CN114712353A - 烟酰胺及含有其的组合物的制药用途 - Google Patents
烟酰胺及含有其的组合物的制药用途 Download PDFInfo
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- CN114712353A CN114712353A CN202210118390.7A CN202210118390A CN114712353A CN 114712353 A CN114712353 A CN 114712353A CN 202210118390 A CN202210118390 A CN 202210118390A CN 114712353 A CN114712353 A CN 114712353A
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Abstract
本发明提供烟酰胺，其水合物、溶剂合物、衍生物、前药或它们的药学上可接受的盐在制备预防和/或治疗皮肤相关疾病或病症的制剂中的应用。所述烟酰胺毒副作用小，价格适中，具有广泛的临床应用前景。
Description
本申请要求2021年2月9日向中国国家知识产权局提交的，专利申请号为202110176845.6，发明名称为“烟酰胺及含有其的组合物的制药用途”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药领域，具体涉及烟酰胺在制备药物制剂中的应用。
背景技术
皮肤药物反应很常见，为可产生各种皮肤表现的药物不良反应。药物不良反应可以是免疫反应(例如药物过敏)或非免疫反应(例如药物不耐受)，多数不良反应是药物固有效应的延伸。
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。尚未有将烟酰胺具体应用于治疗/缓解一些药物引发的诸如皮疹、甲沟炎等皮肤相关疾病或病症的研究。
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、衍生物、前药或它们的药学上可接受的盐在制备预防和/或治疗皮肤相关疾病或病症的制剂中的应用。
根据本发明的实施方案，所述皮肤相关疾病或病症包括皮疹、瘙痒、红斑、皮肤干燥、脱发、毛囊炎、甲沟炎、色素沉积紊乱、手足综合征、脱皮、皮肤萎缩、痤疮、感觉异常、毛细血管扩张、感觉过敏、斑丘疹性皮肤反应、荨麻疹、血管性水肿、固定性药疹、多形红斑、DRESS(伴嗜酸性粒细胞增多症和全身症状的药物反应；也称为药物超敏反应综合征)、Stevens Johnson综合征、中毒性表皮坏死松解症、水泡中的一种或多种。
根据本发明的实施方案，所述皮肤相关疾病或病症是由药物引起的。
根据本发明的实施方案，所述药物选自抗肿瘤药、抗菌药、抗癫痫药物、疫苗、降血脂药、抗糖尿病药、抗结核药、抗心律失常药、解热镇痛药、镇静催眠药、抗生素、皮质类固醇、用于麻醉的肌松剂、磺胺类药物、造影剂中的一种或多种。
根据本发明的实施方案，所述抗肿瘤药选自免疫治疗剂、分子靶向药物、生物制剂、和其他抗肿瘤药中的一种或多种。
所述分子靶向药物包括但不限于蛋白激酶抑制剂。其中，所述的蛋白激酶抑制剂包括但不限于酪氨酸激酶抑制剂、丝氨酸和/或苏氨酸激酶抑制剂，所述抑制剂的靶点包括但不限于EGFR(表皮生长因子受体)、间变性淋巴瘤(ALK)、MET基因、ROS1基因、HER2基因、RET基因、BRAF基因、PI3K信号通路、DDR2(盘状死亡受体2)基因、FGFR1(成纤维生长因子受1)、NTRK1(神经营养酪氨酸激酶1型受体)基因、KRAS基因；所述小分子靶向抗肿瘤药物的靶点还包括COX-2(环氧酶-2)、APE1(脱嘌呤脱嘧啶核酸内切酶)、VEGFR-2(血管内皮生长因子受体-2)、CXCR-4(趋化因子受体-4)、MMP(基质金属蛋白酶)、IGF-1R(胰岛素样生长因子受体)、Ezrin、PEDF(色素上皮衍生因子)、AS、ES、OPG(骨保护因子)、Src、IFN、ALCAM(白细胞活化黏附因子)、HSP、JIP1、GSK-3β(糖原合成激酶3β)、CyclinD1(细胞周期调节蛋白)、CDK4(细胞周期素依赖性激酶)、TIMP1(组织金属蛋白酶抑制物)、THBS3、PTHR1(甲状旁腺素相关蛋白受体1)、TEM7(人肿瘤血管内皮标志物7)、COPS3、组织蛋白酶K。可以列举的小分子靶向抗肿瘤药物包括但不限于厄洛替尼(Erlotinib)、阿法替尼(Afatinib)、克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、威罗菲尼(Vemurafenib)、达拉菲尼(Dabrafenib)、卡博替尼(Cabozantinib)、吉非替尼(Gefitinib)、达可替尼(Dacomitinib)、奥希替尼(Osimertinib)、艾乐替尼(Alectinib)、布格替尼(Brigatinib)、劳拉替尼(Lorlatinib)、曲美替尼(Trametinib)、拉罗替尼(Larotrectinib)、埃克替尼(icotinib)、拉帕替尼(Lapatinib)、凡德他尼(Vandetanib)、司美替尼(Selumetinib)、索拉非尼(Sorafenib)、奥莫替尼(Olmutinib)、沃利替尼(Savolitinib)、呋喹替尼(Fruquintinib)、恩曲替尼(Entrectinib)、达沙替尼(Dasatinib)、恩沙替尼(Ensartinib)、乐伐替尼(Lenvatinib)、itacitinib、吡咯替尼(Pyrotinib)、比美替尼(Binimetinib)、厄达替尼(Erdafitinib)、阿西替尼(Axitinib)、来那替尼(Neratinib)、考比替尼(Cobimetinib)、阿卡替尼(Acalabrutinib)、法米替尼(Famitinib)、马赛替尼(Masitinib)、伊布替尼(Ibrutinib)、rociletinib、尼达尼布(nintedanib)、来那度胺、依维莫斯、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、palbociclib、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、波齐替尼(poziotinib)、DS-1205c、capivasertib、SH-1028、二甲双胍、seliciclib、OSE-2101、APL-101、berzosertib、idelalisib、lerociclib、ceralasertib、PLB-1003、tomivosertib、AST-2818、SKLB-1028、D-0316、LY-3023414、allitinib、MRTX-849、AP-32788、AZD-4205、lifirafenib、vactosertib、mivebresib、napabucasin、sitravatinib、TAS-114、molibresib、CC-223、rivoceranib、CK-101、LXH-254、simotinib、GSK-3368715、TAS-0728、masitinib、tepotinib、HS-10296、AZD-4547、merestinib、olaptesed pegol、galunisertib、ASN-003、gedatolisib、defactinib、lazertinib、CKI-27、S-49076、BPI-9016M、RF-A-089、RMC-4630、AZD-3759、antroquinonol、SAF-189s、AT-101、TTI-101、naputinib、LNP-3794、HH-SCC-244、ASK-120067、CT-707、epitinibsuccinate、tesevatinib、SPH-1188-11、BPI-15000、copanlisib、niraparib、olaparib、veliparib、talazoparib tosylate、DV-281、Siremadlin、Telaglenastat、MP-0250、GLG-801、ABTL-0812、bortezomib、帕比司他(panobinostat)、tucidinostat、vorinostat、resminostat、epacadostat、tazemetostat、entinostat、mocetinostat和quisinostat中的一种或者多种。在一些实施方案中，所述的小分子靶向抗肿瘤药物为索拉非尼、依维莫斯、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威罗菲尼、达拉菲尼、卡博替尼、吉非替尼、达可替尼、奥希替尼、艾乐替尼、布格替尼、劳拉替尼、曲美替尼、拉罗替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、奥莫替尼、沃利替尼、呋喹替尼、恩曲替尼、达沙替尼、恩沙替尼、乐伐替尼、itacitinib、吡咯替尼、比美替尼、厄达替尼、阿西替尼、来那替尼、考比替尼、阿卡替尼、法米替尼、马赛替尼、伊布替尼、尼达尼布中的一种或者多种。
所述免疫治疗剂包括免疫调节剂和促进或介导促进细胞介导的免疫应答的抗原呈递的试剂。所述免疫调节剂包含免疫检查点调节剂，例如免疫检查点蛋白受体及其配体介导T细胞介导的细胞毒性的抑制，并且通常由肿瘤或在肿瘤微环境中的无反应性T细胞上表达，并允许肿瘤逃避免疫攻击。免疫抑制检查点蛋白受体及其配体的活性的抑制剂可以克服免疫抑制性肿瘤环境，以允许肿瘤的细胞毒性T细胞攻击。免疫检查点蛋白质的实例包括但不限于PD-1、PD-L1、PDL2、CTLA4、LAG3、TIM3、TIGIT和CD103。此类蛋白质的活性的调节(包括抑制)可以通过免疫检查点调节剂完成，其可以包括例如靶向检查点蛋白质的抗体、适体、小分子和检测点受体蛋白质的可溶性形式，等等。PD-1靶向抑制剂包括经批准的药物试剂派姆单抗(pembrolizumab)和纳武单抗(nivolumab)，而易普利姆玛(ipilimumab)是经批准的CTLA-4抑制剂。
免疫调节剂还包括白细胞介素(IL)、干扰素(IFN)、肿瘤坏死因子(TNF)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)和巨噬细胞集落刺激因子(M-CSF)等细胞因子。细胞因子对免疫细胞与免疫系统有积极的促进作用，给予机体相关细胞因子有可能达到增强肿瘤患者机体免疫应答与免疫调节的效果。细胞因子还可以与与单克隆抗体进行组合，或与免疫检查点抑制抗体以及免疫原型化疗联合应用，以增强其特异性、减轻不良反应。
生物制剂包括但不限于癌症疫苗、抗体和细胞因子。所述抗体可以是单克隆抗体。所述单克隆抗体可以是人源化抗体或人抗体。
其他抗肿瘤药可以列举的实例包括但不限于铂类药物(例如奥沙利铂、顺铂、卡铂、奈达铂、双环铂(dicycloplatin)、洛铂)、氟嘧啶衍生物(例如吉西他滨、卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷)、紫杉烷类(例如紫杉醇、白蛋白结合的紫杉醇以及多烯紫杉醇)、拓扑异构酶I抑制剂(例如喜树碱及其衍生物、羟基喜树碱、伊立替康、拓扑替康)、拓扑异构酶Ⅱ抑制剂(例如依托泊苷(足叶乙苷)、替尼铂苷)、长春碱类(长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁(vinflunine))、吡柔比星、培美曲塞、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、吡柔比星、氨柔比星、甲氨蝶呤、苯达莫司汀、表阿霉素、阿霉素(多柔比星)、替莫唑胺、LCL-161、KML-001、Sapacitabine、普那布林(plinabulin)、曲奥舒凡(treosulfan)、地匹福林盐酸盐(tipiracil hydrochloride)、153Sm-EDTMP、替吉奥和encequidar中的一种或多种。
