WO2017028660A1 - 一种含有喹啉衍生物或其盐的药物组合物 - Google Patents

一种含有喹啉衍生物或其盐的药物组合物 Download PDF

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WO2017028660A1
WO2017028660A1 PCT/CN2016/091717 CN2016091717W WO2017028660A1 WO 2017028660 A1 WO2017028660 A1 WO 2017028660A1 CN 2016091717 W CN2016091717 W CN 2016091717W WO 2017028660 A1 WO2017028660 A1 WO 2017028660A1
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pharmaceutical composition
composition according
arginine
total weight
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陈爱玲
王聪
刘凯
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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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

Definitions

  • 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-quinolinecarboxamide.
  • a pharmaceutical composition of the salt which has the characteristics of rapid dissolution and good stability.
  • WO2002032872 discloses a quinoline derivative 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, which is known to have inhibitory participation.
  • RTK which is involved in other proangiogenic and oncogenic signaling pathways of 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.
  • VEGF vascular endothelial growth factor
  • 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof is prepared into a pharmaceutical combination
  • the drug is decomposed under the conditions of wetness and heat, and the drug composition absorbs moisture, resulting in a decrease in drug dissolution.
  • Patent CN101001629A discloses a composition comprising 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmaceutically acceptable salt thereof
  • alkaline inorganic compounds such as magnesium oxide
  • silicic acid compounds to solve the problem of drug dissolution.
  • the amount of the silicic acid compound is large, the density of the silicic acid compound is extremely small, and it is easy to fly in production, causing damage to the operator's respiratory system.
  • the risk of uneven material mixing may be caused, which makes the industrialization of the preparation difficult.
  • the pharmaceutical composition provided by the present invention includes an active pharmaceutical ingredient and a basic substance.
  • the active pharmaceutical ingredient is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide or a pharmacologically acceptable salt thereof, and
  • the pharmaceutical compositions described are free of microcrystalline cellulose.
  • Alkaline substances include one or more of the following:
  • the basic amino acid is preferably selected from one or more of lysine, arginine and histidine.
  • the basic substance is a mixture of at least one compound of arginine or meglumine and at least one compound of potassium carbonate or potassium hydrogencarbonate.
  • the basic substance is a mixture of at least one compound of arginine or meglumine and potassium hydrogencarbonate.
  • the basic substance is a mixture of arginine and meglumine.
  • 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, preferably. Between 1:0.5 and 1:2, most preferably 1:1.
  • 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.
  • the content of the basic 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; Most preferably 5-20%.
  • 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%, most preferably from 1% to 15%, based on the total weight of the composition.
  • 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.
  • 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.
  • the pharmaceutical composition provided by the present invention may contain a disintegrating agent, wherein the disintegrant is one of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, and crospovidone. Or a variety.
  • the disintegrant content is from about 1% to about 30%, based on the total weight of the composition.
  • the pharmaceutical composition may contain a binder, which may be selected from the group consisting of hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, and the like.
  • the binder may be present in an amount of from about 0.5% to about 15%, based on the total weight of the composition.
  • 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 silica, 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.
  • composition consists of the following ingredients:
  • composition consists of the following ingredients:
  • the pharmaceutical composition of the present invention can be prepared by a method common in the art, for example, high shear wet granulation, dry granulation, one-step granulation, etc., to prepare granules of a pharmaceutical composition, and then filled into capsules to prepare a hard capsule.
