Syrup

Abstract

The present invention pertains to a syrup preparation containing alectinib or a salt thereof, and provides a syrup preparation containing alectinib or a salt thereof, which is a hardly soluble drug, having improved flowability and / or dosing properties. The syrup preparation of the present invention has an equivalent or superior blood concentration profile compared to a capsule preparation that contains the same amount of alectinib or a salt thereof, or is biologically equivalent thereto, or the syrup preparation has an enhanced oral bioavailability compared to a capsule preparation containing the same amount of alectinib or a salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a syrup containing a poorly soluble agent, particularly alectinib or a salt thereof. [Background technology]

[0002] Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor family (Non-Patent Document 1, Non-Patent Document 2), and it has been reported that genetic abnormalities in ALK lead to 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, and cognitive impairment (Non-Patent Document 2). Providing ALK inhibitors offers effective treatments and preventive agents for these diseases. Alectinib is a tetracyclic compound having a morpholine skeleton represented by the following formula (I) (compound name: 9-ethyl-6,6-dimethyl-8-(4-morpholine-4-ylpiperidine-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile) [ka] Known as (Patent Documents 2, 3, 4, and 5), alectinib hydrochloride is a second-generation ALK (Anaplastic Lymphoma Kinase) inhibitor and is used worldwide as a treatment for cancers with ALK abnormalities. ALK abnormalities are widely observed in various pediatric malignant solid tumors, and in the field of pediatric oncology, ALK inhibitors are considered an important target in the development of therapeutic drugs for cancers with ALK abnormalities. The efficacy of alectinib is being evaluated for rare cancers, including pediatric cancers with ALK abnormalities (Non-Patent Literature). However, since the formulation used in this study is in capsule form, it is difficult for children to swallow. For example, for children under 2 years of age, a method of administering the capsule in a solution suspended in water via tube was used (Non-Patent Literature 3). Alectinib is a poorly soluble basic drug, and in its formulation, it has been reported that a composition containing a solubilizer is used (Patent Document 3), that granules containing alectinib or a salt thereof are formed and these granules are used in combination with a disintegrant to create a capsule with good dissolution properties (Patent Document 5), and that a formulation with good disintegration and dissolution properties is created by using alectinib or a salt thereof and a basic substance in combination with a surfactant (Patent Document 6). [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] JP2009-100783(A) [Patent Document 2] Japanese Patent No. 4588121 [Patent Document 3] Japanese Patent No. 4918630 [Patent Document 4] Japanese Patent No. 5006987 [Patent Document 5] Japanese Patent No. 5859712 [Patent Document 6] WO2020 / 004630 [Non-patent literature]

[0004] [Non-Patent Document 1] Nature, Vol. 448, pp. 561-566, 2007. [Non-Patent Document 2] Neuropsychopharmacology, Vol. 33, pp. 685-700, 2008. [Non-Patent Document 3] JMA-IIA00364, Investigator-initiated clinical trial of alectinib for rare cancers with ALK gene abnormalities (https: / / dbcentre3.jmacct.med.or.jp / JMACTR / App / JMACTRE02_04 / JMACTRE02_04.aspx?kbn=3&seqno=8259) [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] In the circumstances described above, there is a need for syrup formulations of poorly soluble drugs such as alectinib hydrochloride that have good fluidity and / or ease of administration. Furthermore, there is a need for syrup formulations containing alectinib or its salts that have a desirable blood concentration profile, or that are bioequivalent to capsule formulations containing the same amount of alectinib or its salt, or have enhanced oral bioavailability compared to capsule formulations containing the same amount of alectinib or its salt. [Means for solving the problem]

[0006] The inventors have discovered a syrup formulation with good fluidity and / or ease of administration by further coexisting a gelling inhibitor with the poorly soluble drug and / or surfactant in a composition containing a poorly soluble drug such as alectinib hydrochloride and a surfactant. Furthermore, the syrup formulation of the present invention includes a syrup formulation that has an equivalent or better blood concentration profile to, or is bioequivalent to, a capsule formulation containing the same amount of alectinib or its salt, or has enhanced oral bioavailability than a capsule formulation containing the same amount of alectinib or its salt. In other words, the present invention includes the following embodiments.

[0007] One aspect of the present invention is as follows: (A-1) A syrup containing alectinib or a salt thereof, wherein the syrup has a blood concentration profile equivalent to or better than that of a capsule containing the same amount of alectinib or a salt thereof. (A-2) A syrup containing alectinib or a salt thereof, wherein the syrup has an AUC and C content equal to or greater than that of a capsule containing the same amount of alectinib or a salt thereof as the syrup. max A syrup containing the following properties. (A-3) A syrup containing alectinib or a salt thereof, wherein the syrup has biological equivalence to a capsule containing the same amount of alectinib or a salt thereof as the syrup. (A-4) The syrup according to any one of (A-1) to (A-3), wherein the syrup further contains a gelation inhibitor. (A-5) The syrup according to (A-4), wherein the weight ratio of the alectinib or a salt thereof to the gelation inhibitor is 100:30 to 100:90 in terms of the free form. (A-6) The syrup according to any one of (A-1) to (A-5), wherein the syrup further contains a surfactant and a gelation inhibitor. (A-7) The syrup according to (A-6), wherein the gelation inhibitor is a salt. (A-8) The syrup according to (A-7), wherein the salts are water-soluble salts. (A-9) The syrup according to (A-7) or (A-8), wherein the salts are inorganic salts or organic salts. (A-10) The syrup according to (A-9), wherein the inorganic salt is selected from the group consisting of chloride salts, sulfate salts, hydroxide salts, carbonate salts, and bicarbonate salts. (A-11) The syrup according to (A-9), wherein the organic salt is selected from the group consisting of tartrate salts, acetate salts, citrate salts, amino acid salts, alginate salts, and sorbate salts. (A-12) The syrup according to any one of (A-7) to (A-10), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate. (A-13) The syrup according to any one of (A-6) to (A-12), wherein the surfactant is an anionic surfactant. (A-14) The syrup according to (A-13), wherein the anionic surfactant is sodium lauryl sulfate. (A-15) A syrup agent according to any one of (A-6) to (A-14), further containing a pH adjuster. (A-16) The syrup agent according to (A-15), wherein the pH adjuster is tartaric acid. (A-17) A syrup agent according to any one of (A-6) to (A-16), further containing one or more substances selected from a disintegrant, an excipient, and a binder. (A-18) The syrup agent according to any one of (A-6) to (A-17), wherein the weight ratio of the afatinib or its salt to the gelation inhibitor is 100:30 to 100:90 in terms of the free form. (A-19) The syrup agent according to any one of (A-6) to (A-18), wherein the weight ratio of the afatinib or its salt, the surfactant, and the gelation inhibitor is 100:3:30 to 100:50:90 in terms of the free form. (A-20) A syrup agent according to any one of (A-6) to (A-19), further containing one or more substances selected from a preservative, a thickener, a sweetener, and a flavoring agent. (A-21) The syrup agent according to (A-20), wherein the thickener is selected from the group consisting of xanthan gum, hydroxyethyl cellulose, and sodium carboxymethyl cellulose, the sweetener is selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium, and the flavoring agent is selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, black cherry flavor, and yogurt flavor. (A-22) The syrup agent according to any one of (A-1) to (A-21), wherein the syrup agent is a dry syrup agent.

[0008] Another aspect of the present invention is as follows. (B-1) A syrup agent containing afatinib or its salt, a surfactant, and a gelation inhibitor. (B-2) The syrup agent according to (B-1), wherein the gelation inhibitor is a salt. (B-3) The syrup preparation according to (B-2), wherein the salts are water-soluble salts. (B-4) The syrup preparation according to (B-2) or (B-3), wherein the salts are inorganic salts or organic salts. (B-5) The syrup preparation according to (B-4), wherein the inorganic salt is selected from the group consisting of chloride salts, sulfates, hydroxide salts, carbonates, and bicarbonates. (B-6) The syrup preparation according to (B-4), wherein the organic salt is selected from the group consisting of tartrate, acetate, citrate, amino acid salt, alginate, and sorbate. (B-7) The syrup preparation according to any one of (B-2) to (B-5), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate. (B-8) The syrup according to any one of (B-1) to (B-7), wherein the surfactant is an anionic surfactant. (B-9) The syrup preparation according to (B-8), wherein the anionic surfactant is sodium lauryl sulfate. (B-10) A syrup preparation according to any of (B-1) to (B-9), further containing a pH adjuster. (B-11) The syrup preparation according to (B-10), wherein the pH adjusting agent is tartaric acid. (B-12) A syrup preparation according to any one of (B-1) to (B-11), further containing one or more substances selected from disintegrants, excipients, and binders. (B-13) The syrup preparation according to any one of (B-1) to (B-12), wherein the weight ratio of alectinib or a salt thereof to the gelation inhibitory substance is 100:30 to 100:90 on a free form basis. (B-14) The syrup preparation according to any one of (B-1) to (B-13), wherein the weight ratio of alectinib or a salt thereof, the surfactant, and the gelation inhibitor is 100:3:30 to 100:50:90 on a free form basis. (B-15) A syrup according to any of (B-1) to (B-14), further containing one or more substances selected from preservatives, thickeners, sweeteners, and flavorings. (B-16) The syrup according to (B-15), wherein the thickening agent is selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose; the sweetener is selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and the flavoring is selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor. (B-17) The syrup preparation according to any one of (B-1) to (B-16), wherein the syrup preparation is a dry syrup preparation.

