WO2019127295A1 - 含有亚铁氨基酸螯合物的组合物用于制造抑制血管新生的医药品的用途 - Google Patents

含有亚铁氨基酸螯合物的组合物用于制造抑制血管新生的医药品的用途 Download PDF

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WO2019127295A1
WO2019127295A1 PCT/CN2017/119620 CN2017119620W WO2019127295A1 WO 2019127295 A1 WO2019127295 A1 WO 2019127295A1 CN 2017119620 W CN2017119620 W CN 2017119620W WO 2019127295 A1 WO2019127295 A1 WO 2019127295A1
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amino acid
ferrous
composition
cells
use according
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PCT/CN2017/119620
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French (fr)
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林村源
陈木桂
詹勋锦
傅嘉慧
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普惠德生技股份有限公司
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Priority to US16/957,215 priority Critical patent/US20200316113A1/en
Priority to PCT/CN2017/119620 priority patent/WO2019127295A1/zh
Priority to CN201780098096.1A priority patent/CN111565728A/zh
Publication of WO2019127295A1 publication Critical patent/WO2019127295A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the present invention relates to the use of a composition comprising a ferrous amino acid chelate, in particular for the manufacture of a medicament for inhibiting angiogenesis.
  • angiogenesis is generally the process of slow migration, growth and differentiation of cells occurring in the inner vessel wall, and the method of inducing angiogenesis is to release different chemicals, such as vascular endothelial growth factor, through a cell population outside the blood vessel. (vascular endothelial growth factor, VEGF) to achieve.
  • vascular endothelial growth factor vascular endothelial growth factor, VEGF
  • Angiogenesis is an important mechanism of action in the human body. When blood vessels are needed for hypoxia in tissues, it will increase the secretion of vascular endothelial growth factor to create a new blood vessel growth opportunity. Among them, tumor metastasis, diabetic retinopathy, high myopia retinopathy or aging retinopathy can cause angiogenesis.
  • (bevacizumab) is a recombinant humanized monoclonal antibody that selectively binds to vascular endothelial growth factor and binds to receptors Flt-1 and KDR located on the surface of endothelial cells by neutralizing vascular endothelial growth factor. Biological activity reduces tumor angiogenesis to achieve an effect of inhibiting tumor growth.
  • composition comprising a ferrous amino acid chelate compound for use in the manufacture of a medicament for inhibiting angiogenesis, wherein the composition containing a ferrous amino acid chelate has The effect of inhibiting angiogenesis.
  • the present invention provides a use of a composition comprising a ferrous amino acid chelate compound for the manufacture of a medicament for inhibiting angiogenesis, wherein the pharmaceutical composition comprises an effective amount of a composition of a ferrous amino acid chelate compound. And a pharmaceutically acceptable carrier thereof.
  • the "compressed composition containing a ferrous amino acid chelate” is a composition containing a ferrous amino acid chelate prepared by mixing inorganic iron and an amino acid.
  • the ferrous metal chelate compound in the composition containing the ferrous amino acid chelate compound has a chelating ratio of ferrous iron to amino acid of between 1:1 and 1:4.
  • the ferrous metal chelate compound of the ferrous metal chelate-containing composition has a chelating ratio of ferrous iron to amino acid of between 1:1.5 and 1:2.5.
  • the effective dose of the ferrous metal chelate-containing composition is between 0.2 mg (kg/kg/day) and 15 mg/kg/day per day in mice; preferably, 0.3 mg/kg/day to 14 mg/kg/day; more preferably, 0.4 mg/kg/day to 12 mg/kg/day.
  • the effective dose of the composition containing the ferrous amino acid chelate is from 0.016 mg/kg/day to 1.22 mg/kg/day in humans; preferably, from 0.024 mg/kg/day to 1.14 mg/kg/day; more preferably, between 0.032 mg/kg/day and 0.98 mg/kg/day.
  • the above dosages are calculated according to the Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers.
  • the composition containing a ferrous amino acid chelate is a composition containing a ferrous amino acid chelate compound prepared by mixing inorganic iron with an amino acid and heating at 60 ° C to 90 ° C for 8 hours to 48 hours.
  • the weight ratio of inorganic iron to amino acid is between 1:1.2 and 1:1.5.
  • the inorganic iron is ferrous sulfate, ferrous chloride, ferrous pyrophosphate or a combination thereof; the amino acid is glycine.
  • the composition containing the ferrous amino acid chelate compound is 95% to 100% by weight of a ferrous glycine acid chelate; still more preferably, the weight percentage is 98% to 99.9%.
  • the ferrous glycine acid chelate is 95% to 100% by weight of a ferrous glycine acid chelate; still more preferably, the weight percentage is 98% to 99.9%.
  • the "effective dose” as used in the present invention means an amount effective to achieve the desired inhibition of angiogenesis in terms of dosage and for a desired period of time; according to the present invention, it is meant to The composition of the iron amino acid chelate compound can inhibit the migration and invasion of human umbilical vein endothelial cells (HUVEC), or the HUVEC cells cannot form a cell column; according to the present invention, the blood vessel can be inhibited.
  • the effective amount of newborn is an amount effective to achieve the desired inhibition of angiogenesis in terms of dosage and for a desired period of time; according to the present invention, it is meant to The composition of the iron amino acid chelate compound can inhibit the migration and invasion of human umbilical vein endothelial cells (HUVEC), or the HUVEC cells cannot form a cell column; according to the present invention, the blood vessel can be inhibited.
