WO2015032011A1 - 含有亚铁氨基酸螯合物的组合物在制备抗癌症的药物中的用途 - Google Patents

含有亚铁氨基酸螯合物的组合物在制备抗癌症的药物中的用途 Download PDF

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WO2015032011A1
WO2015032011A1 PCT/CN2013/001043 CN2013001043W WO2015032011A1 WO 2015032011 A1 WO2015032011 A1 WO 2015032011A1 CN 2013001043 W CN2013001043 W CN 2013001043W WO 2015032011 A1 WO2015032011 A1 WO 2015032011A1
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cancer
amino acid
ferrous
composition containing
acid chelate
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English (en)
French (fr)
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林村源
陈木桂
陈沧泽
傅嘉慧
詹勋锦
邱雯政
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Profeat Biotechnology Co Ltd
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Profeat Biotechnology Co Ltd
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Priority to CN201380071525.8A priority Critical patent/CN104955452B/zh
Priority to AU2013400082A priority patent/AU2013400082B2/en
Priority to PCT/CN2013/001043 priority patent/WO2015032011A1/zh
Priority to EP13893164.7A priority patent/EP3042652B1/en
Priority to JP2015559400A priority patent/JP5973684B2/ja
Priority to CA2898771A priority patent/CA2898771C/en
Publication of WO2015032011A1 publication Critical patent/WO2015032011A1/zh
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • composition containing a ferrous amino acid chelate compound for preparing an anticancer drug
  • the present invention relates to the use of a composition comprising a ferrous amino acid chelate, and to the use of the composition in the manufacture of a medicament for the fight against cancer. Background technique
  • Cancer or malignant tumor is one of the leading causes of death in the world's population.
  • the cancer death rate is ranked mainly for lung cancer, stomach cancer, liver cancer, colorectal cancer, breast cancer and cervical cancer. According to the statistics of the World Health Organization, nearly 20 years The lung cancer mortality rate is the fastest.
  • the lung cancer is divided into small cell lung cancer and non-small cell lung carcinoma (NSCLC) according to its cell characteristics and clinical manifestations.
  • Small cell lung cancer occurs mostly in men and is closely related to smoking, accounting for 25% of all lung cancer patients; and small cells grow fast and easily spread from lymph or blood to other organs.
  • Non-small cell carcinoma accounts for 75% of all lung cancer patients. Common include: squamous cell carcinoma, adenocarcinoma, large cell carcinoma.
  • Squamous cell carcinoma also known as epidermoid carcinoma
  • epidermoid carcinoma is common in male smokers. It is mostly localized outward extension in the early stage and spreads through the bloodstream in the later stage.
  • Adenocarcinoma is the most common type of lung cancer, often after distant metastasis. Clinical symptoms appear, and lung cancer is often the case in non-smokers; large cell carcinoma, which grows slowly, but also spreads through the blood and lymph.
  • Small cell lung cancer is quite sensitive to chemical and radiation therapy, but after treatment, most cases will recur and develop drug resistance within two years. Although non-small cell lung cancer grows slowly, only about four minutes can be treated with early surgery. One, and most of them are not sensitive to chemical drugs and radiation therapy; for the above reasons, lung cancer patients are generally less and better.
  • liver cancer is the top ten cancers. Apart from surgical resection, it is not only treated by chemotherapy or radiation therapy, but the above treatments often cause unbearable pain and side effects, so the prior art is Targeted therapeutic drugs are used for anti-hepatocarcinoma treatment, and therapeutic purposes are aimed at inhibiting the pathway of mutation, proliferation or proliferation involved in the progression of liver cancer cells, inhibiting angiogenesis of liver cancer cells or promoting the death of liver cancer cells or preventing the spread of cancer cells. Since there is no obvious symptom in the early stage of liver cancer, prevention has become more and more important.
  • compositions containing a ferrous amino acid chelate compound for use in the preparation of a medicament for combating cancer which comprises ferrous metal sequestration
  • the composition of the composition has an anticancer effect.
  • the present invention provides a use of a composition comprising a ferrous amino acid chelate compound for the preparation of a medicament for preventing cancer, wherein the medicament comprises a composition effective for anticancer dose comprising a ferrous amino acid chelate compound and A pharmaceutically acceptable carrier.
  • the "composition containing a ferrous amino acid chelate” is a composition containing a ferrous amino acid chelate prepared by mixing inorganic iron with an amino acid; preferably, The inorganic iron includes, but is not limited to, ferrous sulfate, ferrous chloride, and ferrous pyrophosphate; preferably, the amino acid is glycine.
  • the composition containing the ferrous amino acid chelate compound contains 95% by weight to 100% ferrous glycine acid chelate; more preferably, 98% to 99.9% by weight of ferrous glycine chelate.
  • the composition of the ferrous amino acid chelate is obtained by heating ferrous sulfate and glycine at 60 ° C to 90 ° C for 8 hours to 48 hours, wherein the ferrous sulfate The weight ratio to glycine is between 1: 1.2 and 1: 1.5.
  • the ferrous metal amino acid chelate-containing composition comprises at least one ferrous amino acid chelate compound, and the ferrous metal chelate compound has a chelating ratio of ferrous to amino acid of 1:1 to 1 Between: 4; more preferably, the ratio of ferrous and amino acid chelating of the ferrous amino acid chelate is between 1:1.5 and 1:2.5.
  • the composition containing the ferrous amino acid chelate compound comprises a reducing agent which maintains the oxidation state of the ferrous iron of the composition containing the ferrous amino acid chelate compound, and also enhances the ferrous iron content.
  • the composition of the amino acid chelate is in the intestinal absorption rate of the receptor, wherein the reducing agent includes, but is not limited to, ascorbic acid, citric acid, acetic acid, propionic acid. ), butyric acid, lactic acid, 3 ⁇ 4: malic acid, sulfonic acid, and succinic acid.
  • anti-cancer means an effective inhibition or soothing of cancer
  • effective dose means an amount effective to achieve a desired or inhibited cancer result at a dose and for a desired period of time; It means that the growth of lung cancer or liver cancer tumor can be slowed down, stopped, and even killed.
