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WO2024242538A1 - Composition pour la prévention ou le traitement du cancer, comprenant de l'ivermectine et un agent anticancéreux - Google Patents

Composition pour la prévention ou le traitement du cancer, comprenant de l'ivermectine et un agent anticancéreux Download PDF

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Publication number
WO2024242538A1
WO2024242538A1 PCT/KR2024/095823 KR2024095823W WO2024242538A1 WO 2024242538 A1 WO2024242538 A1 WO 2024242538A1 KR 2024095823 W KR2024095823 W KR 2024095823W WO 2024242538 A1 WO2024242538 A1 WO 2024242538A1
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cancer
ivermectin
anticancer
doxorubicin
paclitaxel
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Korean (ko)
Inventor
김종헌
김수열
서유나
이호
장현철
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National Cancer Center Japan
National Cancer Center Korea
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National Cancer Center Japan
National Cancer Center Korea
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Priority claimed from KR1020240064348A external-priority patent/KR20240167586A/ko
Publication of WO2024242538A1 publication Critical patent/WO2024242538A1/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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a composition for preventing or treating cancer comprising ivermectin and an anticancer agent, and an anticancer adjuvant.
  • Normal cells can grow and suppress regularly and elastically as needed, while cancer cells grow without limit, and are a mass of cells composed of undifferentiated cells, also called a tumor. These cancer cells invade surrounding tissues and metastasize to other organs in the body, causing severe pain and eventually death.
  • the number of cancer patients in Korea has continued to increase, increasing by about 44% over the past 10 years, and the anticancer drug market has also increased internationally, and it has been reported that it has an annual size of about 100 billion dollars.
  • first-generation anticancer drugs such as chemotherapy
  • second-generation anticancer drugs such as targeted anticancer drugs
  • third-generation anticancer drugs such as immunotherapy
  • the biggest problem in current cancer treatment is the recurrence of cancer. This is because cancer mutations are diverse, making it difficult to target specific cancers, and resistance to the anticancer drugs used in the treatment of relapsed cancers is not uncommon. As a result, most patients die from metastasis and relapsed cancer even after the primary cancer is treated. Accordingly, a strategy of combining anticancer drugs to enhance the effectiveness of anticancer drugs has been proposed.
  • FXR farnesoid x receptor
  • FXR farnesoid x receptor
  • FXR activation has been confirmed to increase the expression of several pro-apoptotic genes, including FAS, BAK1, P21, KLF4, FADD, CAS9, and P27, and to induce apoptosis when activated in colon cancer cells, resulting in the elimination of genetically modified tumor cells (Guofeng Xie and Jean-Pierre Retzman, J Cancer Metastasis Treat, 2:24-28, 2016).
  • ivermectin has been reported to have antitumor effects in many cancers, including breast cancer, ovarian cancer, prostate cancer, head and neck cancer, colon cancer, pancreatic cancer, and malignant melanoma, in in vitro experiments, and has been reported to exhibit an antiangiogenic effect as well as an inhibition of cancer cell proliferation and induction of cell death.
  • the inventors of the present invention have made efforts to provide a combination anticancer agent capable of significantly inhibiting cancer cells, and as a result, have confirmed that when ivermectin and an anticancer agent are used in combination, the cancer cell inhibition effect is significantly increased compared to when each is used alone, and have completed the present invention.
  • the purpose of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising ivermectin and an anticancer agent as active ingredients.
  • Another object of the present invention is to provide an anticancer adjuvant comprising ivermectin and an anticancer agent as active ingredients.
  • the present invention relates to ivermectin
  • a composition for preventing or treating cancer comprising at least one anticancer agent selected from the group consisting of irinotecan, cisplatin, gemcitabine, fluorouracil (5-FU), paclitaxel, doxorubicin, and pharmaceutically acceptable salts thereof.
