TWI501950B - Pharmaceutical composition comprising quinoline derivative - Google Patents

Description

Pharmaceutical composition containing quinoline derivative

The present invention relates to a pharmaceutical composition comprising a quinoline derivative useful as a medicament. More particularly, the present invention relates to a pharmaceutical composition for improving the solubility of a quinoline derivative or a pharmaceutically acceptable salt thereof or a solvate thereof.

The quinoline derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof (hereinafter referred to as quinoline derivative (I)) is known to have a strong angiogenesis inhibitory effect (Patent Document 1) and The c-Kit kinase inhibitory effect (Patent Document 2) is also useful as a prophylactic or therapeutic agent for various tumors such as thyroid cancer, lung cancer, melanoma, pancreatic cancer, and as a metastasis inhibitor of these tumors:

Wherein R ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _3-8 cycloalkyl group; and R ² is a hydrogen atom or a methoxy group.

However, it has been found that the quinoline derivative (I) degrades under wet and warm storage conditions when formulated into a pharmaceutical composition. Further, when the pharmaceutical composition absorbs moisture, the active ingredient quinoline derivative (I) is delayed from being dissolved by the pharmaceutical composition due to gelation on the surface of the composition. In order to overcome these problems, a pharmaceutical composition comprising a quinoline derivative (I), (1) a compound (5% (w/w) in an aqueous solution or suspension and having a pH of 8 or higher has been developed. And/or (2) citric acid, a salt thereof or a solvate thereof (Patent Document 3).

List of cited documents Patent literature

Patent Document 1: WO 2002/32872

Patent Document 2: WO 2004/080462

Patent Document 3: WO 2006/030826

However, it has also been desired to develop a pharmaceutical composition having a superior dissolution of the quinoline derivative (I). Accordingly, it is an object of the present invention to provide a pharmaceutical composition which retains superior dissolution of the quinoline derivative (I) even after long-term storage.

The inventors have intensively studied to solve the above problems, and surprisingly have found that the following configurations can solve the above problems and have completed the present invention.

Specifically, the present invention provides the following <1> to <12>.

[1] A pharmaceutical composition comprising

(1) A compound of the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof:

Wherein R ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _3-8 cycloalkyl group; and R ² is a hydrogen atom or a methoxy group, and (2) a basic substance.

[2] The composition according to [1], wherein the alkaline substance is a carbonate.

[3] The composition according to [2], wherein the salt is an alkaline earth metal salt.

[4] The composition according to [3], wherein the alkaline earth metal salt is a magnesium salt or a calcium salt.

[5] The composition according to any one of [1] to [4] which further comprises a disintegrating agent.

[6] The composition according to [5], wherein the disintegrant is sodium carmellose, calcium carboxymethyl ether, sodium carboxymethyl starch, croscarmellose Sodium, low substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone (crospovidone).

[7] The composition according to any one of [1] to [6] wherein R ¹ is a hydrogen atom, a methyl group, an ethyl group, a n-propyl group or a cyclopropyl group.

[8] The composition according to any one of [1] to [7] wherein R ¹ is a cyclopropyl group.

[9] The composition according to any one of [1] to [8] wherein R ² is a hydrogen atom, a methoxy group, or an ethoxy group.

[10] The composition according to any one of [1] to [9] wherein R ² is a hydrogen atom.

[11] The composition according to any one of [1] to [10] wherein the pharmaceutically acceptable salt is a hydrochloride, a hydrobromide, a p-toluenesulfonate, a sulfate, a methanesulfonate Or ethanesulfonate.

[12] The composition according to any one of [1] to [11] wherein the compound of the formula (I) is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy Base 7-methoxy-6-quinoline carboxamide methanesulfonate.

The main action agent quinoline derivative (I) of the pharmaceutical composition of the present invention has a superior dissolution effect and has a superior absorption effect in vivo. The pharmaceutical composition is also a pharmaceutical composition that can be maintained even after long-term storage.

