TW201707702A - Pharmaceutical composition containing quinazoline derivatives or their salts thereof - Google Patents

Pharmaceutical composition containing quinazoline derivatives or their salts thereof Download PDF

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TW201707702A
TW201707702A TW105125414A TW105125414A TW201707702A TW 201707702 A TW201707702 A TW 201707702A TW 105125414 A TW105125414 A TW 105125414A TW 105125414 A TW105125414 A TW 105125414A TW 201707702 A TW201707702 A TW 201707702A
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pharmaceutical composition
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arginine
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TWI739756B (en
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陳愛玲
王聰
劉凱
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江蘇恆瑞醫藥股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids

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  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

The present invention relates to a pharmaceutical composition containing quinazoline derivatives or their salts thereof. More specifically, the present invention relates to a pharmaceutical composition containing 4-(3-chloro-4-(cyclopropylamino-carbonyl)aminophenoxy)-7-methoxy-6-quinoline carboxamide or its pharmacologically acceptable salt, and alkaline amino acids or meglumine, and/or at least one kind of compound selected from the group of potassium carbonate, potassium bicarbonate, and the said composition does not contain microcrystalline cellulose. The pharmaceutical composition has the characteristics of quick dissolution and good stability.

Description

一種含有喹啉衍生物或其鹽的醫藥組成物 Medicinal composition containing quinoline derivative or salt thereof

本發明屬於藥物製劑領域，具體涉及一種含有喹啉衍生物4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其鹽的醫藥組成物，該組成物具有溶出迅速、穩定性良好的特點。 The invention belongs to the field of pharmaceutical preparations, in particular to a quinoline derivative containing 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinoline A pharmaceutical composition of guanamine or a salt thereof, which has a characteristic of rapid dissolution and good stability.

WO2002032872公開了一種喹啉衍生物4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺，已知其具有抑制參與腫瘤增殖的其他促血管生成和致癌信號通路相關RTK，還能夠選擇性抑制血管內皮生長因數(VEGF)受體的激酶活性，臨床上可用於甲狀腺癌、肺癌、黑色素瘤等多種腫瘤的治療。 WO2002032872 discloses a quinoline derivative 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, which is known to have RTK, which inhibits other proangiogenic and oncogenic signaling pathways involved in tumor proliferation, can also selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptor, and is clinically useful for the treatment of various tumors such as thyroid cancer, lung cancer, and melanoma. .

但是，在將4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其藥學上可接受的鹽製備成醫藥組成物時，在濕、熱存在的條件下，藥物發生分解，同時醫藥組成物吸濕，造成藥物溶出度下降。 However, in the preparation of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinylguanamine or a pharmaceutically acceptable salt thereof In the case of a pharmaceutical composition, the drug is decomposed in the presence of moisture and heat, and the pharmaceutical composition absorbs moisture, resulting in a decrease in drug dissolution.

專利CN101001629A公開了含有4-[3-氯-4-(環丙基胺 基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其藥學上可接受的鹽的組合物，採用氧化鎂等鹼性無機化合物來解決藥物的降解問題，同時採用矽酸類化合物來解決藥物的溶出度下降問題。但是矽酸類化合物用量較大，矽酸類化合物密度極小，在生產中極易飄揚，造成對操作人員呼吸系統的傷害。同時在混合過程中，由於其密度與其他輔料相差較大，可能會造成物料混合不均勻的風險，給製劑工業化大生產造成困難。 Patent CN101001629A discloses 4-[3-chloro-4-(cyclopropylamine) a composition of a carbonylcarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarmine or a pharmaceutically acceptable salt thereof, which uses a basic inorganic compound such as magnesium oxide to solve the problem of degradation of the drug, At the same time, tannic acid compounds are used to solve the problem of the dissolution of the drug. However, the amount of the phthalic acid compound is large, the density of the phthalic acid compound is extremely small, and it is easy to fly in the production, causing damage to the operator's respiratory system. At the same time, in the mixing process, due to the difference between the density and other auxiliary materials, the risk of uneven material mixing may be caused, which makes the industrialization of the preparation difficult.

本發明的目的在於提供一種穩定性良好同時溶出迅速的醫藥組成物，並且該醫藥組成物製備工藝簡單，更適合工藝化大生產。 It is an object of the present invention to provide a pharmaceutical composition which has good stability and rapid dissolution, and which is simple in preparation process and more suitable for large-scale production.

