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 highly dosed formulation of a poorly soluble basic drug, particularly a compound represented by formula (I), a high-dose tablet thereof, and the like.

Background Art

[0002] Anaplastic Lymphoma Kinase (ALK) is one of the receptor tyrosine kinases belonging to the insulin receptor family (Non-Patent Document 1, Non-Patent Document 2), and it has been reported that gene abnormalities of ALK cause the production of abnormal kinases fused with other genes. Diseases associated with ALK abnormalities include, for example, cancer and cancer metastasis (Non-Patent Document 1, Patent Document 1), depression, cognitive dysfunction (Non-Patent Document 2), etc. The provision of ALK inhibitors provides effective treatments and prophylactic drugs for those 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) is known (Patent Document 2, Patent Document 3, Patent Document 4, Patent Document 5).

Chemical Formula

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Non-Patent Documents

[0004]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

Problems to be Solved by the Invention

[0005] Improvement of a pharmaceutical composition containing a poorly soluble basic drug, particularly a compound represented by formula (I) or a salt thereof In order to achieve good absorbability, a high-dose formulation having excellent disintegrability and elution property is required. It has been.

Means for Solving the Problems

[0006] Under such circumstances, as a result of intensive studies to solve the above problems, the present inventors added a basic substance to a poorly soluble basic drug, particularly a compound represented by the formula (I) or a salt thereof, to obtain a pharmaceutical composition. By using this composition, it was found that the formation of an impermeable film during disintegration when the composition was made into tablets could be prevented, and a high-dose tablet with good elution property could be obtained. That is, the present invention is as follows. (1) A pharmaceutical composition containing a compound represented by the formula (I) or a salt thereof, a surfactant, and a basic substance. It is. That is, the present invention is as follows. (1) A pharmaceutical composition containing a compound represented by the formula (I) or a salt thereof, a surfactant, and a basic substance. Composition.

Chemical formula

[0007] (11) A tablet comprising the composition according to any one of (1) to (10). (12-1) The compound represented by formula (I) or a salt thereof is contained in a unit dosage form in an amount calculated as a free form. The tablet according to any one of (1) to (11), containing 150 mg to 800 mg. (12-2) The compound represented by formula (I) or a salt thereof is contained in a unit dosage form in an amount calculated as a free form. The tablet according to any one of (1) to (11), containing 150 mg to 400 mg. (12-3) The compound represented by formula (I) or a salt thereof is contained in a unit dosage form in an amount calculated as a free form. The tablet according to any one of (1) to (11), containing 200 mg to 300 mg. Japanese Pharmacopoeia containing 4% polyoxyethylene (10) octylphenyl ether (13-1) The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using the first solution of the Japanese Pharmacopoeia dissolution test solution is 45% or more in 30 minutes, the tablets described in (11) or (12). Japanese Pharmacopoeia containing 4% polyoxyethylene (10) octylphenyl ether (13-2) The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using the first solution of the Japanese Pharmacopoeia dissolution test solution is 60% or more in 30 minutes, the tablets described in (11) or (12). Japanese Pharmacopoeia containing 4% polyoxyethylene (10) octylphenyl ether (13-3) The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using the first solution of the Japanese Pharmacopoeia dissolution test solution is 75% or more in 30 minutes, the tablets described in (11) or (12). Japanese Pharmacopoeia containing 4% polyoxyethylene (10) octylphenyl ether (13-4) The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using the first solution of the Japanese Pharmacopoeia dissolution test solution is 70% or more in 75 minutes, the tablets described in (11) or (12). (13-5) Using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether, the dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test is 45% or more in 30 minutes, the tablets described in (11) or (12). The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using the first solution of the Japanese Pharmacopoeia dissolution test solution is (13-6) Using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether, the dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test is 60% or more in 30 minutes, the tablets described in (11) or (12). The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using the first solution of the Japanese Pharmacopoeia dissolution test solution is (13-7) Using 33 mL of formic acid and 900 mL of purified water containing 2% polyoxyethylene (10) octylphenyl ether, the dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test is 75% or more in 30 minutes, the tablets described in (11) or (12). The tablets according to (11) or (12), wherein the dissolution rate is 75% or more within 30 minutes. (13-8) In the dissolution test paddle method of the Japanese Pharmacopoeia, using 33 mL of formic acid and 900 mL of purified water containing 2% of polyoxyethylene (10) octyl phenyl ether, the dissolution property of the tablets according to (11) or (12) is such that the dissolution rate is 70% or more within 75 minutes. (13-9) In the disintegration test of the Japanese Pharmacopoeia using water as the test solution, at the 30-minute time point, although residues of the sample are observed, the soft substances or substances on mud are slight, for the tablets according to (11) or (12) as described. (13-10) In the disintegration test of the Japanese Pharmacopoeia using water as the test solution, at the 30-minute time point, no residues of the sample are observed, for the tablets according to (11) or (12) (13-11) In the disintegration test of the Japanese Pharmacopoeia using the first elution test solution of the Japanese Pharmacopoeia as the test solution, at the 30-minute time point, although residues of the sample are observed, the soft substances or substances on mud are slight for the tablets according to (11) or (12) as described. (13-12) In the disintegration test of the Japanese Pharmacopoeia using the first elution test solution of the Japanese Pharmacopoeia as the test solution, at the 30-minute time point, no residues of the sample are observed, for the tablets according to (11) or (12) (14) A pharmaceutical composition containing one or more basic substances selected from the group consisting of a compound represented by the formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium hydrogen carbonate, magnesium aluminum metasilicate, magnesium aluminate metasilicate, L-arginine, meglumine, magnesium oxide and magnesium carbonate, sodium carboxymethylcellulose, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate. (14-1) A compound represented by the formula (I) or a salt thereof, L-tryptophan, L-lysine, A pharmaceutical composition containing magnesium hydroxide, magnesium silicate, calcium hydrogen carbonate, magnesium metaaluminosilicate, one or more basic substances selected from the group consisting of magnesium, L-arginine, meglumine, magnesium oxide and magnesium carbonate, calcium carmellose, D-mannitol , and sodium lauryl sulfate. (14-2) A compound represented by formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium hydrogen carbonate, magnesium metaaluminosilicate, one or more basic substances selected from the group consisting of magnesium, L-arginine, meglumine, magnesium oxide and magnesium carbonate, crospovidone, lactose hydrate, and lauryl sulfate sodium. (14-3) A compound represented by formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium hydrogen carbonate, magnesium metaaluminosilicate, one or more basic substances selected from the group consisting of magnesium, L-arginine, meglumine, magnesium oxide and magnesium carbonate, calcium carmellose, D-mannitol , sodium lauryl sulfate, hydroxypropyl cellulose and magnesium stearate . (14-4) A compound represented by formula (I) or a salt thereof, L-tryptophan, L-lysine, magnesium hydroxide, magnesium silicate, calcium hydrogen carbonate, magnesium metaaluminosilicate, one or more basic substances selected from the group consisting of magnesium, L-arginine, meglumine, magnesium oxide and magnesium carbonate, crospovidone, lactose hydrate, lauryl sulfate sodium, hydroxypropyl cellulose and magnesium stearate. ​​​​​ Tablets containing the composition described in (15)(14). (16-1) Per unit dosage form, the compound represented by formula (I) or a salt thereof, in terms of the free form Containing 150 mg to 800 mg, the tablets described in (15). (16-2) Per unit dosage form, the compound represented by formula (I) or a salt thereof, in terms of the free form Containing 150 mg to 600 mg, the tablets described in (15). (16-3) Per unit dosage form, the compound represented by formula (I) or a salt thereof, in terms of the free form Containing 200 mg to 300 mg, the tablets described in (15). (17-1) Japanese Pharmacopoeia dissolution test solution No. 1 containing 4% of polyoxyethylene (10) octylphenyl ether The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using Japanese Pharmacopoeia dissolution test solution No. 1 is 45% or more in 30 minutes, the tablets described in (15) or (16). (17-2) Japanese Pharmacopoeia dissolution test solution No. 1 containing 4% of polyoxyethylene (10) octylphenyl ether The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using Japanese Pharmacopoeia dissolution test solution No. 1 is 60% or more in 30 minutes, the tablets described in (15) or (16). (17-3) Japanese Pharmacopoeia dissolution test solution No. 1 containing 4% of polyoxyethylene (10) octylphenyl ether The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using Japanese Pharmacopoeia dissolution test solution No. 1 is 75% or more in 30 minutes, the tablets described in (15) or (16). (17-4) Japanese Pharmacopoeia dissolution test solution No. 1 containing 4% of polyoxyethylene (10) octylphenyl ether The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using Japanese Pharmacopoeia dissolution test solution No. 1 is 70% or more in 75 minutes, the tablets described in (15) or (16). (17-5) The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using 900 mL of purified water containing 33 mL of formic acid and 2% of polyoxyethylene (10) octylphenyl ether is 3 2% of polyoxyethylene (10) octylphenyl ether The tablets according to (15) or (16), having a dissolution rate of 45% or more within 30 minutes. (17-6) 33 mL of formic acid and polyoxyethylene (10) octylphenyl ether The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using 900 mL of purified water containing 2% is The tablets according to (15) or (16), having a dissolution rate of 60% or more within 30 minutes. (17-7) 33 mL of formic acid and polyoxyethylene (10) octylphenyl ether The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using 900 mL of purified water containing 2% is The tablets according to (15) or (16), having a dissolution rate of 75% or more within 30 minutes. (17-8) 33 mL of formic acid and polyoxyethylene (10) octylphenyl ether The dissolution property in the paddle method of the Japanese Pharmacopoeia dissolution test using 900 mL of purified water containing 2% is The tablets according to (15) or (16), having a dissolution rate of 70% or more within 75 minutes. (17-9) In the Japanese Pharmacopoeia disintegration test using water as the test solution, at the 30-minute time point, the residue of the sample is recognized, but there is little soft substance or muddy substance, the tablets according to (15) or (16) as described. (17-10) In the Japanese Pharmacopoeia disintegration test using water as the test solution, at the 30-minute time point, the sample has no recognized residue, the tablets according to (15) or (16) as described. (17-11) In the Japanese Pharmacopoeia disintegration test using the first solution of the Japanese Pharmacopoeia dissolution test solution as the test solution, at the 30-minute time point, the residue of the sample is recognized, but there is little soft substance or muddy substance present, the tablets according to (15) or (16) as described. (17-12) In the Japanese Pharmacopoeia disintegration test using the first solution of the Japanese Pharmacopoeia dissolution test solution as the test solution, at the 30-minute time point, the sample has no recognized residue, the tablets according to (15) or (16) as described. (18) Dissolve 2.0 g of sodium chloride in 7.0 ml of hydrochloric acid and water to make 1000 mL. Using a test solution containing 4% of polyoxyethylene (10) octylphenyl ether prepared with a solution of pH about 1.2, in the dissolution test by the paddle method with a rotation of 100 rpm per minute, tablets showing an elution of 45% or more after 30 minutes and / or 75% or more after 70 minutes, as described in (15) or (16).

