TWI501950B - Pharmaceutical composition comprising quinoline derivative - Google Patents
Pharmaceutical composition comprising quinoline derivative Download PDFInfo
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- TWI501950B TWI501950B TW100104281A TW100104281A TWI501950B TW I501950 B TWI501950 B TW I501950B TW 100104281 A TW100104281 A TW 100104281A TW 100104281 A TW100104281 A TW 100104281A TW I501950 B TWI501950 B TW I501950B
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本發明係關於一種可用作為藥物之包含喹啉衍生物的藥學組成物。更特別地，本發明係關於一種改良喹啉衍生物或其藥學可接受之鹽或其溶劑化物之溶解性的藥學組成物。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.
式(I)所示之喹啉衍生物或其藥學可接受之鹽或其溶劑化物(下文中稱為喹啉衍生物(I))已知具有強的血管形成抑制效果(專利文獻1)及c-Kit激酶抑制效果(專利文獻2)且有用於作為多種腫瘤(諸如甲狀腺癌、肺癌、黑色素瘤、胰臟癌)之預防或治療劑，且作為這些腫瘤之轉移抑制劑：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:
其中R1 是氫原子、C1-6 烷基或C3-8 環烷基；且R2 是氫原子或甲氧基。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.
然而，已發現：當配製成藥學組成物時，喹啉衍生物(I)在潮濕且溫暖之儲存條件下會降解。此外，當該藥學組成物吸收水分時，由於在該組成物表面上之膠化作用，會延緩活性成分喹啉衍生物(I)由該藥學組成物溶解。為要克服這些問題，已發展一種藥學組成物，其包括喹啉衍生物(I)、(1)一化合物(為5%(重量/重量)之水溶液或懸浮液且具有8或更高之pH)、及/或(2)矽酸、其鹽或其溶劑化物(專利文獻3)。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).
專利文獻1：WO 2002/32872Patent Document 1: WO 2002/32872
專利文獻2：WO 2004/080462Patent Document 2: WO 2004/080462
專利文獻3：WO 2006/030826Patent Document 3: WO 2006/030826
然而，還想要發展出具有更優越之喹啉衍生物(I)溶解作用的藥學組成物。因此，本發明的目的是提供一種即使在長期儲存後喹啉衍生物(I)仍保持優越的溶解作用之藥學組成物。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.
本發明人已密集地研究以解決以上問題，且令人驚訝地已發現以下之構造可以解決上述問題且已完成本發明。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.
具體言之，本發明提供以下<1>至<12>。Specifically, the present invention provides the following <1> to <12>.
[1] 一種藥學組成物，其包含[1] A pharmaceutical composition comprising
(1)式(I)所示之化合物或其藥學可接受之鹽或其溶劑化物：(1) A compound of the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof:
其中R1 是氫原子、C1-6 烷基或C3-8 環烷基；且R2 是氫原子或甲氧基，及(2)鹼性物質。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] 依照[1]之組成物，其中該鹼性物質是碳酸鹽。[2] The composition according to [1], wherein the alkaline substance is a carbonate.
[3] 依照[2]之組成物，其中該鹽是鹼土金屬鹽。[3] The composition according to [2], wherein the salt is an alkaline earth metal salt.
[4] 依照[3]之組成物，其中該鹼土金屬鹽是鎂鹽或鈣鹽。[4] The composition according to [3], wherein the alkaline earth metal salt is a magnesium salt or a calcium salt.
[5] 依照[1]至[4]中任一項的組成物，其另外包含崩解劑。[5] The composition according to any one of [1] to [4] which further comprises a disintegrating agent.
[6] 依照[5]之組成物，其中該崩解劑是羧甲醚纖維素(carmellose)鈉、羧甲醚纖維素鈣、羧甲基澱粉鈉、交聯羧甲醚纖維素(croscarmellose)鈉、低取代之羥丙基纖維素或交聯聚乙烯吡咯烷酮(crospovidone)。[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] 依照[1]至[6]中任一項的組成物，其中R1 是氫原子、甲基、乙基、正丙基或環丙基。[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] 依照[1]至[7]中任一項的組成物，其中R1 是環丙基。[8] The composition according to any one of [1] to [7] wherein R 1 is a cyclopropyl group.