[0009] Yet another aspect of the present invention is as follows: (C-1) A syrup formulation with enhanced oral bioavailability, comprising alectinib or a salt thereof and a gelling inhibitor. (C-2) The syrup preparation according to (C-1), wherein the oral bioavailability is enhanced compared to a capsule preparation containing the same amount of alectinib or a salt thereof as the syrup preparation. (C-3) The syrup agent according to (C-1), wherein the syrup agent further comprises a surfactant. (C-4) The syrup according to any one of (C-1) to (C-5), wherein the syrup further contains a surfactant and a gelling inhibitor. (C-5) The syrup preparation according to (C-4), wherein the gelation-inhibiting substance is a salt. (C-6) The syrup preparation according to (C-5), wherein the salts are water-soluble salts. (C-7) The syrup preparation according to (C-5) or (C-6), wherein the salts are inorganic salts or organic salts. (C-8) The syrup preparation according to (C-7), wherein the inorganic salt is selected from the group consisting of chloride salts, sulfates, hydroxide salts, carbonates, and bicarbonates. (C-9) The syrup preparation according to (C-7), wherein the organic salt is selected from the group consisting of tartrate, acetate, citrate, amino acid salt, alginate, and sorbate. (C-10) The syrup preparation according to any one of (C-5) to (C-8), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate. (C-11) The syrup according to any one of (C-4) to (C-10), wherein the surfactant is an anionic surfactant. (C-12) The syrup preparation according to (C-11), wherein the anionic surfactant is sodium lauryl sulfate. (C-13) A syrup preparation according to any of (C-4) to (C-12), further containing a pH adjuster. (C-14) The syrup preparation according to (C-13), wherein the pH adjusting agent is tartaric acid. (C-15) A syrup preparation according to any one of (C-4) to (C-14), further containing one or more substances selected from disintegrants, excipients, and binders. (C-16) The syrup preparation according to any one of (C-4) to (C-15), wherein the weight ratio of alectinib or a salt thereof to the gelation inhibitory substance is 100:30 to 100:90 on a free form basis. (C-17) The syrup preparation according to any one of (C-4) to (C-16), wherein the weight ratio of alectinib or a salt thereof, the surfactant, and the gelation inhibitor is 100:3:30 to 100:50:90 on a free form basis. (C-18) A syrup according to any one of (C-4) to (C-17), further containing one or more substances selected from preservatives, thickeners, sweeteners, and flavorings. (C-19) The syrup according to (C-18), wherein the thickening agent is selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose; the sweetener is selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and the flavoring is selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor. Furthermore, the present invention also includes the following embodiments. (1) A syrup containing alectinib or a salt thereof, a surfactant, and a gelling inhibitor. (2) The syrup preparation according to (1), wherein the gelling inhibitor is a salt. (3) The syrup preparation according to (2), wherein the salts are water-soluble salts. (4) The syrup preparation according to (2) or (3), wherein the salts are inorganic salts or organic salts. (4a1) The syrup according to (2) or (3), wherein the salts are inorganic or organic salts of metals. (5) The syrup preparation according to (4), wherein the inorganic salt is selected from the group consisting of chloride salts, sulfates, hydroxide salts, carbonates, and bicarbonates. (5a) The syrup according to (4a1), wherein the inorganic salt of the metal is a halide salt, carbonate or bicarbonate, sulfate or hydroxide salt of the metal. (5a1) The syrup preparation according to (2) or (3), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, dipotassium phosphate, sodium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, ammonium carbonate, sodium tartrate, sodium acetate, sodium citrate, sodium glutamate, magnesium aspartate, sodium alginate, and potassium sorbate. (6) The syrup preparation according to (4), wherein the organic salt is selected from the group consisting of tartrate, acetate, citrate, amino acid salt, alginate, and sorbate. (7) The syrup preparation according to any one of (2) to (5), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate. (8) The syrup according to any one of (1) to (7), wherein the surfactant is an anionic surfactant. (9) The syrup preparation according to (8), wherein the anionic surfactant is sodium lauryl sulfate. (10) A syrup preparation according to any one of (1) to (9), further containing a pH adjuster. (10a1) The syrup preparation according to (10), wherein the pH adjusting agent is selected from the group consisting of tartaric acid, citric acid, and maleic acid. (11) The syrup preparation according to (10), wherein the pH adjusting agent is tartaric acid. (12) The syrup preparation according to any one of (1) to (11), further comprising one or more substances selected from disintegrants, excipients, and binders. (12a1) The syrup preparation according to (12), wherein the disintegrant is selected from the group consisting of carmellose calcium, crospovidone, sodium starch glycolate, and croscarmellose sodium, the excipient is selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, and the binder is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder. (12a2) The syrup according to (12), comprising one or more substances selected from crospovidone as the disintegrant, lactose monohydrate as the excipient, and hydroxypropyl cellulose as the binder. (13) The syrup preparation according to any one of (1) to (8), wherein the weight ratio of alectinib or a salt thereof to the gelation inhibitor is 100:10 to 100:70 on a free form basis. (13a1) The syrup according to any one of (1) to (13), wherein the weight ratio of alectinib or a salt thereof to the surfactant and the gelling inhibitor is 100:3:30 to 100:50:90 on a free form basis. (14) The syrup according to any one of (1) to (9), further containing one or more substances selected from preservatives, thickeners, sweeteners and flavorings. (15) The syrup according to (14), wherein the thickening agent is selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose; the sweetener is selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and the flavoring is selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor. (16) The syrup preparation according to any one of (1) to (15), wherein the syrup preparation is a dry syrup preparation. (17) A dry syrup containing alectinib or a salt thereof, sodium lauryl sulfate and calcium chloride. (18) A dry syrup containing alectinib or a salt thereof, sodium lauryl sulfate, calcium chloride and tartaric acid. (19) A dry syrup containing alectinib or a salt thereof, sodium lauryl sulfate, calcium chloride, tartaric acid, and crospovidone. (20) A dry syrup containing alectinib or a salt thereof, sodium lauryl sulfate, calcium chloride, tartaric acid, crospovidone, sodium benzoate, sucralose, lactose monohydrate, and hydroxypropylcellulose. (21) A dry syrup containing alectinib or a salt thereof, sodium lauryl sulfate, calcium chloride, tartaric acid, crospovidone, sodium benzoate, sucralose, lactose monohydrate, hydroxypropylcellulose, xanthan gum, and strawberry flavor.

[0010] Another aspect of the present invention also includes a method for suppressing a decrease in the fluidity of a pharmaceutical composition containing alectinib or a salt thereof and a surfactant. (1b) A method for suppressing a decrease in the fluidity of a pharmaceutical composition comprising the coexistence of a gelling inhibitor with a pharmaceutical composition containing alectinib or a salt thereof and a surfactant. (2b) The method according to (1b), wherein the gelation-inhibiting substance is a salt. (3b) The method according to (2b), wherein the salts are water-soluble salts. (4b) The method according to (2b) or (3b), wherein the salts are inorganic salts or organic salts. (4b1) The method according to (2b) or (3b), wherein the salts are inorganic or organic salts of a metal. (4b2) The method according to (2b) or (3b), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, dipotassium phosphate, sodium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, ammonium carbonate, sodium tartrate, sodium acetate, sodium citrate, sodium glutamate, magnesium aspartate, sodium alginate, and potassium sorbate. (5b) The method according to (4b), wherein the inorganic salt is selected from the group consisting of chloride salts, sulfates, hydroxide salts, carbonates, and bicarbonates. (5b1) The method according to (4b1), wherein the inorganic salt of the metal is selected from the group consisting of chloride salts, sulfates, hydroxide salts, carbonates, and bicarbonates. (6b) The method according to (4b), (4b'), wherein the organic salt is selected from the group consisting of tartrates, acetates, citrates, amino acid salts, alginates, and sorbates. (7b) The method according to any one of (2b) to (5b), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate. (8b) The method according to any one of (1b) to (7b), wherein the surfactant is an anionic surfactant. (9b) The method according to (8b), wherein the anionic surfactant is sodium lauryl sulfate. (10b) The method according to any one of (1b) to (9b), further comprising a pH adjuster. (10b1) The method according to (10b), wherein the pH adjusting agent is selected from the group consisting of tartaric acid, citric acid, and maleic acid. (11b) The method according to (10b), wherein the pH adjusting agent is tartaric acid. (12b) The method according to any one of (1b) to (11b), wherein the pharmaceutical composition further contains one or more substances selected from disintegrants, excipients and binders. (12b1) The method according to (12b), wherein the disintegrant is selected from the group consisting of carmellose calcium, crospovidone, sodium starch glycolate, and croscarmellose sodium, the excipient is selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, and the binder is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder. (12b2) The method according to (12b), comprising one or more substances selected from crospovidone as the disintegrant, lactose monohydrate as the excipient, and hydroxypropyl cellulose as the binder. (13b) The method according to any one of (1b) to (8b), wherein the weight ratio of alectinib or a salt thereof to the gelation inhibitor is 100:10 to 100:70 on a free form basis. (13b1) The syrup according to any one of (1b) to (13b), wherein the weight ratio of alectinib or a salt thereof to the surfactant and the gelling inhibitor is 100:3:30 to 100:50:90 on a free form basis. (14b) The method according to any one of (1b) to (9b), wherein the pharmaceutical composition further contains one or more substances selected from preservatives, thickeners, sweeteners and fragrances. (15b) The method according to (14b), wherein the thickener is selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose; the sweetener is selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and the flavoring is selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor. (16b1) The method according to any one of (1b) to (15b), wherein the pharmaceutical composition is a syrup. (16b2) The method according to any one of (1b) to (15b), wherein the pharmaceutical composition is a dry syrup.

[0011] Another aspect of the present invention also includes a method for producing a syrup containing alectinib or a salt thereof. (1c) A method for producing a syrup containing a pharmaceutical composition comprising alectinib or a salt thereof and a surfactant, wherein a gelling inhibitor is present in the pharmaceutical composition. (1c-1) A method for producing a syrup containing a pharmaceutical composition comprising the presence of a gelling inhibitor in the pharmaceutical composition containing alectinib or a salt thereof, wherein the syrup has a blood concentration profile equivalent to or greater than that of a capsule containing the same amount of alectinib or a salt thereof as the syrup. (1c-2) A method for producing a syrup containing a pharmaceutical composition comprising the presence of a gelling inhibitor in the pharmaceutical composition containing alectinib or a salt thereof, wherein the syrup has an AUC equal to or greater than that of a capsule containing the same amount of alectinib or a salt thereof. (1c-3) A method for producing a syrup containing a pharmaceutical composition comprising the presence of a gelling inhibitor in the pharmaceutical composition containing alectinib or a salt thereof, wherein the syrup is bioequivalent to a capsule containing the same amount of alectinib or a salt thereof. (1c-4) The method according to any one of (1c-1) to (1c-3), wherein the pharmaceutical composition further contains a surfactant. (2c) The method according to any one of (1c) to (1c-4), wherein the gelation-inhibiting substance is a salt. (3c) The method according to (2c), wherein the salts are water-soluble salts. (4c) The method according to (2c) or (3c), wherein the salts are inorganic salts or organic salts. (4c1) The method according to (2c) or (3c), wherein the salts are inorganic or organic salts of a metal. (4c2) The method according to (2c) or (3c), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, dipotassium phosphate, sodium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, ammonium carbonate, sodium tartrate, sodium acetate, sodium citrate, sodium glutamate, magnesium aspartate, sodium alginate, and potassium sorbate. (5c) The method according to (4c), wherein the inorganic salt is selected from the group consisting of chloride salts, sulfates, hydroxide salts, carbonates, and bicarbonates. (5c1) The method according to (4c1), wherein the inorganic salt of the metal is selected from the group consisting of chloride salts, sulfates, hydroxide salts, carbonates, and bicarbonates. (6c) The method according to (4c), wherein the organic salt is selected from the group consisting of tartrates, acetates, citrates, amino acid salts, alginates, and sorbates. (7c) The method according to any one of (2c) to (5c), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate. (8c) The method according to any one of (1c) to (7c), wherein the surfactant is an anionic surfactant. (9c) The method according to (8c), wherein the anionic surfactant is sodium lauryl sulfate. (10c) The method according to any one of (1c) to (9c), further comprising a pH adjuster. (10c1) The method according to (10c), wherein the pH adjusting agent is selected from the group consisting of tartaric acid, citric acid, and maleic acid. (11c) The method according to (10c), wherein the pH adjusting agent is tartaric acid. (12c) The method according to any one of (1c) to (11c), wherein the pharmaceutical composition further contains one or more substances selected from disintegrants, excipients and binders. (12c1) The method according to (12c), wherein the disintegrant is selected from the group consisting of carmellose calcium, crospovidone, sodium starch glycolate, and croscarmellose sodium, the excipient is selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, and the binder is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder. (12c2) The method according to (12c), comprising one or more substances selected from crospovidone as the disintegrant, lactose monohydrate as the excipient, and hydroxypropyl cellulose as the binder. (13c) The method according to any one of (1c) to (12c2), wherein the weight ratio of alectinib or a salt thereof to the gelation inhibitor is 100:10 to 100:70 on a free form basis. (13c1) The syrup preparation according to any one of (1c) to (13c), wherein the weight ratio of alectinib or a salt thereof, the surfactant, and the gelation inhibitor is 100:3:30 to 100:50:90 on a free form basis. (14c) The method according to any one of (1c) to (13c1), wherein the pharmaceutical composition further contains one or more substances selected from preservatives, thickeners, sweeteners and fragrances. (15c) The method according to (14c), wherein the thickener is selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose; the sweetener is selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and the flavoring is selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor. (16c) The method according to any one of (1c) to (15c), wherein the pharmaceutical composition is a dry syrup. (17c) The pharmaceutical composition is the method according to any one of (1c) to (16c) which does not cause a decrease in fluidity when suspended.