Advantages of the Invention

[0008] The composition of the present invention prevents the formation of an impermeable film during disintegration upon tableting, and provides a high-dose formulation with good elution and disintegration properties, containing a poorly soluble basic drug , particularly a compound represented by the formula (I) or a salt thereof as an active ingredient. Further, by enabling the formulation of a high-dose formulation with a good dissolution profile, the number of tablets to be taken can be reduced, contributing to an improvement in the ease of administration. In addition, the pharmaceutical composition of the present invention can obtain high-dose tablets with good elution properties regardless of the formation of granules during tableting. Also, the pharmaceutical composition of the present invention can obtain high-dose tablets with good elution properties regardless of the presence or absence of granule formation during tableting.

Brief Description of the Drawings

[0009]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Modes for Carrying Out the Invention

[0010] The present invention will be described in detail below. In the present invention, the "pharmaceutical composition" refers to a mixture of two or more substances used for the treatment, prevention, etc. of diseases. As one aspect of the present invention, the pharmaceutical composition is used for the production of pharmaceutical preparations. The "pharmaceutical preparation" means a preparation for the treatment, prevention, etc. of diseases, and in the present invention, an oral administration preparation is preferred. The "oral administration preparation" is a preparation that can be administered orally, and the active ingredient is mainly absorbed from the intestinal tract. Oral administration preparations include solid preparations and liquid preparations. In the present invention, solid preparations are preferred. Specifically, solid preparations such as tablets, capsules, solutions, powders, troches, chewable tablets, granules, gels, films, etc. can be mentioned, and among them, tablets are preferred. When producing tablets in the present invention, granules may or may not be used. When producing tablets using granules, the average particle size of the granules may be the average particle size used in normal formulation. The "compound represented by formula (I)" is the compound represented by formula (I)

[0011] and in chemical 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.

Chemical formula

[0012] "Surfactant" means a substance having both a hydrophilic group and a hydrophobic group in the molecule, and the surfactant The agent contains an ionic surfactant and a nonionic surfactant. An ionic surfactant means an ionic surfactant that ionizes into ions (atoms or atomic groups with charges) when dissolved in water. Ionic surfactants are further classified into anionic surfactants, cationic surfactants, and amphoteric surfactants according to the charges of the generated ions.

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

[0014] As anionic surfactants, alkyl sulfates (C12-18, Na, NH4 , alkanolamine), POE alkyl ether sulfates (C12-18, Na, NH4, alkanolamine), POE alkyl phenyl ether sulfates (C12 -18, NH4, alkanolamine, Ca), POE benzyl (or styryl) pheny l (or phenylphenyl) ether sulfates (Na, NH4, alkanolamine ), polyoxyethylene, polyoxypropylene block polymer sulfates (Na, NH4, alkanolamine), etc. sulfate-type surfactants; paraffin (alkane ) sulfonates (C12-22, Na, Ca, alkanolamine), AOS (C14- 16, Na, alkanolamine), dialkyl sulfosuccinates (C8-12, Na , Ca, Mg), alkylbenzene sulfonates (C12, Na, Ca, Mg, NH4, alkylamine, alkanol, amine, cyclohexylamine), mono- or dialkyl (C3-6) naphthalene sulfonates (Na, NH4, alkanolamine, Ca, Mg ), naphthalene sulfonate-formalin condensates (Na, NH4), alkyl (C8-1 2) diphenyl ether disulfonates (Na, NH4), lignin sulfonates (Na , Ca), POE alkyl (C8 - 12) phenyl ether sulfonate (Na), PO E alkyl (C12 - 18) ether sulfosuccinic acid half - ester (Na), etc. of sul fonate - type surfactants; fatty acid salts (C12 - 18, Na, K, NH4, alkanol ami ne), N - methyl - fatty acid sarcosinate (C12 - 18, Na), resin acid salts (Na, K ) and other carboxylic acid - type surfactants; POE alkyl (C12 - 18) ether phos phate (Na, alkanolamine), POE mono - or dialkyl (C8 - 12) phenyl ether phosphate (Na, alkanolamine), POE benzyl (or styryl)ated phenyl (or phenylphenyl) ether phosphate (Na, alkanolamine) , polyoxyethylene - polyoxypropylene block polymer (Na, alkanol ami ne), phosphatidylcholine - phosphatidylethanolimine (lecithin), alkyl (C8 - 12) phosphate and other phosphate - type surfactants, etc. may be mentioned. Preferably, sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate rium, sodium octadecyl sulfate and other mono - alkyl sulfates, dioctyl sodium sul fosuccinate, sodium lauroyl sarcosinate, sodium dodecylbenzenesulfonate rium, etc. may be mentioned. In the present invention, two or more surfactants may be used in an appropriate ratio in combination. In the present invention, the surfactant is preferably an anionic surfactant.