[9] 依照[1]至[8]中任一項的組成物，其中R2 是氫原子、甲氧基、或乙氧基。[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] 依照[1]至[9]中任一項的組成物，其中R2 是氫原子。[10] The composition according to any one of [1] to [9] wherein R 2 is a hydrogen atom.
[11] 依照[1]至[10]中任一項的組成物，其中該藥學可接受之鹽是氫氯酸鹽、氫溴酸鹽、對甲苯磺酸鹽、硫酸鹽、甲磺酸鹽或乙磺酸鹽。[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] 依照[1]至[11]中任一項的組成物，其中式(I)所示之化合物是4-(3-氯-4-(環丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺甲磺酸鹽。[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.
本發明之藥學組成物的主作用劑喹啉衍生物(I)具有優越的溶解作用且在活體內具有優越之吸收作用。該藥學組成物也是一種即使在長期儲存後仍能維持之藥學組成物。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.
本發明之藥學組成物意指一種包含喹啉衍生物(I)及鹼性物質作為必要成分之組成物。該喹啉衍生物(I)與該鹼性物質之混合比例一般是(但不限於)1：0.5至50，較佳是1：1至25，更佳是1：2至12.5。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.
此外，該喹啉衍生物(I)相對該藥學組成物之總重量(排除膠囊殼)的混合比例一般是0.25至50重量%，較佳是0.5至25重量%，更佳是1至12.5重量%。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. %.
該鹼性物質相對該藥學組成物之總重量的混合比例一般是1至60重量%，較佳是5至50重量%，更佳是10至40重量%。可將本發明之至少一種鹼性物質包括在該藥學組成物中，或者也可包括二或多種鹼性物質。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.
該藥學組成物之劑量形式特別是指一種固態製劑，諸如顆粒、細顆粒、錠劑、或膠囊等。較佳是細顆粒、顆粒或填充細顆粒或顆粒之膠囊。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.
該喹啉衍生物(I)是在WO 2002/32872中所揭示之化合物。較佳之喹啉衍生物(I)是選自下列之喹啉衍生物或其藥學可接受之鹽或其溶劑化物：4-(3-氯-4-(環丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺，4-(3-氯-4-(甲基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺，4-(3-氯-4-(乙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺，N6-甲氧基-4-(3-氯-4-(((乙基胺基)羰基)胺基)苯氧基)-7-甲氧基-6-喹啉羧醯胺，4-(3-氯-4-(1-丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺，N6-甲氧基-4-(3-氯-4-(((環丙基胺基)羰基)胺基)苯氧基)-7-甲氧基-6-喹啉羧醯胺，及N6-甲氧基-4-(3-氯-4-(((乙基胺基)羰基)胺基)苯氧基)-7-甲氧基-6-喹啉羧醯胺。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.
更佳之喹啉衍生物(I)是選自下列之喹啉衍生物或其藥學可接受之鹽或其溶劑化物：4-(3-氯-4-(甲基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺，4-(3-氯-4-(乙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺，4-(3-氯-4-(環丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺，N6-甲氧基-4-(3-氯-4-(((環丙基胺基)羰基)胺基)苯氧基)-7-甲氧基-6-喹啉羧醯胺，及N6-甲氧基-4-(3-氯-4-(((乙基胺基)羰基)胺基)苯氧基)-7-甲氧基-6-喹啉羧醯胺。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.
特佳之喹啉衍生物(I)是4-(3-氯-4-(環丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺，或其藥學可接受之鹽或其溶劑化物。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.
本發明之藥學可接受之鹽是指氫氯酸鹽、氫溴酸鹽、對苯磺酸鹽、硫酸鹽、甲磺酸鹽或乙磺酸鹽。較佳是甲磺酸鹽。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.
本發明之溶劑化物是指水合物、二甲基亞碸溶劑化物、或乙酸溶劑化物。The solvate of the present invention means a hydrate, a dimethyl hydrazine solvate, or an acetic acid solvate.
該喹啉衍生物(I)較佳是在WO 2005/063713中所揭示之4-(3-氯-4-(環丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺之鹽的結晶，或其溶劑化物。特佳之喹啉衍生物(I)是4-(3-氯-4-(環丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺甲磺酸鹽之C型結晶。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.
