Marine-derived γ-pyrone compound Asperpyrone A, preparation method thereof, and use thereof

Abstract

The present invention belongs to the field of natural medicines and discloses a γ-pyrone compound or a pharmaceutically acceptable salt thereof having a structure represented by Formula I, obtained from a fungal fermentation product. The present invention uses three blood tumor cell lines (Namalwa, NALM-6, and Raji) as models to determine the inhibitory effect of the γ-pyrone compound on tumor cell proliferation. The experimental results show that the compound has strong cytotoxicity, indicating that the γ-pyrone compound or a pharmaceutically acceptable salt thereof has strong inhibitory activity against a variety of human blood tumor cells. The present invention also discloses the use of the γ-pyrone compound or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating blood tumor diseases. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of natural medicines and relates to a γ-pyrone compound Asperpyrone A, a preparation method and use thereof, and specifically relates to a novel γ-pyrone compound Asperpyrone A obtained from microorganisms, particularly fungal fermentation products, or a pharmaceutically acceptable salt thereof, and use thereof in preparing a drug for preventing and / or treating blood tumor diseases. Background Art

[0002] Malignant tumors, as one of the world's largest public health problems, pose a great threat to human health and will become the number one killer of humans in the new century. Hematological tumors are malignant tumors originating from the lymphohematopoietic system. They are a highly heterogeneous class of diseases that include but are not limited to leukemia, lymphoma, and multiple myeloma. Since the hematopoietic system and immune system are distributed throughout the body, once the disease occurs, it becomes a systemic disease with no resectable lesions and ineffective local treatment, resulting in very limited treatment options. Previous treatment methods were mainly chemotherapy, molecular targeted therapy, and bone marrow transplantation. Except for a few patients who may be cured after successful bone marrow transplantation, most patients with hematological tumors have a poor prognosis, a low overall survival rate, and a high recurrence rate.

[0003] Chemotherapy, as an important treatment for hematologic malignancies, has seen significant development and progress over the past three decades, with examples such as the proteasome inhibitor bortezomib for multiple myeloma and cyclophosphamide, doxorubicin, and vincristine for lymphoma. However, these anti-tumor drugs also have numerous adverse reactions, such as hair loss, vomiting, and the rapid development of drug resistance, which can prevent them from achieving their intended therapeutic effects. Therefore, the research and development of new anti-tumor drugs remains a hot and challenging topic in the pharmaceutical field.

[0004] Secondary metabolites of marine microorganisms are an important source of new drugs. In recent years, a large number of novel compounds, including alkaloids, polyketides, terpenes, and peptides, have been discovered from fungi symbiotic with sponges. Some of these compounds have demonstrated significant anti-tumor, anti-malarial, antibacterial, and neuroprotective activities. Furthermore, microbial secondary metabolites are sustainable resources with minimal environmental impact, thus possessing enormous potential for development and utilization. Summary of the Invention

[0005] The inventors used a single strain multi-product strategy (OSMAC) to culture the fungus Aspergillus puniceus (strain collection number: MCCC 3A00856) from the South China Sea bee sponge in different culture media (including PDB medium, YPD medium and rice medium). With the help of HPLC-DAD-MS analysis and Antibase database analysis and deduplication, they found that the strain may contain a new class of chemical components. Guided by UV and LC-MS, various chromatographic methods were used to achieve directional separation of possible new structures. Various spectroscopic methods, as well as calculations, were used. 13 C NMR and single-crystal X-ray experiments confirmed that Asperpyrone A, a novel γ-pyrone compound with a unique 6 / 6 / 6 / 6 / 6 ring system, exhibits potent inhibitory effects against various hematologic malignancies. Therefore, this compound has promising application prospects in the treatment of human hematologic malignancy-related diseases. Furthermore, the preparation method for Asperpyrone A is simple and time-efficient, significantly reducing drug costs and making it suitable for large-scale production.

