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    • 专利摘要:
    PHARMACEUTICAL COMPOSITION CONTAINING QUINOLIN DERIVATIVE. The present invention relates to a pharmaceutical composition containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a basic substance, it is excellent in dissolution, it is stable even after a long storage time , and a preventive or therapeutic agent against a tumor is useful: (I) wherein, R1 is a hydrogen atom, a C1-6 alkyl group or a C3-8 cycloalkyl group; and R2 is a hydrogen atom or a methoxy group.
    公开号:BR112012003592B1
    申请号:R112012003592-4
    申请日:2010-08-16
    公开日:2020-11-03
    发明作者:Masashi Bando
    申请人:Eisai R&D Management Co., Ltd；
    IPC主号:
    专利说明:

    Technical Field
    The present invention relates to a pharmaceutical composition containing a quinoline derivative, useful as a medicine. More specifically, the present invention relates to a pharmaceutical composition with improved dissolution of a quinoline derivative or a pharmaceutically acceptable salt thereof or a solvate thereof. Background of the technique
    A quinoline derivative represented by formula (I) or a pharmaceutically acceptable salt thereof, or a solvate thereof (hereinafter referred to as quinoline derivative (I)) has been shown to have a potent inhibitory effect on angiogenesis (Patent Literature 1 ) and an inhibitory effect of c-Kit kinase (Patent Literature 2) and be useful as a preventive or therapeutic agent against various tumors such as thyroid cancer, lung cancer, melanoma and pancreatic cancer, and as a metastatic inhibitor against these tumors:
    wherein, R1 is a hydrogen atom, a C1-6 alkyl group or a C3.8 cycloalkyl group; and R2 is a hydrogen atom or a methoxy group.
    However, it was found that the quinoline derivative (I) degrades in wet and hot storage conditions, when formulated in a pharmaceutical composition. In addition, when the pharmaceutical composition absorbs moisture, dissolution of the quinoline derivative (I) which is an active ingredient in the pharmaceutical composition may take time because of gelation on the surface of the composition. To overcome these problems, a pharmaceutical composition was developed that includes the quinoline derivative (I), (1) a compound whose 5% (w / w) aqueous solution or suspension has a pH of 8 or more, and / or (2) silicic acid, salt thereof or solvate thereof (Patent Literature 3). List of citations Patent Literature
    Patent Literature 1: WO 2002/32872 Patent Literature 2: WO 2004/080462 Patent Literature 3: WO 2006/030826 Summary of the Invention Technical problem
    However, it is desired to develop a pharmaceutical composition that is, in addition, excellent in dissolving the quinoline derivative (I). Thus, the present invention aims to provide a pharmaceutical composition that is excellent at dissolving the quinoline derivative (I), and that is maintained even after long-term storage. Solution of the problem
    The present inventors have studied extensively to solve the above problems and, surprisingly, have found that the configuration below could solve the problems, and have completed the present invention.
    Specifically, the present invention provides the following items <1> to <12>. [1] A pharmaceutical composition containing: [1] a compound represented by the formula (I) or, a pharmaceutically acceptable salt thereof or, solvate thereof:
    wherein R1 is a hydrogen atom, a C1-8 alkyl group or a C3-8 cycloalkyl group; and R2 represents a hydrogen atom or a methoxy group; and [2] a basic substance. [3] Composition according to [1], in which the basic substance is a carbonate. [4] Composition according to [2], in which the salt is an alkaline earth metal salt. [5] Composition according to [3], in which the alkaline earth metal salt is a magnesium salt or a calcium salt. [6] Composition according to any one of [1] to [4], additionally containing a disintegrating agent. [7] Composition according to [5], in which the disintegrating agent is carmellose sodium, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, low substituted hydroxypropylcellulose or crospo-vidone. [8] Composition according to any one of [1] to [6], where R1 is a hydrogen atom, a methyl group, an ethyl group, an n-propyl group or a cyclopropyl group. [9] Composition according to any one of [1] to [7], where R1 is a cyclopropyl group. [10] Composition according to any one of [1] to [8], where R2 is a hydrogen atom, a methoxy group or an ethoxy group. [11] Composition according to any one of [1] to [9], where R2 is a hydrogen atom. [12] Composition according to any one of [1] to [10], wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methanesulfonate or ethanesulfonate. [13] Composition according to any one of [1] to [11], wherein the compound represented by formula (I) is 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6- quinolinocarboxamide methanesulfonate. Advantageous Effects of the Invention
    The pharmaceutical composition of the present invention is excellent at dissolving the quinoline derivative (I), which is a major agent, and is also excellent at absorption in a living body. The pharmaceutical composition is also a pharmaceutical composition that is maintained, even after long-term storage. Brief description of the drawings
    Figure 1 shows the dissolution profiles of compound A, of the pharmaceutical compositions obtained in examples 4 to 6 and comparative example 1.
