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WO2012034540A1 - Compositions pharmaceutiques antitumorales - Google Patents

Compositions pharmaceutiques antitumorales Download PDF

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Publication number
WO2012034540A1
WO2012034540A1 PCT/CN2011/079822 CN2011079822W WO2012034540A1 WO 2012034540 A1 WO2012034540 A1 WO 2012034540A1 CN 2011079822 W CN2011079822 W CN 2011079822W WO 2012034540 A1 WO2012034540 A1 WO 2012034540A1
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Prior art keywords
cancer
tyrosine kinase
tumor
pharmaceutical composition
imatinib
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Chinese (zh)
Inventor
赵志全
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Shandong New Time Pharmaceutical Co Ltd
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Shandong New Time Pharmaceutical Co Ltd
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Priority to CN201180044842.1A priority Critical patent/CN103179967B/zh
Publication of WO2012034540A1 publication Critical patent/WO2012034540A1/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
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to an antitumor pharmaceutical composition and a kit of parts and uses thereof. Background technique
  • Neoplastic diseases especially malignant tumors, are a common and frequently-occurring disease that seriously endangers human health.
  • World Health Organization there are more than 10 million new cases of malignant tumors worldwide each year, with more than 7 million deaths, accounting for 12% of the total deaths. In most developed countries, this figure can reach 25 percent. If this trend is not improved, it is expected that by 2020, the number of new cases worldwide will reach 15 million per year; the total number of cancer patients will increase by 73% in developing countries, while that in developed countries will increase by 29%.
  • Clinical treatment of tumors mainly includes surgical treatment, radiation therapy, chemotherapy and traditional Chinese medicine treatment.
  • traditional Chinese medicine treatment has little effect, usually only as an adjuvant therapy, and surgical treatment and radiation therapy are harmful to patients.
  • Recurrence chemotherapy is less harmful, but compared with surgical treatment and radiation therapy, the effect is less significant, and the side effects are large. Therefore, it has been desired to find a chemotherapeutic drug which is effective and has little toxic side effects.
  • Arctigenin is a lignan compound. At present, it has been reported in the literature that arctigenin has the following pharmacological activities: 1) anti-inflammatory and immunomodulatory effects; 2) antiviral (including HIV-1 and influenza virus) effects 3) Inducing apoptosis of tumor cells; 4) Treating effects on nephropathy and diabetes, diabetic complications; 5) Inhibition of heat shock response; 6) Neuroprotection; 7) Dilation of blood vessels; 8) Platelet activating factor Antagonism; 9) anti-aging dementia; 10) inhibition of K + caused contracture and so on. For example, Cho JY, et al.
  • tyrosine kinase inhibitors As a kind of selective targeted therapeutic agent, tyrosine kinase inhibitors have become a hot spot in anti-tumor research because of their significant anti-tumor effect in clinical practice. It acts as a competitive inhibitor of ATP binding to tyrosine protein kinases, thereby affecting tyrosine kinase activation, and also acts as an analog of tyrosine to block peptide sites and tyrosine proteins of the epidermal growth factor receptor. The kinase encodes, inhibits cell proliferation, and ultimately promotes apoptosis. Currently widely used tyrosine kinase inhibitors are erlotinib, gefitinib, and imatinib.
  • erlotinib is an epidermal growth factor receptor tyrosine kinase inhibitor that inhibits signal transduction by inhibiting autophosphorylation of epidermal growth factor receptor tyrosine kinase, thereby inhibiting tumor cell proliferation and activation.
  • Gefitinib is an orally effective selective tyrosinase inhibitor that inhibits epidermal growth factor receptor activation by blocking the activation of tyrosine kinases by competitively binding to extracellular ligands with ATP. It inhibits cell proliferation and angiogenesis and promotes tumor cell apoptosis.
  • These tyrosine kinase inhibitors are ubiquitously present with some serious problems. First of all, they have a lot of toxic side effects.
  • erlotinib Such as significant nausea, vomiting or diarrhea.
  • more than 50% of clinical users experience varying degrees of skin reactions and digestive system diseases.
