Use of platelet factor 4 in the preparation of a medicament for treating or preventing candida albicans infection

Abstract

The present application relates to the use of platelet factor 4 in the preparation of a drug for treating or preventing Candida albicans infection, platelet factor 4 acts on macrophage CXCR3 receptor, antagonizes Candida albicans induced macrophage PANoptosis, thereby reducing the damage of Candida albicans to macrophages, maintaining the survival and normal function of macrophages, enhancing the clearance ability of the body to Candida albicans, reducing the inflammatory response caused by infection, reducing pathological damage, and different from the treatment mechanism of traditional antifungal drugs, the present application does not directly act on fungi, which helps to reduce the formation of drug-resistant strains and the toxic side effects such as liver toxicity and kidney toxicity caused by antifungal drugs, and can provide a more optimal new treatment mode for clinical Candida albicans infection.

Description

Technical Field

[0001] This invention relates to the use of platelet factor 4 in the preparation of drugs for the treatment or prevention of Candida albicans infection, and is applicable to the field of biomedical technology. Background Technology

[0002] Candida albicans is an opportunistic pathogen that causes mucocutaneous and invasive candidiasis. In immunocompromised patients, the mortality rate of disseminated infections can reach as high as 40%, and severe cross-resistance exists. Currently, among the drugs used to treat Candida albicans, echinocandins are first-line drugs, but cases of resistance are increasingly common, and these drugs have low efficacy against biofilm-borne strains, resulting in a treatment failure rate of 30%–50% for catheter-related biofilm infections. Amphotericin B's severe nephrotoxicity limits its clinical application and makes long-term use impossible. Azole drugs also suffer from biofilm resistance and significant hepatotoxicity and nephrotoxicity. Existing treatments not only exhibit high rates of resistance but also have significant side effects, and patients have limited options. These challenges directly lead to the ineffective control of infections and unsatisfactory patient prognoses. Therefore, developing novel drugs or treatment strategies that target new, safe, low-toxicity, and highly effective targets has become an urgent need to reduce the mortality rate of Candida albicans infections and is a core direction for overcoming current treatment bottlenecks and saving more patients' lives.

[0003] Macrophages are core effector cells of the body's innate immune system, playing a crucial role in recognizing, phagocytosing, and clearing Candida albicans. However, Candida albicans can induce a pro-inflammatory programmed cell death called "PANoptosis" in macrophages through various virulence factors (such as hyphal formation and secretion of aspartic acid protease). PANoptosis is a cell death pattern that integrates key features of pyroptosis, apoptosis, and necroptosis. Its consequences not only include a reduction in the number of macrophages, but more importantly, it leads to the release of large amounts of pro-inflammatory factors, exacerbating tissue damage and inflammatory storms, which ironically favors the spread and persistent infection of the fungus.

[0004] As the second most abundant blood component after red blood cells, platelets are increasingly recognized for their role in fungal infections. In fungal infections, platelets activate themselves through pattern recognition receptors (PRRs) and glycoprotein (GP) IIb / IIIa. Activated platelets secrete various cytokines, recruiting and chemotactically attracting immune cells such as macrophages and neutrophils to the infection site, thereby exerting anti-infection functions. Platelet factor 4 (PF4) is one of the important cytokines released after platelet activation, possessing rich biological functions. Studies have confirmed that Candida albicans infection can activate platelets and release large amounts of PF4. However, the specific role of PF4 in infection remains undisclosed, and therefore, no publicly available technology demonstrates its potential application in the preparation of drugs for the treatment or prevention of Candida albicans infection. Summary of the Invention

[0005] To address the shortcomings of the existing technology, this invention proposes the application of platelet factor 4 in the preparation of drugs for the treatment or prevention of Candida albicans infection.

[0006] The technical solution adopted in this invention is: This invention provides the application of platelet factor 4 in the preparation of drugs for treating or preventing Candida albicans infection.

[0007] Furthermore, the drug includes platelet factor 4 and a pharmaceutically acceptable carrier or excipient.

[0008] Furthermore, the drug is a topical, oral, injectable, implantable, rectal, spray, or inhaled administration agent.

