A pharmaceutical composition for improving the treatment effect of liver tumor and use thereof

Abstract

The application belongs to the field of medicine, and particularly relates to a medicine composition for improving the treatment effect of liver tumor and the use thereof. The medicine composition comprises chrysin and hydroxycamptothecine or vincristine, and the weight ratio of the chrysin and the hydroxycamptothecine or vincristine is 1:(1.5-5). The main components of the medicine composition, i.e. the chrysin, the hydroxycamptothecine or the vincristine, are all natural and non-toxic, can be prepared into oral preparations together with common pharmaceutically acceptable carriers, and it is proved through pharmacodynamics experiments that the two components have a synergistic effect, and can greatly improve the treatment effect of liver tumor.

Description

Technical Field

[0001] This invention belongs to the field of medicine, specifically relating to a pharmaceutical composition for improving the therapeutic effect of liver tumors and its uses. Background Technology

[0002] Liver tumors rank third in cancer mortality worldwide, characterized by high invasiveness, rapid proliferation, and high recurrence rate. At least 400,000 new cases are diagnosed annually, with a mortality index of 0.94. Currently, surgery remains the preferred treatment for liver tumors, but the overall surgical resection rate is only 20%–30%. Many patients lose the opportunity for surgery at diagnosis due to tumor size, location, liver function, and overall health. Therefore, standardized comprehensive treatment has become a primary issue in clinical research on liver tumors. Chemotherapy is the most important and common component of this approach. However, the efficacy of traditional chemotherapy is limited by the following factors: (1) intravenously administered antitumor drugs are difficult to achieve effective concentrations within the tumor; (2) systemic adverse reactions caused by intravenous administration limit the dosage; and (3) the short half-life of most antitumor drugs makes it difficult to maintain a stable effective concentration within the tumor.

[0003] Medical professionals worldwide have been making unremitting efforts to enhance the efficacy of antitumor drugs in two main areas: (1) researching antitumor mechanisms and developing novel antitumor drugs; and (2) modifying the dosage form and pharmacokinetic properties of existing chemotherapeutic drugs to allow them to act on tumor tissue in the most suitable manner. The latter is particularly important for solid tumors. However, developing novel antitumor drugs requires considerable time and cost, and the results are not always significant. Almost every possible attempt has been made to modify the dosage form and pharmacokinetic properties of existing drugs, with little progress in recent years. Therefore, new approaches are needed to expand the range of therapeutic drugs for liver tumors.

[0004] Chrysin, also known as 5,7-dihydroxyflavone, is one of the main bioactive components of honey, royal jelly, and propolis, and is also an effective component of traditional Chinese medicine such as the buds and scales of poplar plants. As a common food-source flavonoid, chrysin has the advantage of low or no toxicity. Chrysin exhibits good anti-proliferative activity against various tumor cells, while showing no significant toxicity to normal cells. Chrysin can prevent azomethane-induced precancerous lesions of the colon in obese mice. Chrysin has a pro-apoptotic effect on certain colon cancer, gastric cancer, leukemia, and melanoma cell lines. However, the effect of chrysin on the apoptosis pathway varies in different cell lines. Chinese propolis and chrysin can significantly reduce the mortality rate of human SH-SY5Y neuroblastoma induced by endoplasmic reticulum stress inducers tunicamycin and astrospore, while Brazilian propolis, which does not contain chrysin, has no such effect; among the unique components of Chinese propolis, chrysin is the only one with significant anti-apoptotic activity, suggesting a role in preventing neurodegenerative diseases. Juglansin can also reduce oxidative stress-induced apoptosis or necrosis and improve the survival rate of normal neurons. Juglansin can promote apoptosis in certain tumor cells and protect and inhibit apoptosis in normal cells, which is superior to traditional chemotherapy drugs. Juglansin can downregulate hypoxia-inducible factor HIF-1α, which is closely related to tumor stem cells, and can block the action of the stem cell factor SCF / c-Kit complex. Juglansin may also exert anti-cancer effects by depleting glutathione and inhibiting angiogenesis. Depending on the tumor cell line, juglansin can produce G1 or G2 / M phase blockade effects on the cell cycle. The inhibitory effect of juglansin on matrix metalloproteinases (MMPs) has also attracted attention. Juglansin can inhibit the activity of collagenase (belonging to the MMP family) and prevent skin aging caused by ultraviolet radiation. Juglansin is the main component of propolis flavonoids, and the anti-atherosclerotic activity of propolis flavonoids may be related to the inhibition of MMP-9 expression in vascular endothelial cells. MMPs are involved not only in inflammation, cardiovascular disease, and aging processes, but are also closely related to tumorigenesis and metastasis. It remains unclear whether succinin inhibits the expression and enzyme activity of multiple MMPs, thereby exerting a corresponding anti-tumor effect.