  • the size of the side effects is often related to the dose of the drug, for example, the oral dose of erlotinib is 150mg / d, the oral dose of gefitinib is 250mg / d, imatinib mesylate
  • the oral dose is as high as 400mg-600mg/d. Second, they are prone to drug resistance, which is closely related to long-term high-dose use.
  • imatinib mesylate long-term high-dose administration results in a point mutation in the BCR-ABL protein kinase domain, resulting in a decrease in the affinity of imatinib mesylate to produce imatinib mesylate. Drug resistance.
  • anti-tumor drugs are often selected based on the consideration of drug resistance to single drugs and serious side effects, but not all anti-tumor drugs are suitable for combination therapy.
  • tyrosine kinase inhibitors are used in combination with other chemotherapeutic drugs, but there are still many toxic side effects.
  • transient hepatotoxicity can occur, such as elevated transaminases and hyperbilirubinemia (Li Yufeng, Ding Bang and et al. Therapeutic effect of swipel combined with homoharringtonine on newly diagnosed chronic myeloid leukemia[J].Journal of Southeast University, 2009, 28 ( 5 ): 430-432 ) o Giaccone G et al, Gefitinib in combination with gemcitabine and cisplatin in advanced Non-small-cell lung cancer: a phase III trial— INTACT 1, J Clin Oncol. Mar 1, 2004 vol. 22 no.
  • the present invention provides an antitumor pharmaceutical composition comprising the following active ingredients:
  • the weight ratio of said tyrosine kinase inhibitor to arctigenin in the pharmaceutical composition of the present invention is (0.005-100): 1.
  • the tyrosine kinase inhibitor of the pharmaceutical composition of the invention is gefitinib or a pharmaceutically acceptable salt thereof, imatinib or a pharmaceutically acceptable salt thereof, or erlotidine Or a pharmaceutically acceptable salt thereof, preferably, the pharmaceutically acceptable salt of imatinib is its mesylate salt.
  • the tyrosine kinase inhibitor when the tyrosine kinase inhibitor is imatinib or a pharmaceutically acceptable salt thereof, imatinib or a pharmaceutically acceptable salt thereof is The weight ratio of imatinib to arctigenin is (0.01-100): 1; when the tyrosine kinase inhibitor is gefitinib or a pharmaceutically acceptable salt thereof, gefitinib or its The weight ratio of the pharmaceutically acceptable salt to gibberellin and the burdock aglycone is (0.005-50): 1; when the tyrosine kinase inhibitor is erlotinib or a pharmaceutically acceptable salt thereof, erlotidine The weight ratio of nitrite or its pharmaceutically acceptable salt to bursinini in terms of erlotinib is (0.05-25): 1.
  • the pharmaceutical composition of the present invention is in a form suitable for gastrointestinal or parenteral administration, preferably a tablet, an emulsion, a microemulsion, a capsule, a dropping or a soft capsule. More preferably, the microemulsion preparation preferably has an average particle diameter of from 15 to 80 nm.
  • the bovine aglycone or tyrosine kinase inhibitor is, in terms of its free acid or free base, the content of arctigenin in each preparation unit is 1 mg. -200 mg, the content of the tyrosine kinase inhibitor is 2 mg to 100 mg.
  • the present invention provides an antitumor kit comprising the following active ingredients:
  • the above two active ingredients may be present in the kit as a mixed composition, or may be present in a separate kit in separate forms, regardless of the manner in which they are present in the kit, and ultimately used in combination. It can reflect the synergistic anti-tumor effect, and the toxic side effects and drug resistance are significantly reduced.
  • the weight ratio of tyrosine kinase inhibitor to arctigenin in the kit of the invention is (0.005-100): 1.
  • the tyrosine kinase inhibitor of the kit of the invention is gefitinib or a pharmaceutically acceptable salt thereof, imatinib or a pharmaceutically acceptable salt thereof, or erlot Oriniline or a pharmaceutically acceptable salt thereof, preferably, the pharmaceutically acceptable salt of imatinib is its mesylate salt.