[0015] Preferred surfactants are mono - alkyl sulfates, polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol - Alcohol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, lauromacro - Goal, dioctyl sodium sulfosuccinate, sodium lauroyl sarcosinate, d It is selected from the group consisting of sodium decylbenzenesulfonate and mixtures thereof. More preferred surfactants are monoalkyl sulfates, sorbitan trioleate, poly oxyethylene(105)polyoxypropylene(5)glycol, polyoxyethylene hard ened castor oil 60, polyoxyl 35 castor oil, dioctyl sodium sulfosuccinate, sodium lauroyl sarcosinate, sodium dodecylbenzenesulfonate and mixtures thereof selected from the group consisting of. Even more preferred surfactants are sodium lauryl sulfate, sodium tetradecyl sulfate , sodium hexadecyl sulfate, sodium octadecyl sulfate and mixtures thereof selected from the group consisting of. Particularly preferred surfactants are mixtures 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, its crystals can be those obtained by spray drying or those obtained by crystallization. Incidentally, as crystal polymorphs of sodium lauryl sulfate, monohydrate, 1 / 2 hydrate, 1 / 8 hydrate, and non-solvate hydrates are known (reference: Journal of Crystal Growth 263 (2004) 480-490), but any crystals can be used in the compositions or formulations 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, based on the entire composition. More preferably, it is 7.5% by weight or more, and most preferably 7.5% by weight or more and 30% by weight or less. It is contained as follows. The surfactant contained in the composition or preparation of the present invention preferably has a weight ratio of the compound represented by the formula (I) or a salt thereof to the surfactant of 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 definition of Lewis, more preferably a substance defined as a base according to the definition of Bronsted-Lowry, and there is no particular limitation as long as it is a pharmacologically acceptable component, and known basic substances can be used. The basic substance may be an inorganic basic substance or an organic basic substance. The basic substance may be used alone or in combination of two or more. As the inorganic basic substance, metal oxides such as magnesium oxide, calcium oxide, and aluminum oxide,

[0017] 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, potassium polyphosphate, metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate, sodium silicate, magnesium silicate, calcium silicate, and the like. Sodium silicate, magnesium silicate, calcium silicate, combined Metal silicates such as aluminum metasilicate, sodium magnesium silicate, talc, magnesium aluminum silicate, aluminum magnesium metasilicate, magnesium metaaluminate and other composite silicate-aluminum compounds, composite aluminum-magnesium compounds such as synthetic hydrotalcite, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, ammonium

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

[0019] thereof and the like. Preferably, metal oxides such as magnesium oxide, calcium oxide, aluminum oxide and the like, sodium hydroxide, potassium Metal hydroxides such as aluminum, sodium carbonate, potassium carbonate, magnesium carbonate, Metal carbonates such as calcium carbonate, sodium bicarbonate, potassium bicarbonate, etc. , trisodium phosphate, tripotassium phosphate, tricalcium phosphate, trimagnesium phosphate , sodium pyrophosphate, potassium pyrophosphate, sodium polyphosphate, potassium polyphosphate Metal phosphates such as um, monosodium hydrogen phosphate, monopotassium hydrogen phosphate, etc. Hydrogen salts, sodium silicate, magnesium silicate, calcium silicate, synthetic aluminum silicate nium, synthetic magnesium sodium silicate, talc and other metal silicates, aluminum silicate Magnesium, magnesium aluminum silicate, magnesium metaaluminate Composite silicate-aluminum compounds such as, synthetic hydrotalcite and other composite aluminum-magnesium Compounds, ammonium hydroxide, ammonium carbonate, ammonium bicarbonate, lithium Inorganic ammonium salts such as ammonium monohydrogen phosphate can be mentioned. Or, glycine, L-serine, L-cysteine, L-tryptophan, L-proline, L -aspartic acid, L-lysine, L-histidine, L-arginine, L-lysine hydrochloride, Meglumine, magnesium metaaluminate, magnesium metaaluminate, Magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium carbonate And the like, preferably, L-tryptophan, L-lysine, magnesium hydroxide Magnesium, magnesium silicate, calcium hydrogen carbonate, sodium hydrogen carbonate, metaaluminum Magnesium acid, L-arginine, meglumine, magnesium oxide, magnesium carbonate cium, and more preferably, magnesium metaaluminate, L-arginine, Meglumine, magnesium oxide, magnesium hydroxide, magnesium carbonate, sodium bicarbonate Lithium, and more preferably magnesium aluminometasilicate, magnesium oxide , magnesium carbonate, and most preferably magnesium aluminometasilicate . As the magnesium aluminometasilicate, preferably Neusilin (registered trademark) US2, S2, UFL2, FH2, NS2N (Fuji Chemical Industry Co., Ltd.), PTU-F (Tomita Pharmaceutical Co., Ltd.). More preferably, the magnesium aluminometasilicate is N eusilin (registered trademark) US2, 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, 7.5% by weight or more and 30% by weight or less, based on the whole composition. The weight ratio of the compound represented by the formula (I) or a salt thereof to the basic substance is preferably 1 00:5 to 100:60 in terms of the free form, more preferably 100:10 to 100: 50, and most preferably 100:20 to 100:40.

[0020] The preparation of the present invention is produced by a well-known method using additives such as excipients, lubricants, coating agents, binders, disintegrants, stabilizers, flavoring and odor correctors, diluents and the like. Examples of the "excipient" include starches such as corn starch, potato starch, wheat starch, rice starch, pregelatinized starch, α-starch, porous starch, etc.; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol, sorbitol, etc.; calcium hydrogen phosphate anhydrous, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc. Preferred excipients include starches such as starch, potato starch, corn starch, etc., lactose hydrate, crystalline cellulose, calcium hydrogen phosphate anhydrous, etc. The "disintegrant" in the present invention is a component for promoting the rapid disintegration of a solid preparation after oral administration. Examples of the disintegrant include sodium starch glycolate, low-substituted hydroxypropyl cellulose, calcium carmellose, α-starch, sodium chloride, corn starch, crosscarmellose sodium, crystalline cellulose, anhydrous silicic acid, carmellose, etc. The amount of the 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, particularly preferably 10 % by weight or more based on the whole 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. In addition, when the preparation of the present invention is a preparation having a film such as a coated tablet, etc., the above-mentioned amount used is the amount based on the whole component covered by the film (the whole component filled in the capsule, the whole component covered by the coating).

[0021] Examples of the "binder" include, for example, polyvinylpyrrolidone, macrogol, and the same compounds as the excipient. Specific examples of the binder include, for example, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (poly vinylpyrrolidone), gum arabic powder, etc. 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 10 0 parts by weight of the preparation.

[0022] Preferred examples of the "lubricant" include, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, etc. Examples of the surfactant or emulsifier include, for example, polysorbate 80, polyoxyethylene 40 stearate, lauromacrogol, etc. As the coloring agent, any agent that is permitted to be added to pharmaceuticals can be used, such as, for example, food yellow No. 5 (Sunset Yellow, food yellow No. 6 in the United States), food red No. 2, food blue No. 2, etc. food dyes, food lake dyes, iron sesquioxide, etc.

[0023] Examples of the stabilizer 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 the "flavoring and odor-correcting agent" include, for example, commonly used sweeteners, acidulants, flavors, etc. ​​​As the "fluidizing agent", the fluidizing agent is used for the purpose of improving the fluidity of the mixed powder or granules, and typical examples include light anhydrous silicic acid and hydrous silicon dioxide such as talc and silicon dioxide. Here, the light anhydrous silicic acid may be any one having hydrous silicon dioxide (SiO2·nH2O) (n represents an integer) as the main component. Specific examples thereof include, for example, Silicia 320 (trade name, Fuji Silysia Chemical Ltd.), Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.), and the like. Preferable examples of the "preservative" include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferable examples of the antioxidant include, for example, sulfites, ascorbic acid, and the like. The above-mentioned additives may be mixed and used in an appropriate ratio of two or more. As the solvent for producing the liquid preparation, ethanol, phenol, chlorocresol, purified water, distilled water, and the like can be used.