  • the dose for effectively inhibiting or relieving lung cancer or liver cancer tumor can be administered by administering a specific range of ferrous metal-containing chelate The composition of the composition is obtained by measuring the change in tumor volume over a specific time frame.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, clothing, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible.
  • pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof.
  • preferred compositions include isotonic agents, such as sugars, mannitol, sorbitol polyols or sodium chloride.
  • the pharmaceutically acceptable carrier may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers.
  • the effective dose of the composition containing the ferrous amino acid chelate is between 0.2 mg/kg/day (mg/kg/day) and 15 mg/kg/day; more preferably, 0.3 mg/kg/day to 14 mg/kg/day; preferably, 0.4 mg/kg/day to 12 mg/kg/day.
  • the medicaments of the invention may exist in a variety of forms. Such forms include, but are not limited to, liquid, semi-solid, and solid pharmaceutical forms such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, lozenges, pills, powders, liposomes, and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions lozenges
  • pills pills, powders, liposomes, and suppositories.
  • the preferred form depends on the intended mode of administration and therapeutic application;
  • the medicament of the present invention is in the form of an orally or infusible solution, and the preferred mode of administration is enteral mode, such as oral administration.
  • the medicament comprising a composition effective for anti-cancer dose containing a ferrous amino acid chelate is administered orally.
  • the medicament further comprises an excipient to render the medicament suitable for enteral or parenteral dosage forms.
  • the enteral dosage form is an oral dosage form including, but not limited to, solutions, suspensions, conjugates, and capsules.
  • the cancer includes, but is not limited to, melanoma.
  • the cancer includes, but is not limited to, a brain tumor, a low-grade astrocytoma, a high-grade astrocytoma, a pituitary adenoma ( Pituitary adenoma), meningioma, central nervous lymphoma (CNS lymphoma) oligodendroglioma, craniopharyngioma, ependymoma glial cell Brain stem tumor, head and neck tumor, laryngeal cancer, mouth.
  • a brain tumor a low-grade astrocytoma
  • a high-grade astrocytoma a pituitary adenoma
  • Pituitary adenoma pituitary adenoma
  • meningioma oligodendroglioma
  • craniopharyngioma ependymoma glial cell Brain stem tumor, head and neck tumor, laryngeal cancer, mouth.
  • ⁇ Yue-like carcinoma thyroid cancer
  • oral cancer oral cavity tumor
  • thoracic tumor chest wall tumors
  • small cell lung cancer non-small cell lung cancer (NSCLC) > thymoma, mediastinal tumor, male breast cancer (male Breast cancer), abdomen-pelvis tumor, hepatoma, liver adenocarcinoma, gallbladder cancer, biliary tract cancer, pancreatic Cancer), small intestinal tumor, large intestinal tumor, anal cancer, bladder cancer, renal cell carcinoma, cervical cancer (cervix cancer), endometrial cancer, ovarian cancer, uterine sarcoma, and skin cancer.
  • the cancer is liver cancer or lung cancer.
  • the composition containing the ferrous amino acid chelate compound according to the present invention can be passed through the stomach while maintaining a chelated state with the ferrous iron due to the small molecular weight of the amino acid, and is subjected to the composition containing the ferrous amino acid chelate compound by the present invention. Does not affect the body weight change of the receptor; in addition, in the present invention, a composition containing a ferrous amino acid chelate is compared
  • the application of the commercially available amino acid ferrous iron and inorganic iron (such as ferrous sulfate) has the effect of inhibiting or relieving lung cancer or liver cancer tumor, and therefore, the composition of the ferrous metal chelate-containing composition of the present invention may be used. Used to suppress or soothe cancer, especially lung cancer or liver cancer.
  • Fig. 1 is a graph showing changes in lung cancer tumor volume of a lung cancer tumor cell after administration of a composition containing a ferrous amino acid chelate compound in a rat (BALB/c nu/nu mice) for 1 week;
  • Figure 2 is a bar graph of body weight change after administration of a composition containing a ferrous amino acid chelate compound to rats for 6 weeks
  • Figure 3 is a Severe Combined Immunodeficiency Mice (SCID mice) (hereinafter noted as SCID mouse) a curve of fold change in liver cancer tumor volume of a liver cancer tumor cell after administration of a composition containing a ferrous amino acid chelate for 1 week;
  • SCID mice Severe Combined Immunodeficiency Mice
  • Figure 4 is a graph showing the survival rate of SCID mice injected with liver cancer tumor cells within 5 weeks;
  • Fig. 5 shows the rats divided into five groups, wherein the control group is administered with a phosphate solution, and A is a composition containing a ferrous amino acid chelate compound at a dose of 1.2 mg/kg/day, respectively, containing a ferrous amino acid chelate compound. a composition, 12 mg/kg/day of a composition containing a ferrous amino acid chelate; B is an amino acid ferrous (Ferrochel®) at a dose of
  • the tumor volume changes of lung cancer tumor cells were injected into the lung cancer cells after 7 days in each group.
  • Figure 6 shows the rats divided into five groups, wherein the control group is administered with a citrate solution, and A is a composition containing a ferrous amino acid chelate, at a dose of 4 mg/kg/day, respectively, containing ferrous amino acid chelate.
  • A is a composition containing a ferrous amino acid chelate, at a dose of 4 mg/kg/day, respectively, containing ferrous amino acid chelate.
  • B is an amino acid ferrous (Ferrochel®) at a dose of 4 mg/kg/day
  • C ferrous sulfate at a dose of The dose is 4 mg/kg/day.
  • Each group was given a rat
  • a composition containing a ferrous amino acid chelate of the present invention is used against cancer, wherein the composition containing a ferrous amino acid chelate is mixed with its pharmaceutically acceptable carrier as an inhibitor or treatment Cancer drugs.
  • composition containing a ferrous amino acid chelate is mixed with inorganic iron and amino acid and heated A composition containing a ferrous amino acid chelate prepared at one time.
  • the composition containing a ferrous amino acid chelate compound includes a reducing agent; wherein the reducing agent is ascorbic acid, citric acid, acetic acid, propionic acid, butyric acid, lactic acid, hydroxysuccinic acid, Sulfonic acid or succinic acid.