  • the tyrosine kinase inhibitor when the tyrosine kinase inhibitor is imatinib or a pharmaceutically acceptable salt thereof, imatinib or a pharmaceutically acceptable salt thereof
  • the weight ratio of imatinib to arctigenin is (0.01-100): 1; when the tyrosine kinase inhibitor is gefitinib or a pharmaceutically acceptable salt thereof, gefitinib or The weight ratio of the pharmaceutically acceptable salt to gefitinib to the arctigenin is (0.005-50): 1; when the tyrosine kinase inhibitor is erlotinib or a pharmaceutically acceptable salt thereof, erro
  • the weight ratio of sirinib or its pharmaceutically acceptable salt to bursinini in terms of erlotinib is (0.05-25): 1.
  • the dosage form when the two active ingredients are present in the kit in the form of a composition, the dosage form is suitable for gastrointestinal or parenteral administration.
  • a dosage form preferably a tablet, an emulsion, a microemulsion preparation, a capsule, a dropping pill or a soft capsule, more preferably a microemulsion preparation, the microemulsion preparation preferably having an average particle diameter of 15 to 80 nm, when the two active ingredients are
  • the dosage form is a dosage form suitable for gastrointestinal or parenteral administration, preferably a tablet, an emulsion, a microemulsion preparation, a capsule, a dropping pill or a soft capsule, wherein the burdock aglycone
  • the microemulsion preparation is more preferable, and the microemulsion preparation preferably has an average particle diameter of 15 to 80 nm, and the tyrosine kinase inhibitor is more preferably a tablet.
  • the burdock aglycone or tyrosine kinase inhibitor is a bovine aglycone present in the composition or alone in terms of its free acid or free base.
  • the content in each preparation unit is from 1 mg to 200 mg, and the tyrosine kinase inhibitor present in the composition or in a separate form is contained in an amount of from 2 mg to 100 mg per preparation unit.
  • the two pharmaceutically active components of the kit may be administered simultaneously or sequentially, and when administered sequentially, the two pharmaceutically active components are administered at intervals of no more than 3 hour.
  • kit of parts further includes instructions for use.
  • the present invention provides the use of the pharmaceutical composition or kit of parts for the preparation of a medicament for treating or preventing an antitumor, preferably the tumor is a solid tumor or leukemia, more preferably, the solid tumor is selected From breast cancer, lung cancer, rectal cancer, ovarian cancer, colon cancer, liver cancer, prostate cancer, stomach cancer, cervical cancer, pancreatic cancer, esophageal cancer, cashmere Epithelial cancer, malignant mole, bladder cancer, skin cancer, head and neck cancer, bronchial lung cancer, colorectal cancer, and non-small cell lung cancer, the leukemia is selected from acute promyelocytic leukemia, chronic myeloid leukemia, and retinoic acid tolerance The drug is promyelocytic leukemia, and most preferably, the tumor is non-small cell lung cancer.
  • the present invention provides a method of treating or preventing a tumor by administering the above-described pharmaceutical composition or kit to a human or animal having or at risk of developing a tumor, preferably, the tumor More preferably, the solid tumor is selected from the group consisting of breast cancer, lung cancer, rectal cancer, ovarian cancer, colon cancer, liver cancer, prostate cancer, gastric cancer, cervical cancer, pancreatic cancer, esophageal cancer, and chorionic epithelial cancer.
  • the leukemia is selected from acute promyelocytic leukemia, chronic myeloid leukemia, and retinoic acid resistant promyelocytic Leukemia, most preferably, the tumor is a non-small cell lung.
  • the two pharmaceutically active components of the kit may be administered simultaneously or sequentially. When administered sequentially, the two pharmaceutically active components are administered no more than 3 hours apart.
  • a pharmaceutical composition or kit and a single drug or a combination of a bovine aglycone having low toxicity characteristics extracted from a natural plant burdock and a tyrosine kinase inhibitor are provided.
  • the anti-tumor pharmaceutical composition or the kit of the invention has the advantages of clear composition and simple preparation process, and can be used for the treatment of tumor alone, and can also be combined with radiotherapy and surgery.