Description of specific examples

The pharmaceutical composition of the present invention means a composition comprising a quinoline derivative (I) and a basic substance as essential components. The mixing ratio of the quinoline derivative (I) to the basic substance is generally, but not limited to, 1:0.5 to 50, preferably 1:1 to 25, more preferably 1:2 to 12.5.

Further, the mixing ratio of the quinoline derivative (I) to the total weight of the pharmaceutical composition (excluding the capsule shell) is usually 0.25 to 50% by weight, preferably 0.5 to 25% by weight, more preferably 1 to 12.5 by weight. %.

The mixing ratio of the basic substance to the total weight of the pharmaceutical composition is usually from 1 to 60% by weight, preferably from 5 to 50% by weight, more preferably from 10 to 40% by weight. At least one basic substance of the present invention may be included in the pharmaceutical composition, or may also include two or more basic substances.

The dosage form of the pharmaceutical composition refers in particular to a solid preparation such as granules, fine granules, lozenges, or capsules and the like. Preferred are fine particles, granules or capsules filled with fine particles or granules.

The quinoline derivative (I) is a compound disclosed in WO 2002/32872. The preferred quinoline derivative (I) is a quinoline derivative selected from the group consisting of or a pharmaceutically acceptable salt thereof or a solvate thereof: 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminobenzene Oxy)-7-methoxy-6-quinolinecarboxamide, 4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy)-7-methoxy-6-quin Carboxylaminium, 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, N6-methoxy-4- (3-Chloro-4-((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, 4-(3-chloro-4-(1) -propylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, N6-methoxy-4-(3-chloro-4-(((cyclopropylamine)) (carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, and N6-methoxy-4-(3-chloro-4-(((ethylamino))) Carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide.

More preferably, the quinoline derivative (I) is a quinoline derivative selected from the group consisting of or a pharmaceutically acceptable salt thereof or a solvate thereof: 4-(3-chloro-4-(methylaminocarbonyl)aminophenoxy -7-methoxy-6-quinoline carboxamide, 4-(3-chloro-4-(ethylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline Carboxylamidine, 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, N6-methoxy-4- (3-Chloro-4-((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide, and N6-methoxy-4-( 3-Chloro-4-(((ethylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxamide.

a particularly preferred quinoline derivative (I) is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, or A pharmaceutically acceptable salt or a solvate thereof.

The pharmaceutically acceptable salt of the present invention means a hydrochloride, a hydrobromide, a p-benzenesulfonate, a sulfate, a methanesulfonate or an ethanesulfonate. A mesylate salt is preferred.

The solvate of the present invention means a hydrate, a dimethyl hydrazine solvate, or an acetic acid solvate.

The quinoline derivative (I) is preferably 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy- disclosed in WO 2005/063713. Crystallization of a salt of 6-quinolinecarboxamide, or a solvate thereof. The particularly preferred quinoline derivative (I) is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonic acid C type crystal of salt.

The quinoline derivative (I) can be used as a prophylactic or therapeutic agent for various tumors and as a metastasis inhibitor of tumors. Examples of tumors in which the quinoline derivative (I) is effective against thyroid cancer, non-small cell lung cancer, melanoma, throat cancer, esophageal cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, Bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, gastrointestinal stromal tumor, sarcoma, osteosarcoma, hemangioma, malignant lymphoma, myeloid leukemia, neuroma and glioma.

The basic substance of the present invention means an alkaline inorganic salt. The basic inorganic salt includes barium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, barium carbonate, potassium carbonate, calcium hydrogen phosphate, and titanium oxide. Preferably, it is an alkaline earth metal carbonate, and further preferably magnesium carbonate or calcium carbonate.

The pharmaceutical compositions of the present invention additionally include a disintegrant and are also acceptable. The disintegrant comprises corn starch, partially pregelatinized starch, carboxypropyl starch, carmellose, sodium carboxymethyl ether, calcium carboxymethyl ether, sodium carboxymethyl starch , croscarmellose sodium, low substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone (crospovidone). Preferably, it is croscarmellose sodium, low substituted hydroxypropylcellulose, or crosslinked polyvinylpyrrolidone.