  • microcrystalline cellulose-free pharmaceutical composition provided by the invention has higher stability, reduces the generation of new impurities, and has good dissolution properties.
  • Figure 1 shows the dissolution profiles of the capsules of Examples 1 to 3 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 2 shows the dissolution profiles of the capsules of Examples 4 to 6 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 3 shows the dissolution profiles of the capsules of Comparative Examples 1 to 3 in a 0.1 mol/L hydrochloric acid solution.
  • Example 4 shows the dissolution profile of the capsule of Example 3 and the 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.
  • Figure 5 shows the dissolution profile of the capsule of Example 6 in a 0.1 mol/L hydrochloric acid solution after being placed at a temperature of 40 ° C and a relative humidity of 75%.
  • 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%.
  • 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%.
  • 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%.
  • compound A 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), refined ammonia Acid, potassium bicarbonate, D-mannitol, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, wet granulation by high-speed shear granulator according to the ratio in Table 1, to purify Water is a wetting agent, wet and granules are dried 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.
  • compound A 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate
  • Example 1 Example 2
  • Example 3 Compound A 2.5 4.9 12.3 Arginine 10.0 10.0 10.0 Potassium bicarbonate 20.0 20.0 20.0 D-mannitol 56.5 54.1 46.7 Hydroxypropyl cellulose 3.0 3.0 3.0 Low substituted hydroxypropyl cellulose 5.0 5.0 5.0 talcum powder 3.0 3.0 3.0 total 100 100 100
  • compound A 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter referred to as compound A), refined ammonia Acid, potassium carbonate, D-mannitol, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, wet granulation using a high-speed shear granulator according to the ratio in Table 2, using purified water as a wetting agent Wet granules and drying the wet materials, then dry granules (less than 2% moisture), add the prescribed amount of talc, and mix with a rotary total mixer. The obtained total mixed particles are filled into capsules to prepare capsules.
  • Example 4 Compound A 2.5 4.9 12.3 Arginine 10.0 10.0 10.0 Potassium carbonate 20.0 20.0 20.0 D-mannitol 56.5 54.1 46.7 Hydroxypropyl cellulose 3.0 3.0 3.0 Low substituted hydroxypropyl cellulose 5.0 5.0 5.0 talcum powder 3.0 3.0 3.0 total 100 100 100
  • compound A 4-[3-Chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate (hereinafter abbreviated as compound A) arginine , potassium bicarbonate or potassium carbonate, D-mannitol, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, wet granulation using a high-speed shear granulator according to the ratio in Table 3.
  • Comparative example 1 Comparative example 2 Comparative example 3 Compound A 12.3 12.3 12.3 Arginine 0 10 10 Potassium carbonate 0 20 0 Potassium bicarbonate 0 0 20 D-mannitol 43.7 13.7 13.7 Microcrystalline cellulose 33 33 33 Hydroxypropyl cellulose 3 3 3 Low substituted hydroxypropyl cellulose 5 5 5 talcum powder 3 3 3 total 100 100 100
  • the dissolution rates of the capsules of Examples 1 to 6 were measured according to the second method (paddle method) of the dissolution test of the Appendix 2 of the Chinese Pharmacopoeia. 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. As a result, 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 quickly completed.
  • the dissolution profile is shown in Figure 1 and Figure 2.
  • the dissolution rate of the capsules of Comparative Examples 1 to 3 was measured according to the second method (paddle method) for the dissolution measurement 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 comparative example 1 which did not contain the alkaline adjuvant in the prescription, 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, indicating that the addition of microcrystalline cellulose does not affect the drug Dissolution of matter.
  • the dissolution profile is shown in Figure 3.
  • 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.
  • Example 3 containing arginine and potassium hydrogencarbonate
  • Example 6 containing arginine and potassium carbonate
  • Comparative Example 1 did not contain alkaline adjuvants.
  • 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.
  • Example 3 containing arginine and potassium hydrogencarbonate
  • Example 6 containing arginine and potassium carbonate
  • the dissolution rate of Compound A was 40 ° C and the relative humidity was 75%.

