Method for treating infectious diseases

Abstract

The present invention provides a method for treating infectious diseases. The method comprises administering to a subject in need thereof an effective amount of a micelle having a shell formed by (i) a polymer-flavonoid conjugate, (ii) a flavonoid oligomer, or (iii) one or more polymer-flavonoid conjugates or one or more flavonoid oligomers or a combination thereof, and having a drug encapsulated therein. The method of the present invention is effective for the treatment of viral infections such as severe acute respiratory syndrome coronavirus (SARS-CoV), enterovirus, HIV, hepatitis B virus, MERS-CoV, influenza virus, dengue virus, respiratory syncytial virus, hepatitis C virus, monkeypox virus, human papillomavirus, methicillin-resistant Staphylococcus aureus, Pseudomonas, Mycobacterium tuberculosis, Bacillus anthracis, Clostridium tetani, Streptococcus pneumoniae, Neisseria meningitidis, Escherichia coli, Legionella, Neisseria gonorrhoeae, Neisseria meningitidis, and Salmonella.

Description

Technical Field

[0001] The present invention provides a method for treating infectious diseases such as bacterial and viral infections. The method comprises administering to a subject in need thereof an effective amount of a micelle having a shell formed by (i) a polymer-flavonoid conjugate, (ii) a flavonoid oligomer, or (iii) one or more polymer-flavonoid conjugates or one or more flavonoid oligomers or a combination thereof, and having an active agent encapsulated therein.

Background Art

[0002] Infectious diseases Infectious diseases are diseases caused by pathogens such as bacteria, viruses, fungi, or parasites. Infectious diseases are the invasion of body tissues by the agents causing the disease, their growth, and the reaction of host tissues to the infectious agents and the toxins produced by the infectious agents.

[0003] Bacterial and viral infections constitute the majority of infectious diseases. A host can use the immune system to fight infections. Mammalian hosts often respond to infections by a natural response accompanied by inflammation, followed by an adaptive response. Typical signs and symptoms of infections are signs of host inflammation caused by these pathogens, such as fatigue, loss of appetite, weight loss, fever, night sweats, chills, aches and pains, and skin rashes, cough, or runny nose.

[0004] Bacterial infections A bacterial infection is the growth of harmful bacterial strains in the body or on the body surface. Bacterial infections occur when bacteria enter the body, multiply, and cause a reaction inside the body. Bacteria can enter the body through openings in the skin, the respiratory tract, or the digestive system and cause an infection. Bacteria can infect any part of the body. Pneumonia, meningitis, and food poisoning are just a few of the illnesses that can be caused by harmful bacteria. Bacteria have three basic shapes: rod-shaped (bacilli), spherical (cocci), and spiral (spirilla). Bacteria can also be classified as Gram-positive bacteria and Gram-negative bacteria. Gram-positive bacteria have a thick cell wall, while Gram-negative bacteria do not have a cell wall. Other tests, such as Gram staining, bacterial culture with antibiotic susceptibility determination, and genetic analysis, are used to identify bacterial strains and determine the appropriate course of treatment.

[0005] Bacteria cause disease by secreting or excreting toxins (in the case of botulism), producing toxins internally and releasing them when the bacteria break down (in the case of typhoid fever), or inducing sensitivity to antigenic properties (in the case of tuberculosis).

[0006] Some severe bacterial diseases include cholera, diphtheria, bacterial meningitis, tetanus, Lyme disease, gonorrhea, syphilis, tuberculosis, anthrax, tetanus, leptospirosis, pneumonia, botulism, Pseudomonas infection, MRSA infection, E. coli infection, and bubonic plague.

[0007] Viral infections Viral diseases (or viral infections) occur when pathogenic viruses invade an organism's body and infectious virus particles (virions) attach to and invade susceptible cells. These viruses include, but are not limited to, adenovirus, coxsackievirus, cytomegalovirus, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, HIV, human coronavirus 229E (HCoV-229E), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), human coronavirus OC43 (HCoV-OC43), human herpesvirus, human papillomavirus, influenza virus, measles virus, Middle East respiratory syndrome-related coronavirus (MERS-CoV), mumps virus, parainfluenza virus, poliovirus, rabies virus, respiratory syncytial virus, rubella virus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), varicella-zoster virus.

[0008] A viral infection is the growth of harmful viruses within a host. Viruses cannot replicate without the help of a host. Viruses infect a host by introducing their genetic material into cells and using the cell's internal machinery to produce more virus particles.

[0009] Antibiotic treatment Bacterial infections are treated with antibiotics. However, the new drug pipeline is drying up. For example, about 40 years passed between the introduction of the two most recent molecular classes of antibiotics, fluoroquinolones (such as Cipro) in 1962 and oxazolidinones (such as Zyvox) in 2000. Big pharmaceutical companies have had limited interest in investing their business resources in the antibiotic market because these short-term drugs do not generate as much profit as drugs for treating chronic diseases and lifestyle diseases such as hypertension or high cholesterol. Antibiotic research and development is costly, risky, and time-consuming. Considering that resistance to antibiotics develops over time and ultimately reduces the effectiveness of antibiotics, the return on that investment is unpredictable.

[0010] Flavonoid Flavonoids have a general structure of a 15-carbon skeleton composed of two phenyl rings (A and B) and one heterocyclic ring (C, a ring containing embedded oxygen).

Chemical formula

[0011] This carbon structure is abbreviated as C6-C3-C6. According to the IUPAC nomenclature, flavonoids can be classified as follows: Flavonoids or bioflavonoids; Isoflavonoids derived from the 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure; Neoflavonoids derived from the 4-phenylcoumarin (4-phenyl-1,2-benzopyrone) structure.

Brief Description of the Drawings

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[0013] **Definitions** The term "epigallocatechin gallate" refers to an ester of epigallocatechin and gallic acid and is used interchangeably with "epigallocatechin-3-gallate" or "EGCG".

[0014] The term "oligomeric EGCG" (OEGCG) refers to a compound in which 3 to 20 EGCG monomers are covalently bonded. OEGCG preferably contains 4 to 12 EGCG monomers.

[0015] The term "polyethylene glycol-epigallocatechin gallate conjugate" or "PEG-EGCG" refers to polyethylene glycol (PEG) conjugated to one or two molecules of EGCG. The term "PEG-EGCG" refers to both PEG-mEGCG (monomeric EGCG) conjugate and PEG-dEGCG (dimeric EGCG) conjugate.

[0016] The term "nucleoside analog" refers to a nucleoside in which a natural base (A, T, G, C, or U) or natural ribose / deoxyribose is modified. Nucleoside analogs can be used to prevent viral replication in infected cells.

[0017] The term "nucleotide analog" refers to a nucleotide in which a natural base (A, T, G, C, or U), natural ribose / deoxyribose, or phosphate is modified. Nucleotide analogs can be used to prevent viral replication in infected cells. For example, remdesivir is a nucleotide analog.

[0018] The present invention provides a method for treating an infectious disease. The method comprises administering to a subject in need thereof an effective amount of a micelle having a shell formed by (i) a polymer-flavonoid conjugate, (ii) a flavonoid oligomer, or (iii) one or more polymer-flavonoid conjugates or one or more flavonoid oligomers or a combination thereof, and having a drug encapsulated therein.

[0019] Flavonoid Suitable flavonoids for the present invention have the general structure of Formula I: [Chemical formula] [wherein, R 1 is H or phenyl, R 2 is H, OH, gallate, or phenyl, and the phenyl is optionally substituted with one or more (for example, 2 to 3) hydroxyls, R 3 is H, OH, or =O (oxo), or R 1 and R 2 together form a closed-loop ring structure, or R 2 and R 3 together form a closed-loop ring structure] and has.

[0020] The 2, 3, 4, 5, 6, 7, or 8 position of Formula I can be bonded to a group containing hydrocarbon, halogen, oxygen, nitrogen, sulfur, phosphorus, boron, or metal.

[0021] Examples of flavonoids of formula I include the following: [Chemical formula]

[0022] Preferred flavonoid compounds of formula I include EGCG (CAS number 989-51-5), EC (CAS number 490-46-0), EGC (CAS number 970-74-1), or ECG (CAS number 1257-08-5). [Chemical formula]

[0023] Polymer-flavonoid conjugate As used throughout this specification, the polymer-flavonoid conjugate refers to a conjugate of a hydrophilic polymer and a flavonoid compound of formula I.

[0024] A hydrophilic polymer refers to a polymer that can dissolve in a polar solvent and form hydrogen bonds. Hydrophilic polymers suitable for the polymer-flavonoid conjugate of the present invention include poly(ethylene glycol) (PEG), aldehyde-derivatized hyaluronic acid, hyaluronic acid, dextran, diethyl acetal conjugate (e.g., diethyl acetal PEG), D-alpha-tocopheryl polyethylene glycol succinate, aldehyde-derivatized hyaluronic acid-tyramine, hyaluronic acid-aminoacetyl aldehyde diethyl acetal conjugate-tyramine, cyclotriphosphazene core phenoxymethyl(methylhydrazono) dendrimer or thiophosphoryl core phenoxymethyl(methylhydrazono) dendrimer, acrylamide, oxazoline, imine, acrylic acid, methacrylate, diol, oxirane, alcohol, amine, anhydride, ester, lactone, terephthalate, amide and ether, polyacrylamide, poloxamer, poly(N-isopropylacrylamide), poly(oxazoline), polyethyleneimine, poly(acrylic acid), polymethacrylate, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinyl pyrrolidone), polyether, poly(allylamine), polyanhydride, poly(β-amino ester), poly(butylene succinate), polycaprolactone, polycarbonate, polydioxanone, poly(glycerol), polyglycolic acid, poly(3-hydroxypropionic acid), poly(2-hydroxyethyl methacrylate), poly(N-(2-hydroxypropyl) methacrylamide), polylactic acid, poly(lactic acid-co-glycolic acid), poly(orthoester), poly(2-oxazoline), poly(sebacic acid), poly(terephthalate-co-phosphate), povidone, and copolymers, but are not limited thereto.

[0025] Preferred hydrophilic polymers include poly(ethylene glycol), hyaluronic acid, dextran, polyethyleneimine, poloxamer, povidone, D-alpha-tocopheryl, and polyethylene glycol succinate. The molecular weight of the hydrophilic polymer in the polymer-flavonoid conjugate is generally from 1K to 100K, preferably from 2K to 40K, 2K to 50K, 2K to 80K, 3K to 80K, or 5K to 40K daltons.

