Antiviral composition for prevention or post-exposure treatment of infection or respiratory disease and use thereof

Abstract

The present application relates to an antiviral composition for preventing or treating pathogenic infections and a use thereof. The liposome-state antiviral agent of the composition comprises a liposome and an antiviral agent embedded in the liposome. The antiviral agent is stably encapsulated in liposomes, and it has been demonstrated that the resulting liposome-state antiviral agent can be stably aerosolized or aerosolized for administration via inhalation route to treat an individual in need thereof while reducing side effects.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202180023098.0, filed on March 22, 2021, entitled "Antviral Composition for Prevention or Post-Exposure Treatment of Infections or Respiratory Diseases". Technical Field

[0002] This invention relates to a drug delivery system for delivering antiviral agents. This invention also relates to a method for preparing said drug delivery system. The invention further relates to sustained-release pharmaceutical compositions suitable for pulmonary delivery systems, which have reduced systemic side effects. The invention also relates to the use of said pharmaceutical compositions. Background Technology

[0003] Infectious diseases can be transmitted through various routes, including contact, droplets, and bloodstream transmission. Systemic administration can reduce drug bioavailability within the affected body environment. The penetration of drug delivery systems into target cells of the target tissue is a key obstacle to the effective treatment of infectious diseases, such as inhalation therapy for lung infections. Although drugs remain within liposomes before attaching to target epithelial cells, the rate of diffusion of free, uncharged drugs across the liposome membrane can lead to the conversion from one liposomal drug to another. This largely depends on the physicochemical properties of the lipid barrier in the microenvironment surrounding the liposome and the water environment within the liposome.

[0004] Respiratory diseases caused by infection or other unknown reasons are extremely serious, debilitating lung diseases that can lead to premature death. These are especially those characterized by effective viral replication and virus-induced cell lysis or immunopathological damage. Infected cell lines and post-mortem lung tissue have shown cytopathic effects due to apoptosis, necrosis, or occasionally syncytial formation.

[0005] As described in US Patent Publication No. US20110104259A1, liposomes have been used as drug carriers to mask the unpleasant taste of medications used for the treatment of asthma via inhalation. Liposome encapsulation of drugs can alter their pharmacokinetic characteristics, provide slow drug release in a localized body environment, achieve optimal dosage with less frequent administration, and / or reduce side effects and toxicity. However, it remains unclear whether quinine compounds or other antiviral agents delivered via inhalation via liposomes can effectively perform their desired functions, such as deposition on target cell lines expressing suitable receptors as target sites, simultaneously serving as intracellular target sites for viral entry, and exhibiting the desired pharmacokinetic properties in vivo.

[0006] What remains unclear is whether liposome technology, used to reformulate antiviral agents, can produce inhaled liposomal formulations for use in preventative doses to prevent severe acute respiratory syndrome (ARDS) or therapeutic doses to treat respiratory or infectious diseases, while also reducing side effects. Currently, there are no viable inhaled liposomal drug formulations available for chemopreventive use to prevent or treat mild cases, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or severe acute respiratory syndrome (SARS) caused by viral infections such as coronaviruses, COVID-19 (also known as SARS-CoV-2).

[0007] There remains a need for an inhalable formulation with a predetermined encapsulation efficiency that balances the need to reduce the frequency and / or dosage of antiviral agents (such as quinine and nucleoside compounds) with the preventative or therapeutic window required for lung delivery. Furthermore, formulations suitable for respiratory diseases should possess the following characteristics: be inhalable, exhibit sufficient encapsulation efficiency after nebulization, have improved stability or appropriate resistance to disruption caused by local pulmonary surfactants, and further possess the desired dose strength to ensure the potential to achieve the desired efficacy in the pulmonary environment. This invention addresses this need, along with other requirements. Summary of the Invention

[0008] The present invention provides a liposomal pharmaceutical formulation for treating respiratory or infectious diseases, particularly by inhalation, comprising at least one lipid (optionally a phospholipid and sterol, and / or a phospholipid modified with polyethylene glycol (PEG)) and an antiviral agent encapsulated in an aqueous interior of the liposome.

[0009] To improve existing treatment modalities for respiratory or infectious diseases and to leverage the benefits of slow, sustained drug release, we have developed an antiviral composition comprising a liposomal antiviral agent and a predetermined amount of free antiviral agent in an aqueous suspension, which can be aerosolized and inhaled for the prevention or enhancement of respiratory diseases. In particular, there is a need for an inhalable formulation for the prevention or treatment of SARS.

[0010] This disclosure provides an antiviral composition for the prevention or treatment of respiratory or infectious diseases, particularly against SARS, which has the following advantages: 1) longer therapeutic effect compared to inhaled free drug components; 2) direct delivery of the drug to the disease site or site of viral infection; 3) faster onset of action; 4) reduced adverse drug reactions and systemic effects; 5) bypassing first-pass metabolism observed in oral administration, thereby improving the bioavailability of the drug component (and potentially reducing hepatotoxicity, ocular symptoms of retinopathy, gastrointestinal (GI) effects, including nausea, vomiting, diarrhea, abdominal discomfort, and hepatotoxicity); 6) increased residence time of the drug component in target tissues through sustained release of the drug from liposomal administration; 7) reduced frequency of drug administration; 8) non-invasive inhalation delivery; and / or 9) improved patient outcomes and compliance.

[0011] In one particular embodiment, the antiviral agent according to the present disclosure is encapsulated in liposomes in a predetermined amount to form an antiviral agent composition according to the present disclosure, thereby completing a composition having preferred release properties and reduced toxicity (particularly cardiotoxicity).

[0012] An antiviral agent composition is provided for the prevention or treatment of respiratory or infectious diseases. This composition is inhalable and comprises a liposomal antiviral agent, wherein the liposomal antiviral agent comprises: Liposomes containing at least one lipid, and an antiviral agent encapsulated in the liposomes.

[0013] In some embodiments, the liposome comprises a lipid bilayer consisting of one or more phospholipids and sterols, wherein the sterol is cholesterol, and the molar ratio of the one or more phospholipids to the sterols is 1:1 to 2:1, with a selectivity of 3:2.

[0014] In some embodiments, the one or more phospholipids include phosphocholine (PC), which may include, but is not limited to, hydrogenated soyphosphatidylcholine (HSPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), or mixtures thereof. In other embodiments, the one or more phospholipids include DSPC and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) in a molar ratio of 1:1 or 3:2.

[0015] In some implementations, the liposome-based antiviral agent contains a 4-aminoquinoline compound.

[0016] In some embodiments, the 4-aminoquinoline compound is selected from the group consisting of chloroquine, hydroxychloroquine, and amodiaquine.

[0017] In some embodiments, the antiviral agent is a nucleoside compound as shown in structural formula I: (I), Each R 1 R 2 R 3 R 4 Or R 5 Independently for hydrogen, OR a 、N(R a 2, N3, CN, NO2, S(O) n R a , halogen or methyl, where n is 0, 1 or 2; R 6 It can be CN or hydrogen; Each R a Independently, it can be hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, aryl(C1-C8)alkyl, (C4-C8)carbocycloalkyl, or -C(=O)R 11 —C(=O)OR 11—C(=O)NR 11 R 12 —C(=O)SR 11 —S(O)R 11 —S(O)2R 11 —S(O)(OR) 11 —S(O)2(OR) 11 ), or —SO2NR 11 R 12 ;as well as R 7 It is hydrogen; Each X 1 or X 2 Independent for CR 10 Or N; R 8 Halogen, NR 11 R 12 、N(R 11 (OR) 11 ) , NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, —CH(=NR 11 ), —CH=NHNR 11 —CH=N(OR 11 —CH(OR) 11 )2、—C(=O)NR 11 R 12 —C(=S)NR 11 R 12 —C(=O)OR 11 (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, aryl(C1-C8)alkyl, (C4-C8)carbocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O) n (C1-C8)alkyl, aryl(C1-C8)alkyl, OR 11 or SR 11 Each aryl or heteroaryl group is independently and optionally substituted by one or more Z groups; Each R 9 Or R 10 Independently hydrogen, halogen, R 11 OR 11 SR 11 NR 11 R 12 、N(R 11 (OR) 11 ), NR 11 NR11 R 12 , N3, NO, NO2, CHO, CN, —CH(=NR 11 ), —CH=NHNR 11 -CH=N(OR) 11 —CH(OR) 11 )2、—C(=O)NR 11 R 12 —C(=S)NR 11 R 12 —C(=O)OR 11 ; Each R 11 Or R 12 Independently, it is hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C4-C8)carbocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O). n (C1-C8)alkyl or aryl(C1-C8)alkyl, wherein each aryl or heteroaryl group is independently and optionally substituted by one or more Z groups; or R 11 Or R 12 Together with nitrogen atoms bonded to both of them, they form 3 to 7-membered heterocycles, wherein any carbon atom in the heterocycle may optionally be bonded to —O—, —S— or —NR. a —Alternative; Each Z group is independently a halogen, -O - =O, —OR b —SR b —S - —NR b 2、—N + R b 3. =NR b , —CN, —OCN, —SCN, —N=C=O, —NCS, —NO, —NO2, =N2, —N3, —NHC(=O)R b —OC(=O)R b —NHC(=O)NR b 2. —S(=O)2—, —S(=O)2OH, —S(=O)2R b —OS(=O)2OR b —S(=O)2OH, —S(=O)R b —OP(=O)(OR) b )2、—P(=O)(OR b )2、—P(=O)(O - )2、—P(O)(OR b (O)- —C(=O)R b —C(=O)X, —C(S)R b —C(O)OR b —C(O)O-, —C(S)OR b —C(O)SR b —C(S)SR b —C(O)NR b 2、—C(S)NR b 2、—C(=NR b )NR b 2, where each R b Independently hydrogen, alkyl, aryl, aralkyl, or heterocyclic; wherein one or more non-terminal carbon atoms in each of the (C1-C8) alkyl groups are optionally surrounded by —O—, —S—, or —NR. a -replace.

