WO2022171064A1 - Pharmaceutical use of nicotinamide and composition containing same - Google Patents

Pharmaceutical use of nicotinamide and composition containing same Download PDF

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WO2022171064A1
WO2022171064A1 PCT/CN2022/075446 CN2022075446W WO2022171064A1 WO 2022171064 A1 WO2022171064 A1 WO 2022171064A1 CN 2022075446 W CN2022075446 W CN 2022075446W WO 2022171064 A1 WO2022171064 A1 WO 2022171064A1
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drugs
nicotinamide
patient
skin
drug
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PCT/CN2022/075446
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French (fr)
Chinese (zh)
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陈令武
季世春
王德忠
吴炎
蔡浩
陈遇峰
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扬子江药业集团南京海陵药业有限公司
南京海陵中药制药工艺技术研究有限公司
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Publication of WO2022171064A1 publication Critical patent/WO2022171064A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • the invention belongs to the field of medicine, in particular to the application of nicotinamide in the preparation of pharmaceutical preparations.
  • Dermal drug reactions are common and are adverse drug reactions that can 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.
  • Nicotinamide is a member of the vitamin B family.
  • the chemical name of nicotinamide is 3-pyridinecarboxamide, also known as nicotinamide, the molecular formula is C 6 H 6 N 2 O, the molecular weight is 122.13, and it is a common SIRT1 inhibitor.
  • nicotinamide has been no specific study of nicotinamide in the treatment/relief of some drug-induced skin-related diseases or conditions such as rashes, paronychia, etc.
  • the present invention provides nicotinamide, its hydrates, solvates, derivatives, prodrugs or their pharmaceutically acceptable salts in the preparation of preventing and/or treating skin-related diseases or disorders application in formulations.
  • the skin-related disease or condition includes rash, pruritus, 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 Hypersensitivity syndrome), Stevens Johnson syndrome, toxic epidermal necrolysis, one or more of blisters.
  • the skin-related disease or disorder is caused by a drug.
  • the drug is selected from antitumor drugs, antibacterial drugs, antiepileptic drugs, vaccines, hypolipidemic drugs, antidiabetic drugs, antituberculosis drugs, antiarrhythmic drugs, antipyretic and analgesic drugs, sedative and hypnotic drugs
  • antitumor drugs antibiotics, corticosteroids, muscle relaxants for anesthesia, sulfonamides, and contrast agents.
  • the anti-tumor drug is selected from one or more of immunotherapeutic agents, molecularly targeted drugs, biological agents, and other anti-tumor drugs.
  • the molecularly targeted drugs include, but are not limited to, protein kinase inhibitors.
  • the protein kinase inhibitors include but are not limited to tyrosine kinase inhibitors, serine and/or threonine kinase inhibitors
  • the targets of the inhibitors include but are not limited to EGFR (epidermal growth factor receptor) , Anaplastic lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (disc death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene;
  • the targets of the small molecule targeting antitumor drugs also include COX-2 (cyclooxygenase-2), APE1 (apurine apyrimidine intranucleic acid) Dicer), VEGFR-2 (vascular endotheli
  • Small molecule targeted antitumor 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, Emtrexa Entrectinib, Dasatinib, Ensartinib, Lenvatinib, itacitinib, Pyrotinib, Binimetinib, Erdatinib (Erdafitinib), Ax
  • the small molecule targeted anti-tumor drug is sorafenib, everolimus, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib Alectinib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, lorlatinib, trametinib, larotib Intratinib, Icotinib, Lapatinib, Vandetanib, Selumetinib, Omotinib, Savolitinib, Fruquintinib, Entrectinib, Dasatinib, Ensatinib Nitrile, lenvatinib, itacitinib, pyrotinib, bimetinib, erdatinib, axitini
  • the immunotherapeutic agents include immunomodulatory agents and agents that promote or mediate antigen presentation that promotes cell-mediated immune responses.
  • the immunomodulators include immune checkpoint modulators, such as immune checkpoint protein receptors and their ligands that mediate the inhibition of T cell-mediated cytotoxicity, and are typically caused by tumors or anergic T cells in the tumor microenvironment. cells and allow tumors to evade immune attack. Inhibitors of the activity of immunosuppressive checkpoint protein receptors and their ligands can 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.
  • Immunodethelial growth factor-1-targeted inhibitors include the approved drug agents pembrolizumab and nivolumab, while ipilimumab is an approved CTLA-4 inhibitor.
  • 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.
  • IL interleukin
  • IFN interferon
  • TNF tumor necrosis factor
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • M-CSF macrophage colony stimulating factor
  • Cytokines have a positive promoting effect on immune cells and immune system. Giving the body-related cytokines 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.
