WO2020029441A1 - 尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用 - Google Patents

尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用 Download PDF

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WO2020029441A1
WO2020029441A1 PCT/CN2018/113216 CN2018113216W WO2020029441A1 WO 2020029441 A1 WO2020029441 A1 WO 2020029441A1 CN 2018113216 W CN2018113216 W CN 2018113216W WO 2020029441 A1 WO2020029441 A1 WO 2020029441A1
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sorafenib
nicotinamide
composition
hand
skin reaction
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何俏军
杨波
罗沛华
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浙江大学
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Priority to EP18915796.9A priority Critical patent/EP3636265B1/en
Priority to US16/612,770 priority patent/US11278542B2/en
Publication of WO2020029441A1 publication Critical patent/WO2020029441A1/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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

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  • the invention belongs to the field of medicine and relates to the application of a nicotinamide composition in preparing a medicine for treating sorafenib hand and foot skin reaction.
  • Sorafenib is a tyrosine kinase inhibitor (TKI) targeting the vascular endothelial growth factor (VEGF) family. It is a first-line drug for the treatment of advanced liver and kidney cancer in the clinic. It can significantly improve the non-progressive survival of patients. period.
  • sorafenib has strong toxic side effects, the most common of which is hand-foot skin reaction (HFSR), which is clinically characterized by hyperkeratinization, with an incidence of up to 60%.
  • HFSR hand-foot skin reaction
  • sorafenib-induced HFSR is usually not a life-threatening side effect, it affects the patient's quality of life and may cause dose changes or treatment interruptions, ultimately threatening the patient's life.
  • sorafenib-induced HFSR Because the molecular mechanism of sorafenib-induced HFSR is unknown, there are no good clinical strategies to address this toxic side effect. For mild HFSR, patients can be relieved with keratin softeners or lubricants. Patients who develop severe HFSR during medication need to modify the dose of the drug or even interrupt treatment. These therapies can only reduce these symptoms to some extent, but they cannot cure sorafil-induced HFSR. Therefore, it is of great significance to find the molecular mechanism of sorafenib-induced HFSR and find suitable intervention strategies based on this mechanism to slow the hand-foot skin reaction caused by sorafenib.
  • sorafenib can induce the secretion of heparin and epidermal growth factor HB-EGF by vascular endothelial cells (HUVEC), activate the HB-EGF / SIRT1 signaling pathway, accelerate the keratinization of keratinocytes (HaCat), and eventually lead to hand and foot Skin reactions.
  • HaCat keratinocytes
  • SIRT1 plays a key role in sorafenib-induced HFSR, if SIRT1 inhibitors are used in combination with sorafenib in clinic, it can significantly reduce sorafenib-induced HFSR.
  • Nicotinamide is a member of the vitamin B family and is a common SIRT1 inhibitor. Nicotinamide can be mainly used in the prevention and treatment of pellagra, stomatitis, glossitis, etc., and can also be used to treat coronary heart disease, viral myocarditis, rheumatic heart disease, etc., but it has not been used as a treatment for sorafenib Reports of hand-foot skin reactions.
  • the purpose of the present invention is to provide a nicotinamide composition for preparing a medicine for treating sorafenib hand and foot skin reaction.
  • the composition is composed of nicotinamide and sorafenib, and nicotinamide and sorafenib are dosed according to the dosage.
  • the ratio is a 2: 3 combination.
  • the dose ratio was 2: 3, that is, nicotinamide 10 ⁇ M and sorafenib 15 ⁇ M.
  • nicotinamide is 3-pyridinecarboxamide, with a molecular formula of C 6 H 6 N 2 O and a molecular weight of 122.13.
  • the present invention provides a mechanism for nicotinamide to reduce the hand, foot, and skin reactions caused by sorafenib: sorafenib activates the HB-EGF / SIRT1 pathway, accelerates the process of keratinization, and then leads to hand, foot and skin reactions; the SIRT1 inhibitor nicotinamide can block this The activation of the pathway, thereby alleviating sorafenib-induced hand-foot-skin reactions, therefore, niafamide-induced HFSR can be treated with a nicotinamide composition.
  • the pharmaceutical dosage form is a liquid preparation or a solid preparation, and is prepared from a combination of nicotinamide and sorafenib and pharmaceutically acceptable excipients, including oral solid preparations, oral liquid preparations, injections, lyophilized powder injections, and large infusions. Dosage form, patch, ointment, gel, soft capsule or suppository.
  • the SIRT1 inhibitor nicotinamide and the antitumor drug sorafenib composition provided by the present invention can alleviate hand, foot and skin reactions caused by excessive keratinization caused by sorafenib. This protective effect is achieved by inhibiting the HB-EGF / SIRT1 pathway.
  • the advantages of the present invention are as follows: (1) It provides the mechanism of sorafenib-induced hand-foot skin reaction, that is, the excessive activation of the HB-EGF / SIRT1 pathway, and provides a theory for the clinical study of sorafenib-induced hand-foot skin reactions.
  • Nicotinamide is moderately priced and can be customized as needed Made into a suitable dosage form, high clinical feasibility.
  • Figure 1 shows the effect of sorafenib on the HB-EGF / SIRT1 signal pathway and the effect of inhibiting this pathway on the process of keratinization.
  • Fig. 2 is the effect on the keratinization process of HACat cells treated with nicotinamide and sorafenib-treated HUVEC cell culture medium as a conditioned medium.
  • HUVEC cells were administered with 15 ⁇ M sorafenib, the cells and culture fluids were collected, and the culture medium was concentrated, and the inactive transmembrane structure of pro-HB-EGF in the cells and the active free form of s- in the culture medium were detected by western blot.
  • HB-EGF protein The experimental results are shown in Figure 1A. It was found that the expression level of HB-EGF protein in the cells was down-regulated, and the expression of HB-EGF protein in the culture solution was increased. HUVEC culture medium given sorafenib was used as a conditioned medium for HaCat cells, and the expression of SIRT1 in the cells was detected. The experimental results are shown in Figure 1B.
  • HUVEC cells were given sorafenib 15 ⁇ M, sorafenib 15 ⁇ M, and nicotinamide 10 ⁇ M. After 24 hours, the culture medium was collected as a conditioned medium for HaCat cells. After 24 hours, HaCat cells were collected to detect three types of HaCat cells. Keratin mRNA levels.
  • Figure 2 The results of the study are shown in Figure 2: The mRNA levels of the three keratins in HaCat cells when HUVEC medium treated with both nicotinamide and sorafenib were compared with those of HaCat treated with sorafenib alone. Significant downward adjustments have occurred. This shows that nicotinamide can inhibit the acceleration of keratinization caused by sorafenib.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用，所述组合物由尼克酰胺和索拉非尼按剂量比2:3组成。