The pharmaceutical compositions of the present invention can be prepared by known methods, such as those described in General Rules for Preparations in the Japanese Pharmacopoeia Fifteenth Edition.

For example, in the case of granules, an excipient, a binder, a disintegrant, a solvent or the like may be added to the quinoline derivative (I) as needed for stirring granulation, extrusion granulation, rolling Granules, fluid bed granulation, spray granulation, or the like, and are prepared. Also acceptable, coating with an atomizing agent containing the quinoline derivative (I) and an additive such as corn starch, microcrystalline cellulose, hydroxypropyl cellulose, methyl cellulose, or polyvinylpyrrolidone And simultaneously spray a solution of water or a binder such as sucrose, hydroxypropylcellulose or hydroxypropylmethylcellulose in core materials (such as purified sucrose pellets, lactose/crystalline cellulose pellets, sucrose) / starch pellets or granular cellulose). It is also acceptable to perform screening and grinding as needed.

It is also possible to additionally add an excipient, a binder, a disintegrant, a lubricant, an antioxidant, a flavoring agent, a coloring agent, a fragrance, or the like to the granule prepared in this manner and compress it into an ingot. . The desired excipient can be added to the quinoline derivative (I) to directly compress the mixture into an ingot. It is also possible to use or add an excipient (such as lactose, sucrose, glucose, starch, microcrystalline cellulose, powdered licorice, mannitol, calcium phosphate, or calcium sulfate) to the quinoline derivative (I). The particles of He is filled with capsules.

Examples of such excipients include lactose, sucrose, glucose, fructose, starch, potato starch, corn starch, wheat starch, rice starch, crystalline cellulose, microcrystalline cellulose, powdered licorice, mannitol, erythritol , maltitol, sorbitol, trehalose, phthalic anhydride, calcium citrate, sodium hydrogencarbonate, calcium phosphate, anhydrous calcium phosphate and calcium sulfate.

Examples of the binder include gelatin, starch, gum arabic, tragacanth, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, and some pre-gelatin. Starch, pregelatinized starch, polyvinyl alcohol, sodium sulphate, mucopolysaccharide and glycerin.

Examples of the disintegrant include corn starch, partially pregelatinized starch, hydroxypropyl starch, carboxymethyl ether cellulose, sodium carboxymethyl ether, calcium carboxymethyl ether, sodium carboxymethyl starch, cross-linking Sodium carbocarboxylate, low substituted hydroxypropyl cellulose and crosslinked polyvinylpyrrolidone.

Examples of such lubricants include magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, talc, and macrogol.

Examples of such antioxidants include sodium ascorbate, L-cysteine, sodium sulfite, tocopherol, and soy lecithin.

Examples of such flavoring agents include citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thammago, sodium saccharin, dipotassium glycyrrhizinate, sodium glutamate, 5'-muscle Sodium glycinate and sodium 5'-guanylate.

Examples of the coloring agent include titanium oxide, ferric oxide, ferric oxide yellow, cochineal red, carmine, riboflavin, food grade yellow pigment No. 5, and food grade blue pigment No. 2.

Examples of such flavors include lemon oil, orange oil, menthol, peppermint oil, borneol and vanilla flavor.

The invention will be described in more detail below with reference to examples, but is not limited to these examples.

Examples 1 to 3

Using a high shear granulator (device name: FM-VG-10, manufactured by Powrex Corporation), using pure water as a solvent, according to the formulation ratio in Table 1, using 4-(3-chloro-4-(cyclopropyl) C-form crystal of aminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), D-mannitol (trade name: Mannitol, Merck), precipitated calcium carbonate (trade name: Whiton F, Shiraishi Calcium), hydroxypropyl cellulose (HPC-L, Nippon Soda), low-substituted hydroxypropyl cellulose (trade name: L-HPC ( LH-21), Shin-Etsu Chemical), and microcrystalline cellulose (trade name: Ceolus PH-101, Asahi Kasei Chemicals) were subjected to wet granulation. The water content of the granules was reduced to less than 2% by additional drying, and the granules were sieved using a screening mill (device name: Power Mill P-04S, manufactured by Showa Giken KK) to make the particle diameter smaller than 1 mm. Then, microcrystalline cellulose (trade name: Ceolus PH-102, Asahi Kasei Chemicals) and talc (trade name: Hi-Filler 17, Iwai Chemicals Company) were added to the sieved particles according to the formulation ratio in Table 1. And the mixture was thoroughly mixed using a diffusion (rolling type) mixer (trade name: 10L/20L Exchange-type Tumbler Mixer, manufactured by Toyo Packing Corporation). 100 mg of the obtained granules were filled in a hard capsule of size #4 to prepare a capsule containing Compound A.