[0026] In one embodiment, the polymer contains an aldehyde group which is conjugated to the 5, 6, 7, or 8 position (preferably the 6 or 8 position) of the A ring of the flavonoid compound. In another embodiment, the polymer contains a thiol group which is conjugated to R 1 or R 2 of the B ring of the flavonoid (where R 1 or R 2 is -OH).

[0027] In one embodiment, the polymer-flavonoid conjugate is PEG-EGCG, which is PEG conjugated to one or two molecules of epigallocatechin gallate (EGCG). PEG-EGCG can be prepared, for example, by conjugating PEG by reacting a free aldehyde group with the 5, 6, 7, or 8 position (preferably the 6 or 8 position) of Formula I to attach the aldehyde-terminated PEG to EGCG. See WO2006 / 124000 and WO2009 / 054813. PEG-EGCG can also be prepared by conjugating PEG by reacting a free thio group with R 1 or R 2 (where R 1 or R 2 is a phenyl group) of Formula I to attach the thio-terminated PEG to EGCG. See WO2015 / 171079.

[0028] Flavonoid oligomer A flavonoid oligomer is a conjugate of one flavonoid and one or more flavonoids. The flavonoid oligomer can contain the same flavonoid (homo-oligomer) or different flavonoids (hetero-oligomer). The flavonoid oligomers useful in the present invention generally have 2 to 50 or 2 to 20, preferably 4 to 12, of one or mixed species of flavonoids.

[0029] In some embodiments, the flavonoid oligomer is oligomerized EGCG (OEGCG), oligomerized EC (OEC), oligomerized EGC (OEGC), or oligomerized ECG (OECG). OEGCG refers to a compound in which 3 to 20 EGCG monomers are covalently bonded. For example, OEGCG can be synthesized at the 5, 6, 7, or 8 positions (preferably the 6 or 8 position) of the A ring according to WO2006 / 124000.

[0030] Since the A ring is present in all flavonoids according to Formula I, other oligomeric flavonoids can be similarly produced according to WO2006 / 124000. For example, OEC, OEGC, and OECG can also be produced according to WO2006 / 124000.

[0031] MINC drug MINC (multi-pathway immunomodulatory nanocomplex combination therapy) is a platform technology that utilizes the biological activity of polymer-flavonoid conjugates or flavonoid oligomers that form micelles in solution. The MINC platform can encapsulate additional agents such as drugs to form a nanoparticle composition for combination therapy.

[0032] The MINC drug is a micelle having a shell formed by one or more polymer-flavonoid conjugates or one or more flavonoid oligomers or a combination thereof, and having a drug encapsulated therein. As used herein, the agent refers to a molecule having therapeutic activity for treating infectious diseases caused by bacteria or viruses, including but not limited to anti-inflammatory agents, nucleotide / nucleoside analogs, and agents that enhance the host's immune defense response. Host immune defense agents are mainly anti-inflammatory cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, IFN-α, IFN-β, IFN-γ, TNF-α, G-CSF, GM-CSF, or M-CSF.

[0033] In one embodiment, the MINC drug is a micelle that includes a polymer-flavonoid conjugate, such as a PEG-EGCG conjugate, in the shell and has an encapsulated agent (see Figure 1).

[0034] In another embodiment, the MINC drug is a micelle that includes a polymer-flavonoid conjugate, such as a PEG-EGCG conjugate, in the outer core, includes a flavonoid oligomer, such as oligomeric EGCG (OEGCG), in the inner core, and has an encapsulated agent (see Figure 2).

[0035] "Polymer-flavonoid conjugate" or "flavonoid oligomer" can be used to treat infectious diseases including viral or bacterial infections by mechanisms including but not limited to suppressing viral or bacterial replication, killing viruses or bacteria, preventing viruses or bacteria from invading / infecting target cells / tissues / organs, maintaining the function / activity of infected cells / tissues / organs, and modulating host immunity to kill infectious microorganisms.

[0036] The MINC pharmaceutical composition contains two or more components with therapeutic activity, whose functions are complemented by a backbone component (polymer-flavonoid conjugate or flavonoid oligomer) and an encapsulated drug (agent) to form a multiple-target combination therapy. The MINC drug is stable in a hydrophilic environment such as blood circulation.

[0037] In one embodiment, the agent is a cytokine including, but not limited to, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, IFN-α, IFN-β, IFN-γ, TNF-α, G-CSF, GM-CSF, or M-CSF. These cytokines are for the treatment of cross-disease-types, and the purpose is to induce a host immune response to fight infectious microorganisms, which is not limited to a specific type of infectious disease. These cytokines are suitable for the treatment of viral infections including adenovirus, coxsackievirus, cytomegalovirus, enterovirus, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, HIV, human coronavirus 229E (HCoV-229E), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), human coronavirus OC43 (HCoV-OC43), human herpesvirus, human papillomavirus, influenza virus, measles virus, Middle East respiratory syndrome-related coronavirus (MERS-CoV), mumps virus, parainfluenza virus, poliovirus, rabies virus, respiratory syncytial virus, rubella virus, rotavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or varicella-zoster virus. The cytokines are suitable for the treatment of bacterial infections including, but not limited to, Mycobacterium tuberculosis, Clostridium tetani, Salmonella Typhi, Corynebacterium diphtheria, Treponema pallidum, Mycobacterium lepromatosis, or methicillin-resistant Staphylococcus aureus.

[0038] In one embodiment, the agent is an antiviral antibody for treating SARS-CoV-2 infection that causes COVID-19, including but not limited to anti-SARS-CoV-2-RBD, anti-SARS-CoV-2-SP, anti-SARS-CoV-2-SD1 / SD2, anti-SARS-COV-2-S2, Bamlanivimab, Etesevimab, Casirivimab, Imdevimab, Sillagivimab, Tixagevimab, Sotrovimab, or Regdanvimab.

[0039] In one embodiment, the agent is an antiviral antibody for treating HIV (human immunodeficiency virus) infection that causes AIDS, including but not limited to anti-HIV-gp120, VRC01, 10-1074, anti-HIV-Env, 3BNC117, anti-HIV-gp41, 4E10, 2F5, 2G12, anti-CCR5, PRO 140, anti-CD4, Ibalizumab, or Leronlimab.

[0040] In one embodiment, the agent is an antiviral antibody for treating HPV (human papillomavirus) infection that causes cervical cancer, including but not limited to anti-HPV-E6 or anti-HPV-E7.

[0041] In one embodiment, the agent is an antiviral antibody for treating CMV (cytomegalovirus) infection, including but not limited to anti-CMV-gB, CSJ148, TCN-202, anti-CMV-gH, LPJ539, anti-CMV-gH / gH, MCMV5322A, Sevirumab, or MCMV3068A.

[0042] In one embodiment, the agent is an antiviral antibody for treating influenza virus infection, including but not limited to anti-influenza A hemagglutinin, MHAA4549A, VIS410, CR6261, CR8020, or TCN-032.

[0043] In one embodiment, the agent is an antiviral antibody for treating RSV (respiratory syncytial virus) infection, including but not limited to anti-RSV glycoprotein F, palivizumab, REGN2222, motavizumab, MEDI8897, ALX-0171, or nirsevimab.

[0044] In one embodiment, the agent is an antiviral antibody for treating Ebola virus, including but not limited to ZMapp, atoltivimab, mavivimab, or odesivimab.

[0045] In one embodiment, the agent is an antiviral antibody for treating rabies virus infection, including but not limited to CR57, CR4098, CL184, or RAB-1.

[0046] In one embodiment, the agent is an antiviral nucleoside analog for treating SARS-CoV-2 infection, including but not limited to ribavirin, favipiravir, lopinavir, ritonavir, or nafamostat.

[0047] In one embodiment, the agent is an antibacterial antibody for treating Staphylococcus aureus infection, including but not limited to AR301, MEDI4893, 514G3, or ARN-100.

[0048] In one embodiment, the agent is an antibacterial antibody for treating Pseudomonas aeruginosa infection, including but not limited to MEDI3902 or AR101.

[0049] In one embodiment, the agent is an antibacterial antibody for treating Clostridium difficile infection, including but not limited to polyCAb or Cd-ISTAb.

[0050] In one embodiment, the agent is an antibacterial antibody including, but not limited to, AR401-mAb or VXD-003 for treating Acinetobacter baumannii infections.

[0051] In one embodiment, the agent is an antibacterial antibody including, but not limited to, ASN-4 for treating Escherichia coli (ST131) infections.

[0052] In one embodiment, the agent is an antibacterial antibody including, but not limited to, ASN-5 for treating Klebsiella pneumoniae infections.

[0053] In one embodiment, the agent is an antiviral nucleotide analog including, but not limited to, remdesivir for treating SARS-CoV-2 infections.

[0054] In one embodiment, the agent is an antiviral nucleoside analog including, but not limited to, abacavir, didanosine, emtricitabine, stavudine, or zidovudine for treating HIV (human immunodeficiency virus) infections.

[0055] In one embodiment, the agent is an antiviral nucleotide analog including, but not limited to, tenofovir, tenofovir diphosphate, d4TMP, d4TTP, AzTMP, or AzTTP for treating HIV (human immunodeficiency virus) infections.

[0056] In one embodiment, the agent is an antiviral nucleoside analog such as acyclovir, famciclovir, or valacyclovir for treating HSV (herpes simplex virus) infections.

[0057] In one embodiment, the drug is an antiviral nucleoside analog such as adefovir, emtricitabine, entecavir, lamivudine, telbivudine, tenofovir, or ribavirin for treating HBV (hepatitis B virus) infection.

[0058] In one embodiment, the drug is an antiviral nucleotide analog such as 3TCMP, 3TCTP, acyclovir monophosphate, acyclovir triphosphate, telbivudine monophosphate, or telbivudine triphosphate for treating HBV (hepatitis B virus) infection.

[0059] In one embodiment, the drug is an antiviral nucleoside analog such as sofosbuvir or ribavirin for treating HCV (hepatitis C virus) infection.

[0060] In one embodiment, the drug is an antiviral nucleotide analog such as ribavirin monophosphate or ribavirin triphosphate for treating HCV (hepatitis C virus) infection.

[0061] In one embodiment, the drug is an antiviral nucleoside analog such as cidofovir, ganciclovir, or valganciclovir for treating CMV (cytomegalovirus) infection.

[0062] In one embodiment, the drug is an antiviral nucleoside analog such as famciclovir or valacyclovir for treating VZV (varicella-zoster virus) infection.