Description

尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用 技术领域
本发明属于医药领域，涉及尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用。
背景技术
索拉非尼是一种针对血管内皮生长因子(VEGF)家族的酪氨酸激酶抑制剂(TKI)，是临床上用于治疗晚期肝癌和肾癌的一线药物，能够显著提高患者的非进展生存期。但是，索拉非尼具有较强的毒副作用，其中最常见的是手足皮肤反应(HFSR)，临床特征表现为过度角质化，其发生率高达60％。尽管索拉非尼诱导的HFSR通常不是危及生命的副作用，但是它影响病人的生活质量，还可能导致剂量改变或治疗中断，最终威胁患者的生命。
由于索拉非尼诱导HFSR的分子机制未明，临床上没有很好的策略来解决这一毒副作用。对于轻度HFSR，患者可以使用角质软化剂或者润滑剂来缓解。而用药过程中产生重度HFSR的患者，需要对药物的剂量进行修改甚至中断治疗。上述疗法仅能在一定程度减轻这些症状，但却不能治愈索拉非诱导的HFSR。因此，找到索拉非尼诱导HFSR的分子机制，并基于该机制找到合适的干预策略减缓索拉非尼导致的手足皮肤反应具有重要意义。
我们的研究发现索拉非尼能够诱导血管内皮细胞(HUVEC)分泌肝素结合表皮生长因子HB-EGF，激活HB-EGF/SIRT1信号通路，加速角质形成细胞(HaCat)的角质化进程，最终导致手足皮肤反应。由于SIRT1在索拉非尼诱导的HFSR中的起着关键作用，临床上如果采用SIRT1抑制剂与索拉非尼联用，可以显著减轻索拉非尼诱导的HFSR。
尼克酰胺是维生素B族中的一员，是常见的SIRT1抑制剂。尼克酰胺在临床上可以主要用于防治糙皮病、口炎及舌炎等，还可以用于治疗冠心病、病毒性心肌炎、风湿性心脏病等，但未有将其作为治疗索拉非尼手足皮肤反应的报道。
发明内容
本发明的目的是提供一种尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用，所述组合物由尼克酰胺和索拉非尼组成，尼克酰胺与索拉非尼按剂量比为2∶3组合。
在细胞模型上按剂量比为2∶3组合，即尼克酰胺10μM：索拉非尼15μM。
尼克酰胺的化学名3-吡啶甲酰胺，分子式为C 6H 6N 2O，分子量122.13。索拉非尼化学名4-{4-[({4-氯-3-(三氟甲基)苯基]氨基}羰基)氨基]苯氧基}-N-甲基吡啶-2-甲酰胺，分子式C 21H 16ClF 3N 4O 3，分子量464.83。
本发明提供尼克酰胺减轻索拉非尼导致的手足皮肤反应的机制：索拉非尼激活 HB-EGF/SIRT1通路，加速角质化进程，进而导致手足皮肤反应；SIRT1抑制剂尼克酰胺能够阻断该通路的激活，从而缓解索拉非尼诱导的手足皮肤反应，因此，可用尼克酰胺组合物治疗索拉非尼诱导的HFSR。
所述药物剂型为液体制剂或固体制剂，是由尼克酰胺与索拉非尼组合物与药学上可接受的辅料制备，包括口服固体制剂、口服液体制剂、注射液、冻干粉针剂、大输液剂型、贴剂、软膏剂、凝胶剂、软胶囊剂或栓剂。
本发明提供的SIRT1抑制剂尼克酰胺与抗肿瘤药物索拉非尼组合物，能减轻索拉非尼导致的过度角质化而引起的手足皮肤反应。这种保护作用是通过抑制HB-EGF/SIRT1通路实现的。本发明的优点在于：(1)提供了索拉非尼诱导手足皮肤反应的发生机制，即HB-EGF/SIRT1通路的过度激活，为研究临床上索拉非尼引起的手足皮肤反应提供了理论依据；(2)提供了一种能够有效治疗索拉非尼诱导的手足皮肤反应的药物，在较大程度上扩大了索拉非尼的临床应用；(3)尼克酰胺价格适中，可根据需要制成合适的剂型，临床可行性高。
附图说明
图1是索拉非尼对HB-EGF/SIRT1信号通路的影响以及抑制该通路对角质化进程的影响。
图2是用给予尼克酰胺和索拉非尼处理的HUVEC细胞培养液作为条件培养基作用HaCat细胞后对角质化进程的影响。
具体实施方式
本发明结合附图和实施例做进一步的说明。
实施例1：
