Application of BEZ235 in preparation of medicine for treating or improving retina microangiopathy

Abstract

The invention discloses an application of BEZ235 in preparation of a medicine for treating or improving retina microangiopathy. Experiments show that BEZ235 can inhibit proliferation and migration of retinal vascular endothelial cells, inhibit the tube forming ability of the retinal vascular endothelial cells, inhibit the formation of pathological new vessels under the condition of oxygen-induced retinopathy and the enlargement of a non-vascular perfusion area, and inhibit the proliferation and migration of the retinal vascular endothelial cells and the tube forming ability of the retinal vascular endothelial cells. The number of pre-retinal neovascularization cells under the condition of oxygen-induced retinopathy is reduced, and the structural disorder of the retina is improved. Therefore, BEZ235 is useful in the prevention and treatment of retinal microangiopathy.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to the application of BEZ235 in preparing a medicine for treating or improving retinal microangiopathy. Background Art

[0002] Pathological retinal neovascularization is an important factor leading to vision loss in diseases such as retinopathy of prematurity (ROP), diabetic retinopathy (DR) and age-related macular degeneration (AMD). In these diseases, severe visual impairment is often caused by the formation of fragile and leaky new blood vessels.

[0003] The formation of retinal neovascularization involves a variety of complex biological mechanisms. Vascular endothelial growth factor (VEGF) is the most critical angiogenic factor in neovascularization, which directly stimulates the proliferation of vascular endothelial cells and the formation of new blood vessels. Studies have shown that in a hypoxic environment, cells increase the expression of hypoxia-inducible factor (HIF), thereby promoting the expression of vascular endothelial growth factor (VEGF) (Arrigo A, Aragona E, Bandello F. VEGF-targeting drugsfor the treatment of retinalneovascularization in diabetic retinopathy [J]. Annals of medicine, 2022,54(1): 1089-111.), promoting angiogenesis, and exacerbating the functional abnormalities of pathological neovascularization.

[0004] Currently, patients with ROP and DR can receive retinal photocoagulation or anti-vascular endothelial growth factor (VEGF) therapy to inhibit neovascularization. Because the laser can cause retinal tissue loss, retinal photocoagulation can cause complications such as decreased vision, decreased night vision, and persistent visual field loss. Anti-VEGF therapy is the first-line treatment for retinal neovascular disease, and it has been used clinically to treat patients with ROP and DR. However, anti-VEGF drugs have obvious disadvantages: first, adverse reactions related to VEGF signaling blockade occur, including normal retinal blood vessel growth and impaired retinal function; second, due to the persistence of ischemic / non-perfusion conditions, recurrence of neovascularization after intravitreal injection of anti-VEGF drugs is common in premature infants or diabetic patients. Therefore, there is a large and unmet medical need for alternative treatment strategies for neovascularization.

[0005] The dual PI3K / mTOR inhibitor BEZ235 has shown significant tumor growth inhibition in multiple cancer types, including lung cancer, by targeting the PI3K / AKT / mTOR signaling pathway. The effects of BEZ235 were compared with those of conventional treatments such as rapamycin in renal cell carcinoma, indicating that BEZ235 was superior to rapamycin in inhibiting cell proliferation. This finding supports the broader applicability and potential benefits of BEZ235 in the treatment of various cancers, but so far, it has not been publicly used to improve retinal microvascular disease. Summary of the invention

[0006] The purpose of the present invention is to overcome the shortcomings and deficiencies of the prior art and provide the use of BEZ235 in the preparation of a drug for treating or improving retinal microvascular diseases.

[0007] The purpose of the present invention is achieved through the following technical solutions: Use of BEZ235 in the preparation of drugs for treating or improving retinal microangiopathy.

[0008] The BEZ235 inhibits the proliferation and migration of retinal vascular endothelial cells, inhibits the tube-forming ability of retinal vascular endothelial cells, inhibits the formation of pathological neovascularization and the expansion of the avascular perfusion zone under oxygen-induced retinopathy (OIR), reduces the number of preretinal neovascular cells under oxygen-induced retinopathy (OIR), and improves the structural disorder of the retina, thereby achieving the purpose of treating or improving retinal microvascular diseases.

[0009] The retinal vascular endothelial cells include human retinal vascular endothelial cells (HRVECs).