    Figure 2 shows the dissolution profiles of compound A of the pharmaceutical compositions obtained in examples 7 to 9 and comparative example 2.
    Figure 3 shows the dissolution models of compound A of the pharmaceutical compositions obtained in examples 10 to 12 and comparative example 3.
    Figure 4 shows the dissolution profiles of compound A of the pharmaceutical compositions obtained in examples 13 to 15 and comparative example 4.
    Figure 5 shows the dissolution profiles of compound A of the pharmaceutical compositions obtained in examples 16 to 17 and comparative example 5.
    Figure 6 shows the dissolution profiles of compound A of the pharmaceutical compositions obtained in example 18 and comparative examples 7 to 8.
    Figure 7 shows the dissolution profiles of compound A of the pharmaceutical compositions obtained in example 19 and comparative examples 9 to 10. Description of Modalities
    The pharmaceutical composition of the present invention means a composition containing the quinoline derivative (I) and a basic substance as essential ingredients. The mixing ratio of the quinoline derivative (I) and the basic substance is normally, but not limited to, the range of 1: 0.5 to 50, preferably 1: 1 to 25, even more preferably 1: 2 to 12.5.
    In addition, a mixing rate of the quinoline derivative (I) relative to the total weight of the pharmaceutical composition (excluding the capsule shell) is normally 0.25 to 50% by weight, preferably 0.5 to 25% by weight , even more preferably 1 to 12.5% by weight.
    The mixing rate of the basic substance with respect to the total weight of the pharmaceutical composition is normally 1 to 60% by weight, preferably 5 to 50% by weight, even more preferably 10 to 40% by weight. At least one basic substance of the present invention can be included in the pharmaceutical composition, or two or more basic substances can also be included.
    A dosage form of the pharmaceutical composition specifically means a solid preparation such as granules, fine granules, tablets or capsules and the like. It preferably includes fine granules, granules or capsules filled with fine granules or granules. The quinoline derivative (I) is a compound described in WO 2002/32872. A preferable quinoline derivative (I) is a quinoline derivative or pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of 4- (3-fluoro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7- (2-methoxyethoxy) -6-quinolinocarboxamide, 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6- quinolinocarboxamide, 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7- (2-methoxyethoxy) -6-quinolinocarboxamide, 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7- (2-hydroxyethoxy) -6-quinolinocarboxamide, 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7- ( (2S) -2,3-dihydroxypropyl) oxy-6-quinolinecarboxamide, 4- (3-chloro-4- (methylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinocarboxamide, 4- (3-chloro-4- (ethylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide, N6-methoxy-4- (3-chloro-4 - ((((ethylamino) carbonyl) amino) phenoxy) -7-methoxy-6-quinolinocarboxamide, 4- ( 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7- (2 OK ethoxyethoxy) -6-quinolinocarboxamide, 4- (4 - (((cyclopropylamino) carbonyl) aminophenoxy) -7- (2-methoxyethoxy) -6-quinolinecarboxamide, N- (2-fluoro-4 - [(6-carbamoyl-7-methoxy-4-quinolyl) oxy] phenyl) - N'- cyclopropylurea, N6- (2-hydroxyethyl) -4- (3-chloro-4- (((cyclopropylamino) carbonyl) amino) phenoxy) -7-methoxy-6-quinolinocarboxamide, 4- (3-chloro-4 - (1-propylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinocarboxamide, 4- (3-chloro-4- (cis-2-fluoro-cyclopropylaminocarbonyl) aminophenoxy) - 7-methoxy-6-quinolinocarboxamide, N6-methyl- 4- (3-chloro-4 - (((cyclopropylamino) carbonyl) amino) phenoxy) - 7- (2-methoxyethoxy) -6-quinolinocarboxamide and N6-methyl-4- (3-chloro-4 - (((ethylamino ) carbonyl) amino) phenoxy) -7-methoxy-6-quinolinecarboxamide. A more preferable quinoline (I) derivative is a quinoline derivative or pharmaceutically acceptable salt or solvate thereof, 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-quinolinocarboxamide, 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 preferable quinoline derivative (I) is 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt or solvate thereof.