Examples 4 to 9 and Comparative Examples 1 to 2

Using a mortar and pestle, Compound A, precipitated calcium carbonate, low-substituted hydroxypropylcellulose, D-mannitol, and talc were thoroughly mixed according to the formulation ratios in Tables 2 and 3. 100 mg of the resulting mixture was filled in a hard capsule of size #3 to prepare capsules of Examples 4 to 9. The capsules of Comparative Examples 1 to 2 were also prepared by the same method, but they did not contain precipitated calcium carbonate.

Test case 1

The solubility of Compound A in the capsules of Examples 4 to 9 and Comparative Examples 1 to 2 was examined in accordance with the dissolution test (the Paddle method, test medium: JP1 solution) described in Japanese Pharmacopoeia Fifteenth Edition. As a result, the dissolution of Compound A in the capsules of Comparative Examples 1 to 2 in which calcium carbonate was not mixed was insufficient. In contrast, the dissolution of Compound A in the capsules of Examples 4 to 9 in which calcium carbonate was mixed was good (Fig. 1 and Fig. 2).

Examples 10 to 15 and Comparative Examples 3 to 4

Using a mortar and pestle, Compound A, magnesium carbonate (Kyowa Chemical Industry), low-substituted hydroxypropylcellulose, D-mannitol, and talc were thoroughly mixed according to the formulation ratios in Tables 4 and 5. 100 mg of the resulting mixture was filled in a hard capsule of size #3 to prepare capsules of Examples 10 to 15. Capsules of Comparative Examples 3 to 4 were also prepared by the same method, but they were free of magnesium carbonate.

Test case 2

The dissolution of Compound A in the capsules of Examples 10 to 15 and Comparative Examples 3 to 4 was examined in the same manner as in Test Example 1. The dissolution of Compound A in the capsules of Comparative Examples 3 to 4 in which magnesium carbonate was not mixed was insufficient. In contrast, the dissolution of Compound A in the capsules of Examples 10 to 15 in which calcium carbonate was mixed was good (Fig. 3 and Fig. 4).

Examples 16 to 17 and Comparative Examples 5 to 6

Pure water is added to compound A, precipitated calcium carbonate or magnesium carbonate, hydroxypropyl cellulose and croscarmellose sodium using a mortar and pestle (trade name: Ac-Di-Sol, Asahi Kasei Chemicals) For granulation, the dried granules are then screened to a particle diameter of less than 1 mm. Then, according to the formulation ratios in Table 6, microcrystalline hydroxypropylcellulose (trade name: Ceolus PH-102, Asahi Kasei Chemicals), low-substituted hydroxypropylcellulose, and talc (trade name: Hi-Filler) 17, Iwai Chemicals Company) is added to the screened granules and the mixture is thoroughly mixed. 100 mg of the resulting mixture was filled in a hard capsule of size #4 to prepare capsules of Examples 16 to 17. The capsules of Comparative Examples 5 to 6 were also prepared in the same manner as in the formulation ratios in Table 7, except that they contained neither precipitated calcium carbonate nor magnesium carbonate, but contained mannitol or talc instead.

Test example 3

The dissolution of Compound A in the capsules of Examples 16 to 17 and Comparative Example 5 was examined in the same manner as in Test Example 1. The dissolution of Compound A in the capsule of Comparative Example 5 in which neither calcium carbonate nor magnesium carbonate was mixed was insufficient. In contrast, the dissolution of Compound A in the capsules of Examples 16 to 17 in which calcium carbonate or magnesium carbonate was mixed was good (Fig. 5).