  • the effective amount of newborn is an amount effective to achieve the desired inhibition of angiogenesis in terms of dosage and for a desired period of time; according to the present invention, it
  • the "pharmaceutically acceptable carrier” as used in the present invention includes, but is not limited to, a reducing agent, a solvent, an emulsifier, a suspending agent, a decomposer. , binding agent, excipient, stabilizing agent, chelating agent, diluent, gelling agent, preservative, lubrication Lubricant, surfactant, and other carriers similar or suitable for use in the present invention.
  • the reducing agent comprises, but is not limited to, ascorbic acid, citric acid, acetic acid, propionic acid, butyric acid, lactic acid. , malic acid, sulfonic acid, succinic acid or a combination thereof.
  • the "pharmaceutical” of the present invention may exist in various forms including, but not limited to, liquid, semi-solid, and solid pharmaceutical forms such as solutions, emulsions, suspensions, powders ( Powder), tablet, pill, lozenge, troche, chewing gum, slurry, liposomes, suppositories, and the like
  • the dosage form of the invention may exist in various forms including, but not limited to, liquid, semi-solid, and solid pharmaceutical forms such as solutions, emulsions, suspensions, powders ( Powder), tablet, pill, lozenge, troche, chewing gum, slurry, liposomes, suppositories, and the like.
  • the pharmaceutical product is an enteral or parenteral dosage form.
  • the enteral dosage form is an oral dosage form
  • the oral dosage form is a solution, an emulsion, a suspension, a powder, a lozenge, a pill, an ingot, a tablet, a chewing gum or a capsule.
  • the angiogenesis includes, but is not limited to, related to cancer or eye diseases.
  • the cancer includes, but is not limited to, melanoma, liver cancer, colon cancer, lung cancer, gastric cancer, esophageal cancer. , brain tumor, head and neck cancer, esophageal cancer, chest wall tumors, thymoma, mediastinal tumor, breast cancer ), abdomen-pelvis tumor, 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 Uterine sarcoma), prostate cancer, leukemia or skin cancer.
  • the liver cancer includes, but is not limited to, hepatoma or liver adenocarcinoma.
  • the lung cancer includes, but is not limited to, small cell lung cancer or non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the brain tumors include, but are not limited to, low-grade astrocytoma, high-grade astrocytoma, pituitary adenoma, and cerebrospinal Meningioma, central nervous lymphoma (CNS lymphoma), oligodendroglioma, craniopharyngioma, ependymoma, or brain stem tumor ).
  • the head and neck cancer includes, but is not limited to, laryngeal cancer, oropharyngeal cancer, nasopharyngeal tumor, salivary gland tumor, hypopharyngeal carcinoma. Cancer), thyroid cancer or oral cavity tumor.
  • the ocular diseases include, but are not limited to, diabetic retinopathy, diabetic macular edema, age-related macular degeneration, young macular degeneration, corneal angiogenesis, choroidal neovascularization, retinopathy of prematurity, Retinitis pigmentosa, trachoma, glaucoma, dry eye, neurological eye disease, retinal artery occlusion, uveitis, choroiditis, central serous chorioretinopathy, central exudative chorioretinopathy, polypoid choroid Vascular lesions or post-laser complications.
  • the present invention provides a use of a composition comprising a ferrous amino acid chelate compound for the manufacture of a medicament for treating an angiogenesis-related disease, wherein the pharmaceutical composition comprises an effective amount of a composition of a ferrous amino acid chelate compound and a pharmaceutically acceptable composition thereof Accepted carrier.
  • the angiogenesis-related diseases include, but are not limited to, cancer or eye diseases.
  • an advantage of the present invention is that the composition containing the ferrous amino acid chelate of the present invention can effectively prevent the effects of migration, cell invasion and column formation induced by HUVEC cancer cells, thereby effectively inhibiting the effect of angiogenesis.
  • the A1 composition can also prevent HUVEC cells from being subjected to VEGF-induced migration, cell invasion and column formation, thereby effectively inhibiting angiogenesis.
  • Figure 1 is a line graph of the OD565 value of the human umbilical vein endothelial cells (HUVEC) administered to the human umbilical vein endothelial cells (HUVEC) at 50 ⁇ g/mL, 100 ⁇ g/mL, and the control group according to the present invention.
  • HEVEC human umbilical vein endothelial cells
  • FIG. 2 is a histogram of the control group at each time point after the administration of the A1 composition of 50 ⁇ g/mL and 100 ⁇ g/mL of the present invention and the control group to the HUVEC to detect the OD 565 value by the MTT test.
  • Fig. 3 is a photograph showing the formation of a column after administration of HUVC cells in a 50 ⁇ g/mL, 100 ⁇ g/mL A1 composition of the present invention and a control group.
  • Fig. 4 is a staining diagram of cell creep induced by conditioned medium after administration of HU1 cells in 10 ⁇ g/mL, 25 ⁇ g/mL, 50 ⁇ g/mL, 100 ⁇ g/mL of the A1 composition, the positive control group and the control group.
  • 5 is a reference group of cells in which the cells of the A1 composition of 10 ⁇ g/mL, 25 ⁇ g/mL, 50 ⁇ g/mL, and 100 ⁇ g/mL of the present invention are administered to the conditioned medium after administration of the HUVEC cells to the control group. Histogram.