[0012] Furthermore, yet another aspect of the present invention includes a method for producing an oral bioavailability-enhanced syrup containing alectinib or a salt thereof. (1d) A method for producing an oral bioavailability enhanced syrup containing a pharmaceutical composition comprising alectinib or a salt thereof, wherein a gelation inhibitor is present in the pharmaceutical composition. (2d) The method according to (1d), wherein the gelation-inhibiting substance is a salt. (3d) The method according to (2d), wherein the salts are water-soluble salts. (4d) The method according to (2d) or (3d), wherein the salts are inorganic salts or organic salts. (4d1) The method according to (2d) or (3d), wherein the salts are inorganic or organic salts of a metal. (4d2) The method according to (2d) or (3d), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, dipotassium phosphate, sodium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, ammonium carbonate, sodium tartrate, sodium acetate, sodium citrate, sodium glutamate, magnesium aspartate, sodium alginate, and potassium sorbate. (5d) The method according to (4d), wherein the inorganic salt is selected from the group consisting of chloride salts, sulfate salts, hydroxide salts, carbonates, and bicarbonates. (5d1) The method according to (4d1), wherein the inorganic salt of the metal is selected from the group consisting of chloride salts, sulfates, hydroxide salts, carbonates, and bicarbonates. (6d) The method according to (4d), wherein the organic salt is selected from the group consisting of tartrates, acetates, citrates, amino acid salts, alginates, and sorbates. (7d) The method according to any one of (2d) to (5d), wherein the salts are selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate. (8d) The method according to any one of (1d) to (7d), wherein the pharmaceutical composition further comprises a surfactant. (9d) The method according to (8d), wherein the surfactant is an anionic surfactant. (10d) The method according to (9d), wherein the anionic surfactant is sodium lauryl sulfate. (11d) The method according to any one of (1d) to (10d), further comprising a pH adjuster. (11d1) The method according to (11d), wherein the pH adjusting agent is selected from the group consisting of tartaric acid, citric acid, and maleic acid. (12d) The method according to (11d) or (11d1), wherein the pH adjusting agent is tartaric acid. (13d) The method according to any one of (1d) to (12d), wherein the pharmaceutical composition further contains one or more substances selected from disintegrants, excipients and binders. (13d1) The method according to (12c), wherein the disintegrant is selected from the group consisting of carmellose calcium, crospovidone, sodium starch glycolate, and croscarmellose sodium, the excipient is selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, and the binder is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder. (13d2) The method according to (13d), comprising one or more substances selected from crospovidone as the disintegrant, lactose monohydrate as the excipient, and hydroxypropyl cellulose as the binder. (14d) The method according to any one of (1d) to (13d2), wherein the weight ratio of alectinib or a salt thereof to the gelation inhibitor is 100:10 to 100:70 on a free form basis. (14d1) The syrup according to any one of (1c) to (14d), wherein the weight ratio of alectinib or a salt thereof, the surfactant, and the gelling inhibitory substance is 100:3:30 to 100:50:90 on a free form basis. (15d) The method according to any one of (1d) to (14d1), wherein the pharmaceutical composition further contains one or more substances selected from preservatives, thickeners, sweeteners and fragrances. (16d) The method according to (14c), wherein the thickener is selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose; the sweetener is selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and the flavoring is selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor. (17d) The method according to any one of (1d) to (16d), wherein the pharmaceutical composition is a dry syrup. (18d) The pharmaceutical composition is the method according to any one of (1d) to (17d), wherein the fluidity does not decrease when suspended. [Effects of the Invention]

[0013] According to the present invention, it is possible to provide a syrup containing alectinib or a salt thereof as an active ingredient, which prevents a decrease in fluidity when preparing or taking the syrup, and has good fluidity and / or ease of administration. Furthermore, according to the present invention, it is possible to provide a syrup with a good blood concentration profile or that is bioequivalent. Alternatively, according to the present invention, it is possible to provide a syrup with enhanced oral bioavailability compared to a capsule containing the same amount of alectinib or a salt thereof. [Brief explanation of the drawing]

[0014] [Figure 1] This is a photograph showing the state of gel-like substance formation in Reference Example 1. [Figure 2] This graph shows the results of human taste evaluation. [Figure 3] These are photographs showing the appearance of the suspensions of Examples 30 and 31. [Figure 4] This graph shows the elution profiles for Examples 30 and 31. [Figure 5]This graph shows the plasma concentration profile of alectinib after a single administration of capsules and dry syrup formulations. [Modes for carrying out the invention]

[0015] The present invention will be described in detail below.

[0016] "Alectinib" is given by formula (I) [ka] The compound shown, in its chemical name, is 9-ethyl-6,6-dimethyl-8-(4-morpholine-4-ylpiperidine-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonil. The "salt" of alectinib is preferably a pharmaceutically acceptable salt, and "pharmaceutically acceptable salts" include, for example, sulfonates such as hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, methanesulfonate, and p-toluenesulfonate; carboxylates such as acetate, citrate, malate, tartrate, succinate, and salicylate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; and ammonium salts such as ammonium salt, alkylammonium salt, dialkylammonium salt, trialkylammonium salt, and tetraalkylammonium salt. Preferably, it is a hydrochloride salt, and most preferably, it is a monohydrochloride salt. Alectinib or a salt thereof can be produced by known methods (for example, the method described in Patent Document 2). Alectinib monohydrochloride may be amorphous or crystalline. In the case of crystals, crystals having peaks at diffraction angles (2θ) around 8.4°, 14.0°, 16.7°, 18.8°, and 23.3° in the powder X-ray diffraction pattern are preferred. The amorphous form of alectinib monohydrochloride can be produced by the method described in WO2016 / 021707, and the crystals having these peaks can be produced by the method described in WO2015 / 163447. Alectinib or a salt thereof is contained in an amount of 10 to 60% by weight, preferably 15 to 40% by weight, and more preferably 25 to 30% by weight, on a free basis, relative to the total amount of the composition or formulation of the present invention.

[0017] A "surfactant" is a substance that has both hydrophilic and hydrophobic groups in its molecule, and surfactants include ionic surfactants and nonionic surfactants. Ionic surfactants are those that, when dissolved in water, ionize to form ions (charged atoms or groups of atoms). Ionic surfactants are further classified into anionic surfactants, cationic surfactants, and amphoteric surfactants depending on the charge of the ions they produce. Anionic surfactants are preferred.

[0018] Anionic surfactants include alkyl sulfates (C12-18, Na, NH4, alkanolamines), POE alkyl ether sulfates (C12-18, Na, NH4, alkanolamines), POE alkylphenyl ether sulfates (C12-18, NH4, alkanolamines, Ca), POE benzyl (or styryl) phenyl (or phenylphenyl) ether sulfates (Na, NH4, alkanolamines), polyoxyethylene, polyoxypropylene block polymer sulfates (Na, NH4, alkanolamines) Sulfate-type surfactants such as amines; paraffin (alkane) sulfonates (C12-22, Na, Ca, alkanolamines), AOS (C14-16, Na, alkanolamines), dialkyl sulfosuccinates (C8-12, Na, Ca, Mg), alkylbenzene sulfonates (C12, Na, Ca, Mg, NH4, alkylamines, alkanols, amines, cyclohexylamines), mono or dialkyl (C3-6) naphthalene sulfonates (Na, NH4, alkanolamines, Ca, Mg), naphthalene sulfonates / formaldehyde saturates Sulfonate-type surfactants such as compound (Na,NH4), alkyl (C8~12) diphenyl ether disulfonate (Na,NH4), lignin sulfonate (Na,Ca), POE alkyl (C8~12) phenyl ether sulfonate (Na), POE alkyl (C12~18) ether sulfosuccinate half ester (Na); carboxylic acid-type surfactants such as fatty acid salts (C12~18,Na,K,NH4, alkanolamine), N-methyl fatty acid sarcosinate (C12~18,Na), resin salts (Na,K); POE alkyl (C12~1 8) Examples include ether phosphates (Na, alkanolamine), POE mono- or dialkyl (C8-12) phenyl ether phosphates (Na, alkanolamine), POE benzyl (or styryl) phenyl (or phenylphenyl) ether phosphates (Na, alkanolamine), polyoxyethylene / polyoxypropylene block polymers (Na, alkanolamine), phosphatidylcholine / phosphatidylethanolimine (lecithin), alkyl (C8-12) phosphates, and other phosphate-type surfactants.Preferably, examples include monoalkyl sulfates such as sodium lauryl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate, as well as dioctyl sodium sulfosuccinate, sodium lauroyl sarcosinate, and sodium dodecylbenzenesulfonate. The most preferred surfactant is sodium lauryl sulfate. In the present invention, two or more surfactants may be used in combination in appropriate proportions.

[0019] In the present invention, when sodium lauryl sulfate is used, the crystals can be obtained by spray drying or by crystallization. Note that monohydrate, 1 / 2 hydrate, 1 / 8 hydrate, and non-solvate are known crystalline polymorphs of sodium lauryl sulfate (Reference: Journal of Crystal Growth 263 (2004) 480-490), and any of these crystals can be used in the composition or formulation of the present invention. The surfactant is contained in the formulation in an amount of 2.5% by weight or more, preferably 2.5% to 20% by weight, more preferably 2.5% to 15% by weight, and most preferably 3.75% to 7.5% by weight, relative to the total weight of the formulation. The surfactant contained in the composition or formulation of the present invention preferably has a weight ratio of alectinib or its salt to the surfactant of 100:3 to 100:50, more preferably 100:12.5 to 100:50, and most preferably 100:12.5 to 100:25.

[0020] A "gel-inhibiting substance" refers to a substance that, when present in a composition containing alectinib or its salt and a surfactant, can suppress the formation of a gel-like substance that occurs when the formulation is suspended. Gelling or the formation of a gel-like substance refers to a significant decrease in the fluidity of a suspension due to the interaction between alectinib or its salt and the anionic surfactant sodium lauryl sulfate, or the formation of a substance that causes a significant decrease in the fluidity of the suspension. A decrease in fluidity means a state in which there is no fluidity even when shaken, and solidification is observed to the extent that it interferes with dispensing and administration. Specifically, it refers to a decrease in fluidity when comparing a suspension of a composition containing alectinib or its salt and an anionic surfactant, including sodium lauryl sulfate, with a suspension of a composition containing alectinib or its salt prepared in the same way without the addition of sodium lauryl sulfate. More specifically, conventional granules used in capsules containing alectinib or its salt and an anionic surfactant such as sodium lauryl sulfate, when used in children, suspending the granules (for example, 2000 mg of granules containing 600 mg of alectinib in free form) in a small amount of water (for example, 10 ml) causes a complex to form between alectinib or its salt and the anionic surfactant, creating a gel-like substance and significantly reducing fluidity. When a gel-inhibiting substance is present in a composition containing alectinib or its salt and an anionic surfactant such as sodium lauryl sulfate, it reduces the solubility of alectinib or its salt or the anionic surfactant through common ion effect or ion exchange, thereby suppressing the formation of a gel-like substance between alectinib and the anionic surfactant, and thereby suppressing the reduction in fluidity that occurs during suspension. Salts can be used as the gel-inhibiting substance. One type of gel-inhibiting substance may be used alone, or two or more types may be used in combination.