    Pharmaceutically acceptable salt of the present invention means hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methanesulfonate or ethanesulfonate, preferably methanesulfonate.
    Solvate of the present invention means hydrate, dimethyl sulfoxide solvate or acetic acid solvate.
    The quinoline derivative (I) is preferably a crystal of a salt of 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinocarboxamide, or a solvate thereof, described in WO 2005/063713 . A particularly preferred derivative of quinoline (I) is OK 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinecarboxamide methanesulfonate C.
    The quinoline derivative (I) is useful as a preventive or therapeutic agent against various tumors, and as a tumor metastasis inhibitor. Examples of tumors against which the quinoline derivative (I) is effective include; thyroid cancer, non-small cell lung cancer, melanoma, laryngopharyngeal 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, stromal gastrointestinal tumor, sarcoma, osteogenic sarcoma, angioma, malignant lymphoma, myeloid leukemia, neuroma and neuroglioma.
    The basic substance of the present invention means basic inorganic salt. Such basic inorganic salts include; beryllium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate, barium carbonate, potassium carbonate, calcium hydrophosphate and titanium oxide. It is preferably an alkaline earth metal salt of carbonic acid, more preferably magnesium carbonate or calcium carbonate.
    It is also acceptable to additionally include a disintegrating agent in the pharmaceutical composition of the present invention. This disintegrating agent includes corn starch, partially pregelatinized starch, hydroxypropyl starch, carmellose, carmellose sodium, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, low substituted hydroxypropylcellulose and crospovidone. It is preferably croscarmellose sodium, low substituted hydroxypropylcellulose or crospovidone.
    The pharmaceutical composition of the present invention can be prepared by a method known as; the method described in the General Rules for Preparations in the Japanese Pharmacopoeia, Fifteenth Edition.
    For example, in the case of granules, it is possible to add an excipient, a binder, a disintegrating agent, a solvent, or similar to the quinoline derivative (I), as necessary, to perform agitation granulation, extrusion granulation, drum granulation, fluid bed granulation, spray granulation, or similar, and for its preparation. It is also acceptable to coat with an atomizing agent containing the quinoline derivative (I) and an additive such as corn starch, microcrystalline cellulose, hydroxypropylcellulose, methylcellulose or polyvinylpyrrolidone while spraying water or a binder solution such as sucrose, hydroxypropylcellulose or hydroxypropylmethylcellulose on a core material such as a spherical granule of purified sucrose, a spherical granule of lactose / crystalline cellulose, a spherical granule of sucrose / starch or a granular crystalline cellulose. It is also acceptable to carry out calibration and grinding as needed.
    It is also possible additionally, as necessary, to add an excipient, a binder, a disintegrating agent, a lubricant, an antioxidant, a corrector, a coloring agent, a flavoring agent, or similar to the granule prepared in this way and to compress to form a tablet. A required excipient can be added to the quinoline derivative (I) to directly compress the mixture into a tablet. It is also possible to fill a capsule with the quinoline derivative (I) added / mixed with an excipient such as lactose, sucrose, glucose, starch, microcrystalline cellulose, licorice powder, mannitol, calcium phosphate or calcium sulfate, or with the granule.
    Examples of 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, silicic anhydride, calcium silicate, sodium bicarbonate, calcium phosphate, anhydrous calcium phosphate and calcium sulfate.
    Examples of binders include; gelatin, starch, gum arabic, tragacanth, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, partially pregelatinized starch, pregelatinized starch, poly (vinyl alcohol), sodium arginine, pullulan and glycerin.
    Examples of disintegrating agents include; corn starch, partially pregelatinized starch, hydroxypropyl starch, carmellose, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, croscarmellose sodium, low substituted hydroxypropylcellulose and crospovidone.