[0005] This invention is based on the characteristics of apigenin, which is natural, non-toxic, and has good anti-proliferative activity against a variety of tumor cells. It conducts in-depth research on its therapeutic effects on liver tumors, especially on pharmaceutical compositions that improve the therapeutic effects of liver tumors. Summary of the Invention

[0006] The purpose of this invention is to provide a pharmaceutical composition and its use for improving the therapeutic effect of liver tumors.

[0007] Specifically, the present invention is achieved through the following technical solutions.

[0008] In a first aspect, the present invention provides a pharmaceutical composition for improving the therapeutic effect of liver tumors, the pharmaceutical composition comprising apigenin and hydroxycamptothecin or vincristine.

[0009] Preferably, in the above pharmaceutical composition, the weight ratio of apigenin to hydroxycamptothecin or vincristine is 1:(1.5-5).

[0010] More preferably, in the above pharmaceutical composition, the weight ratio of apigenin to hydroxycamptothecin or vincristine is 1:(2.5-3.5).

[0011] Most preferably, in the above pharmaceutical composition, the weight ratio of apigenin to hydroxycamptothecin or vincristine is 1:3.

[0012] The pharmaceutical composition of the present invention for improving the therapeutic effect of liver tumors further comprises a pharmaceutically acceptable carrier. "Pharmaceutically acceptable carrier" refers to any excipient that can be prepared into a pharmaceutical formulation with styraxin and hydroxycamptothecin or vincristine and used in clinical treatment. It is selected from one or more of starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, mannitol, magnesium stearate, microcrystalline silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, and magnesium lauryl sulfate.

[0013] Preferably, the dosage form of the above-mentioned pharmaceutical composition is an oral dosage form.

[0014] In addition to apigenin and hydroxycamptothecin or vincristine, the pharmaceutical composition for improving the therapeutic effect of liver tumors described in this invention may also contain or exclude other drugs for treating liver tumors, such as 5-fluorouracil (5FU) and its derivatives; doxorubicin (ADM), mitomycin C (MMC) and their respective derivatives; carmustine (BCNU) and its derivatives; thiotepa, methotrexate, etoposide (VP16), ifosfamide, mitoxantrone, minocycline, gemcitabine, etc.

[0015] In a second aspect, the present invention provides the use of the pharmaceutical composition described in the first aspect above in the preparation of a medicament for treating liver tumors.

[0016] Compared with the prior art, the present invention has the following advantages:

[0017] This invention, leveraging my country's strengths in natural compound research, is the first to discover that combining jujube extract with hydroxycamptothecin or vincristine in specific dosage ratios can significantly improve the therapeutic effect on liver tumors. The effect is significantly superior to using the same dosage of jujube extract and hydroxycamptothecin or vincristine alone, indicating a significant synergistic effect. The pharmaceutical composition of this invention shows promise for development into a drug for treating liver tumors, possessing significant social and economic benefits. Detailed Implementation

[0018] The embodiments of the present invention are described in detail below. The embodiments are provided to better illustrate the content of the present invention and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0019] Where specific techniques or conditions are not specified in the examples, they shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels.

[0020] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the experimental materials used in the following embodiments are commercially available products.

[0021] Example 1: Tablet Composition

[0022]

[0023] Weigh out the amount of styraxin, hydroxycamptothecin, and pharmaceutical excipients according to the formula. Mix styraxin and hydroxycamptothecin evenly, then add microcrystalline cellulose and starch, mix well, dry, and pulverize into fine powder. Prepare a soft mass with 50% ethanol, granulate through a 50-mesh sieve, dry the granules, pass them through a 50-mesh sieve, add magnesium stearate, mix well, and compress into tablets to obtain the final product.