Test example 4

The capsules of Examples 16 to 17 and Comparative Example 6 were stored in an open system for 1 week at a temperature of 60 ° C and a relative humidity of 75%, and then the production of the degradation product was measured by high performance liquid chromatography. In the capsule blend of Comparative Example 6 in which neither calcium carbonate nor magnesium carbonate was mixed, the amount of the degradation product increased. In contrast, in the capsules of Examples 16 to 17 in which calcium carbonate or magnesium carbonate was mixed, no increase in degradation products was observed (Table 8).

Examples 18 to 19 and Comparative Examples 7 to 10

The individual components were mixed according to the blending ratios of Tables 9 and 10 by the same methods as in Examples 4 to 9 and Comparative Examples 1 to 2. 100 mg of the resulting mixture was filled in a hard capsule of size #3 to prepare capsules of Examples 18 to 19 and Comparative Examples 7 to 10.

Test example 5

The dissolution of Compound A in the capsules of Examples 18 to 19 and Comparative Examples 7 to 10 was examined by the same method as Test Example 1. As a result, the dissolution of Compound A in the capsules of Comparative Examples 7 to 10 in which calcium oxide, calcium hydroxide, magnesium oxide or magnesium hydroxide was mixed was insufficient. In contrast, the dissolution of Compound A in the capsules of Examples 18 to 19 in which calcium carbonate or magnesium carbonate was mixed was good (Fig. 6 and Fig. 7).

Industrial applicability

The pharmaceutical composition according to the present invention is superior in the dissolution action and stability of the quinoline derivative, and thus can be used as a drug for preventing or treating a tumor.

Fig. 1 shows a change curve of the compound A obtained by dissolving the compositions obtained in Examples 4 to 6 and Comparative Example 1.

Fig. 2 shows a change curve of the compound A obtained by dissolving the composition obtained in Examples 7 to 9 and Comparative Example 2.

Figure 3 shows a graph in which the composition obtained in Examples 10 to 12 and Comparative Example 3 was dissolved to give Compound A.

Fig. 4 shows a change curve of the compound A obtained by dissolving the compositions obtained in Examples 13 to 15 and Comparative Example 4.

Fig. 5 shows a change curve of the compound A obtained by dissolving the composition obtained in Examples 16 to 17 and Comparative Example 5.

Fig. 6 shows a change curve of the compound A obtained by the dissolution of the composition obtained in Example 18 and Comparative Examples 7 to 8.

Fig. 7 shows a change curve of the compound A obtained by dissolving the composition obtained in Example 19 and Comparative Examples 9 to 10.

Claims (9)

A pharmaceutical composition comprising (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof: Wherein R ¹ is a hydrogen atom, a C _1-6 alkyl group or a C _3-8 cycloalkyl group; and R ² is a hydrogen atom or a methoxy group, and (2) an alkaline earth metal carbonate. The composition of claim 1, wherein the alkaline earth metal carbonate is magnesium carbonate or calcium carbonate. The composition of claim 1 or 2 further comprising a disintegrant. The composition of claim 3, wherein the disintegrant is sodium carmellose, calcium carboxymethyl ether, sodium carboxymethyl starch, croscarmellose Sodium, low substituted hydroxypropyl cellulose or cross-linked polyvinylpyrrolidone (crospovidone). The composition of claim 1, wherein R ¹ is a hydrogen atom, a methyl group, an ethyl group, a n-propyl group or a cyclopropyl group. The composition of claim 5, wherein R ¹ is a cyclopropyl group. The composition of claim 1, wherein R ² is a hydrogen atom. The composition of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, a hydrobromide, a p-toluenesulfonate, a sulfate, a methanesulfonate or an ethanesulfonate. The composition of claim 1, wherein the compound of the formula (I) is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy Base-6-quinoline carboxamide methanesulfonate.