CN113101289A - 烟酰胺在制备治疗手足皮肤反应制剂中的应用 - Google Patents
烟酰胺在制备治疗手足皮肤反应制剂中的应用 Download PDFInfo
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- CN113101289A CN113101289A CN202010271271.6A CN202010271271A CN113101289A CN 113101289 A CN113101289 A CN 113101289A CN 202010271271 A CN202010271271 A CN 202010271271A CN 113101289 A CN113101289 A CN 113101289A
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Abstract
本发明提供烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐在制备治疗手足皮肤反应制剂中的应用。经动物体内实验研究证明，SIRT1抑制剂烟酰胺对VEGFR小分子激酶抑制剂引起的手足皮肤反应具有显著的保护效果。本发明能够有效治疗VEGFR小分子激酶抑制剂诱导的HFSR，减轻肿瘤患者由于VEGFR小分子激酶抑制剂使用带来的手足皮肤反应，很大程度上扩大了VEGFR小分子激酶抑制剂的临床使用；所用烟酰胺毒副作用小，价格适中，可根据需要制成合适的剂型，临床可行性高，从而扩大了VEGFR小分子激酶抑制剂的临床使用。
Description
技术领域
本发明属于医药领域，涉及SIRT1抑制剂烟酰胺的新用途，尤其涉及烟酰胺在制备治疗手足皮肤反应制剂中的应用。
背景技术
肿瘤生长依赖于血管生成的概念始于20世纪70年代初，血管生成对肿瘤的生长、侵袭和转移产生重要影响，目前抗血管生成已经成为抗肿瘤的重要策略之一。血管内皮生长因子受体(VEGFR)在血管生成中起着十分关键的作用。VEGFR小分子激酶抑制剂是一种针对VEGFR家族的激酶抑制剂，能够显著提高肿瘤患者的无进展生存期。但是多种VEGFR小分子激酶抑制剂使用过程中伴随手足皮肤反应(HFSR)这一毒副作用的发生，临床特征表现为过度角质化，其发生率高达40％～60％。这一副作用严重影响了病人的生活质量，还可能导致用药剂量下调或治疗中断，最终威胁患者的生命。
由于VEGFR小分子激酶抑制剂诱导HFSR的分子机制未明，目前临床上仍没有有效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，而用药过程中产生中度或重度HFSR的患者，则需要降低药物的剂量甚至中断治疗。上述方法仅能非常有限地缓解这些症状，并不能达到预期的减轻或治愈HFSR的目标。因此，亟需找到VEGFR小分子激酶抑制剂诱导HFSR共同的分子机制，并基于该机制找到合适的干预策略。
烟酰胺是维生素B族中的一员，烟酰胺的化学名为3-吡啶甲酰胺，又称尼克酰胺，分子式为C6H6N2O，分子量122.13，其是常见的SIRT1抑制剂。烟酰胺在临床上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，但尚未有将其作为治疗HFSR的报道。
发明内容
为了解决现有技术存在的技术问题，本发明提供烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐在制备治疗手足皮肤反应制剂中的应用。
根据本发明的实施方案，所述烟酰胺可以缓解和治疗手足皮肤反应(HFSR)。
根据本发明的实施方案，所述HFSR临床症状包括指/趾的热、痛、红斑性肿胀，严重者可发展至脱屑、溃疡和剧烈疼痛。
根据本发明的实施方案，所述HFSR包括1级，2级，3级。
所述HFSR分级(根据CTCAE4.03标准)如下：
1级：轻微皮肤改变或皮肤炎(红斑、水肿、角化过度、不痛)。