  • Biologics include, but are not limited to, cancer vaccines, antibodies, and cytokines.
  • the antibody may be a monoclonal antibody.
  • the monoclonal antibody can be a humanized antibody or a human antibody.
  • antineoplastic drugs include, but are not limited to, platinum-based drugs (eg, oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin), fluoropyrimidine derivatives (eg, gemcitabine, capecitabine, fluorouracil, difurfluorouracil, deoxyfluridine, tegafur, carmofur, trifluridine), taxanes (eg, paclitaxel, nab-paclitaxel, and docetaxel), Topoisomerase I inhibitors (such as camptothecin and its derivatives, hydroxycamptothecin, irinotecan, topotecan), topoisomerase II inhibitors (such as etoposide (etoposide), Teniplatin glycosides), vinblastines (vinorelbine, vinblastine, vincristine, vindesine, vinflunine), pirarubicin, pemetre
  • the tumor includes, but is not limited to, renal carcinoma, lung adenocarcinoma, metastatic pleural tumor, nasopharyngeal carcinoma, breast cancer, and the like.
  • the pharmaceutically acceptable salt of nicotinamide is selected from classes such as acid addition salts derived from inorganic or organic acids, such as hydrochloride, hydrobromide, p-toluenesulfonic acid Acid salt, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, lactate, oxalate, tartaric acid salts and benzoates.
  • acid addition salts derived from inorganic or organic acids such as hydrochloride, hydrobromide, p-toluenesulfonic acid Acid salt, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, lactate, oxalate, tartaric acid salts and benzoates.
  • the formulation may be in any suitable form, such as a solid formulation, a liquid formulation, a semi-solid formulation or a gas formulation.
  • the formulation may be administered orally, intravenously, intramuscularly, subcutaneously, topically, additional routes including sublingual, rectal, intranasal, or pulmonary inhalation; suitable forms of the formulation include but Not limited to aqueous or non-aqueous solutions or suspensions, dispersible powders or granules, tablets, capsules, creams, gels, dispersions, emulsions, foams, mists, mouthwashes, lotions, ointments, ointments , sprays, aerosols, oils, plasters, patches, suspensions or suppositories, etc.
  • the formulation comprises 0.5%-40% by weight of nicotinamide, its hydrates, solvates, derivatives, prodrugs or their pharmaceutically acceptable salts, preferably 1%-30% by weight %weight.
  • the formulation may be administered in a dose of four times a day, three times a day, twice a day, once a day or every other day.
  • the appropriate mode of administration and dosage can be selected according to the severity of different grades. 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, timing of administration, drug combination, and the severity of the specific condition being treated.
  • the formulations of the present invention are administered for at least one year or longer, 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.
  • the nicotinamide, hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof is used as the sole active ingredient in the formulation; in some
  • the preparation further includes other drugs, such as anti-inflammatory and anti-infective drugs, vitamin B, vitamin E, glucocorticoid and the like.
  • the nicotinamide, hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof may be administered separately from the antineoplastic drug , for example, before administration of antineoplastic drugs, or after administration of antineoplastic drugs.
  • the nicotinamide, hydrate, solvate or pharmaceutically acceptable salt thereof can be administered concurrently with an antineoplastic agent.
  • the nicotinamide, its hydrates, solvates, derivatives, prodrugs or pharmaceutically acceptable salts thereof and the antineoplastic drug are formulated in combination form of administration.
  • the combined preparation is further used for alleviating or inhibiting skin-related diseases or conditions during tumor treatment.
  • the present invention has been further verified by clinical trials that the nicotinamide preparation is beneficial for relieving and inhibiting skin-related diseases or conditions, and at the same time, it is also beneficial for further combining with drugs that produce adverse reactions, reducing the generation of adverse reactions, and relieving or inhibiting skin related diseases or conditions;
  • Nicotinamide has little toxicity and side effects, and the price is moderate. It can be made into suitable dosage forms according to the needs, and the clinical feasibility is high.
