[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2017133542A1 - 一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物 - Google Patents

一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物 Download PDF

Info

Publication number
WO2017133542A1
WO2017133542A1 PCT/CN2017/072213 CN2017072213W WO2017133542A1 WO 2017133542 A1 WO2017133542 A1 WO 2017133542A1 CN 2017072213 W CN2017072213 W CN 2017072213W WO 2017133542 A1 WO2017133542 A1 WO 2017133542A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
composition according
acceptable salt
microcrystalline cellulose
disintegrant
Prior art date
Application number
PCT/CN2017/072213
Other languages
English (en)
French (fr)
Inventor
卢韵
张新华
丁欢
张代美
Original Assignee
江苏恒瑞医药股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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 CN201780000891.2A priority Critical patent/CN107405350A/zh
Publication of WO2017133542A1 publication Critical patent/WO2017133542A1/zh
Priority to HK18102971.9A priority patent/HK1243351A1/zh

Links

Images

Classifications

    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K47/30—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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, in particular to a method comprising 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino) A composition of pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmacologically acceptable salt thereof.
  • Breast cancer is one of the most common malignant tumors in women. It has a high incidence and is invasive, but the progress of the disease is slow.
  • the China Population Association released the "China Breast Diseases Investigation Report” in Beijing on February 1, 2010. The report shows that The mortality rate of breast cancer in urban areas in China has increased by 38.91%.
  • Breast cancer has become the most threatening disease for women.
  • At least 156 kinds of breast cancer drugs are currently under research and market, 68% of which are targeted therapeutic drugs.
  • Tumors were found to be abnormally associated with the cell cycle. Mutations in mitotic signaling proteins and defects in anti-mitotic signaling proteins in tumor cells lead to proliferation disorders. At the same time, most tumors have genomic instability (GIN) and genomic instability (CIN). These three basic cell cycle defects are caused directly or indirectly by the loss of control of CDKs. Cyclin Dependent Kinase (CDK) inhibitors are increasingly becoming a hot target.
  • CDK Cyclin Dependent Kinase
  • the second-generation drugs of greatest concern include the CDK4/6 inhibitor PD-0332991, jointly developed by Pfizer and Onyx, which inhibits the phosphorylation of Rb by inhibiting the activity of CDK4/6.
  • the E2F-Rb complex is retained in the cytosol to block the initiation of the cell cycle.
  • Clinical trial results (NCT00721409) showed that progression-free survival (PFS) was 7.5 months in patients treated with letrozole monotherapy, whereas no progress was observed in patients treated with letrozole and PD-0332991. The survival period was extended to 26.1 months, and this remarkable advantage has received wide attention.
  • WO2014183520 discloses a series of CDK4/6 inhibitors of the formula (I) which are structurally similar to PD-0332991, have significant CDK4/6 inhibitory activity and high selectivity, and are expected to be useful for a range of tumors. And can be used in combination with a range of existing anti-tumor agents, including the compound of formula A shown below, having the chemical name 6-acetyl-8-cyclopentyl-5-methyl-2-(5 -(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one:
  • the invention also provides a pharmaceutical composition having good stability.
  • the pharmaceutical composition provided by the present invention contains (6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino) as an active ingredient Pyrido[2,3-d]pyrimidin-7(8H)-one or a pharmacologically acceptable salt thereof, and a disintegrant which is a metal element-free disintegrant.
  • the metal element is an alkali metal or an alkaline earth metal such as sodium, potassium, calcium or magnesium.
  • the disintegrant contained in the composition is a low-substituted hydroxypropyl cellulose or a crospovidone.
  • One or more kinds thereof are not particularly limited, and may be from about 1 to 30% by weight, preferably from 8% to 15% by weight.
  • the pharmacologically acceptable salt of the active ingredient may preferably be selected from the isethionate of the active ingredient.
  • the active ingredient may be included in an amount ranging from 5% to 50%, preferably from 10% to 35%, more preferably from 25% to 35%, based on the total weight of the composition.
  • the pharmaceutical composition provided in the present invention further contains a filler containing mannitol.
  • the filler may contain, in addition to mannitol, one or more of microcrystalline cellulose, pregelatinized starch, and calcium hydrogen phosphate, preferably microcrystalline cellulose.
  • the filler is a mixture of mannitol and microcrystalline cellulose.
  • the content of the filler is not particularly limited and may be 20 to 90%, preferably 30% to 70%, more preferably 40% to 65%, based on the total weight of the pharmaceutical composition, most preferably 45%-60%.
