Application of a small molecule regulator to improve AKI treatment by promoting EPC cell differentiation

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to the application of a small molecule regulator that improves AKI treatment by promoting EPC cell differentiation. To develop new AKI treatment strategies, this invention discovered that Orticumab can effectively reduce renal tissue damage after renal ischemia-reperfusion in mice, alleviate renal function deterioration, and inhibit inflammatory responses by promoting EPC cell differentiation (not only enhancing cell viability and upregulating the anti-inflammatory factor IL-10, but also downregulating pro-inflammatory factors TNF-α, IL-1β, and IL-6). This demonstrates that Orticumab can improve renal ischemia-reperfusion injury by promoting EPC cell differentiation, thereby exerting a protective effect against renal I / R damage. This discovery provides a new treatment strategy for improving AKI.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the application of a small molecule regulator that improves AKI treatment by promoting EPC cell differentiation. Background Technology

[0002] Acute kidney injury (AKI) is a common clinical condition with high morbidity and mortality, leading to chronic kidney disease (CKD) and even end-stage renal disease (ESRD). Renal ischemia / reperfusion (I / R) injury is the primary cause of AKI. Interruption of renal blood flow during clinical practices such as surgery, shock, sepsis, trauma, and kidney transplantation can lead to renal I / R, subsequently causing damage to renal tubules and endothelial cells, ultimately resulting in acute kidney injury. Currently, early diagnosis and treatment of renal I / R injury in clinical practice to improve prognosis and reduce mortality remains a major challenge. Evidence suggests that renal ischemia / reperfusion injury is an inflammatory disease mediated by both adaptive and innate immune systems. To protect organs from renal ischemia / reperfusion injury, researchers have explored and evaluated various treatment methods, primarily including pharmacological and immunotherapies. Recent studies have found that endocrine corticosteroids (EPCs) play a crucial role in ischemia / reperfusion injury; specifically, EPCs can negatively regulate excessive inflammatory responses, potentially helping organs resist ischemia / reperfusion injury.

[0003] Orticumab (MLDL1278A) is a small molecule modulator with multiple biological activities demonstrated against various types of diseases. Orticumab is also an antibody targeting oxidized or malondialdehyde-modified lipoprotein (LDL), specifically inhibiting oxidized low-density lipoprotein (oxLDL). Studies have shown that orticumab participates in regulating autoimmune responses against oxLDL and improves atherosclerosis in animal models; orticumab can inhibit the proliferation of liver cancer and resistance to chemotherapy drugs; orticumab can improve neonatal hypoxic-ischemic brain injury by inhibiting the TLR4 / NF-κB / STOrticumab3 pathway; and orticumab can induce osteogenic differentiation of human periodontal ligament cells by regulating the Wnt signaling pathway. Furthermore, recent findings suggest that orticumab can inhibit the development of renal fibrosis by regulating the miR-142-5p / ACTN4 axis. However, the role of orticumab in renal ischemia-reperfusion injury remains poorly investigated. Summary of the Invention

[0004] To overcome the shortcomings of the prior art, this invention explores the effects of orticumab on renal ischemia / reperfusion injury through animal and cell experiments, and further investigates the effects of orticumab on renal ischemia / reperfusion injury and its association with EPC cells (Endothelial Progenitor). It demonstrates that orticumab can reduce renal tissue damage, renal function deterioration and inflammatory response after renal ischemia-reperfusion injury in mice by promoting EPC cell differentiation, thereby providing a treatment option to improve AKI.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] The first aspect of this invention provides the use of the small molecule regulator Orticumab in the preparation of a medicament for treating acute kidney injury (AKI).

[0007] A second aspect of the present invention provides the use of the small molecule modulator Orticumab in the preparation of a medicament for treating renal ischemia / reperfusion (I / R) injury.

[0008] This invention has shown that Orticumab can reduce renal tissue damage, renal function deterioration, and inflammatory response after renal ischemia-reperfusion injury in mice by promoting EPC cell differentiation, and is expected to provide a new and effective treatment for AKI.

