes, but only a small amount of soft material or muddy material" or "no sample residue is found at 30 minutes", preferably a state in which no sample residue is found at 30 minutes. EXAMPLES

[0043] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these. In Examples 1 to 20, NIKKOL SLS (Nikko Chemicals) was used as sodium lauryl sulfate.

[0044] Reference Example 1: Formation of an impermeable coating (Production of Formulations) Tablets were prepared according to the amounts of each component listed in Table 1. The hydrochloride of the compound of formula (I) (hereinafter, Compound A), sodium lauryl sulfate, and magnesium stearate were mixed by hand in a polyethylene container. The blended powder was compressed with a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) at a compression pressure (500 kgf) to produce tablets (φ=9.0 mm) containing 150 mg of Compound A in terms of free form. [Table 1] (Formulation evaluation and results) For Reference Example 1, a dissolution test (dissolution test 2) was performed at 100 revolutions per minute by the Japanese Pharmacopoeia dissolution test paddle method using 900 mL of the Japanese Pharmacopoeia dissolution test solution No. 1 containing 4% polyoxyethylene (10) octylphenyl ether as the test solution. The dissolution profile of Reference Example 1 is shown in Figure 1. In addition, photographs of the appearance of the preparation before and after the test, and the central cut section after the test are shown in Figure 2. As shown in Figure 1, the dissolution profile of the tablet containing compound A and sodium lauryl sulfate prepared by wet granulation was linear, and the maximum dissolution rate was 40% or less. Also, as shown in Figure 2, the test liquid penetrated only the surface of the tablet from the observation result of cutting the tablet at the center after the test, and the inside was dry. This is thought to be because an impermeable coating was formed on the tablet surface, and the penetration of the test liquid into the inside of the tablet was inhibited, so disintegration did not proceed and a good dissolution profile was not obtained. The impermeable coating refers to a coating formed on the tablet surface by a basic drug and an anionic surfactant in the test liquid.

[0045] Example 1-7: Study on the disintegration of basic substances (Production of Formulations) Tablets were prepared according to the amounts of each component in the tablet formulation shown in Table 2. The substances shown in Table 3 were used as X contained in the final component in the formulation. The granule formulation components were mixed, and the premixed powder was placed in a stainless steel beaker. Purified water was added while stirring with a metal spatula to wet granulate, and then the mixture was dried at room temperature in a vacuum dryer (VOS-301SD, Tokyo Rikakikai Co., Ltd.). The mixture was then sized using a sieve with a size diameter of 850 μm to form granules, which were then further mixed with the final component to obtain a blended powder. Each blended powder was compressed with a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) at a compression pressure (1000 kgf) to produce tablets (15.9 × 8.4 mm) containing 300 mg of compound A in terms of free form. Comparative Example 1 is a tablet prepared using the capsule formulation of Patent Document 5, and the relationship between the type of X and the disintegration time of the tablet was examined by comparing Comparative Example 1 with Examples 1-7. [Table 2] [Table 3]

[0046] For Comparative Example 1 and Examples 1-7, disintegration tests were performed three times for each Comparative Example / Example according to the Japanese Pharmacopoeia Disintegration Test using water and the Japanese Pharmacopoeia Dissolution Test Fluid No. 1 as the test fluid. The disintegration behavior of Examples 1-7 is shown in Table 4. Note that this test was performed in water (Disintegration Test 2) and under acidic conditions (Disintegration Test 1) where disintegration is more difficult than in water. Note that the following symbols used in the tables in this specification have the following meanings. -: Sample residue observed at 30 minutes. +: Sample residue was observed at 30 minutes, but only a small amount of soft material or material on the mud. ++: No residue of sample observed at 30 minutes. [Table 4]

[0047] (Formulation evaluation and results) As shown in Table 4, in Examples 1 to 7, the tablets produced using a basic substance as X showed superior disintegrability to those in Comparative Example 1.