本發明提供的醫藥組成物包括活性藥物成分和鹼性物質。活性藥物成分為4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其藥理學上可接受的鹽，且該醫藥組成物不含微晶纖維素。 The pharmaceutical composition provided by the present invention includes an active pharmaceutical ingredient and an alkaline substance. The active pharmaceutical ingredient is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinylguanamine or a pharmacologically acceptable salt thereof And the pharmaceutical composition does not contain microcrystalline cellulose.

鹼性物質包括下述物質的一種或幾種：(1)鹼性胺基酸，(2)葡甲胺，(3)碳酸鉀或碳酸氫鉀中的至少一種化合物；其中，鹼性胺基酸較佳選自賴胺酸、精胺酸和組胺酸中的一種或幾種。 The alkaline substance includes one or more of the following: (1) a basic amino acid, (2) meglumine, (3) at least one of potassium carbonate or potassium hydrogencarbonate; wherein the basic amino group The acid is preferably selected from one or more of lysine, arginine and histidine.

在本發明較佳的實施方案中，該鹼性物質為精胺酸或葡甲胺中的至少一種化合物與碳酸鉀或碳酸氫鉀中的至少 一種化合物的混合物。 In a preferred embodiment of the present invention, the alkaline substance is at least one of arginine or meglumine and at least one of potassium carbonate or potassium hydrogencarbonate. a mixture of compounds.

在本發明特別較佳的實施方案中，該鹼性物質為精胺酸或葡甲胺中的至少一種化合物與碳酸氫鉀的混合物。 In a particularly preferred embodiment of the invention, the basic substance is a mixture of at least one compound of arginine or meglumine and potassium hydrogencarbonate.

在本發明的另一個較佳的實施方案中，該鹼性物質為精胺酸與葡甲胺的混合物。 In another preferred embodiment of the invention, the basic substance is a mixture of arginine and meglumine.

當本發明的鹼性物質是兩種物質的混合物時，該兩種混合物的比例沒有特別限制，在較佳的實施方案中，它們的重量比例可以在1：0.1至1：10之間，較佳1：0.5至1：2之間，最佳1：1。 When the basic substance of the present invention is a mixture of two substances, the ratio of the two kinds of the mixture is not particularly limited, and in a preferred embodiment, their weight ratio may be between 1:0.1 and 1:10. Good 1: between 0.5 and 1:2, the best 1:1.

該鹼性物質的含量不受限制，只要含少量的上述鹼性物質，即可起到提高溶出，增加穩定性的效果。為了製劑的方便，在本發明較佳的實施方案中，該鹼性物質的含量範圍可以是基於組成物總重量計0.5%-90%；較佳1%-50%；更佳1-35%；最佳5-20%。 The content of the basic substance is not limited, and as long as a small amount of the above-mentioned basic substance is contained, the effect of improving elution and increasing stability can be achieved. For the convenience of the preparation, in a preferred embodiment of the present invention, the content of the alkaline substance may range from 0.5% to 90%, preferably from 1% to 50%, more preferably from 1 to 35%, based on the total weight of the composition. Best 5-20%.

本發明的醫藥組成物中，該活性成分的藥理學上可接受的鹽可以選自鹽酸鹽、氫溴酸鹽、對甲苯磺酸鹽、甲磺酸鹽、硫酸鹽或乙磺酸鹽。基於組成物的總重量，該活性成分的含量範圍可以是基於組成物總重量計0.5%-30%；較佳1%-25%；最佳1-15%。 In the pharmaceutical composition of the present invention, the pharmacologically acceptable salt of the active ingredient may be selected from the group consisting of a hydrochloride, a hydrobromide, a p-toluenesulfonate, a methanesulfonate, a sulfate or an ethanesulfonate. The active ingredient may be included in an amount ranging from 0.5% to 30%, preferably from 1% to 25%, optimally from 1% to 5%, based on the total weight of the composition.

本發明提供的醫藥組成物可以含有填充劑，例如磷酸氫鈣、甘露醇、預膠化澱粉、乳糖等一種或多種。基於組成物的總重量，該填充劑含量為約5%至80%。 The pharmaceutical composition provided by the present invention may contain a filler such as one or more of calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose. The filler content is from about 5% to 80% based on the total weight of the composition.