[0018] In some embodiments, the antiviral composition according to the invention further comprises an antibiotic, a supplement, an antiretroviral drug, or a combination thereof. Examples of antibiotics include penicillins (ampicillin + sulbactam, piperacillin + tazobactam), macrolides, cephalosporins, aminoglycosides, and glycopeptides. In some embodiments, the antibiotic is selected from curlimycin and azithromycin.

[0019] On the other hand, the present invention also provides an antiviral composition for the prevention or treatment of respiratory or infectious diseases, or an aerosolized particulate composition comprising said antiviral composition, having a drug-to-lipid ratio of at least 0.01 mol / mol, and optionally between 0.01 mol / mol and 2.0 mol / mol, between 0.05 mol / mol and 2.0 mol / mol, between 0.05 mol / mol and 1.5 mol / mol, between 0.05 mol / mol and 1.0 mol / mol, between 0.05 mol / mol and 0.5 mol / mol, between 0.05 mol / mol and 0.3 mol / mol, between 0.05 mol / mol and 0.2 mol / mol, between 0.05 mol / mol and 0.15 mol / mol, between 0.01 mol / mol and 1 mol / mol, between 0.05 mol / mol and 0.1 mol / mol. The concentrations range from 0.07 mol / mol to 0.09 mol / mol, or approximately 0.085 mol / mol. Furthermore, the concentrations of the antiviral agents range from 0.1 mg / mL to 10 mg / mL.

[0020] On the other hand, this disclosure also provides an aerosolized particulate composition according to the invention for the prevention or treatment of respiratory diseases, comprising a liposomal quinine compound, and having a drug-to-lipid ratio of at least 0.01 mol / mol, optionally at least 0.05 mol / mol, optionally between 0.01 mol / mol and 2.0 mol / mol, between 0.05 mol / mol and 2.0 mol / mol, between 0.05 mol / mol and 1.5 mol / mol, between 0.05 mol / mol and 1.0 mol / mol, between 0.05 mol / mol and 0.5 mol / mol, between 0.05 mol / mol and 0.3 mol / mol, between 0.05 mol / mol and 0.2 mol / mol, between 0.05 mol / mol and 0.15 mol / mol, optionally 0.5 mol / mol, and the concentration of the quinine compound is from 1 mg / mL to 10 mg / mL based on the composition. Between mg / mL.

[0021] On the other hand, this disclosure also provides an aerosolized particulate composition according to the invention for the prevention or treatment of respiratory diseases, comprising a liposome-like nucleoside compound, and having a drug-to-lipid ratio of at least 0.01 mol / mol, optionally at least 0.05 mol / mol, optionally between 0.01 mol / mol and 1.0 mol / mol, between 0.03 mol / mol and 0.5 mol / mol, between 0.03 mol / mol and 0.15 mol / mol, between 0.03 mol / mol and 0.1 mol / mol, optionally about 0.05 mol / mol, between 0.05 mol / mol and 0.5 mol / mol, between 0.05 mol / mol and 0.15 mol / mol, between 0.05 mol / mol and 0.1 mol / mol, between 0.07 mol / mol and 0.1 mol / mol, optionally about 0.085 mol / mol. The concentration of the nucleoside compound is between 0.1 mg / mL and 5 mg / mL based on the composition.

[0022] On the other hand, the present invention also provides an atomizing spray comprising an antiviral composition for use according to the present invention.

[0023] On the other hand, the present invention also provides an aerosolized particulate composition for the prevention or treatment of respiratory or infectious diseases according to the present invention, the particulate composition comprising an antiviral composition and comprising a liposome-based antiviral agent according to the present invention.

[0024] On the other hand, the present invention also provides a method for preventing or treating respiratory diseases or infectious diseases, comprising: administering an effective amount of an antiviral composition according to the present invention for the prevention or treatment of respiratory diseases to an individual in need.

[0025] On the other hand, the present invention also provides a system for administering an antiviral composition to an individual in need. This system includes an antiviral composition according to the invention, and a pulmonary delivery device. The pulmonary delivery device is capable of nebulizing the antiviral composition, and the nebulized particles comprising a plurality of liposomal antiviral agents contain both free and liposomal antiviral agents, the amount of which effectively provides immediate antiviral activity, while the amount of which effectively provides sustained antiviral activity.

[0026] On the other hand, the present invention also provides a method for reducing complications associated with the treatment of respiratory or infectious diseases in human individuals having said complications, the method comprising administering an antiviral composition according to the present disclosure to the individual in need. According to the present invention, the complications include, but are not limited to, cardiotoxicity or hepatotoxicity. According to the present invention, the complications include, but are not limited to, correction of QT interval (QTc) prolongation.

[0027] Other objects, advantages and novel features of this disclosure will become more apparent when the following detailed description is taken in conjunction with the accompanying drawings. Attached Figure Description

[0028] Figure 1 To demonstrate the pharmacokinetic profiles of HCQ in the lungs of rats after administration of the composition according to this disclosure and free HCQ.

[0029] Figure 2 To demonstrate the pharmacokinetic profiles of HCQ in rat blood after administration of the composition according to this disclosure and free HCQ.

[0030] Figure 3 To demonstrate the pharmacokinetic profile of HCQ in the heart of rats after administration of the composition according to this disclosure and free HCQ.

[0031] Figure 4A and Figure 4B To demonstrate a series of effects described on rat lungs following a single intravenous injection of SBECD-prepared GS-441524 (GS-441524 solution-IV) or intratracheal administration of liposome-formulated GS-441524 (also known as ISPM21) (ISPM21-IT). Figure 4A ) and rat plasma ( Figure 4B Average concentration-time curve of GS-441524 in (); LLOQ: lower limit of quantification. Detailed Implementation

[0032] definition Unless otherwise stated, the following terms used above and throughout the invention should be understood to have the following meanings.

[0033] As used herein, the singular forms “a,” “a,” “the,” and “this” include the plural referents, unless the context clearly indicates otherwise.

[0034] All figures in this document are to be understood as being modified by “about”, and when referring to measurable values ​​such as amount, duration and the like, it means including a variable of ±10%, preferably ±5%, more preferably ±1%, and even more preferably ±0.1% of a specific value, which applies to describing the desired amount of the liposome-based drug, unless otherwise stated.

[0035] As used herein, the term "treating, treated, or treatment" includes preventative (e.g., prophylactic), palliative, and curative uses or outcomes. The term "subject" includes vertebrates suffering from respiratory or other diseases or suspected viral infections. Preferably, the subject is a warm-blooded animal, including mammals, and preferably humans.

[0036] As used herein, the term "drug" refers to an antiviral agent, such as a quinine or nucleoside compound with desired therapeutic activity according to this disclosure. As used herein, the term "drug tolipid ratio" (D / L) refers to the ratio of an antiviral agent to at least one lipid in a composition according to this disclosure. The content of the drug in the free or liposomal form of the liposomal pharmaceutical composition according to this disclosure is determined by, but not limited to, ultraviolet-visible (UV-Vis) absorbance or high-performance liquid chromatography (HPLC). The content or concentration of phospholipids in liposomes and liposomal pharmaceuticals can be determined by, but not limited to, methods using a phosphorus determination method (adapted from G. Rouser et al., Lipids 1970, 5, 494-496) or HPLC to determine the phosphorus content of the liposome and liposomal pharmaceutical sample.

[0037] As used herein, although pharmacokinetic data were obtained in rats, pharmacokinetic characteristics associated with the inhaled compositions according to this disclosure may also be obtained in other mammals, including but not limited to cats, dogs, horses, mice, pigs, non-human primates, and humans.

[0038] Infectious diseases and respiratory diseases The infectious diseases and pathogenic infections referred to in this invention are diseases caused by organisms such as viruses, parasites, and bacteria. In one aspect, the transmission routes of infectious diseases include fecal-oral transmission, droplet contact, sexual transmission, oral transmission, direct contact, transmission via transportation, vertical transmission, iatrogenic transmission, and vector-borne transmission. In another aspect, infectious diseases may include, but are not limited to, urinary tract infections, skin infections, respiratory infections, dental infections, vaginal infections, and intra-amniotic infections.