  • the reducing agent is ascorbic acid, citric acid, acetic acid, propionic acid, butyric acid, lactic acid, hydroxysuccinic acid, Sulfonic acid or succinic acid.
  • the amino acid is glycine, thereby forming a combination containing a ferrous glycoside chelate And have been shown to have the effect of inhibiting cancer cell cells.
  • This example is a composition for preparing a ferrous metal chelating composition which is prepared in the following manner.
  • the ferrous sulfate and the glycine are mixed at a weight ratio of 1:1.3 and heated at 60 ° C to 90 ° C for 8 hours to 48 hours to obtain the composition containing the ferrous amino acid chelate, wherein the ferrous iron
  • the ratio of the ferrous iron to the amino acid chelate of the amino acid chelate is between 1:1 and 1:4; and the obtained composition containing the ferrous amino acid chelate is prepared to a concentration of 0.1 ⁇ / ⁇ , ie, per 100 A microliter containing 10 micrograms), 0.3 ⁇ ⁇ / ⁇ 1, 1 ⁇ ⁇ / ⁇ 1 and 3 compositions.
  • the lung cancer cell line ( ⁇ 549) was contained with 10% fetal bovine serum (FBS), 1% penicillin (100 U/mL)-streptomycin (100 g/mL) (penicillin-streptomycin) and 1% glutamine.
  • FBS fetal bovine serum
  • penicillin 100 U/mL
  • penicillin-streptomycin 100 g/mL
  • glutamine 200 mM
  • Dulbecco's Modified Eagle's medium (DMEM) was cultured in a 37 ° C, 5% carbon dioxide incubator until the cells were attached at 7 to 8 minutes. Subculture is carried out.
  • Wipe liver cancer cells (SK Hepl) with Du's modified Inge with 10% fetal bovine serum (FBS), 1% non-essential amino acid (NEAA) and 1% penicillin-streptomycin Dulbecco's Modified Eagle's medium (DMEM) was cultured in a 37 ° C, 5% carbon dioxide incubator and subcultured for about 3 days to 4 days.
  • FBS fetal bovine serum
  • NEAA non-essential amino acid
  • DMEM penicillin-streptomycin Dulbecco's Modified Eagle's medium
  • Preparation Example 1 was prepared at a concentration of 0.1 ⁇ ⁇ / ⁇ 0.3 ⁇ ⁇ / amino acid composition comprising iron chelate ⁇ 1 ⁇ ⁇ / ⁇ 1 respectively at a dose of 0.4 mg / kg / day, 1.2 mg / Feeding rats (B ALB/c nu/nu mice) at kg/day or 4 mg/kg/day [purchased from National Laboratory Animal Center (Taipei, Taiwan), approximately 5 weeks to 6 weeks of age], and sterile Water as a control group, after applying ferrous amino acid chelate or sterile water for 7 days, the above
  • the resulting culture prepared in Example 2 1 10 7 cell / mL of mouse lung cancer cells were injected into hind trees brachial artery near the subcutaneous tissue, after every 7 days vernier valve and foot volume measuring tumor size, and mice were sacrificed after 6 weeks.
  • the formula for calculating the tumor volume is as follows:
  • the tumor volume is (a X b 2 )/2 and the unit is mm cubic (mm 3 ).
  • the lung cancer tumor volume increased with the number of days, but the composition containing the ferrous amino acid chelate at a dose of 1.2 mg/kg/day or 4 mg/kg/day has a better inhibition of lung cancer tumor volume. Effect. Further, as shown in Fig. 2, the composition containing the ferrous amino acid chelate compound at the aforementioned concentration did not inhibit the normal growth of the rat.
  • the 4 mg/kg/day ferrous amino acid chelate was administered to SCID mice (purchased from the Animal Center of Taiwan University Medical College) 5 times a week (about 6 weeks old), and the sterile water was used as a control group.
  • SCID mice purchased from the Animal Center of Taiwan University Medical College
  • 10 7 cells/mL of liver cancer cells (100 ⁇ M) obtained in the above Preparation Example 3 were injected into the subcutaneous tissue near the lower back of SCID mice. Tumor size and volume were measured with a vernier valve rule every 7 days and sacrificed after 4 weeks.
  • the tumor volume of liver cancer increased with the number of weeks, and at week 4, the volume of liver cancer tumors in SCID mice of the control group increased 3.5 times, but the concentration of administration was 4 mg/kg/day.
  • the volume of the liver cancer tumor of the SCID mouse containing the composition of the ferrous amino acid chelate compound is only increased by 1.8 times as much as the original, and accordingly, the composition containing the ferrous amino acid chelate compound described in the present invention has the tumor volume inhibiting the liver cancer. effect.
  • the survival rate of the SCID mice of the control group was 75%, but the administration concentration was 4 mg/
  • the viability of the ferrous/day ferrous metal chelate-containing composition was 100%, thus indicating that administration of a composition containing a ferrous amino acid chelate can increase the survival rate of SCID mice.
  • the rats were divided into 5 groups, and the first group was given phosphate buffered saline.
  • PBS PBS
  • the composition of the fourth group was administered at a dose of 1.2 mg/kg/day of ferrous iron (Ferrochel®) (purchased from Albion, USA), and the fifth group was administered at a dose of 1.2 mg/kg/day of ferrous ferrous ( After 7 days, the 1 ⁇ 10 7 cell/mL lung cancer cells (100 ⁇ 1 ) obtained in the above Preparation Example 2 were injected into the subcutaneous tissue near the hind leg artery ankle, and then traveled every 7 days. The size and volume of the tumor were measured with a standard valve rule, and the mice were sacrificed after 6 weeks.
  • the dose of 12 mg/kg/day or 1.2 mg/kg/day of the composition containing ferrous amino acid chelate (group A) was 5 weeks later.
  • the composition containing the ferrous amino acid chelate compound has an effect of suppressing the tumor volume of the lung cancer as compared with the amino acid ferrous iron (Ferrochel®) (group B), ferrous sulfate, and the control group.