[0063] In one embodiment, the drug is an antiviral nucleotide analog such as acyclovir monophosphate or acyclovir triphosphate for treating VZV (varicella-zoster virus) infection.

[0064] In one embodiment, the drug is an antiviral nucleoside analog such as ribavirin, 5-azacitidine, 5-fluorouracil, zanamivir, oseltamivir, peramivir, or baloxavir for treating influenza virus infection.

[0065] In one embodiment, the agent is an antiviral nucleotide analogue such as ribavirin monophosphate or ribavirin triphosphate for treating influenza virus infection.

[0066] In one embodiment, the agent is IFN-α for treating viral or bacterial infections. For example, the MINC agent is IFN-α encapsulated in micelles formed by the polymer-flavonoid conjugate PEG-EGCG and the flavonoid oligomer OEGCG. For the structure and the formulation method, refer to WO2009 / 054813.

[0067] In one embodiment, the agent is not an antibiotic.

[0068] Pharmaceutical composition The present invention uses a pharmaceutical composition comprising a polymer-flavonoid conjugate, a flavonoid oligomer, or a MINC pharmaceutical composition described in the present application, and optionally one or more pharmaceutically acceptable carriers. The nanoparticle composition in the pharmaceutical composition is generally about 1 to 90%, preferably 20 to 90%, or 30 to 80% in the case of tablets, powders, or parenteral preparations. The polymer-flavonoid conjugate, flavonoid oligomer, or MINC pharmaceutical composition in the pharmaceutical composition is generally 1 to 100%, preferably 20 to 100%, 50 to 100%, or 70 to 100% in the case of capsule preparations. The nanoparticle composition in the pharmaceutical composition is generally 1 to 50%, 5 to 50%, or 10 to 40% in the case of suspension preparations.

[0069] In one embodiment, the pharmaceutical composition may be in a dosage form such as tablets, capsules, granules, fine granules, powders, suspensions, patches, parenteral preparations, injections, etc. The above pharmaceutical composition can be prepared by conventional methods.

[0070] Pharmaceutically acceptable carriers, which are inert ingredients, can be selected by those skilled in the art using conventional criteria. Pharmaceutically acceptable carriers include physiological saline and aqueous electrolyte solutions; ionic and non-ionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and dextrose; pH adjusters and buffers such as salts of hydroxides, phosphoric acid, citric acid, acetic acid, boric acid, and trolamine; antioxidants such as salts, acids, and / or bases of bisulfite, sulfurous acid, metabisulfite, thiosulfurous acid, ascorbic acid, acetylcysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, and ascorbyl palmitate; surfactants such as lecithin and phospholipids including phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol, but not limited thereto; poloxamers and poloxamines; polysorbates such as polysorbate 80, polysorbate 60, and polysorbate 20; polyethers such as polyethylene glycol and polypropylene glycol; polyvinyls such as polyvinyl alcohol and polyvinylpyrrolidone (PVP, povidone); cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose and their salts; petroleum derivatives such as mineral oil and white petrolatum; fats such as lanolin, peanut oil, palm oil, and soybean oil; monoglycerides, diglycerides, and triglycerides; polysaccharides such as dextran; and components including but not limited to glycosaminoglycans such as sodium hyaluronate. Such pharmaceutically acceptable carriers may be protected from bacterial contamination using well-known preservatives including but not limited to benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenylethyl alcohol, or may be formulated as a preservative-free formulation for single or multiple uses.

[0071] For example, tablets, capsules, or parenteral formulations of the active compound may contain other excipients that have no biological activity and do not react with the active compound. Excipients for tablets or capsules may include fillers, binders, lubricants and glidants, disintegrants, wetting agents, and release rate modifiers. Examples of excipients for tablets or capsules include, but are not limited to, carboxymethyl cellulose, cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, karaya gum, starch, tragacanth gum, gelatin, magnesium stearate, titanium dioxide, poly(acrylic acid), and polyvinyl pyrrolidone. For example, tablet formulations may contain inactive ingredients such as colloidal silicon dioxide, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and titanium dioxide. Capsule formulations may contain inactive ingredients such as gelatin, magnesium stearate, and titanium dioxide. Powder oral formulations may contain inactive ingredients such as silica gel, sodium benzoate, sodium citrate, sucrose, and xanthan gum.

[0072] The pharmaceutical composition can be applied by local administration and systemic administration. Local administration includes topical administration. Systemic administration includes oral, parenteral (intravenous, intramuscular, subcutaneous, or rectal, etc.), and other systemic administration routes. In systemic administration, the active compound first reaches the plasma and then distributes to the target tissue. Parenteral administration and oral administration such as intravenous bolus injection or intravenous infusion are preferred administration routes.

[0073] Method of treatment The present invention relates to a method for treating infectious diseases including viral infections and bacterial infections. The infectious diseases are caused by DNA viruses, RNA viruses, Gram-positive bacteria, or Gram-negative bacteria.

[0074] Suitable viral infections treated by the present invention include, but are not limited to, adenovirus, coxsackievirus, cytomegalovirus, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, HIV, human coronavirus 229E (HCoV-229E), human coronavirus HKU1 (HCoV-HKU1), human coronavirus NL63 (HCoV-NL63), human coronavirus OC43 (HCoV-OC43), human herpesvirus, human papillomavirus, influenza virus, measles virus, Middle East respiratory syndrome-related coronavirus (MERS-CoV), mumps virus, parainfluenza virus, poliovirus, rabies virus, respiratory syncytial virus, rubella virus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or viral infections caused by varicella-zoster virus.

[0075] Suitable bacterial infections treated by the present invention include, but are not limited to, tuberculosis, anthrax, tetanus, leptospirosis, pneumonia, cholera, botulinum poisoning, Pseudomonas infections, MRSA infections, E. coli infections, meningitis, gonorrhea, bubonic plague, or bacterial infections caused by bacilli, cocci, or spirilla that cause syphilis.

[0076] Polymer-flavonoid In a first aspect of the present invention, the method comprises administering to a subject in need thereof an effective amount of a polymer-flavonoid conjugate. As used in this application, "effective amount" means an amount effective to treat a disease by improving the condition or reducing the symptoms of the disease.

[0077] The polymer-flavonoid conjugate of the present invention has immunomodulatory activity, antiviral activity, and antibacterial activity against infections.

[0078] In one embodiment, the flavonoid is EGCG, EC, EGC, or ECG.

[0079] In one embodiment, the polymer is a hydrophilic polymer having a molecular weight of 1,000 to 100,000 daltons and is selected from the group consisting of PEG, hyaluronic acid, dextran, polyethyleneimine, poloxamer, povidone, D-alpha-tocopheryl, and polyethylene glycol succinate.

[0080] A preferred polymer-flavonoid conjugate is PEG-EGCG.

[0081] In one embodiment, the infectious disease is caused by a DNA virus selected from the group consisting of hepatitis B virus, human herpes virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, monkeypox virus, and varicella-zoster virus.

[0082] In one embodiment, the infectious disease is caused by an RNA virus selected from the group consisting of SARS-CoV-2, enterovirus, HIV, MERS-CoV, hepatitis C virus, hepatitis A virus, rotavirus, norovirus, influenza virus, parainfluenza virus, dengue virus, respiratory syncytial virus, and SARS-CoV.

[0083] In one embodiment, the infectious disease is caused by a Gram-positive bacterium selected from the group consisting of methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis, Bacillus anthracis, Clostridium tetani, Streptococcus pneumoniae, Clostridium botulinum, Clostridia, Mycobacterium tuberculosis, Clostridium tetani, Corynebacterium diphtheriae, and Mycobacterium leprae.

[0084] In one embodiment, the infectious disease is caused by a Gram-negative bacterium selected from the group consisting of Pseudomonas, Meningococcus, Leptospira, Neisseria gonorrhoeae, Neisseria meningitidis, Yersinia pestis, Treponema pallidum, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Mycobacterium tuberculosis, Legionella, and Salmonella.

[0085] The dosage of the injectable polymeric flavonoid, such as PEG-EGGC, is generally 0.1 - 10000 mg / kg, 0.6 - 1200 mg / kg (total weight of polymeric flavonoid / body weight of the subject), or 1 - 1000 mg / kg.

[0086] Flavonoid oligomer In a second aspect of the present invention, the method comprises administering an effective amount of a flavonoid oligomer to a subject in need thereof. The flavonoid oligomer of the present invention has immunomodulatory activity, antiviral activity, and antibacterial activity against infectious diseases.

[0087] In one embodiment, the flavonoid is EGCG, EC, EGC, or ECG.

[0088] In one embodiment, the flavonoid oligomer contains 4 - 12 flavonoids of EGCG, EC, EGC, or ECG.

[0089] A preferred flavonoid oligomer is an EGCG oligomer.

[0090] In one embodiment, the infectious disease is caused by a DNA virus selected from the group consisting of hepatitis B virus, human herpes virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, monkeypox virus, and varicella-zoster virus.

[0091] In one embodiment, the infectious disease is caused by an RNA virus selected from the group consisting of SARS-CoV-2, enterovirus, HIV, MERS-CoV, hepatitis C virus, hepatitis A virus, rotavirus, norovirus, influenza virus, parainfluenza virus, dengue virus, respiratory syncytial virus, and SARS-CoV.

[0092] In one embodiment, the infectious disease is caused by a Gram-positive bacterium selected from the group consisting of methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis, Bacillus anthracis, Clostridium tetani, Streptococcus pneumoniae, Clostridium botulinum, Clostridium spp., Mycobacterium tuberculosis, Clostridium tetani, Corynebacterium diphtheriae, and Actinomyces spp.

[0093] In one embodiment, the infectious disease is caused by a Gram-negative bacterium selected from the group consisting of Pseudomonas spp., Neisseria meningitidis, Leptospira, Neisseria gonorrhoeae, Neisseria meningitidis, Yersinia pestis, Treponema pallidum, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Mycobacterium tuberculosis, Legionella spp., and Salmonella spp.

[0094] The dosage of the injectable flavonoid oligomer (e.g., OEGCG) is generally 0.1 - 1000 mg / kg, 0.1 - 100 mg / kg (total weight of flavonoid oligomer / body weight of the subject), or 1 - 100 mg / kg.

