WO2012034540A1 - Anti-tumor pharmaceutical composition - Google Patents

Abstract

An anti-tumor pharmaceutical composition or packaged medicinal kit containing burdock aglycone and tyrosine kinase inhibitor. The joint application of burdock aglycone and tyrosine kinase inhibitor used in the present invention exhibits significant coordination effects in inhibiting tumors, especially in leukemia and solid tumors such as non-small-cell lung cancer, and reduces the poisonous side effect and drug tolerance of tyrosine kinase inhibitor.

Description

 Antitumor drug composition

Technical field

 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. According to the 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. Among them, 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. Immunomodulatory effect of arctigenin, a lignan compound on tumor necrosis factor-α and nitric oxide production, and lymphocyte proliferation [J]. J Pharm Pharmcol. 1999; 51(11): 1267-1273 Angerin has anti-inflammatory and immunomodulatory effects; Gao Y, et al. Activity of in vitro anti-influenza virus of arctigenin [J]. Chinese Traditional and Herbal Drugs (《Chinese Herbal Medicine). 2002; 33(8): 724 -726. It is disclosed that arctigenin has an antiviral effect; Kim SH, et al. Hepatoprotective dibenzylbutyrolactone lignans of Torreya nucifera against CC14-induced toxicity in primary cultured rat hepatocytes [J]. Biol Pharm Bull. 2003; 26(8) : 1202-1205 discloses that arctigenin has the effect of inducing apoptosis of tumor cells. Wang et al., "Progress in the pharmacological action of arctiin and arctigenin" (Chinese herbal medicine, Vol. 39, No. 3, 2008, pp. 467-450) discloses that arctigenin has anti-lung cancer activity. , wherein 4-nitroquinoline-N-oxygen The agent is an initiator, glycerol is used as a promoter to induce lung cancer in rats, and a two-phase carcinogenesis test of rat lung cancer is carried out. The results show that arctigenin has anti-lung cancer activity.

 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. Among them, 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. Such as significant nausea, vomiting or diarrhea. In the case of erlotinib, 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. In the case of 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.

 At present, 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. There are clinical attempts to use tyrosine kinase inhibitors in combination with other chemotherapeutic drugs, but there are still many toxic side effects.

For example, when imatinib mesylate is combined with homoharringtonine, transient hepatotoxicity can occur, such as elevated transaminases and hyperbilirubinemia (Li Yufeng, Ding Bang and et al. Therapeutic effect of nicil 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. 5, 777-784—disclosed in combination with gefitinib, cisplatin, and gemcitabine Technical solution for advanced non-small cell lung cancer. Ulrich Gatzemeier et al, Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non-Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial, JCO April 20, 2007 vol. 25 no. 12, 1545-1552 - published in the text Combination of erlotinib, cisplatin and gemcitabine for treatment Technical solution for advanced non-small cell lung cancer. The other two chemotherapeutic drugs, cisplatin and gemcitabine, used in the latter two literatures are highly toxic, although the combination has a certain synergistic effect, but the side effects are still obvious. Currently, it is necessary to select the appropriate drug from a combination of anti-tumor drugs in combination with a tyrosine kinase inhibitor in order to obtain a therapeutic effect while minimizing the toxic side effects and drug resistance of tyrosine kinase inhibitors. The difficulty is also quite large. Summary of the invention

 Based on the above problems in the art, in one aspect, the present invention provides an antitumor pharmaceutical composition comprising the following active ingredients:

(1) arctigenin; and

(2) Tyrosine kinase inhibitors.

 According to a preferred embodiment, the weight ratio of said tyrosine kinase inhibitor to arctigenin in the pharmaceutical composition of the present invention is (0.005-100): 1.

 According to another preferred embodiment, 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.

 According to another preferred embodiment, in the pharmaceutical composition of the present invention, 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.

 According to another preferred embodiment, 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.

 According to another preferred embodiment, in the pharmaceutical composition of the present invention, 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.

 In another aspect, the present invention provides an antitumor kit comprising the following active ingredients:

 (1) burdock aglycon;

(2) Tyrosine kinase inhibitors. 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.

 According to a preferred embodiment, the weight ratio of tyrosine kinase inhibitor to arctigenin in the kit of the invention is (0.005-100): 1.

 According to another preferred embodiment, 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.

 According to another preferred embodiment, in the kit of the invention, 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.