[0006] The object of the present invention is to provide a γ-pyrone compound or a pharmaceutically acceptable salt thereof having a structure as shown in Formula I for medical use:

[0007]

[0008] The molecular formula of the compound Asperpyrone A is: C 22 H 18 O 11 , relative molecular weight: 458.

[0009] The pharmaceutically acceptable salt of the γ-pyrone compound is a salt formed by the γ-pyrone compound and an inorganic acid, an organic acid, an amino acid or a sulfonic acid; the inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid; the amino acid is alanine, aspartic acid or lysine; and the sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid.

[0010] The gamma-pyrone compounds of the present invention are isolated for the first time from rice fermentation products of the fungus Aspergillus puniceus (strain collection number: MCCC 3A00856) derived from the South China Sea bee sponge.

[0011] Another object of the present invention is to provide a method for preparing the γ-pyrone compound, comprising the following steps:

[0012] The fungus Aspergillus puniceus is fermented with rice to obtain a rice fermentation product. The rice fermentation product is ultrasonically extracted twice with 95% ethanol and once with 50% ethanol. The extracts are filtered, the filtrates are combined, and the filtrates are concentrated under reduced pressure to remove ethanol to obtain a suspension. The suspension is extracted with petroleum ether and ethyl acetate in sequence, and the extracts are concentrated under reduced pressure to obtain a petroleum ether extract and an ethyl acetate extract, respectively. The ethyl acetate extract is subjected to MCI column chromatography using an EtOH-H2O system as an eluent for gradient elution to obtain 45 components, which are respectively recorded as components M1 to M45. Component M16 is subjected to Sephadex LH-20 column chromatography using methanol as an eluent to obtain 8 subcomponents, which are respectively recorded as subcomponent M16-1 to subcomponent M16-8. Subcomponent M16-4 is purified by semi-preparative RP-HPLC (semi-preparative reversed-phase high performance liquid chromatography) to obtain a γ-pyrone compound represented by formula I.

[0013] Preferably, the preparation of the rice fermentation product is as follows: at a temperature of 28° C., the strain Aspergillus puniceus (strain deposit number: MCCC 3A00856) is inoculated on a PDA culture medium plate and cultured at 28° C. for 7 days; the revived strain is inoculated into 100 mL of sterilized PDB seed culture medium, and cultured at a temperature of 28° C. and a rotation speed of 180 rpm for 3 days to obtain a seed culture solution; rice and deionized water are mixed in a mass ratio of 1:1 to obtain a rice culture medium, and the seed culture solution is inoculated into the rice culture medium according to a volume mass ratio of the seed culture solution to the rice culture medium of 1:20 mL / g, and cultured at a temperature of 28° C. for 30 days to obtain a rice fermentation product.

[0014] Preferably, the time for each ultrasonic extraction is 40 minutes.

[0015] Preferably, when ultrasonic extraction is performed with 95% ethanol, the volume ratio of 95% ethanol to rice fermentation product is 3:1. When ultrasonic extraction is performed with 50% ethanol, the volume ratio of 50% ethanol to rice fermentation product is 3:1.

[0016] Preferably, the suspension is extracted three times with petroleum ether, and the volume ratio of petroleum ether to the suspension is 3:1 during each extraction; the suspension is extracted three times with ethyl acetate, and the volume ratio of ethyl acetate to the suspension is 3:1 during each extraction.

[0017] Preferably, when performing MCI column chromatography, MCI GEL CHP20 / P120 is used as the filler, and the EtOH-H2O system is H2O, 10% EtOH, 20% EtOH, 30% EtOH, 45% EtOH, 60% EtOH, 80% EtOH and 100% EtOH, respectively. Each fraction is detected by HPLC, and similar components are merged to finally obtain 45 components (components M1-M45).

[0018] Preferably, the chromatographic column for semi-preparative RP-HPLC is Capcell Pak PFP, with specifications of 5 μm, 10×250 mm; the mobile phase is 15% ACN-0.1% TFA aqueous solution, isocratic elution, and a flow rate of 1.5 mL / min.