  • the weight ratio of mannitol to microcrystalline cellulose is from 2:1 to 10:1, preferably from 2.5:1 to 5:1, most preferably from 2.5:1 to 3:1.
  • the ratio of mannitol to microcrystalline cellulose used is 3:1, which can significantly increase the stability of the sample as well as the rate and extent of dissolution.
  • the pharmaceutical composition provided in the present invention may further contain a binder, for example, the binder is one or more of polyvinylpyrrolidone, pregelatinized starch, hypromellose, and hydroxypropylcellulose.
  • the binder content is from about 0.5% to about 10%, preferably from about 0.5% to about 5%, based on the total weight of the composition.
  • the pharmaceutical compositions provided herein may further comprise one or more lubricants to aid in filling or compressing the capsules.
  • the lubricant may be selected from the group consisting of talc, magnesium stearate, zinc stearate, glyceryl behenate, and the like, based on the total weight of the composition.
  • the lubricant is present in an amount of from about 0.5% to about 5%.
  • composition comprising the following ingredients by weight:
  • ком ⁇ онент selected from one or two of low-substituted hydroxypropylcellulose or crospovidone;
  • binder selected from one or more of polyvinylpyrrolidone, pregelatinized starch, hypromellose;
  • lubricant selected from one or more of magnesium stearate, stearic acid, and glyceryl behenate.
  • compositions of the present invention can be prepared by methods conventional in the art, such as high shear wet granulation, dry granulation, one-step granulation, and the like, to prepare granules of the pharmaceutical composition, which are then compressed into tablets.
  • the composition of the present invention dissolves very rapidly and completely.
  • purified water is used as the dissolution medium, preferably 1000 ml of purified water, and at 37 ⁇ 0.5 ° C
  • the composition of the present invention was subjected to a dissolution test at a paddle speed of 50 rpm, and the dissolution rate was 80% or more in 40 minutes or 45 minutes, preferably 95% or more in 45 minutes or 60 minutes.
  • the pharmaceutical composition provided by the present invention improves the stability thereof by using a filler containing mannitol, and the composition of the present invention is placed in an environment of a temperature of 40 ° C and a relative humidity of 75% for one month. Then, the content of the relevant substance is not more than 1% as determined by HPLC.
  • Figure 1 shows the dissolution profiles of the tablets of Examples 1-5 in purified water.
  • Figure 2 shows the dissolution profiles of the tablets of Examples 6-9 in purified water.
  • Figure 3 shows the dissolution profiles of the tablets of Examples 1 and 10-12 in purified water.
  • Figure 4 shows the dissolution profiles of the tablets of Examples 10 and 13-14 in purified water.
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidine- 7(8H)-ketohydroxyethyl sulfonate hereinafter referred to as compound A
  • lactose lactose
  • microcrystalline cellulose low-substituted hydroxypropyl cellulose or crospovidone
  • croscarmellose sodium carboxymethyl Base starch sodium, according to the ratio in Table 1, wet granulation by high-speed shear granulator, 5% aqueous solution prepared with povidone K30 as wetting agent, wet granulation and drying of wet materials After treatment, dry granules (water content less than 3%) are dry granulated, and a prescribed amount of magnesium stearate is added and mixed well. The resulting total mixed granules were compressed into tablets.
  • Example 1 The tablets in Examples 1 to 5 were subjected to dissolution measurement according to the second method (paddle method) of the dissolution test of the second edition of the Chinese Pharmacopoeia 2015. 1000 ml of purified water was used as the dissolution medium, and the dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm.
  • the results showed that in Examples 2 and 3, the dissolution of Compound A was slow and incomplete; in Example 4, Compound A was completely dissolved.
  • Example 5 Compound A was completely dissolved, and the dissolution rate was slower than that of the tablet of Example 1.
  • the dissolution data are shown in Table 2 below, and the dissolution curve is shown in Figure 1.
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidine- 7(8H)-ketohydroxyethyl sulfonate hereinafter referred to as compound A
  • compound A mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, wetted by a high-speed shear granulator according to the ratio in Table 3.
  • the dissolution rates of the tablets of Examples 6 to 9 were measured according to the second method (paddle method) of the dissolution test of the Appendix 2 of the Chinese Pharmacopoeia. 1000 ml of purified water was used as the dissolution medium, and the dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Examples 6 to 9, the compound A was completely eluted.
  • the dissolution data is shown in Table 4, and the dissolution curve is shown in Figure 2.