  • Fig. 6 is a staining diagram of cell invasion induced by conditioned medium after administration of A1 composition of 10 ⁇ g/mL, 25 ⁇ g/mL, 50 ⁇ g/mL, 100 ⁇ g/mL of the present invention and a control group to HUVEC cells.
  • Fig. 7 is a bar graph showing the number of cells in the conditioned medium-induced cell invasion after administration of HUVEC cells to the A1 composition of 25 ⁇ g/mL, 50 ⁇ g/mL, and 100 ⁇ g/mL of the present invention.
  • Fig. 8 is a photograph showing the formation of a cell column induced by a conditioned medium after administration of a 50 ⁇ g/mL, 100 ⁇ g/mL A1 composition and a control group to HUVEC cells of the present invention.
  • Figure 9 is a line graph of 1 ng/mL, 5 ng/mL, 10 ng/mL, 20 ng/mL VEGF and control group administered to HUVEC to detect OD 565 values by MTT assay.
  • Fig. 10 is a columnar view showing the cell number of VEGF induced by VEGF in the A1 composition of 50 ⁇ g/mL, 100 ⁇ g/mL, 250 ⁇ g/mL, and 500 ⁇ g/mL of the present invention and the control group.
  • This example is a composition for preparing a ferrous metal chelate containing compound which is prepared in the following manner.
  • ferrous sulfate and glycine purity of 98% or more
  • ferrous metal chelate compound has a ferrous and amino acid sequestration ratio of between 1:1 and 1:4, and the composition is referred to as the A1 composition.
  • the conditioned medium for collecting breast cancer cells (MDA-MB-231): (1) planting 3 ⁇ 10 5 cells into a six-well cell culture dish, and allowing the cells to stand until the next day; (2) utilizing The cells were washed once with phosphate buffered saline (PBS), and the serum-free Roswell Park Memorial Institute-1640 (RPMI-1640) was used as the medium and placed in a 37 ° C incubator for 48 hours. (3) The culture medium was collected, centrifuged at low speed for five minutes, and the supernatant was collected as a conditioned medium.
  • PBS phosphate buffered saline
  • RPMI-1640 Roswell Park Memorial Institute-1640
  • Experimental cells are human umbilical vein endothelial cells (HUVEC), and the cells per well Ke 2 ⁇ 10 4 cells were seeded in 24-well plates.
  • the experimental group was a control group (no A1 composition added), 50 ⁇ g/mL A1 composition (taken from Preparation Example 1), and 100 ⁇ g/mL A1 composition (taken from Preparation Example 1), and placed for 0 hours. After 24 hours, 48 hours, and 72 hours, the OD 565 value was measured by the MTT assay to observe the effect of the A1 composition on cell growth.
  • Control group serum-free M199 medium
  • a ring-like structure forming a monolayer was observed to be an angiogenic state; however, cells in the 50 ⁇ g/mL or 100 ⁇ g/mL A1 group were aggregated. And the ring structure of the single cell layer could not be formed. Therefore, the A1 composition helps to inhibit column formation of HUVEC cells.
  • Example 3 Effect of A1 composition on cell migration induced by conditioned medium
  • HUVEC cells were collected and washed once with PBS, and the cells were suspended in 1 mL of M199 medium containing 1% fetal bovine serum (FBS) and placed in a 37 ° C incubator. The cells were starved for two hours; (2) 300 ⁇ L of HUVEC cell solution containing 1 ⁇ 10 5 cells was seeded into the upper chamber, and 1 mL of medium containing different doses of A1 was added as follows:
  • a) positive control group 1% FBS M199; then the upper chamber was placed in a 24-well cell culture dish containing 600 ⁇ L of 10% FBS in M199;
  • Control group 1% FBS M199 medium; then the upper chamber was placed in a 24-well cell culture dish containing 600 ⁇ L of conditioned medium (taken from Preparation 2);
  • Group A1 M199 culture medium containing 1 ⁇ F of 100 ⁇ g/mL A1 composition; then the upper chamber was placed in a 24-well cell culture dish containing 600 ⁇ L of conditioned medium (taken from Preparation 2) in;
  • the concentration of the A1 composition increases, the cells after the crawling decrease, especially the 50 ⁇ g/mL and the 100 ⁇ g/mL A1 group compared with the control.
  • the group was reduced by about 60%. Therefore, the A1 composition can inhibit the creep of HUVEC cells, so that HUVEC cells are not crawled by the influence of the conditioned medium.
  • Invasion assay (1) The cell invasion chamber was placed at room temperature; (2) HUVEC cells were collected, washed once with PBS, and the cells were suspended in 1 mL of M199medium containing 1% FBS. The cells were starved for two hours in a 37 ° C incubator; (3) 500 ⁇ L of serum-free medium was added to the cell invasion chamber, and placed in a 37 ° C incubator for two hours to reconstitute the matrigel in the cell invasion chamber. (4) 300 ⁇ L of cell fluid containing 5 ⁇ 10 4 cells was seeded into the cell invasion chamber, and the A1 medium containing different doses was added as follows:
  • Control group M199 medium with 1% FBS;
  • the concentration of the A1 composition increases, the invading cells decrease, especially the 100 ⁇ g/mL A1 group is reduced by about 70% compared with the control group. . Therefore, the A1 composition can inhibit the invasion of HUVEC cells, so that HUVEC cells are not affected by the conditioned medium.