 According to another preferred embodiment, in the kit of the present invention, 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 When the form is present in a kit, 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.

 According to another preferred embodiment, in the kit of the invention, 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.

 According to one embodiment, 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.

 In addition, the kit of parts further includes instructions for use.

In still another aspect, 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.

 In still another aspect, 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. , 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 resistant promyelocytic Leukemia, most preferably, the tumor is a non-small cell lung. According to a preferred embodiment of the above treatment or prevention method, 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.

 Surprisingly, the inventors have found that 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. Compared to certain other combinations, there is a significant synergistic effect in inhibiting tumors, particularly solid tumors and leukemias such as non-small cell lung cancer, while reducing the toxic side effects and drug resistance of tyrosine kinase inhibitors. 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

 The invention is further described by the following examples, but it should be understood that the invention is not limited to the following examples. Experimental materials and equipment:

 Angerin

 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:

 1. Put the weighed pharmaceutical excipient into the container, dissolve the solvent evenly, and the amount of the solvent is not strictly limited, so it is better to dissolve it.

 2. Add the weighed single or compound anti-tumor active component to a certain weight percentage and shake again.

 3. Remove the solvent, vacuum drying or low temperature drying.

 4. The dried solid composition is made into various shapes.

 5. Dispensing and sterilizing.

 The above process can be appropriately adjusted according to the specific dosage form, and the relevant process steps can be omitted or added if necessary. Pharmaceutical excipients in

(The Daquan of Medicinal Excipients) (page 123, Sichuan Science and Technology Press, published in 1993, edited by Luo Mingsheng and Gao Tianhui) has been described in detail. The pharmaceutical excipients used in the antitumor pharmaceutical compositions or kits of the present invention are conventional excipients known to those skilled in the art. For example, 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. For example, 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

 Angerin 10g

 Gefitinib 0.05g

Soybean oil 35g Polyoxyethylene-23-lauryl ether 60g

 1,2-propanediol 30g

 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

 Angerin aglycone O. lg

 Gefitinib 5g

 Hydrogenated cocoglyceride 5g

 Lauric acid polyethylene glycol-32-glyceride 20g

 1,2-propanediol 5g

 Polyethylene glycol 3350 20g

 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

 Angerin 10g

 Gefitinib 10g

 Safflower oil 35g

 Polyoxyethylene -23-lauryl ether 60g

 1,2-propanediol 30g

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

 Angerin 10g

 Erlotinib 0.5g

 Cottonseed oil 30g

 Decaglyceryl monostearate 55g

 1,2-propanediol 25g

 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

 Angerin 2g

 Erlotinib 2g

 Soybean oil 30g

 Decaglyceryl monostearate 55g

 1,2-propanediol 25g

 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

 Angerin aglycon

 Erlotinib 25g

 Soybean oil 30g

 Decaglyceryl monostearate 55g

 1,2-propanediol 25g

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

 Angerin

 Imatinib mesylate

 Soybean oil

 Decaglycerol monostearate

 1,2-propanediol

 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

 Angerin aglycone 5.0 g

 Erlotinib 50.0 g

 Polyethylene glycol -6000 14.5 g

 Polyethylene glycol -1000 5.0 g

 Made of 1000 capsules

 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

 Content prescription:

 Angerin 10 g

 Imatinib 200 g

 Anhydrous ethanol 10 g

 1,2-propanediol 10 g

 Polyoxyethylene castor oil 50 g

Medium chain fatty acid glyceride 20 g Rubber prescription:

 Gelatin 10 g

 Glycerin 5 g

 Purified water 10 g

 Enteric coating solution:

 Eudragit L30D-55 100 g

 Triethyl citrate 3 g

 Talc 7.5 g

 Purified water 200 g

 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. Weigh the prescribed amount of Eudragit L30D-55, triethyl citrate, talc, and purified water to make an enteric coating liquid. The soft capsule microemulsion contents containing burdock aglycon and imatinib are wrapped in a soft capsule, and the enteric soft capsule is prepared by coating the soft capsule on the casing. Example 10: Pharmaceutical composition capsule preparation of the present invention

 Angerin aglycone 100 g

 Gefitinib 5 g

 Lactose 120 g

 Corn starch 130 g

 Magnesium stearate 5 g

 Preparation process: 100 g of burdock aglycone, 5 g of gefitinib, 120 g of lactose and 130 g of corn starch are mixed in a mixer for 10-15 minutes, and 5 g of magnesium stearate is added and mixed for 1-3 minutes, and then 1000 capsule shells are charged. can. Example 11: Pharmaceutical composition microemulsion preparation of the invention