  • the present invention relates to ivermectin
  • An anticancer adjuvant comprising at least one anticancer agent selected from the group consisting of irinotecan, cisplatin, gemcitabine, fluorouracil (5-FU), paclitaxel, doxorubicin, and pharmaceutically acceptable salts thereof is provided.
  • the cancer may be pancreatic cancer, liver cancer, lung cancer, stomach cancer, colon cancer, prostate cancer, kidney cancer, breast cancer or ovarian cancer.
  • the cancer when the anticancer agent is irinotecan or a pharmaceutically acceptable salt thereof, the cancer is pancreatic cancer, lung cancer or stomach cancer.
  • the cancer is colon cancer or ovarian cancer
  • the cancer is breast cancer or ovarian cancer
  • the cancer is gastric cancer or breast cancer
  • the cancer is pancreatic cancer, stomach cancer, colon cancer, prostate cancer, kidney cancer, breast cancer or ovarian cancer,
  • the cancer may be pancreatic cancer, liver cancer, lung cancer, colon cancer, kidney cancer, breast cancer or ovarian cancer.
  • the ivermectin and the anticancer agent may be included in a concentration ratio of 0.2:1 to 1500:1, more preferably, the ivermectin and irinotecan are included in a concentration ratio of 0.2:1 to 2:1.
  • Ivermectin and cisplatin in a concentration ratio of 0.8:1 to 6:1,
  • Ivermectin and gemcitabine in a concentration ratio of 2:1 to 15:1,
  • Ivermectin and fluorouracil in a concentration ratio of 0.4:1 to 3:1
  • Ivermectin and paclitaxel in concentration ratios of 200:1 to 1500:1,
  • Ivermectin and doxorubicin may be included in concentration ratios ranging from 2:1 to 15:1.
  • the ivermectin and the anticancer agent may be administered sequentially or simultaneously.
  • the present invention also relates to ivermectin.
  • a method for preventing or treating cancer comprising a step of administering to a subject in need thereof a composition comprising, as an active ingredient, at least one anticancer agent selected from the group consisting of irinotecan, cisplatin, gemcitabine, fluorouracil (5-FU), paclitaxel, doxorubicin, and pharmaceutically acceptable salts thereof.
  • at least one anticancer agent selected from the group consisting of irinotecan, cisplatin, gemcitabine, fluorouracil (5-FU), paclitaxel, doxorubicin, and pharmaceutically acceptable salts thereof.
  • composition comprising ivermectin and an anticancer agent of the present invention not only significantly reduced the growth of various cancer cells compared to when ivermectin or an anticancer agent was used alone, but also confirmed an anticancer synergistic effect according to combined administration of anticancer agents. Therefore, the composition of the present invention can be usefully utilized as an effective combined anticancer agent.
  • Figure 1 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs (irinotecan, cisplatin, gemcitabine, fluorouracil, paclitaxel, and doxorubicin) were treated alone or in combination in (A) MIA PaCa-2 cells and (B) Su.8686 cells, which are pancreatic cancer cell lines.
  • Iver. represents ivermectin
  • Irino. represents irinotecan
  • Cis. represents cisplatin
  • Gem. represents gemcitabine
  • 5-FU represents fluorouracil
  • Pacil. represents paclitaxel
  • Doxo. represents doxorubicin.
  • Figure 2 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs were treated alone or in combination to (A) Hep3B cells and (B) SK-Hep1 cells, which are liver cancer cell lines.
  • Figure 3 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs were treated alone or in combination to (A) A549 cell line and (B) H460 cell line, which are lung cancer cell lines.
  • Figure 4 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs were treated alone or in combination to (A) MKN28 cells and (B) AGS cells, which are gastric cancer cell lines.
  • Figure 5 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs were treated alone or in combination to (A) HCT116 cells and (B) HT29 cells, which are colon cancer cell lines.
  • Figure 6 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs were treated alone or in combination to (A) PC-3 cells and (B) Du-145 cells, which are prostate cancer cell lines.