[0048] Examples 8-10: Examination of manufacturing methods for dissolution (Production of Formulations) Tablets were prepared by changing the manufacturing method according to the amount of each component in the tablet formulation shown in Table 5. In Example 8, the formulation components were mixed to obtain a blended powder. In Example 9, the granular formulation components were mixed and compressed into tablets using a Φ16mm punch in a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) at a pressure of 400 kgf, and the resulting molded product was sized using a sieve with a size diameter of 850 μm to obtain granules, which were then further mixed with the final component to obtain a blended powder. In Example 10, the formulation components shown in Table 5 were mixed, and the premixed powder was placed in a stainless steel beaker, and purified water was added while stirring with a metal spatula to perform wet granulation, and then dried at room temperature in a vacuum dryer (VOS-301SD, Tokyo Rikakikai Co., Ltd.). Subsequently, the granules were sized using a sieve with a size diameter of 850 μm to obtain granules, which were then further mixed with the final component to obtain a blended powder. Each blended powder of Examples 8 to 10 was compressed with a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) at a compression pressure (500 kgf) to produce tablets containing 150 mg of compound A calculated as a free form. The dissolution properties of tablets produced by a manufacturing method in which a basic substance was added to the formulation were examined. (Formulation evaluation and results) As shown in Figure 3, in Examples 8 to 10, regardless of the manufacturing method, i.e., regardless of the presence or absence of granule formation, the tablets manufactured using a basic substance in the formulation showed superior dissolution properties to those of Comparative Example 1. This result complies with the dissolution test standards of each country for approved capsule preparations. [Table 5]

[0049] Examples 11-14: Examination of the ratio of excipients and basic substances to dissolution properties (Production of Formulations) According to the amount of each component shown in Table 6, the granule formulation components were mixed, and purified water was added to this premix and wet granulated in the same manner as in Examples 1-7. The granulated powder obtained by wet granulation was dried, sized using a sieve with a size diameter of 850 μm to obtain granules, and further mixed with the final powder component to obtain a blended powder. Each blended powder was compressed with a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) at a compression pressure (1000 kgf) to produce tablets (15.9 × 8.3 mm) containing 300 mg of compound A in terms of free form. The dissolution properties of the tablets were examined depending on the ratio of excipients to the granule formulation components and the ratio of disintegrant and basic substance in the final powder components. [Table 6]

[0050] (Formulation evaluation and results) For Examples 11-14, a dissolution test (dissolution test 1) was performed at 100 revolutions per minute by the Japanese Pharmacopoeia dissolution test paddle method using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether as the test solution. The dissolution profiles of Examples 11-14 are shown in FIG. As shown in Figure 4, by adding a basic substance (magnesium aluminometasilicate), a good dissolution profile was obtained regardless of the type of excipient or the disintegrant ratio in the granule formulation ingredients.

[0051] Examples 15-18: Examination of combinations of excipients and final components for dissolution (Production of Formulations) According to the amount of each component listed in Table 7, the granule formulation components were weighed, mixed using a granulator (VG-05, Powrex Corporation), purified water was added and granulated, and dried in a fluidized bed dryer (FL-LABO, inlet air temperature 60°C) until the loss on drying was 2% or less. The obtained dry powder was granulated using a granulator using a screen with a size diameter of 1.4 mm, and further mixed with the powder component to obtain a blended powder. Each blended powder was converted into a free form using a static pressure tableting machine under the same conditions as in Examples 8-10, and tablets containing 150 mg of compound A were produced and the dissolution properties were examined. [Table 7] (Formulation evaluation and results) For Examples 15-18, a disintegration test (disintegration test 1) was performed according to the Japanese Pharmacopoeia disintegration test using the Japanese Pharmacopoeia dissolution test solution No. 1 as the test solution. For Examples 15-18, no residue of the sample was found at 30 minutes for all tablets. This test (disintegration test 1) was performed under acidic conditions, which are less prone to disintegration than in water. For Examples 15-18, a dissolution test (dissolution test 2) was conducted at 100 revolutions per minute by the Japanese Pharmacopoeia dissolution test paddle method using 900 mL of the Japanese Pharmacopoeia dissolution test solution No. 1 containing 4% polyoxyethylene (10) octylphenyl ether as the test solution. The dissolution profiles of Examples 15-18 are shown in FIG. 5. As shown in Figure 5, the addition of magnesium aluminometasilicate showed good dissolution profile of compound A from tablets, regardless of the combination of excipient and disintegrant. This result complies with the dissolution test standards of each country for approved capsule preparations.