[0024] The solid preparation of the present invention can be produced by mixing the compound represented by the formula (I) together with a basic substance and the above-mentioned additives, and then producing the solid preparation by a general production method. Preferably, it is produced according to the following production method. 1) The solid preparation of the present invention is produced by mixing the compound represented by the formula (I) together with additives such as a basic substance, an excipient, a disintegrant, and a lubricant, and then compression molding. 2) After mixing the compound represented by the formula (I) together with additives such as a basic substance, an excipient, and a binder, a solvent (for example, purified water, ethanol, or a mixed solution thereof) is added or sprayed. ​​​​​Granulate while stirring. To the resulting granulated product, an appropriate amount of lubricant, and if necessary, a disintegrant, etc. are added and mixed, and then compression molding is carried out 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, if necessary, other additives are dispersed or dissolved in a solvent (for example, purified water, ethanol, or a mixture thereof whatever), and granulation is carried out while adding or spraying the resulting liquid. To the resulting granulated product, an appropriate amount of lubricant, and if necessary, a disintegrant, etc. are added and mixed, and then compression molding is carried out 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. As one aspect of the pharmaceutical composition of the present invention, it also relates to a non-granular pharmaceutical composition containing (i) a compound represented by formula (I) or a salt thereof and (ii) a basic substance. Also, as one aspect of the pharmaceutical composition of the present invention, it relates to a pharmaceutical composition containing (i) granules containing a compound represented by formula (I) or a salt thereof and (ii) a powder containing a basic substance. As a further aspect of the pharmaceutical composition of the present invention, (i) granules containing a compound represented by formula (I) or a salt thereof and a surfactant, and (ii) a powder containing a basic compound and a disintegrant are included. As a further aspect of the pharmaceutical composition of the present invention, (i) granules containing a compound represented by formula (I) or a salt thereof, a surfactant, and a disintegrant, and (ii) a powder containing a basic compound and a disintegrant are included.

[0026] In the present invention, "granules" means particles having substantially uniform shape and size, and include powdery, lumpy Raw materials in the form of powder, solution or melt are obtained by granulation using wet granulation method, dry granulation method, 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 granules may contain a compound represented by formula (I) or a salt thereof, a disintegrant, a surfactant, an excipient and a binder. The granules may further contain one or more additives selected from lubricants, coating agents, stabilizers , flavoring agents and diluents, and a composition containing a 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, a diluent, etc. can be produced by granulation using a normal granulation process. The average particle size of the granules may be the average particle size used in normal formulation. The average particle size is obtained by adding 6 g of the sampled granulated product from above a stack of a plurality of sieves with different pore diameters (for example, pore diameters: 850, 500, 355 , 250, 180, 106, 75, 53, 0 μm), shaking for 3 minutes, measuring the weight of the granulated product 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 diameter of each sieve and the cumulative rate under the sieve. In the present invention, "post powder" and "post powder component" mean components added to the outside of the granulated granules. As the post powder component, in addition to the disintegrant, additives such as a lubricant and a fluidizing agent can also be added.

[0027] The disintegrant may be contained in the granules or in the post powder component, and preferably, starch glycol ​​​​​​​Sodium laurate, low-substituted hydroxypropyl cellulose, calcium carmellose, A Modified starch, sodium chloride, corn starch, croscarmellose sodium Selected from lithium, crystalline cellulose, anhydrous silicic acid and carmellose, more preferably Selected from calcium carmellose, crospovidone, sodium starch glycolate and croscarmellose sodium Most preferably calcium carmellose and crospovidone is.

[0028] When a disintegrant is contained in the granules or the post-terminal components, sodium starch glycolate, low Substituted hydroxypropyl cellulose, calcium carmellose, alpha-starch, Sodium chloride, corn starch, croscarmellose sodium, crystalline cellulose Selected from sulfur, anhydrous silicic acid and carmellose, preferably calcium carmellose , Crospovidone, sodium starch glycolate and croscarmellose sodium Selected from, most preferably calcium carmellose or crospovidone.

[0029] In addition, the granules of (i) may contain a basic substance in the granules, in which case the compound represented by formula ( I) or a salt thereof, and a granule containing a basic substance, and (ii) a surfactant An agent, and may be a pharmaceutical composition. The basic substance is more preferably added as a post-terminal component to do. The basic substance contained in the granules of (i) is the substance exemplified as the above-mentioned basic substance , Preferably an inorganic basic substance, a metal salt of an organic acid, an organic amine, a basic amino acid (group) or Selected from, more preferably an inorganic basic substance (group), most preferably magnesium aluminum metasilicate acid.

[0030] When the final component contains a basic substance, the basic substance contained in the final component of (ii) is a substance exemplified as the aforementioned basic substance, preferably selected from the aforementioned inorganic basic substances, metal salts of organic acids, organic amines, basic amino acid(s), more preferably the aforementioned inorganic basic substance(s), most preferably magnesium aluminum metasilicate. The basic substances contained in the granules of (i) and the final component of (ii) are, based on the whole preparation, 5% by weight or more, 5% by weight or more and 30% by weight or less, preferably contained in an amount of 7.5% by weight or more, 7.5% by weight or more and 30% by weight or less.

[0031] In addition to the surfactant, the pharmaceutical composition of the present invention may be added with a solubilizing agent such as an organic polymer described below. It may be added. Examples of the "solubilizing agent" include organic polymers, and the "organic polymers" used in the present invention specifically include hydroxypropyl cellulose (hereinafter also referred to as HPC), hydroxypropyl methylcellulose, methylcellulose, propylene glycol alginate, agar powder, guar gum, zein, polysaccharides such as hydroxyethyl methylcellulose, carboxyvinyl polymer, polyvinyl alcohol, or synthetic resins such as vinyl acetate resin, sodium polystyrene sulfonate, and phosphoproteins such as casein and sodium caseinate. Among organic polymers, polymers having a solubility in water of 1 g / 100 g or more are referred to as water-soluble polymers. Specifically, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, propylene glycol alginate, sodium caseinate, etc. Carboxyvinyl polymer, dried ginger powder, guar gum, copovidone, hydroxyethyl methyl cellulose, polyvinyl alcohol and the like can be mentioned. 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, and those that dissolve rapidly at pH 6 to 8 in the intestine are called enteric polymers. Examples of gastric-soluble high molecules include aminoalkyl methacrylate copolymer E, or polyvinyl acetal diethylaminoacetate, etc. Examples of enteric polymers include methacrylic acid copolymer LD ( emulsion), methacrylic acid copolymer S, purified shellac, carboxymethylethyl cellulose stearate, cellulose acetate phthalate (cellafate), hydroxypropylmethyl cellulose a cetate succinate, casein, zein and the like can be mentioned. Preferred solubilizing agents are, for example, casein, sodium caseinate, skim milk powder, dioctyl sodium sulfosuccinate, polyoxyl 40 stearate, sorbitan trioleate , polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxy ethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, lauromacrogol, lauroyl sarcosine sodium, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium methyl sulfate, sodium ethyl sulfate, butyl sulfate sodium, sodium octyl sulfate, sodium decyl sulfate, sodium dodecylbenzenesulf onate sodium and the like can be mentioned. The solubilizing agent may be in granular form or obtained by spray drying.