[0095] MINC drug In a third aspect of the present invention, the method comprises administering to a subject in need thereof, an effective amount of micelles having an outer shell comprising one or more polymer-flavonoid conjugates, and optionally an inner shell comprising one or more flavonoid oligomers, and a drug encapsulated within the shell, for treating a bacterial or viral infection. In one embodiment, the shell is formed by one or more polymer-flavonoid conjugates. In one embodiment, the outer shell is formed by one or more polymer-flavonoid conjugates and the inner shell is formed by one or more flavonoid oligomers. The polymer-flavonoid conjugate or flavonoid oligomer provides its own therapeutic effect and further delivers the above-mentioned agent for treating the infection.

[0096] In one embodiment, the polymer is a hydrophilic polymer having a molecular weight of 1,000 to 100,000 daltons and is selected from the group consisting of poly(ethylene glycol) (PEG), hyaluronic acid, dextran, polyethyleneimine, poloxamer, povidone, D-alpha-tocopheryl, and polyethylene glycol succinate.

[0097] In one embodiment, the flavonoid oligomer comprises 2 to 20 flavonoids of EGCG, EC, EGC, or ECG.

[0098] In one embodiment, the shell is formed by PEG-EGCG.

[0099] In one embodiment, the shell is formed by PEG-EGCG and OEGCG.

[0100] In one embodiment, the drug in the MINC agent is not an antibiotic.

[0101] In one embodiment, the infectious disease is caused by methicillin-resistant Staphylococcus aureus, and the drug is IFN-α, IFN-γ, IFN-β, an IL-13 topoisomerase inhibitor, an FtsZ inhibitor, a beta-lactamase inhibitor, a ribosome inhibitor, a dihydropteroate synthase inhibitor, a dihydropteroate synthase inhibitor, anti-AR301, anti-MEDI4893, anti-514G3, or anti-ARN-100.

[0102] In one embodiment, the infectious disease is caused by Pseudomonas, and the drug is IFN-α, an OprF vaccine, anti-LPS, anti-alginate, anti-PcrV, anti-OPK, anti-DNABII, a beta-lactamase inhibitor, LptD, LpxD, a bacteriolytic agent, an iron mimetic, a biofilm matrix disruptor, a T3SS inhibitor, anti-MEDI3902, or anti-AR101.

[0103] In one embodiment, the infectious disease is caused by Mycobacterium tuberculosis, and the drug is IFN-α, anti-TNF-α, IFN-γ, GM-CSF, TGF-β, anti-VEGF, IL-2, IL-4, IL-7, IL-10, IL-12, IL-15, IL-23, IL-24, IL-37, anti-IL4 prostaglandin E, a phosphodiesterase inhibitor, an ATP synthase inhibitor, a ribosome inhibitor, a DprE1 inhibitor, a gyrase inhibitor, an MmpL3 inhibitor, a LeuT RNA synthase inhibitor, a MurL inhibitor, an InhA inhibitor, an NDH-2 inhibitor, a QcrB inhibitor, a MenG inhibitor, an FtsZ inhibitor, an EthR inhibitor, or a LepB inhibitor.

[0104] In one embodiment, the infectious disease is caused by Bacillus anthracis, and the drug is IFN-α, anti-PA63, enoyl-ACP reductase, ribonucleotide reductase, nucleoside hydrolase, replicative DNA helicase, acetohydroxy acid synthase, NAD synthase, nicotinate mononucleotide adenylyltransferase, lumazine synthase, the cytoskeletal protein FtsZ, dihydropteroate synthase, or dihydrofolate reductase.

[0105] In one embodiment, the infectious disease is caused by Clostridium tetani, and the drugs are IFN-α, anti-tetanus immunoglobulin, tetanus toxoid, benzodiazepine, magnesium sulfate, intrathecal baclofen, dantrolene, ketamine, propofol, botulinum toxin, human anti-tetanus immunoglobulin, or tetanus toxoid vaccine.

[0106] In one embodiment, the infectious disease is caused by Streptococcus pneumoniae, and the drugs are IFN-α, IL-26, HMGB1, anti-IL-6, anti-TNFα, anti-IL-1β, anti-CXCL8, CD4, IL-4, CD8A, IL-10, anti-PTPRC, JAK inhibitor, anti-manL, anti-cps4L, anti-recU, anti-SP_0645, anti-ezrA, anti-prsA, anti-tarJ, anti-SP_1280, anti-SP_1617, anti-ptsG, anti-DltD, anti-hprK, anti-pepF, anti-coiA, anti-fib, anti-acpS, anti-manA, anti-mvaK2, anti-mtlD, anti-mtlF, or TPCA-1.

[0107] In one embodiment, the infectious disease is caused by Neisseria meningitidis, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, CGRP, anti-PARP, TACE, EGFR, EGF, anti-ATM, ESR-1, anti-CASP8, NGF, anti-sdhA, anti-ribH, anti-ruvA, anti-ruvX, anti-ponA, anti-rr03, anti-fabH, anti-fabZ, anti-metE, anti-recJ, anti-rpsP, anti-plsY, anti-ftsK, anti-dnaE, anti-holB, anti-rsmI, anti-mtf, anti-dnaG, anti-rpoD, anti-pta, anti-rplU, anti-hup, anti-ptsI, anti-rsmG, anti-lgt, anti-greA, anti-secA1, anti-queF, anti-nusG, anti-ackA, anti-dapH, anti-ilvD, or anti-dnaC.

[0108] In one embodiment, the infectious disease is caused by severe acute respiratory syndrome coronavirus 2, and the drugs are IFN-α, IFN-β, IL-6, IL-12, IL-21, anti-IL-6, anti-IL-6R, spike vaccine, RBD vaccine, ACE2 antagonist, anti-TMPRSS2, anti-CD147, anti-VEGFA, anti-GM-CSF, dexamethasone, chloroquine, Nsp12-RdRp inhibitor, hydroxychloroquine, anti-3CLpro, interferon-α, AAK-1 inhibitor, or JAK inhibitor.

[0109] In one embodiment, the infectious disease is caused by enterovirus, and the drugs are IFN-α, IFN-β, capsid binder, 3Cpro inhibitor, 3Dpol inhibitor, 2CATPase inhibitor, 2APro inhibitor, anti-HSP90, anti-PI4KB, anti-OSBP, anti-RdRP, SP40, SP45, SP55, SP81, LVLQTM, VAD, or AAPV.

[0110] In one embodiment, the infectious disease is caused by HIV, and the drugs are IFN-α, anti-tetanus immunoglobulin, tetanus toxoid, benzodiazepine, magnesium sulfate, intrathecal baclofen, dantrolene, ketamine, propofol, botulinum toxin, human anti-tetanus immunoglobulin, or tetanus toxoid vaccine.

[0111] In one embodiment, the infectious disease is caused by hepatitis B virus, and the drugs are IFN-α, IFN-γ, IL-12, IL-6, IL-21, DNA polymerase reverse transcriptase activity inhibitor, preS1 peptide, CRISPR / Cas9, ZFN, capsid assembly modulator, E-neg and E-pos RNAi, lamivudine, adefovir, entecavir, tenofovir, TLR agonist, STING agonist, or cyclophilin inhibitor.

[0112] In one embodiment, the infectious disease is caused by MERS-CoV, and the drug is IFN-α, IFN-β, IFN-γ, anti-DPP4, poly IC, anti-ACE2 antagonist, RdRp inhibitor, chlorpromazine hydrochloride, chloroquine, peptide, endosomal protease inhibitor, TMPRSS2 inhibitor, furin protease inhibitor, anti-clathrin endocytosis, MERS-CoV S DNA, or RBD subunit vaccine.

[0113] In one embodiment, the infectious disease is caused by influenza virus, and the drug is IFN-α, IFN-β, IFN-γ, IL-12, IL-6, IL-15, IL-21, neuraminidase inhibitor, cap-dependent endonuclease inhibitor, M2 ion channel blocker, nucleoprotein inhibitor, anti-NS1-1, anti-CPSF30, anti-PABII, anti-eIF4G1, anti-PABP1, anti-p85, anti-PKR, anti-PACT, anti-NXF1, anti-p15, anti-importin, anti-crk, anti-crkL, anti-RIG-1, anti-nucleolin, anti-TRIM25, anti-Gas8, anti-Akt, anti-p53, anti-PARP10, anti-RIL, anti-Hsp90, anti-PDZ, anti-NOLC1, anti-RAP55, anti-IKK, anti-hPAF1C, or anti-hGBP1.

[0114] In one embodiment, the infectious disease is caused by dengue virus, and the drug is anti-TNF-α, anti-IL-6, anti-RANTES, chloroquine, prednisolone, NS5 nucleoside inhibitor, ER-related α, glucosidase inhibitor, lovastatin, capsid inhibitor, envelope inhibitor, anti-NS4B, anti-NS2B / 3, anti-NS1, or NS1 vaccine.

[0115] In one embodiment, the infectious disease is caused by respiratory syncytial virus, and the drug is IL-15, anti-TNF-α, benzimidazole derivative, disulfonated stilbene, imidazoisoindolone derivative, triphenol compound, anti-envelope glycoprotein, sulfated sialyl lipid, anti-NS1, anti-F glycoprotein, P protein, NS1 protein, or siRNA that inhibits the N protein gene.

[0116] In one embodiment, the infectious disease is caused by SARS-CoV, and the drugs are IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-VEGFA, anti-GM-CSF, spike vaccine, RBD vaccine, ACE2 antagonist, anti-TMPRSS2, anti-CD147, dexamethasone, chloroquine, Nsp12-RdRp inhibitor, hydroxychloroquine, anti-3CLpro, interferon-α, AAK-1 inhibitor, JAK inhibitor, anti-ATM, anti-SIRT1, anti-GSK3B, or anti-TriN-2.

[0117] In one embodiment, the infectious disease is caused by Escherichia coli, and the drugs are IFN-α, IFN-β, anti-IL-1β, anti-TNFα, anti-IL-6, anti-bamD, anti-cydX, anti-dnaT, anti-fabA, anti-ftsB, anti-ftsL, anti-ftsQ, anti-hemD, anti-higA, anti-hipB, anti-holD, anti-iraM, anti-lolA, anti-lolB, anti-lptA, anti-lptD, anti-lptE, anti-mreD, anti-mukB, anti-mukE, anti-mukF, anti-pheM, anti-priB, anti-safA, anti-secE, anti-trpL, anti-tusE, anti-wzyE, anti-ycaR, anti-yciS, anti-ydfO, anti-ydhL, anti-ygfZ, anti-yqeL, anti-yrfF, or anti-zipA.