該喹啉衍生物(I)可用作為多種腫瘤之預防或治療劑且作為腫瘤之轉移抑制劑。該喹啉衍生物(I)能有效對抗之腫瘤的範例包括甲狀腺癌、非小細胞肺癌、黑色素瘤、咽喉癌、食道癌、胃癌、結腸直腸癌、肝細胞癌、腎細胞癌、胰癌、膀胱癌、乳癌、子宮癌、卵巢癌、***癌、睪丸癌、胃腸道基質腫瘤、肉瘤、成骨肉瘤、血管瘤、惡性淋巴瘤、骨髓白血病、神經瘤及神經膠瘤。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.
本發明之鹼性物質是指鹼性無機鹽。所述鹼性無機鹽包括碳酸鈹、碳酸鎂、碳酸鈣、碳酸鍶、碳酸鋇、碳酸鉀、磷酸氫鈣、及氧化鈦。彼較佳是碳酸之鹼土金屬鹽，另外較佳是碳酸鎂或碳酸鈣。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.
本發明之藥學組成物另外包括崩解劑，也是可接受的。所述崩解劑包括玉米澱粉、部分預先凝膠化之澱粉、羧丙基澱粉、羧甲醚纖維素(carmellose)、羧甲醚纖維素鈉、羧甲醚纖維素鈣、羧甲基澱粉鈉、交聯羧甲醚纖維素(croscarmellose)鈉、低取代之羥丙基纖維素及交聯聚乙烯吡咯烷酮(crospovidone)。彼較佳是交聯羧甲醚纖維素鈉、低取代之羥丙基纖維素、或交聯聚乙烯吡咯烷酮。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.
本發明之藥學組成物可以藉由已知方法製備，諸如在General Rules for Preparations in the Japanese Pharmacopoeia Fifteenth Edition中所描述的方法製備。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.
例如，在顆粒之情況中，可能視需要將賦形劑、黏合劑、崩解劑、溶劑或類似者添加至該喹啉衍生物(I)以進行攪拌製粒、擠出製粒、滾動製粒、流化床製粒、噴霧製粒、或類似方式，且將其製備。也可接受地，用含有該喹啉衍生物(I)及添加劑(諸如玉米澱粉、微晶纖維素、羥丙基纖維素、甲基纖維素、或聚乙烯基吡咯烷酮)之霧化劑塗覆，且同時將水或黏合劑(諸如蔗糖、羥丙基纖維素或羥丙基甲基纖維素)之溶液噴灑，在核心材料(諸如純化之蔗糖球粒、乳糖/結晶纖維素球粒、蔗糖/澱粉球粒或粒狀結晶纖維素)上。視需要進行定篩選及研磨，也是可接受的。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.
也可能另外視需要地將賦形劑、黏合劑、崩解劑、潤滑劑、抗氧化劑、調味劑、著色劑、香料、或類似者添加至以此方式所製備之顆粒並將之壓製成錠。可將所需之賦形劑添加至該喹啉衍生物(I)，以直接將混合物壓製成錠。也可能將已添加/混合賦形劑(諸如乳糖、蔗糖、葡萄糖、澱粉、微晶纖維素、粉狀甘草、甘露糖醇、磷酸鈣、或硫酸鈣之該喹啉衍生物(I)或用彼之顆粒填充膠囊。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.
該賦形劑之範例包括乳糖、蔗糖、葡萄糖、果糖、澱粉、馬鈴薯澱粉、玉米澱粉、小麥澱粉、米澱粉、結晶纖維素、微晶纖維素、粉狀甘草、甘露糖醇、赤藻糖醇、麥芽糖醇、山梨糖醇、海藻糖、矽酸酐、矽酸鈣、碳酸氫鈉、磷酸鈣、無水磷酸鈣及硫酸鈣。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.
該黏合劑之範例包括明膠、澱粉、***膠、黃蓍膠、羧甲基纖維素、羥丙基纖維素、羥丙基甲基纖維素、聚乙烯基吡咯烷酮、甲基纖維素、部分預先膠化之澱粉、預先膠化之澱粉、聚乙烯醇、精胺酸鈉、黏多糖及甘油。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.