  • Compound A 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidine- 7(8H)-ketohydroxyethyl sulfonate (hereinafter referred to as Compound A), lactose or mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, according to the ratio in Table 5, using a high-speed shear granulator Wet granulation, 5% aqueous solution prepared with povidone K30 as a wetting agent, wet granules and drying treatment of wet materials, and then dry granules (water content less than 3%) are added and dried. Prescribe the amount of magnesium stearate and mix well. The resulting total mixed granules were compressed into tablets.
  • the dissolution rates of the tablets of Examples 1 and 10 to 12 were determined according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition. 1000 ml of purified water was used as the dissolution medium, and the dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Examples 1 and 10, Compound A was completely dissolved; in Examples 11 and 12, the proportion of microcrystalline cellulose was gradually increased, and the dissolution rate of Compound A was gradually slowed compared with the tablet of Example 1. And the dissolution is not complete.
  • the dissolution data is shown in Table 6 below, and the dissolution profile is shown in Figure 3.
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidine- 7(8H)-ketohydroxyethyl sulfonate hereinafter referred to as compound A
  • compound A mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, wetted by a high-speed shear granulator according to the ratio in Table 7.
  • Method granules respectively, a 5% aqueous solution prepared with povidone K30 and a 3% aqueous solution prepared with hypromellose E5, and a 13% aqueous solution prepared with pregelatinized starch as a wetting agent.
  • Wet and soft materials are wet granulated and dried, then dry granules (water content less than 3%) are dry granulated, and the prescribed amount of magnesium stearate is added and mixed uniformly. The resulting total mixed granules were compressed into tablets.
  • the dissolution rates of the tablets of Examples 10, 13, and 14 were determined according to the second method (paddle method) of the dissolution test of the Chinese Pharmacopoeia 2015 edition. 1000 ml of purified water was used as the dissolution medium, and the dissolution test was carried out at 37 ⁇ 0.5 ° C at a paddle speed of 50 rpm. The results showed that in Example 10, Compound A was completely dissolved; in Example 14, Compound A was incompletely eluted; in Example 13, Compound A was completely dissolved.
  • the dissolution data is shown in Table 8 below, and the dissolution profile is shown in Figure 4.
  • the examples 1 and 10 were placed in an environment of a temperature of 40 ° C and a relative humidity of 75% for 1 month, 2 months, and 3 months, and then the changes of the substances were measured by HPLC.
  • the results of the related substance test showed that the total amount of the starting substance related to the tablet in Example 1 was larger than the total amount of the related substance in the tablet of Example 10; after the tablet was placed in Example 1 for one month, the related substance was increased; After the tablets were placed for 1 month, 2 months, and 3 months, there was no significant change in the relevant substances (see Table 9).
  • Step 1 6-((6-(1-Butoxyvinyl)-8-cyclopentyl-5-methyl-7-carbonyl-7,8-dihydropyrido[2,3-d]pyrimidine Preparation of 2-yl)amino)-5',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-carboxylic acid tert-butyl ester
  • the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with dichloromethane 17.
  • the filtrate was concentrated to dryness under reduced pressure at 65 °C.
  • the residue was dissolved in 137.50 g of dichloromethane, 56.25 g of purified water was added, and the mixture was partitioned and the aqueous phase was extracted with 68.75 g of dichloromethane.
  • the combined organic layers were dried with anhydrous sodium sulfate and filtered, and then filtered and evaporated.
  • Step 2 4-(6-((6-Acetyl-8-cyclopentyl-5-methyl-7-carbonyl-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) Of amino)pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester
  • the residual amount of the intermediate state (6-((6-(1-butoxyvinyl))-8-cyclopentyl-5-methyl-7-carbonyl-7,8-dihydropyrido[2, 3-d]pyrimidin-2-yl)amino)-5',6'-di Hydrogen-[3,4'-bipyridyl]-1 '(2'H)-carboxylic acid tert-butyl ester was removed from the n-butyl-protected but unreduced intermediate of the double bond) ⁇ 0.3%, and the reaction was terminated.
  • the reaction solution was cooled to room temperature, the system was replaced with argon and filtered, and the filter cake was washed with 37.50 g of dichloromethane.
  • the filtrate was concentrated to dryness under reduced pressure at 65 °C.
  • the residue was purged with argon gas and refluxed with 50 g of absolute ethanol for 0.5 h, and then cooled to room temperature with stirring, and stirred for about 4 h in an ice bath. Filter and filter cake was washed with cold anhydrous ethanol 12.50 g x 2 .
  • the obtained wet product was stirred with 31.25 g of dichloromethane, and the insoluble matter was filtered.
  • Step 3 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Preparation of pyrimidine-7(8H)-ketohydroxyethyl sulfonate

