TW202241421A - Pharmaceutical use of nicotinamide and composition thereof - Google Patents

Abstract

The invention provides the use of nicotinamide and a hydrate, a solvate, a derivative, a prodrug or a pharmaceutically acceptable salt thereof in the preparation of medications for the prevention and / or treatment of skin related diseases or conditions. The nicotinamide has low toxicity and little side effect, with moderate price, and has a wide prospect of clinical application.

Description

菸鹼醯胺及含有其的組合物的製藥用途Nicotinamide and pharmaceutical use of compositions containing it

本發明屬於醫藥領域，具體涉及菸鹼醯胺在製備藥物製劑中的應用。The invention belongs to the field of medicine, and in particular relates to the application of nicotinamide in the preparation of pharmaceutical preparations.

皮膚藥物反應很常見，為可產生各種皮膚表現的藥物不良反應。藥物不良反應可以是免疫反應（例如藥物過敏）或非免疫反應（例如藥物不耐受），多數不良反應是藥物固有效應的延伸。Cutaneous drug reactions are common and are adverse drug reactions that produce a variety of cutaneous manifestations. Adverse drug reactions can be immune reactions (such as drug allergy) or non-immune reactions (such as drug intolerance), and most adverse reactions are extensions of the inherent effects of drugs.

菸鹼醯胺是維生素B族中的一員，菸鹼醯胺的化學名為3-吡啶甲醯胺，又稱尼克醯胺，分子式為C ₆H ₆N ₂O，分子量122.13，其是常見的SIRT1抑制劑。尚未有將菸鹼醯胺具體應用於治療/緩解一些藥物引發的諸如皮疹、甲溝炎等皮膚相關疾病或病症的研究。 Niacinamide is a member of vitamin B family. The chemical name of nicotinamide is 3-pyridinamide, also known as nicotinamide. Its molecular formula is C ₆ H ₆ N ₂ O and its molecular weight is 122.13. It is a common SIRT1 inhibitors. There is no research on the specific application of nicotinamide in the treatment/relief of some drug-induced skin-related diseases or conditions such as rashes and paronychia.

本案請求2021年2月9日向中國國家知識產權局提交的，專利申請號為202110176845.6，發明名稱為「煙醯胺及含有其的組合物的製藥用途」的先申請案的優先權。所述先申請案的全文通過引用的方式結合於本案中。This case requests the priority of the previous application filed with the State Intellectual Property Office of China on February 9, 2021, with the patent application number 202110176845.6 and the invention titled "Pharmaceutical Use of Niacinamide and Compositions Containing It". The entirety of said prior application is hereby incorporated by reference.

為了解決現有技術存在的技術問題，本發明提供菸鹼醯胺，其水合物、溶劑合物、衍生物、前藥或它們的藥學上可接受的鹽在製備預防和/或治療皮膚相關疾病或病症的製劑中的應用。In order to solve the technical problems existing in the prior art, the present invention provides nicotinamide, its hydrate, solvate, derivative, prodrug or their pharmaceutically acceptable salt in the preparation of prevention and/or treatment of skin-related diseases or Application in the preparation of diseases.

根據本發明的實施方案，所述皮膚相關疾病或病症包括皮疹、瘙癢、紅斑、皮膚乾燥、脫髮、毛囊炎、甲溝炎、色素沉積紊亂、手足症候群、脫皮、皮膚萎縮、痤瘡、感覺異常、毛細血管擴張、感覺過敏、斑丘疹性皮膚反應、蕁麻疹、血管性水腫、固定性藥疹、多形紅斑、DRESS（伴嗜酸性粒細胞增多症和全身症狀的藥物反應；也稱為藥物超敏反應症候群）、Stevens Johnson症候群、中毒性表皮壞死鬆解症以及水泡中的一種或多種。According to an embodiment of the present invention, the skin-related diseases or conditions include rashes, itching, erythema, dry skin, alopecia, folliculitis, paronychia, pigmentation disorders, hand-foot syndrome, peeling, skin atrophy, acne, paresthesia, Telangiectasia, hyperesthesia, maculopapular skin reaction, urticaria, angioedema, fixed drug eruption, erythema multiforme, DRESS (drug reaction with eosinophilia and systemic symptoms; also known as drug hypersensitivity reaction syndrome), Stevens Johnson syndrome, toxic epidermal necrolysis, and blisters.

根據本發明的實施方案，所述皮膚相關疾病或病症是由藥物引起的。According to an embodiment of the present invention, said skin-related disease or condition is drug-induced.

根據本發明的實施方案，所述藥物選自抗腫瘤藥、抗菌藥、抗癲癇藥物、疫苗、降血脂藥、抗糖尿病藥、抗結核藥、抗心律失常藥、解熱鎮痛藥、鎮靜催眠藥、抗生素、皮質類固醇、用於麻醉的肌肉鬆弛劑、磺胺類藥物以及造影劑中的一種或多種。According to an embodiment of the present invention, the drug is selected from antineoplastic drugs, antibacterial drugs, antiepileptic drugs, vaccines, hypolipidemic drugs, antidiabetic drugs, antituberculosis drugs, antiarrhythmic drugs, antipyretic and analgesic drugs, sedative hypnotics, One or more of antibiotics, corticosteroids, muscle relaxants used for anesthesia, sulfa drugs, and contrast media.

根據本發明的實施方案，所述抗腫瘤藥選自免疫治療劑、分子標靶藥物、生物製劑以及其他抗腫瘤藥中的一種或多種。According to an embodiment of the present invention, the anti-tumor drug is selected from one or more of immunotherapeutic agents, molecular targeted drugs, biological agents and other anti-tumor drugs.