該崩解劑之範例包括玉米澱粉、部分預先膠化之澱粉、羥丙基澱粉、羧甲醚纖維素、羧甲醚纖維素鈉、羧甲醚纖維素鈣、羧甲基澱粉鈉、交聯羧甲醚纖維素鈉、低取代之羥丙基纖維素及交聯聚乙烯吡咯烷酮。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.
該潤滑劑之範例包括硬脂酸鎂、硬脂酸、硬脂酸鈣、硬脂醯反丁烯二酸鈉、滑石及聚乙二醇(macrogol)。Examples of such lubricants include magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, talc, and macrogol.
該抗氧化劑之範例包括抗壞血酸鈉、L-半胱胺酸、亞硫酸鈉、生育酚、及大豆卵磷脂。Examples of such antioxidants include sodium ascorbate, L-cysteine, sodium sulfite, tocopherol, and soy lecithin.
該調味劑之範例包括檸檬酸、抗壞血酸、酒石酸、蘋果酸、阿斯巴甜、阿色番(acesulfame)鉀、索馬甜、糖精鈉、甘草酸二鉀、麩胺酸鈉、5’-肌苷酸鈉及5’-鳥苷酸鈉。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.
該著色劑之範例包括氧化鈦、三氧化二鐵、三氧化二鐵黃、胭脂蟲紅、胭脂紅、核黃素、食品級黃色素5號及食品級藍色素2號。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.
該香料之範例包括檸檬油、橘子油、薄荷腦、薄荷油、冰片(borneol)及香草香料。Examples of such flavors include lemon oil, orange oil, menthol, peppermint oil, borneol and vanilla flavor.
本發明將在下文中參考實例作更詳細地描述，但不限於這些實例。The invention will be described in more detail below with reference to examples, but is not limited to these examples.
使用高切變製粒機(設備名稱：FM-VG-10，Powrex Corporation製造)，利用純水作為溶劑，依照表1中之配製比例，利用4-(3-氯-4-(環丙基胺基羰基)胺基苯氧基)-7-甲氧基-6-喹啉羧醯胺甲磺酸酯之C型結晶(下文中稱為化合物A)、D-甘露糖醇(商標名稱：Mannitol，Merck)、沉澱的碳酸鈣(商標名稱：Whiton F，Shiraishi Calcium)、羥丙基纖維素(HPC-L，Nippon Soda)、低取代之羥丙基纖維素(商標名稱：L-HPC(LH-21)，Shin-Etsu Chemical)、及微晶纖維素(商標名稱：Ceolus PH-101，Asahi Kasei Chemicals)，進行濕式製粒。藉由另外之乾燥將顆粒的水含量降至低於2%，並使用篩選磨機(設備名稱：Power Mill P-04S，由Showa Giken KK製造)對該顆粒進行篩選，以使其顆粒直徑小於1毫米。然後，依照表1中之配製比例，將微晶纖維素(商標名稱：Ceolus PH-102，Asahi Kasei Chemicals)及滑石(商標名稱：Hi-Filler 17，Iwai Chemicals Company)添加至該經篩選的顆粒，且使用擴散(滾動型)混合機(商標名稱：10L/20L Exchange-type Tumbler Mixer，Toyo Packing Corporation製造)，將混合物充分混合。在尺寸#4之硬膠囊內填充100毫克之所得的顆粒以製備含化合物A之膠囊。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.
使用研缽及杵，依照表2及表3中之配製比例，將化合物A、沉澱的碳酸鈣、低取代之羥丙基纖維素、D-甘露糖醇及滑石充分混合。在尺寸#3之硬膠囊內填充100毫克之所得的混合物以製備實例4至9之膠囊。也藉由相同方法製備比較例1至2之膠囊，但其不含沉澱的碳酸鈣。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.
在實例4至9及比較例1至2的膠囊內之化合物A的溶解度依照在Japanese Pharmacopoeia Fifteenth Edition中所述之溶解測試(the Paddle法，測試介質：JP1溶液)被檢驗。結果，在不混合碳酸鈣之比較例1至2的膠囊內之化合物A的溶解作用是不足的。相反地，在混合碳酸鈣之實例4至9的膠囊內之化合物A的溶解作用則是良好的(圖1及圖2)。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).