[0039] In some embodiments, the infectious diseases include, but are not limited to: acute flaccid myelitis (AFM), anaplasmosis, anthrax virus, babesiosis, botulism, brucellosis, campylobacteriosis, carbapenem-resistant infection (CRE / CRPA), chancroid, chikungunya virus infection, chlamydia, ciguatella (harmful algal bloom, HABS), clostridium difficile infection, epsilon toxin, and coccidioidomycosis (Rift Valley fever). Fever, COVID-19 (Coronavirus Disease 2019), Creutzfeldt-jacob disease, infectious spongiform encephalopathy (CJD), cryptosporidiosis, cyclosporidiosis, dengue fever (Dengue 1, 2, 3, 4), diphtheria, Escherichia coli infection, Shiga toxin-producing (STEC), Eastern equine encephalitis (EEE), Ebola hemorrhagic fever, ehrlichiosis, encephalitis, arbovirus or parainfectious diseases, enterovirus infection, non-polio enterovirus, enterovirus infection D68 (EV-D68), giardiasis, glanders, gonococcal infection (gonorrhea), granuloma inguinale, Haemophilus influenzae type b. Hepatitis B (HIB or h-flu), Hantavirus Pneumonia (HPS), Hemolytic Uremic Syndrome (HUS), Hepatitis A (Hep A), Hepatitis B (Hep B), Hepatitis C (Hep C), Hepatitis D (Hep D), Hepatitis E (Hep E), Herpes, Herpes Zoster, Shingles, Histoplasmosis Infection, Human Immunodeficiency Virus / AIDS (HIV / AIDS), Human Papillomavirus (HPV), Influenza, Lead Poisoning, Legionnaires' Disease, Leprosy, Leptospirosis, Listeria Infection (Listeria,Listeria, Lyme disease, Lymphogranuloma venereum (LGV), Malaria, Measles, Glandular rhinitis, Meningitis, Viral meningitis, Meningococcal disease, Bacterial meningitis, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Multisystem inflammatory syndrome in children (MIS-C), Mumps, Norovirus, Ciguatera poisoning, Lice infestation (lice, head lice), Pelvic inflammatory disease (PID), Pertussis, Plague, Bubonic plague, Septicemic plague, Pneumonic plague, Pneumococcal disease (pneumonia), Polio, Powassan encephalitis, Psittacosis, Crabs, Public lice Infestation), impetigo (smallpox, monkeypox, cowpox), Q fever, rabies, ricin poisoning, rickettsial disease (Rocky Mountain spotted fever), rubella (including congenital (German measles)), salmonellosis gastroenteritis (Salmonella), scabies infection (scabies), scombroid, septic shock (septicemia), severe acute respiratory syndrome (SARS), shigellosis gastroenteritis (Shigella), smallpox, staphylococcal infection, methicillin-resistant Staphylococcus aureus (MRSA) infection, staphylococcal food poisoning, enterotoxin-B poisoning (staphylococcal food poisoning), staphylococcal infection vancomycin intermediate (VISA), vancomycin-resistant staphylococcal infection (VRSA), group A streptococcal infection (invasive, strep-A), group B streptococcal infection (Strep-B), streptococcal toxic shock syndrome (streptococcal toxic shock syndrome). Toxic-shock syndrome (STSS, TSS), syphilis (primary, secondary, early latent, late latent, congenital), tetanus infection, tetanus (lock jaw), trichomoniasis, trichinosis, tuberculosis (TB), latent tuberculosis infection (LTBI), tularemia, typhus (group D), typhus, bacterial vaginosis (yeast infection), e-cigarette-related lung injury, varicella-cholerae (cholera), vibriosis, viral hemorrhagic fever (Ebola virus, Lassa virus, Marburg virus), West Nile virus infection, yellow fever, Yersenia, and Zika virus infection.

[0040] According to this disclosure, respiratory illnesses include, but are not limited to, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or severe acute respiratory syndrome (SARS), whose main complications include fluid inflow into the lungs leading to dyspnea or impaired breathing. Typical symptoms include fever, cough, wet cough, dry cough, dyspnea, fatigue or myalgia, chest tightness, and gradually developing shortness of breath. Complications include pulmonary hypertension, heart failure, pneumonia, or pulmonary embolism.

[0041] In some embodiments, the antiviral compositions according to this disclosure are suitable for the prevention and treatment of mild cases, and are also suitable for the treatment of acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or severe acute respiratory syndrome (SARS) caused by coronaviruses or their derivatives.

[0042] Liposomes and liposomal antiviral agents As used herein, the term "liposome" or "liposomal" refers to a group of vesicles, each characterized by an aqueous internal space isolated from the external medium by one or more bilayer membranes. The bilayer membranes of liposomes are typically formed by one or more lipids, i.e., amphiphilic molecules of synthetic or natural origin, comprising spatially separated hydrophobic regions and hydrophilic ends.

[0043] The internal aqueous space of liposomes is essentially free of neutral lipids, such as triglycerides, non-aqueous phases (oil phases), water-oil emulsions, second liposomes, or other mixtures containing non-aqueous phases. Non-limiting examples of liposomes include small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs), and multi-lamellar vesicles (MLVs), with average diameters ranging from 50 nm to 10,000 nm, 50 nm to 500 nm, 50 nm to 450 nm, 50 nm to 400 nm, 50 nm to 350 nm, 50 nm to 300 nm, 50 nm to 250 nm, 50 nm to 200 nm, and 100 nm to 500 nm. Average diameters ranging from 100 nm to 200 nm, between 100 nm and 450 nm, between 100 nm and 400 nm, between 100 nm and 350 nm, between 100 nm and 300 nm, between 100 nm and 250 nm, or between 100 nm and 200 nm, are passable through sterile filter membranes. For example, MLVs can be formed directly from hydrated lipid membranes, spray-dried powders, or lyophilized cakes of selected lipid compositions with a trapping agent; while SUVs and LUVs can be sized from MLVs by ultrasonication, homogenization, microfluidization, or extrusion.

[0044] Generally, liposomes typically comprise a mixture of lipids containing at least one lipid selected from the group consisting of: dilipoprotein lipids, such as phospholipids, diglycerides, and dilipoglycolipids; monolipids, such as sphingomyelin and glycosphingolipids; sterols, such as cholesterol; and derivatives thereof, and combinations thereof.

[0045] Examples of phospholipids according to this disclosure include, but are not limited to: 1,2-Dilauroyl-sn-glycero-3-phosphocholine (DLPC) 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) 1-Palmioyl-2-stearoyl-sn-glycero-3-phosphocholine (PSPC) 1-Palmioyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) Hydrogenated soybean phosphatidylcholine (HSPC) 1,2-Dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt), DMPG 1,2-Dipalmitoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt), DPPG 1-Palmioyl-2-stearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt), PSPG 1,2-Distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt), DSPG 1,2-Dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol), DOPG 1,2-Dimyristoyl-sn-glycero-3-phospho-L-serine (sodium salt, DMPS) 1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine (sodium salt, DPPS) 1,2-Distearoyl-sn-glycero-3-phospho-L-serine (sodium salt, DSPS) 1,2-Dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) 1,2-Dimyristoyl-sn-glycero-3-phosphate (sodium salt, DMPA) 1,2-Dipalmitoyl-sn-glycero-3-phosphate (sodium salt, DPPA) 1,2-Distearoyl-sn-glycero-3-phosphate (sodium salt, DSPA) 1,2-Dioleoyl-sn-glycero-3-phosphate (sodium salt, DOPA) 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) 1-Palmioyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) 1,2-Dipalmitoyl-sn-glycero-3-phospho-(1'-myo-inositol) (ammonium salt), DPPI 1,2-Distearoyl-sn-glycero-3-phosphoinositol (ammonium salt), DSPI 1,2-Dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) (ammonium salt), DOPI Cardiolipin L-α-phosphatidylcholine (EPC), and L-α-phosphatidylethanolamine (EPE).

[0046] According to the liposome-based antiviral agent disclosed herein, a significant portion of polyethylene glycol may be incorporated into the vesicle surface. This can be achieved by incorporating PEG-modified phosphatidylethanolamine (PE) into the vesicle membrane to achieve longer and more sustained drug release, which is safe, effective, and reduces the frequency of administration.

[0047] The liposome-based antiviral agent of this disclosure can optionally bind a large amount of modified negatively charged portion to the surface of the vesicle by incorporating polyethylene glycol-modified phosphatidylethanolamine (PE) or fatty acids into the membrane of the vesicle, thereby preventing the aggregation or flocculation of liposomes in the solution during storage.

[0048] The polyethylene glycol-modified lipid comprises a polyethylene glycol moiety conjugated with the lipid. In some embodiments, the polyethylene glycol moiety has a molecular weight from about 500 to about 20,000 Daltons. In one specific embodiment, the polyethylene glycol-modified lipid is mixed with phospholipids to form liposomes having one or more bilayer membranes. In some embodiments, based on the total amount of phospholipids and sterols, the amount of the polyethylene glycol-modified lipid is from 0.0001 mol% to 40 mol%, optionally from 0.001 mol% to 30 mol%, optionally from 0.01 mol% to 20 mol%, optionally from 0.001 mol% to 10 mol%, optionally from 0.001 mol% to 5 mol%, and particularly not exceeding 6 mol%, optionally not exceeding 5 mol%, not exceeding 3 mol%, or not exceeding 2 mol%. In some embodiments, the polyethylene glycol-modified lipid has a polyethylene glycol moiety having an average molecular weight ranging from 1,000 g / mol to 5,000 g / mol. In some embodiments, the polyethylene glycol-modified lipid is phosphatidyl-ethanolamine (PEG-PE) linked to a polyethylene glycol group. In some other embodiments, the polyethylene glycol-modified phosphatidyl-ethanolamine is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] (or DSPE-PEG).

[0049] In one specific embodiment, the polyethylene glycol-modified phosphatidylethanolamine (PE) or fatty acid is DSPE-PEG, and the amount of DSPE-PEG is from 0.0001 mol% to 40 mol% of the total lipid content of the liposomes, optionally from 0.01 mol% to 20 mol%, and has a PEG portion with an average molecular weight of 2,000 g / mol.

[0050] The terms "liposome-based antiviral agent" or "liposome-based drug" are used interchangeably in this invention. The liposome-based antiviral agent according to this disclosure comprises liposomes encapsulating an antiviral agent, prepared by encapsulating the antiviral agent within the aqueous interior of the liposomes via a transmembrane pH gradient-driven remote loading method.

[0051] In some implementations, liposomes are formed together with a drug component such as hydroxychloroquine or GS-441524 to encapsulate the drug component in the aqueous interior of the liposome, or empty liposomes with a transmembrane gradient are formed separately for subsequent use in drug loading processes, a method known as active loading or remote loading, to form liposomal drugs.

[0052] In some implementations, the transmembrane pH gradient is generated by using a trapping agent, which can be used to remotely load antiviral agents into liposomes, and the trapping agent consists of an ammonium compound and an anionic counterion.