[0009] Furthermore, the dosage forms of the drug include, but are not limited to, solutions, tinctures, liniments, lotions, ointments, plasters, pastes, oils, films, liniments, injections, tablets, granules, capsules, pellets, sustained-release preparations, oral liquid preparations, powders, or gels.

[0010] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art: This invention provides the application of platelet factor 4 (PF4) in the preparation of drugs for the treatment or prevention of Candida albicans infection. On the one hand, PF4 antagonizes Candida albicans-induced macrophage PANoptosis by acting on macrophage CXCR3 receptors, thereby reducing damage to macrophages by Candida albicans, maintaining macrophage survival and normal function, and enhancing the body's ability to clear Candida albicans. Its mechanism of action is consistent with the characteristics of the patient's innate immune response to fungal infection, which is beneficial for regulating macrophage function at the site of infection, thereby reducing interference with normal tissue function, and enabling macrophage survival and functional recovery, thereby reducing inflammatory response and pathological damage. On the other hand, PF4, as a naturally occurring endogenous chemokine in human platelets and various tissues, has a well-defined physiological regulatory function. Administering exogenous recombinant PF4 can maximally mimic physiological processes, avoiding the immunogenic risks that exogenous proteins may bring. It can coordinate immune protection and inflammation control through multiple pathways, achieving precise regulation of fungal infections. Furthermore, unlike the treatment mechanism of traditional antifungal drugs, this application does not directly target fungi, but rather improves the safety of clinical translation from the source. It is suitable for long-term or repeated dosing scenarios in immunocompromised patients, significantly reducing the hepatotoxicity and nephrotoxicity risks of traditional antifungal drugs. In addition, this application focuses on the specific disease model of systemic Candida albicans infection, ensuring the targetedness and high efficiency of the treatment. The sequences and structures of human and murine PF4 proteins are highly conserved, with strong functional cross-reactivity, improving reproducibility and feasibility, reducing variability, and providing a superior new treatment approach for Candida albicans infection in clinical practice. Attached Figure Description

[0011] The following sections will describe some specific embodiments of the invention in a detailed manner, by way of example and not limitation, with reference to the accompanying drawings. The same reference numerals in the drawings denote the same or similar components or parts. Those skilled in the art should understand that these drawings are not necessarily drawn to scale. In the drawings: Figure 1 This is a graph showing the changes in survival time of mice in Example 1 of the present invention; Figure 2 yes Figure 1 The illustrated example shows SDA culture images of mouse spleen and peripheral blood. Figure 3 yes Figure 1 The bacterial load diagram of mouse peripheral blood in the illustrated example; Figure 4 yes Figure 1 The bacterial load diagram of mouse spleen in the illustrated example; Figure 5 This is a graph showing the change in mouse survival time in Example 2 of the present invention; Figure 6 yes Figure 5 The bacterial load diagram of mouse spleen in the illustrated example; Figure 7 yes Figure 5 The bacterial load diagram of mouse kidneys in the illustrated example; Figure 8 yes Figure 5 PAS staining image of mouse tissue shown in the example; Figure 9 yes Figure 5 The mouse plasma pro-inflammatory factor levels in the illustrated examples Figure 1 ; Figure 10 yes Figure 5 The mouse plasma pro-inflammatory factor levels in the illustrated examples Figure 2 ; Figure 11 yes Figure 5 The illustrated example shows the ratio of mouse F4 / 80+CD11b+Ly6G- cells. Figure 1 ; Figure 12 yes Figure 5 The illustrated example shows the ratio of mouse F4 / 80+CD11b+Ly6G- cells. Figure 2 Figure 13 yes Figure 5 The in vitro detection results of THP-1 macrophage-like cells in the illustrated embodiment are shown in the figure. Figure 14 yes Figure 5 Western blot analysis of THP-1 macrophage-like cells in the illustrated example Figure 1 ; Figure 15 yes Figure 5 Western blot analysis of THP-1 macrophage-like cells in the illustrated example Figure 2 ; Figure 16 This is a graph showing the changes in mouse survival time in Example 3 of the present invention; Figure 17 yes Figure 16 PAS staining image of mouse kidney tissue in the illustrated example; Figure 18 yes Figure 16 The mouse F4 / 80+CD11b+ cell ratio in the illustrated example Figure 1 ; Figure 19 yes Figure 16 The mouse F4 / 80+CD11b+ cell ratio in the illustrated example Figure 2 . Detailed Implementation