本發明提供的醫藥組成物可以含有崩解劑，其中崩解劑為交聯羧甲基纖維素鈉、羧甲基澱粉鈉、低取代羥丙基 纖維素及交聯聚維酮中的一種或多種。基於組成物的總重量，該崩解劑含量為約1%至30%。 The pharmaceutical composition provided by the present invention may contain a disintegrating agent, wherein the disintegrant is croscarmellose sodium, sodium carboxymethyl starch, and a low-substituted hydroxypropyl group. One or more of cellulose and crospovidone. The disintegrant content is from about 1% to 30% based on the total weight of the composition.

本發明提供醫藥組成物可以含有黏合劑，該黏合劑可選自羥丙甲纖維素、羥丙基纖維素、羧甲基纖維素鈉、聚乙烯吡咯烷酮、甲基纖維素等一種或多種，基於組成物的總重量，該黏合劑含量為約0.5至15%。 The present invention provides that the pharmaceutical composition may contain a binder, which may be selected from one or more of hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, etc., based on The total weight of the composition, the binder content is from about 0.5 to 15%.

本發明提供的醫藥組成物還可包含一種或多種潤滑劑，有助於灌裝膠囊或壓片。潤滑劑可選自滑石粉、硬脂酸鎂、硬脂酸鋅、山崳酸甘油酯、月桂基硫酸鈉、氫化植物油、膠體二氧化矽等。基於組成物的總重量，該潤滑劑的含量為約0.5%至5%。 The pharmaceutical compositions provided herein may also comprise one or more lubricants to aid in filling the capsule or tableting. The lubricant may be selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal cerium oxide, and the like. The lubricant is present in an amount of from about 0.5% to about 5%, based on the total weight of the composition.

在本發明較佳的實施方案中，該組成物由以下成分組成：(1)4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其藥理學上可接受的鹽；(2)鹼性物質；(3)填充劑；(4)崩解劑；(5)黏合劑(6)潤滑劑。 In a preferred embodiment of the invention, the composition consists of: (1) 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy -6-quinoline mesamine or a pharmacologically acceptable salt thereof; (2) a basic substance; (3) a filler; (4) a disintegrant; (5) a binder (6) a lubricant.

在最佳的實施方案中，該組成物以下成分組成：(1)4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其藥理學上可接受的鹽；(2)精胺酸，5%至20%； (3)碳酸氫鉀，10%至40%；(4)甘露醇，30%至60%；(5)低取代羥丙基纖維素，1%至10%；(6)羥丙基纖維素，1%至5%；(7)滑石粉，1%至5%。 In a most preferred embodiment, the composition consists of the following components: (1) 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- Quinoline meglumine or a pharmacologically acceptable salt thereof; (2) arginine, 5% to 20%; (3) potassium bicarbonate, 10% to 40%; (4) mannitol, 30% to 60%; (5) low-substituted hydroxypropyl cellulose, 1% to 10%; (6) hydroxypropyl cellulose , 1% to 5%; (7) talc, 1% to 5%.

本發明的醫藥組成物可以採用本領域常見的方法製備，例如高剪切濕法製粒、乾法製粒、一步製粒等方法製備醫藥組成物顆粒，然後灌裝膠囊，製備硬膠囊劑。 The pharmaceutical composition of the present invention can be prepared by a method commonly used in the art, for example, high shear wet granulation, dry granulation, one-step granulation, and the like to prepare granules of the pharmaceutical composition, and then filled into capsules to prepare a hard capsule.

本發明提供的不含微晶纖維素的醫藥組成物具有更高的穩定性，減少了新的雜質的產生，且具有很好的溶出性能。 The microcrystalline cellulose-free pharmaceutical composition provided by the invention has higher stability, reduces the generation of new impurities, and has good dissolution properties.

第1圖顯示實施例1至3的膠囊在0.1mol/L鹽酸溶液中的溶出曲線。 Figure 1 shows the dissolution profiles of the capsules of Examples 1 to 3 in a 0.1 mol/L hydrochloric acid solution.

第2圖顯示實施例4至6的膠囊在0.1mol/L鹽酸溶液中的溶出曲線。 Fig. 2 shows the dissolution profiles of the capsules of Examples 4 to 6 in a 0.1 mol/L hydrochloric acid solution.