使用研缽及杵，依照表4及表5中之配製比例，將化合物A、碳酸鎂(Kyowa Chemical Industry)、低取代之羥丙基纖維素、D-甘露糖醇及滑石充分混合。在尺寸#3之硬膠囊內填充100毫克之所得的混合物以製備實例10至15之膠囊。也藉由相同方法製備比較例3至4之膠囊，但其不含碳酸鎂。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.
在實例10至15及比較例3至4的膠囊內之化合物A的溶解作用依照如測試實例1中之相同方法被檢驗。在不混合碳酸鎂之比較例3至4的膠囊內之化合物A的溶解作用是不足的。相反地，在混合碳酸鈣之實例10至15的膠囊內之化合物A的溶解作用則是良好的(圖3及圖4)。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).
使用研缽及杵，將純水添加至化合物A、沉澱的碳酸鈣或碳酸鎂、羥丙基纖維素及交聯羧甲醚纖維素鈉(商標名稱：Ac-Di-Sol，Asahi Kasei Chemicals)以進行製粒，接著篩選乾燥之顆粒以使顆粒直徑小於1毫米。然後，依照在表6中之配製比例，將微晶羥丙基纖維素(商標名稱：Ceolus PH-102，Asahi Kasei Chemicals)、低取代之羥丙基纖維素及滑石(商標名稱：Hi-Filler 17，Iwai Chemicals Company)添加至該經篩選的顆粒，且該混合物充分地混合。在尺寸#4之硬膠囊內填充100毫克之所得的混合物以製備實例16至17之膠囊。也依照表7中之配製比例，同樣地製備比較例5至6之膠囊，但其既不含沉澱的碳酸鈣也不含有碳酸鎂，但含有甘露糖醇或滑石作為代替。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.
在實例16至17及比較例5的膠囊內之化合物A的溶解作用依照如測試實例1中之相同方法被檢驗。在既不混合碳酸鈣也不混合碳酸鎂之比較例5的膠囊內之化合物A的溶解作用是不足的。相反地，在混合碳酸鈣或碳酸鎂之實例16至17的膠囊內之化合物A的溶解作用則是良好的(圖5)。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).
將實例16至17及比較例6之膠囊在溫度60℃之溫度及75%之相對溼度的條件下於開放系統中儲存1星期，接著利用高效能液體層析法測定降解物之產生。在既不混合碳酸鈣也不混合碳酸鎂之比較例6的膠囊調和物中，降解物之量增加。相反地，在混合碳酸鈣或碳酸鎂之實例16至17的膠囊中，沒有觀察到降解物之增加(表8)。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).
藉由與實例4至9及比較例1至2相同的方法，依照表9及10之調和比例，將個別成分混合。在尺寸#3之硬膠囊內填充100毫克之所得的混合物以製備實例18至19及比較例7至10的膠囊。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.
在實例18至19及比較例7至10膠囊內之化合物A的溶解作用藉由與測試實例1相同的方法檢驗。結果，在混合氧化鈣、氫氧化鈣、氧化鎂或氫氧化鎂之比較例7至10的膠囊內之化合物A的溶解作用是不足的。相反地，在混合碳酸鈣或碳酸鎂之實例18至19的膠囊內之化合物A的溶解作用則是良好的(圖6及圖7)。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).
依本發明之藥學組成物在喹啉衍生物之溶解作用上及在安定性上是優越的，且因此可用作為預防或治療腫瘤的藥物。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.
圖1顯示由實例4至6及比較例1中所得之組成物溶解出化合物A的變化曲線。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.
圖2顯示由實例7至9及比較例2中所得之組成物溶解出化合物A的變化曲線。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.
圖3顯示由實例10至12及比較例3中所得之組成物溶解出化合物A的圖形。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.
圖4顯示由實例13至15及比較例4中所得之組成物溶解出化合物A的變化曲線。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.
圖5顯示由實例16至17及比較例5中所得之組成物溶解出化合物A的變化曲線。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.
圖6顯示由實例18及比較例7至8中所得之組成物溶解出化合物A的變化曲線。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.
圖7顯示由實例19及比較例9至10中所得之組成物溶解出化合物A的變化曲線。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.
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