WO2017129087A1 - 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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WO2017129087A1
WO2017129087A1 PCT/CN2017/072155 CN2017072155W WO2017129087A1 WO 2017129087 A1 WO2017129087 A1 WO 2017129087A1 CN 2017072155 W CN2017072155 W CN 2017072155W WO 2017129087 A1 WO2017129087 A1 WO 2017129087A1
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pharmaceutical composition
composition according
weight
wetting agent
polyvinylpyrrolidone
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PCT/CN2017/072155
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English (en)
French (fr)
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卢韵
张新华
王晨阳
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江苏恒瑞医药股份有限公司
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Priority to MX2018008549A priority Critical patent/MX2018008549A/es
Priority to CN201780000923.9A priority patent/CN107405344B/zh
Priority to EP17743702.7A priority patent/EP3378478B1/en
Priority to JP2018533610A priority patent/JP6864691B2/ja
Priority to KR1020187022625A priority patent/KR20180103089A/ko
Priority to BR112018014559-9A priority patent/BR112018014559A2/zh
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to US16/071,157 priority patent/US11065241B2/en
Priority to RU2018128411A priority patent/RU2743014C2/ru
Priority to AU2017212452A priority patent/AU2017212452B2/en
Priority to CA3011525A priority patent/CA3011525C/en
Publication of WO2017129087A1 publication Critical patent/WO2017129087A1/zh
Priority to HK18103054.7A priority patent/HK1243358B/zh

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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
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a compound containing (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano- a pharmaceutical composition of 7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide or a pharmacologically acceptable salt thereof, which has Rapid dissolution characteristics.
  • CN102471312B discloses a small molecule compound (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxy
  • R,E small molecule compound
  • EGFR epidermal growth factor receptor
  • ERBB2 human epidermal factor receptor 2
  • CN102933574B discloses maleate forms of the compounds of formula I which are advantageous in terms of solubility and bioavailability and pharmacokinetics relative to other salts and compounds of formula I.
  • CN103974949B discloses Form I crystals of the compound dimaleate salt of the formula I.
  • the crystal form has good crystal form stability and chemical stability and can be used for the preparation of a medicament for treating diseases associated with the EGFR receptor tyrosine kinase or the HER-2 receptor tyrosine kinase.
  • the process is simple and more suitable for large-scale production.
  • the pharmaceutical composition provided by the present invention comprises an active pharmaceutical ingredient and crosslinked polyvinylpyrrolidone.
  • the active pharmaceutical ingredient is (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3-cyano-7-ethoxyquinoline- Or a pharmacologically acceptable salt of 6-yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide, for example, hydrochloride, maleate, hydrobromide, Tosylate, mesylate, sulfate or ethanesulfonate, preferably maleate, more preferably dimaleate.
  • the content of the active ingredient may range from 5 to 70%, preferably from 10 to 50%, more preferably from 20 to 40%, based on the total weight of the composition, based on the total weight of the composition.
  • the content of the crosslinked polyvinylpyrrolidone may range from about 2 to 20%; preferably from 4 to 15%; more preferably from 6 to 10%, based on the total weight of the composition.
  • the pharmaceutical composition provided by the present invention may further contain a filler such as one or more of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch, lactose and the like.
  • a filler such as one or more of microcrystalline cellulose, calcium hydrogen phosphate, mannitol, pregelatinized starch, lactose and the like.
  • the filler content is from about 5 to 80%, based on the total weight of the composition.
  • the pharmaceutical composition may further contain a binder such as one or more of hypromellose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, methylcellulose, and the like.
  • the binder content is from about 0.5% to about 15%, based on the total weight of the composition.
  • the pharmaceutical composition may further contain other disintegrating agents, such as one or more of croscarmellose sodium, sodium carboxymethyl starch, starch, low-substituted hydroxypropyl cellulose, etc., based on the combination.
  • disintegrating agents such as one or more of croscarmellose sodium, sodium carboxymethyl starch, starch, low-substituted hydroxypropyl cellulose, etc., based on the combination.
  • the total weight of the substance, the disintegrant content is about 0-20%.
  • compositions provided herein may also comprise one or more lubricants to aid in filling the capsule or tableting.
  • Lubricants include 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.
  • the invention also provides a pharmaceutical composition comprising:
  • a binder selected from one or more of polyvinylpyrrolidone, hydroxypropylmethylcellulose and hydroxypropylcellulose;
  • a lubricant selected from one or more of magnesium stearate and talc.