根据本发明的实施方案，所述肿瘤包括但不限于肾癌，肺腺癌，转移性胸膜肿瘤，鼻咽癌，乳腺癌等。
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；所述制剂合适的形式包括但不限于水性或非水性的溶液或悬液，可分散的粉剂或颗粒、片剂、胶囊、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，所述制剂包含0.5％-40％重量的烟酰胺、其水合物、溶剂合物、衍生物、前药或它们的药学上可接受的盐，优选为1％-30％重量。
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，以实现连续缓解皮肤相关疾病或病症。
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、衍生物、前药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、衍生物、前药或它们的药学上可接受的盐可以与所述抗肿瘤药物分开给药，例如，在使用抗肿瘤药物前给药，或在使用抗肿瘤药物后给药。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抗肿瘤药同时给药。
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、衍生物、前药或它们的药学上可接受的盐与所述抗肿瘤药以联合制剂的形式进行给药。所述联合制剂进一步用于在肿瘤治疗时缓解、抑制皮肤相关疾病或病症。
有益效果
(1)本发明经临床试验进一步验证烟酰胺制剂有利于缓解，抑制皮肤相关疾病或病症，同时，也有利于进一步和产生不良反应的药物联用，减少不良反应的产生，以及缓解或抑制皮肤相关疾病或病症；
(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1号患者治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图2是2号患者治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图3是5号患者治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图4是6号患者治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图5是7号患者治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图6是9号患者左脚治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图7是9号患者右脚治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图8是10号患者左脚治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图9是10号患者右脚治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图10是11号患者皮疹治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图11是11号患者左脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图12是11号患者右脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D14天的治疗效果)
图13是12号患者右脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图14是12号患者右脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图15是13号患者右脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图16是13号患者左脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图17是14号患者左脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图18是14号患者双手手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图19是14号患者右脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图20是15号患者左脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图21是15号患者右脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图22是16号患者左脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