所述分子標靶藥物包括但不限於蛋白激酶抑制劑。其中，所述的蛋白激酶抑制劑包括但不限於酪胺酸激酶抑制劑、絲胺酸和/或蘇胺酸激酶抑制劑，所述抑制劑的靶點包括但不限於EGFR(表皮生長因子受體)、間變性淋巴瘤(ALK)、MET基因、ROS1基因、HER2基因、RET基因、BRAF基因、PI3K信號通路、DDR2(盤狀死亡受體2)基因、FGFR1(成纖維生長因子受1)、NTRK1(神經營養酪胺酸激酶1型受體)基因以及KRAS基因；所述小分子標靶抗腫瘤藥物的靶點還包括COX-2(環氧酶-2)、APE1(脫嘌呤脫嘧啶核酸內切酶)、VEGFR-2(血管內皮生長因子受體-2)、CXCR-4(趨化因子受體-4)、MMP(基質金屬蛋白酶)、IGF-1R(胰島素樣生長因子受體)、Ezrin、PEDF(色素上皮衍生因子)、AS、ES、OPG(骨保護因子)、Src、IFN、ALCAM(白細胞活化黏附因子)、HSP、JIP1、GSK-3β(糖原合成激酶3β)、CyclinD1(細胞週期調節蛋白)、CDK4(細胞週期素依賴性激酶)、TIMP1(組織金屬蛋白酶抑制物)、THBS3、PTHR1(甲狀旁腺素相關蛋白受體1)、TEM7(人腫瘤血管內皮標誌物7)、COPS3以及組織蛋白酶K。可以列舉的小分子標靶抗腫瘤藥物包括但不限於厄洛替尼(Erlotinib)、阿法替尼(Afatinib)、克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、威羅菲尼(Vemurafenib)、達拉菲尼(Dabrafenib)、卡博替尼(Cabozantinib)、吉非替尼(Gefitinib)、達可替尼(Dacomitinib)、奧希替尼(Osimertinib)、艾樂替尼(Alectinib)、布格替尼(Brigatinib)、勞拉替尼(Lorlatinib)、曲美替尼(Trametinib)、拉羅替尼(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)、奧莫替尼(Olmutinib)、沃利替尼(Savolitinib)、呋喹替尼(Fruquintinib)、恩曲替尼(Entrectinib)、達沙替尼(Dasatinib)、恩沙替尼(Ensartinib)、樂伐替尼(Lenvatinib)、itacitinib、吡咯替尼(Pyrotinib)、比美替尼(Binimetinib)、厄達替尼(Erdafitinib)、阿西替尼(Axitinib)、來那替尼(Neratinib)、考比替尼(Cobimetinib)、阿卡替尼(Acalabrutinib)、法米替尼(Famitinib)、馬賽替尼(Masitinib)、伊布替尼(Ibrutinib)、rociletinib、尼達尼布(nintedanib)、來那度胺、依維莫斯、LOXO-292、Vorolanib、bemcentinib、capmatinib、entrectinib、TAK-931、ALT-803、palbociclib、famitinib L-malate、LTT-462、BLU-667、ningetinib、tipifarnib、波齊替尼（poziotinib）、DS-1205c、capivasertib、SH-1028、二甲雙胍、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中的一種或者多種。在一些實施方案中，所述的小分子標靶抗腫瘤藥物為索拉非尼、依維莫斯、厄洛替尼、阿法替尼、克唑替尼、色瑞替尼、威羅菲尼、達拉菲尼、卡博替尼、吉非替尼、達可替尼、奧希替尼、艾樂替尼、布格替尼、勞拉替尼、曲美替尼、拉羅替尼、埃克替尼、拉帕替尼、凡德他尼、司美替尼、奧莫替尼、沃利替尼、呋喹替尼、恩曲替尼、達沙替尼、恩沙替尼、樂伐替尼、itacitinib、吡咯替尼、比美替尼、厄達替尼、阿西替尼、來那替尼、考比替尼、阿卡替尼、法米替尼、馬賽替尼、伊布替尼以及尼達尼布中的一種或者多種。The molecular targeted drugs include but are not limited to protein kinase inhibitors. Wherein, the protein kinase inhibitors include but are not limited to tyrosine kinase inhibitors, serine and/or threonine kinase inhibitors, and the targets of the inhibitors include but are not limited to EGFR (epidermal growth factor-regulated body), anaplastic lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (discoid death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1) , NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene and KRAS gene; the targets of the small molecule target antineoplastic drugs also include COX-2 (cyclooxygenase-2), APE1 (apurinic apyrimidine endonuclease), VEGFR-2 (vascular endothelial growth factor receptor-2), CXCR-4 (chemokine receptor-4), MMP (matrix metalloproteinase), IGF-1R (insulin-like growth factor receptor ), Ezrin, PEDF (pigment epithelium-derived factor), AS, ES, OPG (osteoprotective factor), Src, IFN, ALCAM (leukocyte-activating adhesion factor), HSP, JIP1, GSK-3β (glycogen synthesis kinase 3β), CyclinD1 (cell cycle regulatory protein), CDK4 (cyclin-dependent kinase), TIMP1 (tissue inhibitor of metalloproteinase), THBS3, PTHR1 (parathyroid hormone-related protein receptor 1), TEM7 (human tumor vascular endothelial marker Object 7), COPS3 and cathepsin K. Small molecule targeted anti-tumor drugs that can be listed include but are not limited to Erlotinib, Afatinib, Crizotinib, Ceritinib, Vemurafenib (Vemurafenib), Dabrafenib, Cabozantinib, Gefitinib, Dacomitinib, Osimertinib, Alectinib ), Brigatinib, Lorlatinib, Trametinib, Larotrectinib, Icotinib, Lapatinib, Vandetanib, Selumetinib, Sorafenib, Olmutinib, Savolitinib, Fruquintinib, Emtrex Entrectinib, Dasatinib, Ensartinib, Lenvatinib, itacitinib, Pyrotinib, Binimetinib, Erdatinib (Erdafitinib), Axitinib, Neratinib, Cobimetinib, Acalabrutinib, Famitinib, Masitinib , Ibrutinib, rociletinib, nintedanib, lenalidomide, everolimus, LOXO-292, Vorolanib, bemcentinib, capmatinib, entrectinib, TAK-931, ALT-803, palbociclib , famitinib L-malate, LTT-462, BLU-667, ningetinib, tipifarnib, poziotinib, DS-1205c, capivasertib, SH-1028, metformin, seliciclib, OSE-2101, APL-101, berzosertib, idelalisib, lerociclib, ceralasertib, PLB-1003, tomivosertib, AST-2818, SKL B-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, epitinib succinate, tesevatinib, SPH-1188-11, BPI-15000, copanlisib, niraparib, olaparib, veliparib, talazoparib tosylate, DV-281, Siremadlin, Telaglenastat, MP-0250, GLG-801, ABTL-0812, One or more of bortezomib, panobinostat, tucidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mocetinostat, and quisinostat. In some embodiments, the small molecule targeted anti-tumor drugs are sorafenib, everolimus, erlotinib, afatinib, crizotinib, ceritinib, vemurafi Dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, lorlatinib, trametinib, larotib Ni, Icotinib, Lapatinib, Vandetanib, Selumetinib, Omotinib, Savolitinib, Fruquintinib, Enrectinib, Dasatinib, Ensartinib Ni, lenvatinib, itacitinib, pyrotinib, bimetinib, erdatinib, axitinib, neratinib, cobitinib, acatinib, famitinib, masitinib One or more of , ibrutinib and nintedanib.

所述免疫治療劑包括免疫調節劑和促進或介導促進細胞介導的免疫應答的抗原呈遞的試劑。所述免疫調節劑包含免疫檢查點調節劑，例如免疫檢查點蛋白受體及其配體介導T細胞介導的細胞毒性的抑制，並且通常由腫瘤或在腫瘤微環境中的無反應性T細胞上表達，並允許腫瘤逃避免疫攻擊。免疫抑制檢查點蛋白受體及其配體的活性的抑制劑可以克服免疫抑制性腫瘤環境，以允許腫瘤的細胞毒性T細胞攻擊。免疫檢查點蛋白質的實例包括但不限於PD-1、PD-L1、PDL2、CTLA4、LAG3、TIM3、TIGIT以及CD103。此類蛋白質的活性的調節(包括抑制)可以通過免疫檢查點調節劑完成，其可以包括例如標靶檢查點蛋白質的抗體、適體、小分子和檢測點受體蛋白質的可溶性形式，等等。PD-1標靶抑制劑包括經批准的藥物試劑派姆單抗(pembrolizumab)以及納武單抗(nivolumab)，而易普利姆瑪(ipilimumab)是經批准的CTLA-4抑制劑。Such immunotherapeutic agents include immunomodulators and agents that promote or mediate antigen presentation that facilitates a cell-mediated immune response. The immunomodulators include immune checkpoint modulators, such as immune checkpoint protein receptors and their ligands that mediate inhibition of T cell-mediated cytotoxicity, and are typically produced by tumors or by anergic T cells in the tumor microenvironment. Expressed on cells and allows tumors to escape immune attack. Inhibitors of the activity of immunosuppressive checkpoint protein receptors and their ligands could overcome the immunosuppressive tumor environment to allow cytotoxic T cell attack of the tumor. Examples of immune checkpoint proteins include, but are not limited to, PD-1, PD-L1, PDL2, CTLA4, LAG3, TIM3, TIGIT, and CD103. Modulation (including inhibition) of the activity of such proteins can be accomplished by immune checkpoint modulators, which can include, for example, antibodies to target checkpoint proteins, aptamers, small molecules, and soluble forms of checkpoint receptor proteins, among others. PD-1 target inhibitors include the approved pharmaceutical agents pembrolizumab and nivolumab, while ipilimumab is an approved CTLA-4 inhibitor.

免疫調節劑還包括白細胞介素(IL)、干擾素(IFN)、腫瘤壞死因子(TNF)、粒細胞-巨噬細胞集落刺激因子(GM-CSF)和巨噬細胞集落刺激因子(M-CSF)等細胞因子。細胞因子對免疫細胞與免疫系統有積極的促進作用，給予機體相關細胞因子有可能達到增強腫瘤患者機體免疫應答與免疫調節的效果。細胞因子還可以與單克隆抗體進行組合，或與免疫檢查點抑制抗體以及免疫原型化療聯合應用，以增強其特異性、減輕不良反應。Immunomodulators also include interleukin (IL), interferon (IFN), tumor necrosis factor (TNF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage colony-stimulating factor (M-CSF ) and other cytokines. Cytokines can positively promote immune cells and the immune system, and the administration of relevant cytokines to the body may enhance the immune response and immune regulation of tumor patients. Cytokines can also be combined with monoclonal antibodies, or combined with immune checkpoint inhibitory antibodies and immunoprototype chemotherapy to enhance their specificity and reduce adverse reactions.

生物製劑包括但不限於癌症疫苗、抗體以及細胞因子。所述抗體可以是單克隆抗體。所述單克隆抗體可以是人源化抗體或人抗體。Biologics include, but are not limited to, cancer vaccines, antibodies, and cytokines. The antibody may be a monoclonal antibody. The monoclonal antibody may be a humanized antibody or a human antibody.