  • the pharmaceutical composition of the present invention has the effect of greatly increasing the dissolution rate of the active drug due to the addition of the cross-linked polyvinylpyrrolidone, and the dissolution is rapid and complete, which is beneficial to the rapid onset of action of the drug into the body and exerts the drug effect.
  • the present invention also provides a pharmaceutical composition
  • a wetting agent may be added during the preparation of the pharmaceutical composition
  • the wetting agent may comprise at least one organic solvent, and may further comprise water, wherein the organic solvent may be low in toxicity
  • the organic solvent is preferably ethanol, acetone or the like, and more preferably ethanol.
  • the content of the organic solvent may be 20 to 100%, preferably 50 to 95%, more preferably 50 to 80%, based on the total weight of the wetting agent.
  • the wetting agent added in the process of preparing the pharmaceutical composition contains a low-toxic organic solvent such as ethanol, the particle size distribution of the prepared particles is ideal, and the active drug is quickly and completely dissolved, which is convenient for the drug to exert its efficacy.
  • the pharmaceutical composition of the present invention has rapid dissolution and remarkable effect, and can be used for the treatment of cancer such as stomach cancer, lung cancer or breast cancer.
  • the invention also provides a process for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising mixing (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-3 -Cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)-acrylamide or a pharmacologically acceptable salt thereof and crosslinked polyvinylpyrrolidone
  • the granules can be prepared by methods conventional in the art, such as wet granulation, and finally prepared into oral preparations such as tablets and capsules.
  • Fig. 1 shows the dissolution profiles of the tablets of Example 1 and Comparative Examples 1 to 4 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 2 shows the dissolution profiles of the tablets of Examples 2 to 7 in a 0.1 mol/L hydrochloric acid solution.
  • Fig. 3 shows the particle size fractions of Examples 8 to 12 and Comparative Example 5.
  • Figure 4 shows the dissolution profile of a plurality of samples of Comparative Example 5 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 5 shows the dissolution profile of a plurality of samples of Example 8 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 6 shows the dissolution profile of a plurality of samples of Example 9 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 7 shows the dissolution profile of the multiple samples of Example 10 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 8 shows the dissolution profile of a plurality of samples of Example 11 in a 0.1 mol/L hydrochloric acid solution.
  • Figure 9 shows the dissolution profile of a plurality of samples of Example 12 in a 0.1 mol/L hydrochloric acid solution.
  • Example 1 and Comparative Examples 1-4 were tested for dissolution according to the second method of the dissolution test 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 tablet of Example 1 containing the crosslinked polyvinylpyrrolidone in the formulation, Compound A was rapidly dissolved completely, and contained low-substituted hydroxypropylcellulose, sodium carboxymethyl starch, croscarmellose sodium or starch. In the tablets of Comparative Example 1-4, the dissolution of Compound A was slow and incomplete.
  • the dissolution profile is shown in Figure 1.
  • Compound A lactose, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone were mixed at a prescription ratio of Table 2, and wet-granulated with an appropriate amount of an aqueous solution of 93.75 wt% ethanol as a wetting agent, and dried until the water content was less than 2% of the dry granules were added, and a prescribed amount of magnesium stearate was added and mixed using a rotary total mixer. The obtained total mixed granules were tableted and coated to prepare tablets.
  • the dissolution rates of the tablets of Examples 2 to 7 were measured according to the second method (paddle method) of the dissolution test 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 tablets of Examples 2 to 5 containing different ratios of cross-linked polyvinylpyrrolidone in the formulation and the tablets of Examples 6 and 7 containing the different ratios of Compound A in the formulation, the dissolution of Compound A was quickly completed.
  • the dissolution profile is shown in Figure 2.
  • Compound A lactose, microcrystalline cellulose, polyvinylpyrrolidone, and cross-linked polyvinylpyrrolidone were mixed at a prescribed ratio of Table 3, respectively, and an appropriate amount of purified water, an aqueous solution of 20 wt% ethanol, an aqueous solution of 50 wt% ethanol, and 80 wt% of ethanol.
  • the aqueous solution, the aqueous solution of 93.75 wt% ethanol and the anhydrous ethanol are wet granulated as a wetting agent, dried to a moisture content of less than 2% for dry granulation, and a prescribed amount of magnesium stearate is added, and mixed by a rotary total mixer.
  • the obtained total mixed granules were dispensed into 100 g for sieving, and the remaining granules were tableted and coated to prepare tablets.