  • the anti-tumor pharmaceutical composition and the kit of the invention provide a new idea for anti-tumor treatment or prevention, and have a good application prospect. detailed description
  • Gefitinib was purchased from AstraZeneca Pharmaceutical Co., Ltd.
  • Erlotinib was purchased from Shanghai Roche Pharmaceutical Co., Ltd.
  • Imatinib purchased from Beijing Novartis Pharmaceutical Co., Ltd.
  • Imatinib mesylate purchased from Beijing Novartis Pharmaceutical Co., Ltd.
  • Eudragit L30D-55 was purchased from Evonik Rohm Pharmaceutical Resin
  • Laser particle size analyzer was purchased from Beijing Aegis Automation Co., Ltd. It will be appreciated by those skilled in the art that the active components of the antitumor pharmaceutical composition or kit of the present invention, the anthraquinone aglycone and the tyrosine kinase inhibitor, are commercially available, respectively, and are also known in the art. be made of.
  • the general preparation method of the antitumor pharmaceutical composition or the kit of the present invention is as follows:
  • the dried solid composition is made into various shapes.
  • pharmaceutical excipients commonly used in the preparation of microemulsion preparations include, but are not limited to, soybean oil, polyoxyethylene-23-lauryl ether, 1,2-propanediol, hydrogenated coconut glycerin, lauroyl polyethylene glycol-32-glycerol Ester, polyethylene glycol 3350, safflower oil, cottonseed oil, decaglycerin monostearate; pharmaceutical excipients commonly used in the preparation of dropping pills, including but not limited to polyethylene glycol 6000, polyethylene glycol 1000;
  • Pharmaceutical excipients commonly used in capsule formulations include, but are not limited to, lactose and corn starch.
  • Pharmaceutically acceptable carriers commonly used in the preparation of soft capsule preparations include, but are not limited to, medium chain fatty acid glycerides, polyoxyethylene castor oil, 1,2-propanediol, and the like.
  • the administration route of the antitumor pharmaceutical composition or kit of the present invention includes a gastrointestinal route including a non-gastrointestinal route including, but not limited to, subcutaneous, intradermal, arterial, intravenous, muscular, joint, Intrathecal, intracranial, thoracic, intraperitoneal injection or infusion, nasal, buccal, sublingual, tracheal, urethral, rectal or topical local administration.
  • the administration time and the number of administrations of the antitumor pharmaceutical composition or kit of the present invention need to be determined according to the specific conditions, which are within the technical scope of those skilled in the art.
  • a treatment regimen for non-small cell lung cancer in mice is applied to a human, and an effective dose of all drugs to humans can be converted by the effective dose of the drug to the mouse, which is well known to those of ordinary skill in the art. Obvious.
  • Example 1 Microemulsion preparation of pharmaceutical composition of the present invention
  • Soybean oil 35g Polyoxyethylene-23-lauryl ether 60g
  • Preparation process Weigh the prescribed amount of soybean oil, polyoxyethylene-23-lauryl ether, 1,2-propanediol, mix well and stir evenly, then add the burdock aglycone, gefitinib to dissolve, or ultrasonically to accelerate the dissolution A clear solution is obtained, which is a microemulsion preparation of a bovine aglycone and gefitinib pharmaceutical composition.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 15 nm.
  • Example 2 Pharmaceutical composition microemulsion preparation of the invention
  • Preparation process Weigh the prescribed amount of hydrogenated coconut oil, lauroyl polyethylene glycol-32-glyceride, 1,2-propanediol, polyethylene glycol 3350, mix and stir evenly, then add calf aglycone, Jifei The nyanib is dissolved, and it can also be ultrasonicated to accelerate the dissolution to obtain a clear solution, that is, a microemulsion preparation of the burverine and gefitinib pharmaceutical composition. The particle size was measured by a laser particle size measuring instrument, and the average particle diameter was 40 nm.