[0024] Example 2 and Comparative Examples 1-7: Tablet Compositions

[0025] The tablet compositions of Example 2 and Comparative Examples 1-7 were prepared using a method similar to that of Example 1, as shown in Table 1.

[0026] Table 1: Tablet compositions of Example 2 and Comparative Examples 1-7

[0027] Element Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Poplar 1g 4g 0 0 Hydroxycamptothecin 0 0 4g 0 Changchun New Alkali 3g 0 0 4g microcrystalline cellulose 10g 10g 10g 10g starch 5g 5g 5g 5g magnesium stearate 5g 5g 5g 5g

[0028] Example 3: Pharmacodynamic experiments of the pharmaceutical composition of the present invention

[0029] 1. Laboratory animals

[0030] SPF-grade healthy mice, half male and half female, 6 weeks old, weighing 18g-20g, were provided by the Experimental Animal Center of Heilongjiang University of Traditional Chinese Medicine.

[0031] 2. Experimental Methods

[0032] 2.1 Establishment of the mouse model

[0033] Human hepatocellular carcinoma cells (HepG2) in the logarithmic growth phase were harvested and their density was adjusted to 1 × 10⁻⁶ cells using physiological saline. 7 Cells / 200μL. Disinfect the skin under the armpits of nude mice with povidone-iodine, thoroughly mix the cell suspension, and inoculate 200μL / mouse into the armpit. Two weeks later, the appearance of a white, hard mass under the skin of the nude mouse's armpit, which does not shrink or disappear, indicates successful modeling. The tumor is considered successfully established when it reaches 100mm in size. 3 The tumor-bearing nude mice were then randomly divided into two groups. The normal group consisted of nude mice that had not undergone tumor modeling, with 20 mice in each group.

[0034] 2.2 Grouping and Dosing Regimen

[0035] (1) Normal group: physiological saline, administered by gavage.

[0036] (2) Model group: physiological saline, administered by gavage.

[0037] (3) Combined use of eurygin and hydroxycamptothecin: 100 mg / kg, administered by gavage daily as the tablet composition of Example 1.

[0038] (4) Combined use of apigenin and vincristine: 100 mg / kg, administered by gavage daily as the tablet composition of Example 2.

[0039] (5) Phyllanthol group: 100 mg / kg, daily oral gavage of the tablet composition of Comparative Example 1.

[0040] (6) Hydroxycamptothecin group: 100 mg / kg, daily oral gavage of the tablet composition of Comparative Example 2.

[0041] (7) Vincristine group: 100 mg / kg, daily oral gavage of the tablet composition of Comparative Example 3.

[0042] All seven groups were raised under the same conditions for 28 days.

[0043] 2.3 Evaluation Indicators

[0044] After the administration of the drug, 10 mice were randomly selected from each group. After removing the eyeballs of the nude mice and collecting blood, they were euthanized by dislocation of the neck. The tumor tissue was peeled off and removed, and the tumor weight was weighed. The tumor weight of each group was calculated, and the tumor inhibition rate was calculated according to the following formula. The results are shown in Table 2.

[0045] Tumor inhibition rate = (1 - average tumor weight in the treatment group / average tumor weight in the model group) × 100%.

[0046] Peripheral blood was obtained by ocular blood sampling, and CD was detected by flow cytometry. 3+ CD 4+ The percentage of NK cells (natural killer cells) was also measured, and the results are shown in Table 3.

[0047] 2.4 Statistical Methods

[0048] Results were analyzed using SPSS 23.0 statistical software, and data are expressed as mean ± standard deviation. One-way ANOVA was used for comparisons among multiple groups, and t-tests were used for comparisons between two groups. P < 0.05 was considered statistically significant, and P < 0.01 was considered statistically significant.