[0010] The retinal microvascular diseases include retinal microvascular diseases caused by retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), etc., including retinal pathological neovascularization, etc.

[0011] The dosage of BEZ235 can be adjusted according to actual conditions. For example, in cell experiments, the concentration range of the BEZ235 acting on cells is 1 to 10 μM (excluding 1 μM); preferably 10 μM; in animal experiments, the dosage of BEZ235 is calculated based on 1 mg / (kg·d) per individual body weight.

[0012] The drug may further contain one or more pharmaceutically acceptable excipients or carriers.

[0013] The auxiliary material is at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, a surfactant or a lubricant.

[0014] The dosage form of the medicine is capsule, pill, tablet, oral liquid, granule, tincture or injection.

[0015] Compared with the prior art, the present invention has the following advantages and effects: 1. The present invention experimentally found that: (1) BEZ235, a dual inhibitor of PI3K / mTOR, significantly inhibited the scratch healing ability of HRVECs; (2) BEZ235 significantly inhibited the chemotactic migration ability of HRVECs; (3) BEZ235 significantly inhibited the tube-forming ability of HRVECs; (4) BEZ235 significantly inhibited the formation of pathological neovascularization under OIR conditions; (5) BEZ235 significantly inhibited the expansion of the avascular perfusion area under OIR conditions and improved the structural disorder of the retina.

[0016] 2. The present invention provides a new use of BEZ235, which not only expands the application scope of BEZ235 and improves its application value, but also contributes to the further development of new drugs. For example, BEZ235 can be used as a lead compound, and through structural modification or transformation, it is hoped that its activity can be further improved and its side effects can be reduced, thereby providing a safe drug for the prevention and treatment of retinal microvascular diseases, and has good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is the result of scratch experiment of BEZ235 inhibiting HRVECs; A is the cell scratch experiment of different treatment groups; B is the percentage of scratch healing of different treatment groups.

[0018] Figure 2 The figure is the experimental result of BEZ235 inhibiting the chemotaxis and migration ability of HRVECs; A is the cell migration experiment of different treatment groups; B is the percentage of scratch healing of different treatment groups.

[0019] Figure 3 This is the experimental result diagram of BEZ235 inhibiting the tube-forming ability of HRVECs; A is the tubular structure formation of different treatment groups; B is the number of tubular structures in different treatment groups.

[0020] Figure 4 The figure is the experimental result of BEZ235 inhibiting the pathological neovascularization under OIR conditions; A is the section of the eyeball tissue in different treatment groups; B is the number of preretinal neovascular cells in different treatment groups.

[0021] Figure 5The figure is the experimental result that BEZ235 significantly inhibits the expansion of the avascular perfusion area and improves the structural disorder of the retina under OIR conditions; A is the Isolectin B4 staining result of the retinal flat mount in different treatment groups; B is the range of new blood vessels and the area of ​​avascular perfusion area in different treatment groups.

[0022] Figure 6 This is a diagram to verify whether BEZ235 has potential in vivo toxicity at therapeutic doses; A is the retinal electrophysiological results under different treatments; B is the HE staining results of paraffin sections of mouse heart, liver, spleen, lung and kidney under different treatments. DETAILED DESCRIPTION

[0023] The present invention is further described in detail below in conjunction with the examples, but the embodiments of the present invention are not limited thereto. The experimental methods in the following examples are conventional methods unless otherwise specified; the experimental materials used can be purchased from conventional biochemical reagent manufacturers unless otherwise specified.

[0024] BEZ235 (p-toluenesulfonate, CAS No.: 1028385-32-1) involved in the following examples was purchased from MedChemExpress.

[0025] The human retinal vascular endothelial cells (HRVECs) involved in the following examples were purchased from Cell Systems Corp (Kirkland, WA).