  • Figure 7 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs were treated alone or in combination to (A) ACHN cells and (B) CAKI-1 cells, which are renal cell cancer cell lines.
  • Figure 8 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs were treated alone or in combination to (A) MCF-7 cells and (B) MDA-MB-231 cells, which are breast cancer cell lines.
  • Figure 9 shows data confirming the cancer cell growth rate when ivermectin and/or various anticancer drugs were treated alone or in combination to (A) OVCAR-3 cells and (B) OVCAR-8 cells, which are ovarian cancer cell lines.
  • the present invention relates to a method for producing ivermectin
  • the present invention relates to a composition for preventing or treating cancer, comprising at least one anticancer agent selected from the group consisting of irinotecan, cisplatin, gemcitabine, fluorouracil (5-FU), paclitaxel, doxorubicin, and pharmaceutically acceptable salts thereof.
  • at least one anticancer agent selected from the group consisting of irinotecan, cisplatin, gemcitabine, fluorouracil (5-FU), paclitaxel, doxorubicin, and pharmaceutically acceptable salts thereof.
  • the present invention in another aspect, comprises ivermectin;
  • the present invention relates to an anticancer adjuvant comprising at least one anticancer agent selected from the group consisting of irinotecan, cisplatin, gemcitabine, fluorouracil (5-FU), paclitaxel, doxorubicin, and pharmaceutically acceptable salts thereof.
  • the cancer may be pancreatic cancer, liver cancer, lung cancer, stomach cancer, colon cancer, prostate cancer, kidney cancer, breast cancer or ovarian cancer.
  • the cancer is pancreatic cancer, lung cancer or stomach cancer,
  • the cancer is colon cancer or ovarian cancer
  • the cancer is breast cancer or ovarian cancer
  • the cancer is gastric cancer or breast cancer
  • the cancer is pancreatic cancer, stomach cancer, colon cancer, prostate cancer, kidney cancer, breast cancer or ovarian cancer,
  • the cancer may be pancreatic cancer, liver cancer, lung cancer, colon cancer, kidney cancer, breast cancer or ovarian cancer.
  • the ivermectin and the anticancer agent may be included in a concentration ratio of 0.2:1 to 1500:1.
  • the ivermectin and irinotecan are used in a concentration ratio of 0.2:1 to 2:1.
  • Ivermectin and cisplatin in a concentration ratio of 0.8:1 to 6:1,
  • Ivermectin and gemcitabine in a concentration ratio of 2:1 to 15:1,
  • Ivermectin and fluorouracil in a concentration ratio of 0.4:1 to 3:1
  • Ivermectin and paclitaxel in concentration ratios of 200:1 to 1500:1,
  • Ivermectin and doxorubicin may be included in concentration ratios ranging from 2:1 to 15:1.
  • the ivermectin and irinotecan are used in a concentration ratio of 0.5:1 to 1.5:1.
  • Ivermectin and gemcitabine in a concentration ratio of 4:1 to 10:1,
  • Ivermectin and fluorouracil in a concentration ratio of 0.8:1 to 2:1
  • Ivermectin and paclitaxel in a concentration ratio of 400:1 to 1000:1,
  • Ivermectin and doxorubicin may be included in a concentration ratio of 4:1 to 10:1.
  • the ivermectin and the anticancer agent may be administered sequentially or simultaneously.
  • ivermectin and anticancer drugs irinotecan, cisplatin, gemcitabine, fluorouracil, paclitaxel, doxorubicin
  • irinotecan, cisplatin, gemcitabine, fluorouracil, paclitaxel, doxorubicin were treated alone or in combination to cell lines derived from pancreatic cancer, liver cancer, lung cancer, stomach cancer, colon cancer, prostate cancer, kidney cancer, breast cancer, and ovarian cancer, the anticancer synergy effect according to the combined administration of anticancer drugs was confirmed.