[0053] The term "ammonium compound" includes unsubstituted or substituted ammonium, which is a cation represented as NR4+, wherein each R is independently hydrogen or an organic residue, and said organic residue is independently alkyl, alkylene, heterocyclic alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl, or their hydroxylated derivatives, optionally containing a sulfur, oxygen, or nitrogen atom in its hydrocarbon chain, forming an ether, ester, thioether, amine, or amide bond. In one specific embodiment, said ammonium compound is ammonium.

[0054] The term "anionic counterion" refers to an anion or an entity covalently bonded to an anionic functional group. The anion or anionic functional group carries a negative charge in the physiological environment.

[0055] The anion or anionic functional group may be selected from one or more of the following: sulfate, citrate, sulfonate, phosphate, pyrophosphate, tartrate, succinate, maleate, borate, carboxylate, bicarbonate, glucuronide, chloride, hydroxide, nitrate, cyanate, or bromide.

[0056] In one embodiment, the anion or anionic functional group is selected from one or more of the following: citrate, sulfate, sulfonate, phosphate, pyrophosphate, and carboxylate.

[0057] In another embodiment, the entity linked to the anionic functional group can be a natural or synthetic, organic or inorganic compound. Examples of such entities include, but are not limited to, non-polymeric substances selected from alkyl or aryl (e.g., benzene), nucleotides, and sugars. The alkyl group refers to a saturated hydrocarbon group having a specified number of carbon atoms. For example, an alkyl group is selected from the group consisting of alkyl groups with 1 to 4 carbon atoms (C...). 1-4 Alkyl groups, alkyl groups with 1 to 6 carbons (C 1-6 Alkyl groups, alkyl groups with 1 to 8 carbons (C 1-8 Alkyl groups, alkyl groups with 1 to 10 carbons (C 1-10 Alkyl groups, alkyl groups with 1 to 12 carbons (C 1-12 Alkyl groups, alkyl groups with 1 to 14 carbons (C 1-14 Alkyl groups, alkyl groups with 1 to 16 carbons (C 1-16 Alkyl groups, alkyl groups with 1 to 18 carbons (C 1-18 Alkyl groups and alkyl groups with 1 to 20 carbons (C 1-20 alkyl).

[0058] In some embodiments, the anion and counterion are selected from the group consisting of sulfate, phosphate, citrate, and combinations thereof.

[0059] In some embodiments, the trapping agent is selected from the group consisting of: ammonium sulfate, ammonium phosphate, ammonium citrate, ammonium sucrose octasulfate, ammonium dextran sulfate, dimethyl ammonium sulfate, dimethyl ammonium phosphate, dimethyl ammonium citrate, diethyl ammonium sulfate, diethyl ammonium phosphate, diethyl ammonium citrate, diethyl ammonium sucrose octasulfate, diethyl ammonium dextran sulfate, trimethyl ammonium sulfate, trimethyl ammonium phosphate, trimethyl ammonium citrate, triethyl ammonium sulfate, triethyl ammonium phosphate, triethyl ammonium citrate, triethyl ammonium sucrose octasulfate, triethyl ammonium dextran sulfate, copper gluconate, copper glucuronide, and combinations thereof.

[0060] In some embodiments, the average particle size of the liposomal antiviral agent of the present invention is between 50 nm and 1,000 nm. Non-limiting examples of the liposomal antiviral agent have average particle sizes ranging from 50 nm to 20 μm, 50 nm to 10 μm, 50 nm to 1000 nm, 50 nm to 500 nm, 50 nm to 400 nm, 50 nm to 300 nm, 50 nm to 250 nm, 50 nm to 200 nm, 100 nm to 300 nm, or 150 nm to 250 nm.

[0061] In some implementations, antiviral agents include, but are not limited to, antimalarial agents, antiretroviral agents, or combinations thereof. Specifically, antiviral agents are selected from the group consisting of quinine compounds, nucleoside compounds, and combinations thereof.

[0062] The term "quinine compound" refers to substances derived from quinine, a lead compound with antimalarial activity, extracted from the bark of the cinchona tree. Quinine compounds (such as hydroxychloroquine) have been shown to have the potential to inhibit pneumonia progression, improve imaging findings, promote viral seroconversion, and shorten the course of the disease. However, systemic administration of quinine compounds may cause side effects such as blurred vision, nausea, vomiting, abdominal cramps, headache, and diarrhea.

[0063] The quinine compounds disclosed herein include, but are not limited to, quinine and other 4-aminoquinoline compounds, such as quinine, quinidine, cinconidine, cinconidine, chloroquine (CQ), hydroxychloroquine (HCQ), etc. Exemplary quinine compounds CQ and HCQ have been shown to prevent intracellular organelle acidification and inhibit the release of viral genome lysosomes. Additionally, these drugs can interfere with the glycosylation of the angiotensin-converting enzyme 2 (ACE2) receptor on host cells and reduce the binding efficiency between said receptor and the spike protein on the surface of coronaviruses.

[0064] Currently reported potential therapies for RNA virus infections utilize nucleosides as inhibitors of non-structural viral proteins, such as RNA-dependent RNA polymerases (RNA-DIPs). Nucleosides are expected to be absorbed by cells and converted to triphosphates in vivo, competing for nucleotide binding sites on polymerases and thus terminating the polymerase chain reaction. This conversion to triphosphates is typically mediated by cellular kinases, which also impose additional structural requirements on potential nucleoside polymerase inhibitors. The monophosphate formed by nucleoside kinases is generally considered a rate-determining step of three phosphorylation events. US7,964,580 discloses a pronucleoside containing a phosphoramide moiety masked with a neutral lipophilic group to obtain a suitable partition coefficient, thereby optimizing uptake and transport into cells and significantly increasing intracellular concentrations of nucleoside monophosphates compared to administration of the parent nucleoside alone. However, controversial observations suggest that enzyme-mediated hydrolysis of the phosphate moiety may immediately produce the nucleoside itself after cycling, rather than the target nucleoside monophosphate, and that the nucleoside itself may be generated before being targeted to the desired site. For example, via intravenous administration, (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazine-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxacyclopentane-2-onitrile (also known as GS-441524), a known nucleoside compound, is a more stable remdesivir metabolite than its monophosphate form (Humeniuk R, Mathias A, Cao H, et al. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, inHealthy Subjects. Clin Transl Sci. 2020; 13(5):896-906. doi:10.1111 / cts.12840). Efficiently delivering nucleoside compounds to target cellular sites rich in critical rate-limiting nucleoside kinases could be a universal platform solution that avoids the complex manufacturing processes of different pronucleosides across a wide range of nucleoside compounds.

[0065] In some embodiments, the antiviral composition according to this disclosure further comprises an antibiotic, a supplement, or a combination thereof.

[0066] In some embodiments, the antiviral agent comprises one or more 1'-substituted or 2'-substituted hydrocarbon nucleoside compounds as described in U.S. Patent Nos. US8,008,264 and US9,418,704.

[0067] In some implementations, the antiviral agent is targeted at nucleoside compounds, including but not limited to 1'-substituted hydrocarbon nucleoside compounds and their pharmaceutically acceptable salts.

[0068] In some embodiments, the antiviral agent comprises an inhibitor of RNA-dependent RNA virus polymerase, wherein said inhibitor comprises a nucleoside compound represented by structural formula I: (I), Each R 1 R 2 R 3 R 4 Or R 5 Independently for hydrogen, OR a 、N(R a 2, N3, CN, NO2, S(O) n R a , halogen or methyl, where n is 0, 1 or 2; R 6 It can be CN or hydrogen; Each R a Independently hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, aryl(C1-C8)alkyl, (C4-C 8) Carbocycloalkyl, —C(=O)R 11 —C(=O)OR 11 —C(=O)NR 11 R 12 —C(=O)SR 11 —S(O)R 11 —S(O)2R 11 —S(O)(OR) 11 —S(O)2(OR) 11 ), or —SO2NR 11 R 12 ;as well as R 7 It is hydrogen; Each X 1 or X 2 Independent for CR 10 Or N; R 8 Halogen, NR 11 R 12 、N(R 11 (OR) 11 ) , NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, —CH(=NR 11), —CH=NHNR 11 —CH=N(OR 11 —CH(OR) 11 )2、—C(=O)NR 11 R 12 —C(=S)NR 11 R 12 —C(=O)OR 11 (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, aryl(C1-C8)alkyl, (C4-C8)carbocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O) n (C1-C8)alkyl, aryl(C1-C8)alkyl, OR 11 or SR 11 Each aryl or heteroaryl group is independently and optionally substituted by one or more Z groups; Each R 9 Or R 10 Independently hydrogen, halogen, R 11 OR 11 SR 11 NR 11 R 12 、N(R 11 (OR) 11 ), NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, —CH(=NR 11 ), —CH=NHNR 11 -CH=N(OR) 11 —CH(OR) 11 )2、—C(=O)NR 11 R 12 —C(=S)NR 11 R 12 —C(=O)OR 11 ; Each R 11 Or R 12 Independently, it is hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C4-C8)carbocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O). n (C1-C8)alkyl or aryl(C1-C8)alkyl, wherein each aryl or heteroaryl group is independently and optionally substituted by one or more Z groups; or R 11 Or R 12Together with nitrogen atoms bonded to both of them, they form 3 to 7-membered heterocycles, wherein any carbon atom in the heterocycle may optionally be bonded to —O—, —S— or —NR. a —Alternative; Each Z group is independently a halogen, -O - =O, —OR b —SR b —S—, —NR b 2、—N + R b 3. =NR b , —CN, —OCN, —SCN, —N=C=O, —NCS, —NO, —NO2, =N2, —N3, —NHC(=O)R b —OC(=O)R b —NHC(=O)NR b 2. —S(=O)2—, —S(=O)2OH, —S(=O)2R b —OS(=O)2OR b —S(=O)2OH, —S(=O)R b —OP(=O)(OR) b )2、—P(=O)(OR b )2, —P(=O)(O-)2, —P(O)(OR b (O-), —C(=O)R b —C(=O)X, —C(S)R b —C(O)OR b —C(O)O-, —C(S)OR b —C(O)SR b —C(S)SR b —C(O)NR b 2、—C(S)NR b 2、—C(=NR b )NR b 2, where each R b Independently hydrogen, alkyl, aryl, aralkyl, or heterocyclic; wherein one or more non-terminal carbon atoms in each of the (C1-C8) alkyl groups are optionally surrounded by —O—, —S—, or —NR. a —Alternative.