[0012] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0013] Unless otherwise specified, the methods involved in the different embodiments of the present invention described below are conventional methods, and the reagents used are conventional commercially available reagents or reagents prepared according to conventional methods, unless otherwise specified. Furthermore, the technical features involved in the different embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0014] This invention provides the application of platelet factor 4 (PF4) in the preparation of a drug for treating or preventing Candida albicans infection. This drug, through its PF4 component, acts on the macrophage CXCR3 receptor, protecting macrophages and enabling them to antagonize Candida albicans-induced macrophage PANoptosis, maintaining macrophage survival and normal function, and enhancing the body's ability to clear Candida albicans, thereby exerting a therapeutic effect. Specifically, the recombinant PF4 protein is genetically engineered and linked to a vector that can be expressed in E. coli, and then the recombinant vector is introduced into E. coli for translational expression. This protein is a single-chain, non-glycosylated polypeptide chain composed of 76 amino acids, with a molecular weight of approximately 8.2 kilodaltons. Its amino acid sequence is: VTSAGPEESDGDLSCVCVKT ISSGIHLKHI TSLEVIKAGR HCAVPOLIAT LKNGRKICLDRQAPLYKKVI KKILES. SDS-PAGE and HPLC analyses showed that the PF4 protein of this invention had a purity greater than 97%, retained its complete biological function, and showed no inactivation. Its biological activity was determined using a chemotactic bioassay of human neutrophils. The PF4 stock solution was prepared in a 20mM PBS buffer (containing 1.5M NaCl) at pH 7.4. The stock solution was filtered through a 0.2μm filter and then lyophilized for easy storage, reconstitution, and administration. The PF4 of this invention can be formulated as an injection, lyophilized powder, sustained-release formulation, or nanodelivery formulation, and can be combined with pharmaceutically acceptable carriers, stabilizers, excipients, or buffers to form pharmaceutical compositions.

[0015] The dosage of PF4 in mice is 1-50 μg / kg, preferably 40 μg / kg, administered via intravenous injection, and given every other day.

[0016] The experimental materials and methods involved in the various embodiments of this invention are as follows. Unless otherwise specified, all experimental methods are conventional methods, and all experimental materials and reagents not specifically described can be obtained commercially. 1. Culture of Candida albicans: The reference strain of Candida albicans SC5314 was obtained from the Fungal Culture Collection Center of the Chinese Academy of Medical Sciences. It was cultured in YPD liquid medium at 30°C and 180 rpm for 12-16 hours, washed and resuspended in PBS for subsequent experiments.

[0017] 2. CFU Count: After a certain period of infection (24, 48, 72 hours, etc.), mouse kidney or spleen tissue was collected, washed with PBS and weighed. Sterile PBS was added at a dose of 1 mL / 100 mg tissue, and the tissue homogenate was prepared by thorough grinding. After continuous dilution, the tissue homogenate was inoculated on Sabouraud dextrose agar (SDA) plates and incubated at 37°C for 24-48 hours. The colony-forming units were then counted.

[0018] 3. PAS staining: Mouse kidney or spleen tissue was aseptically collected, routinely dewaxed to water, oxidized with 1% periodic acid solution for 15 minutes, washed thoroughly with water, stained with Schiff solution for 20 minutes, rinsed with running water until colorless, lightly stained the nuclei with Harris hematoxylin solution for 2-3 minutes, slightly differentiated and blued with 1% hydrochloric acid alcohol solution, rinsed with running water for 10 minutes, dehydrated with alcohol stepwise, cleared with xylene, and mounted with neutral resin.

[0019] 4. THP-1 Macrophage-like Cell Culture: THP-1 cells (American Type Culture Collection, ATCC) were stimulated for 24 hours with 100 nM PMA (MCE, USA, 16561-29-8) in RPMI 1640 medium containing 10% FBS and 1% penicillin-streptomycin, and then cultured for another 48 hours without PMA to differentiate into macrophage-like cells. After differentiation, the PF4-treated group was pretreated with 0.1 μg / mL PF4 (Prime Gene, Shanghai, China, 201-04) for 2 hours, and the AMG487-treated group was pretreated with 2.5 μM AMG487 (MCE, USA, 473719-41-4) for 4 hours. After treatment, the medium was replaced with fresh medium to remove the corresponding reagents. Subsequently, all groups of cells were co-cultured with Candida albicans at an MOI of 2 for 4 hours.