  • pancreatic cancer pancreas cancer
  • MIA PaCa-2 Irinotecan, paclitaxel, doxorubicin Su.86.86 Irinotecan, cisplatin, gemcitabine, paclitaxel, Doxorubicin Liver cancer (Liver Cancer) Hep3B Irinotecan, 5-FU, paclitaxel, doxorubicin SK-Hep1 Cisplatin, doxorubicin Lung cancer (Lung Cancer)
  • MKN28 Irinotecan, 5-FU, paclitaxel, doxorubicin AGS Irinotecan, cisplatin, 5-FU, paclitaxel, doxorubicin
  • the composition of the present invention may be in various oral or parenteral dosage forms. When formulating the composition, it may be prepared using one or more of a buffer (e.g., saline or PBS), an antioxidant, a bacteriostatic agent, a chelating agent (e.g., EDTA or glutathione), a filler, a bulking agent, a binder, an adjuvant (e.g., aluminum hydroxide), a suspending agent, a thickening agent, a wetting agent, a disintegrating agent, or a surfactant, a diluent, or an excipient.
  • a buffer e.g., saline or PBS
  • an antioxidant e.g., bacteriostatic agent, a chelating agent (e.g., EDTA or glutathione)
  • a filler e.g., a filler, a bulking agent, a binder, an adjuvant (e.g., aluminum hydro
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing one or more compounds with at least one excipient, such as starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methyl cellulose, sodium carboxymethyl cellulose, and hydroxypropyl methyl-cellulose or gelatin.
  • a tablet or a sugar-coated tablet can be obtained by mixing an active ingredient with a solid excipient, grinding the mixture, adding a suitable auxiliary agent, and then processing it into a granule mixture.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances or preservatives may be included.
  • cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as disintegrants, and anticoagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be additionally included.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, or suppositories.
  • Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • Suppository bases may include witepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol, and gelatin.
  • composition of the present invention can be administered orally or parenterally, and when administered parenterally, it can be formulated in the form of an injection for external use on the skin; intraperitoneally, rectally, intravenously, intramuscularly, subcutaneously, intrauterinely, or intracerebrally, according to a method known in the art.
  • suitable carriers for the injection include, but are not limited to, solvents or dispersion media including water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), mixtures thereof, and/or vegetable oils. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene glycol, and 5% dextrose.
  • solvents or dispersion media including water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), mixtures thereof, and/or vegetable oils. More preferably, suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or isotonic solutions such as sterile water for injection, 10% ethanol, 40% propylene
  • various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, and thimerosal may be additionally included.
  • the injection may in most cases additionally include isotonic agents such as sugars or sodium chloride.
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • a pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dosage level can be determined according to the type and severity of the patient's disease, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the excretion rate, the treatment period, the concurrently used drugs, and other factors well known in the medical field.
  • the composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses.
  • the total effective amount of the composition of the present invention can be administered to a patient as a single dose, or can be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by considering all of the above factors, and this can be easily determined by those skilled in the art.
  • the preferred dosage of the composition above varies depending on the patient's condition, weight, degree of disease, drug form, route of administration, and period, but may be appropriately selected by those skilled in the art, and may be administered, for example, at 0.0001 to 2,000 mg/kg per day, more preferably at 0.001 to 2,000 mg/kg. Administration may be once a day or divided into several times. However, the scope of the present invention is not limited by the above dosage.
  • composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.
  • the anticancer adjuvant of the present invention refers to all forms that enhance the anticancer effect of an anticancer agent or suppress or improve the side effects of an anticancer agent.
  • the anticancer adjuvant of the present invention can be administered in combination with various types of anticancer agents or anticancer adjuvants, and when administered in combination, even if the anticancer agent is administered at a lower dose than a conventional anticancer agent, the same level of anticancer treatment effect can be exhibited, so that safer anticancer treatment can be performed.
  • the above-mentioned anticancer adjuvant may be administered via any common route as long as it can reach the target tissue.
  • the anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, orally, intrapulmonary, or rectally, depending on the purpose, but is not limited thereto.