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Abstract

一种药物组合物，含有4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药理学上可接受的盐；以及碱性氨基酸或葡甲胺，和/或选自碳酸钾、碳酸氢钾中的至少一种化合物；且所述组合物不含有微晶纤维素。

Description

一种含有喹啉衍生物或其盐的药物组合物 技术领域
本发明属于药物制剂领域，具体涉及一种含有喹啉衍生物4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其盐的药物组合物，该组合物具有溶出迅速、稳定性良好的特点。
背景技术
WO2002032872公开了一种喹啉衍生物4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺，已知其具有抑制参与肿瘤增殖的其他促血管生成和致癌信号通路相关RTK，还能够选择性抑制血管内皮生长因子(VEGF)受体的激酶活性，临床上可用于甲状腺癌、肺癌、黑色素瘤等多种肿瘤的治疗。
但是，在将4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药学上可接受的盐制备成药物组合物时，在湿、热存在的条件下，药物发生分解，同时药物组合物吸湿，造成药物溶出度下降。
专利CN101001629A公开了含有4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药学上可接受的盐的组合物，采用氧化镁等碱性无机化合物来解决药物的降解问题，同时采用硅酸类化合物来解决药物的溶出度下降问题。但是硅酸类化合物用量较大，硅酸类化合物密度极小，在生产中极易飘扬，造成对操作人员呼吸系统的伤害。同时在混合过程中，由于其密度与其他辅料相差较大，可能会造成物料混合不均匀的风险，给制剂工业化大生产造成困难。
发明内容
本发明的目的在于提供一种稳定性良好同时溶出迅速的药物组合物，并且该药物组合物制备工艺简单，更适合工艺化大生产。
本发明提供的药物组合物包括活性药物成分和碱性物质。活性药物成分为4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药理学上可接受的盐，且所述的药物组合物不含微晶纤维素。
碱性物质包括下述物质的一种或几种：
(1)碱性氨基酸，
(2)葡甲胺，
(3)碳酸钾或碳酸氢钾中的至少一种化合物；
其中，碱性氨基酸优选选自赖氨酸、精氨酸和组氨酸中的一种或几种。
在本发明优选的实施方案中，所述碱性物质为精氨酸或葡甲胺中的至少一种化合物与碳酸钾或碳酸氢钾中的至少一种化合物的混合物。
在本发明特别优选的实施方案中，所述碱性物质为精氨酸或葡甲胺中的至少一种化合物与碳酸氢钾的混合物。
在本发明的另一个优选的实施方案中，所述碱性物质为精氨酸与葡甲胺的混合物。
当本发明的碱性物质是两种物质的混合物时，所述两种混合物的比例没有特别限制，在优选的实施方案中，它们的重量比例可以在1：0.1至1：10之间，优选1：0.5至1：2之间，最优选1：1。
所述碱性物质的含量不受限制，只要含少量的上述碱性物质，即可起到提高溶出，增加稳定性的效果。为了制剂的方便，在本发明优选的实施方案中，所述碱性物质的含量范围可以是基于组合物总重量计0.5％-90％；优选1％-50％；更优选1-35％；最优选5-20％。
本发明的药物组合物中，所述活性成分的药理学上可接受的盐可以选自盐酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐。基于组合物的总重量，所述活性成分的含量范围可以是基于组合物总重量计0.5％-30％；优选1％-25％；最优选1-15％。
本发明提供的药物组合物可以含有填充剂，例如磷酸氢钙、甘露醇、预胶化淀粉、乳糖等一种或多种。基于组合物的总重量，所述填充剂含量为约5％～80％。
本发明提供的药物组合物可以含有崩解剂，其中崩解剂为交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素及交联聚维酮中的一种或多种。基于组合物的总重量，所述崩解剂含量为约1％～30％。
本发明提供药物组合物可以含有粘合剂，所述粘合剂可选自羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素等一种或多种，基于组合物的总重量，所述粘合剂含量为约0.5～15％。
本发明提供的药物组合物还可包含一种或多种润滑剂，有助于灌装胶囊或压片。润滑剂可选自滑石粉、硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、胶体二氧化硅等。基于组合物的总重量，所述润滑剂的含量为约0.5％～5％
在本发明优选的实施方案中，所述组合物由以下成分组成：
(1)4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药理学上可接受的盐；
(2)碱性物质；
(3)填充剂；
(4)崩解剂；
(5)粘合剂
(6)润滑剂。
在最为优选的实施方案中，所述组合物以下成分组成：
(1)4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药理学上可接受的盐；
(2)精氨酸，5～20％；
(3)碳酸氢钾，10～40％；
(4)甘露醇，30％～60％；
(5)低取代羟丙基纤维素，1％～10％；
(6)羟丙基纤维素，1％～5％；
(7)滑石粉，1％～5％。
本发明的药物组合物可以采用本领域常见的方法制备，例如高剪切湿法制粒、干法制粒、一步制粒等方法制备药物组合物颗粒，然后灌装胶囊，制备硬胶囊剂。
本发明提供的不含微晶纤维素的药物组合物具有更高的稳定性，减少了新的杂质的产生，且具有很好的溶出性能。
附图说明
图1显示实施例1至3的胶囊在0.1mol/L盐酸溶液中的溶出曲线。
图2显示实施例4至6的胶囊在0.1mol/L盐酸溶液中的溶出曲线。
图3显示比较例1至比较例3的胶囊在0.1mol/L盐酸溶液中的溶出曲线。
图4显示实施例3的胶囊以及温度40℃、相对湿度75％放置后在0.1mol/L盐酸溶液中的溶出曲线。
图5显示实施例6的胶囊以及温度40℃、相对湿度75％放置后在0.1mol/L盐酸溶液中的溶出曲线。