  • Figure 1 is a picture of the treatment effect of patient No. 1 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
  • Figure 2 is the treatment effect chart of patient 2 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
  • Figure 3 is the treatment effect diagram of patient No. 5 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
  • Figure 4 is a graph of the treatment effect of patient No. 6 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
  • Figure 5 is the treatment effect chart of patient No. 7 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
  • Figure 6 is a picture of the treatment effect of the left foot of patient No. 9 (the left picture shows the patient's symptoms on the 0th day, and the right picture shows the treatment effect of the patient on the D14 day)
  • Figure 7 is a picture of the treatment effect of the right foot of patient No. 9 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
  • Figure 8 is a picture of the treatment effect of patient No. 10's left foot (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
  • Figure 9 is a picture of the treatment effect of 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 the 14th day)
  • Figure 10 is a picture of the treatment effect of the rash of patient 11 (the left picture shows the patient's symptoms on the 0th day, and the right picture shows the treatment effect of the patient on the 14th day)
  • Figure 11 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 11 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on the 14th day)
  • Figure 12 is a picture of the treatment effect of the right foot hand-foot syndrome of 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 days)
  • Figure 13 is a picture of the treatment effect of the right foot hand-foot syndrome of patient 12 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on day 21)
  • Figure 14 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 12 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on day 21)
  • Figure 15 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 13 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D21 day)
  • Figure 16 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 13 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on day 21)
  • Figure 17 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 14 (the left picture shows the patient's symptoms on the 0th day, and the right picture shows the treatment effect of the patient on the D21 day)
  • Figure 18 is a picture of the treatment effect of patient No. 14 with bimanual 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 day)
  • Figure 19 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 14 (the left picture shows the patient's symptoms on the 0th day, and the right picture shows the treatment effect of the patient on the D21 day)
  • Figure 20 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 15 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D21 day)
  • Figure 21 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 15 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D21 day)
  • Figure 22 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 16 (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 21)
  • Figure 23 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 16 (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 21)
  • Subjects were evaluated for treatment according to CTCAE criteria (V4.03) as complete remission (grade 2/grade 3 to grade 0) or partial remission (grade 2 to grade 0-1, grade 3 to 0- Grade 2,), record the effectiveness and evaluate the quality of life; meanwhile, observe the adverse reactions of nicotinamide.
  • Partial remission of skin-related diseases or conditions according to CTCAE criteria (V4.03) adverse reaction criteria to evaluate the grades of skin reactions of hands and feet before and after treatment, referring to skin-related diseases or conditions ranging from grade 3 to grade 1-2, grade 2 to grade 1; skin Complete remission of related diseases or conditions: according to CTCAE criteria (4.03) adverse reaction criteria to evaluate the grade of hand-foot skin reaction before and after treatment, referring to HFSR from grade 2/3 to grade 0;
  • the use period of the preparation is 14 days or more (the experimental period can be increased as appropriate according to the patient's situation).
  • the patient experimental results are shown in Table 2 and Table 3 below.
  • D is the abbreviation of Day, which means the number of days of treatment
  • VAS score the abbreviation of Visual Analogue Scale/Score, which means the visual analogue scale method
  • HF-QOL score HF is the abbreviation of Hand-Foot
  • QOL is the abbreviation of Quality of Life, which means the skin reaction of hands and feet Quality of life score
  • SD rats were given capecitabine by oral gavage to create a hand-foot syndrome model.
  • the test nicotinamide preparation was applied to the hind paws of the rats three times a day. The purpose of the experiment was to observe whether the nicotinamide preparation could relieve capecitabine. Decreased stratum corneum thickness caused by
  • Fifty SD female rats were randomly divided into 5 groups (10/group). Groups 1-4 were given 4000 mg/kg capecitabine by oral gavage once a day + smeared different concentrations of capecitabine on the hind limbs 3 times a day. Niacinamide preparations, the concentration of nicotinamide in the preparations in groups 1-4 were 0%, 5%, 10%, and 20%, and the ointment application interval was 2-3 hours. The fifth group was 4000 mg orally once a day. /kg capecitabine + 70 mg/kg nicotinamide preparation (a homogeneous solution prepared from nicotinamide + physiological saline, with a concentration of 7 mg/ml) orally administered once a day for 28 days. From the 18th day, the animals whose body weight decreased by more than 15% (compared to the first day) were stopped from the gavage administration, and the animals were re-gavaged after the body weight recovered to 5%.
  • the experimental results are as follows:
  • capecitabine + test substance dose groups all developed hand-foot syndrome from Day 21, among which SD rats were given 4000mg/kg/QD capecitabine after the skin stratum corneum thickness was significantly reduced, 10%, 20%, 70mg
  • the reduction of stratum corneum thickness caused by capecitabine modeling was significantly relieved by the nicotinamide preparation per kg, as shown in Table 4 below:

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Abstract

The present invention provides an application of nicotinamide, and a hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salts thereof in preparation of a preparation for preventing and/or treating skin-related diseases or symptoms. The nicotinamide has small toxic and side effects and moderate price, and has wide clinical application prospects.