2级：皮肤改变(剥落、水泡、出血、肿胀、角化过度)，疼痛；影响工具性日常生活活动。
3级：重度皮肤改变(剥落、水泡，出血，水肿、角化过度)疼痛，个人自理能力受限。
根据本发明的实施方案，所述手足皮肤反应是一种VEGFR小分子激酶抑制剂诱导引起的皮肤毒性反应。
根据本发明的实施方案，所述烟酰胺可以缓解VEGFR小分子激酶抑制剂诱导的HFSR。
根据本发明的实施方案，所述烟酰胺的药学上可接受的盐选自如下类别，例如衍生自无机酸或有机酸的酸加成盐，例如盐酸盐、氢溴酸盐、对甲苯磺酸盐、磷酸盐、硫酸盐、高氯酸盐、乙酸盐、三氟乙酸盐、丙酸盐、柠檬酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐和苯甲酸盐。
根据本发明的实施方案，所述以烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐为活性成分、治疗手足皮肤反应的制剂可以是任何适合的形式，如固体制剂、液体制剂、半固体制剂或气体制剂。
根据本发明的实施方案，所述制剂可以通过口服、静脉、肌肉、皮下、局部应用来给药，额外的途径包括舌下、直肠、鼻内、或肺吸入；合适的形式例如水性或非水性的溶液或悬液，可分散的粉剂或颗粒、乳膏、凝胶、分散体、乳剂、泡沫、雾剂、漱口剂、洗剂、软膏、膏剂、喷雾剂、气雾剂、油、硬膏剂、贴剂、混悬剂或栓剂等。
根据本发明的实施方案，所述制剂可以是无菌可注射的水性或非水性(例如油质的)溶液或悬液形式。所述无菌可注射制剂还可以是溶于无毒的且可用于肠胃外的稀释剂或溶剂中的无菌可注射溶液或悬液。可以使用的可接受的运载剂和溶剂有水、磷酸盐缓冲溶液、林格溶液(Ringer′ssolution)和葡萄糖、等渗氯化钠溶液。另外，无菌的不挥发油通常用作溶剂或悬浮介质。出于此目的，可以使用任何温和的不挥发油，包括合成的甘油一酯或甘油二酯。另外，脂肪酸(例如油酸)可以用于注射剂的制备。悬液可以根据现有技术使用那些别处已提及的适合的分散剂或润湿剂以及悬浮剂来制备。
对于舌下递送，可以使用快速溶解的片剂，以及上述的若干形式。所述口服给药可以采用片剂、胶囊或液体形式给药
对于局部递送，可以包含供局部使用的可药用载体，在根据本发明和本文描述的任何局部制剂中使用的基质是能够经皮递送药物组合物中包含的活性化合物的任何可药用载体。以举例的方式，根据本发明，其为乳膏、凝胶、分散液、乳液、泡沫、薄雾、漱口水、洗液、药膏、油膏、油、喷雾剂、气溶胶、栓剂、悬浮液、硬膏剂、贴剂以及通过皮肤和粘膜吸收的各种被动和主动局部装置。
本发明所述的药物制剂还可以是水包油型乳剂的形式。油相可以是植物油，例如橄榄油或花生油；或矿物油，例如液体石蜡；或它们的混合物。适合的乳化剂可以是天然存在的树胶，例如***树胶或黄蓍树胶；天然存在的磷脂，例如大豆、卵磷脂；以及由脂肪酸和己糖醇酐衍生的酯类或偏酯，例如脱水山梨醇单油酸酯和所述偏酯与环氧乙烷的缩合产物，例如聚氧乙烯脱水山梨醇单油酸酯。
提供的局部制剂基质优选用于在皮肤上进行一般施用。基质优选包括常规乳化剂和润肤剂，包括藻酸盐、甘油硬脂酸酯、PEG-100硬脂酸酯、鲸蜡醇、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、丙二醇、山梨糖醇、聚乙氧基化脱水山梨醇单硬脂酸酯、甘油、白凡士林、三乙醇胺、羊毛脂、可可脂、乳木果油等。例如，在将烟酰胺或其药用盐溶解在西土马哥(cetomacrogol)乳膏的基质中后，得到稳定的制剂。
水性悬液包含混合有适于水性悬液制备的赋形剂的活性成分。这样的赋形剂为悬浮剂，例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶和***树胶；分散剂或润湿剂例如天然存在的磷脂，例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七乙烯氧基十六醇(heptadecaethyleneoxycetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的偏酯的缩合产物，如聚氧乙烯与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚氧乙烯脱水山梨醇单油酸酯。所述水性悬液还可以包含一种或多种防腐剂，例如乙基或正丙基对羟基苯甲酸酯，一种或多种着色剂，一种或多种调味剂，以及一种或多种甜味剂，例如蔗糖或糖精。