[0019] The present invention uses three blood tumor cell lines (Namalwa, NALM-6, Raji) as models to determine the inhibitory effect of the γ-pyrone compounds on tumor cell proliferation. The experimental results show that the compounds have strong cytotoxicity and the IC 50 The results were 5.28, 0.38, and 3.59 μmol / L, respectively, indicating that the γ-pyrone compounds or their pharmaceutically acceptable salts have strong inhibitory activity against a variety of human blood tumor cells and can be used to prepare drugs for treating blood tumor-related diseases. Compared with existing similar anti-tumor drugs, the γ-pyrone compounds have superior therapeutic effects.

[0020] Another object of the present invention is to provide the use of the γ-pyrone compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating blood tumor diseases.

[0021] The blood tumor disease is leukemia or lymphoma.

[0022] Another object of the present invention is to provide a pharmaceutical composition, which is an anti-hematological tumor preparation prepared by using the γ-pyrone compound or its pharmaceutically acceptable salt as the active ingredient or main active ingredient and one or more pharmaceutically acceptable carriers.

[0023] The pharmaceutical composition can be used for clinical treatment of blood tumors.

[0024] The γ-pyrone compounds or pharmaceutically acceptable salts thereof can also be combined with known drugs to form compound preparations for the treatment of related cancer diseases.

[0025] In the pharmaceutical composition, the weight ratio of the γ-pyrone compound or its pharmaceutically acceptable salt is 0.1 to 99.9%, and the weight ratio of the pharmaceutically acceptable carrier is 0.1 to 99.9%.

[0026] The pharmaceutical composition exists in the form of a preparation suitable for pharmaceutical use.

[0027] The pharmaceutical composition may be in the form of tablets, capsules, granules, pills, powders, ointments, suspensions, injections, powder injections, suppositories, creams, drops, or patches. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, or sustained-release tablets; the capsules may be hard capsules, soft capsules, or sustained-release capsules; and the powder injection may be lyophilized powder injection.

[0028] The pharmaceutical composition of the present invention, as a preparation, contains an effective amount of γ-pyrone compound or pharmaceutically acceptable salt thereof in each dose of 0.1 to 1000 mg. The term "each dose" refers to each preparation unit, such as each tablet or each capsule, and may also refer to the dosage per administration, such as 100 mg per administration.

[0029] When the pharmaceutical compositions of the present invention are formulated into solid or semisolid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories, and ointments, solid carriers may be used. Suitable solid carriers are preferably one or more substances selected from diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, and bulking agents, or may be encapsulating materials. In powdered preparations, the carrier contains 5 to 70% of the micronized active ingredient. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low-boiling waxes, cocoa butter, and the like. Tablets, powders, cachets, and capsules represent the most advantageous oral solid preparations due to their ease of administration.

[0030] Liquid preparations of the present invention include solutions, suspensions and emulsions. For example, parenteral injections can be in the form of water or water-propylene glycol solutions, with the osmotic pressure adjusted so that the pH value is suitable for the physiological conditions of the living body. Liquid preparations can also be made into solutions in polyethylene glycol or aqueous solutions. Oral aqueous solutions can be prepared by dissolving the active ingredient in water and then adding an appropriate amount of coloring agent, flavoring, stabilizer and thickening agent. Micronized active ingredients can be dispersed in viscous materials such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose and other known suspending agents to prepare aqueous suspensions suitable for oral administration.

[0031] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the above-mentioned pharmaceutical formulations in dosage unit form. A dosage unit form of a formulation refers to a physically discrete unit suitable for use as a single dose, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect. Such dosage unit forms can be packaged forms, such as tablets, capsules, or powders in small tubes or bottles, or ointments, gels, or creams in tubes or bottles.

[0032] While the amount of active ingredient contained in a dosage unit form may vary, it will generally be in the range of 1 to 800 mg, depending upon the potency of the active ingredient chosen.

