WO2022171064A1 - Utilisation pharmaceutique de nicotinamide et composition le contenant - Google Patents

Utilisation pharmaceutique de nicotinamide et composition le contenant 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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English (en)
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/fr

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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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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
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  • Hematology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une application de nicotinamide, et un hydrate, un solvate, un dérivé, un promédicament ou des sels pharmaceutiquement acceptables de celui-ci dans l'élaboration d'une préparation pour prévenir et/ou traiter des maladies ou des symptômes liés à la peau. Le nicotinamide présente de faibles effets toxiques et secondaires et un prix modéré, et possède de vastes perspectives d'application clinique.
PCT/CN2022/075446 2021-02-09 2022-02-08 Utilisation pharmaceutique de nicotinamide et composition le contenant WO2022171064A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN110755432A (zh) * 2019-12-02 2020-02-07 浙江大学 烟酰胺在制备治疗手足皮肤反应制剂中的应用
CN111569078A (zh) * 2020-06-18 2020-08-25 上海馨颖生物技术有限公司 Sirt1抑制剂在vegfr抑制剂与免疫检查点抑制剂联用引起的副作用上的应用
WO2021204223A1 (fr) * 2020-04-08 2021-10-14 扬子江药业集团南京海陵药业有限公司 Composition pharmaceutique comprenant du nicotinamide

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CN110755432A (zh) * 2019-12-02 2020-02-07 浙江大学 烟酰胺在制备治疗手足皮肤反应制剂中的应用
WO2021204223A1 (fr) * 2020-04-08 2021-10-14 扬子江药业集团南京海陵药业有限公司 Composition pharmaceutique comprenant du nicotinamide
CN111569078A (zh) * 2020-06-18 2020-08-25 上海馨颖生物技术有限公司 Sirt1抑制剂在vegfr抑制剂与免疫检查点抑制剂联用引起的副作用上的应用

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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 *
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