 Angerin 2g

 Imatinib 2g

Soybean oil 30g Decaglyceryl monostearate 55g

 1,2-propanediol 25g

 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

 Angerin A.lg

 Imatinib 10g

 Soybean oil 30g

 Decaglyceryl monostearate 55g

 1,2-propanediol 25g

 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

Tumor cells ABCD A+B A+C A+D Leukemia cells 50% 20% 30% 26% 94% 97% 94% Breast cancer cells 45% 40% 45% 61% 92% 89% 88% Lung cancer cells 40% 30 % 45% 42% 97% 92% 96% Rectal cancer cells 46% 40% 50% 40% 86% 89% 87% Ovarian cancer cells 53% 30% 40% 42% 86% 86% 92% Colon cancer cells 50% 35% 35% 30% 95% 96% 94% Liver cancer cells 39% 41% 54% 45% 99% 98% 97% Tumor cells ABCD A+B A+C A+D prostate cancer cells 44% 40% 43% 40% 89% 90% 90% gastric cancer cells 42% 38% 32% 30% 88% 92% 94% cervical cancer cells 55% 30% 35% 31% 99% 96% 96% Note: A is 200ng/ml of arctigenin, B is li^g/ml gefitinib, C is li^g/ml erlotinib, D is 10μ _§ / ηι1 imatinib. As can be seen from Table 1, the tumor inhibition rate of the composition of the tyrosine kinase inhibitors gefitinib, erlotinib, imatinib and arctigenin was significantly higher than that of the tyrosine kinase inhibitor monotherapy group. It was also significantly higher than the arctigenin group, and there was a synergistic effect between the arctigenin and the tyrosine kinase inhibitor on solid tumor suppression. Example 14: Effect of the pharmaceutical composition of the present invention on the growth of human non-small cell lung cancer Α549 cells in nude mice

 1. Materials and methods

 1.1, cell line

 Human non-small cell lung cancer cell line Α549 cell line was purchased from Wuhan University China Culture Collection (Wuhan, Hubei, China).

 1.2, drugs and reagents

 RPMI-1640 medium, purchased from Gibeo; newborn calf serum, purchased from Hangzhou Sijiqing Bioengineering Materials Co., Ltd.; 0.25 % trypsin, purchased from Sigma.

 1.3, human non-small cell lung cancer xenograft tumor treatment experiment

228 SPF-class BALB/c- dishes were provided by China National Institute for the Control of Pharmaceutical and Biological Products (SCXK II -00-0010), 6 weeks old, and weighed 16g-18g. The A549 cells in logarithmic growth phase were adjusted to a concentration of 3× ^{10 7} /mL with sterile PBS. The A549 cells were inoculated subcutaneously in the back of each BALB/c-nu mouse, and the volume of the subcutaneous transplanted tumor was 75 mm ^{3 .} When left and right (about 10d), according to the tumor volume and tumor-bearing rat weight balance principle, 19 groups, 12 in each group. Each treatment group was intragastrically administered after dissolution with physiological saline equivalent to 5% by weight of each mouse.

 Negative control group: Administration by gavage was equivalent to 5% normal saline per mouse.

 Low-quantity group of burdock aglycone: 0.1mg/kg_d burdock aglycone;

 Bovine glycosides in the middle group: intragastric administration of 25mg/kg_d arctigenin;

High dose of arctigenin: 100mg/kg_d burdock aglycone; Gefitinib group: 25mg/kg-d by intragastric administration