[0033] Those skilled in the art can determine the preferred dosage for a particular situation by conventional methods. Generally, the amount of treatment is initially lower than the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved. The total daily dose can be administered once or in divided doses as needed for treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The concentration-survival rate curve of compound Asperpyrone A in killing human Burkitt's lymphoma cells (Namalwa).

[0035] Figure 2 The concentration-survival rate curve of compound Asperpyrone A in killing B cell acute lymphoblastic leukemia cell line (NALM-6).

[0036] Figure 3 The concentration-survival rate curve of compound Asperpyrone A in killing human lymphoma cell line (Raji). DETAILED DESCRIPTION

[0037] The technical solutions of the present invention are described in detail below through examples. The following examples are intended to help those skilled in the art better understand the present invention, but are not intended to limit the present invention in any way.

[0038] Based on the technical solution of the present invention, those skilled in the art can apply it to preparing γ-pyrone compounds from any microorganism, not limited to rice fermentation products from the fungus Aspergillus puniceus.

[0039] Example 1

[0040] Strain source: Aspergillus puniceus, obtained from the shared strain of China Marine Microbial Culture Collection Center, with the strain collection number: MCCC 3A00856.

[0041] PDB seed medium: glucose 15 g / L, potato extract powder 5 g / L, sodium chloride 5 g / L, peptone 10 g / L, NaCl 30 g / L.

[0042] Fermentation of the fungus Aspergillus puniceus:

[0043] The strain Aspergillus puniceus (strain accession number: MCCC 3A00856) was inoculated onto PDA (potato dextrose agar) plates at 28°C and cultured at 28°C for 7 days. The revived strain was then inoculated into a 500mL Erlenmeyer flask containing 100mL of sterilized PDB seed medium. The flask was incubated at 28°C in a shaker at 180 rpm for 3 days to obtain a seed culture. A scaled-up fermentation was performed by preparing 160 fermentation bags, adding 50g of rice and 50mL of deionized water to each bag as a rice culture medium. The bags were sealed, sterilized in an autoclave (121°C, 15 minutes), and cooled. Finally, 5mL of the seed culture was added to each bag in a laminar flow hood and cultured in a 28°C constant-temperature incubator for 30 days to obtain a rice fermentation product.

[0044] Example 2

[0045] Take the rice fermentation product obtained in Example 1, use 95% ethanol ultrasonic extraction (volume ratio of 95% ethanol and rice fermentation product 3: 1), extract 2 times, each 40min, then use 50% ethanol ultrasonic extraction (volume ratio of 50% ethanol and rice fermentation product 3: 1) 40min, filter and merge filtrate after each ultrasonic extraction, then be concentrated under reduced pressure to no alcohol taste and remove ethanol to obtain a suspension of about 2L, then use petroleum ether and ethyl acetate successively to extract the suspension, petroleum ether and ethyl acetate respectively, each extraction, the volume ratio of organic solvent to suspension 3: 1, the extract is concentrated under reduced pressure to obtain petroleum ether part extract and ethyl acetate part extract, respectively.

[0046] Example 3

[0047] Isolation and preparation of compound 1:

[0048] The ethyl acetate extract of Example 2 was subjected to MCI column chromatography using MCI GEL CHP20 / P120 as a filler with an average particle size of 120 μm. Gradient elution was performed with EtOH-H2O (H2O, 10% EtOH, 20% EtOH, 30% EtOH, 45% EtOH, 60% EtOH, 80% EtOH, and 100% EtOH). The fractions were analyzed by HPLC, and similar components were combined to obtain 45 components (denoted as component M1 to component M45).

[0049] Fraction M16 was subjected to Sephadex LH-20 column chromatography using methanol as an eluent to obtain 8 subfractions (denoted as subfraction M16-1 to subfraction M16-8).

[0050] Subfraction M16-4 was subjected to semi-preparative RP-HPLC (Capcell Pak PFP, particle size 5 μm, inner diameter 10 mm × column length 250 mm), mobile phase: 15% ACN-H2O containing 0.1% TFA (i.e., a mixed aqueous solution of 15% by volume acetonitrile and 0.1% by volume trifluoroacetic acid), isocratic elution, flow rate: 1.5 mL / min, to prepare compound 1, which was named Asperpyrone A.