其他抗腫瘤藥可以列舉的實例包括但不限於鉑類藥物(例如奧沙利鉑、順鉑、卡鉑、奈達鉑、雙環鉑(dicycloplatin)以及洛鉑)、氟嘧啶衍生物(例如吉西他濱、卡培他濱、氟尿嘧啶、雙呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟以及三氟尿苷)、紫杉烷類(例如紫杉醇、白蛋白結合的紫杉醇以及多烯紫杉醇)、拓撲異構酶I抑制劑(例如喜樹鹼及其衍生物、羥基喜樹鹼、伊立替康以及拓撲替康)、拓撲異構酶Ⅱ抑制劑(例如依託泊苷(足葉乙苷)以及替尼鉑苷)、長春鹼類(長春瑞濱、長春鹼、長春新鹼、長春地辛以及長春富寧(vinflunine))、吡柔比星、培美曲塞、絲裂黴素、異環磷醯胺、環磷醯胺、阿紮胞苷、吡柔比星、氨柔比星、氨甲蝶呤、苯達莫司汀、表阿黴素、阿黴素（多柔比星）、替莫唑胺、LCL-161、KML-001、Sapacitabine、普那布林(plinabulin)、曲奧舒凡(treosulfan)、地匹福林鹽酸鹽(tipiracil hydrochloride)、 ¹⁵³Sm-EDTMP、替吉奧以及encequidar中的一種或多種。 Examples of other antineoplastic drugs include but are not limited to platinum drugs (such as oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin and lobaplatin), fluoropyrimidine derivatives (such as gemcitabine, capecitabine, fluorouracil, bisfururacil, doxifluridine, tegafur, carmofur, and trifluridine), taxanes (such as paclitaxel, albumin-bound paclitaxel, and docetaxel), Topoisomerase I inhibitors (such as camptothecin and its derivatives, hydroxycamptothecin, irinotecan, and topotecan), topoisomerase II inhibitors (such as etoposide (etoposide) and teniplatin), vinblastines (vinorelbine, vinblastine, vincristine, vindesine, and vinflunine), pirarubicin, pemetrexed, mitomycin, heterocyclic Phosphamide, cyclophosphamide, azacitidine, pirarubicin, amrubicin, methotrexate, bendamustine, epirubicin, doxorubicin (doxorubicin), Temozolomide, LCL-161, KML-001, Sapacitabine, plinabulin, treosulfan, tipiracil hydrochloride, ¹⁵³ Sm-EDTMP, S-1, and encequidar one or more of.

根據本發明的實施方案，所述腫瘤包括但不限於腎癌、肺腺癌、轉移性胸膜腫瘤、鼻咽癌以及乳腺癌等。According to the embodiment of the present invention, the tumor includes but not limited to renal carcinoma, lung adenocarcinoma, metastatic pleural tumor, nasopharyngeal carcinoma, breast carcinoma and the like.

根據本發明的實施方案，所述菸鹼醯胺的藥學上可接受的鹽選自如下類別，例如衍生自無機酸或有機酸的酸加成鹽，例如鹽酸鹽、氫溴酸鹽、對甲苯磺酸鹽、磷酸鹽、硫酸鹽、高氯酸鹽、乙酸鹽、三氟乙酸鹽、丙酸鹽、檸檬酸鹽、丙二酸鹽、琥珀酸鹽、乳酸鹽、草酸鹽、酒石酸鹽以及苯甲酸鹽。According to an embodiment of the present invention, the pharmaceutically acceptable salt of nicotinamide is selected from the following classes, such as acid addition salts derived from inorganic or organic acids, such as hydrochloride, hydrobromide, p- Tosylate, Phosphate, Sulfate, Perchlorate, Acetate, Trifluoroacetate, Propionate, Citrate, Malonate, Succinate, Lactate, Oxalate, Tartrate and benzoates.

根據本發明的實施方案，所述製劑可以是任何適合的形式，如固體製劑、液體製劑、半固體製劑或氣體製劑。According to an embodiment of the present invention, the formulation may be in any suitable form, such as a solid formulation, a liquid formulation, a semi-solid formulation or a gaseous formulation.

根據本發明的實施方案，所述製劑可以通過口服、靜脈、肌肉、皮下或局部應用來給藥，額外的途徑包括舌下、直腸、鼻內或肺吸入；所述製劑合適的形式包括但不限於水性或非水性的溶液或懸液、可分散的粉劑或顆粒、片劑、膠囊、乳膏、凝膠、分散體、乳劑、泡沫、霧劑、漱口劑、洗劑、軟膏、膏劑、噴霧劑、氣霧劑、油、硬膏劑、貼劑、混懸劑以及栓劑等。According to an embodiment of the invention, the formulation may be administered by oral, intravenous, intramuscular, subcutaneous or topical application, additional routes include sublingual, rectal, intranasal or pulmonary inhalation; suitable forms of the formulation include, but are not Aqueous or non-aqueous solutions or suspensions, dispersible powders or granules, tablets, capsules, creams, gels, dispersions, emulsions, foams, sprays, mouthwashes, lotions, ointments, creams, Sprays, aerosols, oils, plasters, patches, suspensions, suppositories, etc.

根據本發明的實施方案，所述製劑包含0.5%至40%重量的菸鹼醯胺、其水合物、溶劑合物、衍生物、前藥或它們的藥學上可接受的鹽，優選為1%至30%重量。According to an embodiment of the present invention, the preparation comprises 0.5% to 40% by weight of nicotinamide, its hydrate, solvate, derivative, prodrug or their pharmaceutically acceptable salt, preferably 1% to 30% by weight.

根據本發明的實施方案，所述製劑可以按照每天四次、每天三次、每天兩次、每天一次或每隔一天一次的劑量施用。可根據不同級別的嚴重程度選擇適宜的給藥方式和劑量。但是應該理解，對於任一具體患者的具體劑量水平將依賴於多種因素，包括年齡、體重、一般健康狀況、性別、飲食、給藥時間、藥物組合以及正在治療的具體病症的嚴重程度。根據本發明，本發明的製劑施用至少一年或更長時間，優選地至少一個月，更優選地至少一周，最優選地至少一天，以實現連續緩解皮膚相關疾病或病症。According to an embodiment of the invention, the formulation may be administered in doses four times a day, three times a day, twice a day, once a day or every other day. Appropriate administration methods and doses can be selected according to different levels of severity. It is to be understood, however, that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, drug combination and the severity of the particular condition being treated. According to the present invention, the formulations of the present invention are administered for at least one year or more, preferably at least one month, more preferably at least one week, most preferably at least one day, to achieve continuous relief of skin-related diseases or conditions.

根據本發明的實施方案，在一些實施方式中，所述菸鹼醯胺，其水合物、溶劑合物、衍生物、前藥或它們的藥學上可接受的鹽作為製劑中的唯一活性成分；在一些實施方式中，所述製劑中還包含其他藥物，例如消炎抗感染類藥物、維生素B、維生素E以及糖皮質激素等。According to embodiments of the present invention, in some embodiments, the nicotinamide, its hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof is used as the only active ingredient in the preparation; In some embodiments, the preparation also includes other drugs, such as anti-inflammatory and anti-infective drugs, vitamin B, vitamin E, and glucocorticoids.

根據本發明的實施方案，在一些實施方式中，所述菸鹼醯胺，其水合物、溶劑合物、衍生物、前藥或它們的藥學上可接受的鹽可以與所述抗腫瘤藥物分開給藥，例如，在使用抗腫瘤藥物前給藥或在使用抗腫瘤藥物後給藥。在一些實施方式中，所述菸鹼醯胺，其水合物、溶劑合物或它們的藥學上可接受的鹽可以與抗腫瘤藥同時給藥。According to embodiments of the present invention, in some embodiments, the nicotinamide, its hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof can be separated from the antitumor drug Administration, for example, before administration of an antitumor drug or after administration of an antitumor drug. In some embodiments, the nicotinamide, its hydrate, solvate or pharmaceutically acceptable salt thereof can be administered simultaneously with an antineoplastic drug.

根據本發明的實施方案，在一些實施方式中，所述菸鹼醯胺，其水合物、溶劑合物、衍生物、前藥或它們的藥學上可接受的鹽與所述抗腫瘤藥以聯合制劑的形式進行給藥。所述聯合制劑進一步用於在腫瘤治療時緩解、抑制皮膚相關疾病或病症。According to embodiments of the present invention, in some embodiments, the nicotinamide, its hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof is combined with the antineoplastic drug administered in the form of formulations. The combined preparation is further used for alleviating and inhibiting skin-related diseases or diseases during tumor treatment.

有益效果Beneficial effect

（1）本發明經臨床試驗進一步驗證菸鹼醯胺製劑有利於緩解、抑制皮膚相關疾病或病症，同時，也有利於進一步和產生不良反應的藥物聯用，減少不良反應的產生，以及緩解或抑制皮膚相關疾病或病症；(1) The present invention has been further verified by clinical trials that the nicotine amide preparation is beneficial to alleviate and inhibit skin-related diseases or diseases, and at the same time, it is also beneficial to further combine with drugs that cause adverse reactions, reduce the occurrence of adverse reactions, and alleviate or Inhibition of skin-related diseases or conditions;

（2）菸鹼醯胺毒副作用小，價格適中，可根據需要製成合適的劑型，臨床可行性高。(2) Niacinamide has low toxicity and side effects, moderate price, can be made into suitable dosage forms according to needs, and has high clinical feasibility.