  • Example 5 100 g of the divided granules obtained in Examples 8 to 12 and Comparative Example 5 were sieved by a 50-mesh, 100-mesh sieve. Compared with Example 5, purified water was used as the wetting agent, and the prepared granules, large particles and fine powder were more, and the particle size distribution was not satisfactory.
  • the particle size distribution of the prepared particles using the wetting agent containing ethanol was carried out in Examples 8-12. More uniform, less large particles and fine powder.
  • the tablets of Examples 8 to 12 and Comparative Example 5 were subjected to dissolution measurement 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.
  • Example 8 The results showed that the particles prepared in Examples 8 to 12 were prepared by using 20 wt% ethanol, 50 wt% ethanol, 80 wt% ethanol aqueous solution, 93.75 wt% ethanol and absolute ethanol as a wetting agent, and the particle size distribution was ideal, and the dissolution of the compound A was rapid. complete.
  • Comparative Example 5 purified water was used as a wetting agent, and the uniformity of dissolution of Compound A was not good in the prepared tablets.
  • a wetting agent containing ethanol was used, and in the prepared tablets, the dissolution uniformity of the compound A was good.

Abstract

本发明提供了一种含有喹啉衍生物或其盐的药物组合物。具体而言，本发明提供了一种药物组合物，含有(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐、交联聚乙烯吡咯烷酮以及至少一种药学上可接受的赋形剂。本发明的药物组合物具有溶出迅速的特点。

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(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺的或其药理学上可接受的盐的药物组合物，该组合物具有溶出迅速的特点。
背景技术
CN102471312B公开了一种小分子化合物(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺，该化合物具有式I所示的结构，
Figure PCTCN2017072155-appb-000001
已知其为小分子受体酪氨酸激酶抑制剂，抑制表皮生长因子受体(EGFR)和人表皮因子受体2(ERBB2)。其可以与细胞内EGFR和ERBB2的激酶区的ATP结合位点共价结合，阻止肿瘤细胞内EGFR和ERBB2的同质和异质二聚体形成，抑制其自身的磷酸化，阻断下游信号通路的激活，从而抑制肿瘤细胞生长。临床上可用于胃癌、肺癌、乳腺癌等多种肿瘤的治疗。
CN102933574B公开了式I化合物的马来酸盐形式，其相对于其他盐和式I化合物本身在溶解度以及生物利用度和药代动力学方面更具优势。
CN103974949B公开了式I化合物二马来酸盐的I型结晶。该晶型具有良好的晶型稳定性和化学稳定性，可用于制备治疗与EGFR受体酪氨酸激酶或HER-2受体酪氨酸激酶有关的疾病的药物。
但是，在将(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药学上可接受的盐制备成药物固体组合物时，由于活性成分溶解于水后在局部产生较大的粘性，不利于制成药物制剂，同时也造成了药物溶出度下降。
发明内容
本发明的目的在于提供一种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交联聚乙烯吡咯烷酮。活性药物成分为(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺的或其药理学上可接受的盐，例如盐酸盐、马来酸盐、氢溴酸盐、对甲苯磺酸盐、甲磺酸盐、硫酸盐或乙磺酸盐，优选马来酸盐，更优选二马来酸盐。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剂计5-70％，优选10-50％，更优选20-40％。交联聚乙烯吡咯烷酮的含量范围可以是基于组合物的总重量约2-20％；优选4-15％；更优选6-10％。