第3圖顯示比較例1至比較例3的膠囊在0.1mol/L鹽酸溶液中的溶出曲線。 Fig. 3 shows the dissolution profiles of the capsules of Comparative Examples 1 to 3 in a 0.1 mol/L hydrochloric acid solution.

第4圖顯示實施例3的膠囊以及溫度40℃、相對濕度75%放置後在0.1mol/L鹽酸溶液中的溶出曲線。 Fig. 4 shows a dissolution profile of the capsule of Example 3 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

第5圖顯示實施例6的膠囊以及溫度40℃、相對濕度75%放置後在0.1mol/L鹽酸溶液中的溶出曲線。 Fig. 5 shows a dissolution profile of the capsule of Example 6 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

第6圖顯示比較例1的膠囊以及溫度40℃、相對濕度75%放置後在0.1mol/L鹽酸溶液中的溶出曲線。 Fig. 6 shows a dissolution profile of the capsule of Comparative Example 1 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

第7圖顯示比較例2的膠囊以及溫度40℃、相對濕度75%放置後在0.1mol/L鹽酸溶液中的溶出曲線。 Fig. 7 shows a dissolution profile of the capsule of Comparative Example 2 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

第8圖顯示比較例3的膠囊以及溫度40℃、相對濕度75%放置後在0.1mol/L鹽酸溶液中的溶出曲線。 Fig. 8 shows a dissolution profile of the capsule of Comparative Example 3 and a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.

藉由以下實施例和實驗例進一步詳細說明本發明。這些實施例和實驗例僅用於說明性目的，而並不用於限制本發明的範圍。 The invention is further illustrated in detail by the following examples and experimental examples. The examples and the examples are for illustrative purposes only and are not intended to limit the scope of the invention.

實施例1至3 Examples 1 to 3

將4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺的甲磺酸鹽(以下簡稱為化合物A)、精胺酸、碳酸氫鉀、D-甘露醇、羥丙基纖維素、低取代羥丙基纖維素，按表1中的比例，採用高速剪切製粒機進行濕法製粒，以純化水為潤濕劑，對濕軟材進行濕整粒及乾燥處理，然後將乾顆粒(水分小於2%)進行乾整粒，加入處方量的滑石粉，採用旋轉總混機進行混合。將得到的總混顆粒灌裝膠囊，製備膠囊劑。 a methanesulfonic acid salt of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A) , arginine, potassium bicarbonate, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, wet granulation using a high-speed shear granulator according to the ratio in Table 1, to purify water As a wetting agent, wet and granules are wet-granulated and dried, then dry granules (less than 2% moisture) are dry granulated, and a prescribed amount of talc powder is added and mixed by a rotary total mixer. The obtained total mixed particles are filled into capsules to prepare capsules.

實施例4至6 Examples 4 to 6

將4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺的甲磺酸鹽(以下簡稱為化合物A)、精胺酸、碳酸鉀、D-甘露醇、羥丙基纖維素、低取代羥丙基纖維素，按表2中的比例，採用高速剪切製粒機進行濕法製粒，以純化水為潤濕劑，對濕軟材進行濕整粒及乾燥處理，然後將乾顆粒(水分小於2%)進行乾整粒，加入處方量的滑石粉，採用旋轉總混機進行混合。將得到的總混顆粒灌裝膠囊，製備膠囊劑。 a methanesulfonic acid salt of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A) , arginine, potassium carbonate, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, according to the ratio in Table 2, using a high-speed shear granulator for wet granulation, with purified water Wetting agent, wet granules and drying of wet materials, then dry granules (less than 2% moisture) are added, and the prescribed amount of talc powder is added and mixed by a rotary total mixer. The obtained total mixed particles are filled into capsules to prepare capsules.

比較例1至3 Comparative Examples 1 to 3

將4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺的甲磺酸鹽(以下簡稱為化合物A)精胺酸、碳酸氫鉀或碳酸鉀、D-甘露醇、微晶纖維素、羥丙基纖維素、低取代羥丙基纖維素，按表3中的比例，採用高速剪切製粒機進行濕法製粒，以純化水為潤濕劑，對濕軟材進行濕整粒及乾燥處理，然後將乾顆粒(水分小於2%)進行乾整粒，加入處方量的滑石粉，採用旋轉總混機進行混合。將得到的總混顆粒灌裝膠囊，製備比較例1至3的膠囊劑。 a methanesulfonic acid salt of 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide (hereinafter referred to as compound A) Arginine, potassium or potassium carbonate, D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, according to the ratio in Table 3, using a high-speed shear granulator Wet granulation, using purified water as a wetting agent, wet granules and drying the wet materials, then dry granules (less than 2% moisture), adding the prescribed amount of talcum powder, using rotary total mixing The machine is mixed. The obtained total mixed particles were filled and capsules, and capsules of Comparative Examples 1 to 3 were prepared.