Description

烟酰胺及含有其的组合物的制药用途Pharmaceutical use of niacinamide and compositions containing the same
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。This application claims the priority of an earlier application with the patent application number 202110176845.6 and the invention titled "Pharmaceutical Use of Niacinamide and Compositions Containing the Same" filed with the State Intellectual Property Office of China on February 9, 2021. The entire contents of said prior applications are incorporated herein by reference.
技术领域technical field
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。The invention belongs to the field of medicine, in particular to the application of nicotinamide in the preparation of pharmaceutical preparations.
背景技术Background technique
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。Dermal drug reactions are common and are adverse drug reactions that can 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.
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C 6H 6N 2O，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。 Nicotinamide is a member of the vitamin B family. The chemical name of nicotinamide is 3-pyridinecarboxamide, also known as nicotinamide, the molecular formula is C 6 H 6 N 2 O, the molecular weight is 122.13, and it is a common SIRT1 inhibitor. There has been no specific study of nicotinamide in the treatment/relief of some drug-induced skin-related diseases or conditions such as rashes, paronychia, etc.
发明内容SUMMARY OF THE INVENTION
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。In order to solve the technical problems existing in the prior art, the present invention provides nicotinamide, its hydrates, solvates, derivatives, prodrugs or their pharmaceutically acceptable salts in the preparation of preventing and/or treating skin-related diseases or disorders application in formulations.
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。According to an embodiment of the invention, the skin-related disease or condition includes rash, pruritus, 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 Hypersensitivity syndrome), Stevens Johnson syndrome, toxic epidermal necrolysis, one or more of blisters.
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。According to an embodiment of the present invention, the skin-related disease or disorder is caused by a drug.
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。According to an embodiment of the present invention, the drug is selected from antitumor drugs, antibacterial drugs, antiepileptic drugs, vaccines, hypolipidemic drugs, antidiabetic drugs, antituberculosis drugs, antiarrhythmic drugs, antipyretic and analgesic drugs, sedative and hypnotic drugs One or more of drugs, antibiotics, corticosteroids, muscle relaxants for anesthesia, sulfonamides, and contrast agents.
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。According to an embodiment of the present invention, the anti-tumor drug is selected from one or more of immunotherapeutic agents, molecularly targeted drugs, biological agents, and other anti-tumor drugs.
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。The molecularly 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 receptor) , Anaplastic lymphoma (ALK), MET gene, ROS1 gene, HER2 gene, RET gene, BRAF gene, PI3K signaling pathway, DDR2 (disc death receptor 2) gene, FGFR1 (fibroblast growth factor receptor 1), NTRK1 (neurotrophic tyrosine kinase type 1 receptor) gene, KRAS gene; the targets of the small molecule targeting antitumor drugs also include COX-2 (cyclooxygenase-2), APE1 (apurine apyrimidine intranucleic acid) Dicer), 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 synthase kinase 3β), CyclinD1 ( cyclin), CDK4 (cyclin-dependent kinase), TIMP1 (tissue inhibitor of metalloproteinase), THBS3, PTHR1 (parathyroid hormone-related protein receptor 1), TEM7 (human tumor vascular endothelial marker 7) , COPS3, cathepsin K. Small molecule targeted antitumor 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, Emtrexa 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, SK LB-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, One or more of bortezomib, panobinostat, tucidinostat, vorinostat, resminostat, epacadostat, tazemetostat, entinostat, mocetinostat, and quisinostat. In some embodiments, the small molecule targeted anti-tumor drug is sorafenib, everolimus, erlotinib, afatinib, crizotinib, ceritinib, vemurafenib Alectinib, dabrafenib, cabozantinib, gefitinib, dacomitinib, osimertinib, alectinib, brigatinib, lorlatinib, trametinib, larotib Intratinib, Icotinib, Lapatinib, Vandetanib, Selumetinib, Omotinib, Savolitinib, Fruquintinib, Entrectinib, Dasatinib, Ensatinib Nitrile, lenvatinib, itacitinib, pyrotinib, bimetinib, erdatinib, axitinib, neratinib, cobitinib, acalatinib, famitinib, masitinib , one or more of ibrutinib and nintedanib.
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。The immunotherapeutic agents include immunomodulatory agents and agents that promote or mediate antigen presentation that promotes cell-mediated immune responses. The immunomodulators include immune checkpoint modulators, such as immune checkpoint protein receptors and their ligands that mediate the inhibition of T cell-mediated cytotoxicity, and are typically caused by tumors or anergic T cells in the tumor microenvironment. cells and allow tumors to evade immune attack. Inhibitors of the activity of immunosuppressive checkpoint protein receptors and their ligands can 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 targeting checkpoint proteins, aptamers, small molecules, and soluble forms of checkpoint receptor proteins, and the like. PD-1-targeted inhibitors include the approved drug agents pembrolizumab and nivolumab, while ipilimumab is an approved CTLA-4 inhibitor.