  • the above-mentioned anticancer adjuvant may be administered via any device through which the active substance can move to the target cell.
  • the anticancer adjuvant of the present invention can be preferably formulated as an anticancer adjuvant by additionally including one or more pharmaceutically acceptable carriers in addition to the effective ingredient for administration.
  • Carriers, excipients or diluents that can be included in the anticancer treatment adjuvant of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the anticancer adjuvant of the present invention may be a formulation for oral or parenteral administration, and the description of the formulation is replaced by the description of the formulation of the pharmaceutical composition.
  • Example 1 Confirmation of anticancer activity against pancreatic cancer according to combined administration
  • pancreatic cancer cell lines MIA PaCa-2 cells and Su.8686 cells, were prepared, and cells (100 ⁇ l) were seeded into 96-well cell culture plates at plating densities ranging from 5,000 to 20,000 cells/well depending on the doubling time of each cell line. After cell seeding, the plates were incubated for 24 h before the addition of experimental drugs.
  • Ivermectin (4 ⁇ M to 10 ⁇ M) and/or anticancer drugs (irinotecan 2.5 ⁇ M, cisplatin 1 ⁇ M, gemcitabine 2.5 ⁇ M, 5-FU 5 ⁇ M, paclitaxel 10 nM, doxorubicin 1 ⁇ M) were treated alone or in combination, and the negative control group was treated with DMSO.
  • the ivermectin treatment concentration was set based on the IC 50 value for each cell.
  • TCA trichloroacetic acid
  • Cells were fixed in situ by gently adding 50 ⁇ l of cold 50% (w/v) TCA (final concentration: 10% TCA) and incubated at 4 °C for 60 min. The supernatant was discarded, and the plates were washed five times with distilled water and then air-dried. A 0.4% (w/v) Sulforhodamine B (SRB) solution (100 ⁇ l) in 1% acetic acid was added to each well, and the plates were left at room temperature for 10 min.
  • SRB Sulforhodamine B
  • the Colby equation was used.
  • the anticancer activity of two compounds combined is greater than the simple sum (expected activity) of the anticancer activities of each compound, this is called a synergistic effect.
  • the predicted synergistic effect according to combined administration of the present invention can be calculated as follows using the Colby equation of the following mathematical formula 1 (S.R, Colby, Weeds, 1967, 15, 20-22).
  • ⁇ and ⁇ are the measured anticancer activity when each compound is treated alone, and E is the predicted value, which is the predicted anticancer activity when ⁇ and ⁇ are mixed.
  • the actual value of anticancer activity according to combined administration was taken as the cancer cell growth inhibition rate (%), and this was substituted into the Colby equation to measure the predicted value (E) according to combined administration. If the actual value is greater than the predicted value, it can be determined that there is a synergistic effect, and in the present invention, in order to additionally verify the synergistic effect of combined administration, the predicted value calculated by the Colby equation was compared with the actual value.
  • the combined administration of ivermectin and irinotecan, paclitaxel, or doxorubicin showed an enhanced anticancer effect in MIA PaCa-2 cells
  • the combined administration of ivermectin and irinotecan, cisplatin, paclitaxel, or doxorubicin showed an enhanced anticancer effect in Su.8686 cells.
  • the combined administration of ivermectin and irinotecan, paclitaxel, or doxorubicin commonly showed an enhanced anticancer effect in pancreatic cancer cell lines.
  • ivermectin and irinotecan in a concentration ratio of 0.7:1 to 1:1 for pancreatic cancer.
  • Ivermectin and paclitaxel in a concentration ratio of 500:1 to 700:1,
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 5:1 to 7:1.
  • ivermectin and paclitaxel in a concentration ratio of 500:1 to 600:1 for liver cancer.
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 5:1 to 6:1.
  • ivermectin and irinotecan in lung cancer at a concentration ratio of 0.8:1 to 0.9:1.
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 5.5:1 to 6.5:1.