實驗例1：溶出實驗 Experimental Example 1: Dissolution experiment

根據中國藥典2010版二部附錄溶出度測定第二法(槳法)，對實施例1至6的膠囊劑進行溶出度測定。使用900ml的0.1mol/L鹽酸溶液作為溶出介質，並在37±0.5℃下以50rpm的槳速進行溶出試驗。結果表明，配方中含精胺酸與碳酸鉀或碳酸氫鉀的實施例1至6的膠囊劑中，化合物A溶出迅速完全。 The dissolution rates of the capsules of Examples 1 to 6 were determined according to the second method (paddle method) of the dissolution test of the second edition of the Chinese Pharmacopoeia 2010 edition. 900 ml of a 0.1 mol/L hydrochloric acid solution was used as a dissolution medium, and a dissolution test was performed at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in the capsules of Examples 1 to 6 containing arginine and potassium carbonate or potassium hydrogencarbonate in the formulation, the dissolution of Compound A was rapid and complete.

溶出曲線圖見第1圖、第2圖。 See Figure 1 and Figure 2 for the dissolution profile.

實驗例2：溶出實驗 Experimental Example 2: Dissolution experiment

根據中國藥典2010版二部附錄溶出度測定第二法(槳法)，對比較例1至3的膠囊劑進行溶出度測定。使用900ml的0.1mol/L鹽酸溶液作為溶出介質，並在37±0.5℃下以50rpm的槳速進行溶出試驗。結果表明，處方中不含鹼性輔料的比較例1，化合物A溶出緩慢；處方中含有精胺酸、碳酸鉀或碳酸氫鉀的比較例2與比較例3的膠囊劑中，化合物A溶出迅速完全，說明微晶纖維素的加入不影響藥物的溶出。 The dissolution of the capsules of Comparative Examples 1 to 3 was measured according to the second method (paddle method) of the dissolution test of the second edition of the Chinese Pharmacopoeia 2010 edition. 900 ml of a 0.1 mol/L hydrochloric acid solution was used as a dissolution medium, and a dissolution test was performed at 37 ± 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Comparative Example 1 which did not contain an alkaline adjuvant in the formulation, the dissolution of the compound A was slow; in the capsule of Comparative Example 2 and Comparative Example 3 containing arginine, potassium carbonate or potassium hydrogencarbonate, the dissolution of the compound A was rapid. Completely, the addition of microcrystalline cellulose does not affect the dissolution of the drug.

溶出曲線圖見第3圖。 See Figure 3 for the dissolution profile.

實驗例3：穩定性研究 Experimental Example 3: Stability study

將實施例3、6的膠囊劑和比較例1至3的膠囊劑，採用高密度聚乙烯包裝，置於溫度40℃、相對濕度75%的環境下放置1個月、2個月、3個月、6個月，然後採用HPLC法測定降解物的生成，採用中國藥典2010版二部附錄溶出度測定第二法(槳法)，對放置後的樣品測定溶出度。 The capsules of Examples 3 and 6 and the capsules of Comparative Examples 1 to 3 were packaged in high-density polyethylene, and placed in an environment of a temperature of 40 ° C and a relative humidity of 75% for one month, two months, and three. After month and 6 months, the formation of the degradant was determined by HPLC. The second method (paddle method) of the dissolution test of the second edition of the Chinese Pharmacopoeia 2010 was used to determine the dissolution of the sample after the placement.