[0069] In some embodiments, the antiviral agent is selected from the group consisting of: , , , , , , Or its pharmaceutically acceptable salt.

[0070] On one hand, the liposome-based antiviral agent comprises: a lipid bilayer comprising: one or more phospholipids, sterols, and optionally polyethylene glycol-modified lipids, particularly polyethylene glycol-modified phosphatidylethanolamine (DSPE-PEG); and an aqueous interior encapsulated by the lipid bilayer and comprising one or more antiviral agents.

[0071] In one embodiment, the one or more phospholipids are neutral phospholipids, and the polyethylene glycol-modified lipid is DSPE-PEG. Based on total phospholipids and sterols, the content of DSPE-PEG is between 0.001 mol% and 5 mol%, optionally between 0.0001 mol% and 40 mol%, optionally less than 6 mol%, and optionally between 0.001 mol% and 30 mol%.

[0072] In one embodiment, the liposome-based antiviral composition has a drug-to-lipid ratio (the ratio of the antiviral agent to at least one lipid) of at least 0.01 mol / mol to 0.1 mol / mol and comprises: a lipid bilayer comprising DPPC and cholesterol; and an aqueous interior coated by the lipid bilayer and comprising one or more antiviral agents captured by a trapping agent, wherein the antiviral agent is (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl)oxacyclopentane-2-onitrile (also known as GS-441524), and the trapping agent is ammonium sulfate.

[0073] Inhalable compositions and their aerosolized particles The antiviral composition according to this disclosure is suitable for preparing inhalable aerosolized particulate compositions comprising the aforementioned liposomal antiviral agent. This composition can be administered by inhalation as a nebulizer or aerosol, and also via intrathecal administration. Inhalation administration is preferred. Overall, the frequency of administration is lower and the therapeutic index is higher compared to free or parenteral formulations. The liposomal antiviral agent in the composition is particularly advantageous because the composition is compatible with lung linings or lung surfactants while protecting the drug.

[0074] In one embodiment, the antiviral composition according to this disclosure has a drug-to-lipid ratio (D / L) of at least 0.01 mol / mol, optionally at least 0.1 mol / mol, and preferably between 0.05 mol / mol and 1.0 mol / mol, optionally between 0.01 mol / mol and 0.7 mol / mol, optionally between 0.015 mol / mol and 0.6 mol / mol, and optionally between 0.15 mol / mol and 0.2 mol / mol. The drug-to-lipid ratio refers to the molar ratio of the antiviral agent to at least one lipid. In a particular embodiment, the at least one lipid comprises a neutral phospholipid and a sterol in a molar ratio of 1:1 or 3:2. Optionally, the neutral phospholipid is DPPC, and the sterol is cholesterol.

[0075] In one embodiment, the concentration range of the at least one lipid in the antiviral composition is between 1 mM and 200 mM, between 1 mM and 100 mM, between 5 mM and 100 mM, between 10 mM and 180 mM, between 15 mM and 140 mM, between 20 mM and 160 mM, between 30 mM and 140 mM, and between 40 mM and 120 mM. Alternatively, the concentration range of the one or more phospholipids in the antiviral composition is between 1 mM and 100 mM, between 5 mM and 100 mM, between 5 mM and 90 mM, between 10 mM and 80 mM, between 15 mM and 70 mM, or between 20 mM and 60 mM.

[0076] In one embodiment, the total concentration range of the quinine compound in the antiviral composition is between 0.1 mg / mL and 80 mg / mL, between 0.5 mg / mL and 60 mg / mL, between 1 mg / mL and 30 mg / mL, between 2 mg / mL and 15 mg / mL, between 0.5 mg / mL and 70 mg / mL, between 0.5 mg / mL and 60 mg / mL, between 0.5 mg / mL and 50 mg / mL, between 0.5 mg / mL and 40 mg / mL, between 0.5 mg / mL and 30 mg / mL, between 0.5 mg / mL and 20 mg / mL, between 0.5 mg / mL and 10 mg / mL, between 0.5 mg / mL and 8 mg / mL, between 0.5 mg / mL and 5 mg / mL, between 1.0 mg / mL and 6 mg / mL, between 1.5 mg / mL and 5.0 mg / mL, and between 1.5 mg / mL and 1.5 mg / mL. The concentration is between 4.0 mg / mL and approximately 2.0 mg / mL.

[0077] In one embodiment, the concentration range of the at least one phospholipid in the antiviral agent composition is between 1 mM and 100 mM, between 5 mM and 100 mM, between 5 mM and 90 mM, between 10 mM and 80 mM, between 15 mM and 70 mM, and between 20 mM and 60 mM; and the drug-to-lipid (D / L) ratio is between 0.01 mol / mol and 1.0 mol / mol, between 0.03 mol / mol and 0.5 mol / mol, between 0.03 mol / mol and 0.15 mol / mol, between 0.03 mol / mol and 0.1 mol / mol, about 0.005 mol / mol, between 0.05 mol / mol and 0.1 mol / mol, between 0.07 mol / mol and 0.09 mol / mol, or about 0.085 mol / mol. mol / mol, wherein the antiviral agent is a 1'-substituted hydrocarbon nucleoside compound or a 2'-substituted hydrocarbon nucleoside compound having a free 5'-OH group.

[0078] In some embodiments, the liposome-based antiviral composition further comprises a free antiviral agent, and the content of the free antiviral agent in the composition according to the present disclosure is based on the total amount of antiviral agent in the composition being less than 60%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or between 10% and 40%, between 15% and 35%, or between 10% and 30%.

[0079] In some embodiments, the aerosolized particulate composition comprising the composition according to the present disclosure is generated by aerosolizing the composition using a nebulizer selected from air-jet nebulizers, ultrasonic nebulizers, vibrating mesh nebulizers, condensation aerosol generators, electro-hydrodynamic nebulizers, or other lung delivery devices known in the art.

[0080] In some embodiments, the mass median aerodynamic diameter of the aerosolized particulate composition is between 0.5 µm and 5 µm, and optionally between 1 µm and 3 µm.

[0081] Upon aerosolization of the composition according to this disclosure, a portion of the antiviral agent becomes free and is not encapsulated within the liposomes due to liposome leakage from the liposome-state antiviral agent. The content of the free antiviral agent generated in the aerosolized composition is less than 60%, 50%, 40%, 30%, 20%, 10%, or 5%; optionally within a controlled percentage range of 0.1% to 50%, 0.5% to 40%, 0.5% to 30%, 0.5% to 20%, 0.5% to 10%, 0.5% to 5%, 10% to 50%, 15% to 45%, 20% to 45%, or 25% to 35%.

[0082] In one particular embodiment, the aerosolized particulate composition is delivered via the lungs to an individual in need, exhibiting a release rate between about 0.5% and 25% per hour based on the administered drug dose, and complete release of the antiviral agent in as little as about 12 to 24 hours.

[0083] This disclosure is further described with reference to the following specific, non-limiting embodiments.

[0084] Example The following examples illustrate the preparation and properties of certain embodiments of this disclosure.

[0085] Example 1: Stability of liposomal antiviral agents The liposome-based antiviral agent according to this disclosure comprises liposomes carrying a captured antiviral agent, which is prepared by active loading or passive loading of known techniques.

[0086] A. Preparation of liposome-based antiviral agents via active loading I. Preparation of empty liposomes A method for preparing empty liposomes for remote loading is performed by a thin-film hydration method or a solvent injection method, and the method may include the following steps: 1. Weigh a lipid mixture of phospholipids and cholesterol in a predetermined molar ratio, with or without DSPE-PEG2000, and add it to 10 mL of chloroform in a round-bottom flask; 2. Place the flask in a rotary evaporator at a suitable temperature according to the lipid composition, stir the flask to dissolve the lipid mixture, and then place the flask under vacuum while stirring to evaporate chloroform to obtain a dry lipid film; 3. The trapping agent is added to distilled water and the solution is vortexed to dissolve the powder, thereby preparing a trapping agent solution (e.g., ammonium sulfate (AS)); 4. Add the capture agent solution to the dried lipid membrane and stir at a suitable temperature according to the lipid composition to form a liposome solution; 5. The liposome solution is freeze-thawed using liquid nitrogen and a water bath at a suitable temperature according to the lipid composition to obtain a liposome sample; 6. The obtained liposome sample is extruded through a 0.2 µm polycarbonate membrane and a 0.1 µm polycarbonate membrane at a suitable temperature according to the lipid composition to obtain the designed particle size; 7. Dialyze the extruded liposome sample to remove free trapping agent, then add the sample to a dialysis bag (MWCO: 25 kD), seal the bag, and stir the dialysis bag in 100 volumes of 9.4% (w / v) sucrose solution, physiological saline, or a suitable buffer solution; after 1 hour and 4 hours, further change the sucrose solution, physiological saline, or a suitable buffer solution, and stir the dialysis bag overnight; and 8. The dialyzed liposome sample was sterilized by filtration through a 0.45 μm polytetrafluoroethylene (PTFE) membrane to obtain empty liposomes.