  • Example 5 Effect of A1 composition on cell column formation induced by conditioned medium
  • Tube formation assay (1) The matrigel was placed at 4 ° C for one night; (2) HUVEC cells were collected, washed once with PBS, and the cells were suspended in M199 medium containing 0.5% FBS. The cells were starved for two hours in a 37 ° C incubator; (3) 96-well cell culture plates were placed on ice, 60 ⁇ L of fully melted Matrigel was added, and then placed in a 37 ° C incubator for more than one hour; (4) Take the hungry HUVEC cells at 2 ⁇ 10 4 per ml, then centrifuge at low speed for 5 minutes to remove the medium; (5) uniformly centrifuge the cells after centrifugation at 500 ⁇ L:
  • control group conditioned medium
  • the control group can clearly observe that the ring structure forming the monolayer is angiogenic; however, the cells in the 50 ⁇ g/mL or 100 ⁇ g/mL A1 group are still dispersed. status.
  • the A1 composition helps to inhibit the formation of column cells induced by cancer cells in HUVEC cells.
  • the A1 composition has the effect of preventing HUVEC cells from undergoing cancer-induced migration, cell invasion and column formation, thereby effectively inhibiting angiogenesis.
  • VEGF vascular endothelial growth factor
  • R&D systems Recombinant human vascular endothelial growth factor
  • the experimental cells were HUVEC, and the cells were seeded in a 24-well plate at 2 x 10 4 cells per well.
  • the experimental group was control group (no VEGF added), 1 ng/mL VEGF, 5 ng/mL VEGF, 10 ng/mL VEGF, and 20 ng/mL VEGF triple repeat, after 0 hours, 24 hours, 48 hours, and 72 hours.
  • the OD 565 value was detected by the MTT assay to observe the effect of the A1 composition on cell growth.
  • the control group is used as a scale reference. Since VEGF has the effect of promoting cell growth and proliferation, the number of cells in the high concentration of 10 ng/mL VEGF and 20 ng/mL VEGF group is increased. There was no significant effect on the growth of 1ng/mL VEGF and 5ng/mL VEGF group in the concentration group.
  • HUVEC cells were collected, washed once with PBS, and the cells were suspended in 1 mL of M199 medium containing 1% FBS, placed in a 37 ° C incubator to starve the cells for two hours; (2) 300 ⁇ L containing 1 ⁇ 10 5 cells of HUVEC cell solution were seeded into the upper chamber, and 1 mL of medium containing different doses of A1 was added as follows:
  • Control group M199 medium with 1% FBS;
  • the concentration of the A1 composition increases, the cells after the crawling decrease, especially the 250 ⁇ g/mL and the 500 ⁇ g/mL A1 group are reduced compared with the control group. More than 80%. Therefore, the A1 composition can inhibit the creep of HUVEC cells, so that HUVEC cells are not crawled by VEGF induction.