[0020] 5. Preparation of mouse kidney single-cell suspension: Sacrificial mouse kidney tissue was isolated and placed in a 1.5 ml centrifuge tube. After mincing, 1 ml of collagenase solution (Roche, USA, 05401020001) was added, and the mixture was incubated at 37°C for 15 minutes. After digestion, the tissue mixture was ground and filtered through a 70 μm filter, then washed with PBS and filtered again through a 40 μm filter. After centrifugation (300 × g, 5 minutes), the supernatant was discarded. 3 ml of erythrocyte lysis buffer (Beyotime, China, C3702) was added to the pellet, and lysis was performed at room temperature for 5 minutes. Then, 30 ml of PBS was added for washing, followed by centrifugation (300 × g, 5 minutes), and the supernatant was discarded. Finally, the cells were resuspended in PBS.

[0021] 6. Preparation of mouse peripheral blood single-cell suspension: Approximately 100 μl of blood was collected from the retro-orbital vein of mice using a capillary tube and added to a blood collection tube containing EDTA-K2, then transferred to a 1.5 ml centrifuge tube. 100 μl of erythrocyte lysis buffer (Beyotime, China, C3702) was added to the centrifuge tube, and the cells were lysed for 5 minutes at room temperature. Afterwards, 1 ml of PBS was added for washing, followed by centrifugation (300×g, 5 minutes), discarding the supernatant, and finally resuspending the cells in PBS.

[0022] 7. Culture of bone marrow-derived macrophages (BMDMs): Bone marrow cells were flushed from the femur and tibia of C57BL / 6J mice and cultured in DMEM containing 10% FBS, 1% penicillin-streptomycin, and 100 ng / mL M-CSF at 37°C and 5% CO2. 2 After culturing for 7 days under the specified conditions, non-adherent cells and M-CSF were removed before the experiment. BMDMs were pretreated with PF4 (0.1 μg / mL, 2 hours) and co-cultured with Candida albicans (MOI=1, 6 hours).

[0023] 8. Flow Cytometry: PRP, THP-1 macrophage-like cells, BMDMs, peripheral blood single-cell suspensions, or kidney single-cell suspensions were pretreated with human Fc Block (BD Pharmingen, 564219) or mouse Fc Block (BD Pharmingen, 553142) for 15 minutes, then pretreated with FVS780 (BD Horizon, 565388) and targeting CD41 (eBioscience, USA, 225-0419-422), CD62P (BD Pharmingen, USA, 304904), CD45 (BD Pharmingen, 553079, 553081, 553081), Ly6G (BD Pharmingen, 560599), CD11b (BD Pharmingen, 552850) (BioLegend, 101228), and F4 / 80 (BD). The cells were stained with a fluorescein-conjugated antibody (FCA) from Pharmingen (565410) (eBioscience, 45-8401-82), with blank tubes and single-dye tubes also prepared. Data were then acquired using a BD FACSVerse flow cytometer and analyzed using FlowJo software.

[0024] 9. Western blot: PRP, THP-1 macrophage-like cells, BMDMs, peripheral blood single-cell suspensions, or kidney single-cell suspensions were collected. Cytoplasm and nuclear proteins were extracted using a commercial kit (ThermoFisher, 78833). Samples were separated by SDS-PAGE and transferred to a PVDF membrane, and blocked with 5% BSA (Bioforxx, Germany, 4240) for 1 hour at room temperature. Then, the samples were probed with the corresponding primary antibody, including GAPDH (CST, 5174S), incubated overnight at 4°C, and washed three times (5 minutes each) with 1×TBST (Solarbio, China, T1082). Subsequently, the samples were incubated with the corresponding HRP-conjugated secondary antibody (CST, 7074) at room temperature for 1 hour, and washed three times (5 minutes each) with 1×TBST (Solarbio, China, T1082). Finally, the signal was detected using ECL reagent (Abkine, USA, BMU102-CN) and imaged using a chemiluminescence imaging system (Amersham ImageQuant800).