非水性(即油质的)悬液可以通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如液体石蜡)中来制备。所述油质悬液可以含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。这些组合物可以通过加入抗氧化剂(如抗坏血酸)来保存。
适于通过加入水来制备水性悬液的可分散的粉剂或颗粒提供了与分散剂或润湿剂、悬浮剂和一种或多种防腐剂混合的活性成分。适合的分散剂或润湿剂以及悬浮剂是已知的。
所述活性成分还可以以栓剂的形式给予以用于所述药物的直肠给药。这些组合物可以通过将所述药物与适合的非刺激性赋形剂混合来制备，所述赋形剂在常温下为固体但在直肠温度下为液体，因此会在直肠中融化以释放所述药物。这样的物质有可可脂和聚乙二醇。
根据本发明的实施方案，所述制剂包含0.5％-40％重量的烟酰胺、其水合物、溶剂合物或它们的药学上可接受的盐，优选为1％-30％重量；所述制剂单次施用量为0.5g-3.5g，优选0.5g-3.0g；单次施用制剂中烟酰胺、其水合物、溶剂合物或它们的药学上可接受的盐的给药量为0.015mg-0.5mg；单次施用制剂中烟酰胺、其水合物、溶剂合物或它们的药学上可接受的盐的给药量优选0.05mg/kg-10mg/kg，更优选0.1mg/kg-8mg/kg。
根据本发明的实施方案，所述制剂可以按照每天四次、每天三次、每天两次、每天一次或每隔一天一次的剂量施用。可根据不同级别的严重程度选择适宜的给药方式和剂量。但是应该理解，对于任一具体患者的具体剂量水平将依赖于多种因素，包括年龄、体重、一般健康状况、性别、饮食、给药时间、药物组合以及正在治疗的具体病症的严重程度。根据本发明，本发明的制剂施用至少一年或更长时间，优选地至少一个月，更优选地至少一周，最优选地至少一天，以实现连续缓解手足皮肤反应。
根据本发明的实施方案，在一些实施方式中，所述烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐作为制剂中的唯一活性成分；在一些实施方式中，所述制剂中还包含其他药物，例如消炎抗感染类药物，维生素B、维生素E，糖皮质激素等。
根据本发明的实施方案，在一些实施方式中，所述烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐可以与诱导HFSR的VEGFR小分子激酶抑制剂分开给药，例如，在使用VEGFR小分子激酶抑制剂前给药，或在使用VEGFR小分子激酶抑制剂后给药。在一些实施方式中，所述烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐可以与诱导HFSR的VEGFR小分子激酶抑制剂同时给药。
根据本发明的实施方案，在一些实施方式中，所述烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐与所述VEGFR小分子激酶抑制剂以联合制剂的形式进行给药。所述联合制剂进一步用于在化疗治疗时缓解、抑制手足皮肤反应。
