Detailed Description
In the present invention, the pharmaceutical composition is a composition containing the quinoline derivative (I) and a basic substance as essential components. The ratio of the quinoline derivative (I) to the basic substance is not particularly limited, but is usually 1: 0.5 to 50, preferably 1: 1 to 25, and more preferably 1: 2 to 12.5.
The ratio of the quinoline derivative (I) to the total mass of the pharmaceutical composition (excluding the capsule) is usually 0.25 to 50 mass%, preferably 0.5 to 25 mass%, and more preferably 1 to 12.5 mass%.
The amount of the basic substance is usually 1 to 60% by mass, preferably 5 to 50% by mass, and more preferably 10 to 40% by mass, based on the total mass of the pharmaceutical composition. The basic substance according to the present invention may be incorporated in the pharmaceutical composition in at least one kind, or may be incorporated in two or more kinds.
The dosage form of the pharmaceutical composition specifically refers to solid preparations such as granules, fine granules (subtitle granules), tablets, capsules and the like. Fine granules, granules and capsules filled with these fine granules and granules are preferable.
The quinoline derivative (I) is a compound disclosed in International publication No. 2002/32872. Preferred quinoline derivatives (I) are quinoline derivatives selected from the following, or pharmacologically acceptable salts thereof, or solvates thereof:
4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide,
4- (3-chloro-4- (methylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide,
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- (((cyclopropylamino) carbonyl) amino) phenoxy) -7-methoxy) -6-quinolinecarboxamide, and
n6-methoxy-4- (3-chloro-4- (((ethylamino) carbonyl) amino) phenoxy) -7-methoxy-6-quinolinecarboxamide.
More preferred quinoline derivative (I) is a quinoline derivative selected from the group consisting of:
4- (3-chloro-4- (methylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide,
4- (3-chloro-4- (ethylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide,
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.
Particularly preferred quinoline derivatives (I) are
4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide, or a pharmacologically acceptable salt thereof or a solvate of either.
In the present invention, the pharmacologically acceptable salt means a hydrochloride, a hydrobromide, a p-toluenesulfonate, a sulfate, a methanesulfonate or an ethanesulfonate. Preferably a mesylate salt.
In the present invention, the solvate means a hydrate, a dimethylsulfoxide compound or an acetic acid compound.
The quinoline derivative (I) is preferably a crystal of a salt of 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide or a solvate thereof disclosed in International publication No. 2005/063713. A particularly preferred quinoline derivative (I) is the C-form crystal of the mesylate salt of 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide.
The quinoline derivative (I) is useful as a prophylactic or therapeutic agent for various tumors and a metastasis preventing agent for tumors. Examples of the effective tumor include thyroid cancer, non-small cell lung cancer, melanoma, hypopharyngeal cancer, esophageal cancer, gastric cancer, colorectal cancer, hepatocellular cancer, renal cell cancer, pancreatic cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, gastrointestinal stromal tumor, sarcoma, osteosarcoma, hemangioma, malignant lymphoma, myelogenous leukemia, neuroma, glioma and the like.
In the present invention, the basic substance means a basic inorganic salt. Examples of the basic inorganic salt include beryllium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, potassium carbonate, calcium hydrogen phosphate, and titanium oxide. Preferably an alkaline earth metal salt of carbonic acid, more preferably magnesium carbonate or calcium carbonate.
A disintegrant may also be incorporated into the pharmaceutical composition of the present invention. Examples of the disintegrant include corn starch, partially gelatinized starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, and crospovidone. Preferably croscarmellose sodium, low substituted hydroxypropyl cellulose or crospovidone.
The pharmaceutical composition according to the present invention can be produced by a known method such as the method described in the general formulation code of the fifth revised japanese pharmacopoeia.