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

本发明公开了一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物。具体而言，所述的组合物包含6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮或其药理学上可接受的盐，以及崩解剂，所述崩解剂为不含金属元素的崩解剂，所述组合物溶出迅速。本发明的药物组合物制备工艺简单，更适合工艺化大生产。

Description

一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物 技术领域
本发明属于药物制剂领域，具体涉及一种含有6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮或其药理学上可接受盐的组合物。
背景技术
乳腺癌是女性最常见的恶性肿瘤之一，具有发病率高，颇具侵袭性，但病程进展缓慢，中国人口协会2010年2月1日在北京发布了《中国乳腺疾病调查报告》，报告显示，我国城市地区乳腺癌的死亡率增长了38.91％，乳腺癌已经成为对妇女健康威胁最大的疾病，目前在研和上市的乳腺癌药物至少有156种，其中68％为靶向治疗药物，大量研究发现肿瘤与细胞周期反常相关，肿瘤细胞中有丝分裂信号蛋白的大量突变和抗有丝分裂信号蛋白缺陷导致增殖紊乱；同时大部分肿瘤都存在基因组不稳定性(GIN)和染色体组不稳定性(CIN)，这三种基本的细胞周期缺陷都直接或间接由CDKs的失控引起。周期素依赖性蛋白激酶(CDK，Cyclin Dependent Kinase)抑制剂日益成为热门靶标。
目前开发的一代二代CDK抑制剂很多，最受关注的二代药物包括Pfizer公司和Onyx公司共同开发的CDK4/6抑制剂PD-0332991，其通过抑制CDK4/6的活性，抑制Rb的磷酸化，使E2F-Rb复合物留滞在胞浆中，阻断细胞周期的启动。临床试验结果(NCT00721409)显示，来曲唑单药治疗的患者的无进展存活期(Progression-free survival,PFS)为7.5月，而来曲唑和PD-0332991药物联用治疗的患者其无进展存活期则延长至26.1月，这一显著优势获得了广泛关注。
WO2014183520公开了与PD-0332991结构相似的一系列满足式(I)通式的CDK4/6抑制剂，具有显著的CDK4/6的抑制活性和高度选择性，并预期这些化合物可能用于一系列肿瘤，并且可以与一系列现有的抗肿瘤剂联合使用，其中包括如下所示的式A化合物，其化学名为6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮：
Figure PCTCN2017072213-appb-000001
申请人在先提交的PCT/CN2016/070636记载了上述化合物的羟乙基磺酸盐及其I晶型。
然而上述文献均没有公开如何获得溶出迅速且完全的药物组合物，同时，上 述化合物稳定性不佳，因此需要深入研究发现溶出良好的组合物，并解决稳定性问题。
发明内容
本发明的目的在于提供一种溶出迅速，且完全的药物组合物，并且该药物组合物制备工艺简单，更适合工艺化大生产。另一方面，本发明还提供了一种稳定性良好的药物组合物。
本发明提供的药物组合物含有作为活性成分的(6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮或其药理学上可接受的盐以及崩解剂，所述崩解剂为不含金属元素的崩解剂。其中所述金属元素为碱金属或碱土金属，例如钠、钾、钙、镁。在本发明优选的实施方案中，组合物中含有的崩解剂为低取代羟丙基纤维素或交联聚维酮中的一种或多种。其含量没有特别限制，以重量计，可以为约1-30％，优选8％-15％。
本发明中提供的药物组合物中，所述活性成分的药理学上可接受的盐可以优选自活性成分的羟乙基磺酸盐。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剂计5％-50％；优选10％-35％，更优选为25％-35％。
本发明中提供的药物组合物中，还含有填充剂，所述填充剂含有甘露醇。在本发明优选的实施方案中，所述填充剂除甘露醇外，还可以含有微晶纤维素、预胶化淀粉、磷酸氢钙中的一种或几种，优选微晶纤维素。在优选的实施方案中，所述填充剂为甘露醇和微晶纤维素的混合物。
本发明的组合物中，填充剂的含量没有特别限制，可以为所述药物组合物的总重的20-90％，优选30％-70％，更优选为40％-65％，最优选为45％-60％。其中甘露醇和微晶纤维素的重量比例为2：1至10：1，优选2.5：1至5：1，最优选2.5：1至3：1。在本发明的一个实施例中，所用甘露醇和微晶纤维素的比例为3:1，可以显著提高样品的稳定性以及溶出速度和程度。
本发明中提供的药物组合物中，还可含有粘合剂，例如粘合剂为聚乙烯吡咯烷酮、预胶化淀粉、羟丙甲纤维素及羟丙基纤维素中的一种或几种，基于组合物的总重量，所述粘合剂含量为约0.5-10％，优选为0.5％-5％。
本发明中提供的药物组合物中，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。基于组合物的总重量，润滑剂可选自滑石粉、硬脂酸镁、硬脂酸锌、山嵛酸甘油酯等。润滑剂的含量为约为0.5％-5％。
在本发明特别优选的实施方案中，提供了一种药物组合物，含有以重量计的如下成分：
1)10％-35％的(6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮或其药理学上可接受的盐；
2)20％-70％的甘露醇；
3)5％-30％微晶纤维素；
4)8％-15％的崩解剂，选自低取代羟丙基纤维素或交联聚维酮中的一种或两种；
5)0.5％-5％的粘合剂，选自聚乙烯吡咯烷酮、预胶化淀粉、羟丙甲纤维素中的一种或几种；