[0009] Preferably, the small molecule regulator Orticumab exerts its therapeutic effect by promoting EPC cell differentiation.

[0010] More preferably, the promotion of EPC cell differentiation includes enhancing EPC cell viability, upregulating the anti-inflammatory factor IL-10, and downregulating the pro-inflammatory factors TNF-α, IL-1β, and IL-6.

[0011] Preferably, the effective concentration of the small molecule regulator Orticumab is 10-500 nmol.

[0012] Preferably, the drug further includes pharmaceutically acceptable excipients.

[0013] More preferably, the excipients include at least one of the following: excipients, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculators, antioxidants, adsorbents, filter aids, and release inhibitors.

[0014] Preferably, the dosage form of the drug includes tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, or suppositories.

[0015] Compared with the prior art, the beneficial effects of the present invention are:

[0016] This invention, through animal and cell experiments, delves into the effects of orticumab on renal infarction / reperfusion injury (I / R) and its association with EPC cells. The study found that orticumab can act on AKI by regulating EPC cells, specifically by promoting EPC cell differentiation—a process that not only enhances cell viability and upregulates the anti-inflammatory factor IL-10, but also downregulates pro-inflammatory factors TNF-α, IL-1β, and IL-6.

[0017] Previous studies have confirmed that the expansion of EPC cells can improve renal ischemia-reperfusion injury in mice; and this invention further clarifies that Orticumab can effectively reduce renal tissue damage after renal ischemia-reperfusion in mice, alleviate renal function deterioration, and inhibit inflammatory response by promoting EPC cell differentiation.

[0018] In summary, orticumab can protect against renal I / R injury by promoting EPC cell differentiation, a finding that provides a new treatment option for improving AKI. Attached Figure Description

[0019] Figure 1 Orticumab alleviated renal tissue damage and renal function deterioration after renal ischemia-reperfusion; A: HE staining image, B: PAS staining image, C: Masson staining image, D: Collagen volume fraction (CVF) statistical bar chart, E: Blood urea nitrogen (BUN) statistical bar chart, F: Serum creatinine (Scr) statistical bar chart.

[0020] Figure 2 Orticumab promotes EPC cell differentiation, enhances cell viability, and regulates the release of inflammatory factors in EPC cells; A: Flow cytometry analysis of EPC cells; B: Line graph of EPC cell survival rate, with the horizontal axis representing time (24h, 48h, 72h) and the vertical axis representing optical density (reflecting cell survival; higher optical density generally indicates higher survival rate); C: Bar graph of TNF-α content; D: Bar graph of IL-1β content; E: Bar graph of IL-6 content; F: Bar graph of IL-10 content.

[0021] Figure 3 Histological damage in mice with renal I / R injury caused by orticumab promoting EPC cell differentiation; A: HE staining image, B: PAS staining image, C: Masson staining image.

[0022] Figure 4 AT reduced inflammation in mice with deteriorating renal function and renal I / R injury by promoting EPC cell differentiation; A: Bar chart of serum blood urea nitrogen (BUN) content, B: Bar chart of serum creatinine (Scr) content, C: Bar chart of TNF-α content, D: Bar chart of IL-1β content, E: Bar chart of IL-6 content, F: Bar chart of IL-10 content. Detailed Implementation