For example, in the case of granules, the quinoline derivative (I) can be produced by adding an excipient, a binder, a disintegrant, a solvent, or the like to the quinoline derivative (I) as needed, and performing stirring granulation, extrusion granulation, rotary granulation, fluidized bed granulation, spray granulation, or the like. Further, a dusting agent containing the quinoline derivative (I) and an additive such as corn starch, crystalline cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone or the like may be coated (coating) while spraying water or a binder solution such as white sugar, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or the like onto a core material such as spherical white sugar particles, spherical lactose/crystalline cellulose particles, spherical white sugar/starch particles, or granular crystalline cellulose. In addition, the granules may be granulated and pulverized as necessary.
Further, if necessary, the granules produced as described above may be added with an excipient, a binder, a disintegrant, a lubricant, an antioxidant, a flavoring agent, a coloring agent, a flavoring agent, and the like, and tableted to prepare tablets. In addition, the quinoline derivative (I) may be added with a necessary excipient and directly compressed into tablets. Further, a substance obtained by adding an excipient such as lactose, white sugar, glucose, starch, microcrystalline cellulose, licorice powder, mannitol, calcium phosphate, or calcium sulfate to quinoline derivative (I), or the granules may be filled in capsules.
Examples of the excipient include lactose, white sugar, glucose, fructose, starch, potato starch, corn starch, wheat starch, rice starch, crystalline cellulose, microcrystalline cellulose, licorice powder, mannitol, erythritol, maltitol, sorbitol, trehalose, silicic anhydride, calcium silicate, sodium hydrogen carbonate, calcium phosphate, anhydrous calcium phosphate, and calcium sulfate.
Examples of the binder include gelatin, starch, gum arabic, tragacanth gum, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, partially gelatinized starch, polyvinyl alcohol, sodium alginate, pullulan, glycerin and the like.
Examples of the disintegrant include corn starch, partially gelatinized starch, hydroxypropyl starch, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, sodium croscarmellose, low-substituted hydroxypropyl cellulose, and crospovidone.
Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, talc, and polyethylene glycol.
Examples of the antioxidant include sodium ascorbate, L-cysteine, sodium sulfite, tocopherol, and soybean lecithin.
Examples of the taste-modifying agent include citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizin dipotassium, sodium glutamate, sodium 5 '-inosinate, and sodium 5' -guanylate.
Examples of the colorant include titanium oxide, iron trioxide, yellow iron trioxide, cochineal, carmine, riboflavin, edible yellow No. 5, and edible blue No. 2.
Examples of the flavor include lemon oil, orange oil, menthol, peppermint oil, borneol, vanillin, and the like.
Examples
The present invention will be described in further detail with reference to examples, but the present invention is not limited to these examples
Examples 1 to 3
With respect to the C-type crystal of the methanesulfonate salt of 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide (hereinafter, referred to as compound A), D-mannitol (trade name: mannitol, merck), precipitated calcium carbonate (trade name: Whiten F, Kaisha), hydroxypropylcellulose (HPC-L, Nippon soda), low-substitution hydroxypropylcellulose (trade name: L-HPC (LH-21), shin-Etsu chemical industry) and crystalline cellulose (trade name: Ceolus PH-101, Asahi Kasei), wet granulation was carried out using a high-speed stirring granulator (device name: FM-VG-10, manufactured by Powlex corporation) in the formulation ratio shown in Table 1 using purified water as a solvent. Further dried and granulated into granules having a moisture content of less than 2% and having a particle size of less than 1mm were granulated by using a grinding and granulating apparatus (apparatus name: Power Mill P-04S, manufactured by Showa Tekkiso K.K.). Then, crystalline cellulose (trade name: Ceolus PH-102, Asahi chemical Co., Ltd.) and talc (trade name: Hi-filler 17, rock well chemical) were added to the whole granules at the formulation ratios shown in Table 1, and thoroughly mixed using a tumbler mixer (trade name: 10L/20L exchange type tumbler mixer, manufactured by TOYO PACKING Co., LTD.). The obtained granules 100mg were filled into No. 4 hard capsules to produce capsules containing compound a.