  • the A1 composition has the effect of preventing HUVEC cells from undergoing VEGF-induced migration, cell invasion and column formation, thereby effectively inhibiting angiogenesis.

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Abstract

一种含有亚铁氨基酸螯合物的组合物用于制造抑制血管新生的医药品的用途，其中医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及其药学上可接受的载剂。其中氨基酸可为甘氨酸，血管新生可与癌症或眼部疾病相关。

Description

含有亚铁氨基酸螯合物的组合物用于制造抑制血管新生的医药品的用途 技术领域
本发明涉及一种含有亚铁氨基酸螯合物的组合物的用途，特别是用于制造抑制血管新生的医药品的用途。
背景技术
在人体内，血管新生一般是发生在内部血管壁中的细胞进行缓慢迁移、生长和分化的过程，而诱发血管新生的方法是经由血管外部的细胞群通过释放不同化学物质，例如血管内皮生长因子(vascular endothelial growth factor，VEGF)来达成。
血管新生是人体重要的作用机制，当组织中因缺氧而需要血管时，将促使血管内皮生长因子分泌量增加，以造就新血管的生长机会。其中，当肿瘤转移、糖尿病视网膜病变、高度近视的视网膜病变或老化型视网膜病变都会造成血管新生。现有技术中，
Figure PCTCN2017119620-appb-000001
(bevacizumab)是一种重组的人化单株抗体，可选择性地结合至血管内皮生长因子，并与位于内皮细胞表面上的受体Flt-1及KDR结合，通过中和血管内皮生长因子的生物活性而降低肿瘤的血管形成，以达成抑制肿瘤生长的效果。
然而，蛋白质疗法中，由于分子量与电荷的缘故，口服、静脉注射、动脉注射、肌肉注射都无法有效将蛋白质投递到需要的部位，除了蛋白质在传递途中可能遭清除代谢外，也可能会传递至不需要的组织而造成浪费。
有鉴于此，如何发展出易于递送且可抑制血管新生的药物，现有技术确实有待改善的必要。
发明内容
为了克服现有技术的缺点，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用于制造抑制血管新生的医药品的用途，其中含有亚铁氨基酸螯合物的组合物具有抑制血管新生的功效。
为达到上述的发明目的，本发明提供一种含有亚铁氨基酸螯合物的组合物用于制造抑制血管新生的医药品的用途，其中医药品含有有效剂量的亚铁氨基 酸螯合物的组合物以及其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组合物」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。
优选的，所述的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介于1：1至1：4之间。
优选的，所述的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介于1：1.5至1：2.5之间。
优选的，所述的含有亚铁氨基酸螯合物的组合物的有效剂量于小鼠是介于每日每公斤0.2毫克(mg/kg/day)至15mg/kg/day；优选的，介于0.3mg/kg/day至14mg/kg/day；更优选的，介于0.4mg/kg/day至12mg/kg/day。
优选的，所述的含有亚铁氨基酸螯合物的组合物的有效剂量于人是介于0.016mg/kg/day至1.22mg/kg/day；优选的，介于0.024mg/kg/day至1.14mg/kg/day；更优选的，介于0.032mg/kg/day至0.98mg/kg/day。以上剂量是根据2005年美国食品药物管理局所公告的实验初期估算方法(Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers)计算而得。
优选的，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60℃至90℃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重量比例为介于1：1.2至1：1.5之间。
更优选的，所述的无机铁为硫酸亚铁、氯化亚铁、焦磷酸亚铁或其组合；该氨基酸为甘胺酸。
更优选的，所述的含有亚铁氨基酸螯合物的组合物为含有重量百分比为95％至100％的亚铁甘胺酸螯合物；又更优选的，重量百分比为98％至99.9％的亚铁甘胺酸螯合物。
本发明所述的「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血管新生的有效的量；依据本发明，是指透过施予特定范围量的含有亚铁氨基酸螯合物的组合物，能够使得抑制人类脐带静脉内皮细胞(human umbilical vein endothelial cell，HUVEC)迁移、侵袭减少，或是HUVEC细胞无法形成细胞管柱；依据本发明，另指能抑制血管新生的有效的量。
本发明所述的「医药学上可接受的载剂」包含，但不限于还原剂(reducing agent)、溶剂(solvent)、乳化剂(emulsifier)、悬浮剂(suspending agent)、分解剂 (decomposer)、黏结剂(binding agent)、赋形剂(excipient)、安定剂(stabilizing agent)、螯合剂(chelating agent)、稀释剂(diluent)、胶凝剂(gelling agent)、防腐剂(preservative)、润滑剂(lubricant)、表面活性剂(surfactant)，及其他类似或适用本发明的载剂。
优选的，所述还原剂包含，但不限抗坏血酸(ascorbic acid)、柠檬酸(citric acid)、乙酸(acetic acid)、丙酸(propionic acid)、丁酸(butyric acid)、乳酸(lactic acid)、羟琥珀酸(malic acid)、磺酸(sulfonic acid)、丁二酸(succinic acid)或其组合。