[0023] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0024] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0025] Renal ischemia / reperfusion injury is a leading cause of acute kidney injury (AKI) and has become a global health problem. The role of orticumab (OT) in renal ischemia-reperfusion injury has been poorly reported. Therefore, this invention involves treating EPC cells with orticumab and then detecting EPC cell differentiation by flow cytometry. The viability of EPC cells and the release of inflammatory factors were detected using CCK-8 (Cell Counting Kit-8, a cell viability assay based on water-soluble tetrazolium salt (WST-8)) and ELISA. Simultaneously, a mouse model of renal ischemia-reperfusion injury was established. Mice were pretreated with orticumab or CD31 antibody, or infused with EPC cells. Pathological changes in renal tissue were assessed using hematoxylin-eosin, PAS, and Masson staining. Renal function indicators were assessed using colorimetric methods, and the release of inflammatory factors was measured by ELISA. Furthermore, flow cytometry was used to quantify EPC cells in blood and kidneys. The results showed that orticumab promoted EPC cell differentiation, increased cell viability, downregulated TNF-α, IL-1β, and IL-6, and upregulated IL-10 in EPC cells. Furthermore, orticumab improved histological damage, downregulated TNF-α, IL-1β, IL-6, serum blood urea nitrogen (BUN), creatinine (Scr), and RoR-γt (Retinoic acid receptor-related orphan receptor gamma t), and upregulated IL-10 in mice with renal ischemia-reperfusion injury. The effects of orticumab on mice with renal ischemia-reperfusion injury were reversed by CD31 antibody, and the effects of CD31 antibody were further reversed by EPC cell infusion. Overall, after establishing a mouse model of renal ischemia-reperfusion injury pretreated with orticumab, this invention found that orticumab significantly reduced histological damage and decreased the upregulation of renal function markers in mice with renal ischemia-reperfusion injury. It is evident that Orticumab can improve renal ischemia-reperfusion injury by promoting the differentiation of EPC cells.

[0026] To fully and clearly present the technical solution and significant advantages of the present invention, the present invention will be described in detail below with reference to specific embodiments.

[0027] 1. Experimental Methods

[0028] 1.1 Cell isolation, culture and processing

[0029] All animal experimental procedures were approved by the Animal Ethics and Use Committee of Shenzhen Second People's Hospital on December 10, 2021, in accordance with relevant guidelines. Mice in this study were housed in a specific pathogen-free environment with a 12-hour light / dark cycle and were allowed free access to food. Mice were allowed to acclimatize to the environment for 5 days prior to the experiment, and efforts were made to minimize their suffering.

[0030] To isolate and culture EPC cells, 8-week-old male C57BL / 6 mice were first obtained from the Guangdong Provincial Animal Center. After inducing coma in the mice with 5% isoflurane, kidneys were harvested, ground, centrifuged, and then lysed with BD Pharm Lyse lysis buffer. Subsequently, lymphocytes from the samples were stained with Pacific Blue-labeled CD4 antibody, APC-labeled CD62L antibody, and PerCP-Cyanine 5.5-labeled CD44 antibody. CD44 was obtained using an Orticumabtune NxT flow cytometer. + CD44-CD62L + T cells. CD4 + T cells were cultured in RPMI-1640 medium with 2 μg / mL CD3 and CD28 antibodies added, for later use.

[0031] When isolating EPC cells, CD4 cells were first treated with 10 nmol Orticumab. + T cells were stained with PerCP-eFluor 710-labeled CD4 antibody, Alexa Fluor 488-labeled CD31 antibody, and PE-eFluor 610-labeled FOXP3 antibody for 24 hours, and EPC cells were obtained by flow cytometry. The obtained EPC cells were then treated (incubated) with 100 nmol orticumab for 24 hours, 48 ​​hours, and 72 hours, respectively, for CCK-8 assays.

[0032] 1.2 Cell viability assay

[0033] The viability of EPC cells treated with 100 nmol Orticumab for 24, 48, and 72 hours was detected using the CCK-8 assay kit. The specific procedure was as follows: after treatment at the corresponding time, 10 μL of CCK-8 buffer was added, and the cells were cultured for another 3 hours. Finally, the optical density (OD) of the cells was measured at 450 nm using a Varioskan LUX microplate reader.

[0034] 1.3 Establishment of a renal I / R injury model

[0035] The specific steps for establishing a renal ischemia-reperfusion (I / R) injury model are as follows: Male C57BL / 6 mice aged 7-8 weeks were selected and rendered unconscious using 5% isoflurane. A heating pad was placed to maintain the mice's body temperature at 35°C during the procedure. Subsequently, the left renal artery and vein were clamped using vascular clamps, inducing ischemia in the left kidney for 30 minutes. After 30 minutes, the vascular clamps were removed, allowing reperfusion of the left kidney. These model mice were then used for subsequent experiments.