6)任选地0.5％-5％的润滑剂，选自硬脂酸镁、硬脂酸、山嵛酸甘油酯中的一种或几种。
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，然后压制成片剂。
本发明的组合物溶出十分迅速且完全，根据中国药典2015版二部附录溶出度测定第二法(桨法)，以纯化水作为溶出介质，优选1000ml的纯化水，并在37±0.5℃下以50rpm的桨速对本发明组合物进行溶出试验，40分钟或45分钟溶出度大于等于80％，优选在45分钟或60分钟溶出度大于等于95％。
另一方面，本发明提供的药物组合物由于采用了含有甘露醇的填充剂，提高了其稳定性，本发明的组合物置于温度40℃、相对湿度75％的环境下，放置1个月，然后采用HPLC法测定，有关物质含量不超过1％。
附图说明
图1显示实施例1-5的片剂在纯化水中的溶出曲线。
图2显示实施例6-9的片剂在纯化水中的溶出曲线。
图3显示实施例1以及10-12的片剂在纯化水中的溶出曲线。
图4显示实施例10以及13-14的片剂在纯化水中的溶出曲线。
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1-5
将6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮羟乙基磺酸盐(以下简称化合物A)、乳糖、微晶纤维素、低取代羟丙纤维素或交联聚维酮、交联羧甲基纤维素钠、羧甲基淀粉钠、按表1中的比例，采用高速剪切制粒机进行湿法制粒，以聚维酮K30配制成的5％的水溶液为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表1
Figure PCTCN2017072213-appb-000002
实验例1：溶出实验
根据中国药典2015版二部附录溶出度测定第二法(桨法)，对实施例1～5中的片剂进行溶出度测定。使用1000ml的纯化水作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例2和3中，化合物A溶出缓慢且不完全；实施例4中，化合物A完全溶出。实施例5中，化合物A完全溶出，溶出速度较实施例1中片剂慢。溶出数据如下表2所示，溶出曲线见图1
表2
Figure PCTCN2017072213-appb-000003
实施例6-9
将6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮羟乙基磺酸盐(以下简称化合物A)、甘露醇、微晶纤维素、低取代羟丙纤维素、按表3中的比例，采用高速剪切制粒机进行湿法制粒，以羟丙甲纤维素E5配制成的3％的水溶液为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表3
Figure PCTCN2017072213-appb-000004
实验例2：溶出实验
根据中国药典2015版二部附录溶出度测定第二法(桨法)，对实施例6～9的片剂进行溶出度测定。使用1000ml的纯化水作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例6～9中，化合物A溶出完全。溶出数据见表4，溶出曲线见图2。
表4
Figure PCTCN2017072213-appb-000005
实施例10～12
将6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮羟乙基磺酸盐(以下简称化合物A)、乳糖或甘露醇、微晶纤维素、低取代羟丙纤维素、按表5中的比例，采用高速剪切制粒机进行湿法制粒，以聚维酮K30配制成的5％的水溶液为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表5
Figure PCTCN2017072213-appb-000006
Figure PCTCN2017072213-appb-000007
实验例2：溶出实验
根据中国药典2015版二部附录溶出度测定第二法(桨法)，对实施例1和10～12的片剂进行溶出度测定。使用1000ml的纯化水作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例1和10中，化合物A溶出完全；实施例11和12中，微晶纤维素的比例逐渐增加，与实施例1中的片剂相比较，化合物A的溶出速度逐渐变慢且溶出不完全。溶出数据如下表6所示，溶出曲线见图3。
表6
Figure PCTCN2017072213-appb-000008
实施例13～14
将6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮羟乙基磺酸盐(以下简称化合物A)、甘露醇、微晶纤维素、低取代羟丙纤维素，按表7中的比例，采用高速剪切制粒机进行湿法制粒，分别以聚维酮K30配制成的5％的水溶液和羟丙甲纤维素E5配制成的3％的水溶液、以预胶化淀粉配制成的13％的水溶液作为为润湿剂，对湿软材进行湿整粒及干燥处理，然后将干颗粒(水分小于3％)进行干整粒，加入处方量的硬脂酸镁，混合均匀。将得到的总混颗粒压制成片剂。
表7
Figure PCTCN2017072213-appb-000009
Figure PCTCN2017072213-appb-000010
实验例4：溶出实验
根据中国药典2015版二部附录溶出度测定第二法(桨法)，对实施例10、13、14的片剂进行溶出度测定。使用1000ml的纯化水作为溶出介质，并在37±0.5℃下以50rpm的桨速进行溶出试验。结果表明，实施例10中，化合物A完全溶出；实施例14中，化合物A溶出不完全；实施例13中，化合物A完全溶出。溶出数据如下表8所示，溶出曲线见图4。
表8
Figure PCTCN2017072213-appb-000011
实验例5：稳定性研究