[0032] In the present invention, examples of excipients that can be included in the granules of (i) include, for example, corn starch Starch, potato starch, wheat starch, rice starch, pregelatinized starch, alpha-starch, perforated starch, etc.; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol, sorbitol; calcium hydrogen phosphate anhydride, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc. Preferred excipients include starches such as starch, potato starch, corn starch, lactose hydrate, crystalline cellulose, calcium hydrogen phosphate anhydride, etc., and mannitol and lactose hydrate are more preferred. The amount of excipient used is preferably 5 to 60 parts by weight, more preferably 10 to 30 parts by weight, based on 100 parts by weight of the composition or formulation. Starches such as alpha-starch and porous starch; sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol, and sorbitol; calcium hydrogen phosphate anhydride, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc. are mentioned. Preferred excipients include starches such as starch, potato starch, and corn starch, lactose hydrate, crystalline cellulose, calcium hydrogen phosphate anhydride, etc., and mannitol and lactose hydrate are more preferred. The amount of excipient used is preferably 5 to 60 parts by weight, more preferably 10 to 30 parts by weight, based on 100 parts by weight of the composition or formulation. Starch, potato starch, corn starch, etc. starches, lactose hydrate, crystalline cellulose, calcium hydrogen phosphate anhydride, etc. are mentioned, and mannitol and lactose hydrate are more preferred. The amount of excipient used is preferably 5 to 60 parts by weight, more preferably 10 to 30 parts by weight, based on 100 parts by weight of the composition or formulation. When the formulation of the present invention is a formulation having a film such as a coated tablet, etc., the above usage amount means the usage amount relative to the entire component covered by the film (the entire component covered by the coating). When the formulation of the present invention is a formulation having a film such as a coated tablet, etc., the above usage amount means the usage amount relative to the entire component covered by the film (the entire component covered by the coating). When the formulation of the present invention is a formulation having a film such as a coated tablet, etc., the above usage amount

[0033] Examples of the binder that can be included in the granules of (i) in the present invention include, for example, hydroxypropyl cellulose, polyvinylpyrrolidone, macrogol, and compounds similar to the above excipients. Specific examples of the binder include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), gum arabic powder, etc., 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, even more preferably 0.5 to 10 parts by weight, based on 100 parts by weight of the composition or formulation. When the formulation of the present invention is a formulation having a film such as a coated tablet, etc., the above usage amount means the usage amount relative to the entire component covered by the film (the entire component covered by the coating). When the formulation of the present invention is a formulation having a film such as a coated tablet, etc., the above usage amount means the usage amount relative to the entire component covered by the film (the entire component covered by the coating). When the formulation of the present invention is a formulation having a film such as a coated tablet, etc., the above usage amount The dosage means the amount used relative to the entire component covered by the film (the entire component covered by the coating). It also means the amount used. In addition, the granules and the post-terminal components may contain a binder, and as such a binder, hydroxypropyl cellulose is preferred. Hydroxypropyl cellulose is preferred.

[0034] In the present invention, suitable examples of the lubricant that can be contained in the granules of (i) include, for example, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, etc. Magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, etc. can be mentioned. Sodium stearyl fumarate and the like can be mentioned.

[0035] In the present invention, examples of the stabilizer that can be contained in the granules of (i) include, for example, paraoxybenzoic acid esters such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. Paraoxybenzoic acid esters such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid can be mentioned. Benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid can be mentioned. Phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid can be mentioned. Thimerosal; dehydroacetic acid; and sorbic acid can be mentioned. Examples of the flavoring and odor-masking agent that can be contained in the granules of the present invention include, for example, sweeteners, acidulants, flavors, etc. that are commonly used. Sweeteners, acidulants, flavors, etc. that are commonly used can be mentioned.

[0036] In addition, as still another aspect of the present invention, a pharmaceutical composition containing a poorly soluble basic drug, an anionic surfactant, and a basic substance can be mentioned. By adding a basic substance, the elution property of the poorly soluble basic drug can be improved, and a composition suitable for a high-dose formulation can be obtained. By adding a basic substance, the elution property of the poorly soluble basic drug can be improved, and a composition suitable for a high-dose formulation can be obtained. "Poorly soluble" means a state where the solubility in a solvent, particularly water, a buffer solution, or gastrointestinal fluid is 1 mg / ml or less, more preferably 100 μg / ml or less, still more preferably 10 μg / ml or less, particularly preferably 1 μg / ml or less, and most preferably 0.1 μg / ml or less. "Poorly soluble" means a state where the solubility in a solvent, particularly water, a buffer solution, or gastrointestinal fluid is 1 mg / ml or less, more preferably 100 μg / ml or less, still more preferably 10 μg / ml or less, particularly preferably 1 μg / ml or less, and most preferably 0.1 μg / ml or less. 1 mg / ml or less, more preferably 100 μg / ml or less, still more preferably 10 μg / ml or less, particularly preferably 1 μg / ml or less, and most preferably 0.1 μg / ml or less. Particularly preferably 1 μg / ml or less, and most preferably 0.1 μg / ml or less, which means such a state. It is preferably poorly soluble in any solvent having a pH of 7 or lower, more preferably poorly soluble in any solvent having a pH of 4 to 7, and even more preferably poorly soluble in a solvent having a pH of 4 and / or pH 7. However, in the case of a compound having a basic group in the molecule, it is preferably poorly soluble in any solvent having a pH of 7 or higher, more preferably poorly soluble in any solvent having a pH of 7 to 9, and even more preferably poorly soluble in a solvent having a pH of 7 and / or pH 9. The solvent for measuring the solubility is not particularly limited. Examples of the solvent having a pH of 4 include acetic acid buffer solution and citric acid buffer solution. Examples of the solvent having a pH of 5 include acetic acid buffer solution, phosphoric acid buffer solution, and phosphate buffer solution. Examples of the solvent having a pH of 7 include water and phosphate buffer solution. Examples of the solvent having a pH of 9 include carbonate buffer solution. In any case, the temperature for measuring the solubility is preferably 20 to 40°C, more

[0037] The "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, triazolyl group, etc.). The amino group includes a hydrazino group (-NH-NH2) and a hydrazo group (-NH-NH-). The basic drug only needs to have at least one basic group, and may have a plurality of basic groups of the same or different types. In addition, the drug may be a salt (for example, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, fumaric acid (to form salts) with organic carboxylic acids such as maleic acid, organic sulfonic acids such as mesylic acid, etc. It may be. Note that cationic or basic drugs include drugs whose metabolites or prodrugs that exhibit activity in vivo are cationic or basic. The type of basic agent is not particularly limited. For example, it may be a drug that acts on the central nervous system, autonomic nervous system, respiratory system, circulatory system, digestive system, metabolic system, etc., or it may be a drug for blood and hematopoietic action, drugs in the ophthalmic or otolaryngologic fields, bioactive substances (autacoids) in vivo, etc. Specifically, it may be an antipyretic, analgesic, anti-inflammatory drug, hypnotic / sedative drug, rheumatoid arthritis treatment drug, antidepressant, antiepileptic drug, antivertigo drug, anti-allergy drug, cardiotonic drug, β-blocker, calcium antagonist, antiarrhythmic drug, diuretic, angina pectoris treatment drug, heart failure treatment drug, myocardial infarction treatment drug, antihypertensive agent (hypertension treatment drug), peripheral circulatory disorder treatment drug, hypertensive agent (hypotension treatment drug), bronchodilator, asthma treatment drug, antituberculosis drug, diabetes treatment drug, diabetic complication treatment drug, hyperlipidemia treatment drug, hyperuricemia treatment drug,