[0087] II. Loading antiviral agents into liposomes to obtain liposome-based antiviral agents. The following method is an exemplary protocol for encapsulating hydroxychloroquine or chloroquine in liposomes via remote loading, comprising the following steps: 1. Prepare a 40 mg / mL solution of hydroxychloroquine or chloroquine of suitable concentration in a 9.4% (w / v) sucrose solution or a suitable medium, and briefly heat the solution at a suitable temperature to obtain a stock solution containing hydroxychloroquine or chloroquine (hereinafter referred to as stock solution); 2. In a conical tube, empty liposomes (in a typical embodiment, having the following conditions: a molar ratio of DPPC to cholesterol of 3:2, 300 mM ammonium sulfate (AS) and 30 mM phospholipid concentration), saline solution and stock solution are mixed to obtain a loading solution with a D / L ratio of 100 g / mol or 0.19 mol / mol; 3. Shake the loading solution continuously at a suitable temperature for 30 minutes or a preset time to form a drug-loaded liposome sample; 4. If necessary, remove free drug, change buffer solution, or adjust drug concentration by dialysis or membrane-based tangential flow filtration (TFF). 5. Size-exclusion column chromatography and HPLC were used to determine the drug encapsulation (i.e., loading efficiency) of the final sample to obtain a liposome-based antiviral composition, wherein, based on the whole composition, the drug concentration is between 2 mg / mL and 10 mg / mL, and the ratio of antiviral agent to lipid is between 0.05 mol / mol and 1.5 mol / mol (see Formulations #1 to #3 below).

[0088] B. Preparation of liposome-based antiviral agents via passive loading Liposomes can be prepared by thin-film hydration or solvent injection. The process for preparing liposomal antiviral agents using the solvent injection method is specified as a method including the following steps: 1. Weigh a lipid mixture of phospholipids and cholesterol in a predetermined molar ratio, wherein DSPE-PEG2000 may or may not be present, and then add them to 10 mL of ethanol in a round-bottom flask to form a solvent phase containing the lipids; 2. Prepare a solution of hydroxychloroquine or chloroquine at a concentration of 40 mg / mL to 60 mg / mL or a suitable concentration in a 0.9% sodium chloride aqueous solution (saline) or a suitable medium to form an aqueous phase; 3. Preheat 40 mL of the aforementioned aqueous phase (40 mg / mL hydroxychloroquine) at 50°C for at least 30 minutes; 4. While stirring, add the dissolved lipid mixture (i.e., the solvent phase) into the preheated aqueous phase using a syringe to form a pro-liposome sample. Then, continuously stir the pro-liposome sample at 50°C for 5 minutes. 5. At a suitable temperature according to the lipid composition, the preliposome sample is extruded from a 0.2µm polycarbonate membrane to obtain the designed particle size; 6. Dialyze the extruded liposome samples with saline (0.9% NaCl) to remove free drug; and 7. The dialyzed liposome sample was sterilized by filtering it through a 0.2µm polycarbonate membrane to obtain the liposome-based antiviral agent.

[0089] The antiviral composition according to this disclosure can be formulated by adding a free antiviral agent in a manner targeting an antiviral agent concentration of 1.0 mg / mL to 4 mg / mL, and the ratio of the antiviral agent to lipid is at least between 0.05 mol / mol and 0.30 mol / mol (see formulations #4 to #6 below), based on the overall composition.

[0090] C. Storage stability of liposome-based antiviral agents The stability of liposomal hydroxychloroquine or chloroquine prepared as described in Sections A and B above, stored at 4°C, can be monitored for at least 2 weeks or a predetermined time. Hydroxychloroquine or chloroquine is prepared by loading empty liposomes with ammonium sulfate, either actively or passively, to obtain liposomal drug samples for study. After storing the liposomal drug samples at 4°C or a suitable temperature for 2 weeks or a predetermined time, the pharmacodynamic and physicochemical properties of the liposomes can be studied over time.

[0091] Example 2: Preclinical evaluation of inhaled liposomal antiviral agents in animal models The toxicity of the exemplary liposomal hydroxychloroquine (HCQ) composition (also referred to as TLC19) prepared in Example 1B was investigated in animals. Preliminary concept pharmacokinetic (PK) and tissue distribution studies were conducted in Sprague-Dawley (SD) rats via a single intravenous (IV) / intrahepatic (IT) administration of HCQ sulfate solution (free HCQ) or an IT administration of the test formulation of TLC19 (study number PK20021). This study aimed to investigate the tissue distribution, primarily in the lungs, and the systemic exposure to HCQ.

[0092] A total of 52 rats were randomly divided into three treatment groups, with each rat receiving a single dose of HCQ via intratracheal administration or a single intravenous injection. Blood and organ / tissue samples, including lung samples, were collected at pre-specified time points at 0.25, 1 (blood only), 4, 24, and 72 hours post-administration for HCQ determination by liquid chromatography-tandem mass spectrometry. The study design is summarized in Table 1 below.

[0093] Table 1: Summary of Research Design (Study No. PK20021)

[0094] The concentrations of HCQ in the blood, lungs, and heart were determined using Analyst. ® Alternatively, the calculations can be performed using MassLynx software, while the pharmacokinetic (PK) parameters are calculated using Phoenix software. ® WinNonlin ® The concentrations of HCQ in the lungs, blood, and heart were measured. The curves showing the concentrations of HCQ in the lungs, blood, and heart relative to time after administration of the TLC19 test reagent and free HCQ are shown below. Figure 1 , Figure 2 and Figure 3 The mean PK parameters in the lungs, blood, and heart are shown in Table 2 below.

[0095] Table 2: Mean pharmacokinetic parameters in the lungs, blood, and heart of rats after administration of the TLC19 test formulation and free HCQ (Study No. PK20021)

[0096] a: Tmax is the median b: The unit for lung and heart function is µg / g; the unit for blood function is µg / mL. c: The unit for lung and heart function is hr*µg / g; the unit for blood function is hr*µg / mL. d: Not applicable Regarding the lung distribution in rats administered free HCQ, HCQ concentrations showed a sustained and rapid decline during the first 24 hours post-administration, particularly in the HCQ IT group; the mean HCQ concentration decreased from 47.8 µg / g to 2.16 µg / g in the HCQ IT group, while in the HCQ IV group, the mean HCQ concentration decreased from 9.4 µg / g to 3.77 µg / g. In contrast, the TLC19 (experimental formulation) group showed significantly greater HCQ deposition in the lungs than the free HCQ group, likely due to the sustained-release properties of the liposomal drug. During the first 24 hours following administration of half the free HCQ dose, the TLC19 group continued to release HCQ in the lungs for a period, with the mean HCQ concentration decreasing from 129 µg / g to 57.1 µg / g.

[0097] In the free HCQ IV and free HCQ IT groups, the half-lives of HCQ in the lungs were 15.2 hours and 17.7 hours, respectively, consistent with the physicochemical properties of HCQ, which allow it to rapidly and freely cross cell membranes at physiological pH. The half-life of HCQ in the TLC19 (test formulation) group (37.5 hours) was approximately twice that of the free HCQ group. When dose-normalized, the AUC of the TLC19 (test formulation) group... 0-72 and C max Lung exposures were 35 and 29 times higher in the free HCQ IV group, respectively. These results indicate that TLC19 (test formulation) is a sustained-release formulation of HCQ, successfully prolonging the residence time of HCQ in the lungs compared to free HCQ administered intravenously or intratracheally. In our study, free HCQ, whether administered intravenously or intratracheally, could not maintain pulmonary HCQ concentrations for an extended period.

[0098] Regarding systemic exposure, HCQ is rapidly absorbed and distributed throughout the body after administration. In the three groups, the median T value of HCQ in the blood was... max The timeframe is 0.25 hours after administration. In the free HCQ IV and free HCQ IT groups, the total systemic exposure, including C... max Both AUC and C2 are similar. For TLC19 (test formulation), the C2 of HCQ in the blood is similar. maxSignificantly lower than free HCQ. A small amount of HCQ showed initial peak concentrations within 1 hour after administration of TLC19 (test formulation). The remaining HCQ remained in the lungs, allowing TLC19 (test formulation) to persist for an extended period of 24 to 72 hours post-administration with consistently low mean plasma concentrations. The lower HCQ plasma concentrations observed over time indicate gradual release of HCQ at the local site. As reflected in the longer half-life, the half-life of TLC19 (test formulation) was longer than that of unreconstituted HCQ solution.

[0099] HCQ has been shown to cause heart disease, including prolongation of the corrected QT interval (QTc). To determine the distribution of TLC19 in the heart, we measured HCQ PK curves in cardiac tissue. Figure 3 Compared to HCQ solution, TLC19 has a lower cardiac exposure (C). max After dose normalization, similar AUCs were observed in all groups. These results suggest that TLC19 causes less cardiotoxicity than conventional HCQ administration, considering the lower doses required for local (i.e., intratracheal) rather than systemic (i.e., oral or intravenous) administration.

[0100] Two preclinical PK studies for the TLC19 optimized formulation will be conducted via IT administration in Sprague-Dawley (SD) rats, and are detailed below.

[0101] (1) Single-dose pharmacokinetic study in SD rats: After a single dose of TLC19 IT, blood pharmacokinetic and tissue concentration studies can be performed in SD rats. Blood and major organs, including the lungs, can be collected at specified sampling time points; and the HCQ concentrations in whole blood and organs can be measured. In this way, the PK curve of TLC19 can be preliminarily determined, and the percentage of TLC19 distributed in the lungs can be calculated.

[0102] (2) Multidose pharmacokinetic study in SD rats: This study aimed to characterize and evaluate the accumulation of TLC19 after multiple doses of IT. Blood and major organs, including the lungs, were collected at specified sampling time points after the first and last administration. The accumulation rate of TLC19 in the blood and lungs was calculated.

[0103] Example 3: Preparation of liposome-based antiviral agents Sulfobutylether-β-cyclodextrin (SBECD) was purchased from Zibo Qianhui Biotechnology Co., Ltd., China. GS-441524 (containing 1.0 mg / mL GS-441524) prepared by dissolving the antiviral agent GS-441524 in a 150 mg / mL SBECD solution with a pH of approximately 4.4 was used as test sample (1): GS-441524 solution-IV.