  • Example 3 Pharmaceutical composition microemulsion preparation of the invention
  • Preparation process Weigh the prescribed amount of safflower oil, polyoxyethylene-23-lauryl ether, 1,2-propanediol, mix and mix evenly, then add the burdock aglycone, gefitinib dissolved, or ultrasonically accelerate to accelerate Dissolved, a clear solution is obtained, which is a microemulsion preparation of a bovine aglycone and gefitinib pharmaceutical composition. Laser particle size analyzer using a particle diameter, an average particle diameter of 36nm 0
  • Example 4 Pharmaceutical composition microemulsion preparation of the invention
  • Preparation process Weigh the prescribed amount of cottonseed oil, decaglyceryl monostearate, 1,2-propanediol, mix and mix evenly, then add the bursin, erlotinib dissolved, or ultrasonic treatment to accelerate the dissolution, A clear solution is obtained, which is a microemulsion preparation of an arctigenin and erlotinib pharmaceutical composition.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 80 nm.
  • Example 5 Pharmaceutical composition microemulsion preparation of the present invention
  • Preparation process Weigh the prescribed amount of soybean oil, decaglyceryl monostearate, 1,2-propanediol, mix and mix evenly, then add caldonia aglycone, erlotinib dissolved, or ultrasonic treatment to accelerate dissolution,
  • the clear solution is a microemulsion preparation of the bovine aglycone and erlotinib pharmaceutical composition.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 47 nm.
  • Example 6 Pharmaceutical composition microemulsion preparation of the invention
  • Preparation process Weigh the prescribed amount of soybean oil, decaglyceryl monostearate, 1,2-propanediol, mix and mix evenly, then add caldonia aglycone, erlotinib dissolved, or ultrasonic treatment to accelerate dissolution,
  • the clear solution is a microemulsion preparation of the bovine aglycone and erlotinib pharmaceutical composition.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 58 nm.
  • Example 7 Pharmaceutical composition microemulsion preparation of the invention
  • Preparation process Weigh the prescribed amount of soybean oil, decaglyceryl monostearate, 1,2-propanediol, mix and mix evenly, then add the burdock aglycone, imatinib mesylate to dissolve, or ultrasonically accelerate to accelerate Dissolved to obtain a clear concentrate, which is a microemulsion concentrate of arctigenin and imatinib mesylate.
  • the particle diameter was measured by a laser granulometer, and the average particle diameter was 56 nm.
  • Example 8 Pharmaceutical composition drip pellet preparation of the invention
  • Preparation process weigh the bovine glucoside and erlotinib which have been prescribed to a 100 mesh sieve, and add to the mixed solution of the prescription polyethylene glycol 6000 and polyethylene glycol 1000 which have been heated and melted on a water bath. Stir, make it uniform, put into a dropper bottle, drop at 95 ⁇ 2 °C; drop into a glass condensation column containing 4-6 mL of methyl silicone oil, take it out after molding, and suck it with absorbent paper. Debonded methyl silicone oil, that is.
  • Example 9 Ingredients for enteric soft capsule preparation of pharmaceutical composition of the present invention
  • Preparation process Weigh the prescribed amount of medium chain fatty acid glyceride, polyoxyethylene castor oil, 1,2-propanediol, absolute ethanol, mix and mix evenly, then add caldonia, imatinib dissolved, or ultrasonic treatment In order to accelerate the dissolution, the concentrate is clarified, which is the burdock aglycone microemulsion concentrate.
  • the microemulsion concentrate obtained above was diluted with water to a clear solution in a weight ratio of 1:10-20 to obtain a soft capsule microemulsion content. Weigh the prescribed amount of gelatin, glycerin, purified water, mix it evenly and press it into rubber.
  • Example 10 Pharmaceutical composition capsule preparation of the present invention
  • the preparation process was the same as in Example 7.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 39 nm.
  • Example 12 Pharmaceutical composition microemulsion preparation of the invention
  • the preparation process was the same as in Example 7.
  • the particle size was measured by a laser granulometer, and the average particle diameter was 58 nm.
  • Example 13 In vitro antitumor effect of the pharmaceutical composition of the present invention
  • the tumor cells used include leukemia cells (HL-60), breast cancer cells (MCF-7), lung cancer cells (Calu-3), rectal cancer cells (Colo320), colon cancer cells (HCT-8), and ovarian cancer cells ( SK-OV-3), liver cancer cells (HepG2), gastric cancer cells (SGC-7901), prostate cancer cells (DU145) and cervical cancer cells (Hela), all of which are from the new drug of Shandong Lunan Pharmaceutical Group Co., Ltd. Pharmacological center cell culture chamber.