[0118] In one embodiment, the infectious disease is caused by Legionella bacteria, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, anti-Hsp60, anti-MOMP, anti-Mip, anti-Les, anti-Lsp, anti-CpxTRA, anti-PilEL, anti-Lvh, anti-IcM, anti-UDP, anti-FtsL, anti-MrdA, anti-RpoH, anti-multidrug resistance protein, anti-amino acid permease, anti-TolB, anti-Kup1, anti-MviN, anti-Tig, anti-MurE, anti-SCD, anti-TTF, anti-UMF1, anti-HMP, anti-HslU, anti-htrB, anti-Kdo, anti-OGT, or anti-RpoH.

[0119] In one embodiment, the infectious disease is caused by Neisseria gonorrhoeae, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, CDP-4-dehydro-6-deoxyglucose reductase, anti-LpxC, anti-SSADH, anti-RNR, anti-DacC, anti-PBP, anti-PIB, anti-dsbA, anti-NarX, anti-Zur, anti-PTS, anti-Hpr, anti-PPP, anti-YgfZ, anti-HP, anti-RimM, anti-BspRI, anti-rluF, anti-FAD, anti-EF-P, anti-dnaN, anti-tilS, or anti-RluD.

[0120] In one embodiment, the infectious disease is caused by Neisseria meningitidis, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, anti-TerC, anti-MscS, anti-OPT, anti-MFS, anti-MscS, anti-NaCT, anti-ABC, anti-TauE / SafE, anti-CBS, anti-NRAMP, anti-OATP, anti-YggX, anti-SstT, anti-PMT, anti-YjgP, anti-yhhQ, anti-TerC, anti-MAPEG, anti-MSG, anti-PilW, anti-PilX, anti-RlpA, anti-Rrf2, anti-IclR, or anti-Rim.

[0121] In one embodiment, the infectious disease is caused by Salmonella, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-6, anti-bamD, anti-cydX, anti-dnaT, anti-fabA, anti-ftsB, anti-ftsL, anti-ftsQ, anti-hemD, anti-higA, anti-hipB, anti-holD, anti-iraM, anti-lolA, anti-lolB, anti-lptA, anti-lptD, anti-lptE, anti-mreD, anti-mukB, anti-mukE, anti-mukF, anti-pheM, anti-priB, anti-safA, anti-secE, anti-trpL, anti-tusE, anti-wzyE, anti-ycaR, anti-yciS, anti-ydfO, anti-ydhL, anti-ygfZ, anti-yqeL, anti-yrfF, or anti-zipA.

[0122] In one embodiment, the infectious disease is caused by hepatitis C virus, and the drugs are IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-EGFR, anti-NS2, anti-NS3, anti-NS4A, anti-NS5A, anti-NS5B, anti-helicase, anti-TLR-9, anti-HCV E2, anti-E1, anti-E2, anti-p7, anti-CD81, anti-SRB1, anti-CLDN1, anti-EphA2, anti-TfR1, anti-NPC1L1, cyclosporine A, anti-alpha glucosidase, anti-DGAT-1, anti-VLDL, anti-CD81, anti-CLDN1, or anti-SR-Bl.

[0123] In one embodiment, the infectious disease is caused by monkeypox virus, and the drugs are IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, rosmarinic acid, myricitrin, quercitrin, ofloxacin, anti-VP37, anti-F13L, anti-E9L, anti-A24R, anti-A48R, anti-H5R, anti-B1R, anti-F10L, anti-E8L, anti-A6R, anti-SPGF, anti-B8R, anti-A50R, anti-I7L, anti-D13L, anti-Top1, or anti-TMPK.

[0124] In one embodiment, the infectious disease is caused by human papillomavirus, and the drugs are IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-EGFR, anti-c-Met, anti-IGF-1R, anti-PI3K, anti-Akt, anti-mTOR, anti-Ras, anti-Raf, anti-MAPK, anti-VEGF, anti-VEGFR, anti-HIF-1 alpha, anti-PD-L1, anti-CD38, anti-PD1, anti-RNR, anti-FGFR, anti-PDGFR, anti-Kit, or anti-Ret.

[0125] The dosage of the MINC drug is based on the known dosage of the drug for treating a specific disease and the condition of the subject. The dosage can be the dosage approved by the US Food and Drug Administration (FDA) or the dosage used in clinical trials.

[0126] In the MINC drug, generally, the dosage of PEG-EGCG combined with OEGCG is 10 μg / kg to 100 mg / kg.

[0127] The concentration of the encapsulated drug can be from a minimum of 0.01 μg / kg (for example, cytokine drugs, IFN-α) to a maximum of 500 mg / kg (for example, antibody drugs, atorizumab).

[0128] For example, to treat SARS-CoV-2, HIV, HPV, or other viral infections in human adults, IFN-α is administered IV at 0.01 - 500 μg / kg (or 0.01 - 500 mIU) once to three times a week. The same effective dose of MINC-IFN-α can be used to treat other viral infections.

[0129] For example, to treat Mycobacterium tuberculosis, Clostridium tetani, Salmonella typhi, Corynebacterium diphtheriae, Treponema pallidum, Mycobacterium lepromatosis, methicillin-resistant Staphylococcus aureus or other bacterial infections in human adults, IFN-α is administered IV at 0.01 - 500 μg / kg (or 0.01 - 500 mIU) once to three times a week. The same effective dose of MINC-IFN-α can be used to treat other bacterial infections.

[0130] For example, to treat SARS-CoV-2, HIV, HPV, or other viral infections in human adults, IFN-β is administered IV at 0.01 - 500 μg / kg (or 0.01 - 500 mIU) once to three times a week. The same effective dose of MINC-IFN-β can be used to treat other viral infections.

[0131] For example, to treat Mycobacterium tuberculosis, Clostridium tetani, Salmonella typhi, Corynebacterium diphtheriae, Treponema pallidum, Mycobacterium lepromatosis, methicillin-resistant Staphylococcus aureus or other bacterial infections in human adults, IFN-β is administered IV at 0.01 - 500 μg / kg (or 0.01 - 500 mIU) once to three times a week. The same effective dose of MINC-IFN-β can be used to treat other bacterial infections.

[0132] Generally, when a MINC drug has a drug that is a cytokine such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-18, IFN-α, IFN-β, TNF-α, G-CSF, GM-CSF, or M-CSF for treating viral and bacterial infections, the cytokine can be administered IV once to three times a week in the range of 0.01 to 500 μg / kg (or 0.01 to 500 mIU).

[0133] For example, to treat SARS-CoV-2 in human adults, bamlanivimab is administered IV once at 10 to 2000 mg. An effective dose of MINC-bamlanivimab in the same dose range can be used to treat SARS-CoV-2.

[0134] For example, to treat HIV in human adults, ibalizumab is administered IV every two weeks at 10 to 6000 mg. An effective dose of MINC-ibalizumab in the same dose range can be used to treat HIV.

[0135] For example, when the MINC drug has a drug comprising an antibody including, but not limited to, f-CoV-2-RBD, anti-SARS-CoV-2-SP, anti-SARS-CoV-2-SD1 / SD2, anti-SARS-COV-2-S2, Bamlanivimab, Etesevimab, Casirivimab, Imdevimab, Sillgavimab, Tisagenevimab, Sotrovimab, Regdanvimab, anti-HIV-gpl20, VRC01, 10-1074, anti-HIV-Env, 3BNC117, anti-HIV-gp41, 4E10, 2F5, 2G12, anti-CCR5, PRO140, anti-CD4, Ibalizumab, Leronlimab, anti-HPV-E6, anti-HPV-E7, anti-CMV-gB, CSJ148, TCN-202, anti-CMV-gH, LPJ539, anti-CMV-gH / gH, MCMV5322A, Sevirumab, MCMV3068A, anti-influenza A hemagglutinin, MHAA4549A, VIS410, CR6261, CR8020, TCN-032, anti-RSV-glycoprotein F, Palivizumab, REGN2222, Motavizumab, MEDI8897, ALX-0171, Nirsevimab, ZMapp, Atoltivimab, Mavtivimab, Odesivimab, CR57, CR4098 or CL184, RAB-1, the drug can be administered IV once a day to once every three weeks in the range of 0.1 to 500 mg / kg.

[0136] For example, when the MINC drug has a drug comprising an antibody including, but not limited to, AR301, MEDI4893, 514G3, ARN-100, MEDI3902, AR101, PolyCAb, Cd-ISTAb, AR401-mAb, VXD-003, ASN-4, or ASN-5 for treating bacterial infections, the drug can be administered IV once a day to once every three weeks in the range of 0.1 to 500 mg / kg.

[0137] For example, for treating SARS-CoV-2 in human adults, Remdesivir is administered IV once a day to once every other day at 10 to 1000 mg. An effective dose of MINC-Remdesivir in the same dose range can be used to treat SARS-CoV-2 or other viral infections.

[0138] For example, to treat SARS-CoV-2, HBV, HCV, influenza virus, or other viral infections in human adults, ribavirin is administered IV at 50 - 10000 mg once a day to once every three days. MINC-ribavirin at an effective dose within the same dosage range can be used to treat SARS-CoV-2 or SARS-CoV-2, HBV, HCV, influenza virus, or other viruses.

[0139] For example, if the MINC drug has a drug that is a nucleoside or nucleotide analog including, but not limited to, favipiravir, lopinavir, ritonavir, acyclovir, famciclovir, valacyclovir, abacavir, didanosine, emtricitabine, stavudine, tenofovir, zidovudine, adefovir, emtricitabine, entecavir, lamivudine, telbivudine, cidofovir, ganciclovir, valganciclovir, famciclovir, valacyclovir, 5-azacitidine, 5-fluorouracil, zanamivir, oseltamivir, peramivir, or baloxavir for treating viral infections, the drug can be administered IV in the range of 0.5 - 25000 mg, 1 - 3 times a week.

[0140] The present invention is useful for the treatment of humans and non-human animals. For example, the present invention is useful for the treatment of mammals such as humans, horses, pigs, cats, and dogs.

[0141] The following examples further illustrate the present invention. These examples are intended to merely illustrate the present invention and should not be construed as limiting.

Example

[0142] Active ingredient in all examples

[0143] OEGCG: OEGCG is oligomerized EGCG. OEGCG was prepared according to WO2006 / 124000.

[0144] PEG-EGCG: PEG-EGCG is PEG conjugated with one or two EGCGs. PEG-EGCG was prepared according to WO2006 / 124000, WO2009 / 054813, or WO2015 / 171079.