  • MKN28 cells showed an enhanced anticancer effect following combined administration of ivermectin and irinotecan, 5-FU, paclitaxel, or doxorubicin
  • AGS cells showed an enhanced anticancer effect following combined administration of ivermectin and irinotecan, cisplatin, 5-FU, paclitaxel, or doxorubicin.
  • gastric cancer cell lines commonly showed an enhanced anticancer effect following combined administration of ivermectin and irinotecan, 5-FU, paclitaxel, or doxorubicin.
  • ivermectin and irinotecan in a concentration ratio of 0.85:1 to 1.5:1 for gastric cancer.
  • Ivermectin and fluorouracil in a concentration ratio of 2.4:1 to 4:1
  • Ivermectin and paclitaxel in a concentration ratio of 600:1 to 1000:1,
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 6:1 to 10:1.
  • both HCT116 cells and HT29 cells were confirmed to exhibit enhanced anticancer effects following combined administration of ivermectin and cisplatin, paclitaxel, or doxorubicin.
  • ivermectin and cisplatin in a concentration ratio of 3:1 to 3.5:1 for colon cancer.
  • Ivermectin and paclitaxel in a concentration ratio of 750:1 to 850:1,
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 7.5:1 to 8.5:1.
  • the combined administration of ivermectin and 5-FU, paclitaxel, or doxorubicin showed an enhanced anticancer effect in PC-3 cells
  • the combined administration of ivermectin and irinotecan, cisplatin, gemcitabine, paclitaxel, or doxorubicin showed an enhanced anticancer effect in Du-145 cells.
  • the combined administration of ivermectin and paclitaxel or doxorubicin commonly showed an enhanced anticancer effect in prostate cancer cell lines.
  • ivermectin and paclitaxel in a concentration ratio of 600:1 to 800:1 for prostate cancer.
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 6:1 to 8:1.
  • the combined administration of ivermectin and irinotecan, cisplatin, gemcitabine, paclitaxel, or doxorubicin showed an enhanced anticancer effect in ACHN cells
  • the combined administration of ivermectin and paclitaxel or doxorubicin showed an enhanced anticancer effect in CAKI-1 cells.
  • the combined administration of ivermectin and paclitaxel or doxorubicin commonly showed an enhanced anticancer effect in renal cell carcinoma cell lines.
  • ivermectin and paclitaxel in a concentration ratio of 800:1 to 1000:1 for renal cancer.
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 8:1 to 10:1.
  • Example 8 Confirmation of anticancer activity against breast cancer according to combined administration
  • the experiment was performed using MCF-7 cells and MDA-MB-231 cells, which are breast cancer cell lines, using the same method as in Example 1.
  • the combined administration of ivermectin and gemcitabine, 5-FU, paclitaxel, or doxorubicin showed an enhanced anticancer effect in MCF-7 cells
  • the combined administration of ivermectin and irinotecan, cisplatin, gemcitabine, 5-FU, paclitaxel, or doxorubicin showed an enhanced anticancer effect in MDA-MB-23 cells.
  • the combined administration of ivermectin and gemcitabine, 5-FU, paclitaxel, or doxorubicin commonly showed an enhanced anticancer effect in breast cancer cell lines.
  • ivermectin and gemcitabine in a concentration ratio of 4:1 to 8:1 for breast cancer.
  • Ivermectin and fluorouracil in a concentration ratio of 0.8:1 to 1.6:1,
  • Ivermectin and paclitaxel in a concentration ratio of 400:1 to 800:1,
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 4:1 to 8:1.
  • Example 9 Confirmation of anticancer activity against ovarian cancer according to combined administration
  • OVCAR-3 cells and OVCAR-8 cells which are ovarian cancer cells, using the same method as in Example 1.
  • ivermectin and cisplatin in a concentration ratio of 1.1:1 to 1.2:1 for ovarian cancer.