本发明所述的「医药品」可以多种形式存在，这些形式包含，但不限于液体、半固体及固体药剂形式，诸如溶液(solution)、乳剂(emulsion)、悬浮液(suspension)、粉末(powder)、锭剂(tablet)、丸剂(pill)、口含锭(lozenge)、片剂(troche)、口嚼胶(chewing gum)、胶囊(slurry)、脂质体、栓剂以及其他类似或适用本发明的剂型。
优选的，所述的医药品为经肠道的或非经肠道的剂型。
更优选的，所述的该经肠道的剂型为口服剂型，其口服剂型为溶液、乳剂、悬浮液、粉末、锭剂、丸剂、口含锭、片剂、口嚼胶或胶囊。
优选的，所述的该血管新生包括，但不限于与以下相关：癌症或眼部疾病。
更优选的，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)、脑部肿瘤(brain tumor)、头颈癌(head and neck cancer)、食道癌(esophageal cancer)、胸廓肿瘤(chest wall tumors)、胸腺瘤(thymoma)、纵隔肿瘤(mediastinal tumor)、乳癌(breast cancer)、腹骨盆(abdomen-pelvis tumor)、胆囊癌(gallbladder cancer)、胆道癌(biliary tract cancer)、胰脏癌(pancreatic cancer)、小肠肿瘤(small intestinal tumor)、大肠肿瘤(large intestinal tumor)、肛门癌(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)、卵巢癌(ovarian cancer)、子宫肉瘤(uterine sarcoma)、前列腺癌(prostate cancer)、血癌(leukemia)或皮肤癌(skin cancer)。
更优选的，所述的肝癌包括，但不限于肝细胞癌(hepatoma)或肝腺癌(liver adenocarcinoma)。
更优选的，所述的肺癌包括，但不限于小细胞肺癌(small cell lung cancer)或非小细胞肺癌(non-small cell lung cancer,NSCLC)。
更优选的，所述的脑部肿瘤包括，但不限于低度星状细胞瘤(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)或胶质细胞肿瘤(brain stem tumor)。
更优选的，所述的头颈癌包括，但不限于喉癌(laryngeal cancer)、口咽癌(oropharyngeal cancer)、鼻咽癌(nasopharyngeal tumor)、唾液腺肿瘤(salivary gland tumor)、下咽癌(hypopharyngeal cancer)、甲状腺癌(thyroid cancer)或口腔肿瘤(oral cavity tumor)。
更优选的，所述的眼部疾病包括，但不限于糖尿病性视网膜病、糖尿病性黄斑水肿、老年性黄斑部病变、青年性黄斑部病变、角膜血管新生、脉络膜血管新生、早产儿视网膜病变、色素性视网膜炎、砂眼、青光眼、干眼症、神经眼部疾病、视网膜动脉阻塞、眼色素层炎、脉络膜炎、中心性浆液性脉络膜视网膜病变、中心性渗出性脉络膜视网膜病变、息肉状脉络膜血管病变或激光后并发症。
本发明提供一种含有亚铁氨基酸螯合物的组合物用于制造治疗血管新生相关疾病的医药品的用途，其中医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及其药学上可接受的载剂。
优选的，所述的血管新生相关疾病包括，但不限于癌症或眼部疾病。
本发明的优点在于本创作的含有亚铁氨基酸螯合物的组合物可有效防止HUVEC细胞癌细胞诱导的迁移、细胞侵袭与管柱形成的功效，进而能有效抑制血管生成的效果。此外，A1组合物亦能防止HUVEC细胞受到VEGF诱导的迁移、细胞侵袭与管柱形成的功效，进而能有效抑制血管生成的效果。
附图说明
图1为本发明50μg/mL、100μg/mL的A1组合物与控制组施予人类脐带静脉内皮细胞(human umbilical vein endothelial cell，HUVEC)以MTT试验侦测OD565数值的折线图。
图2为本发明50μg/mL、100μg/mL的A1组合物与控制组施予HUVEC以MTT试验侦测OD 565数值后，以各时间点的控制组做为基准的柱状图。
图3为本发明50μg/mL、100μg/mL的A1组合物与对照组施予HUVEC细胞后的管柱形成情形的照片。
图4为本发明10μg/mL、25μg/mL、50μg/mL、100μg/mL的A1组合物、正对照组与对照组施予HUVEC细胞后以条件培养基诱导的细胞爬行的染色图。
图5为本发明10μg/mL、25μg/mL、50μg/mL、100μg/mL的A1组合物与对照组施予HUVEC细胞后以条件培养基诱导的细胞爬行的以对照组做为基准细胞数的柱状图。
图6为本发明10μg/mL、25μg/mL、50μg/mL、100μg/mL的A1组合物与对照组施予HUVEC细胞后以条件培养基诱导的细胞侵袭的染色图。
图7为本发明25μg/mL、50μg/mL、100μg/mL的A1组合物与对照组施予HUVEC细胞后以条件培养基诱导的细胞侵袭的以对照组做为基准细胞数的柱状图。
图8为本发明50μg/mL、100μg/mL的A1组合物与对照组施予HUVEC细胞后以条件培养基诱导的细胞管柱形成情形的照片。
图9为1ng/mL、5ng/mL、10ng/mL、20ng/mL VEGF与控制组施予HUVEC以MTT试验侦测OD 565数值的折线图。
图10为本发明50μg/mL、100μg/mL、250μg/mL、500μg/mL的A1组合物与对照组施予HUVEC细胞后，以VEGF诱导细胞爬行，并以对照组做为基准细胞数的柱状图。
具体实施方式
以下配合图式及本发明的优选实施例，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。
制备例1、含有亚铁氨基酸螯合物的组合物的制备
本实施例是用以制备含有亚铁氨基酸螯合物的组合物，其以下述方式制备。首先，将硫酸亚铁与甘胺酸(纯度98％以上)以重量比1：1.3混合并历经60℃至90℃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为介于1：1至1：4之间，并以A1组合物代称该组合物。
制备例2、条件培养基(conditioned medium)的收集