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。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 have a positive promoting effect on immune cells and immune system. Giving the body-related cytokines 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。Biologics include, but are not limited to, cancer vaccines, antibodies, and cytokines. The antibody may be a monoclonal antibody. The monoclonal antibody can be a humanized antibody or a human antibody.
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。 Examples of other antineoplastic drugs include, but are not limited to, platinum-based drugs (eg, oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, lobaplatin), fluoropyrimidine derivatives (eg, gemcitabine, capecitabine, fluorouracil, difurfluorouracil, deoxyfluridine, tegafur, carmofur, trifluridine), taxanes (eg, paclitaxel, nab-paclitaxel, and docetaxel), Topoisomerase I inhibitors (such as camptothecin and its derivatives, hydroxycamptothecin, irinotecan, topotecan), topoisomerase II inhibitors (such as etoposide (etoposide), Teniplatin glycosides), vinblastines (vinorelbine, vinblastine, vincristine, vindesine, vinflunine), pirarubicin, pemetrexed, mitomycin, heterocyclic Phosphoramide, Cyclophosphamide, Azacitidine, Pirarubicin, Amrubicin, Methotrexate, Bendamustine, Epirubicin, Doxorubicin (Doxorubicin), Temozolomide, of LCL-161, KML-001, Sapacitabine, plinabulin, treosulfan, tipiracil hydrochloride, 153 Sm-EDTMP, Sigiol and encequidar one or more.
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。According to embodiments of the present invention, the tumor includes, but is not limited to, renal carcinoma, lung adenocarcinoma, metastatic pleural tumor, nasopharyngeal carcinoma, breast cancer, and the like.
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。According to an embodiment of the present invention, the pharmaceutically acceptable salt of nicotinamide is selected from classes such as acid addition salts derived from inorganic or organic acids, such as hydrochloride, hydrobromide, p-toluenesulfonic acid Acid salt, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinate, lactate, oxalate, tartaric acid salts and benzoates.
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。According to embodiments 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 gas formulation.
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。According to embodiments of the invention, the formulation may be administered orally, intravenously, intramuscularly, subcutaneously, topically, additional routes including sublingual, rectal, intranasal, or pulmonary inhalation; suitable forms of the formulation include but Not limited to aqueous or non-aqueous solutions or suspensions, dispersible powders or granules, tablets, capsules, creams, gels, dispersions, emulsions, foams, mists, mouthwashes, lotions, ointments, ointments , sprays, aerosols, oils, plasters, patches, suspensions or suppositories, etc.
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。According to an embodiment of the present invention, the formulation comprises 0.5%-40% by weight of nicotinamide, its hydrates, solvates, derivatives, prodrugs or their pharmaceutically acceptable salts, preferably 1%-30% by weight %weight.
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。According to embodiments of the present invention, the formulation may be administered in a dose of four times a day, three times a day, twice a day, once a day or every other day. The appropriate mode of administration and dosage can be selected according to the severity of different grades. 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, timing of administration, drug combination, and the severity of the specific condition being treated. According to the present invention, the formulations of the present invention are administered for at least one year or longer, 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。According to embodiments of the present invention, in some embodiments, the nicotinamide, hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof is used as the sole active ingredient in the formulation; in some In an embodiment, the preparation further includes other drugs, such as anti-inflammatory and anti-infective drugs, vitamin B, vitamin E, glucocorticoid and the like.
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。According to embodiments of the present invention, in some embodiments, the nicotinamide, hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof may be administered separately from the antineoplastic drug , for example, before administration of antineoplastic drugs, or after administration of antineoplastic drugs. In some embodiments, the nicotinamide, hydrate, solvate or pharmaceutically acceptable salt thereof can be administered concurrently with an antineoplastic agent.
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。According to embodiments of the present invention, in some embodiments, the nicotinamide, its hydrates, solvates, derivatives, prodrugs or pharmaceutically acceptable salts thereof and the antineoplastic drug are formulated in combination form of administration. The combined preparation is further used for alleviating or inhibiting skin-related diseases or conditions during tumor treatment.
有益效果beneficial effect
(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；(1) The present invention has been further verified by clinical trials that the nicotinamide preparation is beneficial for relieving and inhibiting skin-related diseases or conditions, and at the same time, it is also beneficial for further combining with drugs that produce adverse reactions, reducing the generation of adverse reactions, and relieving or inhibiting skin related diseases or conditions;
(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。(2) Nicotinamide has little toxicity and side effects, and the price is moderate. It can be made into suitable dosage forms according to the needs, and the clinical feasibility is high.