[0104] The research drug (liposome-based GS-441524, also known as ISPM21) was prepared by Taiwan Liposomes Co., Ltd. It consists of GS-441524 encapsulated in liposomes with an average particle size of approximately 200 nm. GS-441524 is a pure, pale yellow powder provided by Formosa Plastics Pharmaceutical Co., Ltd. The liposomes are composed of dipalmitoylphosphatidylcholine (Nippon Fine Chemical Co., Ltd., Japan) and cholesterol (Dishman, Netherlands), both of which are pulmonary surfactants. 23 The natural components are used. Empty liposomes were prepared using a solvent injection method. Simply put, a suitable amount of a lipid mixture (dispalmitoyl-sn-glycerol-3-phosphatidylcholine (DPPC) and cholesterol) was dissolved in ethanol (JT Baker, USA) and then injected into an ammonium sulfate solution while stirring at 50°C. Using an extruder, the liposomes were extruded from a 0.2µm polycarbonate membrane at 50°C, thereby adjusting the liposome size to approximately 200 nm. Unencapsulated ammonium sulfate and ethanol were removed by percolation to obtain the final empty liposomes.

[0105] GS-441524 was encapsulated in liposomes using an active loading method. The pre-formed empty liposomes were mixed with the GS-441524 drug solution and then incubated at 50°C to obtain the final ISPM21 sample (liposome-based drug suspension) with a pH between 6 and 7, which was used as test sample (2): ISPM21-IT.

[0106] A. Preparation of liposome-like nucleoside compounds I. Preparation of empty liposomes Liposomes were prepared using either thin-film hydration or solvent injection methods.

[0107] The process for preparing empty liposomes using solvent injection is specified as a method including the following steps: 1. Weigh a lipid mixture of phospholipids and cholesterol in a predetermined molar ratio, with or without DSPE-PEG200, and then dissolve them in ethanol at an elevated temperature; 2. The trapping agent is added to distilled water, and then the solution is mixed to dissolve the salts, thereby preparing a trapping agent solution (such as ammonium sulfate (AS)); 3. At a suitable temperature according to the lipid composition, the lipid mixture is added to the scavenging agent solution to form a liposome solution; 4. At a suitable temperature according to the lipid composition, the resulting liposome solution is extruded from a polycarbonate membrane to obtain the desired particle size; 5. Percolate the extruded liposomes relative to a sucrose solution, saline solution, or a suitable buffer solution to remove free trapping agent and ethanol.

[0108] II. Loading antiviral agents into liposomes The following method is an exemplary scheme for encapsulating nucleoside compounds in liposomes via remote loading, comprising the following steps: 1. Prepare a solution of nucleoside compound at a concentration of 15.4 mg / mL or a suitable concentration in a suitable medium to obtain a stock solution containing the nucleoside compound (hereinafter referred to as stock solution); 2. In an Erlenmeyer flask, empty liposomes prepared by the process described in Example 1, Section A, and Section I (in a typical specific embodiment, having the following conditions: a molar ratio of DPPC to cholesterol of 3:2, 300 mM ammonium sulfate (AS) as a capture agent, and a phospholipid concentration of 20-50 mM) and stock solution are mixed to obtain a loading solution with a D / L ratio of 25 g / mol or a predetermined D / L ratio. 3. Shake the loading solution continuously at a suitable temperature for 60 minutes or a preset time to form drug-loaded liposomes; 4. Add sodium hydroxide solution or buffer solution to the drug-loaded liposomes to adjust the pH to between 6 and 7; and 5. Use size-exclusion column chromatography and UV-Vis absorbance measurement or HPLC analysis to determine the drug encapsulation (i.e., loading efficiency) of the final sample.

[0109] Table A: Drug loading at different lipid ratios for different drugs

[0110] *Encapsulation efficiency (EE) is calculated using the following formula: Liposome drug (LF) divided by all drug forms (TF): EE (%) = LF / TF*100%.

[0111] B. Storage stability of liposome-based antiviral agents The stability of liposomal nucleoside compounds stored at 4°C can be monitored for at least 2 months or a predetermined time. The study involved loading nucleoside compounds into empty liposomes using 300 mM ammonium sulfate or 75 mM triethylammonium sucrose octasulfate as trapping agents to obtain liposomal drug samples (Table A). After storing the liposomal drug samples at 4°C or a suitable temperature for 2 months or a predetermined time, the pharmacodynamics and physicochemical properties of the liposomes were studied over time.

[0112] Example 4: Release characteristics of liposome-based antiviral agents In vitro drug release in simulated lung fluid The release characteristics of the liposomal antiviral agents prepared in Example 1 were tested to demonstrate their sustained-release properties. The in vitro release (IVR) assay protocol is as follows: 1. Mix 0.5 mL of each liposomal antiviral agent sample with 4.5 mL of simulated lung fluid (preheated at 37°C), thereby diluting the test sample 10-fold, and then place the diluted sample in a 15 mL centrifuge tube; 2. Place the centrifuge tube containing the diluted sample onto the sample well of the Inteli-mixer, rotate at 20 rpm, and incubate at 37°C; 3. Take 1 mL of diluted sample at predetermined time points to analyze encapsulation efficiency.

[0113] The analytical method for determining the encapsulation efficiency of nucleoside compounds is as follows: a. Fill and wash a 2 mL G50 column with the condition solution; b. Add 0.1 mL of sample to the column, then add 0.45 mL of elution buffer, and wait for the solution to elute from the column; c. Add 0.8 mL of eluent to the column and collect the eluent in liposome form; d. Disinfect pre-column and post-column samples (liposome form and all forms) with appropriate solvents; and e. Use ultraviolet-visible light (UV-Vis) or HPLC methods to measure the absorbance of the sample at a specified wavelength to determine the drug concentration of each sample.

[0114] The encapsulation efficiency (EE) of liposomal antiviral agents is calculated using the following formula: liposomal form of the drug (LF) divided by the total form of the drug (TF): EE(%) = LF / TF*100%.

[0115] Release curves can be plotted to describe the relationship between release rate (%) and time. The release rate is calculated using the following formula: initial liposome form minus the liposome form at each time point, then divided by the initial liposome form: (LF t0 -TF t ) / LF t0 *100%.

[0116] To achieve improved efficacy and treatment with low dosing frequency, a prolonged release characteristic of the drug component is desirable. Therefore, we selected liposomal antiviral agents with slow or suitable release characteristics from all formulations and used them to conduct the following toxicity studies.

[0117] Example 5: Pharmacokinetics of inhaled liposome-based antiviral agents in animal models Research Design A total of 48 female SD rats were randomly divided into two treatment groups: (1) GS-441524 solution-IV: 24 rats received a single intravenous injection of GS-441524 at a dose of 0.20 mg / rat; (2) ISPM21-IT: 24 rats received a single administration of 0.20 mg ISPM21 (a liposomal suspension containing 1.0 mg / mL GS-441524) via IT, a clinically simulated inhalation route of administration. Blood samples were collected at 0.25, 1, 4, 24, and 72 hours post-administration, while lung samples were collected at 0.25, 4, 24, and 72 hours post-administration. All surgeries involving the animals were performed at the TLC animal facility and in accordance with the ethical guidelines of the TLC Committee on Laboratory Animal Care and Use (IACUC) (#TLC20IACUC037).

[0118] Collection and processing of blood and lung samples Blood was collected from the jugular vein at the designated sampling time and placed into collection tubes containing K2EDTA as the anticoagulant. Each collection tube was gently inverted to ensure complete mixing of the sample with the anticoagulant. The actual sampling time was recorded. The collected blood sample was centrifuged at 1500 x g for 10 minutes at 2–8°C to obtain plasma. The supernatant plasma was immediately transferred to labeled microtubes. If not processed immediately, the plasma was transferred to a freezer at -80°C. Plasma collection must be completed within two hours of blood collection.

[0119] Animals were euthanized within the prescribed lung sampling timeframe. Each rat was perfused with approximately 100 mL of 2 mM K2EDTA / saline solution using a KD Scientific® pump for at least 8 minutes. After perfusion, the lungs were removed and frozen in liquid nitrogen. After freezing, the lungs were weighed and placed on wet ice until transferred to a freezer at -80°C. All lung samples were stored at -80°C until homogenized.

[0120] Bioanalysis and Pharmacokinetic (PK) Calculations Before thoroughly mixing with methanol to precipitate proteins, an internal standard (6,7-dimethyl-2,3-di-2-pyridylquinoxaline) was added to the blood samples. After centrifugation, the supernatant was injected into a Waters I-Class UPLC coupled to a Waters Xevo™ TQ-S tandem mass spectrometer (LC-MS / MS) for analysis. For lung samples, the tissue / organ was homogenized with 50% methanol and 0.1% formic acid. Before thoroughly mixing with methanol to precipitate proteins, an internal standard (IS) was added to the tissue / organ homogenate. After centrifugation, the resulting sample supernatant was injected into LC-MS / MS for analysis. The concentration of GS-441524 was calculated using MassLynx software. The linear ranges for lung and plasma analyses were 10–10,000 ng / mL and 0.5–500 ng / mL, respectively. The PK parameters of GS-441524 are calculated using the non-compartmental method, with Phoenix® WinNonlin® (8.0 or later) and sparse sampling computation.