图6显示比较例1的胶囊以及温度40℃、相对湿度75％放置后在0.1mol/L盐酸溶液中的溶出曲线。
图7显示比较例2的胶囊以及温度40℃、相对湿度75％放置后在0.1mol/L盐酸溶液中的溶出曲线。
图8显示比较例3的胶囊以及温度40℃、相对湿度75％放置后在0.1mol/L盐酸溶液中的溶出曲线。
具体实施方式
通过以下实施例和实验例进一步详细说明本发明。这些实施例和实验例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1～3
将4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的甲磺酸盐(以下简称为化合物A)、精氨酸、碳酸氢钾、D-甘露醇、羟丙基纤维素、低取代羟丙基纤维素，按表1中的比例，采用高速剪切制粒机进行湿法制粒，以纯化 水为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于2％)进行干整粒，加入处方量的滑石粉，采用旋转总混机进行混合。将得到的总混颗粒灌装胶囊，制备胶囊剂。
表1
成分 实施例1 实施例2 实施例3
化合物A 2.5 4.9 12.3
精氨酸 10.0 10.0 10.0
碳酸氢钾 20.0 20.0 20.0
D-甘露醇 56.5 54.1 46.7
羟丙基纤维素 3.0 3.0 3.0
低取代羟丙基纤维素 5.0 5.0 5.0
滑石粉 3.0 3.0 3.0
总计 100 100 100
单位：质量％
实施例4～6
将4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的甲磺酸盐(以下简称为化合物A)、精氨酸、碳酸钾、D-甘露醇、羟丙基纤维素、低取代羟丙基纤维素，按表2中的比例，采用高速剪切制粒机进行湿法制粒，以纯化水为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于2％)进行干整粒，加入处方量的滑石粉，采用旋转总混机进行混合。将得到的总混颗粒灌装胶囊，制备胶囊剂。
表2
成分 实施例4 实施例5 实施例6
化合物A 2.5 4.9 12.3
精氨酸 10.0 10.0 10.0
碳酸钾 20.0 20.0 20.0
D-甘露醇 56.5 54.1 46.7
羟丙基纤维素 3.0 3.0 3.0
低取代羟丙基纤维素 5.0 5.0 5.0
滑石粉 3.0 3.0 3.0
总计 100 100 100
单位：质量％
比较例1～3
将4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺的甲磺酸盐(以下简称为化合物A)精氨酸、碳酸氢钾或碳酸钾、D-甘露醇、微晶纤维素、羟丙基纤维素、低取代羟丙基纤维素，按表3中的比例，采用高速剪切制粒机进行湿法制粒，以纯化水为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于2％)进行干整粒，加入处方量的滑石粉，采用旋转总混机进行混合。将得到的总混颗粒灌装胶囊，制备比较例1～3的胶囊剂。
表3
成分 比较例1 比较例2 比较例3
化合物A 12.3 12.3 12.3
精氨酸 0 10 10
碳酸钾 0 20 0
碳酸氢钾 0 0 20
D-甘露醇 43.7 13.7 13.7
微晶纤维素 33 33 33
羟丙基纤维素 3 3 3
低取代羟丙基纤维素 5 5 5
滑石粉 3 3 3
总计 100 100 100
单位：质量％
实验例1：溶出实验
根据中国药典2010版二部附录溶出度测定第二法(桨法)，对实施例1～6的胶囊剂进行溶出度测定。使用900ml的0.1mol/L盐酸溶液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，处方中含精氨酸与碳酸钾或碳酸氢钾的实施例1～6的胶囊剂中，化合物A溶出迅速完全。
溶出曲线图见图1、图2。
实验例2：溶出实验
根据中国药典2010版二部附录溶出度测定第二法(桨法)，对比较例1～3的胶囊剂进行溶出度测定。使用900ml的0.1mol/L盐酸溶液作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，处方中不含碱性辅料的比较例1，化合物A溶出缓慢；处方中含有精氨酸、碳酸钾或碳酸氢钾的比较例2与比较例3的胶囊剂中，化合物A溶出迅速完全，说明微晶纤维素的加入不影响药 物的溶出。
溶出曲线图见图3。
实验例3：稳定性研究
将实施例3、6的胶囊剂和比较例1～3的胶囊剂，采用高密度聚乙烯包装，置于温度40℃、相对湿度75％的环境下放置1个月、2个月、3个月、6个月，然后采用HPLC法测定降解物的生成，采用中国药典2010版二部附录溶出度测定第二法(桨法)，对放置后的样品测定溶出度。
降解物测定结果表明，实施例3(含精氨酸与碳酸氢钾)、实施例6(含精氨酸与碳酸钾)的胶囊剂中，降解物没有增加，比较例1不含碱性辅料，降解物随放置时间的延长而明显增加，比较例2和比较例3含碱性辅料和微晶纤维素，温度40℃、相对湿度75％的环境下放置1个月后产生新的杂质1，该杂质随放置时间的延长而明显增加，其他降解物没有增加。(见表4至8)
溶出度结果表明，实施例3(含精氨酸与碳酸氢钾)、实施例6(含精氨酸与碳酸钾)的胶囊剂中，化合物A的溶出度在温度40℃、相对湿度75％的环境下放置后与初期相比仍没有明显下降，溶出完全。比较例1(无碱性辅料)的胶囊剂中，化合物A初期与在温度40℃、相对湿度75％的环境下放置后的溶出均不完全，比较例2、比较例3的胶囊剂中，化合物A的溶出度在温度40℃、相对湿度75％的环境下放置后与初期相比仍没有明显下降，溶出完全(见图4至8)，说明微晶纤维素的加入不影响溶出，但产生杂质1。
表4
Figure PCTCN2016091717-appb-000001
表5
Figure PCTCN2016091717-appb-000002
表6
Figure PCTCN2016091717-appb-000003
表7
Figure PCTCN2016091717-appb-000004
Figure PCTCN2016091717-appb-000005
表8
Figure PCTCN2016091717-appb-000006