[0021] In the present invention, "salts" refers to monovalent to trivalent inorganic salts or organic salts. Preferably, they are water-soluble salts. Here, "water-soluble salts" are salts that have a solubility of 0.1 g or more, preferably 1 g or more, more preferably 3 g or more, and even more preferably 10 g or more in 100 g of water at 20°C. These salts can be used individually, or two or more of them can be used in appropriate combinations. In the present invention, "inorganic salt" refers to a compound in which an anion derived from an inorganic acid and a cation derived from an inorganic base are ionically bonded. Examples of anions constituting an inorganic salt include halide ions, sulfate ions, nitrate ions, phosphate ions, carbonate ions, bicarbonate ions, hydroxide ions, and the like. Examples of cations constituting an inorganic salt include metal ions [e.g., alkali metal ions (sodium ions, potassium ions, etc.), alkaline earth metal ions (calcium ions, magnesium ions, etc.)] and ammonia ions. Preferably, the inorganic salt is water-soluble. The inorganic salt may also form a hydrate. Specific examples of inorganic salts include, as inorganic salts of metals, for example, metal halide salts, carbonates or bicarbonates, sulfates, phosphates, hydroxides, etc., and as inorganic salts of ammonia, for example, ammonia halide salts, carbonates or bicarbonates, sulfates, phosphates, hydroxides, etc. Preferably, they are inorganic salts of metals, and more preferably, inorganic salts of alkali or alkaline earth metals (inorganic salts of sodium, potassium, calcium, and magnesium). Examples of halide salts include halides of alkali or alkaline earth metals, such as sodium chloride, potassium chloride, calcium chloride or their monohydrate, dihydrate, tetrahydrate, or hexahydrate; metal halide salts such as magnesium chloride or its hexahydrate; and ammonia halide salts such as ammonium chloride. Chloride salts are preferred. Examples of carbonates or bicarbonates include carbonates or metal bicarbonates of alkalis or alkaline earth metals, such as sodium carbonate or its monohydrate or decahydrate, sodium bicarbonate, calcium carbonate, ammonium carbonate, and other ammonia carbonates or their hydrates. Examples of sulfates include sulfates of alkalis or alkaline earth metal salts, such as sodium sulfate or its decahydrate, magnesium sulfate or its heptahydrate, calcium sulfate or its hemihydrate or dihydrate, and sulfates or hydrates of ammonias such as ammonium sulfate. Examples of phosphates include phosphates of alkalis or alkaline earth metal salts, such as sodium phosphate, calcium dihydrogen phosphate, calcium monohydrogen phosphate, tricalcium phosphate, and their hydrates, as well as phosphates of ammonia such as ammonium phosphate or their hydrates. Hydroxide salts refer to hydroxide salts of alkalis or alkaline earth metals, and include metal hydroxide salts such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide, as well as ammonia hydroxide salts such as ammonium hydroxide or their hydrates. Sodium hydroxide and calcium hydroxide are preferred. Preferably, the inorganic salt is calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, sodium bicarbonate, calcium dihydrogen phosphate, or a hydrate thereof. More preferably, it is calcium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, or a hydrate thereof. Neutral inorganic salts refer to normal salts composed of a strong acid and a strong base, and specifically include metal halides such as sodium chloride, potassium chloride, and calcium chloride, sodium sulfate, calcium sulfate, or their hydrates. The inorganic salts mentioned above may be synthesized by known methods or may be commercially available. In the present invention, the inorganic salts may be used individually or in any combination of two or more types.

[0022] In the present invention, "organic salt" refers to a compound in which an anion derived from an organic acid and a cation derived from the aforementioned inorganic base are ionically bonded in a 1:1 ratio. Examples of anions constituting organic acids include citrate ions, acetate ions, tartrate ions, amino acid ions, alginate ions, and sorbate ions. Specific examples of organic salts include, for example, metal organic salts such as metal citrate, acetate, tartrate, amino acid salt, alginate, and sorbate, and ammonia organic salts such as ammonia citrate, acetate, tartrate, amino acid salt, alginate, and sorbate. Preferably, the organic salt is a metal organic salt, and more preferably, it is an alkali or alkaline earth metal organic salt (organic salt of sodium, organic salt of potassium, organic salt of calcium, organic salt of magnesium). Examples of citrates include metal citrates such as monosodium citrate, disodium citrate, and calcium citrate, and ammonia citrates such as ammonium citrate. Examples of acetates include metal acetates such as sodium acetate, potassium acetate, and magnesium acetate, and ammonia acetates such as ammonium acetate. Examples of tartrates include metal tartrates such as sodium tartrate and ammonia tartrates such as ammonium tartrate. Examples of amino acid salts include metal amino acid salts such as sodium glutamate and magnesium aspartate, and ammonia amino acid salts such as ammonium glutamate. Examples of alginates include sodium alginate and ammonium alginate, and examples of sorbates include potassium sorbate and ammonium sorbate. These organic salts also include their hydrates (sodium acetate trihydrate, magnesium acetate tetrahydrate, etc.). Preferably, the organic salt is an alkali or alkaline earth metal salt selected from sodium tartrate, sodium glutamate, magnesium aspartate, sodium alginate, and potassium sorbate. The above organic salts may be synthesized by known methods or may be commercially available. In the present invention, the organic salts may be used individually or in any combination of two or more types. The most preferred substance for inhibiting gelation is calcium chloride or its hydrate. The gelation inhibitor is contained in amounts of 10% or more by weight, 10% to 30% by weight, 20% or more by weight, and 20% to 30% by weight, relative to the total weight of the syrup. The weight ratio of alectinib or its salt to the gelation inhibitor is preferably 100:10 to 100:70 on a free form basis, more preferably 100:30 to 100:70, and most preferably 100:60 to 100:70.

[0023] In the present invention, "capsules containing the same amount of alectinib or its salt as the syrup" means a previously approved capsule containing alectinib hydrochloride (for example, Alecensa® Capsules 150 mg, Chugai Pharmaceutical Co., Ltd.), or a generic drug thereof, adjusted in quantity to be the same amount (in free form equivalent) as the syrup of the present invention. Specifically, capsules containing the same amount of alectinib or its salt as a syrup containing 600 mg (in free form equivalent) of alectinib or its salt means four capsules each containing 150 mg (in free form equivalent) of alectinib hydrochloride. In this invention, "blood concentration profile" refers to an indicator of the average plasma concentration profile of alectinib (free form) after a single oral administration of a preparation containing alectinib or a salt thereof to healthy adults. The plasma concentrations of alectinib and its M4 metabolite in venous blood samples are measured by LC-MS / MS and analyzed according to the method described in Bioanalysis (2016) 8(14), 1465-79 (Method 2). In the present invention, "equivalent or superior blood concentration profile" means that the blood concentration profile of the target formulation is equivalent to or higher than that of the comparative formulation. Specifically, it means that the average plasma concentration profile of alectinib (free form) after a single oral administration of a syrup formulation containing alectinib or a salt thereof to healthy adults is equivalent to or higher than that of a control capsule formulation of the same dose. In this invention, "bioequivalence" means that the bioavailability of the target formulation is equivalent to that of the comparative formulation. In single-dose studies, AUC and C max Using C as the bioequivalence determination parameter, max The measured values ​​are used for the parameters, and the AUC is calculated using the trapezoidal rule. Specifically, the mean plasma concentration and AUC of alectinib (free form) after a single oral administration of a syrup formulation containing alectinib or a salt thereof to healthy adults are compared with the same dose of a control capsule. Generally, the test formulation and the reference formulation are judged to be bioequivalent when the 90% confidence interval of the difference in the mean values ​​of the logarithms of the bioequivalence parameters of the test formulation and the reference formulation is in the range of log(0.80) to log(1.25). In this specification, when comparing using the geometric mean of measured values, and with the parameter value of the capsule formulation set to 100%, values ​​between 80% and 125% are considered equivalent. In the present invention, "enhanced oral bioavailability" means that the bioavailability of the target formulation is enhanced compared to the comparative formulation. In this specification, when comparing the geometric mean values ​​of measured values, and the parameter value of the capsule formulation is set to 100%, an increase of more than 125% is considered enhanced. In this invention, "pharmaceutical composition" means a mixture of two or more substances used for the treatment or prevention of diseases. In one aspect of this invention, the pharmaceutical composition is used in the manufacture of a pharmaceutical preparation. "Pharmaceutical preparation" means a preparation for the treatment or prevention of diseases, and in this invention, a syrup preparation is preferred. "Syrup preparation" is a viscous liquid or solid preparation (syrup preparation) containing sugars or sweeteners that can be administered orally, and the active ingredient is mainly absorbed from the intestinal tract. Note that "syrup preparation" refers to a syrup preparation as defined in the General Provisions of the Sixteenth Revised Japanese Pharmacopoeia, and includes dry syrup preparations. "Syrup preparation" is a granular or powder preparation that becomes a syrup preparation when water is added. It is also called a dry syrup preparation. Syrup preparations or dry syrup preparations are used by dissolving or suspending the granular or powder preparation with water or the like at the time of use. Examples of "excipients" include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose monohydrate, fructose, glucose, mannitol, and sorbitol; and crystalline cellulose, precipitated calcium carbonate, and calcium silicate. Preferred excipients include starches such as potato starch and corn starch, lactose monohydrate, and crystalline cellulose. Lactose monohydrate is the most preferred. In this invention, "disintegrant" refers to an ingredient that promotes the rapid disintegration of solid preparations such as tablets or syrups when taking them orally, or when suspending or dissolving syrups or other preparations with water or the like. Examples of disintegrants include sodium starch glycolate, low-substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch, corn starch, croscarmellose sodium, crystalline cellulose, anhydrous silicic acid, and carmellose. Preferably, a selection is made from carmellose calcium, crospovidone, sodium starch glycolate, and croscarmellose sodium, with crospovidone being the most preferred. The amount of disintegrant used is, for example, 5% by weight or more, preferably 7.5% by weight or more, and more preferably 10% by weight or more, relative to the entire composition or formulation of the present invention. The upper limit of the amount used is not particularly limited, but is, for example, 30% by weight.

[0024] Examples of "binders" include polyvinylpyrrolidone, macrogol, and compounds similar to those used as excipients. Specific examples of binders include hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder. Hydroxypropyl cellulose is most preferred. The amount of binder used is preferably 0.1% by weight or more, and more preferably 0.5% by weight or more, relative to the entire composition or formulation of the present invention. The upper limit of the amount used is not particularly limited, but is, for example, 40% by weight.

[0025] Examples of emulsifiers include polysorbate 80, polyoxyl stearate 40, and lauromacrogol. Any "coloring agent" that is permitted to be added to pharmaceuticals is acceptable, such as food colorings like Food Yellow No. 5 (Sunset Yellow, Food Yellow No. 6 in the United States), Food Red No. 2, Food Blue No. 2, food lake colorings, and iron oxide.