  • the rats were divided into 5 groups, the first group was given buffered physiological saline as the control group, the second group was administered with the dose of 4 mg/kg/day of the composition containing the ferrous amino acid chelate, and the third group was applied.
  • the 10 7 cell/mL liver cancer fine color (100 ⁇ l injection) obtained in the above Preparation Example 2 was injected into the subcutaneous tissue near the lower back of the rat, and then every 7 days. Tumor size and volume were measured with a vernier valve ruler and sacrificed after 5 weeks.
  • a composition containing a ferrous amino acid chelate compound (group A) at a dose of 4 mg/kg/day or 12 mg/kg/day, after 5 weeks, contains a combination of ferrous amino acid chelate Compared with the amino acid ferrous iron (Ferrochel®) (group B), ferrous sulfate (group C) and the control group, the substance has an effect of suppressing the tumor volume of liver cancer.

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Abstract

本发明公开了一种含有亚铁氨基酸螯合物的组合物及其在制备抗癌症的药物中的用途，其中药物包含有效抗癌症剂量的含有亚铁氨基酸螯合物的组合物以及其药学上可接受的载剂。本发明所述的含有亚铁氨基酸螯合物的组合物中，氨基酸可与亚铁维持螯合状态通过胃，且不影响受体的体重变化；由含有亚铁氨基酸螯合物的组合物制备而得的药物具有抑制或治疗癌症的效果。

Description

含有亚铁氨基酸螯合物的组合物在制备抗癌症的药物中的用途 技术领域
本发明涉及含有亚铁氨基酸螯合物的组合物的用途， 还涉及该组合物在制备抗 癌症的药物中的用途。 背景技术
癌症或恶性肿瘤是全世界人口主要死亡原因之一， 其中癌症致死率的排名主要 为肺癌、 胃癌、 肝癌、 结肠直肠癌、 乳腺癌及子宫颈癌， 依据世界卫生组织的统计， 近二十年又以肺癌死亡率增加最快， 其中肺癌依据其细胞特性及临床表现分为小细 月色肺癌 (small cell lung cancer)和非小细月包肺癌 (non-small cell lung carcinoma, NSCLC) 两大类， 其中小细胞肺癌多发生于男性， 且与抽烟息息相关， 占全部肺癌患者总数 的 25%; 且小细胞生长快， 并容易由淋巴或血路扩散到其他器官。 非小细胞癌则占 全部肺癌患者总数的 75%, 常见的包括： 鳞状细胞癌、 腺癌、 大细胞癌。 鳞状细胞 癌又称类表皮样癌， 常见于男性吸烟者， 早期多为局部向外延伸的转移， 后期则通 过血路扩散；腺癌为目前肺癌数量最多的类型，经常在远处转移后才出现临床症状， 且无吸烟者所罹患肺癌常为此类； 大细胞癌， 生长速度较慢， 但亦经由血路及淋巴 扩散。 小细胞肺癌对于化学及放射线治疗相当敏感， 但经治疗緩解后， 大多数病例 在两年内会复发并产生抗药性； 非小细胞肺癌虽生长较緩慢， 但可早期开刀治疗的 病例仅约四分之一， 且对于化学药物及放射线治疗大多不敏感； 由于上述原因， 肺 癌病人愈后普遍不佳。 此外， 至今研究显示， 化疗药物对病人往往是一种伤害， 长 期服用会造成患者免疫力下降、 正常细胞凋亡而使得病人存活率下降， 因此， 寻找 一种对于正常细胞无毒性且能够促进肺癌肿瘤细胞生长或凋亡的药物是目前极需 的课题。
此外， 肝癌是十大癌症前几名， 除了外科切除手术之外， 不外乎以化学治疗或 放射线治疗等方式， 但以上治疗方式往往造成病患难以忍受的痛苦及副作用， 因此 现有技术是以标靶治疗药物用于抗肝癌治疗， 并通过抑制肝癌细胞进展过程中所涉 及的突变、 增殖或扩散的通路、 抑制肝癌细胞血管新生或促进肝癌细胞死亡或防止 癌细胞扩散为治疗目的。 由于肝癌初期并无明显症状， 因此预防上也越来越受重视。
Singh等人 (Life Science, 70 49-56， 2001)揭示当细胞内铁离子浓度高时， 双氢青 蒿素 (dihydroartemisinin)与全运铁蛋白（holotransferrin)结合后， 可将全运铁蛋白及双 氢青蒿素送入细胞， 以达到抑制人类乳癌细胞的功效； Green等人 (Clin Cancer Res 7:3574-3579, 2001)揭示吡哆醛异烟碱酰基类（pyridoxal isonicotinoyl) 的铁螯合剂 311 (2-hydroxy 1 -naphthyladehyde benzoyl hydrazon)通过 ?制核苦酸还原 (ribonucleotide reductase)的 R2亚基 (subunit)以用于抑制乳癌细胞、 膀胱癌细胞、 头 颈癌细胞以及 T淋巴母细胞淋巴瘤生长； 欧洲专利 EP2306187 A1揭示亚铁 (Fe2+)或 三价铁 (Fe3+)的铁化合物可抑制乳癌细胞生长。