    Examples of lubricants include; magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, talc and macrogol.
    Examples of antioxidant agents include; sodium ascorbate, L-cysteine, sodium sulfite, tocopherol and soy lecithin.
    Examples of brokers include; citric acid, ascorbic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, dipotassium glycyrrhizinate, sodium glutamate, sodium 5'-inosinate and sodium 5'-guanylate.
    Examples of coloring agents include; titanium oxide, iron sesquioxide, yellow iron sesquioxide, cochineal, carmine, riboflavin, food yellow No. 5 and food blue No. 2.
    Examples of flavoring agent include; lemon oil, orange oil, menthol, peppermint oil, borneol and vanilla flavoring. Examples
    The present invention will be described in more detail below by way of examples, but is not limited to the examples. Examples 1 to 3
    Wet granulation was carried out with solvent-purified water using a high shear granulator (equipment name FM-VG-10, manufactured by Powrex Corporation) with crystalline form C of 4- (3-chloro-4- (3-chloro-4- ( cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinocarboxamide (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 hydroxypropylcellulose (trade name: L-HPC (LH-21), Shin-Etsu Chemical) and microcrystalline cellulose (trade name: Ceolus PH-101, Asahi Kasei Chemicals), according to the formulation proportions of table 1. The granules whose moisture content has been reduced to less than 2% by further drying were calibrated using a sieving device (equipment name: Power Mill P-04S, manufactured by Showa Giken KK) so that the granule diameters were less 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 calibrated granules, according to the formulation ratios in Table 1, and the mixture was mixed thoroughly using a diffusion mixer (tumbler type) (trade name: 10L / 20L Exchange-type Tumbler Mixer, manufactured by Toyo Packing Corporation). Size # 4 hard capsules were filled with 100 mg of the resulting granules to prepare capsules containing compound A. [Table 1]

    Unit:% by weight Examples 4 to 9, comparative examples 1 to 2
    Compound A, precipitated calcium carbonate, low substituted hydroxypropylcellulose, D-mannitol and talc were mixed intensively using a mortar and pistil according to the formulation proportions in Table 2 and Table 3. Hard capsules, size # 3, were filled with 100 mg of the resulting mixtures to prepare capsules of examples 4 to 9. Capsules of comparative examples 1 to 2, which did not contain precipitated calcium carbonate, were also prepared by the same method. [Table 2]
    Unit:% by weight [Table 3]

    Unit:% by weight Test example 1
    The dissolutions of compound A in the capsules of examples 4 to 9 and comparative examples 1 to 2 were examined according to the dissolution test (paddle method, test medium: JP1 solution) described in Japanese Pharmacopoeia, 15th Edition. As a result, dissolutions of compound A in the capsules of comparative examples 1 to 2, in which no calcium carbonate was mixed, were insufficient. In contrast, the dissolutions of compound A in the capsules of examples 4 to 9, in which calcium carbonate was mixed, were good (figure 1 and figure 2). Examples 10 to 15, comparative examples 3 to 4
    Compound A, magnesium carbonate (Kyowa Chemical Industry), hydroxypropylcellulose with low substitution, D-mannitol and talc were mixed intensively using a mortar and pistil, according to the formulation proportions of table 4 and table 5. Hard capsules, size # 3, were filled with 100 mg of the resulting mixtures to prepare capsules of examples 10 to 15. Capsules of comparative examples 3 to 4, which did not contain magnesium carbonate, were also prepared by the same method. [Table 4]

    Unit:% by weight [Table 5]
    Unit:% by weight Test example 2
    Dissolutions of compound A in the capsules of examples 10 to 15 and comparative examples 3 to 4 were examined by the same method as in test example 1. Dissolutions of compound A in the capsules of comparative examples 3 to 4, in which no carbonate of magnesium was mixed, were insufficient. In contrast, the dissolutions of compound A 10 in the capsules of examples 10 to 15, in which the magnesium carbonate was mixed, were good (figure 3 and figure 4). Examples 16 to 17, comparative examples 5 to 6