本发明提供的药物组合物还可以含有填充剂，例如微晶纤维素、磷酸氢钙、甘露醇、预胶化淀粉、乳糖等中的一种或多种。基于组合物的总重量，所述填充剂含量为约5-80％。
本发明提供药物组合物还可以含有粘合剂，例如羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素等中的一种或多种，基于组合物的总重量，所述粘合剂含量为约0.5-15％。
本发明提供药物组合物还可以含有其他崩解剂，例如交联羧甲基纤维素钠、羧甲基淀粉钠、淀粉、低取代羟丙基纤维素等中的一种或多种，基于组合物的总重量，所述崩解剂含量为约0-20％。
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。润滑剂包括滑石粉、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，润滑剂的含量为约0.5-5％。
本发明还提供了一种药物组合物，包括：
1)5-70wt％的(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐；
2)2-20wt％的交联聚乙烯吡咯烷酮；
3)5-80wt％的填充剂，所述填充剂选自乳糖和微晶纤维素中的一种或多种；
4)0.5-15wt％的粘合剂，所述粘合剂选自聚乙烯吡咯烷酮、羟丙基甲基纤维素及羟丙基纤维素中的一种或多种；
5)0.5-5wt％的润滑剂，所述润滑剂选自硬脂酸镁和滑石粉的一种或多种。
在溶出实验中可以看出，本发明的药物组合物由于加入了交联聚乙烯吡咯烷酮，使得活性药物的溶出度大大提升，溶出迅速且完全，有利于药物进入体内迅速起效，发挥药效。
本发明还提供了一种药物组合物，在制备药物组合物的过程中可加入润湿剂，所述润湿剂可包含至少一种有机溶剂，还可包含水，其中有机溶剂可以是低毒性的有机溶剂，优选乙醇、丙酮等，更优选乙醇。基于润湿剂的总重量，所述有机溶剂的含量可以是20～100％，优选50～95％，更优选50～80％。
由于在制备药物组合物的过程中加入的润湿剂包含了乙醇等低毒性有机溶剂，使得制备出的颗粒粒径分布较理想，活性药物溶出迅速完全，便于药物发挥药效。
本发明的药物组合物溶出迅速，起效显著，可用于胃癌、肺癌或乳腺癌等癌症的治疗。
本发明还提供了一种制备药物组合物的方法，包括混合(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐以及交联聚乙烯吡咯烷酮，可采用本领域常见的方法制备成颗粒，例如湿法制粒，最终制备成片剂、胶囊剂等口服制剂。
附图说明
图1显示实施例1以及比较例1～4的片剂在0.1mol/L盐酸溶液中的溶出曲线。
图2显示实施例2～7的片剂在0.1mol/L盐酸溶液中的溶出曲线。
图3显示实施例8～12以及比较例5颗粒粒径分情况。
图4显示比较例5多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图5显示实施例8多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图6显示实施例9多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图7显示实施例10多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图8显示实施例11多片样品在0.1mol/L盐酸溶液中的溶出曲线。
图9显示实施例12多片样品在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，比较例1～4
将(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺的马来酸盐(以下简称为化合物A)、乳糖、微晶纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮，按表1中实施例1的比例混合，以适量93.75wt％乙醇的水溶液为润湿剂进行湿法制粒，干燥至水分小于2％后进行干整粒，加入处方量的硬脂酸镁，采用旋转总混机进行混合。将得到的总混颗粒压片、包衣，制备成片剂。并且采用同样的方法制备含低取代羟丙纤维素、羧甲基淀粉钠、交联羧甲基纤维素钠或淀粉的比较例1～4的片剂。
表1
Figure PCTCN2017072155-appb-000002
Figure PCTCN2017072155-appb-000003
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和比较例1-4的片剂进行溶出度测定。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，处方中含有交联聚乙烯吡咯烷酮的实施例1的片剂中，化合物A溶出迅速完全，含有低取代羟丙纤维素、羧甲基淀粉钠、交联羧甲基纤维素纳或淀粉的比较例1-4的片剂中，化合物A溶出缓慢且不完全。
溶出曲线图见图1。
实施例2～7
以表2的处方比例，将化合物A、乳糖、微晶纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮混合，以适量93.75wt％乙醇的水溶液为润湿剂进行湿法制粒，干燥至水分小于2％进行干整粒，加入处方量的硬脂酸镁，采用旋转总混机进行混合。将得到的总混颗粒压片、包衣，制备成片剂。
表2
Figure PCTCN2017072155-appb-000004
单位：质量％