  • the bovine aglycone and tyrosine kinase inhibitors (the amounts thereof are shown in Table 1) were added to various tumor cells cultured in vitro for 24 hours, and the total number of cells was counted after 48 hours of culture.
  • the tumor growth inhibition effect is shown in Table 1.
  • Table 1 In vitro antitumor effect of the pharmaceutical composition of the present invention
  • Example 14 Effect of the pharmaceutical composition of the present invention on the growth of human non-small cell lung cancer ⁇ 549 cells in nude mice
  • Human non-small cell lung cancer cell line ⁇ 549 cell line was purchased from Wuhan University China Culture Collection (Wuhan, Hubei, China).
  • RPMI-1640 medium purchased from Gibeo; newborn calf serum, purchased from Hangzhou Sijiqing Bioengineering Materials Co., Ltd.; 0.25 % trypsin, purchased from Sigma.
  • Negative control group Administration by gavage was equivalent to 5% normal saline per mouse.
  • Bovine glycosides in the middle group intragastric administration of 25mg/kg_d arctigenin;
  • Imatinib group intragastric administration 25mg/kg-d
  • the effect of drugs on the growth of human lung cancer A549 cells in nude mice was demonstrated by comparison of tumor weight before and after treatment. The adverse reactions were recorded. The adverse reactions were vomiting, nausea, diarrhea, itchy skin and edema.
  • the incidence of adverse reactions the number of animals with the above adverse reactions / the total number of animals in the experimental group X 100%.
  • Table 2 Effect of the pharmaceutical composition of the present invention on the growth of human non-small cell lung cancer A549 cells in nude mice xenograft tumor weight/mg tumor inhibition rate/% adverse reaction rate/% negative Control group 483.50 ⁇ 86.45
  • Gefitinib group 360.14 ⁇ 71.86* 25.52 65.8 Group tumor weight / mg tumor inhibition rate /% incidence of adverse reactions /% erlotinib group 297.64 ⁇ 55.21 * 38.44 56.2
  • Negative control group 200 ⁇ 1 saline
  • Imatinib high group 10 mg/mL imatinib
  • Composition Group A 10.0 mg/mL arctigenin + O.lmg/mL imatinib
  • Composition Group B 1.0 mg/mL arctigenin + 1.0 mg/mL imatinib
  • Composition Group C O.lmg/mL arctigenin + 10.0mg/mL imatinib
  • the above treatment groups were all dissolved using 200 ⁇ l of physiological saline.
  • composition Group A 77.65 ⁇ 16.03 ## " $$ ⁇ 79.62 ⁇ 10.30 ## " ⁇ $$ 64.16 ⁇ 13.56 ## " ⁇ $$ Composition B Group 71.06 ⁇ 13.40 ** $ 80.13 ⁇ 18.51 ## " ⁇ ⁇ $$ 59.34 ⁇ " ⁇ $$ composition group C 81.25 ⁇ 11.67 ##” 10.23 ⁇ $$ 73.65 ⁇ 16.45 ## " ⁇ $$ 51.64 ⁇ 6.58 ##" ⁇ $$$
  • Imatinib compared with low dose group p ⁇ 0.05; $$ imatinib compared with imatinib low dose group, p ⁇ 0.01;
  • arctigenin and imatinib has an anti-tumor synergistic effect, which not only inhibits the growth of human acute promyelocytic leukemia NK4 cells and chronic granulocyte leukemia K562 cells, but more surprisingly, it can It inhibits the growth of retinoic acid-resistant promyelocytic leukemia MR-2 cells.
  • This result has profound guiding significance for clinical acute promyelocytic leukemia, chronic myeloid leukemia and retinoic acid-resistant promyelocytic leukemia.
  • various leukemia cells after the action of the pharmaceutical composition may have obvious morphological characteristics, namely, nucleus. Wrinkles, chromatin agglutination, and cleavage into fragments form an apoptotic body surrounded by a mold. Furthermore, in the composition group B, a part of the cell morphology was transformed into a mature direction, and the cells showed characteristics such as nuclear pyknosis, reduction of nucleoplasmic ratio, and reduction of nucleoli.