 Erlotinib group: intragastric administration 25mg/kg-d

 Imatinib group: intragastric administration 25mg/kg-d

 Astragalus aglycone + gefitinib group A: intragastric administration of 0.1mg/kg_d arctigenin +5mg/kg_d gefitinib; burdock aglycone + gefitinib group B: intragastric administration of 25mg/kg_d burdock Aglycone +25mg/kg_d gefitinib; arctigenin + gefitinib group C: intragastric administration of 100mg/kg_d arctigenin +5mg/kg_d gefitinib; arctigenin + gefitinib D Group: 100 mg/kg _d burdock + 0.5 mg/kg _ gefitinib; burdock aglycone + erlotinib group A: intragastric administration 0.1 mg/kg _d burdock aglycone +2.5 mg/kg _d Lotiinib; burdock aglycone + erlotinib group B: intragastric administration of 25mg/kg_d arctigenin +25mg/kg_d erlotinib; arctigenin + erlotinib group C: intragastric administration of 25mg /kg_d burdock aglycone +2.5mg/kg_d erlotinib; burdock aglycone + erlotinib group D: intragastric administration of 100mg/kg_d burdock aglycone +5mg/kg_d erlotinib; burdock aglycone + y Matinib group A: intragastric administration of 0.1 mg/kg _d arctigenin + 10 mg/kg _d imatinib; burdock aglycone + imatinib group B: intragastric administration of lmg/kg_d burdock aglycone + 20 mg / Kg_d imatinib; burdock aglycone + imatinib group C: Administration by intragastric administration 25mg/kg_d arctigenin +25mg/kg_d imatinib; burdock aglycone + imatinib group D: intragastric administration 100mg/kg_d arctigenin +lmg/kg_d imatinib;

 The drug was administered once a day for a total of 8 times, and the longest diameter (L) and the shortest diameter (w) of the transplanted tumor were measured with a vernier caliper every 4 days during the administration. After 48 hours of the last administration, the mice were sacrificed by dislocation and the transplanted tumor was removed, and the tumor weight was weighed. Tumor inhibition rate (%) IR = (1 - mean tumor weight in the experimental group / mean tumor weight in the control group) x 100%. 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. According to the time course of treatment, the incidence of adverse reactions such as common diarrhea and edema was recorded, and the incidence of adverse reactions was calculated. 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%.

 1.4, statistical processing

 Data were expressed as mean ± standard deviation (X ± S), and analysis of variance was performed using SPSS 15.0 software.

 2. Test results (see Table 2) 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

 Imatinib group 387.91±81.42* 19.77 49.8

 Low caloriin group 442.74±45.36* 8.43 5.2

 Burdock aglycone medium group 371.71±82.23* 23.12 8.4

 High caloriin group 324.28±60.21* 32.93 10.6

 >$$■■

 Angerin + erlotinib group A 160.91±50.77" 66.72 18.3

 '$$▲▲

 Angerin + erlotinib group B 119.90±46.35" 75.20 31.6

Angerin 10 erlotinib C group 95.48±42.34** ^$$AA 80.25 20.2

Angerin + erlotinib group D 91.87 ± 40.27** ^$$ ** 81.00 23.5

 Angerin + gefitinib group A 192.82±60.21 60.12 25.6

 Angerin + gefitinib group B 153.12士53.2 68.33 33.7

 *##♦♦

 Angerin + gefitinib C group 116.24±20.06" 75.96 16.7

 *##♦♦

 Angerin + gefitinib Group D 133.40±26.85*' 72.41 15.6

 Angerin + imatinib group A 257.60±26.53*' 46.72 23.6

 Angerin + imatinib group B 226.34±30.64*' 53.19 25.3

 »&▲

 Angerin + imatinib group C 216.60±60.11*' 55.20 31.5

Angerin + Imatinib Group D 188.5650.21** ^&& * 61.00 11.8

 --no effect

 *p<0.05 compared with the negative control group; "p<0.01 compared with the negative control group;

# ^# Imatinib group compared with gefitinib, p <0.01; ^$$ compared with erlotinib, ρθ.01;

 && compared with the imatinib group, ρθ.01 ; & compared with the imatinib group, p < 0.05;

"Compared with arctigenin low dose group, p <0.01; ^AA compared with the amount arctigenin group, p <0.01;" Compared with arctigenin volume group, p <0.01;

 "P<0.05 compared with the low-quantity group of burdock aglycone; ▲p<0.05 compared with the middle-weight group of arctigenin;

 *Compared with the high concentration of arctigenin, p<0.05 The results of the test in Table 2 indicate:

(1) Compared with the negative control group, the inhibition effect of the treatment group on the growth of human non-small cell lung cancer A549 cells in nude mice was significantly different (p<0.05) or extremely significant (p<0.01). (2) Inhibition of the growth of human non-small cell lung cancer A549 cells in nude mice by the combination of four groups of arctigenin and gefitinib compared with the monotherapy group of gefitinib and arctigenin Very significant difference

(p<0.01) and have a synergistic effect. In addition, we were surprised to find that, regardless of the dose of gefitinib, even in the case of a very low dose of gefitinib, as long as it is a combination of arctigenin and gefitinib, the pharmaceutical composition is not small for humans. The inhibitory effect of cell lung cancer A549 cells on the growth of xenografts in nude mice was very significant and significantly higher than the high dose of gefitinib used alone.

