TW202241421A - Pharmaceutical use of nicotinamide and composition thereof - Google Patents
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Abstract
Description
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
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:
表3 患者治療效果:
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
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).
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