具體實施方式detailed description

下文將結合具體實施例對本發明的技術方案做更進一步的詳細說明。應當理解，下列實施例僅為示例性地說明和解釋本發明，而不應被解釋為對本發明保護範圍的限制。凡基於本發明上述內容所實現的技術均涵蓋在本發明旨在保護的範圍內。The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

除非另有說明，以下實施例中使用的原料和試劑均為市售商品，或者可以通過已知方法製備。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

實施例Example 11

實驗目的：評價菸鹼醯胺在製備預防和/或治療皮膚相關疾病或病症的製劑中的應用的有效性和安全性。 The purpose of the experiment: to evaluate the effectiveness and safety of the application of nicotinamide in the preparation of preparations for preventing and/or treating skin-related diseases or conditions.

實驗方法：根據V4.03 CTCAE標準（參見表1），將接受抗腫瘤藥物治療的腫瘤患者，出現皮膚相關疾病或病症者，分別採用菸鹼醯胺濃度為15%的製劑塗擦，每日3次，一日用量約為5 g，每次進行最佳支持護理治療（如足部皮膚護理，穿戴厚的棉手套和/或襪子，避免接觸熱水、鞋子過緊和過度摩擦等）。 Experimental method: According to the V4.03 CTCAE standard (see Table 1), tumor patients receiving anti-tumor drug treatment and those with skin-related diseases or diseases were rubbed with a preparation with a concentration of 15% niacinamide, 3 times a day. Each time, the daily dose is about 5 g, each time with the best supportive care treatment (such as foot skin care, wearing thick cotton gloves and/or socks, avoiding contact with hot water, tight shoes and excessive friction, etc.).

受試者按照CTCAE標準(V4.03)接受治療評估，按照皮膚相關疾病或病症完全緩解（2級/3級到0級）或部分緩解（2級到0-1級，3級到0-2級）進行有效性記錄，並作生活質量評估；同時觀察菸鹼醯胺不良反應。Subjects received treatment evaluation according to CTCAE standard (V4.03), according to complete remission (grade 2/grade 3 to grade 0) or partial remission (grade 2 to grade 0-1, grade 3 to grade 0- Level 2) Record the effectiveness and evaluate the quality of life; observe the adverse reactions of nicotinamide at the same time.

表1 皮膚相關疾病或病症CTCAE分級 不良事件 分級 1 2 3 皮膚相關疾病或病症 無痛性輕微皮膚改變或皮膚炎（如紅斑，水腫，角化過度） 痛性皮膚改變（如剝落，水泡， 出血， 腫脹， 角化過度）；影響工具性日常生活活動 重度皮膚改變（剝落， 水泡，出血，水腫，角化過度），伴疼痛； 影響個人日常生活活動 Table 1 CTCAE classification of skin-related diseases or conditions Adverse event grading 1 2 3 Skin-Related Diseases or Conditions Painless minor skin changes or dermatitis (eg, erythema, edema, hyperkeratosis) Painful skin changes (eg, peeling, blisters, hemorrhage, swelling, hyperkeratosis); interfering with instrumental activities of daily living Severe skin changes (peeling, blisters, hemorrhage, edema, hyperkeratosis), with pain; affecting personal activities of daily living

患者療效評估與實驗結果：Patient efficacy evaluation and experimental results:

皮膚相關疾病或病症部分緩解：根據CTCAE標準(V4.03)不良反應標準評估治療前後手足皮膚反應的級別，指皮膚相關疾病或病症自3級至1-2級、2級至1級；Partial remission of skin-related diseases or diseases: According to CTCAE standard (V4.03) adverse reaction criteria, evaluate the grades of hand-foot skin reactions before and after treatment, referring to skin-related diseases or diseases from grade 3 to grade 1-2, and grade 2 to grade 1;

皮膚相關疾病或病症完全緩解：根據CTCAE標準(4.03)不良反應標準評估治療前後手足皮膚反應的級別，指HFSR自2/3級至0級；Complete remission of skin-related diseases or conditions: evaluate the grade of hand-foot skin reaction before and after treatment according to the CTCAE standard (4.03) adverse reaction criteria, referring to HFSR from grade 2/3 to grade 0;

製劑使用週期為14天及以上（根據患者情況酌情可增加實驗週期），篩選入組實驗的患者均患有皮膚相關疾病或病症，反饋有劇烈疼痛，嚴重時影響正常生活。患者實驗結果如下表2以及表3所示。The period of use of the preparation is 14 days or more (the experiment period can be increased as appropriate according to the patient’s condition), and the patients screened and enrolled in the experiment all suffer from skin-related diseases or diseases, and report severe pain, which affects normal life in severe cases. The patient test results are shown in Table 2 and Table 3 below.