[0026] As a "fluidizer," fluidizers are used to improve the fluidity of mixed powders and granules. Typical examples include talc and silicon dioxide, specifically light anhydrous silicic acid and hydrated silicon dioxide. Here, light anhydrous silicic acid can be any substance whose main component is hydrated silicon dioxide (SiO2·nH2O) (where n is an integer). Specific examples include, for example, Cylysia 320 (trade name, Fuji Silysia Chemical Co., Ltd.) and Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.). Suitable examples of "preservatives" include, for example, sodium benzoate, para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and potassium sorbate. Suitable examples of "antioxidants" include, for example, sulfites and ascorbic acid. The additives mentioned above may be used by mixing two or more in appropriate proportions. Ethanol, phenol, chlorocresol, purified water, distilled water, etc., can be used as solvents for manufacturing the liquid formulation.

[0027] The syrup formulation of the present invention can be produced by a general method after mixing alectinib or a salt thereof with a surfactant, a gelling inhibitor, and the above-mentioned additives. Preferably, it is produced according to the following method. 1) Alectinib or a salt thereof is mixed with additives such as surfactants, gelling inhibitors, excipients, disintegrants, binders, and sweeteners, and then granulated while adding or spraying a solvent (e.g., purified water, ethanol, or a mixture thereof). The syrup of the present invention is produced by adding an appropriate amount of fragrance, thickener, etc. to the resulting granules and mixing. 2) Alectinib or a salt thereof is mixed with additives such as surfactants, gelling inhibitors, excipients, disintegrants, and sweeteners. Then, a binder and other additives are dispersed or dissolved in a solvent (e.g., purified water, ethanol, or a mixture thereof) and the resulting liquid is added or sprayed while granulation is carried out. An appropriate amount of flavoring, thickener, etc. is added to the resulting granules and mixed to produce the syrup of the present invention. Dry syrup preparations are granules, or preparations in which post-finishing ingredients have been added to granules, and are typically manufactured using sugars or sweeteners in accordance with the method for manufacturing granules.

[0028] The present invention also relates to a pharmaceutical composition containing (i) alectinib or a salt thereof, (ii) a surfactant, and (iii) a gelling inhibitor. One embodiment of the pharmaceutical composition of the present invention also relates to a pharmaceutical composition containing (i) alectinib or a salt thereof, (ii) a surfactant, (iii) a gelling inhibitor, and (iv) a thickener, sweetener, flavoring agent, odoring agent, or fragrance. Furthermore, one embodiment of the pharmaceutical composition of the present invention relates to a dry syrup containing (i) granules containing alectinib or a salt thereof, (ii) a surfactant, and (iii) a gelling inhibitor. A further embodiment of the pharmaceutical composition of the present invention is a dry syrup containing (i) alectinib or a salt thereof, (ii) a surfactant, (iii) a gelling inhibitor, and (iv) a thickener, sweetener, flavoring agent, odoring agent, or fragrance. A further embodiment of the pharmaceutical composition of the present invention is a suspension containing (i) alectinib or a salt thereof, (ii) a surfactant, (iii) a gelling inhibitor, and (iv) a thickener, sweetener, flavoring agent, odoring agent, or fragrance.

[0029] In this invention, "granules" refers to particles having a substantially uniform shape and size, and are obtained by granulating raw materials such as powders, lumps, solutions, or molten liquids using wet granulation, dry granulation, or heat granulation methods. "Non-granular" refers to a state in which granules are not formed. In the present invention, the dry syrup or granules may contain various additives in addition to the surfactants and disintegrants mentioned above. For example, the dry syrup or granules may contain alectinib or a salt thereof, a disintegrant, a surfactant, an excipient, and a binder. The dry syrup or granules may further contain one or more additives selected from lubricants, coating agents, stabilizers, thickeners, sweeteners, flavoring agents, odorants or fragrances, and diluents. A composition containing the compound represented by formula (I) or a salt thereof, and optionally additives such as a disintegrant, surfactant, excipient, lubricant, coating agent, binder, stabilizer, thickener, sweetener, flavoring agent, odorant or fragrance, and diluent can be produced by granulating using a normal granulation process. In the present invention, "post-processing" and "post-processing components" refer to components added to the outside of the granulated granules in a dry syrup preparation. These post-processing components may also include additives such as disintegrants, lubricants, fluidizers, thickeners, sweeteners, flavoring agents, odorants, or fragrances.

[0030] The disintegrant may be contained within the granules of the dry syrup or in the final ingredients, and is preferably selected from sodium starch glycolate, low-substituted hydroxypropyl cellulose, carmellose calcium, pregelatinized starch, corn starch, croscarmellose sodium, crystalline cellulose, anhydrous silicic acid, and carmellose, more preferably selected from carmellose calcium, crospovidone, sodium starch glycolate, and croscarmellose sodium, and most preferably crospovidone.

[0031] Furthermore, the dry syrup formulation of the present invention may contain a gel-inhibiting substance within the granules. In that case, the dry syrup formulation may contain (i) granules containing alectinib or a salt thereof and the gel-inhibiting substance, and (ii) a surfactant. The gel-inhibiting substance is more preferably present as a component within the granules.

[0032] In addition to surfactants, the pharmaceutical composition of the present invention may also contain solubilizing agents such as organic polymers described later. Examples of "solubilizing agents" include organic polymers, and specific examples of "organic polymers" used in the present invention include polysaccharides such as hydroxypropyl cellulose (hereinafter also referred to as HPC), hydroxypropyl methylcellulose, methylcellulose, propylene glycol alginate, agar powder, guar gum, zein, and hydroxyethyl methylcellulose, as well as synthetic resins such as carboxyvinyl polymer, polyvinyl alcohol, vinyl acetate resin, and sodium polystyrene sulfonate, and phosphoproteins such as casein and sodium caseinate. Organic polymers with a solubility in water of 1 g / 100 g or more are called water-soluble polymers. Specifically, examples include hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, propylene glycol alginate, sodium caseinate, carboxyvinyl polymer, agar powder, guar gum, copolyvidone, hydroxyethyl methylcellulose, and polyvinyl alcohol. Organic polymers that dissolve under acidic conditions with a pH of 1.2 to 3.5, which is the pH of gastric juice, are called gastric-soluble polymers, while those that dissolve rapidly at a pH of 6 to 8 in the intestines are called enteric-coated polymers. Examples of gastric-soluble polymers include aminoalkyl methacrylate copolymer E or polyvinyl acetal diethylaminoacetate, while examples of enteric-coated polymers include methacrylic acid copolymer LD (emulsion), methacrylic acid copolymer S, purified shellac, carboxymethyl ethylcellulose, cellulose phthalate acetate (cerafate), hydroxypropyl methylcellulose acetate succinate, casein, and zein. Preferred solubilizers include, for example, casein, sodium caseinate, skim milk powder, dioctyl sodium sulfosuccinate, polyoxyl 40 stearate, sorbitan trioleate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene hydrogenated castor oil 60, polyoxyl 35 castor oil, lauromacrogol, sodium lauroyl sarcosinate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium methyl sulfate, sodium ethyl sulfate, sodium butyl sulfate, sodium octyl sulfate, sodium decyl sulfate, and sodium dodecylbenzenesulfonate. The aforementioned solubilizer may be in granular form or obtained by spray drying.

[0033] Examples of excipients that may be included in the granules of the dry syrup in the present invention include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose monohydrate, fructose, glucose, mannitol, and sorbitol; and crystalline cellulose, precipitated calcium carbonate, and calcium silicate. Preferred excipients include starches such as potato starch and corn starch, lactose monohydrate, and crystalline cellulose, with lactose monohydrate being even more preferred. The amount of excipient used is preferably 5 to 60% by weight, and more preferably 5 to 20% by weight, based on 100% by weight of the composition or formulation.

[0034] Examples of binders that may be included in the granules of the dry syrup formulation in the present invention include hydroxypropylcellulose, polyvinylpyrrolidone, macrogol, and compounds similar to those used as excipients. Specific examples of binders include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder, with hydroxypropylcellulose being preferred. The amount of binder used is preferably 0.1 to 50% by weight, more preferably 0.5 to 40% by weight, and even more preferably 0.5 to 10% by weight, based on 100% by weight of the composition or formulation.

[0035] Examples of lubricants in the present invention include magnesium stearate, calcium stearate, talc, sucrose fatty acid esters, and sodium stearyl fumarate.

[0036] Examples of preservatives in the present invention include para-hydroxybenzoic acid esters such as sodium benzoate, 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 or potassium sorbate. Preferably, sodium benzoate or potassium sorbate is used. Most preferably, sodium benzoate is used. The syrup formulation of the present invention may include, for example, thickeners, sweeteners, flavoring agents, odoring agents, fragrances, pH adjusters, etc., which are commonly used in pediatric formulations. In the case of a dry syrup formulation, these can be used within the granules or as a final ingredient. Preferably, at least one or two of the thickeners, sweeteners, flavoring agents, odoring agents, and fragrances are used as final ingredients. A "thickening agent" is used during the manufacture of syrups or the suspension of dry syrups to uniformly disperse the suspended components in the solution. Specifically, xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose are used. Xanthan gum and sodium carboxymethylcellulose are preferred. Xanthan gum is most preferred. Sweeteners are used to sweeten pharmaceuticals and include natural sugars such as sucrose, mannitol, fructose, and lactose, as well as artificial sweeteners such as licorice powder, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium. Preferably, they are sodium saccharin, sucralose, and acesulfame potassium. Most preferably, they are sucralose. "Flavoring agents" are used to make bitter drugs easier to drink, and the sugars mentioned above are the most commonly used. "Deodorizers" are used to eliminate or reduce the unpleasant odor of medicines, and include l-menthol and peppermint oil. The "flavorings" used include strawberry, raspberry, orange, apple, cherry black, and yogurt flavors. Strawberry flavor is preferred. Examples of pH adjusters include hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid, and trisodium citrate. Tartaric acid, citric acid, and maleic acid are preferred. Tartaric acid is the most preferred.

[0037] Furthermore, the present invention includes a syrup formulation comprising alectinib or a salt thereof, an anionic surfactant, and a gelling inhibitor, which has better drug dissolution properties compared to the composition without the gelling inhibitor; The above-mentioned syrup preparation in granular form; and The above-mentioned syrup preparation, which is a dry syrup; A syrup formulation comprising alectinib or a salt thereof, an anionic surfactant, and a gelling inhibitor, wherein the syrup formulation has better fluidity and / or palatability compared to the composition without the gelling inhibitor; This is also included. Furthermore, the present invention includes a method for reducing the fluidity of a composition containing alectinib or a salt thereof and an anionic surfactant by co-containing a gelation-inhibiting substance, compared to a composition without a gelation-inhibiting substance; A method for improving the fluidity and / or palatability of a composition containing alectinib or a salt thereof and an anionic surfactant by co-containing a gelling inhibitor, compared to a composition without a gelling inhibitor; and The method also includes a step of co-administering a gelling inhibitor to a composition containing alectinib or a salt thereof and an anionic surfactant, thereby producing a syrup preparation having better drug dissolution properties than a composition without a gelling inhibitor.