[ Table 1]
| Example 1 | Example 2 | Example 3 |
| Compound A | 1.25 | 5 | 12.5 |
| Precipitated calcium carbonate | 33 | 33 | 33 |
| D-mannitol | 19.75 | 16 | 8.5 |
| Hydroxypropyl cellulose | 3 | 3 | 3 |
| Low substitution degree hydroxypropyl cellulose | 25 | 25 | 25 |
| Crystalline cellulose (PH-101) | 10 | 10 | 10 |
| Crystalline cellulose (PH-102) | 5 | 5 | 5 |
| Talc | 3 | 3 | 3 |
| Total of | 100 | 100 | 100 |
Unit: mass%
Examples 4 to 9 and comparative examples 1 to 2
Compound A, precipitated calcium carbonate, low-substituted hydroxypropylcellulose, D-mannitol and talc were thoroughly mixed using a mortar and pestle at the formulation ratios of Table 2 and Table 3. The obtained mixture (100 mg) was filled in a hard capsule No. 3 to prepare capsules of examples 4 to 9. In addition, capsules of comparative examples 1 to 2, which did not contain precipitated calcium carbonate, were produced in the same manner.
[ Table 2]
Unit: mass%
[ Table 3]
Unit: mass%
Test example 1
The capsules of examples 4 to 9 and comparative examples 1 to 2 were examined for the dissolution of Compound A according to the dissolution test method (Paddle method, test solution: solution 1) described in the Japanese pharmacopoeia as a fifteenth amendment. As a result, the capsules of comparative examples 1 to 2, in which calcium carbonate was not blended, were insufficient in elution of the compound A. On the other hand, in the capsules of examples 4 to 9 containing calcium carbonate, the elution of compound a was good (fig. 1 and 2).
Examples 10 to 15 and comparative examples 3 to 4
Compound A, magnesium carbonate (Cogeneration chemical industry), low-substituted hydroxypropylcellulose, D-mannitol and talc were thoroughly mixed using a mortar and pestle at the formulation ratios of Table 4 and Table 5. 100mg of the obtained mixture was filled in No. 3 hard capsules to prepare capsules of examples 10 to 15. Capsules of comparative examples 3 to 4 containing no magnesium carbonate were produced in the same manner.
[ Table 4]
Unit: mass%
[ Table 5]
Unit: mass%
Test example 2
The dissolution properties of Compound A were examined for the capsules of examples 10 to 15 and comparative examples 3 to 4 in the same manner as in test example 1. In the capsules of comparative examples 3 to 4 containing no magnesium carbonate, the elution of compound A was insufficient. On the other hand, in the capsules of examples 10 to 15 containing magnesium carbonate, the elution of compound a was good (fig. 3 and 4).
Examples 16 to 17 and comparative examples 5 to 6
Purified water was added to compound a, precipitated calcium carbonate or magnesium carbonate, hydroxypropyl cellulose, croscarmellose sodium (trade name: Ac-di-sol, asahi chemical), granulated using a mortar and pestle, and the dried granules were then sized to a particle size of less than 1 mm. Then, crystalline cellulose (trade name: Ceolus PH-102, Asahi Kasei Co., Ltd.), low-substitution hydroxypropylcellulose and talc (trade name: Hi-filler 17, Ichwell chemical) were added to the whole granules in the formulation ratios shown in Table 6, and mixed thoroughly. 100mg of the obtained mixture was filled in No. 4 hard capsules to prepare capsules of examples 16 to 17. In addition, capsules of comparative examples 5 to 6 containing neither precipitated calcium carbonate nor magnesium carbonate, but mannitol or talc were prepared in the same manner at the formulation ratios shown in table 7.