图23是16号患者右脚手足综合征治疗效果图(左图显示患者0天症状，右图显示患者D21天的治疗效果)
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
实验目的：评价烟酰胺在制备预防和/或治疗皮肤相关疾病或病症的制剂中的应用的有效性和安全性。
实验方法：根据V4.03 CTCAE标准(参见表1)，将接受抗肿瘤药物治疗的肿瘤患者，出现皮肤相关疾病或病症者，分别采用烟酰胺浓度为15％的制剂涂擦，每日3次，一日用量约为5g，每次进行最佳支持护理治疗(如足部皮肤护理，穿戴厚的棉手套和/或袜子，避免接触热水、鞋子过紧和过度摩擦等)。
受试者按照CTCAE标准(V4.03)接受治疗评估，按照皮肤相关疾病或病症完全缓解(2级/3级到0级)或部分缓解(2级到0-1级，3级到0-2级，)进行有效性记录，并作生活质量评估；同时观察烟酰胺不良反应。
表1皮肤相关疾病或病症CTCAE分级
患者疗效评估与实验结果：
皮肤相关疾病或病症部分缓解：根据CTCAE标准(V4.03)不良反应标准评估治疗前后手足皮肤反应的级别，指皮肤相关疾病或病症自3级至1-2级、2级至1级；皮肤相关疾病或病症完全缓解：根据CTCAE标准(4.03)不良反应标准评估治疗前后手足皮肤反应的级别，指HFSR自2/3级至0级；
制剂使用周期为14天及以上(根据患者情况酌情可增加实验周期)，筛选入组实验的患者均患有皮肤相关疾病或病症，反馈有剧烈疼痛，严重时影响正常生活。患者实验结果如下表2，表3所示。
表2.入组患者信息：
表3.患者治疗效果：
注：D为Day简写，表示治疗天数；VAS评分：Visual Analogue Scale/Score缩写，表示视觉模拟评分法；HF-QOL评分：HF为Hand-Foot缩写，QOL为Quality of Life缩写，表示手足皮肤反应生活质量评分
实施例2烟酰胺缓解卡培他滨引起的皮肤相关症状
利用卡培他滨经口灌胃给予SD大鼠，造手足综合症模型，每天3次、对大鼠后爪涂抹供试品烟酰胺制剂，试验目的是观察烟酰胺制剂能否缓解卡培他滨引起的皮肤角质层厚度降低。
采用50只SD雌性大鼠，随机分为5组(10只/组)，第1-4组为每天1次经口灌胃给予4000mg/kg卡培他滨+每天3次后肢涂抹不同浓度的烟酰胺制剂，第1-4组烟酰胺在制剂中的浓度依次为0％、5％、10％、20％，药膏涂抹间隔为2-3h，第5组为每天1次经口灌胃4000mg/kg卡培他滨+每天1次经口灌胃70mg/kg烟酰胺制剂(烟酰胺+生理盐水配制得到的均一溶液，浓度为7mg/ml)，给药期限均为28天。第18天起，对于体重降低超过15％(与自身第一天相比)的动物停止灌胃给药，待体重恢复至5％后重新灌胃给药。实验结果如下：
卡培他滨+受试物各剂量组均于Day 21起出现手足综合征，其中SD大鼠给予4000mg/kg/QD卡培他滨后皮肤角质层厚度明显降低，10％、20％、70mg/kg的烟酰胺制剂对卡培他滨造模引起的角质层厚度降低明显缓解，具体参见下表4：
表4角质层厚度
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 (10)
1.烟酰胺，其水合物、溶剂合物、衍生物、前药或它们的药学上可接受的盐在制备预防和/或治疗皮肤相关疾病或病症的制剂中的应用。
2.根据权利要求1的应用，其特征在于，所述皮肤相关疾病或病症包括皮疹、瘙痒、红斑、皮肤干燥、脱发、毛囊炎、甲沟炎、色素沉积紊乱、手足综合征、脱皮、皮肤萎缩、痤疮、感觉异常、毛细血管扩张、感觉过敏、斑丘疹性皮肤反应、荨麻疹、血管性水肿、固定性药疹、多形红斑、DRESS(伴嗜酸性粒细胞增多症和全身症状的药物反应；也称为药物超敏反应综合征)、Stevens Johnson综合征、中毒性表皮坏死松解症、水泡中的一种或多种。
3.根据权利要求1或2的应用，其特征在于，所述皮肤相关疾病或病症是由药物引起的。
4.根据权利要求3的应用，其特征在于，所述药物选自抗肿瘤药、抗菌药、抗癫痫药物、疫苗、降血脂药、抗糖尿病药、抗结核药、抗心律失常药、解热镇痛药、镇静催眠药、抗生素、皮质类固醇、用于麻醉的肌松剂、磺胺类药物、造影剂中的一种或多种。
5.根据权利要求4的应用，其特征在于，所述抗肿瘤药选自免疫治疗剂、分子靶向药物、生物制剂、和其他抗肿瘤药中的一种或多种。
6.根据权利要求1-5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。
7.根据权利要求1-6任一项所述的应用，其特征在于，所述制剂选自固体制剂、液体制剂、半固体制剂或气体制剂。
8.根据权利要求1-6任一项所述的应用，其特征在于，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；所述制剂合适的形式包括但不限于水性或非水性的溶液或悬液，可分散的粉剂或颗粒、片剂、胶囊、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。
9.根据权利要求1-6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、衍生物、前药或它们的药学上可接受的盐，优选为1％-30％重量。
10.根据权利要求1-6任一项所述的应用，其特征在于，所述制剂中，所述烟酰胺，其水合物、溶剂合物、衍生物、前药或它们的药学上可接受的盐与抗肿瘤药以联合制剂的形式进行给药。
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| 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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