[0038] Specific examples of basic agents include antipyretic / analgesic / anti-inflammatory drugs (antipyretic and analgesic drugs such as dimethothiazine mesylate, headache drugs such as dihydroergotamine mesylate, romeridine hydrochloride, sumatriptan succinate, anti-inflammatory drugs such as fenamic acid, mefenamic acid, flufenamic acid, progulmetacin maleate, epirizole, tiaramide hydrochloride, etc.), antirheumatic drugs (penicillamine, methotrexate, etc.), hyperuricemia treatment drugs (allopurinol, etc.), hypnotic / sedative drugs (Riluzole hydrochloride, Zolpidem tartrate, etc.), antidepressants (Nortriptyline hydrochloride, Imipramine hydrochloride, Amitriptyline hydrochloride, Clomipramine hydrochloride, Fluvoxamine maleate , Milnacipran hydrochloride, etc.), antivertigo agents (Isoprenaline hydrochloride, Betahistine mesilate , etc.), antiallergic agents (Diphenhydramine hydrochloride, Difenpyramide theoclate, Clemastine fumarate, Chlorpheniramine maleate, Alimemazine tartrate, Promethazine hydrochloride , etc.; antihistamines such as Ketotifen fumarate, Azelastine hydrochloride, Epinastine hydrochloride , etc.), cardiotonic agents (Denopamine, Isoprenaline hydrochloride, etc.), antianginal agents (Nicorandil, Ethafenone hydrochloride, Dipyridamole, Trapidil, Trimetazidine hydrochloride, etc.), β-blockers (Propranolol hydrochloride, Difenidol hydrochloride, Bufetolol hydrochloride, Bupranolol hydrochloride, Bopindolol malonate, Oxprenolol hydrochloride, Alprenolol hydrochloride, Indenolol hydrochloride, Acebutolol hydrochloride, Celiprolol hydrochloride, etc.), calcium antagonists (Manidipine hydrochloride, Verapamil hydrochloride, Diltiazem hydrochloride, etc.), antiarrhythmic agents (Aprindine hydrochloride, Pyridocaine hydrochloride, Propafenone hydrochloride, Amiodarone hydrochloride, Nifekalant hydrochloride, Sotalol hydrochloride, Bepridil hydrochloride, etc.), diuretics (Hydrochlorothiazide, Penflutizide, Bendroflumethiazide, Bumetanide, Azosemide, Triamterene, etc.), antihypertensive agents (Clonidine hydrochloride, Methyldopa, Guanabenz acetate, Guanfacine hydrochloride, Reserpine, Prazosin hydrochloride, Bunazosin hydrochloride, Terazosin hydrochloride, Doxazosin mesylate, etc., sympatholytic agents, Hydralazine hydrochloride, Budralazine, Todralazine hydrochloride n, vasodilators such as cadralazine, enalapril maleate, delapril hydrochloride, lisinopril, benazepril hydrochloride, etc., angiotensin II receptor antagonists such as candesartan cilexetil, valsartan, etc., peripheral circulatory disorder therapeutic agents (inositol hexanicotinate, hepronicate, trizoline hydrochloride, isoxsuprine hydrochloride, etc.) , ACE inhibitors such as captopril, enalapril maleate, delapril hydrochloride, lisinopril, benazepril hydrochloride, etc., angiotensin II receptor antagonists such as candesartan cilexetil, valsartan, etc., peripheral circulatory disorder therapeutic agents (inositol hexanicotinate, hepronicate, trizoline hydrochloride, isoxsuprine hydrochloride, etc.) , peripheral circulatory disorder therapeutic agents (inositol hexanicotinate, hepronicate, trizoline hydrochloride, isoxsuprine hydrochloride, etc.), pressor agents (metaraminol bitartrate, methoxamine hydrochloride, midodrine hydrochloride, amezinium methylsulfate, etilefrine hydrochloride, phenylephrine hydrochloride, etc.), bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.) , peripheral circulatory disorder therapeutic agents (inositol hexanicotinate, hepronicate, trizoline hydrochloride, isoxsuprine hydrochloride, etc.), pressor agents (metaraminol bitartrate, methoxamine hydrochloride, midodrine hydrochloride, amezinium methylsulfate, etilefrine hydrochloride, phenylephrine hydrochloride, etc.), bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.) , pressor agents (metaraminol bitartrate, methoxamine hydrochloride, midodrine hydrochloride, amezinium methylsulfate, etilefrine hydrochloride, phenylephrine hydrochloride, etc.), bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.), antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.) , pressor agents (metaraminol bitartrate, methoxamine hydrochloride, midodrine hydrochloride, amezinium methylsulfate, etilefrine hydrochloride, phenylephrine hydrochloride, etc.), bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.), antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.) , bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.), antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.), antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.) , bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.), antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.), antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.) , bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.), antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.), antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.) , bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.), antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.), antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) , bronchodilators and asthma therapeutic agents (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbutamol hydrochloride, terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, clenbuterol hydrochloride, etc., β2 - adrenergic receptor stimulants, xanthine derivatives such as theophylline, aminophylline, choline theophylline, proxiphylline, etc.), antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.), antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) , antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.), antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) , antitussives (dextromethorphan phosphate, tipepidine hibenzate, oxeladin citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, benproperine phosphate, etc.), antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) , antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) , antidiabetic agents (tolbutamide, acetohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensalmetformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) , expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) , expectorants (L - methylcysteine hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) , peptic ulcer therapeutic agents (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., pirenzepine hydrochloride) Muscarinic receptor antagonists such as zepin), antibiotics (clarithromycin, kitasamycin icin, josamycin, midecamycin, rokitamycin, azithromycin, etc.) , narcotics (amphetamine, meperidine, etc.), vitamins [thiamine hydrochloride, thiamine nitrate ne, disethiamine hydrochloride, ciclotiamine, benfotiamine, bisibuthiamine, flursul thiamine, prosultiamine, octothiamine, bisbentiamine, thiamine disulfide such as vitamin B1; riboflavin, riboflavin sodium phosphate, riboflavin butyrate , vitamin B2 such as flavin adenine dinucleotide sodium; pyridoxine hydrochloride , vitamin B6 such as pyridoxine acetate, pyridoxal phosphate; nicotinic acid, ni cotinic acid amide and other nicotinic acid; mecobalamin, cyanocobalamin, hydroxocoba lamin (hydroxocobalamin hydrochloride, hydroxocobalamin acetate, etc.)), methylcobal min and other vitamin B12; folic acid, pantothenic acids, biotin, vitamin P (hesperi din, etc.), antiplasmin agents (epsilon - aminocaproic acid, tranexamic acid, etc.) and the like can be mentioned. These basic drugs can be used alone or in combination of two or more according to the purpose of prevention or treatment, etc. .

[0039] In addition, the present invention provides a composition comprising a poorly soluble basic drug, an anionic surfactant, and a basic substance, which has good drug elution properties; a composition comprising a poorly soluble basic drug, an anionic surfactant, and a basic substance, which has good drug disintegration properties; the above composition wherein the composition is an oral dosage form; and the above composition wherein the composition is a tablet; is also included. Furthermore, the present invention provides a method for improving the elution property of a preparation by adding a basic substance to a preparation containing a basic agent and an anionic surfactant; a method for improving the disintegration property of a preparation by adding a basic substance to a preparation containing a basic agent and an anionic surfactant; and a method for producing a preparation having good elution property of a drug, which includes a step of adding a basic substance to a preparation containing a basic agent and an anionic surfactant. ; and In the present invention, by containing a basic drug substance and an anionic surfactant, an impermeable film is formed by the ionic interaction between the basic substance and the anionic surfactant, thereby causing poor disintegration. It has been found that a basic substance can suppress the formation of the impermeable film. is also included.

[0040] In the present invention, by containing a poorly soluble basic drug such as a compound represented by the formula (I) and a surfactant, a basic substance is added to obtain good elution property of the preparation. Here, "good elution property" means that when an elution test (elution test 1) is carried out at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test using 900 mL of purified water containing 33 mL of formic acid and 2% of polyoxyethylene (10) octylphenyl ether as a test solution, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. Alternatively, 900 mL of the first elution test solution of the Japanese Pharmacopoeia containing 4% of polyoxyethylene (10) octylphenyl ether as a test solution, preferably, a test solution obtained by mixing about 3 g of polyoxyethylene (10) octylphenyl ether with 75 mL of the first elution test solution. It has been found that an impermeable film is formed by the ionic interaction between the basic substance and the anionic surfactant, thereby causing poor disintegration. It has been found that a basic substance can suppress the formation of the impermeable film. It has been found that a basic substance can suppress the formation of the impermeable film. was found.