表2 入組患者信息： 患者編號 疾病 用藥史 目前用藥 目前皮膚不良反應 名稱 主要靶點 名稱 表現 1 腎癌 抗癌藥：阿西替尼用藥22個月，耐藥，皮膚不良反應為皮疹 皮疹用藥：針對皮疹使用過***、999皮炎平、消炎癬濕藥膏，均無緩解 樂伐替尼（10 mg） VEGFR 皮疹 腿部 2 肺腺癌，轉移胸膜 抗癌藥：吉非替尼17個月耐藥，皮膚不良反應為甲溝炎 甲溝炎用藥：碘伏消毒、頭孢膠囊粉，無緩解 阿法替尼（40 mg） EGFR 甲溝炎 雙足 5 腎癌 抗癌藥：索坦，耐藥後用阿西替尼 ，皮膚不良反應為皮疹 皮疹用藥：999皮炎平、蘆薈，無緩解 阿西替尼（5 mg） VEGFR 皮疹 頸部 6 肺腺癌 抗癌藥：順鉑、吡咯替尼、伊立替康；2020.12月開始用波齊替尼，皮膚不良反應為皮疹 、甲溝炎               皮疹用藥：莫匹羅星軟膏、夫西地酸乳膏、曲安奈德乳膏、紅黴素、丁酸氫化可的松，無緩解  甲溝炎用藥：膚寧皮膚抑菌粉，無緩解 波齊替尼（12 mg） HER-2 甲溝炎 左右大腳趾 7 鼻咽癌 抗癌藥：卡培他濱 ，皮膚不良反應為手足症候群及毛囊炎            手足綜合徵用藥：用過潤膚乳，無緩解 毛囊炎用藥：阿達帕林、過氧苯甲醯，無緩解 卡培他濱 化療藥 毛囊炎 背部 9 肺腺癌 抗癌藥：吡咯替尼、阿帕塔尼、波齊替尼，皮膚不良反應為皮疹及甲溝炎 皮疹用藥：用過氫化可地松軟膏、標婷維E，目前不嚴重； 甲溝炎用藥：碘伏+中藥泡腳，無緩解 波齊替尼 HER-2 甲溝炎 雙足 10 鼻咽癌 抗癌藥：洛鉑、氟尿嘧啶5-fu  ，皮膚不良反應為手足症候群                手足綜合徵用藥：用過百雀羚、碘伏，效果不明顯 洛鉑+氟尿嘧啶5-fu 化療藥 手足症候群 雙足脫皮、開裂、疼痛 11 乳腺癌 抗癌藥：白蛋白紫杉醇+多柔比星注，皮膚不良反應為手足症候群   手足綜合徵用藥：用過維E、紅黴素、尿素糠酸莫米松乳膏，無緩解 白蛋白紫杉醇+多柔比星注 化療藥 手足症候群、皮疹 雙足開裂、疼痛、紅腫；腹部皮膚皮疹 12 乳腺癌 抗癌藥：卡培他濱，馬來酸吡咯替尼，維生素B6，皮膚不良反應為手足症候群 ； 皮疹藥：黃苓油膏、維E軟膏；使用後疼痛無緩解 卡培他濱 (0.5 g) 化療藥 手足症候群 1. VAS評分：疼痛評分5分 2. 皮損表現  左足：足底紅斑，足跟皸裂，乾燥伴少量鱗屑  右足：足底彌漫性紅斑腫脹，側緣皸裂，少量鱗屑 手部：輕度紅斑，少量鱗屑 3. HF-QOL評分：1）足部疼痛明顯，明顯皸裂，燒灼感；2）生活自理能力受限；3）走路受到輕度影響；4）上下樓梯緩慢，勞動困難；5）社交能力受到一定影響，活動減少，不自信，無助；6）手部紅腫，伴少量鱗屑，伴疼痛 4. 患者主訴：服藥後疼痛加重，停藥時伴有疼痛 13 乳腺癌 抗癌藥：卡培他濱，皮膚不良反應為手足症候群 ； 手足綜合徵用藥：護手霜、燙傷膏，疼痛感無法緩解 卡培他濱 (0.5 g)  化療藥 手足症候群 1. VAS評分：疼痛評分8分 2. 皮損表現  左足：足底及側緣明顯紅斑腫脹，伴輕度破損，皸裂，伴有少許鱗屑   右足：足底及側緣明顯紅斑腫脹，伴輕度破損，皸裂，伴有明顯鱗屑  3. HF-QOL評分：1）足底部疼痛明顯，明顯紅腫，燒灼感，皸裂；2）手部紅腫，紅斑，伴少量鱗屑，伴疼痛；3）生活自理能力受限；4）走路困難，無力；5）上下樓梯緩慢，勞動困難；6）社交活動減少，不自信 4. 患者主訴： 服藥後疼痛持續，程度恒定 14 鼻咽癌 抗癌藥：卡培他濱，皮膚不良反應為手足症候群 ； 手足綜合徵用藥：尿素軟膏，緩解疼痛無效 卡培他濱 (0.5 g)  化療藥 手足症候群 1. VAS評分：疼痛評分7分 2. 皮損表現  左足：鱗屑程度較重，角化過度，局部紅斑，皸裂    右足：鱗屑程度較重，角化過度，局部紅斑，皸裂  手部：雙手鱗屑程度較重，角化過度，局部紅斑，皸裂 3. HF-QOL評分：1）足底部紅斑，疼痛明顯，燒灼感，麻木，皸裂；2）手部紅斑疼痛，燒灼感，鱗屑較多，少量水皰3.生活自理能力明顯受限；3）走路困難，無力；4）上下樓梯緩慢，勞動困難；5）社交能力嚴重影響     4. 患者主訴：疼痛持續，日常生活受限 15 乳腺癌 抗癌藥：比洛替尼，卡培他濱，皮膚不良反應為手足症候群 ； 手足綜合徵用藥：凡士林、蘆薈汁液；緩解疼痛無效 卡培他濱 (0.5 g) 化療藥 手足症候群 1. VAS評分：疼痛評分7分 2. 皮損表現  左足：足底彌漫性紅斑腫脹，局部皮膚輕度硬化，少許鱗屑  右足：足底輕度紅斑，少許鱗屑，輕度硬化 3. HF-QOL評分：1）足底部紅斑，疼痛明顯，燒灼感，麻木，偶發水皰；2）手部紅斑疼痛，燒灼感，鱗屑較多，麻木；3）生活自理能力輕度受限3.走路困難，無力；4）上下樓梯緩慢，勞動困難；5）社交能力受限 4. 患者主訴：疼痛持續，日常生活受限 16 乳腺癌 抗癌藥：卡培他濱，赫賽汀，吡咯替尼，皮膚不良反應為手足症候群 ； 手足綜合徵用藥：凡士林、護手霜；未緩解 卡培他濱 (0.5 g) 化療藥 手足症候群 1. VAS評分：疼痛評分8分 2. 皮損表現  左足：足底及側緣彌漫性紅斑皸裂，伴輕度硬化，角化過度及鱗屑  右足：足底及側緣彌漫性紅斑皸裂，伴輕度硬化，角化過度及鱗屑 3. HF-QOL評分：1）足底部紅斑，疼痛明顯，燒灼感，麻木，偶發水皰；2）手部紅斑疼痛，紅斑，燒灼感，鱗屑較多，麻木；3）生活自理能力輕度受限；4）走路困難，無力；5）上下樓梯緩慢，搬物困難；5）社交能力明顯受限 4. 患者主訴：疼痛持續，日常生活受限 Table 2 Information of enrolled patients: patient number disease medication history current medication Current skin adverse reactions name main target name which performed 1 kidney cancer Anticancer drug: Axitinib has been used for 22 months, drug resistance, skin adverse reaction is rash Medication for rash: I have used dexamethasone, 999 Piyanping, and anti-inflammatory ringworm wet ointment for the rash, but there is no relief Lenvatinib (10 mg) VEGFR rash legs 2 Lung adenocarcinoma, metastases to pleura Anticancer drug: gefitinib resistance for 17 months, skin adverse reaction is paronychia Medication: iodophor disinfection, cephalosporin capsule powder, no relief Afatinib (40 mg) EGFR Paronychia two feet 5 kidney cancer Anticancer drug: Sutent, Axitinib after drug resistance, skin adverse reaction is rash Medication for rash: 999 Piyanping, aloe vera, no relief Axitinib (5 mg) VEGFR rash neck 6 Lung adenocarcinoma Anticancer drugs: cisplatin, pyrotinib, irinotecan; Poziotinib started in December 2020, skin adverse reactions were rash, paronychia rash Drugs: mupirocin ointment, fusidic acid cream, koji Acetide cream, erythromycin, hydrocortisone butyrate, no relief for paronychia Medication: Funing skin antibacterial powder, no relief Poziotinib (12 mg) HER-2 Paronychia left and right big toes 7 nasopharyngeal carcinoma Anticancer drug: capecitabine, skin adverse reactions are hand-foot syndrome and folliculitis Medication for hand-foot syndrome: used moisturizer, no relief for folliculitis Medication: adapalene, benzoyl peroxide, no relief Capecitabine Chemotherapy drugs Folliculitis the back 9 Lung adenocarcinoma Anticancer drugs: pyrotinib, apatanib, bozitinib, skin adverse reactions are rash and paronychia rash Medication: used hydrocortisone ointment, Biaoting vitamin E, not serious at present; paronychia Medication: Povidone iodine + traditional Chinese medicine soaking feet, no relief Poziotinib HER-2 Paronychia two feet 10 nasopharyngeal carcinoma Anticancer drugs: lobaplatin, fluorouracil 5-fu, skin adverse reaction is hand-foot syndrome Drugs for hand-foot syndrome: used Pechoin, iodophor, the effect is not obvious Lobaplatin+fluorouracil 5-fu Chemotherapy drugs hand foot syndrome Peeling, cracking, painful feet 11 breast cancer Anticancer drugs: nab-paclitaxel + doxorubicin injection, skin adverse reaction is hand-foot syndrome Medication for hand-foot syndrome: vitamin E, erythromycin, urea mometasone furoate cream, no relief Nab-paclitaxel + doxorubicin injection Chemotherapy drugs hand-foot syndrome, rash Cracking, pain, redness in feet; skin rash on abdomen 12 breast cancer Anticancer drugs: capecitabine, pyrotinib maleate, vitamin B6, skin adverse reaction is hand-foot syndrome; rash drugs: Huangling ointment, vitamin E ointment; no pain relief after use Capecitabine (0.5 g) Chemotherapy drugs hand foot syndrome 1. VAS score: Pain score 5 points 2. Lesions left foot: plantar erythema, heel chapped, dry with a small amount of scales Right foot: plantar diffuse erythema swelling, lateral chapped, a small amount of scales A small amount of scales 3. HF-QOL score: 1) Obvious foot pain, obvious chapping, burning sensation; 2) Limited self-care ability; 3) Mildly affected walking; 4) Slow up and down stairs, labor difficulties; 5) Social interaction The ability is affected to a certain extent, the activity is reduced, the self-confidence is low, and helplessness; 6) The hands are red and swollen with a small amount of scales and pain 4. The patient's main complaint: the pain worsens after taking the medicine, and it is accompanied by pain when the medicine is stopped 13 breast cancer Anticancer drug: capecitabine, skin adverse reaction is hand-foot syndrome; drug for hand-foot syndrome: hand cream, burn ointment, pain can not be relieved Capecitabine (0.5 g) Chemotherapy drugs hand foot syndrome 1. VAS score: Pain score 8 points 2. Skin lesion performance Left foot: obvious erythema and swelling on the sole and lateral margin, with mild damage, chapped, and a little scale Right foot: obvious erythema and swelling on the sole and lateral margin, with mild Damaged, chapped, accompanied by obvious scales 3. HF-QOL score: 1) Obvious pain in the sole of the foot, obvious redness, burning sensation, chapped; 2) Redness, swelling, erythema, with a small amount of scales, and pain in the hands; 3) Self-care ability Limited; 4) Difficulty walking, weakness; 5) Slow going up and down stairs, labor difficulties; 6) Decreased social activities, low self-confidence 4. The patient's main complaint: After taking the medicine, the pain persists and the degree is constant 14 nasopharyngeal carcinoma Anticancer drug: capecitabine, skin adverse reaction is hand-foot syndrome; drug for hand-foot syndrome: urea ointment, ineffective for pain relief Capecitabine (0.5 g) Chemotherapy drugs hand foot syndrome 1. VAS score: Pain score 7 points 2. Lesions left foot: severe scale, hyperkeratosis, local erythema, chapped Right foot: severe scale, hyperkeratosis, local erythema, chapped Hands: scaly hands Severe degree, hyperkeratosis, local erythema, chapped 3. HF-QOL score: 1) erythema on the sole of the foot, obvious pain, burning sensation, numbness, and chapped; 2) erythema pain, burning sensation, more scales on the hands, a small amount Blisters 3. Self-care ability is obviously limited; 3) Difficulty walking and weakness; 4) Slow going up and down stairs, labor difficulties; 5) Social skills are seriously affected 4. The patient’s main complaint: persistent pain and limited daily life 15 breast cancer Anticancer drugs: bilotinib, capecitabine, skin adverse reaction is hand-foot syndrome; drugs for hand-foot syndrome: petrolatum, aloe juice; pain relief is ineffective Capecitabine (0.5 g) Chemotherapy drugs hand foot syndrome 1. VAS score: Pain score 7 points. 2. Lesions on the left foot: diffuse erythema and swelling on the plantar surface, mild sclerosis of the local skin, and a little scaling. Right foot: mild erythema on the plantar, a little scaling, and mild sclerosis. 3. HF-QOL Score: 1) erythema on the sole of the foot, obvious pain, burning sensation, numbness, and occasional blisters; 2) erythema pain, burning sensation, more scales, and numbness on the hands; 3) Slightly limited self-care ability 3. Difficulty walking and weakness ;4) Slow up and down stairs, labor difficulties; 5) Restricted social skills 4. The patient complained of persistent pain and limited daily life 16 breast cancer Anticancer drugs: capecitabine, Herceptin, pyrotinib, skin adverse reaction is hand-foot syndrome; drugs for hand-foot syndrome: Vaseline, hand cream; no relief Capecitabine (0.5 g) Chemotherapy drugs hand foot syndrome 1. VAS score: Pain score 8 points 2. Skin lesion performance Left foot: diffuse erythematous chapping on the sole and lateral margin, with mild sclerosis, hyperkeratosis and scales Right foot: diffuse erythematous chapping on the sole and lateral margin, with mild sclerosis Degree of sclerosis, hyperkeratosis and scales 3. HF-QOL score: 1) erythema on the sole of the foot, obvious pain, burning sensation, numbness, and occasional blisters; 2) erythema pain on the hands, erythema, burning sensation, more scales, and numbness; 3) Slight limitation of self-care ability; 4) Difficulty in walking and weakness; 5) Slow up and down stairs, difficulty in moving; 5) Significant limitation of social skills