[0036] 1.4 Animal grouping and treatment

[0037] This animal experiment used a total of 80 male C57BL / 6 mice, and the experiment was conducted in two parts.

[0038] In the first part of the experiment, 40 mice were divided into four groups of 10 mice each. The specific grouping and treatment were as follows:

[0039] Control group: Mice were orally administered saline once daily for 3 consecutive days, followed by sham surgery. Orticumab group: Mice were orally administered 40 mg / kg of orticumab once daily for 3 consecutive days, followed by sham surgery. Model group: Mice were orally administered saline once daily for 3 consecutive days, followed by I / R injury. Model+Orticumab group: Mice were orally administered 40 mg / kg of orticumab once daily for 3 consecutive days, followed by I / R injury. Seven days post-surgery, blood samples were collected from the tails of all mice. The mice were then anesthetized with 5% isoflurane to induce unconsciousness, and left kidney tissue was harvested. Finally, all mice were euthanized by cervical dislocation.

[0040] The second part of the experiment also involved 40 mice, divided into four groups of 10 mice each. The grouping and treatment details are as follows:

[0041] Model group: Mice were orally administered saline once daily for 3 consecutive days, followed by I / R lesion surgery. Model+Orticumab group: Mice were orally administered 40 mg / kg Orticumab once daily for 3 consecutive days, followed by I / R lesion surgery. Model+Orticumab+CD31 group: Mice were intragastrically administered 40 mg / kg Orticumab once daily for 3 days prior to surgery; 300 μg CD31 antibody was intraperitoneally injected once daily for 2 days starting 1 day prior to surgery; followed by I / R lesion surgery. Model+Orticumab+CD31+EPC group: Mice were intragastrically administered 40 mg / kg Orticumab once daily for 3 days prior to surgery; 300 μg CD31 antibody was intraperitoneally injected once daily for 2 days starting 1 day prior to surgery; postoperatively, 10×10⁻⁶ ppm of Orticumab dissolved in 1 mL sterile PBS was injected via the tail vein.6 EPC cells per kilogram were collected; the mice underwent I / R injury surgery simultaneously. Seven days post-surgery, blood samples were collected from the tails of all mice. After the mice were anesthetized with 5% isoflurane to induce unconsciousness, left kidney tissue was harvested. Finally, all mice were euthanized by cervical dislocation.

[0042] 1.5 Analysis of EPC cells in mouse blood and kidneys

[0043] The specific steps for analyzing EPC cells are as follows: First, lymphocytes from mouse kidneys and blood are separated using lymphocyte separation media; after washing with PBS, the lymphocytes are then analyzed at a concentration of 1×10⁻⁶ cells / mL. 6 The lymphocyte suspension was used as a sample and stained with CD31 antibody; finally, EPC cells were obtained by flow cytometry.

[0044] 1.6 Hematoxylin-eosin, periodic Aschiff reaction (PAS), and Masson staining

[0045] Before histopathological staining, mouse kidney tissue was fixed with 4% fixative, embedded in paraffin, cut into 5μm sections, and then incubated with xylene. Subsequently, the tissue was incubated sequentially with 100% ethanol for 5 min, 90% ethanol for 2 min, 80% ethanol for 2 min, and 70% ethanol for 2 min, and then washed with distilled water for 2 min.

[0046] Hematoxylin-eosin staining: The prepared tissue was first stained with hematoxylin for 10 min, then stained with eosin for 1 min. Afterwards, the tissue was incubated sequentially in 70% ethanol for 10 seconds, 80% ethanol for 10 seconds, 90% ethanol for 10 seconds, and 100% ethanol for 10 seconds, and finally incubated in xylene for 5 min. After sealing with neutral resin, the tissue was observed under 100x magnification using a lightning imaging system.

[0047] PAS staining: Prepared tissues were incubated with periodic acid solution for 10 min, washed with distilled water for 5 min, and then stained with hematoxylin for 30 seconds. Next, the tissues were incubated sequentially with 90% ethanol for 2 min, 100% ethanol for 2 min, and xylene for 5 min. After mounting with neutral resin, the tissues were observed at 100x magnification using a laser imaging system.