降解物測定結果表明，實施例3(含精胺酸與碳酸氫鉀)、實施例6(含精胺酸與碳酸鉀)的膠囊劑中，降解物沒有增加，比較例1不含鹼性輔料，降解物隨放置時間的延長而明顯增加，比較例2和比較例3含鹼性輔料和微晶纖維素，溫度40℃、相對濕度75%的環境下放置1個月後產生新的雜質1，該雜質隨放置時間的延長而明顯增加，其他降解物沒有增加。(見表4至8) The results of the degradation product measurement showed that in the capsule of Example 3 (containing arginine and potassium hydrogencarbonate) and Example 6 (containing arginine and potassium carbonate), the degradation product was not increased, and Comparative Example 1 did not contain the alkaline adjuvant. The degradant increased significantly with the extension of the standing time. Comparative Example 2 and Comparative Example 3 contained alkaline excipients and microcrystalline cellulose, and the new impurities were produced after being left for 1 month in a temperature of 40 ° C and a relative humidity of 75%. The impurity increases significantly with the extension of the standing time, and the other degradants do not increase. (See Tables 4 to 8)

溶出度結果表明，實施例3(含精胺酸與碳酸氫鉀)、實施例6(含精胺酸與碳酸鉀)的膠囊劑中，化合物A的溶出 度在溫度40℃、相對濕度75%的環境下放置後與初期相比仍沒有明顯下降，溶出完全。比較例1(無鹼性輔料)的膠囊劑中，化合物A初期與在溫度40℃、相對濕度75%的環境下放置後的溶出均不完全，比較例2、比較例3的膠囊劑中，化合物A的溶出度在溫度40℃、相對濕度75%的環境下放置後與初期相比仍沒有明顯下降，溶出完全(見第4圖至第8圖)，說明微晶纖維素的加入不影響溶出，但產生雜質1。 The dissolution results showed the dissolution of Compound A in the capsule of Example 3 (containing arginine and potassium bicarbonate) and Example 6 (containing arginine and potassium carbonate). After being placed in an environment of a temperature of 40 ° C and a relative humidity of 75%, there was no significant decrease compared with the initial stage, and the dissolution was complete. In the capsule of Comparative Example 1 (without alkaline adjuvant), the dissolution of the compound A at the initial stage and the environment at a temperature of 40 ° C and a relative humidity of 75% was incomplete, and in the capsules of Comparative Example 2 and Comparative Example 3, The dissolution rate of the compound A was not significantly decreased compared with the initial stage after being placed in an environment of a temperature of 40 ° C and a relative humidity of 75%, and the dissolution was complete (see FIGS. 4 to 8 ), indicating that the addition of the microcrystalline cellulose did not affect. Dissolution, but produces impurities 1.

由於本案的圖為實驗數據，並非本案的代表圖。故本案無指定代表圖。 Since the picture in this case is experimental data, it is not a representative figure of this case. Therefore, there is no designated representative map in this case.

Claims (31)