 (3) Inhibition of the growth of human non-small cell lung cancer A549 cells in nude mice by the combination of four groups of arctigenin and erlotinib compared with the erlotinib group and the bursin aglycone group Very significant difference

(p<0.01) and have a synergistic effect. In addition, we were surprised to find that, regardless of the dose of erlotinib, even in the case of a very low dose of erlotinib, as long as it is a combination of arctigenin and erlotinib, the pharmaceutical composition is not small for humans. The inhibitory effect of cell lung cancer A549 cells on the growth of xenografts in nude mice was very significant and significantly higher than the high dose of erlotinib used alone.

 (4) Compared with the imatinib monotherapy group, three groups (groups A, B, and C) of the four groups of bovine aglycon and imatinib were administered to human non-small cell lung cancer A549 cells in nude mice. There was a significant difference in the inhibition of tumor growth (p<0.05). There was a significant difference in the inhibition of human non-small cell lung cancer A549 cells transplanted in nude mice (P<0.01). Compared with the bovine glycoside monotherapy group, the drug composition of four groups of arctigenin and imatinib significantly inhibited the growth of human non-small cell lung cancer A549 cells in nude mice (p<0.05). o indicates that the pharmaceutical composition of arctigenin and imatinib has a synergistic effect on the growth inhibition of human non-small cell lung cancer A549 cells in nude mice. In addition, we were surprised to find that, regardless of the dose of imatinib, even in the case of a low dose of imatinib, as long as it is a combination of arctigenin and imatinib, the pharmaceutical composition is not small for humans. The inhibitory effect of cell lung cancer A549 cells on the growth of xenografts in nude mice was very significant and significantly higher than the high dose of imatinib used alone.

 (5) The incidence of adverse reactions of tyrosine kinase inhibitors alone is generally greater than 50%, and the incidence of adverse reactions after the combination of arctigenin and tyrosine kinase is significantly lower than that of the group administered alone. Example 15: Experiment on the effect of the pharmaceutical composition of the present invention on the growth of leukemia cells

 1. The experimental grouping and final drug concentration are as follows:

 Negative control group: 200μ1 saline

 Low amount of arctigenin: 0.1mg/mL arctigenin

High concentration of arctigenin: 10mg/mL arctigenin Imatinib low group: 0.1 mg/mL imatinib

 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 μl of physiological saline.

 2. The experimental plan and results are as follows:

Human acute promyelocytic leukemia ΝΚ4 cells, chronic myeloid leukemia Κ562 cells, retinoic acid-resistant promyelocytic leukemia MR-2 cells (all of the above three cells are from the new drug pharmacology center cells of Shandong Lunan Pharmaceutical Group Co., Ltd., China) The culture chambers were inoculated separately in RPMI-1640 medium, cultured in a 5% CO ₂ incubator at 37 ° C, seeded in 96-well culture plates, and the corresponding concentrations of drugs were added in groups at the time of inoculation. After 5 hours, the tumor growth inhibition rate was determined by MTT reduction reaction after 48 hours. The experimental data were statistically analyzed by Excel system. See Table 3 for details. Table 3: Effect of the pharmaceutical composition of the invention on the growth of leukemia cells

 NK4 cell inhibition rate

 Group K562 cell inhibition rate (%) MR-2 cells (%)

 (%)

 Negative control group 0.52±0.06 0.13±0.02 0.22±0.02

 Low-quantity group of arctigenin 27.26±6.31 10.45±4.58 28.56±5.68

 High caloriin group 36.54±5.38 40.26±9.54 22.48±3.25

 Imatinib low volume group 42.36±8.56 9.89±2.12 3.21±1.52

 Imatinib high volume group 59.4±8.21 47.67±8.33 9.25±2.58

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 ## "¥¥ $$ 51.64 ± 6.58 ##" ¥¥ $$

# Compared with the low-quantity group of burdock aglycone, p<0.01; "p<0.01 compared with the high-quantity group of burdock aglycone;