[0025] 10. RT-qPCR: Total RNA was extracted from Candida albicans or mouse kidney tissue using an RNA extraction kit (AG21017, Accurate Biotechnology, Hunan, China), and then reverse transcribed into cDNA. Real-time quantitative PCR was performed using a LightCycler 480 II automated real-time PCR system (Roche, Basel, Switzerland) to determine the expression levels of the target genes. The relative gene expression levels were calculated using the 2^(-ΔΔCt) method, and normalized using ACT1 or GAPDH as internal control genes.

[0026] Example 1: The effect of thrombocytopenia on systemic Candida albicans infection a. Mice were randomly divided into two groups: a control group and a platelet clearance group. On day 0 of the experiment, mice in the platelet clearance group were injected with rabbit anti-mouse platelet serum (AIA31440, Accurate Chemical & Scientific Corporation, USA) via the ophthalmic vein at a dose of 15 μL / 20 g body weight, and mice in the control group were injected with control rabbit serum at the same dose. Subsequently, mice were injected with 2 × 10⁻⁶ mmol / L platelet serum per 20 g body weight. 5 The corresponding dose of Candida albicans was injected into mice in the control group and platelet clearance group via the ocular vein, and the corresponding serum was injected again every other day thereafter. b. On day 6 of the experiment, three mice from the control group and three mice from the platelet clearance group were randomly selected. Peripheral blood was collected intravenously, and the mice were then euthanized and samples of the kidneys and spleen were collected. The remaining mice continued to be injected with the corresponding serum until the mice died, and the survival curves were recorded.

[0027] The collected samples were subjected to relevant experiments using the above experimental methods. The results showed that the survival time of mice in the control group was longer than that in the platelet clearance group (see attached figure). Figure 1 (As shown in the attached image); and the bacterial load in the peripheral blood and spleen of mice in the platelet clearance group was higher than that in mice in the control group (as shown in the attached image). Figure 2 , 3 (As shown in Figures 4). The above results indicate that thrombocytopenia increases the fungal load in mice infected with systemic Candida albicans and reduces their survival time, demonstrating that platelets play an important role in combating Candida albicans infection.

[0028] Example 2: The effect of PF4 on the prognosis of Candida albicans infection: a. Construct control mice, infection mice, and infection + PF4 supplementation mice, at a dosage of 2 × 10⁻⁶ ppm per 20g body weight. 5The dose of Candida albicans was injected into mice in the infection group and the infection + PF4 supplementation group via the tail vein. b. After infection, recombinant PF4 was injected into mice in the infected + PF4 supplemented group via the ophthalmic vein every other day at a dose of 40 μg per kg of body weight. c. Six days after infection, some mice were randomly selected from the control group, infection group, and infection + PF4 supplementation group. Peripheral blood was collected intravenously, and then the mice were euthanized and samples such as kidneys and spleens were collected.

[0029] The collected samples were subjected to relevant experiments using the above experimental methods. The results showed that the survival time of mice in the infection + PF4 supplementation group was significantly longer than that of mice in the infection group (see attached figure). Figure 5 (As shown in the attached image); and the bacterial load in the spleen and kidneys of mice in the infection + PF4 supplementation group was significantly reduced (as shown in the attached image). Figure 6 , Figure 7 As shown); in the PAS staining results of kidney tissue pathological sections, the number of Candida albicans spores and hyphae in the lesions of the infection + PF4 supplementation group was significantly reduced (as shown in the attached figure). Figure 8 (As shown in the attached image); the levels of pro-inflammatory factors such as IL-1β and TNF-α in the plasma of mice in the infection + PF4 supplementation group were also significantly decreased (as shown in the attached image). Figure 9 , Figure 10 (As shown in the figure); the above experimental results indicate that platelets reduce target organ damage, decrease inflammatory response, and prolong survival time in mice infected with Candida albicans by secreting PF4.

[0030] Further details are attached. Figure 11 , 12 As shown, the proportion of macrophages in mice infected with PF4 supplementation was significantly higher than that in the infection group; and in in vitro experiments, PF4 itself did not affect macrophage mortality, but under Candida albicans infection conditions, PF4 significantly reduced cell mortality (as shown in the attached figure). Figure 13 As shown in the attached image); Western blot analysis revealed that PF4 simultaneously inhibited the activation of GSDMD, PARP, Caspase-3, and MLKL in THP-1 macrophage-like cells induced by Candida albicans, and also inhibited the increase in ZBP-1 expression (as shown in the attached image). Figure 14 , 15 As shown in the figure); the above experimental results indicate that PF4 can inhibit Candida albicans-induced macrophage PANoptosis and maintain macrophage survival.