将实施例1、10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，然后分别采用HPLC法测定有关物质的变化。
有关物质检测结果表明，实施例1中片剂的起始有关物质总量大于实施例10中片剂的有关物质总量；实施例1中片剂放置1个月后，有关物质增加；实施10中片剂放置1个月、2个月、3个月后，有关物质没有明显变化(见表9)。
表9
Figure PCTCN2017072213-appb-000012
实施例15：6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮羟乙基磺酸盐的合成
步骤1：6-((6-(1-丁氧基乙烯基)-8-环戊基-5-甲基-7-羰基-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-5',6'-二氢-[3,4'-联吡啶]-1'(2'H)-甲酸叔丁酯的制备
Figure PCTCN2017072213-appb-000013
氩气保护下，将(10g，29.06mmol)2-氨基-6-(1-丁氧乙烯基)-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(按WO2014183520公开方法制备)、碳酸铯(14.22g，43.75mmol)、Pd2(dba)3(2.12g，2.31mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(2.69g，4.69mmol)和125.00g二氧六环投入三口反应瓶中，搅拌均匀后加热至回流，缓慢滴加原料4-(6-氯吡啶-3-基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(10.34g，35.00mmol,购自盐城市瑞康医药化工有限公司)和二氧六环(65.62g，0.74mol)的混合液(滴加时间约5h)。滴毕继续回流搅拌反应1～1.5h，TLC监控原料2-氨基-6-(1-丁氧乙烯基)-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮反应完全(展开剂：石油醚：乙酸乙酯＝2:1，原料Rf＝0.6，产物Rf＝0.7)，终止反应。反应液冷却至室温，过滤，滤饼用二氯甲烷17.19g×3洗涤。将滤液于65℃减压浓缩干。残留物加入137.50g二氯甲烷溶解，加入56.25g纯化水，分液，水相再用68.75g二氯甲烷萃取。合并有机相，无水硫酸钠干燥，过滤，滤饼用23.44g二氯甲烷洗，滤液于45℃减压浓缩至油状液体。加入150g丙酮溶解，室温搅拌约2h，冰水浴搅拌约3h。过滤，滤饼用冷丙酮25g×4洗涤，室温减压干燥8～10h，得固体约14.84g，收率：80～92％，HPLC检测纯度不低于90％。ESI/MS:[M+H]＝601.43。
步骤2：4-(6-((6-乙酰基-8-环戊基-5-甲基-7-羰基-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-1-甲酸叔丁酯的制备
Figure PCTCN2017072213-appb-000014
将6-((6-(1-丁氧基乙烯基)-8-环戊基-5-甲基-7-羰基-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-5',6'-二氢-[3,4'-联吡啶]-1'(2'H)-甲酸叔丁酯(14.84g，24.69mmol)和75g乙酸投入三口反应瓶中，通氩气保护。加入10％Pd/C(5g)，氢气置换三次，搅拌下于50～60℃常压加氢反应30～32h。HPLC法监测中间态剩余量(6-((6-(1-丁氧基乙烯基)-8-环戊基-5-甲基-7-羰基-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-5',6'-二 氢-[3,4'-联吡啶]-1'(2'H)-甲酸叔丁酯脱掉正丁基保护但双键未被还原的中间体)＜0.3％，终止反应。反应液冷却至室温，体系氩气置换后过滤，滤饼用37.50g二氯甲烷洗涤。将滤液于65℃减压浓缩至干。残留物氩气保护用50g无水乙醇回流打浆0.5h，搅拌下自然冷却至室温，冰浴搅拌约4h。过滤，滤饼用冷无水乙醇12.50g×2洗涤。所得湿品加入二氯甲烷31.25g搅拌，过滤不溶物，滤液搅拌下缓慢加入异丙醇118.75g，冰浴搅拌约3h，过滤后减压干燥8～10h得固体约8.75g，产率：60～72％，HPLC检测纯度不低于98％。ESI/MS:[M+H]＝547.26。
步骤3：6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮羟乙基磺酸盐的制备
Figure PCTCN2017072213-appb-000015
将4-(6-((6-乙酰基-8-环戊基-5-甲基-7-羰基-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)吡啶-3-基)哌啶-1-甲酸叔丁酯(8.75g，15.94mmol)和56.25g无水甲醇投入三口反应瓶中，搅拌均匀。将80％羟乙基磺酸(8.81g，55.94mmol)和水0.94g溶于13.75g无水甲醇中，滴加到上述溶液中，溶液变澄清。滴毕加热回流搅拌反应3～3.5h，TLC检测原料反应完全(石油醚：乙酸乙酯＝1:1，原料Rf＝0.3，产物Rf＝0)，终止反应，趁热过滤。滤液搅拌下滴加三乙胺(4.00g，39.38mmol)，滴毕继续搅拌约1h，冰浴搅拌约3h。过滤，滤饼用冷无水甲醇7.19g×2洗涤，40℃减压干燥6～8h得固体约7.97g，收率：82～93％，HPLC检测纯度不低于98％。
TOF-MS:[M+H]＝447.2503(6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮结合一个氢离子的离子峰)。