Imatinib compared with low dose group, p <0.05; ^$$ imatinib compared with imatinib low dose group, p <0.01;

f vs. imatinib high dose group, p<0.05 _; ^{¥¥ compared} with imatinib high dose group, p<0.01. As can be seen from the results of Table 3 above, the compositions of Group A, Group B and Group C have compared with the low dose group of arctigenin. The significant difference (p<0.01) was also significantly different from the high dose group of bovine aglycone (p<0.01), which was significantly different or significantly significant compared with the two dose groups of imatinib. Sexual differences. This indicates that the combination of 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. In addition, compared with the negative control group, various leukemia cells after the action of the pharmaceutical composition, whether K562 cells, NK4 cells, or MR-2 cells, 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

1. 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. 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.

 2. The experimental grouping and final drug concentration are as follows:

 Negative control group: Administration of physiological saline equivalent to 5% of body weight per mouse

 Low amount of burdock aglycone: 0.1mg/kg anthraquinone

 High dose of arctigenin: 10mg/kg burdella

 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

 3. The experimental results are as follows:

Before administration, the active ingredients of each drug were dissolved in physiological saline, and each nude mouse was administered once in the morning and evening. Observation of each group after administration The growth of nude mice, the tumor volume was measured weekly, and the nude mice were sacrificed after 14 days of treatment. The intact tumor pieces were removed, weighed, and taken for examination. See Table 4 for the specific results. Table 4: Inhibitory effect of the pharmaceutical composition of the present invention on K562 cells in nude mice Group tumor weight/mg tumor inhibition rate/% incidence of adverse reactions/% negative control group 450.62±62.75

Low-quantity group of burdock glycosides 428.26±52.63 4.96 5.3 high-quantity group of burdock aglycone 384.62±46.26 14.7 11.4 low-volume group of imatinib 411.56±36.65 8.67 45.3 high-value group of imatinib 374.32±35.86 16.9 57.6 Composition group A 180.86 ± 26.84 ** ^$$ 59.8 19.8 group composition B 149.78 ± 25.87 ** ^$$ 66.8 15.6 group composition ^{C 121.54 ± 16.98 ## "¥¥ 73.1} 11.7

 -no effect

 Compared with the low amount of arctigenin, p<0.01; "p<0.01 compared with the high dose of arctigenin;

Compared with the low dose group of imatinib, p<0.01 _; ^{¥¥ compared} with the high dose group of imatinib, p<0.01. From the results of Table 4 above, it can be seen that the therapeutic effects of the treatment groups were significantly different from those of the negative control group (p<0.05), and the compositions of Group A, B and C were compared with the low dose group of arctigenin. There was a significant difference (p < 0.01), and there was a significant difference (p<0.01) compared with the high dose group of arctigenin, which was significantly different from the two dose groups of imatinib or Very significant difference. This indicates that the combination of arctigenin and imatinib inhibits the growth of leukemia cells in vivo, which can significantly inhibit the growth rate of tumors and even reduce the weight of tumors, while reducing the side effects and adverse reactions of imatinib alone. The incidence is significantly reduced.

 In the above Examples 15 and 16, the replacement of the tyrosine kinase inhibitor imatinib with another tyrosine kinase inhibitor such as gefitinib and erlotinib achieved similar therapeutic effects. It shows that the combination of arctigenin and tyrosine kinase inhibitor can achieve significant synergistic effect in the treatment of leukemia, and at the same time reduce the side effects of imatinib alone, and the incidence of adverse reactions is significantly reduced.

In summary, the above Examples 13-16 show that the pharmaceutical composition or kit of the burdock aglycone and the tyrosine kinase inhibitor has a remarkable synergistic antitumor effect both in vitro and in vivo, while reducing tyrosine The toxic side effects of kinase inhibitors, due to the synergistic effect, are significantly reduced in clinical dose compared with the drug alone, and the drug resistance potential Must be reduced. This is of great significance in clinical applications. Although the present invention has been described by the above embodiments, those skilled in the art will recognize that any equivalents are obvious to the present invention and are included in the present invention, that is, without departing from the scope of the invention or Various changes and modifications can be made to the invention without departing from the spirit. Accordingly, the invention is intended to embrace all such modifications and alternatives