[0052] Examples 19 and 20: Tablet weight study (Production of Formulations) According to the amount of each component listed in Table 8, the granule formulation components were weighed and mixed using a fluidized bed granulation dryer (FG-602, Freund Corporation), purified water was added by spraying, granulated, and dried using the same machine at an inlet air temperature of 60°C until the loss on drying was 2% or less. The obtained dried powder was sized using a granulator using a screen with a size diameter of 1.4 mm, and the obtained granules and the latter powder components were further mixed to obtain a blended powder. The blended powder was tableted using a rotary tableting machine (AQUARIUS-C, Kikusui Seisakusho) at a hitting pressure (10 kN), and tablets (17.3 x 8.0 mm) containing 300 mg of compound A in terms of free form were produced. The relationship between tablet weight and disintegration was examined by comparing with Examples 15-18. [Table 8] For Examples 19 and 20, a disintegration test was performed according to the Japanese Pharmacopoeia Disintegration Test using the Japanese Pharmacopoeia Dissolution Test Solution No. 1 as the test solution. For the tablets of Examples 19 and 20, no residue of the sample was found at the 30 minute mark. This test was a disintegration test (disintegration test 1) under acidic conditions where disintegration is slower than in water. (Formulation evaluation and results) Even though the tablet weight increased by adding magnesium aluminometasilicate, a basic substance, good disintegrability was observed as in Examples 15-18.

Claims

1. Formula (I): 【Chemistry 1】 or a salt thereof, a surfactant and a basic substance, the method comprising mixing the compound represented by formula (I) with the surfactant, a basic substance and an additive, followed by compression molding, wherein the solid preparation contains 150 mg to 800 mg of the compound represented by formula (I) or a salt thereof in terms of free form per unit preparation, and the basic substance is one or more substances selected from the group consisting of magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, magnesium hydroxide, magnesium carbonate and sodium hydrogencarbonate.

2. The method according to claim 1 , wherein the surfactant is an anionic surfactant.

3. The method of claim 2, wherein the anionic surfactant is sodium lauryl sulfate.

4. The method according to any one of claims 1 to 3, further comprising a disintegrant.

5. The process according to any one of claims 1 to 4, wherein the weight ratio of the compound represented by formula (I) or a salt thereof to the surfactant is from 100:3 to 100:

50.

6. The method according to claim 4, wherein the disintegrant is contained in an amount of 5% by weight or more.

7. The method according to claim 4 or 6, wherein the disintegrant is one or more substances selected from the group consisting of carmellose calcium, crospovidone, sodium starch glycolate and croscarmellose sodium.

8. A method for producing a pharmaceutical composition according to any one of claims 1 to 7, wherein the solid formulation is a tablet.

9. The method according to claim 1 , wherein the basic substance is contained in an amount of 5% by weight or more.

10. Formula (I): 【Chemistry 2】 or a salt thereof, a surfactant and a basic substance, wherein the solid preparation is a compression-molded solid preparation containing 150 mg to 800 mg of the compound represented by formula (I) or a salt thereof in terms of free form per unit preparation of the solid preparation, and the basic substance comprises one or more substances selected from the group consisting of magnesium aluminometasilicate, L-arginine, meglumine, magnesium oxide, magnesium hydroxide, magnesium carbonate and sodium hydrogencarbonate.

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