根据本发明的实施方案，所述VEGFR小分子激酶抑制剂有多种，包括但不限于：PAN-90806、Foretinib、他菲替尼(Tafetinib)、康尼替尼(Kanitinib)、阿帕替尼(Apatinib)、Tanibirumab、安罗替尼(Anlotinib)、德立替尼(Lucitanib)、Vatalanib、西地尼布(Cediranib)、西奥罗尼(Chiauranib)、多韦替尼(Dovitinib)、多纳非尼(Donafenib)、法米替尼(Famitinib)、Sitravatinib、特拉替尼(Telatinib)、L-21649、TAS-115、卡博替尼(Cabozantinib)、噻尔非尼(Thiophenib)、呋喹替尼(Fruquintinib)、布立尼布(Brivanib)、索凡替尼(Sulfatinib)、Ramucirumab、Glesatinib、尼达尼布(Nintedanib)、普喹替尼(Puquitinib)、阿西替尼(Axitinib)、EDP317、索拉非尼(Sorafenib)、麦他替尼(Metatinib)、Tivozanib、瑞格非尼(Regorafenib)、Midostaurin、培唑帕尼(Pazopanib)、HLX-06、Altiratinib、宁格替尼(Ningetinib)、舒尼替尼(Sunitinib)、AL-8326、Rebastinib、帕纳替尼(Ponatinib)、乐伐替尼(Lenvatinib)等或以上药物的可药用盐。
有益效果
(1)本发明经动物体内实验研究发现，SIRT1抑制剂烟酰胺可以用于治疗VEGFR小分子激酶抑制剂诱导的HFSR，因而提供了一种能够有效治疗VEGFR小分子激酶抑制剂诱导的HFSR的药物，减轻肿瘤患者由于VEGFR小分子激酶抑制剂使用带来的手足皮肤反应，很大程度上提高了VEGFR小分子激酶抑制剂临床使用的安全性，从而扩大了VEGFR小分子激酶抑制剂的临床使用，同时也提供了一种全新的治疗HFSR的策略；
(2)烟酰胺毒副作用小，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是在小鼠模型中证明瑞格非尼会导致小鼠发生HFSR，SIRT1抑制剂烟酰胺可以逆转瑞格非尼诱导的ICR小鼠爪部角质层增厚即逆转瑞戈非尼诱导的HFSR。
图2是在小鼠模型中证明安罗替尼会导致小鼠发生HFSR，SIRT1抑制剂烟酰胺可以逆转安罗替尼诱导的ICR小鼠爪部角质层增厚即逆转安罗替尼诱导的HFSR。
图3是在小鼠模型中证明阿帕替尼会导致小鼠发生HFSR，SIRT1抑制剂烟酰胺可以逆转阿帕替尼诱导的ICR小鼠爪部角质层增厚即逆转阿帕替尼诱导的HFSR。
图4示意给予VEGRF小分子抑制剂和烟酰胺处理的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(图4a：SUNI+NAM；图4b：CABO+NAM；图4c：AXI+NAM；图4d：PONA+NAM)。
图5示意烟酰胺治疗索拉菲尼：瑞戈非尼、安罗替尼、阿帕替尼引起的手足皮肤反应的临床效果。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1
20只雌性ICR小鼠，随机分成4组，分别为空白对照组、瑞格非尼组、烟酰胺组、瑞格非尼+烟酰胺合用组，每组5只，以灌胃的方式给药。瑞格非尼给予的剂量为25mg/kg/day，烟酰胺剂量为20mg/kg/day，连续给药4周。4周后处死小鼠，取下其爪部。H&E染色结果显示，瑞格非尼组的小鼠爪部角质层相较于空白对照组明显增厚，说明瑞格非尼可引起小鼠发生HFSR。烟酰胺可以逆转瑞格非尼引起的爪部角质层增厚现象，即逆转它们所引起的HFSR。结果参见图1。
实施例2
20只雌性ICR小鼠，随机分成4组，分别为空白对照组、安罗替尼组、烟酰胺组、安罗替尼+烟酰胺合用组，每组5只，以灌胃的方式给药。安罗替尼给予的剂量为2mg/kg/day，烟酰胺剂量为20mg/kg/day，连续给药4周。4周后处死小鼠，取下其爪部。H&E染色结果显示，安罗替尼组的小鼠爪部角质层相较于空白对照组明显增厚，说明安罗替尼可引起小鼠发生HFSR。烟酰胺可以逆转安罗替尼引起的爪部角质层增厚现象，即逆转它们所引起的HFSR。结果参见图2。
实施例3
20只雌性ICR小鼠，随机分成4组，分别为空白对照组、阿帕替尼组、烟酰胺组、阿帕替尼+烟酰胺合用组，每组5只，以灌胃的方式给药。阿帕替尼给予的剂量为100mg/kg/day，烟酰胺剂量为20mg/kg/day，连续给药4周。4周后处死小鼠，取下其爪部。H&E染色结果显示，阿帕替尼组的小鼠爪部角质层相较于空白对照组明显增厚，说明阿帕替尼可引起小鼠发生HFSR。烟酰胺可以逆转阿帕替尼引起的爪部角质层增厚现象，即逆转它们所引起的HFSR。结果参见图3。