[0049] 3. Experimental Results

[0050] Table 2: Effects of the pharmaceutical composition of the present invention on tumor weight and tumor inhibition rate in model mice

[0051] Group Number of animals (individuals) Tumor weight (g) Tumor inhibition rate (%) Model group 10 1.165±0.261 _ The combination therapy of phytohexidine and hydroxycamptothecin 10 <![CDATA[0.326±0.126 #* ]]> 72.02 The combination therapy of leucine and vincristine 10 <![CDATA[0.389±0.196 #* ]]> 66.61 Populus group 10 <![CDATA[0.638±0.196 # ]]> 45.24 Hydroxycamptothecin group 10 <![CDATA[0.782±0.196 # ]]> 32.87 Changchun Xinjian Group 10 <![CDATA[0.705±0.196 # ]]> 39.48

[0052] Note: Compared with the model group: # P<0.01; Compared with the poplarin group: * P<0.01

[0053] As shown in Table 2, the tumor inhibition rates of the apigenin + hydroxycamptothecin combination group and the apigenin + vincristine combination group in model mice were 72.02% and 66.61%, respectively. Compared with the model group, the tumor weight of the two combination groups, the apigenin group, the hydroxycamptothecin group, and the vincristine group was significantly reduced (P<0.01); compared with the apigenin group, the tumor weight of the apigenin + hydroxycamptothecin combination group and the apigenin + vincristine combination group was significantly reduced (P<0.01). These results show that the combined effect of apigenin with hydroxycamptothecin or vincristine is significantly better than that of apigenin or hydroxycamptothecin or vincristine alone, indicating that the combined use of apigenin with hydroxycamptothecin or vincristine has a significant synergistic effect in reducing tumor weight and improving tumor inhibition rate in mice.

[0054] Table 3: Effects of the pharmaceutical composition of the present invention on CD in model mice 3+ CD 4+ and the effect of NK cell content

[0055]

[0056]

[0057] Note: Compared with the model group: # P<0.05, ## P<0.01; Compared with the poplarin group:* P<0.01

[0058] As shown in Table 3, compared with the model group, the salicylic acid group, hydroxycamptothecin group, and vincristine group can improve CD. 3 + CD 4+ The levels of NK cells were significantly increased (P<0.05), while the combined treatment groups of apigenin + hydroxycamptothecin and apigenin + vincristine significantly increased CD4+ levels. 3+ CD 4+ and NK cell levels (P<0.01); compared with the apigenin group, the apigenin + hydroxycamptothecin combination group and the apigenin + vincristine combination group also significantly increased CD40 levels. 3+ CD 4+ and NK cell count (P<0.01). These results show that the combined use of apigenin with hydroxycamptothecin or vincristine was significantly more effective than either apigenin, hydroxycamptothecin, or vincristine alone. This indicates that the combined use of apigenin with hydroxycamptothecin or vincristine significantly improves CD4+ levels. 3+ CD 4+ It has a significant synergistic effect on the content of NK cells.

[0059] Obviously, the above embodiments are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make various modifications and variations to the present invention without departing from the spirit and scope of the invention. Therefore, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention also intends to include these modifications and variations.

Claims

1. A pharmaceutical composition for improving the therapeutic effect of liver tumors, characterized in that, The pharmaceutical composition comprises apigenin and vincristine in a weight ratio of 1:(2.5-3.5).

2. The pharmaceutical composition for improving the therapeutic effect of liver tumors according to claim 1, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier.

3. The pharmaceutical composition for improving the therapeutic effect of liver tumors according to claim 2, characterized in that, The pharmaceutically acceptable carrier is selected from one or more of starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, mannitol, magnesium stearate, micronized silica gel, talc, hydrogenated vegetable oil, polyethylene glycol, and magnesium lauryl sulfate.

4. The pharmaceutical composition for improving the therapeutic effect of liver tumors according to any one of claims 1-3, characterized in that, The pharmaceutical composition is in the form of an oral dosage form.

5. The pharmaceutical composition for improving the therapeutic effect of liver tumors according to claim 1, characterized in that, The pharmaceutical composition further comprises one or more of 5-fluorouracil, doxorubicin, mitomycin, carmustine, thiotepa, methotrexate, etoposide, ifosfamide, mitoxantrone, minocycline, and gemcitabine.

6. Use of the pharmaceutical composition according to any one of claims 1-5 in the preparation of a medicament for treating liver tumors.

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