[0051] Structural identification of compound 1:

[0052] Compound 1 is an orange-red needle-shaped crystal (methanol). HR-ESI-MS detected a quasi-molecular ion peak of m / z 459.0905 [M+H] + The molecular composition is C 22 H 18 O 11 (calcd for C 22 H 19 O 11 ,459.0922), the degree of unsaturation is 14. 1 HNMR spectrum (600 MHz, DMSO-d6) showed two trisubstituted double bonds [δ H 6.54 (1H, brt, J = 1.2 Hz) and 6.50 (1H, brt, J = 1.2 Hz)]; 2 hydroxymethylene groups [δ H 4.46 (4H, overlap)]; 2 isolated methyl groups [1.30 (3H, s) and 1.81 (3H, s)]; 1 linked oxymethyl group [δ H 3.30 (3H, s)]; and 3 active [δ H 5.46 (1H, s), 5.87 (1H, t, J = 6 Hz), 5.83 (1H, t, J = 6 Hz)] proton resonance signals. 13 The C NMR spectrum showed 22 carbon signals, and combined with DEPT spectrum analysis, it showed that in addition to the carbon signals corresponding to the groups in the above hydrogen spectrum, there were 13 quaternary carbon signals, including 3 conjugated carbonyl carbons (δ C 195.5, 170.2 and 168.8); 3 olefinic carbons (δ C 109.9, 119.1, 122.4) and 5 oxyolefin carbons (δ C 154.7, 142.4, 141.4, 140.4 and 140.2); and two oxygen-linked sp 3 Quaternary carbon (δ C 98.5 and 79.4).

[0053] The chemical structure of the γ-pyrone compound Asperpyrone A was determined to be as shown in Formula I by various modern spectral techniques such as 1D NMR, 2D NMR, HRESIMS, IR, UV, ECD, and single crystal X-ray diffraction (copper target) analysis.

[0054]

[0055] Table 1. NMR data of compound 1 (600 MHz, DMSO-d6)

[0056]

[0057] Example 4

[0058] Test of the ability of compound 1 to kill tumor cells

[0059] The Cell Counting Kit is a cell proliferation and cytotoxicity assay based on water-soluble tetrazolium salts (WST). Its principle is that, in the presence of an electron coupling reagent, WST is reduced to a soluble orange-yellow formazan by mitochondrial dehydrogenases. The amount of formazan is proportional to the number of viable cells. The color becomes darker with faster cell proliferation, lower cytotoxicity, and a higher cell count. The color depth shows a good linear relationship with cell number.

[0060] Preparation of drug solution: 2 mg of compound Asperpyrone A was prepared with 100 μL DMSO to prepare a 20 mg / mL (43.7 mM) stock solution of compound Asperpyrone A. The stock solution of compound Asperpyrone A was diluted 10 times with complete culture medium. 4 The concentration of the drug solution was doubled to 4.37 μM, and then serially diluted to obtain a series of drug solutions.

[0061] Cells: Namalwa cells (human Burkitt's lymphoma cells), NALM-6 cells (B cell acute lymphoblastic leukemia cell line), and Raji cells (human lymphoma cell line) were cultured in RPMI-1640 complete medium.

[0062] Procedure: Namalwa cells (human Burkitt's lymphoma cells), NALM-6 cells (B cell acute lymphoblastic leukemia cell line), and Raji cells (human lymphoma cell line) in logarithmic growth phase were digested with 0.25% trypsin and the cell concentration was adjusted to 2.5×10 4 / mL. Plate the plate and add the cell culture medium after adjusting the concentration into a 96-well plate, 200μL per well, block the periphery with serum-free culture medium, and culture the cells in an incubator until the logarithmic phase. Discard the original culture medium, and add 200μL of drug solution of different concentrations to each well of the drug-treated group. Set up 3 replicates for each concentration, and set up a blank control group and a solvent control group. The blank control group was cultured with complete culture medium, and the solvent control group was cultured with complete culture medium containing DMSO (200μL system contains 0.02μLDMSO). Continue to culture in a cell culture incubator for 48h. Remove the 96-well plate, discard the supernatant, add 100μL of complete culture medium containing 10% CCK solution to each well, continue to culture in a cell culture incubator for 1-4 hours, and measure the absorbance at 450nm with an enzyme reader.