    Purified water was added to compound A, precipitated calcium carbonate or magnesium carbonate, hydroxypropylcellulose and crucose-sodium melose (trade name: Ac-Di-Sol, Asahi Kasei Chemicals) to perform the granulation using a mortar and pistil, followed by calibration of the dry granules so that the granule diameters are less than 1 mm. Then, microcrystalline cellulose (trade name: Ceolus PH-102, Asahi Kasei Chemicals), low substituted hydroxypropylcellulose and talc (trade name: Hi-Piller 17, Iwai Chemicals Company) were added to the calibrated granules according to the formulation proportions of the table 6, and the mixture was thoroughly mixed. Size # 4 hard capsules were filled with 100 mg of the resulting mixtures to prepare capsules 5 of examples 16 to 17. Capsules of comparative examples 5 to 6, which did not contain precipitated calcium carbonate or magnesium carbonate, but contained mannitol or talc as a substitute, were also prepared in a similar manner, according to the formulation proportions of table 7. [Table 6]
    Unit:% by weight [Table 7]
    Unit:% by weight Test example 3
    Dissolutions of compound A in the capsules of examples 16 to 17 and comparative example 5 were examined by the same method as in test example 1. Dissolution of compound A in the capsules of comparative example 5, in which neither calcium carbonate nor carbonate of magnesium were mixed, it was insufficient. In contrast, the dissolutions of compound A in the capsules of examples 16 to 17, in which calcium carbonate or magnesium carbonate were mixed, were good (figure 5). Test example 4
    The capsules of examples 16 to 17 and comparative example 6 were stored for 1 week in an open system in an environment with a temperature of 60 ° C and a relative humidity of 75%, after which the production of degradants was determined by high performance liquid chromatography. . In the capsule formulation of comparative example 6, in which neither calcium carbonate nor magnesium carbonate was mixed, the amount of degradants was increased. In contrast, in cases 16 to 17, in which calcium carbonate or magnesium carbonate were mixed, there was no increase in the amount of degradants (Table 8). [Table 8]
    Examples 18 to 19, comparative examples 7 to 10
    The respective ingredients were mixed according to the formulations in tables 9 and 10, using the same method as examples 4 to 9 and comparative examples 1 to 2. Hard capsules, size # 3, were filled with 100 mg of the resulting mixtures to prepare capsules of examples 18 to 19 and comparative examples 7 to 10. [Table 9]
    Unit:% by weight [Table 10]
    Test example 5
    Dissolutions of compound A in the capsules of examples 18 to 19 and comparative examples 7 to 10 were examined by the same method as in test example 1. As a result, dissolutions of compound A in the capsules of comparative examples 7 to 10, in which oxide of calcium, calcium hydroxide, magnesium oxide or magnesium hydroxide were mixed, they were insufficient. In contrast, the dissolutions of compound A in the capsules of examples 18 to 19, in which calcium carbonate or magnesium carbonate were mixed, were good (figure 6 and figure 7). Industrial Applicability
    The pharmaceutical composition of the present invention is excellent in dissolving the quinoline derivative, and also in stability, and is therefore useful as a drug for the prevention or treatment of a tumor.
    权利要求:
    Claims (4)
    [0001]
    1. Pharmaceutical composition, characterized by the fact that it comprises: (1) 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolinocarboxamide or a pharmaceutically acceptable salt thereof, (2) carbonate magnesium or calcium carbonate; and (3) a disintegrating agent.
    [0002]
    Composition according to claim 1, characterized by the fact that the disintegrating agent is carmellose sodium, carmellose calcium, carboxymethyl sodium starch, croscarmellose sodium, low substituted hydroxypropylcellulose, or crospovidone.
    [0003]
    Composition according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt is hydrochloride, hydrobromide, p-toluenesulfonate, sulfate, methanesulfonate, or ethanesulfonate.
    [0004]
    Composition according to any one of Claims 1 to 3, characterized in that the pharmaceutically acceptable salt is methanesulfonate.
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-05-28| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2020-01-28| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|
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    优先权:
    申请号 | 申请日 | 专利标题
    JP2009-190145|2009-08-19|
    JP2009190145|2009-08-19|
    PCT/JP2010/063804|WO2011021597A1|2009-08-19|2010-08-16|Quinoline derivative-containing pharmaceutical composition|
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