表3 患者治療效果： 病例編號 治療前分級 治療後分級 治療效果 治療效果圖 1 2 0 D2疼痛瘙癢緩解；D14天腿部皮疹消失 圖1 2 3 1 D3雙足甲溝炎結痂趨勢；D14雙足甲溝炎結痂，趨於好轉，繼續用藥； 圖2 5 2 1 D7/D10/D14瘙癢改善，頸部處顏色逐漸變淡，繼續用藥； 圖3 6 3 1 D2雙足甲溝炎有結痂趨勢；D5雙足甲溝周圍有消腫；D9雙足右結痂趨勢；D14雙足甲溝炎結痂，繼續用藥； 圖4 7 3 0 患者背部毛囊炎趨於好轉，疼痛感消失，背部光滑度增加 圖5 9 3 0 D3雙足甲溝炎明顯好轉、不流膿；D6疼痛緩解，無壓痛感； D14雙足紅腫消失，無疼痛感，繼續用藥； 圖6、圖7 10 3 1 D5天雙足疼痛緩解，疼痛感緩解明顯 D7天雙足疼痛、瘙癢緩解； D8雙足角質化脫皮，長出新皮膚； D14雙足疼痛感無、增厚角質層脫離，恢復成正常皮膚中，繼續用藥； 圖8、圖9 11 手足症候群：3 皮疹：3級 手足症候群：1級 皮疹：0級 D3雙足疼痛消失，瘙癢、角質化均有緩解； D4雙足角質化部分開始掉皮；皮疹部位好轉，皮膚不乾燥也不脫皮； D7雙足開裂部位基本能結痂脫落； D14雙足結痂，開始脫落，繼續用藥；皮疹消失； 圖10、圖11、圖12 12 3 1 1.VAS評分：疼痛評分0分 2. 皮損表現 左足：皸裂緩解少量，紅斑略有緩解 右足：紅斑明顯消退，皸裂緩解，少量鱗屑  手部：皮損明顯消退 3.HF-QOL評分：1）足部紅斑明顯緩解，疼痛消退，麻木感；2）鍛煉較少；3）上下樓梯及走路明顯緩解；4）生活自理能力有明顯緩解；5） 手部：疼痛緩解；6）社交能力無明顯影響 4. 患者主訴：疼痛緩解，紅斑消退，鱗屑緩解 圖13、圖14 13 3 1 1. VAS評分：疼痛評分3分 2. 皮損表現  左足：足底及側緣紅斑腫脹消退，皮膚硬化增加，足底鱗屑減少，皸裂消退 右足：足底及側緣紅斑腫脹消退，輕度硬化，足底鱗屑增多，皸裂消退  3. HF-QOL評分：1）足部紅斑明顯緩解，疼痛明顯緩解，麻木感，鱗屑；2）手部偶爾疼痛，輕度硬化，輕度燒灼感，麻木感緩解；3） 鍛煉較少，可鍛煉，重體力少；4）上下樓梯及走路明顯緩解；5）生活自理能力明顯緩解；6）社交能力有緩解  4. 患者主訴：用藥後角質化及腫脹有緩解 圖15、圖16 14 3 1 1.VAS評分：疼痛評分0分 2.皮損表現  左足：鱗屑明顯緩解，皮膚逐漸光滑，伴有輕度紅斑 右足：鱗屑明顯緩解，皮膚逐漸光滑，伴有輕度紅斑 手部：鱗屑明顯緩解，紅斑輕度緩解，角化過度緩解 3.HF-QOL評分：1. 足部紅斑明顯緩解，疼痛偶發，壓痛緩解，麻木感，鱗屑緩解；2.手部紅斑緩解，疼痛及鱗屑緩解3. 鍛煉較少，重體力少4.上下樓梯及走路恢復正常；5. 生活自理能力不受限6. 社交能力無明顯緩解 4.患者主訴：   用藥後疼痛及腫脹有緩解，硬化緩解 圖17、圖18、圖19 15 3 0 1.VAS評分：疼痛評分0~2分 2. 皮損表現  左足：紅斑腫脹消退，皮膚略有硬化 右足：鱗屑明顯緩解，皮膚逐漸光滑，伴有輕度紅 3. HF-QOL評分：1）足部紅斑明顯緩解，疼痛消失，壓痛緩解，麻木感，鱗屑均消退；2）手部恢復正常；3）鍛煉較少，重體力少；4）上下樓梯及走路恢復正常；5）生活自理能力不受限6. 社交能力明顯緩解 4. 患者主訴：用藥後疼痛及腫脹均明顯消退，輕度脫屑 圖20、圖21 16 3 1 1.VAS評分：疼痛評分0分 2. 皮損表現  左足：紅斑緩解，腫脹消退，皸裂明顯減輕，伴少許鱗屑 右足：紅斑緩解，腫脹消退，皸裂明顯減輕 3. HF-QOL評分：1）足部紅斑明顯緩解，疼痛消失，壓痛緩解，麻木感，水皰，鱗屑均消退；2）手部緩解，疼痛及鱗屑減輕；3） 鍛煉較少，重體力少；4）上下樓梯及走路恢復正常；5）生活自理能力不受限；6）社交能力明顯緩解 4. 患者主訴：疼痛及皸裂均消退 圖22、圖23 注：D為Day簡寫，表示治療天數；VAS評分：Visual Analogue Scale/Score縮寫，表示視覺模擬評分法；HF-QOL評分：HF為Hand-Foot縮寫，QOL為Quality of Life縮寫，表示手足皮膚反應生活質量評分。 Table 3 Treatment effect of patients: case number Grading before treatment Grading after treatment treatment effect Treatment effect map 1 2 0 Pain and itching relieved on D2; leg rash disappeared on D14 figure 1 2 3 1 D3 Scab trend of biped paronychia; D14 Scab of biped paronychia tends to improve, continue medication; figure 2 5 2 1 On D7/D10/D14, the itching was improved, and the color of the neck gradually became lighter, and the medication was continued; image 3 6 3 1 D2 The paronychia tends to scab; D5 There is swelling around the nail groove; D9 The right foot tends to scab; D14 The paronychia scabs, continue to use the medicine; Figure 4 7 3 0 The patient's back folliculitis tends to improve, the pain disappears, and the back smoothness increases Figure 5 9 3 0 D3 The paronychia of both feet improved obviously, without pus; D6 Pain relief, no tenderness; D14 Redness and swelling of both feet disappeared, no pain, continued medication; Figure 6, Figure 7 10 3 1 On D5, the pain in both feet was relieved, and the pain was relieved obviously; on D7, the pain and itching in both feet were relieved; on D8, the keratinization and peeling of both feet, and new skin grew; on D14, there was no pain in both feet, and the thickened cuticle was detached, and the skin returned to normal , continue medication; Figure 8, Figure 9 11 Hand-foot syndrome: 3 Rash: Grade 3 Hand-foot syndrome: Grade 1 Rash: Grade 0 D3 The pain in both feet disappeared, and itching and keratinization were relieved; D4 The keratinized part of the feet began to peel off; the rash area improved, and the skin was not dry or peeling; D7 The cracked parts of the feet were basically able to scab off; D14 The feet were knotted The scabs began to fall off, continue to use the drug; the rash disappeared; Figure 10, Figure 11, Figure 12 12 3 1 1. VAS score: Pain score 0 points 2. Skin lesions on left foot: chapped slightly relieved, erythema slightly relieved Right foot: erythema subsided obviously, chapped relieved, a small amount of scales Hand: skin lesions subsided obviously 3. HF-QOL score: 1 ) Foot erythema was significantly relieved, pain subsided, and numbness; 2) Less exercise; 3) Up and down stairs and walking were significantly relieved; 4) Self-care ability was significantly relieved; 5) Hands: Pain relief; 6) Social skills were not Obvious effect 4. Patient's chief complaint: pain relief, erythema subsided, scales relieved Figure 13, Figure 14 13 3 1 1. VAS score: Pain score 3 points 2. Skin lesion performance Left foot: erythema and swelling on the sole and lateral margin subsided, skin hardening increased, scales on the plantar decreased, chapped and subsided Right foot: erythema on the sole and lateral margin subsided, mild sclerosis , increased plantar scales, chapped subsided 3. HF-QOL score: 1) Significant relief of foot erythema, pain relief, numbness, scales; 2) Occasional hand pain, mild sclerosis, mild burning sensation, numbness Relief; 3) Less exercise, can be exercised, less heavy physical strength; 4) Significant relief of going up and down stairs and walking; 5) Significant relief of self-care ability; 6) Relief of social skills ease Figure 15, Figure 16 14 3 1 1. VAS score: Pain score 0 points 2. Skin lesion performance Left foot: The scales were obviously relieved, the skin gradually smoothed, accompanied by mild erythema Right foot: The scales were obviously relieved, the skin gradually smoothed, accompanied by mild erythema , mild relief of erythema, relief of hyperkeratosis 3. HF-QOL score: 1. Significant relief of foot erythema, occasional pain, relief of tenderness, numbness, relief of scales; 2. Relief of hand erythema, relief of pain and scales 3. Less exercise, less physical strength 4. Going up and down stairs and walking back to normal; 5. Self-care ability is not limited 6. Social skills are not significantly relieved 4. The patient's main complaint: Pain and swelling are relieved after medication, and sclerosis is relieved Figure 17, Figure 18, Figure 19 15 3 0 1. VAS score: Pain score 0-2 points 2. Skin lesion performance Left foot: erythema and swelling subsided, skin hardened slightly Right foot: Scale was relieved, skin gradually smoothed, accompanied by mild redness 3. HF-QOL score: 1) The erythema of the foot was significantly relieved, the pain disappeared, the tenderness was relieved, the numbness, and the scales all subsided; 2) the hands returned to normal; 3) less exercise and less physical strength; 4) up and down stairs and walking returned to normal; 5) self-care ability Unlimited 6. The social ability is obviously relieved 4. The patient's main complaint: After taking the medicine, the pain and swelling are obviously subsided, and the desquamation is mild Figure 20, Figure 21 16 3 1 1. VAS score: Pain score 0 points 2. Skin lesion performance Left foot: erythema relieved, swelling subsided, chapped significantly reduced, with a little scale Right foot: erythema relieved, swelling subsided, chapped significantly reduced 3. HF-QOL score: 1) Foot The erythema on the skin was significantly relieved, the pain disappeared, the tenderness was relieved, the numbness, blisters, and scales all subsided; 2) the hands were relieved, and the pain and scales were relieved; 3) Less exercise and less physical strength; 4) Up and down stairs and walking returned to normal; 5) Self-care ability is not limited; 6) Social ability is significantly relieved 4. The patient's main complaint: pain and chapped all subsided Figure 22, Figure 23 Note: D is the abbreviation of Day, indicating the number of treatment days; VAS score: the abbreviation of Visual Analogue Scale/Score, indicating the visual analogue scale method; HF-QOL score: HF is the abbreviation of Hand-Foot, and QOL is the abbreviation of Quality of Life, indicating the hand-foot skin reaction Quality of life score.