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)，对实施例2～7的片剂进行溶出度测定。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，处方中含有不同比例交联聚乙烯吡咯烷酮的实施例2～5的片剂和处方中含有不同比例化合物A的实施例6、7的片剂中，化合物A溶出迅速完全。
溶出曲线图见图2。
实施例8～12，比较例5
以表3的处方比例，将化合物A、乳糖、微晶纤维素、聚乙烯吡咯烷酮、交联聚乙烯吡咯烷酮混合，分别以适量纯化水、20wt％乙醇的水溶液、50wt％乙醇的水溶液、80wt％乙醇的水溶液、93.75wt％乙醇的水溶液和无水乙醇为润湿剂湿法制粒，干燥至水分小于2％进行干整粒，加入处方量的硬脂酸镁，采用旋转总混机进行混合。将得到的总混颗粒分装100g用于筛分，其余颗粒压片、包衣，制备成片剂。
表3
Figure PCTCN2017072155-appb-000005
单位：质量％
实验例3：筛分实验
选取50目、100目筛网对实施例8～12以及比较例5得到的100g分装颗粒进行震荡筛分。比例较例5用纯化水作为润湿剂，制备的颗粒，大颗粒和细粉均较多，粒径分布不理想，实施例8～12使用含有乙醇的润湿剂，制备的颗粒粒径分布较均一，大颗粒和细粉均较少。
筛分结果见图3。
实验例4：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8～12和比较例5的片剂进行溶出度测定。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，实施例8～12用20wt％乙醇、50wt％乙醇、80wt％乙醇的水溶液、93.75wt％乙醇、无水乙醇作为润湿剂，制备的颗粒，粒径分布较理想，化合物A溶出迅速完全。比例较例5用纯化水作为润湿剂，制成的片剂中，化合物A溶出均一性不好。实施例8～12使用含有乙醇的润湿剂，制成的片剂中，化合物A溶出均一性较好。
溶出曲线图见图4～9，图中所示R1～R6为试验样品片1～片6。

Claims (15)

  1. 一种药物组合物，包括：
    1)活性药物，其为(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐；以及
    2)交联聚乙烯吡咯烷酮。
  2. 根据权利要求1所述的药物组合物，其中所述药理学上可接受的盐为马来酸盐，优选二马来酸盐。
  3. 根据权利要求1所述的药物组合物，其中交联聚乙烯吡咯烷酮的含量为基于组合物总重量的2％～20％，优选4％-15％，更优选6-10％。
  4. 根据权利要求1所述的药物组合物，其中所述活性药物的含量为基于组合物总重量的5％-70％，优选10％-50％，更优选20-40％。
  5. 根据权利要求1所述的药物组合物，其特征在于还包含粘合剂，所述粘合剂优选羟丙甲纤维素、羟丙基纤维素、羧甲基纤维素钠、聚乙烯吡咯烷酮、甲基纤维素中的一种或多种，优选其含量为基于组合物总重量计的0.5％～15％。
  6. 根据权利要求1所述的药物组合物，其特征在于还包含填充剂，所述填充剂优选微晶纤维素、磷酸氢钙、甘露醇、预胶化淀粉和乳糖中的一种或多种，优选其含量为基于组合物总重量计的5％～80％。
  7. 根据权利要求1所述的药物组合物，其特征在于还包含润滑剂，所述润滑剂优选滑石粉、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、胶体二氧化硅中的一种或多种，优选其含量为基于组合物总重量计的0.5％～5％。
  8. 一种药物组合物，包括：
    1)5-70wt％的(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐；
    2)2-20wt％的交联聚乙烯吡咯烷酮；
    3)5-80wt％的填充剂，所述填充剂选自乳糖和微晶纤维素中的一种或多种；
    4)0.5-15wt％的粘合剂，所述粘合剂选自聚乙烯吡咯烷酮、羟丙基甲基纤维素及羟丙基纤维素中的一种或多种；
    5)0.5-5wt％的润滑剂，所述润滑剂选自硬脂酸镁和滑石粉的一种或多种。
  9. 根据权利要求1所述的药物组合物，其特征在于在制备药物组合物的过程中加入润湿剂，所述润湿剂包含至少一种有机溶剂。
  10. 根据权利要求9所述的药物组合物，所述润湿剂还包含水。
  11. 根据权利要求9所述的药物组合物，所述有机溶剂为乙醇或丙酮，优选乙醇。
  12. 根据权利要求9所述的药物组合物，所述有机溶剂的含量为基于润湿剂总重量计的20-100wt％，优选50-95wt％，更优选50-80wt％。
  13. 根据权利要求1至7任一项所述的药物组合物，其为口服固体制剂，优选片剂和胶囊剂，更优选片剂。
  14. 权利要求1至13任一项所述的药物组合物在制备治疗癌症的药物中的用途；所述癌症优选胃癌、肺癌或乳腺癌。
  15. 制备权利要求1至13任一项所述的药物组合物的方法，包括混合(R,E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-3-氰基-7-乙氧基喹啉-6-基)-3-(1-甲基吡咯烷基-2-基)-丙烯酰胺或其药理学上可接受的盐以及交联聚乙烯吡咯烷酮。
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EP3378478A1 (en) 2018-09-26
MX2018008549A (es) 2018-09-19
RU2018128411A (ru) 2020-02-27
CN107405344B (zh) 2018-08-14
US11065241B2 (en) 2021-07-20

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