然而， Kato等人 (Int. J. Cancer: 80, 693-698, 1999)揭示大肠直肠癌的风险是随着 高脂肪饮食结合较多总铁摄入相关； Simonart等人 (Gynecologic Oncology 85, 95-102, 2002)揭示排铁剂（DFO 及 deferiprone)以时间依赖性 (time-dependent)及剂量依赖性 (dose-dependent)的方式抑制人类乳突病毒相关癌细胞生长， 并可将人类乳突病毒相 关癌细胞停止于细胞周期的 GQ/G1期， 以及促进人类乳突病毒相关癌细胞死亡或凋 亡 (apoptosis)。
综上所述， 现有技术并无法确认铁离子或铁化合物是否具有抑制或治疗癌症的 功效， 然而化学药物用于治疗诸如肺癌或肝癌等癌症往往会产生副作用， 并引起患 者不适而导致放弃治疗； 因此， 寻找可抗癌症、 无副作用且可被人体吸收的药物是 当务之急。 发明内容
鉴于现有技术化学药物的治疗癌症产生副作用的缺点， 故本发明的目的在于提 供一种含有亚铁氨基酸螯合物的组合物在制备抗癌症的药物中的用途， 其中含有亚 铁氨基酸螯合物的组合物具有可抗癌的功效。
为达上述目的， 本发明提供一种含有亚铁氨基酸螯合物的组合物在制备抗癌症 的药物中的用途， 其中药物包含有效抗癌症剂量的含有亚铁氨基酸螯合物的组合物 以及其医药学上可接受的载剂。
依据本发明， "含有亚铁氨基酸螯合物的組合物" 是由无机铁与氨基酸混合所 制得的含有亚铁氨基酸螯合物 (ferrous amino acid chelate)的组合物； 较佳的， 所述的 无机铁包括， 但不限于硫酸亚铁、 氯化亚铁及焦磷酸亚铁； 较佳的， 所述的氨基酸 是甘胺酸。
更佳的， 所述的含有亚铁氨基酸螯合物的组合物是含有重量百分比为 95%至 100%的亚铁甘胺酸螯合物； 又更佳的， 为重量百分比为 98%至 99.9%的亚铁甘胺酸 螯合物。
较佳的， 亚铁氨基酸螯合物的组合物是将硫酸亚铁 (ferrous sulfate)与甘胺酸 (glycine)经 60 °C至 90 °C加热 8小时至 48小时所获得， 其中硫酸亚铁与甘胺酸的重 量比例介于 1 : 1.2至 1 : 1.5之间。 依据本发明， 所述的含有亚铁氨基酸螯合物的 组合物包含至少一种亚铁氨基酸螯合物， 亚铁氨基酸螯合物的亚铁与氨基酸的螯合 比例介于 1 : 1至 1 : 4之间； 更佳的， 亚铁氨基酸螯合物的亚铁与氨基酸的螯合比 例介于 1 : 1.5至 1 : 2.5之间。
较佳的， 所述的含有亚铁氨基酸螯合物的组合物中包括还原剂， 该还原剂可维 持含有亚铁氨基酸螯合物的组合物的亚铁的氧化态， 亦可提升含有亚铁氨基酸螯合 物的组合物于受体的肠道吸收率， 其中还原剂包括， 但不限于抗坏血酸 (ascorbic acid)、 4宁檬酸 (citric acid)、 乙酸 (acetic acid)、 丙酸 (propionic acid)、 丁酸 (butyric acid)、 乳酸 (lactic acid)、 ¾：玻白酸 (malic acid)、 石黄酸 (sulfonic acid)及丁二酸 (succinic acid)。
依据本发明， "抗癌症" 是指有效抑制或舒緩癌症； "有效剂量" 是指在剂量上 及对于所需要的时间段而言对达成所要抑制或舒緩癌症结果有效的量； 依据本发 明， 是指能够使得肺癌或肝癌肿瘤的生长减緩、 停止， 甚致死亡， 其如本发明所例 示者， 有效抑制或舒緩肺癌或肝癌肿瘤的剂量可通过施予特定范围量的含有亚铁氨 基酸螯合物的组合物， 并于特定时间范围内测量肿瘤体积变化而得。
依据本发明， "医药学上可接受的载剂" 包括生理上兼容的任意及所有溶剂、 分散介质、 衣料、 抗菌剂及抗真菌剂、 等张剂及吸收延緩剂及其类似物。 药学上可 接受的载剂的实例包括水、 盐水、 磷酸盐緩沖生理食盐水、 右旋糖、 甘油、 乙醇及 其类似物的一或多种及其组合。 在许多情况中， 较佳的组合物包括等张剂， 例如糖、 甘露醇、 山梨糖醇的多元醇或氯化钠。 药学上可接受的载剂可进一步包含微量辅助 物质， 诸如湿润剂或乳化剂、 防腐剂或緩沖剂。
较佳的， 所述的含有亚铁氨基酸螯合物的组合物的有效剂量是介于 0.2毫克 /公 斤 /天 (mg/kg/day)至 15 mg/kg/day; 更佳的， 介于 0.3 mg/kg/day至 14 mg/kg/day; 较 佳的， 介于 0.4 mg/kg/day至 12 mg/kg/day。
本发明所述的药物可以多种形式存在。 该等形式包括， 但不限于液体、 半固体 及固体药剂形式， 诸如液体溶液 (例如可注射及可输注溶液)、 分散液或悬浮液、 锭 剂、 丸剂、 粉剂、 脂质体及栓剂。 较佳的形式取决于预期的投药模式及治疗应用； 较佳的， 本发明的药物是呈可口服或可输注溶液形式， 且较佳的投药模式为经肠模 式， 诸如口服。 在本发明的实施例中， 包含有效抗癌症剂量的含有亚铁氨基酸螯合 物的组合物的药物是通过口服施予。
较佳的， 所述的药物更包括一赋形剂（excipient), 使药物适用于经肠道的或非经 肠道的剂型。
较佳的， 所述的经肠道的剂型是口服剂型， 其包括， 但不限于溶液、 悬浮液、 键剂及胶嚢。
较佳的， 所述的癌症包括， 但不限于黑色素瘤（melanoma). 肝癌（liver cancer)、 结肠癌 (colon cancer)、 肺癌 (lung cancer)、 胃癌 (gastric cancer)、 食道癌 (esophageal cancer)、 #L癌 (breast cancer)、 前歹1 J腺癌 (prostate cancer)及血癌 (leukemia)。