附图说明Description of drawings
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)Figure 1 is a picture of the treatment effect of patient No. 1 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
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)Figure 2 is the treatment effect chart of patient 2 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
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)Figure 3 is the treatment effect diagram of patient No. 5 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
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)Figure 4 is a graph of the treatment effect of patient No. 6 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
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)Figure 5 is the treatment effect chart of patient No. 7 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
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)Figure 6 is a picture of the treatment effect of the left foot of patient No. 9 (the left picture shows the patient's symptoms on the 0th day, and the right picture shows the treatment effect of the patient on the D14 day)
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)Figure 7 is a picture of the treatment effect of the right foot of patient No. 9 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
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)Figure 8 is a picture of the treatment effect of patient No. 10's left foot (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D14 days)
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)Figure 9 is a picture of the treatment effect of 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 the 14th day)
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)Figure 10 is a picture of the treatment effect of the rash of patient 11 (the left picture shows the patient's symptoms on the 0th day, and the right picture shows the treatment effect of the patient on the 14th day)
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)Figure 11 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 11 (the left picture shows the symptoms of the patient on day 0, and the right picture shows the treatment effect of the patient on the 14th day)
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)Figure 12 is a picture of the treatment effect of the right foot hand-foot syndrome of 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 days)
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)Figure 13 is a picture of the treatment effect of the right foot hand-foot syndrome of patient 12 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on day 21)
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)Figure 14 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 12 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on day 21)
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)Figure 15 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 13 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D21 day)
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)Figure 16 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 13 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of the patient on day 21)
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)Figure 17 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 14 (the left picture shows the patient's symptoms on the 0th day, and the right picture shows the treatment effect of the patient on the D21 day)
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)Figure 18 is a picture of the treatment effect of patient No. 14 with bimanual 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 day)
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)Figure 19 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 14 (the left picture shows the patient's symptoms on the 0th day, and the right picture shows the treatment effect of the patient on the D21 day)
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)Figure 20 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 15 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D21 day)
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)Figure 21 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 15 (the left picture shows the patient's symptoms on day 0, and the right picture shows the treatment effect of patient D21 day)
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)Figure 22 is a picture of the treatment effect of the left foot hand-foot syndrome of patient No. 16 (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 21)
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)Figure 23 is a picture of the treatment effect of the right foot hand-foot syndrome of patient No. 16 (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 21)
具体实施方式Detailed ways
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。The technical solutions of the present invention will be described in further detail below with reference to 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 implemented based on the above content of the present invention are covered within the intended protection scope of the present invention.
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。Unless otherwise stated, the starting materials and reagents used in the following examples are commercially available or can be prepared by known methods.
实施例1Example 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。Experiment purpose: To evaluate the efficacy and safety of the application of nicotinamide in the preparation of preparations for preventing and/or treating skin-related diseases or disorders.
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)。Experimental method: According to the V4.03 CTCAE standard (see Table 1), the tumor patients receiving anti-tumor drug treatment and those with skin-related diseases or symptoms were rubbed with a preparation with a concentration of 15% nicotinamide, 3 times a day. , the daily dose is about 5g, each time with the best supportive care treatment (such as foot skin care, wear thick cotton gloves and/or socks, avoid contact with hot water, shoes that are too tight and excessive friction, etc.).
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。Subjects were evaluated for treatment according to CTCAE criteria (V4.03) as complete remission (grade 2/grade 3 to grade 0) or partial remission (grade 2 to grade 0-1, grade 3 to 0- Grade 2,), record the effectiveness and evaluate the quality of life; meanwhile, observe the adverse reactions of nicotinamide.
表1皮肤相关疾病或病症CTCAE分级Table 1 CTCAE classification of skin-related diseases or conditions
Figure PCTCN2022075446-appb-000001
Figure PCTCN2022075446-appb-000001
患者疗效评估与实验结果：Patient efficacy evaluation and experimental results:
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；Partial remission of skin-related diseases or conditions: according to CTCAE criteria (V4.03) adverse reaction criteria to evaluate the grades of skin reactions of hands and feet before and after treatment, referring to skin-related diseases or conditions ranging from grade 3 to grade 1-2, grade 2 to grade 1; skin Complete remission of related diseases or conditions: according to CTCAE criteria (4.03) adverse reaction criteria to evaluate the grade of hand-foot skin reaction before and after treatment, referring to HFSR from grade 2/3 to grade 0;
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。The use period of the preparation is 14 days or more (the experimental period can be increased as appropriate according to the patient's situation). The patients who were screened and enrolled in the experiment suffered from skin-related diseases or conditions, and reported severe pain, which in severe cases affected their normal life. The patient experimental results are shown in Table 2 and Table 3 below.