Claims (19)

  1. 一种药物组合物，含有4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药理学上可接受的盐，以及碱性物质，所述碱性物质选自下述物质的一种或几种：
    1)碱性氨基酸，
    2)葡甲胺，
    3)选自碳酸钾、碳酸氢钾中的至少一种化合物；
    其中，所述组合物不含微晶纤维素。
  2. 根据权利要求1所述的药物组合物，其中所述碱性氨基酸选自赖氨酸、精氨酸或组氨酸中的一种或几种。
  3. 根据权利要求1所述的药物组合物，其中所述碱性物质为葡甲胺。
  4. 根据权利要求1所述的药物组合物，其中所述碱性氨基酸为精氨酸。
  5. 根据权利要求1所述的药物组合物，其中所述碱性物质为葡甲胺与赖氨酸、精氨酸或组氨酸中的至少一种化合物的混合物。
  6. 根据权利要求1所述的药物组合物，其中所述碱性物质为精氨酸与碳酸钾或碳酸氢钾中的至少一种化合物的混合物。
  7. 根据权利要求1所述的药物组合物，其中所述碱性物质为葡甲胺与碳酸钾或碳酸氢钾中的至少一种化合物的混合物。
  8. 根据权利要求1所述的药物组合物，其中所述碱性物质的含量为基于组合物总重量计0.5％-90％；优选1％-50％；更优选1-35％；最优选5-20％。
  9. 根据权利要求1至8中任意一项所述的药物组合物，其中含有崩解剂。
  10. 根据权利要求9所述的药物组合物，其中崩解剂为交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素及交联聚维酮中的一种或多种。
  11. 根据权利要求1至8任意一项所述的药物组合物，所述的组合物由如下成分组成：
    1)4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药理 学上可接受的盐；
    2)碱性物质；
    3)填充剂；
    4)崩解剂；
    5)粘合剂
    6)润滑剂。
  12. 根据权利要求11所述的药物组合物，其中所述填充剂选自磷酸氢钙、甘露醇、预胶化淀粉、乳糖等一种或多种，优选所述填充剂含量为基于组合物总重量计5％～80％，更优选30％～60％。
  13. 根据权利要求11所述的药物组合物，其中所述崩解剂选自交联羧甲基纤维素钠、羧甲基淀粉钠、低取代羟丙基纤维素及交联聚维酮中的一种或多种，优选其含量为基于组合物的总重量计1％～30％，更优选1％～10％。
  14. 根据权利要求11所述的药物组合物，其中所述粘合剂选自羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素等一种或多种，优选其含量为基于组合物的总重量计0.5～15％，更优选1％～5％。
  15. 根据权利要求11所述的药物组合物，其中所述润滑剂选自滑石粉、硬脂酸镁、硬脂酸锌、山嵛酸甘油酯、月桂基硫酸钠、氢化植物油、胶体二氧化硅等，基于组合物的总重量，优选其含量为基于组合物的总重量计0.5％～5％，更优选1％～5％。
  16. 根据权利要求11所述的药物组合物，其特征在于由以下成分组成：
    1)4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺或其药理学上可接受的盐；
    2)精氨酸，5～20％；
    3)碳酸氢钾，10～40％；
    4)甘露醇，30％～60％；
    5)低取代羟丙基纤维素，1％～10％；
    6)羟丙基纤维素，1％～5％；
    7)滑石粉，1％～5％。
  17. 根据权利要求1至8中任意一项所述的药物组合物，其中药理学上可接受的盐选自盐酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐。
  18. 根据权利要求17所述的药物组合物，其中药理学上可接受的盐为甲磺酸盐。
  19. 根据权利要求1至18中任意一项所述的药物组合物在制备治疗癌症的药物中的用途；所述癌症优选甲状腺癌、肺癌或黑色素瘤。
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