Claims (14)

  1. 一种药物组合物，含有作为活性成分的(6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮或其药理学上可接受的盐以及崩解剂，所述崩解剂为不含金属元素的崩解剂。
  2. 根据权利要求1所述的药物组合物，所述金属元素为碱金属或碱土金属。
  3. 根据权利要求1所述的药物组合物，所述崩解剂为低取代羟丙基纤维素或交联聚维酮中的一种或多种。
  4. 根据权利要求1所述的药物组合物，其中所述崩解剂以重量计，含量为约1-30％，优选8％-15％。
  5. 根据权利要求1所述的药物组合物，还含有填充剂，所述填充剂含有甘露醇。
  6. 根据权利要求5所述的药物组合物，所述填充剂还含有选自微晶纤维素、预胶化淀粉、磷酸氢钙中的一种或几种，优选微晶纤维素。
  7. 根据权利要求5或6所述的药物组合物，所述填充剂的含量为所述药物组合物总重的20-90％，优选30％-70％，更优选为40％-65％，最优选为45％-60％。
  8. 根据权利要求6所述的药物组合物，其中甘露醇和微晶纤维素的重量比例为2：1至10：1，优选2.5：1至5：1，最优选2.5：1至3：1。
  9. 根据权利要求1所述的药物组合物，还含有粘合剂，所述粘合剂选自聚乙烯吡咯烷酮、预胶化淀粉、羟丙甲纤维素及羟丙基纤维素中的一种或几种。
  10. 根据权利要求1所述的药物组合物，还含有润滑剂，所述润滑剂选自硬脂酸镁、硬脂酸、山嵛酸甘油酯中的一种或几种。
  11. 根据权利要求1至10中任意一项所述的药物组合物，其中所述活性成分的药理学上可接受的盐为羟乙基磺酸盐。
  12. 一种药物组合物，含有以重量计的如下成分：
    1)10％-35％的(6-乙酰基-8-环戊基-5-甲基-2-((5-(哌啶-4-基)吡啶-2-基)氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮或其药理学上可接受的盐；
    2)20％-70％的甘露醇；
    3)5％-30％微晶纤维素；
    4)8％-15％的崩解剂，选自低取代羟丙基纤维素或交联聚维酮中的一种或两种；
    5)0.5％-5％的粘合剂，选自聚乙烯吡咯烷酮、预胶化淀粉、羟丙甲纤维素中的一种或几种；
    6)任选地0.5％-5％的润滑剂，选自硬脂酸镁、硬脂酸、山嵛酸甘油酯中的一种或几种。
  13. 根据权利要求1-12中任意一项所述的药物组合物的制备方法，所述方法选自湿法制粒、干法制粒工艺和粉末直接压片中的一种，优选湿法制粒。
  14. 根据权利要求1-12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；所述癌症优选乳腺癌，更优选雌激素受体阳性的乳腺癌。
PCT/CN2017/072213 2016-02-04 2017-01-23 一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物 WO2017133542A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201780000891.2A CN107405350A (zh) 2016-02-04 2017-01-23 一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物
HK18102971.9A HK1243351A1 (zh) 2016-02-04 2018-03-01 一種含有吡啶並嘧啶類衍生物或其可藥用鹽的藥物組合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610080476 2016-02-04
CN201610080476.X 2016-02-04

Publications (1)