表2.入组患者信息：Table 2. Enrolled patient information:
Figure PCTCN2022075446-appb-000002
Figure PCTCN2022075446-appb-000002
Figure PCTCN2022075446-appb-000003
Figure PCTCN2022075446-appb-000003
Figure PCTCN2022075446-appb-000004
Figure PCTCN2022075446-appb-000004
Figure PCTCN2022075446-appb-000005
Figure PCTCN2022075446-appb-000005
表3.患者治疗效果：Table 3. Patient treatment effects:
Figure PCTCN2022075446-appb-000006
Figure PCTCN2022075446-appb-000006
Figure PCTCN2022075446-appb-000007
Figure PCTCN2022075446-appb-000007
Figure PCTCN2022075446-appb-000008
Figure PCTCN2022075446-appb-000008
Figure PCTCN2022075446-appb-000009
Figure PCTCN2022075446-appb-000009
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Note: D is the abbreviation of Day, which means the number of days of treatment; VAS score: the abbreviation of Visual Analogue Scale/Score, which means the visual analogue scale method; HF-QOL score: HF is the abbreviation of Hand-Foot, and QOL is the abbreviation of Quality of Life, which means the skin reaction of hands and feet Quality of life score
实施例2烟酰胺缓解卡培他滨引起的皮肤相关症状Example 2 Niacinamide relieves skin-related symptoms caused by capecitabine
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。SD rats were given capecitabine by oral gavage to create a hand-foot syndrome model. The test nicotinamide preparation was applied to the hind paws of the rats three times a day. The purpose of the experiment was to observe whether the nicotinamide preparation could relieve capecitabine. Decreased stratum corneum thickness caused by
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：Fifty SD female rats were randomly divided into 5 groups (10/group). Groups 1-4 were given 4000 mg/kg capecitabine by oral gavage once a day + smeared different concentrations of capecitabine on the hind limbs 3 times a day. Niacinamide preparations, the concentration of nicotinamide in the preparations in groups 1-4 were 0%, 5%, 10%, and 20%, and the ointment application interval was 2-3 hours. The fifth group was 4000 mg orally once a day. /kg capecitabine + 70 mg/kg nicotinamide preparation (a homogeneous solution prepared from nicotinamide + physiological saline, with a concentration of 7 mg/ml) orally administered once a day for 28 days. From the 18th day, the animals whose body weight decreased by more than 15% (compared to the first day) were stopped from the gavage administration, and the animals were re-gavaged after the body weight recovered to 5%. The experimental results are as follows:
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：The capecitabine + test substance dose groups all developed hand-foot syndrome from Day 21, among which SD rats were given 4000mg/kg/QD capecitabine after the skin stratum corneum thickness was significantly reduced, 10%, 20%, 70mg The reduction of stratum corneum thickness caused by capecitabine modeling was significantly relieved by the nicotinamide preparation per kg, as shown in Table 4 below:
表4角质层厚度Table 4 Cuticle thickness
Figure PCTCN2022075446-appb-000010
Figure PCTCN2022075446-appb-000010
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。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims (13)

  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。Use of nicotinamide, its hydrates, solvates, derivatives, prodrugs or their pharmaceutically acceptable salts in the preparation of preparations for preventing and/or treating skin-related diseases or disorders.
  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。The use according to claim 1, wherein the skin-related diseases or conditions include rash, 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 One or more of drug hypersensitivity syndrome), Stevens Johnson syndrome, toxic epidermal necrolysis, blisters.
  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。The use according to claim 1 or 2, characterized in that the skin-related disease or condition is caused by a drug.
  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。The application according to claim 3, wherein the drug is selected from the group consisting of antitumor drugs, antibacterial drugs, antiepileptic drugs, vaccines, hypolipidemic drugs, antidiabetic drugs, antituberculosis drugs, antiarrhythmic drugs, antipyretic and analgesic drugs One or more of drugs, sedative-hypnotics, antibiotics, corticosteroids, muscle relaxants for anesthesia, sulfonamides, and contrast agents.
  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。The application according to claim 4, characterized in that, the anti-tumor drug is selected from one or more of immunotherapeutic agents, molecularly targeted drugs, biological agents, and other anti-tumor drugs.
  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。The use 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 or organic acids, such as salts acid salt, hydrobromide, p-toluenesulfonate, phosphate, sulfate, perchlorate, acetate, trifluoroacetate, propionate, citrate, malonate, succinic acid Salt, lactate, oxalate, tartrate and benzoate.
  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。The application according to any one of claims 1-6, wherein the preparation is selected from solid preparation, liquid preparation, semi-solid preparation or gas preparation.