  • Ivermectin and gemcitabine in a concentration ratio of 3:1 to 3.5:1,
  • Ivermectin and paclitaxel in a concentration ratio of 750:1 to 850:1,
  • Ivermectin and doxorubicin showed enhanced anticancer effects when treated at a concentration ratio of 7.5:1 to 8.5:1.
  • composition comprising ivermectin and an anticancer agent of the present invention not only significantly reduced the growth of various cancer cells compared to when ivermectin or the anticancer agent was used alone, but also confirmed an anticancer synergy effect according to combined administration of anticancer agents, and therefore can be usefully utilized as an effective combined anticancer agent.

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Abstract

La présente invention concerne : une composition pour la prévention ou le traitement du cancer, la composition comprenant de l'ivermectine et un agent anticancéreux ; et un adjuvant anticancéreux. La composition comprenant de l'ivermectine et un agent anticancéreux, selon la présente invention, réduit non seulement significativement la croissance de diverses cellules cancéreuses par rapport à l'utilisation de l'ivermectine ou de l'agent anticancéreux seul, mais il s'avère également qu'elle présente un effet synergique anticancéreux lorsqu'elle est co-administrée avec un agent anticancéreux. Ainsi, la composition selon la présente invention peut être efficacement utilisée en tant qu'agent anticancéreux co-administré efficace.
PCT/KR2024/095823 2023-05-19 2024-05-17 Composition pour la prévention ou le traitement du cancer, comprenant de l'ivermectine et un agent anticancéreux Pending WO2024242538A1 (fr)

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KR10-2023-0065087 2023-05-19
KR20230065087 2023-05-19
KR1020240064348A KR20240167586A (ko) 2023-05-19 2024-05-17 이버멕틴 및 항암제를 포함하는 암 예방 또는 치료용 조성물
KR10-2024-0064348 2024-05-17

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160106042A (ko) * 2013-11-01 2016-09-09 피트니 파마슈티컬스 피티와이 리미티드 암 치료용 약학적 배합물
KR20220066938A (ko) * 2019-10-21 2022-05-24 아큐라 나노메디슨 코퍼레이션 암 치료 방법

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
KR20160106042A (ko) * 2013-11-01 2016-09-09 피트니 파마슈티컬스 피티와이 리미티드 암 치료용 약학적 배합물
KR20220066938A (ko) * 2019-10-21 2022-05-24 아큐라 나노메디슨 코퍼레이션 암 치료 방법

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CHEN LIANG, BI SHUNING, WEI QIUREN, ZHAO ZHIJUN, WANG CHAOJIE, XIE SONGQIANG: "Ivermectin suppresses tumour growth and metastasis through degradation of PAK1 in oesophageal squamous cell carcinoma", JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, UNIVERSITY PRESS CAROL DAVILA, BUCHAREST, RO, vol. 24, no. 9, 1 May 2020 (2020-05-01), RO , pages 5387 - 5401, XP055941178, ISSN: 1582-1838, DOI: 10.1111/jcmm.15195 *
LEE DA EUN, KANG HYEON WOONG, KIM SO YI, KIM MYEONG JIN, JEONG JAE WOONG, HONG WOOSOL CHRIS, FANG SUNGSOON, KIM HYUNG SUN, LEE YUN: "Ivermectin and gemcitabine combination treatment induces apoptosis of pancreatic cancer cells via mitochondrial dysfunction", FRONTIERS IN PHARMACOLOGY, FRONTIERS RESEARCH FOUNDATION, CH, vol. 13, CH , XP093242878, ISSN: 1663-9812, DOI: 10.3389/fphar.2022.934746 *
NUNES MARIANA, DUARTE DIANA, VALE NUNO, RICARDO SARA: "Pitavastatin and Ivermectin Enhance the Efficacy of Paclitaxel in Chemoresistant High-Grade Serous Carcinoma", CANCERS, MDPI AG, CH, vol. 14, no. 18, CH , pages 4357, XP093242876, ISSN: 2072-6694, DOI: 10.3390/cancers14184357 *

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