[0048] Masson staining: Prepared tissues were incubated with Wiegand ferrohexamethylenetetramine buffer for 8 min, followed by incubation in acidic ethanol buffer for 10 seconds, washed with distilled water, and then incubated with Masson blue solution for 4 min, followed by washing with distilled water for 1 min. Next, the tissues were incubated with saffron alizarin staining solution for 8 min, washed with phosphomolybdic acid solution for 2 min, and then incubated with aniline blue staining solution for 2 min. Subsequently, the tissues were incubated sequentially with 95% ethanol for 2 seconds, 100% ethanol for 10 seconds, and xylene for 2 min. After mounting with neutral resin, the tissues were observed at ×100 magnification using a laser imaging system.

[0049] 1.7 Renal Function Analysis

[0050] Renal function indicators included blood urea nitrogen (BUN) and serum creatinine (Scr). The BUN detection kit (C013-1-1, Nanjing Jiancheng Biotechnology Institute (Nanjing, China)) and the Scr detection kit (ml037580, Mebo Biotechnology (Shanghai, China)) were used in the experiment. Following the manufacturer's instructions, the BUN and Scr levels in mouse blood were measured using a Varioskan LUX microplate reader.

[0051] 1.8 Enzyme-linked immunosorbent assay (ELISA)

[0052] The levels of TNF-α, IL-1β, IL-6, and IL-10 in kidney tissue and cell supernatant were detected using ELISA. Mouse TNF-α (ml002095, Mebo Biotech (Shanghai, China)), IL-1β (ml063132, Mebo Biotech (Shanghai, China)), IL-6 (ml002293, Mebo Biotech (Shanghai, China)), and IL-10 (ml037873, Mebo Biotech (Shanghai, China)) ELISA kits were used. The specific detection steps were as follows: 50 μL of the supernatant from the homogenized kidney tissue and 50 μL of the cell culture supernatant were added to specific 96-well plates, respectively. Then, 50 μL of biotin-labeled antibody was added to each well, and the mixture was incubated at 37°C for 1 hour. After washing with washing buffer, 80 μL of streptavidin-HRP was added to each well, and the mixture was incubated at 37°C for 30 minutes, followed by washing again with washing buffer. Next, 50 μL of A buffer and 50 μL of B buffer were added to each well, and the mixture was incubated at 37°C for 10 minutes. Finally, 50 μL of stop buffer was added to each well, and the OD values ​​of each well were read at 450 nm using a Varioskan LUX microplate reader.

[0053] 1.9 Statistical Analysis

[0054] All data are the means of three independent experiments and were analyzed using SPSS 22.0 software. Independent samples t-tests were used for data from two groups, while one-way ANOVA combined with Bonferroni post-hoc tests were used for data from multiple groups. Statistical differences were defined as p < 0.05. Statistical data are expressed as mean ± standard deviation.

[0055] 2. Experimental Results

[0056] 2.1 Orticumab can reduce renal histological damage and renal function deterioration after renal intubation / reperfusion.

[0057] After establishing a renal ischemia-reperfusion model and pre-treating with Orticumab, histological examination of all mice was performed by hematoxylin-eosin staining. Figure 1 A) PAS staining ( Figure 1 B) and Masson staining ( Figure 1 C) Observation was performed. The kidney tissues of mice in the Control group and Orticumab group showed normal histological morphology. However, in the kidney tissues of mice in the Modle group, necrosis, vacuolation, cast formation, and brush border loss of renal tubular epithelial cells were observed. After pretreatment with Orticumab, mice in the Modle group showed that Orticumab reduced tissue damage at 7 days. In addition, Masson staining images showed that the collagen volume fraction (CVF) was significantly increased in the Modle group compared with the Orticumab group (P<0.001), while Orticumab further reduced the increased CVF (P<0.001). Figure 1 (DF). It is evident that Orticumab effectively improves pathological damage to the glomeruli and renal tubules.