收集乳癌细胞(MDA-MB-231)的条件培养基(conditioned medium)：(1)种植3×10 5颗细胞至六孔细胞培养盘里，细胞种完后静置至隔日；(2)利用磷酸盐缓冲 溶液(phosphate buffered saline,PBS)清洗细胞一次，以无血清的洛斯维帕克纪念研究所-1640(Roswell park memorial institute,RPMI-1640)做为培养基，放置37℃培养箱培养48小时；(3)收集培养后的培养基，低速离心五分钟，收集上清液即为条件培养基。
实施例1、A1组合物对于细胞生长的影响
实验细胞为人类脐带静脉内皮细胞(HUVEC)，并将细胞以每孔2×10 4颗细胞种植于24孔盘中。其中，实验组分别为控制组(未添加A1组合物)、50μg/mL A1组合物(取自制备例1)、及100μg/mL A1组合物(取自制备例1)三重复，放置0小时、24小时、48小时及72小时后，以MTT试验侦测OD 565数值，以观察A1组合物对细胞生长情形的影响。
请参阅图1及图2所示，以控制组做为比例基准，无论是施予50μg/mL或100μg/mL A1组合物于0小时、24小时、48小时及72小时，对于HUVEC细胞生长均无显著影响。
实施例2、A1组合物对于细胞管柱形成的影响
管柱形成试验：(1)将基质胶放入4℃融解一个晚上；(2)收集HUVEC细胞，用PBS清洗一次后，使细胞悬浮在含0.5％FBS的M199培养基，并置入37℃培养箱使细胞饥饿两小时；(3)将96孔细胞培养盘置于冰上，加入60μL已完全融解的基质胶，接着放入37℃培养箱使其凝固一个小时以上；(4)取饥饿过的HUVEC细胞为每毫升2×10 5颗，接着低速离心5分钟，去除培养基；(5)将离心后的细胞均匀悬浮于500μL的不同剂量的A1的培养基如下：
a)对照组：无血清M199培养基；
b)50μg/mL A1组：含有50μg/mL A1组合物的无血清M199培养基；
c)100μg/mL A1组：含有100μg/mL A1组合物的无血清M199培养基；
以上各组分别取100μL到分别覆盖有基质胶(matrigel-coated)的96孔细胞培养盘中，每个条件三重复；(6)置于37℃培养箱，观察4小时。
请参阅图3所示，对照组可明显观察到有形成单细胞层的环状结构为血管新生的态样；然而，无论于50μg/mL或100μg/mL A1组别中的细胞均呈现聚集状态、且未能形成单细胞层的环状结构。因此，A1组合物有助于抑制HUVEC细胞的管柱形成。
实施例3、条件培养基诱导下A1组合物对于细胞迁移的影响
细胞迁移分析(migration assay)：(1)收集HUVEC细胞，用PBS清洗一次后，使细胞悬浮在1mL含1％胎牛血清(fetal bovine serum,FBS)的M199培养基，置入37℃培养箱里使细胞饥饿两小时；(2)取300μL含有1×10 5颗细胞的HUVEC细胞液种入上层腔室(chamber)中，并添加1mL配置含有不同剂量的A1的培养基如下：
a)正对照组：1％FBS的M199；接着将上层腔室放入含600μL 10％FBS的M199的24孔细胞培养盘中；
b)对照组：1％FBS的M199培养基；接着将上层腔室放入含600μL条件培养基(取自制备例2)的24孔细胞培养盘中；
c)10μg/mL A1组：含有10μg/mL A1组合物的1％FBS的M199培养基；接着将上层腔室放入含600μL条件培养基(取自制备例2)的24孔细胞培养盘中；
d)25μg/mL A1组：含有25μg/mL A1组合物的1％FBS的M199培培养基；接着将上层腔室放入含600μL条件培养基(取自制备例2)的24孔细胞培养盘中；
e)50μg/mL A1组：含有50μg/mL A1组合物的1％FBS的M199培培养基；接着将上层腔室放入含600μL条件培养基(取自制备例2)的24孔细胞培养盘中；
f)100μg/mL A1组：含有100μg/mL A1组合物的1％FBS的M199培培养基；接着将上层腔室放入含600μL条件培养基(取自制备例2)的24孔细胞培养盘中；
(3)将含有上层腔室的24孔细胞培养盘置入37℃培养箱里，使细胞爬行4小时；(4)取出上层腔室，并将细胞培养液移除，接着将上层腔室浸入甲醇中，固定细胞8分钟后，取出上层腔室风干；(5)用10倍稀释的吉姆萨染液(Giemsa solution)染上层腔室的细胞，接着用棉花棒将上层腔室的上方擦拭干净；(6)最后计数爬行后的细胞。
请参阅图4及图5所示，以对照组做为比较基准，随着A1组合物浓度的增加，爬行后的细胞跟着递减，尤其是50μg/mL与100μg/mL A1组别相较于对照组减少约60％。因此，A1组合物能抑制HUVEC细胞爬行，使HUVEC细胞不会受条件培养基的影响而进行爬行。
实施例4、条件培养基诱导下A1组合物对于细胞侵袭的影响
细胞侵袭实验(invasion assay)：(1)将细胞侵袭室(invasion chamber)置于室温状态；(2)收集HUVEC细胞，用PBS清洗一次后，使细胞悬浮在1mL含1％FBS的M199medium，置入37℃培养箱里使细胞饥饿两小时；(3)加500μL无血清培养基到细胞侵袭室中，置入37℃培养箱里培养两小时，使细胞侵袭室内的基质胶(matrigel)复水；(4)取300μL含有5×10 4颗细胞的细胞液种入细胞侵袭室中，并于添加1mL配置含有不同剂量的A1培养基如下：
a)对照组：1％FBS的M199培养基；
b)10μg/mL A1组：含有10μg/mL A1组合物的1％FBS的M199培养基；
c)25μg/mL A1组：含有25μg/mL A1组合物的1％FBS的M199培养基；
d)50μg/mL A1组：含有50μg/mL A1组合物的1％FBS的M199培养基；
e)100μg/mL A1组：含有100μg/mL A1组合物的1％FBS的M199培养基；接着将细胞侵袭室放入含有600μL条件培养基(取自制备例2)的24孔细胞培养盘中；(5)将含有细胞侵袭室的24孔细胞培养盘置入37℃培养箱里，使细胞爬行16小时；(6)取出细胞侵袭室，并将细胞培养液移除，接着将细胞侵袭室浸入甲醇中，固定细胞8分钟后，取出细胞侵袭室风干；(7)用10倍稀释的吉姆萨染液染细胞侵袭室内的细胞1小时，接着用棉花棒将细胞侵袭室的上方擦拭干净；(8)最后计数侵袭的细胞。
请参阅图6及图7所示，以对照组做为比较基准，随着A1组合物浓度的增加，侵袭的细胞跟着递减，尤其是100μg/mL A1组别相较于对照组减少约70％。因此，A1组合物能抑制HUVEC细胞侵袭情形，使HUVEC细胞不会受条件培养基的影响而进行侵袭。
实施例5、条件培养基诱导下A1组合物对于细胞管柱形成的影响