[0038] The syrup in this invention specifically includes a surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid, and trisodium citrate, a preservative selected from sodium benzoate, parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, starch, lactose monohydrate, and crystalline cellulose. A syrup or dry syrup containing an excipient selected from the group consisting of lullose, a disintegrant selected from the group consisting of carmellose calcium, crospovidone, sodium starch glycolate, and croscarmellose sodium, a binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and acacia powder, a sweetener selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium, and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor; A syrup or dry syrup containing alectinib or its salt, a surfactant such as sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from the group consisting of sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, a binder such as hydroxypropylcellulose, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavor selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor;

[0039] A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid and trisodium citrate, a preservative selected from the group consisting of sodium benzoate, parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate and crystalline cellulose, carmellose calcium, crospovidone, starch A syrup formulation containing a disintegrant selected from the group consisting of sodium lycolate and croscarmellose sodium, a binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and acacia powder, a sweetener selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium, and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor, wherein the syrup formulation or dry syrup formulation has a blood concentration profile equivalent to or better than that of a capsule formulation containing the same amount of alectinib or a salt thereof as the syrup formulation; A syrup containing alectinib or a salt thereof, a surfactant such as sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, a binder such as hydroxypropylcellulose, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavor selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the syrup or dry syrup has a blood concentration profile equivalent to or better than that of a capsule containing the same amount of alectinib or a salt thereof as the syrup; A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid and maleic acid, a preservative selected from sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate and crystalline cellulose, a disintegrant such as crospovidone, a binder such as hydroxypropylcellulose, and A syrup or dry syrup containing a sweetener selected from the group consisting of sodium kkalin, sucralose, and acesulfame potassium, and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the weight ratio of alectinib or its salt to the gelation inhibitor is 100:30 to 100:90 on a free form basis, and / or the weight ratio of alectinib or its salt to the surfactant and the gelation inhibitor is 100:3:30 to 100:50:90 on a free form basis, and having a blood concentration profile equivalent to or better than that of a capsule containing the same amount of alectinib or its salt as the syrup;

[0040] A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid and trisodium citrate, a preservative selected from sodium benzoate, parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate and crystalline cellulose, carmellose calcium, A syrup containing a disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, and sodium croscarmellose; a binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder; a sweetener selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor, wherein the syrup has an equivalent or greater AUC and C than a capsule containing the same amount of alectinib or a salt thereof. max A syrup or dry syrup having one or more blood concentration profiles selected from the group consisting of the following; A syrup containing alectinib or a salt thereof, a surfactant such as sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from the group consisting of sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, a binder such as hydroxypropylcellulose, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavor selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the syrup contains an equivalent or greater AUC and C than a capsule containing the same amount of alectinib or a salt thereof. max A syrup or dry syrup having one or more blood concentration profiles selected from the group consisting of the following; A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, and hydroxypropyl A syrup containing a cellulose binder, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavor selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the weight ratio of alectinib or its salt to the gelation inhibitor is 100:30 to 100:90 on a free form basis, and / or the weight ratio of alectinib or its salt to the surfactant and the gelation inhibitor is 100:3:30 to 100:50:90 on a free form basis, and which has an equivalent or greater AUC and C than a capsule containing the same amount of alectinib or its salt as the syrup. max A syrup or dry syrup having one or more blood concentration profiles selected from the group consisting of the following;

[0041] A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid and trisodium citrate, a preservative selected from sodium benzoate, parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate and crystalline cellulose, carmellose calcium, A syrup containing a disintegrant selected from the group consisting of crospovidone, sodium starch glycolate, and sodium croscarmellose; a binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder; a sweetener selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor, wherein the syrup has an equivalent or greater AUC and C than a capsule containing the same amount of alectinib or a salt thereof. max A syrup or dry syrup containing; A syrup containing alectinib or a salt thereof, a surfactant such as sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from the group consisting of sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, a binder such as hydroxypropylcellulose, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavor selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the syrup contains an equivalent or greater AUC and C than a capsule containing the same amount of alectinib or a salt thereof. max A syrup or dry syrup containing; A syrup preparation containing alectinib or a salt thereof, a surfactant which is sodium lauryl sulfate, calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and a gelling inhibitor selected from the group consisting of sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethyl cellulose, and sodium carboxymethyl cellulose, an excipient selected from the group consisting of starch, lactose hydrate, and crystalline cellulose, a disintegrant which is crospovidone, a binder which is hydroxypropyl cellulose, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavor selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and black cherry flavor, wherein the weight ratio of the alectinib or a salt thereof to the gelling inhibitor is 100:30 to 100:90 in terms of the free form, and / or the weight ratio of the alectinib or a salt thereof to the surfactant to the gelling inhibitor is 100:3:30 to 100:50:90 in terms of the free form, and having an AUC and C equal to or higher than those of a capsule preparation containing the same amount of alectinib or a salt thereof as the syrup preparation; max A syrup preparation or a dry syrup preparation having;

[0042] A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid and trisodium citrate, a preservative selected from the group consisting of sodium benzoate, parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate and crystalline cellulose, carmellose calcium, crospovidone, de A syrup or dry syrup containing a disintegrant selected from the group consisting of sodium ammonium glycolate and sodium croscarmellose, a binder selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder, a sweetener selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium, and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor, wherein the syrup or dry syrup is bioequivalent to a capsule containing the same amount of alectinib or a salt thereof as the syrup; A syrup containing alectinib or a salt thereof, a surfactant such as sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, a binder such as hydroxypropylcellulose, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavor selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the syrup or dry syrup is bioequivalent to a capsule containing the same amount of alectinib or a salt thereof as the syrup; A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, and a crystalline cellulose such as hydroxypropylcellulose. A syrup or dry syrup containing a combination agent, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the weight ratio of alectinib or its salt to the gelation inhibitor is 100:30 to 100:90 on a free form basis, and / or the weight ratio of alectinib or its salt to the surfactant and the gelation inhibitor is 100:3:30 to 100:50:90 on a free form basis, and which is bioequivalent to a capsule containing the same amount of alectinib or its salt as the syrup;

[0043] A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, acetic acid, maleic acid and trisodium citrate, a preservative selected from the group consisting of sodium benzoate, parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate and crystalline cellulose, carmellose calcium, crospovidone, starch A syrup formulation containing a disintegrant selected from the group consisting of sodium lycolate and croscarmellose sodium, a binder selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and acacia powder, a sweetener selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium, and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor, wherein the oral bioavailability is enhanced compared to a capsule formulation containing the same amount of alectinib or a salt thereof as the syrup formulation; A syrup containing alectinib or a salt thereof, a surfactant such as sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from the group consisting of sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, a binder such as hydroxypropylcellulose, a sweetener selected from the group consisting of sodium saccharin, sucralose, and acesulfame potassium, and a flavor selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the oral bioavailability is enhanced by 110-160% compared to a capsule containing the same amount of alectinib or a salt thereof; A surfactant such as alectinib or its salt, sodium lauryl sulfate, a gelation inhibitor selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate, a pH adjuster selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, and maleic acid, a preservative selected from sodium benzoate and potassium sorbate, a thickener selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose, an excipient selected from the group consisting of starch, lactose monohydrate, and crystalline cellulose, a disintegrant such as crospovidone, a binder such as hydroxypropylcellulose, and saccharin. A syrup or dry syrup containing a sweetener selected from the group consisting of sodium, sucralose, and acesulfame potassium, and a flavoring selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, and cherry black flavor, wherein the weight ratio of alectinib or a salt thereof to the gelation inhibitor is 100:30 to 100:90 on a free form basis, and / or the weight ratio of alectinib or a salt thereof to the surfactant and the gelation inhibitor is 100:3:30 to 100:50:90 on a free form basis, and the oral bioavailability is enhanced by 110 to 160% compared to a capsule containing the same amount of alectinib or a salt thereof as the syrup.

[0044] The syrup formulation of the present invention can be used as a therapeutic agent for childhood cancer. Examples of childhood cancers include pediatric malignant solid tumors and malignant lymphoma. Pediatric malignant solid tumors include sarcomas such as inflammatory myofibroblastic tumors, rhabdomyosarcomas, Ewing sarcoma family tumors (including Ewing sarcomas of bone and non-bone, anaplastic ectodermal tumors (PNETs), and Askin tumors (PNETs originating in the chest wall)), leiomyosarcoma, central nervous system tumors such as neuroblastoma, glioma, neuroblastoma, and malignant peripheral nerve sheath tumors, skin tumors such as malignant melanoma and Spitz tumors, lung cancers such as retinoblastoma and non-small cell lung cancer, renal cell carcinoma, anaplastic thyroid carcinoma, thymic carcinoma, and ovarian cancer, as well as epithelial tumors of the gallbladder and extrahepatic bile ducts, thyroid cancer, germ cell tumors, and malignant fibrous histiocytoma. Malignant melanoma includes (1) acrolescent melanoma (ALM), (2) superficial spreading melanoma (SSM), (3) nodular melanoma (NM), and (4) lentigo malignant melanoma (LMM). Spitz tumors include malignant Spitz tumors, malignant juvenile melanoma, Spitz melanoma, and Spitz nevus-like melanoma. Preferred childhood cancers include inflammatory myofibroblastic tumors, neuroblastomas, thymic carcinomas, ovarian cancers, anaplastic thyroid carcinomas, neuroblastomas, Spitz tumors, malignant melanomas, rhabdomyosarcomas, Ewing's sarcoma, retinoblastomas, and gliomas of the central nervous system. Preferred childhood cancers include inflammatory myofibroblastic tumors, diffuse large B-cell lymphoma, and neuroblastoma. Furthermore, the syrup formulation of the present invention can also be used to treat thymic carcinoma, ovarian cancer, Spitz tumor, malignant melanoma, retinoblastoma, diffuse large B-cell lymphoma, or pediatric cancers such as gastric cancer, colorectal cancer, breast cancer, or rare tissue subtypes of liver cancer, all of which have ALK abnormalities. Preferably, the childhood cancer is one in which prior treatment has been ineffective, or the lesion is refractory or recurrent. "Ineffective prior treatment" refers to cases where prior treatment was ineffective and discontinued. Prior treatments include chemotherapy, radiation therapy, and surgery using other drugs with similar or different mechanisms of action. Specifically, this includes cases where resistance develops after administration of crizotinib. "Relapse" means that the best response to the most recent treatment was complete remission or partial remission, while "refractory" means that the best response to the most recent treatment was stable or progressing. Alternatively, it may also include conditions such as metastasis or unresectable disease.