實施例Example 22 菸鹼醯胺緩解卡培他濱引起的皮膚相關症狀Nicotinamide relieves capecitabine-induced skin-related symptoms

利用卡培他濱經口灌胃給予SD大鼠，造手足綜合症模型，每天3次、對大鼠後爪塗抹供試品菸鹼醯胺製劑，試驗目的是觀察菸鹼醯胺製劑能否緩解卡培他濱引起的皮膚角質層厚度降低。Capecitabine was given to SD rats by oral gavage to create a model of hand-foot syndrome, and 3 times a day, the test product nicotine amide preparation was applied to the hind paws of the rats. The purpose of the test was to observe whether the nicotine amide preparation could Relief of capecitabine-induced reduction in stratum corneum thickness.

採用50隻SD雌性大鼠，隨機分為5組（10隻/組），第1至4組為每天1次經口灌胃給予4000 mg/kg卡培他濱+每天3次後肢塗抹不同濃度的菸鹼醯胺製劑，第1至4組菸鹼醯胺在製劑中的濃度依次為0%、5%、10%、20%，藥膏塗抹間隔為2至3小時，第5組為每天1次經口灌胃4000 mg/kg卡培他濱+每天1次經口灌胃70 mg/kg 菸鹼醯胺製劑(菸鹼醯胺+生理食鹽水配製得到的均一溶液，濃度為7 mg/ml)，給藥期限均為28天。第18天起，對於體重降低超過15%（與自身第一天相比）的動物停止灌胃給藥，待體重恢復至5%後重新灌胃給藥。實驗結果如下：Fifty SD female rats were randomly divided into 5 groups (10 rats/group). Groups 1 to 4 were given 4000 mg/kg capecitabine by oral gavage once a day + smearing different concentrations on hind limbs 3 times a day The concentration of nicotine amide in the preparations of groups 1 to 4 was 0%, 5%, 10%, and 20% in turn, and the ointment interval was 2 to 3 hours. Oral gavage of 4000 mg/kg capecitabine once a day + oral gavage of 70 mg/kg nicotinamide preparation (uniform solution prepared by nicotinamide + normal saline, the concentration is 7 mg/kg) ml), and the duration of administration was 28 days. From the 18th day, the animals whose body weight decreased by more than 15% (compared with the first day) were given intragastric administration, and the intragastric administration was resumed after the body weight recovered to 5%. The experimental results are as follows:

卡培他濱+受試物各劑量組均於Day 21起出現手足症候群，其中SD大鼠給予4000 mg/kg/QD卡培他濱後皮膚角質層厚度明顯降低，10%、20%以及70 mg/kg的菸鹼醯胺製劑對卡培他濱造模引起的角質層厚度降低明顯緩解，具體參見下表4：All dose groups of capecitabine+test substance had hand-foot syndrome on Day 21, and SD rats were given 4000 mg/kg/QD capecitabine. The mg/kg nicotine amide preparation significantly alleviated the reduction in the thickness of the stratum corneum caused by capecitabine modeling, see Table 4 below for details:

表4 角質層厚度 組別 卡培他濱 +菸鹼醯胺(0%) 卡培他濱 +菸鹼醯胺(5%) 卡培他濱+菸鹼醯胺(10%) 卡培他濱+菸鹼醯胺(20%) 卡培他濱+菸鹼醯胺(70 mg/kg) 發生時間 Days 21-28 Days 21-28 Days 21-28 Days 21-28 Days 21-28 角質層平均厚度 207 nm 213 nm 257 nm 240 nm 265 nm Table 4 Thickness of stratum corneum group Capecitabine + Nicotinamide (0%) Capecitabine + Nicotinamide (5%) Capecitabine + Nicotinamide (10%) Capecitabine + Nicotinamide (20%) Capecitabine + Nicotinamide (70 mg/kg) Time of occurrence Days 21-28 Days 21-28 Days 21-28 Days 21-28 Days 21-28 Average thickness of stratum corneum 207 nm 213 nm 257 nm 240 nm 265 nm