管柱形成试验(tube formation assay)：(1)将基质胶放入4℃融解一个晚上；(2)收集HUVEC细胞，用PBS清洗一次后，使细胞悬浮在含0.5％FBS的M199培养基，并置入37℃培养箱使细胞饥饿两小时；(3)将96孔细胞培养盘置于冰上，加入60μL已完全融解的基质胶，接着放入37℃培养箱使其凝固一个小时以上；(4)取饥饿过的HUVEC细胞为每毫升2×10 4颗，接着低速离心5分钟，去除培养基；(5)将离心后的细胞均匀悬浮于500μL的：
a)对照组：条件培养基；
b)50μg/mL A1组：含有50μg/mL A1组合物的条件培养基；
c)100μg/mL A1组：含有100μg/mL A1组合物的条件培养基；
以上各组分别取100μL到分别覆盖有基质胶(matrigel-coated)的96孔细胞培养盘中，每个条件三重复；(6)置于37℃培养箱，观察3小时。
请参阅图8所示，对照组可明显观察到有形成单细胞层的环状结构为血管新生的态样；然而，无论于50μg/mL或100μg/mL A1组别中的细胞仍然呈现分散的状态。因此，A1组合物有助于抑制HUVEC细胞受癌细胞诱导的管柱形成。
综上所述，A1组合物具有防止HUVEC细胞受到癌细胞诱导的迁移、细胞侵袭与管柱形成的功效，进而能有效抑制血管生成的效果。
实施例6、VEGF与A1组合物对于细胞生长的影响
重组人类血管内皮生长因子(VEGF)购买自R&D systems；Cat No.293-VE。实验细胞为HUVEC，并将细胞以每孔2×10 4颗细胞种植于24孔盘中。其中，实验组分别为控制组(未添加VEGF)、1ng/mL VEGF、5ng/mL VEGF、10ng/mL VEGF、及20ng/mL VEGF三重复，放置0小时、24小时、48小时及72小时后，以MTT试验侦测OD 565数值，以观察A1组合物对细胞生长情形的影响。
请参阅图9所示，以控制组做为比例基准，由于VEGF具有促进细胞生长增值的效果，因此在高浓度10ng/mL VEGF与20ng/mL VEGF组别中的细胞数有增加情形，在其他浓度组别中1ng/mL VEGF与5ng/mL VEGF组别细胞生长无显著影响。
此外，以0μg/mL、50μg/mL或100μg/mL A1组合物预处理24小时，再给予10ng/mL VEGF放置0小时、24小时、48小时及72小时后，各个时间点中各组细胞生长比率均无显著影响。
实施例7、VEGF诱导下A1组合物对于细胞迁移的影响
细胞迁移分析：(1)收集HUVEC细胞，用PBS清洗一次后，使细胞悬浮在1mL含1％FBS的M199培养基，置入37℃培养箱里使细胞饥饿两小时；(2)取300μL含有1×10 5颗细胞的HUVEC细胞液种入上层腔室(chamber)中，并添加1mL配置含有不同剂量的A1的培养基如下：
a)对照组：1％FBS的M199培养基；
b)50μg/mL A1组：含有50μg/mL A1组合物的1％FBS的M199培养基；
c)100μg/mL A1组：含有100μg/mL A1组合物的1％FBS的M199培养基；
d)250μg/mL A1组：含有250μg/mL A1组合物的1％FBS的M199培养基；
e)500μg/mL A1组：含有500μg/mL A1组合物的1％FBS的M199培养基；接着将上层腔室放入含有10ng/mL VEGF重组蛋白的无血清M199培养基的24孔细胞培养盘中；(3)将含有上层腔室的24孔细胞培养盘置入37℃培养箱里，使细胞爬行4小时；(4)取出上层腔室，并将细胞培养液移除，接着将上层腔室浸入甲醇中，固定细胞8分钟后，取出上层腔室风干；(5)用10倍稀释的吉姆萨染液染上层腔室的细胞，接着用棉花棒将上层腔室的上方擦拭干净；(6)最后计数爬行后的细胞。
请参阅图10所示，以对照组做为比较基准，随着A1组合物浓度的增加，爬行后的细胞跟着递减，尤其是250μg/mL与500μg/mL A1组别相较于对照组减少约80％以上。因此，A1组合物能抑制HUVEC细胞爬行，使HUVEC细胞不会受VEGF诱导而进行爬行。
综上所述，A1组合物具有防止HUVEC细胞受到VEGF诱导的迁移、细胞侵袭与管柱形成的功效，进而能有效抑制血管生成的效果。
以上所述仅是本发明的优选实施例而已，并非对本发明做任何形式上的限制，虽然本发明已以优选实施例公开如上，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，当可利用上述公开的技术内容作出些许改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质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 (10)

  1. 一种含有亚铁氨基酸螯合物的组合物用于制造抑制血管新生的医药品的用途，其中医药品含有有效剂量的亚铁氨基酸螯合物的组合物以及其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为介于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为介于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为介于每日每公斤0.016毫克至每日每公斤1.22毫克。
  5. 根据权利要求1至4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为由无机铁与氨基酸混合并历经60℃至90℃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重量比例为介于1：1.2至1：1.5之间。
  6. 根据权利要求5所述的用途，其中无机铁为硫酸亚铁、氯化亚铁、焦磷酸亚铁或其组合；该氨基酸为甘胺酸。
  7. 根据权利要求5所述的用途，其中医药品含有药学上可接受的载剂包括还原剂，该还原剂系抗坏血酸、柠檬酸、乙酸、丙酸、丁酸、乳酸、羟琥珀酸、磺酸、丁二酸或其组合。
  8. 根据权利要求1所述的用途，其中医药品为经肠道的或非经肠道的剂型。
  9. 根据权利要求8所述的用途，其中该经肠道的剂型为口服剂型，其口服剂型为溶液、乳剂、悬浮液、粉末、锭剂、丸剂、口含锭、片剂、口嚼胶或胶囊。
  10. 根据权利要求1所述的用途，其中该血管新生与以下相关：癌症或眼部疾病。
PCT/CN2017/119620 2017-12-29 2017-12-29 含有亚铁氨基酸螯合物的组合物用于制造抑制血管新生的医药品的用途 WO2019127295A1 (zh)

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