一種醫藥組成物，含有4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其藥理學上可接受的鹽，以及鹼性物質，該鹼性物質選自下述物質的一種或幾種：1)鹼性胺基酸，2)葡甲胺，3)選自碳酸鉀、碳酸氫鉀中的至少一種化合物；其中，該組成物不含微晶纖維素。 A pharmaceutical composition comprising 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarbamamine or a pharmacologically acceptable thereof a salt, and a basic substance selected from one or more of the following: 1) a basic amino acid, 2) meglumine, and 3) at least one selected from the group consisting of potassium carbonate and potassium hydrogencarbonate. A compound wherein the composition is free of microcrystalline cellulose. 如申請專利範圍第1項所述的醫藥組成物，其中該鹼性胺基酸選自賴胺酸、精胺酸或組胺酸中的一種或幾種。 The pharmaceutical composition according to claim 1, wherein the basic amino acid is one or more selected from the group consisting of lysine, arginine or histidine. 如申請專利範圍第1項所述的醫藥組成物，其中該鹼性物質為葡甲胺。 The pharmaceutical composition according to claim 1, wherein the alkaline substance is meglumine. 如申請專利範圍第1項所述的醫藥組成物，其中該鹼性胺基酸為精胺酸。 The pharmaceutical composition according to claim 1, wherein the basic amino acid is arginine. 如申請專利範圍第1項所述的醫藥組成物，其中該鹼性物質為葡甲胺與賴胺酸、精胺酸或組胺酸中的至少一種化合物的混合物。 The pharmaceutical composition according to claim 1, wherein the basic substance is a mixture of meglumine and at least one compound of lysine, arginine or histidine. 如申請專利範圍第1項所述的醫藥組成物，其中所述鹼性物質為精胺酸與碳酸鉀或碳酸氫鉀中的至少一種化合物的混合物。 The pharmaceutical composition according to claim 1, wherein the alkaline substance is a mixture of arginine and at least one of potassium carbonate or potassium hydrogencarbonate. 如申請專利範圍第1項所述的醫藥組成物，其中該鹼性物質為葡甲胺與碳酸鉀或碳酸氫鉀中的至少一種化合物的混合物。 The pharmaceutical composition according to claim 1, wherein the alkaline substance is a mixture of meglumine and at least one of potassium carbonate or potassium hydrogencarbonate. 如申請專利範圍第1項所述的醫藥組成物，其中該鹼性物質的含量為基於組成物總重量計0.5%至90%。 The pharmaceutical composition according to claim 1, wherein the alkaline substance is contained in an amount of from 0.5% to 90% by weight based on the total mass of the composition. 如申請專利範圍第8項所述的醫藥組成物，其中該鹼性物質的含量為基於組成物總重量計1%至50%。 The pharmaceutical composition according to claim 8, wherein the alkaline substance is contained in an amount of from 1% to 50% by weight based on the total mass of the composition. 如申請專利範圍第9項所述的醫藥組成物，其中該鹼性物質的含量為基於組成物總重量計1至35%。 The pharmaceutical composition according to claim 9, wherein the alkaline substance is contained in an amount of from 1 to 35% by weight based on the total weight of the composition. 如申請專利範圍第10項所述的醫藥組成物，其中該鹼性物質的含量為基於組成物總重量計5至20%。 The pharmaceutical composition according to claim 10, wherein the alkaline substance is contained in an amount of 5 to 20% by weight based on the total weight of the composition. 如申請專利範圍第1至11項中任意一項所述的醫藥組成物，其中含有崩解劑。 The pharmaceutical composition according to any one of claims 1 to 11, which contains a disintegrating agent. 如申請專利範圍第12項所述的醫藥組成物，其中崩解劑為交聯羧甲基纖維素鈉、羧甲基澱粉鈉、低取代羥丙基纖維素及交聯聚維酮中的一種或多種。 The pharmaceutical composition according to claim 12, wherein the disintegrant is one of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. Or a variety. 如申請專利範圍第1至11項中任意一項所述的醫藥組成物，該組成物由如下成分組成：1)4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其藥理學上可接受的鹽；2)鹼性物質；3)填充劑；4)崩解劑；5)黏合劑6)潤滑劑。 The pharmaceutical composition according to any one of claims 1 to 11, which is composed of the following components: 1) 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminobenzene Oxy]-7-methoxy-6-quinolinecarbamide or a pharmacologically acceptable salt thereof; 2) a basic substance; 3) a filler; 4) a disintegrant; 5) a binder 6) Lubricant. 如申請專利範圍第14項所述的醫藥組成物，其中該填充劑選自磷酸氫鈣、甘露醇、預膠化澱粉、乳糖中的一 種或多種。 The pharmaceutical composition according to claim 14, wherein the filler is selected from the group consisting of calcium hydrogen phosphate, mannitol, pregelatinized starch, and lactose. Kind or more. 如申請專利範圍第15項所述的醫藥組成物，其中該填充劑含量為基於組成物總重量計5%至80%。 