给予HUVEC细胞15μM索拉非尼后分别收集细胞和培养液，浓缩培液后，用western blot检测细胞中无活性的跨膜结构的pro-HB-EGF以及培养液中有活性游离形式的s-HB-EGF蛋白。实验结果如图1A所示，发现细胞中的HB-EGF蛋白表达水平下调，培液中的HB-EGF蛋白表达增加。取给予索拉非尼的HUVEC培养液为条件培养基作用HaCat细胞，检测细胞中SIRT1的表达。实验结果如图1B所示，HaCat细胞中SIRT1的表达上调。之后构建HB-EGF敲除的HUVEC细胞，施加索拉非尼后取其培养液作用HaCat细胞，检测角质化进程指标keratin 1,keratin 10和Loricrin的mRNA水平。实验结果如图1C所示，敲除HB-EGF后三种角质蛋白mRNA的表达下调。取施加索拉非尼的HUVEC培养液为条件培养基作用敲除SIRT1的HaCat细胞，检测三种角蛋白mRNA水平，实验结果如图1D所示，三种角蛋白mRNA水平同样发生了下调。上述实验结果表明索拉非尼加速角质化进程，进而导致手足皮肤反应的原因是由于HB-EGF/SIRT1通路的过度激活。
实施例2：
在体外细胞实验模型中，分别给予HUVEC细胞索拉非尼15μM，索拉非尼15μM和尼克酰胺10μM，24小时后收集培养液作为条件培养基作用HaCat细胞，24小时后收集HaCat细胞检测三种角质蛋白mRNA水平。研究结果如图2所示：给予同时经尼克酰胺和索拉非尼处理的HUVEC培养基后的HaCat细胞中三个角蛋白的mRNA水平与仅给予索拉非尼单独处理条件培养基的HaCat相较发生了显著下调。说明尼克酰胺可以抑制索拉非尼导致的角质化进程加速。

Claims (3)

  1. 一种尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用，其特征在于，所述组合物由尼克酰胺和索拉非尼组成，尼克酰胺的化学名3-吡啶甲酰胺，分子式为C 6H 6N 2O，分子量122.13，索拉非尼化学名4-{4-[({4-氯-3-(三氟甲基)苯基]氨基}羰基)氨基]苯氧基}-N-甲基吡啶-2-甲酰胺，分子式C 21H 16ClF 3N 4O 3，分子量464.83。
  2. 根据权利要求1所述的一种尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用，其特征在于，所述组合物中尼克酰胺与索拉非尼按剂量比为2∶3。
  3. 根据权利要求1所述的一种尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用，其特征在于，所述药物由尼克酰胺与索拉非尼组合物与药学上可接受的辅料制备，所述药物剂型为液体制剂或固体制剂。
PCT/CN2018/113216 2018-08-07 2018-10-31 尼克酰胺组合物在制备治疗索拉非尼手足皮肤反应药物中的应用 WO2020029441A1 (zh)

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EP18915796.9A EP3636265B1 (en) 2018-08-07 2018-10-31 Application of nicotinamide composition in preparing drug for treating sorafenib-induced hand-foot skin reaction
US16/612,770 US11278542B2 (en) 2018-08-07 2018-10-31 Use of nicotinamide composition in preparation of drug for treating hand-foot skin reaction induced by sorafenib

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CN110652586A (zh) * 2019-09-30 2020-01-07 浙江大学 Hbegf抗体在防治索拉非尼手足皮肤反应中的应用
CN110755432A (zh) * 2019-12-02 2020-02-07 浙江大学 烟酰胺在制备治疗手足皮肤反应制剂中的应用

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