Publication Number Publication Date
WO2017133542A1 true WO2017133542A1 (zh) 2017-08-10

Family

ID=59500122

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/072213 WO2017133542A1 (zh) 2016-02-04 2017-01-23 一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物

Country Status (4)

Country Link
CN (1) CN107405350A (zh)
HK (1) HK1243351A1 (zh)
TW (1) TWI737673B (zh)
WO (1) WO2017133542A1 (zh)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020253808A1 (zh) * 2019-06-20 2020-12-24 江苏恒瑞医药股份有限公司 一种药物组合物以及其制备方法
WO2022184113A1 (zh) * 2021-03-03 2022-09-09 苏州盛迪亚生物医药有限公司 一种包含吡啶并嘧啶类衍生物的药物组合物及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014183520A1 (zh) * 2013-05-17 2014-11-20 上海恒瑞医药有限公司 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用
WO2016169422A1 (zh) * 2015-04-22 2016-10-27 江苏恒瑞医药股份有限公司 一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3501696A1 (de) * 1985-01-19 1986-07-24 Bayer Ag, 5090 Leverkusen Pyridopyrimidine, mehrere verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014183520A1 (zh) * 2013-05-17 2014-11-20 上海恒瑞医药有限公司 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用
WO2016169422A1 (zh) * 2015-04-22 2016-10-27 江苏恒瑞医药股份有限公司 一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020253808A1 (zh) * 2019-06-20 2020-12-24 江苏恒瑞医药股份有限公司 一种药物组合物以及其制备方法
CN113993505A (zh) * 2019-06-20 2022-01-28 江苏恒瑞医药股份有限公司 一种药物组合物以及其制备方法
CN113993505B (zh) * 2019-06-20 2023-12-12 江苏恒瑞医药股份有限公司 一种药物组合物以及其制备方法
WO2022184113A1 (zh) * 2021-03-03 2022-09-09 苏州盛迪亚生物医药有限公司 一种包含吡啶并嘧啶类衍生物的药物组合物及其制备方法

Also Published As

Publication number Publication date
HK1243351A1 (zh) 2018-07-13
TWI737673B (zh) 2021-09-01
TW201728329A (zh) 2017-08-16
CN107405350A (zh) 2017-11-28

Similar Documents

Publication Publication Date Title
AU2020203497B2 (en) Formulations of 2-(tert-butylamino)-4-((1R,3R,4R)-3-hydroxy-4-methycyclohexylamino)-pyrimidine-5-carboxamide
AU2015229214B2 (en) Pharmaceutical compositions of therapeutically active compounds
TWI845657B (zh) (s)-1-(4-氟苯基)-1-(2-(4-(6-(1-甲基-1h-吡唑-4-基)吡咯并[2,1-f][1,2,4]三嗪-4-基)哌嗪基)-嘧啶-5-基)乙-1-胺之晶形及其製造方法
TWI706951B (zh) 一種週期素依賴性蛋白激酶抑制劑的羥乙基磺酸鹽、其結晶形式及製備方法
TW201638090A (zh) 一種週期素依賴性蛋白激酶抑制劑的結晶形式及其製備方法
CN107137409A (zh) 一种cdk4/6抑制剂与雌激素受体拮抗剂联合在制备治疗乳腺癌的药物中的用途
EP3279201A1 (en) Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor
WO2017133542A1 (zh) 一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物
CN107028899B (zh) 一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物
TW202016114A (zh) 抑制ｃｄｋ４／６活性化合物的晶型及其應用
CN110650960B (zh) Acalabrutinib的新晶型及其制备方法和用途
CN105407892B (zh) 一种化合物的药物组合物、其固体形式及它们的使用方法
CN114306255B (zh) 一种甲基酮类衍生物药物制剂及其制备方法
EP3650025A1 (en) Pharmaceutical composition and method for preparing same
CN111362871B (zh) 取代的吡啶-2-甲酰胺类化合物及其用途
CN113372345B (zh) 氘代杂环类激酶抑制剂
CN107266468A (zh) 含吡唑啉结构的噻喃并嘧啶类化合物的制备及应用
WO2024040241A1 (en) Pharmaceutical formulations, processes for preparation, and methods of use
CN117582438A (zh) 吡啶类衍生物的药物组合物、制备方法及用途
CN112220785A (zh) 一种pde4抑制剂药物组合物及其制备方法与用途
CN112300132A (zh) 芳基喹唑啉类dna-pk抑制剂
CN113272295A (zh) 含有哌嗪酮的喹唑啉二酮盐类化合物、其制备方法、药物组合物和用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17746862

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17746862

Country of ref document: EP

Kind code of ref document: A1