[0121] result Pharmacokinetics of GS-441524 in the lungs Following a single administration of ISPM21 via IT, compared with GS-441524 solution-IV (Table 3), ISPM21-IT showed a longer half-life (22.8 hours) and higher GS-441524 concentrations in the lungs. Figure 4A Since the concentration was only measurable at the first time point (0.25 hours), the half-life and AUC of GS-441524 solution-IV in the lungs could not be calculated. It is noteworthy that the C10 of a single 0.2 mg ISPM21-IT dose... max The value was 74.9 µg / g, and the AUC was... 0-72 The value was 369 h*µg / g, indicating that ISPM21-IT significantly increased lung exposure compared to GS-441524 solution-IV, and that ISPM21-IT's C... max It is 207 times that of GS-441524 solution-IV (Table 4).

[0122] Table 3: Pharmacokinetic (PK) parameters of GS-441524 in rat lungs and plasma after single administration of GS-441524 solution-IV and ISPM21-IT.

[0123] Table 4: Ratio of ISPM21-IT to GS-441524 solution-IV, representing the dose-normalized maximum concentration and area under the concentration-time curve.

[0124] Pharmacokinetics of GS-441524 in plasma Following a single dose, ISPM21-IT exhibited similar pharmacokinetic (PK) characteristics in plasma compared to GS-441524 solution-IV. Figure 4B The plasma half-life of ISPM21-IT (9.98 hours) was slightly longer than that of GS-441524 solution-IV (7.43 hours). Notably, ISPM21-IT showed a lower systemic exposure in plasma (37% of Cmax) compared to GS-441524 solution-IV (Table 4).

[0125] In this rat pharmacokinetic study, we investigated the targeted delivery of inhaled ISPM21 to the lungs and demonstrated sustained release of GS-441524 into the lungs, along with significantly higher exposure levels. Following a single IT administration of ISPM21, the mean concentration of GS-441524 in lung tissue was 1.07 µg / g (3.67 µM, assuming a lung tissue sample density of 1 g / mL) 72 hours post-administration. This indicates that ISPM21 can maintain relatively high GS-441524 concentrations, which are 19-fold higher than the in vitro antiviral EC50 (0.18 µM) against SARS-CoV-infected human airway epithelial (HAE) cells.

Claims

1. An antiviral composition for inhalation administration, comprising a liposomal antiviral agent, wherein the liposomal antiviral agent comprises: Liposomes, wherein the liposomes comprise at least one lipid. Capture agent, and Antiviral agents; The antiviral agent is encapsulated in the liposome by the trapping agent. The trapping agent is composed of an ammonium compound and anions and counterions. The molar ratio of the antiviral agent to the lipid is from 0.01 mol / mol to 2.0 mol / mol, and The antiviral agent described herein is a nucleoside compound of structural formula (I): （I）， Each R 1 R 2 R 3 R 4 Or R 5 Independently for hydrogen, OR a 、N(R a 2, N3, CN, NO2, S(O) n R a , halogen or methyl, where n is 0, 1 or 2; R 6 It can be CN or hydrogen; Each R a Independently, it can be H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, aryl(C1-C8)alkyl, (C4-C8)carbocycloalkyl, or —C(=O)R 11 —C(=O)OR 11 —C(=O)NR 11 R 12 —C(=O)SR 11 —S(O)R 11 —S(O)2R 11 —S(O)(OR) 11 —S(O)2(OR) 11 ), or —SO2NR 11 R 12 ;as well as R 7 It is hydrogen; Each X 1 or X 2 Independent for CR 10 Or N; R 8 Halogen, NR 11 R 12 、N(R 11 (OR) 11 ) , NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, —CH(=NR 11 ), —CH=NHNR 11 —CH=N(OR 11 —CH(OR) 11 )2、—C(=O)NR 11 R 12 —C(=S)NR 11 R 12 —C(=O)OR 11 (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, aryl(C1-C8)alkyl, (C4-C8)carbocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O) n (C1-C8)alkyl, aryl(C1-C8)alkyl, OR 11 or SR 11 Each aryl or heteroaryl group is independently and optionally substituted by one or more Z groups; Each R 9 Or R 10 Independently hydrogen, halogen, R 11 OR 11 SR 11 NR 11 R 12 、N(R 11 (OR) 11 ), NR 11 NR 11 R 12 , N3, NO, NO2, CHO, CN, —CH(=NR 11 ), —CH=NHNR 11 -CH=N(OR) 11 —CH(OR) 11 )2、—C(=O)NR 11 R 12 —C(=S)NR 11 R 12 —C(=O)OR 11 ; Each R 11 Or R 12 Independently, it is hydrogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C4-C8)carbocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O). n (C1-C8)alkyl or aryl(C1-C8)alkyl, wherein each aryl or heteroaryl group is independently and optionally substituted by one or more Z groups; or R 11 Or R 12 Together with the nitrogen atom attached to both of them, they form a 3- to 7-membered heterocycle, wherein any carbon atom in the heterocycle may optionally be replaced by —O—, —S— or —NR. a -replace; Each Z group is independently a halogen, -O - =O, —OR b —SR b —S- —NR b 2、—N + R b 3. =NR b , —CN, —OCN, —SCN, —N=C=O, —NCS, —NO, —NO2, =N2, —N3, —NHC(=O)R b —OC(=O)R b —NHC(=O)NR b 2. —S(=O)2—, —S(=O)2OH, —S(=O)2R b —OS(=O)2OR b —S(=O)2OH, —S(=O)R b —OP(=O)(OR) b )2、—P(=O)(OR b )2, —P(=O)(O-)2, —P(O)(OR b (O-), —C(=O)R b —C(=O)X, —C(S)R b —C(O)OR b —C(O)O-, —C(S)OR b —C(O)SR b —C(S)SR b —C(O)NR b 2、—C(S)NR b 2、—C(=NR b )NR b 2, where each R b Independently hydrogen, alkyl, aryl, aralkyl, or heterocyclic, wherein one or more non-terminal carbon atoms in each of the (C1-C8) alkyl groups are optionally surrounded by —O—, —S—, or —NR. a -replace.

2. The antiviral composition according to claim 1, wherein the antiviral agent is selected from: 、 、 、 、 、 、 Or its pharmaceutically acceptable salt.

3. The antiviral composition according to claim 1, wherein the at least one lipid comprises one or more phospholipids and sterols, and the molar ratio of total phospholipids to the sterols is 1:1 to 2:

1.

4. The antiviral composition according to claim 3, wherein the sterol is cholesterol.

5. The antiviral composition according to claim 1, wherein the at least one lipid is selected from the group consisting of: hydrogenated soybean phosphatidylcholine (HSPC), 1,2-distearyl-sn-glycerol-3-phosphorylcholine (DSPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine (DPPC), 1,2-dipalmitoyl-sn-glycerol-3-phosphorylethanolamine (DPPE), and combinations thereof.

6. The antiviral composition according to claim 1, wherein the average particle size of the liposome-based antiviral agent ranges from 50 nm to 1000 nm.

7. The antiviral composition according to claim 1, wherein the anion and counterion are selected from: sucrose octasulfate, dextran sulfate, sulfate, citrate, glucuronide, sulfonate, phosphate, pyrophosphate, tartrate, succinate, maleic acid, borate, carboxylate, bicarbonate, glucuronide, chloride, hydroxide, nitrate, cyanate, bromide, and combinations thereof.

8. The antiviral composition of claim 3, wherein the liposomes further comprise polyethylene glycol (PEG) modified lipids, wherein the amount of the PEG modified lipids is from 0.0001 mol% to 10 mol% based on total lipids.

9. The antiviral composition of claim 8, wherein the polyethylene glycol-modified lipid has a polyethylene glycol portion having an average molecular weight ranging from about 1,000 g / mol to about 5,000 g / mol.

10. The antiviral pharmaceutical composition according to claim 8, wherein the polyethylene glycol-modified lipid is 1,2-distearate-sn-glycerol-3-phosphorylethanolamine-N-[methoxy(polyethylene glycol)] (DSPE-PEG).

11. The antiviral pharmaceutical composition of claim 10, wherein the amount of DSPE-PEG is from about 0.001 mol% to about 5 mol% based on total phospholipids and sterols.

12. The antiviral composition according to claim 1, further comprising an antibiotic.

13. The antiviral composition according to claim 12, wherein the antibiotic is selected from azithromycin and azithromycin.

14. The antiviral composition of claim 1, wherein the concentration of the lipid is from 1 mM to 100 mM.

15. The antiviral composition according to claim 1, further comprising a free antiviral agent.

16. The antiviral composition according to claim 1, wherein the molar ratio of the antiviral agent to the lipid is from 0.05 mol / mol to 2.0 mol / mol.

17. The antiviral composition of claim 1, wherein the amount of said antiviral agent is from about 0.1 mg / mL to about 80 mg / mL.

18. The antiviral composition according to claim 1, wherein the antiviral composition is an atomizing spray.

19. An aerosolized particulate composition comprising an antiviral composition according to any one of claims 1 to 18, the aerosolized particulate composition being intended for administration via inhalation to prevent or treat infectious or respiratory diseases.

20. The aerosolized particulate composition of claim 19, wherein the median mass aerodynamic diameter of the plurality of particles is about 0.5 µm to about 5 µm.

21. Use of the antiviral composition according to any one of claims 1 to 18 in the preparation of a medicament for treating or preventing infectious or respiratory diseases.

22. The use according to claim 21, wherein the respiratory disease is selected from: acute respiratory infection with severe pneumonia (SARI), acute respiratory distress syndrome (ARDS), sepsis, and septic shock.

23. The use according to claim 21, wherein the infectious disease is caused by an influenza virus, a retrovirus, a coronavirus, or SARS-CoV-2.

24. Use of the antiviral composition according to any one of claims 1 to 18 in the preparation of a medicament for reducing complications associated with the treatment of respiratory or infectious diseases in human individuals.

25. The use according to claim 24, wherein the complications include cardiotoxicity or hepatotoxicity.

26. The use according to claim 24, wherein the complication includes correction of QT interval (QTc) prolongation.

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