更佳的， 所述的癌症包括， 但不限于脑部肿瘤 (brain tumor), 低度星状细胞瘤 (low-grade astrocytoma)、高度星状细胞瘤 (high-grade astrocytoma)、垂体腺瘤 (pituitary adenoma)、 脑脊髓膜瘤 (meningioma)、 中枢神经淋巴瘤（CNS lymphoma) 寡树突神 经胶细胞瘤 (oligodendroglioma)、 颅咽管瘤 (craniopharyngioma)、 室管膜瘤 (ependymoma) 胶质细胞胂瘤 (brain stem tumor)、 头颈瘤 (head and neck tumor)、 喉 癌 (laryngeal cancer)、 口。因癌 (oropharyngeal cancer)、 鼻11因癌 (nasopharyngeal tumor)、 唾液腺肿瘤 (salivary gland tumor) 下咽癌 (hypopharyngeal cancer) ^ 曱状腺癌 (thyroid cancer) > 口腔肿瘤（oral cavity tumor)、胸廓肿瘤（chest wall tumors)、小细胞肺癌（small cell lung cancer)、 非小细月包肺癌（non-small cell lung cancer, NSCLC) > 胸腺瘤 (thymoma)、 纵隔肿瘤（mediastinal tumor)、 男性乳癌（male breast cancer)、 腹骨盆 (abdomen-pelvis tumor)、 肝细胞癌 (hepatoma)、 肝腺癌 (liver adenocarcinoma)、 胆嚢 癌 (gallbladder cancer)、 月旦道癌 (biliary tract cancer)、 月夷脏癌 (pancreatic cancer)、 小肠 月中瘤 (small intestinal tumor)、 大肠月中瘤 (large intestinal tumor)、 肚门癌 (anal cancer)、 膀胱癌 (bladder cancer)、 肾细胞癌 (renal cell carcinoma)、 子宫颈癌 (cervix cancer)、 子 宫内膜癌 (endometrial cancer)、 巢癌 (ovarian cancer)、 子宫肉瘤 (uterine sarcoma)及 皮肤癌 (skin cancer)。
较佳的， 所述的癌症是肝癌或肺癌。
本发明所述的含有亚铁氨基酸螯合物的组合物中， 由于氨基酸分子量小， 可与 亚铁维持螯合状态通过胃， 且经本发明证实施予含有亚铁氨基酸螯合物的组合物并 不影响受体的体重变化； 此外， 在本发明施予含有亚铁氨基酸螯合物的组合物相较 于施予市售的氨基酸亚铁及无机铁 (诸如硫酸亚铁)更具有抑制或舒緩肺癌或肝癌肿 瘤的效果， 因此， 本发明所述的含有亚铁氨基酸螯合物的组合物的药物可做为用于 抑制或舒緩癌症， 尤其是肺癌或肝癌。 附图说明
图 1是棵鼠 (BALB/c nu/nu mice)施予含有亚铁氨基酸螯合物的组合物 1周后， 再注射肺癌肿瘤细胞的肺癌肿瘤体积变化曲线图；
图 2是将含有亚铁氨基酸螯合物的组合物施予棵鼠 6周后的体重变化柱状图； 图 3是重症联合免疫缺陷小鼠 (Severe Combined Immunodeficiency Mice; SCID mice) (以下注记为 SCID小鼠)施予含有亚铁氨基酸螯合物的组合物 1周后， 再注射 肝癌肿瘤细胞的肝癌肿瘤体积变化倍数曲线图；
图 4是 SCID小鼠注射肝癌肿瘤细胞 5周内的存活率曲线图；
图 5是将棵鼠分成五个组别， 其中对照组施予磷酸盐溶液、 A为含有亚铁氨基 酸螯合物的组合物， 剂量分别为 1.2 mg/kg/day含有亚铁氨基酸螯合物的组合物、 12 mg/kg/day 含有亚铁氨基酸螯合物的组合物； B 为氨基酸亚铁 (Ferrochel®), 剂量为
1.2 mg/kg/day; C为硫酸亚铁， 剂量为 1.2 mg/kg/day。 以上各组分别施予棵鼠 7天 后， 再注射肺癌肿瘤细胞的肺癌肿瘤体积变化曲线图；
图 6是将棵鼠分成五个组别， 其中对照组施予嶙酸盐溶液、 A为含有亚铁氨基 酸螯合物的组合物， 剂量分别为 4 mg/kg/day含有亚铁氨基酸螯合物的组合物、 为 12 mg/kg/day含有亚铁氨基酸螯合物的组合物； B为氨基酸亚铁 (Ferrochel®), 剂量 为 4 mg/kg/day; C为硫酸亚铁， 剂量为剂量为 4 mg/kg/day。 以上各组分别施予棵鼠
7天后， 再注射肝癌肿瘤细胞的肝癌肿瘤体积变化倍数曲线图。 具体实施方式
以下配合图式及本发明的较佳实施例， 进一步阐述本发明为达成预定发明目的 所采取的技术手段。
本发明的一种含有亚铁氨基酸螯合物的组合物被使用对抗癌症， 其中所述含 有亚铁氨基酸螯合物的组合物是与其医药学上可接受的载剂相互混合而作为抑制 或治疗癌症的药物。
所述的含有亚铁氨基酸螯合物的组合物是由无机铁与氨基酸混合并历经加热 一时间所制得的含有亚铁氨基酸螫合物的组合物。
在本发明的一较佳实施例中， 含有亚铁氨基酸螯合物的组合物包括还原剂； 其中还原剂是坏血酸、 柠檬酸、 乙酸、 丙酸、 丁酸、 乳酸、 羟琥珀酸、 磺酸或丁 二酸。
在本发明的较佳实施例中， 其中无机铁是硫酸亚铁、 氯化亚铁或焦磷酸亚铁， 所述的氨基酸是甘胺酸， 藉以形成含有亚铁甘胺酸螯合物的组合物， 且经证实具 有抑制癌细胞细胞的功效。
制备例 1 制备含有亚铁氨基酸螯合物的组合物
本实施例是用以制备含有亚铁氨基酸螯合物的组合物， 其是以下述方式制备。 首先， 将硫酸亚铁与甘胺酸以重量比 1 : 1.3混合并历经 60 °C至 90°C加热 8小时至 48 小时， 以获得该含有亚铁氨基酸螯合物的组合物， 其中亚铁氨基酸螯合物的亚 铁与氨基酸螯合比例介于 1 : 1 至 1 : 4之间； 再将所获得的含有亚铁氨基酸螯合 物的组合物调制成浓度为 0.1 μξ/μ 即每 100微升含有 10微克） 、 0.3 μδ/μ1、 1 μδ/μ1 及 3 的组合物。