[0041] In a preparation containing a poorly soluble basic drug such as a compound represented by the formula (I) and a surfactant, by adding a basic substance, good elution property of the preparation can be obtained. Here, "good elution property" means that when an elution test (elution test 1) is carried out at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test using 900 mL of purified water containing 33 mL of formic acid and 2% of polyoxyethylene (10) octylphenyl ether as a test solution, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. Alternatively, it means that when an elution test is carried out using 900 mL of the first elution test solution of the Japanese Pharmacopoeia containing 4% of polyoxyethylene (10) octylphenyl ether as a test solution, preferably, a test solution obtained by mixing about 3 g of polyoxyethylene (10) octylphenyl ether with 75 mL of the first elution test solution, at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. By adding a basic substance to a preparation containing a poorly soluble basic drug such as a compound represented by the formula (I) and a surfactant, good elution property of the preparation can be obtained. Here, "good elution property" means that when an elution test (elution test 1) is carried out at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test using 900 mL of purified water containing 33 mL of formic acid and 2% of polyoxyethylene (10) octylphenyl ether as a test solution, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. Alternatively, it means that when an elution test is carried out using 900 mL of the first elution test solution of the Japanese Pharmacopoeia containing 4% of polyoxyethylene (10) octylphenyl ether as a test solution, preferably, a test solution obtained by mixing about 3 g of polyoxyethylene (10) octylphenyl ether with 75 mL of the first elution test solution, at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. Here, "good elution property" means that when an elution test (elution test 1) is carried out at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test using 900 mL of purified water containing 33 mL of formic acid and 2% of polyoxyethylene (10) octylphenyl ether as a test solution, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. 0) octylphenyl ether as a test solution, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. When an elution test (elution test 1) is carried out at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. 5% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. means that when an elution test is carried out using 900 mL of the first elution test solution of the Japanese Pharmacopoeia containing 4% of polyoxyethylene (10) octylphenyl ether as a test solution, preferably, a test solution obtained by mixing about 3 g of polyoxyethylene (10) octylphenyl ether with 75 mL of the first elution test solution, at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. 4% of polyoxyethylene (10) octylphenyl ether as a test solution, preferably, a test solution obtained by mixing about 3 g of polyoxyethylene (10) octylphenyl ether with 75 mL of the first elution test solution, at 100 revolutions per minute by the paddle method of the Japanese Pharmacopoeia elution test, an elution property of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes. When an elution test (Elution Test 2) using a paddle method with a rotation speed of 100 rpm is performed it means that an elution rate of 45% or more, preferably 60% or more, more preferably 75% or more is obtained after 30 minutes Preferably, in either Elution Test 1 or Elution Test 2, the above elution rate is obtained, and more preferably, when Elution Test 2 is performed, after 30 minutes an elution rate of 45% or more, preferably 60% or more, more preferably 75% or more is obtained Particularly preferably, when Elution Test 2 is performed, it means that 70% or more elutes within 75 minutes . Incidentally, Japanese Pharmacopoeia Elution Test Solution No. 1 is a solution prepared by dissolving 2.0 g of sodium chloride in 7.0 ml of hydrochloric acid and water to make 1000 mL, which is colorless and clear and has a pH of about 1.2 . "Improvement of elution rate" means bringing the elution rate of a drug below the above elution rate range to within the above elution rate range By improving the elution rate, the pharmaceutical active ingredient can be efficiently absorbed and the drug efficacy can be exerted promptly . Incidentally, in foreign countries other than Japan such as the United States, Europe, and Israel Elution Test 2 is set as the elution standard test method for the already approved capsule formulations of the pharmaceutical active ingredient . The elution rate by Elution 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 within 75% after 30 minutes and 75% or more after 70 minutes in the EU region is desirable .

[0042] Also, according to the present invention, by adding a basic substance to a formulation containing a poorly soluble basic drug such as a compound represented by the formula (I) and a surfactant good disintegrability can be obtained. Here, " good disintegrability" means that the disintegration time of the formulation is usually such that Japanese Pharmacopoeia Elution Test Solution No. 1 is used as the test solution When the disintegration test (disintegration test 1) is carried out in the Japanese Pharmacopoeia disintegration test using it, it means that it disintegrates within 30 minutes, preferably within 15 minutes. Alternatively, when the disintegration test (disintegration test 2) is carried out in the Japanese Pharmacopoeia disintegration test using water as the test solution, it means that it disintegrates after 10 minutes, preferably within 5 minutes. Preferably, it means that the above-mentioned disintegration property can be obtained by either disintegration test 1 or disintegration test 2, and more preferably, when disintegration test 2 is carried out, it means that it disintegrates within 3 minutes. "Improvement of disintegration property" means making the disintegration property of a preparation below the above-mentioned disintegration property range fall within the above-mentioned disintegration property range. Here, "disintegrates" means a state where "residue of the sample is recognized at the 30-minute time point but the amount of soft substance or muddy substance is small" or "no residue of the sample is recognized at the 30-minute time point", and preferably it is a state where no residue of the sample is recognized at the 30-minute time point.

Examples

[0043] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. In Examples 1 to 20, sodium lauryl sulfate was NIKK OL SLS (Nikkan Chemicals) was used.

[0044] Reference Example 1: Formation of Impermeable Coating (Manufacture of Preparation) Tablets were prepared according to the amounts of each component described in Table 1. The hydrochloride salt of the compound of formula (I) (hereinafter, compound A), sodium lauryl sulfate, and magnesium stearate were manually mixed using a polyethylene container. The blended powder was compressed (50 0 kgf) with a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) to produce tablets (φ = 9.0 mm) containing 150 mg of compound A in free form. 0 kgf) to produce tablets (φ = 9.0 mm) containing 150 mg of compound A in free form. was prepared.

Table 1

[0045] Tablets were prepared according to the amounts of each component of the tablet formulations described in Table 2. X contained in the final components in the formulation was each substance shown in Table 3. The granule formulation components were mixed, and this premixed powder was put into a stainless steel beaker, and purified water was added while stirring with a metal spatula for wet granulation . . . .Subsequently, it was dried at room temperature using a vacuum dryer (VOS-301SD, Tokyo Rika Kikai Co., Ltd.). Subsequently, sieving was performed with a sieve having a size diameter of 850 μm to form granules, and the granules were further mixed with the powder component to obtain a formulated powder. Tabletting was carried out on each formulated powder using a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) at a pressure of 1000 kgf to produce tablets (15.9×8.4 mm) containing 300 mg of Compound A in terms of the free form. Note that 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 tablets was examined by comparison with Comparative Example 1 and Examples 1-7. Tabletting was carried out on each formulated powder using a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) at a pressure of 1000 kgf to produce tablets (15.9×8.4 mm) containing 300 mg of Compound A in terms of the free form. Note that 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 tablets was examined by comparison with Comparative Example 1 and Examples 1-7. Tabletting was carried out on each formulated powder using a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) at a pressure of 1000 kgf to produce tablets (15.9×8.4 mm) containing 300 mg of Compound A in terms of the free form. Note that 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 tablets was examined by comparison with Comparative Example 1 and Examples 1-7. [Table 2] [Table 3]

[0046] For Comparative Example 1 and Examples 1-7, water and the first dissolution test solution of the Japanese Pharmacopoeia were used as the test solutions, and the disintegration test was carried out 3 times for each comparative example / example using the Japanese Pharmacopoeia disintegration test. The disintegration behavior of Examples 1-7 is shown in Table 4. Note that this test is a disintegration test under acidic conditions (disintegration test 1) where disintegration is more difficult to proceed compared to water (disintegration test 2). In this specification, the following symbols used in the table indicate the following meanings. For Comparative Example 1 and Examples 1-7, water and the first dissolution test solution of the Japanese Pharmacopoeia were used as the test solutions, and the disintegration test was carried out 3 times for each comparative example / example using the Japanese Pharmacopoeia disintegration test. The disintegration behavior of Examples 1-7 is shown in Table 4. Note that this test is a disintegration test under acidic conditions (disintegration test 1) where disintegration is more difficult to proceed compared to water (disintegration test 2). In this specification, the following symbols used in the table indicate the following meanings. In this specification, the following symbols used in the table indicate the following meanings. -: Residue of the sample is observed at the 30-minute time point. +: Residue of the sample is observed at the 30-minute time point, but there is a small amount of a soft substance or a muddy substance. There is a small amount of a soft substance or a muddy substance. ++: No residue of the sample is observed at the 30-minute time point. [Table 4]

[0047] (Formulation Evaluation and Results) As shown in Table 4, in Examples 1-7, the tablets prepared using a basic substance as X showed disintegration properties superior to those of Comparative Example 1.