实施例4
研究舒尼替尼、卡博替尼、阿西替尼以及帕纳替尼对HaCaT细胞分化指标的影响，以及尼克酰胺(NAM)的潜在治疗作用。采用250nM的舒尼替尼(sunitib，标记为SUNI)、2.5μM卡博替尼(Cabozanib，标记为CABO)、70nM阿西替尼(axitinib，标记为AXI)和140nM帕纳替尼(Ponatinib，标记为PONA)分别刺激HUVEC细胞24h，收集上清作为条件培养基(CdM)；对照组用DMSO作用HUVEC细胞24h，收集细胞培养液作为对照条件培养基(CdMCTRL)。之后将CdMCTRL、CdM、CdMCTRL+NAM(10mM)和CdM+NAM(10mM)作用HaCaT细胞24h，之后收集细胞进行RT-PCR实验，考察分化指标keratin 1(KRT1)和loricrin(LORICRIN)的变化。结果如图4a，4b，4c，4d所示，NAM能够逆转CdMSUNI、CdMCABO和CdMAXI对HaCaT细胞分化指标的上调作用。而CdMPONA对HaCaT分化指标无显著影响，与NAM合用也未发生明显变化。
结果表明，在体外水平上，NAM能够抑制CdMSUNI、CdMCABO和CdMAXI加速的角质化进程从而抑制他们诱导的手足皮肤反应(HFSR)。
实施例5：测试烟酰胺针对接受VEGFR抑制剂治疗后产生严重HFSR的癌症患者的临床疗效
临床试验对象分别为服用索拉非尼(800mg/天)的晚期肝癌病人、服用瑞戈非尼(160mg/天)的转移性结直肠癌病人、服用安罗替尼(12mg/天)的晚期非小细胞肺癌病人以及服用阿帕替尼(500mg/天)的晚期胃癌病人。在知情同意和伦理学批准的情况下，患者连续两周连续服用烟酸片(100mg，每天三次，烟酸进入体内转化为烟酰胺发挥作用)，之后对HFSR进行评级。结果显示(参见图5)，所有患者的HFSR均被完全缓解。因此，烟酰胺可以作为对抗多种VEGFR抑制剂诱导的HFSR的潜在药物。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (5)
1.烟酰胺，其水合物、溶剂合物或它们的药学上可接受的盐在制备治疗手足皮肤反应制剂中的应用。
2.根据权利要求1的应用，其特征在于，所述手足皮肤反应是一种VEGFR小分子激酶抑制剂诱导引起的皮肤毒性反应。
3.根据权利要求1-2任一项所述的应用，其特征在于，所述烟酰胺的药学上可接受的盐选自如下类别，例如衍生自无机酸或有机酸的酸加成盐，例如盐酸盐、氢溴酸盐、对甲苯磺酸盐、磷酸盐、硫酸盐、高氯酸盐、乙酸盐、三氟乙酸盐、丙酸盐、柠檬酸盐、丙二酸盐、琥珀酸盐、乳酸盐、草酸盐、酒石酸盐和苯甲酸盐。
4.根据权利要求1-3任一项所述的应用，其特征在于，所述治疗手足皮肤反应制剂选自固体制剂、液体制剂、半固体制剂或气体制剂。
5.根据权利要求1-4任一项所述的应用，其特征在于，所述制剂包含0.5％-40％重量的烟酰胺、其水合物、溶剂合物或它们的药学上可接受的盐，优选为1％-30％重量，优选的，单次施用0.5g-3.5g所述制剂，更优选的，单次施用0.5g-3.0g所述制剂；单次施用制剂中烟酰胺、其水合物、溶剂合物或它们的药学上可接受的盐的给药量为0.015mg-0.5mg，优选为0.05mg/kg-10mg/kg，优选为0.1mg/kg-8mg/kg。
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| CN114712353A (zh) * | 2021-02-09 | 2022-07-08 | 扬子江药业集团南京海陵药业有限公司 | 烟酰胺及含有其的组合物的制药用途 |
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