The pharmaceutical composition according to claim 15, wherein the filler content is from 5% to 80% by weight based on the total weight of the composition. 如申請專利範圍第16項所述的醫藥組成物，其中該填充劑含量為基於組成物總重量計30%至60%。 The pharmaceutical composition according to claim 16, wherein the filler content is from 30% to 60% by weight based on the total weight of the composition. 如申請專利範圍第14項所述的醫藥組成物，其中該崩解劑選自交聯羧甲基纖維素鈉、羧甲基澱粉鈉、低取代羥丙基纖維素及交聯聚維酮中的一種或多種。 The pharmaceutical composition according to claim 14, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. One or more. 如申請專利範圍第18項所述的醫藥組成物，其中該崩解劑含量為基於組成物的總重量計1%至30%。 The pharmaceutical composition according to claim 18, wherein the disintegrant content is from 1% to 30% based on the total weight of the composition. 如申請專利範圍第19項所述的醫藥組成物，其中該崩解劑含量為基於組成物的總重量計1%至10%。 The pharmaceutical composition according to claim 19, wherein the disintegrant content is from 1% to 10% based on the total weight of the composition. 如申請專利範圍第14項所述的醫藥組成物，其中該黏合劑選自羥丙甲纖維素、羥丙基纖維素、羧甲基纖維素鈉、聚乙烯吡咯烷酮、甲基纖維素中的一種或多種。 The pharmaceutical composition according to claim 14, wherein the binder is selected from the group consisting of hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and methylcellulose. Or a variety. 如申請專利範圍第21項所述的醫藥組成物，其中該黏合劑含量為基於組成物的總重量計0.5至15%。 The pharmaceutical composition according to claim 21, wherein the binder content is from 0.5 to 15% based on the total weight of the composition. 如申請專利範圍第22項所述的醫藥組成物，其中該黏合劑含量為基於組成物的總重量計1%至5%。 The pharmaceutical composition according to claim 22, wherein the binder content is from 1% to 5% based on the total weight of the composition. 如申請專利範圍第14項所述的醫藥組成物，其中該潤滑劑選自滑石粉、硬脂酸鎂、硬脂酸鋅、山崳酸甘油酯、月桂基硫酸鈉、氫化植物油、膠體二氧化矽。 The pharmaceutical composition according to claim 14, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, colloidal dioxide Hey. 如申請專利範圍第24項所述的醫藥組成物，其中該潤滑劑，基於組成物的總重量，其含量為基於組成物的總 重量計0.5%至5%。 The pharmaceutical composition according to claim 24, wherein the lubricant is based on the total weight of the composition, and the content is based on the total composition The weight is from 0.5% to 5%. 如申請專利範圍第25項所述的醫藥組成物，其中該潤滑劑，基於組成物的總重量，其含量為基於組成物的總重量計1%至5%。 The pharmaceutical composition according to claim 25, wherein the lubricant is contained in an amount of from 1% to 5% based on the total mass of the composition, based on the total weight of the composition. 如申請專利範圍第14項所述的醫藥組成物，其特徵在於由以下成分組成：1)4-[3-氯-4-(環丙基胺基羰基)胺基苯氧基]-7-甲氧基-6-喹啉甲醯胺或其藥理學上可接受的鹽；2)精胺酸，5%至20%；3)碳酸氫鉀，10%至40%；4)甘露醇，30%至60%；5)低取代羥丙基纖維素，1%至10%；6)羥丙基纖維素，1%至5%；7)滑石粉，1%至5%。 The pharmaceutical composition according to claim 14, which is characterized by the following components: 1) 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7- Methoxy-6-quinoline mesamine or a pharmacologically acceptable salt thereof; 2) arginine, 5% to 20%; 3) potassium hydrogencarbonate, 10% to 40%; 4) mannitol, 30% to 60%; 5) low substituted hydroxypropyl cellulose, 1% to 10%; 6) hydroxypropyl cellulose, 1% to 5%; 7) talc, 1% to 5%. 如申請專利範圍第1至11項中任意一項所述的醫藥組成物，其中藥理學上可接受的鹽選自鹽酸鹽、氫溴酸鹽、對甲苯磺酸鹽、甲磺酸鹽、硫酸鹽或乙磺酸鹽。 The pharmaceutical composition according to any one of claims 1 to 11, wherein the pharmacologically acceptable salt is selected from the group consisting of a hydrochloride, a hydrobromide, a p-toluenesulfonate, a methanesulfonate, Sulfate or ethanesulfonate. 如申請專利範圍第28項所述的醫藥組成物，其中藥理學上可接受的鹽為甲磺酸鹽。 The pharmaceutical composition according to claim 28, wherein the pharmacologically acceptable salt is a mesylate salt. 一種申請專利範圍第1至29項中任意一項所述的醫藥組成物的用途，其係用在製備治療癌症的藥物。 The use of the pharmaceutical composition according to any one of claims 1 to 29 for the preparation of a medicament for treating cancer. 如申請專利範圍第30項所述的用途，其中該癌症為甲狀腺癌、肺癌或黑色素瘤。 The use of claim 30, wherein the cancer is thyroid cancer, lung cancer or melanoma.
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TWI739756B (en) 2021-09-21
CN106999483A (en) 2017-08-01
WO2017028660A1 (en) 2017-02-23

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