Claims

Rights request An antitumor pharmaceutical composition comprising the following active ingredients:  (1) burdock aglycon;  (2) Tyrosine kinase inhibitors.  2. An anti-tumor kit comprising the following active ingredients:  (1) burdock aglycon;  (2) Tyrosine kinase inhibitors.  The pharmaceutical composition according to claim 1 or the kit according to claim 2, wherein the weight ratio of the tyrosine kinase inhibitor to arctigenin is (0.005-100): 1 .  The pharmaceutical composition or kit of parts according to any one of claims 1 to 3, wherein the tyrosine kinase inhibitor is imatinib or a pharmaceutically acceptable salt thereof, gefitinib Or a pharmaceutically acceptable salt thereof, or erlotinib or a pharmaceutically acceptable salt thereof, wherein, preferably, the pharmaceutically acceptable salt of imatinib is its mesylate salt.  The pharmaceutical composition or kit according to claim 4, wherein when the tyrosine kinase inhibitor is imatinib or a pharmaceutically acceptable salt thereof, imatinib or its The weight ratio of the medicinal salt to imglucin in terms of imatinib is (0.01-100): 1;  When the tyrosine kinase inhibitor is gefitinib or a pharmaceutically acceptable salt thereof, the weight ratio of gefitinib or a pharmaceutically acceptable salt thereof to gefitinib is (0.005-50) ): 1;  When the tyrosine kinase inhibitor is erlotinib or a pharmaceutically acceptable salt thereof, the weight ratio of erlotinib or a pharmaceutically acceptable salt thereof to bursinini in terms of erlotinib is (0.05-25) ): 1. The pharmaceutical composition or kit according to any one of claims 1 to 5, wherein the pharmaceutical composition is in 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, more preferably a microemulsion preparation, wherein the microemulsion preparation preferably has an average particle diameter of 15 to 80 nm; in the kit of parts, when When the active ingredient is present in the kit in the form of a composition, the dosage form is a form suitable for gastrointestinal or parenteral administration, preferably a tablet, an emulsion, a microemulsion, a capsule, a dropping pill or a soft a capsule, more preferably a microemulsion preparation, wherein the microemulsion preparation preferably has an average particle diameter of 15 to 80 nm, and when the two active ingredients are present in a separate form in a kit, the dosage form is suitable for gastrointestinal or non-stomach The dosage form for enteral administration is preferably a tablet, an emulsion, a microemulsion preparation, a capsule, a dropping pill or a soft capsule, wherein the bovine aglycone is more preferably a microemulsion preparation, and the microemulsion preparation preferably has an average particle diameter of 15 to 80 nm. The tyrosine kinase inhibitor is more preferably a tablet. The pharmaceutical composition or kit according to claim 6, wherein in the pharmaceutical composition, the arctiin or tyrosine kinase inhibitor is measured by its free acid or free base , the content of arctigenin in each preparation unit is 1 mg-200 mg, and the content of tyrosine kinase inhibitor is 2 mg-100 mg; in the kit, the burdock aglycone or tyrosine kinase inhibitor is The content of the burdock aglycone present in the composition or in the form of the free acid or the free base is from 1 mg to 200 mg in each preparation unit, and the tyrosine kinase inhibitor is present in the composition or in the form of each in each preparation. The content in the unit is 2 mg to 100 mg.  The use of the pharmaceutical composition or kit of any one of claims 1 to 7 for the preparation of a medicament for treating or preventing a tumor, preferably, the tumor is a solid tumor or leukemia, more preferably, Solid tumors are 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, chorionic epithelial cancer, malignant mole, bladder cancer, skin cancer, head Cervical cancer, bronchial lung cancer, colorectal cancer, and non-small cell lung cancer, the leukemia is selected from the group consisting of acute promyelocytic leukemia, chronic myeloid leukemia, and retinoic acid resistant promyelocytic leukemia, and most preferably, the tumor is non-small Cell lung cancer.  A method for treating or preventing a tumor, which comprises administering the pharmaceutical composition or kit of any one of claims 1 to 7 to a human or animal having a tumor or at risk of developing a tumor, preferably The tumor is a solid tumor or leukemia. 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, and esophageal cancer. , chorionic 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 Most resistant to promyelocytic leukemia, most preferably, the tumor is non-small cell lung cancer. 10. The method of treatment or prevention according to claim 9, wherein the two active components of the kit, the anthraquinone and the tyrosine kinase inhibitor, are administered simultaneously or sequentially, wherein When administered sequentially, the two active ingredients are administered no more than 3 hours apart.