[0045] Furthermore, in yet another aspect of the present invention, there is a pharmaceutical composition comprising a poorly soluble drug, an anionic surfactant, and a gelation inhibitor. By including the gelation inhibitor, a composition can be obtained in which the dissolution of the poorly soluble drug is improved or the ease of administration is improved compared to the composition without the gelation inhibitor. Preferably, the poorly soluble drug is a basic drug. "Slightly soluble" means a state in which the solubility in a solvent, particularly water, buffer solution, or gastrointestinal fluid, is 1 mg / ml or less, more preferably 100 μg / ml or less, even more preferably 10 μg / ml or less, particularly preferably 1 μg / ml or less, and most preferably 0.1 μg / ml or less. It is preferable that the compound is slightly soluble in any solvent with a pH of 7 or lower, more preferably slightly soluble in any solvent with a pH of 4 to 7, and even more preferably slightly soluble in solvents with a pH of 4 and / or pH of 7. However, in the case of a compound having a basic group in its molecule, it is preferable that the compound is slightly soluble in any solvent with a pH of 7 or higher, more preferably slightly soluble in any solvent with a pH of 7 to 9, and even more preferably slightly soluble in solvents with a pH of 7 and / or pH of 9. The solvent for measuring solubility is not particularly limited, but examples of a pH 4 solvent include acetate buffer and citrate buffer. Examples of a pH 5 solvent include acetate buffer, citrate buffer, and phosphate buffer. Examples of solvents with a pH of 7 include water and phosphate buffer. Examples of solvents with a pH of 9 include carbonate buffer. In both cases, the measurement temperature for solubility is preferably 20 to 40°C, and more preferably 37°C. A "basic drug" has at least one basic group, such as a primary amino group (-NH2), a secondary amino group (imino group -NH-), a tertiary amino group (>N-), an amide group, or a basic nitrogen-containing heterocyclic group (pyrrolyl group, imidazolyl group, pyrazolyl group, pyrazinyl group, prinyl group, quinolyl group, pyridyl group, piperidino group, piperidyl group, piperazinyl group, triazolo group, etc.). Note that amino groups also include hydrazino groups (-NH-NH2) and hydrazo groups (-NH-NH-). A basic drug only needs to have at least one basic group, and may have multiple basic groups of the same or different types. Furthermore, the drug may form salts (for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; organic carboxylic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, and maleic acid; and organic sulfonic acids such as mesylic acid). Furthermore, cationic or basic drugs include drugs whose metabolites or prodrugs that exhibit activity in the body are cationic or basic.

[0046] Poorly soluble drugs may form salts (for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid; organic carboxylic acids such as acetic acid, tartaric acid, citric acid, fumaric acid, and maleic acid; and organic sulfonic acids such as mesylic acid). The uses of poorly soluble drugs are not particularly limited. For example, they may be drugs that act on the central nervous system, autonomic nervous system, respiratory system, circulatory system, digestive system, metabolic system, etc., and may also be blood and hematopoietic agents, ophthalmic or otolaryngological drugs, or endocrine active substances (autacoids). Specific examples of these drugs may include antipyretics, analgesics, anti-inflammatory drugs, hypnotics / sedatives, rheumatic drugs, antidepressants, antiepileptic drugs, anti-vertigo drugs, anti-allergic drugs, cardiac stimulants, beta-blockers, calcium channel blockers, antiarrhythmics, diuretics, angina drugs, heart failure drugs, myocardial infarction drugs, antihypertensive drugs (hypertension drugs), peripheral circulatory disorder drugs, vasopressors (hypotensive drugs), bronchodilators, asthma drugs, anti-tuberculosis drugs, diabetes drugs, diabetic complication drugs, hyperlipidemia drugs, hyperuricemia drugs, cough suppressants and expectorants, peptic ulcer treatments, thyroid disease drugs, benign prostatic hyperplasia drugs, anticancer drugs, osteoporosis drugs, Alzheimer's disease drugs, antibiotics, vitamins, antiplasmin agents, etc.

[0047] Specific examples of poorly soluble drugs include antipyretics, analgesics, and anti-inflammatory drugs (such as antipyretics and analgesics like dimethothiazine mesylate, headache medications like dihydroergotamine mesylate, lomerizine hydrochloride, and sumatriptyline succinate, and anti-inflammatory drugs like fenamic acid, mefenamic acid, phloxaphenin, proglummetacin maleate, epirizole, and tiaramide hydrochloride), antirheumatic drugs (such as penicillamine and methotrexate), drugs for treating hyperuricemia (such as allopurinol), hypnotics and sedatives (such as rilmazafone hydrochloride and zolpidem tartrate), and antidepressants (such as nortriptyline hydrochloride, imipramine hydrochloride, and iripramine hydrochloride). Mitriptyline, clomipramine hydrochloride, fluvoxamine maleate, milnacipran hydrochloride, etc.), anti-vertigo agents (isoprenaline hydrochloride, betahistine mesylate, etc.), anti-allergic agents (antihistamines such as diphenhydramine hydrochloride, diphenylpyraline theoclate, clemastine fumarate, chlorpheniramine maleate, alimethazine tartrate, promethazine hydrochloride; histamine H1 antagonists (or basic anti-allergic agents) such as ketotifen fumarate, azelastine hydrochloride, epinastine hydrochloride, etc.), cardiac stimulants (denopamine, isoprenaline hydrochloride, etc.), anti-angina agents Symptomatic drugs (niconandil, etafenone hydrochloride, dipyridamole, trapidil, trimetazidine hydrochloride, etc.), beta-blockers (propranolol hydrochloride, diphenidol hydrochloride, bufetrol hydrochloride, bupranolol hydrochloride, bopindolol malonate, oxprenolol hydrochloride, alprenolol hydrochloride, indenolol hydrochloride, acebutol hydrochloride, celiprolol hydrochloride, etc.), calcium channel blockers (manidipine hydrochloride, benidipine hydrochloride, amlodipine besylate, verapamil hydrochloride, diltiazem hydrochloride, etc.), antiarrhythmic agents (aprindine hydrochloride, pirsicainide hydrochloride, propafenol hydrochloride) (e.g., amiodarone hydrochloride, nifekalant hydrochloride, sotalol hydrochloride, bepridil hydrochloride), diuretics (e.g., hydrochlorothiazide, penflutizide, bentylhydrochlorothiazide, bumetanide, azosemide, triamterene), antihypertensive agents (e.g., clonidine hydrochloride, methyldopa, guanabenz acetate, guanfacine hydrochloride, reserpine, prazosin hydrochloride, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, etc.), vasodilators (e.g., hydralazine hydrochloride, budralazine hydrochloride, todralazine hydrochloride, cadralazine hydrochloride, enalapril maleate, delapril hydrochloride),ACE inhibitors such as lisinopril and benazepril hydrochloride, angiotensin II receptor antagonists such as candesartan cilexetil and valsartan, peripheral circulatory disorder treatments (inositol hexanicotinate, hepronicate, trizoline hydrochloride, isoxuprine hydrochloride, etc.), vasopressors (methalaminol bitartrate, methoxamine hydrochloride, midodrine hydrochloride, amezinium methylsulfate, etilephrine hydrochloride, phenylephrine hydrochloride, etc.), bronchodilators and asthma treatments (ephedrine hydrochloride, methyl ephedrine hydrochloride, isoprenaline hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, salbumol hydrochloride, Beta-2 adrenergic receptor stimulants such as terbutaline hydrochloride, formoterol fumarate, tulobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, and clenbuterol hydrochloride; xanthine derivatives such as theophylline, aminophylline, cholinetheophylline, and proxyphylline; cough suppressants (such as dimemorphan phosphate, tipepidine hihenzate, oxerazine citrate, dextromethorphan hydrobromide, pentoxyverine citrate, cloperastine, and benproperine phosphate); diabetes medications (tolbutamide, acetaminophen Tohexamide, glibenclamide, glimepiride, buformin hydrochloride, ensanmethformin, pioglitazone hydrochloride, voglibose, etc.), expectorants (L-methylcysteine ​​hydrochloride, ambroxol hydrochloride, bromhexine hydrochloride, etc.), peptic ulcer treatments (H2 receptor antagonists such as cimetidine, ranitidine hydrochloride, famotidine, etc., proton pump inhibitors such as lansoprazole, omeprazole, etc., muscarinic receptor antagonists such as pirenzepine hydrochloride, etc.), antibiotics (clarithromycin, kitasamycin, josamycin, midekama, etc.) (e.g., isine, loxtamycin, azithromycin), narcotics (e.g., amphetamine, meperidine), vitamins [Vitamin B1s such as thiamine hydrochloride, thiamine nitrate, dicethiamine hydrochloride, shikotiamine, benfotiamine, bisibthiamine, fursultiamine, prosultiamine, octotiamine, bisbentiamine, thiamine disulfide; Vitamin B2s such as riboflavin, riboflavin sodium phosphate, riboflavin butyrate, flavin adenine dinucleotide sodium; Pyridoxine hydrochloride, pyridoxine acetate,Examples include vitamin B6 compounds such as pyridoxal phosphate; nicotinic acid compounds such as nicotinic acid and nicotinamide; vitamin B12 compounds such as mecobalamin, cyanocobalamin, hydroxocobalamin (hydroxocobalamin hydrochloride, hydroxocobalamin acetate, etc.), and methylcobalamin; folic acid, pantothenic acids, biotin, vitamin P (hesperidin, etc.); antiplasmin agents (epsilon-aminocaproic acid, tranexamic acid, etc.); and poorly soluble basic drugs with a morpholine skeleton, such as anticholinergics (mosapride citrate) and morpholine antifungal agents (amorolfine hydrochloride). These poorly soluble drugs can be used alone or in combination of two or more, depending on whether they are for preventive or therapeutic purposes.

[0048] Furthermore, the present invention relates to a composition comprising a poorly soluble agent, an anionic surfactant, and a gelling inhibitor, which has better agent elution properties compared to a composition without a gelling inhibitor; A composition comprising a poorly soluble drug, an anionic surfactant, and a gelling inhibitor, having better palatability than a composition without the gelling inhibitor; The above composition is a syrup; and The composition is a dry syrup; This is also included. Furthermore, the present invention provides a method for improving the dissolution of a drug compared to a composition without a gel-inhibiting substance by coexisting a gel-inhibiting substance with a composition containing a poorly soluble drug and an anionic surfactant; A method for improving the fluidity and / or palatability of a formulation compared to a composition without a gel-inhibiting substance, by coexisting a gel-inhibiting substance with a composition containing a poorly soluble drug and an anionic surfactant; and The method also includes a step of co-administering a gelling inhibitor to a composition containing a poorly soluble drug and an anionic surfactant, thereby producing a formulation having better fluidity and / or palatability than a composition without a gelling inhibitor.

[0049] In the present invention, during the study of a syrup containing alectinib or a salt thereof, a poorly soluble basic drug having a morpholine skeleton, and an anionic surfactant, a problem arose in that ionic interactions between alectinib or its salt and the anionic surfactant caused gel formation during suspension, resulting in a decrease in fluidity and / or palatability. To address this problem, it was confirmed that the formation of gel during suspension could be suppressed by coexisting a gel-inhibiting substance with alectinib or its salt and the anionic surfactant.

[0050] A formulation with good dissolution properties can be obtained by co-administering a gelation inhibitor to a formulation containing alectinib or a salt thereof and a surfactant. "Good dissolution properties" means that when an dissolution test is performed using a paddle method rotating at 50 rpm per minute with 900 mL of hydrochloric acid / sodium hydrochloride solution (pH 1.8) containing 4% polyoxyethylene lauryl ether as the test solution, the dissolution rate of the formulation is 60% or more after 60 minutes. The test solution is preferably a colorless, clear solution prepared by dissolving 20.0 g of sodium chloride in 10,000 mL of water, adjusting the pH to approximately 1.8 with 37% hydrochloric acid, and then mixing in approximately 400.0 g of polyoxyethylene lauryl ether. [Examples]

[0051] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. In Examples 1-32, NIKKOL SLS (Nikko Chemicals) was used as sodium lauryl sulfate.