[ Table 6]
| Example 16 | Example 17 |
| Compound A | 10 | 10 |
| Precipitated calcium carbonate | 15 | 0 |
| Magnesium carbonate | 0 | 15 |
| Hydroxypropyl cellulose | 2 | 2 |
| Croscarmellose sodium | 10 | 10 |
| Low substitution degree hydroxypropyl cellulose | 20 | 20 |
| Crystalline cellulose (PH-102) | 41 | 41 |
| Talc | 2 | 2 |
| Total of | 100 | 100 |
Unit: mass%
[ Table 7]
| Comparative example 5 | Comparative example 6 |
| Compound A | 10 | 10 |
| Mannitol | 15 | 0 |
| Talc | 0 | 15 |
| Hydroxypropyl cellulose | 2 | 2 |
| Croscarmellose sodium | 10 | 10 |
| Low substitution degree hydroxypropyl cellulose | 20 | 20 |
| Crystalline cellulose (PH-102) | 41 | 41 |
| Talc | 2 | 2 |
| Total of | 100 | 100 |
Unit: mass%
Test example 3
The dissolution properties of compound a were examined for the capsules of examples 16 to 17 and comparative example 5 in the same manner as in test example 1. In the capsule of comparative example 5 in which calcium carbonate and magnesium carbonate were not blended, the elution of compound a was insufficient. On the other hand, the capsules of examples 16 to 17 containing calcium carbonate or magnesium carbonate exhibited good elution of compound a (fig. 5).
Test example 4
The capsules of examples 16 to 17 and comparative example 6 were stored in an open system at a temperature of 60 ℃ and a relative humidity of 75% for one week, and then the formation of decomposition products was measured by using a high performance liquid chromatograph. In the capsule of comparative example 6 in which calcium carbonate and magnesium carbonate were not blended, the decomposition product increased. On the other hand, in the capsules of examples 16 to 17 containing calcium carbonate or magnesium carbonate, no increase in decomposition products was observed (Table 8).
[ Table 8]
Examples 18 to 19 and comparative examples 7 to 10
The components were mixed according to the recipes shown in tables 9 and 10 in the same manner as in examples 4 to 9 and comparative examples 1 to 2. Capsules of examples 18 to 19 and comparative examples 7 to 10 were prepared by filling 100mg of the obtained mixture in No. 3 hard capsules.
[ Table 9]
| Example 18 | Comparative example 7 | Comparative example 8 |
| Compound A | 20 | 20 | 20 |
| Precipitated calcium carbonate | 10 | 0 | 0 |
| Calcium oxide | 0 | 10 | 0 |
| Calcium hydroxide | 0 | 0 | 10 |
| Low substitution degree hydroxypropyl cellulose | 20 | 20 | 20 |
| D-mannitol | 47 | 47 | 47 |
| Talc | 3 | 3 | 3 |
| Total of | 100 | 100 | 100 |
Unit: mass%
[ Table 10]
| Example 19 | Comparative example 9 | Comparative example 10 |
| Compound A | 20 | 20 | 20 |
| Magnesium carbonate | 10 | 0 | 0 |
| Magnesium oxide | 0 | 10 | 0 |
| Magnesium hydroxide | 0 | 0 | 10 |
| Low substitution degree hydroxypropyl cellulose | 20 | 20 | 20 |
| D-mannitol | 47 | 47 | 47 |
| Talc | 3 | 3 | 3 |
| Total of | 100 | 100 | 100 |
Unit: mass%
Test example 5
The dissolution properties of Compound A were examined for the capsules of examples 18 to 19 and comparative examples 7 to 10 in the same manner as in test example 1. As a result, the dissolution of the compound A was insufficient in the capsules of comparative examples 7 to 10 containing calcium oxide, calcium hydroxide, magnesium oxide or magnesium hydroxide. On the other hand, in the capsules of examples 18 to 19 containing calcium carbonate or magnesium carbonate, the elution of compound a was good (fig. 6 and 7).
Industrial applicability
The pharmaceutical composition of the present invention is excellent in the elution property and stability of the quinoline derivative, and therefore is useful as a drug for the prevention and treatment of tumors.