[0048] Examples 8-10: Examination of manufacturing methods for dissolution properties (Manufacture of preparations) Tablets were prepared by changing the manufacturing method according to the amounts of each component in the tablet formulation described in Table 5. In Example 8, the formulation components were mixed to obtain a blended powder. In Example 9, the granule formulation components were mixed and tabletted at a pressure of 400 kgf using a Φ16 mm punch in a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.). The obtained formed product was sized using a sieve with a size diameter of 850 μm to obtain granules, which were further mixed with the final powder components to obtain a blended powder. In Example 10, the formulation components described in Table 5 were mixed, and this premixed powder was placed in a stainless steel beaker. Purified water was added with stirring using a metal spatula for wet granulation, and then dried at room temperature using a vacuum dryer (VOS-301SD, Tokyo Rika Kikai Co., Ltd.). Subsequently, the product was sized using a sieve with a size diameter of 850 μm to obtain granules, which were further mixed with the final powder components to obtain a blended powder . The blended powders of Examples 8-10 were tabletted at a pressure of 500 kgf using a static pressure tableting machine (P-16, Riken Seiki Co., Ltd.) to produce tablets containing 150 mg of Compound A in free form. The dissolution properties of the tablets prepared by the manufacturing method when a basic substance was added to the formulation components were examined. (Formulation evaluation and results) As shown in Figure 3, in Examples 8-10, regardless of the manufacturing method, that is, regardless of the presence or absence of granulation, the tablets prepared using a basic substance in the formulation components showed dissolution properties superior to those of Comparative Example 1. These results meet the dissolution test standards of various countries for the approved capsule formulations.

Table 5

[0049] Examples 11 - 14: Examination of the ratio of excipients and basic substances with respect to dissolution (Manufacture of the preparation) According to the amounts of each component described 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 with a sieve having a size diameter of 850 μm to obtain granules, and the blend powder was obtained by further mixing with the fine powder component. Each blend powder was tabletted by pressing (1000 kgf) using a static pressure tabletting machine (P - 16, Riken Seiki Co., Ltd.) to produce tablets (15.9×8.3 mm) containing 300 mg of Compound A in terms of the free form. The dissolution of the tablets was examined according to the ratio of the excipient to the granule formulation components and the ratio of the disintegrant and the basic substance in the fine powder component.

Table 6

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

[0051] Examples 15 - 18: Examination of the combination of excipients and fine powder components with respect to dissolution (Manufacture of the preparation) ​​​​​​​​​​Weighed the granule formulation components according to the amounts of each component described in Table 7, mixed them using a granulator (VG-05, Powrex Corporation), added purified water, granulated them, and dried them in a fluidized bed dryer (FL-LABO, inlet air temperature 60°C) until the loss on drying was 2% or less. The obtained dried powder was granulated using a sizing machine with a screen diameter of 1.4 mm, and the compounded powder was obtained by further mixing with the fine powder components. Each compounded powder was converted into a free form using a static pressure tableting machine under the same conditions as in Examples 8-10 to produce tablets containing 150 mg of Compound A, and the dissolution property was examined. For Examples 15-18, the disintegration test (Disintegration Test 1) was carried out according to the Japanese Pharmacopoeia disintegration test using the first solution of the Japanese Pharmacopoeia dissolution test solution as the test solution. For Examples 15-18, no residue of the sample was observed at the 30-minute time point for all tablets. This test is a disintegration test (Disintegration Test 1) under acidic conditions where disintegration is more difficult compared to water. For Examples 15-18, the dissolution test (Dissolution Test 2) was carried out at 100 rotations per minute using 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test solution containing 4% polyoxyethylene (10) octylphenyl ether as the test solution according to the paddle method of the Japanese Pharmacopoeia dissolution test. The dissolution profiles of Examples 15-18 are shown in Figure 5. As shown in Figure 5, due to the addition of magnesium aluminometasilicate, the dissolution profile of Compound A from the tablets showed good dissolution properties regardless of the combination of excipients and disintegrants. This result conforms to the dissolution test specifications of approved capsule formulations in various countries. Examples 19, 20: Examination of tablet weight (Manufacture of formulation) [Table 7] (Formulation evaluation and results) For Examples 15-18, the first solution of the Japanese Pharmacopoeia dissolution test solution was used as the test solution, and the disintegration test (Disintegration Test 1) was carried out according to the Japanese Pharmacopoeia disintegration test. For Examples 15-18, no residue of the sample was observed at the 30-minute time point for all tablets. This test is a disintegration test (Disintegration Test 1) under acidic conditions where disintegration is more difficult compared to water. For Examples 15-18, 900 mL of the first solution of the Japanese Pharmacopoeia dissolution test solution containing 4% polyoxyethylene (10) octylphenyl ether was used as the test solution, and the dissolution test (Dissolution Test 2) was carried out at 100 rotations per minute according to the paddle method of the Japanese Pharmacopoeia dissolution test. The dissolution profiles of Examples 15-18 are shown in Figure 5. As shown in Figure 5, due to the addition of magnesium aluminometasilicate, the dissolution profile of Compound A from the tablets showed good dissolution properties regardless of the combination of excipients and disintegrants. This result conforms to the dissolution test specifications of approved capsule formulations in various countries.

[0052] Examples 19, 20: Examination of tablet weight (Manufacture of formulation) According to the respective component amounts described in Table 8, the granule formulation components were weighed, and using a fluidized bed granulation dryer (FG -602, Freund Industry Co., Ltd.), they were mixed, and purified water was added by spraying and granulated , and dried at an air supply temperature of 60°C using the same machine until the loss on drying was 2% or less. The obtained dried powder was sized using a sizing machine with a screen of 1.4 mm in diameter, and the obtained granules and post-powder components were further mixed to obtain a formulated powder. The formulated powder was compressed (10 kN) using a rotary tablet press (AQUARIUS-C, Kikusui Seisakusho Ltd.) to produce tablets (17 .3×8.0 mm) containing 300 mg of Compound A in free form. By comparing with Examples 15-18, the relationship between tablet weight and disintegration was examined.

Table 8

Claims

1. Formula (I): 【Chemistry 1】 or a salt thereof, a surfactant and a basic substance. The present invention relates to a method for producing a pharmaceutical preparation, comprising the steps of: and then compression molding the mixture, the basic material being metasilica. Magnesium aluminate, L-arginine, meglumine, magnesium oxide, magnesium hydroxide One or more selected from the group consisting of magnesium, magnesium carbonate, and sodium bicarbonate A manufacturing method for the substance.

2. The manufacturing method described in claim 1, wherein the surfactant is an anionic surfactant.

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

4. A method for producing a product described in any one of claims 1 to 3, further comprising a disintegrant.

5. A method for preparing a composition comprising the steps of: (I) a compound represented by formula (I) or a salt thereof and a surfactant, the weight ratio of which is 100:3 to 100:

50. The method according to claim 1 , wherein the molecular weight of the polymer is 100 or more.

6. The manufacturing method described in claim 4, containing 5% by weight or more of the disintegrant.

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

8. The basic substance is selected from the group consisting of inorganic basic substances and organic basic substances. The method of any one of claims 1 to 7, wherein the one or more substances.

9. The method according to any one of claims 1 to 8, wherein the basic substance is contained in an amount of 5% by weight or more. Law.

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

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