[0052] Reference Example 1: Formation of a gel-like substance (Manufacturing of pharmaceutical products) A suspension was prepared according to the amounts of each component listed in Table 1. Approximately 85% of the total volume of purified water was added to a glass beaker, and sodium lauryl sulfate and alectinib hydrochloride (hereinafter referred to as compound A) were added while stirring with a magnetic stirrer, and stirred until completely dispersed. The pH of this suspension was measured, and after adjusting the pH to 4.0 by adding citric acid solution, the volume was made up to 60 mL with purified water. [Table 1] (Formulation evaluation and results) For Reference Example 1, the appearance of the suspension was visually observed immediately after preparation and two days later at room temperature. Figure 1 shows a photograph of the appearance two days later at room temperature. The suspension in Reference Example 1 showed increased fluidity and the formation of a gel-like substance 5 minutes after preparation. As shown in Figure 1, the suspension maintained a high viscosity even after 2 days at room temperature, and it was confirmed that its fluidity as a suspension had significantly decreased. The formation of a gel-like substance refers to the significant decrease in fluidity in the suspension due to compound A and sodium lauryl sulfate.

[0053] Test Example 1: Inhibitory effect of salts on gel-like substance formation (Manufacturing of pharmaceutical products) Suspensions were prepared according to the amounts of each component listed in Table 2. The saturated aqueous solutions of X included in the formulation were the substances shown in Table 3. Sodium lauryl sulfate was added to a glass bottle, and then 20 mL of each saturated solution was added. Compound A was then added and mixed until completely dispersed to prepare the suspension.

[0054] [Table 2]

[0055] (Formulation evaluation and results) The appearance of the suspensions in Comparative Example 1 and Examples 1-10 was visually observed after 1 day at room temperature. Table 4 shows the inhibitory effect on gel-like substance formation in Examples 1-10. In this specification, the following symbols used in the table have the following meanings. ―: Formation of a gel-like substance is observed, or no inhibitory effect on gel-like substance formation is observed. +: Observed an inhibitory effect on gel-like substance formation. As shown in Table 4, in Examples 1-9, no gel formation was observed in the suspensions prepared using saturated aqueous solutions of salts as X, confirming that the salts in Examples 1-9 have an inhibitory effect on gel-like substance formation.

[0056] Test Example 2: Changes in Formulation (Manufacturing of pharmaceutical products) Tablets were prepared according to the amounts of each component in the tablet formulations listed in Tables 5 and 6. The substances Y and Z included in the formulations were those shown in Tables 7 and 8. Compound A and sodium lauryl sulfate were added to a glass bottle in a 1:1:1 ratio with each additive Y, or a 10:10:1 ratio with each additive Z. The mixture was then mixed at 32 rpm for 5 minutes using a mixer, and then molded using a static pressure tablet press in a 12 mm diameter circular tablet mold to obtain 600 mg tablets. As Comparative Example 2, tablets containing 600 mg of compound A were prepared similarly. The tablets were placed in glass bottles and subjected to a 14-day storage test at 70°C / 75%RH. The content and the amount of related substances produced were evaluated for each stored sample.

[0057] [Table 3]

[0058] [Table 4]

[0059] (Formulation evaluation and results) In Examples 11-25, additives were selected that showed minimal changes in composition from the standpoint of content and total amount of related substances. As a pH adjuster, tartaric acid was selected as the additive to be incorporated into the formulation because it showed the smallest increase in the total amount of related substances compared to citric acid and maleic acid. For thickeners and flavorings, no significant changes were observed in content or total amount of related substances for any of the additives, and it was confirmed that they are acceptable as additives to be incorporated into the formulation. As sweeteners, sucralose and acesulfame potassium were confirmed to have a smaller total amount of related substances compared to sodium saccharin. As a preservative, sodium benzoate was selected as the additive to be incorporated into the formulation because it showed the smallest increase in the total amount of related substances compared to potassium sorbate.

[0060] Test Example 3: Human Taste Test (Manufacturing of pharmaceutical products) The solvent was prepared according to the amounts of each component listed in Table 10. 200 mL of purified water was added to a glass beaker, and while stirring with a magnetic stirrer, sodium benzoate, sodium lauryl sulfate, sucralose, and strawberry flavor were added in that order, mixing until dissolved. Then, calcium chloride dihydrate was added and stirred for about 10 minutes. The pH of this solvent was measured, and 0.1 M hydrochloric acid was added to adjust the pH to 2.50-4.0, after which purified water was added to make up the total volume to 300 mL. Compound A was added to 5 mL of the prepared solvent to prepare a suspension. [Table 5]

[0061] For Examples 26-29, 12 subjects tasted each suspension and scored their taste on a 9-point scale to provide an overall evaluation. Scores of 1-3 were categorized as "bad," scores of 4-6 as "neither good nor bad," and scores of 7-9 as "good." The results are shown in Figure 2.

[0062] (Formulation evaluation and results) As shown in Figure 2, in Examples 28 and 29, the palatability of the suspension was improved by adding stable sweeteners and flavorings, and it was confirmed that the taste was at an acceptable level.

[0063] Test Example 4: Dry Syrup (Manufacturing of pharmaceutical products) According to the amounts of each component listed in Table 11, the granular formulation components were weighed, mixed using a high-speed stirring granulator, and granulated with purified water. The resulting granulated powder was processed into granules using a granulator with a screen diameter of 3.962 mm, and dried in a dryer at 50°C while heating until the drying loss was 3% or less. The resulting dried powder was processed into granules using a granulator with a screen diameter of 1.143 mm, and further mixed with the final components to obtain a dry syrup. Suspensions were prepared by reconstituting 2000 mg of the dry syrup with 10 mL of purified water or 3000 mg of the dry syrup with 127.5 mL, and their appearance and dissolution properties were examined. [Table 6]

[0064] (Formulation evaluation and results) The appearance of the suspensions in Examples 30 and 31 was observed visually. As shown in Figure 3, it was demonstrated that the presence of calcium chloride, a salt, suppresses gelation and ensures the fluidity and / or palatability of the suspension.

[0065] (Formulation evaluation and results) Figure 4 shows the elution profiles for Examples 30 and 31, when tested using the paddle method at 37°C and 50 revolutions per minute with 900 mL of a 4% polyoxyethylene lauryl ether (trade name Brij® 35) hydrochloric acid / sodium chloride solution (pH 1.8) as the test solution. The test solution was a colorless, clear solution prepared by dissolving 20.0 g of sodium chloride in 10,000 mL of water, adjusting the pH to approximately 1.8 with 37% hydrochloric acid, and then mixing in approximately 400.0 g of polyoxyethylene lauryl ether. As shown in Figure 4, the coexistence of calcium chloride, a salt, did not result in the feared decrease in dissolution. In the dissolution test, more than 60% dissolution was obtained after 60 minutes, confirming that the suspension also exhibits good dissolution properties.

[0066] Test Example 5: Relative Bioavailability Test of Capsules and Dry Syrup An open-label, single-center Phase I clinical trial was conducted in healthy subjects to evaluate the relative bioavailability of a single dose of the capsule formulation and the dry syrup formulation of the present invention. For the suspension administration of the dry syrup formulation of the present invention, a suspension was prepared with 10 mL of water, the bottle was rinsed three times with 40 mL of water after administration, and then taken with a total of 240 mL of water including the rinse water. For the powder formulation, it was administered without suspension, the bottle was rinsed three to six times with 40 mL of water after administration, and then taken with a total of 240 mL of water including the rinse water. For the capsule formulation, four 150 mg capsules of Alecensa® (Chugai Pharmaceutical Co., Ltd.) were taken with 240 mL of water.

[0067] The pharmacokinetics (PK), relative bioavailability, and safety of the dry syrup formulation were verified by comparing it with the approved capsule formulation. Relative bioavailability testing identified dry syrup formulations that achieved serum concentrations equivalent to or higher than those of the approved capsule formulation.

[0068] Furthermore, this study evaluated the safety and tolerability of the dry syrup formulation in healthy subjects based on the following evaluation criteria. - Incidence, nature, and severity of adverse events - Standard 12-lead electrocardiogram (ECG) parameters - Vital signs - Clinical laboratory results (clinical chemistry tests, blood tests, urine tests) - Physical examination

[0069] This study evaluated two types of dry syrup formulations, Examples 30 and 31, using the adult daily dose of the approved 150 mg capsule formulation listed in Table 12 below as a control. [Table 7]

[0070] The relative bioavailability of capsules and two types of dry syrups after single-dose administration was confirmed. A drug-free period of at least 10 days was provided between each administration. The effect of food on exposure levels was evaluated.

[0071] The formulations evaluated during each period are listed in Table 13. [Table 8]

[0072] Venous blood samples were collected by indwelling cannula or venous puncture according to the time schedule shown in Table 14 below. [Table 9] Plasma concentrations of alectinib and its M4 metabolite in venous blood samples were measured by LC-MS / MS at Q2 Solutions Biosciences LLC and analyzed according to the method described in Bioanalysis (2016) 8(14), 1465-79 (Method 2).

[0073] Cmax (ng / mL), AUC of capsule formulations (0-last) (ng.h / mL), AUC (0-inf) The geometric mean of (ng.h / mL) is set to 100, and the ratios of each dry syrup are shown in Table 15. The following symbols used in this specification and in the table have the following meanings. ↑: Geometric mean ratio is 125% or higher →: The ratio of the geometric mean is within the range of 80-125%. [Table 10] When the suspensions of the dry syrup formulations (Examples 30 and 31) were administered orally as a single dose on an empty stomach, the AUC and Cmax of Example 30 were increased compared to the capsule formulation, while the Cmax of Example 31 was approximately the same, and the AUC was increased. Figure 5 shows the plasma concentration profiles after a single administration of capsules and dry syrup. A single administration of the dry syrup suspension (Examples 30 and 31) showed exposure levels equivalent to or higher than those of the capsules. Furthermore, administration of the dry syrup suspension (Example 31) showed exposure levels equivalent to or higher than those of administration of the dry syrup powder (Example 31).

Claims

1. A syrup containing alectinib or a salt thereof, a surfactant, and a gelling inhibitor, wherein the gelling inhibitor is selected from the group consisting of calcium chloride, sodium chloride, potassium chloride, sodium sulfate, calcium sulfate, calcium dihydrogen phosphate, sodium hydroxide, calcium hydroxide, and sodium bicarbonate.

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

3. The syrup according to claim 2, wherein the anionic surfactant is sodium lauryl sulfate.

4. The syrup according to claim 1, further containing a pH adjuster.

5. The syrup according to claim 4, wherein the pH adjusting agent is tartaric acid.

6. The syrup preparation according to claim 1, further comprising one or more substances selected from disintegrants, excipients, and binders.

7. The syrup according to claim 1, wherein the weight ratio of alectinib or a salt thereof to the gelation inhibitor is 100:30 to 100:90 on a free form basis.

8. The syrup according to claim 1, wherein the weight ratio of alectinib or a salt thereof, the surfactant, and the gelation inhibitor is 100:3:30 to 100:50:90 on a free form basis.

9. The syrup according to claim 1, further containing one or more substances selected from preservatives, thickeners, sweeteners, and flavorings.

10. The syrup according to claim 9, wherein the thickening agent is selected from the group consisting of xanthan gum, hydroxyethylcellulose, and sodium carboxymethylcellulose; the sweetener is selected from the group consisting of sucrose, mannitol, fructose, lactose, sodium saccharin, aspartame, xylitol, erythritol, sucralose, and acesulfame potassium; and the flavoring is selected from the group consisting of strawberry flavor, raspberry flavor, orange flavor, apple flavor, cherry black flavor, and yogurt flavor.

11. The syrup agent according to claim 1, wherein the syrup agent is a dry syrup agent.

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