[0026] Example 1: BEZ235 significantly inhibits the scratch healing ability of HRVECs HRVECs cell migration ability experiment (scratch experiment), the specific experimental steps are as follows: (1) Cell planting: HRVECs cells were planted in 6-well plates to ensure that the cell density was moderate so that the cells could grow evenly in the plate. For each experimental group, two additional wells were prepared as replicates; (2) Scratch preparation: When the cell confluence reaches 95% or above, use a 1 ml pipette tip to directly make a single scratch on the bottom of the well, taking care to keep the width and position of the scratch as consistent as possible; (3) Washing and treatment: Gently aspirate the supernatant in the well and rinse twice with PBS to remove cells that may have fallen off during the scratching process. Subsequently, specific culture media were added according to different experimental groups: the control group (CON) added serum-free conventional ECM culture medium; the BEZ235-treated group added serum-free ECM culture medium containing different concentrations of BEZ235 (first prepare BEZ235 with solvent DMSO to make a drug stock solution, and then add it to the serum-free ECM culture medium) (the final concentration of BEZ235 in the BEZ235-treated group was 1nM and 10nM); the DMSO group (solvent control group) added serum-free ECM culture medium containing an equal volume of DMSO.

[0027] (4) Image acquisition: Use an optical microscope to image the scratch area at the beginning of the experiment (0 hours) and 24 hours later to record the progress of cell healing; (5) Data analysis: ImageJ software was used to analyze the scratch healing area and the original scratch area, and the horizontal migration rate was calculated, which is the ratio of the healing area to the original scratch area. Based on the obtained data, a graph was drawn to visually demonstrate the difference in cell migration ability.

[0028] (6) Experimental results: The scratch is marked by a yellow line in the images before treatment (0 h) and 24 h after treatment (24 h), demonstrating the ability of HRVEC cells to migrate across the scratch. Figure 1 As shown, the results showed that the normal control group (CON) and DMSO solvent group cells showed similar percentages of wound healing, with no significant difference, indicating that DMSO itself had no effect on HRVEC migration. In the BEZ235-treated group, 1nM BEZ235 had no significant effect on wound healing. However, the 10nM BEZ235-treated group significantly reduced the percentage of wound healing, and the degree of wound healing was significantly lower than that of the DMSO solvent group ( Figure 1 A and Figure 1 B). This result shows that BEZ235 at a concentration of 10 nM can significantly inhibit the migration ability of HUVEC.

[0029] Experiments confirmed that BEZ235 significantly inhibited the scratch healing ability of HRVECs.

[0030] Example 2: BEZ235 significantly inhibits the chemotactic migration ability of HRVECs Evaluation of HUVECs cell migration ability (Transwell experiment), the specific experimental steps are as follows: (1) Culture medium preparation: 600 μl of ECM complete culture medium (blank control group), ECM complete culture medium containing an equal volume of DMSO (solvent control group), and ECM complete culture medium containing different concentrations of BEZ235 (final concentration of BEZ235 is 1 nM and 10 nM) were added to each well of a 24-well experimental plate (refer to Example 1 for the preparation method); (2) Transwell chamber installation: Use sterile tweezers to gently place the Transwell chamber in the well that has been added with culture medium, making sure that the bottom of the chamber is not in direct contact with the culture medium to avoid the formation of bubbles. Add 300 μl of 2×10 4 Prepare a cell suspension of HRVECs cells (resuspended in serum-free ECM medium) and incubate the entire plate in a 37°C incubator; for each experimental group, prepare two more wells as replicates; (3) Incubation and fixation: After 24 hours, gently aspirate the culture medium in the upper chamber, carefully remove the Transwell chamber, and gently rinse twice with PBS. Then, put the chamber back to the original well, add 4% paraformaldehyde fixative to the upper and lower chambers (300 μl in the upper chamber and 700 μl in the lower chamber), and fix at 4°C for 30 minutes; (4) Staining and washing: After fixation, remove the paraformaldehyde and wash twice with PBS. Put the chamber back into the well plate, add 0.1% crystal violet staining solution to the upper and lower chambers, and stain for 20 minutes with tin foil to block light. (5) Cleaning and microscopic observation: After staining, gently pick up the chamber and wash it three times with PBS. Use a sterile cotton swab to gently wipe the upper surface of the chamber membrane to remove non-migrated cells. After the chamber is dried, observe and photograph the lower surface of the membrane under a microscope at 100x magnification, and randomly select 10 fields of view to record the number of migrated cells; (6) Data statistics: ImageJ software was used to count and analyze the number of migrated cells in the captured images to evaluate the migration ability of cells in each experimental group.