  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。The use according to any one of claims 1-6, wherein the formulation can be administered orally, intravenously, intramuscularly, subcutaneously, topically, additional routes including 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, aerosols , mouthwash, lotion, ointment, ointment, spray, aerosol, oil, plasters, patches, suspensions or suppositories.
  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。The use according to any one of claims 1-6, wherein the preparation comprises 0.5%-40% by weight of nicotinamide, its hydrates, solvates, derivatives, prodrugs or their pharmaceutics Acceptable salts are preferably 1% to 30% by weight.
  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。The use according to any one of claims 1-6, characterized in that, in the preparation, the nicotinamide, its hydrate, solvate, derivative, prodrug or their pharmaceutically acceptable salt It is administered in the form of a combined preparation with an antineoplastic drug.
  11. 一种预防和/或治疗皮肤相关疾病或病症的方法，包括给予烟酰胺，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。A method of preventing and/or treating a skin-related disease or disorder comprising administering nicotinamide, a hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof.
  12. 根据权利要求11所述的方法，包括将所述烟酰胺，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给药。The method of claim 11, comprising administering the nicotinamide, its hydrate, solvate, derivative, prodrug, or pharmaceutically acceptable salt thereof, and an antineoplastic agent in a combined formulation.
  13. 根据权利要求11所述的方法，包括将所述烟酰胺，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物分开、先后、同时给药。The method of claim 11, comprising administering the nicotinamide, hydrate, solvate, derivative, prodrug or pharmaceutically acceptable salt thereof and the antineoplastic drug separately, sequentially, and simultaneously.
PCT/CN2022/075446 2021-02-09 2022-02-08 Pharmaceutical use of nicotinamide and composition containing same WO2022171064A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110755432A (en) * 2019-12-02 2020-02-07 浙江大学 Application of nicotinamide in preparation of preparation for treating hand-foot skin reaction
CN111569078A (en) * 2020-06-18 2020-08-25 上海馨颖生物技术有限公司 Use of SIRT1 inhibitors for side effects caused by combination of VEGFR inhibitors and immune checkpoint inhibitors
WO2021204223A1 (en) * 2020-04-08 2021-10-14 扬子江药业集团南京海陵药业有限公司 Pharmaceutical composition including nicotinamide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110755432A (en) * 2019-12-02 2020-02-07 浙江大学 Application of nicotinamide in preparation of preparation for treating hand-foot skin reaction
WO2021204223A1 (en) * 2020-04-08 2021-10-14 扬子江药业集团南京海陵药业有限公司 Pharmaceutical composition including nicotinamide
CN111569078A (en) * 2020-06-18 2020-08-25 上海馨颖生物技术有限公司 Use of SIRT1 inhibitors for side effects caused by combination of VEGFR inhibitors and immune checkpoint inhibitors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CUNHA PAULO ROWILSON, THOMAZESKI PATRÍCIA, HIPÓLITO ÉRICA, MICHALANY NÍLCEOU S., BYSTRYN JEAN-CLAUDE: "Bullous pemphigoid in a 2-month-old infant.", INTERNATIONAL JOURNAL OF DERMATOLOGY, WILEY-BLACKWELL PUBLISHING LTD., UK, vol. 37, no. 12, 31 December 1998 (1998-12-31), UK , pages 935 - 938, XP009538927, ISSN: 0011-9059, DOI: 10.1046/j.1365-4362.1998.00615.x *
GU YOUSHOU: "Application and Prospect of Niacinamide in Dermatology", JOURNAL OF DIAGNOSIS AND THERAPY ON DERMATO-VENEREOLOGY, vol. 15, no. 4, 31 August 2008 (2008-08-31), pages 251 - 252, XP055958559, ISSN: 1674-8468 *
WEN HAIQUAN, ZHOU YING, ZHU JIAOYUAN: "One Case of Hyponiacinosis after Long-term Administration of Fluorouracil", LINCHUANG-PIFUKE-ZAZHI : SHUANGYUEKAN = JOURNAL OF CLINICAL DERMATOLOGY, LINCHUANG-PIFUKE-ZAZHI BIANJIBU, vol. 32, no. 4, 31 December 2003 (2003-12-31), pages 216, XP055958536, ISSN: 1000-4963 *
ZHU MINGANG, WEI SHENG, WANG YIN ET AL: "Clinical Analysis of 68 Patients with Photosensitization Drug Eruption", CHINA JOURNAL OF LEPROSY AND SKIN DISEASES, vol. 31, no. 6, 31 December 2015 (2015-12-31), pages 360 - 362, XP055958548, ISSN: 1009-1157 *

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