[0145] MINC drug: The MINC drug was prepared in the same manner as MINC-doxorubicin according to WO2011 / 112156 or WO2015 / 171079. Alternatively, the MINC drug can be prepared by encapsulating the drug in micelles formed by PEG-EGCG and OEGCG according to the methods of WO2006 / 124000 or WO2009 / 054813.

[0146] Example 1: OEGCG has antibacterial activity against MRSA Materials OEGCG is oligomerized EGCG. OEGCG was prepared according to WO2006 / 124000.

[0147] Methods To understand the effectiveness of the MINC platform in antibacterial therapy, OEGCG was used in the treatment of methicillin-resistant Staphylococcus aureus (MRSA). OEGCG was prepared at 100 μg / mL. The concentration of the bacterial suspension was approximately 1.0×10 8 ~1.0×10 9 CFU / mL. After adding 0.1 mL of MRSA to 10 mL of the OEGCG to be tested and control sterile saline, the incubation procedure was carried out according to "ASTM E2315-16, Standard Guide for Assessment of Antimicrobial Activity Using a Time-Kill Procedure". Each group was inoculated into the medium, growth was observed, and the number of colonies was recorded. The reduction rate = 100×(1 - 10 LR )(LR = Log(control) - Log(OEGCG)) is presented as the data.

[0148] Result Figure 3 shows that OEGCG reduces the colony formation of methicillin-resistant Staphylococcus aureus (MRSA), indicating its effect of suppressing the growth of MRSA. Staphylococcus belongs to Gram-positive bacteria, and this result demonstrates its effectiveness in the treatment of this bacterial group.

[0149] Example 2: OEGCG has antibacterial activity against Pseudomonas aeruginosa Method To understand the effectiveness of the MINC platform in antibacterial therapy, OEGCG was used in the treatment of Pseudomonas bacteria. OEGCG was prepared at 100 μg / mL. The concentration of the bacterial suspension was approximately 1.0×10 8 ~1.0×10 9 CFU / mL. After adding 0.1 mL of Pseudomonas aeruginosa to 10 mL of the OEGCG to be tested and the control sterile physiological saline, the incubation procedure was carried out according to the "ASTM E2315-16, Standard Guide for the Evaluation of Antibacterial Activity Using the Time-Kill Procedure". Each group was inoculated into the medium, the growth was observed, and the number of colonies was recorded. The reduction rate = 100×(1 - 10 LR )(LR = Log(control) - Log(OEGCG)) is used to present the data.

[0150] Result Figure 4 shows that OEGCG reduced the colony formation of Pseudomonas aeruginosa, suggesting its effectiveness in suppressing the growth of Pseudomonas aeruginosa. Pseudomonas belongs to Gram-negative bacteria, and the result demonstrates its effectiveness in the treatment of this bacterial group.

[0151] Example 3: OEGCG and PEG-EGCG inhibit SARS-CoV-2 infection Materials As an alternative to SARS-CoV-2, human coronavirus (nCoV-Luc-D614G) was obtained from the Academia Sinica siRNA core.

[0152] HEK293T-hACE2 cells were generated by transducing VSV-G pseudotyped lentivirus with the human ACE2 gene into HEK-293T / 17 (ATCC® CRL-11268TM).

[0153] Method Using a Beckman Biomek i5 liquid handling system, HEK293T-hACE2 cells were seeded at 1×10 4 per well in a 96-well plate. Day 1: Cells were seeded and incubated at 37 °C in a CCh incubator for 16 - 18 hours. The next day, 100 μL of serial diluted OEGCG or PEG-EGCG was added to 4,000 TU of SARS-CoV-2 pseudovirus in 100 μL of medium. Each OEGCG and PEG-EGCG was incubated with the virus at 37 °C for 1 hour. After incubation, 50 μL of the mixture was added to 50 μL of pre-seeded HEK293T-hACE2 cells and incubated at 37 °C for 24 hours. After 24 hours, 80 μL of the medium was removed and 50 μL of culture medium (DMEM containing 10% FBS) was added to the 96-well plate. 72 hours after infection, 50 μL of Bright-Glo-Luciferase reagent was added to each well and mixed uniformly using a Beckman liquid handling system (Beckman program: white plate ace2-Day5-Luciferase-3 or 6plate-deep well-SPL). Relative light units (RLU) were detected using a microplate reader Tecan Infinite F500 (program: Luminescence Nunc White96_100ms).

[0154] Results The anti-SARS-CoV-2 efficacy of OEGCG was shown by ID50 and ID90 values of 13.5 nM and 24.6 nM, respectively (Figure 5A). The anti-SARS-CoV-2 activity of PEG-EGCG was measured at concentrations of 5 μM and 20 μM, showing inhibitions of 18.4% and 28.3%, respectively (Figure 5B). The results indicate that both OEGCG and PEG-EGCG have antiviral activity against SARS-CoV-2. [No, I do not agree with the conclusion]

[0155] Example 4: OEGCG Inhibits Enterovirus Infection Materials Rhabdomyosarcoma (RD) cells were obtained from ATCC CCL-136TM.

[0156] Methods To evaluate the antiviral activity of OEGCG against EV71, RD cells were seeded in 96-well plates at 2×10 4 cells / well and incubated at 37 °C for 16 - 18 hours. For virus infection, different concentrations of OEGCG were co-incubated with EV-D68 virus at a multiplicity of infection (MOI) of 0.1 in 96-well plates containing RD at 33 °C or 37 °C for 1 hour. Forty-eight hours after infection, cell viability was examined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay (Sigma-Aldrich, USA). Absorbance (O.D.) was read at 570 nm using a microplate reader. Antiviral activity (%) was calculated as [(O.D. value of OEGCG-treated sample) - (O.D. value of virus only)] / (O.D. value of virus only) × 100%.

[0157] Results The results indicate that EV D68 infection was inhibited by OEGCG treatment (Figure 6). The antiviral activity of OEGCG showed a dose-dependent increase, with corresponding increases of 8.3%, 29.2%, and 53.1% at 50 μM, 75 μM, and 100 μM, respectively.

[0158] Examples 5 and 6 show MINC drugs formed by different flavonoid oligomers and polymer-flavonoid conjugates.

[0159] Example 5: Method for preparing MINC-anti-HER2 using different flavonoids in flavonoid oligomers and polymer-flavonoid conjugates Materials The anti-HER2 is trastuzumab obtained from Eirgenix.

[0160] Method MINC anti-HER2 nanoparticles were prepared according to WO2009 / 054813. Briefly, the anti-HER2 was incubated in PBS. Subsequently, different flavonoid oligomers containing OEGCG or OECG were added to the anti-HER2, followed by the addition of different polymer-flavonoids containing PEG-EGCG, PEG-ECG, or PEG-EC. After incubating the mixture at room temperature, unreacted oligomeric flavonoids and polymer-flavonoids were removed using a 10K MWCO centrifugal filter. The size of the nanoparticles was measured using DLS (Anton Paar Litesizer 500), and the results are shown in Figure 7.

[0161] Results Figure 7 shows that all different polymer-flavonoid conjugates and different flavonoid oligomers successfully generated MINC-anti-HER2 micelles with a particle size of approximately 100 nm. The results indicate that homogeneous nanoparticles (micelles) were formed with an expected size of approximately 100 nm, different from the unencapsulated anti-HER (approximately 5 - 10 nm).

[0162] In this example, the different flavonoid oligomers used were OEGCG (Figures 7A, 7C, and 7D) and OECG (Figure 7B), and the different polymer flavonoids used were PEG-EGCG (Figures 7A and 7B), PEG-EC (Figure 7C), and PEG-ECG (Figure 7D).

[0163] These data support that MINC nanoparticles can be formed by different flavonoid oligomers and different polymer-flavonoid conjugates.

[0164] Example 6: Method for preparing MINC-BSA using different polymers and different polymer-flavonoid conjugates Materials BSA was purchased from Sigma-Aldrich.

[0165] Method According to WO2009 / 054813, MINC (Multi-target Immune Nanocarrier Combination)-BSA nanoparticles were prepared. Briefly, BSA was incubated in PBS. Then, OEGCG or OEGCG was added to BSA, followed by addition of different polymer flavonoids including PEG-EGCG, HA-EGCG, and dextran-EGCG. After incubating the mixture at room temperature, unreacted OEGCG and polymer flavonoids were removed using a 10K MWCO centrifugal filter. The size of the nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0166] Results Figure 8 shows that MINC-BSA can be successfully generated using different polymers in the polymer-flavonoid conjugate. The results indicate that homogeneous nanoparticles (micelles) were successfully formed and no small peak of unencapsulated BSA (about 5 - 10 nm) was observed. These different polymers were PEG (Figure 8A), HA (Figure 8B), and dextran (Figure 8C). Overall, these data support that MINC nanoparticles can be formed by different polymer-flavonoid conjugates.

[0167] Examples 7 to 13 indicate the successful formation of MINC-IFN-α, MINC-IFN-γ, MINC-IL-12, MINC-IL-2, MINC-IL-6, MINC-IL-15, and MINC-IL-21.

[0168] OEGCG and PEG-EGCG used in Examples 8 to 13 were prepared according to the same protocol as described in Example 7.

[0169] Example 7. MINC-IFNα formulation Materials IFN-α was purchased from Pharma Essentia.

[0170] Methods MINC-IFN-α nanoparticles were prepared according to Example 5. The size of MINC-IFN-α nanoparticles was measured using DLS (Malvern Zetasizer Nano ZS).

[0171] Results Figure 9 shows the success of the formulation of MINC-IFN-α.

[0172] Example 8. MINC-IFN-γ formulation Materials IFN-γ was purchased from Bio Legend.

[0173] Methods MINC-IFN-γ nanoparticles were prepared according to Example 5. The size of MINC anti-IFN-γ nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0174] Results Figure 10 shows the success of the formulation of MINC-IFN-γ.

[0175] Example 9. MINC-IL-12 formulation Materials IL-12 was purchased from Bio Legend.

[0176] Method MINC-IL-12 nanoparticles were prepared according to Example 5. The size of the MINC anti-IL-12 nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0177] Results Figure 11 shows the success of the formulation of MINC-IL-12.

[0178] Example 10. MINC-IL-2 formulation Materials IL-2 was purchased from Bio Legend.

[0179] Method MINC-IL-2 nanoparticles were prepared according to Example 5. The size of the MINC-anti-IL-2 nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0180] Results Figure 12 shows the success of the formulation of MINC-IL-2.

[0181] Example 11. MINC-IL-6 formulation Materials IL-6 was purchased from Bio Legend.