[0031] (7) Experimental results: The experimental results are as follows Figure 2 As shown, the results showed that the normal control group (CON) and DMSO solvent group cells showed similar chemotactic migration percentages, with no significant differences, indicating that DMSO itself had no effect on HUVEC migration. In the BEZ235-treated group, 1nM BEZ235 had no significant effect on chemotactic migration. However, the 10nM BEZ235-treated group significantly reduced the percentage of chemotactic migration, and the degree of cell chemotactic migration was significantly lower than that of the DMSO solvent group ( Figure 2 A and Figure 2 B). This result shows that BEZ235 at a concentration of 10 nM can significantly inhibit the migration ability of HUVEC.

[0032] Experiments confirmed that BEZ235 significantly inhibited the chemotactic migration ability of HRVECs.

[0033] Example 3: BEZ235 significantly inhibits the tube-forming ability of HRVECs HRVECs cell tube formation experiment, the specific experimental steps are as follows: (1) Preparation: Place Matrigel (Corning) in a 4°C refrigerator overnight to pre-cool. Also pre-cool a 96-well plate and a 200 μl pipette tip at 4°C for later use. (2) Preparation of Matrigel: Take out the pre-cooled 96-well plate, add 60 μl of 10 mg / mL cooled Matrigel to each well, and then place the plate in a 37°C incubator to allow the Matrigel to solidify within 1 hour. (3) Cell planting and observation: HRVEC cells of the CON group, DMSO treatment group, and BEZ235 treatment group were inoculated on the solidified matrix gel (treatment method was the same as in Example 2) at a density of 1×10 4 cells / well; for each experimental group, two more wells were prepared as replicates; at the time points of 6, 12, and 24 hours, images of cell tube formation were captured from five randomly selected fields of view using an intelligent inverted fluorescence microscope; (4) Data analysis: ImageJ software was used to perform quantitative analysis on the captured images and calculate and count the relevant indicators of cell tube formation.

[0034] (5) Experimental results: In an in vitro tube-forming model of angiogenesis, we investigated the ability of BEZ235 to affect the formation of blood vessel-like structures by human retinal vascular endothelial cells (HRVECs) by quantitative analysis. Figure 3 As shown, the microscopic images show the tubular structure formation in the normal control group (CON), DMSO solvent group, and 1nM and 10nM BEZ235 treatment groups ( Figure 3 A). In the CON group, HRVECs formed a series of tubular structures with rich branches and tight connections, showing good tubular formation ability. However, no significant difference was observed in the number of tubular formations between the DMSO group and the CON group, indicating that the solvent itself did not interfere with the formation of normal tubular structures of HRVECs. Under the influence of BEZ235, 1nM BEZ235 failed to significantly change the tubular formation ability of HRVECs compared with the DMSO solvent group. The number of tubular structures formed in the 10nM BEZ235 treatment group decreased significantly, indicating that BEZ235 has a strong inhibitory effect on the tubular formation ability of HRVECs at this concentration ( Figure 3B). This result indicates that BEZ235 inhibits the tube-forming ability of HRVECs by reducing the formation of junctions and branch points between endothelial cells.

[0035] Experiments confirmed that BEZ235 significantly inhibited the tube-forming ability of HRVECs.

[0036] Example 4: BEZ235 significantly inhibits the formation of pathological neovascularization under OIR conditions (1) Establishment of oxygen-induced retinopathy (OIR) model: 1) Selection of appropriate experimental animals: Healthy C57BL / 6 mice (purchased from Guangdong Medical Animal Center) at 7 days after birth (P7) were selected to ensure that the animals were from the same litter to reduce experimental variation; the experiment was divided into 4 groups, with 6 mice in each group; 2) Setting up the oxygen exposure environment: Place the mice together with the lactating mothers in a special oxygen chamber, set the ambient oxygen concentration to 75%±2%, maintain the temperature at 20-26°C and the humidity at 40-70%, and continue the exposure for 5 days (i.e. until P12).