制备例 2 肺癌细胞培养
将肺癌细胞株 (Α549)以含有 10%胎牛血清 (fetal bovine serum, FBS)、 1%青霉素 (100U/mL)-链霉 素（100 g/mL)(penicillin-streptomycin) 以 及 1%麸酰胺酸 (glutamine)(200 mM)的杜氏改良英格尔培养基 (Dulbecco's Modified Eagle's medium, DMEM)培养于 37 °C、 5%二氧化碳的培养箱中， 待细胞贴附 7至 8分满时， 再进 行继代培养。
制备例 3 肝癌细胞培养
将肝癌细胞抹 (SK Hepl)以含有 10%胎牛血清 (fetal bovine serum, FBS)、 1%非 必需氨基酸 (non-essential amino acid, NEAA)以及 1%青霉素-链霉素的杜氏改良英 格尔培养基 (Dulbecco's Modified Eagle's medium, DMEM)培养于 37°C、 5%二氧化碳 的培养箱中， 约 3天至 4天继代培养一次。
实施例 1测量肿瘤细胞的体积
将制备例 1所制得的浓度为 0.1 μβ/μΚ 0.3μβ/μΚ 1 μβ/μ1的含有亚铁氨基酸螯 合物的組合物分别以剂量为 0.4 mg/kg/day、 1.2 mg/kg/day或 4 mg/kg/day施予喂食 棵鼠 (B ALB/c nu/nu mice) [购自于国家实验动物中心（台湾台北），约 5周至 6周龄]， 并以无菌水作为对照组， 施予亚铁氨基酸螯合物或无菌水历经 7 天后， 再将前述 制备例 2培养所得的 1 107 cell/mL的肺癌细胞注射至棵鼠后腿动脉肱附近皮下組 织， 之后每 7天以游标阀尺测量肿瘤大小及体积， 并于 6周后牺牲小鼠。
其中肿瘤体积计算公式如下：
假设最长径为 a， 最短径为 b， 则肿瘤体积大小为 (a X b2)/2 , 单位为毫米立方 (mm3)。
如图 1 所示， 肺癌肿瘤体积随着天数增加， 但施予剂量为 1.2 mg/kg/day或 4 mg/kg/day 的含有亚铁氨基酸螯合物的组合物具有较佳抑制肺癌肿瘤体积的效果。 此外， 如图 2所示， 喂食前述浓度的含有亚铁氨基酸螯合物的组合物并不会抑制棵 鼠正常生长。
将 4 mg/kg/day亚铁氨基酸螯合物以每周施予 5次喂食 SCID小鼠 (购自于台湾 大学医学院动物中心) (约 6周龄)， 并以无菌水作为对照组， 历经 1周后， 将 SCID 小鼠麻醉并施予 0.75 Gy放射线照射， 再将前述制备例 3培养所得的 107 cell/mL的 肝癌细胞 (100 μ ΐ)注射至 SCID小鼠下背部附近皮下组织，之后每 7天以游标阀尺测 量肿瘤大小及体积， 并于 4周后牺牲小鼠。
如图 3所示， 肝癌肿瘤体积随着周数增加， 且于第 4周时， 对照组 SCID小鼠 的肝癌肿瘤的体积已增加为原始 3.5倍， 然而， 施予浓度 4 mg/kg/day的含有亚铁氨 基酸螯合物的组合物的 SCID小鼠的肝癌肿瘤的体积仅增加为原始 1.8倍， 据此， 本案所述的含有亚铁氨基酸螯合物的组合物具有抑制肝癌肿瘤体积的效果。
实施例 2 分析受体存活率
如图 4所示， 施予浓度为 4 mg/kg/day含有亚铁氨基酸螯合物的组合物 4周后， 对照组的 SCID小鼠的存活率为 75%,然而施予浓度 4 mg/kg/day的含有亚铁氨基酸 螯合物的组合物的存活率为 100%， 由此显示， 施予含有亚铁氨基酸螯合物的组合 物可提高 SCID小鼠的存活率。
实施例 3 其他含铁化合物的对照实验
将棵鼠分成 5 个组别， 第一组施予緩沖生理食盐水 (phosphate buffered saline,
PBS)为对照组， 第二组施予剂量为 1.2 mg/kg/day含有亚铁氨基酸螯合物的组合物， 第三組施予剂量为 12 mg/kg/day含有亚铁氨基酸螯合物的组合物， 第四组施予剂量 为 1.2 mg/kg/day氨基酸亚铁 (Ferrochel®) (购于美国 Albion公司）， 第五组施予剂量为 1.2 mg/kg/day石 酸亚铁 (无机铁)历经 7天后， 再将前述制备例 2培养所得的 1X107 cell/mL的肺癌细胞 (100 μ 1)注射至棵鼠后腿动脉肱附近皮下组织， 之后每 7天以游 标阀尺测量肿瘤大小及体积， 并于 6周后牺牲小鼠。
如图 5所示， 虽然肺癌肿瘤体积随天数增加， 但施予剂量分别为 12 mg/kg/day 或 1.2 mg/kg/day含有亚铁氨基酸螯合物的组合物 (A组) 5周后， 含有亚铁氨基酸螯 合物的组合物相较于氨基酸亚铁 (Ferrochel®)(B 组）、 硫酸亚铁及对照组具有较佳抑 制肺癌肿瘤体积的效果。
将棵鼠分成 5个組别， 第一组施予緩沖生理食盐水为对照组， 第二组施予剂量 为 4 mg/kg/day含有亚铁氨基酸螯合物的组合物， 第三组施予剂量为 12 mg/kg/day 含有亚铁氨基酸螯合物的组合物， 第四组施予剂量为 4 mg/kg/day 氨基酸亚铁 (Ferrochel®), 第五组施予剂量为 4 mg/kg/day硫酸亚铁历经 2周后， 再将前述制备 例 2培养所得的 107 cell/mL的肝癌细色 (注射 100 μ 1)注射至棵鼠下背部附近皮下组 织， 之后每 7天以游标阀尺测量肿瘤大小及体积， 并于 5周后牺牲小鼠。
如图 6所示， 施予剂量为 4 mg/kg/day或 12 mg/kg/day含有亚铁氨基酸螯合物 的组合物 (A 组） 5 周后， 含有亚铁氨基酸螯合物的组合物相较于氨基酸亚铁 (Ferrochel®)(B组）、 硫酸亚铁 (C组)及对照组具有较佳抑制肝癌肿瘤体积的效果。