[0182] Method MINC-IL-6 nanoparticles were prepared according to Example 5. The size of the MINC-anti-IL-6 nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0183] Results Figure 13 shows the success of the formulation of MINC-IL-6.

[0184] Example 12. MINC-IL-15 formulation Materials IL-15 was purchased from Bio Legend.

[0185] Method MINC-IL-15 nanoparticles were prepared according to Example 5. The size of the MINC anti-IL-15 nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0186] Results Figure 14 shows the success of the formulation of MTNC-TL-15.

[0187] Example 13. MINC-IL-21 formulation Materials IL-21 was purchased from Bio Legend.

[0188] Methods MINC-IL-21 nanoparticles were prepared according to Example 5. The size of the MINC anti-IL-21 nanoparticles was measured using DLS (Anton Paar Litesizer 500).

[0189] Results Figure 15 shows the success of the formulation of MINC-IL-21.

[0190] Example 14. MINC-IFN-α inhibits the replication of SARS-CoV-2 (prophetic example) Materials Vero E6 cells (American Type Culture Collection, Manassas, VA) are used. SARS-CoV-2 (Wuhan strain or BA.1) is used.

[0191] Methods The antiviral activity of MINC-IFN-α is evaluated using a cytopathic endpoint assay. Briefly, 100 μL of serial 10-fold dilutions of MINC-IFNα or IFNα are incubated with 100 μL of VeroE6 cells so that the final cell number per well in a 96-well plate is 20,000. The cells are incubated in 5% CO 2Incubate overnight at 37°C. On the second day, add 10 μL of virus at a concentration of 10,000 PFU / well to each test well. Incubate the plate in 5% CO 2 Incubate at 37°C for 3 days and observe the cytopathic effect (CPE) daily. The endpoint is the drug dilution that inhibits CPE by 100% in four (quadruplicate) wells.

[0192] Results In this study, MINC-IFN-α inhibits Vero cell death (CPE) caused by SARS-CoV-2 infection. MINC-IFN-α is expected to have a lower IC50 (50% inhibitory concentration) than IFN-α alone at equivalent IFN-α concentrations.

[0193] Example 15: MINC-IFN-α inhibits the growth of MRSA (predictive example) Materials Use Staphylococcus aureus strain LAC (pulsed-field type USA300 strain).

[0194] Methods For the MRSA killing assay, incubate 4×10 5 neutrophils in RPMI medium containing PBS, MINC-IFN-α, or IFN-α (100 ng / ml), followed by the addition of 50 μL of MRSA (1:1800 dilution with an optical density (OD600) of 0.25 at 600 nm) pre-incubated in 10% autologous serum. At the desired time point, add saponin (22 μL of 1% solution, final concentration of 0.1%) to each well or tube, mix the contents, and incubate the plate or tube on ice for 15 minutes. Then, pass the MRSA through a 25-gauge blunt-end needle (to disperse cell clumps) and plate on LB agar medium. The next day, count the surviving bacteria. The survival rate is calculated by the following formula by comparing the number of surviving bacteria with the number of bacteria at t = 0: (CFU+ at t / CFU- at 0 t)×100.

[0195] Results MINC-IFN-α promotes the phagocytic activity of neutrophils to eliminate MRSA. MINC-IFN-α treatment is expected to reduce the number of MRSA colony formations compared to the vehicle control (physiological saline). MINC-IFN-α is expected to more effectively reduce the number of colonies than IFN-α alone at the same IFN-α concentration.

[0196] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0197] The above has described the preferred embodiments of the present invention. It should be understood that modifications may be made without departing from the scope of the present invention described in the claims. To specifically indicate and clearly claim the subject matter regarded as the invention, this specification is concluded by the following claims.

Claims

1. A pharmaceutical composition for treating bacterial or viral infections, comprising an effective amount of micelles, each micelle having an outer shell containing one or more polymer-flavonoid conjugates, optionally an inner shell containing one or more flavonoid oligomers, and a drug encapsulated within the shell. The polymer is a hydrophilic polymer having a molecular weight of 1,000 to 100,000 daltons, and is selected from the group consisting of poly(ethylene glycol) (PEG), hyaluronic acid, dextran, polyethyleneimine, poloxamer, povidone, D-alpha-tocopheryl, and polyethylene glycol succinate. The flavonoid is EGCG, EC, EGC, or ECG, as shown in the following structure: 【Chemistry 1】 The flavonoid oligomer contains 2 to 20 EGCG, EC, EGC, or ECG flavonoids. A pharmaceutical composition in which the aforementioned infection is caused by bacteria or viruses selected from the group consisting of severe acute respiratory syndrome coronavirus (SARS-CoV), enterovirus, HIV, hepatitis B virus, MERS-CoV, influenza virus, dengue virus, respiratory syncytial virus, hepatitis C virus, monkeypox virus, human papillomavirus, methicillin-resistant Staphylococcus aureus, Pseudomonas, anthrax, tetanus, pneumococcus, meningococcus, Escherichia coli, Legionella, Neisseria meningitidis, and Salmonella.

2. The pharmaceutical composition according to claim 1, wherein the micelle has an outer shell containing PEG-EGCG and an inner shell containing an EGCG oligomer.

3. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by severe acute respiratory syndrome coronavirus 2, and the drug is IFN-α, IFN-β, IL-6, IL-12, IL-21, anti-IL-6, anti-IL-6R, spike vaccine, RBD vaccine, ACE2 antagonist, anti-TMPRSS2, anti-CD147, anti-VEGFA, anti-GM-CSF, dexamethasone, chloroquine, Nspl2-RdRp inhibitor, hydroxychloroquine, anti-3CLpro, interferon-α, AAK-1 inhibitor, or JAK inhibitor.

4. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by an enterovirus, and the drug is IFN-α, IFN-β, a capsid binder, a 3Cpro inhibitor, a 3Dpol inhibitor, a 2CATPase inhibitor, a 2APro inhibitor, an anti-HSP90, an anti-PI4KB, an anti-OSBP, an anti-RdRP, SP40, SP45, SP55, SP81, LVLQ™, VAD, or AAPV.

5. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by HIV, and the drug is IFN-α, anti-tetanus immunoglobulin, tetanus toxoid, benzodiazepine, magnesium sulfate, intrathecal baclofen, dantrolene, ketamine, propofol, botulinum toxin, human anti-tetanus immunoglobulin, or tetanus toxoid vaccine.

6. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by hepatitis B virus, and the drug is IFN-α, IFN-γ, IL-12, IL-6, IL-21, DNA polymerase reverse transcriptase activity inhibitor, preS1 peptide, CRISPR / Cas9, ZFN, capsid assembly modulator, E-neg and E-pos RNAi, lamivudine, adefovir, entecavir, tenofovir, TLR agonist, STING agonist, or cyclophylline inhibitor.

7. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by MERS-CoV, and the drug is IFN-α, IFN-β, IFN-γ, anti-DPP4, polyIC, anti-ACE2 antagonist, RdRp inhibitor, chlorpromazine hydrochloride, chloroquine, peptide, endosomal protease inhibitor, TMPRSS2 inhibitor, furin protease inhibitor, anti-clathrin endocytosis, MERS-CoV S DNA, or RBD subunit vaccine.

8. The aforementioned infection is caused by the influenza virus, and the drugs are IFN-α, IFN-β, IFN-γ, IL-12, IL-6, IL-15, IL-21, neuraminidase inhibitors, cap-dependent endonuclease inhibitors, M2 ion channel blockers, nucleoprotein inhibitors, anti-NS1-1, anti-CPSF30, anti-PABII, anti-eIF4G1, anti-PABP1 The pharmaceutical composition according to claim 1 or 2, wherein it is anti-p85, anti-PKR, anti-PACT, anti-NXF1, anti-p15, anti-importin, anti-crk, anti-crkL, anti-RIG-1, anti-nucleolin, anti-TRIM25, anti-Gas8, anti-Akt, anti-p53, anti-PARP10, anti-RIL, anti-Hsp90, anti-PDZ, anti-NOLC1, anti-RAP55, anti-IKK, anti-hPAF1C, or anti-hGBP1.

9. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by the dengue virus, and the drug is an anti-TNF-α, anti-IL-6, anti-RANTES, chloroquine, prednisolone, NS5 nucleoside inhibitor, ER-related α, glucosidase inhibitor, lovastatin, capsid inhibitor, envelope inhibitor, anti-NS4B, anti-NS2B / 3, anti-NS1, or NS1 vaccine.

10. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by respiratory syncytial virus, and the drug is IL-15, anti-TNF-α, benzimidazole derivative, disulfonated stilbene, imidazoisoindrone derivative, triphenol compound, anti-enveloped glycoprotein, sulfated sialyl lipid, anti-NS1, anti-F glycoprotein, P protein, NS1 protein, or siRNA that inhibits the N protein gene.

11. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by SARS-CoV, and the drug is IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-VEGFA, anti-GM-CSF, spike vaccine, RBD vaccine, ACE2 antagonist, anti-TMPRSS2, anti-CD147, dexamethasone, chloroquine, Nsp12-RdRp inhibitor, hydroxychloroquine, anti-3CLpro, interferon-α, AAK-1 inhibitor, JAK inhibitor, anti-ATM, anti-SIRT1, anti-GSK3B, or anti-Trin-2.

12. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by hepatitis C virus, and the drug is IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-EGFR, anti-NS2, anti-NS3, anti-NS4A, anti-NS5A, anti-NS5B, anti-helicase, anti-TLR-9, anti-HCV E2, anti-E1, anti-E2, anti-p7, anti-CD81, anti-SRB1, anti-CLDN1, anti-EphA2, anti-TfR1, anti-NPC1L1, cyclosporine A, anti-alpha-glucosidase, anti-DGAT-1, anti-VLDL, anti-CD81, anti-CLDN1, or anti-SR-Bl.

13. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by monkeypox virus, and the drug is IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, rosmarinic acid, myricitrin, quercitrin, ofloxacin, anti-VP37, anti-Fl3L, anti-E9L, anti-A24R, anti-A48R, anti-H5R, anti-B1R, anti-F10L, anti-E8L, anti-A6R, anti-SPGF, anti-B8R, anti-A50R, anti-I7L, anti-D13L, anti-Top1, or anti-TMPK.

14. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by human papillomavirus, and the drug is IFN-α, IFN-β, IL-21, anti-IL-6, anti-IL-6R, anti-EGFR, anti-c-Met, anti-IGF-1R, anti-PI3K, anti-Akt, anti-mTOR, anti-Ras, anti-Raf, anti-MAPK, anti-VEGF, anti-VEGFR, anti-HIF-1alpha, anti-PD-L1, anti-CD38, anti-PD1, anti-RNR, anti-FFFR, anti-PDGFR, anti-Kit, or anti-Ret.

15. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by methicillin-resistant Staphylococcus aureus, and the drug is IFN-α, IFN-γ, IFN-β, IL-13 topoisomerase inhibitor, FtsZ inhibitor, beta-lactamase inhibitor, ribosome inhibitor, dihydropteroic acid synthase inhibitor, dihydropteroic acid synthase inhibitor, anti-AR301, anti-MEDI4893, anti-51403, or anti-ARN-100.

16. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by Pseudomonas bacteria, and the drug is IFN-α, OprF vaccine, anti-LPS, anti-alginate, anti-PcrV, anti-OPK, anti-DNABII, beta-lactamase inhibitor, LptD, LpxD, bacterial lysate, iron mimetic, biofilm matrix disruptor, T3SS inhibitor, anti-MEDI3902, or anti-AR101.

17. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by Mycobacterium tuberculosis, and the drug is IFN-α, anti-TNF-α, IFN-γ, GM-CSF, TGF-β, anti-VEGF, IL-2, IL-4, IL-7, IL-10, IL-12, IL-15, IL-23, IL-24, IL-37, anti-IL4 prostaglandin E, phosphodiesterase inhibitor, ATP synthase inhibitor, ribosome inhibitor, DprE1 inhibitor, gyrase inhibitor, MmpL3 inhibitor, Leut RNA synthase inhibitor, Murl inhibitor, InhA inhibitor, NDH-2 inhibitor, QcrB inhibitor, MenG inhibitor, FtsZ inhibitor, EthR inhibitor, or LepB inhibitor.

18. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by Bacillus anthrax, and the drug is IFN-α, anti-PA63, enoyl-ACP reductase, ribonucleotide reductase, nucleoside hydrolase, replication DNA helicase, acetohydroxy acid synthase, NAD synthase, nicotinic acid mononucleotide adenylyltransferase, lumazine synthase, cytoskeletal protein FtsZ, dihydropteroic acid synthase, or dihydrofolate reductase.

19. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by Tetanus bacillus, and the drug is IFN-α, anti-tetanus immunoglobulin, tetanus toxoid, benzodiazepine, magnesium sulfate, intrathecal baclofen, dantrolene, ketamine, propofol, botulinum toxin, human anti-tetanus immunoglobulin, or tetanus toxoid vaccine.

20. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by Streptococcus pneumoniae, and the drug is IFN-α, IL-26, HMGB1, anti-IL-6, anti-TNFα, anti-IL-1β, anti-CXCL8, CD4, IL-4, CD8A, IL-10, anti-PTPRC, JAK inhibitor, anti-manL, anti-cps4L, anti-recU, anti-SP_0645, anti-ezrA, anti-prsA, anti-tarJ, anti-SP_1280, anti-SP_1617, anti-ptsG, anti-DltD, anti-hprK, anti-pepF, anti-coiA, anti-fib, anti-acpS, anti-manA, anti-mvaK2, anti-mtlD, anti-mtlF, or TPCA-1.

21. The infection is caused by meningococcus, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti- TGF-β, CGRP, anti-PARP, TACE, EGFR, EGF, anti-ATM, ESR-1, anti-CASP8, NGF, anti-sdhA, anti-ribH, anti-ruvA, anti-ruvX, anti-ponA, anti-rr03, anti- fabH, anti-fabZ, anti-metE, anti-recJ, anti-rpsP, anti-plsY, anti-ftsK, anti-dnaE, anti-holB, anti-rsmI, anti-mtf, anti-dnaG, anti-rpoD, anti-pta, anti-rplU, anti-hu The pharmaceutical composition according to claim 1 or 2, which is anti-ptsI, anti-rsmG, anti-lgt, anti-greA, anti-secA1, anti-queF, anti-nusG, anti-ackA, anti-dapH, anti-ilvD, or anti-dnaC.

22. The aforementioned infection is caused by Escherichia coli, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-6, anti-bamD, anti-cydX, anti-dnaT, anti-fabA, anti-ftsB, anti-ftsL, anti-ftsQ, anti-hemD, anti-higA, anti-hipB, anti-holD, anti-iraM, anti-lolA, anti-lolB, anti-lptA, anti-lp The pharmaceutical composition according to claim 1 or 2, wherein the anti-lptE is anti-mreD, anti-mukB, anti-mukE, anti-mukF, anti-pheM, anti-priB, anti-safA, anti-secE, anti-trpL, anti-tusE, anti-wzyE, anti-ycaR, anti-yciS, anti-ydfO, anti-ydhL, anti-ygfZ, anti-yqeL, anti-yrfF, or anti-zipA.

23. The aforementioned infection is caused by Legionella, and the drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, anti-Hsp60, anti-MOMP, anti-Mip, anti-Les, anti-Lsp, anti-CpxTRA, anti-PilEL, anti-Lvh, anti-IcM, anti-UDP, anti-FtsL, anti-MrdA, anti-RpoH, anti-multidrug resistance protein, anti-amino acid permease (Anti-Amino acid) The pharmaceutical composition according to claim 1 or 2, wherein it is anti-permease, anti-TolB, anti-Kup1, anti-MviN, anti-Tig, anti-MurE, anti-SCD, anti-TTF, anti-UMF1, anti-HMP, anti-HslU, anti-htrB, anti-Kdo, anti-OGT, or anti-RpoH.

24. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by Neisseria gonorrhoeae, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, CDP-4-dehydro-6-deoxyglucose reductase, anti-LpxC, anti-SSADH, anti-RNR, anti-DacC, anti-PBP, anti-PIB, anti-dsbA, anti-NarX, anti-Zur, anti-PTS, anti-Hpr, anti-PPP, anti-YgfZ, anti-HP, anti-RimM, anti-BspRI, anti-rluF, anti-FAD, anti-EF-P, anti-dnaN, anti-tilS, or anti-RluD.

25. The pharmaceutical composition according to claim 1 or 2, wherein the infection is caused by Neisseria meningitidis, and the drug is IFN-α, anti-IL-1β, anti-TNFα, anti-IL-8, anti-MIP-2, anti-MIP-1α, anti-MMP, anti-TGF-β, anti-TerC, anti-MscS, anti-OPT, anti-MFS, anti-MscS, anti-NaCT, anti-ABC, anti-TauE / SafE, anti-CBS, anti-NRAMP, anti-OATP, anti-YggX, anti-SstT, anti-PMT, anti-YjgP, anti-yhhQ, anti-TerC, anti-MAPEG, anti-MSG, anti-PilW, anti-PilX, anti-RlpA, anti-Rrf2, anti-IclR, or anti-Rim.

26. The aforementioned infection is caused by Salmonella bacteria, and the aforementioned drugs are IFN-α, anti-IL-1β, anti-TNFα, anti-IL-6, anti-bamD, anti-cydX, anti-dnaT, anti-fabA, anti-ftsB, anti-ftsL, anti-ftsQ, anti-hemD, anti-higA, anti-hipB, anti-holD, anti-iraM, anti-lolA, anti-lolB, anti-lptA, anti The pharmaceutical composition according to claim 1 or 2, wherein the anti-lptD is anti-lptE, anti-mreD, anti-mukB, anti-mukE, anti-mukF, anti-pheM, anti-priB, anti-safA, anti-secE, anti-trpL, anti-tusE, anti-wzyE, anti-ycaR, anti-yciS, anti-ydfO, anti-ydhL, anti-ygfZ, anti-yqeL, anti-yrfF, or anti-zipA.

27. A pharmaceutical composition for treating bacterial or viral infections, comprising an effective amount of polymer-flavonoid conjugate, The polymer is a hydrophilic polymer having a molecular weight of 1,000 to 100,000 daltons, and is selected from the group consisting of PEG, hyaluronic acid, dextran, polyethyleneimine, poloxamer, povidone, D-alpha-tocopheryl, and polyethylene glycol succinate. The flavonoid is EGCG, EC, EGC, or ECG, as shown in the following structure: 【Chemistry 2】 The aforementioned infectious disease is caused by a DNA virus, RNA virus, Gram-positive bacteria, or Gram-negative bacteria, and is a pharmaceutical composition.

28. The pharmaceutical composition according to claim 27, wherein the polymer-flavonoid conjugate is PEG-EGCG.

29. A pharmaceutical composition for treating bacterial or viral infections, comprising an effective amount of flavonoid oligomer, The flavonoid is EGCG, EC, EGC, or ECG, as shown in the following structure: 【Transformation 3】 The flavonoid oligomer is composed of 4 to 12 EGCG, EC, EGC, or ECG flavonoids. The aforementioned infectious disease is caused by a DNA virus, RNA virus, Gram-positive bacteria, or Gram-negative bacteria, and is a pharmaceutical composition.

30. The pharmaceutical composition according to claim 29, wherein the flavonoid oligomer is an oligomer of EGCG.

31. The pharmaceutical composition according to any one of claims 27 to 30, wherein the infectious disease is caused by a DNA virus selected from the group consisting of hepatitis B virus, human herpesvirus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, monkeypox virus, and varicella-zoster virus.

32. The pharmaceutical composition according to any one of claims 27 to 30, wherein the infectious disease is caused by an RNA virus selected from the group consisting of SARS-CoV-2, enterovirus, HIV, MERS-CoV, hepatitis C virus, hepatitis A virus, rotavirus, norovirus, influenza virus, parainfluenza virus, dengue virus, respiratory syncytial virus, and SARS-CoV.

33. The pharmaceutical composition according to any one of claims 27 to 30, wherein the infection is caused by Gram-positive bacteria selected from the group consisting of methicillin-resistant Staphylococcus aureus, Mycobacterium tuberculosis, Bacillus anthrax, Clostridium tetani, Streptococcus pneumoniae, Clostridium botulinum, Clostridium bacterium, Mycobacterium tubercurocystis, Clostridium tetani, Mycobacterium diphtheriae, and Mycobacterium leprae.

34. The pharmaceutical composition according to any one of claims 27 to 30, wherein the infection is caused by Gram-negative bacteria selected from the group consisting of Pseudomonas, Neisseria meningitidis, Leptospira, Neisseria gonorrhoeae, Neisseria meningitidis, Plague bacillus, Treponema pallidum, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, Mycobacterium tuberculosis, Legionella, and Salmonella.

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