[0037] (2) Drug administration: 1) Drug preparation: BEZ235 was first dissolved in DMSO solvent to prepare a 2.5 mg / ml stock solution, and then 20 μl of the stock solution was added to each EP tube and diluted to 1 ml with corn oil to prepare a liquid with a final concentration of 0.05 mg / mL of BEZ235; the DMSO group was prepared with a DMSO liquid of the same concentration (diluted with corn oil), and the DMSO concentration was kept below 5%; 2) Return to normoxic environment and drug treatment: At P12, the mice were taken out of the hyperoxic environment and transferred to a normal indoor air environment for continued feeding. The experimental group gave BEZ235 group mice oral administration at a fixed time every day on P12, P13, P14, P15, and P16 at a drug weight ratio of 1 mg / kg (OIR+BEZ235), and the Corn oil_DMSO group was given an equal dose of DMSO dilution as a solvent control group (OIR+Corn oil_DMSO). At the same time, OIR mice and healthy mice were used as controls. The OIR mice were taken out of the hyperoxic environment at P12 and transferred to a normal indoor air environment for continued feeding, while the healthy mice were fed normally under normoxic environment.

[0038] 3) Monitoring and care: Throughout the experiment, closely monitor the health of the mice, including body weight, activity, and appetite, and ensure adequate food and water supply; 4) Sampling: At P17, mice were anesthetized with isoflurane, then the animals were killed and eyeball tissues were collected for further histological or molecular biological analysis.

[0039] (3) Experimental results: The eyeball tissue was paraffin-embedded and sectioned, and further stained with hematoxylin-eosin (H&E). Cell morphology was analyzed by optical microscopy. Figure 4 As shown, the results showed that the retina of the normal control group (CON) mice showed a regular retinal hierarchical structure, the cells were neatly arranged, and there were no obvious pathological changes. The retina of the OIR group showed obvious structural disorder, with a large number of neovascular cells that broke through the inner limiting membrane in front of the retina. These cells were irregularly distributed and increased in density along with the neovascular tissue (marked by red arrows). At the same time, the OIR+Corn oil_DMSO solvent group showed similar pathological characteristics to the OIR group, indicating that the solvent had no significant effect on the course of the disease. In OIR mice treated with BEZ235 by oral gavage, we observed that the number of neovascular cells in front of the retina was significantly reduced compared with the OIR+Corn oil_DMSO solvent group ( Figure 4 A) The density of these marked pathological neovascular structures was significantly reduced in the BEZ235-treated group, demonstrating the therapeutic potential of BEZ235. The quantitative bar graph ( Figure 4 B) The number of preretinal neovascular cells in different treatment groups was counted, and the OIR+BEZ235 group showed a significant decrease compared with the OIR+ Corn oil_DMSO solvent group, confirming the effectiveness of BEZ235 in reducing pathological neovascularization. These findings emphasize the efficacy of BEZ235 as an anti-angiogenic therapeutic agent in inhibiting retinal neovascularization in OIR mice, providing important experimental basis for the clinical treatment of related diseases in the future.

[0040] Experiments confirmed that BEZ235 significantly inhibited the formation of pathological neovascularization under OIR conditions.

[0041] Example 5: BEZ235 significantly inhibited the expansion of the avascular perfusion area under OIR conditions and improved the structural disorder of the retina This experiment investigates the therapeutic effect of BEZ235 in oxygen-induced retinopathy (OIR) model mice. The specific experimental steps are as follows: Based on the above Example 4, a dose of 1 mg / kg was used, and the drug was administered once a day by oral gavage from P12 to P16. The mouse eyeballs were removed at P17, and the retinas were isolated. The retinal flat mounts were stained with Isolectin B4, and the morphological changes of the retinal blood vessels of the mice, especially the morphology and number of new blood vessels, and the size of the avascular perfusion area were observed to evaluate the effect of BEZ235 on neovascularization.

[0042] By staining the retina with Isolectin B4 in different treatment groups and normal group, we noticed that in the normal P17 mouse retina, the vascular network was regularly distributed and had a complete structure. In sharp contrast, the retina of the OIR group and the OIR model mouse treated with Corn oil_DMSO solvent showed obvious neovascularization and vascular network disorder ( Figure 5 A). These abnormal structures often appear as localized vascular dilation, a pathological hallmark of hypoxia-driven vascular proliferation.

[0043] Through vascular staining, we found that there was no significant difference in the area of ​​new blood vessels and non-vascular perfusion area between the OIR group and the Corn oil_DMSO solvent group, while the range of new blood vessels and non-vascular perfusion area in the BEZ235 treatment group was reduced compared with the Corn oil_DMSO solvent control group ( Figure 5 B). These data suggest that BEZ235 can effectively inhibit the formation of pathological neovascularization under OIR conditions and may improve retinal vascular perfusion.