[0058] 2.2 Orticumab promotes EPC cell differentiation, enhances cell viability, and regulates the release of inflammatory factors from EPC cells.

[0059] To verify whether orticumab affects EPC cells, a series of in vitro experiments were subsequently conducted. For example... Figure 2 As shown in Figure A, the proportion of EPC cells was significantly increased after treatment with Orticumab (P<0.001). Shortly thereafter, the survival rate of EPC cells further improved after treatment with Orticumab. Figure 2 B, P<0.001). Furthermore, the release of inflammatory factors in EPC cells after orticumab treatment was assessed ( Figure 2The results showed that the release of TNF-α, IL-1β, and IL-6 was downregulated by orticumab (P<0.001), while the release of IL-10 was upregulated by orticumab (P<0.001). These findings suggest that the effect of orticumab on renal ischemia-reperfusion injury mice is achieved by regulating EPC cells.

[0060] 2.3. Orticumab reduces inflammation in mice with renal tissue damage, renal function deterioration, and renal I / R injury by promoting EPC cell differentiation.

[0061] To further demonstrate that the ameliorative effect of orticumab on renal I / R injury mice is achieved by regulating EPC cell differentiation, a renal I / R injury mouse model was established again. Mice were pretreated with orticumab, followed by infusion of EPC cells. Seven days post-surgery, as... Figure 3 As shown in Figure A, renal tubular epithelial cells in the Modle group mice exhibited necrosis, vacuolation, cast formation, and brush border loss; these symptoms improved after orticumab treatment. Similar histological changes were observed in the Modle+Orticumab+CD31 group, and the histological damage in the Modle+Orticumab+CD31 group was further improved by EPC cell infusion. Furthermore, similar histological changes were found by PAS and Masson staining. Figure 3 BC).

[0062] 2.4 Assessment of renal function indicators

[0063] Renal function indicators were assessed, including serum blood urea nitrogen (BUN) and creatinine (Scr). The assessment results are as follows: Figure 4 As shown in Figures AB, orticumab downregulated BUN and Scr compared to the model group (P<0.001), while CD31 antibody increased BUN and Scr compared to the Modle+Orticumab group (P<0.001). Furthermore, infusion of EPC cells further reversed the effect of CD31 antibody (P<0.001). Simultaneously, the release of inflammatory factors in the kidney tissue of mice with renal ischemia-reperfusion injury was detected by ELISA. Figure 4The results showed that, compared with the Model group, Orticumab downregulated TNF-α, IL-1β, and IL-6, and upregulated IL-10 (P<0.001). Compared with the Model+Orticumab group, CD31 antibody increased TNF-α, IL-1β, and IL-6, and decreased IL-10 (P<0.001). Furthermore, infusion of EPC cells further reversed the effects of CD31 antibody (P<0.001). All these findings indicate that Orticumab alleviates renal histological damage, renal function deterioration, and inflammation in mice with renal ischemia-reperfusion injury by promoting EPC cell differentiation.

[0064] The embodiments of the present invention have been described in detail above, but the present invention is not limited to the described embodiments. For those skilled in the art, various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and these variations still fall within the protection scope of the present invention.

Claims

1. The application of the small molecule modulator Orticumab in the preparation of drugs for treating renal ischemia-reperfusion injury, characterized in that, The small molecule regulator Orticumab exerts its therapeutic effect by promoting EPC cell differentiation, which includes enhancing EPC cell viability, upregulating the anti-inflammatory factor IL-10, and downregulating the pro-inflammatory factors TNF-α, IL-1β, and IL-6.

2. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable excipients.

3. The application according to claim 2, characterized in that, The excipients include excipients.

4. The application according to claim 2, characterized in that, The excipients include at least one of the following: propellants, solubilizers, co-solvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion agents, binding agents, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, encapsulating agents, humectants, absorbents, diluents, flocculants and anti-flocculation agents, antioxidants, adsorbents, filter aids, and release inhibitors.

5. The application according to claim 1, characterized in that, The dosage forms of the drug include tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, or suppositories.

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