[0063] Tumor cell survival rate % = (fluorescence absorbance value of the drug-administered well - fluorescence absorbance value of the blank well) / (fluorescence absorbance value of the solvent control well - fluorescence absorbance value of the blank well) × 100%

[0064] The survival rate of tumor cells at each concentration was measured, and the IC of the tested samples was calculated using SigmaPlot software. 50 value.

[0065] Experimental results: IC of compound Asperpyrone A killing 3 tumor cell lines 50 The values ​​and concentration-survival rate curves are shown in Tables 2 and Figure 1 The results show that the compound Asperpyrone A has strong inhibitory activity against human blood tumor cells and can be used to prepare drugs for treating blood tumor-related diseases.

[0066] Table 2. IC of Asperpyrone A against three tumor cell lines 50 value

[0067] tumor cells <![CDATA[IC 50 (μmol / L)]]> Namalwa cells 5.28 NALM-6 cells 0.38 Raji cells 3.59

Claims

1. A γ-pyrone compound or a pharmaceutically acceptable salt thereof having a structure as shown in Formula I: 。 2. The γ-pyrone compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The pharmaceutically acceptable salt of the γ-pyrone compound is a salt formed by the γ-pyrone compound and an inorganic acid, an organic acid, an amino acid or a sulfonic acid.

3. The γ-pyrone compound or pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid; the amino acid is alanine, aspartic acid or lysine; and the sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid.

4. A method for preparing the γ-pyrone compound according to claim 1, characterized in that: The following steps are involved: fungi Aspergillus puniceus After rice fermentation, a rice fermentation product is obtained. The rice fermentation product is ultrasonically extracted twice with 95% ethanol and once with 50% ethanol. The extracts are filtered, the filtrates are combined, and the filtrates are concentrated under reduced pressure to remove ethanol to obtain a suspension. The suspension is extracted with petroleum ether and ethyl acetate in sequence, and the extracts are concentrated under reduced pressure to obtain a petroleum ether extract and an ethyl acetate extract, respectively. The ethyl acetate extract is subjected to MCI column chromatography and gradient elution using an EtOH-H2O system as an eluent to obtain 45 components, which are respectively recorded as components M1 to M45. Component M16 is subjected to Sephadex LH-20 column chromatography and eluted with methanol as an eluent to obtain 8 subcomponents, which are respectively recorded as subcomponent M16-1 to subcomponent M16-8. Subcomponent M16-4 is purified by semi-preparative RP-HPLC to obtain a γ-pyrone compound represented by formula I.

5. The method for preparing γ-pyrone compounds according to claim 4, characterized in that: When performing MCI column chromatography, MCI GEL CHP20 / P120 was used as the filler.

6. The method for preparing γ-pyrone compounds according to claim 4, characterized in that: The semi-preparative RP-HPLC column was a Capcell Pak PFP column with specifications of 5 μm, 10×250 mm; the mobile phase was 15% acetonitrile-0.1% trifluoroacetic acid aqueous solution, with isocratic elution and a flow rate of 1.5 mL / min.

7. Use of the γ-pyrone compound or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for preventing and / or treating a blood tumor disease, wherein the blood tumor disease is leukemia or lymphoma.

8. A pharmaceutical composition, characterized in that: The pharmaceutical composition is a preparation prepared by using the γ-pyrone compound or a pharmaceutically acceptable salt thereof as the active ingredient or the main active ingredient and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8, characterized in that: The preparation is in the form of tablets, capsules, granules, pills, powders, ointments, suspensions, injections, powder injections, suppositories, creams, drops or patches.

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