以上，對本發明的實施方式進行了說明。但是，本發明不限定於上述實施方式。凡在本發明的精神和原則之內，所做的任何修改、等同替換、改進等，均應包含在本發明的保護範圍之內。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

無none

[圖1]係1號患者治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖2]係2號患者治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖3]係5號患者治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖4]係6號患者治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖5]係7號患者治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖6]係9號患者左腳治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖7]係9號患者右腳治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖8]係10號患者左腳治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖9]係10號患者右腳治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖10]係11號患者皮疹治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖11]係11號患者左腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖12]係11號患者右腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D14天的治療效果）。 [圖13]係12號患者右腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖14]係12號患者右腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖15]係13號患者右腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖16]係13號患者左腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖17]係14號患者左腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖18]係14號患者雙手手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖19]係14號患者右腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖20]係15號患者左腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖21]係15號患者右腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖22]係16號患者左腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [圖23]係16號患者右腳手足症候群治療效果圖（左圖顯示患者0天症狀，右圖顯示患者D21天的治療效果）。 [Figure 1] The treatment effect chart of patient No. 1 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 2] The treatment effect chart of patient No. 2 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 3] The treatment effect chart of patient No. 5 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 4] The treatment effect diagram of patient No. 6 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 5] The treatment effect diagram of patient No. 7 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 6] The effect of treatment on the left foot of patient No. 9 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 7] The treatment effect diagram of the right foot of patient No. 9 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 8] The treatment effect diagram of the left foot of patient No. 10 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 9] The picture of the treatment effect on the right foot of patient No. 10 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D14). [Figure 10] Diagram of the treatment effect of rash on patient No. 11 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14). [Figure 11] The treatment effect diagram of patient No. 11's left leg hand-foot syndrome (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on D14 days). [Figure 12] The treatment effect diagram of patient No. 11's right foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D14 days). [Figure 13] The treatment effect diagram of patient No. 12's right foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D21 day). [Figure 14] The treatment effect diagram of patient No. 12's right foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D21 day). [Figure 15] The treatment effect diagram of patient No. 13's right foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D21 day). [Figure 16] The treatment effect diagram of patient No. 13's left foot hand-foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D21 day). [Figure 17] The treatment effect diagram of patient No. 14's left foot hand-foot syndrome (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D21). [Fig. 18] Treatment effect diagram of patient No. 14's hand-foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D21). [Figure 19] The treatment effect diagram of patient No. 14's right foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D21 day). [Figure 20] The treatment effect diagram of patient No. 15's left foot hand-foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D21 day). [Figure 21] The treatment effect diagram of patient No. 15's right foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D21 day). [Figure 22] The treatment effect diagram of patient No. 16's left foot syndrome (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on day D21). [Figure 23] The treatment effect diagram of patient No. 16's right foot syndrome (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on D21 day).

Claims (10)

菸鹼醯胺，其水合物、溶劑合物、衍生物、前藥或它們的藥學上可接受的鹽在製備預防和/或治療皮膚相關疾病或病症的製劑中的一種應用。An application of nicotinamide, its hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof in the preparation of preparations for preventing and/or treating skin-related diseases or conditions. 如請求項1所述的應用，其中，該皮膚相關疾病或病症包括皮疹、瘙癢、紅斑、皮膚乾燥、脫髮、毛囊炎、甲溝炎、色素沉積紊亂、手足症候群、脫皮、皮膚萎縮、痤瘡、感覺異常、毛細血管擴張、感覺過敏、斑丘疹性皮膚反應、蕁麻疹、血管性水腫、固定性藥疹、多形紅斑、DRESS（伴嗜酸性粒細胞增多症和全身症狀的藥物反應；也稱為藥物超敏反應症候群）、Stevens Johnson 症候群、中毒性表皮壞死鬆解症以及水泡中的一種或多種。The application according to claim 1, wherein the skin-related diseases or diseases include rash, itching, erythema, dry skin, hair loss, folliculitis, paronychia, pigmentation disorder, hand-foot syndrome, peeling, skin atrophy, acne, Paresthesia, telangiectasia, hyperesthesia, maculopapular skin reaction, urticaria, angioedema, fixed drug eruption, erythema multiforme, DRESS (drug reaction with eosinophilia and constitutional symptoms; also known as Drug hypersensitivity syndrome), Stevens Johnson syndrome, toxic epidermal necrolysis, and blisters. 如請求項1或2所述的應用，其中，該皮膚相關疾病或病症是由藥物引起的。The application according to claim 1 or 2, wherein the skin-related disease or condition is caused by drugs. 如請求項3所述的應用，其中，該藥物選自抗腫瘤藥、抗菌藥、抗癲癇藥物、疫苗、降血脂藥、抗糖尿病藥、抗結核藥、抗心律失常藥、解熱鎮痛藥、鎮靜催眠藥、抗生素、皮質類固醇、用於麻醉的肌肉鬆弛劑、磺胺類藥物以及造影劑中的一種或多種。The application as described in claim 3, wherein the drug is selected from antineoplastic drugs, antibacterial drugs, antiepileptic drugs, vaccines, hypolipidemic drugs, antidiabetic drugs, antituberculosis drugs, antiarrhythmic drugs, antipyretic analgesics, sedatives One or more of hypnotics, antibiotics, corticosteroids, muscle relaxants used for anesthesia, sulfa drugs, and contrast media. 如請求項4所述的應用，其中，該抗腫瘤藥選自免疫治療劑、分子標靶藥物、生物製劑以及其他抗腫瘤藥中的一種或多種。The application according to claim 4, wherein the anti-tumor drug is selected from one or more of immunotherapeutic agents, molecular targeted drugs, biological agents and other anti-tumor drugs. 如請求項1至5中任一項所述的應用，其中，該菸鹼醯胺的藥學上可接受的鹽選自如下類別，例如衍生自無機酸或有機酸的酸加成鹽，例如鹽酸鹽、氫溴酸鹽、對甲苯磺酸鹽、磷酸鹽、硫酸鹽、高氯酸鹽、乙酸鹽、三氟乙酸鹽、丙酸鹽、檸檬酸鹽、丙二酸鹽、琥珀酸鹽、乳酸鹽、草酸鹽、酒石酸鹽以及苯甲酸鹽。The application according to any one of claims 1 to 5, wherein the pharmaceutically acceptable salt of nicotinamide is selected from the following categories, such as acid addition salts derived from inorganic acids or organic acids, such as salts salt, hydrobromide, p-toluenesulfonate, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, Lactate, oxalate, tartrate and benzoate. 如請求項1至6中任一項所述的應用，其中，該製劑選自固體製劑、液體製劑、半固體製劑以及氣體製劑。The application according to any one of claims 1 to 6, wherein the preparation is selected from solid preparations, liquid preparations, semi-solid preparations and gas preparations. 如請求項1至6中任一項所述的應用，其中，該製劑可以通過口服、靜脈、肌肉、皮下或局部應用來給藥，額外的途徑包括舌下、直腸、鼻內或肺吸入；該製劑合適的形式包括但不限於水性或非水性的溶液或懸液、可分散的粉劑或顆粒、片劑、膠囊、乳膏、凝膠、分散體、乳劑、泡沫、霧劑、漱口劑、洗劑、軟膏、膏劑、噴霧劑、氣霧劑、油、硬膏劑、貼劑、混懸劑或栓劑。The application according to any one of claims 1 to 6, wherein the formulation can be administered orally, intravenously, intramuscularly, subcutaneously or locally, and additional routes include sublingual, rectal, intranasal or pulmonary inhalation; Suitable forms of the formulation include, but are not limited to, aqueous or non-aqueous solutions or suspensions, dispersible powders or granules, tablets, capsules, creams, gels, dispersions, emulsions, foams, sprays, mouthwashes , lotion, ointment, paste, spray, aerosol, oil, plaster, patch, suspension or suppository. 如請求項1至6中任一項所述的應用，其中，該製劑包含0.5%至40%重量的菸鹼醯胺、其水合物、溶劑合物、衍生物、前藥或它們的藥學上可接受的鹽，優選為1%至30%重量。The application as described in any one of claims 1 to 6, wherein the preparation comprises 0.5% to 40% by weight of nicotinamide, its hydrate, solvate, derivative, prodrug or their pharmaceutical Acceptable salts are preferably from 1% to 30% by weight. 如請求項1至6中任一項所述的應用，其中，該製劑中，該菸鹼醯胺，其水合物、溶劑合物、衍生物、前藥或它們的藥學上可接受的鹽與抗腫瘤藥以聯合制劑的形式進行給藥。The application according to any one of claim items 1 to 6, wherein, in the preparation, the nicotinamide, its hydrate, solvate, derivative, prodrug or their pharmaceutically acceptable salt is combined with Antineoplastic drugs are administered in the form of combined preparations.

Images