[0044] Experiments confirmed that BEZ235 significantly inhibited the expansion of the avascular perfusion area under OIR conditions and improved the structural disorder of the retina.

[0045] Example 6: BEZ235 has no significant in vivo toxicity at therapeutic doses and does not cause significant retinal or systemic toxicity To evaluate the potential toxicity of BEZ235 on retinal function and vital organs, we performed electroretinogram and histological examinations in mice treated with 1 mg / kg dose of BEZ235 as follows: (1) Experimental grouping and drug administration: Healthy C57BL / 6 mice at 7 days after birth (P7) were selected and divided into 2 groups, with 6 mice in each group; the experimental group mice were intragastrically administered with 1 mg / kg of drug body weight ratio (CON+BEZ235) at a fixed time every day on P12, P13, P14, P15, and P16, and the control group mice were given an equal dose of DMSO dilution as a solvent control group (CON+Corn oil_DMSO) (the drug preparation method was the same as that in Example 4); (2) Monitoring and care: Throughout the experiment, the health status of the mice was closely monitored, including body weight, activity, and appetite, and adequate food and water supply was ensured; (3) Sampling: At P17, mice were anesthetized with isoflurane and then killed. Visceral tissues were collected for further histological or molecular biological analysis.

[0046] (4) Electroretinogram (ERG): The mouse grouping, drug administration method and concentration were consistent with the HE staining method of histological examination. Drugs were administered at fixed times every day on P12, P13, P14, P15, and P16, and electroretinogram testing was performed on P21.

[0047] (5) Results: Electroretinogram (ERG): Before the test, mice were dark-adapted for 12 hours in a completely light-proof room. The next day, the laboratory was kept dark-proof, the electrode wires were plugged in, the 37°C constant temperature platform was turned on, and the corresponding program was selected. The mice were dilated with tropicamide eye drops and anesthetized with tribromoethanol intraperitoneal injection. The electrodes were connected, and the resistance of the corneal electrode and the reference electrode was observed on the system to see if it was <10Ω. After dark adaptation for 15 minutes, flash stimulation of corresponding intensity was performed, and data and images were recorded. ERG results showed that compared with the control group, BEZ235 had no significant effect on the retinal function of mice ( Figure 6 A).

[0048] Histological examination: Visceral tissues were paraffin-embedded and sectioned, and further stained with hematoxylin-eosin (H&E). Cell morphology was analyzed by light microscopy. After BEZ235 treatment, HE-stained sections of the heart, liver, spleen, lung, and kidney showed no systemic toxicity ( Figure 6 B) These results suggest that BEZ235 may target retinal pathological angiogenesis without causing significant retinal or systemic toxicity.

[0049] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present invention shall be equivalent replacement methods and shall be included in the protection scope of the present invention.

Claims

1. Use of BEZ235 in the preparation of drugs for treating or improving retinal microvascular diseases.

2. The use according to claim 1, characterized in that: The BEZ235 inhibits the proliferation and migration of retinal vascular endothelial cells, inhibits the tube-forming ability of retinal vascular endothelial cells, inhibits the formation of pathological neovascularization and the expansion of the avascular perfusion zone under oxygen-induced retinopathy, reduces the number of preretinal neovascularization cells under oxygen-induced retinopathy, and improves the structural disorder of the retina, thereby achieving the purpose of treating or improving retinal microvascular diseases.

3. The use according to claim 1, characterized in that: The retinal microvascular disease includes retinal microvascular disease caused by retinopathy of prematurity, diabetic retinopathy or age-related macular degeneration.

4. The use according to claim 1, characterized in that: The retinal microvascular disease includes pathological retinal neovascularization.

5. The use according to claim 1, characterized in that: The medicine also contains one or more pharmaceutically acceptable excipients or carriers.

6. The use according to claim 1, characterized in that: The auxiliary material is at least one of a sustained-release agent, an excipient, a filler, a binder, a wetting agent, a disintegrant, an absorption promoter, a surfactant or a lubricant.

7. The use according to claim 1, characterized in that: The dosage form of the medicine is capsule, pill, tablet, oral liquid, granule, tincture or injection.

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