以上所述仅是本发明的较佳实施例而已， 并非对本发明做任何形式上的限制， 虽然本发明已以较佳实施例揭露如上， 然而并非用以限定本发明， 任何熟悉本专业 的技术人员， 在不脱离本发明技术方案的范围内， 当可利用上述揭示的技术内容作 出些许更动或修饰为等同变化的等效实施例， 但凡是未脱离本发明技术方案的内 容， 依据本发明的技术实盾对以上实施例所作的任何简单修改、 等同变化与修饰， 均仍属于本发明技术方案的范围内。

Claims

权 利 要 求
I .一种含有亚铁氨基酸螯合物的组合物在制备抗癌症的药物中的用途， 其中所 述的药物包含有效剂量的含有亚铁氨基酸螯合物的组合物以及其医药学上可接受 的载剂。
2.根据权利要求 1 所述的用途， 其中含有亚铁氨基酸螯合物的组合物中的亚铁 氨基酸螯合物的亚铁与氨基酸的螯合比例是介于 1 : 1至 1 : 4之间。
3.根据权利要求 1 所述的用途， 其中含有亚铁氨基酸螯合物的组合物中的亚铁 氨基酸螯合物的亚铁与氨基酸的螯合比例是介于 1 : 1.5至 1 : 2.5之间。
4.根据权利要求 1 所述的用途， 其中含有亚铁氨基酸螯合物的组合物的有效剂 量介于 0.2 mg/kg/day至 15 mg/kg/day。
5..根据权利要求 1所述的用途， 其中含有亚铁氨基酸螯合物的组合物的有效剂 量是介于 0.4 mg/kg/day至 12 mg/kg/day。
6.根据权利要求 1至 5中任一项所述的用途， 其中含有亚铁氨基酸螯合物的组 合物是由无机铁与氨基酸混合并历经 60 °C至 90°C加热 8小时至 48小时所制得的含 有亚铁氨基酸螯合物的组合物， 其中无机铁与氨基酸的比例是介于 1 : 1.2至 1 : 1.5 之间。
7.根据权利要求 6所述的用途， 其中无机铁是硫酸亚铁、 氯化亚铁或焦磷酸亚 铁； 该氨基酸是甘氨酸。
8.根据权利要求 6所述的用途， 其中含有亚铁氨基酸螯合物的组合物中包括还 原剂， 该还原剂是抗坏血酸 (ascorbic acid)、 柠檬酸 (citric acid)、 乙酸 (acetic acid)、 丙 酸 (propionic acid)、 丁酸 (butyric acid)、 乳酸 (lactic acid)、 ^：玻白酸 (malic acid)、 石黄酸 (sulfonic acid)或丁二酸 (succinic acid)„
9.根据权利要求 1所述的用途， 其中药物是经肠道的或非经肠道的剂型。
10.根据权利要求 9所述的用途，其中该经肠道的剂型是口服剂型，其包括溶液、 悬浮液、 锭剂或胶囊。
I I .根据权利要求 1所述的用途， 其中癌症是黑色素瘤 (melanoma)、 肝癌、 结肠 癌 (colon cancer)、月申癌、 胃癌 (gastric cancer)、 食道癌 (esophageal cancer)、 癌 (breast cancer)、 前歹1 J腺癌 (prostate cancer)或血癌 (leukemia)。
12.根据权利要求 1所述的用途， 其中癌症是脑部肿瘤 (brain tumor), 低度星状 细月包瘤 (low-grade astrocytoma)、 高度星状细月包瘤 (high-grade astrocytoma)、 垂体腺瘤 (pituitary adenoma) > 脑脊髓膜瘤（meningioma)、 中枢神经淋巴瘤（CNS lymphoma), 寡树突神经胶细胞瘤（oligodendroglioma)、 卢贞咽管瘤 (craniopharyngioma)、 室管膜瘤 (ependymoma)、 股质细月包月中瘤 (brain stem tumor)、 头颈瘤 (head and neck tumor)、 喉 癌 (laryngeal cancer)、 口11因癌 (oropharyngeal cancer)、 鼻11因癌 (nasopharyngeal tumor)、 唾液腺月中瘤 (salivary gland tumor)、 下咽癌 (hypopharyngeal cancer)、 曱状腺癌 (thyroid cancer) ^ 口腔肿瘤（oral cavity tumor)、胸廓月中瘤（chest wall tumors)、 小细胞肺癌（small cell lung cancer)、 非小细月包肺癌（non-small cell lung cancer, NSCLC)、 胸腺瘤 (thymoma)、 纵隔肿瘤（mediastinal tumor)、 男性乳癌（male breast cancer)、 腹骨盆 (abdomen-pelvis tumor)、 肝细胞癌 (hepatoma)、 肝腺癌 (liver adenocarcinoma)、 胆嚢 癌 (gallbladder cancer)、 月旦道癌 (biliary tract cancer)、 胰脏癌 (pancreatic cancer)、 小肠 月中瘤 (small intestinal tumor) 大肠月中瘤 (large intestinal tumor) ¾ 肚门癌 (anal cancer)、 膀胱癌 (bladder cancer)、 賢细胞癌 (renal cell carcinoma)、 子宫颈癌 (cervix cancer)、 子 宫内膜癌 (endometrial cancer)、 卵巢癌 (ovarian cancer)、 子宫肉瘤 (uterine sarcoma)或 皮肤癌 (skin cancer)。
13.根据权利要求 1所述的用途， 其中癌症是肝癌或肺癌。
PCT/CN2013/001043 2013-09-05 2013-09-05 含有亚铁氨基酸螯合物的组合物在制备抗癌症的药物中的用途 Ceased WO2015032011A1 (zh)

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