  • Example 16 Inhibition of the pharmaceutical composition of the present invention on leukemia cell line K562 cells in nude mice
  • Leukemia cell line K562 model 80 female BALB/C nude mice (SCXK II -00-0010) provided by 5-6 weeks old were selected, with an average body weight of 18-20 g.
  • K562 cell line was cultured in RPMI1640 medium containing 1 million U/L of penicillin, 800,000 U/L of streptomycin and 100 ml/L of inactivated calf serum at 37 ° C under 5% CO 2 culture. .
  • K562 cells in logarithmic growth phase were washed twice with PBS, adjusted to a concentration of 5 ⁇ 10 5 /mL, and subcutaneously injected into the right anterior and posterior iliac crest of 0.4 ml.
  • nude mice The growth of nude mice was observed every other day after injection, and it was accessible after 10 days. Tumor block, tumor size is about 0.5cm 3 . According to the tumor volume and weight-bearing principle of tumor-bearing mice, they were divided into 8 groups, 10 in each group. Each treatment group was intragastrically administered after dissolution using physiological saline equivalent to 5% by weight of each mouse.
  • Negative control group Administration of physiological saline equivalent to 5% of body weight per mouse
  • Imatinib low group 0.1 mg/kg imatinib
  • Imatinib high group 10 mg/kg imatinib
  • Composition Group A 10.0 mg/kg arctigenin + 0.1 mg/kg imatinib
  • Composition Group B 1.0 mg/kg arctigenin + 1.0 mg/kg imatinib
  • Composition Group C 0.1 mg/kg arctigenin + 10.0 mg/kg imatinib

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Abstract

La présente invention concerne une composition pharmaceutique antitumorale ou un nécessaire médicinal conditionné contenant de l'aglycone de bardane et un inhibiteur de protéine tyrosine kinase. L'association, entre l'aglycone de bardane et l'inhibiteur de protéine tyrosine kinase selon l'invention, s'avère particulièrement efficace pour coordonner l'inhibition des tumeurs, en particulier dans le cas de la leucémie et des tumeurs solides telles que le cancer bronchopulmonaire "non à petites cellules". En outre, cette association réduit les effets secondaires toxiques et la tolérance aux médicaments de l'inhibiteur de la protéine tyrosine kinase.
PCT/CN2011/079822 2010-09-19 2011-09-19 Compositions pharmaceutiques antitumorales Ceased WO2012034540A1 (fr)

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CN102397547B (zh) * 2010-09-19 2013-06-12 山东新时代药业有限公司 一种抗癌药物组合物
US9907852B2 (en) 2014-04-10 2018-03-06 National University Corporation University Of Toyama Anticancer agent and side-effect-alleviating agent
CN107412777B (zh) * 2017-08-08 2021-03-09 四川九章生物科技有限公司 一种抗肿瘤联合用药物及其在制备抗癌药物中的用途
CN108498575B (zh) * 2018-05-30 2021-06-22 南阳市中心医院 一种治疗食管鳞癌的药物及其制备方法
CN111110685A (zh) * 2018-10-31 2020-05-08 正大天晴药业集团股份有限公司 一种含伊布替尼的药物组合物及其应用
CN113491771A (zh) * 2020-03-18 2021-10-12 苏州大学 小分子化合物在制备glut5摄取转运果糖的抑制剂中的应用
CN114470216B (zh) * 2020-10-23 2024-08-06 和记黄埔医药（上海）有限公司 多受体酪氨酸激酶抑制剂与化疗剂的药物组合及其使用方法

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CN102397547B (zh) * 2010-09-19 2013-06-12 山东新时代药业有限公司 一种抗癌药物组合物
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WANG, LU ET AL.: "Advances in studies on pharmacological effects of arctiin and arctigenin.", CHINESE TRADITIONAL AND HERBAL DRUGS, vol. 39, no. 3, 2008, pages 468 - 469 *

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