[0031] Example 3: Mechanism of PF4 regulating macrophage PANoptosis Protein-protein interaction (PPI) analysis using the STRING database revealed an interaction between CXCR3 and PF4. AMG487, a known inhibitor of the CXCR3 receptor, was used here to block the effect of PF4 on macrophages. Based on this: a. Mice were randomly divided into 3 groups: infection group, infection + PF4 group, and infection + PF4 + AMG487 group; administered 2 × 10⁻⁶ mg / 20g body weight. 5 Candida albicans was injected via the ocular vein into mice in the infection group, infection + PF4 group, and infection + PF4 + AMG487 group, respectively. b. Recombinant PF4 (Prime Gene, Shanghai, China, 221-04) was injected into mice in the infection + PF4 group and the infection + PF4 + AMG487 group via the tail vein at a dose of 40 μg per kg of body weight, once every other day; additionally, 250 μM AMG487 solution (MedChemExpress, New Jersey, USA, HY-15319) was injected intravenously into mice in the infection + PF4 + AMG487 group at a dose of 25 μL per 20 g of body weight, once daily. c. Monitor and record the weight and survival status of mice daily. Eight days after infection, select some mice from the infection group, infection + PF4 group, and infection + PF4 + AMG487 group, respectively, and collect peripheral blood via vein. Then, euthanize the mice and collect samples such as kidneys and spleens. The remaining mice continue to be weighed daily until all mice are killed.

[0032] The collected samples were subjected to relevant experiments using the above experimental methods. The results showed that the survival time of mice in the +PF4+AMG487 infection group was significantly lower than that of mice in the infection group and the +PF4 infection group (see attached figure). Figure 16 (As shown in the attached image); PAS staining results of kidney tissue showed that, compared with the infection + PF4 group, the infection + PF4 + AMG487 group of mice had more spores and hyphae in the infection lesions (as shown in the attached image). Figure 17 (As shown in the attached image); the proportion of macrophages in the infection + PF4 + AMG487 group was significantly lower than that in the infection + PF4 group (as shown in the attached image). Figure 18 , 19 As shown in the figure), the above experimental results demonstrate that PF4 can antagonize Candida albicans-induced macrophage PANoptosis by acting on the macrophage CXCR3 receptor, maintain macrophage survival and normal function, thereby enhancing the body's ability to clear Candida albicans, reducing inflammatory response, and avoiding pathological damage.

[0033] In summary, the application of platelet factor 4 provided by this invention in the preparation of drugs for treating or preventing Candida albicans infection antagonizes Candida albicans-induced macrophage PANoptosis by acting on macrophage CXCR3 receptors, thereby reducing damage to macrophages caused by Candida albicans, maintaining macrophage survival and normal function, enhancing the body's ability to clear Candida albicans, reducing the inflammatory response caused by infection, and reducing pathological damage. Furthermore, unlike the treatment mechanism of traditional antifungal drugs, this application does not directly act on the fungus, reducing the formation of drug-resistant strains and the potential hepatotoxicity, nephrotoxicity, and other toxic side effects of antifungal drugs. This provides a superior new treatment method for Candida albicans infection in clinical practice. The above embodiments are only for illustrating the technical concept and features of the present invention. Their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. Application of platelet factor 4 in the preparation of drugs for the treatment or prevention of Candida albicans infection.

2. The application according to claim 1, characterized in that: The drug includes platelet factor 4 and a pharmaceutically acceptable carrier or excipient.

3. The application according to claim 1, characterized in that: The drug is a topical, oral, injectable, implantable, rectal, spray, or inhaled drug.

4. The application according to claim 1, characterized in that: The dosage forms of the drug include, but are not limited to, solutions, tinctures, liniments, lotions, ointments, plasters, pastes, oils, films, liniments, injections, tablets, granules, capsules, pellets, sustained-release preparations, oral liquid preparations, powders, or gels.

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